Superficial Neurocristic FET::ETS Fusion Tumor: Expanding the Clinicopathological and Molecular Genetic Spectrum of a Recently Described Entity

Superficial neurocristic EWSR1::FLI1 fusion tumor is a very recently described, clinically indolent tumor of the skin and superficial soft tissues, which differs in essentially all ways from Ewing sarcoma, despite harboring an identical fusion event. The EWSR1 and FLI1 genes are members of the FET and ETS gene family, respectively, and very rare examples of Ewing sarcoma harbor alternative FET::ETS fusion events, such as EWSR1::ERG, FUS::FLI1, FUS::ERG, EWSR1::ETV4, and others. We report 5 new cases of this very rare entity, harboring in 3 cases alternative FET::ETS fusion events. The tumors occurred in 2 males and 3 females (median age, 14 years, range, 8-69 years) and presented as solitary dermal/subcutaneous masses of the thigh, foot, shoulder, arm, and back (median size, 1.8 cm; range, 1-2 cm). All patients underwent wide excisions; one received adjuvant chemotherapy. Clinical follow-up on 3 patients (median, 24 months; range, 18-31 months) showed all to be without disease. Morphologically, all tumors displayed typical features of this entity as described, with nests of cytologically bland, diffusely S100 protein/SOX10-positive round cells without mitotic activity, surrounded by fibrous bands containing spindled cells with similar nuclear features. The tumors also showed membranous CD99 (4/5) and nuclear NKX2.2 (3/3) expression. RNA sequencing (5 cases) demonstrated FUS::FLI1, FUS::ERG, EWSR1::FLI1, EWSR1::ERG, and a novel FUS::ETV5. Methylation profiling (4 cases) showed all to cluster with previously reported superficial neurocristic EWSR1::FLI1 fusion tumors and apart from conventional and “adamantinoma-like” Ewing sarcoma. Our findings confirm the distinctive clinicopathological features of this very rare, recently described entity and expand its molecular genetic spectrum. Reflecting on these findings, we propose modifying the name of this entity to “superficial neurocristic FET::ETS fusion tumor.”