Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia

Our plain-English summary of Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia, by M. Yoshimura, Y. Kinoshita, M. Hamasaki, et al (Lung Cancer, 2019).

The study

• Authors: M. Yoshimura, Y. Kinoshita, M. Hamasaki, S. Matsumoto, T. Hida, Y. Oda, A. Iwasaki, K. Nabeshima
• Journal: Lung Cancer
• Published: 2019;130:187-193
• Cited by: 44 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objective: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with poor prognosis. Loss of BRCA-associated protein 1 (BAP1) protein expression as detected by immunohistochemistry (IHC) and homozygous deletion (HD) of the 9p21 locus as detected by fluorescence in situ hybridization (FISH) permits differentiation of MPM from reactive mesothelial hyperplasia (RMH). We have previously reported that detecting the loss of methylthioadenosine phosphorylase (MTAP) using IHC is a surrogate assay for 9p21 FISH. Furthermore, enhancer of zeste homolog 2 (EZH2), which encodes a component of polycomb repressor complex 2 (PRC-2), has been overexpressed in various tumors as well as MPM. In the current study, we investigated whether EZH2 IHC assay, alone or in combination with BAP1 and MTAP IHC, is useful for distinguishing MPM from RMH.

Materials And Methods: We examined IHC expression of EZH2, BAP1, and MTAP, and 9p21 FISH in MPM (n = 38) and RMH (n = 29) and analyzed the sensitivity and specificity of each detection assay for distinguishing MPM from RMH.

Results And Conclusion: EZH2, BAP1, and MTAP IHC, and 9p21 FISH were characterized by a 100% specificity each and 44.7%, 52.6%, 47.4%, and 65.8% sensitivities, respectively. A combination of EZH2 and BAP1 IHC, and 9p21 FISH showed the greatest sensitivity (89.5%). Using IHC alone (EZH2, BAP1, and MTAP IHC) also yielded a good sensitivity of 86.9%; this level is high enough for routine diagnostics. There were no statistically significant associations between expression of EZH2 and that of other markers (BAP1 and MTAP IHC) or 9p21 HD. However, a high expression level of EZH2 was significantly associated with short survival (P = 0.025). In conclusion, adding a high expression level of EZH2 to a combination of BAP1 and MTAP loss, all detected by IHC, demonstrated useful for discriminating MPM from RMH.

Copyright © 2019 Elsevier B.V. All rights reserved.

In plain English

This laboratory study from Fukuoka University Hospital, Japan, tested whether staining tissue for the protein EZH2 helps pathologists tell malignant pleural mesothelioma apart from reactive mesothelial hyperplasia, a benign condition that can look similar. It tested EZH2 alone and alongside two other stains, BAP1 and MTAP. The authors examined 38 mesothelioma and 29 hyperplasia cases from 2001 to 2015. They also used a genetic test for loss of the 9p21 region (FISH). The study did not look at asbestos exposure. Each test was 100% specific: no hyperplasia case tested positive. But each test alone detected only some mesotheliomas: 44.7% for EZH2, 52.6% for BAP1, 47.4% for MTAP and 65.8% for 9p21 FISH. Combining EZH2, BAP1 and 9p21 FISH detected 89.5%, and the three stains together without FISH detected 86.8%. High EZH2 was not significantly linked to the other markers. Among mesothelioma patients, high EZH2 was associated with shorter survival (P = 0.025). This effect was seen in epithelioid cases but not in biphasic or sarcomatoid cases. The authors concluded that adding EZH2 raised diagnostic sensitivity. They named the small sample size as a major limitation.

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: Laboratory diagnostic study of archived pathology cases, comparing immunohistochemistry stains (EZH2, BAP1, MTAP) and 9p21 FISH, with a survival analysis
• Who was studied: 38 malignant pleural mesothelioma (MPM) cases and 29 reactive mesothelial hyperplasia (RMH) cases from the pleural lesion file of the Department of Pathology, Fukuoka University Hospital, Japan, 2001 to 2015. The MPM cases were 27 epithelioid, 6 biphasic and 5 sarcomatoid, with a mean age of 65.3 years. All RMH cases came from male patients with bullae formation, mean age 32.5 years.
• Exposure: The article does not report asbestos or any other exposure. It studied tissue markers: EZH2, BAP1 and MTAP by immunohistochemistry, and 9p21 homozygous deletion by FISH.
• Main results:
  • Each single test had 100% specificity. Sensitivity for detecting MPM was 44.7% for EZH2 IHC, 52.6% for BAP1 IHC, 47.4% for MTAP IHC and 65.8% for 9p21 FISH.
  • The combination of EZH2 IHC, BAP1 IHC and 9p21 FISH gave the highest sensitivity, 89.5% (34 of 38 MPM). The stain-only combination of EZH2, BAP1 and MTAP reached 86.8% (33 of 38 MPM). Specificity stayed at 100% for all combinations.
  • BAP1 IHC combined with 9p21 FISH had a sensitivity of about 80% (81.6% in Table 1).
  • The share of cells staining for EZH2 ranged from 4.5% to 93.9% in MPM cases and stayed below 40% in all RMH cases.
  • High EZH2 expression was not significantly associated with 9p21 deletion (P = 0.053), BAP1 loss (P = 0.973) or MTAP loss (P = 0.284).
  • Across all MPM patients with follow-up, the high-EZH2 group had significantly shorter overall survival than the low-EZH2 group (P = 0.025).
  • By subtype, the survival effect of EZH2 was seen only in epithelioid MPM (P = 0.008). It was not seen in biphasic and sarcomatoid MPM (P = 0.831).
  • Overall survival was significantly longer in epithelioid MPM than in sarcomatoid MPM (P = 0.041).
• The authors' conclusion: The authors concluded that adding EZH2 to the stain panel for telling MPM from RMH increased diagnostic sensitivity, and that high EZH2 expression was associated with poor prognosis.
• Limitations the authors state:
  • The authors called the relatively small sample size a major limitation and said further studies are needed.
  • Some MPM cases had EZH2 positivity near the 50% cut-off, so the authors advised care in interpreting those cases.

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1, MTAP, Immunohistochemistry, Pleural Mesothelioma, Reactive Mesothelial Hyperplasia, Neoplasm, Prognosis, Homozygous Deletion.

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• Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma — Y. Kinoshita, M. Hamasaki, et al. (2020)
• BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests — T. Hida, M. Hamasaki, et al. (2016)
• A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis — Y. Kinoshita, M. Hamasaki, et al. (2018)
• Utility of highly expressed EZH2 in pleural effusion cytology for the diagnosis of mesothelioma — M. Yoshimura, M. Hamasaki, et al. (2020)

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