Genomic Profiling Uncovers a Broader Spectrum of Dermatofibrosarcoma Protuberans: Implications for Diagnosis and Therapy.

Abstract

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive cutaneous neoplasm driven by PDGFB or, rarely, PDGFD gene fusions. In some cases, DFSP progresses to a fibrosarcomatous form with metastatic potential, which may respond to tyrosine kinase inhibitors. This study explores whether comprehensive genomic profiling can reveal a broader clinical, anatomic, and pathologic spectrum for DFSP. Using the database of a large tumor sequencing reference lab, we identified tumors with PDGFB or PDGFD fusions and reviewed their histologic features, clinical information, exome sequencing data, and copy number alterations. Statistical significance was determined using Mann-Whitney U and Fisher's exact tests. A total of 59 cases with PDGFB or PDGFD fusions were identified: 55 COL1A1::PDGFB, 3 EMILIN2::PDGFD, and 1 COL1A2::PDGFB. The cohort included 51 primary tumors and 8 metastases (31 males, 28 females, median age 49 years). Primary tumors were mainly located in the skin and soft tissues, including 35 in the trunk, 9 in the head and neck, and 9 in the extremities. Additionally, 6 tumors arose in visceral organs (4 in the uterus, 1 in the cervix, and 1 in the lung). Among cases with slides available for pathology review, 21 were classified as classic DFSP and 31 as fibrosarcomatous DFSP (FS-DFSP). Notably, 21 tumors (36%) were initially misclassified, often due to atypical locations or histology. FS-DFSPs displayed a higher incidence of genomic alterations beyond PDGFB/PDGFD (75% vs. 23.8%, p=0.0005), including TERT promoter and NF1 variants, and demonstrated a significantly elevated tumor mutational burden (p=0.0037) and TERT mRNA expression (1.27 vs. 0.13 transcripts per million, p<0.0001) compared to classic DFSP. These findings underscore the value of genomic profiling for recognizing FS-DFSPs with unusual clinical or histologic features, particularly in guiding targeted therapy. Furthermore, by identifying molecular features specific to fibrosarcomatous variants, such as TERT reactivation, this study offers insights into potential molecular drivers of tumor progression in DFSP.