Reply to Commentary on “Cytokeratin 20-negative Merkel cell carcinoma is infrequently associated with the Merkel cell polyomavirus”

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To the editor: We appreciate the comments by Iwasaki et al regarding our recent article, ‘Cytokeratin 20-negative Merkel cell carcinoma is infrequently associated with the Merkel cell polyomavirus.’ They report findings in an independent cohort of cytokeratin 20-negative Merkel cell carcinomas (MCCs), the majority of which are negative for Merkel cell polyomavirus (MCPyV), in agreement with our observations.

Among MCCs classified as MCPyV positive in our study, one case (#13) had relatively low MCPyV by quantitative PCR (qPCR). Although qPCR is accepted as the gold standard for MCPyV detection in MCC, there is debate about whether low levels of MCPyV represent tumorigenic virus or contamination by background wild-type virus.1, 2, 3 In addition, the sensitivity of any given primer pair may vary dramatically from case to case.1 Hence, currently there is no universally accepted threshold for considering a tumor MCPyV positive by qPCR. We agree with Iwasaki et al that immunohistochemistry for MCPyV large T antigen (LTAg), while less sensitive than qPCR, may be informative in some cases that are borderline by qPCR. We performed immunohistochemistry for LTAg expression in case #13 using CM2B4 antibody as previously described.4 This demonstrated moderate to strong nuclear staining for LTAg in >80% of tumor cells, validating our classification of this tumor as MCPyV positive.

We agree that loss of cytokeratin-20 expression may be associated with loss of differentiation in MCC. However, further study is needed to determine the molecular similarity of these tumors to conventional (cytokeratin 20-positive) MCC.


  1. 1

    Rodig SJ, Cheng J, Wardzala J et al. Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest 2012;122:4645–4653.

  2. 2

    Matsushita M, Iwasaki T, Kuwamoto S et al. Merkel cell polyomavirus (MCPyV) strains in Japanese merkel cell carcinomas (MCC) are distinct from Caucasian type MCPyVs: genetic variability and phylogeny of MCPyV genomes obtained from Japanese MCPyV-infected MCCs. Virus Genes 2014;48:233–242.

  3. 3

    Bhatia K, Goedert JJ, Modali R et al. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. Int J Cancer 2010;126:2240–2246.

  4. 4

    Fisher CA, Harms PW, McHugh JB et al. Small cell carcinoma in the parotid harboring Merkel cell polyomavirus. Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:703–712.

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Correspondence to Steven D Billings.

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