The “Brescia panel” (Claudin‐4 and BRCA‐associated protein 1) in the differential diagnosis of mesotheliomas with epithelioid features versus metastatic carcinomas

Abstract

Background The distinction between mesothelioma with epithelioid features and metastatic carcinoma may be challenging, particularly on cytology. A novel 2‐hit Claudin‐4 and BRCA‐associated protein 1 (BAP1) panel was investigated. Methods The objective of this study was to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the panel on cytology from pleural effusions and matched biopsies, including 49 malignant mesotheliomas on cytology with 43 matched biopsies, 49 normal/reactive mesothelial proliferations, and 49 pleural metastatic carcinomas from different primaries with 21 matched pleural biopsies. The diagnostic role of the 4 categories obtained by crossing the immunostaining results was analyzed. Results Claudin‐4 strongly stained all metastatic carcinomas and tested completely negative in normal mesothelium, benign reactive mesothelial hyperplasia, and malignant mesothelioma. All normal and benign mesothelial proliferations and all carcinomas except 1 were immunoreactive for BAP1, whereas BAP1 loss was observed in 88% of malignant mesotheliomas. The expression of Claudin‐4 alone excluded all benign and malignant mesothelial growth, consistently characterizing all metastatic carcinomas. Double negativity was evident in all malignant mesotheliomas, and double positivity was observed in all metastatic carcinomas. BAP1‐positive/Claudin‐4–negative status was observed only in malignant mesotheliomas and benign mesothelial proliferations. A single metastatic anal squamous cell carcinoma had BAP1‐negative/Claudin‐4–positive staining. Conclusions Claudin‐4 expression was completely specific and sensitive for metastatic carcinoma, excluding mesothelial proliferations. BAP1 staining characterized 98% of metastatic carcinomas and 100% of benign mesothelial proliferations, whereas negativity was observed almost exclusively in mesotheliomas. This 2‐hit panel is probably the best compromise for differentiating malignant mesothelioma and metastatic carcinoma on either cytology or biopsy specimens.

When the Diagnosis of Mesothelioma Challenges Textbooks and Guidelines

“…In order to maximize the diagnostic sensitivity and specificity of immunohistochemical markers, Bernardi et al [ 93 ] demonstrated that the coordinated use of two mesothelial negative biomarkers, namely claudin 4 and BAP1, had the best performance in differential diagnosis between epithelioid or biphasic mesothelioma and metastatic carcinomas. The expression of claudin-4 alone excluded MPM and double negativity was evident in all MPM.…”

“…This study summarized previous experiences singly investigating claudin-4 and BAP1 [ 94 , 95 , 96 , 97 , 98 ], and was performed on cell blocks and the corresponding pleural biopsies. In a practical algorithm [ 93 ], BAP1 and claudin-4 seems to represent the best panel for differentiating MPM with epithelioid features and metastatic carcinoma either on cytology or biopsy. More recently, cytoplasmic loss of methylthioadenosine phosphorylase (MTAP) has emerged as a specific marker of malignancy in mesothelial proliferations [ 99 , 100 , 101 ].…”

The International System for Reporting Serous Fluid Cytopathology: How to Incorporate Molecular Data in Cytopathology Reports

“…Additional ancillary tests may then be employed as necessary. Further studies are expected to validate this promising approach [14,48].…”

The Brescia panel and The International System for Reporting Serous Fluid Cytopathology

“…Although the value of BRCA‐associated protein 1 (BAP1) and Claudin‐4 has been documented by many studies, Bernardi and colleagues were the first to draw attention to these 2 markers through their earlier publications. In this issue of Cancer Cytopathology , they propose the name of Brescia panel for the combination of these 2 markers 1 . The panel presents the opportunity to use only 2 markers, given the high sensitivity and specificity of the panel to differentiate between mesothelioma (BAP1‐negative/Claudin‐4–negative) from metastatic carcinoma (BAP1‐positive/Claudin‐4–positive).…”

“…In this issue of Cancer Cytopathology, they propose the name of Brescia panel for the combination of these 2 markers. 1 The panel presents the opportunity to use only 2 markers, given the high sensitivity and specificity of the panel to differentiate between mesothelioma (BAP1-negative/Claudin-4-negative) from metastatic carcinoma (BAP1-positive/Claudin-4-positive).…”