Report

Epidemiology and clinical evolution of non-melanoma skin cancer in renal transplant recipients: a single-center ~o Paulo, Brazil experience in Sa Marina Zoega Hayashida, MD, Victor Miguel Coutinho Fernandes, MD, Diana Rosa de Melo Fernandes, MD, Marılia Marufuji Ogawa, MD, PhD, and Jane Tomimori, MD, PhD

Department of Dermatology, Escola Paulista de Medicina (Paulista School of ~o Paulo Medicine), Federal University of Sa ~o Paulo, Brazil (UNIFESP), Sa

Abstract

Correspondence Jane Tomimori, MD, PHD Department of Dermatology ~o Paulo Federal University of Sa Rua Borges Lagoa 508 ~o Paulo, CEP 04038-001 SP Sa Brazil E-mails: [email protected], [email protected], jane. [email protected]

RTRs in tropical countries.

Conflicts of interest: None. ~o de Amparo a  Funding: FAPESP (Fundacßa ~o Paulo) Pesquisa do Estado de Sa scholarship for the first author.

Background Non-melanoma skin cancer (NMSC) is very common among renal transplant recipients (RTRs) as a result of the immunosuppressed status of these patients and other factors. Few studies have examined the clinical characteristics and evolution of NMSC in Objectives The aim of this study was to characterize the epidemiology and clinical evolution of NMSC in RTRs. Methods We conducted a retrospective study including 68 RTRs with NMSC diagnosed from July 2004 to December 2009 with a minimum follow-up of three years. We analyzed demographic and transplant- and NMSC-related data. Results The mean age of patients at the first diagnosis of NMSC was 51 years (range: 29–71 years). Most first diagnoses occurred within nine years post-transplant. The majority of patients (n = 48) had Fitzpatrick skin phototype II, although NMSC was also observed in those with skin phototypes III and IV. Forty-six (67.6%) RTRs had received a kidney from a living donor. Fifty-five (80.9%) RTRs had received cytotoxic immunosuppressives, 51 (75.0%) had received calcineurin inhibitors, and two (2.9%) had received mTOR inhibitors. Most of the RTRs developed about eight NMSC lesions, but up to 25 NMSC lesions were diagnosed in one patient. Most lesions (67.6%) were located on sun-exposed areas. Squamous cell carcinoma (SCC) represented the predominant tumor type, accounting for 70.6% of all tumors, whereas basal cell carcinoma accounted for 29.4% of all tumors. Invasive SCC predominated over in situ SCC. Finally, 48.5% of patients had a previous history of viral warts. Conclusions Long-term use of immunosuppressive therapy increases the risk for tumor occurrence. Multiple NMSC tumors can develop in patients in tropical countries, even in patients with a high skin phototype. Therefore, RTRs should understand the high risk for the development of malignant tumors and should be properly informed about the prevention and treatment of NMSC.

Introduction Non-melanoma skin cancer (NMSC) is a very common tumor in renal transplant recipients (RTRs) and accounts for almost 50% of malignancies affecting this population.1,2 The incidence of NMSC in these immunosuppressed patients is reported to be 10–250 times higher than in the normal population.3 Several factors are involved in elevating the risk for skin cancer, including the receipt of immunosuppressive drugs, exposure to sunlight, viral infection, individual genetic background, age, and a low ª 2015 The International Society of Dermatology

skin phototype.2–4 Some studies have indicated prevalences of NMSC in RTRs, but the clinical characteristics and outcomes of these patients have not been fully established. Thus, the main objectives of this study were to evaluate the frequency and clinical development of NMSC in RTRs seen at the Federal University of S~ ao Paulo, in S~ ao Paulo City, Brazil. We performed a 5-year retrospective study by analyzing the medical records of RTRs diagnosed with NMSC in order to establish their clinical evolution based on demographic parameters and associations with transplantation and with skin cancer itself. International Journal of Dermatology 2015, 54, e383–e388

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Non-melanoma skin cancer in renal transplant recipients in Brazil

Materials and methods This retrospective study was based on a review of medical

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Table 1 Characteristics of renal transplant patients diagnosed with non-melanoma skin cancer (n = 68)

records of RTRs admitted to the Department of Dermatology at ~o Paulo, Brazil, from July 2004 to the Federal University of Sa

Characteristic

December 2009. The minimum period of follow-up was three

Sex

years. Patients were required to be aged >18 years, to have undergone a single renal transplantation, and to have demonstrated NMSC after this procedure. During this period, about 900 new RTRs attended for consultation in the Department of Dermatology.

Data collection The following parameters were analyzed: gender; age; Fitzpatrick skin type; type of donor (deceased or living); immunosuppressive drugs; time from transplantation to the appearance of the first tumor; association with human papillomavirus (HPV) infection; total number of NMSC lesions developed so far; body sites affected; and histological type of tumor. Statistical analysis Statistical analysis was performed using the chi-squared test. A P-value of 40 years. Age did not correlate with any other parameter analyzed. Patients were classified by Fitzpatrick skin types I–IV: 48 patients had skin type II; 17 patients had skin type III or IV; and only three patients had skin type I. No patients with skin of phototypes V and VI were observed. Transplanted kidneys had been sourced from living donors in 46 (67.6%) patients and from deceased donors in 18 (26.4%) patients. Donor type was not reported for four patients (Table 1). Among the immunosuppressive drugs administered, 55 (80.9%) patients used at least one cytotoxic drug (azathioprine, anti-OKT3, mycophenolate sodium, and mycophenolate mofetil), 51 (75.0%) patients received calcineurin inhibitors (tacrolimus and cyclosporine A), and two (2.9%) patients used mTOR inhibitors (sirolimus) after renal transplantation. An earlier onset of NMSC was associated with the use of tacrolimus (P < 0.001) and also with the use of mycophenolate sodium (P = 0.003). Patients using calcineurin inhibitors showed a lower latency for first tumor occurrence than did those using cytotoxic agents (P = 0.004). The subgroups of patients International Journal of Dermatology 2015, 54, e383–e388

Age, years, mean, range Fitzpatrick skin type, n (%) I II III IV V VI Donor type,% Living Deceased Not reported Immunosuppressive drug use, patients,% CSA + AZA AZA CSA FK + AZA FK + MFNa CSA + MFNa CSA + MFMF FK MFNa MFMF FK + MFMF RAPA + MFMF RAPA + CSA OKT3 + MFMF Period of immunosuppression, mean (range) Presence of warts, patients,%

73.5% male, 26.5% female 51 (29–71) 3 48 11 6 0 0

(4.4%) (70.6%) (16.2%) (8.8%)

67.6% 26.4% 5.9% 30.8% 11.7% 11.7% 7.3% 5.9% 5.9% 4.4% 4.4% 4.4% 4.4% 1.5% 1.5% 1.5% 1.5% 8.7 years (5 months to 25 years) 48.5%

AZA, azathioprine; CSA, cyclosporine A; FK, tacrolimus; MFMF, mycophenolate mofetil; MFNa, mycophenolate sodium; OKT3, anti-OKT3; RAPA, rapamycin (sirolimus).

using cytotoxic drugs and calcineurin inhibitors had higher numbers of tumors (P = 0.015 and P < 0.001, respectively). The shortest time from transplantation to the appearance of the first tumor was 150 days (approximately 5 months). Among the RTRs studied, 33 patients (48.5%) had a previous history of viral warts. Infection with HPV was associated with squamous cell carcinoma (SCC) in 54.9% of patients and with basal cell carcinoma (BCC) in 34.5% of patients. Patients who had used azathioprine had a higher incidence of viral warts (P = 0.015). All patients were followed up for ≥ 3 years, during which most patients (86.8%) presented fewer than 10 tumors, although some demonstrated more than 10 tumors, and one patient developed 25 tumors. The number of tumors did not correlate with patient phototypes. ª 2015 The International Society of Dermatology

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However, it was associated with the use of calcineurin inhibitors (P < 0.001) and cytotoxic agents (P = 0.015). Most NMSC lesions (67.6%) developed on areas of skin that had been exposed to sunlight, such as the face, forearms, hands, legs, and knees, whereas 30.3% of lesions occurred on photoprotected regions, such as the trunk, arms, shoulders, and thighs. A histological analysis of tumor types showed a higher incidence of SCC on the cephalic segment (63.3%) and lower trunk (9.4%) compared with BCC (P = 0.013) and lesions of Bowen’s disease (P = 0.001), which showed no predominance on the cephalic segment (Table 2). Of the NMSC developed by RTRs, 70.6% were SCCs and 29.4% were BCCs. Occurrences of SCC were further divided into invasive, in situ, and Bowen’s disease types. Thus, patients showed varied combinations of NMSC. Whereas some patients showed only one type of tumor, others developed more than one type (Fig.1). No statistical correlation emerged between histological tumor type and patient phototype or type of immunosuppression. Discussion Squamous cell carcinoma is the most common type of NMSC in RTRs, followed by BCC. Among transplant recipients, occurrences of SCC outnumber those of BCCs by a ratio of 3 : 1; in the general population, this ratio is inverted. Whereas the incidence of BCC increases linearly over the period of immunosuppression, that of SCC does so exponentially.5–7 Some patients develop multiple SCCs or SCCs with invasive behavior.8 Wisgerhof et al.9 demonstrated a high risk for the development of a subsequent NMSC in RTRs after a first diagnosis of NMSC, with a substantially high risk for SCC. A retrospective study of 1736 RTRs reported a recurrence rate from initial diagnosis of NMSC of 41.0%, with a metastatic disease rate of 15.4% and mortality of 25.6%.10

Table 2 Sites of tumors in renal transplant patients diagnosed with non-melanoma skin cancer (n = 68) Tumor type, n (%) Site

Invasive SCC

SCC in situ

BCC

Total

Cephalic Trunk Limbs Anogenital Not reported Total

88 13 35 0 3 139

37 33 32 1 0 103

49 17 31 0 4 101

174 63 98 1 7 343

(63.3%) (9.4%) (25.2%) (2.2%)

(35.9%) (32.0%) (31.1%) (1.0%)

(48.5%) (16.8%) (30.7%) (4.0%)

SCC, squamous cell carcinoma; BCC, basal cell carcinoma. ª 2015 The International Society of Dermatology

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Figure 1 Types of tumor in renal transplant patients diagnosed with non-melanoma skin cancer (n = 68). SCC, squamous cell carcinoma; BCC, basal cell carcinoma

Tumors in NMSC have been shown to be more aggressive in recipients of solid organ transplants; one of the factors responsible for this aggressiveness may be the presence of angiogenic factors in the tumor that stimulate its growth.11 Other rare skin tumors also occur at an increased incidence in the solid organ transplant population, such as Merkel cell tumor, angiosarcoma, cutaneous lymphoma, Kaposi’s sarcoma, and sebaceous carcinoma.12 Of all the extrinsic factors related to the increased incidence of NMSC in RTRs, the most important are exposure to ultraviolet (UV) radiation, the use of immunosuppressive drugs, and HPV infection. In recent years, several papers have illustrated an increased incidence of skin cancer in RTRs, which may be explained by the increased survival of these patients coupled with the chronic use of immunosuppressive drugs and exposure to various carcinogens, such as UV radiation and HPV.1,2,6 Brazil is the leading country for renal transplantation in Latin America: in 2012 the number of kidney transplants performed in Brazil hit 5385 according to the Brazilian Association for Organ Transplantation.13 The present institution is one of the biggest Brazilian kidney transplant centers and performs three transplants per day. It is located in the city of S~ ao Paulo in a tropical region (23°320 51″ S). A total of 68 renal transplant patients with diagnoses of NMSC were followed up. During the period of the study, about 900 RTRs attended the dermatology department at the study institution for consultation. Thus, these 68 NMSC patients represent about 7.6% of patients attending for a first dermatological consultation. The Brazilian Health Ministry estimates that about 2.2% of dermatological consultations can be attributed to occurrences of NMSC in the general population.14 International Journal of Dermatology 2015, 54, e383–e388

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Male patients are usually reported to have a higher risk for the development of NMSC.2,5,15 This is supported by observations in our population, in which 73.5% of patients were male, resulting in a male:female ratio of 2.77 : 1. This ratio may be attributable to several factors: men are submitted to renal transplantation more frequently; historically, men have greater exposure to UV radiation, and men are less likely to adhere to photoprotection guidelines. The average age at diagnosis of the first NMSC was 51 years, which is slightly higher than the mean ages of 41 years reported by Ramsay et al.5 and 45 years reported by Fuente et al.6 However, cutaneous carcinomas appear earlier in RTRs than they do in the immunocompetent population. The mean time between kidney transplant and the appearance of the first NMSC was nine years. This was longer than the periods of 4.7 years reported by Ramsay et al.5 and 3.3 years reported by Fuente et al.6 These increases in latency time and patient age may relate to the time of the first dermatological visit and perhaps to the prevalence of a high skin phototype in this population. In line with the difficulties inherent in retrospective research, most of our records did not indicate the time at which the first lesion appeared, and thus we decided to define latency time as the period between the date of transplantation and histopathological examination of the NMSC. The occurrence of NMSC was observed during maintenance immunosuppressive drug therapy, as reported in the literature.5,6 Incidences of NMSC occurred primarily in patients of skin types II and III (70.6% and 16.2%, respectively). It is interesting to observe the incidence of NMSC even among patients of skin type IV (8.8%), because in the general population, NMSC occurs more frequently in patients with skin types I and II. The high frequency of NMSC in RTRs with higher skin phototypes compared with that in immunocompetent individuals demonstrates the role of immunosuppression in the pathogenesis of skin tumors, coupled with the latitude of the region in which the study was conducted. Most of the renal transplant patients in the present study had received an organ from a living donor (67.6%). Renal transplant recipients who receive an organ from a living donor have a higher degree of compatibility than those who receive an organ from a deceased donor. Thus, the latter category of RTR is submitted to a stronger immunosuppression regimen. In this center, the frequency of patients submitted to transplantation of a living donor kidney is higher than in other countries. Rates of living donor transplantation range from 15% to 30%.5,8,9 Thus it might be assumed that RTRs who receive a kidney from a deceased donor will present International Journal of Dermatology 2015, 54, e383–e388

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a higher incidence of NMSC. However, in the present study, the degree of immunosuppression did not seem to influence the incidence of NMSC. The oncogenic potential of HPV to raise the risk for SCC has been consolidated in the literature. The incidence of HPV in RTRs is much higher than in the general population as a result of this population’s chronic immunosuppression, which increases the risk for developing SCC.16–18 This study found that among 68 renal transplant patients with NMSC, 33 (48.5%) had a history of viral warts. Of these 33 patients, 29 (87.9%) showed tumors of epidermoid lineage, which highlights the proximity of the relationship between viral warts and SCC. However, statistical analysis also indicated a significant relationship between the use of azathioprine and the presence of viral warts, which increases the potential of this immunosuppressive drug to induce skin cancer. We found a total of 343 NMSC lesions which occurred at an average of five tumors per patient, demonstrating the importance of regular follow-up. The most common tumors represented SCC, which echoes findings reported in the literature of evaluations of populations with similar characteristics (phototypes I–IV living in areas with high incidences of UV radiation).2,5 In combination, SCC in situ (considered to be equivalent to tumors of Bowen’s disease in the present study) and invasive SCC accounted for 70.6% of NMSC tumors in the present series, whereas BCC accounted for 29.4%. This gives an SCC:BCC ratio of 2.4 : 1, which is consistent with ratios described in the literature.3,19 Thus, we observed an increased rate of NMSC in RTRs and a reversal of the SCC:BCC index relative to data reported in the literature for immunocompetent individuals.3,19,20 Various combinations of NMSC were found in our patients, among whom 26.4% had a single tumor and 73.6% had more than one tumor. Follow-up in the latter patients showed the rapid development of multiple tumors that did not relate to phototype. However, when data for patients using each of the two main groups of immunosuppressive drugs were analyzed separately, both calcineurin inhibitors and cytotoxic agents were found to be related to tumor multiplicity. As for the site most affected by skin tumors, our findings were similar to those reported in the literature2,5 in that tumors demonstrated a clear preference for sunexposed areas (67.6%). The cephalic segment was the main site of occurrence of both SCC and BCC and accounted for 174 (50.7%) of the 343 tumors found. Of tumors that occurred in photoprotected areas, the majority were found on the trunk (18.4%). The distribution of tumors on the body was similar to that observed among immunocompetent individuals (head, limbs, and trunk, in descending order). ª 2015 The International Society of Dermatology

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Another important factor in the development of NMSC is post-transplant immunosuppressive therapy. All routine immunosuppressive regimens cause nonspecific immunosuppression and thereby increase the risk for infections and malignant lesions.21 Immunosuppressive drugs may accelerate the development of NMSC by two mechanisms. The first reflects the direct carcinogenic action of these drugs, whereas the second refers to the fact that chronic immunosuppression weakens immunosurveillance and the eradication of precancerous lesions.4 Several prospective studies have confirmed a direct carcinogenic effect of calcineurin inhibitors.4,22,23 In this study, the separate analysis of immunosuppressive agents showed a higher and statistically significant incidence of NMSC in patients treated with either calcineurin inhibitors or immunosuppressive cytotoxics. However, most patients in the study used both drugs, and thus it was difficult to separately analyze the real influence of each class of immunosuppressive on the number of tumors. Currently, some studies have demonstrated real benefits to be derived by exchanging calcineurin inhibitors for sirolimus, an immunosuppressive drug of the mTOR inhibitor class, especially in RTRs who already have at least one SCC lesion.24–30 Sirolimus derives its antitumor effects from the inhibition of proliferation of cancer cells, suppression of angiogenesis, and promotion of apoptosis of cancer cells.25 Type of immunosuppression also demonstrated a significant relationship with the time from renal transplantation to the appearance of the first NMSC. This period was shorter in patients using tacrolimus and mycophenolate sodium. Cyclosporine A, one of the most commonly used calcineurin inhibitors in this study, can increase the production of growth factors during tumor progression.4 By contrast, mycophenolate mofetil has antiproliferative effects, which, in theory, lead to the slower development of skin tumors and other solid tumors.31 The present study is limited by its method of retrospective analysis. This did not allow for an analysis of pretransplant skin cancer because screening for cutaneous tumors prior to transplantation is not routine. In conclusion, NMSC presented with great potential for morbidity among RTRs. The incidence of NMSC is higher in renal transplant patients than in the immunocompetent population, probably as a result of associated risk factors such as the use of immunosuppressive drugs, exposure to sunlight, viral infection, individual genetic profiles, low phototype, and advanced age. Immunosuppressive therapy is a major determinant of the early onset of NMSC tumors, particularly with reference to calcineurin inhibitors and cytotoxic drugs. Further studies comparing the outcomes of the use of various immunosuppressive drugs are required and will make ª 2015 The International Society of Dermatology

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important contributions to efforts to determine which drugs are most suitable for providing adequate immunosuppression after transplantation and increasing the latency of onset of skin tumors in kidney transplantation. Acknowledgments We thank FAPESP (Fundacß~ ao de Amparo  a Pesquisa do Estado de S~ ao Paulo) that provided a scholarship to Marina Z. Hayashida. References 1 Moloney FJ, Comber H, O’Lorcain P, et al. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 2006; 154: 498–504. 2 Falsarella PM, Alves-Filho G, Mazzali M. Skin malignancies in renal transplant recipients: a Brazilian center registry. Transplant Proc 2008; 40: 767–768. 3 Athar M, Walsh SB, Kopelovich L, et al. Pathogenesis of non-melanoma skin cancers in organ transplant recipients. Arch Biochem Biophys 2011; 508: 159–163. 4 Fekecs T, K ad ar Z, Batty ani Z, et al. Incidence of nonmelanoma skin cancer after human organ transplantation: single-center experience in Hungary. Transplant Proc 2010; 42: 2333–2335. 5 Ramsay HM, Fryer AA, Hawley CM, et al. Nonmelanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol 2002; 147: 950– 956. 6 Fuente MJ, Sabat M, Roca J, et al. A prospective study of the incidence of skin cancer and its risk factors in a Spanish Mediterranean population of kidney transplant recipients. Br J Dermatol 2003; 149: 1221–1226. 7 Karczewski M, Stronka M, Karczewski J, et al. Skin cancer following kidney transplantation: a single-center experience. Transplant Proc 2011; 43: 3760–3761. 8 Mackenzie CA, Wells JE, Lynn KL, et al. First and subsequent non-melanoma skin cancers: incidence and predictors in a population of New Zealand renal transplant recipients. Nephrol Dial Transplant 2010; 25: 300–306. 9 Wisgerhof HC, Edelbroek JRJ, de Fijter JW, et al. Subsequent squamous and basal cell carcinomas in kidney transplant recipients after the first skin cancer: cumulative incidence and risk factors. Transplantation 2010; 89: 1231–1238. 10 Zavos G, Karidis PN, Tsourouflis G, et al. Nonmelanoma skin cancer after renal transplantation: a single-center experience in 1736 transplantations. Int J Dermatol 2011; 50: 1496–1500. 11 Mackenzie KA, Miller AP, Hock BD, et al. Angiogenesis and host immune response contribute to the aggressive character of non-melanoma skin cancers in renal transplant recipients. Histopathology 2011; 58: 875–885.

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12 Ho WL, Murphy GM. Update on the pathogenesis of post-transplant skin cancer in renal transplant recipients. Br J Dermatol 2008; 158: 217–224. 13 Brazilian Association for Organ Transplantation. Brazilian Records of Transplants. S~ ao Paulo, SP: Brazilian Association for Organ Transplantation, 2012. .http://www.abto.org.br/. [Accessed March 30, 2013.] 14 Ministerio da Sa ude. Secretaria de Atencß~ ao  a Sa ude. Instituto Nacional de C^ ancer. Coordenacß~ ao de Prevencß~ ao e Vigil^ancia de C^ ancer. Estimativas 2010: Incid^encia de C^ancer no Brasil. Rio de Janeiro: INCA, 2009. .http:// www1.inca.gov.br/estimativa/2010/index.asp? link=conteudo_view.asp&ID=5 [Accessed November 4, 2013.] 15 Moosa MR, Gralla J. Skin cancer in renal allograft recipients – experience in different ethnic groups residing in the same geographical region. Clin Transplant 2005; 19: 735–741. 16 Harwood CA, Surentheran T, McGregor JM, et al. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 2000; 61: 289–297. 17 H€ opfl R, Bens G, Wieland U, et al. Human papillomavirus DNA in non-melanoma skin cancers of a renal transplant recipient: detection of a new sequence related to epidermodysplasia verruciformis associated types. J Invest Dermatol 1997; 108: 53–56. 18 Tessmer CS, Magalh~ aes LV, Keitel E, et al. Conversion to sirolimus in renal transplant recipients with skin cancer. Transplantation 2006; 82: 1792–1793. 19 Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003; 348: 1681– 1691. 20 Ulrich C, Schmook T, Sachse M, Sterry W, Stockfleth E. Comparative epidemiology and pathogenic factors for nonmelanoma skin cancer in organ transplant patients. Dermatol Surg 2004; 30: 622–627. 21 Vegso Gy, T oth M, Hidvegi M, et al. Malignancies after renal transplantation during 33 years at a single center. Pathol Oncol Res 2007; 13: 63–69.

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22 Berardinelli L, Messa PG, Pozzoli E, et al. Malignancies in 2753 kidney recipients transplanted during a 39-year experience. Transplant Proc 2009; 41: 1231–1232. 23 Berg D, Otley C. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002; 47: 1–18; quiz 18–20. 24 Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin cancer prevention in kidney transplantation. N Engl J Med 2012; 367: 329–339. 25 Campbell SA, Walker R, Su Tai S, et al. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for non-melanoma skin cancer. Am J Transplant 2012; 12: 1146–1156. 26 Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant 2004; 18: 446–449. 27 Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol 2006; 17: 581–589. 28 Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009; 87: 233–242. 29 Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-ofrapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005; 80: 883–889. 30 Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposis sarcoma in renal transplant recipients. N Engl J Med 2005; 352: 1317–1323. 31 Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005; 56: 23–46.

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Epidemiology and clinical evolution of non-melanoma skin cancer in renal transplant recipients: a single-center experience in São Paulo, Brazil.

Non-melanoma skin cancer (NMSC) is very common among renal transplant recipients (RTRs) as a result of the immunosuppressed status of these patients a...
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