Undifferentiated round cell sarcomas with CIC-DUX4 gene fusion: expanding the clinical spectrum

Round cell sarcomas are a heterogeneous group of mesenchymal neoplasms with overlapping morphology and immunohistochemical profile. Ewing sarcoma is the most well-known tumour in this group characterised by EWSR1/FUS rearrangements with members of the ETS family of transcription factors. Undifferentiated round cell sarcomas lacking these rearrangements, known as 'Ewing-like' sarcomas, usually show atypical clinical presentation and focal CD99 positivity. This group of tumours can be subdivided into: capicua transcriptional repressor (CIC)-rearranged sarcomas, Bcl6 corepressor (BCOR)-rearranged sarcomas, sarcomas with EWSR1 fusion to non-ETS family members and unclassified round cell sarcomas. We describe seven new cases of CIC-DUX4 rearranged sarcomas with their clinicopathological features, two of which presented in unusual locations (skin and lymph node). Patient age ranged between 23 and 54 years, three of whom were female. In five cases, aggressive behaviour was observed with rapid disease progression and lethal outcome within 15 months. One patient achieved a complete response after chemotherapy. The last patient whose tumour was located purely in the dermis demonstrated no residual tumour in the re-resection specimen, was not given any further treatment and showed no sign of disease after 24 months. Immunohistochemically, tumour cells in all cases showed focal membranous CD99 positivity, while WT1 N-/C-terminus were positive in all 5/5 cases (nuclear and/or cytoplasmic). NGS analysis revealed a CIC-DUX4 fusion in all cases. This study expands the spectrum of anatomical locations of CIC-DUX4 rearranged sarcomas, highlighting the inclusion of this rare entity in the differential diagnosis of undifferentiated tumours in various anatomical locations outside of soft tissues.