Loss of BRCA1-associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions

Our plain-English summary of Loss of BRCA1-associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions, by I. Cozzi, F.A. Oprescu, E. Rullo, et al (Diagnostic Cytopathology, 2018).

The study

• Authors: I. Cozzi, F.A. Oprescu, E. Rullo, V. Ascoli
• Journal: Diagnostic Cytopathology
• Published: 2018;46(1):9-14
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: The important diagnostic challenge facing the cytopathologist is whether a mesothelial proliferation on effusions represents a malignant mesothelioma (MM) or a benign mesothelial hyperplasia (MH). Here, we evaluated the diagnostic utility of BAP1 immunohistochemistry (IHC) in distinguishing between reactive and neoplastic mesothelial cells.

Methods: In pleural and peritoneal effusions from 147 patients with diagnosed MM or with a differential diagnosis of MM and MH, the expression of BAP1 was examined by IHC on paraffin-embedded cell blocks (n = 121) and biopsies (n = 44). Included were also synchronous and methacronous cytology/biopsy pair samples. BAP1 IHC was evaluated for nuclear staining as positive or negative on target mesothelial cells, with appropriate internal control.

Results: In MM cases, loss of BAP1 nuclear staining was observed in 76.5% of the cell blocks and 47.5% of the biopsies. All BAP1-negative cases with a differential diagnosis of benign and malignant mesothelial proliferations were MM at follow-up. All MH cases, the 29% of epithelial MM and the 90% of nonepithelial MM, retained BAP1 expression. Synchronous and methacronous biopsy/cytology pairs showed matching BAP1 results.

Conclusion: In effusions with mesotheliomatous cells or atypical mesothelial cells of uncertain significance, negative BAP1 IHC strongly supports a diagnosis of MM. With prudence in interpreting immunostaining, BAP1 may be included in IHC panels for MM cytodiagnosis, given its high specificity and sensitivity.

© 2017 Wiley Periodicals, Inc.

In plain English

This retrospective laboratory study from Sapienza University of Rome, Italy, used 165 archived specimens from 140 patients. They were samples of fluid from around the lungs or abdomen (pleural and peritoneal effusions) and biopsies from people diagnosed with malignant mesothelioma, benign mesothelial hyperplasia, or an uncertain diagnosis between the two. The authors stained them for the BAP1 protein in cell nuclei. Among cases finally diagnosed as mesothelioma, 69 of 105 (66%) had lost nuclear BAP1 staining: 68 of 95 epithelial and 1 of 10 nonepithelial tumors. All 35 cases negative for malignancy at follow-up kept BAP1 staining. Across these 140 cases, nuclear BAP1 loss as a test for mesothelioma had 65.7% sensitivity (95% confidence interval 55.81 to 74.70), 100% specificity (90.00 to 100.00), 100% positive predictive value (90.00 to 100.00) and 49.3% negative predictive value (42.73 to 55.89). The authors concluded that negative BAP1 staining strongly supports a mesothelioma diagnosis. They added that mesothelioma cannot be diagnosed on this test alone, and that retained BAP1 staining does not exclude it. The study did not examine asbestos exposure.

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 diagnostic laboratory study of archived pathology samples (immunohistochemistry for BAP1), with diagnoses checked against follow-up
• Who was studied: 165 specimens (74 formalin-fixed cell blocks, 47 alcohol-fixed cell blocks, 44 biopsies) from 140 patients in the pathology archives of Sapienza University of Rome. The specimens came from pleural and peritoneal effusions and biopsies. Initial diagnoses were mesothelioma (94 cases), reactive mesothelial cells or mesothelial hyperplasia (35 cases), or uncertain between the two (11 subjects). 158 samples could be evaluated after 7 without an internal control were excluded. Patients without a mesothelioma diagnosis were followed for 12 to 312 months. The study years are not given.
• Exposure: No asbestos or other exposure was studied. The study assessed a laboratory test: staining for BAP1 protein (anti-BAP1 antibody, clone C-4), read as nuclear staining lost or retained in the target mesothelial cells.
• Main results:
  • Samples with an initial diagnosis of mesothelioma: loss of nuclear BAP1 staining in 52 of 68 effusion cell blocks (76.5%) and in 19 of 40 biopsies (47.5%). All 19 biopsies with loss were epithelioid mesothelioma.
  • By final diagnosis, 69 of 105 mesotheliomas (66%) showed loss of nuclear BAP1 staining: 68 of 95 epithelial (71%) and 1 of 10 nonepithelial (a biphasic tumor).
  • All 35 cases negative for malignancy at follow-up retained BAP1 staining.
  • For BAP1 loss as a test for mesothelioma in 140 cases (105 mesotheliomas, 35 negative for malignancy): sensitivity 65.7% (95% CI 55.81 to 74.70), specificity 100% (95% CI 90.00 to 100.00), positive predictive value 100% (95% CI 90.00 to 100.00), negative predictive value 49.3% (95% CI 42.73 to 55.89).
  • In several samples without nuclear staining, BAP1 staining was confined to the cytoplasm.
  • In the group with an uncertain initial diagnosis (15 samples, 11 subjects), all BAP1-negative samples were mesothelioma at follow-up (6 subjects).
  • Among effusions first diagnosed as mesothelial hyperplasia, 4 showed BAP1 loss, and these were mesothelioma at follow-up.
  • BAP1 results matched between paired cytology and biopsy samples in 8 patients sampled at the same time. They also matched in 4 patients sampled at different times.
• The authors' conclusion: The authors concluded that, in effusions with mesothelioma cells or atypical mesothelial cells of uncertain significance, negative BAP1 staining strongly supports a diagnosis of mesothelioma. They also stated that the diagnosis cannot rest on BAP1 staining alone.
• Limitations the authors state:
  • The authors described their case series as small (in discussing samples taken at different times).
  • BAP1 staining in effusions is hard to evaluate because samples need internal control cells, which may be absent.
  • BAP1 staining in alcohol-fixed samples, even after formalin postfixation, was weaker than in formalin-fixed cell blocks.
  • No standard cutoff for evaluating BAP1 staining has been defined.
  • A positive (retained) BAP1 staining result does not exclude mesothelioma and does not distinguish mesothelioma from mesothelial hyperplasia.
  • A mesothelioma diagnosis cannot be based solely on negative BAP1 staining. Other cancers must be excluded and imaging and other findings must agree.

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, Cytopathology, Malignant Mesothelioma, Reactive Mesothelial Hyperplasia, Immunohistochemistry, Mesothelial Cells, Differential Diagnosis, Cell Block.

Related studies

• Loss of BRCA1-associated protein 1 (BAP1) expression is rare in non-small cell lung cancer — D. Owen, B.S. Sheffield, et al. (2017)
• 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)
• The value of BRCA-1-associated protein 1 expression and cyclin-dependent kinase inhibitor 2A deletion to distinguish peritoneal malignant mesothelioma from peritoneal location of carcinoma in effusion cytology specimens — W. Althakfi, S. Gazzo, et al. (2020)
• Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology — J. Andrici, A. Sheen, et al. (2015)
• Loss of BAP1 expression is very rare in peritoneal and gynecologic serous adenocarcinomas and can be useful in the differential diagnosis with abdominal mesothelioma — J. Andrici, J. Jung, et al. (2016)
• Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens — K.B. Berg, A.M. Churg, et al. (2020)

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