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Of Merkel Cell Polyomavirus and Its Clinical&Nbsp COMMENTARY In North America, the majority of Clinical Implications Merkel cell carcinoma (MCC) tumors Heat treatment induces antiviral factors APOBEC3A and APOBEC3G in have Merkel cell polyomavirus genital warts. (MCPyV) DNA integrated into their genomes. Considering the poor survival APOBEC3A and APOBEC3G induce mutations in the human papilloma virus rates seen in patients with MCC, it is E2 gene. essential to understand disease risk Hyperthermia may induce regression of genital warts via APOBEC-dependent factors and prognostic markers to guide antiviral and immunological mechanisms. prevention and treatment strategies. Presently, Moshiri et al. (2017) report the largest retrospective case series to against the virus. Hyperthermia, in pattern is widespread in human cancers. Nat date addressing the impact of MCPyV Genet 2013;45:970e6. contrast to cryotherapy, would be an status on MCC prognosis. As there is no elegant way to expose the virus in a Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 gold standard assay for detecting virus, meaningful way to immune reactivity infection and is suppressed by the viral Vif they employed a consensus of the three and even prevent recurrences, an effect protein. Nature 2002;418:646e50. methods for virus detection. Analyzing similar to that of imiquimod when used Turelli P, Mangeat B, Jost S, Vianin S, Trono D. MCC samples from 282 patients, the to treat genital warts. Inhibition of hepatitis B virus replication by authors showed improved progression- APOBEC3G. Science 2004;303:1829. CONFLICT OF INTEREST free survival and disease-specific Vartanian JP, Guetard D, Henry M, Wain- survival in the 81% of patients with The authors state no conflict of interest. Hobson S. Evidence for editing of human papillomavirus DNA by APOBEC3 in benign MCPyV-positive tumors. However, the REFERENCES and precancerous lesions. Science 2008;320: effect of virus status on prognosis was e Ahmed Z, Kawamura T, Shimada S, Piguet V. The 230 3. not independent of tumor stage on role of human dendritic cells in HIV-1 infection. Yang Y, Wang H, Zhang X, Huo W, Qi R, Gao Y, e multivariate analysis. J Invest Dermatol 2015;135:1225 33. et al. Heat increases the editing efficiency of Currently, the clinical implications of Huo W, Gao XH, Sun XP, Qi RQ, Hong Y, human papillomavirus E2 gene by inducing McHepange UO, et al. Local hyperthermia at 44 upregulation of APOBEC3A and 3G. J Invest MCC viral status are poorly understood. degrees C for the treatment of plantar warts: a Dermatol 2017;137:810e8. One reason for this is that there is no randomized, patient-blinded, placebo- Zhu LL, Gao XH, Qi R, Hong Y, Li X, Wang X, validated clinical test for MCPyV controlled trial. J Infect Dis 2010;201:1169e72. et al. Local hyperthermia could induce antiviral detection. The present study used a Roberts SA, Lawrence MS, Klimczak LJ, activity by endogenous interferon-dependent Grimm SA, Fargo D, Stojanov P, et al. An pathway in condyloma acuminata. Antiviral multimodal viral detection method to APOBEC cytidine deaminase mutagenesis Res 2010;88:187e92. show that four in five MCC tumors in their patient population tested positive for MCPyV. More significantly, they See related article on pg 819 showed that detecting MCPyV in tumor samples is imperfect with both immunohistochemistry (IHC) and Seeking Standards for the quantitative PCR (qPCR) approaches. Compared with the consensus virus Detection of Merkel Cell detection of two antibodies and one set of qPCR primers, staining for MCPyV Polyomavirus and its large T antigen with CM2B4 antibody showed the highest sensitivity (88.2%) Clinical Significance and specificity (94.3%). This approach to MCPyV detection can be imple- 1 2 2 Mary Eid , Jannett Nguyen and Isaac Brownell mented easily in most pathology labs, and it has the advantage of using a Merkel cell carcinoma is a rare skin cancer associated with Merkel cell poly- commercially available monoclonal omavirus in most cases. Prior studies associating Merkel cell carcinoma viral antibody. Their PCR assay was less fi status with prognosis have inconsistent ndings. Moshiri et al. used multimodal robust, with a sensitivity of 82.5% and virus detection to determine that the 81% of patients with virus-positive Merkel specificity of 81.1%. cell carcinoma tumors had earlier stage disease and better outcomes relative to Many qPCR approaches have been virus-negative cases. used to detect MCPyV DNA in patient Journal of Investigative Dermatology (2017) 137, 797e799. doi:10.1016/j.jid.2016.12.024 samples. Published PCR MCPyV detection assays vary in the virus- specific primer sequences used, the 1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of 2 number of virus primer sets used, the Health, Bethesda, Maryland, USA; and Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA reference human sequence that is Correspondence: Isaac Brownell, Dermatology Branch, 10 Center Drive, 12N240C, Bethesda, Maryland amplified, and the thresholds used to 20892-1908, USA. E-mail: [email protected] consider a test positive. The present ª 2017 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. study used only one optimized primer www.jidonline.org 797 COMMENTARY Regardless of the cause, the low Clinical Implications threshold needed to detect MCPyV Merkel cell polyomavirus-positive Merkel cell carcinomas are less aggressive. DNA reliably in virus-positive tumors decreases assay specificity and impedes Virus status is not an independent prognostic marker for Merkel cell the use of PCR as a clinical test. carcinoma. The challenges with PCR detection of Antibody staining works, but a gold-standard assay for Merkel cell poly- MCPyV could explain why so many omavirus is still needed. divergent qPCR assays have been developed and why some laboratories use multiple primer sets. At least four prior studies (Busam et al., 2009; Chun set to detect virus DNA, and like most given MCC tumor genome, it is not et al., 2013; Leroux-Kozal et al., 2015; published assays, the threshold to call a uncommon for qPCR to detect only a Rodig et al., 2012) have used PCR sample positive was set at a level well fraction of virus copies per cell in approaches in addition to IHC to detect below 1 viral copy per cell (0.01). MCPyV-positive tumor samples. Stro- MCPyV in MCC patient samples. All Despite this, the authors detected many mal cells, blood, and adjacent tissues four studies detected virus in more (n ¼ 40) false-negative PCR tests in are not expected to harbor MCPyV samples by PCR than by IHC, suggest- their study (samples negative by PCR, DNA, but they contribute a minor ing that PCR detection is more sensi- but positive with both antibodies by fraction of the total DNA extracted from tive. In contrast, the current study IHC). Lowering the PCR test threshold clinical tumor samples. An interpreta- detected virus in more tumors using for viral positivity to include more of tion that only a fraction of tumor cells IHC than with their PCR assay. these tumors would decrease speci- contain viral DNA is at odds with the Considering their diversity, it is possible ficity, as detection of background concept that clonal viral integration is that the most sensitive and specific PCR MCPyV was already noted in 10 MCC an early event in MCC carcinogenesis assay for MCPyV detection has yet to be tumors and 3 of 16 non-MCC skin (Feng et al., 2008) and that IHC staining compared with IHC assays. tumors negative by IHC. These findings for viral T antigen is typically present in The present study found better are indicative of seemingly inherent close to all tumor cells in MCPyV- progression-free survival and MCC- difficulties in using PCR to amplify positive tumors (Figure 1). It seems specific survival in patients with virus- integrated MCPyV DNA from patient more likely that MCPyV detection by positive tumors. Prior studies on the samples. PCR is compromised in some MCC prognostic implications of MCPyV sta- Despite the fact that multiple virome tumor samples rather than virus being tus have generally shown either a trend copies can be clonally integrated into a absent in up to 99% of tumor cells. toward or significantly better survival associated with virus-positive tumors (Bhatia et al., 2010; Brummer et al., 2016). Some studies showed better prognosis with virus-positive tumors on univariate analysis, but viral status was not an independent prognostic factor on multivariate analysis (Nardi et al., 2012). Similarly, the present study also demonstrated that virus status is not an independent prognostic factor when tumor stage is considered. Taken together, these results suggest that MCPyV-positive tumors are less aggressive and that the less favorable outcomes associated with virus- negative tumors are, in part, due to their higher propensity to present with regional or distant metastases. The better prognosis associated with MCPyV-positive MCC tumors is analo- gous to the finding that human papillomavirus-positive head and neck squamous cell carcinoma has a more favorable prognosis over human papillomavirus-negative head and neck Figure 1. Merkel cell carcinoma with immunostaining for Merkel cell polyomavirus large T antigen using the CM2B4 antibody (brown) and hematoxylin counterstain. Four virus-positive tumors squamous cell carcinoma (Mallen-St demonstrating that although staining intensity can vary from cell to cell, almost all tumor cells stain for Clair et al., 2016; Okami, 2016). virus. Staining is notably absent in stromal fibroblasts and endothelial cells. Scale bar ¼ 50 mm. Because of better treatment responses 798 Journal of Investigative Dermatology (2017), Volume 137 COMMENTARY and more favorable prognosis in human between viral detection methods will MCPyV-positive and MCPyV-negative Merkel papillomavirus-positive head and neck require further investigation.
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