BRCA1-Associated Protein 1 (BAP1) Immunohistochemical Expression as a Diagnostic Tool in Malignant Pleural Mesothelioma Classification: A Large Retrospective Study

Our plain-English summary of BRCA1-Associated Protein 1 (BAP1) Immunohistochemical Expression as a Diagnostic Tool in Malignant Pleural Mesothelioma Classification: A Large Retrospective Study, by L. Righi, E. Duregon, S. Vatrano, et al (Journal of Thoracic Oncology, 2016).

The study

• Authors: L. Righi, E. Duregon, S. Vatrano, S. Izzo, J. Giorcelli, M. Rondón-Lagos, V. Ascoli, E. Ruffini, L. Ventura, M. Volante, M. Papotti, G.V. Scagliotti
• Journal: Journal of Thoracic Oncology
• Published: 2016;11(11):2006-2017
• Cited by: 82 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive disease with limited therapeutic options. Histological subtype remains among the most reliable prognostic factors, because the epithelioid subtype associated with the best prognosis and the sarcomatoid subtype with the worst. The biphasic subtype has an intermediate prognosis, but its definitive histological diagnosis may be challenging owing to the difficulty of assessing the neoplastic nature of the stromal component. Recent data identified BRCA1-associated protein 1 gene (BAP1) as one of the most frequently mutated genes in MPM. Immunohistochemical testing for BRCA1-associated protein 1 (BAP1) has been proposed to be predictive for the detection of BAP1 mutation in neoplastic cells. The aim of the present study was to define the diagnostic usefulness of immunohistochemical determination of BAP1 in MPM, with clinicopathological correlation.

Methods: A series of 143 MPMs were investigated for BAP1 protein expression in correlation with clinical and pathological data, including with a newly proposed nuclear grade. A pilot series of 20 selected cases were also investigated for BAP1 mutational status.

Results: Negative nuclear staining for BAP1 occurred in 62% of MPMs (including 27% with a cytoplasmic pattern) and was significantly associated with the presence of BAP1 mutation, epithelioid subtype, and a better prognosis. In a subgroup of cases, the pattern of expression of BAP1 in stromal cells supported their distinction as reactive versus neoplastic, thus helping achieve the correct classification of biphasic histological subtype.

Conclusions: We showed that BAP1 protein determination is a diagnostic tool to correctly distinguish biphasic MPM from epithelial subtypes with an atypical/activated reactive stroma and an independent prognostic parameter in MPM.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This retrospective study from Turin, Italy, examined tumor tissue from 143 patients with malignant pleural mesothelioma, including 101 surgical samples from 2000 to 2012. It stained the tissue for BAP1, a protein whose gene is often altered in mesothelioma. Asbestos exposure was not reported. Nuclear BAP1 staining was absent in 89 of 143 tumors (62%), including 24 with staining only outside the nucleus. In the article's table, absence ranged from 22% of sarcomatoid to 77% of biphasic tumors. The text gives 75%, in pleomorphic tumors, as the top. Of 20 genetically tested cases, all 10 with cytoplasmic staining had BAP1 alterations. Of 9 fully negative cases, 6 had mutations and 3 had one gene copy deleted. In 5 of 13 tumors classed as biphasic, the spindle cells kept BAP1, which suggested they were reactive rather than cancerous. Tumors keeping nuclear BAP1 had a worse prognosis. In multivariate analysis, only stage and nuclear grade were significant, and BAP1 was borderline (p = 0.055). The authors concluded that the staining predicts BAP1 mutation and helps separate biphasic from epithelioid tumors. They noted that few cases were genetically tested.

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 pathology study of tumor samples, with BAP1 protein staining (immunohistochemistry), gene sequencing in a selected subset, and survival analysis
• Who was studied: 143 malignant pleural mesothelioma cases from two pathology units in Turin, Italy. These were 101 consecutive surgically resected samples diagnosed 2000 to 2012, plus 42 consecutive thoracoscopic biopsy samples added to enrich the series for sarcomatoid and biphasic cases. Mean age was 60 years and the male-to-female ratio was 108:35. On review there were 107 epithelioid (including 12 pleomorphic), 13 biphasic and 23 sarcomatoid tumors.
• Exposure: Asbestos exposure was not reported. The factors studied were BAP1 protein staining in tumor and stromal cells (counted as positive when weak to strong nuclear staining was present) and BAP1 gene mutation status in 20 selected cases.
• Main results:
  • Nuclear BAP1 staining was absent in 89 of 143 tumors (62%). This included 24 cases (27% of the 89) with granular cytoplasmic staining.
  • Loss of BAP1 differed by subtype (p less than 0.0001). The text describes a range from 22% in sarcomatoid to 75% in pleomorphic tumors. Table 1, however, reports nuclear negativity in 10 of 13 biphasic tumors (77%).
  • Among the 20 genetically tested cases, all 10 with nuclear-negative, cytoplasmic-positive staining carried BAP1 alterations. The one nuclear-positive case was wild type.
  • Of the 9 tested cases with no BAP1 staining at all, 6 had BAP1 mutations found by sequencing. In the remaining 3, FISH found heterozygous deletions (loss of one copy of the gene) in 34%, 59% and 66% of analyzed nuclei.
  • In all epithelioid tumors with atypical stroma, the stromal spindle cells stained positive for BAP1.
  • In 5 of 13 biphasic tumors, BAP1 was negative in the epithelioid part and positive in the spindle cell part. The authors took this to suggest that the spindle cells were reactive.
  • In 3 such biphasic tumors where the two parts were tested separately, BAP1 mutations were found only in the epithelioid areas.
  • All patients had died, and median overall survival was 15 months.
  • Tumors with nuclear BAP1 positivity (54 cases) had a worse prognosis than tumors with the other BAP1 patterns (log-rank p = 0.0006).
  • In multivariate analysis, only stage and nuclear grade were significant independent prognostic factors (nuclear grade II to III vs I: hazard ratio 2.03, 95% CI 1.31 to 3.16). BAP1 was borderline (hazard ratio 0.67, 95% CI 0.45 to 1.01, p = 0.055).
• The authors' conclusion: The authors concluded that BAP1 staining reliably predicts BAP1 mutation when nuclear staining is absent or cytoplasmic. They stated that in BAP1-mutated tumors the staining helped distinguish epithelioid from biphasic subtypes, restricting the biphasic diagnosis to rare cases (3.5% of their series). They also stated that a prognostic impact was confirmed for BAP1 together with nuclear grade and stage.
• Limitations the authors state:
  • Genetic testing was done on a limited number of cases that were not representative of the whole series.
  • In cases with high-grade epithelial and stromal features, the authors could not show for certain that the stromal cells were not cancerous.

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, Pleural Mesothelioma, Histological Subtype, Epithelioid, Prognosis, Sarcomatoid, Biphasic Mesothelioma, Nuclear Grade.

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