key: cord-0035194-5i2o9mz4
authors: Hammar, Samuel P.
title: Nonneoplastic Pleural Disease
date: 2008
journal: Dail and Hammar’s Pulmonary Pathology
DOI: 10.1007/978-0-387-68792-6_30
sha: 420fe94775e9e8d6c6c5825d90f79a653c858604
doc_id: 35194
cord_uid: 5i2o9mz4

This chapter discusses the etiology, epidemiology, and laboratory features of pleural effusions, and the pathologic features of selected pleural diseases.

The visceral pleura can be divided into five layers: (1) outermost mesothelial cell layer, (2) submesothelial interstitial connective tissue layer, (3) outer thick elastic fiber layer, (4) inner interstitial connective tissue layer, and (5) inner thin elastic fiber layer (see Fig. 2 .35A in Chapter 2).1 In the resting condition, the different layers of the pleura may be inconspicuous and the mesothelial cells are only about 111m thick ( Fig. 30.1 ). However, these cells are extremely reactive to any type of injury and frequently undergo hypertrophy and hyperplasia to produce a much thicker mesothelial cell layer with a significantly increased number of mesothelial cells ( Fig. 30 .2). The layers of parietal pleura are not as distinct as in the visceral pleura. The landmark that may be used to identify the parietal pleura is the fatty tissue between the skeletal muscle of the chest wall and the connectiveelastic tissue of the parietal pleura (see Fig. 2 .35B in Chapter 2).

The surface mesothelial layer is best appreciated by scanning electron microscopy, which shows the numerous microvilli that arise from mesothelial cells and project into the pleural space ( Fig. 30.3 ).2 In normal conditions, the microvilli measure about O.ll1m in diameter and up to about 311m in length. When the pleura is injured and there is hypertrophy and hyperplasia of mesothelial cells, the number and length of the microvilli increase. The exact function of the microvilli is not entirely understood. At one time it was thought that they increased the absorptive surface of the visceral pleura, but later studies showed that the visceral pleura did not absorb pleural fluid to any significant degree. 3 Current thought is that microvilli serve as an increased surface area to release hyaluronic acid, which serves as a lubricant between the visceral and parietal layers of the pleura during movement of the lung in respiration. 3 The density of the microvilli is greater on the visceral mesothelial cells than on the parietal mesothelial cells. The mesothelial cytoplasm is rich in pinocytotic vesicles, mitochondria, and other organelles, as well as prekeratin fibrils (Fig. 30.4) . The visceral and parietal pleura have an extensive lymphatic network, although in the normal resting state, these lymphatic channels are inconspicuous. Openings between the mesothelial cells, "called stomata," occur on the parietal surface and range between 2 and 1211m in diameter ( Fig. 30 .5).4-6 These stomata communicate directly with lymphatic lacunae. The stomata are thought to represent exit points for pleural fluid, protein, and cells that come from the pleural spaceY Pleural Fluid Formation Pleural fluid formation has been discussed in detail by Sahn 3 , 8 and Pistolesi et a1. 9 Most of the pleural fluid is produced by the parietal pleura, and there is a dynamic interaction between production and resorption. As described by Sahn/ six mechanisms have been postulated for the accumulation of abnormal volumes of pleural fluid: (1) increase in hydrostatic pressure in the microvascular circulation, (2) decrease in oncotic pressure in the microvascular circulation, (3) decrease in pressure in the pleural space, (4) increased permeability of the microvascular circulation, (5) impaired lymphatic drainage from the pleural space, and (6) movement of fluid from the peritoneal space.

The diagnostic techniques used in examining pleural fluid and the significance of the findings have been discussed in detail by Sahn 3 

Besides examining the characteristics of pleural fluid , closed and open pleural biopsies may be performed to diagnose pleural diseases. What type of biopsy, if any, depends on the clinical situation and the information needed. Open pleural biopsy is the standard against which closed pleural biopsy and thoracoscopic pleural biopsy are compared. As one might expect, open pleural biopsies have a higher diagnostic yield than closed pleural biopsies or thoracoscopic pleural biopsies. As discussed later, in my opinion thoracoscopic pleural biopsies are often adequate for diagnosing nonneoplastic and neoplastic conditions. As long as an adequate tissue S.P Hammar sample containing diagnostic material is obtained that can be studied by a variety of methods, a fairly accurate diagnosis is possible in most cases.

The correct way of handling pleural tissue samples is determined to some degree by the clinical history of the patient being biopsied. It is important for the pathologist to communicate with the pulmonologist or surgeon who is performing the biopsy in order to gain insight into the reason for doing the biopsy. For example, if the patient is thought to have an infectious pleuritis, a portion of the biopsy should be sent for culture. If the clinical diagnosis is cancer, then a portion of the specimen should be sent for cytologic evaluation, including potential evaluation by immunohistochemistry and electron microscopy (see Chapter 43 on pleural neoplasms). Fine-needle aspiration biopsy specimens usually provide a small amount of tissue, which can provide a great deal of information if appropriately handledY-21 Most fine-needle aspiration biopsies are performed on masses thought to represent neoplasms. Small pieces of tissue obtained from such biopsies can be directly processed for electron microscopic examination or prepared as a cell block on which immunohistochemical analyses can be done. Rinses from the needle and the syringe can be directly put into fixative, centrifuged, and processed in a "beam" capsule for electron microscopy (see Chapter 43) .

Antony22 reviewed the immunologic mechanisms involved in pleural disease, and reported that the pleura is a dynamic, metabolically active membrane that is involved in maintaining homeostasis as well as responding to various inflammatory and neoplastic insults. Antony described the importance of mesothelial cells in maintaining homeostatic balance and the changes that occurred in mesothelial cells and other cells in infectious and neoplastic pleural disease. Pleural fluid cytokines observed in infectious disease and malignant disease are shown in Table 30 Pleural disease, in general, is associated with an infiltration of a number of inflammatory cells, including neutrophils, eosinophils, lymphocytes, and plasma cells in various proportions depending on the course and etiology of the underlying disease. 23 Mesothelial cells have been demonstrated to actively participate in pleural inflammation via release of various mediators and proteins, including platelet-derived growth factor, interleukin-8, monocyte chemotactic peptide, nitric oxide, collagen, antioxidant enzymes, and plasminogen activation inhibitor. As discussed by Kroegel and Antony,23 several inflammatory mediators have been detected in increased concentrations within pleural fluid, including lipid mediators, cytokines, and proteins such as adenosine deaminase,lysozyme, eosinophil-derived cationic proteins, and products of the coagulation cascade. The presence of these mediators underlies the concept of pleural inflammation, and certain cytokines seem to be characteristic of specific etiologies of pleuritis (Table 30 The authors concluded the diagnostic separation of pleural effusions could be done cost-effectively by utilizing pleural fluid absolute lactic dehydrogenase (FLDH) and total protein (TPR) alone with the elimination of serum LDH.

Heffner et a1. 27 studied patients with diagnoses of exudative or transudative pleural effusions who underwent thoracentesis and laboratory analysis. Data were obtained on 1448 patients from seven primary investigators or extracted from dot plots in published reports. Likelihood ratios were calculated from extracted data stratified across ranges of test result values. The authors reported there were sufficient data available to calculate multilevel likelihood ratios for the elements of Light's criteria, pleural fluid protein, ratio of pleural fluid to serum cholesterol, pleural fluid cholesterol, and gradient of pleural fluid to serum albumin. Each test provided levels of likelihood ratios through the most clinically relevant range (0 to 10). The authors published the use of likelihood ratios to categorize a pleural effusion (Table 30 .5) and concluded that multilevel likelihood ratios combined with the clinician's estimation of the pretest probability of an exudative effusion improved the diagnostic accuracy of discriminating between exudative and transudative pleural effusions. Likelihood ratios were used to avoid the confusing terms such as pseudoexudates that were derived from the use of a single cutoff point for pleural fluid tests.

Others have looked at different methods for differentiating transudates from exudates. Guleria et a1. 28 evaluated pleural fluid cholesterol in differentiating transudative from exudative pleural effusions. They studied the lipid profile of pleural fluid in 50 patients with exudative (25 tuberculous and 25 nontuberculous) and 25 with transudative effusions. The criteria that best identified an exudative pleural effusion was a pleural fluid cholesterol ~60mg/dL, pleural fluid to serum cholesterol ratio ~O.4, pleural fluid triglyceride ~40mg/dL, and a pleural fluid to serum triglyceride ratio ~0.3 mgldL. The pleural fluid cholesterol had a sensitivity of 88% and a specificity of 100% for exudates with an accuracy of 92 %. The pleural fluid to serum cholesterol ratio had a sensitivity of 98% and a specificity of 84%. The authors concluded these results were superior to the criteria proposed by Light et al. ll , 24 The authors further concluded that the pleural fluid cholesterol estimation was an effective and cost-efficient method of differentiating exudative from transudative effusions, but that the lipid profile did not help in diagnosing a tuberculous effusion.

Yilmaz-Turay et a1. 29 reported the use of pleural fluid C-reactive protein (CRP) in diagnosing pleural effusions. The aim of the study was to determine whether CRP was a sensitive marker for discriminating between transudative and exudative pleural effusions and to evaluate whether it could be used to distinguish inflammatory pleural effusions from other types of effusions. The authors compared CRP levels among transudates and exudates, inflammatory effusions, and other types of effusions. According to the criteria used, 16 patients were 32 Judson et al. 33 Areno et al. 34 Bourantas et al. 35 Diot et al. 36 Uchikov et al. 37 Goldsby et al. 38 Ray et al. 39 Pleural effusion following lung transplantation Pleural effusion due to acute lung rejection Persistent pleural effusions following coronary artery bypass surgery Pleural effusion in association with chronic myelomonocytic leukemia Wegener's disease mimicking acute infectious pleurisy Pleural effusions in acute pancreatitis Pleural effusions in pediatric patients treated with STI -571 (Gleevec) Pleural effusion caused by urinothorax in a patient with metastatic bladder cancer Assouad et al.'''' Karachalios et al. 41 Valstar et al. 42 Pleural effusion complicating cirrhosis Pleural effusion associated with temporal arteritis Pleural effusion in giant cell arteritis Toh et al. 43 Malignant pleural effusion in association with breast edema Breccia et al. 44 Pleural effusion complicating treatment with Imatinib in patients with CML Patel et al. 45 Berk 46 Cerebrospinal fluid-pleural fistula causing recurrent pleural effusion Pleural effusion in systemic amyloidosis caused by infiltration of pleura by amyloid included in the transudate group and 81 in the exudate group. Pleural fluid CRP levels were significantly lower in the transudate group. The ratio of pleural fluid to serum CRP was significantly lower in the transudate group.

In the exudate group, 35 patients had neoplastic effusions, 10 chronic nonspecific pleurisy, 19 tuberculous pleurisy, 16 parapneumonic effusions, and 1 postmyocardial injury (Dressler) syndrome (see below). When these subgroups were compared, the ratio between the fluid and serum CRP was significantly higher in the parapneumonic effusion subgroup than in the neoplastic subgroup. The authors concluded that in the differential diagnosis of pleural effusions, higher CRP levels could prove to be a rapid, practical, and accurate method of differentiating parapneumonic effusion from other exudative-type effusions and could be helpful in discriminating exudative from transudative effusions. Chierakul et al. 30 published a study to determine the validity of pleural fluid CRP concentrations or pleural fluid to serum CRP ratio for differentiating tuberculous pleuritis from malignant pleural effusion in patients presenting with lymphocytic exudative pleural effusions. The authors found the pleural fluid and serum CRP levels were significantly higher in the tuberculous pleuritis group than in the malignant pleural effusion group, and concluded that in patients presenting with lymphocytic exudative pleural effusion, a simple marker of raised pleural fluid CRP could be helpful in discriminating between tuberculous pleuritis and malignant pleural effusion (see Chapter 9) . Ryu 

Since the publication of the previous edition of this book, a number of papers have been published that describe very unique or unusual causes of pleural effusion?2-46 These are listed in Table 30 .6.

Effusions are sometimes referred to as non-large, large, or massive. The etiology of pleural effusions characterized as large or massive were reported by Porcel and Vives. 47 In this study, pleural effusions were deemed to be non-large (slight or moderate) if they occupied less than two-thirds of the hemithorax; large if they affected two-thirds or more of the hemithorax without reaching its complete length; or massive if they opacified the entire hemithorax. The causes of these pleural effusions were reported to have been determined by well-established clinical criteria. The authors evaluated chest radiographs from 766 patients during the study. Large effusions were identified in 70 patients (9%) and massive pleural effusions were identified in 93 patients 30 . Nonneoplastic Pleural Disease (12 %) . A similar etiologic spectrum was observed in patients with either large or massive pleural effusions. The most frequent cause of large/massive pleural effusions was malignancy (89 patients; 55%), followed by complicated para pneumonic effusion or empyema (36 patients; 22%), and tuberculosis (19 patients; 12%). The authors found that in patients with large or massive pleural effusions those with malignant effusions were more likely to have higher pleural fluid red blood cell counts and lower adenosine deaminase levels, which were the two parameters that were selected by the logisticregression model as being independent predictors of malignancy. The authors concluded that the presence of large or massive pleural effusion enabled the clinician to narrow the differential diagnosis of pleurisy since most effusions were secondary to malignancy or infection, either bacterial or mycobacterial. Bloody pleural fluid with a low adenosine deaminase level favored a malignant condition.

Light et a1. 48 reported large pleural effusions occurring after coronary artery bypass grafting. They graded the size of the pleural effusion differently than did Porcel and Vives. 47 In their scheme they defined a grade 2 effusion as "more than blunting of the costophrenic angle but less than 25% of the hemithorax occupied by pleural fluid," a grade 3 effusion as "pleural fluid occupying 25-50% of the hemithorax," a grade 4 effusion as "pleural fluid occupying 50-75% of the hemithorax," and a grade 5 effusion as "pleural fluid occupying more than 75% of the hemithorax." They concluded that large pleural effusions could develop in a small proportion of patients who underwent coronary artery bypass grafting, but the cause of the effusions was unclear.

Lazicka-Frelek et a1. 49 reported an unusual case of a massive pleural cavity effusion as a manifestation of a pancreaticopleural fistula.

Several reports of eosinophilic pleural effusions or eosinophilic pleuritis have been reported in the last several years. In 2004, Kalomenidis and Light 50 reviewed the pathogenesis of eosinophilic pleural effusions. These authors defined eosinophilic pleural effusions as those that contained at least 10% eosinophils. They found that eosinophilic pleural effusions accounted for 5% to 16% of exudative pleural effusions and that the pathogenesis was poorly understood. They reviewed the mechanisms that potentially lead to pleural effusions, reporting that they were caused by air or blood or both in the pleural space, infections or other inflammatory diseases, malignancy, pulmonary emboli, asbestos exposure, and drug reactions. The difference in the clinical features suggested that a variety of mechanisms were 1145 operative to induce eosinophilic pleural effusion. Both human and animal studies have suggested that interleukin-5 is important in the pathogenesis of eosinophilic pleural effusions.

Matthai and Kini 51 performed a prospective study on 26 eosinophilic pleural effusions found in 444 consecutive effusions investigated at a tertiary health care center over a 30-month period. Of the 26 eosinophilic pleural effusions studied, five were associated with tuberculosis and three with metastatic disease. Nineteen patients had significant associated lymphocytosis. Twenty-four patients with extended follow-up were in good health with no recurrence of the effusion. The eosinophilic pleural effusion was possibly associated with inflammatory, benign, or malignant conditions, and that a closer search for a definite etiologic agent was warranted in a setting of such an effusion, especially in populations endemic for tuberculosis, such as India, and in populations where there was a high prevalence of malignancy.

Martinez Garcia et a1. 52 investigated the potential relationship among the number of eosinophils in the pleural fluid samples, the type (with or without pleural biopsy), and the time elapsed between repeated thoracenteses. The authors did not observe any significant change in the percentage of eosinophils in relation to the number of thoracenteses performed per patient. They also observed this lack of relationship in a subgroup of patients who required one or more pleural biopsies. The authors concluded that their results suggested that repeated thoracenteses were not an important risk factor for the development of eosinophilic pleural effusions regardless of the time elapsed between consecutive thoracenteses. The authors also concluded that multiple punctures should no longer be considered a prevalent cause of pleural eosinophilia.

Moufarrege et a1. 53 reported an eosinophilic exudative pleural effusion after treatment of chronic low back pain (as a result of a work-related injury) with tizanidine (Zanaflex). Six weeks after starting tizanidine, a large pleural effusion was noted incidentally on a computed tomography (CT) scan of the thorax. Further evaluation showed no other potential cause of the effusion, and 4 weeks after tizanidine was discontinued, the pleural effusion resolved.

Ashwath et a1. 54 reported a case of eosinophilic pleural effusion associated with human toxocariasis. The authors pointed out that human toxocariasis, a helminthozoonosis caused by Toxocara species in which the larval migration of organisms through the tissues could cause an eosinophilia associated with a broad spectrum of clinical manifestations (see Chapter 14) . In this case, the patient developed an eosinophilic pleural effusion and had a CD8 cell deficiency associated with the Toxocara infection. The patient's symptoms were reported to have promptly responded to a nonsteroidal antiinflammatory medication (naproxen). The report stated this was only the fourth reported case of pleural effusion associated with Toxocara.

Killen et al. 55 described a 50-year-old woman who presented with increased breathlessness and a sensation different from her mild asthma, which was controlled with inhaled beclomethasone dipropionate and occasional salbutamol. On physical examination, the patient was found to have small bilateral pleural effusions and inspiratory crackles at the left base. She had a normocytic anemia with blood eosinophilia and an elevated CRP of 95 mg/L, with the normal range being less than lOmg/L.A chest radiograph confirmed the small bilateral pleural effusions and showed patchy parenchymal shadowing in both lower lobes. A high-resolution CT scan of the chest showed pronounced interlobular and peribronchovascular nodular interstitial thickening and bilateral pleural effusions, but no distortion of the lung architecture. Nerve conduction studies were normal. The patient developed nodular skin lesions, and a fascial biopsy from the right forearm showed subcutaneous infiltration by eosinophils, predominantly in a perivascular distribution. The patient was started on enteric-coated prednisone 30 mg daily and improved sufficiently for discharge from the hospital. Six months later she was well, with no induration, no chest symptoms, and normal chest radiograph, and she was currently taking prednisone at a dose of 5 mg/daily and inhaled beclomethasone dipropionate. This case report is of some interest in that fluticasone dipropionate present in the inhaled drug Advair has been reported to cause an eosinophilic pleural effusion and eosinophilic pleuritis. I have personally encountered such a case recently.

As reported by Mattison et al.,56 pleural effusions occur frequently in the medical intensive care unit (ICU). These authors reported on 100 patients whose length of stay in the medical ICU at the Medical University of South Carolina exceeded 24 hours. The prevalence of pleural effusions in 100 consecutive patients was 62%, with 41 % of the effusions detected at admission. Fifty-seven (92 %) of 62 pleural effusions were small. Causes of the pleural effusions included heart failure, atelectasis, uncomplicated parapneumonic effusions, hepatic hydrothorax, hypoalbuminemia, malignancy, pancreatitis, uremic pleurisy, and empyema. When compared to patients who never had effusions during their ICU stay, patients with pleural effusions were typically older, and had lower serum albumin concentrations, higher acute physiology S.P. Hammar assessment and chronic health evaluation scores, and longer mechanical ventilation. The authors concluded that pleural effusions in medical ICU patients were common, and that most were detected by careful review of chest radiographs taken with the patient in an erect or semi-erect position.

Pleural effusions occur less frequently in children than in adults, and can be caused by a variety of infectious and noninfectious agents. Among adults, the most frequent cause of a transudate is congestive heart failure, and the most frequent causes of an exudative effusion are bacterial pneumonia and malignancy. In children, pleural effusions are most commonly caused by infectious agents (50% to 70%), whereas congestive heart failure causes only 5% to 15%, and malignancy is a rare cause of effusion ( 

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The pleura is an extremely reactive tissue, and it is perhaps not surprising that it undergoes a variety of nonspecific changes. Pleural inflammation, increased vascularity, and mild fibrosis are often associated with an underlying pneumonia or pulmonary infarct ( Fig. 30.6 ). Following a pulmonary infarct, there may be a relatively well-localized area of pleural reaction characterized by an increased vascularity, inflammation, and a layer of fibrin on the outer surface of the visceral pleura ( Fig. 30.7) . Mesothelial cell hypertrophy and hyperplasia ( Fig. 30 .8) are asso-ciated with numerous conditions that involve the lung parenchyma, such as idiopathic pulmonary fibrosis, asbestosis, and peripheral lung cancers, when pulmonary involvement is close to the pleural surface. Yokoi and Mark 59 reported seven cases of primary carcinoma of the lung close to the pleural surface that were associated with atypical mesothelial cell hypertrophy and hyperplasia. In my experience, not only is hypertrophy and hyperplasia of epithelial surface mesothelial cells a frequent finding in this setting, but often a proliferation of multipotential subserosal spindle cells may be seen as well. 60 By immunohistochemistry, these subserosal cells express keratin, vimentin, and muscle-specific actin, and by elec-FIGUR E 30.7. A. Pleura overlying pulmonary infarct shows nonspecific increased vascularity, inflammation, fibrosis, and fibrin on outer surface, change referred to as fibrinous pleuritis. B. Organizing fibrinous exudate. Another nonspecific feature is fibrous thickening of the visceral pleura, usually associated with varying degrees of inflammation, which can be seen in a wide variety of pleural injuries of known cause or in idiopathic pleural fibrosis ( Fig. 30.9 ).61 Reactive eosinophilic pleuritis, a condition that may be confused with pulmonary eosinophilic granuloma, is an inflammatory process described in 1977 by Askin et a1. 62 In their report, it was seen primarily in persons who had spontaneous pneumothoracesspecifically, in 22 of 57 cases. None of the patients had clinical or radiographic evidence of interstitial lung disease, and a follow-up of 20 patients from 6 months to 5 years showed no evidence of other conditions. Their paper distinguished reactive eosinophilic pleuritis from pulmonary eosinophilic granuloma (pulmonary Langerhans' cell histiocytosis; see Chapter 16) because the macrophages associated with the eosinophils often had convoluted nuclei and mimicked the appearance of Langerhans' cells. In my experience reactive eosinophilic pleuritis may be seen in all types of conditions as it is a relatively common, nonspecific reaction to injury (see Figs. 16.48 and 16.49 in Chapter 16) . For reasons discussed previously, eosinophils are common inflammatory cells in pleural disease and are seen in a variety of conditions.

Venekamp et a1. 63 attempted to answer the question as to whether idiopathic pleuritis exists. They pointed out that even after a complete workup, including thoracoscopic biopsies, a significant number of patients with pleural exudates were diagnosed with nonspecific pleuritis, and the natural evolution of these patients was poorly understood. The objective of their study was to determine the natural evolution of patients with nonspecific pleuritis diagnosed after thoracoscopy and to evaluate whether the histologic diagnosis of nonspecific pleuritis corresponded with a clinical diagnosis of idiopathic pleuritis. The authors studied the evolution of pleuritis in 75 patients (49 men and 26 women) who underwent diagnostic thoracoscopy for evaluation of an unexplained exudative pleural effusion and in whom the histologic diagnosis of nonspecific pleuritis was made. Follow-up data were obtained through medical files or telephone contacts with the patients' family doctors; 8.3% of the 75 patients eventually developed a malignancy during the 1150 follow-up period, and in the remaining 91.7% the clinical evolution followed a benign course. A probable cause was established on clinical grounds in 40 patients. True idiopathic pleuritis was observed in 25 patients with a histologic diagnosis of nonspecific pleuritis. The authors found recurrence of the effusion in 10 out of 60 (16.7%) patients after a mean period of 26.2 months. The authors concluded the majority of patients with nonspecific pleuritis followed a benign course with a spontaneous resolution of the effusion in 81.8% of cases. In the majority of patients, a probable cause of pleuritis was identified, and idiopathic benign pleuritis occurred in only a minority (25%) of patients. 

Apical pleural fibrosis is seen in most cases of moderate to severe centrilobular emphysema, and is a relatively nonspecific form of fibrosis, except that the fibrous tissue often has a more granular or less organized appearance than well-formed collagenous fibrosis ( 

Apical cap lesions are usually identified radiographically as areas of increased opacity in the apex of one or both hemithoraces. 64 • 65 In most instances, the cause of apical cap lesions is unknown. Morphologically, they usually measure no more than 5 mm in thickness and have a sharply marginated, smooth, or undulating lower surface. The prevalence increases with age, being identified in 6% of patients younger than 45 years and in 16% of patients older than 45 years. 64 , 65 The prevalence is similar in men and women. 64 Pathologically, apical pleural cap lesions consist of the combination of pleural and pulmonary parenchymal fibrous tissue, the latter usually having high concentrations of grayish elastin in hematoxylin and eosin (H&E)-stained sections or blackish-gray color in Movat pentachrome-stained sections (Fig. 30.10 ). Occasional areas of calcification and ossification are seen in apical cap lesions. The pathogenesis of the fibrosis is uncertain. In one autopsy study, histologic evidence of chronic bronchitis and pulmonary artery narrowing were identified, and the investigators suggested that intermittent or continuing low-grade infection combined with relative apical ischemia might be responsible for the fibrosis. 66 Apical cap lesions have been reported to be more common in patients who have upper lobe fibrosis secondary to tuberculosis. 67 Yousem 68 reported on 13 cases of apical cap lesions resected for exclusion of a diagnosis of lung cancer. In this study lesions occurred in older individuals, particularly in the apices of the upper lobes, and by radiographic examination appeared as spiculated masses ranging from 1151 0.7 to 5.2cm in diameter. Microscopically, subpleural scars were pyramidal-shaped with overlying pleural adhesions and hyaline-type pleural plaques. They were composed of dense pulmonary fibrous tissue with old, mature collagen and an underlying elastic skeleton contracted in an accordion-like fashion with reduplicated curls of elastic fibers. Scar emphysema was observed at the periphery of the fibrous nodules. Yousem urged that pulmonary apical caps should be recognized for their unique histology because their appearance in the surgical pathology laboratory would likely increase in incidence with the evolution of more sensitive pulmonary radiographic studies. A chronic ischemic etiology was favored.

Pleural space infections are potentially serious disease processes that show a spectrum ranging from bacterial pneumonia associated with a small pleural effusion to the other end of the spectrum, that is, empyema, in which pus accumulates in the pleural space that may result in visceral and parietal pleural fibrosis, trapped lung, systemic sepsis, respiratory infection, or respiratory failure. At least 50% of all pneumonias are associated with an exudative effusion, which can be divided into three entities: (1) simple parapneumonic effusion, characterized by uninfected pleural fluid with clear appearance, normal pH, glucose and LDH, with most of these resolving with antibiotic treatment alone (drainage usually not required);

(2) complicated parapneumonic effusion, characterized by fluid that is infected but not purulent, appearing either clear or turbid, with a pH of <7.3, a low glucose, an elevated LDH, a pleural fluid Gram stain that mayor may not be positive, and the effusion usually requires drainage for resolution; and (3) empyema, in which there is pus in the pleural space with pleural fluid Gram stain or culture frequently being positive, and definitely requiring drainage for resolution. A classification scheme of pleural infections is shown in Table 30 .11.

Two excellent review articles appeared in the literature in 1999 concerning definitions and epidemiology of pleural space infections, and the pathophysiology of pleural space infections. 69 ,7o The review article by Antony and Mohammed 69 addressed the pathobiology of the pleural space, and reported that the pleural space is in equilibrium, with a minute quantity of transudative pleural fluid, and with a protein content of less than 1.5 g/ dL. The normal volume of pleural fluid in a 70-kg adult varies between 3 and 7 mL, with a predominance of lymphocytes, macrophages, and mesothelial cells. The authors reported that the pleura is functionally a dynamic layer that covers the chest wall and lung and is composed of a monolayer of mesothelial cells on the surface of the pleura. The authors stated that the pleural mesothelium, which was originally considered to be a simple membrane, has emerged as a dynamic cellular organ with multiple key functions, including its ability to phagocytose structures such as asbestos fibers, bacteria, and other particulate matter. The pleural mesothelial cells also release nitrous oxide, which has a number of effects on bacterial and mycobacterial organisms and has been implicated in their demise. In addition, the pleural mesothelial cells are stimulated by tumor necrosis factor-a, interleukin-1~, interferon-y, and lipopolysaccharide (LPS) that can produce large amounts of nitrous oxide. The release of oxidant intermediates by mesothelial cells is thought to playa role in killing bacteria. The authors conceptualized the participation of the mesothelial cell as having a primary and secondary response in the pathogenesis of parapneumonic effusions and empyema. This is shown in Figure 30 .12.

The sentinel role of the mesothelial cell in orchestrating the recruitment and facilitating the transmigration of neutrophils and mononuclear phagocytes into the pleural space is a critically important event that is responsible for the development of the pleural effusion after infections in the pleural space. The mesothelial cells express adhesion molecules, which cause adherence of neutrophils and monocytes to the mesothelium. Pleural mesothelial cells also release several cytokines that are capable of recruiting phagocytic cells from the vascular compartment into the pleural space (Fig. 30.13 ).

Interleukin-8 (IL-8) is a member of the supergene family of C-X-C chemotactic cytokines. It has been found in significant quantities in pleural fluid obtained from patients who developed parapneumonic effusions. It is considered to contribute between 30% and 60% of the chemotactic bioactivity of empyema pleural fluids. A significant correlation has been noted between IL-8 levels and the number of neutrophils in empyema fluid. Inter- 30. Nonneoplastic Pleural Disease leukin-8 is relatively resistant to proteolytic degradation, which could explain why IL-8 remains active in empyema pleural fluid. In vitro studies have shown that IL-1~, tumor necrosis factor-a, and LPS cause mesothelial cells to release IL-8.

Pleural space infections may be caused by penetrating chest wounds with direct bacterial contamination of the pleural space, or by iatrogenic infections that occur when preexisting pleural fluid becomes infected by thoracentesis or some other type of invasive procedure.

The most common cause of pleural space infections or parapneumonic effusions is an underlying pneumonia. Uncomplicated parapneumonic effusions do not require drainage and respond to antibiotic therapy alone for the underlying pneumonia. Complicated parapneumonic effusions do not respond to antibiotic therapy alone and require drainage to prevent the formation of a frank empyema.

Strange and Sahn 70 evaluated epidemiologic factors of patients with parapneumonic effusions. They found that comorbid conditions increased the risk of pleural space infections in patients with pneumonia. Contributing conditions included preexisting pulmonary diseases such as bronchiectasis, chronic obstructive pulmonary disease, and lung cancer. Diabetes was reported as a comorbid factor in 23% of patients in one series. 71 The coexistence of malignancy increased the risk of death in patients with an empyema. The clinical factors that predicted the presence of an anaerobic pneumonia included poor dentition, sedative drug use, alcohol use, seizures, mental retardation, and gastroesophageal reflux (see Chapters 5 and 8). 72 The causes of bacterial pleural space infections are listed in Table 30 .12. 

Bacterial-induced pneumonia often involves the peripheral portion of the lung and is characterized by a significant pleural neutrophil inflammatory infiltrate that initially may be associated with a sterile pleural effusion. 3 Approximately 60% of cases of pneumococcal pneumonia and 40% of all bacterial-caused pneumonias are associated with an exudative pleural effusion. 73 . 74 If the condition is not treated, the bacteria invade into and through the pleura resulting in exudative pleural effusion and empyema (Fig. 30.14) . The bacteria frequently activate the clotting system, causing a somewhat gelatinous pleural fluid that can serve as a lattice for organization and proliferation of fibroblasts. The most common causes of empyema in North America are anaerobic bacteria, either alone or in concert with aerobic bacteria. 75 

Tuberculous pleuritis is a relatively infrequent condition in North America, with an incidence of about 1100 cases per year. 77 Pleural effusion is commonly associated with this infection, and usually is serous or serosanguineous in nature, with a protein content greater than 4 g/dL. Tuberculous pleuritis occurs when a focus of tuberculosis below the visceral pleura ruptures into the pleural space. 78 ,79 These infections may be accompanied by a granuloma- tous inflammatory reaction, which occasionally can be identified by a closed pleural biopsy (see Chapter 9 for an extended discussion of tuberculous pleuritis, and see Fig. 9 .14).

Primary fungal pleuritis is an uncommon condition, and in my experience is seen predominantly in people with a variety of malignant neoplasms (often lymphoma or leukemia) treated with chemotherapeutic agents. It has also been described following lobectomy or pneumonectomy for tuberculosis or lung cancer, usually in association with a bronchopleural fistula. 3 81 These infections are rare and usually are not seen by pathologists in pleural biopsy specimens. As listed in Table 30 .13, some of these infections produce changes in the pleural fluid that assist in their diagnosis. Soubani et al. 82 evaluated the spectrum of conditions associated with pleural effusions in patients with acquired immune deficiency syndrome (AIDS). Evaluation of thoracentesis fluid from 24 men and six women showed an infectious cause in 21 (70%) cases and a noninfectious cause in nine (30%) cases. Bacterial pneumonia was the most common cause of pleural effusion (57%). Streptococcus pneumoniae and Staphylococcus aureus were the major organisms recovered. Mycobacterial infections were identified in three patients and Nocardia species in one patient. Non-Hodgkin's lymphoma was the leading noninfectious cause of pleural effusion, followed by Kaposi's sarcoma and adenocarcinoma of the lung. The authors concluded that pleural effusion was an important problem in patients with advanced HIV infections and was most commonly associated with bacterial pneumonia.

Trejo et al. 83 2-year period. The patients were grouped according to the stage of the effusion. Thirteen patients had empyema, 12 had complicated parapneumonic effusions, and five had uncomplicated parapneumonic effusions. Protein and glucose levels decreased, and the leukocyte count, neutrophil ratio, tumor necrosis factor-a levels, nitrite levels, and IL-8 levels increased progressively as the stage of the disease progressed. The IL-8 levels but not the tumor necrosis factor-a and nitrite , levels, were statistically different among the groups. The IL-8, tumor necrosis factor-a, and nitrite levels all correlated positively with each other and pH correlated negatively with these markers. At a cutoff value of 701.6pg/mL, IL-8 differentiated complicated parapneumonic effusions from uncomplicated parapneumonic effusions with a sensitivity of 80%, a specificity of 80%, and an accuracy of 86%. The authors concluded that biochemical markers were interrelated during stages of pleural inflammation and that IL-8 may be used as an alternative marker for discriminating between complicated pleural effusions and uncomplicated pleural effusions in pediatric patients with parapneumonic effusions.

Several review articles have been published on empyema. 85 -87 According to the article by Bryant and Salmon,85 the formation of empyema is arbitrarily divided into an exudative phase, during which pus accumulates; a purulent phase, during which fibrin deposition and loculation of pleural exudates occur; and an organization phase, during which fibroblast proliferation and scar formation cause lung entrapment. Pleural effusions are nutritionally rich culture media in which white blood cell defenses are severely impaired. This may be due to the fact that effective phagocytosis of bacteria by neutrophils requires a structure upon which white blood cells can move and ingest bacteria prior to the development of specific antibodies. Bacteria in pleural fluid enlist a complex series of host defense responses that are incompletely understood, despite significant recent advancements in our knowledge. Empyema fluid is relatively deficient in opsonins and complement, and becomes progressively more acidic, hypoxic, and depleted of glucose as infection proceeds. During the inflammatory process, leukocytes release certain substances such as bactericidal permeability-increasing proteins, defensins, lysozyme, cationic proteins, lactoferrin, and zincbinding proteins. Bacteria within empyemas are relatively unresponsive to antibiotics and may release ~-lactamase enzymes capable of degrading ~-lactamase-susceptible ~-lactam antibiotics. The conditions and causes that contribute to bacterial empyema are shown in Table  30 .14.

Immunocompromised patients are susceptible to pleural involvement with fungal or aerobic gramnegative bacillary organisms, whereas in patients with malignancy, fungal or tuberculous foci may become reactivated and empyema may develop. Fungal or mycobacterial empyema may develop in transplant recipients and AIDS patients. The bacteria that have been isolated from nontuberculous pleural empyema fluid in various studies are shown in Table 30 .15.

Tuberculous empyema has been reviewed by Sahn and Iseman. 88 Tuberculous empyema represents a chronic, active infection of the pleural space and is relatively rare compared to tuberculous pleural effusion. According to Sahn and Iseman, the inflammatory process may be present for years with a paucity of clinical symptoms. The clinical diagnosis of tuberculous empyema is somewhat characteristic by CT scan, showing a thick, calcified pleural rind and rib thickening surrounding loculated pleural fluid (see also Chapter 9) .

An eosinophilic empyema was associated with crack cocaine, which is a known cause of eosinophilic pneumonia. Strong et a1. 89 suggested that a pleural effusion that appears to be grossly purulent in the setting of cocaine abuse should not be drained until an eosinophil predominant effusion is ruled out. If infection is excluded, an eosinophilic empyema in the setting of crack cocaine should be treated with corticosteroids.

Pharmaceutical drugs continue to be a potential cause of pleural disease. 90 -92 As reviewed by Huggins and Sahn,n the pathogenetic mechanisms for most drug-induced pleural diseases remain speculative. Possible mechanisms include (1) hypersensitivity or allergic reaction, (2) direct toxic effect, (3) increased oxygen free radical production, 

Source: Bryant 

Pleural Disease

Rheumatoid arthritis is associated with the highest incidence of pleural involvement of all the collagen vascular diseases. 94 -96 Rheumatoid pleuritis occurs in approximately 5% of patients with rheumatoid disease,96,97 and may be associated with visceral pleural fibrosis, rheumatoid nodules involving the visceral pleura ( Fig. 30.16) , or, occasionally, fibrosis and inflammation of the visceral and parietal layers of the pleura with adhesions. Autopsy studies suggest pleural involvement in rheumatoid disease approaches 50%, although most patients are apparently asymptomatic. In contrast to the overall incidence of rheumatoid arthritis, symptomatic rheumatoid lung disease is more common in men than in women, and that 1163 holds true for rheumatoid pleuritis. The typical patient who develops rheumatoid pleuritis is a man in the sixth decade with a pleural effusion within 5 years after the onset of rheumatoid disease. In most instances, patients with rheumatoid pleuritis have a high rheumatoid factor titer, and this antibody is also found in the pleural fluid. The most striking consistent features of rheumatoid pleural effusions are low pleural fluid glucose, low pH, and high LDH (see Chapter 20 on collagen vascular diseases). Involvement of the pleura in patients with systemic lupus erythematosus occurs to some degree in 50% to 75% of patients diagnosed with lupus, and may be the presenting manifestation in up to 5% of patients. 3 The changes in the pleura are nonspecific and can consist of acute and chronic inflammation and fibrosis (Fig. 30.17) .

In most instances, the pleuritis is associated with an exacerbation of the basic disease. In contrast to the pleural fluid in rheumatoid pleuritis, in lupus pleuritis the pleural fluid glucose and pH are usually within normal limits. One can identify LE cells in the pleural fluid, although other serologic studies, such as DNA binding and extract-S.P Hammar Table 30 .17. 

Sarcoidosis is a nonnecrotizing granulomatous disease involving lymph nodes, pulmonary parenchyma, and other tissues and organs. Not infrequently, sarcoid involves the pleura (see Fig. 18 .11 in Chapter 18), and in one retrospective study of more than 200 patients with biopsy-proven sarcoidosis, 10% had radiographic evidence of pleural thickening or effusion and 7% had evidence of pleural effusion. 98 Most patients with pleural involvement by sarcoid have at least radiographic stage II disease (see Chapter 18) . The pleural fluid may be a transudate or an exudate, and often has an increased number of lymphocytes, specifically helper-inducer (CD4positive) lymphocytes.

As discussed in Chapter 29, Wegener's granulomatosis is characterized by a necrotizing granulomatous inflammatory process typically involving the lungs and not infrequently involving the kidneys and other tissues and organs. As described by Mark et al.,99 the basic lesion is necrobiosis of collagen that incites the inflammatory reaction. If these areas of necrosis and inflammation occur close to or involve the pleural surface, one would expect an inflammatory reaction to be located in that region (Fig. 30.18 ). In some series/Do pleural effusion has been observed in as many as 55% of cases, although in most instances the incidence of pleural effusion is much less than that. The characteristic features of pleural fluid in Wegener's granulomatosis have not been fully defined. A case of pleural effusion associated with Wegener's granulomatosis is described by Diot and colleagues. 36 Postcardiac Injury Syndrome-Dressler Syndrome

The occurrence of pleuropericarditis and parenchymal pulmonary infiltrates, usually occurring approximately 3 weeks following injury to the myocardium or pericardium, is referred to as postcardiac injury syndrome and is characterized by the onset of fever with the pleuropericarditis. The incidence of this syndrome varies from approximately less than 1 % to 15%,101.102 and is thought to be related to an immunologic reaction characterized by antibodies to myocardial tissue. 103 ,104 The pleuropulmonary manifestations are the most significant in this syndrome, and most patients present with pleuritic chest pain. Pleural fluid is characteristically a serosanguineous or bloody exudate, and may result in chronic pleural thickening with varying degrees of inflammation (Fig. 30.19 ).

Kim and Sahn lo5 described in 1996 an immunologic assessment of pleural fluid in a patient with postcardiac injury syndrome. They identified antimyocardial antibodies in the pleural fluid. A publication in 2004 by Bendjelid and Pugin106 suggested that the incidence of postacute myocardial infarction syndrome had decreased in the reperfusion era, most likely due to the extensive use of therapies that significantly decreased the size of myocardial necrosis.

Huggins and Sahn 107 reviewed the conditions that resulted in pleural fibrosis. They pointed out that a variety of inflammatory processes, including dust exposure, immunologic diseases, infection, medications, malignancy, postcoronary bypass surgery, and uremic pleurisy, could result in pleural fibrosis. Those that were reported to cause a trapped lung are shown in Table 30 .18. The authors concluded that pleural fibrosis could result from diverse inflammatory conditions, and the development of pleural fibrosis followed severe pleural inflammation, which was typically associated with an exudative effusion. Another critical factor stated to be important in pleural fibrosis S.P. Hammar was the formation of fibrinous intrapleural neomatrix. The neomatrix was stated to result from a disorder of fibrin turnover whereby fibrin formation was upregulated and fibrin dissolution was downregulated. The authors reported that transforming growth factor-~ (TGF-~) and tumor necrosis factor-a (TNF-a) facilitated the disordered fibrin turnover, and that clinically significant pleural fibrosis required involvement of the visceral pleura.

Hemothorax refers to the presence of blood within the pleural cavity. It is occasionally seen as an almost invariably fatal complication of a ruptured thoracic aortic aneurysm or a traumatic rupture of the aorta. A moderate amount of blood causing a bloody pleural effusion can be seen in other conditions, such as asbestos-induced pleural disease, tuberculosis, and a variety of neoplasms such as mesothelioma and primary lung cancers invading the pleura. The pathologic features of these conditions depend on the specific etiology.

Chylothorax refers to accumulation of lymphatic fluid within the pleural cavity that has the features of lymph fluid, containing a high concentration of emulsified neutral fats and fatty acids with a low concentration of cholesterol. A chyliform effusion results from degeneration of malignant and other cells in pleural fluid, and a pseudochylous effusion results from the presence of cholesterol crystals and occurs most commonly in tuberculosis, rheumatoid disease, and nephrotic syndrome. Chylothorax may be bilateral, although it is more commonly seen on the left side. There are numerous causes of chylothorax. lOS These are listed in Table 30 . 19 .

A definitive diagnosis of chylothorax is made by laboratory analysis of pleural fluid. The presence of chylomicrons on lipoprotein electrophoresis is confirmatory. Staats et al. 109 performed a study in which triglyceride values were determined for 142 effusions defined as chylous or nonchylous by the gold standard test of lipoprotein electrophoresis. Using the Gaussian distribution method, it was estimated that fluid with a triglyceride value of more than 110 mg/dL had less than a 1 % chance of not being chylous, and fluid with a triglyceride value of less than 50mg/dL had no more than a 5% chance of being chylous. Chylothorax rarely occurs as a complication of coronary artery bypass surgery as a result of injury to the left internal mammary lymphatics during dissection of the vessel or from injury to the parasternal nodesYo Tuberculosis is also an unusual cause of chylothorax. ll1 Another rare condition in which chylothorax may occur is lymphangioleiomyomatosis. ll2 The mechanism of chylothorax in lymphangioleiomyomatosis includes (1) chyle leak secondary to proximal lymphatic obstruction or direct involvement of the thoracic duct or its tributaries, (2) general oozing from pleural lymphatics or collateral vessels, and (3) trans diaphragmatic flow of chylous ascites (see Chapter 39). Pneumothorax Pneumothorax refers to air or gas in pleural cavities and may be spontaneous, traumatic, or therapeutic. Spontaneous pneumothoraces are caused by abnormalities of the parenchyma that allow the escape of air into the pleural cavity. These may be caused by blebs and bullae associated with emphysema, by an abscess cavity that communicates with the pleural space, or occasionally by asthma, which results in areas of overexpansion of the lung paren-1167 chyma that then ruptures. Therapeutic pneumothorax was once commonly used to treat tuberculosis. Pneumothoraces occasionally occur during fine-needle aspiration biopsy attempts, and when inserting various catheters into the subclavian vein. Primary spontaneous idiopathic pneumothorax characteristically affects young persons (predominantly young males of asthenic body habitus), is associated with cigarette smoking, and in most cases is due to ruptured apical blebs and bullae. 113 . 114 Recurrent attacks are frequent and disabling, and often require surgical intervention to "roughen" the pleural surface with the hope of causing scarring and preventing further air leaks. Histologically, resected apical lung tissue in patients with primary spontaneous pneumothorax shows, in addition to pleural chronic inflammation and reactive eosinophilic pleuritis, parenchymal changes of band-like subpleural fibrosis, blebs, and paracicatricial emphysema. 113 • 115 Increased pigment-laden macrophages in distal air spaces are consistent with a cigarette smoking history. Parenchymal blood vessels in the vicinity of the pleura may exhibit medial hypertrophy and intimal fibrosis, but these changes should not be interpreted as indicative of pulmonary hypertension. 116 Rarely, eosinophils may infiltrate the underlying lung parenchyma and prominently infiltrate blood vessels, mimicking the changes in Churg-Strauss syndrome or Langerhans' cell histiocytosis (Fig. 30.20 ) (see also Chapters 16 and 29) . 117 Air leak in the absence of trauma or iatrogenic causes within the pleural cavity is referred to as spontaneous pneumothorax and can be either primary, in which there is no obvious clinical or radiographic evidence of significant pulmonary disease, or secondary, in which a disease is present. Primary spontaneous pneumothorax is caused by rupture of air-containing spaces in the visceral pleura or immediately below the visceral pleura. The most common causes are bullae, which are defined as sharply FIGURE 30.20 . Eosinophilic vascular infiltration in spontaneous pneumothorax. A muscular pulmonary artery is densely infiltrated by eosinophils. demarcated regions of emphysema greater than 1 cm in diameter. 1l3 A bleb is defined as a gas-containing space situated entirely within the pleura (see Chapter 24 on emphysema). It is thought that most air-containing spaces associated with pneumothorax are bullae. Computed tomography scans demonstrate areas of emphysema in more than 80% of patients who have spontaneous pneumothorax, even in lifelong nonsmokers. 118 ,119 Spontaneous pneumothoraces are multifactorial in causation. 120 The common causes are listed in Table 30 .20. Iatrogenic causes of pneumothorax are listed in Table 30 Butnor and Guinee 121 recently reported on the pathologic features of the Birt-Hogg-Dube syndrome, a rare inherited genodermatosis characterized by distinct cutaneous lesions with an increased risk of renal and colonic cancer and the development of pleuropulmonary blebs and cysts. Histologically, the lung shows basilar cysts composed of intra parenchymal collections of air surrounded by normal parenchymal or thin fibrous walls, and blebs consisting of collections of air within the pleura. The authors point out that these histologic findings are nonspecific, although their predominantly basilar location contrasts with the apical distribution of well-recognized causes of spontaneous pneumothorax, such as emphysematous bullae and idiopathic blebs. As suggested by the authors, it is important for pathologists to be aware of this rare cause of spontaneous pneumothorax because Birt-Hogg-Dube syndrome can radiographically simulate other causes of pulmonary cysts, and the lung and pleura may be the initial site of involvement of this condition.

Pleuropulmonary endometriosis is a rare condition and it is discussed in Chapter 41. It can be an uncommon cause of pneumothorax and can present as a bloody pleural effusion. Deciduosis can also occur in areas of pleural endometriosis and occasionally may be confused with deciduoid mesothelioma. 122 -128 Other Uncommon Causes of Pleural Effusion As reported by Jarratt and Sahn,129 pleural effusions have been seen in hospitalized patients receiving long-term hemodialysis. Although heart failure was the most common cause, other diseases were responsible for most of the effusions, and a unilateral effusion suggested a diagnosis other than heart failure, most commonly parapneumonic effusion or atelectasis, which warranted prompt thoracentesis.

Patients with recurrent pneumothorax or uncontrolled recurrent pleural effusions may require iatrogenic symphysis of the parietal and visceral pleura in order to maintain lung inflation and prevent recurrent episodes. 130 Relatively common indications include spontaneous idiopathic pneumothorax in young adults, pneumothoraces in patients with cystic fibrosis or bullous emphysema, and recurrent malignant pleural effusions. Techniques for inducing pleural adhesions include mechanical pleural abrasion, chemical pleurodesis with sclerosing agents like tetracycline derivatives or bleomycin, or instillation of 1169 talc into the pleural space. l3l -I33 The fibroinflammatory response following chemical pleurodesis is a nonspecific organizing fibrinous pleuritis leading to pleural fibro-sisY4. 135 Experimentally, a neutrophil-rich exudative pleural effusion is followed by an increase in mononuclear cells. 135 The mechanism of tetracycline pleurodesis includes production of a fibroblast growth factor by stimulated mesothelial cells. 136 Talc, instilled into the pleural space by poudrage or slurry, is the most frequent agent currently used for pleurodesis. 130 Mixed talc, with a mean particle size of 15 11m, is typically utilized.137 Talc induces a histiocytic and granulomatous foreign body reaction followed by pleural fibrosis, surrounding brightly birefringent talc particles (Fig. 30.21) . Occasionally the talc accumulates in the dependent regions of the pleural space producing macroscopic friable chalky yellow-tan pleural deposits (Fig.  3D .21e). Intrapleural talc instillation has been associated with hypoxemia and rare instances of acute respiratory FIGURE 30.21. Talc pleurodesis. A. The pleural membrane is thickened by histiocytes and foreign-body giant cells containing refractile gray-green talc particles (arrows). B. Polarized light highlights the birefringent talc. C. Talc pleurodesis in a patient with metastatic mammary carcinoma. Note pleural-diaphragmatic symphysis (black arrow) and chalky yellow deposits of talc (white arrow) in the dependent regions. The lung parenchyma exhibits lymphangitis carcinomatosa with thickening of interlobular septa.

Pleural cell biology in health and disease

Surface morphology of the human pleura: a scanning electron microscopic study

The pleura

The mesoderm and the coelom of vertebrates

The preformed stomas connecting the pleural cavity and lymphatics in the parietal pleura

Permeability of the diaphragmatic mesothelium: The ultrastructural basis for "stomata

Physiological significance of lymph drainage of the serous cavities and lungs

The differential diagnosis of pleural effusions

Pleural liquid and solute exchange

Pleural fluid analysis

Clinical manifestations and useful tests

Subcutaneous metastases of sarcomatoid mesothelioma with its differential diagnosis on fine needle aspiration-a case report

Malignant biphasic pleural mesothelioma metastatic to the liver diagnosed by fine needle aspiration

Fine needle aspiration cytology of well-differentiated papillary mesothelioma: a case report

Electron microscopy renders the diagnostic capabilities of cytopathology more precise: an approach to everyday practice

Primary diagnosis of malignant mesothelioma by fine-needle aspiration of a supraclavicular lymph node

Slatnik 1. Cytopathology of malignant mesothelioma of the pleura in fineneedle aspiration biopsy

Occult metastatic mesothelioma-diagnosis by fine-needle aspiration. A case report

Aspiration biopsy cytology of mesothelioma

Electron microscopy in the diagnosis of percutaneous fine needle aspiration specimens

Diagnosis of peritoneal mesothelioma: computed tomography, sonography, and fine-needle aspiration biopsy

Immunologic mechanisms in pleural disease

Immunobiology of pleural inflammation: potential implications for pathogenesis, diagnosis and therapy

Pleural effusions

Shortness of breath in a 74-yearold woman. Case study

Do we need all three criteria for the diagnostic separation of pleural fluid into transudates and exudates? An appraisal of the traditional criteria

Multilevel likelihood ratios for identifying exudative pleural effusions

Role of pleural fluid cholesterol in differentiating transudative from exudative pleural effusion

Use of pleural fluid C-reactive protein in diagnosis of pleural effusions

A simple C-reactive protein measurement for the differentiation between tuberculous and malignant pleural effusion

The implication of elevated carcinoembryonic antigen level in pleural fluid of patients with non-malignant pleural effusion

Pleural effusions following lung transplantation. Time course, characteristics, and clinical implications

Pleural effusion from acute lung rejection

Persistent pleural effusions following coronary bypass surgery

Pleural effusion in chronic myelomonocytic leukemia

Wegener's disease mimicking acute infectious pleurisy

Pleural effusions in acute pancreatitis

Unexpected pleural effusions in 3 pediatric patients treated with STI-571

Urinothorax: unexpected cause of a pleural effusion

Recurrent pleural effusion complicating liver cirrhosis

Pleural effusion in temporal arteritis

Pericardial and pleural effusion in giant cell arteritis

Unilateral breast edema in two patients with malignant pleural effusion

Pleural-pericardic effusion as uncommon complication in CML patients treated with Imatinib

Meter 11. Intracranial hypotension and recurrent pleural effusion after snowboarding injury: a manifestation of cerebrospinal fluidpleural fistula

Pleural effusions in systemic amyloidosis

Etiology and pleural fluid characteristics of large and massive effusions

Large pleural effusions occurring after coronary artery bypass grafting

Massive pleural cavity effusion as the manifestation for the pancreatico-pleural fistula

Pathogenesis of the eosinophilic pleural effusions

Diagnostic value of eosinophils in pleural effusion: a prospective study of 26 cases

Repeated thoracentesis: an important risk factor for eosinophilic pleural effusion?

Eosinophilic exudative pleural effusion after initiation of tizanidine treatment: a case report

A presumptive case of toxocariasis associated with eosinophilic pleural effusion: case report and literature review

Eosinophilic fasciitis with pulmonary and pleural involvement

Pleural effusions in the medical ICU: Prevalence, 1171 causes and clinical implications

Efrati 0, Barak A. Pleural effusions in the pediatric population

Resolution of pleural effusions

Atypical mesothelial hyperplasia associated with bronchogenic carcinoma

Reactive and neoplastic serosal tissue. A light microscopic, ultrastructural and immunocytochemical study

Cryptogenic bilateral fibrosing pleuritis

Reactive eosinophilic pleuritis: a lesion to be distinguished from pulmonary eosinophilic granuloma

Does "idiopathic pleuritis" exist? Natural history of non-specific pleuritis diagnosed after thoracoscopy

The apical cap

The apical cap

Kleinerman 1. The pulmonary apical cap

Apical opacity associated with pulmonary tuberculosis: high-resolution CT findings

Pulmonary apical cap: a distinctive but poorly recognized lesion in pulmonary surgical pathology

Pathophysiology of pleural space infections

The definitions and epidemiology of pleural space infection

Treatment of complicated parapneumonic effusions and pleural empyema: a four-year prospective study

The clinical course and management of thoracic empyema

Parapneumonic effusions

The incidence and clinical correlates of parapneumonic effusions in pneumococcal pneumonia

Bacteriology of empyema

Politis 1. Empyema thoracis during a ten-year period

Extrapulmonary tuberculosis in the United States

Operative and pathologic findings in twenty-four patients with syndrome of idiopathic pleurisy with effusion, presumably tuberculosis

Current concepts of tuberculous pleurisy with effusion as derived from pleural biopsy studies

Pleural mucormycosis (zygomycosis)

Pleural pneumocystis carinii infection

Pleural fluid findings in patients with the acquired immunodeficiency syndrome: correlation with concomitant pulmonary disease

Pleural effusion in patients infected with the human immunodeficiency virus

Childhood parapneumonic effusions: Biochemical and inflammatory markers

Pleural empyema

Diagnosis and management of empyema

Empyema thoracis: Therapeutic management and outcome

Tuberculous empyema

Eosinophilic "empyema" associated with crack cocaine use

Drug-induced pleural disease

Drugs and the pleura

Drug-induced pleural disease

Pulmonary lesions in "rheumatoid disease" with remarks on diffuse interstitial fibrosis

Studies of rheumatoid pulmonary disease:A comparison of roentgenographic findings among patients with high rheumatoid factor titers and with completely negative reactions

Pulmonary lesions and rheumatoid arthritis

The pleural and pulmonary complications of rheumatoid arthritis

Pleural involvement in sarcoidosis

The pulmonary biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis: a study based on 35 open lung biopsies

Wegener's granulomatosis

Incidence and significance of heart muscle antibodies in patients with acute myocardial infarction and unstable angina

Pericarditis of acute myocardial infarction

Zabriskie 1. The postcardiotomy syndrome and anti-heart antibodies

Anti-heart antibodies in the postpericardiotomy and post-myocardial infarction syndromes

Postcardiac injury syndrome: an immunologic pleural fluid analysis

Is Dressler syndrome dead?

Causes and management of pleural fibrosis

Chinnock BE Chylothorax: case report and review of the literature

The lipoprotein profile of chylous and nonchylous pleural effusion

Left pleural effusion in a woman with coronary artery by-pass grafting

Tuberculous chylothorax: case report and review of the literature

Chylothorax in lymphangioleiomyomatosis

Spontaneous pneumothorax in young subjects. A clinical and pathological study

Spontaneous pneumothorax

Pleura in pneumothorax-comparison of patients with cystic fibrosis and "idiopathic" spontaneous pneumothorax

Pulmonary vasculopathy in idiopathic spontaneous pneumothorax in young subjects

Reactive eosinophilic pulmonary vascular infiltration in patients with spontaneous pneumothorax

Computed tomography and the etiologic assessment of idiopathic spontaneous pneumothorax

Nonsmoking, non-alpha 1-antitrypsin deficiency-induced emphysema in nonsmokers with healed spontaneous pneumothorax, identified by computed tomography of lung

Diagnosis of diseases of the

Nonneoplastic Pleural Disease chest

Pleuropulmonary pathology of Birt-Hogg-Dube Syndrome

Thoracic endometriosis syndrome: new observations from an analysis of 110 cases

Thoracic endometriosis: a case report and literature review

Catamenial pneumothorax: a prospective study

Catamenial pneumothorax caused by endometriosis in the visceral pleura

Endometriosis presenting as bloody pleural effusion and ascites-report of a case and review of the literature

Extrapelvic endometriosis

Pleuro-pulmonary endometriosis and pulmonary ectopic deciduosis: a clinicopathologic and immunohistochemical study of 10 cases with emphasis on diagnostic pitfalls

Pleural effusions in hospitalized patients receiving long-term hemodialysis

State of the art: pleurodesis

Chemical pleurodesis for malignant pleural effusions

Intrapleural tetracycline for malignant pleural effusions

Talc pleurodesis for the treatment of pneumothorax and pleural effusion

Temporal evolution of pleural fibrosis induced by intrapleural minocycline injection

The effect of tetracycline on rabbit pleura

Mechanism of tetracycline-hydrochloride-induced pleurodesis. Tetracycline-hydrochloride-stimulated mesothelial cells produce a growth-factor-like activity for fibroblasts

Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size

Adult respiratory distress syndrome following intrapleural instillation of talc

Acute pneumonitis with bilateral pleural effusion after talc pleurodesis

Respiratory failure following talc pleurodesis

Respiratory failure due to insufflated talc

Pro/Con Editorials. Talc should/should not be used for pleurodesis

distress syndrome (ARDS), including fatal ARDS. [137] [138] [139] [140] [141] This systemic response has been especially associated with small (:::;10 !lm) particles which probably gain access to the systemic circulation.137J42