Angiogenic and Stromal Remodeling Associated With Aggressive Fibrosarcomatous Dermatofibrosarcoma Protuberans

Although collagen type 1 alpha 1 (COL1A1)-platelet-derived growth factor B-chain (PDGFB) gene fusion is a characteristic driver alteration in fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP), an aggressive DFSP variant, the tumor microenvironment (TME) underlying the aggressive phenotype remains unclear. We investigated microenvironmental and molecular differences between pure-DFSP and FS-DFSP using integrated histopathologic and transcriptomic analyses of archival samples from 122 patients, including 39 with FS-DFSP. Histopathologic evaluation, immunohistochemistry, and transcriptomic analyses were performed to assess vascular features, cancer-associated fibroblasts (CAFs), macrophage infiltration, and angiogenesis-related molecular alterations. FS-DFSP demonstrated increased CD31-positive vascular structures without a corresponding increase in αSMA-positive vascular structures, suggesting immature vascular features. CAF markers, including periostin and fibroblast activation protein, were significantly upregulated in intratumoral and invasive front regions of FS-DFSP. Gene expression analysis was performed separately for the fibrosarcomatous and DFSP components of the FS-DFSP cases and for the pure-DFSP cases. By targeted transcriptomic profiling, the DFSP and fibrosarcomatous components within the FS-DFSP cases shared molecular features, suggesting early tumor microenvironment-associated alterations that preceded overt fibrosarcomatous morphology. Integrated transcriptomic and protein analyses revealed upregulation of angiogenesis-related molecules, including vascular endothelial growth factor A (VEGFA), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine receptor 4 (CXCR4) in FS-DFSP. Periostin-positive CAFs coexpressed VEGFA and CCL2, potentially contributing to angiogenic features within the tumor microenvironment. These findings reveal that FS-DFSP is characterized by coordinated angiogenic and stromal remodeling involving tumor cells and CAFs and suggest that the tumor microenvironment may represent a potential focus for future therapeutic investigation.