BAP1 Immunohistochemistry and p16 FISH in the Diagnosis of Sarcomatous and Desmoplastic Mesotheliomas

Abstract

The separation of sarcomatous and desmoplastic mesotheliomas from benign organizing pleuritis can be morphologically very difficult. Deletion of p16 (CDKN2A) by fluorescence in situ hybridization (FISH) testing appears to be a reliable marker of malignancy in mesothelial proliferations, and more recently it has been reported that, in this setting, loss of BAP1 by immunohistochemistry is only seen in malignant mesotheliomas. To determine how useful these tests are with sarcomatous and desmoplastic mesotheliomas, we examined 20 such tumors. Loss of BAP1 was seen in 3/20 (15%) and deletion of p16 by FISH was seen in 16/20 (80%) cases. Loss of one or the other marker was observed in 17/20 (85%). We also examined 13 sarcomatoid carcinomas, an important differential diagnosis of sarcomatoid mesotheliomas, and found that BAP1 was never lost, but p16 was deleted in 3/11 (27%). We conclude that: (1) BAP1 immunohistochemistry is relatively insensitive in the context of sarcomatous and desmoplastic mesotheliomas, but as a matter of time and cost efficiency may nonetheless be a useful first approach to the problem; (2) deletion of p16 by FISH is considerably more sensitive, but there remain a proportion of cases in which p16 is not deleted; (3) a small improvement in sensitivity can be achieved by using both markers; (4) in the context of a spindle cell malignant tumor in the pleura or peritoneum, which morphologically might be a metastatic sarcomatoid carcinoma or a mesothelioma, the finding of BAP1 loss favors mesothelioma, but p16 FISH cannot be used to separate sarcomatous mesotheliomas from sarcomatoid carcinomas.

Loss of BRCA1‐associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions

“…Considering the final diagnosis of MM cases and regardless of specimen type, the difference in BAP1 negativity between epithelial and nonepithelial variants (71% vs 10%) is in line with other studies related to MM 13,20 or to other tumors, as uveal melanoma. 28 Regarding the site of MM, peritoneal tumors showed a lower percentage of BAP1 negativity compared to pleural tumors (66% vs 71%, respectively), at variance with previous studies 16 ; however, this difference is not relevant.…”

“…So far, the BAP1 antibody has been tested primarily on biopsies. [13][14][15][16][17][18][19][20] Only a few studies have used BAP1…”

Novel insights and recent discoveries on the genetics and pathogenesis of malignant mesothelioma

“…Loss of BAP1 nuclear immunoreactivity can be found in 40-70% of pleural and peritoneal mesotheliomas, whereas BAP1 nuclear expression is retained in all reactive mesothelial proliferations (7,15,16). Nonetheless, it is important to note that loss of BAP1 protein expression is a relatively specific but not a sensitive finding in the diagnosis of malignant mesothelioma, since a significant subset of malignant mesothelioma retained nuclear BAP1 expression, including those tumors with rare large structural alterations (see below) and most cases with sarcomatoid or desmoplastic histology (17).…”

Molecular markers and new diagnostic methods to differentiate malignant from benign mesothelial pleural proliferations: a literature review

“…Moreover, BAP1 and p16 have been specifically investigated for the discernment between sarcomatous and desmoplastic mesotheliomas from benign organizing pleuritis. Hwang et al analyzed 20 sarcomatous and desmoplastic mesotheliomas, determining that BAP1 IHC was relatively insensitive in this context and that deletion of p16 by FISH was considerably more sensitive; however, a proportion of cases remained in which p16 was not deleted (37). BAP1 and p16 examinations do not allow the detection of all MPM cases, even when the combined assay approach is utilized, because the two markers are only deleted in a proportion of mesotheliomas.…”