Etiology

Exposure to asbestos is the principal risk factor; about 80% of patients have a history of asbestos exposure.[8][9][10] The latency period between exposure and development of malignancy is 20-40 years.[11]

​There are three main types of asbestos: chrysotile (white asbestos), amosite (brown asbestos), and crocidolite (blue asbestos). Crocidolite, which is composed of long and narrow fibers, seems to be the primary type of asbestos associated with the development of mesothelioma.[12]​ The mechanism of carcinogenesis is not known with certainty.

Other possible etiologies include prior exposure to radiation therapy (a known carcinogen); genetic predisposition (e.g., mutation of the BRCA1-associated protein-1 [BAP1] gene); and the simian virus 40 (SV-40).[13][14][15][16][17][18][19]​​​​​​​​​​​ Germline mutations in the gene encoding BAP1 can predispose carriers to mesothelioma. Other cancers, in particular uveal and cutaneous melanomas, basal cell carcinomas, and renal cell carcinomas, have been described in individuals with mutation of the BAP1 gene.[20][21]​​​

Numerous other factors have been proposed as possible risks for developing malignant pleural mesothelioma; however, further epidemiologic studies are needed to determine their significance.[22]

Pathophysiology

Asbestos exposure is considered the primary causal factor. Studies suggest that exposure to asbestos fibers results in recruitment and activation of alveolar macrophages and neutrophils, with subsequent generation, possibly iron-catalyzed, of reactive oxygen and nitrogen species.[9][23]​​[24]​​ Chronic inflammation and oxidative stress may culminate in DNA damage, alterations in gene expression (proto-oncogenes and tumor suppressor genes), and eventual malignant transformation.[25]​ However, exactly how these asbestos-induced changes foster the development of malignant pleural mesothelioma remains a topic of considerable investigation and uncertainty.

Genetic analyses have identified several genetic and genomic alterations in malignant mesothelioma. The most frequent somatic mutations are neurofibromatosis type 2 (NF2), BRCA1-associated protein-1 (BAP1), and Cullin 1 (CUL1) genes.[16][26]​​​ The genomic alterations in human malignant mesothelioma that have been previously reported include losses of chromosome arms 1p, 3p, 4q, 6q, 9p, 13q, 14q, 22q and gains of chromosome arms 1q, 5p, 7p, 8q, 17q.[25][27][28]​​ In addition, dysregulation in signal transduction pathways, related to cell survival and proliferation, has also been demonstrated.

Classification

Anatomical variants

Mesothelioma arises from serosal cells that line body cavities and includes the following variants:[2]

  • Pleural (about 85% of mesotheliomas)

  • Peritoneal (15%)

  • Pericardial (<1%)

  • Testicular (<1%)

Common histologic subtypes

The common subtypes are:[2][3]​​

  • Epithelioid (i.e., epithelioid-to-round cells)

  • Sarcomatoid (i.e., spindled cells with tapered nuclei)

  • Biphasic (i.e., contains elements of both epithelioid and sarcomatoid mesothelioma, with each element comprising ≥10% of the tumor)

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