Malignant Mesothelioma, BAP1 Immunohistochemistry, and VEGFA: Does BAP1 Have Potential for Early Diagnosis and Assessment of Prognosis?

Our plain-English summary of Malignant Mesothelioma, BAP1 Immunohistochemistry, and VEGFA: Does BAP1 Have Potential for Early Diagnosis and Assessment of Prognosis?, by E. Pulford, K. Huilgol, D. Moffat, et al (Disease Markers, 2017).

The study

• Authors: E. Pulford, K. Huilgol, D. Moffat, D.W. Henderson, S. Klebe
• Journal: Disease Markers
• Published: 2017;2017:1310478
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes. Early diagnosis and accurate prognostication remain problematic. BAP1 is a tumour suppressor gene commonly mutated in MM. Germline BAP1 mutation has been associated with early onset and less aggressive disease compared with sporadic MM. Sporadic BAP1 mutations are common and are associated with improved survival in MM, contrary to other malignancies. This study investigated the prognostic role of BAP1 in matched cytology and surgical specimens and aimed to investigate the association between BAP1 and the established prognostic marker VEGFA from a cohort of 81 patients. BAP1 mutation was found in 58% of histology and 59% of cytology specimens. Loss of BAP1 expression in both surgical and cytology specimens was significantly associated with poorer survival in a multivariate analysis when controlling for known prognostic indicators. Increased levels of VEGFA in pleural effusions were associated with poor survival. We conclude that the prognostic significance of BAP1 mutations in MM cannot be determined in isolation of other prognostic factors, which may vary between patients. Pathologists should employ caution when commenting on prognostic implications of BAP1 status of MM patients in diagnostic pathology reports, but it may be useful for early diagnosis.

In plain English

This retrospective study examined stored tissue and fluid samples from 81 patients diagnosed with malignant mesothelioma at Flinders Medical Centre, South Australia, between 2006 and 2015. Eighty had pleural disease and one had peritoneal disease. The study did not assess asbestos exposure. The authors treated loss of BAP1 protein staining in tumour cell nuclei as a sign of BAP1 mutation. Staining was lost in 47 of 81 surgical samples (58%) and 34 of 57 fluid (cytology) samples (59%). It was not lost in any of 18 fluid samples from malignant effusions caused by metastatic lung adenocarcinoma. After allowing for age, sex and tumour subtype, BAP1 loss was associated with shorter survival. In surgical samples, median survival was 6 months (95% confidence interval 4.3 to 7.7) with loss and 11 months (6.9 to 15.1) without. In 17 patients, high VEGFA in pleural fluid was reported as linked to poorer survival, though the article's own survival figures for this point conflict. The authors concluded that pathologists should be cautious in linking BAP1 status to prognosis, and that BAP1 may be useful for early diagnosis.

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 study of archival tumour tissue and pleural fluid samples, with BAP1 immunohistochemistry (antibody staining) and survival analysis (Kaplan-Meier and Cox regression); VEGFA measured in stored pleural fluid
• Who was studied: 83 patients were recruited and 81 were eligible for analysis of surgical samples; 57 of these also had cytology samples. All were diagnosed with malignant mesothelioma at Flinders Medical Centre, South Australia, 2006 to 2015. Of the 81, 80 had pleural and 1 had peritoneal mesothelioma; 63 were male and 18 female; median age 74. A comparison group of 18 cytology specimens came from patients with malignant effusions due to metastatic lung adenocarcinoma.
• Exposure: The study did not record or analyse asbestos exposure, fibre types or jobs. The factors studied were BAP1 protein status in tumour samples, judged by loss of nuclear staining, and VEGFA levels in pleural fluid.
• Main results:
  • BAP1 staining was lost in 58% of surgical (histology) samples (47 of 81) and 59% of cytology samples (34 of 57).
  • None of the 18 metastatic lung adenocarcinoma fluid samples showed loss of BAP1 nuclear staining.
  • Two earlier pleural fluid samples from BAP1-negative patients, diagnosed as reactive (non-cancerous) at the time, showed BAP1 loss when stained retrospectively.
  • Without adjusting for other factors, BAP1 loss in surgical samples was significantly associated with poorer survival (p = 0.014). BAP1 status in cytology samples was not significant in this analysis (p = 0.205).
  • After adjusting for age, sex and histological subtype, BAP1 loss was significantly associated with poorer survival. Surgical samples: hazard ratio 2.226, p = 0.003. Cytology samples: hazard ratio 1.882, p = 0.047 in Table 4, given as 0.04 in the text.
  • Surgical samples: median survival was 6 months (95% CI 4.3 to 7.7) with BAP1 loss (47 patients) and 11 months (6.9 to 15.1) with BAP1 retained (34 patients).
  • Cytology samples: median survival was 8 months (95% CI 5.6 to 10.4) with BAP1 loss and 9 months (5.7 to 12.3) with BAP1 retained.
  • Among epithelioid cases only, BAP1 loss in histology samples was associated with worse outcomes (p = 0.038). This was not seen in other subtypes or in the cytology group.
  • In 17 patients with stored pleural fluid, all with epithelioid mesothelioma, high VEGFA (2000 pg/mL or more) was reported as associated with worse outcomes (p = 0.005). However, the article prints median survival as 13 months for high and 7 months for low VEGFA, which contradicts that finding.
  • Of the 7 patients with high VEGFA, 6 were BAP1 negative. The discussion instead says 7 of 8.
• The authors' conclusion: The authors concluded that the prognostic significance of BAP1 cannot be judged apart from other prognostic factors, so pathologists should be cautious about commenting on prognosis from BAP1 status. They suggested BAP1 may be useful for early diagnosis, including testing of pleural fluid samples.
• Limitations the authors state:
  • BAP1 status was judged only by immunohistochemistry, without genetic sequencing or qPCR, and this may not detect all BAP1 mutations.
  • Nuclear staining was sometimes hard to judge, and malignant cells were hard to tell from reactive cells, especially in fluid samples. This caused some disagreement between the two pathologists (initial kappa 0.88).
  • Three cytology samples, all epithelioid, did not match the BAP1 result of the corresponding tissue sample.
  • Compared with other studies, the cohort had more biphasic and sarcomatoid cases and an older age at diagnosis. It also included referred cases that may be unusual and harder to diagnose, which may be linked to shorter survival.

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: Malignant Mesothelioma, BAP1, Immunohistochemistry, Prognosis, BAP1 Tumor Predisposition Syndrome, Cytology, Histology, Multivariate Analysis.

Related studies

• 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)
• BAP1 Immunohistochemistry and p16 FISH in the Diagnosis of Sarcomatous and Desmoplastic Mesotheliomas — H.C. Hwang, S. Pyott, et al. (2016)
• 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)
• 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)
• 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)

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