iS tetseete as: sasree ts See CORNELL UNIVERSITY THE lower Weterinary Library FOUNDED BY ROSWELL P. FLOWER. for the use of the N. Y. STATE VETERINARY COLLEGE 1897 This Volume is the Gift of Dr. V. A. Moore. 356 wn 9 A TEXT-BOOK of PATHOLOGY BY ALFRED STENGEL, M. D., Sc. D. Professor of Medicine, University of Pennsylvania; Physician to the Pennsylvania and to the University Hospitals AND HERBERT FOX, M. D. Director of the Pepper Laboratory of Clinical Medicine, University of Pennsylvania; Pathologist to the Philadelphia Zodlogical Garden SIXTH EDITION, RESET WITH 468 TEXT ILLUSTRATIONS, MANY IN COLORS, AND 15 COLORED PLATES PHILADELPHIA AND LONDON Ww. B. SAUNDERS COMPANY 1915 Copyright, 1898, by W. B. Saunders. Revised, reprinted, and recopyrighted March, 1899. Reprinted August, 1899; November, 1899. Revised, reprinted, and recopy- righted October, 1900. Reprinted July, 1901; September, 1902, Revised, reprinted, and recopyrighted July, 1903. Reprinted March, 1905. Revised, reprinted, and recopyrighted September, 1906, Re- printed November, 1907, August, 1909, August, 1910, July, rorz, and June, 1912. Revised, entirely reset, reprinted, and recopyrighted August, rors CopyRIGHT, 1915, BY W. B. SaunDeERS COMPANY PRINTED IN AMERICA PRESS OF W. B. SAUNDERS COMPANY PHILADELPHIA PREFACE TO THE SIXTH EDITION In the preparation of the present (the sixth) edition of the Text- book of Pathology I am fortunate in having the co-operation of Dr. Herbert Fox, whose active interest in general and comparative pathology and in clinical pathology peculiarly fit him for collabora- tion in a book designed especially for the needs of students and prac- titioners preparing for or engaged in the work of practical medicine. The book hereafter will appear under our joint authorship, each having contributed largely to the present edition. Extensive revision has been found necessary to bring the work fully to date. In the first portions, devoted to general pathology, the sections on Inflammation, Retrogressive Processes, Disorders of Nutrition and Metabolism, General Etiology, and Diseases due to Bacteria have been very largely recast or almost wholly rewritten. A new section on Transmissible Diseases has been added; the Terata have been incorporated with a brief synoptical chapter on Teratology; the Glands of Internal Secretion and their pathology have been made the subject of a separate chapter; and new sections on the pathology of the eye, ear, and skin, brief and general in scope, but, we hope, sufficient for a work of this character, have been added. It has seemed best to us to omit the chapter on Technic, which formed a part of previous editions, because the necessary brevity of such a chapter deprives it of practical usefulness. Special works on technic should be consulted by the student and laboratory worker. The chapters on Diseases of the Nervous System occupied a dispropor- tionately large part of previous editions and have, therefore, been curtailed. Numerous revisions have been made in other sections and chapters of special pathology where advances in knowledge have re- quired such alterations. Many new illustrations—upward of 100 in black and white or color—have been added, and by reason of the liberal policy of the publishers, to whom our thanks are due, the whole work has been reset and appears in a new and greatly improved form. ALFRED STENGEL. PHILADELPHIA, Pa., August, 1915. 7 CONTENTS PART I—GENERAL PATHOLOGY CHAPTER I PAGE THe HTIOLOGY OF DISHASEs 632s: acdc aaa genes Sees SSUse4a% be REE SEER ESS 19 Pathological Disposition, 20—Traumatism, 24—Physical Conditions, 25 —Poisons, 29—Vegetable and Animal Parasites, 37. CHAPTER II DIsoRDERS OF NUTRITION AND METABOLISM... .. 0.00.00. 000 ccc vee ee cues 39 Food, 39—Diminished Supply of Food, 39—Increased Supply of Food, 40 —Metabolism of Fat, 40—Excessive Tissue Destruction, 40—Acid Intoxi- cation, 42—Disorders -of Protein Metabolism, 44—Disorders of Purin Metabolism, 45—Gout, 46—Diseases of Carbohydrate Metabolism, 47— Diabetes Mellitus, 49—Fever, 53. CHAPTER III DISTURBANCES OF THE CIRCULATION OF THE BLOOD................2020000. 56 General Disturbances, 56—Local Anemia, 58—Local Hyperemia, 59— Hemorrhage, 60—Embolism, 64—Infarction, 66—Thrombosis, 67—Edema, 72. CHAPTER IV RETROGRESSIVE PROCESSES... 1... eee tenet e neers 76 Atrophy, 76—So-called Infiltrations and Degenerations, 78—Cloudy Swelling, 78—Fatty Infiltration, 80—Fatty Degeneration, 82—Albuminoid Degenerations, 85—Hyaline Degeneration, 85—Mucoid Degeneration, 88— Colloid Degeneration, 90—Amyloid Infiltration, 91—Glycogenic Infiltration, 94—Dropsical Infiltration, 95—Calcification, 96—Ossification, 98—Uratic Infiltration, 98—Pigmentation, 99—Necrosis, 105—Coagulation Necrosis, 107—Liquefaction Necrosis, 109—Caseation, 110—Fat Necrosis, 111— Gangrene, 112—General Pathology of Cellular Necrosis, 114—Alterations in Cell Nuclei in Necrosis, 114—Alterations in Form of Cells in Necrosis, 114—Altered Karyokinesis in Necrotic Cells, 115—Postmortem Altera- tions, 115. CHAPTER V INFLAMMATION AND REGENERATION... 0.0.0.0. c cece eects enn ee 117 Inflammation, 117—Regeneration, 149—Metaplasia, 155. CHAPTER VI PROGRESSIVE TISSUE CHANGES... 2.0.0.0. cece cece eee ree eee 157 Hypertrophy, 157—Tumors, 158. Connective Tissue Tumors, 169—Fibroma, 169—Myxoma, 173—Lipoma, _—_......- - - 174—Xanthoma, 175—Chondroma, 176—Osteoma, 179. 9 10 CONTENTS PAGE Angiomata, 181—Lymphangioma, 181—Hemangioma, 182—Lymph- adenoma, 184—Sarcoma, 189—Spindle-celled Sarcoma, 192—Round-celled Sarcoma, 193—Giant-celled Sarcoma, 195—Melanosarcoma, 197—Muxed Tumors, 198—Mycosis Fungoides, 199—Angiosarcoma, 200—Cylindroma, 202—Endothelioma, 203—Psammoma, 204. Tumors from Nerve Tissues, 204—Glioma, 205—Glioma Ganglionare, 207—Neuroma, 208—Leiomyoma, 209—Rhabdomyoma, 211. Epithelial Tumors, 212—Papilloma, 212—Adenoma, 215—Carcinoma, 219—Epithelioma, 227—Glandular Carcinoma, 229—Special Forms of Cancer, 230—Cysts, 231—Epithelial Cysts, 232. CHAPTER VII TBRATOWOGY dea alate. gue at4 ad Wah Ee de MAGRreNe TAR Rb eDeiardll Ra Add Danhuc ee ee 235 Teratomata, 235—Dermoid Cyst, 236—Other Teratoid Tumors, 236— Syncytioma Malignum, 238—Terata or Monsters, 239. CHAPTER VIII Bacteria, THEIR NATURE AND ACTION. 2.20... c ccc teen teenies 241 Classification, 241—Morphology, 248—Biology, 245—Functions and Products of Bacteria, 247—Products in Culture-medium, 250—Local Effects of Bacteria, 251—Effect of Toxic Products of Bacteria, 251—Im- munity, 255. CHAPTER IX Diseases DuE TO BACTERIA... ncn teens 273 Diseases Due to Cocci, 273—Suppurative Diseases, 273—Gonorrhea, 278 —Croupous Pneumonia, 280—Other Forms of Pneumonia, 283. Diseases Due to Bacillary Forms, 285—Diphtheria, 285—Typhoid Fever, 289—Bacillus Coli Communis, 295—Dysentery Bacillus, 297—Influenza, 298—Bordet-Gengou Bacillus of Whooping-cough, 299—Bubonic Plague, 300—Soft Chancre, 302—Malta Fever, 303—Rhinoscleroma, 303—Gland- ers, 304—Tetanus, 306—Anthrax, 308—Malignant Edema, 311—Infectious Emphysema, 312—Tuberculosis, 3813—Pseudotuberculosis, 324—Fowl- tuberculosis, 325—Leprosy, 326—Bacterium Mucosum Capsulatum Group, 329. Diseases Due to Spirilla, 330—Cholera, 330—Organisms Resembling the _ Cholera Vibrio, 333. Diseases Due to Spirochetes, 334—Syphilis, 334—Relapsing Fever, 339 —Vincent’s Angina, 340—Frambesia or Yaws, 341. Diseases Due to Higher Bacteria, 341—Actinomycosis, 341—Mycetoma, 3846—Thrush, 347—Saccharomycosis or Blastomycosis, 348. Other Bacteria Not Causing Specific Infection, 349—The Hemorrhagic Diseases, 349—Proteus Infection, 350. Infectious Diseases Whose Cause is Not Certainly Known. Filterable Viruses, 351—Yellow Fever, 351—Measles, 352—NScarlet Fever, 353— Mumps, 354—Variola and Vaccinia, 354—Varicella, 355—Typhus Fever, 355—Rabies, 356—Rheumatism, 358—Beriberi, 359—Pellagra, 360— Dengue, 360—Poliomyelitis, 361—Foot-and-mouth Disease, 362—Tra- choma, 362—Rocky Mountain Fever, 362—Chlamydozoa, 363. CHAPTER X ANIMAL PaRASITES AND DisEAsEs CAUSED BY THEM.....:................. 364 Protozoa, 364—Rhizopoda, 364—Entamceba Histolytica, 364—Enta- meeba Coli, 366—Other Amebe, 366—Mastigophora, 366—Cercomonas CONTENTS 11 s PAGE Hominis, 366—Cercomonas Coli Hominis, 367—Trichomonas Intestinalis, 367—Trichomonas Vaginalis, 368—Other Forms of Trichomonas, 368— Lamblia Intestinalis, 368—Trypanosoma, 369—Hemosporidia, 372— Parasites of Malaria, 372—Coccidia, 377—Coccidium Cuniculi, 377— °* Sarcosporidia, 378—Infusoria, 379—Balantidium Coli, 379—Animal Para- sites and Molluscum Contagiosum, 379. Vermes, 380—Trematodes, or Fluke-worms, 380—F'asciola Hepatica, 380 —Dicroceelium Lanceatum, 381—Opisthorchis Felineus, 382—Opisthorchis Sinensis, 382—Schistosomum Hematobium, 382—Schistosomum Japoni- cum, 383—Paragonimus Westermanii, 383—Other Fluke-worms, 384. Cestodes, or Tapeworms, 384—Tenia Solium, 386—Tvenia Saginata, 388 —Hymenolepis Nana, 389—Hymenolepis Diminuta, 389—Dipylidium Caninum, 390—Davainea Madagascariensis, 390—Teenia Echinococcus, 390 —Dibothriocephalus Latus, 393—Dibothriocephalus Cordatus, 394—Both- riocephalus Mansoni, 394—Diplogonoporus Grandis, 394. Nematodes, or Round Worms, 395—Ascaris Lumbricoides, 395—Ascaris Canis, 395—Oxyuris Vermicularis, 396—Trichinella Spiralis, 396—Ankylos- toma Duodenale, 397—Necator Americanus, 399—Strongyloides Intestina- lis, 400—Trichocephalus Trichiuris, 401—Filaria Medinensis, 401—Filaria Bancrofti, 402—Other Forms of Filarie, 404—Echinorhynchus Gigas, 404 —Eustrongylus Gigas, 405—Strongylus Apri, 405—Strongylus Subtilis, 405 —Annelides, 405—Arthropoda, 405—Linguatula Rhinaria, 406—Poroceph- alus Constrictus, 406—Myiasis, 406. CHAPTER XI Tue Metuops or TRANSMISSION OF THE COMMUNICABLE DISBASES.......... 407 Direct Infection, 408—Indirect Transmission, 409. PART II—SPECIAL PATHOLOGY CHAPTER I DISHASHS OF THE: BLOOD a xe 3004, Hand e's $4) tne CA OES BE a 412 Anatomy, 412—Blood Formation, 419—Pathological Changes in the Red Corpuscles, 420—Pathological Changes in the Leukocytes, 422—Patholog- ica] Changes in the Plasma, 423—Plethora, 424—Oligemia, 424—Hydremia and Anhydremia, 425—Lipemia, 425—Melanemia, 426—Hemocytolysis; Hemoglobinemia, 426—Polycythemia, 427—Leukocytosis, 428—Leuko- penia, 430—Anemia, 431—The Secondary Anemias, 431—The Primary Anemias, 433—Chlorosis, 433—Progressive Pernicious Anemia, 435— Aplastic Anemia, 437—Hemolytic Ictero-anemia, 438—Leukemia, 438— Hodgkin’s Disease, 441—Pseudoleukemia Infantum, 441—Foreign Bodies and Parasites, 442. i CHAPTER II Diseases or THE LYMPHATIC TISSUES... 0.2.0... ee 443 Spleen, 443—Abnormal Development and Situation, 444—Circulatory Disturbances, 444—Inflammation, 445—Atrophy and Degenerations, 448— Leukemia and Hodgkin’s Disease, 449—Tumors and Parasites, 449— Infectious Diseases, 450. 12 CONTENTS PAGE Lymphatic Glands, 450—Atrophy, 452—Hypertrophy, 452—Status Lymphaticus, 452—Degenerations, 453—Inflammation, 454—Infectious Diseases, 456—Leukemia and Hodgkin’s Disease, 459—Tumors, 461. Bone-marrow, 462—Degenerations, 463—Atrophy, 464—Hypertrophy, 464— Inflammation, 465—Tumors, 466. CHAPTER III DISEASES OF THE CIRCULATORY SYSTEM... 2.0.02 cece eee eee teens 467 Heart, 467—Congenital Diseases and Deformities, 468—Circulatory Disturbances, 471—Endocardium, 472—Inflammation, 473—Myocardium, 481—Degenerations, 481—Inflammation, 486—Hypoplasia and Atrophy, 492—Hypertrophy and Dilatation, 494—Aneurysm, 496—Wounds and Rupture of Heart, 497—Infectious Diseases, 497—New Growths and Para- sites, 497—Pericardium, 498—Circulatory Disturbances, 498—Inflamma- tion, 498—Infectious Diseases, 502—Tumors and Parasites, 502—Pneumo- pericardium, 503. Arteries, 503—Congenital Defects, 503—Hypertrophy, 503—Atrophy, 504—Degenerations, 504—Inflammation, 505—Infectious Diseases, 511— Aneurysm, 511. Veins, 517—Circulatory Disturbances, 517—Degenerations, 518—In- flammation, 518—Dilatation, 519—Tumors, 520—Infectious Diseases, 520. Lymphatic Channels, 521—Inflammation, 521—Dilatation, 521—Infec- tious Diseases, 522—Tumors, 522—Parasites, 523. Thoracic Duct, 523. CHAPTER IV DISEASES OF THE RESPIRATORY SYSTEM..... 000000000 cece eee ee 524 Nasal Cavities, 524—-Congenital Abnormalities, 524—Circulatory Dis- turbances, 524—Inflammations, 525—Infectious Diseases, 525—Tumors, 526—Parasites and Foreign Bodies, 526. Larynx, 526—Congenital Abnormalities, 526—Circulatory Disturbances, 527—Inflammations, 527—Infectious Diseases, 528—Tumors, 529—Para- sites and Foreign Bodies, 530. Trachea, 530—Malformations, 530—Circulatory Disturbances, 531— Inflammations, 531—Infectious Diseases, 531—Tumors, 531. Bronchi, 531—Congenital Malformations, 532—Circulatory Disturbances, 532—Inflammations, 532—Stenosis and Obstruction, 534—Dilatation, 535 —Infectious Diseases, 536—Tumors, 536—Parasites and Foreign Bodies, 537. : Lungs, 537—Congenital Defects, 538—Circulatory Disturbances, 538— Hypertrophy and Atrophy, 543—Emphysema, 543—Atelectasis, 546— Inflammation or Pneumonia, 548—Gangrene, 565—Infectious Diseases, 566 Syphilis, 578—Glanders, 579—Actinomycosis, 580—Tumors, 580—Para- sites, 584. Pleura, 585—Inflammation, 586—Infectious Diseases, 591—Tumors and Parasites, 592. CHAPTER V DISEASES OF THE GASTRO-INTESTINAL TRACT. .......0.00 0000-0000 cece. 594 Mouth, 594—Congenital Abnormalities, 594—Circulatory Disturbances, 594—Inflammation, 594—Atrophy and Degenerations, 598—Infectious Diseases, 598—Tumors, 600. Teeth, 601. CONTENTS 13 PAGE Pharynx and Tonsils, 602—Circulatory Disturbances, 602—Inflamma- tions, 602—Pressure Necrosis, 606—Infectious Diseases, ee 608. Salivary Glands, 608. Esophagus, 609—Congenital Defects, 6a Giaalstory Disturbances, 609—Inflammations, 610—Stenosis, 610—Dilatation, 611—Perforation and Rupture, 611—Infectious Diseases, 612—Tumors, 612. Stomach, 613—Congenital Defects, 613—Circulatory Disturbances, 613 —Inflammation, 614—Gastric Ulcer, 617—Atrophy and Degenerations, 620 —Alterations in Position and Size, 621—Infectious Diseases, 622—Tumors, 622. Intestines, 626—Congenita] and Acquired Abnormalities, 626—Intestinal Obstruction, 629—Prolapse of Rectum, 630—Atrophy and Degenerations, 631—Circulatory Disturbances, 631—Inflammations, 633—Inflammations of Special Parts, 635—Infectious Diseases, 639—Tumors, 648—Parasites, 651—Intestinal Rupture and Foreign Bodies, 652. Liver, 653—Malformations and Changes of Position, 653—Circulatory Disturbances, 654—Atrophy and Degenerations, 657—Rupture of the Liver, 671—Infectious Diseases, 671—Tumors, 673—Parasites, 677. Biliary Ducts and Gall-Bladder, 678—Inflammations, 678—Stenosis and Dilatation, 680—Gall-stones; Cholelithiasis, 681—Tumors, 683—Jaundice, 683. Pancreas, 685—Congenital Abnormalities, 685—Circulatory Disturb- ances, 685—Atrophy and Degenerations, 685—Inflammations, 687—Infec- tious Diseases, 689—Tumors, 689—Pancreatic Duct, 690. Peritoneum, 691—Congenital Abnormalities, 691—Circulatory Disturb- ances, 691—Inflammations, 693—Infectious Diseases, 696—Tumors, 698— Parasites, 698. CHAPTER VI DISEASES OF THE DUCTLESS GLANDS... 0.0... 000 o ccc eee c eee eees 699 Thyroid Gland, 699—Congenital Defects, 699—Disturbances of Circula- tion, 699—Inflammations, 700—Struma or Goiter, 700—Infectious Diseases, 705—Tumors and Parasites, 705—General Results of Thyroid Disease, 705. Suprarenal Bodies, 708—Congenital Anomalies, 709—Degenerations, 709 —Infectious Diseases, 709—Circulatory Disturbances, 710—Inflammation, 711—Tumors, 711. Thymus Gland, 711. Pituitary Body, or Hypophysis Cerebri, 712. Pineal Gland, or Epiphysis Cerebri, 715. CHAPTER VII DISEASES OF THE URINARY ORGANS... 2... cece eees 717 Kidneys, 717—Congenital Anomalies, 717—Changes of Position, 717— Circulatory Disturbances, 718—Inflammations, 720—Nephritis, 720— Acute Parenchymatous Nephritis; Bright’s Disease, 722—Acute Inter- stitial Nephritis, 724—Chronic Nephritis, 726—Chronic Parenchymatous Nephritis, 726—Chronic Interstitial Nephritis, 729—Atrophy and Hyper- trophy, 737—Degenerations, 737—Concretions in Uriniferous Tubules, 740 —Infectious Diseases, 741—Tumors, 741—Parasites, 747. Pelvis of Kidney and Ureter, 748—Congenital and Acquired Malforma- tions, 748—Calculus, 749—Inflammation, 749—Infectious Diseases, 750— Tumors, 751—Parasites, 751. : 14 CONTENTS PAGE Urinary Bladder, 752—Malformations, 752—Changes of Position, 752— Rupture, 753—Circulatory Disturbances, 753—Inflammation, 753—In- fectious Diseases, 755—Calculi and Foreign Bodies, 755—Tumors, 757— Abnormal Conditions of Urine, 758—Chemical Changes and Sediments, 764. Urethra, 766—Inflammations, 767—Injuries, 770—Infectious Diseases, 770—Tumors, 770. CHAPTER VII DISEASES OF THE REPRODUCTIVE ORGANS... 2... ee 771 Uterus, 771—Congenital Abnormalities, 771—Alterations of Position, 772—Stenosis, Dilatation, and Rupture, 775—Circulatory Disturbances, 775—Inflammations, 777—Infectious Diseases, 7830—Atrophy and Degen- eration, 783—Hypertrophy and Hyperplasia, 783—-Tumors, 784—Parasites, 790. Ovaries, 790—Congenital Abnormalities, 790—Changes in Position, 790 —Circulatory Disturbances, 791—Inflammation, 791—Infectious Diseases, 792—Tumors, 792—Cysts of Parovarium, 796—Cysts of Kebelt, 797. Fallopian Tubes, 797—Congenital Abnormalities, 797—Changes of Posi- tion, 797—Stenosis, 798—Dilatation, 798—Circulatory Disturbances, 798— Inflammations, 799—Infectious Diseases, 801—Parametrium, 803—Extra- uterine Pregnancy, 803. Vagina, 805—Prolapse of Walls, 805—Stenosis, 805—Wounds and Fistule, 805—Circulatory Disturbances, 806—Inflammations, 806—Infec- tious Diseases, 807—Tumors, 807. Vulva, 807—Wounds, 808—Circulatory Disturbances, SO8—Inflamma- tion, 808—Infectious Diseases, 809—Tumors, 809. Decidua, Placenta, and Fetal Membranes, 810—Abnormalities of Devel- opment, 810—Circulatory Disturbances, 811—Inflammation, 811—Infec- tious Diseases, 812—Hyperplasia, 812. : Penis and Scrotum, 814—Congenital Abnormalities, 814—Inflammation, 814— Infectious Diseases, 815—Tumors, $15—Injuries, 816. Testicles, 816—Anatomical and Physiological Considerations, 816— Congenital Abnormalities, 816—Atrophy and Hypertrophy, 817—Degenera- tions, 817—Circulatory Disturbances, 818—Inflammation, 818—Infec- tious Diseases, 821—Tumors, 822—Parasites, 824. Prostate Gland, 824—Inflammation, 824—Atrophy and Degeneration, 824—Concretions, 825—Infectious Diseases, 825—Hypertrophy and Tumors, 825. Cowper’s Glands, 828. Seminal Vesicles, 828. Mammary Glands, 829—Congenital Abnormalities, 829—Circulatory Disturbances, 829—Inflammations, 829—Atrophy and Hypertrophy, 830— Degenerations, 831—Infectious Diseases, 831—Tumors, 831. - CHAPTER IX DISHASES) OF THE BONES sxx 4 accxsia ee pcaaee cates epee we aie es KAR Oh INS A oe laws 836 Disorders of Development, 836—Rickets, 837—Regeneration, 839— Circulatory Disturbances, 841—Inflammations, 842—Degenerative Condi- tions, 846—Hypoplasia and Atrophy, 847—Infectious Diseases, 849— Tumors, 853. CHAPTER X DISBASES OF THE! JOINTS & x iocces cass hnwe dee wasted anion Reha Gwe wearin we Hau muate nga 355 Distortions, 855—Circulatory Disturbances, 856—Inflammations, 856— Infectious Diseases, 860—Tumors, 862—Tendon-sheaths and Burse, 862. CONTENTS CHAPTER XI DISEASES OF THE VOLUNTARY MUSCLES... 2... cece ects Hypertrophy, 863—Circulatory Disturbances, 863—Inflammations, 864 —atrophy and Degenerations, 866—Infectious Diseases, 869—Tumors and Parasites 869. ‘ CHAPTER NII DISEASES OF THE BRAIN AND ITS MEMBRANES..............000 00000 eee Dura Mater, 870—Circulatory Disturbances, 870—Infectious Diseases, 872—Tumors, 872—Cysts, 873. Pia-arachnoid, 873—Circulatory Disturbances, 874—Inflammation, 874 —Infectious Diseases, 878—Tumors, 880. Brain, 882—Development and Anatomy, 882—Postmortem Degenera- tive Conditions, 886—Congenital Abnormalities, 887—-General Pathological Anatomy of Nervous System, 891—Blood-vessels, 900—Circulatory Dis- turbances, 902—Inflammation, 910—Injuries to Central Nervous System, 917—Infectious Diseases, 918—Tumors, 919—Choroid Plexus, 922. CHAPTER XIII DISEASES OF SPINAL Corp AND ITs MEMBRANES Dura Mater, 928. Pia-arachnoid, 929—Circulatory Disturbances, 929—Degenerations, 929 —Inflammations, 930—Infectious Diseases, 930. Cord, 931—Anatomy, 931—Congenital Abnormalities, 933—Hydromy- elia and Syringomyelia, 934—Circulatory Disturbances, 936—Inflamma- tion, 938——Primary Degenerations, 943—Secondary Degenerations, 953— Tumors, 957. CHAPTER NIV DISEASES OF THE PERIPHERAL NERVOUS SYSTEM............00.0 00.00 c eee ee Ganglia of Cranial and Spinal Nerves, 958. Nerves, 958—Circulatory Disturbances, 958—Regeneration after Injury, 959—Inflammations, 960—Infectious Diseases, 962—Tumors, 963. CHAPTER XV SUSE se Hai Sacto aa teks een hte ees eh ioe en Mh al Roe aes Se garni neat eae al Anatomy, 964—Congenital Abnormalities, 965—Conjunctiva, 965— Lachrymal Organs, 970—Cornea, 970—Sclera, 972—Crystalline Lens, 973— Vitreous Humor, 974—Iris, 974—-Ciliary Body, 976—Choroid, 977—Retina, 978—Sympathetic Ophthalmitis, 980—Glaucoma, 980—Optic Nerve, 981— Orbit, 983—Lids, 983. CHAPTER XVI Anatomy, 984—Congenital Defects, 985—External Ear, 985—Tympanic Membrane, 986—Tumors of External Ear, 986—Middle Ear, 987—Eu- stachian Tube, 989—Internal Ear, 989. CHAPTER XVII MPR GHIG SSIRTN Gs, Si dccuo Ges Boe Oak AEA LE a SERED Shes So eh ed ee ee Anatomy, 990—Congenital Abnormalities, 991—Atrophy, Hypertrophy, and Degenerations, 991—Variations in Pigmentations, 993—Circulatory Disturbances, 993—Inflammation (Dermatitis), 994—Specific Inflamma- tions, 1002—Tumors, 1005. Structures Within the Skin, 1006—Sebaceous Glands, 1006—Sweat- glands, 1007—Hair, 1008—Nails, 1008. 870 928 958 964 984 990 A TEXT-BOOK OF PATHOLOGY PART | GENERAL PATHOLOGY PaTHoLoey is the science that deals with disease in all its aspects. It includes the study of the causes, the manifestations, and the results of disease. Three important subdivisions of the study of pathology are recog- nized, viz., etiology, or the study of the causes of disease; morbid or pathological anatomy, the study of the gross and microscopical structural changes in disease; and morbid or pathological physiology, the study of disturbances of function. In the latter group is included pathological chemistry, as morbid chemical action and its results are the outcome of disturbed function. Pathology may be divided into general and special pathology. The former treats of causes of disease and pathological processes irre- spective of any individual part; the latter deals with the causes or processes in individual diseases, organs, or parts. Disease itself is not a separate entity, but may be defined as ab- normality in structure, in function, or in both combined. It is doubt- ful whether alteration of function can occur without some alteration in structure, but it frequently happens that functional disturbances are present though no structural alterations are discoverable even by ‘the most precise methods of investigation. It is obvious from the foregoing that it is impossible to define sharply either disease or health. Health, or fully harmonious action of all physical and physiological units, is subject to the same laws of mode and mean as any other group of varying but comparable units, and as the examples or phenomena digress from the mean, they approach the abnormal or the unnatural. This will suggest the merging of the healthy into the diseased state. Assuming further that health is controlled by a harmonious and uniform set of impulses, the interruption of one of them or the introduction of a foreign stimulus will unbalance the cycle, or the natural impulses may be destroyed by the foreign intrusion. Many slight abnormalities of stimulation or minor intrusions are quickly removed and the general physiology rights itself promptly. If, how- 2 17 18 A TEXT-BOOK OF PATHOLOGY ever, the interruption or intrusion affect an important structure, an organ like the liver or lung, the cycle of physiology of the remaining parts must be constructed upon a new temporary plan in a compensa- tory manner. The various organs or systems have different values in throwing compensatory work upon others. For example, the failing lung throws work upon the kidneys, skin, and intestines, and the failing heart strains the lungs and kidneys. Organs in pairs complement each other or one may attempt to assume the duties of both. The loss of the liver or kidneys is incompatible with life, while a large part of these organs or even of the brain may be destroyed without cessation of life. The gross alteration in diseased organs is fundamentally the effect of pathological changes in constituent cells, as Virchow’s philosophy has taught us. The severity of an abnormality stands in direct re- lation to the number of cells affected, the degree of change, and the importance of the cells. The more highly specialized a cell, the less able it is to regenerate its kind, and, therefore, the more lasting is the effect of its destruction. The cells of the brain and the germ cells do not reproduce. While disease is still viewed as a process which begins anatomically, it is obvious from the above that all diseased states are probably pre- ceded or at least always accompanied by chemical and physiological dis- turbances. This part of the subject will be taken up in particular in the next chapter. The cause of these anatomical and chemical changes are factors either within or without the body. The specific diseases are usually indicated by an equally specific set of anatomical and chemical changes from the normal. The symptoms of disease are the expressions of abnormal functional activity, and are, therefore, properly discussed under the head of Pathological Physiology; but they are so important from a practical standpoint, and form so extensive a subject of investigation, that they are usually considered apart from pathology, in special treatises dealing with diagnosis and the practice of medicine. CHAPTER I THE ETIOLOGY OF DISEASE THE study of the causation of disease embraces and must account for the predisposing factors and the determining causes. The former prepare the system and make it susceptible to the latter, or immediate and specific causes of disease. The predisposing factors may increase the receptivity of the body for more than one kind of disease agent. The term “predisposition’’ is at times used for a hereditary or acquired tendency toward certain diseased states. Thus, one might exemplify hereditary predisposition by the lowered resistance to tuberculosis of the young of tuberculous parents. Another phase of this hereditary influence is shown in the tendency for cells to exhibit an abnormal metabolism because of a family or hereditary tendency, and leading to abnormal states of health (Baumgarten’s anlage). (See Heredity.) Acquired predispo- sition is due to vices of living, previous disease, or to a summation of several predisposing factors leading in one direction. This has been termed “disposition” by some writers. Predisposing Factors.—The normal system is able to cope with the determining causes of disease to a certain point by its general vitality and regulative functions. Thus, heat and cold may prove harmless if not too intense or prolonged. In the case of exposure to heat, the superficial capillaries become dilated, sweating increases, and there is increased heat dissipation from the surface at the same time that increased respiratory function occasions evaporation and loss of heat through the lungs. In the case of exposure to cold, increased muscu- lar exercise leads to greater heat production, while contraction of the superficial blood-vessels restricts the elimination of heat. When, however, a certain point of intensity is reached in the case of heat, cold, or other causes of disease, the normal organism is unable to oppose sufficient resistance, and disease or injury results. Chemical relations in body cells and fluids, such as equilibrum of colloids in solid and liquid condition or enzyme power, may be destroyed by prolonged exposure to heat and cold, and the former may also destroy red blood-cells. The degree of resistance differs in different individuals, in different races, or people living under varying climatic conditions, etc. In some the degree of resistance may be so great that certain diseases are never contracted. The term wnmunity (q. v.) is applied to this state. Certain predisposing factors may now be taken up in order. 1. Age.—This plays a large part in the vulnerability of an individual. The exanthemata are much more common in childhood, while car- cinoma is commonest in adult life. The rate of repair is also greater in 19 20 A TEXT-BOOK OF PATHOLOGY youth. Tuberculosis assumes somewhat different forms when develop- ing in childhood, adolescence, or adult life. There is a decided varia- tion in the amount of protective antibody in the blood at different ages. 2. Sex.—The influence of sex is not great aside from disease of the sexual organs. Man is subject to more traumatisms and diseases due to the wider social life he leads. _He suffers more often from cancer, aside from genitalia, than the female. There are more cases of gout, diabetes, and organic nervous disease in men. Women are more often attacked by functional nervous diseases and affections of the thyroid gland. 3. Race.—Certain peoples are prone to or immune against certain diseases. Negroes are resistant to malaria and endure yellow fever well. Aside from the unsanitary conditions in which many live, they have a low resistance to tuberculosis. The effect of zodlogical order is more pronounced than race differences. The dog is resistant to tuber- culosis; the chicken, to tetanus. This has hampered experimental work upon infectious diseases, because it is often difficult to fulfil Koch’s pos- tulates (q. 2.). 4, Nutrition —Failure to obtain wholesome pure food will, of course, reduce resistance. The presence of putrefaction or disease-producing agents will cause disease. Prolonged hunger reduces general resistance. Habits of any sort that tend to disturb digestion reduce resistance. The maintenance of what is apparently the amount of fat normal to the individual is helpful to resistance. The relation of bodily activity and stored-up reserve has an influence upon later demands of exertion. 5. Idiosyncrasy is the peculiar susceptibility of individuals to cer- tain poisons or infections and sometimes even to ordinary foods. This should not be confused with diathesis or predisposition (gq. 2.). The presence of one infection may favor the reception of another. 6. Conditions of life. Habitation in places infested with disease-trans- mitting insects materially influences morbidity. Unsanitary dwellings directly affect health. Occupation: Workers in paint suffer from lead- poisoning; handlers of hides contract anthrax; miners get anthracosis of the lungs. Prolonged mental anxiety has some depressing effect upon resistance. 7. Injury. 8. Heat and cold. 9. Physical forces, like electricity and z-ray, and atmospheric pressure. 10. Potsons of all kinds. Items 1 to 5 may be called intrinsic or internal, while 6 to 10 are extrinsic or external. PATHOLOGICAL DISPOSITION Under this heading come those instances in which physical or physiological departures from the type or from the standard are expressed in the unusual susceptibility of the whole or a part. Idiosyncrasies might be classed here. This pathological disposition refers chiefly to those conditions in which slow healing of skin wounds or the lack of THE ETIOLOGY OF DISEASE 21 sweat and sebaceous secretions render the skin more susceptible to spreading infections. We might also include here the sensitive state of some individuals to certain organic proteins which makes them subject to intoxications with these compounds, not toxic to other persons. (See Immunity.) There is a rélated pathological disposition at seats of chronic in- flammation, chronic irritation, or chronic injury, as it has lately been called. Here malignant change may occur. Whether this pathological disposition is hereditary or acquired is difficult to say, as it is equally impossible to decide whether it is due to absence of immunity reactions. Occasionally organ or system disposition is mentioned, by which is meant a peculiar visceral distribution of lesions, which may be anatom- ical or physiological. It covers such instances as the frequency of infarction of the spleen and lung, and the involvement of the spleen in liver disease. Heredity or inheritance is a factor of importance in the etiology of disease. In some cases the disease itself is transmitted to the offspring, but more frequently the predisposition only. A distinction must be made between weakness of a child at birth (congenital weakness) and a definitely inherited weakness. Thus, an alcoholic mother. or one sub- jected to hardships during pregnancy may give birth to a child which is feeble and lacking in resistance to disease. This feebleness is congen- ital, but not inherited. The same statement applies to diseases such’as tuberculosis and syphilis, which may be acquired from the mother by the fetus in utero, but are not inherited. If the father is the original source of infection, he first infects the mother, from whom the child then acquires the disease. One cannot in these cases properly use the term ‘‘hereditary.’’ Heredity, strictly speaking, applies only to the transmission of parental or ancestral characteristics to the offspring through the paren- tal germ-plasm. We may distinguish between racial, familial, and direct inheritance. The term direct inheritance indicates transmission from parent to offspring. The term indirect is sometimes used to indicate transmission of characters latent in one generation to subse- quent ones. Atavism is a more frequent designation of this derivation of characteristics from ancestors after they had been latent in one or more generations. Ina broader sense the term “‘atavism’”’ has also been applied to reversion to racial characteristics that had been dormant through many generations. Collateral inheritance is a term used in cases in which an individual manifests characters present in uncles, aunts, or other collaterals, but not in his parents or immediate ancestors. The laws of heredity explain this occurrence. In some cases there is crossed transmission. A peculiar form of heredity is seen in hemophilia and some other diseases, which are trans- mitted through the female members of a family, who generally remain unaffected, to the male offspring. Hereditary traits sometimes pre- dispose to a number of allied affections. This is particularly striking 22 A TEXT-BOOK OF PATHOLOGY in the case of the neuropathic heredity, in which various forms of nervous disease may appear alternately or irregularly in members of an affected family. Réssle says normal and pathological characters, but not diseases, are inherited. The ovum is not infected with the cause of syphilis, but the fetus is infected with the germ cells or through the placenta. The influence of maternal conditions is naturally the greater. Abnormalities in offspring of consanguineous parents are now explained as a summa-~ tion of the natural tendencies of both parents. Hereditary Congenital Pathological Conditions —Such conditions as hemophilia and color-blindness, familial nervous disorders, joint mal- formations, and skin anomalies are placed in this group. Pathological Conditions of Later Infe Depending Upon Heredity.— This heading refers to the related subjects of predisposition and diathetic reversion or inheritance. Such diseases as gout, diabetes, and insanity are covered. Here one may place the undeveloped physique and con- stitutional lack of resistance to tuberculosis in the children of affected parents. A number of theories have been constructed to explain the mechan- ism of heredity. Darwin, in his hypothesis of pangenesis, suggested that minute particles are given off from all of the cells of the body; these are collected in the reproductive cells, which, in consequence, represent all of the bodily characteristics, hereditary and acquired. Weismann denies the transmissibility of acquired characteristics, and holds that in the process of reproduction a certain amount of “germ-plasm”’ passes from the parent cell into the offspring, where it remains, and is in turn passed on to succeeding generations, thus perpetuating ancestral char- acteristics. Another theory of heredity is called epigenesis, or that process through which an ovum goes in its maturation process when it develops under its appropriate biological environment. This theory does not accept the statement that in the ovum there is a preformed molecule that will eventually develop into a particular part, as is the case with the two previous theories. It assumes that the development of the indi- vidual occurs in harmony with that of the race. However, it has been shown that with the earliest stages of a de- veloping ovum certain differentiations occur which apparently stand as forerunners of certain bodily parts, and the development depends upon the preserved integrity of these primary divisions of the ovum. It has also been shown that an embryo when dividing shows distinct polarity. These facts militated against the epigenetic theory and gave rise to the mosaic theory, which assumes the control of bodily parts by definite molecules or blastula segments. It must not be forgotten in the study of heredity that, while the atomical changes are measures of evolution and heredity, the chemistry of the biological mass must be similarly affected. If, as has been maintained by some authors, the disproportion between the surface tension in nucleus and protoplasm combined with alterations in the THE ETIOLOGY OF DISEASE 23 chemical consituents as a result of this, be the cause of cell growth, then any disturbance of the cell tension or chemistry will be felt by new cells the product of the division. If the parent cell has established for itself a definite chemical cycle its progeny will continue this cycle. This is another application of Baumgarten’s anlage, and shows the close association of heredity and predisposition. The theories and experiments upon heredity have given rise to certain generalizations and laws which are now explained. Racial inheritance expresses itself in functional or anatomical varia- tion. Races are peculiar in resistance to parasitic diseases and in the maintenance of certain physical characters. Familial inheritance is similar in principle to the former, and is well illustrated in hemophilia (g. v.). Blended and Particulate Inheritance—The former means a har- monious admixture of characters of the parent, while the latter means the domination of some particular character. Mendel’s law: The observations of Gregor Mendel upon self-fertilizing plants showed the transmission of character to follow a very definite law. When two or- ganisms, one so-called dominant, the other recessive, reproduce, the off- spring contains a mixture of the two, although dominant characters may show more clearly. The second generation shows one pure dom- inant, two admixtures of dominant and recessive, and one recessive. Self-fertilization will produce always dominant from dominant and recessive from recessive. Offspring of admixtures will produce, as in the second generation, a dominant which will continue a dominant, a recessive following this type in its progeny, and mixtures of dominant and recessive and recessive and dominant. These last two will then follow the same course by producing two pure and two mixed prog- enies. This law has been worked out with many plants and some small animals. It has not been directly applied to man, but it is obvious that the domination of characters must have influence upon offspring. Galton’s law claims that the parents each supply a quarter of the influence to the offspring; the four grandparents, each a sixteenth, and so backward to the completion of the unit. For the mosaic inheritance and atavism see above. Reversionary inheritance is atavistic reversion to a lower condition or incomplete type. Diathetic inheritance is a transmitted tendency in a particular direction. (See Pathological Disposition and Predisposition.) Cumulative inheritance is a summation or exaggeration of charac- ters from both parents. Mutation is the assumption of character not peculiar to the given species. Determining Causes.—Among the immediate or determining causes of disease are those which originate outside the body and those which are generated within the body. Among the former are included trau- matism, heat, cold, and other physical agents, poisons, and living organ- isms, including bacteria and various animal parasites. The causes of 24 A TEXT-BOOK OF PATHOLOGY disease originating within the body itself are less definitely known, but it has been found in chemical studies that various products of normal metabolism when accumulated in abnormal quantity, or products of disturbed metabolism, may occasion local or widespread disease of various sorts. This self-poisoning is designated auto-intoxication. The term “auto-intoxication” is frequently applied to poisoning by products of intestinal putrefaction. This application of the term is not, strictly speaking, correct. The same poisons might have been produced by putrefaction of food outside the body, when the use of the name auto- intoxication would be manifestly absurd. If poisons are produced by imperfect digestion, and these affect the organism, the condition could properly be termed auto-intoxication. TRAUMATISM Traumatism, or mechanical injury, may be of various sorts, gradual or sudden, small or large; and the effects are dependent upon the form and severity of the injury. Pressure brought to bear upon a part leads to disturbances of the circulation and more or less direct injury of the cellular elements. When the pressure is gradual, true atrophy of the part may occur, as in the case of the atrophic liver resulting from lacing. When the pressure is greater and the circulation is completely arrested, more destructive change may result, such as necrosis or gan- grene. This is seen in the necrotic atrophy of bone resulting from the pressure of aneurysms, or the gangrene of extremities resulting from ligation. Wounds.—Frequently, inflammatory reaction occurs in the surrounding tissues when traumatic injuries have been sustained. This is illustrated in all forms of wounds, and it is through the inflam- mation and subsequent regeneration of tissue that the areas of destruc- tion are restored. In cases of injury by fine particles, as in powder- marks of the skin, or the surface injuries sustained by miners and metal- workers, or in individuals inhaling sharp particles like coal-dust, marble- dust, or steel-filings, small injuries of the tissues result. The foreign bodies may be subsequently discharged, leaving a focus of inflamma- tion, or the inflammation may surround the particle embedded in the tissue, and encapsulation by fibrous-tissue formation may occur. Large injuries in which the tissues are contused or broken may lead to extensive inflammation, in part the result of the direct injury to the tissues and in part the result of injury of the blood-vessels. An injured surface presents a locus minoris resistentie which offers an entrance to organisms already in the locality or to those that might . actually driven into the tissue or blood-stream by the damaging orce. ; _ Gross traumatism of the body as a whole, as in falls, crushing injuries, etc., causes various disturbances according to the part mainly involved. Rupture of the viscera, as the lungs, heart, liver, spleen, stomach, or intestines, may occur. When the head is violently struck, unconsciousness is common as a consequence of either disseminated punctiform hemorrhages, large focal hemorrhages, or obscure and THE ETIOLOGY OF DISEASE 25 possibly only functional disturbances. Commotio cerebri, the condition occurring in such cases, may be fugacious or may lead to permanent disorder dependent upon organic changes in the brain. Spinal symp- toms, met with after railway injuries and like accidents, may be due to hemorrhage and secondary morbid processes in the cord, or may be due to the uncertain pathological conditions constituting hysteria. The relation of a single trauma to tumors is not entirely clear. It seems that a new growth has been observed at a point where an in- jury has been sustained. Repeated minor traumata or continued irri- tation seem to precede some epithelial growths. The most notable example is the epithelioma of the lip of clay-pipe smokers. The injury in these cases can hardly be a determining cause. The occurrence of a. tumor at a site of injury is not inconsistent with any of the principal theories of cancer origin. Epithelial cysts may arise at points of injury by the displacement of epithelial cells to a position below the surface. These are not true neo- plasms. PHYSICAL CONDITIONS ; Heat.—High temperatures produce local or general results ac- cording to the mode of application and degree of heat. Local excess of heat produces various lesions. Moderate excess leads to relaxation of the walls of the blood-vessels; with increasing grades of temperature there is, in addition, necrotic change in the cells of the part, and exudation of serum causes vesicle formation. Still higher grades. of temperature produce immediate destruction, perhaps with charring, of large or small areas, while the surrounding tissues suffer from reactive inflammation and hyperemia. Extensive burns involving one-third or more of the surface of the body frequently cause death. In these cases it is likely that poisonous products are formed, either directly through tissue and blood. destruction, or indirectly through disturb- ances of the functions of the skin or internal organs. The immediate manner of death is often in the form of shock; when the termina- tion is delayed, various vascular, hemic, and tissue disturbances may occur. Intravascular coagulation is not unusual, and is not improbably the result of the liberation into the blood of tissue elements set free in the areas of local destruction, or to substances produced by direct ~ destruction of the blood. The same substances may account for the existence of fever (ferment intoxication). The intravascular coagula- tion caused in this or other ways may induce venous stasis and localized hemorrhages. Focal necrosis or degeneration of the tissues of various. organs, such as the liver, kidneys, or the mucous and serous membranes, may be due to thrombotic occlusion of vessels, or to the influence of cir- culating poisons without thrombosis, or to both. It seems probable that the cause of all these physical changes is a necrotizing toxin arising in the burned skin. (Some manifestations of this condition resemble anaphylaxis.) Marked changes are found in the lymphatic glands as well as in the Malpighian bodies of the spleen and in the bone-marrow. These changes present themselves as areas of leukocytic degeneration 26 A TEXT-BOOK OF PATHOLOGY containing actively phagocytic endothelial cells and surrounded by a zone of lymphocytic invasion. The lesions are not unlike those pro- duced by abrin, ricin, and bacterial toxins. Duodenal ulcer is often referred to as an occasional result of extensive burns. The blood itself may present evidence of disease in the form of degenerations of the corpuscles, in the reduction of their number, and of the amount of coloring-matter; while regenerative changes frequently present them- selves some time later (nucleated red corpuscles). Changes in the urine may occur in cases of extensive burns, in consequence of the tissue destruction (hemoglobinuria, albumosuria). Exposure to general high temperature varies in its effects according to the manner of exposure (dry air, steam, etc.). An animal exposed to a constant temperature somewhat above the usual surrounding tem- perature presents a slight increase of its body heat, which is compen- sated for by increase in the respirations and pulse-rate. Much higher temperatures may cause death by coagulation of the tissue proteins, notably in the muscular structure of the heart or the respiratory muscles. Before this extreme is reached, however, it may be found that the con- sumption of the tissues of the body is greatly in excess, though the res- piratory quotient is altered in favor of the amount of oxygen consumed. Continuous exposure to excessive heat frequently causes peculiar dis- turbances in man, known as heat-stroke, sunstroke or insolation and heat exhaustion. In these conditions hyperemia and edema, or even inflammation of the meninges, may occur. These lesions are some- times supposed to be the result of the direct effect of the heat; but there is reason to believe that they may be occasioned by poisonous substances produced within the body by disturbed metabolism, as a result of the heat. One evidence of the effect on the blood of continued elevation of temperature is the appearance in the red blood-corpuscles of baso- philic granules—granular degeneration of Grawitz. (See chapter on Blood.) Exposure to high temperatures for long periods, such as steamship stokers are subjected to, produces cramps in the muscles, chiefly of the extremities. The excitability of the muscles is greatly increased. The autopsy upon a death from heat-stroke shows an early rigor mortis and decomposition, general passive congestion due to weak heart action, a fluid condition of the blood, and sometimes hemorrhages into the medulla. A portion of the body, as an arm or a leg, may be exposed for a limited time to excessive temperatures (300° to 400° F.) in dry air without injury. The general temperature is slightly elevated, but metabolism is practically unaffected. The effects of general or local heat are much increased when the organism as a whole or in the part involved is below par. A paralyzed limb is burned or scalded at comparatively low temperatures. . _Cold.—Exposure to extreme degrees of cold may cause results quite similar to those produced by heat. Exposure of the skin to lique- fied air, solidified mercury, or other substances at excessively low THE ETIOLOGY OF DISEASE 27 temperatures produces vesiculation and necrosis of the tissues like those produced in burns. Exposure of the body to greatly reduced but bearable temperatures of the surrounding atmosphere causes vascular disturbances followed by necrosis of the tissues and inflammatory changes. The parts so affected are the extremities or projections of the body, like the toes and fingers, nose and ears. The primary result of cold is vascular constriction and local anemia. These serve the purpose of preserving the body heat by preventing heat radiation; later the blood-vessels are paralyzed and extreme hyperemia results. Then cellular exudation and necrosis may occur. These changes are well seen in the condition termed chilblain. In prolonged exposure to cold there are a gradual reduction in the activity of the various organs and a gradual obtunding of the sensibility until the patient becomes comatose. The retention of excrementitious products of metabolism, or the formation of products of abnormal metabolism, may be important in causing this condition. There is a reduction of hemoglobin and red cells, increase of CO: ex- cretion, and disappearance of glycogen. Autopsy shows edema of lungs, with or without congestion, and transudates into serous cavities. Exposure to cold plays an important part as a clinical cause of dis- ease. Various forms of pharyngitis and coryza or bronchitis so fre- quently follow such exposure that the term ‘‘cold” is generally used. Other conditions, like rheumatism, pleurisy, pneumonia, and the like, bear a similar relation. It is now recognized that in most of these cases cold is merely a predisposing cause, the immediate cause being in many, if not all, cases specific micro-organisms. The mode of action of the exposure is uncertain; probably it causes a reduction in the resist- ing powers of the organism and thus favors the activity of bacteria. The hyperemia following exposure to cold is associated with lowered alkalinity of the blood, thus favoring bacterial increase. The phago- cytie action of leukocytes is reduced by exposure to cold, and it is said that complement and antibody do not combine so readily with . antigen. This is true in vitro. Increased Atmospheric Pressure.—Exposure to extreme pressure of several atmospheres may occur among deep-sea divers or in men working in caissons used in bridge building. But little disturbance may be caused at first or for a long time; but on return of the workmen to the usual atmospheric conditions symptoms make their appearance (caisson disease). Among these symptoms are bleeding from the nasal or other mucous membranes, great depression, delirium, and paralytic conditions. Congestion, degenerations, and vacuolations in the spinal cord have been discovered in some cases. The cause of the lesions is a hypertension of nitrogen within tissues. Tissues hold much more nitrogen than the blood, so that this gas is held in them because the blood becomes saturated each time it passes through the lungs. When the person returns to normal atmospheric pressure the tissues give up to the blood their retained gas. The blood and lungs can excrete but slowly, so that bubbles of nitrogen under release 28 ‘A TEXT-BOOK OF PATHOLOGY of pressure appear in tissues and vessels. These bubbles are the cause of hemorrhages, fissures, and gas embolism. Decreased Atmospheric Pressure.—Effects of decreased press- ure are seen in inhabitants of high altitudes and in persons ascending in balloons. Marked excitement of the vascular system, hemorrhages, somnolence, weakness, vomiting, and similar symptoms are observed; — in less marked cases a general excitement of the nervous system, sleep- lessness, etc., occur. These symptoms have been attributed to lack of oxygen, and compressed air and oxygen have been successfully used to combat them; but experiments show that the air-pressure may be as low as 400 mm. of mercury without interference with the respiratory exchange of gases. To a certain extent the symptoms are probably mechanical and due directly to the reduced pressure on the exterior. Recent studies show that the blood contains greatly increased numbers of red corpuscles in a given volume, and the percentage of hemoglobin is correspondingly increased. This is probably due, to some extent, to disturbance in the distribution of the corpuscles with stagnation in the peripheral vessels (see Diseases of the Blood). Insufficiency of Respiratory Air.—A certain amount of air is necessary for the continuance of health or life. Insufficiency may be due to diseases which obstruct the air-passages or affect the pulmonary tissue itself, and to foreign bodies (solid bodies, water in drowning) within the air-passages. Changes in the atmosphere or gases taken into the lung may cause insufficiency in the supply of oxygen, notably in CO-poisoning, in which the foreign gas enters into firm combination with the hemoglobin of the blood and thus excludes oxygen. The respiratory rhythm is maintained by the appropriate stimula- tion of the respiratory center by the appropriate mixture of carbon dioxid and oxygen in the circulating fluids. If, by repeated deep in- spiration, the amount of CO, in the blood decreases (called acapnia), there is no stimulation of the respiratory center and a condition of true apnea ensues. This view of apnea is maintained by some, while others claim that apnea may be induced after section of the vagus, and that, therefore, the gases in the blood are always responsible for apnea. This term should be used for the interruption of respiration due to the above causes, and not to cessation by mechanical or voluntary causes. Moderate decrease of the supply of air causes labored and rapid breathing, more or less cyanosis, depression, and stupor. This con- dition is termed asphyxia. Complete lack of air causes increase of these symptoms and death by suffocation. In these cases the blood is ex- ceedingly dark and fluid, and hemorrhages may be found in various situ- ations. The latter result from excessive blood-pressure during the death agony. Long-continued insufficiency of oxygen may. directly or indirectly occasion degenerative diseases of the tissues.! 1 It has oft en i i because the Bleed a coon eee oe eee A a matter of fact, however, physiological experiments have demonstrated that the respiratory exchange (inhalation of oxygen and exhalation of ¢ i i i but little affected and is as frequently increased as decreased. eae eae THE ETIOLOGY OF DISEASE 29 Electrical Influences.—The effects of powerful electrical currents and discharges on the tissues resemble those produced by burns. Locally, a dry, crisp, excavated lesion is produced. Later, hyperemia and ap- pearances resembling moist gangrene develop. The underlying muscles are more or less paretic. Changes in the blood-vessels and a fluid state of the blood, extending to some distance from the local lesion, have been observed. Very powerful and fatal discharges in some cases produce hemorrhages in the floor of the fourth ventricle and petechie in the serous membranes and elsewhere. There are degenerations of nerve- cells, particularly in ganglia. Death seems to be caused by powerful inhibition of the heart. Lightning stroke leaves branching linear burns. Less powerful discharges, such as dynamo workers receive, cause sting- ing sensations in the absence of burns. If prolonged, there is loss of consciousness, depending for its depth upon the amount of and duration of the current. There is no definite amount that the body will always endure. Effects of X=rays.—Exposure of healthy or unhealthy tissues to x-rays causes cellular degenerations and necroses with secondary in- flammatory reaction. The skin—being most immediately exposed— is the most susceptible of normal tissues; but diseased tissues and new growths are still more readily affected, probably because of their less stable condition. The point of severest attack is the nucleus of young specialized cells. The epithelial cells of the skin suffer first and most intensely; the glandular cells of the skin are less prone to degeneration. The damage to the skin by x-ray is followed by a chronic dermatitis like xeroderma pigmentosum. This shows a tendency to go over into epithelioma. The x-ray affects the hematopoietic organs by destroying the essential early leukocytes (karyorrhexis in the germ centers in lymph- tissue and reduction of the myelocyte series in bone-marrow). There is some basophilic degeneration and polychromatophilia of the erythro- cytes. X-rays may affect the genital organs by destroying the sperma- tozoa without producing physical impotence; by causing menstrual dis- turbances and abortion. After prolonged raying sexual gland atrophy may ensue. X-ray affects metabolism by increasing uric acid nitrogen and phosphorus excretion and by splitting body lecithin. Swelling and degeneration of the endothelial and other cells of the blood-vessels and thromboses may in part account for some of the results of 2-ray exposure. POISONS Definition.—The term “poison” may be applied to substances which when introduced in relatively small amounts into the living organism disturb its structure or functional activity. The Action of Poisons in General.—Gaseous poisons act primarily upon the respiratory mucous membranes with which they come in contact, or after absorption into the blood disorganize this fluid or lead to disturbances of the nervous system. Liquid poisons are generally absorbed through the gastro-intestinal mucous membrane, but may be 30 A TEXT-BOOK OF PATHOLOGY received directly into the tissues by injection under the skin. They are rarely absorbed through the skin. Solid poisons must in all cases first be dissolved, and are then absorbed like the liquid poisons. They may by their strong attraction for water absorb the latter directly from the tissues, and by this process alone may bring about important changes. . The lesions due to a poison may be entirely local, as in the case of certain corrosives or caustics; in other cases the point of entrance is unaffected, the pathological manifestations being entirely due to the changes in different parts of the body, or to nervous disturbances result- ing from the circulation of the poison in the blood. Some poisons act immediately in destroying cells (caustics), while others must combine with them before the toxic effect is manifest; in other words, there is a latent period. The fate of poisons after ingestion is very different in different cases. Some poisons circulate with the blood and are eliminated’ un- changed. Others may suffer chemical change within the stomach or other cavities of the body before absorption, and may be either com- pletely neutralized, or may be converted into forms which are subse- quently slowly absorbed. After absorption into the blood other chemical reactions may occur, and the poison may be more or less neutralized, the system then suffering either from the resulting compounds or from the changed condition of the blood. Active destruction of the poison may occur in the blood or in the various organs, especially the liver. In these processes, however, the glandular organs may suffer seriously, various forms of degeneration or necrosis resulting. Cer- tain poisons, like the toxins, enter into chemical combination with cells of the body and remain fixed in this way. (For further details see Immunity.) The defense of the body against poisons lies in substances natural to it, and probably not increased in response to intoxication. This does not apply to the bacterial toxins in bacterial infection, but if injected in the absence of general infection some of the bacterial toxins may be de- toxicated as are inorganic or higher vegetable poisons. Among the defensive bodies are the blood, bile salts and acids, sulphuric acid as such or as sulphates, and the fatty acids. The processes at work are rapid elimination, oxidation, reduction, and hydrolysis. Poisons may be changed in form by precipitation or altered by combination with body proteins. The effect of poisons depends upon the dose as well as upon the nature of the substance, and also upon the individual. The repeated ingestion of certain poisons, such as arsenic or opium, may generate a considerable degree of immunity or tolerance (mithridatization). Simi- lar immunity may be a natural characteristic of a given individual or of classes or species. Susceptibility to the action of poisons is further influenced by age and constitutional vigor. Children bear certain poisons better, comparatively speaking, than adults, while the reverse is true of other substances. Sometimes there are idiosyncrasies which THE ETIOLOGY OF DISEASE 3l lead to peculiar results not observed in the average individual. In consequence of this, substances ordinarily not toxic may be extremely injurious to certain persons. (See Allergie.) Sometimes poisons are comparatively innocuous when administered in one way, though powerfully toxic to the same animal when other- wise introduced. ' Thus in dogs intravenous injection of atropin is very slightly injurious, but injection of minute doses into the spinal cord causes rapid poisoning. Some experiments would indicate that the leukocytes are capable of fixing inorganic poisons and thus acting as defensive agencies. Non-fatal doses of poisons (arsenic) cause, first, diminution of the polymorphonuclear leukocytes, followed by leuko- cytosis; and the poison is found in abundance in these leukocytes. Fatal doses are unattended with the secondary stage of leukocytosis or . the leukocytic fixation of the poison. These results need further con- firmation. In general, the action of poisons may be immediate destruction, stimulation to exhaustion and disintegration, or inhibition gradually to cessation of function. There are poisons with special predilection, e. g., strychnin for the nervous system; phosphorus for bone; snake- venom for blood, nervous tissue, and spleen. Elimination.—The excretion of poisons may take place through the kidneys, lungs, the mucous membrane of the gastro-intestinal tract, the mammary glands, or the skin. Jn some instances a poison is eliminated without change in the excreta; in other cases it suffers com- plete change, and is not present at all in the excretions. The rate of elimination varies greatly, and is more or less dependent upon condi- tions of the system. Some poisons, as phosphorus and mercury, may ‘be stored up within the body for a considerable period, subsequently suffering slow elimination. Classification.—The number of substances which may act as poisons is very great, and the manifestations are of very different sorts. Classi- fication of poisons is, therefore, difficult and not entirely satisfactory. We may crudely distinguish between gaseous, liquid, and solid poisons; between animal and vegetable; organic and inorganic; but these classi- fications have no scientific value. From the point of view of the action of the poisons we may dis- tinguish corrosive poisons, or those which have a local action; organic or parenchyma poisons, or those which act less strongly at the point of application than upon the various organs to which they are conveyed through the blood; blood-poisons, or those which exercise their effects primarily upon the blood; and the nerve-poisons, or those which disturb the functional activity of the nervous system without producing de- finitely discoverable lesions. Corrosive Poisons; Escharotics; Caustics——Under this heading are included various acids, alkalies, and mineral poisons, such as sul- phuric, nitric, oxalic, carbolic, and hydrofluoric acids, caustic potash or soda and ammonium, and gases like chlorin and bromin. Nitrate of silver, bichlorid of mercury, sulphate of copper, and other inorganic 32 A TEXT-BOOK OF PATHOLOGY compounds have a similar action, and certain organic bodies, such as cantharidin and croton oil, belong to the same class. All these poisons exercise a destructive effect upon the cells with which they come in contact, partly by abstraction of water and partly as a result of a coagulating power or similar action. The acids and mineral caustics usually produce dry and more or less discolored areas of necrosis; the caustic alkalies cause a sort of gelatinous change or a saponification of the tissue. The degree of injury depends upon the poison and the amount in contact with the tissues. There may be only a superficial injury of the outer layer of epithelial cells, or extensive destruction. Reactive inflammation, is almost always present, and often, especially in the mucous membranes, the inflammatory reaction is extensive, though the corrosive action of the poison is limited in depth and extent. The affected part may present slight areas of necrosis with reactive hyperemia and inflammation beneath and around them, or deep eschars, vesicles, or large bulla. In the process of healing, extensive scars may form, and these may be serious in their effects, as in the case of strictures of the esophagus. Organic Poisons; Parenchyma Poisons.—This large group includes many metallic compounds that have a local corrosive or escharotic effect, but which may in smaller dose gain entrance to the blood and cause extensive organic lesions. It also includes poisons of vegetable origin and products of bacterial growth. In general, these poisons have a similar action. The kidneys and the mucous membrane of the intes- tines are especially active in their elimination and suffer most seriously. Degenerations of the epithelial cells of various sorts are. met with, such as nuclear degenerations, coagulation necrosis, fatty degeneration, and even calcification. The changes may be diffuse or may occur in small foci. In the latter case small areas of granular appearance, having a lighter color than the surrounding tissues, are seen; and on staining the cells are found to color poorly or not at all, the nuclei often showing this change first. Nuclear degenerations (fragmentation, hyperchromatosis, etc.) are observed, and in some instances marked fatty degeneration of the cells occurs. Around the foci of degeneration there is more or less cellular infiltration (polymorphonuclear cells), and to a less degree the degenerated area itself is infiltrated. In cases in which diffuse change occurs there is equally diffuse round-cell infil- tration. After the acute process has subsided, hyperplasia of the con- nective tissues may occur and the affected part becomes more or less sclerotic or indurated. Regeneration of the parenchyma cells is less apt to occur. Some of the more important of the poisons of the group may now be separately considered. Phosphorus is a poison of considerable activity in the yellow form; the red variety is inert. Workmen in match factories are the most frequent victims of this form of intoxication, but occasionally accidental poisoning by swallowing occurs. In the latter the manifestations are acute. The pathological changes are catarrhal inflammation of the THE ETIOLOGY OF DISEASE 33 gastro-intestinal mucous membrane and more or less widespread fatty degeneration of various tissues and organs. The liver suffers most severely, being enlarged, light yellow or reddish in color, and friable or doughy. Microscopically, the liver-cells are found extensively de- generated (fatty). Similar but less marked fatty degeneration is found in the renal tubules, gastro-intestinal epithelia and heart-muscle, and in the intima of the blood-vessels. Extensive jaundice is frequent and numerous hemorrhages may occur. In the more chronic poisoning of match-makers the poison enters through the mouth and respiratory passages, being inspired as dust. Chronic catarrhal inflammation of the respiratory tract may occur and a peculiar form of necrosis of the bones (see Bones) is met with. Arsenic is poisonous in certain forms (white arsenic, arsenous acid) and inert in other forms (the sulphids). Acute poisoning occurs when toxic forms are swallowed in large doses; the chronic forms of poisoning result from gradual ingestion or the inhalation of dust con- taining arsenic. Cases of the latter sort occur when wall-paper, hang- ings, and the like, colored with arsenic pigments, are used. The lesions in acute arsenic-poisoning resemble those produced by phosphorus. The gastro-intestinal inflammation is, however, more severe; while the fatty degeneration of the organs is less marked. In chronic arsenic- poisoning changes in the peripheral nerves (degeneration and inflam- mation) are most important. It is likely that focal or diffuse myelitis may likewise be caused by this poison. Chronic inflammations of the gastro-intestinal or respiratory mucous membranes are met with in some cases. Inflammatory lesions and pigmentation of the skin may occur. Lead.—Among the compounds leading to acute or subacute poison- ing the chromate, the acetates, the carbonate, and oxid are most im- portant. Chronic poisoning occurs in workmen in paint manufactories and among type-setters and painters, and in persons drinking certain waters that have been conducted through lead pipes. Less rarely the use of cosmetics, dyestuffs, etc., containing lead causes chronic poison- ing. In the acute forms of lead-poisoning moderate gastro-enteritis occurs. In the chronic form changes in the nervous system are most important. Peripheral neuritis is the most frequent lesion, but changes in the large ganglionic cells of the gray matter of the cord have some- times been found. Diffuse sclerosis of the blood-vessels, interstitial nephritis, and the lesions of gout may be present. Atrophy and fatty degeneration of the muscle-fibers are less important results. A blue line on the gums at the junction with the teeth (due to deposit of sulphid of lead) is a lesion of clinical importance. A constant and diagnostically suggestive change is found in a peculiar degeneration (basic degenera- tion) of the erythrocytes. (See chapter on Blood.) Mercury.—Poisoning with mercury may be acute, subacute, or chronic. The first is due especially to the corrosive chlorid and other mercuric salts; the second, to calomel or small doses of those of the former group. Chronic poisoning occurs as a result of inhalation of 3 34 A TEXT-BOOK OF PATHOLOGY fumes or dust containing mercury, and is seen in workmen in mirror manufactories. In the acute cases violent inflammatory and necrotic lesions of the gastro-intestinal tract are seen. Parenchymatous de- generation, fatty change, and even calcification of the renal epithelium may occur; and fatty degeneration in other organs may sometimes be met with. In subacute cases marked by ptyalism some change is doubt- - less present in the salivary glands, but the nature of this has not been determined. Ergot is a poison capable of producing intense toxic results. It contains two important toxic principles, sphacelinic acid and an alkaloid, cornutin. Acute poisoning sometimes results from over- dosage; while chronic intoxication occurs from the use of affected grain, particularly in famine years. Widespread poisoning of communities has sometimes resulted. The lesions produced are not definite or uni- form. Gastro-intestinal inflammation and erosion of the mucous mem- brane have been observed, but are not constant; sclerotic change in the spinal cord has been found in a few cases. Gangrene is a frequent lesion, probably resulting from vascular obstruction due to contrac- tion of the blood-vessels. Enlargement of the spleen has sometimes been noted. Toxalbumins from Plants——Certain vegetable bodies, like ricin, de- rived from the castor bean, and abrin, derived from jequirity bean, are exceedingly toxic, acting in part as blood-poisons, but also as parenchyma poisons. Injected into animals these substances cause violent intoxica- tion and focal areas of necrosis in various situations, notably in the liver. In part these lesions result from vascular thrombosis; in part, from direct action. The study of the action of these poisons is of par- ticular interest from the resemblance of the lesions to those caused by certain bacteria and bacterial poisons. Toxic Products of Bacteria.—In the growth and multiplication of various bacteria definite toxic substances are created, and through the latter the lesions of infection are to a large extent produced. Such poisonous bodies may be generated in the growth of the bacteria out- side of the body, as well as within the body. In the latter case the pathological lesions at the point of infection may be the focus of origin of toxic substances which are then distributed throughout the body. This is eminently true of tetanus and, to a large degree, of diphtheria. In other cases the bacteria themselves are transported to various parts of the body and, finding lodgment in the tissues, set up changes by which their toxic products are evolved. The latter increase the local foci of pathological change and then spread in the circulation and cause general intoxication. Further reference to these poisons will be made when discussing the individual bacteria. The venom of serpents and of various insects contains toxic bodies, some of which are albuminous in nature. These vary in their action, being to some extent blood-poisons, but more particularly parenchyma poisons. The lesions produced are local and general. Locally, there are intense inflammatory reaction and edema around an area of cellular THE ETIOLOGY OF DISEASE 35 necrosis or destruction where the poison has come in immediate con- tact with the tissues. The blood seems to suffer great disorganization and corpuscular change. Petechial hemorrhage and foci of cellular necrosis occur in various organs, and edema of the lungs is frequently present. The action of the venom of different animals varies in kind and intensity to a certain extent, but is, in general, of a similar type. Snake-venom has the peculiarity of setting up immunity reactions similar to those induced by bacterial toxins. It contains several differ- ent fractions, those toxic to blood, nervous tissue, kidney, etc. Blood-poisons.—Various liquid or gaseous substances are termed “‘blood-poisons” because of their especial action upon this tissue. The blood-poisons may be classified as (a) those which combine with the hemoglobin without changing the corpuscles; (b) those which alter the red corpuscles and the coloring-matter; (c) those which affect the blood as well as the tissues generally; (d) those which cause changes in the blood-plasma, increasing or decreasing the tendency to clotting; and (e) those which destroy leukocytes. (a) Among the poisons which act by entering into combination with the hemoglobin without changing the corpuscles, carbon monoxid, cyanogen, and hydrogen sulphid are important. In carbon-monoxid poisoning, which often results from inhalation of the fumes of charcoal burning with insufficient air, the blood has a light color and light pete- chial discolorations may be seen in various parts of the body. In cyano- gen-poisoning the blood is similarly light in color; while in H25-poisoning the blood is often dark, sometimes quite black. (b) Among the poisons which disorganize the blood-corpuscles and later the hemoglobin are a large number of chemical agents used in medical practice or in the arts, including potassium chlorate, nitro- -glycerin, anilin, nitrobenzol, various coal-tar derivatives, and arseni- uretted hydrogen. Certain poisonous plants (toadstools) act similarly. These poisons lead to a reduction of the hemoglobin with formation of methemoglobin and at the same time destruction of the corpuscles themselves, with release of the hemoglobin into the serum. The altered condition of the blood often induces secondary changes, such as fatty degeneration and hemorrhages in various organs. The blood-corpuscles are found in variously degenerated conditions, showing microcytosis and poikilocytosis in particular. Nucleated red corpuscles may be present as in other conditions of blood destruction with attempted regeneration. (c) Among the poisons which disorganize the blood and at the same time cause changes in the parenchyma of organs, reference has been made to abrin and ricin. In addition to the organic changes, these substances cause certain alterations in the blood itself, increasing the coagulability and thus inducing thrombosis. Le (d) Various substances introduced in sufficient quantity are capable of affecting the plasma of the blood or the corpuscles in such a way as to affect its coagulability. Calcium salts, carbonic acid gas, and fibrin ferment are active in this way, but the last alone produces toxic results 36 A TEXT-BOOK OF PATHOLOGY through this function. Ferment intoxication may occur in consequence of various other intoxications, when corpuscular or tissue destruction has liberated the ferment. Among the poisons which decrease coagula- bility peptone (albumose) is important. (e) Saponin and benzol destroy leukocytes. Injection of large quantities of water or hypotonic salt solution may have a hemolytic effect. The blood-serum of one individual may contain hemolytic agents for the cells of another person, and more frequently for those of another species Nerve-poisons.—This group contains a large number of substances capable of producing violent symptoms and even death without definite change in the tissues of the body. Certain investigations showing cer- tain alterations in the finer structure of the nervous system in disease and in cases of intoxication suggest that histological changes in the central neurons may be found to result from poisoning by these sub- stances. Changes of this kind (changes in size and form of the cell and nucleus, thickening, contraction, or disappearance of dendrites, altera- tions in the chromophilic bodies, etc.) have been described in the gray matter of animals poisoned with alcohol and certain toxins of bacterial origin. It is not unlikely that similar changes will be found in other conditions. Among the nerve-poisons are alcohol, chloroform, ether, and various alkaloids like morphin, atropin, etc. In this same group might be included some of the poisons contained in the venom of serpents and other animals, but these usually cause definite lesions in the blood or tissues of the body. Ptomain Intoxications.—Another group of poisons with action similar to the last are those produced within the body by putrefactive action or in various foodstuffs before ingestion. Frequently cases have been observed in which all the members of a family or even large numbers of people have been poisoned by eating certain meats, sausages, ice- cream, and other foods. In some of these cases it has been found that the toxic element was a basic compound resembling the alkaloids in chemical structure. To these putrefactive compounds the name ptomain is given. One of these compounds, which occurs in cheese, and occasionally in milk, has been termed ‘‘tyrotoxicon.” Intoxications of this class must be distinguished from infections resulting from the use of food contaminated with micro-organisms. The symptoms may be so rapidly developed (absence of incubation period) and so immediately generalized that the distinction can be arrived at clinically, but the absolute diagnosis is made bacteriologically. (See p. 37.) : These conditions in food are usually set up by anaérobic bacteria. The pathological results are paresis of the centers of special sense, de- generation of ganglion cells, and hyperemia of all organs. The intoxica- tions usually arise from the intestinal tract and are due to changes in meat by bacteria present in the slaughtered animal before death. The poison is thermostabile and does not affect the appearance or odor of meat and may not change the flavor. The symptoms are vomiting, THE ETIOLOGY OF DISEASE 37 colic, and diarrhea, followed by collapse. The active agents are bac- terial products in the meat, but which can also be obtained by growth of the same organisms in wtro. It is an intoxication and not a bacterial infection. Bacillus enteritidis of Giirtner is the most important single ‘organism in this group. A considerable number of ptomains have been separated, includ- ing neurin, obtained from putrid flesh; muscarin and ethylendiamin, derived from decayed fish; mydalein, and mydatoxin. Some of these substances produce toxic results indistinguishable clinically from those produced by certain alkaloids. This fact has become one of great importance in medicolegal investigations. VEGETABLE AND ANIMAL PARASITES Vegetable parasites are by far the most important causes of dis- ease. The belief in a living cause or contagium vivum is by no means a recent acquisition, but the actual demonstration that diseases may be caused by minute living organisms has only recently been reached. The micro-organisms in question (bacteria) belong for the most part to the vegetable kingdom and constitute the lowest orders of fungi. Their biological characters and their relations to special diseases will be described in a subsequent chapter. Etiological Relationship of Bacteria to Disease.—It is difficult to prove the specific relation of bacteria to disease. JXoch has laid down four important laws which must be conformed with before the etiologi- cal réle of a bacterium is admitted. These are: (1) The bacterium must be found in the diseased person; (2) it must be cultivable upon media outside the body; (3) pure cultures introduced into a healthy animal must produce the disease in the animal; and (4) the bacterium must be recoverable from the body of the animal. In a number of dis- eases micro-organisms have been proved to be the specific causes according to the requirements of Koch’s rules. In other diseases it has not been possible to furnish absolute proof, though the presumptive evidence, furnished by constant occurrence of the bacteria, suggestive association with the lesions of the disease, absence of the bacteria in other diseases, etc., is sufficient to satisfy all but the most skeptical. Classification of Diseases Due to Bacteria—The general term infectious disease is applied to all such as are caused by bacteria. In some cases the diseases are readily communicated from person to person, even though contact has not been immediate. These are termed con- tagious diseases, while the term non-contagious is given to those in which such ready transference is not observed. As a matter of fact, the dis- tinction is artificial, Any infectious disease may be communicated from the diseased to the healthy if the germs or bacteria are transferred. In some diseases this transference readily occurs, even through the air and at considerable distances; in others actual contact is necessary; while in still others secretions or excretions of the diseased must be con- veyed to the healthy. Contagiousness is, therefore, a matter of degree 38 A TEXT-BOOK OF PATHOLOGY only. It is better to use the terms communicable or transmissible dis- eases for those in which every case is dependent upon a preéxisting one, the mode of transmission being either direct or indirect. Malaria is an indirectly transmissible disease requiring the intervention of the mos- quito, while diphtheria is a directly communicable infection, no agent being required for its spread. Infectious diseases may at times spread in communities, affect- ing large numbers of people. Such a dissemination is termed epidemic, and the disease an epidemic disease. When the disease spreads over large areas, as a whole country or continent, the term pandemic dis- ease is applied. Other infections are constantly present in a locality; for such the terms endemic and endemic disease are used. Some endemic diseases are restricted to certain localities and seem in some measure dependent upon local conditions (of atmosphere, soil, etc.) for their con- tinuance. These are called mzasmatic diseases. The soil, etc., have, of course, nothing directly to do with disease, but merely afford the con- ditions necessary for the propagation of the infecting agent, as, for example, swamps and the malarial mosquito. Infectious diseases are frequently described as local or general. Local infections are those that present specific pathological change in a restricted part of the body; the general organism suffers more or less in consequence. Examples of this are erysipelas and diphtheria. General infections are marked by an immediately generalized disease, as in typhus fever or plague. Strictly speaking, most if not all of the so- called general infections are at first local. Among purely local infec- tions might be named the diseases of the skin due to vegetable micro- organisms. Entrance of Micro-organisms into the Body.—Bacteria may be inhaled or swallowed, may enter through abrasions in the mucous membrane or skin, and may be transfered in utero from the maternal to the fetal blood. The mode of entrance in individual diseases de- pends upon the nature of the bacterium, its habitat, and surrounding conditions. Some may enter in but one way; others gain access in any of the different ways. Details regarding this subject will be given in the discussion of special infections. Animal parasites of various kinds act as causes of disease. This group of diseases is termed the parasitic diseases or invasion diseases. In some instances microparasites cause a clinical course similar to that of infectious diseases (malaria, dysentery, trichinosis); in other cases the manifestations bear little resemblance to infections. CHAPTER II DISORDERS OF NUTRITION AND METABOLISM Food.—In the life of the organism certain substances are needed for growth, for the repair of tissues consumed in the wear and tear of life, and to supply heat and other energy. Among these foods are proteins, carbohydrates, fats, inorganic salts, and water. A continuance of normal existence requires more or less definite proportions of the first three and at least a sufficiency of salts and water. The amount of food and the exact proportions vary somewhat in individual cases and under varying circumstances. Voit, the pioneer in this work, found that a laboring man under ordinary conditions requires 118 gm. of protein, 56 gm. of fats, and 500 gm. of carbohydrates. This diet contains 3055 calories. Recent studies all tend to show that the amount of protein is excessive and that some reduction of Voit’s figure is desirable, though the low protein figures of Chittenden and others err on the other side. The minimum figure is perhaps from 60 to 70 gm. The weight of the individual and the amount of the daily work must determine the requisite diet, 35 calories per kilo of weight being an average figure for a man doing light work. The proteins of the diet are necessary to restore tissue waste, since the organism cannot build up proteins from simpler compounds. This consumes part of the nitrogenous foodstuffs. The rest, with most of the fats and carbohydrates, is mainly useful in contributing energy. Diminished Supply of Food; Inanition; Starvation.—Either the want of food or diseases of the digestive organs with lack of ab- sorption may lead to insufficient nourishment. This causes a loss of body weight, as the necessary heat-producing and energy-giving sub- stances must be supplied to maintain life, and the tissues are consumed for this purpose. During the first two to five days of starvation in previously well-nourished persons the glycogen supply of the body is largely consumed, and the amount of protein consumption is corre- spondingly less than on subsequent days. In prolonged starvation the average requirement of from 28 to 32 calories per kilo has been found quite constantly, and with like constancy about 13 per cent. of this energy is supplied by protein and 87 per cent. by fat. In fat persons or animals the amount of protein consumption is relatively less than in those less supplied with fat. Toward the end of long fasting periods the nitrogen elimination falls to low figures. At the same time the urea- nitrogen is especially reduced, partly on account of the reduction of exogenous proteins in the metabolism and partly on account of acidosis. (See Acid Intoxication.) The subcutaneous and other fat depots suffer first in the emaciation of starvation; later, the glandular organs, muscles, 39 40 A TEXT-BOOK OF PATHOLOGY nervous system, bones, and heart. The chlorids in the urine are regu- larly diminished, while calcium salts are increased in correspondence with the destruction of osseous tissue. The functions of various organs suffer greatly: the respirations and heart action are weak, muscular exertions are reduced to a minimum, the endurance and nervous force decline, the body temperature sinks, and finally death may occur from exhaustion or secondary affections consequent upon the disturbed nutrition. (See Acid Intoxication.) The blood in starvation preserves its chemical constitution and corpus- cular richness surprisingly, even after prolonged abstinence. There is probably a reduction in the total mass of blood. Increased Supply of Food; Overfeeding.—The effect of this depends upon individual conditions, such as the amount of exercise, the surrounding temperature, and less easily demonstrable peculiarities of the individual. An excess of protein food leads to increased excretion of the end-product of its metabolism—urea. Experiments have shown that to a slight extent a reserve amount of albuminous tissue may be built up by excess of protein food. Great excess of protein eventually disturbs digestion and leads to its own discharge with the feces. The carbohydrates and fats are broken up in the body and excreted mainly as carbonic acid and water. An excess of these foods tends to cause increased deposition of reserve fat and glycogen, which may be called upon at subsequent times of need. This deposition is a normal or physiological process and has the distinct purpose just indicated. Exceptionally in the condition called obesity the storing up of fat is inordinate and probably pathological. Metabolism of Fat.—The fat of the body has two sources: the fat of the diet and sugar either ingested or made within the body. In the case of ingested fats the deposited fat is of like composition, and may, therefore, be widely different in its composition from the fat peculiar to the species; in the case of fat made from sugar it is always specific for the species. Thus, a dog fed upon mutton fat deposits mutton fat in his tissues, while in making fat from sugar fat peculiar to his species and differing from mutton fat is deposited. The sugar from which fat is built up may be ingested as such or may be derived from the carbo- hydrates, fats, or proteins of the diet or tissues. Causes of Obesity.—Excessive ingestion of food by persons‘ having active digestion and leading sedentary lives may occasion unusual depo- sition of fat. It is difficult, however, to determine the limits between physiological and pathological fatness. In some cases patients assert that the amount of food has not been excessive, and this may be actually true. Obesity in such individuals is undoubtedly pathological and due to some inherent abnormality of metabolism. A further proof of the ex- istence of such a tendency is seen in certain families in which excessive fatness is common, even in childhood. The nature of this metabolic disorder is obscure. It has often been held that the power of oxi- dation is lacking, and, as a matter of course, the amount of oxygen consumed is deficient in comparison with the amount of food ingested. DISORDERS OF NUTRITION AND METABOLISM 41 This must be true or the fat could not accumulate; but it remains to be shown whether the diminished oxygen consumption is the primary cause or only an incident in the disease. Experimental investigations have shown that the basal heat production (that exhibited by the normal body when fasting and with the external temperature at 37° C.) is not exceeded in a downward direction in obesity, though the figure may be consistently low in this condition. The explanation of this circumstance may be found in the fact that in fat persons equivalent weights represent an undue amount of inactive (adipose) tissue, and that large deposits of subcutaneous fat afford an external protection against loss of heat; consistently low figures of heat requirement may, therefore, indicate, if not pathological, at least continuously low, oxida- tion; and it is possible that the methods of observation and the range of error of these methods may prevent the detection of slight deficiencies in oxidation that in the long run (over periods of weeks or longer) could explain fatty accumulations. Some experiments seem to indicate retardation of oxidation though no actual reduction. Pathological Anatomy.—The excessive adipose tissue in this condi- tion is found in the skin and subcutaneous tissues, in the omentum and peritoneum, around the kidneys, heart, and mediastinal tissues, in the liver, and less commonly elsewhere. The amount varies from slight excess to monstrous deposits. Secondary changes in the organs (not- ably the heart muscle) may be due to pressure or functional inactivity. Associated Conditions.—Fatness is more or less closely related to certain other diseases of metabolism, such as diabetes and gout. Anemia is frequently present and has sometimes been regarded as a cause, operating by reducing oxidation. The occurrence of fatness in certain types of nervous disease, such as hysteria and idiocy, suggests a nervous perversion of fat metabolism, though possibly other conditions, for example, disease of the glands of internal secretion, may be fundamentally involved. It is well known that castration and the menopause are frequently followed by in- crease of fat, and certain diseases of the hypophysis and thyroid are likewise attended by obesity. There may or may not be manifest nervous symptoms in these cases. Excessive Tissue Destruction.—This has been referred to in con- nection with inanition; but it may be independent of the amount of food ingested. Among the conditions in which this is observed may be mentioned fever, infectious or of other forms; chronic infectious diseases, with or without fever; tumors, especially carcinoma; intoxica- tions of various sorts; some cases of Graves’ disease, etc. In all of these conditions the fats of the body may waste as in simple inanition; but there is an early and marked tendency to consumption of the more important protein structures. The nature of the metabolic disturbances in these cases is obscure, though it is likely that toxic substances of various sorts are the direct causes. This is most probable in the case of direct intoxications (phos- 42 A TEXT-BOOK OF PATHOLOGY phorus), but is also likely in other cases. In Graves’ disease and car- cinoma, as well as in fevers, there are doubtless poisonous substances in the blood, but whether these are the cayses of the metabolic changes or not requires further study. The fact that thyroid extract is capable of causing excessive destruction of tissue in normal or obese persons is significant in this connection. ._ Acid Intoxication.—In the final metabolic transformation of pro- tein there are produced ammonium, urea, kreatinin, and other nitrog- enous substances. The formation of urea is still obscure in some par- ticulars. It is certain that a large part is produced in the liver and some is formed in the glandular organs. The intermediate steps in the manufacture of urea have not been definitely determined, but it is known that the liver is capable of converting ammonium salts directly into urea, and it is probable that ammonium is an important inter- mediate product of protein transformation. An excess of acids in the body (either from introduction from without or production in the body) is in part neutralized by alkaline bases in the blood and tissue juices and in part by ammonium. In consequence of this consump- tion of ammonium the urea of the urine decreases and the ammonium salts are increased. The quantity of such salts is, therefore, in a measure an indication of the condition which has been termed “acid intoxica- tion.” When the fixed alkalies (sodium and potassium) are more or less exhausted in the neutralization of acids, symptoms of acid intoxication result. Fortunately, this is usually prevented by the abundance of ammonium, but in extreme cases of acid intoxication the ammonium does not suffice. Experimental acid intoxication is easily produced in animals by feeding them with foods deprived of alkaline bases or by direct ad- ministration of acids. In the former case the acids (sulphuric from the sulphur of albuminous food, and phosphoric from the phosphorus) resulting from transformation of food and tissues must be neutralized by the alkalies of the body and the ammonium incidental to the process of urea formation in the liver; in the latter case there is direct excess of acid. Such acid intoxication is readily produced in herbivorous animals, as the amount of protein food is small, and in consequence but little ammonium is produced. Various nervous symptoms are observed. The animal breathes quickly, the pulse grows rapid, muscular weakness, ataxia, and tremor develop, and finally coma or collapse terminates the disease. The administration of alkalies may completely arrest the progress of the condition and full restoration may occur. Acid Intoxication in Man.—Somewhat similar symptoms are seen in man in certain diseases in which increased elimination of ammonium, with decrease of urea and the excretion in the urine of certain organic acids, have been discovered. The assumption is warranted that these are cases of acid intoxication. _ Etiology.—Among the conditions in which this occurs are fever, diabetes, carcinoma, acute yellow atrophy of the liver, narcosis, severe anemia, phkosphorus-poisoning, advanced gastro-intestinal disease, DISORDERS OF NUTRITION AND METABOLISM 43 and inanition. Sometimes no discoverable cause can be detected (cryptogenic acid intoxication). Gastro-intestinal disorders are very possibly the occasion of this form of obscure acidosis. Poisons pro- duced in the intestines may, perhaps, set in play the metabolic dis- turbances which terminate in overproduction of acids. Among the acids concerned are lactic, sarcolactic, sulphuric, phos- phoric, diacetic, and beta-oxybutyric. These in part combine with the fixed alkalies and with ammonium, and in part are excreted as such. Some, as sarcolactic acid, usually suffer decomposition in the body, and are, therefore, rarely met with in the urine. The important acids are oxybutyric and diacetic, and with these is frequently combined acetone. The ketonic acids, beta-oxybutyric and aceto-acetic, are now known to be due to the combustion of fat. In normal catabolism of fat there is first a cleavage into glycerol and fatty acids. The for- mer is converted into sugar; the latter oxidized in successive stages until the higher acids are converted into butyric acid. At this stage the process of oxidation becomes somewhat changed, and beta-oxy- butyric acid, aceto-acetic acid, and, finally, through acetic and formic acid, the end-products (carbon dioxid and water) are produced. At the stage of aceto-acetic (diacetic) acid a side reaction occurs whereby acetone is formed. Normally this occurs to the extent of traces only, but when fat is burned in large quantities the acetone formation in- creases considerably beyond the proportionate increase of the fat con- sumption. In diabetes and sometimes in other conditions in which considerable fat consumption takes place, either as a result of the ex- cess of fat catabolism or from failure of certain fermentations con- cerned, the conversion of beta-oxybutyric acid and aceto-acetic acid into acetone is halted or diminished and the blood is flooded with the ketone acids, which then act injuriously by abstracting bases from the tissues or as direct poisons. There is always reduction of oxidation in cases of acid intoxication, but it is not known whether this is the primary disturbance or whether it is but an accompaniment. Experimentally it has been shown by several observers that diminution in the supply of oxygen will lead to increase of these acids. They owe their presence to excessive production and to the failure of the normal oxidation. Other substances may result from protein destruction with insufficient oxidation. Among these are the amino-acids, leucin and tyrosin, as well as lactic acid, found in the urine in phosphorus-poisoning and acute yellow atrophy of the liver as well as in other conditions. The symptoms of acid intoxication in man may be quite similar to those seen in experiments upon animals. Marked dyspnea (air hunger), rapidity of the pulse, depression, stupor, and deep coma (coma carcinomatosum; diabeticum) are some of the more pronounced mani- festations. The explanation of the symptoms occurring in acid in- toxication is not entirely clear. The extreme dyspnea, which is one of the most characteristic symptoms, was first naturally referred to as- 44 A TEXT-BOOK OF PATHOLOGY phyxia; but as it has been found that the blood contains an adequate amount of oxygen and a greatly diminished quantity of COs, this ex- planation cannot hold. It is probable, however, that the dyspnea is due to the inability of the blood to carry off carbon dioxid from the cells, in consequence of the reduction of available alkali owing to its fixation by the acids. There is thus a decrease of oxidation from the accumulation of carbon dioxid in the cells, but not asphyxia in the ordinary sense of the word. Some have believed that the symptoms of acid intoxication are due to certain as yet unknown toxins which are produced at the same time as the acids. There is no direct proof of this, and the evidence at hand would indicate that the acids in them- selves, by reducing the available alkaline bases of the blood and by dis- turbing the metabolic processes in the cells, are sufficient to cause the symptoms. , Disorders of Protein Metabolism.—Proteins are complex bodies made up of combinations of various amino-acids in proportions differ- ing widely in the proteins of the various tissues of the body and in those of different species. Within the gastro-intestinal tract the digestive ferments convert proteins into proteoses and peptone, and finally into the constituent amino-acids. There are thus set free the elements from which reconstruction of proteins of composition characteristic of the species in question can be effected. Some of the amino-acids from the foreign protein of the food may be unsuitable for the recon- struction of these new proteins, while some may be present in super- fluous amount. These fractions are catabolized and excreted in the form of end-products. The major part is used for the resynthesis of protein. This was until recently thought to occur exclusively in the wall of the intestine, so that there should be delivered into the blood re-formed proteins similar to those of the blood. More recently it has been learned that the amino-acids are absorbed, in part at least, into the blood and utilized for rebuilding of new protein in the liver or other tissues. During youth and the growth period and after exhaustive wasting of the tissues considerable portions of the food proteins may be utilized directly for the upbuilding of the tissues. At other times only a small portion is thus utilized to repair the waste of cells and to replace dead cells. The greater part of protein food is quickly catab- olized and excreted. The level of protein content of the blood is maintained very tenaciously, and in case of starvation the blood ab- stracts proteins from the cells to maintain the level, while as a result of overfeeding some of the protein is deposited as a storage within cells, while the larger part is quickly catabolized. There is no capacity for storage of protein comparable to the storage of carbohydrates, as glyco- gen in the liver and muscles, or of fat in the various areolar tissues. The catabolism of proteins is exactly comparable to their digestion in the intestinal tract, but takes place within the cells under the influence of endotrypsin. First proteoses and peptone are formed, then amino- acids, and, finally, end-products varying somewhat with the source of the protein involved. The exogenous proteins, those derived directly wen) Se Oe Oe, eS DISORDERS OF NUTRITION AND METABOLISM 45 from food, are mainly excreted as urea and ammonium; the endogenous, those of the tissues of the body, when catabolized vield only small portions of the urinary urea and ammonium, and those of the muscles in particular are excreted as creatinin. The latter substance is derived from the creatin of muscles, which in turn is probably an anabolic product of amino-acids made by a special muscle metabolism. In the normal man excess of protein feeding is speedily followed by marked increase of elimination of the end-products, urea and ammo- nium. Only a fractional retention occurs. In certain pathological con- ditions, such as nephritis and gout, considerable nitrogen retention may occur, especially in the form of non-protein nitrogenous bodies. In fasting and starvation the nitrogenous elimination falls to very low levels, in which the exogenous nitrogen end-products (urea and am- monium) are specially affected. The amount of creatinin is maintained at a quite fixed level, being reduced only to the extent of the subtrac- tion of the relatively small amount of creatinin derived from the meat and meat extracts of diet. Under conditions of rapid catabolism of protein, such as in leu- kemia, carcinoma, and internal suppurations, the proteoses and peptone may be liberated in such quantity as to be in part excreted in the urine (proteosuria, peptonuria, albumosuria). These proteoses and peptones, however, being derivatives of native protein, are non-toxic, contrasting with the toxic proteoses and peptone derived from foreign proteins in the digestive tract. Whether or not any of the latter are absorbed into the blood and excreted in the urine in pathological conditions is un- certain. In certain other conditions of rapid protein catabolism (as in autolytic destruction of liver substance—acute yellow atrophy, phos- phorus-poisoning, etc.) amino-acids may be excreted in the urine. In the catabolism of protein, under conditions in which the utiliza- tion of carbohydrates is greatly reduced, as in diabetes, considerable sugar may be an end-product. This is derived from the amino-acids, which lose their NHz by a process of deaminization and yield oxy- fatty acids, which are finally converted into dextrose. This process ac- counts for much of the persistent dextrosuria of severe cases of diabetes after the glycogen storage has been exhausted and the diet has been deprived of all carbohydrate matter. Creatinin elimination in the urine may be utilized as an indication of the state of muscle metabolism. In cases of rapid muscular waste from fever or other causes an excessive output of creatinin is met with; and in certain extreme cases creatin itselfi—the substance in muscle from which creatinin is derived—is thus excreted, probably as an ex- pression of failure of conversion into creatinin. In muscular dystro- phies the elimination of creatinin may be decreased. Disorders of Purin Metabolism.—By purin metabolism is meant the metabolism of cellular nuclei. The nuclei contain nucleoproteins which are combinations of globulin and nucleic acid, the latter being com- posed of phosphoric acid, pentose-sugar, and a base, either purin or pyrim- idin. The important purin bases are the aminopurins, adenin and guanin, 46 A TEXT-BOOK OF PATHOLOGY and the oxypurins, hypoxanthin and xanthin. In the normal purin ca- tabolism there is first a separation of the globulin and nucleic acid, and then, under the influence of special enzymes, the latter is broken up into its components and the purin bases deaminized and oxidized to uric acid. In the final urinary excretion both purin bases and uric acid are present, so that the catabolism does not wholly proceed to the end- product. Under ordinary conditions of diet the urine contains more purin of exogenous than of endogenous origin. The foods that yield this are such cellular gland foods as thymus, pancreas, liver and kidney, and, to a less extent, muscle (meat); leguminous vegetables; and coffee, tea, and cocoa. On a purin-free diet the excretion falls to a low level of fair constancy. Apparently the exogenous purins are excreted in toto, no part being utilized in the anabolism of nucleic acid. To a certain extent uric acid is oxidized in the body to form urea and is excreted as such. Under normal conditions the blood contains from 0.5 to 1.0 mg. of uric acid in 100 c.cm. Under certain circumstances this quantity may rise to 8 or 10 mg. either temporarily or for longer periods. Among these conditions are chronic nephritis, gout, lead-poisoning, after heavy feeding on purin foods, during resolution of pneumonia, in sepsis, etc. In the last three of the conditions named there is excessive cellular metabolism and consequently temporary overproduction of purin bodies. In the first three the higher level of uric acid is probably due to some alteration of the renal permeability which maintains a higher threshold for the elimination (see below), rather than to any increased production of uric acid. Gout.—In its typical form gout is a paroxysmal disease marked by deposits of urates in the joints and other structures, and by coincident or consequent inflammatory disturbances. There are many varieties, however, of irregular gout in which. the paroxysms may be partly or wholly wanting, and in which the disease takes the form of a general systemic disorder, or of organic maladies of various sorts. Etiology.—Gout is essentially a hereditary diathetic affection, the heredity not rarely being polymorphous. By this is meant that in certain families gout and other diseases, such as obesity, diabetes, and arterial sclerosis, may occur interchangeably. Gout usually develops in the later years of life, and among the contributing causes are the use of alcohol, overeating, sedentary life, and chronic lead-poisoning. Pathological Anatomy.—The conspicuous anatomical lesions are those of the joints, and consist of the deposit of urate of sodium in the cartilages and connective tissue, and secondary inflammatory changes. The latter may cause great distortion and fibrous overgrowth. Similar urate deposits may occur in the cartilages of the ear, eye and nose, and in the subcutaneous connective tssue or elsewhere. These deposits, called the gouty tophi, may subsequently disappear by absorption or by discharging through the skin. Cirrhosis in various organs and tissues of the body frequently occurs in the course of gout. Among these the cirrhotic or gouty kidney is most important. Atheroma, cirrhosis of DISORDERS OF NUTRITION AND METABOLISM 47 the liver, hypertrophy and fibroid change in the heart, and chronic val- vular disease are also frequent. Pathogenesis.—For a long time some disorder in the formation and excretion of uric acid has been held responsible for the manifestations of gout. Garrod first demonstrated an excess of uric acid in the blood, and recent exact chemical studies have confirmed this observation. There are, however, as has been shown, diseases, such as leukemia, nephritis, and pneumonia, in which excess of uric acid in the blood occurs without any of the results seen in gout. It is possible, of course, that the accu- mulation in the blood may be due to different causes in these conditions, but it is evident that other factors beside the mere presence of excessive uric acid are operative in gout. The excretion of uric acid in the urine is found reduced just before an acute paroxysm of gout, increases above the normal during the attack, and then falls to about the normal. In chronic cases without attacks the excretion is about normal. The increased quantity in the blood might then be due to increased production or to a reduced transforma- tion to simpler metabolic products. Neither of these explanations seems justified. At present the more probable reason seems to be a change in renal permeability (without any special renal lesion), as a result of which the threshold of excretion is raised. The reduction of uric acid before attacks has been attributed to the deposition of acid urate of soda in the joints and elsewhere, though the amount of uric acid in all the deposits falls far short of that which could explain this. Possibly changes in diet or intestinal absorption may play a part in this reduction. The pathogenesis of the urate deposits remains obscure. Ebstein first insisted that local necrosis, itself perhaps the result of excess of uric acid in the blood, is the direct occasion for the deposits, and some recent authorities believe that a primary and essentially gouty local inflam- mation invites urate deposits, the uric acid itself having no importance in the first condition. Experiments have, however, shown that uric acid is capable of causing local inflammatory lesions. Traumatism and circulatory conditions may play a part in localizing gouty precipita- tions. Possibly the conditions in which uric acid is held in solution in the blood may differ in gout from those in health and other diseases. Studies of the general metabolism in gout show a uniform tendency to nitrogen retention, apart from any possible reduction in uric acid ex- cretion. There is also a reduction of intestinal absorption, with in- creased excretion of indican. Diseases of Carbohydrate Metabolism.—The carbohydrates of the diet are converted into dextrose or glucose before absorption, this conversion being accomplished by salivary and gastro-intestinal en- zymes. After absorption into the blood the dextrose is converted into glycogen and stored in the liver cells, or, in cases of excess above the hepatic capacity of storage, in the muscles. Normally, there is a storage 48 A TEXT-BOOK OF PATHOLOGY of glycogen sufficient to supply the nutritional needs for as much as five days; in fasting experiments it has been clear that the nutritional needs have been supplied by glycogen during the first few days. It has been a subject of much investigation and discussion whether or not other sources of sugar exist besides the ingested carbohydrates. Recent studies have shown beyond doubt that the amino-acids of protein catabolism may furnish considerable quantities of sugar by deaminization and sub- sequent conversion of the oxyfatty acids into glucose. In severe diabetes this may be a noteworthy source of sugar. It is conceivable that the glycerole derived from the splitting of fat may also furnish sugar, and this derivation seems probable, though it has not been definitely proved. The blood maintains a fairly constant sugar content under normal conditions—the amount being about 0.080 gm. per 100 c.em. With normal quantities of sugar in the blood, glucose ordinarily fails to appear in the urine because a certain threshold of retention prevents its excretion through the kidneys. When the blood sugar is reduced the glycogen stores of the liver will replace the loss. There is thus main- tained a fairly constant level of sugar concentration. When the sugar reaches a high level—beyond the storage capacities for glycogen in the liver and muscles—the excess is deposited as fat in the areolar tissues. Still higher levels of sugar concentration may exceed the. capacity for storage as glycogen or fat and the threshold of renal permeability. Glu- cosuria then results. Ultimately, sugar is oxidized in the muscles and converted into CO, and H,O. The glycogen stores in the liver are in cases of need con- verted into dextrose, delivered to the blood, and finally burned in the muscles. The glycogen stores of the muscles are not available for maintaining the sugar content of the blood, but are utilized only by oxidation in the muscles themselves. Hyperglucemia.—Excess of blood sugar—a condition termed “hy- perglucemia”—may be a temporary result of ingestion of starches or sugar, or a more lasting condition in certain diseases (diabetes, thyroid diseases, hypophysis diseases, cancer). Under normal circumstances the liver is capable of storing as glycogen any amount of sugar derived from mixed or starchy diet. The processes of digestion and absorption do not furnish to the-blood amounts of sugar sufficient to overbalance the storage capacity of the liver. Pathologically, the livers may fail to store the sugar and the excess in the blood may occasion excretion in the urine (hyperglucemia-glucosuria). In normal cases the blood sugar after a meal may increase in one or one and one-half hours to 100 or 125 mg. per cubic centimeter, but the amount quickly falls to its former level. Alimentary Glucosuria.—When large quantities of sugar (dextrose, fructose, or other forms) are ingested the capacity for storage may be exceeded and glucose may appear in the urine. Under certain patho- logical circumstances (diseases of the liver, alcoholism, thyroid disease) the ingestion of relatively small amounts of sugars may be followed by glucosuria (glucosuria e saccharo), and even starch ingestion may occasion DISORDERS OF NUTRITION AND METABOLISM 49 a like result (glucosuria ex amylo). Sometimes the glucosuria in such cases may perhaps be due to the fact that the liver is already stored to its capacity and cannot accommodate additional deposits of glycogen. Glucosuria Due to Excessive Hepatic Glycolysis——Under certain circumstances the liver converts its stored glycogen into glucose so rapidly that hyperglucemia and glucosuria result. This seems to be the explanation of the glucosuria occasioned by Claude Bernard’s classical experiment of puncture of the medulla and by certain poisons such as chloral, morphin, antipyrin, etc. General Scheme of Possible Causes of Glucosuria 1. Alimentary—excessive ingestion of starches and sugars beyond the storage capacity of liver and muscles. 2. Defective hepatic glycogenesis—incapacity of the liver to trans- form and store as glycogen. 3. Excessive hepatic glycolysis—too rapid conversion of glycogen into glucose. 4, Defective muscular glycogenesis—incapacity of the muscles to transform sugar and store as glycogen. 5. Excessive muscular glycolysis—conversion of muscle glycogen into sugar and excretion as such. 6. Inability of the muscles to oxidize sugar. (See Diabetes.) 7. Increased renal permeability for sugar. (See Diabetes.) Clinical Causes of Glucosuria.—Glucose appears in the urine under a variety of conditions, including dietary excesses; various infectious diseases; intoxications (morphin, strychnin, chloral, acetanilid, etc.); concussion, injury and diseases of the central nervous system; after convulsions; in thyroid and hypophysis diseases, and in diabetes melli- tus. Diabetes mellitus is a disease in which polyuria and glucosuria are marked symptoms. It is not improbable that the term includes disorders of quite different sorts, but no certain differentiation of such is possible at the present time. A mld and a severe form are distin- guished, and these present some striking differences, to which reference will be made below. Etiology.—Diabetes is frequently a hereditary disease, occurring in families in which the same disease or obesity and gout have occurred. The Jews seem particularly liable to it. Overeating, sedentary life, and gout are causes of some importance, especially of the milder form. Sometimes abnormal conditions of the nervous system may be the underlying cause. Among these are functional depressions, as in cases of excessive grief; traumatic injuries with concussion of the brain; and local diseases at the base of the brain in the vicinity of the medulla. Disease of the pancreas is the probable cause in many cases, and may possibly play a part in all cases, though demonstrable lesions of the pancreas are not present in all. Diabetes may occur in the young or after middle life, the milder cases more frequently occurring at the latter period. 4 50 A TEXT-BOOK OF PATHOLOGY Pathogenesis.—In the milder cases of diabetes the same explana- tion may be applicable as that given for glucosuria, viz., the liver and muscles do not store up the carbohydrates carried to them, and the excess of sugar is not burned up in the tissues. Hyperglucemia with consequent glucosuria results. In these cases the withdrawal of car- bohydrate food or temporary abstinence from all food causes disap- pearance of the glucosuria. There is, however, the fundamental differ- ence between mere glucosuria and true diabetes that in the former the capacity to burn sugar is unimpaired, while in the latter even in mild cases this function is more or less disturbed. In severe diabetes sugar continues to appear in the urine in spite of complete abstinence from starches or sugars. This is explained by the conversion of glycogen into sugar and when this supply is exhausted by the formation of sugar from the amino-acids of protein catabolism, and possibly also by conversion of the glycerol of fat catabolism into sugar. In normal individuals, and even in those suffering with mild diabetes, any sugar thus liberated is burned in the tissues. Glucosuria does not, therefore, occur. Severe and mild diabetes differ only in degree: in one case the power to consume sugars is greatly deficient, in the other only moderately so. The nature of the metabolic disturbances that lead to this inability to dispose of carbohydrates is still very obscure. The influence of the nervous system is undoubted. Reference may here be made to the occur- rence of diabetes after puncture of certain parts of the brain (medulla). Very possibly this experiment as well as certain clinical causes of dia- betes act by increasing hepatic glycolysis, and in consequence by flooding the blood with sugar. Older pathological studies showed that diseases of the pancreas are frequently associated with diabetes, and recent experimental investiga- tions emphasize this relationship. Total extirpation of the pancreas in the lower animals causes diabetes. The relationship between the pancreas and diabetes has not been certainly established. Formerly Lepine and others believed that the pancreas elaborates a “glycolytic ferment,” absence of which in cases of disease of the pancreas would oc- casion accumulation of sugar in the blood and consequent glucosuria. More recently it has been found that a codperation of muscle extracts with pancreatic extracts is necessary to the destruction of sugar, from which it would appear that normally pancreatic secretions are carried to the muscles and activate the process of oxidation of sugar. It seems to have been established that the final oxidation of sugar occurs in the muscles and not in the liver. The secretion of the pancreas involved in this function is doubtless a product of the islands of Langer- hans. (See Pancreas.) Other glands of internal secretion seem to have some relation to the pancreas and perhaps to the muscles in the development of diabetes. It is known that epinephrin when injected into the body may occasion glucosuria, and diseases of the hypophysis cerebri also occasion glucosuria. The adrenals and the hypophysis may act by restraining normal pancreatic function. DISORDERS OF NUTRITION AND METABOLISM 51 Renal Glucosuria—Experimentally, glucosuria may be produced by injections of phloridzin, a glucoside which is composed of phloretin and glucose. Formerly the explanation of the glucosuria resulting from injections of phloridzin was as follows: Splitting of the glucoside into glucose and phloretin was supposed to occur in the kidneys, the glucose being excreted as such, and the phloretin returning to the circulation and reuniting with glucose in the liver or elsewhere to form new phloridzin, which underwent the same process as that first administered. Careful investigations, however, have shown that phloretin itself does not act in this manner, and that the cleavage of phloridzin in the kidney, as assumed, is improbable. At the present time the more trustworthy explanation of phloridzin glucosuria is that it causes some change in renal permeability which occasions active excretion of sugar when the sugar concentration of the blood is at or even below the normal level. It was early recognized that in cases of phloridzin glucosuria the amount of sugar in the blood is not above normal, and this fact was one of the confusing conditions that required explanation. In the light of present knowledge it would seem that the blood tends to maintain its normal sugar content by obtaining glucose from the liver and the diet, while the lowered renal threshold allows sugar to escape in the urine. The process of excretion of the sugar is probably not an entirely passive one, to be regarded as a mere overflow when the concentration of the sugar in the blood is above the limits of renal retention; more likely there is an active eliminative process in the kidneys that becomes effective when the sugar reaches a certain concentration. It is believed by many that certain cases of glucosuria in man are due to a similar disorder of renal permeability, and in particular the glucosuria associated with gout, arteriosclerosis, and chronic nephritis may be explainable on this basis. It is impossible at present to make more positive statements. The view that diabetes is due to increased formation of sugar has been definitely disproved. Metabolism in Diabetes.—The essential metabolic disturbance in diabetes is the inability of the body to consume and utilize sugar. In mild cases this is a moderately developed’defect; in severe diabetes it is more and more pronounced, though probably never absolute. As a result the sugar concentration of the blood is increased and amounts to from 0.120 to 0.180 gm. per 100 cubic centimeters, with even higher figures soon after ingestion of carbohydrates or sugar. The inability to utilize sugar causes increased consumption of fat and proteins and leads to emaciation. In mild cases and for a time in severe diabetes overfeeding with fats and proteins may prevent loss of weight from destruction of the fats and proteins of the body, but eventually this protection of the tissues fails to be effective. There is always a tendency to excessive destruction of proteins and nitrogenous loss, as the diabetic is unable to utilize carbohydrates to protect the proteins. The fats also are con- sumed to an excessive degree and their oxidation tends to be abnormal, as a result of which the ketone acids and acetone are formed in exces- sive amounts. (See Acid Intoxication.) Increased elimination of 52 A TEXT-BOOK OF PATHOLOGY ammonium and other bases (alkalies, calcium, magnesium) are expres- sive of the overproduction of acids and their neutralization by the bases in question. . Pathological Anatomy.—Aside from the lesions already referred to as in some way related to the causation of the disease, there are found pathological changes of various kinds that result from it. The lesions of gout (arteriosclerosis and cirrhotic kidneys) may be of the nature of mere concomitants, but similar lesions may be direct results of diabetes. Renal diseases are of peculiar interest. Late in diabetes albuminuria frequently develops and interstitial nephritis may follow. When this occurs the glucosuria and other symptoms of diabetes sometimes sub- side. Changes in the liver (cirrhosis) have often been found, and have been regarded as causative in some cases. A peculiar form of diabetes with hepatic disease and general staining (hemochromatosis) of the skin and other tissues has been described under the title diabéte bronzé. Skin eruptions (eczema, furuncles, carbuncles) are frequent in certain forms of diabetes, and gangrene of the extremities is common. Pneumonia and pulmonary tuberculosis are among the frequent developments of late stages of the disease. Chronic endocarditis, neuritis, and cataract are not uncommon lesions. Pentosuria.—Pentose (a sugar containing five carbon atoms) is found normally in the nuclei of cells, the total amount in the whole body being estimated as approxi- mately 20 gm. Occasionally pentosuria is met with either in combination with glucose in diabetes or as an independent condition unattended by symptoms and tending to occur in several members of a family. It is certainly not due to the inges- tion of pentoses in the diet, and is probably an independent metabolic disorder sometimes associated with diabetes, but at other times wholly independent. Oxaluria—This term is, strictly speaking, applicable only to increase of oxalic acid in the urine, but is usually employed for cases in which crystals of oxalate of lime are found abundant in the urine. The normal maximum of oxalic acid is 20 mgr. for twenty-four hours. True oxaluria determined by chemical estimation of the total excretion of oxalic acid has been found in jaundice and in some cases of diabetes. The source of oxalic acid in the urine is still somewhat in doubt. Several investigators claim to have found that the older view regarding its presence in excess in the urine following certain kinds of vegetable diet is erroneous, and that there is no such thing as “alimentary oxaluria.” The weight of opinion, however, still favors the older view. There is some experimental evidence for the belief that intestinal fermentation is an important factor in the formation of oxalic acid. While this may be true, there seems little doubt but that the oxidation of uric acid accounts for the presence of much of the oxalic acid in the urine, and that nucleins and nucleo-albumin are, therefore, important sources of derivation. The authors who have argued in favor of a specific disease marked by nervous symptoms and oxaluria based their observations on the presence of an excess of oxalate sediment, rather than on chemical examinations. Increased sediment occurs in certain in- stances of gout in which the oxalates alternate with uric acid or coexist with this. In these cases, as in cases of oxalate calculus in the kidney or bladder, the impor- tant causative factor is most probably some alteration in the constitution of the urine, such as conversion of monosodic phosphate into the disodic phosphate, that reduces the solvent power of the urine for oxalate of lime. Metabolism of Phosphorus.—Phosphorus exists in the body in the nuclei of cells in combination as nucleic acid, in the bones as phosphates, and in the lipoids of the nervous system. The phosphorus of food is absorbed as phosphoric acid, which combines with sodium, calcium, and magnesium, and from these combinations is DISORDERS OF NUTRITION AND METABOLISM 53 utilized in the anabolism of phosphatic compounds of the tissues. The excretion of phosphorus takes place through the kidneys and intestinal tract. Phosphorus of the diet may fail of normal absorption in the presence of excess of calcium, which, combining with phosphoric acid, is discharged in the feces. Under ordinary condi- tions the phosphorus of the urine, like purin output, is a measure of nucleic metab- ae Excess of phosphorus elimination may be encountered in cases of destruction of bone. Phosphaturia—This term should be restricted to increased excretion of phos- phoric acid rather than to the presence of increased phosphate sediment in the urine. The latter may be due simply to want of acidity of the urine. The daily maximum of phosphoric acid with ordinary diet is from 3.5 to 4gm. The term “‘phos- phaturia” might also be applied to cases in which no absolute excess of phosphoric acid is found, but in which this substance is relatively in excess when compared with the excretion of nitrogen. The normal proportions are from 17 to 20 parts of phsophoric acid for 100 parts of nitrogen. Phosphaturia in the sense just described has been found in some cases of inanition. Decided increase in the phosphatic excretion, absolute as well as relative, occurs in some cases of diabetes; also in cases of tuberculosis and disease of the bones, such as ostitis and osteomyelitis. In considering the question of phosphatic excretion in the urine it is important to remem- ber that the greatest portion of phosphoric acid is derived from the food, only minor quantities coming from the metabolic consumption of tissues. Further, it must be remembered that much of the phosphoric acid of metabolism is excreted through the bowel. Recent observations show that when there is some intestinal disorder preventing excretion of calcium from the intestines there may be excess of phos- phoric excretion in the urine in combination with calcium. The term diabetes phos- phaticus has been used by Teissier for phosphaturia in the sense of increased total excretion, and four varieties have been described: (a) cases with polyuria and marked nervous symptoms; (b) cases preceding or accompanying pulmonary diseases, espe- cially tuberculosis; (c) cases in which phosphaturia alternates with or coexists with glycosuria; and (d) cases in which oxaluria, polyuria, and slight albuminuria are present and in which there is some relationship with gout. The nature of the metabolic disturbances in phosphaturia are obscure. Some- times the disorder of metabolism seems to be merely quantitative; in other cases, doubtless qualitative. FEVER Definition.—It is not easy to define this term accurately, though we may regard as fever a condition in which the temperature of the body is elevated above the normal (98.4° F.; 37° C.) and in which the tissue-metabolism is altered in the direction of increased consumption. There are cases in which the latter is insignificant or wanting, and there are other instances in which the temperature remains normal or sub- normal under influences that ordinarily provoke fever. It is doubtful whether mere elevation of temperature, such as occurs in experimental injury of certain parts of the brain, constitutes fever; but unquestionably it would be improper to apply this term to conditions of excessive tissue destruction without elevation of temperature. Nature.—It is important, first, to consider the regulation of the temperature in health. In the normal individual heat is produced in the body by constant oxidation and other metabolic activities, and the excess is dissipated by radiation from the surface and the heating or evaporation of excreta. These processes of heat production and heat dissipation are regulated in an orderly manner under the influence of the nervous system. Special centers for the production, dissipation, and 54 A TEXT-BOOK OF PATHOLOGY regulation of heat have been described by the physiologists, though their location and method of operation still remain in doubt. , What- ever the exact mechanism may be, it is quite certain that in some way the nervous system exercises a control over production and discharge of heat. 7 The excessive heat of fever may conceivably be due to excess of heat production, to diminution of the dissipation, to both of these con- ditions, or to increase of both with greater excess of production. In most instances of fever in man it appears that production and dissipa- tion are both increased, though the latter is insufficient. At the onset heat dissipation may for a time be diminished. The increased produc- tion results from increased oxidation and other metabolic processes. A study of the respiratory exchange of gases shows that oxygen is con- sumed in greater quantity than normally, and the quantity of CO; is correspondingly increased. The excess may amount to as much as 20 per cent., but in part this increased oxidation is due to the stimulation of muscular contractions in rigor, etc. Investigation of the excreta shows at the same time evidences of more or less rapid and extensive’ tissue waste. The quantity of nitrogen eliminated is in excess of that consumed in the food, and wasting of the tissues results. The albu- minous elements suffer particularly in the metabolic wasting, the de- crease of fat being more especially dependent on insufficiency of food. Etiology.—The causes of fever doubtless vary greatly. Direct exposure to heat does not affect the temperature more than a fraction of a degree in healthy persons, unless the surrounding temperature is very great. Ordinarily the heat-regulating mechanism maintains a proper adjustment. Excessive heat may, however, bring on fever, as in the case of sunstroke. Here, it has been held that the heat leads to direct disturbances of the regulating apparatus in the central nervous system; but recent investigations seem to show that there are first produced toxic substances which secondarily influence the heat-centers of the brain. In another class of cases still more direct disturbance of heat regulation seems to occasion fever. Among these cases are the in- stances of fever in hysteria and other nervous diseases. In the great majority of cases of fever it is quite certain that toxic substances are the cause of the febrile disturbances. These substances may be of quite different sorts. In the case of infections it is known that certain substances contained within the bacteria themselves may cause fever, and that products of the growth of the micro-organisms may have the same effect. These substances are probably of albuminous nature. Other albuminous bodies resulting from normal or disturbed metabo- lism, independent of the action of bacteria, such as albumoses, peptone, tissue-fibrinogen, etc., may be equally potent; and various ferments, such as pepsin, fibrin-ferment, diastase, etc., are known to have the same power. These facts explain the multiplicity of causes capable of produc- ing fever, as any chemical, mechanical, or bacterial injury of the tissues may liberate toxic substances, which in turn act upon the nervous sys- tem and occasion the phenomena of fever. DISORDERS OF NUTRITION AND METABOLISM «BS Pathological Physiology.—Fever is accompanied by or leads to a variety of disorders. The appetite is lost, there is excessive thirst, emaciation is habitual, and the functions of the various organs are more or less disturbed. To a large extent these results are doubtless due to the presence of toxic substances in the blood and to other changes in this fluid. There is always a tendency to inspissation of the blood, the number of corpuscles being augmented (relatively) and the specific gravity increasing. This is not, however, invariably the case, as de- struction of the solid matters of the blood may exceed the loss of liquid. The alkalinity of the blood is more or less reduced by the production of various acids in the increased tissue destruction. A common and possibly characteristic metabolic process is the hydration of the albuminous tissues with formation of albumoses. There is little accurate knowledge of the toxic substances in the blood. The original poisons that caused the fever may be toxic for the entire organism, and other poisons may . produced by the elevation of temperature and the disturbed metab- olism. Pathological Anatomy.—Definite morbid changes may occur in the various tissues of the body, notably the muscles, heart, liver, and kidneys. Among these changes are cloudy swelling, fatty degeneration, and coagulation necrosis. It is unlikely that these changes are the direct result of the increased temperature. More probably they result from the action of toxic substances generated in the course of the fever. Conservative Effects of Fever.—While fever occasions many dis- turbances and leads to various pathological consequences, it is not im- probable that there is a certain measure of usefulness in it. Some authors have called attention to the fact that rapid reduction of the temperature under the influence of antipyretics is often followed by harmful consequences. This does not necessarily prove the usefulness of the fever, as the antipyretics are all capable of harm in themselves. A more definite proof of the uses of fever is that obtained by subjecting infected animals to high temperatures or to febrile conditions, and then studying the progress of the infection. Under these circumstances it has been found that the course of various infections, such as with the Diplococcus pneumonia, the bacillus of typhoid fever, and other organ- isms, is much milder and the consequences less serious than in animals not placed under the same conditions. These results agree very well with experiments with bacteria outside the animal body. For example, it is known that many of the bacteria are influenced unfavorably in their growth and virulence by excessive temperatures (104° to 107.6° F.; 40° to 42° C.). Whether in the body the temperature affects the micro- organisms directly or indirectly through the production of antitoxic substances, or in other ways, remains unsettled. It is not unlikely that increased circulation and respiration favor the elimination of the toxins that cause the fever. Increased toxicity of the urine has been found, but the methods employed are open to criticism. CHAPTER III DISTURBANCES OF THE CIRCULATION OF THE BLOOD GENERAL DISTURBANCES TuE circulation of the blood is maintained by the rhythmic con- tractions of the auricles and ventricles of the heart, aided by the elas- ticity of the arteries; by the compression of the veins by the muscles; and by the suction of the inspiratory movements of the chest. General disturbances of the circulation result from lessened or excessive heart power, from arterial disturbances, or from changes in the quantity or character of the blood. Muscular and respiratory weakness may be contributing causes. Weak Heart.—There are various forms of heart disease that may lead to disordered circulation. The muscle itself may be weakened from overstrain, the fevers or other diseases, the action of poisons or insuf- ficient nourishment, as in the anemias or from narrowing of the coro- nary artery. The muscle may be soft and cloudy, fatty, or hardened by sclerotic changes. There may be no evident muscular disease, but merely functional weakness. The valves or orifices of the heart may be diseased, and regurgitation or obstruction of the blood-flow results. Sometimes blood-clots form within the heart and similarly cause ob- struction of the current. Finally, pericardial effusions or adhesions or tumors pressing upon the heart may seriously disturb its action. The result of the weakened state of the heart must be the accumula- tion of blood in the venous system. The place of engorgement depends upon the part of the heart specially weakened. If the left ventricle fails, the blood backs into the left auricle and the lungs. As long as the right heart maintains its power the venous congestion goes no further; but when this fails, repletion of the right auricle and of the systemic veins ensues. When the right heart is first at fault, general venous con- gestion is an earlier manifestation. In all cases the arterial pressure falls and the blood-current is slowed, whereas the venous pressure is increased. Sudden and complete failure of the heart causes anemia of the brain and syncope, which may prove fatal if not instantly relieved. Hypostatic Congestion.—In cases of serious weakness of the heart, in which it is quite unable to maintain an active circulation, the blood tends by the force of gravity to sink to dependent parts. This condi- tion is known as hypostatic congestion. It occurs very frequently in low fevers and quite commonly just before slow death resulting from any cause. Dilatation of the vessels from vasomotor paresis, general muscular weakness, and the failure of vigorous inspiratory efforts are secondary causes. 56 DISTURBANCES OF THE CIRCULATION OF THE BLOOD 57 The blood accumulates in the skin of the back, especially about the buttocks. The skin is of a livid color, but is bloodless over the bony points; the tissues tend to become sodden from transudation of liquid from the blood-vessels. Sloughing and gangrene (bed-sores) may result. Internally, hypostatic congestion affects the lungs par- ticularly, and a form of pneumonia may follow. Postmortem lividity is allied to hypostatic congestion. After death the blood gravitates to the dependent parts and accumulates in the veins, as the arteries contract when the heart-action ceases. Overaction of the heart is less frequent than weakness. Tem- porary overaction occasions increased activity of the circulation and elevation of blood-pressure, sometimes sufficient to cause hemorrhage. More prolonged overaction due to overwork, to excessive feeding, or to nervous stimulation, as in Graves’ disease, causes hypertrophy of the left ventricle, and later of the whole organ. In consequence the circu- lation may be more or less permanently overactive. Arterial Disorders.—Both organic and nervous disturbances are important. Of the organic disturbances the most frequent is sclerosis of the arteries, which offers a constant impediment to the arterial circula- tion. Hypertrophy of the heart overcomes the obstacle, but when the heart fails venous congestion and dropsy ensue. Sclerosis may also affect the veins, but much less commonly. Local diseases of the aorta, as congenital narrowing, compression by enlarged glands or tumors, aneurysms, and blood-clots may obstruct the flow of blood to the arteries, and thereby cause stagnation of the blood in the heart, lungs, and venous system. V'asomotor disturbances are dependent upon the nervous system. Under the influence of certain diseases of the nervous system or of poisons (as carbonic acid gas in asphyxia) acting locally on the vessels or upon the vasomotor center in the brain, contraction of the smaller arterioles occurs; and in consequence the blood-pressure is greatly elevated, the heart is impeded, and venous congestion results. On the other hand, the arterioles may distend from vasomotor paresis, the blood-pressure falls, and unless the heart is active there is a tendency to hypostatic congestion. Changes in the Blood.—Increase and decrease of the quantity of the blood are generally merely passing conditions to which the circulation readily adapts itself by dilatation or contraction of the vessels. Sudden losses of blood, if large, may be fatal by syncope. Smaller losses are soon repaired by absorption of water from the tissues and by regeneration of blood. Increase in the quantity of the blood by ingestion of liquids never disturbs the circulation greatly. Rapid excretion soon reduces the quantity to the normal. Changes in the character of the blood may affect its circulation. The accumulation of carbonic acid and probably other effete products of tissue change impede the flow by exciting vasomotor contraction. This is probably brought about by the action of the poisons on the terminal nerve-filaments in the blood-vessels or directly on the walls of 58. A TEXT-BOOK OF’ PATHOLOGY the vessels. This is the best explanation of the increase of pressure in cases of Bright’s disease without arteriosclerosis. The poisons in this case are quite possibly retained substances which the damaged kidney cannot excrete. The changes in pressure cited above may be largely due to changes in the viscosity of the blood. In general, anything which increases the . cellular content or molecular concentration increases pressure, while the reverse is naturally the case. The chromaffin system, particularly of the adrenals, seems to have a stimulating effect upon blood-pressure. It is believed by some observers that an overproduction of epinephrin is responsible for chronic arterial disease. LOCAL ANEMIA Local anemia or ischemia is the condition in which a tissue contains less than its proper quantity of blood. This may be direct when it results from causes obstructing the flow into the arteries, or collateral when it is due to withdrawal of blood into hyperemic areas in other parts of the body. Of the causes acting directly, pressure is the most frequent. There may be general pressure upon an organ or localized area of the body, as in the application of elastic band- ages; or pressure upon the vessels within the tissue itself, as in amyloid disease, the amyloid substance compressing the arteries and capil- laries, or there may be direct compression of an artery by tumors. The circulation in an artery may be impeded by sclerosis of the ves- sel walls and by emboli or thrombi within the vessel. Local anemia of moderate or even severe grade may be due to nervous influences acting through the vasomotor system, as in the earlier manifestations of Raynaud’s disease. Collateral anemia is well illustrated by the anemia of the brain occurring in animals in which the splanchnic nerves have been cut, a with the consequent production of abdominal Fig. 1.—Anastomoses hyperemia. When ischemia is due to obstruc- Tele tion of a single vessel the circulation is gener- dog (Porta). ally soon restored by collateral anastomosis; the collateral vessels sometimes reach consider- able dimensions (Fig. 1). When an artery which has few anastomoses and which soon splits up into capillaries is obstructed the phenomena of infarction (see page 66) ensue. An anemic area is pale, reduced in size and temperature, and func- tionally less active than normal. If the condition persists, fatty de- generation and necrosis results. When a severe local anemia is relieved it is apt to be followed by hyperemia of the same area, due to exhaustion or degenerative weakness of the vessel walls. DISTURBANCES OF THE CIRCULATION OF THE BLOOD 59 LOCAL HYPEREMIA Local hyperemia is increase in the quantity of blood in a part of the body. This may be due to increase of the flow to that part, or to ob- struction of the outflow. The former is called active or arterial hyperemia or congestion; the latter, passive or venous hyperemia. Active hyperemia occurs in organs during periods of functional activity, the increased blood-supply here being due to increased demand for nutrition. Pathologically, active hyperemia is due to causes which lead to dilatation of the arteries of a certain part. This dilatation may be due to influences acting through the vasomotor nervous system or to local affections of the vessel walls. The vasomotor nervous system may be affected at its center in the medulla or peripherally. The latter is seen when the sympathetic nerves, which contain vasoconstrictor fibers, are severed or compressed by tumors, the vessel walls thereby becoming paralyzed (neuroparalytic hyperemia). The superficial congestive hy- peremia in fevers is probably due to the central vasomotor action of the toxic causes of fever. On the other hand, the vasodilator fibers in the spinal nerves may be stimulated, as in certain cases of neuritis, with a similar result (neurotonic hyperemia). Direct injury to the vessel walls by heat, traumatism, inflammation, chemicals, or by the vascular fatigue following temporary stoppage of the circulation is a frequent cause. : Active hyperemia is spoken of as collateral when anemia in one part leads to overfilling of the vessels of an adjoining or even distant part. The hyperemic area is bright red in color, the temperature is ele- vated, and there is slight swelling, due to the increase of blood in the part and transudation of serum into the tissues. After death the dis- tended arteries and capillaries may contract and the part grows paler. Arterial hyperemia is one of the phenomena of beginning inflamma- tion, and in any case if prolonged may terminate in inflammation. Functional activity is increased by moderate congestions. Passive hyperemia is due to impediments to the outflow of the blood through the veins. This may be brought about by compression of veins by tumors, by thickening of their walls, or by thrombi within. Little disturbance results from obstruction of a small vein, because of the freedom of collateral circulation, provided the heart is active. In cases of weak heart-power, however, slight obstructions may de- termine local venous hyperemia, or by gravity alone the blood may accumulate in dependent parts. The latter constitutes hypostatice con- gestion. Areas the seat of passive hyperemia are dark red (cyanosis) and lowered in temperature. The veins are distended, and very soon the watery elements of the blood transude and the part becomes edematous and swollen. In severe cases red blood-corpuscles escape by diapedesis. This occurs in the small veins and capillaries, but not in the ar- teries. In consequence of the increased intravascular pressure the red corpuscles are pushed through the wall of the vessel at the angular 60, A TEXT-BOOK OF PATHOLOGY junction of adjacent endothelial cells. At these points the cement sub- stance is found in greater abundance than along the borders of the cells, and the escape of the corpuscle takes place through the semisolid cement substance. Os Later fatty degeneration results from the imperfect nutrition of the tissues; or even necrosis and gangrene may occur. In long-con- tinued moderate passive hyperemia over- growth of connective tissue, due either to direct irritation or a replacement process, or both, and pigmentation of the tissue by broken-down blood-corpuscles is ob- served (brown induration). Complete stoppage of the circulation in a localized area is called stasis (Fig. 2). This may be an extreme grade of passive hyperemia. The blood-corpuscles accu- mulate in the small vessels (arteries, capillaries, and veins), and the plasma is slowly pressed through the vessel wall or onward in the vessel. There results a fill- ing of the vessel with a homogeneous red material, which is composed of the red AS corpuscles so closely packed as to be in- = ee distinguishable. On relief of the stasis Fig. 2.—Stasis of blood in the the corpuscles become free again. Stasis superficial vessels in a case of val- : vular disease and heart failure May also be produced by chemical agents (modified from Ziegler). which rapidly withdraw the plasma from the vessels, leaving the corpuscles unable to circulate; or similarly by rapid evaporation of the liquor sanguinis from internal structures (as the peritoneum) exposed to the air. Passive congestion of any grade and stasis interfere with functional activity in two ways: by the reduction of nutrition of the cells and by the pressure exercised upon them by the accumulating blood and serum. These areas are at first protected against infection because of the excess of venous blood, which has a high restraining power upon germs. HEMORRHAGE By hemorrhage is meant the escape of the several constituents of the blood from the blood-vessels. It is said to be arterial, venous, or capil- lary, according to the vessel from which the flow of blood takes place, and parenchymatous when it comes from all of the vessels. Hemorrhage may occur either by diapedesis and extravasation through intact vessels (hemorrhage per diapedesin) or by actual rupture of a vessel (hemorrhage per rhexin). The former process is seen only in the capillaries and smaller veins; the latter occurs mainly in the arteries and veins. Emigration and Diapedesis.—Under normal conditions a certain number of white corpuscles, by virtue of their ameboid movements, DISTURBANCES OF THE CIRCULATION OF THE BLOOD 61 escape from the capillaries, and become wandering cells which move about in the tissues or are carried by the lymph-stream. This process is called emigration. There is at the same time some transudation of plasma, which, with the leukocytes, enters the lymphatic circulation. Under certain abnormal conditions the red corpuscles also pass through the vessel wall and collect in the tissues. This is known as diapedesis (Fig. 3). It may be studied very readily under the microscope in the mesentery of a living frog. It is noticed that the red corpuscles approach certain parts of the wall of the capillary or vein and become fixed; then a small projection appears outside the vessel, opposite the corpuscle, and as this increases the corpuscle within grows smaller, until the whole body has gradually passed through. Not rarely several corpuscles pass i mae oo an a Fig. 3.—Diapedesis of the red blood-corpuscles through a capillary of a frog’s tongue (after Thoma). through in one mass, as has been particularly noted by Thoma. Out- side the vessel the corpuscle at once assumes its ordinary shape. Diapedesis was first studied by Stricker and Cohnheim. Arnold, whose investi- gations are most important, first believed that the emergence of the red corpuscles takes place through orifices or stomata; but later recognized, as is now generally believed, that the supposed stomata are merely accumulations of intercellular sub- stance in certain places between adjoining endothelial cells or at the junction of several cells. The active cause of the extrusion of the red corpuscles is the pressure of the blood. It has been thought that chemical changes in the endothelial cells or the so-called stomata must precede the diapedesis. The leukocytes emigrate from the vessel in exactly the same way as the red corpuscles, but mainly by their own ameboid movements. At the same time there is a more or less copious overflow of plasma. Diapedesis is readily induced by mechanical compression of a vein, which elevates the blood-pressure; or it may follow elevation of blood-pressure from any other cause. On the other hand, with normal pressure increased permeability of the vessel walls may occasion diapedesis. Such degenerative conditions of the vessels may be due to the action of poisons, to various infectious diseases, to moderate trauma- 62 A TEXT-BOOK OF PATHOLOGY tism, or to temporary obstruction to the flow of blood into a certain area. Perhaps also altered states of the blood may play a part when both the vessels and pressure are normal. Hemorrhages by diapedesis are generally small and punctate (petechie), but may be quite large, as sometimes in the conjunctiva. The solution of the endothelia or the intercellular cement substance may be caused by many toxins, and seems not to be dependent on any one chemical substance. Multiple ecchymoses may result from obstruction of capillaries or small blood-vessels. Such obstructions occur in the form of hyaline thrombi in various infections, as a result of burns or freezing of the skin, as well as from exogenous and endogenous poisoning. Fat embolism and embolism of parenchymatous cells may bring about the same result. Causes of Hemorrhage.—The ordinary form of hemorrhage per rhexin may be due to traumatism, to diseases of the vessels, to increase of the blood-pressure, and to certain vague nervous influences. 1. Traumatic hemorrhage may be due to direct laceration of a vessel or to contusions which merely weaken the vessel wall and lead to sub- sequent rupture. : 2. Diseases of the blood-vessels causing hemorrhage generally originate from causes within the vessel, and are due to such conditions as poisoning, infections, cachexias, or the anemias. Among the diseases of the vessels are fatty degeneration of the intima or media, atheroma, and miliary aneurysm. On the other hand, the outer coat may be eroded by surrounding disease and hemorrhage ensues (hemorrhage per diabrosin). This is seen in phthisic cavities in the lungs. 3. Increase of blood-pressure may be absolute or relative. The former occurs from emotional excitement, from hypertrophy of the heart, during paroxysms of whooping-cough, croup, and various con- vulsive disorders. In asphyxia there is decided increase of blood- pressure both from vasomotor contraction and from the violent muscular efforts. Relative increase of pressure occurs when the pressure external to the vessel is reduced, as in balloon ascensions, or in the pleura in cases in which during violent inspiratory efforts the air cannot enter the lungs, as in the fetus attempting to breathe during labor. 4. Neuropathic Hemorrhage.—The nervous system exercises a peculiar influence upon the vessels. In cases of apoplexy, of epilepsy, and of section of the spinal cord and in other nervous conditions spon- taneous hemorrhages from the nose or stomach, or into the lungs, suprarenal bodies, and other organs, are not infrequent. In the same group also are to be reckoned the instances of vicarious hemorrhage due to suppression of the menses and the remarkable cases of stigmatiza- tion. The last named is a condition in which under nervous exaltation or hysteria spontaneous hemorrhages occur from various parts of the body, especially from the parts wounded in the Crucifixion. 5. The Hemorrhagic Diathesis.—Certain persons present an in- herited tendency to bleed spontaneously or after very trivial injuries. Such persons are known as “bleeders,” and the condition as hemophilia. DISTURBANCES OF THE CIRCULATION OF THE BLOOD 63 The exact pathological condition which occasions the hemorrhages is still uncertain. Hemophilia is a familial disease manifested by extraordinary tendency to bleed either spontaneously or upon trivial injury. The hem- orrhage may be external, submembranous, or interstitial. The diathesis is transmitted by the females and expressed by the males. The reverse has been known to occur. There is a lower coagulability of the blood, a prolongation of the clotting time, and probably a lowered tonicity of vessel walls. Rudolph and Cole cite two cases in which the clotting times were nine and one-half and nineteen minutes. A hemorrhagic diathesis may also-be developed as a result of various diseases, as typhus fever, anthrax, septicemia, or phosphorus- poisoning. The same is observed in the severe forms of anemia, like progressive pernicious anemia and leukemia. In these cases altered blood states and disease of the vessel walls are doubtless the causes at work. Classification of Hemorrhages.—Hemorrhage may occur on free surfaces or into the tissues. In the former case various names are ap- plied to designate the locality, such as epistaxis, nosebleed; hemoptysis, hemorrhage from the lungs; hematemesis, from the stomach; enteror- rhagia, from the bowel; metrorrhagia, uterine hemorrhage between, and menorrhagia, at the menses. Hemorrhages into the tissues take their names from the size and nature of the lesion. A hemorrhagic infiltration beneath a surface, as of the skin or mucous membrane, is called an ecchymosis, which if small and well defined is a petechia, but if large and diffuse, a suggillation or suffusion. A distinct accumulation of blood, constituting a veritable blood-tumor, is known as a hematoma. Infiltrations of a peculiar sort, involving localized portions of a tissue or organ, are known as hemor- rhagic infarcts (q. v.). Results of Hemorrhage.—A very large hemorrhage may cause sudden death by cerebral anemia. More frequently the patient remains collapsed for a time and then slowly recovers. The hemorrhage ceases spontaneously by the diminution in heart action, by clotting of the blood at the point of rupture, by retraction of the elastic vessels, and by pressure of the surrounding tissues. Blood extravasated in the tissues soon coagulates and subsequently undergoes disorganization, the red corpuscles breaking down into pigment matter, which may be carried away or deposited at the seat of hemorrhage. The fluid elements may be completely absorbed, or, stained with coloring-matter, may remain as a cyst in which cholesterol plates are usually found. The solution of a large blood collection is due to leukocytic enzymes and products of tissue cell destruction. A focus of hemorrhage may set up reactive in- flammation and lead to encapsulation by new connective tissue. Some- times hemorrhagic accumulations become inspissated and undergo calci- fication. Blood in the serous sacs does not readily coagulate, but mingles with the normal liquid secretion. It may be gradually absorbed or may undergo degenerative changes, especially when infected by micro-organ- isms. Large hemorrhages cause acute anemia; repeated small extrava- 64 A TEXT-BOOK OF PATHOLOGY sations may lead to profound secondary anemia. (These conditions will be more fully discussed under Diseases of the Blood.) EMBOLISM Embolism is the process in which foreign bodies of various kinds are carried in the blood and deposited in the smaller arteries or capil- laries through which their size does not permit them to pass. The bodies deposited are called emboli. Sources and Nature of Emboli.—The most common form of' em- bolism is that in which portions of thrombi situated in the heart, the large veins of the extremities or pelvis, or on atheromatous patches in the aorta, are swept into the circulation and lodge in the smaller vessels. Softening of the original thrombus is generally the immediate cause. More rarely portions of a diseased heart-valve or of the intima of the heart or arteries, liver or placental cells, or parts of tumors are carried in the circulation and deposited as emboli. Embolism of large giant cells of the bone-marrow is common. Disorganization of the blood may cause embolism of pigment particles, as in malaria, or of small hyaline masses, as in burns and certain forms of poisoning. In cases of fracture of bones particles of fat may be dislodged from the marrow and enter the circulation, while in wounds of the large veins of the neck or elsewhere air-embolism is observed. Finally, masses of bacte- ria, scolices of echinococcus,-and other parasites are serious forms of emboli. Dust-embolism.—Small particles of coal, iron, marble, or clay entering the lungs in respiration sometimes penetrate the tissues, are largely taken up by phagocytic cells, and for the most part are carried to the bronchial lymphatic glands. If the latter are surcharged and soften, the dust particles may gain access to the circulation through the efferent lymph-channels of the gland or by rupture of the gland into neighboring veins. More rarely dust particles may enter the blood-vessels in the lungs directly by penetration. After their entrance into the blood they are depos- ited in the capillaries and substance of the liver, spleen, and bone-marrow, where they may remain permanently, either free or enclosed in fixed cells, or whence they may be removed by wandering cells. The final discharge occurs especially from the lungs, the tonsils, the lymphatic structures of the intestines, and from the liver in the bile. Air-embolism.——Small quantities of air may occasion no serious disturbances; but when large quantities enter the veins the right heart is found full of frothy blood and the pulmonary arterioles are occluded by small bubbles. Sudden death in these cases is not unusual. Some"experiments in dogs seem to cast doubt on the serious- ness of air-embolism, but the matter is not yet settled. (See Caisson Disease.) Fat-embolism.—Sudden death may occur when a large number of the pulmon- ary vessels are obstructed by embolic oil-drops. When the process is less extensive, little disturbance arises, as the oil is soon broken up into droplets and passes through the pulmonary capillaries, or it may be absorbed in the lungs. Seats of Embolism.—The final place of lodgment of an embolus depends mainly on its source. Those derived from the general venous circulation are usually carried through the right heart to the lungs, where they occlude branches of the pulmonary artery. Emboli in the portal circulation may lodge in the liver, or pass through the liver to the heart and lungs. DISTURBANCES OF THE CIRCULATION OF THE BLOOD 65 Retrograde Embolism.—Sometimes portions of thrombi, tumor masses, other cellular emboli, or micro-organisms may be transported in the veins in a direction opposite to the normal blood-current. Thus emboli may be carried upward in the inferior vena cava and into the hepatic veins and so into the liver; or from any of the larger veins or even from the right heart backward toward the peripheral veins. This condition, known as retrograde embolism, is observed when some pulmonary disease, such as whooping-cough, emphysema, etc., causes increased intrathoracic pressure and consequently a positive instead of negative pressure in the large intrathoracic veins. There may be an actual retrograde current of blood, or the centrifugal transportation of the embolus may be more gradually accomplished by repeated im- pulses directed toward the periphery, each of which pushes it a little further. Emboli coming from the left heart or from the aorta are distributed in the general arterial circulation. They are most frequently found in the spleen, kidneys, and brain. Other organs or the peripheral vessels may likewise be affected, but the results of embolism are less marked in them and are frequently overlooked. Emboli from the veins may reach the general circulation in cases in which the foramen ovale or septum ventriculorum is perforated (paradoxical embolism), or by being - broken up into smaller emboli in the lungs and thus passing through the pulmonary capillaries. The latter is not infrequent in cases of fat- embolism of the lungs. Results of Embolism.—A large embolus may cause sudden death by occluding one of the main branches of the pulmonary artery, one of the coronary arteries, or a large cerebral vessel. If the vessel is not wholly occluded, secondary thrombosis may complete the obstruction and death may be slow. In the case of less important vessels merely local anemia results. This may be relieved by establishment of collateral circulation, or may cause more or less extensive necrosis if not relieved. The original embolus and the secondary thrombus may undergo soften- ing or organization in the same manner as ordinary thrombi (¢. 2.). The results of occlusion of smaller vessels by emboli depend on the nature of the embolus. They are either purely mechanical when the embolus is aseptic, or septic when the embolus contains micro-organisms. The important mechanical result of small emboli is the pathological con- dition called infarction. Metastasis.—The process of metastasis of tumors and of infectious diseases is closely allied to that of ordinary embolism, and should be considered as that form of embolism in which there arises at the point of settlement a condition similar to that at its origin. Small particles of tumors in the one case, or of infected thrombi or tissue in the other, enter the blood-vessels or the lymphatic channels and are carried to neighboring or distant parts of the body, where they lodge in capillary vessels. In the case of tumor-embolism the embolus may grow and occasion a metastatic nodule; in case of infectious processes secondary foci of the infectious disease result. 5 66 A TEXT-BOOK OF PATHOLOGY INFARCTION Infarcts occur in situations in which there are small arteries having only capillary or, at most, very slight arterial anastomosis with neigh- boring arteries. Such arteries were called end-arterves by. Cohnheim. They are found especially in the kidney, spleen, lungs, retina, base of the brain, and parts of the heart. When one of these is occluded by an embolus infarction may occur. Infarcts are situated in the peripheral part of the organ, and are harder than the surrounding tissue. They are wedge shaped, the base being outward toward the periphery of the organ. In- farcts may sometimes result from occlusion of a number of adjoin- ing arterioles or capillaries, and in this case are irregular in out- line. There are two forms of in- farction, the red or hemorrhagic, and the white or anemic. The former are dark red in color, and have the appearance of wedge- shaped areas of hemorrhage with coagulation. Anemic or white infarcts present the same general features, but are less elevated and are yellowish or grayish in color. They are frequently surrounded Fig. 4.—Old anemic infarct of spleen. by a zone of congestion or hemor- rhage (Fig. 4). Formation of Infarcts.—The first effect of occlusion of an end-artery by an embolus is stoppage of the circulation beyond the embolus. A wedge-shaped anemic area results. This may remain anemic and undergo coagulation necrosis, with the formation of an anemic or white infarct. In other cases, however, the vessels of the occluded area, after a temporary period of anemia, become overfilled with blood, ex- travasation occurs, and a hemorrhagic infarct results. Various theories are offered to explain the persistence of anemia in the first case and the overfilling with blood in the second. In anemic infarcts the persistent anemia in some cases is due to thrombosis in the venules which receive the blood from the occluded end-artery and in the anastomotic capil- laries. At times rapid swelling of the parenchymatous cells of the organ compresses the capillaries and maintains the anemia. Some con- tend that white infarcts are frequently formed by rapid absorption and removal of the coloring-matter of the blood from hemorrhagic infarcts. In the latter the overfilling of the vessels results either from a back DISTURBANCES OF THE CIRCULATION OF THE BLOOD 67 flow of blood from the veins (Cohnheim) or from free capillary anas- tomosis. The latter would be especially apt to occur when the general or local blood-pressure was previously elevated, or when the lodgment of the embolus caused reflex contraction of the surrounding vessels, and thus overflow of blood into the occluded area through the capillary anastomoses. The hyperemia thus produced soon leads to extravasation of blood, because the vessels of the occluded areas rapidly undergo degenerative changes. The continuance of the dark color in the hemor- rhagic infarct is due to deposition of iron-bearing pigment derived from hemolysis by autolytic or tissue enzymes. Infarcts in the lungs are nearly always hemorrhagic; those in the kidneys and especially the spleen are frequently anemic. In the brain irregularly shaped areas of anemic necrosis (softening) are the usual result. Subsequent Changes.—In anemic infarcts coagulation necrosis and caseation are the marked degenerative changes. The broken-down tissue is gradually absorbed and reactive inflammation and organization cause cicatrization. Not infrequently a small amount of calcareous matter is deposited, especially in infarcts of the lungs. In hemorrhagic infarcts the extravasated blood breaks up into pigment matter and the tissues suffer degenerations similar to those seen in anemic infarcts. The final result in either case is generally a scar, which is pigmented in cases of hemorrhagic infarcts. More rarely infarcts undergo liquefac- tion and cyst formation, especially in the brain. The infarct may become infected by micro-organisms after its formation and abscess may result, as in cases in which the embolus itself was an infectious one. Infectious embolism occurs in cases of purulent softening of thrombi, in cases of local suppuration or necrosis, in ulcerative endocarditis, and the like. The first effect may be the formation of a hemorrhagic or anemic infarct; but the micro-organisms soon multiply and invade the tissues, causing suppurative or gangrenous processes. Metastatic ab- scesses are produced in this manner. Similar results follow when an infarct is secondarily infected. This is not infrequent in the lungs, where the air-passages furnish a ready path for the entrance of micro-organisms. Pulmonary infarcts may be due to embolic occlusion of the blood-vessels, but also to obstruction of a bronchiole. Any kind of hemorrhagic extravasation in the lungs may assume a wedge shape, because the area infiltrated is the wedge-shaped area included in the divisions of a terminal bronchiole. (For details, see the chapter on the Lungs.) THROMBOSIS Thrombosis is the coagulation of blood within the blood-vessels or heart during life. At the very beginning of the process the formation is not a coagulum in the ordinary sense, but subsequently coagulation is the essential feature. After death clots form within the heart and vessels, as in blood removed from the body. Causes.—The conditions favorable to hnemnbosis are alterations in the blood-current, changes in the vessel walls, and alterations in the 68 A TEXT-BOOK OF PATHOLOGY blood itself. For the most part two or all of these conditions are present in cases of thrombosis. Alterations in the Blood-current——Anything which slows the current, such as narrowing of the blood-vessels, weakness of the heart, or pressure upon the vessels, favors thrombosis. Complete arrest of the current ina part may lead to ordinary clotting, such as occurs postmortem, but with careful precautions a vessel may be ligated at two points without the occurrence of clotting in the occluded portion—at least for a long time. Some change in the blood-vessel wall is generally necessary in addition. Some sudden change in blood-pressure or rate of flow, some back pres- sure or blood eddy may permit the settling upon the intima of sufficient blood-platelets to start a clot. Thrombi due to slowing of the current are frequently seen in the heart, the vessels of the lower extremities, and in the sinuses of the brain in the course of exhausting fevers or other asthenic conditions. They are called marantic thrombi. In many of the latter micro-organisms have important etiological relations. Changes in the vessel walls play an important part. Atheroma, inflammatory or degenerative changes in the vessels of areas of in- flammation or necrosis, ligation and other traumatic injuries, and dis- eases of the endocardium are all examples of conditions leading to thrombosis. In many cases of thrombosis apparently due to slowing of the current of blood micro-organisms have been the more important factors by causing primary infective lesions of the endothelium. Dila- tation of the arteries (aneurysm) or veins (phlebectasia) or of the cavi- ties of the heart acts largely by slowing the current of blood or by pro- ducing irregular currents. Alterations in the Blood.—It is believed by Aschoff that some altera- tion in the blood itself is necessary, and that without this, changes in the vessel wall are insufficient. These blood alterations may consist of clumping of platelets, collections of hemolyzed red blood-cells, and the like. Experimentally, thrombosis may be induced by injection into the circulation of extracts of the thymus gland, the suprarenal bodies, the testicles, and other organs. These extracts contain large quantities of the fibrin-ferment regarded by Schmidt as an essential factor in coagula- tion. Pathologically, it is probable that the tendency to thrombosis in typhoid fever, sepsis, and other diseases is due to increase of similar fibrin-forming factors in the blood. The name ferment thrombosis is applied in these cases. ‘ The presence of bacteria in the blood in cases of thrombosis and within the thrombi themselves indicates a probable relationship of great importance. Some bacteria (especially staphylococci) seem particularly potent, while others apparently have little effect. The mode of action of the bacteria has not been fully established, but hemolytic activity and injurious effects on the lining of the blood-vessels may now be con- sidered sufficient to explain thrombosis, on the basis of a reduction of the anticoagulating power of endothelium. Bacteria seem able to in- duce hyperinosis, or an increase in the fibrin-forming elements. DISTURBANCES OF THE CIRCULATION OF FHE BLOOD 69 Hemolytic action is also the probable explanation of the frequent thrombosis met with in various mineral poisonings and in auto-intoxica- tion such as follows freezing or burns. According to present-day views, coagulation of the blood is the result of a special form of gelatinous precipitation of fibrinogen, a normal constituent of the blood-plasma under the influence of fibrin-ferment or thrombin. The latter is prob- ably not a true ferment in its mode of action, but seems rather to enter into a physical or physicochemical combination with the fibrinogen. Thrombin is a derivative of various cells of the body, especially the leukocytes and vascular endo- thelia. It occurs in the cells as prothrombin, which requires for its activation or conversion into thrombin, calcium salts and probably also certain so-called thrombo- plastic substances derived from tissues. In the blood within normal blood-vessels coagulation is prevented by the action Of antithrombin (Howell). According to the views here expressed the process of coagulation may be tabulated as follows: Cells — thromboplastic substance. Thromboplastic substance + calcium + prothrombin = thrombin. Thrombin + fibrinogen = fibrin. Pathological Anatomy.—The appearance and the construction of thrombi depend upon the manner of formation. When formed in consequence of almost complete stoppage of the circulation they are dark-colored, soft, red clots, similar in every way to postmortem coagula; and under the microscope show fibrillar fibrin enclosing mainly red corpuscles. Yellowish or white thrombi are formed slowly from actively cir- culating blood and are more consistent. Their composition will be under- stood from the mode of formation. In the normal circulation the red corpuscles move in a column in the center of the stream, separated from the wall of the vessel by a plasmatic zone in which the leukocytes may be seen. When the circulation is slowed, plaques approach the vessel wall, and tend to adhere in small masses to any point of disease in the endo- thelium and also to each other. This has been termed conglutination of the blood-plaques. In the ordinary thrombus, after primary conglutination of the plaques, leukocytes are added, and red corpuscles in great or small numbers, according to the manner of formation of the clot, whether rapid or slow. White thrombi consist of conglutinated plaques, leuko- cytes, and fibrin. They first appear as hyaline, viscid masses, but sub- sequently become granular from partial disintegration. If the circula- tion is alternately slow and more rapid, distinct layers are seen in the thrombus, first dark colored from admixture of red corpuscles, then lighter in hue. Such thrombi are called stratified. If the circulation is irregular from dilatation of the vessels or from other causes, the light and dark areas of the thrombus may be more irregularly disposed. The thrombus first formed is the primary thrombus. Subsequently it extends by additions (secondary thrombus) in the direction of the current of blood as far as the next collateral branch of the vein or artery, into which the thrombus frequently extends as a rounded prom- inence. In the case of the veins a new thrombus may start from such projection (Fig. 5), and eventually the clot may in rare cases extend as 70 A TEXT-BOOK OF PATHOLOGY far as the heart (Fig. 6). The thrombus may be lateral—that is, when it lies against the vessel wall—or obstructive, when the lumen is completely obliterated. In the veins small thrombi are frequently formed in the valvular pouches in marantic subjects. In the heart thrombi are espe- cially common on diseased valves, in the auricular appendages, and in Fig. 5.—Thrombus in the femoral vein in a case of phlebitis (from a specimen in the Museum of the Philadelphia Hospital). the intertrabecular spaces. They frequently appear as polypoid masses, and may be attached by slender pedicles. A curious form, called ball thrombi, is seen in the auricles. These are rounded clots wholly or almost wholly separated from the wall, and may occasion serious obstruction Fig. 6.—Cystic thrombi of heart chamber. at the orifices of the heart. The internal softening is probably due to leukocytic enzymes acting in the center, protected there from the anti- enzyme of the blood. Effects.—Frequently the collateral circulation is so quickly estab- lished that no untoward results are seen. When a large vein is ob- DISTURBANCES OF THE CIRCULATION OF THE BLOOD 71 structed, venous congestion and dropsy may follow; obstruction of an artery causes local anemia, and subsequently, if the collateral cir- culation is not established, degenerations or necrosis. Thrombotic obstruction of small arteries may cause hemorrhagic infarction. Em- bolism and, if the thrombus is infected, general pyemia may result from softening of the thrombus. Subsequent Changes.—After their formation all thrombi contract. In this way the red forms may become light colored by extrusion of the red corpuscles, or by hemolysis if bacteria or toxins are responsible for the thrombosis. In small vessels red thrombi often become light colored by removal of hemoglobin and a species of hyalin transformation. These may have the appearances of white thrombi and are only dis- tinguished by careful examination. After the thrombus has contracted it may undergo various de- generative changes. Frequently the white corpuscles, plaques, and Fig. 7.—Thrombosis in cardiac chambers, Fig. 8.—Branch of the brachial artery showing cyst-like structure (Orth). after amputation, showing vascularization of the thrombus, Th (Weber). fibrin are broken down into an emulsion by liquefaction necrosis and fatty degeneration, and the red corpuscles converted into granular pig- mented masses. These softened portions are swept into the circulation and occasion embolism. Frequently this form of simple softening occurs in the center of large thrombi and gives rise to cyst-like formations (Fig. 7). A more serious form of softening occurs when the thrombus is in- fected by micro-organisms. In this case true purulent softening takes place, and the wall of the blood-vessel shares largely in the suppurative processes. This form occurs especially in the thrombi blocking blood- vessels of suppurating or necrotic tissues. General pyemia and infec- tious embolism result. , A more favorable termination of a thrombus is calcification. This 72 A TEXT-BOOK OF PATHOLOGY is most frequent in the clots in dilated veins, the calcareous thrombi being known as phleboliths. Arterioliths and cardioliths are rarely met with. Organization of the thrombus may result from the irritation it occasions. New blood-vessels and proliferating connective-tissue cells spring from the vasa vasorum and lining membrane of the blood-vessel as well as from endothelial cells covering the thrombus, and penetrate the thrombus (Fig. 8). From these organization proceeds as elsewhere, and as it advances the thrombus itself is absorbed. Finally, the clot is fully replaced by connective tissue enclosing a small amount of blood- pigment or calcified remains of the thrombus. The blood-vessel may be converted into a solid fibrous cord, or may be distorted and narrowed by bands of connective tissue in the interior. Sometimes after partial vascularization of a thrombus small vessels running parallel with the lumen of the obstructed vessel become dilated and thus partly reéstablish Fig. 9.—Canalization of a thrombus (Karg and Schmorl). the channel. This is termed canalization of the thrombus (Fig. 9). In other cases canalization may begin as a process of simple softening. The clotting of blood within body cavities, in extravasations, or upon wounds is favored by the presence of tissue coagulins and bacteria in addition to the leukocytes and platelets. Hyaline thrombi seen in small vessels and free in organs are due to an agglutination of erythro- cytes or platelets by bacterial or other toxins. They are probably free of fibrin, although staining like it. EDEMA Definition.—The term “edema” is applied to a condition in which the liquid within the tissues is increased in quantity. Etiology.—It is primarily necessary to understand the methods by which the liquids normally present in the tissues escape from the blood- vessels, their original source. DISTURBANCES OF THE CIRCULATION OF THE BLOOD 73 Several processes are concerned in this escape of fluid. In the first place, the pressure of the blood serves to cause a certain amount of direct filtration, just as liquid enclosed in tubes of permeable animal membrane escapes when the pressure outside is less than within. In this process of direct filtration the state of the tissues themselves plays a part. If the normal elasticity of the tissues and degree of pressure of the liquid in the interstitial spaces are lowered, liquid escapes through the capillary walls to equalize the pressure. A second process at work is that known as ’ diffusion or osmosis. In this there is an exchange between the blood and the tissue liquids, certain substances being taken into the blood in ex- change for water and other constituents of the blood-plasma. The liquid thus discharged from the blood-vessels enters into the metabolic activity of the tissues to a greater or less degree, is somewhat altered in character, and the surplus is carried off in the lymphatic capillaries as lymph. Cer- tain physiologists (Heidenhain et al.) believe that there is a further and very important factor of a vital sort. This is described as an active secretory function of the endothelial cells of the capillaries and lymphatic spaces; so that, according to this view, lymph formation is in a measure at least a direct secretion. This view, though not generally accepted, is supported by many facts. Meltzer suggests that endothelium acts as a carrier of lymph and solid particles from the blood to the tissues. Briefly, then, lymph formation may be described as the escape of water and other substances through a more or less permeable membrane, the capillary walls, in consequence of direct filtration, osmosis, and prob- ably secretion. The quantity present in the tissues depends upon the quantity escaping from the blood-vessels and the amount carried away by the lymphatic circulation. The causes of increased accumulation of liquid in the tissues may then be readily determined. Among these are: (a) increase of blood- pressure, or (b) decrease of tissue elasticity and pressure; (c) alterations of the blood rendering it more diffusible, or (d) of the liquids in the tissues increasing the osmotic power of these; (e) increased permeability of the walls of the blood-vessels; (f) obstruction to the flow in the lymphatic vessels. These causes will be considered separately with reference to certain well-known clinical types of edema. (a) Increased blood-pressure always occasions increased escape of liquid from the vessels (transudation) and thus increased formation of lymph. In active hyperemia with excess of pressure the amount of liquid rarely becomes so great that the lymphatic vessels cannot carry it off, and edema does not, therefore, occur. In passive congestions, how- ever, as in heart disease, pressure upon veins, etc., the escape of liquid becomes more rapid and copious, and the lymphatic circulation is insuf- ficient. Edema or dropsy results. In this process of direct filtration the transudate consists mainly of the water and saline constituents of the plasma and to a relatively small degree of the albuminous constituents. (b) Decreased tissue elasticity and pressure are rarely factors of prime importance, though they may be contributing causes in many cases. In one class of cases termed ‘‘cedema ex vacuo” they are the 74 A TEXT-BOOK OF PATHOLOGY principal causes. In these cases liquid escapes from the blood-vessels to fill a space left vacant by disease or atrophy of tissue elements. This is frequently seen in the subarachnoid spaces of the brain and in other parts of the central nervous system. (c) Alterations of the blood, though theoretically very important as direct causes, probably act indirectly. It has been found by experi- ment that artificial hydremia, even though combined with considerable increase of the bulk of blood, does not cause edema unless by some means the walls of the blood-vessels have been injured. It is probable, therefore, that the edema of anemic and marantic persons is similarly due to increased permeability of the vessels. This in itself might occa- sion edema, though the degree is probably greater as a consequence of the anemic state of the blood. The vascular disease itself is probably in some way (perhaps by the action of circulating toxic substances) brought about by the condition of the blood. (d) Increased permeability of the capillary walls is of great im- portance and probably plays a part in every case of edema. Experi- mentally it is easy to prove that this factor alone may cause pathological transudation. Applications of heat to a part or the introduction of poisons capable of causing disease of the walls of the blood-vessels may thus occasion edema. Clinically this factor is of importance in the edema of Bright’s disease. Formerly the dropsies of renal disease were attributed to hydremia, but the experiments cited above show this factor to be insufficient. On the other hand, changes of the vascular system are known to occur in Bright’s disease, and particularly in cases usually attended with marked edema (glomerulonephritis). Changes in the blood may, of course, contribute, as may also stasis due to cardiac weakness. Disease of the capillary walls is also an important cause of edema in and about areas of inflammation (inflammatory edema). In these cases the toxic causes and products of inflammation doubtless attack the walls of the vessels and render them more porous. Such edema may occur only in the vicinity of an inflamed area, or may be widespread. Thus in some cases edema of the lungs and other internal organs may be occasioned by bacterial toxins derived from a distant focus of infection. Cases of hereditary edema have been described. These may owe their origin to a congenital excess of vascular permeability. Finally, there are cases of edema in which the nervous system seems to exercise an influence. Among these are the dropsies attending cases _ of neuritis, neuralgia, or organic diseases of the cord. In these instances changes in the blood-vessels and perhaps in the tissue elasticity may be important causes. An interesting form of this sort is that known as angioneurotic edema, in which local edema of various forms (often as giant urticaria) makes its appearance under the influence of nervous uritations. (e) Obstruction of the lymphatic circulation does not ordinarily occasion edema because the collateral circulation is sufficient to carry away the lymph. When, however, a larger trunk, especially the thoracic DISTURBANCES OF THE CIRCULATION OF THE BLOOD 75 ~ duct, or numerous smaller lymphatics are obstructed edema may result. This is observed in the chylous ascites due to obstructions of the thoracic duct and in the edema of elephantiasis. (f) Alterations of the liquids of the tissues may, conceivably, occa- sion increased diffusion of liquid, but practically little is known of the operation of this element. While the escape of fluid from vessels to tissues may be explained under the preceding headings, other factors must account for its re- maining outside lymph- and blood-vessels. This has been explained by the statement that dropsical tissues and fluids contain an excess of sodium chlorid. This is not always the case. Fischer claims that in parts subject to edema there is increase in acids, in the presence of which colloids are altered so that they take up and hold more water. The acids accumulate as a result of overproduction through improper oxidation or becaus® of abnormal retention. Pathological Anatomy.—Edema may take various forms, according to its situation. In some cases it is localized, affecting a limited part of the body, as a single organ or member. In other cases it is widespread in the subcutaneous tissues and skin, when the term “anasarca”’ is ap- plied. It may occur in the serous cavities in the form of serous transu- dates (hydrothorax, ascites, hydropericardium, etc.). The liquid itself varies in character according to the cause. In the ‘pure transudates due to increased filtration the liquid is watery, low in specific gravity (below 1016), and comparatively poor in blood- corpuscles and albuminous constituents. In cases in which disease of the vessel walls has played a large part in the causation, especially in the inflammatory edemas, the liquid is more dense and contains more corpuscles and albuminous bodies. The transudate first occupies the lymph-spaces or interstices of the tissues, causing a more or less uniform swelling and bogginess. The tissue pits on pressure, and on section more or less abundant liquid exudes. The solid organs (kidneys, liver) are lighter in color, less dense, and more moist on section than normal; but the appearances of edema are here less characteristic than in the subcutaneous or submucous tissues, or in the softer organs like the lungs and brain. Microscopically, the tissue elements are seen to be pushed apart by the transudate, and in some cases the cells themselves may be dis- eased. (See Dropsical Infiltration.) Results of Edema.—The function of edematous parts is necessarily impaired. Sometimes serious consequences ensue, as in the case of edema of the epiglottis, the lungs, or the brain. Secondary changes may occur in parts the seat of continued edema. Among these are various degenerations of the cells and a productive change in the con- nective tissues. The latter is well illustrated in the sclerotic change in the subcutaneous tissues of long-standing dropsy, elephantiasis, etc. CHAPTER IV RETROGRESSIVE PROCESSES ATROPHY Definition.—Atrophy is a condition in which a tissue or organ under- goes a more or less uniform diminution without definite disease of its constituent parts. It is extremely difficult to draw a sharp line between atrophy and degeneration. Frequently one of these conditions merges into the other. Hypoplasia——This term is applied to a condition in which certain organs or tissues fail of their normal development. Thus the heart and blood-vessels and the internal genitalia have been found incompletely developed in some cases of chlorosis; and similar conditions have been found in other diseases or apart from manifest . disease. It is difficult to determine in some cases whether the lack of development is purely the result of deficiency in the developmental processes or the result of congen- ital disease. Thus, in the state called infantilism, in which the body as a whole re- mains undeveloped, there is sometimes a relationship with cretinism or other dis- eases of glands of internal secretion, and primary disordered action or deficiency of the thyroid gland, hypophysis, etc., is the underlying cause. Occasionally an organ or part of the body is entirely wanting. To this condition the name aplasia is given. Etiology.—The causes of atrophy may be varied. It occurs as a result of want of functional demand, as in the atrophies affecting palsied limbs; and sometimes as a result of disturbances of the trophic nervous system, as in diseases of the anterior horns of the spinal gray matter. In the latter instances lack of use is a contributing cause. In the invo- lution processes of old age there is more or less general atrophy, which might be designated as physiological. Similar normal or physiological atrophy occurs in certain organs before the general manifestations of old age. Thus, the atrophy of the thymus gland in early childhood and of the genital organs at the menopause are instances of cessation of function, and consequent or concomitant atrophy of physiological char- acter. Atrophy may be more definitely pathological and the result of distinct causes, such as want of local or general nourishment by occlu- sion of the vessels, pressure, etc. In these cases the process may be purely atrophic, or there may be distinct degenerative disease of the cells with diminution of bulk. Pathological Anatomy.—Atrophy may be simple or numerical. In the former kind, to which the term “true atrophy” might also be applied, the individual cells decrease in size without manifest disease; in the latter the cells are reduced in number, and are usually first altered by some form of degenerative disease, so that the process is not, strictly speaking, 76 RETROGRESSIVE PROCESSES 77 true atrophy. The parenchyma of organs suffers first and most char- acteristically, the connective tissues remaining unaffected or even undergoing hyperplasia. In ‘true atrophy the cells may present no definite alteration, excepting perhaps slightly increased pigmentation. This is sometimes due to the fact that the normal pigment does not suffer reduction as do the other constituents of the cell, but in other cases there is actual deposition of pigment (hematogenous). Cases of the latter kind are designated as brown atrophy (Fig. 10). . This is seen most strikingly in the heart muscle in advanced old age or in per- sons dead of some chronic cachectic disease. In some of the conditions generally described as atrophy the cells show degenerations of various forms, such as cloudy swelling, coagulation ne- crosis, fatty degeneration with vacuolization, and other gross alterations of structure. Secondary degenerative changes may occur in the connective tissues after the parenchyma cells have become atrophic. Thus, after the physi- ological atrophy of the thymus gland has oc- _. Sooner: ae the oe ea of fie gland and a of the surrounding parts become converted into fatty tissue. In other cases myxomatous change may be observed. Such a fatty or myxomatous change may give rise to pseudohypertrophy. Organs which have undergone atrophy are often quite irregular on the surface from unequal involvement of the different constituents. The consistency may be little changed or may be greatly reduced, par- ticularly when some form of cellular degeneration is present. On the other hand, the organ may be hard and tough from secondary hyper- plasia of the connective tissue. The capsule is generally wrinkled from the shrinkage of its contents, and secondary thickening is not unusual, especially in the heart and spleen. The color of the organ, like that of the individual cells, often becomes darker than normal, and may be decidedly changed in brown atrophy. In cases of pressure-atrophy various distortions of the affected organ may be observed. These are particularly marked in the livers of women who have laced excessively. The right lobe of the organ often presents a deep groove or furrow corresponding with the lower border of the ribs, and each of the ribs with which the organ comes in contact may cause a depression. ‘Pathological Physiology.—The function of an atrophic organ is necessarily impaired. In the atrophies of old age this may be of little consequence, as the functional demand grows less and less. In premature atrophies general as well as local disturbances may occur. These dis- turbances vary with the varying functions of the organs, and will be separately discussed. 78 A TEXT-BOOK OF PATHOLOGY THE SO-CALLED INFILTRATIONS AND DEGENERATIONS There are certain pathological processes of a retrogressive character to which the names “‘infiltration” and “degeneration” have been given. Data are growing to show that several of these may be but stages of cell necrosis, and that a sharp distinction is not possible between infiltration and degeneration. In order not to confuse the reader the subjects will be taken up under their customary names and an attempt will be made to show their relationships. CLOUDY SWELLING Definition.—Cloudy swelling, also termed ‘“albuminous infiltra- tion” and “parenchymatous degeneration,’ may be defined as an edema of the cellular protoplasm, with granular alteration in the pro- toplasmic protein and the production of opacity. f Etiology.—Cloudy swelling is an almost universal accompaniment of inflammations. Circulatory disturbances (anemia) were formerly supposed to be important, but are now considered to be of little sig- nificance. Fever per se can produce cloudy swelling, probably not so much the result of the simple degree of heat as of metabolic disturbances induced thereby. The most frequent cause of cloudy swelling is in- toxication, either by bacterial toxins, as in the various infectious con- ditions, or by innumerable organic and inorganic substances. Cloudy swelling is also caused by nutritional disturbances; starvation of an organ will produce it, as the first stage of atrophy; and, on the contrary, the cells may in other cases be so overloaded with nutritional sub- stances as to become temporarily transformed into this condition, as in the glandular epithelium of the liver during active digestion. It is further known that excessive cellular activity may result in a cloudi- ness of the protoplasm, as in the kidney and in glands excited by nervous stimulation. ‘These latter processes should be viewed as normal phe- nomena analogous to the physiological fatty degenerations. . Pathological Anatomy.—The swollen cells present a fine opacity which under high powers is seen to be due to the presence of diffuse refrac- tile granules (Fig. 11). The normal protoplasmic granulations (Altmann’s granules) may partly or wholly disappear; in muscle-fibers the stria- tions are obscured or obliterated. WVacuolation may be seen in the late stages. The cell wall becomes indistinct, so that the cells appear to have coalesced. The nuclei may be little altered, but are commonly obscured by the degeneration. The nuclei are somewhat more deeply stained’ at first, but shortly undergo some chromatolysis, becoming indistinct when their sharpness is destroyed by both the smaller cytoplasm and their own degeneration. Generally the chromatin becomes diffusely stained; it may elect the acid stains or may refuse all staining. In late stages the entire cell may lose its normal reactions to staining reagents. The distinctive granules are not soluble in alcohol or ether, but are dissolved by acetic acid and alkalies. Cloudy swelling may be the forerunner of, or at least go over into, fatty degeneration. RETROGRESSIVE PROCESSES 79 The large glandular organs, the liver and kidneys, illustrate the condition exquisitely. The entire organ is symmetrically swollen; the general consistency perhaps a little decreased. On section, the surface may be found a little moist and the parenchyma protrudes. The tissue presents an opaque pallor, suggesting the appearance of boiled flesh. Seats —The glandular epithelia (liver and kidney) and the muscle- fibers are the striking seats of this degeneration. Pathological Physiology.—The opacity seems to be due to a coagu- lation or precipitation of a part or all of the protoplasmic protein. Some systematic writers have attempted to divide it into two groups: albu- minous infiltration, in which the material has been deposited in the cell and then been precipitated; and albuminous degeneration, in which the inherent cellular protein has been precipitated. It is doubtful whether this division is justified. The chemical relations are entirely obscure. It is as yet incomprehensible how bacterial toxins, them- Fig. 11.—Cloudy swelling and necrosis of the epithelial cells of the renal tubules, due to sublimate-poisoning (Karg and Schmorl). selves apparently proteins, can precipitate other and higher proteins. In the case of inorganic poisoning (metallic salts, acids) the process is more readily understood. The swelling of the cell is probably a simple edema, due, it may be inferred, to disturbed osmotic relations. This has been termed “granular disintegration,’’ and may be considered as a stage midway between cloudy swelling and dropsical degeneration (q. v.). Bell has lately shown that fatty and dropsical conditions of the organs give the gross appearance of cloudy swelling, and that all such degenerations need not be of the same microscopical appearance. He thus believes that the gross diagnosis ‘‘cloudy swelling” covers several states, and even the minute picture does not indicate an entity. The function of organs is more or less disturbed by this form of degeneration. Complete recovery is easy and frequent. If, however, the causes persist, the cells pass into other degenerations, usually fatty metamorphosis. 80 A TEXT-BOOK OF PATHOLOGY FATTY INFILTRATION Definition.—Fatty infiltration is the deposition of fats derived from the circulation in cells and tissues which normally contain none, or the deposition of an excess of fats in cells and tissues in which it nor- mally occurs. Sue ; Etiology.—Fatty infiltration may be physiological or pathological. In conditions of general obesity the regular consumption of excessive quantities of nourishment may lead to the most marked degrees of fatty infiltration; an inherited predisposition and lack of exercise act as contributing causes. In rare instances it seems possible that with the normal physiological diet persons of exceptional digestive power and living under conditions which restrict combustion may become affected with pathological fatty infiltration. The condition may occur during pregnancy, and is frequent at the menopause. In a large class of cases an abnormal diet, or the presence in the diet of substances which aid in Fig. 12.—Fatty infiltration of the liver. the formation of fats, such as alcohol, are responsible for the condition. It is doubtful whether poisons produce general fatty infiltration; they frequently, however, indirectly produce local or visceral infiltrations. Arsenic and antimony are examples. In cachexias certain organs may become loaded with fats, as is sometimes seen in the liver in phthisis. In carcinoma the cells of the neoplasm may become infiltrated with fats. In organic diseases of the nervous system accompanied by extensive dis- integration of myelin, in bone diseases, and even following fractures of or operations on bones, the liberated fats are taken up by the circula- tion and deposited in susceptible localities. There is a rare form prob- ably entirely of senile origin, and also a type which appears at puberty. Of general diseases that may cause general fatty infiltration, chlorosis and diabetes may be mentioned. Fats may be deposited locally as substitution tissue, as in the capsule about sclerosed kidneys, in the place of atrophied muscular fibers, in the bones, and about areas of ae eee Ee Tat. SN = RETROGRESSIVE PROCESSES sl focal disease. The protective areas of fibrous tissue which wall off pathological processes of various kinds may become extensively infil- trated. Pathological Anatomy.—The fat may be diffuse, in localized areas, or in streaks along the planes of fibrous tissue. The appearances naturally vary with the tissue affected. The connective tissue rather than the parenchyma usually displays the disease. The microscopical picture in connective tissues is precisely the same as that of normal adipose tissue. The deposits in connective tissue are most prominent in various fascie and along the fibrous strands, wnder the endothelial membranes, about the lymph-channels, between the muscular fibrille, and to a marked extent just beneath the true skin. In the kidney the collections are be- tween the tubules; in the liver, in the fibrous trabecule, but especially in the hepatic cells; in the heart, underneath the serosa and between the bundles of fibers. Within the parenchyma cells, and this is most marked in glandular epithelial cells, the fat is seen as distinct drops within the cell wall. The fat-drops are always of considerable size, and soon run together, forming one drop, which pushes the protoplasm and nucleus against the cell wall, giving the so-called seal-ring appearance. The nuclei, though flattened, are usually normally distinct, show a nucleolus, and stain well; the cell protoplasm is clear and presents its normal granules; the cell wall is intact, though often bulging to accommodate the excess of contents. In rare, prolonged, and extreme instances the bulk of the fat may be such as to interfere with the functions and nutrition of the cells, whose nuclei and protoplasm will then show pathological alterations. Crystalline formations, as of margarin and cholesterin, and tiny balls of lecithin may be present, but are more often seen in fatty degenerations. The fat may be stained with osmic acid or sudan III. Seats.—The favorite seats of fatty infiltration are the subcutaneous and subserous tissues, the mesenteries and omentum, along the fascie, between the muscles, about the kidneys, and in the liver and heart. The lungs and central nervous organs are rarely and only slightly affected. Pathological Physiology.—The above description is intended to define this condition rigidly as an infiltration of fat into otherwise normal cells or tissues, distinct from any possible formation of fat in them. Infiltration arises whenever there is an abnormal quantity of fat in the circulation; the causes of this were pointed out in the etiology. Infiltration into imperfect or diseased cells may, however, occur with only normal quantities of circulating fat. All cells and tissues are not of the same degree of susceptibility; when, therefore, isolated areas occur in unusual localities a pre-existing disease should be suspected. The assumption of fat and its retention in the form of globules must be referred to an inadequacy of the oxidative powers of the cell. This same is true for fatty degeneration, but here we may have added a destruction of the natural fat combination in the cell. Here also the absorbed fat remains in small globules or granules. é 82 A TEXT-BOOK OF PATHOLOGY Unless very extreme, fatty infiltration does not seriously embarrass the functions nor threaten the existence of tissues, and complete recov- ery and restitution are the rule. It may, however, cause mechanical em- barrassment or may lead to secondary degenerations, which, particularly in the heart, may be of serious consequence to the organ. FATTY DEGENERATION Definition.—This was formerly defined as a metamorphosis, the con- version of the cellular protoplasm into fat. The classical physiological illustration is the fat production in the secretion of milk. Here the nature of this process has not, however, been determined. The major- ity of the secreting cells neither die nor show pathological alterations; while in the case of such as are cast off, as colostrum cells, it has not been shown that their fat was not an infiltration. Etiology.—Fatty degenerations frequently follow upon cloudy swelling, and the causes detailed for the one apply also to the other. Of all agents, poisons are the most important. These may be metallic, as mercury, arsenic, lead, phosphorus—indeed, most of the metals. Compounds which directly bind the hemoglobin or reduce it, or break up the red corpuscles, likewise produce it; such are carbonic oxid, chlor- ates, pyrogallic acid, some coal-tar compounds, etc. Certain poisons, like chloroform, ether, iodoform, and the acids, seem to act directly on the cell nutrition. In the case of most of these substances it seems to have been shown in more or less accurate chemical studies that the poison acts by disturbance of the cellular metabolism. The toxins of bacteria are causes of importance, but their mode of action is not clear, and the analogy with the metallic poisons which naturally sug- gests itself has not been made out. In anemias and cachexias fatty degeneration is common; it is rare in uncomplicated chlorosis. The degeneration in these cases was formerly regarded as due to suboxida- tion. Since, however, it has been shown that no suboxidation occurs in such chronic anemias, the degeneration may best be classed as toxic. It seems possible, however, that extreme hemorrhage can produce fatty degeneration by suboxidation. Metabolic diseases can also pro- duce it, as is sometimes seen in diabetes. Fever can produce it, but the temperature must be high and prolonged. Local fatty degenerations may be caused by local disturbances in nutrition, if not too sudden. This is seen in cases of congestion, throm- bosis, embolism, atheroma, in tumors, and in tuberculous and syph- ilitic deposits. The fatty changes of senility are probably of like origin. In the involution of tissues, as in the thymus, corpus luteum, uterus, etc., fatty degenerations are common. ‘Trophic disturbances produce the degeneration, as is seen in the voluntary muscles. In many pathological processes, as in caseation, liquefaction necrosis, and the resolution of pneumonia, this metamorphosis plays an important réle. In rare instances, as mentioned, fatty infiltration may pass into fatty de- generation. it It ti = wz ee SR ee Be TF RETROGRESSIVE PROCESSES 83 Pathological Anatomy.—Organs the subject of marked fatty de- generation are often somewhat increased in size; to this, however, there are many exceptions: a notable one is acute yellow atrophy of the liver. The consistency is usually lessened, though associated fibrosis may render the affected part abnormally dense. The specific gravity of the Fig. 13.—Fatty degeneration of the epithelium of the renal tubules; stained with osmic acid (Simmonds). tissue is notably reduced. In the nervous system and in caseation and allied conditions liquefaction may occur. The color in typical instances is a pale yellow; the existence and degree of congestion, pigmentation, jaundice, or other associated conditions will obviously alter the color. The areas of degeneration may be uniform or isolated. In the heart and liver particularly streaks or irregular areas may produce a mottled appearance. On section, free fat may drip from the knife and cut surface; in other cases no fat-droplets can be seen macroscopically. In rare instances fat-crystals may be visible to the naked eye. Microscopical Appearances.—The parenchyma cells are first and most extensively affected, though the con- nective tissue may become involved. The cells are usually somewhat enlarged. The natural granules of the protoplasm disappear, and in their stead are fine mu dark granules, which usually stain black with osmic 4 Fig. oo ga acid (Figs. 13, 14), and which are dissolved by alco- the heart muscle. hol, ether, ete., but not by acetic acid. A peculiar reaction of the granules is their staining with fuchsin (fuchsinophile granules). Usually the granules are very fine and only slightly refrac- tile; they may, however, be large, and considerable droplets may appear or the entire cell become one large fat-drop, as in fatty infiltration. ia | 84 A TEXT-BOOK OF PATHOLOGY The nuclei in many cases of moderate degree show no changes; later in the process, however, the chromatin becomes diffused and refuses to stain and the nucleus may entirely disappear. When the fat is dis- solved out of the cell a vacuolated protoplasm may be observed. In early stages the protoplasm has been asserted to be unaltered when thus examined. The cell membrane sooner or later breaks down, and the fatty contents and detritus fill the space. Cholesterin, lecithin, and fatty crystalline formations are often seen. Seats.—Fatty degeneration occurs in nearly all tissues. The epi- thelial structures, especially the liver and kidneys, the heart muscle, and the central nervous organs are the tissues most frequently affected. As before stated, interstitial as well as parenchymatous tissues may be involved. The cellular constituents of exudates and transudates are also liable to the change, and the liquid may thus present the appearance of an emulsion. Pathological Physiology.—Recent investigations tend to destroy the old theory that fatty degeneration results from a transformation of the protoplasm of cells into fat. Investigations have shown that the cells of many of the tissues and organs, notably glands, contain fat, and that this is undoubtedly derived from the blood, also that the fat in true fatty infiltration has the same origin. In so-called fatty degeneration the protoplasm is diseased and in advanced stages completely de- stroyed. This would seem to sustain the old view of direct transforma- tion of protoplasm into fat; but the most accurate chemical investigations do not confirm the possibility of such a transformation. Further, when animals were poisoned with phosphorus and a fat foreign to the animal was administered the fatty organs contained the foreign fat. These considerations have led to a quite general belief that fatty degeneration results from an infiltration of fat derived from the blood and remotely from the fat deposits of the body or from food. The significant difference between fatty infiltration and fatty degeneration is that the former is a deposition of fat in otherwise normal cells as a result of excessive supply of fat, or possibly a lowered metabolic activity which normally disposes of fat, while the latter represents a deposit of fat in a diseased cell, the disease inviting the deposition or greatly reducing the capacity of the cell to dispose of fat even in normal quantities. For these reasons the terms ‘fatty infiltration” and ‘degenerative fatty infiltration” have been suggested for the respective conditions. It seems certain that to some extent at least the granular and molecular fat contained in cells the seat of ‘fatty degeneration” represents normal fat of the cells which had previously been in some form of combination and invisible, but as a result the degeneration became free and visible. This view has been expressed by a number of pathologists and has some experimental support. In some experiments in which starving frogs were poisoned with phosphorus the direct conversion of protoplasm into fat seemed to have been demonstrated, but even in these experiments the glycogen of the liver may have been the source of the fat produced, and, besides, ob- bi I RETROGRESSIVE PROCESSES 85 jection has been raised against the chemical methods relied on in these experiments. It would seem probable that both factors may be active in some cases, but Wells maintains that in kidneys and muscles the metamor- phosis of intracellular fat is more important than absorption. In either case it is to be assumed that the enzymic power of the cells has been damaged.! Fatty degeneration tends to cause secondary changes in the proto- plasm of the affected cell, or the degeneration which in the first instance underlies the condition tends to increase until the cell is practically de- stroyed. Cellular function is, therefore, eventually impaired or per- verted, but experiments have shown that considerable fatty degenera- tion of the heart muscle may exist without impairment of the heart’s power (Romberg, Krehl). The same may be true of other organs. Mild grades, with preservation of the nuclei of the cells, admit of recovery; severe grades go on to total necrobiosis. Lipoid metamorphoses are found either as infiltrates or degenera- tions in cancer necroses, atheromatous blood-vessels, and syphilitic lesions. They were formerly considered fatty, but it is now strongly suspected that they have to do with protein destruction. The lipoids are commonly found as cholesterol esters and appear as doubly refrac- tile or cuboidal crystals under the polarizer. THE ALBUMINOID DEGENERATIONS The hyaline, mucoid, and colloid degenerations represent protein metamorphoses which are closely related. In typical instances they can be quite clearly differentiated from each other, and for the sake of clear- ness and convenience they will be separately described. It must be understood, however, that the products are closely related substances whose chemical characteristics and relations are not clear, and which cannot in many cases be distinguished. HYALINE DEGENERATION Definition.—This term probably comprises a group of retrogressive processes characterized by the appearance of a clear, firm, homogeneous protein substance of obscure nature. It is probable that various proc- esses, defined as hyaline, may have entirely different characters. 1A. E. Taylor while engaged in systematic analyses of the liver and kidneys in fatty degeneration noticed that these degenerated organs retained less of their fat on etheral extraction than do normal organs. He, therefore, carried out experiments on frogs by producing a fatty degeneration with phosphorus and extracting the fat, which was then compared with that from normal frogs. As a result of his experi- ments he offers the hypothesis that the combined fat is a metabolic constituent of the protoplasm of the cell. During the course of the disease causing the fatty degenera- tion this combination is broken after the manner of the action of ferments, and the previously combined fat is set free, when it appears as fatty granules in the proto- plasm. Following this comes fat transportation and infiltration of the affected cells. The reason for such infiltration is, however, not understood. 86 A TEXT-BOOK OF PATHOLOGY . Certain cases are allied to amyloid, mucoid and colloid metamorphoses, and some to coagulation necrosis. The hyaline change of epithelium of older authors is now, by general consent, classed as a mucoid trans- formation. ae Etiology—Hyaline degeneration occurs under the following patho- logical circumstances: in the muscles during infections and septic proc- esses and following traumatism; in intoxications, as by lead; in inter- stitial hemorrhages and hematoma; in struma; in cicatrices; in the blood- vessels in old age, arteriosclerosis, or aneurysm; in all forms of arteritis, especially in vessels of the nervous system; in the endocardium and cardiac valves in all diseases affecting them; in the granulomata; in neoplasms, especially cylindromata and keloids; in the lungs in pneumonia; in the Fig. 15.—Cylindroma, showing a number of blood-vessels whose walls have become converted into hyaline material. kidneys in nephritis; and in all conditions of coagulation necrosis and fibrinous exudation, for in these processes hyaline degeneration seems to be a factor. Very probably the process is not the same in all of these cases, but the similarity of appearance, staining reaction, and general pathological behavior prevents a definite differentiation. Pathological Anatomy.—Hyaline change is not usually massive enough to be macroscopically appreciable. When so, the organ or tissue is enlarged, dense, and presents a pale, homogeneous, opaque appear- ance. Upon the mucous and serous membranes small collections may be readily seen, and may present either a pseudomembranous appearance or may occur as opaque plates upon or beneath the surface. Micro- scopically, there are three chief sites: (a) In the blood-vessels, where the degeneration may appear in the endothelium, beneath it, between the RETROGRESSIVE PROCESSES 87 coats and fibers of the vessel, or surrounding the vessel. The wall is thickened, the lumen is narrowed or obliterated; the endothelium may be loosened or in a state of proliferation. Perivascular hyaline change is well seen in certain tumors—cylindromata (Fig. 15). (6) In the inter- stitial tissues, as between the muscle-fibers, the hepatic cells, the renal tubules, in the reticulum of lymph-glands, in the retina, and in neo- plasms and cicatrices. It may be uniform in distribution, but is more often irregularly clumped or may be in concentric whorls. In tubercu- lous foci the reticular fibrillaze become swollen and gelatinous in appear- ance. They may swell to such a degree that the whole focus has a uniformly waxy appearance, the cells enclosed in the meshes meantime undergoing complete necrosis. In scleroses, as in the liver, the newly formed connective tissue may assume a hyaline character, the fibers being so closely packed together and transformed that the mass has a homogeneous appearance. (c) Within the cells. This condition is probably limited to mesodermic cells. It may be seen in muscle and giant cells, and in endothelium, leukocytes, or wandering cells to a less degree. Whether the epithelial cells take part in this transformation in the coagulation necrosis of mucous membranes and in the produc- tion of casts in nephritis has not been decided. It has not been possible, in the intercellular or interstitial varieties, to decide whether the sub- stance was formed there or deposited there; in the vascular form, and especially in coagulation necrosis and fibrinous exudations, it is prob- able that it is formed in loco. “Hyaline thrombi” cannot be distinguished in their appearance from hyaline masses elsewhere. Whether or not they are examples of true hyaline material is uncertain. Russell's Fuchsin Bodies —These are round bodies, of variable size, situated within or between the cells of epithelial tumors or many normal tissues. They resemble hyaline material.in appearance and staining reactions, especially in their affinity toward acid fuchsin. Unstained, hyaline substance has a glistening, waxy appearance; it is less translucent than amyloid. Typically it evinces an affinity for the acid anilin stains. Stained with van Gieson’s mixture of picric acid and acid fuchsin, the hyaline substance takes on a brilliant red -eolor. It may or may not take the fibrin stains; it often takes basic stains in a modified manner. In truth, the reactions of hyaline material are very uncertain and shifting: in many instances it can scarcely be distinguished from amyloid, and the change is then called hyalo-amyloid; in other instances the product closely resembles mucin and the colloid . substance. The cells of affected parts often show fatty degeneration or other alterations. Seats.—The locations most often affected are the muscles, especially the rect? abdominalis in typhoid or other fevers, the mucous membranes, the liver, kidneys, ovaries (corpora lutea in particular) and adrenal bodies, the cardiovascular system, the nervous system, the serous membranes, and the retina and choroid coats of the eye. The other locations are suggested in the discussion of the etiology. 88 A TEXT-BOOK OF PATHOLOGY Pathological Physiology.—Von Recklinghausen believed it to be a coagulation of normal protein upon the death of the cells; this explana- tion is, however, insufficient. It appears more likely either that it con- sists of protein modified in loco by disturbed action of cells, or that it is a deposition by cellular carriers of insoluble material formed elsewhere. The exact nature of the transformation is entirely obscure; it cannot be held analogous to the coagulation of proteins by heat; nor to the pre- cipitation by metals or salts, since in these events the proteins are not usually rendered permanently insoluble in water and are in other ways clearly different. Hyaline material can undoubtedly be reconverted, absorbed, and removed. Its presence rarely compromises the paren- chymatous structures to an extreme degree. MUCOID DEGENERATION Definition.—Theoretically, this is the conversion of cellular pro- toplasm into mucin. Mucin is a glycoprotein which contains no phos- phorus, and which by virtue of its carbohydrate moiety reduces cupric sulphate in alkaline solution. Chondroitin sulphuric acid has been found in some mucins, showing the relationship of this albuminoid degeneration to amyloid infiltration. It is quite insoluble in water, but has itself a marked capacity for taking up water. It is very soluble in alkaline solutions, but is precipitated by saturations with most neutral salts. It is precipitated by acetic acid from solutions poor in salts; also by heat, alcohol, and many of the metals. It does not dialyze. The secretions from different classes of epithelium differ notably among themselves, and the pathological mucins differ still more. Etiology.—Mucoid transformation should be distinguished from hypersecretion of mucin. Hypersecretion is a common result of in- flammation or irritation of all sorts; it is seen in the pulmonary, gastro- intestinal, and urinary mucous membranes, in the glands of Cowper, the gall-bladder, the salivary glands, in the antrum of Highmore, in the lacrimal glands, and in the testicles. The product of the epithelium of the urinary tract and gall-bladder, usually called mucin, is more often nucleo-albumin. Mucoid degeneration, in the strict sense, occurs mest frequently in mesoblastic tissues, the abnormal substance lying be- tween the cells. It is in some way connected with inflammatory proc- esses, as, apart from its occurrence in tumors, it is found only in tissues the seat of inflammation. Any of the connective tissues of the body may be affected. Widespread myxomatous degeneration of the subcutaneous tissues may be seen in myxedema. In some cases of myxedema, sclero- derma, and the other pachydermic affections mucin has been extracted from the skin; other attempts in similar cases have failed. Neoplasms comprise the third group of conditions presenting mucoid phenomena. The transformation occurs in sarcomata, carcinomata, fibromata, lipo- mata, chondromata, and especially in the myxomata, in which mucin is the essential element, while in the other growths it is an accidental and occasional transformation. In the epithelial tumors the epithelial cells themselves may be affected. RETROGRESSIVE PROCESSES 89 Pathological Anatomy.—The gross appearances may consist in nothing but the appearance of the mucin. Upon catarrhal mucous membranes is a coat of thick, tenacious mucus, with or without con- gestion or other changes. In localities where the mucin becomes pent up it swells markedly, dilates the containing spaces, flattens the epithe- lium (which may then atrophy), and later becomes converted into a simple albuminous fluid. Such a process is seen in the antrum of High- more, in Cowper’s glands, in the salivary glands, in the gall-bladder, in the vermiform appendix, etc.; in these cases the appearances are those of a cyst. In mucoid degenerations in the connective tissues the appear- ances are often not characteristic of mucin; the tissues are soft and elastic and tear easily. In tumors, cysts are usually formed along with diffuse mucoid infiltration. In cystic ovarian neoplasms the produc- tion is often massive, and the substance is often peculiar in refusing precipitation by acetic acid, and has, therefore, been termed ‘‘pseudo- mucin.” In myxomata the substance is usually much more dense. Microscopical Appearances—In ca- tarrhal mucous membranes the goblet- cells are seen in excessive quantity. Only in extreme instances is the process accompanied by the death of the cell. The cells are much swollen, and the dis- tal end is especially bulged out with its drop of mucin. There is usually a sub- mucous inflammatory reaction, and pus- cells containing mucoid material may be seen. In the connective tissues it is Ce rN seen that the mucin lies between the a ee cells and that the ground substance has_ 5 ee RS Se aS disappeared—. e., been converted into Fig. 16.—Myxomatous degenera- mucus (Fig. 16). The cells very rarely tion of a sarcoma, showing stellate cells separated by mucoid intercellu- present mucous change, but are often lar material (Karg and Schmorl). degenerated in other ways. In tumors the change may occur in and between the cells and in the form of cysts, whose walls may or may not present a cellular lining. The blood-vessels are rarely affected. In all situations mast-cells may be seen, often abundantly. Mucin is best fixed with corrosive sublimate. Asa rule, it elects basic stains. It stains only moderately with hematoxylin, but very well with methylene-blue and, indeed, with most of the basic anilin stains. Thionin and toluidin-blue are the best stains, giving it a purple-red color. These staining reactions are not entirely distinctive, and it is often im- possible to differentiate mucoid from colloid material, and even from hyaline and amyloid material. Seats.—Of normal epithelial tissues, the mucosa of the respiratory and gastro-intestinal tracts, the salivary glands, and the uterus are most often affected; any epithelium may, however, be involved. The con- nective tissues have been sufficiently considered. Of neoplasms, ovarian 90 A TEXT-BOOK OF PATHOLOGY cysts, abdominal carcinomata, and mesoblastic tumors anywhere are most liable. ; Pathological Physiology.—Since the deposition of mucin seems to be excluded, the only explanation is to assume the conversion of other proteins into mucin. The causes and modus operandi are not clear; the fact, however, that in the cysts the mucin may be reduced to simple albumin shows the possibility of such transformations. Unless the disease is very prolonged, affected mucous membranes may recover. The connective-tissue forms do not of themselves threaten the life of the tissue; and the deposit is often removed by reabsorption. In neoplasms the degeneration seems an evidence of cell death. COLLOID DEGENERATION Definition.—This consists in the abnormal appearance of a sub- stance whose physical prototype is the colloid material of the thyroid gland. It is not precipitated by acetic acid or alcohol, does not take up water avidly, and is, therefore, much like the pseudomucin already noted. Etiology.—It occurs in goiters and in thyroid neoplasms, in the hypophysis cerebri, in the kidneys (some cases of congenital cysts) and the adrenal bodies, in the prostate and seminal vesicles, in the atrophic gastric mucosa, in cysts of the lips and larynx,, and in the cervix uteri. Colloid transformation in neoplasms apart from those of the thyroid body is very rare. The natural and increased colloid of the thyroid gland, and sometimes that found in the hypophysis, con- tains iodin, associated with a globulin and a nucleoprotein. Because of the absence of iodin in other so-called colloid conditions, cancers and cysts, many authorities restrict the word “colloid” to the iodin-contain- ing kind of the thyroid, and call the homogeneous metamorphosis in cancers mucoid. Colloid is believed to be a direct product of altered cell metabolism, and, aside from the thyroid, is usually mucin, pseudo- mucin, or some other protein which has assumed a jelly-like form in a tightly closed space. There is no uniform organic chemical substance that may be identified as colloid. Pathological Anatomy.—Affected organs may be enlarged and may be hard or quite soft. On section, the colloid areas appear as yellowish- brown, translucent bodies; rarely they are arranged in large clumps. They may be macroscopically invisible or, on the contrary, may form large cystic collections with thin, flattened walls. Colloid degenera- tion may be accompanied by serous transudation, due probably to vascular disturbances. The serous transudation seems to dissolve the colloid material, so that finally the cysts form compartments filled with a chocolate-colored fluid containing pus, blood, and crystals of choles- terin, sodium chlorid, and calcium oxalate (Fig. 17). Microscopically, the material is found in the glandular acini, in the cells, and in the connective tissues. There are often signs of pres- sure, and, probably from the same cause, the areas are anemic and have RETROGRESSIVE PROCESSES 91 a poor vascular supply. The arrangement is usually in balls or whorls, homogeneous as a rule, but often with concentric or radiating lines. The areas often intercommunicate, and extensions may be traced into the adjacent tissues. The cells usually show degenerative changes, and inflammatory reactions are often present. Crystals of calcium oxalate are common. Acid stains are usually elected, as in hyaline degeneration. The indefiniteness of the reactions may make it impossible to exclude hyaline and mucoid changes. Fig. 17.—Colloid degeneration of the thyroid gland, showing masses of colloid matter in the gland acini (Karl and Schmorl). Pathological Physiology.—This is obscure, but seems to be analo- gous to that of mucoid change. The substance is undoubtedly produced an loco. Colloid is a grave degeneration, usually connected with marked cellular disturbances. AMYLOID INFILTRATION Definition.—Amyloid deposits are nowadays thought infiltrative, although formerly regarded as degenerative. Amyloid, a name given by Virchow because of certain reactions suggesting starch, is not a starch, but a glycoprotein, an abnormal combination of chondroitin sulphuric acid, such as is normal in tendon, with a protein. The exact chemistry is not known and the combination is believed to be due to faulty metabolism in loco. It differs from most retrogressive changes in that it affects the interstitial tissues, and not the cellular contents. The presence of balls of amyloid within cells has been maintained by some authors. The names “lardaceous disease” and “lardacein’”’ are used by some writers, denominations warranted by the gross appearance at least. Amyloid disease may be local or general, the latter being calle “amyloidosis.” 92 A TEXT-BOOK OF PATHOLOGY Etiology.—The common conditions under which amyloid infiltra- tion arises are prolonged suppuration and ulceration. In tuberculosis, especially of the lungs and skeleton, particularly in cases of mixed infection and in syphilitic ulceration, are found the conditions most favorable to its production. It occurs, however, in connection with ulcerations of various sorts, gastro-enteritis, and actinomycosis. Rarely it occurs under conditions of cachexia without suppuration, as in cancer, malaria, leukemia. Sometimes it is found without any apparent cause. Certain local “amyloid” formations (corpora amylacea) are probably in nowise connected with the general condition and, undoubtedly, are often entirely physiological. Their relation to amyloid disease is doubted by many, but they do give modified iodin and gentian-violet tests. It is said that they grow by deposit of crystals containing some protein. Fig. 18.—Amyloid degeneration of the kidney, showing amyloid substance in the walls of the blood-vessels of the glomerulus at 6, and hyaline tube-casts in the renal tubules at g, g (Ziegler). Pathological Anatomy.—In marked instances the organs are en- larged and their specific gravity increased. On section, the tissue is firm; the cut surface is smooth and neither contracts nor extrudes. The consistency varies with the coexistence and degree of fibrosis, fatty degeneration, etc. Amyloid substance is more inelastic than any other infiltrative material. The color of the organ is usually pale, but may obviously be altered by congestion, pigmentation, or fatty degeneration. The amyloid substance itself has a glistening, waxy, translucent appear- ance which is almost pathognomonic. This waxy appearance is not al- ways uniform. Slight or even moderate degeneration may not occasion macroscopical appearances; in fact, apparently quite normal tissues may RETROGRESSIVE PROCESSES 93 be highly amyloid microscopically. The special appearances in various organs will be described in the appropriate chapters. Lipoid or actual fatty deposits are found associated with amyloid infiltration, especially in syphilitic conditions. They are either deposits from body fluids or arise from tissue degenerations in the vicinity. Microscopical Appearances.—The favorite seats are the outer surface of capillary blood-vessels and the intima and media of larger blood- vessels, the adventitia being rarely affected, the endothelium apparently never. The fixed connective tissues of the organs, elastic tissues, and basal membranes of glandular acini, or between them and the gland cells, are the parts affected, the wandering cells and leukocytes being rarely involved. Muscle-cells are undoubtedly susceptible; but recent studies seem to show that glandular and lining epithelium is never involved. Such cells may, and often do, show fatty or other degenera- tions or necrosis, but the presence of amyloid substance within their protoplasm has not been shown. The substance appears as irregular clumps or streaks in the interstitial tissues, often compressing the cells and blood-vessels. It presents a glistening, homogeneous appear- ance. The cells usually present evidences of atrophy and other de- generations. In the renal glomeruli and in the Malpighian corpuscles of the spleen the appearances are perhaps most distinctive. Without staining, amyloid degeneration cannot always be distinguished from other degenerations; indeed, not always with staining reactions. The substance is highly resistant to bacterial decomposition and to diges- tion. Reactions.—(See also below.) The gentian-violet reaction seems to be the most invariable. In sections of tissue fixed (preferably in alcohol) for microscopical study gentian-violet colors the normal tissues blue; the amyloid substance is a light pink or red. Jodin-green gives a similar red reaction. A mahogany-red reaction with Lugol’s solution of iodin is quite constant, but fails in the isolated amvloid bodies. It is easily obtained in fresh specimens freed of blood. The red color is changed to a blue by treating with sulphuric acid or chlorid of zine. Seats.—In the order of frequency amyloid degeneration affects the kidney, liver, and spleen, then the larger blood-vessels, the intestinal mucosa, the lvmph-glands, the skeleton, the adrenal bodies, and the heart. It rarely affects the pulmonary mucosa, the bladder and genitalia, the thyroid body, the voluntary muscles, and, apart from the local amy- loid bodies, the nervous system or the integument. Local Amyloid Formations.—These occur in the nervous system, especially in advanced years and in scleroses, grouped about the blood- vessels, and most marked in the posterior cord and in the brain; in the prostate gland; about inflammatory areas; in infarcts; in granulo- mata, especially syphilis; as tumor-like swellings in the upper air- passages, and in neoplasms. They present themselves as small round bodies which usually have a concentric arrangement resembling starch granules. They do not usually present the typical amyloid reactions; often they react more like hyaline substance, and, indeed, the blood- 94 A TEXT-BOOK OF PATHOLOGY vessels of the affected part seem especially affected with hyaline change. Ribbert says the small vessels are curiously free from change. The neighboring lymph-vessels and glands are usually attacked. The special appearances and reactions of the amyloid bodies of the nervous system will be described in connection with Neuropathology. Pathological Physiology.—As stated, amyloid substance seems to be a combination of chondroitin sulphuric acid with a protein. It is composed of hydrogen, nitrogen, carbon and sulphur, and is insoluble in weak alkalies. Chondroitic acid is normally present in bones, carti- lages, and elastic tissue. It seems to have been shown that an amyloid- like substance exists in the elastic coat of the blood-vessels—perhaps a different combination of chondroitic acid. Our present knowledge sug- gests that amyloid substance is not entirely abnormal, but rather an abnormal combination of normal substances. It seems to result from protein alterations in connection with the pathological processes already detailed, having as a result the liberation of large amounts of chondroitin sulphuric acid. That bacterial influences are not necessary is suggested, though not proved, by the fact that amyloid change has been produced by long-continued aseptic suppuration induced by turpentine injection. Amyloid change is an infiltration, the constituents being deposited from the blood and assuming their peculiar characters locally, for amyloid is not found preformed in the blood itself. Possibly local cellular condi- tions favor the deposition by reason of a loss of power to dispose of the constituent substances brought by the blood. Hyaline degeneration seems at times a preliminary stage in the process. Amyloid degeneration interferes with functional activity by pres- sure upon the parenchyma and by vascular disturbances. By its situa- tion in and around the blood-vessels it may occasion thrombosis. Reab- sorption of amyloid substance is possible, as it has been known to occur when part of the diseased area has been extirpated. Such reabsorption does not, however, occur when extensive amyloid change exists. GLYCOGENIC INFILTRATION Definition.—This condition consists in the presence of glycogen in cells which normally contain none, or the presence of an excess in cells which normally contain it, as in the liver, cartilages, muscles, leukocytes, in the embryo in all tissues, and in the uterus. The attempt has been made to separate glycogenic infiltration from a glycogenic degeneration, but the conversion of protoplasmic protein into glycogen has never been demonstrated. Etiology.—The condition is not infrequent. It is seen in the tissues in diabetes, especially in the kidneys (Henle’s loop in particular), muscles, liver, and circulating leukocytes. It occurs in neoplasms, especially in malignant growths of mesoblastic origin, being rare in most carcinomata. It may be said that the more cellular the tumor, the more the glycogen, except in carcinomata, where the amount is small and variable. In leukocytosis of different varieties the cells may con- RETROGRESSIVE PROCESSES 95 tain granules of glycogen or a substance resembling glycogen, and similar granules may float free in the plasma (see Iodophilia). In puru- lent collections and in inflammatory areas the cells may be markedly infiltrated. The infectious granulomata, however, seem exempt. The amylaceous bodies of the prostate are closely allied to glycogen. Pathological Anatomy.—Tissues rich in glycogen may present a hyaline appearance; usually there are no macroscopical alterations. Microscopically, the material is generally found within the cells; it may, however, be in the intercellular substance, and may be free in the plasma of blood or the fluid of exudates. It is commonly deposited as round balls, which may be concentrically striated. In fresh tissues it is soluble in water, but loses its solubility after fixation by alcohol, etc. Tissues to be studied for glycogen must be fixed in absolute alcohol, since watery solutions add a molecule of water to the glycogen and change it to sugar, C.H..O; + H,O = C.Hw.Os. Glycogen is stained brown by iodin, but the brown is not turned blue on the application of sulphuric acid. Ptyalin or amylopsin con- verts glycogen into sugar, with the loss of the color-reaction. The pathological physiology is obscure. In diabetes it is simply an expression of the general hyperglycemia. At the end of long exhaust- ing diseases glycogen may not be found in the cells. The cells are left swollen. In neoplasms and suppurations the collections are prob- ably depositions. DROPSICAL INFILTRATION By dropsical infiltration is meant edema of the cells, the presence in cells of an excess of plasma. It may be considered as of two kinds: Fig. 19.—Dropsical infiltration of the epithelial cells of a carcinoma of the breast: a, Ordinary epithelial cells; b, 6, dropsical cells; c, dropsical nuclei; d, enlarged nucleoli (Ziegler). (a) Dropsical degeneration, a fine granular disintegration of the cyto- plasm preceding or associated with cloudy swelling. (6) Dropsical infiltration, grosser collections of vacuoles or droplets of fluid disturbing the general architecture. This does not always occur in general dropsy, 96 A TEXT-BOOK OF PATHOLOGY the fluid being between the cells and often compressing them to a marked degree. In other instances the cells take up the fluid. In burns and pemphigus and in other skin lesions presenting vesiculation, and in various inflammations of organs, edema of the cells occurs. It is also a part of the degeneration termed “cloudy swelling.” The cells are enlarged, often to an extreme degree, and they may even burst. The protoplasm sooner or later becomes cloudy and often presents degenerative changes—fatty metamorphosis in particular. Vacuolation is frequently observed (Fig. 19). The condition is probably a purely physical phenomenon in the dropsies. In the cutaneous lesions other factors are operative. The diffusion of water into the cell may be explained by a toxic disturbance of the internal chemistry with an increase of crystalloids which attract water. CALCIFICATION Definition.—Calcification consists in the abnormal deposition in tissues of earthy salts, without organization and the anatomy of bone. It may be considered as evidence of local or general senescence, but is never a primary process. The phosphates and carbonates of cal- cium are the chief salts concerned; oxalates, however, are often present; and the corresponding magnesium salts may be mixed with them. The best physiological examples are the senile change in the vascular apparatus and the formation of the brain-sand (acervulus cerebri). Calcification of the skeletal tissues is usually accomplished as a physiological process through the activities of special cells; this is an essential element in ossification. Etiology.—The deposition generally occurs in diseased tissues, especially in those the seat of vascular disorders. Local necrosis or fibrosis antedates intercellular calcification, and the process may be accompanied by atrophy and absorption of certain cellular elements. In neoplasms, abnormal cellular conditions certainly predispose; but here, too, the vascular relations are of notable importance. Hyaline and fatty degenerations often precede or accompany calcification. In rare instances no local predispositions can be determined. Cases of this kind occur in old age, and in these cases it is inferred that, owing to increased lime-resorption from the skeleton, the system is saturated to the point of precipitation (metastatic calcification). Similar super- saturation of the blood with calcareous matter may occur in cases of extensive disease of bones, and may lead to widespread deposition. It is noteworthy that the precipitation of the bone salts circulating in excess occurs most frequently where acid is excreted—lung, stomach, and kidney. Local anemia favors calcification. v. Kossa found that corrosive sublimate, acetate of lead, copper salts, iodin, and iodoform all are capable of producing calcification experimentally. Pathological Anatomy.—Early in the process no macroscopical signs areapparent. On microscopical examination the salts are seen as fine gran- RETROGRESSIVE PROCESSES 97 ules scattered through the intercellular substance. Cellular infiltration, however, is not uncommon, and in such instances the cells show more or less extensive nuclear and protoplasmic degenerations. By the coalescence of the granules larger, irregularly spherical bodies may be formed. These usually have a concentric arrangement (psammoma bodies). Definite crystals are rare, but may be seen. The next adjacent tissue may present an opaque appearance. In certain localities, espe- cially the blood-vessels and serous membranes, calcareous plates are formed. The depositions may attain a surprising size, especially in the vessels and in neoplasms. The color of the deposits is usually white, grayish, or yellow; accidental pigments may, however, produce dis- colorations. On staining, the deposition takes up both carmine and hematoxylin, but exhibits no elective attraction for the anilin dyes. The salts are dissolved. by acids, best by hydrochloric acid; in the case of carbonates, with evolution of carbonic acid gas. Fibrosis, cellular necroses, and degenerations can be demonstrated in the tissues by suit- able methods. Seats.—It is in the cardiovascular system that the condition is of the most importance. It often occurs as a simple senile change, usually connected with an atrophy of the elastic tissues of the vessel walls, hyaline degeneration of the connective tissue, and general fibrosis. It is almost invariably an accompaniment of sclerotic endocarditis and arteriosclerosis. In the endocardium the valves are most frequently affected; of the vessels, the aorta, the coronary arteries, and the cerebral vessels. The process is, however, often universal, and the splanchnic | vessels and radial arteries seem very susceptible. It affects chiefly the intima and media. In the pericardium the deposition is uncommon without the previous occurrence of pericarditis; in adherent pericar- dium the heart may be literally enclosed in a calcified sac. In the myo- cardium calcification is usually interfibrillar, but may involve the fibers. Large collections may occur in the pituitary body, the meninges, and in the ventricular plexuses. It is common in the joints, uncommon in the pleura, rare in the peritoneum. In the muscles local formations are not rare, and usually occur at the seat of previous injury or irritation. In the lungs and liver it is not unusual in and around foci of necrosis due to various causes (tuberculosis, parasites, etc.). Cicatricial tissue often be- comes calcified. In the walls of cysts, in the biliary and urinary bladders, in the limiting wall of old abscesses and hematomata, in thromboses, and even in cutaneous scars calcification, as a crust or infiltration, is a common incident. In the kidneys infarcts of these salts may be formed. The neoplasms most subject are the avascular tumors: uterine fibro- mata, fibromata in general, dermoid cysts, goiters, scirrhous carcinomata, tumors of the pituitary bodies, and especially neoplasms involving bones - or cartilages. It may, however, occur in the most vascular sarcomata. The special term “psammoma”’ (q. v.) is applied to certain calcified neo- plasms. Lithopedia are the calcified fetuses of extra-uterine pregnancy. Apart from neoplasms, the most striking intracellular depositions are seen in the ganglion-cells in areas of softening and in the renal cells 7 98 A TEXT-BOOK OF PATHOLOGY following certain metallic poisonings (mercury). It is interesting to note that the intestinal epithelium, which normally secretes the larger part of the lime-salts discharged from the body, is rarely infiltrated by them. Pathological Physiology.—It seems probable that calcium is car- ried in the blood, in the form of tribasic calcium carbon phosphate, by the agency of the proteins with an appropriate amount of carbon dioxid. In both normal and pathological bone salt deposit there seem to be two forces at work, a local chemical condition favoring the precipitation of the least soluble crystalloids from the blood and the existence of some tissue element having an affinity for calcium. The latter factor has been said to be phosphoric acid by some writers and ascribed to physical factors, such as the concentrated colloid of car- tilage, by others. The local chemical changes favoring calcium deposit are said to be a decrease in protein concentration when the tissue pabulum is thoroughly used up in loco, and increased alkalinity with decreased carbon dioxid. There is, however, some experimental evi- dence to show that the fatty acids formed in necrobiotic tissue combine with calcium to form soap, the combined acid later giving way to acid radicals of stronger affinity for the base, carbonic and phosphoric. It must not be forgotten that we are dealing with a secondary process in a tissue whose metabolism is not and has not for some time been normal. Calcareous deposits are probably never removed, but once formed, remain permanently. There is no doubt that they influence the ad- jacent tissues, causing degenerations. OSSIFICATION This term implies the deposition of lime-salts and other changes through the agency of osteoblastic cells. It occurs in cartilages and in tumors connected with the bones, cartilages, and periosteum. Ossifica- tion of the muscles may occur as a local process or as a widespread and progressive disease. (See Myositis Ossificans.) The salts are regularly deposited and are usually in masses between the cells. An accurate differentiation from calcification can in some instances be made only by the detection of osteoblasts after decalcification of the material. The essential difference lies in the fact that in ossification an attempt is made to reproduce the architecture of bone. URATIC INFILTRATION Deposits of urate of sodium in the cartilages and fibrous tissues of ~ joints and in various other situations occur in the course of gout. (See Disturbances of Metabolism and Diseases of J oints.) It is not known whether this occurs in normal or necrotic tissue, but such a deposit is not normal to cells. The urates occur as slender needles. In the kidneys of babies shortly after birth there occur deposits of urates, chiefly of ammonium, to which the name “uratic infarct” was formerly given. RETROGRESSIVE PROCESSES 99 This gives a false impression, since it is merely a collection of urates of which the kidney cannot rapidly rid itself. Cholesterin deposits are not really infiltrations, but result from cell- ular degeneration, or some as yet undetermined cause. They appear in cysts and tumors, as in the thyroid and in atheroma, as flat, rhombic plates with an angular defect in one corner. With sulphuric acid they give first a red then a violet color. Concrements.—There may collect in bodily or organ spaces, within the organs or their tubular entrances and exits, masses of inorganic matter. These are called concrements. By this is not meant that masses of foreign matter are introduced solely from without, like hair balls, but those whose components are recruited from the body fluids. Concrements may be started by a nucleus of desquamated covering or a product of inflammation, or by concentration, inspissation, or precipita- tion of some otherwise normal secretion or excretion. The first is ex- emplified by the collection of mineral salts around a bit of vesical mucosa that has been separated from the bladder wall or around a mass of bacteria clumped in the gall-bladder by the bile, and floating in it. The second type is exemplified by collection of urates occurring as sand in the urine, with either clumping or growth by accretion. The so-called fecal stones arise by stagnation and inspissation of feces, with later accumulation of earthy salts. All stones probably have some organic matter in them either as a nucleus or caught in their growth. Small foreign bodies may penetrate viscera and cavities and form the nucleus of a stone. The chemistry of calculi varies with their origin. (See Urinary, Biliary, etc.) It has been suggested that the word “calculi” be restricted to bodies arising from precipitation of glandular secretion, and the word “concrements” to the deposits of calcareous matter locally in organ passages, leading to the formation of solid masses. This may be convenient, but is apt to lead away from the thought that a nucleus of some sort is necessary for concrements. PIGMENTATION According to the origin and variety of the pigments, pigmenta- tions may be divided into four groups: 1, those in which the pigments are derived from external sources; 2, those derived from the hemo- globin; 3, those derived from the bile; 4, those derived from cellular activity within the organism. Pigmentation from the Exterior Of the first group, those caused by entrance of foreign bodies through the air-passages are the most important. The condition now generally termed pneumonokoniosis is commonly a disease of occupation. Coal, iron, and stone are the most frequent foreign substances inhaled. Vegetable particles, as grain-dust and textile fibers, and animal hairs and furs, are not uncommonly the cause of such pigmentations. Corre- 100 _A TEXT-BOOK OF PATHOLOGY sponding to the agent, there are such terms as “anthracosis”’ (coal-dust pigmentation), “siderosis” (iron), “calcicosis” (stone), ete. (Fig. 20). Fig. 20.—Tuberculosis of the lung, showing anthracotic pigmentations in the lower part. Inhaled substances probably do not reach the alveoli, but are caught by the bronchial cellular cilia. In part they are coughed up or otherwise Fig. 21.—Phagocytic cells of the bronchial secretion (sputum) containing black particles of dust and carbon; the cells on the right are stained with methylene-blue (Jakob). cast off with the bronchial secretions; in part they penetrate the bronchial walls or are carried by phagocytic cells into the submucosa (Fig. 21). RETROGRESSIVE PROCESSES 101 They may become deposited in the latter situation, or may be carried in the lymphatic circulation to the peribronchial and mediastinal glands, the fibrous tissue of the lung, or the subpleural tissues. In rare in- stances, supposedly by rupture or inflammation of a lymph-node, the pigment finally reaches the general circulation, following which it is deposited largely in the spleen, liver, intestinal mucosa, and kidneys. In such cases it shows a periarterial deposition in the secondary location. Some investigators have attempted to explain anthracosis of the lungs by absorption of coal particles through the alimentary tract. They assert that the particles pass through the abdominal lymph- nodes, up the posterior chain into the mediastinum, and thence to the lung. They would use this reasoning also to explain the course of in- fection in pulmonary tuberculosis. The theory is not widely accepted. Pigmentation through the alimentary tract is well illustrated by argyria following the excessive ingestion of soluble salts of silver. The depositions seem to consist of a reduced form of a silver albuminate. In the skin the pigment lies directly under the epithelial layer, between the cells, and in the intercellular tissue and lymph-spaces. The gastric and intestinal walls are deeply affected. The liver and kidneys are usu- ally involved; in the former the deposition is periportal, in the latter the glomeruli and the corticomedullary boundary contain the pigment; in both the cells are free. Among the rarer sites are the choroid plexus, the various glands of the body, and the walls of the blood-vessels. Pigmentation by cutaneous absorption apart from tattooing is problematic; it has been alleged to occur in workers in copper. Hematogenous Pigmentation This concerns the deposition of pigments derived from the hemo- globin, of which there are two groups, the siderous and the non-siderous. The chief siderous pigment is hemosiderin, which has, however, many modifications; the non-siderous pigments are derivatives of hematin— hematoidin, hemofuscin, melanin, etc. In the course of time the siderous pigments may lose their iron. Probably all formation and further elabora- tion of these pigments are the result of specific cellular activities. Two groups of hematogenous pigmentations may be distinguished: (1) those in which hemolytic agents act in the circulating blood or the asso- ciated organs, and (2) those in which the reductions occur locally. (1) To the first group belong the general hemolyses. In pernicious anemia and leukemia, in malaria, in severe cachexias, in occasional in- fectious and septic processes, in poisonings (as by pyrogallic acid, chlorates, arseniuretted hydrogen, by some mollusks, by pyridin and toluylendiamin, etc.), the hemoglobin is set free in the circulation. It is promptly excreted by the kidneys, and to a limited extent by the intestines; much is converted into bile in the liver, some little passing into the bile unchanged. A certain amount is reduced by the tissues (apparently by the liver) to the two before-mentioned series of pig- ments, which are then carried in the lymphatic and vascular circulation, 102 A TEXT-BOOK OF PATHOLOGY and by means of cellular carriers are deposited in various places. As time passes, these pigments seem to become reduced, the iron being largely excreted by the intestine and the remainder by the kidneys as urobilin. In the liver the depositions are mainly in the periphery of the lobule; in the spleen, in the region of the follicles, and especially in the endo- thelium; in the kidney the most marked collections are in and about the glomeruli and the tubules. In all tissues the depositions are both inter- cellular and intracellular; the cells may either take up pigment or have it deposited in them. Hemochromatosis.—Von Recklinghausen first described under this name a condition in which iron-containing pigment is deposited in the epithelia of the abdominal glands, especially the liver and pancreas, and iron-free pigment in the smooth muscle-fibers of the intestines, and the walls of blood-vessels and lymph-vessels, as well as in connective tissues. He found cirrhosis of the affected organs associated with the pigmenta- tion. Later a form of widespread pigmentation of the same character and involving the structures named, as well as other organs, and notably the skin, and attended with glycosuria, was described by French writers under the name of diabéte bronzé. In this condition there is pronounced cirrhosis of the liver and pancreas, and the diabetic association is at- tributed to the involvement of the latter organ. Cases without pan- creatic cirrhosis of a certain grade or kind are unattended with diabetes. Alcoholism, cachexia, and suppositious toxemias of other sorts have been regarded as of etiologic importance. The pigment is certainly of hematogenous origin, and is believed to be due to an altered metabolism in pigment-carrying proteins. The deposits in the cells cause degenera- tion and death of the latter and consequential cirrhosis. The appearance of organs with marked hematogenous pigmenta- tion varies with the variety and stage. A rusty-red color is the usual early appearance; later a brown, then a greenish, color may be pro- duced, and finally a dark blackish brown. The association of jaundice, which is common, alters appearances very much. (2) The two chief causes of local pigmentation are thrombosis and interstitial hemorrhage and coagulation. The pigmentations seen in the indurations resulting from prolonged venous stagnations and congestions are of analogous origin. ‘Under these circumstances the hemoglobin is diffused from the blood-cells, and a portion passes directly into the plasmatic circulation and is carried away to be eliminated; soon, however, the area becomes walled off and the two sets of pigments are then formed within. The siderous pigments are most frequently seen in small lesions and at the periphery of large - ecchymoses; the hematoidin series is most prevalent within the cystic contents. The pigments change in color (the color changes in a bruise are due to this), and finally become a brownish amorphous matter, ‘which in turn disappears. Phagocytic cells take up all forms of the pigments (Fig. 22) and carry them to various parts of the body, espe- cially to the liver, hematopoietic organs, intestines, and glands; the depositions in them are known as pigment metastases. RETROGRESSIVE PROCESSES 103 The distinctive reactions of the various pigments are not well known. Of hematin and hemin it is known that they are insoluble in water, alcohol, and ether; slightly soluble in weak acetic and mineral acids; easily soluble in chloroform and in weak alkalies, from which solution they are precipitated on the addition of lime- or baryta-water. Fig. 22.—Phagocytic cells of the sputum containing blood-pigment, from a case of cardiac congestion of the lungs (Jakob). Hematoidin differs from these in being somewhat soluble in ether, but insoluble in weak acetic acid, and gives with strong nitric acid the spectral play of colors. Apart from the iron reactions little is known of hemosiderin. The iron is best demonstrated by its conversion into the Fig. 23.—Hematoidin crystals from an old hemorrhagic focus (Jakob). sulphid by means of ammonium sulphid, or by the Prussian-blue reac- tion with weak hydrochloric acid and potassium ferrocyanid (Perls’ test). Microscopically, hematogenous pigment presents three chief appear- ances: small needles, rhombic crystals, and amorphous masses or fine balls clumped together (Fig. 23). The first two forms are very 104 A TEXT-BOOK OF PATHOLOGY rarely seen within cells, the last form commonly. The colors vary from a pink-red to a deep rubin, from pale vellow-green to a deep brown or absolute black. Hepatogenous Pigmentation Pigmentations derived from the bile are due to bilirubin (isomeric with hematoidin) and its oxidation product, biliverdin. Jaundice ordi- narily is of hepatic origin, but late observations would seem to indicate that bilirubin can be formed in the body without the action of the liver. The importance of this is not yet understood. Jaundice can also appear when a great hemolysis occurs, for if too much hemoglobin be thrown upon the liver, all the bilirubin cannot be discharged with the bile and is reabsorbed. The presence of bile or its salts in the blood occurs as a result of external obstruction to the bile flow, or of internal mechanicochemical conditions favoring abnormal retention. The bile passes into the blood mostly by way of the lymph-channels, but may go into the vessels directly, as in cases of acute yellow atrophy. The bile-salts and_pig- ments are both in the blood in icterus and are responsible for some toxic effects, such as degeneration of endothelium with hemorrhage and depression of the central nervous system. The deposition of these pigments may be either in solution in the tissues, in granular precipitations, or in crystals (needles and rhombic plates). The cerebral substance alone seems never, except in the new- born, to be pigmented. The liver, skin, mucous membranes, the end- arteria and other serous membranes, and the glandular and fatty tissues are especially susceptible. The color is first yellow and gradually deepens to a deep olive, the urine presenting similar transitions. The lacrimal and salivary glands, the mamme, and the intestinal mucosa seem to be able to keep the pigment from passing out with their secre- tions. The ocular fluids are colored. The pigment in solution saturates the tissues. The granular pig- ments, yellow, brown, or greenish in color, may be seen in the cells or in the interstitial tissues; the crystals, yellow or red in color, are usually extracellular. The pigment displays the spectral play of colors on con- ots with strong nitric acid, and is turned green by weak tincture of iodin. A special form of deposition is the bilirubin infarct in the urinary tubules. These are seen in severe jaundice of the newborn, but may occur in deep icterus of adults, as in acute yellow atrophy. Metabolic Pigmentation The pigmentation derived from cellular activity may be properly termed ‘“‘metabolic.”” We know isolated facts about the different forms, but there is little systematic fundamental knowledge. Two facts, however, seem clear: that these pigments are formed by migratory and resident pigment-building cells, which with leukocytes and plasma cells RETROGRESSIVE PROCESSES 105 accomplish the transportation and deposition of the pigments; and that hemoglobin is in some way or other the raw material for their manu- facture; some authors, however, think that protein under the influence of ferments produces these metabolic pigments, of which melanin is an example. The manifestations may be local or general. Among the former are the pigmentations of nevi and moles, of pregnancy, of the corpus luteum, freckles, some scars, certain skin diseases, as chloasma and xanthelasma, of the lesions secondary to some cutaneous parasites, etc. A special local type is that seen in tumors, notably in melanosar- comata. Lipomata and sarcomata (chloromata) may be analogously affected. Among the general pigmentations are those of Addison’s disease, of certain severe anemias and cachexias, of tuberculosis of the peritoneum, intestines, and retroperitoneal glands, of abdominal neoplasms, and of senility. The cases associated with abdominal lesions are held to be con- nected with disturbances of the adrenal bodies or of the chromaffin sys- tem, which has been considered to have control of pigment formations. Oéchronosis is a black pigmentation of cartilage and related tissues, sometimes including fibrous tissues, and on occasion associated with melanuria. It probably belongs with the metabolic pigmentations. The metabolic: pigments are very varied, and a detailed discussion of them here would be unprofitable. They may have a high percentage of sulphur and may or may not contain iron. They are commonly de- posited in and between the cells as granules, but may be crystalline. They do not give a play of colors with nitric acid, and have varying solubility. NECROSIS Definition.—Necrosis may be defined as the death of tissues. The death of individual cells is termed necrobiosis; death of tissue en masse, usually accompanied by putrefactive changes, constitutes gangrene. Etiology.—All classes of cellular death may be brought under four etiological groups: 1, those due to nutritional and circulatory dis- turbances; 2, those due to trophic disturbances; 3, those due to poisons —animal, vegetable, bacterial, and inorganic; and, 4, those due to trau- . matism, employing the term in its broadest sense. It has been at- tempted, without success in our opinion, to class the trophic necroses as identical with those due to circulatory and nutritional disturbances; similarly, the poisons and traumatism have been considered as acting only through the circulatory and nutritional paths, but it seems evident that in the light of our present knowledge the four groups are to a greater or less degree distinct. The various causes do not produce constant types of necrosis, but occasion one form in some cases, another in other cases. Promi- nent among these varying circumstances are the native health of the tissues and their vital resistance, the circulatory relations of the part 106 A TEXT-BOOK OF PATHOLOGY involved, the activity and duration of the causal agents, the age of the subject, the presence of other diseases, the temperature of the tissues, etc. It will, therefore, be better first to consider collectively the causes of necrosis, and subsequently detail the varieties of it. There can be no doubt, however, that in the direct forms of necrosis the results are to a marked extent individual to the agent; for example, cells killed by the action of acids, alkalies, and metallic salts present appearances quite characteristic of each. Circulatory Derangements.—The circulatory disturbances include many conditions. Acute and chronic ischemia, however produced —by embolism, thrombosis, arteriosclerosis and atheroma, by extra- arterial pressure, by cardiac weakness or by arterial spasm, as in Ray- naud’s disease and perhaps in ergotism—are important conditions. Venous stagnations are responsible for many instances. Actual stasis due to mechanical obstructions and such poisonings as produce coagula- tions is a rare cause. Heat and cold act partly by circulatory disturb- ances. Among the general disorders of circulation and nutrition may be mentioned the anemias, the cachexias, senility, and certain meta- bolic diseases, such as diabetes. In these conditions there is much probability that poisoning by metabolic products plays an important part. Trophic Derangements.—Forms of necrosis due to trophic dis- turbances are well illustrated by bed-sores (decubitus), myelitic cystitis, the ulcerations seen in trigeminal neuritis, and the arthropathies. These forms of cell death cannot be brought under the circulatory, toxic, or traumatic classification. They can be explained only by the assumption that the biological mechanism of the cell is disturbed, and that in conse- quence death occurs. Intoxications——The group due to poisons is very extensive and the particular subdivisions numerous. The toxins of bacteria furnish many examples of direct necrosis, and act indirectly in cases which seem circulatory or traumatic, though they are not really so, since these factors only lower the resistance of tissues, which then become suscep- tible to bacterial action. Experimentally the most exquisite forms of cell degenerations and necrosis can be produced by the injection of toxins or analogous substances like ricin and abrin. The alkaloids possess marked power in the production of necrosis. Acids, alkalies, metallic salts, and innumerable other chemical substances may produce direct necrosis, or indirect necrosis by the preliminary production of degenerations. The same substances often cause both circulatory and mechanical disturbances, which augment their direct effects. Heat and cold act like chemicals; heat alters the properties of proteins; cold affects the fluids rather than the protoplasmic substances; both also induce marked circulatory disturbances. Mechanical Agents——The mechanical causes of necrosis are many and varied. Pressure per se may cause the death of cells, but is often aided by the circulatory disturbances which it occasions. That tension causes necrosis is an old surgical truth, well illustrated by the results RETROGRESSIVE PROCESSES 107 of collections of exudates below the periosteum and by the results of strangulations. The pressure of calculi, concretions, enteroliths, and exostoses may cause important necrotic processes. Circulatory dis- turbances often are a very active factor—indeed, many forms of trau- matism act solely through them. Inflammation, whatever its original inception, may become so ex- treme as to lead to necrosis. Necrosis, on the other hand, often leads to inflammation, the dead cells constituting the primary irritants. All forms of necrosis are accompanied to a greater or less extent by the various degenerations. In particular the cellular alterations are constantly present, and constitute the evidences of morbific action. The changes are due to disturbances of cell chemistry, among which enzyme action is, of course, the most important. (Reference will be made below to the cellular changes.) There are several general forms of necrosis which, however pro- duced, have a sufficiently distinct character to warrant separate de- scriptions. They are coagulation necrosis, liquefaction necrosis, casea- tion, fat necrosis, hemolysis, and gangrene. COAGULATION NECROSIS Definition.—This is defined as that form of death of tissue in which the protein suffers a change similar to or identical with coagula- tion. It is seen only in those tissues which are rich in proteins, and possibly is due to coagulation of some of these by ferments set free by cell necrosis. The process is partly at least a species of fibrin formation, and is allied to hyaline degeneration. It may be chemically distinct from the coagulation of inflammatory exudate, as fibrin is not always demonstrable. Physically the two are almost exactly the same. Etiology.—The causes of this condition are those above de- tailed for necrosis in general. Circulatory disturbances, except throm- bosis or infarctions, play a minor réle here. Chemical irritants and high temperatures frequently produce it. Bacterial poisons are very prone to produce it, especially those elaborated by the pyogenic bacteria, the tubercle bacillus, and the diphtheria bacillus. About every abscess is found more or less coagulation necrosis; it is one of the early changes in tubercles and the fundamental element in the production of pseudo- membranes. All exudates and transudates are liable to coagulation. The serous and mucous membranes are most susceptible; next the muscular tissues (often the myocardium). Pathological Anatomy.—The tissue has a glazed, opaque, waxy appearance, and is firmer and paler than normal. In later stages the color becomes gray and the tissue inclines to soften. Microscopically . it is seen that there is an exudate which has been fixed in the tissues; fibrin is seen (with suitable stains) in the form of granules and fibrils. In addition to the fibrin there is more or less homogeneous matter (fibrinoid) which does not react to stains like fibrin, but which is never- theless closely allied to that substance. The cells soon lose their elec- 108 A TEXT-BOOK OF PATHOLOGY tion for stains (Fig. 24). Early in the process the nuclei may stain faintly and present a homogeneous appearance; later the cell disintegrates com- pletely (Fig. 25). In muscles the striations disappear; and in the car- diac muscle the intercellular cement substance seems to be dissolved, hh Coury , Fig. 24.—Embolic abscess of the pancreas. The darker area in the center represents closely packed staphylococci, filling a blood-vessel and invading the surrounding tissues. The light area around this represents cellular necrosis. The peripheral darker zone shows abundant invasion of leukocytes. The extreme periphery of the illustration shows pan- creatic tissue little altered. for the cells often lie separated and present vacuolation and fragmenta- tion. Pus, leukocytes, and red blood-cells in the affected areas all suffer the fate of the fixed tissue. The blood-vessels at the margin of the area are seen to be thrombosed. In the kidneys the tubules may contain firm casts. te NS sc MESO | Fig. 25.—Coagulation necrosis of the hepatic cells in a case of puerperal eclampsia (Karg and Schmorl). _ Morbid Physiology.—Many chemicals cause coagulation by direct action. In the larger number of instances, however, it must be assumed that the fibrinogenetic substances which bring about the coagulation of the proteins are derived from the necrobiotic cells in the area or are carried thither by the lymphatic cells. There is consid- RETROGRESSIVE PROCESSES 109 erable evidence that bacterial products may act fibrinogenetically. It has been contended that coagulation necrosis is simply a species of in- spissation of the tissues. This is certainly not the case. An area of coagulation may be cast off by the process of ulcer- ation, may undergo liquefaction, caseation, or suppuration, may be encysted, and apparently may be dissolved and reabsorbed. The area of disease may finally be converted into scar-tissue by secondary regeneration. More or less complete loss of function results from this form of necrosis. LIQUEFACTION NECROSIS Definition.—This change consists in the death of tissue with colliquation. It may be divided into primary and secondary forms. Secondary liquefaction necrosis is the form in which other varieties of necrosis or degeneration are followed by liquefaction. Thus, areas of coagulation necrosis, cheesy necrosis, and of inflammation, gangrenous tissue, and tumors may become liquefied. Among the special forms may be mentioned vesicle formation and the softening of caseous tuberculous lesions. A very frequent seat of liquefaction necrosis is the central nervous system, where the condi- tions are unfavorable to coagulation, so that liquefaction here follows pathological conditions which would elsewhere produce coagulation. Cir- culatory disturbances, traumatism, and intoxications all cause soften- ing in the central nervous system; the peripheral nerves are much less susceptible. Pathological Anatomy.—In the early stages the tissue is softer than normal and very rich in fluid. Later, when the solution of the fibrillar tissues is advanced, the area becomes filled with a liquid of greater or less consistency, depending upon the tissue involved. The cells in the area are seen in all stages of degeneration; later, nothing but detritus is visible. In some instances, instead of becoming more and more fluid, the exudate undergoes coagulation. The color may be white, from the presence of an emulsion of .fats; yellow, from fats and pigments; red and brown, from the presence of blood-pigment; and deeply colored when jaundice is associated. The process consists in the infiltration of fluid into tissues and the more or less complete solution of the tissue elements in it. It has been compared to the alterations of proteins by digestion—a reasonable de- duction, since the solution of the tissue or infiltrate occurs by digestive ferments. Should the process be of bacterial origin, the enzymes of the organisms are added to those of the infiltrative cells. Should bacteria be.absent, the ferments are freed chiefly after disintegration of the cells. (See Autolysis.) Areas of liquefaction may discharge their contents, may coagulate, may be reabsorbed, encysted, or, in uncommon instances, organized. 110 A TEXT-BOOK OF PATHOLOGY CASEATION This is the crude name applied to a complex process whose product has a cheese-like appearance. Sy eat ; The condition is most frequently seen in connection with tubercu- losis, although it is found in the other granulomata, and also in other pathological processes. The preliminary conditio sine qua non of caseation is coagulation necrosis. The modern view of the origin of caseation seems to be that it is a failure of an infiltrate to undergo complete lique- faction necrosis because the enzyme-bearing leukocytes are not attracted, and such enzymes as may be present are inhibited by the unsaturated fatty acids of the tubercle bacilli. Anemia of caseous areas, tuberculous or other kinds, plays a large part in the incomplete softening. Caseous matter is composed of coagulated protein and fatty matter. — Second- ary infection brings blood-serum, which dilutes the enzyme-inhibiting soaps. & DD eet Sas Fig. 26.—Large tubercle of the lung, showing cheesy necrosis. The early tubercle, before the occurrence of softening, has an appear- ance like that of cheese, but is less homogeneous and more granular (Fig. 26). A form of caseation quite similar in appearance occurs in pneumonia, in tumors, and especially in svphilis. Soft caseation is usually coagulation necrosis advanced to liquefaction, together with fatty metamorphosis, so that the appearances are those of soft, creamy cheese. The liquefaction necrosis of the central nervous system may present similar appearances. Microscopically, the tissues in caseation show no cells preserving their staining reactions; everything is converted into débris. Around the affected area is usually found a zone of coagulation, of inflamma- tion, or both. Tissues that have undergone caseation may be cast off, reabsorbed, or encysted; resolution is not possible. Calcification is a frequent termination. RETROGRESSIVE PROCESSES j11 FAT NECROSIS This term is now used to designate a peculiar type of necrosis to which the fatty tissues are subject, and is distinct from ordinary fatty metamorphosis. In human beings it is seen almost exclusively in the abdomen, abdominal walls, and subperitoneal fat. In nearly all in- stances it appears in connection with pancreatic disease—cysts, tumors, obstruction to the duct, and the various forms of acute pancreatitis. In rare instances the pancreas has not seemed especially diseased. In one case known to one of us of hypertrophic cirrhosis of the liver the omentum was affected, while the pancreas showed nothing but a moder- ate degree of fibrosis. The affected areas are white in color, usually not larger than a pea; they may be soft or quite gritty. Inflammatory reaction may or may not surround them. On microscopical examination crystals of the fatty acids may be seen, together with more abundant crystals of a combination of lime with the fatty acids. This combination, it ap- pears, is not a primary feature in the necrosis, suggesting that the fatty acids are first set free and then unite with lime-salts. In experi- mental work by Hildebrand, Williams, and Flexner it seems to have been shown that the typical condition may be the result of direct action of the fat-splitting ferment of the pancreatic secretion. It is certain, however, that in some cases of pancreatic cysts containing steapsin no fat necrosis has occurred. Bacteria have been supposed by some to be the essential agents causing the change, but this has not been demon- strated. H. Gideon Wells, after quite extensive experiments on animals, states that fat necrosis is merely a special form of necrosis of fat tissue, differing from the simple necrosis chiefly in the sharp limitation of the affected area, usually by a wall of leukocytes and later by connective tissue, and the filling of the necrosed cells by the products of fat splitting. It seems to be due to the action of one of the ferments of the pan- creatic juice, most probably lipase (steapsin). As this ferment cannot be isolated, absolute proof is wanting. It may be that the lipase causes the fat splitting after some other ingredient of the pancreatic secretion has injured the cell. The digestive enzyme is supposed to reach the fatty tissues of the abdomen by weakness of the pancreatic duct wall or pancreas capsule due to obstruction or inflammation. In such a condition bacteria may also escape and assist in the fat necrosis. Entrance of bile or intes- tinal contents into the pancreatic duct is said to favor the production of fat necrosis. Lipase acting on the fat cells splits up their contained fat into glycerin and fatty acids. Glycerin diffuses, leaving behind the fatty acids. The cells become necrotic and eventually the fatty acids com- bine with calcium salts and are precipitated, while a new growth of con- nective tissue encapsulates the area and diminishes its size. 112 A TEXT-BOOK OF PATHOLOGY Dissemination of fat necrosis outside of the abdominal cavity has been observed as early as twelve hours after intraperitoneal injection in animals, the route of spreading being probably by the lymphatics. The suggestion made at one time that bacteria might be the cause of fat necrosis has been entirely given up at the present time. Focal Necroses.—This is a condition of multiple small necroses in areas barely visible to the naked eye or discoverable microscopically. They occur in all parenchymatous organs and glands. The chief causes are vegetable toxins. In the small areas the nuclei first lose their staining reactions, the cytoplasm later. There occurs an influx of leukocytes, giving the appearance of an early abscess. These necroses are accounted for in two ways: bacteria or their products may be present directly in the foci, or the necroses may be due to obstruction of capillaries. The obstruction may be embolic or, as Pearce suggests, in the nature of a thrombosis due to hemolysis with collection of ery- throcyte débris. Hemolysis, or blood destruction, is a term limited to the red cells, and indicates destruction of the cell with dispersion of its hemoglobin. (The causes and other features are described under Pigmentation and Diseases of the Blood.) GANGRENE Definition.—Gangrene, formerly defined as the death of tissue en masse, is perhaps best defined as the putrefaction of areas of necrosis. It may be primary, when a particular bacterium produces a gangrenous inflammation as its direct result, as in malignant edema; or secondary, when saprophytic bacteria decompose an area already necrosed from other causes. It may be dry or moist, according to the location and supply of fluids. It may, furthermore, be circumscribed, progressive, or metastatic. Primary gangrene constitutes a specific affection or, rather, a number of specific affections. Malignant edema, infectious emphysema, and some forms of anthrax may be included in this group. In these condi- tions there is violent infective inflammation, with practically immediate gangrene of the affected parts. Secondary gangrene is more common, and the appearances are very varied. The essential condition is putrefaction of a necrosed area. Dry gangrene is usually due to vascular disturbances. As a result of arterial obstruction it is seen in the extremities in senility, and follow- ing arterial embolism or thrombosis of whatsoever nature if the collateral circulation be insufficient to nourish the part. Freezing may produce a dry form of gangrene, the vessels being blocked by thrombosis. Ergot- ism causes dry gangrene as a rule; the same may be said of Raynaud’s disease. Finally, dry gangrene may result from the moist form, when putrefaction is slow and evaporation of the fluids occurs. The putre- factive processes in the dry type are not marked and may cease entirely. Dry gangrene is generally circumscribed and the end-result of a typical case is mummification. The color is usually dark, finally black; early RETROGRESSIVE PROCESSES 113 it may be yellow or brown; rarely the tissues are very pale. There is little toxic absorption in these cases. Moist gangrene presents numerous varieties. It is rarely produced by arterial occlusion, but is the usual result of extensive venous occlusion. Internal emboli, as in the pulmonary arteries or veins or mesenteric arteries, not infrequently cause gangrene of this form. It also occurs in the lungs as a result of inspirational or other pneumonias, abscess, neoplasms, bronchiectasis, and in diabetes. It is seen as a result of trau- matism and pressure in severe contusions (especially with vascular injuries), in intussusception and strangulation of the bowel; as a result of torsion in movable kidneys, spleens, or tumors. It is frequent in the obstructed or strangulated vermiform appendix. Extensive moist gangrene of the extremities or other parts is not rare in connection with diabetes. The mucous membranes may become gangrenous as a result of various infections. A particular form is noma of the mouth and geni- talia. It is seen as a rare condition in certain skin diseases; and is not unusual in severe trophic lesions, as decubitus, cystitis, mal perforans, etc. In moist gangrene the consistency of the part becomes progress- ively softer. There may be local or widespread emphysema. The color is usually dark brown, due to disorganized blood-pigment; the skin commonly becomes black and is covered with blebs. About the area there may be a zone of coagulation necrosis with vascular throm- bosis, or a zone of inflammatory reaction which will produce a line of demarcation. In ‘some cases, especially the diabetic, neither of these zones is formed. The cells first succumb. The protoplasm and nuclei exhibit various evidences of degeneration, the nuclei disappearing and the cells becom- ing converted into granular detritus. Fat and the myelin-sheaths of nerve-fibers are reduced to free fat and fatty crystals. The muscle cells lose their striations and become fragmented; the axis-cylinders of nerves fibrillate. Hemorrhages into the area are common, due either to erosion of vessels and expulsion of their thrombi by the pressure of the blood-current, or to a genuine hemorrhagic condition the result of toxemia. Connective tissue and elastic fibers resist longer than the cells, but finally become liquefied. The affected area contains crystals of pigment, fatty acids, cholesterin, leucin, tyrosin, phosphates, and carbonates. Ammonia, the fatty acids, indol and skatol, sulphuretted hydrogen, carbonic acid and other gases, usually of pronounced odor, are formed. There is more or less toxic absorption from these areas. But two things can happen to an area of gangrene: it may progress and cause the death of the individual, or may become circumscribed. In dry gangrene and in the vascular forms of moist gangrene, limitation is the rule; the other moist forms tend to be progressive. In the cir- cumscribed form a line of demarcation is formed by inflammatory reac- tion, and the mass is finally cast off as a sphacelus or slough if the area be superficial, or encysted if the area be internal. The latter cases may be followed by reabsorption of the contents and calcification of the sac. 8 114 A TEXT-BOOK OF PATHOLOGY GENERAL PATHOLOGY OF CELLULAR NECROSIS The cell as an individual element is liable to pathological processes of various kinds that merit brief consideration, apart from definite forms of tissue degeneration and necrosis. ; : Etiology—The causes of cellular degeneration and necrosis are numerous, including mechanical, thermal, electrical, chemical, and vital (trophic) influences of various kinds. It is easy to demonstrate the influence of some of these causes in the unicellular organisms, such as amebe, and the changes thus produced may also be seen under proper conditions in the cells of the animal body. : : Pathological Anatomy.—The cell as a whole may show various forms of distortion, or internal change. Increased irritability and mobility of the protoplasm cause the projection of pseudopodia, and these may be separated from the body of the cell as rounded particles more or Jess resembling the original cell. This is easily demon- strable in red blood-corpuscles subjected to heat. Sometimes particles are discharged from the cell and vacuolations (expulsion vacuoles) result. Certain influences, like cold and metallic salts or other poisons, cause a reduced mobility and general con- traction of the cell. ALTERATIONS IN CELL NUCLEI IN NECROSIS 1. Karyorrhexis. a. Degeneration of the Cell Membrane (Chromatolysis). b. Budding of the Cell Membrane. c. Pyknosis. a. Degeneration of the cell membrane is a regular phenomenon of grad- ual physiological cell destruction, as in the ovary, testis, epithelia, ete. The membrane thickens (hyperchromatosis) and shows clumped areas. b. In the budding process the nucleus may be small and deeply and homogeneously stained and surrounded by small spherical, bud-like projections, or there may be very large club-like projections which extend to the periphery of the cell or even outside the cell. c. The pyknotic nucleus is smaller than normal, deeply staining and homogeneous in character. Contraction of the nucleus leaves a vacant zone about it, so that it seems to lie in a vacuole. 2. Karyolysis. The nucleus undergoes a gradual solution, but its size and shape may still be recognized by the delimitation of the surrounding proto- plasm even after complete solution. This, in contradistinction to the various types of karyorrhexis, is essentially a postmortem change and occurs when dead cells are still surrounded by tissue fluids. ALTERATIONS IN THE FORM OF CELLS IN NECROSIS In association with pyknosis of the nucleus the cells shrink and become jagged. In conditions in which there is fluid surrounding necrotic cells, the cells at first swell and later contract. Various irregularities of shape may occur. Among the various forms of degenerative change in the cell preceding its necrosis are vacuolization, cloudy swelling, and dropsical degeneration, loss of pre-existing granules or granulation of previously homogeneous protoplasm, pigmentation, and hyaline and glycogenic change. These degenerations may affect only part of the cell, the surrounding protoplasm remaining healthy. In such cases the appearance of alien inclusions is given, and such areas of degeneration have frequently been mis- taken for animal parasites. Russell’s fuchsin bodies are examples of this condition. Among the changes observed, alterations in the Altmann granules, which occur in many cells, are significant. These granules first become larger and more readily RETROGRESSIVE PROCESSES 115 demonstrable, their affinity for acid anilin stains increasing. These changes are variously ascribed to increase of acid radicals from protein cleavage in autolysis, to precipitation of colloids, and to condensation of colloids by pressure when the endos- mosis of water and solids is greater than the exosmosis of metabolic products. The changes are exemplified in the cellular degenerations known as cloudy swelling and hydropic degeneration. Certain methods, such as hardening in a mixture of 2 per cent. osmic acid solu- tion and{5 per cent. potassium bichromate solution, staining in hot 20 per cent. anilin-oil acid-fuchsin solution, differentiation with alcohol, picric acid solution, are necessary to demonstrate the granules. In the degenerated cell even the fresh tis- sue or that hardened in alcohol or formol and stained with acid anilin suffices. Next the granules lose their characteristic arrangement; they partly dissolve and partly aggregate in large spherical masses which may be extruded from the cells. In the third stage there is an altered chemical composition evidenced by changed staining affinity. The granules without special preparation of the tissue may be stained with Weigert’s fibrin method, or they may lose their staining capacity, or in the third place, acidophilic granules may become basophilic or the reverse. ALTERED KARYOKINESIS IN NECROTIC CELLS 1. The chromosomes may become notably thickened, especially in cases in which injuries are inflicted on cells already dividing. 2. Granular fragmentation and alteration of staining reaction of the chromo- somes. The cell itself may be vacuolated. The nuclear fragments be- come acidophilic. 8. Hypochromatic Mitosis. The number of chromosomes may be reduced to 6 or 8 or to an uneven number, as 7 or 5. Such changes are seen in rapidly growing malignant tumors and in rapidly regenerating tissue acted upon by destructive agencies. 4. Broken Chromosomes. Parts of chromosomes broken off from the main body are scattered about in the cell outside the nuclear spindle. The process seems to be one essentially affecting the achromatic spindle. Thickening, clumping, and oxyphilic change of the chromosomes are asso- ciated conditions. Such changes have been found in cells unfavorably influenced after division was under way. : : 5. Asymmetrical Mitosis. The daughter stars may have an unequal number of chromosomes and thus be of unequal size. This has been found in carcinomata, sarcomata, adenomata, and regeneration of the epidermis. 6. Hyperchromatic and Multiple Mitosis. The number of chromosomes may be excessive and there may be pluripolar mitosis, the number of centrosomes and corresponding spindles being 4-6, 8, and even 20. POSTMORTEM ALTERATIONS Certain changes take place after death which may suggest in their appearances antemortem disease. It is, therefore, necessary to recognize these in postmortem examinations. The most striking change is the rigidity or rigor mortis, which is due to a coagulation of the muscle albumin or myosin, probably by reason of the lactic acid present. This occurs at different intervals, according to the cause and nature of death. Sometimes, as in deaths after electrical discharges, it occurs almost in- stantaneously; more commonly its beginning is delayed for some hours. It appears early in cases dying with active muscle metabolism, and late in wasting diseases. After twenty-four or forty-eight hours the rigidity disappears. Occasionally irregular postmortem contractions of the muscles take place, and distortions or even move- ments are thus produced. 116 A TEXT-BOOK OF PATHOLOGY Circulatory Phenomena.—as is noted elsewhere (see Congestion), the blood- vessels, especially the arteries, contract after death, and drive the blood into the capillaries and veins. It is then more or less free to sink to dependent parts through the influence of gravity, and in consequence the lower parts of the organs and of the body in general are congested. This is particularly marked in the lungs, but occurs in practically all organs. The blood may remain entirely within the blood-vessels, but not rarely the coloring-matter diffuses itself through the tissues and causes pigmented areas (ivores mortis) that may suggest antemortem bruises. : The blood in the heart and other vessels tends to coagulate, though in some: cases this is long delayed and remains imperfect. Usually dark red clots are found in the cavities of the heart and in the large vessels. Yellowish fibrinous clots are _ Jess likely to be postmortem, but more often occur in eases in which death has taken a lingering form. Postmortem Degeneration of Tissues.—Some time after death the tissues may become macerated and putrefactive changes may occur. To a large extent these are due to invasion of micro-organisms. It has been found that during the terminal stages of disease various forms of infection (especially micrococcic) occur. This terminal infection is often the immediate cause of death, and it is also concerned in the postmortem change in the tissues. Histologically, a striking peculiarity of such postmortem change is the absence of evidences of reaction (cellular infiltration and proliferation), such as characterize the response of living tissues to irritation. Postmortem softening of the mucous membranes may be due to the action of the secretions. This is especially marked in the stomach, where it is common to observe a macerated condition of the mucosa of the posterior wall. In this case the gastric juice is the direct cause of the alteration in the mucous membrane. Autolysis——After death, either local or general, tissues tend to soften, the process being due to intracellular enzymes in the absence of bacteria. The activity of these ferments is held in check during life by the antiferment action of blood-plasma. All inhibitive agencies being removed by death, favoring factors appear in the shape of a slightly acid reaction due to overneutralization of tissue alkalinity by acids formed in fermentation and putrefaction. The intracellular enzyme is now freed and digests the cell. This is essentially what occurs in the resorption of pathological processes during life. All cellular enzymes are not identical. The most conspicuous cell ferment is that contained in the wandering leukocytes which acts as a solvent in inflammatory exudates. CHAPTER V INFLAMMATION AND REGENERATION INFLAMMATION _ Definition.—Inflammation is the local reaction caused by agents that have produced tissue injury. The essential element in this reaction is fluid and cellular exudation and the attraction to the place of injury of wandering cells. A less essential but almost invariable feature is local hyperemia, while the processes of repair or regeneration usually accompany, but are not strictly a part of, inflammation. By reason of the fact that the term “inflammation” was originally a clinical one and designated all the results of local injury, that is, damage, defensive processes, and repair, and further, by reason of the fact that injury and repair naturally go hand in hand in living tissues, it has always been a matter of difficulty for pathologists to determine what part of the proc- esses occurring in an area of inflammation constitute its essence, and what part represents results or consequences. In the present state of knowledge we recognize and can distinctly separate two sets of phe- nomena following local injury, the first being reactive and defensive; the second, reparative. The latter, while intimately interwoven with the former, do not differ from regenerative processes that are known to occur without inflammation. Viewed in this light the term “inflamma- tion” is restricted to the defensive processes that follow injury, while the repair of damage is a natural sequel manifesting the vital capacity of tissues to restore themselves. There are certain other consequences of inflammation that are some- times included among its essential phenomena. Thus, certain pathol- ogists insist that inflammation is general, not merely local; that the whole body participates in certain ways. There can be no doubt that the irri- tants causing inflammation as well as products of tissue distruction do gain access to the circulation to some extent, and thus occasion general results throughout the body, and it is also true that widespread co- operation may be induced through the action of the nervous system. These are results or sequels of inflammation, but not an essential part of the condition. When the local defensive mechanisms occurring in inflammation (let us assume, of bacterial origin) are inadequate, the micro-organisms may gain access to the general circulation and general “infection” result; when products of tissue destruction similarly escape into the general circulation an “intoxication” results. Neither of these is an essential part of inflammation, but rather the evidence that this process has been inadequate to fulfil its purposes. Such coéperation of the whole body as may be induced through the nervous 117 118 A TEXT-BOOK OF PATHOLOGY system is reactive and is similar to that which must of necessity attend any local disease. It, too, is a consequence, but not an essential part, of inflammation. 5 For purposes of description, however, it is better to include in the chapter on inflammation the regenerative processes that accompany it, and also some account of the general reactions of the whole body. Regeneration independent of inflammation, or with but slight evidences of preceding inflammation, will be separately considered later. Historical—The earliest conception of inflammation was that of a specific entity. Subsequently various theories were offered in explanation of the several phenomena or symptoms. First, the blood-vessels were supposed. to be influenced through the nervous system (vascular theories). Next, it was taught that the inflam- matory irritant excites proliferative changes in the tissues (thus giving rise to round cells), and that this stimulation of the cellular activity invites more blood to the part (hence the hyperemia). This was the cellular and attraction theory of Virchow. Others, notably Cohnheim, described the emigration of leukocytes from the blood- vessels, and held this to be the essential feature of inflammation. This emigration was first described by Dutrochet (1824), Waller (1842), and Stricker; but Cohnheim was the first to systematize the emigration theory. According to Virchow, the first step is a formative stimulation of the cells; according to Cohnheim, degeneration of the vessels leading to emigration; according to Weigert, at least in many cases, the first step is necrosis of the parenchymatous cells. Metchnikoff and his students would elevate phagocytosis to the position of the essential feature of inflammation, but the prevailing opinion is that reactive tissue changes and enzyme activity are equally important, both within and without the cell. Galen and his followers defined inflammation by giving the cardinal symptoms: heat (calor), redness (rubor), pain (dolor), and swelling (tumor). To these may be added altered function (functio lesa). Phenomena of Inflammation in Vascular Tissues.—These may be well studied in the mesentery or tongue of a frog. When the mesen- tery is exposed and spread under a microscope and a localized area in- jured, the first visible effect is a very temporary contraction of the arteries, which may disappear before the examination can be made. It is followed by dilatation of the arteries, and then of the capillaries and veins. The tissue becomes distinctly more vascular than normal as capillaries in which there had been only plasma or a few corpuscles become distended with blood, and, therefore, more distinct. The blood- current is at first more rapid than normal, then slower, and may finally stop entirely (stasis), especially in the capillaries and veins in the center of the inflamed area. Notable changes are seen in the circulating cor- puscles. It will be recalled that under normal conditions the corpuscles circulate in the middle of the vascular stream, leaving a clear plas- matic zone adjacent to the vessel wall; in this zone may be seen leuko- cytes traveling somewhat more slowly than the central corpuscular stream. As the current becomes slower the leukocytes in the plasmatic zone increase in number and stick to the vessel walls, at first here and there, holding on uncertainly, but finally becoming more firmly attached and arranging themselves in a continuous row. In the capillaries clumps of leukocytes frequently alternate with masses of red corpuscles, or of INFLAMMATION AND REGENERATION 119 red and white corpuscles in their customary proportion. Next, it may be observed that the leukocytes are passing through the walls of the capillaries and veins and spreading in the outside tissues. At first a bud- like projection pushes itself through the vessel wall, then more and more follows until the whole leukocyte has escaped into the tissue space outside the vessel. At the same time a certain number of red cor- puscles pass through the capillary walls, and altered plasma escapes and infiltrates the tissues. Some of the leukocytes enter the lymph-channels and thus return to the circulation; others suffer degeneration and de- struction locally. In the perivascular tissue the emigrated leukocytes are found in tissue spaces and tend to accumulate where the injury is greatest. If there be a large area of destruction, these cells surround it. The leuko- cytes soon exhibit their phagocytic power by enclosing bacteria, fragments of dead cells, and débris. The enclosed parts are dissolved by the intracellular ferments and are soon unrecognizable. Some of the phagocytes are themselves destroyed in this attempt to remove invading bacteria and degenerated cells; and becoming, in turn, degenerated, break down into a débris upon which other phagocytes feed. There appear within the cellular exudate also large mononuclear phagocytic cells with large palely staining nuclei, the so-called macrophages. These take up all kinds of débris or even whole leukocytes and red blood-cells. Their origin and functions will be considered later. While this is going on, reparative processes appear in the shape of round newly formed connective-tissue cells which alter their form to spindle or irregular contour, and finally produce fibrillar projections. These are fibroblasts, the principal regenerative cells. In structures in which there are parenchymatous (archiblastic) cells the latter undergo various degenerative changes, such as cloudy swelling, edema, mucous degeneration, fatty degeneration, or even necrosis. Less frequently proliferation of the parenchymatous cells takes place. Every case of inflammation does not present all these phenomena, nor is the subsequent fate of the exudate and altered cells always the same. Phenomena of Inflammation in Avascular Tissues.—Some of the processes of inflammation have been best elucidated by experi- mental inflammation of the cornea. It will be recalled that this struc- ture is composed of layers of parallel fibers, the direction of the fibers in one layer being at angles to that of the fibers of adjacent layers. Anastomosing lymph-channels occupy the spaces between the fibers and layers, but there are no blood-vessels. A very slight injury of the cornea may be followed by no other result than slight swelling of the corneal corpuscles around the point of injury and subsequently multi- - plication of these cells to repair the damage. This slight change cannot be readily demonstrated. Usually there is seen around the injured spot a hazy zone which is composed of masses of leukocytes that have been attracted to the center of irritation. These escape from the hyperemic conjunctival vessels at the periphery of the cornea. The alteration 120 A TEXT-BOOK OF PATHOLOGY (dilatation, degeneration of the walls) of these vessels may be due in part to reflex nervous influences, and in part to the direct action of toxic substances generated at the site of the primary corneal injury and dif- fused to the surrounding tissues. The corneal corpuscles themselves swell, undergo nuclear division, and to some extent perhaps become free (phagocytic) cells. In more intense grades of inflammation the local degeneration of the corneal corpuscles causes a visible defect (erosion, ulcer), and the surround- ing zone of leukocytic invasion is pronounced. In cases of marked’ corneal inflammation new blood-vessels are later formed at the sides of the cornea, and pushed into its previously avascular structure; the subsequent phenomena are practically the same as those found in in- flammation of vascular tissues. In the case of inflammation of the heart-valves no migration of leukocytes to the diseased focus occurs in the early stages. The endo- thelial cells at the point of injury (near the free edge of the valve) swell and present nuclear division and also more or less degenerative change; the tissues at the base of the leaflets become hyperemic and some emigration of leukocytes occurs in this situation. Thus, as in the case of the cornea, cellular destruction and proliferation occur at one place (the point of injury), while the vascular phenomena and emigration of leukocytes are found at some distance. In both cases there may event- ually be an ingrowth of loops of capillary blood-vessels from the vascu- lar periphery into the avascular structure, and then local emigration of leukocytes from these capillaries may take place. The phenomena must now be separately considered. 1. Changes in the Vessels.—The first effect of irritation may be momentary contraction of the arteries; but this is rarely observed. Usually the arteries dilate at once, and dilatation of the capillaries and veins promptly follows. This is at first a regular or uniform dis- tention, but shortly becomes irregular, causing inequality of caliber and tortuosity. The cause of this dilatation was formerly located in the nervous system, and undoubtedly nervous influences do play a part in some cases at least, but the more important cause is probably some degeneration of the vessel walls. The primary dilatation may be due to the direct effects of the toxic agent causing the inflammation or to products of cell degeneration it has occasioned. It may be purely func- tional at first, but later is surely degenerative. The microscope does not reveal this, but some of the phenomena connected with exudation and the circulation of the blood show that there is some lesion of the vessel walls. There are certain visible changes in the vessels, such as swelling of the endothelial cells and increase of the intercellular sub- stance, and some undoubted though invisible changes, such as increased adhesiveness of the endothelial cells. The last-mentioned condition and the swelling of the endothelial cells which thus encroach upon the lumen of the vessels are conditions that, together with the dilatation of the blood-vessels, occasion slowing of the blood-current and adhesion of the leukocytes to the vessel wall. INFLAMMATION AND REGENERATION 121 In the later stages of inflammation karyokinetic changes and con- sequent multiplication of the endothelial cells of the capillaries are ob- served. The new-formed endothelial cells are utilized in the production of new blood-vessels. (See Granulation Tissue.) Influence of the Nervous System.—lIt is likely that the nervous system through its vasomotor mechanism plays an important réle both centrally and peripherally in the vascular and exudative phenomena of inflam- mation. Dilatation of the vessels may be favored by weakness of the constrictors or stimulation of the dilators. This is illustrated by the severe inflammations resulting from trivial causes in paralytic parts, and by the occurrence of sympathetic inflammation in one eye following disease of the other. -In the latter instance the trophic nerves are also concerned. 2. Exudation.—As the blood-current grows slower the leukocytes in the plasmatic zone of thé blood-stream increase in number and cling to the wall of the vessel. This is partly a mechanical result of the Fig. 27.—Inflammation of the mesentery, showing overfilling of the blood-vessels, with emigration of leukocytes and diapedesis of red corpuscles (Ziegler). slower rate of the blood-curtent, and partly the result of the adhesiveness of the vessel walls and projection of the endothelial cells. Possibly the attractive (chemotactic) influence of the agents causing the inflammation may play some part by drawing the leukocytes to the walls of the vessels (see below). Finally, the leukocytes pass through the vessel walls between the endothelial cells and collect on the outside of the blood-vessel, whence they more slowly migrate through the tissue (Fig. 27). The passage of the leukocytes through the vessel wall can be studied in the mesentery of the frog. At first a bud-like projection pushes itself through the wall between the endothelial cells, then more and more of the corpuscle follows until the whole cell has escaped. When outside the blood-vessel the cell creeps through the tissues in the inter- cellular spaces, often elongating itself in narrow places to a linear form, and again swelling to its normal rounded form where fluid exudate has widened the spaces. This emigration of leukocytes occurs to a slight extent normally, but is abnormal in degree in inflammation. Cohn- 122 A TEXT-BOOK OF PATHOLOGY heim ascribed it to disease of the vessels—increased permeability—the leukocytes being purely passive. Later observation indicates that the chief réle in this excessive emigration must be assigned to the stimulated ameboid movements of the leukocytes. Degeneration of the vessel walls, especially swelling and softening of the cement substance between the endothelial cells, and the pressure of the blood, aid, but only to a minor extent. The cause of this active ameboid motion and tendency to emigration has recently been found to be an attractive force peculiar to the causes of inflammation. Stahl, and later Pfeffer, found that certain substances exert an attractive or repellent force upon low forms of vegetable and animal life, upon spores of plants, and upon bacteria. To this force the name chemotaxis has been given,.and the terms positive and negative chemotaxis are used to designate the attraction and the repulsion respectively. The irritant substances which directly cause inflammation are positively chemotactic in action; and in cases in which mechanical injury causes inflammation, such substances first result from mechanical destruction of cells and then incite the subsequent phenomena of inflammation. The leukocytes that emigrate under the influence of a chemotactic agent are almost exclusively the polymorpho- nuclear forms, and these constitute the majority of the cells of an inflammatory exudate in its earlier stages. They are not, however, the only forms ef leukocytes found in an inflammatory area. Frequently the first to appear are the eosinophiles. Sometimes these cells are very abundant in the inflamed part. In somewhat later stages lympho- cytes also emigrate, and as the polynuclear forms disappear the lympho- cytes become more and more predominant. In part these doubtless emigrate from the blood-vessels, but the greater number is derived from the lymph-channels and regional lymphoid collections, for such collections are exceedingly widespread throughout various tissues and organs. The lymphocytes are prone to occur in groups, which has led some authorities to attribute their presence to hyperplasia of existing lymphoid collections, and to some extent to the attraction exerted on the lymphoid cells of the neighboring lymph-spaces toward the existing lymph-nodes in the affected area. While the tendency is to group together, they also increase among the growing fibroblasts, and, as said above, crowd out the polymorphonuclears. Plasma-cells! and mast- cells are also found, but as the significance of these is still doubtful, 1 Plasma-cells.—The cell described under this term by Unna is a small cell whose protoplasm stains a violet blue with methylene-blue. There are no distinct granules, though sometimes the protoplasm is slightly granular. The granules have some relation to those in the lymphocyte. This cell is one of the so-called lymphocyte series. The nucleus is usually eccentrically placed and surrounded by dark masses of chromatin. The cell varies in size from that of the small lymphocyte to that of the large mononuclear leukocyte. Karyokinesis has been observed in a few cases. The plasma-cell is probably an altered lymphocyte which has escaped from the blood-vessels. Some hold that it is a form of connective-tissue cell and that it is concerned in regeneration of connective tissue. This is unproved and unlikely. The plasma-cell is found in inflammatory exudates of all ae and in the lesions of the specific infectious diseases—tuberculosis, leprosy, syphilis, etc. : The plasma-cell of Waldeyer is different from that above described. It is identical with the mast-cell of Ehrlich. This is a cell containing large basophilic granules. (See Diseases of the Blood.) It occurs in inflammatory processes of a chronic character and in various tumors and degenerative lesions. Its significance and nature are uncertain. INFLAMMATION AND REGENERATION 123 separate reference will be made to them below. The plasma-cell un- doubtedly plays an important réle in some cases, as the inflammatory exudate may consist almost wholly of this type of cell. The microscopical appearance of the tissues after emigration of the leukocytes is characteristic. The capillaries are dilated and ob- secured by a mantle of exuded white corpuscles, and the tissue around swollen by fluid and infiltrated with migratory leukocytes. The sub- sequent distribution and appearance of the leukocyte depends very much upon the character of the inflammation and of the tissues in which it occurs. The changes going on within the cell consist of fatty, cloudy, albu- minoid, or dropsical degeneration of organ cells, while hyaline or mucoid metamorphosis is seen in connective-tissue cells. The cellular character of the exudate varies somewhat with the tissue involved and the nature of the irritant. For example, in the pyogenic infections at the height of the condition one sees almost exclusively polynuclears. In tuberculous inflammations lymphocytes predominate; while in pneumonia, polynuclears and epithelial cells are in greatest numbers. Diapedesis of Red Corpuscles—Finally, a certain number of red corpuscles escape from the capillaries by diapedesis. This is a purely passive process so far as the red corpuscles are concerned, being due to pressure of the blood. It is particularly marked when stasis and con- sequent intravascular thrombosis has occurred. In very intense in- flammation accidental hemorrhage per rhexin may add to the blood in an exudate. Réle and Fate of the Leukocytes —The most essential element in the defense against the injurious agents that cause inflammation is the emi- grated polymorphonuclear leukocyte. This cell possesses a marked capacity to swallow or ingest bacteria or other foreign bodies, which has given the process the name phagocytosis, and the cell exercising this function the name phagocyte. When bacteria (especially py ogenic micrococci) or small particles of insoluble material, such as carmin or carbon, are introduced into the tissues or into serous cavities, polymor- phonuclear leukocytes speedily gather about and incorporate the foreign bodies in their protoplasm. So far as bacteria are concerned, some preliminary action is exerted on them by the blood-serum of the fluid exudate (see below). This is demonstrated by the fact that the poly- morphonuclear cells will take up larger numbers of micrococci from a suspension in serum than from one in normal salt solution. The sub- stances which act to prepare the micro-organisms are termed opsonins (see p. 258). Possibly precipitins and agglutinins also aid in some measure. After their ingestion the micro-organisms are either digested within the phagocytic leukocyte and thus disappear, or the phagocyte with its contents enters lymphatic channels and reaches the regional lymphatic nodes. Thus the micro-organisms are disposed of and re- moved from the center of infection as speedily as possible. Insoluble foreign bodies and products of tissue destruction (fatty globules and 124 A TEXT-BOOK OF PATHOLOGY detritus) are also taken up by the phagocytic leukocytes and dissolved or removed to the neighboring lymphatic nodes. In this combat with the foreign invaders a certain number of the leukocytes perish and may be found in various stages of disintegration. Some of them are ingested by other polymorphonuclear leukocytes, but in the later stages of inflam- mation they are found enclosed in other phagocytic cells of large mono- nuclear type, which will be described presently. The various processes described bring about a removal of the micro- organisms or other causes of inflammation, and at the same time a steady diminution of the number of polymorphonuclear leukocytes at the point of inflammation. The lymphocytes now begin to be more con- spicuous in number. Their rdle, however, is less definitely determined. Some of them seem to undergo a swelling and transformation into the large mononuclear phagocytic cells that will be described below. It was formerly held that some of them become engaged in the process of reproduction of tissue, being first converted into formative or fibroblastic cells. This view is probably erroneous, the evidence being that neither the ordinary lymphocyte nor the variety known as plasma-cell has such a function. The eosinophile leukocytes may sometimes be abundant in inflam- matory exudates, and it has been suggested that they are active in throwing out bacteriolytic substances. Further proof of this assump- tion must be forthcoming. In all of these processes in which the emigrating leukocytes are concerned soluble substances and enzymes are essential. These will be referred to after the liquid exudation has been discussed. Large mononuclear phagocytic cells become conspicuous in the area of inflammation after the primary leukocytic phase begins to subside, and in certain inflammations they are so almost from the beginning. These cells are of variable size, always large, and sometimes of giant proportions. The rather large pale nucleus and the phagocytic prop- erty of the cells are their distinguishing characteristics. The general term “macrophages” may be used to designate them, though it indi- cates no special derivation. The origin, indeed, is still uncertain, but among the possible sources of derivation are the lymphocytes, the endothelium of lvmph-glands and channels, blood-vessel endothelium, and various wandering tissue-cells. It is not probable that the fixed tissue-cells of the locality give origin to them. The macrophages are specially concerned in taking up leukocytes and fragments of cellular destruction. Sometimes a number of polymorphonuclear phagocytes, with their own inclusions, all more or less degenerated, are found within a macrophage, and there may be, in addition, red corpuscles and débris of other cells. The complete digestion of these contents may occur in part in the area of inflammation, but some of the macrophages, like some of the polymorphonuclear phagocytes, perhaps find their way to regional lymphatic nodes; and similar cells primarily make their appearance in the lymphatic nodes when the polymorphonuclear phagocytes invade these structures. INFLAMMATION AND REGENERATION 125 Grant-cells, containing multiple nuclei, are found in certain forms of protracted or chronic inflammation. They will be described later. Exudation of Liquids—Coincidentally with leukocytic emigration there is exudation of more or less altered blood-plasma. The amount of liquid exudation and the character of the exudation vary with the nature and condition of the tissue affected and the character of the irritant. In loose cellular tissues and in inflammation of membranes lining cavities large quantities of liquid are poured out of the vessels, while the reverse is seen in denser parts. Some intense irritants occasion free exudation, while others, by their very intensity or peculiar charac- ters, at once destroy the tissues, and exudation is comparatively slight. The exudate is richer in albumin and more coagulable than dropsical fluid, which is a further indication that the blood-vessels are more per- meable in inflammation than in health or mere congestion. It is prob- able, moreover, that the capillary walls act in a secretory manner, as do the walls of the lymphatic channels. This would in some measure explain the difference between inflammatory exudate and dropsical liquids. The accumulation of exudate in the tissue may be so abundant that the term inflammatory edema is justified. In such cases, as in all inflammations to a less extent, the cause of the retention of liquid in the inflammatory area is in part a reduction of tissue tone or elasticity which prevents the movement of the fluid toward the efferent lymph-channels. Thrombosis of lymphatic vessels, induration of surrounding tissues, and edematous and cellular swelling of regional lymph-nodes are also causes for the retention of liquid exudate in an inflamed area. After its exudation the fluid may undergo coagulation by inter- action with fibrin ferment derived from disintegrated leukocytes, with formation of fibrin and consequent solidification of the inflamed area. When inflammations affect mucous membranes there is usually active stimulation of the epithelial cells and outpouring of mucus, which materially alters the exudate. The exudate plays an important réle in inflammation. Among its uses may be mentioned that it serves as a diluent of noxious bodies, that it brings from the blood substances that aid in destroying the irri- tants, and that it may carry similar substances derived from the leuko- cytes, either secretions or products of their degeneration. Occasionally it has the unfavorable action of carrying away and thus spreading throughout the system the causes (bacteria, for example) or products of the inflammation. In the case of fibrinous inflammation, the fibrin serves to strengthen the limiting wall by which an inflamed area is sur- rounded. The highly nutritious character of the liquid is doubtless of importance in the proliferative processes that are presently to be described. 3. Chemical Processes Involved in Inflammation—Many of the features of inflammation have been made clearer by recent studies of certain chemical relations of the cellular and fluid exudates. It has been found that the leukocytes carry in their substance an active proteolytic enzyme which acts best in an alkaline medium. This enzyme doubtless 126 A TEXT-BOOK OF PATHOLOGY operates to dissolve bacteria and other albuminous bodies ingested by the phagocytic leukocyte. When this enzyme 1s liberated by disintegration of emigrated leukocytes it is capable of attacking the tissues and soften- ing them or digesting them, but this result is prevented when sufficient fluid exudate is present, because the latter contains an anti-enzyme which destroys or in some manner neutralizes it. This is, perhaps, the same anti-enzyme which is present in normal blood-serum, and which is capable of restraining the action of trypsin. Should leukocytic exuda- tion become excessively abundant, owing, for example, to virulent highly chemotactic micro-organisms, or should the physical nature of the tis- sues prevent an adequate fluid exudate, the amount of leukocytic en- zyme liberated becomes disproportionate to the amount of anti-enzyme, and there results a proteolytic softening of the tissues and exudate with resulting pus formation. This disproportion of enzyme and anti- enzyme, therefore, determines the occurrence of suppurative instead of non-suppurative inflammation. In the later stages of inflammation, when the leukocytes have largely disappeared and the mononuclear phagocytes are in evidence, a differ- ent proteolytic enzyme is found. This has been studied especially in tuberculous tissues with abundant epithelioid cells. This enzyme acts best in an acid medium, and is probably active in the destruction of leukocytes and various cellular remnants ingested by the macrophages, from which it is derived. Opie has suggested the names leukoprotease and lymphoprotease for the enzymes derived from the leukocytes and mononuclear cells respectively. Other chemical processes besides those mentioned are involved in inflammation. The first effect of the action of inflammatory irritants, whether merely mechanical or micro-organismal, is cellular destruction, and consequent liberation of substances that are chemotactic and to some extent toxic. There follows the exudation of leukocytes and liquid. Chemical combination between fibrin ferment derived from disintegration of leukocytes or other cells and the liquid exudate causes fibrin for- mation, and thus some solidification of the inflammatory exudate. Later, this fibrin, together with the more or less degenerated cells in the area of inflammation, may be digested by the action of the leuko- protease before described, and perhaps by the action of similar if not identical enzymes derived from the blood-serum. Micro-organisms call forth special chemical defenses. As has been related, the micro-organisms are in large part ingested by phagocytic leukocytes and are in some way destroyed within these. It has been shown that substances called opsonins are important in preparing micro- organisms for this ingestion by phagocytes, and probably bactericidal substances derived from the blood-serum in the inflammatory exudate, as well as precipitins and agglutinins, are also important agents in the preparation for phagocytic destruction of micro-organisms. It has, indeed, been shown that living and virulent organisms may be taken up by phagocytes, but their preliminary destruction or devitalization seems to be the rule. Some of the micro-organisms, doubtless, are destroyed INFLAMMATION AND REGENERATION 127 and carried off into the lymphatic channels without the aid of phago- cytes. It is asserted by some observers that besides the enzymes of blood- and tissue-cells described above, there is in these cells a separate and extractable substance which can destroy bacteria. Its office in inflammation is not understood. 4. Proliferative Changes.—Sooner or later in an inflamed area, and especially at the periphery, there are evidences of cellular pro- liferation which occasions the ap- pearance in the tissue of round cells closely resembling lymphocytes or mononuclear leukocytes. They differ, however, in being somewhat larger, in having a larger and paler nucleus, which is round or oval, and in their frequently exhibiting evidences of karyokinesis. These cells are direct derivatives of the WSS fixed connective-tissue cells and of SES é SP cea NSN at endothelium lining lymph-spaces. eee The parent cells first undergo en- largement by swelling of their pro- toplasm, then mitosis of the nuclei and cell division follow. The new- formed round connective-tissue cells may in part become wandering cells and more or less phagocytic, but the greater number remain fixed and become elongated or polymorphous in shape, produce intercellular sub- stance, and thus assume a purely regenerative role. These are desig- nated fibroblastic cells. (See Re- generation.) At the stage under considera- tion the cellular elements of in- flamed tissue consist of emigrated leukocytes, now reduced to a small a aE RS S number, many lymphocytes, large J 28 Aout append the mononuclear leukocytes, and round coats of the appendix. connective-tissue cells. The ap- pearance is characteristic of the more advanced stages of acute in- flammation and of chronic infammation. It is termed rownd-cell infil- tration (Fig. 28). Virchow held proliferative changes to be the essential feature in inflammation, and believed that all round cells are concerned in this process; Cohnheim denied that proliferation is the important feature of inflammation, ahd ascribed to emigration the essential réle. Later, it was held that the proliferative changes are not, in reality, a part of om 128 A TEXT-BOOK OF PATHOLOGY inflammation, but rather regenerative and for the purpose of repairing the tissue injuries after inflammation (Fig. 29). | At the present time many regard as factors in inflammation both emigration and prolifera- tion, whether the latter in any individual case is due to direct stimula- tion of the cells, or is secondary to destructive changes, or is merely the result of increase of nutrition from the inflammatory congestion. It is conjectured by some that under chemotactic influences the cell contents of fixed cells are incited to movements terminating in karyo- kinesis, just as the whole cell is influenced in the case of movable cells. The proliferation of the fixed connective-tissue cells may be an early process, but does not usually occur until some time after the exudative changes have taken place. The new-formed cells have at first the characters above described, but later they become irregular and many of them spindle shaped (formative cells or fibroblasts). In chronic Fig. 29.—New blood-vessels and fibroblastic cells in a beginning adhesion of the pericardial ayers. inflammations, especially such as surround foreign bodies, giant-cells are found. These have distinct phagocytic functions. Giant-cells may be divided into: (a) Foreign body giant-cells with peripherally located nuclei and a homogeneous, somewhat degenerated center. They arise in degenerating tissue, probably by coalescence of multiplying endothelial or large plasma-cells. Some authors think they are due to direct nuclear division or nuclear division too rapid for the protoplasm to keep pace with it. (6) Myeloplaves are giant-cells with uniformly distributed nuclei and a homogeneous protoplasm such as are seen in the bone-marrow and tumors. (c) Parenchymatous giant- cells are found in tumors, in regenerating interstitial tissues, or in the parenchyma of organs. The nuclei may be irregularly distributed, but are commonly connected by narrow isthmuses of chromatin. They arise by rapid nuclear division. Granulation Tissue—When the proliferative changes are active, new blood-vessels, formed by multiplication and lateral outgrowth of INFLAMMATION AND REGENERATION 129 the endothelium of the pre-existing vessels, are a conspicuous feature. These, surrounded by the various forms of round cells above described, and sometimes giant-cells, constitute granulation tissue. (See also Repair of Wounds and Regeneration.) Such granulation tissue is especially conspicuous on the floor of ulcers, and exemplifies the regenerative proc- esses which follow immediately in the wake of the frank inflammatory reaction. Proliferative Changes in the Parenchymatous Cells —Swelling and, later, mitosis may occur in the early stages of inflammation, but are of slight extent. In certain chronic inflammations also, such as some forms of cirrhosis of the liver, proliferation of parenchymatous cells may be observed. In the latter instance the process is rather definitely of regenerative character. The changes in the earlier stages of inflamma- tion are more truly inflammatory, though the new-formed cells, unlike some of the proliferative connective-tissue cells, do not migrate or take on phagocytic action. 5. Degenerative Changes in the Tissues—The first attack of in- flammatory irritants is made upon cells of fixed tissues, that is, upon cells of the parenchyma of an organ, upon the connective-tissue cells, or upon the walls of blood-vessels. The emigration of leukocytes and their combat with the irritants follows. In the case of bacteria which contain within their substance positively chemotactic bodies, it would seem probable that there is an immediate activity of these bodies; but various considerations make it more probable that even in the case of bacteria the first effect is exercised upon fixed cells. In the case of mechanical irritants damage or complete destruction of cells is the first step toward inflammation. Weigert, Neumann, and others hold that the “primary effect” in inflammation is always such tissue injury, which, in turn, excites exudation and, later, proliferation. The demon- stration that tissue degenerations liberate positively chemotactic sub- stances explains how the phenomena of inflammation are brought about. The degenerative changes may be merely physiological (some form of altered functional activity), or there may be structural alterations, such as cloudy swelling, mucoid degeneration, liquefaction, fatty change, coagulation, or other forms of necrosis. The nature of the degeneration depends largely upon the severity of the irritation. Very powerful irritants cause necrosis at once, and not inflammation. It is the irri- tants which disorder, but do not entirely destroy, cells that are especially apt to excite inflammation. The cellular degenerations now under dis- cussion are entirely different in significance from the more conspicuous secondary cellular degenerations considered below. The primary degen- erations occasioned by the first attack of the irritant are often incon- spicuous and inferential rather than demonstrable. Secondary Cellular Degenerations——When inflammations attack tissues containing epithelia or other parenchymatous cells the latter often suffer secondary degenerative changes, cloudy swelling, fatty or mucoid degeneration, and total necrosis. These secondary cellular changes may serve to spread and intensify the original inflammation, 9 130 A TEXT-BOOK OF PATHOLOGY and are, moreover, especially harmful to the functional activity of the diseased organ or tissue. The cause of these degenerations may be the same toxic agent which initiated the whole process or, on the other hand, the pressure of exudates and the circulatory disturbances incident to the inflammation. ; Etiology.—Irritation by mechanical, chemical, thermal, or infec- tious agents causes inflammation when it is severe enough to dis- turb the vitality of the tissue and not sufficient to cause extensive necrosis at once. When the irritant is brought to bear upon the tissues directly, there is probably, first, cell degeneration, followed by vas- cular disturbances and emigration. Mlicro-organisms may act by first destroying the cells, or may liberate from their substance some poison (protein) which is irritant and chemotactic. Disturbances of circu- lation, innervation, or metabolism may so alter cellular processes as to occasion the liberation of irritating and chemotactic products. In the experience of surgeons bacteria stand out conspicuously as the almost invariable cause of “inflammation.” This term, however, is used in a clinical rather than a true pathological sense. The proc- esses concerned in the healing of uninfected wounds and in other cases of injury unaccompanied by infection are just as truly inflam- matory. It must be recognized that non-bacterial injuries to tissues liberate substances by cell destruction which are capable of producing the phenomena of inflammation. Among the causes of inflammation in this pathological sense must be included certain endogenous proc- esses, notably of circulation, innervation, and metabolism, which cause local cellular degeneration, followed by exudative and reparative phe- nomena. Special Forms of Inflammation.—Various classifications may be used in describing forms or types of inflammation. The most natural is that which follows the anatomical changes. Thus we may distinguish (1) exudative inflammation, or the form in which the fluid and cellular exudation from the blood-vessels is the predominating element in the pathological process; (2) parenchymatous or degenerative inflammation, or the form in which destruction of the parenchyma cells is the leading feature; and (3) productive inflammation, in which prolif- eration is the striking characteristic. The nature of the cause, as well as the resistance of the organism or of the affected part, determine the particular form in a given case. A number of subvarieties may be described, but it must always be remembered that inflammation is essentially the same in all cases. The three processes—exudation, degeneration, and _ proliferation—are present in greater or less degree in all forms, although in some cases one ° feature, in other cases another, may be most conspicuous. Types of Inflammation.—1. Edematous or serous inflamma- tion is characterized by a copious exudation of fluid with compara- tively little cellular matter, as in edema of the larynx, serous effusions in the serous sacs, etc. The local forms of edematous or serous inflam- mation are usually expressions of intensely irritant causes; the serous INFLAMMATION AND REGENERATION 131 inflammations of serous cavities, however, are not necessarily of this severe grade. Indeed, in many cases serous inflammation may be a mild, subacute or chronic, process, which may subside gradually, leaving the serous membranes slightly thickened or adherent. This adhesion is due to the fact that fibrin collects upon the serous surface during the acute stage, the fluid remaining free in the sac. The fluid is removed by absorption; the fibrin, by digestion. Lasting adhesions remain when proliferative changes are firmly established before the digestive processes can complete their work of removing the fibrin deposits. The fluid in inflammatory exudations differs from dropsical fluid in containing more albumin, leukocytes, and fibrin factors. 2. Fibrinous Inflammation—The plasmatic and cellular exudate may form a fibrinous membrane on free surfaces or a network within the tissues; this is termed ‘‘fibrinous inflammation” because the most conspicuous physical change is the excess of coagulum. In purely fibrinous inflammations of serous surfaces there is a whit- ish or yellowish-white deposit of variable thickness, which is more or less adherent to the underlying surface. When removed, there may be seen beneath it a pronounced injection of the blood-vessels and rough- ness and rawness of the surface. This is due to beginning granulations. (See Repair of Wounds.) Microscopically, the fibrinous deposit con- sists of an irregularly arranged mass of fibrillar, granular, or homo- geneous fibrin, with leukocytes and endothelial cells (more or less degenerated) enclosed in the deposit. The fibrin may be found in star- like formations made up of a more or less degenerated central leukocytic mass and radiating threads of fibrin extending from it in every direc- tion. This may be significant of the liberation of fibrin ferment from the degenerating cells and consequent formation of fibrin about this as a center. Some authorities believe that fibrinous inflammation can never occur independently of destruction of fixed cells. In other words, they doubt the possibilits of fibrin formation from purely exudative elements. Some experimenters have, however, described fibrinous inflammations of serous surfaces with an unbroken lining of endothelial cells under the fibrinous deposit, and have concluded that the fibrin is wholly exu- dative. Others regard the lining cells as cells of lymph-spaces, and not the original surface cells; and consequently conclude that cellular destruc- tion always plays a part in the fibrin formation. Fibrinous inflamma- tion in serous sacs is often associated with serous exudation, and the term serofibrinous is applied. In other cases (especially in peritoneal inflammations) the exudate is likely to become purulent—fbrinopurulent inflammation. Inflammations of the serous membranes are nearly always more or less fibrinous. 3. Pseudomembranous or diphtheritic inflammation differs from the last in having associated with the coagulation of the exudate decided coagulation necrosis of the cells of the part inflamed. The difference is one of degree rather than of kind, and is largely dependent upon the character of the tissue in which the inflammation occurs. Diph- 132 A TEXT-BOOK OF PATHOLOGY theritic inflammation occurs especially in the pharynx and larynx, where it occasions pseudomembranes (Fig. 30). This is most frequently due to the specific bacillus of the disease called diphtheria; but diphtheritic inflammation may result from a variety of severe irritants, such as other bacteria, superheated steam, and chemical agents. The diphtheritic membrane consists of a network of fibrin or of homogeneous or granu- lar fibrin masses enclosing degenerated epithelial cells and emigrated leukocytes. Sometimes it is quite superficial, involving only the surface layer of epithelium; at other times the whole depth of the mucous mem- brane is implicated. The former are sometimes called croupous and the latter diphtheritic false membranes. These terms, how- ever, are ill-defined and objec- tionable. The use of the terms fibrinous and pseudomembranous, omitting crowpous and diphthe- ritic as unnecessary, if for no other reason, is good practice. In any event it must be ob- served that the term “ diphthe- 5 ritic’’ as used in this place refers Fig. 30.—Pseudomembranous inflamma- to a type of fibrinous inflamma- tion of the uvula: a, a, masses of micrococet; tion rather than to a process a, a eee EER Oanie only to the diphtheria bacil- lus. This organism is the most frequent cause of such inflammation, but other agents, as before noted, occasion the same type of inflammatory lesion. 4, Suppurative inflammation is characterized by unusual abun- dance of emigrated leukocytes and by the tendency to liquefaction. Bacteria are most frequently the cause; but it has been shown experi- mentally that croton oil, calomel, turpentine, and other substances are capable of producing suppuration. Of the bacteria, the commonest are the so-called pyogenic staphylococci and streptococci; but numerous forms, not commonly pyogenic, may occasionally prove so. Such are the bacillus of typhoid fever, the gonococcus, the Bacillus coli, and others. The implantation of bacteria of suppuration at the point of disease may take place directly through wounds, or somewhat indirectly through the circulation, the micro-organisms having gained access to the system through small abrasions in the mucous membranes or skin. Some local injury may then serve to determine the suppurative inflammation at a given place. Recent studies ascribe to chemotaxis the important réle in the action of bacteria in inflammation and suppuration. Either the prod- ucts of the bacteria or substances derived from their own protoplasm (endogenous substances) exercise a powerful chemotactic influence, and thus occasion the massing of emigrated leukocytes (Fig. 31). The preponderance of cellular over liquid exudation and the consequent excess tt} INFLAMMATION AND REGENERATION 133 of leukoprotease over anti-enzyme prevent fibrin formation, or cause a solution of fibrin already formed and a liquefaction of degenerated tissue elements and cells. The sequence of events is as follows: bacteria directly implanted in the tissue or carried to the capillaries in the blood- stream first cause local cellular changes (degeneration or necrosis); then congestion and exudation of leukocytes and plasma occur around this focus; next more or less fibrin formation results from the exudation, and finally, after more and more leukocytic emigration, softening of the whole area completes the formation of pus. The essence of suppurative in- flammation is the excessive emigration of leukocytes, the softening of the tissues, and the failure of the fluid exudate to coagulate and form fibrin. The excessive leukocytic invasion is chargeable to inordinate chemotaxis due to the micro- « anos organismal or other causes of the inflammation or to their products. Pus consists of a liquid part, the liquor puris, a modified blood- plasma, which differs from ordi- nary plasma in being less coagu- lable and in containing notable quantities of albumose (peptone); and a corpuscular part, consisting chiefly of polymorphonuclear leu- kocytes more or less degenerated. The leukocytes are chiefly poly- morphonuclear and filled with neutrophilic granules. Neverthe- i See, less it is not possible to identify _ Fig. 31—Embolic abscess in the myocar- these pus-cells absolutely. They Si ioukooytes (Kang and Sehmosye ee often contain globules of glyco- gen and fat. Some proliferated connective-tissue cells or wandering cells may be added from the neighboring tissue, but these constitute but a minority of the whole number. The pus-cells present a distinctly granular protoplasm and fragmented nuclei. Abscess.—When circumscribed suppuration occurs in the substance of a tissue or organ, the lesion is called an abscess. This consists of a collection of pus which usually has a creamy yellow color, but may _ be variously altered by subsequent changes. The abscess grows by further liquefactive changes in the surrounding tissues because of the attraction of leukocytes with their ferments from the hyperemic vessels in the peripheral structures. Around the abscess the tissues present an indurated zone or wall in which the proliferative changes and fibrin formation described as part of inflammation are conspicuous features. There are numerous round cells, differing from emigrated leukocytes and often showing mitotic figures in the nuclei, and there are new blood-vessels and beginning organization. (See Regeneration.) Fibrin in the form of interlacing threads or in masses, the product of plasmatic exudate and of coagulation necrosis, adds to the embankment. In 134 A TEXT-BOOK OF PATHOLOGY slowly forming abscesses the surrounding wall of condensed tissue is often quite firm. This restraining wall was formerly erroneously regarded as a pus-producing membrane, and, therefore, called the pyogenic mem- brane. As a matter of fact, on the contrary, it represents the inflam- matory changes at the periphery of a suppurating area where the actively chemotactic effects of the pyogenic agent are sufficiently re- duced in activity that the liquefication characteristic of pus formation is minimized in favor of coagulation and formative processes. Abscesses tend to soften the surrounding tissues in the direction of least resistance, and thus to break on the surface, discharging their contents by sinuous tracts or sinuses. This discharge not only evacuates the pus, but reduces pressure and permits a renewed flow of fresh blood through the so-called pyogenic membrane, bringing with it the anti- enzymes and bacterial antibodies of the serum. Sometimes. the pus of an abscess becomes inspissated by absorption of the liquid part, and the residue undergoes various degenerative changes, such as mucous, fatty, or calcareous. At the same time the surrounding membrane may advance to complete organization, and thus encapsulates the abscess. Phlegmonous Inflammation.—Suppurative inflammation may have a less definitely circumscribed character than that seen in abscesses. It may take the form of a purulent infiltration in which the tissues are extensively infiltrated with emigrated leukocytes and more or less soft- ened by liquefactive processes, or by abundance of fluid exudate that does not coagulate. In other cases a nearer approach to the conditions seen in abscesses is observed when the purulent process spreads along planes of tissue or neighboring foci coalesce to form a diffuse suppura- tive condition. To this the terms phlegmon and phlegmonous inflam- mation are applied. Ulcer.—Suppurative inflammation with erosion of areas of the skin or mucous surfaces occasions ulcers. The floor of an ulcer has the same histological construction as the wall of an abscess. In it may be seen small red points or granulations, which consist of loops of capillary blood- vessels surrounded by round cells. (The histology of granulation. tissue is more minutely described under Regeneration.) The clinical features of ulcers vary widely. Sometimes rapid de- struction of the tissues causes large and spreading ulcers, called phage- denic. Others extend in one direction while healing in other parts, and are called serpiginous. The granulations may be too rapid in growth, forming red fungous masses (proud flesh) which fill up the ulcer. In other cases the ulcer remains dry and indolent, showing little tendency to heal. Some ulcers are not primarily of inflammatory origin. For example, the round or peptic ulcer of the stomach is formed by digestion, through the action of the gastric juice, of a part of the stomach which has be- come lowered in vitality or possibly necrotic. Similarly, the beginning change in the perforating ulcer of the foot in tabes and in decubitus (bed- sores and other forms of pressure ulceration) is not inflammatory, but, ~ INFLAMMATION AND REGENERATION 135 rather, necrotic. Secondarily, however, the necrotic tissues in these cases become active irritants and occasion true inflammatory ulceration. Suppurative inflammations of serous membranes lining closed sacs cause collections of pus in the cavities. The pus usually contains more or less fibrin, and there is a fibrinopurulent exudate on the serous surface. 7 Suppurative inflammation of the skin and subcutaneous tissues may be localized or diffuse. Of the localized type, there are various pustules, furuneles or boils, and carbuneles. , A furuncle is a suppurative and necrotic inflammation beginning in one of the sweat-glands, sebaceous glands, or hair-follicles. A car- buncle is a more extensive but similar process beginning in several of the glands or hair-follicles simultaneously, and causing considerable necrosis or gangrene of the skin and subcutaneous tissue. ; 5. Hemorrhagic Inflammation.—More or less diapedesis of red corpuscles generally occurs in inflammation; but sometimes the irritat- ing cause falls with such peculiar force on the blood-vessels or the general condition of the patient (cancer, tuberculosis, hemophilia, scurvy) is such that the exudate is unusually rich in red corpuscles. Certain micro-organisms (organisms of hemorrhagic septicemia) more or less regularly cause hemorrhagic inflammation. Intravascular throm- bosis and obstruction of capillaries with masses of micro-organisms play an important part in causing the hemorrhagic exudation. These are always serious inflammations, and are to be distinguished from ordinary inflammations in which accidental hemorrhage occurs. Hemorrhagic inflammation, in a pathological sense, may be an early stage of other forms, particularly of the fibrinous variety of the lungs. There is severe congestion, diapedesis, and transudation of plasma, which almost at once make fibrin. This hemorrhagic state is transient and is not to be compared with the continued outpouring of blood in the hemorrhagic infections. The cause of the last is bacterial toxins acting upon vessel walls, decreasing their resistance. The effect is greatest where they are naturally thin, in a condition of stasis or already affected by local or ‘general disease (syphilis). 6. Catarrhal Inflammation.—This term is used to designate inflam- mations of mucous membranes. The character of the inflammation de- pends to a large extent upon the individuality of the mucous membrane affected, differing greatly in the nose, throat, stomach, bowel, etc. There is always considerable congestion of the mucosa, and generally a great deal of serous exudation, which is discharged from the surface as a rule, but is to some extent retained in the tissue, causing edematous swelling. This is especially marked when the submucosa is considerably implicated. The epithelial cells of the surface suffer degeneration (mucous or fatty) and necrosis, and are discharged with the serous exudate; they may be recognized as goblet-cells (mucous), or as granu- lar cells (fatty), or as fragmented necrotic structures. Coincidently with the serous exudation, and in greater measure after the latter has become less marked, leukocytes escape from the blood-vessels or emi- 136 A TEXT-BOOK OF PATHOLOGY grate from their resting-places in the submucosa and make their way to the surface between the epithelial cells (Fig. 32). At this stage also - mucus becomes a more or less pronounced feature in the exudate. There is little fibrin formation in catarrhal inflammation, since the exudate moves toward the surface and escapes. The features of this form are the superficial exudation and desquamation after degeneration. When fibrin appears this catarrhal form becomes pseudomembranous. When in great abundance (as in some nasal catarrhs) the process may be a purulent or suppurative one; more frequently there is sufhi- cient mucus to require the term mucopurulent. Superficial erosions of the epithelium and hemorrhages are frequently met with. ; When catarrhal inflammations are chronic, there is usually consider- able productive inflammation, with consequent thickening, and later, when the new fibrous tissue contracts, there may be uniform thinning Fig. 32.—Acute bronchial catarrh, showing the escape of leukocytes from the submucous tissue between the epithelial lining cells (Thoma). of the mucosa or irregularly distributed areas of hyperplasia intermixed with areas of thinning. In some cases, however, progressive atrophy of the mucosa occurs without previous productive changes. This is espe- cially marked in the bowel, where, doubtless, constant distention plays an important part. When the contractions of the fibrous tissue are irregular, the mucosa between the fibrous areas may be elevated, espe- cially if there is at the same time proliferation of the surface epithelium and the glandular elements in the mucosa. In such cases a granular surface or polypoid elevations result. These are common in the stom- ach and the bowels. 7. Parenchymatous or Degenerative Inflammation.—This term may be applied to certain inflammations, such as forms of nephritis in which degeneration (cloudy, fatty, etc.) of the parenchyma cells is more con- spicuous than the exudative processes. The changes in the parenchyma INFLAMMATION AND REGENERATION 137 in such cases are often secondary to the inflammation; in other cases they are precedent. Strictly speaking, the parenchymatous changes are not essentially a part of the inflammation, but in those cases in which much degeneration of parenchymatous cells accompanies inflammations the term ‘“‘parenchymatous inflammation” is convenient and expressive. 8. Necrotic or gangrenous inflammations depend for their occur- rence upon the severity of the irritation or the state of the general system. 9. Productive Inflammation.—In this form the proliferative changes predominate over exudation and degeneration. This may be due to the nature of the etiological factor, to peculiarities in the tissue reac- tion, or local conditions affecting the removal of the irritant. In all cases in which inflammation for any of the above reasons becomes chronic the proliferative changes in the affected tissues become more or less predominating. Some degree of primary tissue destruction appears to be essential to the productive process, which, therefore, must be regarded as always reactive or regenerative. It is desirable to differentiate between (a) productive processes as the last stage of acute inflammation, (b) the newly formed connective tissue as the result of acute inflammation, and (c) the progressive pro- duction of fibrous tissue as the result of continued irritation. The lines between the three are not sharp. The repair of serous membrane in- flammation may be a simple thickening of the layer itself, but if granu- lations attach two or more areas together, we have adhesions which are in excess and probably not necessary for the healing of the original defect. Thus, again, in cicatrices we have nature’s expression of excessive pro- duction for repair. When the cause of the inflammation ceases the productive changes usually cease, unless the tissue already made acts as a foreign body and continues as a mechanical irritant. If it cease, we have a finished reparative process as the result of inflammation. Should the irritant continue its action, there is continued response as expressed in the infectious granulomata and chronic fibroses. The last are really chronic inflammations. Repair of Wounds.—Productive inflammation is well illustrated in the healing of wounds. If the lips of a clean, incised wound are drawn together at once and kept closely apposed, rapid healing occurs, which is called healing by immediate union. In these cases a microscopical ex- amination shows slight exudation from the surfaces of the wound and proliferated connective-tissue cells. The epithelial continuity is restored by proliferation of the old epithelial cells. Should apposition be less immediate or less accurate, the amount of exudation is greater. If the wounded surfaces are examined twenty-four hours after the injury, they are found red and swollen and soon they become glazed in appearance. The microscopical features here are the same as in the case of healing by immediate union, excepting the amount of exudation is greater. Healing proceeds in the same way, but more slowly, and is called healing by first intention. In neither case is there great congestion. If the wound be irritated by foreign bodies or kept exposed, there will be seen on the sur- 138 A TEXT-BOOK OF PATHOLOGY faces, after two or three days, small red elevations, known as granula- tions, which consist of loops of new-formed capillaries covered by emi- grated and new-formed round cells, and sometimes (after longer inter- vals of time) giant-cells (Fig. 33). The surface may be covered with considerable pus. The proliferated round cells gradually elongate and form new fibrous tissue (see Regeneration), which afterward contracts, forming cicatrices or scars. The epithelial continuity is re-established by multiplication of the old epithelial cells at the edges of the wound. This form of healing is called healing by second intention or healing by granulations. The formation of adhesions following inflammation of the serous surfaces occurs in much the same way as wounds heal. The primary exudation is largely fibrin- ous and causes agglutina- tion of neighboring sur- faces. Subsequently the proliferative connective-tis- sue cells, having become actively wandering cells, penetrate this fibrinous exu- HY ed A ae BEGGS Vp Se eae Wi I) Fig. 33.—Loops of blood- Fig. 34.—Adhesive pericarditis, showing fibrin vessels in granulation tissue deposit, with new blood-vessels extending upward (Thiersch). into it. date, as do new-formed blood-vessels (Fig. 34). Thus a union of vas- cular channels is effected between the adjacent inflamed surfaces, and organization follows. : Precisely similar changes occur in the tissues surrounding a foreign body, as a piece of sponge or around a portion of dead tissue. In these cases the exudative and proliferated cells tend to penetrate into the foreign mass, as occurs also in the organization of thrombi. There is in these cases a greater tendency to the formation of giant-cells than in ordinary granulations. If the foreign mass can be softened and absorbed, this gradually occurs, and later merely a scar will remain; if it cannot be absorbed, connective tissue eventually encloses or encapsulates it. . General Fibrosis.—A tendency to widespread productive inflam- mation is noted in certain individuals. This affects the blood-vessels especially (general arteriocapillary fibrosis, general angiosclerosis), and ; x : r INFLAMMATION AND REGENERATION 139 also the liver (cirrhosis of the liver), the kidneys (interstitial nephritis), and other organs (Fig. 35). Some form of degeneration or necrosis of the parenchymatous cells is doubtless the preliminary stage in all of these cases. First the endothelia or the muscle cells are affected in the cases of, blood-vessels; the hepatic cells in case of the liver; the epithelia of the tubules and glomeruli in case of the kidney, etc. The resulting fibrosis is, however, out of all proportion to any demonstrable change of parenchyma. In some cases it is evident that the fibrosis is merely a compensatory regeneration to replace degenerated parenchyma and that the process is not primarily inflammatory, although some of the his- tological changes are akin to inflammation. It is asserted that the cause of this degeneration of parenchyma cells may sometimes be repeated protein intoxication. (See Anaphylaxis.) i Fig. 35.—Chronic interstitial nephritis: great increase of connective tissue around the glomeruli, renal tubules, and blood-vessels; from a case of arteriocapillary fibrosis. Productive inflammation may effect other tissues than the fibrous connective tissues. Reference has already been made to epithelial proliferation in the healing of wounds. Similar epithelial processes of greater activity or duration may lead to warty growths of the skin or polypoid outgrowths on the mucous membranes. In pharyngeal ca- tarrhs considerable proliferation of the adenoid tissues is not unusual. ‘So also thickening of cartilages, bones, or the periosteum is not an un- usual result of inflammation of these structures. Pathological Physiology.—Inflammation represents increased and altered activity of tissues as a result of irritation; its primary object is the removal of the irritant. It is a pathological state per se, but considered from the point of view of its result (the removal or confinement of the irritant and the resulting tissue destruction) inflammation is essentially conservative and useful. In this process no new forces or activities are 140 A TEXT-BOOK OF PATHOLOGY involved: the phenomena are all observed in normal tissues, though to a less degree and in more orderly behavior. The liquid and cellular exudation has its prototype in the formation of lymph and in the normal wandering cells of the tissues; the increased vascularity is the result of increased demand, and is abnormal in degree only; the cellular destruc- tion is an accentuation of the ordinary death of cells resulting from wear and tear, though the form of the cell destruction is more violent and probably different; the postinflammatory regeneration is effected by karyokinetic multiplication of cells, as in normal tissues. In the destruction and removal of the irritant, phagocytosis (q. 2.) is important; it is accomplished by the leukocytes, by endothelial cells, the wandering connective-tissue cells, and giant-cells. Though a local process, inflammation often has widespread results. The causes of the inflammation gain access to the blood via the lymph- vessels and regional nodes before a wall of fibrin and leukocytes has been built up around the inflamed locality. When once the local tissue reac- tion has developed and the lymph-nodes are prepared, further dis- semination is halted. The primary invasion of the blood-stream may be advantageous in stimulating the antibodies of the body, which can then be carried to the focus of infection in the blood-plasma. The products of tissue change (primary cellular necrosis, degeneration of the emigrated leukocytes, softening of the tissue and coagulated exudate) entering the blood may occasion fever and other evidences of toxemia. The functional activity of a part the seat of inflammation is often increased, though somewhat altered. An inflamed gland may _pro- duce an excessive but abnormal secretion. In other cases functional activity is lessened; chronic inflammations almost certainly lessen functional power. Secondary parenchymatous changes, by altering organic action, may be highly injurious to the whole organism. Resolution after Inflammation.—In cases of trivial exudation the emigrated leukocytes may re-enter the blood-current through the lymphatics. The liquid exudate is similarly disposed of, while the pro- liferated connective-tissue cells remain in loco or become wandering cells. When the exudate is more abundant, the liquid elements may be re- moved in the same way, but the cells first undergo degenerative soft- ening and are reduced to the form of an emulsion, which is gradually absorbed. In purulent inflammations the pus may be discharged through external openings or into cavities of the body or may become inspissated. (See Purulent Inflammation.) The degenerated paren- chyma in inflammation may recover if the degeneration is not severe, or may be softened and removed. Phagocytic cells play a prominent part in the removal of broken-down cellular remains, pigment masses, and the like. The reparative changes in inflammation may be so slight as to lead to no discoverable lesion after the process is completed; but when large damage has been done there is apt to be a permanent scar or some other productive lesion. INFLAMMATION AND REGENERATION 141 Specific Inflammations or Infectious Granulomata.—Tubercu- losis.—Structure and Evolution of the Tubercle ——When the tubercle bacil- lus is received into any tissue or organ, its first effect, according to the investigations of Baumgarten, is to stimulate or irritate the fixed con- nective-tissue elements and endothelial cells and cause a proliferation of round cells, which resemble in their abundance of protoplasm the epi- thelial cells, and are, therefore, known as epithelioid cells. These have usually a single nucleus, of rather clear vesicular appearance, not deeply staining, and a relatively large amount of protoplasm. They may be produced in greater or less abundance, as the first reactive change of the tissues to the irritation of the tubercle bacilli. They represent primarily the cellular reaction on the part of the endothelial and fixed tissue cells, and later assume a fibroblastic character. Next there follows an infiltration with leukocytes from the surrounding blood- vessels or lymphoid collections common to all tissues, and the focus of irritation thus becomes surrounded with numerous small round cells, mostly mononuclear, with darkly staining nucleus and a small proto- plasmic body (Fig. 36). In more acutely formed lesions polymorpho- nuclear leukocytes are more abun- dant. This leukocytic infiltration represents the reaction of the vas- cular system to the tuberculous irri- tation or infection. The number of small round cells varies greatly in different instances. Sometimes, as in certain tubercles of lymphatic glands, they may be relatively few, while the epithelioid cells are present in abundance. In other cases the . Fig. 36.—Miliary tubercles in the liver, leukocytes are so quickly attracted showing abundant round cells in the per- and in such numbers that the tu- ipheral parts, epithelioid and giant-cells within. bercle seems composed of these cells alone, no epithelioid cells appearing in view. These tubercles are known as the “lymphoid.” In the later stages the round cells may disappear by degeneration, exposing the previously hidden epithelioid cells. At the stage of the tubercle when it is composed mainly of epithe- lioid and lymphoid cells it appears to the naked eye as a grayish, some- what translucent, pearly body. It is avascular, no tendency toward for- mation of new blood-vessels being apparent. In the further evolution of the lesion degenerative changes take place. These are hyaline de- generation, coagulation necrosis, fatty change, and eventually a trans- formation into cheesy material, the so-called caseous necrosis. These changes result from the specific action of the tubercle bacillus, though in part also from the avascular condition of the tissue. Avascu- larity alone, however, is not the cause of caseous necrosis. One of the 142 A TEXT-BOOK OF PATHOLOGY first changes noted is a granular change in the cell protoplasm which lessens the affinity of the cell protoplasm and of the nucleus for ordinary stains. There may be seen among the cells of the tubercle here and there individuals which show this beginning necrosis. These are usually grouped in the center of the tubercle, though at times also at different points. The outlines of these cells become less distinct and they are progressively less deeply stained, until with advanced necrosis the cell is broken down into particles or débris (Fig. 37). In the early stages of necrosis the epithelioid cells tend to form giant-cells either by coalescence of neighboring epithelioid cells or by division of the nucleus without division of the cell body. This is the Langhans giant-cell with its nuclei arranged about the periphery. The giant-cell is not char- acteristic of tuberculosis, as it may be found in many of the specific inflammations and also in foci of chronic irritation due to foreign bodies, Fig. 37.Large tubercle of the lung, showing cheesy necrosis in the center; the epithelioid and giant-cells around the cheesy center are more or less degenerated. as well as in tumors. In no condition, however, are they so abundant or so conspicuous as in tuberculosis. In some cases they may not be seen, in the tubercles at any stage. In other cases they are very numerous. The giant-cell falls an early victim to the advancing necrosis. Perhaps, in fact, the formation of the giant-cell is an evidence of beginning necro- sis and the division of nuclei without division of the cell is an evidence of the degenerative change. As necrosis of the cell advances the proto- plasm becomes granular and opaque, and eventually breaks down com- pletely. This change usually occurs at the opposite side of the cell from that in which the nuclei are gathered; or in cases in which the nuclei are near the periphery of the cell the necrotic changes begin in the center. Finally, a tubercle undergoes almost complete necrosis and is trans- formed into a cheesy mass, the surrounding connective tissue perhaps still showing proliferative changes which may eventually cause encap-~ INFLAMMATION AND REGENERATION 143 sulation of the tubercle. Calcification may ensue in the cheesy mass and thus lead to permanent arrest of activity in the nodule. The forezgn body tubercle, that due to pieces of silk, hairs, etc., usu- ally under the skin, differs from the specific kind in failing to undergo caseation, and in the prominence of connective-tissue new growth with some giant-cells. Tubercles arising from acid-fast organisms not the true tubercle bacillus are almost exactly like the specific tubercle and must be differentiated by bacteriological methods (Fig. 38). In the growth of tuberculosis the normal tissue elements of the part effected are pushed aside, or may be softened and destroyed by the disease processes. The connective-tissue fibers of the part, how- ever, are longest retained, and remain as a reticulum or tubercle stroma long after the other elements of the tissue have disappeared or been pushed aside. Fig. 38.—Foreign body tubercle in subcutaneous tissue, showing foreign body (wood) in the center and an atypical giant-cell. In soft tissues, such as the lungs, spread of tuberculous lesions is easy, and a diffuse inflammatory exudate may arise with only an occa- sional miliary tubercle. If several tubercles meet, their limiting walls may fuse and a conglomerate tubercle ensue. A conglomerate tubercle may also arise by the transportation of organisms from the center of an already formed focus, through its outer zone, by means of epithelioid cells or lymph-currents. Tubercles tend to coalesce, forming larger tubercular masses, and sometimes distinct tuberculous tumors are so produced. In the lower animals, particularly in cattle, such tuberculous tumors of the serous surfaces are not uncommon. They may simply stud the membranes, or they may hang as polypoid masses; the term “‘pearl disease”’ is applied to these cases (Fig: 39). Somewhat similar tuberculous tumors are met with in human tuberculosis, especially in the brain (Fig. 40). Asa rule, however, increasing areas of tuberculous disease of organs are only 144 A TEXT-BOOK OF PATHOLOGY Fig. 40.—Bovine tubercle of pearl disease. INFLAMMATION AND REGENERATION 145 partly composed of tubercles, the bulk of the diseased area presenting evidences of ordinary or peculiar inflammatory changes to which the presence of the tubercles has stimulated the tissues. Again, in general lymphatic tuberculosis, one may see diffuse epi- thelioid and round-cell increase without special arrangement, but dis- placing or distorting lymph-gland architecture (Fig. 41). N ¢) NS QA YAR Dor =k @ ewan) = HAD Fig. 41.—Tuberculous lymphatic gland: a, a, Lymphadenoid tissue; 5, b, large round cells (epithelioid); c, c, large spindle cells (Ziegler). This is the diffuse form and bears resemblance to Hodgkin’s disease. The tubercle bacilli in the earliest stages of the tubercle may be seen lying in the tissue and perhaps between the epithelioid cells first formed. With the evolution of the disease they are more and more abundant, are largely within the cells, and the giant-cells in particular may contain large numbers (Fig. 42). As the necrotic changes increase, the bacilli become less conspicuous, and eventually none may be visible. The existence of the bacilli, however, can- not be doubted, since injection of por- tions of such tubercles produces the disease in guinea-pigs. Syphilis.— Histology.—In syphilitic processes of all kinds and in all of the stages there is a tendency to accumulation of round cells and pro- liferation of connective-tissue cells, } : the processes being first manifest Hing 40(--t8iani-cell . containine around the smaller blood-vessels, but bacilli, (from _a photograph made by . Dr. William M. Gray). subsequently extending to other parts of the tissue. The walls of the blood-vessels themselves are frequently involved, and thickening of the inner or of all the coats may be ob- served. Complete destruction of the vascular channels is not rarely the consequence. Some authors locate the earliest changes in the small veins and lymphatics. In the subsequent course of the disease there is a tendency: to the formation of distinct cicatricial connective tissue, 10 146 A TEXT-BOOK OF PATHOLOGY giving rise to indurated scars, strictures, or diffuse sclerosis; and a less pronounced tendency to the occurrence of degenerations, mucoid and fatty, causing areas of degenerative softening. The Chancre.—The initial lesion first presents small areas of round- cell infiltration in the deeper layers of the skin or mucous membrane and, as a rule, in the neighborhood of the blood-vessels. The connective tissue at the same time undergoes proliferative change, and spindle- shaped cells or irregular embryonal connective-tissue cells are found mingled with the round lymphoid cells, or surrounding foci of the latter. Giant-cells are rarely present. Thickening of the blood-vessels may be observed in the later stages or from the very first. The tissue elements of the skin and of the subcutaneous tissue are usually sepa- rated by infiltrating liquid, and the latter may loosen the tissues of the surface and cause exfoliation of the superficial epidermis, and thus lead to the development of the primary vesicle or the erosion so commonly Fig. 43.—Gummatous meningo-encephalitis (Ziegler). seen. The induration of the chancre is probably the result of the sclero- sis of the vessels and the general connective-tissue hyperplasia, as well as in part due to the tense infiltration of serous liquid. It is characteristic of syphilis that the periarterial change occurs first, to be followed by the parenchymatous. This process may go on during all the secondary stage. Obliterating endarteritis is a type of change in syphilis that may occur at any stage. The Mucous Patch—The condyloma latum is very similar in struc- ture to the initial lesion. There is, first, round-cell infiltration of the deeper layers of the mucous membrane, with serous exudation and erosion of the surface. Later, there is a tendency to connective-tissue hyperplasia, though this is less marked than in the case of the chancre. The Tertiary Lesions—The gumma is composed in large part of round cells derived from the blood-vessels and proliferated connective- tissue cells, having a spindle shape or various irregular forms. Epi- INFLAMMATION AND REGENERATION 147 thelioid cells are less abundant, and giant-cells, though occurring at times, are usually few in number. Plasma-cells may be abundant in syphilitic lesions, and mast-cells occur in small numbers. The blood- vessels are nearly always more or less affected, the intima being thick- ened and the adventitia being also involved to a variable extent. Peri- arterial changes are very conspicuous. There is some new formation of blood-vessels, the lesion in this respect differing from the nodular lesion of tuberculosis (Fig. 43). Secondary changes are almost always seen in gummata of considerable dimensions, being more diffuse and irregular than in tuberculosis. Among these may be recognized a gradual necrotic transformation of the cells in the center of the lesion, with dis- tinct fatty degeneration or myxomatous change. The degenerated tissue may be infiltrated by leukocytes in a state of fair preservation. The differential diagnosis between a tubercle and a gumma is by no means easy, and there are cases in which it is well nigh impossible. Stains for the bacilli or the spirals should be used. In the diffuse tertiary lesions of syphilis the tissues of the affected organ are indurated, the connective tissue showing more or less pro- nounced hyperplasia. These processes cannot be certainly distinguished by their microscopical or general features from sclerosis due to other causes, unless there are associated miliary or massive gum- mata. Leprosy.—The nodule or leproma is a some- what indurated growth resembling the tubercle, but differing from it in its greater vascularity and in the absence of the tendency to cheesy necrosis. Microscopically, it is composed very largely of proliferated connective-tissue cells of different forms, plasma-cells, and endothelioid . Fig. 44.—Lepra bacilli > : 5 in a lepra cell (Karg and cells. New blood-vessels are discovered in more — §chmorl). or less abundance, the newly made tissue fol- lowing their course, and a tendency to complete organization with the formation of fibrous tissue may be seen in the character of the cells and the presence of fibrous intercellular material. Elastic fibers degenerate. The bacilli occur within the cells and possibly also between them, arranged either singly, in pairs, or in bundles like wrapped-up cigars. They are always found in groups and usually in large numbers. They multiply within the cells, the protoplasm of the latter at the same time undergoing a process of swelling and degeneration. This at first spares the nucleus, but finally the nucleus itself is broken down and the cell is thus converted into a sac containing degenerated protoplasm and abundant bacilli (Fig. 44). The term lepra cell has been given to these. The bacilli also occur in the connective-tissue cells, in fatty tissue, and very often in the adventitia of blood-vessels. Giant-cells may be formed, though they are not frequent and are rarely typical, being much vacuolated. In a pure lesion polymorphonuclear cells are usually absent. Secondary infections or injuries may lead to suppurative or 148 A TEXT-BOOK OF PATHOLOGY other forms of softening, and the final termination, either with or without previous softening, may be cicatrization. In some instances the lesions of the internal organs met with in supposedly leprous cases, notably those of the lungs, intestine, kidney, and serous surfaces, have been found avascular, with more tendency to necrosis and containing more giant-cells; in some of these cases inoculation has shown that the lesions contained tubercle bacilli. Whether these were strictly tubercles, or whether they were lepromata with secondary infection with tubercle bacilli, cannot be decided. They were certainly not pure leprosy, and more probably were purely tuberculous. The anesthetic areas and pigmented or light colored spots of the anes- thetic form present somewhat the same histological features as the leprous nodule, though in a diffuse form. Formerly these lesions were considered entirely the result of trophic changes. In these cases the more con- spicuous lesion is that of the nerves. These may show nodular thick- ening of the perineurium with inflammatory and degenerative changes of the nerve itself. The bacilli are present in these lesions, lying mostly within the cells of the perineurium. The effect is at first to irritate the nerve and later a compression and degeneration of the nerve-fibers. Changes in the spinal cord have occasionally been discovered. Glanders.—In acute glanders there is a local necrosis of the fixed tissues with a fibrillary or granular degeneration sprinkled with chroma- tin débris and surrounded by a zone of polynuclear leukocytes. The elastic fibers remain in good condition for some time, but finally swell and degenerate. In chronic glanders the nuclei are retained for some time and the cells present an epithelioid type. Considerable connective tissue is formed. Polynuclear cells, but not typical giant-cells, may be seen. Actinomycosis.—The first lesion of this infection is a simple sup- purative focus. This shortly assumes a tubercle arrangement by the appearance of giant- and epithelioid cells. It, however, soon proceeds to softening and central necrosis. The surrounding tissue is occupied by an active granulation process, losing all specific character except a tend- ency to fatty degeneration of the cells. The pus contains the sulphur granules of the organism, but the mycelium with its swollen end may be found penetrating the granulation tissue. The histological changes in other streptothrix infections—mycetoma, pulmonary streptothricosis—are essentially the same. Rhinoscleroma.—The histological lesions of this condition are usually quite specific, although some authors still express doubt of the etiological importance of the Bact. rhinoscleromatis. The specificity of this chronic granulation tissue lies in the large Mikulicz’s cells, a form of plasma- cell with hydropic or hyaline degeneration and a relatively small nucleus. They contain the bacilli. (See also page 303.) Saccharomycosis.—This condition gives rise to nodular necrotic masses surrounded by irregularly placed abundant giant-cells and active connective-tissue formation in the immediate neighborhood. The masses grow actively and may form considerable tumors. The budding INFLAMMATION AND REGENERATION 149 yeasts may be found in the pus and some are seen in the giant-cells. The more acute the process, the more necrotic. Chronic cases tend to show tumefactions. Sporothricosis——The peculiarities of this granulation tissue consist in a diffuse growth of epithelioid and plasma-cells and connective tissue. There is no nodular growth. The new growth and its supporting struc- ture do not tend to undergo degeneration. Mycosis fungoides may be a granuloma. Its exact nature is as yet uncertain. Its discussion is found under the Tumors, p. 199. REGENERATION Definition.—The term “regeneration” is applied to the formation of new cells or tissues to take the place of those destroyed. Regeneration may be physiological or pathological. The former is that which occurs in the normal life of the organism and by which the cellular wear and tear is counterbalanced. Pathological regeneration is the more mas- sive and often atypical reconstruction follows disease or injuries. Re- generation is one of the essential elements in inflammation, as has been shown in the preceding pages, but it is not always an inflammatory process. Etiology.—The cause or mechanism by which normal regeneration is brought about is more or less obscure. The cells have an inherent tendency to multiply, and this goes on to a certain point, at which the normal development is complete. This limit is probably maintained by some restraining influence, but the nature of this is unknown. In the skin and mucous membranes, where physiological regeneration is most active, new cells are constantly produced and the older cast off. In what manner the balance is so maintained that production and de- struction keep their equal pace is as yet matter only for speculation. The idea of action and reaction occurs naturally to the mind, and it seems probable that the reproductive processes are dependent in some way upon the loss of substance. In some cases the normal restraining influence seems to be deficient and giant growth results. In all forms of normal or physiological regeneration the reconstructed cells are exactly like the pre-existing cells, and the status of the tissue is unaffected. In highly specialized cells, such as those of the nervous system, regenera- tion seems to be intracellular—that is, the cells are constantly rejuven- ated by supplies of nutriment rather than by reproduction in toto. It may be said in general that the lower the type of cell in specialization, the greater its power of self-propagation by cell division. -The reverse is likewise true. A cell will also reproduce better when young and in its normal position than otherwise. In pathological regeneration there seems to be abnormal stimulation of the reproduction of cells as well as a reduced restraint. It is not improbable that various toxic substances have the power of stimulating the formative process, though this has not been actually demonstrated. In all cases in which degeneration is due to mechanical, thermal, or 150 _ A TEXT-BOOK OF PATHOLOGY toxic causes there is, first, destruction of cells, then regeneration. In such cases the relief from the accustomed pressure may serve as a with- drawal of restraint, but at the same time there is doubtless augmented formative energy. In other words, nature repairs defects in excess. . The stimulus may be the same agency as that which caused the primary cell destruction, or it may be due to the influence of formative irritants derived from the dying and dead cells. The demonstration that micro- organisms are able to produce substances having a strong attractive or repellant influence upon leukocytes gives some warrant to the belief that similar substances are at work in the regenerative changes that accompany bacterial diseases. In the case of tissue destruction due to other causes similar products possibly play a part. It seems fair to assume from the work of Loeb and Miescher and others that certain conditions involving oversupply of protein and some alterations in chemical reaction in functionating tissues may be sufficierit cause for proliferation. If this be true of relatively normal tissues, somewhat similar conditions may play a part in the proliferative changes occur- ring in pathological states. Pathological Anatomy.—In the normal regeneration of cells the process is one of gradual cell multiplication without marked changes of any sort. Pathological regeneration may be equally simple, but more often there are complicated changes in the pre-existing tissues and new formation of blood-vessels may precede or accompany the regeneration. The vascular regeneration is a necessary preliminary, having the pur- pose of supplying abundant nutriment to the tissues undergoing pro- liferation. Cell multiplication occurs in two ways, the direct and the indirect. The former method is one of simple cleavage, by which the cell is divided into two or more parts. This mode of division is unusual. Amitosis or direct cell division is a retrograde process in every in- stance. In some cases it is simply a fragmentation of the nucleus owing to altered conditions in the cell and probably not in any sense an at- tempt at cell division. When numerous fragments are formed, and some growth of the nucleus attends the process, giant-cells may result because the protoplasm does not divide. Evidences of degeneration of the protoplasm are apt to be met with in such cells. Of these, vacu- _ olization, granular or hyaline change, fatty degeneration, and even cal- cification may occur. The common method is called, indirect segmentation, karyokinesis, or karyomitosis. In this method complicated changes begin in the nucleus and finally lead to division of the cell into two or, rarely, into several parts. It is unnecessary to refer to the histological stages in detail, but in a general way we may describe the process as follows: (1) The nucleus of the cell enlarges and the chromatin fibers become thicker and less closely woven than normally; (2) U-shaped loops of chromatin fibers arrange themselves around a central clear space or polar field to form a mother wreath; (3) these loops then undergo longitudinal cleav- age and the separated parts move one to one pole and the other to the INFLAMMATION AND REGENERATION 151 opposite pole of the cell, forming daughter stars, which eventually become coarse and then fine skeins of new nuclei; (4) the protoplasm of the cell finally divides and the process becomes complete. Regeneration of Epithelium.—In its simplest form, as, for instance, after a very slight injury to the cornea, regeneration occurs by a direct replacement of the injured cells by multiplication of the cells of the same kind at the point of injury. The intact cells become some- what swollen, then undergo ordinary cell division, and new cells are formed. In the reconstruction of surface epithelium involving to some extent the underlying tissues, as in lesions of the mucous membranes or skin, the surface epithelium undergoes the same kind of multiplication as that just described, and the mass of new-formed cells dips down some- what into the space caused by the injury. In the deeper tissue new formation of connective tissue takes place in the manner already described under the head Healing of Wounds, and to be presently discussed more fully. In the subsequent stages the redundancy of epithelium caused by the dipping down of the mass of new cells into the injured area is reduced by condensation and gradual disappearance of some of the cells, so that eventually the epiderm or the layer of epi- thelium on the mucous surfaces does not differ from that in the surround- ing parts. When large areas of epithelium have been destroyed the replacement of the epithelial covering occurs by gradual increase of the cells. at the periphery of the denuded area, until in time the whole surface becomes covered. When skin-grafting is practised by the surgeon, a similar growth of the epithelial cells starts from each of the grafts placed upon the denuded surface. The repair of defects in endothelial sur- faces follows the same general laws as lately shown by Carrel. In lymph-vessels the endothelium may regenerate or may possibly be in- volved in connective-tissue formation. Regeneration of Fibrous Connective Tissue.—In all cases of exten- sive injury the connective tissues take an active part in regeneration, and in the case of highly specialized tissues new-formed connective tissue takes the place of the specialized tissue, which itself is less capable of regeneration. There is almost always an excess of cellular reproduc- tion and consequently an enlargement of the part affected by the in- jury. Subsequently the cells contract, and thus the bulk-of the new tissue approximates that destroyed. The new tissue must, of necessity, be more firm, as a larger number of cells are condensed in the space previously occupied by a less number. The important processes in regeneration of the connective tissues are: swelling and multiplication of the connective-tissue cells, migra- tion of the new cells into the area of injury, and the formation of new 1 Abnormal Cell Division.—-There are certain disorders of cell multiplication that , may be here described. Karyokinesis, instead of being a regular process of division of the nucleus into two daughter nuclei, may proceed irregularly. Sometimes the process is asymmetric, t. e., does not lead to equal division; in other cases it is multipolar, several instead of two daughter nuclei resulting. Other less definite irregularities are some- times observed, and some have held that cell division may occur by a process of mixed karyokinesis and amitosis. It is important to recognize that some of the forms of nuclear degeneration (karyorrhexis, hyperchromatosis) may be mistaken for normal or abnormal karyokinesis. Pathological karyokinesis is most frequently seen in malignant tumors. 152 A TEXT-BOOK OF PATHOLOGY blood-vessels. The old connective-tissue cells increase in size and then undergo division by mitosis of the nuclei. As a result, new cells of rounded outline and with rather pale nuclei result. These may remain at the point of their formation or may actively migrate, like leukocytes, toward the center of injury. Subsequently they tend to undergo a change of form, becoming elongated and spindle-shaped or irregular in outline (Fig. 45). It is these cells, and not the polymorphonuclear leukocytes, which are active in the final restoration of the tissues, and the terms “formative cells” and “fibroblasts” are, therefore, appropriate. It is believed by most observers that endothelium can go over into con- nective tissue. It seems certain that this membrane has something to do with the organization of a thrombus. With continued irritation the cells change from a flat plate to almost a cubic form. When the new cells have been formed, increase of intercellular substance takes place. The fibrils may be derived from the cells themselves by separation of filamentous prolongations growing out from the pointed extremities of the spindle cells, or they may result from a cleavage of a homogeneous intercellular substance in which the cells are at first embedded. This Fig. 46.—Formation of new blood-vessels, (Ziegler). as seen in the tail of a tadpole (Arnold). intercellular substance doubtless is a product or a secretion of the cell. In either case the fibrils are essentially a result of cellular activity. In the later stages of connective-tissue regeneration the fibrils contract, and the tissue thus becomes more compact, especially when the amount of intercellular substance is excessive. Collagen and fibroglia fibrils are reproduced and at some places also elastic fibers. The cells at the same time decrease in size and some are so compressed as to be almost ob- literated. It is characteristic of new-formed connective tissue, how- ever, that up to the latest stages the tissue is more cellular than normal tissue. According to Marchand three forms of round or lymphoid cells are also represented in connective-tissue regeneration: one the small lymph- cell, and two called leukocytoid cells. One of the two is somewhat larger than the small lymph-cell, possessing a relatively palely stain- ing nucleus, and considerable slightly granular or vacuolated protoplasm. This is the polyblast of Maximow and it may come from the blood- INFLAMMATION AND REGENERATION 153 stream or the tissue cells. The third variety is the plasma-cell, which has been described on p. 122. Giant-cells of the foreign body or proliferative type are common in regeneration, and they act as phagocytes to remove substances which are not dissolved. New formation of blood-vessels is an important factor in regenera- tion of connective tissue when the extent of injury has been consider- able. Repair of very trifling injuries, such as an incised wound followed by a close apposition of the injured surfaces, does not involve any new formation of blood-vessels, though the pre-existing vessels become some- what hyperemic. When the injury is more extensive, vascularization is a necessary step in the repair. The new vessels result from extensions from the pre-existing vessels (Fig. 46). The endothelium of the cap- illaries becomes swollen and here and there processes are sent outward. These may unite with similar processes from adjacent capillaries or from the same one at a point somewhat distant, and central vac- uolization may convert the loop into a primitive channel which event- ually becomes a fully formed capillary by multiplication of the endo- thelial nuclei and formation of definite endothelial cells. Sometimes the new vessel is formed by parallel outgrowths from adjacent endothelial cells of the parent capillary, leaving a space between the new-formed cellular extensions. Such new vessels occur around the site of injury and project in the form of loops into the area of injury itself, being sur- rounded by the new-formed connective-tissue cells above described. Usually the area of injury is first filled with a blood-clot or coagulated exudate derived from the injured tissues. This forms a matrix in which the new-formed connective-tissue cells migrate and the capillary loops project. The clot or coagulated exudate is subsequently absorbed as the process of cellular replacement advances. The young connective tissue thus formed later contracts and the small blood-vessels are largely reduced by compression, so that the appearance of the tissue may become that of a quite avascular structure. In regeneration of connective tissues, elastic fibers are not observed in the earlier stages. Subsequently they are formed more or less abun- dantly. Regeneration of cartilage and bone takes its origin from the peri- chondrium in the former case and from the periosteum or marrow in the latter. The process begins as a proliferation of chondroblasts or osteo- blasts respectively, which have the power to lay down a matrix which attracts chondromucin or bone-salts, as the case may be. The adult bone and cartilage cells have not the power to regenerate. In both instances embryonal connective tissue, such as that which occurs in regeneration of fibrous connective tissues, is first formed. Later, in the case of cartilage, areas of homogeneous intercellular substance appear, and thus cartilaginous substance is developed. Very commonly, how- ever, regeneration of fractures of cartilages is mainly fibrous, and there may be little if any true cartilage. Regeneration of bone in the case of fractures proceeds in much the same fashion, an abundance of cellular 154 A TEXT-BOOK OF PATHOLOGY tissue first appearing around the fractured ends of the bone, within the marrow cavity at the point of fracture, and between the broken ends of the bone. In this embryonal connective tissue branching and radiat- ing columns of rudimentary osseous tissue appear as a sort: of network in which complete ossification occurs at subsequent stages. Later, much or all of the embryonal tissue around the fracture and within the marrow cavity is absorbed, and the repair of the fracture is made com- plete by thorough ossification of the part between the ends of the bone. When bone-salt deposit is deficient, cartilaginous union results. _ Regeneration of adipose tissue begins with a formation of fat-free cellular tissue. Later the cells become infiltrated with fat. Regeneration of Muscle Tissue.—Striated muscle after injury or excision is capable of some regeneration by, as a rule, amitotic multi- plication of the muscle nuclei. The area of destruction if considerable is first occupied by regenerating connective tissue into which irregular protoplasmic projections from the ends of the divided muscle-fibers extend. Subsequently these elongate and form new muscle-fibers, but they are apt to be narrow and more or less irregularly arranged, so that the regeneration is rarely complete. Regeneration of smooth muscle by mitosis takes place in some cases (uterus), but connective-tissue formation occurs instead when the areas of destruction are large. Regeneration of Glandular Organs.—In epithelial glandular organs, such as the liver, kidney, mammary or salivary glands, considerable new fcrmation of epithelial cells may take place. It has been taught that gland cells are replaced by tissue cells below the basement-mem- brane. This is undoubtedly incorrect. Glandular cells are recruited from glandular cells or occasionally from the cells of small ducts. In the liver there may be active proliferation of cells and formation of new biliary ducts. This is seen in experimental injuries and also in asso- ciation with some forms of cirrhosis. In the case of the kidney, re- generation may occur in the cells of the straight tubules, while in the mammary glands, salivary glands, and the smaller glands of mucous membranes new formation of acini and ducts proceeds from the smaller excretory ducts of the affected glands. In this way an atypical glandular structure may result. This will be discussed under Adenoma. Skin glands and their outlets are regenerated if the fundal parts have not been destroyed by the surface damage. Regeneration of Nervous Tissue.—Nerve-fibers are capable of con- siderable regeneration, which proceeds from the sheath of Schwann. The medullary substance is differentiated within the sheath, and the new axis-cylinder is an outgrowth from the existing axis-cylinder or the nerve-cell. Regeneration of the nervous fibers in the brain and cord takes place to but a slight extent. Injuries here are usually repaired by the formation of new connective tissue and regenerating glia. The large multipolar nerve-cells seem to be capable of intra- cellular repair after partial injuries, but complete regeneration is never accomplished. It is possible, however, that they may be capable of INFLAMMATION AND REGENERATION 155 limited proliferation, as such cells occur in certain tumors. Neuroglia proliferates, but less readily than fibrous tissue. , Pathological Physiology.—Regeneration is the more or less effective effort of nature to replace injured or excised tissue. The restoration is complete in proportion as the tissues lack in higher organization and differentiation. ‘The younger the individual, the more complete the regeneration of his tissues; and the lower the type of tissue, the more complete will be its restoration. In glandular organs, though some pro- liferation of epithelial structures occurs, the new-formed glandular ele- ments are but little capable of glandular activity. Newly developed nervous tissue is least capable of restoring the original function. METAPLASIA This is the term applied to the transformation of one form of tis- sue into another without the intervention of ‘a stage of regeneration by cellular multiplication. It is exemplified under normal conditions by the transformation of cartilage into bone. It occurs with great fre- quency under pathological conditions, and may be here described as a col- lateral or inferior specialization in a tissue of the same original character, for mutations of tissue types donot occur. Thus, cartilaginous tissue may have an abnormal deposit of bony salts, fibrous tissue may become bony or fatty or myxomatous, but these never become glandular structures, nor does gland tissue ever become nervous tissue. The process may be a purely interstitial affair and the cells suffer secondary changes. In other cases of metaplasia the cells may be primarily altered, as when ordinary connective tissue is changed to fatty tissue. a The process, except where accommodative or defensive, is not easily understood. Cells of the embryo destined to be epithelium are differ- entiated so that they may assume their adult normal form and func- tion; by metaplasia one type of epithelium may adopt the form and at times the function of another. The same facts are true for connect- ive-tissue cells. Fully differentiated fibrous tissue may become calca- reous without the agency of osteoblasts from bones, connective-tissue cells acting the réle of the latter. Although it has been claimed that fat cells are descended from the mucoid embryonal cells, some observers seem to think that connective- tissue cells not descendants of these fetal elements may become fat cells by metaplasia. The metaplasia of epithelial cells, as, for example, a change from cylin- drical to squamous cells on the surface of mucous membranes, has been doubted by some authorities. They assume that such apparent trans- formations are due either to ingrowths of the new order of cells from sur- rounding areas or by enlargements of islets of mucosa covered with such cells. Experiments, as those of Fiitterer, however, indicate that metaplasia does occur. In this process not only the old epithelia are altered by the changed conditions, but the new-formed epithelia, under the altered conditions of environment, develop into the new order of cells rather than into the parent form. 156 A TEXT-BOOK OF PATHOLOGY The causes of metaplasia are, naturally, changes in physical relations, including alterations of pressure and irritation, carrying with them some differentiation of function and changes in nutrition. Injury or chronic irritation may bring these factors into play. Examples of metaplasia are to be found in the change of the bladder epithelium to a horny layer from a calculus; the flattening of the bronchial epithelium in bronchiectasis; the appearance of calcareous deposits in chronically in- flamed connective tissues, especially around joints. Changes similar to these repeatedly occur in neoplasms. The term retrograde change (Ribbert) has been applied to an altera- tion of cells in which under pathological conditions a lower order of differ- entiation is assumed, but in which the new order of cells do not acquire specific characteristics of a different sort. Thus, cylindrical epithelia of glandular tubules may be changed to cuboid cells lacking the original functional characters and not possessed of a new function such as would be the case with squamous cells. Similarly, in the atrophy of striped muscle, non-striated, narrow fibers with abundance of nuclei give evi- dence of a retrograde change toward embryonal conditions. CHAPTER VI PROGRESSIVE TISSUE CHANGES Tuts term may be used to designate pathological conditions in which there is a tendency to the formation of new and functionally active tissue. HYPERTROPHY Definition.—The term “hypertrophy” is applied to a pathological condition in which a certain part increases beyond the normal size, without marked alterations from the normal structure. The term hypertrophy is frequently used loosely to designate enlargements of various kinds in which but one tissue of an organ is increased, or in which there is deposit of abnormal exudate. Such instances are not, strictly speaking, cases of hypertrophy. Etiology.—The causes of hypertrophy are quite numerous. In some cases there is a distinct increase of functional demand brought about in some way or other, as in the hypertrophy of the muscles of athletes; in the hypertrophy of a kidney after disease or removal of its fellow; or in the hypertrophy of a limb after injury to the opposite limb. The direct increased demand for work occasions the hypertrophy. Sometimes there appears to be a special tendency to hypertrophy, as is evidenced by the occurrence of congenital or hereditary giant growth. Most of these, however, are instances of peculiar and abnormal develop- ment, rather than of hypertrophy, the latter being a condition developed pathologically in parts previously well formed. Disturbances of the nervous system and internal secretions may play a part in the develop- ment of some hypertrophies, but these influences are obscure. Con- tinued congestion undoubtedly stimulates tissue growth, but this ele- ment is the means whereby hypertrophy is effected rather than the original cause. In the compensatory or vicarious functional hypertrophies we must assume that two factors are at work—first, the stimuli resulting from increased demand, and second, the adaptive mechanism of the part ad- justing reaction to stimulation. It may be further assumed that there is always a margin of safety between the work thrown upon a part and the limit of work possible. During continued activity the cell enlarges, for which it must have increased nutrition and some period of rest. Should the stimulation continue without rest and increased nutrition, degeneration may occur. Some of the hypertrophies, such as that of the breast during preg- nancy and lactation, are undoubtedly due to internal secretions, prob- ably of ferment nature. The hormones belong to this class. We may also 157 158 A TEXT-BOOK OF PATHOLOGY include in a similar group the growth taken on by some organs, like hair- follicles and mamme, at puberty. Derangements of the ductless glands may lead to hypertrophies, among which the most conspicuous example is acromegaly from disease of the hypophysis. Pathological Anatomy.—Parts the seat of genuine hypertrophy are uniformly increased in size. This is well seen in the condition termed “giant growth,” or “gigantism,” in which the bony framework and other tissues may be uniformly affected, the individual growing to excessive size. Sometimes local giant growth of the skeleton and external tissues is observed, as in the case of one member or a single finger. This has often been found in corresponding members on the two sides of the body. In certain-cases termed “hypertrophy,” in which this designation is more or less justified, lack of uniformity in the increase of the organ or part affected causes irregular increase in size. Hyper- trophy and hyperplasia may be used by the economy to make up loss of bulk the result of disease. Histologically, hypertrophy may be simple or true hypertrophy, and numerical (hyperplasia). In the former there is increase in the size of the individual cells; in the latter the cells increase in number, though the individuals are not excessive in size, and, indeed, often smaller than the normal cells. In the hypertrophy of the uterus during pregnancy and of the heart muscle in compensatory enlargement, simple hyper- trophy predominates. Hyperplasia is very commonly a factor in hy- pertrophy of any kind, but may be so strictly limited to one tissue of an organ, notably the connective tissue, that the term “hypertrophy” is in no way applicable. Between these extremes there are all grades of cases, in many of which it is difficult to determine whether the desig- nation hypertrophy is applicable or not. In some cases the clinical designation hypertrophic enlargement is used, though the condition is strictly one of hyperplasia of the connective tissue, with a tendency rather to atrophy than hypertrophy of the proper substance of the organ. Instances of this are hypertrophic cirrhosis of the liver, some cases of hypertrophy of the heart muscle, etc. Pathological Physiology.—Hypertrophy results from an increased demand upon an organ or member, and leads to increased functional capacity. Thus, in the case of a diseased kidney, the opposite kidney may be capable of compensating for the deficiency; in the case of laborers the enlarged muscles may meet every demand made upon them. There are occasional instances of more or less genuine hypertrophy resulting from diseased conditions, in which the excessive functional capacity causes marked disturbances, as, for example, in case of enlargement of the thyroid gland. TUMORS Synonyms.—New Growth, Neoplasm, Pseudoplasm. Definition.—In its broadest etymological significance the term “tu- mor” designates an abnormal swelling in any part of the body. This definition, however, is not applicable to tumors in the ordinary sense. PROGRESSIVE TISSUE CHANGES 159 Inflammatory growths and collections, such as abscesses, hyperplastic deposits, and the like, are excluded. Pathologists, however, have al- ways found it difficult to construct an accurate definition for tumors or to draw sharp lines of separation between them and the inflammatory or infectious swellings that occur in various diseased conditions. An attempt to establish an ultimate boundary-line is evidenced by the term autonomous new growths, applied by Thoma. This name is used to designate the supposed spontaneous origin of new growths and their independence of ordinary causes, such as are recognized in the production of inflammatory outgrowths and the like. It cannot be said, however, that tumors are causeless, and in the discussion of the etiology we shall have occasion to refer to certain definite factors known to aid in their production. It is true, however, that the growth of tumors is practi- cally always out of proportion to the amount of local irritation or tothe severity of other factors that may be conceived as playing some part in the etiology; and in the great majority of cases the causes, whatever they may be, are obscure or unknown. A negative definition perhaps best suits for the delimitation of this term “tumor.’’ Thus, we may ex- clude from the category of tumors all swellings in which some sufficient ' cause is discoverable, and include the apparently causeless growths among the true tumors. A further characteristic of tumors is their independence. Excepting the blood-supply, there seems to be no de- pendence on the organism in which they occur, and they contribute noth- ing to the continuance of its life and its integrity. Nor is there any apparent restraint to the indefinite growth of the tumor comparable to that which keeps normal growth and even pathological processes of other kinds within certain bounds. Despite all of these characteristics, there are cases in which pathol- ogists cannot determine positively whether certain growths are to be classified as tumors or some other conditions. Etiology.—A great number of theories have been suggested to explain the causation of tumors. Among the older writers there was a disposition to attribute the occurrence of tumors to a constitutional dyscrasia, or a diseased state of the fluids of the body, a cause as obscure as the tumor. Recently a number of more elaborate theories have been con- structed that resemble this older one, in ascribing the growths to some form of disturbance of vital activity and of cell proliferation, without explaining the cause of such disturbance. For example, we may refer to the theory that tumors result from a retrograde change in vital proper- ties of certain cells, so that they tend toward the original characteristics of the germ-cells and multiply in a purposeless and indeterminate man- ner. This theory was based upon the fact that asymmetrical karyo- mitosis is frequently observed in tumors. It was assumed that in this unequal division of the cells the peculiar, differentiating qualities of the cell are cast off with the smaller portion, causing the larger, in the course of several generations, to become anaplastic or retrograded. It has, however, been shown that the same sort of asymmetrical mitosis also 160 A TEXT-BOOK OF PATHOLOGY occurs in non-tumorous conditions; and an additional factor that must enter into the theory, the nature of the stimulus that causes the ana-- plastic cells to proliferate actively, is wholly unexplained. According to the late observations by Slye upon mouse tumors, neo- plasms represent “a manner of growth” transmissible to progeny in a Mendelian sense, the faulty character being dominant or recessive, so that by proper mating it can be made to remain a dominant inherited feature or to die out. Another theory would explain the occurrence of new growths some- what upon the basis of infection, assuming, instead of an exogenous infection with micro-organisms, an endogenous infection. This was sug- gested by the discovery of leukocytes within the tumor-cells. The author of this theory explains that in consequence of some thermic, chemical, or other irritation certain cells may become, so to speak, infec- tious, assuming the réle of a sperm-cell and stimulating the adjacent cells to abnormal multiplication. Such theories, however, are entirely speculative, and leave the etiology as little settled as before. Virchow strongly advocated the theory of external irritation, and was able to cite numerous examples of tumors that had arisen in consequence of more or less definite traumatism. Thus, in cases of carcinoma of the breast, in the epithelioma occurring on the lips in pipe-smokers, and in the epithelioma of chimney-sweeps, there is at times a definite history of unusual irritation, and the relation of cause and effect seems easily traceable. It must be admitted, however, that there is some further underlying cause which renders one individual liable to tumor growth, while another is not thus predisposed, and though it is probable that some tumors owe their origin to irritation as the exciting cause, all cases cannot be thus explained. Cohnheim advanced the interesting theory that defective develop- ment lies at the basis of tumor formation. According to his theory, there are frequently small errors of development leading to the inclusion or misplacement of portions of the original blastoderm in the midst of tis- sues derived from a different layer of the embryo. These inclusions, or embryonic rests, are independent of the function of the part in which they lie, and are assumed to be liable to subsequent sprouting, with the con- sequent formation of tumors. There is evidence that this theory con- tains a certain measure of truth, and some tumors, as, for example, certain ovarian growths, tumors of the parotid region, and others, seem to originate in this way. The theory, however, is not by any means universally applicable, and it leaves unexplained the final proliferation of the embryonal rests that had previously remained dormant. The assumption, however, that such rests would quite readily take on active growth as a result of various simple irritations, or when the vitality of the part was stimulated, is less forced than that which would attribute such proliferative activity to cells in their normal relation to surrounding tissues. Similar conditions may be brought about by disease or injury of various tissues. This is the essence of Ribbert’s “disturbance of tissue tension” theory. If certain cells or parts of the tissue are displaced PROGRESSIVE TISSUE CHANGES 161 from their normal relations to the surrounding structures, the same conditions are established as by the embryonal displacement of por- tions of tissue. Not improbably this sometimes occurs either as a result of accident or of disease, and subsequently the displaced por- tions may prove the starting-point of tumor growth. Some authorities have insisted upon this as a frequent occurrence and as explanatory of - many tumors. Experiments have shown that certain types of epi- thelium (epidermis), both adult and fetal, as well as certain fetal con- nective tissues (cartilage), may be experimentally removed from their normal position and implanted in another part of the same animal and still retain their potentiality of growth. Such transplanted fetal tissues do not continue to reproduce the fetal stage, but tend to reproduce the ultimate stage of the transplanted tissue. Furthermore, in no case has there been found any infiltration of surrounding tissues by trans- planted tissue, nor any tendency to metastasis. All of this shows that there is something additional in the development of tumors beyond the mere dissociation of structures from the surrounding tissues. Hansemann’s theory, based upon the defective mitotic figures seen in tumors, assumes that this want of normality causes the cell function to be disturbed and it fails to undergo its proper specialization (ana- plasia), so that it becomes parasitic; it is itself the parasite. Oertel also assumes the primary change to be in the nucleus, there being a removal of part of the chromatin. Adami’s modification of Hauser’s theory assumes that the cell which started the growth lost its specialization, but not its power of reproduction. The relief of other demands upon it permitted the cell to apply all its energy to the dominant remaining function and acquire the habit of growth. This theory is at least con- sistent with our knowledge that a tumor serves no useful purpose to the body. Yet it must not be forgotten that as far as we know tumor-cells are nourished and have a cell chemistry closely like normal cells. They are at least dependent upon the same pabulum, although the end-prod- ucts may be different. Recently an infectious character has been ascribed to malignant and benign growths, and there is no doubt that in certain respects tumors resemble infectious processes of definitely ascertained kinds. Their effect upon the general health and their tendency to metastasis are very significant facts. Furthermore, the discovery that various patho- logical processes characterized by nodule formations resembling tumors in gross appearance are, in reality, infectious growths lends color to the suspicion. The resemblance of such growths to tumors is, however, merely superficial. As far as metastasis is concerned, tumors differ notably from infections, for, in the former, parts of the growth itself are conveyed to some place at a distance from the starting-point, there to proliferate and occasion a metastatic nodule; while in the case of infections the micro-organisms alone are carried to the secondary situa- tion, where they occasion changes in the local cells similar to those found in the original focus. Numerous investigations have been made to determine a possible uu 162 A TEXT-BOOK OF PATHOLOGY connection of bacteria with tumors. These have proved beyond doubt that no bacterium of ordinary sort has any such relation. The possi- bility of ultramicroscopical organisms and even of such as, through ex- cessive parasitic character, could not live except within cell hosts, has been considered. Secondary and accidental invasions of bacteria into tumors may occur, and sometimes confusion has been occasioned by this circum- stance. Various investigators since Hanau have found it possible to trans- plant certain tumors from man to animals or from one animal to an- other. This has sometimes been interpreted as an evidence of the infectiousness of tumors, though with doubtful propriety, since the trans- plantation of the tissue from one site to another, like the phenomenon of metastasis, proves only the proliferative tendency of the cells of the growth and not, of necessity, any infectious origin. The transplantation of part of the tumor from one animal to another or from one part to another in the same animal does not differ from the transference of por- tions of the tumor to distant places in ordinary metastasis. Fig. 47.—Inclusions in cancer cells: a and 6, early stages of “parasitic” bodies; c, late stages, showing division by segmentation; d, cancer cell containing leukocytes (Ruffer). The experiments of Rous have shown that certain tumors of the fowl may be transmitted to a susceptible bird by suspensions of cells or a filtrate from this suspension which has been passed through a porce- lain filter that would hold back bacteria. He assumes that for these tumors there is a contagiwm vivum. These viruses only produce the kind of tumor from which they come. In carcinomata and other epithelial new growths, as well as in sarcomata, certain forms of supposed animal parasites have been de- scribed. In 1889 Thoma found in the protoplasm and nuclei of car- cinoma cells bodies which he regarded as coccidia; and about the same time Malassez and Albarran found similar structures in the cells of an epithelioma of the maxilla. Darrier found bodies of the same kind in Paget’s disease of the nipple, and many subsequent investigators have described similar formations. Among these supposed protozoan or-- ganisms some are intranuclear, some extranuclear, and some wholly ex- tracellular. All sorts of bodies have been described in tumors, and to them their ' ' respective observers have clung tenaciously as the cause of neoplasms. They have no relation to the causation of tumors, for they have not withstood close investigation. Figures 47 and 48 show some of those de- PROGRESSIVE TISSUE CHANGES 163 scribed. Members of many protozoal and arthropodal genera have been described, even to as large a parasite as Sarcoptes. Many of the smaller ones were doubtless artefacts or can be ascribed to the Chlamy- dozoa of Prowaczek. The larger ones were artefacts or accidental in- clusions. We may still learn that such protozoan or metazoan organ- isms have something to do with neoplasms, judging from Fibiger’s results, but we are not vet prepared to accept any of them as the cause. Recently blastomycetes have been thought of some etiological im- portance in the causation of carcinoma, but a careful r review of the literature is convincing that the evidence does not suffice to establish any such connection. Blastomy- cetes do not constantly occur in malignant tumors, and when present are not in such numbers or in such relation to the tissue as to establish an etiological significance. The lesions definitely known to be due to blastomycetes are of entirely different character from those of tumor growths, being strictly exuda- tive and inflammatory, with proliferation of endothe- lium and connective tissue, such as occurs in infec- tious inflammations. The proliferation of epiderm seen in the blastomycetic skin lesions of man is en- tirely secondary to the chronic inflammation of the underlying tissues. The latest important communi- 3 cation upon the relation of organized bodies and _ Fig. 48—Rhopa- new growth comes from J. Fibiger, who found nem- leeeunalys {Korot atodes in a papillomatous glandular gastric cancer _ neff) of wild rats. These nematodes are carried by the roach, Periplaneta americana, and can be transferred to unaffected rats, when, if the animal be susceptible (not all are), a carcinoma of constant type will be produced. Predisposing Conditions.—Whatever may eventually prove to be the immediate cause of tumors, it is certain that predisposing causes are often of great importance. The occurrence of certain forms of tumors in persons of advanced age and in persons whose vitality has been re- duced by disease gives evidence that a constitutional predisposition is sometimes requisite for the formation of the new growth. The nature of this vital defect has sometimes been speculated upon, and retrograde vital metamorphosis of the cells or other like changes have been assumed to occur. These theories, however, are purely speculative. In some cases there is evidence of a family predisposition, and heredity was formerly regarded as of great importance. While this element cannot be entirely denied, it has certainly been overestimated. The Structure of Tumors.—In their histological structure tumors do not differ absolutely from healthy tissues. In all cases they conform more or less with the structure of some one or more tissues. The cells composing tumors invariably represent some one or several types of normal cells, though they may differ in being larger or smaller than the normal cells, or in being of embryonal or undeveloped character. 164 A TEXT-BOOK OF PATHOLOGY It may be said that the tissue from which a tumor arises is revert- ing to a state from which perfect differentiation into the normal adult structures cannot or does not occur. They have not lost all differ- entiation or specialization, since glandular tissue will always produce tumors with a glandular basis, but what is lost keeps the tissues near the parent or embryonal cell type. Not infrequently asymmetrical and otherwise abnormal mitosis of the cells is observed. Some reference to the varieties of such mitoses will be found in the section on Cellular Necrosis (p. 104). It is important to note that such mitoses are not confined to tumors, but occasionally occur in inflammatory and infectious cellular proliferations. In the arrangement of their cells tumors differ greatly from normal tissues, and they may be described as being atypical proliferations as far as their organic or tissue arrangement is concerned. The orderly dis- position of cells and stroma or intercellular substance seen in the normal tissues and organs is wanting, particularly in the tumors in which organic arrangement is simulated. There may be in some cases entirely typical glandular acini, but the relation of these to each other and the absence of regularly disposed excretory ducts render the tissue, as a whole, atypical. In the histological examination of tumors it is customary to find scattered through the stroma and between the tumor cells various forms of leukocytes, especially the polymorphonuclear forms and lympho- cytes. The imperfect development of the walls of blood-vessels of tumors permits of ready emigration of leukocytes, and there is, there- fore, in practically every tumor a certain amount of leukocytic infil- tration. Sometimes leukocytes are found in enormous numbers; and when a tumor undergoes inflammatory change, massive accumulations and abscess formations may be met with. Plasma-cells, which are prob- ably altered lymphocytes, are sometimes conspicuous, and mast-cells (basophilic granular cells of doubtful significance) are sometimes found in benign as well as in malignant tumors. They are frequently abundant near the edges of the growth. Eosinophilic leukocytes are occasionally quite numerous. The leukocytes are often found within the tumor cells in the form of inclusions. These, doubtless, have been mistaken for parasites in some instances. The blood-vessels of tumors have comparatively fragile and poorly ° developed walls. In the malignant growths or rapidly developing tumors of any sort the vessels are mere spaces between the tumor cells, with little attempt at the development of firm walls. Tumors do not appear to have special nerves. Lymph-vessels are variable. In some they are well developed, having been included and modified from pre-existing ones; in others they are entirely lacking. Regenerative changes are constantly met with in tumors. In this way the connective-tissue framework of the growth is formed just as such tissue is normally produced, and in this process elastic as well as ordinary connective tissue may be formed. In rapidly growing malig- nant tumor the framework of the tumor is, for the greatest part, derived PROGRESSIVE TISSUE CHANGES 165 from the pre-existing connective tissue of the affected part, and only in very small measure from regeneration of connective tissue. The structure of tumors is always closely related to that of the tissue from which it springs, a primary tumor invariably growing in a part in which there is tissue of the type simulated by the tumor, and it is from this tissue, doubtless, that the tumor takes its origin. A con- nective-tissue growth invariably springs from a part in which connective tissue of some form has pre-existed, and epithelial growths, from a part in which there has been epithelium. Transformation of one variety of tissue into another variety, with the production of a hetero- logous tumor, does not occur. This statement, though applicable also to secondary tumors, is sometimes difficult of demonstration from the fact that the secondary growths take origin from cells transported to the seat of the metastatic growth, though not normally found in the part in which the secondary tumors have arisen. The occasional dis- covery of a primary tumor in a locality in which the form of tissue composing the tumor does not occur may be explained upon the assump- tion (based on some actual demonstrations) that embryonic rests had been deposited at the seat of the tumor by faulty development. The Shape of Tumors.—This depends to a large extent upon their manner of growth, their situation, and the influence of surround- ing parts. We may distinguish, first of all, between circumscribed and infiltrating, growths. The former may be of various shapes, but are dis- tinguished by their sharp delimitation and often by the existence of a distinct capsule; the latter are indeterminate, and the extent to which they involve the healthy tissues cannot be accurately determined. Cir- cumscribed tumors usually grow centrally or in an expansive manner, the new cells being produced in the interior and gradually pushing the older parts outward toward the surrounding tissues. The infiltrating growths are eccentric in development, and may result from a gradual extension of parts of the periphery of the original growth, or by the development of secondary nodules in the neighborhood which become confluent with the original mass. Of the circumscribed growths, we may distinguish small nodules of spherical or ovoid form buried in the substance of the tissue or projecting from some surface as more or less hemispherical elevations. These may be large or small, and the terms miliary, tubercular, nodular, and the like are employed to designate the individual grades. When a tumor projects from the surface in such a manner that the projecting part is larger than the part between the projection and the surface of the body or the organ involved, the term fungiform or fungoid tumor may be applied, while in the cases in which the new growth is attached by a more or less narrow pedicle the name polyp or polypoid tumor is applicable. Wart-like growths are known as verrucose or papillary tumors, and those in which a distinct cauli- flower form is developed are called dendritic. The Number of Tumors.—Primary tumors are usually solitary at their onset, though examples of multiple primary growths, such as carcinoma involving both breasts simultaneously, or simultaneous 166 A TEXT-BOOK OF PATHOLOGY appearance of carcinomata or sarcomata in different parts of the mucous membrane or elsewhere, may be observed. In these cases it is often likely that there was a single tumor at the very onset, with secondary growths originating before the primary growth had reached any con- siderable magnitude. Primary benign tumors are usually solitary, but sometimes may be found in considerable number, and there may be enormous numbers scattered in various parts of the body. Thus, in cases of multiple enchondromata or multiple fibromata the number may, from the first, be very great. Secondary tumors are usually multiple. In most cases the number of nodules found postmortem or during life is considerable, and some- times they are so numerous that large portions of the body may be literally studded with new growths. This is seen very well in the secondary sarcomatous or carcinomatous nodules involving the peri- toneum and the other serous surfaces, in which cases the degree of involvement is equalled only by that seen in miliary tuberculosis. The rate of growth of tumors is extremely variable. Those in or consisting of dense tissue tend to grow slowly, while those of more cellular nature in looser parts grow more rapidly. There may be periods of entire cessation of growth. No rule can be laid down for any group of new growths. Instances of multiple primary tumors of different kinds are on record. For example, carcinoma and sarcoma may occur in the same individual as can epithelioma and adenoma. Pathological Physiology.—In most cases tumors take no part in the functional life of the part in which they occur or of the individual. What influence they may bear to the general metabolism is as yet prac- tically unknown. Cases, however, are recorded in which large lipo- matous or other tumors have been found to suffer practically no change, while the individual in whom they occurred was undergoing progressive emaciation from starvation. That there is a certain amount of function, however, in some cases is shown by the fact that biliary pigment is detected in the cells in certain carcinomatous tumors of the liver, or abortive milk formation in cancers of the breast. It may be that the want of proper organic arrangement, and particularly the lack of excretory ducts, accounts for the lack of function; but, whatever the cause, it is certain that, as a rule, the functional activity is practically nil, or at all events perverted. The occurrence of large quantities of glycogen in certain tumors is perhaps of interest as indicating an attempt at functional activity, but is more probably significant only of active proliferation. With very few exceptions it may be said that tumors are entirely parasitic, living at the expense of the organism and contributing nothing to its development or nutrition. Certain tumors disturb the general health. This result may be due to secondary degenerative or inflammatory changes dependent upon lack of nutrition or upon irritation and bacterial infection. The progressive cachexia of carcinoma is still unexplained, though in some cases hemorrhage and interference with organic function play a part. PROGRESSIVE TISSUE CHANGES 167 The chemical constitution of tumors and the relation this bears to the body in general and to the changes in body fluids are subjects that have had very important advances in the past few years. They have led to better understanding of the place of a tumor in the body, if not to its etiology. As has been said, the chemistry of tumors is closely like that of the tissue from which they spring. This is also true of metas- tases. There has been no isolation from tumors of substances that are peculiar to them in general or to any particular variety. Because of their high cell content some tumors contain much nucleoprotein, but this will vary as the parent tissue varies. The digestion products of these proteins are abundant because autolysis is active within tumors. Glycogen also accumulates in tumors because of lowered cellular ac- tivity. It is, of course, in highest amount in tumors, the original tissues of which naturally store it. Enzymes of the parent cells are retained in neoplasms. The inorganic elements are present in the proportion of the proteins that they help to form, and not specifically otherwise. Enzymes are said to be more abundant in tumors than in normal tissues, and the extensive autolysis of new growths certainly bears this out. Some observers assert that the ferments are different or peculiar to tumors, but this is not proved. Tryptic action is very prominent; so much so, indeed, that carcinoma patients develop a high antitryptic power in the blood. Many tumors have the power of continuing the natural internal secretions of the parent tissue. Thus, thyroid and adrenal tumors and their metastases may produce colloid and epinephrin respectively. It may be that the cachexia of cancer patients is due to a constant dissemination of the products of autolysis. Some of the products of tumor growth and extracts of the new tissue have hemolytic properties, but the exact relation of this power to anemia and cachexia is not understood. Metabolism is essentially the same as in wasting disease in general, there being an excessive excretion of pro- tein degradation products and mineral salts except the chlorids. Tumors fail to set up any constant immune bodies that protect the system against them. The normal blood has a low anticancer-cell power and blood-serum of cancer patients has a lower value. Immunity tests, such as complement fixation and precipitation, are sometimes present, but too variable to permit any conclusions as to their value for diagnosis or relation to etiology. Tumors may be classified as benign or malignant. The former do not affect the general health of the patient in any notable degree, and are dangerous mainly by reason of the pressure they may exert on vital structures or the secondary changes (hemorrhages, softening, suppuration) to which they are liable. Malignant tumors generally disturb the general health from the first, and, in addition, tend to recur after removal and spread to other parts of the body (by direct invasion or by metastasis through the circulation or lymphatic channels). Metastasis, or the transplantation of a tumor from one part of the 168 A TEXT-BOOK OF PATHOLOGY body to another, may occur in several’'ways. The growth may invade surrounding lymphatic or venous channels, and extend in a linear manner sometimes to considerable distances. Thus, a growth of the neck may extend in the jugular vein and vena cava as far as the right heart. More commonly, single tumor cells or small numbers are carried as emboli along the lymphatic or venous channels to some new location, where a secondary growth results. Some tumor cells, especially of the connective-tissue type, are said to be capable of independent ameboid movement; this would favor penetration into capillaries. A third method is that in which parts of the tumor are spread over free surfaces, such as the peritoneum or pleura, and thus occasion new foci. Sometimes, though rarely, this happens on mucous surfaces also. Occasionally tumors that are ordinarily benign recur after removal or cause metastasis. The former circumstance is not infrequent in the case of nasal polypi and keloids of the skin; the latter in the case of adenomata of the thyroid gland, chondromata, leiomyomata, hemangio- mata, and occasionally some others. The manner of growth (central proliferation) doubtless accounts for the infrequency of metastasis of benign tumors. Tumors have been known to disappear spontaneously. This is rare in human beings, but is commoner in animals suffering from either spontaneous or experimental tumors. The cause isnot known. Tumor cells are susceptible to mechanical influences when directly applied. They are more susceptible to x-rays and direct sunlight than normal cells. These agents destroy the vital ferments, but not the autolytic ones. Pressure upon and injury to a tumor seems to favor metastasis. It has been suggested that injury favors metastasis because endo- thelial proliferation succeeding a trauma supplies a stroma in which a tumor cell may conveniently lodge and multiply. The terms primary and secondary tumors refer to the original and the metastatic growths respectively. Classification of Tumors.—No very satisfactory classification is possible at the present time, and it is unlikely that any will be constructed until more definite knowledge regarding the etiology is obtained. The older classifications were based upon the shape, the physical properties, or the nature (whether destructive or harmless) of various forms. Virchow offered a classification based on the histol- ogy of the new growths (histogenetic classification). According to this classification, fibroma, osteoma, chondroma, lymphoma, and sarcoma are included under the heading of connective-tissue tumors or tumors reproducing more or less accurately connective tissues. The different forms of tumors comprising the group are distinguished by their resem- blance to one or another of the forms of connective tissue. Among the epithelial growths are papilloma, adenoma, and carcinoma, and in the same group should be placed glioma, which, though it superficially re- sembles connective-tissue tumors and arises from the neuroglia, a tissue resembling connective tissue in function, is really an epithelial growth, as the neuroglia is an ectodermal derivative. Among the tumors re- PROGRESSIVE TISSUE CHANGES 169 producing muscle tissue are the two forms of myomata—the leiomyoma and rhabdomyoma. This classification is eminently satisfactory in some cases, but fails in the case of mixed tumors containing a variety of tissues and in which the primary or essential constituent is not always obvious. Thus, in papillomata it is sometimes difficult to determine whether the growth was originally epithelial or originally of connective-tissue type. Recently it has been suggested (Mallory) that a more careful study of the histological differentiation of the cells and intercellular substance may serve as a basis of classification of tumors. Three forms of fibrils, called neuroglia, myoglia, and fibroglia fibrils, have been distinguished, and have respectively been found in gliomata of various types, in leio- myomata, and in connective-tissue growths, including fibromata, fibro- sarcomata, and spindle-celled sarcomata. The fibrils differ sufficiently to form the basis for the recognition of the character of the cells from which they originate, irrespective of the rate of growth or physical properties of the tumor. , Other pathologists have grouped tumors according to the embryo- logical derivation of the tissues from which the new growths originate or of the tissue composing the tumor. It is perhaps wisest to attempt no classification of any kind, and in the following sections we have ar- ranged the various tumors according to their histological characters, fol- lowing in a general way the adult tissue types without attempting to establish groups. CONNECTIVE-TISSUE TUMORS FIBROMA Definition.—A fibroma is a tumor composed of connective-tissue cells and fibers resembling those seen in fibrillar tissue. It is derived from mesodermal cells which have the power to produce various kinds of fibrils. It varies from a slowly growing tumor composed of fibers almost exclusively up to rapidly growing new growths composed of cells, with little tendency to proceed to fiber formation. In the lat- ter case it approaches a sarcomatous nature. Etiology.—The causes of fibroma are as obscure as those of tumors in general. There are many facts, however, which point to the importance of irritation or injury as exciting causes. Among these may be mentioned the development of peculiar forms (keloids) in scar tissue and the resemblance of these tumors to spontaneous fibromata, and the appearance of fibrous nodules in the skin at points of friction or definite pressure or in places irritated by discharges. It is impossible to draw sharp lines between fibromata and hyper- plasias of connective tissue following irritation. In the skin and super- ficial tissues there occur hyperplastic connective-tissue processes, con- stituting elephantiasis, which in some cases are distinctly the result of irritation, and in other cases seem purely spontaneous. The ele- phantiasis of tropical countries, often due to occlusion of the lymphatic 170 A TEXT-BOOK OF PATHOLOGY channels by filarie, and the thickening of the skin and adjacent con- nective tissue of the legs around old ulcerations or eczematous areas, are instances in which distinct irritation is the cause. On the other hand, congenital elephantoid conditions of the skin are seemingly spontaneous or causeless, and some of the cases in later life have the same char- acteristic. The diffuse hyperplasias of the viscera, though often dis- tinctly inflammatory, may appear without adequate discoverable cause, and, according to the view of some authorities, are to be looked upon -as diffuse fibrosis or fibromatosis, rather than as inflammatory condi- tions. In ordinary cases of sclerosis of the organs the connective-tissue growth is entirely diffuse, but thickenings may occur in certain situa- tions, and the resemblance to tumor formation is then much more striking. This is sometimes the case in the liver, but particularly in the kidneys. In the breast there are cases in which no dividing line can be drawn between chronic interstitial mastitis and fibroma. The microscopical appearances are practically identical. A distinction, if Fig. 49.—Hard fibroma (Warren). ~ STS BV Lee DY, x Mt SS SE et eS See * WSS} ‘» Ne ko Ne NY & as eS Y ~ wt ie x by ie Sh SF sy a ei oe S SNe Wena MG aN 7 V) he fy J, x % iH N. Hs a) », ! edd! Ns 1a es Iw ™~ ww ‘i Wwe ae x » A &Y Ned NY Z 4) = at hii Za 4, Sif SSAWARY, SUNG qa — Wess Eo ~ (sm A We 4 OR (LESS Fig. 50.—Soft fibroma of the subcutaneous tissue. any can be made, is based upon the nodular character and spontaneous origin in the one and the opposite conditions in the other. Appearance.—The naked-eye appearance of fibromata is usually quite characteristic. The tumor may be hard (Fig. 49) or soft (Fig. 50), according as it resembles dense or loose connective tissue in struc- ture and according to the amount of edematous liquid or associated myxomatous degeneration of the intercellular substance. The growth is more or less rounded and usually enclosed in a distinct capsule. In the substance of organs it is spherical or tuberous, and when near the surface projects more or less. When it springs from a mucous or serous membrane or from the skin the weight of the tumor may gradually lead to a polypoid formation. Some of the fibromata of the skin are arbores- cent or dendritic in form, and keloids are frequently irregular or star- like in outline. The rounded and encapsulated tumors may be lobu- lated, though more frequently they. occur in a uniform mass. Seats.—The points of origin from which fibroid tumors arise are PROGRESSIVE TISSUE CHANGES 171 very numerous, though they always spring from pre-existing connect- ive tissue. Among some of the more common localities may be men- tioned the subcutaneous connective tissue, the submucous tissue, the periosteum of bones, tendons and tendon-sheaths, and the fibrous covering of nerves. Of the internal organs, the uterus, the ovaries, the kidneys, and heart muscle are the most important. Less frequently fibromata are found in the serous membranes of the chest and abdo- men or of the central nervous system. The fibroids of the skin, uterus, the nerves (see Neuroma), and the mucous membrane of the nose are the most important. The mammary gland presents several interesting forms of inflam- matory or fibromatous new growth. First, there is a diffuse form of interstitial mastitis in which the entire breast becomes indurated; this is distinctly infammatory. In other cases nodular or lobular areas of thickening occur, and in these the evidences of inflammatory action are sometimes obscure or wholly wanting. Some of these are certainly instances of true fibroma (fibroma mamme nodulum). In still another group of cases the fibromatous proliferation of the connective tissue projects into the tubules and acini of the gland, pushing the epithelium . before it and sometimes sprouting or proliferating in polypoid form within the tubules. The gland in such cases may present a striking macroscopical appearance on section. Numerous cystic formations may be visible, with projecting dendritic formations within, causing an appear- ance somewhat like that of a section through a cauliflower (Fig. 51). Microscopically, the proliferations of the connective tissue between the tubules and projecting within the tubules constitute the charac- teristic features. The term intracanalicular fibroma has been given to such cases. Obstruction of the tubules in certain areas may lead to very marked cystic distention. Combinations with sarcoma are . frequent. Structure.—The definition explains the structure of fibromata. On section through the body of the tumor the fibrous nature may be revealed by a distinct concentric or radiating striation, particularly 172 A TEXT-BOOK OF PATHOLOGY in the case of hard fibromata. The softer varieties are much less likely to present this feature. The color is usually gray or whitish, and may be glistening when there is mucous degeneration, or yellow in the case of associated fatty tissue. Microscopically, a striking feature is the connective-tissue cell, which is rounded, star-like, and branching in the softer tumors, and compressed, spindle shaped, or elongated in the case of the hard varieties. Some authorities maintain that they are merely different stages of the same process. There are all gradations in this series. The intercellular substance is composed of a fibrillar network and homogeneous or granular material traversed by thin-walled blood- vessels, ofttimes having merely an endothelial coat. The parallel and wavy bundles of fibrils are the most conspicuous feature of hard fibro- mata. In softer varieties the fibrils are less often in bundles, and are twisted or irregularly curled. The fibrillar substance may be so closely packed that the intercellular substance has a glistening, hyaline appear- ance. This is very marked in keloids. Sometimes actual hyaline change affects the fibrils. Cavernous dilatation and rupture of the vessels may cause a distinct hemorrhagic appearance of the section, but such con- ditions are rare. A true keloid is a fully formed connective tissue tumefaction without a capsule and tending to show hyalin degeneration. It ‘is commonest in negroes. The epidermal layers and papille are correctly preserved. A false keloid arises in scar tissue. It is apt to show a limitation, but not by a distinct capsule, and the epidermis and papille are absent or distorted. Secondary Changes in Fibroma.—In some cases embryonal round cells may be abundant and a distinct sarcomatous transforma- tion of the tumor may occur. This, however, is rare. In other in- stances, as has already been remarked, myxomatous tissue may be conspicuous, and all grades of transformation, from a pure fibroma to a pure myxoma, may be met with, especially in the case of soft fibroma. Fatty degeneration of the cells and lipomatous infiltration or associated lipoma are also frequent. These forms, the myxomatous and lipomatous, are particularly frequent in the submucous and sub- cutaneous connective tissues. Calcareous change occurs in large fibro- matous tumors, particularly in those of the uterus, and very rarely true ossification has been reported. Less commonly association of fibroma with other forms of tumor growth is found. Among these the com- bination of fibroma with leiomyoma is usual in the uterus. Small fibromata about nerve-endings may be hard or soft. Some arise from the connective tissue of the nerve-sheath or from Schwann’s membrane. A kind occurring on the skin in disseminated form is called molluscum fibrosum. There is also a painful variety upon or - near nerve-endings. The nerve-fibers pass through or are caught by the fibroma and are not themselves changed. Nature.—Fibroma is essentially a benign tumor, though recurrence occasionally takes place after removal, this being particularly the case with keloids and some of the polypoid growths of mucous membranes. PROGRESSIVE TISSUE CHANGES 173 In some of these instances there is undoubtedly a resemblance to sar- coma, if not actual sarcomatous transformation. As a rule, fibroid tumors are destructive only in so far as they are capable of producing mechanical injury by pressure. The growth of the tumors is usually exceedingly slow. Metastases of pure fibroma do not occur, and the mass does not recur if removed completely. MYXOMA Definition——Myxoma is a tumor composed of connective-tissue celis and an intercellular substance containing mucoid material in more or less abundance. The gelatinous substance of Wharton in the um- bilical cord and the vitreous humor of the eye are normal tissue types which myxomata resemble in their structure. Etiology.—The causes and the nature of myxomata are prac- tically the same as those of fibromata, and intermediate forms make it difficult to draw a sharp line between the two. Less frequently myxo- mata are sarcomatous growths with myxomatous change. Appearance.—A typical myxoma is a soft, more or less flabby growth, enclosed by a capsule and having a rounded outline. It may project from the surface of the body or of an organ as a hemispherical elevation, or may hang by a narrowed pedicle in the form of a distinct polyp. The latter is frequent in the mucous membranes, but may occur in the skin as well. Sometimes the tumor is lobulated, and the lobules may be visible or may be easily felt. Occasionally myxomatous growths grb tiees %,0 sie enclon te fae toe are diffuse, having no capsule and . Se marked by no definite limits. ae eS Seats.—Among the common i oN situations are the subcutaneous and _ gw HN submucous tissues and the connect- of ive tissues of certain organs, notably a a 9 the mammary glands. They may os occur along the course of nerves, a ae and in the brain or the spinal cord. = gw ; They sometimes spring from sub- | 4%! { serous tissues, notably from the in-_ , 5 ea ae I terauricular septum and valves of I = ; af the heart. The tumor may be soli- “~~~ ae i - 7 5 tary or, like fibroma, may be met ceils separated by a gelatinous (mucoid) with in numbers. Congenital myx- intercellular material. oma has frequently been found. Structure.—Microscopically, the characteristic features are stellate or spindle-shaped connective-tissue cells which lie within a matrix of myxomatous material (Fig. 52). The latter is homogeneous or slightly granular, and somewhat refractive to light, giving the surface a glisten- ing quality. The cells themselves may be entirely normal young con- nective-tissue cells, or they may present evidences of fatty degenera- 174 A TEXT-BOOK OF PATHOLOGY tion. Round, connective-tissue cells are met with in some instances, either scattered. through the tumor or in certain areas, and may be so abundant as to justify the term “‘myxosarcoma.” The vascular supply is usually poor, and the blood-vessels resemble those of fibroma in being only partially developed. Association with fibroma and lipoma is fre- quent. Cartilaginous tissue may be found in myxomatous tumors of the parotid gland or testicle, and in these cases the myxomatous portion is rather an association than a degeneration of an original chondroma, Myxomatous degeneration of chondromata, osteomata, fibromata, and sarcomata is, however, a frequent occurrence. Nature.—Myxoma is benign like fibroma, but recurrence is not in- frequently observed, and in a few instances metastasis has been reported. In these cases the growth was doubtless sarcomatous, with associated mucoid tissue. When myxoma becomes sarcomatous the cellular content increases and the mucoid material is absorbed. The growth of myxomata is slow. LIPOMA Definition.—A lipoma is a tumor composed of fatty tissue like that of the normal subcutaneous tissue. The epiploic appendages of the intestines are the normal type which lipomata resemble. They are derived from the fat cells and not from fibroblasts. The fat is the same as natural subcutaneous adipose tissue in chemistry, except that the lecithin is somewhat less in amount. Etiology.—There seems to be a tendency, consisting perhaps in some derangement of the trophic nervous system, to the growth of these tumors. It is difficult at times to draw a sharp line between circum- scribed lipomata and diffuse fatty growth. Localized fatty or myxo- lipomatous accumulations in myxedema and a curious and apparently causeless deposit of fatty tissue sometimes observed in the subcutaneous tissue of the neck in men, represent the border-line between lipomata and ordinary obesity. Some individuals have a marked liability to constant overgrowth of fat in different parts of the body, and the term “lipomatosis” is not inapplicable. This fatty growth does not appar- ently depend upon the character or quantity of food, nor even upon sedentary life in some ‘cases, but rather on an cbscure tendency to adipose accumulation. The importance of the hypophysis and gonads to such conditions has been the subject of much fruitful investigation in recent years. Traumatism seems to play no part in the etiology of lipoma, though fatty infiltrations are prone to occur around areas of injury or disease and in degenerated organs. Appearance.—Lipomata are usually circumscribed and_ encap- sulated tumors having a lobulated character, the latter being due to septa of connective tissue. On the surface of the body they appear as somewhat hemispherical elevations which may reach enormous propor- tions. Rarely they become polypoid. In the interior of the body, as, for example, when they arise in the submucous or subserous connective PROGRESSIVE TISSUE CHANGES 175 tissue, they are very frequently, though not always, polypoid. Some- times they become detached and may be retained in one of the cavities of the body as free bodies. On section, the appearance is that of fatty tissue, though in some cases it is more firm from the association of fibrous tissue, and in.other cases less firm from the nature of the fatty tissue itself or from associated myxomatous change. Lipomata may be soli- tary tumors or there may be many. As a rule, they appear in adult years or middle life, but congenital lipomata are not very rare; occa- sionally they are found: to begin in childhood. Seats.—Among the situations in which lipomata occur the most common are the subcutaneous fatty tissue of the back, shoulders, buttocks or limbs, the submucous and the subserous tissues. They may arise either in the normal fatty tissue or in connective tissues in which fat is not normally present. Some authors, however, deny the possibility of lipomata arising excepting from pre-existing fatty tissue. Of the organs, the mammary gland and the kidney are most frequently involved. Structure.— Microscopically, lipomatous tumors resemble the normal fat. It is notable that the cells are larger—that is, contain more oil— than the normal fat cells, and this is strikingly the case in some instances, but is not always demonstrable. The vascular supply is about the same as in normal fat, though occasionally large vessels with thin walls are seen. Associated myxomatous or fibrous change may cause a variation of the microscopical appearance. Lipomata may undergo softening from necrosis, but more frequently become calcareous in part or completely. Nature.—This is the most benign form of tumors. Recurrence after more or less complete removal does, however, at times occur. A lipoma is dangerous only from its weight or position. It does not contribute to the support of the system in case of starvation. XANTHOMA Definition.—This term is applied to two possibly distinct though similar forms of new growth. The xanthoma vulgare occurs most fre- quently in the eyelids and may be confined to that situation. The growth appears in the form of flat elevations of a yellow color. Gener- alized xanthoma beginning about the eyes is less frequent. Xanthoma diabeticorum is a similar affection of diabetic patients. It occurs at a more advanced age, is more distinctly inflammatory, the masses are more rounded, and the eyelids and face are rarely affected. Xanthoma is frequently associated with hepatic disease. Structure.—The histology of xanthoma is that of modified fatty tissue. It resembles embryonal adipose tissue, and there is usually more or less round-cell infiltration as well. Some authors regard the latter as a tendency to sarcomatous change; others look upon it as inflammatory. It lies chiefly in the corium, but the subcutaneous tissue may be involved. Cholesterol combinations have been found in these tumors. 176 A TEXT-BOOK OF PATHOLOGY Nature.—Xanthoma is eminently benign. The diabetic form is subject to sudden and apparently causeless involution. The ordinary form may similarly subside, though much less commonly. CHONDROMA Definition.—A chondroma is a tumor composed largely or entirely of cartilage. The parent cell is, of course, the chondroblast in the perichondrium, a fibroblastic cell which has, in addition, the power to lay down a ground substance of chondromucin. When this predominates in tumors they have a hyaline appearance, but when the fibers pre- dominate the resulting mass follows the white fibrous or yellow elastic cartilage types. It is difficult to draw a sharp line between outgrowths of cartilage from existing cartilage or bone due to irritation from definite and independent tumor-like growths. A group of cases of intermediary character is that including cartilaginous nodules formed in tendons of muscles subjected to frequent irritations, as in the deltoid muscles in soldiers carrying heavy arms, and in the adductor muscles in the thigh in horseback riders. In these cases normal connective tissue seems to be directly transformed into cartilage, though the influence of irritation is undoubted. Etiology.—A congenital disposition, sometimes hereditary, is un- questionably present in certain cases. Virchow maintained that chon- dromata often spring from remnants or islands of cartilage left in ab- normal situations, as in the midst of bone, as the result of imperfect fetal development. The same explanation would account for parotid chondro- mata on the assumption that parts of the branchial arches are misplaced and remain in the substance of the parotid gland. Other evidences of the truth of the theory are the frequent occurrence of chondromata at the epiphyseal ends of bones, and the appearance of such growths in early life and especially in rachitic individuals. ; Irritation has been referred to. Direct traumatism is sometimes the cause of cartilaginous outgrowths from bone, particularly when fractures have occurred. Appearance.—Two distinct forms may be considered, and these are somewhat different in appearance. They are: (1) cartilaginous outgrowths, ecchondroses or ecchondromata, and (2) cartilaginous tumors or chondromata proper, originating in non-cartilaginous tissues. Ecchondromata present themselves as encapsulated, rounded, or somewhat irregular outgrowths from cartilages. Sometimes they are wart-like in form, and may occur in rows or groups. They may be firmly attached, or may be loosely united to the cartilage from which they spring. The most frequent (though not strictly neoplastic) are the outgrowths in the articular cartilage occurring in chronic arthritis, par- ticularly in arthritis deformans. Occasionally they become detached after their formation, and in the joints may thus become free bodies. More characteristically tumor-like ecchondromata originate from the surfaces of the laryngeal cartilages or from the costal cartilages. PROGRESSIVE TISSUE CHANGES 177 Chondromata proper most frequently occur in bones or the peri- osteum, and have a rounded or lobular appearance. Chondromata springing from the inner surface of bones (possibly originating from the marrow itself) may grow uniformly by repeated or constant proliferation and occasion globular swellings of the affected bones (Fig. 53). The true bony covering becomes more and more thin until it may actually be perforated. The true chondromata are usually rounded bodies of dense elastic consistency and the pale blue color of cartilage; they present lobular irregularity when they reach considerable size, the lobules being sepa- rated by connective tissue. Chondromata are usually hard, though secondary softening may occur. In cases in which association of mucous, sarcomatous, or other soft tissue is present the consistency is correspondingly less. In some cases central softening leads to cystic formation. The liquid in the cyst is more or less turbid and occasionally sanguinolent. Seats. — Ecchondroses and chondromata, for the most part, take their origin from bone, carti- lage, or periosteum. The ecchon- dromata originate from the peri- chondrium rather than from the cartilage itself. In some cases chondromata originate in connect- ive tissue, as that of the tendons, by a process of cartilaginous meta- Fig. 53.—Chondroma of the thumb (War- plasia. Cartilage tumors are met ren). with in some of the glandular organs, notably the parotid gland, testicle, and ovary; and rarely they occur in the lungs, especially at the root and springing from the peri- bronchial cartilages. Ecchondroses are most frequent about the long bones, as those of the extremities, and particularly at the epiphyseal attachments, where they may reach considerable proportions. Situations of great clinical importance are the interpubic and occipitosphenoidal junc- tions. In the former situation ecchondroses projecting inward may interfere seriously with labor, and in the latter place cartilaginous out- growths may penetrate the dura and exercise injurious compression on the brain. Allusion has been made to the ecchondroses of the joints in arthritis. Chondromata proper may occur in the neighborhood of bones, in the muscles and tendons near their bony attachments, and in the organs mentioned, but in the last situation are rarely pure, myxoma being the most frequent associate. Structure.—Chondromata resemble hyaline, fibrous, or elastic car- tilage, the first named being much the most frequent. The tissue 12 178 A TEXT-BOOK OF PATHOLOGY differs from normal cartilage in the fact that the cells are frequently without capsules and are much less regularly arranged (Fig. 54). The intercellular substance is more abundant, and is frequently gelatinous, mucoid, or fibrous, and not rarely the different types of cartilage occur within narrow limits. Association with myxoma and sarcoma, or both, is common, especially in the parotid and testicles, the proportion of the several ingredients varying greatly. Tumors of this kind are spoken of as mixed tumors. Calcification and true ossification are not infrequent, particularly in cartilage tumors intimately connected with bone. The term osteochondroma is applied in such cases. The name osteoid chon- droma is applied to chondromata in which the intercellular substance is trabecular in arrangement, suggesting bone structure, but in which actual ossification has not occurred. Such growths are met with about the bones and, as a rule, spring from the periosteum. The cartilag- inous part of these tumors is without blood-vessels. Fig. 54.—Chondroma of the hyaline type. Degenerative changes are frequent because while the tumor as a whole is vascular the islands of cartilage are not, and the parts removed from the vessels get little nutrition. Myxomatous degeneration may occur, though myxoma is more frequent as an association than as a degeneration. Softening may occur in the center of the mass, and may lead to cyst formation, this being particularly common in the myxo- chondromata. Growths of this kind are frequently quite vascular and hemorrhages into the cysts may occur. Eventually such cases may show scarcely any cartilage cells, a few being perhaps detected in some part of the cyst wall. A single hard lump may be left at one side of the cyst, the rest of the tumor having softened. The more cellular the tumor, the greater the tendency to sarcomatous degeneration. Fibrillation and cell increase are early indications of such a change. Nature.—Chondromata are usually benign, and are dangerous only through the pressure they exert. Removal of a part of the tumor may PROGRESSIVE TISSUE CHANGES 179 have a beneficial influence in causing calcification of the remainder. Metastasis may undoubtedly occur in pure chondromata through transportation of particles in the circulation; such cartilaginous emboli have often been demonstrated. The secondary growths are most fre- quent in the lungs. Metastatic chondromata are, however, more fre- quently chondrosarcomata than pure chondromata. OSTEOMA Definition.—An osteoma is a tumor composed of osseous tissue. Osteomata are closely allied to cartilaginous tumors, and frequently transformations occur. The cell of origin is the osteoblast, as adult bone cells do not reproduce. Etiology.—The same difficulty is experienced in distinguishing in- flammatory outgrowths or exostoses from true bony tumors, as in the case of cartilaginous growths. Enlargement of the facial bones in leontiasis ossea, of the bones of the extremities in acromegaly and Fig. 55.—Exostoses of the elbow-joint. hypertrophic pulmonary osteo-arthropathy, and ossification of the muscles in myositis ossificans, are instances of border-line conditions separating true tumors from inflammatory hyperostoses. Irritation and traumatism undoubtedly play a part in the etiology, even in neo- plasms unattached to the bone, and in the case of bony outgrowths injury is generally the immediate cause. An underlying predisposition undoubtedly exists, and explains the occurrence of congenital multiple bony tumors. Appearance.—Two forms may be distinguished, as in the case of chondromata: (1) outgrowths or exostoses and osteophytes, and (2) the osteomata proper, or heteroplastic osteomata. Exostoses and osteo- phytes are distinguished one from the other by their shape and appear- ance rather than by any essential difference. The former are direct outgrowths of more or less wart-like character; the latter are more ex- tensive and present the appearance of bony deposits upon bones, and are less closely attached (Fig. 55). In both forms the surface of the growth is irregular, nodulated, or wart-like (Fig. 56). The consistency 180 A TEXT-BOOK OF PATHOLOGY is that of bone, and the size varies from that of small outgrowths to masses as large as a fist. On section, two forms may be distinguished: the hard or osteoma durum, after the nature of compact bone with fairly well imitated architecture; and the soft or osteoma spongiosum, after the character of spongy bone, but less well arranged, more of the em- bryonic cell type and more apt to show degenerative changes. Some- times the substance of the tumor is exceedingly dense, and the term osteoma eburneum is applied. This form is without the completed Haversian sys- tems, and osteoblasts are apt to be wanting over large areas. There may be osteomata of endosteal origin arising from endosteum or mis- placed cartilage. The heteroplastic osteomata, or those separated from the bone, are more rounded and, when of considerable size, usually nodulated and lobulated. In the serous membranes they occur as flat bony plates. Fig. 56.—Osteoma of the lower jaw Seats.—Osteomata Spring from the (Warren). bone or cartilage, or from connective tissue near the bones. More rarely they arise in other connective tissues, in the serous membranes, or in certain organs, notably the testicle and parotid gland. , Osteomata connected with bones are most frequent about the epiphyses, at the attachments of muscles, or at the seat of old frac- tures from which abundant callus has been deposited. The skull bones may be affected on the outer or inner surface, and often an ele- vation is noted without and within at the same spot. A form of clinical importance is that in which exostoses occur on the inner aspect of the metatarsal bone of the great toe from compression of tight shoes. In the maxillary bones osteomata may originate about the roots of mal- formed teeth. In cases of accumulation of cement substance beginning at the neck of the tooth the term dental osteoma is applied; these are strictly comparable to osteomata. In cases in which proliferation of the dental pulp has occurred the term odontoma is applicable, and the tumor is not of osseous character. The bony growths sometimes seen in the serous surfaces nearly always arise in areas in which there has been thickening from chronic inflammation. They are most frequent in the dura mater of the brain, particularly the falx cerebri, though the membranes of the cord, the pleura, endocardium, or pericardium may be involved. 5 Structure.—Microscopically, osteomata resemble more or less accu- tately bone tissue. They vary, however, in different areas, and mixtures of cartilage with bony tissue are frequent. Secondary degenerative changes (softening) may occur, and association with tumors of other character are not infrequent (chondroma, myxoma, fibroma, sarcoma). PROGRESSIVE TISSUE CHANGES 181 Nature.—These growths are eminently benign, slow of growth, do not recur, and do not give metastasis. Their situation sometimes makes them troublesome or dangerous. ANGIOMATA This name is given to tumors the chief part of which is made up of vessels with a relatively small amount of supporting tissue. It is by growth of new vessels or increase of tortuosity of those existing that these tumors grow. The interstitial tissue may undergo change, but the principal feature is vessel sprouting. LYMPHANGIOMA A lymphangioma is a tumor composed of dilated lymph-vessels or lymph-spaces, more frequently the latter. It is difficult to separate dilatations of lymphatic channels due to obstruction from hyperplastic processes. Congenital enlargements of certain parts are met with which seem entirely dependent upon the abnormal development of the lymph-spaces. These constitute the condition called elephantiasis congenita mollis, in which the subcutaneous tissues are boggy or edem- atous, and even distinct cystic formations occur. Congenital cystic hygroma is an instance of dilatation of the lymph-spaces. Congenital enlargement of the tongue, termed macroglossia; of the lips, macrocheilia; and of the skin, nevus lymphaticus, are other instances of the same process. In all of these, in addition to the dilatation of the lymphatic spaces, a marked proliferation of the connective tissues as well as the muscle (in the case of the tongue) is striking; but the process, in all probability, originates as a dilatation of the lymph-spaces. The term lymphangioma cavernosum has been suggested for these cases of dila- tation of the lymph-spaces. On staining with silver-salts the endo- thelial lining of the spaces may be readily demonstrated. Actual enlargement and varicosity of existing lymphatic vessels may occur, but is extremely rare in the form of circumscribed growths; it is met with more frequently in association with general processes, such as elephantiasis. The bursting of dilated lymphatics may lead to lym- phorrhea or external discharge of lymph when the process involves the skin, or to effusions of lymphatic character when the serous cavities are involved. Chylous pericarditis, pleuritis, and ascites are thus produced. Rupture of dilated lymphatics along the urinary tract (kidney or bladder) occasions chyluria. Lymphangioma is a benign process in the pathological sense. This classification is here limited to those tumors in which vessel change is the only feature, growths arising from lining or covering membranes being placed among the endothelio- mata. _ JItis maintained by some that these are not true tumors, as they have no power of independent growth and keep pace with the body growth by reason of obstruction or an error of tissue resistance. The term ‘hamartoma”’ has been applied to them. 182 A TEXT-BOOK OF PATHOLOGY HEMANGIOMA Definition.—A hemangioma, or angioma, as it is more fre- quently called, is a tumor-like formation composed principally of blood-vessels. Two varieties may be described, that which simulates merely distended capillaries and veins (angioma telangiectaticum), and that in which there are enlarged spaces lined with endothelium (angioma cavernosum or cavernoma). In many tumors the blood-vessels are: somewhat enlarged; these are spoken of as telangiectatic tumors. Etiology.—Congenital malformation certainly plays some part in some cases, as the frequency of hemangiomata in the newborn and particularly at the junction of the branchial arches would indicate. Injury, however, and mechanical causes generally also play a part, and pre-existing disease, particularly fibroid inflammatory processes, may contribute to the subsequent dilatation and proliferation of the vessels (see below). Appearance and Seats.—The angioma telangiectaticum may consist merely of delicate capillaries and arterioles, and in this case a bright red color is observed. The tumor appears as a spot on the surface of the skin, more or less sharply outlined from the surrounding tissue. It is not elevated and has the same consistency as the healthy parts. Usually it occurs as a multiple condition, and the larger are often surrounded by smaller spots. The skin is the favorite seat; but the sub- cutaneous adipose tissue and sometimes the mucous membranes are involved. Less commonly larger (venous) channels occur in the tumor, when a dark red color is observed (port-wine stains). If a circumscribed portion of the circulation is uniformly involved, the vessels thicken and elongate, and a peculiar form of hemangioma results. In these cases the arteries are greatly thickened and tortuous, and form bunches under the skin, suggesting to palpation a bundle of earth-worms; while the surface of the skin presents peculiar irregular ele- vations without, of necessity, any change of color (aneurysma racemosum seu cirsoideum). This is not infrequent in the scalp. A similar condi- tion of the vessels is observed in the varicosity of the legs, labia, or other parts. It is most frequent in the hemorrhoidal veins, constituting the ordinary hemorrhoids. (These conditions do not strictly constitute tumors and will be more fully described in discussing the diseases of the vessels.) Cavernous angiomata present themselves as more distinctly tumor- like formations of dark venous color, involving the skin or subcutaneous tissues, the retrobulbar tissue of the eye, the mucous membranes of the nose or pharynx, and certain organs, as the mammee, the kidney, the spleen, but particularly the liver. Like the other variety, they may be congenital, but more frequently arise in later life, especially that of the liver, which is most common in old persons. The appearance is that of a more circumscribed tumor, sometimes showing a distinct capsule and - varying in consistency with the degree of distention of the blood-spaces. In the skin it projects slightly from the surface (nevus prominens). PROGRESSIVE TISSUE CHANGES 183 Structure.—The definition explains the structure in general. The blood-vessels of telangiectatic angiomata may be simply dilated capillaries with a lining of endothelium ‘and a fibrous outer coating. More commonly the vessels are considerably thickened and held together by a reticular connective tissue. In rare instances the vessels are so closely packed and the walls so thickened that when the blood is re- moved the appearance is not unlike that of the tubules of a sweat-gland. The congeries of vessels of a telangiectatic angioma represents the elongated and tortuous vessels of the affected area, and also new-formed vessels originating from the former. The only connection of the angioma with the general circulation is through one or a few afferent arterioles and efferent veins. The growth is not merely an enlargement of pre- existing vessels, but an actual new formation. or M A } ar Seat Secon cor ee Fig. 57.—Cavernous angioma (Warren). oa The cavernous angiomata present large spaces lined with endothelial cells (Fig. 57). Between these spaces are parallel fibers of connective tissue which form the framework of the tumor. In cases involving the liver the proper substance of this organ disappears completely, leaving only anastomosing spaces with a fibrous framework. Virchow taught that the fibrous process was primary, and by traction and pressure gradually induced dilatation of the vessels and atrophy of the liver sub- stance. Some of the more recent writers believe that the dilatation of the vessels is the primary condition. The capsule sometimes found surrounding the cavernous angioma is certainly a secondary formation. Angiomata of the skin may enclose the hair-follicles and sweat- glands; those of the subcutaneous tissue frequently show areas rich in 184 A TEXT-BOOK OF PATHOLOGY fatty tissue (angiolipoma); secondary angiomatous change of tumors is probably the result of dilatation of the pre-existing or new-formed ves- sels. Sometimes secondary change may occur in the connective tissue of the vessels of an angioma, as in the plexiform angiosarcomata, in which the blood-vessels are surrounded by ensheathing sarcoma-cells (see Fig. 57). Certain cylindromata have the same origin. Nature.—Angioma is essentially benign, and may continue through life without enlarging. Hemorrhage and inflammatory or necrotic changes are its dangerous consequences. LYMPHADENOMA Definition.—This term is here used to designate a more or less malignant form of new growth affecting the lymphatic glands or other lymphadenoid tissues, and having the structure of lymphatic tissue. From a clinical and anatomical standpoint the manifestations of this condition are manifold, but histologically they have the same origin. They all arise from the lymphoblast, the endothelia, or both. Thus in the varieties lymphosarcoma and Hodgkin’s disease the younger cells, or those nearer the parent cell, predominate, while in lymphoma and lymphatic leukemia the last stages of the lymphocyte series are more numerous. We shall consider under this heading the hyperplasias of lymph-tissue giving rise to tumors, leaving for the chapter on the Blood the leukemias, whose histogenesis is the same. (For discussion of Tumors of Lymph-glands, see p. 461.) There are several grades of lymphomatous disease, starting with simple lymphoma of nearly typical lymph-tissue structure and ending with true sarcoma of lymph-nodes, which, of course, are of the small round-cell type. To differentiate between closely related conditions is a problem of great difficulty and questionable utility. There are dis- cussed here simple lymphoma, lymphomatosis, and Hodgkin’s disease, conditions ‘affecting the lymphocyte-producing organs, yet, curiously enough, failing to produce any marked alteration of lymphocyte content in the blood. With the exception of simple lymphoma, a rare, probably hyperplastic or inflammatory condition, these diseases seem to be sys- temic, since change in one locality is followed by lymphoid overgrowth almost universally in the body. Etiology.—There are cases of infectious enlargement of the glands and traumatic swellings that cannot be clearly distinguished from lympb- adenoma. In some cases even the clinical course is the same and a sepa- ration seems impossible. For example, the glands in a number of in- stances of Hodgkin’s disease (as far as the clinician can establish this diagnosis) have been found to contain tubercle bacilli. We must con- clude that general lymphatic tuberculosis may occur in clinical forms indistinguishable from Hodgkin’s disease, but cannot assert that this establishes the pathological identity. Tubercle bacilli have been dis- covered in some cases diagnosed as lymphomatosis (Sternberg and Gross), and in other cases where they were absent, Frinkel and Much PROGRESSIVE TISSUE CHANGES 185 have found Gram-positive rods or coccus-like bodies which Much claims to have shown are tubercle bacilli having lost acid-fast properties. The large number of eosinophiles in the gland speaks rather against the tuberculous nature of the growth. The presence of tubercle bacilli may, furthermore, be explained as sometimes the result of secondary infec- tion. In a number of well-studied cases the absence of tubercle bacilli has been proved by the inoculation of animals. Various micrococci and bacilli have been discovered in glands from cases of Hodgkin’s disease. This condition has lately been ascribed to a pseudodiphtheria bacillus which can be isolated from the glands by a special technic. Some have claimed to have reproduced the dis- ease in monkeys by injection of the bacteria, but this must be corrob- orated. Others claim good results in treatment of clinical cases by the use of bacterins of this newly discovered organism. It is important, however, to note that similar diphtheroid organisms have been iso- lated from other diseases of lymphatic glands. In a few instances bodies resembling protozoa have been discovered. Appearance and Seats.—Lymphadenomata present themselves as enlargements of the lymphatic glands of a single group or, more com- monly, of a number of groups in different parts of the body. All of the glands of the group may be involved, or only a few. The individual glands retain their shape, as there is usually no tendency to extension beyond the capsule of the gland. In exceptional cases, however, the process is of a more infiltrating kind and the capsule is penetrated or destroyed. These instances merit the special term ‘‘lymphosarcoma.” Lymphadenomata may be soft or hard, according to the amount of connective tissue and the denseness of the cellular infiltration and proliferation. On section, the tumors are found to be grayish or whit- ish in appearance, and exceptionally may show slight areas of necrosis or softening. Extensive softening is exceedingly rare. The individual glands of the group may be clearly distinct, or may be fused together by interglandular connective-tissue overgrowth or by the penetration of the lymphadenomatous process through the capsule. When superficial lymphatic groups are involved, tumors of various sizes are produced, and project as knobby or rounded enlargements be- neath the skin. The latter is freely movable over the tumor unless the growth has penetrated the capsule or secondary inflammatory changes have occurred. In the case of internal glands large intrathoracic or ab- dominal growths may be formed, and may exercise destructive com- pression of vital parts. Similar lymphadenomatous growths may spring from the lymphatic tissues of the gastro-intestinal tract—tonsils, lymphatic follicles of gas- tric and intestinal mucosa. Sometimes the primary growth seems to begin in the thymus gland or its remnant (Fig. 58). Tumors of considerable size are produced in these cases, and their origin is recognized by their shape (two lateral parts united by a sort of isthmus) and by the absence of the appearance of a conglomeration of glands. In these cases the adjacent glands 186 A TEXT-BOOK OF PATHOLOGY and, later, more distant groups are involved. Lymphadenoma may be confined to the glands, but frequently extends to the solid organs by metastasis. The spleen, liver, and kidneys are the organs most fre- quently affected. They become enlarged and indurated, and on section show light colored areas of lymphadenoid tissue. Similar “lymphoid infiltration” may be seen in the heart, lungs, or other parts. Lymphadenoma may affect the bone-marrow secondarily and _per- haps primarily. (Reference will be made to this under the title Mye- loma.) Sometimes the tumors have a yellow or green color and are called chloromata (q. v.). Meats ease Fig. 58.-—Lymphadenoma (lymphosarcoma) probably originating in remnant of thy- mus gland: the tumor covered the upper part of the heart like a hood. The illustration shows the tumor turned upward and exposing the pericardium on its under surface. Structure.—Histologically, the glands in the earlier stages show a hyperplasia of lymphadenoid tissue with predominance of small cells (lymphocytes). Later larger cells with pale nuclei make their appear- ance. Most of these are bizarre forms of the proliferating lymph-cells, while some are swollen endothelium from the sinuses. They may enlarge to form mononuclear or polynuclear giant-cells, the nuclei dividing by amitosis. Sometimes large areas of nucleated protoplasm (syncitial tissue) are observed. At this time the gland section is gener- ally homogeneous in arrangement, all parts actively growing, and the architecture of follicles, cords, and sinuses is largely obliterated. Coin- cidently with the appearance of these epithelioid and giant-cells there is formed a reticular fibrous network which increases with the age of the process until the gland becomes quite indurated. A somewhat char- PROGRESSIVE TISSUE CHANGES 187 acteristic, though not constant, feature of the histology is the presence of numerous eosinophile leukocytes scattered through the tissue or in small masses. These may be mononuclear or polymorphonuclear. Plasma- cells and mast-cells may be present, but are not characteristic. In the rapidly growing form, commonly called “lymphosarcoma,” the cells, while still near the parent type, are more uniform in size and shape, more deeply staining, more active in proliferation, and there are fewer endothelioid and eosinophilic cells than in the Hodgkin’s type. The clinical history may be the same, and one cannot now state the reasons for these differences, unless they be stages of the same process, a view held by some observers. The above description leads one from the hyperplastic lyvmph-gland to the fully developed adenoma, made up of imperfectly differentiated cells. It is well to emphasize that in Hodgkin’s disease the picture is dominated by large endothelioid cells in group arrangement mixed with groups of small lymphoid cells; many eosinophiles are to be found. There is a fine fibrosis running through the tissue. Focal necroses are common. The spleen may show similar changes, beginning in the Malpighian bodies, but in many cases is affected in but slight degree or not at all. _ The bone-marrow presents a picture of proliferation of myelocvtes. The liver, kidneys, lungs, gastro-intestinal mucosa, and other tissues may be extensively involved, presenting new formations of the lym- phoid cells similar to those in the glands and originating from the lymphoid masses normal to these parts. These lesions were formerly re- garded by most authorities as simple metastases, but are now thought by many to be proliferations of existing lymphoid tissue. Some, as Ribbert, hold that they are metastatic and are due to proliferation of metastatic cells, which, however, are attracted to pre-existing lymphoid collections by a species of chemotaxis that seems to invite the deposit of cells in areas where similar cells exist. The occasional perforation by the growths of small blood-vessels with proliferation within the vessels is an argument in favor of the neoplastic nature of the process. Nature.—Lymphadenoma is variably malignant. In a small pro- portion of the cases this malignancy is of local character—that is, the growth tends to invade the neighboring parts. In most instances there is rather a tendency to general involvement of the lymphatic system, with secondary growths in various organs. To cases of this kind the terms ‘‘Hodgkin’s disease,’ “pseudoleukemia,”’ and “‘adenia” have been given. These cases present themselves in the form of a progressive ane- mia (lymphatic anemia—Wilks), often with irregularly relapsing fever (chronic relapsing fever—Epstein), and especially with lymphadenoma- tous tumors in the superficial or deep lymphatic groups (axillary, cervical, inguinal, mediastinal, or abdominal). The disease progresses more or less rapidly, and terminates in death from cachexia and exhaus- tion in from one to three years. Occasionally the course is rapid, re- peated hemorrhages or purpura may occur, and a fatal termination 188 A TEXT-BOOK OF PATHOLOGY is reached in a few weeks or months. The whole course of the disease is in these cases suggestive of an infectious process. The chronic cases may be infectious or due to some form of toxemia, but are at present more appropriately considered under the head of Tumors. The relation of Hodgkin’s disease and leukemia, especially the lymphatic type, is certainly very close. The glandular tumors and the secondary changes in the organs are somewhat similar, excepting that the lymphatic glands are more prominently involved in ordinary lymph- adenoma and the marrow changes more striking in leukemia. The striking difference is found in the blood. In leukemia there is marked and characteristic leukocytosis; in the other condition this is absent. Many cases have, however, been observed in which Hodgkin’s disease has apparently become leukemia; and some authors do not hesitate to speak of the two diseases as identical and. representing merely two stages of a common affection. According to this view, we might classify different cases as either leukemic or aleukemic lymphadenomata. The blood in aleukemic cases shows more or less pronounced reduc- tion in the number of red cells, and a normal, reduced, occasionally a moderately increased, number of leukocytes. The small mononuclear leukocytes are sometimes in relative excess. In acute cases nucleated red cells may be found. The causes and nature of the irregular fever are uncertain. It may be due to an infectious cause, or may be the result of breaking up of leukocytes and liberation of ferments. Multiple Myeloma.—This growth affects the sternum, ribs, vertebra, skull, and, less frequently, other bones. The tumor at first suggests a hyperplastic condition of the marrow; later the substance of the bone is replaced by the growth, which may finally break through the shell of bone covering it and invade the soft tissues. Metastasis is very rare. The growth has a mottled grayish and reddish appearance and is rather soft. Microscopically it is composed of small round cells and a vascular network of thin-walled vessels. The cells resemble small myelocytes or, possibly in some cases, plasma-cells. There is also a type, the lymphoid, in which lymph-cells predominate. Bence-Jones albumose is found in the urine in cases of myeloma. Chloroma is the name given to the greenish solid hyperplasias of the bone-marrow growing from the premyelocytes and owing their color to an abundance of lipochromes. This color vanishes on exposure to air. The tumor is probably merely a condensation of hyperplastic marrow in cases of myelogenous leukemia, as certain differentiations of the com- ponent cells into granular myelocytes, the occurrence of typical leu- kemic metastases, and the development of an enzyme acting in alkaline medium, all point in the direction of a hyperplasia of leukocytic ele- ments. The superficial resemblance of the premyelocytes and large lymphatic cells has led to the erroneous opinion that chloroma was a lymphosarcoma, so that the names “myeloid” and “lymphoid” have been given to those cases in which respectively the granular and non- granular myelocytes have predominated. The similarity of the latter PROGRESSIVE TISSUE CHANGES 189 and large lymphatic cells is marked, but all the cells of chloroma are now thought to be derived from the myelocytic series. SARCOMA Definition.—The term “sarcoma” is applied to tumors composed of connective-tissue cells with very little intercellular substance. It is often said that sarcoma-cells resemble those of embryonal connective tissue; properly speaking, they may be likened to the ordinary con- nective-tissue cell falling short of complete development—that is, no formation of fibrous intercellular substance, but a great tendency to continuous cell proliferation. Etiology.—Of all the tumors, sarcoma furnishes the best ground for Cohnheim’s theory. Its frequent occurrence in young persons, the relation of melanosarcomata to congenital pigment-spots of the skin, and the sarcomatous mixed tumors of the parotid and testis were cited by Cohnheim among the evidences pointing to a congenital origin. Traumatism and inflammation certainly play some part, either in stimu- lating sudden growth of a latent sarcoma or in developing a lesion from which sarcoma springs. The parasitic theory has gained many adher- ents in recent years, though no specific organism has been demonstrated. Experiments at implantation of the disease in animals have been par- tially successful, but do not establish an infectious character, as has been shown in preceding pages. It is not improbable that certain lympho- sarcomata may be due to the action of bacteria. Appearances.—Sarcomata are generally more or less rounded tumors, often enclosed by a limiting reactive inflammation of the neigh- boring tissues; they may, however, be irregular, infiltrating, and, therefore, unencapsulated. The growth of sarcomata is from the tumor cells themselves. The tumor spreads into the surrounding tissue and absorbs it, probably only retaining such connective tissue as it requires. A true fibrous capsule, ‘made by the tumor and within which it grows, does not occur in sarcomata. Some forms appear on surfaces, spreading as flat elevations more or less irregular in outline. The consistency is soft or hard according to the number of cells and the amount of intercellular substance, or according to the kind and amount of associated tissue (myxomatous, chondromatous). Typical sarcoma, as the name implies (ad, flesh), is flesh-like in consistency, and frequently, on section, the color is pink or of a flesh-tint. Many of the sarcomata, however, are quite white or gray, and a whitish liquid exudes from the surface on section. Dilatation of the blood-vessels may cause a decidedly hemorrhagic appearance, and actual hemorrhages may take place, causing blood- cysts or, subsequently, serous cysts. Other degenerative changes, such as necrosis, mucoid change, and simple liquefaction necrosis, may render sarcomata soft and often cystic. Sarcomata of glandular organs like the breast may present a cystic appearance in consequence of compression, and subsequent dilatation of the glandular ducts and acini. 190 A TEXT-BOOK OF PATHOLOGY Angiosarcomata (the variety in which sarcoma-cells spring from the adventitia of blood-vessels) present themselves as more or less irregular growths, frequently flattened and branching when the surfaces of organs are involved. Secondary sarcomata are nodular in character and nearly always present a capsule if the size is at all considerable (Fig. 59). They are usually white or pinkish; rather firm on section, but with a tendency to central necrosis or softening. In some cases almost every part of the body may be studded with minute white spots scarcely distinguishable from miliary tubercles. This condition is called sarcomatosis. Seats.—Sarcomata _ spring from pre-existing connective tis- sues, such as the subcutaneous, intermuscular, periosteal, or tendinous tissues; bone, cartil- age, fat, lymphatic glands, the submucous and serous surfaces. They may arise in the internal organs: kidney, liver, spleen, thyroid glands, testis. The in- dividual seats will be further considered under the different forms. Structure.—The sarcoma- cell is rounded, cylindrical, spin- dle shaped, or of polymorphous forms, the latter usually being ‘ larger than the round or spin- . ° ee ee - 4 dle forms. The large number ano S05 Sroonsary serosa. of ths ng: of cells in comparison with the pleura. amount of intercellular sub- stance is always conspicuous. The cells themselves contain rather large nuclei of a somewhat vesicular appearance, though sometimes quite granular and hyperchromatic. In rapidly growing tumors karyokinetic figures may be very abun- dant; less frequently the cells show evidence of direct division of the nuclei. Nuclear degenerations (karyorrhexis, karyolysis, and hyper- chromatosis) are frequent, and doubtless cause some of the appeal- ances supposed to be protozoa. The arrangement of the cells in sarco- mata is usually very irregular; in some cases, however, particularly in spindle-celled sarcomata, the cells lie in fasciculi or parallel columns. These are the alveolar sarcomata. The intercellular substance consists of a homogeneous matrix with a few fibers in the case of the spindle- celled variety, but with few if any in other cases. The cells may be all of one type, but more frequently different forms or shapes occur in PROGRESSIVE TISSUE CHANGES 191 the same tumor. Among the polymorphous forms of cells may be noted large flattened cells resembling endothelial plates and giant-cells resem- bling myeloplaques. (These forms will be discussed under the headings Endothelioma and Giant-celled Sarcoma.) When grown in serum outside the body, sarcoma cells at first multi- ply more rapidly than normal ones, but soon lose this power. Irregular mitoses are seen, but direct division is not. The blood-vessels of sarcoma are usually channels lined with a single endothelial coat (see Fig. 61), but there may be more fully developed vessels. There is growth of these imperfectly formed vessels, following, in general, the laws of new capillary development. In some cases the vascular network is very conspicuous and forms the skeleton of the tumor, the sarcoma-cells being ranged round the vessels in the form of mantles and probably springing from the adventitia. In spreading, sarcoma shows a tendency to follow vessels. It has no lymphatics and only such nerves as it encloses in its growth. Secondary changes may occur in the cellular masses surrounding the vessels, and peculiar forms of tumors thus result. (See Cylindroma.) The general architecture of a sarcoma has a decided influence upon its character. ‘The round-cell tumors are usually of rapid growth and the small round-cell type of the greatest malignancy among the simple sarcomata. The soft loose-textured ones are usually most malignant. Combinations of sarcoma with other forms of tumors are not rare. All grades between the true sarcoma and the fibroma may be met with, and it is difficult to draw a line of distinction. Wherever a tendency to cellular proliferation is conspicuous and the formation of fibroblastic cells with elongated fibrous projections is not conspicuous, it is warranted to record the tumor as sarcomatous. Primary fibromata may become sarcomatous, and sarcomatous tumors perhaps at times become more benign by fibromatous transformation. Combinations with chondroma, osteoma, myxoma, and other connective-tissue tumors; with adenoma, rhabdomyoma, and fibromyoma are not infrequent. More rarely the fibrous tissue of the benign tumors may undergo sarcomatous change. The structure of individual forms of sarcoma will be separately considered. Names have been applied to the different forms which describe the micro-anatomy, and in a sense are instructive in suggesting the relative activity and possible nature of the growth. It must not be forgotten, however, that round- and spindle-cell sarcomata both de- scend from the same parent cell and may be phases of differentiation. Nature.—Sarcoma is essentially malignant. It tends to recur after removal; it affects the general health of the patient, and metastasis is frequent. Metastasis occurs through the circulation chiefly, but “may spread through the lymphatics. The degree of malignancy varies greatly. The small round-celled and melanotic varieties are the most dangerous. Some forms, as the giant-celled and the fibrosarcomata, are comparatively benign. The relatively benign form of tumor, called recurrent fibroid tumor by Paget, is, in reality, a fibrosarcoma. The 192 A TEXT-BOOK OF PATHOLOGY growth of sarcomata is usually rather rapid, but shows a tendency to irregularity, and may become very rapid in consequence of irritation, Sarcomata are injurious to the general health in some obscure way. The evidence of this is the anemia and leukocytosis and the irregular. fever observed in various cases. The anemia may be trivial or severe, and may become extreme. Leukocytosis is frequent, but rarely marked. The polymorphous elements may be specially increased, but we have found the lymphocytes excessive in a number of cases. Irregular fever is often noted in lymphosarcoma and sarcomatosis. Necrotic change may increase the tendency to fever. The exact influence of sarcoma on metabolism is unknown. Spindle-celled Sarcoma This form may consist of either large or small spindle-shaped cells with attenuated and sometimes branching extremities, and a spindle- shaped nucleus in the small cell variety, while the large cells have an oval, bladder-like nucleus (Fig. 60). Angular or stellate cells are not Fig. 60.—Cells from a large spindle-celled sarcoma (Ziegler). infrequent. The cells may be ranged in parallel columns, so that the tissue becomes quite compact; and fasciculi of such cell masses may run in different directions, interlacing, and thus giving the section a fibrous appearance. In some cases the cells present no definite arrangement. Spindle-celled sarcomata are harder than the round-celled varieties and usually more grayish or flesh colored. They may be quite soft and white or degenerated and cystic. The amount of intercellular substance in some cases, particularly of the small cell type, is quite considerable, and the term “‘fibrosarcoma” may be justified. The intercellular fibrils are of the fibroglia type and are indistinguishable from those of fibromata. It is very difficult some- times to decide whether the tumor is sarcomatous or purely fibromatous. The large cell type is more cellular. Spindle-celled sarcomata occur in the dense connective tissue of the periosteum, tendons, and fascie; less frequently, in the softer tissues. They are slow of growth, relatively benign, some cases showing no tend- ency to metastasis, though recurring after removal. PROGRESSIVE TISSUE CHANGES 193 Round-celled Sarcoma Sarcomata may be composed almost entirely of spherical or round cells, small or large in size. The designations “small” and ‘‘large round- celled sarcomata” are used, but do not really define separate varieties. The round cells when small resemble those of lymphatic organs. There is little intercellular substance. The blood-vessels may be quite large Fig. 61.—Small round-celled sarcoma: in the center is seen a blood-vessel with its wall of endothelium. and hemorrhages with secondary changes may occur (Fig. 61). The larger cells contain relatively more protoplasm, frequently several nuclei, and not rarely different forms of cells (spindle shaped and polymorphous) are associated. The naked-eye appearances of round-celled sarcomata are usually quite characteristic. They are milky-white, gray, or pink in color; Fig. 62.—Lymphosarcoma of nasal mucous membrane: a on left side, a blood-vessel; a on right side, reticulum; b, cells of reticulum; c, sarcoma-cells (Ziegler). sometimes quite soft or cheesy in the center, and a milky liquid exudes. Cystic changes and even calcification may occur in the center. The small-celled variety is, as a rule, softer than the larger, though both are soft. : Round-celled sarcomata are always malignant, the small-celled form being perhaps the most malignant of all varieties. 13 194 A TEXT-BOOK OF PATHOLOGY Lymphosarcoma is a variety of round-celled sarcoma. The ap- pearance is the same as that of the other forms, but, microscopically, a close resemblance of structure with that seen in lymphatic glands is discovered. The principal characteristic is the reticulum or stroma formed by branching stellate cells united by their prolongations. In the meshes of this reticulum lie lymphoid round cells (Fig. 62). The stroma may not be plainly visible unless sections are shaken to dislodge the cells from the reticulum. The lymphosarcoma cell has a rather large round eccentric nucleus surrounded by a basophilic granular protoplasm. The distinctions of lymphosarcoma from lymphadenoma have been discussed under the latter heading. The principal feature of differentiation is the tendency of lymphosarcomata to extend beyond the normal limitations of the gland or other structures in which they originate, whereas lymphadenomata are confined by the glandular capsule. Fig. 63.—Alveolar sarcoma (Warren). Alveolar sarcoma is a subvariety of round-celled sarcoma, though there are always spindle cells as well. It is distinguished by the occur- rence of structures suggesting acini and filled with large round cells having a more or less decided epithelioid appearance. The stroma forming the acini is composed largely of spindle-shaped cells with a certain amount of fibrillar intercellular substance (Fig. 63). The blood- vessels supplying the tumors traverse these trabecule. The round cells within the alveoli may vary greatly in size, though they are usually large. The macroscopical appearance is not specially distinctive; many of the cases, however, are pigmented (see below). Alveolar sarcoma is most frequent in the skin, where it springs from moles and warts. It | may also occur in the lymphatic glands, the serous membranes, and other parts. In some cases the alveolar appearance of the sarcoma is due to the fact that the sarcomatous proliferation has occurred in the adventitia soe NON PROGRESSIVE TISSUE CHANGES 195 of blood-vessels, forming a plexus. In this way the meshes of the vascu- lar plexus become filled with round cells and the alveolar appearance results. In other cases the alveolar character is due to the occurrence of sarcomatous foci of circumscribed character in a connective tissue. These in their growth push the connective-tissue elements aside and thus form alveolar structures. Giant-celled Sarcoma This variety is characterized by the presence of large multinuclear cells resembling exactly the myeloplaques of bone. The remaining portions of the tumor may be spindle celled or round celled; perhaps more frequently round and spindle cells are associated. The giant- cells are often exceedingly large and contain several or many nuclei in 4 sok Fig. 64.—Giant-celled sarcoma (Warren). the center of the cell (Fig. 64). The formation of these cells is most likely due to rapid nuclear multiplication. In some cases they would seem to be caused by obliteration and transformation of capillary blood-vessels; but the theory that they result from a fusion of cells seems unwarranted. Ziegler and others maintain that the presence of giant-cells does not form an essential characteristic of a peculiar type of tumor, but that it is accidental, resulting from continued irri- tation. The occurrence of giant-cells in sarcomata of bones would then be explained by the constant irritation of the bony particles, while in other cases the presence of masses of blood-pigment in the sarcoma ac- counts for the development of giant-cells in the vicinity. This view is supported by considerable authority and seems reasonable. Giant-celled sarcomata occur most frequently about bone, and the terms osteosarcoma (a term to be avoided for this growth) and myeloid 196 A TEXT-BOOK OF PATHOLOGY sarcoma have been given in consequence. They may, however, occur in other situations. Their nature is usually benign, metastasis being rare. The giant-celled sarcoma of bone is usually rather slow in growth, and gives rise to hard and irregular tumors, firmly attached to the bone structures. It may begin within the bone as a myelogenous form (Fig. 65) or from the periosteum. Secondary myxomatous or other change may cause more or less softening. The bone most frequently in- volved is the maxilla, the tumor known as epulis (sarcoma springing ! Fig. 65.—Myelogenous osteosarcoma of the tibia (modified from Kast and Rumpel). from the gums or alveolar processes) being generally a giant-celled. sarcoma. ; The true osteosarcoma is a more definitely neoplastic process involving a growth of young, irregular connective-tissue cells with imperfect bone formation. There may be giant-cells, but they do not dominate the field as in the tumor just described. There may be several kinds of cells in the osteosarcoma. Such tumors are definitely progressive and malig- nant, as against the less active giant-cell myeloid tumor above. With their growth they absorb bony tissue, and lay down new atypical osseoid material. They may be cartilaginous, or chondro-osteosarcomatous, oF any combination of bone, cartilage, and sarcoma. The various kinds of cells found in sections of this tumor indicate alterations in cells natural to bone, either taking part in the sarcoma or being modified by the new growth. Thus one may find cells resembling adult bone PROGRESSIVE TISSUE CHANGES 197 or cartilage cells and sarcoma-cells. When growing within a bone these tumors thin the shaft so that the thinned-out bone gives the i 1 Fig. 66.—Bony structure of osteosarcoma of tibia. “egg-shell crackle.” The more cellular and less bony, the more malig- nant is the tumor, and vice versa (Fig. 66). Melanosarcoma Melanosarcoma, melanoma, chromatophoroma, or pigmented sar- coma is a form in which the tumor presents a dark color on account of the presence of black or brown pigment. The latter, according to care- ful chemical studies of Berdez and Nencki, contains no iron, and is, therefore, not a simple blood-pigment, but melanin, a product of cell metabolism. Iron-containing pigment has been found in some tumors, and sometimes in true melanosarcomata, being found outside the cells and probably accidental, the result of hemorrhagic extravasations. The true melanin pigmentation occurs in the cells, in the cellular pro- longations, or the intercellular fibrils. It is most frequently present in 198 A TEXT-BOOK OF PATHOLOGY the form of brownish-black granular matter, or may occur as a diffuse stain. Melanosarcoma most commonly arises in the skin, especially in pig- mented moles or warts, in the choroid coat of the eye, or in the pia mater. The growth is found to consist of cells of various shapes, some- times round or irregular, sometimes spindle shaped, but there is a very constant tendency, especially in the pigmented sarcomata of the skin springing from warts, to assume an alveolar arrangement. In these, the cells around the periphery of the alveoli are more or less spindle shaped, while those in the center are large, irregular, or rounded cells, sometimes epithelium-like. Melanotic sarcomata of the choroid are composed very largely of cells hay- ing an elongated character with drawn out extremities. These re- semble the normal pigment cells of the choroid coat. Melanosarcoma is extremely ma- lignant, recurring when removed and frequently causing extensive metas- tasis (Fig. 67). The latter involves the local lymphatic glands in the first place, but later various organs, es- pecially the liver. The metastases may be of the same structure as the original growth, but sometimes non-pigmented metastatic growths occur in association with the pig- mented ones. Occasionally the sec- ondary deposits are more pigmented than the primary growths. The melanoma originates from the pig- ile ment-containing cells or chromato- Fig. 67.—Metastatic melanosarcoma phores of the part in which they of lung, angie plemented and non-tie originate, Tn the skin these at possession of Dr. Allen J. Smith). found in close association with the lower layers of the epidermis, and some authors have insisted that they are essentially epithelial in origin and that the tumors should, therefore, be considered as carcinomata. There is, however, considerable ground for believing that the chromatophores are invariably connective-tissue cells. Melanosarcoma is a definite growth and not merely a sarcoma that happens to be pigmented. MIXED TUMORS All forms of connective-tissue tumors may be associated one with another; association of several forms are known as mixed tumors. Verv frequently there is more or less sarcomatous tissue in such growths. With this will be found myxomatous, fibromatous, chondromatous, or PLATE 1 MMeoelinosureonia. PROGRESSIVE TISSUE CHANGES 199 osteomatous elements. The various constituents of the tumor are arranged with no special order, but simply present themselves as masses of cells or intercellular substance of different forms combined to make a heterogeneous tissue. Among the frequent seats of such mixed tumors the parotid gland and the testicle are most important. A not infre- quent combination is that of sarcomatous and adenomatous tissue. Tumors of this character are supposed to develop from embryonal “tests,” and are particulary common in the kidney, where they often reach large sizes. (See also Teratomata.) Fig. 68.—Mixed tumor of thyroid gland. Adrenal “rests’”’ in the kidney give origin to the Grawitz tumor or hypernephroma, a tumor largely composed of cells resembling adrenal cells, arranged in adenomatous fashion. (See Tumors of Kidney.) Mycosis Fungoides Mycosis fungoides or granuloma fungoides is a pathological condition of the skin and subdermal structures, having certain resemblances to sarcoma and to some of the infectious inflammations. Etiology.—Very little is known regarding the causes of this disease. Various bacteria, principally micrococci, have been discovered in the lesions, but none of these has been shown to be pathogenic. A few observers have found bodies resembling protozoa; but it is not certain that these were really animal organisms. Appearance.—The disease frequently presents distinct stages. First, the skin becomes somewhat swollen and red and presents eczema- 200 A TEXT-BOOK OF PATHOLOGY tous lesions. In some cases the appearance is that of an erysipelatous inflammation. In the next stage nodular elevations occur, and finally tumors of considerable size, sometimes as large as an orange, and more or less fungoid in appearance. Necrosis is frequent and watery or bloody liquid is discharged. The tumors may have an angry, red appearance, and have been likened to tomatoes. Rapid disappearance and reappear- ance of the tumors is a peculiar feature. Any part of the body may be affected, and usually the lesions are multiple. Structure.—Microscopically, the structure of the tumors is allied to that of lymphadenomata. There is a proliferation of connective-tissue cells about the blood-vessels and glands at the base of the papillee of the skin, forming a network or reticulum i in which round (lymphoid) cells are embedded. The cells, however, may be irregular in form and size. Mitotic figures may be found. Early in the disease the new-formed cells degenerate considerably, but later proliferation predominates, and the tumor results. The epithelium covering the growth may be thinned to a single layer, or it may show thickening. In the latter case enlarged papille dip down into the round-cell collections and the sections have somewhat the appearance of carcinoma. Epithelioid cells and giant- cells may occur. The tumors are poorly supplied with blood-vessels, and to this is attributed the tendency to central necrosis. Inflammatory infiltration (polymorphous leukocytes) is not observed to any consider- able degree, excepting in the latter stages around and in the areas of necrosis. Mast-cells are often abundant. Associated Conditions.—In some cases enlargement of the lym- phatic glands, liver, and spleen has been observed, and has suggested the term pseudoleukemia cutis. Occasionally the blood presents leukemic characters. Nature.—The disease presents many resemblances to sarcoma or lymphadenoma, and it has frequently been described as multiple sarcoma of the skin. In other respects it is allied to the infectious inflammations, though there is much less evidence of true inflammatory infiltration than in these. The relationship to leukemia and pseudoleukemia is un- settled. Angiosarcoma The angiosarcomata are growths depending upon a proliferation of endothelium and an expression of the tendency of these cells to make new vessels. The tumors arising in lymph-channels are called lymphangio- endothelioma or lymphangioma, while those in blood-vessels are called hemangio-endothelioma, or simply angiosarcoma. In the second variety the sarcomatous proliferation may begin in the adventitious coat of blood-vessels (perithelioma). Angiosarcomata are met with in the serous membranes, in the skin, and especially in the salivary glands. Very rarely they occur in other parts of the body. The tumor is, as a rule, quite vascular, but may not be strikingly so. Sometimes telangiectatic change in the blood-vessels is PROGRESSIVE TISSUE CHANGES 201 noted. Histologically these growths are characterized by round-celled masses surrounding the blood-vessels. The origin of the cells from the ad- ventitia may be evident or obscure. In cases in which a vascular network is involved and each vessel has a coating of sarcoma-cells a plexiform appearance or arrangement results (plexiform angiosarcoma). In other instances in which a network of vessels is involved the sarcoma-cells accumulate in the vascular meshes in the form of cell-nests, and thus give rise to an alveolar form (alveolar angiosarcoma). Such forms occur in sarcomata springing from moles or warts. They are prone to melanotic change. The endothelium of the vessel is also the point of origin of vascular sarcomata. The proliferation of the endothelium leads to increase in vessels, narrowing of the lumen by irregular fibrosis. Fig. 69.—Angiosarcoma with myxomatous degeneration (cylindroma): the figure rep- resents one of the blood-vessels with the sarcomatous cells springing from its walls, and outside of these myxomatous tissue. Sometimes the original adventitia remains about the same size, but the lumen is filled with endothelium. The angiosarcomata are liable to degenerations, chiefly myxomatous (Fig. 69) and hyaline, and thus a certain proportion of the cases of cylin- droma (see below) have their origin. The blood-vessels may give way and hemorrhagic infiltration results. Angiosarcomata are, in a measure, benign, metastasis being very rare in the ordinary forms. The alveolar and melanotic varieties are highly malignant. Lymphangiomata are moist, gray, soft, spongy growths, commonest in the spleen. They are, however, quite rare. They consist of _pro- liferated lymph-channels with well-marked swollen endothelial lining cells. 202 A TEXT-BOOK OF PATHOLOGY Cylindroma This term was originally applied by Billroth to tumors showing gelatinous masses or trabecule traversing their substance. Histologically different forms of growths may be distinguished. We deal here only with sarcomatous cylindromata. The latter may be simply sarcomata in which hyaline or myxoma- tous degeneration has occurred in more or less insular fashion, or in which sarcoma and myxoma are peculiarly combined. Nearly always there is some hyaline change with the myxomatous. In most cases it is the angiosarcomata that present this peculiar condition. The sarcoma- _ cells surrounding the blood-vessels become converted into hyalomyxo- matous tissue or cause the formation of this. There result branching ' Fig. 70.—Cylindroma showing pronounced Hyalne degeneration of the walls of the blood- vessels. : columns of hyalomyxomatous character traversing the sarcoma. In some cases the walls of the blood-vessels themselves may be the seat of hyaline change (Fig. 70), the proliferated sarcoma-cells surrounding the vessel being merely pushed aside. The term angiosarcomata myxoma- todes is given to these vascular forms. Cylindromata occur in the salivary glands, the brain, the lacrimal glands, and rarely in the sub- cutaneous tissues. In nature they are more or less benign. We have grouped in the following pages those tumors now believed to be sarcomatous alterations of the covering and lining of blood- and lymph-vessels. These tissues are derived from the mesoderm, as is the case with tissues giving rise to sarcomata, and resemble these tumors in their manner of growth. The individual cells approach, however, the epithelial or carcinoma type. PROGRESSIVE TISSUE CHANGES 203 ENDOTHELIOMA This tumor, which is also sometimes designated endothelial cancer, resembles cancer very closely in histological appearances in some cases. It affects the pleura, peritoneum, and membranes of the brain most frequently, but may be found in the skin, walls of the blood-vessels, periosteum, bone-marrow, lymphatic glands, gums, ovary, testicle, liver, and salivary glands. The serous membranes when affected become greatly thickened, tough, and white in color (Fig. 71), and irregular elevations or nodules may occur. Metastasis is infrequent, but the adjacent organs are sometimes involved, and occasionally more f Saas arene ; Fig. 71—Endothelioma of pleura: the pleural cavity was distended with effusion and the lung was compressed and invaded by secondary nodules. distant structures: Endotheliomata of the dura mater spring from the inner surface of that membrane and have a flattened nodular char- acter. Histologically they may present the concentric whorls of cells and calcification characteristic of psammomata. Histologically endothelioma is characterized by more or less tubular or acinus-like aggregations of endothelial cells. The latter vary in character from those which are distinctly endothelial to the most differ- - entiated, which may be almost typical cylindrical epithelium (Fig. 72). Between these cellular columns or acini the connective tissue of the part affected may be seen in a normal state, though it is more frequently thickened by proliferation, and may grow into and around cell groups 204. A TEXT-BOOK OF PATHOLOGY to such an extent that they seem admixed or that the tumor cells de- generate. In the endotheliomata of serous membranes inspection of the sections shows that the columns of epithelioid cells occupy lymph-chan- nels, and it may be possible to demonstrate that the endothelium of the latter has been the starting-point of the cellular proliferation. [pn cases of carcinoma with penetration into the lymphatic channels it js notable, on the other hand, that the endothelial lining of the channels is uninvolved. Endotheliomata may in rare cases originate in the endo- “pbb Lene / He OLE ne = i —— = go eee = > QOS <9 TS Ese a NE al Da Fig. 72.—Microscopical section from the case shown in Fig. 71. thelium of capillary blood-vessels. In these growths anastomotic chan- nels lined with endothelial cells or anastomozing columns of endothe- lial cells proclaim the origin from vessels. Psammoma This represents no distinct species of tumor growth, but rather a peculiarity of different kinds. The name refers to the presence of cal- careous matter like that of the brain-sand (acervulus cerebri), and psam- moma has sometimes been called acervuloma. The calcareous matter occurs in the form of rounded masses or concentrically arranged whorls. The tumor elements themselves may be fibromatous, gliomatous, sarcomatous, endotheliomatous, or even adenomatous or carcinoma- tous. In most instances it is endotheliomata that present these appearances. Psammomata are met with in the membranes of the brain, the choroid plexus, and the pineal gland. TUMORS FROM NERVE TISSUES The various elements of adult nervous tissue are the descendents of the ectodermic cells lining the neural canal of the embryo. The tumors arising in nerve tissues contain the different elements in vary- ing grade of differentiation, and the tumors are usually named from the PROGRESSIVE TISSUE CHANGES 205 state of development. Naturally, the gangliomata and those containing chromaffin cells are of a higher grade than the tumors composed of abnormally proliferating simple nerve-cells, a very rare occurrence, or of glia. The ganglionar growths and those of some structures like the adrenal medulla, whose genesis is closely associated with the ner- vous system, frequently contain cells whose protoplasm stains granular brown when fixed with chrome salts (chromaffin cells). The glioma when pure is a well differentiated tumor, and is of sufficiently frequent occurrence and clinical importance to warrant separate treatment. Glia tissue plays an important part in most neuroblastomata. GLIOMA Definition.—The term “glioma” is applied to tumors composed of neuroglia with incompletely differentiated cells and many glia fibrils. It is difficult to draw a sharp line between the circumscribed tumors of this structure and the diffuse neurogliar hyperplasia or gliomatosis met with in certain cases. (See section on Diseases of the Nervous System.) Etiology.—It is probable that congenital defects of development play some part in the causation of these tumors, particularly in the forms more frequently spoken of as gliosis. Appearance.—A typical glioma is usually a solitary tumor, rounded in outline, though its limits are difficult to determine, as it merges gradually into the surrounding nervous tissue. Gliomata are some- what harder than the normal brain substance, and often the color is a little different, either more grayish or pink or reddish. Sometimes they are quite vascular and dark red. The normal shape of the part may be little disturbed, or there may be indefinite elevation. In size the tumor varies up to masses as large as a lemon. Diffuse gliomatosis causes a swelling of the af- fected parts, sometimes quite regular, at other times irregular. When the i : spinal cord is affected its thickness may pig 73.—Glioma of the corpora be considerably increased. On section, quadrigemina (Perls). the area of gliomatosis is rather firm and grayish in color. Nearly always there is a tendency to excavation or cyst formation. In the cord this leads to the development of con- siderable cavities, as a rule communicating with the central canal. Seats.—Gliomata occur in the brain and less frequently in the spinal cord. In rare cases the cranial nerves have been involved (Fig. 73). In one case a glioma was found over the coccyx and sacrum, originating from the remains of the lower end of the neural canal. Glioma of the eyeball will be referred to below. Diffuse gliomatosis is particularly common in the cord. It is usually met with in the vicinity of the cavi- ties of the brain or cord. 206 A TEXT-BOOK OF PATHOLOGY Structure.—The minute structure of glioma varies consider- ably according to the type of neuroglia represented. In the typical glioma the cells contain rounded or oval nuclei, and the protoplasm is scanty. Polynuclear cells may occur among the glia elements. The glia cells possess great numbers of exceedingly fine fibrils attached and separate from the interstitial fibrils. Wavy intercellular fibrils (neurog- lia fibrils) lying parallel to the axis of the cells to which they belong are characteristic structures. They are not prolongations of the cells, but merely touch the cells at their sides, the extremities of the fibrils being free. These fibrils are distinguishable from the finer fibroglia fibrils of connective-tissue growths. The abundance of the fibrils varies in different gliomata, but is generally a rather marked feature. The more rapid the growth, the fewer the fibrils. These give the section a granular appearance when seen under low magnification. In other cases the cells are of the ependymal type, and occasionally they may be arranged around the blood-vessels in rosette-forms. These formations, however, constitute only a small part of the structure, the bulk being composed of round glia-cells. The number of cells and the density of the intercellu- lar network vary greatly. Asa rule, the cells are larger than the normal neuroglia cells, and sometimes they contain several nuclei. The tumor is generally quite vascular, and occasionally telangiectatic vessels may be observed. Secondary hemorrhages are prone to occur in the latter case. Softening may occur, and occasionally sarcomatous transforma- tion has been described, though with doubtful propriety. Embryologic- _ ally the glia is an epithelial structure, and gliomata should, therefore, be classified as epithelial tumors, and sarcomatous transformation is im- probable. Diffuse gliomatosis has similar microscopical appearances, though the tissue is likely to be more compact and less vascular. In the spinal cord the process begins as a subepithelial proliferation of the glia at the posterior raphé of the central canal, the lining epithelium of this, at the same time, undergoing a certain amount of proliferation. Sub- sequently the gliomatosis increases and cavities form within. These may be lined with epithelial or epithelioid cells which are occasionally ciliated. Gliomatosis in the brain or cord may also present itself in the form of scattered nodular hyperplasias of the neuroglia. Nature.—Glioma is essentially benign. It is dangerous mainly on account of the pressure it exerts. Active proliferation and eccentric growth may occasion a considerable local malignancy in some cases. It is these that were formerly described as cases of sarcomatous trans- formation. The growth of the tumor is rather slow. They do not seem to give metastasis outside of the nervous system. Glioma of the Retina.—This tumor is a primary one of the retina, but may later extend to the eyeball and along the optic nerve. It is com- posed of round cells with large nuclei, often arranged around blood- vessels in a way suggesting the structure of angiosarcoma. This appear- ance is due to the fact that the cells surrounding the blood-vessels are preserved, while those at a distance are degenerated. In addition to the PROGRESSIVE TISSUE CHANGES 207 round cells, there are often found cells resembling epithelium in their appearance and their arrangement, the latter being that of epithelial rosettes. Ganglional cells have occasionally been discovered. The cells re- sembling epithelium have been regarded as derivatives of the outer layers of the retina, and the term neuro-epithelioma has, therefore, been applied by some authors. Others regard it as a glioma in the strict sense of the word. In either case the origin of the tumor is undoubtedly ectodermic, and the growth must be classified among the epithelial tumors. It occurs most frequently in children, particularly in early life (two to four years), and often on both sides simultaneously. Family predis- position, in some cases, is very striking. Extension along the optic nerve or externally, and a tendency to recurrence after removal, indicate the malignant character of the growth. Glioma Ganglionare Definition.—This term indicates a form of mixed tumor composed of neuroglia and nerve-fibers with large ganglionar nerve-cells; also called neuroma ganglionare. Fig. 74.—Ganglio-glioma of corpus callosum. Note the large irregular, imperfect ganglion cells, the deeply staining round glia nuclei with large wavy hypertrophic fibrils. Etiology.—Probably congenital abnormality of development fur- nishes the groundwork for the subsequent development of these tumors. 208 A TEXT-BOOK OF PATHOLOGY Appearance.—A ganglionar glioma may resemble the ordinary glioma, occurring as a solitary tumor, the outlines of which are difficult to distinguish from the surrounding tissue. More frequently it occurs in the form of multiple nodular condensations scattered through the brain or cord. The contour of the affected parts may not be altered, and on section the growths may be recognized only by the light-colored patches and areas of increased density. A few cases of ganglionar gliomata of the spinal or sympathetic ganglia have been described. In these cases the tumors appear as rounded enlargements of the affected ganglia. Occasionally the nerve-roots are seats of these tumors; the suprarenal capsules may also be affected. Structure.—The definition indicates the usual structure. The glia fibrils are generally conspicuous in number, the nuclei being compara- tively few. Traversing the tumor there may be more or less abundant nerve-fibers with or without medullary sheaths. Large ganglionar cells may be found in considerable abundance or in small number. The vascularity of the growths differs greatly. Nature.—The nature of these tumors is the same as that of the ordi- nary glioma. NEUROMA Definition.—Strictly speaking, neuroma is the term applied to tumors composed of nerve-cells and nerve-fibers. Ordinarily, however, the name is given to fibrous growths springing from the perineurium or endoneurium of nerves. The terms true and false neuroma distinguish between the two forms. True neuromata are rare, but Wright has called attention to the true neurocytoma or neuroblastoma made of cells like those of sympathetic ganglia associated with delicate fibrils. The last do not stain like neuroglia tissue. The cells are small, with round, deeply staining nuclei and relatively little protoplasm. They frequently assume a rosette- or acinus-like arrangement. Etiology.—Very little is known regarding the causation. Injury may play a part, as in the case of amputation neuromata. Appearance.—False neuromata occur as nodular thickenings along the course of nerves. They may be fusiform or elongated, may extend considerable distances along the nerves, and may form networks of ridges or elevations when the peripheral nerves are involved (plexiform neuroma). Asa rule, they are multiple, and sometimes occur in exceed- ingly great numbers, scattered over the entire body or involving a single part of the body, as the nerves of the arm or leg. After amputations rounded thickenings may occur at the ends of the nerves and cause painful conditions of the stump. Seats.—The peripheral nerves are most frequently involved, but the nerves may be implicated near their roots, or the terminal fibers within the organs may become affected. Structure.—Ordinary false neuroma consists of fibrous tissue in the form of reticular connective tissue with greater or less abun- dance of cells pushing aside or surrounding the nerve-fibers proper. PROGRESSIVE TISSUE CHANGES 209 The latter are prone to degenerate in consequence of the pressure. Proliferation of the nerve-fibers has sometimes been described, but it is doubtful whether such actually occurs. More probably the existing fibers increase in length and form a mass by curling at the end. True neuromata of two kinds are described: those composed of medul- lated, and those consisting of non-medullated, nerve-fibers. The former are called myelinic; the latter, amyelinic. ‘‘ Neurosarcoma ”’ is a modified neuroma in which atypical unrestrained proliferation occurs with a markedly inconspicuous interstitial tissue. In some the proliferated cells are of the epithelioid type. These tumors may occur in the cord. Occa- sionally a suggestion is given of acinus-like arrangement, and to this has been given the name “neuro-epithelioma.” Nature.—Neuromata are painful tumors, but benign in a patho- logical sense. Their growth up to a certain point is often rapid. LEIOMYOMA Definition.—Leiomyoma, or myoma levicellulare, is a tumor growing from smooth muscle-fibers. Nearly always there is a cer- tain amount of fibrous tissue associated, and in the most common form, myomata of the uterus, there is always considerable fibrous tissue, and the term “fibromyoma”’ is appropriate. Occasionally a few unstriped muscle cells may be seen in tumors of other kinds. Etiology.—Some of the myomata of the uterus exhibit glandular acini in the interior, which suggest their origin from congenitally mis- placed portions of the Wolffian body or duct of Miiller. These misplaced structures are assumed to cause an irritation of the surrounding muscle cells. This, however, is by no means certain. In other cases there are features suggesting that irritation is the important cause, though this also remains to be proved. Appearance.—Leiomyomata are usually rounded growths, vary- ing in size from minute nodules to huge solid masses weighing as ‘much as 60 to 70 pounds. The largest (heaviest) solid tumor ever seen by us was a degenerated fibromyoma weighing 80 pounds. Leio- myomata are surrounded by a capsule more or less well developed and are generally quite hard, though secondary degeneration at times alters the consistency, making the tumor quite soft in the case of mucoid transformation, or stony hard when calcification has occurred. On section through the growths the stratified or fasciculated arrangement of the cells is visible to the naked eye. Concentric layers may be ap- parent, or a more wavy irregularity may be seen. They are grayish or flesh colored, or in rare instances quite red (myoma cavernosum), in consequence of enlarged vascular channels. Central softening may lead to cystic change (myoma cysticum). When the myomata spring from the submucous or subserous tissues they may become polypoid, hanging from a point of attachment by a narrow pedicle. In rare instances the latter is severed and the tumor becomes a free body. Submucous myomata of the uterus may thus 14 210 A TEXT-BOOK OF PATHOLOGY eventually be discharged after a spurious labor. Subserous myomata may become free in the peritoneal cavity. Gross myomata of the uterus may have three situations—submucous, subserous, or interstitial. Originally, all true forms begin as interstitial, In the latter the tumor occupies the wall of the uterus without any particular projection on either surface. Uterine myomata are usually multiple, occur during the third and fourth decades of life, continuing their growth until the menopause, and usually decreasing after that epoch. They endanger life by their pressure and by the copious uterine hemorrhages which they occasion. Very frequently salpingitis is associated, and recently attention has been called to degenerated conditions of the myocardium in patients suffering from uterine fibroids. Myomata of the skin occur in younger patients, even in childhood, and are generally multiple and often painful (tubercula dolorosa). Seats.—The common situations are the uterus, the gastro-intestinal tract, and the ovaries; the less common seats are the walls of the blood- vessels, the skin, and the nipple. In all situations the tumor springs from pre-existing unstriped mus- cle-fiber. In most cases, accord- ing to some authors, the origin is in the walls of the minute blood- vessels, but direct origin from the muscular layer of the affected organs, or from the erectores pilo- rum in the case of the skin, cannot be denied. Myomatous meta- plasia of the connective tissue, as in the case of myomata originat- a ing in the areas of old pleural Fig. 75.—Leiomyoma. thickening, has been assumed, but a is improbable. Structure.—Microscopically, the tumor presents a charaeteristic ap- - pearance. Bundles of muscle cells are seen running in different directions. Those cut longitudinally show cylindrical nuclei as the most conspicuous feature, the outlines of the cell being indistinct (Fig. 75). The proto- plasm stains well with eosin. Lying between the muscle cells are colla- gen and so-called myoglia fibrils, the latter being coarse lines lying along the sides of the cells, while the former are more delicate and are associ- ated with fibrous tissue cells. The picture of a leiomyoma is often sug- gestive of sarcoma, but may be distinguished by the greater regularity in direction of the cells in different bundles and by the more distinctly cylindrical outline of the nucleus. The cells of leiomyomata may be isolated by maceration of the sections in 20 per cent. solution of nitric acid for twenty minutes, or in 30 per cent. solution of caustic potash for fifteen minutes. They are spindle-shaped structures containing @ nucleus about one-third the length of the entire cell. On section they PROGRESSIVE TISSUE CHANGES 211 can be differentiated from fibrous tissue cells by showing an appreciable amount of protoplasm around a rod-shaped nucleus, while the connect- ive-tissue cell has very little protoplasm about a short spindle-shaped nucleus. Considerable elastic tissue is found in some leiomyomata, es- pecially in the younger areas. Leiomyomata are generally poor in blood-vessels, but may show a telangiectatic condition of the vessels. The lymphatic channels may similarly dilate, forming cystic spaces containing spontaneously coagu- lable material. Of the degenerative changes, calcification is the most common, par- ticularly in the uterine fibromyomata. This begins in the center of the tumor, but may eventually involve the whole mass. Myxomatous change may occur in myomata containing much fibrous tissue, and sarco- matous transformation has been described, but is rare. The sarcomatous change has been explained by some as a metaplasia of the muscle cells, by others as arising from fibroblasts. The latter is probably correct. Many so-called sarcomata coming from smooth muscle tumors are doubtless merely actively proliferating, therefore softening, leiomyomata. Uterine myomata do not all present the same appearance. Some are all of muscular nature, some are wholly fibrous, and we have all possible intermediate grades. Those in which fibrous tissue preponderates may be called “fibroids.” Young tumors are mostly muscular; old ones, mostly fibrous. Whether this is purely a metaplasia or an overgrowth of the muscle by fibrous supporting tissue is not settled. The origin of the myomatous tissue is said by some not to be the uterine muscle bundles, but the muscularis of blood-vessels. The vessels of myomata have very wide walls with wide muscular coats. Adenomyoma of the uterus is a myoma with structures like gland acini. These are variously explained as coming from remains of the Wolffian body or Miiller’s duct, from the mucous glands, or inversions of the serous covering. They may undergo carcinomatous increase, but adenomyomata are not malignant per se. Nature.—The nature is eminently benign. Myomata of the digestive tract may cause occlusion or strangulation, or by their weight may exercise serious traction. Uterine myomata are dangerous in the ways already indicated. The growth is usually slow. RHABDOMYOMA Definition.—Rhabdomyoma, or myoma striocellulare, is a tumor containing more or less striped muscle-fiber. Usually there is but a small quantity of the latter, the bulk of the tumor being of some other tissue, most frequently sarcomatous. Etiology.—Congenital defective development seems an important cause, as the tumors occur in early life and in situations in which striped muscle-fiber does not normally occur. 212 A TEXT-BOOK OF PATHOLOGY Appearance and Seats.—The rhabdomyomata of the kidney (the most frequent seat) present themselves as large rounded or irregular masses, more or less encapsulated. In the testicle they are similar, though of smaller size. A few cases have been described in which irregu- lar tumors of the retroperitoneal tissues have contained muscle-fibers. Structure.—The microscopical appearance is usually that of a spindle-celled sarcoma, containing more or less striped muscle-fibers. These are elongated spindle-shaped cells, partly striated, and suggesting embryonal muscle-tissue and rarely more fully developed muscle-fibers. Large areas of the tumor may contain no muscle-fiber at all, while certain portions are richly supplied. Adenomatous elements are not rarely associated. The tumors of the kidney which contain striped muscle-fibers are, in the main, sarcomatous or adenosarcomatous. Nature.—These tumors are malignant in proportion as the sar- comatous element is predominant. This sarcomatous nature is indi- cated by activity of proliferation, spread, and metastasis. Metastasis is, however, infrequent. General cachexia and hemorrhages reduce the vitality and lead to fatal termination. EPITHELIAL TUMORS This heading covers all the tumors in which the cellular unit is the epithelial cell of covering or glandular tissues, supported by more or less connective tissue, the relations of the two determining the character of the growth. In some arrangements there is simply an exaggeration of the normal, the so-called typical epithelial growths, while in others there is wholly new or atypical arrangement of the elements. The first, like papilloma, are essential benign, while the second group is best exempli- fied by the malignant carcinoma. PAPILLOMA Definition.—The term “papilloma” indicates a tumor arising from a surface and covered with epithelium somewhat as the epidermis caps the papillee of the corium. Etiology.—It is difficult to draw a line between certain papillo- matous growths that are the result of chronic irritation and others that arise in a seemingly spontaneous manner. It would appear that irti- tation is an important factor in most, if not all, cases, but there is also, no doubt, some form of predisposition. Whether this resides in structural peculiarities or not is difficult to determine. A peculiar form of inflam- matory growth resembling the spontaneous papillomata is that known as venereal wart. It occurs about the genitalia or anus and especially after gonorrhea. Another form of inflammatory papillomata is that found in the mucous membranes surrounding carcinomata or chronic ulcerations of syphilitic or other kinds (Fig. 76). Appearance.—The most familiar form of papilloma is that which occurs in the skin and which is commonly called wart. Warts or pap- PROGRESSIVE TISSUE CHANGES 213 illomata may be single, but more frequently occur in groups, and there may be many growths in widely scattered areas of the body. A wart may be simply a smooth hemispherical elevation, or it may have a cauli- flower appearance. The epidermis covering it is, as a rule, somewhat more granular or rough than that of the normal skin. The size of these growths varies from minute points to nodules as large as a walnut. On the mucous surfaces, especially where the epithelial covering is colum- nar, the papilloma presents itself as a soft and more distinctly cauliflower growth (Fig. 77). It is red in color, or, if the epithelium is stratified and squamous, grayish or pink. The growth is usually comparatively hard when covered by squamous epithelium. Fig. 76.—Various grades of warts and cutaneous papillomata (Perls). Two varieties are sometimes distinguished: the hard papillomata, such as those which occur in the skin; and the soft papillomata, or the form usually seen in the mucous membranes. Seats.—Papillomata occur in the skin of the neck, hands, back, and other parts, and in the mucous membranes, particularly in the bladder, larynx, nasal chambers, and gastro-intestinal tract. Small papillomatous outgrowths may spring from the lining membrane of glandular ducts, as in the breast or ovary. These may lead to subse- quent cystic change in the organ, or they may arise after cystic change has begun by proliferation of the lining membrane of the cyst. Ina simi- lar manner papillomatous elevations may occur within the cavities of cystic adenomata (see below). 214 A TEXT-BOOK OF PATHOLOGY Structure.—The essential parts of papilloma are the center or groundwork of connective tissue containing blood-vessels and the epi- Fig. 77.—Papillomata of the vocal cords (from a specimen in the Museum of the Philadelphia Hospital). thelial covering. In the skin the growth imitates the normal papille, all portions of the latter, however, being greatly ex- aggerated, and the papilla with its cover- ing of epidermis being raised above the surface instead of having its usual seat below the surface with the epidermal covering level with the surrounding parts. When there is tendency to cauliflower ap- pearance the papilloma shows a branch- ing form on vertical section. Each of the branches contains a connective-tissue framework with an epithelial covering. The latter consists of stratified, squamous cells and shows a decided tendency to horny change. Distinct concentric whorls of horny epithelium, such as occur frequently in epitheliomata of the skin, may be met with in papillomata. In some cases the amount of connective-tissue groundwork in the papilloma is excessive; in others the new growth consists almost entirely of pro- liferated epithelium. In some of these latter cases the resemblance to epithelioma may be quite suggestive, but a distinction can be made, by observing that the tumor tends to grow outward rather than into the deeper Fig. 78.—Finer details of papilloma, showing connective stalk and stratified squamous epithelium. structures, and always shows some connective-tissue stroma at least. The papillomata of the mucous membranes differ according to their PROGRESSIVE TISSUE CHANGES 215 situation. In the larynx and other portions covered with squamous epithelium they may present much the same appearance as that seen in the skin, though the epithelium, as a rule, remains softer. -There are cases, however, in which a distinct pachydermatous change is found in the epithelial covering of papillomata. In the gastro- intestinal tract and in the bladder papillomata are prone to be soft and villous in appearance and are cov- ered with a scantier epithe- lial coating. Cystic change is not unusual as a result of degenerative processes or of distention of the mucous glands. Occasionally hem- orrhage occurs from papil- loma, particularly of the . villous variety. Melanotic pigment is sometimes found in warts. .Nature.—The nature of cs these tumors is benign, but Fig. 79.—Papilloma of the scalp. The branching they may be destructive of fibrous stroma is covered by an abnormally thick- : ened, irregular epithelium (Boyce). the general health in con- sequence of repeated hemorrhages or by interfering with the function of the organ or part in which they are situated. In some cases they are supposed to become malignant, but this has not been definitely proved. pes e ADENOMA Definition.—This is the term applied to a new growth corre- sponding more or less in structure with compound epithelial glands, and, therefore, presenting acini or tubules containing glandular epithelial cells (cylindrical or polyhedral) growing upon a basement-membrane, and a reticulum of connective tissue and blood-vessels. It is difficult to separate from true adenoma simple glandular hyperplasia on the one hand and carcinoma on the other. This will be discussed in re- ferring to the structure. Etiology.—The causation of adenoma is obscure. In some cases congenital misplacements of tissue-elements appear to play a part, as is seen in the cases of adenomata of the kidney having the structure of suprarenal bodies. These tumors which, it is true, some authorities refuse to consider as adenomata, have a general resemblance to adeno- mata and spring from remnants of suprarenal tissues embedded in the kidney substance. Traumatism may be a factor in the etiology by exciting the proliferation of such misplaced tissue elements. In other cases the ordinary glandular structures seem to be stimulated to 216 A TEXT-BOOK OF PATHOLOGY abnormal hyperplasia and tumor growth in consequence of continued irritation. Instances of this sort are frequently seen in the gastro- intestinal mucous membranes, notably in the stomach and lower part of the colon, in certain cases of chronic gastritis and old dysenteries. Appearance.—The appearances of adenomata vary greatly with their seat. On the mucous surfaces there may be a simple thickening or more or less diffuse and irregular elevation of the surface, or in other cases distinct papillomatous outgrowths and rarely definite nodular tumors. In some of these cases the condition is purely one of inflamma- tory hyperplasia; in other cases there is undoubted tumor growth. No sharp demarcation can be established. In the substance of the organs adenomata occur as nodular tumors, usually singly and well circum- scribed, and not rarely surrounded by a fibrous capsule. They are moderately firm, and on section whitish or pink in color. Sometimes cystic change occurs as the result of dilatation of the glandular acini or in consequence of degenerative softening; in these cases the consistence is correspondingly altered. Seats.—Among the situations in which adenoma is frequent may be mentioned the mucous membranes, the skin, and certain organs, - notably the mammary gland, liver, kidney, suprarenal bodies, thyroid gland, and ovaries. Clinically important seats are the pylorus, the duod- enal papilla, the rectum, and the uterus. In these situations adenomata spring from the epithelial tubules or mucous glands. In the skin the points of origin are the sebaceous and sweat-glands. ; Structure.—The definition in general indicates the structure of these tumors. They are more or less typical; that is to say, there are acini of normal appearance presenting a single layer of columnar epithelium, with perhaps in places a tendency to heaping up the several rows of epithelial cells. In the simple adenomata there is usually one layer. The greater the number of layers of epithelial cells, the greater the tendency to malignant growth; such a condition is found in adenoma malignum along with other features. The acini are well inclosed by a surrounding connective-tissue reticulum, and the appearance of normal gland tissue is thus produced. Unlike normal glands, there are no excretory ducts, or, at most, imperfectly developed ducts. Two varieties of adenoma are sometimes distinguished: the tubular and the racemose or alveolar. In the former the glandular system is simple and consists of tubular formations lined with columnar epithelial cells; in the latter the appearance is that of more complicated glands with closely aggregated acini of circular outline containing columnar and often cubical or polyhedral cells. The number of varieties may be carried further, however, for in the liver the adenomata resemble the normal liver structure rather than the ordinary glandular formation above described. In the suprarenal capsules and kidney the appear- ance is that of slightly atypical suprarenal structure, or in other cases that of embryonal renal tubules distended to form considerable cystic spaces, with partitions and inwardly projecting papillomatous elevations. With the further growth of adenomata the appearance may be little PROGRESSIVE TISSUE CHANGES 217 changed. In some cases considerable variations occur, and there is a tendency, more marked in some situations than in others, to active pro- liferation of the epithelium, which may cause a considerable alteration in the histology of the tumor, and eventually transformation into definite carcinoma. The terms ‘‘adenocarcinoma,”’ ‘‘destructive adenoma,” and ‘malignant adenoma’ are sometimes applied in such cases. The same names, however, are given to a type of adenoma characterized by the formation of abundant anastomosing or separated tubules and acini with comparatively little reticular tissue, and by the tendency to repe- tition of the same structure in the local extensions from the original growth and even in metastases (Fig. 80). Fig. 80.—Destructive adenoma (Beyea). The connective-tissue stroma of adenomata may be moderate in quantity or may be considerable. In some adenomatous prolifera- tions of the mucous membranes the number of gland acini or tubules may be relatively small, while the interglandular connective tissue shows active round-cell infiltration to a very considerable degree. Sometimes the interglandular tissue is distinctly sarcomatous (adeno- sarcoma). In other instances the bulk of the tumor may consist of connective tissue of fibrous character in which are embedded a rela- tively small number of glandular alveoli. In all of these cases it is difficult to determine whether the connective-tissue process was pri- mary and the epithelial secondary, or the reverse. As has been suggested, it is well-nigh impossible to distinguish between some adenomata and some hyperplasias. This is particularly true of hyperplastic growth without fibrous tissue. This condition is, how- ever, apt to follow the general architecture of the gland in question and is not apt to be encapsulated. The adenomata have a tendency to show small, normal sized, and cystic acini in the same field. It is like- 218 A TEXT-BOOK OF PATHOLOGY wise a task to differentiate chronic inflammation and fibro-adenoma. In the former nearly all gland tissue is compressed and cysts are rare. When present they soon loose their epithelium. In fibro-adenoma epi- thelial reduplication is pronounced and the fibrous tissue increase is more diffusely distributed. : Secondary changes are common, the adenomata of the stomach and uterus being particularly prone to change their character to that of. carcinoma. In these cases there may be noted active proliferation of the epithelial cells, so that acini or alveoli become completely filled, or that the ends of tubular structures become blocked up. There is a tendency to extension of epithelial infiltration beyond the limits of the acini, cancerous outgrowths being the result. In other cases the Fig. 81.—Adenoma of the mammary gland, with cystic enlargement of acini and abundant interglandular hyperplasia of connective tissue. malignancy is manifested by the excessive epithelial proliferation in the form of new acini of irregular character (see Fig. 80). Eventually the tumor may become purely carcinomatous; in other cases, however, it continues to increase in size, always retaining its adenocarcinomatous appearance, but never becoming typically carcinomatous. Degenerative changes may be met with in adenomata as in other tumors. Hyaline transformation or production of hyaline or myxoma- tous tissue in the stroma may give the tumor an appearance justifying the term “cylindroma” or “‘cylindro-adenoma.” Such cases are rare. Myxomatous and even calcareous change may sometimes be observed. The connective-tissue stroma may proliferate actively and assume sar- comatous appearance—adenosarcoma. Cystic change may result from PROGRESSIVE TISSUE CHANGES 219 gradual dilatation of the glandular acini or from distention of normal ducts or alveoli of the gland in which the tumor occurs. In these cases the terms “cystic adenoma” or ‘“‘cystadenoma” are applicable (Fig. 81). Nature.—Adenomata are benign tumors. In some cases, however, a pure adenoma may give rise to metastasis. Those of the liver, for example, not rarely cause secondary deposits in the spleen and less frequently elsewhere. The adenomata of the thyroid gland similarly cause metastasis, though their structure does not in any way suggest a malignant growth. Destructive adenomata or adenocarcinomata are malignant in proportion to the amount of carcinomatous transformation on the one hand, or of atypical glandular proliferation on the other. The effect of adenomata on the general health is variable. They do not contribute to the general metabolism as far as is known, though occasionally biliary pigmentation of the adenomata of the liver, and even of their metastases, and the secretion of milk-like fluid in mammary adenomata evidence the partial preservation of function by the cells. The general health may be unfavorably influenced by adenomata of the mucous surfaces in consequence of their interference with normal functions or in consequence of secondary ulceration and hemorrhage. CARCINOMA Definition.—The terms “carcinoma” or ‘cancer’ may be applied to tumors in which epithelial proliferations in the form of solid blocks or columns, or in the form of atypical acini, separated by more or less con- nective tissue, present themselves, the epithelial proliferation showing a tendency to extend beyond normal anatomical limits. It is extremely difficult to construct a definition that will be universally. applicable. Some have regarded the tendency of the epithelial proliferation to break through the normal limits, and extend beyond the confines of the epi- thelial structures from which it rises, as the important fundamental element of carcinoma. Others have held that there is a peculiar atypical character in the epithelial cells themselves, shown by irregular cell division, hyperchromatosis, and other features. The older authors believed that polymorphism and certain irregularities of cell contour suffice to distinguish carcinoma-cells from normal cells or those of other tumors; but this polymorphism is now recognized to be the result entirely of compression in the growth of the tumor, and to be, therefore, accidental. Some have believed that the term “‘carcinoma” should include all epi- thelial tumors giving rise to metastasis, but this necessarily restricts the term too greatly on the one hand, and, on the other, includes cer- tain tumors probably purely adenomatous. We prefer to regard as car- cinoma any epithelial growth atypically reproducing certain glandular or other structures and showing a manifest tendency to irregular extension. Etiology.—The causes and nature of carcinoma are still obscure. A number of theories have been offered. These have been referred to in the discussion of the etiology of tumors in general. A brief reconsid- eration may be useful in this place: 220 A TEXT-BOOK OF PATHOLOGY (a) Congenital Theory.—The theory of Cohnheim regarding the etiology of tumors in general is less applicable to cancer than to certain other growths. There are a few examples, however, which would seem to prove that misplaced epithelial cells undergo carcinomatous pro- liferation; for example, there are cases of apparently primary carcinoma springing from bones which would seem to require this explanation. It is not always certain, however, that such cases are actually primary. The rarity of carcinomata in early life would seem to negative the congenital theory, and, at all events, would show that other influences of importance are requisite. (b) Traumatic Theory.—Clinicians are inclined to give great weight to this. A single traumatism probably has little importance, though women frequently state that they recall distinct injuries from which carcinomata of the breast have seemed to originate. It must be recalled that such injuries are sustained by practically every woman, and the presence of carcinoma would readily be attributed to a preceding hurt. In cases of epitheliomata of the lip in pipe-smokers, in the carcinomata of the scrotum and limbs in chimney-sweeps and paraffin-workers, in the skin of tar workers, and in cases of uterine carcinomata following lacera- tion of the cervix, the effect of chronic irritation would seem to be im- portant. The frequent association of gall-stones with carcinoma of the gall-bladder has often been considered in the same light. (c) Infectious Theory.—The peculiar growth of cancer, its destruc- tiveness of the general health, and its metastasis readily suggest an infective origin. Bacteriologists sought to isolate micro-organisms without success; later investigators have turned their attention to low forms of animal life—protozoa. (For further discussion, see p. 161.) A few successful experiments have been made at implantation from man to animals, or from one animal to another; but as Hanau, one of the early experimenters in this work, himself states, these experiments do not prove infectiousness. The secondary growths in the second animal may be simply of the nature of metastasis, due to implantation of the cancer-cells, followed by their proliferation. A renewal of activity in the study of the etiology of cancer during recent years, and with all the advantages of modern methods, has thus far led to no positive result. Statistical evidence, the probable cases of accidental infection in surgeons and others, the more or less suggest- ive results of experimental inoculation, and the distribution of cancer— lend some probability to the infectious theory, but it must be confessed that the evidence is far from positive. Among vegetable organisms to which etiological significance has been attributed are the blastomycetes, which some investigators claim to have found in every cancerous growth examined, and the assumed importance of which is further based upon the results of experimental infections with cultures of the organisms. The invariable occurrence of blastomycetes has, however, been disproved, and the experimental lesions are not really analogous with carcinoma. Many inter- and intracellular cancer parasites have been described. There are within PROGRESSIVE TISSUE CHANGES 221 and between the cells certain unusual bodies with rather definite stain- ing reactions seeming to pass through a metamorphosis. These are now explained as the results of nuclear degeneration or discharge of its chromatin. Still other intracellular bodies in cancer are to be ex- plained as the remains of ingested masses, since the cancer-cell in its progression into the surrounding tissue consumes cell detritus. None of these bodies can be held as proved causes of cancer. (d) Tumor Dyscrasia.—This indefinite term is supposed to indicate that certain peculiarities of the liquids of the body occasion the tend- ency to cancerous growth. No proof of the existence of any definite dyscrasia has ever been furnished, though it is not unlikely that some form of disposition to this growth acts as the predisposing cause, even if traumatism, infection, or other factors are the immediate cause. Certain conditions are supposed to precede and favor some cancers. Paget’s disease of the nipple may precede mammary cancer, as also gastric ulcer may pave the way for carcinoma of the stomach. Previous benign epithelial growths may become carcinomatous, as indicated by their penetrative and greater proliferative powers, but not necessarily by any alteration of the cells themselves. Age plays an important part in the formation of carcinoma, as this tumor is essentially one of advanced years. Among 275 cases collected by Lubarsch, 55.6 per cent. occurred between the ages of forty-five and sixty-five. There were a few instances in childhood and early life. Be- tween fourteen and nineteen there were 1.46 per cent.; between twenty and twenty-five, 1.8 per cent.; between twenty-six and twenty-nine, 1.1 per cent. The frequency in later life was formerly ascribed to some alteration in the vitality of the epithelial cells, rendering them more liable to abnormal proliferation. The nature and cause of such altera- tion, however, remain obscure and theoretical, though there is certainly a greater tendency to cancer growth as age increases. Heredity was formerly regarded as of great importance. Certainly in some cases there seems to be hereditary transmission of the tendency to develop carcinoma: Appearance.—Carcinomata differ considerably in appearance in different parts of the body. Those of the surface present themselves as more or less nodular, flat elevations. In the skin the nodules may remain hard and rather smooth, or they may soften upon the surface, forming unsightly ulcerations. In the mucous membranes the growths are more frequently soft and polypoid or cauliflower excrescences (Fig. 82). Ulceration may occur on the surface of such elevations, or from the first the tumor may be of ulcerative character, causing spreading ex- cavations limited by thickened projecting edges. Carcinomata of the glandular organs form more or less nodular tumors or irregular infiltra- tions. These vary greatly in consistency, some being almost stony hard, others soft in consequence of their preponderating cellular character or of secondary degenerations. On section, the tumor is found to be white or grayish in color, generally somewhat translucent and _ glistening; milky liquid may ooze from the surface. Capsule formation is rarely 222 A TEXT-BOOK OF PATHOLOGY seen, though in occasional instances the normal connective tissue of the organ is pressed outward by the growth of the tumor, and thus forms an imperfect capsule. The primary growth is generally solitary. Occa- sionally instances are observed in which two separate masses develop simultaneously and apparently independent of each other, as in the two breasts. More fre- quently apparent multiplicity is caused by the early appear- ance and rapid growth of met- astases. Secondary carcinomata are nodular in character and nearly always multiple. The larger are often distinctly en- capsulated. Central softening or contraction of connective tissue may give the surface of the nodule an umbilicated character (Fig. 83). The num- Fig. 82.—Carcinoma of the duodenal papilla ‘ (modified from Kast and Rumpel). ber varies greatly, from a few large or small nodules to in- numerable tubercle-like forms in general carcinomatosis. In some situa- tions, as in bones, secondary carcinoma has an. infiltrating character. Seats.—The situations in which carcinomata occur are very numer- ous; they invariably arise from pre-existing epithelial structures. In ios acacia . 2 naa, Fig. 83.—Metastatic nodules of carcinoma on the surface of the liver (Hanot and Gilbert). the rare instances in which a presumably primary carcinoma has oc- curred in bone or other connective tissues the presumption is war- ranted that the tumor originated from remnants of epithelial tissue left by faulty development. Among the frequent places of origin the most PROGRESSIVE TISSUE CHANGES 223 important are the uterus, the skin, the gastro-intestinal tract, particu- larly the esophagus, pylorus, and rectum, the mammary gland, the ovaries; less frequently the liver, kidney, thyroid gland, prostate, or testicle may be the starting-point. Secondary carcinomata curiously do not often affect parts in which the primary growth is frequent. Of the many seats of secondary carcinoma, the lymphatic glands, the liver, spleen, lungs, heart, and serous membranes are the most im- portant. Secondary carcinoma of the bones is specially frequent after carcinoma of the breast or the thyroid gland. Structure.—The histology of carcinoma varies greatly in different situations and in different forms. There are two distinct elements in- volved—viz., epithelial cells and a connective-tissue stroma. The pi F @ e 1: Si Gee ‘£38 e ‘of 62 Sai ie gO /E Fig. 84.—Epithelioma of skin, showing concentric arrangement and degeneration of cells. epithelial cells are medium sized or large, and have a rather large and clear nucleus; the shape of the cell, however, differs widely. In epi- theliomata of the skin the cells are large and usually of a squamous variety. In carcinomata of mucous membranes they are more often cylindrical or columnar, and there is a tendency to the formation of cu- boid or polyhedral epithelium. The last-named forms are habitually present in the cancers of glandular organs. The mutual compression exercised may occasion a polymorphous character, and the older writers wrongly regarded this as a feature by which a carcinoma-cell could be recognized as such. Secondary changes may occasion wide variations in the appearance of the cells; thus, the epithelia of cancers of the skin tend to become arranged in concentric whorls and at the same time to become somewhat glistening from horny transformation (Fig. 84). 224 A TEXT-BOOK OF PATHOLOGY The nucleus may be clear and quite structureless, or may show a dis- tinct nucleolus and a definite chromatin network. Karyokinetic fig- ures may be quite abundant and are frequently atypical. Degenerative changes (dropsical infiltration, myxomatous change, fatty degeneration) may alter the nucleus as well as the body of the cell. 8 The epithelial cells are usually grouped as cylindrical and branching or anastomosing columns, or as irregular tubular formations, the tubules being of varying lengths. The explanation of the structure of the col- umns or tubules is that they are formed by the extension of the masses of proliferated cancer-cells along the lymph-channels and spaces of the tissue. Very often the section shows all the tubules cut transversely, and thus the appearance of glandular acini is given. In some cases the tubules are short and acinus-like; as a rule, however, the appearance is Fig. 85.—Carcinoma of uterus. only due to the manner of section. The acini differ strikingly from those of adenoma in showing several or many layers of cells instead of one, and there is the further difference that cellular outgrowths may be seen at the periphery of the acini, the cells having broken through the retaining wall (basement-membrane) and proliferated outside to form new clumps (Fig. 85). On examination of the epithelia within the acini it is found that those of the peripherai layer frequently retain the columnar character seen in the normal alveoli of the gland from which the tumor springs. The connective-tissue stroma of carcinoma is more or less dense, but practically is always of fibrous character. It is arranged in such manner as to form hollowed spaces or columns in which the epithelial structures already described are embedded. The connective tissue PROGRESSIVE TISSUE CHANGES 225 carries the blood-vessels. The lymph-vessels probably connect directly with the cell-nests. In general, the more connective tissue in a cancer, the less its malignancy; while the more cells, the greater its tendency to metastasis and recurrence. Recently attention has been called to the fact that elastic tissue is formed in the stroma of the tumor in varying abundance. Frequently infiltrating leukocytes and plasma-cells or mast-cells are seen within the stroma. When the stroma begins to grow and show atypical proliferative tendencies we have what is called carcinoma sarcomatodes. The above description applies to the ordinary carcinoma of glandu- lar organs. Some difference is observable in the cancers of the skin and other external surfaces. In these the structure is rather that of much enlarged papille, the interpapillary epithelial plugs penetrating into the deeper tissues. The cells in their early stages are similar to those of the deeper layers of the skin, are larger and more translucent than those of glandular cancers. Subsequently the cells tend to become of the squamous type and undergo more or less horny change. Hollow alveoh and acini are unusual in cancers of the skin, though such structures may occur in some cases. Degenerative Changes.—Carcinomata are quite prone to degenera- tions.. In nearly all cases in which the tumor has reached considerable size more or less fatty degeneration of the cells becomes apparent. Preceding this or associated with it may be cloudy swelling or dropsical infiltration of the cells, rendering the nuclear outline less distinct and sometimes causing vacuolations. Irregular and multiform nuclear de- generations are met with, and probably occasion some at least of the structures known as parasites of cancer. The epitheliomata of the skin are particularly prone to a horny transformation, this occurring first and most prominently in the concentric whorls already described. In the adenocarcinomata of the ovaries and other genital organs of women the degenerated epithelial cells frequently undergo calcareous infil- tration, and psammomata are thus formed. Colloid degeneration of the epithelial cells is a rare event, and the term “‘colloid cancer” is gener- ally a misnomer, the real degeneration in most of these being myxoma- tous, affecting the connective tissue principally, though the epithelial cells are to a certain extent involved. Complete degeneration by myxomatous or associated myxomatous and fatty change may de- stroy all of the characteristics of the original tumor. In some cases cystic transformation occurs in organs the seat of cancer, or in the cancer itself. This may be due to occlusion and subsequent dilatation of the ducts of the organ or of the acini in the tumor, the cystic spaces becom- ing filled with mucoid or gelatinous material. In some instances cystic carcinomata are secondary developments originating in cystic adeno- mata. Hyalin change and pigmentation are rare in cancer. Hemorrhage occurs by ulceration of a large vessel. Inflammatory processes are quite common. Cancers on free surfaces are prone to undergo ulceration in consequence of irritation and infection. Among the micro-organisms discovered in such instances the staphylococcus 15 226 A TEXT-BOOK OF PATHOLOGY and streptococcus are conspicuous. A distinct erysipelatous inflamma- tion may occur in cancers as in other structures. Invasion of tubercle bacilli and the growth of miliary tubercles in carcinoma are rare events, though they sometimes occur. Associations of carcinoma and tubercu- losis or syphilis may in other cases result from the secondary growth of cancer in pre-existing gummatous or other syphilitic lesions or in lupus. Practically all carcinomata show some leukocytic infiltration. The amount of this, however, varies greatly. In the healthy tissue border- ing carcinomata there is always an inflammatory infiltration of round cells, but this does not limit the growth like a capsule. A carcinoma is probably never sharply marginated. Nature.—Carcinoma is essentially malignant, the degree of malig- nancy depending, however, upon the seat and upon certain peculiarities of the individual. Sometimes a small growth may remain practically latent for a long time, until accidental circumstances, like traumatism, intercurrent disease, pregnancy, or the like, stimulate active growth. Its rate of growth is variable, but chiefly it is progressive, regardless of speed. Occasionally there are remissions or even cessations, with retro- gression and absorption, but this latter is rare. Carcinoma exhibits all the elements of malignancy: the tendency to recur after removal, metastasis, and general deterioration of the health. Recurrence after removal is most readily explained upon the assumption that the entire growth has not been removed. Microscopical studies show that the area of infiltration is usually much greater than the naked- eye appearances would indicate, and this explains why the surgeon seldom removes the whole disease. Metastasis, as a rule, follows the lymphatic channels, and thus primarily involves the lymphatic glands in the neighborhood of the growth. The process may be explained as follows: Some of the epithelial cells in their advancing prolifera- tion penetrate the lymphatic channels and are carried in the lymph- stream to the nearest lymphatic gland, where they again proliferate and form secondary nodules; from these a similar extension occurs, and eventually widespread metastasis results. Less frequently the primary growth penetrates the walls of a vein and metastasis occurs through the circulation. This is quite common in the case of cancers of the stomach or intestines. The metastatic foci first spread through the portal circulation to the liver. In still other instances secondary growths result from mechanical transportation in the movements of the body; thus, in carcinomata of the abdominal organs the peristaltic move- ments may transfer particles to different parts of the abdominal cavity. Pathological’ Physiology.—The general health of patients suffering with carcinoma is affected very profoundly, though the manner in which this occurs remains obscure. It would seem to be of the nature of a toxemia. (See page 161.) Emaciation and loss of strength are habitual, though often, perhaps, in large part the result of interference with organic functions, as, for example, in carcinoma of the stomach. Progressive anemia may make its appearance, the red corpuscles becom- ing less abundant and the quantity of hemoglobin falling decidedly. PROGRESSIVE TISSUE CHANGES 297 There is usually a moderate amount of leukocytosis, the large mononu- clear forms increasing particularly. Toward the end of life the tissue destruction increases greatly, though the excretory products of such may not be notably increased in the excretions in consequence of failing circulation and imperfect renal function. At this stage the accumula- tion of such products in the blood may lead to sudden death from coma. (See Acid-intoxication.) Hemorrhages and ulcerations may also con- tribute to the impairment of health in cases of cancer. VARIETIES OF CARCINOMA There are several forms of cancer sufficiently different to require separate description. The classification of these is generally based upon the character and arrangement of the epithelium. We may distinguish (1) epitheliomata, carcinomata composed of surface epithe- lium, either (a) squamous or (b) cylindrical, and (2) glandular carcino- mata, having either (a) more or less distinct adenomatous structure or (b) solid plugs or columns of epithelial cells, or (¢) a mixture of acini and solid columns. Epithelioma This form, which consists of surface epithelium, is of two varieties, the squamous and the cylindrical. Squamous epithelioma occurs in the skin or mucous mem- branes, where squamous epithelium exists normally. Among the fre- quent seats are the lips, the esophagus, the larynx, and the cervix uteri. Occasionally squamous epithelioma arises in parts normally covered by other kinds of epithelium, as, for example, in the fundus of the uterus. In these instances there is probably a primary metaplasia of the epi- thelium followed by carcinomatous growth. Even in carcinomata of the breast some of the acini may present metaplasia of the cells to the squamous type. Squamous epitheliomata present themselves as nodu- lar, wart-like elevations of the skin or mucous membrane, tending to become ulcerated on the surface, with little tendency to hemorrhage. Those of the mucous surfaces are more elevated and softer. Grossly, on section, they appear as firm white or gray masses, with soft areas of cel- lular growth and shiny white strie of connective tissue. Histologically there are seen branching columns of epithelial ceils extending downward into a stroma, well dotted with round cells from the papille of the skin, into the deeper structures. These consist of large translucent squamous cells which show a tendency to arrange themselves in certain places concentrically to form epithelial perles, taking acid dyes well. The latter frequently undergo a horny transformation and sometimes even calcareous change (Fig. 86). The same structures occasionally occur in papillomata, but much less frequently. Metastasis is frequently seen in the neighboring lymphatic glands, but the malignancy is less marked than in glandular carcinomata. Some authors have described as a separate form skin cancers com- 228 A TEXT-BOOK OF PATHOLOGY posed of cuboid or polymorphous cells resembling those of the basal layer (Malpighian layer) of the skin and their embryonal equivalents. This is the so-called epithelioma or carcinoma basocellulare. Rodent ulcer belongs to this group, and while we do not agree that this is a different tumor, it varies from the typical in having greater cellular content of polymorphous cells and a_ paucity of pearls. As a matter of fact, all cancers of the skin originate from the basal cells, and the special variety alluded to differs from the ordinary type only in the fact that the cells do not become transformed, as in the normal growth of skin and in ordi- nary epitheliomata, into squamous wigan Ie cells. Such forms originate from the Fig. §6.—Squamous, epithelioma, hair-follicles, sweat-glands and seba- showing whorls of epithelial cells with central degeneration (from a photo- ceous glands, as well as from the mReRE Tey Ds We MU Soren basal layer of the epiderm. Other varieties of epithelioma have been described depending upon the shape, arrangement, and alteration in the cell-nests. The cystic epi- thelioma is of the basal cell type, with degeneration of cell-nests and i co eee Soe SNe Ba Bel, S097 re ie } ais 4 ia a Popes an! ask Ve 2 AN NS AN A N S/ £ ™ Fig. 87.—Cylindrical epithelioma of the intestine (Perls). the formation of cysts. All such forms are but accidental modifications and have no separate place in histogenesis. The name “epidermoid carcinoma” is given to those infiltrating growths which so retain the PROGRESSIVE TISSUE CHANGES 229 stratification of the epidermal layers, or which assume this arrangement when not growing from epidermis. Cylindrical Epithelioma.—This form is composed of columnar or cylindrical epithelium. It is frequent in the mucous membranes, especially in the gastro-intestinal tract and the uterus. The epi- thelial cells of the tubular glands or sometimes those of the surfaces form the starting-point of the growth. More or less acinus-like tubular structures, composed of a layer of epithelial cells, or more frequently of a number of layers of epithelia, the outer layer being often distinctly columnar, constitute the characteristic feature of the tumor (Fig. 87). In the later stages the acini become filled with proliferated epithelial cells of various shapes and the cylindrical or tubular character of the lining is lost. Carcinomata of the kidney, liver, and mammary gland, though not originating from surface epithelium, strictly speaking, may be of the cylindrical form. Cylindrical epitheliomata more nearly re- semble the glandular carcinomata in their malignancy and general be- havior than the squamous variety. Glandular Carcinoma This term includes the carcinomata that have a resemblance to racemose glands in their histological structure. They consist of acini or alveoli containing epithelial cells, usually in several layers or completely filling the lu- men, and a stroma of con- nective tissue. Some authors distinguish three forms: the simple, the medullary or en- cephaloid, and the scirrhous. These are simply variations of the same tumor. In the simple form there is a com- bination of epithelium and stroma in about the propor- tion seen in normal glands. The tumor is, therefore, el neither strikingly hard nor ov soft. In the medullary or Fig. 88.—Medullary carcinoma of breast. soft carcinoma the amount of epithelium is excessive and the tumor has a soft character (Fig. 88); while the scirrhous, or hard, cancer is an indurated form, due to excess of fibrous tissue and deficiency of the epithelium (Fig. 89). The glandular cancers are more or less nodular or infiltrating growths, varying in consistency in different cases, but having, on section, a glisten- ing white color with a certain amount of translucency. Milky liquid exudes from the surface on section. This is composed of albuminous fluid containing degenerated epithelium and free oil-droplets. Among 230 A TEXT-BOOK OF PATHOLOGY the seats in which these forms occur the most important are the pylorus and other mucous surfaces, the mammary gland, the pancreas, kidneys, ovaries, and testicles. Widespread metastasis and other features of malignancy are noted. In the case of the scirrhous form the primary tumor may be strik- ingly small in comparison with the amount of metastatic de- posit. We may further divide glandular cancers according to the source from which they arise or as to the general archi- tecture they retain during the earlier stages. Thus we may speak of (1) columnar epithe- lial carcinoma when through- out the formative stages the long narrow cells are retained. These grow from tubular glands with cylindrical epithe- lium like in the intestinal tract. (2) Duct cancer when cuboidal cells predominate and the general arrangement is tubular. (3) Acinous cancer when the acinus grouping, with more or less distinct cell-nests having a low or polymorphous epithelium, predominates. Fig. 89.—Scirrhous cancer of breast (Warren). SPECIAL FORMS OF CANCER There are degenerations in some cancers which give them peculiar physical and chemical properties. Such alterations do not justify a Fig. 90.—Colloid cancer of the breast, showing myxomatous change in the stroma and fatty degeneration and partial disappearance of the epithelial cells (Perls). pathological separation, but clinically they have an importance. The most important are mucoid and colloid. In the former the interstitial tissue undergoes myxomatous change, making the tumor soft and dis- PROGRESSIVE TISSUE CHANGES 231 tended with a viscid material. In colloid cancer the cells undergo the change. The term “colloid” is usually a misnomer, as most of the colloid cancers contain no colloid material. The name gelatinous would be more appropriate, but has not been generally accepted. Such colloid can- cers are met with in the stomach and intestinal tract, in the mammary gland, and in the ovaries. The tumor has a peculiar transparent, glis- tening appearance. The entire mass may be uniformly jelly-like or only portions of it are affected. Mi- croscopically mucoid degeneration of the epithelial cells and stroma is dis- covered (Fig. 90). In some cases no trace of carcinomatous tissue may be discoverable, the whole tumor having undergone degeneration. De- generative cancers frequently spread by direct extension, and the entire abdominal cavity may become filled with material representing degener- ated secondary growths. Occasion- ally the same kind of peritoneal growths seem to originate primarily in the peritoneum; the origin of these may be fetal remnants of epi- thelial tissue (Fig. 91). True collovd cancer—that is, car- cinoma, with colloid s degeneration Fig. 91.—Colloid cancer of the peritoneum of the epithelium—is sometimes (modified from Birch-Hirschfeld). seen, though it is very rare. It oc- casionally causes a gross appearance resembling that of sarcomatous cylindroma, and the term carcinomatous cylindroma has been applied. CYSTS Definition.—This term includes pathological formations of varied character. Some are true tumors; others are of quite different nature. The term “cyst” is applied to pathological formations consisting of a more or less well-defined wall and enclosing liquid or semiliquid con- tents of different character from the surrounding parts. This definition is not entirely applicable, as certain structures that do not present a definite capsule are sometimes termed ‘“‘cysts.” Accordingly, we may dis- tinguish between true cysts and cyst-like formations or cystoids, the for- mer being enclosed by a capsule lined with epithelium or endothelium; the latter merely presenting a circumscribed collection of softened material. Classification.—According to the method of formation, we dis- tinguish retention cysts, softening cysts, cysts due to the presence of 232 A TEXT-BOOK OF PATHOLOGY foreign bodies, and proliferation cysts. There are also cysts which owe their origin to some faulty development in utero. They are in a sense teratomatous and we shall consider them under a separate heading. Retention cysts are formed when the excretory ducts of a gland become occluded and the secretions accumulate and cause distention of the acini or of parts of the duct. Among such cysts may be named the distended sebaceous glands of the skin in the formations called wens; the cysts of the salivary or small mucous glands or ducts under the tongue, called ranule; retention cysts formed in the uriniferous tubules, the tubules of the ovary, or in the parovarium, in the acini and ducts of the mamme, pancreas, and other glands. An entire organ may become converted into a cyst, as in cases of distention of the kidney (hydronephrosis) from obstruction of the ureter. These cysts are distinguished by the fact that they have a dis- tinct connective-tissue wall lined with epithelium or endothelium. The contents of the cyst depend upon the part in which the formation has taken place. Softening cysts occur in consequence of degenerative softening of normal or pathological tissues. They are not rarely the result of hemor- rhage, the blood-clot first becoming inspissated and then serous exuda- tion occurring in the area of hemorrhage. Softening cysts are very common in tumors of different kinds. Cysts due to foreign bodies are, in part, softening cysts. The tissues in the immediate vicinity may be injured and undergo necrotic soften- ing, while connective-tissue reaction produces a capsule. This form of cyst is most frequently the result of invasion of parasites, and the cyst contents may be composed of the parasite or the parasite and tissue elements more or less degenerated. Proliferation Cysts.—This term is applied to formations more closely analogous to true tumors than those mentioned before. They merit more extended description than the other forms of cysts, and may be designated as epithelial cysts. Epithelial Cysts Definition.—In certain glandular organs, notably the ovary and mammary gland, cystic formations occur which present striking appear- ances, and, though perhaps they represent adenomatous or carcinomatous new growths, are so striking as to deserve special mention. Etiology.—These growths, in part at least, result from obstruction of excretory ducts and subsequent irritation by retained secretions. Congenital abnormalities of structure may possibly play a part in their causation. Appearance.—Cystomata may be single or multiple, the entire tumor being composed either of a single cyst or of one large cyst sub- divided into many smaller ones; or, again, of numerous separate and un- connected cysts of varying size. On section, the cystic cavities are found to contain more or less serous or gelatinous liquid, and sometimes hemor- PROGRESSIVE TISSUE CHANGES 233 thagic fluid is observed. Most frequently the liquid is gelatinous or ropy, and is commonly spoken of as colloid material. The inner lining of the cyst may be smooth, like a serous or mucous surface, or elevated irregularly in the form of polypoid outgrowths into the cavity of the cyst. The entire cyst may thus be filled with papillomatous elevations from the epithelial lining. The term papilliferous or proliferative cysto- mata is given to these forms (Fig. 92). The size of cystomata varies from minute tumors not larger than a pea to enormous masses weighing as much as 60 or 80 pounds. Secondary degenerations may occur in the form of softening, hemorrhage, or calcification. Seats.—The mammary gland and ovary are the principal situations in which tumors of this description are met with, but analogous growths may make their appearance in any of the glandular organs. as re #2 Fig. 92.—Papilliferous adenocystoma of the kidney (Karg and Schmorl). Structure.—Microscopically, these growths present cystic cavities lined with typical or modified columnar epithelium and a stroma or reticulum of connective tissue. The amount of the latter and the ap- pearance of the cysts themselves vary in different cases. At times the stroma is very abundant and takes the form of well-organized fibrous tissue, while the cysts and acini are small and few in number. In these cases the appearance suggests a primary proliferative connective-tissue process with secondary implication of the epithelial elements. Such cases occur particularly in the mammary gland, and there is difficulty in separating them sharply from instances of chronic interstitial mastitis or diffuse fibroma. In other instances the process manifestly begins with the formations of epithelial acini, and the hyperplasia of the con- nective tissue is certainly secondary. The acini in these cases present themselves as hollow spaces of varying shape and size, often branching, and lined with columnar epithelium in a single layer or sometimes with several layers of more or less well differentiated columnar epithelium. 234 A TEXT-BOOK OF PATHOLOGY Nature.—These cystic growths often have a decided tendency to malignancy. They may remain benign throughout; but frequently they undergo carcinomatous change and spread widely or give rise to metastasis. The malignancy is generally in proportion to the amount of the epithelial proliferation and papilliferous change, but there are in- stances in which metastasis occurs from adenocystomata having regular gland acini lined with single layers of typical columnar cells. The cysto- mata of the ovary not rarely extend to the surface of the organ, break through the capsule, and present upon the surface as papillary growths, and frequently they extend to the peritoneum and neighboring struc- tures. The entire abdomen may be involved. At the same time, or in other cases independent of such direct extension, metastatic deposits may be seen in nearby lymphatic glands. Somewhat the same conditions may be observed in cystoma of the breast, but in this situation the tumor is much more frequently confined within the capsule of the organ. CHAPTER VII TERATOLOGY Tuts subject includes all those abnormalities which are due to con- genital defect. Such a subject, while not exactly a part of the progres- sive tissue change, is ushered in here by the necessity of taking up cer- tain tumors having a polymorphous character more or less dependent upon formative defects. Teratomata or mixed or polymorphous tumors or those due to formative defect will first be considered, and the terata will then be discussed. The word ‘‘terata” may be applied to any ab- normalities of growth, but is best confined to monsters. In order to show the position of the various abnormalities we here give a short classification (Birnbaum’s), which also indicates in a measure what we know of the etiology: (a) Single monsters. (1) Malformations due to arrest of development. (2) Malformations due to excess of development. (3) Malformations due to errors of development. (4) Malformations due to displacement of tissue and per-. sistence of fetal structures. (5) Malformations due to fusion of several characters. (b) Double monsters. Two theories are given for monster formation. One is that there is some inherent fault in the germinal cell, and the other ascribes mal- formation to malign influences upon the developing ovum. The latter is more generally accepted. It is assumed that the damage is chiefly felt before the gastrula stage in a single ovum. Since all organs or organ systems do not progress to their develop- ment in a regular progression, but in an irregular saltatory manner, the correct development of any one depends upon the proper mutual relations of adjacent or associated units or groups. If, therefore, the progress and restraint of one unit be removed, this allows abnormal growth in those dependent upon it. In this way one can explain head- ings a, 1-3, 5; while the double monsters are expressions of the above effects upon a doubly impregnated ovum. Twins can arise from one ovum. TERATOMATA Definition.—The term “‘teratomata”’ is applied to tumors of peculiar mixed character, representing different elements of complex tissues or structures in a situation in which these do not normally occur, growing typically, atypically, or both. For example, the most frequent form of 235 236 A TEXT-BOOK OF PATHOLOGY teratoma contains various epidermal structures, such as hair, teeth, etc., and occurs in internal organs. Those containing fetal tissue or abnormally placed tissue come under heading a, 4. Etiology.—The causation of teratoid tumors or teratomata is to be sought in congenital misdevelopments. We may, with Klebs, dis- tinguish endogenous forms in which inclusions of superficial tissues are retained in internal parts by a process of constriction; and ectogenous forms, in which a separate fetal deposition is the origin of the tumor. The latter form represents a separate and ill-developed fetus within the developed organism—a fetus in fetu. They are also called “em- bryomata.” A regular gradation may be traced from distinct teratoid tumors having irregular mingling of tissue elements to malformations in which a more or less systematic outgrowth, somewhat approaching double monstrosities, occurs. Of the distinct teratoid tumors, the most frequent is the dermoid cyst. DERMOID CyYsT This ectogenous tumor presents itself as a cystic formation with a connective-tissue membrane and an inner lining resembling the skin. This may present all the elements of the skin, such as stratified epi- dermis, a papillary layer, and even subcutaneous connective tissue. Hair-follicles and sebaceous glands are frequent, and habitually long, light-colored hairs are found within the contents, and teeth may be ‘found in the lining membrane or free in the contents of the cyst. The cyst is filled with a semifluid, cheesy mass consisting of epithelial cells, fatty matter, and other detritus. Occasionally dermoid cysts may contain nerve tissue, muscle, thyroid tissue, or structures resembling intestine. : . The dermoid cysts vary in size from minute bodies no larger than a pea to huge masses, the latter being most frequent in the ovaries. Among the situations in which dermoids occur the ovaries are most common; less frequently they are found in the testicles, in the perito- neum, in the membranes of the brain, about the eye, in the neck, floor of the mouth, and elsewhere. Growth is very slow, and they may remain practically latent through life. 2 The nature of these tumors is usually benign, though carcinomatous change may occur, and in the ovaries cystoma is prone to be associated, and the latter may be malignant. Other Teratoid Tumors Mixed tumors are terata arising from embryonal cells which are capable of a differentiation to approximate more than one type of adult tissue. They may descend from cells of one or all layers of the embryo, and may be ascribed to the power of syncytial cells to develop into an embryo, or the inclusion of one ovum in another. These are the tera- tomata proper, to which reference has been made, while mixed tumors TERATOLOGY 237 represent usually two or, at most, three types of cells. The most con- spicuous examples are Wilm’s congenital adenosarcoma of the kidney and adrenal carcinoma. Nodular masses may appear about the head or neck or in various parts of the body, consisting of mingled tissues of various kinds, such as glandular tissues, connective tissues, nerve, muscle, etc. Sometimes they resemble some definite organ, as in the case of growths appearing at the umbilicus of the newborn and simulating the structure of normal intestine. In the neck there are sometimes seen more or less cystic growths lined with epithelium and having in their walls muscle-fibers, lymphoid tissue, cartilage, etc. These growths probably spring from remnants of the embryonal branchial clefts. The mixed tumors of the parotid gland (see Sarcoma) are allied to these. Fig. 93.—Cholesteatoma from the membranes of the brain. Cholesteatoma.—This tumor is characterized by glistening, whitish, or pearly bodies composed of concentric layers of cells resembling epi- thelium (Fig. 93). Sometimes crystals of cholesterin are found in the center of these bodies, whence the name cholesteatoma. Cholesteato- mata are found in the membranes or substance of the brain, and present themselves as single or multiple nodules. They are usually soft and glistening in appearance. Some authors consider them endotheliomata, but Ziegler has found hair-follicles and hairs in certain specimens, and from this, as well as from the horny change to which the cells in the pearly bodies are prone, classifies them among the teratoid growths. They probably originate in ectodermal fetal inclusions or rests. Somewhat similar tumors occur in the pelvis of the kidneys, in the testicles, parotid glands, ovaries, and middle or external ear. 238 A TEXT-BOOK OF PATHOLOGY SYNCYTIOMA MALIGNUM This term is applied to a form of tumor originating at the placental site during pregnancy or the puerperium. It has also been called “deciduoma malignum,” “sarcoma deciduocellulare,” ‘destructive epithelial tumor of the placental site,’ and “chorionepithelioma” (Fig. 94). It may follow a hydatid mole (q. 2.). The tumor occurs as a hemorrhagic infiltrating growth, somewhat resembling placental tissue in gross appearance, and frequently causes metastasis by breaking into the blood-vessels. The metastatic nodules are found in the external genitalia, frequently in the lungs, less often in the liver, spleen, or other organs. The growth is rapid, the uterine wall Fig. 94.—Chorionepithelioma or syncytioma malignum. (By the courtesy of Dr. Barton Cooke Hirst from a painting made for him from a slide belonging to Dr. Herbert Fox.) being quickly invaded and metastasis occurring in a short time. It has no vessels, but grows within placental blood spaces, and is prone to hemorrhage by infiltration and ulceration of maternal vessels. The cells are loosely enough arranged to separate and enter vessels to form metastasis. The nature of this tumor is still the subject of some controversy. Two types of cellular elements are recognized in its structure. One of these consists of irregular masses of protoplasm containing dark nuclei (syncytial tissue). The nuclei probably multiply by direct divi- sion. These protoplasmic masses are arranged in islands or in branch- ing columns which form a network. In the meshes of this network are blood spaces containing thrombi or masses of blood corpuscles. Sometimes masses like those above described are found within the TERATOLOGY 239 blood spaces. The second form of cells consists of smaller irregular- shaped elements, which are unusually rich in glycogen, and in which cell division by karyokinesis is observed. These cells lie in masses, of greater or less size, between and beside the larger protoplasmic areas before described. In the later stages of the growth obliterative throm- bosis of the vessels leads to necrosis of the cellular constituents, particu- larly of the columns of large epithelium-like cells. These are converted into homogeneous fibrinous masses, and even the thrombi themselves may degenerate. The view of Marchand regarding the nature of these tumors is most widely accepted. He holds that the larger cells are deriva- tives of the syncytium (a structure composed of epithelial cells, probably of fetal origin), while the smaller cells are formed from the deeper epithelial covering of the chorion villi (Langhans’ cells). The tumor, therefore, is epithelial in nature, and it has malignant properties. It differs, however, from ordinary epithelioma and from carcinoma in its peculiar structure and in its clinical course and dissemination. Syncytial cells are occasionally found in tumors of the adult unasso- ciated with pregnancy. They are supposed to be either fused cells or to have a tendency to the formation of chorionic cells, possibly from germ cells. These cells have been found in brain and testicular growths. The name “syncytial carcinoma” or “epithelioma”’ is given. Terata or Monsters We refer the student to books on normal and abnormal embryology and teratology for a full discussion of the terata. Here will be given _ only examples of the various headings on p. 235: (a) Single Monsters—(1) Malformations by arrest of development are exemplified by the failure of closure of the median fissure of the body or the failure of union of organs developing in both sides and intended to be one, e. g., the bifid uterus. (2) Malformation in excessive development occurs in the form of supernumerary fingers or internal organs, the spleen, for example. (3) Malformations of error are seen in club-feet, hernia, or when the testicle is not included in the scrotum. Hermaphroditism exem- plifies failure of fusion of sexual elements from the two sides. (4) Malformation by displacement is exemplified by transposition of all the viscera (situs transversus) or of single organs, as when the heart is found on the right side. Persistence of a remnant of the omphalomesenteric duct, so-called Meckel’s diverticulum, and of the truncus arteriosus are instances of the retention of embryonal structures. (5) Under this heading are found fusion of esophagus and trachea, and of the two kidneys, forming a horseshoe-shaped organ. (b) Double monsters are the results of superfetation, or the fusion of incompletely formed fetuses. When the two fetuses are joined together by the ventral surface they are called anterior duplications; when joined by the head, craniopagus; by the sacral region, pygopagus. When they are fused at the pelvis they are ischiopagi; and if the trunk 240 A TEXT-BOOK OF PATHOLOGY and legs are fused, leaving the head and neck free, we have dicephalus, Syncephalus means fusion of heads with the two bodies free. The cysts of antenatal origin are mostly examples of endogenous, constriction, or inclusion cysts, or remains of fetal structures intended for removal. The thyrolingual cyst is due to failure of closure and obliteration of the thyrolingual duct. It is in the midline of the neck. Branchial cysts at the side of the neck are mucous or sebaceous collec- tions in the remains of the branchial clefts. Persistent portions of the Wolffian body or duct may give rise to uni- or multilocular cysts of the ovary or broad ligament. Cyst sof the kidney are due to imperfect development of the portion of the Wolffian body which makes the secreting part of the kidney. CHAPTER VIII BACTERIA, THEIR NATURE AND ACTION History.—Although for many centuries there had existed the idea that disease and decay are due to the action of minute organisms, it was not until the use of the lens enabled the Dutch naturalist Leeuwen- hoeck actually to demonstrate their presence in water and in human intestinal contents that the hypothesis of a ‘“contagium vivum”’ became more than mere guesswork. He discovered, even with his imperfect instruments, short rods, curved and straight, and described their motility. Miller (1785), by the use of the compound microscope, at- tempted a more systematic classification of these micro-organisms, and from that time many investigators have added much to our knowledge of microbes, that group of organisms which had been denominated by Linneeus by the term “‘chaos.”” To the German Henle is due the credit of having first introduced an idea of order into this disorder. He held that fermentation was the result of organic life, and that the action of a contagium was analogous to that of a ferment. The earliest systematic experimental work was that of Pasteur, in which he established beyond doubt this relation between fermentation and the life and development of bacteria. The first definite ideas of the physiology of these micro- organisms are found in his experiments on lactic-acid fermentation, and the pathogenesis of micro-organisms was established by his demon- stration of the etiology of the silkworm disease (1869). Davaine and Rayer about the same time established the causal relation of a bacillus found in the blood of a sheep dead of anthrax to that disease. CLASSIFICATION Bacteria (schizomycetes, or cleft fungi) is the name given to a branch of the lowest and simplest of the orders of the vegetable kingdom. They belong to the class Thallophyta and order Schizophyta or Schizomy- cetes. Other orders of this class are unimportant except the Eumycetes, comprising the moulds and yeasts. They are small, unicellular organ- isms, generally free of chlorophyl, and colorless; they possess a cell- membrane albuminoid in composition, and homogeneous protoplasmic cell contents. They range in size from a fraction of a micromillimeter up to 40 uw. Some varieties are motile. Nuclei are absent, though in the opinion of some the whole body may be regarded as a nucleus. Bacteria multiply by cell division, sexual distinctions being absent. In many species resistant bodies—spores—occur. Many classifications, all of them being to a certain extent artificial, have been made by different authors. Probably one of the most use- ful and scientific is that of Migula, as modified by Chester: 16 241 242 A TEXT-BOOK OF PATHOLOGY Schizomycetes I. Coccacez.—Spherical cells dividing in one, two, or three directions. Endospores rare. 1. Streptococcus—Division in one direction, the individuals cohering to form chains. Motility absent. 2. Micrococcus —Division in two directions, the individuals when coherent forming groups of four. Flagella absent. 3. Sarcina-—Division in three directions, forming packets of eight, increas- ing in geometrical ratio. Motility absent. 4. Planococcus——Division in two directions, as in the micrococcus. Motility present. 5. Planosarcina—As the sarcina. Motility present. II. Bacteriaceze—Rod-like, cylindrical cells, dividing at right angles to the long axis. 1. Bacterium.—Cells without flagella, often with spores. 2. Bacillus—Cells with peritrichous flagella, often with spores. - 3. Pseudomonas—Cells with polar flagella, spores rare. : Ill. Spirillaceze.—Cells cylindrical, curved, bent, or spiral. Division as in II. 1. Spirosoma.—Cells rigid, without flagella. 2. Microspira—Cells rigid, with one, rarely two or three, polar flagella. 3. Spirillum.—Cells rigid, with five to twenty polar flagella. 4. Spirocheta.—Cells flexible, motile, but without flagella; perhaps possessing an undulating membrane. IV. Chlamydobacteriaceze.—Cells united in a simple unbranched filament. Division in one direction. Forms non-motile; conidia. 1. Mycobacteriacee —Short or long cylindrical units or filaments, clavate, cuneate, irregular, or regular in form; may have false or true branching. No spores. Gonidia bodies may occur; non-motile; transverse division; no sheath. a. Mycobacterium—Short cylindrical, bent cuneate. May show true branching. b. Actinomyces——-Long branching filaments, gonidia, end organs, dry growth (very close to next genus, Streptothrix). 2. Streptothrix—Cells united in a simple unbranched filament. Division in one direction. Forms non-motile; conidia, true branching. 3. Cladothrix—Cells united in a filament, with a false branching. 4. Crenothrix—Cells united in an unbranched filament, and dividing in three directions into small rounded cells. 5. Phragmodiothrix—Cells at first united in an unbranched filament, and dividing in three directions. Later the separate cells break through the thin membrane and grow out as branches. 6. Thiothrix—Cells united in an unbranched filament contained in a thin mem- brane. Division in one direction. Cells contain granules of sulphur. V. Beggiatoaceze.—Cells united in a filament without sheath. Motile, the move- ment being due to an undulating membrane. Eumycetes True fungi are of some pathological importance in skin diseases and occasion- ally in general infections. The classification is given of the most important genera. This is one of the orders of the Thallophyta. 1. Suborder Phycomycetes. Family Mucorine, Genus Mucor. 2. Suborder Hemiascomycetes. Family Saccharomycetacez, Genus Saccharomyces, Subgenus Blastomyces. 8. Suborder Euascomycetes. tay Aspergillaceee, Genus Aspergillus, Genus Penicellium, Genus idium. BACTERIA, THEIR NATURE AND ACTION 243 The simple elementary forms that occur are of three kinds: the coccus, the bacillus, and the spirillum (Fig. 95). Coccus.—This is a spherical cell, varying in size up to 1 « in diam- eter. It takes the anilin stains readily. Spore formation and motility are rare. When the cocci are found in groups, the individuals being entirely separate, they are termed staphylococci, from the resemblance of the groups to a bunch of grapes; when in pairs, diplococci; when in chains, streptococci; when in groups of four, tetrads, or merismopedia; when in packets, sarcine. Bacillus.—A rod-shaped, cylindrical cell of varying length and thick- ness. Spore formation and motility are common. Most of the group © Bg Sf See oO oO °o °O %6 0 oO I 2 3.4 5 mA got 0S UR Fa 6 See iol mn Yd 7 8 9 lo «43 Fig. 95.—Various forms of bacteria: 1 and 2, Round and oval micrococci; 3, diplococci; 4, tetracocci, or tetrads; 5, streptococci; 6, bacilli; 7, bacilli in chains, the lower showing spore formation; 8, bacilli showing spores, forming drumsticks and clostridia; 9 and 10, spirilla; 11, spirochetes. stain easily with the anilin dyes, but some require special methods of staining. Spirillum.—A cylindrical, rod-shaped cell, curved or spiral, some- times motile. It stains readily. MORPHOLOGY Cell Contents.—The body of the organism in unstained conditions appears as a perfectly homogeneous protoplasmic mass. On staining with anilin dyes a granular appearance is often observed, which under high powers is resolved into a hyaline mass containing numerous chromophilic granules. Vacuolations also are often present. Some observers (Biitschli e¢ al.) have made out a network immediately within the membrane and surrounding a central body which readily stains with the nuclear dyes. This latter they regard as a nucleus. Others, however, affirm that this appearance is due to a concentration of the cell protoplasm (endoplasm), the result of the rather complicated method of staining. The question of the presence or absence of a nucleus is still an open one. In many organisms, as the diphtheria bacillus from a blood-serum culture, for example, there exist certain transparent re- fractive bodies which stain differently from the rest of the microbe. These metachromatic bodies, as they are called, are regarded by Ernst as nuclear in character. Others look upon them as possibly the primary stage of spore formation. Most authorities today merely accept that a bacterium has both chromatic and cytoplasmic parts, and do not insist that the large central area staining by nuclear methods is a definite nucleus. Some of the chromatic bodies seem to have the power of growing out into a full rod when freed from the parent rod into favorable media (Ixneass). 244 A TEXT-BOOK OF PATHOLOGY Spore.—The spore is a non-vegetative resistant form that the microbe assumes when the conditions for growth are unfavorable. The endo- plasm seems to concentrate and become a small oval, highly refractive body, separated from the bacterial protoplasm by a membrane of its own. It is generally of the same diameter or somewhat smaller than the bacillus itself, and is situated either in the middle (equatorial) or at the end of the microbe (polar spore). It may be larger in diameter than the microbe and cause a swelling at that point. When in the center of the rod this gives rise to the form known as clostridium; when polar, to the so-called drumstick form (as in the Bacillus tetant). The spore is extremely resistant to conditions to which the vegeta- tive form readily succumbs; to the action of certain chemical reagents, light, heat, ete. Bacteria that are grown on media poor in nutrient material tend to become asporogenous. A certain temperature is also necessary for spore formation. Thus, although the anthrax bacillus develops well at a temperature of 14° C. (57° F.), it does not form spores below 18° C. (64° F.). To obligate anaérobes oxygen is necessary for their development, and aérobic cultures present them in the ab- sence of that gas. Placed under conditions favorable to its vegetation the spore loses its clearness, absorbs water, and swells. A small promi- nence presents at the side or end, which gradually lengthens and develops into a young bacillus. The membrane of this new microbe is formed from the inner layer of the spore membrane (endosportum), while the outer layer (exosporiium) is cast off. In not all of the varieties of bacilli does sporulation take place, and even where it does occur there may, under certain conditions, as in growth at high temperatures, arise races which have lost this power (asporogenous races). The spore does not stain readily with the ordinary anilin stains, and special methods have been devised for coloring it. The polar or Babes-Ernst granules are condensations of endoplasm which stain by particular methods. They are due to the chemical reactions of the medium upon which the organisms are growing. Their biological importance is small, but they assist in identification at times. Cell-membrane.—Surrounding each organism is a membrane (ectoplasm) denser and more highly refractive than the cell contents (endoplasm). In most cases this is not to be differentiated from the endoplasm; but in a few it is larger, and under certain conditions be- comes a gelatinous mass. In this case it is easily seen, especially after appropriate staining. This is called the capsule. In general, this occurs only when the bacteria develop within the animal organism, and not upon artificial culture-media. It is probable that the ectoplasm is not a mere protective envelope, but has to do with the functional activity of the bacterium. The fact that the flagella, to which is due the motility of certain microbes, are directly continuous with and are simply pro- longations of this membrane, points to this view. The cell-membrane is not easily colored by ordinary methods. Flagella.—Motility is often a property of bacteria. It is manifested in different ways, and is often characteristic of special varieties of bac- BACTERIA, THEIR NATURE AND ACTION 245 teria. Some move slowly forward across the field; others, with great rapidity; others, again, dart hither and thither, slowly or so quickly as to be with difficulty observed. They may at the same time have a rotary movement around their long or their short axes. After appropriate staining the cause of this motility is seen to be the presence of slender, whip-like prolongations, originating directly from the ectoplasm (Babes). They may be twenty times as long as the body of the bacterium, and are arranged in the different species in different ways. Bacteria that possess no flagella are termed “gymnobacteria”; those that have these organs, “‘trichobacteria.” There may be but one flagellum, situated at the pole (monotrichous), or a number may be present (lophotrichous). When they are situated at both poles the microbe is termed amphitrichous; when distributed over the whole body of the bacteria, peritrichous. The presence and the activity of flagella depend on many factors: on the condition of the medium, bacteria grown on liquid media being more active than those on solid; on temperature; on presence of air; on light; and on the age of the culture. They are easily broken off from the microbe, and care must be used in staining them. Involution Forms.—By involution form is meant the irregular appearance a microbe often assumes when its conditions of growth are unfavorable. Numerous bacteria melt together and become irregular chains, or they appear pear or club shaped. The protoplasm becomes retracted and irregular staining takes place. Sometimes forms with branching projections are discovered. These have often been described as involution forms, but are now more commonly regarded as normal, though unusual, structures. This applies to tubercle bacilli, diphtheria bacilli, and some others. This true branching (dichotomy) must not be confounded with false or pseudodichotomy due to mere apposition of separate organisms, as seen in various bacilli, streptococci, etc., and habitually in the cladothrices. Chemistry.—The bacterial cells are of variable composition, de- pending to a great extent upon the kind of nutrient matter. They con- sist mainly of water (85 per cent.). The chief solid material is albumin. This varies according to the medium of growth, and has been given the general name of mycoprotein (Nencki). Fat is also present. The nuclein bases—xanthin, guanin, adenin—and cellulose have been found by some. Some contain certain coloring-matters, bacteriopurpurin, and a green substance similar to chlorophyl. Organic acids and ferments of differ- ent kinds are also found. In some special forms—the sulphur bacteria— sulphur is present. BIOLOGY Bacteria may be divided into two great classes: those that live only on dead organic matter are termed saprophytes; those that develop in and at the expense of the living organism, parasites. These latter by their growth cause certain pathological conditions in the host, and are called pathogenic. By obligate saprophytes or parasites we mean those that 246 A TEXT-BOOK OF PATHOLOGY can exist only under the conditions named; by facultative saprophytes or parasites, those that can develop under either condition. Conditions of Growth.—Certain surrounding conditions are neces- sary to bacteria, and any marked change in them will inhibit the growth or totally destroy it. Mechanical Conditions.—A slight shaking of a liquid culture seems to help the development of bacteria, while a more violent and long-continued agitation destroys them. Physical Conditions.— Electrical currents destroy the growth, prob- ably by the action of certain products of the electrolysis and not by direct action. Light—Diftused daylight inhibits the growth of bacteria: sunlight and, to a less extent, electric light destroy them. This is probably due to oxidation. Heat.—A certain temperature is necessary, the degree varying with the species of microbe. Most of the water bacteria and saprophytes grow between 0° and 30° C. (32° and 86° F.), the optimum being 15° to 20° C. (59°-68° F.) (psychrophilic). The pathogenic flourish between 10° and 45° C. (50° and 113° F.), best at the body temperature, 37° C. (98.6° F.) (mesophilic). There are some that develop well at 40° to 70° C. (104°-158° F.) (thermophilic). Above these limits the members of the several groups are killed, and each bacterium has its own thermic death-point. That of most of the pathogenic varieties lies between 50° and 60° C. (122° and 140° F.). Below the lower limit, down to the degree at which any multiplication will occur, the growth is inhibited only. Temperatures below zero destroy only the most feeble of para- sites. Very low temperatures (—250° C.; —418° F.) have been used without preventing the future development of the microbe. “Spores are extremely resistant to higher temperatures. While no bacterium can live after exposure to 100° C, (212° F.), the spores of some of the earth microbes are killed only after exposure for an hour to steam heated to 115° C. (239° F.). Chemical Conditions.—The essential substances for the growth of bacteria are water, carbon, nitrogen and oxygen, and certain salts. For the carbon, they require already prepared carbon compounds, as the sugars, glucose, saccharose, lactose, etc., mannite, glycerin—in fact, most of such as are soluble in water. Most of the proteins and many simpler substances, even such as ammonium carbonate, furnish the nitrogen. Free oxygen is necessary for many microbes. Those for which this is absolutely required are termed “obligate aérobic.” Facul- tative aérobes are those that grow best in the presence of oxygen, but may develop in its absence. Anaérobic microbes are those that grow best without atmospheric oxygen and are also obligate and facultative. They obtain it as they need it by reducing oxygen-containing materials in the culture-medium. It has been found possible to produce races which, although naturally obligate anaérobic, develop also in an atmos- phere of oxygen. BACTERIA, THEIR NATURE AND ACTION 247 FUNCTIONS AND PRODUCTS OF BACTERIA The study of the substances that result from the action of the life of bacteria and the changes that they produce in their various media of growth is really a branch of organic chemistry. The function of bacteria is essentially a destructive one. They split up the higher nitrogenous and non-nitrogenous compounds into simpler substances. The ,various substances that are found in cultures of bacterial growth comprise: (1) the components of the bacterial cell proper, as the proteins; (2) the secretions of the cell, as the ferments and toxins; and (3) substances that are the result of the action of microbes upon the medium of growth. The toxic substances in bacterial cultures may be classed as (a) intracellular and (b) extracellular, according as they are contained within the bacterial cell or are made from or excreted into the culture-medium. The extracellular substances may be purely products of bacterial secretion which have been separated from the cell, or they may be decomposition products derived from the culture- medium. The bacterial proteins may produce suppuration (pyogenic) or fever (pyrogenic), or they may be the cause of an inflammatory process (phlogo- genic). ‘These substances are comparatively resistant to heat and are thus sharply distinguished from the ferments and toxins. The best- known examples are mallein, derived from the bacillus of glanders, and tuberculin, from that of tuberculosis. These are pyrogenic when injected into animals suffering respectively from glanders or tubercu- losis, but have no, or at least very slight, effect upon healthy subjects. Other proteins are shown to have similar effects on tuberculous animals, but not in the minimal doses which suffice when tuberculin is used. Vaughan and his associates claim that the protein of bacteria. is divisible into a highly toxic non-specific portion, and a non-toxic fraction specific for each kind of organism. Upon this result and his further experimentation he has elaborated a theory of infection to be discussed later. The endotoxins are certainly closely bound with the bacterial proteins, but their exact seat is not known. The second group of products includes the ferments and possibly the toxins. Ferments.—A ferment is a complex body about which we know but little except the effects that it produces. By its presence, and probably without entering into intimate chemical combination, it pos- sesses the power of breaking up more highly organized nitrogenous and non-nitrogenous compounds into simple and more diffusible mole- cules. They are termed enzymes or unformed ferments in contradistinc- tion to the bacteria themselves, which are called formed or living fer- ments. That the action of ferments is not due directly to the microbe is shown by the facts that bactericidal substances, such as phenol (5 per cent.), chloroform, ether, etc., have no effect on them, and that cultures freed from bacteria by filtration still possess fermentative power. The action of ferments is termed fermentation, but this term 248 A TEXT-BOOK OF PATHOLOGY is more especially limited to the effect of certain ferments upon non- nitrogenous compounds, particularly the carbohydrates. The result of fermentation upon nitrogenous material is called putrefaction, which generally occurs with, though often without, the formation of odorous gases and other substances. The intracellular origin of certain ferments has been demonstrated by their experimental separation from the bacteria when placed under high pressures. The resulting bacteria- free liquid possesses the same fermenting qualities as the culture itself. The ferments, like toxins, are of unknown composition, are highly destructible by chemical agents and heat, cause effects out of all pro- portion to their bulk or amount, and are frequently mechanically precipitated with various indifferent bodies. When injected into ani- mals both are capable of exciting the formation of antibodies (anti- ferments and antitoxins). Bacteria, as animal cells, have autolytic ferments. In this self-solu- tion certain substances are freed that may be of importance in immunity reactions—endotoxins and aggressins. The exact relation of bacterial digestion products, whether autolytic or by the agency of blood-serum or tissue fluids, is not exactly known. The demonstrable enzymes of bacteria have little to do with the specific infection caused by the growth aside from the softening of exudates and the like. This ex- ample is given to show also that one of the most important enzymes of bacteria is proteolytic in action. The principal bacterial ferments are: Proteolytic Ferments.—These transform albumins into more soluble and diffusible substances. One form very often met with is that which liquefies gelatin. This acts in an alkaline medium, and is, therefore, akin to the animal ferment trypsin. This liquefaction of the gelatin affords a means of distinguishing many species of microbes. Diastatic Ferments.—These transform the starches into sugars, and are found in many bacterial cultures, as of Bactertwm mallei, B. pneumonie, ete. Inverting Ferments.—These change the non-fermentiscible sugars into those that undergo direct fermentation. Such ferments are found, for instance, in cultures of Spirillum cholere and S. metschnikovii. Coagulating Ferment.—One of the means of differentiation of bacteria is the coagulation of milk used as a culture-medium for the bacteria under observation. This coagulation is due not to acidity produced in the medium, but to the action of a ferment. Some varieties of microbes produce a ferment that has the power of dissolving this coagulum when formed (casease); and still others produce both ferments—the coagulating and the dissolving. Hydrolytic ferments are exemplified by such as break up urea a ammonium carbonate and hippuric acid into glycocol and benzoic acid. Fat-splitting ferments split the fats into glycerin and the fatty acids. Oxidizing and nitrifying ferments are other less important forms. BACTERIA, THEIR NATURE AND ACTION 249 Effects of Ferments.—The single or combined action of these various ferments causes certain special kinds of fermentation distin- guished by the principal substance produced. Alcoholic, lactic acid, and butyric acid fermentation of the sugars, acetic acid fermentation of alcohol (Bacillus acidilactici, B. butyricus, B. acidi butyrict, ete.); cellu- lose fermentation with the production of carbonic acid gas and ammonia; nitrification, in which oxidation of ammonium leads to production of nitrates (Winogradsky’s nitrosomonas), and secondarily conversion of nitrates into nitrites (nitrobacter); mucoid fermentation of glucose and invert-sugar are examples. Toxins.—The pathogenic bacteria produce certain toxic substances that are akin in action to the poisonous venom of certain serpents and other animals, and to certain poisonous principles of plants, as abrin and ricin, and are almost certainly of protein nature. These are of in- definitely determined character, and act deleteriously upon the host only after the lapse of a certain time—a period of incubation. They are considered the specific toxins of the several bacteria. According to some, these give all the reactions of albumin, and have been termed tovalbumins (Brieger). It is probable, however, that the toxalbumin is but an impure form of the true toxin, a combination of it and various substances derived from the medium of growth. Most recent investiga- tors look upon the toxin as akin to the ferments. Roux and Yersin, in their monograph on the diphtheria bacillus, held this view and more recent investigators support the theory. The analogous pathological action of the toxins and ferments, their common origin, their destruc- tion (oxidation) in the presence of light, their precipitation by alcohol, their precipitation from solutions by colloid bodies, their long and im- perfect dialysis, all point to this. High temperatures affect both similarly, both being destroyed at from 60° to 100° C. (140°-212° F.). Chemical substances that have no effect (chloroform, ether, etc.) on the ferments are without action upon the toxins; and, vice versd, those that destroy the ferments (formaldehyd) are also injurious to toxins. They are, curiously enough, digested by proteolytic ferments. Both may be swallowed with impunity, although they are pathogenic when injected subcutaneously or intraperitoneally. When the microbe is grown in some inorganic medium or in a non-albuminous one (as Uschinky’s solution), the toxic principle obtained corresponds in its chemical reac- tions to a ferment. lost important is the fact that extremely minute doses are effective. Ferments act without regard to the mass em- ployed, and it would seem that toxins act in almost imponderable amounts. It has been estimated that zeys gm. of tetanus toxin will kill a horse weighing 600 kg.—six hundred million times its weight; and that rosy mg. of tuberculin causes a reaction in a diseased man weigh- ing 60 kg.—sixty trillion times its weight. Finally, both act only after a definite period of incubation. ; Considerable light has been thrown upon the nature of toxins by the recent investigations of Ehrlich and others who have followed him. These investigations have been mainly concerned with the 250 A TEXT-BOOK OF PATHOLOGY behavior of the toxin toward the antitoxin bodies. Ehrlich has found that the serum contains at least three distinct substances: the toxin proper, toxoid, and toxon. The toxin is the active poisonous element; but, aside from its toxic property, it has a distinct combining ability, go that it enters into combination with antitoxin. A given serum, how- ever, will combine with a greater quantity of antitoxin than the toxic power of the serum would indicate. In other words, there are other combining bodies which have no toxic power, or less toxicity than the toxin. A serum as it grows older loses in toxic power without losing in combining power. This is due to the conversion of toxin into toxoid. The toxon has, similarly, the combining power for antitoxin, but is slightly toxic, being capable, in the case of diphtheritic serum, for ex- ample, of producing the postdiphtheritic paralyses. It is, however, not a derivative of the toxin, but results from a direct action of the bac- terium, and is produced simultaneously with the toxin. The dissocia- tion of combining power and toxic power is explained upon the assump- tion that each molecule of toxin contains a group of atoms specially adapted for combining with vulnerable cells or with antitoxin and a toxic group. To the former the name haptophore group and to the latter the term toxophore group has been given. The probable nature of these will be referred to in the discussion of Ehrlich’s theory of im- munity. Fate of Toxins. —It is certain that there exist in various cells of the animal organism certain oxidizing ferments by which the toxin is de- stroyed. Not all of the toxin is thus oxidized. A part is eliminated unchanged through the kidneys in the urine and to some extent through the liver in the biliary secretion. Besides these there is still another method of defence of the organism against the action of toxin—the antitoxin (q. ¥.). PRODUCTS IN CULTURE-MEDIUM. _ The third group of poisons found in bacterial cultures are the products of decomposition of the culture-medium under the influence of the bacterial growth. This is the class of poisons called ptomains, protein degradation bodies, with their nitrogen in the amino form. They act as a direct poison and require no specific incubation period. They differ from toxins in the fact that their elaboration is more closely dependent on the character of the medium than is that of the former. The toxin of tetanus or diphtheria may be produced in various, even in non-albuminous, media, but the elaboration of certain ptomains and other decomposition products is more narrowly restricted to growth of certain organisms in appropriate media. The substances produced by bacteria from the culture-media and tissues are varied and numerous. Besides those produced by the various fermentative processes there are: the products of digestion of albumin, albumoses, peptone, etc.; the ptomains; nitrogenous substances, as leucin and tyrosin, methyl-, di- methyl-, ethyl-propylamins; organic fatty acids, formic, acetic, propionic, ' BACTERIA, THEIR NATURE AND ACTION 251 butyric, margaric, lactic, ete.; certain aromatic compounds, as indol, phenol, kresol, skatol, mercaptan, hydrochinon, etc.; and finally, hydro- gen, carbonic dioxid, hydrogen sulphid, ammonium, water, etc. All of these are more or less toxic and may contribute to the unfavorable action of bacteria, but are not the specific toxic agents that occasion the characteristic pathological effects of the various micro-organisms. Chromogenesis.—Many bacteria form colors which give to the culture a characteristic appearance. The production of the pigment depends to some extent upon the constitution of the medium, and it is possible to produce cultures and even races of pigment-forming bacteria by the use of appropriate media. It has no importance in the patholog- ical relations of the organisms. Photogenesis.—The phenomenon of phosphorescence observed in decaying fish is due to the action of bacteria. This production of light is observed in many of the cholera group of vibriones. THE LOCAL EFFECTS OF BACTERIA These may be either (a) mechanical or (b) histological, the mechanical effects being least in importance. (a) Sometimes masses of micro- organisms more or less completely occlude small blood-vessels and occasion secondary changes in the tissues in this mechanical way. In other cases the obstruction is incomplete, but occasions thrombosis in the blood-vessels and various consequential disorders. (6) The histo- logical changes occasioned by bacteria are proliferative and destructive, among the latter being various degenerations and necrosis. The pro- liferative changes may be non-specific or specific—that is, there may be simply proliferation such as occurs from any irritation; or there may be special forms of proliferation more or less characteristic of the individual micro-organism in extent, distribution, and nature. This is seen in the peculiar lesions of tuberculosis, glanders, rhinoscleroma, ete. The cellular degenerations and necroses occur coincidentally or subsequent to the proliferative changes. On the contrary, in many cases the first ~ effects of bacterial invasion seem to be degeneration or necrosis of the tissues immediately around the organisms. EFFECT OF TOXIC PRODUCTS OF BACTERIA This section of the subject is devoted to a consideration of the modus operandi of the foregoing bacterial products upon the body. The general principles apply to protozoan and metazoan parasites, but we deal here chiefly with bacteria. The action of all the animal parasites is not understood, and comment upon them will be reserved for the appropriate chapter. Infection is the successful invasion of the tissues by bacteria and the evidences of their presence. Infestation is the term applied to the presence and action of animal parasites within the body. The sources of infection (here and throughout this chapter we use 252 A TEXT-BOOK OF PATHOLOGY the term very broadly) are polluted objects—food, water, and insects, The action of each will be described when discussing the diseases to which they apply. This is the principal subject of hygiene and should be studied in works devoted to it. It must not be forgotten that bacteria, even some pathogenic forms, are constantly present upon and within the human body. They are held in abeyance or destroyed by the primary defenses—the skin and mucous membranes. Should a lowering of these defenses or a great in- crease in the invasive powers of the bacteria occur, infection follows. The character of the infection depends somewhat upon the portal of entry or so-called infection atrium. Typhoid bacilli will not produce typhoid fever if rubbed upon the skin, but may if swallowed. Pus cocci may cause furunculosis if rubbed upon the skin, but will not if swallowed. All openings to the body present possible infection-atria, and pre-exist- ing disease of any part lowers the resisting powers of that part in par- ticular and possibly of other parts. The most important infection-atria are the respiratory and alimentary tracts. Bacteria are inhaled or swallowed and lodge upon the mucous membranes. As has been said, these membranes are part of the primary defenses, but it has been shown that bacteria may pass them without leaving a trace. The invaders are met then by the resistance of the lymphatic system in which they are carried through the lymph-channels, or by the antibacterial power of the blood. Pathogenicity is the power of the germ to produce disease. This does not always run parallel with virulence, as will be seen in the sub- acute infections. The power of the germs to resist the bodily defenses and, by their extra- or intracellular poisons, to produce a pathological effect, is their virulence. Ehrlich explains virulence by the statement that a bacterium is virulent to the extent that it has haptophorous or binding receptors to bind and sidetrack the defensive receptors of the body tissues. (See pp. 262, 263, and Immunity.) An attractive theory has been suggested by Bail to explain the unusual virulence of micro-organisms under certain circumstances. It was found by Koch that intraperitoneal inoculation with fresh cul- tures of tubercle bacilli causes a rapid destruction of tuberculous ani- mals. Bail found that if tubercle bacilli and sterilized tuberculous exudate were injected into healthy animals, sudden death resulted. Neither the sterile exudate nor the tubercle bacilli alone had such an effect. He, therefore, assumed that something in the exudate increases the virulence of the micro-organisms and gave the name “aggressin” to the hypothetic substance. The exudate found in the peritoneal cavity in these cases was found to consist solely of lymphocytes, and Bail suggests that the aggressin acts by paralyzing the polymorphonuclear leukocytes and thus prevents phagocytosis. The lymphocytic character of tuber- culous exudates is explained by the presence of the aggressin in the tuber- culous animal or man, and the consequent prevention of migration of polymorphonuclear leukocytes. Similar phenomena have been found BACTERIA, THEIR NATURE AND ACTION 253 in cases of other micro-organisms. Anti-aggressins have been produced by repeated inoculation of animals with exudates containing the aggres- sins. Some bacteria or their toxins have a predilection for certain tissues, as, for example, tetanotoxin for the nervous system. This and other phases of virulence will be considered under Immunity. The probability of a successful infection varies directly with the number of organisms introduced, the virulence of the invaders, and with the resistance offered by the individual. Intoxication and Infection.—In one class of diseases the in- fecting microbe remains localized at the point of inoculation, and is never or only exceptionally found in the fluids of the body, the general symptoms of the disease being due to absorption of the toxic products. In such cases the general symptoms of the disease are true intoxica- tions. In other cases the microbe is found circulating in the blood throughout the body and finds lodgment in most of the organs. These are called infections in the strict sense. Tetanus is the type of the first class; anthrax, of the second. There is, however, no distinct line to be drawn, for the symptoms of all infections are doubtless due to toxins or other toxic products, whether produced locally at the point of implantation of the organism or throughout the body when it is dissem- inated. The distinction between intoxication and infection depends upon the method of toxin production. The intoxications form a small class, of which diphtheria, tetanus, and botulism are the only practically important members. These diseases are due to extracellular poisons, commonly called toxins, which are made from the medium upon which the bacteria are living. For example, diphtheria bacilli growing on the pharynx pervert the normal bodily protoplasm to a toxic form. The toxin is negative, or at least antichemotactic (see Inflammation), and thus prevents the phagocytic action of the leukocytes; while most other bacterial products and the bacterial proteins are positively chemotactic. The second class, the infections, is much larger. While it is possi- ble that a modicum of extracellular poison is formed by microbes causing infection, it is certain that by far the greater amount is not available until the bacterial body is digested and the protoplasm lib- erated (endotoxin). The lysis of the germs may be focal or in the circulation, in either case due to the bacteriolytic power of the blood or to phagocytosis. Under Immunity and Allergie theories of the pathological action of these toxins will be discussed. A virulent microbe is one that invades the animal body and there produces its more or less powerful toxin; an avirulent one produces but little, if any, toxin, and is destroyed by bacteriolytic substances and by phagocytosis, either with or without suppuration. The number of or- ganisms, as well as the virulence, is important in determining the char- acter of the effects. Sapremia, Septicemia, and Pyemia.—From local suppurative foci, or necrotic areas due to saprophytic or non-virulent germs, toxic 254 A TEXT-BOOK OF PATHOLOGY products may be absorbed into the general circulation, and a con- dition known as sapremia results. The infecting bacterium itself may invade the blood-current without giving rise to any secondary lesions. This is termed septicemia. When, however, the microbe is carried to various parts of the body and there gives rise to secondary suppuration, the condition is called pyemia. Bacteremia is a term that may be used to indicate merely the circulation of bacteria in the blood with- out implying any clinical condition. Infections may also be divided into fulminating, acute, chronic, and Adami’s subinfection. Fulminating infections are sudden overwhelming attacks by bacteria, in which all bodily defenses are destroyed and death results before new defenses can be raised. ’ Acute infections are those manifested by a short clinical course of more or less definite type and are the evidences of a brief depression of bodily defenses. They tend to be self-limited. Chronic infection is the expression of struggle between the disease agent and bodily defenses over a long period and without definite stages. Tuberculosis is typical of such a disease. Between this and the second form there is another, called variously subacute and chronic remittent. This may be a continuation of an acute condition or arise insidiously and cryptogenetically. The cases have constantly some evidences of infection, but are subject to remissions, acute in form, followed by disappearance of the more evident signs of infection when the exacerbation has passed. In cases studied by us there is persistent bacteremia. ‘The cause seems to lie in a condition of balance between the bodily defenses and the bacterial offenses. Sometimes we have found that the failure of defense is on the part of the leukocyte; at others, on the part of the serum. The bacteria in these cases are in a condition known as “fast” or ‘fixed.’ We can only state that they seem to have immunized themselves in some way against the bodily defenses, and in so doing do not give rise to new defenses or antibodies. The bacteria may be considered as possessing a fairly well- marked pathogenecity, but a low virulence. Subinfection, according to Adami, is a condition of repeated infec- tion from the bowel or respiratory tract due to congestion or mild inflammation. These changes enable bacteria or their products to pass to the lymph or parenchymatous organs, where they are de- stroyed, their remains being found as amorphous granules resembling, but distinguishable from, pigment. The effect is that of continued or repeated irritation, and Adami believes they are factors in the production of cirrhosis and anemias. The focal infections of some writers belong in the subinfections. Mixed Infections —This is a state in which the effect of one agent is superimposed upon another, with usually an intensification of the symp- toms or a rendering of them slightly atypical. BACTERIA, THEIR NATURE AND ACTION 255 IMMUNITY’ Definition.—In the present state of our knowledge of the condi- tion of immunity it is most difficult to give a precise definition of this term. It denotes that condition of an organism which enables it to resist the attacks of bacteria and their toxic products. In one sense it is the reverse of susceptibility. An animal that is not susceptible to an infection is said to be immune, and the term “‘immunization’’ is ap- plied to the process by which an animal becomes thus refractory. Varieties.—Two principal forms of immunity, with a number of subdivisions, are recognized: (a) Natural immunity; (6) Acquired immunity. (a) Natural immunity is the power of resistance to certain bacteria and toxins manifested by races or classes of men and animals, or even by certain individuals. It is always or nearly always an inheritance from’ immune ancestors, and can readily be accounted for on the principles of heredity. We may distinguish: 1. Natural Bacterial Immunity—In this case the resistance is offered to some specific bacterium. Thus, none of the lower animals is susceptible to naturally acquired syphilis, measles, or leprosy; man is in- susceptible to rinderpest; dogs and Algerian sheep, to anthrax; chickens, to tetanus; and in epidemics of various kinds some individuals regularly escape. This bacterial immunity? is only exceptionally absolute; usually it is merely relative, the susceptibility or insusceptibility varying with the environment or individual conditions. 2. Natural Toxin Immunity —Just as the hog is naturally resistant to snake-venom, so certain animals are immune to certain bacterial toxins. Rats are resistant to diphtheria toxin; chickens, to tetanus toxin, etc. (b) Acquired Immunity.—This may be naturally acquired, as when an animal has passed through an infectious disease; or artzficially acquired, when an animal or man has been inoculated with bacteria or bacterial products. We may again distinguish two subvarieties, as in the case of natural immunitv: 1. Acquired Bacterial Immunity—In this form the animal or man has been rendered immune by previous naturally acquired disease, or by inoculation with the specific organisms that have been first reduced 1 Certain definitions and synonyms must be understood to read properly this and other articles on immunity: : Antigen, or exciting substance, is the bacterium cell or substance used for immu- nizing to produce antibodies; these, then, are substances formed against antigens. Toxin, ferments are the soluble products of disease agents. Tozxophore, the poisonous or intoxicating fraction of an antigen. Haptophore, the binding fraction of antibody or antigen. Complement, cytase, alexin, the normal thermolabile antisubstance in blood-serum. Zymophore, the toxic radical in agglutinins and precipitins. Cytophile fraction of antibody combines with cells. Complementophile fraction of antibody combines with complement. __ . Immune body, amboceptor, intermediate body, fixateur, substance senstbilisatrice, prepara- teur, copula, and desmon are synonyms for the thermostabile body raised against antigens. 2 The various immunities of animals are not always absolute under experimental con- ditions. It is possible to give monkeys and, probably, rabbits syphilis, but they do not have syphilis as an endemic among them; it is not natural to lower animals. 256 A TEXT-BOOK OF PATHOLOGY in virulence or killed by heating and other means. Acquired bacterial immunity does not follow all infections. In the case of gonorrhea, for example, it is wanting; and in erysipelas there seems to be increased susceptibility; but in most of the infections immunity is produced. It is of variable duration, sometimes lasting throughout life, some- times only brief periods of time. 2. Acquired Toxin Immunity——In this form the immunity is produced by the injection into animals of the toxins from bacterial cultures, or by injection in men or animals of serum of animals that have been rendered naturally or artificially immune. The terms “active” and “passive” are used in connection with types of immunity to designate the active or passive part taken by animals or men in the acquirement of the immunity. Active Acquired Immunity.—This term is applied when artificial bacterial immunity or toxin immunity has been produced by inocula- tion with living or dead bacteria or by injection of filtrates of cultures, because in these cases there is active production of the immunizing sub- stances in the body of the experimental animal. Passive Acquired Immunity.—This term is applied to the protec- tion afforded by injections of serum of immune animals, because in this case the process is passive as far as the recipient of the antitoxic injection is concerned. Active immunity is relatively much more last- ing than passive. In many cases immunity asserts itself against both the infecting microbe and its specific toxin, as in the rat with regard to the diphtheria bacillus and its toxin; but more often an animal is resistant to the infection, though susceptible to the toxin. An example of this is the action of the guinea-pig toward tetanus (Vaillard). The reverse may be true, and we see an injection of tuberculin without effect upon a healthy animal that is very susceptible to tuberculous infection. Most commonly natural immunity exists toward the infecting microbe and not its toxin. Theories of Immunity.—All the phenomena of immunity have not been satisfactorily explained, but the subject is at least much clearer than formerly. Bacterial Immunity.—Alerin Theory—The blood-plasma and fluids of a naturally immune animal are capable of destroying the bacteria toward which the animal is immune. That the destructive agent is contained in the blood itself is shown by the fact that the defibrinated blood and pericardial effusions of dogs and rabbits destroy anthrax bacilli outside the body. This bactericidal action is not, how- ever, specific nor confined to serum from animals naturally immune to certain infections. On the contrary, the destructive action is mani- fested toward all micro-organisms in varying degrees, and the serum of man or animals always manifests bactericidal power, though not al- ways decidedly. This bactericidal action was attributed by Buchner to certain albuminous bodies which he termed “‘alexins.’’ These are unstable substances resembling ferments in action and easily destroyed by heating BACTERIA, THEIR NATURE AND ACTION 257 the serum to from 55° to 60° C. (131°-140° F.). It has been recently shown that the protection in bacterial immunity is not afforded by a single body or alexin, but by two distinct substances, each of which is necessary. (See Ehrlich’s Side-chain Theory.) Phagocytosis—Metschnikoff proposed the very attractive theory of phagocytosis. He has, however, modified his older views because of new experimental work along the lines laid down by Ehrlich. He now maintains that phagocytosis is the principal factor in immunity and that soluble immune bodies in the plasma are derived from leukocytes. Even extracellular digestion of bacteria is due to substances from leuko- cytes. The infecting microbes are taken up by certain cells of the organism and are destroyed by intracellar digestion, or are dissolved by ferment-like bodies derived from phagocytes when they break (phago- lysis). These cells—phagocytes—are of two kinds: the microphages, including the polymorphonuclear leukocytes; and the macrophages, in- cluding mononuclear leukocytes, the vascular endothelial cells, cells of the bone-marrow and spleen, certain connective-tissue cells and Kup- fer’s cells, and even those of the nerve and muscle tissue. The micro- phages are mainly concerned in the absorption and destruction of bac- teria; the macrophages, in the destruction of cells, portions of dead tis- sues, and the like. After injection of a culture into the subcutaneous tissue of an animal naturally or artificially immune, he noticed that the bacteria were all taken up by the leukocytes. That these microbes were still living and virulent, and were not taken up as mere dead matter, Metschnikoff regards as fully established. One proof he cites is the fact that an exudate containing no free bacteria, but all intracellular, is capable of producing cultures on artificial media and causing infection in susceptible animals. The ferment freed by disintegration of phago- cytes Metschnikoff called “cytase.” Certain important features of Metschnikoff’s theory and results must be emphasized. Increase of resistance to bacteria is usually associated with an increased phagocytic power, but not always, and occasionally an infection, during which the blood and leukocytes possess high pha- gocytic power, results fatally. In some infections an immunity results, although we cannot perceive any change in the leukocytes. It has not been proved that antibodies arise from phagocytes. The cellular theory of Metschnikoff is not incompatible with the humoral or side-chain theory of Ehrlich, but merely explains certain phases of immunity reactions. The phagocytes are, undoubtedly, very important bodily defenses. One of the most difficult phases to explain in terms of this theory is the mechanism of the ill-understood increase in virulence. Organisms are resistant to phagocytosis directly as virulence changes, yet it is possible to get an immunity to a virulent organism without phagocytic action. Bacteriolytic Theory.—Pfeiffer opposed to Metschnikoff’s theory the experiment of injecting cholera vibriones into the peritoneum of — artificially immunized guinea-pigs. He observed a complete destruc- tion of the microbe by the peritoneal fluid—an agglutination into 17 258 A TEXT-BOOK OF PATHOLOGY masses and a gradual degeneration. There were few, if any, leukocytes present, and he, therefore, claimed that such destruction was entirely ex- tracellular and humoral in character. This property of destroying or dissolving bacteria has been termed the “lytic” action of serum. How- ever, if a preliminary injection of some substance that determines a local leukocytosis is made, there may occur, instead of the reaction of Pfeiffer, a true phagocytosis. Metschnikoff interprets Pfeiffer’s phenomenon as the result of a dissolution of the leukocytes by bacterial action, and solution in: the peritoneal fluid of the bacteriolytic substances. While an important part must be admitted to phagocytes in the ultimate destruction of bacteria, bacteriolysis may occur independently of phagocytes. The bacteriolytic substance has been found to operate outside of the body, though not so actively as in the peritoneal cavity. When it has been partly destroyed by long standing or heat, the addition of a small quantity of normal serum from the same animal species restores the bacteriolytic power. (These phenomena will be again referred to in the discussion of Ehrlich’s Theory.) The sources of the bacteriolytic substances are the spleen, bone-marrow, lymphatic glands, thymus gland, and doubtless other organs as well. It is probable that the source differs in different infections. Bacteriolysins differ from Buchner’s alexin in being specific in action, and, therefore, operative only in the case of bacteria to which the animal has been immunized. The bacteriolysins are closely related to, if not identical with, hemolysins, substances occurring in the plasma under certain conditions and capable of destroying red blood-corpuscles. (See Ehrlich’s Theory.) Opsonins.—Wright and others have demonstrated in the serum of animals certain thermolabile bodies which, acting upon bacteria, sensitize them for phagocytosis. These substances, which have been termed opsonins, are analogous in constitution to toxins in having a. haptophore group by which they attach themselves to the bacteria, and an opsoniferous group, which resembles the complements, and, acting like a ferment, completes the sensitization of the bacterium. The natural serum opsonin is thermolabile, but that arising in im- mune animals is decidedly more resistant to heat. It is believed by many that native opsonin is akin to complement or alexin, while that appearing after active immunization is in the nature of a specific anti- body and, therefore, a new development. Such antibodies are certainly specific for the type of organism, if not individually specific. There has been a tendency to minimize the effect of the leukocytes by those engaged in opsonin work. The phagocytes are not inactive or neutral, leaving all the work to the serum opsonin. Whether or not we accept the theory that all such free serum bodies come from the leukocytes, these cells are undoubtedly responsible for certain increase or decrease of phagocytic power, as we have found in certain subacute infections (see p. 254). Leukocytes and their extracts have a slight bactericidal effect in vitro, as shown by Petterson. This may have some effect in m0, BACTERIA, THEIR NATURE AND ACTION 259 but such an action is not considerable. The substances extracted from leukocytes are called ‘‘endolysins” by Petterson. The knowledge of opsonins and phagocytosis has led to the modern uses of dead bacteria or their products for increasing immunity. This process has been called vaccination because of its similarity in principle to the antismall-pox vaccine. In typhoid vaccination there may be no high tide of opsonin or other antibody value maintained for a great length of time, but after exposure to typhoid there seems to be a prompter and greater response in the vaccinated than in the unvac- cinated person. Bacterial Agglutination.—Investigations by Gruber, Durham, Widal, and others have shown that the serum of animals or men rendered immune (naturally or experimentally) to infection with the bacilli of typhoid fever, cholera, the Bacillus coli, etc., causes agglutina- tion and flocculent precipitation of the respective bacteria from their bouillon cultures. Such reactions may be obtained with dead bacilli under certain conditions and even with inert matters held in suspension. (For further details see Typhoid Fever.) This phenomenon (reaction of Gruber-Widal) has been interpreted as representing the mode of de- fence of the body against infection, and the reaction has, therefore, been considered as one of immunity. The reaction, however, bears no rela- tion to the severity of the infection or the degree of immunity. The serum may be highly agglutinative and yet have no immune properties. Some have thought that the agglutination is closely associated with bacteriolysis, perhaps as a preparatory step, but the two functions are certainly distinct. Recent experiments seem to show that two substances are con- cerned in agglutination—an agglutinable and an agglutinating body. The latter appears to be albuminous or related to serum-globulin, as it is precipitated with the latter by magnesium sulphate. It is much more resistant to heat than alexin. Ferment Theory.—A ferment theory has been offered in explanation of some of the phenomena of immunity, but it is of only restricted inter- est or importance. Certain bacteria, like pyocyaneus, typhoid, and cholera bacilli, are capable of elaborating ferment-like bodies that have been designated pyocyanase, typhase, and cholerase. These have some bacteriolytic power, and natural immunity has been explained by assuming the presence in the plasma of such ferments. The action of these ferments is not, however, specific, and their relations to other bacteriolytic bodies is still obscure. Toxin Immunity—The probable nature of toxins has been dis- cussed on page 249. It is found in some cases that an animal is suscep- tible to the action of the toxin of a certain bacterium, though refractory to the bacterium itself, and the reverse may also occur. It is clear, there- fore, that the resistance to bacteria and to toxins are distinct processes, though the two are in most instances associated in the same animal. Natural Toxin Immunity—Certain classes of animals exhibit natu- ral toxin immunity just as we have seen natural bacterial immunity 260 A TEXT-BOOK OF PATHOLOGY existing in certain animals. The immunity of the hog to snake venom, of the chicken to tetanus toxin, of the rat to diphtheria toxin, and other examples might be cited. The explanation of this natural immunity is still uncertain. It is supposed that the immunity, which is an hereditary one, originally occurred in the ancestors as a result of the infection or intoxication in question. They then trans- mitted the immunity to their descendants. With the discovery of antitoxin (to be described below) it seemed likely that an explanation of natural toxin immunity had been discovered, but it was found that, in the case of the chicken and rat, not a trace of antitoxin is present in the blood, though these animals are highly immune to the toxins of tetanus and diphtheria respectively. It was also found that in these animals the introduction of the toxins, while producing no symptoms, rendered the serum highly toxic, and that, transferred to other animals, this serum produced the symptoms of the diseases named. The toxin evidently circulates in an unaltered state at least for some time, and the immunity is not due either to destruction of the toxin or to its rapid elimination; and as antitoxin is absent, it seems likely that the im- munity rests upon an unreceptive quality in the cells of the body. Recent experiments have made it clear that toxins attach themselves closely to certain cells, as, for example, the nerve-cells in the case of tetanus; and it may easily be conceived that if these cells are not recep- tive, the toxin might circulate harmlessly in the serum. Experimental proof of this view will be cited later. The term antitoxin is applied to a substance or substances in the - serum of an animal that protect against the toxin of a specific disease. Acquired Toxin Immunity —This condition was first explained by Behring in a manner similar to the explanation at that time offered for natural toxin immunity—that is, he taught that the tissues of the body become accustomed to the toxin, a sort of Mithridatization. Later he recognized that the resistance is due to the presence of an antitoxin. This at first was regarded by many as an altered form of toxin, and among other experiments offered to prove this view was that of generating antitoxin in vitro by the action of either a continuous electrical current or a rapidly interrupted direct current. It is very likely, however, that the supposed antitoxin in this case was simply a toxin of lower virulence, and that its seemingly antitoxic character was really due to its capacity for developing immunity when injected into animals. Behring first produced antitoxin of diphtheria, but since his investi- gations antitoxins of tetanus, snake-venom, and of various infectious poisons, mainly of laboratory interest, have been produced. The pro- duction of antitoxin is accomplished by treating an animal at first with small, and later with larger, doses of the toxin until the antitoxic quality is developed. As a matter of practical procedure in some cases (e. g., diphtheria) cultures that have been sterilized by heat or cultures containing bacteria of low virulence are frequently used in the early injections, and later, when a certain degree of immunity has been pro- BACTERIA, THEIR NATURE AND ACTION 261 duced, the animal is inoculated with virulent cultures until the antitoxin reaches a maximum. When toxin of sufficient strength can be obtained, the antitoxin can be most surely prepared by using the toxin alone. Occasionally antitoxin is found in the normal animal or in man without previous occurrence of the infection under consideration; thus, in a notable proportion of normal horses, diphtheria antitoxin is found in the blood, and the same is true of children and of adult human beings. In these latter, of course, the possibility of a slight attack of the disease occurring in early life and having been overlooked must be considered. In animals, such as horses, in which the disease does not occur spon- taneously, this explanation does not hold. In the light of recent knowl- edge it seems probable that antitoxin may be produced by the cells under stimulation other than that of the specific toxin, and while anti- toxins are specific to a very large degree, so that that of diphtheria pro- tects only against the diphtheria poison and that of tetanus only against the tetanus poison, this specificity is not absolute. It is known that diphtheria toxin protects against abrin-poisoning, and the antitoxin of abrin protects against abrin- and ricin-poisoning, while the tetanus antitoxin is partially preventive against snake-venom. In other words, the blood has some natural antitoxic power which is increased as a non-specific body at the same time that specific antitoxins are being formed. Moreover, there are certain common constituents in various antitoxins that may possess a generic antitoxic power. Several years ago Theobald Smith showed that a nearly neutralized mixture of toxin and antitoxin produced a more lasting immunity to toxin than simple toxin. This has lately been put to practical use by Behring and his students. The loose chemical union of the two, formed in vitro, is broken up in part by the body, which then proceeds to form its own antitoxin. A too rapid effect of freed toxin is held in check by the accompanying antitoxin. Action of Antitoxin.—It was first thought by Behring that the toxin and antitoxin enter into a chemical combination which completely de- stroys the identity of the two substances. This was disproved by the discovery that a mixture of snake toxin and its antitoxin, which ordi- narily has no effect when injected into an animal, becomes highly toxic when heated to 70° C. (158° F.). It is known that the antitoxin is de- stroyed at this temperature, while the toxin is not. It is very probable that the toxin and antitoxin enter into a form of loose chemical com- bination without losing their identity, just as hydrochloric acid enters into loose combination with albumin in gastric digestion. The Chemical Nature of Antitoxin.—But little is known regarding the antitoxins excepting that they are relatively resistant to heat and other external agencies. Thus, the tetanus antitoxin bears a temperature of up to 70° C. (158° F.), as well as the action of sunlight, and even putrefaction, without being destroyed. It seems likely that the anti- toxins are albuminous bodies or that they are closely associated with such bodies. Transmission of Antitoxin—The hereditary transmission of anti- 262 A TEXT-BOOK OF PATHOLOGY toxin has been studied, and it has been found that transmission takes place from the mother to the offspring through the fetal circulation or, after birth, through milk. There is no transmission from an immune male parent to the offspring. In experimental work the transmission of - immune substance could not be traced as far as the second generation. Elimination.—Antitoxin is probably eliminated through all the secretory organs. It has been found in the urine and to a large extent in the milk. Brieger and Ehrlich obtained a quite concentrated form of antitoxin by precipitation of the globulin by ammonium sulphate and purification by dialysis. As in the case of toxins, the whole of the antitoxin seems to be carried down by the precipitated globulin. All the phenomena of immunity have been explained by Ehrlich in a very comprehensive theory called the side-chain theory. The applications of this to toxin immunity will be first considered for the sake of simplicity. Ehrlich’s Side-chain Theory.—Toxin Immunity.—This theory explains the facts regarding the action of toxins and the formation of antitoxins better than any that has been suggested. It is based upon the hypothesis that bacterial toxins, like assimilated foodstuffs, enter into chemical combination with the cells of the body. In this respect toxins differ from ordinary poisons which do not enter into such com- bination, and this may explain the failure of all experiments at produc- tion of antitoxins for such poisons. Some non-bacterial poisons, such as snake-venom, abrin, ricin, etc., resemble toxins in combining with the cells, and it is notable that in the case of these poisons antitoxins have been produced. The combination between a toxin and a cell is effected by atom groups or radicals (to borrow terms from organic chemistry), the group of the cell entering into combination with the group of the toxin. It is assumed that the body-cell is like a complex chemical sub- stance with unsatisfied bonds, to which is added the power to combine with substances having affinity for it through these bonds, and to cast them off after this new combination is effected. These groups which effect the junction of the cell and the toxin are termed haptophore groups. In addition to its haptophore group, the toxin molecule con- tains a toxophore growp which carries the toxic capacities, but the toxo- phore group cannot operate upon a cell until the toxin has been anchored to the cell by the junction of the haptophore groups (Fig. 96). When a toxin is introduced into the body, it finds cells with haptophore groups having affinity for its own haptophore group. These haptophore groups of the cells, from their receptive function, are called receptors, and they are specific in so far as the receptors of certain cells will combine with the haptophore groups for which they have affinity and with no others. In this way it may happen that a highly toxic body may circulate harmlessly in the body, as there are no receptors for which it has affinity. (This matter was referred to in the paragraph on Natural Toxin Immunity.) When the receptors of the cells are utilized by combination with the haptophores of the toxin they may be regarded as neutralized or practi- 8 BACTERIA, THEIR NATURE AND ACTION 263 cally destroyed, and the cell has suffered a “defect”? which must be re- placed by regenerative processes. This usually follows promptly, accord- ing to the well-known theory of Weigert that destruction is followed by regeneration. In accordance with the same theory this regeneration often more than replaces the loss, so that in the case under discussion there is an overproduction of receptors in the cell, and some of these are extruded from the cell into the blood-plasma. The actual extrusion or separation of the haptophore groups requires the stimulus of the toxo- phore group. The separated haptophore groups now free in the blood- plasma constitute the antitoxin, since they are now free and able to com- bine with the toxins before these can reach cells susceptible to the action of the toxophore group. The toxin thus combined with a liberated recep- Fig. 96.—Receptors of three orders (Ehrlich). Ehrlich has described receptors of three orders: 1, The receptor of the first order is a single combining group without any other function. On this account Ehrlich speaks of it asauniceptor. In Fig. 96, J, such receptors are shown ata. On the right hand, the receptor has become united with a toxin molecule, b. The latter shows its haptophore group at c, and its toxophore group at d. It is the receptor of the first order that con- stitutes antitoxin when liberated from the parent cell. 2. Receptors of the second order (Fig. 96, IJ, c) have a haptophore group, e, and a zymophore group, d. The latter is so named because of its ferment-like capacities. On the right hand is seen a molecule of nutrient matter, f, combined with the haptophore group of the receptor, in such position that the zymophore group can act upon it. Having but one haptophore group, like the receptors of the first order, those of the second order also are included under the term of “aniceptors.”’ The phenomena of agglutination and precipitation are probably occasioned by this second order of receptors. 3. Receptors of the third order (Fig. 96, III, 7) carry two haptophore groups, e and g. One of these combines with a molecule or cell, f, for which the receptor has affinity, and the other combines with the haptophore group of the complement, k, which, when so combined, can act upon the molecule anchored to the other haptophore group. The complement has two groups—one, its haptophore, h, and the other, its zymotoxic group, z tor (antitoxin) is incapable of harm, as its own haptophore group is promptly joined to the antitoxin and cannot, therefore, become an- chored to a vulnerable cell, which is the prerequisite for the operation of the toxophore group upon a cell. After antitoxin formation has begun, it may continue for some time, causing successive discharges of the antitoxic material into the blood-stream. This is shown by the continued presence of antitoxin in animals that have been bled so- abundantly that practically all the original blood must have been with- drawn. All the steps in this theory have been practically demonstrated. In the first place, it has been shown that the toxin enters into firm combination with the cell by mixing tetanus toxin and emulsions of 264 A TEXT-BOOK OF PATHOLOGY normal brain tissue. Under these circumstances a certain proportion, or all, of the toxin unites with the nerve-cells, and the mixture is found to be harmless when injected into animals. In the second place, it has been shown that the receptor formation results from the combination of the haptophore groups of the toxin and of the cell, and is independent of the toxophore group. This was demonstrated by producing increased susceptibility to the action of toxin in animals inoculated with toxoid (a body derived from toxin, but having no toxic qualities). The toxoid has the same combining capacity for receptors of the cells as has the toxin, but it simply lacks the toxophore groups, which somehow have disappeared or become altered. In the experiment just quoted there was no trace of antitovin in the blood; hence the toxoid was capable of causing increased production of receptors on the cells, but not free in the blood as antitoxin. Other experiments show that the stimulus of the toxophore group is necessary to cause the separation of new-formed Fig. 97.—I. Scheme showing cell with receptors (a). One receptor has been occupied by a toxin molecule (b). There has resulted an overproduction of receptors, and two of these (a’) have become separated from the cell. II. Scheme showing toxin molecules (b) attached to free receptors (a’) in the blood. The toxin is thus prevented from attaching itself to the receptors (a) of the cell, and the toxophore group (d) is harmless. receptors from the cell. In the third place, it has been shown that the antitoxin formation takes place in the fixed tissue cells, where the toxin finds suitable receptors, and not in the circulating blood itself, since antitoxin could be extracted with salt solutions from the blood-making organs of animals that had been treated with toxin, but had not yet any antitoxin in the blood. Of course, the period of time during which such an experiment could succeed must be a very brief one, but it has been accomplished. Numerous experiments have shown that the antitoxin is not altered toxin, but a new production, as stated in this theory. The large amount of antitoxin produced by a small amount of toxin alone would suffice to disprove the theory of transformation. Haptophore groups or receptors still in-connection with the parent cell are not to be regarded as antitoxin; rather the contrary, for they serve to anchor the toxin to the cell where the toxophore group is in BACTERIA, THEIR NATURE AND ACTION 265 position to injure the cell (Fig. 97). The experiment quoted above showed this, for the animal treated with toxoid developed increased vulnerability to toxin (because of the increased number of receptors) and had no trace of antitoxin in its blood. It is only haptophore groups that are free in the circulation, and therefore capable of fixing toxin and keeping it away from the cells that constitute antitoxin. This antitoxin production Ehrlich ascribes to his wniceptors or receptors of the first order. It is the simple union of toxin haptophores and fixed or free cell receptors. Bacterial Immunity.—(a) Bacterial immunity as applied to agglu- tination and precipitation is next in order. These processes are ex- plained by Ehrlich’s receptor of the second order. This assumes ‘that the cell receptor has two parts, one to combine with the haptophore of the bacterium or other body, the other a zymophoric part, to act upon the toxophoric part of the bacterium (see Fig. 96). These processes—agglutination and precipitation—are not actively concerned in the phenomena of immunity, but may be referred to in this place on account of their illustrating the applications of the side-chain theory. Agglutination.— Bacterial agglutination (Pfeiffer-Gruber-Durham phenomenon) is explained by Ehrlich’s theory somewhat in the same way as bacteriolysis and hemolysis. In the case of agglutination, how- ever, there is but one agent—a liberated amboceptor having a hapto- phore group, which attaches itself to the bacterium, and a zymophore group, which plays a part similar to that of the complement in bac- teriolysis (see Fig. 96, IZ, d). It differs from the complement, however, in that the zymophore group is an integral part of the amboceptor, and not a separate body, which attaches itself to the latter. A serum which has the property of agglutinating the bacteria of a certain disease (as e. @., typhoid fever) contains liberated amboceptors that were set free by the cells of the body and that have the property of attaching them- selves to the specific bacteria concerned in that disease. When so attached, their ferment-like group or zymophore group, which is the active agent, produces agglutination. The zymophore of the antibody is the agglutinating substance or agglutinin, while the corresponding fraction of the bacterium is the agglutinable body. This was mentioned on p. 259. (See also Typhoid Bacillus.) Agglutinins are also found in normal blood, although in but small quantity. They are thermostabile, and resist drying of the serum. Precipitin—The phenomena of precipitation of various substances that have been introduced into an animal organism by the action of serum derived from the blood of such animals have been ascribed to specific “precipitins.’’ Thus, when the blood of human beings is repeat- edly introduced into the peritoneal cavity of rabbits, the rabbit-serum acquires the property of precipitating human blood. When the blood of several animals in succession is introduced into an animal of a differ- ent species from each of these, it is found that the precipitation is a specific process, since the specific power to precipitate the blood of each 266 A TEXT-BOOK OF PATHOLOGY of the species employed can be successively demonstrated. When albuminous liquids or such a complex mixture as milk is introduced into animals, the blood-serum of the animals acquires the property of precipitating the albumin used or the milk (casein). This and other experiments show the wide range of applicability of the principle of precipitation. Ehrlich explains the process of precipitation in the same way as that of agglutination, by the assumption that amboceptors carrying haptophore groups with an affinity for the precipitable body are set free in the serum, and that associated as an integral part of these amboceptors are zymophore groups capable of producing the phenomenon of precipitation or agglutination. The zymophore groups are destruct- ible by heat, though the degree of heat is much higher than that re- quired to destroy the complements concerned in bacterial destruction and hemolysis. (b) Bacterial Immunity as Applied to Bacteriolysis and Cytolysis.— The application of Ehrlich’s theory to the phenomena of bacterial immunity is quite as satisfactory as it is to the formation of antitoxins. When a bacterium is introduced into the body, the problem of the defence of the organism against the invading bacterium is much more complicated than that of the defence against a toxin, because the bac- terium contains a variety of substances, such as its protein and various ferments, and may elaborate specific toxins in the culture-medium. In consequence, the defence of the animal organism against the bac- terium is a complicated one, involving formation of antitoxin and other antagonistic bodies, including those which attack the bacterium itself in contradistinction to the products of the bacterium. The defense against the bacterium is the process that has been referred to previously in describing Pfeiffer’s phenomena of bacteriolysis. This process, according to Ehrlich’s investigations, is practically identi- cal with that of hemolysis, or destruction of red corpuscles, which occurs when the blood of one animal is injected into another, or when certain hemolytic agents, like snake-venom, are introduced into the blood. As the study of hemolysis is practically much easier than that of bacteriolysis, the theory was elaborated on the bases of experiments in hemolysis, and two distinct substances or bodies are involved in the process... One of these Ehrlich formerly designated as the intermediary body in the case of hemolysis, or the immune body in the case of bacterial immunity; the second is a complementary body, and is designated the complement. The intermediary body, or immune body, is a product of cell activity under the influence of infectious, toxic, or other agencies, which is set free in the same manner as the haptophore group or re- ceptor in the case of antitoxin formation. It has two haptophore groups—one having affinity for the complement, and therefore desig- nated complementophilic; and the other having affinity for the bacterium, red corpuscle, or other cell, and therefore designated cytophilic. On account of this possession of two haptophore groups Ehrlich later desig- nated the intermediary body by the term amboceptor. This is Ehrlich’s receptor of the third order. It is a stable substance, not influenced by BACTERIA, THEIR NATURE AND ACTION 267 moderate heat. The complement, on the other hand, is a ferment-like body, and is a constituent of normal blood-plasma. Its ferment-like character is evidenced by its ready destructibility by heat (55° or 56° C.; (131° or 132° F.). The origin of complement has been variously ascribed to leukocytes, lymph-glands, and liver. Without the complement the amboceptor is ineffective, and without the amboceptor the comple- ment cannot affect the cells (bacteria, red blood-corpuscles, etc.). The cytophilic group of an amboceptor is more or less specific, so that, unless the receptors (haptophore groups) of the bacteria, red corpuscles, etc., are homologous with the cytophilic haptophore of the amboceptor, combination will not occur—in other words, the amboceptors are more or less specific and must be homologous with the receptive haptophores or receptors of the cells. There must, then, be a great many varieties of receptors—perhaps hundreds or thousands—in order to fix the equally numerous varieties of amboceptors, and the same is perhaps true of the complement. Various substances doubtless act as complements. Thus, in experiments on snake-venom, Kyes found that lecithin is the complement. : The bacteriolysin of Buchner, called by him alexin, is, according to recent views, a compound substance, one part being the amboceptor, the other the complement. Explanation of Pfeiffer’s Phenomenon.—The phenomenon of Pfeif- fer’s bacteriolysis may be explained in the following manner: When a bacterium, with a quantity of immune serum, is introduced into the peritoneal cavity of a non-immunized animal, amboceptors derived from the immune serum attach themselves to it. The complement present in the peritoneal fluid then becomes anchored to the complementophilic haptophore group of the amboceptor, and in this position is able to bring about the solution of the bacterium and its destruction. The phe- nomena of hemolysis may be explained in the same way: the amboceptor first attaches itself to the red corpuscle, and the complement (hemolysin) in turn attaches itself to the amboceptor. The necessity for two bodies in the production of these phenomena has been thoroughly demonstrated. It is known that serum capable of producing Pfeiffer’s phenomena zn vitro loses this power when subjected for a certain length of time to heat or sunlight. A prompt restoration of the power follows the addition of small quantities of normal (unheated) serum of the same animal species. This proves that a ferment-like body (destroyed by heat) is a necessary factor, and that this ferment is present in the normal serum of the animal. The importance of the complement has been further demonstrated by the formation of anti- complements, which are capable of combining with it and thus stopping its action. When the anticomplement is withdrawn, the complement is again capable of operating. In a similar manner anti-amboceptors have been produced, and have sometimes been found in the blood of normal animals. The following scheme represents graphically the relations of the amboceptor and complement to the cell and the possibilities of the 268 A TEXT-BOOK OF PATHOLOGY various antibodies, such as the anticomplement and anti-amboceptor (Fig. 98). ; ; Cytolysin.—Injections of emulsions of various cells into animals have been found to generate destructive substances in the serum of the experimental animals. These destructive bodies are specific for the cells used in the experiment. Thus, spermatolysin, epitheliolysin, and hep- atolysin are substances which will cause destruction of spermatozoa, Complement free anticomplement complemen amboceplar anh amboceptar free amboceptor Fig. 98.—I. Diagram representing the amboceptor and complement free and attached to the cell by means of the appropriate receptor. JJ and III. Scheme showing (1) pos- sible antibodies; (2) anti-amboceptor; (3) anticomplement; both of these have been demonstrated as possible antibodies. a, Cytophilic group; 6, complementophilic group. epithelia, and hepatic cells respectively. The phenomena involved in such cytolysis are closely allied with those of bacteriolysis and hemolysis. The following tables (modified from Miiller) will show in a con- densed form the varieties of immunity detailed in the foregoing para- graphs: Antitoxie Immunity I. Cellular. A. Lack of appropriate receptors. (a) Congenital. (b) Acquired (loss of the receptors). B. Lack of susceptibility to the toxophore group of the toxin. (a) Congenital. (b) Acquired (?). C. Attachment of the toxin to insusceptible tissues. (a) Congenital. (b) Acquired (development of new receptors in insusceptible tissues). II. Hematogenic. A. Active. (a) Manifest form (abundance of antitoxin in the blood). (b) Latent form (no antitoxin present, but capacity for making it quickly and abundantly). B. Passive. Antitoxin is introduced: (a) Through the placenta to the fetus. (b) Through milk to the nursling. (c) By direct injection. BACTERIA, THEIR NATURE AND ACTION 269 Antibacterial Immunity I. Natural (congenital). (a) The animal organism is an unsuitable medium for the growth of the bacterium. (b) The organisms are destroyed at the point of infection by amboceptors and complements (bacteriolysis). (c) Amboceptors present, but no complements. The latter are supplied by— 1. Increased supply of tissue fluids. 2. Advent of wandering cells. (d) Complement present, but no amboceptors. The latter are supplied— 1. Locally. 2. By the lymphoid blood-making organs. (e) Phagocytosis and intraphagocytic bacteriolysis. II. Artificially increased, but not specific (pseudo-immunity). Injection of irtitating substances which cause local accumulation of phagocytes and bacteriolysins. II. Naturally acquired specific immunity. IV. Artificially acquired specific immunity. (a) Active immunity. 1. Abundant presence of specific amboceptors in the blood and tissue fluids. 2. No preformed amboceptors, but increased capacity to manufacture such, by prophylactic injection. (b) Passive immunity. Specific amboceptors in the blood (derived from another animal). Complement Deviation and Fixation—When complement is bound in such manner that it cannot enter into combination with antigen and amboceptor in bacteriolysis or cytolysis, it is said to be ‘‘deviated”’ or “fixed.” The terms, however, are used for slightly different conditions. If more antibodies be employed in tests or injections than the antigen can use, the excess combines with complement and prevents it from acting with the antibodies bound to the antigen. This is complement deviation, and of slight moment here, except to be contrasted with complement fixation as a diagnostic procedure. If the serum of rabbits immunized against sheep erythrocytes be mixed with sheep red cells in the presence of complement derived from normal guinea-pig serum, hemolysis results. When, however, complement is absorbed, as now to be shown, hemolysis will not occur. A mixture of the serum of a person suffering from a micro-organismal disease, an emulsion of the causative microbe, and guinea-pig serum containing complement results in the solution of the germs, 7. ¢., bacteriolysis, because the three factors —antigen, amboceptor, and complement—are present and are bound together. If, now, we were to add to this same mixture the antisheep cells rabbit serum and the sheep cells, no solution of the hemoglobin would result because the complement has been fixed by the first combina- tion. This is the principle of the Wassermann reaction in syphilis. It can be and is used chiefly for determination of the presence of antibody in the blood of infected persons. The application to syphilis will be discussed later. We refer to works on immunology for deeper con- sideration. 270 A TEXT-BOOK OF PATHOLOGY Anaphylaxis or hypersusceptibility is a condition of increased or altered susceptibility of the animal organism to foreign protein. In a sense, then, it is a condition opposed to immunity, although in some cases it may act to protect the body against infection. The term allergie has been suggested by von Pirquet to express the altered and usually increased property of the body to react to foreign protein. Hypersusceptibility may be natural or acquired. The former is exemplified by the susceptibility of certain persons to pollen in rose-cold and hay-fever, or to fish and oysters which is shown by skin eruptions. Acquired hypersusceptibility is expressed when the body, once having received a foreign protein, is exposed to it a second time. For example, if a guinea-pig receive a small dose of horse serum, no symptoms will arise, but when a somewhat larger second dose is given, after an incuba- tion period of eight to ten days, it will almost immediately become depressed and nervous, scratch its nose, develop violent dyspnea, and die; the fatal outcome occurs usually within an hour, but may appear in afew minutes. Upon postmortem examination there will be found spas- tic dilatation of the pulmonary alveoli of local and central origin, hemorrhage into and ulceration of the gastric mucosa, and scattered petechial hemorrhages. The death is due to respiratory failure, as the heart continues to beat after respiration has ceased. This sudden and violent reaction is called “anaphylactic shock,” a condition most clearly expressed by the guinea-pig, which animal seems to exhibit the most pronounced reactions in allergie tests. Any animal, however, is capable of anaphylactic phenomena, and the symptoms, signs, and pathology are similar in all. The reactions differ in degree, of course, depending upon the amount and nature of protein injected, the incubation period, and the receptivity of the animal. If the amount of serum injected the second time into the guinea-pig be too small, or if introduced so that the absorption is quite slow, symptoms will be delayed, milder, and may not proceed beyond nervousness and scratching. If the dose be given into the skin instead of under it or into the circulation, only a local reaction of redness and edema may be occasioned. The injection first given is called the sensitizing dose; the second, the intoxicating dose. In the discussion of infection and allergie given below it will be seen that previous exposure to a protein (bacterial) acts as the first dose, while the place of the intoxicating dose is taken by the protein (bacteria) from which the infection immediately arises. Hypersusceptibility is specific, that is, an animal will be intoxicated only by the protein with which it has been sensitized. Guinea-pigs may be sensitized to several proteins and react specifically to each. The allergic state is transmissible to young from the mother only; if the father only be sensitized the offspring does not inherit the condition. During the anaphylactic reaction there will be found leukopenia with eosinophilia, lengthening of the blood coagulation time, and a fall in blood-pressure. The allergic state is sometimes seen in human beings after the injec- tion of antisera, notably diphtheria antitoxin. The reaction takes the BACTERIA, THEIR NATURE AND ACTION 201 form of “serum sickness” or anaphylactic shock. Serum sickness oc- curs after an incubation period of a week to ten days, and is character- ized by nervous depression, skin irritation, urticarial eruptions, fever, and malaise; occasionally the condition may be quite severe, appearing like an acute general infection. Anaphylactic shock in human beings after serum injections is similar to that outlined for guinea-pigs, and death may ensue in a few minutes. The vast majority of cases in which this acute reaction has been observed have suffered from asthma. In this connection an explanation has been sought in the fact that the anaphylactic reaction sets up spasm in involuntary muscle; that the muscles of the bronchi are contracted and shut off the alveoli. Allergie also explains the responses obtained when the skin of a person suffering from an infectious disease is inoculated with some of the virus, of that disease. This phenomenon is exemplified by the skin reaction against tuberculin exhibited by the tuberculous, and the luetin reaction in syphilitics. It is a local manifestation of general anaphylaxis. There is a general tendency now to use this anaphylaxis, or the allergic state, to explain the contraction of infectious disease. It is assumed that when a person contracts such a disease he has been susceptible to the organism as an individual peculiarity, or has been prepared, sensitized, in some way. One explanation of this phenomenon asserts that the body is unpre- pared for protein introduced at other places than the alimentary tract, and must prepare a ferment against it. This it does after the first dose, but in accord with Weigert’s overproduction theory, it produces a superabundance of this ferment, which, when acting upon the second dose, breaks it up so quickly that various digestion products are thrown on the organs suddenly and poison them. Another theory assumes that toxic protein circulates in the blood after the first dose; the body cells are poisoned by it, but gain an affinity for it, so that they attract it in large quantity after the second injection, being then fatally injured. Friedberger views the anaphylactic reaction as the effect of toxic pro- teins upon cells through their sessile receptors, thus permitting a direct injury to the cell protoplasm. It is not until several injections have been given that receptors are freed and combine with toxic substances, apart from cells. This is in accord with Ehrlich’s theory that cells are vulner- able in proportion to the number of their sessile receptors. Friedberger has used the principle to develop his anaphylotoxin theory of infection. He assumes that an organism circulating in the body combines with the antibodies it has stimulated. This combina- tion is then rendered toxic when acted upon by complement. Jobling goes further than this, asserting that bacteria absorb the unsaturated fatty acids of the blood, which hold in check the tryptic power of the serum, permitting the serum to break up bacterial and natural proteins and allowing escape of their toxic elements. = of Vaughan believes that the invasion of the body by bacteria stimu- lates a ferment which, acting upon the organisms, frees their toxic pro- tein. The ferment is specific for the infecting germ and will react 272 A TEXT-BOOK OF PATHOLOGY, quickly when this enters the body the second time. The toxic fraction of all bacteria is the same. He explains infection and allergie on this basis. The specific antibodies are stimulated by the specific protein, so that typhoid bacilli have their own, pneumococci theirs, etc. It certainly seems that the anaphylactic state is due to degradation products of proteins and that the substances giving rise to it are complex proteins. The body fluids seem to react to the parenteral introduction of proteins by the elaboration of ferments having the power to break down these substances into simpler combinations like the amino-acids. Abderhalden has shown that in the serum of pregnant women there are ferments capable of digesting placental tissue. It may be that all im- munity phenomena are protein reactions on the part of the body. Chemistry of Antigens and Immune Bodies.—The exact comiposi- tion of the various elements that have been brought to light by immunity researches is not known. Some observers maintain that only proteins can give rise to the immunity phenomena, but others believe that some lipoids and glucosids can act as antigens. No substances simpler in composition than peptones seem able to act as antigens. Judging from the work of Vaughan and Abderhalden upon bacterial and other pro- tein intoxication, the defenses of the body seem all to be directed against foreign protein. These proteins are specific, in that protection or sus- ceptibility toward one will not protect or dispose toward another. The various substances in the serum involved in immunity or allergie are precipitated with protein fractions, seem inseparable from them, and cannot be obtained in a pure state. The method of action, be it chemical, mechanical, or electrolytic, is not known. It might be well to emphasize here that in speaking of this parenteral introduction of pro- tein a substance foreign to the tissue is implied. Meiostagmin Reaction.—This is a test for showing the reduction of surface tension by the combination of antigen and specific antibody. For this purpose Traube’s stalagmometer, an instrument to determine the number of drops in a given bulk, is used. If homologous antibody and antigen are mixed and incubated at body temperature for two hours, there will be found an increase of drops over the number determined before incubation. Some have used this test as an argument for the physicochemical explanation of immune reactions. Its significance is not yet fully understood. CHAPTER IX DISEASES DUE TO BACTERIA Tue bacterial diseases form a large and increasing group. In some cases it has been shown by the positive application of Koch’s rules (see p. 37) that the suspected micro-organisms are the actual causes of the diseases under consideration; in more numerous instances all of the rules cannot be applied, but other considerations go far toward establishing the specific nature of the suspected bacteria; in still other cases the evidence warrants a strong suspicion of the pathogenicity of bacteria found in connection with certain diseases, but there is nothing approaching actual demonstration. DISEASES DUE TO COCCI SUPPURATIVE DISEASES Definition.—Under this heading we include for the present various forms of suppurative inflammation, such as furunculosis, abscess formation, and allied diseases, like osteomyelitis, endocarditis, cellulitis, etc. Etiology.—Numerous organisms have been found to have the power of producing suppuration (pyogenic organisms). Among these the staphylococcus group is most important. The Streptococcus pyogenes seu erysipelatis is also of great significance; less frequently the Diplo- coccus pneumonie, the pneumobacillus of Friedlander, the Bacillus pyocyaneus, the typhoid bacillus, the Bacillus coli communis or the Bacillus pyogenes fetidus, the gonococcus, and others. Some cases of suppurative disease are due to a single organism; in many there is double or multiple infection. 1. The Staphylococcus Group——Among these have been described three important forms: the Staphylococcus pyogenes aureus, albus, and citreus. The Staphylococcus pyogenes aureus is a minute, rounded body about 0.5 to 1 w in diameter, having no motility and not forming spores. When found in the tissues the cocci are apt to be associated in clusters, whence the term “‘staphylococcus.”’ Sometimes they are grouped in pairs, and may thus present a resemblance to gonococci. The op- _ posed surfaces, however, are flat instead of concave, as is the case with the gonococci. The staphylococcus may be stained with ordinary anilin solutions and is beautifully demonstrated by Gram’s method. Cul- tures are easily obtained upon the ordinary media. The most charac- teristic growth is that upon agar. Along the line of inoculation a moist 18 273 274 A TEXT-BOOK OF PATHOLOGY colony develops, with at first a whitish but soon an orange-yellow color, especially under the influence of light. The growth in gelatin causes rapid liquefaction and the precipitation of orange-yellow particles. The growth is best obtained at oven-temperatures (25° to 35° C.; 77°-95° F.), but may be secured at lower degrees. Distribution —The Staphylococcus aureus is frequently found upon the skin or in the various external secretions of healthy individuals. It does not seem to flourish anywhere apart from the bodies of men or animals, but may remain in an active state in the dust of rooms or upon clothing and the like. It has been found in various lesions of the body, notably, however, in furuncles, abscesses, and carbuncles, and in ulcerative conditions of the exterior or of the mucous membranes. It is also frequent in internal suppurative inflammations, such as malig- nant endocarditis, osteomyelitis, appendiceal abscesses, etc. In many of these lesions other organisms may be associated. Pathological Physiology.—Filtrates of the cultures and the bodies of the staphylococci (killed by heat) contain highly toxic substances capable of producing intense inflammation and suppuration. Certain of their products are markedly hemolytic. When injected into the subcutaneous tissue the staphylococcus produces local effects. The organisms may become liberated, gain entrance to the circulation, and produce widespread results; but it does not seem to produce extracellular toxins that cause generalized results. The effects of the staphylococcus seem to be due rather to a certain poisonous body contained in the organism itself. This has been termed “bacterial protein,” and it has been thought to belong to the group of alkaline albuminates. This body by its chemotactic effect causes the leukocytic accumulations found in suppurative inflammations. The staphylococcus also leads to liquefaction in the tissues, as in gelatin, both directly and through the accumulation of bodies derived from leukocytes. The defence of the organism against the staphylococcus is partly mechanical and partly vital. The leukocytes probably englobe a certain number of organisms and cause their destruction, while soluble bactericidal bodies seem to be produced in the course of the infection. Injection of cocci gives rise to antibodies—agglutinins, opsonins, and bacteriolysins. Upon them depends the use of bacterin or vaccination treatment. Pathogenicity—When virulent cultures are injected into animals, abscesses are produced and a fatal termination may follow. In the latter case dissemination through the blood is found, and infarcts of the kid- neys, lungs, and other organs caused by bacterial emboli are discovered. Multiple abscesses may be seen. The organism readily loses its virulence, as in the case of those found upon the skin of healthy persons and in other accidental situations. When rubbed in a virulent state into the skin of man it produces abscesses or boils. It may remain dormant within an enclosed abscess or sequestrum in a bone, or apparently in a subacutely inflamed heart valve or muscle, and light up upon some secondary infection. Staphylococcus infection tends to remain local, with DISEASES DUE TO BACTERIA 275 occasional spread to the circulation. Its local lesions are of slower pro- gression than those of the streptococcus. Its presence sometimes favors the growth of other organisms, notably the influenza bacillus. Staphylococcus pyogenes albus (ig. 99).—This organism is practically identical with the last-named in morphology, but in culture produces a white instead of a yellow growth. One of its forms has been found as a frequent harmless parasite of the skin (Staphylococcus epidermidis albus of Welch). It occurs in abscesses and various suppurative diseases, but rarely alone. As a rule, it is associated with the golden staphylococcus or other organisms. It is distinctly less virulent than the aureus. Staphylococcus pyogenes citreus.—This form is the least important of the three. It is not so common and, asa rule, less virulent. It differs in the brilliant lemon color obtained upon culture in various media. 2. The Streptococcus pyogenes seu erysipelatis——Under the name streptococcus are included various spherical bacteria which divide only Fig. 99.—Staphylococcus pyogenes albus Fig. 100.—Streptococcus pyogenes (Jakob). (Jakob). in one plane and form chains of varying length. The different forms resemble each other so closely that some authors group them all, includ- ing the Streptococcus pneumonia, under one general head. The last, however, seems sufficiently differentiated to merit separate classifica- tion. The Streptococcus pyogenes was first studied by Rosenbach in cases of suppuration. A similar organism was afterward described as the Streptococcus erysipelatis by Fehleisen. It would seem, however, that these two organisms are identical. The streptococcus is a small spherical organism of variable size (0.5-1 «), frequently associated in chains of from three to twenty or more individuals (Fig. 100). Not rarely it occurs in diplococcus forms (as pairs). It is easily stained with ordinary anilin solution or by Gram’s method. The cocci are not motile. Spore formation has not been observed, but occasionally in chains one of the individual members is larger than the rest, suggesting arthrospores. Upon artificial media scanty but rather characteristic growths are ob- 276 A TEXT-BOOK OF PATHOLOGY tained. On the gelatin plate there are formed small, translucent, whitish or yellowish colonies of irregular outline. The gelatin is not liquefied, Upon agar a very thin, transparent growth forms around the line of inoculation. It consists of separate colonies which usually do not coalesce. On mixed agar and blood plates the colony of the true streptococcus produces a pale gray dot surrounded by an area of hemol- ysis. Certain varieties lack this power. In milk the growth is usually abundant and attended with lactic acid formation and coagulation of the casein. In the species Streptococcus pyogenes there are several varieties that have been found so frequently under special conditions that they seem worthy of separate mention. The principal one is the Streptococcus viri- dans, which is common in streptococcal endocarditis. It is not hemolytic and grows in green colonies on blood-agar. Streptococcus mucosus is a mucus-producing organism found usually in the throat or in enclosed abscesses. The streptococci of the feces have minor peculiarities differ- ing from the true type. Another variety seems to have a predilection for joint cavities (Streptococcus rheumaticus). It has been asserted by Rosenow that the members of the strepto- coccus-pneumococeus group are but variants of one species, and he claims to have been able to follow a mutation from one to another under artificial conditions. Under prolonged artificial cultivations these organisms do surely lose some minor characters, but mutation must be stationary to be actual. The distribution of the streptococcus is much the same as that of the staphylococci, though it is less commonly discovered about the healthy body. It may, however, be found upon the mucous membranes or in the various secretions or excretions of the body. It is probably a strict parasite, multiplying only within the living organism. In disease it has been found in various forms of suppuration, such as phleemonous forms of inflammation of the subcutaneous or sub- mucous tissues, either alone or in association with other organisms. It occurs occasionally in focal suppurations, such as abscesses, though these are more commonly due to staphylococci alone. The streptococcus occurs at times in ulcerative endocarditis, not rarely in infectious endo- metritis and in generalized septicopyemia. Streptococcic inflammations of the throat are of great interest. They may occur in persons previously in good health, or in the course of infectious diseases, like scarlatina, measles, or influenza. To the clinician the resulting lesion may be indistinguishable from that of diphtheria; bacteriological examination alone serves to establish the diagnosis. Deep involvement of the tonsil is one infection-atrium for the cocci to enter the blood. Following such an entrance we may have serous membrane involvement, particularly in the heart valves. The streptococcus is found in all cases of erysipelas in the tissues and in the other exudations. Pathological Physiology and Pathogenesis.—The streptococcus seems to be more active in the production of soluble toxins than staphy- lococci. The toxin has been made by inoculating small quantities of DISEASES DUE TO BACTERIA 277 ’ bouillon with virulent cocci, allowing these to grow for several weeks, and then destroying the organisms by heat. The injection of the toxins thus produced leads to local and general reaction. While there is a certain amount of this extracellular toxin, it seems that most of the toxic substances of streptococci are embodied in the micro-organism itself. In virulent cultures actively hemolytic bodies are often present, and certain streptococcic infections in man are attended with hemor- rhages and evidences of hemolysis. The principal pathological character of streptococcal infections is their spread. Instead of localizing like the staphylococcus, a diffuse spreading inflammatory edema results with involvement of lymphatics and blood- vessels, by either of which routes the cocci get into the blood-stream. Serous membranes are especially susceptible to streptococci, and throm- bophlebitis or arteritis is the first lesion arising when the germ reaches a vessel. In these infections there is more often bacteremia than is the case with staphylococci. Injected into animals (intravenously) virulent streptococci may occasion septicemia, but it is notoriously difficult to obtain cultures of great virulence and the succeeding generations soon lose their power. White mice and rabbits are the most susceptible animals. A single attack of erysipelas or streptococcic infection confers no immunity on man and, similarly, one inoculation occasions no immunity in animals. By repeated injections, however, an antistreptococcus serum of some potency has been obtained. Recent studies show that more satisfactory practical results may be obtained when the antistrepto- coccus serum has been prepared with a strain of organisms similar to that present in the case under treatment. For this reason mixtures of serum prepared with several strains are used (polyvalent sera), so that in a clinical case (because of the difficulty in distinguishing various strains) a specifically active antiserum may be administered. The efficacy of such polyvalent sera, however, is somewhat doubtful. Streptococcus intracellularis meningitidis (Weichselbaum).—This organism, also called meningococcus or Diplococcus meningitidis, is found in the meningeal pus, in the blood, nasal mucus, sputum, and urine of individuals affected with epidemic cerebrospinal meningitis. This micro-organism in some respects resembles very closely in its form and intracellular occurrence the gonococcus. The organism appears as a biscuit-shaped diplococcus, irregular in size, sometimes occurring as tetrads or in clumps, and occasionally as short chains in which the line of cleavage between the diplococci is in the same direction as that of the chain. The coccus is Gram-negative, but here and there will be found a few units that retain the blue of the gentian-violet. It is easily stained with Loffler’s methylene-blue. In the meningeal exudates it is usually found within polymorpho- nuclear leukocytes, like the gonococcus. Some have described its occurrence within the cellular nuclei; this is doubtful. It grows well at 37.5° C. (100° F.) on blood-agar, serum-agar, and plain agar. On the latter there appear, in forty-eight hours, flat. 278 A TEXT-BOOK OF PATHOLOGY grayish-white, faintly granular and viscid colonies that do not coalesce. On blood-agar the colonies are more luxuriant. — The cultures may live for weeks, but often die in a few days, and, therefore, require frequent transplantation. Distribution —The meningococcus is found in the _ seropurulent exudate of epidemic cerebrospinal meningitis and is readily demon- strated in the fluid obtained by lumbar puncture. It has frequently been found in the nasal mucus of patients suffering from the disease and in healthy individuals more or less closely associated with the patient. The assumption is, that the meningeal infection occurs by passage of the organisms through the lymph-channels from the nose or sinuses adjacent to the meninges. Recent experiments seem to indicate that the organisms may travel in the opposite direction, for in monkeys infected by intradural inoculation the organisms were found in the nasal cavities after a short interval. Organisms resembling the meningococcus and probably actual meningococci have been found in the lungs in cases of bronchitis and pneumonia complicating epidemic meningitis. Pathological Physiology and Pathogenesis—Large subcutaneous in- jections may cause death, and intrapleural and intraperitoneal injec- tions may kill animals and cause a fibrinopurulent inflammation of the serous membrane. Subdural inoculation (spinal and cerebral) in dogs and monkeys have caused lesions identical with those found in man. The toxins of the meningitis coccus are endocellular and are freed in vitro by autolysis. Agglutinins and lysins are developed in patients and -experimental animals. Flexner, Jobling, and Wassermann have devel- oped an antiserum from goats which when used intraspinally dissolves the organisms. Other Organisms in Meningitis —The pneumococcus, Streptococcus pyogenes, Staphylococcus pyogenes, typhoid and colon bacilli, influenza bacillus, and, less commonly, some other forms have been isolated in cases of primary meningitis or meningitis secondary to infection else- where. GONORRHEA Definition.—Gonorrhea is an infectious inflammation of the urethral or other mucous membranes due to a specific organism, the Micrococcus gonorrhee or gonococcus discovered by Neisser in 1879. Etiology.—There is no doubt that the gonococcus is the specific cause of gonorrhea. This organism is a micrococcus, usually arranged in pairs, the opposed surfaces of each being slightly concave. This arrangement has suggested the designation “biscuit-shaped” diplo- coccus (Fig. 101). Sometimes groups of four or more are found, while in other cases the cocci occur singly. The organisms are abundant in the pus of acute gonorrhea, less abundant in advanced stages, in the pus of gonorrheal salpingitis or other conditions, and may not be dis- covered at all. They generally occupy the pus-cells, lying in the proto- DISEASES DUE TO BACTERIA 279 plasm, either in small numbers or so abundantly as to fill the cell uni- formly. In the tissues the same intracellular position is usual, but here, as in the free pus, some organisms may generally be found between the cells. The gonococcus stains readily with ordinary solutions of anilin dyes, and is distinctly Gram-negative. Cultivation of the gonococcus is difficult. Growths may, however, be obtained at 37° C. (98.6° F.) upon agar-agar streaked with human blood or on media prepared from human ascitic or pleuritic fluid or albuminous urine. Later generations may grow well on ordinary media, but usually require the serum additions. The growth in blood-serum consists of small colonies of grayish color that coalesce and form a film on the surface of the medium; around the colony may generally be seen an irregular and inconspicuous extension. : The gonococcus cannot be positively distinguished by its morphol- ogy nor by the intracellular position. Other organisms may in certain stages of their growth show a typ- ical biscuit form (staphylococci and others); and the intracellular position is not rarely assumed by a variety of bacteria: The failure to stain by Gram’s method and the failure to grow on ordinary media are strong points suggesting the gonococcus. Typical cultures alone establish the diagnosis. A number of organisms resembling the gonococcus were found by Bumm in the vaginal mucus. The Micrococcus catarrhalis also resembles ‘it closely. No similar micrococcus ,. 3 has anne been found in the male ** ee ees ane urethra. Pathogenicity—It has been demonstrated by direct implantation of pure colonies upon the healthy urethra that this organism will cause characteristic gonorrhea. Urethritis may, however, be due to other organisms; the specific form termed “gonorrhea’”’ is probably always due to the gonococcus. Secondary lesions, such as salpingitis, odphoritis, arthritis, peritonitis, conjunctivitis, endocarditis, ete., may also be due to this organism, no other form of bacteria being present. Sometimes, however, complications, such as periurethral abscesses, suppurative adenitis, etc.. are due to secondary infections. Gonococci stimulate the formation of slight amounts of agglutinins, opsonins, and bacteriolysin. Antisera are of little value, but bac- terins or vaccines may be useful. The toxin is intracellular. Pathological Anatomy.—The lesions of gonorrhea will be considered elsewhere. Suffice it to say in this place that the organism causes sup- purative catarrh of the mucous surfaces with which it comes in contact. There is abundant cellular exudation and the organisms tend to pene- trate deeply into the tissues. Z8U A TEXT-BOOK OF PATHOLOGY Pathological Physiology.—Gonorrhea is in most cases a purely local disease. Little is known of its power to produce soluble toxins. The effects are probably due to an intracellular toxin. The distant lesions are in all cases, as far as we definitely know, dependent upon trans- portation of the specific organism. These have been found in the effusions of arthritis, in meningeal exudates, and in the vegetations of gonococcal endocarditis, as well as in the blood in the last-named condi- tion. CROUPOUS PN EUMONIA Definition.—There are a number of forms of inflammation of the pulmonary tissues to which the term ‘“‘pneumonia”’ is applicable. The most definite form of disease is that spoken of as croupous, fibrinous, or lobar pneumonia. In its typical form this is a specific and well charac- terized disease. It is infectious, more or less contagious, and caused by a specific organism. Etiology.—The organism most frequently found in the lung in croupous pneumonia and doubtless the specific cause of the disease in such cases is the Diplococcus pneumonia, belonging to the genus Strepto- coceus. It is less regularly the etiological agent in bronchopneumonia and atypical pneumonias, but even in these cases it is found more fre- quently than other bacteria. The organism is also called the pneumococcus, the Micrococcus lan- ceolatus, and sometimes the Strep- tococcus pneumonie seu lanceolatus. The diplococcus of pneumonia was recognized in the saliva of healthy persons by Sternberg and Pasteur, but its relation to croupous pneu- monia was first demonstrated by Frankel, and later by Weichsel- : baum. The individual organism ' suai has a somewhat elongated, lanceo- Fig. 102.—Diplococcus pneumonie in the late shape, and has, therefore, blood (Frankel and Pfeiffer). been considered a bacillus, though it does not always show this pseudobacillary shape distinctly (Fig. 102). In the sputum and lungs and in the blood of inoculated animals it is commonly found in pairs; the broader ends of the organisms adjacent, and the pointed ends projecting outward; the group is surrounded by a transparent capsule, which does not readily take stains and, therefore, becomes con- spicuous (Fig. 103). Sometimes the organism forms chains, in which, however, the pairs of micrococci are a little distance apart. Chain formation is especially marked when the organism is grown in fluid media. The capsule is not seen when the organism is obtained from cultures. The diplococcus does not possess individual motility and has no flagella. It does not seem to produce spores. DISEASES DUE TO BACTERIA 281 It may be readily demonstrated in the sputum or in the tissues by staining with the ordinary anilin dyes or by Gram’s method. Cultivation——The diplococcus grows readily upon ordinary media, excepting potato. It forms characteristic colonies upon agar-agar plates or in gelatin. Upon the surface of the agar there appear transparent drop-like colonies hardly visible to the naked eye, which under the microscope have a finely granular appearance. Upon gelatin plates similar growths are produced, while in gelatin punctures the growth occurs along the path of the wire as granular whitish spots separated from each other. The addition of serum or ascitic liquid to agar makes a medium in which larger and more conspicuous grayish colonies of circular outline appear on the surface. In the paler marginal zone of the colony, diplococci or short chains may be seen. On blood-agar pneumococci produce small round greenish colonies without hemolysis. Tn bouillon a cloudiness is produced when the culture is from twelve to twenty-four hours old; later the organisms precipitate and the bouillon becomes clear. ilk is acidified and at times coagulated by the pneumococcus. When inulin is added to a serum medium the pneumococcus ferments the inulin and coagu- lates the serum. The organism tends to die out very readily in cultures, and also loses its Fig. 103.—Diplococcus : pneumoniz: a, Cocci, with- pathogenic property when propagated for out capsules; b, single and several generations. In solid media contain- paired cocci, with capsules; 2 : ‘ c, chain form; d, colony of ing serum and more particularly in fluid media cocci (Ziegler). the virulence may be preserved for a long time, sometimes for months. It is most luxuriant at 37° C. (98.6° F.). Pneumococci are dissolved by bile or solutions of its salts, in this being different from the streptococci. Pathogenicity—The specific character of this organism has not been definitely proved according to the rules of Koch, but it is highly probable that it is the usual cause of pneumonia. The diplococcus is frequently found in the saliva of healthy persons. When this is introduced into animals, particularly rabbits, the animal dies, with evidences of rapid sepsis (sputum septicemia). The postmortem shows some fibrinous exudate and occasionally a little pus at the point of inoculation. The spleen is enlarged, and capsulated bacteria of distinct lanceolate form are widespread throughout the body. Injections of lung tissue or of pneu- monic sputum produce similar results, and the organism in pure cul- ture likewise causes this form of septicemia. It has been shown that injection of pneumonic exudate aspirated from the consolidated lung into the lungs of rabbits will produce true pneumonia. Typical pneumonia has been produced by injection of virulent pneumo- cocci into the lungs of rabbits previously immunized against the pneumococcus to prevent the occurrence of general pneumococcus septicemia. ; The most successful attempts at producing pneumonia were made 282 A TEXT-BOOK OF PATHOLOGY by Rosenau and later by Meltzer, who atomized pneumococcus cultures into the trachea of dogs. The toxin of the pneumococcus is intracellular. Some antibodies may be formed. Besides the diplococcus there are certainly other elements which contribute to the causation of the disease, else the frequent occurrence of the micro-organism in question in the saliva would make pneu- monia a much more common affection. The nature of the contributing causes is, however, obscure. Exposure to cold, general depression of the system, traumatism, alcoholism, and other causes certainly predispose or help to determine the occurrence of the disease. These causes may act by temporarily increasing the virulence of the diplococcus or by lower- ing the resistive power. Certain irregular forms of lobar pneumonia may be caused by streptococci, staphylococci, the Bacterium pnewmonie of Friedlinder, the influenza bacillus, that of typhoid fever, etc.; but true croupous pneumonia is probably always due to the Diplococcus pneumone. Pathological Anatomy.—(See Diseases of the Lungs.) Pathological Physiology.—The diplococcus produces, in the first place, local lesions of the lungs; and in the second place, systemic infection and possibly also general intoxication by toxins of uncertain character. The infection-atrium is almost always the respiratory tract. In the case of systemic infection the organism itself gains access to the blood and may produce secondary lesions in other organs. Infection with the diplococcus of pneumonia causes a pronounced reaction on the part of the blood in the form of leukocytosis. This is not invariable, but is usually seen. After the attack of pneumonia there is temporary im- munity, and it has been found that animals may be immunized for con- siderable lengths of time by repeated injection of pneumococci. The serum of the immunized animal has a certain protective and curative value which has recently been attributed to the formation of opsonins, which are operative by rendering the pneumococci liable to rapid ingestion by phagocytes. There are several varieties of the pneumonia coccus with slightly differing biological characters, and it may not be possible to obtain a therapeutic antiserum against them all. Cole insists that a polyvalent serum will not answer, but that one should use an antiserum against the type of pneumococcus present in each individual case. The antiserum supplies immune bodies including, perhaps, antitoxin. The author just mentioned has been able to divide the pneumococci into four main groups into which practically all strains fall. For two of these he has a separate antiserum. It has also been possible to use with advantage as a therapeutic agent autolysates of pneumococcus cul- tures at that stage of autolysis when the specific protein is freed. The Diplococcus in Other Diseases.—The Diplococcus pneumonia has been found in various conditions complicating pneumonia, and occasionally in lesions unassociated with croupous pneumonia. Among other lesions, meningitis, pleurisy, and other inflammations of the DISEASES DUE TO BACTERIA 283 serous surfaces, abscesses, otitis media, and arthritis have been found to be due to this organism; or, at least, this organism alone has been found in some of these cases. Endocarditis is frequently caused by the pneumococcus. It may be primary or secondary. OTHER FORMS OF PNEUMONIA Among other varieties of pneumonia may be mentioned the catar- rhal or lobular form, the tuberculous form, and various irregular pneu- monias, partly cellular, partly fibrinous, partly purulent or hemorrhagic. Though the pneumo- @ Q@ coccus is more frequently present than any other @ ~ J single organism in bronchopneumonias after in- @ § ® a fi fectious diseases like measles and diphtheria and @ in various irregular types of bronchopneumonia, SS different organisms may be found in such cases, Fig. 104.—Bacterium and some of these may be of etiologicimportance pneumonie of Fried- : ~ Tt lander. in certain cases. Not rarely the pulmonary disease is the result of mixed (double or multiple) infection. Bacterium pneumonize of Friedlander.—This organism was re- garded at one time as the cause of croupous pneumonia. It prob- Fig. 105.—Friedlander’s pneumonia, showing the enormous number of bacteria in the exudate. ably occurs in most cases as a mixed infection, though it may occa- sionally be the cause of catarrhal or irregular forms of pneumonia or of ordinary croupous pneumonia. With this organism also Meltzer has been able to produce pneumonia in dogs by atomized insufflation. 284 A TEXT-BOOK OF PATHOLOGY The cases of pneumonia due primarily to the pneumobacillus are char- acterized by their virulence and a peculiar viscid character of the exudate in the lung. Friedliinder’s organism occurs as a distinct bacil- lus, usually in pairs and surrounded by a capsule like that of the diplo- coccus (Fig. 104). Sometimes it may form chains of three, four, or more organisms. It stains well with the anilin dyes, but is decolorized by Gram’s method. A characteristic culture is obtained in gelatin. The puncture-culture is characterized by a luxuriant growth at the top and a considerable vegetation all along the track. This leads to a nail-shaped growth. The gelatin does not liquefy. Upon agar a con- siderable whitish or yellowish moist growth occurs upon the surface. There is formation of gas in media containing glucose, and often also on potato. A number of organisms closely related to Friedlander’s pneumo- bacillus have been classified under the generic name Bacteriwm muco- sum capsulatum. Among these are the B. lactis aérogenes, B. acidi lactici, B. ozene, and B. rhinoscleromatis. The several types differ some- what in their power to ferment various carbohydrates. Other Organisms in Pneumonia.—Among the various organisms that have been found in bronchopneumonia or less commonly fibrinous pneumonia are the Streptococcus pyogenes, more rarely the influenza bacillus, the Bacillus coli communis, the typhoid bacillus, the bacillus of glanders, of the plague, and occasionally other organisms. In some of these cases the disease may be the result of double infection. Tubercle Bacillus —A uniform pneumonic process may be due to simple infection with the tubercle bacillus, or to mixed infections. Micrococcus tetragenus——This form is a Gram-positive micrococcus from 1 to 2 “ in diameter, and receives its name from the peculiar asso- ciation in groups of four. It occurs in the sputum and contents of cavities in pulmonary phthisis, and occasionally elsewhere. It may give rise to general sepsis. Micrococcus catarrhalis is a micro-organism found by Pfeiffer in cases of bronchitis in which there was a great deal of expectoration, and in which the symptoms resembled those of influenza. It is a small coccus, usually occurring in diplococcic form, and resembling the micro- coccus of gonorrhea. It often is seen within the pus-cells, and occurs in large numbers in the sputum and nasal secretion of individuals suffering from bronchitis. It does not cause the constitutional disturbance that is caused by the bacillus of influenza, but is often found as an associated infective agent in cases of pneumonia due either to the Diplococcus pneumonie or to the bacillus of influenza. To obtain it in pure culture it is best grown on blood-agar. It grows as sharply defined, somewhat raised, granular, yellowish, non-transparent colonies on the surface of agar. It resembles the Staphylococcus pyogenes aureus, but the colonies are much more raised and harder. They can be picked up on the end of the needle, and are crushed with difficulty. The needle can be drawn across the culture without destroying the integrity of the individual colonies. After the first generation the micrococcus grows well on DISEASES DUE TO BACTERIA 285 ordinary agar, but it must be transferred every three or four days to be kept alive. It is decolorized by Gram’s method. Its pathogenicity is as yet undetermined. In its behavior toward animals it resembles the bacillus of influenza. It seems to be of importance in the pneumo- coccal or streptococcal anginee, since, according to the work of one of the authors, a culture of one of these cocci is much increased in patho- genicity for guinea-pigs when mixed with Micrococcus catarrhalis. DISEASES DUE TO BACILLARY FORMS DIPHTHERIA Definition.—Diphtheria is an infectious and contagious disease caused by a specific bacillus. Etiology.—The Bacterium diphtherie was discovered by Klebs, but more accurately studied by Léffler, and is, therefore, called the Klebs- Léffler bacillus. This organism is a rod varying in length from 1 to 6 u, rather thick, and with somewhat swollen ends. It is readily demon- Fig. 106.—Diphtheria bacilli from an eighteen-hour blood-serum culture. strated in the local lesions of the mucous membranes or skin, where it may be quite abundant; the individual bacilli, however, are separate from one another. The organism is peculiar in its great irregularity of shape and size, particularly in cultures (Fig. 106). Seemingly branched forms have been observed, and some investigators have viewed the organism as a streptothrix or even as one of the hyphomycetes. 286 A TEXT-BOOK OF PATHOLOGY Frequently one end is especially large, giving a club-shaped appear- ance; some of the bacilli are very large; some present rounded granules at either end, the so-called polar granules or Ernst bodies. The bacillus is readily stained with aqueous solutions of basic stains, especially with those rendered slightly alkaline. (Léffler’s solution—saturated aqueous solution of methylene-blue, 30 c¢.c., in aqueous solution of potassium hydrate, 1: 10,000, 100 ¢.c.—is the favorite stain.) The color is retained when stained by Gram’s method. The stained specimen shows the mor- phology of the bacillus very clearly. The rounded ends generally stain more deeply than the shaft of the bacillus, so that the appearance somewhat suggests a diplococcus, or as a row of cocci. Not rarely transverse fractures give the organism the appearance of disjointed segments. There are no flagella, and the bacillus is not motile. Spores have not been demonstrated. Cultivation—The most characteristic cultures are obtained upon blood-serum, especially such as contain a small amount of glucose. Upon this medium there is formed within six, twelve, or twenty-four hours a thin, whitish or yellowish-white layer of irregular outline, often showing separate smaller colonies around the edge. A small portion of the colony may be removed and stained, and the diagnosis thus established with ease in a short time. Other organisms found in the throat are slower in growth, and do not, therefore, interfere with the diagnosis. Pathogenicity—When cultures in bouillon are injected beneath the skin of a guinea-pig a fibrinous inflammation with more or less widespread edema results, and the animal dies in from twenty-four to thirty-six hours. Congestion of the adrenal, necrotic foci in the liver and other organs are found postmortem; the neighboring lymphatic glands are enlarged. If the animal survive, paralysis may make its . appearance, as in human beings recovering from the disease. The pathogenicity has also been shown by inoculation of various other animals, and definitely by accidental infection of man. Klebs-Loffler bacilli may be found in the pharynx of a person show- ing no indication of disease. This indicates that the organism has not found a favorable soil for its development or no abrasion or opening into tissues that will support its growth. The bacillus may, however, thrive and multiply for a considerable time upon the mucous membrane of such a throat, as it may upon food, clothing, or other infected mate- rials. Mixed Infection in Diphtheria —Other organisms, notably strep- tococci, staphylococci, and pneumococci, may be associated with the diphtheria bacillus, and may be actively concerned in the local or general pathological processes. The streptococcus is especially potent as an associated cause. The streptococcic infection may precede or follow the diphtheritic infection. Various organisms of a saprophytic nature may cause putrefactive changes in the pseudomembrane. Predisposing Causes.—Some predisposition is necessary for the development of the disease. In part this is personal, some individuals being highly susceptible, others scarcely at all. In part, accidental DISEASES DUE TO BACTERIA 287 conditions, such as pharyngitis, laryngitis, abrasions, ete., furnish a favorable opportunity for the infection. The diphtheria of birds, calves, and certain other animals is distinct from the human disease; and the organisms are in no way related. Human diphtheria may occur in cats, and these animals may propagate epidemics. Pseudomembranous (fibrinous) inflammation is not invariably caused by the diphtheria bacillus (see Inflammation). Among the organisms capable of causing somewhat similar pseudomembranes, the most fre- quent is the Streptococcus pyogenes; another important one is the pneumococcus. Distribution of the Bacilli—The organisms are abundant in the pseudomembranes of diphtheria, but are only exceptionally found in the blood or internal organs. The visceral or nerve lesions are usually due to the toxins, and not to the bacillus. The same is true of experi- mental diphtheria. The internal lesions may be produced by injection of the toxin obtained by filtering a bouillon-culture through a Pasteur filter. Pathological Anatomy.—Diphtheria is primarily a local disease of the pharynx (pharyngeal), of the larynx (laryngeal), of the nose (nasal), or of the skin (dermal). The bacillus lodges in the mucous membrane or skin, and produces a pseudomembrane. This consists of fibrinous exudation in the form of fine granular material or a fibrillar network, in which are embedded the epithelial cells and other tissue elements and infiltrating leukocytes. The epithelial cells rapidly undergo coagu- lation necrosis or granular degeneration, as do also the connective tissues when the process extends beneath the mucosa. The blood-vessels become obstructed by thrombosis or compression, and the tissue is, therefore, avascular. Nearly always the pseudomembrane thus formed is attached to the underlying tissues, and when removed a raw and bleeding surface is exposed. The depth of involvement, however, varies; sometimes the submucosa is soon involved; more often the disease is practically confined to the mucosa. The macroscopical appearance is that of a whitish, dirty-yellowish, or brownish membrane upon the mucous lining of the throat. This begins as one or several patches upon the tonsil, and spreads rapidly to the neighboring parts. In other situations the appearance is much the same. Inflammatory swelling beneath and around the diseased area is habitual. It is of great clinical importance to recognize that true diph- theria may occur in the form of typical follicular tonsillitis. Internal or visceral lesions may occur in the course of diphtheria or during convalescence. They are usually due to the action of the toxin, and not of the bacillus. Necrotic foci in the liver, showing advanced cell- ular degeneration of the cells with hyperchromatosis of the nuclei, and similar lesions of other organs, may be seen in the human body, as in animals killed with the organism or its toxin. Swelling of lymph-tissue is common, the principal point of attack being endothelium. This may go on to focal necrosis. Myocarditis and myocardial degenera- 288 A TEXT-BOOK OF PATHOLOGY tion, renal degeneration and nephritis, and, most interesting of all, de- generation of the peripheral nerves and neuritis may be met with. All of these will be described elsewhere. This is believed to be due to the toxone fraction of the toxin. Pathological Physiology.—As has been said, the disease is pri- marily local, and the bacilli nearly always remain localized in the superficial lesions. They have been found in the internal organs, showing that they can enter the blood-stream. The local effects are believed by some to be due to an endocellular toxin. The general manifestations—fever, prostration, and the visceral lesions— are caused by poisonous substances elaborated by the growth of the bacilli. There are probably several substances of this sort, but one in particular—the tovin—is most important. This may be obtained by filtering bouillon-cultures through porcelain, and by its injection the constitutional and some of the local manifestations of the disease may be induced in animals. Successive introduction of increasing doses of toxin causes the development of antitoxic substances that may finally accumulate in the blood to such extent that the animal becomes immune to the most virulent bacilli. The antitoxic substance or substances, or antitoxin, found in the blood and the blood-serum of immunized animals will render other animals immune for a time, or combat and overcome the disease if already existing. Simultaneous injection of antitoxin and of many times the ordinarily fatal dose of toxin or diphtheria-cultures leaves an animal unharmed. The value of the antitoxin in animal experimentation is beyond doubt. In the human being there is scarcely any doubt of its potency, though, of course, crucial experiments cannot be made. Experience has shown that its therapeutic use in diphtheria should never be omitted. After an attack of diphtheria there is temporary immunity, but this passes off and successive attacks may thus occur in the same person. Diphtheria-like bacilli are sometimes found in the pharynx of healthy individuals in some cases, as well as upon the hands, hair, or in other parts of the body. They are also found in various forms of rhinitis, conjunctivitis, and non-diphtheritic angina. These may differ from the virulent bacilli in being somewhat shorter and in growing more lux- uriantly. Their distinctive character, however, is their relative harm- lessness when injected into animals. Pathogenic powers have been ascribed to certain members of the pseudodiphtheria group of bacteria. Some seem to be able to pro- duce a transmissible angina that is not favorably influenced by diph- theria antitoxin. Others of the group may cause general infection or severe local disturbance. The exact relationship of the members of the diphtheria group is not yet decided, but the classification of Emerson is quite good: “(1) Bacilli with typical morphology, typical cultural characteris- tics, especially the ability to form acid from glucose, and which produce the typical lesions in animals, are, in the opinion of all observers, Bacillus diphtherie. DISEASES DUE TO BACTERIA 289 “(2) Bacilli with typical morphology and typical cultural reac- tions, especially the ability to form acid from glucose, but which are not pathogenic to animals, may be called avirulent diphtheria bacilli. “(3) Bacilli with typical morphology, but which do not conform in their cultural reaction with the diphtheria bacillus, and which are not pathogenic for animals or do not produce typical lesions, may properly be called pseudodiphtheria bacilli. “(4) Finally, there are a number of organisms which resemble Bacillus diphtherie in many ways, but whose morphology is not ex- actly the same, . . . and which have different cultural characteristics, and differ in their pathogenicity. This group certainly includes the pseudodiphtheria bacillus of Hoffmann, the xerosis bacillus, and others.” The pathogenic members belong in the first and third or possibly the second and third groups. A difference of the pseudo- and true diph- theria bacilli not mentioned above is that the former do not produce a soluble toxin, but upon injection excite a bactericidal serum in experi- mental animals specific for each variety. The so-called virulent pseudo- diphtheria bacilli have been found in cystitis, septicemia, and other conditions. They are very common in mixed infections, and have been said to be more potent in continuing an infection than in inciting it. TYPHOID FEVER Definition.—Typhoid fever is an infectious disease, with char- acteristic lesions of the intestines, and due to a specific bacillus. It is important to recall the fact that local or general typhoid infection may occur without the intestinal lesions or usual clinical features of typhoid fever. In such cases local inflammatory lesions, suppurations, necroses, or septicemia have been observed. Etiology.—Certain predisposing features make individuals more liable at one time than another to this disease. It occurs in adoles- cence and the young, but rarely in the old. Climatic conditions are supposed to play some part, and doubtless do have an influence. Ty- phoid fever is especially a disease of the temperate zones, and is most abundant in the autumn. Drainage and other conditions affecting the surroundings of persons may influence the predisposition. One attack usually confers immunity for the rest of life; exceptions, however, are met with. The Bacillus.—The Bacillus typhi abdominalis, the specific organism, was discovered by Eberth and isolated by Gaffky. It is a short bacillus, from 1 to 4 in length and 0.5 to 0.8 u in thickness. The ends are rounded and often somewhat plump. In culture these rods or bacilli occasionally form long chains, but in the tissues they are never so arranged. The organism is actively motile, this being due to flagella, of which there are eighteen or twenty attached to the periphery (Fig. 107). When stained with alkaline methylene-blue or other stains there are sometimes seen dark-colored spots at the ends of the organism. These were formerly regarded as spores, but are now recognized as areas of protoplasmic 19 290 A TEXT-BOOK OF PATHOLOGY condensation. Under certain circumstances the condensation is seen in the center and vacuole-like formations are found at the ends. The organism is readily stained, but decolorizes very easily, and is, therefore, difficult to demonstrate in tissue. The bacilli are, as a rule, found in clusters. These groups may, however, be few in number, and thus difficult to detect in the organs. Cultivation.—Artificial cultures of the bacillus have been obtained from the spleen and other organs, as well as directly from the blood, stools, and urine of patients suffering from the disease. They grow very well upon the ordinary culture-media, such as agar-agar, gelatin, and potato, the temperature of the body being most favorable, but-some growth occurs at the ordinary temperature of the room. Upon gelatin and agar there are formed irregularly whitish films, which on close inspection with the lens show a granular appearance. This growth, TERS TI ooh Fig. 107.—Bacillus typhi abdominalis, from an agar-agar culture six hours old, showing the flagella stained by Léffler’s method; x 1000 (Frankel and Pfeiffer). however, is not distinctive. Upon acid potato a characteristic transpar- ent pellicle is formed. This may be invisible except to the trained eye, but on scraping the surface with a platinum wire the pellicle can be raised, and on microscopical examination it is found to be composed of bacilli. Sometimes the pellicle is yellowish or brownish. When culti- vated in milk there is slight acidity, but coagulation does not occur. When grown in agar containing a little glucose no fermentative gas results. Another feature of importance is the absence of indol reaction, the addition of potassium nitrite and sulphuric acid to bouillon-cultures causing no rose color, such as occurs with some other organisms. The biological characters of the typhoid bacillus are distinct enough when isolated, but as it occurs so frequently in company with the colon bacillus, whose colonies are similar, numerous technics have been devised for its isolation. These must be studied in books on bacte- DISEASES DUE TO BACTERIA 291 riology. (Compare Cultivation of Typhoid and Colon Bacilli, pages 290 and 296.) One of the most reliable tests for the identification of the typhoid bacillus is the Widal reaction, the clumping of the organism by the blood of typhoid patients, or, better, by the serum of animals , immunized against a known culture of the Bacillus typhosus. Human typhoid serum may clump colon bacilli also in low dilutions. Pathogenicity——Animal experimentation has thus far been unsat- isfactory. A few observers have succeeded in producing illness and intestinal lesions by feeding animals with typhoid cultures, particularly after the stomach and intestines have been rendered alkaline with soda and peristalsis has been checked with opium. In most cases in- jection of the typhoid bacillus has produced septicemic manifestations. The anthropoid apes have been infected by feeding and injection with typhoid bacilli, the resulting intestinal and other lesions bearing a rather distinct similarity to those in man’s natural disease. The constant occurrence of the germ, its absence from other conditions, and the absence of any other germ as a constant accompaniment of typhoid fever, have led to the general acceptation of this as the specific cause. Moreover, its properties are such that the spread of the disease in the acknowledged ways is entirely compatible with the acceptance of the bacillus as the specific cause. Distribution.—The typhoid bacillus occurs both within and without the human body, and doubtless multiplies greatly in the external world when the conditions are favorable. It is found with great regu- larity in the blood of typhoid patients, especially in the first week of the disease. It occurs in the lesions of the intestines and in the intes- tinal contents, especially during the second and third weeks of the ‘disease. It is usually less abundant, but often present in the spleen, liver, and kidneys; it may occur in considerable abundance in these organs when there are local complications. It is almost always present in the gall-bladder in cases of typhoid fever, and frequently occasions cholecystitis and not rarely initiates the formation of gall-stones. It also occurs in the lungs, in the parotid gland, and in other organs, and posttyphoidal abscesses may contain the organism in abundance. Complicating lesions of other organs may be dependent solely upon the specific bacillus, it being capable even of acting as a pyogenic organ- ism, or they may be dependent upon secondary or mixed infections. The typhoid bacillus is peculiarly resistant, and may thrive upon clothing, in soil, and in water for a long time. Cold has no effect, the germ being virulent after freezing and thawing. It has rather more resistance to carbolic acid than other members of the typhocolon group. These features help to explain the spread of the disease and its general prevalence. The organisms are discharged from the body of a patient suffering from the disease mainly in the stools, but in part also in the urine, sweat, and other excreta. If they are not at once destroyed, contamination of clothing, soil, water, etc., may occur, and subsequent infection of susceptible individuals takes place through drinking-water or food with which the infected water or other matters have come in 292 A TEXT-BOOK OF PATHOLOGY contact. It is possible that infection may occasionally take place through the lungs by inhalation of dust. This must be very rare. Intra- uterine infection undoubtedly occurs in some instances in which the mother is suffering from typhoid fever. One means of transmission of typhoid is by means of “carriers,” Carriers are persons who after recovery from a typhoid infection harbor somewhere within themselves virulent bacilli without active evidence thereof. They are usually in the gall-bladder, but may be in lymph- nodes or liver. They may be excreted and pollute water or surrounding objects. The reason for this carrying of germs may lie in the fact that their focus is protected from the antibodies of the blood, or they may be “fast’’ strains. Pathological Anatomy.—The lesions of typhoid fever are con- sidered with the diseases of the intestines. It is important, however, to add in this place that widespread changes may occur in this disease as a result of the action of the bacillus. Thus there may be focal necroses in the spleen and liver, degenerative changes in the kidneys and muscles, and inflammatory changes in various glandular organs, the periosteum, the bones, or the connective tissues, the result of the direct action of the bacillus. There is a reaction on the part of lymph- adenoid tissue everywhere throughout the body, including all organs, even the larynx, in which definite lymphoid swellings occur in the mucosa, at times leading to ulceration. Pathological Physiology.—The typhoid bacillus elaborates toxic substances which give rise to fever and other general symptoms as well as to local lesions. Brieger and Frankel claim to have separated a specific toxalbumin. Whether this be the poison or not, there is no doubt that some form of a toxic body is present, and is endotoxic, not extracellular. During the existence of the disease the system reacts, in some way as yet unknown, to check its progress and to bring it toa termination at the end of four weeks, and lasting immunity is usually conferred. Whether or not there are distinct antitoxic substances remains to be determined. Protective vaccination with killed typhoid bacilli has been practised. The results of the English and American armies are most encourag- ing. Both the morbidity and mortality have been reduced. Russel, of the United States Army, concludes that it is a harmless efficient protection against infection and carriers, seldom giving any dis- comfort, and resulting in an immunity that probably lasts over two years. Vaccination treatment has been tried during an attack, but with indifferent results. No efficient antiserum has been found. Agglutination; Gruber-Durham Phenomenon; Widal Reaction.— This reaction is due to the presence, in the serum of inoculated animals or in that of man, of a substance capable of causing massing together and loss of motility of the specific micro-organisms concerned in the infection from which the animal or man furnishing the serum is suffering. This phenomenon may be studied macroscopically or microscopically. DISEASES DUE TO BACTERIA 293 Macroscopically, we speak of a positive reaction when a distinct sedi- ment is seen in the glass containing the culture in a liquid medium, while the rest of the fluid remains clear, whereas before the phenomenon has taken place the whole fluid has had a diffuse cloudiness. Microscopically, we speak of a positive reaction when there occur a clumping and loss of motility of the bacteria, and, at the same time, the control remains free from all massing together. A certain amount of spontaneous clumping often occurs in the controls, but the organisms in the clump still exhibit motility, or there are actively motile individuals at the periphery or a little separated from it. Agglutination has been studied in reference to the bacilli of typhoid fever, plague, cholera, diphtheria, paratyphoid bacilli, the colon bacillus, proteus, and pyocyaneus. In order to obtain agglutination of the diphtheria bacillus it is necessary to immunize an animal highly with the bacteria themselves. The agglutination reaction is considered specific, except in the case of the colon group and proteus. With these two bacilli it is necessary to use the same strain of bacteria with which the animal has been immunized. Agglutination has also been studied with tubercle bacilli, but in this case it is necessary to destroy all the natural clumping of the bacilli by means of shaking with porcelain balls and then filtering. In studying agglutination with special reference to the Widal reaction, the best results are obtained when one always uses a definite quantity of the culture with a definite quantity of the serum. Cultures grown at temperatures of 25° to 35° C. (77°-95° F.) are better adapted to the reac- tion than those grown at 37° C. (98.6° F.). The more virulent the cul- ture, the less readily is agglutination obtained. In reference to typhoid bacilli, it is true that a twenty-four-hour culture is the best, since in older cultures pseudo-agglutination shows itself more readily. Widal and Foerster found no difference in the agglutinating properties of typhoid bacilli which had been formalized five months previously from the agglutination seen in fresh cultures. The time that it takes for agglu- tination to occur is dependent upon the activity of the serum and upon the temperature. At what day after the last injection in the immuni- zation of an animal the agglutination will appear, or at what day after the beginning of the disease in man agglutinin will first show itself, cannot be determined definitely. In men who are ill with typhoid fever the reaction has been demonstrated as early as the third day after the first appearance of the disease, but is often delayed much longer. Agglutinin remains in the blood for varying periods. In chil- dren recovering from typhoid fever the average time has been about two months after the convalescence; in adults the average length of time is half a year. In the differentiation between the typhoid and coli bacilli by agglutination a very active serum is necessary. By im- munizing an animal with typhoid bacilli we can obtain a serum which will agglutinate both the typhoid bacilli and the colon bacilli, but this occurs in different dilutions. With the typhoid bacilli the dilution may be as high as 1 : 40,000 or 1 : 100,000, while with the coli the highest effective dilution will probably be 1: 2000. The explanation of this is 294 A TEXT-BOOK OF PATHOLOGY that there are group agglutinins which have a certain effect on any one of a group of allied but not identical organisms, and possibly even the specific agglutinins have a certain limited effect (shown when the dilu- tion is not high) on other organisms than those for which they are specific. In the clinical use of the test the dilution of the serum should be not less than 1:50. An active serum will respond very quickly with dilu- tions of 1: 100 or more. Concerning the nature of agglutinin, we note that it probably has a relation with globulin. It can be precipitated by magnesium sulphate. It is destroyed by heating to 70° C. (158° F.). The reaction is regarded by some German authors as being analogous to the phe- nomenon of coagulation, since the presence of salts is necessary. This reaction was found in 2283 cases of typhoid fever reported by various writers, and was absent in 109 cases of typhoid fever. It was absent in 1365 non-typhoid cases, and present in 22 non-typhoid patients. It was, therefore, found in 95.5 per cent. of the typhoid cases, and was absent in 98.4 per cent. of the non-typhoid cases; or, taking the entire 3779 cases, the correct result for diagnosis was arrived at in 96.5 per cent. The reaction sometimes persists for some years after the attack of typhoid fever. Sometimes it occurs in cases in which there is typhoid infection without typhoid fever in the ordinary sense. These facts may explain some of the positive results obtained in non-typhoid cases. (See also Immunity.) Paracolon Infection; Paratyphoid Infection.—This is an acute infec- tion appearing sporadically and in epidemics resembling typhoid fever clinically, but in which the Widal reaction is persistently absent, and in which bacilli closely resembling the typhoid or colon bacilli, though differing in some essential particulars, are isolated from the blood and tissues. The intermediate organisms here referred to differ from the bacillus of typhoid by their ability to produce gas in glucose-containing media, and to produce an alkaline reaction in some media. They differ from the Bacillus coli communis by not coagulating milk, not fermenting lactose, and by failing to form indol. The group of intermediates has been divided into a paracolon and a paratyphoid group, according to the closer resemblance to the colon group on the one hand or the typhoid bacillus on the other. The paratyphoids have been divided by Schottmiiller into “A” and “B” groups, depending upon the acid reaction in milk. The “A” strains are biologically nearer the bacillus of Eberth, while the “B” organisms are nearer the paracolons. Infections with the “B” paratyphoid bacillus outnumber those with “A.’’ Members of the paracolon group are less closely related—as, for example, in the matter of interagglutina- tion—than those of the paratyphoid group. The paratyphoids give rise to a milder form of infection than typhoid fever, but the condition is transmissible in the same manner. The diagnosis is to be made by differential agglutinin tests when the bacillus cannot be isolated from the case. The paracolons are closely allied to the Bacillus psittacosis of DISEASES DUE TO BACTERIA 295 Nocard, the B. icteroides of Sanarelli, the bacillus of hog-cholera, the B. enteritidis of Gartner! (meat-poisoning bacillus), and the B. dysen- terre of Shiga. The B. fecalis alkaligenes of Petrushki is nearly related and sometimes causes typhoid-like infection, but it does not belong to the group. Pathological Anatomy.—H. G. Wells and L. O. Scott (1903) summarize the pathological findings in 5 cases of fatal paratyphoid infection, the cases of Strong, Longcope, Sion and Negel, Lucksch, and their own. The most constant change is splenic enlargement, which is in all re- spects the same as that of typhoid fever or septicemia. The endothelial cells are loaded with pigment evidently the result of hemolysis. Intestinal Lesions—In Longcope’s and Strong’s cases the intes- tines were quite unaffected; in the other three, ulcerations resembling those of dysentery rather than those of typhoid fever were discovered. Peyer’s patches and the solitary follicles were practically unaffected, as were also the mesenteric glands. In no case was there generalized glandular hyperplasia. In the cases of Longcope and Wells and Scott focal necroses in the liver, differing from those of typhoid in not containing endothelial cells, were found. The changes of proliferation and phagocytosis described by Mallory for typhoid fever were almost entirely absent in the intes- tinal lesions and very slight in the mesenteric glands, not being more conspicuous than that seen in simple enteritis. The anatomical picture was that of a septicemia with splenic enlarge- ment and occasionally non-specific ulceration in the intestines. The escape of Peyer’s patches suggests an essential if obscure biological dif- ference between the typhoid and paratyphoid organisms. Nature of Paratyphoid Infection—The tendency of most pathol- ogists at the present time is to regard paratyphoid infection as distinct in a bacteriological sense rather than in a clinical or general pathological sense, in the same way as pneumonias of varying bacteriology are dis- tinguished only etiologically. It cannot be denied that there are decided pathological differences, but the practical clinical identity and the near relationship of the bac- terial agents warrant the classification of paratyphoid infection as a subvariety of typhoid infection and the rejection of the term “para- typhoid fever’ as significant of a separate disease. BACILLUS COLI COMMUNIS Synonyms.—Bacterium coli commune. It is customary to speak of the “colon group,” since it has been recognized that several and per- haps many forms, varying in their ferment action only, have been classed under the name Bacillus colt communis. A number of organ- isms described under different names are probably identical. Among these are Bacillus neapolitanus of Emmerich, B. pyogenes fetidus of Passet. Several other organisms are either closely allied or identical. _ |} Gartner’s Bacillus enteritidis has characters somewhat aberrant from the type here discussed. (See p. 37.) 296 A TEXT-BOOK OF PATHOLOGY Morphology.—The Bacillus coli communis is an organism almost exactly like the typhoid bacillus in appearance. It is rod shaped, but sometimes elongated and filamentous; at other times (young forms) short and rather rounded—coccus-like. It is motile, and has flagella attached to the periphery of the bacillus. The flagella are shorter, more slender, and less numerous than those of Eberth’s bacillus (three to ten in number), and the motility of the organism is less uniform and active. It may be stained by ordinary solutions of anilin dyes, particu- larly with alkaline or carbolized solutions. It is decolorized by Gram’s staining method. The stained bacillus shows light-colored or unstained portions like those of the typhoid bacillus. True spores have not been detected. Cultivation.—The organism grows luxuriantly upon ordinary media. The most distinctive growth is obtained upon acid potato. An elevated brownish colony is produced, which is usually easily dis- tinguished from the typhoid culture in the same medium. When culti- vated in gelatin or agar containing glucose, active gas production results, In liquid media (bouillon) a peculiar odor is developed. Addition of nitrites and pure hydrochloric or sulphuric acid causes a rose-red color —indol reaction. Milk is readily coagulated, partly as a result of acid formation and partly by the elaboration of a coagulating ferment. Distribution and Pathogenicity.—The colon bacillus is a normal inhabitant of the gastro-intestinal tract. It seems to exercise a bene- ficial effect in restraining (by its own active growth and acid formation) the growth of putrefactive and possibly pathogenic organisms. In certain inflammatory diseases of the intestines, however, it seems to increase in numbers and doubtless also in virulence. The organism may be found outside the body in various situations, particularly in water. The Bacillus colt is capable of producing inflammatory conditions in different situations. Injected into the peritoneal cavity of animals it gives rise to acute fibrinopurulent peritonitis, and in other parts of the body has analogous effects. It has been found in various diseases of the gastro-intestinal tract, of the biliary passages, of the urinary system, and of other parts, and is doubtless the direct cause of some of these, as the conditions present are practically the same as those produced by experimental inoculation of pure cultures. The lesions in the liver may be necrotic, or interstitial or catarrhal in- flammation. Colon bacilli are said to precipitate bile-salts. Whether by this means or by inflammatory products, they probably have a part in the production of gall-stones. Among the gastro-intestinal troubles it has heen found in suspicious abundance in various forms of enteritis, in the distended and suppurat- ing appendix, and even in Asiatic cholera. It is known that the strangu- lation of a knuckle of intestine by a ligature leads to rapid increase of virulence of the contained bacilli. It is possible that in appendicitis and in other intestinal diseases similar conditions lead to increased infectivity, and thus cause an ordinarily harmless organism to become DISEASES DUE TO BACTERIA 297 virulent. In the cases of Asiatic cholera in which this organism has been found the specific germ of cholera has probably been overlooked or has disappeared during the rapid multiplication of the saprophytic Bacillus colt. Peritonitis may result from escape of the bacillus through a rup- tured intestine or directly through the wall of the bowel. The latter is particularly prone to occur in cases of strangulation of the intestines. Various inflammatory diseases of the urinary tract, such as cystitis, pyelitis, and pyelonephritis, are occasioned by this same germ, which first reaches the bladder through the urethra or by penetration of the wall of the bowel and then of the bladder, or, in other cases, infects the kidney primarily, having been carried there by the blood. Finally, there are cases of peritonitis secondary to enteritis, pleurisy, endocarditis, and other inflammatory diseases, apparently caused by this organism. Pathological Physiology.—Little is known of the toxic effects of coli infection. Some toxic substance is doubtless produced, which, according to Vaughan, is a highly thermostabile intracellular substance. A reac- tion similar to the Widal reaction obtained with the typhoid germ has been found to occur when cultures of the colon bacillus are subjected to the action of serum from an animal inoculated with this organism or from a person suffering with appendicitis or other diseases, either due to coli infection or accompanied by such. Occasionally the colon bacilli agglutinate and their motility is checked by typhoid serum. The ex- planation of this may be that in certain cases of typhoid fever the colon bacillus is also active in the intestines, and in consequence a mixed form of infection is present. In part it is also the result of the presence of group agglutinins that act on different but allied organisms. There is no antiserum for colon infections, but vaccination treat- ment has been used with success. THE DYSENTERY BACILLUS Certain types of dysentery in the tropics and of acute dysentery of temperate climates are accompanied by bacilli, first recognized by Shiga, and afterward studied by Flexner, Park, Kruse, and others. The organisms resemble those of the typhoid group, except that they are questionably motile bacilli with few, if any, flagella. In gelatin culture the colonies resemble those of typhoid bacilli. In bouillon a diffuse cloudiness without production of indol is observed. In glucose bouillon the bacillus does not produce gas or acid. The organisms, as observed by different observers, have differed in some particulars. The original form recognized by Shiga does not ferment mannite, maltose, or saccharose. Some of the later types have been found to ferment mannite and to produce indol, while still others actively ferment mannite and also maltose and saccharose. The bacillus produces a highly toxic poison, probably of both intra- and extracellular nature. It is resistant up to 70° C. (158° F.), and to 298 A TEXT-BOOK OF PATHOLOGY proteolytic ferments. Upon experimental animals the organism has a pre- dilection for the colon. An antiserum has been prepared containing both antitoxic and bactericidal properties. Agglutinins occur during infection. Bacilli almost identical with the true tropical dysentery bacillus have been found in the summer diarrheas of children. The cases may occur in epidemic or sporadic form. Agglutination tests are used to separate them in the same way that the paratyphoids, typhoids, and paracolons are separated. The pathological anatomy and physiology of dysentery will be con- sidered in the section on Diseases of the Intestines. INFLUENZA Definition.—Influenza is an infectious disease occurring in wide- spread epidemics and caused by a specific bacillus. Etiology.—The Mycobacterium influenze was discovered by Pfeiffer and Canon in 1892. The bacilli are extremely small and usually occur singly, though they are occasionally united by the ends, forming short chains. They may be stained with the ordinary anilin dyes, especially with carbol-fuchsin, but are decolorized by Gram’s method. The ends of the bacillus are somewhat, swollen and usually stain rather more deeply than the shaft. This gives the organism somewhat the appearance of a diplococcus or dumbbell-shaped bacillus. It is not motile. The first generation of the bacilli will grow only in the presence of hemoglobin’ and are, therefore, cultivated upon glycerin-agar the surface of which has been smeared with rabbit or human blood, forming minute dew-drop- like colonies, seen with difficulty with the naked eye, but clearly with the aid of a lens. The colonies do not coalesce. The appearance of the growth is somewhat like that of condensed moisture on the surface of the culture-medium. Later generations of bacilli may be cultivated on agar or in bouillon. The bacilli occur abundantly in the sputum of the disease, decreas- ing in quantity as the case advances. When purulent expectoration ceases the bacillus disappears entirely. Not rarely the organisms are readily recognized in the sputum by simple staining methods. A certain diagnosis is not possible in this way and even in cultures other organisms (see below) have a puzzling resemblance. In fatal cases it has been found in abundance in the tissues of the lung, particularly in cases in which complicating pneumonia has existed. Animal experi- mentation has thus far been unsatisfactory, though the organism has proved pathogenic for rabbits and monkeys. The symptoms are sug- | gestive of human influenza, but entirely conclusive results have never been obtained. The specific character of the organism is, therefore, inferred rather than demonstrated. Pathological Anatomy.—There are no specific lesions in this dis- ease. The organisms provoke intense catarrhal processes and, doubt- less at times, pneumonia. .In some cases the pneumonia of influenza is caused by mixed or secondary infection. Resistant influenzal infec- DISEASES DUE TO BACTERIA 299 tions of the bronchial tubes, with bronchiectasis, constitutes a clinical type of chronic influenza. Inflammatory lesions and hemorrhagic infiltrations in the membranes of the brain and just beneath the mem- branes have been observed. A true influenzal meningitis is met in children and can be produced in monkeys. There is an associated bacteremia. Antibody-containing serum can be obtained by injecting the bacilli into goats. This may prove of value in influenzal meningitis, as it has a power of stimulating phagocytosis in the spinal fluid. - Bacterins have been used in the treatment of catarrhal influenza. Agglutinins are formed during an attack. Pathological Physiology.—Very little is known regarding the mode of activity of the bacteria. The constitutional symptoms suggest toxemia, but the nature of the poison is obscure. The immunity from the disease must be exceedingly short, as recurring attacks and relapses may be frequent and succeed one another rapidly. It has been found that the influenza bacillus may remain in the bronchial tubes, especially in tuberculous cases, for months or years. From time to time renewed acute infection takes place. Certain complications and sequels, such as inflammations of the serous surfaces and neuritis, indicate generalized infection and intoxication. The organism does not seem to thrive or multiply in the blood. It has been found in otitis media and other con- ditions which suggest a metastatic deposit. In general, however, in- fluenza seems to be a local infection with general toxemia, but rarely general infection. Organisms Resembling the Influenza Bacillus—A very similar organism, called the pseudo-influenza bacillus, has been described. It is somewhat larger and tends to form long filaments. The Koch-Weeks bacillus of epidemic conjunctivitis differs in its manner of growth and in the fact that hemoglobin is not necessary in the media. It is non-pathogenic in animals. Another influenza-like organism found in conjunctivitis is the Morazx-Avenfeld bacillus (Bacillus lacunatus). This is, however, larger and grows only in the presence of blood or serum, liquefying the latter. These two organisms seem specific for the conjunctiva. BORDET-GENGOU BACILLUS OF WHOOPING-COUGH This organism is now accepted as constantly present in cases of per- tussis. According to the studies of Wright, it lies between the cilia of the bronchial epithelia, and so interferes with their movements that violent efforts to remove it cause the prolonged coughing attacks. By many authorities, notably the discoverers of the germ, it is looked upon as the cause of the disease, because they can use cultures of it as antigen and fix the complement from the hemolytic series. The organism is a minute ovoid, sporeless, non-motile, poorly staining, Gram-negative rod. It grows aérobically upon media containing glycerin, potato, blood, and agar. The effects are due to an endotoxin. Conditions similar to per- 300 A TEXT-BOOK OF PATHOLOGY tussis have been produced in monkeys and dogs by injection and in- sufflation of cultures. Agglutinins are said to be formed. Bacterins can be used. BUBONIC PLAGUE Definition.—The bubonic plague, or pest, is an infectious disease due to a peculiar bacillus, Bacterium pestis. Etiology.—The bacillus of bubonic plague was discovered by Yersin in 1894. In blood drawn from a puncture of the skin and in pus from the affected glands may be found small bacilli somewhat resem- bling the influenza bacillus. These organisms may be stained readily, and often more deeply at the poles than in the center (Fig. 108). This —— Fig. 108.—Plague or pest bacilli in smear from spleen. gives them an appearance resembling that of the diplococci, and in specimens from the blood or tissues there is an indistinct capsule. The organism is rather oval in shape, but club-shaped forms are frequent, and in cultures long chains are met with. It is not motile; Gram-nega- tive; it may live in gelatin between 5° and 20° C. (17° and 68° F.) without liquefying the medium. It thrives best in the presence of a high degree of moisture. Pure cultures have been obtained upon various media. Upon glycerin-agar moist, rounded, whitish, or bluish- white colonies are formed. Portions of such colonies removed for examination show the bacilli ranged in chains. The growth in bouillon is very characteristic, as stalactite formations hanging from the surface of the fluid. Pathogenicity.—The bacillus has been found pathogenic for mice, DISEASES DUE TO BACTERIA 301 rats, guinea-pigs, rabbits, and, indeed, any domestic animal; and the symptoms produced by pure cultures are the same as those induced by inoculating animals with blood or portions of tissue from diseased persons. The lymphatic glands may be swollen and petechial hemor- rhage may occur as in the human disease. Distribution—In the human being suffering from bubonic plague the bacilli are found in the local lesions of the lymphatic glands, the buboes; and also in the blood and various organs. Yersin showed that flies die of the disease, and succeeded in obtaining the bacillus from their dead bodies. They do not flourish in water, but thrive in milk, butter, and cheese, and these food-stuffs may spread the contagion. The pneumonic form is usually caused by inhalation of dust that has not dried sufficiently long to destroy the bacteria, but is not necessarily due to inhalation of the germs in all cases. It has been shown that the breath during quiet respiration of plague pneumonia patients does not contain germs, but they are expelled by coughing. The rat and its fleas are the means of propagation of plague. It has been said that plague is primarily a disease of rats, and that man is only an accidental host. Transmission from animal to animal and animal to man takes place by the rat flea, which will bite man. Bacilli, existing in the saliva and digestive tract, may easily be deposited upon the surface of an animal or man and rubbed into any small wound of the skin, such, for instance, as may be made by the flea-bite. Bacilli may also be deposited by fleas or rats upon food or household utensils. Not only rats but most rodents are susceptible to plague. Ground squirrels of California have been found extensively affected, and the marmot of Tibet is a constant source of infection in that country. It is said that mild, unrecognized cases may act as “‘carriers.” Pathological Anatomy.—There are three forms of plague according to the chief clinical and anatomical manifestations: the bubonic, pneu- monic, and septicemic. The organism produces swelling and suppuration of lymphatic glands, particularly those of the groin, and, secondarily, lesions of internal organs. The lymphatic glands swell quickly, become tender and congested, and then soften, forming a rather thick pus. This is sometimes blood tinged. Histologically, the exudate is chiefly large mononuclears, actively phagocytic of the very numerous pest bacilli. This form of exudate soon gives way to necrosis and spread of bacilli outward. Petechial hemorrhages and blood-stained effusions into the serous cavities may occur. Petechie of the skin are apt to develop as a result of slight traumatisms. Thus, the bite of an insect, instead of producing its usual results, may cause distinct ecchymoses in persons suffering from the disease. The pulmonary form produces a bloody edematous form of pneumonia; fibrin appears relatively late. This may be quite independent of glandular enlargements externally. A “septicemic form” is characterized by general infection with wide- spread involvement of the lymphatic glands, but without distinct buboes. Areas of necrosis take the place of pest abscesses. 302 A TEXT-BOOK OF PATHOLOGY Pathological Physiology.—It seems that the distribution of the bacillus in the blood, as well as toxic substances, chiefly endotoxic, contribute to the general disturbance of health. By successive inocu- lation immunity has been produced, and antitoxic sera have thus been obtained. The serum has been used in man with considerable success as a protective and also a curative agent. It often fails in advanced cases. Haffkine used his method of inoculation as in cholera and obtained encouraging results. SOFT CHANCRE Definition.—The soft chancre or chancroid is an infectious venereal sore appearing upon the external genitalia. The bacillus of Ducrey is said to be the specific organism. Etiology.—The soft chancre occurs almost exclusively upon the genital organs or the surrounding parts. It is always caused by direct contagion. The bacillus of Ducrey and Unna is a rod-shaped organism about 1.8 uw in length and 0.5 mw in thickness, and appears somewhat com- pressed in the middle, so that it has a figure-of-8 shape. The ends are rounded and the organisms often occur in chains, or later in the disease in pairs, as a diplobacillus. The demonstration of the bacillus in the pus is comparatively easy. The specimen is stained with alkaline solutions of methylene- blue and quickly decolorized with weak acetic acid solution. It may be well stained with carbol-fuchsin, alcohol being used to decolorize. It is Gram-negative. In the tissues the demonstration is more difficult. Growth is most luxuriant in a medium of fresh blood and bouillon, but unmixed human blood is the best medium for obtaining cultures from a source open to contamination, the fresh blood apparently in- hibiting to a certain extent the growth of extraneous organisms. The best solid medium consists of 2 parts of alkaline agar and 1 part of fresh rabbit’s blood if seeded with material obtained by aspiration of a ‘bubo. Cultures on ordinary media have thus far been unsuccessful. The bacillus is found in the pus of the soft chancre, as well as in the deeper parts, lying between the cells and frequently within the leuko- cytes. It has also been discovered in the pus and walls of ulcerating buboes, but is generally absent in the pus of unopened buboes. Mixed Infectton— Various other organisms have been found asso- ciated with the bacillus, including streptococci, staphylococci, the gonococcus, and bacilli of uncertain nature. Pathological Anatomy.—The soft chancre is an ulcer of variable character. Usually it is a simple ulcer, with suppurating base and edges, not differing from ulcers due to other causes. Sometimes the ulcera- tion seems more malignant and takes on a phagedenic or serpiginous character (see Ulceration). The neighboring lymphatic glands are usually enlarged and sometimes undergo suppurative softening (bubo). DISEASES DUE TO BACTERIA 303 Pathological Physiology.—Little is known of the existence of special toxic bodies in this disease. It is believed, however, by some that toxins are produced by the bacilli, and that these are capable of pro- ducing secondary lesions (bubo) without the presence of the bacilli themselves. ; MALTA FEVER Synonyms.—Mediterranean Fever; Gibraltar Fever; Febris Undu- lans. Definition.—This disease has been described as a form of irregular fever occurring along the Mediterranean coasts. It was formerly regarded as an aberrant form of typhoid fever, but is certainly inde- pendent. Etiology.—The micro-organism discovered by Bruce, and designated Micrococcus melitensis, is by many regarded as the specific cause. This is an oval micrococcus about } { in diameter, occurring singly or in pairs, and in cultures as short chains. By Babes it is regarded as-a bacillus, and certainly agglutinates with more readiness than cocci are wont todo. It has no motility of its own. It may be stained with ordinary solutions of anilin dyes, but not by Gram’s method. It occurs abundantly in the spleen, and is occasionally found in the blood by blood-cultures. Pure cultures have been obtained, and inoculation in monkeys has seemed to give positive results. Malta fever is not con- tagious. The micro-organisms seem to enter the body through the respiratory or the intestinal tract. Agglutination occurs readily with patients’ serum, and may be used in diagnosis. The organism is excreted in urine and milk. The goat, which is used largely for milk supply in Malta, may carry the germs and excrete them without being actively infected with the disease. Pathological Anatomy.—The mucous membrane of the small in- testine is red and the solitary follicles and Pever’s patches are some- times swollen. The mucosa of the large intestine is generally dark red and presents small round or larger irregular ulcerations, from which intestinal hemorrhages occur. In some cases lesions of the ileum resembling those of typhoid fever have been described; but it is doubtful if the cases in which these occurred were Malta fever. The spleen is enlarged and hyperemic. Pathological Physiology.— Malta fever is characterized by irregular febrile movements. The cause of this irregularity and the nature of the toxic substance generated in the disease are unknown. RHINOSCLEROMA This is a disease affecting the skin about the anterior nares and adjacent parts, and probably caused by a specific bacillus. The dis- ease has been especially observed in central Europe. It presents itself in the form of nodular thickening of the skin of the nose and lip, and sometimes spreads to the neighboring mucous membranes—mouth, B04 A TEXT-BOOK OF PATHOLOGY pharynx, or larynx. In the latter situations ulceration of the surface is frequent; the lesions of the skin rarely ulcerate. Histologically, the growth consists of round granulation tissue cells. Frequently the cells suffer hyaline degeneration, forming rounded hyaline bodies, with small granular nuclear masses. These are called Mikulicz cells. The bacilli may be found between the cells and within them, especially such as present hyaline degeneration. The micro-organism resembles the ba- cillus of Friedlander, but by some is said to be Gram-positive. This is denied by others. When cultivated upon blood-serum or agar it retains its capsule. Inoculation experiments have thus far failed to produce the disease in animals. The etiological relationship of the so-called Bac- terium rhinoscleromatis is doubted by many observers. It is very close to Friedliinder’s pneumobacillus, but does not form gas in sugar media. GLANDERS Definition.—Glanders is an infectious and contagious disease of horses and asses, sometimes communicated to other animals and to man, and caused by a specific bacillus. Etiology.—The Mycobacterium maller was first isolated by Loffler and Schiitz. It is an organism resembling the tubercle bacillus, though somewhat shorter and thicker. In cultures it may grow to long fila- ments and not rarely it breaks up into coccus-like fragments. It occurs in the lesions of the disease singly or in clumps, and has been found in the blood. The bacillus is non-motile and does not possess flagella. Stained specimens show parts that do not receive the stain. These have been regarded as spores, but are more generally thought to be areas of degeneration. Ordinary solutions of anilin dyes, and especially alkaline solutions, stain the organism very well. The demonstration of the bacillus in the tissues requires prolonged staining and rapid decoloriza- tion. It is Gram-negative. Cultivation —Cultures are best obtained from softened nodules of guinea-pigs inoculated with infected pus, or from the testicles after injection of infective matter into the peritoneal cavity. The organism grows quite readily upon ordinary media, but the most characteristic culture is seen upon boiled potato. The colony first appears as a honey- like layer, which becomes brownish in color. The potato itself becomes greenish brown beneath and around the colony. The cultivation is most successful between 30° and 40° C. (86° and 104° F.). Drying and elevated temperatures rapidly destroy the organism, and germicides kill it quite readily. The bacillus is a pure parasite, multiplying only in the body of infected animals or man. Pathogenicity—The specific character of the bacillus is unques- tionable. Inoculation of guinea-pigs, rabbits, field-mice, or other ani- mals with infected pus or with pure cultures leads to nodular lesions at the point of introduction, with subsequent softening and ulceration. Secondarily, the lymphatic glands enlarge and after from two to four weeks suppurate. In male guinea-pigs a practically pathognomonic DISEASES DUE TO BACTERIA 305 condition (great enlargement of the testicles) is observed within two or three days after intraperitoneal inoculation with pure cultures or exudate from the lesions of the disease. After death nodules are found in the liver, spleen, kidneys, or other organs, and these contain the bacilli. In horses and asses characteristic lesions of the mucous mem- branes have been produced experimentally; while in man accidental infection of hostlers or others coming in contact with diseased animals, and of bacteriologists working with cultures, have been repeatedly observed. In one case in our own knowledge a man was infected in a stable in which a glandered horse was kept, and the bacteriologist who isolated the organisms from the patient accidentally infected himself with the cultures. The spontaneous infection occurs through some abrasion or wound. There are two fairly distinct forms of glanders, the acute and chronic. The former is septicemic with abscesses, both widely scattered in the organs and in the lymphatics of the skin (farcy buds). The term farcy is given to the form with subcutaneous abscesses, usually an acute condition in man, but commonly more chronic in horses. The chronic form is slow of progression, chiefly attacking the lymphatic organs, and showing slowly progressive lesions either local or general. Pathological Anatomy.—In horses glanders presents characteristic lesions of the mucosa of the nose. At first there are found slightly ele- vated nodules, which have a marked tendency to soften, forming irreg- ular ulcerations that become confluent. The floor and-edges of the ulcers are yellowish and necrotic in appearance, and discharge more or less purulent matter. The lymphatic glands of the neck and elsewhere enlarge and may suppurate. In the skin the lesions are much the same, but more sluggish. Nodules are not rarely met with in the lungs. These are grayish or pinkish in color, and tend to rapid necrosis. More rarely nodules or ulcers are found in the mucosa of the gastro-intestinal tract. In man similar nodules and ulcerations may be found in the nose, larynx, or trachea; and external lesions resembling small or large car- buncles are found. Histologically, the lesions of glanders consist of aggregations of round cells of lymphoid or polymorphonuclear type surrounded by a zone of spindle and epithelioid cells. Some of the latter swell, and their nucleus divides by direct division, causing a kind of giant cell. There is a marked tendency to suppurative or necrotic softening, and some- times hemorrhagic infiltration may be pronounced. Pathological Physiology.—A toxic substance called mallein (a bac- terial protein) has been obtained from cultures of the bacilli. Injected into infected animals this acts somewhat as does tuberculin in tubercu- losis. A special toxin is probably active in the production of the general symptoms of the disease. By repeated dosage with mallein it is claimed that immunity may be conferred. The poison of Mycobacteriwm maller is endotoxic. Agglutinins are produced during an attack, and a com- plement-fixing body can be discovered in most cases. 20 306 A TEXT-BOOK OF PATHOLOGY TETANUS Definition.—Tetanus is an acute infectious disease due to a specific bacillus, the Bacillus tetani, discovered by Nicolaier and isolated by Kitasato. Etiology.—The bacilli occur in the form of cylindrical rods, which are frequently swollen at one end, due to the presence of a rounded spore (Fig. 109). They are slightly motile in the vegetative state, being supplied with peritrichous flagella; in the spore stage they are non- motile. They usually occur singly, though occasionally a few may be seen end to end. They occur in the local lesions from which traumatic tetanus takes its origin, and may sometimes be readily demonstrated by spreading some of the pus or exudate upon a cover-glass and staining with the ordinary anilin stains. They also stain by Gram’s method. The bacillus does not diffuse itself through the body, but in a few cases as —— Fig. 109.—Bacillus tetani; x 1000 (Frankel and Pfeiffer). it has been found in the central nervous system. The organism is read- ily destroyed by heat, but its spores are quite resistant. Cultivation of the tetanus bacillus is difficult. It is obtained from garden-earth or the pus of infected wounds by submitting the material to sufficient heat to destroy other organisms, even the bacillus of tetanus itself, leaving the spores uninjured. With this material animals are inoculated, and from the products of the local lesions or directly from the original material cultures are made in gelatin. The organism is strictly anaérobic. The typical culture is obtained in the depth of gelatin. Deep beneath the surface there are formed along the line of puncture pointed processes standing out at right angles from the puncture. After a week liquefaction of the gelatin occurs, and an accumulation containing grayish-white turbid liquid is formed. When the growth is formed on the surface of gelatin in an atmosphere of hydrogen a similar radiating structure is found in the colonies, the cen- DISEASES DUE TO BACTERIA 307 ters of which are rather dense. Liquefaction of the gelatin subsequently takes place. Considerable gas with a pungent odor is produced in the growth of this bacillus. Distribution—The tetanus bacillus is found very frequently in garden-earth, in the intestinal discharges of animals, and upon various articles about stables. Infection occurs in human beings or animals through punctures made by nails, splinters, and the like. Pathogenicity.—The bacillus placed upon an open wound may not give rise to the disease, from the fact that the presence of oxygen pre- vents its growth. Subcutaneous inoculation, however, causes rapid _ destruction of animals with typical symptoms. The period of incuba- tion may be only a few hours, or one or two days, or it may be several weeks. The association of certain other organisms, such as the pus- producing organisms, seems to favor the development of the disease by preventing phagocytic action of leukocytes, or by consuming oxygen and thus allowing the tetanus bacillus to flourish. The toxin is manufactured in loco and taken up by the nervous tissue, for which it has a predilection. Pathological Anatomy.—No characteristic lesions are found in this disease. Locally, a wound or injury through which inoculation has taken place may be discovered; but this is only exceptionally extensive. Sometimes no local injury can be discovered, and it is supposed that in- fection at times occurs through the gastro-intestinal tract or through other mucous membranes. Intense congestion of parts of the nervous system and granular degeneration of the anterior spinal motor cells may be found at the autopsy, but these are not characteristic. Pathological Physiology.—Two distinct toxins have been recog- nized—tetanospasmin, which is the predominant poison and that which causes the spasms, and tetanolysin, a hemolytic substance of uncertain importance. The toxin of tetanus is almost inconceivably poisonous, a fact which accounts for the development of a fatal disease in cases in which the number of bacilli is minimal. The spasmodic seizures first affect the muscles near the point of inoculation and in mild infections may be confined to these muscles. This has been explained by the experiments of Meyer and Ransom and others, who showed that the toxin reaches the nerve-cells of the spinal cord by traveling from the muscular end-plates of the motor nerves through the axis-cylinders to the cord. The toxin injected into the blood does not pass directly to the nerve-centers, but always travels up the motor nerves as described. The parts first affected by spasm are, therefore, those about the point of inoculation and of elaboration of the toxin. Tetanus antitoxin has been obtained by successive inoculations of animals with the toxin, and in laboratory experiments has been found specific and exact in its antagonism to the toxin. In treating the dis- ease in man or animals the results have been disappointing, but this is now known to be due to the manner in which the toxin and antitoxin are respectively distributed and absorbed, and to the fact that the toxin 308 A TEXT-BOOK OF PATHOLOGY has usually reached the vulnerable nerve-centers, and been tightly anchored in them, at the time when the antitoxin is injected. The antitoxin must be first absorbed by the lymphatics and carried to the blood, with which it is distributed to the fluids of the body, whence it is again absorbed by the nerves. It is not taken up directly from the blood by either the central or peripheral nervous tissue. For these reasons the subcutaneous injection of antitoxin fails to effect the neu- tralization of much of the toxin, since the latter is quickly absorbed by the peripheral nerves. Intravenous, intraneural, and subdural (spinal) injections are more rapid in their effects and, therefore, preferred. To prevent combination of toxin and nervous tissue antitoxin must be introduced before symptoms arise. It is, therefore, more useful as a pre- ventive than as a curative. ANTHRAX Definition.—Anthrax is a specific infection due to a characteristic bacillus. It occurs most frequently in cows and sheep; it may affect other animals and man. Dogs, cats, birds, and cold-blooded animals are quite immune. In animals it is called splenic fever; in man, malig- nant pustule and wool-sorters’ disease. Fig. 110.—Bacterium anthracis, stained to show the spores (Frankel and Pfeiffer). Etiology.—The Bacterium anthracis was first observed by Pollender in 1849, and shown to be the specific cause of anthrax by Davaine in 1863. In 1879 Koch, Pasteur, and others succeeded in making pure cultures and in demonstrating their pathogenicity. It was, therefore, the first pathogenic organism definitely isolated. The anthrax bacillus is a non-motile rod-shaped organism that has a decided tendency to form long chains. The individual bacillus is from 5 to 20 u in length and from 1 to 1.25 «in thickness. The chains appear as threads often with a little thickening at the ends of the individual bacilli showing the points of contact. The ends are squared or slightly concave. In artificial cul- DISEASES DUE TO BACTERIA 309 tures in the presence of oxygen spores are formed within the bacilli. These are elliptical or oval in shape, and do not alter the configuration of the bacillus (Fig. 110). The organism is easily stained with the simple anilin dyes, and may be demonstrated in the blood or the tissues by Gram’s or Weigert’s stains. There are no flagella. Cultivation —The anthrax bacillus may be obtained in pure culture from the diseased organs upon various media. The culture in gelatin is most characteristic. Upon plates there are formed whitish colonies, which under low powers of the microscope show a tufted, irregular character at the edges and upon the surface, suggesting bunches of twisted wool-fibers. The gelatin is slightly liquefied. The tufts may be removed by pressing a cover-glass against the surface of the colony, and when stained are found to consist of curved parallel chains of bacilli. In puncture-cultures filaments project at right angles to the puncture toward the sides of the test-tube, and the growth at the surface, where oxygen is abundant, is luxuriant, while that in the depth is compara- tively sparse. Pathogenicity.—The infectiveness of the bacillus is undoubted. A small portion introduced into a susceptible animal gives rise to marked symptoms in twelve or twenty-four hours, and death soon follows. The bacilli may be demonstrated in the blood and in various organs in great abundance. When the bacillus is killed and the spores are introduced into the body similar results follow. The spores are highly . resistant and may preserve their virulence for years. Sporeless varie- ties of anthrax bacilli have been encountered and have been produced by cultivation under unfavorable conditions. Distribution.—The anthrax bacillus occurs in all of the local lesions, and from these is carried into the blood and the organs, particularly the spleen, liver, kidneys, and lungs, where it is found in the capillaries in immense numbers. The structure of these organs is, as a rule, little affected, probably because death occurs before changes can take piace. The organisms may be present in only small numbers in the blood of the general circulation when the capillaries of the various organs are filled with them. The organisms are discharged from the body in the stools, urine, and other discharges, and are thus conveyed to other animals. At one time it was supposed that they were scattered about by earth- worms obtaining them from cadavers; this is scarcely probable. Mul- tiplication of the organisms outside the body does not occur to any extent, but the organisms, and particularly the spores, may live a long time, and may be conveyed to great distances in infected materials, particularly wool, hides, bristles, and the like. Mode of Infection—In animals infection most frequently occurs through the gastro-intestinal tract, the bacilli being swallowed with fodder that has been contaminated. The organisms may, however, gain entrance through the lungs or through external abrasions. The latter form of infection is most common in man, though gastro-intestinal and pulmonary infection sometimes occur. 310 A TEXT-BOOK OF PATHOLOGY Pathological Anatomy.—The lesions produced by anthrax are more or less local, but occasionally are septicemic. In man, after infection of the skin through abrasions in persons handling the hides or wool or other materials from diseased animals, a swelling of greater or less size develops. This is intensely inflammatory, often covered and surrounded by slight bullous vesicles, and attended with considerable edema. Ero- sion of the surface may take place and sanious liquid may be discharged, with the formation of crusts. Histologically, the process consists of rapid infiltration of the corium and papillary bodies with leukocytes. The bacilli are found in abundance between the cells, and hemorrhagic infiltration and serosanguinolent edema are observed. Necrosis sub- sequently occurs, though not to a considerable extent. When infection takes place through the gastro-intestinal tract, as is sometimes ob- served in man and very commonly in animals, lesions somewhat like the above are formed in the mucosa and submucosa of the small intestine, less frequently of other parts. At first these lesions appear as hemor- rhagic extravasations, then swelling follows, and finally the surface ulcerates, leaving irregular excavations with blood-stained bases and edges. Profuse diarrhea with bloody discharges may occur. Infection through the lungs occurs in men engaged in handling infected wool (wool-sorters’ disease), and in persons working in paper factories, where infected rags carry the germs. In these instances the bacilli lodge in the alveoli of the lungs, causing rapid cellular exudation with considerable edema and hemorrhagic infiltration. The process is lobular in charac- ter, but large areas of the lungs may be simultaneously involved. Sero- sanguinolent pleurisy, swelling of the lymphatic glands of the medias- tinum, and hemorrhagic extravasations of the mediastinum are not unusual. In all forms there is acute inflammatory or hemorrhagic swelling of the spleen. Pathological Physiology.—The presence of the anthrax bacillus probably leads to the formation of toxic materials in the blood, although while a poisonous albumose has been obtained from cultures, its nature is not understood and its identity doubted by some. The general symptoms, however, are probably in large measure the result of dis- semination of the bacilli themselves and their local effects. = Their action seems to be directed primarily against the circulatory system, as the toxin calls forth leakage of serum and escape of blood. Much fibrin is formed, but there is little tendency to cellular accumula- tion or suppuration. It has been found possible by cultivation at high temperatures, by introducing the organisms into insusceptible animals, and also by adding chemical agents to cultures to alter the pathogenicity of the bacillus to such an extent as to make it harmless, even to white mice. By introduction of such cultures and subsequent successive inoculation with cultures of increasing virulence protection has been afforded. Antitoxic substances have been obtained from the blood of protected animals, but the method of successive vaccinations rather than the use of antitoxic serum is at present relied upon to combat the disease. DISEASES DUE TO BACTERIA 311 MALIGNANT EDEMA Definition.—Malignant edema is a form of intense infective in- flammation and necrosis observed in certain animals and in man, and is due to a specific micro-organism. The condition has frequently been described by clinicians as gaseous gangrene, traumatic gangrene, gangrene foudroyante, etc. Infectious emphysema (g. v.) has doubt- - less often been mistaken for this disease. Etiology.—The micro-organism of malignant edema was described by Pasteur and: named the Vibrion sep- tique. Koch showed that it does not flourish in the blood, and that the name given by Pasteur is, there- fore, not appropriate. He, therefore, named it Bacillus edematis malignt. This organism:is widely distributed. It is very commonly present in the soil, particularly in garden-earth, and is often found in dust and in the intestinal contents of animals. Introduced into the subcutaneous tissue of animals it multiplies greatly and sets up a violent local process. The bacilli are readily obtained from the diseased area, and may be stained with the ordinary anilin dyes, but not by Gram’s method. The bacillus resembles the anthrax bacillus very closely, but is somewhat more slender. It is prone to occur in pairs or in chains or long filaments, the several bacilli being joined end to end. Movement of the organisms is frequently observed, and lateral flagella are found by appropriate stains. In the spore forma- tion the center of the organism swells and the spore is developed within. The cultivation of this organism is generally easy. : White mice or other susceptible animals are first | Fig. 111.—Ba- infected by introducing powdered garden-earth into US of malig: t < nant edema grow- a subcutaneous sac. Direct infection of an open ing in glucose- wound will not succeed, as the organism is strictly an- oa aérobic. ' From the pus in the subcutaneous tissues growths may be obtained upon the surface of gelatin in an atmosphere of hydrogen, or in puncture- cultures in gelatin from which oxygen has been excluded. On the surface of the gelatin are formed small grayish-white bodies, which in- crease in size with advancing age. Portions removed from these and stained show masses of bacilli in the form of long filaments. In the gelatin-tube there are formed whitish spherical colonies of a somewhat cloudy appearance. These consist of a turbid liquid, the gelatin under- going liquefaction. There is also some gas production, the gas formed having a peculiar and unpleasant odor. This is marked when the medium contains glucose (Fig. 111). Distribution.—The bacillus of malignant edema occurs only in the subcutaneous tissues near the point of inoculation, in the muscles, and 312 A TEXT-BOOK OF PATHOLOGY in the peritoneal cavity at the time of death. It does not invade the blood, as the amount of oxygen there present prevents its growth, and it flourishes in the subcutaneous tissue because this is least accessible to oxygen. In bodies dead some time the organism may spread to the blood and the organs of the body. The distribution of the organisms outside the body has been referred to. Pathogenicity—The bacillus of malignant edema is undoubtedly the cause of the disease in question, as has been proved by inocula- tions upon mice, guinea-pigs, and other animals. Cats and dogs are less susceptible than other animals; cattle seem to be almost wholly immune. Pathological Anatomy. —The lesions of malignant edema consist of various forms of rapid suppuration and necrotic inflammation of the subcutaneous tissues. These may rapidly form emphysematous and gangrenous alterations of the subcutaneous tissues, with sometimes pus formation, at other times extensive hemorrhagic infiltration. Pathological Physiology.—Toxins are doubtless formed, but these have not as yet received special attention. Artificial immunity has been secured by injections of sterilized cultures of the bacillus in bouillon, and by other methods. A few cases of malignant edema have been re- ported in man, some following injection of musk in the course of typhoid fever, some occurring in the puerperium, and some apparently without external injury. Infection in the latter probably occurred from the mucous surfaces. In all cases the general vitality of the patient was reduced by some previous disease. INFECTIOUS EMPHYSEMA Definition.—This term is provisionally applied to a form of infec- tion that has been described under various names, such as gaseous gangrene, gas phlegmon, emphysematous necrosis, and the like. Un- doubtedly it has been mistaken for malignant edema in certain cases. The disease is caused by the Bacillus aérogenes capsulatus of Welch and Nuttall. Etiology.—The bacillus in question is a non-motile organism of variable size, 3 to 6 “ in length, and about the thickness of an anthrax bacillus, with adjacent ends slightly rounded or square cut, and occur- ring singly, in pairs, clumps, or sometimes in short chains. Very rarely it occurs in long threads. It is easily stained with the ordinary anilin dyes or Gram’s stain. A capsule is sometimes demonstrable in specimens obtained from the body or from agar-cultures. The bacillus does not form spores. It is probably identical with the Bacillus phlegmones emphysematose of Frankel. Cultivation.—The organism is anaérobic, no growth occurring on the surface of solid media in the presence of oxygen. In media contain- ing fermentable material gas formation is regularly observed. The colonies in agar are grayish-white or slightly brownish; those in the depth appearing as small spheres or ovals slightly flattened, with knob- DISEASES DUE TO BACTERIA 313 like or feathery projections. The cultures in gelatin show slight and slowly developing liquefaction. Pathogenicity.—By experiments on animals exactly the same lesions are produced as those found in man. Pathological Anatomy.—The lesions of this infection are wide- spread. At the point of inoculation there may be found edematous in- filtration, with blood-stained fluid, and emphysema due to gas formation. Rapid necrosis or gangrenous softening of the tissue may occur. The entire surface of the body sometimes becomes emphysematous, and at the autopsy the organs, especially the myocardium, kidneys, liver, and spleen, present a characteristic appearance. They are lighter in color, and on inspection are found to be filled with minute vacuoles or gas-bubbles. The blood of the heart and vessels presents a foamy condition, due to the gas formation. Practically, any of the tissues of the body may be affected. Microscopically, the occurrence of gas- vesicles with numerous bacilli in their walls is the most striking feature. Regarding the mode of infection, it seems likely that in all cases the organisms enter through some injury or abrasion connected with the external world. Some cases have followed traumatic injuries, others occur in connection with disease marked by ulcerations of the surface of mucous membranes, and at least one instance has been carefully studied in which the disease occurred during the puerperium, probably _ due to uterine infection. It is not improbable that some of the cases of supposed air-embolism from douching of the uterus after labor are, in reality, cases of this form of infection. Other bacteria, notably Bacterium mucosus capsulatus, B. coli, and B. perfringens, have been found in gaseous edema, or as gas producers in inflammatory exudates. TUBERCULOSIS Definition.—The term “tuberculosis” refers to various condi- tions due to infection with the tubercle bacillus, Mycobactervwm tubercu- losis, no matter what the form or individual peculiarities of the case. The name was originally employed because of the occurrence of small nodules or “‘tubercles.”’ It must be remembered, however, that other diseases show small miliary nodules, perhaps indistinguishable to the naked eve from miliary tubercles, and that tuberculosis sometimes occurs without a single definite tubercle.! Etiology.—Tuberculosis is infectious and contagious, the bacilli being transferred by the secretions and excretions from diseased per- sons to a susceptible individual through the air, food, drink, or in other ways. The infectious character of the disease was long suspected, but was definitely proved by Villemin in 1865, and in 1882 loch suc- ceeded in isolating the infective bacillus. Predisposing causes are of some importance. Formerly family susceptibility was thought an all- 1In this book the adjective ‘“‘tuberculous” applies to the specific disease caused by the bacillus of Koch, other conditions being called ‘‘tubercular.”’ 314 A TEXT-BOOK OF PATHOLOGY important cause, and the disease was supposed to be transmitted directly in families. At the present time we recognize the transmission of susceptibility, and very rarely transmission of the disease itself, from parent to child. Warthin has found many cases in literature and his own observation where direct transplacental passage of tubercle bacilli has occurred, both with or without lesions in the placenta. Tubercle bacilli have been found in the semen. (See Placenta.) Susceptible persons frequently show delicate organization with poor development of the body, particularly of the chest. When this susceptibility or pre- disposition exists, there is naturally greater receptivity for bacilli spread around by tuberculous associates. Besides inherited suscepti- bility, acquired _ predisposition “> , may result from occupations which lower vitality, from grief, ae ed : prolonged nervous strain, and ex- as ‘ haustion; and some one of the es organs may be specially predis- posed by injuries, as in cases of tuberculosis occurring in the lungs ee as of those inhaling sharp particles of metal, coal, and the like. Such mechanical lesions prepare a place of lesser resistance, and tubercle ; a bacilli more easily gain a footing — reiKif 112-— Tubercle acili ip the sputum: than in normal tissues. Come fied about 1000 diam. tinued local anemia seems to predispose. The human tubercle bacillus is a rod-shaped organism, 1.5 to 3.5 u in length and from 0.2 to 0.5 «in breadth. Sometimes it is even longer, especially after cultivation. It often occurs in pairs or in groups arranged end to end, but not overlapping, and evidently not attached the one to the other. It also occurs either straight or more or less curved, and may often be found S-shaped or in branching forms. When stained, it may either appear uniformly colored or may present a beaded appear- ance, regarded by some as due to spores, a view that has not been proved. The condition is caused by the alternation of portions well stained and intervening parts with little or no stain (Fig. 112). These light areas, formerly regarded as spores (Koch), are now believed to be the result of fragmentation of the bacillus and retraction of the sub- stance of the organism causing vacant areas. In other words, the light areas are due to degeneration. They are certainly not spores. There appears to be a narrow capsule closely applied to the organism, and the capsule seems to contain in especial abundance the wax-like substance that occasions the peculiar acid-fast staining properties of the bacillus. The bacillus is non-motile and does not have flagella. It is, therefore, transported by outside agencies entirely. The tubercle bacilli found in man, cattle, and fowl exhibit struc- tural and cultural differences, though they are probably the same Y ( DISEASES DUE TO BACTERIA 315 bacilli exhibiting different characteristics caused by their growth in different environments. The bovine bacillus is much shorter and thicker than the human bacillus, being from 1.5 to 2 u in length and of an oval shape, the length being not more than double the breadth. It is straight, and does not exhibit the curved and branching forms of the human bacilli. When stained, it is more uniformly colored, the beading being usually absent. Cultures of the bovine organism in glycerin broth are at first acid, but become alkaline, while those of the human species never become alkaline. Tuberculin made from the bovine species is alkaline; that from the human species is highly acid. The human type is more easily grown. The bovine type will infect rabbits uniformly, while great quantities of human culture are necessary. Human bacilli will not infect calves with progressive lesions. Fig. 113.—Culture of tubercle ~ Fig. 114.—Bacillus tuberculosis; adhesive cover- bacilli on glycerin-agar, four weeks glass preparation from a fourteen-day-old blood- old (Frankel and Pfeiffer). serum culture; x 100 (Frankel and Pfeiffer). _ The avian tubercle bacillus differs from the human bacillus in that it is more often club shaped and branching, and that it grows more luxuriantly upon glycerin-agar and blood-serum, and at a much higher temperature—45° C. (113° F.). It will also grow on ordinary agar, but not on potato. It is much more resistant to heat, especially as re- inte its virulence. It will not infect guinea-pigs with a progressive esion. Artificial culture of the Mycobacterium tuberculosis was first success- fully accomplished by the use of blood-serum as a medium. The bacillus grows very slowly; after ten days or two weeks the surface of the medium shows dry flakish deposits, somewhat resembling the scales in certain 316 A TEXT-BOOK OF PATHOLOGY skin diseases (Fig. 113). The edges of these flakes tend to elevate them- selves a little, and the substance of the growth has a crumbled appear- ance. Placed under a cover-glass in mass and examined with the microscope these flakes are found to be composed of contorted masses of bacilli (Fig. 114). Pure cultures are best obtained from the lymphatic glands of animals artificially infected and destroyed before the tuber- culous foci have advanced to the stage of necrotic change. Cultures may be obtained with some difficulty from the sputum or other excreta. At the present time blood-serum is less frequently used, as it has been found that agar-agar slightly acidulated and containing a large pro- portion of glycerin, and bouillon containing glycerin, serve as useful media. The original culture is still, as a rule, obtained in blood-serum or coagulated egg. Even potato and other simple substances are found to be satisfactory media. The bacillus ees a rather even tempera- ture for its growth: it flourishes best at 37.5° C. (99.5° F.), and does not grow below 29° C. (84° F.) or above 42° C. (107. 6° F.). Exposure to higher temperatures (75° C.; 167° F.) rapidly destroys it, and strong sunlight is destructive. It requires considerable air and always grows upon the surface of the medium in which it is cultivated. Prolonged cultivation upon artificial media lessens its virulence. The demonstration of the tubercle bacillus by staining methods is extremely easy and satisfactory. It has been found that this organism, like that of lepra and the smegma bacillus, does not readily stain, but after receiving a stain retains it despite the action of strong mineral acids. Upon this principle the methods of staining are based. Koch used as a stain a gentian-violet solution containing anilin oil, the latter playing the part of a mordant or an agent to fix the stain in resistant bacilli. The specimen was then decolorized by treating it with a solu- tion of a mineral acid, which removes the stain from everything but the tubercle bacillus. A counterstain might then be used to render the de- tection of the bacilli more easy. The most convenient method is the following: Sputum is spread in a film upon thin cover-glasses or slides. These are allowed to dry in air and then thoroughly fixed by drawing the specimen through a Bunsen flame three times; a drop or two of Ziehl’s solution of carbol- fuchsin are added and heated until the liquid steams. After two or three minutes the stain is washed off with water and a few drops of Gabbett’s solution (methylene-blue, 2; sulphuric acid, 25; water, 75) are placed upon it and allowed to remain a minute or two. The specimen is again washed with water, and should then be uniformly blue; if not, a little more Gabbett’s solution is added as before. In this method the carbol- fuchsin stains everything, including the tubercle bacillus; the sulphuric acid of the second solution decolorizes everything but the tubercle bacillus; and the methylene-blue at once stains the cells and other. elements, leaving the bacilli dark red. Even more satisfactory results may be obtained by allowing the carbol-fuchsin to stain at ordinary temperatures for twelve hours; and in the staining of bacilli in tissues this prolonged cold staining is particularly desirable. Gram’s method DISEASES DUE TO BACTERIA 317 gives positive results. Pappenheim’s solution or repeated treatments with absolute alcohol are necessary when it is desired to exclude smegma bacilli. Distribution of the Tubercle Bacillus——This organism is probably a pure parasite, occurring and multiplying only in the body or excreta of diseased individuals, human or animal. Sputa or other excreta contain- ing the bacillus may dry and retain the bacillus in a dormant though still potential form for long periods of time, outside the body. Multiplication of the organism, however, probably very rarely occurs, except within the body. The bacillus is found in the lesions of all parts of the body. Modes of Infection.—The bacillus may gain access to the body either by direct inoculation, by the inhalation or swallowing of the germs, or by intra-uterine transference through the placenta. Direct inoculation through external wounds is perhaps more frequent than is believed. Definite lesions of the skin have been caused by vaccination, and are not infrequent upon the hands of anatomists in the form of the so-called anatomical tubercles. In some of the cases of scrofulous glands of the neck in children it is likely that the bacillus gains entrance through abrasions of the skin or of the mucous membrane of the mouth or pharynx. Genital tuberculosis is quite possibly frequently produced by direct implantation. The most common form of infection is through the inspired air. The breath of phthisical patients does not ordinarily contain bacilli, but the dust of rooms in which tuberculous patients have lived may contain numerous bacilli in a dry state, and these readily be- come mixed with the air and are thus inhaled. Tuberculosis of the lungs or, more rarely, of other parts of the respiratory tract is thus produced in susceptible persons. Despite the activity of some in- vestigators to inculpate the intestinal tract in the origin of all lung lesions, it is now generally accepted that most pulmonary tuberculosis arises by inhalation. The bacilli lodge upon the mucosa, are taken into it, or by lymph-radicals, and carried to nearby lymph-nodes. Occa- sionally they reach the smaller bronchi and start the lesion there. The swallowing of tuberculous material may lead to tuberculosis of any part of the gastro-intestinal tract by the direct inoculation that results. Thus intestinal tuberculosis in particular is produced. Some- times, however, the bacilli pass through the wall of the intestine and cause a primary lesion in the lymphatic glands of the abdomen, and it is not improbable that even the mesenteric lymphatic glands may escape without discoverable lesion or wholly, and the final lodgment of the infecting organism may be the lungs. The bacilli are swallowed with milk or meat, or they may gain access to the mouth, in the form of dust or particles of various kinds, and be swallowed with the saliva. Some assert that tuberculosis of the tonsil is of alimentary origin. The milk and meat of infected cattle frequently contain bacilli, and undoubted instances of infection in this way have occurred. The proof of this is that in some cases of abdominal tuberculosis in young children the organisms obtained in cultures have shown the character- istics of the bovine species. 318 A TEXT-BOOK OF PATHOLOGY The intra-uterine transmission of tuberculosis is rare, but does occur, Most of the cases, however, of tuberculosis in early life may be ex- plained as postnatal infections through milk, inspired air, etc. Some authorities assume that a few tubercle bacilli transferred from the mother to the fetus may lie dormant in the fetus and child and later cause active infection. This hypothesis rests upon no demon- strated facts. Relation of Human to Animal Tuberculosis.—Tuberculosis attacks the lower animals with varying frequency. It is most common in cattle, and because of the peculiarities of the bacilli and lesions this form of the disease is termed “bovine tuberculosis.” Many experi- ments have been made to establish the relation existing between the bovine and human forms of the disease, and Koch, in 1901, made the statement that the two were different diseases and probably were not intercommunicable. Ravenel disproved this assertion by producing the disease in cattle with bacilli obtained from human sources, although the animals exhibited a high grade of resistance to such an infection. At the same time he reported 4 cases of accidental local infection in man with the bovine bacillus. He, therefore, maintains “that human and bovine tuberculosis are but slightly different manifestations of one and the same disease, and that they are intercommunicable.” The present situation of the subject is best illustrated by the results of Park and Krumwiede. After exhaustive studies of the literature and their own material, these authors conclude that while bovine infection for the adult is practically negligible, in children a noteworthy per- centage of tuberculosis of glands, abdominal organs, and meninges is due to the bovine tubercle bacillus. There is no positive proof now at hand to show a mutation from one type to the other. Less frequently tuberculosis occurs in hogs, goats, horses, dogs, cats, sheep, rats, guinea-pigs, and rabbits. All these animals are more susceptible when kept in confinement. Captive monkeys are highly susceptible. In all these animals the disease is probably intercom- municable with human tuberculosis, but the lesions are not always identical with those found in the latter disease. Birds and fowl of various kinds are susceptible, though the disease is somewhat different in them from that seen'in man. (See Fowl-tuberculosis.) Tubercu- losis of cold-blooded animals has also been recognized. ‘The form of disease in the latter is atypical, and the bacillus shows peculiar char- acteristics, but tends to approach the form of the human bacillus by successive passage through animals. Animals may become infected from man, and may further spread the infection by their discharges and excretions. In the case of cattle the danger of dissemination is particularly great, because of the danger to man of infection through the digestive tract by means of tuberculous milk or meat insufficiently cooked. According to the best testimony available at the present time it seems likely that the human, bovine, avian, and other animal species are simply variations of one common bacterial organism. Not im- DISEASES DUE TO BACTERIA 319 probably the peculiar characteristics may be acquired in the human body or the animal after the original infection. Thus the proof of the original source of the infection may be lost. Pathological Anatomy.—Tuberculosis is characterized by the erup- tion of small nodules, varying in size from 1 to 2 mm. in diameter to that of a small pea. These are known as miliary tubercles. As already mentioned, the latter in gross appearance are not distinctive of tuber- culosis, as similar nodules are met with in other diseases. Besides the tubercle there are inflammatory lesions occurring between the tubercles and varying with the anatomical character of the organs affected. Thus in the lungs the tubercle may be inconspicuous, whereas the pneumonic infiltration of the lung tissue surrounding the tubercles and filling in the spaces between them gives the organ its most striking anatomical characters. There are instances of tuberculosis in which the whole process runs its course without the development of any definite tuber- cles. For example, in the lungs the inhalation of tubercle bacilli in con- siderable numbers may be followed by rapid tuberculous pneumonia without definite tubercles, and in other situations similar results may be produced. In the further progress of a case of tuberculosis caseous change is important. This may present itself in the form of areas of considerable size having a dull, opaque, lusterless, grayish or whitish character, and not inaptly likened to the appearance of cheese. These centers of caseous necrosis may finally become liquefied, and cavity formations may result. These changes are particularly frequent in tuberculosis of the lungs; less frequent in bones, skin, glands, or kidneys. In connection with tuberculosis of bones there may be formed small or large cavities filled with liquefied caseous or puriform material. These may involve the surrounding tissues as well as the bones them- selves. The term “cold abscess” is applied to them. Small tuberculous areas and sometimes even large foci are prone to. be surrounded by reactive fibrous-tissue hyperplasia, and thus a complete encapsulation may result. Small foci may be uniformly transformed by organization of proliferating connective tissue and may be thus entirely healed. In other cases simple encapsulation occurs, the tuberculous mass within perhaps undergoing calcification. These changes will be more particu- larly referred to below. Tuberculous lesions of the mucous membranes frequently begin with the formation of distinct tubercles occupying the deeper layers of the mucosa or the submucosa. These by confluence may form con- siderable areas of tuberculous disease, while at the same time reactive inflammation of the surrounding tissues adds to the mass. Sooner or later ulcerative changes upon the surface make their appearance, and irregular, more or less necrotic, ulcers result. The caseous appearance of these and the occurrence of distinct tubercles in the edges or base manifest the character of the process. The histogenesis and anatomy of the tubercle has been considered on page 141, and we shall only here consider its pathological relations. After the establishment of the local lesion of tuberculosis in any 320 A TEXT-BOOK OF PATHOLOGY part of the body two opposing tendencies struggle for supremacy: the tendency of the tuberculous disease to spread and the tendency of the normal tissues to encapsulate or limit the spread of the invading disease, In most cases the former succeeds and the secondary tubercles first appear in adjacent parts, the transportation of the bacilli from the primary to the secondary focus being accomplished either by the flow of the lymph or juices of the body, by continuity, or by the activity of phagocytes. The last take from the edges of the tubercle some of the bacilli and transport them either by their own ameboid activ- ities or in the lymph-stream to neighboring parts, where they them- selves fall victims to the organisms they have appropriated, and thus deposit the germs of new foci of disease. The dissemination of tuber- cles to more distant parts may occur in various ways. In the case of tuberculosis of the mucous membranes bacilli may be cast off from the surface and spread to other parts of the mucous tracts with the contents of these, as in the case of tuberculosis of the gastro-intestinal tract. In the case of pulmonary lesions the ulcerative processes, or attacks of coughing, may loosen infected particles from lesions of the bronchi, and the deep inspiratory efforts following the cough, or the ordinary inspirations, may carry the bacilli into the finer bronchioles, where new foci arise. If the tuberculous lesions involve the walls of the lymphatics, particularly the larger lymph-channels, like the cervical or thoracic ducts, bacilli may gain access to the lymph-stream and thus be trans- ported to the venous circulation, and then through the heart to the lungs or perhaps to other organs. When the tuberculous lesion invades the wall of a vein the dissemination of the bacilli is even more rapid and widespread, as the organisms find their way to the heart by a more direct route. In rare instances an artery is invaded and the organisms are scattered through the terminal distribution of this. The lesions of vessel walls arise either as primary tubercles, as extension processes, or secondary to intimal lesions leading to thrombosis, a condition which favors the settling of tubercle bacilli. Upon surfaces the disease may spread by direct continuity or by the movements of the body. Thus, lesions of the peritoneum may become almost universal in consequence of the peristaltic movements, though more frequently the extension occurs along the lymphatic channels. The condition which results from general infection and formation of tubercles in various situations is known as miliary tuberculosis. In these cases the progress is usually rapid and a fatal termination is not long delayed. The tubercles, therefore, remain small, and at autopsy are still typically gray miliary tubercles. Sometimes, however, miliary tuberculosis may assume a more chronic form, perhaps in consequence of the gradual admission of bacilli to the circulation and the formation of small crops of tubercles during a considerable period of time. Occasionally, tubercle bacilli invade the blood and do not give rise to miliary tuberculosis. Why they do not is not clear. Miliary tuberculosis may be local or general. In the former case the bacilli are admitted to the vascular distribution of a restricted DISEASES DUE TO BACTERIA 321 area only; in the latter, widespread dissemination through the blood occurs, and practically all parts of the body may be involved. Local- ized miliary tuberculosis is most frequent in the lungs. The progression of tuberculosis is accomplished by the coalescing of formed tubercles or an exaggeration of the inflammatory characters, especially in the presence of mixed infection, or to both. Regressive tuberculosis is either latent (q. v.) or cicatrizing. The latter is that form in which the most pronounced lesion is fibrous tissue formation, which may or may not finally wholly replace the tuberculous tissue. Such a process is responsible for the healing of tuberculosis. It has been asserted that two-thirds of all adults have some such healed lesion of tuberculosis in them. The healing of tuberculous lesions follows the general rules of repair. The fibroblasts grow both within and without the tubercle and gradu- ally replace it. Wherever fibrin has been deposited the tubercle grows and attempts to form a new tubercle. It is noteworthy that in healing of tuberculosis a great amount of fibrous tissue is produced and ad- hesions are common. Seats of Tuberculosis.—Among the frequent situations in which tuberculosis makes its appearance are the lungs, the lymphatic glands, the bones and joints, the mucous membranes, particularly those of the larynx and intestines, the serous membranes, the prostate, testicles, ovaries, Fallopian tubes, kidneys, uterus, suprarenal capsules, brain, liver, spleen. In some of these situations the lesions are practically always secondary, as, for example, in the liver and spleen. In others they are most frequently primary, as in the lungs. The occurrence of primary tuberculosis in the internal organs may be difficult to explain. It is possible, however, for the bacilli to gain access to the lymphatic or blood circulation without causing a lesion at the point of entrance. Their deposit in some internal organ then occasions the first or primary focus of disease. Thus, primary tuberculosis of the mesenteric glands, of the lymphatic glands of the neck, or of the postbronchial glands may occur without primary disease of the intestines, of the mouth or skin, or of the lungs in the several instances. Similarly, primary tuberculosis of the kidney or of the suprarenal capsule may occur without any evidence of the point of entrance of the micro-organisms. In some cases, of course, the primary lesion may be so small and in such a hidden situation that it escapes notice. After the discovery of the tubercle bacillus a number of diseases not previously recognized as tuberculous became identified as forms of this disease. Among these is lupus vulgaris of the skin. The histological examination shows numerous tuberculous granulations, sometimes ar- ranged in striate fashion along the small blood-vessels of the skin and containing epithelioid and lymphoid cells and giant cells. The presence of the bacilli and the proved infectiousness of the tissue, with the histology, render the nature of this disease certain. The warty forma- tions frequently acquired by anatomists at points of injury have like- wise been shown to be in many cases due to tuberculous infection. 21 322 A TEXT-BOOK OF PATHOLOGY Scrofula, which was formerly regarded as a special condition prediposing strongly to tuberculosis, is now regarded as actual tuberculosis. The scrofulous glands of the neck constitute tuberculous adenitis, the infec- tion in many cases gaining access through the mucous membranes of the mouth and pharynx or through the skin. Scrofulous rhinitis and sinuses have similarly been shown to be forms of tuberculous disease. Many cases of joint disease regarded as scrofulous are likewise dependent upon the action of the tubercle bacillus. Latent Tuberculosis.—A tuberculous lesion may become encap- sulated and limited in its extent before it has invaded tissues widely, and may so remain for years without giving rise to manifest clinical symptoms. Subsequently, however, the encapsulating membrane may be penetrated and widespread infection, local or general, may occur. Such latent tuberculosis is particularly frequent in the postbronchial glands. These glands are often found enlarged at autopsies in which no tuberculous disease of other organs is found. Injections of emulsions of such glands in a notable proportion of cases produce tuberculosis in guinea-pigs, and thus it has been determined that the glands in question are frequently the seat of latent tuberculous disease. The existence of such lesions explains the cases of sudden generalized miliary tuberculosis, in which no primary focus of the disease was recognized during life. It is perhaps well to emphasize the difference between latent and healed tuberculous foci. The former are arrested and surrounded by a limiting wall of connective tissue through which it is possible for degenerations or inflammations to extend and free the tubercle bacillus, or awaken it to activity, while in healed foci it is assumed that all infective agents have been destroyed, and the original lesion wholly replaced by fibrous tissue. Pathological Physiology.—The effect of tuberculosis upon the gen- eral health varies greatly. Undoubtedly the bacillus contains or is capable of producing toxic substances that have an effect upon the general organ- ism; the nature of these, however, still remains undetermined. The tuberculin of Koch, a glycerin extract from cultures of the tubercle bacil- lus, produces fever with the general symptoms characteristic of pyrexia and local reactive changes in existing tuberculous lesions. Among the latter, redness or increased vascularization of the tubercles, and soften- ing or necrosis of the cells surrounding the bacilli, are most important. The last named change deters the growth and multiplication of the bacilli themselves, but at the same time makes their escape from the focus of disease more easy and thus exposes the individual to the liability of general infection. The active substance contained in tuberculin is probably a thermostabile polypeptid that is destroyed by pepsin and trypsin, but not by erepsin. It is positively chemotactic for leukocytes. It does not act upon the tubercle bacillus directly and is not an anti- toxin. The tubercle bacillus seems able also to excrete lipase during its vegetative life. In addition to this, the tubercle bacillus in its dead state contains some body or bodies capable of influencing the organism, as was shown by the experiments of Prudden and Hodenpyl, who DISEASES DUE TO BACTERIA 323 were able to produce nodular lesions by injecting dead bacilli into the circulation of animals. Mention has already been made under Caseation of the unsaturated fatty acids of tubercle bacilli in the production of necrosis. Such substances are also present in dead bacillary bodies. These lesions, of course, are not strictly tuberculous, though they _possess some elements of the natural tubercle. It is altogether prob- able, however, that in addition to the tuberculin of Koch and the chemotactic substances contained in the body of the tubercle bacilli, there are other poisonous substances produced by the growth and multiplication of the bacilli in the tissues, that lead to a general de- terioration in the health of victims of this disease. Trudeau, Pear- son and Gilliland, and others have been able to immunize animals by repeated inoculations with bacilli of lowered virulence. Human bacilli if injected into cows will raise their resistance to virulent bovine bacilli. A form of immunity called “isopathic’”’ (Behring) is thus pro- duced. The sera of such immunized animals is not protective or cura- tive to other animals. None of the supposed “antitoxic’” sera thus far produced has been proved to have antitoxic or immunizing power. : Tuberculosis is primarily a local process, but influences the general organism by its direct effect upon the organic functions of the parts in which it is located by the development of these as yet unknown toxic substances, and later by the widespread infection of the organism. Amyloid disease is a sequel of prolonged tuberculosis. The mechanism of defence against tuberculosis is only partly ‘known. In the case of local lesions of the lungs or other parts the reaction of the tissues prob- ably resulting from the activity of chemotactic substances in the body of the bacilli themselves, or of similar substances produced by the cellular necrosis, leads to the formation of an embankment of cellular or fibrous tissue that serves to hold the disease in check. Subsequently, the disease may be wholly eradicated by degenerative changes terminat- ing in calcification. That such favorable results are not uncommon is proved by the frequent occurrence at autopsies of small sclerotic or calcareous areas in the lungs. Tuberculosis is frequently cured in these early stages, but after it has reached the degree of intensity or the wide- spread character that makes it recognizable by our present methods of physical examination, the reactive processes are usually no longer able to cope with its progress. The defensive reactions of the blood against the tubercle bacillus are not very potent. In the serum there appear agglutinins, opsonins, and a complement-fixing body in excess of those found in non-infected persons. Use is made of the opsonins in bacterin therapy, as it is possi- ble to increase their strength by injection of some of the products of the tubercle bacillus or of killed cultures. Repeated injections of the bacilli or their products into lower animals have not developed any valuable antiserums for therapeutic purposes, but claims have been made that active immunization with living bacilli will raise the resistance of animals and man. Such methods are, to say the least, hazardous. 324 A TEXT-BOOK OF PATHOLOGY PSEUDOTUBERCULOSIS This name has been applied to conditions occasionally met with in which nodular lesions resembling tubercles, but containing micro- organisms of different kinds, have been found in the liver, kidneys, and other organs. Pseudotuberculosis is not a specific disease, as a number of distinct infections assume this pathological character. Among the organisms isolated are various streptothrices and acid-proof bacilli resembling the tubercle bacillus to some extent (see below). In the lower animals, and very rarely in man, certain animal parasites cause lesions of the same kind. The Smegma Bacillus——A bacillus quite closely resembling the tubercle bacillus was discovered in the smegma and later on the skin of various parts of the body. It not only resembles the tubercle bacillus morphologically, but behaves in a similar manner toward stains. In particular this bacillus holds its stain when attempts are made to decolorize with acids. The bacillus is frequently found in urine, and thus may cause an erroneous diagnosis of tuberculosis of the kidney or bladder. It may usually, though not certainly, be distinguished by its easy discolorization with absolute alcohol. Other Acid-proof Bacilli—Several other bacilli that are refractory to decoloriza- tion with acid or alcohol have been discovered in milk and butter, in sputa, and in purulent or gangrenous collections in the lungs and elsewhere. Injections of pure cultures of some of these cause fibrinous inflammations in the peritoneum of guinea- pigs and rabbits, or pseudotuberculous formations, but not the specific lesions of tuberculosis. The lesions resulting from inoculation with acid-fast bacilli show a striking resemblance to those of tuberculosis, and only a careful microscopical examination serves to distinguish them. Examined with a microscope, the lesions of this spurious tuberculosis present a more inflammatory appearance and show a tendency toward abscess formation. In very rare instances, however, an approach toward the typical histologic conditions of genuine tuberculosis, characterized by the formation of giant cells, epithelioid cells, and caseation, is seen in this form of pseudotuberculosis. The causative organisms in such infections range in a biological series from short, bacillary, rigidly acid-fast forms very like tubercle bacilli to longer threads slightly acid fast, to groups of higher bacteria growing in mycelia and not acid fast, related to actinomyces and streptothrix. The streptothrices may produce infiltrative and proliferative lesions like the organisms just discussed. They have been found in various parts of the body as the causative factors in abscesses. The lung process is infiltrative, then suppura- tive, then necrotizing. Some of the streptothrix infections may resemble pul- monary tuberculosis and can be diagnosed only by isolating the organisms or by skin tests. It has been found possible to differentiate the various infections with these higher bacteria by means of skin tests. Preparations made from cultures of the various organisms, tubercle bacilli, partly acid-fast organisms, and those of strepto- thrix type, are rubbed upon an abraded skin surface; a swollen red area will arise in response to the preparation made from the causative bacterium and not to others. Pneumonomycosis aspergillina—In man and in animals pulmonary infection with forms of aspergillus, especially Aspergillus fumigatus, may occur in a pseudotubercu- lous form. The lesions are exudative and proliferative, and central caseation may be conspicuous. The fungi which belong to the group of hyphomycetes are readily dis- tinguished by the abundant mycelial threads and the conidia. Infection of other organs may occur spontaneously or experimentally. Pharyngomycosis leptothricia.—The Leptothrix buccalis is a normal inhabitant of the mouth, and occasionally produces a pathological lesion DISEASES DUE TO BACTERIA 325 of clinical interest. The organism probably belongs to the group of pleomorphic bacteria, though its exact position is not determined. It consists of fine threads, of wavy or spiral character, composed of rod- like segments. Occasionally spore-like bodies are found at the free ends of the filaments. The organism sometimes penetrates and multiplies in the crypts of the pharynx, causing a chalk-like nodule or deposit. Secondary inflammation may be occasioned. (See also Diseases of the Pharynx.) FOWL-TUBERCULOSIS Tuberculosis in various forms of fowl and birds (avian tuberculosis, Tuberculosis gallinarum) is a disease similar to, but not identical with, human tuberculosis. The spontaneous disease of birds occurs most frequently in the liver, the lungs being never primarily involved. In the liver are found nodules composed of a large central necrotic area sprinkled with chromatin débris surrounded by a zone of large epithelioid cells containing numerous nuclei, intermixed with small round cells. Tubercle bacilli are present in enormous numbers. The structural and cultural differences of the human and avian bacilli have been discussed on page 315. : Despite the similarity of the bacilli of the human and avian types of tubercle bacilli, it does not seem that the latter can produce tubercu- losis in man. In the few cases in which avian bacilli have been isolated from human lesions, the simultaneous presence of human bacilli was not satisfactorily excluded. Experimental inoculations of bacilli isolated from the spontaneous disease will produce the same disease in birds; but if animals, such as guinea-pigs or dogs, which are very susceptible to human tuberculosis, are inoculated, they frequently resist infection, though they occasionally succumb to very large doses. In the latter case tubercles are usually absent, but large numbers of bacilli are found in the organs and in the ab- scesses which result at the point of inoculation. According to Nocard, rab- bits show a marked degree of susceptibility to this form of tuberculosis. Although there is no doubt that fowl in some instances have become infected through human sources, yet experimentally they exhibit a very high degree of resistance to human bacilli. If, however, the human bacilli are passed through birds for three or four generations, or are placed in the peritoneum of fowl in collodion sacs, for the same length of time, the virulence to birds is not only heightened, but the bacillus changes in its structural and cultural characteristics, assuming those of the bacillus isolated from spontaneous avian tuberculosis. The same is true of avian bacilli when these are inoculated in animals sus- ceptible to human bacilli. With each passage through such an animal the virulence of the bacillus is increased, and the form and cultural char- acteristics become more and more like those of the human bacillus. From these experiments it appears that the avian tubercle bacillus is only a modification of the ordinary tubercle bacillus caused by its growth in the tissues of the bird. 326 A TEXT-BOOK OF PATHOLOGY LEPROSY Definition.—Leprosy, lepra, or elephantiasis Greecorum, is an infectious and mildly contagious disease caused by a specific bacillus, the Mycobacterium lepre, discovered by Hansen. Etiology.—The essential cause of leprosy is a bacillus which closely resembles the tubercle bacillus, though it is less frequently curved and is somewhat more easily stained. Further, it differs in its grouping in the tissues and in its character of growth. The organism is usually found in large numbers in the leprous lesions and in the nasal mucus, whether there be definite leprous ulcerations in the nose or not. In the tissues the bacilli are found within large cells of the specific granulation tissue (lepra cells). In the anesthetic form it is found in the nerves and central nervous tissues. The organism has been demonstrated in the blood in certain cases of the tubercular type. It is readily stained by any of the methods applicable for the tubercle bacilli or by Gram’s method. It frequently shows light areas like those of the tubercle bacillus; these have been regarded as spores, but are more probably produced by fragmentations, as in the case of the tubercle bacillus. Musgrove, Clegg, and Duval have succeeded in cultivating the leprosy bacillus upon media containing tryptophan. The organisms do not possess the power of digesting the protein molecule to liberate this substance, so that it must be introduced artificially or supplied to them by means of symbiotically growing amebe or bacteria. Two kinds of cultures have been observed, one growing in a luxuriant yellow form, the other as a scanty, almost colorless colony. The importance of the two is not yet understood. Some believe that the scanty growth is the true lepra bacillus. Wolbach and Honeij’s work upon human and rat leprosy would suggest that four kinds of organisms—diphtheroids, pigmented acid-fasts, non-pigmented acid-fasts, and anaérobics—have been cultivated in different parts of the world. It would seem that they may all be involved, or that two are present as varying examples of one organism. What has been called typical leprosy has been pro- duced in rabbits’ eyes, mice, and especially monkeys. Flies of the genera Musca and Stomoxys have been accused of carrying lepra bacilli. In one case the disease has been given to a condemned criminal by direct. inoculation. Besides the specific bacillus, other conditions are important in the etiology. Thus, the disease flourishes in certain localities extensively and little in other places. It is uncommon in the United States, but some of the Gulf States, particularly Louisiana, have considerable colonies, and in the Northwest and on the Pacific Coast it is met with among the Norwegian and Chinese immigrants. In Mexico, South America, Nor- way and Sweden, India, and other Asiatic countries it is common, and the Sandwich Islands are particularly affected. During the Middle Ages it flourished in Europe as a universal scourge, unsanitary conditions probably acting as the predisposing cause. Certain articles of diet are believed to occasion it, particularly fish; this view, however, lacks proof. DISEASES DUE TO BACTERIA 327 The disease must be regarded as contagious, though less so than tuberculosis. Intimate association for a long time seems to be necessary for its transference. Insects have been thought to transmit the disease, but proof is as yet not forthcoming. It is probably transmitted from parent to offspring in rare instances. The bacilli have been found in the hyalin substance, the syncytial cells, chorionic villi, and vessel walls of the placenta. The importance of the nose as a seat from which leprosy bacilli are disseminated is emphasized by the facts that the bacilli are present Fig. 115.—Nodular leprosy (Goldschmidt). here even when no leprous lesions exist, and that ulcers are common on the septum. The lesions when present are softer than those on the skin and may be found in both the tubercular and anesthetic forms. Pathological Anatomy.—Leprosy presents itself in two forms— the tubercular and the anesthetic. In the former there are developed in the skin of the face, the extensor surfaces of the elbows and knees, about the hands, or less frequently elsewhere, small or large nodular ‘elevations. These at first are reddish in color, with apparent inflam- matory reaction. Later they lose their redness and remain as indolent lesions that grow very slowly or remain stationary. They may break 328 A TEXT-BOOK OF PATHOLOGY down, forming ulcerations which do not readily heal, or they may be gradually converted into fibrous cicatricial tissue, causing unsightly deformities of the skin. The appearance of the patient’s face is highly characteristic, and is known as leontiasis leprosa (Fig. 115). The mucous membranes and some of the internal organs may be involved. The anesthetic form is usually marked by less conspicuous lesions, but sub- jective symptoms, such as hyperesthesia and neuralgic pains, and later ulcerations partly trophic in nature, may make it a more serious variety. In the skin there are found whitish or brownish spots, slightly if at all elevated or altered in consistency. Later, ulcerations may appear. Very commonly the anesthetic and tubercular varieties are coexistent. The chief seats of the leprous nodule are in the corium and sub- mucous tissues. It invades, by cellular extension, the adjacent nerves, vessels, muscles, and sweat-glands, and may be found in the epithelial coverings. The nodules occurring in the liver, spleen, and testes in this disease are admitted to be similar to the nodules of the skin; those found in the lungs, kidneys, and intestines, as well as those of the serous surfaces, are believed by many to be tuberculous and the result of secondary infection. These two diseases are certainly frequently associated; probably 40 per cent. of the cases of lepra become tuberculous. Other forms of secondary infection occur. Thus injuries of super- ficial lesions may allow pyogenic infection, and extensive ulcerations and gangrenous necrosis may ensue. The terms lepra mutilans and lepra gangrenosa are applied to such; and various micrococci and sapro- phytic organisms have been discovered in such cases. The histology of leprosy is given on p. 147. Pathological Physiology.—Infection with the lepra bacillus leads to local rather than general disturbances. The toxins of the disease, if such there be, are not of great virulence, and constitutional symptoms are, therefore, wanting as a rule. In the later stages fever and other systemic disorders may be occasioned by secondary infections. A supposed antitoxic substance has been prepared and has been largely used. It is impossible to claim or disclaim the antitoxic nature of this, as no toxins have as yet been isolated or obtained in any form, and the supposed antitoxic substances cannot, therefore, be tested. In the anesthetic form it was formerly customary to regard the pigmented or light-colored spots as a result of trophic disturbance, and more destructive lesions, such as ulceration and gangrene, received a similar explanation. Recent investigations, however, seem to show that in these cases there is usually from the first a leprous change in the tissues due probably to thickening of vessel walls, and that sec- ondary infections frequently play a part, though trophic disturbances must still be admitted to a certain extent. DISEASES DUE TO BACTERIA 329 BACTERIUM MUCOSUM CAPSULATUM GROUP This is a very large group, chiefly saprophytic, in the intestinal tract of men and animals, but includes a few important highly patho- genic varieties. They are all Gram-negative, non-motile, blunt-end rods, growing luxuriantly on artificial media, and with active ferments against carbohydrates. Some possess capsules in the body only, others in certain artificial media as well. Perkins divides them into three convenient groups: (a) The Bacterium aérogenes type ferments all carbohydrates, with the formation of gas. (b) Bactervwm pneumonie type ferments all except lactose, with gas. (c) Bacterium lactis aérogenes ferments all as above, except saccha- rose. This order represents their frequency and pathogenicity. The first class is found in abscess, pneumonias, and inflammations of serous membranes. The most important member of the second group is commonly called “Friedlander’s bacillus,’ an organism seldom found aside from pneumonia. (See Friedlinder’s Pneumonia, p. 283.) The third group contains very few pathogenic varieties, but is most com- monly concerned in milk souring. The exudates caused by all the pathogenic members of this group have one or both of two characters. The exudate may be viscid or it may contain swelled up cells in which the organisms lie (Alikulicz cells and swollen cells of Friedlander’s pneumonia). The bacteria pos- sess a mild lytic effect upon epithelium and endothelium. The organ- isms give rise to very few antibodies. A very important non-pathogenic organism not far removed from the third division is the Bacterium bulgaricum of Massol. This breaks up the carbohydrates of milk and produces lactic acid. This is recom- mended by Metschnikoff as an intestinal antibacterial agent. Other Organisms of Less Importance The Bacillus pyocyaneus is a Gram-negative, occasionally pathogenic organism found in pus having a bluish or greenish color. The bacillus is small in size, fre- quently occurring in chain formation, and is actively motile. Upon artificial media it produces colored growths and a soluble pigment, which gives to the culture-medium for some distance from the growth a greenish, or in some cases a dark blue, coloration. The organism in pure culture is highly virulent, producing intense suppurative inflammations. Occasional instances of general pyo- cyaneus infection have been observed. In these cases there are most commonly thin purulent exudates in serous cavities and cellulitis. The organism acts destructively upon other bacteria, so that a fatal dose of Bacillus anthracis may be rendered innocuous by the simultaneous injection of B. pyocyaneus. The destructive effect has been demonstrated in vitro. It seems dependent on ferments as well as intracellular substances contained in the bacillus. The toxin is hemolytic and parenchymatous degeneration arises in the liver, kidneys, etc. 330 A TEXT-BOOK OF PATHOLOGY DISEASES DUE TO SPIRILLA CHOLERA Definition.—Cholera is an acute infectious disease caused by a spirillum or vibrio. Etiology.—The specific cause of cholera is the Spirillum or Vibrio cholere asiatice. This organism is frequently spoken of as the comma bacillus of Koch. It is a short rod, from 0.8 to 2 « in length, and usually. somewhat curved. The term “comma bacillus’ is applied to it on account of the latter fact. It is found abundantly in the rice-water discharges of choleraic patients, and is not rarely arranged in threads, though the vibriones are not actually attached to one another (Fig. 116). It is motile, the motility being due to a single flagellum attached at one end. In artificial cultures the organisms are actually joined to form Fig. 116.—Spirillum of Asiatic cholera, from a bouillon-culture three weeks old, showing numbers of long spirals; x 1000 (Frankel and Pfeiffer). spirals of greater or less length, and these may present a rapid rotary movement. The demonstration of the cholera spirillum is usually easy, as ordi- nary stains color it intensely. It is Gram-negative. Even the flagel- lum may be stained by the ordinary stains, though more definitely shown by special methods. The cultivation of the spirillum is usually easy. Cultures may be obtained upon agar-agar, blood-serum, or other media, but the gelatin- culture is most characteristic. In puncture-cultures the growth occurs along the entire length of the puncture, but particularly at the top, where the supply of oxygen is abundant; and the gelatin becomes lique- fied. This gives rise to a peculiar nail-shaped or funnel-shaped forma- tion (Fig. 117). In plate-cultures the growths first appear in the lower DISEASES DUE TO BACTERIA 331 strata of the gelatin as small granular whitish spots which extend toward the surface, liquefy the gelatin, and thus produce excavations. The appearance to the naked eye suggests small air-bubbles in the media. Under low powers of the microscope the culture is seen to be coarsely granular, the size of the granules varying with the age of the culture. The bottom of the growth presents an appearance like that of a surface sprinkled with powdered glass. When grown in bouillon or other liquid media the cholera microbe produces nitrites and indol so abundantly that the addition of a little pure sulphuric acid or hydrochloric acid (without nitrite solution) leads to a reddish coloration—‘‘cholera-red.”” The indol reaction is not absolutely diagnostic, since other spirilla may cause it. Negatively, however, the test is extremely useful, since its absence excludes the cholera germ. A definite quantity of peptone is necessary to make the test reliable. Therefore, in- stead of bouillon an alkaline 1 per cent. peptone solution containing 0.5 per cent. of sodium chlorid is preferable (Dunham). The cultures of cholera grow best at a temperature about that of the body, but they may thrive at much lower degrees of heat. Exposure to a temperature of 52° C. (125.6 °F.) for four minutes may cause their destruction, but ten or fifteen minutes’ exposure at 55° C. (131° F.) does not always prove destructive. They may thrive in distilled water or in water con- taining saline matter; in or upon various forms of : food; upon clothing, and the like. The resistance, guns“ulture in wel however, is not very great, and this has been urged ee ee as an objection to the likelihood of the organism being 61d. (Shakespeare). the cause of a disease having such evident tenacity. Distribution.—The cholera spirillum is found in the intestinal con- tents and mucosa. The organism is not found in the blood nor in any organ or tissue except the gastro-intestinal tract. The pathogenicity of the cholera spirillum is now admitted uni- versally. Injected into the peritoneum of animals it causes a rapid fall of temperature, abdominal tenderness, and collapse. The perito- neum shows signs of beginning inflammation, and the organisms are found in abundance within the cavity. It has been possible also to pro- duce intestinal changes almost if not identical with those of human cholera in animals by arresting the peristalsis of the intestines with injections of opium, rendering the liquids of the stomach alkaline with sodium carbonate, and then feeding cultures. In man a few auto-infections have occurred, the experimenter swallowing cholera cultures. In one case at least typical cholera was admitted by Petten- kofer, the most important opponent of the acceptance of this germ, as the specific cause. The celebrated case of Dr. Oergel, who died as a result of laboratory auto-inoculation, seems practically conclusive. 332 A TEXT-BOOK OF PATHOLOGY Other Causes Operating in Cholera.—Infected water is the chief source of transmission of cholera. The microbe may live in water for months. It is said that the Ganges River contains the spirilla constantly. Certain climatic conditions favor the development of the disease. Thus it is constant in certain regions of India, and spreads thence when the con- ditions become favorable. The evidence shows that the germ is carried by individuals, or by infected food and the like. The disease flourishes in warm seasons of the year, and an epidemic is usually brought to a close by winter frosts. Individual disposition plays a part in the occurrence of the dis- ease, for the germ is easily destroyed by the acid gastric secretions, and infection is, therefore, most likely to occur when gastro-intestinal derangements furnish a favorable predisposition. Pathological Anatomy.—The lesions of this disease are found in the intestinal tract, and will be described in the appropriate section. Secondary lesions of other organs are met with in severe cases, and result from the circulation of toxic substances produced by the bacillus. Pathological Physiology.—A number of toxins have been isolated from the blood of cholera patients and from cultures. The exact nature of these and the relations of the several forms remain to be determined. It is certain, however, that toxins produced in the intestinal tract give rise to many of the symptoms of the disease. Injection of the filtrate of cultures causes collapse and other symptoms like those of the algid stage of the disease. The principal toxic substance seems to be closely attached to the organism itself (endotoxin), but a secreted extracellular toxin may also be found in the culture fluid when the organisms are enclosed in a collodion sac. The human or animal organism in some way develops immunizing or protective substances in the course of infection, and it has been found possible by a process of vaccination with cultures of gradually increasing virulence to protect animals and human beings from the disease. Haffkine’s protective vaccination of human beings yielded very encouraging results. He at first used an attenuated culture and then one of high virulence. The injections are made under the skin, where the spirilla soon die, but their bodies set up the antibodies. He inoculated 200,000 persons in India. Pfeiffer found that the serum of animals so vaccinated had a distinct action upon cholera spirilla, causing their agglutination or destruction, and possibly in this way exercising a protective influence. These antibodies may be used to diagnose a case of cholera, either by agglutination, like the typhoid Widal test, or by the Pfeiffer intraperitoneal test. The rapid and copious intestinal discharges of cholera lead to con- siderable inspissation of the blood, and doubtless contribute to the causation of some of the symptoms of the disease. Examination of the blood during the height of the malady may show greatly increased numbers of the red blood-corpuscles. DISEASES DUE TO BACTERIA 333 Organisms Resembling the Cholera Vibrio Spirillum of Finkler and Prior.—This organism was discovered by the investigators, whose names it bears, in the stools of a case of cholera nostras. It resembles the vibrio of Asiatic cholera in its shape and somewhat in its manner of growth and its production of the indol reac- tion. It differs, however, in being somewhat longer and more slender and in coagulating milk when this is used as the culture-medium. The growth upon gelatin is more rapid, so that within twenty-four hours in the case of a puncture-culture the liquefaction has proceeded so far along the puncture that an elongated sac-like excavation is formed, in which turbid liquid is contained. It has not yet been proved that this organism has an etiological relation to cholera nostras; its pathogenicity is improbable. Spirillum tyrogenicum is an organism discovered in old cheese by Denecke. It resembles the last-named variety very closely, and differs from the vibrio of cholera in liquefving gelatin quickly, though the rapidity is not so great as in the case of the Finkler and Prior organism. Spirillum Metschnikovii—This organism was discovered by Gama- leia in the intestines of chickens affected with choleriform disease. It is somewhat shorter and thicker than the cholera spirillum. In culture it resembles the vibrio of cholera very closely, though the trained bacte- riologist can easily distinguish them. The organism is non-pathogenic for man, but chickens, pigeons, and guinea-pigs are highly susceptible. Besides these spirilla or vibriones which have been discovered in various diseases, a number of organisms that resemble closely the spirillum of cholera have been found in the water of streams supplying the drinking-water of cities. Among these Neisser described the Sprril- lum berolinense, obtained from the water of the Spree in 1893. Dunbar and Oergel isolated a similar organism from the water of the Elbe, and a number of others of like character are known. ‘The relations, however, of the different forms to each other and the differentiation of these varieties have not as yet been definitely determined. Pathogenicity—Some of the forms described produce violent gastro-intestinal disturbance and death in a certain proportion of ani- mals prepared by injection of opium and alkalinization of the intestinal tract with soda and then fed with pure cultures of the organisms. They are evidently highly irritating bacteria, and some remote relationship seems to exist between them. ‘This, however, cannot be positively asserted. The separation of these forms from the true cholera spirillum is by no means easy. It is best done by the agglutination and bacteriolytic tests. For this purpose it is necessary to have the serum of an animal immunized against the cholera germ, and to this only the cholera spiril- lum will react. 334 A TEXT-BOOK OF PATHOLOGY DISEASES DUE TO SPIROCHETES SYPHILIS Definition.—Syphilis is a specific contagious disease of man, believed to be caused by the Spirocheta pallida or Treponema pallidum. The disease does not occur spontaneously in any of the lower animals. Etiology.—Many organisms have been described for this disease, the most discussed being Lustgarten’s bacillus and Schaudinn’s spiro- chete. The former is a large rod, said to lie in and between the cells of lesions, of general tubercle-bacillus-like morphology. It has not been cultivated. It has now been given up as the cause of syphilis. In 1905 Schaudinn discovered an organism in syphilitic lesions which he named Spirocheta pallida. Later during the same year and with the co-operation of Hoffman he was able to demonstrate the organ- ism in every case of uncomplicated syphilitic disease examined by him. The spirochete is described by Schaudinn (Fig. 118) as an extremely Fig. 118.—Spirocheta pallida from chancre, stained by Levaditi’s method; x 1500 (Bulletin No. 1, Medical Department, U. 8. Army, 1913). delicate, actively motile, faintly refractive, spiral, long, thread-like or- ganism, tapering at both extremities and terminating in pointed ends. It propels itself during life by rotating around its longitudinal axis, first in one direction and then in another. In the resting state undu- lating movements may be observed passing along the length of the organism, suggestive of an undulating membrane. In addition, bend- ing, twisting, twining, and whipping movements of the whole body may be noticed. The organism varies from 4 to 14 u in length, ranging in thickness from a size too minute for measurement to 0.25 « in the largest specimens. The spirals range from six to fourteen in number; they are reg- ular, narrow and deep, corkscrew-like, and appear constantly so, no matter whether the specimen be derived from initial lesions, papules, lymphatic glands, spleen, etc., or from the scleroses of apes. The curves are large DISEASES DUE TO BACTERIA 339 arcs of a small circle, while other spirochetes occurring with the pallida show smaller arcs of a large circle. By means of Léffler’s method of staining flagella a long delicate flagellum has been noted at each end of the organism; in some specimens two flagella at one end were seen, giving the appearance of an attempt at longitudinal division. Novy could find no evidence whatever of longitudinal division. Schau- dinn has failed to discover any signs of an undulating membrane or a nucleus in the stained specimens, though the latter has been reported by Wechselmann and Loewenthal in specimens examined with the aid of the ultramicroscope. At present there is some difficulty in distinguishing positively between the Spirocheta pallida and some common non-path- ogenic forms. Too much weight cannot, therefore, be given to the dis- covery of spiral organisms unless the investigator has had considerable experience. The Spirocheta pallida has been found in the initial lesions, the secondary papules, the enlarged lymphatic glands, the mucous patches, the secretions, blood, and lately, by Noguchi, in the parasyphilitic dis- ease paresis. Many of the most conservative authorities accept this as the cause of syphilis. As will be seen below practically all of Koch’s postulates have been fulfilled. Schaudinn maintained that the spirochetes are animal organ- isms belonging to the group of flagellates and proposed the name Treponema pallidum. The researches of Novy seem to be conclusive that this is not the case. He could find no evidence of an undulat- ing membrane, nucleus, or longitudinal division, and, on the contrary, only the transverse fission characteristic of bacteria. Wherever later studies place this spiral organism, certain characters have been made known by recent work suggesting its bacterial nature. It has now been cultivated by many persons after a technic elabor- ated by Noguchi. It grows anaérobically in colonies resembling those of bacteria and indicates its essential parasitic nature by requiring in this anaérobic culture fresh animal tissue. It does not require any intermediate stage to be infective, for, as we shall see, infection usually arises by direct contact, and, as the work of Noguchi has also shown, it will cause syphilitic lesions in rabbits’ testes by inoculation of cultures, or of fresh material from human lesions. Syphilis can be produced in the anthropoid apes by inoculation of fresh human material or cul- tures upon the skin, and a skin affection will result from the same treatment in the lower monkeys. When animals are infected with syphilis by experimental methods, the spirochete can be recultivated from their lesions. The cultures at hand develop a protein-like body whick has some relation to the infection, because when a sterile solution thereof is applied to an abraded skin area an inflammatory papule results. This is the so-called “luetin reaction,’ and it has been used as a diagnostic test. The results of this and the Wassermann or complement-fixation test (g. v.) indicate the active antibody forma- tion on the part of the body. Agglutinins are also formed. All of 336 A TEXT-BOOK OF PATHOLOGY these recently discovered features favor a classification among the spirochetes. Whatever the nature of the organism, it is quite certain that the disease is definitely infective. In the great majority of cases infection, occurs by direct inoculation in sexual intercourse. It may, however, be conveyed in many other ways. Physicians are sometimes infected in performing surgical operations or in examining syphilitic cases; persons have frequently been inoculated in the process of tattooing or vaccination when saliva or vaccine-lymph from diseased individuals was employed. Infection may be caused by kissing, or indirectly by the use of drinking-vessels which have been employed by the diseased. The newborn may be syphilitic in consequence of disease of the father or mother; and healthy wet-nurses may be infected by syphilitic nurslings, In addition to the specific cause, surrounding conditions and individual susceptibility doubtless play a part. During the Middle Ages this dis- ease at times and in certain places almost attained the character of a universal scourge. Its manifestations were severe, its course rapid, and in every sense its nature was malignant. Cases of this description are exceedingly rare at the present day. Pathological Anatomy.—The pathological course of this disease may be divided into three stages: the initial, the secondary, and the tertiary. The disease may abort at any stage, but such an occurrence is rare. Not infrequently, especially in women, the first and even the second stage as well may be overlooked. Chancre.—In the initial stage there is formed at the point of inocu- lation a primary lesion, commonly termed ‘‘chancre.”’ This may make its appearance first as a somewhat red and inflamed papule, or as a vesicle which ruptures and thus produces an erosion. When it begins as a papule the surface soon becomes eroded, and thus a superficial ulceration is established. The peculiar feature of this lesion, to which Hunter called particular attention, is its hardness or induration, and it is by this feature largely that it is distinguished from the soft chancre or chancroid. The initial or primary lesion may remain indolent or as a small erosion for a long time, or it may soon cicatrize and leave a more or less definite scar. The chancre occurs upon the glans penis or prepuce, or within the urethra of the male; and in the vagina, urethra, or upon the cervix uteri and external genitalia of the female. Extragenital chancres may be observed in the rectum or anus, on the lips or tongue, tonsils or pharynx, the fingers, or other parts. Secondary Lesions.—At the end of a variable period of time after the eruption of the initial sore secondary manifestations of the disease make their appearance. The spread at first follows the lymph-channels, but when once the infiltrative lesions of the blood-vessels begin, as in late primary syphilis, the dissemination is by the blood-stream. The first secondary lesions, as a rule, are swelling and induration of the neighbor- ing lymphatic glands (syphilitic bubo). Later the superficial lymph- - glands of the entire body become swollen and, like those in the neighbor- hood of the lesion, indurated. At the same time eruptions upon the skin DISEASES DUE TO BACTERIA 337 and mucous membranes make their appearance. The interval between the primary and the secondary manifestations is variable. Sometimes it is but a few weeks (three or four), at other times it may be several months. The manifestations of the secondary stage may begin with fever and constitutional symptoms, suggesting sudden and recent in- fection, and at the same time changes in the blood (rapid reduction of red corpuscles, moderate leukocytosis) make their appearance. Among the lesions of the skin various forms of papules, macules, and scaly eruptions are most frequent and characteristic. The lesions are usually symmetrically arranged on the two sides of the body and cause but little irritation. The color of the skin is frequently said to be somewhat coppery. On the mucous membranes and neighboring skin the most characteristic lesion of this stage is the condyloma latum, or mucous patch. This appears as a somewhat elevated patch with superficial erosion or ulceration. The surface has a necrotic appearance and may be cov- ered with more or less secretion. Fig. 119.—Gummata of the liver. Tertiary Lesions.—These may take the form of ordinary inflam- matory changes of the mucous membranes or of other parts, with a pronounced tendency to fibrous-tissue overgrowth and thickening, or of definite nodules—the syphilitic gummata, or syphilomata. Among the diffuse syphilitic changes of the tertiary stage may be ranked nodular thickening of the intima of the blood-vessels, certain changes in the liver, spleen, kidneys, and heart muscle, and also similar alter- ations in the nervous system. The localized lesions of the tertiary stage—the gummata—are most frequent in the bones (tibia, sternum, and skull); and in the in- ternal organs, such as the liver, lungs, kidneys, heart, and brain. The gumma presents itself as a nodular mass, varying in size from small tubercle-like formations (miliary gummata) to tumors the size of an orange or larger (Fig. 119). It is hard, and has frequently an elastic character, which has suggested the name “gummy tumor” or 22 338 A TEXT-BOOK OF PATHOLOGY “oumma.”’ On section, the substance is frequently found to be gelatin- ous or mucoid in appearance; but there is nearly always considerable induration, either peripheral, in the form of a capsular enclosure, or striate, in the form of bands extending from the center to the periphery and into the surrounding tissue. Occasionally gummata soften very rapidly and become converted more or less completely into puriform collections. When situated in the mucous membranes or adjacent to the surfaces of the body, suppurative, fatty, or necrotic softening may lead to the formation of superficial ulcerations. These may remain indolent or may gradually become cicatrized. Sometimes a gummatous lesion disappears entirely by absorption without leaving a trace of its ex- istence. The histology of syphilis is given on p. 145, among the specific infections, so that it is only necessary here to review the general features of the pathologic anatomy. The primary effect of the invasion of the spirochete is to injure the cells and incite round- and tissue-cell proliferation, followed by fluid and connective-tissue cell increase. The blood-vessels are attacked early and the spirochete characteristically excites endothelioid increase in all of the coats. The intimal changes are obstructive, leading to anemia and connective tissue replacement both in the vessel itself and the tissues supplied by it. The central necrosis of gumma is doubtless due to this. The fibrosis is largely due to the prolonged irritative effect of the spirals and to the débris of cellular destruction. Scars of considerable size are formed in the liver, brain, kidneys, etc., by the excessive scar tissue. The spirochetes seem to prefer those places where blood-supply and cellular activity are greatest, such as the bone-forming layer of the peritoneum and epiphysis and the sinusoids of the liver. Amyloid disease is frequently seen as the result of syphilis. Parasyphilis is a name given by Fournier to certain diseases, chiefly of the nervous system, in the clinical history of which syphilis is practi- cally always noted. The pathological lesions are similar but not identi- cal with those of syphilis, and some have doubted their luetic nature. Noguchi has lately found the Spirocheta pallida in the brain of paresis, a discovery which leaves hardly any doubt as to the syphilitic nature of this condition. He has, moreover, produced lesions in rabbits by in- jecting the brain of paretics. Pathological Physiology.—Syphilis is one of the most persistent of the infectious diseases, and occasions widespread changes that are doubtless toxic in character. The nature of the toxic principles, how- ever, is entirely unknown. In the tertiary stage pronounced anemia (cachexia) is frequent; and in the secondary stage rapid chloro-anemia with leukocytosis is quite common. Congenital Syphilis Syphilitic lesions may be found in the newborn or may develop some time after birth. Spirocheta pallida and histological changes DISEASES DUE TO BACTERIA 339 of syphilis have been found in the placenta. Not rarely they occur in the newborn fetus and cause its premature death. Frequently there is maceration of the fetus prior to expulsion. The infection is in the ovum when the mother is infected before conception, and in the placenta when infection occurs during pregnancy. Among the lesions ob- served, sclerotic changes in the lungs, liver, spleen, pancreas, and other organs are conspicuous; and a certain condition of the bones is quite characteristic. The latter consists of a hyperplasia of connective tissue and fatty degeneration at the junction of the epiphyses of the long bones with the shafts. Various superficial lesions of the skin in the form of vesicles or bullee, fissures, and the like may be observed. The blood may present considerable excess in the number of leukocytes. An almost distinctive condition of second dentition is that known as Hutchinson’s teeth. This consists of a notched indentation of the cutting surface of the upper central incisors. In addition, the teeth are often wedge Fig. 120.—Hutchinson’s teeth. shaped and peg-like (Fig. 120). All cases of inherited syphilis do not present this condition, and it occasionally occurs in non-syphilitic children. RELAPSING FEVER Definition.—Relapsing fever, or typhus recurrens, is an infectious disease caused by a specific organism which is found in the blood. There are four varieties, depending upon the biology of the spiro- chete concerned, but differing very little clinically: European relapsing fever, Spirocheta obermeieri; African relapsing fever, Spirocheta duttoni, transmitted by the tick Ornithodorus mou- bata; American relapsing fever, Spirocheta novyi; Bombay relapsing fever, Spirocheta carteri. The transmission of the first, third, and fourth is not known, but is probably due to some tick. Nicolle’s result would indicate that the human form may be transmitted mechanically by the louse, but not by the biting of this parasite. Spirocheta obermeieri is described as the type. Opinion is still divided as to the proper classification. Etiology.—The Spirocheta obermeieri is a flexible spiral organism with six to twenty curves, in length several times the width of the red corpuscle (16 to 40 “). It is found in the fresh blood, and presents active corkscrew, serpentine, and vibratory movements due to rotation and a flagellum-like extremity (Fig. 121). Recently it has been claimed by Schaudinn that this and other spirochetes belong to the group of flagellates (animal parasites) and are closely related to the trypanosomes. Novy’s investigations appear to have completely disproved this view. 340 A TEXT-BOOK OF PATHOLOGY The organism stains well with ordinary anilin dyes, but not by Gram’s, The relation of this spirillum to the disease can hardly be questioned, as it is invariably present and appears in the blood during the paroxysms of fever and disappears in the intervals, thus showing its relation to the symptoms of the C disease. In the case of Spirillum duttoni Ws the female tick bites, becomes infective in a GQ week, remains so all its life, and transmits “fe the virus to the young. All forms have now been cultivated by Noguchi in anaérobic Se wk SS cultures of defibrinated patient’s blood in © 6 Oo ascitic fluid agar to which fresh tissue has cep © Ge been added. They breed true to type. 7 o eh 4 The spirochetes may be transformed to Fig. 121.—Spirochwta ober- mice and monkeys. They are numerous in Tach. oT ae the blood during the fever, but rapidly dis- appear at the crises, due to the presence of a spirochetolytic substance in the blood. Immune bodies also appear and can be used to impart passive immunity to other animals. Pathological Anatomy.—The spleen becomes greatly enlarged; it frequently presents a variegated appearance on section, due to areas of anemic infarction and necrosis, or fatty degeneration alternating with deeply congested portions. The spirochetes can be found in this organ, particularly in cells. The lymphatic tissues are swollen throughout the body. Pathological Physiology.—The peculiar feature of relapsing fever, the one that has given it its name, is the recurring paroxysms of fever. The cause of this periodicity is as yet unknown, though it is likely that the development of the spirochete is such as to determine the relapses. 9 OSS @ @ VINCENT’S ANGINA This is an acute infectious, pseudomembranous and ulcerative form of pharyngitis and tonsillitis giving a grayish or greenish exudate. The process below the membrane is usually necrotizing and spreading, and may persist for a long time. There are constitutional symptoms and involvement of the regional lymph-glands. The organism of the dis- ease is found in two forms, the Bacillus fusiformis and the Spirillum vincenti. They are believed to be two forms of the same organism, as the spiral has been said to grow from the rod. - The rod is irregularly staining and pointed, 3 to 12 pw long by 0.3 to 0.8 u wide. The spiral is long, wavy, uniformly staining, flexible, and has pointed ends. The rod forms spores. The organisms are anaérobic, growing best upon ascitic fluid agar, on which they appear as minute gray colonies. Gas is formed in glucose media. Cultures have a fetid odor. The patho- genesis of the organism for lower animals is practically nil; no immunity reactions are known (Fig. 122). DISEASES DUE TO BACTERIA 341 Fig. 122.—The fusiform rods and spirilla of Vincent’s angina. Smear direct from throat. FRAMBESIA OR YAWS This is a tropical disease resembling syphilis in its primary indurated sore and secondary rash, caused by a spirochete (Spirocheta pertenur Castellani), similar to the Spirocheta pallida. The eruption is vellow- ish, papular, covered with crusts, and consists histologically of epi- thelial hyperplasia, in the form of papillomatous growths or extensions downward, associated with increase of leukocytes, plasma, and eosino- phile cells. The disease tends toward recovery, except in children and debilitated persons. The productive character of the lesions is not so marked as in lues. The disease has been transmitted to monkeys. DISEASES DUE TO HIGHER BACTERIA ACTINOMYCOSIS Definition.—A tinomycosis is a chronic infectious process char- acterized by inflammatory reaction of the tissues with a tendency to the formation of suppurative foci, and due to the specific action of a micro-organism, the Actinomyces bovis. Etiology.—Actinomycosis is a disease of cattle, horses, swine, sheep, the llama, the elephant, deer, dog, and occasionally of man. The specific cause of the disease is an organism which occurs in the tissues in the form of clusters having a radiate structure, and it has, therefore, been termed the “ray fungus.” These clusters may be so small as to be invisible to the naked eye, or they may reach considerable dimensions by their growth and aggregation. _ The central part of the 342 A TEXT-BOOK OF PATHOLOGY cluster frequently has a granular appearance, suggesting a mass of micro- cocci. Reaching out from this may be seen more or less regularly diverg- ing strize or rays, and the periphery is composed of what appear to be bulbous extremities of the rays (Fig. 123). Bostroem, in 1890, and Wolff and Israel, in 1891, published notable articles on actinomycosis and respectively isolated an aérobic and an anaérobic growth. The relation of the former to actinomycosis has, however, been disproved, while the anaérobic growth alone is important. The aérobe of Bostroem was ap- ee i aaa -." parently a contaminating organism SP EN as cram ame ~ related to the branching organisms ae ee : which occur in the outer world, and that have been variously classified as streptothrix, cladothrix, etc. As these occur on various grains and on the spears of the oat seed, etc., Bostroem believed that the organ- ism was derived from such sources. More recently accurate studies like those of Wright (Jour. Med. Re- search, May, 1905) seem to have dis- proved the connection of the aérobic es organism and to have established me er ea eee een the independence of the true actino- myces from the group of branching organisms referred to. Wright insists that these should be classified as a separate genus under the name of Nocardia. Cultivation of the Organism.—Growths have been obtained upon sugar-agar, in bouillon, and various other media. Suspension cul- tures in dextrose or glucose sugar show in the course of two to four days scattered colonies in the depth of the agar and a very few within 5 to 10 mm. of the surface. A shallow zone of closely set colonies giving the appearance of a dense cloudiness in the media and about 2 to 4 mm. wide is generally found at a point about 5 to 10 mm. below the surface. Below this zone the colonies are more scattered. The growths are essentially anaérobic, and grow best at body tem- perature. Under the microscope the smaller colonies are found to be spherical masses of branching filaments radiating from the center. The branching is true branching and increases as the colony grows older. In stab-cultures in sugar-agar the growth appears as a dense gray streak or line of small nodules in the deeper parts of the stab. No growth occurs near the surface. In bouillon, solid white masses form at the bottom of the tube; none appear near the surface. In bouillon the growths occur both under aérobic and anaérobic conditions, but in the case of the former Wright suggests that on account of the compactness of the masses there are really anaérobic conditions within the colony. : While this anaérobic organism may be the most important one In het is dae DISEASES DUE TO BACTERIA 3843 actinomycosis, an aérobic growth has been cultivated, and it seems that both forms may cause the disease. The cultivation of these organisms presents unusual difficulties, owing chiefly to the frequent presence of other bacteria in the lesions, which usually grow more rapidly and more luxuriantly than does the specific organism. In a few cases pure cultures were obtained by planting the granules directly in bouillon. In some instances of contamination, by allowing the tube to stand for several days, the contaminating organisms died out and transplants then vielded pure cultures. Generally sugar-agar was the medium employed for isolation of the micro-organism. It grew well only in agar and bouillon cultures and in the incubator at 37° C. (98.6° F.). In the other usual cultural media and at room temperature it grew very poorly or not at all. It was essentially an anaérobe, and did not form spore-like reproductive elements. In cultures its colonies were similar in character to those in the lesions. The vitality of the micro-organism was variable. In general, it did not seem to survive as long in cultures as when dried on the sides of test-tubes. It was killed by exposure to a temperature of from 60° to 64° C. (140°-147.2° F.) for ten minutes. The micro-organism stained well by Gram’s method, the clubs losing the stain and taking the contrast stain; it is not acid fast to Gabbet’s decolorizing solution after staining with carbol-fuchsin. The filaments of colonies immersed in animal fluids, such as blood- serum and serous pleuritic fluid, may under certain unknown conditions become invested with a layer of hyaline eosin-staining material of vary- ing thickness and the filament may then disappear. Thus structures are produced that seem to be identical with the characteristic ‘clubs’ of actinomyces colonies in the lesions. Pathogenicity.—Inoculation experiments on animals with cultures of the micro-organism result in producing in the tissues of the inocu- lated animal characteristic ‘‘club’’-bearing colonies. This club forma- tion Wright is inclined to believe represents a kind of protective mem- brane for the mass of the colony against the destructive action of the juices and cells of the tissue. After the inoculation of animals nodular lesions and in some instances relatively extensive lesions were produced. They, however, showed little tendency to progress and only in a few cases did multiplication of the organism in the body of the animal seem probable. In other words, these results simulate closely the negative or ambiguous results obtained by other observers who inoculated animals with the lesions of actinomycosis. It would seem, therefore, probable that the micro-organism in the cultures was identical with the micro-organism in the lesions. Wright recognized but one micro-organism as the characteristic in- fectious agent in typical actinomycosis, and applies to it the generic and specific name of Actinomyces bovis, as given by Bollinger and Harz. There is not sufficient difference between the actinomyces from the human and bovine cases to justify their classification as separate species. . The manner of infection with the actinomyces is not completely 344 A TEXT-BOOK OF PATHOLOGY determined. Formerly it was thought that the parasite was carried to the tissues by various vegetable substances, particularly the spears of the oat-seed and other grains. Sometimes these have been found embedded in the lesions; in other cases splinters of wood have been discovered. The fact that the organism prefers anaérobiosis and grows Fig. 124.—Actinomycosis of the jaw-bone of an ox. The dark areas and the broken-down part in the center of the picture are foci of the disease. The whole bone is enlarged. only at body temperature tends to disprove this view, and it is likely that the actinomyces is a normal inhabitant of the mouth and gastro- intestinal tract and always derived from these sources, although, of course, infection by infected grain or communication with infected animals or persons can transmit the disease. Carious teeth and lesions of the mucous membranes may play a part in the etiology. DISEASES DUE TO BACTERIA 345 Pathological Anatomy.—The pathological changes induced by the actinomyces consist of round-celled infiltration and _ proliferative changes in the connective tissue surrounding the parasite, and some- times secondary softening, necrosis, or suppuration. The granulation tissue of actinomycosis is especially rich in leukocytes, and not infre- quently these form dense foci, which later develop purulent collections. In cattle the disease affects the lower jaw, less frequently the upper jaw or other bones; the tissues of the neck, the tongue, and other parts. In man it is met with in the gums, the cheeks, and floor of the mouth; in the lungs, intestines, and other internal organs. The naked-eye appearance of the lesions may first be simply that of a hard red papular formation, with more or less induration surrounding it; later this tends to increase in size and may break down, forming necrotic or suppurative excavations. The process of repair or cicatrization may proceed in some parts to the extent of almost complete repair, while the suppura- tive or necrotic change advances in other directions, and thus cavities and irregular communicating sinuses are established. The part in which the disease exists may be considerably disfigured and much enlarged. The pus or necrotic material within the lesions contains peculiar granular ‘bodies, the “sulphur granules” or actinomycosis bodies. The sand-like or sulphur granules measure 0.2 to 0.6 to at times 1.2 mm. They are of a gray, yellow, green, to red color; when young, soft; when older, much tougher in consistency. Occasionally calcification of the diseased area may take place. When the jaw-bone is affected the disease, as a rule, begins abeut carious teeth, fistulee communicating with the roots of teeth (Fig. 124). In the case of disease of the lungs some have observed a preliminary catarrhal inflammation of the bronchi. More frequently, however, there are from the first nodular areas of bronchopneumonia, which tend to undergo changes similar to those already described. The sur- rounding lung tissue frequently becomes indurated from interstitial pneumonitis. Extension may occur to the pleura, pericardium, and mediastinal tissues. In the case of actinomycosis of the intestinal tract there are first elevations of the mucous membrane, the disease involving the mucosa and the submucosa. Subsequent softening of these leads to the forma- tion of ulcerations. Extension to the peritoneum and to the other organs of the abdomen may take place. In any case of actinomycosis a penetration of the blood-vessels or lymph-channels may lead to metastases. Thus in actinomycosis of the abdominal cavity the liver is frequently involved; and other parts of the body may be similarly affected. Actinomycotic lesions of the brain (abscesses) are sometimes seen in such instances. In other cases of cerebral involvement there may be no evidence of the original focus or point of entrance of the germ. Microscopically, the characteristic feature of this disease is the parasite itself surrounded by lymphoid cells in considerable numbers, with some epithelioid cells and occasionally giant cells. When the 346 A TEXT-BOOK OF PATHOLOGY process tends to a favorable termination by cicatrization, fibrous-tissue formation proceeds in the usual manner. Pathological Physiology.—The actinomyces is mainly active as a local parasite, the general disturbances of health being comparatively slight. There is a marked tendency to limitation or retardation of the disease, and sometimes this is effected completely. MYCETOMA Mycetoma, or madura-foot, is an infectious disease occurring in India and elsewhere, and probably caused by several organisms, cer- tainly two, grouped under the name Streptothrix or Actinomyces madure. Babes asserts that the black variety is due to a mucor or asper- gillus. The disease is not infrequent in Madura, Delhi, and other parts of India, and has been observed in Africa, south- ern Europe, and America. Etiology and Pathological An- atomy.—As its name indicates, the dis- ease affects the foot, and usually follows injuries, particularly thorn wounds. In rare cases the hands or other parts are affected. At first there is nodular in- flammatory swelling, beginning on the plantar surface or dorsum of the foot and spreading to the sides. These swell- ings are hard and painless. Later, soft- ening occurs and rupture takes place. Thin, watery pus is discharged, and this contains grayish or reddish granular bodies or black granules resembling par- ticles of gunpowder. In the former case the term “pale mycetoma” is ap- plied; the latter variety is called black = - or melanoid. In the later stages of the on F125. Streptothrix madure disease discharging sinuses may remain, iseased tissue (Vin- . : cent). while newer nodules, in turn, are formed and soften. Finally, the member af- fected becomes greatly deformed, the portions not involved growing thin, while the diseased part increases in size. Death occurs from ex- haustion or complications. Histologically, the nodules resemble large tubercles, but are highly vascular. The bulk of the growth consists of granulation tissue cells, those in the center being small, those near the outer edge often large and containing two or more nuclei. True giant cells are rare. In the center may be found a branching micro-organism, called Streptothrix madure (Vincent). This stains by Gram’s method, and sometimes shows some- what bulbous swelling of the ends of the threads and their branches (Fig. 125). The mycelia of the black variety of mycetoma are described DISEASES DUE TO BACTERIA 347 by Laveran as thicker and coarser than those of the pale form, and he believes the organisms are of a distinct variety or species. Around the organism may be seen an area of degeneration, having a striate arrange- ment suggesting that seen in actinomycosis. Extensive degeneration and pus formation occur in the center of the diseased areas in the later stages; and hemorrhage may occur from the new blood-vessels. Histo- logical examination of the granules in the pus shows the micro-organisms in the form of interlacing threads. Bodies resembling spores have occasionally been described. The organism has not as yet been definitely classified. It is cer- tainly allied with the actinomyces, but probably not identical. It has been cultivated upon various media, particularly infusions of hay and the like, rendered slightly acid in reaction. It forms small nodular and hard growths, which become rose-red in color when they cling to the sides of the test-tube near the surface of the liquid, or brownish when they sink to the bottom. Upon agar isolated grayish or, later, rose-red clusters are formed. Inoculation experiments have thus far met with little success. Local reaction has been so produced, but not a definite disease. Several investigators have reached the conclusion that there are two or more kinds of micro-organisms that have an etiological relation to cases of Madura foot. It has in particular been suggested that the white and black varieties of the disease have a distinct bacteriology. These views need further confirmation. THRUSH This condition occurs in newborn infants and in older children or adults who have become weakened by disease. The organism called Oidiwm albicans is a budding fungus, though some believe it a form of mould. If some of the milky de- posits on the mucous membrane of the mouth which characterize the dis- ease be removed and examined mi- croscopically, mycelial threads and conidia are observed. The organ- ism may be cultivated upon gelatin plates, in the form of whitish colonies on the surface, or granules with radi- ating processes in the depth of the medium. On potato and on bread . itformsa white coating. The organ- ism is present in the air and in vari- Fig. 126.—Thrush fungus (Endomyces ous articles of food, so that infection albicans) (Kolle and Wassermann). readily takes place. The organisms first grow upon the surface of the mucosa, but later may penetrate to considerable depth, and may attack blood-vessels. If this occurs, metastasis may result, with abscesses in different organs, notably brain and kidney. 348 A TEXT-BOOK OF PATHOLOGY SACCHAROMYCOSIS OR BLASTOMYCOSIS This is a subacute infection, chiefly of the skin, caused by forms of yeast, Saccharomyces hominis or S. busse. There are probably several different species capable of setting up infection, but their action is essentially the same. Saccharomyces tumefaciens and Blastomyces dermatitidis are also names given to yeasts causing disease in the skin. The yeast is a rounded or elongated (up to 30 «), doubly contoured, highly refractile body, with vacuolated, granular or clear cytoplasm; multiplication occurs by budding. The organisms are best stained by polychrome methods. They grow with difficulty and require carbo- hydrates. They are most easily obtained by inoculating guinea-pigs under the skin and culturing the pus. They produce an active cellular © rat Op ae 66% Fig. 127.—Blastomyces in pneumonic exudate (from a photograph by Dr. S. S. Kneass). exudate in which fibrin is abundant. Necrosis is common. A toxin of moderate potency is produced. The lesions are said to be primarily cutaneous or pulmonary, although some question the latter. The spread is probably hematogenic, as scattered abscesses and osteomye- litis may occur. The lesion is usually a mixture of suppuration and granulation tissue (see p. 148). The disease may be transferred to the lower animals. No immunity reactions are of value. Coccidiosis, or Oidiomycosis, is an acute infection due to the Coccid- ioides immitis, an organism closely related to the Oidia, and has some of the characters of both the classes, Blastomyces and Hyphomyces. It is a doubly refractile circular body in the tissue, occasionally growing out into mycelia, and always doing this in cultures. It develops by intracellular sporulation and not by budding. The infection usually DISEASES DUE TO BACTERIA 349 has its seat in the skin, but may become generalized. The lesion resembles a tubercle in the cellular and degenerative characters. Eosin- ophiles may be present. Sporothricosis.—This is a disease consisting of cutaneous eruptions and multiple abscesses, usually in the skin, but not infrequently in the mucous membranes, muscles, tendons, and mammary gland. It is caused by the Sporothrix beurmanni, after the investigator who first accurately described it. The organism appears in several slightly different varie- ties. It occurs in lesions as round or oval yeast-like bodies, but on cultivation shows long mycelial threads from which grow yeast-like spores or gonidia. The spore body measures 3 to 6 by 2 to4 u. In the tissues usually only the yeast-like stage is seen, but short mycelia may form. The organism is aérobic and requires the presence of carbohy- drate for its growth. The disease is subacute. In addition to the above-mentioned lesions, the mould may produce a nodular lymph- angitis in man as it can in the lower animals. A disseminated form with the moulds in the blood is reported and considered a grave condition. The disease is transmissible to the lower animals. The blood contains an agglutinin and a complement-fixing body against the mould. For histology of the lesions, see p. 149. Dermatomycosis.—Besides the above infections, there are several moulds which infest the skin and produce more or less specific reactions of clinical rather than pathological importance. The following skin diseases are included under this heading: Favus, caused by Achorion schénleinti; ringworm, including Tinea tonsurans, Tinea sycosis, Tinea circinata, and Tinea versicolor, due to varieties of the genus of moulds Trichophyton. The moulds infest the epidermis or penetrate the gland ducts. Their action is to cause the epithelium to degenerate and desquamate, while a round and polynuclear cell invasion occurs in the dermis. There is little specificity pathologically. Granuloma pyogenicum, or human botryomycosis, is a granulating pyogenic and ulcerative condition of the dermis, penetrating to the sur- face, said by some to be due to bacteria, but lately ascribed by others to an intracellular protozoén-like body. OTHER BACTERIA NOT CAUSING SPECIFIC INFECTION THE HEMORRHAGIC DISEASES These diseases constitute a group of affections of probably quite divergent character, which, however, are similar in presenting hemor- rhages in and from the mucous membranes, in the skin, serous sur- faces, and in the deeper tissues or organs. The general causes of hemorrhage must be considered in connection with these diseases. Among the causes capable of producing hemor- rhages such as occur in the hemorrhagic diseases are mechanical condi- tions, as atheroma or other diseases of the walls of the blood-vessels; torte conditions, such as poisoning by the venom of animals and by various blood-poisons, and probably obscure poisons produced in the 350 A TEXT-BOOK OF PATHOLOGY course of anemia or other diseases; infectious conditions, such as occur in hemorrhagic variola, scarlatina, ete.; and nervous conditions, as are illustrated in the hemorrhages following injuries to the brain and those accompanying certain states of cerebral excitation. Clinically, the hemorrhagic diseases or purpuras may be classified as primary and secondary, the former occurring without any definite preceding disease; the latter being symptomatic of various disorders. Among the primary there are: (1) infectious forms, including, with more or less probability, purpura, scurvy, and various forms of crypto- genetic sepsis; (2) toxic forms, as those due to drugs and venom of ani- mals; (3) mechanical forms, as, perhaps, hemophilia, to the extent that vascular weakness may be a factor. Among the secondary purpuras are: (1) infectious forms, as scarlatina, variola and the like; (2) mechan- ical forms, as those due to cardiac and arterial diseases, or embolism; (8) torte forms, as those resulting from intestinal auto-intoxications, jaundice, pernicious anemia, etc.; and (4) nervous forms, as those due to hysteria, diseases of the brain, etc. The underlying conditions in cases of infection whose most im- portant manifestation is hemorrhage are to be sought first in the blood- vessels and then in the blood. In the former case the poison has a dele- terious effect upon the permeability of the blood-vessels, while in the latter hemolysis occurs in the blood-stream; thus escape is easy. It is probable that the two actions are to be found in all hemorrhagic con- ditions. The hieiaiee purpuras interest us particularly in the present place. Various micro-organisms have been found in different forms of hemor- rhagic disease. Kolb described a bacillus pathogenic for animals which occurred in 5 cases of hemorrhagic purpura. Babes and Oprescu isolated a bacillus from one case of hemorrhagic septicemia, and others have found various micrococci, especially the streptococcus. It is not un- likely that various micro-organisms may assume a peculiar virulence and acquire the power to produce hemorrhages under certain circum- stances. Some recent investigations seem to indicate that scurvy is a tox- emia due to poisons generated in preserved meat foods as a result of autolysis. In scurvy, however, several micro-organisms have been described, but the one which has the best claim for consideration is that discovered by Babes, a delicate bacillus occurring in the gums. Streptococci were found in association with it. Some Japanese investi- gators have recently claimed to have discovered a specific bacillus in the blood and viscera, agglutinable by the serum of scorbutic patients. Present indications, however, do not very strongly substantiate the probability of a bacterial cause for this disease. PROTEUS INFECTION The Bacillus proteus and its several subvarieties occur in decom- posing animal matter and in association with necrotic and gangrenous DISEASES DUE TO BACTERIA 351 processes in the living body. The organism is a small, motile bacillus, occurring in pairs and less often in chain formations. It is abun-_ dantly supplied with flagella. — Cultivation and Demonstration.—The organism grows very well at ordinary temperatures, and forms characteristic growths on gelatin- plates. At first yellowish colonies with outgrowths are formed; the gelatin liquefies, and the outgrowths move about in a tortuous manner and become separated from the original growth. Peculiar figures are formed, and the term Bacillus figurans has been applied. The cul- tures have a putrid odor. The organism is readily stained with ordinary solutions like carbol-fuchsin. Pathogenicity.—Injected intravenously in animals, hemorrhagic vomiting and diarrhea result. In man the bacillus has been found asso- ciated with phlegmonous inflammations, gangrenous processes, cystitis, pyelitis, and in infectious icterus (Weil’s disease). It is sometimes the cause of meat poisoning. INFECTIOUS DISEASES WHOSE CAUSE IS NOT CERTAINLY KNOWN. FILTERABLE VIRUSES YELLOW FEVER Definition.—Yellow fever, or typhus icteroides, is now recognized as infectious and transmissible through the bite of a certain form of mosquito, the Stegomyia fasciata or calopus. The specific organism has not been identified. Etiology.—Many different organisms have been described as the cause of yellow fever, most prominent of them being the Bacillus icteroides of Sanarelli. It seems now that none of the many is of any importance whatever, as the disease is transmitted by mosquitoes in which no bacillary form of infective agent has been found, and because the virus is filterable. The Réle of Mosquitoes—The experiments of Reed, Carroll, and Agramonte demonstrated the importance of mosquitoes as agents in the transmission of the disease. It was definitely proved by Reed and his associates that a special form of mosquito, the Stegomyia fasciata, carries the contagion from one person to another. The germ must pass a certain incubation period in the body of the mosquito, as the bite of the latter is not found to cause infection until after an inter- val of twelve days or more from the time it has fed on the yellow-fever patient. A bite at an earlier period after contamination did not confer immunity against a subsequent attack of the disease. This indicates that a cycle of development must occur in the mosquito. Without the Stegomyia fasciata there can be no yellow fever, as there can be no malaria without Anopheles. The mosquito must feed on a yellow-fever patient during the first three days of the fever, and after the twelve-day period is infective for at least fifty-seven days. The spread of the disease is checked by preventing the mosquito from biting patients or by its whole- 352 A TEXT-BOOK OF PATHOLOGY sale destruction. The blood of patients is infective even after passage through a Berkefeld filter. One attack confers immunity. Experiments were conducted directly on non-immune volunteers, and the transmissi- bility of the disease was positively proved. The incubation period of the disease, the time elapsing from the time of the mosquito’s bite up to the first definite symptoms, varied from forty-one hours to five days and seventeen hours. The results of the practical measures of quaran- tine instituted at Havana in accordance with Reed’s work—destruction of all mosquitoes and careful exclusion of mosquitoes from the patients, with entire disregard of clothing, bedding, etc.—show that the disease is not directly contagious. Non-immune nurses attend yellow-fever patients with impunity. The disease can also be transmitted experi- mentally by subcutaneous injections of blood taken from patients in the first and second days of the disease, which proves the presence of the parasite, in the blood at least, in the earlier stages of the disease. The passage of the parasite through an intermediary host is, therefore, not essential. In this respect yellow fever resembles malaria. Pathological Anatomy.—The lesions of this disease are mainly those of the internal organs—liver and kidneys. In the liver extensive fatty degeneration leads to swelling and light color of the organ, and on section there may be a mottled appearance due to the alternation of healthy and fatty areas. In the kidneys degenerative changes of the parenchyma and extravasation of blood are associated in varying pro- portions. The appearance may be that of an acute hemorrhagic nephri- tis or, more particularly, that of degenerative nephritis. Hemorrhages in the mucous and serous surfaces are frequent, particularly extravasa- tions in the mucosa of the stomach. Pathological Physiology.—The organism of yellow fever probably produces abundant toxin. MEASLES? Measles, or rubeola, is an infectious and contagious disease, in all probability due to some micro-organism. A number of micro- organisms have been described. Several observers (Canon and Pielicke, Czajkewski) have found a bacillus somewhat resembling that of in- fluenza; others have found bacilli resembling the pseudodiphtheria bacil- 1 Certain investigators have discovered bodies having some of the appearances of protozoa in measles, scarlet fever, pernicious anemia, leukemia, sarcomata of various sorts, and in a number of other diseases. "These observations, however, do not merit further discussion in this place. Future investigations must decide whether they have been accurate or not. Mallory (Jour. Med. Res., January, 1904) found in the skin of 4 cases of scarlet fever, dying in the early stages of the disease, certain bodies which in their morphology suggest that they may be various stages in the developmental cycle of a protozodn. They were found once in small numbers in the epidermis of the tongue. They were not present in the skin of 6 cases dying in the early stages of the disease, nor in a number examined in the desquamative stage. They occur in and between the epithelial cells of the epidermis, and free in the superficial lymph-vessels and spaces of the corium. There are in addition to these forms larger coarsely reticulated forms which may represent stages in sporogony or degenerations of the other forms. : The name Cyclasterion scarlatinale has been proposed by Mallory for this organism. These and other protozoén-like bodies, such as described by Doehle, Ross, and others, are now considered by many writers as belonging to the Chlamydozoa. DISEASES DUE TO BACTERIA 353 lus, but the bacteriology is still unsettled. Doehle described a protozoan organism occurring in the blood. Hektoen has inoculated healthy per- sons with the blood from cases of measles and has demonstrated the transmissibility. The disease is at present regarded as due to an ultramicroscopic virus which will pass through a porcelain filter. The virus is present in the blood, buccal and nasal secretions, and can be transmitted to monkeys, in which it produces an atypical infection. It may be found im the blood before the Koplik spots or eruption appear. It has not been cultivated. Mild catarrhal inflammations of the faucial, nasal, and conjunctival membranes and of the bronchial mucosa are customary lesions. With these conditions is associated some congestive and inflammatory enlarge- tment of the regional lymphatic glands. In severe cases pseudomem- branous inflammations of the throat are sometimes met with, and bronchopneumonia and parenchymatous nephritis are occasional complications. The eruption of the skin is the visible evidence of a moderate dermal and subdermal inflammation. Focal necroses of the liver have been described. Many of the lesions are doubtless caused by secondary infections. SCARLET FEVER Scarlet fever, or scarlatina, is an infectious and contagious disease probably due to a micro-organism. A variety of organisms have been discovered in cases of scarlet fever, but none as yet has proved to be specific. Among other bacteria the pyogenic micrococci (streptococci) have been regarded as etiological agents. This, however, is by no means established. Protozoan organisms have also been described (Doehle). Mallory has described under the name of Cyclasterion scarlatinale! structures which present the appearance of protozoa. The virus is now believed to be filterable and ultramicroscopical. An atypical infection is produced in monkeys by injection of a patient’s blood during the height of the attack. The claim that scarlatina is due to streptococci or to the leukocyte inclusion bodies of Doehle cannot be substantiated. Lesions of the mucous membranes and glands similar to those of measles, but usually more intense, are generally present. Suppuration of the glands of the neck is a possible termination, and severe inflam- mations of the throat, middle ear, larynx, and trachea, with endo- carditis or pericarditis, are much more frequent than in measles. Many of these complicating conditions are caused by secondary infection with the Streptococcus pyogenes. Diphtheria (as contrasted with streptococcic lesions of the throat presenting a similar appearance) is not rare as a complication. Parenchymatous nephritis is a lesion of great clinical interest, while focal necroses of various organs are observed in fatal cases. 1See note, page 352. 23 354 A TEXT-BOOK OF PATHOLOGY MUMPS The bacteriology of mumps is uncertain. Charrin and Capitan isolated a number of organisms, mainly micrococci and motile bacilli. A number of other authors subsequently obtained similarly indefinite results. Laveran and Catrin in 1893 found a diplococcus. The pathology of mumps is that of an acute inflammation of the parotid or submaxillary gland. This rarely terminates in suppuration or, on recovery, in induration of the gland. VARIOLA AND VACCINIA A number of bacteria have been described from time to time in. these diseases, and various micrococci in particular have been found in the pustules, but none of these can be considered as specific. Several bacilli, one form resembling the diphtheria bacillus, have been recently described. In 1887 Pfeiffer and van der Loeff independently described a proto- zoan parasite of the order Sporozoa, which occurs in the cells of the rete. This organism was found in variola as well as in vaccinia. Pfeiffer, Guarnieri, and other investigators found that by inoculation of the cornea of rabbits large numbers of the supposed parasites make their appearance in the epithelial cells. These organisms are rounded bodies lying in the protoplasm of the cells, sometimes singly, sometimes in groups of two or three. Slow ameboid movements are visible and the organisms present one or more nuclei. Spore formation has been ob- served by several investigators. Guarnieri suggested the name Cytoryctes variole seu vaccine. Councilman, Magrath, and Brinckerhoff in 1903 confirmed the find- ings of Guarnieri in 1892 and of Wasielewski some years later as to cell inclusions in lesions of vaccinia and variola. They look upon them as living organisms and the probable etiological factor of vaccinia and variola. In vaccinia the cytoryctes occurs as a structureless mass in the cytoplasm, where it is thought to undergo asexual division by break- ing up into small round segments. In variola the parasite is said to invade the nucleus also, undergoing there segmentation into ring-like bodies; this is supposed to be the sexual phase. The formation of the exanthem may be due to the infected endo- thelial cells of the capillaries or lymph-spaces being carried to the skin capillaries by the blood-current. No differential method of staining has as yet been offered. The nature and significance of these supposed organisms have not yet been positively determined. Some authorities, as Ewing, look upon them as products of cell degeneration. Lately the view has been defended that they are the Chlamydozoa of Prowaczek, probably due to a virus acting upon the chromatin, with lysis thereof. Secondary infections with various micrococci or other organisms are common in small-pox and vaccination, and may play an important part in pustulation, and in the more definite complications, such as DISEASES DUE TO BACTERIA 355 septicemia, pneumonia, hemorrhagic septicemia, erysipelas, and the like. Councilman, in discussing the relations of variola vera, vaccinia, and variola inoculata, points out that vaccinia differs from small-pox in three ways: first, the period of incubation is shorter, being five days in man and three days in calves, while that of variola is twelve days. Second, in vaccinia the general eruption is absent. Third, for the de- velopment of vaccinia the virus must be placed in contact with a suscep- tible epithelial surface, and cannot be carried by the air. In his studies of 52 autopsies careful study was made to determine the existence of a primary variolus pustule from which the general infection might have occurred. None was found, nor are there any symptoms of such a primary lesion. Nevertheless, a simple pox, in the lungs, for instance, might occasion no distinctive signs. He believes that the infection passes through the air and enters the system through the _ lungs. The virus is filterable through porcelain in diluted condition. Regarding immunity conferred by vaccination, he states that all the evidence goes to show that it is due to germicidal power of the blood-serum which enables the serum to destroy the virus of vaccinia and small-pox. VARICELLA The etiology of chicken-pox is even less definitely determined than that of small-pox. Pfeiffer discovered the same organism described by him in vaccinia and variola. Bacteria of one sort or another have been occasionally found. TYPHUS FEVER An acute epidemic disease attended with a fairly typical clinical course and macular eruption, supposed to be transmitted by the louse, Pediculus vestamenti. The virus is found best in the blood toward the end of the disease, is filterable, and may be transmitted to monkeys. Many different organisms have been discovered and described, but none are now believed to be the real cause. The organism now receiv- ing most attention is a non-motile rod with a palely staining central area, circulating in the blood. It is said to grow feebly under anaérobic conditions if cultures are made between the sixth and ninth day of the attack. It will act as an antigen in the complement fixation series. The severe typhus of Mexico is called ‘“‘tabardillo.” There is a mild infection called “Brill’s disease,’ after the observer, believed to be a sporadic form of typhus. It has been observed among the Hebrews of New York and other American cities. The lesions of typhus fever suggest an intense infection and in- toxication. The blood is often dark-colored and rapidly putrifies. Various organs, such as the liver, kidneys, and heart, show pronounced cloudy swelling or fatty degeneration of the cells. The spleen is notably enlarged, often quite soft, and may present infarctions due to thrombus formation. 356 A TEXT-BOOK OF PATHOLOGY Inflammations of the mucous membranes, especially bronchitis, pharyngitis, and laryngitis, are common, and pneumonia is a frequent result. RABIES Etiology.—We have every reason to believe that rabies is due to a specific germ. In 1903 Negri described an organism which has received considerable recognition as the probable specific cause of the disease. The ‘Negri bodies’ have been found in the large nerve-cells of the central nervous system, especially in the cornua ammonis, in various animals and human beings affected with rabies. ‘They are absent in other conditions. In early stages of the disease the bodies are sparsely present and are exceedingly minute structureless spherules lying in the protoplasm of the nerve-cells. Later the bodies increase in number and size and contain one or more darkly staining granules. Stained by the Nocht-Romanowsky method the bodies are robin-egg blue, the granules darker in color. Virus.—In rabic animals the virus is found principally in the saliva and in the central nervous system. It is occasionally known to pass into other organs, such as the lacrimal gland and the pancreas. It is never found in the blood or in the liver, spleen, kidney, or the muscle tissues. The contents of the stomach may contain it, owing to the swallowing of the saliva. It affects principally the central nervous system, and is found in the most concentrated form in the medulla oblongata. The virus may be present in the saliva for at least three days before the animal shows any symptoms of madness, and it may be present eight days before any symptoms appear. It may be present in the central nervous system two days before the appearance of any symptoms. The symptoms do not show themselves until the poison or virus has remained in the nervous tissue long enough to produce structural and functional change. After it is introduced into the body it undoubtedly “multiplies itself’ during the period of incubation. It is a ‘‘solid body,” as it may be removed from the saliva by filtration through porcelain. There is, however, almost undoubtedly a stage of development of the virus when it is small enough to pass through porcelain. An emulsion of brain of an infected dog will give a filtrate infective for rabbits. It is found in human milk, tears, aqueous humor, and cerebrospinal fluid. The virus penetrates to the nervous system by following the nerve-trunks from the site of injury to the spinal cord. This has been proved by com- parison of portions of the cord and of the nerves at varying periods after ee The virus is destroyed by drying and by the action of ight. Noguchi has lately demonstrated that the virus of rabies may be cultivated upon anaérobic serum-cultures. It takes the form of minute masses of chromatin surrounded by a clear zone and a membrane, and as very minute granular and somewhat coarser pleomorphic chromatoid bodies. The former multiply by budding and division and suggest - DISEASES DUE TO BACTERIA 357 protozoa. Similar pictures may be found by dark-field examination of hydrophobia brains. The bodies are from 1 to 12 yu across. The loss of virulence by drying is gradual and regular; hence this is taken advantage of for the production of “vaccine.” The virus is com- pletely destroyed at a temperature of 50° C. (122° F.) in one hour. It remains uninjured by exposure to extremes of cold—10 or 20 degrees below zero. The Danger from Bites —The richer the nerve-supply, the greater the danger, and punctures are more dangerous than lacerated wounds. The wolf, the cat, and the dog, in the order named, are the most dan- gerous animals. Period of Incubation—Man, forty days; cats, fourteen to twenty- eight days; dogs, twenty-one to forty days. Other animals vary from fourteen to fifty-six days. The Season.—More frequent during the period from April to Sep- tember than any other part of the year. Preventive Inoculation—Pasteur devised a method of treatment which consists essentially i in successive inoculations with emulsions of spinal cords of increasing virulence. The virulence of the material used for the first inoculations is decreased by drying the cords for varying periods, and the injections are begun with the older cords and continued with increasingly virulent material. Pseudohydrophobia or Lyssophobia.—This is simply a condition of fright, and the patients invariably recover. Pathology.—Gross Appearances in Organs.—There is no gross lesion that can be considered specific of the disease. The cadavers are apt to be emaciated and to become putrid rapidly. The blood is usually dark and thick. The brain and the membranes may be congested, and may even show slight hemorrhages. The gastro-intestinal tract and the respiratory tract may be congested and also show slight hemorrhages. Rabid dogs frequently swallow wood, straw, stones, and the like, which are found in the stomach postmortem. Microscopical Appearance.—There is nothing distinctive outside of the nervous system. Changes are found in the ganglia of the cerebro- spinal and sympathetic systems, and are especially marked in the plexiform ganglion of the pneumogastric nerve and in the Gasserian ganglion. Normally, these ganglia are composed of supporting tissue holding in its meshes the nerve-cells. These nerve-cells are surrounded by an endothelial laver and capsule. The rabic virus brings about an abundant multiplication of the cells lining this capsule, leading finally to the destruction of the normal ganglion, and leaving in its place a collection of round cells. All ganglion cells are not markedly changed; some are slightly or not at all changed; others are entirely destroyed. These changes are particularly marked in the dog, less so in man, and still less so in the rabbit. The ganglion of the pneumo- gastric nerve is the one generally chosen for examination, and it should be removed immediately after death and placed in absolute alcohol or in formalin solution. 358 A TEXT-BOOK OF PATHOLOGY RHEUMATISM Definition.—Acute articular rheumatism is probably an infectious condition; the nature of the infectious agent, however, is uncertain. Etiology.—The manifestations of rheumatism agree very well with those of infectious diseases, and some of the lesions frequently com- plicating the disease, such as endocarditis, are invariably infective. The relationship between tonsillitis and} rheumatism has been ex- plained by some as that between primary and secondary disorder. It is supposed that the infectious agents effect an entrance into the body through the tonsils, causing primary tonsillitis and secondary general infection, with localization in the joints. In other cases it has been held that the organisms enter through abrasions of the skin or in other ways. Leyden and others have described a streptococcus, and it has been shown that this organism is capable of producing arthritis, endocar- ditis, and pericarditis in experimental animals. A considerable number of recent investigators have isolated a micrococcus or streptococcus from cases of rheumatism and have succeeded in producing joint lesions, endocarditis, and pericarditis in animals inoculated with it. Others, however, have produced similar lesions with streptococci from other sources. The organism now receiving most attention is the Streptococcus rheumaticus of Poynton and Paine. This is a hemolytic acidifying diplococcus requiring blood for its best cultivation. It has been found in synovial fluids and tissues, in the blood, and in heart-valve vegeta- tions. It is suggestively like the chorea micrococcus. It produces arthritis and endocarditis in experimental animals. Achalme described a bacillus which he and others found in a number of cases of acute articular rheumatism. It is a large bacillus resembling that of anthrax; sometimes it is motile; it stains well with anilin dyes and with Gram’s stain; may have a capsule, and forms polar spores much larger than the bacillus. This organism is obligate-anaérobic, growing best in liquid media, in which it forms small bubbles of gas. The organism is closely allied to or identical with Welch’s Bacillus aérogenes. Thioroloix claims to have produced typical symptoms in the rabbit; and the inoculation experiments of others have given sug- gestive results. This bacillus was obtained from the blood in a number of cases; and from the pericardial fluid and blood in a state of purity in one case. The organisms have been found in sections of the heart muscle and valves. The fact that one organism or another produces inflammatory ° lesions in the joints, endocardium, or pericardium of animals when injected intravenously does not prove a specific relation of the organism to rheumatism. Doubtless various organisms are capable of producing such lesions, and it is not improbable that the clinical disease rheuma- tism may include a variety of infections. 5 (For the pathological anatomy of rheumatism, see Diseases of the oints.) DISEASES DUE TO BACTERIA 399 BERIBERI Definition.—Beriberi, or kakke, is an epidemic or endemic specific polyneuritis, with alterations of sensation and motility, and associated disturbances of digestion. This disease was long regarded as an infec- tion, and in some particulars strongly suggests an infection, but is of uncertain etiology. It occurs in tropical and subtropical countries, and is characterized by muscular weakness, generalized muscle pains, dropsy, and cardiac failure. Etiology.—Beriberi occurs among young persons and usually affects numbers of people. It is most frequent along ocean coasts and great rivers, and is most prevalent during damp seasons of the year. It does not seem to be contagious. Dietary conditions, such as may arise from defective food on ships and in institutions, appear important in its etiology. The cause of beriberi is unknown; no virus has been isolated to establish its infective nature, and it is now believed to lie in certain foods, notably, rice and canned meats, of which the former is the more important. In milling and polishing rice, the pericarp, rich in valuable phosphorus, is removed. Much information has been gleaned by the experimental production of a degenerative peripheral neuritis in ‘birds by feeding with such polished rice, and a similar experiment has been made with condemned prisoners. The importance of the unknown substance in the covering of the rice grain is shown by the fact that improvement follows the use of rice-bran in beriberi and experimental polyneuritis. This substance is either necessary to nutrition, or its absence disturbs metabolism in the nervous tissues. Some observers believe toxins are formed by cooking improperly preserved or spoiled rice. Moszkowski produced beriberi in himself by a diet of polished rice. His symptoms indicated no change in the motor nerves, the sensory only being affected, and the reflexes were increased. There was excessive nitrogen excretion, but the phosphorus metabolism seemed normal. The disease may be transmitted to the young through the milk. The form chiefly associated with superficial dropsies is called ‘“‘kakke,’’ be- lieved by some to be an independent disease. This is denied by others. The sensory phenomena take the form of areas of reduced tactile sense and are commonly met upon the dorsum of the foot, finger-tips and dorsum of the hand, around the mouth, and upon the abdomen. Edema of the superficial parts may or may not be seen. Then follow palsies of the dorsal muscles of leg and hand, and at times of the cranial nerves supplying face and neck. Death occurs by exhaustion or intercurrent infections. The pathology, except in the nervous system, is in no way specific. There is a slight anemia and leukocytosis. Edema in several isolated areas may be found. Congestions and early inflam- mations are common. This is particularly true of the gastro-intestinal tract, where the mucosa is cyanotic, but the glands are little if any changed. Parenchymatous degenerations are met. In the peripheral nerves there is degenerative neuritis with increase of nuclei, probably from the sheath of Schwann. The ganglia on the posterior roots and occasionally the roots themselves are degenerated. 360 A TEXT-BOOK OF PATHOLOGY PELLAGRA : This is a chronic, relapsing, non-febrile disease characterized by a more or less specific cutaneous eruption and nervous and digestive dis- turbances. Its etiology is not certainly known, but it has been supposed to be due to the use as food of Indian corn in which a toxin has arisen by infestation with certain aspergillus species. This is in accord with its appearance in the spring and summer. Various bacilli and amebe have been considered causes of pellagra, and lately Sambon asserts that it is transmitted by an insect. Late observations indicate that it may be transmitted to monkeys by Berkefeld filtrates from tissues of human cases. It occurs most commonly in white females between twenty and forty, beginning in May and June. Poor environment and living conditions favor its development. The cutaneous manifestations take the form of an erythematous dermatitis on exposed parts, which are aggravated by exposure to sun- light. The skin may swell or vesicles may form. The distribution is apt to be symmetrical and the patches limited. Thickening of the super- ficial layers, with pigmentation and parchment-like appearance, is the common condition in later stages. The nervous conditions comprise anesthesias, paresthesias, early increase of reflexes, and tremors. Later, evidences of dementia set in. There is no specific pathology. There are congestion and pig- mentation, and sometimes fatty degeneration of parenchymatous organs. Ulcers in the colon may be found. In the nervous system meningitis of a low order, degeneration of a few nerve- and ganglion cells, perivascular infiltration of round cells and degeneration of the posterior and lateral columns have been reported. The cerebrospinal fluid is usually abundant, possibly under pressure, limpid, clear, sterile, and contains some increase in protein and lymphocytes. There seems to be a lowered and somewhat perverted protein metabolism in pellagra. Judging from the known facts that hyper- acidity exists in the stomach, we may assume that digestion is defi- cient in the intestine. The microscopical changes in the skin are degeneration in the corium, followed by mild granulation tissue and thickening accompanied by proliferation in the spinous and granular epithelium in which pigment is prominent. The last two diseases, beriberi and pellagra, seem to be due to the absence from the diet of substances necessary to the construction of the phosphatids of nervous tissue, to which Funk has given the name “vitamins.”’ Their exact nature is not yet clear, but they do not seem to be proteins or carbohydrates. DENGUE This is an acute infection common in the tropics, due to a filterable virus, transmitted by the mosquito Culex fatigans. The virus is in the blood. There are fever, with an intermission, rheumatoid pains, and varied skin eruptions. One attack gives no immunity. DISEASES DUE TO BACTERIA 361 POLIOMYELITIS This disease of the central nervous system has assumed a position of great interest during the past decade, for during that time it has been pandemic, at least in Europe and North America. It was formerly known as a sporadic disease of childhood, but its recent manifestations have been those of a transmissible epidemic disease affecting almost any age, though especially frequent in childhood. The infection begins with a mild febrile attack, to which is shortly added muscular and joint pains, followed by palsy, and later by distinct paralysis. (For the pathology of the disease, see Nervous System.) Etiology.—The exact nature of the causative agent of this disease is not yet certainly known, but Noguchi has lately been able to cultivate from the central nervous system a tiny, poorly staining, bacterium-like body, with cultures of which he claims to be able to produce the disease in monkeys. Not only has this observer been able to grow these bodies, but he has found them in sections of nervous tissue. While little is as yet known of this tiny bacterium, much has been learned of the distribution and behavior of the virus. It is to be found in the brain, spinal cord, ganglia, spinal fluid, nasal mucosa, lymphatic organs, and intestinal contents. If emulsions of parts containing the virus be injected into the brain of a monkey the animal will develop symptoms, signs, and the pathology of poliomyelitis. If, instead of the emulsion, a filtrate of it, through a Berkefeld filter, be used, infection will also result; the virus is, therefore, filterable. Heating to 50° C. (122° F.) one-half hour destroys the virus, but it will withstand drying, 50 per cent. glycerin, and tissue autolysis. The virus is said to be con- -stantly in the nasal secretions of infected persons, sometimes in those of attendants, and also in surroundings, notably in dust. Transmission.—T wo theories are proposed for the transmission of poliomyelitis: first, that it is spread by insects; and, second, that con- tact, direct or indirect, is responsible. The insect transmission theory is based upon the appearance of the disease usually in summer, and upon the discovery by Rosenau that it was possible to transmit the disease from monkey to monkey by the bite of the stable fly (Stomozys calcitrans). The contact infection theory is based upon the fact that the virus is present upon and in the nasal mucosa of patients and healthy attend- ants. The latter are suspected of being carriers. Much more impor- tant than these, however, are the so-called ‘abortive’ cases of polio- myelitis. These are instances in which only a mild febrile affection occurs, but which do not go on to palsies, or, at most, show only transient weakness; therefore, so atypical that they escape recognition, and, going abroad, actively disseminate the virus. The nose as a portal of entry gains somewhat in probability when one considers the short distance the virus has to travel to reach the central nervous system by passing along the olfactory tract. Immunity.—One attack of poliomyelitis, either natural or experi- 362 A TEXT-BOOK OF PATHOLOGY mental, gives immunity, but this immunized power cannot be trans- ferred to another individual. As yet no therapeutically valuable anti- serum has been found. The serum of an immune person or animal does, however, possess the power to neutralize the virus. If such a serum and a known virus be mixed, incubated, and injected into a mon- key, no paralysis will occur, while a control animal injected with the same virus not exposed to the immune serum will develop poliomyelitis, This test has made it possible to detect abortive cases, because no unin- fected person gives serum with this property. FOOT-AND-MOUTH DISEASE This infection of cattle may be transmitted to human beings who use milk from affected cows, or directly from infected animals. There is a vesicular eruption in the mouth and on the feet and hands com- parable to the lesions in cows. The virus is in the vesicular fluid; it has not been cultivated, but is filterable. One attack probably gives no immunity; the blood-serum has therapeutic and preventive properties. TRACHOMA This is a transmissible disease of the conjunctiva characterized by tiny granulations on the palpebral surfaces, said by some to be due to an invisible filterable virus; by others it is believed to be caused by an influenza-like bacterium. Some observers have found an intracellular body which they believe to be the cause. This has been placed among Prowaczek’s Chlamydozoa. (See chapter on Eye.) ROCKY MOUNTAIN FEVER This is an acute transmissible disease characterized by evidences of general infection, severe pains, and a macular or erythematous erup- tion. It is transmitted by the tick Dermacentor occidentalis. It is practi- cally confined to the Rocky Mountain States and is most frequent and severe in Montana. It is a disease of adult life, occurring chiefly among those who work abroad, and is prevalent in summer. The tick obtains the virus by blood-sucking, and transmits it to another person by biting. The female tick transmits it to the eggs and young. The virus is in the blood of the patient and is destroyed if this be heated to 50° C. (122° F.) or is dried; it will not pass a Berkefeld filter. The disease may be trans- mitted by the introduction of infected blood into a guinea-pig, rabbit, or horse, and the clinical course in these animals is closely comparable to that seen in man. The serum of experimentally infected animals has an immunizing value for other animals, but it possesses little if any therapeutic power. It has been claimed that there is in the infected blood and ticks a minute diplococcoid body resembling an organism of the hemorrhagic septicemia group. No bacteriological cultivation has been successful, so that the cause of the disease is not known. One attack, in the laboratory animals at least, confers immunity. DISEASES DUE TO BACTERLA 363 THE CHLAMYDOZOA This is a name given by v. Prowaczek to certain intracellular bodies whose zodlogical position is not clear, but which have some characters suggestive of the protozoa. They undergo a change in appearance which has been interpreted by some observers as a metamorphosis. No exact life cycle has been accepted by all authorities as certainly pointing to protozoal nature. The group includes the Negri bodies of rabies, the cytoryctes of vaccinia and variola, the cyclasterion of scarlet fever, the trachoma bodies, etc. Prowaczek and his followers interpret these chlamydozoa as the result of cellular infestation by ultramicroscopical bodies, in response to which the nucleus or nucleolus extrudes into the cytoplasm some of its material. The intracellular body seems at first to be either a clear space or a minute dot until it is sur- rounded by the chromatin material as above derived. The chlamydozoén then assumes the form of an irregular mass of chromatin with one or more clear spaces. It appears in any imaginable form, giving the im- pression of metamorphosis. Cytoplasm seems to form, but if this be de novo or only a part of altered cell protoplasm is not known. The virus causing these protozo6n-like changes within the cell is filterable, associated with colloids, and has a predilection for epiblastic tissues. No chlamydozoén is known apart from the cell manifestation, and none has been cultivated. CHAPTER X ANIMAL PARASITES AND DISEASES CAUSED BY THEM PROTOZOA Classification..—CiassI. Rhizopoda (Sarcodina), forms resembling the ameba, and characterized especially by the presence of pseudopods. Cuass II. Flagellata (Mastigophora), protozoa characterized by the presence of one or more long lash-like flagella, used for progression or acquirement of food. Cuass III. Sporozoa, forms living as parasites in the tissues of other animals, receiving their food only by osmosis. Reproduction by means of encysted spores. Crass IV. Infusoria (Ciliata), cell-body of fixed shape with cilia; living free in water or as parasites. Cuass V. Suctoria, cell-body provided with suctorial tubes. Usually ecto- parasites in water animals and plants. The protozoa differ from the bacteria in producing a progressive disease without evidences of immunity. Trypanosome infection shows the presence of some immune bodies in the blood, but any increase of antiprotozoal power of the serum does not seemr to limit the course of disease, nor can the serum be used to immunize another person. Some of the protozoa produce a toxin, but most of them exert their noxious power by mechanical injury or obstruction, acting with the products of tissue destruction or with bacteria. Protozoa do not as a class have a pronounced chemotactic power for leukocytes. They pro- duce proteolytic enzymes and their activity is followed by an increase of acid in their vicinity. , Most protozoa have tissues of predilection, such as malaria plas- modia, the blood; amebe, the colon and liver; sarcosporidia, the muscles. RHIZOPODA ENTAMCEBA HISTOLYTICA Description.—This organism is an ameboid body from 20 to 30 p in diameter, consisting of a clear protoplasmic refractive outer portion and a finely or coarsely granular protoplasm within (Fig. 128). It frequently shows vacuoles and sometimes a vesicular nucleus. It presents active ameboid movements when studied on a warm stage of the microscope; and frequently contains foreign bodies, such as bacteria, pigment-par- ticles, and portions of blood-corpuscles or other cells. In the movements of the organism pseudopodia are projected from some part of the periphery. These at first draw upon the clear periph- eral zone, but after their formation the granuloplasm flows into the projected pseudopods. When in unfavorable surroundings the organ- 1 Braun, Die tierischen Parasiten des Menschen, 1903. 364 ANIMAL PARASITES AND DISEASES CAUSED BY THEM 365 ism undergoes a form of change called the encysted state. In this the body becomes spherical, and the wall is eventually stiff and firm, and usually presents a double contour. The division into a clear and a granular protoplasm is lost, the organism being uniformly granular. Fig. 128.—Entameba histolytica. Living organisms. Note absence of nucleus. All three of the parasites contain red blood-corpuscles; x 750 (Bulletin No. 1, Medical Department U.S. Army, 1913). Schaudinn differentiates two forms of the dysentery amebe, calling them Entameba histolytica (Fig. 128) and Entameba tetragena (Fig. a7 x SPT Fig. 129.—Entameeba tetragena. Living specimens. Note nucleus in upper enta- meba. The three lower entamebe contain red blood-corpuscles; x 750 (Bulletin No. 1, Medical Department U. 8. Army, 1913). 129). Craig and others now consider them to be different stages of development of the same species, but this opinion is not held by all parasitologists. 366 A TEXT-BOOK OF PATHOLOGY Distribution and Pathogenesis.—The organism in question has been found abundantly in the stools of patients suffering from dysentery. It is readily detected in the necrotic particles or the mucus of the stools, and has also been found in the tissues of the bowel wall adjacent to the dysenteric ulcers and in the liver abscesses secondary to dysentery. Liver abscess is a frequent complication or sequel of amebic dys- entery. The protozoa reach the liver through the blood-stream, prob- ably by penetrating radicles of the mesenteric vein, and are found in the wall of the abscesses. Whether they alone can produce pus is not known. There may be abscesses elsewhere. Musgrave and Clegg have cultivated amebee with cultures of bac- teria, and should a colony grow free of bacteria it may be kept alive for a short time on an agar media to which extracts of tissue have been added. The injection of mucus containing the amebe into the rectum of cats and other animals has occasionally produced typical dysentery, but this does not prove the pathogenicity of the amebe. Lesions closely similar to the natural disease have been produced in monkeys, and a human case with very suggestive clinical course was caused by swallowing capsules containing amebe. The Entameba histolytica produces a moderately strong poison which causes cellular necrosis, but not much acute inflammation. ENTAMGBA COLI This smaller ameba (10 to 20 u in diameter), also differing from the Entameba histolytica in having a less greenish color, less distinct ec- toplasm and endoplasm, less distinct pseudopodia, in the usual absence of vacuoles, the almost invariable presence of a nucleus and well-defined nuclear membrane, and in rarely ingesting red corpuscles, has been found in the feces of from 50 to 70 per cent. of healthy persons in various localities. Possibly under certain conditions the ameba may become pathogenic; usually it has been found in persons entirely well. OTHER AMEBZ Several other amebe of lesser importance have been discovered. Among these are the Entameba urinalis, found in the urine in cases of cystitis, and several forms met with in the mouth, especially about the teeth. Entameba buccalis has lately been held responsible for pyorrhcea alveolaris. An ameboid organism of uncertain pathogenic significance has been discovered in the abdominal fluid of cases of ascites. It has been named Leydenia gemmipara. It has a pulsating vacuole and nucleus and multiplies by budding or division. MASTIGOPHORA (Flagellata) CERCOMONAS HOMINIS This organism is a pear-shaped body with a sharp anterior extremity provided with a delicate short cilium. The broader posterior end is ANIMAL PARASITES AND DISEASES CAUSED BY THEM 367 provided with a long, tail-like flagellum. A large and a small variety have been described (Fig. 130). The former is the variety usually found and is from 10 to 12 uw in length. A minute oval aperture has been found at the anterior extremity. Significance.—The organism has been discovered in great numbers in various diarrheal conditions, especially in cholera. It has, however, A B Fig. 130.—Cercomonas hominis: A, large; B, small, variety (Davaine). been found in the stools of from 10 to 25 per cent. of healthy persons in tropical countries and is not known to have definite pathogenic powers. It is not improbable that the organism is, in reality, a form of _ trichomonas. Other closely allied cereomonads have been found in the urine (Bodo urinarius, Cercomonas urinarius). CERCOMONAS COLI HOMINIS A single observation of this organism was made by May. The body of the parasite was not quite the size of a red corpuscle; rather granular and glistening and slightly greenish. It was spindle shaped, the anterior end more blunt than the posterior. Four cilia were found at- tached to this end, and upon one side of the organism was seen an undulating membrane. In the same case smaller bodies, less developed and probably younger parasites, were discovered. The patient suffered from carcinoma of the stomach and chronic diarrhea. TRICHOMONAS INTESTINALIS This organism is pear shaped; from 10 to 15 uw in length and 7 u in breadth (Fig. 131). The anterior end is blunt; the posterior end is Fig. 181.—Trichomonas intestinalis (Zenker). prolonged into a sharp, tail-like projection. The body is granular and contains one or two bodies resembling vacuoles. Near the anterior end at one side may be seen a row of ten or twelve cilia, which give the or- ganism active motility. It has also ameboid movements. Stgnificance.—This organism has been found in cases of diarrhea, but its significance is doubtful. 368 A TEXT-BOOK OF PATHOLOGY TRICHOMONAS VAGINALIS This form is rather smaller than the last, with an attenuated caudal end and a more blunt anterior portion, provided with three or four flagella; there is a lateral undulating membrane with six or seven short cilia. Significance—The organism has been found in cases of vaginitis due to various causes, but also in the vagina in the absence of evident disease. It has been claimed by some writers that the four forms of flagellates just described are, in reality, but variants of a single species or inaccur- ately described members of the same variety. They accompany some forms of amebe. Their most important pathological seat is the bladder, where they can set up an irritation. OTHER FORMS OF TRICHOMONAS Sternberg has found several forms in the mouth, and especially about the teeth. These have been termed Trichomonas flagellata, T. caudata, and T. elongata. A trichomonas closely related to Tricho- monas vaginalis has been found in gangrene of the lung and in putrid bronchitis. LAMBLIA INTESTINALIS This organism in its active state is irregularly pear shaped, and presents at its broad end a cup-shaped depression situated obliquely at Fig. 132. Fig. 133.. Figs. 132 and 133.—Lamblia intestinalis from the intestines of a mouse (Grassi and Schewiakoff). one side (Figs. 132 and 133). On the anterior edge of the depression are attached two long cilia, and at one point of the posterior lip are two pairs ANIMAL PARASITES AND DISEASES CAUSED BY THEM 369 of cilia. In the base of the depression are seen two vesicular structures (nuclei) united by a band. The protoplasm is finely granular and is sur- rounded by a delicate capsule. When free the organism is capable of rather rapid motion, but in the intestine it is attached to the epithelial cells by its cup-shaped depression. The organism exists in this form in the duodenum and jejunum. In the colon or other unfavorable situ- ations it forms oval encysted bodies showing the nuclei and cilia within. Significance—Lamblia is a frequent parasite of the mouse, but has been found in the intestines of other animals, and occasionally in man. It has been found especially in chronic diarrheal conditions, and at times appears in the stools in immense numbers. No definite lesions have been found, and the pathogenicity of the germ is uncertain. TRYPANOSOMA Several varieties of trypanosomes have been recognized in animals, notably in horses and cattle. Among these, Trypanosoma evansi (Steel) has been found in the disease ‘“‘surra” in horses and mules in India and Burmah; the 7. bruce: (Plimmer and Bradford) has been found in “nagana,”’ a disease of horses and cattle in Central Africa; a form prob- ably identical with T. brucet has been found in ‘‘mal de Caderas,” a disease similar to surra and nagana in Central South Africa and Brazil; T. equiperdum (Doflein) or T. rowgeti (Laveran) in the disease of horses known as “dourine” in Algeria and other countries. .A comparatively harmless variety (7. lewisi, Kent) occurs in a large proportion of wild rats. It has been the form on which many of the studies of trypano- somes have been made. A few other forms have been recognized. The trypanosome was discovered in the blood of a human patient by Dutton. The earlier reported cases of Nepvieu are open to some doubt. Dutton’s patient, an Englishman, had been along the Gambia River, and his symptoms were much the same as those met with in animals from the same parasitic invasion. Great wasting and weakness, especially in the legs; irregular relapsing fever; edema, especially about the eyes; injection of the skin and conjunctive; enlargement and tenderness of the spleen, and frequent pulse and respirations, were the principal symptoms. Castellani announced in 1902 his discovery that the sleeping fever of the African negro is caused by a variety of trypano- some. The name Trypanosoma gambiense (Dutton) has been proposed for the parasite of man (Fig. 134). The trypanosome is a minute, worm-like body, difficult to see in the fresh blood with a magnification of 300 diameters. One end of the parasite is drawn out into a flagellum; the other end is bluntly conical. An undulating membrane is attached along the body, which is short, thick, and granular. Near the posterior end is found a refractile spot (vacuole). The parasite moves forward or backward by means of the flagellum, but usually toward the direction of the flagellated end. Reproduction occurs by longitudinal fission, and, in addition, it is 24 z 370 A TEXT-BOOK OF PATHOLOGY thought, can occur by sexual reproduction. The organism readily dies in fresh preparations. In the stained preparation it was found 18 to 25 w in length and from 2 to 2.8 w in width. Novy and McNeal succeeded in cultivating trypanosomes in arti- ficial media composed of 1 part of nutrient agar and 2 parts of fresh defibrinated or laked rabbit or rat blood. The organisms retain their virulence in cultures for long periods of time. The trypanosome of man has been found pathogenic for certain monkeys and for dogs, cats, and rats. Transmission of the Disease-—The transmission of the parasite is effected by various blood-sucking flies. The 7'rypanosoma gambiense is conveyed by the Glossina palpalis; T. brucei, mainly by the tsetse fly, G. morsitans; T. lewisi, by fleas. The fly conveying the human para- site acts as a host, for it becomes infective three days after biting, and remains so four weeks, thus indicating that some form of metamorphosis takes place. Fig. 134.—Trypanosoma gambiense: (1) From the blood; (2) from serosanguinolent fluid; (3) form showing rounded posterior extremity and granular protoplasm; (4) dividing form; X about 2000 (Laveran and Mesnil). : The organism may exist in the blood of man for a long time without causing symptoms. Later it enters the cerebrospinal fluid and then causes the characteristic manifestations. As a rule, there is first irregu- lar fever, later pains and swelling of the extremities, and finally coma. The lesions discovered at autopsy consist of cerebrospinal meningeal congestion with increased fluid, and enlargement of the spleen and liver. The cerebrospinal fluid is in excess and cloudy, but not purulent. The arachnoid may be lifted from the convolutions and the pia has been found abnormally tight. The lymph-nodes are almost universally enlarged and the spleen frequently shows a myeloid transformation. Immunization of animals has been accomplished by repeated in- oculations and immune sera of decided potency have been produced. Human trypanosomiasis is transmissible to monkeys. Leishmaniosis.—This term may be given to a group of three dis- eases prevalent in Africa and Southern Asia, known as “kala-azar” or oe 062 “dumdum fever,” “infantile kala-azar,” and “oriental sore” or “Aleppo ANIMAL PARASITES AND DISEASES CAUSED BY THEM 371 button.” The causative organism is a near relative of the trypano- somes, among the Flagellata. The symptoms of the first two are moderate anemia and fever, associated with splenomegaly. The spleen shows little microscopical change aside from hyperplasia. The prognosis is grave. Oriental sore is characterized by the appearance on skin surfaces of spreading suppurating and ulcerating granulomata. These lesions tend to heal and leave disfiguring scars. The causative organism is known as Leishmania donovani, after the men who discovered and described it. It varies but slightly in the three clinical forms above, only differing in size and appearance upon cultivation. It may be grown upon the medium described for trypano- somes. In the body the parasite exists as an intracellular round or oval (2.5 by 3.5 uw) mass containing two more deeply staining large granules. The larger, or nucleus, lies excentrically, parallel to the Fig. 135.—Leishmania donovani. Flagellated forms from a culture. Wright's stain; x 1800 (Bulletin No. 1, Office of the Surgeon General, January, 1913). long axis of the parasite. The smaller granule is probably the blepharo- blast. Vacuoles may be present. The parasites stain palely, while the granules are dark. They lie within lymphocytes and endothelial cells. They do not appear in any numbers in the circulating blood, but may be found in lymph-tissue and marrow (Fig. 135). The manner of transmission is not known, but insects and bedbugs are suspected. Histoplasmosis is a condition characterized by anemia, prostration, splenomegaly, fever, and emaciation, caused by the Histoplasma capsu- latum (Darling), a flagellate related to the trypanosomes. The organs may occasion spreading granulomata and the intestines show ulcera- tion. The organism is intracellular, has an irregular oval nucleus, vacuoles, and a wide capsule. The organism has not been cultivated. The disease was found in the Panama Canal Zone. 372 A TEXT-BOOK OF PATHOLOGY HEMOSPORIDIA THE PARASITES OF MALARIA The organisms which are now recognized as the cause of malaria belong to the protozoa. Most authors regard them as Sporozod, suborder Hemosporidia. They are found in the blood and the vascular channels of the various organs, deriving their nourishment, for the most part, directly from the blood-corpuscles. Malaria has been regarded as a water-borne and as an air-borne disease, but no proofs have been obtained for either view. Direct conta- gion does not occur, but it has been shown that the blood is infectious when introduced into the circulation of a healthy person. The drinking of the blood does not give rise to the disease. Certain external. condi- Fig. 136.—Plasmodium vivax. Half- Fig. 136a.— Plasmodium malariz. grown parasite. Wright’s stain; < 1500 Half-grown parasite, the so-called band (Craig, Bulletin No. 6, War Department). form. Wright’s stain; x 1800 (Craig, ’ Bulletin No. 6, War Department). tions are favorable or necessary to the development of the disease. These external conditions are moist, marshy soil, atmospheric humidity, and high temperature. The disease occurs in the lowlands or bottom- lands, and very rarely in high and dry ground. Extensive excavations and the like may cause the appearance of the disease or increase it, and, on the other hand, suitable drainage may cause its diminution or disappearance. The relation of all these conditions to malaria is ex- plained by the demonstration of the part played by mosquitoes in the transmission of the contagion. Three distinct species have been identified: the organism of tertian fever (Plasmodium vivax, Figs. 136-138), that of quartan fever (P. malarie), and that of estivo-autumnal fever (P. falciparum). Each of these has a double life cycle, one within the human host, the other in the body of the mosquito. In the human circulation, spleen, or else- where asexual reproduction (schizogony) of the parasite occurs until it ANIMAL PARASITES AND DISEASES CAUSED BY THEM 373 has exhausted its reproductive power or antagonistic bodies have de- stroyed it; while in the mosquito sexual reproduction (sporogony) occurs by conjugation. Plasmodium Vivax.—tThe cycle of development in the blood of man begins with a small hyaline spherule (schizont) about 2 u in diameter which is attached to and later within a red corpuscle. Soon pigment particles appear within the parasite, being derived from altered hemo- globin. The pigment particles are more or less actively motile, due to currents in the protoplasm. Later the body increases in size and the corpuscle in which it is contained swells and becomes paler. Finally, the sphere increases to perhaps twice the size of a normal corpuscle. In all stages ameboid changes in the shape of the organism may be observed, but become less and less marked as the plasmodium enlarges. In the spleen, and to a less extent in the circulating blood, division of the Fig. 187.—Plasmodium vivax. Fully de- Fig. 138.—Plasmodium vivax. Fully de- veloped macrogametocyte. Wright’sstain; veloped microgametocyte. Wright’s stain; x 1800 (Bulletin No. 1, Medical Depart- xX 1800 (Bulletin No. 1, Medical Depart- ment U. 8. Army, 1913.) ment U.S. Army, 1913): parasite may be observed about the time of the expected paroxysm of the disease. The pigment collects in the center, the organism forms a rosette and then divides into fifteen or twenty rounded segments or merozoites. These escape from the destroyed red corpuscle and are then ready to attack a new corpuscle and begin the same cycle. In the earlier stages the hyaline body appears as a light area on an otherwise normal red corpuscle; somewhat later its rounded shape sug- gests a ring and the term “ring-bodies” is given. This is conspicuous in preparations stained with a chromatin stain such as in the Nocht- Romanowsky method. The body of the parasite is blue and at one point in the periphery may be seen red chromatin matter, thus suggest- ing a signet ring. Before segmentation the chromatin collects in the center and eventually divides, a portion being found in each of the merozoites. The cycle of development of this form occupies about forty- eight hours. 374 A TEXT-BOOK OF PATHOLOGY Plasmodium Malarie—The organism of quartan fever differs from the tertian in that it is less pigmented and the pigment is usually coarser, more characteristically arranged at the periphery of the para- site, and usually motionless. ‘The segmentation is more regular, forming a wheel-like figure with nine to twelve segments which form the sporules or merozoites. The segmentation occurs only in the circulating blood and the cycle occupies seventy-two hours. The corpuscle containing the organism does not enlarge nor grow pale as in the case of the ter- tian form, but instead presents a greenish appearance. Plasmodium Falciparum.—The organism of estivo-autumnal fever is believed by Italian and tropical investigators to occur in two forms: a tertian and quotidian, which have certain distinguishing features. The organism is characterized by its tendency to develop marked signet-ring forms, by its relatively small size, and by its fine granulation and highly refractive protoplasm. Segmentation occurs in forty-eight hours and takes place mainly in the spleen, bone-marrow, liver, and capillaries of the brain. The segments are from seven to ten in number. Sporogony.—A certain number of the plasmodia of any one of the three varieties, when of mature size, instead of undergoing segmenta- tion become differentiated as male and female forms or gametocytes. In the tertian and quartan varieties the male form, or microgametocyte, is a rounded body with centrally placed nucleus, having an abundance of chromatin and a considerable amount of actively motile and diffused pigment matter (Fig. 138). The macrogametocyte, or female form, has an excentrically placed nucleus with less chromatin and coarser pigment arranged in clumps about the periphery of the organism (Fig. 137). In the case of the estivo-autumnal parasite the gametocytes first appear as oval bodies within the red corpuscles, but soon they assume the well-known form of crescents, which even when quite mature may present on the concave border remains of the red cell in which they developed. The crescent contains rod-shaped pigment in a cluster either at its center or one pole, and a male and female form can be distinguished. These sexual forms (gametocytes) of malarial plasmodia are less abundant in the earlier stages of infection than later when schizogony or asexual division becomes less active. When blood is drawn and kept for a time under a cover-glass further changes take place in the gametocytes, which are similar to those which occur in the body of the mosquito. The microgametocyte presents active movements of its pigment and finally a protrusion of several flagella which extend to two or three times the diameter of the cell. These flagella, or microgametes, the male element concerned in the process of fertilization, become detached from the cell and penetrate the female organism, macrogametocyte, after the latter has undergone a prepara- tory change (certain nuclear extrusions) and has thus been converted into a macrogamete. Further stages in the sexual cycle of reproduction occur only in the body of the mosquito. Parthenogenesis.—It has been claimed by Schaudinn, but denied by others, that parthenogenesis of the macrogametocyte may restore to the PLATE 2 ag a2) Ta 10 ry rh; f2 I3 14 , ert ik me} 3 tal Rereaee a. ‘ae! IS 16 7 t . abe uae a r oy t wank 16 19 20 2/ 22 23 24 2s 26 27 va : *. - # So % © Various forms of malarial parasites (Thayer and Hewetson): Figs. 1 to 10 inclusive, tertian organisms; Figs. 11 to 17 inclusive, quartan organisms; Figs. 18 to 27 inclusive, estivo-autumnal organisms. Fic. 1.—Young hyaline form; 2, hyaline form with beginning pigmentation; 3, pig- mented form; 4, full-grown pigmented form; 5, 6, 7, 8, segmenting forms; 9, extracellular pigmented form; 10, flagellate form. : IG. 11.—Young hyaline form: 12, 13, pigmented forms; 14, fully developed pig- mented form; 15, 16, segmenting forms; 17, flagellate form. : Fics. 18, 19, 20.—Ring-like and cross-like hyaline forms; 21, 22, pigmented forms; 23, 24, segmenting forms; 25, 26, 27, crescents. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 375 blood a new generation of merozoites when schizogony is becoming feeble. According to this view, the gametocytes represent resistive forms which are able to withstand unfavorable conditions developed in the course of an infection (antibody formation?). The female, or macrogametocyte, is particularly resistive, may remain in the blood after other forms have disappeared, and may then by a process of parthenogenetic segmentation produce a new generation of merozoites. This theory would explain certain cases of late reappearance of infection after apparent recovery. Bass has lately succeeded in cultivating the asexual cycles in the species of vivax and falciparum by using equal parts of 0.5 per cent. glucose bouillon and blood, or Locke’s fluid minus calcium chlorid plus ascitic fluid. The blood is defibrinated in flat-bottom tubes of such size that the clear fluid layer above the cells is at least 4 inch in height. The parasites grow in the upper layer of red cells and can be transferred by a pipet to fresh tubes of uninjured cells for a secondary growth. Leukocytes and serum are prejudicial to the growth of the plasmodium; the former by phagocytosis, the latter by lytic effects. The Relations of the Mosquito to Malaria.—It has been positively demonstrated that when certain mosquitoes (of the genus Anopheles) are allowed to feed upon malarial patients and later upon normal indi- viduals, the latter acquire the disease. Also, it has been shown that susceptible persons may live in the most malarious districts without acquiring the disease, provided they are carefully screened from mos- quitoes. Some of the earlier investigations in this direction failed be- cause specimens of Culex and other genera (not Anopheles) were used. The Anopheles claviger, maculipennis, or quadrimaculata and others of this genus alone seem capable of conveying the disease. When the mosquito takes the blood of the malarial patient into its stomach (midintestine), flagellate forms (microgametocytes) are developed, and the flagella (microgametes), each containing some part of the nuclear substance of the parent cell, are discharged, and, moving toward other of the parasites which do not form flagella (macrogametes), fertilize these by penetration. The fertilized parasites then invade the intes- tinal walls, entering between the epithelia, and lodge in the surrounding tissues, where they segment and develop a distinct capsule. The cystic structures so formed (odcysts) contain numerous minute rods or sporo- zoites that have resulted from the segmentation of the parasite. The odcysts project into the ccelom cavity of the mosquito and eventually rupture into this, whence the sporozoites, discharged into it, are carried to different parts of the body and eventually to the salivary glands, from which they are introduced into any person subsequently stung by the insect. In this manner the extracorporeal cycle of development of the organism is completed and the perpetuation of the disease provided for. The recognition of the relation of the mosquito to malaria explains certain hitherto obscure facts regarding the conditions that favor the development of the disease. This knowledge has also led to the intro- duction of sanitary measures that have proved extremely useful. 376 A TEXT-BOOK OF PATHOLOGY Pathological Anatomy.—The most important fact in malarial infection is the destruction that it occasions in the blood. Rapid anemia with liberation of the hemoglobin (hemoglobinemia) and the appearance of granular pigment in the blood are among the results. The pigment accumulates in the spleen, liver, bone-marrow, and in other situations, Extreme disorganization of the blood may occasion hemoglobinuria and widespread pigmentation. Congestive enlargement of the spleen, and, after long-continued attacks, cirrhotic changes in that organ, may be observed. Thrombi of the capillaries and arterioles are not rare, and to these, in part at least, are due the focal necroses observed in the liver and elsewhere. The anemia is usually ascribed to the continued attacks of the parasites upon successive numbers of erythrocytes; some late observations lay the hemolysis to the circulation of free hema- tin, which substance, if injected into rabbits, produces a blood-picture like that seen in human malaria. Pathological Physiology.—The curiously paroxysmal seizures of . malaria are probably the result of the liberation of toxic substances at the time of segmentation of the hematozoon. The periodicity depends upon the cycle of development of the organism. A single’ group of tertian organisms causes a tertian fever (a paroxysm every other day). Infection with two groups of tertian organisms, maturing on alternate days, produces a quotidian fever (a paroxysm every day). One group of quartan organisms causes quartan fever (a paroxysm every third day); three groups (maturing on successive days) cause quotidian fever. The febrile course in estivo-autumnal infection is more irregular, and this is explained by the discovery of organisms of various ages in the blood. Thus there results a constant succession of maturations and segmentations with less distinct periodicity, because the intervals which occur in tertian and quartan infection are wanting. Texas Fever of Cattle-—This disease is of interest in connection with mnalaria because of the relationship of the parasitic cause. The organism is a small, actively ameboid body which occupies the red blood-cor- puscles. Frequently it occurs in pairs in the corpuscles, and the name Pirosoma bigeminum was given to it on this account. Texas fever is characterized by acute fever and frequently by hemiglobinuria. The spleen is enlarged and hemorrhages are observed in various organs. When the blood of a diseased animal is injected into a healthy one, the latter acquires the disease. Transmission has been traced to the cattle tick (Ixodes bovis). The mother tick, after its detachment from the in- fected animal on which it has fed, transmits the infectious agent to its larvee through the ova. The young ticks then convey the infection to healthy cattle. Sporozoa in Birds and Cold-blooded Animals.—Many blood para- sites have been studied in birds, reptiles, and other cold-blooded ani- mals. In birds two species, Hemoproteus danalewskyi and Halteridium danalewskyi, have been closely studied, thus throwing much light on the life history of the malarial organisms. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 377 CoccIDIA COCCIDIUM CUNICULI: Description.—The coccidia are small bodies from 30 to 40 wu in length and from 15 to 20 » in width, having a delicate outer coating, and within this a tough, double-contoured capsule. The body is filled with granular material, which is not rarely aggregated in the center. Outside the body sporulation takes place. The granular protoplasm divides into four rounded capsulated spores, each containing a granular Fig. 1389.—Coccidium oviforme, showing method of reproduction. resting body lying in the concavity between two sickle-shaped daughter- spores. Sometimes endogenous sporulation is said to occur, the para- site simply breaking up into a large number of sickle-shaped bodies. The term psorospermie is applied to the rounded spores found in the coccidium (Fig. 139). Fig. 140.—Coccidia in the wall of the bile-duct. The cut shows in the center active pro- liferation of the wall of the duct, with numerous ovoid coccidia massed in the tissue. The coccidium can also pass through a sexual reproduction (sporog- ony) with a cycle comparable to that of malarial parasites in the development of young and adult male and female forms. Occurrence and Pathogenesis.—The coccidium is a frequent para- site of rabbits and certain other animals. It leads to the formation of 378 A TEXT-BOOK OF PATHOLOGY yellowish nodules in the liver. It is an intracellular parasite, first in- vading the cells of the biliary passages and afterward the surrounding hepatic cells as well (Fig. 140). Less frequently it occurs in the intes- tinal tract, giving rise to nodular thickenings or ulcerations. The parasite escapes from the body in the stools and then under- goes sporulation. Other animals are probably infected by ingestion of the spores or sporulating coccidia. Occasionally the disease decimates rabbits or guinea-pigs kept in confinement. The animals become languid, lose their appetite, emaciate, and have fever. Later they suffer from convulsions, stupor or coma, and die in this condition. A few cases of coccidial disease of the liver have been observed in man. The lesions present themselves as cystic nodules springing from the bile-ducts, or less commonly as a diffuse involvement of the liver with cirrhosis and causing jaundice. Coccidial lesions of the intestines have also been discovered in man, and less commonly invasion of the heart, of the kidneys, and other parts. The close association of the organism with the lesions, and the number of organisms discovered in the tissues, justify the belief that it is the specific cause of the lesions. The coccidium of the intestinal tract is generally smaller and the sporulation more rapid than that of the hepatic form. It was, therefore, supposed by Leuckart to be a special variety, and has been called Coccidium perforans or C. hominis. More recently this has been re- garded as identical with the ordinary form. Coccidium Bigeminum (Stiles) —This variety has been found in dogs, cats, pole-cats, and man. The cyst divides into two parts and then forms four spores. Eimeria Hominis.—Eimeria is characterized by the formation in each adult parasite of a single spore containing an indefinite number of sporozoites. The Eimeria hominis was discovered in the purulent exu- date of a case of pleurisy. The spores were of large size and contained from ten to twenty sporozoites, accompanied by a protoplasmic rem- | nant. The exact origin of the organisms in this case was not determined. Somewhat similar organisms were found by Virchow in a tumor of the liver, and by Severi in the lung. SARCOSPORIDIA The sarcosporidia, also called ‘‘Rainey’s’” and ‘“Miescher’s tubes,” are met with in a number of mammals. The organism is composed of a protoplasmic mass covered with a capsule, and forming at the stage of maturity a large number of sickle-shaped or falciform sporozoites. The organisms usually occur in muscles, either within or between the muscle bundles, and are, therefore, elongated or tubular in shape. In connective tissues the organism may be rounded and sometimes grows to the size of a small cherry. Several varieties have been described, and a few observations have been made in man. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 379 INFUSORIA BALANTIDIUM COLI Balantidiwm or Paramecium colt is a rounded body from 0.07 to 0.1 mm. in length and slightly less in breadth (Fig. 141). It is sur- rounded by a coat of cilia closely set. There is an oral aperture at one end and an anal opening at the other. The substance of the parasite is granular, and contains a bean-shaped nucleus, within which is a round nucleolus and two contractile vacuoles, besides various foreign matters. The parasite possesses ameboid motion. Encysted forms with a thick- ened capsule have been described. Significance—The hog is the natural host of this parasite. an is probably infected through drink- ing-water or contaminated food-stuffs. It is found particularly in the northern countries of Europe, and occurs in cases of diarrhea, principally involving the large intestine. The parasite penetrates between the epithelial cells by its ameboid motion. Chronic catar- rhal inflammation and dysenteric lesions have been described. The lesions are chiefly purulent, necrotic, . ae and ulcerative in the colon. The parasite may be dante. GOL found mixed with the degenerative mass. Occa- (Malmsten). sionally liver ‘abscess is seen and a penetration to the blood-vessels has been observed. It is possible for it to penetrate the lymph-nodes of the intestinal wall or as far as the mesenteric glands. The organism is probably irritating, but whether pathogenic or not is unknown. Epidemics have been observed in monkeys, the manifesta- tion being prolonged diarrhea. Balantidium Minutum.—This species resembles the Balantidium coli, but is smaller (40 long), has a more prominent mouth, and but one vacuole. It has been found in association with Strongyloides, Ankylostoma, and Amebe. Its significance is uncertain. ANIMAL PARASITES AND MOLLUSCUM CONTAGIOSUM Definition.—Molluscum or epithelioma contagiosum is an infectious disease of the skin marked by the appearance of w hite and pink papules. Etiology.—The cause of this disease is, no doubt, a micro-organism of some sort. Its contagiousness is evidenced by the occurrence of epi- demics in houses or asylums, by the occurrence of accidental inocula- tions, and by direct experiments. The incubation period seems to be a long one—sometimes extending to several months. The lesions have been found to contain small bodies whose resemblance to coccidia was long ago pointed out by Virchow. It is uncertain whether these are really parasites or epithelial degenerations. Some authors are positive regarding ‘the parasitic nature of the bodies; others are equally con- vinced of their non-parasitic character. The most ably defended theory 380 A TEXT-BOOK OF PATHOLOGY for the parasitic nature of the virus ascribes it to an organism called _ Strongyloplasma hominis. It has been shown that the virus is filterable, and many consider it should be placed among the Chlamydozoa. The large pale body, with the later appearance of internal structure, seen only by appropriate staining, strongly supports this view. Appearances.—The disease occurs as single or, more frequently, multiple papules, at first quite small, but later becoming nodules of con- siderable size. In the larger a central depression or umbilication is seen, and on pressure cheesy matter may be expressed from this. After reach- ing about 3 or 4 mm. in diameter the papules remain stationary, or undergo softening and suppuration. In exceptional cases the tumor may reach the size of a small orange. Seats.—This disease occurs on the face, neck, chest, sent, or sometimes scattered over the whole body, sparing only the palms and soles. The lesions have occasionally been found on the mucous mem- branes. Structure.—Microscopically, the lesions of this disease are found to consist of epithelial proliferations having a somewhat acinous arrange- ment, a hair-follicle occupying the center of each group of cells. The interior of the nodules is filled with soft, cheesy matter which may be expressed. The epithelial cells are arranged in several layers, the upper being normal cells with large nuclei, the deeper layers showing besides the nucleus, small droplets, or rounded spherules, the so-called molluscum bodies. These bodies grow in size and may be so large as to fill the cell, pushing the protoplasm and nucleus to one side. In this process the cell wall and protoplasm become horny, and practically the entire body consists of the enlarged molluscum corpuscle. Certain granulations and more or less definite segmentations within these bodies have been described as sporulating conditions. (See Skin.) VERMES TREMATODES, OR FLUKE-WORMS The fluke-worms are usually flattened organisms, somewhat tongue shaped, and provided with powerful suckers and occasionally with hooklets. The intestinal canal begins in the oral orifice anteriorly, but is closed at the posterior extremity. Reproduction may take place directly or by the formation of an intermediate organism which is parasitic to certain lower animals. In this stage they are actively motile, swimming about in water, and are known as the cercariz. Their action is irritative and obstructive. FASCIOLA HEPATICA OR DISTOMUM HEPATICUM The Fasciola hepatica, or liver-fluke, i is from 15 to 35 mm. in length and 6 to 20 mm. in breadth; it is pointed at either end, and anteriorly is provided with two suckers, one at the head and one upon the ventral surface, somewhat posterior to the first (Fig. 142). The genital pore lies ANIMAL PARASITES AND DISEASES CAUSED BY THEM 381 between the two suckers. The eggs are oval in shape, 0.14 to 0.15 mm. in length, and provided with a lid at one pole. The adult organism occupies the biliary ducts and is a frequent parasite of sheep. It is occasionally met with in man, usually occurring in considerable numbers.’ It gives rise to obstruction of the biliary pas- sages and consequent enlargement, congestion, and later degeneration Fig. 142.—The common liver-fluke (Fas- Fig. 143.—Ventral vein of a compressed ciola hepatica), enlarged to show the ana- specimen of a lung-fluke (P. westermanii) tomical characters (after Stiles). from a hog; greatly enlarged (after Stiles and Hassall). of the liver. The gall-ducts above the point of obstruction have sometimes been found considerably dilated or cystic. Clinically, ascites and jaundice have been found, with gastro-intestinal symptoms and fasciola eggs in the stools. DICROCG:LIUM LANCEATUM This form measures from 8 to 10 mm. in length and 2 to 2.5 mm. in breadth. The two suckers are far apart, and the genital pore lies between them. The eggs are 0.04 to 0.05 mm. in length and 0.03 mm. in breadth. This parasite is frequently associated with the previous one, and occupies the biliary passages of sheep and cattle. It is occasionally met with in other animals and in man. 382 A TEXT-BOOK OF PATHOLOGY ' OPISTHORCHIS FELINEUS This form varies in size with the degree of contraction, but is usually 8 to 11 mm. in length and 1.5 to 2 mm. in breadth. The two suckers are far apart, and the genital pore is just in front of the ventral sucker. The eggs are oval, operculated, measuring 0.03 mm. in length and.0.01 mm. in breadth, and contain a ciliated embryo when deposited. This parasite inhabits the gall-bladder and bile-ducts of the domestic cat in particular, but is also found in the dog, fox, and man. It has been observed in France, Germany, Russia, Holland, Italy, and Japan. OPISTHORCHIS SINENSIS This parasite resembles the Opzsthorchis felineus. The length is 10 to 14 mm.; the breadth, 2.4 to 3.9 mm. The eggs are oval with a sharply defined operculum at the pointed pole; they measure 0.030 mm. in length and 0.017 mm. in breadth. This parasite inhabits the bile-ducts and gall-bladder of domestic dogs and cats as well as of human subjects. It is found frequently in Japan, also in China and India. SCHISTOSOMUM HAMATOBIUM OR DISTOMUM HAEMATOBIUM This organism, sometimes called Bilharzia, occurs in sexually dis- tinct forms, the male and female, however, occurring together. The male is 12 to 14 mm. in length and 1 mm. thick, and the body back of the large ventral sucker is somewhat flattened and curved ventralward to form a groove, in which the female is attached (Fig. 144). The latter is 16 to 18 mm. long, and 0.13 mm. thick. The eggs are 0.135 to 0.180 mm. long and 0.055 to 0.060 mm. broad, not opercu- lated, and having a spine at one end or at the side of one end. The adult parasite occupies the portal vein and the veins of the spleen, mesentery, and the plexuses of the bladder and rectum. The eggs of the organism may be found in any of the organs, notably in the liver, in the intestinal walls, and in the mucous mem- branes of the urinary passages. They probably ~ WW AES Fig. 145.—Papillary thick- ening of the mucous mem- : brane of the bladder, show- Fig. 144.—Schistosomum hematobium, with eggs (von ing schistosomum eggs i Jaksch). situ (Mosler and Peiper). occupy the vascular system ordinarily, but cause rupture of the walls of the vessels and thus escape into the tissues. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 383 The pathological changes caused by this parasite and included in the term “‘bilharziasis” are more strikingly seen in the ureters and blad- der in acute cases. Hyperemic spots or small hemorrhages may be seen in the mucous membrane, and the surface is covered with blood-stained mucus containing the eggs. In cases of longer standing roughness of the mucous membranes and usualy small ecchymotic elevations or out- growths, suggesting papillomata, are observed (Fig. 145). Section through these shows that they consist of proliferated cells with enlarged blood-vessels, from which the adult worm may be removed. The tissues surrounding the vessels may contain eggs in enormous numbers. The mucous membrane is frequently covered with a calcareous deposit composed of urate and oxalate of sodium, and the excrescences may be converted into calcified polyps. Among the final results may be cica- tricial strictures of the ureter, pyelitis, and distention of the pelvis of the kidney, with atrophy of the kidney substance. Similar pathological processes may be found in the rectum. When the portal vein is occupied the eggs of the Bilharzia may be abundant in the liver substance. Schistosomum hematobium is a parasite occurring with enormous fre- quency in northern Africa and neighboring countries. It is compara- tively rare in other parts of the world. SCHISTOSOMUM JAPONICUM Schistosomum japonicum, or S. cattot, has recently been discovered in eastern Asia and Japan. This parasite inhabits the arterial side of the portal system. It is somewhat smaller than Schistosomum hematobium, and the male is distinguished by his non-tuberculated integument. The ovum has no spine, is regularly oval, perfectly smooth, and with a much thinner shell. It resembles closely the ovum of Ankylostoma duodenale. The ova are deposited in the mucosa and submucosa of the large and small intestine, especially the former. From here they escape with the feces. No more is known of the life-history from this point than is the case with the Schistosomum hematobium. It causes a peculiar kind of chronic enteritis and anemia, associated with enlargement of the spleen and liver, terminating in a fatal cachexia. Cats are susceptible to this parasite as well as man. PARAGONIMUS WESTERMANII This organism is from 8 to 10 mm. in length and from 5 to 6 mm. in breadth. The eggs are brownish, and from 0.08 to 0.1 mm. in length. The worm occurs in the lungs, occupying excavated spaces, usually near the periphery of the organ. These cavities contain reddish or quite hemorrhagic mucopurulent liquid and abundant eggs. The cavi- ties are in communication with the bronchi, and clinically the disease is marked by cough and hemorrhagic expectoration or even repeated hemoptysis. The parasites themselves are rarely coughed up. The small tumors or burrows have also been found in the scrotum, liver, and brain. 384 A TEXT-BOOK OF PATHOLOGY In the brain they may give rise to grave nervous symptoms, often simulating those of intracranial tumor. This parasite occurs very frequently in Japan, China, and Corea, and has been observed several times in this country. OTHER FLUKE-WORMS Among other forms of fluke-worms of less importance are Fasciolopsis buskii, met with a few times in the intestine; Cotylogonimus heterophyes, Agamodistomum ophthalmobium, found in the lens of the eye; Opis- thorchis noverca, occurring in the liver; and the Monostomulum lentis, occurring in the eye. The Gastrodiscus hominis occurs in the intestinal tract. Two forms, the Hexathyridiwm venarum and H. pinguicola, are possibly forms of encapsulated Fasciola hepatica. Fasciolopsis rathouisi is a fluke found in the intestinal canal of Asiatics. CESTODES, OR TAPEWORMS General Biology.—The life-history of the different forms of tape- worms is much the same. They have two states of existence, the larval, which is generally found in one species of animals (the intermediary host), and the adult, usually occurring in another species (the host). It is supposed that in the case of one or two tapeworms an inter- mediary host is unnecessary, but this is doubtful. The adult worm, or tapeworm (strobile), occupies the intestinal tract of man or the lower (vertebrate) animals. It consists of a head (scolex), by which the worm fastens itself to the mucous surface; and after the head, a neck of greater or less size and length, and a body consisting of separate links or pro- glottides. The latter represent complete organisms, containing a com- plicated genital apparatus, hermaphroditic in nature, which produces numerous eggs. The eggs are partly discharged from the segments in the intestinal tract through a genital pore, but especially escape into the outer world when the ripe segments are separated from the body of the worm, are discharged from the bowel, and subsequently rupture and scatter the contained ova (Fig. 146). The egg or ovwm encloses an immature larval organism, which, when received into a suitable inter- mediary host, penetrates the walls of the stomach or intestine and finds its way to the muscles or organs, where it embeds itself and forms the well-known measles (Figs. 146 and 147). These are seen with the naked eye as small cyst-like bodies lying between the muscle-fibers. They contain a scolex or head, like that of the adult worm, inverted into a sac filled with clear, watery liquid. When the measles or cysticerci occur in hollow cavities, such as the ventricles of the brain, they may reach considerable size. They differ somewhat in different forms of tapeworm, as will be described in connection with the individual species. When flesh infested with larval tapeworms is eaten by man or some suitable animal, the cysts are dissolved and the scolex fastens itself upon the mucous membrane of the intestine. The body of the worm is then slowly or rapidly formed. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 385 Man is the host of tapeworms of adult or of larval type, most fre- quently the former. In one case, the Tenia echinococcus, only the larval worm occurs in the human body, in the form of hydatid cysts. Fig. 146.—Segments of (1) Teenia saginata; (2) Bothriocephalus latus; and (3) Tenia solium, showing arrangement of uterus. Pathological Physiology.—Adult tapeworms may exist in the intes- tines of man without calsing disturbances of any kind. Frequently, however, digestive disturbances and pain and various reflex manifes- Fig. 147.—Eggs of various worms found in the alimentary canal of man: a, Ascaris lumbricoides; 8, c, Oxyuris vermicularis; p, Trichocephalus trichiurus; 5, Ankylostomum duodenale; F, Fasciola hepatica; c, Dicrocceelium lanceatum; Hu, Tenia solium; 1, Tenia saginata; x, Dibothriocephalus latus; x 400. tations arise. These may be caused by the action of the worm as a simple foreign body, or may result from poisonous agents generated by the worm in its normal life, or as a consequence of death and degenera- tion of the segments. When there are many worms (as in the case 25 386 A TEXT-BOOK OF PATHOLOGY of Hymenolepis nana) the disturbances of digestion may be largely mechanical; under similar circumstances, or when a single worm be- comes coiled and forms a mass, intestinal obstruction may be occasioned. In the case of Dibothriocephalus latus poisonous substances are un- doubtedly produced, and to these must be ascribed the severe forms of anemia caused by this worm. The toxic substance is produced by the worm and is within its body, but can be absorbed by the intestine. That such occurs is indicated by the precipitation reaction between blood of patients and extracts from the worm. ‘The poison is a hemo- lytic lipoid body. Other tapeworms rarely occasion anemia, and never the pernicious type just referred to. TENIA SOLIUM This form, sometimes called the pork tapeworm, occurs in the adult state in man as a worm 2 or 3 meters in length; and in the hog or rarely in man in its larval condition. The head is about the size of a pin-head and very dark. Anteriorly it has a rostellum armed with a double row of from twenty-two to thirty-two hooklets. At the sides of the head are four suckers (Fig. 148). Attached to the head is a neck of thread-like appearance, which terminates. at once in the fairly developed segments of the anterior part of the body. The seg- ments at first are broad and short, but become longer in proportion to the breadth toward the posterior end. The sexually mature segments are found at the middle and the posterior end of the worm. They contain a uterus consist- ing of a median tube and six to twelve lateral branches (see Fig. 146, 3). The genital pore is found at one side of the segment, irregularly alternating in successive proglottides. The eggs, which may be squeezed from the segments or obtained free in the feces, are either oval or spherical, from 0.030 to 0.035 mm. in diameter, eS ; and consist of a peripheral striated zone and a Fiz. 148—Head of Central granular portion, showing indistinctly Tenia solium (Mosler and six lines representing hooklets (see Fig. 146). Paper). Groups of segments may be discharged from the bowel from time to time, but this is not frequent; the discharge of single segments is quite unusual. The pro- glottides have independent movement, and may sometimes be seen to move about upon the bed-clothes. The cysticercus stage which gives rise to the Tenia solium lives normally in the intramuscular connective tissue and organs of the domestic pig, but it is known to exist also in a few other mammals as well as in man. The Larval State in Man.—When the ova are taken into the stom- ach the shell is digested and the embryo with its six hooklets is set free. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 387 This penetrates the wall of the stomach or intestine, and in some un- certain manner reaches the muscles or organs, where it effects a lodg- ment. The hooklets are discarded and a little cyst containing clear liquid is formed, and at one point may be found a bud-like projection into the sac. This develops a scolex or head, which eventually becomes identical with the head of the fully formed worm. The cyst may be surrounded by a wall of reactive connective tissue. The duration of this process of formation of the cysticercus varies somewhat (five to ten or twelve weeks). The size of the cysts in the muscles varies from minute points to that of a pea. In the ventricles of the brain the cysticerci may be as large as a small cherry. Occasionally compound or racemose cysticerct are met with. In some cases the adult worm and the larval form have been found in the same individual (man). This is explained by the assumption that Fig. 149.—Measled pork; two-thirds the natural size (Leuckart). the eggs have reached the stomach, where the larve have been set at liberty to penetrate the wall of the stomach and thus reach the tissues of the body. Among the seats of special interest are the brain, the muscles, espec- ially the peripheral muscles, tongue and heart muscle, and the sub- cutaneous tissues. The Adult Worm in Man.—When measled meat (hog, occasionally that of deer, sheep, and other animals) is eaten in insufficiently cooked form by man the capsules of the cysticerci (Fig. 149) are dissolved, the scolex attaches itself to the mucous membrane of the small intestine, and the worm is developed. Usually there is but one worm; occasion- ally several occur in the same case. The worm may remain in the intestine for years, despite repeated efforts to dislodge it. In other cases it is spontaneously discharged. Reverse peristalsis may cause portions to be carried to the stomach, whence they may be discharged by vomiting. Geographical Distribution.—The Tenia soliwm is an exceedingly rare parasite in America. It seems to be more common in certain parts of Europe. 388 A TEXT-BOOK OF PATHOLOGY THNIA SAGINATA This form, sometimes called the beef tapeworm, is the common tapeworm of man. It is larger than the preceding form, being from 4 to 8 meters in length, though it may reach a length of 35 meters. The head is large (2 mm. broad), cuboidal, and provided with four suckers. There is an abortive rostellum, but no hooklets (Fig. 150). The neck is rather long and slender and the segments rapidly become broader than long, but in the posterior half of the worm, where the sexually mature proglottides are found, the segments are longer than broad. The uterus is formed like that of the Tenia solium, but the lateral branches are more numerous (twenty to thirty, and often di- By Fig. 150.—Head of Tenia saginata (Mosler Fig. 151.—Cysticercus of Tenia saginata; and Peiper). natural size (Leuckart). chotomously branched; see Fig. 146, 1). The eggs are rather more oval and larger than those of Tenia solium, but otherwise closely resemble the latter. . The larval form, or cysticercus, occurs in the ox and sometimes in the giraffe. The measles are found in the muscles, liver, lungs, and occasionally in other organs (Fig. 151). The adult form occurs only in man, and occupies the small intes- tine. The presence of the worm does not seem to occasion any definite disease of the intestines, except in rare cases, when a number are found present in a coiled mass, or when one worm is similarly coiled. This may cause intestinal obstruction, and possibly in exceptional instances rupture of the bowel. The symptoms ascribed to tapeworms are some of them doubtless reflex; but it is noteworthy that they are often absent until the patient discovers segments in the stools. (Further reference to possible patho- logical results is made in the discussion of Dibothriocephalus latus.) It is an exceedingly common parasite in certain countries (Africa and the East), but is more or less commonly found in all parts of the world. There is probably no precipitin reaction in the blood, but a comple- ment-fixing body has been found. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 389 HYMENOLEPIS NANA This form, sometimes called the dwarf tapeworm, in its adult state is 1 to 1.5 cm. in length (may reach 2.5 em.) (Figs. 152 and 153). It has a rounded head, with a rostellum that may ‘be protruded or retracted and that bears a single circle of twenty-two to thirty hooklets. The mature segments of the posterior end of the worm have a yellow color. The genital pore is on the same side in all the segments. The eggs are oval in shape, whitish and transparent; they are from 0.036 to 0.056 mm. long and 0.032 to 0.042 mm. broad. The intermediary host of this form is not certainly known, but is supposed to be some form of insect or snail. In the rat the larval form occurs in the intestinal walls at the base of the villi in the form of a cysticercoid, which discharges its contained embryo into the intes- tine, where it matures. The same sequence ‘may occur in man. The adult parasite alone Fig. 152—Hymenolepis nana, about nat- Fig. 153.—Hymenolepis nana, much en- ural size (Mosler and Peiper). larged (Mosler and Peiper). occurs in man. The head attaches itself deeply in the mucous mem- brane of the bowel, and may cause considerable local disturbance. There are usually several or many worms associated; sometimes there may be several thousands. HYMENOLEPIS DIMINUTA This form (probably identical with Tenia flavopunctata) is from 20 to 60 cm. in length; the head is elongated and verges gradually into the neck. The suckers are small, but there is neither rostellum nor hooklets. The segments are marked by a yellowish spot which repre- sents the male genital organs. It seems to be commonest in children. The intermediate host is a species of small moth (Asopia farinalis). It has also been found in several other small insects. 390 A TEXT-BOOK OF PATHOLOGY DIPYLIDIUM CANINUM This form is identical with the worm formerly known as Tenia elliptica, and is a common parasite of dogs and cats. The length is from 15 to 30 cm.; the head is provided with a rostellum bearing sixty hooklets ranged in four rows; the ros- tellum may be protruded or retracted. At the junc- tion of the segments there is a considerable contraction of the diameter of the worm, giving the body a mark- ‘edly linked character (Fig. 154). The mature seg- ments have a reddish-brown color from the presence of the eggs. Each proglottis has a double sexual ap- paratus, with a genital pore at each side. The inter- mediary host is probably the louse of the dog and oc- casionally the flea. The adult worm usually occurs in numbers in the intestinal tract, and in some cases U seems to produce inflammatory disturbances. DAVAINEA MADAGASCARIENSIS This form is from 25 to 30 cm. in length; the head _ Fig. 154.—Dipyl- ig marked by four large suckers and a rostellum bear- idium caninum (Mosler and Peiper). ing about ninety hooklets. TANIA ECHINOCOCCUS The Tenia echinococcus or Echinococcus granulosus in its adult form occurs in the upper part of the intestine of the dog, less commonly of the wolf and jackal, the larval condition occurring in man and in some of the lower animals. The mature worm is about 2.5 or 5 mm. in length, and consists of four segments (Fig. 155). The head, which constitutes the first, is provided with four suckers and a rostellum bearing two to four dozen hooklets in a double row. The second segment is about the breadth of the head, but somewhat shorter. The third is considerably larger; and the fourth is the largest of all, constituting about one-half or two-thirds of the entire worm. The uterus consists of a median portion with a few lateral branches. The eggs are oval, from 0.030 to 0.036 mm. in diameter, and the shell is rather thinner than in the eggs of other tapeworms. These eggs, deposited in water, or on vegetables, or conveyed by tactile communication from the body of Fig. 155.— Teenia echinococ- cus, enlarged (Mosler and Pei- per). ‘the dog, are received into the mouth of man, and several of the lower animals and a few birds. From the stomach or intestine the embryo, liberated by solution of the egg capsule, bores its way into the vascular system, by which it may be conveyed to any part of the body of its host. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 391 Echinococcus Cysts.—When the eggs reach the stomach or, more probably, the intestine of man the embryo is freed and penetrates the mucous membrane. From each egg a single scolex or several scolices Fig. 156.—Finer structure of wall of echinococcus cyst, showing scolices in delicate cysts (from a specimen in the collection of Dr. Allen J. Smith). may arise (Fig. 156). The scolex is carried by the blood or lymphatic stream to the liver or other organs, where it develops an echinococcus cyst (Fig. 157), of which there may be several varieties. The wall of the cyst Fig. 157.—Echinococcus cyst of the liver (from a specimen in the Museum of the Phila- delphia Hospital). is composed of two layers, an outer cuticular and an inner parenchym- atous, granulocellular layer. The whole is surrounded by an adven- titious capsule of fibrous tissue derived from the organ of the host. 392 A TEXT-BOOK OF PATHOLOGY Within the cyst is a clear, limpid, sometimes amber-colored fluid, having a specific gravity of from 1009 to 1015, of neutral or alkaline reaction, and containing no albumin or only traces, but a considerable quantity of chlorid of sodium, cholesterol, and lipase have been found. A carbo- hydrate is sometimes found in the fluid. Hooklets are usually present and are of considerable diagnostic value. Such a cyst may increase in size, but with no alteration in its general structure, thus forming an acephalocyst (Leennec). This form is found in some of the lower animals and in cattle, where it may attain the size of an apple or an orange. In other cases large numbers of small hollow “brood capsules” are formed within the internal space, in which the order of layers is just the reverse to what it is in the parent cyst, that is, they are lined inside by a thin cuticle and have the parenchymatous layer on their external surface. From the “brood capsules” the scolices or echino- coccus heads develop as external protrusions, at the distal end of which the suckers and hooklets of the scolex are formed (Fig. 158). Some claim that the scolices may develop directly from the cyst wall without the medium of the brood capsules. To this form is given the term Echinococcus veterinorum or E. sco- lictpariens. It occurs chiefly in domesticated animals. Fig. 158.—Formation of ‘‘brood cap- Fig. 159.—Echinococcus multilocularis sules’’ upon the parenchymatous layer (Luschka). (Leuckart). In man and only rarely in cattle the mother-cyst may develop “daughter-cysts,’ which, though smaller than the parent, resemble it in the structure of their walls, which are covered externally by a stratified cuticle and internally by the parenchymatous layer. They arise from small detached portions of the parenchymatous layer in the strata of the cuticle of the mother-cyst; they may bulge inwardly or outwardly and may separate themselves entirely from the mother-cyst. The “daughter-cysts’” may remain sterile or may produce brood capsules and ‘scolices or other cysts (‘‘granddaughter-cysts”). To this cyst the term “hydatid,” or Echinococcus hominis or E. altricipariens is applied. There is another form of echinococcus occurring in man as well as ‘in animals and termed Echinococcus multilocularis (Fig. 159). It varies from the size of a fist to a child’s head, presents a collection of cysts from 0.1 to 5 mm. in diameter, and is embedded in a connective-tissue stroma. Each cyst is covered with stratified cuticle, and according to the size contains either solid cellular contents or a cavity lined with a parenchymatous layer. The fluid in this cavity may be transparent ANIMAL PARASITES AND DISEASES CAUSED BY THEM 393 or opaque, due to the presence of fat globules, bile-pigment if the cyst be in the liver, hematoidin, and fat crystals. The cysts are usually sterile, though scolices may be present in some. In man the center of the mass disintegrates, leaving a large cavity filled with a brown or greenish fluid containing shreds of the wall, calcareous bodies, small cysts, scolices and hooklets, fat, hematoidin, margarin, cholesterin, and con- cretions of lime. Nothing positive is known as to the development of this form, that is, whether it springs from a single oncosphere or from a number of oncospheres, or whether its conformation is brought about by peculiarities in its surroundings. Echinococcus cysts may continue to grow until they have renched huge dimensions without undergoing any secondary changes. In other cases the parasite may die and the growth may cease, or active proliferation of the tissues around the cyst may lead to early destruction. In still other cases suppurative change occurs in the cyst or its wall. In all cases when the cyst reaches a certain size the tissues around it produce a connective-tissue capsule of greater or less thickness. When the parasite dies, inspissation of the liquid occurs, and it may eventually disappear or be converted into a thick whitish material; the cyst walls and the connective-tissue capsule at the same time shrivel and present peculiar concentric lamellations that are very characteristic. Event- ually calcification of the wall of the cyst and, to a certain extent, of its contents takes place. The blood of patients suffering from hydatid disease will fix the complement away from the hemolytic series if the contents of a cyst be used as antigen. This complement-fixation may be used diagnostically. The contents of the cyst seem to be toxic, for if they escape in the body a severe intoxication results, taking the form of local irritation, inflam- mation, fever, and urticaria. Seats.—Echinococcus cysts are most frequent in the liver. They also occur in the lungs, kidneys, spleen, and omentum, and less frequently in the brain or other parts of the nervous system. The pathological effects are usually produced by direct mechanical pressure, but may be due to the toxin as noted above. The geographical distribution is extensive, but the disease is com- mon only in restricted localities, especially in northern countries (north of Europe, Iceland). DIBOTHRIOCEPHALUS LATUS The Dibothriocephalus latus is the largest tapeworm of man, reaching the length of from 2 to 9 meters or more. The head is flat- tened and club shaped and presents two groove-like suckers at its . sides (Fig. 160). The neck is thin and gradually increases in diameter. The ripe segments are quadrate, and are distinguished by a rosette-like formation of the uterus, which is plainly visible in the center of each proglottis (see Fig. 146, 2). The genital pore is upon the flat surface of the segment and always upon the same side of the worm. The eggs are 394 A TEXT-BOOK OF PATHOLOGY oval in shape and enclosed in a shell presenting a hinged lid at one pole. The intermediary host is some form of fish, most frequently the pike. The eggs first undergo a certain amount of development in water, the embryo becoming free and floating about, or being propelled by a ciliated outer covering, and then en- tering the digestive tract of fish. Transmission of the parasite to its human host is believed to be con- fined to the eating of the flesh of infected fish im- perfectly salted or cooked. The toxic effect of this worm is believed to be due to a hemolytic lipoid which is excreted by the worm or liberated by its enzymes when acting upon Fiz. 160.—Head detached proglottides. Extracts of the worm have andneckof Diboth- a marked digestive power on protein. tecseeny ue The geographical distribution is comparatively restricted. It is frequent in certain northern coun- tries, as in Sweden and in parts of central Europe, especially in Switzerland. It is only occasionally met with in America in immi- grants. DIBOTHRIOCEPHALUS CORDATUS This variety is much smaller than the last, the maximum being from 1 to 1.25. The head is short, broad, and heart shaped, and the suckers are placed upon the flat surface. The uterine structure differs from that of Dibothriocephalus latus in being narrower and more elon- gated, and also in having lateral branches. The body of the worm con- tains granular calcareous matter. This parasite is found commonly in the seal, the walrus, and the dog in Greenland and Iceland, occa- sionally in man also. No doubt its larva lives in fishes. BOTHRIOCEPHALUS MANSONI This variety occurs only in the larval form in man, nothing being known of the character of the adult worm. It has been found in the region of the loins, in the urinary passages, and in the tissues about the eyes. The head of the worm is distinguished by a papilla-like projection. DIPLOGONOPORUS GRANDIS This parasite measures up to 10 meters in length. The scolex is unknown. On the ventral surface are two grooves in which lie the genital pores. The ova are brownish, oval, measuring 0.063 mm. in length and 0.048 mm. in width. It has been observed in Japan. ANIMAL PARASITES AND DISEASES CAUSED BY THEM 395 NEMATODES, OR ROUND-WORMS ASCARIS LUMBRICOIDES The Ascaris lumbricoides, or ordinary round-worm, is one of the most frequent intestinal parasites. The male may reach a length of 25 cm. and a thickness of 2 to 4 mm.; the female is longer, up to 40 cm., and thicker, up to 5 or 6 mm. The body of the worm is brownish or sometimes pinkish in color, and pre- sents parallel ridges or rings somewhat like those of the earth-worm. The head is provided with three rounded prominences or lips, between which the mouth is placed (Fig. 161). The male shows two chitinous spicules at the cloaca. The eggs of the worm are produced in great numbers; they are elliptical, measuring 0.05 to 0.07 mm. in length, and 0.04 to 0.05 in breadth and are covered with a tough shell, surrounding which is a clear material in an irregular mass. The contents of the eggs consist of a granular ma- terial, sometimes showing the linear outlines of an embryo. The ascaris develops in man from swallow- ing the eggs in infested drinking-water or food. The parasites may be present singly or in num- bers. They occupy the small intestine, but fre- quently migrate, entering the gall-ducts, the stomach, the esophagus, and even the larynx or nasal cavities. : Pathological Physiology.—Ascarides may give rise to violent symptoms by obstruction of various passage-ways, and when in numbers or united in masses even intestinal obstruction may be caused. It is probable that ascarides produce oo : . irritating secretions, as it has been observed a eee that considerable dermatitis sometimes arises in C; egg, magnified 300 diam- . ; i eters; b, head, magnified persons handling them. The toxic action has (after Perls). been ascribed to fatty acids and irritating vola- tile aldehyds which have been found in them. Occasionally abscess cavities containing lumbricoids are found in connection with ulcera- tions and perforation of the intestines. These abscesses were believed by older authors to be caused by the worms; at the present time it is more generally held that the worms play no important part, their presence being due only to their coincidence in the intestine. ASCARIS CANIS This form, which is common in cats and dogs, is rarely met with in man. It is much smaller than the ordinary round-worm, the male 396 A TEXT-BOOK OF PATHOLOGY reaching a length of 45 or 60 mm., and the female 120 to 130 mm, The head is distinguished by two lateral wing-like projections com- posed of chitinous material. OXYURIS VERMICULARIS The oxyuris, seat-worm, or pin-worm, is one of the commonest para- sites of man. The male is 2.5 to 5 mm. in length; the female, 10 to 12 mm. (Fig. 162). The posterior end of the male is blunt and curved upon itself; in the female it is elongated. The eggs of the oxyuris, which are produced in great numbers, are oval or elliptical and about 0.05 mm. long. The embryo is visible within as a lobulated body. The parasite is developed directly from the eggs. When these are swallowed the outer coating is dis- solved in the stomach and the embryos escape, to reach their full development in the small in- testine. The impregnation occurs in the small intestine within a short time after the swallow- Fig. 162.—Oxyuris ver- ing of the eggs. After impregnation and ripen- micularis: a, female; b, ing the female parasites move toward the rectum male (Mosler and Peiper). ? é and may be discharged, or may leave by their own movements. The life of the worm is short, but there is always the possibility of reinfection. Oxyuris is especially common in childhood. It is probable that the worms sometimes cause inflammatory troubles. In cases in which they accumulate in numbers a form of verminous diarrhea may be pro- duced. In female children vaginitis frequently results from the migration of the parasites into the vagina. a b TRICHINELLA SPIRALIS This organism occurs in its larval form in the muscles or organs of man and in the lower animals; in the adult form it is found in the intes- tines of man or animals. The adult male is about 1.5 mm. in length and 0.04 mm. in thick- ness. At the posterior end there is a retractile cloaca flanked by two projections. The female is 2 to 4 mm. in length and 0.06 mm. in thick- ness. The eggs are provided with a very thin shell, and the embryos escape from this within the uterus. They are produced in immense numbers. The young embryos found in the intestinal tract are from 0.1 to 0.16 mm. in length, the anterior end being thicker than the pos- terior. In part they escape with the feces and die; the greater part pene- trate the intestinal wall and are carried to various parts of the system, embedding themselves especially in the muscles, where they undergo further changes. Here the organism coils itself and becomes surrounded with a capsule, which is at first transparent, but ANIMAL PARASITES AND DISEASES CAUSED BY THEM 397 may subsequently undergo calcareous change and become opaque (Fig. 163). Trichinelle are acquired by man by eating improperly cooked ham. The capsules are digested and the larval trichinelle set free. In the small intestine they reach their maturity in about three days; here impregna- tion takes place, after which the males die, while the females either bore more or less deeply into the villi or, by way of the glands of Lieber- kiihn, penetrate the mucous membrane, and so reach the lymphatic spaces, where they deposit their young. These are disseminated throughout the body by their own migra- tions or by means of the lymph- and blood- streams. ? The favorite seat is the striated muscle tissue, and they lie within the muscle bun- dles themselves or, less frequently, between them. They reach their destination in ten Fig. 163.—Trichinella cap- days after the primary invasion, but subse- _ sule with its connective-tissue : covering: a, early stage; b, quent crops are deposited as the young con- calcified (Leuckart). tinue to mature in the intestines. In two or three weeks they begin to become encysted in the muscles, where they remain alive, capable of development for many years. When the embryos are liberated in the stomach and intestines they occasion violent gastro-intestinal irritation, with vomiting, diarrhea, and often more or less pronounced collapse. In their later migration the worms set up intense muscular pains of rheumatoid character, with edematous swelling and fever. The disseminated disease is called “trichiniasis.””. The pathology of this condition includes, besides myo- sitis and gastro-enteritis, fatty liver, nephritis, and infarcts. There is undoubtedly an irritative toxin produced, but whether this is wholly within the worm or in part made from the degeneration of muscle tissue is not certain. There is usually a marked eosinophile increase, the cells arising in the bone-marrow from toxin action. The worm uses the glycogen stored in the muscles during its growth. No passive im- munity can be produced with the blood of injected animals. Trichiniasis is common in all parts of the world, but has been largely reduced by greater care in the cooking of pork. ANKYLOSTOMA DUODENALE OR UNCINARIA DUODENALIS The Ankylostoma duodenale is a cylindrical worm, the female being from 12 to 18 mm. in length; the male, from 8 to 10 mm. The head is rounded, bent back like a hook, and is armed with six sharp, hook-like teeth, two pairs ventrally, one pair dorsally. The female is usually of a brownish or reddish color, due to the ab- sorption of coloring-matter from the blood. The elliptical eggs are easily distinguished, from 0.056 to 0.063 mm. in length and 0.036 to 0.04 398 A TEXT-BOOK OF PATHOLOGY mm. in thickness. The shell is separated from the contents, and the latter have a granular appearance, are brownish, and in a state of seg- mentation. The eggs may appear in the stools in great numbers. If now they meet with the proper conditions, chief of which are a warm climate and damp earth, they hatch out and the active embryo is set free. It rapidly acquires organs of digestion and, after casting its skin several times and undergoing other evolutionary changes, is ready to re-enter a human host. Loos has proved quite conclusively that, while the organism may rarely enter the human alimentary canal by the mouth, the probable method of entrance is far more complicated. After completing its exogenous phase of development, a suitable opportunity offering, the little worm penetrates the skin, generally of the feet and legs, of the coolies or others working in or passing through the contaminated earth in which the ankylostome ova had been previously deposited. The embryo enters the skin through some follicle, thence Fig. 164.—Ankylostoma duodenale: a, Male, natural size; b, female, natural size; c, male, magnified; d, female, magnified; e, head, greatly magnified; f, f, f, eggs (von Jaksch). passes into a blood-vessel, and so is carried finally to the lungs. Here it leaves the blood-vessels and, undergoing further changes to enable it to resist the gastric juice, enters an air vesicle, passes to a bronchus, and so, by way of the trachea, esophagus, and stomach, finally arriving at the small intestine. Sexual characters are now assumed and reproduc- tion commences, the ova falling into the contents of the gut and so passed out in the stools. The adult worm may be present in small or large numbers, and is usually rather firmly attached to the mucous membrane. Changes in the latter, however, are not pronounced. The method of entrance of the ankylostome to its human host throws important light on the condition known as “‘coolie itch” or “ground itch,” which often is a forerunner of the intense anemia and other symptoms of the condition known as ankylostomiasis; “coolie itch” is a sort of papulopustular dermatitis generally attacking the ANIMAL PARASITES AND DISEASES CAUSED BY THEM 399 feet and legs, and at times other surfaces as well, of the coolie laborers on plantations. It is probably caused by the passage of the ankylostome embryos through the skin. Ankylostomiasis or uncinariasis is charac- terized by severe and intense anemia, abdominal discomfort or pain, general wasting, often followed by death. This parasite was also found in many cases of Egyptian chlorosis, and was the cause of the intense anemias (pernicious anemia) of the laborers engaged in building the St. Gotthard tunnel. NECATOR AMERICANUS OR UNCINARIA AMERICANA This parasite is shorter and more slender than the Ankylostoma duodenale, the male being 6 to 9 mm. long, and the female 8 to 15 mm. Pigaa aaa 7 BFS CT er a Ariterior Duceal Jip ; for Wueealslip, Buceal teetir> Thucend Hooks: | - Dorsal conten) oul { | | Fig. 165.—A, Dorsal view of head end of Ankylostoma duodenale; B, dorsal view of head end of Necator americanus. (Drawn to scale to show difference in size. A. J. Smith.) Jong. There are also minute differences in the head and body, though the general structure of the two parasites is the same. In place of the xc 2 Dorsal ray ese fern 9 aa AN tateral ray De tral ee ray Ventrolutern)\ Veutral ray Fig. 166.—A, Caudal bursa and tail of male Ankylostoma duodenale; B, caudal bursa 4 i of male Necator americanus. (Drawn to scale to show difference in size. A.J. mith. ventral and dorsal oval teeth there are plates or suckers, while deep in the mouth opening there is one central tooth and one pair of narrow Ee Bie Aig ED Mii. anew Fig. 167.—Ova of (A) Ankylostoma duodenale; (B) Necator americanus. (Drawn to scale to show comparative size. A.J. Smith.) straight teeth ventrally and dorsally. The ova are larger than those of the Ankylostoma duodenale, being 0.068 mm. in length and 0.038 mm. 400 A TEXT-BOOK OF PATHOLOGY in breadth, otherwise they are similar. This form has been found especially in tropical and subtropical America and in the West Indian islands. The conditions produced by the American hookworm are similar to those caused by the Old World form, but are probably less intense. The pathological effect of uncinariasis is toxic. The worms remove some blood from the gut wall for their nourishment, but not. enough to cause the severe anemia of the disease. Small hemorrhages appear in the gut. A weak hemolysin is formed, can be extracted from the worm, and is probably absorbed by the intestine. There is also an active coagulating body in the head of the dog hookworm. There are to be found in the body fatty degeneration and hyperplasia of the bone- marrow. : STRONGYLOIDES INTESTINALIS This parasite occurs in two generations or types: the parasitic, in which the individual of female habitus represents both sexes and reproduces by parthenogenesis; and the free living generation, in which the two sexes are represented by different individuals. The parasitic generation (Anguillula intestinalis) lives in the upper intestinal tract, boring deeply into the mucous membrane and frequently into the epi- thelium of Lieberkiihn’s glands both for nourishment and oviposition. This form is 2.2 mm. in length and 0.034 mm. in breadth; the mouth is surrounded by four lips, the esophagus is almost cylindrical and a quar- ter the length of the entire body; the eggs measure 0.050 to 0.058 mm. in length and 0.030 to 0.034 mm. in breadth. The eggs develop in the intestinal wall, and the rhabditiform larvae, which measure 0.2 mm. in length, reach the lumen of the intestine and grow to double or three times that size until they are passed out with the feces. With the proper temperature (26° to 35° C.; 78.8°-95° F.) they develop in about thirty hours into the free living generation (Anguillula stercoralis). This form is sexually differentiated; its body is smooth and cylindrical, with pointed tail end. The mouth has four distinct lips; the esophagus is short with a double (rhabditic-like) dilatation; there are three small curved spicules at the base of the tail. In the males the posterior end is rolled up, in the females it is straight and pointed. The males measure 0.7 mm. in length and 0.035 mm. in breadth. The females measure 1 mm. in length and 0.05 mm. in breadth. The ova are thin shelled, yellowish, and measure 0.07 mm. in length and 0.045 mm. in breadth. The embryo as it emerges from the egg often within the uterus measures 0.22 mm. in length and resembles the parent form. After growing to about 0.55 mm. in length it moults and then takes on the characteristics of the parasitic form (strongyloid or filariform larve). In the European strongyloides the free living generation is absent. This may also be true in the strongyloides of tropical origin where external conditions are unfavorable to the development of the rhabditic form. There are, as has been mentioned, two methods of reproduction: that by direct transformation of the rhabditiform larve into filariform ANIMAL PARASITES AND DISEASES CAUSED BY THEM 401 and then into adults, and the indirect, through the intermediate genera- tion. By this arrangement the parasite may reproduce directly if external conditions are unfavorable, and indirectly when conditions are favorable. The latter method seems to be more common in the tropics than in colder countries. The adult form alone is parasitic in the true sense; the other form representing only a stage for the perpetuation of the species. Unlike the ankylostome, eggs of strongyloides are rarely found in the stools excepting after purgation. Infection prob- ably occurs through tainted water and food, but some experiments seem to indicate that the embryo may penetrate through the skin and thus gain access to the body. Strongyloides is common in tropical countries, and was first dis- covered in cases of Cochin China diarrhea. It is probably capable of causing intestinal irritation, and seems rarely present in healthy persons, but its pathogenicity is still uncertain. It has recently been discov- ered in the United States. TRICHOCEPHALUS TRICHIURUS The anterior portion of this parasite is thin and thread-like, while the posterior portion is thicker. The length of the worm is from 4 to 5 cm., the male being somewhat the smaller. The thicker part of the male is curled upon itself and blunt at the end, while that of the female is straight and more pointed (Fig. 168). The eggs are very characteristic, being brownish in color, covered with a thick capsule, and having at either pole a button-like projection (see Fig. 146, pb). Be. 168. iehodephdlus. Gricht The egg is 0.050 to 0.054 mm. in length — urus; natural size: a, Female; b, male and 0.023 mm. in breadth. Aen The parasite, commonly known as the ‘‘whip-worm,” occupies the cecum in man, occasionally the vermiform appendix, and sometimes the small intestine. It is one of the most common intestinal parasites in this country and appears to be well distributed over the entire surface of the globe, being particularly frequent in children in Syria and Egypt. It does not, as a rule, produce serious disturbance, but may cause in- testinal or reflex nervous symptoms. Recently it has been claimed that the parasite causes considerable disturbance by abstracting blood and producing a soluble toxin. FILARIA MEDINENSIS The Filaria or Dracunculus medinensis is a round-worm infesting the subcutaneous tissue and the skin. The male has not been recog- nized with certainty, though two observers have found a smaller degenerated and partly calcified form in association with the female filaria. The female sometimes reaches a length of 50 to 80 cm.; it is 26 402 A TEXT-BOOK OF PATHOLOGY yellowish in color and exceedingly elastic; the anterior extremity jis roundish, the posterior terminating in a spine. In general appearance it resembles a string of catgut. The body of the worm contains a highly developed uterus, which practically fills the cavity of the worm, the intestinal tube being crowded to one side. The uterus is found to con- tain innumerable small embryos; these escape when the parasite is rup- tured. The process or place of impregnation is unknown. When ovulation, however, is completed the parasite moves down to the leg or foot of her host, whence she will be better able to deposit her young in water, which is absolutely necessary for their development. Here she drills a small hole in the derma, but does not penetrate the epidermis. Over this a small blister or bulla forms which soon ruptures, disclosing the small opening in the center of a superficial erosion. When the host now enters the water a portion of the uterine tube is forced out through the mouth of the worm by the contraction of the musculocutaneous integument and ruptures, setting free myriads of the embryo worms. This is re- peated at intervals until the entire uterus is expelled and parturition is completed. This takes, as a rule, two to three weeks. The worm now dies, and is expelled or pulled out bit by bit or entire, with or without suppuration. Forcible attempts at removal of the worm from the tis- sues may result in its rupture, thus setting free millions of embryos in the tissues, whose presence, associated with suppuration, which usually follows, results in a condition of considerable danger to the patient. It is, therefore, better to wait until parturition is completed before attempting removal of the worm. The embryos having been deposited in the water take up their abode in the intermediary host, the body cavities of a species of cyclops. They enter by penetrating the delicate membrane that unites the plates of the ectoskeleton of the crustacean. The life-history from here on is a blank. It has been thought that after proper development the parasite is swal- lowed in drinking-water while still in the body of the crustacean, or it may be after it has escaped from this intermediary. Or it may obtain entrance to its human host by boring its way through the skin. The organism occurs very abundantly in tropical countries of the Old World, notably Arabia, along the coast of the Caspian Sea, in Abyssinia, and Guinea. The parasite is sometimes called the Guinea-worm. FILARIA BANCROFTI Several varieties of filarize have been found in the blood and are included under this generic term. The discovery of the organism or, rather, of the embryos was made by Wucherer in a case of hema- turia. The embryos of Filaria bancrofti or F. sanguinis hominis appear in the blood, urine, the lymph, and the tissues as thread-like structures, varying in size in the different varieties. The ordinary form has a thickness of about the diameter of a red corpuscle, and is as much as ANIMAL PARASITES AND DISEASES CAUSED BY THEM 403 0.13 to 0.3 mm. in length. It consists of a transparent sheath, almost completely filled with the embryo, the ends, however, projecting a little beyond the organism in a sac-like fashion (Fig. 169). The embryo is actively motile, squirming, thrashing, or curling and uncurling itself rapidly, and thus producing more or less agitation of the corpuscles or solid bodies in its vicinity. The number of the embryos found in the blood varies greatly; in many cases a search through several cover-glass preparations may be necessary to detect a single one. Usually they are more abundant. A feature of importance is that they occur only during the night, unless the patient reverses the usual conditions and rests during the day. The adult worms occupy the lymphatic channels, the male and female _ being found together. The male is colorless and measures about 40 mm. in length and 0.1 mm. in thickness. The cephalic extremity is a little thickened, the posterior extremity is bent and rounded, but not spiral. The female is brownish, 76 to 80 mm. in length and 0.2 to 0.3 mm. in thickness. Both extremities are rounded. Almost the entire body Fig. 169.—Filaria embryo, alive in the blood (F. P. Henry). is occupied by the two uterine tubes, in which may be seen the ova and already developed larval filariz. These enter the circulation and are discharged in various ways, especially in the urine. The common tropical mosquito (Culex fatigans) has been found to act as the inter- mediary host in which the embryo reaches its fuller development. The embryo filarize are taken into the midgut of the mosquito together with a certain amount of blood at a time when the filarie are found in the peripheral circulation. Here in the thickened plasma the embryos are able by their active movements to break through their sheath. Now, by means of a short delicate spine and a circle of hooked lips at the head end, the organism bores its way to the thoracic muscles of the mosquito. Here in the course of one to three weeks it goes through a series of changes and increases considerably in size. It now works its way to the head of the mosquito, and finally passes down into the labium or sheath of the proboscis, where it awaits the opportunity to enter a human host when the mosquito next feeds on man. It then finds its way into the lymphatic trunks, where the sexes come together and the young are born. 404 A TEXT-BOOK OF PATHOLOGY Filariasis is particularly common in the warmer climates, but is occasionally met with in this country, especially in the Southern States, One of its most frequent forms is characterized clinically by hemato- chyluria. The embryos in these cases may be found in the blood and also in the chylous urine. Pathologically, no gross changes may be found, but there may be in other cases evident distention of the lymphatic channels and blood-vessels of the pelvis of the kidneys, ureters, or bladder; and the embryos may be found in the substance of the kidneys or in the walls of the blood-vessels. Another form of filariasis is ele- phantiasis. In these cases there is obstruction of the lymphatic vessels in consequence of the presence of the parasites, of thrombi, or of inflam- matory lesions, and as a result of these conditions dilatation of the peripheral lymphatic vessels occurs. The skin may be ruptured and chylous liquid may exude. The embryos may be found in this on micro- scopical examination. Varieties——Manson has described three varieties of embryonal filarie—the original form, or Filaria nocturna; a second variety, in which the embryos are found at any time, night or day, called Filaria perstans, characterized also by its small size (0.2 mm. in length), great motility, and absence of a sheath; this he believes is the cause of certain skin diseases (craw-craw) of Africa; the adult worm is unknown. The third form is the Filaria diurna, which appears in the blood only during the day. The last is probably the embryo of Filaria loa, a wandering form frequently occurring in the eye, lying under the conjunctiva. It is found in Africa and tropical America. Manson believes that the mangrove fly is the intermediary host. OTHER FORMS OF FILARIZ The Filaria lentis was found in the lens in a case of cataract; the F. labialis was discovered in a pustule on the lip of a student in Naples; the F. hominis oris was found by Leidy in the mouth of a child; and F. restiformzs was found in the urine of a patient by the same observer. The F. immitis is the common filaria of the dog, and has been found in man. The F. ozzardi was found in the blood of Caribs of British Guiana. The F. loa is confined to Western Africa. The F. bronchialis was found in the bronchial lymphatic glands in a case of phthisis, and has also been found in the trachea and bronchi. The F. demarquayi and F. magalhesi are forms whose identity has not been sufficiently established. F. conjunctive, F. lymphatica, and F. romanorum-ortentalis are others that have been described. ECHINORHYNCHUS GIGAS This is a large round-worm, the body being marked by distinct, transverse, parallel rings. The male may be from 7 to 10 cm. in length, the female from 31 to 50 cm. There is a retractile rostellum, with six rows of hooklets at the anterior end, each row composed of eight spicules. The parasite occupies the small intestine of the hog, and has been found ANIMAL PARASITES AND DISEASES CAUSED BY THEM 405 occasionally in man. The intermediate host seems to be the grub of the cockchafer and the June-bug. Other varieties of echinorhynchus have been described, but are not well-determined species. EUSTRONGYLUS GIGAS The female of this species may reach a length of 1 meter; the male is but one-third the size. The anterior end of the worm is retracted and the mouth surrounded by six papille. The posterior end is expanded and provided with a spicule projecting from the cloaca. The color of the worm is brownish or blood red. The parasite is found in the pelvis of the kidneys, ureters, and bladder of dogs, horses, cattle and other animals, and rarely in man. Among its results are enlargement of the pelvis of the kidney and atrophy of the kidney substance. STRONGYLUS APRI This parasite was found in the lungs of a child. It resembles the strongylus met with in the lungs of sheep and other animals. STRONGYLUS SUBTILIS This organism has been described by Loos as being found in the intestines at autopsies of natives of the Egyptian lowlands. ANNELIDES Two forms of leeches are of some pathological importance. The Hirudo ceylonica is a form occurring with great frequency in Ceylon and other islands, and in parts of South America. It is found in vegeta- tion, and attaches itself to the skin of the legs and to other parts of man by means of a sucker and its short teeth. It may give rise to painful ulcerations when removed. The Hirudo vorax is met with in parts of Europe and Africa. It gains access to the mucous membranes of the mouth, larynx, trachea or nasal chambers, and leads to inflammatory troubles. It is not able to effect a lodgment upon the skin. ARTHROPODA A number of parasites belonging to the groups Arachnoidea and Insecta are met with in man. Most of these, however, are purely external parasites, and are fully described in works upon diseases of the skin. There are two forms, however, that merit brief description here: the Linguatula rhinaria, its larval form of Pentastoma tenioides; and the larvee of various flies, the presence of which in the gastro-intestinal tract and other parts of the body is termed myiasis.: 406 A TEXT-BOOK OF PATHOLOGY LINGUATULA RHINARIA This parasite is occasionally found in the liver, and rarely in the spleen, intestinal walls, lungs, and kidneys of man. It is discovered in small nodular lesions, which consist of the more or less degenerated parasite lying in a cheesy or semicalcified material, surrounded by a fibrous or calcareous capsule. The parasite is from 4 to 5 mm. in length and 1.5 mm. in breadth; has a rather rounded body, which is encircled by parallel rings armed with spicules; and is provided with two pairs of stout chitinous hooklets, one pair lying on either side of the mouth. The adult form, Linguatula rhinaria, resembles its larva in structure, but is considerably larger, the male being from 16 to 18 mm. long, the female from 80 to 100 mm. This form lodges in the nasal cavities and frontal sinuses of the dog and other animals, and produces eggs contain- ing the embryos, which escape with the nasal secretion and eventually gain access to the alimentary tract of other animals or of man. POROCEPHALUS CONSTRICTUS This species has been discovered in man in a few cases, and only in its larval form. It differs from Linguatula rhinaria in being larger (10 to 14 mm. in length) and having a smooth surface. It has been found in the peritoneal cavity, intestines, liver, and lungs. MYIASIS A number of flies, of the orders Estride, Musca, Lucilia, and Sar- cophaga, may deposit their eggs in wounds or in cavities of the body to which they gain access, such as the nasal or pharyngeal chambers and the communicating passages. The eggs so deposited are hatched, and the larval insects may be retained and may occasion intense irritation. Sometimes the larve are found in the gastro-intestinal tract, the eggs having been swallowed with food. Immense numbers may be discharged from the intestines, and in some cases the larvee seem to occasion intes- tinal irritation. The term myiasis is given to the invasion of these larval insects. CHAPTER XI THE METHODS OF TRANSMISSION OF THE COMMUNI- CABLE DISEASES THE acquisition of a communicable or infectious disease requires the entrance into the animal or human body of the disease-producing agent, which must exist in nature in a form which can be conveyed to or into the body. The paths of infection have already been discussed, and it remains to be considered here how the viruses are brought to these paths. Sanitarians have supplied data which permit the classi- fication of the transmission of disease as direct, indirect, and through an intermediate host in which the virus must pass through some cycle of development. There are some diseases whose method of propagation is not yet known, and these will be discussed separately. The sources from which diseases are disseminated are human beings and lower animals. There are a few conditions, like ergot-poisoning and pellagra, exhibiting a clinical and pathological course much like an infec- tion, which seem at this time to be traceable to the vegetable kingdom. The diseases that pass from human being to human being far out- number those contracted from animals, and many are truly specific for man; for example, the acute exanthemata are diseases of the human race alone, and only very exceptionally can be transmitted experimentally to the lower races. As a natural corollary it follows that man is the greatest disseminator of infectious disease among men. Many infec- tions more or less specific for the lower animals are transmissible to man, but do not, as a rule, assume epidemic forms; while acute infections peculiar to man and spread by him tend to appear epidemically or endemically. In like manner, animals are the most important means of dissemination of infection among animals. ‘The transmission of disease from man to man occurs by direct con- tact, such as handling or kissing; indirectly, as in the use of infective linen, eating utensils or taking infective material into the mouth, or by an intermediate host, as the mosquito in malaria. From animals men are infected chiefly by handling or by the par- taking of infected milk or meat. Biting is of great importance, as exemplified by rabies. Man is infected by plants usually by eating, but simple handling of some plants, like poison ivy, produces a condition akin to infection in susceptible persons. Diseases are propagated among animals chiefly by direct contact or by infective food. When one animal of a herd or flock becomes infected it is easy for it to infect the common food supply, be it pasture, crib, or pan. The importance of this lies in the fact that a milk-giving herd may be infected throughout by one new member and render the milk unfit for human use. 407 408 A TEXT-BOOK OF PATHOLOGY Direct Infection.—Contact Infection —This group embraces those diseases which demand for their dissemination a rather intimate personal relation of the sick and well, either by touching or the intervention of air or droplets in the expired air. It is doubtful if any infection is trans- ferred in this manner only, but certain diseases are so contracted in the vast majority of cases. For example, the venereal diseases—lues, gonorrhea, and chancroid—are practically always acquired by the intro- duction of the germs into skin or mucous membrane abrasions by direct inoculations from infected persons. Their causative organisms survive exposure to conditions outside the human body for a very short time. Drying is fatal to the Spirocheta pallida and the gonococeus in a few hours. Chicken-pox is an acute infection that seems at the present day only transmissible directly, that is, it is not carried by a third person. Rabies is a good example of direct infection, for it is obligatory that the fresh virus be introduced beneath the skin. While the exact means of transmission of leprosy is not known, it is probable that direct contact is necessary for its acquisition. Aside from these contact infections, direct transmission is air borne by the dissemination of bare germs or those contained in finely divided droplets of sputum or saliva, or carried in dust. It is to be emphasized that no sharp line can be drawn between direct and indirect transmission, because all those diseases which may be carried by fomites and food can be acquired by the direct passage of infective matter from the sick to the well. There are some infections, like diphtheria, scarlatina, mumps, small-pox, and measles, whose spread is possible merely through the air and yet can be carried by fomites and by a third person, possibly by a “carrier” (g. v.). These may be called the air-borne infections when emanations from the sick person are carried to the well merely through the air. The exact course of travel is not known for those diseases whose causative agent has not been isolated, e. g., small-pox. In the bacterial diseases, like tuberculosis, diphtheria, pneumonia, plague, influenza, micro-organisms are loosened from the patient’s person by coughing, or the drying of secretions or excretions, and blown about by air cur- rents. They may settle upon surfaces, whence they are again carried to the well by air or contact. The most important factors in dis- semination of bacteria by such means are coughing and sneezing, which forcible expiratory actions project infective matters considerable distances. It is said that tubercle bacilli may be thrown twenty feet in front of a coughing consumptive. Few, if any, micro-organisms are to be found in the breath during quiet respiration. The bacteria are carried by droplets of sputa. These fall and dry upon surfaces, to be pulverized and removed by air or contact. Dust is also a carrier of germs and serves as a protection for them, as it keeps away light. The viruses of communicable diseases are for the most part quickly destroyed by exposure to direct light, but if protected by some envelope, as mucus about a tubercle bacillus, their infectivity is indefinite. Disease germs are common in dust and dirt that dry upon floors and walls of public con- veyances. In public places or conveyances, houses, hospitals, schools, METHODS OF TRANSMISSION OF THE COMMUNICABLE DISEASES 409 and workshops this sputum and dust transmission is of great importance. Bacteria are not widely disseminated by air currents, since they soon perish by exposure. They are not carried far by air currents from sewers or drains, notwithstanding popular belief to the contrary. Bacteria may be propelled several feet by the bursting of bubbles in a sewer opening, but this is of little or no importance in the transmission of disease. Indirect Transmission.—This takes place when the agent passes from the sick to the well by some conveyance which permits the virus to grow or at least to sustain life. The vehicle may be water, food, soil, . insects or human beings, or more passive carriers, called fomites, like infected bed or body clothing, towels, drinking cups, and eating utensils. In these transmissions we assume that the germs are simply carried by the vehicle as a passenger and that the vehicle itself exerts no influence upon them. By a prolonged existence in the vehicle and, therefore, ab- sence from the human body, the pathogenic organisms may become reduced in virulence. Water transmission, according to present knowledge of disease, is confined to typhoid, cholera, and perhaps dysentery, both of the bacil- lary and amebic type. No definite limit can be set for the life in water for the germs of these diseases, but it may be months. Food Transmission—The most important food-carrier of disease is milk. Typhoid fever, diphtheria, septic sore throat, and scarla- tina are carried by milk when contaminated during collection and dis- tribution by persons suffering from these diseases or by carriers. In- fected water used to wash cans or to dilute milk may introduce typhoid bacilli. Diseases originating in the animal supplying the milk, as tuber- culosis, foot-and-mouth disease, and Malta fever, are transmissible to man. The transmission of tuberculosis by milk of tuberculous animals cannot be doubted. _ Vegetables convey disease only when contaminated by surround- ings in cultivation or in the process of preparation for food. Oysters and other shell-fish when taken from polluted water may convey typhoid fever and cholera. Meat conveys animal parasites and acute bacterial and toxin diseases like paracolon and paratyphoid fever, botulism, and ptomain-poisoning. Tuberculosis is undoubtedly transmissible by in- fected meat. Soil Transmission.—There are many organisms in soil, but few of the varieties are pathogenic for man. Certain pathogens, like typhoid and plague bacilli and cocci, are occasionally to be found, but are of little Importance in hygiene. In plague centers the soil is said to be fre- quently infected with plague bacilli. The organisms most frequently found in the soil that produce specific infections in man are those of tetanus, anthrax, malignant edema, and symptomatic anthrax. The life of these germs in soil is favored by their spore formation. _ Ansect Transmission.—This may be direct or indirect. The former includes those transmissions in which the insect acts as an interme- diate host of the virus, permitting some developmental phase in it, 410 A TEXT-BOOK OF PATHOLOGY a subject to be considered later. Indirect or mechanical transmis- sion occurs when the insect becomes infested with human pathogens and carries them passively to situations where they can infect human beings. Thus, flies may carry typhoid bacilli upon their bodies from dejecta to food; fleas transfer plague bacilli from human cases or infected rats. There is a class of disease transmitted by biting insects in which it seems that the virus does not pass through a cycle of development in the body of the insect. The virus remains in an infective condition within the intermediate host for various lengths of time and may be transmitted to the young. In this class may be included typhus, re- lapsing fevers, Rocky Mountain fever, and trypanosomiasis. It may be found later that a cycle of development occurs in these insect bearers. Animal Transmission.—Animals may act as passive carriers of such diseases as diphtheria, scarlet fever, or measles by association with in- fected persons. The cat is one of the commonest of such conveyors; it is frequently responsible for the spread of the mycosis favus. Animals act as active carriers of various worms. Certain diseases, like actino- mycosis, may be transmitted to man by animals. Human Transmission.—Human beings transfer infection in one of three ways: (a) when actively suffering from disease; (b) passively from sick to well upon person or clothing, and (c) as “carriers.” The opera- tion of the first and second methods is obvious; it is to be understood that under the second heading the conveying person is not ill with the disease he is transmitting. “Carriers’’ are persons who having suffered with a disease have not destroyed or discharged all the virus from the body when recovery took place. This virus has remained in some locality protected from the action of the blood-serum, or by long sojourn in the body has become immune or “‘fixed”’ or ‘‘fast’’ to the bodily defenses. Under certain circumstances it may leave the body and infect others. Thus, after typhoid fever, typhoid bacilli may re- main in the alimentary tract for years, passing out with feces and con- taminating surroundings or the water and food supply. This also occurs after cholera and diphtheria; in the latter case Klebs-Léffler bacilli remain in the throat a long time. These persons might be called ‘‘chronic carriers,’ while the persons who merely passively transfer infection might be termed “accidental carriers.’’ During an infectious disease the patient is, of course, a carrier, and might be spoken of as an “‘infected carrier.”’ Transmission by inanimate objects or fomites is purely mechanical. It is of importance in all infectious diseases except those only transferred by insects. Insect Transmission with a Cycle of Development in the Interme- diate Host.—This is a group differing from the indirectly insect-borne diseases, in that a period of time must elapse between the reception of the virus in the body of an insect until it becomes infective for man. The diseases whose transmission by this means seems now proved beyond doubt are malaria, yellow fever, filariasis, and dengue. Mosquitoes are the “intermediate host” and man is called the “definitive host.” Ticks, METHODS OF TRANSMISSION OF THE COMMUNICABLE DISEASES 411 flies, and other insects also transmit disease and may permit some form of development, but this is not yet proved. Despite the fact that in all insect-borne diseases the viruses do not have the same biological history, there are many analogies among them. The insects concerned are biting or suctorial, and include mosquitoes carrying the viruses above mentioned; ticks, transmitting relapsing fever, Rocky Mountain fever, and tick fever; flies, transmitting trypano- somiasis; and lice, believed to convey typhus. The viruses of yellow fever, dengue, and the tick fevers have not yet been isolated, but epidemiologically their connection with. insects is well established. The insect transmitting African relapsing fever is known, but the other forms are still in doubt. (See page 339.) These insect-borne diseases are transmitted always by the same species of intermediate host, and the virus seems specific for species in the definitive host. One insect seems to carry only one form of virus. The contagium does not harm the carrier so far as known. The diseases appear only where their respective insects live, and when they spread it is the definitive host which carries them, since the insects do not travel far. These infections are not directly communicable. There is a definite and quite constant incubation period peculiar to each disease for both the intermediate and definitive host. Ticks are the only ones that transfer the virus to their young. Method of Transmission Unknown.—In this class only one disease is of importance—poliomyelitis. This acute infection appears and spreads in a manner which baffles investigation. The following theories have been offered to explain the spread of infantile paralysis: 1. That it is passed from person to person via the nose and throat, these localities being constant seats of the virus and the most probable infection atrium; that it is carried in the nose or upon the person by hidden or abortive cases or by an accidental carrier. 2. That it resists conditions outside the body long enough for it to pass through the air long distances, and to remain virulent in dust. 3. That it is transmitted by insects. Rosenau showed that the disease can be transmitted from monkey to monkey by the bite of the stable fly (Stomorys calcitrans). None of these theories cover all cases. It is certainly not easily transmitted by direct contact, because frequently only a single member of a large family of children may be affected. PART II SPECIAL PATHOLOGY CHAPTER I DISEASES OF THE BLOOD ANATOMY Tue blood is a liquid tissue composed of corpuscles or cells and a fluid intercellular substance. The cells are of three kinds: the red corpuscles, or erythrocytes; the white corpuscles, or leukocytes; and the Fig. 170.—Unstained red blood-cells, showing rouleaux formation. (Picture prepared under direction of C. Y. White.) blood-plaques, or platelets. The fluid element of the blood, the lquor sanguinis, or plasma, is an albuminous and saline liquid of a slightly varying composition. The blood as a whole is red in color, rather viscid, 412 DISEASES OF THE BLOOD 413 and alkaline to ordinary indicators, though actually neutral in reac- tion. The total quantity is about one-thirteenth of the body-weight. The erythrocytes, or red corpuscles, are biconcave disks averag- ing 7 w in diameter and having a yellowish or amber color. They are quite uniform in size and regularly rounded. Histologically they are composed essentially of an albuminous substance containing hemoglobin embedded in a delicate stroma. The hemoglobin is the important ele- ment, and constitutes about 95 per cent. by weight of the corpuscles. In early fetal life most of the red corpuscles are nucleated, but the nu- cleated forms later decrease in number and are comparatively scanty at the time of birth. Within the first few months of postfetal life all of them disappear, and in subsequent years nucleated corpuscles are Fig. 171.—Unstained red blood-cells, showing crenation and similarity to sporulating malarial plasmodia. (Picture prepared under direction of C. Y. White.) present only in cases of disease. According to some recent investiga- tions it would appear that the red cells of adult human blood always contain nuclei demonstrable only by certain staining methods. The sup- posed nuclei shown in some of these methods are certainly artefacts. As to others, further investigation is needed. There are about 5,000,000 red corpuscles in the cubic millimeter of the blood of normal individuals. The figures vary slightly at different times in the same individual, and many influences contribute to the production of more lasting changes in number (see pp. 420, 431). The volume of the red corpuscles in a given bulk of blood is dependent upon their number and their size. Observers have reached varying results in 414 A TEXT-BOOK OF PATHOLOGY studying the volume, but it may be placed at between 40 and 50 per cent. of the total bulk of the blood. Skeined Cells.—The method of vital staining that has been recently introduced discloses certain varieties of erythrocytes that have excited discussion. A drop of blood is mixed with oxalated sodium chlorid solu- tion, to which brilliant cresyl-blue has been added. The sedimented red corpuscles are then placed under a cover-glass and examined. A certain proportion of the erythrocytes are found to present a skeined or reticulated appearance, which is due to the presence of granules con- nected by fine threads or a variously arranged network of threads or granules stained by the coloring-matter used. These cells have been regarded by some as degenerative forms, but are more probably young cells. In various anemias in which active hemogenesis is going on the skein cells are more abundant than in normal blood. The leukocytes, or white corpuscles, are rounded or spherijcal bodies presenting a more or less granular appearance in the fresh state. They vary in size from the diameter of the red corpuscles to several times the ‘size of the latter. There are several more or less distinct varieties of leukocytes, but as transitional forms occur classification is Fig. 172.—Unstained leukocytes. difficult (Fig. 172). The terminology introduced by Ehrlich is still in quite general use, though recent authorities have disputed many of his views regarding the relationship and source of different forms. Refer- ence will be made to these points in the discussion of the origin of leu- kocytes. Ehrlich distinguished the following forms in normal blood: (1) Lymphocytes; (2) large mononuclear; (3) transitional; (4) polymorpho- nuclear, and (5) eosinophiles. A sixth form, basophiles, may be added, though they occur in only very small numbers in normal blood, and when in larger proportions signify pathological conditions (Fig. 173). 1. Lymphocytes.—These are, on the average, about the size of red corpuscles, some a little larger, others smaller; they are spherical in shape and contain a relatively larger round nucleus surrounded by a narrow band of protoplasm often so slight that it is scarcely visible. The nucleus is rich in chromatin, staining deeply with basic stains, and containing one or two nucleoli. Occasionally it is oval or slightly in- dented on one side. The protoplasm is slightly basophile and with Giemsa or Leishman’s stain may present somewhat sparse, fine or coarse granules (azur granulation). The lymphocytes constitute 20 to 25 per cent. of the normal leukocytes. DISEASES OF THE BLOOD 415 2. Large Mononuclear Leukocytes.—These are called by some “large lymphocytes,” and, undoubtedly, with certain stains a distinction between the larger forms of lymphocytes and certain large mononuclear forms is impossible. The size varies from 15 to 25 u; the cell is ovoid and contains a rather large (7 to 10 w) round nucleus which is relatively poor in chromatin, so that in the stained blood it is much paler than that of the lymphocyte. There is no nucleolus. The protoplasm is feebly basophile, with only occasional granulation (azur granules). The clear non-granular character of the protoplasm has suggested the term “hyaline cell.” 3. Transitional Leukocytes.—These are similar to the last, but differ in that the nucleus is indented or somewhat irregular in outline. It is very often impossible to determine satisfactorily whether a certain cell is a large mononuclear or a transitional form, and the two may be Fig. 173.—Various forms of blood-corpuscles: a, Lymphocyte; b, lymphocyte approach- ing c; c, large mononuclear; d, transitional; e, polymorphonuclear neutrophile; f, poly- morphonuclear eosinophile; g, broken eosinophile; hk, neutrophilic myelocyte; 7, eosino- philous myelocyte; 7, basophile mast-cell; k, red corpuscles; J, nucleated red corpuscles. considered as practically the same. The protoplasm may be free of granules, or may present fine neutrophilic granulation. The large mononuclear and transitional forms together make up 4 to 8 per cent. of the normal leukocytes. 4. Polymorphonuclear Leukocytes; Polynuclear Leukocytes; Neu- trophiles.—These are the most numerous forms. They are somewhat smaller than the large mononuclear elements, being from 10 to 12 y in diameter, and are distinguished by a polymorphous nucleus which is richer in chromatin than that of the large mononuclear form, though less rich than that of the lymphocyte. The nuclei are elongated and variously curved or distorted, so as to resemble the letters S, U, V, Z, etc., and in some cases they are wreath shaped. Frequently, parts of the nucleus are so thin that they are scarcely visible, or actually be- come broken, and the term “polynuclear” was, therefore, applied. This name is, however, less accurate than the term “polymorphonu- 416 A TEXT-BOOK OF PATHOLOGY clear.”’ The amount of chromatin in the nucleus varies greatly, and the size of the nucleus is correspondingly variable. The protoplasm usually contains fine granules, which are closely set and almost com- pletely fill the cell. These granules have a strong affinity for neutral mixtures of anilin or other stains, especially for the triacid stain, and have, therefore, been called the neutrophilic granules (see p. 418). The polymorphonuclear neutrophiles constitute 60 to 70 per cent. of the normal leukocytes. 5. Eosinophiles—These are slightly larger than the polymorpho- nuclear neutrophiles, their nuclei are polymorphous, though not so much divided and not so basic in staining affinity as the nuclei of the neutrophile. The protoplasm contains large granules which stain in- tensely with acid stains. In pathological conditions certain other cells containing eosinophile granules are met with (see Myelocytes). They constitute 1 to 4 per cent. of the leukocytes of the normal blood. 6. Basophiles.—These are polymorphonuclear cells the nucleus of which stains poorly with basic stains. The protoplasm contains irregu- lar sized granules of intense basic affinity. About 0.5 per cent. of the leukocytes of the normal blood are of this type. Pathologically, certain other forms of cells of the leukocyte series occur in the blood. Among these are: (a) Myelocytes, (b) plasma cells, and (c) leukoblasts. Occasionally myeloplaxes, or marrow giant cells, are present. (a) Myelocytes.—These are large cells identical with the large granular cells of the bone-marrow. They are often three or four times the size of the red corpuscles, and are distinguished by a large, pale, oval nucleus generally placed close to one side of the cell. The proto- plasm is sometimes entirely free of granulations, but usually contains fine neutrophile granules. Eosinophile and basophile myelocytes are less frequent, but are sometimes seen in fairly considerable numbers in leukemia. The nucleus is frequently somewhat irregularly outlined, and not rarely suffers degenerative change. Smaller cells, resembling the typical myelocyte in the character of the nucleus and protoplasm, are sometimes observed, and are difficult to classify. Myelocytes occur in exceedingly small numbers, if at all, in normal blood. They are abun- dant in certain forms of leukemia, and also occur in pernicious anemia and various infectious and systemic diseases. (6) Plasma Cells, Stimulation Cells, Irritation Cells (Tiirck).— These are oval cells, varying in size from 5 to 15 w in diameter; and contain an eccentrically placed round or oval nucleus. Both nucleus and cytoplasm are decidedly basophile, especially the latter. There are no true granules, but the deeply stained cytoplasm often presents an indefinite granular appearance. Great variation in the character and staining reactions have been noted by different investigators, and an accurate definition is, therefore, difficult. (c) Leukoblasts.—In various blood diseases, especially i in acute leu- kemia, there are found certain spherical cells varying in size from 8 to 20 w in diameter, and containing a large, somewhat eccentric nucleus, DISEASES OF THE BLOOD if 417 poor in chromatin, and a non-granular cytoplasm. These cells have been regarded as large lymphocytes or as non-granular myelocytes, but are now more generally considered as primitive or mother-cells of the leukocyte series, and have, therefore, been named leukoblasts, myeloblasts, primordial cells, ete. (d) Myeloplaxes, or megakaryocytes, are large cells, sometimes several times the size of myelocytes, containing a large, highly poly- morphous nucleus, and a moderately granular cytoplasm. These cells are occasionally found in the circulating blood in severe anemias. The granules of the leukocytes are classified according to their behavior with the anilin stains. Ehrlich distinguished four important types of granules (Fig. 174). Fig. 174.—Leukocytes, showing various forms of granulation: a, Neusser’s basophilic perinuclear granules; 6, large mononuclear cells with 6-granules; c, mast-cell granules; d, basophilic lymphocytes, 6-granules; the stain in b, c, and d was a mixture of eosin and hematoxylin, the cover-glass being kept in the stain several hours at 37° C. (98.6° F.). (1) a-Granules, Eosinophile Granules, or Oxyphile Granules.— These are coarse granules giving the appearance in the unstained blood of minute fat-droplets; they are highly refractive, and have been shown to be composed of albuminous material. They are distinguished by their strong affinity for acid stains, and in particular for eosin. This circum- stance has given rise to the names eosinophile and oxyphile (Fig. 175). The eosinophile granules in the normal blood occur only in poly- morphonuclear leukocytes. (2) 7-Granules; Mast-cell Granules.—These are intensely basophilic, coarse granules, occurring in mononuclear cells. The mast-cell is identical with Waldeyer’s plasma-cell of the tissues. It is present in small proportions in the normal blood (Fig. 174). (3) 0-granules are fine basophilic granules occurring in the lympho- cytes or large mononuclear cells (Fig. 174). 27 418 A TEXT-BOOK OF PATHOLOGY (4) ¢-Granules; Neutrophilic Granules.—These are the most abun- dant and the most important of all the forms. They occur as fine granu- lations, filling up the protoplasm of the polymorphous cells, and they are occasionally present in transitional leukocytes. They are dis- tinguished by their affinity for the neutral mixtures of Ehrlich (Fig. 175), It must be recognized, however, that these granules are, in reality, faintly oxyphilic, receiving the acid stains, such as eosin or acid fuchsin, more readily than basic stains. In recent years by newer methods (Leishman, Giemsa) a special form of granule, “azur-granules,” has been distinguished and has been regarded as highly significant, especially of cells of the lymphocytic series. This view, however, is far from being established. Not im- probably immature granules of myeloid cells also present this staining reaction. Altmann and, later, Schridde and others have described certain fuchsinophile extranuclear granules which are regarded by some as gree, a fe sete * oa wits, ) : > aes eo Hk ” Eee Fig. 175.—Blood in lienomedullary leukemia, showing several mononuclear neutro- philes (myelocytes), one polymorphonuclear neutrophile, and an eosinophile; a nucleated red corpuscle and a lymphocyte are seen in the lower part of the illustration; stained with Ehrlich’s triple mixture. highly characteristic of the lymphocytic series of cells. The significance of these granules is still very uncertain. The nature of the granules of the blood is still obscure. They are un- undoubtedly connected in some way with the specific function of the leukocytes, but whether they are specific cellular secretions (Ehrlich) or essential anatomical structures (Altmann) is unknown. The number of leukocytes in the normal blood varies considerably. The average number, however, is between 6000 and 8000. Alterations in the number under various circumstances will be discussed later. Proportions of the Different Forms.—The relative proportions (“differential count’) of the different leukocytes are determined by counting large numbers and calculating the percentage proportion of each form. Approximately there are 20 to 30 per cent. lymphocytes, 60 to 70 per cent. polymorphonuclear forms (neutrophiles and eosino- DISEASES OF THE BLOOD 419 philes), 4 to 8 per cent. transitional and large mononuclear. About 1 to 3 per cent. of all the leukocytes contain eosinophile granules, and occa- sionally a larger proportion is met with in normal blood. About 0.5 per cent. of the normal leukocytes are basophilic. Blood=plaques or Platelets.—These are small disks somewhat re- sembling the red corpuscles, though smaller and without the character- istic biconcavity of the latter. They contain a chromatic body and have been described as nucleated by some observers. They rarely exceed 3 w in diameter, and are often much less. They are viscid, and tend to adhere to the other corpuscles or to become agglutinated in clusters. The total number has been estimated at from 150,000 to 500,000 per cubic millimeter. The origin of the platelets is still uncertain. Accord- ing to some they are derived from the erythrocytes by a process of ex- trusion from the cytoplasm of the latter; others have held that they are formed by the breaking down of leukocytes. Wright claims to have shown that they are products of the megakaryocytes of the bone- marrow. The plasma of the blood is an albuminous liquid containing mainly serum-albumin and serum-globulin and various saline compounds. The relative proportion of serum-globulin to serum-albumin is as 1 to 1 or 14. Of the saline constituents, sodium salts are most important, the phos- phates, carbonates, sulphates, and chlorids being most abundant. Various other nitrogenous and non-nitrogenous substances are present in small proportions. Reference will be made to some of these below. BLOOD FORMATION The process of blood formation is still a matter of uncertainty in some particulars. The prevailing opinion is that all of the blood-cor- puscles, erythrocytes and leukocytes, are derived from mesoblastic cells which become differentiated to form the lining endothelia of blood- vessels and lymphatics. From the former group the primitive cells which give rise to erythrocytes and the granular leukocytes take their origin; from the lymphatic endothelia are developed the primitive cells which originate the lymphocytic series. The earliest clearly differen- tiated blood-cell is a large hemoglobin-containing cell with pale nucleus, found in the mesoblastic columns in which the blood-vessels are differ- entiated. This is the primitive erythroblast. According to older in- vestigators the erythroblasts were derived from this cell. More recent investigations, however, seem to show that this is but a temporary phase in fetal blood formation. Later, the endothelia of the blood- vessels give rise to (1) certain basophilic erythroblasts, containing no ‘ hemoglobin, from which the red cells are derived; and (2) myeloblasts from which the myelocytes and their derivatives take their origin. The lymphocytic series, by a similar process of differentiation, is derived from the endothelia of lymphatic channels. During the earlier portion of fetal life the liver is the principal seat of blood formation; after the third month the spleen and bone-marrow 420 A TEXT-BOOK OF PATHOLOGY participate, but the spleen ceases to be active somewhat before the end of fetal life and the liver shortly after birth. The lymphatic glands are the chief source of lymphocytes in intra- and extra-uterine life. It is noteworthy that in many anemic conditions a return to fetal processes of blood formation is observed. PATHOLOGICAL CHANGES IN THE RED CORPUSCLES The size of the red corpuscles varies in diseases of different kinds. The term anisocytosis has been suggested for this irregularity. There may be dwarf corpuscles, 2 to 4 or 5 wu in diameter (microcytes); or, on the other hand, giant cells (megalocytes), from 9 to 15 uw or even 20 u in diameter. The small forms frequently have a spherical shape rather than the disk-like form of the normal corpuscle, and may be deeply pig- mented. The large corpuscles are often irregular in shape, and are Fig. 176.—Blood from a case of pernicious anemia: a, Megalocytes; b, microcytes; c, poi- kilocytes; d, nucleated erythrocytes; e, normal erythrocytes; f, leukocytes. prone to be paler and more basic than normal corpuscles, and usually appear without the concavity of the normal cell (Fig. 176). Some ob- servers have found that the average size of the red corpuscle is greater in certain diseases than in health. This is sometimes the result of hy- dropic conditions. The shape of the corpuscles often suffers great change, and many forms of irregularity may be observed. The term poikilocytosis is ap- plied to this condition (Fig. 176). Some of the poikilocytes may be ex- ceedingly small and may present active movements. These have been termed “pseudobacilli” by Hayem. These changes of form in red cor- puscles are regarded by many authorities to be the result of degenerative changes in the protoplasm with consequent ameboid movement which occasions irregular projections. The small forms are doubtless in many cases the result of fragmentation. Ehrlich used the term “schistocyte” to indicate this fact DISEASES OF THE BLOOD 421 Dust=corpuscles.—Miiller described certain small spherical bodies somewhat resembling the leukocytic granules, but lying free in the plasma and often actively motile. These he termed hemokonie, or dust-corpuscles. They occur in normal blood as well as in that of various diseases. A number of theories have been offered regarding the nature of these bodies. Some authors regard them as extruded leukocytic granules; others, as portions of protoplasm of the leukocytes. Our own belief is that they are fragments of red corpuscles, similar to those that may be produced by heating fresh blood under a cover-glass to destruc- tive temperatures. Under these circumstances small, bud-like processes are formed on the periphery of the red corpuscles, and some of these may break off and float free in the plasma. Visible ameboid movements may sometimes be observed under the microscope, especially in severe anemias, such as pernicious anemia. Nucleated Red Corpuscles, or Erythroblasts.—The red corpuscle when first formed is always nucleated, and throughout fetal life a dimin- ishing proportion of the erythrocytes remains so. At birth and through- out extra-uterine life the erythrocyte is non-nuclear. The loss of the nucleus was formerly attributed to a process of extrusion, but is now believed to be always due to pyknosis, karyorrhexis, and karyolysis within the cell. Nucleated erythrocytes occur in the severe anemias as in fetal blood. They are more frequent in the severest cases, and in particular in the anemias of children. Some are exceedingly small (microblasts), some about the size of the normal red corpuscle (normoblasts), and some large and irregular (megaloblasts). The stained nucleus of the normo- blast is darker and more compact than that of the megaloblast, and is often near the periphery of the cell or apparently partly extruded. The smaller forms appear first and in the more moderate anemias; occa- sionally they occur in great numbers or crops from time to time (blood crises). Degenerations of nucleated red corpuscles may occur, and very frequently are seen in the circulating erythroblast. The usual forms are karyolysis—solution of the chromatin; karyorrhexis—fragmenta- tion of the nucleus; and pyknosis—clumping or condensation of the nuclear structure. Granular degeneration, vacuolation, and nuclear atrophy also occur. Karyokinetic figures are occasionally seen in the nuclei of erythro- blasts, in pernicious anemia, in leukemia, in dibothriocephalus anemia, and in certain anemias of children. Shadow corpuscles are red corpuscles that have lost their color almost completely and are scarcely visible. They may be observed in severe anemias, and especially in cases of intoxication with blood- poisons. Ring Bodies.—Cabot, by means of Wright’s modification of Leish- man’s stain, has demonstrated in the red cells of anemic blood the presence of ring bodies, which he is inclined to believe represent the remains of a previously existing nucleus. They were found in 3 cases of pernicious anemia, 3 of lead-poisoning, and 1 of lymphatic leukemia, 422 A TEXT-BOOK OF PATHOLOGY in all of which normoblasts were also found. The rings appear to be made up of a series of granules in some cells; in others, of a continuous line. They usually stain red, though blue is not uncommon. Polychromatophilia.—The normal red corpuscle has a special affinity for acid stains. In diseased conditions it may develop an affinity for basic stains, and when colored with mixtures of acid and basic stains may present tints combining all the stains employed. Thus in staining with eosin and hematoxylin the degenerated corpuscles may present a purplish or violet color, instead of a pink. Vacuolation and pigmentation of the red corpuscles are rare forms of degeneration. The pigmentation is due to separation of the hemo- globin in the form of irregular granules. Basic degeneration is a form of degeneration in which minute or rather coarse granules that stain with certain basic stains are found in the substance of the red corpuscles. The number of granules in the cell may be small or large; the cell may be otherwise little altered; it may be polychromatophilic. The condition has been found in various diseases, such as leukemia, pernicious anemia, and malaria, but is most frequent in lead-poisoning. Some observers, by using certain special staining methods, claim that the basic granules are nuclear fragments and regard the process as regenerative rather than a degeneration. It is very probable, however, that the granules seen in these studies have not been those now under discussion. Alterations of Isotonicity.—All forms of cells have certain osmotic relations, in consequence of which they retain their constituent elements in the presence of surrounding liquids of certain osmotic tension. If the osmotic relations vary or the surrounding liquids are altered, the constitu- ents of the cell may be extruded. In the case of blood-corpuscles distilled water rapidly abstracts the hemoglobin and other substances, but saline solutions of certain strengths do not so affect the corpuscle. The exact strength of a certain saline solution may be determined which will pre- serve the corpuscle, and this is known as the isotonic strength of the corpuscle expressed in percentage terms of the saline used. Degener- ated corpuscles more readily yield their constituents, and the isotonic saline solution is, therefore, of higher percentage. In normal blood the isotonicity of the red corpuscle is generally 0.46 to 0.48 per cent. NaCl; that is, solutions of common salt of this strength do not affect the red corpuscles. In certain anemic diseases the isotonic solutions may be from 0.5 to 0.6 per cent., but often, on the contrary, solutions from 0.40 to 0.44 per cent. may be isotonic. PATHOLOGICAL CHANGES IN THE LEUKOCYTES Very frequently degenerations of the nuclei of the leukocytes are observed in the form of fragmentations or karyolytic change. Atten- tion has been called (Neusser) to the presence of basophilic granules about the nucleus in certain forms of disease, such as leukemia, gout, and lithemia in its widest sense. These granules are supposed to be sig- DISEASES OF THE BLOOD 423 nificant of disintegration of the nuclei in the process of uric-acid forma- tion. Their nature and significance, however, are unsettled. Occa- sionally vacuolization and fatty degeneration of leukocytes are observed, and sometimes, as in infectious fevers and in suppuration, glycogen may be found in abnormal quantities. In cover-glass preparations the leuko- cytes are sometimes found broken or fragmented; or fenestrated, basket- like, pale-staining forms are seen. The latter doubtless occur to some extent in the circulating blood and are frequently spoken of as “leuko- cytic shadows.” Iodophilia—This term is applied to a condition of the blood in which there are found in the leukocytes or the plasma granules that stain with iodin, like glycogen. The term “glycogenic reaction” was formerly applied, though recently some question has arisen as to the glycogenic nature of the granules in question. The leukocytes involved in this form of granulation are chiefly the polymorphonuclear. Baso- philic leukocytes may be affected, but never the eosinophiles. The intracellular material is found in the form of small granules of regular shape and size, which stain a yellowish-red or brown color with iodin. Less commonly the leukocytes may be diffusely stained, the granules being wanting or so small as to be indistinguishable as granules. The extracorpuscular granules are found in more advanced cases. They resemble the intracorpuscular granules in appearance. The significance of iodophilia has not been positively determined. The condition is found in association with leukocytosis or less com- monly in the absence of leukocytosis, but it bears no quantitative rela- tion to the degree of leukocytosis. It has been found in various forms of toxemia, in grave anemias due to loss of blood or to other causes, in fevers, and in various other conditions. The blood-film, without previous fixation, is stained with iodin and iodid of potash in a gum-arabic solution. PATHOLOGICAL CHANGES IN THE PLASMA Various disorders of the plasma have been studied. These are mainly of a chemical sort, and consist of the presence of abnormal substances or of normal constituents in excessive quantity. Urea is present in large quantities in some cases of nephritis and uremia, and older authorities believed the symptoms of uremia due to the presence of this substance. This view is no longer held. Uric acid occurs in small quantities in health; but in larger quantities in gout, leukemia, in some forms of leukocytosis, and other disorders of the blood. Sugar is found in excessive quantities in diabetes, in cases of high blood-pressure, in thy- roid diseases, and, according to some observations, in"cases of carcinoma. Levulose and other carbohydrates are rare constituents of the plasma. Fatty acids may be present in leukemia, diabetes, acute yellow atrophy of the liver, and some other diseases. The quantity of sodium in the plasma increases in anemic diseases. Certain changes occur in the plasma or serum in certain anemic dis- eases, as a result of which the globulicidal character is increased. The 424 A TEXT-BOOK OF PATHOLOGY nature of these changes is obscure. The presence of toxic substances the result of bacterial action is referred to in the discussion of bacteria. Hypertonicity of the serum is a term indicating that the salinity of the plasma or serum is such that the blood may be somewhat diluted without destruction of the corpuscles. By graduated dilutions the de- gree of hypertonicity may be estimated, and is found less in certain diseases than in health. (See Isotonicity of the Red Corpuscles.) Hyperinosis and hypinosis are terms designating increased and decreased capability for fibrin formation. The former is met with at times in chlorosis, leukemia or other anemic affections, and in certain | infectious diseases. The latter is notably present in leukemia, perni- cious anemia, and some cases of hemolysis. There has been much theorizing in regard to these conditions, but very little knowledge of practical importance has been acquired. PLETHORA This is the name applied by the older writers to a condition in which the total quantity of blood was supposed to be excessive. It is now recognized that plethora is much less frequent and permanent than was formerly believed. Several varieties were described. Plethora vera was the name given to the condition in which the quantity of the blood was supposed to be increased without change in its quality. Persons supposed to have this condition are described as robust, with high color and vigorous circulation. They are generally individuals living in luxury. The term “full-blooded” is still applied, but it is recognized that the fulness of the superficial vessels is the result of peculiarities of the circulation rather than of increase in the quantity of blood. Plethora apocoptica is the term given to conditions in which there is local increase in the blood. Plethora hydremica is a condition in which the total quantity of the blood is increased by dilution. This was regarded as frequent in cases of cachexia, after hemorrhages, etc. Experimental evidence might be referred to to substantiate the view that plethora in the strict sense does not often occur as a lasting condi- tion. Temporary plethora is produced by the drinking of large quanti- ties of liquid, but the excretory organs soon dispose of this excess. OLIGEMIA This is a term indicating reduction in the quantity of blood. This is met with temporarily after hemorrhage, but very soon serous liquid from the tissues enters the blood-vessels and restores the original quantity. At the time of the hemorrhage the quantity may be imme- diately reduced to a very great degree without causing death. Serious consequences are averted by the activity of the vasomotor system, the blood-vessels accommodating themselves by contraction to the reduced quantity of blood. Subsequently when liquid of the tissues is absorbed into the blood-vessels the latter dilate and their natural volume is soon DISEASES OF THE BLOOD 425 restored. The blood, however, becomes hydremic, or watery. Oli- gemia or quantitative anemia may possibly occur in certain cachectic and anemic diseases, but this has not been proved, and the relative proportion between the mass of blood and the weight of the body is certainly not much disturbed in any case. HYDREMIA AND ANHYDREMIA Hydremia, a diluted or watery condition of the blood, may occur from excessive consumption of water, but active excretion of liquid soon restores the blood to its previous condition. Hemorrhage leads to hydremia in the manner above described; and in the chronic anemias there is possibly some dilution of the serum. It has never been shown, however, in any of the many experiments made to determine this point that the plasma in anemias is less rich in solid consituents than normal plasma. The reduction in solid matter in the blood as a whole is due to the diminution in the number of red corpuscles and changes in their composition. Anhydremia is a condition in which the plasma of the blood is thickened by the loss of watery elements. This may occur in con- sequence of excessive sweating or excessive discharge of water from the bowels, kidneys, etc. The number of red corpuscles in a given bulk of blood increases. The specific gravity and the solid residue of the blood as a whole increase correspondingly. LIPEMIA This is a pathologic condition in which fat occurs free in the blood- plasma. Fat is always present as a normal constituent of blood, and Fig. 177.—Blood from a case of lipemia, stained with osmic acid: upper half of field cleared with oil of turpentine; lower half shows the fat-droplets and granules stained with osmic acid between the blood-corpuscles; enlargement, 100 diameters (after Gum- precht; Deutsch. med Woch., Sept. 27, 1894). 426 A TEXT-BOOK OF PATHOLOGY is in slight excess during the process of digestion. Lipemia occurs in cases of chronic nephritis, diabetes, pulmonary tuberculosis, alcohol- ism, and some other conditions, and may reach marked grades of sever- ity. The blood may have a milky appearance to the naked eye, and under the microscope highly refractive droplets or granules are observed. The latter stain black with osmic acid (Fig. 177). The appearance of fat in the blood is ascribed by some to an altera- tion in its character when being transported and to a decrease in tissue and blood lipase. It may appear in conditions of reduced nutrition when the fat is transferred from fat depots to other situations for metabolic use. MELANEMIA This condition is distinguished by the occurrence of dark pigment or granular matter in the circulating blood. It occurs in cases of malaria and certain other fevers. The pigment may be free in the plasma in the form of yellowish or blackish granules; or may be found as small par- ticles in the leukocytes. : HEMOCYTOLYSIS~HEMOGLOBINEMIA Definition.—Hemocytolysis is the term applied to the conditions in which the red blood-corpuscles are destroyed. The name hemolysis is generally employed in the same sense, though it refers to destruction of all of the elements of the blood. In this condition hemoglobin is . liberated and is dissolved in the plasma. To this the term “hemoglobi- nemia” is applicable, but the name ‘‘methemoglobinemia” is more ap- propriate, as the hemoglobin is usually present in the serum in this altered form. Etiology.—Hemolysis constantly takes place in the liver, the coloring-matter of the blood being converted into bile-pigments. Path- ological hemolysis results from the action of various infectious and toxic agents. It occurs in the course of severe malaria, relapsing fever, pneu- monia, and various hemorrhagic infections; and is occasioned by many poisons (see Blood-poisons). Excessive cold may be a contributing cause, as seems to be the case in some instances of paroxysmal hemo- globinuria (g. 2.). The serum of certain animals has more or less hemolytic effect when injected into other animals. By repeated injections the serum of the animal under experiment may acquire hemolytic properties. Anti- hemolysins have also been produced in experimental investigations and promise to be of practical use, as in the case of certain hemolytic venoms. The explanation of hemolysis elaborated by Ehrlich and later con- firmed by Flexner and Noguchi is referred to in the section on Immunity. Pathological Anatomy.—The blood may present striking morpho- logical changes in the red corpuscles, such as microcytosis, megalocy- tosis, poikilocytosis, fragmentation, and vacuolation. Shadow cor- 5 DISEASES OF THE BLOOD ~ 427 puscles may be abundant, and in the later stages of the process begin- ning regeneration of the blood causes the presence of nucleated red cor-’ puscles. The blood as a whole is often quite dark in color. Associated changes are frequently met with in the liver, kidneys, and skin. The hepatic cells are often swollen and more or less degener- ated and bile stained. Excessive production of bile (polycholia) may occur. This overproduction, with the swelling of the hepatic cells and the consequent obstruction of the biliary channels, occasions reab- sorption of bile and consequent jaundice (so-called “hematogenous jaun- dice”). The excess of hemoglobin, which cannot be disposed of by the liver, may be excreted in the urine (hemoglobinuria). Sometimes hemoglobin infarcts are met with in the renal tubules; and thrombosis of the renal or other blood-vessels is occasionally observed. Acute nephritis is a rare result. Pathological Physiology.—Hemocytolysis leads to more or less pronounced disturbance of the internal or tissue respiration, as the al- tered hemoglobin is incapable of carrying oxygen. Dyspnea and various nervous symptoms are the result. The liberation of cellular con- stituents (from destruction of the red and white corpuscles) occasions increased coagulability of the blood and the formation of thrombi in arterioles and capillaries. Fever and other general symptoms may be due to the same cause (ferment intoxication). POLYCYTHEMIA Polyeythemia, or erythrocytosis, is a condition in which the number of red corpuscles in a given bulk of blood is increased. It is met with . in a variety of conditions, including certain cardiac diseases with slow failure of compensation, and especially in congenital cyanosis; in car- bon-monoxid poisoning and other forms of cyanosis; in residents of high altitudes; in the newborn; and in cases of cholera or other diseases in which liquid discharges cause inspissation of the blood. The explana- tion of the increased number of corpuscles in some of these conditions has occasioned considerable controversy. It is manifestly possible that erythrocytosis may be relative when the number of corpuscles is not actually increased, but their proportion in a given bulk of blood en- hanced by diminution in the amount of plasma; or actual when there is an increase in the total number of red cells in the body. It does not seem probable that relative erythrocytosis could have more than a brief duration, as in cases of cholera. It is possible, however, that in certain conditions in which the peripheral circulation is stagnant the number of corpuscles in a given bulk of blood drawn from the finger or ear might be relatively increased, without any actual general erythrocy- tosis. The higher count of red corpuscles in the blood of dependent parts or in a finger congested by constriction or cold lends some color to this view. Recent investigators tend toward the opinion that lasting erythrocytosis is an evidence either of stimulation of the bone-marrow, as a result of conditions which interfere with oxidation, or of abnormal 428 A TEXT-BOOK OF PATHOLOGY activity of the spleen. The association of marked splenic enlargement in some cases is cited as evidence of the latter view; but convincing proof of the relationship is lacking. Polycythemia with Chronic Cyanosis and Enlarged Spleen.—A clinical entity comprising these symptoms, together with weakness, prostration, and vertigo, has recently been recognized. No explanation has thus far been given for this condition. In some cases the spleen was found to be tuberculous; in others only chronic hyperplasia was found. Besides the conditions before referred to as causing cyanosis and polycythemia, certain pulmonary diseases, such as emphysema and chronic poisoning with coal-tar products, such as acetanilid and anti- pyrin, must be recalled. In some of these cases the spleen may be enlarged and the condition may simulate the one just under considera- tion. In the reported cases of chronic cyanosis with polycythemia, however, these causes of the polycythemia and cyanosis as well as the ones before referred to are wanting. LEUKOCYTOSIS The term “leukocytosis” is given to a more or less transient, but ex- ceptionally chronic, increase in the number of leukocytes, under the stimulus of a foreign agent, bacterial or toxic, or of diseases outside the blood-making organs. The terms ‘“polymorphonuclear leuko- cytosis,” “lymphemia,” “eosinophilia,” and ‘“myelocythemia’”’ are used to designate increase of the polymorphonuclear leukocytes, lympho- _ cytes, eosinophiles, and myeloid elements respectively. Etiology.—The causes of leukocytosis are varied. An excessive num- ber of leukoctyes in comparison with the figures found in adults is gen- erally observed as a normal condition in the newborn, the number of corpuscles remaining in slight excess during the first year of life. ‘“Phys- iologic leukocytosis” also occurs in many cases of pregnancy; and is quite constant during the period of digestion in healthy persons, protein food being more striking in the effect than a farinaceous or mixed diet. In some diseases of the stomach postdigestive leukocytosis seems not to occur. Inflammatory and Infectious Leukocytosis—Among the strictly pathological forms of leukocytosis the most important are those due to inflammations and infections of various kinds. Croupous pneu- monia occasions considerable increase of leukocytes in most cases, and this is continuous until the final decline of the fever. Suppurations of all kinds act in a similar manner. Inflammations of the serous mem- branes—peritonitis, pleurisy, meningitis—may be attended by moderate or severe leukocytosis. Among the acute infectious fevers there are some in which leukocytosis occurs and others in which this is wanting, and this fact often proves valuable to the clinician. Among those in which the leukocytes do not increase in number are typhoid fever, in- fluenza, malaria, and acute miliary tuberculosis. DISEASES OF THE BLOOD 429 Cachectic leukocytosis occurs in a variety of marantic conditions, and toward the end of life in any case of wasting disease there may be a great increase in the number of leukocytes. This agonal or terminal leukocytosis is either cachectic (toxic) in nature or it may be due to terminal infections. Malignant tumors frequently cause leukocytosis. Hemorrhage may occasion increase in the number of white corpuscles, more or less proportioned to the quantity of blood lost. Mechanical and Thermal Causes.—Massage and cold baths fre- quently cause increase in the number of leukocytes for a time. Medicinal leukocytosis, or that due to the introduction of various drugs, is probably allied to infectious and cachectic leukocytosis in the manner of its production. Pathogenesis.—The nature of leukocytosis has been the subject of much controversy. The earliest view regarding the pathogenesis of leukocytosis was that in some manner excessive production of leuko- cytes took place either in the blood or elsewhere. Later some investiga- tors claimed that there was evidence that the leukocytes were not de- stroyed as rapidly as in health. Still.later the presence of chemotactic substances, positive or negative, in the blood was regarded as the cause of increase or decrease of leukocytes. At present it seems correct to interpret leukocytosis as a reaction of the blood-making tissues to agents which stimulate them to overactivity. Such influence is most frequently manifested in the bone-marrow (which occasions the preva- lent type of leukocytosis—polymorphonuclear), but sometimes the lymphatic glands are principally affected and lymphemia results. Dormant myeloid elements in the spleen or elsewhere may be stimulated to activity and may play a considerable part in the de- velopment of leukocytosis. This is more likely to be the case in more chronic types. According to present conceptions, the explanation of leukocytosis on the basis of chemotactic effects of circulating toxic agents, the blood- making organs being only passive participants, must be abandoned. As a reaction on the part of blood-making tissues is the important feature in the process, it follows that toxic agents too feeble to excite such reaction may fail to produce leukocytosis; and overactive irritants may have a paralyzing effect. Character of the Blood.—The blood in seiueene varies consider- ably in character. The number of leukocytes may be only moderately increased (10,000 to 20,000) or may be excessive (50,000 to 100,000). In the majority of cases of leukocytosis the polymorphonuclear elements are in relative as well as actual excess, the mononuclear ele- ments being actually increased in number, but relatively deficient (Fig. 178). The proportion of polymorphonuclear elements is frequently 80 to 85 per cent., and sometimes 90 or 95 per cent., instead of 65 to 70 per cent. In the leukocytoses following hemorrhage, in cachectic leuko- cytosis, in septic leukocytoses, and that due to malignant tumors the polymorphonuclear cells are usually increased, while in the leukocytosis 430 A TEXT-BOOK OF PATHOLOGY of the newborn and in some tumors, especially lymphomata, the mono- nuclear elements predominate. Lymphemia is occasionally met with in infections in which ordinarily polymorphonuclear leukocytosis would occur. Some unknown factor, perhaps individual, operates in such cases. Lymphemia is also observed in pertussis, syphilis, typhoid fever, and scarlatina. Eosinophilia has been observed in a variety of skin diseases, in animal parasitism, especially trichinosis, in anaphylaxis, asthma, etc. Myelocythemia has been found in various severe infec- tions and in cases of metastasis of tumors to the bone-marrow. It is often pronounced in the so-called anemia pseudoleukemica infantum. Pathological Physiology.—Leukocytosis certainly exercises some profound influence upon the system, but the exact nature of this influence is unsettled. Those who contend in favor of the phagocytic theory of immunity claim, more or less directly, that the increase of leukocytes is a protective process, the purpose being the removal and destruction of . irritants. This view seems to have gained ground with increased Fig. 178.—Septic leukocytosis, showing marked increase of polymorphonuclear leukocytes. knowledge of the mechanism of infection. Others believe that leuko- cytosis is part of the cellular processes concerned in the production of immunizing substances. There is certainly more active destruction of leukocytes in leukocytosis than in health, as is evidenced by the increase of xanthin bases and uric acid in the urine; and it may be that in this destruction protective substances are liberated. LEUKOPENIA This is a condition in which there is deficiency in the number of leukocytes. This is met with in moderate degree in various diseases, such as tuberculosis, typhoid fever, some cases of cachexia, inanition, splenomegaly, progressive pernicious anemia, etc. The nature of the condition is not entirely clear. Some have held that it is due to destruc- tion of leukocytes (lewkolysis), while others claim that it is the result of altered distribution of the leukocytes. It has been shown by experi- mentors that the injection of certain micro-organisms or toxic sub- DISEASES OF THE BLOOD 431 stances may produce, first, a decrease in the number of leukocytes, and then an increase. The primary leukopenia is explained by some as the result of active destruction of leukocytes, but the conditions of the urine do not give evidence of such active destruction, and others have shown that the capillaries of the lungs, liver, and other organs are overfilled with leukocytes during this stage. The assumption, therefore, seemed warranted that leukopenia might result from disturbance in the distribution of the leukocytes. According to more modern conceptions, however, leukopenia may be regarded as a result of unfavorable action upon the blood-making tis- sues of toxic agents. ANEMIA Definition—This term includes a variety of conditions in which the blood is reduced in quality in one constituent or another. The term oligocythemia indicates a reduction in the number of red corpuscles, while the name oligochromemia indicates a reduction in the coloring- matter of the corpuscles. Usually these conditions are associated. Classification of Anemias.—It is not as yet possible to offer a strictly scientific classification, but for ordinary purposes the old division into primary and secondary anemias may be retained. The term ‘‘primary anemia” may be given to forms in which the anemia is the striking path- ological condition. The older writers used the name to indicate that the anemia was an essential disease of the blood itself and dependent upon no preceding affection, excepting possibly a disturbance of the hemato- poietic organs. The term ‘“‘secondary anemia,’ or “symptomatic anemia,’ may be used to designate anemic conditions in which some underlying disease that has occasioned the anemia is conspicuous. Ac- cording to the classification here offered, all anemias are recognized as secondary in the strict sense, but those in which the underlying disease is not conspicuous are classified as primary, and those in which the orig- inal disease is conspicuous as secondary. Another aspect of the matter, within the terms of the definition, is that in the diseases classified as primary, the effects of the original condition, whether toxemia, infec- tion, or of other sort, are manifested most strikingly in the blood-making apparatus. In the secondary anemias such effects are subsidiary in importance and relatively inconspicuous. THE SECONDARY ANEMIAS Etiology.—Various unsanitary conditions may influence the char- acter of the blood by the constant disturbance of the organic functions. A cause of immediate anemia is hemorrhage. This first leads to reduc- tion in the quantity of blood; and later by absorption of liquid from the tissues to dilution of the blood, or hydremia. Finally, after a variable period, the character of the blood is restored by regeneration of cor- puscles and of coloring-matter. Parasites of various sorts may lead to anemia. Among the more important are the intestinal worms, 432 A TEXT-BOOK OF PATHOLOGY Uncinaria duodenalis, Dibothriocephalus latus, and Anguillula intes- tinalis. The mode of action of these is not entirely clear. Some have held that they cause anemia by loss of blood through the intestine, and this is probably true in the case of Anguillula and Uncinaria, but marked anemia may occur from the presence of Bothriocephalus, which is not a blood-sucker and does not occasion hemorrhage. An explanation worthy of consideration in these cases is that the parasites generate poisons either in their ordinary life or by their death and decomposi- tion, and that these poisons are the cause of the anemia. Recent in- vestigations seem to indicate that certain lipoids are the direct hemolytic cause of the anemia in cases of bothriocephalus invasion. Other in- testinal parasites may occasion more or less anemia directly or indi- rectly. The parasites occurring in the blood itself, notably the malarial organism, may cause extreme anemia. Infectious diseases, especially streptococcus infections, frequently lead to impoverishment of the blood. In the acute febrile diseases, such as typhoid fever, rheumatism, and pneumonia, the anemia may not be conspicuous during the progress of the disease, but becomes apparent after the fever has subsided. This may be explained by the assumption that increased respiration and sweating cause inspissation of the blood and relative increase in the number of red corpuscles during the existence of fever, so that the anemia is unnoticed. In chronic infections, such as syphilis and tuberculosis, marked anemia may occur. Among the poisons capable of producing anemia are lead, arsenic, phosphorus, and other metallic sub- stances, and experimentally pyrogallol, nitrobenzol, pyrodin, and various coal-tar products have been used to produce anemia. The anemias of various infectious diseases are undoubtedly toxic in character, and very probably those occurring in gastro-intestinal and nutritional diseases are similarly the result of the action of poisons generated within the body. Organic diseases and new growths of various sorts may occasion anemia by the general disturbance of health, by toxic products gener- ated in the course of disease, or by hemorrhage. Pathological Anatomy.—The condition of the blood in secondary anemias varies with the duration and grade of the anemia. In moderate cases the number of red corpuscles decreases slightly (4,000,000 to 3,000,000), and the hemoglobin is correspondingly reduced, though usually somewhat more strikingly than the corpuscles. The fresh blood may show no visible changes under the microscope, and even in stained preparations the appearance may be normal. More marked anemia is distinguished by greater reduction, the number of corpuscles sinking to 2,500,000 or 2,000,000 per cubic millimeter in extreme cases. Examina- tion of the fresh blood shows pallor of the corpuscles and various irregu- larities in size (microcytes and megalocytes) and shape (poikilocytes). Nucleated red corpuscles may be present in small numbers, normo- blasts predominating. The stained blood may disclose degeneration of the corpuscles by the presence of polychromatophilic forms. The leukocytes do not play an essential part in this form of anemia. Their number may be normal or reduced; in other cases leukocytosis is present. DISEASES OF THE BLOOD 433 The relative proportions of the different forms is usually about normal. Myelocytes are occasionally present. Associated changes in various organs may be met with. Among these are parenchymatous and fatty degeneration of the heart, kidneys, and liver. These conditions have often been ascribed to reduced oxidation, which was supposed to be due to poverty in hemoglobin. Physiological studies, however, do not establish the existence of a reduction in the respiratory exchange of gases. It is likely that toxic conditions of the blood occur in anemia, and that the poisons act directly upon the affected organs. Pathological Physiology.—The process of oxidation is of particular interest in anemia, and, as has been stated, recent investigations show that the consumption of oxygen and elimination of carbon dioxid are normal. To accomplish this result more active circulation and greater energy of the tissues are required. Partly in consequence of the latter, diseases of the organs named in the last paragraph result; and at the same time some of the characteristic symptoms (palpitations, dyspnea) are produced. In severe secondary anemias increased tissue-waste oc- curs, and nitrogen is discharged in excess of that digested. THE PRIMARY ANEMIAS The principal conditions included under this title are chlorosis, progressive pernicious anemia, leukemia, and Hodgkin’s disease. The modern tendency is to discuss the last two apart from anemias; but not only established custom, but the involvement of blood-making organs and the occurrence of actual anemia in these diseases justify the classi- fication adhered to. The term simple primary anemia is sometimes used to designate a form of anemia without distinct cause, and characterized by moderate oligocythemia. There are, it is true, occasional cases of moderate anemia in which no definite precedent disease can be discov- ered; but these are exceptional cases, and are to be considered as second- ary anemias in which the underlying disease is latent. Cases of this sort do not conform to a definite type, and cannot, therefore, be con- sidered as illustrating a special form of anemia. Another term fre- quently used is splenic anemia. This is even less satisfactorily defined. Splenic enlargement may occur in any of the primary anemias, and may in some cases be excessive. Moreover, some of the distinctly secondary anemias (as those of rickets, syphilis, and malaria) are very often attended with splenic enlargement. There is a group of conditions properly included under the title splenomegaly in which more or less anemia may occur, but this title rather than splenic anemia is prefer- able. . 2 CHLOROSIS Definition.—Chlorosis is a primary anemia due to retarded hemo- genesis, characterized by a peculiar pallor and marked reduction in the percentage of hemoglobin, and occurring almost exclusively in young girls and women. 28 434 A TEXT-BOOK OF PATHOLOGY Etiology.—Chlorosis is most frequent at the time of beginning men- struation and during the years immediately following this. A form of late chlorosis has been described in women above thirty years of age and at the menopause; but the nature of this is doubtful. Chlorosis in the male is still more doubtful, though a few cases have been described by competent observers. Hereditary tendencies are of etiological impor- tance. The disease occurs more frequently in families in which tuberculo- sis is common than in those not so affected. Constitutional predispo- sition is also an important factor, poorly developed girls, and particularly those of delicate mould, being especially liable to the disease. Virchow found hypoplasia of the heart and great vessels, and Rokitansky the same condition in the generative organs, and pathologists have been inclined to regard these as important factors in the development of the disease. Various exciting causes have been considered as of more or less importance. Emotional excitement was regarded as a prime cause by ancient authorities, and in consequence such terms as icterus seu febris amantium were applied. Home-sickness, grief, ete., are causes of moment. Intestinal auto-intoxication has been regarded as the essen- tial factor by many, but physiological chemists fail to find evidences of the existence of such intoxication. Menstrual disturbances are im- portant as symptoms, and have often been regarded as causes. The hypoplasia of the genital organs adds some probability to this view, but more definite evidence is wanting. Von Noorden strongly ad- vocates a theory that chlorosis is due to a failure of some internal secre- tion of the ovaries. At the present time it seems most likely that chlorosis is due to faulty development, and especially to a want of proper hemogenetic power. Pathological Anatomy.—The hypoplasia of the vascular and gener- ative systems has been referred to. These are primary lesions, and possibly causal. Various secondary diseases may be encountered, as in other anemias. Among these, myocardiac degeneration and dilatation are most important, though they do not attain high grades of severity. The spleen is frequently a little enlarged. Peculiar yellowish or greenish pigmentation of the skin is a striking feature. The pigment is doubtless altered hemoglobin, but its exact nature is unknown. The blood is paler than normal and watery. The specific gravity decreases progressively, and the solid matter is deficient. Increased coagulability is sometimes observed. The number of red corpuscles may be normal, even in well-developed cases, but the proportion of hemoglobin sinks progressively. In prolonged cases the corpuscles become reduced in number, but the deficiency of hemoglobin continues to be excessive. Severe cases of chlorosis frequently show 3,000,000 or 2,000,000 red corpuscles per cubic millimeter and 30 to 20 per cent. of hemoglobin. The red corpuscles may be little altered in appearance in the early stages; later, great pallor of the cells, and irregularities in size and shape are frequent, nucleated red corpuscles (especially normo- Pernicious anemia. (Drawing made under the direction of Dr. C. Y. White.) Chlorosis. (Drawing made under the direction of Dr. C. Y. White.) DISEASES OF THE BLOOD 435 blasts) make their appearance. The latter sometimes occur in great numbers in crops (blood crises). The leukocytes are usually normal in as and kind; but in some cases myelocytes have been met with. During the process of recovery from chlorosis the red corpuscles increase in number before any change occurs in the percentage of hemo- globin. Pathological Physiology.—Chlorosis resembles the secondary ane- mias in most particulars, as far as its influence on the general health is concerned. Some of the symptoms (cardiac and menstrual) are doubt- less due to primary abnormalities of structure. The preservation of the subcutaneous fat despite advancing anemia is a striking feature. It is explained by von Noorden on the assumption that the quiet and warmth which chlorotics find necessary to their comfort lead to accu- mulation of fat. Decreased oxidation is certainly not the cause. PROGRESSIVE PERNICIOUS ANEMIA Definition.—Progressive pernicious anemia is a form of hemolytic anemia characterized by certain hematologic features significant of pathological activity of the bone-marrow. It is probably always fatal, though a few instances of recovery have been reported by competent authorities. An exact definition and a positive clinical differentiation from certain other conditions are not possible. Etiology and Pathogenesis.—The disease was first described by Addison as a wholly causeless anemia, that is, an anemia independent of preceding disease of any sort. Subsequent investigation seemed to show that it might be secondary to other diseases. Thus intense anemias were found during pregnancy and lactation, in certain gastro- intestinal affections, including atrophy of the gastric and intestinal mucosa, ulcerations and carcinoma, and in cases of intestinal parasit- ism (uncinaria, bothriocephalus). A rigid scrutiny of such cases dis- closes the fact that these are usually instances of intense secondary anemia, though the resemblance to true pernicious anemia may be puzzlingly close. In the cases in which true pernicious anemia must be admitted the relation may be merely a coincidence. Considerable evidence has, however, accumulated to show that gastro-intestinal infections and toxemias may be the underlying cause of the disease. First, it was shown that pernicious anemia is essentially a hemolytic anemia from the facts that the blood-picture is in many respects that of direct experimental hemolytic anemias, that the pigmentation of the liver and spleen indicate hemolysis, and the urine and feces give evidence of excessive liberation of blood-pigment. Second, it was noted that the distribution of pigment in the liver and spleen strongly suggested hemol- ysis in the area of the portal circulation; and third, the frequent asso- ciation of oral infection (glossitis, ulcers in the mouth, on the gums, etc.) or gastro-intestinal disease further strengthened this view. The discovery of hemolytic substances in the bodies of bothriocephalus taken 436 A TEXT-BOOK OF PATHOLOGY in conjunction with the anemia occasioned by this parasite was another factor in the evidence. There is some ground for believing that some sort of primary vul- nerability of the bone-marrow may be of importance; but it is much more probable that the marrow is affected by toxic agents derived from outside sources than that there is a primary disease of the marrow. Among clinical causes: age (usually after adult years have been reached); sex (more often females); nervous shocks, privation, and insanitary surroundings have been noted. Malaria, syphilis, tubercu- losis, and other infections, as well as repeated hemorrhages, have been regarded as causes. In connection with all of these it must be remem- bered that the differentiation of intense secondary anemia from per- nicious anemia is often very difficult. Pathological Anatomy.—Various secondary changes are met with, those in the blood-making organs being most important. The bone- marrow of the long bones is red and softened and often quite hemor- rhagic (for details, see Bone-marrow). This change was formerly re- garded as a primary and causal one. At the present time it is looked upon as secondary and reactive to a toxemia and, in part, to the hemolytic anemia itself. In part, at least, it represents the effort of the bone- marrow to compensate for the active blood destruction. The spleen is sometimes enlarged, and may be considerably so. (Pigmentation of the spleen will be referred to below.) The liver, kidneys, and especially the heart suffer degenerative changes (fatty) in severe cases. Similar alterations in the blood-vessels may cause punctate hemorrhages (especially in the retina), or larger hemorrhages in various situations. The lesions of the gastro-intestinal tract have been referred to. Some of them are doubtless secondary to the anemia; others may be primary. Degenerations of the posterior and lateral columns of the spinal cord are frequent. They seem to be due to a toxic agent rather than to hemorrhages. Pigmentation of the liver, spleen, kidneys, and other organs is a significant condition in evidence of the active hemolysis supposed to occur in this disease. The pigmentation of the liver is most impor- tant, and seems to be characteristic. It occurs in the hepatic cells at the periphery of the lobules and in the endothelial cells of the lymphatic channels and capillaries in the same situation. The pigment is iron- containing, and may be well demonstrated by applying the iron reac- tions (sulphid of ammonium; hydrochloric acid and ferrocyanid of potassium—forming Prussian blue). The Blood.—The color of the blood is often strikingly pale; though it may be dark in spite of marked anemia. In some strikingly hemol- ytic cases the blood-plasma may be deeply tinged with hemoglobin or with bile-pigment. The specific gravity is reduced. The marked feat- ures of the disease are pronounced oligocythemia, marked changes in the character of the red cells, and a color-index somewhat above normal, which contrasts with the low color-index of severe secondary anemias. DISEASES OF THE BLOOD 437 The oligocythemia progresses rapidly, and in ordinary cases the number of red corpuscles sinks to 1,000,000 or less per cubic millimeter; at the same time changes in size (microcytes and megalocytes) and in shape (poikilocytes) make their appearance, and reach grades rarely attained in other diseases (Fig. 179). An important feature is the number of macrocytes. A general survey of the microscopical field at once indicates that the average size of the corpuscles is evidently increased. Nu- cleated red corpuscles are always present in some numbers and are usually abundant (Fig. 179). The larger and polychromatophilic forms (megaloblasts), as a rule, predominate; but in some cases the smaller forms are more abundant. Karyokinetic figures may be found in the nuclei. Polychromatophilia and basic granulation are generally pro- nounced. The leukocytes may be decreased or normal in number; in the late stages leukocytosis is not uncommon, and it may become quite Fig. 179.—Blood in pernicious anemia, showing irregularity in the size and shape of the red corpuscles; one nucleated red corpuscle (megaloblast) and two lymphocytes; stained with Ehrlich’s triple mixture. marked. The larger mononuclear leukocytes are usually more abun- dant than in health, and myelocytes often occur in considerable numbers. In the terminal leukocytosis of pernicious anemia the lymphocytes often predominate. APLASTIC ANEMIA Occasional cases of severe anemia running a rapid course to a fatal termination have been reported, in which the bone-marrow has shown a high grade of hypoplasia or even total aplasia. In these cases the blood gives evidence (marked reduction in the number of red cells, low color-index, great reduction of the proportion of polymorphonuclear cells, relative and actual increase of lymphocytes, absence of myelo- cytes and very few nucleated red cells) of the inactivity or aplasia of the marrow. These cases seem classifiable as types of progressive pernicious anemia in which the response of the bone-marrow to the demand for hemogenesis is nearly or quite wanting. Possibly the toxic agent may be directly destructive to the bone-marrow, as it is to the blood. The bone-marrow is yellow or white, and on microscopical section the specific marrow cells may be wholly wanting. 438 A TEXT-BOOK OF PATHOLOGY HEMOLYTIC ICTERO-ANEMIA In recent years several clinical types of hemolytic anemia with jaundice have been described. These may properly be discussed here because of the close relationship in pathogenesis and the difficulty in fully differentiating some of these conditions, either clinically or pathologically, from genuine pernicious anemia. The evidences of hemolysis are more striking in these diseases, while the indications of bone-marrow reaction are less marked, but border-line cases merge gradually into the picture of pernicious anemia. A congenital and an acquired form of hemolytic ictero-anemia have been described. In each there is more or less pronounced anemia, jaundice, and splenic enlargement. The congenital form often affects several members of a family, is comparatively mild, and may continue for years without grave disturbance of health. Splenic enlargement is marked. In the acquired form the anemia and jaundice are more marked and splenic enlargement usually less so. The prognosis is more grave. In both, the evidences of hemolysis (jaundice, without acholic stools, urobilinuria, hemorrhagic tendencies) are pronounced. ‘The red corpuscles show decided fragility, being hemolyzed in much more concentrated salt solutions than are normal red corpuscles. LEUKEMIA Definition.—Leukemia is a hyperplastic disease of the hemogenic organs accompanied by increase in the number of leukocytes in the circulating blood, and by the presence also of cell types not found normally outside the blood-making tissues. Etiology.—The actual cause of leukemia, as well as the essential nature of the disease, remain obscure. Various diseases (malaria, syphilis, rickets, etc.) have been regarded as predisposing causes. The same is true of pregnancy, lactation, traumatism, exposure, and other in- fluences. To some, heredity has seemed to be an important element. Infection has been suspected as the direct cause of leukemia by many observers, and various forms of bacteria have been discovered in the blood and tissues. There are certainly some very striking facts in favor of an infectious nature, the most important being the apparent con- tagiousness in a few cases. The various micro-organisms need not be enumerated, as none of them has been proved to be pathogenic. Bodies resembling protozoa have been found in the blood and in the organs (lymphatic glands), but the nature and significance of these are un- certain. Pathological Anatomy.—It is impossible to classify leukemia with certainty, but the evidence at present seems to justify the belief that it is closely related to neoplastic processes. Reference to this aspect of the matter will be found in the sections on Lymphatic Glands and Bone- marrow. In a certain sense the lesions of leukemia might be classed as hyper- DISEASES OF THE BLOOD 439 trophy or hyperplasia of the hemogenic tissues; but there is evidence of a progressive process that goes beyond the limits of ordinary hypertro- phies. Enlargement of the spleen or of the lymphatic glands is the conspicuous pathological feature. The secondary lesions in organs that have ceased to be active hemogenic structures (spleen, liver, and peri- vascular tissues elsewhere) appear to be metaplastic, in the sense that the endothelia may reassume a latent capacity and as in fetal life initiate new series of blood-making cells. This process rather than metastasis or mere deposition accounts for the foci of myeloid or lymphadenoid tissue found in practically all parts of the body. Two types of leukemia may be distinguished: the myeloid or myeloic and the lymphatic. The former originates in the bone-marrow, and is characterized by hyperplasia of the myelocytic series of cells. Not only myelocytes, but their predecessors, myeloblasts and various intermediary stages representing undeveloped myelocytes, may make up the bulk of the tissue. The erythroblastic cells are- crowded out, though not invariably, and exceptionally may be conspicuous. In certain cases, especially in very acute forms, myelo- blastic cells difficult to distinguish from cells of the lymphocytic series may be conspicuous both in the lesions of the bone-marrow and other organs and in the blood. Many if not most of the cases of so-called acute lymphatic leukemia belong in this group. Lymphatic leukemia originates in the lymphatic glands or other lymphadenoid tissues, and consists essentially in an active _ proliferation of lymphocytes. The bone-marrow, spleen, and other organs may be secondarily involved. The contention that all forms of leukemia originate in the bone-marrow, which was at one time commonly believed, was largely based upon the discovery that sometimes in ‘so-called acute lymphatic leukemia the bone-marrow was found affected and not the lymph- oie Ae atic glands. In the light of present i, 180— Lymphoid indltrations knowledge these cases were probably of leukemia. instances of myeloblastic leukemia. Occasionally the primary disease is in the lymphadenoid tissues of the gastro-intestinal tract. Primary dermal leukemia has been de- scribed (lymphodermia perniciosa), but is not satisfactorily established. Among the secondary lesions of leukemia are invasions of the liver, kidneys, lungs, heart, and other tissues. The organs show areas of light color, or a streaked or inottled appearance, due to masses of myelo- cytic or lymphoid cells (Fig. 180). Secondary degenerations of the heart, liver, and kidneys may result from the deposits, or from the im- poverished state of the blood and the presence of toxic substances. Scleroses of the spinal cord may be met with, as in pernicious anemia. 440 A TEXT-BOOK OF PATHOLOGY The blood is often light in color and may be quite milky in appear- ance. The specific gravity is lowered. Coagulation is slow; this. has been attributed to the presence of albumoses in the blood. The conspicuous feature in the blood is the increased number of leukocytes. In moderate cases there are from 100,000 to 300,000 white corpuscles per cubic millimeter. In severe cases the number is much greater; while in mild or beginning cases, or in cases under active treat- ment, the number may for a time be normal or subnormal. Rapid fluctuations in number are very common. Leukemia is usually a chronic disease. The blood-picture indicates the type of the lesions, and we may thus recognize a myeloid or lymphatic form. Myeloid Type.—Enlargement of the spleen is the conspicuous clin- ical feature. The blood presents a great excess of white corpuscles and more or less decided poverty in red cells. The proportion of white to red corpuscles is often 1:3, 1:2, or even 1:1. The larger mononuclear leukocytes (including normal mononuclear and _transi- tional elements and myelocytes) predominate over the lymphocytes and polymorphonuclear elements (see Fig. 175). The latter two forms, however, are actually increased. Myelocytes are usually found in great numbers, and evidence the myeloid nature of the disease. Not only the typical neutrophilic myelocyte, but more or less abundant eosinophilic and basophilic forms and some without granules or with a mixture of basophile and neutrophile granules may be found. Cells corresponding to the myeloblasts may also be found, sometimes abun- dantly, especially in acute cases. There is usually an actual increase in the number of eosinophile elements, but the percentage proportion is rarely increased. Basophilic leukocytes (mast-cells) are present in numbers greatly in excess of those found in health. Karyokinetic leuko- cytes are found in small numbers. The red corpuscles present the usual features of anemic blood, and nucleated forms, especially normoblasts, may be abundant. The blood-picture is an extremely variegated one, and the predominence of large cells is the feature that stands out most prominently. A peculiar constituent of the blood are the Charcot-Neumann crys- tals. These are polyhedral, needle-shaped crystals of uncertain com- position, met with in the blood after death or some time after removal from the body, and exceptionally in the fresh blood. They were first detected in the bone-marrow. Lymphatic Type.—Enlargement of lymphatic glands is the most conspicuous clinical feature. The leukocytes are usually less abundant than in the myeloid type. The lymphocytes predominate very greatly, but actual excess of large mononuclear forms and polymorphonuclear leukocytes is observed. Contrasted with myeloid leukemia the striking feature is the abundance of small cells—lymphocytes. The larger lymphoblasts are rarely conspicuous except perhaps in certain acute cases. Myelocytes occur in small numbers; exceptionally in consider- Chronic lymphatic leukemia. (Drawing made under the direction of Dr. C. Y. White.) DISEASES OF THE BLOOD 441 able proportion. The number of red corpuscles is decreased and nucle- ated red cells may be present. Acute Leukemia.—A separate description of acute leukemia is de- sirable, because in its clinical manifestations there are striking differences from those seen in chronic leukemia and because it is difficult to deter- mine whether a given case is myeloid or lymphatic. In the rapid progress of the disease cells of great immaturity are cast into the circu- lation and opinions vary as to their nature. Some hold that these are lymphoblastic; others, that they are myeloblasts. Upon the whole, the latter view seems to be more tenable. Acute leukemia seems, in some respects, a distinct type of the dis- ease, and the symptoms are strongly suggestive of an infectious condi- tion. The duration is usually from a few weeks to a few months after the first symptoms are noted. Gastro-intestinal lesions (ulcers in the mouth, stomach, and intestines) and hemorrhagic manifestations (purpura) are frequent. Moderate enlargement of the lymphatic tissues and infiltrations of the organs are discovered, and parenchy- matous changes in the organs are constantly present. The blood shows a varied picture. The total number of leukocytes may vary from a very moderate increase above the normal to several hundred thousands per cubic millimeter. Mononuclear elements are conspicuous, the predominating cell being one that resembles lympho- cytes or lymphoblasts, and also the smaller myeloblasts. The nuclei are large, round, or horseshoe shaped, and stain faintly; the protoplasm forms a somewhat narrow rim around the nucleus. The polymorpho- nuclear cells and eosinophiles may be actually, but not relatively, in- creased in number; myelocytes are occasionally present. Considerable reduction in the number of red corpuscles is a usual feature of acute leukemia. Nucleated red corpuscles (especially normoblasts) are gener- ally present. HODGKIN’S DISEASE This disease presents a certain superficial resemblance to leukemia in the enlargement of the lymphatic glands and sometimes of the spleen, and to a less extent in the histology of the lesions. As the differentia- tion has become more definite the old term pseudoleukemia has been generally abandoned. Hodgkin’s disease does not present an increase in the number of leukocytes in the blood, or, at most, a very moderate increase. There is a moderate but progressive anemia, with occasionally decided eosino- philia. In certain cases the polymorphonuclear elements are relatively excessive. The lymphatic glands enlarge more quickly than in leukemia, and the spleen and marrow are less frequently involved. (See Lymph- atic Glands.) Pseudoleukemia Infantum Under this name von Jaksch described a form of leukocytosis, with enlargement of the spleen and liver, occurring in children. There is rapid 442 A TEXT-BOOK OF PATHOLOGY and excessive oligocythemia, and the leukocytosis is pronounced. Leu- kocytes of all types are present, and give to the blood a curiously variegated appearance. There is no striking difference, however, from the characters of the blood met with in other cases of leukocytosis in infancy. Rickets and congenital syphilis seem to be closely related to this form of disease. The enlargement of the spleen and liver is not of the nature of that seen in leukemia, but is simply a chronic hyperplastic condition. FOREIGN BODIES AND PARASITES Foreign Bodies in Blood.—Various kinds of particles may gain access to the blood-current and may be carried to peripheral parts of the circulation. In anthracosis a lymphatic gland may attach itself and, after softening, rupture into.a vein. The particles of carbon are thus distributed in the blood. Small portions of tumors, of the heart- valves, calcareous particles from atheromatous plates, and portions of thrombi are frequently transported by the blood. Charcot crystals are met with in leukemia, and pigment-matter, due to disintegration of the blood itself, is seen in malaria. Parasites in the Blood.—Among the animal parasites are the mala- rial plasmodium, which occurs within the red corpuscles or free in the plasma; the Schistosomum hematobium, which occupies the portal vein; the embryos of the Filaria bancrofti, and the trypanosomes. (These are more fully described in the section on Parasites.) Portions of hydatid cysts or of cysticerci and trichine are occasionally conveyed in the circulation. Vegetable Parasites.—Mould-fungi sometimes gain entrance into the circulation and lead to serious embolism, as does also the Strepto- thrix actinomyces.. Of the pathogenic bacteria, the spirochete of relaps- ing fever and the bacillus of anthrax are most abundant in the blood. Other micro-organisms are more difficult of demonstration, though many kinds of micro-organisms have been demonstrated morpho- logically and in culture. CHAPTER II DISEASES OF THE LYMPHATIC TISSUES THE SPLEEN Anatomical Considerations.—The spleen is practically a com- plicated lymphatic gland with close relations to the circulation. It is enclosed in a fibrous capsule, from which trabecule enter into the substance of the organ and give off subdivisions that unite and form a framework, in the meshes of which lymphoid tissue is embedded. The splenic artery enters at the hilum and subdivides into numerous branches which traverse the trabecule. Side branches are given off from the trabecular arterioles; these penetrate the splenic pulp and are surrounded by denser aggregations of lymph-cells, which are visible to the naked eye as the Malpighian bodies. All of the terminal arteries discharge their blood directly into the spaces of the splenic pulp, from which it is re-collected into the veins. The spaces contain, in addition to lymphoid cells and red blood-corpuscles, larger cells, endothelial in type, often containing pigment granules or even blood-corpuscles. The weight of the spleen in the adult varies from 140 to 200 gm. The splenic function remains in doubt. It seems to have some con- nection with the process of manufacture of leukocytes, and is one of the sources of red blood-corpuscles in early life. It may also be the place of destruction of red corpuscles, and in cases of general hemolysis, or blood-destruction, the blood-pigment and fragmented corpuscles are especially arrested in this organ. It has something to do with the iron chemistry of the body. The muscular tissue of the capsule contracts and expands, assisting thus in the propulsion of blood and lymph. Pathological Physiology.—The relations of diseases of the spleen to the general health are still obscure. It has been held by some pathol- ogists that this organ plays an important part in the process of im- munization or combating infectious diseases. The fact that bacteria and foreign bodies circulating in the blood are arrested to a large extent in the spleen warrants the suspicion that this organ is important in dis- posing of irritants, and thus preventing their gaining access to more vital parts. Experimenters, however, have found no uniform increase of susceptibility to micro-organismal inoculation on the part of splenec- tomized animals. For the present, therefore, we can only suspect that removal or disease of the spleen renders individuals more vulnerable to infections. The effect of removal of the spleen in human beings is surprisingly slight. A certain amount of anemia and general deterioration of health follow the operation, but seem to be the result of the operation per se, 443 444 A TEXT-BOOK OF PATHOLOGY rather than of removal of the organ. Subsequently, complete health is regained. Some compensatory (?) enlargement of the lymphatic glands has been observed after splenectomy. ABNORMAL DEVELOPMENT AND SITUATION Complete absence of the spleen has sometimes been noted in children that lived for several years. More commonly slighter defects, such as unusual smallness or excessive lobulation, occur. Very often small accessory spleens, the size of a pea or a marble, are found, occurring chiefly in the abdominal cavity, but also found elsewhere. Movable Spleen.—The organ may be quite movable, either as a congenital condition or as the result of enlargement and resulting traction upon its attachments. Downward displacement and mova- bility are frequently found in cases of splanchnoptosis. Twisting of the pedicle of a movable spleen may lead to strangulation of the circulation and consequent necrosis. CIRCULATORY DISTURBANCES Anemia may occur in cases of general anemia resulting from hemor- rhage or inanition. The spleen presents a contracted appearance, the capsule being wrinkled, and on section the substance is found to be lighter in color and the fibrous stroma is more prominent than normal. Hyperemia may be active or passive. Active hyperemia is a physio- logic condition during digestion, when the spleen increases somewhat in size. Intense congestion occurs in a number of diseases, but so com- monly passes into inflammation that it will be described under that heading. Passive congestion is most marked in cases of cirrhosis of the ‘liver, but also occurs in association with hyperemia of other organs as the result of cardiac failure, of emphysema, or of other diseases obstruct- ing the larger venous channels. The spleen is greatly enlarged and of a dark-red color, and the capsule is often tensely distended; the Mal- pighian bodies are less distinct than normally. After long continuation of the process hyperplasia of the trabecule and the fibrous stroma generally takes place. The spleen may be greatly enlarged and very dense at this stage. Subsequently contraction of the newly formed fibrous tissue may lead to atrophy of the proper splenic substance and increased induration of the organ (cyanotic induration). Considerable pigmentation is found in such cases from the destruction of the stag- nated blood (see p. 448). H. A. Christian, in a study of the spleen in cases of chronic passive congestion and cirrhosis of the liver, found no change of any kind in the Malpighian bodies of the spleen. The pulp was relatively poor in cells and the blood sinuses generally dilated. There was also, as a rule, a definite layer of low cuboidal endotheial cells lining the sinuses. In a majority of the cases there was increase of the connective-tissue framework. In the 10 cases with no increase in connective tissue, the spleen felt almost equally firm, showing that DISEASES OF THE LYMPHATIC TISSUES 445 the firmness was due to vascular distention. The same factor probably enters into the production of firmness in all of the cases. Proliferation of the reticular tissue of the pulp with little or no change in the white fibrous and elastic tissue of the organ, constituted the main connective tissue change. An increase of connective tissue around the small splenic arteries and within the Malpighian bodies was sometimes seen. Hemorrhages in the spleen may be the result of traumatism, when large hematomata may form, especially just beneath the capsule. Small areas of hemorrhage are not infrequent in intense infections with splenitis, but it is difficult to draw a line between hemorrhage and the overfilling of the spaces by congestion, since the blood under normal conditions enters directly into the splenic pulp. Embolism of the splenic artery is very common in cases of endo- carditis or thrombosis in the left heart or aorta. As the spleen contains abundant ‘‘terminal arteries,’ infarction is the common result. The area may remain light colored, constituting an anemic infarct; or it may become overfilled with blood, when hemorrhagic infarction results. In either case there is a wedge-shaped lesion, with the base toward the surface of the organ and the apex within, harder than the surrounding tissue and usually somewhat elevated. The swelling and elevation in the case of anemic infarction are partly due to a zone of hyperemia which usually surrounds it. Complete resolution may occur, but more commonly the area involved undergoes coagulation necrosis and soften- ing, and as absorption takes place fibrous overgrowth gives rise to the formation of a scar. There may be numerous infarcts of small size or a single large one sometimes occupying as much as half of the organ. (Septic infarction and its results are discussed under Abscess of the Spleen.) Thrombosis of the splenic vein may occur in association with throm- bosis of the portal vein. It causes intense passive hyperemia of the spleen. Occasionally calcification of thrombi gives rise to the forma- tion of splenic stones. INFLAMMATION OF THE SPLEEN, OR SPLENITIS Splenitis occurs in a variety of conditions, and may present itself in several forms, among which the acute enlargement of the spleen of infectious diseases and localized splenitis, or abscess of the spleen, are the principal. Diffuse Splenitis.—The splenic enlargement of infection occurs particularly in typhoid fever, malaria, septicemia, typhus, and relapsing fevers; and less markedly in pneumonia, scarlet fever, small-pox, and influenza. In the earlier stage the spleen is simply congested and pre- sents a dark-red color; is firm, and the capsule more or less distended. On section, the Malpighian bodies are usually obscured, and there may be visible areas of hemorrhagic extravasation. Microscopically at this stage the blood-vessels are all found overdistended, and the spaces within the splenic pulp are filled with red and white blood-corpuscles. 446 A TEXT-BOOK OF PATHOLOGY If the process has continued for some time, pigment masses and de- generated corpuscles are visible, but there are as yet no evidences of inflammatory hyperplasia of the splenic pulp or stroma. As the process advances the spleen may become softer and may be quite diffluent. On section, the substance is now found to be lighter in color, the Malpighian bodies are distinct, and, particularly in violent septic cases, are decidedly prominent, presenting themselves as yellow- ish-gray puncte, somewhat resembling miliary tubercles. The capsule of the organ may still be tensely distended, but in other cases is wrinkled, as if some shrinkage of the spleen had occurred in the change from the first stage of congestion to that of well-defined inflammation. Micro- scopically there is now apparent a great increase of the cells of the splenic pulp, particularly of those constituting the Malpighian bodies. That this increase is partly at least due to active proliferation is known from the abundance of mitoses. There is also hyperplasia of the stroma and trabecule, and of the endothelial cells of the spaces. In still later stages signs of degeneration may become prominent. This is apparent in the increasing softening of the organ, while under the microscope there are found cellular degenerations leading to the formation of detritus, to fragmentation of the nuclei of the cells, and to pigmentation by disintegration of red blood-corpuscles. Terminations.—Most frequently complete resolution occurs. Some- times, however, persistence of the inflammation is noted; and, when repeated attacks of the infection occasion repeated attacks of splenitis, chronic inflammatory hyperplasia is the result. This is especially marked in the “ague-cake’” spleen of malaria. Spontaneous rupture or rupture from slight trauma may result from the softened and dis- tended condition of the organ. Finally, suppuration may ensue, either in the form of a diffuse softening and purulent infiltration of the entire organ, or in the form of a localized abscess beginning at the point of greatest involvement. Circumscribed Splenitis, or Abscess of the Spleen.—This may be the termination of an acute diffuse splenitis, particularly in septi- cemia and typhoid fever; or it may be caused by extension of diseases of neighboring structures, by septic embolism, or traumatic injuries. In the last case, the mechanical injury of the spleen merely furnishes suit- able conditions for the action of bacteria conveyed to it through the cir- culation, or the spleen is actually penetrated and infected. Occa- sionally abscess may result from the perforation of gastric ulcers or from the extension of other inflammations in the vicinity. An important group of cases is that in which the abscesses are embolic and metastatic (Fig. 181). Such cases are met with in malignant endocarditis or throm- bosis of the heart or aorta, and in cases of pyemia following other in- fective conditions. The first effect of the embolism is a hemorrhagic or anemic infarction, but this soon undergoes suppurative softening, beginning at the apex of the infarct. Metastatic abscesses are most common near the surface of the organ and are usually multiple, though a single cavity occupying the greater part of the organ may occur. DISEASES OF THE LYMPHATIC TISSUES 447 Small collections may become absorbed or inspissated, leaving a necrotic or cheesy collection as a residue. Larger collections may be discharged by perforation into the stomach or intestines, or they may break into the peritoneal or pleural cavity, causing septic peritonitis or pleuritis. Chronic Inflammation or Chronic Hyperplasia of the Spleen. —Attention has already been called to the slow hyperplasia of the con- nective tissue and sometimes of the splenic pulp occurring in conse- quence of chronic passive congestion and of repeated attacks of acute splenitis. The spleen is large in size and firm. The capsule is often tensely distended and may be greatly thickened. The thickening is either diffuse or circumscribed, patches of almost cartilaginous hardness occur- ring in the latter case. Attachments by fibrous adhesions may fix the spleen to the diaphragm or the neigh- boring organs. On section the spleen is found dark in color from the pres- ence of abundant pigment, and the excess of fibrous tissue may be visible ‘to the naked eye. Microscopically, increased thickness of the fibrous trabecule, hyperplasia of the con- nective tissue about and within the follicles and that of the walls of the small blood-vessels, and pigmenta- tion with altered blood-pigment are the conspicuous features. A somewhat different form of chronic hyperplasia is dependent upon syphilis, especially upon the congenital form. In this the appear- Fig. 181.—Embolic abscess, of the = spleen (from a specimen in the Museum ances are much the same as in the of the Philadelphia Hospital). cases following splenitis or conges- tion, but, as a rule, the color is somewhat lighter from the fact that the process is a slowly hyperplastic one without acute inflammatory or con- gestive manifestations. Somewhat similar appearances result from rickets. The indurative processes in the spleen following cirrhosis of the liver may be due at times to thrombosis of the liver veins, but this does not always exist. It has been suggested that circulating toxins are responsible. ; Splenic Anemia; Splenomegaly.—These terms have been used to describe a clinical condition distinguished by chronic enlargement of the spleen due mainly to fibrosis beginning in the follicles, gastro-intestinal disturbances, a tendency to hemorrhages from the stomach, and later by progressive weakness and ascites. Anemia of chlorotic type may occur, especially in the hemorrhagic cases, but is not essential, and the name “splenic anemia” is, therefore, ill chosen. The development of 448 A TEXT-BOOK OF PATHOLOGY ascites is due to secondary cirrhosis of the liver. Cases presenting this association are designated Banti’s disease. The so-called primary or idiopathic splenomegaly of Gaucher is an enlargement of the spleen due to accumulations of endothelial cells without much cirrhotic change, associated with enlargement of the liver, anemia, and pigmentations of the skin, or hemorrhages. The liver and lymph-glands may show the endothelial changes as in the spleen. The etiology and nature of these cases is probably varied. At autopsy some show merely chronic congestion of the spleen, others a more definite chronic hyperplasia, a few have been found to present a peculiar proliferation of the endothelium of the sinuses (see Tumors). Formerly splenic anemia was regarded as a splenic type of Hodgkin’s disease. This view has been disproved by the absence of the usual histological features of the latter disease. ATROPHY AND DEGENERATIONS Atrophy of the spleen is very common in old age. The capsule is usually wrinkled and somewhat thickened, and on section the organ is more fibrous in appearance on account of atrophy of the splenic pulp and proliferation of the stroma. Thickening of the capsule some- times appears in the form of white plates of cartilaginous hardness, which result from inflammatory overgrowth of the capsule (perisplenitis cartilaginea). Amyloid infiltration occurs more frequently in the spleen than in any other organ. The causes are those which lead to amyloid disease elsewhere. In most cases the degeneration begins in the Malpighian bodies, affecting the walls of the blood-vessels- (Plate 5) and the lymph- oid elements. On section in such a case there are seen small round areas about the size of a currant-seed, of gelatinous, translucent appearance. These have been likened to grains of boiled sago, and the term sago spleen is not inappropriate. In other cases a more uniform involvement of the whole organ is noted, and the section presents the appearance of boiled ham or dried beef (bacony spleen). Considerable enlargement of the organ is noted in such instances, and the tissue is much harder than normal. Beginning amyloid degeneration may be difficult to determine microscopically, but is readily demonstrated by the microscopical stain- ing reactions. (See Amyloid Degeneration.) _ Hyaline degeneration has been observed in association with amy- loid and independent of the latter. It affects the small blood-vessels and the reticulum more particularly. Pigmentation is a very common result of chronic congestion as well as of repeated acute splenitis; the spleen in cases of cirrhosis of the liver and in chronic malaria is, therefore, habitually pigmented. The deposit occurs first in the walls of the blood-vessels and later throughout the splenic structure, either within the cells or lying free in the tissue. Occasionally pigment particles derived from the external world are deposited in the spleen. This is especially true of dust particles which PLATE 5 Amyloid degeneration of the spleen, showing a degenerated Malpichian body; specimen stained with hematoxylin and cosin. DISEASES OF THE LYMPHATIC TISSUES 449 have reached the circulation from softened bronchial glands. In cases of diseases of other kinds leading to discharge of foreign bodies or tissue elements into the circulation, the arrest not rarely occurs in the spleen, and reactive congestion or inflammation with enlargement of the spleen may result (spodogenous splenitis). Pigmentation of the spleen is seen in progressive pernicious anemia and other conditions in which hemolysis occurs. The pigments resulting from the destruction of red corpuscles are deposited in the liver, spleen, and other organs. Biliary pigmentation of the spleen occurs in various forms of jaundice. Pig- ment is removed or at least ingested by endothelium, lying along trabecule and sinuses. Hematoidin is found in infarcts. Calcification occurs in the thickened capsule of chronic splenitis and in old infarcts, tuberculous or syphilitic areas, and occasionally in thrombi of the splenic vein. Parasitic cysts may be surrounded by calcification. LEUKEMIA AND HODGKIN’S DISEASE The spleen is usually involved in leukemia and occasionally in Hodgkin’s disease. The former condition is primarily an affection of the bone-marrow (myeloid type) or of the lymphatic glands (lymph- atic type). In either case, however, the spleen is usually involved. In the earlier stages the organ is enlarged and soft, and on section exhibits evidences of intense congestion. Later, the characteristic hyperplasia of myeloid or lymphatic elements causes a lighter color or areas of lighter color between the more congested portions. Infarc- tions, sometimes of considerable size, and hemorrhagic or anemic and necrotic, may add to the variegated appearance of the surface of section. Histologically in myeloid cases there are found areas of myelocytic or myeloblastic hyperplasia, sometimes with giant: cells and erythro- blasts, characteristic of myeloid structure. In lymphatic cases abundant lymphocytes replace the normal splenic tissue. In Hodgkin’s disease the characteristic histological features (see Lymphatic Glands) may be found in the enlarged spleen. TUMORS AND PARASITES Sarcoma and Carcinoma.—Primary sarcoma of the round- celled or fibrosarcomatous variety has been observed. Secondary sarcoma, particularly melanotic sarcoma, is more common than the primary growth, and secondary carcinoma occurs. Endothelioma.—A few of the cases of the clinical syndrome called splenic anemia have presented a remarkable proliferation of the endo- thelium of the splenic sinuses, and authors have variously regarded the process as an endothelial hyperplasia or as endothelioma. In a case reported by Stengel the process strongly suggested a tumor. Cysts are occasionally discovered. They are small and are prob- ably due to dilatation of the lymphatic spaces, or to atrophy and cystic degeneration of the Malpighian follicles. 29 450 A TEXT-BOOK OF PATHOLOGY Others are said to be due to an intracapsular injury and hemorrhage, with absorption of the solid parts and subsequent encapsulation. Lamina of clot may be found on the walls. Some authors believe that cysts may be due to an invagination of peritoneum. Fibroma, angioma, and lymphangioma are very rare. Parasites.— Linguatula rhinaria, echinococcus cysts, and cysticerci have been observed. INFECTIOUS DISEASES Tuberculosis of the spleen may occur in the form of minute miliary tubercles, which have a grayish translucent appearance, and are usually present in large numbers, especially near the cap- sule. They may be distinguished from enlarged Malpighian bodies by their greater opacity and their grayish rather than yellowish color. Tuber- culosis also occurs in the form of larger caseous nodules, especially in children (Fig. 182). In these cases there are seen nodular masses the size of a pea or cherry studding the surface and deeper structure of the spleen. This form is called Affentuberculose by the Germans, from - the resemblance of the large nodules to tubercles met with in monkeys. Histological examination proves the nodules to be composed of aggrega- tions of tubercles undergoing caseation. Prim- ary tuberculosis of the spleen has never been observed. : Syphilis may present itself in the form ‘ of syphilitic gummata, which are usually mul- tiple and may be either small or large. They Re cage- are distinguished by their central degenera- spleen of a child (Orth). tion or by the fibrous tissue striations at the exterior. Diffuse hyperplasia of the spleen is a frequent or almost constant lesion of congenital syphilis. The spleen is the seat of secondary deposits in actinomycosis, glanders, and leprosy, the lesions following the type characteristic for these dis- eases. Perisplenitis.—The capsule of the spleen may be inflamed as a part of acute splenitis or from a peritonitis. It is usually of a fibrinous character and may resolve or continue into a chronic stage, in which case it may have adhesions to adjacent organs or extension into the trabecule, or both. The capsule becomes gray and opaque. THE LYMPHATIC GLANDS Anatomical Considerations.—The lymphatic glands or nodes are accumulations of lymphadenoid tissue enclosed in a fibrous capsule, DISEASES OF THE LYMPHATIC TISSUES 451 into which a number of small afferent lymphatic vessels enter, and from which a somewhat smaller number of larger efferent lymphatic vessels emerge. The nodes are composed at the periphery of spherical lymphatic follicles made up of lymphadenoid tissue, and at the center-of medullary cords of the same structure. Under the outer capsule and alongside of the fibrous trabeculee which dip down between the follicles and cords are spaces lined with endothelial cells, the lymph-sinuses. Through this system of channels the lymph conveyed by the afferent vessels filters to the hilum of the glands, where the efferent vessels take their origin. Histologically, the lymph-follicles present at their centers collections of somewhat large and pale-staining cells with numerous mitotic figures. These are the germ centers composed of lymphoblasts. Surrounding these are smaller and more deeply staining cells—lymphocytes. Functions of the Lymphatic Glands.—Two important functions of the glands are recognized: a filtering action and blood-cell formation. The filtering action of the glands is readily explained by the anatomical features described, and is exhibited by the accumulation of bacteria or pigment in the lymphatic glands adjacent to an infective lesion or a source of pigmentary deposit. What part the regional lymphatic glands may play in the local inhibition of infective processes by destroying micro-organisms arrested by them is a matter of theory rather than present knowledge. The blood-cell formation of the lymphatic glands is concerned with the production only of lymphocytes and the plasma-cells. Both of these cell forms are apparently derivatives remotely of the endo- thelium of the lymphatic vessels or sinuses, and more immediately of lymphoblasts. The lymphocytes are relatively small cells with deeply staining nuclei, a marked nuclear membrane, and a somewhat granular basophilic protoplasm. These are derived from lympho- blastic cells (such as are seen in the germ centers of the follicles) —larger cell forms with paler nucleus and protoplasm. From these forms under pathological conditions may be derived plasma-cells, which are mainly distinguished by the eccentric position of the nucleus and the deeply staining (basophilic) protoplasm. These cells are especially abundant in the round-cell infiltration of inflammation. Hemolymph Glands.—Certain of the lymphatic glands of the retroperitoneal region differ from ordinary lymphatic glands in having blood-sinuses instead of lymph-sinuses. These have been termed “hemolymph glands.” Such glands are less frequently found in other situations, such as in the mediastinum, thymus region, cervical region, etc. They are usually embedded in fat tissue, and, as a rule, are near the wall of some large vessel. The number and size of the blood-vessels connected with these glands are remarkable, showing the relation to the hemic circulation. Transitional condi- tions between the typical lymphatic gland and the hemolymph gland are met with. Some of the glands resemble splenic tissue, and others the marrow tissue. Warthin suggests the terms “splenolymph” and “marrow-lymph gland.” Pathologically these glands have been found congested or showing evidences of increased pigment forma- tion in various types of anemia. They appear to have an active hemogenic function m such conditions. 452 A TEXT-BOOK OF PATHOLOGY ATROPHY This condition of the lymph-glands occurs in old age and in various marasmic conditions. The glands suffer considerable diminution in size, the cellular elements being particularly affected; they are, therefore, hard, dry, and often irregular in shape. Fatty infiltration may occur simultaneously with atrophy, the gland in such cases preserving its size and having a decidedly fatty appearance. HYPERTROPHY This is so closely allied to the conditions designated by the name of “lymphoma” that it is difficult to separate the cases which might be con- sidered as strictly hypertrophy. In cases of experimental or surgical splenectomy, hypertrophy of the lymphatic glands has been observed. Chronic enlargement of the tonsils and generalized lymphatic enlarge- ment in status lymphaticus may also be considered as forms of hyper- trophy. STATUS LYMPHATICUS This condition is one in which there is a marked preservation after early infancy or childhood of the relative excess of lymphatic tissue that characterizes the earlier years of life. A pronounced feature of the anatomy of childhood is the richness in lymphatic tissue and the high percentage of lymphocytes in the blood. After the first few years, but especially after puberty, this excess of lymphadenoid structures disap- pears, but in certain individuals it persists. In such cases the term “status lymphaticus” is applied. Formerly this condition was regarded as closely identified with status thymicus, in which persistence of the thymus gland after the time of its normal atrophy is met with. Certain recent authors separate the two conditions, and certainly status lymphat- icus is much more frequently unaccompanied by persistent thymus than accompanied by it. Among the physical features of the lymphatic status are hypertro- phies of the lymphadenoid tissues of the pharynx, the back of the tongue, the nasal passages, enlarged tonsils, cervical lymphatic glands, Peyer’s patches, ete. The blood-vessels are usually hypoplastic and the heart may be in the same condition. Enlargement of the spleen and a persistent thymus may be found. The blood presents the infantile excess of mononuclear elements (mononucleosis), especially lymphocytes; in some cases the bone-marrow remains persistently infantile (red) in type. In recent years particular attention has been called to a lack in development of the chromaffin system. The adrenals are deficient and the other structures containing chromaffin elements are more or less defective. To this lack of chromaffin substance, and the consequent deficiency of its secretions (adrenalin, etc.), may be due the low tension of circulation, and perhaps sudden death, which sometimes occurs. Certain writers describe as a separate form from the type above discussed, and which they regard as primary status lymphaticus, a second- DISEASES OF THE LYMPHATIC TISSUES 453 ary form which is developed in childhood or, later, in persons who had previously shown no abnormal structural conditions. Such secondary forms are said to occur as a result of rickets, syphilis, tuberculosis, and other infections, asthma and various diseases of the glands of internal secretion, such as Addison’s disease, Graves’ disease, myxedema, etc. The physical peculiarities are the same, but less pronounced than in the primary form. Rather too much weight seems to us to have been given to the blood condition (mononucleosis; lymphocytosis) in suggesting the existence of a status lymphaticus in some of these diseases. DEGENERATIONS Fatty infiltration is sometimes seen in cases of general obesity and also, as before mentioned, in atrophy of the glands. Amyloid infiltration is met with in cases of general amyloid dis- ease, and particularly in the cases in which the intestines are affected. The lymphatic glands may, however, be independently involved in cases of tuberculosis attended with suppuration. In such instances the adjacent lymphatic glands are most likely to suffer amyloid change. The morbid process rarely leads to marked alteration of the glands, but the amyloid material may be dem- onstrated by the staining reactions peculiar to it. The connective tis- sue of the trabecule and around the blood-vessels is first affected; later, the endothelial cells. Hyaline degeneration has been observed. It affects the blood-vessels and connective tissue of the glands. Calcification not infrequently forms the terminal condition in cases of oe or induration of Fig. 183.—Anthracosis of a bronchial the glands in consequence of tuber- lymph-gland (Orth). culous or simple inflammation. There may be small calcareous granules scattered through the gland, or the entire gland may be infiltrated. Necrosis may occur in consequence of tuberculous or syphilitic affections, or of simple inflammation. In the former cases, particularly in tuberculosis, the center of the gland or the entire gland becomes cheesy and soft, often liquefying and discharging the contents by rupture of the capsule. In consequence of simple inflammation, as in certain infectious fevers (typhoid, diphtheria, scarlet fever), a different form of necrosis is met with, areas of the gland becoming soft, pulta- ceous, and sometimes putrid. The gland may rupture, discharging its contents, or absorption of the liquid with inspissation and a pseudo- caseous form of degeneration may result. Finally, the degenerated area may become calcareous. 454 A TEXT-BOOK OF PATHOLOGY Pigmentation may follow acute inflammations or traumatism of the glands, the extravasations of blood occurring in such conditions leading to hematogenous pigmentation. The blood-pigment occurs in granular masses within the cells of the stroma or within the lymphatic cells themselves. Blood pigmentation may also occur in the glands adjacent to areas of hemorrhagic extravasation, the pigment in such cases reaching the glands through the lymphatic vessels and being de- posited in the lymph-sinuses, or even in the follicles and cords. Analo- gous pigmentation from external sources may result from tattooing, and oceurs regularly in the bronchial glands as the result of the inhalation of various dust-particles which penetrate the walls of the bronchioles and alveoli, and eventually find their way to the bronchial glands through the lymphatic stream (anthracosis) (Fig. 183). The glands may be completely black in such cases, and the lymphatic circulation through them may be obliterated. Secondary inflammatory changes result in most cases (see p. 455). INFLAMMATION; LYMPHADENITIS Acute lymphadenitis is commonly secondary to inflammations in the neighborhood, the irritants being carried by the afferent lymph- atics. Sometimes direct extension of inflammation by contiguity of structure may lead to involvement of the lymphatic glands. Occa- sionally lymphadenitis is seemingly primary in cases in which the in- fective irritants have caused no lesion at the portal entrance to the body. Pathological Anatomy.—The glands become enlarged, hyperemic, and considerably infiltrated with liquid. When the inflammation is intense there may be minute hemorrhages. Microscopically, the lymph-sinuses are found distended with cells—leukocytes, red blood- cells, and proliferated and desquamated endothelial cells from the lining membrane of the sinuses. The follicles and cords are increased in size from infiltration and probably also from proliferation of the lymphoid cells. The process may become arrested and resolution to the normal condition may ensue. If mild inflammation of this character has con- tinued for a great length of time, or if the condition is repeated, hyper- plasia of the trabecular connective tissue, of the blood-vessels, and of the capsule of the gland may lead to a termination in chronic enlargement and induration of the glands. The changes in the sinuses are spoken of as “sinus catarrh.” The proliferated lining endothelial cells in some places dominate the field. They may have more than one nucleus; they are actively phagocytic. In cases of greater intensity of the infective cause, necrotic or suppurative changes may occur. In the cases of necrosis such as occur in typhoid fever and in diphtheria there may be noted small spots of yellowish-white color in the hyperemic glands, and subsequently these undergo well-marked necrosis. Complete necrotic softening and even rupture of the gland may ensue, or, if the necrosis remains limited in DISEASES OF THE LYMPHATIC TISSUES 455 extent, inspissation and sometimes calcification may terminate the process. Suppurative lymphadenitis is not uncommon. It is seen in the glands below Poupart’s ligament in cases of infective wounds of the leg; in the inguinal glands as a result of chancroid or gonorrheal urethri- tis; in the glands of the neck in association with diphtheritic, scarlatinal, or other inflammations of the throat, or following erysipelas; in the axillary glands as a result of wounds of the arm; and in the internal lymphatics in various infective diseases. The term bubo is applied to suppurative lymphadenitis of superficial glands. Of particular interest is the tendency to this condition in the plague of the East, or the bubonic plague (q. 2.). Pathological Anatomy.—The changes noted in the gland at the outset are similar to those in the simple inflammations, but under the microscope a greater accumulation of leukocytes is apparent, and the gland tends to soften, with the formation of more or less creamy pus. The capsule may prove resistant for a time, and reactive inflammation around it may establish an additional wall. A single gland of a group may be affected, but more commonly the several glands are together involved. Eventually rupture may take place, but in instances in which the process has been circumscribed, inspissation of the pus and, finally, . calcification may occur. In the most intense forms of lymphadenitis hemorrhagic or gan- grenous conditions are developed. These acute inflammations usually have associated with them an infiltration and edema in the surround- ing tissues (perilymphadenitis). Chronic lymphadenitis leads to induration with enlargement. It occurs as the result of repeated acute attacks or in consequence of long-continued irritation by particles carried to the lymphatic glands from some focus of disease. Pathological Anatomy.—As a rule, the process affects the connective- tissue elements of the gland in particular, and there results a consider- able amount of induration, sometimes associated with atrophy or necrosis of the proper lymphoid structure. Occasionally, however, the lymphoid elements themselves are hyperplastic, and the normal relation of fibrous tissue, follicles, and medullary cords is preserved. Microscopically, the overgrowth of the connective tissue springing from the trabeculee, around the blood-vessels, and of the reticulum of the pulp is apparent. This may consist of round cells and fibrous connective tissue, or there may be a tendency to the formation of epithelioid cells and even giant cells. Pathological Physiology.—Inflammations of the lymphatic glands are the result of the arrest of irritants of various sorts carried to the glands in the lymphatic channels. This arrest not unlikely serves the purpose of a protection against general dissemination of irritants, and may be of great importance in this way. Complete occlusion of the lymph-sinuses by deposition of solid particles (as coal-dust) or by . disease of the glands may obstruct the lymphatic flow entirely, and a 456 A TEXT-BOOK OF PATHOLOGY retrograde inflammatory process may result from the damming back of infected lymph or from extension of disease along the lymphatic chan- nels. INFECTIOUS DISEASES Tuberculosis of the lymphatic glands is due in nearly all cases to infection by bacilli reaching the gland through the afferent lymphatics, though occasionally hematogenous infection occurs. Under the heading “tuberculosis” we must include what the older writers designated as scrofulous glands, for in the majority of such cases, if not in all, the disease is essentially tuberculosis, though the mode of infection is not always apparent. Pathological Anatomy.—The first visible change is the formation of small grayish nodules in the gland, and sometimes the eruption of these Fig. 184.—Tuberculosis of lymph-gland, showing early miliary tubercle and hyaline connective tissue. is attended with hyperemia and inflammation. Later, these tubercles increase in size and undergo caseous changes (Fig. 185) as elsewhere, and eventually the entire gland may be converted into a cheesy mass, which may liquefy and not rarely discharges through the ruptured cap- sule. Microscopically, the first appearance is that of gray tubercles containing giant cells and epithelioid cells, surrounded by a zone of round cells (Fig. 184). Later, the characteristic appearances of hyaline transformation and of caseation are observed. Sometimes the glands in tuberculosis become enlarged and harder than normal, and_ present DISEASES OF THE LYMPHATIC TISSUES 457 areas of grayish color, but do not tend so markedly to undergo necrosis. In these instances the microscopical examination presents foci com- posed for the most part of epithelioid cells, and much less abundant in Fig. 185.—Tuberculous lymphatic gland: a, a, Recent tubercle with giant cell (c, c); a, caseous tubercle with giant cell (c,); 6, b, b, lymphadenoid tissue; d, d, d, epithelioid cells (Ziegler). round cells than are tuberculous tissues as a rule (Fig. 186). Giant cells may be wanting, or a few may be found on prolonged search. The histological picture in these cases somewhat suggests sarcoma, and cells (epithelioid); c, c, large spindle cells (Ziegler). the clinical as well as pathological findings have led some to regard cases of this type as Hodgkin’s disease, and erroneously to conclude that ie de disease is really a form of tuberculosis of the lymphatic glands. 458 A TEXT-BOOK OF PATHOLOGY Scrofula——The tuberculous nature of scrofulous lymphadenitis was first shown by demonstrations of the infectiousness of the soft- ened glandular material when injected into animals. The micro- organisms themselves may be demonstrable in the earlier stages in the epithelioid or giant cells, or lying between these; but when the process is at all advanced it is extremely difficult or impossible to demonstrate bacilli. Individual Groups of Glands.—Among the more commonly affected groups of glands are the cervical (Fig. 187), the bronchial, and the mesenteric. Tuberculous cervical glands occasion considerable tumors Fig. 187.—Tuberculous lymphadenitis of the cervical glands (from a case in the Children's Hospital). in the neck, and it is these in particular that have been classified as scrofulous. Not rarely they advance to complete softening and rupture on the surface. Sometimes, however, they penetrate deeply, and may rupture into the trachea or esophagus, or into the pleural cavity. The mode of infection is rarely apparent, but in many cases no doubt the micro-organisms enter through the mucosa of the mouth or pharynx, or the tonsils, where they may or may not first occasion specific lesions. The bronchial glands are affected very frequently in cases in which the bacilli, entering through the lungs, have left no trace of tubercu- Jous disease at the portal of entrance; while in cases of actual tubercu- DISEASES OF THE LYMPHATIC TISSUES 459 losis of the lungs the bronchial glands are quite constantly involved (Fig. 188). The glands are usually cheesy and may become calcareous, but softening not rarely occurs. Perforation of one of the bronchi may lead to acute bronchogenetic tuberculosis of the lungs; or the softened gland may discharge into a large vein and thus occasion disseminated miliary tuberculosis. The mesenteric glands are es- pecially involved in children, this condition being known as tabes mesenterica. The infection occurs through the intestinal tract, and has sometimes been shown to be due to the ingestion of infected milk or meat. The intestines may first suffer, or the bacilli may penetrate the intestinal mucosa without causing local lesions. Syphilis. — Enlargement of the lymphatic glands may occur in the vicinity of the initial lesion during the primary period; and is habitually present in all parts of the body during the secondary period, the post-cervical, axillary, inguinal, and epitrochlear groups being most characteristically in- volved. Theglands are hard, and, Hig 198-_Tuberslgus lymphatic lands do not tend to soften or suppu- specimen in the Museum of the Philadelphia rate. Microscopically, there is Hospital). found proliferation of the con- nective-tissue elements throughout the gland, with some endothelial hyperplasia, giving pictures very suggestive of tubercles minus giant cells. In the tertiary period gummata (bubo tertiaris) may be observed, especially in the lymphatic glands adjacent to the diseased viscera. Leprosy and actinomycosis occasionally involve the lymphatic glands. (See General Pathology.) LEUKEMIA AND HODGKIN’S DISEASE It is difficult to classify these diseases, which in some respects appear to be related to pure hypertrophies, while in other features (mainly clinical) they suggest infections. Finally, there are certain facts which indicate a close kinship with tumors, as, for example, the similarity in histological features, the malignant nature of the diseases, the wide- spread lesions (metastasis?), and the fact that certain accepted tumors (chloromata) are accompanied by a leukemic character of the blood. For all of these reasons leukemia and Hodgkin’s disease are here con- sidered between hypertrophy and infections on the one hand, and tumors on the other. 460 A TEXT-BOOK OF PATHOLOGY Leukemia.—The lymphatic glands are especially involved in the type of leukemia designated lymphatic, which usually, if not always, originates in the lymphatic glands. The view formerly held by many that all forms of leukemia originate in the bone-marrow was based upon an erroneous interpretation of the derivation of the cells in the blood and bone-marrow in certain cases. These cells, instead of being lympho- cytic, were myelocytic in nature, and the supposed lymphocytic process is now recognized as myelocytic or myeloblastic. _Fig. 189.—Hodgkin’s disease, showing marked enlargement of the glands of the right axilla, with consequent dropsy of the arm; less marked involvement of the submaxillary, cervical, and inguinal lymph-glands. The glands in lymphatic leukemia may be uniformly large in all parts of the body, or those of certain groups, such as the cervical, axillary, mediastinal, or inguinal, may be specially involved. Macroscopically, the glands are usually fairly firm, sometimes quite hard, or in other cases soft; are not greatly fused together when a whole group is affected; and on section the substance presents a grayish, pinkish to yellowish color. Areas of softening or hemorrhage may occur in exceptional cases. Histologically, the whole gland is uniformly infiltrated with lympho- cytic and lymphoblastic cells closely packed together and eradicating PLATE 6 39% “ Bea, ) = ® wih eee 2 Bey, WMG Se So vee Fee % ewe . @ So B ages of the pithelioid cells The illustration shows various st: To the right of this, in what is probaby a sinus, there , in which are also polymorphonuclears, cosino- At the bottom there is great increase of the fibrous tissue ge mononuclears, an excess of eosinophiles, fibroblasts, and fibers. e picture are found masses of large mononuclears, sepa- In the upper left corner there is hyperplasia of large e o eT EE e Boy o opa oO g an Me gees oo,8Suwo4r SaBhoss wy Te need woe Hee os S He OT Fa, ba oe eas bes 2_ BLS bee olan s ma vpn & ce ee oe see ome co Seod >a ASCE RRS “Anh aroos BS @GB ao May Moos Panga 8 BSA. ag c=] BRAS a nQMag ad Haebeogs ReSsSee sae faa DISEASES OF THE LYMPHATIC TISSUES 461 all signs of the normal structure of the gland (follicles, medullary cords and sinuses). Sometimes the gland may be only partially involved, and the unaffected portion may then exhibit more or less normal histo- logical features. The walls of small blood-vessels are frequently pene- trated by the lymphocytic proliferations, which perhaps accounts for the entrance of the cells into the circulating blood. Similar histological features are found in the spleen and bone-marrow, and to a less extent in the liver and various other organs. Certain investigators have described cases with precisely the same histological features, but without the leukemic blood-picture, and have proposed names such as aleukemic lymphadenia or lymphadenosis. That such cases may occur is easily understood when it is recalled that the blood-picture may become practically normal, either spontaneously or under treatment, without any notable change in the size of the glands or spleen. Hodgkin’s Disease.—It is difficult to define this affection accu- rately, either clinically or pathologically, though a certain histological picture seems to be fairly distinctive (Plate 6). Macroscopically, Hodgkin’s disease presents considerable enlarge- ments of certain groups of lymphatic glands, notably the cervical, axillary, and inguinal. Other groups may, however, be similarly in- volved. The glands are more or less fused together, though rarely to a single uniform mass. Exceptionally, the glands may be quite separate from one another. On section, the substance is more or less firm, of _ yellowish or grayish color, and not infrequently exhibits areas of necrosis. Histologically, there are found numerous elongated (fibroblastic?) cells, often arranged in a somewhat trabecular manner, between which lymphocytic elements are found in variable abundance. In some cases the most striking feature of the histological picture is the large number of eosinophile cells seen in the section. Giant cells are sometimes fairly numerous. There is a fine fibrosis between the cells. Here and there will be found a large palely staining cell like a large endothelial cell, sometimes with more than one nucleus or occasionally a ring of nuclei, suggesting an origin from the compression of a lymph-channel. Similar histological features are observed in the lesions of the spleen and liver met with in Hodgkin’s disease. TUMORS LYMPHOMA, LYMPHADENOMA; LYMPHOSARCOMA Lymphoma or lymphadenoma is a benign tumor affecting the lymphatic glands of a single group, or occurring in a more generalized orm. Masses, sometimes of considerable size and of variable con- sistency (hard and soft lymphoma), are formed, but the process does not extend to surrounding tissues nor by metastasis to distant parts. Histo- logically, the growth presents the usual features of lymphadenoid tissue with more or less conspicuous hyperplasia of the reticular cells and endothelia in some cases (hard lymphoma). 462 A TEXT-BOOK OF PATHOLOGY It is extremely difficult to differentiate these growths from chronic lymphadenitis or lymphatic hypertrophy. The basis on which the distinction is made is rather the absence of adequate cause and the excessive growth of the glandular enlargements than any histological features. It must be recalled that very marked enlargements of lymph- atic glands may be found in the neck or elsewhere in association with long-continued irritations, such as bad dentition or oral infections. In these cases it is difficult to determine whether the glandular process is inflammatory, infectious, or neoplastic. Lymphosarcoma differs from lymphoma mainly in its manifest tendency to extend beyond the limits of the affected gland or group of glands to surrounding structures, and by metastasis to various parts of the body. The histological structure differs from that of lymphoma only in the less typical features of lymph-gland architecture. There is less differentiation of follicles, sinuses, and a more uniform undiffer- entiated lymphadenoid structure. Lymphosarcomata are especially common in early life, and occur in the cervical glands, tonsils, and mesenteric glands. Chloroma (see pp. 188 and 466) is a closely allied form of growth characterized by its greenish color. Endothelioma of the lymph-glands may occur, according to Ewing, but it is difficult to determine in any given case whether it be truly neoplastic or secondary to a granulomatous disease of the nodes. A long-continued inflammation of the gland may occasion a neoplastic growth of the endothelium and overshadowing or obliteration of the lymphadenoid tissue. Sarcoma.—Other forms of sarcoma are sometimes met with as primary localized new growths of the lymphatic glands. Such are not rarely seen in the mediastinum. In these instances the capsule of the gland is penetrated and local extension to neighboring glands and other surrounding structures is commonly observed, but the entire group of glands is not, as a rule, affected. General metastasis may occur, but affects the larger organs rather than the lymphoid tissues. Round- cell, spindle-cell, alveolar sarcoma, and endothelioma are the forms described. Secondary sarcoma occasionally involves the lymphatic glands. Carcinoma is always secondary, the regional lymphatic glands being the most frequent seat of secondary cancer. The metastatic deposits are first seen in the peripheral lymph-sinuses of the gland, but later enlarge and may invade the whole gland or spread beyond the capsule. BONE-MARROW Anatomical Considerations.—The marrow of the bones is a tissue composed of a reticulum of connective-tissue cells, supporting a rich network of capillaries and venules of unusual width. The cells proper of the marrow are rounded and vary greatly in size. They contain a clear nucleus, a slightly acidophilic protoplasm, and many of them neutrophilic granules. In addition to these myelocytes there are occa- DISEASES OF THE LYMPHATIC TISSUES 463 sional giant cells (megakaryocytes or myeloplaxes) lying near the bony trabecule; also nucleated red corpuscles, non-nucleated red corpuscles, and large cells enclosing corpuscles. After the first few years of life the marrow of the long bones loses its reddish color and becomes more or less yellow, and there is then found, microscopically, a great pre- ponderance of fat-cells. The marrow of the vertebre, sternum, ribs, and other flat bones remains more or less red throughout life, and islands of red marrow tissue may also be found in the marrow of the long bones in later years. The marrow cells are descendants of the endothelial cells of blood- vessel walls. From these are derived somewhat large rounded cells containing a relatively large nucleus and having a basic non-granular protoplasm. These cells, termed myeloblasts, are the mother-cells from which the myelocytes (neutrophilic, eosinophilic, and basophilic) take their origin. This stage of the process of marrow-cell and blood forma- tion is seen only in the latter months of fetal life and for a short time after birth; and pathologically in certain diseases affecting the blood. Soon after birth the myeloblasts are no longer found, and the myelocytes then represent the earliest phase in the process of leukocyte formation. The red blood-corpuscles of the blood (erythrocytes) also trace their origin from the endothelial cells of blood-vessels. In the fetal marrow and under certain pathological conditions in later life may be found certain large hemoglobin-containing cells with a large pale nucleus (primary erythroblast or megaloblast) which are probably direct deriva- tives of the endothelial cells. In later periods of life a rounded, baso- philic cell, containing a rather small and dark-staining nucleus, is the intermediary stage between the endothelial cell and the hemoglobin- containing erythroblasts. The latter also contain a darker and smaller nucleus than that of the “primary erythroblast.” In the ultimate formation of non-nucleated red cells the nuclei of the erythroblasts un- dergo a process of pyknosis and karyorrhexis. The older idea of nuclear extrusion is probably incorrect. In addition to the important réle of blood formation the bone-mar- row doubtless also plays some part in the defensive processes against for- eign invaders. The large giant cells are occasionally greatly increased in size and number and exhibit active phagocytic properties in conditions attended with marked leukocytosis; myelocytes are greatly increased in number in certain infections, and sometimes myeloblasts become conspicuous. Finally, a more or less mechanical r6le may be indicated by the lodgment of large numbers of malarial plasmodia or other micro- organisms in the marrow. DEGENERATIONS Fatty Infiltration.—The fat which occurs normally in the marrow may be excessively developed in conditions of general obesity, but also at times in marantic individuals, or as a result of atrophy of the bony tissues. 464 A TEXT-BOOK OF PATHOLOGY Mucoid degeneration is occasionally seen, and necrosis may form a part of the processes of inflammation. : Pigmentation occurs in the bone-marrow in cases of destruction of blood, as in malaria or various hemolytic toxemias. ATROPHY Atrophy of the bone-marrow is not infrequent in old age or in marasmic conditions. With this atrophy there may occur a gelat- inous or mucoid transformation. HYPERTROPHY Hypertrophy of the bone-marrow occurs in various conditions in which an increased functional activity is required (1) to replace the cellular elements of the blood in case of hemorrhage or blood destruc- tion, or (2) to provide greater numbers of certain cells in cases of infec- tion. The gross appearance of the bone-marrow and its histological features differ considerably in different cases. In anemic conditions resulting from repeated losses of blood or from hemolytic agencies the bone-marrow frequently exhibits a change from the adult (yellow or fatty) to the fetal or infantile type. In extreme cases the marrow of the long bones may be uniformly altered and sometimes is quite dark red in color; in less pronounced cases islands of pink or red- dish color are scattered through the unaltered fatty marrow. The highest grade of transformation is seen in typical instances of perni- cious anemia. Histologically, the marrow in the affected areas contains numerous nucleated red cells, many with mitotic nuclei, and also many myelocytes of different types and sometimes the primary myeloblasts. In pernicious anemia, in addition to these elements, there are found the primary erythroblasts or megaloblasts, and the spleen, liver, and lymph- atic glands may contain areas of myeloid (myelocytic) tissue. The sharp distinction between various milder anemias and pernicious anemia here suggested is difficult to establish in many cases, and all investigators are not in agreement that there is a fundamental distinction, some holding that the marrow changes differ only in degree. In infectious conditions, such as typhoid fever, pneumonia, strep- tococcus and staphylococcus infections, the marrow is the seat of marked changes. Areas of necrosis, degenerative changes in the blood-forming cells, and edema indicate the destructive effects of the infection, while hyperplastic processes are evidenced by large numbers of myelocytes, sometimes (especially in typhoid fever) myeloblasts and large numbers of phagocytic cells (megakaryocytes). Similar combina- tions of necrotic or degenerative processes and compensatory hyper- plasia are found adjacent to metastatic tumors invading the bone- marrow. The Bone-marrow in Leukemia.—The pathological changes in the bone-marrow as well as in other situations (liver, spleen, lymphatic PLATE 7 Cyjedtany pue js) “BUUYUB SNOLItIed Ul “BIMIAYN] UT MOIIEWU-sU0g—z “BLY MOLICU-OUOG—' T “ALT DISEASES OF THE LYMPHATIC TISSUES 465 glands) are difficult to classify, but are included under the heading hy- pertrophy because the conspicuous feature in the histological changes is the hyperplasia of the blood-forming cells. It is difficult, however, to distinguish the lesions of the marrow from those in certain conditions quite generally recognized as tumors (myeloma, chloroma), and even the composition of the circulating blood may be quite the same in some of these cases (chloroma) as in typical instances of leukemia. The bone-marrow in myelogenous leukemia presents a variegated appearance. Sometimes it is reddish, more often grayish or mottled, and occasionally quite yellowish (pyoid). Histologically, the conspic- uous feature is the abundant hyperplasia of myelocytic cells. These, like the myelocytes in the circulating blood, may vary considerably in their size and staining reactions. The typical neutrophilic myelocytes are most abundant, but eosinophilic and basophilic forms, as well as non-granular cells and occasionally forms containing two different sorts of granules, may be observed. The red-corpuscle-forming elements are rather inconspicuous even in comparison with normal bone-marrow. In myeloblastic leukemia (formerly designated acute lymphatic leu- kemia) the basophilic myeloblasts form the predominating histological element. The secondary foci of leukemic change (seen in the spleen, liver, lymphatic glands, and in various other organs) have a similar structure and represent local hyperplasis of marrow cells—either metastatic or originating locally from reversion of endothelial cells of the blood- vessels to their embryonal condition and potency. In lymphatic leukemia the bone-marrow may present a quite similar macroscopical appearance, but histologically the myeloid elements are inconspicuous, while lymphoid cells constitute the bulk of the patho- logical areas. (See further under Lymphatic Glands.) INFLAMMATION Osteomyelitis, or inflammation of the marrow, is infectious in nature, and may occur in the course of various diseases, such as typhoid fever, relapsing fever, small-pox, septicemia, and the like; or as a result of traumatism and direct infection. Staphylococci and the typhoid bacillus (in typhoid cases) are the most frequent organisms encoun- tered. The marrow disease may be the only expression of an infection which has arisen in an obscure manner (cryptogenetic osteomyelitis). In the cases occurring in the course of infectious diseases the changes are comparable to those which occur in the spleen under the same circum- stances. The marrow assumes a redder color than normal, and it may be studded with punctate hemorrhages. In other cases areas of necrosis and granular degeneration of the cells may be present, and increased numbers of white blood-corpuscles may be discovered. Large phago- cytic cells may be conspicuous. Sometimes the marrow is quite purulent. (See Diseases of Bone.) 30 466 A TEXT-BOOK OF PATHOLOGY TUMORS The bone-marrow may be invaded by extension of tumors involving the bone, or may be the seat of metastatic growths, especially carcinoma. Greater interest, however, attaches to the primary tumors of the bone- marrow, which may be included under the general terms ‘‘myeloma”’ ~ and “chloroma.” Myeloma.—This occurs in the form of multiple primary growths involving the vertebre, ribs, and, somewhat less frequently, the long and flat bones. The growths are grayish, yellow, and sometimes pink or quite deep red in color; sometimes by confluence a uniform growth occupies the whole marrow cavity. The surrounding bone sometimes becomes eroded and spontaneous fractures may occur. Metastasis does not occur. Histologically, myelomata are usually composed of myelo- cytes (granular or non-granular), but in some cases have been made up entirely of plasma-cells (plasmocytoma). In rare instances erythroblasts may be conspicuous. Sometimes the tumor is greenish (myelocytic chloroma). The blood in myeloma rarely if ever presents leukemic features, but a striking clinical feature is the presence of Bence-Jones’ albumin in the urine. Chloroma.—This term is applied to tumors presenting a greenish appearance on section, and involving the bone-marrow as well as the lymphatic glands, thymus, and the lymphatic tissues along the gastro- intestinal tract. The periosteum of the bones of the head and face is an especially common seat. Histologically, two forms may be distin- guished: a lymphoidal, in which large lymphocytic cells make up the substance of the growth, and a rarer form, the myelocytic, in which the cells are of the bone-marrow type. The cause of the green color is unknown. Sometimes parts of the growths or certain of the metastases fail to present the green color seen elsewhere. An interesting feature is the leukemic character of the blood, which suggests the close relation- ship of leukemia to processes manifestly neoplastic. CHAPTER III DISEASES OF THE CIRCULATORY SYSTEM THE HEART Development of the Heart.—At the earliest period of fetal life the heart is represented by a hollow tube, lying toward. the ventral aspect of the neck. Later this assumes an S shape, and still later a transverse constriction marks the position which the auriculoventricular grooves subsequently occupy. Finally, vertical grooves divide the lateral halves into the respective auricles and ventricles; and the truncus arteriosus, which is at one of the ends of the primitive tube, becomes divided into two parts, forming the pulmonary artery and aorta. The separation of the cavities within is accomplished by the outgrowth of septa springing from the walls of the primary cavities. The septum dividing the ventricles is the first to appear, and springs forward from the posterior wall. Next a budding is seen in the position which is later occupied by the tissue between the auriculoventricular orifices of the two sides; still later the auricular cavity is divided into two parts by a process beginning at the lower and posterior part. The septum which divides the trwncus arteriosus is essentially connected with or is a part of the septum which separates the ventricles. All of these changes begin from the seventh to the ninth or tenth week of fetal life. Anatomical Considerations.—The heart consists of three layers— the endocardium, muscular layer, and pericardium. The endocardium is the inner lining of the organ, and is composed of a layer of endothelial cells resting upon a stratum of connective tissue. It is continuous with the lining membrane of the arteries, and by duplications forms the valves. The muscle of the heart is arranged in layers which run in differ- ent directions—circular, longitudinal, and obliquely. There is no con- tinuity of the musculature of the auricles with that of the ventricles, except in the case of the special muscle cells, which will be mentioned presently. The muscle of the two sides of the heart is in part con- tinuous. Thus both auricles and both ventricles have certain muscle layers in common, but in part, especially in the ventricles, the muscula- ture is wholly independent. In recent years much attention has been given to a separate system of muscle cells or fibers (the Purkinje cells) which are found just be- neath the endocardium in the auricles and ventricles. They are now known to make up a well-ordered system which begins with the sub- endocardial fibers in the right auricle where it is spread out widely. At the auriculoventricular junction it becomes contracted to a narrow band or cord (the bundle of His) which passes downward into the interven- 467 468 A TEXT-BOOK OF PATHOLOGY tricular septum, in the upper part of which it divides into a right and left branch. These branches run to the respective ventricles and their fibers spread out under the endothelium, and eventually extend to all parts of the musculature. This system, composed of somewhat less completely differentiated muscle cells than those of the body of the heart, is concerned with the conduction of impulses to contraction from the auricle to the ventricle. At two positions there are found nodes or massed cells of this tissue—one in the wall of the right auricle adjacent to the mouth of the superior cava, the other at the auriculoventricular junction. The former is now recognized to be the site where the rhythmic impulses that occasion the cardiac contractions originate. The fibers of the heart muscle are peculiar in being branched and in being devoid of a sarcolemma. The pericardium resembles the endo- cardium in structure. The blood-vessels supplying the heart muscle are branches of the coronary arteries. They divide and subdivide, and afford abundance of blood proportionate to the needs of so active an organ. Anastomosis be- tween the ends of the myocardial vessels is by no means perfect, so that infarcts occur the more easily. The lymphatic system is equally de- veloped. The nervous system includes numerous ganglionic centers in the furrows between the ventricles and between the auricles and ven- tricles. Other ganglion-cells are found within the muscle itself. Details regarding the gross structure of the organ need not be men- tioned here. The weight of the heart in the adult male is about 300 gm., in the adult female about 250 gm. The volume of the entire organ in the adult male is about 290 to 310 c.c., in the adult female about 260 to 280 e.c. CONGENITAL DISEASES AND DEFORMITIES Abnormalities of the heart may be discovered in the newborn and are the result of developmental defects or, less commonly, of fetal endo- carditis and myocarditis. The older pathologists attributed to inflam- matory changes many of the conditions which more accurate knowledge of the development of the heart clearly indicates are the result of defects in development. Abnormality of Position.—The heart may retain its position high up toward the cervical region, and may even be entirely in the neck. Occasionally it is completely exposed or, merely covered with peri- cardium, lies immediately beneath the skin, the sternum in such cases being divided in the middle line. Sometimes it lies beneath the skin of the abdomen. Abnormality in Size.—Congenital smallness, or hypoplasia, of the heart and aorta is occasionally observed. Particular attention has been called to this condition in cases of chlorosis (see p. 434). Defective Development.—There may be complete absence of the heart in acardiac monsters. Sometimes the septa dividing the auricles and ventricles are wholly wanting and a bilocular heart results; or the auricular septum alone is absent, when the organ is trilocular. More DISEASES OF THE CIRCULATORY SYSTEM 469 commonly than these conditions, the organ is completely reversed, lying on the right side of the body and having the blood-vessels entering it and leaving it reversed, so that the general venous blood enters the left auricle, the pulmonary blood the right auricle, while the aorta springs from the right ventricle and the pulmonary artery from the left. This condition is spoken of as dextrocardia. The abdominal vis- cera may be reversed at the same time, the liver being on the left and the spleen on the right side (sttus inversus). Other abnormalities in the arrangement and origin of the great blood-vessels, such as an un- divided truncus arteriosus, are rare. Stenosis and atresia of the pulmonary artery result from abnormal situation of the septum which divides the truncus. Complete atresia is very rare. Stenosis is one of the commonest developmental defects of the heart, and in some cases is due to fetal myocarditis about the orifice. It may involve the root, the conus, or the trunk of the vessel. The septum of the ventricles is usually defective and the foramen ovale re- mains patulous. When the stenosis is considerable the pulmonary cir- culation is often maintained by the persistence of the ductus arteriosus botalli, and the right ventricle is greatly hypertrophied. Stenosis and atresia of the aorta are less frequent than the same conditions affecting the pulmonary artery. They arise from the same cause, and are usually accompanied by the same defects of the septa and patency of the ductus arteriosus. Stenosis of the trunk of the aorta at the isthmus—. e., at a point between the left subclavian artery and the mouth of the ductus arteriosus—is not infrequent in moderate degree. More rarely there may be almost complete atresia, or the aorta may be entirely wanting at this point. The circulation is maintained by collateral anastomosis of the branches of the subclavian with the descending aorta. In all of these cases hypertrophy of the left ventricle is usually present. Defects of the ventricular septum may be unaccompanied by other abnormalities; but, as a rule, they are of secondary importance, occur- ring in cases of abnormality of the pulmonary artery or aorta. The septum may be completely wanting or there may be partial defects, these latter usually lying anteriorly and above, in what is known as the membranous portion or the undefended space. Defects of the auricular septum are comparatively rare, but a patulous condition of the foramen ovale is one of the most frequent of congenital affections of the heart. It is due to the failure of the valve of the foramen to unite at the edges, as normally occurs some time after birth. Slit-like openings are seen very frequently in postmortem examinations, while more decided patency is occasionally observed without other cardiac abnormalities. This is especially likely to occur when congenital atelectasis or some other pulmonary affection causes continuance of high blood-pressure in the right heart after birth. Stenosis and atresia of the auriculoventricular orifices are rare congenital conditions, and in the former fetal endocarditis doubtless plays an important part. When there is complete atresia the auricular 470 A TEXT-BOOK OF PATHOLOGY septum must remain widely open, and the septum of the ventricle is usually deficient and the ductus botalli patulous. Patulous Ductus Botalli—This condition is frequent in cases of stenosis of either the aorta or pulmonary artery, and serves to convey the blood from the patulous artery into that which is obstructed. Like the patulous foramen ovale, it may occur as an independent condition resulting from congenital atelectasis of the lung which leads to the continuance of the fetal conditions of circulation. Valvular Defects.—Not rarely there may be but two semilunar valves at the aortic or pulmonary orifice, and, on the other hand, four may be observed, the latter being a relatively common condition. Similar numerical abnormalities occur at the auriculoventricular valves. Abnormal length or shortness of the leaflets may also be observed, or the segments may be united, forming a complete ring. The latter con- dition must not be mistaken for the agglutination of endocarditis. The leaflets may be fenestrated. iz I MM >t Fig. 190.—Congenital cardiac dis- Fig. 191.—Clubbing of the fingers in congeni- ease, showing peculiar thickness of tal cardiac disease; from same case as Fig. 190 lips and nose (Hichhorst). (Eichhorst). Pathological Physiology.—Congenital heart diseases occasion serious disturbances of the circulation, leading to overfilling of the venous channels and often abnormal mixture of the arterial and venous blood. In consequence of these conditions blueness or cyanosis is a common symptom, and the terms congenital cyanosis and morbus ceruleus are applied. The imperfect oxidation of the blood doubtless causes profound effects, but these have not as yet received accurate study. The imperfect circulation causes certain changes in the tissues, notable among which are thickness of the lips and nose, giving rise to a peculiar facial expression (Fig. 190) and ‘‘clubbing” of the finger ends (Fig. 191). The blood in congenital cyanosis often contains an excess of red blood-corpuscles. (See Polycythemia.) DISEASES OF THE CIRCULATORY SYSTEM 471 CIRCULATORY DISTURBANCES Thrombosis of the cavities of the heart results from the causes which induce thrombosis elsewhere in the circulatory system. These are, mainly, slowing of the current of blood, some roughness or disease of the endocardial lining, and diseased conditions of the blood itself, which render it more liable to coagulation. Slowing of the circulation is the most frequent cause of intracardiac thrombosis, and leads to the forma- tion of the clots found postmortem in cases of gradual death. If the cir- culation has been slow for a considerable length of time, there may be found more or less grayish or white thrombi in the appendages of the auricles or in the ventricles between the muscular trabecule, especially near the apex. The formation of these is explained by the gradual slowing of the current of blood, which leads to the deposit’ of the leukocytes and blood-plaques upon the endocardium and the deposi- tion of fibrin. The color may be almost completely white; but if the current is almost stagnated, admixture of red corpuscles occurs and pinkish or quite red clots (currant-jelly clots) are formed. Of this latter sort are the thrombi formed in the heart during the agonal period and postmortem. They are further distinguished from the thrombi formed intra vitam by the fact that they are not closely attached to the endocardium and between the trabecular muscles. Among the diseases in which the circulation is prone to be sluggish, and which are frequently accompanied by cardiac thrombosis, pneu- monia, tuberculosis of the lungs, the asthenic fevers, and diseases of the muscle of the heart may be named. Dilatation of the chambers of the heart and cardiac aneurysm lead to thrombosis by their effect upon the rapidity of the circulation either in the general heart- cavity in the first, or in the aneurysmal dila- tation in the second. Among the endocardial lesions which occasion thrombosis the most important is acute endocarditis. In this condition there is habitually deposited upon the affected part of the valves or mural endo- cardium a capping of fibrin deposited from the blood passing over the diseased area. i/f As In chronic endocarditis, especially when ea there are irregular calcareous deposits ren- Fig. 192.—Thrombosis _ in dering the surface rough and uneven, con- failiae chambers, showing eyst- siderable thrombotic deposit may occur. Pathological Anatomy.—Cardiac thrombi, formed some time before death, usually appear as deposits upon the heart wall of a yellowish or whitish color and rather firmly attached between the muscular trabec- ule. Occasionally they have a stratified appearance, due to the fact that the circulation varied in rapidity during the formation of the thrombi. Secondary changes are not rare, the most striking being softening of the fibrinous mass in places, with the formation of cyst-like 472 A TEXT-BOOK OF PATHOLOGY cavities varying in size from a split pea to a cherry (Fig. 192). Some- times thrombi project from the endocardial surface in a polypoid form, and these may present the appearance of fibroid tumors. A curious form occurs in the auricles, the thrombus presenting itself as a round mass attached to the endocardium by fine pedicles or lying entirely free (ball-thrombi, globular thrombt). Lesions in Other Organs.—Thrombosis of the heart may occasion serious disturbance of the circulation by weakening the heart muscle or by obstructing the valvular orifices. The latter is especially common in the case of the globular thrombi or the polypoid thrombi of the auricles. Passive congestion of the various organs and the secondary changes due to this condition follow. Thrombosis may lead to another and more serious danger, that of embolism. When portions of the thrombus are broken off they are carried into the circulation and lodge in the small arteries of the spleen, the kidney, the brain, the lungs, or elsewhere, causing infarctions, or, in case micro-organisms be present in the original thrombus, metastatic abscesses and pyemia. Thrombosis and Embolism of the Coronary Artery.—The former condition is much the more common, as the coronary arteries are frequently the seat of advanced atheromatous narrowing and rough- ening, which predispose strongly to thrombosis; and, on the other hand, the mouths of the coronary arteries are so placed that emboli are unlikely to enter. The lodgment of an embolus seriously compromises the heart’s action, as has been shown experimentally in animals, and marked pathological change is, therefore, unlikely to occur before death ensues. When a partially obstructing embolus lodges or a thrombus is formed there results almost complete anemia of the area supplied by the artery affected, and, in consequence, an anemic infarct. The muscle-fibers of the affected area become hyaline or granular, and do not take the stain when subjected to ordinary histological examination. To the naked eye the diseased portion presents itself as a white, and later as a yellowish, area of softening, and the condition is spoken of as myomalacia cordis. It is found most frequently in the anterior or posterior wall of the left ventricle, near the apex, from the fact that the descending branch of the left coronary artery is the most commonly occluded vessel. Next in frequency to these points the anterior portion of the septum is found to be affected. Small areas may heal by absorption of the degenerated tissue, and by infiltration and proliferation of connective tissue. In this manner a scar is formed which may remain, or may subsequently lead to aneurysmal dilatation. On the other hand, rupture of the heart may be occasioned either with or without the formation of an acute aneurysmal dilatation at the degenerated area. DISEASES OF THE ENDOCARDIUM The endocardium, both mural and valvular, is subject to edema and hemorrhage either independently or as forerunners of inflamma- tion. Hematomata have been seen in the valves. Fatty, mucoid, hyaline, amyloid, and calcareous changes have been seen. DISEASES OF THE CIRCULATORY SYSTEM 473 INFLAMMATION Inflammation of the endocardium, or endocarditis, may be acute or chronic; the latter is in most cases merely a continuation of the former. Acute endocarditis affects the endocardium of the valves in the great majority of cases, but it is sometimes found in the endocardium of the cavities of the heart, when it is spoken of as mural endocarditis. Etiology.—Endocarditis is practically always a secondary process, and is in nearly all, if not all, cases due to the action of micro-organisms. Cold and traumatism, upon which the older writers insisted as causal factors, act merely as predisposing causes. Endocarditis occurs most frequently in association with acute articular rheumatism. Next to this cause, scarlet fever, pneumonia, and various forms of sepsis are most important, but in any case of suppurative or infectious disease endocarditis is a possible complication. Even the seemingly mild in- fections like tonsillitis may occasion endocarditis. It occurs at times also in Bright’s disease and in conditions of great malnutrition, such as carcinoma and certain nervous affections. These cases have been cited as opposing the view that endocarditis is always infectious and due to micro-organisms. It may be that toxic substances resulting from im- proper metabolism act upon the endocardium as do micro-organisms, or that portions of the endocardium suffer degeneration as a result of depressed nutrition, but it is more probable that terminal or intercur- rent infection from some hidden source may occur in these chronic dis- eases, with resulting endocarditis. As to the micro-organisms themselves, the most important are the Staphylococcus pyogenes aureus, the Streptococcus pyogenes, and the Diplococcus pneumonia. A special form of streptococcus distinguished by certain rather marked cultural features, the Streptococcus viridans, has in recent years been found especially frequent in certain cases of sub- acute endocarditis or recurrent endocarditis. There are many forms which have been less frequently detected. Among those reported are the Staphylococcus pyogenes albus, the Micrococcus endocarditidis capsu- latus and rugatus, the Bacillus endocarditidis griseus and capsulatus, B. pyogenes fetidus, B. coli communis, the B. diphtherie, the B. aérogenes capsulatus (Welch), or the bacillus of Achalme, and the bacillus of ty- phoid fever. The tubercle bacillus has been found in a few cases, but it is generally believed that its presence is explained as a secondary deposit rather than as the cause of the endocarditis. The gonococcus has been found capable of causing endocarditis. The bacteria causing the valvular inflammation settle upon the endo- thelium from the blood-stream in all probability, but an infection through the base of the valve cannot be entirely excluded. When, by reason of toxins circulating in the blood, or forceful impact of the leaflets, due to overaction of the heart, or disturbed lymph-supply of the valve stalk, the endothelium swells, it forms a favorable settling place for bacteria passing over the valve in the blood-stream. When the bacteria have become attached they are taken up by the phagocyte power of the 474 - A TEXT-BOOK OF PATHOLOGY endothelium. Over such a section of turgid endocardium strands of coagulum may appear; this adds another factor favoring bacterial attrac- tion by showing the current at that point. In all cases of general infection there is a myocarditis and, as the blood- and lymph-supply of the valves are scanty, edematous swelling of the free part of the leaflet may arise. From a lesion in the muscle near a valve base it is possible that bacteria may spread into the valve stalk. Valves are not supplied with blood-vessels, but it has been suggested that mild inflammations in early life leave some vascularized scar tissue in which capillaries may serve as avenues to the distal end of the valves, where lesions will occur upon a subsequent infection. Pathological Anatomy.—It is customary to distinguish two varie- ties: a simple or verrucose, or benign endocarditis; and an ulcerative, septic, mycotic, diphtheritic, or malignant form; but it seems unnecessary at the present time to maintain strictly such a distinction. The cases Fig. 193.—Section through a segment of the aortic valve and adjacent parts of the aorta and heart, showing vegetations on the aortic valve (magnified): 6, Aortic valve segment; c, c, vegetations; f’, calcareous particles in the base of the aortic valve (Bramwell). vary in anatomical appearance and in malignancy, but there is no essen- tial difference and no sharp dividing line. The most common seats, in order of frequency, are the mitral valve, the aortic valve, the pulmonary valve, and the endocardium of the left ventricle, the left auricle, and the right ventricle. The part of the valve first involved is a line running across the leaflet at about a dis- tance of 2 mm. from the free edge. It is along this line that the valves impinge in closing, and it is probable that the mechanical injury sus- tained predisposes to endocarditis. In the cavities the lesions are fre- quently found upon the chorde tendinee, and of the parts of the mural endocardium proper most apt to be affected may be mentioned the por- tion of the left ventricle near to the septum and the aortic valves, and the endocardium of the left auricle on the es and outer wall above the posterior mitral leaflet. The first appearance of endocarditis is that ais an area of opacity or slight roughness extending in a line across the valve or involving the endocardium elsewhere. Later, small nodular elevations, not unlike DISEASES OF THE CIRCULATORY SYSTEM 475 a row of small beads, may form; and finally there is a distinct, irregular, and wart-like fibrinous elevation (Fig. 193). To cases of this character the name verrucose endocarditis (Fig. 194) has been given; or, from the usually benign character, the name simple endocarditis; or, from its most frequent cause, rheumatic endocarditis. In other cases the mass of fibrinous deposit is more abundant and more irregular, while in still others the deposit of fibrin does not take place, or, if so, is soon detached, while ‘necrotic changes occur in the endocardium, leading to the formation of irregular ulcers. Secondary deposits of fibrin may cover an ulcer after its formation, or its edges may be heaped with fibrin; and not rarely the active necrotic process in the endocardium is not visible until the fibrin- ous coating, which is usually considerable in such cases, is removed. Fig. 194.—Acute vegetative (verrucose) endocarditis. These forms of endocarditis are those that have been termed malignant, diphtheritic, septic, mycotic, or ulcerative. They are especially frequent after puerperal sepsis or other septic diseases and in pneumonia, but there is no well-established dividing line between the benign cases and the severe cases, either in etiology, in morbid anatomy, or in the clinical course and termination, so that we prefer to regard them as varying grades of the same general process. Microscopically, the endocardium beneath the coat of fibrin shows desquamation of the endothelial cells, with frequently some hyaline degeneration or coagulation necrosis. Below this there are round-cell infiltration and, as the process continues, proliferation of fibroblastic cells. The fibrinous covering of the valve itself consists of flakes or 476 A TEXT-BOOK OF PATHOLOGY granular masses, or a fibrillar network. By the proper staining methods masses of bacteria may frequently be demonstrated in the superficial layers of the endocardium, in the fibrinous deposit, and usually at the bases of the leaflets or in the muscle. The simple differs from the malignant forms of endocarditis merely in the lesser activity of the necrotic changes in the endothelium and the greater prominence of reparative processes (round-cell infiltration, proliferation of connective tissue). Associated with endocarditis will always be found some degree of myocarditis. The myocarditis is usually degenerative, but in the severe septic cases is infiltrative and necrotizing. Such myocarditides are almost always replaced by cicatrization, except in rheumatic myo- carditis (q. v.). Results.—Simple endocarditis may be healed by the gradual ab- sorption or breaking off of the fibrinous deposit and its dissemination Fig. 195.—Aneurysm of the mitral valve, with rupture of the valve-cusp, seen from the auricular surface: a, Wall of left auricle; 6, anterior segment of the mitral valve, the chorde tendinez have been cut short; c, aneurysm with triangular opening (Bramwell). in the circulation, with coincident thickening of the endocardium at the point of disease by the formation of fibroblastic cells and sclerotic connective tissue. When the process is very limited, and especially when the mural endocardium is affected, merely a white spot of thick- ening on the endocardium results. When the process is deep there may be decided distortion by contraction of the new-formed connective tissue. When the deposit of fibrin is large it frequently undergoes cal- cification, and remains as an irregular, calcareous mass attached to the valve. In the severer or malignant cases destruction of an entire valve or of one of the chords tendinee may occur. When one of the layers of the valve alone is penetrated acute valvular aneurysm may be formed by a pouching of the other layer of the valve (Fig. 195). Mural endocarditis of malignant type may lead to myocarditis DISEASES OF THE CIRCULATORY SYSTEM 477 of a purulent character, and may even penetrate to the pericardium and set up a purulent pericarditis. Lesions in Other Organs.—The most serious danger of endocarditis is embolism. Small fragments of the fibrinous deposits are liable to be carried off into the peripheral circulation, and in ulcerative cases frag- ments of the valves themselves may be so conveyed. They are prone to lodge in the arteries of the spleen, kidneys, and brain, forming hemor- rhagic infarcts or metastatic abscesses, according to the non-infective or infective character of the embolus. Subacute or chronic malignant or recurrent endocarditis is that form in which the pathological change in the valve is not of a rapidly progressive nature, but is often sluggish or chronic in its patho- logical and clinical behavior. The term “recurrent” has been used to indicate that cases of old valvular lesions are especially prone to this type of reinfection. There is commonly a bacteremia, the most com- mon organism found being a streptococcus similar to both the pyogenic streptococcus and the pneumococcus, called the Streptococcus viridans. We have discussed the nature of the infection under the general sub- ject of remittent infections; the reason for the persistence of the organ- ism in the body for so long a time will be found by consulting the text upon fixed or fast bacterial strains. The pathological lesions are those of low-grade vegetative endocarditis, with the evidences of continued congestion of the lymphatic tissues and bone-marrow. Nephritis may arise. The termination may be gradual exhaustion, an acute exacer- bation and death, or transition to a cicatrizing endocarditis. Chronic endocarditis usually affects the valves of the heart and leads to the distortion of the valves constituting chronic valvular heart disease. Clinically, there are signs of disturbances, and eventually more or less complete failure of the circulation. Etiology —Chronic endocarditis may be merely the continuation of acute endocarditis, or it may occur as an insidious process, chronic from the outset. In the former group of cases the causes are, of course, those of acute endocarditis, and it is particularly the rheumatic form that is likely to pass on to a chronic condition. The severer grades of acute endocarditis, or those commonly spoken of as malignant endo- carditis, are usually fatal, though occasionally they may terminate by reparative overgrowth of fibrous tissue. The group of cases in which the disease is chronic from the start has much in common with arterio- sclerosis and atheroma, as far as etiology is concerned. They may be toxic in their origin. These cases occur more frequently in persons of advanced years and in those whose occupation has been laborious. Chronic alcoholism, gout, lead-poisoning, syphilis, and diabetes are among the recognized causes. Not rarely the endocardial disease is secondary to the arteriosclerosis, and it may be directly due to it, resulting from the constant elevation of blood-pressure due to that disease. Laborious occupations act in a similar manner. Pathological Anatomy.—In brief, the changes that occur in the endocardium are overgrowth of fibrous tissue, causing thickening with 478 A TEXT-BOOK OF PATHOLOGY subsequent contraction and distortion of the valves. The chorde tendinese are frequently involved and become converted into sclerotic cords of a whitish color, and less frequently white elevations are seen upon the mural endocardium. Microscopically, there are found the characteristic appearances of new-formed connective tissue, with occasionally, in the earlier states, the appearances of granulation tissue. New-formed blood-vessels may be found within this tissue, though frequently these are degenerated (hyaline and obliterated). Subsequently other degenerations take place. The area of thickening becomes more translucent and hyaline, then opaque and soft; coagulation necrosis and fatty degeneration take place, and there may thus be formed beneath the endocardial surface a lesion somewhat resembling a minute abscess. This may rupture upon the endocardial surface, forming a so-called atheromatous ulcer, upon which fibrinous deposits may collect; or it may be slowly inspissated and converted into a calcareous patch. In cases in which acute endo- carditis with thrombotic deposits passes into chronic endocarditis the fibrinous masses of the surface may be rendered calcareous at the same time that the sclerotic processes are taking place in the valve. Sub- sequently the same degenerative changes and calcification may occur in the tissue of the valve itself as are seen in the atheromatous form of the disease. In the late stages it is often quite impossible to deter- mine whether the case began as an acute endocarditis, or whether it was chronic from the first. The segments of the valves are frequently greatly shortened and rounded, so that they become mere stumps, or they may be curled upon themselves or drawn back and firmly adherent to the wall of the aorta, pulmonary artery, or the ventricular cavity. The individual segments may be agglutinated and united as a ring or diaphragm pro- jecting from the valvular insertion. The valvular function is interfered with in two ways: first, obstruc- tion may be offered to the outflow of blood by the rigid projecting valves and contracted orifice, a condition to which the term stenosis is applied; or, on the other hand, the valves may be so distorted, shortened, or drawn backward that they are no longer able to close, and insufficiency results. The semilunar valves are particularly prone to be shortened, thickened, and recurved, and insufficiency is, therefore, most likely to occur. The mitral valve i is frequently thickened and converted into a funnel-like formation by agglutination of the edges of the anterior with those of the posterior segment. There may thus be merely a slit-like orifice (button-hole mitral), which occasions great obstruction to the outflow of blood from the auricle. Somewhat similar changes are met with at the tricuspid valve. The pulmonary valve is rarely affected in later life, but is sometimes the seat of fetal endocarditis, leading to permanent changes. Resulting Changes in the Heart—The valvular defects can be overcome in only one way—by increase of the power of the heart muscle. Hypertrophy is, therefore, the natural result. This affects DISEASES OF THE CIRCULATORY SYSTEM 479 first the cavity upon which excessive work falls as the result of the regurgitation of blood in cases of insufficiency, or as the result of the excessive strain placed upon the heart wall to force the blood through the narrowed orifice in stenosis. The amount of hypertrophy varies with the condition of the general health of the individual and with the seriousness of the heart lesion itself. When the general health is good there is apt to be commensurately adequate hypertrophy, and when the ‘lesion is not of sufficient gravity to interfere with the circulation in the coronary arteries, and the heart is, therefore, constantly supplied with a sufficiency of blood, hypertrophy is well maintained. Eventually, as the result of continued overwork and of continuously increasing em- barrassment of the circulation or of intercurrent diseases, the heart muscle suffers fatty or fibroid degeneration, the cavities dilate, and the circulation fails. Changes in Other Organs.—The passive congestions resulting from failure of the muscle of the heart are often extreme, and may lead to profound changes in various organs, notably the lungs, liver, and kidneys. These are discussed in the appropriate sections. Embolism is a not infrequent accident in chronic endocarditis, the emboli being parts of the valvular deposits or parts of thrombi in the cavities of the heart. Pathological Physiology.—Endocarditis, acute and chronic, leads to various disturbances of the circulation and of the general health. In acute endocarditis the lesions may become the center of dissemination of infectious material, and the disease may run its course with all the manifestations of an obscure septicemia. This is particularly true of the cases usually designated as malignant. Serious disturbance of the heart action occurring in acute cases is sometimes difficult to explain. The lesions upon the valves may be seemingly very insignificant, and yet the heart may be very irregular in action and exceedingly weak. In part this may be reflex and in part it is probably the result of associated disease of the myocardium. Some investigations, made according to modern methods, have shown the heart muscle impli- cated more often than has been suspected. Acute myocarditis and diseases of the blood-vessels of the myocardium (thrombosis) have been discovered. Chronic endocarditis (valvular disease) occasions more or less pro- found mechanical disorders of the circulation. The severity of these depend upon the condition of the heart muscle more than upon the severity of the valvular lesion. There is always a tendency to com- pensatory hypertrophy of the heart muscle, and for a time this may suffice to avert serious disturbances; but with hypertrophy there is always some degenerative change (fibrous myocarditis and, later, fatty degeneration), as a result of which the cardiac power eventually fails, and symptoms of venous congestion develop. The degree of hypertrophy and of degeneration depends upon the nature and severity of the val- vular lesion, upon the age and general condition of the individual, and upon associated local conditions, such as disease of the coronary artery. 480 A TEXT-BOOK OF PATHOLOGY When compensation fails the various organs of the body suffer con- gestion. The lungs are first. affected in disease of the left heart (mitral and aortic disease). The capillaries of the pulmonary alveoli become overfull, and encroach upon the lumen of the alveoli, or by elongation stretch the alveolar walls and render them inelastic. In either case proper respiration is prevented—a condition which is further aided by the retarded pulmonary circulation. As a result of these conditions, dyspnea (cardiac asthma), cough, and expectoration develop. In ex- treme cases edematous exudation takes place, and in long-continued cases cyanotic induration of the lung occurs. In such instances there may be continuous cough and respiratory insufficiency. When the right heart fails, the liver, spleen, gastro-intestinal mucosa, the kidneys, and the peripheral circulation suffer congestion. The liver may become greatly engorged, and in certain cases (tricuspid regurgita- tion) actually pulsates with each ventricular systole. The swollen liver cells and the engorged vessels cause obstruction of the biliary capil- laries, and consequently produce jaundice. To some extent this may be due to associated congestion of the biliary channels. Congestion of the gastro-intestinal mucosa may occasion various forms of gastric or in- testinal derangement. Metabolic disturbances of various sorts may occur in consequence of the imperfect circulation. The respiratory exchange of gases, in some cases at least, is reduced, though the degree of cyanosis cannot be taken as an index of the reduced oxidation. In man cyanosis is dependent upon stagnation of circulation rather than reduced oxidation. The products of metabolism excreted in the urine may indicate the reduc- tion in oxygen in the tissues. The metabolic consumption of the pro- teins of the body seems to be increased, but the explanation of this fact has not yet been satisfactorily determined. Some regard it as a con- sequence of molecular necrosis due to insufficiency of the supply of oxy- gen. The excretion of nitrogenous elements may, however, be reduced when transudates are forming. This is due to the storing up of meta- bolic products in the transudates. The urine may present albumin as a result of chronic congestion and secondary renal disease; the hepatic functions are disturbed by congestion and jaundice may result; and in the more severe instances hydrobilinuria occurs. The condition of the blood is of special interest. During periods of failing compensation the concentration of the blood is increased or normal, and the number of blood-corpuscles may be excessive. In part, at least, these conditions are explained by the assumption that the corpuscles are retained in the peripheral parts of the circulation in greater measure than the fluid elements (see Polycythemia). When the cardiac compensation is well maintained some anemia may be apparent, especially in cases of aortic disease. Disturbance of the rate or rhythm of the heart is not infrequent. The rate is usually more rapid, but in aortic stenosis it may be slow. This is in effect a conservative process, as it enables the ventricle to dis- charge its contents through the narrowed orifice. Arrhythmia is gener- DISEASES OF THE CIRCULATORY SYSTEM 481 ally proportioned to the grade of degeneration of the muscle of the heart. and is especially marked in cases in which the walls of the auricles are involved. The attempt to connect disorders of rhythm with disease of the intracardiac nervous mechanism has thus far failed of demonstration. On the other hand, the relation of myocardial disease to arrhythmias has become increasingly evident. Increased irritability of the heart muscle in certain stages of myocardial disease readily explains some of the ~ cases of extrasystolic irregularity. Lesions of the bundle of His may occasion partial or complete dissociation of the auricular and ventricular contractions (partial or complete “‘heart-block”). Various other types of arhythmia may also be explained by myocardial disease. MYOCARDIUM CIRCULATORY DISTURBANCES Anemia of the heart muscle may be part of a general anemia. It may occur in cases of narrowing or obstruction of the coronary arteries, and it may be the result of the pressure of pericardial effusions. When long continued it leads to fatty degeneration of the heart, but is itself of little consequence. Hyperemia of the heart muscle may occur when there is obstruction to the return of the blood to the right heart through its venous channels. It may be part of a general hyperemia in a failing compensation of valvu- lar or muscular diseases of the heart. The heart muscle assumes a dark- red color, and the veins are seen under the epicardium as dilated bluish vessels. Hemorrhages in the heart muscle may result from obstruction of the coronary arteries, when the hemorrhage assumes the form of an infarct. There may also be hemorrhages in cases of intense myocarditis or sur- rounding abscesses of the heart muscle, and finally points or streaks of hemorrhagic infiltration may be seen between the muscle-fibers in per- sons who have died from some form of hemorrhagic diathesis, from sepsis, or from various intoxicants. DEGENERATIONS Parenchymatous degeneration, or cloudy swelling of the heart, was designated by Virchow as parenchymatous myocarditis. It is es- sentially a degenerative process and should be so described, though it forms a not inconsiderable part of the pathological changes occurring in the heart in acute myocarditis. Etiology.—The immediate cause is infection. It is met with in the course of diphtheria, typhoid fever, scarlet fever, rheumatism, and other infections. It may be that elevation of the temperature alone suffices to bring it about, and in these cases no doubt abnormal sub- stances resulting from disordered metabolism are the direct toxic agents, but, as a rule, it is the specific toxin of the infections that occa- 31 482 A TEXT-BOOK OF PATHOLOGY sions the myocardial disease. Localized parenchymatous degeneration may be found in the heart-fibers adjacent to areas of endocarditis or pericarditis, and doubtless the same etiological factors are at work in this as in more generalized instances. Pathological Anatomy.—The changes are more marked in the left ventricle than elsewhere, though any part of the heart may be affected. As a rule, parenchymatous degeneration occurs as a diffuse process, but there may be only limited areas here and there. The myocardium be- ‘°° ' comes pale in color; it is softer than normal, the heart walls are usually flabby, and the cavities somewhat dilated. Microscopically, the fibers are found to be filled with fine granules of albuminoid nature, which may completely obscure the striations and even the nuclei, but which may be cleared up by the addition of acetic acid. Multiplication of the nuclei and round-cell infiltration of the intermuscular connective tissue may be observed, but these are inflammatory changes rather than de- generative, and are not, therefore, strictly a part of the disease in question. Parenchymatous degeneration may be complicated by a form of hyaline degeneration, the affected fibers becoming converted into cylinders of waxy appearance. When cloudy swelling persists, fatty degeneration is usually the terminal change. Amyloid infiltration results from the causes which induce amyloid disease in other organs. It is not infrequently found in minute areas here and there, but only rarely has it been seen as a widespread process affecting the connective tissue between the muscle-fibers and beneath the endocardium and pericardium. In such cases the same wax-like appearance is seen as in the liver or spleen, and the characteristic reac- tion with iodin may be demonstrated. Hyaline degeneration is sometimes associated with amyloid, and gives rise to a glassy or waxy transformation of the connective tissue. It is usually seen in small areas, but may be quite widespread. Zenker described a form of hyaline disease (vitreous degeneration) of the muscle-fibers themselves as occurring in typhoid and other infectious fevers, and affecting the heart muscle as well as the muscles of the abdominal wall. ‘This is usually associated with parenchymatous de- generation and occurs in limited areas. Microscopically, there may be seen small hyaline masses or globular areas embedded in the muscle- fiber, the rest of the fiber showing the appearances of cloudy swelling. | Fatty infiltration, or obesitas cordis, is but an increase of the normal condition. In the normal heart there is a certain amount of fatty deposit beneath the epicardium, especially in the furrows and along the Jines of the blood-vessels. In disease this may become enormously increased and there may be penetration of the adipose tissue into the wall of the heart between the muscle-fibers, sometimes as far as the sub- endocardial fibrous layer. Etiology.—The causes are those which induce general obesity. Thus, it may be the consequence of a hereditary tendency or sedentary habits, with overeating and drinking; it is more common in advanced years than in early life. Very frequently it is met with in women who DISEASES OF THE CIRCULATORY SYSTEM 483 have grown stout at the menopause; sometimes, however, considerable deposit about the heart may occur in persons otherwise presenting no tendency to fatness. Pathological Anatomy.—The adipose tissue beneath the visceral peri- cardium may be slightly increased in amount, or the heart may be em- bedded within an enormous deposit of fat, which may involve not alone the epicardium, but the parietal layer and the mediastinum as well. On section through the heart wall, trabecule of adipose tissue may be seen passing through the heart’s substance, and sometimes deposits may be seen as a uniform infiltration beneath the endocar- dium, or as localized deposits projecting into the heart cavity. Mi- croscopically, fatty infiltration presents the ordinary appearances of adipose cells lying between the heart muscle-fibers (Fig. 196). The muscle-fibers themselves are not involved; but may become atrophic Fig. 196.—Fatty infiltration of the heart, from a section through the wall of the right auricle (Bramwell). from pressure, and in such instances present a more yellowish or brownish color than normal, and microscopically show an abundance of granules. In other cases pronounced fatty degeneration is seen in the muscle-fibers. Results.—Weakening of the heart muscle must necessarily result from the mechanical impediment imposed upon it. Circulatory dis- turbances are, therefore, met with, as in valvular disease or fatty de- generation. Occasionally rupture of the heart occurs, due to the atrophic condition of the muscle proper and a want of resisting power of the infiltrating adipose tissue. It is especially prone to occur when the disease is localized. Fatty degeneration affects the muscle-fibers themselves. Etiology.—Fatty degeneration results from malnutrition or from toxic agencies. The most frequent cause is anemia, either local or general. Local anemia is due to sclerosis and narrowing of the coronary 484 A TEXT-BOOK OF PATHOLOGY arteries; or it may be the consequence of improper circulation in the coronary vessels attending the final stages of valvular disease of the heart. Fatty degeneration is, therefore, a terminal condition in arterial sclerosis affecting the coronary vessels and in valvular disease. The remote or antecedent causes are those which bring about arteriosclerosis. We find it, therefore, in elderly persons of the male sex who have had syphilis, who have used alcohol excessively, or have gout or chronic Bright’s disease. The fatty degeneration of the heart resulting from general anemia is most typically seen in pernicious anemia, in which the most extreme grades of fatty disease are sometimes witnessed. Of the cases which are due to toxic agents, we may distinguish those resulting from specific infections and those occurring in various chemical intoxica- tions. In the specific fevers, in which intense parenchymatous de- generation occurs, and among these diphtheria is most prominent, fatty degeneration is sometimes the terminal condition. Among the external poisons capable of producing the disease phosphorus and arsenic are important. Pathological Anatomy.—Fatty degeneration may be a localized or a diffuse process. As a rule, a considerable portion of the heart is affected, Fig. 197.—Fatty degeneration of the heart in a case of pernicious anemia; some of the fibers in the lower part of the illustration are normal (Birch- Hirschfeld). but only isolated fibers or groups of fibers are involved. There results a somewhat speckled or mottled condition (tigration), which is especi- ally visible beneath the endocardium. Streaks or lines of a yellowish or whitish color alternate with the darker portions of normal muscle. When the process is uniform the entire muscle assumes a yellowish hue. It is softer than normal, the cavities tend to dilate, and the walls may be considerably thinner than normal. Microscopically, the muscle-fibers are found to be filled with small granules of a dark color or with small droplets of high refractive power (Fig. 197). These may completely obscure the nucleus, or they may be arranged in groups at the poles of the nucleus. Sometimes distinct vacuolization of the fibers is seen, especially in cases in which fibroid myocarditis accompanies the fatty change. The nature of the granules and droplets within the fibers is well demonstrated by treating the section with osmic acid, when the fat-droplets become intensely black. Associated Conditions.—In cases of coronary sclerosis, or valvular heart disease with failure of compensation, fatty degeneration is rarely DISEASES OF THE CIRCULATORY SYSTEM 485 the sole pathological condition. As a rule, fibroid myocarditis accom- panies it, and the latter may be the more extensive and important condi- tion of the two. Fatty infiltration is often met with as an associated condition, and may be the direct cause of the degeneration by the pres- sure exerted upon heart muscle-fibers by the infiltrating fat. Rupture of the heart may occur in cases in which fatty degeneration affects local- ized areas, as is often the case near the apex of the heart. Segmentation of the Fibers.—This is an interesting condition occasionally observed, especially in cases in which sudden death has taken place. It consists in a transverse splitting of the fibers, by which they are converted into columns of varying length separated by trans- verse fissures (Fig. 198). It has been described under the name of état ségmentaire or myocardite ségmentaire by French writers. A con- siderable discussion as to its significance has arisen, some holding that Y its - a "aha ene Fig. 198.—Marked general segmentation with great diastasis of the pieces; x 120 (from the American Journal of the Medical Sciences) (Hektoen). it is a condition of clinical as well as of pathological importance; others, that it occurs during the death-agony or postmortem. Whether the latter statement be true or not, the segmentation seems to indicate an abnormal fragility of the fibers and in particular of the cement- substance, though it may not be demonstrable by our present means of examination. Some observers maintain that it occurs when there has been excessive dilatation of the heart just antemortem. This fragility may be due to digestive action of bacteria or bacterial prod- ucts, as has been suggested. Some investigations seem to indicate that segmentation is purely artificial, and brought about by the imper- fect adjustment of the knife in cutting. Degeneration of the intracardiac ganglia has been noted by a num- ber of observers in myocarditis and in cases of angina pectoris without gross cardiac alteration. The changes observed are swelling or granular, 486 A TEXT-BOOK OF PATHOLOGY fatty and hyaline degeneration of the ganglion-cells, and infiltration with round cells and sclerotic formation between the nerve-cells. The importance of these changes has not been determined. Pathological Physiology.—The functional disorders in degenera- tions of the myocardium may be due to the direct injury of the fibers, or to disturbances of the nervous mechanism of the heart. The latter seems to be the case in instances in which marked cardiac irregularity, or arhythmia, occurs. The disease of the fibers explains the weakness of the heart’s action; and this is especially marked in cases of fatty and fibroid disease in which the circulation through the coronary arteries is insufficient. Recent investigations have shown that fatty degeneration _ of the heart muscle in itself causes much less cardiac weakness than has generally been supposed. Sometimes the heart is arrested and sudden death occurs in cases of myocardial degeneration due to infectious fevers (diphtheria). This was formerly ascribed to heart-clots, but is now recognized as a form of sudden and complete asystole due to the myo- cardial disease or to associated nervous disorders, organic (in the intra- _ cardiac ganglia or in the cardiac nerves) or reflex. The disturbances of the general circulation in myocardial disease and their results are similar to those met with in valvular disease. (See also Pathological Physiology of Fibroid Degeneration of the Heart.) The result of physiological investigations has been to give greater importance to the integrity of the muscle-fibers than to that of any intracardiac nervous mechanism in the maintenance of regular rhythmic action of the heart. It has been found that the muscle-cells have the properties of stimulability, conductivity, and contractility. The impulse to contraction originates near the opening of the supe- rior vena cava, and is conducted through certain muscle-fibers (con-— ductivity) and received by the fibers of the auricle and the ventricle (stimulability), which are thus made to contract (contractility) in an orderly fashion. If any one of the properties is disordered, arhythmia or altered rates of contraction result. In passing from the auricle to the ventricle the impulse traverses a narrow band of muscle (atrioventricu- lar bundle of His), the only muscular connection; and both physiological experiment and autopsy findings in cases of Stokes-Adams’ disease have shown that destruction of His’ bundle causes independent contraction of the auricles and ventricles, the former beating as frequently as 80 or 100, the latter between 20 and 30. The term “‘heart-block’’ has been given to this condition by physiologists. INFLAMMATION Inflammation of the heart muscle, or myocarditis, may be either acute or chronic, diffuse or circumscribed. Acute myocarditis was designated “carditis” by the older writers, though the same term was applied to endocardial and pericardial in- flammations as well. It may be circumscribed or diffuse, the former appearing most frequently in the form of abscesses of the heart muscle. DISEASES OF THE CIRCULATORY SYSTEM 487 Acute circumscribed myocarditis, or abscess of the heart, may occur in connection with penetrating endocardial lesions or in association with pericarditis. More frequently the infection takes place through the coronary circulation, and the metastatic abscesses of the heart are but a part of a general pyemic disease (Fig. 199) such as occurs in puerperal sepsis, in osteomyelitis, and other intensely septic diseases, but par- ticularly in malignant endocarditis. Pathological Anatomy.—When the infectious emboli are large, a single abscess or a few abscesses result, while in cases of finely dis- seminated infectious particles the heart substance may be-studded with innumerable suppurating points. These are more common in the left ventricle and in the anterior wall than elsewhere. At first the lesion may present itself as a minute, hemorrhagic, or necrotic area, but soon the focus softens and forms a purulent collection. In size the abscesses vary from the merest points to cavities the size of a cherry, and as much Fig. 199.—Embolic abscess of the myocardium. as an ounce of pus has been removed from a single cavity. Perforation may take place into the heart itself, and acute cardiac aneurysm or even rupture of the heart may ensue. On the other hand, the abscess may discharge into the pericardial sac, or without such rupture may set up purulent pericarditis. Occasionally the pus becomes inspissated and fibrous overgrowth causes its complete encapsulation, or finally, the area may be rendered calcareous. Such terminations, however, are rare, the patient usually perishing of the pyemic process, as a part of which the abscesses in the heart occur. In suppurative myocarditis occurring from extension in consequence of malignant endocarditis communicating sinuses may be established between the chambers of the heart. A non-suppurating form of interstitial myocarditis may occur, and Aschoff has called attention to such a process in rheumatic conditions associated with endocarditis. A similar lesion has been found in the 488 A TEXT-BOOK OF PATHOLOGY heart in chorea. There is a leukocytic infiltrate and local cell hyper- plasia, sometimes in nodular form, following the blood-vessels. There may be a small amount of fibrin. This lesion occurs most commonly in the left ventricular wall. It may be removed without leaving a trace, or a small fibrotic patch may remain. These bodies are not producible in experimental animals by injec- tion of the cocci which can cause endocarditis and are said to cause rheumatism. Acute diffuse myocarditis occurs in various forms of infectious fevers. It was first recognized in typhoid fever, but is more common in diphtheria and scarlet fever, and is met with in acute rheumatism, puerperal septicemia, and various other infections. It is most likely that the toxins of the infectious diseases named are the immediate causes, and not the specific bacteria themselves. The process may be entirely diffuse, but in most cases the left ventricle is more seriously in- volved than other parts, and often there are merely localized areas of myocarditis scattered about in various parts of the ventricular wall. Pathological Anatomy.—The affected heart muscle is soft and often distinctly friable. In the earlier stages there may be spots of hemor- rhagic infiltration, but, as a rule, the color is rather lighter than that of the normal organ. It may be noticeable that the bundles of fibers easily separate from one another. The cavities of the heart are fre- quently dilated, particularly the left ventricle. Microscopically, the important changes are diffuse infiltration of round cells in the connective tissue between the muscle-fibers (Fig. 200), and proliferation of the connective tissue itself, with formation of rounded or spindle-shaped fibroblastic cells. There is no tendency to suppuration. The blood-vessels are usually somewhat distended with blood, and there may be distinct proliferative thickening of their walls. Degenerative changes of the muscle-fibers themselves are rarely, if ever, absent, and it is most probable that the first stage in the process is a toxic degenera- ; : tion of the muscle-fibers, and that Fig. 200.—Acute myocarditis, showing the intermuscular infiltration and degeneration of the muscle-fibers and mass- : : : ive accumulation of leukocytes. proliferation are consequent upon the primary degeneration. The fibers become granular and opaque, the striations are indistinct; oc- casionally there may be vacuolization, and sometimes the segmenta- tion to which so much attention has been directed. Proliferation or swelling of the nuclei of the muscle-fibers is frequent, and the hyaline transformation of Zenker is sometimes observed. Results.—Under entirely favorable conditions acute, diffuse, and non-suppurative myocarditis usually terminates in complete resolu- tion. It is, however, quite likely that the proliferative changes noted DISEASES OF THE CIRCULATORY SYSTEM 489 in the intermuscular connective tissue often advance to complete organization and formation of localized areas of sclerosis. Death from dilatation of the cavities and cardiac failure is not uncommon. Chronic myocarditis, or fibrous myocarditis, like the acute form, may be diffuse or localized, though in this case the circumscribed form is the more common. Etiology.—It is not unlikely that many cases are consequent upon acute diffuse myocarditis, as has been already suggested. In such cases the myocarditis may be looked upon as a primary affection. It may be a result of infection with Spirocheta pallida or various intoxications. More commonly the process is secondary, and is dependent upon pri- mary disease in, or disturbances in, the circulation of the coronary arteries. It is, therefore, very common to find areas of sclerosis in cases of atheroma of the coronary arteries or in valvular disease of the heart in which the coronary circulation has finally become deficient. In view of the foregoing and the fact that the condition is not accompanied by a continued inflammatory exudate, this condition takes a place with ‘the reparative fibroses. The primary lesion is always degenerative. Among the remote antecedent causes are the conditions which are prone to occasion arteriosclerosis, such as old age, alcohol, gout, syphilis, and the like. The connection between the arterial disease and the resulting myocardial sclerosis has been the subject of considerable dispute. No doubt, in some instances, the circumscribed areas of fibrous overgrowth met with in the distribution of branches of the coronary artery repre- sent the scars of healed infarctions. In other cases, however, it would seem more likely that a slow degenerative change with gradual over- growth of the connective tissue occurs in consequence of the disturbed circulation through the damaged coronary vessels. Diffuse sclerosis may be associated with hypertrophy in cases of valvular disease and other conditions causing cardiac enlargement. Dehio has suggested that fibroid degeneration or myofibrosis is a conservative process designed to strengthen a heart wall that has become impaired by some degener- ation or functional weakness, just as, according to Thoma, the fibrous nodules in arteriosclerosis serve to strengthen parts of the arterial wall that have become weakened by disease of the muscularis. Localized myocarditis with fibroid overgrowth is very commonly met with at the tips of the papillary muscles in association with chronic endocarditis and disease of the chorde tendinee. Superficial myocarditis of a fibroid character may be seen beneath the pericardium or endocardium which has been thickened by chronic inflammation. The association of fibroid myocarditis with uterine myofibromata is of some practical importance. Pathological Anatomy.—The characteristic change is the formation of sclerotic areas in the muscle substance. These appear either as more or less irregular spots, or as streaks or lines running in the direction of the fibers of the heart. They are most common in the anterior wall of the left ventricle, near the apex, in the septum, and at the tips 490 A TEXT-BOOK OF PATHOLOGY of the papillary muscles; but the entire substance of the heart may be involved and thickening of the walls may result. The impediment offered to the muscle of the heart by the intermuscular sclerosis may lead to true hypertrophy. Later, there is degeneration of the fibers in consequence of the pressure of the new-formed tissue, and yel- lowish areas of fatty degenera- tion are frequently observed. Microscopically, the diseased areas are found to consist of more or less well-organized connective tissue lying between the muscle- fibers and pressing them far apart, or taking the place of atrophic muscle-fibers (Figs. 201 and 202). Sometimes certain portions sarki 2.< Bae of an ares of Shrous mye. show the earlier stages of the connective tissue (Orth). process, round-cell infiltration and proliferation of the connec- tive tissue being the important features (Fig. 203). As a rule, however, the diseased areas are found in a completely organized condition. The muscle-fibers themselves suffer granular and fatty degeneration, and not infrequently distinct vacuolization is observed. Fig. 202.—Chronic myocarditis, showing extensive destruction of fibers. Results.—In cases in which a considerable area of chronic myocarditis has developed, as is not uncommonly observed at the apex in conse- quence of thrombotic or embolic obstruction of the anterior coronary artery, an aneurysm of the heart may result from gradual stretching of the fibroid area. In cases in which the process is diffuse the heart muscle DISEASES OF THE CIRCULATORY SYSTEM 491 may at first undergo hypertrophy in consequence of the excessive labor imposed upon it, but eventually degeneration from pressure upon the fibers gains the ascendency, dilatation of the cavities ensues, and general failure of the circulation is the terminal result. It is not unusual to find diffuse arteriosclerosis and fibroid disease of other organs associated with chronic myocarditis. In such cases the antecedent cause is the arterial disease, which, in turn, may be dependent upon some systemic disorder. Pathological Physiology.—The immediate effect of chronic myo- carditis or fibroid degeneration of the heart is a loss of power. By some it has been held that the fibroid tissue is designed as a sup- Fig. 203.—Endomyocarditis, showing, a, thickened endocardium; b, bands of muscle- ay with interstitial infiltration of round cells and proliferated connective tissue (Bram- well). : port for the heart muscle weakened by other causes, such as degenera- tion of the muscle-fibers themselves, just as it has been claimed that nodules of arteriosclerosis are intended as support for areas of weak- ness of the muscular layers of the arterial walls. This theory is not generally accepted; but, on the other hand, it is certain that the pres- ence of fibrous tissue weakens the heart so far as its proper function (contractility) is concerned. For a time hypertrophy of the muscular elements may counterbalance the functional weakness occasioned by the fibroid change, but eventually the muscle fails, and this failure is usually hastened by fatty degeneration and atrophy of the muscle- fibers, which changes, in turn, are doubtless occasioned by the fibrosis, 492 A TEXT-BOOK. OF PATHOLOGY especially that involving the walls of the small nutrient arteries. In the early stages, with adequate hypertrophy, symptoms may be wanting, though a strong action of the heart and an increase in its size may be detected. Later, progressively increasing weakness of the circulation, and eventually all the signs of cardiac failure develop, just as in ad- vanced valvular disease. Irregularity of the heart’s action is much more pronounced than in valvular disease, and is particularly promi- nent when the walls of the auricles are especially involved. It has been ascribed to implication of the intracardiac mechanism, but no satisfac- tory demonstrations of this have been made. For the present it can only be said that. the irregularity of action results from the disease of the muscle and the consequent disturbance of its automatic contractility and other functions. Angina Pectoris—In many cases of fibroid heart, paroxysms of pain occur. These may be moderate in severity and without definite characters, or they may be severe and of a uniform kind. The latter constitute the condition called angina pectoris. This is especially marked and frequent in cases of fibroid heart associated with advanced sclerosis of the coronary arteries. The cause of the paroxysms is uncer- tain. The seizures may possibly be due to minute embolisms and throm- boses of branches of the coronary arteries, or to muscle cramp caused by cardiac strain under effort or excitement in cases in which the coronary disease prevents a sufficient supply of blood. The former explanation derives some support from the recognized painful seizures that attend arterial occlusion everywhere, and from the disseminated patches of sclerosis of the heart muscle in cases of fibroid heart with coronary dis- ease and a history of angina. These patches of sclerosis may have had their origin in such embolisms or thromboses as are postulated. The muscle-cramp theory has its best support in the analogy of anginal paroxysms, with the symptoms of intermittent claudication of the legs in cases of generalized arteriosclerosis. Neither of these explanations, however, suffices for all cases. Changes in the intracardiac ganglia and in the fibers of different parts of the cardiac nervous mechanism have been described, but are of uncertain significance. HYPOPLASIA AND ATROPHY Hypoplasia of the heart is a congenital condition in which the heart is insufficiently developed and remains undersized throughout life. This condition is frequently. associated with hypoplasia of the aorta and other large vessels, and sometimes with a similar condition of the generative organs. Persons presenting status lymphaticus and women who develop chlorosis not rarely present the conditions referred to. These individuals are often of delicate structure, with feeble or unstable circulation, and, in the case of males, of effeminate nature and appearance. The heart is small in size and, as a rule, uniformly affected in all parts. The epicardium may be somewhat wrinkled, and this condition, no doubt, has often led to the description DISEASES OF THE CIRCULATORY SYSTEM 493 of cases of this sort as instances of atrophy. Many cases of supposed ‘hypoplasia are doubtless instances of true atrophy, the size of the heart being strictly proportioned to the emaciated body. Atrophy of the heart is usually described as occurring in two varie- ties, simple and brown atrophy. It is very doubtful, however, if simple atrophy ever occurs. Many of the cases so designated were doubtless hypoplasias, and other cases probably brown atrophies. Etiology.—Atrophy of the heart usually occurs in persons of ad- vanced age; but is occasionally met with in the young. It results from simple senility or from various cachectic or wasting diseases, such as tuberculosis, carcinoma, and the like. Pathological Anatomy.—The heart is small in size, sometimes weighing but a third or fourth of its normal weight. The capsule, or epicardium, is wrinkled, and may be somewhat thickened by fibrous tissue overgrowth or by fatty or mucoid change. The vessels are conspicuously tortuous (Fig. 204). The muscle is flabby and © often quite dark in color. Fig. 204.—Atrophy of the heart, seen Fig. 205.—Brown atrophy of the heart — from the front (two-thirds natural size) muscle. (Bramwell). Microscopically, the fibers are found smaller than normal and con- tain excess of pigment. The latter is brownish or black, and at first situated at the poles of the muscle nuclei (Fig. 205). Later the whole fiber may be uniformly pigmented. Sometimes the muscle-fiber is converted into a hollow sheath, containing scattered pigment granules and more or less fragmented nuclei. Complete destruction of the fiber may lead to the apparent occurrence of pigment between the muscle- fibers. The pigment does not contain iron, and seems to be a deriva- tive of the albuminous constituents of the fibers. Localized atrophy of the fibers may occur around areas of disease of the heart muscle, such as foci of myocarditis, tubercles, gummata, etc. The fibers present the same appearances as those just described. Pathological Physiology.—Atrophy of the heart muscle does not often occasion striking results or symptoms, as the process is in most 494 A TEXT-BOOK OF PATHOLOGY cases commensurate with the general emaciation and decreased de- mand. Occasionally irregular action of the heart is noted, and sudden death has sometimes occurred. HYPERTROPHY AND DILATATION Hypertrophy and dilatation are usually associated and result from the same causes, the degree of hypertrophy or of dilatation present in a given case depending upon the suddenness of action or the intensity of the cause, and upon the state of the heart itself. A sudden strain may cause immediate dilatation; repeated strains of less severity cause hypertrophy in a well-nourished heart, or increasing dilatation in one the seat of myocardial weakness or degeneration. Etiology.—The influence of valvular diseases (q. v.) of the heart in developing hypertrophy has been sufficiently discussed. Various other causes may lead to overwork or cardiac strain, and occasion hypertrophy or dilatation. We may classify the causes in accordance with their operation upon either or upon both ventricles. Causes Acting on the Left Ventricle.—All forms of arterial disease, ’ but especially diffuse arteriosclerosis, increase the work of the left ventricle notably, and may cause marked changes in it. Aneurysms of the aorta, however, have surprisingly little effect. Chronic Bright’s disease, especially the interstitial form, is a well-known cause. It prob- ably acts in several ways: partly by the associated arterial disease, partly by vascular contraction due to toxic products, and partly by the direct stimulation of cardiac action by the same substances. Excessive exercise or laborious occupations (mining, blacksmithing, etc.) may act upon the whole heart, but especially upon the left ventricle. Causes Acting on the Right Ventricle——Diseases of the lungs and pleura, such as emphysema, fibroid phthisis, and pleural synechie, are frequent causes of hypertrophy and dilatation of the right ventricle. Causes Acting on the Heart as a Whole.—General functional over- stimulation may cause uniform enlargement of the organ. This may be seen in cases of hysteria, exophthalmic goiter, and other diseases in which the overaction is due to nervous influences. Excessive eating and drinking affect the left more than the right ventricle, but influence both sides to some extent. Habitual excessive beer-drinking is most striking in its effects, and doubtless acts through the constantly recur- ring overdistention of the blood-vessels, as well as through the excess of nutriment and direct stimulus conveyed to the organ. Pericardial adhesions may occasion continuous overaction of. both ventricles. Any of the causes named may occasion hypertrophy or dilatation, or both. The degree of hypertrophy is dependent upon the previous in- tegrity of the heart muscle, the state of the general health, and the manner of action of the cause. Sudden strains are more likely to cause dilatation, and pure dilatation may result if the muscle of the heart is degenerated. This is illustrated by cases of acute dilatation of the heart in the course of infectious fevers. DISEASES OF THE CIRCULATORY SYSTEM 495 Pathological Anatomy.—Four forms of enlargement of the heart may be distinguished: First, the walls are thickened and the cavities are smaller than normal; this is known as concentric hypertrophy, but it is likely that the decreased size of the cavities is due to postmortem contraction; second, hypertrophy of the walls with normal cavities is spoken of as simple hypertrophy; third, hypertrophy with cavities of increased size is known as eccentric hypertrophy, or hypertrophy with dilatation; and, fourth, there may be pure dilatation without hyper- trophy. In hypertrophy the muscle substance is darker than normal and is increased in consistency. Microscopically, the fibers are in- creased in thickness, and there is probably also increase in the number of the fibers. ‘The nuclei of the muscle are swollen and multiply; myo- cardial degeneration (fibrofatty) is often associated. When dilatation is present the heart muscle is usually softer, more flabby, and generally somewhat lighter in color, due to associated degeneration. Fig. 206.—Hypertrophy of the left ventricle. The shape of the heart varies from the normal. When the left ventricle is hypertrophied the organ is increased in length and extends further to the left than normal (Fig. 206). When the right ventricle is hypertrophied the organ assumes a rounded shape; its apex is less sharp and the transverse measurement of the organ is greatly increased. The weight and size of the heart may increase enormously, and the term cor bovinum is often highly appropriate. Weights of from 500 to 800 gm. are not infrequent, and may be greatly exceeded. Stokes recorded a case in which the weight was 1980 gm. Pathological Physiology and Results——Hypertrophy is a relative process which serves to counterbalance the valvular or other impedi- ments to the circulation. Occasionally there may be excessive hyper- trophy, but, as a rule, it is merely sufficient to maintain the circulation 496 A TEXT-BOOK OF PATHOLOGY under ordinary conditions with less reserve power than is met with in health. In consequence, valvular lesions or arteriosclerosis may occasion no symptoms for a long time, provided the individual leads a quiet life. Eventually, however, when intercurrent diseases have determined cardiac weakness, or when the impediment to the circulation has advanced to an excessive degree, dilatation ensues and failure of the circulation is the consequence. When the left ventricle is at fault congestion of the pulmonary system occurs, and edema, hemorrhage from the lungs, or thrombosis with infarction of the lungs may take place. When the right ventricle fails, general systemic congestion, cyanosis, and dropsy are the consequence. Great hypertrophy, while it results from arterial disease, very fre- quently reacts upon the arteries and increases existing arterial disease, or occasions arterial disease when it has not previously existed. This is due to the increased force with which the blood is projected from the ventricular cavity and the increased distention which the arteries suffer in consequence. ANEURYSM This is a rare condition of the heart. It is usually found in the ante- rior wall of the left ventricle, near the apex, but may affect any part of ties at ‘ Fig. 207.— Aneurysm of the left ventricle: the sac through which the probe was passed was situated posteriorly; the unopened aneurysm on the right was anterior; the heart is somewhat twisted out of its usual shape to show both sacs in the illustration (Sailer). the auricles or ventricles (Fig. 207). Sometimes it is difficult to distinguish simple dilatation from aneurysm. The usual cause of aneurysm is coro- DISEASES OF THE CIRCULATORY SYSTEM 497 nary obstruction, with resulting degeneration of localized areas of the wall of the heart. First, there is softening (myomalacia), and this may occasion acute aneurysmal dilatation and even rupture of the heart. In other cases the degenerated area becomes fibrous and subsequently dilates. Acute aneurysm of the heart wall may similarly occur in cases of mural endocarditis. Rupture in such chronic cases is a rare termina- tion. WOUNDS AND RUPTURE OF THE HEART Non-penetrating and even penetrating wounds of the heart wall are sometimes recovered from, the injury being repaired by scar-tissue or fibrous myocarditis. As a rule, penetrating injuries occasion rapid death by hemorrhage into the pericardium. Spontaneous rupture of the heart may be occasionally the result of severe strain of a normal heart, but, as a rule, it occurs when there is myocardial disease. Myo- malacia cordis, fatty degeneration, malignant endocarditis, and abscess are the conditions most likely to occasion rupture. INFECTIOUS DISEASES Tuberculosis may occur in the form of acute miliary tuberculosis, affecting either the endocardium, myocardium, or pericardium; while caseous tubercles result from extension of tuberculous adenitis from the anterior or middle mediastinum. Syphilis is rare, but may occur in the form of gumma or of diffuse infiltration. In the latter case generalized fibrous myocarditis, indis- tinguishable in its gross appearances from non-syphilitic cases, may occur. Gummata may lie immediately beneath the pericardium or en- docardium, and after softening by degeneration may rupture on the surface. The degenerated areas may be unaccompanied by circum- ferential reaction, and may go into almost complete resolution without scar-tissue. On the other hand, the fatty area may have about it infil- trative and proliferative inflammation and other degenerations. The spirochetes are numerous in early stages. These areas are replaced by fibrous tissue whether or not they were originally associated with inflam- matory processes. They are probably due to colonization of spirochetes. Actinomycosis may involve the heart by extension from the medi- astinum or by embolism. White or grayish nodules are formed, and subsequently degenerate. NEW GROWTHS AND PARASITES Primary tumors of the heart are extremely rare. Sarcoma, fibroma, hpoma, myxoma, and myoma with muscle cells comparable to the cardiac cells have been met with, and usually occur in the form of wart-like growths projecting into the cavities beneath the endocardium. Organ- wed pediculated thrombi have frequently been mistaken for tumors. Secondary tumors are more common. Sarcomata of the medi- astinum may involve the pericardium, or even the heart wall, by direct 32 498 A TEXT-BOOK OF PATHOLOGY extension, while secondary carcinomata and sarcomata may affect the myocardium by metastasis. In the latter instances nodular forma- tions are seen embedded in the heart muscle. Parasites.—Echinococcus cysts are occasionally seen beneath the endocardium or pericardium, and may rupture into the cavities of the heart, with resulting embolism. The cysticerci of Tenia solium and of T. saginata have occurred in man, but are more common in animals. The larval Linguatula rhinaria is a rare parasite of the heart. THE PERICARDIUM The pericardium is a membranous sac enclosing the heart and the root of the great blood-vessels. It is composed of a fibrous outer layer, and is lined within by flat endothelial cells. Normally it, con- tains from 5 to 50 c.c. of clear serous liquid. Partial or complete absence of the pericardium is sometimes seen, especially in cases of ectopia of the heart. Occasionally diverticula are present congenitally. CIRCULATORY DISTURBANCES Hyperemia of the pericardium may occur in valvular heart disease or in cases of tumor or aneurysm causing intrathoracic pressure. Hemorrhages.—Extreme passive congestion with ecchymotic hemor- rhages is found postmortem in cases of death from asphyxia. Small punctate hemorrhages are also occasioned by various infectious diseases and by certain poisons, as phosphorus. They are also seen in pernicious anemia, scurvy, purpura, and other blood diseases. Hemopericardium is a term applied to accumulation of blood in the pericardial sac. It may result from rupture of the heart or of aneurysms: of the aorta, pulmonary artery, or coronary arteries. The serous effusion of inflammatory conditions of the pericardium may some- times contain considerable blood which has escaped from the small blood-vessels in the inflamed tissue. This is more common in inflam- matory effusions of the pericardium than of other serous membranes, and is particularly true of tuberculous and cancerous cases. Hydropericardium, or dropsy of the pericardium, may occur when passive congestion is continued, or as a part of anasarca. Occasion- ally the liquid is milky (chlyous hydropericardium). INFLAMMATION Inflammation of the pericardium, or pericarditis, is the most important pathological process affecting this serous sac. Etiology.—Pericardial inflammations may be primary or secondary. In the former the irritants are conveyed to the pericardium through the blood, while in the latter the inflammation results from extension. Primary pericarditis occurs in association with various infectious dis- eases, notably acute rheumatism, scarlet fever, small-pox, influenza, and DISEASES OF THE CIRCULATORY SYSTEM 499 intense septic infections. These cases are termed “primary” because they are not extension processes, but hematogenic. It is also met with in the course of nephritis, either acute or chronic. Secondary peri- carditis may result from extension of inflammation from the pleura, the lung, the mediastinal glands, the sternum, the esophagus and stomach, or from the heart itself. In many instances, even when the pericarditis has occurred in the course of an infectious disease, micro-organisms are not discovered in Fig. 208.—Acute pericarditis (Bramwell). the exudate; this may be due to the arrest of the micro-organisms in the pericardial tissues; staphylococci, streptococci, pneumococci, and tubercle bacilli have all been found. Pathological Anatomy.—Several varieties may be distinguished, though one form may merge into another. : ‘Fibrinous or Dry Pericarditis—The first change noted in pericarditis Is a dulness or lusterless condition of the surface of the membrane. Somewhat later distinct granulations, or a thin coating of fibrin, appear upon the surface, and this may increase until the deposit has a notable 500 A TEXT-BOOK OF PATHOLOGY thickness. The movements of the heart may give the latter a marked roughness or rugosity, and the term applied by older writers, cor villosum, is not inappropriate (Fig. 208). Microscopically, there is seen a deposit of granular or fibrillar fibrin upon the surface, while the endothelial cells are loosened and partly degenerated, and the subendothelial tissues are infiltrated with round cells. The blood-vessels are generally widely dilated, and punctiform hemorrhages may be observed. Serofibrinous Pericarditis—The pericardial exudate rarely remains purely fibrinous in character. Usually there is some serous outpour- ing, and the sac becomes distended with more or less abundant tur- bid, serous liquid, in which flakes of fibrin are suspended. In such cases the fibrinous deposit is generally slight. Later the fluid may be reab- sorbed, leaving a simple fibrinous pericarditis. Purulent pericarditis, or pyopericardium, may begin as a fibrinous or serofibrinous process, or it may assume the suppurative form from the very start. In these latter cases the cause of the pericarditis is usually some intense general infection, as in puerperal pyemia and septicemia, or it may be a local infection, as in cases in which an esophageal or gastric ulceration has ruptured into the pericardium, or in which a caseous tuber- culous focus or purulent pleurisy has found a similar discharge. The pericardial sac is filled with purulent or seropurulent liquid, and the pericardium itself is covered with fibrinopurulent exudate. The superficial layers of the myocardium are frequently involved by in- flammatory edema, myocarditis, or fatty degeneration. Hemorrhagic pericarditis is met with in individuals of low vitality and in persons suffering from scurvy, purpura, and similar affections. Pericarditis accompanying tuberculosis or cancer of the pericardium is specially prone to assume a hemorrhagic type. Usually the exudate is serous, but distinctly colored with blood; sometimes it is almost com- pletely hemorrhagic. Terminations of Acute Pericarditis—Any of the forms described may persist for a considerable length of time without change, but usually certain alterations are noted. In the fibrinous variety or in the serofibrinous form, after the liquid has been reabsorbed, the visceral and the parietal pericardium lie in contact and are agglutinated by the exu- date. Gradually the inflammatory processes beneath the fibrinous exudate extend into the fibrinous coating; connective-tissue hyperplasia and new formation of blood-vessels follow, and granulation tissue unites the adjacent layers of pericardium. At the same time the fibrinous exudate is reabsorbed and subsequently organization of the granulation tissues 'is completed. Fibrous adhesions binding the two layers of the pericardium together ensue, and at times complete obliteration of the sac is the consequence (Figs. 209 and 210). In cases in which the in- flammation is slight, or in which the layers are kept apart by persistent serous exudate, the areas of inflammation gradually become thickened by new-formed fibrous tissue, and there remain upon the surface of the pericardium sclerotic spots, often spoken of as “milk spots.” Occa- sionally portions of the fibrinous exudate remain unabsorbed, and DISEASES OF THE CIRCULATORY SYSTEM 501 together with the thickened membrane itself and the adhesions suffer calcareous infiltration. The heart may thus be encased in calcareous plates of considerable thickness. An infrequent termination is the Fig. 209.—Adhesive pericarditis, showing fibrin deposit, with new blood-vessels extending upward into it (Perls). retention of tabs of thick fibrin, covered by connective tissue, con- taining considerable fluid. These give the impression of small peduncu- lated cysts. Fig. 210.—New blood-vessels and fibroblastic cells in a beginning adhesion of the peri- cardial layers. _ Purulent pericarditis may terminate by discharge of the exudate into the esophagus, stomach, pleura, or even into the bronchi, and by - 602 A TEXT-BOOK OF PATHOLOGY the subsequent adhesion of the two layers of the sac. In other cases gradual inspissation of the pus takes place and the cheesy residue may remain or eventually become calcareous. Associated Conditions.—While, on the one hand, pericarditis often follows inflammatory processes in the surrounding parts, it, on the other hand, not infrequently occasions disease of the adjacent structures. In most cases of severe acute pericarditis there is some associated inflammation of the mediastinal structures and of the pleura contiguous to the pericardium. Cases which terminate with the formation of fibrous adhesions within the pericardial sac usually also present me- diastinal and pleural adhesions with the external surface of the peri- cardium (pericarditis interna et externa). Myocarditis extending to a depth of 1 or 2 mm. is seen in nearly every case of pericarditis. In cases in which considerable pericardial exudate is present the heart muscle is pressed upon and impeded in function, so that venous congestions are commonly observed. Adhesive pericarditis leads to hypertrophy and, later, dilatation of the chambers of the heart. INFECTIOUS DISEASES Tuberculosis of the pericardium may result from the extension of pulmonary or pleural tuberculosis, or of tuberculous affections of the mediastinal glands. More rarely direct infection may occur through the medium of the circulation. Miliary tubercles are formed in the sub- serous and serous layers of the membrane, while the surface is covered . with fibrinous exudation. The attendant pericarditis may be entirely fibrinous and the tubercles may be hidden from view by a thick deposit. In other cases there is serous, hemorrhagic, or purulent exudation, the latter especially in cases in which vomice containing infective matter have ulcerated into the pericardial sac. Tuberculous pericarditis may terminate by gradual absorption of the exudate and fibrous adhesion, sometimes with calcareous infiltration. In other cases the necrotic and destructive changes characteristic of tuberculous processes elsewhere gain the ascendency, and the disease proves fatal by the seriousness of the cardiac involvement. Syphilis is an extremely rare condition. Certain indurative changes in the pericardium have, however, been met with in association with syphilis of the heart. Actinomycosis may result from extension of actinomycosis of the mediastinum or of the lungs. TUMORS AND PARASITES Primary tumors, such as lipoma and fibroma, are extremely rare. Secondary carcinoma and sarcoma are more frequent. They result from similar growths in neighboring structures. Hydatid cysts and cysti- cerci are occasionally met with. DISEASES OF THE CIRCULATORY SYSTEM 503 PNEUMOPERICARDIUM Pneumopericardium (air in the pericardium) may result from perforation of the sac in cases of fracture of the ribs or from penetration of foreign bodies through the esophagus into the pericardium. It also results from rupture of gastric or esophageal ulcers, and a certain amount of gaseous accumulation complicates purulent pericarditis when the exudate undergoes decomposition. The association of air and pus (pneumopyopericardium) more often results from secondary purulent inflammation after the development of pneumopericardium. THE ARTERIES Anatomical Considerations.—The arteries and veins consist of three coats, called, respectively, the intima, or inner coat; the media, or middle coat; and the adventitia, or external coat. The intima con- sists of a layer of endothelial lining cells, below which there is a thick fibrous layer and then an elastic membrane. The middle coat con- sists of smooth muscle- and elastic fibers, while the outer coat is composed of fibro-elastic tissue. Small blood-vessels, the vasa vaso- rum, ramify through the adventitia and outer media, but the in- tima and immediately subjacent media are avascular, and probably nourished from within the vessel. CONGENITAL DEFECTS Certain defects of distribution and of origin of the larger trunks have been referred to in the discussion of congenital defects of the heart. Very commonly there are anomalies in the arrangement of the periph- eral branches, but these are merely of anatomical interest. Hypoplasia.—A condition of importance is congenital smallness, or hypoplasia. This may affect the aorta and larger vessels together with the heart, or it may be confined to the blood-vessels, the heart being normal. Vascular hypoplasia has been especially met with in chlorotic girls, and also occurs in cases of status lymphaticus. The aorta is sometimes so small that it barely admits the little finger, and the walls are usually correspondingly decreased in thickness. Decided elasticity of the coats of the vessels may be observed. HYPERTROPHY This occurs when a collateral circulation is established in conse- quence of obstruction of an artery. Similarly, in the new formation of tissue the blood-vessels first formed are delicate vascular channels, which subsequently hypertrophy and are converted into well-developed arterioles. In this case there is a uniform overgrowth of each of the component parts of the blood-vessel, and not a mere hyperplasia of one or another coat. 504 A TEXT-BOOK OF PATHOLOGY ATROPHY This may occur in a part which is undergoing general atrophy, or where there is pressure and anemia of certain areas. Degeneration of the walls usually takes place in such cases, and the conditions are, therefore, more properly considered among degenerations. DEGENERATIONS Fatty Degeneration.—Any one of the coats may be affected, but the process is most common in the intima. Fatty degeneration is one of the important factors in atheroma; more rarely it occurs as an inde- pendent affection of the blood-vessels. In the latter case disturbances of circulation and toxic agencies in the blood are the immediate causes. Small white or yellowish spots or streaks may be seen in the endo- thelium, and microscopically the endothelial cells may be found granular or filled with fat-drops. In cases of greater severity there may be actual erosion of the endothelial surface. In cases in which the media is affected the muscle-cells undergo fatty degeneration. Fatty degenera- tion may occasion rupture of the blood-vessels, or calcareous infiltra- tion may ensue. Calcareous infiltration is the common termination of atheroma, but sometimes calcification of the intima or media, or even of the entire wall of the: vessel, may be observed without arteriosclerosis. The process is most common in the intima and media, and, aside from the instances in which it is a part of atheroma, it may occur in consequence of circulatory disturbances, or as the result of bone disease, with de- struction of osseous tissue and surcharge of the blood with earthy salts. Hyaline degeneration is a condition the nature and uniform char- acter of which remain in doubt. A form of hyaline degeneration is very common in the hyperplastic tissue of arteriosclerosis, and is generally the first evidence of beginning degeneration. It is met with in small blood- vessels which are obstructed by thrombi, or which are subjected to de- structive pressure by inflammatory new growths or other causes. Not infrequently it is due to infectious fevers or intoxications, and in these cases the small arteries and the capillaries are prone to be affected. Hyaline degeneration of the blood-vessels is the striking feature of certain cylindromata (see Fig. 70). The artery may show a uniform or a more nodular, firm, opaque thickening, and under the microscope the subendothelial tissue, the adventitia, or the entire wall of the blood- vessel may be found converted into vitreous substance. Rupture of the affected vessel is a not infrequent result. Amyloid infiltration commonly begins in the blood-vessels of the parts of the body in which this disease is found. In the kidneys the capillary tufts of the Malpighian bodies, and in the spleen the capil- laries within the follicles, are first affected. In these cases the entire wall of the vessel is involved, and presents the characteristic appear- DISEASES OF THE CIRCULATORY SYSTEM 505 ances of the disease. Amyloid disease is sometimes found in the intima of the larger blood-vessels, occurring in small linear or punctate areas, and scarcely to be recognized excepting by chemical tests. INFLAMMATION Inflammation of the arteries may affect the inner, the middle, or the outer coat, and in a strict anatomical sense the terms endarterttzs, mesarteritis, and peri-arteritis are justified; but, as a rule, all three coats are more or less involved at the same time, and no practical dis- tinction can be drawn. There may be acute or chronic inflammation. Acute Arteritis Acute arteritis may be of two kinds: a suppurative or necrotic form and a productive form. Acute suppurative arteritis occurs in the arteries traversing areas of suppurative inflammation, and results from the extension of the suppurative process. It may also occur in consequence of the lodg- ment of infected emboli or as a result of infection of thrombi within the vessels. When the process extends from without, the adventitia and then the media are infiltrated with round cells, and in cases of some of the larger vessels there may be visible points or collections of pus. The process may extend as deeply as the intima, and may completely per- forate the wall of the vessel, leading to hemorrhage. The intima itself is not directly involved by the suppurative process from the lack of inde- pendent blood-supply, but the emigrated leukocytes may infiltrate it, and degenerative changes are common in the endothelium. Where the process begins by infection within, as through softened thrombi or in- fectious emboli, there is first necrotic or degenerative destruction of the intima, and subsequently infiltration of the media and adventitia with emigrated round cells (Fig. 211). A form of infectious arteritis resembling malignant endocarditis has been observed in association with that condition in a few instances. Ulcerated patches are seen in the intima of the aorta, and acute aneurys- mal dilatation or even perforation has been met with. Acute productive arteritis (also called proliferating or obliter- ating, according to its result) is most commonly the result of tissue changes surrounding the arteries, and is, therefore, constantly met with in diseases of organs leading to overgrowth of connective tissue. The con- dition is chronic rather than acute in such instances. Acute productive arteritis also occurs as a consequence of thrombosis, either of non-septic embolic origin or arising in loco, within the blood-vessels when the latter are not infected. The term thrombo-arteritis has been applied to these cases. It is by thrombo-arteritis that wounds of vessels are closed and the lumen of the blood-vessels at the point of ligation permanently obliterated. 506 A TEXT-BOOK OF PATHOLOGY It has been asserted that generalized thrombo-angiitis is an infective process or has infiltrative, if not, indeed, suppurative, lesions as its char- acteristic early manifestation. It is most often seen in the extremities associated with subcutaneous nodosities. The changes affect mainly the intima and the adventitia, both of which coats are densely infiltrated with round cells. The thrombus, which was the original cause of the arteritis or which has resulted therefrom, becomes similarly infiltrated with round cells, and as the process advances is found to be penetrated by fibroblastic cells, which probably take origin from proliferation of the endothelial lining cells or from other connective-tissue cells in the walls of the vessels. New blood- Fig. 211.—Septic thrombo-endo-arteritis of coronary in vegetative endocarditis. vessels spring from the vasa vasorum and penetrate the thrombus, and a lesser number of new vessels may enter the thrombus directly from the lumen of the occluded vessel itself (see Fig. 8). The process of organiza- tion takes place as in the serous surfaces generally, and as new connec- tive tissue is formed the thrombus is gradually removed and the lumen of the vessel may become completely obliterated (endarteritis obliterans). Less extensive involvement of the vessel may lead to the formation of bands of adhesion passing from one side of the vessel to the other, and causing considerable deformity and distortion. In other cases there may be merely thickening of the intima as a final result, the thrombus having been washed away or absorbed. The media usually takes very little part in the process, being merely infiltrated with round cells, but the DISEASES OF THE CIRCULATORY SYSTEM 507 entire wall of the vessel may become fibroid in the terminal stages and the separate coats may be indistinguishable. Peri-arteritis Nodosa.—Under this name has been described a form of productive inflammation of the adventitia leading to the formation of fibrous nodules. In some of these cases there is no doubt a different pathology, as in the instances in which the intima has been found to protrude in a hernia-like manner through defects in the media, but in most cases the disease is a productive peri-arteritis (see also under Aneurysm). The medial changes seem secondary, this coat showing necroses and hemorrhages, and finally atrophy. Intimal thickening occurs later. The disease is an acute one frequently and has been as- scribed to syphilis. The etiology cannot always be established. Arteriosclerosis Arteriosclerosis, or endarteritis chronica deformans, is a chronic degenerative and inflammatory disease of the arterial system. It may be confined to the arteries, or may be more extensive, involving the capillaries as well, when the term arteriocapillary fibrosis (Gull and Sutton) is applicable. Sometimes the veins also are involved, and for this condition the name angiosclerosis has been proposed. Etiology.—Arteriosclerosis is a physiological process of old age, and probably begins as early as middle life in most persons. The earlier occurrence of the disease or the more extreme grades of its severity are dependent upon a variety of causes, among which certain chronic intoxi- cations—viz., syphilis, gout, chronic alcoholism, and chronic nephritis— are prominent. An important cause is muscular exertion, and it is not uncommon to find marked instances in persons whose life or occupation has subjected them to unusual muscular strain. Cachectic conditions of various kinds may play a part, as in cases of carcinoma, tuberculosis, or inanition; and sometimes the chronic arterial disease follows after acute infections, such as rheumatism, scarlet fever, typhoid fever, and the like. Overfeeding may be an important cause. Pathogenesis.—Not a little difference of opinion has existed in regard to the manner in which the recognized causes of arteriosclerosis operate. At first it was generally maintained that the infectious and toxic agencies directly irritate the inner lining of the blood-vessels and produce inflammatory thickening. This view has, however, been quite generally abandoned, and it now seems established that degenerative changes and loss of elasticity in the vessel wall are the result of the prim- itive causes, and that the hyperplastic processes in the intima and other parts of the arterial wall are the ultimate expression of a reparative process. In cases of arteriosclerosis occurring in old age, for example, the first disturbance of the blood-vessel consists in a loss of elasticity in the muscularis and an overdilatation of the blood-vessels. Secondarily, in consequence of this loss of elasticity, there is a hyperplasia of the intima, which serves in some measure to contract the lumen of the 508 A TEXT-BOOK OF PATHOLOGY vessels and thus restore the vascular channels to their normial calibre. In cases of purely pathological arteriosclerosis similar functional weak- ness of the muscularis or more pronounced and demonstrable degenera- tive changes may be the primary conditions, which in the end lead to arteriosclerosis. In all cases the direct effect of elevations of blood-pres- sure may play an important part, and in cases of muscular overwork or of hypertrophy of the heart the increased vascular tension may be the all-important cause. It may be said that generally sclerotic changes occur most frequently in vessels that feel, or are subject to, frequent alterations in blood-pressure. In explaining the minuter origin of the vessel-wall changes one must think of those which begin as a chronic productive inflammatory process and those in which the change is degenerative at first. The line between is by no means sharp, and the latter may be but a forerunner of the former. The inflammatory kind is exemplified by syphilitic arteritis (q. v.); the degenerative, by the senile form. It has been supposed by some that degenerations of the media, with giving away of its muscular, elastic, and fibrous tissue, are due to compression by proliferated intimal endothelium acting under toxic influences. These alterations have been explained by others as purely toxic degenerative medial changes. Regardless of inception, the pro- liferation of the intima and the degenerated media are replaced by connective tissue or by atheroma. In the senile form, granular, fatty, and calcareous degeneration of the media is the first change. Aschoff has suggested that in some way plasma penetrates the vessel walls, liberating colloids and inorganic salts which would act as a starting- point of degenerative or proliferative processes. In the Ménckeberg type of sclerosis, affecting either large or small vessels, the medial coat is most prominently affected. Degeneration and calcification appear early, the muscle-fibers shortly disappear, and with the loss of tissue, which acts to regulate the caliber of the vessel, irregular dilatation of the lumen results. Pathological Anatomy.—Arteriosclerosis may be a diffuse process, affecting more or less uniformly a large part of the arterial system, or it may be a circumscribed or nodular condition. In the latter instances, which are most common in the aorta and large vessels, there are seen on the inner lining of the vessel nodular elevations, varying from the merest points to areas the size of a small coin. These are raised a milli- meter or two above the surface, and in their earlier stages have a trans- lucent grayish color; they are covered with smooth, unaltered endo- thelium. Later, degenerative changes ensue and the nodule becomes dull-white or yellowish in color, and finally calcification may render it extremely hard (atheromatous plate). The focus may, on the other hand, soften completely by degeneration and may discharge into the lumen of the vessel, leaving a necrotic, ulcerated patch (atheromatous ulcer). Calcareous change may now occur, and the surface may be covered with thrombotic fibrinous deposits. These circumscribed areas of arteriosclerosis may be few in number and widely separated. In such DISEASES OF THE CIRCULATORY SYSTEM 509 cases the openings into the coronary arteries and the other branches of the aorta are the favorite seats. In other cases the plates may be so numerous and thickly set that the aorta is completely transformed. Diffuse arteriosclerosis is es- pecially frequent in elderly per- sons, and is more common in the small vessels than in the aorta. Sometimes it is associated with the nodular form; sometimes the nodular change is wanting. Microscopically, the nodular elevations are found to consist of dense sclerotic tissue in which deeply staining cells of elongated character may be visible, the hyperplasia affecting the subendo- thelial part of the intima in the earliest stages (Fig. 212). There is swelling of the endothelia, Fig. 212.—Transverse section of a cere- with fatty detritus and globules bral vessel, in a case of endarteritis nodosa § ‘ (Birch-Hirschfeld). collecting in these cells, pos- sibly the collection of fibrin upon the surface, and the appearance of polynuclears. Subsequently degeneration of the nodule becomes mani- fest. At first the intercellular material assumes a hyaline character and becomes glassy in appearance. The cells themselves may suffer fatty Fig. 213.—Atheromatous degeneration of a cerebral artery (Karg and Schmorl). degeneration from pressure. Later the whole area undergoes myxoma- tous or, more particularly, fatty degeneration, and breaks down, forming a pultaceous detritus in which fat-drops and cholesterol plates are prominent (Fig. 213). Eventually calcareous granules are deposited. In diffuse arteriosclerosis the changes resemble those met with in the nodular form. There is widespread thickening of the arterial coats 1n- 510 A TEXT-BOOK OF PATHOLOGY volving the subendothelial tissue at first and later the entire wall. Secondary degenerative changes in areas or patches occur in the large arteries, but are less common in the small vessels. The endothelium attempts repair over defects except calcareous ulcers. It is heaped up over subintimal and medial swellings. Fatty degeneration and calcification may also be apparent in the media, and more or less hyperplastic connective-tissue overgrowth may be seen in the adventitia. In cases of diffuse arteriosclerosis the media, as a rule, is thickened by hypertrophy of the muscle-fibers as well as by sclerosis; but in the nodular forms the media is usually dis- tinctly thinner than normal. This hypertrophy only affects those that are wholly intact and is compensatory, as destroyed media muscle- fibers do not regenerate. Repair occurs in direct relation to the freedom of blood-supply to the diseased parts, either from the vasa vasorum or from the lumen of the affected vessel. This brings nutrition and stimu- lates cells of the fibroblastic series. Even elastic fibers may be restored. Késter pointed out that round-cell infiltration surrounding the small branches of the vasa vasorum in the media is the earliest change in some instances. Rupture of the elastic coat is doubtless an important early change in many cases. Considerable round-cell infiltration may be seen in the deeper layers of the intima and in the media, and new formation of blood-vessels may be quite pronounced. Such changes, however, are not usual and not characteristic. Results——In the smaller blood-vessels, particularly in those of the brain, the hyperplastic process in the intima may proceed to such a degree that the lumen of the vessels is almost completely obliter- ated (endarteritis obliterans). Complete obliteration may take place by direct union of the opposite walls of the vessel, or there may be first . thrombosis, with subsequent organization of the thrombus. In the aorta and in some of its larger branches the loss of elasticity consequent upon the formation of fibrous tissue and subsequent degenerations leads to gradual dilatation of the blood-vessel walls, either in the form of dif- fuse ectasia or of localized aneurysmal sacs. Sometimes the degenera- tion of the diseased area occasions spontaneous rupture of the vessel. Portions of the thrombotic deposits upon the roughened lining of the vessels, or portions of the degenerative tissue itself, may be discharged into the circulation, and may be carried to the peripheral parts as emboli. Changes in Other Organs.—Diffuse arteriosclerosis places an im- pediment upon the heart which leads to hypertrophy of its walls, and, in particular, of the walls of the left ventricle. When the process affects the small blood-vessels in the substance of the various organs, degenerative changes due to anemia and react- ive hyperplasia of connective tissue are common results. Thus, in cases of sclerosis affecting the cerebral vessels, cerebral softening is commonly met with, while in cases in which the branches of the coronary or of the renal arteries are affected, degeneration and fibroid changes are seen in the heart and kidneys. DISEASES OF THE CIRCULATORY SYSTEM 511 INFECTIOUS DISEASES Syphilis may involve the blood-vessels in a variety of ways. No doubt syphilitic infection is a most potent cause in the production of arteriosclerosis, but more specific involvement of the vessels occurs. Recent investigators have described a special type of arteriosclerosis as syphilitic. In this the ascending aorta is often notably affected, the lesions presenting themselves as scar-like changes which cause marked deformity of the endarterial surface. This can proceed toward the heart and affect the valve bases or the leaflets themselves. Micro- scopically, the media and adventitia are much more decidedly in- volved than in ordinary arteriosclerosis. The process begins as a peri- vasa-vasorum infiltrate of round cells in the media and adventitia, shortly followed by atrophy of muscularis and elastica. In areas of syphilitic infiltration and induration or adjoining gummata the small blood-vessels present noteworthy changes. The intima and the ad- ventitia, but particularly the former, undergo great hyperplasia, and the lumen of the vessel may be almost obliterated. The changes are first noted in the intima, where large numbers of epithelioid cells are formed, while, later, infiltration of round cells is observed. The adventitia is similarly, but less extensively, affected. The outcome of this arteritis is fibrous scar-tissue; atheroma and calcification occur very seldom in pure syphilitic arteritis. The scar-tissue, while dense, is without elasticity, so that at the points of cicatrization variations of lumen occur (syphilitic aneurysms, gq. 2.). Tuberculosis.—The arteries may become involved in areas of tuber- culosis, though, as a rule, they prove resistant for a long time. Typical caseous degeneration may be seen in the walls of the blood-vessels, beginning in the adventitia and gradually advancing toward the inte- rior. In the lungs these changes are not infrequently seen in the walls of tuberculous cavities, and as a result there may be small aneurysmal dilatations at the points where the wall of the vessel has become eroded and weakened. It is from such vessels that the severe hemorrhages of the late stages of phthisis take place. Sometimes the blood-vessels of the tuberculous area present productive change leading to great thickening of the adventitia and of the intima, and there may be con- siderable narrowing of the lumen of the vessel. This, however, is less common than the degenerative changes before alluded to. There may be solitary tubercles in the intima or subintimal layers of the media. They are of ordinary architecture and may open into the vessel lumen. They start as endothelial tubercles when the organisms are taken up by these lining cells in capillaries. ANEURYSM _ Definition.—By aneurysm is meant a more or less localized dilata- tion of the arterial walls. The term has, however, been applied also to collections of blood outside of an artery enclosed by an adventitious 512 A TEXT-BOOK OF PATHOLOGY wall and consequent upon a rupture of the vessel. The name false or spurious aneurysm has been specially applied to such cases, while the term true aneurysm is reserved for such as conform to the first defini- - tion. It is preferable to confine the single word aneurysm to the latter. Etiology.—Aneurysms are always due to some weakness of the walls of the blood-vessel and to the distending force of the blood within. It is, therefore, most common to find the disease in persons beyond the age of forty or forty-five years, and particularly in those who have acquired arteriosclerosis. Among the remote causes, therefore, are those of arterial disease—syphilitis, gout, alcoholism, lead-poisoning, and other chronic intoxications. Of all the causes, syphilis is most impor- tant. Sometimes it would seem that there is hereditary weakness of the arterial coats, and instances of aneu- rysm occurring in successive genera- tions have been recorded. Even con- genital aneurysms have been observed. As contributing causes may be ranked all conditions which increase the blood- pressure. Thus, laborious occupations, hypertrophy of the heart, and dis- eases which occasion constant excess of blood-pressure give rise to arterial degeneration and also to dilatation of the vessel in a purely mechanical way. Sudden aneurysmal dilatation of a weakened vessel may occur after severe straining efforts, as in coughing, during labor, in the strain- ing of obstinate constipation, etc. More acute degenerative changes in the blood-vessels may lead to aneurysmal dilatations. Thus, in the rare instances of acute aortitis in Fig. 214.—Worm aneurysm of the association with malignant endocar- Nene Cer) ditis, small aneurysmal dilatations and even rupture of the aorta may occur. Embolism plays a part in a similar manner. Sometimes a calcareous embolus from a diseased valve of the heart, or from an atheromatous plate in the aorta, may lacerate the walls of a peripheral vessel, leading to the formation of a dilatation. In other cases infected emboli (as in malignant endocarditis or thrombosis with secondary degeneration of the clot) lodge in the peripheral vessels and occasion acute inflammatory or degenerative lesions of the walls, and eventually aneurysmal dilatation. These cases are analogous to the aneurysms of lower animals caused by animal parasites (Fig. 214). The artery most commonly affected is the aorta, and in particular the thoracic portion. A majority of the aneurysms affecting the thoracic DISEASES OF THE CIRCULATORY SYSTEM 513 part of this vessel arise from the ascending limb, and not rarely it is one of the sinuses of Valsalva that first suffers dilatation. Next to the aorta in point of frequency, the popliteal, femoral, carotid, subclavian, innominate, axillary, and iliac vessels are affected. An interesting form, and one of great frequency and clinical sig- nificance, is that which affects the small blood-vessels of the brain, par- ticularly the branches supplying the lenticulostriate body. This is the so-called miliary aneurysm, which is commonly the cause of cerebral hemorrhage (Fig. 215). It is simply a small saccular aneurysm due to weakening of the blood-vessel walls by sclerosis or degeneration. In some cases of the condition de- scribed as peri-arteritis nodosa (see p. 507) there has been discovered a hernia- like projection of the intima through defects of the media. These have been recorded as instances of congenital aneurysm, but this explanation does not suffice for all cases. (See Arteritis.) In phthisical lungs there are often found somewhat similar hernia-like brain. aneurysms, due to erosion of the ad- ventitia and media by the tuberculous process; and it is from these that the severe hemorrhages of the late stages of phthisis occur. Pathological Anatomy.—Aneurysms may be of three kinds: (1) Those in which there is quite general dilatation of all of the coats of the vessel, which, therefore, present themselves in the form of a more or less uniform dilatation (ectatic aneurysm); (2) those in which a local weaken- ing leads to the formation of a saccular pouch, often communicating with the artery by a narrowed orifice (saccular aneurysm); and (3) those in which a rupture of the intima, and usually of portions of the media as well, has led to infiltration of blood between the tunics of the vessel wall (dissecting aneurysm). 1. Ectatic Aneurysm.—There is more or less uniform dilatation in these cases, and there may be distinguished fusiform or spindle-shaped and cylindrical varieties, according to the shape assumed (Fig. 216) In some instances the vessel is rendered tortuous by the unequal involve- ment of different portions, and to this form the term cirsoid aneurysm may be applied. The same term, as well as the name anastomotic aneurysm, is given to certain conditions of the arteries of the scalp and other parts which lead to the formation of tortuous vessels standing out prominently beneath the skin; but these are instances rather of hyper- trophy of the coats, with increase of length and thickness of the walls, without, in reality, any aneurysmal dilatation at all. In ectatic aneurysms the intima and adventitia are usually thickened, and there are generally atheromatous patches in the former. The media is generally thinner than normal, and may be actually deficient in places. Ectatic aneurysms may show a certain amount of thrombosis in the form 33 514 A TEXT-BOOK OF PATHOLOGY of laminated clots, when there are pouchings or inequalities in the dila- tation, but very frequently there is no thrombosis. 2. Saccular Aneurysm.—This is the most important variety. Ac- cording to Thoma and others, the first step in the process is the weak- ening or giving way of the media, followed by gradual dilatation of the intima and adventitia. There results a saccular dilatation commu- nicating with an artery, from which it arises by a more or less narrow orifice (Figs. 217-219). The aneurysmal sac grows larger and larger, and may eventually rupture; but even then a secondary retaining wall may be formed by condensation and reac- tive hyperplasia of the surrounding tissues. The wall of the aneurysmal sac consists of thickened adventitia aN ( \\\ Fig, 216.—Cylindrical and some- i \ \y H what cirsoid aneurysm of the abdom- \ > inal aorta: an opening has been made to ? show the clot within (from a specimen Fig. 217.—Saccular aneurysm of the arch of in the Museum of the Philadelphia the aorta, projecting forward and attached to Hospital). the ribs (Ziegler). and intima, the media being usually thinned and often completely wanting. The intima is generally covered with atheromatous plates, and the cavity, as a rule, contains more or less abundant laminated clots, which tend to contract and organize, or to suffer subsequent degenera- tion. The aneurysm, if small, may be completely healed by the organiza- tion of the clots within. The tissues surrounding the aneurysm are pushed aside or com- pressed, and may suffer extensive necrosis. In cases of aneurysm of the thoracic aorta the sternum and ribs may be eroded, and the aneurysm DISEASES OF THE CIRCULATORY SYSTEM 515 may project beneath the skin anteriorly and eventually rupture (Fig. 220). In other cases the trachea, bronchial tubes, or lungs are com- pressed, and rupture takes place through the trachea or bronchi (Fig. 221). In still others the sac projects posteriorly, erodes the bodies of the vertebrae and ribs, and may compress the spinal cord or may project beneath the tissues of the back. Occasionally, communication is established with the large venous trunks, particularly the descending vena cava. Complete arrest or cure of an aneurysm may take place by organization of the clots contained, but such a result is rare. A — mre Bee Fig. 218.—Saccular and partly ectatic aneu- Fig. 219.—Saccular aneurysm of rysm of the descending part of the archof theaorta the ascending part of the arch of the (from a specimen in the Museum of the Philadel- aorta (from _a specimen in the Mu- phia Hospital). seum of the Philadelphia Hospital). 3. Dissecting aneurysm is most common in the aorta. As the result of degenerative lesions or of mechanical injury rupture of the intima occurs, and the blood finds its way between the coats of the artery, often burrowing to considerable distances. In a case under the observation of one of the authors the walls of the aorta were dis- sected as far as the bifurcation, where secondary ruptures had occurred in the intima (Fig. 222). Usually the dissection takes place in the media, which is thus separated into two parts. Subsequently the ad- ventitious canal may become lined with endothelium, and in the case quoted atheromatous plates had formed in the latter. 516 A TEXT-BOOK OF PATHOLOGY Associated Conditions in Other Parts——Some hypertrophy of the heart may occur when an aneurysm is situated near the root of the aorta, and particularly in instances in which direct pressure is brought 4 Fig. 220.—Aneurysm of the aorta: erosion of the sternum and projection of the sac ‘ beneath the skin. to bear upon the heart. As a rule, however, the amount of hyper- trophy is much less than might be expected. Pressure upon the venous Fig. 221.—The trachea, showing perforation of an aneurysm of the aorta (from a specimen in the Museum of the Philadelphia Hospital). channels is an early manifestation, and léads to passive congestion and often to dropsy and cyanosis. Necrosis of the parts which are directly compressed has already been alluded to. Portions of the clot within DISEASES OF THE CIRCULATORY SYSTEM 517 the aneurysmal cavity not rarely become separated, and are carried as emboli to the peripheral parts of the circulation. False or spurious aneurysms most commonly result from trauma- tism, though sometimes spontaneous rupture of the vessel is the imme- diate cause. The blood may find its way from the ruptured artery into the surrounding tissues, forming a blood-tumor, or hematoma, which becomes encapsulated by condensation of the surrounding tissues and by reactive overgrowth of connective tissue stimulated to activity by the fibrin formation and liberation of leukocytes. The retaining wall thus formed may in some cases be lined with endothelial cells, and secondary inflammatory thickening or atheromatous plates may form. When an artery and vein are both injured, as is sometimes the case in phlebotomy, the blood may enter the vein and distend this markedly. The term aneurysmal vari is applied to such cases. In other instances the artery Fig. 222.—Dissecting aneurysm of the aorta: the aneurysm began near the aortic valves and extended to the iliac branches, converting the aorta into a double tube: a, Transverse section; b, longitudinal section. and vein communicate by an intermediate sac formed by the condensa- tion of the intervening tissues, and for such the name varicose aneurysm is used. Aneurysms may arise when by erosion of the adventitia and outer media the support of the vessel is so weakened that dilatation occurs in the direction of this lessened resistance. THE VEINS Anatomical Considerations.—The veins resemble the arteries, excepting that the muscular coat is less well developed, and that most of the veins are supplied with endothelial reduplications or folds, which act as valves and prevent the backward flow of the blood. CIRCULATORY DISTURBANCES Thrombosis of the veins is the most important condition. This, however, has been sufficiently considered under Thrombosis (see p. 67). 518 A TEXT-BOOK OF PATHOLOGY DEGENERATIONS Fatty degeneration of the intima and media may occur as in the arteries, but it is comparatively rare and unimportant. Calcification is met with in veins which have become dilated or varicose, or otherwise diseased. INFLAMMATION, OR PHLEBITIS Acute phlebitis is a comparatively common affection. It may occur as the result of inflammation, particularly of infectious nature, in the neighborhood of the vein. In such cases the outer coat is first involved, and the term “periphlebitis” is properly applied. This condition is met with in association with infected wounds and phleg- monous inflammations of the subcutaneous tissues. The veins beneath the skin may be distinctly visible as blue streaks running in various directions. Microscopically, there is found to be an invasion of the adventitia with round cells, and actual foci of suppuration are not un- common. The cellular infiltration may extend to the media and some- Fig. 223.—Thrombophlebitis of the femoral vein (from a specimen in the Museum of the Philadelphia Hospital). times to the intima, and not rarely thrombosis occurs within. The thrombi thus formed may secondarily become infected, soften, and occasion septic embolism. In another group of cases phlebitis begins from within, and is the consequence of primary thrombosis of the vein (Figs. 223 and 224). To such the name thrombophlebitis is applicable. The histological changes are similar in these to those which occur in thrombo-arteritis, and as terminal results localized thickening of the venous wall or irreg- ular contractions by the formation of fibrous adhesions and even com- plete obliteration of the venous channel may result. When the thrombus is thus organized or partially organized calcification may eventually occur, and in this manner pfleboliths, or vein-stones, are formed. Chronic phlebitis, or phlebosclerosis, corresponds to chronic arte- ritis or arteriosclerosis. A certain amount of chronic inflammatory thick- ening of the vein ensues as a consequence of thrombophlebitis. Phlebo- sclerosis may also be due to overdistention of a vein resulting from thrombosis or other forms of obstruction, and thus plays a secondary part in dilatation of the veins, or phlebectasia. : Phlebosclerosis may, however, occur as a widespread affection in DISEASES OF THE CIRCULATORY SYSTEM 519 association with arteriosclerosis, though rarely in equal degree, in con- sequence of certain systemic conditions—syphilis, alcohol, gout, etc. The changes occurring in the vein are much the same as those in the artery, but the new-formed fibrous tissue in the intima less commonly undergoes degenerative changes and calcification than in arterial scle- rosis. Sections of the affected veins show, as a rule, absence of signs of inflammation and of marked degeneration. The essential change is a proliferation of the cells of the intima and of the connective tissue of the media. The condition resembles more a functional hyperplasia, the result of mechanical forces, than a chronic inflammation. _ Fig. 224.—Phlebitis and periphlebitis of the umbilical vein of the newborn: purulent a of the intima and adventitia; calcareous particles in the media (Birch-Hirsch- eld). In cases of congenital syphilis an interesting form of thickening of the intima, leading to stenosis or even complete obstruction, has been found in the veins of the umbilical cord, and less frequently in the portal vein. Similar hyperplastic endophlebitis has been found in the veins of the extremities in syphilis of adults. ' DILATATION OF THE VEINS; PHLEBECTASIA; VARICOSITY Etiology.—Dilatation of the veins occurs from mechanical obstruc- ‘tion to the circulation or from weakness of their walls. It presents itself more commonly in dependent portions of the body, and is particularly frequent in the veins of the legs, of the rectum, of the neck of the bladder, of the spermatic cord, of the scrotum, and of the vagina. 520 A TEXT-BOOK OF PATHOLOGY Mechanical causes are most important. Thus, in cases of cirrhosis of the liver, of obstinate constipation, and of pelvic tumors, dilatation of the veins of the rectum, causing hemorrhoids, is frequent. In cases of abdominal tumors, repeated pregnancy, or other causes of obstruction to the venous return of the blood from the lower extremities, varicosity of the veins of the legs is frequently observed. Always, however, local disease of the veins themselves tends to make the dilatations more pronounced, and, in addition, systemic depression and, particularly, car- diac weakness are contributing causes which operate by aiding in the stagnation of the blood, which otherwise might pass by collateral channels to its proper destination. Pathological Anatomy.—The veins in phlebectasia become dilated and also elongated, so that they soon assume a tortuous character. Not rarely masses of much-dilated veins lie closely aggregated in groups or clumps beneath the surface of the skin; and communications may be established between the adjoining pouches of dilatation, and thus a cavernous tissue is formed. The walls of the dilated veins are usually considerably thickened (phlebosclerosis), and even calcification may occur in the intima. , Results.—The circulation of the blood is slowed and thrombosis is, therefore, frequent. The thrombi may undergo organization or calci- fication, or in other cases may soften and occasion embolism. When varicosities are established in the veins of any submucous tissue, catar- rhal inflammation of the overlying mucosa is occasioned and generally proves obstinate. At the same time a certain amount of hyperplasia of the connective tissue between the dilated veins takes place and thicken- ing of the mucous membrane results. When the subcutaneous veins are involved the skin is prone to become thickened and to present eczema- tous inflammation, while the subcutaneous tissue may be greatly in- creased in thickness and density (phlebectatic elephantiasis or pachy- dermia). Not rarely ulcerations of the skin of the lower extremity owe their origin to varicosity of the veins, and such ulcers are prone to prove indolent and obstinate. Hemorrhage may occur from varicosities of the submucous veins, particularly in case of hemorrhoids and in the esopha- geal varicosities of drunkards. TUMORS Tumors rarely begin in the walls of the veins, though myoma and sarcoma have been described. More commonly the walls of the veins are secondarily involved in cases of tumors surrounding them. Aschoff lays stress upon the involvement of veins by leukemic infiltrates and myeloma. INFECTIOUS DISEASES Tuberculosis not rarely attacks the veins, particularly those of the lungs. Perforation of the wall may take place, and miliary tubercu- losis is a frequent consequence. Syphilis of the veins has already been referred to. DISEASES OF THE CIRCULATORY SYSTEM 521 THE LYMPHATIC CHANNELS Anatomical Considerations.—The lymphatic system begins in the lymph-spaces, which are the spaces between the tissue elements in all parts of the body. These lymph-spaces unite to form definite lymphatic capillaries, which are channels having walls composed of a single layer of endothelial cells. The lymphatic capillaries unite to form larger vessels, and in these connective-tissue coats support the endothelial lining. Lymph coagulates very slowly—ten to twenty minutes—due to the small amount of thrombokinase in it. Intralymphatic thrombosis does occur after ligation, but it is much favored by destruction of tissue locally, such a condition freeing thrombokinase. Opie has shown this by addition of tissue extracts to freshly drawn lymph. Bacterial inva- sion of lymph-channels assists in freeing thrombokinase. INFLAMMATION Inflammation of the lymphatic vessels, or lymphangitis, is always secondary to inflammatory affections of the parts surrounding the lymphatics, or of those parts from which the lymphatics take their origin. In cases of infective lesions of the extremities, red lines, indi- cating the position and course of the inflamed lymphatics, may not in- frequently be seen beneath she skin, extending upward to the nearest lymphatic glands. Histologically, the first change in such cases is swelling and ofttimes multiplication of the endothelial cells of the lvmphatic vessel; later, there may be accumulation of leukocytes within, and the lymphatic channel may be uniformly filled with pus or dis- tended at different points. Usually a certain amount of perilymphangi- tis accompanies the process, and in cases of violent septic infection the surrounding tissues may become extensively involved in phlegmonous inflammation. Thrombosis may take place within the lymphatic channel in cases of moderate severity and thus obstruction ensue. The termina- tion is either in resolution or suppuration, with more or less widespread involvement of the surrounding tissues. Resolution may be only - partial, the inflammatory changes going on to the formation of con- nective tissue, which may obliterate the channels, or the restitution of the wall of the lymphatic vessel may be imperfect and subsequent dilatation results. A primary chronic lymphangitis may arise from prolonged obstruc- tion to the lymph flow or by continued irritation, as by foreign particles which the channels are draining to the lymph-nodes. The vessels are changed to a solid band of endothelial cells surrounded by a thickened fibrous coat. DILATATION OF THE LYMPHATICS, OR LYMPHANGIECTASIA This condition may be an acquired or a congenital affection. — Acquired dilatation of the lymphatics results from obstruction to the larger channels, as in cases of pressure upon or thrombosis of the 522 A TEXT-BOOK OF PATHOLOGY thoracic duct, or of obstruction of the lymphatic channels by filarie. In other cases it is due to inflammations surrounding the lymphatics and leading to weakness of their walls. It is very commonly observed in the subcutaneous lymphatics, and constitutes the endemic elephan- tiasis of warmer countries. This condition is particularly common in the lower extremities, scrotum, and labia, but may affect other parts. The skin is greatly thickened and the surface often of irregularly lobu- lated character. On incision into it there is found an abundant exuda- tion from the subcutaneous tissue of serous or of milky liquid. Obstructive dilatation of the intra-abdominal lymphatics is not unusual. Rupture of dilated branches in the genito-urinary tract may lead to chyluria; similarly, chylous ascites or hydrothorax may arise by obstruction or rupture of the thoracic duct. Congenital lymphangiectasia may take the form of a diffuse condi- tion affecting the lymphatics more or less regularly in certain parts of the body, or it may appear in circumscribed areas, often in situations in which the ordinary lymphatic supply is not abundant. The diffuse form occasionally presents itself in the newborn in the form of edema- tous or semicystic swellings of the subcutaneous tissue, resembling those of elephantiasis. In the same group of cases belong the instances of con- genital enlargement of the tongue (macroglossia) and of the lips (macro- cheilia). In some of these instances the development of the condition does not occur until some time after birth, though the process is, in reality, congenital. Localized lymphatic dilatations constitute the form of new growth known as lymphangioma. (See General Pathology.) INFECTIOUS DISEASES Tuberculosis.—The lymphatics play an important part in the dis- semination of tuberculosis within the organs, and they may themselves be involved in the disease. This is beautifully illustrated in cases of intestinal tuberculosis with ulceration. In such cases the lymphatic channels in the serous coat may be seen radiating from a point opposite the ulceration toward the mesentery, and small miliary nodules are seen in their course. Syphilis.—The lymphatics may be involved in syphilitic processes in their vicinity, but the changes are not characteristic. TUMORS In addition to the lymphangiomata referred to, the lymphatic vessels are the primary seat of tumors resulting from multiplication of the lining endothelial cells, which are known as endotheliomata. These tumors are especially common in the serous surfaces, but may also be met with in the skin and elsewhere. The lymphatics bear an important relation to the metastasis of malignant tumors, particularly of carcino- mata. The carcinoma cells enter the lymphatics and are carried by the stream to distant parts of the body; sometimes the lymphatics near carcinomata are found densely packed with cancer cells. DISEASES OF THE CIRCULATORY SYSTEM 523 PARASITES The adult of the Filaria bancroft: resides in the lymphatic vessels, and the embryos may be present in large numbers. (See General Pathology.) THE THORACIC DUCT Pathological processes involving the thoracic duct resemble in general character those of the other lymphatic vessels, but the size of the duct and its anatomical relations make the diseases affecting it of somewhat greater significance than the same diseases when occurring in the smaller lymphatics. Thrombosis may occur in association with inflammation of the duct or without such, and there may be a permanent occlusion in consequence. Dilatation of the lower parts of the duct, as well as of the lymphatic vessels of the abdomen, may ensue, and sometimes the receptaculum or other portions of the duct may become cystic. Chylous ascites may likewise result. More commonly collateral circulation re-establishes communications and serious consequences are not observed. Dilatation of the thoracic duct may also result directly from cardiac failure with engorgement of the greater veins. The outflow of lymph is impeded, and in some cases the backward pressure of the blood through the superior cava may fill and distend the upper part of the thoracic duct with blood. Inflammation occurs in consequence of various inflammatory dis- eases of the abdomen or of the pelvis, by the invasion of irritants through the lymph received from the affected areas. There may also be direct extension of inflammation in cases of abdominal disease, or in pleurisy or other intrathoracic affections. Tuberculosis affecting the abdominal portion of the duct is some- times observed in cases of intestinal or mesenteric tuberculosis, and may occasion secondary miliary tuberculosis, particularly the form in which the disease is subacute or chronic in its course (Weigert). It occurs in periductal or intimal form. In the latter case it may be either as a soft spreading lesion leading to erosion and ulceration, or as a poly- poid outgrowth into the lumen. Tumors.—Primary tumors (sarcoma, fibroma) are sometimes ob- served, and secondary carcinoma is more commonly met with. CHAPTER IV DISEASES OF THE RESPIRATORY SYSTEM THE NASAL CAVITIES Anatomical Considerations.—The mucous membrane of the nose is usually prominent, especially over the lower turbinated bone, where it is 4 mm. thick. In the lower or respiratory parts of the nose the epithelium is stratified, ciliated, columnar in type. The submucosa is replete with a venous network, giving it, particularly over the inferior turbinated bone, the appearance of erectile tissue. In the olfactory regions non-ciliated columnar cells, which become attenuated at the: inner end, line the surface. Between the filiform prolongations within lie round and tapering olfactory cells. Small tubular and racemose serous and mucous glands are freely distributed in the mucosa. CONGENITAL ABNORMALITIES Deviations of the septum and other slight anomalies are common. Atresia, absence of the septum or other parts, or complete absence of the nose are rare defects. Harelip and cleft palate frequently involve the nasal cavities. CIRCULATORY DISTURBANCES Active hyperemia occurs in consequence of exposure to great heat or cold, or of ascending elevations, and when the heart is overstimulated. Certain odors or finely divided dust-particles may provoke transient congestion. Frequently, however, such congestion terminates in in- flammation. Passive hyperemia may be due to cardiac weakness, obstructive diseases of the lungs, and local pressure on veins. Hemorrhage.—In either passive or active congestion and in inflam- mations of the mucous membrane hemorrhage (epistaxis) may occur. Bleeding may also result from blood-diseases (hemophilia, pernicious anemia, leukemia), from disease of the blood-vessels (arteriosclerosis), or in a paroxysmal form from obscure causes. Epistaxis is a frequent prodromal symptom of typhoid fever; less frequently it occurs in influenza and other infections. Trauma may cause nosebleed. It also may occur vicariously when normal menstruation fails. Edema of the mucous membrane may be associated with inflam- mation. 524 DISEASES OF THE RESPIRATORY SYSTEM 525 INFLAMMATIONS Acute nasal catarrh (acute rhinitis, coryza) commonly results from exposure to cold. Irritant fumes may cause it; often it seems infectious and contagious. It may occur as an associated condition in various infections, as grip, typhoid fever, measles, etc. Hay-fever and its related disorders are forms of acute rhinitis. Gout and other nutri- tional disorders may predispose to rhinitis or cause it. The mucosa is at first intensely red and dry; then an irritating serous, followed by mucous and finally mucopurulent, exudation is discharged. Herpes or ecze- matous eruptions of the lips are common. Considerable inflammatory edema of the mucous membrane of the nose and accessory cavities may occur. It may spread to the middle ear, to adjacent sinuses, or to the brain. This is especially true in the purulent form. Pyemia of the antrum of Highmore may start in this way. Chronic rhinitis follows repeated acute attacks, especially in tuberculous or syphilitic persons. The mucosa, especially over the inferior turbinated bone, becomes thickened (hypertrophic rhinitis) and may remain so, or undergo atrophy (rhinitis atrophica). In the atrophic form the exudate is scanty and appears as dry, greenish crusts, which sometimes occasion extensive ulcerations and become horribly offensive. To such cases the term ozena is applied. Various forms of bacilli and micrococci have been discovered, the most frequent being an organism resembling the bacillus of Friedlander, which is considered the cause of the disease by many observers. Fetid discharges may also occur in syphilitic or tuberculous diseases of the nose (ozena syphilitica seu tuberculosa). In the hypertrophic variety the openings of the sinuses about the nose may be slowly closed, with resultant chronic inflammation, which may lead to widespread phlegmon or necrosis. In this form there is increase of the submucosa and but little change in the epithelial layer, except for occasional glandular distention or distortion of mucous glands. While secondary atrophy may occur, what is called atrophic rhinitis (as above described) is said by some to be atrophic from the start, there being atrophy of both eas and supporting tissue. INFECTIOUS DISEASES Diphtheritic rhinitis is usually secondary to pharyngeal diphtheria. Primary diphtheritic rhinitis of rather benign character is occasionally observed. Non-specific pseudomembranous rhinitis is a very rare con- dition. Syphilis in the secondary stage and in congenital cases sometimes occasions simple catarrhal rhinitis. Mucous patches may occur, or gummata spring from the mucous membrane or from the periosteum or perichondrium. The latter tend to ulcerate and cause destruction. The purulent discharge may be fetid. Tuberculosis may occur as disseminated or aggregated tubercles of the mucous membrane, or as ulcers and carious processes. These 526 A TEXT-BOOK OF PATHOLOGY are all rare, but “scrofulous catarrhs” of children, probably often due to tuberculous lesions, are common. Lupus of the face may extend to the nose. Glanders occasions intense purulent and hemorrhagic rhinitis, or nodular growths with ulceration. Nodules and ulcers are common in leprosy. Irregular swelling and induration of the mucous membrane of the nose and the adjoining skin in rhinoscleroma are rare conditions. TUMORS The commonest form of tumor is the polyp, which is sometimes distinctly the result of hypertrophic rhinitis, at other times obscure in origin. Polypi present the ordinary structure of the nasal mucosa, with a tendency to cystic change from occlusion of the glands, or to adenomatous appearances from proliferation of the glandular elements. Fibroid, myxomatous, and sarcomatous polypi also occur. In all cases there is a tendency to recurrence after removal. A rare form of hairy polyp has been described. Chondromata, osteomata, sarcomata, and epithelial or glandular cancers may be found. PARASITES AND FOREIGN BODIES Larve of various flies may occur in the nasal chambers and set up serious inflammatory lesions. Foreign bodies may become incrusted with lime-salts and lead to the formation of rhinoliths. These formations may also arise around a nucleus of epithelial crusts, mucus, or desqua- mated epithelia in obscure niches of the nasal cavity after prolonged catarrh. The sinuses (frontal, ethmoid, and sphenoid) and the antrum of Highmore are frequently involved in inflammations of the nasal mucosa, and when their outlets are obstructed by swelling of the nasal mucosa chronic lesions (catarrhal or suppurative) may occur. These may occa- sion generalized infections or infectious toxemias of various forms. Empyemata of the sinuses may open into the nose, the cranial cavity, the mouth, or may discharge externally. THE LARYNX Anatomical Considerations.—The lining epithelium of the larynx is stratified squamous as far as the false vocal cords. Below these and throughout the ventricles it is stratified, ciliated, columnar, and thus continues into the trachea and bronchi, excepting over the true vocal cords, which are covered with stratified squamous epithelium. The tunica propria contains much yellow elastic fiber, and the submucosa is quite loose, especially over the base of the epiglottis and the aryepi- glottic folds. CONGENITAL ABNORMALITIES Minor defects in shape of the constituent parts of the larynx are not rare. Congenital fistule communicating with the exterior, and dilata- DISEASES OF THE RESPIRATORY SYSTEM 527 tion of the ventricles similar to the normal pouching found in certain monkeys, are occasionally met with. Abnormal largeness and smallness, the latter especially in persons having poorly developed sexual organs and those castrated early in life, are more frequent conditions. CIRCULATORY DISTURBANCES Anemia may occur in general anemia, and is sometimes found in tuberculous and chlorotic subjects in pronounced degrees. Active hyperemia follows exposure, overuse of the voice, and irri- tation by gases, dust, and the like. Passive hyperemia occurs in heart diseases, intrathoracic tumor, and other conditions obstructing the venous circulation. In active conges- tion the larynx is bright red; in passive congestion it is dark red in color, and distended veins may be prominent. Hemorrhages are seen in the mucosa after death from asphyxia, in cases of purpura or other hemorrhagic conditions, as well as in intense inflammation of the larynx. Large hemorrhages may occur in cases of cancer. Edema of the epiglottis, the aryepiglottic folds, and other parts of the larynx may be part of anasarca in Bright’s disease or heart dis- ease, or may result from local pressure upon the veins. The parts be- come greatly swollen and of an anemic, translucent appearance. Great stenosis of the larynx commonly results. Generally ‘edema of the larynx” is inflammatory in nature (see below). INFLAMMATIONS Acute catarrhal laryngitis results from chemical or mechanical irritation; it accompanies whooping-cough, measles, small-pox, typhoid fever, and other infections. The mucous membrane is bright red and swollen. A scanty mucous or mucopurulent exudate is usually noted. Intense laryngitis is attended with small hemorrhagic ecchymoses or erosions; true ulcers are rare. Follicular ulcers are sometimes seen, and rarely small vesicles arise upon the surface (herpetic laryngitis). As is the case with all surface inflammations, laryngitis may assume a catarrhal, fibrinous, pseudomembranous, purulent, or ulcerative form. They merge into one another and, with the exception of the specific forms, have no peculiar etiology or pathology. Pathological Physiology.—Acute laryngitis may cause considerable disturbance of breathing by the swelling of the mucous membrane, and in children often leads to spasmodic contraction of the laryngeal muscles, with paroxysmal dyspnea (false croup). Chronic catarrhal laryngitis may follow the acute form or begin gradually. Overuse of the voice and exposure to cold or irritating gases or dust are the common causes. The mucous membrane is usually thickened and somewhat granular or even papillomatous. There is a tendency for the epithelium to assume a squamous or epidermoid char- 528 A TEXT-BOOK OF PATHOLOGY acter (pachydermia laryngis). In the later stages atrophic changes may ensue. Fibrous thickening and stenosis of the larynx sometimes result from the chronic irritation of foreign bodies, such as intubation tubes. Edematous laryngitis is generally known as edema of the larynx. Nearly always it is a true inflammatory edema, due to violent irrita- tion, general or local infection, or severe local lesions of a chronic nature, such as tuberculous or syphilitic ulceration and perichondritis; it is also seen in angioneurotic edema. The looser submucous tissues at the base of the epiglottis and over the aryepiglottic folds become greatly swollen, and the surface is more or less translucent. Sometimes the edematous infiltration is yellowish, or even quite purulent, especially in cases in which phlegmonous suppurations have extended from neigh- boring parts (retropharyngeal abscess, erysipelas). When circumscribed areas are affected abscess results. Perichondritis, inflammation of the perichondrium of the cartilages of the larynx, is usually secondary to serious laryngeal diseases, as syphilitic or tuberculous ulcers, carcinoma, etc. It may be primary in typhoid fever or other infections. Frequently suppuration and necro- sis of the cartilage result, but merely localized induration and swelling may occur. INFECTIOUS DISEASES Diphtheritic and croupous inflammations may be part of the ana- tomical changes in diphtheria, but may also occur in typhoid fever, scarlet fever, small-pox, or other infectious diseases (due in such cases to streptococci or other organisms), or from violent irritation by steam or the like. The surface of the larynx is covered with a more or lessad- herent grayish or yellowish pseudomembrane, which consists of a net- work or masses of fibrin entangling degenerated round cells and epithe- lium. The membrane is most adherent where the epithelium is squa- mous. Diphtheritic laryngitis usually follows a similar process in the pharynx. (See Diphtheria and Pseudomembranous Inflammation, Part I, page 131.) Tuberculosis is nearly always secondary to pulmonary tubercu- losis; primary lesions are exceedingly rare. Small localized tuberculous masses or more diffuse tuberculous infiltration are found in the mucosa and submucosa, especially on the posterior wall of the larynx, and may remain for long periods as the infiltrative type, but caseation and ul- ceration are usually early developments (Fig. 225). There is no reason to divide the tuberculous lesions in the larynx into different forms, as they do not have peculiar courses. Simple catarrhal inflammation or hypertrophic conditions of the mucous membrane between the tubercu- lous masses, giving rise to warty or polypoid growths or edematous laryngitis and perichondritis, may complicate the tuberculous lesions. Lupus of the nose and pharynx may extend to the larynx, where it occasions nodular thickenings and ulceration. Primary laryngeal lupus has been observed. as a Al i DISEASES OF THE RESPIRATORY SYSTEM 529 Syphilis may occasion simple catarrh of the larynx, mucous patches, or infiltration and erosion of the mucous membrane secondary to pharyngeal involvement. The latter conditions are most frequent in the epiglottis, the posterior wall of the larynx, and the vocal cords. Gum- mata may occur in the same situ- ations independent of pharyngeal syphilis, and lead to deeper ulcers. In the healing of syphilitic ulcers irregular papillomatous elevations of the healthy mucosa or extreme contractions and deformities of the larynx may occur. Lepra and glanders sometimes occur in the form of nodular swell- ings and ulcers. Swelling and ulceration of the lymphatic follicles, chiefly at the base and side of the epiglottis, anal- ogous to the lesions in the intes- tines, may occur in typhoid fever; and in small-pow there may be small areas of infiltration and epithelial degeneration, or even pseudomem- branes. s Atrophy of the mucous mem- Fig. 225.—Tuberculous erosion and 1 : . ulceration of the larynx, causing extensive branes with various degenerative destruction of the vocal cords (from a ° changes or deposits may occur in _ specimen in the Museum of the Philadel- the larynx as the result of chronic PP Hospital). inflammation in loco, or as a part of a constitutional disease (gout, rheumatism). Stenosis is due to pressure from without or by contraction of healed ulcers. TUMORS Papilloma.—Over one-half of all tumors of the larynx belong to _ the group of papillomata or papillomatous fibromata. These are simply hypertrophied papille covered with a thick mantle of squamous epi- thelium (Fig. 226). The stroma may be insignificant and the epithelium considerable (hard papilloma), or the stroma may be excessive, highly vascular, and infiltrated with round cells, while the epithelial covering is thin (soft papilloma). Papillomata are most frequent on the false vocal cords or on the other parts of the larynx lined with squamous epithelium. They usually occur in numbers, but may be solitary. Chronic inflammation often determines their occurrence, and they are not infrequent around chronic ulcers or carcinoma of the larynx. Simple yperplasia of mucous membrane, of normal structure, occurs in various chronic inflammatory conditions of the larynx. 34 530 A TEXT-BOOK OF PATHOLOGY Fibroma.—Nodular, sessile, or polypoid fibromata constitute one- third of all tumors. They are most frequent on the vocal cords and in the upper part of the larynx. Cystic dilatation of the glands may occa- sion mucous polypt. Adenoma, lipoma, myx- oma, sarcoma, and chondroma are rare tumors. Tumor-like masses of heterotopic thyroid-gland tissue have been found in the larynx. Carcinoma may be primary or, less fre- quently, secondary. Primary carcinoma is usu- ally of the squamous variety and occurs about the vocal cords. Nodular thickening with ulceration results. Papillomatous thickening of the mucous membrane frequently surrounds the growth. Secondary involvement of the cervical glands and esophagus may occur. : . Of 1100 tumors of the larynx collected by of Gece eee Bruns, 602 were papillomata; 346, fibromata; specimen in the Museum of 73, mucous polyps; and 27, cysts; 76 per cent. the Philadelphia Hospital). 4 -cypied the true cords or the anterior com- missure of the cords. Mackenzie found 67 per cent. papillomata and 16 per cent. fibromata. PARASITES AND FOREIGN BODIES The larval Trichinella spiralis may infest the laryngeal muscles; _ and lumbricoids occasionally enter from the pharynx. Echinococcus cysts are very rare. Large foreign bodies may cause death by suffocation. Smaller bodies may rest in the larynx, especially the ventricles, for years, be- coming surrounded by hyperplastic mucous membrane or a capsule of fibrous tissue. Calcareous concretions may form around small foreign bodies or spontaneously in the ventricles. THE TRACHEA MALFORMATIONS Congenital Malformations.—Complete absence of the trachea oc- curs in acephalic monsters. Congenital decrease in length or diameter, in the number or completeness of the cartilages, and similar minor deform- ities are more common. An adventitious bronchus is occasionally seen, especially on the right side, and fistulous communications with the exterior or with the esophagus are rare congenital defects. Diverticula may be due to a rudimentary condition of a supernumerary bronchus. Congenital cysts may occur between the trachea and esophagus when fistulous communications between them become closed at either end. DISEASES OF THE RESPIRATORY SYSTEM 531 Acquired Malformations.—Dilatations of the trachea may be diffuse or localized. They depend for their occurrence upon weakness of the walls and some impediment to expiration. Saccular dilatations are usually on the posterior wall. Narrowing of the lumen may be due to pressure of tumors or aneurysms, to new growths or cicatricial contrac- tions (especially syphilitic), or to foreign bodies within. CIRCULATORY DISTURBANCES Anemia and active and passive congestion result from the same causes as in the larynx, and the pathological anatomy is the same. INFLAMMATIONS Inflammations are usually associated with laryngitis or bronchitis, and are due to the same causes. Simple catarrhal and pseudomem- branous inflammations are met with. Foreign bodies may cause exten- sive and deep inflammation, leading to ulceration and sometimes per- foration. Chronic inflammation assumes a proliferative and, later, an atrophic character. Proliferative (polypoid) inflammation is not infre- quent after tracheotomy, and may occasion serious obstruction. Ozena of the trachea may be associated with nasal ozena. INFECTIOUS DISEASES Tuberculosis and syphilis occur under the same circumstances as in the larynx. Syphilis may, however, affect the trachea and bronchi independent of disease of the pharynx or larynx. TUMORS Primary tumors are rare. Secondary involvement by cancer, ex- tending from the esophagus or thyroid gland, or by sarcoma, from the surrounding lymphatic structures or thymus gland, is more frequent. Ecchondroses and osteomata may spring from the cartilages, and multiple chondromata have been found in the mucous membrane. Retention-cysts of the mucous glands are occasionally seen on the posterior wall, protruding outside the trachea. THE BRONCHI Anatomical Considerations.—The larger bronchi correspond very closely to the trachea in structure. The smaller divisions have thinner walls, being less provided with cartilaginous rings, but having instead small cartilage-plates and a greater abundance of muscle-fibers. The tubes having a diameter less than 1 mm. are called the terminal bron- chioles, and lead into yet smaller tubes, the alveolar passages, which open into dilated infundibula, and the last named are finally surrounded by 532 A TEXT-BOOK OF PATHOLOGY air-sacs. The lining epithelium is stratified columnar ciliated down to the terminal bronchioles, where it becomes simple columnar. In the alveolar passages there is first polygonal, then flat, epithelium; while in the infundibula and air-sacs there are practically only flat epithelial cells. CONGENITAL MALFORMATIONS These are rare and unimportant. Dilatations or narrowing and anomalous division of the tubes have been noted. (See Trachea.) CIRCULATORY DISTURBANCES Anemia and hyperemia occur under the same circumstances as in the trachea and larynx. Hemorrhage.—Intense congestion may occasion hemorrhages into the mucous membrane or into the bronchi themselves. More fre- quently hemorrhage is due to catarrhal inflammation, tuberculous ulceration, or a general hemorrhagic tendency. Aneurysms of the aorta (see Fig. 220) and the small aneurysms of the pulmonary arterioles in tuberculosis of the lungs not infrequently rupture through the bronchi. INFLAMMATIONS Both acute and chronic bronchitis are common conditions, and there are several forms. Acute catarrhal bronchitis results from exposure, from inhalation of irritating gases, and from downward extension of tracheal catarrhs. The terminal bronchioles are frequently affected secondarily in pul- monary diseases. Bronchitis is constantly associated with some of the infectious fevers—typhoid fever, measles, whooping-cough, etc. Various micro-organisms have been found in bronchitis. Among these are the pyogenic micrococci, the diplococcus of Frankel, the bacillus of Fried- lander, the Bacillus influenze, the B. colt, with many others. The mucous membrane presents an intensely red color; at first it is dry, but later a mucous or mucopurulent exudate is formed (see Fig. 32). The exudation may be excessive in quantity, in which case the condition is called bronchorrhea. This may be serous or purulent, and is sometimes very offensive in odor (fetid bronchitis). Accordingly, as the exudate assumes a serous, mucous or mucopuru- lent, or fibrinous character, these names are applied. They have no etiological significance aside from the specific infections. All forms may go over into gangrenous bronchitis by retention and putrefaction of exudate. Microscopically, the bronchial mucous membrane is infiltrated with round cells, especially in the purulent cases; the epithelial cells are de- generated, many being converted into goblet-cells; and the mucous glands are distended with mucus. The mucosa of the bronchi is covered with mucopurulent material containing degenerated epithelial cells and DISEASES OF THE RESPIRATORY SYSTEM 533 detritus. The inflammatory conditions may extend outward as far as the peribronchial tissue, and occasionally there is some perichondritis. Capillary bronchitis is a form confined, at least in the early stages, to the finest bronchioles, and it may go over into a catarrhal pneumo- nitis. Pathological Physiology—Bronchitis may occasion no other dis- turbance than cough. In many cases, however, the infection may cause fever and general depression. Substernal soreness or pain is not infre- quent, while generalized thoracic pain may result from the violent coughing. Dyspnea is rare excepting in children and old persons, in whom cardiac weakness and spasmodic contractions of the bronchi seem to be operative. Chronic catarrhal bronchitis occurs after repeated attacks of the acute form, and especially in old persons or in those who have some cardiac weakness which tends to cause congestion of the bronchi. Gout seems to constitute a dis- tinctly predisposing cause. Chronic bronchitis is frequently associated with chronic diseases of the lungs. In chronic cases the mucous mem- brane may undergo considerable alteration. Frequently the ciliated cells disappear entirely and are re- placed by columnar or polygonal epithelium; and hypertrophic con- ditions of the mucous membrane are sometimes present. More fre- quently the bronchus is uniformly thickened by cellular infiltration and overgrowth of fibrous tissue. It may, indeed, become hypertro- phic, and when the overgrowth en- croaches bia the lumen with ee Fig. 227.—Large bronchial _coagulum; gressive granulation tissue an ob- chronic fibrinous bronchitis (Vierordt). literating bronchitis occurs. The exudate in chronic bronchitis is purulent and is accompanied by dis- arrangement and alterations in the bronchial epithelia. Fibrinous bronchitis occurs under a variety of conditions. It ismost frequent in association with laryngeal and tracheal diphtheria, but may also be due to inhalation of powerful irritants. Fibrinous inflammation of the finer bronchi occurs in both croupous and catarrhal pneumonia. Finally, there is a form of chronic or essential fibrinous bronchitis, characterized by periodic attacks, in which fibrinous casts of the bronchi are formed and discharged (Fig. 227). In all forms of fibrinous bronchitis there are often found in the sputa, on microscopical examina- tion, fine spirals wound about a central fiber (Curschmann’s spirals); and within these or associated with them the small octahedral crystals described by Charcot and Leyden (Fig. 228). 534 A TEXT-BOOK OF PATHOLOGY Bronchiolitis Exudativa.—This term was given by Curschmann to the condition of the terminal bonchioles he assumed to be present in cases of asthma. The sputa contain the spirals that bear his name and Charcot-Leyden crystals. The sputa in these cases are further char- acterized by the abundance of eosinophile cells (Figs. 228 and 229). Fig. 228.—Sputum from a case of asth- ma, showing Curschmann spirals, Charcot- Leyden crystals, leukocytes, and numerous free eosinophile granules; unstained speci- men (Jakob). Fig. 229.—Sputum from a case of asthma, showing leukocytes, some containing eosino- phile granules, free eosinophile granules, and micrococci; stained with eosin and methylene-blue (Jakob). Ulcers of the bronchi are met with in severe catarrhal inflammations, but more frequently are tuberculous, syphilitic, or due to extension of ulcerative processes from neighboring parts. It is not unusual to find ulceration in the main bronchus opposite the point of pressure of an aneurysm. Peribronchitis may occur from direct extension of inflammation from within, or it may be due to extension along the lymphatic channels from the pleura or interlobular septa of the lung. It is found most frequently as a part of pulmonary tuberculosis, and may be fibrous, caseous, or purulent. STENOSIS AND OBSTRUCTION OF THE BRONCHI The smaller bronchial tubes may be considerably occluded by catarrhal swelling of the mucosa and accumulation of exudate within. Clinically, this is often so marked in bronchitis affecting the terminal bronchioles as to have suggested the name “‘suffocative catarrh.”’ (This capillary bronchitis is always merely a part of bronchopneumonia, and will be considered under that head.) More serious obstructions of the bronchi occur when old ulcers have healed, leaving cicatrices; or in cases of tumors of the bronchi or pressure upon the outside. If the ob- struction be total and permanent, atalectasis of the lung occurs in that part supplied by the affected tubes. In temporary obstruction a mild DISEASES OF THE RESPIRATORY SYSTEM 535 local emphysema occurs beyond the obstruction. Foreign bodies are usually coughed up, but may remain for long periods and occasion ob- struction. BRONCHIECTASIS, OR DILATATION OF THE BRONCHI This is due to increased pressure within the bronchi or to some weakness of the walls, or to both, when the fault lies primarily in the bronchial walls. The weakening of the walls is most frequently due to chronic bronchitis. If it is extreme, simply the force of the inspired air may suffice to cause dilatation, but the increased expiratory efforts of coughing may aid materially. When a part of the lung is collapsed (atelectasis) the impediment to the entrance of air leads to dilatations of the bronchi above the collapsed area. This is especially noted in children. The weight of accumulating secretions in the tubes is an occa- sional cause of bronchiectasis. Finally, in fibrous pneumonia the trac- tion of the connective tissue, attaching itself, on the one hand, to the outer wall of the bronchus, and, on the other hand, to the pleura, may bring about considerable dilatations. An analysis of series of cases shows that chronic bronchitis and chronic cough stand at the head of the etiological antecedents. Probably in a much larger proportion of cases than is now recognized there is an association of bronchial dilatation with chronic bronchitis. The clini- cian and pathologist also have in the past given little attention to cases in which the dilatations were not pronounced or saccular. Clinically, there can, however, be recognized a group of cases of chronic bronchitis with excessive sputa in which the bronchi are probably uniformly though slightly dilated. Among the other causes tabulated a b are preceding pneumonia, pleurisy, “4 tumor, foreign body in the bronchus, aneurysm. A congenital varicose dilatation of bronchi is sometimes seen. The enlargement of the bronchus may be localized, when it is termed saccular bronchiectasis; or more uni- form, when the names cylindrical and fusiform are applied, accord- ans ing to the shape of the bronchus ee ee (Fig. 230). The. mucous mem- (Orth). brane may be almost normal in ap- pearance in small dilatations, but more commonly is thickened and irregular on the surface. There may even be actual polypoid out- growths, and ulcerations may occur when the secretions are specially abundant and irritating. Microscopically, the epithelium is found to approach the squamous type; the wall of the bronchus is generally infiltrated and cirrhotic. The exudation is generally purulent and copious, and may be very fetid. Occasionally it is thick and cheesy. 536 A TEXT-BOOK OF PATHOLOGY Bronchiolectasis.—Cases of extensive dilatation of the small bronchi and bronchioles have been observed. They are especially com- mon in childhood and may be of a bronchitic type when bronchitis is the precedent condition, and an obscure pneumonic form in which the bronchiolar dilatation is associated with pneumonic consolidation. Fig. 231.—Honey-comb lung, illustrating the extreme results of generalized acute bron- chiolectasis of the bronchitic type (H. Morley Fletcher’s case). Bronchiolitis may be acute or chronic in its course and localized or quite general. In some cases the lung is quite honey-combed in appear- ance (Fig. 231). INFECTIOUS DISEASES Tuberculosis of the bronchi is usually associated with pulmonary tuberculosis, and appears in the form of miliary or larger nodules in the mucosa or submucosa, which tend to break down to form ulcers. Syphilis sometimes occurs in the form of eruptions and ulcers. There may be dense scar formation and deformity in consequence of the healing of such ulcers. TUMORS Polypoid conditions of the mucosa occur in cases of chronic bronchi- tis. Fibroma, chondroma, and lipoma are rare forms of tumors. Pri- DISEASES OF THE RESPIRATORY SYSTEM 537 mary cancers may spring from the mucous glands or from the surface epithelium, but are very rare. Leukemic nodules are seen in the bronchi at times, and lymphosarcomata are not rarely found to spring from the peribronchial lymphatic tissues. PARASITES AND FOREIGN BODIES Bronchiectatic cavities may contain a growth of aspergillus— mycosis aspergillina. Round worms may enter by migration, and hydatid cysts are met with. The Paragonimus westermanii is a rare parasite invading the bronchi. _ Foreign bodies from the exterior usually enter the right bronchus. They often lead to serious inflammation and suppuration, unless they are coughed up. Bronchial concretions sometimes form by inspissa- tion of the secretions, especially in bronchiectatic cavities. Very rarely cartilaginous or bony masses, derived by outgrowth and later separa- tion from the bronchial cartilages, are observed. THE LUNGS Anatomical Considerations.—The structure of the lungs in their unexpanded condition is very similar to that of an epithelial gland, consisting of ducts, the bronchi; and glandular tissue, the pulmonary parenchyma. The terminal bronchioles divide into several alveolar passages, which open into infundibula, and these, in turn, are surrounded by air-sacs. The groups of infundibula connected with a terminal bron- chiole constitute an acinus. Neighboring acini unite to form lobules, and the lobules unite to form lobes. The epithelial lining cells of the air- sacs are large flat plates, which resemble endothelial cells very closely. Beneath these cells is a layer of elastic tissue, which gives the lungs their characteristic elasticity, and in which is embedded a rich net- work of capillaries, that carry on the proper respiratory function of the lungs. These capillaries are the terminal ends of the pulmonary artery. Another set of blood-vessels, the bronchial arteries, serve only to nourish the walls of the bronchi and the structure of the lungs them- selves. The return circulation is mainly carried on by the pulmonary veins, which receive the blood of the pulmonary arteries and much of that of the bronchial arteries. The distribution of the lymphatic ves- sels in the lungs is of the greatest significance in pathological anatomy, especially with regard to the dissemination of infectious diseases in the lung itself. One system of lymphatics begins in the lymph-spaces be- tween the cells of the intervesicular septa. These lymph-spaces deliver their contents to lymphatic capillaries in the same region, and these, in turn, follow the alveolar passages, surrounding the latter on all sides. Where the several alveolar passages unite to form a terminal bronchiole the smaller lymphatic capillaries also unite to form larger branches, which follow the bronchioles. Other lymphatic vessels surround the pulmonary veins, constituting a perivascular system. Still another 538 A TEXT-BOOK OF PATHOLOGY system begins in small subpleural capillaries, which unite, enlarge, and then penetrate the lung along the interlobular septa. Some of them, however, pass at once to the peribronchial and perivesicular tissues. All the lymphatic trunks leave the lung at the root and eventually discharge into the thoracic duct. Collections of lymphoid cells are found in various places along the lymphatics in the tissue of the lung. Near the root these are of consider- able size, and merit the name of lymphatic nodes or glands. Still larger and more important ones are found surrounding the bronchi just outside the lungs and around the end of the trachea. CONGENITAL DEFECTS Complete absence of the lungs has been noted in certain monsters. One lung may be absent, or its parenchyma may be undeveloped, while the bronchi are dilated even to a cystic condition. The opposite lung is compensatorily enlarged. Minor abnormalities in the division of the lobes and the like are not rare; and in a few instances accessory lobes, wholly disconnected from the rest of the lung, have been observed. CIRCULATORY DISTURBANCES Anemia of the lung occurs as a part of general anemia, from pres- sure upon the lung, or from obstruction or obliteration of the blood- vessels. The last is the cause of the great pulmonary anemia in emphy- sema of the lungs. The lungs are pale in color or of a mottled appear- ance in elderly persons, in whose organs considerable pigment is usually present. The apex is the first part to show anemia. Active Hyperemia or Congestion.— Exercise constantly leads to in- creased flow of blood to the lungs, and this may be extreme, causing rapid death (apoplexia pulmonum vascularis). In cases of irritation of the lungs by the inhalation of heated or cold air, or of irritating gases, and in certain lesions of the base of the brain there may be more or less active congestion of the lungs (Fig. 232). Collateral hyperemia occurs when the opposite lung or some other part of the body becomes anemic through a stoppage of the circulation in that part. The lung in active hyperemia has a dark-red color, and on section blood flows from the surface of section. The alveoli may contain free blood, and in marked cases there is blood in the sputa during life. Passive hyperemia is, for the most part, a chronic condition due to causes which prevent the outflow of blood from the lungs. The most frequent cause is valvular disease, particularly mitral stenosis and re- gurgitation; but weakness of the left ventricle from fatty disease or fibroid degeneration acts in a similar manner. Any local cause of hin- drance to the outflow of the blood in the veins leads to similar passive congestion. It is often found in the dependent parts of the lungs in cases of great asthenia, as in typhoid fever, when the respiratory movements are ineffectual in properly emptying the pulmonary vessels. DISEASES OF THE RESPIRATORY SYSTEM 539 This is called hypostatic congestion; not infrequently it leads to hypo- static pneumonia when irritants are inspired or descend through the bronchi to the parts of the lung affected. Postmortem there is often a similar hypostatic congestion, but without any evidences of catarrhal as 7, oh Fig. 232.—Acute congestion of the lung (Karg and Schmorl). inflammation of the bronchi, such as always occurs in the cases de- veloped during life. The lung in passive hyperemia is dark-red in color and heavy. In the more acute cases it is moist on section, being infiltrated with serous Fig. 233.—Phagocytic cells of the sputum, containing blood-pigment, from a case of cardiac congestion of the lungs (Jakob). exudate and blood; in chronic cases, as in slow heart-failure, the tissue is dry and indurated. Microscopically, the blood-vessels in the alveolar walls are seen to be greatly distended, irregular, tortuous, and project into the alveoli. Red and white blood-corpuscles are seen within 540 A TEXT-BOOK OF PATHOLOGY the alveoli and in the interstitial tissues. In the later stages the red corpuscles either re-enter the circulation or break down to form dark pigment-granules within the alveolar epithelial cells, the leukocytes, or lying free in the tissues of the alveolar walls. In such cases there are at the same time considerable hyperplasia and induration of the con- nective tissue of the lung; and the whole process is called cyanotic induration. In cases of heart disease with congestion of the lungs there are very commonly found in the sputa pigmented epithelial cells and leukocytes, such as those described above (Fig. 233). These have been called heart-failure cells (Herzfehlerzellen). They are of some diagnostic importance. Edema occurs most frequently as a result of passive hyperemia and is due to disproportion in the expulsive force of the two ventricles. The acute edema of nephritis may possibly be due to the inability of the left heart to empty because of the continued circulatory hypertension. In other cases the edema is the consequence of general septic condi- tions which lead to unusual permeability of the blood-vessels. In this group of cases belong the instances of “acute idiopathic edema” which are apparently independent of cardiac weakness and probably depend- ent on some form of infection. This is sometimes seen as an acute fatal attack in persons suffering from vascular disease, especially of the aorta, and in nephritics. Similar edema, not dependent on passive congestion, occurs in the parts of the lung surrounding inflammatory areas, and in some cases sudden pulmonary edema seems dependent on > vasomotor relaxation. In cases of stenosis of the larynx, edema of the lung may result from the reduced pressure of air in the alveoli and the consequent suction of blood to the pulmonary circulation. In the cases of edema due to passive congestion the lungs are dark-red in color, firmer than normal, pit on pressure, do not show normal crepitation, and on section more or less serous fluid, rendered frothy by admixture of air, exudes from the cut surface. In long-standing cases the exuding fluid may be dark by admixture of degenerated blood. In the other forms of edema the lung may be quite light in color, generally grayish, but on section the same frothy serum exudes from the surface. Microscopically, little is to be seen. There is some congestion of the septa, with a few epithelial cells and a hyaline coagulum in the alveoli. Hemorrhage.—Small punctate hemorrhages occur in cases of severe congestion or inflammation, in the hemorrhagic or infectious diseases, and in consequence of high blood-pressure, as in death from asphyxia or in whooping-cough. The cause of such hemorrhages is inflammatory or degenerative weakening of the vessel walls or an obstruction of the lumen. When the former exists, and the latter supervenes, the production of hem- orrhage is easier and more extensive. When hemorrhage from congestion is combined with serous effusion the lung assumes an appearance not unlike that of a hyperemic spleen (splenization). A form of apparent hem- orrhage is seen in cases in which the blood is aspirated from the bronchi. In such cases lobular spots of hemorrhagic infiltration are found at the bases. Large hemorrhages into the substance of the lungs may be DISEASES OF THE RESPIRATORY SYSTEM 541 traumatic, or they may be due to rupture of an adjacent aneurysm into the lung. Small or large pulmonary hemorrhages are at times due to lesions of the nervous system, especially of the base of the brain. Hemorrhage from the lungs, discharging externally through the bronchial tubes, is most commonly due to tuberculosis, and is particu- larly frequent in the late stages, when cavities have formed. The im- mediate source of the bleeding is generally an eroded vessel in the wall of the cavity, and a small miliary aneurysm is commonly found at the point of erosion. Hemoptysis may be the first indication of the existence » of pulmonary tuberculosis, but the old belief that hemorrhages cause phthisis is ill founded. A hemorrhage or any other lesion of the lungs may, of course, add to the liability to infection; but, as a rule, the cases in question are instances of hemorrhage occurring before the other evidences of the pulmonary disease have become marked. Occasionally, hemoptysis is due to congestion of the lungs, to erosion of small blood- vessels from gangrene, abscess or the like, or to vicarious menstruation. Hemorrhagic infarcts may occur in the lungs, as in other places, from obstruction of the arteries by emboli. The latter come from the right heart or from the general venous system, and lodge in the smaller branches of the pulmonary artery, frequently at their points of sub- division. Very often, however, emboli are not found, or, if so, are so small as to have been unable to cause obstruction without the associated thrombosis, or there may be purely thrombotic occlusion. Valvular lesions and muscular weakness of the heart aid greatly in the produc- tion of infarctions by causing a sluggish circulation in the pulmonary vessels, and thus encouraging thrombosis. Infarctions are occasionally due to thrombosis of the pulmonary veins without obstruction of the arteries; more rarely they are caused by occlusion of one of the bronchial tubes. The latter condition leads to collapse (atelectasis) of the part of the lung associated with that tube, to consequent congestion (see Ate- lectasis), and, sometimes, when the congestion is severe, to hemorrhage. In addition, it is to be remembered. that hemorrhages into the lungs are likely to have the shape and appearances of ordinary infarcts, be- cause they occupy the area supplied by the bronchus into which the blood finds its way. Contributory causes are to be found in emphysematous lungs or those with senile or chronically altered arteries. These act as conditions favoring embolism and, secondarily, thrombosis by reason of degenerated vessel walls, and a loss of accommodative power by the pulmonary vascular and tissue tension. Infarctions are most frequently found in the lower lobes and in the right lung; they are usually multiple (Fig. 234) and have the characteristic wedge shape, the base of the wedge directed toward the pleural surface. They are hard, airless, dark colored, and project above the other parts on section and on the pleural surface. The pleural surface is at first shining and dry; later it becomes moist, then cloudy, and a layer of lymph appears, sometimes to be fol- lowed by a distinct fibrinous or adhesive pleuritis. Microscopically, there is seen a uniform hemorrhagic infiltration of the tissues (Fig. 235) and not infrequently hyaline thrombosis of the smaller blood-vessels. 542 A TEXT-BOOK OF PATHOLOGY Toward the apex of the infarct there is more fibrin in the blood-vessels, and the main vessel may be found obstructed by an embolus or throm- bus. Small infarcts may be wholly removed through the vascular and lymphatic channels after liquefaction and granular degeneration of the inn Fig. 234.—Double hemorrhagic infarct of lung (from a specimen in the collection of Dr. Allen J. Smith). blood-clot. More commonly a pigmented scar is left. Softening and cyst formation may occur, or in cases in which the original embolus was infected by micro-organisms, or in which the infarct becomes in- fected through the bronchial tubes, abscess or gangrene may result. Fs UE Fig. 235.—Hemorrhagic infarction of the lung (from a photograph by Dr. Wm. M. Gray). Embolism without infarction is not infrequent in the lungs. An interesting form is fat-embolism, resulting from fracture of a bone with disorganization of the marrow, and less frequently from traumatic disturbances of other fat tissues. When large branches of the pulmonary DISEASES OF THE RESPIRATORY SYSTEM 543 artery are occluded in this way, or when numerous vessels are ob- structed, sudden death may result. In other cases there are merely great dyspnea and oppression. Air-embolism, embolism of hydatid cysts and of portions of tumors are rare. Attention has been called to the embolism of placental cells in certain cases of eclampsia. HYPERTROPHY AND ATROPHY Hypertrophy.—True hypertrophy, in the sense of increase of all the constituents of the lung tissue, is extremely rare, and probably only occurs when areas of the pulmonary tissue have been rendered useless early in infancy or in fetal life. Cases have been observed, however, in which a single lung occupied the entire side of the thorax to which it belonged, and also a part of the other side, where complete atrophy of the other lung had existed. It may be that limited areas of hyper- trophy occur more frequently than we at present believe, but evidence is wanting. Partial Hypertrophy—The muscular tissue of the intervesicular septa and of the smaller bronchioles not infrequently undergoes pro- liferation or hyperplasia when there has been obstruction in the air- passages, so that greater expiratory force was required. Similarly, the elastic tissues may become increased; but these are not instances of true hypertrophy. Atrophy.—Aside from that which occurs as a part of emphysema, atrophy does not take place. EMPHYSEMA By this term is indicated an increase of the air contained within the lungs, either in the normal tubes and alveoli or in the interstitial connective tissue. Two varieties of emphysema may be distinguished by their essentially different nature. These are the interstitial and the vesicular. Interstitial emphysema of the lungs is similar to the emphysema of the subcutaneous tissues—. e., the term refers to the existence of air within the fibrous tissue of the lung. This occurs in the course of affec- tions in which there is some obstruction to the expiration, combined with severe coughing or forcible expiratory efforts, leading to rupture of the intervesicular septa and extravasation of air. Degenerative or in- flammatory weakness of any part of the pulmonary structure would, of course, act as a primary cause. Interstitial emphysema is most com- monly observed in such diseases as whooping-cough and membranous croup; it may also result simply from straining efforts, as in women during labor, or from forcibly blowing wind-instruments, ete. The air from the ruptured air-vesicle finds its way into the interalveolar and in- tervesicular septa, and, passing along these, eventually reaches the inter- lobular and subpleural connective tissue, where it is seen in the form of small blebs, movable from place to place. The process may extend to 544 A TEXT-BOOK OF PATHOLOGY the roots of the lungs, and even to the mediastinal tissues or to the sub- cutaneous tissues of the neck. When an air-vesicle near the pleural surface ruptures, pneumothorax may result. Vesicular emphysema is the term used to designate overdistention of the alveoli and air-sacs of the lung. Two factors play a part in the causation of this condition: first, increase of the pressure under which the air exists in the lung; and, second, degenerative or inflammatory weakness, with loss of elasticity of the lung structure itself. There are several varieties, and the causes vary somewhat in each. (a) Acute vesicular emphysema results simply from excessive air- pressure within the alveoli, and may be more or less widespread. It occurs in cases in which inflammatory swelling or mucous secretions within the bronchi obstruct the expiration of air, but are-not sufficient to impede the more vigorous inspiratory force. There results over- distention of the alveoli and air-vesicles. Somewhat similar conditions are present when the entrance of air into certain parts is impeded by obstruction or disease of the bronchi or by consolidations of the pul- monary tissue. Localized emphysema of other parts results (see Fig. 237); the term vicarious emphysema is applied to such cases. This is not unusual in the lobules of the lung surrounding areas of pneumonic or tuberculous consolidation, and may affect an entire lobe or lung when the entrance of air into the other lobes or the other lung is prevented (compensatory emphysema). Pathological Anatomy.—In these cases of acute and _ vicarious emphysema there is simply overdistention of the alveoli, and the tissue presents a paler color than normal and a cotton-like sensation when grasped in the fingers. Microscopically, nothing beyond overstretching of the septa and some anemia of the vessels is apparent. If the causes continue to operate, changes similar to those found in chronic vesicular emphysema ensue. (b) Chronic vesicular emphysema is the ordinary form of emphy- sema, and is sometimes spoken of as substantial emphysema. Etiology—Chronic vesicular emphysema commonly occurs in elderly persons, and is predisposed to by attacks of bronchopneumonia and by the existence of other inflammatory and congestive conditions of the lungs. These conditions lead to weakness or loss of elastic tissue in the lungs. Heredity plays a part in the same direction, and it is supposed by some that there is an abnormal lack of development of the elastic tissue in the lungs of such persons, rendering them more sus- ceptible to this disease. The direct exciting cause of emphysema is increase of the air-pressure within the alveoli, and much speculation has been indulged in to discover whether inspiration or expiration plays the more important part in increasing the pressure. It seems likely that the expiratory force is the more important one, as in the case of constant coughing in chronic bronchitis, the blowing of. wind-instru- ments, and the constant straining in certain pelvic disorders, all of which may lead to emphysema. Unusual rigidity of the chest walls, as in abnormal ossification of the costal cartilages, is held responsible for DISEASES OF THE RESPIRATORY SYSTEM 545 some cases, the extra force necessary to expand the vesicles being answerable for their dilatation. Pathological Anatomy.—The lung increases in size, and very often remains distended when the thorax is opened postmortem. The edges are rounded; the organ is light in color, and has a cotton-like feeling when squeezed between the fingers. On section into it the alveoli may be seen to be distended, and there may be cavities of quite considerable size, often as large as a pea, and sometimes even that of a cherry or plum (Fig. 236). Large spaces of this kind are not unusual near the pleural surface; the term bullows emphysema has been used in reference to such cases. The pigment matter of the lung is very much lessened, and may be distributed in radiating or parallel lines. This lessening of the pigment is not alone due to its distribution over a greater space, but there is also actual disappearance by removal through the lymphatic channels and through expectoration. ts 5 % 4 reset @ , J a TOS & : Fig. 236.—Emphysema of the lungs (Karg and Schmorl). Chronic emphysema may be a general process affecting all parts of both lungs, or it may be localized. In the latter case it is the apex and anterior edges that are most commonly involved, but spots of emphysema may be seen here and there in other parts of the lung, interspersed with normal tissue. The involvement of the apex and an- terior portions is due to the fact that the expiratory force is more apt to distend these portions of the lung than the lateral and basal portions, which receive the uniform support of the sides of the chest and the diaphragm as these contract against the lung. Microscopically, emphysema is found to consist in enlargement of the vesicles and alveoli by distention and by atrophy and disappear- ance of the intervesicular and interalveolar septa (atrophic emphysema). Studied from the earliest stage, there will be found, first, overdistention of the air-sacs, then a gradual thinning, and finally vacuolization of the intervesicular septa at their thinnest parts. Coincidentally, the small 35 546 A TEXT-BOOK OF PATHOLOGY capillaries are compressed, and are finally converted into hyaline cords. The anemia consequent upon this determines additional atrophy and degeneration of the septa and fatty degeneration of the loosened epi- thelium, so that eventually the whole of the septum disappears. Later, adjacent alveoli intercommunicate and large spaces are thus formed. The obstruction to the pulmonary circulation due to the obliteration of the capillaries leads to collateral hyperemia of the larger branches supplying the bronchi, and thus prolongs the chronic bronchitis, which in the first instance may have been the cause of the emphysema. Sub- sequently, collateral anastomosis between the pulmonary arteries and the bronchial system of blood-vessels is established. Associated Conditions in Other Organs.—The shape of the thorax in emphysema is characteristic. The chest is in a constant state of ex- treme inspiration, the clavicles elevated, the sternum protruded, the back arched. It has a shape well likened to that of a barrel. The dia- phragm is usually depressed and the liver is below its normal position; the heart is almost or completely covered over in front.and usually pressed somewhat backward from the chest wall. Pathological Physiology.—The effect of emphysema upon the circu- lation is important. The obstruction of the pulmonary capillaries leads to increase of pulmonary pressure, and eventually hypertrophy of the right heart; later, dilatation of the right ventricle ensues, and character- istic cardiac dropsy with general cyanosis may result. (c) Senile emphysema is due to thinning of the intervesicular septa, the result of the atrophic processes to which old age predisposes. There is not necessarily any element of increased air-pressure in the causation of this form of emphysema, and the volume of the lung may not be notably increased, though the tissue is lighter and the air- spaces are found to be increased. The lung is light in color and often collapses readily. ATELECTASIS The term “atelectasis” is applied to two distinct conditions, one occurring as a congenital affection, in which the lung has never been properly expanded by air; the other occurring in after life, in which the lung is compressed or collapsed, so that the alveoli and air-vesicles are rendered airless. Congenital atelectasis is found in newborn babes in whom the inspiratory power has been so deficient, as the result of general weakness or compression of the thorax, or of compression of the brain by cerebral hemorrhage, that the lungs, or parts of them, have never been expanded. It may also take place in a purely mechanical way by obstruction to the air-passages by meconium or other foreign matter. Pathological Anatomy.—Congenital atelectasis commonly affects the bases and posterior portions of the lung. The area of disease is of a dark reddish color; it is rather tough, and on section presents a smooth appearance; pressure gives no sign of crepitation. Ifa portion be thrown into water, it sinks. Usually a considerable part of the lung is involved, DISEASES OF THE RESPIRATORY SYSTEM 547 but sometimes merely lobular areas are affected. By inserting a blow- pipe into the bronchi the lung may be inflated, and resumes its normal appearance, provided the condition has not persisted for any length of time. If the child does not perish, secondary changes take place. The epithelium of the alveoli degenerates, more or less proliferation of the connective tissues of the septa occurs, and the pleura over the diseased area is prone to become thickened. The atelectatic portion of the lung in such cases remains collapsed; it is smooth on section, free of pigment, and can no longer be inflated. Secondary dilatation of the bronchioles and bronchi may ensue. It is of interest, in a medicolegal sense, to recognize that atelectasis re- sembling the congenital form may be met with in the bodies of infants that have lived, breathed, and even cried lustily. The explanation of this is that collapse occurs some time after birth, and, that as the lung has practically still its fetal characteristics, the resulting atelectasis is the exact counterpart of ‘the congenital form. Atelectasis in later life occurs under a variety of conditions. It may simply be the result of compression of the lung by pleural effusions, by deformities of the chest, by tumors, aneurysms, and the like. It may also be met with in cases in Fic, 287 —itelesingis due ip which the bronchial tubes have become bronchial obstruction: acute em- obstructed. The larger bronchi may - Sane oe Eee be occluded by the pressure of tumors or aneurysms, or by foreign bodies, and the resulting atelectasis’ is of considerable extent; the smaller bronchi and bronchioles are frequently obstructed by intense catarrhal thickening of their mucosa, and in con- sequence lobular areas of atelectasis are developed. The latter is espe- cially frequent as one of the pathological features of bronchopneumonia (q. 0.). The explanation of atelectasis as the result of bronchial obstruction has occasioned much discussion, and several theories have been pro- posed. In some cases it is not unlikely that mucous secretions within the bronchi may prevent inspiratory entrance of air into the lungs with- out opposing any obstacle to expiration, so that collapse is gradually de- veloped. In other cases it is likely that both inspiration and expiration are prevented, while the air contained within the air-vesicles is gradu- ally absorbed. It is claimed that first the oxygen, later the carbonic acid, and finally the nitrogen are absorbed; the collapse of the alveoli then becomes complete. It is possible, also, that atelectasis may be developed as the result of the failure of respiratory motions on one side, or affecting a certain part of the lung. As a result of this, the elasticity 548 A TEXT-BOOK OF PATHOLOGY of the pulmonary tissue would gradually press the air out of the affected area, while new air was not supplied by inspiration. Such a condition, however, must be rare. Pathological Anatomy.—The part affected by atelectasis is dark in color and is much reduced in size, so that when lobular areas are affected the pleural surface may be considerably depressed (see Fig. 237). On sec- tion, the surface is smooth and generally dry, though in some instances passive hyperemia, which is generally present to some extent, reaches such a grade that bloody liquid flows freely from the surface of section. The term splenization is properly applied to such cases, whereas the in- stances in which the surface is dry are often spoken of as carnification. The lung does not crepitate, and sinks when placed in water. In the earlier stages the diseased portion may be inflated through the bronchial tubes; but when the condition has persisted, connective tissue over- growth springing from the septa causes permanent induration and collapse. The lung in such cases is hard and of a dark color, due to the deposit of hematogenous pigment, the result of disintegration of the blood present. The bronchi may be compressed, but sometimes atelectatic bronchiectasis results from the increased pressure of air sus- tained by the bronchi in consequence of the collapsed state of the lung tissue. INFLAMMATION, OR PNEUMONIA ~ Classification.—Inflammation of the lungs, pneumonia, or pneu- monitis may arise in a variety of ways, and present itself in a number of widely varying forms, both as to the distribution and the nature of the pathological changes in the pulmonary structure. In all cases some irritant is conveyed to the lung either (a) from the upper air-passages or external world through the bronchi (bronchogenic pneumonia); (b) from some other part of the body through the blood (hematogenic pneumonia); or (c) from the pleura by direct extension or through the lymph-channels (pleurogenic pneumonia). Anatomically, pneumonia is classified according to the nature of the inflammatory products, and there are thus distinguished: fibrinous pneumonia, in which the air-vesicles and terminal bronchioles contain an exudate especially rich in fibrin; catarrhal, or bronchopnewmonia, in which the exudate is composed of an albuminous liquid containing numerous epithelial cells and blood-corpuscles; purulent pneumonia, in which pus-cells are the noteworthy element in the exudate; cheesy pneumonaa, in which cellular desquamation and cheesy necrosis are prominent; and productive or fibrous pneumonia, in which there is overgrowth of fibrous connective tissue. It is to be remembered, how- ever, that mixed cases are of frequent occurrence and that the essen- tials of inflammation are present in all types. Thus, in many in- stances localized areas of decided fibrinous pneumonia are found in the midst of larger areas of catarrhal pneumonia; some distinctly purulent exudation may be met with in many instances of fibrinous or catarrhal pneumonia; and more or less productive inflammation and _ fibrous DISEASES OF THE RESPIRATORY SYSTEM 549 overgrowth may be seen in any of the other varieties. Typical cases, however, present little mixture of the lesions. The terms “parenchymatous” and “interstitial pneumonia’’ are sometimes employed, but are of doubtful significance. The proper parenchyma of the lungs, the alveolar septa and their contained blood- vessels, are never the sole seat of inflammation, and the term “parenchy- matous pneumonia,” as usually applied to inflammations of the lining epithelium of the air-vesicles, is, therefore, misused. It is appropriate to call the fibrous variety “interstitial pneumonia.” Fibrinous Pneumonia Definition.—Fibrinous, or croupous, or lobar pneumonia is an acute infectious form of pneumonia, generally caused by the Dzplococcus pneumonie, and usually involving an entire lobe or more than one lobe of one or both lungs. Pathologically, it is characterized by an exuda- tion within the air-vesicles and terminal bronchioles, mainly composed of fibrin; clinically the disease is marked by a definite and character- istic course. Etiology.—The important factor in the causation of fibrinous pneumonia is the Diplococcus pneumonie (Frankel-Weichselbaum). This micro-organism is found in the sputa and in the lungs, and is un- doubtedly the cause of the pneumonia in the great majority of cases, but some other micro-organisms seem able to occasion typical fibrinous pneumonia. Among these are the pneumobacillus of Friedlander, streptococci, staphylococci, the bacillus of typhoid fever, the bacillus of influenza, and the Bacillus coli communis. In some cases in which bacteria other than the diplococcus are supposed to be the cause there is, doubtless, mixed infection; but it must be accepted at the present time that a number of micro-organisms are capable of causing the disease. The fibrinous pneumonia which occurs in the course of tuberculosis is certainly due to secondary infection, and the same thing frequently happens in the course of typhoid fever and influenza, though the specific bacilli of these diseases may alone cause pneumonia. The micro-organisms usually gain access to the lungs through the bronchi. In the case of the Diplococcus pneumonia the frequent oc- currence of this organism in the mouth and upper respiratory passages furnishes a ready explanation of one source of infection. More rarely the bacteria may be directly inspired from without, or, exceptionally, they may reach the lungs through the circulation. : There are certain predisposing factors which have long been recog- nized clinically as causes of pneumonia. These probably act by render- ing the pulmonary tissues less resisting, or by increasing the virulence of the diplococci of the mouth. Among these causes are exposure to cold, injury of the lungs by traumatism, fatigue, and systemic depression. (For the description of the Diplococcus, see p. 280.) Latest studies have placed this disease, at least when caused by the Pneumococcus, among the acute specific infections. There is almost 550 A TEXT-BOOK OF PATHOLOGY always a bacteremia. While admitting the effect of disposing causes in the production of the disease, attention has been called to acute localized congestions in the lung or bronchioles, as starting-points of the general involvement. Such, says Cole, are the most likely beginnings of the pneumonia because they offer colonizing places for pneumococci. The virulence of the bacterium has little relation to its pathogenicity, but the more virulent, the more fatal. There is no parallel between the severity of the infection and the extent of the anatomical lesions. The leukocytes and their phagocytic power are both increased toward the end of an attack. At its height the infection continues by reason of a state of balance between the phagocytic power of the leukocytes and certain antibodies in the blood on the one hand, and the infectious organisms on the other. When the defensive group neutralizes the offensive, the balance is destroyed and crisis takes place. (See Immun- ity and Pneumococcus, pages 256 and 280.) Pathological Anatomy.—The lesions most frequently involve the lower lobe of the right lung; next in order is the lower lobe of the left lung; the apices alone are least frequently involved. In all cases there is a tendency to the involvement of a whole lobe, and, as a rule, the entire area of disease is affected uniformly and simultaneously. There are wide variations, however; for, on the one hand, typical fibrinous pneumonia may occasionally appear as a more or less lobular disease (particularly in influenza), and, on the other hand, the process may spread from one part of the lung to another (pneumonia migrans). In typical cases not only is the process uniformly distributed, but it passes through distinct stages: first, of congestion, then of consolida- tion, and finally, of resolution. Stage of Congestion or Engorgement.—The affected area is dark-red 1n color; it is swollen and heavy, and on pressure crepitates less than a healthy lung. The pleura over the diseased part is dull and lusterless. On section through the lung, bloody liquid exudes, and when the part is compressed with the fingers this liquid shows a few air-bubbles. The condition is simply one of intense congestion, with exudation into the alveoli and terminal bronchioles of serous liquid and blood-corpuscles (see Fig. 232). Microscopically, the small blood-vessels of the septa are seen to be greatly distended and project inward toward the alveoli. Within the latter may be found many red corpuscles, a lesser number of leukocytes, and some detached epithelial cells. Stage of Consolidation, or Hepatization.—The diseased lung is now completely solid and liver-like in consistency (hepatization). It is swollen, and marked on the surface by indentations of the ribs. The surface of section is at first red in color (red hepatization, Plate 8), but later becomes white or gray, or in elderly persons (in whom the lungs are usually darkly pigmented from inhalation of dust) of a variegated appearance, resembling granite (gray hepatization, Plate 9). The cut surface is entirely dry, and is finely granular on account of the projection of small plugs of fibrin from the alveoli and bronchioles. The pleura is generally covered with fibrinous exudation. Microscopically, the PLATE 8 Croupous pneumonia, stage of red hepatization (Bollinger). PLATE 9 Croupous pneumonia, stage of gray hepatization (Bollinger), DISEASES OF THE RESPIRATORY SYSTEM dol alveoli are found distended with a network or particles of fibrin, in which the same cellular constituents as occur in the stage of congestion are embedded. The fibrinous network is beautifully demonstrated by staining the sections after the method of Weigert (Fig. 238). The blood-vessels are less prominent than in the first stage. As the disease ad- vances to the period of gray hepatiza- tion the number of leukocytes within the exudate increases and the blood- vessels become still less prominent (Figs. 239 and 240). This change of appearance is due to destruction of red blood-cells and leukocytes, a solu- tion of fibrin by enzymes from leuko- cytes, and the arrival of new leuko- cytes, which act as scavengers of the destroyed material. Under the mi- Fig. 238.—Red hepatizaticn of the croscope the exudate has retracted lung (from a photograph by Dr. Wm. from the septa and liquefactive ne- crosis appears. Stage of Resolution Gradually softening of the exudate occurs and the lung becomes more moist. Puriform liquid may be squeezed from the surface of section, or may be seen in the bronchioles and bronchi. Crepitation is re-established. Microscopically, fatty degeneration of M. Gray). ¢ ; egat. ee ete Me at es Ook ees a aa 8 a PERSE fais ata Pd ai « Faas Fig. 239.—Croupous pneumonia: beginning gray _ Fig, 240.—Advanced gray hepatiza- hepatization (Karg and Schmorl). Lea a photograph by Dr. Wm. . Gray). the cells of the exudate is apparent. Softening is further contributed to by simple liquefaction. The result of these processes is emulsification of the exudate, which is finally carried off by the lymphatics or ex- pectorated. 552 : A TEXT-BOOK OF PATHOLOGY Resolution occurs by action of the ferments liberated from the’ infiltrated cells upon their disintegration, and somewhat from the fer- ments of the bacteria. The digestion products of the ferment action are absorbed, not the cells and fibrin as such. Before the process of resolution is completed the epithelial cells of the alveoli and bronchioles proliferate, so as to repair the diseased portions. At the same time proliferative changes may be seen in the tissues of the septa. These conditions exist throughout the disease to a slight extent, but become more apparent in the stage of resolution. Eventually the lung is restored to its previous condition. Unusual Characters.—In some cases the pathological changes vary somewhat from the typical form described. Not rarely there are considerable congestion and even edema of the lung throughout the disease; in drunkards or cachectic individuals the exudate is more mark- edly hemorrhagic than is usually the case; and sometimes, particularly _in instances accompanied by streptococcus infection, the exudate is more cellular than customary. In still other cases proliferative changes in the septa are prominent. In thinking of the outcome of a pneumonia one must not forget that, in this acute lobar form at least, large parts of the respiratory tissue are functionless, and are deprived of blood-, lymph-, and probably nerve- supply. Associated Lesions and Pathological Physiology.—The portions of the lung not involved by the pneumonic process are usually some- what emphysematous and congested, and edema may develop. The latter is, however, not so common as has often been assumed. The larger bronchial tubes, as a rule, remain normal or, at most, become congested. The finer bronchi are more frequently hyperemic, and excess of mucus coats the surface. In practically every case there is a “certain degree of fibrinous pleurisy, either on the costal surface of the pleura or between the lobes. Extensive pleurisy is rare and serous exudation is uncommon. The pleurisy is directly attributable to the micro-organism which has caused the underlying pneumonia. Though fibrinous pneumonia is sometimes a local infection anatomic- ally, systemic intoxication is usually present, and general infection may further aid to develop widespread pathological changes. Leukocytosis is present in the great majority of cases; its absence is generally significant of unusually intense systemic intoxication. In fatal cases white clots are often detected in the chambers of the heart and in the large blood- vessels leaving the heart. Cardiac and respiratory embarrassment, often ascribed to mechanical causes, such as heart-clot or extensive consolidation, is probably in many cases due to the action upon the nervous system of the toxins of the disease. Myocardial degenerations aid in producing circulatory. weakness. The heart muscle and the kidneys may suffer parenchymatous degeneration as in other febrile infections, and acute exudative inflammation (myocarditis, nephritis) may occur in either of these organs. Albuminuria is not infrequent, and albwmoses may be found in the urine, especially during the stage of DISEASES OF THE RESPIRATORY SYSTEM 053 resolution. Calcium, chlorin, and sodium are decreased in excretion, while magnesium and potassium are increased. The spleen is enlarged and soft. Pericarditis is frequent, and endocarditis, either of the simple or of the malignant type, is more common than in any other acute infection, excepting rheumatism. Meningitis is occasionally noted. Fibrinous or pseudomembranous bronchitis, laryngitis, gastritis, colitis, and cystitis are sometimes met with. Inflammation of the joints and abscesses in various organs may occur. Unusual Terminations.—Secondary infection with pyogenic micro- organisms may lead to termination in abscess; or this result may be due to the fact that the pneumonia was primarily caused by active pus formers. The affected area may suffer gangrene even more com- monly than suppuration. Gangrene is especially prone to occur when Fig. 241.—Induration of the lung (carnification) in a case of pneumonia of five weeks’ uration: a, a, a, New connective tissue of the septa; b, intra-alveolar proliferation of con- nective tissue; c, c, c, desquamated epithelium in the alveoli; e, e, e, new blood-vessels; f, lining epithelium of the alveoli (Kaufmann). the exudation is distinctly hemorrhagic and in cases in which the circu- lation is specially weak. Finally, resolution may be delayed and pro- ductive changes may occur in the septa and even within the alveoli. There results a solidification (carnification) of the lungs, or, as it is termed, fibrous pneumonia (Fig. 241). Catarrhal Bronchopneumonia Definition.—Catarrhal bronchopneumonia, or lobular pneumonia, is an acute inflammatory affection of the pulmonary tissue, occurring . in localized areas and consequent upon inflammation of the terminal bronchioles. Pathologically, the disease is characterized by inflam- mation of the terminal bronchioles and by exudation into the alveoli of albuminous liquid containing desquamated epithelial cells, together with red blood-corpuscles and leukocytes in varying number; clinically, the disease is marked by an indefinite and irregular course. _ Etiology.—Catarrhal pneumonia may be produced experimentally im animals by causing them to inhale steam or various irritating vapors. 554 , A TEXT-BOOK OF PATHOLOGY Still more characteristic lesions are produced when the vapors inhaled hold decomposing organic matter in suspension. The same result is accomplished by cutting the vagus nerves, as a consequence of which the vocal bands and esophagus are paralyzed and irritating secretions and particles of food are conveyed into the lung by inspiration. In man, tumors, enlargements of the thyroid gland, or inflammatory exuda- tion may compress the vagi and lead to forms of pneumonia similar to the experimental pneumonia of dogs. Somewhat analogously, in the late stages of various diseases, particles of food and mucous secre- tions may sink to the dependent parts of the lungs, or may be drawn in - by the inspiratory air and set up catarrhal pneumonia in the parts al- ready predisposed to inflammation by hypostatic congestion (hypostatic pneumonia). Of the same etiological sort are the catarrhal pneumonias which occur in diphtheria, epithelioma of the larynx, and inflammatory conditions of the mouth and pharynx, in which irritating particles are carried to the finer bronchi by inspiration (aspiration pneumonia, deglutition pneumonia). Catarrhal pneumonia of this kind is not infre- quent in the newborn as a result of vigorous inspiratory efforts made while the head is descending through the vagina. Most frequent, however, of all forms of catarrhal bronchopneumonia is that which occurs in the course of measles, whooping-cough, influenza, or other infectious fevers attended with bronchitis. The manner of in- volvement of the alveolar structures will presently be described; for the present it may be said that the inflammatory process extends from the bronchi by continuity and contiguity, or by aspiration of irritating bronchial secretions. The immediate cause of catarrhal pneumonia is some bacterium, the most frequent being the Diplococcus pnewmonie, which occurs in over 50 per cent. of all cases, either alone or in combination with the Streptococcus pyogenes, staphylococci, the pneumobacillus of Friedlander, the bacillus of influenza or of typhoid fever, or the Bacillus colt communis. Any of the other forms named, and especi- ally the pyogenic micrococci, may cause catarrhal pneumonia without the diplococcus of Friinkel; but in the case of fevers (typhoid fever, influenza) in which the specific micro-organisms are found there is usually mixed infection with the Diplococcus pneumoniae. Pathological Anatomy.—The lesions vary somewhat in different cases, and we may distinguish three important types: the simple, or ordinary catarrhal bronchopneumonia, the hypostatic form, and aspiration pneumonia. 1. Simple Catarrhal Bronchopneumonia.—The lung in such cases presents more or less distinct external appearances. On the pleural surface may be seen lobular areas of dark- or light-red or grayish color, which are somewhat elevated and harder than the normal lung. Sur- rounding these the pulmonary tissue is emphysematous, while here and . there may be seen dark-red or lead-colored and somewhat depressed areas of pulmonary collapse (atelectasis). The lung as a whole is crepit- ant, while the pneumonic and atelectatic areas are consolidated and air- DISEASES OF THE RESPIRATORY SYSTEM 550 less and sink in water. On section through the lungs the same general appearances are visible, though the consolidated patches are most abundant near the surface. Both lungs are, as a rule, involved, and any portion is liable to the disease. The smaller and medium-sized bronchi and the bronchioles contain mucopurulent secretion, which may be squeezed out; the areas of pneumonic consolidation are smooth and moist on the surface of section, or exceptionally somewhat granular as a result of admixture of some fibrinous exudate. Occasionally there may be puriform liquid or small purulent collections around the bron- _ chiole in the center of the lobule. The area of collapse (atelectasis) is dark red, as a rule, and on pressure bloody liquid exudes. In the very earliest stages of the disease the areas of consolidation — and collapse may be inflated by inserting a tube into the bronchus supplying the part and by blowing gently into it. Later this is not pos- sible, as the consolidation increases. At the same time it is noted that the consolidated areas become lighter in color, until at last they are grayish yellow; while the areas of collapse become pneumonic and present a similar change of color. Microscopically, the terminal bronchioles and alveolar passages present somewhat swollen walls and contain variable amounts of fluid exudate with many desquamated cells. In the areas of consolidation the alveoli and the air-sacs are filled with liquid and variable numbers of epithelial cells, red corpuscles, and leukocytes (Fig. 242). The epi- ~ thelial cells are desquamated from the lining membrane either singly or in groups, and there is evidence that active proliferation is taking -» .place as well. In most cases the number of red corpuscles and leuko- ‘cytes is small, but in some instances, particularly in cases in which streptococci and staphylococci are operative, the exudation may be quite hemorrhagic or, later, purulent. The alveolar septa regularly pre- sent considerable round-cell infiltration, and the blood-vessels are sur- 556 A TEXT-BOOK OF PATHOLOGY rounded by emigrated leukocytes. The blood-vessels in the septa are distended and tortuous. The atelectatic areas present even greater congestion of the blood- vessels, and the alveolar cavities are obliterated by the collapse of the walls, or contain, at most, a little hemorrhagic exudate. The epithelial cells tend to lose their characteristic shape and become cuboidal. As resolution advances, the cellular exudate becomes lighter in color as a result of fatty degeneration, and eventually it is absorbed or ex- pectorated. Coincidently the round-cell infiltration disappears from the septa, and the pulmonary tissue returns to the normal, excepting that the epithelial cells of the alveoli tend to remain more or less cuboidal for a time. Resolution probably takes place as in the case of fibrinous pneumonia. Pathogenesis.—The manner of development of the lesions is of con- siderable interest. In the ordinary catarrhal bronchopneumonia now under discussion there is always a primary bronchitis of the terminal bronchioles, a bronchiolitis, or capillary bronchitis, as it is termed. This may be spread to the alveolar structure in several ways. In most in- stances, no doubt, the inflammation travels downward along the bron- chioles to their termination by continuity, or outward through their walls to the surrounding alveoli by contiguity. In either case there results a patch of catarrhal pneumonia surrounding a terminal bron- chiole. Less commonly the affected lobule first becomes atelectatic and then pneumonic. The atelectasis results from the obstruction of the bronchioles by mucus or by their swollen walls, and is due to the gradual absorption of the air contained within the alveoli and the inability of more to enter (see Atelectasis). Subsequently the collapsed area becomes inflamed by the entrance of micro-organisms from the bron- chioles or by extension of surrounding inflammation. Unusual Characters—Marked variations are seen in the nature of the process and in its distribution. In some instances there is but little pneumonic consolidation, while the bronchiolitis, or capillary bronchitis, is a striking feature. In other cases the exudate is decidedly hemor- rhagic or purulent, and it may in certain areas be quite fibrinous. Regarding the distribution, the most striking variation is the tendency in some cases to lobar involvement by confluence of the lobular areas (pseudolobar form). Associated Lesions.—The constant association of bronchitis has been sufficiently noted. Pleurisy is less common than in fibrinous pneu- monia, but the patches near the surface are frequently covered with fresh pleural exudation. It has long been recognized that purulent pleurisy i is more apt to occur after pneumonia in children than in adults, and in many of these cases the antecedent pneumonia is catarrhal. Wide- spread toxic and infective lesions may occur, as in fibrinous pneumonia. Unusual Terminations.—In cases in which micro-organisms, more virulent than usual, cause the pneumonia, suppuration and gangrene may result. Fetid and pultaceous foci, or purulent collections sur- rounded by considerable areas of congestion and inflammatory edema, DISEASES OF THE RESPIRATORY SYSTEM : 5007 result. In other instances the process of resolution is slow, and fibroid overgrowth of the septa and proliferation of connective tissue within the alveoli ensue, with the production of more or less extensive sclerotic hardening and contraction of the lung structure. Within such areas the alveolar exudate may lie for a long time as a fatty mass; but this is very unusual; and true caseation, of which so much was formerly said, does not occur. The instances in which this was supposed to have occurred were cases of subsequent infection with tubercle bacilli, or cases of tuberculous pneumonia ab initio. 2. Hypostatic Pneumonia.—The bases and posterior portions of the lungs are commonly involved in these cases. The process occurs as a terminal affection in many diseases. It begins as an intense hypostatic congestion and hemorrhagic edema of the dependent parts of the lungs. Subsequently, the irritants which make their way to the congested area through the bronchi set up a form of inflammation of the terminal bronchioles and air-vesicles which is largely catarrhal, but more fibrinous than ordinary bronchopneumonia. The inflammatory process is also more diffuse, and is at the most insignificant compared with the ante- cedent and associated congestion and edema. 3. Aspiration Pneumonia.—Of the dust which we constantly inhale, the greatest part is arrested in the upper air-passages or in the larger bronchi, and is expectorated. A part, however, reaches the finer bronchi and bronchioles, and sets up a certain amount of local irritation and congestion, with desquamation of epithelial cells and emigration of leukocytes. Ordinarily, these processes are exceedingly trivial and can rarely be demonstrated. In persons, however, whose occupations (e. g., steel-grinding, coal-mining, marble-cutting, etc.) subject them to excessive dust inhalation the pulmonary changes are extensive and severe. This is one form of aspiration bronchopneumonia, but the irri- tation rarely stops at the point of catarrhal inflammation; on the con- trary, the irritant particles penetrate the walls of the bronchioles and are distributed by the lymphatics, causing fibroid changes of greater or less extent. The pneumonia thus produced is, therefore, more appro- priately considered as a form of fibrous pneumonia (q. 2.). In the course of various affections of the pharynx, larynx, trachea, _ and bronchi during anesthesia, as well as in cases in which through palsy of the larynx, or through general depression, particles of food or secre- tions of the mouth enter the air-passages, irritating matters may be in- spired or “aspirated” into the finer divisions of the bronchial system. There results intense local irritation, with catarrhal inflammation and consolidation. The exudate is largely epithelial, but more often serous, hemorrhagic, or purulent than in simple catarrhal pneumonia. The condition may be circumscribed to small patches, but if large particles are aspirated and the larger bronchial tubes are obstructed, widespread consolidation, of the character described, results. The inflammatory process in these cases of aspiration pneumonia are habitually intense, and often terminate in suppuration or necrosis, with considerable sur- Tounding hyperemia and edema. 558 A TEXT-BOOK OF PATHOLOGY Cheesy or Tuberculous Pneumonia Definition.—Cheesy or tuberculous pneumonia is an acute or sub- acute form of pneumonia caused by the tubercle bacillus, involving lobular areas or, by confluence of such, an entire lobe or lung. Patho- logically, it is characterized by proliferation and desquamation of epi- thelial cells, infiltration of the alveolar septa, and, finally, by cheesy necrosis in the area of disease. Clinically, the disease presents itself as a more or less acute pneumonic tuberculosis. Caseous pneumonia is frequently associated with miliary or peribronchial tubercles, affecting the alveoli adjacent to the tubercles. : The pneumonic form of phthisis florida is a caseous pneumonia. Bronchopneumonia of coccus origin may supervene upon chronic ulcera- tive phthisis, or tuberculous lesions may be implanted upon a pneumonia. Etiology.—Cheesy pneumonia as an independent condition is more common in children than in adults. The immediate cause is the tubercle bacillus. Infection occurs by rupture of a tuberculous gland or cavity into one of the bronchi and dissemination of the infective material throughout the lung. Likewise, bacilli may be inhaled from outside, or from tuberculous foci in the bronchi, larynx, or nose. In cases of disseminated tuberculosis of the lungs areas of caseous pneu- monia are habitually encountered in the pulmonary structure between the tubercles. Finally, infection may take place through the blood, but the occurrence of caseous pneumonia rather than miliary tubercu- losis in such cases is assuredly rare. Theoretically, it is possible to have a sudden and overwhelming generalization of the tubercle bacil- lus with involvement of a whole lung, but such an occurrence is rare. Such cases have been described, but it is difficult to estimate the importance of the tubercle bacillus in the presence of other germs capable of producing the inflammation. The process is a catarrhal pneumonitis universalis without the tubercular changes characteristic of caseous pneumonia. It has, indeed, been questioned whether the tubercle bacillus alone can cause this caseous pneumonia, since the typical tuberculous in- flammation is a productive one of lymphatic or interstitial origin. On the other hand, a caseous pneumonitis without tubercle bacilli is not known. In those cases reported as primary diffuse tuberculous pneu- monia the pre-existence of a focus discharging bacilli into the trachea or bronchi could not be satisfactorily excluded. Mixed infection with Diplococcus pneumonie is not infrequent, but it is not, as some investigators have. maintained, essential to the disease. Pathological Anatomy.—In its most typical form caseous pneu- monia is a lobular process beginning around the terminal ends of the bronchioles, where the infective material lodges. The lung presents on section areas of consolidation not unlike those seen in catarrhal broncho- pneumonia. At first these are congested and red in color, but very soon degenerative changes cause a grayish or yellowish color. The surface of section is usually smooth, but often somewhat granular from asso- PLATE to Subacute caseous (tuberculous) pneumonia (Bollinger). DISEASES OF THE RESPIRATORY SYSTEM 559 ciated fibrinous exudation. When abundant infection has occurred the areas may be thickly set, and a lobar form is thus established (Plate 10); or there may be a gradual involvement of new areas, receiving their infection from those first formed, causing a similar, but less uniform, lobar pneumonia. The distribution of caseous bronchopneumonia depends upon its origin. If this be from the upper air-passages, the involvement may be more or less regular and symmetrical, while if entrance of the bacilli be gained through a rupture of a gland into a bronchus, it will follow the course of this tube and spread from it. ea Fig. 243.—Peribronchial tubercle of the lung and caseous pneumonia of the adjacent, alveoli. Caseous pneumonia shows no tendency to resolution, but, on the contrary, tends to progressive cheesy degeneration, and at last to the formation of cavities. The entire lung may be riddled with small ex- cavations, presenting ragged, cheesy walls. Usually the cavities are small, even though there be few; exceptionally, large ones are seen. Though resolution does not occur, limited areas may be healed by reactive fibrous overgrowth springing from the alveolar septa and en- capsulating the diseased area, or penetrating it, and transforming the whole into a fibrous mass. Microscopically, the exudation has many of the characters seen in catarrhal bronchopneumonia. Essentially, the exudate is cellular, and is principally composed of large epithelial cells. These are the des- quamated and proliferated lining cells of the alveoli. A smaller number 560 A TEXT-BOOK OF PATHOLOGY of red blood-corpuscles and leukocytes is noted, but they are unessential. Sometimes a fibrinous network may be seen in the alveoli, but quite as often this is wholly wanting. The blood-vessels are engorged at first, and the septa are infiltrated with round and spindle cells. The walls of the blood-vessels themselves may be thickened by proliferation of the connective tissue. As the process advances the cellular exudate and the alveolar walls as well undergo cheesy degeneration, and pre- sent a granular appearance under the microscope (Fig. 243). Associated Lesions.—Cases of typical caseous pneumonia, as above described, are rare; as a rule, more specific tubercular lesions (tubercles) are associated. The smaller bronchi are commonly attacked in asso- ciation with caseous pneumonia, and tuberculous bronchitis and _peri- bronchitis tending to cheesy change result. The pleura may be cov- ered with inflammatory exudation, or may present miliary tubercles over the area of disease. Associated pleural involvement is especially com- mon between the lobes. The lymphatic glands of the anterior medias- tinum and around the bronchi are frequently enlarged, and may be cheesy in the later stages. Fibrous Pneumonia Definition.—Fibrous, or productive, pneumonia is a chronic process resulting from continued irritation, and involving small or large areas of the pulmonary structure. Pathologically, it is characterized by over- growth of connective tissue, and clinically it is marked by signs of more or less extensive mechanical impairment of the pulmonary functions. Classification.—Several quite distinct forms, depending upon differ- ent modes of causation, may be described. The principal varieties are: (1) The pneumonokonioses, or fibrous pneumonias, due to dust inhala- tion; (2) the secondary indurative pneumonias, such as sometimes follow croupous, catarrhal, or caseous pneumonia, or more frequently chronic congestion of the lungs or atelectasis; (3) pleurogenetic fibrous pneu- monia, in which the process arises by extension of chronic pleural dis- ease; and (4) peribronchial and perivascular fibrous pneumonia, in which the process follows the bronchi and pulmonary arteries. 1. Pneumonokoniosis.—Of the dust we constantly inhale, but a small part reaches the finer divisions of the bronchial tree. Most of it adheres to the walls of the upper respiratory tract and is discharged with the sputa, either free or enclosed in leukocytes or epithelial cells (dust- cells, Staubzellen). When fine particles reach the terminal bronchioles they occasion catarrhal inflammation, marked by proliferation of the epithelium and exudation of leukocytes. These cells may envelop the irritant particles and remove them through the expectoration. When, however, the dust has sharp edges (as in coal-dust, iron-dust, marble- dust, etc.), and especially when the quantity inhaled is considerable, removal by expectoration becomes more difficult. In such cases the foreign particles penetrate the walls of the bronchioles and alveoli, passing between the epithelial cells. They may be arrested in the DISEASES OF THE RESPIRATORY SYSTEM 561 alveolar septa and in the tissue surrounding the bronchioles by the for- mation of a zone of inflammatory exudation, which eventually organizes, forming a fibrous capsule. Some of the particles, however, move along the lymph-spaces into the lymphatic vessels, being carried by phagocytes or floating free in the liquid. These particles may be arrested at various points along the lymphatics, and may occasion fibrous thickening of the vessels or of the perilymphatic tissue. The greater portion, however, passes to the lymphatic glands at the root of the lung and surrounding the bronchi, and indurative enlargement of these structures results. In exceptional instances the irritant particles may be conveyed still further, being deposited in the glands about the smaller curvature of the stomach and beneath the fissure of the liver. This unusual distribution in a direc- tion opposite the usual lymphatic current is explained by the assumption that obstruction of the larger pulmonary lymphatics causes a reversal of the current. Metastatic distribution of dust-particles may also be due to rupture of one of the affected lymphatic glands into a vein. (See discussion of Pneumonokoniosis, page 99.) Pathological Anatomy.—The appearance of the lung varies with the amount of dust inhaled and with its nature. In cases of moderate’ degree small areas of fibrous thickening, with puckering, are the only abnormality. On section, these are found to be hard and of grayish color; often, however, darkly pigmented, owing to the character of the particles inhaled as well as on account of the formation of hemorrhagic pigmentation. The fibrous tissue may be arranged in a stellate fashion, or concentrically around a nucleus of foreign matter. Secondary changes are not uncommon; calcification is frequently observed, and true bone- formation is occasionally noted. Such areas of localized pneumono- koniosis are very commonly met with near the apices. More extensive induration is rare, and is rather more frequent at the bases. Large areas of induration may completely destroy the vesicular character of the lung structure. Firm bands of connective tissue may follow the bronchi and radiate into the peripheral portions of the lung, or thickened trabecule may pass from the pleural surface toward the interior, or, again, a more uniform sclerosis may exist throughout. the organ. The organ is contracted; the pleura, as a rule, is thickened and drawn inward; and the bronchi may be widely dilated as a result of the traction of the contracting connective tissue and as a consequence of accumulating secretions within. Extensive adhesions to the chest wall often cause deformities of the chest, and the pericar- dium, heart, and other mediastinal structures may be drawn from their normal positions. In rare cases the epithelium of the alveoli and finer bronchioles proliferates, and later undergoes a certain amount of fatty degenera- tion, giving rise to an appearance not unlike caseation. In still other cases necrosis, suppuration, and cavities (non-tuberculous) are observed. Microscopically. —In the beginning stages round-cell infiltration and connective-tissue proliferation may be seen around the foreign particles in the septa, and a certain amount of catarrhal inflammation 36 562 A TEXT-BOOK OF PATHOLOGY may be present in the alveoli. Sharp-edged particles often occasion small hemorrhages. In the later stages dense sclerotic tissue charac- terizes the process. Proliferative inflammation of the epithelium of the alveoli may be present, but more often the cells undergo atrophy and disappear. Varieties.—Certain varieties, dependent upon the kind of dust inhaled, have been described. The term anthracosis is applied to those instances in which coal-dust is the irritant. To a moderate extent this is seen at every autopsy in persons of adult age, but the cases in which conspicuous sclerosis has occurred from this cause are met with only in coal-miners and persons of similar occupations. The lung is of a marble- like or slate-like appearance, and the lymphatic glands around the bronchi are intensely pigmented. Svderosis is the designation of the cases of pneumonokoniosis due to iron-dust, as seen in grinders, founders, etc. Chalicosis is the term applied to the form due to stone-dust, as seen in potters, marble-cutters, etc. The variety of pigment may be distinguished by microchemical re- actions. 2. Secondary fibrous pneumonia sometimes occurs after croupous or catarrhal pneumonia, or atelectasis, and in these cases appears in the form of uniform or localized indura- tion of the pulmonary structure. It is due to reactive inflammation of the septa, causing thickening of the latter, as well as proliferation within the alveolar exudate. Similar reac- tive fibrous change is seen in some cases of caseous pneumonia, and in ; : . chronic phthisis the cavities are quite eS ee eal generally walled by fibrous tissue. Finally, chronic congestion of the lung, such as occurs in valvular diseases of the heart, particularly mitral disease, frequently leads to diffuse sclerosis of the lung. Such cases are distinguished by dilatation of the veins and by hematogenous pigmen- tation. 3. Pleurogenic fibrous pneumonia is an occasional consequence of chronic pleurisy. The lung presents on section dense trabecule of fibrous tissue, which extend from the thickened and sclerotic pleura deep into the pulmonary structure (Fig. 244). +. Peribronchial and perivascular fibrous pneumonia may be asso- ciated with the pleurogenic form, or the overgrowth of connective tissue around the bronchi and vessels may start at the root of the lung and extend toward the periphery. The latter form has been described by some observers as especially liable to result from syphilis. More moder- tao DISEASES OF THE RESPIRATORY SYSTEM 563 ate peribronchial and perivascular fibrous pneumonia occurs in asso- ciation with other forms, as the pneumonokonioses and secondary fibrous pneumonias, but in these cases it is but a minor part of the process. Congenital Syphilitic Pneumonia.—A form of productive pneumonia, as distinguished from fibrous pneumonia in the strict sense that the latter is characterized by formation of sclerotic fibrous tissue, is met with in congenital syphilis. This is the pnewmonza alba of some writers. Spiro- chete pallide are present in countless numbers. It is characterized by great proliferation of round and irregular connective-tissue cells, with more or less multiplication and degeneration of epithelial cells in the alveoli and bronchioles. The lung is solid, airless, and white in color (white pneumonia). Gummata may be associated. Purulent Pneumonia Definition.—Purulent pneumonia is an acute form of pneumonia in which the exudate undergoes purulent softening, usually caused by the pus producing cocci. Pathologically, it is characterized by purulent and hemorrhagic exudation in the connective tissue, lymphatic channels, or terminal bronchioles and alveoli; and clinically it is marked by evidences of intense septic infection as well as by great pulmonary embarrassment. This subject is given a separate heading by reason of its clinical rather than pathological importance, as the dominant factor is septicemia. The infection in purulent pneumonia may reach the lungs through the bronchi (bronchogenic), the blood-vessels (hematogenic), or the sub- pleural lymphatics (pleurogenic or ly mphogenic). Bronchogenic purulent pneumonia has already been referred to in the description of fibrinous pneumonia and catarrhal broncho- pneumonia. It is particularly frequent in the latter, in some cases of which considerable purulent exudation may be seen in the alveoli or, in the form of small purulent collections, in the intervesicular septa. The pathological changes are those of catarrhal pneumonia, with an excessive infiltrate of polynuclear leukocytes. These are instances of intense infection, and the majority of such cases are due to the Strepto- coccus pyogenes or to staphylococci. The pneumococcus may, however, be found alone. The most decided purulent bronchopneumonia is seen in instances of aspiration pneumonia secondary to a suppurative process in the upper respiratory passages, in which particles of infective material are inspired and lodge in the bronchioles. Purulent pneumonia is rarely met in the course of fibrinous pneu- monia, but sometimes occurs as a terminal condition. Abscesses of con- siderable size may be formed. Hematogenic purulent pneumonia is secondary to suppurative or gangrenous processes in other parts of the body, and is a manifestation of pyemic infection. It is frequent in puerperal septicemia, in suppura- tive osteomyelitis, and like conditions. The micro-organisms are 564 A TEXT-BOOK OF PATHOLOGY carried by the veins to the right heart, and may first set up malignant endocarditis, from which embolism takes place, or they may pass directly through the right heart to the lungs. As a rule, the micro- organisms in question are either streptococci or staphylococci; but in certain specific infections (as typhoid fever) the specific organisms may alone occasion purulent pneumonia. When large embolic masses reach the lungs occlusion of larger branches of the pulmonary artery occurs and hemorrhagic infarcts are formed. In the earliest stages these appear as more or less well-circum- scribed areas of hemorrhagic infiltration of dark-red color. Very soon change of color occurs, and the foci alter to a grayish, then a.yellowish, color, and finally liquefy, forming suppurative cavities, with irregular walls. The lesion at this stage constitutes what clinicians describe as abscess of the lung, and though such abscesses may result from fibrinous pneumonia or other conditions, the most frequent variety is that follow- ing embolism or thrombosis of the pulmonary artery. The tissue around the abscess is intensely engorged and edematous, and not rarely quite hemorrhagic. Microscopically, the lesion in the earlier stages presents the appearances of a catarrhal and hemorrhagic pneumonia. The abscesses frequently break into the bronchi and discharge their contents; more rarely rupture into the pleural sacs occurs. The pleura itself is intensely inflamed over the embolic areas, and, as a rule, is covered with fibrinopurulent exudate. Extensive purulent pleurisy (empyema) may occur. When the micro-organisms reach the lung in'a more disseminated manner they pass at once to the smaller arterioles and capillaries. The organisms circulating in the blood are, in all probability, single, but when they meet the intricacies of the pulmonary capillary network they are arrested. The oxygen present favors agglutination of bacteria, especially of the pneumococci. The swelling of the vascular endo- thelium by toxic agencies, in all general infections, favors the settling of bacteria. Embolic infarcts are wanting in such cases, but there is diffuse serous, hemorrhagic, catarrhal, and purulent exudation, which causes consolidation of a somewhat gelatinous character. Small foci of suppu- ration (miliary abscess) may be seen, and the purulent process may vis- ibly extend to neighboring parts of the lung along the lymphatic vessels. Terminations.—In either of the above forms, the localized embolic or the diffuse, necrosis or gangrene of the pulmonary tissue may occur. Occasionally recovery takes place by absorption of the purulent exu- date or by its discharge. As a rule, the disease is fatal. - Pleurogenic purulent pneumonia follows intense pleurisy, usually of purulent type. Infection of the subpleural lymphatics first ensues, and later the purulent process extends into the lung within and around these vessels (purulent lymphangitis and perilymphangitis), in the form of yellowish streaks or bands, which surround the veins and bronchi and follow the interlobular fibrous tissue in various directions. The lobules of the lung may be so pushed apart that the term pneumonia DISEASES OF THE RESPIRATORY SYSTEM 565 desiccans is quite applicable. The proper substance of the lung adjoin- ing the paths of purulent invasion, and under the pleura, frequently shows the same form of hemorrhagic and purulent pneumonia as occurs in the diffuse hematogenic form. Associated Lesions.——Widespread pyemic and toxic lesions are often found in association with purulent pneumonia, but they are often merely coincident results of the same primary disease to which the pneumonia owed its origin, rather than the consequences of the purulent pneumonia itself. Secondary infections may, however, occur, such as malignant endocarditis of the left side of the heart, septic nephritis, and the like. GANGRENE Gangrene of the lung results from the action of putrefactive micro- organisms in necrotic areas of the lung tissue. It may be the conse- quence of direct extension of carious conditions of the ribs or other adjacent bony structures through the pleura into the lung, or of the extension of necrotic processes from ulcers or cancerous disease of the . -esophagus or stomach. In other cases the infective materials reach the lung through the inspired air, coming from ulcerative processes in the upper air-passages or from without. When foreign bodies lodge in the bronchi, or the latter are obstructed by the pressure of tumors or aneurysms, there may be, first, more or less congestion and pneumonic consolidation, followed by secondary infection and gangrene. In still other instances the infective material reaches the lung through the blood. Finally, gangrene is sometimes a terminal process in pneu- monia, tuberculosis, and hemorrhagic infarction of the lungs. Certain general conditions predispose more or less to it. Thus, in diabetic indi- viduals, congestions or pneumonia are prone to terminate in this way, and engorgement of the veins or passive hyperemia always renders the lung more liable. Pathological Anatomy.—Gangrene may appear as a circumscribed or diffuse process. In circumscribed gangrene more or less extensive areas of lung present a dark, reddish, brownish, or even greenish appearance, and are surrounded by a zone of intense congestion or of pneumonic consolidation, often of purulent or hemorrhagic type. The diseased part is soft, pultaceous, and foul in odor. Later it may break down into a putrid mass, and may discharge through the bronchial tubes, severe pulmonary hemorrhages sometimes occurring at the same time. The bronchi and the blood-vessels often escape the process, and may pass through the gangrenous area without being themselves materially affected; but usually the bronchi are penetrated, and the blood-vessels, after they become occluded by thrombosis, suffer the fate of the other tissues. The process may extend widely from a single focus, or react- ive inflammation may establish a fibrous capsule, sad after discharge of the gangrenous material through the bronchi, healing by the forma- tion of a scar may terminate the disease. Diffuse gangrene does not differ much in its general appearances, 566 A TEXT-BOOK OF PATHOLOGY but is less intense and, in general, more widespread. The affected area is of a dark-red or greenish-black color, soft and edematous, or some- times dry, and has a somewhat fetid odor, as in the circumscribed form. Spots of hemorrhagic infiltration and of softening, with formation of cavities, may be noted. The sputa in gangrene are mucopurulent, of a vellowish-gray or brownish color, and intensely fetid. When placed in a conical vessel they separate into three layers: the upper frothy, the lower puriform and brownish in color, and the middle layer more fluid and yellowish. INFECTIOUS DISEASES Tuberculosis Tuberculosis of the lungs is usually a local process at first, but in many cases becomes generalized by subsequent spread of the infec- tion. Sometimes the pulmonary disease is from the beginning only a part of a general tuberculosis. Infection of the lungs occurs through the bronchial tubes (broneho- genic tuberculosis), through the blood-vessels (hematogenie tuberculosis), or through the lymphatic system (lymphogenic tuberculosis). 1. The first of these three modes of infection is probably far more frequent than the other two combined. The tubercle bacillus, dissemi- nated by the drying of sputa or other infected discharges from tubercu- lous patients, is carried directly to the lungs in the inspired air or, more rarely, it may lodge in the pharynx, upper air-passages, or bronchi, and produce primary tuberculous lesions from which the lungs are second- arily affected. Immediate infection of the lungs is more frequent than the secondary form. 2. Hematogenic infection is clearly evident in cases in which a tu- berculous disease of some other part (as the bronchial glands, prostate,’ bones, etc.) has become generalized by entrance of the tubercle bacilli into the circulation and in which tuberculous lesions make their ap- pearance in various parts of the body, including the lungs. Sometimes the point of rupture of a tuberculous focus into a vein has been demon- strated. The bacilli entering the venous circulation are carried through the right heart to the lungs, and are, for the most part, arrested in them. When finely divided in the blood some may pass through the pulmonary circulation and may thus be distributed widely through the body. In many cases, however, the lungs arrest all the bacilli and be- come affected without general tuberculosis. Sometimes perhaps the lungs are infected through the vascular channels without pre-existing lesions elsewhere. This may occur when tubercle bacilli traverse the mucous membranes and enter the circulation without causing a primary lesion at the portal of entrance. How frequently this may happen cannot very well be estimated, but many facts speak in favor of its not infrequent occurrence. Tuberculosis of the mesenteric glands without intestinal lesions is not uncommon, and cannot be explained DISEASES OF THE RESPIRATORY SYSTEM 567 except on the assumption that the bacilli passed through the mucosa and into the lymphatics without causing a lesion at the portal of en- trance. Other facts (as, for example, the occurrence of primary tuber- culosis of bones) indicate that the bacilli may be distributed widely in the circulation without local lesions at the places where they entered the body. Lung tuberculosis can doubtless occur in the same way, and some authorities believe this a frequent mode of infection. In view of the demonstrated intercommunicability of human and bovine tubercu- losis, the possibility of pulmonary infection from the consumption of tuberculous meat and milk and the passage of the bacilli through the mucosa of the digestive tract is apparent. In some cases of hematogenic tuberculosis the bacilli gain entrance to the blood in an indirect. manner, as, for example, when a lesion of the abdominal or thoracic lymph-glands penetrates the thoracic duct. The bacilli carried in the lymphatic stream pass through the thoracic duct and eventually reach the blood and are disseminated in the lungs and other organs. Localized hematogenic tuberculosis of the lungs may occur when an old tuberculous lesion of the lung or a caseous bronchial lymph-gland penetrates a branch of the pulmonary artery and thus disseminates bacilli in the lungs. This mode of occurrence of the disease in the lung is rarely observed. 3. Lymphogenic infection of the lungs is secondary to tuberculous pleurisy, tuberculous bronchial lymphadenitis, mediastinitis, ete. In these cases the pleural and subpleural lymphatics become infected and the process spreads along these channels to the lungs. A combination of the aérogenic and lymphogenic routes is possible. It is believed that tubercle bacilli may settle on the mucosa of the upper air- and alimentary passages, be carried thence to the regional lymph- nodes, and finally to the mediastinal or bronchial glands, where they may involve the lung by extension or rupture. Still, again, the lymphatic channels may combine with the alimentary tract, and, as has been dis- cussed under Anthracosis and the Tubercle Bacillus, the organisms may reach the root of the lung by the lymphatic chain along the posterior midline of the body. This and the direct bronchogenic invasion form the principal infection tracts for Koch’s bacillus. Bronchogenic Tuberculosis Larger masses of infective material inhaled in respiration may lodge in the bronchi or larger bronchioles and set up tuberculous ulcera- tions, from which smaller particles may be secondarily aspirated into the finer divisions of the bronchial tree. Such an occurrence, how- ever, is extremely rare. More commonly the tubercle bacilli are in- haled in a state of extreme dissemination, and are not arrested until they reach the point of division of the terminal bronchioles into the alveolar passages. One of two results may occur at this point: either there is set up a limited area of caseous or tuberculous pneumonia, 568 A TEXT-BOOK OF PATHOLOGY or the bacillus penetrates between the epithelial cells without pro- ducing a definite intra-alveolar lesion and causes specific tuberculous changes in the peri-alveolar and peribronchial connective tissues (miliary tubercles). It has been the occasion of some dispute among _ pathologists to decide which of these processes is most apt to arise when the infection occurs through the bronchial tubes. Undoubtedly, both kinds of change may take place, and it seems likely that in most instances there is a mixture of the two forms. When the infective material is in great abundance and is particularly virulent, and in cases in which the individual is especially vulnerable, caseous pneumonia predominates over the formation of tuberculous nodules. On the other hand, a less abundant infection or greater resisting power on the part of the individual determines a greater liability to the formation of nodules and less likelihood of extensive caseous pneumonia. Whichever lesion, however, is primary, the other soon becomes associated. Thus, if the epithelia of the alveoli are first affected with production of caseous pheumonia, the peri-alveolar connective tissues are soon involved, and tubercles form 2 loco, or, by dissemination of the bacilli along the lymphatic channels of the peri-alveolar connective tissues, tubercles appear at some distance from the first lesion. The alveoli contiguous to such secondary tubercles may in the next place become involved in caseous pneumonia. When the primary lesion is a tubercle in the peri- alveolar connective tissue, the adjacent alveoli in the same manner suffer caseous pneumonia. Thus, the disease spreads through neighboring lobules and in time affects considerable areas of the lung. Degenerative changes soon make their appearance. The areas of pneumonia, which began as small foci or as larger areas of lobular tuberculous pneumonia, change their color from a grayish to a yellow- ish color and become completely caseated; while the secondary tubércles in the neighborhood, or those which were primarily formed, similarly become opaque and lusterless, and finally yellowish by caseation. The blood-vessels in caseous pneumonia or in the tubercles are inadequate to supply sufficient nourishment to the tissue. In the pneumonic areas this is due to proliferative changes in the intima and to direct pressure of the exudate, while in the tubercles it is due to hyaline and other forms of degeneration, with collapse of the walls. Coincidently with the process just described, round-cell infiltration and proliferative changes are manifest in the structures surrounding the diseased areas. In the case of the areas of caseous pneumonia, infiltra- tion and proliferation of the connective tissue of the septa, as well as proliferative changes in the blood-vessels of these parts, are observed. There is a wide variation in particular instances in the degree of these reparative processes, and in general it may be said that the more acute the disease, the more apt is degenerative caseation to take place and the less likely regeneration to occur. Similar overgrowth and infiltration may be seen around the tubercles, and in favorable instances the latter may eventually be completely encapsulated or converted into a fibrous nodule. In instances in which the reparative processes are very exten- DISEASES OF THE RESPIRATORY SYSTEM 569 sive there may eventually be a preponderance of connective tissue over caseous pneumonia or miliary tubercles. Varieties.—We may distinguish all of the forms of bronchogenic tuberculosis by the name of pneumonic tuberculosis, from the fact that the element of caseous pneumonia is always an important one, and. separates them sharply from hemogenic and lymphogenic tuberculosis, in both of which the formation of miliary tubercles predominates over other processes. It must, however, be remembered that in some cases of hemogenic tuberculosis the lesion may take the form of a localized pneumonic tuberculosis by reason of the fact that the first-formed miliary tubercles are soon obscured by a more extensive pneumonic process. Three forms of pneumonic tuberculosis are met with: the acute, which is frequently spoken of as acute caseous phthisis, or galloping consumption; the chronic, which is also known as chronic ulcerative phthisis; and the form in which fibrous overgrowth predominates, and which is, therefore, known as fibrous or fibroid phthisis. While typical instances of these forms are quite distinct, there is no sharp dividing line separating the groups, and individual forms merge insensibly one into the other. Acute pneumonic tuberculosis is more common in children than in adults. “Two elements play a part in its occurrence: first, a high degree of susceptibility; and, second, abundant infection with virulent bacilli. The latter may be derived from without the body by direct inhalation, or may come from the discharge of older caseous areas in the lungs which have broken into the bronchial tubes, or from some focus of tuberculosis in the upper air-passages. Pathological Anatomy.—This form of tuberculosis is lobular, but very frequently by confluence of the affected areas an entire lobe may be involved. Either the base or the apex may be first affected. On section the lung presents a more or less variegated appearance in the earlier stages, due to the formation of minute patches and lobular areas of caseous pneumonia having a grayish appearance, and the coincident congestion of surrounding portions of the lung tissue. Sections through the lung which cut a terminal bronchiole in a longitudinal direction show it more or less filled with cheesy exudate and surrounded by peri- bronchial caseation (Fig. 245). Transverse sections give the appearance of a section through a large tubercle or an aggregation of tubercles, but the lumen of the bronchiole may usually be discovered in the center or to one or the other side. Small miliary tubercles may be apparent in the edges of the pneumonic patches, and even for some distance around them, but the connective tissue involvement is more apt to appear as a diffuse infiltration along the peribronchial and perivascular lymph- atics than as distinct tubercles. As the process increases the lung tissue becomes more and more extensively involved and uniformly gray or yellowish and consolidated (Fig. 246). The cut section is generally somewhat granular in the earlier stages from admixture of fibrinous exudation in the alveoli; but later progressively increasing caseation and softening render the suihiee of section smooth and moist. Not infre- 570 A TEXT-BOOK OF PATHOLOGY quently complete destruction takes place and cavities are formed. These are usually small and present no marked tendency to the forma- tion of an organized wall, but appear simply as necrotic excavations with irregular, ragged outlines. The pleura over the surface of such a lung is usually inflamed and covered with more or less fibrinous or fibrinopurulent exudation, and not rarely with an abundant crop of tubercles. Sometimes a superficial lesion may rupture into the pleural cavity and cause pneumothorax or, later, pyopneumothorax. When the process is less active and the infection less abundant, con- fluence of the lobular areas is less likely to occur, and there are seen merely disseminated patches of cas- eous pneumonia scattered through various parts of the lung, which is, in general, more or less congested. In such instances, too, the evidences of reparative change are more de- cided. Complete encapsulation with subsequent calcification may ensue, or fibrous overgrowth may convert cS Se eee, Fig. 245.—Bronchogenic tuberculosis of Fig. 246.—Extensive bronchogenic the lung, showing the involvement of the tuberculosis (caseous pneumonia) of the tissues surrounding the terminal bronchioles _ base of the lung (Orth)). (Birch-Hirschfeld). the entire area into a cicatricial mass. If the cheesy area is simply en- closed with fibrous tissue, it may remain quiescent for a time, possibly for years, and subsequently penetrate the enclosing wall and occasion a fresh extension of the whole process. Chronic pneumonic tuberculosis is the ordinary form of pulmonary phthisis. It begins in the apices of the lungs in the great majority of cases, though children are as likely to be first affected at the bases as at the apices. The apices present areas of low resistance because of their short excursion of motion and the slow gaseous interchange. They are slightly less vascular than lower lung portions. DISEASES OF THE RESPIRATORY SYSTEM 571 While there is no doubt that chronic phthisis is usually due to infec- tion through the inspired air, it must be admitted that occasionally the onset of the process is due to infection through the blood or lymphatic channels (see p. 566). In the instances of the latter kind there may first be established a localized lesion which caseates and penetrates a bronchial tube, discharging its contents, and thus leading to widespread bronchogenic infection. The further development of the disease takes place in several distinct ways (see below). Pathological Anatomy. — When there has been a pre-existing bron- chitis, adhesion of the bacilli may occasion tuberculous bronchitis with ulceration and secondary involve- ment of the ‘surrounding tissues. More commonly the bacilli lodge , in the finer bronchioles or alveo- | ' lar passages, as in acute pneu- / monic phthisis, and give rise to ' lobular areas of caseous pneumonia, * surrounded by tubercles which are formed along the course of the ~ lymphatic vessels leading out from the first-formed caseous foci. There oe ene ee is a tendency to a constant in- of lung communicating with bronchus, as ‘ shown by rod (from a specimen in the col- crease of the area of disease by the lection of Dr. Allen J. Smith). discharge of caseous material into contiguous bronchi and its aspiration into other parts of the lung, and also by dissemination of the infection along the lymphatic vessels traversing the connective tissue around the blood-vessels and bronchi. Section through the lung discloses more or less consolidated tissue of an opaque, grayish or yellowish appearance, in which the bronchi may be seen as open spaces or filled with mucopurulent liquid. Little distinc- tion between caseous pueumonia and the tubercles can be made in the center of such an area, but at the edges, where the process is seen in the earlier stages, such distinction may be possible. At times areas of a fibrinous or cellular pneumonia are formed. These differ from caseous pneumonia in presenting a granular or gelat- inous appearance, and in their liability to partial or complete resolu- tion. The process is serofibrinous and cellular in character, and often, though not always, due to secondary infections. The same tendencies to degeneration and softening, on the one hand, and to the processes of repair, on the other, are seen in chronic pneumonic phthisis as are apparent in the acute form. There is the difference, however, that these changes are less rapid, and that, asa tule, proliferation of connective tissue with the formation of fibrous tissue is more pronounced than in the acute disease. 572 A TEXT-BOOK OF PATHOLOGY The degenerative and necrotic processes lead to a most characteris- tic lesion of tuberculous lungs—the cavity (Fig. 247). Cavities are formed either through the dilatation of the bronchioles (bronchiectasis), due to their ulcerated and weakened condition and to the pressure of retained secretions, with subsequent ulceration and breaking down of the sur- rounding caseous tissue; or, on the other hand, to liquefaction of caseous areas not in connection with a bronchial tube. In the latter case, how- ever, communication with the bronchi is frequently established by ex- tension. A single cavity may grow larger and larger by constant ulcera- tive processes, in which not alone the caseous tuberculous degeneration Fig. 248.—Chronic phthisis pulmonalis with cavities of left lung; note communicating cavities near apex, disseminated miliary tuberculosis of right lung (from a specimen in the collection of Dr. G. W. Norris). takes a part, but also active ulcerative changes dependent upon mixed infection through inspiration of pyogenic organisms. As a rule, how- ever, larger cavities are formed by the confluence of separate smaller ones, and there may be found a series of excavations communicating more or less extensively with each other (Fig. 248). The cavity, or vomica, con- tains a variable amount of ill-smelling, putrid secretion, consisting of broken-down cheesy matter, pus-cells, degenerated epithelial cells and fibers of elastic tissue, and containing tubercle bacilli, pyogenic organisms, and occasionally mould fungi. The walls of the cavity are generally: formed by reparative fibrous proliferation, and are covered DISEASES OF THE RESPIRATORY SYSTEM 573 with a “pyogenic membrane,” usually darkly pigmented. The inner surface is very rough and ribbed by projecting bands. The latter represent the trabeculee and blood-vessels of the lung tissue, which have resisted ulceration more obstinately than the surrounding structure of the lung. This resistance may continue to such an extent that the blood-vessel is left as a cord passing directly through the center of the cavity; but, as a rule, the lumen of the vessel is soon obliterated by thrombosis and the vessel itself destroyed. Not infrequently examina- tion of the blood-vessels in the wall of the cavity or passing through it show small aneurysmal dilatations which result from the weakening of the wall by the surrounding necrotic process and from the pressure of the blood within. It is from aneurysms of this character that the large and often fatal hemorrhages of the later stages of tuberculosis take place, though hemorrhage may also occur directly from erosion of blood-ves- sels without aneurysmal dilatation. The smaller hemorrhages of the early stages of phthisis, which occasion only a streaking of the sputa with blood, are due to early erosion of small vessels of the bronchioles or to capillary ruptures dependent upon congestion. The reparative processes (connective-tissue formation) in chronic pneumonic tuberculosis may cause cessation of the disease when only limited areas of the lung are affected, by surrounding and thus encap- sulating the diseased parts, or by complete fibrosis of the areas. These changes are dominant in the form next to be described. Fibroid Phthisis——The reparative or fibrous processes which tend to counteract caseation and destruction may begin before cavity forma- tion or after it. When beginning in the earlier stages the caseous areas will be found to present a capsule of more or less well-developed fibrous tissue, which may completely surround and separate them from the neighboring tissue of the lung. The capsule tends to contract and shrink, and the caseous material within may become completely cal- careous. In this manner a limited focus of tuberculosis of the lungs not infrequently becomes completely arrested. When the capsule is not so firm, after a period of quiescence or latency extending over even a number of years, fresh extension may begin, the capsule may be per- forated, and acute pneumonic phthisis may be established, or the tuber- culous process may extend more slowly through the contiguous areas as chronic ulcerative phthisis. When the tuberculous lesion is limited and consists of minute foci not too closely conjoined, the fibrous tissue proliferation may intersperse the lesion so that the whole is converted into sclerotic tissue instead of being merely surrounded by a capsule. The fibrous capsules surrounding the cavities, which have already been alluded to, may be of varying prominence. In case of small vomice with pronounced fibrous walls the contraction of the latter may almost obliterate the cavities, leaving only narrow and distorted spaces containing a small amount of putrid material (cicatrices fistuleuse of Laennec). Complete healing of a cavity of notable size probably never occurs. When the excavations are of large size the reparative processes consist simply in the formation of a thick wall of fibrous tissue, which 574 A TEXT-BOOK OF PATHOLOGY prevents the further extension, for a time at least, of the tuberculous process. Complications in Bronchogenic Pneumonia.—Of first importance in tuberculosis of the lung is the condition of the pleura. In the acute pneumonic form the pleura adjoining the diseased areas is generally more or less inflamed and may present considerable fibrinopurulent exudation, as in croupous pneumonia. Serous or seropurulent exuda- tion may likewise be present, and eruption of miliary tubercles in the pleura is not unusual. The same processes may occur in chronic pneu- monic tuberculosis or chronic phthisis. More commonly there are found simply fibrous adhesions binding the one surface of the pleura to the other, especially at the apex. Extension of the tuberculous process may also take place directly upward along the air-passages, and is due, for the most part, to direct infection by the sputa. There may thus occur tuberculous ulceration of the larger bronchi, of the trachea, of the larynx, or of the pharynx. When the sputa are swallowed, as is especially likely to happen in children, or in adults during sleep, intestinal tuberculosis is apt to occur. Finally, dissemination of the tuberculous disease through the blood is frequent. A caseous area adjacent to one of the veins may penetrate the lumen of the vessel and discharge its contents into the circulating blood, or may first occasion tuberculous proliferation in the intima of the vein or infectious thrombosis, from which the blood is secondarily infected. There results general miliary tuberculosis, the tubercles occurring especially in the spleen, the liver, the kidneys, the choroid coat of the eye, or in the membranes of the brain or other serous membranes. Acute pneumonia may accompany either acute or chronic pneu- monic tuberculosis, and certain authors insist that in practically all cases there is more or less mixed infection. This is probably not the case, but complicating pneumonia is undoubtedly frequent. In most of such cases localized patches of catarrhal bronchopneumonia are seen between the caseous lobules; but sometimes a frank fibrinous consolida- tion may occupy the lower lobe of a lung in which the upper lobe pre- sents beginning tuberculosis. Quite frequently there are small areas of pneumonic consolidation of fibrinous character in the lobe which is itself the seat of tuberculous involvement. Toward the end of life there is usually extensive edema of the bases and posterior portions of the lungs. The heart has interesting relations with tuberculosis of the lungs. Early writers called attention especially to the fact that phthisical sub- jects frequently present unusual smallness (hypoplasia) of this organ, and later attention was directed to the fact that congenital stenosis of the pulmonary orifice predisposes to tuberculosis of the lungs. Some have claimed that there is an antagonism between cardiac disease and tuberculosis. This view is not well founded, though it is probable that the chronic congestion of cardiac disease renders the lung somewhat less vulnerable to tuberculous infection than the normal lung. Where DISEASES OF THE RESPIRATORY SYSTEM 575 there is a long-standing tuberculous consolidation, hypertrophy, espe- cially of the right ventricle, is likely to occur. Tuberculous pericarditis may be found in association with tuberculous pleurisy; and tubercles may also, though much more rarely, be found upon the endocardial lining. The latter are due to infection through the blood. Hematogenic Tuberculosis This form occurs when a focus of tuberculous disease ruptures into a blood-vessel and the infective contents are disseminated in the cir- culation. As a rule, hemogenic tuberculosis of the lungs is only a part of a general tuberculosis of the entire body. The points from which the primary infection may take place are, of course, numerous, but caseous lymph-glands of the cervical or peribronchial group, or old foci of tuberculosis at the apex of the lung, are perhaps the most fre- quent. The organs and structures of the body likely to be involved by general hemogenic tuberculosis are the spleen, the liver, the kidney, the choroid coat of the eye, the meninges, and, more prominently than any other organ, the lungs. In the rare cases in which rupture of an old pulmonary focus has occurred into one of the branches of the pul- monary artery, only one lung, or but a part of a lung, may be involved. Some writers think that intimal tubercles of the pulmonary artery and its branches are the sources of continued infection of the lungs. Atten- tion has been previously directed to the probability that in some, if not many, cases what appears to be bronchogenic pulmonary tuberculosis is, in reality, hemogenic, the bacilli having entered the body at some obscure point without causing a lesion at the portal of entrance, and having produced a localized lesion in the lung instead of the more typical disseminated tuberculosis usually found in hematogenous infections. Pathological Anatomy.—The pathological feature of importance in hematogenic tuberculosis is the formation of miliary tubercles. These appear as gray or translucent areas, the size of millet seeds, around and involving the terminal arterioles or capillaries in the intervesicular septa. At first they may be so small that the naked eye scarcely dis- covers them, and they are so translucent that oblique light is necessary to make them appear to view. Later, they increase in size and become more grayish and opaque. Microscopically, there are the well-known characteristics of the miliary tubercle embedded in the perivascular connective tissue. These tubercles, however, are prone to distinguish themselves from the characteristic tubercles seen elsewhere by their more irregular outline and the more irregular arrangement of their com- ponent histological elements. When the tuberculous process is particu- larly rapid and virulent, giant cells are few in number, and the tubercle 1s composed mainly of proliferated connective-tissue cells of the ordi- nary type, some epithelioid cells, and round infiltration cells, all of them more or less granular, and the entire nodule surrounded by a zone of caseous, catarrhal, or even hemorrhagic pneumonia of the contiguous alveoli of the lung (Fig. 249). The tubercles are rarely seen in the stage 576 A TEXT-BOOK OF PATHOLOGY of advanced necrosis, but this may take place in instances of a more chronic course in which the bacteria are admitted to the lungs slowly Fig. 249.—Miliary tuberculosis of the lung, showing two tubercles with degenerated centers. Fig. 250.—Hematogenic tuberculosis, showing many scattered miliary tubercles and several clusters (modified from Bollinger). and perhaps in a state of lesser virulence than common. In those in- stances of what may be termed “chronic miliary tuberculosis” there may be a considerable amount of caseation of the tubercles, and the patches, DISEASES OF THE RESPIRATORY SYSTEM 577 as a rule, become decidedly larger than in the ordinary acute form (Fig. 250). An explanation of this form of chronic miliary tuberculosis has been offered by certain authors, who hold that these are instances of in- fection through the thoracic duct and blood-vessels. The infective material enters the thoracic duct from caseous lymphatic glands in the abdomen or thorax, and is discharged with the lymph into the veins in a gradual manner, only a little being allowed to pass at a time. The ordinary and typical acute miliary tuberculosis presents itself clinically as an acute infectious disease, running its course rapidly and causing early dissolution. ‘The disease is rather a general toxemia than a local process, and toxemic changes may be present in various organs, such as occur in other infectious and toxemic diseases. The heart, liver, the kidneys, and, in general, the parenchymatous structures are prone to become degenerated, and when the febrile infection continues there may be extensive fatty degeneration. In addition to the eruption of miliary tubercles in other organs, to which allusion has already been made, there is also involvement of the pleura which belongs properly to the pulmonary process itself, and is simply a continuation of the same infection which gave rise to the pulmonary involvement. Lymphogenic Tuberculosis It is possible for tuberculous infection of the lungs to occur through the lymphatic channels in several ways. In speaking of acute miliary tuberculosis, particularly of the more gradual type, reference was made to the fact that infective material is sometimes carried by the thoracic duct from the lymphatic glands of the abdomen and posterior medi- astinum, as well as possibly from carious thoracic vertebre to the blood- vessels, and thence distributed through the blood to the lungs as a hema- togenic infection. Direct infection, however, through the lymphatic channels may take place. Thus, tuberculous pleuritis, either primary or secondary to tuberculous disease of the vertebre or ribs, sometimes spreads directly into the lung through the lymphatic vessels traversing the interlobular connective tissue; and in cases of caseous tuberculosis of the peribronchial glands the infective material may be conveyed into the lungs either by a reversal of the current of lymph in the vessels run- ning to these glands or by direct extension along the lymphatic walls. A form of lymphogenic tuberculosis of the lungs may also be referred to in which caseous lymph-glands directly perforate the lung tissue, but the actual dissemination of the process in the lungs in these cases is usually through the bronchial tubes into which the bacilli gain entrance. Pathological Anatomy.—It is characteristic of lymphogenic tuber- culosis to find small nodular areas which microscopically are seen to be more or less characteristic tubercles. These are scattered along the lymphatic vessels running in the interlobular septa or surrounding the blood-vessels and bronchi. In the instances of lymphogenic tuber- culosis secondary to pleuritis suppurative lymphangitis and perilymph- angitis (see Pneumonia) are not infrequently associated. 37 578 A TEXT-BOOK OF PATHOLOGY SYPHILIS It has been the occasion of much dispute whether the many forms of pulmonary disease attributed to this cause can be really so classified. Among such doubtful cases are certain pulmonary consolidations in secondary syphilis, and lesions of the lungs in old syphilitics that have the superficial appearances of tuberculosis. Undoubtedly some of the conditions attributed to syphilis are cases of tuberculosis, or of some other form of pulmonary disease. But there are other varieties which can unquestionably be spoken of as syphilitic. Among these are the diffuse infiltration of the newborn and the tertiary gummata. Diffuse syphilitic infiltration of the lungs is occasionally met with in the newborn. As a rule, infants showing this are stillborn. It manifests itself as a more or less lobar consolidation and induration of the lung tissue. On section, the lung is light gray or almost white in color, and completely airless, so that the name pneumonia alba, given by older writers, was highly significant. Microscopically, there are seen widespread round-cell and spindle-cell infiltration and prolifera- tion in the interalveolar and interlobular connective tissues, with more or less compression of the bronchioles and alveoli. The epithelium of the latter may be somewhat proliferated and desquamated, and shows a tendency to fatty degeneration and necrosis. In some instances the de- generative changes do not take place, and the proliferated epithelium of the alveoli is massed within the alveolar lumen, and is, for the most part, of a cuboidal character. The blood-vessels commonly show proliferation of the adventitia as well as of the intima, and may be completely obliterated. According to Birch-Hirschfeld, syphilitic fe- tuses of the sixth or seventh month sometimes present limited disease of this nature, and of such distribution that it is recognized to begin as a peribronchial and peri-alveolar infiltration of lobular distribution. In this type Spirochete pallide are very numerous. | Syphilitic gummata may be associated with the diffuse form of congenital syphilis, or may be present in the newborn without the latter. Gummata are occasionally seen in adults. They are present most frequently near the root of the lung beneath the pleura, but may be scattered through other parts of the organ. As a rule, the number is limited. They appear as more or less rounded nodules of a grayish to yellowish color, with more or less fibrous overgrowth sur- rounding them and often radiating from them into the surrounding lung tissue. Central necrosis may proceed to such extent that cavities are formed. Occasionally the contents of a gumma may be discharged through the bronchial tubes, or they may be absorbed and a cicatricial pucker- ing of the lung tissue may mark the place of the former disease. Spiro- chete pallide can be found, but are not numerous. Syphilitic fibrous induration of the lung, so-called, has been described, and it seems likely that some of the cases embraced in the description are really syphilitic in nature. The process begins, as a rule, DISEASES OF THE RESPIRATORY SYSTEM 579 at the root of the lungs, from which it radiates through the tissue toward the pleura. The fibrous tissue, for the most part, surrounds the bronchi and blood-vessels (Fig. 251). In another group of cases the process spreads from the pleura and occasions the formation of dense bands of fibrous tissue passing inward into the lung structure. In still other cases the fibroid overgrowth is so diffuse that the appearance presented resembles so closely that of pneumonokoniosis that is is practically in- distinguishable. It is quite probable that many instances _in which appearances such as these are met with are not at all syphilitic; but Fig. 251.—Syphilis of lungs: a, a, Thickened alveolar walls or stroma; }, partly longi- tudinal section of bronchus; c, uninfiltrated alveoli; d, new connective tissue infiltrated with small round cells; e, cells lining alveoli; f, artery showing thickened walls; g, des- quamated lining cells (Linsley). the occurrence of changes of this description in association with gum- mata, and, again, the occurrence of such changes without gummata in undoubtedly syphilitic individuals, make it likely that some at least are of this origin and nature. Spirochete pallide are exceedingly difficult to find, and only can be found, indeed, where there is a frank infiltrate among the fibrous tissue. GLANDERS Glanders occasionally affects the pulmonary tissue, the infection taking place either by inhalation from ulcerated lesions in the nose or other portions of the upper air-passages, or, more rarely, by distribu- 580 A TEXT-BOOK OF PATHOLOGY tion of the bacilli through the blood. The lesions are of two kinds. There may be merely a grayish or purulent infiltration of a diffuse character, with the formation of abscesses and often with associated hemorrhagic infiltration. Considerable areas of the lung may be con- solidated in this manner, or the process may be localized and lobular. In other cases nodular patches varying from the size of a hemp-seed to that of a pea are seen in various parts of the lung. These consist of masses of round cells, and show an early tendency to degeneration. More or less hemorrhagic and catarrhal inflammation of the alveoli sur- rounding these nodules may be present. ACTINOMYCOSIS Actinomycosis is a rare affection of the lungs. It may result from the direct extension of actinomycosis of the lymphatic tissues and cellular structures in the anterior or posterior mediastinum, when there are formed in the pulmonary tissue fistulous necrotic tracts containing more or less cheesy and purulent material, in which the characteristic yellowish actinomycosis granules arefound. The latter, on microscopical study, show the actinomyces. The infection may also take place by a gradual descent of the process from the mouth or upper respiratory passages along the trachea and bronchi to the lung; or, more commonly still, by aspiration of the infective agents. In the latter cases nodules consisting of round cells are formed, and present themselves as grayish or grayish-red patches varying in size from that of a pea to that of a cherry, and showing a decided tendency to fatty degeneration and purulent softening. The surrounding lung tissue is commonly con- solidated, and presents the appearances of purulent and catarrhal or even hemorrhagic pneumonia. In many cases there is also a manifest tendency to productive changes, which lead eventually to the formation of more or less fibrous tissue within the alveoli and in the interalveolar and interlobular connective tissues. Not rarely this indurative process completely surrounds areas of degeneration and softening. Infection with streptothrix follows the same general character. TUMORS ° The lungs are, comparatively speaking, rarely the seat of tumors, though a variety of both primary and secondary growths occur. Connective-tissue Tumors.—Small nodular fibromata have occa- sionally been observed scattered through the lungs in the peribronchial connective tissue, and a few instances of similar nodules of lipoma are recorded. Chondroma is more common than either of these, and doubtless takes origin from the bronchial cartilages. Secondary chon- dromata have been observed in cases of chondroma elsewhere. True osteoma is rare, but more frequently ossification of sclerotic areas is met with in instances of pneumonokoniosis. Sarcoma is the most frequent connective-tissue tumor of the lungs. DISEASES OF THE RESPIRATORY SYSTEM 581 The lymphosarcoma form may originate in the lymphatic glands sur- rounding the bronchi at the roots of the lungs, from the lymphatic nodes surrounding the smaller bronchi within the lungs, from the lymphatic vessels themselves, or from the subpleural or other con- nective tissue of the lung itself. Primary sarcoma is less common than secondary. In one form it presents itself as rounded masses of grayish or yellowish color lying around the bronchi in the root of the lung (Fig. 253). On section through this it is seen to consist of more or less en- larged and transformed lymphatic glands, and there may be secondary nodules scattered through the lung. This form of sarcoma is particularly common in pneumonokoniosis, as seen in the fibroid lungs of the cobalt-miners of Schneeberg. Primary sarcoma may also be of the form called endothelioma, arising either within the lung tissue or from the pleura. The lymphatic vessels in the peribronchial tissue become filled with proliferated cells, and their ramification may be distinctly visible on section as a network traversing the pul- monary tissue. Primary sarcoma of the spindle-cell or round-cell variety may spring from the subpleural connective _ tissue. Giant-cell sarcoma has been observed. Secondary sarcoma is extremely common. It is seen in nearly all instances in which metastasis has occurred from a primary growth in any part of the body. In these cases there are found well-defined nodules of varying size, situated for the most part near the surface of the lung (Fig. 25+). They are whitish in color and tend to soften. The lung tissue between may be congested, and there may even be pneumonic con- solidation. Secondary sarcoma of the lung may also occur from direct extension of mediastinal sarcoma or of sarcoma in other fe 7 Fig. 252. — Sarcomatosis of of the surrounding structures. An interest- tung, hematogenous in origin, ] . howing distribution from hilus. ing type of secondary involvement of the *"0W™8 GStipunontrem lungs by sarcoma or a process resembling sarcoma occurs in “malig- nant lymphoma” or “lymphadenoma,” either with or without leu- kemia. These may be considered as allied to generalized lympho- sarcoma. The lungs are found to contain small nodules, consisting of round cells without stroma or embedded in a more or less reticular matrix of stellate and spindle cells. Epithelial Tumors.—Carcinoma is practically the only form to be considered, though adenoma of the lung has been described. Carcinoma of the lung is certainly less frequent than was formerly believed, sarcoma 582 A TEXT-BOOK OF PATHOLOGY Fig. 253.—Lymphosarcoma of the postbronchial glands, invading the lung; the lung is divided by a long incision and the halves laid open. Ta ee ER, Fig. 254.—Secondary sarcomata of the fun the primary growth was attached to the pleura. having been confused withit. Massive cancer may start from the mucous glands of the larger bronchi near the root of the lung. The DISEASES OF THE RESPIRATORY SYSTEM 583 Fig. 255.—Secondary metastatic lymphosarcoma of lung (from a specimen in the collection : of Dr. Allen J. Smith). Fig. 256.—Metastatic carcinoma of lungs from a primary pyloric growth (photograph by Dr. Ayer). tumor is irregular, soft, and tends to ulcerate in the center, forming cavities. Secondary nodules within the lung tissue are seen along the 584 A TEXT-BOOK OF PATHOLOGY lymphatic vessels surrounding the bronchi. Primary carcinoma may also start from the epithelium of the finer bronchial tubes. The pro- liferation soon penetrates the wall of the bronchus and extends along the lymphatic vessels in the peribronchial connective tissue. In this manner bands of new growth are seen traversing the lung. Occasionally squamous-celled carcinoma may originate in the epithelium of the terminal bronchioles and alveoli. Secondary carcinoma of the lungs is less frequent than secondary sarcoma. It may occur by metastasis from cancer elsewhere, and in these instances the appearance of the nodules is much the same as that of sarcoma. Secondary cancer of the lung may also result from exten- sion of esophageal carcinoma or of cancer of the breast penetrating the thoracic walls and pleura. Finally, in carcinoma of the upper respira- tory passages or of the mouth, inhalation of cancerous particles may lead to secondary nodules in the lungs, associated at times with areas of bronchopneumonia. Cysts.—Congenital cysts have been described, but they are probably merely dilatations of the bronchi. (See Bonchiolectasis.) | Adeno- matous proliferation of the epithelial lining of such dilatations may take place. Dermoid cysts are rarely encountered. They may dis- charge through the bronchial tubes. PARASITES Besides the specific and pathogenic micro-organisms that have been referred to as occurring in tuberculosis, pneumonia, and other infec- tious diseases, various forms of bacteria and mould fungi are met with as accidental and non-specific parasites. Such micro-organismal collec- tions are most frequent in areas of gangrene, in degenerated infarcts, and in dilated bronchi or tuberculous cavities. Sarcine, leptothrices, streptothrices, and several varieties of aspergillus have been noted. The general term Pnewmonomycosis aspergillina is applied to the occurrence of the last-named mould fungi in the lungs. Sometimes they are so abundant that they are readily discovered in the sputa; and it is likely © that certain inflammatory conditions of the lungs are directly due to such organisms. The clinical course may suggest tuberculosis, and pathologically diffuse or irregular consolidation of the lungs may char- acterize such cases. (See p. 324.) Animal Parasites.—Of the lowest forms of animal life or pretozoa, the Monas lens, cercomonas, and paramecium have been observed. These are entirely accidental, occurring in cases of gangrene, putrid bronchitis, and similar conditions. The class of Vermes furnishes the more important parasitic affections of the lungs. The Paragonimus westermant is not infrequent in parts of Asia. It occasions serious hemoptysis. The Strongylus apri, echinococcus cysts, and Cysticercus cellulose are occasionally seen. Linguatula rhinaria has been observed. DISEASES OF THE RESPIRATORY SYSTEM 585 THE PLEURA Anatomical Considerations.—The pleura is a membrane composed of fibrillar connective tissue and elastic fibers, containing a rather abun- dant network of capillaries. It is lined on the surface with a single layer of flat endothelial cells, between which there are openings from the pleural cavity into the subpleural lymphatics. The latter form a rich network in the subpleural connective tissue and play an important part in the pathological processes affecting the pleura. It must be remem- bered that the two pleural surfaces are normally in apposition, that is, no cavity exists. They move over one another with the movements of the chest. CIRCULATORY DISTURBANCES Active Hyperemia.—This arises as the early stage of inflamma- tion or as the result of decrease in tension, such as occurs when fluid in the cavity is removed. Passive hyperemia occurs in various diseases interfering with the respiration, and still more intensely in cases in which there is pressure upon the azygos veins or diffuse intrathoracic pressure. Petechial hemorrhages may occur when the congestion is intense. They are particularly frequent and prominent in cases of death from suffocation, but are also seen in various disorders of the blood and hemorrhagic diatheses, such as pernicious anemia, purpura, and in- toxications of various kinds. Hemothorax is the term applied to the presence of free blood in the pleural cavity. It may be due to wounds of the chest wall, causing rupture of blood-vessels, to fracture of the ribs, and to rupture of aneurysms into the pleural sac. In some cases the etiology is obscure. If the pleura is in a healthy condition and secondary infection does not take place, more or less rapid absorption of the blood ensues. When infection occurs, secondary inflammations of the pleura and disorganiza- tion of the blood result. Hydrothorax, or dropsy of the pleural cavity, may be but a part of a general edema occurring in chronic kidney or heart disease. It is usually bilateral, and the fluid presents the ordinary characteristics of a serous effusion. Unilateral hydrothorax is, however, not infre- quent in cardiac disease attended with great enlargement of the organ. The hydrothorax in such cases is generally right sided, and is probably due, according to Fetterolf and Landis, to pressure by some dilated segment of heart upon the pulmonary veins which drain those from the visceral pleura. The pleura itself is not particularly disordered, but very frequently some opacity and loss of luster is noted, and there may be edema of the subpleural fibrous tissue. The lungs are pressed back- ward toward the root and against the spinal column, and may be con- siderably compressed. Unilateral hydrothorax may be due to pressure upon the veins of one side by tumors or aneurysm. A small amount of serous outpouring into the pleural sacs occurs quite commonly just 586 A TEXT-BOOK OF PATHOLOGY prior to death. The fluid of hydrothorax has the usual characters of transudates, low specific gravity, pale color, alkalinity, moderate pro- tein content, and very low cell content. Chylous effusion in the pleuree is due to obstruction or rupture of the thoracic duct or some large lymphatic channel, with the appearance of a milky opaque fluid containing fat-droplets. Hydrothorax causes compression of the lungs and displacement of the other adjacent viscera. The seriousness of the results are in pro- portion to the amount of effusion. Pneumothorax designates the presence of air in the pleural cavities. It may result from rupture of tuberculous vomice, gangrenous areas, softened hemorrhagic infarcts, or abscesses of the lungs, or rupture of emphysematous air-vesicles beneath the pleura, allowing egress of air into the pleural sac. It may also occur after an empyema has ruptured into the lung and established a fistulous communication between the pleural sac and the bronchioles. Very rarely it is due to a penetrating wound of the chest. The pleural sac may be more or less tensely distended with air; the lung collapses against the spine, is more or less grayish or brownish in color, indurated, and airless. The pleura itself may present no abnormality, and the air may be absorbed; but very frequently infection takes place, and purulent exudation from the pleura collects in the sac. The condition is then spoken of as pyopneumo- thorax. The neighboring organs are often greatly displaced, particularly the heart, the diaphragm, and the liver. In left-sided pneumothorax the heart may be pushed far to the right of the sternum, and when the right side is affected the liver may be pushed downward considerably below the ribs. The condition of the air inlet and outlet has some- thing to do with the outcome of the condition. If the fistulous channel from a lung cavity permits air only to pass to the pleura with inspira- tion, and does not permit its escape upon expiration, the accumulation will continue. The air, once within the cavity, may remain in about the original amount, or it may undergo variations when a free ingress and egress is afforded. Pneumothorax may be circumscribed by pleural adhesions, and then is termed “‘closed.” INFLAMMATION Inflammation of the pleura, or pleuritis, is designated by the clinical name pleurisy. Etiology.—It may result from local or from general causes. Among the local causes the most important are extension of inflammation from the lungs in the various forms of pneumonia, in gangrene and tuber- culosis; extension from pericarditis or mediastinal diseases, and extension from inflammatory affections of the spine, of the ribs, or of the chest walls. Less directly, peritonitis, hepatic abscess, and other abdominal affections may occasion pleuritis by extension, and in rare cases perfora- tion of esophageal or gastric ulcers, or abscess of the spleen or liver, may be the cause. DISEASES OF THE RESPIRATORY SYSTEM 587 In the group of cases due to general causes the pleural inflamma- tion is the result of infection or intoxication involving the pleura through the blood. Thus, in pyemia and septicemia, in rheumatism and in other acute infectious diseases, and in Bright’s disease, acute inflam- mation of the pleura is not uncommon. Cold and traumatism have long been regarded as important causes, but their action is doubtless only a predisposing one, the immediate cause being some infection for which the traumatism or the exposure to cold has paved the way. It is to be remembered that the pleura is made up of a visceral and a parietal layer, two smooth surfaces bathed by a small quantity of lymph, sliding over one another in respiratory movements. While the incep- tion of pleurisy may be localized the process soon spreads over both surfaces. It is, of course, possible to have an acute or chronic pleurisy localized by reactive connective-tissue growth, as when due to a purely local cause, such as an indented broken rib. The micro-organisms found in pleurisy are quite numerous. In the cases secondary to ordinary pneumonia, pneumococci are frequently discovered, and these micro-organisms may be present even though there be no pneumonia at all.” In the instances secondary to tubercu- losis of the lungs, as well as sometimes in cases of primary pleurisy without affection of the lungs, tubercle bacilli are discovered. It is important to note the fact that in many instances a small and unrecog- nized tuberculous lesion of the lung may be the source of infection in cases which seemingly are primary pleurisies due to exposure, cold, etc. It would, however, be a mistake to assume that all of such apparently primary pleurisies have a tuberculous etiology. In the purulent cases, as well as in some instances of simple fibrinous or serofibrinous pleurisy, staphylococci and streptococci are detected. When there is abundant liquid it is always difficult to discover the micro-organisms, and in many instances in which bacteria have not been found it is probable that the difficulty of their demonstration, even by animal experimenta- tion, rather than their absence, accounts for the failure to demonstrate them. In rare instances the Bacillus coli communis, the typhoid bacil- lus, the bacillus of anthrax, and other organisms have been found. Pathological Anatomy.—Several forms of pleuritis may be recog- nized, though one of these merges into the other, and a single case may pass from one into another form at its various stages. It is well, however, to separate these stages as distinct forms, since many cases maintain a uniform character throughout. The forms are the fibrinous, serofibrinous, purulent, and hemorrhagic; after any of these forms there may be left chronic pleural thickening or adhesions of a fibroid char- acter. Fibrinous pleuritis begins with congestion and loss of luster of the pleural surface, after which there soon follows exudation of a fibrinous character, forming a thin, whitish pellicle on the surface. This may be- come yellowish and increase in thickness, so that the pleural surfaces become agglutinated, and when separated present an appearance lik- ened to the appearance of two pieces of buttered bread separated after 588 A TEXT-BOOK OF PATHOLOGY having been pressed together (bread-and-butter pleurisy). This process may be confined to small areas of the pleura, or it may be quite universal. Sometimes it is limited to the reflections of the pleura separating the lobes of the lung. al i i E | ae Nae | i ad Fig. 257.—Transverse section of lung from a case of pleuropneumonia, showing great thick- ening of the pleura (A) and consolidation of one of the lobes of the lung (B). Microscopically, the exudate consists of fibrils or flakes or granular masses of fibrin more or less infiltrated with round cells. Beneath this the endothelium of the pleura is found to be somewhat thickened by proliferation and some of the cells are detached. Two conflicting views have been entertained regarding the origin of fibrin formation in the DISEASES OF THE RESPIRATORY SYSTEM 589 pleura. According to one, the deposit is purely exudative and the endo- thelium is in nowise involved, being found intact under the fibrinous layer. According to the other view the fibrin formation is partly de- pendent upon destruction of endothelial cells. Whichever explanation is correct, there almost always remains a broken layer of endothelial cells in the acute and subacute stages. This may be removed when ad- hesions and chronic thickening obliterate the membrane. The con- nective tissue beneath the endothelium and the subpleural connective tissue are infiltrated with round cells and the blood-vessels are hyper- emic. In favorable cases and when the process has been slight a gradual reabsorption of the exudate takes place, and the integrity of the pleura may be restored completely. When the exudate has been more exten- sive and the agglutination of the pleural surfaces has been considerable, new blood-vessels from the capillaries of the pleura penetrate the fibrinous exudate, fibroblastic cells develop from the older connective- tissue cells, and gradually organization takes place, so that the adjacent layers of pleura are bound together by connective tissue, the fibrinous exudate gradually undergoing absorption and disappearing. The ad- hesions thus formed are at first delicate and quite cellular, but are later converted into dense, sclerotic bands. When fibrinous pleurisy occurs repeatedly, as in tuberculosis of the lungs, and is not sufficiently ex- tensive to cause adhesions, the surface of the pleura may become thick- ened and opaque in spots from proliferation of the connective tissue. In this way considerable chronic thickening of the pleura may ensue. Serofibrinous. pleuritis may be simply a further stage of the fore- going form, though in many instances it begins almost at once as a serous exudation into the pleural sac. The liquid is heavier than -dropsical fluid and contains flakes and shreds of fibrin. Microscopic- ally, it is found to contain white and red blood-corpuscles in small numbers, and occasionally detached endothelial cells. Sometimes the number of red corpuscles increases considerably, and there may be a gradual transition to the hemorrhagic form of pleuritis. The amount of liquid varies from a few cubic centimeters to several liters; and the pleura itself shows a more or less extensive coating of fibrinous exudate. The lung is pressed backward, as in pneumothorax or hydrothorax, and the adjacent organs (heart, liver) are displaced. Purulent pleuritis, empyema, or pyothorax, is always the result of mi- cro-organismal infection. The process may begin as a purulent pleuritis, or as a primary serofibrinous pleurisy, secondary pyogenic infection occurring either from within the body or through infected aspirating instruments from without the body. It may supervene upon pneu- monia, tuberculosis, or abscesses in adjacent parts (subdiaphragmatic). When a transition of the latter kind occurs the exudate is seen to be- come more and more turbid; the number of pus-corpuscles gradually increases until the liquid is quite purulent. Spontaneous discharge of empyema may occur and most frequently takes place through the lung and bronchi. More rarely rupture occurs through the chest walls anteriorly between the ribs. When rupture has occurred through the 590 A TEXT-BOOK OF PATHOLOGY lung and bronchi the fistulous communication may remain open and pneumothorax may ensue. The pleura in empyema shows more or less abundant granulations, which in case of discharge of the liquid serve eventually to unite the costal and pulmonary pleura by firm fibrous adhesions. Occasionally the pus may be completely absorbed, or it may undergo gradual inspissa- tion, remaining as a more or less cheesy detritus, which may finally become calcareous. Such terminations, however, are rare. Again, the adhesions may surround an area of much compressed lung and enclose the exudate over this area. Thus, we have encapsulated pleurisy. In the healing of empyema, retracting scars are common, with the result that the lungs, chest wall, or both are distorted. Hemorrhagic pleuritis is generally the result of tuberculous infec- tion or of malignant disease of the lungs and pleura. Pleuritis may also take a hemorrhagic form in old and cachectic individuals, or in persons suffering from scurvy, purpura, and similar diseases. As a rule, the liquid is serous, with considerable admixture of blood, but in tuberculous and malignant pleuritis it is sometimes well nigh pure blood. Chronic Pleural Thickening —This term is used to include cases of thickening of the pleural membrane following various forms of acute pleu- risy, and also cases of a progressive productive character. To the latter alone the term chronic pleurisy is, strictly speaking, applicable. In either case the pleura is thickened by fibrous overgrowth, sometimes uniformly, at other times in the form of localized thickenings or adhesions. The subpleural pulmonary tissue may become implicated. Eventually, the thickened pleura contracts, and if adherent to the chest wall may cause retractions. The pulmonary tissue is compressed and the bronchi not rarely become distorted. In either primary or secondary chronic pleu- ritis there may be a total obliteration of the pleural cavity. The pleura becomes thick, opaque, and is poorly supplied with blood-vessels. Car- tilaginous or calcareous change may occur. Associated Lesions in Other Parts.—Though pleuritis is frequently the result of acute or chronic affections of the lung, it often occasions secondary disorders in the latter organ. The subpleural lymphatics are commonly distended with cells, and the inflammatory process may extend for considerable distances along these channels into the inter- lobular septa of the lung. In empyema the resulting purulent lymph- angitis and perilymphangitis lead to striking pathological appearances (see Pneumonia). The lung also suffers from direct pressure in serous and purulent pleuritis. If the compression to which it is subjected is not relieved by absorption of the liquid or by its removal by aspiration, the alveolar epithelium degenerates and proliferative inflammation takes place in the connective tissue, so that a permanent contraction of the lung results. The removal of the liquid at this stage is not followed by the return of the lung to its proper size and function. On the contrary, the removal or absorption of the liquid in these cases, especially when they occur in young children, causes a sinking in of the ribs and curvature DISEASES OF THE RESPIRATORY. SYSTEM 591 of the spinal column, and the heart and other adjacent organs may be permanently displaced. Most remarkable deformities of the chest may occur. Less extensive contraction of one side of the chest, or displace- ment of the heart, may result from the contraction of bands of adhe- sions, without marked collapse of the lung. Pathological Physiology.—Acute pleurisy occasions marked local symptoms, beginning with sharp pain on the side affected. This is usually due to the local inflammation and rubbing of the affected parts. There may, however, be extensive neuralgic pains radiating from the center of infection. With the development of effusion, the pain, as a rule, subsides, as does also the irritative cough which attends the first stage, but shortness of breath develops in correspondence with the amount of effusion. Very extensive effusion in the chest may, however, cause even more marked pain and tenderness than dry pleural inflam- mation. The infection in simple pleurisy seems to be a mild one, as fever and constitutional symptoms are rarely marked. Sometimes the temperature is a fluctuating one, and sweating and constitutional de- pression further suggest suppuration, though the effusion is purely serous. Irregular fever and constitutional symptoms of the kind indi- cated are habitual in empyema. INFECTIOUS DISEASES Tuberculosis of the pleura, or tuberculous pleuritis, may be either primary or secondary. Cases of the former are comparatively rare. In most instances the pleural disease is secondary to tuberculosis of the lungs or to tuberculosis of other adjoining parts. Hematogenic infec- tion may occur under the same conditions as hematogenic infection of the lungs, and frequently the lungs and pleure are studded with miliary tubercles at the same time. When the pleural disease is secondary to tuberculosis of the lungs the appearances vary considerably. In many cases small gray or yellow tubercles are found in the subpleural connective tissue and in the pleura, and the surface may be coated with fibrinous exudate, while the cavity of the pleura may be more or less distended with serofibrinous, hemor- thagic, or purulent liquid. Not rarely the liquid effusions are reab- sorbed and dense adhesions are formed, or great thickening of the pleura results. Sometimes considerable calcification of the thickened pleura and of the inspissated exudate is the terminal result. The tubercle bacilli are often difficult to demonstrate in the liquid, even by injec- tions into animals, though they may be present in the pleura itself. Syphilis of the pleura is a doubtful condition. Fresh pleuritis may be found in the neighborhood of a syphilitic gumma; and there are cases of considerable pleural thickening in syphilitic persons in which the disease may possibly be syphilitic, though in these cases, as in similar indurative conditions in the lungs, there is considerable doubt as to the essential nature of the disease. 592 A TEXT-BOOK OF PATHOLOGY TUMORS AND PARASITES Tumors of the pleura are comparatively rare. Fibromata and lipomata are occasionally seen as small nodular masses in the serous or subserous coat of the costal or visceral pleura. Chondromata and even osteomata have been observed. More frequently calcification and ossi- fication of portions of the thickened pleura take place after pleuritis. Primary sarcoma may spring from the subpleural connective tissue, and, according to Coats, is especially common in children, and is most frequently of the spindle-cell variety. Primary endothelioma of the pleura (Fig. 258) has been studied by a number of investigators. Ina case under the observation of one of us it presented itself as a more or less uniform Fig. 258.—Endothelioma of pleura. thickening of the pleura of one side, involving the diaphragmatic re- flection in particular. The cavity was filled with hemorrhagic fluid and there were some nodular enlargéments on the surface (Figs. 259 and 260). This is the usual appearance presented. Metastasis may occur in the lung beneath the diseased pleura, or even in more distant parts. There is a tendency for pleural endothelioma to be accompanied by fibrosis, and oftentimes adhesions are seen. Secondary tumors of the pleura may occur by metastasis or by direct extension. In the former manner sarcomata and carcinomata sometimes involve this structure; by the latter method of involvement mammary tumors and new growths of the mediastinum, the ribs, or other adjacent structures may extend to the pleura. DISEASES OF THE RESPIRATORY SYSTEM 593 Parasites.—Echinococcus cysts may originate in the subserous con- nective tissue of the costal or the visceral pleura, and may rupture into a , | } RET gery ee eee OS Fig. 259.—Endothelioma of pleura: the pleural cavity was distended with effusion, and the lung was compressed and invaded by secondary nodules. aban 77% 6! wa eyes PE ih é HN TES WdOE : YEE: Fig. 260.—Microscopical section from Fig. 259. the pleural cavity. Psorospermie have been found in pleural effusions. The dysenteric ameba has been found in the pus of empyema following hepatic abscess. 38 CHAPTER V DISEASES OF THE GASTRO-INTESTINAL TRACT THE MOUTH CONGENITAL ABNORMALITIES Tue most frequent defects in the development of the mouth are cleft palate and harelip. In the former of these the entire hard palate may be divided, generally to one side of the middle line; and there may be associated harelip and fissure of the soft palate. Anteriorly, the division occurs between the superior maxillary bone and the inter- maxillary bone, the fissure of the lip being also to one side and often extending into the nostril. The soft palate is divided along the middle line, and the uvula may be separated into lateral halves. The lip may be cleft on both sides, so that there is a small central portion connected with the septum of the nose and separated from the lateral portions of the lip. Harelip is more frequently unassociated with cleft palate. Complete absence of the lips, or unusual shortness, especially of the upper lip, excessive largeness of the mouth by extension of the fissure outward toward the ear, and imperfect development of the lower jaw- bone, are rare congenital conditions. Macrocheilia (large lips), macroglossia (large tongue), and ankylo- glossia (tongue-tie) are congenital malformations. CIRCULATORY DISTURBANCES Anemia of the mucous membranes of the mouth is seen in cases of general anemia, and is often one of the most striking evidences of that condition. It is particularly noticeable in the lips. Hyperemia.— Active hyperemia occurs in the early period of various inflammations, or as a forerunner of some infectious diseases not local- ized to the mouth; while passive hyperemia is met with as the result of obstruction of the circulation in pulmonary and cardiac diseases. Hemorrhages in the form of small petechie occur in purpura and other hemorrhagic diseases, and sometimes in infectious fevers. INFLAMMATION Inflammation of the mucous membrane of the mouth is termed stomatitis; inflammation of the tongue is designated by the name glossitis. Stomatitis may be of varying character and intensity. 594 DISEASES OF THE GASTRO-INTESTINAL TRACT 595 Catarrhal stomatitis may result from direct irritation by hot liquids or chemical substances, or may occur in depressed conditions of the general system, possibly as a consequence of infection. It is more com- mon in children than in adults. The mucous membrane of the mouth is red and usually covered with considerable liquid exudation. When the inflammation is intense, small vesicular cysts may form from dis- tention of the mucous glands, and even localized erosions may appear. When the inflammation has continued for a long time, or has been re- peated, there may form upon the surface silvery-white, slightly elevated spots, which result from a hyperplasia of the epithelium, a form of kera- tosis. This condition has been designated by the name of leukoplakia. Mild catarrhal conditions of the mucous membrane of the mouth are especially common on the tongue, the epithelium of which con- stantly desquamates. In the course of gastro-intestinal and other dis- eases the desquamation may be more active, the cells, however, being retained upon the surface. Portions of food and bacteria cling to the masses of desquamated cells, and in this manner the whitish or brownish furring of the tongue so commonly met with in various diseases is formed. Sometimes the heaping of epithelial cells takes place in localized areas, and extends in peculiarly irregular patches, which, from their resem- blance to maps, have given rise to the term “geographical tongue.” In chronic cases the whitish spots of leukoplakia alluded to above are formed. Aphthous stomatitis occurs in children under conditions of mal- hygiene and debility, or as a result of gastro-intestinal and other dis- eases. Local irritation often plays an important part. There appear in the mucous membrane, especially of the lower lip and gums, small whitish spots lying upon an inflamed base. Usually these are separated, but sometimes confluence occurs, though there is rarely extensive spreading. The whitish membrane covering or constituting the spots ~ is composed of degenerated epithelium, and sometimes of fibrin, so that the term “croupous stomatitis’? may in some cases be applied. The lesions are superficial and rarely lead to actual ulceration. It has been held that the preliminary lesion is a vesicle; this, however, does not appear to be frequent, and is certainly not essential. Foot-and-mouth Disease.—A similar affection occurs in animals, particularly in cows, sheep and goats, and is designated foot-and-mouth disease. This condition is contagious, and considerable epidemics have occurred among persons drinking the milk of infected animals. The specific cause is unknown; the virus is ultramicroscopical and filter- able. The process is one of hyperemia and thickening of the corium with vesicle formation in the epithelium. These may rupture and form shallow ulcers. Bednar’s aphthe are small ulcers found in the mouths of sucking infants and situated at the lateral portions of the palate over the ends of the pterygoid processes, on other parts of the hard palate, or occa- sionally on the soft palate. They are probably caused by traumatism occurring in the act of sucking. 596 A TEXT-BOOK OF PATHOLOGY Ulcerative stomatitis may be met with in various parts of the mouth, especially in the gums. In young children it is frequently the result of malnutrition and lack of cleanliness of the mouth. Various sapro- phytic micro-organisms normally found in the mouth may, under suit- able conditions, aid in the production of ulcerative stomatitis. Among these the Leptothrix buccalis, Indococcus vaginatus, Bacillus maximus buccalis, Spirillum sputigenum, and Spirocheta dentiwm have been iso- lated. Pyogenic cocci may also play a part in its etiology. In various cachectic diseases, particularly in scurvy, the gums become soft and spongy and tend to ulcerate. Mercurial and other forms of poisoning may lead to extensive ulcerations. Deeper ulcerations are found upon the sides of the tongue or the inner part of the lip in cases of injury due to the sharp edges of broken or carious teeth. Ulcerative stomatitis may be secondary to necrotic conditions of the bones or suppurative inflammations about the roots of teeth. Ulceration beneath the tongue is met with in many cases of whooping-cough, and is due to the irritation of the teeth in the paroxysms of coughing. In ordinary cases of ulcerative stomatitis the gums at the junction with the teeth become reddened and soft, and may present hemorrhagic infiltration. Later, the epithelium of the surface is destroyed and open ulcers result. Considerable suppuration may occur, and the teeth may be loosened and dislodged. A form of disease about the necks of the teeth and secondarily involving the gums has been termed pyorrhea alveolaris. The process is one of cementitis and pericementitis with a separation of the cemen- tum from the lining of the alveolar socket. The cementum is thus de- prived of its nourishment normally supplied by this peridental mem- brane. The discharge of pus from the gums surrounding the teeth gives the disease its name. It has been ascribed to infection with spirochetes, anaérobes, and amebe, especially the Endameba buccalis. The impor- tance of the last is strengthened by the fact that pyorrhea is improved by the use of emetin. This condition has been viewed by some as a focal infection from which, as a source, bacteria and their products are swallowed or transferred by the blood to other organs, and there set up intoxications or infections. Thus, arthritis deformans, chronic adenop- athy, and aspiration pneumonia are supposed to arise sometimes. The method of origin of pyorrhea alveolaris is probably that tartar collects upon the teeth down to the gingival margin, below which food particles collect and infection occurs. This process, having at best a very limited outlet, turns to a purulent inflammation, leading to gingivi- tis and retraction of the gums. Pseudomembranous stomatitis is most frequently due to the action of the bacillus of diphtheria, and is, therefore, strictly speaking, diph- theria of the mouth. It is usually secondary to pharyngeal diphtheria, but may occur primarily upon the lips or other parts of the mouth. In some cases of aphthous stomatitis the lesion is, in reality, a pseudo- membranous one. Phlegmonous stomatitis is more common in the lips than in other DISEASES OF THE GASTRO-INTESTINAL TRACT 597 parts of the mouth, and may be the result of traumatic injuries with - intense infection, or a secondary condition after facial erysipelas or other cellular inflammations of the face. The lips and cheeks may be greatly swollen, and suppuration may occur, forming abscesses which tend to rupture into the mouth. A chronic form of inflammation of the deeper tissues of the lips may lead to hypertrophy. This is especially common in the upper lip as the result of long-standing coryza, or eczema. Gangrenous stomatitis, or noma, affects the mucous membrane of the cheeks, and occurs in ill-nourished children, especially after measles and other infectious fevers. There is formed a sloughing ulcer on the inner side of the cheek, and inflammatory induration involving 9 pe i a : ee Fig. 261.—Case of noma (Children’s Hospital). the entire thickness of the cheek. The skin at first presents a dark-red or bluish discoloration, and later extensive destruction (gangrene) may occur (Fig. 261). The pathological changes are those of a rapid necrosis of all the tissues, and micro-organisms of suppuration and _ sapro- phytes are usually present. Pseudodiphtheria bacilli have been found in some cases. Various spirochetes have been observed. The most common finding is a micro-organism belonging to the necrosis bacilli, but its pathological importance is not established. Putrefactive changes cause a fetid odor. Intense septic infection and intoxication generally attend. Milder forms of gangrenous stomatitis affecting the gums around carious teeth are occasionally observed. 598 A TEXT-BOOK OF PATHOLOGY Associated Conditions in Stomatitis—In many cases the inflam- mation may extend from the mucous membrane of the mouth poste- riorly to the pharynx. Very commonly the lymphatic glands of the neighborhood are involved, with enlargement of the submaxillary or even the cervical glands. In some cases, especially in mercurial stoma- titis, the salivary glands are coincidently or consecutively swollen and inflamed. Increased flow of saliva (ptyalism or sialorrhea) is a fre- quent symptom. In intense cases, especially in gangrenous stomatitis, parenchymatous degenerations of other organs may result from general toxemia. Glossitis.—Superficial catarrhal inflammations have been referred to. The tongue may be involved in the various forms of stomatitis and shows similar changes. More extensive inflammations of the tongue, leading to parenchymatous glossitis, may result from injuries, especially when accompanied by infection. The entire organ may in these cases be swollen, and there is round-cell infiltration with a tendency to suppura- tion. Localized parenchymatous glossitis with ulceration may occur from injury by carious teeth. Hemilateral glossitis, sometimes attended with the formation of herpetic vesicles, is occasionally observed, and is probably dependent upon disease of the chorda tympani nerve. ATROPHY AND DEGENERATIONS Atrophy of the muscles of the tongue and cheeks may occur in association with nervous diseases (bulbar palsy). Physiological atrophy of the gums follows loss of the teeth in old age. Degenerations of the mucous membrane usually accompany in- flammations. Under the name of nigrities, or black tongue, is described a form of hypertrophy of the papille of the tongue with pigmentation. The dorsum of the tongue may be covered with a hair-like coating of dark- brown or blackish color. The cause of this affection is obscure. INFECTIOUS DISEASES Thrush, or parasitic stomatitis, is met with in young children, and is due to the action of a micro-organism known as Oidium albi- cans. There are formed upon the mucous membrane white patches resembling curdled milk, and varying in size from mere points to large areas. These tend to coalesce and to spread. The mucous membrane is reddish and inflamed. The back and sides of the tongue and the inner parts of the cheeks are favorite seats. Microscopically, the white coating is composed largely of mycelial threads of the parasite, with which are mingled degenerated epithelial cells and generally also other micro- organisms, notably micrococci. The process may extend to the pharynx, and sometimes as far as the bronchi or the stomach, through the larynx and esophagus. DISEASES OF THE GASTRO-INTESTINAL TRACT 599 Tuberculosis of the mouth may be primary or secondary. The latter is especially frequent at the root of the tongue, and is secondary to tuberculosis of the larynx or pharynx (Fig. 262). Small nodular masses of tubercles are formed, and tend to undergo cheesy degeneration, forming ulcerated areas. Primary tuberculosis leading to ulceration may occur upon the lips or upon the tongue as a result of direct in- oculation, as in the kissing of a tubercu- lous person. Nodular masses are formed, which at first present themselves as papil- lary elevations, but subsequently undergo characteristic necrosis. Tuberculous ul- cers are usually irregular or undermined, and the bases are more or less caseous and infiltrated by tubercles. The injury a z EE? AS ee ae a. ‘ } pants Heel g i a : a Pit eae ug (Sa. (FA eel Seki eke: 3 Pr. ‘ < 7 : Bs DELETE NS Fig. 262.—Tubercle of the tongue (Karg and Schmorl). of the tongue by the teeth, and the favorable soil offered for the re- tention and multiplication of the micro-organisms in carious teeth, may play a part in the causation. ee ae a ' | | Fogle | & oo dl Fig. 263.—Actinomycosis of the cheek (Illich). Lupus of the face may extend to the mouth. It is distinguished by the associated cicatrization. Secondary carcinomatous change may occur in the base of the lesion (lupus carcinoma). Syphilis is most frequently secondary, occurring in the form of 600 A TEXT-BOOK OF PATHOLOGY mucous patches upon the lips or tongue, or as more elevated condylo- . mata, which in healing cause irregular contractions or whitish or opaline thickenings of the mucous membrane. A simple syphilitic catarrhal angina may occur. Gummatous infiltrations may appear in a localized form or as irregular involvements. On the dorsum of the tongue, their commonest seat in this organ, they produce deep, ragged excavations. They are usually deep seated and, on healing, fissuration and deformity may result. The tongue is the most frequent seat. The primary syphilitic lesion (chancre) resulting from direct inoculation is occa- sionally observed upon the lips, tongue, or pharynx. Actinomycosis affects the tongue, gums, and jaw-bone, and is char- acterized by a slowly infiltrating process with a tendency to necrosis and suppuration, in which the alveolar processes of the jaw-bone are generally attacked. The lesion in the mouth may be insignificant, while the secondary involvement of the cheeks or of the lymphatic glands below the jaw and in the neck may be extensive (Fig. 263). Leukemic Stomatitis.——In acute leukemia ulcers of the mouth are frequent at the onset and throughout the disease. The gums may present an ulcerated appearance resembling that seen in scurvy. Con- siderable necrosis and hemorrhagic infiltration are common. Nodular infiltration of the adenoid tissues at the base of the tongue and in the pharynx also occur in acute leukemia, but more commonly in the chronic form. TUMORS Papillomatous growths of the mucous membrane are occasionally observed. Fibroma, lipoma, myxoma, and even chondroma are rare forms of tumors of the submucous tissue of the tongue or other parts of the mouth. Not rarely they are congenital. Lymphadenoma or lymphosarcoma may occur at the root of the tongue, where it takes origin from the lymphatic follicles or the lingual tonsil. Sarcoma of other parts of the mouth is rare, excepting as an extension from sarcoma of the jaw-bone and other parts. Eptthelioma or carcinoma is the most important new growth of the mouth, and in nearly all cases is of the squamous-celled variety. The favorite seats are the lower lip, usually toward one side of the mouth, and the tongue. It appears as an irregular nodular elevation which tends to ulcerate upon the surface and spread to adjacent structures. Metastasis usually occurs to the submaxillary and cervical lymphatic glands. The name “epulis” is a clinical term applied to tumors arising from the alveolar process. Sarcoma and endothelioma are the commonest forms. Nodular masses having the structure of the normal thyroid gland have been found at the base of the tongue. Cystic formations, due to agglutination of the mouths of the mucous glands, are met with upon the tongue and lips. Cysts are especially frequent beneath the tongue, at the sides of the DISEASES OF THE GASTRO-INTESTINAL TRACT 601 frenum. These have been termed ranula, and are formed by the dilata- tion of the ducts of the small mucous glands. At times ranula may be a cystic dilatation of a duct of the sublingual salivary gland or that of a submaxillary gland. Ranula is usually found as a rounded or elliptical tumor which may fill the floor of the mouth and displace the tongue backward and upward. The contents consist of somewhat gelatinous albuminous liquid. They may be due to stenosis of the excretory duct by inflammation or blocking by a stone. Cysts may arise at the base of the tongue from the remains of the thyroglossal duct. Hemangioma, both of the teleangiectatic and cavernous varieties, is occasionally seen, but a more important tumor is lymphangioma, affecting the tongue and lips and giving rise to the conditions known as macro- glossia and macrocheilia. In these conditions there is a uniform enlarge- ment of the tongue or lips, and on section distended lymphatic spaces more or less filled with liquid and round cells are detected. Such en- largements are usually congenital, and are especially met with in cretins. Angiomata of sarcomatous or carcinomatous nature have been seen in the tongue. THE TEETH Anomalous Development.—Unnatural largeness or, on the con- trary, lack of development is frequently observed. Complete absence of the teeth has been noted. Numerical increase or decrease is fre- quent. Delay in the eruption of the teeth and irregularity in their for- mation occur in rachitis; and a form of maldevelopment of the upper central incisor teeth of the permanent set is observed in cases of con- genital syphilis (Hutchinson’s teeth). The characteristics of this condi- tion are the wedge shape of the teeth, the cutting-edge being smaller than the crown, and the concave notching of the cutting-edge (see Fig. 119). Hutchinson’s teeth are not entirely peculiar to congenital syph- ilis, being sometimes seen in rachitis. Caries of the teeth results from malnutrition, digestive disturbances, and lack of cleanliness. Micro-organisms which lead to acid fermenta- tion contribute to the causation by forming acids which dissolve calcium salts, soften the enamel, and occasion fissures through which other bacteria (bacilli and micrococci) may gain entrance into the channels of the dentin. The soft teeth of pregnant women are due to the reduction of calcium which is being given to the fetus. The carious process consists in a gradual disintegration of the enamel and dentin, with the formation of more or less granular detritus in which bacteria are abundant. The process may penetrate to the pulp of the teeth and set up a secondary inflammation, or pulpitis. Inflammation of the pulp of the teeth may occur in association with caries, or sometimes independently. The pulp becomes reddened and swollen, and may present hemorrhages and, later, suppuration. The inflammatory process tends to spread through the roots of the teeth to the tissues surrounding the roots and to the alveolar perios- 602 A TEXT-BOOK OF PATHOLOGY teum. Abscesses may thus be formed about the teeth, and may spread to the tissue of the gums (alveolar abscesses), eventually rupturing upon the surface. Tumors composed of tissue resembling the normal dentin are spoken of as odontomata, and may be solid or cystic. They arise from the pulp during the process of development and form irregular outgrowths of the crown or roots. Similar outgrowths, resembling the enamel or dentin, or cement substance, are more frequent in later life, and have been desig- nated as odontinoids. Sarcomata and fibromata may spring from the pulp during the de- velopment of teeth or from the connective tissue about the roots; and polypoid outgrowths (hypertrophied granulations) from the pulp may be met with in association with caries of the teeth and pulpitis. The most important tumor is the giant-celled sarcoma of the alveolar process of the jaw. This is known by the name of “‘epulis,”’ though, strictly speaking, the term is applied rather to the situation than to the kind of tumor. Extensive enlargements of the jaw-bone and destruction of the surrounding tissues may ensue. Cysts are met with in the alveolar processes, and arise from the primary follicles in which the teeth are developed. These may contain epithelium and teeth. There are also cystic tumors of the teeth-sockets from the periosteum of the jaw-bone. THE PHARYNX AND TONSILS CIRCULATORY DISTURBANCES Anemia of the soft palate and other portions of the pharynx occurs in general anemia and in cases of phthisis or other wasting diseases. The mucous membrane may be decidedly pallid. Active hyperemia or congestion occurs in the beginning states of inflammation and when irritants have been in direct contact with the mucous membranes. Passive hyperemia is seen in heart disease, emphysema, phthisis, and other chronic pulmonary affections. In these cases the mucous membrane is dark red, and not rarely becomes somewhat edematous. Edema of the pharyngeal tissues is found in association with in- flammatory affections, and may occasion considerable stenosis. Hemorrhages may be the result of direct injury, as in the swallowing of fish-bones and the like, or may occur in the form of petechiz in pur- pura and other hemorrhagic diseases and in intense infections (small-pox, septicemia). INFLAMMATIONS Catarrhal pharyngitis, or angina, may affect the entire lining mem- brane of the pharynx, or may be limited to the tonsils or other parts. It results from direct irritation by hot liquids or chemical substances, from exposure to cold, and particularly from infections. Angina, or DISEASES OF THE GASTRO-INTESTINAL TRACT 603 sore throat, is met with in many of the infectious fevers, or may appear as an independent infection. The mucous membrane presents a bright-red color, is somewhat swollen, and covered with tenacious exudation composed of mucus and desquamated cells. Small vesicular elevations may form, and after the rupture of these, erosions or even superficial ulcers are sometimes seen. Occasionally there are hemorrhagic extravasations. A form of catarrhal pharyngitis, known as herpetic angina, is analo- gous to herpes of the skin, and may accompany facial or labial herpes. Chronic catarrhal pharyngitis is met with in persons who use the voice excessively, especially in the open air. It may also result from the abuse of tobacco or alcohol. The posterior wall of the pharynx and the pillars of the soft palate are particularly involved. The mucous mem- brane is swollen in the earlier stages, but later becomes atrophic, and is marked by slight granular elevations, which are either hyperplastic lymph-follicles or distended mucous glands. The veins in the sub- mucous tissue are enlarged, and are visible through the atrophic mucous membrane as tortuous channels. Chronic hyperplasia of the tonsils and chronic laryngitis are frequently associated. Phlegmonous pharyngitis may result from wounds of the pharynx, or may be associated with intense infections, such as pseudomem- branous tonsillitis and pharyngitis, particularly the forms due to streptococci. It may result from pustular pharyngitis in small-pox, or from glanders of the pharynx. Phlegmonous tonsillitis sometimes ex- tends to the peritonsillar tissues as far as the retropharyngeal wall. The soft palate, uvula, arches, or other parts affected are swollen and tensely distended. There may be congestion or deep cyanosis and edematous exudation. The usual termination is suppuration, but sometimes gangrenous necrosis ensues. General septicemia is fre- quently the result. Retropharyngeal Abscess.—This condition may occur secondarily after traumatic or infectious pharyngitis as above described. Phleg- monous pharyngitis primarily affecting the retropharyngeal tissues may be due to caries of the cervical vertebre; occasionally it occurs in the infectious fevers in consequence of embolism, or infection of the deep- seated lymphoid nodes of the pharynx. Pseudomembranous pharyngitis may be caused by the Mycobac- terium diphtheria, in which case the disease is diphtheria, or it may be due to a variety of other micro-organisms, or to irritating gases, steam, and like causes. Non-diphtheritic pseudomembranous pharyngitis is especially common as a complication of scarlatina, measles, and other infectious diseases, and seems in these cases to be caused by the Strepto- coccus pyogenes. The appearance of the throat may be identical with that observed in diphtheria, but extensive necrosis is more common, while typical pseudomembranes are less frequent. The mucous membrane and the underlying parts, especially the tonsils, become greatly swollen and edematous, and subsequently suffer necrotic changes. 604 A TEXT-BOOK OF PATHOLOGY There is formed upon the surface of the throat a whitish or yellowish patch, or several patches, which tend to coalesce and extend from the region of the tonsils to the pillars of the fauces and the uvula, or to the mouth, nose, or larynx. The pseudomembrane is quite firmly attached to the mucous membrane, and cannot be removed without tearing away part of the underlying tissues. Microscopically, the deposit is found to consist of granular or fibrillar fibrin entangling more or less degenerated leukocytes and epithelial cells. In the deeper layers intense congestion and round-cell infiltration are observed; in the superficial strata de- generated cells and detritus, together with masses of bacteria, are conspicuous. The neighboring lymphatic glands, notably those below the angle of the jaw, enlarge and may suppurate, and sometimes extensive cellu- litis and suppuration of the floor of the mouth (Ludwig’s angina) occur. There are intense systemic intoxication and infection, and secondary lesions are frequently developed in various organs (nephritis, myocardi- tis, etc.). The non-diphtheritic forms of pseudomembranous pharyn- gitis may be distinguished from the diphtheritic forms, in typical cases, by the greater intensity of the local (necrotic) processes, the earlier and more marked involvement of the local lymphatic glands, and by the greater tendency to nephritis; but, unfortunately, atypical cases are very common, and an absolute diagnosis can be made by bacteriological study alone. Tonsillitis may be a part of a general pharyngitis, or it may occur as an independent affection. Several varieties are described. Catarrhal tonsillitis results from the same causes as catarrhal phar- yngitis in general, and presents similar appearances. The tonsils are usually somewhat enlarged. Lacunar or follicular tonsillitis occurs from similar causes, and may involve the normal tonsil or one affected by chronic hypertrophy. The surface of the tonsil is marked with small white or yellowish spots, into which the end of a probe may be inserted. These are the lacune or crypts distended with masses of epithelial cells more or less degenerated. Bacteria of various kinds may be found in the contents of the lacune, and doubtless play an important part in the etiology. Fig. 264.—Crypts in cases taphylococci, streptococci, pneumococci, tu- of tonsillitis: A, Acute lacu- bercle bacilli, and the bacillus of diphtheria te ee ee have all been observed. The latter two cumulated contents of crypt; forms may be present merely as accidental c, lymphoid follicles surround- ee ‘ i ing crypt (Kaufmann). associations, but may possibly play an eti- ological part. Ulceration may occur in the walls of the lacune, and the surface of the tonsil may be con- siderably broken down. In other cases the bacteria may penetrate the tonsil at the bottom of the lacune, and phlegmonous tonsillitis, or quinsy, may result (see below). The contents of the lacunz may be DISEASES OF THE GASTRO-INTESTINAL TRACT 605 discharged upon the surface, and may adhere for a time as a yellowish- white caseous pellicle, resembling diphtheritic pseudomembranes in appearance. In other cases the contents of the crypts are retained, undergo inspissation, and may even calcify. A certain amount of catarrhal pharyngitis may be associated, but the follicular ulcers are rarely seen beyond the tonsils. Phlegmonous tonsillitis, abscess of the tonsil, or quinsy, may be the result of simple catarrhal or of follicular tonsillitis, or may be asso- ciated with phlegmonous inflammation of other parts of the pharynx. One or both of the tonsils may be affected. Redness and swelling are. noted in the earlier stages, but later the mucous membrane is pallid or even yellowish. Microscopically, diffuse round-cell infiltration and eventually focal collections leading to abscess formation are detected. The peritonsillar tissues may be involved, and spreading phlegmonous inflammation results. Rupture may take place into the pharynx, or the ulceration may extend outward, causing discharge upon the neck at the angle of the jaw. The internal carotid artery may be perforated. Enlargement of the submaxillary and cervical lymphatic glands is commonly observed. General septicemia of mild type is not infre- quent; myocarditis, endocarditis, and nephritis may result. The asso- ciation of tonsillitis and rheumatism has occasioned much discussion. It is very probable that rheumatism frequently follows tonsillitis, the latter being the first effect of micro-organismal invasion, which eventually causes rheumatism. Chronic tonsillar hypertrophy may result from repeated attacks of simple catarrhal or of follicular tonsillitis. ‘The lymphatic constitution or status lymphaticus is a factor of importance. The tonsils are en- larged, usually irregularly so, and are harder than normal. On section the connective-tissue reticulum and septa are found increased, and the lymphoid follicles are likewise hyperplastic. Pressure upon the orifices of the lacune not rarely causes obstruction and repeated attacks of lacunar tonsillitis. Retention and calcification of the contents of the crypts are particularly common in the lacunar tonsillitis of hypertrophic tonsils. Chronic hypertrophy of the tonsils very often occurs in rachitic or badly nourished children in association with hyperplasia of the lingual tonsil and nasopharyngeal adenoid tissues—the clinical adenoids. Distinct evidences of inflammation are wanting in such cases, and the condition seems rather a form of simple hyperplasia of the lymphoid structures. Pathological Physiology.—Acute tonsillitis may occasion only local symptoms, such as pain, difficulty in swallowing, etc., but in many cases there are general symptoms—fever, disturbances of appetite, etc. The latter vary in severity according to the particular infectious cause of the disease. A chronically enlarged tonsil probably always contains bacteria, and this may constitute a focal infection, whence bacteria may be liberated to cause damage elsewhere. The streptococci of the tonsils have been suspected of responsibility for chorea, arthritis deformans, and 606 A TEXT-BOOK OF PATHOLOGY other subacute infections. Chronically diseased tonsils have been found to contain a toxic substance, which when absorbed excites antibodies like a parenterally introduced protein, and acts as a protoplasm poison. The glands containing streptococci seem to contain most of this poison. This may aid in the production of the above diseases. PRESSURE NECROSIS This condition occurs upon the anterior and posterior walls of the pharynx, opposite the cricoid cartilage. It is met with in marantic persons occupying a dorsal decubitus, and is caused by the backward pressure of the cricoid cartilage against the opposite vertebra. The mucosa becomes necrotic, and more or less extensive ulcerations are formed. Complete perforation of the pharyngeal wall sometimes occurs. INFECTIOUS DISEASES Diphtheria of the pharynx usually begins in the mucous mem- brane covering the tonsils, and spreads to the pillars of the fauces, to the uvula, the posterior wall of the pharynx, the cheeks and tongue, the posterior nares, or to the larynx. It rarely invades the esophagus, but may sometimes extend along this structure as far as the stomach. The specific cause is the Myco- bacterium diphtherve (see Diph- theria, p. 285). The character- istic lesion is a pseudomembrane, which is formed on the surface and within the mucous mem- brane. This first appears as a grayish or yellowish-white pel- licle, more or less firmly attached to the mucosa; it spreads rapidly, and may cover the whole of the pharynx in a day or two. In other cases the disease progresses slowly or remains quite limited. _ Fig. 265.—Pseudomembranous inflamma- The underlying tissues become - tion of the uvula: a, a, masses of micrococci; : : b, b, necrotic cells; c, c, round-cell infiltration; swollen by inflammatory infiltra- d, d, fibrin network (Ziegler). tion (cellular and edematous), and swallowing and_ breathing may then be greatly obstructed. When the pseudomembrane is re- moved from the surface a raw and more or less necrotic base is ex- posed. Microscopically, the surface of the pseudomembrane is found to consist of a mass of débris, often containing micrococci and other bacteria, as well as the specific organisms, in great numbers. Some- what more deeply the membrane is composed of a fibrinous reticulum or masses of fibrin entangling degenerated epithelial cells and leuko- cytes. Still more deeply the tissues of the phaynx are found intensely DISEASES OF THE GASTRO-INTESTINAL TRACT 607 congested and infiltrated with round cells (Fig. 265). In the late stages of the disease extensive necrosis of the mucosa and submucosa may occur. In some cases diphtheria may undoubtedly present the lesions of an ordinary lacunar tonsillitis, and the clinician may be unable to deter- mine the nature of the disease. Associated Conditions.—Some enlargement of the lymphatic glands at the angle of the jaw is usual, and exceptionally this may terminate in suppuration. Lesions of the internal organs, especially the heart and kidneys, are not infrequent, and disease of the peripheral nerves is a common sequel (see Diphtheria, p. 287). Vincent’s angina is a mildly infectious disease characterized by superficial ulceration upon which a lightly adherent pseudomembrane lies. ‘The process usually begins upon or near the tonsils and spreads slowly; it is a superficial ulceration of the epithelium, while in the corium there is a moderate round-cell infiltration. The fusiform bacilli, and the spirilla probably growing from them, are found in the mem- brane and on the base of the ulceration (see page 340). Pharyngomycosis Leptothricia.—This condition is met with on the tonsils, and less frequently the pillars of the fauces, uvula, and other parts of the pharynx. It occurs in persons of lowered vitality, and seems to be caused by the Leptothrix buccalis, a form of bacterium very commonly met with in the collections around the necks of the teeth. The lesions present themselves as milky-white and somewhat chalk-like outgrowths arising from the tonsillar crypts and the mucous glands. These are often tightly adherent, but occasion very little inflammation of the surrounding tissues. Microscopically, the thread- like parasite is found in abundance. Tuberculosis may occur in the pharynx in the form of subepithelial tubercles, which break down and occasion more or less extensive ulcera- tions. Tuberculosis of the tonsils may be primary or secondary. In the former case infection probably occurs from the invasion of the crypts by tubercle bacilli; this condition is doubtless more common than has generally been supposed. Secondary tonsillar tuberculosis usually follows tuberculosis of the lungs or larynx. In either case there are formed in the tonsils small tubercles which rapidly increase in size, fuse, and subsequently undergo caseous change. Discharge of the caseous matter upon the mucous surface is not unusual, and occasions ulcer-like formations. Secondary infection of the cervical and submaxillary lymphatic glands is not infrequent. Syphilis may occur in the pharynx in the form of the primary lesion or chancre, as simple catarrhal angina, as mucous patches, or as gummata. The last are prone to undergo ulceration with secondary cicatrization. Extensive distortion of the pharyngeal structures may be the result of the scar formation. Glanders and lepra sometimes invade the pharynx. Typhoid ulcers are occasionally met with. 608 A TEXT-BOOK OF PATHOLOGY TUMORS Among the tumors of the pharynx, fibroma, lipoma, and papilloma are occasionally found on the soft palate, uvula, or tonsils. Of the malignant tumors, sarcoma of the tonsils is most important. It is usually of the lymphosarcomatous variety, and is rapid in growth and highly destructive. Epithelioma may occur at the base of the tongue, in the soft palate, or tonsils. Other varieties of cancer are rare. Polypoid tumors of the nasopharynx and hyperplastic adenoid growths of the same situation frequently extend downward into the pharynx proper. THE SALIVARY GLANDS Inflammation of the salivary glands affects the parotid most fre- quently. Parotitis may be the expression of an independent infection (mumps) ; or may be secondary to various infectious diseases, such as typhoid fever, typhus fever, or pyemia. Parotitis sometimes occurs in associa- tion with diseases or injuries of the abdomen or pelvic organs. A reflex or “sympathetic” inflammation has been assumed as the cause of the parotid disease by some, but recent investigation seems to indicate that in all cases the real cause is infection through the duct. The specific cause of mumps has not been isolated (see page 354). The infection probably occurs through the parotid duct, and in some instances inflammations of the mucous membrane of this duct have been found to precede the parotitis. The gland is swollen and tensely distends its capsule. The inflammatory exudate is probably largely serous, as it may be absorbed and removed in the course of a very short time. The disease scarcely ever terminates in suppuration. Orchitis is an occasional complication, and may be followed by atrophy of the testes. The secondary parotitis occurring in the course of various infectious diseases is characterized by a marked tendency to abscess formation, and at all stages of the affection round-cell infiltration is conspicuous. After the formation of an abscess perforation may take place upon the cheek or into the mouth, and sometimes salivary fistule (see below) are established. Chronic induration of the gland may remain after attacks of inflammation. Chronic parotitis may also result from certain intoxi- cations (lead, mercury, iodid of potash) or may occur in chronic nephritis or syphilis. Mikulicz described a form of simultaneous enlargement of the parotid, submaxillary, and lachrymal glands. The etiology is unknown. The submaxillary gland is occasionally affected with the parotid, or independently, in mumps. The sublingual gland rarely becomes in- flamed. Angina Ludovici, or Ludwig’s angina, is a septic inflammation of the tissues of the floor of the mouth surrounding the submaxillary gland. It may result from carious processes at the roots of the teeth, DISEASES OF THE GASTRO-INTESTINAL TRACT 609 or from infection of the submaxillary lymphatic glands in the course of various infectious diseases, particularly scarlet fever. The most frequent termination is abscess formation, with perforation externally or into the mouth. Occasionally rapid necrosis or gangrene results. Many different organisms have been found, but to none is ascribed any specific importance. The characteristic of this affection is the density of the infiltration, there being almost a wooden hardness. The parts are dark red. Tumors.—The parotid gland is more frequently the seat of tumors . than the other salivary glands. Benign tumors, such as fibroma, lipoma, _or chondroma, are rare. The most common new growth is the so-called “mixed tumor,” which is essentially sarcomatous, with the addition of fibroma, chondroma, or myxoma, and at times of all these. Some of the mixed tumors are said to be endotheliomata, but the decision is difficult because of the atypical growth of the glandular acini. Ade- noma and carcinoma are occasionally primary. Diseases of the Salivary Ducts.—Salivary fistule may result from traumatic injuries or from the perforation of abscesses. They most frequently affect the duct of the parotid. Concretions composed of phosphate and carbonate of calcium are occasionally observed, and may lead to obstruction of the ducts. Cystic dilatation of Steno’s or Wharton’s duct, or of those of the sublingual glands, may be due to concretions or to inflammatory proc- esses at the mouths of the ducts. Oval or elliptical tumors are formed, and contain transparent, viscid liquid. Such cysts belong to the group of conditions designated as ranula, but more frequently this is due to obstruction of the small mucous glands beneath the tongue. THE ESOPHAGUS CONGENITAL DEFECTS Occasionally the esophagus is double, being divided into two parts by a septum. Complete absence of the esophagus may occur in certain ‘monstrosities; more frequently there is partial absence of the lumen about the middle of the tube. The lower end of the esophagus in such cases communicates with the trachea, while the upper end terminates as a blind pouch. The intermediate defective portion may be repre- sented by a fibromuscular cord, or may be entirely wanting. Fistulous communications may pass from the sidé of the neck to the upper end of the esophagus or pharynx. They are due to incomplete closure of the branchial clefts. CIRCULATORY DISTURBANCES Anemia may be due to general anemia; active hyperemia, to the irritation of hot liquids or chemicals. Passive congestion results from diseases of the heart or lungs, or from portal cirrhosis of the liver. In the latter condition large varicosi- 39 610 A TEXT-BOOK OF PATHOLOGY ties may be established in the lower end of the esophagus, due to the communications between the left coronary vein of the stomach, the esophageal veins, and vena azygos. Hemorrhage may occur from these dilated veins, as they lie close beneath the mucous surface. INFLAMMATIONS Catarrhal esophagitis is characterized by hyperemia and desquama- tion of epithelium, with very little liquid secretion. It may be due to the ingestion of irritating acid or alkaline liquids, to scalding, or occa- sionally to direct traumatic irritation. Superficial erosions are some- times met with. Chronic catarrhal esophagitis is found in cases of passive conges- tion continued for a long time, and particularly in alcoholics. The mucous membrane is thickened and irregularly pigmented. Occasionally erosions are met with, and more commonly areas of hypertrophy of the mucosa. Pseudomembranous esophagitis may result from extension of pharyngeal diphtheria or pseudomembranous pharyngitis, or it may be primary in rare instances. Ulcerative esophagitis may occur as the result of pustular eruption in small-pox, or in consequence of irritation of foreign bodies. It is not unusual to find small or even large ulcers in the mucosa of esophageal diverticula. These are occasioned by the retention of food. Peptic ulcers similar to those occurring in the stomach are occasionally found in the lower end of the esophagus. Phlegmonous esophagitis is rare. It may result from the extension of intense inflammation of the mucous membrane into the submucous tissue, or to penetration of the mucosa by sharp points of fish-bones and the like. The inflammation arising after swallowing corrosive or irritant substances may partake of all the above forms. It is usually, with milder substances, a desquamative process, but these may penetrate and produce a pseudomembranous condition due to destruction and separa- tion of the mucosa. With the more corrosive agents a rapid necrosis of mucosa or even submucosa may occur, with later development of hemor- rhages or dry ulcers. Suppuration, diffuse or localized, may occur. Connective-tissue overgrowth leads to alterations in the lumen. After severe damage the whole thickness of the mucosa may not be restored, there being merely a coating of epithelium for the scar tissue. STENOSIS Stenosis of the esophagus may be due to the pressure of tumors or aneurysms upon the esophagus, to the lodgment of foreign bodies, to the growth of tumors in the esophageal walls, or to stricture of the esophagus. The last most frequently results from the healing of ulcera- tions caused by the swallowing of corrosive liquids. Syphilitic and DISEASES OF THE GASTRO-INTESTINAL TRACT 611 posttyphoidal strictures are rare. Carcinoma of the esophagus may obstruct by the growth within or by the attendant contraction of the walls. Occasionally stenosis by malformation is congenital. Acute stenosis is a muscular spasm of the walls due to irritation, or as a part of hysteria or general convulsions. DILATATION Dilatation of the esophagus may occur in the form of a simple dilatation or ectasia, or in the form of diverticula. The former variety is common at the lower end of the esophagus, and is occasioned by ob- structions at the cardiac end of the stomach, or at the point where the esophagus passes through the diaphragm. The dilatation may reach considerable size. The mucous membrane is usually thin and often ulcerated. An “idiopathic form” has been described, in which there is more or less uniform or spindle-shaped widening, probably due to atony of the musculature or to vagus disease. Spasmodic contraction of the cardia is also described as a cause. Diverticula may be of two kinds, those due to pressure from within (pulsion diver- ticula) and those due to traction from with- out (traction diverticula) (Fig. 266). The former are more commonly found in the upper portion of the esophagus or the lower part of the pharynx, and arise from the posterior wall of the esophagus. They are due to thinning of the muscular coat and to hernia-like protrusion of the mucous membrane. They may reach considerable size by gradual distention. The traction diverticula are most frequently found near the lower end, opposite the bifurcation of the trachea. They are caused by adhesion y, of diseased bronchial glands and subsequent _Fig. 266.—Traction divertic- contraction of the attachments. They occupy eee the anterior wall of the esophagus and have a somewhat funnel shape. Perforation may occur, with the development of septic infection of the pleura, pericardium, or lungs. Perforation of the pulmonary arteries may lead to fatal hemorrhage. PERFORATION AND RUPTURE The esophagus may be perforated by necrotic or suppurative proc- esses surrounding it, or as the result of ulcers proceeding from within. Aneurysms of the thoracic aorta occasionally rupture into the esophagus. Retropharyngeal abscesses and phlegmonous inflammations of the deep cervical tissues may likewise discharge into the esophagus. Per- 612 A TEXT-BOOK OF PATHOLOGY foration by ulcers beginning within may be due to the lodgment of foreign bodies, or to the pressure of the cricoid cartilage in cases of great asthenia (see Pharynx). Perforation of the lower end of the esophagus may result from peptic ulcers or esophagomalacia due to regurgitation of gastric liquid either before or after death. Spon- taneous rupture of the esophagus occasionally takes place. In these cases there is doubtless always some antecedent weakness of the walls. INFECTIOUS DISEASES Tuberculosis of the esophagus is extremely rare, and most frequently results from extension of tuberculous adenitis of the bronchial glands. Syphilis occasionally occurs in the form of ulceration and cicatrization, leading to stenosis. Typhoid ulceration is probably more fre- quent than has been generally thought. Oc- casionally stenosis is caused by the cicatrices of the healed ulcers. Thrush may extend from the mucous mem- brane of the mouth and pharynx. Foreign bodies, like small bones, have been found embedded in the esophageal wall. TUMORS Fibroma, myoma, lipoma, or even sarcoma may occur as somewhat polypoid submucous tumors, but are rare. Papillomata, in the form of outgrowths of the mucous membrane, are more common. The most important tumor is carcinoma, Tie bey Carnaaiua wi which is usually found in the lower part, gener- upper end of esophagus ally at the position where the left bronchus crosses (even apenas | tlie esophagus, or near the passage of the tube Smith). through the diaphragm. It may, however, be found at any part. The squamous variety is the most common, though a few instances of glandular carcinoma are recorded. The tumor usually involves the entire lumen of the esophagus, projecting inward and forming irregular elevations of the mucous mem- brane. Later, the growth extends outward through the muscular coat to the fibrous outer layer, and even to the surrounding tissues. Dilata- tion occurs above the tumor, and occasionally perforation results from ulcerations caused by retained food. Local or more distant metastasis may take place. Cysts of the esophagus may occur. They are supposed to be due to misplaced lung or tracheal tissue. Many of them contain ciliated epi- thelial lining, strongly suggesting the latter origin. DISEASES OF THE GASTRO-INTESTINAL TRACT 613 THE STOMACH CONGENITAL DEFECTS Complete absence of the stomach has been found in certain mon- strosities; but stenosis or atresia of the pylorus, division by the forma- tion of septa, and hour-glass contractions have been more frequently observed. In cases of transposition of the viscera the stomach may be reversed in its position, the pylorus being on the left side, the cardiac end to the right. Congenital hypertrophic stenosis of the pylorus with or without dilatation of the stomach has been found more common than previously thought. The hypertrophy may affect either the pyloric mucosa or muscularis, or both. This is entirely apart from spastic stenosis of the pylorus in children, which has no anatomical basis. There may be some inflammation with the pyloric stenosis. There is occasionally a hypertrophy of the middle of the stomach wall which gives a picture somewhat like hour-glass stomach, and, of course, this condition can be simulated in later life by cicatricial con- traction. During digestion the midpiece of the organ contracts so far that there is a similarity to congenital hour-glass deformity. CIRCULATORY DISTURBANCES Anemia of the mucous membrane is found in cases of general anemia, particularly in pernicious anemia. The mucosa has an extremely pallid appearance, and is prone to undergo fatty degeneration and atrophy. Hyperemia.— Active congestion occurs in the beginning stages of in- flammation of the mucous membrane of the stomach, and results from irritating mechanical or chemical agents. The mucosa is bright red in color and may present minute hemorrhages. Moderate hyperemia is functional during the period of digestion. Passiwe hyperemia occurs as a result of obstructive heart disease or, more particularly, from obstruction of the portal circulation by cirrhosis or other diseases of the liver. Pulmonary affections, by interfering with the outflow of blood from the right side of the heart, may also occasion congestion of the stomach. The mucosa is dark red in color, swollen, and often edematous. Minute hemorrhages may occur, and small erosions may appear upon the surface. The changes are more marked near the pyloric end of the stomach. When the congestion has per- sisted for some time, dark reddish or bluish pigmentation, usually occurring in punctate form, is developed and chronic gastritis results. Hemorrhage in the mucous membrane or from the mucous mem- brane of the stomach results from a variety of causes. Small petechize are met with in active or passive congestion and in acute inflammations, and they may follow thrombosis or embolism of the gastric vessels. Milder poisons cause them. They are also present in various infectious 614 A TEXT-BOOK OF PATHOLOGY or hemorrhagic diseases, such as purpura, scurvy, septicemia and the like, and in anemic affections like pernicious anemia. In many cases punctiform hemorrhages are developed just before death. These are all submucous hemorrhages, from the overlying mucosa of which the gastric juice may digest the covering, leaving erosions which may go on into distinct ulcerations. Larger hemorrhages, and particularly hemorrhages into the cavity of the stomach, result from intense passive congestion in cardiac dis- ease or cirrhosis of the liver, and from gastric ulceration or carcinoma. When large vessels have not been eroded the blood escapes gradually, and may be vomited in a semidigested and disorganized condition (coffee-ground vomit). This is peculiarly significant of carcinoma. When one of the larger vessels has been eroded, large quantities of fresh blood may be vomited and rapid death may occur. Occasionally hemor- rhage from the stomach in considerable quantity occurs in cases in which there is no visible lesion of the mucosa. Melena neonatorum, the vomiting of blood by the newborn, results from gastric hemorrhage due to disturbances of circulation because of insufficient respiration, and possibly in other cases is a variety of infec- tious hemorrhagic disease. INFLAMMATION Acute inflammation of the mucosa, or acute gastritis, results from irritation by chemical, mechanical, or thermal agents. Some cases are doubtless due to infection. The mucous membrane is bright red and covered with more or less viscid mucous exudate. Punctate hemor- rhages may occur. Microscopically, there are found: marked mucous degeneration of the cylindrical cells of the tubules, and desquamation and granular degeneration of the cuboidal cells in the fundus of the glands. The mucous membrane between the tubules is infiltrated with round cells, and not rarely the same process occurs in the submucosa. The collections of lymphatic tissue (follicles) in the mucous membrane are often hyperplastic. Acute gastritis is more frequently found near the pyloric end than elsewhere. In considering the réle of bacteria in the causation of gastritis it must be remembered that the bacteria normal to the stomach are few and not pathogenic. Most pathogenic bacteria are destroyed in the normal stomach. When, however, gastric mucosa and juice are altered by irritant poisons or by the fermentations and putrefactions arising in food taken to excess, especially in the presence of deficient propelling power by the muscular coat, the natural protective powers of the stom- ach are reduced. In such cases pathogenic germs introduced with the food thrive and attack the damaged walls. The normal flora comprises sarcine, moulds, and yeasts. Pseudomembranous gastritis may result from the ingestion of cor- rosive poisons, and is occasionally seen in small-pox, typhus fever, and various forms of septicemia. It may be met with in diphtheria, and DISEASES OF THE GASTRO-INTESTINAL TRACT 615 may be due to direct extension of the process along the esophagus. The surface of the mucosa is covered with an irregular membrane, and necrosis and ulceration are not rarely observed, especially in cases due to corrosive poisons. Ulcerative Gastritis.—Small erosions may be found in cases of ex- treme congestion or petechial hemorrhage, as well as in acute gastritis. Actual ulceration is seen in pseudomembranous gastritis, and occa- sionally as a result of septic embolism in the mucosa in cases of malignant endocarditis. Infectious ulcerations occur in gastro-intestinal tubercu- losis, anthrax, and in typhoid fever, but are very rare. Chronic gastritis may result from repeated attacks of acute gas- tritis, and is especially prone to occur from improper habits of eating or from the abuse of alcohol. Chronic congestion, such as occurs in heart disease, strongly predisposes. Le Fig. 268.—Chronie gastritis, showing polypoid projections of the mucosa. Pathological Anatomy.—The appearance of the mucous membrane varies greatly. In the milder cases the surface is more or less irregular and granular, and is covered with mucous exudate. The color may be grayish, but in cases in which passive congestion has preceded the de- velopment of gastritis it is often slate colored from pigmentation. Microscopically, there may be found mucous degeneration of the cylindrical epithelium of the tubules, and desquamation and not rarely proliferation of the secretory epithelium in the fundus of the glands. The glands may be considerably dilated and filled with mucous exudate and desquamated cells. The interglandular tissues are infiltrated, and may be thickened by the formation of new connective tissue; the same process may involve the submucous coat. The blood-vessels of the latter are often greatly dilated and their walls may be thickened. In the later stages the glands may undergo progressive atrophy, the epi- thelium disappearing almost entirely and the lumen of the gland be- 616 A TEXT-BOOK OF PATHOLOGY coming less and less distinct. Coincidently with these changes, and to some extent causing them, there is fibrous overgrowth of the intergland- ular tissues. : In some instances the contraction of the new-formed connective tissue causes protrusions of the mucous membrane or polypoid eleva- tions (Fig. 268). These may still further enlarge by proliferation and cystic distention of their glandular elements.. In other cases the pro- liferative changes in the interglandular tissues may be more diffuse and the mucous membrane more regularly thickened. To both of these forms the name hypertrophic gastritis may be applied. In still other cases the formation of fibrous tissue causes pressure-atrophy of the glands; the surface in these cases becomes smooth and the mucosa greatly thinned (atrophic gastritis). The sclerotic process may involve not only the mucous membrane, but also the submucous and even the muscular coat. In such cases the thickness of the walls of the stomach may increase greatly, and the size of the organ greatly diminish by contraction. The terms interstitial gastritis, linitis gastrica, and leather-bottle stomach have been applied to such cases. It is sometimes difficult to distinguish such cases from diffuse scirrhous carcinoma. Pathological Physiology in Gastritis.—All forms of gastritis cause disturbances of the functions of the stomach, designated by the terms dyspepsia and indigestion. These disturbances are due to abnormal secretion of the gastric glands, reduced motor power of the walls of the stomach, and altered conditions of the nervous mechanism. The most important alteration of secretion is reduction of the amount of hydro- chloric acid. This is almost constant in uncomplicated gastritis; in some cases there is practically no hydrochloric acid reaction. The ferments, pepsin and curdling ferment, may be produced in insufficient amount, but are very rarely absent. In cases in which certain general conditions or nervous affections coexist with moderate gastritis, excess of hydro- chloric acid secretion occurs. Reduction in the amount of hydrochloric acid causes delay and inadequacy of digestion of proteins. When the - acid is wholly wanting, decomposition of the proteins may occur, and sulphuretted hydrogen and other products of decomposition result. Excess of hydrochloric acid interferes with salivary digestion in the stomach, and, in consequence, fermentation of carbohydrates, with pro- duction of lactic, butyric, or acetic acid and of various gases, takes place. Such fermentation, however, is not, as a rule, observed unless the motor power of the stomach is deficient and the food is retained in the stomach beyond the usual time. It is not improbable that toxic substances are produced in some cases by protein decomposition, but accurate ob- servations are wanting. The motor power is usually deficient in proportion to the intensity of the gastric disease. In some cases the food is retained many hours longer than the usual periods, and fermentation and decomposition are thus greatly favored. Dilatation of the stomach may be brought about by the retention of food and the accumulation of gases of decomposition, DISEASES OF THE GASTRO-INTESTINAL TRACT 617 and the dilatation, in turn, increases the motor insufficiency of the wall. Altered conditions of the nervous mechanism of the stomach mani- fest themselves in a variety of ways. Sometimes there is excessive irritability of the mucosa, causing vomiting; in other cases a feeling of heaviness or pain. Alterations of appetite and of gastric motility are other results probably brought about, in part at least, through nervous disturbances. The general metabolism suffers profoundly in gastric disease— mainly in consequence of the insufficient food eaten or digested. Ema- ciation and systemic depression are the clinical consequences. It is possible that toxic substances produced in the stomach contribute to the metabolic disturbances, but this remains to be proved. GASTRIC ULCER Gastric, peptic, or round ulcers are roughly circular defects of the mucosa and part of the submucosa, probably due to the digestive action of the gastric juice upon a section of stomach wall previously deprived of its natural resistance. Similar lesions may occur in the upper end of the duodenum and in the lower end of the esophagus. Mayo has insisted that duodenal ulcers are much more frequent than has been heretofore believed, and that they are more common in men than in women. Etiology.—Many cases occur in young women suffering from chlorosis or anemia and general malnutrition, but the majority of peptic ulcers occur in males. The pathogenesis of these ulcers has occasioned much dispute. It is admitted that they are due to the action of the gastric juice upon parts of lowered vitality, and the term wlcus ea digestone is, therefore, appropriate. Increased acidity of the gastric juice is an undoubted factor. The lowered vitality which localizes the ulceration has been ascribed to many causes. Embolism or throm- bosis with infarction was suggested by the shape of the ulcers, and may be the explanation for some cases. Spasm of the blood-vessels: in localized areas, possibly due to stimulation of the vagus, and thickening of the walls of the vessels, leading to anemia, have been suggested, as have also direct traumatic injuries of the mucous membrane and ex- ternal traumatism, causing rents of the mucous surface. Circulatory disturbances due to tight lacing are supposed by some to be important. When these peptic ulcers occur beyond the pylorus in the duodenum, they very rarely appear below where the intestinal contents are acid. For the chronic ulcers, alterations in the position and rugosity of the mucosa probably play a part. If the mucosa be thrown or drawn mechanically into abnormal folds the circulation is naturally altered and resistance to autodigestion decreased. Adhesions without may also have such a result. By some authors blood-vessel changes are held responsible, as arteriosclerosis, endo-arteritis, and thrombosis are exceedingly common in the vessels supplying the affected parts. It is 618 A TEXT-BOOK OF PATHOLOGY probably well at this time, when the question is as yet unsettled, to explain peptic ulcers as the result of the action of gastric juice, probably high in acidity, upon a small locality deprived of its resistance. The ‘multiple benign ulcers seen in general infections or blood dyscrasias are doubtless of the same origin. They seldom if ever perforate, and give no symptoms. Gastric ulcers have been attributed to streptococcal embolism and thrombosis. Superficial ulcerations are said to occur if bile enter the stomach when there is 0.5 per cent. or more of hydrochloric acid present. Both of the above statements gain somewhat in value in view of the ex- perimental observations that streptococci are resistant to the antibac- terial action of the bile. Trypsin from the duodenal contents, entering an atonic stomach by reason of a relaxed pylorus, is said to have a potent effect on ulcer production. These observations by American workers may assist in clearing up the etiology of peptic ulcers. Fig. 269.—Peptic ulcer, showing erosion into a blood-vessel in the floor of the ulcer (Bol- nger). Pathological Anatomy.—Peptic ulcers are usually single, but may be multiple. They are commonly situated in the lesser curvature and the posterior wall of the stomach, near the pylorus; occasionally they are found at the fundus or at the cardiac end. A striking form is the large saddle-shaped ulcer which has a narrow part in the lesser curvature and large spreading wings in the anterior and posterior wall of the stomach. They vary in diameter from a few millimeters to 3 or 5 em. Their shape is characteristic in that they have sloping edges, giving them a funnel form, with the apex toward the muscular coat. The shape corresponds to the distribution of the gastric arterioles. The edges may be irregular and rough, but are often, especially in older ulcers, quite smooth and rounded. Two dangers are always imminent—hemorrhage and perforation. Constant oozing of blood may be due to erosion of the surface, and larger hemorrhages may result from ulceration of one of the larger DISEASES OF THE GASTRO-INTESTINAL TRACT 619 arterial branches of the stomach (Fig. 269). Perforation is less common than hemorrhage. When the ulcer is situated posteriorly perforation is prevented by adhesions attaching the stomach to the head of the pancreas or other structures. When the ulcer is in the anterior wall per- foration is more liable to take place (Fig. 270). The rupture may occur into the peritoneal cavity or into any of the surrounding structures, and fistulous communications may be established with the pleural or peri- cardial cavities, or even with the exterior through the abdominal walls. Abscesses of the liver, spleen, or pancreas may result from perforation into these organs. Fig. 271.—Stellate scar of a healed ulcer of the stomach (Bollinger). Microscopically, there is little to be seen aside from loss of surface tissue. In the older cases a slight circumferential fibrous tissue in- crease, especially at the thickened margin, may be found. In the healing of the ulcers scars are formed in the wall of the stom- ach. These have usually a rather characteristic stellate shape (Fig. 271). 620 A TEXT-BOOK OF PATHOLOGY In case of large ulcers extensive scars and considerable contraction of portions of the walls of the stomach result. Hour-glass contraction of the organ, or pyloric stenosis, may follow, and secondary changes, such as gastric dilatation, may ensue. Carcinomatous transformation is a not infrequent result of long-standing ulceration. ATROPHY AND DEGENERATIONS Atrophy of the glands or gastric tubules is frequently seen in chronic gastritis. The same condition occurs as a senile change and in asso- ciation with various chronic diseases, especially pernicious anemia. A certain amount of atrophy of the entire mucous membrane results in a purely mechanical way from gastric dilatation. Decrease in the size of the stomach as a whole may be the result of chronic gastritis, when the new-formed connective tissue contracts. In such cases the stomach may become quite small, the walls, however, increasing in thickness. Somewhat similar shrinkage in the size of the stomach occurs in some instances of infiltrating cancer of the stomach. The tumor may involve all parts of the organ equally, and cause more or less thickening of its walls, but the size of the organ is diminished by contraction of the connective tissues. A form of true atrophy is sometimes caused by obstruction of the cardiac orifice; it is probably due, in part at least, to the insufficiency of food admitted to the stomach. Degenerations of the mucous membrane of the stomach are met with either in association with inflammation or as independent affec- tions. Fatty degeneration of the epithelial cells of the glands may be the result of intoxications (phosphorus, arsenic), or of conditions such as those which lead to simple atrophy. The occurrence of atrophy and fatty degeneration of the gastric tubules in cases of pernicious anemia is of great importance, though it remains unsettled whether these conditions are the cause or result of the anemia. Pigmentation is met with as a result of chronic congestion or hemor- rhage into the mucous membrane. The mucosa has a dark red or often a slaty discoloration, which is prone to be distributed in lines or in cir- cumscribed patches. Bluish pigmentation of the stomach sometimes occurs from the ingestion of silver. Amyloid infiltration may be found around the blood-vessels of the submucosa, or more rarely of the mucosa itself, in cases of general amy- loid disease. Amyloid ulcerations may occur. Calcification has been met with in cases of bone disease with sur- charge of the blood with earthy salts. It appears in the form of scales or plates of calcification upon the mucosa. Gastromalacia, or simple softening of the walls of the stomach, is usually a postmortem condition, and is due to the action of the gastric juice. The nature of this process has occasioned much discussion, but it is now recognized as a postmortem condition, or as a condition occurring DISEASES OF THE GASTRO-INTESTINAL TRACT 621 during life only in the agonal period. It affects the fundus or posterior part of the stomach. The mucous membrane becomes soft and more or less gelatinous, and is grayish or yellowish in color if the mucosa was anemic, or brownish in cases in which there was congestion before death. Rupture and discharge of the contents of the stomach into the peritoneal cavity, spleen, or other adjacent organs may occur. The walls of the stomach in the affected area show granular degeneration of the component cells, but no evidences of inflammatory reaction, and when rupture has occurred there are no reactive inflammatory lesions of the peritoneum, showing that the perforation occurred after death. ALTERATIONS IN POSITION AND SIZE Alterations in Position.—The stomach may be displaced into the thoracic cavity in cases of perforation or rupture of the diaphragm (diaphragmatic hernia). It may be displaced anteriorly as a congenital malposition in consequence of defects of the anterior abdominal walls, and may in such cases be quite exposed. Downward dislocation, or gastroptosis, is either congenital or acquired. The acquired form may be due to diseases of the stomach, particularly dilatation, to the traction of inflammatory adhesions, to enlargement of the spleen, and probably to tight lacing. Occasionally in anemic and relaxed women all of the ab- dominal viscera tend to descend (splanchnoptosis). Dilatation, or gastrectasia, most frequently results from obstruction of the pylorus. The latter may be due to cicatrization the result of the healing of ulcers, to fibroid overgrowth and contraction the result of chronic gastritis, or to pyloric carcinoma. The pressure of tumors, of a movable kidney, or of aneurysms may act similarly. At first, pyloric stenosis may be compensated by hypertrophy of the muscular layer of the stomach, but soon dilatation occurs; food stagnates, fermentation takes place, and the dilatation is increased. The mucosa becomes thin and ofttimes degenerated and atrophic, the exact changes being those of the specific variety of gastritis existing. A second group of cases (atonic dilatation) is independent of stenosis of the pylorus, but due to weakness of the walls of the stomach. The latter may be the result of chronic gastritis or of a general atonic state. Constant overeating may play an important part in some cases. Finally, dilatation may result mechanically from abnormal adhesions of the stomach. Dilatation of the stomach occasions great stagnation of food and, in consequence, imperfect digestion and decomposition of the food. When hydrochloric acid is absent (as in cancerous stenosis of the pylorus and marked atonic dilatation) lactic acid fermentation is pronounced; when hydrochloric acid is present lactic acid is less abundant or absent. Sulphuretted hydrogen and inflammable gases are occasionally formed, especially in cases in which hydrochloric acid is present. The mucous membrane of dilated stomachs loses its absorptive power to a large de- gree. This, together with the retention of ingested liquid in the stom- 622 A TEXT-BOOK OF PATHOLOGY ach and the consequent lessening of intestinal absorption, leads to great emaciation, and especially to desiccation of the tissues. The muscu- laris shows hyaline change and thinning, with elongation of the fibers, The mucosa shows atrophic glands, with fatty cells. Among the micro-organisms met with in the gastric contents the Sarcine ventricult are of interest. These occur in bundles of peculiar square form. The sarcina is more frequent in non-cancerous than in cancerous dilatation. In cases of dilatation due to cancer of the stom- ach the Oppler-Boas bacillus is found (see below). An acute form of gastric dilatation sometimes occurs after anes- thesia, following indiscretions in diet, as a result of pressure on the duo- denum when the mesentery is pulled upon by twists of the intestine, after traumatism, and at times without demonstrable cause. The most frequent anatomical factor is twisting of the intestinal loops, especially in the presence of an abnormally long mesentery. The method of action of these causes is not clear, but they probably operate by paralyzing the gastric wall. INFECTIOUS DISEASES A few cases of tuberculous ulceration have been recorded, and syph- alitic gummata or ulceration may occur. The tuberculous processes may be hematogenic or localized, in which latter case they are secondary to peptic ulcer; they assume a ragged, punched-out appearance and seldom perforate. Diffuse cirrhosis and ordinary gastritis may be dependent upon syphilis, but the etiological connection is uncertain. Anthrax may lead to necrotic and hemorrhagic ulcers of the mucosa. Thrush is rarely met with, though the spores of the saccharomyces are frequently present in the stomach when the mouth is affected. TUMORS Connective-tissue Tumors.—Fibroma, myoma, and lipoma are occa- sionally met with as submucous or subserous polypoidal tumors. Sar- coma is rare. It affects the lymphoid tissues of the deeper parts of the mucosa, and rapidly spreads to the submucosa. Most cases are of the round-cell variety. Lymphoid infiltrates of the adenoid tissues of the stomach may be one of the lesions of leukemia or Hodgkin’s disease. Epithelial Tumors.— Polypoid elevations, sometimes with cystic en- largement of the glands, occur as a result of chronic inflammation, and may be large enough to be regarded as tumors in a clinical sense. Adeno- matous proliferation of the glands is met with in the form of irregular, flat tumors, but these so rapidly become carcinomatous that pure ade- noma scarcely exists. Carcinoma is the most frequent tumor of the stomach. It occurs at middle age, and more often in the male sex than in the female. The pyloric end of the organ and the lesser curvature are the favorite sites, but other parts may be affected and the entire organ may be in- volved. Cancer of the stomach may appear as a ring-like swelling of the DISEASES OF THE GASTRO-INTESTINAL TRACT 623 mucous membrane and submucous tissue, surrounding the pylorus and causing stenosis; as more or less circular, flat elevations in the lesser curvature or elsewhere; and, finally, as a diffuse infiltration of the mu- cosa, submucosa, or all of the coats of the entire organ. The mucous surface is generally irregularly elevated, and tends to become ulcerated, especially in medullary cancer and in the cases in which there are local- ized flat elevations. Sometimes portions of the cancerous tissue may be found in the vomitus, and the diagnosis of the disease may be thus established (Fig. 272). Perforation of the wall of the stomach may result from necrotic and ulcerative processes (Fig. 273). The neighbor- ing lymphatic glands, especially those in the lesser curvature of the Fig. 272.—Fragment of carcinomatous tissue found in stomach-washings (Reinevoth). stomach, are usually implicated through the lymphatic vessels. Direct extension to the peritoneum may occur, especially in cases of colloid cancer; and metastasis through the blood-vessels is extremely common. Cancerous emboli are frequently found in the portal radicles within the liver, and multiple cancer-nodes of the liver are usually found in cases which have existed for some length of time. Hematogenous metastasis is most common in soft, ulcerating cancers. Varieties —There may be distinguished hard or scirrhous cancers, soft or medullary cancers, adenocarcinomata or malignant adenomata, and cylindrical-celled or squamous-celled carcinomata. All forms begin in the mucous membrane and spread to the submucosa. The muscu- 624 A TEXT-BOOK OF PATHOLOGY laris may be penetrated and infiltration of the serosa, or even of sur- rounding tissues, may be observed. Scirrhous cancer may appear as a circular constricting new growth at the pylorus (Fig. 274). In other cases the disease is extensive, and Fig. 273.—Carcinoma of the cardiac end of the stomach; extension into duodenum: S, ae esophagus; K, ulcerated carcinoma; G, a perforating ulceration; M, stomach (Orth). the entire organ may be involved by uniform infiltration, and macro- scopically the appearance of a simple cirrhosis of the stomach is pre- sented. In the last-mentioned variety the organ may be greatly reduced in size, though the walls are greatly thickened. The mucous surface rarely ulcerates in scirrhus. lilt HT He iy (\ as Fig. 274.—Scirrhus of the pylorus, causing pyloric stenosis: D, Duodenum; P, pylorus; K, carcinomatous projections on the mucosa (Orth). Medullary or soft cancer usually appears as a localized tumor at the pylorus or in the lesser curvature. The mucous membrane is irreg- ularly elevated, ofttimes in a cauliflower manner (Fig. 275). Ulcera- tion on the surface is common, and hemorrhagic extravasation into the DISEASES OF THE GASTRO-INTESTINAL TRACT 625 stomach is, therefore, frequent. Metastasis through the blood is liable to occur. Complete perforation of the stomach may take place. Malignant adenoma, or adenocarcinoma, begins as a proliferation of gastric tubules. The new-formed acini are, however, atypical in arrangement and number, and there is a tendency to conversion of the normal cylindrical cells into cuboidal cells, and to extensive cancerous infiltration by excessive formation of acini or tubules, as well as by de- struction of the basement-membrane of the acini and irregular cellular invasion. The appearance of the tumor and its tendencies are the same as those of soft cancer. Cylindrical cancer, or cylindrical epithelioma, probably arises from the cvlindrical lining cells of the stomach, or from the cells in the upper parts of the tubules. Atypical tubular aggregations of cylindrical cells with a tendency to conversion into cuboidal cells are observed. The pylorus is the common seat. Fig. 275.—Cauliflower carcinoma of pylons ) M, Stomach; P, pylorus; D, duodenum rth). Squamous cancer occurs at the cardiac end, and generally in asso- ciation with carcinoma of the lower end of the esophagus, from which the squamous epithelium extends a short distance into the stomach. It is rare. Colloid cancer of the stomach appears as a localized or, more fre- quently, diffuse infiltrating, gelatinous new growth of the mucosa and submucosa. Rapid extension through the walls of the stomach and to the peritoneum is frequent. The cells and the stroma of the tumor show myxomatous degeneration; and the epithelial elements may in the later stages entirely disappear. Extensive invasion of the perito- neum is not infrequent. Pathological Physiology and Results.—Carcinoma of the stomach is most frequently situated at or near the pylorus, and, therefore, inter- feres with the propulsion of food. Stagnation of the stomach contents and fermentation result. The latter is favored by the absence of hydro- chloric acid secretion so habitually observed. In consequence of the 40 626 A TEXT-BOOK OF PATHOLOGY stagnation the stomach dilates and may reach enormous size, not rarely filling a large part of the abdominal cavity. Lactic acid fermentation is frequently pronounced. Disturbances of metabolism, with loss of flesh and strength, are marked. Among the micro-organisms present in the stomach contents a long, thread-like bacillus (Oppler-Boas) has at- tracted much attention, and has been supposed by some to occur only in cancer of the stomach. It is certainly frequent, but just as certainly not peculiar to the disease. THE INTESTINES CONGENITAL AND ACQUIRED ABNORMALITIES Occasionally total absence of large parts of the intestinal tract is found in monstrosities. Lesser defects, leading to narrowing or dis- tortion of the intestines, are more frequent. Marked developmental de- fects most frequently occur in the rectum, which may be completely absent, or may be obliterated at the lower end. In such cases there may be fistulous communications with the urogenital tract, or there may be a persistent cloaca, as in fetal life. Congenital Enlargement of the Intestines.—The colon is most apt to be affected, and may be greatly enlarged, the most important exam- ple of which is Hirschsprung’s disease or megacolon. This may affect the whole colon or only the descending part. By some, atony or incom- pletion of the musculature is held responsible, while others look upon it as obstructive from abnormalities in the mesocolon. Diverticula.—Localized dilatations, constituting diverticula, are frequent, the most common form being Meckel’s diverticulum. This usually arises from the ileum, about 1 meter above the ileocecal valve, and is attached to the intestine opposite the mesentery. It represents the remains of the omphalomesenteric duct of fetal life. Occasionally it has been found patulous to the umbilicus. More commonly there is merely a short diverticulum of the intestines, vary- ing from a few to several centimeters in length, and having a closed extremity which may be somewhat dilated. The extremity may be connected with the umbilicus by a cord, but is usually free. Diverticula are also formed in later life. Very commonly, in cases of constipation, small pouchings or dilatations occur in the large intes- tine, particularly in the descending colon and rectum. Another form affects the small intestine more commonly than the large bowel. In this there are found small pouches lying near the mesenteric attach- ment, and owing their origin to localized weakness or separation of the muscle-fibers of the bowel. Protrusion of the mucosa takes place, prob- ably as a result of pressure from within; and the pouch is, therefore, a hernia-like projection of the mucosa and serosa through separated mus- cular fibers. Such diverticula may be multiple or single. The importance of the diverticula, especially the Meckel variety, is that they may be involved in inflammation which may lead to per- DISEASES OF THE GASTRO-INTESTINAL TRACT 627 foration or to adhesions. In the latter case coils of intestines may be constricted and lead to ileus. Meckel’s diverticulum, when not inflamed but if attached at the umbilicus, sometimes catches a knuckle of gut and leads to intestinal obstruction. Congenital Abnormalities in Position.—The position of the several parts of the intestinal tract may vary widely from the normal. Not rarely the ascending colon and cecum are situated on the left side; the sigmoid flexure and descending colon being on the right side. Cecum mobile is an abnormal looseness of cecum, sometimes leading to surgical conditions in this organ or the appendix. Enterocystoma.—A congenital cystic condition found at the um- bilicus has been described as cystic dilatation of parts of the original omphalomesenteric system of the fetus, and has been named “entero- cystoma.” Dilatation.—More or less uniform enlargement of the intestines may result from long-standing constipation. Enormous dilatation of the colon is sometimes seen. In this the wall of the intestine undergoes compensatory hypertrophy, and small pouchings or diverticula are commonly observed, especially in the rectum. This is the chronic dilatation. Acute dilatation is due to sudden obstruction, as from a foreign body or by paresis of the muscular wall, as occurs by blows on the abdomen. Again, the dilatation may be acute, but not necessarily sudden, when the gut walls are paralyzed by peri- tonitis or by toxins of diseases not localized to the abdomen (menin- gitis). Acute dilatation occurs in surgical shock. Narrowing, or stenosis, of the intestine at any part may be due to pressure of new growths or displaced viscera, to cicatricial constric- tions following ulcerations, or to neoplasms. Cicatricial stenosis is par- ticularly common in the rectum following dysenteric or syphilitic ulcers. Narrowing of the lumen may be due to an ingrowth of carcinoma or the presence of papillomatous or polypoid tumors within. Hernia.—This term is applied to malposition of any of the viscera, with displacement of the organ from the cavity in which it normally lies; but it has been more particularly applied to such displacements of the intestines, and the single term “‘hernia”’ is significant of intestinal hernia. Occasionally herniz are congenital; more often they are acquired. Hernia occurs at the points where the abdominal wall or the peritoneum is naturally weak from the emergence of vessels or the existence of natu- ral outlets, or has become weakened by injury or surgical operation. Etiology.—The predisposition to hernia may consist in unnatural weakness of the abdominal wall, especially at the points where hernia is likely to occur, resulting from imperfect closure of such portions or from general muscular weakness. Abnormal movability of the intes- tines, resulting from natural or acquired elongation of the mesenteric attachments and increased weight of the abdominal contents from the deposit of peritoneal fat, contributes largely to the formation of hernie. The immediate exciting cause in many cases is strain, and probably in all’ 628 A TEXT-BOOK OF PATHOLOGY cases repeated strain helps in the development of the protrusion. The most frequent form of ventral hernia is the umbilical, which occurs especially in infants as the result of imperfect closure of the abdominal walls at the umbilicus. There may be distinguished two groups or varieties—the internal and the external hernie. Internal Hernia.—By this term are designated hernia-like displace- ments of the intestines into other cavities within the body, the most im- portant being upward displacement into the thorax through congenital or acquired clefts of the diaphragm (diaphragmatic hernia); and back- ward displacement through the peritoneum into the retroperitoneal space (retroperitoneal hernia). External hernia may be inguinal, femoral, ventral, vaginal, rectal, perineal, ischiatic, or obturator. The most frequent of these are the in- guinal and the femoral. In the former the protrusion may occur through the external inguinal ring, the intestine descending through the in- guinal canal, sometimes as far as the scrotum (andirect inguinal hernia). In another group of cases the intestine pushes directly forward through the abdominal wall and external inguinal ring, and may present ante- riorly under the skin, or may descend through the lower part of the inguinal canal to the scrotum (direct inguinal herma). The indirect inguinal hernize are sometimes congenital, and are due to the failure of closure of the peritoneal reflection which passes downward through the inguinal canal. Femoral herniz are especially common in women, and are formed by protrusion of the intestine through the femoral ring, the hernia present- ing on the inner side of the thigh, at the position of the saphenous opening. Pathological Anatomy.—The hernia consists of a sac or wall and of the contents of the hernia. The sac is usually constricted at its junction with the general peritoneal cavity (neck), and distended and dilated outside of or below this point (fundus or body of sac). The sac of the hernia is always lined with the protruded portion of the peritoneum. The contents of the hernia may be coils of intestine or portions of omentum, or both. Most frequently some part of the small intestine occupies the hernia, and sometimes simply a Meckel’s diver- ticulum has been discovered. In rare cases the sigmoid flexure or other parts of the great bowel may be found. Secondary changes often ensue. Inflammation of the ining mem-. brane of the sac and of the intestinal coils may lead to fibrous adhesions constricting the neck of the sac and binding the intestines firmly in place. If the contents of the hernia have receded, such inflammation may obliterate the sac completely or merely at its neck, the body of the sac in the latter case becoming distended with serous liquid. In cases - in which portions of omentum are included in the hernia, hypertrophic overgrowth of the adipose tissue may occur, and may lead to appear- ances not unlike those of a lipoma. Hernie are described as being reducible and irreducible, according to the ability of replacing the contents into the peritoneal cavity or not. DISEASES OF THE GASTRO-INTESTINAL TRACT 629 Herniz become irreducible when the coils of intestine are distended by the accumulation of fecal matter, when fibrous adhesions have narrowed the neck of the sac or bound the coils firmly in place, or when additional coils of intestine or portions of the omentum have descended into the hernia. Strangulated Hernia.—This term is applied to hernia in which pres- sure at the neck by inflammatory exudation or constriction, or in- veterate obstruction by accumulating contents of the bowel, has led to obstruction of the circulation in the intestinal coils of the hernia. Intense passive congestion, inflammation of the peritoneal covering of the intestines within the hernia, and, finally, gangrenous necrosis are the frequent results. INTESTINAL OBSTRUCTION Complete obstruction of the intestines, or ileus, may be due to in- ternal strangulation by bands of adhesions, to a twist or volvulus, or to intussusception or invagination. Internal strangulation may be due to the obstruction of a coil of intestine by fibrous peritoneal adhesions, or by a coil slipping through abnormal openings or perforations in the mesentery or omentum. The persistence of the cord passing from the end of a Meckel’s diverticulum to the umbilicus is an unusual cause. The results of internal strangulation are generally serious. Great dilatation occurs above the point of obstruction, the intestine below becoming collapsed. Great congestion and subsequently peritonitis occur at the point of stricture, and necrosis with perforation may ensue. The constitutional symptoms may be due to absorption of toxic sub- stances developed in the strangulated parts, that is, in the gut walls by autolysis. The results are essentially the same for obstruction of all parts of the intestines, but appear more rapidly when the upper parts are affected. The loss of water is due to drainage of large quantities into the gut lumen. These theories hold for all forms of obstruction, including the postoperative intestinal paresis. Volvulus is the term applied to a twist of some part of the intestinal canal. Occasionally there is simple rotation of the bowel about its own axis, but more commonly a loop of intestine twists about on its mesenteric attachment. Abnormal laxity of the mesentery is an important pre- disposing cause, and may be a congenital condition, or may result from the absorption of fatty deposit between the mesenteric layers. The immediate cause is generally strain or abdominal compression. The most frequent seat of volvulus is the sigmoid flexure. The bowel above the point of obstruction becomes distended, as in internal strangulation, while the coil included in the twist itself is engorged with blood and often presents hemorrhagic infarctions in consequence of obstruction of the veins in the mesentery. Gangrene of the bowel may result. Complete knots are occasionally observed in volvulus. Intussusception, or invagination, is a condition in which one part of intestine slips into an adjoining part, as one may invert the finger of a glove (Fig. 276). The upper part of the intestine is usually indu- 630 A TEXT-BOOK OF PATHOLOGY plicated and pushed into the lower part. Irregular peristalsis, resulting from intestinal disorders, and particularly from atony of one part with increased activity of adjoining parts, is the most frequent cause, and con- tinuing in the disturbed part further propels the outer over the inner segment, or vice versd, as it would a mass of feces. Occasionally poly- poid tumors within the bowel are dragged forward by the peristalsis, and carry the higher part of the intestine to which they are attached into the lower part. Intussusception is more common in children than in adults, and affects the ileocecal region most commonly. Not infre- quently multiple invaginations are found in the small intestine of children; these probably occur during the death agony or postmortem. The portion of the gut slipping into the re- ceiving part is called the intussusceptum; the outer or receiving section, the intussuscipiens. The appearance of intussusception is simply that of one part of intestine pushed into the ad- joining part, with secondary inflammatory and congestive changes. Most frequently invagina- tion begins at the ileocecal region, the valve and ileum being carried forward into the ascending colon. Very rarely the ileum itself invaginates through the valve. The attachment of the mesen- tery leads to a sharp angulation of the area of in- vagination, and the extent to which the protrusion may occur will depend upon the length of the a eee mesentery. Occasionally the ileocecal valve may ception (from a speci- be carried through the colon and rectum and ren Peale Hoswe present externally. The adjoining serous surfaces tal). of the invagination tend to unite by peritonitis, and the intussuscepted portion may become gan- grenous and be discharged with re-establishment of the lumen. If peritonitis has established union between the ensheathed and the en- sheathing section of the gut, recovery may ensue. Otherwise perfora- tion leads to fatal peritonitis. PROLAPSE OF THE RECTUM Prolapse of the rectum in consequence of weakness of the sphincter and other parts of the wall, together with repeated straining, is a common condition in infants, and is occasionally met with in adults. In children any form of diarrhea may be complicated by prolapse; in adults chronic proctitis is the most frequent cause. The weakened con- dition of the sphincter in proctitis furnishes the predisposition, and the characteristic tenesmus of the disease is the immediate cause. Prolapse may be only an occasional condition, or may be constant. Secondary inflammation, ulceration, and even necrosis of the prolapsed portion may occur. DISEASES OF THE GASTRO-INTESTINAL TRACT 631 ATROPHY AND DEGENERATIONS Atrophy of the mucosa is frequently met with as a part of chronic enteritis in its later stages. This is especially marked in young children suffering from chronic intestinal catarrh and marasmus. Occasionally atrophy of the mucosa or of all of the coats of the intestines may occur as an independent affection, or as the result of marantic or cachectic conditions. Pigmentation may be due to hemorrhages in the mucosa or sub- mucosa, and not infrequently after intense hemorrhagic inflammation the bowel may be quite black from the deposit of hematogenous pig- ment. Brownish pigment deposited in the muscle-cells, analogous to that of brown atrophy of the heart, is occasionally observed in old and cachectic individuals. Similar pigmentation of the muscle-cells and also of the submucosa or mucosa, of even more decided character, occurs in youthful persons addicted to alcohol. The intestines alone may be thus affected, or the liver, spleen, lymphatic glands, and skin are simul- taneously involved. The term hemochromatosis (q. v.) has been proposed for this condition. It is said that pigmentation of the colon may re- sult from absorption of bile derivatives. Pick accounts for some of the obscure pigmentations of the colonic mucosa by assuming a deposit of melanin-like bodies, probably protein digestion products under the in- fluence of tyrosinase. Amyloid infiltration is met with in association with amyloid dis- ease of the liver, kidneys, or spleen, and particularly in cases in which there is tuberculous ulceration of the intestines. The mucous mem- brane is principally involved, and becomes somewhat hardened and pre- sents a peculiar grayish luster. Superficial erosions and even ulcers may result. The process begins, as elsewhere, in and around the small blood-vessels. CIRCULATORY DISTURBANCES Active hyperemia may occur from acute irritation, and forms a part of inflammation. Passive hyperemia results from causes similar to those producing congestion of the stomach. Among these, obstructive diseases of the liver, notably cirrhosis, and cardiac and pulmonary affections are most prominent. The intestinal mucosa becomes somewhat swollen, ofttimes edematous, dark bluish-red in color, and occasionally marked by punc- tate hemorrhages. The mesenteric veins are widely dilated. Occasion- ally hemorrhagic liquid is found within the intestines, the points of hemorrhage remaining undiscovered. Hemorrhage.—Petechie are found in many cases of violent septic or infectious diseases, in intense anemias, and as the result of marked passive hyperemia. Embolism in cases of ulcerative or malignant endo- carditis may lead to petechial hemorrhages, and the same are observed as a part of the morbid anatomy of intestinal anthrax. Large intestinal hemorrhages may occur from typhoid, tuberculous, dysenteric, or syph- 632 A TEXT-BOOK OF PATHOLOGY _ ilitic ulcerations, or from the perforation of a large arterial branch by a peptic ulcer in the duodenum. Hemorrhoids may occasion consider- able hemorrhages from the rectum. Edema of the mucosa may result from passive congestion, and at- tends acute or chronic inflammations, especially the more intense forms. Embolism and thrombosis of the mesenteric arteries are rare conditions, due most often to cardiac embolism, but also to arteriosclero- sis in loco and to downward thrombosis from the portal vein. Embolism may lead to hemorrhagic infarction because of some inadequacy of the anastomosis of the mesenteric vessels, which usually is rich. The re- sult is a stretch of paralyzed, reddened, and swollen gut within which hemorrhage and, later, sloughing occur, corresponding to the distribu- tion of the occluded vessel. Hemorrhoids result from varicose enlargement of the veins of the rectum. They are usually found in the lower part of the rectum, inside or outside the sphincter, and a distinction is made between in- ternal and external hemorrhoids. Etiology— Obstruction of the venous circulation is ihe important eti- ological factor. It may be due to chronic diseases of the liver (cirrhosis), repeated pregnancies, pelvic tumors, or chronic constipation with fre- quent retention of feces in the rectum. The last-named condition acts in a twofold manner. On the one hand, it causes venous obstruction, and, on the other hand, chronic proctitis, which in turn occasions disease of the veins of the rectum, and thus predisposes them to dilatation. In all cases of hemorrhoids, constipation and the resulting proctitis are important as auxiliary causes. The anal veins are poorly supported by connective tissue, so that when the sphincter contracts it holds the blood within the distended vessels. Hemorrhoids are rarely met with before adult age. Pathological Anatomy.—The hemorrhoid presents itself as a small polypoid elevation of more or less congested appearance. On section it is found to be highly vascular and to consist of dilated veins. There may be a congeries of slightly enlarged veins or cavities of considerable size. Between the veins there is more or less abundant inflammatory connective tissue. Thrombosis often occurs within the cavities; and occasionally the fibrous tissue around them undergoes active prolifera- tion, when a structure resembling a fibro-angioma results. Hemorrhagic extravasations may occur from the veins, and free hemorrhage from the surface is a common symptom. Infective inflammation and phlebitis of the veins sometimes occur, in which cases the hemorrhoid enlarges and becomes inflamed and edematous. Inflammation of the adjoining tissues may occur (proctitis, periproctitis). Hemorrhoids may cause marked anemia by the repeated hemor- rhages, and sometimes occasion septic infections when they have them- selves become infected and inflamed. Other varices may arise in the intestines, as, for example, in cirrhosis of the liver. DISEASES OF THE GASTRO-INTESTINAL TRACT 633 INFLAMMATIONS Inflammation of the intestines, or enteritis, may affect any part of the intestinal canal, and involve the mucosa and submucosa more particularly. It'is more frequently present in children and in the aged than at other periods of life. Etiology.—The causes of enteritis are similar to those of gastritis, and among them may be reckoned all forms of irritating foods or foreign matter taken with the food. Poisons of various kinds operate in a similar manner. In many cases the irritant poisons which occasion enteritis are developed within the body in consequence of improper digestion and fermentation. Bacteria play an important réle in this process, and are themselves the direct cause of enteritis in instances in which improprieties of diet or digestive disturbances have furnished favorable conditions for their growth and multiplication. The normal ‘colon bacillus is perhaps the most frequent and important micro- organism of ordinary non-specific enteritis, but other organisms doubt- less frequently play a part. The colon bacillus probably increases in virulence under certain conditions and then occasions irritation. The bacteria of the intestines comprise many species, chiefly sapro- phytic, but which may under appropriate circumstances cause enteritis. They are engaged in fermentation and putrefaction, the two forces being balanced in the normal state. When, however, one or the other is ex- cessive, it reduces the natural protective forces. The normal intestinal wall and juice are protective, but if disturbed are attacked either by the normally present germs or others to whose entrance in food the dam- aged organ offers no resistance. The mechanical conditions mentioned in the discussion of bacteria in the stomach play a similar réle in the intestines. Pathological Anatomy.—There are a number of varieties of enteritis, and different types may be described, though individual cases rarely conform to a single variety. Of the acute forms of enteritis, the impor- tant are the catarrhal, suppurative, and the pseudomembranous. Catarrhal enteritis may affect any part of the intestinal tract. The mucosa is swollen and usually light-red in color; the arteries are visibly distended, and not rarely there are petechial hemorrhages. The surface is covered with mucous exudate containing desquamated and degenerated epithelial cells and emigrated leukocytes; while the intestinal contents are rendered liquid by serous exudation. The solitary follicles or agminated collections of lymphoid tissue may be particularly swollen and cause projections above the surrounding mucosa. The term follicular enteritis is applied to such cases (Fig. 277). In other instances the desquamation of epithelium is more prominent than the mucous exudation, and considerable shreds of mucosa may be loosened and discharged. The term croupous enteritis is suggested by such conditions. The so-called toxic enteritis, such as is seen in toxic (not bacterial) meat-poisoning, is of the catarrhal type, with much hyperemia and edema. Superficial necrosis or hemorrhage may occur. 634 A TEXT-BOOK OF PATHOLOGY Suppurative enteritis differs from the catarrhal form in the greater degree of emigration of leukocytes. The exudate upon the surface may be largely composed of white corpuscles, and in intense cases the surface may be covered with almost pure pus. Round-cell infiltration of the mucosa and the submucosa is present, and focal collections leading to submucous abscesses or to ulcers upon the mucous surface are occasionally seen. The solitary follicles are enlarged and tend to break down, form- ing follicular ulcers. Pseudomembranous enteritis is characterized by the formation of a grayish membrane upon the surface of the intestine. The large intestine is more frequently involved, and the process is especially met with in dysentery (see p. 639). True diphtheria of the bowel with pseudomembranous deposit may sometimes occur. The term ulcerative enteritis is sometimes used, but, as a matter of fact, non-specific ulcerations are relatively rare. Erosions are commoner. It is better to speak of the pathological type of enteritis with ulceration, Fig. 277.—Hemorrhagic follicular enteritis, as the ulcerative forms are considered under typhoid, tuberculosis, and the like. Ulceration of the intestines occurs in a variety of conditions. Peptic ulcers, similar to those met with in the stomach (¢. v.), are occasion- ally found in the duodenum, and are there explained as given for gastric round ulcer. They have the same characters and tendencies as those of the stomach; they may occasion sudden death from hemorrhage. Ulcers in the duodenum are also an occasional result of extensive burns of the skin; and attention has been called to the frequency of duodenal ulcera- tion in cases of chronic Bright’s disease. Ulcerations of the ileum are habitual in typhoid fever and tuberculous enteritis, and are occasionally due to anthrax or actinomycosis. Ulcers may be found in all forms of enteritis of childhood, especially in intense forms and in cases com- plicating the exanthemata. Sarcomata and carcinomata are rare causes. Ulcerations of the large bowel are met with in chronic colitis and dys- entery. A form of peculiar clinical interest is anal fissure. This is a linear ulceration of the rectum in the region of the sphincter. It may be associated with hemorrhoids or may be independent. DISEASES OF THE GASTRO-INTESTINAL TRACT 635 Chronic enteritis results from acute attacks or from repeated irri- tation. Chronic congestion in consequence of hepatic or cardiac affec- tions is a predisposing cause of importance. In the early stages the mucous membrane is usually more or less swollen, and sometimes proliferative changes in the glandular elements may lead to distinct polypoid elevations. These are especially pro- nounced in cases in which the healing of ulcers of acute enteritis has occasioned cicatricial constrictions and thus elevated adjoining parts of the mucosa. The elevated portions may undergo proliferative in- flammation, and polypoid formations result. In the later stages of chronic enteritis atrophy may ensue, in part as the result of the over- growth of the stroma of the mucosa and the degeneration of the glandu- lar elements, in part also as the result of the overdistention or tympany resulting from fermentation of the intestinal contents. This atrophy may affect the mucous membrane alone, but more commonly also in- volves the muscularis. Hyperplastic processes in the lymphoid ele- ments may be a prominent feature in the hypertrophic stage of chronic enteritis, and may give place to atrophy in the later stages. On the other hand, the enlargement of the solitary follicles and Peyer’s patches may persist for a long time after atrophy has led to great thinning of the remaining portions of the mucosa. Pathological Physiology.—Enteritis may occasion profound dis- turbances in a variety of ways. In cases of infective character general systemic intoxication may result from the absorption of bacterial prod- ucts or substances resulting from decomposition of the intestinal con- tents. In other cases the intensity of the local irritation may, through the nervous system, occasion great depression or shock; and subse- quently the exudations into the intestines may cause depletion of the vascular system and failure of the circulation. The local effects and the resulting behavior of the bowels differ in different cases. Sometimes the peristaltic movements are arrested by the intensity of irritation and obstinate constipation results; more frequently hurried peristalsis and the abnormal exudation (serous or mucous) occasion diarrhea. The digestive processes fail from the diseased condition of the bowel, as well as from the rapid peristalsis and premature discharge of the intestinal contents; more or less profound disturbance of health results. INFLAMMATIONS OF SPECIAL PARTS Duodenitis occurs in association with gastritis from irritating food and the like. The appearances are the same as in gastritis. Du- odenitis is prone to occasion obstruction of the terminal portion of the common bile-duct by the inflammatory thickening of the mucosa and the accumulation of mucus in the mouth of the duct; and in this way gives rise to obstructive jaundice (catarrhal jaundice). The inflamma- tion may extend into the liver or pancreas along the respective ducts. Inflammation of the ileum presents no special characteristics, ex- cepting that enlargement of the follicles (follicular enteritis) is fre- 636 A TEXT-BOOK OF PATHOLOGY quently conspicuous. Follicular ileitis is particularly common in children suffering from infectious fevers, such as diphtheria and scarla- tina. Peyer’s patches may be considerably enlarged and even ulcerated. The ulcers are generally small, and several may occur in a single Pever’s patch instead of single ulcers, such as occur in typhoid or tuberculous enteritis. It is a curious fact that some of the lymph-follicles may be free from gross alterations even in severe follicular enteritis. Typhlitis or cecitis (inflammation of the cecum) may be due to the irritation of the intestinal contents in consequence of constipation (stercoral typhlitis). This affection is probably very frequent, though it leads to no severe consequences and occasions no urgent symptoms. Typhlitis is probably generally of the simple catarrhal variety, but in obstinate constipation or obstruction of the colon ulceration may occur. Perforation or extension to the surrounding tissues (perttyphlitis) is the rarest of all consequences. Usually the latter is secondary to inflam- mations of the appendix vermiformis. Appendicitis may be a primary condition, or it may result from primary typhlitis or cecitis. The inflammation of the mucosa of the cecum may extend directly to that of the appendix; or may cause ob- struction of the mouth of the appendix in the same manner as duodenitis causes obstruction of the common bile-duct. There results a retention of the contents of the appendix and multiplication with increase in viru- lence of the contained bacteria (Bacillus coli communis, staphylococcus, streptococcus, and others). The mucosa of the appendix, rendered less resistant in consequence of the overdistention and associated congestion, may be penetrated by the micro-organisms and appendicitis results. There may be some slight defect in the surface epithelium into which the bacteria pass. Superficially there is little change, but it is characteristic of the appendix that lesions spread into the deep layers to a greater ex- tent than on the surface. This deep spread is probably due to early if not primary involvement of the lymph tissue, which in swelling ob- structs the lumen of the tube and creates recesses within which bac- teria multiply. In many cases fecal concretions are found within the appendix, and less commonly foreign bodies of various sorts have been found. These have been assumed to be the direct cause of the disease, and doubtless may play a part by irritating the mucosa, or injuring it in such manner that micro-organisms easily penetrate it. On the other hand, there is much reason to believe that the fecal concretions are often formed in consequence of the accumulation of mucous and desqua- mated epithelial cells and the stagnation of the contents of the appendix, after the disease has begun. The position of the appendix and rapid swelling of its mucosa favor retention of foreign bodies and exudates, while its movability renders kinking easy. Typhoid .and tuberculous ulcers and actinomycosis have been found in the appendix. Thege lesions may occasion secondary appendicitis of an ordinary sort, or they may in themselves cause the symptoms of appendicitis. Obstruction of the arterial supply of the appendix was formerly regarded as an im- portant element in the etiology, but probably is only of secondary im- DISEASES OF THE GASTRO-INTESTINAL TRACT 637 portance. Appendicitis is less frequent in women than in men. This has been ascribed to the existence of a more adequate blood-supply (the supplemental part derived from the ovary) in women. The pathological anatomy of appendicitis varies in different cases, and we may, for convenience, distinguish a catarrhal, a necrotic or gan- grenous, and an interstitzal form. - In the mildest or catarrhal form there is merely retention of the contents of the appendix and slight disease (swelling and erosion) of the mucosa. The muscularis and serous coat may be congested and edema- tous, but are not extensively in- volved. The contents of the ap- pendix are more or less mucopuru- lent in character, and may, of course, become pure pus. In the necrotic or gangrenous form the mucous membrane suffers rapid destruction and the muscular and serous coats are quickly in- vaded. Fibrinous peritonitis soon develops in the serous coat and over the adjacent intestines, either as a result of penetration of bacteria through the walls of the appendix, or in consequence of perforation of the walls. The local peritonitis serves the purpose of restraining the infective disease and prevents dif- fuse peritonitis. In cases of rapid gangrene, with early rupture or es- cape of abundant bacteria, general peritonitis may result before a re- straining wall can be formed. The term “interstitial appendi- citis’ may be used to designate cases in which all of the coats of the appendix are involved and in which there is a special tendency to pro- ductive changes in the connective Fig. 278.—Acute appendicitis, with round-cell infiltration and hyperplasia of tissues. In reality, all cases of ap- pendicitis show more or less inter- stitial change of this character (Fig. 278); but in some it is the con- connective tissue in all of the coats. In large part the round cells of the mucosa and submucosa belong to the normal lymphoid tissue of these parts. spicuous feature. These cases frequently terminate in chronic thicken- ing of the appendix. Results.—Mild cases of catarrhal appendicitis may subside after free purgation, with relief of the obstruction at the mouth of the ap- pendix. In more serious inflammations and in cases in which the ob- 638 A TEXT-BOOK OF PATHOLOGY struction remains, the disease spreads through the walls of the ap- pendix to the peritoneum and occasions local peritonitis; or rupture of the appendix occurs, and more intense local or general peritonitis fol- lows (Figs. 279-281). In either case fibrinous deposits are formed upon the peritoneum, and not rarely a localized abscess (periappendiceal abscess) results. The appendix itself may be separated from the cecum, and may lie free in the abscess, or it may be firmly embedded in the fibrinous wall of the abscess. The latter may subsequently undergo inspissation, but more commonly ruptures into the general peritoneal cavity, into some part of the intestines, into the ureter, bladder, or externally. In cases with favorable outcome the appendix is usually bound down by adhesions which attach it to neighboring coils of intestine or to other structures. The appendix in such cases is usually distorted and greatly thickened, and repeated attacks of inflammation (relapsing or recurring Fig. 279-281.—Ulcerative and perforative appendicitis, showing perforations; two fecal concretions from other cases of appendicitis (modified from Bollinger). appendicitis) are not unusual. Chronic appendicitis may arise in this manner, that is, as a remnant from an acute process; but it also occurs without involvement of the peritoneum, the lesions being confined to the appendiceal mucous and muscular layers. Chronic appendicitis may be divided into the catarrhal and sclerosing forms. In the former type we have alterations in the structure of the inner coats as the most prominent change, while in the sclerotic form connective-tissue over- growth occurs throughout all coats, so that finally, by contraction, the glandular structures are destroyed, and the organ becomes a fibrous cord (obliterating appendicitis). There is generally more or less systemic intoxication and infec- tion with appendicitis, and degenerative changes and metastatic ab- scesses may be found in distant organs. Not rarely pylephlebitis and metastatic abscesses of the liver are encountered. DISEASES OF THE GASTRO-INTESTINAL TRACT 639 Colitis, aside from the specific form (dysentery), is most frequently due to irritation by fecal accumulations, and the sigmoid flexure is the common seat. The entire colon may, however, be involved. It may assume catarrhal, ulcerative, or pseudomembranous forms, the most conspicuous of the last being “mucous colitis.” Thickening of the mucous membrane and abundant exudation of mucus are the prom- inent features of the earlier stages; while in the later stages atrophy and thinning are observed. Ulcerations are not uncommon. When the mucous exudation and the desquamated cells accumulate upon the surface the appearance of a pseudomembrane is simulated, and casts of the bowel or masses of mucus may be discharged from time to time. The other forms of colitis are in no manner peculiar. Proctitis, or inflammation of the rectum, may be due to direct irritation by retention of fecal matter, by parasites, or by toxic agents; or it may occur secondarily after various other diseases of the rectum, such as tumors, hemorrhoids, and the like. The inflammation tends to become chronic. The rectum is generally involved with the colon in cases of mucous colitis. . The mucous membrane is considerably swollen, often edematous, and usually presents petechial hemorrhages. Ulceration may occur secondarily, and extension of the ulcerative process to the surrounding tissues (periproctitis) is not unusual. In the latter cases fistulous _ communication may be established between a perirectal abscess and the rectum (incomplete fistula), or a fistulous communication may form between the rectum and the exterior (complete fistula in ano). Some- times proctitis is secondary to periproctitis occurring in diseases such as typhoid fever, pyemia, and the like. INFECTIOUS DISEASES Dysentery is a name applied to two varieties of infectious colitis whose etiology is now quite definitely accepted. One form, bacillary dysentery, is due to a non-motile bacillus of typhocolon morphology (see p. 297), while the other form, amebic dysentery, is caused by a pro- tozoén, Entameba histolytica (see p. 365). Bacillary dysentery is a communicable colitis, presenting acute, subacute, or chronic characters, due to one of the varieties of the Bacillus dysenterie. It appears as epidemics in the tropics, in camps and insti- tutions, or may occur sporadically. It seems to be a general infection in the acute cases, but there is rarely a bacteremia, except shortly be- fore death. The bacteria may at times find their way to the lymph- glands draining the affected bowel. Rare instances of septicemia are reported. The hygiene and bacteriology have already been discussed. The morbid lesions are usually confined to the colon, but may at times extend to the ileum. In the large gut the whole length is usually in- volved in, at first, a congestive and mucocatarrhal inflammation. This is rapidly overshadowed by a superficial necrosis which affects the tips of the ruge. Great swelling of the mucosa enlarges and distorts these 640 A TEXT-BOOK OF PATHOLOGY folds. Over the mucous surface there appears a delicate necrotic film which can be rubbed away by the finger, leaving eroded or superficially ulcerated surfaces. The mucosa as a whole is swollen, but the process is more superficial than in amebic dysentery. In fulminating cases the mucosa becomes hemorrhagic or even gangrenous. In subacute and chronic cases these changes are not so intense, the follicles being more involved and becoming prominent. Amebic dysentery is a communicable colitis, usually chronic, but at times acute, due to Entameba histolytica, endemic in some tropical and subtropical countries, occasionally appearing in epidemic or sporadic forms in higher latitudes, and showing a great tendency to involve the liver with abscess formation. It is commonest among white male adults. The lesions are usually confined to the upper colon, although the sigmoid and rectum are often involved. When the amebe penetrate the mucosa they infest the submucosa, causing great swelling and thicken- ing by edema, round-cell infiltration, and proliferation of fixed tissue cells. This swelling interferes with the nutrition of the overlying mu- cosa, and ulceration is early and extensive; the infiltration is so wide- spread and rapid in its extension that intercommunicating swellings, and then undermined ulcerations, are produced. The ulcers are of all conceivable shapes, and as the infiltration or destruction in the sub- mucosa is greater in extent than the loss of surface, mucous membrane bridges only may separaté the surface’s defects. Penetration to the muscular or serous coats is known, and perforation is sometimes seen. Healing occurs by granulation tissue, beginning around the base of the ulcer. Microscopically, the infiltrate is of round and tissue cells, and few polynuclears are found. LEosinophiles are common. The character- istics of amebic dysentery are the marked infiltration and thickening of the submucosa, in which lie amebe occupying spaces in the cel- lular collections, and in lymph- or small blood-vessels. The liver lesions consist of single or multiple abscesses or focal necroses with parenchymatous degenerations. Abscesses occur chiefly in the right lobe near the colonic or diaphragmatic surface. The contents vary from serous to a reddish-brown, puriform, necrotic material, in which, near the wall, amebe may be found. This wall consists of a layer of dense tissue cell proliferation and infiltration of round cells, with great congestion about it. These abscesses may rupture, the com- monest direction being through the diaphragm to pleura and lung. Cholera.—Cholera epidemica or Asiatica is an acute specific inflammation of the small and large intestines due to the comma bacillus or vibrio of Koch. This micro-organism is found in the great majority of cases, but occasionally it is not discovered, while other micro-organisms, Bacillus colt communis and streptococci, are present. It is probable that in these instances errors of observation cause the failure of detection. Pathological Anatomy.—Cholera is characterized by redness and swelling, and not rarely by petechial ecchymosis of the mucous mem- DISEASES OF THE GASTRO-INTESTINAL TRACT 641 brane, particularly of the small intestine (ileum). The superficial epi- thelium suffers early an extensive degeneration, perhaps a form of coagulation necrosis. The solitary follicles and the agminated glands may enlarge and may suffer ulceration. The intestines contain and discharge a serous exudation, often in large quantities, in which are grayish or whitish particles, consisting of flakes of desquamated and Fig. 282.—Typhus abdominalis: medullary Fig. 283.—Typhus abdominalis: ulcers swelling. with slough removed. degenerated epithelium. The term “rice-water discharges” is applied to the evacuations. Extensive areas of the mucous membrane may be laid bare by the desquamation of the epithelium. When cholera has passed to its later stages, secondary pseudomembranous inflammation of the mucous membrane is not unusual, and is probably the result of secondary infection. 41 642 A TEXT-BOOK OF PATHOLOGY Associated Conditions.—The blood is thickened and dark red in color; thrombosis in the heart or venous sinuses is frequent. These are due to the great loss of water by the diarrhea. The kidneys present marked congestion and degeneration, which are dependent upon the action of the toxins of the disease. Lobular pneumonia is a common complication. There is apt to be a slight fibrinous peritonitis, while the gut itself is thin and atrophic. Fig. 284.—Typhus abdominalis: superficial necrosis. Typhoid fever is distinguished by an acute, specific inflammation of the lymphoid elements of the intestines, particularly of the ileum and upper portion of the colon (Figs. 282-285). The specific cause is the Bacillus typhi abdominalis, described by Eberth and Gaffky. This or- ganism enters the gastro-intestinal tract with drinking-water, milk, or other food, and multiplies in the small intestine (see page 289). DISEASES OF THE GASTRO-INTESTINAL TRACT 643 Pathological Anatomy.—The specific lesions of typhoid fever occur in the lymphatic structures, notably in the solitary follicles, Peyer’s ' patches, mesenteric glands, and spleen. It is, however, wise to remem- ber that a few cases of typhoid bacillus infection giving a Widal reaction, but without intestinal lymph-gland ulcers, have been observed, or with only small atypical mucous membrane lesions. The bacteremia and. parenchymatous lesions may be otherwise as typically described. The solitary follicles and Peyer’s patches of the lower end of the ileum are first affected, but later, or exceptionally in the beginning, the lymphoid collections of the upper part of the ileum and jejunum, or of the cecum and colon, may be involved. At first the follicles and patches are swollen and somewhat reddened by congestion. Within a few days of the onset, however, they lose their congested appearance and _ pre- sent themselves as grayish or white elevations projecting from one to several millimeters above the surface (Fig. 282). Microscopically, the lymphoid elements are found in a state of active proliferation, and, Fig. 285.—Typhoid fever, showing necrosis of Peyer’s patches and intense congestion of the bowel (modified from Kast and Rumpel). in addition, large round cells (endothelioid) are more or less abundant. These large cells are actively phagocytic, and have been discovered in the lymphatic channels at some distance from the local lesions, as well as in the mesenteric glands and in distant parts. These cells in- crease in number, and may in some areas outnumber the small round cells. The surrounding mucosa may be normal in appearance or may be some- what inflamed. The dense cellular packing gives a pale color to this stage of medullary infiltration, which remains unchanged for some days or a week. After the first week necrosis is prone to occur. The center of the solitary follicles or part of the Peyer’s patch becomes more and more soft and yellow, or sometimes reddish from absorption of blood- pigment. The necrotic portions are discharged after a few days, leaving an ulcerated surface of regular or irregular outline, and presenting over- hanging necrotic edges with hemorrhagic infiltration (Figs. 284-287). Sometimes not all of the swollen glands slough away, and a knobby or granular appearance results from the retention of isolated lymph-follicles. 644 , A TEXT-BOOK OF PATHOLOGY The ulcers resulting from destruction of the solitary follicles are small and rounded, while those involving the Peyer’s patches are elon- Fig. 286.—Typhoid fever. Swelling of lymph-follicles, cross-section of Peyer’s patch (Karg and Schmorl). gated, the long axis being parallel with the axis of the intestine. The bases are smooth except, perhaps, for muscular ridging. The ulcers Fig. 287.—Typhoid fever, slough formation, showing edge of Peyer's patch becoming necrotic. The mucosa to the right shows catarrhal inflammation which usually accom- panies the follicular lesions (Karg and Schmorl). are usually found in an acute stage at the end of the second or at the beginning of the third week of the disease. Resolution may occur with- out necrosis and ulceration, but more commonly ulcers are formed and DISEASES OF THE GASTRO-INTESTINAL TRACT ' 645 healing proceeds more slowly. The lymphoid elements of the follicles and patches are usually permanently destroyed, and healing takes place by proliferation of the fibrous stroma. A covering for the bared muscle is made from the mucosa after the inflammatory swelling has left the edges of the ulcer. Occasionally, however, complete restitu- tion of the normal tissues occurs. When the lymphoid follicles of the patches have become necrotic and have been infiltrated with blood, dark pigmented spots are formed, and give rise to the condition desig- nated as the “shaven-beard” appearance. Complications.—Extensive necrosis may lead to erosion of a blood- vessel and hemorrhage; or the wall of the intestine may be completely perforated by the necrotic process, and fatal peritonitis may result. In other instances peritonitis occurs without perforation by direct extension of the inflammatory process through the intestinal wall. Very commonly slight reactive peritonitis is found on the serous surface opposite the ulcers. Extensive peritonitis rarely occurs in this way. Peritonitis in rare instances results from necrosis of the mesentery glands, or from rupture of the spleen. The mesenteric glands are characteristically enlarged, those nearest the points of ulceration being first and most prominently involved. In the first stage they are soft and dark red in color, exuding a small amount of liquid on section. Later, they become larger, harder, and of whitish appearance; they may finally suffer necrosis and rupture. Usually, however, resolution takes place after the first stage. The spleen is enlarged in most cases, and presents the characteristics of acute splenic tumor. Very rarely perisplenitis or abscess may occur. In the bone-marrow there is an increase of the small round cells and large phagocytic endothelial cells. The typhoid bacillus seems to have the power to stimulate the endo- thelial cells, for we now look upon the large cells of the lesions in Peyer’s patches as endothelial, and certain it is that these cells, in lymph-glands, spleen, and bone-marrow, are found in great abundance. They are phagocytic for necrotic cells and bacilli. Lesions in Other Parts.—The muscles, particularly those of the abdominal walls, frequently show spots of degeneration of a waxy or hyaline character, as described by Zenker. Very rarely petechial or considerable hemorrhages may be found in the muscles; and abscesses are sometimes met with as sequele. The heart muscle is involved in perhaps a majority of the cases. The muscle-fibers suffer parenchymatous and hyaline degeneration, and less commonly the intermuscular tissues present the characteristics of acute myocarditis. Acute endocarditis and inflammations of other serous surfaces are rare in typhoid fever as compared with some other infectious diseases. Acute degeneration of the kidney and acute nephritis are quite common, and the kidney substance may present small lymphomatous. foci. Similar lymphomata occur in the liver and throughout the peri- toneum. Small necrotic foci are also found in the kidney and liver. 646 A TEXT-BOOK OF PATHOLOGY Acute lobular pneumonia and croupous pneumonia are frequent complications. Osteomyelitis is rare. The blood in typhoid fever, unlike other infections, presents no leukocytosis, but, on the contrary, usually shows a leukopenia, the mononuclear leukocytes predominating. Cholecystitis and gall-stones have been traced to typhoid fever. Thrombosis, particularly of the veins, has been known, and more lasting alterations in arteries, Thayer believes, may be caused by the typhoid bacillus. Paratyphoid Fever.—This infection occasions variable lesions in the intestines. There may be simple or follicular enteritis, or ulceration of the lymph-nodes has been seen. The systemic condition is more of a bacteremia without definite localizing manifestations. It is to be differentiated from typhoid by bacteriological tests. Tuberculosis of the intestines may be primary or secondary. It may, in rare cases, occur primarily from the drinking of infected milk Fig. 288.—Tuberculous ulceration of the intestine. or consumption of the meat of tuberculous animals. Primary tuber- culosis of this character is most often seen in young infants. More commonly tuberculosis of the intestines is secondary to pulmonary or laryngeal tuberculosis, and is due to the swallowing of sputa. In following the course of the tubercle bacillus in its production of intestinal tuberculosis one must remember that this organism can pass the undamaged mucosa without leaving a trace. It may settle in a submucous lymphatic, or be carried to a mesenteric gland. In the former case the primary lesion is a submucous tubercle which can extend (a) along the transverse lymphatic vessels, (b) through the muscularis to a position under the serosa, and (c) toward the mesenteric insertion and to the mesenteric gland. If no lesions occur in the gut wall, but begin in the mesenteric glands, then the lesion may extend toward the gut along the mesentery, and break out as subperitoneal tubercles which have the power to penetrate along the lymphatic vessels com- PLATE 11 teeta Tuberculous ulceration in intestine showing miliary and infiltrative lesions beneath peritoneum and in mesentery. DISEASES OF THE GASTRO-INTESTINAL TRACT 647 municating between the submucosa and peritoneum. Tuberculous peritonitis, which usually assumes a plastic nature, may arise this way. The usual situation of the lesions is the lower end of the ileum, and it is the lymphoid tissues that are prone to be attacked. At first the follicles or Peyer’s patches become enlarged and project above the surface. Soon they undergo necrosis and discharge their contents, leaving more or less irregular caseous ulcers. The follicular ulcers are small and rounded, but the more characteristic lesion is an irregular ulcer extending transversely to the long axis of the bowel and often involving one-half or more of the entire circumference (Fig. 288). Microscopically, the changes are found to involve the mucous mem- brane and the adjacent submucous coat. Early caseation is charac- teristic. On the serous coat may often be seen granular elevations in clusters opposite the ulcers in the mucosa, and extending in lines from the region of ulceration around the bowel toward the mesentery (Fig. Fig. 289.—Miliary tubercles in clusters and disseminated over the serosa (peritoneum) of the intestine; the clusters are situated opposite ulcerations of the mucous membrane (modified from Bollinger). 289). These represent tuberculous lymphangitis and small miliary tubercles in the course of the subserous lymphatic vessels. Tuberculous ulceration rarely causes perforation of the bowel, ex- cepting in the rectum, where periproctitis and fistula in ano may result. The ulcers may heal, causing cicatricial distortion or stenosis. Very commonly there is associated tuberculous enlargement of the mesenteric glands, and sometimes the latter are extensively diseased, though the primary intestinal involvement is insignificant. Generalized enteritis of catarrhal character may accompany the specific ulcerative disease. There can be hematogenous miliary tuberculosis of the gut arising as a part of the general form, as peritoneal, subperitoneal, submucosal, or interstitial tubercles. ~ Occasionally a hyperplastic intestinal tuberculosis occurs in which the productive tissue growth exceeds the caseation. Syphilis is most frequent in the rectum, though cases of syph- ilitic disease of the small intestine or colon, in the form of localized 648 A TEXT-BOOK OF PATHOLOGY or diffuse gummatous involvement, sometimes with secondary ulcera- tion, have been observed, particularly in cases of congenital syphilis. In the rectum syphilis may appear in the form of warty eleva- tions or as a chancre; also as mucous patches, gummatous nodules, or infiltrations. Considerable thickening of the mucosa and submucosa, with ulceration and secondary cicatrization and stenosis (syphilitic stricture), may result. Anthrax occasionally affects the small intestine in persons exposed to infection by their occupations. It is met with among wool-sorters, brushmakers, tanners, and the like. More or less extensive ulceration is seen in the small intestine, and sometimes in the large intestine. The ulcers are dark colored and necrotic in appearance, and are com- monly surrounded by a hemorrhagic zone. Considerable edema and hemorrhagic infiltration of the neighboring parts of the intestine may accompany the ulceration. The neighboring lymph-glands and the spleen are enlarged. The bacilli of anthrax are found in considerable numbers in the ulcers and in the surrounding tissues. Actinomycosis of the intestines is very rare. It most commonly affects the region of the cecum, causing first infiltrations, and then ulcerations of the mucosa and submucosa. Enteromycosis is a term applied to intestinal affections resulting from the ingestion of putrid meat, fish, sausages, and the like. Occa- sionally considerable epidemics may occur. The intestines may present the lesions of catarrhal enteritis or of intense croupous or pseudomem- branous inflammation, and there may be erosions or ulceration. Micro- organisms of various sorts have been discovered, but no specific form is recognized. The acute general symptoms, and even the local lesions, may be caused by poisons elaborated by bacteria in tainted foods rather than by the micro-organisms themselves. TUMORS Connective-tissue Tumors.—Among the benign tumors of the intestines, fibroma, myxoma, and lipoma are occasionally met with in the submucosa as small nodular tumors or as pendulous polyps. They may occasion intestinal obstruction and even invagination. Sarcoma of the intestine is rare. Lymphosarcomatous or lymph- adenomatous enlargement of the solitary follicles or Peyer’s patches may be met with in leukemia or pseudoleukemia. Round-celled sarcoma springing from the submucosa and deeper layers of the mucosa, and sometimes infiltrating the mesentery, may also occur as an independent and primary affection. Nodules of secondary sarcoma are not rarely met with in the mucosa and submucosa of the intestines (Fig. 290), and the serous covering may be studded with miliary nodules in sarcomatosis. Epithelial Tumors.—Among the epithelial tumors may be included inflammatory papilloma, adenoma, and carcinoma. Inflammatory hyperplasia of the mucous membrane may occur in association with chronic inflammations, especially in the large intes- DISEASES OF THE GASTRO-INTESTINAL TRACT 649 tine, and may lead to the formation of papillomatous or polypoid eleva- tions of considerable magnitude. Adenomata are more strictly of the nature of tumors, being inde- pendent of inflammatory processes, although no sharp dividing-line can be drawn between the inflammatory proliferations and the adeno- mata proper. The latter may occur in the form of flat elevations hav- ing a more or less uneven surface and a tendency to hemorrhage and ulceration; or in the form of papillomatous elevations of a cauliflower character. Adenomata arise by hyperplasia of the crypts of Lieberkiithn in the duodenum, or of Miiller’s glands, and in their structure they pre- sent typical glandular acini, the tubules having a basement-membrane lined with cylindrical epithelium. Adenomata are most frequent in the Fig. 290.—Nodule of secondary sarcoma in the mucosa of the intestine (Kast and Rumpel). rectum, but may occur in other parts of the large intestine and in the duodenum. Carcinoma is the most frequent tumor of the intestines. It occurs in the duodenum, especially at the papilla of the common bile-duct (Fig. 291); at the ileocecal valve, at the flexures of the colon, and in the upper or lower part of the rectum. The appearance is that of a soft, irregular, often ulcerated and bleeding elevation, projecting into the lumen of the gut and causing considerable narrowing, or surrounding the bowel by circular involvement of the entire circumference. The car- cinomata of the bowel are, for the most part, cylindrical epitheliomata (Fig. 292) or glandular cancers, consisting of atypical acini and tubules, with irregular proliferation and infiltration of the neighboring tissues A TEXT-BOOK OF PATHOLOGY 650 eae Leaner rie 900 Feed 780 pace crite eon ove Ud ses aan org gun eeann TT ¢ apo orv.s 80, (oe ROS OC 1] Loa st Aaa, s Ss 02) ieee > 09 a pees 307000009 ‘e, 7. 3 a — feos ee Fig. 291.—Carcinoma of papilla of Vater (Kast and Rumpel). .—Cylindrical epithelioma of the intestine (Perls). Fig. 292 DISEASES OF THE GASTRO-INTESTINAL TRACT 651 with masses of epithelial cells. Cases are met with, especially in the rectum, in which there is a clear transition of adenoma into carcinoma (adenocarcinoma), and, in general, adenomata of the bowel have a tendency to such transformation (Fig. 293). At the lower end of the rectum squamous epithelioma may occur. The results of carcinoma of the bowel are the same as those of stenosis due to other causes, together with the consequences of the cancerous cachexia and of metastasis. Ulceration of the tumor may lead to per- foration. Metastasis occurring to liver and other structures in the peritoneum is not uncommon. Outside of this cavity the secondary growths are rare. Secondary growths in the intestine are not so common. Se ee a a 3 De: = i SS ee arn ae =