Kelly L. Harms

Dermatofibrosarcoma protuberans (DFSP) is a fibroblastic malignancy characterized in most cases by COL1A1::PDGFB fusion. Rare cases exhibit alternative rearrangements involving PDGFD . Here, we describe a female patient in her third decade of life who presented with a spindle cell proliferation on the shoulder. Expression of pan‐TRK and S100, together with absence of PDGFB overexpression, supported an initial impression of NTRK ‐rearranged spindle cell tumor. However, molecular analysis revealed PDGFD rearrangement, and re‐excision demonstrated classic DFSP morphology in the residual tumor. Our findings underscore the importance of continued consideration for DFSP in tumors with focal S100 expression.

Relative read depth across the MCPyV genome in each VP-MCC tumor. Left column shows MCPyV genome position (RefSeq NC_010277).

Summary of definitive treatment modalities for MCC patients in our cohort, stratified by stage. Data presented as n (%). a Including sentinel lymph node biopsy ± completion lymphadenectomy of regional lymphatic basin.

Summary of NGS data by individual tumor.

Summary of all MCPyV SNV calls in VP-MCC tumors.

Summary of all somatic genomic alterations identified in our MCC cohort.

List of human genes included in our targeted NGS panel.

Summary of all MCPyV integration events in VP-MCC tumors.

Primary tumor histopathologic parameters for patients with MCC treated with surgery. Data presented as n (%) or median (range).

Merkel cell carcinoma (MCC) is an aggressive disease with poor survival outcomes and increasing incidence. There is a clear and present need for enhanced understanding of cellular mechanisms of tumorigenesis, validation of robust genetic signatures predictive of aggressive disease, and novel informatics tools to simplify analysis of Merkel cell polyomavirus (MCPyV)–host genome interactions. Genomic DNA was harvested from 54 MCC tumors for exome sequencing and in-depth genetic profiling of a 226-gene panel. We further developed a robust informatics package (MCPyViewer) optimized for MCPyV integration site analysis with graphical output to simplify usability for end users. Finally, we assessed the prognostic impact of specific genetic signatures on MCC-specific survival in our cohort. Our study included 54 patients (n = 44 MCPyV positive), 11 (20.4%) of whom had died of MCC at last follow-up. Human genes altered at high frequency included LRP1B (n = 10, 18.5%), FAT1 (n = 9, 16.7%), KMT2D (n = 9, 16.7%), and RB1 (n = 7, 13.0%). In 36 of 44 (81.8%) MCPyV-positive tumors, we identified viral integration into the human genome with a median of two events per tumor. In six tumors, MCPyV integrated into Catalogue of Somatic Mutations in Cancer tier 1 or tier 2 cancer-related human genes.Implications:A combined genomics score incorporating tumor mutational burden and copy-number variation was strongly prognostic of MCC-specific survival controlling for lymph node metastases and tumor MCPyV status; thus, our study adds critical understanding to prognostic markers and tumorigenic mechanisms in MCC.