0041-1337/00/7010-1479/0TRANSPLANTATION Vol. 70, 1479–1484, No. 10, November 27, 2000Copyright © 2000 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A.

RISK OF NONMELANOMA SKIN CANCER IN ITALIAN ORGANTRANSPLANT RECIPIENTS. A REGISTRY-BASED STUDY

LUIGI NALDI,1,8 ANNA BELLONI FORTINA,2 SILVIA LOVATI,1 ANNALISA BARBA,3 ELIANA GOTTI,4

GIANPAOLO TESSARI,3 DONATELLA SCHENA,3 ANDREA DIOCIAIUTI,5 GIUSEPPE NANNI,6

ILARIA LESNONI LA PAROLA,7 CINZIA MASINI,5 STEFANO PIASERICO,2 ANDREA PESERICO,2

TULLIO CAINELLI,1 GIUSEPPE REMUZZI4

Departments of Dermatology and Nephrology, Ospedali Riuniti, Bergamo;Department of Dermatology University of Padua, Padua; Department of Dermatology University of Verona,

Verona; Departments of Dermatology and Surgery, Universita Cattolica, Rome;Department of Dermatology Istituto S. Maria e S. Gallicano, Rome, Italy

Background. Organ transplant recipients are at anincreased risk of nonmelanoma skin cancer. Few dataconcern heart transplantation and populations fromsouthern Europe.

Methods. A total of 1329 patients who received theirfirst kidney (1062 subjects) or heart allograft (267 sub-jects) were included in a partly retrospective cohortstudy to evaluate the risk of skin cancer. The inci-dence rate per 1000 person-years and the cumulativeincidence were computed. Standardized morbidity ra-tio was estimated by comparison with Italian cancerregistry data. To analyze the role of potential prognos-tic factors, Cox’s regression method was used.

Results. The overall incidence rate of nonmelanomaskin cancer was 10.0 cases per 1000 posttransplantperson-years (95% confidence interval 8.2–11.7). Thisestimate was far higher than expected in the generalpopulation. The overall risk of developing skin cancerincreased from a cumulative incidence of 5.8% after 5posttransplant years to an incidence of 10.8% after 10years of graft survival. In a Cox proportional hazardrisk model, the most important factors that appearedto favor the development of skin cancer were age attransplantation and sex. After adjustment for age attransplantation and sex, no definite increased riskwas documented among heart as compared with kind-ney transplant recipients.

Conclusions. Our study confirms the increased riskof nonmelanoma skin cancer among organ transplantrecipients in a southern European population.

It has been repeatedly shown that patients receiving organtransplants are at an increased risk of selected tumors in-cluding cutaneous squamous cell carcinoma (SCC) and basalcell carcinoma (BCC) (1–12). The cumulative incidence ofthese tumors in transplant recipients rises as survival timeincreases (8). A reversal of the BCC/SCC ratio in comparison

with the general population has also been reported (2, 3, 5,7–9, 11, 13).

Epidemiological data have shown that constitutional char-acteristics such as pigmentary traits play an important rolein the development of skin cancer (10, 14–16). Solar radia-tion, immunosuppression and, limited to transplant patients,viral warts, are also believed to be important risk factors (3,6, 8, 17–20). It should be noted that most of the data concern-ing the incidence of skin cancer in transplant patients per-tain to kidney recipients in populations from northern Eu-rope (2, 8). Scanty data are available for populations with adarker prevalent phenotype, such as the populations of theMediterranean area. In addition, few data concern hearttransplantation where a higher degree of immunosuppres-sion compared with kidney transplantation is expected (3, 11,13, 21–23). Furthermore, the role of the immunosuppressivetherapeutic regimen is imprecisely defined (24–29). Interest-ingly, a higher risk of skin cancer has been suggested in hearttransplant recipients as compared with kidney recipients(3–21). Moreover, some data suggest that a higher incidenceof skin cancer may be associated with immunosuppressiveregimens including cyclosporine (28).

Our study, based on a multicenter registry of transplantpatients, was carried out to estimate the incidence of non-melanoma skin cancer in Italian transplant recipients and toexplore predictors for the development of the tumor. Thestudy was conducted in collaboration with the Italian Groupfor Epidemiologic Research in Dermatology (GISED).

MATERIALS AND METHODS

In 1996 we set up a registry of major cutaneous complications intransplant patients including all patients who had received a renalor a heart transplant since May 1969 at the transplantation units ofBergamo, Padua, Rome, and Verona. For the purpose of this analy-sis, data on kidney and heart transplantation from Padua and Ve-rona and kidney transplantation only from the other centers wereextracted. For patients who had received a second or a third renaltransplant, only the first transplant was considered in the analysis.All patients with a functioning graft were seen regularly at theoutpatient nephrological or cardiosurgical clinic and those with cu-taneous complications were also seen by a dermatologist. In additionto reassessing any dermatological diagnosis at the study centers,every effort was made to collect information on any dermatologicaldiagnoses made outside the study centers. The following data wererecorded in our registry: sex, age of the patient at transplantation,disease causing organ failure and its date of diagnosis, date of first or

1 Department of Dermatology University of Milan, OspedaliRiuniti.

2 Department of Dermatology, University of Padua.3 Department of Dermatology, University of Verona.4 Department of Nephrology, Ospedali Riuniti.5 Department of Dermatology, Universita Cattolica del Sacro

Cuore.6 Department of Surgery, Universita Cattolica del Sacro Cuore.7 Department of Dermatology, Istituto S. Maria e S. Gallicano.8 Address correspondence to: Luigi Naldi, Clinica Dermatologica,

Ospedali Riuniti, L.go Barozzi 1, 24100 Bergamo, Italy.1479

second transplant, immunosuppressive therapy, date of diagnosis,type, number and localization of skin cancer, and date of diagnosis ofany other major dermatological disease.

The immunosuppressive therapy showed some variations accord-ing to centers. However, until 1985, it usually consisted of azathio-prine (1 to 2.5 mg/kg/day) in combination with oral metylpred-nisolone (8–10 mg/day). After 1985, it included oral cyclosporine (3–9mg/kg/day) with or without azathioprine and usually associated withlow dose oral metylprednisolone.

For each tumor category, the incidence rate per 1000 person-yearsand the cumulative incidence were computed. The number of person-years was calculated between arbitrarily chosen opening and closingdates. The date of transplantation was used as the opening date; thedate of diagnosis of the first skin cancer, the patient’s death, loss tofollow-up or the end of the study in December 1998 were used as theclosing dates. Because a history of subsequent primary skin tumorsis not unusual, for each histological type, i.e., SCC and BCC, only thefirst tumor diagnosed was considered. More specifically, when sepa-rately examining each histological type, i.e., BCC or SCC, eachpatient contributed his/her first tumor of the given histological typeirrespective of whether the other type had already been diagnosed.Conversely, when taking into account BCC and SCC together, sub-jects with a history of both SCC and BCC contributed only once withtheir earlier tumor. The incidence of SCC and BCC in the studypatients was compared with the estimated incidence in the generalpopulation by calculating the standardized morbidity ratio (SMR).This is the ratio of the number of events, i.e., tumors, observed in thestudy group to the number that would be expected if the studypopulation had the same specific rates as a standard reference pop-ulation. A 95% confidence interval (CI) was constructed, assuming aPoisson distribution for the observed number of cases. A SMR of 1.0indicates no difference between observed and expected cases al-though a failure of the usual 95% confidence interval to include 1.0indicates that the rate of the event is statistically different from theexpected rate, with P,0.05. Because it is commonly assumed thatnonmelanoma skin cancer can be under-reported, we decided toobtain the most conservative estimate of SMR by using the highestpopulation-based incidence rates available in Italy during the studyperiod to calculate the number of expected cases. Accordingly, datafrom the cancer registry of Trieste, a city in the north of Italy, and forthe period 1988 to 1992 were used to estimate the expected numberof tumors. Life-table derived data were used to estimate the cumu-lative incidence. To analyze the role of potential prognostic factors,accounting simultaneously for several potential confounders, Cox’sregression method was used. Variables whose values could changeduring the study period, e.g., exposure to OKT3, were accounted forin the analysis as time-dependent variables. An assumption of Cox’sregression method is that the hazards for different strata of eachindependent variable are proportional over time. This assumptionwas verified using a graphical method. The survival curves for thevariable strata were plotted on a log-log scale. If the curves wereroughly parallel then the assumption of the proportional hazardswas considered as satisfied (30).

RESULTS

In the period from May 1969 to December 1998 a total of1329 patients (962 males and 367 females) received theirfirst kidney (1062 subjects) or heart allograft (267 subjects)at the study centers. The median age at transplantation was37.5 years for the renal transplant recipients (RTRs) and 54years for the heart transplant recipients (HTRs), respec-tively. The median follow-up time up to December 1998 was4 years (range 3 months-26 years) for the RTRs and 2.5 years(range 2 months-10 years) for the HTRs.

During the follow-up period, 20 males (2%) and 4 females(1%) developed a first SCC, 49 males (5%) and 12 females

(3%) developed a first BCC, and 9 male patients (1%) devel-oped both a SCC and a BCC. The ratio of BCC to SCC was2.1:1. There were 71 patients who developed a tumor amongthe RTRs and 23 patients among the HTRs. The median ageat transplantation of the patients who developed skin cancerwas 45 years for the RTRs and 56 years for the HTRs. Themedian interval from transplantation to the first diagnosis ofcancer was 7 years (range 6 months-21 years) for SCC and 6years (range 6 months-21 years) for BCC. About 80% of SCCsand 60% of BCCs occurred on sun-exposed areas of the skinwith a highest prevalence for the face and the backs of thehands. BCCs were also found on the trunk (26%) (Fig. 1).

The overall incidence rate of nonmelanoma skin cancerwas 10.0 cases per 1000 posttransplant person-years (95% CI8.2–11.7). It was 9.1 per 1000 persons-year (95% CI 7.2–10.9)in the RTRs and 14.7 (95% CI 9.1–18.8) in the HTRs. Theincidence rate of SCC was 3.5 per 1000 persons-year (95% CI2.2–4.5) while it was 7.3 (95% CI 5.7–8.8) for BCC. Overallthe incidence rate rose with the time elapsed since the date ofthe transplant procedure from 9.1 per 1000 persons-year(95% CI 7.2–10.1) within the first 4 years after transplanta-tion to 12.2 (95% CI 8.3–15) in the period 5–8 years aftertransplantation and to 20.2 (95% CI 8.3–31.4) after morethan 8 years of transplantation. In addition, the incidence ofSCC and BCC rose with age at transplantation and wasfound to be higher in males than in females (Tables 1 and 2).

The incidence rates observed in transplant patients werehigher than expected in the general population. The SMR fornonmelanoma skin cancer was 1392 (95% confidence interval1100–1740) among men and 1130 (95% confidence interva646-1835) among women. The overall risk of developing skincancer increased from a cumulative incidence of 5.8% after 5posttransplant years to an incidence of 10.8% after 10 yearsof graft survival (Fig. 2). For SCC these figures were 2.5%after 5 years and 3.9% after 10 years and for BCC 3.4% after5 years and 6.9% after 10 years. The cumulative incidence fornommelanoma skin cancer after 5 years was 4.3% in theRTRs and 8.8% in the HTRs. At 10 years it was 9.7% in theRTRs and 11.4 in the HTRs.

In a Cox proportional hazard risk model, the most impor-tant factors that appeared to favor the development of skincancer, among those taken into account, were age at trans-plantation and sex (Table 3). Those kidney and heart trans-plant recipients who received their transplant after the age of50 years had a nine times higher risk than recipients whoreceived their transplant before the age of 30 years(P,0.000). Male patients had about twice the risk of femalepatients of developing a nonmelanoma skin cancer. Afteradjustment for age at transplantation and sex, other factorswere relatively unimportant. The risk of nonmelanoma skincancer was not increased in HTRs as compared with RTRs.No association emerged with any specific treatment modal-ity, including the use of OKT3 or ATG. The risk of nonmela-noma skin cancer among 947 subjects treated with cyclospor-ine as compared with those not using the drug was 1.2(0.7–2.0). It was 1.1 (0.5–2.8) for SCC and 1.4 (0.8–2.5) forBCC. In Cox’s model, the risk of nonmelanoma skin canceramong 480 (36.1%) subjects with a history of transplantrejection episodes as compared with subjects lacking such ahistory was 1.1 (95% CI 0.7–1.7). The risk was 1.2 (95% CI0.6–2.5) for SCC and 1.2 (0.7–2.0) for BCC. Receiving a firstdiagnosis of nonmelanoma skin cancer of a given histological

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type seemed to affect the risk of developing a second tumor ofa different histological type. The risk of BCC in subjects witha history of SCC, as compared with subjects without such ahistory, was 2.8 (95% CI 1.3–5.7). Similarly, the risk of SCCin subjects with a history of BCC was 3.0 (95% CI 1.4–6.8).Analyses were also carried out according to transplant center

and no important differences were documented (data notshown).

DISCUSSION

Our study documents that transplant recipients are at ahigher risk of developing skin cancer also in southern Euro-

FIGURE 1. Distribution of 33 SCC (A) and 70 BCC (B) in 94 patients.

NALDI ET AL.November 27, 2000 1481

pean populations. Overall, the incidence of skin cancer roseprogressively with duration of graft survival from a cumula-tive risk of 7.5% after 5 years to a risk of 28.6% after 15 years.This is in agreement with the experience from other Euro-pean countries. The overall incidence of skin cancer in RTRsin the Netherlands rose from a cumulative risk of 3% after 5years to 24% after 15 years and 40% after 20 years of graftsurvival (2). An even higher cumulative incidence was docu-mented in Spain with a risk of 18.1% after 3 years of kidneygraft survival (8). The cumulative incidence for SCC andBCC was higher in heart as compared with kidney trans-plant recipients with a cumulative incidence of 11.4% at 10years follow-up as compared with 9.7% in kidney transplantpatients. It should be noted that the median age at trans-plantation of heart transplant patients was higher than theage in kidney transplant patients and that the incidencerates rose progressively with age at transplantation. Theobserved incidence was far higher than expected in the gen-eral population. However, we should sound a note of cautionon interpreting SMR when comparing an intensively sur-veyed cohort, i.e., transplanted subjects, with the generalpopulation. For comparison, a SMR of 253 for SCC and 10 for

BCC was documented in a Dutch study using similar meth-ods (2).

Overall, the increase in incidence of BCC paralleled that ofSCC in our transplant cohort and we did not observe thereverse ratio of BCC to SCC documented in several otherstudies (2, 3, 5, 7, 9, 11, 13, 17, 23, 31, 32). No figures fromItaly are available concerning, separately, the incidence ofBCC and SCC in the general population. However, based ondata from the Cancer registry of the Swiss Canton of Vaud(33), a BCC to SCC ratio of about 2.6:1 can be reasonablyexpected. This estimate fits well with the estimate in ourtransplant population, suggesting that the incidence is am-plified but the pattern of skin tumors is not significantlymodified. Interestingly, BCC to SCC ratio of 3.1:1 have beenreported in transplant patients from Spain (8). Ferrandiz etal. (8) explained the BCC/SCC ratio found in their study as amatter of length of immunosuppression. However, in ourstudy the median time to the development of BCC (6 years)was similar to that for SCC (7 years). The BCC to SCC ratiocould be influenced by other factors such as the geneticbackground of the population, the pattern of exposure toultraviolet radiation, or the immunosuppressive treatment.A much more prominent reversed BCC/SCC ratio has beenobserved in kidney compared with heart transplant recipi-ents (3). At variance with these data, in our cohort, theBCC/SCC ratio was 1.1:1 among heart and 2.6:1 among kid-ney transplant patients. The anatomical distribution of SCCand BCC diagnosed in transplanted subjects roughly paral-leled the distribution observed in the general population.Based on data from the Swiss Canton of Vaud, which is oneof the few registries to provide detailed information on non-melanoma skin cancer, about 76% of SCC and 72% of BCCare found on the head and neck, 16% of BCC and only 5% ofSCC are found on the trunk and about 19% of SCC and lessthan 9% of BCC are found on the upper and lower limbs (33).These figures are roughly in agreement with our data.

In our multivariate analysis, age at transplantation andsex were the most important risk factors for the developmentof nonmelanoma skin cancer. Interestingly, after controlling

TABLE 1. Incidence rate of SCC and BCC (per 1000 person year) according to age at transplantation andposttransplant years

Squamous cell carcinoma Basal cell carcinoma Both tumors

Age at transplantation (yr)

Yr posttransplant ,30 30–50 .50 ,30 30–50 .50 ,30 30–50 .500–4 2.4 6.5 4.4 13.9 5.4 20.85–8 4.2 8.7 1.1 15.7 11.2 1.1 18.5 18.6.8 2.2 7.8 6.7 6.7 12.3 6.9 9.5 17.8 14.9Total (95% C.I.) 0.6 4.1 7.1 2.1 9.1 12.7 2.8 11.5 19.8

(0.0–1.4) (2.2 –5.7) (3.1 –10.2) (0.6 –3.6) (6.1 –11) (7.7 –16) (0.9 –4.4) (8.0 –13.6) (14.8 –24.5)

TABLE 2. Incidence rate of SCC and BCC (per 1000 person year) according to sex and posttransplant years

Yr posttransplantSquamous cell carcinoma Basal cell carcinoma Both tumors

Males Females Males Females Males Females

0–5 3.6 0.8 6.9 2.3 9.7 3.26–10 4.5 1.3 12.7 2.6 15.8 3.9.10 6.7 3.0 8.7 10.9 13.4 14.4Total (95% C.I.) 4.3 1.4 8.7 4.3 11.8 5.8

(2.8–5.7) (0.0–2.7) (6.6–10.5) (2.0–6.5) (8.8–13) (3.1–8.2)

FIGURE 2. Cumulative incidence of nonmelanoma skin can-cer in RTRs and HTRs.

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for these two factors, no important differences were observedbetween heart and kidney transplant patients in terms ofskin cancer incidence even if some heterogeneity in riskestimates between SCC and BCC was observed. Overall, thisresult is at variance with data from other studies document-ing a 2-fold increase in all malignancies in heart versuskidney transplant recipients (3, 22, 34). Possibly, the shorterfollow-up time of heart transplant recipients as comparedwith kidney recipients influenced our results. However, it isunlikely that a remarkably higher risk is confined to hearttransplant patients. Giving the importance of age at trans-plantation and sex in influencing the risk of nonmelanomaskin cancer, we strongly advice using age- and sex-adjustedestimates when confronting incidence rates of RTRs andHTRs.

Conflicting data exist regarding the role of the immuno-suppressive regimen and, particularly, cyclosporine in thedevelopment of cutaneous malignancies (12, 21, 26–29, 35–37). Some previous studies (21, 35–37) have indicated thatcyclosporine-treated transplant patients had an increasedrisk of nonmelanoma skin cancer as compared with patientstreated with other immunosuppressive modalities. After con-trolling for potential risk factors, such as age and sex, we didnot document such an increased risk. Our results are inagreement with some previous studies showing no variationsin skin cancer incidence according to the immunosuppressiveregimens (12, 26–29), suggesting that the increased risk ofskin cancer following immunosuppression is possibly inde-pendent of the agents used, being a result of the degree ofimmunosuppression per SE We were unable to perform amore refined analysis taking into account the cumulativedosage or an index of the total amount of immunosuppres-sion. However, an indirect evidence for the limited role ofspecific therapeutic regimens was provided by the lack of riskvariations according to centers. ATG and OKT3, used as graftrejection therapy, represent an additional immunosuppres-sive load in a limited time period. Induction therapy withOKT3 has been found to be a risk factor for posttransplan-tation lymphoproliferative disease (38) and possibly skin can-

cer (23). Again, in accordance with a few previous studies (21,39), we were unable to document such an increased risk. Ourdata suggest that prolonged immunosuppression is more im-portant than short-term immune disregulation. Beyond acritical threshold in terms of immunosuppression, effectsmay consist of an “all-none” phenomenon.

In conclusion, our study confirms the increased risk ofnonmelanoma skin cancer among heart and kidney trans-plant recipients. The development of skin cancer wasstrongly associated with age at transplantation and sex al-though the transplanted organ and the immunosuppressiveregimens were relatively unimportant. The development ofskin cancer is a serious problem in terms of morbidity andquality of life. In the absence of new developments in thestrategies to prevent graft rejection, the problem is expectedto increase in importance, with the steadily rising number oforgan transplant recipients and the improved graft survival.Regular surveillance and ensuring that all organ transplantrecipients have easy access to a dermatologist are advised, aswell as biopsy of all suspicious lesions.

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TABLE 3. Factors associated with the development of nonmelanoma skin cancer in transplant recipients

No.Relative riska (95% c.i.)

SCC (n533) BCC (n570) Both tumors (n594)

Age at transplantation,30 369 1b 1b 1b

30–50 590 7.0 (1.6–30.3) 4.9 (2.1–10.9) 4.6 (2.3–9.5). 50 370 12.5 (2.6–60.9) 9.4 (3.8–23.0) 9.4 (4.3–20.5)

SexFemale 367 1b 1b 1b

Male 962 2.7 (1.1–6.9) 2.0 (1.1–3.9) 2.0 (1.1–3.4)Graft organ

Kidney 1062 1b 1b 1b

Heart 267 1.8 (0.4–7.4) 0.8 (0.3–1.8) 1.0 (0.6–1.7)Treatment modalities

Azathioprine1steroids 382 1b 1b 1b

Cyclosporine1steroids 374 1.0 (0.3–2.8) 1.3 (0.6–2.5) 1.1 (0.6–2.0)Cyclosporine1azathioprine6steroids 573 1.3 (0.5–3.3) 1.5 (0.8–2.8) 1.4 (0.8–2.5)

Use of OKT3 or ATGNo 1069 1b 1b 1b

Yes 260 0.3 (0.1–1.0) 0.6 (0.2–1.4) 0.6 (0.3–1.0)a Multivariate estimates derived by a Cox’s proportional hazard model including terms for age, sex, graft organ, and treatment proceduresb Reference category.

NALDI ET AL.November 27, 2000 1483

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Received 27 December 1999.Accepted 23 May 2000.

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