Journal of the National Cancer Institute Advance Access originally published online on June 17, 2009
JNCI Journal of the National Cancer Institute 2009 101(13):905-907; doi:10.1093/jnci/djp162
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© The Author 2009. Published by Oxford University Press.
EDITORIALS |
Does Detection of Merkel Cell Polyomavirus in Merkel Cell Carcinoma Provide Prognostic Information?
Affiliation of author: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Correspondence to: James A. DeCaprio, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Mayer 440, 44 Binney St, Boston, MA 02115 (e-mail: james_decaprio{at}dfci.harvard.edu).
Awareness of Merkel cell carcinoma (MCC) is increasing within the scientific and medical communities. MCC is a highly lethal skin cancer: Approximately 30% of all MCC patients die from metastatic disease within 2 years of diagnosis (1). The incidence of this relatively rare skin cancer has increased threefold over the past 20 years (2). Approximately 1500 new cases of MCC were diagnosed in the United States in 2008 (1). Remarkably, a new human polyomavirus (later named Merkel cell polyomavirus [MCPyV]) was discovered last year when viral DNA was found to be integrated into the tumor chromosomal DNA from eight of 10 cases of MCC (3). In one of these cases, DNA from the virus was integrated at the same site in the primary tumor and in a metastasis, indicating that clonal integration of the virus occurred in the primary tumor before metastasizing. In this issue of the Journal, a new report by Sihto et al. (4) provides important insights into the frequency and clinical characteristics of MCPyV DNA–positive MCC.
Tang and Toker (5) first described MCC and suggested that it derived from Merkel cells. Merkel cells are normally found in the basal layer of the epidermis and near hair follicles and have features of both mechanoreceptor and neuroendocrine cells. MCCs are comprised of small round cells that are predominantly blue when stained with hematoxylin–eosin and resemble small cell lung cancer (SCLC) cells. MCCs are immunohistochemically distinguished from SCLC by their expression of cytokeratin 20 and lack of expression of thyroid transcription factor 1. Merkel cells have neuroendocrine features, including expression of synaptophysin and chromagranin A. Risk factors for development of MCC include sun exposure and age. In addition, there is an increased risk for developing MCC among patients who are immunocompromised due to HIV infection, lymphoma, or solid organ transplantation (6,7).
In the new study, Sihto et al. (4) reviewed 207 reports of MCC that occurred in Finland from 1979 to 2004. Given the quality of the national cancer registry in Finland, this number probably reflected most if not all of the diagnosed cases of MCC that occurred in Finland over that 26-year span. Clinical data regarding the age and sex of the patient, the size and location of the primary tumor, evidence for metastases, and other medical conditions were collected. Formalin-fixed paraffin-embedded (FFPE) tumor samples were available for 170 of these cases. The clinical information and pathology samples were reviewed, and several cases were excluded from further analysis for several reasons, including insufficient clinical information, incorrect diagnosis, or an unknown primary tumor. After these exclusions, 114 cases of MCC were analyzed for the presence of viral DNA by polymerase chain reaction (PCR) amplification using two different primer sets as well as a primer set for quantitative PCR. MCPyV DNA was detected in 91 (79.8%) of 114 MCCs. The amount of viral DNA was compared with a chromosomal gene reference standard and found to vary between a few copies per 10 000 cells to more than 4000 copies per cell. Most MCCs had a substantial amount of viral DNA, and only nine of the 91 MCC DNA–positive samples had less than one copy of viral DNA per 10 cells. Notably, the chromosomal reference standard used in this study was the protein tyrosine phosphatase gamma receptor (PTPRG) gene. This gene is located in a common fragile site that is frequently deleted or mutated in a variety of cancers and is the site in one case of MCC in which MCPyV was found to be integrated (3,8,9). Therefore, it is possible that this study overestimates the copy number of MCPyV DNA if one or both copies of the PTPRG gene were deleted in any given tumor.
MCPyV resembles a typical polyomavirus with a circular double-stranded DNA genome and expresses large and small T antigens and three viral coat proteins. Upon integration in a Merkel cell genome, MCPyV DNA apparently preserves the intact small T antigen–coding sequences but frequently harbors mutations that delete or truncate the carboxyl-terminal half of the large T antigen (10). In addition, the viral coat protein genes are not always present in the integrated viral DNA. Sihto et al. (4) detected viral capsid protein 1 sequences in only 12 of the 91 viral DNA–positive cases. In addition, the challenges posed by PCR amplification of DNA extracted from FFPE samples are particularly relevant here. The use of shorter probes that detected the presence of sequences within the amino-terminal half of large T was the most sensitive probe for detecting the presence of MCPyV DNA. This study did not address whether there were mutations present in the large T antigen sequences or whether the viral DNA was integrated because PCR cannot distinguish episomal from integrated viral DNA. Southern blot analysis of chromosomal DNA or in situ hybridization of viral DNA within the nucleus would support the presence of integrated viral DNA. In addition, detection of fusion transcripts containing T antigens and cellular genes would also indicate integrated viral DNA (3).
Several features of this new comprehensive review of Finnish cases of MCC over a 24-year period are noteworthy. Consistent with reports that the incidence of MCC is increasing (2), there were an average of three cases per year from 1979 through 1999 and then 10 per year from 2000 through 2004. It cannot be excluded that increasing recognition of MCC by physicians and pathologists could account for at least some of the increased incidence. Perhaps more important is that the fraction of MCC that was positive for viral DNA did not change between these two time periods, suggesting that MCPyV is not an emerging new threat that accounts for the increasing incidence of MCC.
Does the presence of viral DNA give any insight into MCC? Can MCPyV DNA–positive MCC be distinguished from MCPyV DNA–negative MCC? MCPyV DNA–positive and MCPyV DNA–negative MCCs appear to be indistinguishable from each other by histology. Cytokeratin 20 and neuroendocrine markers are expressed in nearly all tumors. In this study, however, MCPyV DNA–positive MCC tended to present on the extremities more frequently than MCPyV DNA–negative MCC. Even more remarkable is that patients with MCPyV DNA–positive MCC had better overall survival than those with MCPyV DNA–negative MCC (5-year survival: 45% vs 15% in both univariate and multivariable analyses of survival). Perhaps MCC may parallel our experience with another virus-associated cancer. The presence of human papillomavirus (HPV) in oropharyngeal squamous cell cancers is associated with a better prognosis and response to therapy (11,12). It is not clear why the presence of HPV and perhaps MCPyV would predict a better prognosis. Perhaps expression of the viral oncogenes can induce or promote the development of cancers that have fewer host cell chromosomal abnormalities, which may result in tumors with simpler genomic abnormalities. Alternatively, the viral oncogenes may specifically perturb host signaling pathways, including immune surveillance, that render them less aggressive or lethal.
NOTES
J. A. DeCaprio serves as a consultant to Merck & Co, Inc. (Whitehouse Station, NJ).
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