The role of next-generation sequencing in achieving diagnostic precision for dermatofibrosarcoma protuberans and its fibrosarcomatous variant.

Abstract

e23531 Background: Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive skin and subcutaneous fibroblastic neoplasm, characterized by COL1A1:: PDGFB fusions and, less frequently, PDGFD fusions. Approximately 10-15% of DFSP cases progress to distant metastases, yet the genetic mechanisms behind this transformation to fibrosarcomatous DFSP (FS-DFSP) or metastatic development remain unclear. Reports of DFSP in deeper tissues suggest a broader occurrence than previously recognized. We hypothesize that conventional histopathology may not adequately identify certain DFSP variants, especially those in deep tissues, potentially missing critical opportunities for targeted therapy with FDA-approved tyrosine kinase inhibitors. Methods: We searched Caris’s database to identify solid tumors with PDGFB or PDGFD fusions, markers of DFSP or FS-DFSP. We reviewed histologic features and clinical information, along with exome sequencing and copy number amplifications. Significance was tested using Mann Whitney U and Fisher’s exact tests as appropriate. Results: We identified 59 cases with PDGFB or PDGFD fusions: 55 COL1A1:: PDGFB, 3 EMILIN2:: PDGFD, and 1 COL1A2:: PDGFB cases. Of these, 51 were primary specimens and 8 metastatic. The patients included 31 males and 28 females, with a median age of 49 years (range: 14-93). Primary tumors occurred mainly in the skin/subcutis or deep soft tissues (35 trunk, 9 head and neck, 7 lower extremity, 2 upper extremity), but 6 were found in visceral organs (4 uterus, 1 cervix, 1 lung). Histologically, 20 cases were conventional DFSP and 32 were FS-DFSP. Notably, 21 tumors (36%) had been initially misclassified; most of which had metastatic presentation, unusual histology, or atypical location. Tumor sequencing revealed a higher incidence of genetic changes in addition to the PDGFB/ PDGFD fusions: concurrent mutations were detected in 66% of FS-DFSP cases versus 25% of DFSP cases (p = 0.009). Moreover, tumor mutational burden was significantly higher in FS-DFSP than DFSP (p = 0.006). The most prevalent mutations were in the TERT promoter and NF1, found exclusively in FS-DFSP cases. Conclusions: Conventional histology commonly fails to recognize FS-DFSP, leading to missed opportunities for targeted therapy. This highlights the essential role of next-generation sequencing in achieving greater diagnostic accuracy for DFSP and its fibrosarcomatous variant. While no single gene mutation consistently differentiates DFSP from FS-DFSP, the occurrence of additional genetic alterations is notably more common in FS-DFSP cases.