The molecular landscape of nodular fasciitis: novel USP6 fusions, genomic stability, and an exploratory clinicopathological model – a 20‐year retrospective study

Nodular fasciitis (NF) is a benign myofibroblastic neoplasm characterized by rapid growth and recurrent USP6 rearrangements. Despite its benign nature, NF may exhibit worrisome histologic or clinical features that mimic sarcoma, posing diagnostic challenges. The relationship between molecular diversity and morphologic heterogeneity remains incompletely understood. We retrospectively analyzed 283 NF cases diagnosed between 2000 and 2024 at a tertiary referral center. Molecular testing for USP6 rearrangements was performed in 44 cases using targeted RNA sequencing. Histologic features, clinical parameters, and fusion partner distribution were evaluated, with emphasis on lesions showing infiltrative or worrisome morphology. Selected cases underwent additional genomic profiling, including hybrid-capture DNA sequencing and copy-number analysis. Among 44 molecularly confirmed cases, 18 distinct USP6 fusion partners were identified. The most frequent fusion was MYH9::USP6 (40.9%), followed by COL1A1::USP6, MIR22HG::USP6, and RRBP1::USP6. Rare and previously unreported fusions, including CLK1::USP6 and FOSL2::USP6, further expanded the molecular spectrum. Two cases with infiltrative, aggressive-appearing morphology showed no additional pathogenic alterations and a genomically stable profile. Based on these findings, we propose an exploratory, hypothesis-generating framework to summarize the observed clinicopathological spectrum of NF. NF demonstrates substantial molecular heterogeneity but retains a genetically simple and largely benign biological behavior. Even lesions with alarming morphology appear genomically stable and clinically indolent. The proposed framework may facilitate diagnostic interpretation and provide a conceptual framework for future studies but requires validation before any biological or clinical implications can be inferred.