Download Incidence of skin cancer in 5356 patients following organ

British Journal of Dermatology 2000; 143: 513±519.
Incidence of skin cancer in 5356 patients following organ
transplantation
È BEL² AND R.S.STERN³
B.LINDELOÈ F, B.SIGURGEIRSSON,* H.GA
Department of Dermatology, Karolinska Hospital and Institute, Box 120, S-171 76 Stockholm, Sweden
*Department of Dermatology, University of Iceland, Reykjavik, Iceland
²The Transplant Unit, National Board of Health and Welfare, Stockholm, Sweden
³Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, U.S.A.
Accepted for publication 16 March 2000
Summary
Background Skin cancer following solid organ transplantation is an important cause of morbidity in
long-term survivors. This risk is well known but imprecisely quantified.
Objectives We aimed to determine: (i) the skin cancer risks in transplant patients more precisely; (ii)
whether the risk of malignant melanoma is altered; and (iii) whether the risk of epithelial cancers
occurring at non-exposed sites is comparable with that seen in sun-exposed sites.
Methods We linked a population-based cohort of 5356 patients who had received organ transplants
in Sweden between 1970 and 1994 with the compulsory Swedish Cancer Registry, to identify all
cancer cases except basal cell carcinomas, which are not registered.
Results After a mean follow-up of 5´6 years post-transplantation, 172 of 5356 patients developed
325 non-melanoma skin cancers (excluding basal cell carcinomas) and six malignant melanomas.
The relative risk of non-melanoma skin cancer was 108´6 [95% confidence interval (CI) 94´6±
123´1] for men and 92´8 (95% CI 73´2±116´0) for women. The highest risks were noted for upper
limbs, and the risk increased with time. No significant increase in malignant melanomas was noted:
the relative risk was 1´6 (95% CI 0´5±3´7) for men and 0´5 (95% CI 0´0±2´6) for women. Except
for the lip, which is also sun-exposed, other epithelial sites did not show comparable increases in
cancer risk.
Conclusions We conclude that organ transplant recipients are at a highly increased risk for nonmelanoma skin cancer and must be closely followed throughout their lives. Cancer risk associated
with transplantation is higher for sun-exposed than for non-sun-exposed epithelial tissues, even
among populations living in regions with low solar insolation.
Key words: cancer, skin, transplantation
Cutaneous disorders that occur in organ transplant
recipients are of three main types: persistent viral
warts, premalignant actinic keratoses and frank
cutaneous neoplasms.1 Recipients are at an increased
risk for skin cancer, most frequently squamous cell and
basal cell carcinomas.1±28 Moreover, skin cancer in
renal transplant recipients is associated with a higher
risk of metastasis than skin cancer in the general
population.1,16 Skin cancer is also a major cause of
morbidity and long-term mortality in heart transplant
patients.28
Immunosuppressive therapy, papillomavirus infection and solar radiation are believed to be the most
Correspondence: Bernt LindeloÈf. E-mail: [email protected]
q 2000 British Association of Dermatologists
important risk factors for the development of skin
cancers in renal transplant recipients.1,17,29,30 Furthermore, the renal graft itself may also be important as an
aetiological factor;31±33 long-term antigenic stimulation by a poorly matched graft is thought to induce skin
cancer, either by a direct effect or indirectly by
necessitating a higher dose of immunosuppressive
therapy.32,33
In order to qualify and quantify the risk of skin
cancer in organ transplant patients, we linked a
population-based cohort of 5356 patients who had
received organ transplants in Sweden between 1970
and 1994 with the Swedish Cancer Registry, to identify
all cancer cases. The risks were then calculated by
using cancer incidence in the general population from
513
514 B.LINDELOÈ F et al.
Table 1. Number of patients receiving organ transplantations in
Sweden 1970±94, reported in the In-patient Registry
Organ
Men
Women
Total
% of total
Kidney
Liver
Heart
Heart and lung
Pancreas
Liver, lobules
Pancreas, segment
2862
153
152
27
31
11
3
1850
150
42
43
21
10
1
4712
303
194
70
52
21
4
87Š´9
5Š´7
3Š´6
1Š´3
1Š´0
0Š´4
0Š´1
Total
3239
2117
5356
100Š
which the patients originated as a reference. The
transplantations were performed in a homogeneous
population with well-documented cancer incidence.
Subjects and methods
Patients
In 1964, the Swedish National Board of Health and
Welfare began collecting information about people who
were hospitalized. Since 1970 the In-patient Registry
has been nation-wide and has included all hospitalized
patients in Sweden. The information collected includes
a unique identification number for each person, used in
all population statistics in Sweden, the dates of
admission and discharge, the diagnosis, and the nature
and dates of any surgical procedures, based on International Classification of Diseases codes.
From this registry we selected the diagnoses of organ
transplantation (1970±94), and identified 5356 organ
transplant recipients who had received a total of
6731 transplants. Details about the type and number of
transplantations are given in Table 1, and Figure 1
shows the age distribution at first organ transplantation. Apart from 1970/71, when fewer than 50
transplants were performed, the number of organ
transplantations per year registered in the In-patient
Registry has increased approximately linearly from
about 120 at the start of the study period to almost 400
by 1993/94. The mean follow-up was 5´6 years (range
0±24).
The Swedish Cancer Registry and Cause of Death Registry
Information from the Swedish Cancer Registry from
1958 to 1994 was correlated with the records of the
Figure 1. Age distribution (years) at first organ transplantation.
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SKIN CANCER FOLLOWING ORGAN TRANSPLANTATION 515
Table 2. Number of skin and adjacent mucosal cancers diagnosed by site in 5356 patients following organ transplantation
Men
Site of cancer
Observed/expected
Skin cancer (excluding melanoma)
Lip
Malignant melanoma
Oral/pharyngeal
Anal/rectal
Cervical
All sites
248Š/2´3
18Š/0´5
5Š/3´2
8Š/1´6
9Š/3´2
497Š/65´6
Women
RR
95% CI
108Š´6
37Š´8
1Š´6
5Š´0
2Š´8
94Š´6±123´1
22Š´4±59´7
0Š´5±3´7
2Š´2±9´9
1Š´3±5´3
7Š´6
6Š´9±8´3
Observed/expected
77Š/0´8
9Š/0´1
1Š/2´2
2Š/0´5
5Š/1´8
3Š/1´9
252Š/52´9
RR
95% CI
92Š´8
126Š´4
0Š´5
4Š´0
2Š´8
1Š´6
4Š´8
73Š´2±116´0
57Š´8±240´0
0Š´0±2´6
0Š´5±14´5
0Š´9±6´5
0Š´3±4´6
4Š´2±5´4
RR, relative risk; CI, confidence interval.
5356 patients to identify those with cancer. Nationwide information on the incidence of cancer in Sweden
is available for all years since 1958, when compulsory
registration began.34 The Cancer Registry collects
information on diagnosed cancers from clinicians and
pathologists. If a person has more than one cancer,
each one is registered separately. Basal cell carcinomas
are not registered. The completeness of registration is
close to 100% for all cancers.35
The Cause of Death Registry includes information on
all deceased persons listed in the parish registers,
whether they died in Sweden or abroad.36 The
underlying cause of death is generally determined
from data on medical death certificates, which were
designed in accordance with the internationally established norm.
Statistical analysis
We estimated the expected number of cancers in our
study group using incidence data from the Cancer
Registry and a specially developed computer program,
CANEST (CANcer ESTimates).37 The program calculated the risk of cancer for each patient individually.
The calculation was based on incidence data for the
years between the first organ transplantation and 1994
(or death, if earlier). Information about deaths in the
cohort was obtained from the Cause of Death Registry.
Total risk was calculated as the sum of the individual
risks. The relative risk (RR) of cancer, which is the ratio
between the actual and the expected number of
cancers, was used to assess the risk of cancer. The
actual number of cancers in the cohort was obtained
from the Cancer Registry. We calculated the confidence
interval (CI) for the RR assuming a Poisson distribution.38 This method has been described in detail
elsewhere.37 Where the lower limit of the 95% CI
exceeded 1´0, this was taken to indicate statistical
significance. All tabulations and all statistical analyses
not performed with the CANEST program were
performed with the SPSS or STATA statistical package.
Results
Following organ transplantation a total of 172 persons
with 325 non-melanoma skin cancers (NMSCs) and six
malignant melanomas was diagnosed in the 5356
patients. The RR of NMSC was 108´6 (95% CI
94´6±123´1) for men and 92´8 (95% CI 73´2±
116´0) for women. Lip cancer risk was also substantially increased after transplantation: RR was 37´8
(95% CI 22´4±59´7) and 126´4 (95% CI 57´8±240´0)
for men and women, respectively. No significant
increase in the risk of malignant melanoma was
noted. For all cancer sites the RR was 7´6 in men
(95% CI 6´9±8´3) and 4´8 in women (95% CI 4´2±
5´4). Although in some cases the risk was significantly
elevated compared with that expected for the general
population, the increase in risk for the other epithelial
cancers that we studied was significantly less than for
NMSC (Table 2). For all cancer sites that were not sunexposed, i.e. excluding the skin and lip, the RR was 3´8
in men (95% CI 6´9±8´3) and 3´3 in women (95% CI
4´2±5´4).
Further analysis of the distribution of NMSC showed
the highest risks to be on the upper limbs: RR was
157´0 (95% CI 114´9±209´4) and 165´1 (95% CI
99´4±257´8) for men and women, respectively. All
NMSCs and lip cancers were squamous cell carcinomas
except for two cases of Kaposi's sarcoma and one case
of adenoid cystic carcinoma in the lip.
The 172 patients with NMSC developed an average
of 1´9 NMSCs; 64 patients developed multiple NMSCs
(Table 3). Based on life table analysis, 25% of patients
with NMSC develop a second tumour within 13 months
and 50% a second tumour within 3´5 years. In
univariate analyses using the Cox survival models we
identified three factors associated with a higher risk of
q 2000 British Association of Dermatologists, British Journal of Dermatology, 143, 513±519
516 B.LINDELOÈ F et al.
Table 3. Number of individuals with one or more skin cancers
(excluding melanoma) following organ transplantation
Number of skin cancers
Men
Women
Total
1
2
3
4
5±18
76
27
5
10
7
32
7
3
3
2
108
34
8
13
9
Total
125
47
172
developing a second NMSC: gender (relative hazard:
male, 1´3; female, 0´6; P , 0´2), age at first transplantation (relative hazard: age , 50 years, 1´4; age
$ 50 years, 0´8; P ˆ 0´2) and years from organ
transplantation to first NMSC (relative hazard: , 10
years, 0´9; $ 10 years, 1´5; P , 0´05). In a multivariate model incorporating these three predictor
variables, only gender (hazard ratio male vs. female
1´84, 95% CI 1´02±3´35) was a significant risk factor
for a second NMSC.
Table 4 presents the RR for different time periods
before and after the first transplantation. An increase
in RR for NMSC was noted during the first 5 years after
transplantation, and was greatly elevated from 5 years
after transplantation. The magnitude of increased risk
was subsequently relatively stable. In contrast, the RR
of cancer at all sites was almost constant during the
whole observation period.
Table 5 presents the number of NMSCs diagnosed
before and after 1983, the year of introduction of
cyclosporin in Sweden. The average follow-up for the
recipients before 1983 (n ˆ 1658) was 17´6 years and
after 1983 (n ˆ 3698) was 5´5 years.
Discussion
The increased incidence of warts and skin cancer in
renal transplant recipients was first noted in Australia
in the 1970s.2,5,7 Thereafter, a large number of studies
reported an increased incidence of NMSC.1±24,26±28
However, reliable information from epidemiological
studies with long follow-up is sparse,3,9,23,27 and
these studies have shown a three- to fourfold increased
risk of all cancers. In our study the risk was slightly
higher, 7´6-fold increased for men and 4´8-fold
increased for women. When cancers in sun-exposed
sites are excluded, the risk of cancer post-transplantation is increased about threefold. In contrast, the risk of
NMSC was more than 100-fold elevated and that of lip
cancer more than 50-fold elevated. The higher risks in
our study are probably due to longer and more
complete follow-up as well as the low baseline risks of
NMSC in the Swedish population.
Apart from avoiding sun exposure in order to
decrease the risk of skin cancer in organ transplant
recipients, the type and dose of immunosuppression
may be important. In our material the patients were
immunosuppressed predominantly by azathioprine and
prednisone in the beginning of the observation
period,39 but since the introduction of cyclosporin in
1983, most patients have received this drug in combination with azathioprine and prednisone. The link
between cancers and cyclosporin is thought to be doserelated,40 and it has been shown in a randomized study
of renal transplant recipients that a low-dose regimen
with cyclosporin was associated with fewer malignant
disorders than a high-dose regimen.41 Our study shows
Table 4. Relative risk of cancer in 5356 patients by time since first transplantation (P , 0´05)
Years after first transplantation
Sex
0±3 years before
transplantation
All sites
M
F
1Š´6
1Š´6
5Š´8
4Š´1
5Š´9
4Š´4
8Š´7
4Š´0
6Š´6
3Š´1
Skin cancer (excluding
melanoma)
M
F
8Š´0
0Š´0
42Š´8
43Š´4
97Š´6
103Š´6
167Š´2
85Š´3
99Š´0
79Š´7
Site of cancer
0±4 (n ˆ 5356)
5±9 (n ˆ 2571)
10±14 (n ˆ 1136)
$ 15 (n ˆ 399)
Table 5. Number of skin cancers (excluding melanoma) diagnosed before and after 1983 (the year of introduction of cyclosporin) following organ
transplantation (n ˆ 5356)
Men
Before 1983 (n ˆ 1658)
After 1983 (n ˆ 3698)
Women
Observed/expected
RR
95% CI
138/1´0
110/1´6
134Š´5
70Š´7
113Š´0±158´9
58Š´1±85´2
Observed/expected
33/0Š´4
44/0Š´5
RR
95% CI
84Š´6
80Š´8
58Š´2±118´7
58Š´7±108´4
RR, relative risk; CI, confidence interval.
q 2000 British Association of Dermatologists, British Journal of Dermatology, 143, 513±519
SKIN CANCER FOLLOWING ORGAN TRANSPLANTATION 517
a decreased RR of NMSC for male transplant recipients
after the introduction of cyclosporin, but this could be
due to the shorter follow-up for this group of patients,
and further studies are needed.
In our analysis we quantified the post-transplantation risk of NMSC at sites where sun exposure is likely
to be the most important risk factor, as well as the
incidence of other epithelial malignancies for which the
risk is primarily related to factors other than ultraviolet
(UV) radiation exposure. Our study demonstrated that,
even within a population with limited solar exposure
and resultant low innate risk of skin cancer, the risks
of NMSC increase to about 100-fold by 5 years after
transplantation. Even within the first 5 years after
transplantation, the incidence of these tumours had
increased approximately 40-fold above that expected.
Increases in lip cancer risk, where smoking and alcohol
consumption are risk factors in addition to sun
exposure, are about half as great. Overall, UV radiation-related epithelial tumours accounted for the
majority of tumours occurring 5 or more years after
transplantation, but accounted for only about 3% of
tumours in an age- and sex-matched Swedish population. NMSC incidence is nearly three times higher in
Swedish men than women. The increase in RR of NMSC
and lip cancer was, however, comparable for men and
women in our study. Although risk was not as
increased as much for the lip as for skin, lip cancer
was the only other epithelial tumour with a greater
than 10-fold increase in risk in transplant patients.
Other epithelial cancers, for which UV radiation is not
considered an important aetiological factor, including
those located in the mouth, anus, rectum and cervix,
showed only modest increases in risk after transplantation. The increased risks for these epithelial tumours
were comparable with the elevated risk noted for all
other cancers occurring on non-sun-exposed sites. This
suggests that, despite the greatly increased risk of warts
in transplant recipients, immunosuppression has at
most a limited effect on papillomavirus-associated
carcinogenesis, as well as limited effects on epithelial
neoplasms for which smoking and alcohol consumption are the predominant risk factors.
Once an individual develops a first NMSC, the risks of
developing a subsequent independent cancer are very
high. One-quarter of patients with skin cancer will
develop another skin cancer within 13 months and
one half will develop an additional skin tumour within
3´5 years. Men were more likely to have additional skin
cancers. Age did not significantly affect skin cancer
risk. We did not detect an increased risk of malignant
melanoma. In contrast to NMSC, this form of cancer is
often fast-growing and fatal. This is in contrast to
earlier findings that suggested that transplant recipients also have an increased risk of melanoma.23,25,27,42
Since the early 1960s, more than 400,000 transplantations of various organs have been performed
world-wide,43 and dermatologists play an increasingly
important part in the diagnosis and management of the
common skin problems experienced by these patients.
The highest rates of skin cancer have been reported
from Australia. The experience from Queensland shows
a prevalence of skin cancer of 20% at 5 years after
transplantation, 45% at 10 years, and 75% at 20
years.26 In the Netherlands the prevalence of skin
cancer after renal transplantation is 10% at 10 years,
increasing to 40% at 20 years.18 This geographical
difference in incidence is probably due to the influence
of solar UV radiation. Owing to the fact that even a
serious side-effect must be accepted for transplant
recipients, for whom there is no life-sustaining option
apart from transplantation, preventive care is most
important. Therefore, all potential transplant patients
should receive advice on strict sun avoidance, protective clothing and use of high-factor UVA and UVB
sunscreen on exposed skin surfaces and on the lips.
However, despite verbal advice and written information
at the time of hospital discharge for all newly transplanted patients, only half of them subsequently recall
receiving advice, and compliance with sun protection
measures is poor.44 Unfortunately, much of posttransplantation skin cancer risk probably reflects sun
exposure prior to the transplantation. After transplantation, annual examination with prompt surgical
removal of suspicious lesions should be sufficient in
most patients.45 Those patients who have already had
very high UV radiation exposure and have extensive
dysplasia need more frequent assessment, particularly
with increasing time from transplantation; skin examination every 3 months is recommended for these
patients. Retinoids may be helpful in such cases,
although skin cancers may continue to develop during
treatment29,46,47 and lesions recur when treatment is
stopped. The experience using acitretin 0´3 mg kg21
daily over a 5-year period has recently been reported: a
significant chemoprophylactic effect was shown for up
to 4 years of treatment.48
In conclusion, our findings suggest that, even in
individuals from a low-risk background population, the
risks of NMSC post-transplantation are elevated about
100-fold. The increase in risk begins within a few years
of transplantation and reaches very high levels within
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518 B.LINDELOÈ F et al.
5 years. This increase in risk appears quite specific to
sun-exposed areas, i.e. the lip and skin, whereas other
epithelial tissues (mouth, anus, rectum, cervix) with
other presumed carcinogens as risk factors do not show
comparable increases. Melanoma risk is not increased
substantially. There has been a modest decrease in risk
since the introduction of cyclosporin, but the risk
remains high even with this change in transplant
regimen. Therefore, immunosuppression in organ transplant patients appears to have specific effects on UV
radiation-related carcinogenesis and is much less likely
to be important in papillomavirus or other types of
carcinogenesis. These high risks necessitate the need
for careful surveillance and prompt treatment of
cutaneous lesions among organ transplant patients.
Acknowledgments
This study was supported by a grant from the Swedish
Medical Product Agency. We are indebted to Mr CurtLennart Spetz, Centre for Epidemiology, National Board
of Health and Welfare, Stockholm, for data processing.
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