New Markers for Separating Benign From Malignant Mesothelial Proliferations: Are We There Yet?

Our plain-English summary of New Markers for Separating Benign From Malignant Mesothelial Proliferations: Are We There Yet?, by A. Churg, B.S. Sheffield, F. Galateau-Salle (Archives of Pathology & Laboratory Medicine, 2016).

The study

• Authors: A. Churg, B.S. Sheffield, F. Galateau-Salle
• Journal: Archives of Pathology & Laboratory Medicine
• Published: 2016;140(4):318-21
• Cited by: 115 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Context: The separation of benign from malignant mesothelial proliferations is crucial to patient care but is frequently morphologically difficult.

Objective: 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.

Design: Literature review with emphasis on p16 FISH and BAP1 immunohistochemistry.

Results: 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.

Conclusions: 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.

In plain English

This was a literature review of laboratory tests for telling malignant mesothelioma from benign mesothelial reactions. The authors wrote that five older stains (GLUT-1, p53, IMP-3, epithelial membrane antigen and desmin) worked only in a statistical sense and could not be relied on in an individual case. They focused on two newer tests: p16 FISH, which detects p16 gene deletion, and BAP1 immunohistochemistry, which detects BAP1 protein loss. In the reports reviewed, none of roughly 220 benign reactions showed homozygous p16 loss. None of the truly benign cases in three BAP1 series (0 of 53, 0 of 23, 0 of 25) showed BAP1 loss. p16 FISH sensitivity averaged 64% in pleural epithelial mesotheliomas and 38% in peritoneal epithelial mesotheliomas. In the authors' own study, one test or the other found loss in 7 of 9 pleural epithelial mesotheliomas (78%). The authors concluded that, among mesothelial proliferations, either finding had so far appeared only in mesothelioma, and that a normal result does not exclude mesothelioma. Because both changes also occur in other cancers, they wrote, the lesion must first be confirmed as mesothelial.

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: Literature review (published as a special article), with emphasis on p16 FISH and BAP1 immunohistochemistry
• Who was studied: Published reports, plus the authors' own published and unpublished data, on mesotheliomas and benign mesothelial reactions tested in tissue sections and effusion cytology specimens
• Exposure: Not an exposure study. The article does not discuss asbestos or any other exposure. It concerns diagnostic laboratory tests (p16 FISH, BAP1 immunohistochemistry and older immunohistochemical stains).
• Main results:
  • Older stains (GLUT-1, p53, IMP-3, EMA, desmin) showed only group-level differences between mesotheliomas and benign reactions. The authors judged them not usable in an individual case.
  • p16 FISH: across the reports reviewed, none of roughly 220 benign reactions showed homozygous p16 loss (specificity 100%).
  • p16 FISH sensitivity in pleural epithelial mesotheliomas ranged from approximately 45% to 85% (average 64%).
  • p16 FISH sensitivity in peritoneal epithelial mesotheliomas ranged from approximately 14% to 50% (mean 38%).
  • BAP1 in benign reactions: the authors found loss in none of 53 reactive mesothelial proliferations.
  • BAP1 in benign reactions: none of 23 benign cases from the French Mesothelioma Panel showed loss.
  • BAP1 in benign reactions (Cigognetti et al): 2 of 27 apparently benign reactions showed loss, but on follow-up both turned out to be mesotheliomas. None of 25 truly benign reactions showed loss.
  • BAP1 loss appeared more frequent in epithelial mesotheliomas than in mixed or sarcomatous forms.
  • In the authors' tissue microarray study, across all tumor morphologies and sites: BAP1 was lost in 7 of 26 cases (27%) and p16 was deleted in 14 of 27 (52%). One or the other was lost in 14 of 24 (58%).
  • In the same study, restricted to pleural epithelial mesotheliomas: BAP1 was lost in 5 of 9 (56%) and p16 in 7 of 12 (58%). One or the other was lost in 7 of 9 (78%).
  • The authors noted that BAP1 loss and p16 deletion are not specific to mesothelioma and can occur in other malignancies. They said the process must first be confirmed as mesothelial with established stains.
• The authors' conclusion: The authors concluded that the existing data suggest homozygous p16 loss by FISH or BAP1 loss by immunohistochemistry is never seen in benign mesothelial reactions. They added that both markers are lost in only a proportion of mesotheliomas, and that more BAP1 data on benign reactions are needed. They proposed running the BAP1 test first, followed by p16 FISH if BAP1 is not lost, after first confirming that the process is mesothelial.
• Limitations the authors state:
  • Few data exist on BAP1 staining in benign reactions, and more are needed.
  • Both tests have limited sensitivity, so a mesothelial proliferation that retains BAP1 may still be malignant.
  • The review of the older markers was not meant to be complete.

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: Fluorescence In Situ Hybridization (FISH), BAP1, Immunohistochemistry, Desmin, Epithelial Membrane Antigen (EMA), Homozygous Deletion, Malignant Mesothelioma, Mesothelioma.

Related studies

• 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 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations — M. Cigognetti, S. Lonardi, et al. (2015)
• 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)
• Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma — R. Pillappa, J.J. Maleszewski, et al. (2018)
• BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations — B.S. Sheffield, H.C. Hwang, et al. (2015)
• Cyclin D1 immunohistochemical staining to separate benign from malignant mesothelial proliferations — J. Pors, J. Naso, et al. (2020)

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