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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 87´9 5´7 3´6 1´3 1´0 0´4 0´1 Total 3239 2117 5356 100 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. q 2000 British Association of Dermatologists, British Journal of Dermatology, 143, 513±519 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 248/2´3 18/0´5 5/3´2 8/1´6 9/3´2 497/65´6 Women RR 95% CI 108´6 37´8 1´6 5´0 2´8 94´6±123´1 22´4±59´7 0´5±3´7 2´2±9´9 1´3±5´3 7´6 6´9±8´3 Observed/expected 77/0´8 9/0´1 1/2´2 2/0´5 5/1´8 3/1´9 252/52´9 RR 95% CI 92´8 126´4 0´5 4´0 2´8 1´6 4´8 73´2±116´0 57´8±240´0 0´0±2´6 0´5±14´5 0´9±6´5 0´3±4´6 4´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 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 1658) was 17´6 years and after 1983 (n 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 1´6 1´6 5´8 4´1 5´9 4´4 8´7 4´0 6´6 3´1 Skin cancer (excluding melanoma) M F 8´0 0´0 42´8 43´4 97´6 103´6 167´2 85´3 99´0 79´7 Site of cancer 0±4 (n 5356) 5±9 (n 2571) 10±14 (n 1136) $ 15 (n 399) Table 5. Number of skin cancers (excluding melanoma) diagnosed before and after 1983 (the year of introduction of cyclosporin) following organ transplantation (n 5356) Men Before 1983 (n 1658) After 1983 (n 3698) Women Observed/expected RR 95% CI 138/1´0 110/1´6 134´5 70´7 113´0±158´9 58´1±85´2 Observed/expected 33/0´4 44/0´5 RR 95% CI 84´6 80´8 58´2±118´7 58´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 q 2000 British Association of Dermatologists, British Journal of Dermatology, 143, 513±519 518 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. References 1 Boyle J, MacKie RM, Briggs JD et al. Cancer, warts and sunshine in renal transplant recipients: a case-control study. Lancet 1984; i: 702±5. 2 Walder BK, Robertson MR, Jeremy D. Skin cancer and immunosuppression. Lancet 1971; ii: 1282±3. 3 Hoover R, Fraumeni JF Jr. Risk of cancer in renal-transplant recipients. Lancet 1973; ii: 55±7. 4 Koranda FC, Dehmel EM, Kahn G et al. Cutaneous complications in immunosuppressed renal homograft recipients. JAMA 1974; 229: 419±24. 5 Marshall V. Pre-malignant and malignant skin tumours in immunosuppressed patients. 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