BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma

Our plain-English summary of BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma, by S.M. McGregor, J. McElherne, A. Minor, et al (Human Pathology, 2017).

The study

• Authors: S.M. McGregor, J. McElherne, A. Minor, J. Keller-Ramey, R. Dunning, A.N. Husain, W. Vigneswaran, C. Fitzpatrick, T. Krausz
• Journal: Human Pathology
• Published: 2017;60:86-94
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

BRCA-associated protein 1 (BAP1) immunohistochemistry (IHC) and CDKN2A (p16) fluorescence in situ hybridization (FISH) have shown clinical utility in confirming the diagnosis of malignant pleural mesothelioma (MPM), but the role for using these 2 markers to guide clinical management is not yet clear. Although p16 loss is predictive of poor prognosis, there is controversy as to whether BAP1 loss is predictive of a more favorable prognosis; how these results interact with one another has not been explored. We performed CDKN2A FISH on a previously published tissue microarray on which we had performed BAP1 IHC, revealing combined BAP1/p16 status for 93 MPM cases. As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135). There was no association between BAP1 loss and p16 loss, as 26%, 28%, 30%, and 16% of overall cases demonstrated loss of BAP1 alone, loss of p16 alone, loss of both BAP1 and p16, or neither abnormality, respectively. Although multivariate analysis demonstrated that BAP1 IHC is not an independent predictor of prognosis, when viewed in combination with homozygous CDKN2A deletion, risk stratification was evident. More specifically, patients with CDKN2A disomy and loss of BAP1 expression had improved outcomes compared with those with CDKN2A disomy and retained BAP1 expression (hazard ratio, 0.2286; P = .0017), and this finding was notably evident among epithelioid cases. We conclude that BAP1 IHC provides prognostic information within the context of CDKN2A FISH that may have clinical utility beyond diagnosis.

Copyright © 2016 Elsevier Inc. All rights reserved.

In plain English

This University of Chicago study tested tumor tissue from 93 patients with malignant pleural mesothelioma in two ways. One was a BAP1 protein stain. The other was a genetic test (FISH) for CDKN2A (p16) gene deletion. The article did not report asbestos exposure. Both CDKN2A copies were deleted in 53% of cases according to the text, but 58% according to a table; 29% had both abnormalities. Together the tests detected 84% of mesotheliomas, with 100% specificity against benign controls. Among 88 patients with survival data, CDKN2A deletion was linked to shorter survival after adjusting for tumor subtype, chemotherapy and BAP1 status (hazard ratio 2.2553, 95% confidence interval 1.1867 to 4.2863). BAP1 loss was linked to longer survival in a simple analysis, but not after adjusting for subtype and chemotherapy. Tumors with BAP1 loss and no CDKN2A deletion had a median survival of 776 days, versus 185, 223 and 268 days in the other three groups. This appeared in epithelioid but not biphasic tumors. The authors concluded that BAP1 staining does not independently predict survival across mesothelioma overall, but adds risk stratification alongside p16 status and tumor subtype.

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 and survival study of archived tumor samples on a previously described tissue microarray, with chart review
• Who was studied: 93 cases of malignant pleural mesothelioma at the University of Chicago, including 9 sarcomatoid cases. Mean age was 68 years (range 43-89); there were 74 males and 19 females. 88 cases were included in the survival analysis. Study years are not stated.
• Exposure: No asbestos or fiber exposure is reported. The factors studied were BAP1 protein loss by immunohistochemistry, homozygous CDKN2A (p16) deletion by FISH, and a four-group combined BAP1-p16 score.
• Main results:
  • The results text reports homozygous CDKN2A (p16) deletion in 53% of mesothelioma cases overall (48% epithelioid, 69% biphasic, 67% sarcomatoid). Table 2 gives 58% overall for CDKN2A FISH. The abstract's subgroup percentages (28% p16 loss alone plus 30% both) also add to 58%.
  • Loss of both BAP1 and p16 was found in 29% of cases overall (33% epithelioid, 33% biphasic, 0% sarcomatoid).
  • The two tests combined had a sensitivity of 84% and a specificity of 100% for malignant pleural mesothelioma. By subtype, combined sensitivity was 92% in epithelioid, 78% in biphasic and 67% in sarcomatoid cases (Table 2).
  • p16 loss was an independent predictor of poorer disease-specific survival. In the multivariate analysis, which included histologic subtype, chemotherapy and BAP1 status, the hazard ratio was 2.2553 (95% CI 1.1867-4.2863).
  • BAP1 loss was associated with improved survival in univariate analysis (hazard ratio 0.5381, 95% CI 0.3055-0.9479). This association did not hold in multivariate analysis including histologic subtype and chemotherapy (hazard ratio 1.1441, 95% CI 0.5095-2.2205).
  • Cases with retained p16 and loss of BAP1 (n=24) had a median survival of 776 days. The other three groups had medians of 185 days (BAP1 expressed, p16 retained), 223 days (BAP1 expressed, p16 deleted) and 268 days (BAP1 lost, p16 deleted). In the multivariate analysis, the retained-p16, BAP1-lost group had a hazard ratio of 0.2286 (95% CI 0.0915-0.5707), relative to the BAP1-lost, p16-deleted group used as the reference in Table 3.
  • The survival difference by combined BAP1/p16 status appeared in a sub-analysis of epithelioid cases but not in biphasic cases.
• The authors' conclusion: The authors concluded that BAP1 staining is not independently predictive of survival across malignant pleural mesothelioma as a whole. When placed in the context of histologic subtype and p16 status, it gives additional risk stratification that may have value beyond diagnosis.
• Limitations the authors state:
  • The authors state that the mechanisms behind the combined BAP1/p16 survival finding are unclear and that further study is warranted.
  • The authors state that additional studies are needed before these findings are applied in routine practice.

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, Immunohistochemistry, CDKN2A, Fluorescence In Situ Hybridization (FISH), Pleural Mesothelioma, Prognosis, Hazard Ratio, Multivariate Analysis.

Related studies

• Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma — D. Wu, K. Hiroshima, et al. (2017)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma — D.B. Chapel, J.J. Schulte, et al. (2020)
• 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)
• 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)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)

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