The Etiology and Epidemiology of

Merkel Cell Carcinoma

erkel cell carcinoma (MCC) is a rare, aggressive skin cancer
M characterized by high incidence of local recurrences, regional
nodal metastases, distant metastases, and high mortality rates.
Usually, MCC presents as a painless, not descriptive skin lesion on the
sun-exposed skin of elderly whites who seek medical attention because of
the lesion’s rapid growth.1 MCC was first described by Toker in 19722 as
trabecular carcinoma of the skin because of its histological appearance. In
their 1978 ultrastructural studies,3 Tang and Toker identified dense-core
granules in the cytoplasm of the tumor cells. Merkel cells are the only
cells in the skin known to contain this kind of granules.4,5 Therefore,
Tang and Toker postulated that trabecular carcinoma of the skin origi-
nated from Merkel cells.3 Since then, the origin of MCC has been debated
across multiple disciplines.5-9 Today, most authors believe that MCC
originates from Merkel cells5,10 and it is widely accepted that Merkel
cells are of neuroendocrine origin.5,11 However, other authors propose
that MCC originates from a pluripotent stem cell.7,8
Because of the uncertainty of its origin, MCC has been described under
many different names.12 The most frequently used names, trabecular
carcinoma of the skin, cutaneous neuroendocrine carcinoma, and MCC,
correspond to the sequential acquisition of knowledge on the cellular
origin of this cancer.9 The name MCC was proposed in 198013 and it is
the most prevalent term used today; however, several authors still refer to
MCC as cutaneous neuroendocrine carcinoma.14-16
The estimated overall age-adjusted incidence rate of first primary MCC
in the USA is 0.32 per 100,000 person-years.9 The rarity of MCC and the
difficulty in distinguishing it from other primary and metastatic skin
cancers1,17 have greatly limited the studies on MCC etiology, risk factors,
and preventive and therapeutic approaches. Population-based data on
MCC have become available only recently1 and they derive from the data
collected by cancer registries that carry out cancer surveillance on large
geographic areas.1,9,18-22 These studies have provided the demographic

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14 Curr Probl Cancer, January/February 2010

characteristics of first primary MCC in the general population; they have
clarified first primary MCC incidence trends, potential risk factors, and
predictors of survival. Concurrently, advances in molecular biology
techniques have resulted in the identification of genetic mutations9 and of
a new polyomavirus that may be involved in the etiology of MCC.23
Epidemiology of First Primary Merkel Cell Carcinoma
To study the epidemiology and survival of MCC, Agelli and Clegg
analyzed the population covered by the Surveillance Epidemiology and
End Results (SEER) Program24,25 of the National Cancer Institute. The
SEER population included in these studies, and corresponding to 10%-
14% of the US population, was studied as a prospective cohort from 1973
to 19991 and from 1992 to 2001.9 Cases were identified using the 2nd
edition of the International Classification of Diseases for Oncology
(ICD-O-2),26 as described elsewhere.1,9 Only first primary MCC were
included in these studies to ensure the calculated incidence rates were an
accurate measure of risk for MCC in the general population. The size of
the SEER population allowed also to analyze separately first primary
MCC presenting at mucosal anatomic sites, which is extremely rare.9
Overall Incidence Trends
The size of the SEER population allowed the calculation of the
incidence rate of first primary MCC by sex, age, race, and geographic area
at diagnosis since its first description in 1972.1,9 Until 1980, first primary
MCC has been reported only sporadically; after that, the age-adjusted1
incidence rate of first primary MCC has been increasing steadily1,9 (Fig 1).
A previous study on the SEER population had reported the incidence of all
primary MCC in 1986-94.20 The year 1986 was chosen as the starting year
because in this year a histological code associated with the name MCC was
introduced for the first time (in the field trial edition of the ICD-O).27 For
comparability, Agelli and Clegg calculated first primary MCC overall
age-adjusted incidence rate also in 1986-99, and it was found to be 0.24 per
100,000 person-years.a However, the largest proportion of first primary MCC
cases was after 1992 (more than 73%, 758 of 1034 cases). In 1992, the
importance of staining for cytokeratin-20 (CK-20) in the differential diagno-
sis of carcinomas was published28 and an immunological profile specific
for MCC was being identified.9 Therefore, Agelli and Clegg recalcu-
lated the overall age-adjusted incidence rate of first primary MCC for
the decade 1992-2001 and it was found to be 0.32 per 100,000

a
To the year 2000 standard population for the United States.
Curr Probl Cancer, January/February 2010 15
FIG 1. Age-adjusted incidence of first primary Merkel cell carcinoma (MCC) per 100,000
person-years according to calendar year at diagnosis in the 25 years after first description of
MCC. Arrows: 1980s, introduction of electron microscopy (EM)3 in major diagnostic centers;
1983, staining for neuron-specific enolase (NSE)29-31; 1986, morphology code associated
with the name “Merkel cell carcinoma”27; 1992, staining for cytokeratin-20 (CK-20).28
(Modified from Agelli and Clegg.1)

person-years.9 Figure 1 shows the incidence of first primary MCC in

relation to the diagnostic landmarks for this cancer.3,27-31

Incidence Rates by Sex, Age, Race, and Ultraviolet B

(UVB) Radiation Exposure
The incidence of first primary MCC is higher in males than in females
in all ethnic groups, with a ratio of 2:1 in whites and in blacks, and a ratio
of 1.5:1 in all other ethnic groups.1,9 First primary MCC is a disease of
elderly people. It is only sporadically reported before age 50; then, its
overall age-adjusted incidence rate starts increasing gradually, from age
50 to age 65, then progressively in both males and females1,9 (Fig 2).
Whites have an overall age-adjusted incidence of 0.36 per 100,000
person-years, more than 8 times the incidence rate of blacks (0.045) and
almost double the incidence of other ethnic groups (0.2).1,9 In the studies
of Agelli and Clegg,1,9 the UVB radiation index32 of the pertinent SEER
geographic areas was used to indicate UVB radiation exposure for the
16 Curr Probl Cancer, January/February 2010
FIG 2. Age-specific incidence of first primary MCC per 100,000 person-years by sex Œ — Œ ⫽
males;  —  ⫽ females. (Modified from Agelli and Clegg.1)

people living in that geographic area. The overall age-adjusted incidence

of first primary MCC in whites is highest in Hawaii, the geographic
location with the highest UVB radiation index. Furthermore, a statisti-
cally significant correlation (r ⫽ 0.84, p ⫽ 0.005) is present between the
age-adjusted incidence of first primary MCC of the head-and-neck in
whites and the UVB radiation index of the SEER geographic areas.1,9
Characteristics of First Primary MCC Cases, Anatomic
Localization, and Stage at Diagnosis
Characteristics of cases are described in detail elsewhere.1 Males are
younger than females at diagnosis (age mean: males 71 years; females 76
years; p ⬍ 0.0001).1 In both sexes the most frequent localization of first
primary MCC at diagnosis is the head-and-neck (48%), followed by
localization at the upper limb (19%), at the lower limb (16%), and at the
trunk (11%). Interestingly, in males the anatomic site most frequently
affected at diagnosis varies with age (p ⬍ 0.0001), with the proportion of
cases at the head-and-neck increasing from 30% in males younger than 65
years to 55% in males older than 75 years. In males younger than 65
years, the largest proportion of cases occurs at the trunk and limbs.1,9
Curr Probl Cancer, January/February 2010 17
 Overall, only about 50% of cases have a localized disease (stage I) at
diagnosis.1,9 There is a statistically significant association between stage
at diagnosis and the anatomic site of presentation. In fact, localization at
the limbs is associated with less advanced disease compared with all other
anatomic sites, whereas localization at the trunk is most frequently
associated with distant metastases at the time of diagnosis.1,9

Survival Analysis
The probability of survival is better for patients with MCC presenting at
the upper limb than at any other anatomic site (Fig 3A). The overall
5-year relative survival of first primary MCC is 62%. The probability of
survival decreases sharply when first primary MCC progresses from local
to regional and to metastatic disease (Fig 3B). Overall, only 32% of
patients with distant metastases at diagnosis are still alive after 2 years
compared with 86% of patients diagnosed with localized disease. The
probability of survival 5 years after diagnosis is 25% for those with
distant metastases compared with 75% for those with localized disease.1,9
Factors associated with survival were identified through the calculation of
the hazard ratios (HR) and corresponding 95% confidence intervals (CI)
using Cox proportional hazard regression analysis (Table 1).1,9 Because
females have a better probability of survival than males (HR, 0.71; 95% CI,
0.59-0.87),1 survival analysis was carried out for males and females sepa-
rately (Table 1). Localization at the upper limb is independently associated
with better survival in both sexes compared with any other anatomic
site; however, conventional statistical significance was reached only
with respect to localization at the head-and-neck in males and at the
trunk in females. As with most cancers, the presence of distant
metastases at the time of diagnosis is associated with very poor
survival in both genders. Advanced age is independently associated
with poor survival in both males and females. The oldest patients have
a poor prognosis even if MCC is the first primary tumor and is
localized at diagnosis (Table 1).

Epidemiology of Merkel Cell Carcinoma Presenting

at Mucosal Anatomic Sites
About 5% of all cases of first primary MCC present at mucosal
anatomic sites. In 1992 through 2001, the total number of cases of first
primary MCC was 1,027, with 50 cases presenting at mucosal anatomic
sites.9
18 Curr Probl Cancer, January/February 2010
FIG 3. Relative survival of patients diagnosed with first primary MCC by anatomic site (panel A) and
by stage at diagnosis (panel B). (A) head ⫽  — ; trunk ⫽  — ; upper limb ⫽ Œ — Œ; lower
limb ⫽ □ — □. (B) Localized ⫽  — ; regional ⫽  — ; distant metastasis ⫽ Œ — Œ. The relative
survival rate is the ratio of the observed survival to the expected survival of the general population
of the same age, sex and race of the patient group, and for the same calendar year of observation.
(Modified from Agelli and Clegg.1)

Incidence Rates
The overall age-adjusted incidence of first primary MCC at mucosal
anatomic sites is 0.015 per 100,000 person-years in 1992-2001. The male
to female incidence ratio is 1.3:1 (males, 0.017; females, 0.013). The
Curr Probl Cancer, January/February 2010 19
Table 1. Hazard ratios (HRs) of death and 95% confidence intervals (CIs) for males and females
diagnosed with first primary Merkel cell carcinoma by age, stage, and anatomic site at time of
diagnosis
Males Females
HR 95% CI HR 95% CI
Age in years*
⬍65 ⫽ Reference category 1.0 — 1.0 —
65-74 1.5 1.1-2.1 1.4 0.8-2.3
75⫹ 2.3 1.7-3.1 3.3 2.2-5.1
Anatomic site†
Upper limb ⫽ reference category 1.0 — 1.0 —
Head 1.7 1.2-2.3 1.2 0.8-1.8
Trunk 1.3 0.9-2.1 2.8 1.7-4.6
Lower limb 1.4 0.9-2.2 1.2 0.7-1.9
Other 1.1 0.6-1.9 1.0 0.5-2.3
Stage at diagnosis‡
Localized ⫽ reference category 1.0 — 1.0 —
Regional 1.5 1.1-2.0 1.5 1.1-2.2
Distant 3.5 2.3-5.2 4.0 2.5-6.4
Unstaged 1.9 1.3-2.6 2.1 1.4-3.0
Modified from Agelli and Clegg.1
*Controlling for stage and anatomic site.
†Controlling for age and stage at diagnosis.
‡Controlling for age and anatomic site.

age-adjusted incidence of first primary MCC at mucosae in whites (0.016)

is 1.8 times greater than in blacks (0.009), and 1.2 times greater than in
other ethnic groups (0.013).9
Characteristics of Cases, Anatomic Localization, and
Stage at Diagnosis
Males are younger than females at time of diagnosis (mean age: males
59 years; females 64 years), even if conventional statistical significance
was not reached (p ⫽ 0.23)9 (Table 2). At diagnosis, cases with first
primary MCC at mucosae are significantly younger than cases with first
primary MCC at the skin, with a mean age of 62 years and of 74 years,
respectively (p ⬍ 0.0001), and have a more advanced disease, with stage
II and III being the most frequent stages at the time of diagnosis9 (Table
2). The larynx is the most frequently affected mucosal anatomic site in
both sexes,9 followed by the nasal cavity, the pharynx, and the mouth and
tongue (Table 3).
Survival Analysis
The relative survival of individuals with first primary MCC at
mucosae is poorer than that of individuals with first primary MCC at
20 Curr Probl Cancer, January/February 2010
Table 2. Characteristics of patients diagnosed with first primary Merkel cell carcinoma presenting
at the skin and at mucosal anatomic sites
Skin Mucosae
N ⴝ 977 % N ⴝ 50 %
Sex
Male 556 57 26 52
Female 421 43 24 48
Age groups (yr)
⬍65 195 20 27 54
ⱖ65-74 782 80 23 46
Race
White 912 93 43 86
Black 9 1 3 6
Other 56 6 4 8
Stage at diagnosis
Localized 503 52 16 32
Regional 290 30 23 46
Distant 79 8 10 20
Unstaged 105 11 1 2

Table 3. Anatomic localization of patients diagnosed with first primary Merkel cell carcinoma
presenting at mucosal anatomic sites
Total Men Women
N ⴝ 50 N ⴝ 26 N ⴝ 24
N % N % N %
Mouth and tongue 7 14.0 4 15.4 3 12.5
Nasal cavity 12 24.0 6 23.1 6 25.0
Pharynx 8 16.0 6 23.1 2 .3
Larynx 27 54.0 9 34.6 10 41.7
Genitalia 3 6.0 0 0.0 3 12.5
Other* 1 2.0 1 3.8 — —
*Other ⫽ overlapping mucosal anatomical sites of the head.

the skin (HR, 1.6; 95% CI, 1.09-2.36) even after controlling for age,
sex and stage at diagnosis. The 2-year relative survival rate is 49% for
first primary MCC at mucosae compared with 76% for first primary
MCC at the skin (Fig 4). Published case reports describe the clinical
course of mucosal MCC as aggressive, with high risk for local
recurrence and regional and distant metastasis. Fulminating courses
have also been reported.33
Etiology
Little is known about specific etiologic factors in the pathogenesis of
MCC. Recent population-based studies,1,9 the analysis of the largest case
Curr Probl Cancer, January/February 2010 21
FIG 4. Relative survival of patients diagnosed with first primary MCC presenting at the skin and at
mucosal anatomic sites. Skin (N ⫽ 977,  — ) and mucosal (N ⫽ 50,  — ) primary MCC.

series, and the careful compilation of the many case reports and case
series published in the literature since MCC’s first description34-38 have
pointed to possible and probable risk factors. Concurrently, advanced
molecular biology techniques have allowed the identification of molecu-
lar and genetic alterations that may be in the etiologic pathway of
MCC9,39 and of the sequence of a new polyomavirus that may also play
a role in the etiology of MCC.23,40 Despite these progresses, the etiology
of MCC is largely unknown.
Iatrogenic Immunosuppression
Cases of MCC have been observed in almost every autoimmune
disease41-47 and they have been increasing in frequency in the last decade
with the introduction of potent immunosuppressant drugs in the treatment
of these diseases.41-46,48-50 Partial regression of metastatic MCC has been
reported after discontinuation of immunosuppressive therapy.51,52
MCC has been reported to occur after transplantation of the kidney,
liver, heart, and bone marrow; however, most reported cases are in kidney
transplant patients.53-60 The Cincinnati Tumor Registry alone identified
45 transplant patients with one or more MCC.59,60 MCC presents on
average 7 years after organ transplant. In organ transplant patients, at the
time of MCC diagnosis, the mean age is 53 years with 49% of patients
22 Curr Probl Cancer, January/February 2010
less than 50 years old; MCC is multifocal in 20% of cases and in 70% of
cases presents as advanced disease (stage II and III). As in the general
population, most cases occur in whites (80%) and in males (69%); 49%
of cases occur at the head-and-neck, followed by localization at the limbs
and at the trunk. In 57% of kidney transplant patients, MCC is associated
with other malignancies, including other skin cancers (49%). Of the 45
post-transplant patients diagnosed with MCC, 60% died of MCC an
average of 18 months from MCC diagnosis.59,60
The observations from MCC occurring in transplant recipients and the
increasing number of cases reported in patients with autoimmune diseases
since the introduction in their treatment of potent immunosuppressant drugs
clearly indicate that long-term iatrogenic immunosuppression, which sup-
presses selectivity cellular immune response, increases the risk of MCC.
Long-term iatrogenic immunosuppression is not a risk factor specific for
MCC. In fact, organ transplant recipients are at increased risk of any other
malignancy, including other skin cancers, compared with the general popu-
lation. However, severe immunosuppression appears to increase the risk of
MCC more than that of malignant melanoma. The ratio of melanoma to
MCC in the post-transplant population is 6:1 compared with about 65:1 in the
general population.59

Immunosuppression in Acquired Immunodeficiency

Syndrome
There are several case reports in the published data of MCC occurring in
individuals with acquired immunodeficiency syndrome (AIDS).7 The study
of 309,265 individuals with AIDS through the linkage of AIDS and cancer
registries indicates that individuals with AIDS have a relative risk (RR) of
13.4 (95% CI, 4.9-29.1) (N ⫽ 6) of developing MCC when compared with
the general population.61 The increased risk of MCC in AIDS patients is most
likely directly related to the damages to the immune system caused by the
human immunodeficiency virus (HIV) which compromises cellular immu-
nity, leaving HIV-infected patients susceptible to opportunistic, bacterial, and
viral infections and to cancer development.62

Association With Other Malignancies

Multiple case reports and case series have described the association of
MCC with other cancers, especially with cutaneous or lympho-hemato-
poietic cancers.35,48,63,64 Squamous cell carcinoma is the tumor most
commonly linked with MCC, which has been reported associated with
squamous cell carcinoma in almost 40% of cases.8,65-72
Curr Probl Cancer, January/February 2010 23
 In a population-based study that analyzed the data collected by the
Israel Cancer Registry, 50% of cancers associated with MCC (ie,
preceding, concurrent, or following the diagnosis of MCC) were non-skin
solid tumors.73 In the SEER population,74 all cases of first primary
cancers taken together (N ⫽ 2,048,739) had a statistically significant
increased risk of developing MCC as a second primary cancer (N ⫽ 221)
(SIR,b 1.36, 95% CI, 1.19-1.55) and 89% of second primary MCC (N ⫽
197) developed within one year from the diagnosis of the first primary
cancer. Most cancers were associated with an increased risk of MCC as
second primary cancer. However, conventional statistical significance
was found only for multiple myeloma (N ⫽ 4), chronic lymphocytic
leukemia (N ⫽ 14), non-Hodgkin lymphoma (N ⫽ 16), and malignant
melanoma (N ⫽ 16), probably because the numbers of MCC cases per
specific cancer type are very small.
The data from the Israel Tumor Registry show an increased risk of
second primary cancers occurring during MCC follow-up (3.6 years on
average). The estimated actuarial risk of developing a second primary
cancer after the diagnosis of a first primary MCC was 2.1% for each year
of follow-up.73 In the SEER population,74 the average follow-up time for
patients with first primary MCC was 3.5 years and the estimated risk of
developing a second primary cancer after the diagnosis of a first primary
MCC was especially high during the first year of follow up (SIR, 1.71,
95% CI, 1.21-2.33).
Skin Radiation Exposure
MCC has been reported most frequently in association with exposure to
UVB and ultraviolet A (UVA) radiation, but also with exposure to
ionizing radiation75,76 and infrared radiation.8,67,68
Sun exposure (ie, exposure to UVB radiation) is considered an
important factor in the etiology of MCC.1,9,20 However, proving that
UVB radiation exposure is indeed a major risk factor for MCC has been
elusive. The concurrence of MCC with actinic keratosis, squamous cell
carcinoma, basal cell carcinoma, lentigo maligna, malignant melanoma,
and solar elastosis has been widely reported. This association has
suggested the interpretation that all these conditions share UVB radiation
as a common etiologic factor.20,69,70,77-80 Epidemiologic studies have
reported a probable association between MCC and sun exposure and a
positive correlation between the incidence of first primary MCC of the
head-and-neck in whites and UVB radiation indexes.1,9 Recently, C¡ T

b
SIR ⫽ standardized incidence ration.
24 Curr Probl Cancer, January/February 2010
and CC¡ TT mutations of the TP53 suppressor gene have been identified
in MCC.72,81 These distinctive mutations are considered diagnostic of
UV-induced DNA damage82-85 and they suggest that UVB radiation
exposure may be an important factor for the development of MCC.
In addition to the cumulative direct damage to the skin, animal86,87 and
human88-90 studies indicate that chronic UVB radiation suppresses local
immune response in exposed skin. In humans, UVB radiation exposure
produces a change in the local epidermal and dermal environment
characterized by depletion of CD1⫹ CD36⫺ DR⫹ Langerhans-like
dendritic antigen-presenting cells and by the selective expansion of a
CD1⫺CD11b⫹ CD36⫹ DR ⫹ monocyte/macrophage subpopulation89,90
phenotypically identical to the monocytic/macrophagic antigen-present-
ing cells that appear in the epidermis after UV-caused injury.89
UVA radiation is a much stronger mutagen than UVB radiation.82 The
incidence of MCC in patients with psoriasis who were treated with oral
methoxsalen (psoralen) and UVA photo-chemotherapy has been reported
to be about 100 times higher than expected in the general population.91,92
Arsenic Exposure
The association between the consumption of arsenic-contaminated
water and skin cancer has been documented since the 1960s.93,94 Arsenic
is an important environmental carcinogen that affects millions of people
worldwide. Arsenic is a potent gene and chromosome mutagen that also
causes mitochondrial damage.95 Inorganic arsenicals increase the risk of
skin cancer, solid organ cancers, and cancers of the lympho-hematopoi-
etic system. MCC has been reported in individuals with Bowen’s disease
and in areas of endemic chronic arsenicism.94,96,97
Advancing Age
In the elderly, the immune response is impaired because of immunose-
nescence98 and of a chronic proinflammatory status, often referred to as
the inflamm-aging effect.99-101 These age-related immunodeficiency and
dysregulation of the immune system cause a progressive deterioration in
the ability to respond to infections and possibly to cancer, and it may
explain why MCC occurs in the elderly as well as the poor survival of
stage I first primary MCC in the oldest patients.
Viral Infection
Like many other cancers that are more common among immunosup-
pressed patient populations, MCC may have a viral etiology. As such, the
laboratory of Drs. Patrick Moore and Yuan Chang recently screened
Curr Probl Cancer, January/February 2010 25
MCC tissues for novel viral sequences using digital trascriptome subtrac-
tion and two cDNA libraries generated from 4 MCC tumor tissues.40
Based on this approach, they characterized a new polyomavirus, naming
it Merkel cell polyomavirus (MCV or MCPyV).40 Since its initial
discovery, accumulating evidence has suggested that MCV may play a
role in MCC etiology.
Polyomaviruses are small viruses (40-50 nanometer in diameter) with a
double-stranded, circular, supercoiled, DNA genome.102 To date, 14
polyomaviruses have been described, including 5 known to infect
humans: JC virus (JCV), BK virus (BKV), KI, WU, and MCV.23 The
oncogenic potential of human polyomaviruses has been documented in
studies of experimentally infected animals in which JCV and BKV have
been shown to induce tumor formation.103,104,105 Polyomaviruses encode
for large and small T-antigens, non-structural proteins which bind to host
proteins to force the host cell into the S phase (of DNA replication) and
facilitate viral replication.106,107 In addition, the large T-antigen binds to
and inactivates tumor suppressor proteins p53 and pocket retinoblastoma
(pRb).108
The findings for MCV in MCC have been quite consistent with an
etiologic association. Subsequent to their initial discovery of MCV in
2008, Feng and colleagues investigated the presence of MCV in a
separate set of MCC tissue samples obtained from 10 MCC patients.
In this original series, the tissues from 8 patients (80%) were positive
for MCV sequences, and monoclonal viral integration was observed in
the MCC tissues from 5 of 10 (50%) patients.40 MCC from different
patients had distinct viral integration patterns, implying that MCV
integrated at different locations within the human genome in different
patients. When available, primary and metastatic MCC tissues from
the same patient showed an identical viral integration pattern, indi-
cating that the integration of MCV preceded the metastatic spreading
of the cancer.40
Sequencing of the MCV genome obtained from 8 patients with MCC
positive for MCV revealed that the large T-antigen oncoprotein locus of
MCV had conserved all major features of other polyomavirus large
T-antigens, but that all 8 MCV large T-antigen sequences had mutations
or deletions prematurely truncating the exon 2 encoding the helicase
domain.40,109 The origin-binding domain and the helicase domain are
necessary for free polyomavirus replication, but they are not required for
maintaining integrated virus that replicates as an inserted element in the
host genome. In tissue samples obtained from patients without MCC that
tested positive for MCV, the coding sequences of the large T-antigen
26 Curr Probl Cancer, January/February 2010
locus were complete with no truncating mutation. The authors concluded
that truncating mutations at the large T-antigen locus are a feature of
polyomavirus-mediated carcinogenesis in humans and that they may be
used as a genetic marker to distinguish tumorogenic versus non-tumoro-
genic MCV strains in humans.40,109
Since Feng and colleagues’ original report, several independent groups
have confirmed the presence of MCV DNA in a large proportion of MCC
tissues.40,110-125 ranging in prevalence from 40%119 to 100%117 (Table 4).
However, methodologic differences limit the comparability of results
across studies. For example, different primers were used across studies,
and only a few studies measured the number of viral copies per cell
equivalent, thus it is difficult to discern differences in prevalence from
difference in assay sensitivity. Kassem and colleagues111 have reported
that formalin fixation may fragment DNA, which in turn may result in
different rates of amplification across primer sets that vary in length (i.e.,
number of base pairs). Finally, most tumor studies did not assess the
presence of monoclonal viral integration and whether or not the MCV
DNA harbored a truncating mutation.
Although these metholodologic differences hinder the ability to clearly
define the proportion of MCC tissues that are MCV-positive, the
consistent detection of MCV DNA in large proportions of MCC tissues
across studies contrasts the inconsistent findings from previous studies of
JCV and BKV in human tumor tissues. Furthermore, in addition to
evidence from DNA-based tumor studies, recently developed immunoas-
says have facilitated comparisons of MCV seroreactivity in MCC cases
versus controls.126 These studies indicate that MCV antibody levels are
significantly higher in MCV-positive MCC cases as compared to healthy
individuals (p ⬍ 0.001).127
Little is known about the natural history of MCV infection. Preliminary
serology studies suggest that exposure to MCV is common, with 40-50%
of children demonstrating seroreactivity to MCV by age 15128,129 and a
seroprevalence of 80% among individuals ages 50 and older.128 However,
the mode of transmission, site of initial infection, and existence of a latent
phase have not yet been characterized for MCV. Two of the other known
human polyomaviruses, JCV and BKV, have been shown to establish
latency in the kidney and reactivate upon severe immunosuppression to
cause disease. If the natural history of MCV follows a similar pattern of
reactivation in the context of immunosuppression, and MCV is involved
in the etiology of MCC, then this model would be consistent with the
observation that MCC incidence is higher among immunosuppressed
individuals.
Curr Probl Cancer, January/February 2010 27
Table 4. Summary of findings for Merkel cell polyomavirus (MCV) sequences in Merkel cell
carcinoma (MCC) tissues by PCR
MCV in normal MCV in other
Study MCV in MCC tumors
tissues cancers
Feng et al, 8 (80%) of 10 were 16% of 25 normal skin —
200840 MCV⫹ for at least one tissues
(USA) primer
Garneski et al, 43% of 37 0% of 15 normal skin 13% of 15 squamous
2009110 tissues cell carcinomas of
(North the skin
America and
Australia)
Kassem et al, 30 (77%) of 39 were 0% of 45 PBMC —
2008111 MCV⫹ for at least one
(Germany) primer
Becker et al, 75 samples were tested — 3 (13%) of 24 basal
2009112 from 53 pts; tumors cell carcinomas of
(Germany) from 45 pts (85%) were the skin
MCV⫹
Foulongne et 8 (89%) of 9 were MCV⫹ 0% of 15 benign —
al, 2008113 for at least one primer proliferative or
(France) inflammatory skin
disease
Bhatia et al, Tumors from 17 (74%) of Results from 1 (2%) of 52 non-
2009114 23 patients were lymphocytes are MCC tumors (20
(USA) MCV⫹ included in the box breast, 12 colon,
to the right 20 normal
peripheral blood
lymphocytes)
Varga et al, 7 (88%) of 8 MCC tissues — 0% of 13 squamous
2009115 from 6 patients were cell carcinomas,
(Hungary) MCV⫹ for at least one 10 basal cell
primer carcinomas, 3
basosquam
carcinomas, and 3
melanomas
Touze et al, 21 (66%) of 32 were — 0% of 9 other
2009116 MCV⫹, including neuroendocrine
(France) 9 (45%) of 20 FFPE carcinomas (5
tissues and 12 (100%) small cell lung
of 12 frozen tissues carcinomas, 3
intestinal
carcinomas, 1
cervical carcinoma)
Sastre-Garau 10 (100%) of 10 were — 0% of 1241 tumors
et al, MCV⫹ for at least on (32 skin, 44 cervix,
2009117 primer 39 large bowel,
(France) 114 liver, 45 uveal
tract, 172 ovary,
687 breast, 104
bone and soft
tissue, 4 other)

28 Curr Probl Cancer, January/February 2010

Table 4. Continued
MCV in normal MCV in other
Study MCV in MCC tumors
tissues cancers
Duncavage et 41 tissues from 29 — —
al, 2009118 patients were tested:
(USA) 22%-78% were
determined to be
MCV⫹ depending on
the primer set used
Wetzels et al, 4 (40%) of 10 were — 0% of 10 small cell
2009119 (the MCV⫹ lung cancers were
Netherlands) MCV⫹
Helmbold et al, 90 (92%) of 98 MCC 3 (17%) of 18 normal —
2009120 tissues from 91 skin samples and
(Germany) patients were MCV⫹ 1 (4%) of 26 blood
samples were
MCV⫹
Sihto et al, 91 (80%) of 114 were — —
2009121 MCV⫹ by qPCR
(Finland)
Andres et al, 21 (64%) of 33 FFPE — 2 (17%) of 12
2009122 tissues were MCV⫹ seborrheic
(Germany) including keratosis, 0% of
11 basal cell
carcinomas, and
0% of 10
malignant
melanomas
Nakajima et al, 11/14 (79%)were MCV⫹ — —
2009123 for at least one primer
(Japan) set
Loyo et al, 6 (86%) of 7 tissues were 21 (26%) of 82 66 (11%) of 192
2009124 MCV⫹ for at least one cutaneous, cancers including
(USA) primer set aerodigestive, cutaneous SCC,
respiratory and oral, esophageal,
genitourinary normal liver, colon, lung,
tissues kidney, bladder,
prostate cancers
and seminomas
Busam et al, 15 (88%) of 17 fresh — —
2009125 frozen tissues were
(USA) MCV⫹

Conclusion and Future Directions

Primary MCC appears to be multifactorial in origin and to occur in
elderly whites after a lifelong accumulation of environmental mutagenic
insults to the skin, when the efficiency of their immune system decreases
because of immunosenescence and inflam-aging.98,100,101,130-132 Further
Curr Probl Cancer, January/February 2010 29
studies are needed to understand the etiology of this rare and lethal cancer
and to identify risk factors and factor associated with survival.
Individuals with HIV infection, the subpopulation of solid organ transplant
recipients, patients treated with immune suppressant drugs, people with
another primary cancer, especially older whites recently diagnosed with
another malignancy, are at particularly high risk of MCC and they should be
screened for MCC at the skin and at mucosae regularly.
Epidemiological studies should aim to achieve comparability of inci-
dence rates within and between populations over time. When calculating
incidence rates to measure the risk of MCC in the general population,
MCC that are not first primary cancers should be excluded. In 1992, a
specific immunologic profile for MCC was established and most MCC
cases have been diagnosed after 1992. Thus, 1992 should probably be
considered as the reference year to ascertain whether the incidence of first
primary MCC is increasing in the general population. Survival analysis
should include patient immune competency status, which could be
ascertained through linkage of cancer registries to transplant registries,
AIDS registries, Medicare, or other large population databases.
The potential role of MCV in MCC is an exciting advance; however, the
existing tumor studies are insufficient for establishing causality. Future
tumor studies should incorporate multiple primers to facilitate compari-
sons with previously published studies. In addition, both formalin-fixed
and fresh frozen MCC tissues should be tested using the same set of
primers to investigate the effects of tissue preservation on assay sensi-
tivity. Additional markers of MCV infection should also continue being
investigated in MCC patients, including expression of the MCV T-antigen
in MCC tissues and the presence and titers of antibodies directed against
the MCV capsid126,128 and T-antigen. Molecular biology laboratories
should continue elucidating the mechanism(s) by which MCV induces
carcinogenesis; the effects of silencing the large and small T-antigens in
MCV-positive MCC cell lines by si/shRNA or overexpressing them in
NIH3T3 cells should be studied. Such experiments will only be possible
when MCV-positive MCC cell lines become readily available. Although
additional evidence is needed to characterize the role of MCV infections
in MCC, MCV may be a promising target for future MCC treatment and
prevention strategies.

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