merkel cell carcinoma: the first human cancer shown to be

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Presse Med. 2014; 43: e405–e411 on line on� 2014 Elsevier Masson SASAll rights reserved.

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VIRUSES ASSOCIATED WITH SKIN AND MUCOSAL CANCERSwww.sciencedirect.com

In this issue

Viruses associated with skinand mucosal cancersPierre Coursaget, Tours,France

Merkel cell carcinoma: Thefirst human cancer shown tobe associated with apolyomavirusMahtab Samimi et al., Tours,France

Origin and immunoescape ofuterine cervical cancerDorien van Hede et al.,Liège, Belgium

HPV in genital cancers (atthe exception of cervicalcancer) and anal cancersSilvia de Sanjosé et al.,Barcelona, Spain

Human papillomavirus(HPV) and oropharyngealsquamous cell carcinomaTina Dalianis, Stockholm,Sweden

Cutaneous HPV and skincancerRosita Accardi et al., Lyon,France

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Quarterly Medical Review

Merkel cell carcinoma: The first human cancershown to be associated with a polyomavirus

Mahtab Samimi1,2, Antoine Touzé1

1. University of Tours, Molecular virology and immunology, ISP 1282, INRA, 37044 Tours cedex, France2. University Hospital of Tours, Dermatology department, 37044 Tours cedex, France

Correspondence:
Mahtab Samimi, University of Tours, Hospital Center of Tours, dermatology department, Molecular virology andimmunology, ISP 1282, INRA, avenue de la République, 37044 Tours cedex, [email protected]
Summary

Merkel cell carcinoma (MCC) is

usually affecting elderly, white pwith strong propensity to metastreatment, with no curative trewas thought to be caused by tinvestigation of a predominant mwas successful. A real revolutiowhen a new human polyomavirskin cancer. Following the discoconfirmed worldwide, with detebeen shown that MCPyV infectthought to be persistent residenthe host cell, the viral cycle andmay be two subtypes of MCC: Mvarious studies have reported aThe discovery of MCPyV in MCC

persistence of expression of MCPpromising therapeutic targets.

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a rare, malignant primary neuroendocrine cancer of the skin,eople in sun-exposed areas. This is a highly aggressive tumortasize. Surgery and radiation therapy remain the mainstay ofatment in case of disseminated metastases. Until 2008, MCChe malignant transformation of resident Merkel cells, but no

olecular pathway that could be involved in MCC pathogenesisn in MCC understanding and management occurred in 2008,us (MCPyV) was found to be the main etiological agent of thisvery of MCPyV, the association of MCPyV with MCC has beenction of MCPyV in about 80% of MCCs. At the same time it hadion is almost ubiquitous in healthy subjects, and MCPyV ist of the skin microbiome although the route of transmission,/or latency remain unknown. Most studies suggest that there

CPyV-positive (80%) and MCPyV-negative (20%) MCCs, and better prognosis associated with MCPyV infection.patients opens up new therapeutic insights. The necessity andyV oncoproteins during MCC development make these proteins

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Figure 1

Clinical appearance of primary MCC: a dome-shaped violaceousnodule of the left thigh in an elderly woman

M Samimi, A Touzé

© 2015 Elsevier Masson

Merkel cell carcinoma (MCC) is a rare skin cancer that hasbeen shown to be caused by a human polyomavirus, i.e. Merkelcell polyomavirus (MCPyV). This discovery in 2008 renewedinterest in polyomaviruses, known to be oncogenic in animalsbut never previously associated with a human cancer. MCPyVinfection is ubiquitous, and MCPyV-driven oncogenesis seemsto be distinct from other oncogenic viruses and remains widelyunknown.

Merkel cell carcinoma: a rare aggressiveskin cancerMCC is a malignant primary neuroendocrine cancer of the skin.The denomination ‘‘MCC’’ is related to its presumed origin cell,i.e. Merkel cells, located in the basal part of epidermis. Merkelcells are receptor cells involved in skin mechanoreception, inassociation with sensory nerve endings in the upper part ofdermis. Their cytoplasm contains dense core granules, as doother cells of the dispersed neuroendocrine system. Subse-quently, when MCCs were first described in 1972 as ‘‘trabecularcarcinomas’’ harboring similar dense coregranules, they werelogically speculated to derive from the resident Merkel cells [1].However, recent studies suggest that MCCs may have anotherorigin, probably an unidentified progenitor cell in the epidermisor in the dermis [2].Due to its rarity, little information is available on MCC epi-demiology. Its incidence in the USA and Europe has beenestimated to be 0.24 per 100,000 person-years [3] and 0.3per 100,000 person-years [4], respectively, and to haveincreased over the last 20 years. MCC usually affects elderly,white people of both sexes, predominantly in sun-exposedareas. The most frequently affected sites are the head andneck (� 50%), trunk (� 30%), and limbs (� 10%) [3]. MCC

Figure 2

Histological appearance of MCCHyperbasophilic tumor cells located in the dermis (panel A), with positive staining wit

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can however affect any site of body, including the mucosae.Its clinical appearance is non-specific. The tumor presents as adome-shaped erythematous or violaceous nodule with asmooth surface, and can be misdiagnosed as an epidermalcyst or a nodular basal cell carcinoma or a spinocellularcarcinoma (figure 1). In later stages, the nodule may becomeulcerated with satellite in transit metastases. Due to therapidly growing course, the malignant nature of the noduleis usually obvious and requires the patient to be referred to adermatologist rapidly for a diagnostic skin biopsy.Diagnosis of MCC depends on histopathological examination(figure 2). The tumor is round-shaped and located in thedermis, usually without any connection with the epidermis.Tumor cells are hyperbasophilic, monomorphous, with scantcytoplasm and hyperchromatic nuclei. Immunohistochemistryinvestigation is mandatory for diagnosis, and MCC tumors

h CK20 (panel B) and chromogranin A (panel C).

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Figure 3

Numerous in transit cutaneous metastases of a MCC of the leftthigh in an elderly woman (same patient as in figure 1)

Figure 4

AJCC 2010 Merkel cell carcinoma staging

Merkel cell carcinoma: The first human cancer shown to beassociated with a polyomavirus VIRUSES ASSOCIATED WITH SKIN AND MUCOSAL CANCERS

© 2015 Elsev

display epithelial and neuroendocrine markers. More than 90%of MCCs express CK20, as well as a range of neuroendocrinemarkers (chromogranin A, synaptophysin, Neuron Specific Eno-lase, etc.). Negativity for TTF1 allows differential diagnosis fromcutaneous metastases from small cell lung carcinoma.MCC is a highly aggressive tumor with strong propensity tometastasize (figure 3). At presentation, 66% of patients pre-sent local disease, and 27% and 7% present regional anddistant metastases, respectively [5]. Interestingly, almost10% of patients have isolated lymph node MCC metastaseswith an unknown (or occult) primary [6,7].Management of MCC patients depends on guidelines develo-ped by American, German and French societies [8–10]. Diseasestaging at baseline requires clinical examination in order todetect any in transit and distant metastases. This is usuallycompleted with an ultrasonography of the regional lymphnodes and a thoraco-abdominopelvian CT-scan to detect anyoccult metastases. Additional imaging with 18-FDG positronemission tomography or scintigraphy with somatostatin ana-logs can be discussed, but are not systematically required.This initial evaluation allows classification according to the AJCCstage that is based on the main prognostic factors identified sofar (figure 4). Five-year survival ranges between 50 to 60%[3,5,11]. Five-year relative survival rates for local disease,regional nodal disease and metastatic disease are 64%,39%, and 18%, respectively [12]. MCC treatment depends

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on tumor stage and should be evaluated within multidiscipli-nary team discussions [8–10].Surgery remains the mainstay of treatment for both localizedand regionally extended disease (stages I, II and III). Itrequires wide excision of the primary tumor (2–3 cm) andany in transit metastases, completed with lymph node dis-section in cases of clinically palpable lymph node metasta-ses. When there are no clinically obvious lymph nodemetastases, a sentinel lymph node biopsy (SLNB) shouldbe undertaken at the time of excision of the primary tumor.This procedure identifies occult lymph node metastases inabout one third of patients, which should lead to a radicallymph node dissection.Adjuvant radiation therapy (50 Grays) is systematically recom-mended at the site of the primary tumor. Radiation of theregional lymph nodes is recommended when the SLNB cannotbe performed, and also after radical lymph node dissection formicroscopic or macroscopic metastases. When the SLNB hasbeen performed and there is no evidence of any metastases,radiation therapy of the lymph nodes can be avoided, althoughit can be discussed in head and neck locations and in the case ofa primary tumor with aggressive features. Adjuvant radiationtherapy has shown to be beneficial in terms of recurrence-freesurvival in several studies [12,13], but its effect on overallsurvival remains a matter of debate.In cases of distant metastases (stage IV) that cannot properly bemanaged by surgery, the prognosis is poor and there is nocurative treatment. Due to the rarity of MCC, randomized trialshave been difficult to undertake and there is little evidence todetermine the optimal strategy. Palliative cytotoxic chemothe-rapies include anthracyclines (doxorubicin), cyclophosphamide,etoposide, vincristine and platinum derivatives. Chemotherapyregimens, alone or in combination, can lead to tumoral res-ponses in up to 60% of patients, but the duration of theresponse is limited to a few months and overall survivalremains poor [14].At the time of targeted therapies, many molecular targets andsignalization pathways have been investigated in MCCs (C-KIT,PI3 K/AKT/mTOR, regulators of apoptosis, etc.) with no clearevidence of a key pathway. Some case reports have suggestedthe interest of tyrosine kinase inhibitors, somatostatin analogs,apoptosis analogs, and many early phase studies are currentlyunder investigation in this field (reviewed recently [15]).Similarly, escape from the immune system seems to play acrucial part in MCC progression, and immunotherapies that havehopefully changed the management of metastatic melanoma,such as CTLA-4 or PD1 antagonists, should be soon evaluated inMCC patients [15].The real revolution in MCC understanding and managementoccurred in 2008, when Chang and Moore’s team, from thePittsburgh Cancer Institute, identified the implication of a newhuman polyomavirus in this skin cancer [16].


Merkel cell polyomavirus: from discovery tounderstandingUntil 2008, MCC was thought to be caused by the malignanttransformation of resident Merkel cells, but no investigation ofa predominant molecular pathway that could be involved inMCC pathogenesis was successful. Interestingly, Chang andMoore had already discovered that Kaposi sarcoma that isclosely related to the immune status of the patient is causedby an infectious agent, Human Herpes Virus 8. Knowing that therisk of MCC was increased in cases of immunosuppression (HIVinfection, organ transplant recipients), the same team decided toinvestigate whether an infectious agent could cause this cancer.Using an approach called ‘‘digital transcriptome subtraction’’,they extracted the transcripts from two MCC specimens and‘‘subtracted’’ in silico all the known human cDNA sequencesto demonstrate two polyomavirus-related sequences. This pro-ved to be the discovery of a new human polyomavirus (the 5thhuman polyomavirus), which they subsequently called ‘‘Merkelcell polyomavirus’’ (MCPyV) [16]. After completion of thegenome sequencing, they evidenced these sequences in 8 outof 10 MCCs. Moreover, they identified that the viral DNA wasintegrated in a clonal fashion between primary tumors andmetastases in the tumor cell genome.Polyomaviruses (family of Polyomaviridae) are quite close tothe papillomaviruses in terms of genome organization, struc-ture, ubiquity as well as oncogenic properties. Polyomavirusesare small (50 nm) non-enveloped viruses, with a circulardouble stranded 5.4 kb DNA. The genome encodes earlynon-structural proteins (‘‘T antigens’’, regulating virus replica-tion) and late structural proteins (‘‘VP proteins’’, constitutingthe viral capsid) (figure 5). Polyomaviruses naturally infect manyanimals including mammals (particularly rodents and primates)and birds. Some animal polyomaviruses, including the murinepolyomavirus (MPyV), the hamster polyomavirus (HaPyV) andthe raccoon polyomavirus (RaPyV), have been shown to provoketumors in their natural hosts. Moreover, the simian polyomavirusSV40 was proven to be oncogenic in rodent models. The onco-genic properties of polyomaviruses are related to the ‘‘T anti-gens’’ (T standing for ‘‘tumor’’) resulting from alternative splicingof the same transcript from the early region of the viral genome.The oncogenic mechanisms of polyomaviruses are largely unk-nown. The large T antigen (LTAg) of SV40 and MCPyV containshighly preserved domains that bind to the suppressor tumorproteins p53 and pRb. There is here another strong similarity withthe oncogenic properties of papillomaviruses, whose E6 and E7oncoproteins also bind to P53 and Rb, respectively. The role of thesmall T antigen (sTAg) is less understood, but is probably crucial.sTAg binds to PP2A, that is involved in regulation of transcriptionand thus cell proliferation.The oncogenic properties of polyomaviruses had not beenevidenced in humans before 2008. The four polyomavirusesidentified in humans were BKPyV (responsible for nephropathy


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Figure 5

MCPyV genomeCircular, double stranded DNA. Early genes encode regulatory, oncogenic proteins

(LTAg, sTAg). Late genes encode structural proteins (VP1, VP2 and VP3). The NCCR

(non-coding control region) regulates viral gene expression and replication.

Source: Reference: Merkel cell polyomavirus isolate MCVw156, complete

genome, GenBank: HM355825.1).


© 2015 Elsev

and graft loss in renal organ recipients), JCPyV (responsible forprogressive multifocal leuco-encephalopathy in HIV patients),and WUPyV and KIPyV (identified in the respiratory tract with noassociated disease). The discovery of MCPyV, the first humanpolyomavirus found to be associated with a human cancer, ledto a huge increase in interest and advances in the field ofpolyomaviruses. Eight other human polyomaviruses have beenidentified since 2008, i.e. HPyV6, 7 and 9 (skin of healthysubjects), TSPyV (skin of patients with spinulosis trichodyspla-sia), MWPyV, SLPyV and HPyV12 (stools of healthy subjects) andNJPyV13 (endothelial cells from an immunosuppressed patientwith vasculitis).Following the discovery of MCPyV, the association of MCPyVwith MCC has been confirmed worldwide, with detection ofMCPyV in about 80% of MCCs [17–19]. At the same time, it hadbeen shown that MCPyV infection is almost ubiquitous inhealthy subjects [20,21]. MCPyV DNA is identified in cutaneousswabs from a high proportion of healthy people [21], butMCPyV virions have never been identified in any of the sitesinvestigated. Together with other polyomaviruses and papillo-maviruses, MCPyV is currently thought to be a persistentresident of the skin microbiome (so-called, skin ‘‘virome’’)


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although the route of transmission, the host cell, the viralcycle and/or latency remains unknown [22].Sero-epidemiological studies of MCPyV infection are based onassessment of humoral immunity against the highly immuno-genic major capsid protein VP1 (anti-VP1 antibodies) [23]. Thefirst detection of such antibodies, reflecting MCPyV primaryinfection, occurs before 5 years of age [24,25]. Anti-VP1 anti-bodies persist throughout life in more than 80% of healthypeople [26]. MCPyV infection is thus ubiquitous, the primaryinfection is asymptomatic, and the virus persists in a latent or atleast minimally replicative state throughout life in an uniden-tified location.The ubiquity of MCPyV infection has led to controversy regard-ing its etiological role in MCC pathogenesis. However, itsinvolvement in MCC pathogenesis is supported by severalarguments, with the result that MCPyV is classified as a class2A carcinogen by the IARC [27]. First, MCC patients carry higherMCPyV viral loads than healthy subjects and have higher anti-VP1 antibody titers. More importantly, MCPyV in MCC tumorshas unique characteristics, considered as a ‘‘molecular signa-ture’’ specific to MCCs. First, the MCPyV genome is clonallyintegrated in MCC tumor cells [16]. Genome integration iscrucial for other oncogenic viruses (human papillomaviruses,hepatitis B virus) but has not been evidenced in oncogenicpolyomaviruses other than MCPyV. MCPyV integration can occuranywhere in the host cell genoma, without any integration ‘‘hotspots’’ that could explain activation/inactivation of host genepromoters [28]. MCPyV integration is associated with eithermutations or deletions, leading to stop codons that truncate theC-terminal part of the LTAg protein [29]. This double pheno-menon (integration, truncation) seems to be necessary for the‘‘harmless resident MCPyV’’ to become an ‘‘oncogenic MCPyV’’.The truncation of the C-terminal part of the LTAg protein leadsto loss of replicative properties (abortion of virus cycle andvirion production) and overexpression of a truncated LTAg thatcould promote tumor transformation. Interestingly, LTAg trun-cation leads to the loss of the P53-binding domain, indicatingthat the oncogenic mechanism associated with MCPyV is uniqueand distinct from papillomaviruses and other polyomaviruses.Experimental findings have shown that the expression of theLTAg and sTAg in MCPyV-positive MCC cells is necessary for themaintenance of tumor cell lines [30–32]. The Rb-bindingdomain of the truncated LTAg is also necessary for maintenanceof cell lines [33]. Moreover, the expression of sTAg is able toinitiate transformation of rodent fibroblasts [32]. Furtherresearch must be undertaken to understand fully the oncogenicstages of MCPyV in the development of MCC.

Investigation of the Merkel cellpolyomavirus in MCC patientsMCPyV markers have been widely investigated in MCC patientssince 2008, with conflicting results. First, it is not known whether

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all MCC tumors are related to MCPyV infection. MCPyV being theunique cause of MCC was supported by one study reportingnearly 100% MCPyV DNA and LTAg expression in the MCC tumorsinvestigated [34]. However, most studies suggest that there maybe two subtypes of MCC: MCPyV-positive (80%) and MCPyV-negative (20%) MCCs. MCPyV-negative MCCs are thought toresult from alternative oncogenic pathways, mostly involvingUV-induced DNA damage and chromosomal aberrations [35].Another hypothesis is that all MCCs are initiated by MCPyVinfection, a small proportion of which subsequently ‘‘lose’’ theMCPyV genome (‘‘hit-and-run phenomenon’’) [36]. It seems thatMCPyV-positive and MCPyV-negative MCCs display distinct phe-notypes and evolution – though the latter issue is a matter ofdebate [26,37,38]. Various studies have reported a better pro-gnosis associated with MCPyV infection (assessed by higherintratumoral viral loads or LTAg expression, and higher plasmaanti-VP1 antibody titers).

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It was also evidenced that the humoral response against TAg(anti-TAg antibodies) was detected in about 40% of MCCpatients and not in controls, thus constituting a specificmarker of the disease. Interestingly, the anti-TAg antibodieswere related to the disease burden. They progressivelybecame undetectable in disease-free patients whereasthey were increased in cases of disease progression andrecurrence [39].MCPyV markers may therefore be of prognostic value for thiscancer, both at baseline and for disease monitoring. Moreover,the discovery of MCPyV in MCC patients opens up new thera-peutic insights. The necessity and persistence of expression ofMCPyV oncoproteins during MCC development makes theseproteins promising therapeutic targets.

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