• Merkel cell carcinoma;
  • polyomavirus;
  • virus-like particles;
  • T antigen;
  • VP1


  1. Top of page
  2. Abstract
  3. MCPyV Virology and Genomic Organization
  4. MCPyV Epidemiology
  5. MCPyV Pathology
  6. Conclusions
  7. References

The Merkel cell polyomavirus (MCPyV), identified in humans in 2008, is associated with a relatively rare but aggressive neuroendocrine skin cancer, the Merkel cell carcinoma (MCC). MCC incidence is increasing due to the advancing age of the population, the increase in damaging sun exposure and in the number of immunocompromised individuals. MCPyV must be considered as the etiological agent of MCC and thus is the first example of a human oncogenic polyomavirus. MCPyV infection is common, and seroprevalence studies indicate that widespread exposure begins early in life. The majority of adults have anti-MCPyV antibodies and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV suggesting that MCPyV infection persists throughout life. However, the mode of transmission, the host cells, and the latency characteristics of this virus remain to be elucidated. In addition, it is still not clear whether MCPyV is associated with diseases or lesions other than Merkel cell carcinoma. The etiologic role of MCPyV in MCC opens up opportunities to improve the understanding of this cancer and to potentially improve its treatment.

57k Tag

57 kilo Dalton tumor antigen


American Joint Committee on Cancer


Antibody to LTag


Antibody to sTag


BK human polyomavirus

VP1, VP2 and VP3

Capsid proteins

CK20 and CK7

Cytokeratin 20 and cytokeratin 7


Enzyme-linked immuno sorbent assay

HES staining

Hematoxylin erythrosine saffron staining


Human polyomavirus


JC human polyomavirus


Merkel cell carcinoma


Merkel cell polyomavirus


Large Tumor antigen


Small Tumor antigen


Monoclonal antibody


Non-coding control region


Origin of replication


Polymerase chain reaction


Quantitative PCR


Rolling circle amplification


Sentinel lymph node biopsy


Type I interferon


Thyroid transcription factor 1


Virus-like particles

The Merkel cell polyomavirus (MCPyV), a new human polyomavirus identified in 2008 by Feng et al. [1] is detected in the majority of Merkel cell carcinomas (MCCs) [1, 2] and was recently classified as a 2A carcinogen [3]. MCC is a relatively rare but aggressive form of cutaneous cancer, and the incidence of this cancer increases with age, immunodeficiency and sun exposure [4-6]. MCC tumor cells do not seem to produce viral particles [7, 8] and the specific cells in which MCPyV virions are produced have not been identified to date. It has also been shown that UV irradiation induces an increase in MCPyV small T antigen (sTag) transcripts that may explain the association between sun exposure, MCPyV infection, and the development of MCC [9]. As for other human polyomaviruses, primary MCPyV exposure occurs in early childhood and the majority of adults have anti-MCPyV antibodies, and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV.

MCPyV Virology and Genomic Organization

  1. Top of page
  2. Abstract
  3. MCPyV Virology and Genomic Organization
  4. MCPyV Epidemiology
  5. MCPyV Pathology
  6. Conclusions
  7. References

MCPyV is a non-enveloped double stranded DNA virus belonging to the family Polyomaviridae, genera Orthopolyomavirus as other human polyomavirus (HPyV) species like BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV). Its genome of about 5.4 kb is divided into early and late regions by a non-coding control region (NCCR) (Fig. 1). The early region encodes three proteins, large T (LTag), small T (sTag), and 57 kT (57 k Tag) antigens. Due to alternative splicing, these antigens share a common 78 amino acid sequence at their N-terminus that contains B-cell epitopes [10]. This has also been observed for BKPyV [11] and it must be noted that the expression of sT contributes to the development of antibodies against LTag. In MCC cells, mutations, insertions, and deletions within the Tag gene result in the production of truncated LTag and 57 k Tag proteins. The late region encodes three capsid proteins (VP1, VP2, and VP3). When expressed in mammalian or insect cells, VP1 proteins (or VP1 + VP2 proteins) self-assemble into 45–55 nm diameter virus-like particles (VLPs) (Fig. 2) that are used in serological assays [7, 12-14].


Figure 1. Genome organization of Merkel Cell Polyomavirus. The genome encodes early proteins including the LTag (purple), the sTag (blue) and the 57 k Tag (pink) and three late proteins (capsid proteins): VP1 (red), VP2 (orange) and VP3 (yellow). These two coding regions are separated by the promotor/replication origin region (Ori = replication origin).

Download figure to PowerPoint


Figure 2. Electron micrograph of virus-like particles (VLPs) obtained by expression of MCPyV VP1 gene in insect cells. Scale bars, 100 nm.

Download figure to PowerPoint

Little is known concerning the viral MCPyV replication cycle as it has not been possible to cultivate this virus. Although infectious MCPyV molecular clones induce the production of low levels of virions in different cell lines [15-17], secondary transmission to uninfected cells has not been reported. There is an orderly gene expression cascade for MCPyV, LTag, and 57 k Tag proteins being expressed first, followed by expression of sTag and then VP1 proteins [15]. MCPyV replication and encapsidation are increased by overexpression of MCPyV sTag, consistent with sTag being a limiting factor during virus replication [15]. The findings also suggested that MCPyV had restrictive cell tropism and that the late phase of MCPyV replication may be governed by cell differentiation [15-17]. It is not known whether epidermal non-transformed Merkel cells or their progenitors [18] are susceptible to infection by MCPyV.

MCPyV Epidemiology

  1. Top of page
  2. Abstract
  3. MCPyV Virology and Genomic Organization
  4. MCPyV Epidemiology
  5. MCPyV Pathology
  6. Conclusions
  7. References

The virus is ubiquitous and MCPyV is frequently established as a persistent skin infection in healthy subjects. Detection of the viral DNA on the skin of almost all adults has suggested that most MCPyV infections occur by direct skin to skin contact or from the environment, since MCPyV DNA seems to be frequently detected on environmental surfaces [19], but the exact mode(s) of MCPyV transmission, site(s) of initial infection, and the existence of a latent phase have not yet been characterized [20, 21]. In the absence of a cell culture system, detection of current MCPyV infection is based on detection of the viral DNA by PCR amplification, and current and past exposure by the detection of specific antibodies.


Anti-MCPyV antibodies are detected by ELISA, or luminex-based multiplex serological assays using VP1 or VP1 plus VP2 VLPs produced in insect cells (Fig. 2) or 299 TT cells, and GST-VP1 recombinant protein (capsomeres) [12-14, 22, 23]. Not all tests for the detection of anti-VP1 antibodies are equivalent. Assays using BKPyV VLPs have been shown to be more sensitive in detecting anti-VP1 antibodies than assays using GST-VP1 proteins [11], although no difference between GST-capsomers and VLPs has been demonstrated for the detection of monoclonal antibodies against human papillomaviruses [24]. In addition, assays using VP1 monomers have been shown to underestimate seroprevalence for both BKPyV and MCPyV in comparison with assays using VLPs [11, 23].

Neutralization assays using MCPyV pseudovirions produced in human embryonic kidney 293TT cells have also been used [7]. There is no evidence of cross-reactivity between MCPyV with JCPyV, BKPyV, or HPyV9 [12-14, 23] and neutralization assays using MCPyV pseudovirions also confirm the specificity of the MCPyV reactivity [7].

Seroprevalence of 50–95% is reported in adults [7, 12-14, 25-29]. The age-specific seroprevalence of MCPyV (Fig. 3) indicates that exposure occurs early in life [13, 14, 22] with seroprevalence of 20–40% in children aged 1–5 years [23, 29]. In addition, MCPyV antibody titers are correlated with the viral load on the skin surface [26, 30]. Merkel cell polyomavirus is the first polyomavirus to be clearly implicated as a causal agent underlying a human cancer, Merkel cell carcinoma. Infection with MCPyV is common in the general population, and a majority of adults shed MCPyV from the surface of their skin [21]. In this study, MCPyV DNA was quantitated in skin swab specimens from healthy volunteers sampled at different anatomical sites over time periods ranging from 3 months to 4 years. The volunteers were also tested using a serological assay that detects antibodies specific for the MCPyV pseudovirion. There was a positive correlation between MCPyV virion-specific antibody titers and viral load at all anatomical sites tested (dorsal portion of the hands, forehead, and buttocks) (Spearman r = 0.644, p < 0.0001). The study results are consistent with previous findings suggesting that the skin is primary site of chronic MCPyV infection in healthy adults and suggest that the magnitude of an individual's seroresponsiveness against the MCPyV virion generally reflects the overall MCPyV DNA load across wide areas of the skin. In light of previous reports indicating a correlation between MCC and strong MCPyV-specific seroresponsiveness, this model suggests that poorly controlled chronic MCPyV infection might be a risk factor in the development of MCC. To validate whether Merkel cell polyomavirus serology correlates with MCPyV infection, MCV viral load from various skin lesions and healthy skin from 434 patients has been compared to MCV serology results using virus-like particle based ELISA and neutralization assays. Sixty-five percent of participants were MCPyV seropositive and 18% were MCPyV DNA positive [26]. The presence of antibodies was correlated with the presence of virus DNA [odds ratio, 27.85 (95% confidence interval, 6.6–166.5)], with 97% of patients who tested positive for MCPyV DNA being MCPyV seropositive [26]. High antibody levels correlated with high MCPyV load (p < 0.01) [26, 30], indicating that individuals with persistent and active skin shedding of MCPyV virions have high levels of anti-VP1 antibodies. This also suggests that the skin is the primary site where MCPyV virions are produced and the reservoir of the virus, although this does not exclude the possibility that additional sites of virus replication exist [26, 30].


Figure 3. Age-specific seroprevalence of MCPyV [adapted from Touzé et al. [13] and Nicol et al. [29]].

Download figure to PowerPoint

Detection of the viral genome

Viral DNA has been detected by PCR, nested PCR, quantitative PCR (qPCR), multiplex PCR, and Rolling circle amplification (RCA) in MCC tumor tissues collected around the world. MCPyV genome sequences have been detected using different primers specific to the MCPyV LTag, sTag, and VP1 genes. These methodological differences between studies may explain the reported variations in prevalence. It is possible that the primers used may affect the detection of variant MCPyV strains. It has also been reported that formalin fixation may fragment DNA and result in differences in DNA amplification according to the size of the amplicons. This is particularly important for samples containing very low copy numbers per cell [30, 31]. Comparison of results regarding MCPyV DNA prevalence and viral load must therefore be undertaken with caution.

MCPyV DNA has been detected at varying levels of frequency (0–100%) in skin samples, and in anal and penile swabs [1, 9, 20, 21, 26, 32-38]. The MCPyV viral load on the skin surface varies from less than 1 copy per 1000 cells to 1000 copies per cell [9, 26, 30, 39-41]. The mean DNA copy per cell in normal skin has been reported to be 0.02–0.07 [42]. It has also been reported that low levels of MCPyV sequence can be amplified from many human tissues where it may undergo low-level replication or latency [1, 39, 43, 44]. MCPyV DNA has also been detected in the oral cavity, with prevalence ranging from 8% to as high as 60% [34, 35, 39]. The sensitivity of the detection of MCPyV DNA is affected by variations in the number of cells present in different samples. Numbers are generally lower in swabs compared with biopsies, but there is also variation in the percentage of tumor cells between different biopsies (10–100% of cells). However, variation in the number of cells per sample had limited impact on the determination of the number of DNA copies per cell (viral load). Although viral load is depending on the primers and housekeeping gene used, comparison of data is preferably achieved by comparing viral loads. The presence of MCPyV DNA has also been reported in monocytes of MCC patients, in the buffy coat of healthy subjects and in normal lymph nodes [36, 45, 46]. These findings suggest that MCPyV could persist in peripheral monocytes and leukocytes and that this may serve as a tissue reservoir.

MCPyV Pathology

  1. Top of page
  2. Abstract
  3. MCPyV Virology and Genomic Organization
  4. MCPyV Epidemiology
  5. MCPyV Pathology
  6. Conclusions
  7. References

Merkel cell carcinoma (MCC) is a rare skin neoplasm whose incidence has been estimated at 0.35 per 100 000 person-years in the Netherlands [47] and 0.24 per 100 000 person-years in the USA [4], where approximately 1500 cases are identified each year [48]. Due to its rarity, few epidemiological studies are available on MCC, and data from cancer registries indicate that MCC preferentially affects whites, males, and those older than 65 years [4]. Increased incidence of MCC in immunosuppressed patients has been reported in organ transplant recipients [49] and in HIV patients [5], leading to the hypothesis of an infectious etiology for MCC [1]. MCC is a rare tumor caused by a very common viral skin infection as, in addition to loss of immune surveillance, viral integration and LTag deletion and/or mutations eliminating both T antigen replication capacity and expression of highly antigenic major capsid protein are required for MCC cell survival [50].

Merkel cell carcinoma (MCC) usually presents as an asymptomatic, rapidly growing, solitary, erythematous or violaceous, dome-shaped lump or plaque, most commonly under a smooth, sometime telangiectatic skin surface (Fig. 4). It is often located on sun exposed areas, most commonly the head and neck, followed in frequency by the limbs and the trunk [4] but it can affect any part of the body including the mucosae [51]. The acronym AEIOU summarizes the most characteristic features of MCCs: Asymptomatic, Expanding rapidly (≤3 months), Immunosuppression, Older than age 50, UV-exposed site [6]. Interestingly, skin areas that predominantly contain Merkel cells (lips, nipple, volae, genital skin) are not especially prone to develop MCC, thus raising concerns about the origin of MCC. MCPyV-positive MCCs do not seem to harbor specific clinical features, though it has occasionally been suggested that they are more often associated with female sex and located on a limb, in comparison with cases of MCPyV-negative MCC [52-54]. On diagnosis, the majority of patients have local disease (66%) followed by nodal disease (27%), and distant metastatic disease (7%) [55]. MCC can also be revealed by nodal or distant metastasis of unknown origin, with no primary skin or mucosal MCC on diagnosis [56].


Figure 4. Clinical appearance of Merkel cell carcinoma lesion: A 2 cm, dome-shaped Merkel cell carcinoma on the buttock of an 84-year-old woman.

Download figure to PowerPoint

This aggressive skin neoplasm evidences a high propensity to metastasize both to lymph nodes and as distant metastases. In the majority of studies, relative five-year survival ranges between 50 and 60% [4, 55, 57-59]. Prognosis is related to the MCC staging according to the 7th American Joint Committee on Cancer (AJCC), mainly based on primary tumor size, microscopic and macroscopic lymph node involvement and distant metastases [60]. Five-year overall survival rates for AJCC stage I, II, III, and IV are 81%, 67%, 52%, and 11%, respectively [57, 61-63] (Table 1). Other factors associated with poor prognosis of MCC are summarized in Table 2. It must be noted that the prognostic value of these factors is either controversial or need to be confirmed on large prospective studies at the exception of immunosuppression.

Table 1. Prognosis and treatment for Merkel cell carcinoma (MCC) according to American Joint Committee on Cancer (AJCC) stage (based on references [57], [61-63])
AJCC stagePrognosisTreatment
 OS 2 yearsaOS 5 yearsbWide local excision (2 cm)Lymph node dissectionRadiotherapy (tumoral site)Radiotherapy (lymph node site)Chemotherapy
  1. a

    Overall survival at 2 years.

  2. b

    Overall survival at 5 years.

Size < 2 cm (stage I)67%81%++
Size > 2 cm (stage II)59%67%++±
Nodal disease (stage III)49%52%++++
Systemic metastases (stage IV)23%11%±±±±+
Table 2. (A) Factors associated with poor outcome (recognized factors are in bold), (B) controversial factors associated with poor outcome. Most factors have to be confirmed on larger prospective studies as being independently associated with poor prognosis
Clinical factors Histological and immunohistochemistry factors Biological and Virological factors
-AJCC stage based on tumor size and presence of metastases [4, 47, 55, 64-68]Lymphovascular infiltration [58, 71, 72]No or low anti-VP1 titers [8]
-Immunosuppression [65, 69, 70]

Low tumor infiltrating lymphocytes [64, 71, 73]

Low tumor infiltrating CD8 + T cells [64]

Seroconversion or persistance of Anti-LTag antibodies [76]

P53 expression and TP53 gene mutations [54, 68]

P63 expression and TP63 gene mutations [68, 74]

Ki67 index > 50% [68, 75]

Vitamin D deficiency [70]
Male sex [4, 8, 47, 59, 64-67, 70]Infiltrative growth pattern (vs nodular) [68, 71, 77]Low intra-tumoral viral load [53, 54, 67, 79-84]
Older age (>70 years) [4, 64-66]Depth of invasion [54, 67, 68, 71, 77, 78]No or low levels of LTag intra-tumoral expression [54, 79, 85]
Head and neck location [4, 66, 86]  
History of secondary malignancy [65, 66, 86]  

The origin of MCC is still controversial [87]. It has been mainly thought to derive from the resident Merkel cells distributed in the basal layer of the epidermis and associated with nerve fiber endings involved in skin mechanoreception properties. Indeed, MCC and Merkel cells share common ultrastructural features, namely intracytoplasmic neurosecretory dense core granules reflecting their neuroendocrine differentiation. A more recent theory is that MCC might derive from epidermal stem cells located in the basal layer of the epidermis or in hair follicles displaying the capacity for both neuroendocrine and epidermoid differentiation [88]. However, this hypothesis is not supported by the dermal location of MCC with no connection with the epidermis. Identifying the natural tropism of the MCPyV would probably assist the understanding of the natural history and the cell origin of MCC.

MCPyV viral markers in MCC patients

MCPyV DNA has been detected in 59–100% of MCCs [1, 8, 21, 25, 32, 53, 82, 89-94]. Viral loads of 0.1 to thousands of copies per cell have been observed in about 80% of MCCs. The mean viral load has been reported to be 1–5 copies per cell, in agreement with integration of the viral genome into chromosomal DNA [1, 90, 93, 94].

Anti-VP1 antibodies have been detected in 88–100% of MCC cases [7, 8, 14, 25]. In addition, the capsid antibody titer in many of these MCC cases is much higher than observed in control populations. The anti-VP1 geometric mean titer in MCC patients is 14–59 times higher than in controls [7, 8]. One explanation is that loss of immune surveillance in some patients enhances active replication of the virus and, as a consequence, the recombination of virus genome fragments with the host genome. [50]. This could also explain why most MCC patients have high anti-VP1 antibody titers as it was shown that individuals with persistent and active skin shedding of MCPyV have high levels of anti-VP1 antibodies [26, 30].

An assay for the detection of antibodies against LTag has also been developed using GST recombinant proteins as antigens [76]. Anti-MCPyV LTag antibodies are rarely detected in the general population, but are detected in around 40% of MCC patients. The detection of anti-LTag appears to be a useful marker to confirm the involvement of MCV in MCC tumors and, more importantly, in monitoring tumor progression, as anti-LTag antibodies have been found to disappear or decrease after tumor removal, and then reappear or increase in cases of recurrence or progression of the disease [76].

MCC histopathology and detection of MCPyV antigens in MCC

Merkel cell carcinoma (MCC) appears on pathology sections as a small, round, tumor usually located in the dermis with various depth extensions into the underlying tissues, and separated from the epidermis by a ‘grenz’ zone. On hematoxylin erythrosine saffron (HES) staining, the tumor cells had monomorphous morphology (Fig. 5), they were hyperbasophilic with a scant cytoplasm and round hyperchromatic nuclei, and can display a solid, trabecular or diffuse pattern of growth [95]. Positive diagnosis of MCC is based on immunohistochemistry, as MCC expresses both neuroendocrine and epithelial markers. MCC tumor cells display paranuclear dot-like staining with cytokeratin 20 and absence of staining with cytokeratin 7 (CK20+/CK7−), although very rare variants with CK20−/CK7+ expression have been reported [96]. Positive staining with a neuroendocrine marker (synaptophysin or chromogranin A) is therefore a clue for diagnosis. Negativity for thyroid transcription factor-1 (TTF-1) allows differential diagnosis from cutaneous metastases of neuroendocrine carcinomas of the lung [95].


Figure 5. Histological features of Merkel cell carcinoma. Hematoxylin erythrosine saffron (HES) staining: Dermal proliferation of blue cells separated from the epidermis by a ‘grenz’ zone (panel A), monomorphous hyperbasophilic cells with high mitotic rates (panel B). Positive immunostaining with CK20 antibody (panel C) with a paranuclear dot like pattern (panel D). Positive nuclear immunostaining for MCPyV LTag in a MCPyV -positive Merkel cell carcinoma (MCC) (panel E).

Download figure to PowerPoint

Immunodetection of MCPyV antigens on MCC tissues could be used as diagnostic markers. Interestingly, the VP1 capsid protein is not detected in MCC tumor cells [7, 8], in agreement with the absence of viral replication in MCC [10]. On the other hand, using the CM2B4 monoclonal antibody [91], MCPyV LTag is detected (Fig. 5) in the nuclei of 58–96% of MCCs [82, 91, 97-103]. According to these studies, immunodetection of LTag expression is found to be less sensitive but more specific than detection of MCPyV DNA by PCR. Absence of LTag expression seems to be correlated with the absence of detection of MCPyV DNA [101], supporting the hypothesis of the existence of a subset of MCPyV -negative MCCs. CM2B4 immunostaining also appears to be a reliable tool for the positive diagnosis of MCC in daily practice when the tumor displays an unusual differentiation pattern [104] and might be helpful for pathologists in the diagnosis of MCC in the future. One case of basal cell carcinoma positive for both moderate levels of MCPyV DNA and strong LTag expression was recently reported, raising the question of specificity of these markers or the role of MCPyV in the pathogenesis of at least certain other tumors [42]. Another monoclonal antibody generated against a specific epitope of the sTag antigen has been found to be more sensitive than CM2B4 antibody, with 92% of MCCs positive for sTag expression compared with 75% positive for LTag [105]. However, using another Mab directed against the same LTag sequence as CM2B4 Mab, MCPyV LTag expression was recently reported in 96% of 58 tumors [106].

MCPyV status and MCC prognosis

Factors recognized as associated with poor prognosis are size of the tumor and presence of metastases according to the AJCC staging [4, 47, 55, 64-68], and immunosuppression [65, 69, 70]. Recently, histological and immunochemistry markers have been described as potentially associated with poor outcome like low tumor infiltrating CD8 + T cells [101] and P53 and P63 expression and gen mutations [54, 68, 74] (Table 2). However, these factors have to be confirmed as independently associated with poor outcome in larger prospective studies. In addition, other controversial clinical factors such as male sex, head and neck location, and history of secondary malignancy, and controversial histology factors such as depth of invasion and infiltrative growth pattern have also been advanced. Recently, Vitamin D deficiency has also been associated with a poor prognosis [70].

Whether the MCPyV status influences MCC outcome is still a matter of debate, although a range of findings argues for a more favorable prognosis of MCPyV-positive MCCs (Table 2). Detection of MCPyV DNA in MCC tumor samples was not found to be associated with a better MCC outcome in three studies [82-84], whereas high viral levels of DNA copies in MCC tumors seemed to be a favorable prognostic factor in three others [53, 80, 81]. Such differences might reflect differences in DNA detection techniques, tissue heterogeneity, and type of material investigated (frozen vs paraffin embedded). Similarly, there is a controversy regarding the prognostic value of LTag detection using CM2B4 antibody. Detection of LTag expression together with high MCPyV DNA levels has been found to be associated with better prognosis in two studies [54, 79], whereas LTag expression did not influence MCC outcome in another [85]. Serological investigations have also suggested that patients with higher anti-VP1 antibody titers have a better prognosis [8]. On the contrary, persistence or reappearance of anti-LTag antibodies has been associated with poor prognosis [76].

MCPyV and B-cell proliferative disorders

An epidemiological association between MCC and B-cell lymphoproliferative disorders has been reported [107, 108], leading to the hypothesis that immunosuppression induced by these hematological malignancies promotes the development of MCC. Another hypothesis for this association is the possible involvement of MCPyV in the pathogenesis of B-cell lymphoproliferative disorders. Lymphocytes may be a reservoir for MCPyV [46]. Detection of various levels of MCPyV DNA in B-cell lymphoproliferative disorders [46, 91] is not a valid argument for an etiological link, as MCPyV is also detected in a wide range of control tissues. However, clonal integration and truncated mutation of MCPyV DNA, a molecular signature of MCPyV oncogenesis, were evidenced in a subset of patients with chronic lymphocytic leukemia [109]. Whether MCPyV has a role in the pathogenesis of a subset of B-cell lymphoproliferative disorders remains to be demonstrated.

Therapeutic implications

Conventional treatment of MCC depends on disease stage (Table 1). Appropriate staging is based on clinical examination, especially looking for satellite cutaneous metastases, palpable lymph nodes, and any sign of distant metastases. Appropriate imaging, including regional lymph node sonography or whole body CT scan is performed based on clinical findings. When there are no palpable regional lymph nodes, a sentinel lymph node biopsy is necessary as the presence of micrometastases has been reported to be associated with poorer outcome [55]. Overall, these findings allow appropriate disease staging according to the American Joint Committee on Cancer (AJCC classification for therapeutic management). In addition, it has been suggested that detection of MCPyV DNA in a histologically normal sentinel lymph node could be considered a risk factor for regional relapse [110], but this remains to be demonstrated.

Surgical removal with wide margins (2–3 cm) remains the gold standard for treatment of localized tumors. Microscopic as well as macroscopic involvement of regional lymph nodes requires lymph node dissection. Adjuvant radiation therapy of the tumor site and, if involved, of the regional lymph node site after surgery has been found to be associated with decreased risk of locoregional relapse, with no benefit demonstrated on overall survival [51, 111-113]. For unresectable tumors, radiation alone is the recommended option, as MCC appears to be a relatively radiosensitive tumor [114]. For metastatic disease, various regimens of chemotherapy including anthracyclines, cyclophosphamide, etoposide, and platinum derivatives, alone or in combination have been reported. Response to chemotherapy is observed in about 60% of MCC patients, but prognosis remains poor, with a median overall survival of 21.5 months [115].

Before the discovery of MCPyV, the molecular pathogenesis of MCC was unclear and this has resulted in a lack of MCC-specific targeted therapies. Identification of MCPyV and progressive understanding of its involvement in the pathogenesis of MCC, like the inhibition of apoptosis regulated by proteins such as bcl-2 and survivin, has led to new therapeutic possibilities.

Drugs inhibiting MCPyV-positive MCC cell lines have been identified in vitro. For instance, type I interferon (IFN) was found to reduce expression of MCPyV LTag, in association with apoptosis of MCPyV-positive MCC cell lines [116]. However, no clinical response was reported after IFN treatment of two patients with advanced MCC [117]. Another drug, YM155, a selective inhibitor of survivin, a protein reported to play a critical role in the survival of MCPyV -positive MCC cell lines, was found to induce cell death in MCPyV -positive cells and at least a cytostatic effect on MCC xenograft tumors in mice [118]. As expression of MCPyV T antigens has been found to be necessary for survival of MCPyV -positive MCC cell lines [2, 105], T antigens also appear to be a potential therapeutic target for MCPyV -positive MCC management. Specific T-cell lymphocytes recognizing various epitopes of MCPyV have been identified, especially within the tumor, and also in the blood of some MCC patients [100]. The persistence of tumor growth despite development of these specific T cell responses has suggested that immune evasion mechanisms, namely inhibition of the T cell cytotoxic effects or promotion of T-regulatory lymphocytes, remain to be identified. Nevertheless, using a mouse model of MCC, it was recently reported that DNA vaccine encoding the first 258 aminoacids of LT antigen generates antitumor effects mainly mediated by CD4+ T cells against LT expressing tumors [119], and this may represent an additional approach for the control of MCC.


  1. Top of page
  2. Abstract
  3. MCPyV Virology and Genomic Organization
  4. MCPyV Epidemiology
  5. MCPyV Pathology
  6. Conclusions
  7. References

MCPyV infection is common, and age-specific seroprevalence studies indicate that widespread exposure begins early in life. The detection of MCPyV DNA on the skin surface of most adults suggests that MCPyV infection persists throughout life. However, the mode of transmission, the host cells, and the latency characteristics of this virus remain to be elucidated.

MCPyV is the etiological agent of MCC and thus is the first example of a human oncogenic polyomavirus. MCC is a rare neuroendocrine skin cancer with increasing incidence due to the advancing age of the population, and the increase in damaging sun exposure and in the number of immunocompromised individuals. In addition, it is still not clear whether MCPyV is associated with diseases or lesions other than Merkel cell carcinoma. The etiologic role of MCPyV in MCC opens up opportunities to improve the understanding of this cancer and to potentially improve its treatment.


  1. Top of page
  2. Abstract
  3. MCPyV Virology and Genomic Organization
  4. MCPyV Epidemiology
  5. MCPyV Pathology
  6. Conclusions
  7. References
  • 1
    Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008;319:1096100.
  • 2
    Houben R, Shuda M, Weinkam R, Schrama D, Feng H, Chang Y, et al. Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. J Virol 2010;84:706472.
  • 3
    Bouvard V, Baan RA, Grosse Y, Lauby-Secretan B, El Ghissassi F, Benbrahim-Tallaa L, et al. Carcinogenicity of malaria and of some polyomaviruses. Lancet Oncol 2012;13:33940.
  • 4
    Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49:83241.
  • 5
    Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW. Merkel cell carcinoma and HIV infection. Lancet 2002;359:4978.
  • 6
    Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang LC, Peñas PF, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 2008;58:37581.
  • 7
    Pastrana DV, Tolstov YL, Becker JC, Moore PS, Chang Y, Buck CB. Quantitation of human seroresponsiveness to Merkel cell polyomavirus. PLoS Pathog 2009;5:e1000578.
  • 8
    Touzé A, Le Bidre E, Laude H, Fleury MJJ, Cazal R, Arnold F, et al. High levels of antibodies against merkel cell polyomavirus identify a subset of patients with merkel cell carcinoma with better clinical outcome. J Clin Oncol 2011;29:16129.
  • 9
    Mogha A, Fautrel A, Mouchet N, Guo N, Corre S, Adamski H, et al. Merkel cell polyomavirus small T antigen mRNA level is increased following in vivo UV-radiation. PLoS ONE 2010;5:e11423.
  • 10
    Shuda M, Feng H, Kwun HJ, Rosen ST, Gjoerup O, Moore PS, et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci USA 2008;105:162727.
  • 11
    Bodaghi S, Comoli P, Bösch R, Azzi A, Gosert R, Leuenberger D, et al. Antibody responses to recombinant polyomavirus BK large T and VP1 proteins in young kidney transplant patients. J Clin Microbiol 2009;47:257785.
  • 12
    Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ, Moschos S, et al. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer 2009;125:12506.
  • 13
    Touzé A, Gaitan J, Arnold F, Cazal R, Fleury MJ, Combelas N, et al. Generation of Merkel cell polyomavirus (MCV)-like particles and their application to detection of MCV antibodies. J Clin Microbiol 2010;48:176770.
  • 14
    Viscidi RP, Rollison DE, Sondak VK, Silver B, Messina JL, Giuliano AR, et al. Age-specific seroprevalence of Merkel cell polyomavirus, BK virus, and JC virus. Clin Vaccine Immunol 2011;18:173743.
  • 15
    Feng H, Kwun HJ, Liu X, Gjoerup O, Stolz DB, Chang Y, et al. Cellular and viral factors regulating Merkel cell polyomavirus replication. PLoS ONE 2011;6:e22468.
  • 16
    Neumann F, Borchert S, Schmidt C, Reimer R, Hohenberg H, Fischer N, et al. Replication, gene expression and particle production by a consensus Merkel Cell Polyomavirus (MCPyV) genome. PLoS ONE 2011;6:e29112.
  • 17
    Schowalter RM, Reinhold WC, Buck CB. Entry tropism of BK and Merkel cell polyomaviruses in cell culture. PLoS ONE 2012;7:e42181.
  • 18
    Boulais N, Misery L. Merkel cells. J Am Acad Dermatol 2007;57:14765.
  • 19
    Foulongne V, Courgnaud V, Champeau W, Segondy M. Detection of Merkel cell polyomavirus on environmental surfaces. J Med Virol 2011;83:14359.
  • 20
    Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 2010;7:50915.
  • 21
    Foulongne V, Dereure O, Kluger N, Molès JP, Guillot B, Segondy M. Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol 2010;162:5963.
  • 22
    Chen T, Hedman L, Mattila PS, Jartti T, Ruuskanen O, Söderlund-Venermo M, et al. Serological evidence of Merkel cell polyomavirus primary infections in childhood. J Clin Virol 2011;50:1259.
  • 23
    Kean JM, Rao S, Wang M, Garcea RL. Seroepidemiology of human polyomaviruses. PLoS Pathog 2009;5:e1000363.
  • 24
    Rizk RZ, Christensen ND, Michael KM, Müller M, Sehr P, Waterboer T, et al. Reactivity pattern of 92 monoclonal antibodies with 15 human papillomavirus types. J Gen Virol 2008;89:11729.
  • 25
    Carter JJ, Paulson KG, Wipf GC, Miranda D, Madeleine MM, Johnson LG, et al. Association of Merkel cell polyomavirus-specific antibodies with Merkel cell carcinoma. J Natl Cancer Inst 2009;101:151022.
  • 26
    Faust H, Pastrana DV, Buck CB, Dillner J, Ekström J. Antibodies to Merkel cell polyomavirus correlate to presence of viral DNA in the skin. J Infect Dis 2011;203:1096100.
  • 27
    Tolstov YL, Knauer A, Chen JG, Kensler TW, Kingsley LA, Moore PS, et al. Asymptomatic primary Merkel cell polyomavirus infection among adults. Emerg Infect Dis 2011;17:137180.
  • 28
    Sadeghi M, Riipinen A, Väisänen E, Chen T, Kantola K, Surcel H-M, et al. Newly discovered KI, WU, and Merkel cell polyomaviruses: no evidence of mother-to-fetus transmission. Virol J 2010;7:251.
  • 29
    Nicol JT, Robinot R, Carpentier A, Carandina G, Mazzoni E, Tognon M, et al. Age-specific seroprevalence of Merkel cell polyomavirus, Human polyomaviruses 6, 7 and 9 and Trichodysplasia Spinulosa-associated polyomavirus. Clin Vaccine Immunol 2013;20:3638.
  • 30
    Pastrana DV, Wieland U, Silling S, Buck CB, Pfister H. Positive correlation between Merkel cell polyomavirus viral load and capsid-specific antibody titer. Med Microbiol Immunol 2012;201:1723.
  • 31
    Kassem A, Schöpflin A, Diaz C, Weyers W, Stickeler E, Werner M, et al. Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res 2008;68:500913.
  • 32
    Garneski KM, Warcola AH, Feng Q, Kiviat NB, Leonard JH, Nghiem P. Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol 2009;129:2468.
  • 33
    Foulongne V, Kluger N, Dereure O, Mercier G, Molès JP, Guillot B, et al. Merkel cell polyomavirus in cutaneous swabs. Emerg Infect Dis 2010;16:6857.
  • 34
    Wieland U, Mauch C, Kreuter A, Krieg T, Pfister H. Merkel cell polyomavirus DNA in persons without merkel cell carcinoma. Emerg Infect Dis 2009;15:14968.
  • 35
    Dworkin AM, Tseng SY, Allain DC, Iwenofu OH, Peters SB, Toland AE. Merkel cell polyomavirus in cutaneous squamous cell carcinoma of immunocompetent individuals. J Invest Dermatol 2009;129:286874.
  • 36
    Mertz KD, Junt T, Schmid M, Pfaltz M, Kempf W. Inflammatory monocytes are a reservoir for Merkel cell polyomavirus. J Invest Dermatol 2010;130:114651.
  • 37
    Andres C, Belloni B, Puchta U, Sander CA, Flaig MJ. Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. J Cutan Pathol 2010;37:2834.
  • 38
    Mangana J, Dziunycz P, Kerl K, Dummer R, Cozzio A. Prevalence of Merkel cell polyomavirus among Swiss Merkel cell carcinoma patients. Dermatology (Basel) 2010;221:1848.
  • 39
    Loyo M, Guerrero-Preston R, Brait M, Hoque MO, Chuang A, Kim MS, et al. Quantitative detection of Merkel cell virus in human tissues and possible mode of transmission. Int J Cancer 2010;126:29916.
  • 40
    Katano H, Ito H, Suzuki Y, Nakamura T, Sato Y, Tsuji T, et al. Detection of Merkel cell polyomavirus in Merkel cell carcinoma and Kaposi's sarcoma. J Med Virol 2009;81:19518.
  • 41
    Matsushita M, Kuwamoto S, Iwasaki T, Higaki-Mori H, Yashima S, Kato M, et al. Detection of Merkel cell polyomavirus in the human tissues from 41 Japanese autopsy cases using polymerase chain reaction. Intervirology 2013;56:15.
  • 42
    Ota S, Ishikawa S, Takazawa Y, Goto A, Fujii T, Ohashi K, et al. Quantitative analysis of viral load per haploid genome revealed the different biological features of Merkel cell polyomavirus infection in skin tumor. PLoS ONE 2012;7:e39954.
  • 43
    Kantola K, Sadeghi M, Lahtinen A, Koskenvuo M, Aaltonen L-M, Möttönen M, et al. Merkel cell polyomavirus DNA in tumor-free tonsillar tissues and upper respiratory tract samples: implications for respiratory transmission and latency. J Clin Virol 2009;45:2925.
  • 44
    Bergallo M, Costa C, Terlizzi ME, Astegiano S, Curtoni A, Solidoro P, et al. Quantitative detection of the new polyomaviruses KI, WU and Merkel cell virus in transbronchial biopsies from lung transplant recipients. J Clin Pathol 2010;63:7225.
  • 45
    Pancaldi C, Corazzari V, Maniero S, Mazzoni E, Comar M, Martini F, et al. Merkel cell polyomavirus DNA sequences in the buffy coats of healthy blood donors. Blood 2011;117:7099101.
  • 46
    Toracchio S, Foyle A, Sroller V, Reed JA, Wu J, Kozinetz CA, et al. Lymphotropism of Merkel cell polyomavirus infection, Nova Scotia, Canada. Emerg Infect Dis 2010;16:17029.
  • 47
    Reichgelt BA, Visser O. Epidemiology and survival of Merkel cell carcinoma in the Netherlands. A population-based study of 808 cases in 1993–2007. Eur J Cancer 2011;47:57985.
  • 48
    Wang TS, Byrne PJ, Jacobs LK, Taube JM. Merkel cell carcinoma: update and review. Semin Cutan Med Surg 2011;30:4856.
  • 49
    Lanoy E, Costagliola D, Engels EA. Skin cancers associated with HIV infection and solid-organ transplantation among elderly adults. Int J Cancer 2010;126:172431.
  • 50
    Arora R, Chang Y, Moore PS. MCV and Merkel cell carcinoma: a molecular success story. Curr Opin Virol 2012;2:48998.
  • 51
    Lewis JS Jr, Duncavage E, Klonowski PW. Oral cavity neuroendocrine carcinoma: a comparison study with cutaneous Merkel cell carcinoma and other mucosal head and neck neuroendocrine carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:20917.
  • 52
    Paik JY, Hall G, Clarkson A, Lee L, Toon C, Colebatch A, et al. Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population. Hum Pathol 2011;42:138590.
  • 53
    Sihto H, Kukko H, Koljonen V, Sankila R, Böhling T, Joensuu H. Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst 2009;101:93845.
  • 54
    Sihto H, Kukko H, Koljonen V, Sankila R, Böhling T, Joensuu H. Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel cell carcinoma. Clin Cancer Res 2011;17:480613.
  • 55
    Lemos BD, Storer BE, Iyer JG, Phillips JL, Bichakjian CK, Fang LC, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 2010;63:75161.
  • 56
    Deneve JL, Messina JL, Marzban SS, Gonzalez RJ, Walls BM, Fisher KJ, et al. Merkel cell carcinoma of unknown primary origin. Ann Surg Oncol 2012;19:23606.
  • 57
    Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 2005;23:23009.
  • 58
    Fields RC, Busam KJ, Chou JF, Panageas KS, Pulitzer MP, Allen PJ, et al. Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma. Cancer 2012;118:331120.
  • 59
    Kukko H, Böhling T, Koljonen V, Tukiainen E, Haglund C, Pokhrel A, et al. Merkel cell carcinoma - a population-based epidemiological study in Finland with a clinical series of 181 cases. Eur J Cancer 2012;48:73742.
  • 60
    Breuninger H. Seventh edition American Joint Committee on Cancer staging of cutaneous non-melanoma skin cancer. Am J Clin Dermatol 2011;12:155.
  • 61
    Miller SJ, Alam M, Andersen J, Berg D, Bichakjian CK, Bowen G, et al. Merkel cell carcinoma. J Natl Compr Canc Netw 2009;7:32232.
  • 62
    Becker JC. Working Group for Dermatologic Oncology (ADO). J Dtsch Dermatol Ges 2008;6:525.
  • 63
    Boccara O, Girard C, Mortier L, Bens G, Saiag P, Guillot B, et al. Guidelines for the diagnosis and treatment of Merkel cell carcinoma. Eur J Dermatol 2012;22:3759.
  • 64
    Paulson KG, Iyer JG, Tegeder AR, Thibodeau R, Schelter J, Koba S, et al. Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 2011;29:153946.
  • 65
    Tarantola TI, Vallow LA, Halyard MY, Weenig RH, Warschaw KE, Grotz TE, et al. Prognostic factors in Merkel cell carcinoma: analysis of 240 cases. J Am Acad Dermatol 2013;68:42532.
  • 66
    Güler-Nizam E, Leiter U, Metzler G, Breuninger H, Garbe C. Eigentler T k. Clinical course and prognostic factors of Merkel cell carcinoma of the skin. Br J Dermatol 2009;161:904.
  • 67
    Smith VA, Camp ER, Lentsch EJ. Merkel cell carcinoma: identification of prognostic factors unique to tumors located in the head and neck based on analysis of SEER data. Laryngoscope 2012;122:128390.
  • 68
    Asioli S, Righi A, De Biase D, Morandi L, Caliendo V, Picciotto F, et al. Expression of p63 is the sole independent marker of aggressiveness in localised (stage I-II) Merkel cell carcinomas. Mod Pathol 2011;24:145161.
  • 69
    Paulson KG, Iyer JG, Blom A, Warton EM, Sokil M, Yelistratova L, et al. Systemic immune suppression predicts diminished Merkel cell carcinoma–specific survival independent of stage. J Invest Dermatol 2013;133:6426.
  • 70
    Samimi M, Touzé A, Laude H, Le Bidre E, Arnold F, Carpentier A, et al. Vitamin D deficiency is associated with greater tumor size and poorer outcome in Merkel cell carcinoma patients. J Eur Acad Dermatol Venereol 2013;doi:10.1111/jdv.12101. [Epub ahead of print]
  • 71
    Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer 2008;113:254958.
  • 72
    Ng L, Beer TW, Murray K. Vascular density has prognostic value in Merkel cell carcinoma. Am J Dermatopathol 2008;30:4425.
  • 73
    Sihto H, Böhling T, Kavola H, Koljonen V, Salmi M, Jalkanen S, et al. Tumor infiltrating immune cells and outcome of merkel cell carcinoma: a population-based study. Clin Cancer Res 2012;18:287281.
  • 74
    Asioli S, Righi A, Volante M, Eusebi V, Bussolati G. p63 expression as a new prognostic marker in Merkel cell carcinoma. Cancer 2007;110:6407.
  • 75
    Llombart B, Monteagudo C, López-Guerrero JA, Carda C, Jorda E, Sanmartín O, et al. Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology 2005;46:62234.
  • 76
    Paulson KG, Carter JJ, Johnson LG, Cahill KW, Iyer JG, Schrama D, et al. Antibodies to merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in merkel cell carcinoma patients. Cancer Res 2010;70:838897.
  • 77
    Mott RT, Smoller BR, Morgan MB. Merkel cell carcinoma: a clinicopathologic study with prognostic implications. J Cutan Pathol 2004;31:21723.
  • 78
    Lim CS, Whalley D, Haydu LE, Murali R, Tippett J, Thompson JF, et al. Increasing Tumor Thickness is Associated with Recurrence and Poorer Survival in Patients with Merkel Cell Carcinoma. Ann Surg Oncol 2012;19:332534.
  • 79
    Bhatia K, Goedert JJ, Modali R, Preiss L, Ayers LW. Immunological detection of viral large T antigen identifies a subset of Merkel cell carcinoma tumors with higher viral abundance and better clinical outcome. Int J Cancer 2010;127:14936.
  • 80
    Bhatia K, Goedert JJ, Modali R, Preiss L, Ayers LW. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. Int J Cancer 2010;126:22406.
  • 81
    Andres C, Belloni B, Puchta U, Sander CA, Flaig MJ. Re: clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst 2009;101:16556.
  • 82
    Schrama D, Peitsch WK, Zapatka M, Kneitz H, Houben R, Eib S, et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Dermatol 2011;131:16318.
  • 83
    Handschel J, Müller D, Depprich RA, Ommerborn MA, Kübler NR, Naujoks C, et al. The new polyomavirus (MCPyV) does not affect the clinical course in MCCs. Int J Oral Maxillofac Surg 2010;39:108690.
  • 84
    Vlahova L, Doerflinger Y, Houben R, Becker JC, Schrama D, Weiss C, et al. P-cadherin expression in Merkel cell carcinomas is associated with prolonged recurrence-free survival. Br J Dermatol 2012;166:104352.
  • 85
    Hall BJ, Pincus LB, Yu SS, Oh DH, Wilson AR, McCalmont TH. Immunohistochemical prognostication of Merkel cell carcinoma: p63 expression but not polyomavirus status correlates with outcome. J Cutan Pathol 2012;39:9117.
  • 86
    Eich HT, Eich D, Staar S, Mauch C, Stützer H, Groth W, et al. Role of postoperative radiotherapy in the management of Merkel cell carcinoma. Am J Clin Oncol 2002;25:506.
  • 87
    Dadzie O, Teixeira F. What can primary cutaneous neuroendocrine carcinomas with squamoid and neuroendocrine differentiation teach us about the origin of Merkel cells? Int J Dermatol 2009;48:913.
  • 88
    Lemasson G, Coquart N, Lebonvallet N, Boulais N, Galibert MD, Marcorelles P, et al. Presence of putative stem cells in Merkel cell carcinomas. J Eur Acad Dermatol Venereol 2012;26:78995.
  • 89
    Touzé A, Gaitan J, Maruani A, Le Bidre E, Doussinaud A, Clavel C, et al. Merkel cell polyomavirus strains in patients with merkel cell carcinoma. Emerg Infect Dis 2009;15:9602.
  • 90
    Sastre-Garau X, Peter M, Avril M-F, Laude H, Couturier J, Rozenberg F, et al. Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J Pathol 2009;218:4856.
  • 91
    Shuda M, Arora R, Kwun HJ, Feng H, Sarid R, Fernández-Figueras M-T, et al. Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int J Cancer 2009;125:12439.
  • 92
    Werling AM, Doerflinger Y, Brandner JM, Fuchs F, Becker JC, Schrama D, et al. Homo- and heterotypic cell-cell contacts in Merkel cells and Merkel cell carcinomas: heterogeneity and indications for cadherin switching. Histopathology 2011;58:286303.
  • 93
    Laude HC, Jonchère B, Maubec E, Carlotti A, Marinho E, Couturaud B, et al. Distinct merkel cell polyomavirus molecular features in tumour and non tumour specimens from patients with merkel cell carcinoma. PLoS Pathog 2010;6:e1001076.
  • 94
    Martel-Jantin C, Filippone C, Cassar O, Peter M, Tomasic G, Vielh P, et al. Genetic variability and integration of Merkel cell polyomavirus in Merkel cell carcinoma. Virology 2012;426:13442.
  • 95
    Plaza JA, Suster S. The Toker tumor: spectrum of morphologic features in primary neuroendocrine carcinomas of the skin (Merkel cell carcinoma). Ann Diagn Pathol 2006;10:37685.
  • 96
    Calder KB, Coplowitz S, Schlauder S, Morgan MB. A case series and immunophenotypic analysis of CK20-/CK7+ primary neuroendocrine carcinoma of the skin. J Cutan Pathol 2007;34:91823.
  • 97
    Busam KJ, Jungbluth AA, Rekthman N, Coit D, Pulitzer M, Bini J, et al. Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am J Surg Pathol 2009;33:137885.
  • 98
    Reisinger DM, Shiffer JD, Cognetta AB Jr, Chang Y, Moore PS. Lack of evidence for basal or squamous cell carcinoma infection with Merkel cell polyomavirus in immunocompetent patients with Merkel cell carcinoma. J Am Acad Dermatol 2010;63:4003.
  • 99
    Nakamura T, Sato Y, Watanabe D, Ito H, Shimonohara N, Tsuji T, et al. Nuclear localization of Merkel cell polyomavirus large T antigen in Merkel cell carcinoma. Virology 2010;398:2739.
  • 100
    Iyer JG, Afanasiev OK, McClurkan C, Paulson K, Nagase K, Jing L, et al. Merkel cell polyomavirus-specific CD8+ and CD4+ T-cell responses identified in Merkel cell carcinomas and blood. Clin Cancer Res 2011;17:667180.
  • 101
    Kuwamoto S, Higaki H, Kanai K, Iwasaki T, Sano H, Nagata K, et al. Association of Merkel cell polyomavirus infection with morphologic differences in Merkel cell carcinoma. Hum Pathol 2011;42:63240.
  • 102
    Ly TY, Walsh NM, Pasternak S. The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites. Hum Pathol 2012;43:55766.
  • 103
    Erovic BM, Al Habeeb A, Harris L, Goldstein DP, Ghazarian D, Irish JC. Significant overexpression of the Merkel cell polyomavirus (MCPyV) large T antigen in Merkel cell carcinoma. Head Neck 2012;35:1849.
  • 104
    Adhikari LA, McCalmont TH, Folpe AL. Merkel cell carcinoma with heterologous rhabdomyoblastic differentiation: the role of immunohistochemistry for Merkel cell polyomavirus large T-antigen in confirmation. J Cutan Pathol 2012;39:4751.
  • 105
    Shuda M, Kwun HJ, Feng H, Chang Y, Moore PS. Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J Clin Invest 2011;121:362334.
  • 106
    Rodig SJ, Cheng J, Wardzala J, DoRosario A, Scanlon JJ, Laga AC, et al. Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest 2012;122:464553.
  • 107
    Koljonen V, Kukko H, Pukkala E, Sankila R, Böhling T, Tukiainen E, et al. Chronic lymphocytic leukaemia patients have a high risk of Merkel-cell polyomavirus DNA-positive Merkel-cell carcinoma. Br J Cancer 2009;101:14447.
  • 108
    Tadmor T, Liphshitz I, Aviv A, Landgren O, Barchana M, Polliack A. Increased incidence of chronic lymphocytic leukaemia and lymphomas in patients with Merkel cell carcinoma - a population based study of 335 cases with neuroendocrine skin tumour. Br J Haematol 2012;157:45762.
  • 109
    Pantulu ND, Pallasch CP, Kurz AK, Kassem A, Frenzel L, Sodenkamp S, et al. Detection of a novel truncating Merkel cell polyomavirus large T antigen deletion in chronic lymphocytic leukemia cells. Blood 2010;116:52804.
  • 110
    Loyo M, Schussel J, Colantuoni E, Califano J, Brait M, Kang S, et al. Detection of Merkel cell virus and correlation with histologic presence of Merkel cell carcinoma in sentinel lymph nodes. Br J Cancer 2012;106:13149.
  • 111
    Veness MJ, Morgan GJ, Gebski V. Adjuvant locoregional radiotherapy as best practice in patients with Merkel cell carcinoma of the head and neck. Head Neck 2005;27:20816.
  • 112
    Agrawal S, Kane JM 3rd, Guadagnolo BA, Kraybill WG, Ballo MT. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer 2009;115:583644.
  • 113
    Jouary T, Leyral C, Dreno B, Doussau A, Sassolas B, Beylot-Barry M, et al. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multicentric prospective randomized study. Ann Oncol 2012;23:107480.
  • 114
    Pape E, Rezvoy N, Penel N, Salleron J, Martinot V, Guerreschi P, et al. Radiotherapy alone for Merkel cell carcinoma: a comparative and retrospective study of 25 patients. J Am Acad Dermatol 2011;65:98390.
  • 115
    Tai PT, Yu E, Winquist E, Hammond A, Stitt L, Tonita J, et al. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 2000;18:24939.
  • 116
    Willmes C, Adam C, Alb M, Völkert L, Houben R, Becker JC, et al. Type I and II IFNs inhibit Merkel cell carcinoma via modulation of the Merkel cell polyomavirus T antigens. Cancer Res 2012;72:21208.
  • 117
    Biver-Dalle C, Nguyen T, Touzé A, Saccomani C, Penz S, Cunat-Peultier S, et al. Use of interferon-alpha in two patients with Merkel cell carcinoma positive for Merkel cell polyomavirus. Acta Oncol 2011;50:47980.
  • 118
    Arora R, Shuda M, Guastafierro A, Feng H, Toptan T, Tolstov Y, et al. Survivin is a therapeutic target in merkel cell carcinoma. Sci Transl Med 2012;4:133ra56.
  • 119
    Zeng Q, Gomez BP, Viscidi RP, Peng S, He L, Ma B, et al. Development of a DNA vaccine targeting Merkel cell polyomavirus. Vaccine 2012;30:13229.