Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens

Our plain-English summary of Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens, by H.C. Hwang, B.S. Sheffield, S. Rodriguez, et al (The American Journal of Surgical Pathology, 2016).

The study

• Authors: H.C. Hwang, B.S. Sheffield, S. Rodriguez, K. Thompson, C.H. Tse, A.M. Gown, A. Churg
• Journal: The American Journal of Surgical Pathology
• Published: 2016;40(1):120-6
• Cited by: 123 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The diagnosis of malignant mesothelioma in effusion cytology specimens is controversial. BAP1 immunohistochemistry and p16 fluorescence in situ hybridization (FISH) have recently been reported as reliable markers of malignancy in biopsies of mesothelioma. To determine whether these markers, singly or in combination, might also be useful in effusion cytology specimens, we examined 15 biopsies of epithelial mesotheliomas and 3 benign mesothelial reactions and corresponding effusion cytology paraffin-embedded cell blocks. Four cytology specimens were too scanty for p16 FISH analysis but were interpretable for BAP1 immunohistochemistry. Overall, loss of BAP1 and/or deletion of p16 was seen in 11/11 (100%) of matched cytology and tissue biopsy specimens. BAP1 loss alone was seen in 10/15 (67%) biopsies and 10/15 (67%) cytology specimens. Homozygous deletion of p16 by FISH was found in 12/15 (80%) biopsy specimens and 8/11 (73%) evaluable cytology specimens. Seven of 15 (47%) biopsies and 5/11 (42%) cytology specimens showed loss of both markers. All mesothelioma biopsy/cytology pairs showed exactly the same pattern of BAP1 or p16 retention or loss in the biopsy and cytology specimens. The 2 peritoneal mesothelioma cases demonstrated loss of BAP1 but not p16. None of the benign mesothelial reactions or corresponding cytology specimens showed loss of either marker. We conclude that both BAP1 immunohistochemistry and p16 FISH analysis provide reliable markers of mesothelial malignancy in effusion cytology specimens, especially where the atypical mesothelial proliferation is well sampled. BAP1 is easier to interpret with scanty specimens. On the basis of small numbers of cases, use of both markers appears to increase sensitivity.

In plain English

This laboratory study asked whether two tests could help diagnose malignant mesothelioma from fluid drained from the chest or abdomen (effusion cytology) instead of tissue biopsy. From Vancouver General Hospital files, the authors took 15 patients with epithelial mesothelioma (13 pleural, 2 peritoneal), and also studied 3 with benign mesothelial reactions. Each mesothelioma patient had a biopsy and a fluid sample taken within 3 months; the benign cases also had paired samples. Both samples were tested for loss of the BAP1 protein and for deletion of the p16 (CDKN2A) gene. Among the mesotheliomas, BAP1 loss was seen in 10/15 biopsies and 10/15 fluid samples. p16 deletion was seen in 12/15 biopsies and 8/11 fluid samples; 4 fluid samples had too few cells for the p16 test. All 11 fluid samples tested for both markers showed loss of at least one, and fluid results matched the biopsies. No benign case lost either marker. The authors concluded both tests are potentially very valuable, noted the small numbers, and cautioned that these losses also occur in other cancers. Asbestos exposure was not reported.

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 laboratory (diagnostic) study comparing matched tissue biopsies and effusion cytology cell blocks from the same patients
• Who was studied: 15 patients with epithelial malignant mesothelioma (13 pleural, 2 peritoneal), taken from the surgical pathology files of Vancouver General Hospital, Canada. Each had a biopsy and an effusion cytology specimen obtained within 3 months of each other. The authors also studied 3 patients with benign mesothelial reactions who had paired biopsy and cytology specimens; the article does not say how these benign cases were selected or how far apart their samples were taken. Dates of the cases are not given.
• Exposure: No asbestos or other environmental exposure is reported. The study evaluated two laboratory markers: BAP1 loss by immunohistochemistry (IHC) and homozygous deletion of p16 (CDKN2A) by fluorescence in situ hybridization (FISH).
• Main results:
  • In the mesothelioma cases, BAP1 loss was seen in 10/15 (67%) tissue biopsies and 10/15 (67%) cytology specimens, with 100% concordance between the two.
  • In the mesothelioma cases, p16 deletion by FISH was seen in 12/15 (80%) biopsy specimens and 8/11 (73%) evaluable cytology specimens, again with 100% concordance.
  • In 4 mesothelioma cases the cytology specimen had too few cells for FISH analysis. BAP1 could be evaluated in all cytology specimens.
  • Among mesotheliomas, 7/15 (47%) biopsies and 5/11 (42%) cytology specimens lost both markers, and all cases lost one or both. Counting all 15 cytology specimens, including the scanty ones, 14/15 (93%) showed loss of BAP1, p16 or both.
  • In the pleural mesotheliomas, BAP1 loss was seen in 8/13 (62%) biopsies and 8/13 (62%) cytology specimens. p16 loss was seen in 10/13 (77%) biopsies and 6/9 (67%) evaluable cytology samples.
  • The 2 peritoneal mesothelioma cases showed loss of BAP1 but not loss of p16, in both biopsy and cytology specimens.
  • None of the 3 benign cases showed loss of either marker, in biopsy or cytology specimens.
• The authors' conclusion: The authors concluded that p16 FISH and BAP1 IHC, alone or in combination, are potentially very valuable approaches to diagnosing mesothelioma in effusion cytology specimens. They found BAP1 easier to use in scanty specimens and reported that testing both markers improves sensitivity when there are enough cells. They proposed running BAP1 first and then p16 FISH if BAP1 is not lost.
• Limitations the authors state:
  • The conclusion about combining markers rests on small numbers of cases.
  • No conclusions can be drawn about peritoneal mesothelioma from only 2 cases.
  • p16 FISH needs 50 to 100 cells counted, so very scanty specimens may not be suitable. It also requires assessing only the atypical mesothelial cells among background reactive cells.
  • Loss of either marker also occurs in other malignant tumors, so the cells must first be confirmed as mesothelial, along with supporting clinical evidence.
  • When neither marker is lost, the tests are not useful, and the process may still be a mesothelioma.

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, CDKN2A, Fluorescence In Situ Hybridization (FISH), Malignant Mesothelioma, Cytology, Mesothelioma, Cell Block.

Related studies

• BAP1 Immunohistochemistry and p16 FISH in the Diagnosis of Sarcomatous and Desmoplastic Mesotheliomas — H.C. Hwang, S. Pyott, 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 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)
• BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations — B.S. Sheffield, H.C. Hwang, et al. (2015)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• Sarcomatoid Mesothelioma: A CDKN2A molecular analysis of 53 cases with immunohistochemical correlation with BAP1 — M. Zaleski, N. Kalhor, et al. (2020)

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