Molecular pathways and diagnosis in malignant mesothelioma: A review of the 14th International Conference of the International Mesothelioma Interest Group

Our plain-English summary of Molecular pathways and diagnosis in malignant mesothelioma: A review of the 14th International Conference of the International Mesothelioma Interest Group, by D.B. Chapel, A. Churg, E. Santoni-Rugiu, et al (Lung Cancer, 2019).

The study

• Authors: D.B. Chapel, A. Churg, E. Santoni-Rugiu, T. Tsujimura, K. Hiroshima, A.N. Husain
• Journal: Lung Cancer
• Published: 2019;127:69-75
• Type of article: Review
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The pathologist plays a central role in the diagnosis and management of malignant mesothelioma, including definitive tissue-based diagnosis in conjunction with clinical and radiographic data; diverse ancillary studies of diagnostic, prognostic, and predictive importance; and research efforts to better define the pathobiology of mesothelioma and develop novel clinical applications. The pivotal role of pathology in care of mesothelioma patients was on display at the recent meeting of the International Mesothelioma Interest Group (iMig) in Ottawa, Canada. This review summarizes the key findings of the "Molecular Pathways and Diagnosis in Malignant Mesothelioma" plenary session, including a large multi-institutional validation of a composite nuclear grading system for pleural mesothelioma, including incorporation of tumor necrosis as an additional independent prognostic factor; the correlation between nuclear grading in small biopsies and paired resection specimens in pleural mesothelioma; a multi-institutional study of important clinical and pathologic prognostic factors in peritoneal mesothelioma; the diagnostic role of HEG1 immunohistochemistry as a highly sensitive and specific marker of mesothelial lineage; the prevalence and diagnostic significance of MET protein overexpression in mesothelioma, as well as the correlation between MET protein overexpression and MET gene amplification; and the prognostic role of EZH2 protein overexpression in mesothelioma, together with data indicating an important pathogenic role for EZH2 in mesothelioma tumorigenesis. Special consideration is given to the convergence of diagnostic, prognostic, and predictive tools and their role in guiding highly personalized patient-centered management, and to the translation of novel research findings to practical techniques for routine pathologic practice.

Copyright © 2018 Elsevier B.V. All rights reserved.

In plain English

This article is a review, not a single original study. The authors summarized research presented at one session of the 2018 International Mesothelioma Interest Group meeting in Ottawa, Canada. In 776 epithelioid pleural mesothelioma cases from 17 institutions, nuclear grade combined with tumor necrosis sorted patients into four groups, with median survival ranging from 29 months down to 8 months. In 102 peritoneal mesothelial proliferations from five institutions, asbestos exposure (HR 6.5) and the presence of asbestos bodies (HR 7.4) were associated with shorter overall survival in malignant peritoneal mesothelioma on univariate analysis. They were not listed among the independent predictors in the multivariate analysis. Another study presented there found that the marker HEG1 stained most mesotheliomas but none of 29 lung adenocarcinomas. In a matched case-control cohort, MET abnormalities were associated with lower response to first-line platinum-pemetrexed chemotherapy and with shorter survival. Whether MET tests can guide treatment with MET-targeted drugs remained unknown. High EZH2 expression was associated with shorter survival. The authors concluded that pathologists play a central role in diagnosing and managing mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review summarizing studies presented at one plenary session of the 14th International Mesothelioma Interest Group (iMig) conference
• Who was studied: Several separate studies. The main ones were: 776 epithelioid pleural mesothelioma cases from 17 institutions, diagnosed 1998 to 2014; 48 epithelioid cases with paired biopsy and resection at one institution; 102 peritoneal mesothelial proliferations from five institutions, diagnosed 1967 to 2016; HEG1 testing in tissue microarrays and biopsies of mesotheliomas, lung carcinomas and benign conditions; 155 consecutive mesothelioma cases treated 2015 to 2017; and mesothelioma cases and cell lines in the EZH2 work
• Exposure: This was not mainly an exposure study. Asbestos exposure was one clinical variable collected in the peritoneal mesothelioma study; no fiber types or doses are given.
• Main results:
  • In the 776 epithelioid pleural mesothelioma cases, adding necrosis to nuclear grade gave four prognostic groups. Median survival was 29 months for grade I tumors without necrosis, 16 months for grade I with necrosis or grade II without necrosis, 10 months for grade II with necrosis, and 8 months for grade III.
  • In the single-institution study of 48 epithelioid cases, 12 (25%) had different nuclear grades on biopsy and resection. Of these, 11 of 12 (92%) were upgraded on resection.
  • In malignant peritoneal mesothelioma, univariate analysis found shorter overall survival associated with asbestos exposure (HR 6.5, p less than 0.0001) and presence of asbestos bodies (HR 7.4, p less than 0.0001), among other factors
  • On multivariate analysis of all malignant peritoneal mesothelioma cases, four factors independently predicted shorter overall survival: biphasic or sarcomatoid growth, increased nuclear pleomorphism, increased mitotic rate, and increased Ki67 index
  • In the HEG1 study presented in the session, whole-slide biopsy sections were HEG1-positive in all 47 epithelioid, 17 of 18 (94%) biphasic and 18 of 23 (78%) sarcomatoid mesotheliomas. HEG1 was expressed in 0 of 29 pulmonary adenocarcinomas and focally in 4 of 14 pulmonary squamous cell carcinomas.
  • Of the 155 mesothelioma specimens, 22 (17%) had a MET score of 3+ and 22 (17%) a score of 2+. In a case-control cohort, MET abnormalities (a 3+ or 2+ MET protein score, with or without MET gene copy number gain) were associated with a lower therapy response rate (p = 0.04) and shorter overall survival (p = 0.018) after first-line platinum-pemetrexed chemotherapy. The cohort was matched for gender, age, performance status, tumor stage, histotype, asbestos exposure, smoking habit and surgical resection.
  • MET gene copy number gain was found in only 12 of 44 (27%) cases with 3+ or 2+ MET protein scores
  • Overall survival was significantly shorter in mesothelioma patients with high EZH2 expression than in those with low expression. No case numbers are given.
• The authors' conclusion: The authors concluded that the session showed the central role of the pathologist in mesothelioma diagnosis and management
• Limitations the authors state:
  • The biopsy-versus-resection grading study was done at a single institution, with grading by a single pathologist. A confirmatory multicenter study is ongoing.
  • Whether MET testing predicts response to targeted MET inhibitors remains unknown

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelioma, Pathology, IMIG, Composite Nuclear Grading System, Pleural Mesothelioma, Necrosis, Nuclear Grading.

Related studies

• Highlights of the 14th international mesothelioma interest group meeting: Pathologic separation of benign from malignant mesothelial proliferations and histologic/molecular analysis of malignant mesothelioma subtypes — A. Churg, K. Nabeshima, et al. (2018)
• Imaging in pleural mesothelioma: A review of the 14th International Conference of the International Mesothelioma Interest Group — S.G. Armato, R.J. Francis, et al. (2019)
• Progress of malignant mesothelioma research in basic science: A review of the 14th international conference of the international mesothelioma interest group (iMig2018) — L. Wu, I. Dell'Anno, et al. (2019)
• The role of radiation treatment in pleural mesothelioma: Highlights of the 14th International Conference of the International mesothelioma interest group — R.M. MacRae, M. Ashton, et al. (2019)
• Imaging in pleural mesothelioma: A review of the 13th International Conference of the International Mesothelioma Interest Group — S.G. Armato, K.G. Blyth, et al. (2016)
• Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group — A.N. Husain, T.V. Colby, et al. (2018)

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