Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry

Our plain-English summary of Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry, by T. Hida, M. Hamasaki, S. Matsumoto, et al (Lung Cancer, 2017).

The study

• Authors: T. Hida, M. Hamasaki, S. Matsumoto, A. Sato, T. Tsujimura, K. Kawahara, A. Iwasaki, T. Okamoto, Y. Oda, H. Honda, K. Nabeshima
• Journal: Lung Cancer
• Published: 2017;104:98-105
• Cited by: 135 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Differentiating malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH) is still challenging. Detection of homozygous deletion (HD) of 9p21 region including p16INK4A (p16) by fluorescence in situ hybridization (FISH) and immunohistochemical detection of loss of BRCA1 associated protein 1 (BAP1), are reliable markers for MPM diagnosis. However, not all laboratories are equipped to perform 9p21 FISH; immunohistochemistry (IHC) is a more common and feasible technique. Thus, we sought to develop a IHC-based method that could predict the deletion of p16 in MPM in concordance with 9p21 FISH.

Materials And Methods: We examined the expression of the 9p21.3-related proteins (p14, p15, p16, and methylthioadenosine phosphorylase (MTAP)) and BAP1 using IHC in 51 MPM and 25 RMH cases, and assessed their correlation with HD of p16 detected by FISH. The diagnostic usefulness of IHC of the 9p21.3-related proteins and BAP1 and their combinations was assessed using the cut-off values set by receiver operating characteristic (ROC) analysis.

Results: Among the 9p21.3-related proteins, MTAP IHC findings showed best concordance with 9p21 FISH results (kappa coefficient of 0.69) and a specificity of 100%. We also examined the combinations of MTAP IHC with the other products. The loss of p16 and MTAP had better concordance (kappa coefficient of 0.71), although lower specificity (85%). For differentiating MPM from RMH, only MTAP showed 100% specificity among the 9p21.3-related proteins, as did BAP1 IHC and 9p21 FISH. Among BAP1 combinations, only that of BAP1 with MTAP showed 100% specificity. Its sensitivity was 76.5%, which was lower than BAP1 IHC and 9p21 FISH combination (84.3%), but higher than BAP1 IHC alone (60.8%) or 9p21 FISH alone (60.8%).

Conclusions: A combination of MTAP or BAP1 loss detected by IHC can likely detect MPM with good sensitivity and 100% specificity, and serve as useful ancillary IHC for discriminating MPM from RMH.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In plain English

This laboratory study tested whether routine tissue staining (immunohistochemistry, IHC) could help tell malignant pleural mesothelioma (MPM) apart from reactive mesothelial hyperplasia (RMH), a non-cancerous condition whose appearance can mimic MPM. The authors examined archived tissue from 51 MPM cases (44 epithelioid, 7 biphasic; sarcomatoid tumors excluded) and 25 RMH cases from patients with bullae, collected in Fukuoka, Japan, between 2001 and 2015. They stained for loss of the proteins p14, p15, p16, MTAP and BAP1 and compared the results with a genetic test, 9p21 FISH. Among the proteins tested, MTAP staining agreed best with FISH (kappa 0.69). MTAP loss was seen in 23 of 51 MPM cases and none of the 25 RMH cases. Loss of BAP1 or MTAP flagged 76.5% of MPM cases and no RMH cases. That was higher than BAP1 staining alone or FISH alone (each 60.8%) but lower than BAP1 plus FISH (84.3%). The authors concluded that combined MTAP and BAP1 staining could serve as a useful additional test. They named the relatively small sample size as a major limitation. The study did not examine asbestos exposure.

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: Diagnostic test comparison on archived pathology tissue: immunohistochemistry for 9p21.3-related proteins and BAP1 compared with 9p21 FISH, with cut-offs set by ROC analysis
• Who was studied: 51 malignant pleural mesothelioma cases (42 male, 9 female; mean age 63.8; 44 epithelioid, 7 biphasic) and 25 reactive mesothelial hyperplasia cases (all male; mean age 34.4) from patients with bullae formation, from the pleural lesion files of Fukuoka University Hospital and Kyushu University Hospital, Japan, 2001 to 2015; sarcomatoid tumors excluded
• Exposure: No asbestos exposure was studied. The study evaluated laboratory tests: immunohistochemistry for p14, p15, p16, MTAP and BAP1, and 9p21 FISH for homozygous deletion of p16.
• Main results:
  • For predicting p16 homozygous deletion by FISH among the 51 MPM cases, MTAP IHC had the best concordance: loss in 23 of 31 FISH-positive and 0 of 20 FISH-negative cases, sensitivity 74.2%, specificity 100%, kappa 0.69
  • Loss of p16 or MTAP in combination had slightly better concordance with FISH (kappa 0.71) but lower specificity (85%)
  • Among the 51 MPM cases, loss or decrease was found by IHC in 28 (54.9%) for p14, 10 (19.6%) for p15, 21 (41.2%) for p16, 23 (45.1%) for MTAP and 31 (60.8%) for BAP1
  • 31 (60.8%) of the 51 MPM cases were p16 homozygous deletion-positive by FISH
  • Among the 25 RMH cases, p14, p15 and p16 showed loss or decrease in 9, 1 and 5 cases respectively, while none showed MTAP or BAP1 loss or FISH deletion
  • Combining p14, p15, p16 and MTAP raised sensitivity for distinguishing MPM from RMH to 74.5% but lowered specificity to 60.0%
  • BAP1 plus MTAP IHC had 100% specificity and 76.5% sensitivity for MPM versus RMH. This was lower than BAP1 IHC plus 9p21 FISH (84.3%) but significantly higher than BAP1 IHC alone or 9p21 FISH alone (each 60.8%; P = 0.0386 and 0.0229)
  • MTAP loss was found in 8 of the 20 MPM cases with preserved BAP1 expression
• The authors' conclusion: The authors concluded that combined MTAP and/or BAP1 loss detected by IHC can likely detect MPM with good sensitivity, higher than BAP1 IHC alone or 9p21 FISH alone. They added that it could serve as a useful ancillary method for distinguishing MPM from RMH, although BAP1 IHC combined with 9p21 FISH remains the most accurate ancillary tool.
• Limitations the authors state:
  • Relatively small sample size
  • The status of the p14ARF, p15INK4B, p16 and MTAP genes was not investigated directly
  • Sarcomatoid tumors were excluded; more sarcomatoid cases are needed to judge MTAP IHC in that subtype

Topics

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

Medical terms in this study, explained in our Lexicon: MTAP, BAP1, Mesothelioma, Fluorescence In Situ Hybridization (FISH), Immunohistochemistry, Pleural Mesothelioma, Reactive Mesothelial Hyperplasia, Homozygous Deletion.

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)
• CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival — A.M. Krasinskas, D.L. Bartlett, et al. (2010)
• 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)
• Evaluation of MTAP immunohistochemistry loss of expression in ovarian serous borderline tumors as a potential marker for prognosis and progression — N. Nilforoushan, N.A. Moatamed (2020)
• 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)

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