PLEOMORPHIC dermal sarcoma (PDS) showed a genetic profile more closely resembling metastatic cutaneous squamous cell carcinoma (CSCC) than soft-tissue sarcoma (STS), according to a retrospective cohort study.
Researchers compared tumour sequencing data from nine patients with PDS, 15 with metastatic CSCC, and 25 with STS. The study was conducted at a single centre between January 2015 and October 2025 and included tumours analysed using a 447-gene sequencing assay.
PDS is classified as a sarcoma, but it can share clinical and biological characteristics with cutaneous carcinomas. These include a tendency to develop on sun-exposed skin and a high tumour mutational burden (TMB). The researchers sought to determine whether its genetic profile more closely reflected CSCC or other STSs.
The mean TMB was substantially higher in PDS and CSCC than in STS. Mean TMB was 44.6 for PDS, 54.1 for CSCC, and 4.2 for STS.
There was no statistically significant difference in TMB between PDS and CSCC, whereas significant differences were observed between both PDS and STS and CSCC and STS.
All PDS and CSCC tumours also demonstrated ultraviolet (UV) signature mutations, while none of the STSs showed this pattern.
At pathway level, mutations affecting TP53, cell cycle, NOTCH, and receptor tyrosine kinase–Ras pathways were prominent in both PDS and CSCC. In contrast, the STS group lacked major pathway-level mutations.
Unsupervised analysis of the mutational data further supported the similarity between PDS and metastatic CSCC. Principal component analysis showed overlapping PDS and CSCC clusters, while STSs formed a separate cluster.
The findings suggest that PDS may be genetically distinct from conventional STS and more closely aligned with metastatic CSCC. This distinction could be relevant when considering treatment approaches for a tumour for which management strategies remain limited.
However, the study included only nine PDS tumours and was retrospective and single-centre. The findings therefore provide evidence of genetic similarity rather than establishing that PDS should be managed according to CSCC treatment paradigms.
Further research will be needed to determine whether these molecular similarities can translate into changes in the clinical management of patients with PDS.
Reference
Neff H et al. Comparison of pleomorphic dermal sarcoma to advanced cutaneous squamous cell carcinoma and soft-tissue sarcoma. JAMA Dermatol. 2026;DOI: 10.1001/jamadermatol.2026.3297.
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