Nodular fasciitis in unusual (and usual) locations: lessons learned from a challenging diagnosis

Nodular fasciitis is a benign, rapidly growing myofibroblastic neoplasm that can mimic sarcomas, typically posing a diagnostic challenge. This retrospective, single-institution series presents 29 cases of nodular fasciitis collected over 9 years. Two-thirds of the cases (19/29) presented as non-specific soft-tissue lesions that did not initially raise suspicion for nodular fasciitis and/or showed alarming histological features. Among these, five exhibited unusual localisations, including three deep-seated, subfascial lesions (two intraneural) and two juxta-articular lesions. Histopathology was consistent with nodular fasciitis in all cases. Fluorescence in situ hybridisation (FISH) and next-generation sequencing (NGS) confirmed the diagnosis: USP6 rearrangements were identified in all 19 non-specific cases, with FISH detecting alterations in 15 cases (83.3% of those tested). Although useful, FISH posed interpretive challenges; NGS resolved ambiguous cases and identified three rare USP6 fusion partners (MIR22HG, CTNNB1, and SRSF3), which showed distinctive cellular histomorphology despite longer pre-operative age, two of which appeared in atypical locations. This series offers an integrated clinicopathological and molecular overview of diagnostically challenging nodular fasciitis, emphasising the importance of including it in the differential diagnosis of mesenchymal tumours in both superficial and deep sites. We believe this series contributes to the understanding of USP6-associated neoplasia and will aid pathologists in recognising nodular fasciitis in challenging settings, enhance diagnostic confidence, and support targeted use of advanced molecular techniques.