BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations

Our plain-English summary of BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations, by B.S. Sheffield, H.C. Hwang, A.F. Lee, et al (The American Journal of Surgical Pathology, 2015).

The study

• Authors: B.S. Sheffield, H.C. Hwang, A.F. Lee, K. Thompson, S. Rodriguez, C.H. Tse, A.M. Gown, A. Churg
• Journal: The American Journal of Surgical Pathology
• Published: 2015;39(7):977-82
• Cited by: 139 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

A variety of immunohistochemical (IHC) stains have been proposed to mark either benign or malignant mesothelial proliferations. Loss of the p16 tumor suppressor (CDKN2A), through homozygous deletions of 9p21, is a good marker of mesotheliomas but lacks sensitivity. Recent reports indicate that some mesotheliomas are associated with loss of BRCA-associated protein 1 (BAP1) expression. Here we investigate BAP1 and p16 as potential markers of malignancy and compare test characteristics with previously proposed markers using a well-characterized tissue microarray. BAP1 protein expression was interrogated by IHC. The p16 locus was examined by fluorescence in situ hybridization (FISH) directed toward chromosome 9p21. Loss of BAP1 was identified in 7/26 mesotheliomas and 0/49 benign proliferations. Loss of p16 was identified in 14/27 mesotheliomas and 0/40 benign proliferations, yielding 100% specificity and positive predictive value for each marker. Together, BAP1 IHC and p16 FISH were 58% sensitive for detecting malignancy. Various combinations of p53, EMA, IMP3, and GLUT1 showed reasonably high specificity (96% to 98%) but poor to extremely poor sensitivity. Combined BAP1 IHC/p16 FISH testing is a highly specific method of diagnosing malignant mesotheliomas when the question is whether a mesothelial proliferation is benign or malignant and is particularly useful when tissue invasion by mesothelial cells cannot be demonstrated. However, combined BAP1/p16 FISH testing is not highly sensitive, and negative results do not rule out a mesothelioma. The test characteristics of previously proposed markers EMA, p53, GLUT1, IMP3 suggest that, even in combination, these markers are not useful tools in this clinical setting.

In plain English

This laboratory study tested whether two markers could help pathologists tell benign growths of mesothelial cells from malignant mesothelioma. The authors used a tissue microarray, a slide holding small samples from many cases. It contained 31 malignant mesotheliomas (27 pleural, 3 peritoneal, 1 pericardial) and 52 benign mesothelial proliferations. The original diagnosis served as the reference. They stained for the BAP1 protein and used a genetic test (FISH) to look for deletion of the p16 gene. BAP1 was lost in 7 of 26 mesotheliomas and none of 49 benign cases. p16 was deleted in 14 of 27 mesotheliomas and none of 40 benign cases. With both tests together, 14 of 24 mesotheliomas showed a loss, and none of 37 benign cases did. Combinations of older markers (IMP3, GLUT1, p53, EMA), partly using the authors' earlier data on the same samples, reached 96% to 98% specificity but detected 20% to 43% of mesotheliomas. The authors concluded that the pair allows a diagnosis in about 60% of mesotheliomas, but a negative result cannot exclude mesothelioma. The article did not address 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 accuracy study on a previously described tissue microarray, with the original histologic diagnosis as the reference standard
• Who was studied: 83 mesothelial proliferations on a tissue microarray: 31 malignant mesotheliomas (27 pleural, 3 peritoneal, 1 pericardial) and 52 benign mesothelial proliferations. Indeterminate cases were excluded. Dates and patient details are not given.
• Main results:
  • BAP1 loss was seen in 7 of 26 scorable malignant mesotheliomas (27%)
  • No benign mesothelial proliferation showed BAP1 loss (0 of 49)
  • For diagnosing malignant mesothelioma, BAP1 loss had a sensitivity of 27% (95% CI 17%-37%) and a specificity of 100% (100%-100%)
  • p16 deletion by FISH was seen in 14 of 27 malignant mesotheliomas (52%) and in 0 of 40 benign proliferations
  • For diagnosing malignant mesothelioma, p16 FISH had a sensitivity of 52% (40% to 64%) and a specificity of 100% (100% to 100%)
  • Combining the two tests, 14 of 24 mesotheliomas showed either BAP1 loss or p16 deletion
  • Neither BAP1 loss nor p16 deletion was found in any of the 37 benign cases tested with both markers
  • The combined BAP1/p16 panel had a sensitivity of 58% (46%-71%) for mesothelioma, with 100% specificity
  • Used alone, p53 had a specificity of 53% and EMA a specificity of 84%
  • p53 positivity together with strong membranous EMA staining had 88% specificity and 25% sensitivity
  • Previously published data on the same microarray showed that IMP3 plus GLUT1 had 43% sensitivity and 96% specificity
  • Adding p53 or EMA to IMP3 plus GLUT1 lowered sensitivity from 43% to 36% and 20%, respectively
  • Specificity rose modestly, from 96% to 98%, with the combined panel of EMA, IMP3 and GLUT1
• The authors' conclusion: The authors concluded that a BAP1/p16 FISH panel allows a diagnosis of malignant mesothelioma in about 60% of cases, but that it is not sensitive enough to exclude mesothelioma when the panel result is negative.
• Limitations the authors state:
  • The test characteristics were calculated on small tissue microarray sections. For FISH, this limited the number of nuclei that could be assessed.
  • The tissue microarray method limits assessment of variation within a tumor
  • The approach only applies to growths already established as mesothelial. It cannot separate mesothelioma from other tumors.
  • Retained BAP1 or p16 does not mean a growth is benign, because 40% of mesotheliomas will not show loss of these markers
  • The authors cautioned against applying the tests blindly. They stated the tests should be reserved for cases in which tissue invasion cannot be demonstrated or is equivocal.

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, Fluorescence In Situ Hybridization (FISH), CDKN2A, Homozygous Deletion, Mesothelioma, GLUT1, Malignant Mesothelioma.

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)
• 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)
• Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ Fails to Separate Benign From Malignant Mesothelial Proliferations — B.S. Sheffield, J. Lorette, et al. (2016)
• BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations — M. Cigognetti, S. Lonardi, et al. (2015)
• Highlights of the 14th international mesothelioma interest group meeting: Pathologic separation of benign from malignant mesothelial proliferations and histologic/molecular analysis of malignant mesothelioma subtypes — A. Churg, K. Nabeshima, et al. (2018)

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