BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations

Abstract

The distinction between malignant mesothelioma and reactive mesothelial proliferation can be challenging both on histology and cytology. Recently, variants of the BRCA1-associated protein 1 (BAP1) gene resulting in nuclear protein loss were reported in hereditary and sporadic mesothelioma. Using immunohistochemistry, we evaluated the utility of BAP1 expression in the differential diagnosis between mesothelioma and other mesothelial proliferations on a large series of biopsies that included 212 mesotheliomas, 12 benign mesothelial tumors, and 42 reactive mesothelial proliferations. BAP1 stain was also performed in 70 cytological samples (45 mesotheliomas and 25 reactive mesothelial proliferations). BAP1 was expressed in all benign mesothelial tumors, whereas 139/212 (66%) mesotheliomas were BAP1 negative, especially in epithelioid/biphasic compared with sarcomatoid/desmoplastic subtypes (69% vs 15%). BAP1 loss was homogeneous in neoplastic cells except for two epithelioid mesotheliomas showing tumor heterogeneity. By fluorescence in situ hybridization, BAP1 protein loss was paralleled by homozygous deletion of the BAP1 locus in the vast majority of BAP1-negative tumors (31/41, 76%), whereas 9/10 BAP1-positive mesotheliomas were normal. In biopsies interpreted as reactive mesothelial proliferation BAP1 loss was 100% predictive of malignancy, as all 6 cases subsequently developed BAP1-negative mesothelioma, whereas only 3/36 (8%) BAP1-positive cases progressed to mesothelioma. On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma. BAP1 stain also showed utility in the differential of mesothelioma from most common pleural and peritoneal mimickers, such as lung and ovary carcinomas, with specificity and sensitivity of 99/70% and 100/70%, respectively. Our results show that BAP1 protein is frequently lost in mesothelioma, especially of epithelioid/biphasic subtype and is commonly associated with homozygous BAP1 deletion. BAP1 immunostain represents an excellent biomarker with an unprecedented specificity (100%) in the distinction between benign and malignant mesothelial proliferations. Finding BAP1 loss in mesothelial cells should prompt to immediately reevaluate the patient; moreover, it might be useful in mapping tumor extent and planning surgical resection.

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

“…23 As well, the 100% specificity for BAP1 has been similarly reported in a few studies. 8,23 However, other studies reported lower specificity. For instance, Andrici et al 9 reported 95% specificity (interpreted by them as more likely due to artefactual negative staining), and Walts et al (Table 1), specificity would be 88.6% in our case series (by excluding from the formulae cases with an initial diagnosis uncertain between MM and MH).…”

“…8,9,[21][22][23][24][25] 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.…”

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…Cigognetti and co-workers provided evidence of homozygous deletions in association with heterozygous deletions of the BAP1 locus by FISH analysis in a few cases among their IHC BAP1-negative MM series [40]. Intra-tumor differences in BAP1 LOH were recently reported in sarcomatoid and carcinomatous elements in clear renal cell carcinomas [41].…”

Clinical Pearls in Anaesthesia for Pleurectomy/Decortication for Malignant Mesothelioma

“…Biallelic inactivation of the tumor suppressor gene BRCA1-associated protein 1 (BAP1) occurs in several cancers (colorectal, renal and malignant mesothelioma). BAP1 deletion on staining and immunohistochemistry is the latest discovery, of special interest to the pathologist, and a very useful marker for a definitive diagnosis of malignant mesothelioma distinguishing it from atypical reactive mesothelial proliferations in effusions [5,6]. Presence of BAP1 deletion increases cancer-specific mortality and risk of recurrence in all cancers, except mesothelioma, where it correlates with a better prognosis [7].…”