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.
无论是从组织病理学还是从细胞学来说，鉴别恶性间皮瘤与间皮细胞反应性增生都是极其困难的。最近，BRCA1相关蛋白1（BAP1）基因变异导致核蛋白缺失在遗传性和散发性间皮瘤都有报道。我们收集了大宗活检标本，包括212例间皮瘤、12例良性间皮肿瘤和42例反应性间皮增生，利用免疫组化方法，检测了BAP1表达对间皮瘤与其他间皮细胞增生的鉴别诊断价值。同时也对70例细胞学标本（包括45例间皮瘤和25例反应性间皮增生）进行了BAP1染色。BAP1在所有良性间皮细胞肿瘤中表达，而139 / 212（66%）间皮瘤BAP1为阴性，尤其是上皮/双相型与肉瘤样/促结缔组织增生性亚型相比（69% vs 15%）。BAP1缺失除两例上皮样恶性间皮瘤显示为杂合性外，其余肿瘤细胞均显示为纯合性。荧光原位杂交技术证实，绝大多数BAP1阴性肿瘤（31/41，76%）BAP1蛋白丢失同时，存在BAP1基因位点纯合性缺失，而9/10 BAP1阳性间皮瘤均正常。活检诊断为反应性间皮增生伴BAP1缺失的病例100%为恶性肿瘤前兆，因为所有6例病例最后均进展为BAP1阴性间皮瘤，而只有3/ 36（8%）BAP1阳性病例进展为间皮瘤。细胞学/细胞块标本，良性间皮细胞总是BAP1阳性，而64%的间皮瘤显示BAP1蛋白质缺失；6例细胞学BAP1阴性的病例组织学诊断为BAP1阴性间皮瘤。BAP1染色对间皮瘤与胸膜和腹膜常见类似病变，如肺癌和卵巢癌的鉴别诊断也有一定价值，其特异性和敏感性分别为99/70%和100/70%。我们的研究结果表明，间皮瘤尤其是上皮样/双相型间皮瘤常常显示BAP1蛋白缺失，通常与BAP1纯合性缺失相关。BAP1免疫染色对良、恶性间皮增生性病变的鉴别诊断是一个前所未有的特异性好（100%）的标志物。间皮细胞发现BAP1缺失应立即重新检查患者；此外，它还可用于确定肿瘤程度和计划手术切除范围。