key: cord-0036039-5c79bxrn
authors: Krueger, Gerhard R. F.; Wagner, Mathias; Oldham, Sandra A. A.
title: Pathology of the Respiratory Tract
date: 2012-11-27
journal: Atlas of Anatomic Pathology with Imaging
DOI: 10.1007/978-1-4471-2846-5_3
sha: fbc9823ed5ec16696414d8ea10ba5e0ddf70ac13
doc_id: 36039
cord_uid: 5c79bxrn

This chapter discusses six common entities of respiratory disease: obstructive and restrictive disorders of gas exchange, infectious and inflammatory diseases, immunologic disorders, vascular diseases of the lung, tumors of the lung and pleura, and miscellaneous other diseases of the respiratory tract.

This chapter discusses six common entities of respiratory disease: obstructive and restrictive disorders of gas exchange, infectious and in fl ammatory diseases, immunologic disorders, vascular diseases of the lung, tumors of the lung and pleura, and miscellaneous other diseases of the respiratory tract.

Chronic obstructive pulmonary disease (COPD) comprises a number of different respiratory diseases, with pathologic obstruction of pulmonary air fl ow as the common pathogenetic mechanism. Major examples of such diseases include chronic bronchitis, bronchiolitis and asthma, cystic fi brosis (CF), bronchiectasis, and a 1 -antitrypsin de fi ciency. COPD causes progressive and destructive emphysema and recurrent in fl ammation with destruction of lobular tissues and small vessels and fi nally may lead to cor pulmonale secondary to reduced intrapulmonary blood fl ow, pulmonary hypertension, and right heart insuf fi ciency.

There are different types of emphysema, with a different extent of the lesion (centriacinar, panacinar, bullous) or different pathogenesis (acinar, paraseptal, interstitial). In radiology (and partly in pathology), the term lobular is used more commonly than acinar , although they are not completely congruent (acini being smaller units than lobes). The pathophysiology of COPD as determined by spirometric function tests is de fi ned by a normal or increased total lung capacity (TLC) and forced vital capacity (FVC) in combination with decreased forced expiratory volume (FEV). COPD follows either increased resistance to air fl ow (e.g., luminal narrowing of air ducts) or the loss of elastic recoil (passive widening of air spaces). The fi gures present gross features of the most common examples of COPD. ( c ) COPD in this patient leads fi nally to bullous emphysema. Asthma bronchiale (AB) is a chronic lung disease with recurrent episodes of air fl ow obstruction caused by various inhaled antigens. The initial response consists of bronchospasm followed by a type I eosinophilic allergic (IgE type) reaction with sustained bronchoconstriction, increased vascular permeability, and secretion of highly viscous mucus. Causes of AB include exogenous allergic stimuli (e.g., pollen, hair, house dust), infectious organisms (e.g., in fl uenza and parain fl uenza virus, rhinovirus), drugs (e.g., nonsteroidal anti-in fl ammatory drugs, aspirin, b -adrenergic antagonists), occupational exposures (e.g., fur exposure by animal handlers, vegetable dusts, metal salts, pharmaceuticals, wood by woodworkers), and reactions induced by stress or exercise (e.g., nonspeci fi c stimulation of sensitized persons by air temperature or dryness) a c b Fig. 3. 2 Chronic exposure to "nontoxic" dusts (common air pollution, cigarette smoking, anthracosis) causes chronic bronchitis, emphysema, and COPD. The type of emphysema is usually centriacinar. Note the decreased consistency of the lung, with bulging and sunken-in parts ( a ); focal deposits of dust pigment ( b ); and centriacinar (centrilobular) pronounced emphysema ( c ). The pathogenesis consists of induction of either nonspeci fi c in fl ammation or allergic sensitization (see Fig. 3 .1 ). More extensive panacinar (panlobular) emphysema may develop either in the further course of exposure to these nontoxic dusts or ab initio by loss of alveolar septae in inherited diseases such as a 1 -antitrypsin de fi ciency Interstitial emphysema (right lung), a form of localized emphysema, shows air bubbles resembling a string of pearls in interstitial tissue ( arrows ). It is caused by bronchoalveolar rupture secondary to highpressure arti fi cial respiration. Air may extend into the mediastinum and skin with compression of vessels and air spaces, causing severe respiratory and circulatory problems. Other localized emphysemas, such as paraseptal emphysema, may be caused by deposits of speci fi c toxic substances (e.g., occupational exposure to chromium oxide). Irregular emphysema commonly develops around pulmonary scars of varying etiology a b ( a , b ) . A microscopic overview ( c ) shows severe overproduction of mucus (red parts in glands, double arrow ) as well as bronchiectasis ( single arrows ) and mucous plugging. CF is an autosomal recessive disorder with de fi cient exocrine functions or glands in a number of organs, including the pancreas, liver, lungs, small intestines, and others. The disease results from a genetic defect of the CF transmembrane conductance regulator (CFTR) protein, which is responsible for regulating the function of the chloride channel. It most often affects white children, with an incidence of about 1 in 2,500 births. Pathologically, CF is responsible for chronic bronchiolitis and bronchitis with severe mucous plugging and bronchial cyst formation. Chronic pancreatitis and secondary biliary cirrhosis are among other complications a b Fig. 3 .10 Similar bronchiectases and COPD may be caused by a hereditary de fi ciency of a 1 -antitrypsin, a circulating glycoprotein produced in the liver and responsible for inhibiting proteases including trypsin, chymotrypsin, elastase, thrombin, and various bacterial proteases. Note bullous emphysema and focal interstitial fi brosis ( a ), as well as striking bronchiectasis and mucoid metaplasia of the bronchial epithelium ( b ). a 1 -Antitrypsin de fi ciency in the lung decreases the inhibition of neutrophil elastase and thus will cause emphysema. In the liver, it is associated with the development of cirrhosis 

Restrictive pulmonary diseases (RPDs) include a number of disorders that have in common a progressive limitation of respiratory expansion of the lungs. Both acute and chronic forms are de fi ned: Acute RPDs include adult respiratory distress syndrome (ARDS) and acute hypersensitivity pneumonitis, whereas chronic RPDs include idiopathic pulmonary fi brosis (IPF), sarcoidosis, collagen vascular diseases affecting the lung (see the section on Immunologic Diseases), and pneumoconioses. Chronic diseases progress to extensive pulmonary fi brosis with honeycombing, and (as with COPD) pulmonary hypertension and cor pulmonale may develop. Spirometric function tests in RPDs show signi fi cantly reduced respiratory compliance (reduced FVC with normal or reduced FEV). a c b Fig. 3 .13 Adult respiratory distress syndrome: voluminous lung with a glistening, fl eshy cut surface ( a , b ). Microscopy shows alveolar and interstitial edema, hyaline membrane formation ( c ), and (depending on the duration of the lesion) increasing interstitial in fl ammatory in fi ltration with fi brogenesis (see also "shock lung" in Fig. 3 .64 ). ARDS is the clinical term for diffuse alveolar damage (DAD) resulting from alveolar epithelial and endothelial damage of various etiologies. Among the etiopathogenetic processes leading to DAD are circulatory shock of any kind, infections (e.g., bacterial septicemia, certain viruses), aspiration, and certain drugs (e.g., oxygen, toxic gases, cytotoxic drugs, heroin). Leakage of proteinaceous fl uid into the alveolar space, accompanied by destruction of type I pneumocytes, will initiate fi brin-rich precipitates in alveoli (hyaline membranes) and alveolar walls, with subsequent proliferation of type II pneumocytes and an in fl ammatory reaction. In patients who survive the acute phase, defective recovery usually leads to interstitial (and partly alveolar) fi brosis Fig. 3 .14 Idiopathic pulmonary fi brosis (interstitial lung disease, idiopathic interstitial pneumonias) with varying alveolar and interstitial in fl ammatory in fi ltrates, progressive interstitial fi brosis, secondary hypertensive vascular disease, and a fi nal stage with honeycombing of the lungs. Note the fl eshy gross appearance of the lungs in earlier stages ( a ), with various microscopic interstitial in fi ltrates ( b -d ) and gross honeycombing at the end stage ( e ). For further subclassi fi cation, see Microscopy shows extensive scarring related to pigment deposits and surrounding (local) emphysema. For further subclassi fi cation, see Table 3 . Diffusely distributed, small focal anthracosilicosis, initially centriacinar and peribronchiolar with many carbon-laden macrophages and perifocal emphysema. Extent of fi brosis depends on admixture of quartz Silicosis Acute silicosis (uncommon) Alveolar lipoproteinosis and progressive diffuse interstitial fi brosis secondary to inhalation of small, particulate silica crystals (e.g., after sand blasting) Nodular silicosis (common) a Multiple growing silicotic nodules, usually 2 mm to 1 cm in diameter; fi brosing granulomas with concentric fi brous layering, some anthracotic pigment, small slitlike spaces, and needle-shaped crystalline spicules on polarization; perifocal emphysema Progressive massive silicosis Multiple silicotic granulomas up to 10 cm in diameter, both lungs involved, massive and rapidly progressive fi brosis Asbestosis and asbestos-related diseases

Alveolitis with progressive interstitial fi brosis, deposition of asbestos bodies (golden-brown beaded rods consisting of asbestos fi bers coated by ferroproteinaceous material); honeycombing lung in fi nal stage Pleural plaques and rounded atelectasis Recurrent pleural fi brinous effusions, pleural fi brosis and pleural plaques ("sugar coating"), focal atelectasis secondary to pleural fi brosis Neoplasms Malignant mesothelioma (increased risk of bronchogenic carcinoma) Berylliosis Berylliosis Acute and recurrent pneumonitis, systemic sarcoidlike and fi brosing granulomas Talcosis Talcosis Foreign-body granulomas with birefringent talcum deposits; micronodular and diffuse interstitial fi brosis a Caplan's syndrome occurs in patients with rheumatoid arthritis and some form of nodular silicosis. Deposition of microparticulate iron causes siderotic macrophage response with secondary focal or diffuse interstitial fi brosis 

Pathologic features of pulmonary infections are quite variable, depending on the etiologic organism and its toxicity, replication, and persistence, as well as on the quality and intensity of host defense mechanisms. Bacterial pneumonias (bronchogenic or hematogenous) commonly are suppurative, abscessing, necrotizing, or hemorrhagic. Viral pneumonias (through immune T-cell stimulation) are preferentially lymphocytic and, in severe cases, are necrotizing and hemorrhagic (e.g., classic in fl uenza). Fungal infections in the lung stimulate macrophages and frequently cause granulomas (also an immune T-cell reaction); depending on their toxicity, they may cause additional necroses and vascular invasion with thromboses. Parasitic infestations and mycobacterial infections also stimulate phagocytosis and may cause granulomas. Only acute pneumonias without signi fi cant tissue necrosis can show complete resolution and healing. Longerlasting or chronic pneumonitides will resolve incompletely with residual scarring. Chronic, persistent infections consequently also present a risk of the development of chronic restrictive lung diseases. Several newer classi fi cation schemes for the stages of tuberculosis (TB) are available. The classic scheme is presented here in order to consider the three main factors determining the course and outcome of the disease: the toxicity of the mycobacterium, the reactivity of the infected, and the time after initial infection. The degree of immune reactivity (not resistance to disease) may be monitored by tuberculin skin testing; the toxicity of tubercle bacteria is partly determined by the "cord factor" a b Characteristically, all granulomas are of the same size (i.e., the same age), indicating that they developed within a short time window. This typically happens in late primary TB with nearly normal immune sensitivity, when mycobacteria disseminate hematogenously. Bacteria seed to various organs without major in fl ammatory response (typhobacillosis), resensitizing the host's body.

Once suf fi cient immune reactivity has been regained, multiple granulomas of the same age will develop at sites of mycobacterial colonies. This mechanism signi fi cantly distinguishes miliary TB from the more common hematogenous TB with a still-active primary site. In this case, tuberculous granulomas develop immediately as bacteria settle in various tissues, so the granulomas are of different sizes and ages. Miliary TB may even develop in patients not known to have had TB (with a clinically occult focus and "normal" immune sensitivity) a b Fig. 3.36 ( a , b ) Axial CT scans of a right upper lobe cavitary tuberculosis. Shown for comparison is a large lesion in the same lung, representing a tuberculous cavity superinfected with Aspergillus species ( a ). Note the irregular shadows within the large cavity of this aspergilloma Caplan's syndrome in a patient with rheumatoid arthritis also exposed to silica or coal dust. The image shows pulmonary nodules, preferentially in the upper lobes, which may cavitate. The differential for such pulmonary nodules (which cavitate) includes septic pulmonary emboli, lung metastases (usually from primary SCC), Wegener's granulomatosis, or sarcoidosis (compare also Fig. 3 .57 ). The most common chest manifestations in rheumatoid arthritis include pleural effusion, lower lobe subsegmental atelectasis, and basal interstitial lung disease, including the UIP pattern ( see Table 3 .1 ) a c d b Fig. 3 .53 Wegener's granulomatosis. Wegener's granulomatosis is a rare form of systemic vasculitis ( see Table 1 .1 ) affecting the upper respiratory tract, lungs, kidneys, and, rarely, any other organ. The etiology is unknown; it is thought to be a pneumogenic, autoimmune disorder characterized by the development of antineutrophil cytoplasmic antibodies. Pulmonary changes in Wegener's granulomatosis feature necrotizing granulomas of various sizes ( a , b ) with possible cavitation. Necroses are punctate or geographic, with neutrophilic in fi ltration and nuclear dust, and occasionally bronchocentric or complicated by hemorrhage. Lymphoid cells, as well as giant cells and some eosinophils, occur ( c , d ). Wegener's granulomatosis is generally fatal; immunosuppressive drugs may produce remissions, but recurrences are frequent 

Vascular lung diseases include primary or secondary changes of the structure of blood vessels. Most common are plexiform vessel disease (the end stage of pulmonary hypertension) and primary pulmonary glomangiosis (Masshoff and Röher disease [MRD] ). Another group of vascular diseases in the lung occurs secondary to clotting disorders, with occlusion of intrapulmonary blood vessels by thromboembolism or local thrombosis (e.g., with the use of hormonal contraceptives). Structural vascular alterations, including extensive thromboses of small vessels, are commonly accompanied by severe pulmonary hypertension and cause cor pulmonale.

Thromboembolic and major thrombotic disorders may cause pulmonary hemorrhagic infarction (in cases of left ventricular heart failure) and ultimately also pulmonary hypertension. Acute massive thromboembolism of major pulmonary arteries will cause acute right heart failure and sudden death. A related condition is "shock lung," although it is caused by systemic circulatory failure rather than being a primary disease of the lung vasculature. Shock lung not infrequently determines the fi nal outcome of the patient's clinical course.

(See also the fi gures on Wegener's granulomatosis under "Immunologic Diseases of the Lung.") a b immobilized. Acute, massive embolism of pulmonary arteries may cause immediate death. Surviving patients who also suffer from left heart failure will develop pulmonary infarcts (No infarcts will occur without left heart failure; see also Chap. 2 ) a b Fig. 3 .59 Goodpasture's syndrome. Goodpasture's syndrome is a systemic vasculitis ( see Table 1 ( a -d ) Four axial CT images of the chest with contrast, following the pulmonary embolus protocol, in a patient with acute saddle pulmonary embolus. The embolus straddles the bifurcation of the pulmonary trunk into the right and left pulmonary arteries and also extends into the lower lobe lobar and segmental pulmonary arteries. The embolus is the dark fi lling defect in the pulmonary artery, which is otherwise opaci fi ed (white) because of the iodinated contrast given intravenously for this study. Most often, the pulmonary embolus is nonocclusive Fig. 3.62 Posterior chest radiograph of a 17-year-old boy with proven Goodpasture's syndrome who presented to the hospital with hemoptysis. He improved without treatment, but the disease recurred months later a b Fig. 3 .63 Pulmonary arterial hypertension. A posteroanterior chest radiograph ( a ) and axial CT scan with intravenous contrast ( b ) show a markedly enlarged pulmonary trunk and right and left pulmonary arteries that taper abruptly in the periphery. On the CT image, the pulmonary trunk should measure approximately the same as the ascending aorta, which sits adjacent to it. In this case, the pulmonary trunk is easily 3.5 times larger than the ascending aorta. To make the diagnosis of pulmonary arterial hypertension (PAH), there must be enlargement of the pulmonary trunk and right and left pulmonary arteries with peripheral tapering of the vessels. If the pulmonary trunk and the right and left pulmonary arteries are enlarged but the peripheral vessels are not tapered but rather enlarge, then the image would be indicative of rightto-left shunt. Other clues on CT scans pointing to a diagnosis of PAH include evidence of right heart failure, such as contrast leaving the heart into the intrahepatic veins and inferior vena cava, indicating elevated right heart pressure, or convexity of the interventricular septum. Normally, the interventricular septum is straight or bowed toward the right ventricle during ventricular systole (interventricular septum is convex toward the lower pressure of the right ventricle). With PAH, the septum may be deviated toward the left ventricle, again a sign of elevated right heart pressure Fig. 3 .64 Shock lung. Shock is a microcirculatory and metabolic disturbance resulting in inadequate perfusion of vital organs (lungs, kidneys, heart, liver, adrenals, and others). It may be caused by various mechanisms: cardiogenic, hypovolemic, septic, traumatic, toxic, or allergic. Microvascular hypoxic or toxic damage to the endothelium initiates a cascade activation of cytokines (e.g., tumor necrosis factor, interleukin [IL]-1 and IL-6, platelet activation factor), which add to the local damage with hypoperfusion, stasis, and thrombosis. Shock is always a systemic reaction leading to multiple organ disease (i.e., multiple organ dysfunction syndrome). Various forms of acute and chronic in fl ammation develop, depending on the chronicity of the disturbance and the length of survival of the patient. Shock lung (compare ARDS and DAD) is characterized by diffuse, "cloudy" pulmonary in fi ltrate on radiography ( a ). Grossly, the lungs are pale (unless congested), voluminous, and of a "jellylike" consistency, with a humid cut surface ( b ). Microscopy shows a diffuse alveolar and interstitial edema with subsequent formation of hyaline membranes ( c , d ) and hyaline platelet aggregates ("shock bodies") in capillaries and venules 

Tumors of the lungs essentially comprise epithelial neoplasms (carcinomas), mesenchymal tumors (sarcomas), and metastases. All are classi fi ed according to the cell of origin (e.g., squamous cell carcinoma [SCC] of the bronchus, adenocarcinoma of the bronchial glands, or the alveolar pneumocytes). Sarcomas may include angiosarcomas, neurosarcomas, and lymphosarcomas. Other tumors include large cell or small cell carcinomas or tumors of specialized neuroendocrine cells in the lung, identi fi ed as carcinoids. Finally, the lungs are frequent targets for tumor metastases from cancers of the breast, pancreas, testes, bone, skin (e.g., malignant melanoma), and essentially from other sarcomas. Mesenchymal tumors of the pleura identi fi ed as mesothelioma can mimic epithelial adenoid structures. nodes consistent with lymphoma. The lungs are clear. The differential diagnosis for masses in the anterior mediastinum includes the "4 Ts": thyroid, thymus, teratomas, and "terrible" lymph nodes (e.g., lymphoma, granulomatous disease, metastases, infection)

Additional images in this chapter depict some entities not covered in the earlier paragraphs: lipid pneumonia (LP), alveolar proteinosis, pulmonary fl uid overload syndrome (PFOS), pulmonary hypoplasia, and sequestration of the lung. LP may be either exogenous or endogenous. Most reported cases of exogenous LP have resulted from inhalation of mineral oil or petrolatum or occupational exposure to oil mist (steel industry, airline engine maintenance). Endogenous LP is rare; it is independent of exogenous lipid exposure, and its etiology is often unclear. It has been described as accompanying diseases of airway obstruction ("resorptive pneumonitis") as well as in certain infections or parasitic infestations. The latter may cause overproduction of surfactant by type II pneumocytes, with accumulation of related substances in lipid-fi lled macrophages. Pulmonary alveolar proteinosis (PAP) is a rare disease with excessive accumulation of granular phospholipoproteinaceous materials in air spaces. Patients suffer from progressive dyspnea and are treated with repeated bronchopulmonary lavage. The etiology is unknown; primary (idiopathic) forms have been described, as well as secondary PAP occurring after inhalation of substances such as silicates, beryllium, aluminum, and insecticides. PAP also occurs more frequently in patients with hematologic malignancies or in immunosuppressed persons.

Pulmonary fl uid overload syndrome is a serious complication of hyperinfusion and poor electrolyte balance. The lungs show a massive alveolar and interstitial edema, with fi broplasia if the disorder persists over a prolonged period. PFOS may be further complicated by bronchospasm and acute respiratory distress syndrome, in which antibodies against plasma proteins and neutrophils initiate anaphylactic reactions.

Pulmonary hypoplasia and pulmonary sequestration are developmental disorders. Pulmonary hypoplasia is frequently related to urogenital malformations of the fetus, such as urethral aplasia (prune belly syndrome). Pulmonary sequestration consists of abnormal development of a lung segment (or lobule) that is separated from the normal lung (located either within or outside it). This segment usually receives its arterial blood supply directly from the aorta and its venous drainage via the inferior pulmonary vein or azygos or hemiazygos veins. Impaired bronchial drainage will cause changes previously described as cystic alveolar dysplasia. showing bilateral opacities in a patient with PAP. The CT scan shows the typical "crazy paving" pattern consisting of ground-glass opacities and thickening of the interlobular septae, as described for PAP. The differential diagnosis is more extensive, however, including certain types of pneumonia (such as Pneumocystis species), edema, or hemorrhage if acute. In chronic cases, considerations in addition to PAP include UIP, IPF, NSIP, hypersensitivity pneumonitis, COP, chronic eosinophilic pneumonia, and diffuse BAC a b d c Fig. 3 .89 Pulmonary fl uid overload syndrome (PFOS) designates a fl uid imbalance with grave clinical consequences. It is a rare disturbance resulting from clinical hyperinfusion in patients with limited fl uid clearance (e.g., postoperative or postpartum patients with infusion of large volumes of fl uid and limited renal excretion; usually the fl uid and electrolyte balance are not closely monitored). Fluids accumulate in interstitial tissues (edema) and in the lungs to an extent that they cause life-threatening circulatory and respiratory de fi ciencies. The gross appearance at autopsy shows voluminous lungs of "water-pillow" consistency ( a ). Microscopy shows massive alveolar and interstitial fl uid retention ( b , c ). The result is right heart failure and cardiogenic shock (see "shock bodies" in pulmonary capillaries [ c ]), or if the patient survives, secondary pneumonia ( d ) Fig. 3.92 ( a , b ) Radiologic images of pulmonary sequestration. Anterior and lateral radiographs show an abnormal opacity behind the heart in the right lower lobe. ( c -e ) Three axial chest CT images with contrast demonstrate the low attenuation of the smoothly marginated mass in the right lower lobe; this mass does not contain air and is fed by a large, anomalous vessel coming directly from the descending thoracic aorta. Sequestrations are an anomaly of the tracheobronchial branching with persistence of a separate, "sequestered" lung fragment, which retains its embryonic blood supply. There are two types of sequestration: intralobular and extralobular. Intralobular sequestration (as in this patient) is more common; the sequestered lobe fragment is enveloped in the lobe's visceral pleura. It is part of the normal lobe. Two thirds of cases occur in the left lower lobe and one third in the right lower lobe, without other anomalies. Extralobular sequestration is rare and is more commonly seen in neonates and young children with respiratory distress. Ninety percent of cases of extralobular sequestration occur in the left lower lobe and have associated anomalies

Practical pulmonary pathology: a diagnostic approach