title: Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities.
abstract: A growing number of studies suggest critical tumor suppressor roles of the SWI/SNF chromatin remodeling complex in a variety of human cancers. The recent discovery of SMARCA4-deficient thoracic sarcomas has added to the list of tumor groups with the SMARCA4 inactivating mutation. To better characterize these tumors and establish their nosological status, we undertook a clinicopathological and molecular analysis of 12 SMARCA4-deficient thoracic sarcomas and compared them with three potentially related disease entities. Eleven men and one woman with SMARCA4-deficient thoracic sarcomas (aged 27-82 years, median 39 years) were included in the study. Most of the patients had heavy smoking exposure and pulmonary emphysema/bullae. The primary tumors were large and involved the thoracic region in all cases and simultaneously affected the abdominal cavity in 3 cases. The patients followed a rapid course, with a median survival of 7 months. Histologically, all tumors showed diffuse sheets of mildly dyscohesive, relatively monotonous, and undifferentiated epithelioid cells with prominent nucleoli. Immunohistochemically, all tumors demonstrated a complete absence (8 cases) or diffuse severe reduction (4 cases) of SMARCA4 expression. Cytokeratin, CD34, SOX2, SALL4, and p53 were expressed in 6/12, 10/12, 10/12, 10/12, and 7/10 cases, respectively. SMARCA2 expression was deficient in 11/12 cases, and none (0/8) expressed claudin-4. Targeted sequencing was performed in 5 cases and demonstrated the inactivating SMARCA4 mutation in each case and uncovered alterations in TP53 (5/5), NF1 (2/5), CDKN2A (2/5), KRAS (1/5), and KEAP1 (1/5), among others. Comparative analysis supported the distinctiveness of SMARCA4-deficient thoracic sarcomas as they were distinguishable from 13 malignant rhabdoid tumors, 15 epithelioid sarcomas, and 12 SMARCA4-deficient lung carcinomas based on clinicopathological and immunohistochemical grounds. SMARCA4-deficient thoracic sarcomas constitute a unique, highly lethal entity that requires full recognition and differentiation from other epithelioid malignancies involving the thoracic region.
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.|Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.|Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: Division of Translational Genomics, Exploratory Oncology Research &Clinical Trial Center, National Cancer Center, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.|Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodaira
authors.affiliation: Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Motoi
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Motoi
authors.affiliation: Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.|Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Yonemori
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.affiliation: Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Shun-Ichi
authors.initials: SI
authors.lastname: Watanabe
authors.affiliation: Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.|Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawai
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Department of Pathology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kishimoto
authors.affiliation: Division of Translational Genomics, Exploratory Oncology Research &Clinical Trial Center, National Cancer Center, Tokyo, Japan.|Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hiraoka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000235:genetics; D004265:DNA Helicases / Q000172:deficiency* / Q000235:genetics; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D012509:Sarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013899:Thoracic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases