title: A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma.
abstract: Differential diagnosis of small round cell sarcomas (SRCSs) grouped under the Ewing sarcoma family of tumors (ESFT) can be a challenging situation for pathologists. Recent studies have revealed that some groups of Ewing-like sarcoma show typical ESFT morphology but lack any EWSR1-ETS gene fusions. Here we identified a novel gene fusion, CIC-FOXO4, in a case of Ewing-like sarcoma with a t(X;19)(q13;q13.3) translocation. The patient was a 63-year-old man who had an asymptomatic, 30-mm, well-demarcated, intramuscular mass in his right posterior neck, and imaging findings suggested a diagnosis of high-grade sarcoma. He was treated with complete resection and subsequent radiotherapy and chemotherapy. He was alive without local recurrence or distant metastasis 6 months after the operation. Histologic examination revealed SRCS with abundant desmoplastic fibrous stroma suggesting a desmoplastic small round cell tumor. Immunohistochemical analysis showed weak to moderate and partial staining for MIC2 (CD99) and WT1, respectively. High-throughput transcriptome sequencing revealed a gene fusion, and the genomic rearrangement between the CIC and FOXO4 genes was identified by fluorescence in situ hybridization. Aside from the desmoplastic stroma, the CIC-FOXO4 fusion sarcoma showed morphologic and immunohistochemical similarity to ESFT and Ewing-like sarcomas, including the recently described CIC-DUX4 fusion sarcoma. Although clinicopathologic analysis with additional cases is necessary, we conclude that CIC-FOXO4 fusion sarcoma is a new type of Ewing-like sarcoma that has a specific genetic signature. These findings have important implications for the differential diagnosis of SRCS.
authors.affiliation: Departments of *Surgical Pathology ∥Pathology ¶Orthopedic Surgery, Sapporo Medical University School of Medicine, Sapporo †Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo Departments of ‡Diagnostic Pathology §Hematology and Medical Oncology, Japan Labour Health and Welfare Organization, Kanto Rosai Hospital, Kanagawa, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sugita
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Arai
authors.forename: Akiko
authors.initials: A
authors.lastname: Tonooka
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.forename: Tomoki
authors.initials: T
authors.lastname: Fujii
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Aoyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Asanuma
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tsukahara
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Kaya
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001859:Bone Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D003937:Diagnosis, Differential; D051858:Forkhead Transcription Factors; D050939:Gene Fusion; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009334:Neck Muscles / Q000737:chemistry / Q000473:pathology; D060787:Neoplasm Grading; D010641:Phenotype; D011237:Predictive Value of Tests; D012097:Repressor Proteins / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D018228:Sarcoma, Small Cell / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D014408:Biomarkers, Tumor; C498610:CIC protein, human; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors