The link between asbestos exposure and malignant pleural mesothelioma has been well documented in both human studies and animal models, and it is estimated that up to 5% of asbestos miners will develop MPM. The mechanism of asbestos-induced mesothelioma is thought to involve inhalation of insoluble fibers, which lead to chronic inflammation, genetic changes, and subsequent cellular oncogenic dysregulation. The incidence of MPM is ∼2500 cases per year in the United States, and reflects a 25- to 40-year latency between exposure and tumor development. Outside of the United States, death rates from mesothelioma mirror national asbestos exposure, with high rates seen in Australian, New Zealand, Western Europe, and the United Kingdom. Although a dose–response relationship exists with all types of asbestos fibers in animal models of carcinogenicity, epidemiologic studies in humans suggest that amosite and crocidolite carry a higher risk that chrysotile fibers. Other nonasbestos mineral fibers, such as erionite (found in high levels in areas of Turkey as well as in regions of the western United States), also show a strong relationship to MPM prevalence.

The threshold exposure level below which MPM will not develop remains unclear. Professions other than miners with lower level exposure, such as plumbers, insulators, and carpenters, may also develop mesothelioma from asbestos exposure that is higher than that of the general population, but still much lower than that experienced by miners. As in our hypothetical patient, reports have shown that even wives of insulators have developed mesothelioma, presumably through exposure to their contaminated clothing. Other professions with cases of documented asbestos exposure include aircraft mechanics, aerospace workers, electricians, shipyard workers, auto mechanics, pipe fitters, construction workers, boilermakers, railway workers, mining, asbestos removal, and sheet metal workers. While the relationship between asbestos exposure and the development of MPM is incontrovertible, the level and type of exposure that lead to mesothelioma formation are unclear and remain a topic of intense research.

Although over 80% of MPM is attributable to asbestos exposure by patient histories, other factors may also predispose people to mesothelioma formation. Simian virus 40 (SV40) is a DNA tumor virus that has been associated with the formation of mesothelioma. Although animal studies show that pleurally injected SV40 alone can lead to MPM formation, controversial human studies suggest that SV40 may act as a co-carcinogen in asbestos-exposed individuals. Tobacco exposure’s role in mesothelioma formation remains controversial, but it is generally not considered a strong risk factor for MPM formation, unless there is a history of consumption of Kent cigarettes, whose micronite filter was constructed with asbestiform fibers. Other factors that may lead to malignant transformation are radiation and chronic inflammation of the pleura, such as tuberculosis, collagen vascular disease, and empyema thoracis. Genetics also clearly plays a key role in cancer formation, with implicated genetic predisposition through mutations in the neurofibromatosis gene, among others, and the recent observations of familial mesothelioma and uveal melanomas in individuals with germline mutations of the BAP1 gene.

Diagnosis of MPM is suggested by risk factors, clinical presentation, physical exam, and radiographic imaging, but it ultimately depends on tissue diagnosis. The most common presenting symptoms are nonpleuritic chest pain (60%) and dyspnea (50–70%). Patients typically report several months of symptoms before seeking attention, with as many as 25% reporting more than 6 months of symptoms. On physical exam, evidence of effusion is common, and digital clubbing may reflect poor respiratory function secondary to entrapped lung. Weight loss (cachexia) is common in late-stage disease.

Mesothelioma can have a diverse radiographic appearance and may be confused with benign entities, such as pleural plaques or parenchymal pulmonary fibrosis. Chest radiograph classically shows pleural effusion, diffuse pleural thickening, and nodularity and more commonly affects the right side (60%). Often the lower chest demonstrates a loculated effusion, which may encase and trap the lung. Chest computed tomography (CT) can more clearly demonstrate the nature of the pleural thickening and effusion. CT accurately visualizes the involvement of the pericardium, diaphragm, and extrathoracic organs, such as the liver and stomach, but is poor in other regards. While certain radiographic “patterns” suggest malignant disease, CT radiographic criteria are insensitive and prevent the use of CT as the sole method of diagnosis. Positron emission tomography (PET) and the radionuclide imaging agent [¹⁸F] fluoro-deoxyglucose (FDG) can be used to identify pleural malignancies and predict prognosis in patients with mesothelioma. However, studies of FDG-PET have shown poor sensitivity in identifying lymph node metastases, and therefore FDG-avid lesions should be pathologically confirmed before proceeding with a stage-defined treatment algorithm.

Soluble markers for mesothelioma are a promising new strategy for screening patients at risk for mesothelioma and improving diagnostic accuracy in patients with unclear diagnoses. The Mesomark assay (Fujirebio, Malvern, PA) is a commercially available assay that measures soluble mesothelin-related proteins (SMPRs); it has a high specificity (95%) but low sensitivity (32%), limiting its use as a screening test. Fibulin-3 has recently been identified as a specific (>95%) and sensitive (>90%) serum and pleural fluid marker of MPM, and it can accurately distinguish healthy persons with asbestos exposure from patients with mesothelioma. Although not commercially available, Fibulin-3 is a promising screening tool for mesothelioma.

Pathologic confirmation ultimately establishes the diagnosis of MPM, but it also carries a risk of equivocation. Patients with unexplained pleural effusions should undergo thoracentesis and closed pleural biopsy. Modern cell-block techniques have improved the diagnostic accuracy of pleural fluid analysis, but they remain imperfect with a reported sensitivity of only 70–80%. Patients who have negative pleural fluid and biopsy (or whose effusions recur after initial drainage) should undergo thoracoscopic evaluation. Video-assisted thoracoscopic surgery (VATS) is invaluable in providing diagnostic information and is the method of choice in acquiring tissue for analysis. VATS is also useful prognostically in that patients with more widespread disease on thoracoscopic evaluation showed consistently worse outcomes. In patients whose disease precludes the use of VATS due to obliteration of the pleural space, open (but limited) pleural biopsy is necessary, preferably in line with a potential cytoreductive incision for later removal.

Given the phenotypic heterogeneity of MPM, pathologic evaluation of pleural specimens is complex and outside the scope of this review. In general, evidence of stromal invasion remains the gold standard in diagnosis. However, the number of proliferating cells, their distribution, inflammation, and the presence of necrosis are important factors to consider. While significant controversy exists over the use of antibody panels, immunohistochemistry, and fluorescence in situ hybridization (FISH), the use of these adjunctive stains can facilitate diagnosis in certain cases, and usually reveals tumor cells that stain for cytokeratins, calretinin, and Wilms tumor 1.