Nineteen percent of Merkel cell carcinomas are not driven by the Merkel cell polyomavirus and are substantially more aggressive than those that are virus positive, according to a report published online in the Journal of Investigative Dermatology.

This and other findings from a retrospective analysis of samples from 282 Merkel cell carcinomas in a Seattle repository “suggest that it may be clinically indicated to determine tumor viral status at the time of diagnosis, as the results may affect prognosis as well as optimal clinical management,” wrote Ata Moshiri, MD, who was with the University of Washington, Seattle, at the time of the study, and his associates.

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Given that virus-negative Merkel cell carcinomas carry a markedly higher risk of recurrence, progression, and patient mortality, “clinicians may consider larger initial surgical margins, larger radiotherapy fields, and the use of regional nodal therapy even in the absence of documented nodal metastasis. Closer clinical follow-up and more frequent radiologic surveillance may be justified for patients with virus-negative tumors because ... serologic monitoring is not feasible for this patient population,” the investigators noted.

The incidence of Merkel cell carcinoma, a rare and aggressive neuroendocrine skin cancer with an overall disease-related mortality of 40%, has quadrupled during the last 20 years. This is likely because of the increasing prevalence of risk factors for the cancer, including advanced age, increased cumulative exposure to ultraviolet light, and systemic immune suppression.

Data concerning the presence of Merkel cell polyomavirus in these cancers are conflicting, with estimates of virus positivity ranging from 20% all the way to 100% in some studies. Part of the reason for this wide range of estimates is that there is no accepted preferred method for measuring the viral status of these tumors. Moreover, the prognostic significance of that viral status is also debated. Thus, most Merkel cell cancers are not routinely analyzed for the presence of Merkel cell polyomavirus.

To pin down the prevalence of virus positivity and establish whether it impacts clinical outcomes, Dr. Moshiri and his associates analyzed 282 Merkel cell specimens collected since 1980 and stored in a Seattle repository, along with clinical data. They tested each specimen using an immunohistochemical assay to detect one antibody (CM2B4), a different immunohistochemical assay to detect another antibody (Ab3), and a quantitative PCR assay for polyomavirus DNA. To be considered virus positive, each specimen had to show the presence of the virus on at least two of these tests.

By these criteria, 53 tumors (18.8%) were found to be virus negative and 229 (81.2%) to be virus positive.

Virus-negative tumors tended to be smaller than virus-positive tumors at presentation. Despite their smaller size, virus-negative tumors tended to be more advanced at presentation: 66.7% had nodal or distant metastases, compared with 48.3% of virus-positive tumors.

A total of 66.7% of virus-negative carcinomas progressed, compared with only 43.6% of virus-positive carcinomas. The median time to progression was 1.2 years for virus-negative cancers, but was not reached for virus-positive cancers. In a univariate analysis, virus-negative tumors had a nearly twofold higher risk of progression. In a multivariate analysis that adjusted for differences in disease stage at presentation, the HR fell slightly to 1.55.

Cancer-specific mortality was 45.3% for virus-negative tumors, compared with 26.3% for virus-positive tumors. Median time to death from Merkel cell carcinoma was 3.7 years for virus-negative tumors but was not reached for virus-positive tumors. In a univariate analysis, virus-negative tumors carried a nearly twofold higher risk of death from Merkel cell carcinoma. In a multivariate analysis that adjusted for differences in disease stage at presentation, the HR fell somewhat to 1.50.

Median overall survival was 3.3 years for patients with virus-negative tumors, compared with 4.6 years for patients with virus-positive tumors.

These findings indicate that a more advanced cancer stage at diagnosis accounts for some but not all of the poorer clinical outcomes seen with virus-negative tumors, the investigators said.

This study could not assess why virus-negative Merkel cell carcinomas are more aggressive and lethal than virus-positive ones, but previous studies have proposed some plausible biological mechanisms. Virus-negative tumors carry a greater number of chromosomal aberrations, a greater burden of nucleotide mutations, and a greater number of mutations in known oncogenic pathways. They also may be more immunogenic “due to their constitutive expression of oncoproteins that may serve as targets for cytotoxic tumor-infiltrating lymphocytes,” Dr. Moshiri and his associates said.

They added that in this study, the immunohistochemical assay for CM2B4 antibodies was the test that most accurately identified tumors that had worse outcomes. “We believe that the CM2B4 antibody test may be well-suited for routine clinical use” because of its sensitivity and specificity in this application, its commercial availability, “and the ease with which it could be included in the work flow of clinical laboratories accustomed to immunohistochemistry.”

Dr. Moshiri is currently at the University of Pennsylvania, Philadelphia.

The National Institutes of Health, the Colin Johnston Fund, and the Janet Canning Fund supported the study. Dr. Moshiri reported having no relevant financial disclosures; one of his associates reported that her institute received research funding from Valeant and Pfizer unrelated to this work.