Round cell
sarcomas harboring CIC-DUX4 fusions have recently been described as highly aggressive soft tissue
tumors of children and young adults. Due to partial morphologic and immunohistochemical overlap with
Ewing sarcoma (ES), CIC-DUX4-positive
tumors have generally been classified as ES-like and managed similarly; however, a systematic comparison at the molecular and immunohistochemical levels between these two groups has not yet been conducted. Based on an initial observation that CIC-DUX4-positive
tumors show nuclear immunoreactivity for WT1 and
ETS transcription factors, FLI1 and ERG, we performed a detailed immunohistochemical and molecular analysis including these markers, to further investigate the relationship between CIC-DUX4
tumors and ES. The study group included 21 CIC-DUX4-positive
sarcomas and 20 EWSR1-rearranged ES. Immunohistochemically, CIC-DUX4
sarcomas showed membranous CD99 positivity in 18 (86%) cases, but only 5 (24%) with a diffuse pattern, while WT1 and FLI1 were strongly positive in all cases. ERG was positive in 18% of cases. All ES expressed CD99 and FLI1, while ERG positivity was only seen in EWSR1-ERG fusion positive ES. WT1 was negative in all ES. Expression profiling validated by q-PCR revealed a distinct gene signature associated with CIC-DUX4 fusion, with upregulation of
ETS transcription factors (ETV4, ETV1, and ETV5) and WT1, among top overexpressed genes compared to ES, other
sarcomas and normal tissue. In conclusion, the distinct gene signature and immunoprofile of CIC-DUX4
sarcomas suggest a distinct pathogenesis from ES. The consistent WT1 expression may provide a useful clue in the diagnosis in the context of round cell
sarcomas negative for EWSR1 rearrangement. © 2014 Wiley Periodicals, Inc.