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A Prospective Study of Incident Nonmelanoma Skin Cancer in Heart Transplant Recipients

2000; Elsevier BV; Volume: 115; Issue: 6 Linguagem: Inglês

10.1046/j.1523-1747.2000.0202a-3.x

1523-1747

Agustı́n España, Miguel Ángel Martínez‐González, Marta Garcı́a-Granero, I. Sánchez‐Carpintero, Gregorio Rábago, José Miguel Cisneros,

Cutaneous lymphoproliferative disorders research

To the Editor: The high incidence of nonmelanoma skin cancer (NMSC) in transplant recipients is mainly due to immunosuppressive treatment (España et al., 1995España A. Redondo P. Fernández A.L. Zabala M. Herreros J. Llorens R. Skin cancer in heart transplant recipients.J Am Acad Dermatol. 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (82) Google Scholar;Bouwes-Bavinck et al., 1996Bouwes-Bavinck J.N. Hardie D.R. Green A. et al.The risk of skin cancer in renal transplant recipients in Queensland, Australia.Transplantation. 1996; 61: 715-721Crossref PubMed Scopus (431) Google Scholar;Jensen et al., 1999Jensen P. Jensen P. Hansen S. et al.Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.J Am Acad Dermatol. 1999; 40: 177-186Abstract Full Text Full Text PDF PubMed Scopus (670) Google Scholar;Ong et al., 1999Ong C.S. Keogh A.M. Kossard S. Macdonald P.S. Spratt P.M. Skin cancer in Australian heart transplant recipients.J Am Acad Dermatol. 1999; 40: 27-34Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). An increased exposure to ultraviolet radiation may lead to an even higher risk (Kelly et al., 1987Kelly G.E. Meikle W. Sheil A.G.R. Effects of immunosuppressive therapy on the induction of skin tumors by ultraviolet irradiation in hairless mice.Transplantation. 1987; 44: 429-434Crossref PubMed Scopus (92) Google Scholar;Gallagher et al., 1995Gallagher R.P. Hill G.B. Bajdik C.D. et al.Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma.Arch Dermatol. 1995; 131: 164-169Crossref PubMed Scopus (262) Google Scholar;Krutman et al., 1997Krutman J. Human photoinmunology: The relevance of ultraviolet radiation-induced-immunosuppression for photocarcinogenesis.in: Altmeyer P. Hoffmann K. Stücker Skin Cancer and UV Radiation. Springer-Verlag, Berlin1997: 738-743Crossref Google Scholar). We describe the incidence of NMSC in heart transplant recipients (HTR) from a single Spanish center and assess their main risk factors. Out of 150 HTR between January 1984 and December 1997, those who had a follow-up time superior to 6 mo after transplantion (n = 124) were included in our assessment. Their follow-up times were: >3 y, 80 patients; >5 y, 52 patients; >7 y, 27 patients; >9 y, 15 patients. These selection criteria ensured that this series was comparable with other reports (Couetil et al., 1990Couetil J.P. McGoldrick Wallwork J. English T.A. Malignant tumors after heart transplantation.J Heart Transplant. 1990; 9: 622-626PubMed Google Scholar), including a previous shorter assessment by our group (España et al., 1995España A. Redondo P. Fernández A.L. Zabala M. Herreros J. Llorens R. Skin cancer in heart transplant recipients.J Am Acad Dermatol. 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (82) Google Scholar). The median follow-up time was 69 mo (range: 6–161 mo). Eighty-eight per cent of the patients were male and their mean age was 49 y. All patients were living in Spain (latitude 40°-45° North). All patients were counselled to avoid sun exposure and to use sunscreens. Immunosuppressive protocols received by these patients are fairly homogenous (España et al., 1995España A. Redondo P. Fernández A.L. Zabala M. Herreros J. Llorens R. Skin cancer in heart transplant recipients.J Am Acad Dermatol. 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (82) Google Scholar). All patients were carefully examined by the same dermatologist (AE) every 6 mo. We assigned a score (hereafter referred to as total sun burden (TSB)) to each patient according to a questionnaire that they completed. To build this score we summed the points during four periods of lifetime until receiving the transplant (< 20 y, 20–40 y, 41–60 y, >60 y) related to their exposure to three factors: usual residence (nonsunny = 0 points, sunny = 1 point); occupational sun exposure (never = 0, < 20 h per wk = 1, ≥ 20 h per wk = 3), sun exposure during vacations (nothing = 0, < 14 d per y = 1; ≥ 14 d per y = 2). This system could theoretically lead to values ranging 0–24, but we obtained actual scores ranging 1–20. We categorized the patients in three roughly similar groups of TSB. All patients in our series belonged to categories I–IV of skin-type (ST) (Fitzpatrick, 1988Fitzpatrick T.B. The validity and practicality of sun-reactive skin types I through VI.Arch Dermatol. 1988; 124: 869-871Crossref PubMed Scopus (2656) Google Scholar). We merged ST I–II into a single category; and ST III–IV into another category. We calculated with the Kaplan-Meier method (using the first episode as event) the cumulative incidence of NMSC for each group of patients according to their TSB exposure and to their ST. We compared incidence rates with the log-rank test. We performed sensitivity analyzes considering deaths as censor or as events for patients not developing any NMSC. Multivariable Cox models were used to control for some potential confounders (gender, age, smoking, incident warts). At the end of follow-up (161 mo), 33 patients had developed either SCC, BCC, or both. All patients with ST-I developed at least one NMSC. This proportion was 53% for ST-II, 13% for ST-III, and none for ST-IV (only four patients). The higher the TSB was, the higher was the incidence of SCC and BCC (Table 1). The group with highest TSB previous to transplant exhibited highly significant adjusted relative risks for SCC (19.86), BCC (6.08), and any of both (13.71) (Table 1). The relative risk reduction associated with having a ST III/IV were 87% (SCC), 62% (BCC), and 83%, for any of them (Table 1). This estimate was not significant for BCC. Contrary to what was expected, the development of warts after the heart transplant was not predictive of a higher risk of SCC or BCC, and even an inverse association was found for any of them (p = 0.02). When we considered deaths as events the results did not substantially change (data not shown).Table IRelative risk of NMSC in HTR according to several risk factorsaSCC, squamous-cell carcinomas; BCC, basal-cell carcinomas; NMSC, non-melanoma skin cancer; HTR, heart transplant recipient.Relative risk of SCC (95% confidence intervals)Relative risk of BCC (95% confidence intervals)Relative risk of any skin cancer (95% confidence intervals)ExposureCrudeMultivariate adjustedbAdjusted for all other variables shown in the table. The small number of women in the sample precluded to compute the relative risk of gender for BCC.CrudeMultivariate adjustedbAdjusted for all other variables shown in the table. The small number of women in the sample precluded to compute the relative risk of gender for BCC.CrudeMultivariate adjustedbAdjusted for all other variables shown in the table. The small number of women in the sample precluded to compute the relative risk of gender for BCC.Total sun burden score Low ( 10)19.39 (2.52–149.38)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).19.86 (2.18–180.61)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).8.90 (1.11–71.26)*p<0.056.08 (0.6021–61.45)12.24 (2.79–53.64)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).13.71 (2.60–72.40)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).Skin types Burns in sun (I/II)1 (ref.)1 (ref.)1 (ref.)1 (ref.)1 (ref.)1 (ref.) Tans in sun (III/IV)0.131 (0.055–0.314)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).0.128 (0.051–0.317)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).0.270 (0.098–0.772)*p<0.050.381 (0.120–1.21)0.183 (0.090–0.373)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).0.169 (0.078–0.365)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).Gender Male1 (ref.)1 (ref.)1 (ref.)1 (ref.) Female0.547 (0.072–4.16)1.02 (0.112–9.30)0.228 (0.031–1.67)0.599 (0.073–4.89)Age (every year older)1.07 (1.02–1.11)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).1.03 (0.974–1.09)1.06 (1.00–1.12)*p<0.051.03 (0.962–1.09)1.06 (1.02–1.10)***p<0.001 in the likelihood ratio text (Cox proportional hazard regression).1.026 (0.977–1.078)Incident wartscAfter heart transplant and previous to NMSC development.0.559 (0.191–1.64)0.446 (0.124–1.60)0.236 (0.031–1.80)0.319 (0.040–2.55)0.385 (0.135–1.101)*p<0.050.288 (0.088–0.945)*p<0.05Smoking Never smokers1 (ref.)1 (ref.)1 (ref.)1 (ref.)1 (ref.)1 (ref.) Ex-smokers1.22 (0.495–3.00)1.28 (0.44–0.71)0.591 (0.172–2.02)0.621 (0.149–2.59)1.26 (0.576–2.75)1.24 (0.489–3.16) Curent smokers0.740 (0.274–2.00)0.721 (0.249–2.09)1.21 (0.299–4.87)1.48 (0.310–7.08)0.714 (0.302–1.69)0.705 (0.272–1.83)** p<0.01a SCC, squamous-cell carcinomas; BCC, basal-cell carcinomas; NMSC, non-melanoma skin cancer; HTR, heart transplant recipient.b Adjusted for all other variables shown in the table. The small number of women in the sample precluded to compute the relative risk of gender for BCC.c After heart transplant and previous to NMSC development.* p<0.05*** p<0.001 in the likelihood ratio text (Cox proportional hazard regression). Open table in a new tab ** p 10; 8.67 for ST I/II and TSB = 6–10, and 20.19 for ST I/II and TSB score >10.Table IIRisk of developing NMSC along the follow-up period (120 mo) according to the joint exposure to TSB (previous to transplant) and ST in HTRaNMSC, non-melanoma skin cancer; TSB, total sun burden; ST, skin type; HTR, heart transplant recipientsSkin typeTans in sun (III/IV)Burns in sun (I/II)Absolute risks: percentage developing NMSC (95% confidence intervals)Total sun burden score (see Table 1)Low ( 10)29.4% (11.7–53.7)100% (76.2–100.0)Relative risks: hazard ratios for developing NMSC (95% confidence intervals)Total sun burden score (see Table 1)Low ( 10)4.15 (1.31–13.21)20.19 (7.71–72.84)a NMSC, non-melanoma skin cancer; TSB, total sun burden; ST, skin type; HTR, heart transplant recipients Open table in a new tab Our study, which included a follow-up longer than previously published reports (Olivari et al., 1990Olivari M.T. Diekmann R.A. Kubo S.H. Braunlin E. Jamieson S.W. Ring W.S. Low incidence of neoplasia in heart and heart-lung transplant recipients receiving triple-drug immunosuppression.J Heart Transplant. 1990; 9: 618-621PubMed Google Scholar;España et al., 1995España A. Redondo P. Fernández A.L. Zabala M. Herreros J. Llorens R. Skin cancer in heart transplant recipients.J Am Acad Dermatol. 1995; 32: 458-465Abstract Full Text PDF PubMed Scopus (82) Google Scholar;Euvrard et al., 1995Euvrard 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: 222-229Abstract Full Text PDF PubMed Scopus (206) Google Scholar;Jensen et al., 1999Jensen P. Jensen P. Hansen S. et al.Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.J Am Acad Dermatol. 1999; 40: 177-186Abstract Full Text Full Text PDF PubMed Scopus (670) Google Scholar), identified two major risk factors explaining the high incidence of NMSC in HRT: ST and the total amount of exposure to sunlight, previously to the transplant. In addition, our data do not support the consideration of viral warts as an early marker for tumor development among HTR. In the general population of Spain (Zubiri et al., 1981Zubiri A. Berrino F. del Moral A. et al.Estadística de los cánceres cutáneos epiteliales en los países europeos de lengua latina.Acta Dermo-Sif. 1981; 5–6: 241-250Google Scholar), the ratio SCC/BCC is 0.3/1. We found a slightly higher incidence of BCC during the earlier period of follow-up, but progressively the ratio of SCC/BCC was reversed, reaching 1.66/1 at the end of the study. There are few published studies assessing the role of ST in determining the risk of NMSC among HTR and among transplant recipients in general (McLelland et al., 1988McLelland J. Ress A. Williams G. et al.The incidence of immunosuppression-related skin disease in long-term transplant patients.Transplantation. 1988; 46: 871-874Crossref PubMed Scopus (65) Google Scholar). Our main results lead us to think that patients who are candidates for heart transplant and have a ST I or II will experience extremely high rates of NMSC in the long run. This risk must be taken into account for thoroughly balancing it against the potential benefits of a heart transplant. Our results also support the importance of TSB previously to receiving the transplant. We provide strong evidence to recommend that when patients with a high TSB receive a transplant, they must undergo an especially stringent dermatologic surveillance for skin cancer. The system we have used to score TSB in HTR has been shown to predict rates of developing NMSC in these patients. When combined with the ST, it can be used as a practical approach for classifying HRT according to their risk of developing these malignancies. This information could help improve the setting of priorities in selecting patients for heart transplant; however, we acknowledge that an external prospective validation of this scoring system with a different series of patients is needed.