title: Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases.
abstract: Clear cell sarcoma (CCS) of soft tissue is a rare sarcoma with morphologic similarities to malignant melanoma but a distinct genetic background including a chromosomal translocation, t(12;22)(q13;q12), or a resultant EWSR1-ATF1 fusion gene. In addition, the tumors occurring in the gastrointestinal tract may have a variant fusion gene EWSR1-CREB1. This study analyzed the clinicopathologic and molecular genetic features of 33 CCSs of soft tissue. The patients' ages ranged from 13 to 73 years (median, 30 y), and there was a male predominance (20 males, 13 females). The tumors were located in the deep soft tissues of the extremities (N=25) or in the trunk or limb girdles (N=8). The median tumor size was 4 cm (range, 1 to 15 cm). The tumor cells were either spindle or epithelioid, and they were arranged predominantly in a short fascicular (N=19) or a solid sheetlike growth pattern (N=14). Minor histologic variations included the existence of rhabdoid cells (N=8), bizarre pleomorphic cells (N=6), alveolar structures due to loss of cellular cohesion (N=3), and a seminomalike pattern (N=2). Tumor necrosis was evident in 14 tumors, and the mitotic activity ranged from 0 to 43 mitotic figures (MF)/10 high-power fields (HPF) (mean: 4 MF/10 HPF). Immunohistochemically, the tumors were consistently positive for S-100 protein (33/33) and variably or focally for HMB45 (32/33), microphthalmia transcription factor (26/32), Melan A (23/32), CD57 (25/33), bcl-2 (30/32), synaptophysin (14/32), CD56 (7/32), epithelial membrane antigen (12/33), cytokeratin (AE1/AE3) (1/32), CD34 (3/32), c-erbB-2 (10/32), c-kit (5/32), and c-met (5/32). alpha-Smooth muscle actin, desmin, and cytokeratin (CAM5.2) were negative. Reverse transcription-polymerase chain reaction using RNA extracted from formalin-fixed, paraffin-embedded tissues demonstrated transcripts of the EWSR1-ATF1 (31/33) or EWSR1-CREB1 fusion gene (2/33). In 26 cases with available clinical information, local recurrences and metastases developed in 2 and 15 patients, respectively. Ten patients were dead of the disease, and the overall survival rate was 63% at 5 years. However, no clinicopathologic or molecular variables associated with the patients' prognosis were identified. This study confirms that CCS is an aggressive soft tissue tumor with a melanocytic phenotype and wider morphologic variations than had been generally considered. In cases with unusual histologic findings, molecular detection of the EWSR1-ATF1/CREB1 fusion genes provides critical information regarding the diagnosis of the tumor.
authors.affiliation: Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. hisaoka@med.uoeh-u.ac.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Hisaoka
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ishida
authors.forename: Tseng-Tong
authors.initials: TT
authors.lastname: Kuo
authors.forename: Atsuji
authors.initials: A
authors.lastname: Matsuyama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Imamura
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nishida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuroda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Inayama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Oshiro
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakajima
authors.forename: Toshio
authors.initials: T
authors.lastname: Fukuda
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ae
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D018959:CD57 Antigens / Q000032:analysis; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D005260:Female; D050939:Gene Fusion; D019254:Genes, bcl-2; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis; D058965:MART-1 Antigen; D008297:Male; D058950:Melanoma-Specific Antigens; D051739:Microphthalmia-Associated Transcription Factor / Q000032:analysis; D008875:Middle Aged; D018396:Mucin-1 / Q000032:analysis; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000032:analysis; D009364:Neoplasm Recurrence, Local; D011506:Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D009418:S100 Proteins / Q000032:analysis; D018227:Sarcoma, Clear Cell / Q000737:chemistry / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D012983:Soft Tissue Neoplasms / Q000737:chemistry / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D015996:Survival Rate; D016708:Synaptophysin / Q000032:analysis; D014178:Translocation, Genetic
chemical_list: D018952:Antigens, CD34; D000951:Antigens, Neoplasm; D018959:CD57 Antigens; D002148:Calmodulin-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D007633:Keratins; D058965:MART-1 Antigen; D058950:Melanoma-Specific Antigens; D051739:Microphthalmia-Associated Transcription Factor; D018396:Mucin-1; D009363:Neoplasm Proteins; D011506:Proteins; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D009418:S100 Proteins; D016708:Synaptophysin; C115163:CREB1 protein, human; C500986:EWSR1 protein, human; C548667:MLANA protein, human; C079238:alcohol O-acetyltransferase