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

Abstract

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 MCPyV DNA using quantitative PCR. Tumors were called MCPyV-positive if two or more of these three assays indicated presence of this virus. 53 of 282 (19%) 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]). We confirm that approximately 20% of MCCs are not driven by MCPyV, and that such virus-negative MCCs, which can be quite reliably identified by immunohistochemistry using the CM2B4 antibody alone, represent a more aggressive subtype that warrants closer clinical follow-up.