Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma

Our plain-English summary of Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma, by D.B. Chapel, J.L. Hornick, J. Barlow, et al (Modern Pathology, 2022).

The study

• Authors: D.B. Chapel, J.L. Hornick, J. Barlow, R. Bueno, L.M. Sholl
• Journal: Modern Pathology
• Published: 2022;35(10):1383-1397
• Cited by: 64 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural mesotheliomas (51 epithelioid, 27 biphasic, 6 sarcomatoid) by a hybrid-capture next-generation sequencing (NGS) panel including complete coverage of coding and splicing regions for BAP1, CDKN2A/MTAP, NF2, and TP53 and correlated molecular findings with diagnostic immunostains for BAP1, MTAP, Merlin, and p53, respectively. Fifty-seven reactive mesothelial proliferations served as benign comparators. Loss of BAP1, MTAP, and Merlin protein expression were, respectively, 54%, 46%, and 52% sensitive and 100% specific for mesothelioma. Two-marker immunopanels of BAP1 + MTAP, BAP1 + Merlin, and MTAP + Merlin were 79%, 85%, and 71% sensitive for mesothelioma, while a three-marker immunopanel of BAP1 + MTAP + Merlin was 90% sensitive. Diffuse (mutant-pattern) p53 immunostaining was seen in only 6 (7%) tumors but represented the only immunohistochemical abnormality in 2 cases. Null-pattern p53 was not specific for malignancy. An immunopanel of BAP1 + MTAP + Merlin + p53 was 93% sensitive for mesothelioma, and panel NGS detected a pathogenic alteration in BAP1, MTAP, NF2, and/or TP53 in 95%. Together, 83 (99%) of 84 tumors showed a diagnostic alteration by either immunohistochemistry or panel NGS. Adding Merlin to the standard BAP1 + MTAP immunopanel increases sensitivity for mesothelioma without sacrificing specificity. p53 immunohistochemistry and panel NGS with complete coverage of BAP1, CDKN2A/MTAP, TP53, and NF2 may be useful in diagnostically challenging cases.

© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.

In plain English

This retrospective study at Brigham and Women's Hospital, Boston, examined 84 pleural mesotheliomas (51 epithelioid, 27 biphasic, 6 sarcomatoid) diagnosed from December 2012 to August 2020. They were compared with 57 benign reactive mesothelial proliferations. The authors stained tissue for BAP1, MTAP, Merlin and p53 and ran a gene-sequencing panel on the tumors. BAP1 staining was lost in 45 tumors (54%), MTAP in 39 (46%) and Merlin in 44 (52%). All 57 reactive samples kept MTAP and Merlin. Fifty-six kept BAP1; the one that lost it met criteria for mesothelioma in situ but could not be characterized further because the patient died of esophageal adenocarcinoma after 9 months. A diffuse p53 pattern appeared in 6 (7%) tumors. Adding Merlin to the standard BAP1 plus MTAP stains raised sensitivity from 79% to 90%. Sequencing found a relevant gene change in 80 (95%) of 84 tumors. Sequencing plus the four stains found a diagnostic change in all but one tumor. The authors concluded that adding Merlin improves the standard panel and may be recommended after independent validation. The study covered only pleural mesothelioma and did not examine asbestos.

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 validation study comparing immunohistochemistry (tissue staining) with next-generation gene sequencing in mesothelioma, with benign reactive lesions as comparators
• Who was studied: 84 pleural mesotheliomas (51 epithelioid, 27 biphasic, 6 sarcomatoid) from resection specimens, diagnosed between December 2012 and August 2020 at Brigham and Women's Hospital, Boston. The comparators were 57 pleural reactive mesothelial proliferations diagnosed between 2013 and 2019, with median follow-up of 60 months.
• Main results:
  • Loss of BAP1 staining was seen in 45 (54%) of the 84 mesotheliomas. BAP1 was retained in 56 (98%) of 57 reactive proliferations.
  • The one apparently reactive proliferation with BAP1 loss met criteria for mesothelioma in situ. It could not be characterized further because the patient died of esophageal adenocarcinoma after 9 months of follow-up.
  • MTAP staining was lost in 39 (46%) mesotheliomas. All 57 reactive proliferations retained MTAP.
  • Merlin staining was lost in 44 (52%) mesotheliomas. All 57 reactive proliferations retained Merlin.
  • Diffuse (mutant-pattern) p53 staining was seen in 6 (7%) tumors. Null-pattern p53 staining was no more common in mesothelioma than in reactive proliferations (P=0.18).
  • Adding Merlin to BAP1 plus MTAP raised sensitivity from 79% to 90% across all mesotheliomas (P=0.03).
  • Gene sequencing alone found a pathogenic alteration in BAP1, CDKN2A, TP53 and/or NF2 in 80 (95%) of 84 tumors. Sequencing combined with the four-marker stain panel found diagnostic alterations in all but one tumor.
• The authors' conclusion: The authors concluded that adding Merlin significantly improves the standard BAP1 plus MTAP stain panel, and that routine use of this three-marker panel may be recommended following independent validation.
• Limitations the authors state:
  • Only pleural mesotheliomas were studied, so the findings may not apply to peritoneal or other sites.
  • Only 6 sarcomatoid mesotheliomas were included, which limits conclusions about this type.
  • The study did not include FISH or other cytogenetic testing.
  • In some cases, staining and sequencing were done on different specimens or tissue blocks.
  • The authors said independent studies of p53 and Merlin staining are needed before routine use.

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, MTAP, Merlin, Immunohistochemistry, Pleural Mesothelioma, Mesothelioma, Epithelioid, Biphasic Mesothelioma.

Related studies

• A combination of MTAP and BAP1 immunohistochemistry in pleural effusion cytology for the diagnosis of mesothelioma — Y. Kinoshita, T. Hida, et al. (2018)
• Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia — M. Yoshimura, Y. Kinoshita, et al. (2019)
• A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis — Y. Kinoshita, M. Hamasaki, et al. (2018)
• 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)
• 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)

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