Skin Cancer in Heart Transplant Recipients
Risk Factor Analysis and Relevance of Immunosuppressive Therapy
Background—The frequency of skin tumors of all types and specifically of squamous cell carcinoma (SCC) is increased in heart transplantation (HT), but the predisposing risk factors are controversial.
Methods and Results—We studied 300 patients (age 49±15 years, 258 men, mean follow-up 4.6 years, follow-up range 1 month to 12 years) who were receiving standard double (cyclosporin plus azathioprine) or triple (cyclosporin plus azathioprine plus prednisone) therapy. The first-year rejection score was calculated for endomyocardial biopsy samples (International Society for Heart and Lung Transplantation grade 0=0, 1A=1, 1B=2, 2=3, 3A=4, 3B=5, and 4=6) and used as an indirect marker of the level of immunosuppression. Multivariate analysis (Cox regression) included age at HT, sex, skin type, first-year rejection score, presence of warts and solar keratosis, lifetime sunlight exposure, and first-year cumulative dose of steroids. The incidence of skin tumors of all types increased from 15% after 5 years to 35% after 10 years after HT according to life-table analysis. Age at HT of >50 years (P=0.03, RR=5.3), skin type II (P=0.05, RR=2.6), rejection score of 19 (P=0.003, RR=5.7), solar keratosis (P=0.001, RR=6.9), and lifetime sunlight exposure of >30 000 hours (P=0.0003, RR=7.6) were risk factors for SCC.
Conclusions—Older age at HT, light skin type, solar keratosis, greater sunlight exposure, and high rejection score in the first year were independently associated with an increased risk of SCC. The progressive increase in cancer frequency during follow-up and the association with high rejection scores suggest that both the length and level of immunosuppression may be relevant. Because cumulative immunosuppressive load is cumbersome to calculate, a high rejection score in the first year may provide a useful predictor for patients at risk.
An increased frequency of neoplastic disorders is a recognized complication of solid organ transplantation. Skin cancers are the most common malignancies that occur in transplant recipients1 ; their frequency increases with time after transplantation.1
Skin cancers develop on sun-exposed areas2 3 and are more frequent in individuals with fair skin, blue eyes, and blonde or red hair.2 3 4 A reversed squamous cell carcinoma (SCC)/basal cell carcinoma (BCC) ratio has been observed in transplant recipients compared with the general population as a result of an excess incidence of SCC.5 6 7 Moreover, SCC is believed to be more aggressive, with a higher risk of metastasis in transplant recipients than in the general population.8
Because of the longer experience with kidney transplantation, many investigations have been conducted in kidney transplant recipients2 9 10 11 12 13 14 ; some of results suggest that the risk of skin cancer might be related to the overall amount of immunosuppression.9 13 14 It has been shown that the risk of SCC is increased in renal transplant recipients mismatched for HLA-B antigens, which may be markers for a cohort of patients at a higher risk of rejection, who receive more intense immunosuppression.10 Although several studies have documented the risk of skin cancers in heart transplant (HT) recipients,3 5 6 9 15 16 17 18 only 2 of these studies included multivariate analysis.6 9 Thus, the risk factors for the development of skin cancers among HT recipients, including immunosuppressive load, remain controversial.
In the present study, we performed univariate and multivariate analyses of risk factors for skin cancer in HT recipients followed at 1 institution. The first-year post-HT rejection score, based on an adaptation of the International Society for Heart and Lung Transplantation (ISHLT) histological grading of rejection on endomyocardial biopsy, was calculated and used as an indirect marker of immunosuppressive load in risk factor analysis.
Patients and Study Protocol
We studied 300 HT recipients (258 men, mean age at HT 49±15 years, mean post-HT follow-up 4.6 years, follow-up range 1 month to 12 years). Each patient underwent regular dermatological follow-up visits with the same experienced dermatologist. The patients attended the clinic every 3 months, and on that occasion, the entire skin was thoroughly examined.
Excision specimens and skin biopsy samples were examined in the Pathology Department. The histopathological diagnoses of BCC, SCC, malignant melanoma, Bowen’s disease, solar keratosis, and Kaposi’s sarcoma were established in accordance with accepted criteria.
A standard questionnaire and examination sheet were completed for each patient and included baseline demographic features, cause of heart failure before transplantation, date of transplantation, skin type according to Fitzpatrick’s standard criteria,19 and history of lifetime sunlight exposure. For statistical purposes, patients with skin type III or V were clustered with the skin type IV group. There were no patients with skin type I or VI. For technical reasons, skin type data were available for 258 of the 300 patients. Each patient’s cumulative lifetime sun exposure was calculated in hours. As previously described,20 3 cutoff levels of exposure were used for statistical purposes: (1) low (10 000 hours), (2) intermediate (20 000 hours), and (3) high (30 000 hours).
HT recipients were treated with cyclosporin A (CsA) and azathioprine (Aza) (double therapy, n=62) or with CsA, Aza, and oral prednisone (triple therapy, n=238). Oral prednisone was associated with CsA and Aza in the presence of repeated or persistent rejection or of CsA nephrotoxicity. Induction immunosuppression included a single dose of CsA (5 mg/kg) and Aza (3 mg/kg) administered 6 hours before surgery and a bolus of methylprednisolone (1000 mg IV) during cardiopulmonary bypass. Immunosuppression was started on the day of surgery with increasing dosages of CsA up to 2 to 12 mg · kg−1 · d−1 and of Aza up to 0.5 to 2 mg · kg−1 · d−1. The CsA dose was adjusted to maintain a whole blood trough level of 150 to 300 ng/mL, as assessed with radioimmunoassay and based on the patient’s renal function (as assessed with serum creatinine level). The Aza dose was adjusted to maintain a total white blood cell count of ≥4000/mm3. Postoperatively, the majority (83%) of patients received antilymphocyte globulin (ALG) or antithymocyte globulin (ATG), or both, for 3 to 5 days. Graft rejection was monitored with endomyocardial biopsy according to established protocols (weekly during the first month, biweekly until the third month, monthly until the first year; in the presence of grade 2 rejection, in the next 10 to 15 days). Endomyocardial biopsy samples were obtained via the right internal jugular vein (Caves-Schultz bioptome). At least 4 adequately sized specimens from each patient were fixed in 10% phosphate-buffered formalin (pH 7.35); 7-μm paraffin-embedded serial sections were cut, stained with hematoxylin and eosin, and graded according to the ISHLT standardized grading system.21 Acute rejection episodes, defined as ISHLT grade of >2, were treated with the intravenous administration of methylprednisolone, combined with ALG or ATG in the presence of symptoms (n=84 patients, or 28%). A rejection score was assigned based on a modification of the ISHLT grading as follows: 1A=1, 1B=2; 2=3, 3A=4, 3B=5, and 4=6.22 Mean rejection scores were calculated at 1 year after HT and were used as an indirect marker of the level of immunosuppression. The cumulative prednisone load of each patient at 1 year after HT (PDN 1 year) was also calculated (in mg/kg), as was cumulative methylprednisolone at 1 year (MethPD 1 year) and the cumulative total steroid load at 1 year (TotCORT 1 year=PDN 1 year+MethPD 1 year), after the conversion of each MethPD dose to an equivalent PDN dose (4 mg MethPD=5 mg PDN).
Statistical analyses were performed with the SPSS software package. Results are expressed as mean±SD, unless otherwise specified. A comparison of mean values was made by Student’s t test. The ordinal data were analyzed by a χ2 test. Kendall’s rank test was used to correlate quantitative data. To represent Kendall’s rank correlation coefficient, τ varied from +1 for complete positive correlation to 0 for no correlation to −1 for complete negative correlation.
The risk of skin cancer with time after transplantation was evaluated by Kaplan-Meier survival analysis. Outcomes of interest in the analysis included the time from transplantation to the first diagnosis of skin cancer, the date of patient’s death, the date of loss to follow-up, or the end of the study period. Differences between actuarial curves were analyzed by the Mantel-Haenszel log-rank test. A P value of <0.05 was considered to be statistically significant. Multivariate analysis of potential risk factors was performed by the stepwise proportional hazards method of Cox. Results are expressed with the hazard ratios (ie, antilog of the coefficient of Cox regression) and their associated 95% CIs. Variables included in both univariate and multivariate analyses of risk factors for skin cancer were age at HT, sex, presence of warts and of solar keratosis, skin type, lifetime sunlight exposure, rejection score at 1 year, PDN 1 year, MethPD 1 year, and TotCORT 1 year.
Frequency and Distribution of Skin Tumors
A total of 104 skin tumors were diagnosed in 48 HT patients, of whom 12 developed >1 histological type; the frequencies of the different types are detailed in Table 1⇓. All patients with tumors except 3 were alive at the last follow-up; these 3 patients died of early metastasis of melanoma (n=1), merkeloma (n=1), and Kaposi’s sarcoma (n=1). The SCC/BCC ratio was 1.43:1; the large majority of lesions occurred on the head and neck (73, or 70%), and the remainder were on the trunk (9, or 9%), upper limbs (18, or 17%), and lower limbs (4, or 4%). The cumulative risk of skin cancer in HT patients by life-table analysis is shown in the Figure⇓. The risk increased from 15% after 5 years to 35% after 10 years and was similar in men and women. The mean interval between HT and detection of the first skin cancer correlated with age at transplantation (P<0.01, τ −0.365). Overall, HT patients aged >50 years had an earlier onset of skin cancer lesions than those aged <50 (4±3 versus 6±3 years, P<0.001).
Risk Factors for Skin Tumors on Univariate Analysis
Baseline demographic and dermatological features in the study patients with and without skin tumors of any histological type are shown and compared in Table 2⇓. HT patients who developed skin tumors were older at transplantation than those who did not develop skin tumors (P=0.008). Skin type II was more common than other skin types in HT recipients with tumors compared with those without (P=0.0007), as was solar keratosis (P=0.00001), and total sunlight exposure was higher (P=0.001). Conversely, 1-year rejection score, cumulative steroid load, and use of ALG/ATG as induction therapy or as treatment for rejection were similar in patients with and without tumors. However, patients with a rejection score of 19 compared with those with a score of <19 had higher values for PDN 1 year (51±28 versus 30±35 mg/kg, P=0.0001), MethPD 1 year (107±56 versus 62±55 mg/kg, P=0.0001), and TotCORT 1 year (184±77 versus 108±77 mg/kg, P=0.0001).
Baseline demographic and dermatological characteristics of patients with and without tumors of the SCC type are shown and compared in Table 3⇓. The associations with skin type II (P=0.03) and high sunlight exposure (P=0.0001) were confirmed; in addition, solar keratosis was more common among patients with SCC (P=0.00001). Patients with SCC tended to be older at transplantation than those without SCC (P=0.05). Again, 1-year rejection score, cumulative steroid load, and use of ALG/ATG as induction therapy or as treatment for rejection were similar in patients with and without SCC.
Risk Factors for Skin Tumors on Multivariate Analysis
Risk factors for skin tumors of any histological type by multivariate analysis are detailed in Table 4⇓. Age at transplantation was found to be the most important risk factor; patients aged >50 years had a 7.3 times higher risk of developing cancer than did those aged <50 years (P=0.0001). Total sunlight exposure of >10 000 hours and skin type II were additional risk factors (P=0.0055, hazard ratio 2.7; P=0.0002, hazard ratio 3.4, respectively). High rejection score (>19) tended to be associated with higher risk (P=0.06). Conversely, sex, presence of solar keratosis, presence of warts, and cumulative steroid load in the first posttransplantation year did not reach statistical significance.
Risk factors for skin tumors of SCC type on multivariate analysis are shown in Table 5⇓. When patients with SCC were analyzed separately, multivariate analysis confirmed older age (>50 years) at HT (P=0.03, hazard ratio 5.3) and high sunlight exposure (P=0.0003, hazard ratio 7.6) as risk factors, whereas skin type II tended to be significant (P=0.05, hazard ratio 2.6). Two additional risk factors for SCC were the presence of solar keratosis (P=0.001, hazard ratio 6.87) and a rejection score of >19 (P=0.003, hazard ratio 5.7). The remaining variables included in the analysis did not reach statistical significance.
Skin Cancer in HT: Frequency and Conventional Risk Factors
In the present study, we confirmed the previously described increased frequency of skin cancer of all types and specifically of SCC in HT recipients.1 3 5 6 9 15 16 17 18 The SCC/BCC ratio in our HT patients, calculated as 1.43:1, was reversed compared with the normal value of 1:4.23 However, others reported a large preponderance of SCC over BCC (ratios of 3:1 to 16:1).5 6 7 In such studies, there probably is an underestimation of BCC, resulting in an excess of SCC, because skin cancer data were not, as in our investigation, obtained through prospective dermatological screening but rather were derived from medical records and tumor registries. Thus, these workers may have not included all cases of BCC, because these tumors are often treated with nonsurgical methods.6 In keeping with this interpretation, a very high SCC/BCC ratio was not found in follow-up studies that included a careful dermatological evaluation and were carried out at a single center.3 12 16
In the present study, we found that age at transplantation was the most important risk factor for skin cancer of any type. Older patients (>50 years) not only had an increased risk but also showed a shorter mean interval between transplantation and development of the first skin cancer, as already reported.11 Two previous investigations had used multivariate analysis6 9 and identified older age at transplantation6 9 as a risk factor but did not evaluate other conventional risk factors, notably sunlight exposure4 10 12 or skin type.2 4 In the present study, skin type and lifetime sunlight exposure were relevant risk factors. In fact, on univariate analysis, patients with skin cancer had a higher mean cumulative sunlight exposure than patients without skin cancer, and on multivariate analysis, transplant recipients with skin type II or sunlight exposure of >10 000 hours had a 3-fold higher relative risk for skin cancer development. This is not surprising, because UV exposure is a recognized risk factor for skin malignancies in the general population.24 In keeping with these findings, the cumulative incidence of skin cancer in HT was reported to be greater in countries with a high level of UV radiation, such as Australia.6 The preferential location of skin cancers on sun-exposed areas, which we found in our patients, is in agreement with previous studies7 21 and further supports the pathogenic role of sunlight. Experimental data suggest that UV light may be a keratinocyte mutagen, acting like a tumor initiator and promoter.24 In addition, UV light radiation can induce immunological unresponsiveness. In particular, low doses of UV light radiation reduce the number and the antigen presenting cell function of epidermal Langerhans cells, impairing their role in the immune response against virus-infected and -transformed cells.25 UV light radiation can also induce systemic immunosuppression by inducing the generation of soluble mediators, such as cis-urocanic acid, interleukin-10, and tumor necrosis factor-α.24 25 Thus, sunlight exposure may exert an additive or a potentiating immunosuppressive effect in transplant recipients who are already receiving long-term pharmacological immunosuppression therapy. Interestingly, in the present study, sunlight exposure was a more powerful risk factor for SCC (relative risk 7.6) than for skin tumors of any type (relative risk 2.7); in addition, solar keratosis was a risk factor for SCC but not for all skin tumors. This may indicate different etiopathogenetic pathways in SCC and provides strong evidence in support of sun protection measures as well as close dermatological surveillance in HT patients.
High Rejection Score as Risk Factor for SCC in HT
We found on multivariate analysis that high rejection score at 1 year, used as an indirect marker of the level of immunosuppression, was independently associated with the development of SCC but not with all histological types of tumors. On the other hand, cumulative steroid load in the first year, which we calculated because steroids represent the standard treatment of uncomplicated acute rejection episodes in HT, failed to be identified as a risk factor for skin cancer, although cumulative steroid load was higher in patients with high rejection scores. Our interpretation of these apparently intriguing results is 2-fold. First, the risk of SCC may be related to cumulative immunosuppressive dosage rather than to a specific immunosuppressive drug, as hypothesized by others.3 5 6 13 14 Clearly, further attempts should be made to assess the role of CsA and Aza, alone and in association with steroids, as risk factors. Second, the lack of association between cumulative dose of steroids and skin cancer that we found, despite a high rejection score being a risk factor for SCC, may indicate that in HT patients who develop skin cancer, the dose of steroids exceeds a certain threshold value, above which the risk of skin cancer is not further increased by the use of a higher level of these drugs. The “threshold effect” has already been proposed to explain similar results in renal transplant recipients.10 The finding that rejection score was a risk factor for SCC rather than all tumor types again suggests distinct etiopathogenetic factors for SCC and is in keeping with the previously reported increased risk of SCC in renal transplant recipients mismatched for HLA-B antigens.10 The underlying mechanism by which a poorly matched grafted organ may contribute to the induction of skin cancer is unknown at the present; there are no experimental data that show skin cancer is induced through long-term exposure to alloantigens. It has been speculated that after transplantation, tolerance might develop to the alloantigens of the graft, as well as tolerance to the antigens associated with SCC, leading to tumor escape mechanisms.10
The present study showed a progressive increase in the incidence of skin cancer in HT patients with the time from transplantation, and we identified older age at surgery, light skin type, lifetime sunlight exposure, and high rejection score at 1 year posttransplantation as significant risk factors. The progressive increase in cancer frequency during follow-up and the association with high rejection scores suggest that both the length and level of immunosuppression may be relevant. Because cumulative immunosuppressive load is cumbersome to calculate, a high rejection score in the first year may provide a useful predictor for patients at risk.
- Copyright © 2000 by American Heart Association
Penn I. Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am. 1993;7:431–445.
Bouwes Bavinck JN, De Boer A, Vermeer BJ, et al. Sunlight, keratotic skin lesions and skin cancer in renal transplant recipients. Br J Dermatol. 1993;129:242–249.
Euvrard S, Kanitakis J, Pouteil-Noble C, et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol. 1995;33:222–229.
McLelland J, Rees A, Williams G, et al. The incidence of immunosuppression-related skin disease in long-term transplant patients. Transplantation. 1988;46:871–874.
Lampros TD, Cobanoglu A, Parker F, et al. Squamous and basal cell carcinoma in heart transplant recipients. J Heart Lung Transplant. 1998;6:586–591.
Ong CS, Keogh AM, Kossard S, et al. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999;40:27–34.
Barr BBB, Benton EC, McLaren K, et al. Human papilloma virus infection and skin cancer in renal allograft recipients. Lancet. 1989;1:124–129.
Penn I. The changing pattern of posttransplant malignancies. Transplant Proc. 1991;23:1101–1103.
Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:177–186.
Bouwes Bavinck JN, Vermeer BJ, van der Woude FJ, et al. Relations between skin cancer and HLA antigens in renal-transplant recipients. N Engl J Med. 1991;325:843–848.
Webb MC, Compton F, Andrews PA, et al. Skin tumors posttransplantation: a retroactive analysis of 28 year experience at a single centre. Transplant Proc. 1997;29:828–830.
Ferràndiz C, Fuente MJ, Ribera M, et al. Epidermal dysplasia and neoplasia in kidney transplant recipients. J Am Acad Dermatol. 1995;33:590–596.
Bouwes Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia: a follow-up study. Transplantation. 1996;61:715–721.
Dantal J, Hourmant M, Cantarovich D, et al. Effects of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998;351:623–628.
Olivari MT, Diekman RA, Kubo SH, et al. Low incidence of neoplasia in heart and in heart-lung transplant recipients receiving triple-drug immunosuppression. J Heart Transplant. 1990;9:618–621.
España A, Redondo P, Fernàndez AL, et al. Skin cancer in heart transplant recipients. J Am Acad Dermatol. 1995;32:458–465.
Bernstein DB, Baum D, Berry G, et al. Neoplastic disorders after pediatric heart transplantation. Circulation. 1993;88:230–237.
Couetil JP, McGoldrick JP, Wallwork J, et al. Malignant tumors after heart transplantation. J Heart Transplant. 1990;9:622–626.
Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124:869–871.
Vitaliano PP, Urbach F. The relative importance of risk factors in nonmelanoma carcinoma. Arch Dermatol. 1980;116:454–456.
Billingham ME, Cary NRB, Hammond EH, et al. A working formulation for the standardisation of nomenclature in the diagnosis of heart and lung rejection: heart rejection study group. J Heart Transplant. 1990;8:587–593.
Livi U, Milano A, Caforio ALP, et al. Influence of rejection on late graft function after heart transplantation. Transplant Proc. 1994;26:2727–2728.
Gallagher RP, Ma B, McLean DI, et al. Trends in basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin from 1973 through 1987. J Am Acad Dermatol. 1990;23:413–421.
Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer. Arch Dermatol. 1997;133:1263–1270.
Streilein JW, Taylor JR, Vincek V, et al. Relationship between ultraviolet-induced immunosuppression and carcinogenesis. J Invest Dermatol.. 1994;103:107S–111S.