title: 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.
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Cigognetti
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Fisogni
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Balzarini
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Vilma
authors.initials: V
authors.lastname: Pellegrini
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tironi
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bercich
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Bugatti
authors.affiliation: Department of Pathology, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Department of Pathology, Ospedale Dell'Angelo, Venezia-Mestre, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Murer
authors.affiliation: Unit of Surgical Pathology, S. Chiara Hospital, Trento Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.affiliation: Unit of Surgical Pathology, S. Chiara Hospital, Trento Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giuliani
authors.affiliation: Department of Pathology, Azienda Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cavazza
authors.affiliation: Department of Pneumology, Spedali Civili, Brescia, Italy.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Marchetti
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, Brescia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D003937:Diagnosis, Differential; D015536:Down-Regulation; D004848:Epithelium / Q000201:enzymology* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008654:Mesothelioma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000032:analysis* / Q000235:genetics; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase