An Unusual Presentation of Dermatofibrosarcoma Protuberans (DFSP): The Role of Advanced Molecular Testing in Collagen Type I Alpha 1 Chain (COL1A1)-Negative Cases

Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade cutaneous fibroblastic sarcoma of the dermis that typically presents as a slow-growing red or violet colored plaque. It is classically driven by a collagen type I alpha 1 chain::platelet-derived growth factor subunit B (COL1A1::PDGFB) fusion and is characterized by indolent but locally infiltrative growth with a high risk of local recurrence. Here, we present a 39-year-old woman with a past medical history of breast cancer 1 (BRCA1)/ataxia-telangiectasia mutated (ATM) mutations and invasive lobular carcinoma of the left breast status post bilateral mastectomy, who presented with a tender right calf lump for one year. On physical exam, a well-circumscribed, mobile 2 cm mass was palpated in the right calf without overlying skin changes. Biopsy revealed a CD34-positive, low-grade, cellular, spindle cell neoplasm measuring 2.2 × 1.4 × 0.9 cm, extending to the biopsy margins. Histologically, DFSP is characterized by uniform spindle cells with diffuse CD34 staining. Loss of Rb staining was noted in lesional cells, an atypical finding that initially favored a diagnosis of lipoma over DFSP, complicating the initial differential. Fluorescence in situ hybridization (FISH) analysis for COL1A1 rearrangement was negative, necessitating advanced molecular testing. Solid tumor next-generation sequencing fusion panel identified a COL6A3::PDGFD gene fusion, which accounts for about 2% of DFSP cases. The histologic and molecular findings supported a diagnosis of DFSP with an uncommon translocation. The differential diagnosis included spindle cell lipoma and cellular fibrohistiocytic neoplasm, but these were excluded based on immunohistochemistry and genetic data. Given the extension of lesional cells to biopsy margins, re-excision was performed with negative margins. This case exhibits an atypical presentation of DFSP with a rare COL6A3::PDGFD fusion undetectable by standard FISH, demonstrating the importance of advanced molecular testing in suspected DFSP when FISH is negative for the COL1A1 rearrangement. Additionally, DFSP typically presents on the trunk with overlying skin surface changes, making a calf lesion without cutaneous involvement unusual.