28 Unusual Presentation of Molecularly Confirmed Atypical Nodular Fasciitis with Aberrant S-100 Expression

Introduction/Objective Nodular fasciitis (NF) is a benign USP6-rearranged clonal neoplastic proliferation characterized by rapid growth, infiltrative growth pattern, and high mitotic rate. These features can lead to misinterpretation as a sarcoma, particularly when atypical mitotic figures are observed. Methods/Case Report A retrospective study was performed to evaluate the case. Results Here, we report a case of a 19-year-old female presenting with a round, cystic, painful nodule (up to 2.5 cm). Histological evaluation showed a well-circumscribed subcutaneous spindle cell lesion with cystic change and spiculated border. Mitotic figures were present throughout the lesion, with up to 5 mitoses per high-power field (HPF). Notably, a single multipolar mitotic figure and multiple osteoclast-like giant cells were identified. Immunohistochemically, the tumor cells were diffusely positive for smooth muscle actin and patchy positivity for S-100. Fluorescence in situ hybridization confirmed a USP6 rearrangement. The combination of clinical, histopathological, and molecular findings supports the diagnosis of NF with aberrant S-100 expression. Conclusion To the best of our knowledge, this represents the first reported case of NF exhibiting both S-100 positivity and an atypical multipolar mitotic figure. We hope this case increases awareness among pathologists to consider NF as a differential diagnosis for benign spindle cell neoplasms with S-100 positivity, which will prevent misdiagnosis of a benign process as malignant.