INI1-deficient epithelioid MPNST of the ulnar nerve harboring a novel CEP170::RAD51B fusion and CUX1 p.Ala827Thr missense mutation: A novel molecular finding in a nerve-derived sarcoma

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is a rare subtype of MPNST that can closely mimic melanoma and PEComa. With increasing next-generation sequencing (NGS) use, lineage-ambiguous fusions may complicate classification. A 16-year-old female presented with an incidentally discovered 5.5-cm fusiform mass centered on the ulnar nerve at the elbow. Resection showed a high-grade epithelioid sarcoma confined to the epineurium, with brisk mitotic activity and geographic necrosis. Immunohistochemistry demonstrated focal S100 reactivity, minimal SOX10 positivity, partial loss of INI1 in >60% of tumor nuclei, retained H3K27me3, focal SMA and calponin, rare PR positive nuclei, and negative melanocytic markers (HMB45, Melan-A, MITF). TLE1 was weakly positive in ~70% of tumor cells, but SS18 FISH was negative. RNA sequencing revealed an in-frame CEP170::RAD51B fusion; DNA NGS showed CUX1 p.Ala827Thr (c.2479 G>A) mutation at 40.4% VAF. The patient underwent complete excision and adjuvant radiation and remains disease-free on imaging. Despite atypical immunophenotype and an unexpected fusion previously reported in PEComa-associated molecular contexts, the tumor’s strict intraneural origin, morphology, and INI1 loss support EMPNST. This case expands the molecular spectrum of EMPNST and highlights the primacy of anatomic context in the classification of diagnostically ambiguous sarcomas with epithelioid morphology.