ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements.
By RT-PCR, fusion transcripts involving CIC (19q13) and DUX4 (4q35) were confirmed to be present in both primitive round cell sarcomas, further defining the breakpoints seen by genomic analysis.
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.
As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available.
A histologic comparison of the CIC-rearranged sarcomas with 20 EWSR1-rearranged Ewing sarcomas showed significantly higher degrees of lobulation, nuclear pleomorphism, the prominence of the nucleoli, spindle cell elements, and myxoid changes in the CIC-rearranged sarcomas.