JNCI J Natl Cancer Inst (2015) 107(2): dju382
doi:10.1093/jnci/dju382
First published online January 8, 2015
Article
article
Risk of Merkel Cell Carcinoma After Solid Organ
Transplantation
Christina A. Clarke, Hilary A. Robbins, Zaria Tatalovich, Charles F. Lynch,
Karen S. Pawlish, Jack L. Finch, Brenda Y. Hernandez, Joseph F. Fraumeni Jr.,
Margaret M. Madeleine, Eric A. Engels
Affiliations of authors:Cancer Prevention Institute of California, Fremont, CA (CAC); Department of Health
Research and Policy, Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, CA
(CAC); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health,
Bethesda, MD (HAR, ZT, JFFJr, EAE); Department of Epidemiology, University of Iowa, Iowa City, IA (CFL); New
Jersey State Cancer Registry, New Jersey Department of Health, Trenton, NJ (KSP); Colorado Central Cancer
Registry, Colorado Department of Public Health and Environment, Denver, CO (JLF); University of Hawaii
Cancer Center, Honolulu, HI (BYH); Program in Epidemiology, Fred Hutchinson Cancer Research Center,
Seattle, WA (MMM); Department of Epidemiology, University of Washington, Seattle, WA (MMM).
Correspondence to: Christina A. Clarke, PhD, MPH, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538-2334
(e-mail: [email protected]).
Abstract
article
Background: Solid organ transplant recipients have elevated risks of virus-related cancers, in part because of long-term
immunosuppression. Merkel cell carcinoma (MCC) is an aggressive skin cancer recently found to have a viral origin, but
little is known regarding the occurrence of MCC after transplant.
Methods: We linked the US Scientific Registry of Transplant Recipients with data from 15 population-based cancer registries
to ascertain MCC occurrence among 189 498 solid organ transplant recipients from 1987 to 2009. Risks for MCC following
transplantation were compared with the general population using standardized incidence ratios, and Poisson regression
was used to compare incidence rates according to key patient and transplant characteristics. All statistical tests were ­
two-sided.
Results: After solid organ transplantation, overall risk of MCC was increased 23.8-fold (95% confidence interval = 19.6 to
28.7, n = 110). Adjusted risks were highest among older recipients, increased with time since transplantation, and varied
by organ type (all P ≤ .007). Azathioprine, cyclosporine, and mTOR inhibitors given for maintenance immunosuppression
increased risk, and non-Hispanic white recipients on cyclosporine and azathioprine experienced increasing MCC risk with
lower latitude of residence (ie, higher ultraviolet radiation exposure, P = .012).
Conclusions: MCC risk is sharply elevated after solid organ transplant, likely resulting from long-term immunosuppression.
Immunosuppressive medications may act synergistically with ultraviolet radiation to increase risk.
Received: April 29, 2014; Revised: August 5, 2014; Accepted: October 21, 2014
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
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C. A. Clarke et al. | 2 of 9
Methods
Transplant Cancer Match Study
The TCM Study (http://transplantmatch.cancer.gov) is described
in detail elsewhere (20). Briefly, computer-based linkages
were performed between the Scientific Registry of Transplant
Recipients (SRTR) and 15 US central cancer registries. The SRTR
includes structured data regarding all US solid organ transplants
since 1987, including recipient demographic characteristics,
characteristics of the transplanted organs, and immunosuppressive medications prescribed at time of transplant. Transplants
performed on the same person at different times are considered
separately.
Serial record linkages were completed between the SRTR and
15 cancer registries, altogether covering 46% of US transplants:
California (years of coverage: 1988–2008), Colorado (1988–2009),
Connecticut (1973–2009), Florida (1981–2009), Georgia (1995–
2008), Hawaii (1973–2007), Illinois (1986–2007), Iowa (1973–
2009), Michigan (1985–2009), New Jersey (1979–2006), New York
(1976–2007), North Carolina (1990–2007), Seattle (1974–2008),
Texas (1995–2006), and Utah (1973–2008). Linkages were performed using a computer algorithm (incorporating name, sex,
date of birth, and social security number), followed by manual
review and confirmation of potential matches. Analyses were
restricted to transplant recipients residing in geographic areas
covered by cancer registries during the specified time periods.
The TCM Study was approved by human subjects research
review committees at the National Cancer Institute (NCI) and,
as required, the participating cancer registries.
For the present study, we considered a cohort of 208 096 solid
organ transplants performed from 1987 to 2009, from which
we successively excluded five transplants with a pretransplant
history of MCC and two groups of transplants among which no
MCC cases were observed: 18 379 in persons age 0 to 19 years at
transplant, and 214 in persons with known HIV infection. The
final cohort thus included n = 189 498 transplants.
MCC Outcome and Follow-up
MCC cases in transplant recipients were identified through
linked cancer registry data, using the International Classification
of Diseases (ICD) for Oncology, 3rd edition histology code 8247
(introduced in 1986). Patient follow-up began at the latest of
transplantation or start of cancer registry coverage and ended
at the earliest of MCC diagnosis, death, failure of a transplanted
organ, subsequent transplant, loss to follow-up, or end of cancer
registry coverage.
Variable Definitions
We obtained cancer-related information from cancer registries
regarding cancer diagnoses, including date and age at diagnosis and tumor characteristics. We obtained transplant-related
information from the SRTR, including organ(s), date, age at
transplant, and baseline immunosuppressive medications. We
grouped medications that are often prescribed together as follows: the “cyclosporine/azathioprine” category included recipients prescribed both cyclosporine and azathioprine but not
tacrolimus or mycophenolate mofetil (MMF); the “tacrolimus/
MMF” category included recipients prescribed both tacrolimus
and MMF but not cyclosporine or azathioprine; and remaining
recipients were categorized as “other.”
Neither the SRTR nor cancer registries collect information
regarding patient history of UVR exposure. Thus, we derived
proxy, ecologic measures of UVR exposure based on their residence at time of entry onto the transplant waitlist or transplant, when available. We assigned latitude to each transplant
using a public database providing latitudes for US zip codes
(21). Separately, we linked transplants by county of residence to
AVGLO, a measure of potential UVR exposure previously shown
to be associated with melanoma risk (22,23). AVGLO is based
on the predicted 30-year average daily global solar radiation,
defined as the total direct and diffuse solar radiation received on
a horizontal surface measured in watt-hours per square kilometer (Wh/km2). Latitude and AVGLO measures were categorized
into quintiles by dividing the range of each measure into equal
segments (see footnote to Table 2 for details, including imputation for n = 2282 transplants for whom county information was
not available).
Statistical Analysis
We measured MCC risk in transplant recipients relative to the
general population using the standardized incidence ratio (SIR)
(ie, observed/expected number of case patients). Expected numbers were calculated by applying general population MCC incidence rates, based on MCC cases ascertained in cancer registries,
to person-time at risk among transplant recipients, stratified by
sex, five-year age group, race/ethnicity, calendar year, and registry. Rates for non-Hispanic whites, non-Hispanic blacks, and
article
Merkel cell carcinoma (MCC) is an uncommon skin cancer of
neuroendocrine differentiation. MCC behaves aggressively, and
five-year relative survival is only 62% (1). Like other skin cancers,
MCC largely affects light-skinned populations (2,3), especially
those highly exposed to ultraviolet radiation (UVR) (4). Recently,
a previously unknown virus, Merkel cell polyomavirus (MCV),
was detected in most but not all MCC tumors tested (5). This
discovery has revived interest in MCC epidemiology, especially
regarding the role of impaired immunity in promoting viral
carcinogenesis. However, details regarding the relevant type of
immunosuppression are poorly understood.
Immunosuppression is suspected as important to MCC causation, as risk is increased among persons with human immunodeficiency virus (HIV) (6,7), chronic lymphocytic leukemia, (3,8)
and other hematologic malignancies (8). MCC risk is also elevated following solid organ transplantation (9–12), after which
patients must be pharmacologically immunosuppressed to prevent graft rejection. Also, some immunosuppressant medications used in transplantation may have direct skin carcinogenic
effects, including interacting with UVR to enhance DNA damage
(13–18). These direct effects may relate to the very high risks of
squamous cell skin cancers in transplant recipients (19). Prior
studies of transplant-related MCC have included fewer than 50
case patients and have not provided information on how risk
differs by age, timing of transplant, or specific immunosuppressive medications (9–12).
In the present study, we evaluated the occurrence of MCC
among solid organ transplant recipients in the Transplant
Cancer Match (TCM) Study, a large, population-based cohort of
US transplant recipients for which cancer ascertainment was
conducted uniformly via linkage with cancer registries. We
quantified MCC risk overall and according to recipient demographic characteristics, transplanted organ, UVR exposure based
on place of residence, length of time since transplant, and type
of immunosuppressive drugs received.
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Asians/Pacific Islanders were obtained from participating registries. Rates for Hispanics (available 1992 onward) were obtained
from the NCI Surveillance, Epidemiology, and End Results program. We derived exact confidence intervals around each SIR.
To compare MCC risk between categories of transplant
recipients, we calculated incidence rates (ie, cases/100 000 person-years) and corresponding incidence rate ratios (IRRs). We
compared incidence across categories defined by age at transplant, transplanted organ, successive time intervals after transplant, and calendar year of follow-up attained by the recipient
(ie, attained calendar year). We calculated P values using a likelihood ratio test.
To explore possible interactions of photosensitizing medications and UVR exposure, we analyzed trends in MCC incidence
across categories of latitude and AVGLO, stratified by maintenance medication category. These analyses were restricted to
non-Hispanic whites, who are most susceptible to UVR damage. Finally, to identify independent predictors of MCC risk, we
constructed a multivariable Poisson model of MCC incidence
restricted to non-Hispanic whites. Covariables included sex,
age at transplant, transplanted organ, time since transplantation, and variables capturing the effects of medications and
UVR exposure observed in univariate analyses. We included a
reduced, two-level maintenance medication regimen variable
comparing cyclosporine/azathioprine recipients (as described
above) to all other regimens, and further included latitude quintile (modeled with one degree of freedom) and an interaction
term between cyclosporine/azathioprine maintenance regimen
and latitude quintile. Accordingly, we present IRRs representing
the adjusted trend in MCC incidence across latitude quintile,
separately for cyclosporine/azathioprine and other maintenance regimens. All statistical tests were two-sided.
Results
article
We evaluated risk of MCC in 189 498 solid organ transplants
with 859 789 person-years of follow-up (Table 1). Sixty-two percent of transplant recipients were male, and the median age at
transplant was 49 years. Recipients were racially and ethnically
diverse, with 37% of transplants occurring in persons who were
not non-Hispanic white. Kidney transplants were most common, but 35% of transplants were liver, heart, or lung transplants, and 6% included less common or multiple organs.
A total of 110 MCC diagnoses among transplant recipients
were identified. The median age at diagnosis of MCC was 62 years
(range = 34–80). More than half of all MCC case patients were
diagnosed on the head or neck (51%, n = 56), while smaller proportions were diagnosed on the upper extremities (26%, n = 29),
the trunk (12%, n = 13), lower extremities (8%, n = 9) or unknown
sites (3%, n = 3). Among MCCs with known stage at diagnosis
(n = 95), the majority (62%) were diagnosed at localized stage,
while 29% had regional and 9% had distant stage; this distribution was similar to the expected distribution (data not shown).
The overall incidence rate of MCC was 12.8 (95% confidence
interval [CI] = 10.5 to 15.4) per 100 000 person-years. When compared with the general population, this corresponded to a nearly
24-fold elevation in risk (SIR = 23.8, 95% CI = 19.6 to 28.7). As
shown in Table 2, incidence rates increased steeply with increasing age at transplant, and 73% of cases were in people older than
age 50 years at transplant. MCC incidence was 70% higher in
male compared with female transplant recipients (IRR = 1.7, 95%
CI = 1.1 to 2.6). Ninety-one percent of MCC cases were in whites,
and incidence was five-fold higher in white than in non-white
recipients.
Table 1. Characteristics of 189 498 US solid organ transplants evaluated for risk of Merkel cell carcinoma
Characteristic
No. of transplants
Total
Sex
Male
Female
Age at transplant, y
20–34
35–49
50–64
65+
Race/ethnicity
Non-Hispanic white
Non-Hispanic black
Hispanic
Asian/Pacific Islander
Transplanted organ
Kidney only
Liver only
Heart only
Lung only
Other or multiple
Calendar year of transplantation
1987–1994
1995–1999
2000–2004
2005–2009
189498
% of total
100
116933
72565
61.7
38.3
31621
64868
75431
17578
16.7
34.2
39.8
9.3
119419
31865
27674
10540
63.0
16.8
14.6
5.6
111775
40238
17693
7946
11846
59.0
21.2
9.3
4.2
6.3
34249
47609
59409
48231
18.1
25.1
31.4
25.5
MCC incidence rates increased statistically significantly with
time since transplant, with highest incidence occurring 10 or
more years after transplant (Table 2). MCC rates also increased
over the time period studied, with the highest rate observed from
2003 to 2005. For the cohort overall, MCC risk did not vary statistically according to ecologic proxies of UVR exposure, including
quintiles of AVGLO and latitude of residence. Incidence also was
not different between recipients of kidneys and other organs,
although the test for heterogeneity (P = .019) suggested statistically significant variation among organ types, as did subsequent
multivariable regression (see below).
We examined MCC rates according to receipt of specific
medications (Table 3). About 44% of the transplant population
received induction medications at the time of transplantation.
We observed a statistically significantly protective association
of monoclonal antibody induction with MCC, as fewer than 2%
(n = 2) of MCC case patients had received monoclonal antibodies, but a higher proportion (5.4%) without MCC had received
them. With respect to individual maintenance immunosuppressive medications, we observed higher incidence among persons
receiving cyclosporine, azathioprine, or mTOR inhibitors, and
decreased incidence in those receiving tacrolimus or MMF, compared with recipients not receiving these medications. The combination regimen of cyclosporine/azathioprine was associated
with highest MCC risk (Table 3).
We hypothesized that the effects of UVR would be most
apparent in non-Hispanic whites who were given cyclosporine
and azathioprine, given the reported photosensitizing and carcinogenic effects of these medications (18,24). Figure 1 shows
that latitude and AVGLO were not associated with statistically
significant variations in incidence among non-Hispanic white
persons receiving tacrolimus/MMF or other regimens. However,
for those receiving cyclosporine/azathioprine, MCC incidence
increased statistically significantly with decreasing latitude
C. A. Clarke et al. | 4 of 9
Table 2. Risk of Merkel cell carcinoma according to demographic characteristics, transplanted organ, and time since transplant
Sex
Female
Male
Age at transplant, y
20–34
35–49
50–64
65+
Race/ethnicity
White
Nonwhite
Transplanted organ
Kidney only
Liver only
Heart only
All other
Time since transplant
<1 year
1 to <3 y
3 to <5 y
5 to <10 y
≥10 y
Attained calendar year
1987–1998
1999–2002
2003–2005
2006–2009
Residential latitude quintile*
1 (lowest UVR)
2
3
4
5 (highest UVR)
Residential AVGLO quintile*
1 (lowest UVR)
2
3
4
5 (highest UVR)
MCC patients
Incidence rate
(per 100 000 person-years)
Incidence rate ratio
(IRR) (95% CI)
30
80
8.9
15.3
Ref.
1.7 (1.1 to 2.6)
7
23
64
16
4.5
7.2
19.7
25.7
Ref.
1.6 (0.7 to 3.7)
4.3 (2.0 to 9.5)
5.7 (2.3 to 13.8)
100
10
17.6
3.4
Ref.
0.2 (0.1 to 0.4)
70
15
20
5
13.8
8.4
20.5
6.7
Ref.
0.6 (0.3 to 1.1)
1.5 (0.9 to 2.4)
0.5 (0.2 to 1.2)
6
23
17
44
20
3.4
9.5
10.0
21.0
33.1
Ref.
2.8 (1.1 to 6.9)
2.9 (1.2 to 7.5)
6.2 (2.6 to 14.5)
9.8 (3.9 to 24.3)
13
32
38
27
6.5
14.5
17.6
12.0
Ref.
2.2 (1.2 to 4.2)
2.7 (1.4 to 5.0)
1.8 (0.9 to 3.6)
12
43
29
20
2
16.8
11.1
13.0
14.7
38.9
Ref.
0.7 (0.3 to 1.2)
0.8 (0.4 to 1.5)
0.9 (0.4 to 1.8)
2.3 (0.5 to 10.4)
3
36
17
41
8
13.2
11.6
11.1
13.9
16.9
Ref.
0.9 (0.3, 2.9)
0.8 (0.2 to 2.9)
1.1 (0.3 to 3.4)
1.3 (0.3 to 4.8)
P
.009
Ptrend < .001
<.001
.019
Ptrend < .001
Ptrend = .096
Ptrend = .478
Ptrend = .308
* For latitude (in degrees), quintiles corresponded to ≥42.8 (lowest UV exposure), 36.6–42.7, 30.4–36.5, 24.2–30.3, and <24.2 (highest UV exposure). For AVGLO (predicted
30-year average daily global solar radiation, defined as the total amount of direct and diffuse solar radiation received on a horizontal surface measured in watt-hours
per square kilometer), quintiles corresponded to <3552 (lowest UV exposure), 3552–4091, 4092–4631, 4632–5171, and ≥5172 (highest UV exposure). AVGLO was imputed
for transplant recipients for whom county was not available, but who lived in states whose range of county-level mean AVGLO values were within a single quintile,
(ie, all Connecticut, New Jersey, and New York residents were assigned to quintile 2, and North Carolina residents to quintile 3). For Hawaii residents, AVGLO was not
available but the AVGLO measures for Mexico City (at a similar latitude to Hawaii) fell within our highest quintile, so all Hawaii residents were assigned to quintile
5. The analysis cohort was reduced for these two variables because of missing zip code data or AVGLO that could not be imputed (n = 183 703 recipients included for
latitude analyses and n = 184 721 included for AVGLO analyses). Poisson regression analysis; All statistical tests were two-sided. CI = confidence interval; UVR = ultraviolet radiation.
(P = .003) (Figure 1A) and increasing AVGLO (P = .023) (Figure 1B),
ie, conditions of higher average UVR exposure.
In a multivariable model restricted to non-Hispanic white
recipients, we confirmed that most of these characteristics were
independent risk factors for MCC (Table 4). Specifically, MCC risk
was higher with male sex, older age at transplant (older than
age 50 years vs 18–49 years), receipt of kidney transplant, longer
time since transplant, receipt of no induction therapy or induction therapy other than monoclonal antibodies, maintenance
therapy with mTOR inhibitors, and lower residential latitude (ie,
higher UVR) among those receiving cyclosporine and azathioprine (P = .012).
Discussion
In this study of transplant-related MCC, we found that solid
organ transplant recipients had steeply elevated risk, with
incidence almost twenty-four times higher than in the general population. MCC incidence rose with advancing time since
transplant, suggesting an etiologic role of long-term, chronic
immunosuppression, as opposed to the more acute, intense
immunosuppression induced at the time of transplantation.
Given the nature of transplant-related immunosuppression, and
the increased risk of MCC seen in HIV-infected people (7), the
relevant immunosuppression may primarily involve T-cell deficiency. There may also be an additional role for B-cell deficiency,
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Demographic and
clinical characteristics
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Table 3. Risk of Merkel cell carcinoma according to induction and maintenance medications prescribed at time of transplantation*
Medications
Induction medications
Monoclonal antibodies (T-cell depleting)
No
Yes
Polyclonal antibody
No
Yes
IL2 receptor antagonist
No
Yes
Maintenance medications
Cyclosporine
No
Yes
Tacrolimus
No
Yes
Azathioprine
No
Yes
MMF
No
Yes
mTOR inhibitors
No
Yes
Corticosteroids
No
Yes
Maintenance medication regimen
Tacrolimus/MMF
Cyclosporine/Azathioprine
Other
MCC patients
Incidence rate
(per 100 000 person-years)
Incidence rate ratio
(IRR)(95% CI)
P
.007
108
2
13.6
3.1
Ref.
0.2 (0.1 to 0.9)
94
16
13.0
11.5
Ref.
0.9 (0.5 to 1.5)
96
14
13.0
11.7
Ref.
0.9 (0.5 to 1.6)
39
71
10.0
15.2
Ref.
1.5 (1.0 to 2.3)
84
26
15.6
8.1
Ref.
0.5 (0.3 to 0.8)
66
44
11.2
16.3
Ref.
1.5 (1.0 to 2.1)
71
39
15.1
10.0
Ref.
0.7 (0.4 to 1.0)
100
10
12.2
23.6
Ref.
1.9 (1.0 to 3.7)
10
100
12.4
12.8
Ref.
1.0 (0.5 to 2.0)
19
43
48
9.0
18.1
11.7
Ref.
2.0 (1.2 to 3.5)
1.3 (0.8 to 2.2)
.630
.727
.031
.002
.059
.036
.069
.919
.021
* Poisson regression analysis. All statistical tests were two-sided. CI = confidence interval; IL2 = interleukin 2; MMF = mycophenolate mofetil; mTOR = mammalian
target of rapamycin.
article
which is prominent in another predisposing condition, chronic
lymphocytic leukemia (8). Presumably, long-term immune deficits in transplant recipients allow for expression of the MCV
viral proteins required for carcinogenesis.
Nonetheless, it is also likely that UVR works in concert with
immunosuppression to cause MCC. UVR exposure is a key contributor to MCC and other skin cancers in light-skinned populations (4), with the presumed mechanism involving direct
DNA damage and mutation, especially with cumulative, prolonged exposure to ionizing ultraviolet wavelengths in sunlight. Supporting the relevance of UVR exposure in transplant
recipients, we found greater risk in whites than in other groups,
and most cases occurred on sun-exposed sites. Also, incidence
increased steeply with age, as is seen in the general population
(2,3), likely reflecting chronic skin damage over many years of
sunlight exposure.
While the mechanism by which UVR contributes to DNA
damage is well-understood (25), there are practical difficulties
in measuring lifetime cumulative UVR exposure in an epidemiologic study. Thus, we used residential latitude and AVGLO
as broad, ecologic surrogates of individual UVR exposure. These
measures did not associate meaningfully with MCC incidence
across the whole cohort, but we did observe interesting associations among a subset, specifically white recipients who
received cyclosporine and azathioprine. In basic science settings, azathioprine has been shown to increase the DNA mutation frequency associated with a given level of UVR exposure
(13,16,18,24). Cyclosporine is thought to reduce capacity for DNA
repair (14,15,17). Although our analyses for cyclosporine and
azathioprine were prespecified, we point out that they involve
a test for interaction in a cohort subgroup and should be considered somewhat exploratory. Nonetheless, our study provides
the first epidemiologic evidence suggesting a synergistic effect
of these medications with UVR exposure in the development of
MCC. Although patterns of medication use have changed over
time, we consider it unlikely that our observed associations are
confounded by attained year or calendar year of transplant, as
inclusion of these variables in sensitivity analyses did not alter
the multivariable associations with any medication regimen
(not shown).
We also found statistically significantly higher risk of MCC
associated with use of mTOR inhibitors for maintenance, which
was unexpected, because these medications decrease risk of
cutaneous squamous cell carcinoma (26). Interestingly, however,
the MCV small T antigen interacts with downstream proteins
in the AKT pathway, bypassing mTOR itself, and, perhaps as a
result, mTOR inhibitors do not inhibit MCC tumor cell growth
(28). One possible explanation for the adverse association we
Figure 1. MCC incidence rates among non-Hispanic whites according to maintenance medication type and ultraviolet radiation as measured by quintile of residential
A) latitude and B) AVGLO. AVGLO is predicted 30-year average daily total global solar radiation (Wh/km2). Results are presented for transplants associated with maintenance immunosuppression with cyclosporine/azathioprine, tacrolimus/mycophenolate mofetil, and other regimens (see Methods for details). Vertical lines depict
95% confidence intervals of incidence rate estimates (some upper limits are out of range and so are not shown). Ptrend values are shown, and Pinteraction values are .016 for
residential latitude and .086 for AVGLO. Latitude quintiles 4 and 5 are combined because of small numbers (5139 person-years in quintile 5). All statistical tests were
two-sided.
observed with MCC could be that mTOR inhibitors were preferentially prescribed as part of an initial regimen to recipients
perceived by clinicians to be at risk of UV-related skin cancers.
Of note, mTOR inhibitors are also often prescribed following initial discharge from the hospital after transplantation because of
their negative effects on wound healing, but we did not capture
this pattern of use. We also found significantly reduced risk of
MCC with use of monoclonal, T-cell depleting antibodies but not
with polyclonal antibodies.
Our estimate of 23.8-fold higher risk of MCC in transplant
recipients relative to the general population is substantially
higher than previous estimates for immunosuppressed populations. To our knowledge, the only other published estimate for
transplant-related MCC was based on the SEER-Medicare database, a linkage of the US cancer registry and Medicare claims
data (11). That study, which included only elderly white adults,
reported about five-fold increased risk following organ transplantation (odds ratio = 4.95, 95% CI = 2.62 to 9.3) (11), about
half the risk we found for recipients over age 65 years (SIR = 9.9,
95% CI = 5.6 to 16.0). Our estimate is also higher than the two
published estimates of MCC risk among persons with HIV/AIDS.
A population-based linkage of US AIDS and cancer registries (7)
identified six cases of AIDS-related MCC, corresponding to a relative risk of 13.4 (95% CI = 4.9 to 29.1) compared with the general
population. The SEER-Medicare analysis reported a two-fold elevated risk of MCC (odds ratio = 2.30, 95% CI = 0.94 to 5.67) associated with HIV among older, white adults (11). We found higher
MCC incidence in male recipients, consistent with the studies
reporting higher MCC rates in males in the general population
(2,4) but different than others finding higher rates in females (3).
This study has several important strengths. It is the first
cohort study of transplant recipients with a sufficient number of
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Table 4: Multivariable analysis of risk factors for MCC (n = 100) among non-Hispanic white transplant recipients
Characteristic
Incidence rate ratio (IRR) (95% CI)
Sex
Female
Male
Age at transplant, y
20–34
35–49
50–64
65+
Organ
Kidney only
Liver only
Heart only
Other/multiple
Time since transplant, y
<1
1 to <3
3 to <5
5 to <10
≥10
Induction therapy with T-cell–depleting monoclonal antibodies
Maintenance therapy with mTOR inhibitors
Maintenance regimen including cyclosporine and azathioprine, and interaction with latitude
Maintenance therapy with cyclosporine/azathioprine*
Latitude quintile, among recipients of cyclosporine/azathioprine†
Latitude quintile, among recipients of other maintenance medication regimens†
P
.002
Ref.
2.1 (1.3 to 3.4)
<.001
Ref.
2.0 (0.8 to 5.4)
5.4 (2.1 to 13.5)
7.4 (2.7 to 20.7)
.007
Ref.
0.4 (0.2 to 0.7)
0.6 (0.4 to 1.1)
0.5 (0.2 to 1.3)
<.001
Ref.
5.4 (1.6 to 18.0)
5.3 (1.5 to 18.3)
12.0 (3.7 to 39.0)
21.0 (6.0 to 73.4)
0.2 (0.1 to 0.9)
3.0 (1.5 to 5.9)
1.6 (1.0 to 2.5)
.008
.006
.076
1.6 (1.1 to 2.2)
1.0 (0.7 to 1.3)
.012
.808
* Incidence rate ratio corresponds to the effect of cyclosporine/azathioprine in the middle quintile of latitude. Analyses are adjusted for all variables shown in table.
CI = confidence interval. Poisson regression analysis. All statistical tests were two-sided.
† Latitude quintile is modeled with 1 degree of freedom such that the highest quintile is the lowest latitude ie, experiences the highest UVR exposure. Incidence rate
ratios correspond to the effect of an increase of one quintile of latitude. The Pinteraction between latitude and medication = 0.033.
article
incident MCC case patients to allow assessment of risk in subgroups defined by age, race, and transplanted organ. Prior efforts
to quantify these risks were limited by small size or restriction
to specific subpopulations, eg, Medicare beneficiaries over age
65 years (11). Our cohort included a well-defined, populationbased sample representing nearly half of US transplants, and
linkage with corresponding state-mandated, population-based
cancer registries allowed for complete ascertainment of MCC
in transplant recipients. The population-based cancer registries
also provided a large and well-standardized resource for accurate estimation of expected cases and the SIR.
Among the study’s limitations, we note that MCC was identified from cancer registry abstractions of medical records, and
pathology laboratories may not have utilized standardized
diagnostic protocols. We observed a substantial increase in
transplant-related MCC over time (as was noted in the general
population [3]), perhaps because of changes in dermatological or
pathologic practices (including growth in the use of CK20 staining as a diagnostic tool in the 1990s) or in registration following
the introduction of the distinct ICD code for MCC in 1986. Risks
reported here may be underestimated if MCCs were diagnosed
in transplant recipients after they had migrated out of the cancer registry catchment area, although this was likely infrequent
(20). Surveillance bias is another possible limitation of studying
cancer in a population receiving intensive medical attention;
however, it is unlikely that MCC frequently escapes diagnosis,
even in the general population, because of its aggressive behavior. Available transplant medication data represent those prescribed at time of transplant. Regimens are somewhat stable
for most patients (29,30), but we could not account for changes
in medications over time. Finally, despite the large size of our
study, statistical power for evaluating risks in patient subgroups
was still limited.
In summary, we found strikingly high risks of MCC among
transplant recipients as compared with the general population.
We interpret these patterns as indicating important roles in
MCC development for sustained, long-term immunosuppression, UVR, and photosensitizing effects of some maintenance
medications. Future studies should explore the specific interplay between carcinogenic viruses, immune dysfunction, and
UVR as they relate to skin cancer etiology. Transplant recipients
should be encouraged to adopt sun safety practices and limit
UVR exposure to reduce their likelihood of developing MCC and
other skin cancers for which they are at exceedingly high risk
(31).
Funding
This work was supported in part by the Stanford Cancer Institute
and the National Cancer Institute of the National Institutes of
Health.
Notes
The authors gratefully acknowledge the support and assistance
provided by individuals at the Health Resources and Services
Administration (Monica Lin), the Scientific Registry of Transplant
Recipients (SRTR) (Ajay Israni, Bertram Kasiske, Paul Newkirk,
Jon Snyder), and the following cancer registries: the states of
California, Colorado, Connecticut (Lou Gonsalves), Georgia (Rana
Bayakly), Hawaii, Iowa, Illinois (Lori Koch), Michigan (Glenn
Copeland), New Jersey (Xiaoling Niu), New York (Amy Kahn),
North Carolina (Chandrika Rao), Texas (Melanie Williams),
and Utah (Janna Harrell), and the Seattle-Puget Sound area of
Washington. We also thank analysts at Information Management
Services for programming support (David Castenson, Matthew
Chaloux, Michael Curry, Ruth Parsons).
The views expressed in this paper are those of the authors
and should not be interpreted to reflect the views or policies
of the National Cancer Institute, Health Resources and Services
Administration, SRTR, cancer registries, or their contractors. This research was supported in part by Stanford Cancer
Institute and the Intramural Research Program of the National
Cancer Institute.
During the initial period when registry linkages were performed,
the SRTR was managed by Arbor Research Collaborative for Health
in Ann Arbor, MI (contract HHSH234200537009C); beginning in
September 2010, the SRTR was managed by Minneapolis Medical
Research Foundation in Minneapolis, MN (HHSH250201000018C).
The following cancer registries were supported by the National
Program of Cancer Registries of the Centers for Disease Control
and Prevention: California (agreement 1U58 DP000807-01),
Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois
(5658DP000805-04), Michigan (5U58DP000812-03), New Jersey
(5U58/DP003931-02), New York (U58DP003879), North Carolina
(U58DP000832), and Texas (5U58DP000824-04). The following cancer registries were supported by the SEER Program of the National
Cancer Institute: California (contracts HHSN261201000036C,
HHSN261201000035C, and HHSN261201000034C), Connecticut
(HHSN261201000024C),
Hawaii
(HHSN261201000037C,
N01-PC-35137, and N01-PC-35139), Iowa (HSN261201000032C
and
N01-PC-35143),
New
Jersey
(HHSN261201300021I,
N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and
Utah (HHSN261201000026C). Additional support was provided by
the states of California, Colorado, Connecticut, Illinois, Iowa, New
Jersey, New York (Cancer Surveillance Improvement Initiative
14–2491), Texas, and Washington, as well as the Fred Hutchinson
Cancer Research Center in Seattle, WA.
The authors have no conflicts of interest to declare.
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