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

Usefulness of ulceration and hyperkeratosis as clinical predictors of Merkel cell polyomavirus‐negative and combined Merkel cell carcinoma: A retrospective study

“…Most studies investigating the prevalence of MCPyV in MCC have used the polymerase chain reaction technique to detect viral sequences, although routine use of this technique is beyond the scope of most standard surgical pathology laboratories. In contrast, immunohistochemical detection of MCPyV using the commercially available CM2B4 antibody can be performed easily in most pathology laboratories . Since the initial reports describing the prevalence of MCPyV, several independent research groups have indicated that the prevalence of MCPyV among MCC cases is approximately 75%, based on values ranging from 24% in Australia to 100% in Europe and Korea, with a wide range of viral load values .…”

“…A later study of 60 MCC patients revealed that virus‐negative status was univariately associated with poor overall and recurrence‐free survival rates, although these associations disappeared when tumor stage and nodal involvement were incorporated into the analysis . The largest published study to date (282 MCC patients) has also indicated that MCPyV‐negative MCC is associated with significantly increased risks of MCC progression and related death . However, patients’ viral status does not seem to alter their clinical management, as targeted immunotherapy (programmed cell death protein 1 inhibitor) provides a response in 44% of MCPyV‐negative patients and 62% of MCPyV‐positive patients …”

Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA In Situ Hybridization Assay

“…In addition, the differing genetic drivers and mutational profiles of MCPyVpositive and MCPyV-negative MCC may have translational significance for prognosis and therapeutics, suggesting further rationale for characterization of MCPyV status (4-6). Although reports on prognostic significance have been mixed regarding whether the presence of MCPyV detection is associated with improved outcome, a recent large prospective study of 282 cases using multimodal MCPyV detection with qPCR and IHC demonstrated significantly better outcome for MCPyV-positive tumors (28). In addition, the presence of MCPyV may influence tumor sensitivity to immunotherapy and targeted therapy (5,29,30).…”

S2k guidelines for Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) – update 2018

“…Histological characteristics of prognostic significance include tumor thickness and the presence or absence of tumor‐infiltrating lymphocytes, especially CD8 + T cells . The prognostic significance of the histological subtype (trabecular, small‐cell, intermediate) and the molecular or immunohistochemical detection of the Merkel cell polyomavirus continues to be the subject of controversial debate . However, more recent studies seem to indicate that tumors not associated with the Merkel cell polyomavirus have a worse prognosis .…”