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

Abstract

Background: The important diagnostic challenge facing the cytopathologist is whether a mesothelial proliferation on effusions represents a malignant mesothelioma (MM) or a benign mesothelial hyperplasia (MH). Here, we evaluated the diagnostic utility of BAP1 immunohistochemistry (IHC) in distinguishing between reactive and neoplastic mesothelial cells. Methods:In pleural and peritoneal effusions from 147 patients with diagnosed MM or with a differential diagnosis of MM and MH, the expression of BAP1 was examined by IHC on paraffinembedded cell blocks (n 5 121) and biopsies (n 5 44). Included were also synchronous and methacronous cytology/biopsy pair samples. BAP1 IHC was evaluated for nuclear staining as positive or negative on target mesothelial cells, with appropriate internal control.Results: In MM cases, loss of BAP1 nuclear staining was observed in 76.5% of the cell blocks and 47.5% of the biopsies. All BAP1-negative cases with a differential diagnosis of benign and malignant mesothelial proliferations were MM at follow-up. All MH cases, the 29% of epithelial MM and the 90% of nonepithelial MM, retained BAP1 expression. Synchronous and methacronous biopsy/cytology pairs showed matching BAP1 results. Conclusion:In effusions with mesotheliomatous cells or atypical mesothelial cells of uncertain significance, negative BAP1 IHC strongly supports a diagnosis of MM. With prudence in interpreting immunostaining, BAP1 may be included in IHC panels for MM cytodiagnosis, given its high specificity and sensitivity. 1 An effusion is the only available sample in specific settings, as in the elderly or in patients with co-morbidities. Based on cytomorphology alone, the differential diagnosis between MM, mesothelial hyperplasia (MH), and metastatic carcinoma may be difficult. It is necessary to use ancillary techniques, primarily immunohistochemistry (IHC). 1 IHC markers to distinguish epithelioid MM from metastatic carcinoma are well-defined, 2,3 whereas those to distinguish epithelioid MM from MH are less definite, except for GLUT-1, IMP-3, Desmin, and EMA. Regarding the practical utility of the latter two markers, Desmin shows low sensitivity 4 and EMA shows low specificity. 5-7Recently, a new marker has been proposed to aid in distinguishing MM from MH, namely BRCA1-associated protein 1 (BAP1 The aim of this study was to evaluate the utility of BAP1 IHC in the diagnosis of MM in effusions. To do this, we investigated the BAP1 protein expression on a large series of cell blocks from pleural/peritoneal effusions, with a definite diagnosis of MM or an uncertain diagnosis between MM and MH, and benign effusions. BAP1 immunostaining was also performed on biopsy samples with the same diagnoses to evaluate the differences between effusion and tissue samples. | M A TE RI A L S A ND M E TH ODSThis study was designated as exempt by the ethics committee due to its retrospective nature; moreover, no protected health information The following formulae of BAP1 testing for the outcome MM were calculated: sensitivity, defined as ...

Pleura revisited: From histology and pathophysiology to pathology and molecular biology

“…Thus, BAP1 loss of expression and homozygous deletion of p16 by FISH confirms a diagnosis of mesothelioma in the case of a mesothelial proliferation but their negative result does not exclude diagnosis and further biopsies should be obtained. Regarding their usefulness in cytologic material, few studies exist showing that p16 deletion can be detected also in this material and that the results correlate well with the underlying invasive mesothelioma tissue. It should be noted, that p16 immunohistochemistry despite being an easier and more accessible technique, it does not replace FISH.…”

“…As for ancillary techniques in this distinction, various markers have been claimed to be of use for the discrimination between malignant and reactive effusion, with most often reported being desmin for benign conditions and GLUT‐1, p53, EMA, IMP‐3 for malignant ones, but their value in individual diagnosis is limited, as when judging them in regard to prognosis, they fail to predict the correct diagnosis . On the contrary, BAP1 immunohistochemical expression and p16 FISH are very promising as they have shown 100% specificity till now in histological specimens . The main caveat is low sensitivity, which varies from 45% to 85% for p16 FISH in epithelioid mesotheliomas but reaches 100% for sarcomatoid ones, and from 15% to 81% for BAP1 .…”

The role of BRCA1‐associated protein 1 in the diagnosis of malignant mesothelioma in effusion and fine‐needle aspiration cytology

“…Few studies have demonstrated high specificity for loss of nuclear BAP1 IHC staining in cytologic samples of MM . The reported sensitivities have ranged from 27% to 81% .…”

“…Few studies have demonstrated high specificity for loss of nuclear BAP1 IHC staining in cytologic samples of MM. [16][17][18][19] The reported sensitivities have ranged from 27% to 81%. 17 Andrici et al reported that 57% of effusion cytology samples of biopsy-confirmed MM exhibited loss of nuclear BAP1 IHC staining.…”

“…Cases were dichotomised into positive and negative cohorts. As previously described, positivity was defined as >50% loss of nuclear BAP1 IHC staining in mesothelial cells (Figure ). Partial positivity or heterogeneous loss of BAP1 IHC was defined as >5% but <50% loss of nuclear BAP1 IHC staining in mesothelial cells.…”