review
Annals of Oncology 22: 250–256, 2011
doi:10.1093/annonc/mdq308
Published online 29 June 2010
Merkel cell carcinoma, chronic lymphocytic leukemia
and other lymphoproliferative disorders: an old bond
with possible new viral ties
T. Tadmor1* , A. Aviv2 & A. Polliack3
1
Hematology-Oncology Unit, Bnai-Zion Medical Center, Haifa; 2Hematology-Oncology Unit, Emek Medical Center, Afula; 3Department of Hematology, Hadassah
University Hospital and Hebrew University Medical School, Jerusalem, Israel
review
Received 29 January 2010; revised 1 April 2010; accepted 2 April 2010
Merkel cell carcinoma (MCC) is a rare and aggressive skin tumor. The link between tumorigenesis and
immunosuppression is well known and the increased prevalence of MCC in human immunodeficiency virus carriers and
organ transplant recipients and in patients with hemato-oncological neoplasias is now well recognized over the past
decade. In this respect, chronic lymphocytic leukemia (CLL) seems to be the most frequent neoplasia associated with the
development of MCC. Very recently, a newly described virus, the Merkel cell polyomavirus, was found in 80% of
MCC tumor samples and is in fact the first member of the polyomavirus family to be associated with human tumors. The
virus appears to play a role in the pathogenesis of MCC and may constitute the missing link between immunosuppression
and the development of MCC. This review summarizes the current knowledge relating to MCC and its pathogenesis,
stressing the link with hematologic neoplasias in general and to CLL in particular. We describe the permissive
immunologic environment, which enables the virus-containing tumor cells to survive and proliferate in disorders like CLL.
More studies are still needed to confirm this appealing theory in a more convincing manner.
Key words: cetuximab, comorbidity, elderly, metastatic colorectal cancer
introduction
Merkel cell carcinoma (MCC) is a rare and aggressive skin
tumor reported to occur with increasing prevalence in the past
decade [1, 2]. One of the established features of MCC is its
tendency to occur in association with other primary tumors,
mostly skin and hematologic malignancies and in particular B
lymphoproliferative disorders. In this respect, patients with
chronic lymphocytic leukemia (CLL) seem to have the highest
relative risk of developing this tumor [3–5]. Indeed, secondary
malignancies are well recognized as one of the complications
occurring in the course of CLL. It has been postulated that CLL
itself as well as the different chemotherapeutic agents given for
the disease permit the survival and proliferation of malignant
cells, which would otherwise probably be eliminated by an
intact and more effective immune system [5, 6].
Recently, a major contribution to the improved
understanding of the pathogenesis of MCC was made with the
discovery of the association of polyomavirus with this rare
tumor. This virus may indeed constitute the ‘missing link’ in
relation to MCC and may explain in part the epidemiological
*Correspondence to: Dr T. Tadmor, Hematology-Oncology Unit, Bnai-Zion Medical
Center, 47 Golomb Street, Haifa 31048, Israel. Tel: +972-4859407;
Fax: +972-48359962; E-mail: [email protected]
TT and AV contributed equally to this manuscript.
association between B-cell malignancies and this tumor. This
review focuses on the possible relation between MCC and
lymphoproliferative diseases in general, with special emphasis
on CLL as exemplified by the complex interplay of immune
dysregulation and an infectious agent.
merkel cell carcinoma
Merkel cells were termed as such as they were first described by
the German anatomist, Friedrich Merkel in 1875, as small
round or oval basophilic cells located at the end of nerve axons
and within the basal layer of the epidermis [7]. These cells have
characteristic dense-core granules containing a variety of
neuropeptides, plasma membrane spines and cytoskeletal
filaments. The function of Merkel cells is still controversial
today, but it is agreed that they are associated with the nerve
terminals acting as mechanoreceptors, although the mechanism
of transduction has as yet not been clearly defined. Other
Merkel cells that have no contact with nerve terminals appear
to have an endocrine function [3, 7, 8].
MCC, also termed apudoma of the skin, trabecular cancer or
small-cell neuroepithelial tumor of the skin, is an uncommon
but aggressive cutaneous neuroendocrine tumor, first described
by Toker in 1972 [9]. These were first reported as unusual skin
tumors histopathologically, with anastomosing trabeculae and
cell nests in the dermis and because of this the term ‘trabecular
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
Annals of Oncology
carcinoma of the skin’ was first used. Tumor cells are
characterized by the presence of electron-dense neurosecretory
granules, typically seen in cells associated with amine precursor
uptake and the decarboxylation system, and since Merkel cells
are the only type of cutaneous cells expressing such granules,
the nomenclature of the tumor was changed to MCC [8].
MCC is a rare tumor of the elderly with a median age of 70
years at diagnosis but its incidence has apparently increased
threefold over the past 20 years and is estimated to be 4/
1 000 000/year. It is twice as frequent in males as in females and
most of the cases are of Caucasian origin [3, 7, 8]. MCC
generally develops rapidly over a period of weeks to months,
often spreading to local, regional and more distant sites. The
mortality rate within 2 years of diagnosis is 28%, mostly
because it is already metastatic at presentation. The 5-year
survival rate for primary MCC is 75%, declining to 59% for
patients with local metastases and 25% for those with distant
metastases. Up to 50% of the patients will have disease
recurrence within the first 2 years [3, 7]. Risk factors reported
to be associated with the development of MCC include
ultraviolet (UV) light exposure and immunosuppression. Most
of the cases (81%) occur in the sun-exposed skin and the most
common sites for tumor development are the head, neck and
extremities, which also explains its frequent association with
other skin cancers, such as squamous and basal cell carcinoma
and Bowen’s disease [8].
Clinically, MCC usually presents as a firm red-violet
cutaneous tumor nodule mostly dome-shaped while superficial
ulceration, seen mostly in the later stages of disease, is
uncommon [10]. The tumor spreads into the reticular dermis
and subcutis usually sparing the papillary dermis, epidermis
and adnexa. Essentially three histopathologic patterns are
described, depending on the arrangement and appearance of
the tumor cells—a trabecular form, an intermediate one and
the small cell type. The mitotic index of the cells is usually high.
Definitive diagnosis is established by positive staining for
chromogranin, synaptophysin, neuron-specific enolase and the
neural cell adhesion molecule (Figure 1), which represents both
review
epithelial and neuroendocrine antigens present in normal
Merkel cells. The expression of cytokeratin 20, found in the
tumor cells in a dot-like paranuclear pattern and along the
cytoskeleton, allows for unequivocal identification. The latter
findings have been shown to be very useful in distinguishing
MCC from metastatic small-cell carcinoma of the lung
(cytokeratin 7+ and thyroid transcription factor 1+), small-cell
melanoma (s100+) and non-Hodgkin’s lymphoma (NHL)
(leukocyte common antigen+) [11, 12].
Clinical staging of the disease is based on tumor size (up to 2
cm or more) and the presence of local or distant metastases at
presentation [13]. Basically, treatment options include surgery
with or without adjuvant radiotherapy for localized disease and
systemic chemotherapy for disseminated or recurrent disease
[13]. It is not within the scope of this review to encompass the
full details of available therapeutic options available but in
short, the most effective treatment appears to rely on complete
surgical excision (with a 3-cm margin of excision due to the
high likelihood of local recurrence). Because of the high
probability of lymphatic spread, a sentinel lymph node biopsy
is usually carried out during surgery, and if micrometastases are
identified, a wider lymph node dissection follows [13]. MCC is
a radiosensitive disease and adjuvant radiotherapy delivered to
original tumor site and the regional lymph nodes is also
recommended. This addition has been shown to be effective in
reducing recurrence and increasing the 5-year survival rate.
There is no standard therapeutic regimen for metastatic MCC
and the common chemotherapy regimens applied are based on
those designed for small-cell bronchial carcinoma [13], which
includes anthracyclines, antimetabolites, bleomycin,
cyclophosphamide, etoposide and platinum derivatives. This
therapy is usually not curative but can be effective in reducing
tumor bulk [13].
Understanding of the pathogenesis and molecular events
occurring in MCC is still limited. Although multiple
chromosomal abnormalities including gains, losses and
rearrangements have been detected [3], the relationship of these
genetic abnormalities to the pathogenesis of MCC remains
Figure 1. (A and B) Hematoxylin–eosin stain of a cutaneous nodule demonstrating a dense subdermal lesion surrounded by a pseudocapsule of squamous
cells. The lesion is composed of small, blue round cells with a large nucleus (yellow arrow). Both features are typical to Merkel cell carcinoma (MCC). (C)
Cytokeratin 20 stain of a skin biopsy with a dot-like appearance of cytoplasmic stain. (D) Diffuse cytoplasmic positive synaptophysin stain. (E) Merkel cells
staining positively for CD56. (F) A positive chromogranin stain in a skin biopsy of MCC.
Volume 22 | No. 2 | February 2011
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unclear. In MCC, the most frequent chromosomes affected
are 1, 11 and 13 and the pattern of chromosome gains and
losses is similar to those encountered in small-cell carcinoma of
the lung. Structural abnormalities involving chromosome
1p have been noted in up to 40% of examined cases and
because deletion of chromosome 1 has also been associated
with the development of malignant melanoma and
neuroblastoma, it has been suggested that a tumor suppressor
gene may be located in this region [7]. Despite extensive
research on this topic, the understanding of molecular basis of
MCC is still limited, and results of the analysis of the expression
of target molecules such as bcl2 or involvement of the Wnt
pathway remain controversial [8]. A recent report
demonstrated a very high expression (88%) of Mcl-1, which is
part of the bcl2 protein family and functions as an antiapoptotic
protein in MCC. The same study also showed an increased
expression (78%) of Bmi-1, a transcriptional repressor
belonging to the polycomb-group family of proteins involved
in the regulation of proliferation [14]. In several studies,
expression of C-kit, a receptor tyrosine kinase, which is
a potential activator of the mitogen-activated protein kinase
pathway, was also found to be present in 15%–90% of MCC
samples [14, 15]. Considering the limitations of the current
therapies available for MCC and the relatively good results of
targeted anticancer drugs and anti-angiogenesis agents, it seems
likely that future clinical trials for MCC will be based on the use
of multitargeted tyrosine kinase inhibitors.
the role of immune dysregulation
Many malignancies are considered to develop on
immunosuppressive grounds. In this regard, the link with
lymphoid neoplasias is especially important because they
directly affect a major component of the immune system with
associated influences on other non-lymphoid immune
functions as well [16].
Immunosuppression and dysregulation are well-established
features of CLL and despite the fact that CLL is primarily a Blymphocyte-derived neoplasia, both cellular and humoral
immunity are affected in this disease, including defects in both
B- and T-lymphocytic functions, intercellular cross talk, natural
killer cell activity, cytokine balance, complement levels and
activity, as well as granulocytic and monocytic function [17,
18]. Especially prominent immune abberations in CLL include
the presence of B-cell anergy [19], hypogammaglobulinemia
[20, 21], decreased T-lymphocyte response to mitogens,
abberant T-cell receptor and molecular expression on T cells
[22], increased numbers of regulatory T cells [23] and the
inversion of the CD4+/CD8+ ratio, especially after treatment
with purine analogues [17, 24]. A summary of the various
immune dysfunctions encountered and described in CLL is
presented in Table 1.
Review of the available literature reveals a close link between
MCC and immune dysfunction. Indeed, in the recently
published ‘AEIOU’ acronym describing the clinical features of
MCC, the letter ‘A’ = asymptomatic, E = expanding rapidly, ‘I’
= immunosuppression, O = older than 50 years and U = UV
exopsed [10]. Chronically immune-suppressed individuals are
15 times more likely to develop MCC than age-matched
252 | Tadmor et al.
Annals of Oncology
Table 1. Summary of the main categories of immune dysfunction in CLL
B cells
T cells
Cellular cross talk
Cytokines
Complement
Phagocytic function
Poor antigen presentation
B-cell anergy (via shutdown of the AKT pathway)
Hypogammaglobulinemia (via CD95-mediated
plasma cell apoptosis)
Decreased response to mitogens
Decreased expression of CD25, CD152
Restricted and skewed T-cell receptor repertoire
Inversion of CD4+/CD8+ ratio
Depletion of effective cytotoxic T-cell pool (CD30mediated T-cell death)
Aberrant CD30–CD30L interactions
Soluble CD27 (‘decoy receptor’)
Expression of human leukocyte antigen-G
(interference with natural killer and T-cell
response)
IL-2 downregulation
Soluble IL-2 receptor (decoy receptor)
Overexpression of IL-10 in advanced disease
Transforming growth factor b overexpression
(immune ‘pan-inhibitor’)
Reduced complement levels
Neutropenia (bone marrow infiltration by CLL,
therapy induced)
Deficient granules (lysozyme, b-glucuronidase
myeloperoxidase)
Abnormal chemotaxis
CLL, chronic lymphocytic leukemia; IL, interleukin.
controls [7, 25] and the disease occurs at a younger median age
of 53 years. MCC also occurs more frequently after organ
transplantation and after human immunodeficiency virus
(HIV) infection and in patients with CLL. Sporadic association
has also been reported in patients with multiple myeloma and
in NHL [3] and even in patients with hairy cell leukemia years
after therapy with purine analogues when patients are in
clinical remission [26]. Based on a retrospective review of data
during 1968–2000 conducted by Buell et al. [25], 8% of all
reported cases with de novo MCC have undergone solid organ
transplant, mostly kidney (93%) but also heart (4%) and liver
(4%) transplantations. MCC presented at a mean time of 82.5
(range 5–290) months after transplantation, usually with
aggressive tumor spread with multiple sites of local or regional
involvement (19% of patients) and a rapidly disseminating
disease (51%) [25]. A recent retrospective study conducted by
Heath et al. [10] on 195 patients with MCC showed that 7.8%
of the patient cohort had some form of immunosuppression.
CLL was particularly overrepresented (4.1%), with an ageadjusted incidence of 2.4% for 50- to 69-year-old patients and
6.5% for CLL patients >70 years old. This represents a 48-fold
and 34-fold increased incidence, respectively, above that
expected in the general population for these age groups [10]. In
addition, Engels et al. [27] studied the incidence of MCC in
309 365 individuals with acquired immunodeficiency
syndrome (AIDS), using linked AIDS and cancer registries, and
reported that the incidence of MCC increased 11-fold for
individuals with AIDS.
Volume 22 | No. 2 | February 2011
review
Annals of Oncology
There are in addition >10 reports of patients with
spontaneous MCC regression and these seem to occur after
incomplete tumor excision, biopsy or fine needle aspiration
[28–31], while two cases of partial tumor regression after
withdrawal of immunosuppressive therapy have also been
reported [32, 33]. The latter data all seem to imply a crucial role
of the immune system in the pathophysiology of MCC.
Although the epidemiological link between immunesuppression and MCC is well established, it is still uncertain
what the basic defects in the immune system are that permit the
development, survival and growth of MCC tumors in immunecompromised patients. An RT-PCR-based analysis carried out
on MCC tumor specimens has shown that the existence of
a local cytokine imbalance might reflect a local permissive
immune state [21], but these findings still need further
consolidation in order to really understand why MCC develops
in these patients.
hematologic malignancies, particularly
CLL and MCC
Although not yet fully understood, the link between MCC and
hematologic malignancies, especially those of lymphoid
derivation, is already well recognized [1, 3, 4, 6, 10, 34].
Possible explanations for this association include
a predisposing genetic instability leading to an increased rate of
mutation, exposure to oncogenic environmental factors and
decreased immune surveillance associated with in the primary
cancer, all permitting the development of second malignancies.
These observations on MCC incidence may also reflect a certain
degree of bias because of the closer follow-up carried out by
minded physicians accompanied by more frequent clinic visits
as well as an increased awareness by cancer patients after their
diagnoses. Nevertheless, despite the latter assumptions, the
consistency of data suggests that there is a true link between
MCC and lymphoid neoplasias. The published reports imply
a sort of a ‘bidirectional’ linkage between these diseases as there
is an increased risk of MCC occurring in CLL patients while
there is also an increased incidence of CLL evident in the MCC
cohorts [3, 4, 10, 34]. Until now, more than 50 patients with
concomitant CLL and MCC have been reported, mostly with
CLL as the primary tumor. In 12 cases, MCC was the primary
tumor, while in 2 cases, both were diagnosed simultaneously. A
summary of these associations is given in Table 2.
The most comprehensive study on the association of CLL
with MCC was conducted by Howard et al. [3] on more than 2
million cancer patients’ registries in the NCI Surveillance,
Epidemiology, and End Results (SEER) program from 1986 to
2002 [3]. They identified an increased risk for developing NHL
after MCC [standardized incidence ratio (SIR) = 2.56, 95%
confidence interval (CI) 1.23–4.71, P = 0.007]; however, the risk
for developing CLL following MCC was not seen as statistically
significant (SIR = 2.72, 95% CI 0.55–7.94). Another recently
published Finnish study by Koljonen et al. [4] found 2 patients
among 172 with MCC (during the period of 1979–2006) who
subsequently developed CLL. These findings reflect
a significantly increased risk for CLL developing in patients with
MCC (SIR = 17.9, 95% CI 2.2–64.6, P < 0.001) as opposed to
Volume 22 | No. 2 | February 2011
Table 2. Reported cases of simultaneous occurrence of MCC and CLL
First author
Year
Cases
Kuhajda
1986
2
Safadi
1996
1
Quaglino
Ziprin
1997
2000
1
2
Brenner
2001
3
Warakaulle
2001
1
Cottoni
2002
1
Cohen
2002
1
Vlad
Sinclair
2003
2003
1
1
Pandey
2003
1
Agnew
2004
2
Papageorgiou
2005
1
Ben-David
2005
1
Robak
2005
1
Cervigón
Howard
2006
2006
1
14
Barroeta
2007
1
Heath
2008
8
Koljonen
2009
2
4
Craig
2009
1
Turk
2009
1
Case description
Reference
CLL of several years’ duration
followed by MCC
Fatal MCC in an established
case of CLL
MCC after treatment for CLL
MCC occurring after
immunosuppressive
therapy for CLL
Survey among 67 Israeli
MCC patients
MCC 10 months after
CLL diagnosis
BCC, MCC,
keratoacanthoma and
KS occurring sequentially
1–3 years after
chlorambucil for CLL
MCC in SLL after therapy
with fludara + rituximab
Fatal MCC in CLL patient
MCC of eyelid 11 months
after diagnosis of CLL
CLL occurring in recently
diagnosed MCC
Retrospective analysis of
750 patients with CLL
MCC, 8 years after
diagnosis of CLL
MCC, 3 years after
diagnosis of CLL
MCC after cladribine +
rituximab treatment
for CLL
MCC in a CLL patient
Surveillance, Epidemiology,
and End Results-based
registry, including
17 315 CLL patients
CLL with a skin lesion
showing both
MCC and CLL
Australian survey of 195
MCC patients
Finnish survey of 172 patients
with previous MCC
Survey among 4164 patients
with previous CLL
Skin lesion with MCC and
CLL in same tumor
Spontaneous regression of
MCC after fine needle
aspiration in CLL
[35]
[36]
[37]
[38]
[34]
[39]
[40]
[26]
[41]
[42]
[43]
[44]
[12]
[45]
[46]
[47]
[3]
[48]
[10]
[4]
[49]
[31]
CLL, chronic lymphocytic leukemia; MCC, Merkel cell carcinoma; KS,
Kaposi sarcoma; SLL, small lymphocytic lymphoma/leukemia.
doi:10.1093/annonc/mdq308 | 253
review
the data from the United States. Heath et al. [10] also published
a survey on 195 Australian patients with MCC diagnosed during
1980 and 2007 and found 8 to have CLL. These figures represent
a 34- to 48-fold overrepresentation compared with an agematched population, although an SIR analysis was not carried
out. In contrast to the latter, the data showed that there was an
increased risk for patients with CLL to develop MCC, which was
much more substantial and some of it is summarized in Table 2.
Koljonen on behalf of the Finnish registry found among 4164
CLL patients 4 cases of subsequent MCC, which does show
a statistically increased risk (SIR = 15.7, 95% CI 3.2–46.0, P <
0.01). The author concluded that ‘patients diagnosed with CLL
have a greatly increased risk for developing MCC, and vice
versa, compared with the non-CLL general population’ [4].
Furthermore, the SEER-based survey noted a significantly
increased risk for developing MCC after any primary tumor
(SIR = 1.36, 95% CI 1.19–1.55) but especially following CLL
(SIR = 6.89, 95% CI 3.77–11.57). The latter report identified 14
patients with MCC who formerly had a diagnosis of CLL. In
addition, an increased incidence of MCC was also observed in
patients with multiple myeloma (SIR = 3.70, 95% CI 1.01–9.47)
and NHL (SIR = 3.37, 95% CI 1.93–5.47) [3].
Whether this apparent epidemiological assymetry between
CLL and MCC is due to major differences in tumor prevalence
rates (CLL is a common disease while MCC is a very rare one)
or basically represents a manifestation of the permissive
immunosuppression accompanying B-cell malignancies that
allows for the development of secondary tumors is still
a debatable issue. Another possible explanation for this
observation lies in the fact that the median survival of patients
with MCC is significantly shorter than CLL (median survival of
31 versus 120 months, respectively), which may imply that MCC
patients do not live long enough to develop an indolent tumor
while the reverse situation applies for CLL. In this respect, it is
of interest to note that at least two case reports described not
only the coexistence of both tumors in the same patient but
even within the same skin lesion [48, 49]. Pathologically, both
tumors belong to the ‘small round and blue cell tumors’ family,
linking them both to the same differential diagnosis, sometimes
with a confounding overlap [50, 51].
Current available data and knowledge does not support
a common origin for both these tumors, which arise from
entirely different stem cells but there may perhaps be a common
local transforming event, such as UV exposure or polyomavirus
infection. A more plausible theory, however, would be of a first
tumor causing an ‘immunologic microrenvironment’
facilitating the local development of a second tumor. All the
above, in addition to the individual case reports, the small
reported series and all the literature reviews recorded since the
mid-1990s [12, 26, 31, 35–47, 48, 49], strengthen the line of
evidence, implying that immune dysfunction may well play
a key role in the pathogenesis of MCC.
polyomavirus association with MCC
Murine polyomavirus was first discovered by Gross in 1953,
while the first human polyomaviruses, BK virus (BKV) and JC
virus (JCV), were coincidently isolated in 1971 by two
independent groups. BKV was isolated from the urine of a renal
254 | Tadmor et al.
Annals of Oncology
transplant patient who had ureteral stenosis [52] and JCV was
found in the brain tissue of a patient with Hodgkin lymphoma
who developed progressive multifocal leukoencephalopathy
[53]. Almost four decades later, DNA sequences, representing
three new members of the human polyomavirus family, were
discovered. The viral genomes cloned from these sequences
have been designated KI polyomavirus (KIPyV), WU
polyomavirus (WUPyV) and Merkel cell polyomavirus
(MCPyV), respectively. KIPyV and WUPyV were identified from
large-scale high-throughput screenings of respiratory secretions
from patients with respiratory tract infections [54, 55], while
MCPyV was identified in MCCs using digital transcriptome
subtraction, a methodology developed to identify foreign
transcripts utilizing human high-throughput complementary
DNA (cDNA) sequencing data [56]. In contrast to the four
previously described human polyomaviruses, which belong to
the simian virus 40 subgroup, MCPyV is phylogenetically related
to murine polyomaviruses and is closely related to the African
green monkey lymphotropic polyomavirus. Since the 1950s,
polyomaviruses have been recognized as cancer viruses in
animals, but MCPyV was basically the first polyomavirus
suspected of causing human tumors. However, like in the case of
other established tumor viruses, most individuals infected with
MCPyV do not develop MCC and as yet, the additional steps
required for the eventual development of cancer after infection
with MCPyV are still unknown.
The human polyomaviruses, like other polyomaviruses, are
composed of small, nonenveloped, icosahedral virions with
a supercoiled double-stranded DNA genome (5200 base pairs)
(Figure 2). The genomes are divided into three regions: first,
the early coding region, which encodes for the large (Tag) and
the small tumor antigen (tag); second, the late coding region,
which encodes for the viral capsid proteins VP1, VP2 and VP3
and the nonstructural agnoprotein and third, the noncoding
control region, which contains the viral promoters and the
origins of replication. The MCPyV was first described in 2008
by Feng et al. who generated two cDNA libraries from four
MCC tumors and then searched for rare viral sequences. They
were able to define a previously unknown human
polyomavirus, which they called Merkel cell polyomavirus
(MCV or MCPyV) because of its close association with MCC.
Figure 2. Transmission electron microscopy of MCPyV, virus-like
particles at ·50 000 magnification shows characteristic polyomaviral
icosahedral capsid structures. Bar represents 100 nm. Figure was adapted
from Int J Cancer 2009; 125 (6): 1250–1256 with the permission of the
authors Dr Tolsov and Dr Moore.
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Annals of Oncology
Sequences corresponding to MCPyV were found in 8 of the 10
MCC tumors compared with 5 of the 59 control tissues. Viral
DNA in six of the eight MCPyV-positive MCC specimens
showed a clonal integration pattern [56]. Since the discovery of
the MCPyV, other researchers have obtained the same results,
showing that 80% of MCCs have MCPyV integrated within
the tumor, in a monoclonal pattern, indicating that the virus is
present in a precursor cell before it becomes neoplastic.
However, it should be noted that at least 20% of MCC are not
infected with MCPyV, suggesting that MCC may have other
nonviral causes as well [57, 58].
MCC-related polyomaviruses have specific mutations of the
large T antigen that render the virus noninfectious [59]. Such
mutations were not detected in viral genomes from nonneoplastic cells, indicating that MCC cells undergo selection for
Large T antigen mutations thus preventing autoactivation of
integrated virus replication that would be detrimental to cell
survival. Because these mutations render the virus ‘replication
incompetent’, MCPyV is not regarded as a ‘passenger virus’,
which infects MCC secondarily.
All in all, these results support the hypothesis that altered
replication or integration of MCPyV may be involved in MCC
tumorigenesis [59]. In this respect, it is worthwhile noting the
observations of Shuda et al. who studied the MCPyV T antigen
expression in normal lymphoid tissues and lymphoid tumors
and in peripheral blood mononuclear (PBMN) cells obtained
from healthy controls and HIV-positive patients without MCC
in an attempt to assess the degree of MCPyV lymphotropism as
described in other human polyomavirus infections. None of the
samples obtained from healthy controls were positive for viral
DNA; however, in PBMN collected from adult HIV/AIDS
patients without MCC, 9.5% of cases were found to be positive
for T antigen, suggesting that immunosuppression may indeed
lead to reactivation of the latent virus [60]. They conclude that
examination of the whole PBMN fraction is unlikely to reliably
detect MCPyV in most infected individuals because of the
dilution effect from the nonpermissive peripheral blood cells.
On the other hand, they imply, like in the case of infections
with other similar lymphotrophic viruses (e.g. Kaposi’s
sarcoma-associated herpesvirus) in which only a proportion of
the peripheral blood mononuclear cells are positive in infected
persons, that the lymphocyte pool may indeed serve as a tissue
reservoir for MCPyV infection [60].
In a recent study, Sihto et al. [61] reviewed 207 reports of
MCC patients diagnosed in Finland during 1979–2004 and
suggested that individuals with MCPyV-positive MCC tumors
had a better prognosis than those without MCPyV infection (5year survival: 45% versus 15% in univariant and multivariant
analyses). An important observation gained from that study
was a steady proportion of MCC cases that was positive for
viral DNA during the two time periods studied, suggesting that
MCPyV is probably not a new emerging threat, accounting for
the increasing incidence of MCC [58]. It is obvious that in the
near future a routine serological test needs to be developed in
order to accurately measure exposure to MCPyV. Furthermore,
we will also have to learn how to utilize the presence of the
T antigen as a marker for MCC tumor cells and to determine
whether this antigen can be exploited as a unique nonhuman
target for specific anticancer therapy for MCC.
Volume 22 | No. 2 | February 2011
conclusions
The incidence of MCC, an aggressive skin tumor, has
apparently been increasing over the past 20 years and it
represents a new emerging complication in immunecompromised patients. Recognizing this entity is becoming an
essential issue for hemato-oncologists today because an early
diagnosis before the appearance of distant metastases is
imperative due to the fact that this very aggressive tumor has
a particularly poor overall survival when diagnosed late. The
discovery of a new virus, the MCPyV, represents an important
breakthrough in the attempts to understand the pathogenesis of
MCC. The next steps, which are now under intensive research
and need to be applied, relate to how to make an early diagnosis
of MCC, through the detection of specific antigen markers and
new serologic tests, and more importantly how to improve the
therapeutic management of this aggressive tumor. Basic
questions about the virus and its interaction with the host still
remain unanswered and these include identification of the
healthy carrier, determination of the mode of transmission of
the virus in the normal population and the issue of its affinity
to the cutaneous Merkel cells. Other questions relate to
establishing whether there is anything unique about the Merkel
cells that make them so susceptible to oncogenesis by this virus.
Development of new antiviral drugs, using small molecules
that could perhaps interfere with the T antigen, and targeting
MCPyV–tumor suppressor interactions are also now under
development. Additional ongoing studies are in process and
hold great promise for the ability to detect and combat these
tumors in the not too distant future.
disclosure
None of the authors declare conflicts of interest.
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Volume 22 | No. 2 | February 2011