A t(17;22)(q21;q11.2) Scalp Ewing Sarcoma with No EWSR1 Gene Rearrangement and Harboring EWSR1::ETV4 Fusion

Summary: Ewing sarcoma (ES) is a malignant round cell tumor typically characterized by gene fusions involving the EWSR1 gene on chromosome 22q12 and ETS-family transcription factors including FLI1 (85%), ERG (10%), and other uncommon ETS genes. We report an infant with ES harboring EWSR1::ETV4 fusion, an exceedingly rare EWSR1::ETS variant fusion with <5 cases. A 3-month-old male infant with an uncomplicated pregnancy and delivery presented with a progressively enlarging nodule on the left occipital scalp. Magnetic resonance imaging showed a well-circumscribed heterogenous soft-tissue mass. Biopsy and resection of the scalp mass revealed sheets of small round to short spindle-shaped blue cells with high nuclear-to-cytoplasmic ratios, scant vacuolated cytoplasm, and extensive necrosis. Immunohistochemistry showed diffuse nuclear positivity for NKX2.2 and membranous CD99, with negative markers for desmin, myogenin, S-100, and CD34, while INI-1 was retained. Targeted RNA sequencing identified the rare EWSR1::ETV4 fusion. Subsequent chromosomal analysis confirmed the presence of a unique t(17;22)(q21;q11.2) translocation. This is the fourth reported case of EWSR1::ETV4 fusion, typically seen in young patients with extra-skeletal involvement, highlighting a potential ETV1/4 predisposition to non-osseous sites. This case reinforces the importance of ETV4 in driving sarcomagenesis, broadening our understanding of the clinical and molecular spectrum of Extra-skeletal ES.