title: Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology.
abstract: Although most mesotheliomas present with pleural effusions, it is controversial whether mesothelioma can be diagnosed with confidence in effusion cytology. Therefore, an ancillary marker of malignant mesothelial cells applicable in effusions would be clinically valuable. BRCA-1-associated protein (BAP1) is a tumor suppressor gene, which shows biallelic inactivation in approximately half of all mesotheliomas. We investigated whether loss of BAP1 expression by immunohistochemistry can be used to support a diagnosis of mesothelioma in effusion cytology. Immunohistochemistry for BAP1 was performed on cell blocks and interpreted blinded. 43 of 75 (57%) effusions associated with confirmed mesothelioma showed negative staining with positive internal controls. Of 57 effusions considered to have atypical mesothelial cells in the absence of a definitive diagnosis of mesothelioma, 8 cases demonstrated negative staining for BAP1. On follow-up six of these patients received a definitive diagnosis of mesothelioma in the subsequent 14 months (two were lost to follow-up immediately, and mesothelioma could not be excluded). Only 5 of 100 consecutive benign effusions were interpreted as BAP1 negative. One of these patients died soon after and mesothelioma could not be excluded. On unblinded review the four other patients with apparently negative BAP1 staining but no malignancy lacked convincing positive staining in non-neoplastic cells suggesting that BAP1 immunohistochemistry may have initially been misinterpreted. 47 effusions with adenocarcinoma were BAP1 positive. We conclude that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology. We caution that interpretation of BAP1 immunohistochemistry on cell block may be difficult and that convincing positive staining in non-neoplastic cells is required before atypical cells are considered negative. We also note that BAP1 loss is not a sensitive test as it occurs in only half of all mesotheliomas and cannot be used to exclude the diagnosis.
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Juliana
authors.initials: J
authors.lastname: Andrici
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Amy
authors.initials: A
authors.lastname: Sheen
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Loretta
authors.initials: L
authors.lastname: Sioson
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Wardell
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.|Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Watson
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.|Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Mahsa S
authors.initials: MS
authors.lastname: Ahadi
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.|Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Farzin
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|Histopath Pathology, Sydney, NSW, Australia.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Toon
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Sydney, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.|Sydney Vital Translational Research Centre, Royal North Shore Hospital, Pacific Highway St Leonards, Sydney, NSW, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D003581:Cytodiagnosis / Q000379:methods; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis*; D008875:Middle Aged; D016066:Pleural Effusion, Malignant / Q000175:diagnosis / Q000209:etiology*; D010997:Pleural Neoplasms / Q000175:diagnosis*; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000096:biosynthesis*; D043222:Ubiquitin Thiolesterase / Q000032:analysis / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase