Comparison of Pleomorphic Dermal Sarcoma to Advanced Cutaneous Squamous Cell Carcinoma and Soft-Tissue Sarcoma.

IMPORTANCE: Pleomorphic dermal sarcomas (PDSs) are classified as sarcomas; however, they share features with cutaneous carcinomas, such as presentation on sun-exposed areas and high tumor mutational burden (TMB). Data regarding management of PDS are limited, and it is unclear whether sarcoma or cutaneous cancer treatment paradigms should apply. At present, there are no published data comparing the mutational genetics of PDSs to other cutaneous tumors and to other soft-tissue sarcomas (STSs). OBJECTIVE: To compare TMB, UV signature, and single-nucleotide and pathway-level mutational profiles of PDS to cutaneous squamous cell carcinoma (CSCC) and STS. DESIGN, SETTING, AND PARTICIPANTS: This single-center retrospective cohort study was performed at the Dana-Farber Cancer Institute and Brigham and Women's Hospital from January 1, 2015, to October 20, 2025. Patients diagnosed with PDS, metastatic CSCC, and STS were identified by electronic medical records and included if a 447-tumor gene sequencing assay was performed on tumor tissue. MAIN OUTCOMES AND MEASURES: The primary end point was to compare the single-nucleotide variant profiles of PDS, metastatic CSCC, and STS using unsupervised machine learning analysis. The secondary end points were to compare mean TMB, pathway-level mutations, and UV signature status. RESULTS: A total of 9 PDSs, 15 metastatic CSCCs, and 25 STSs were included. At the pathway level, TP53, cell cycle, NOTCH, and receptor tyrosine kinase-Ras pathways were highly mutated in PDS and CSCC, whereas STS lacked major pathway mutations. The mean TMB was 44.6 (95% CI, 37.5-51.8) for PDS, 54.1 (95% CI, 40.4-67.8) for CSCC, and 4.2 (95% CI, 3.2-5.2) for STS. Statistically significant differences in mean TMB were observed between CSCC and STS and between PDS and STS but not between CSCC and PDS. All PDSs and CSCCs displayed UV signature mutations, while none of other STSs did. Principal component analysis of mutational variants and TMB on sequencing assay showed completely overlapping PDS and CSCC clusters and separate, narrow STS clustering. CONCLUSIONS AND RELEVANCE: In this cohort study, PCA analysis of single-nucleotide variants and comparison of TMB, UV signature, and pathway-level alterations between groups suggested similar genetic profiling between metastatic CSCC and PDS, which were distinct from STS.