Aetiology

Exposure to asbestos is the principal risk factor; about 80% of patients have a history of asbestos exposure.[10][11][12] As of 2013 approximately 125 million people have been exposed to asbestos at work.[13] Moreover, 50,000 people had malignant mesothelioma and 34,000 died from the disease.[14] Certain subtypes of asbestos, iron-containing crocidolite and amosite in particular, are thought to be more carcinogenic than others. There also seems to be a dose-response relationship. The latency period between exposure and development of malignancy is 20 to 40 years.[5]

Other possible aetiologies include prior exposure to radiotherapy (a known carcinogen); genetic predisposition (e.g., mutation of the BAP1 gene); and the simian virus 40 (SV-40).[15][16][17][18]​ Germline mutations in the gene encoding BRCA1 associated protein-1 (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 these individuals.[19][20]​ Numerous other factors have been proposed as possible risks for developing malignant pleural mesothelioma; however, further epidemiological studies are needed to determine their significance.[21]

Pathophysiology

Asbestos exposure is considered the primary causal factor. Studies suggest that exposure to asbestos fibres results in recruitment and activation of alveolar macrophages and neutrophils, with subsequent generation, possibly iron-catalysed, of reactive oxygen and nitrogen species.[11][22]​​[23]​​ Chronic inflammation and oxidative stress may culminate in DNA damage, alterations in gene expression (proto-oncogenes and tumour suppressor genes), and eventual malignant transformation. 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.[24] 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. 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 histological subtypes

The common subtypes are:[2]

  • 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 tumour)

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