Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology

Our plain-English summary of Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology, by J. Andrici, A. Sheen, L. Sioson, et al (Modern Pathology, 2015).

The study

• Authors: J. Andrici, A. Sheen, L. Sioson, K. Wardell, A. Clarkson, N. Watson, M.S. Ahadi, M. Farzin, C.W. Toon, A.J. Gill
• Journal: Modern Pathology
• Published: 2015;28(10):1360-8
• Cited by: 79 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Although most mesotheliomas present with pleural effusions, it is controversial whether mesothelioma can be diagnosed with confidence in effusion cytology. Therefore, an ancillary marker of malignant mesothelial cells applicable in effusions would be clinically valuable. BRCA-1-associated protein (BAP1) is a tumor suppressor gene, which shows biallelic inactivation in approximately half of all mesotheliomas. We investigated whether loss of BAP1 expression by immunohistochemistry can be used to support a diagnosis of mesothelioma in effusion cytology. Immunohistochemistry for BAP1 was performed on cell blocks and interpreted blinded. 43 of 75 (57%) effusions associated with confirmed mesothelioma showed negative staining with positive internal controls. Of 57 effusions considered to have atypical mesothelial cells in the absence of a definitive diagnosis of mesothelioma, 8 cases demonstrated negative staining for BAP1. On follow-up six of these patients received a definitive diagnosis of mesothelioma in the subsequent 14 months (two were lost to follow-up immediately, and mesothelioma could not be excluded). Only 5 of 100 consecutive benign effusions were interpreted as BAP1 negative. One of these patients died soon after and mesothelioma could not be excluded. On unblinded review the four other patients with apparently negative BAP1 staining but no malignancy lacked convincing positive staining in non-neoplastic cells suggesting that BAP1 immunohistochemistry may have initially been misinterpreted. 47 effusions with adenocarcinoma were BAP1 positive. We conclude that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology. We caution that interpretation of BAP1 immunohistochemistry on cell block may be difficult and that convincing positive staining in non-neoplastic cells is required before atypical cells are considered negative. We also note that BAP1 loss is not a sensitive test as it occurs in only half of all mesotheliomas and cannot be used to exclude the diagnosis.

In plain English

This Australian study tested whether a laboratory stain for the protein BAP1 could help diagnose mesothelioma from fluid drained from around the lungs (effusion cytology). A single pathologist read the stains without knowing each patient's diagnosis. Of 75 patients with a definitive diagnosis of thoracic mesothelioma, 43 (57%) showed loss of BAP1. That was 32 of 59 confirmed by tissue biopsy and 11 of 16 diagnosed from cytology alone. All 47 effusions containing adenocarcinoma kept BAP1 staining. Of 100 benign effusions, 5 were read as BAP1-negative. One of those patients may have had undiagnosed mesothelioma. The authors thought the other four may have been misread because normal cells nearby did not stain convincingly. Of 57 effusions with atypical mesothelial cells, 8 lost BAP1. Six of those patients were later diagnosed with mesothelioma within 2 to 14 months, and two died of unknown cause. The authors concluded that BAP1 loss, while not definitive, supports a mesothelioma diagnosis. They cautioned that the stain can be hard to interpret, and that normal staining cannot rule mesothelioma out.

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 study of stored effusion cell blocks from five patient groups. A single pathologist read the BAP1 immunohistochemistry blinded to the diagnosis.
• Who was studied: 279 patients with effusion cell blocks at the Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia. The groups were: 59 with thoracic mesothelioma confirmed on tissue biopsy (tissue diagnoses January 1991 to August 2014); 16 with mesothelioma diagnosed on cytology alone (June 1998 to August 2014); 100 consecutive benign effusions and 47 consecutive effusions with adenocarcinoma (2010); and 57 pleural effusions with atypical mesothelial cells and no tissue diagnosis of mesothelioma (June 1998 to August 2014). Abdominal mesotheliomas were excluded.
• Exposure: Not an asbestos exposure study. What was studied was a laboratory test: immunohistochemical staining for BAP1 (BRCA1-associated protein 1) on effusion cell blocks. Negative staining was defined as completely absent nuclear staining in the target cells while non-neoplastic cells stained positively as an internal control.
• Main results:
  • Patients with mesothelioma confirmed on tissue biopsy: 32 of 59 (54%) showed negative BAP1 staining.
  • Patients whose mesothelioma was diagnosed on cytology alone: 11 of 16 (69%) showed negative BAP1 staining.
  • All patients with a definitive diagnosis of mesothelioma: 43 of 75 (57%) showed negative BAP1 staining.
  • Patients with adenocarcinoma in pleural effusions: all 47 showed positive BAP1 staining in the malignant cells.
  • Benign effusions: 5 of 100 (5%) were read as BAP1-negative when scored blinded. One patient was thought likely to have had unbiopsied mesothelioma. On unblinded review, the staining in the other four was thought possibly misinterpreted, and perhaps should have been classed as non-contributory.
  • Effusions with atypical mesothelial cells: 8 of 57 (14%) showed BAP1 loss.
  • Of those 8 atypical cases, six patients were confirmed to have mesothelioma on tissue biopsies or autopsies at other institutions over the following 2 to 14 months. The other two died of unknown cause 2 and 9 months later, so mesothelioma could be neither excluded nor confirmed.
• The authors' conclusion: The authors concluded that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology.
• Limitations the authors state:
  • BAP1 staining may be difficult to interpret in effusion specimens. A positive internal control in non-neoplastic cells is required before negative staining is given weight.
  • Only about half of mesotheliomas lose BAP1, so positive staining cannot be used to exclude mesothelioma.
  • Tissue from the later outside biopsies in the atypical group was not available to confirm the BAP1 status of those mesotheliomas.
  • BAP1 loss has been reported in some other tumors, such as some cholangiocarcinomas, renal carcinomas and uveal melanomas. Its use to tell mesothelioma apart from other cancers therefore depends on the clinical context.

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1, Mesothelioma, Cytology, Pleural Effusion, Mesothelial Cells, Tumor Suppressor Gene, Immunohistochemistry, Cell Block.

Related studies

• 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)
• Loss of expression of BAP1 predicts longer survival in mesothelioma — M. Farzin, C.W. Toon, et al. (2015)
• 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)
• 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)
• 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)
• Loss of expression of BAP1 is very rare in non-small cell lung carcinoma — J. Andrici, T.R. Parkhill, et al. (2016)

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