Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma

Our plain-English summary of Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma, by A. Shinozaki-Ushiku, T. Ushiku, S. Morita, et al (Histopathology, 2017).

The study

• Authors: A. Shinozaki-Ushiku, T. Ushiku, S. Morita, M. Anraku, J. Nakajima, M. Fukayama
• Journal: Histopathology
• Published: 2017;70(5):722-733
• Cited by: 68 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Aims: Malignant mesothelioma is a highly aggressive cancer that is usually diagnosed at advanced stages; thus, highly sensitive and specific markers are necessary for its early definitive diagnosis. The aim of this study was to evaluate the diagnostic utility and prognostic significance of BAP1 and EZH2 in malignant mesothelioma.

Methods And Results: The expression of BAP1 and EZH2 was investigated by immunohistochemistry in 32 malignant mesotheliomas and 44 benign mesothelial proliferative lesions, including well-differentiated papillary mesothelioma (n = 4), mesothelial inclusion cyst (n = 22), and reactive mesothelial hyperplasia (n = 18). BAP1 loss and high EZH2 expression were observed in 17 (53%) and 22 (66%) malignant mesothelioma cases, respectively, whereas none of the benign lesions showed BAP1 loss or high EZH2 expression. The combination of BAP1 loss and high EZH2 expression as markers to differentiate epithelioid/biphasic malignant mesothelioma from benign mesothelial lesions was highly sensitive (90%) and specific (100%). There were no statistically significant associations between parameters such as age and sex of patients, tumour location, asbestos exposure, treatment, histology, and BAP1 or EZH2 expression. Survival analysis revealed that BAP1 loss, but not high EZH2 expression, was associated with a better prognosis.

Conclusions: BAP1 loss and high EZH2 expression were highly specific to malignant mesothelioma in differentiating it from benign mesothelial proliferations, and the combination of these two markers improved the diagnostic accuracy.

© 2016 John Wiley & Sons Ltd.

In plain English

This University of Tokyo study tested whether two tissue-staining markers, BAP1 and EZH2, could help tell malignant mesothelioma from benign mesothelial growths. The authors examined archived samples, collected between 1990 and 2016, from 32 patients with malignant mesothelioma and 44 benign or low-grade lesions. Loss of BAP1 was seen in 17 of 32 mesotheliomas (53%) and high EZH2 in 21 of 32 (66%). No benign lesion showed either change. Together, the two markers picked out all but three of the 23 epithelioid and 7 biphasic mesotheliomas (sensitivity 90.0%, 95% confidence interval 73.5 to 97.9) and flagged no benign lesion (specificity 100%, interval 88.2 to 100). Eight mesothelioma patients had a definite or possible history of occupational asbestos exposure. Neither marker had a statistically significant link to asbestos exposure, age, sex, tumor location or treatment. Patients whose tumors had lost BAP1 had better overall survival. The authors concluded that both markers were highly specific to malignant mesothelioma when distinguishing it from benign growths. They noted that the study had few cases, especially sarcomatoid ones, and did not test other cancers.

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: Retrospective laboratory study of archived pathology samples, using immunohistochemistry (tissue staining) to assess diagnostic accuracy and links with survival
• Who was studied: 32 patients with malignant mesothelioma (25 males, 7 females; average age 64.7, range 32 to 85; tumor in the thoracic cavity in 27 and the abdominal cavity in 5; 23 epithelioid, 7 biphasic, 2 sarcomatoid). Also 44 benign or low-grade mesothelial lesions: 4 well-differentiated papillary mesotheliomas, 22 mesothelial inclusion cysts and 18 reactive mesothelial hyperplasias. All from the University of Tokyo Hospital archives, 1990 to 2016.
• Exposure: The study measured tissue markers (BAP1 loss and high EZH2 expression), not asbestos exposure. Eight of the 32 mesothelioma patients had a definite or possible history of occupational asbestos exposure. No fiber types or doses were reported.
• Main results:
  • BAP1 loss was found in 17 of 32 malignant mesotheliomas (53%): 14 epithelioid (61%) and 3 biphasic (43%). Neither of the 2 sarcomatoid cases showed BAP1 loss.
  • High EZH2 expression was found in 21 of 32 malignant mesotheliomas (66%).
  • All 44 benign or low-grade mesothelial lesions kept BAP1 expression, and none showed high EZH2 expression.
  • Among the epithelioid (23) and biphasic (7) mesotheliomas, only three (10%) showed neither BAP1 loss nor high EZH2, so all others were picked out by the combination.
  • Using the two markers together, sensitivity was 87.5% across all mesothelioma types and 90.0% for epithelioid and biphasic cases. Specificity and positive predictive value were 100%.
  • For epithelioid and biphasic cases, the combination's sensitivity of 90.0% had a 95% confidence interval of 73.5 to 97.9, and its specificity of 100% had a 95% confidence interval of 88.2 to 100 (Table 3).
  • Among the mesothelioma patients, neither marker had a statistically significant association with age, sex, tumor location, history of asbestos exposure or treatment.
  • Mesothelioma patients with BAP1 loss had better overall survival than those with retained BAP1 (P = 0.0372). In multivariate analysis, BAP1 loss was the only independent prognostic factor (P = 0.0469).
  • High EZH2 expression tended toward worse overall survival. The difference was not statistically significant by the log-rank test (P = 0.0722) but was significant by the Peto-Peto-Wilcoxon test (P = 0.0434).
  • Epithelioid mesothelioma showed better overall survival than the other subtypes (P = 0.0331).
• The authors' conclusion: The authors concluded that BAP1 loss and high EZH2 expression were both highly specific to malignant mesothelioma when distinguishing it from benign mesothelial proliferations. They also concluded that combining the two improved diagnostic accuracy, especially in epithelioid and biphasic mesothelioma.
• Limitations the authors state:
  • The number of cases was relatively small, especially sarcomatoid mesothelioma.
  • Cancers other than mesothelioma were not included, so the markers were not tested against them.
  • The authors stated that the prognostic findings need confirmation in a large cohort or a meta-analysis.

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, Malignant Mesothelioma, Immunohistochemistry, Well-Differentiated Papillary Mesothelioma, Reactive Mesothelial Hyperplasia, Epithelioid, Biphasic Mesothelioma, Asbestos Exposure.

Related studies

• Loss of expression of BAP1 predicts longer survival in mesothelioma — M. Farzin, C.W. Toon, et al. (2015)
• 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)
• 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 — M. Yoshimura, Y. Kinoshita, et al. (2019)
• Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens — H.C. Hwang, B.S. Sheffield, et al. (2016)
• Loss of BRCA1-associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions — I. Cozzi, F.A. Oprescu, et al. (2018)
• Diagnostic value of BRCA1-associated protein-1, glucose transporter-1 and desmin expression in the discrimination between reactive mesothelial proliferation and malignant mesothelioma in tissues and effusions — S. Önder, E. Özogul, et al. (2019)

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