title: Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma.
abstract: Malignant mesothelioma is a highly aggressive neoplasm, and the histologic subtype is one of the most reliable prognostic factors. Some biphasic mesotheliomas are difficult to distinguish from epithelioid mesotheliomas with atypical fibrous stroma. The aim of this study was to analyze p16/CDKN2A deletions in mesotheliomas by fluorescence in situ hybridization (FISH) and BAP1 immunohistochemistry to evaluate their potential role in the diagnosis of biphasic mesothelioma. We collected 38 cases of pleural mesotheliomas. The results of this study clearly distinguished 29 cases of biphasic mesothelioma from 9 cases of epithelioid mesothelioma. The proportion of biphasic mesotheliomas with homozygous deletions of p16/CDKN2A in total was 96.6% (28/29). Homozygous deletion of p16/CDKN2A was observed in 18 (94.7%) of 19 biphasic mesotheliomas with 100% concordance of the p16/CDKN2A deletion status between the epithelioid and sarcomatoid components in each case. Homozygous deletion of the p16/CDKN2A was observed in 7 (77.8%) of 9 epithelioid mesotheliomas but not in fibrous stroma. BAP1 loss was observed in 5 (38.5%) of 13 biphasic mesotheliomas and in both epithelioid and sarcomatoid components. BAP1 loss was observed in 5 (62.5%) of 8 epithelioid mesotheliomas but not in fibrous stroma. Homozygous deletion of p16/CDKN2A is common in biphasic mesotheliomas, and the analysis of only one component of mesothelioma is sufficient to show that the tumor is malignant. However, compared with histology alone, FISH analysis of the p16/CDKN2A status and BAP1 immunohistochemistry in the spindled mesothelium provide a more objective means to differentiate between biphasic mesothelioma and epithelioid mesothelioma with atypical stromal cells.
authors.affiliation: Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Owada-Shinden 477-96, Yachiyo, Chiba 276-8524, Japan. Electronic address: wu.dier@twmu.ac.jp.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Owada-Shinden 477-96, Yachiyo, Chiba 276-8524, Japan. Electronic address: hiroshima.kenzo@twmu.ac.jp.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.affiliation: Department of General Thoracic Surgery and Asbestos Disease Center, Chiba Rosai Hospital, Tatsumidai-higashi 2-16, Ichihara 290-0003, Japan. Electronic address: toshikazu_yusa@chibah.johas.go.jp.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yusa
authors.affiliation: Department of Pathology, Chiba Rosai Hospital, Tatsumidai-higashi 2-16, Ichihara 290-0003, Japan. Electronic address: oz-d@umin.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ozaki
authors.affiliation: Department of Thoracic Surgery, Tokyo Women's Medical University Yachiyo Medical Center, Owada-Shinden 477-96, Yachiyo, Chiba 276-8524, Japan. Electronic address: eitetsuk@gmail.com.
authors.forename: Eitetsu
authors.initials: E
authors.lastname: Koh
authors.affiliation: Department of Thoracic Surgery, Tokyo Women's Medical University Yachiyo Medical Center, Owada-Shinden 477-96, Yachiyo, Chiba 276-8524, Japan. Electronic address: sekine.yasuo@twmu.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sekine
authors.affiliation: Department of Pathology, Fukuoka University School of Medicine and Hospital, Nanakuma 7-45-1, Jonan-ku, Fukuoka 814-0180, Japan. Electronic address: matsu@minf.med.fukuoka-u.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Department of Pathology, Fukuoka University School of Medicine and Hospital, Nanakuma 7-45-1, Jonan-ku, Fukuoka 814-0180, Japan. Electronic address: kaznabes@fukuoka-u.ac.jp.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nabeshima
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, Hyogo 663-8501, Japan. Electronic address: asato@hyo-med.ac.jp.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, Hyogo 663-8501, Japan. Electronic address: tohru@hyo-med.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.affiliation: Department of Thoracic Surgery, Yarita Hospital, Goi 899, Ichihara 290-0056, Japan. Electronic address: hisa46ym@za2.so-net.ne.jp.
authors.forename: Hisami
authors.initials: H
authors.lastname: Yamakawa
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan. Electronic address: ytada@faculty.chiba-u.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Department of Surgery, School of Medicine, Toho University, Omorinishi 6-11-1, Ota-ku, Tokyo 143-8541, Japan. Electronic address: hideaki.shimada@med.toho-u.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Nitona 666-2, Chuo-ku, Chiba, Chiba 260-8717, Japan. Electronic address: mtagawa@chiba-cc.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis* / Q000235:genetics*; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000175:diagnosis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: Fluorescence in situ hybridization; Mesothelioma; p16