Undifferentiated round cell sarcoma with CIC::NUTM1 fusion: expanding the clinicopathologic spectrum of a rare molecular variant of CIC-rearranged sarcoma.

CIC::NUTM1-rearranged sarcoma is a rare molecular variant of CIC-rearranged undifferentiated round cell sarcoma (URCS), with fewer than 20 cases reported to date. We present eight additional cases from two institutions to expand the clinicopathologic spectrum of this emerging variant. Our cohort comprised eight patients (five females, three males) with a median age of 8 years (range 2-15). Tumors arose predominantly in axial sites, including paraspinal soft tissue (n = 4), head and neck soft tissue (n = 2), temporal lobe meninges (n = 1), and distal extremity (right index finger; n = 1). Histologically, tumors showed sheets of round cells with variable rhabdoid or spindled features within myxoid or chondromyxoid stroma, frequently with necrosis. Immunohistochemically, tumors expressed NUT (6/6), CD99 (7/7), and WT1 (3/5); DUX4 was negative in all tested cases (0/6). RNA sequencing confirmed CIC::NUTM1 fusions involving CIC exons 16-18 and NUTM1 exons 5-6. Among five patients with follow-up, three died of disease (12, 28, and 34 months), one was alive with disease, and one was alive without disease. Pooled survival analysis of 21 total cases demonstrated a median overall survival of 17 months and median progression free survival of 9 months, without statistically significant survival difference compared to deep-seated CIC::DUX4 sarcoma. CIC::NUTM1 sarcoma is an aggressive malignancy with a predilection for pediatric patients and axial sites. Given its morphologic and immunohistochemical variability, diagnosis requires high index of suspicion. An immunopanel of NUT, CD99, WT1, and DUX4 serves as a valuable screening tool in the appropriate histologic context.