Abstract

Nodular fasciitis (NF) is a rapidly growing, benign, self-limited myofibroblastic neoplasm. The high cellularity, mitotic activity with its histologic variations, is a reason by NF becomes a common case sent in consultation to expert soft tissue pathologists. The USP6 gene rearrangement is the most common pathogenetic driver, indicating a neoplastic nature rather than a reactive proliferation. Multiple fusion partners of USP6 have been reported, with MYH9 being one of the most frequent partners. In this report, we present a case of a 22-year-old patient with a 1.5 cm nodular lesion on the forearm. Morphologically, the lesion demonstrated relatively well-circumscribed, cellular proliferation of spindle cells in a mucinous matrix background. Immunohistochemistry testing revealed strong and diffuse positivity for CD68 and SMA in the tumor cells, while desmin, caldesmon, CD31, CD34, and Factor XIIIa were negative. Notably, the tumor exhibited unusual features, including a prominent component of histiocyte-like epithelioid cells, and foci of osteoclast-like giant cells. Given these observations, genetic analysis was performed, revealing a novel SETD5::USP6 fusion. SETD5 acts as a tumor driver by inhibiting tumor suppressor gene transcription through H3K9 methylation. It has been associated with aggressiveness in prostate, mammary, and lung cancer, as well as resistance to MEK inhibition in pancreatic ductal adenocarcinoma. Although extremely rare, nodular fasciitis can undergo malignant transformation, as seen with the PPP6R3::USP6 fusion. This report adds a potentially new fusion partner to USP6 in NF, reinforces the utility of such molecular testing in challenging cases to establish the diagnosis of NF.