The Use of Immunohistochemistry, Fluorescence in situ Hybridization, and Emerging Epigenetic Markers in the Diagnosis of Malignant Pleural Mesothelioma (MPM): A Review

Our plain-English summary of The Use of Immunohistochemistry, Fluorescence in situ Hybridization, and Emerging Epigenetic Markers in the Diagnosis of Malignant Pleural Mesothelioma (MPM): A Review, by E. Rozitis, B. Johnson, Y.Y. Cheng, et al (Frontiers in Oncology, 2020).

The study

• Authors: E. Rozitis, B. Johnson, Y.Y. Cheng, K. Lee
• Journal: Frontiers in Oncology
• Published: 2020;10:1742
• Type of article: Review
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive asbestos related disease that is generally considered to be difficult to diagnose, stage and treat. The diagnostic process is continuing to evolve and requires highly skilled pathology input, and generally an extensive list of biomarkers for definitive diagnosis. Diagnosis of MPM requires histological evidence of invasion by malignant mesothelial cells often confirmed by various immunohistochemical biomarkers in order to separate it from pleural metastatic carcinoma. Often when invasion of neoplastic mesothelial cells into adjacent tissue is not apparent, further immunohistochemical testing - namely BAP1 and MTAP, as well as FISH testing for loss of p16 (CDKN2A) are used to separate reactive mesothelial proliferation due to benign processes, from MPM. Various combinations of these markers, such as BAP1 and/or MTAP immunohistochemistry alongside FISH testing for loss of p16, have shown excellent sensitivity and specificity in the diagnosis of MPM. Additionally, over the recent years, research into epigenetic marker use in the diagnosis of MPM has gained momentum. Although still in their research stages, various markers in DNA methylation, long non-coding RNA, micro RNA, circular RNA, and histone modifications have all been found to support diagnosis of MPM with generally good sensitivity and specificity. Many of these studies are however, limited by small sample sizes or other study limitations and further research into the area would be beneficial. Epigenetic markers show promise for use in the future to facilitate the diagnosis of MPM.

Copyright © 2020 Rozitis, Johnson, Cheng and Lee.

In plain English

This article was mainly a review of published research on tests used to diagnose malignant pleural mesothelioma (MPM). It focused on separating MPM from cancers spread to the pleura and from benign "reactive" pleural changes. It did not describe how the studies it covered were chosen. From earlier studies, the text reported that BAP1 protein loss on tissue staining had 61 to 67% sensitivity and 100% specificity for MPM versus reactive mesothelium; the review's summary table gave a wider sensitivity range, 36.7 to 67.0%. Sensitivity is the share of mesotheliomas a test detects; specificity, the share of non-cancer cases it rules out. One cited study (Berg et al.) found 90% sensitivity and 100% specificity combining MTAP and BAP1 staining. The review covered experimental epigenetic markers, including DNA methylation, long non-coding RNAs, microRNAs, circular RNAs and histone changes. The authors also reported their own preliminary work (9 MPM patients, 2 with normal mesothelium), finding 290 circular RNAs increased in MPM samples. The authors concluded that BAP1 and MTAP staining have enough evidence for clinical use, while epigenetic markers are promising but need larger studies.

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: Narrative review of published literature on diagnostic tests (immunohistochemistry, FISH, epigenetic markers) for malignant pleural mesothelioma. No search method is described. It also reports the authors' own preliminary circular RNA findings.
• Who was studied: Mainly published studies. The authors' own preliminary circular RNA work used RNA from 9 MPM patients and 2 patients with normal mesothelium.
• Exposure: Not an exposure study. Asbestos is mentioned only as the main cause of MPM, and no fiber types are named. The review is about diagnostic markers (BAP1, MTAP, p16/CDKN2A, epigenetic markers).
• Main results:
  • From earlier studies (body text): BAP1 immunohistochemistry used to separate MPM from reactive mesothelium had a sensitivity of 61 to 67% and a specificity of 100%
  • The review's Table 4 gives a wider sensitivity range for BAP-1 IHC alone, 36.7 to 67.0% (specificity 100%)
  • From three earlier studies of combined BAP1 IHC loss and p16 deletion by FISH: specificity was 100%, with sensitivities of 58%, 93% and 100%
  • Berg et al. found a sensitivity of 90% and a specificity of 100% for MPM when MTAP and BAP1 IHC were combined to separate benign from malignant mesothelial proliferations
  • Earlier studies reported p16 deletion in about 80% of MPM cases overall, in 90 to 100% of sarcomatoid types, and in about 70% of epithelioid and mixed types
  • Wright et al. established a panel of long non-coding RNAs that distinguished reactive mesothelium from MPM with a sensitivity of 71.1% and a specificity of 100%
  • Birnie et al. found that a combination of three microRNAs (miR-200c, miR-210 and miR-143) separated MPM from other pleural disease with an AUC of 0.92 (95% CI 0.84 to 0.99)
  • In the authors' own preliminary study (9 MPM patients, 2 with normal mesothelium), 290 circular RNAs were increased in the MPM samples. A manuscript was in preparation.
• The authors' conclusion: The authors concluded that BAP1 and MTAP immunohistochemistry have enough evidence for clinical use in separating reactive mesothelial proliferation from MPM. They judged epigenetic markers encouraging but said larger studies are needed to clarify their clinical relevance.
• Limitations the authors state:
  • Data on microRNA markers are still limited and results often vary; larger patient cohorts are needed
  • Loss of BAP1 is uncommon in sarcomatoid and desmoplastic forms of mesothelioma, which limits that test for those forms
  • Epigenetic markers are not currently used in the diagnosis of MPM

Topics

Medical terms in this study, explained in our Lexicon: Immunohistochemistry, Fluorescence In Situ Hybridization (FISH), Pleural Mesothelioma, Pathology, Biomarker, Mesothelial Cells, Carcinoma, BAP1.

Related studies

• MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma — D.B. Chapel, J.J. Schulte, et al. (2020)
• Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma — D. Wu, K. Hiroshima, et al. (2017)
• Utility of Methylthioadenosine Phosphorylase Compared With BAP1 Immunohistochemistry, and CDKN2A and NF2 Fluorescence In Situ Hybridization in Separating Reactive Mesothelial Proliferations From Epithelioid Malignant Mesotheliomas — K.B. Berg, S. Dacic, et al. (2018)
• BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma — S.M. McGregor, J. McElherne, et al. (2017)
• Fluorescence in situ hybridization in the definitive diagnosis of malignant mesothelioma in effusion cytology — S. Savic, N. Franco, et al. (2010)
• 9p21 deletion in the diagnosis of malignant mesothelioma, using fluorescence in situ hybridization analysis — M. Takeda, T. Kasai, et al. (2010)

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