Polyomavirus-negative Merkel cell carcinoma: a more aggressive subtype based on analysis of 282 cases using multi-modal tumor virus detection

Previous studies have reached conflicting conclusions regarding the proportion of Merkel cell carcinomas (MCCs) that contain the Merkel cell polyomavirus (MCPyV) and the clinical significance of tumor viral status. To address these controversies, we detected MCPyV large T antigen using immunohistochemistry with two distinct antibodies and viral DNA using quantitative PCR. Tumors were called virus-positive if two or more of these three assays indicated presence of MCPyV. 53 of 282 (19%) of MCC tumors in this cohort were virus-negative using this multimodal system. Immunohistochemistry with the CM2B4 antibody had the best overall performance (sensitivity=0.882, specificity=0.943) compared to the multimodal classification. Multivariate analysis including age, sex and immunosuppression showed that, relative to MCC patients with virus-positive tumors, virus-negative MCC patients had significantly increased risk of disease progression (HR=1.77 [95% CI: 1.20 – 2.62]) and death from MCC (HR=1.85 [95% CI: 1.19 – 2.89]). 29 and 41 percent of these respective associations was due to a greater likelihood of virus-negative cases to present at a more advanced clinical stage, even though virus-negative tumors tended to be smaller at presentation. We confirm that a subset of MCCs lack biologically significant levels of MCPyV, and that such tumors represent a more aggressive subtype warranting closer clinical follow-up.