Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.

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Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment. CA Cancer J Clin 2019;69:402-429.

Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-inducible factor (HIF) that induces expression of genes involved in angiogenesis, erythropoiesis, and cell metabolism, proliferation, and survival. Germ-line mutations in the prolyl hydroxylase domain 2 gene (PHD2) have been reported in patients with familial erythrocytosis but not in association with tumors. We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation. This mutation affects PHD2 function and stabilizes HIF-alpha proteins. In addition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene.

A new World Health Organization (WHO) Classification of Tumors of the Pleura has recently been published. While the histologic classification of pleural malignant mesothelioma remains the same in the 2015 WHO classification as it was in the 2004 classification, multiple new observations have been recorded. First, more detailed study has been performed of histologic subtyping of epithelioid mesothelioma. In particular, it has been recognized that the pleomorphic subtype is associated with a poor prognosis, similar to that of sarcomatoid malignant mesothelioma. Second, there is improved understanding of the role of immunohistochemistry in distinguishing mesothelioma from carcinomas of various sites. Third, the criteria for distinguishing malignant mesothelioma from reactive mesothelial proliferations has been further refined. Fourth, additional studies of sarcomatoid mesothelioma have defined the frequency and spectrum of various histologic and immunohistochemical features, including heterologous elements. Finally, pleural well-differentiated papillary mesotheliomas are better defined and cases with invasive foci are recognized. In addition, several promising observations in mesothelioma pathology and genetics have been made in the past decade. These are now the subject of further investigation to determine if they can be validated in ways that will significantly impact clinical practice. These include a preliminary study of grading, suggesting that nuclear atypia and mitotic count are independent prognostic markers. The discovery of inactivating mutations in the BRCA1-associated protein 1 gene in sporadic and hereditary mesothelioma has opened up a variety of novel molecular, clinical, and diagnostic investigations. One possible diagnostic application includes the setting of separating mesothelioma from reactive mesothelial proliferations, where it may play a role in conjunction with p16 FISH. Another useful discovery was that the NAB2-STAT6 fusion is characteristic of solitary fibrous tumors. This led to development of a STAT6 antibody that is a reliable immunohistochemical marker for solitary fibrous tumors. Genetic studies also led to the finding that WWTR1-CAMTA1 fusions are useful diagnostic markers for epithelioid hemangioendotheliomas, which can present as pleural-based masses. Finally, desmoid type fibromatosis, a locally aggressive tumor that can present in the pleura, has been shown to frequently have CTNNB1 gene mutations and express β-catenin by immunohistochemistry.

The separation of benign from malignant mesothelial proliferations is crucial to patient care but is frequently morphologically difficult.Context.— To briefly review adjunctive tests claimed to be useful in this setting and to examine in detail 2 new tests: p16 fluorescence in situ hybridization (FISH) and BRCA1-associated protein 1 (BAP1) immunohistochemistry.Objective.— Literature review with emphasis on p16 FISH and BAP1 immunohistochemistry.Design.— Glucose transporter-1, p53, insulin-like growth factor 2 messenger RNA–binding protein 3 (IMP-3), desmin, and epithelial membrane antigen have all been claimed to mark either benign or malignant mesothelial processes, but in practice they at best provide statistical differences in large series of cases, without being useful in an individual case. Homozygous deletion of p16 by FISH or loss of BAP1 has only been reported in malignant mesotheliomas and not in benign mesothelial proliferations. BAP1 appears to be lost more frequently in epithelial than mixed or sarcomatous mesotheliomas. Homozygous deletion of p16 by FISH is seen in pleural epithelial, mixed, and sarcomatous mesotheliomas, but it is much less frequent in peritoneal mesothelioma. The major drawback to both these tests is limited sensitivity; moreover, failure to find p16 deletion or BAP1 loss does not make a mesothelial process benign.Results.— In the context of a mesothelial proliferation, the finding of homozygous deletion of p16 by FISH or loss of BAP1 by immunohistochemistry is, thus far, 100% specific for malignant mesothelioma. The limited sensitivity of each test may be improved to some extent by running both tests.Conclusions.—

Introduction: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes.Conclusions: These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.

- Currently, most pleural mesotheliomas (70% to 90%) in men in Europe and North America are attributable to asbestos exposure; for peritoneal mesothelioma the proportion is lower. In North America few mesotheliomas in women at any site are attributable to asbestos exposure, but in Europe the proportion is higher and varies considerably by locale. In certain geographic locations other types of mineral fibers (erionite, fluoro-edenite, and probably balangeroite) can induce mesothelioma. Therapeutic radiation for other malignancies is a well-established cause of mesothelioma, with relative risks as high as 30. Carbon nanotubes can also induce mesotheliomas in animals but there are no human epidemiologic data that shed light on this issue. Chronic pleural inflammation may be a cause of mesothelioma but the data are scanty. Although SV40 can induce mesotheliomas in animals, in humans the epidemiologic data are against a causative role. A small number of mesotheliomas (probably in the order of 1%) are caused by germline mutations/deletions of BRCA1-associated protein-1 ( BAP1) in kindreds that also develop a variety of other cancers. All of these alternative etiologies account for a small proportion of tumors, and most mesotheliomas not clearly attributable to asbestos exposure are spontaneous (idiopathic).