Angiogenic and Stromal Remodeling Associated With Aggressive Fibrosarcomatous Dermatofibrosarcoma Protuberans

ABSTRACT 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.