Polyomavirus-Negative Merkel Cell Carcinoma: A More Aggressive Subtype Based on Analysis of 282 Cases Using Multimodal Tumor Virus Detection

J Invest Dermatol. 2017 Apr;137(4):819-827. doi: 10.1016/j.jid.2016.10.028. Epub 2016 Nov 1.


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. A total of 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 with 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 (hazard ratio = 1.77, 95% confidence interval = 1.20-2.62) and death from MCC (hazard ratio = 1.85, 95% confidence interval = 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Biopsy, Needle
  • Carcinoma, Merkel Cell / mortality
  • Carcinoma, Merkel Cell / pathology
  • Carcinoma, Merkel Cell / virology*
  • Cohort Studies
  • Confidence Intervals
  • Disease Progression
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Merkel cell polyomavirus / genetics
  • Merkel cell polyomavirus / isolation & purification*
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Invasiveness / pathology
  • Neoplasm Staging
  • Prognosis
  • Proportional Hazards Models
  • Real-Time Polymerase Chain Reaction / methods
  • Reference Values
  • Retrospective Studies
  • Risk Assessment
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Skin Neoplasms / virology*
  • Survival Analysis
  • Tumor Virus Infections / mortality
  • Tumor Virus Infections / pathology*
  • Tumor Virus Infections / virology