USP6-FISH Negative Nodular Fasciitis: Benign Impostor of the Orbit

Nodular fasciitis (NF) is a benign, rapidly growing myofibroblastic proliferation that can closely mimic sarcoma clinically, radiographically, and histologically, posing a significant diagnostic challenge. We report a case of an 11-year-old boy presenting with a painless but progressively enlarging periorbital mass initially suspected to be a dermoid cyst. Although his ultrasound was reassuring, MRI showed an enhancing lesion concerning for neoplasm, prompting surgical excision. Histopathologic evaluation revealed spindle-cell proliferation within a myxoid stroma consistent with NF. However, the USP6 fluorescence in situ hybridization analysis was negative. Further genomic analysis identified a rare USP6-PAFAH1B1 fusion. This case highlights a diagnostically challenging subset of NF in which conventional USP6 fluorescence in situ hybridization testing may be negative, necessitating next-generation sequencing for a definitive diagnosis. Increased awareness of NF and its clinical, histologic, genetic, and radiographic presentation is essential to avoid misdiagnosis and to guide appropriate management.