Mesothelioma and Other Asbestos-Related Pleural Diseases

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1 pulmonary Disease Board Review Manual Statement of Editorial Purpose The Hospital Physician Pulmonary Disease Board Review Manual is a peer-reviewed study guide for fellows and practicing physicians preparing for board examinations in pulmonary disease. Each manual reviews a topic essential to current practice in the subspecialty of pulmonary disease. PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White editorial director Debra Dreger Senior EDITOR Robert Litchkofski associate EDITOR Rita E. Gould Mesothelioma and Other Asbestos-Related Pleural Diseases Series Editor and Contributor: Gregory C. Kane, MD, FACP, FCCP Professor of Medicine, Internal Medicine Residency Program Director, Vice-Chairman, Department of Internal Medicine, Jefferson Medical College, Philadelphia, PA Contributor: Rodrigo Cavallazzi, MD Fellow, Division of Pulmonary and Critical Care Medicine, Thomas Jefferson University Hospital, Philadelphia, PA assistant EDITOR Farrawh Charles executive vice president Barbara T. White executive director of operations Jean M. Gaul PRODUCTION Director Suzanne S. Banish PRODUCTION assistant Nadja V. Frist ADVERTISING/PROJECT Director Patricia Payne Castle sales & marketing manager Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine. Table of Contents Introduction Malignant Pleural Mesothelioma Pleural Plaques Diffuse Pleural Thickening Rounded Atelectasis Benign Pleural Effusion References Cover Illustration by Kathryn K. Johnson Copyright 2008, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA ,. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. Hospital Physician Board Review Manual

2 Pulmonary Disease Board Review Manual Mesothelioma and Other Asbestos-Related Pleural Diseases Rodrigo Cavallazzi, MD, and Gregory C. Kane, MD, FACP, FCCP INTRODUCTION Asbestos is a definitive carcinogen when inhaled or ingested that has an established causal relationship with cancer of the lung, mesothelioma of the pleura and peritoneum, cancer of the larynx, and certain gastrointestinal cancers. Furthermore, asbestos exposure causes asbestosis, a progressive fibrotic disease of the lung, and several types of benign pleural diseases. 1 This article reviews the most common asbestos-related pleural diseases, with a primary focus on malignant pleural mesothelioma (MPM) given its high mortality rate. Aspects of the following benign asbestos-related pleural diseases are discussed as well: pleural plaques, diffuse pleural thickening, rounded atelectasis, and benign pleural effusion. MALIGNANT PLEURAL MESOTHELIOMA Case presentation An 85-year-old white man with chronic obstructive pulmonary disease diagnosed several years ago presents to the outpatient clinic with shortness of breath and chest pain. His symptoms started 2 months prior to his visit and are characterized by progressive shortness of breath and dull, nonpleuritic anterior chest pain not related to exertion. He also has noticed anorexia and a 20-lb weight loss over the same period. His social history is significant for a 50-pack-year smoking history. He worked as a school teacher and has lived most of his life in a neighborhood near a company that repairs roofs. Physical examination reveals decreased breath sounds and dullness to percussion at the right hemithorax. Chest radiograph reveals volume loss of the right hemithorax with moderate right pleural effusion and nodular pleural thickening. He undergoes therapeutic and diagnostic thoracocentesis, and analysis of the pleural fluid reveals a lymphocytic exudate with atypical mesothelial cells. Chest computed tomography (CT) after thoracocentesis reveals findings suggestive of MPM (Figure 1). The patient undergoes thoracoscopic pleural biopsy, which establishes the diagnosis of MPM. Definition and Epidemiology Malignant mesothelioma is a tumor that arises from the surface serosal cells of the pleural, peritoneal, and pericardial cavities and from the tunica vaginalis. 2 The overall age-adjusted US incidence rate of mesothelioma was 1.11 cases (95% confidence interval [CI], ) per 100,000 persons, according to an analysis that used cancer registry data covering 88% of the US population. 3 The male-to-female ratio was 5.1:1, and whites had a higher incidence than African Americans, Native Americans and Alaska Natives, and Asian/ Pacific Islanders. The incidence was higher in non- Hispanics than in Hispanics. The sex predilection is largely related to gender differences in occupational exposures. The incidence rate rises with increasing age, peaking at the 75-to-84-year age-bracket, with 8.66 cases (95% CI, ) per 100,000 persons. Pleural mesothelioma accounted for 83% of all cases, and peritoneal mesothelioma accounted for 7%. Among females, however, peritoneal tumors made up 15% of the total, and 74% were pleural. 3 While estimates indicate that the incidence of mesothelioma is declining in the United States, 4,5 estimates for Western European countries and Australia predict that the incidence of mesothelioma will peak between 2010 and Developing countries are also expected to experience a peak rate of mesothelioma in the future due to increasing asbestos production and consumption. 9 For the period 1999 to 2001, the overall mortality rate (number of deaths per million persons per year) due to mesothelioma adjusted to the 2000 US standard population was 11.52, with males (22.34) showing a 6-fold higher rate than females (3.94). 10 Several case-control and cohort studies have demonstrated a clear association between asbestos exposure and malignant mesothelioma. 11,12 The term asbestos encompasses different fibrous silicate materials, each with unique physical, chemical, and biologic properties. pulmonary Disease Volume 13, Part 5

3 Figure 1. Transverse section chest computed tomography scan (5-mm collimation) without contrast showing volume loss of the right hemithorax and marked nodular circumferential right pleural thickening, which extends into the fissure and mediastinum abutting the pericardium. Small nodular opacities are present throughout the right lung parenchyma and are less prominent in the left lung parenchyma. All forms of asbestos are hazardous, but the risk of mesothelioma changes with exposure to different fiber types. 13 Asbestos fibers can come from naturally occurring sources or from the wearing down or disturbance of manufactured products, including insulation, automotive brakes and clutches, ceiling and floor tiles, dry wall, roof shingles, and cement. 14 Asbestos fibers belong to the mineral families serpentine and amphibole. The serpentine family contains chrysotile, an asbestos fiber heavily used in industry. The amphibole family contains crocidolite and amosite, which have been used in many industries, as well as anthophyllite and tremolite, which can occur as trace minerals in chrysotile and talc deposits. 2 A quantitative analysis found that the specific risk for malignant mesothelioma associated with occupational exposure for the 3 main commercial asbestos types is highest for crocidolite followed by amosite and then chrysotile. 15 However, it is important to emphasize that all asbestos fiber types can cause mesothelioma in exposed individuals. 12 Moreover, in industrial applications, it would be rare to encounter asbestos of only 1 fiber type. In addition to fiber type, other factors determining mesothelioma risk include the time from exposure to asbestos the median latent period is 32 years after initial exposure and cumulative exposure to asbestos. 2,16 In the United States, the adjusted proportionate mortality ratio (PMR) of malignant mesothelioma is elevated for the following industries: ship and boat building and repairing (PMR 5.95 [95% CI, ]), industrial and miscellaneous chemicals (PMR 4.81 [95% CI, ]), petroleum refining (PMR 3.8 [95% CI, ]), electric light and power (PMR 3.08 [95% CI, ]), and construction (PMR 1.55 [95% CI, ]). By occupation, the following have an elevated adjusted PMR: plumbers, pipefitters, and steamfitters (PMR 4.76 [95% CI, ]); mechanical engineers (PMR 3.04 [95% CI, ]; electricians (PMR 2.42 [95% CI, ]); and elementary school teachers (PMR 2.13 [95% CI, ]. The PMR corresponded to the total number of deaths with the condition of interest divided by the expected number of deaths with that condition. 10 A number of studies have also demonstrated an elevated risk of mesothelioma from nonoccupational asbestos exposure. The 2 main types of environmental asbestos exposure are household and neighborhood. Common sources of household asbestos exposures include the installation, removal, and degradation of asbestos-containing products and asbestos dust brought home from the workplace on the clothes. Common neighborhood exposures include residence close to asbestos mining and manufacture, release of fibers from buildings, and erosion of asbestos from rocks. 17 Pathogenesis Inhaled asbestos fibers may pass the alveolar barrier and reach the lung interstitium due to their relatively indestructible nature. In the lung interstitium, fibers can be pulled into the lymph flow and eventually reach the blood stream with subsequent distribution to the whole body, but for the most part they remain undigested in the lung. The translocation process develops over decades and is influenced by fiber length and other factors such as the presence of inflammation, which induces vessel permeability. 18 Asbestos fibers are phagocytized by mesothelial cells and induce injury to them by promoting intracellular oxidation, DNA strand breakage, apoptosis, and cell-cycle delay. 19 These events are linked to carcinogenesis. Although exposure to asbestos is the primary cause of malignant mesothelioma, with more than 80% of malignant mesotheliomas developing in individuals with more than background exposure to asbestos, less than 10% of individuals heavily exposed to asbestos develop malignant mesothelioma. 20,21 The differential susceptibility to development of mesothelioma among those heavily exposed to asbestos underscores the importance of cofactors in mesothelioma carcinogenesis. Hospital Physician Board Review Manual

4 The neurofibromin 2 gene (NF2) is located in chromosome band 22q12 and encodes merlin, a member of the cytoskeleton-associated proteins. Merlin seems to have an important function in the link between cell membrane and cytoskeletal proteins, in cell-cell and cell-matrix contact signaling, and as a tumor suppressor gene. 22 Expression of merlin inhibits p21-activated kinase signaling, which promotes cell motility. Mutations in the NF2 gene are present not only in neurofibromatosis type 2 but also in malignant tumors unrelated to neurofibromatosis type 2, including malignant mesothelioma. In this light, a study found lack of expression of NF2 in 14 (56%) of 25 malignant mesothelioma cell lines. 22 Furthermore, malignant mesothelioma cell lines frequently have deletions of chromosome 9p21, which contains the tumor suppressor genes p16(ink4a), p14(arf), and p15(ink4b). 23 Platelet-derived growth factors are overexpressed in malignant mesothelial cells and act as a regulatory factor in cell proliferation. 24 Other factors may contribute to the pathogenesis, but their role is disputed: malignant mesothelioma has occurred after irradiation for other types of cancer, and simian virus 40 was detected in patients with mesothelioma in some but not all studies investigating their association. 24,25 As is clear from this discussion, several mechanisms can render mesothelial cells prone to malignant transformation. Robinson and Lake 26 have enumerated 6 features commonly present in cancer cells and also found in malignant mesothelioma: growth advantage, immortalization by the action of telomerase, absence of tumor suppressor genes, induction of anti-apoptotic processes, increased angiogenesis, and matrix interactions. Clinical Manifestations The onset of clinical manifestations of MPM is gradual, and patients usually present with dull, nonpleuritic pain and shortness of breath. 27,28 It is not unusual for symptoms to be present for months to a year or more before the diagnosis is established. Pain can be localized to the shoulder, arm, chest wall, and upper abdomen. Although typically described as heaviness or aching, pain may have a neuropathic component due to entrapment of intercostal thoracic, autonomic, or brachial plexus nerves. Patients occasionally have unexplained chest pain and a normal chest radiograph. 29 On the other hand, patients may not always have chest pain. In a series of 272 patients, one third had pleural effusion accompanied by breathlessness but no chest pain. 28 Other clinical features include lassitude, weight loss, cough, and chest wall mass. 27,28 Dullness to percussion over the thorax or decreased breath sounds due to pleural effusion are the most common abnormal physical findings. 30 Rarely, Table 1. Computed Tomography Findings Suggestive of Malignancy with Diffuse Pleural Thickening Parietal pleural thickening > 1 cm Circumferential involvement Irregularity of pleural contour Fissural involvement Extrapleural fat plane invasion Hilar or mediastinal adenopathy Mediastinal involvement clubbing may be present. 26 Patients with peritoneal mesothelioma may present with abdominal pain, which is localized and related to a dominant tumor mass, or with ascites and prominent abdominal distention. 31 Radiologic evaluation The characteristic feature of MPM noted on plain chest radiograph is unilateral pleural effusion with associated nodular pleural thickening. Pleural thickening can be focal or extensive. Extensive thickening is present in 60% of cases and encases the entire lung surface, producing a decrease in size of the affected hemithorax. Bilateral pleural effusion is present in 10% of cases. In some instances, pleural masses are present without an effusion, or the effusion may be too small to be detected by plain chest radiograph Even in the presence of massive pleural effusion, contralateral mediastinal shift is not a common finding with malignant mesothelioma since it tends to encase the lung, invade the fissures, and freeze the hemithorax. 34 Although suggestive of MPM, circumferential pleural thickening is not specific, and it can be found in other diseases such as adenocarcinoma and asbestos-related benign pleural disease. 34,35 Chest CT is considered the primary imaging modality for evaluation and staging of patients with MPM. It gives significant anatomic information and precludes surgery in those with metastasis or tumor extension into the chest wall, mediastinum, or peritoneum. In chest CT, the tumoral encasement of the lung gives an orange rind-like appearance, and the fissure involvement is often apparent. 36 Table 1 describes chest CT findings suggestive of malignancy. While chest CT provides far more information than plain radiographs, it has distinct limitations in distinguishing simple contiguity of tumor with chest wall or mediastinum from actual invasion. 36,37 Magnetic resonance imaging (MRI) can help in this regard. MRI is typically reserved to address equivocal findings on chest CT in patients considered for surgery. 38 MRI has the potential to improve evaluation of mediastinal, pulmonary Disease Volume 13, Part 5

5 Figure 2. Histology of a pleural biopsy sample showing malignant mesothelioma, epithelial type. (A) Low-power view. (B) Highpower view. A B chest wall, and diaphragmatic invasion. 39 Integrated positron emission tomography-ct (PET-CT) is useful in identifying occult metastasis and may aid in determining prognosis and treatment response of patients with malignant mesothelioma. Integrated PET-CT has suboptimal accuracy for detecting mediastinal nodal metastasis and subtle transdiaphragmatic extension; however, it is valuable for detecting extrathoracic metastases not suspected after conventional clinical and radiologic evaluation. 38 Diagnosis After appropriate history, physical examination, and imaging studies are undertaken, a diagnostic thoracocentesis is the next step in a patient with pleural effusion. Cytologic analysis is useful in determining that the process is mesothelial but less helpful in separating benign from malignant proliferations. 39 Immunomarkers contribute to the cytologic diagnosis of MPM. 26 If the data converge to a diagnosis of mesothelioma, one can accept the diagnosis based on the combination of cytology and clinical data. However, caution should be exercised as it is often difficult to reliably differentiate malignant mesothelial cells from highly reactive cells. Thus, when there is uncertainty or conflicting data, pleural biopsy should be performed. 29 Importantly, cytology alone cannot be used to exclude mesothelioma, as a prospective study found a sensitivity of only 26%. 40 When patients present with diffuse pleural thickening but no effusion, chest CT with contrast enhancement is the first step. The presence of CT findings suggestive of MPM (Table 1) should prompt pleural biopsy, which is usually performed via video-assisted thoracoscopy. 29 In recent years, new biomarkers have been investigated for both diagnosis and prognosis of malignant mesothelioma. Osteopontin, a glycoprotein overexpressed in several types of cancer, is regulated by proteins in cell-signaling pathways that are associated with asbestos-induced tumorigenesis. One study found that serum osteopontin had a sensitivity of 77.6% and a specificity of 85.5% for diagnosing malignant mesothelioma. 41 Mesothelin, another glycoprotein thought to have a role in cell adhesion, is expressed in ovarian cancer and other types of cancer. Elevated levels of serum soluble mesothelin-related proteins were shown to have a sensitivity of 84% and a specificity of 83% for mesothelioma in a study that compared protein levels in patients with histologically proven mesothelioma with patients who had been exposed to asbestos but did not develop mesothelioma. 42 Importantly, the study found that some of the asbestos-exposed patients with elevated serum soluble mesothelin-related proteins developed mesothelioma and lung carcinoma within 1 to 5 years. These studies highlight the potential to use simple serum biomarkers as screening tests for early diagnosis of mesothelioma in selected populations with high exposure to asbestos. While helpful in suggesting the malignant nature of a pleural process, at this point biomarkers have not replaced histopathologic confirmation of the malignant tissue. Pathology There are 3 broad pathologic patterns of malignant mesothelioma: epithelial, sarcomatous/fibrous, and biphasic or mixed. Approximately 50% of pleural and 75% of peritoneal mesotheliomas demonstrate the epithelial pattern; 30% are biphasic; and 15% to 20% are sarcomatous. 2 The epithelial pattern tends to form proliferations of the serosal membranes that appear as nondescript solid sheets of neoplastic cells. Other arrangements of the epithelial pattern are less difficult to distinguish from other tumors; these include a pure tubular configuration in which flattened-to-cuboidal cells encircle hollow spaces, and a tubulopapillary configuration of branching tubules mixed with papillae and trabeculae. The appearance of the sarcomatous/fibrous pattern ranges from fibroblast-like spindle cells arranged in a form reminiscent of fibrosarcoma to malignant fibrous histiocytoma-like tumors with anaplastic and sometimes multinucleated cells. The biphasic pattern exhibits both epithelial and sarcomatous components. 43 Figure 2 displays a histology sample from a patient with an epithelial type of MPM. Desmoplastic malignant mesothelioma, a subgroup Hospital Physician Board Review Manual

6 that can present as a paucicellular and collagenous tumor, often mimics reactive fibrous scar tissue. Attanoos and Gibbs 2 have suggested that bland collagen necrosis and involvement of submesothelial adipose tissue are features that help distinguish desmoplastic mesothelioma from reactive fibrosis. The spectrum of morphologic appearances in malignant mesothelioma is broad, making it difficult in many cases to determine whether the process in question is mesothelial and not a metastatic malignancy. 39 The main differential diagnosis with the epithelial pattern is metastatic adenocarcinoma, and both can present with a similar configuration. Furthermore, it is difficult to distinguish between the sarcomatous pattern and sarcoma. Because of the histologic overlap between malignant mesothelioma and other malignancies, additional analyses to clarify the diagnosis are often required. 43 To this end, immunohistochemistry markers are used mainly to aid in distinguishing pleural mesothelioma from adenocarcinoma, but studies have also explored their role in separating sarcomatous mesothelioma from sarcoma, desmoplastic mesothelioma from reactive fibrosis, and well-differentiated mesothelioma from reactive papillary hyperplasia. 2 D2-40, a monoclonal antibody with immunoreactivity for lymphatic endothelium, is a novel marker with high sensitivity for cells of mesothelial origin and relatively high specificity for the differentiation of epithelial malignant mesothelioma from pulmonary adenocarcinoma. EMA and p-53 positivity suggests malignancy and helps differentiate benign from malignant mesothelial processes. 39 Several other immunohistochemistry markers are commonly used; however, none of the markers has absolute sensitivity or specificity for the diagnosis of malignant mesothelioma. Commonly, a panel of markers will be employed. 44 Staging MPM rarely metastasizes to distant sites, but most patients present with locally advanced disease. As imaging studies may provide inconclusive results, mediastinoscopy and video-assisted thoracoscopy are helpful preoperative staging procedures. The international staging system for MPM emphasizes the extent of disease after surgery and stratifies patients in prognostic categories according to traditional tumor-node-metastasis system. 45 Treatment The 3 traditional modalities of treatment for MPM are surgery, chemotherapy, and radiotherapy. They can be used individually or in combination and with curative intent or for palliation of symptoms. Several authors have emphasized the importance of trimodality treatment for a selected group of patients who present with early disease. 46 Additionally, appropriate symptomatic treatment of pain and shortness of breath is of paramount importance. Pleurodesis is an important procedure for palliation of shortness of breath in patients with MPM. Surgery can accomplish 3 objectives: relief of dyspnea, debulking to increase efficacy of other treatments, and radical resection to eradicate disease. 47 One of the commonly used radical surgery techniques consists of extrapleural pneumonectomy, which is selected for patients with good performance status, early-stage disease without mediastinal lymph node involvement, epithelial histology, and adequate pulmonary function. 45 Although extrapleural pneumonectomy has been advocated as the standard radical surgery for treatment of malignant mesothelioma, some experts have expressed concern that it has not been studied in a randomized trial and has not been shown to confer benefit over debulking or no surgery. 47 In a series of 328 consecutive patients who underwent extrapleural pneumonectomy, 60.4% had complications and 3.4% died. 48 In 85% to 90% of patients, the disease is unresectable at diagnosis, and chemotherapy is the mainstay of treatment for most of these patients. 49 Platinum-based regimens have greater activity than non platinum-based combinations. 49 Recently, 2 phase III trials showed that the combination of a third-generation antifolate with cisplatin provides survival benefit over cisplatin alone in chemotherapy-naïve patients. 50,51 Furthermore, the antifolate pemetrexed plus best supportive care as secondline chemotherapy in previously treated patients leads to significant tumor response and delayed disease progression compared with best supportive care alone. 52 Table 2 summarizes the 2 phase III trials evaluating the combination antifolate and cisplatin in chemotherapynaïve patients with MPM. 50,51 Radiotherapy is used for palliation of symptoms and as adjuvant therapy after surgery. In the palliative setting, pain is the main indication for radiotherapy, and pain relief can be achieved in at least 50% of patients with radiotherapy. 53 Due to the propensity of MPM to spread along the tracks of chest tubes, surgical incisions, and biopsy needles, radiotherapy has also been advocated as prophylactic therapy to prevent seeding after invasive procedures. However, prophylactic radiotherapy after invasive procedures did not show benefit in a recent randomized prospective trial. 54 Experimental Therapies Investigators have been exploring the role of new types of treatment for MPM in animal studies or phase I and II clinical trials. Potential therapies include intrapleural pulmonary Disease Volume 13, Part 5

7 Table 2. Phase III Clinical Trials Evaluating the Combination Antifolate and Cisplatin Author Patients Treatment Primary Randomi- Outcome zation Blinding Allocation Concealment Results Vogelzang et al chemotherapynaïve patients with MPM not eligible for curative surgery van Meerbeeck et al chemotherapynaïve patients with MPM not eligible for radical surgery Pemetrexed and cisplatin (n = 226) versus cisplatin (n = 222)* Raltitrexed and cisplatin (n = 126) versus cisplatin (n = 124) Survival Yes Singleblinding Not clear Median survival: 12.1 mo in pemetrexed/cisplatin group versus 9.3 mo in cisplatin group (P = 0.02) Survival Yes No Not clear Median survival: 11.4 mo in raltitrexed/cisplatin group versus 8.8 mo in cisplatin group (P = 0.048) MPM = malignant pleural mesothelioma. *Dexamethasone was given the day before, day of, and day after pemetrexed dosing to reduce skin rash. During the study, the protocol was changed to include folic acid and vitamin B 12 supplementation to all enrolled patients after 3 deaths occurred in the experimental group. gene transfer using an adenoviral vector, anti-mesothelin immunotoxin, antibody against vascular endothelial growth factor, and selective modalities of irradiation Prognosis The median survival from diagnosis was 8.9 months in a recent population-based study in the United Kingdom. 59 Shorter survival has been associated with pleural involvement, lactate dehydrogenase level greater than 500 U/L, poor performance status, chest pain, platelet count greater than 400,000 cells/µl, nonepithelial histology, and increasing age older than 75 years. 60 Surgical predictors of poor prognosis include positive resection margins and metastatic extrapleural nodes. 61 More recently, new serum biomarkers and gene expression data have been identified and shown to correlate with clinical outcome. 62 surveillance. Chest radiograph reveals a localized area of increased density along the peripheral chest wall. When visualized en face rather than in profile, pleural plaques may appear as a lung nodule. Oblique films usually reveal the pleural location. In 15% of cases, calcification is present on plain radiographs. 69 CT is especially useful in eliminating false-positive diagnoses of noncalcified plaques caused by subpleural fat and prominent intercostal muscles. 70 Figure 3 shows a chest CT scan of a patient with pleural plaque. In a longitudinal study, the presence of pleural plaques in workers with previous asbestos exposure did not predict loss of lung function. 71 However, the presence of pleural plaques has been independently associated with abnormal lung function. 72,73 Pleural plaques indicate increased risk for asbestosis and should therefore prompt monitoring for development of interstitial fibrosis or MPM. 65 PLEURAL PLAQUES Pleural plaques are characterized by thickening of the parietal pleura and are the most common asbestosrelated disorder. For example, a field-based, crosssectional study in villages from Turkey found pleural plaques in 14.4% of the villagers. 63 Pleural plaques are a useful surrogate of past asbestos exposure; however, the extent of their surface does not seem to correlate with cumulative asbestos exposure. 64 They typically follow the ribs on the lower posterior thoracic wall or are located over the central tendons of the diaphragm. 65 The visceral pleura, costophrenic angles, and lung apices are usually spared. 66 Patients with pleural plaques can be asymptomatic or manifest with shortness of breath and chest pain. 67,68 Asymptomatic pleural plaques are found incidentally or when asbestos-exposed individuals undergo imaging DIFFUSE PLEURAL THICKENING In most cases, diffuse pleural thickening is the sequela of previous benign asbestos effusion or the result of multiple confluent plaques. Extension of pulmonary fibrosis to the visceral and parietal pleura, previously thought to be the main cause of diffuse pleural thickening, was responsible for only 10% of the cases in a series of 185 cases. 74 Common differential diagnosis includes the residue of malignant effusion, previous infection, or trauma. 74 The pathogenesis of diffuse pleural thickening depends on its cause. In the case of pleural fibrosis induced by asbestos exposure, it has been postulated that inhaled fibers can accumulate in the pulmonary interstitial space and be transported to the subpleural space by means of lymphatic flow. Then, there is perturbation of fibroblasts, which produces extracellular matrix proteins and respond to injury by producing Hospital Physician Board Review Manual