A Novel CIC-FOXO4 Gene Fusion in Undifferentiated Small Round Cell 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.

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

“…Recent studies have identified that some of these cases carry translocations involving BCOR-CCNB3 (28-30), CIC-DUX4 (31, 32), or CIC-FOXO4 (33,34). These variants are genetically distinct from Ewing sarcoma and portend different prognoses, for example, with BCOR-CCNB3 tumors (28,29) showing good chemosensitivity, which must now be considered as distinct entities for treatment selection.…”

Head and Neck Round Cell Sarcomas: A Comparative Clinicopathologic Analysis of 2 Molecular Subsets: Ewing and CIC-Rearranged Sarcomas

“…The diagnosis of CRS in the HN is extremely rare, only 11 cases being described to date [12,13,17,18,22,23,27]. As CRS is a relatively new pathologic entity, without a specific immunoprofile, it remains under-recognized outside specialist sarcoma centers.…”

“…The 2-year overall survival (OS) rate for HN-CRS patients was 78%, while for HN-ES it was 100%. The OS of ES and CRS showed a trend toward a favorable and BCOR-related fusions involving CCNB3, MAML3, and ZC3H7B gene partners [11][12][13][14][15][16][17][18]. As most of the initial series have included a limited number of cases of each molecular subset, definitive classification of these tumors within or outside the more common ES spectrum has been difficult to establish.…”

CIC (capicua transcriptional repressor)

“…Consistent with this, EWSR1-ETV1 and EWSR1-ETV4 fusions, which presumably function as aberrant versions of the transcription factors ETV1 and ETV4, respectively, have been observed in EFTs (Jeon et al 1995;Kaneko et al 1996). EFTs with CIC-FOXO4 fusions have also been reported (Sugita et al 2014;Solomon et al 2014). …”