A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma

Am J Surg Pathol. 2014 Nov;38(11):1571-6. doi: 10.1097/PAS.0000000000000286.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Bone Neoplasms / chemistry
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / pathology
  • Cell Cycle Proteins
  • Cell Differentiation*
  • Diagnosis, Differential
  • Forkhead Transcription Factors
  • Gene Fusion*
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Muscle Neoplasms / chemistry
  • Muscle Neoplasms / genetics*
  • Muscle Neoplasms / pathology
  • Muscle Neoplasms / therapy
  • Neck Muscles* / chemistry
  • Neck Muscles* / pathology
  • Neoplasm Grading
  • Phenotype
  • Predictive Value of Tests
  • Repressor Proteins / genetics*
  • Sarcoma, Ewing / chemistry
  • Sarcoma, Ewing / genetics*
  • Sarcoma, Ewing / pathology
  • Sarcoma, Small Cell / chemistry
  • Sarcoma, Small Cell / genetics*
  • Sarcoma, Small Cell / pathology
  • Sarcoma, Small Cell / therapy
  • Transcription Factors / genetics*
  • Translocation, Genetic

Substances

  • Biomarkers, Tumor
  • CIC protein, human
  • Cell Cycle Proteins
  • FOXO4 protein, human
  • Forkhead Transcription Factors
  • Repressor Proteins
  • Transcription Factors