Organ transplant recipients are at greater risk for de

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1 Risk Factors for Development of De Novo Neoplasia After Liver Transplantation Xavier Xiol, * Jordi Guardiola, Susana Menendez, * Carmen Lama, Juan Figueras, Joaquim Marcoval, Teresa Serrano, Jose M. Botargues, * Meritxell Mañer, * and Rosa Rota * Liver transplant recipients are at greater risk for de novo neoplasia, especially lymphoma and nonmelanoma skin cancer; however, risk factors for this complication have not been well studied. Clinical and pathological records of 137 consecutive liver transplant recipients who had survived for at least 1 year were reviewed to register de novo neoplasia. Ten variables were analyzed for their association with the development of de novo malignancies by means of a log-rank test and stepwise selection in a multivariate analysis using the Cox proportional hazard model. Thirty de novo neoplasias appeared in 22 of 137 transplant recipients between 12 and 104 months after orthotopic liver transplantation (OLT; median follow-up, 69 months): 14 patients had 21 skin cancers, 6 patients had solid-organ cancer, and 3 patients developed a lymphoproliferative disease. Probabilities of de novo neoplasia were 13% at 5 years post-olt and 26% at 8 years post-olt. The only associated risk factor for any neoplasia was age. Age and hepatocarcinoma were independent risk factors associated with skin cancer. That hepatocarcinoma in the explanted liver is an independent risk factor for skin cancer suggests there is individual susceptibility to both neoplasias. (Liver Transpl 2001;7: ) Organ transplant recipients are at greater risk for de novo neoplasia. This has been reported in renal, 1 bone marrow, 2 heart, 3 and liver 4-8 transplant recipients and is related to an increased number of nonmelanoma skin cancers 9 and lymphomas. 5,6 Although immunosuppression has a central role in the development of cancer, the risk for de novo tumor after orthotopic liver transplantation (OLT) has not been well studied. The aim of our study is to identify risk factors associated with de novo malignancies in liver transplant recipients. Patients and Methods Patients All recipients of a first liver transplant in a tertiary teaching hospital between January 1990 and January 1995 were studied. We selected those who had survived for at least 1 year and for whom the indication was other than re-olt. They were followed up as outpatients, with regular visits every 3 to 4 months until death or September 1998, when all patients still alive were visited by some of the investigators. Medical and pathological records of these transplant recipients were evaluated to register de novo neoplasias. Only histologically confirmed malignancies were included on the study. Table 1. Pre-OLT Characteristics of 137 Survivors 1 Year After OLT Age at OLT (yr) 48.9 (15-65) Male sex 89 (65) Diagnosis of liver disease Hepatic cirrhosis 105 (24 with hepatocarcinoma) Hepatitis C virus 41 Alcohol 32 Hepatitis C virus plus alcohol 12 Hepatitis B virus 8 Autoimmune 3 Other causes 7 Cholestatic disease 18 (1 with hepatocarcinoma) Primary biliary cirrhosis 12 Sclerosing cholangitis 3 Secondary biliary cirrhosis 3 Intrahepatic bile duct hypoplasia 1 Hepatic tumors 12 Cholangiocarcinoma 7 Fibrolamellar hepatocarcinoma 5 Fulminant hepatic failure 2 Malignancy before OLT No 100 Yes 37 Hepatocarcinoma 30 Cholangiocarcinoma 7 NOTE. Values expressed as mean (range) or number (percent). One hundred thirty-seven patients were studied. During the study period, they received 161 livers because of 24 re- OLTs. Patient characteristics are listed in Table 1. Indications for OLT were decompensated hepatic cirrhosis, 81 patients; From the Departments of *Gastroenterology, General Surgery, and Pathology and Dermatology Unit, Hospital de Bellvitge Princeps d Espanya, L Hospitalet de Llobregat; and the Gastroenterology Unit, Hospital de L Alt Penedès; Barcelona, Spain. Address reprint requests to Xavier Xiol, MD, Department of Gastroenterology, Hospital de Bellvitge Princeps d Espanya, Feixa Llarga s/n, L Hospitalet de Llobregat, Barcelona, Spain. Telephone: ; FAX: ; xxiol@csub.scs.es Copyright 2001 by the American Association for the Study of Liver Diseases /01/ $35.00/0 doi: /jlts Liver Transplantation, Vol 7, No 11 (November), 2001: pp

2 972 Xiol et al hepatic tumors, 37 patients (30 patients, hepatocarcinoma, 25 of them associated with cirrhosis; 7 patients, cholangiocarcinoma); cholestatic diseases, 17 patients; and fulminant liver failure, 2 patients. Twenty-three patients died during followup. Median follow-up of the remaining patients was 69 months (range, 43 to 104 months). Immunosuppression All patients were treated with a four-drug immunosuppression schedule, as previously reported 10 : thymoglobulin, 2 mg/kg of body weight for 5 days; methylprednisolone, 1 g before implant revascularization, and prednisone, 0.5 mg/kg for 2 weeks, gradually reduced to 0.15 mg/kg and withdrawn after 3 to 6 months; cyclosporine, to maintain levels of 200 ng/ml during the first 3 months post-olt and 100 ng/ml thereafter; and azathioprine, 50 mg/d. Rejection episodes were treated with methylprednisolone, 1 g, intravenously for 3 days. Steroid-resistant rejection was treated with OKT3 monoclonal antibody. Statistical Analysis Kaplan-Meier survival analysis was performed to estimate the risk for malignant neoplasm with time after OLT. The date of onset of a de novo neoplasia was the date on which the neoplasm was confirmed pathologically. Eleven variables (nine variables, pretransplantation; two variables, posttransplantation) were analyzed for their association with the development of de novo malignant neoplasia (Table 2). The logrank test was used in univariate analysis. Those variables that showed a significant association (P.05) with the development of malignancy were included as candidate variables for stepwise selection in a multivariate analysis using the Cox Table 2. Variables With and Without Prognostic Significance in Univariate Analysis Variable No. of Patients Any Cancer 8-Yr Probability % (95% CI) P Skin Cancer 8-Yr Probability % (95% CI) P Age (yr) ( ) ( ) ( ) 30.4 ( ) Sex Men ( ) ( ).57 Women (5-35.8) 13.3 ( ) Hepatitis B Virus Yes 8 25 (0-55) (0-24.2).667 No ( ) 16.3 ( ) Hepatitis C virus Yes ( ) ( ).101 No (7.6-34) 12.4 (8-23.9) Hepatocarcinoma Yes ( ) ( ).001 No ( ) 7.9 ( ) Cholangiocarcinoma Yes 7 20 (15-55) No ( ) 16.7 ( ) Alcoholism Yes (0-26.5) (0-19.4).036 No ( ) 20.6 ( ) Cirrhosis Yes ( ) ( ).710 No (7-43.5) 11.8 (0-24.7) Cholestatic disease Yes ( ) ( ).893 No ( ) 16.9 (0-26.6) Rejection Yes ( ) ( ).819 No ( ) 18 (6.1-30) Re-OLT Yes ( ) (0-27.3).987 No ( ) 17.1 ( ) Abbreviation: CI, confidence interval.

3 De Novo Neoplasia After Liver Transplantation 973 proportional hazards model. Analyses were performed using the SPSS statistical package (University of California Press, Berkeley, CA). Results Thirty de novo neoplasias appeared in 22 of the 137 transplant recipients between 12 and 104 months after OLT (Table 3). One patient had both skin and lung cancer, and 6 patients had more than one malignant skin lesion. Cumulative risks for any de novo neoplasia and for skin cancer were 13% and 8% at 5 years after OLT and 26% and 16.6% at 8 years after OLT, respectively (Fig. 1). The incidence of skin cancer in our series is 20 cases/1,000 person-years. In univariate analysis, age, presence of hepatocarcinoma in the explanted liver, and history of alcoholism were associated with risk for the development of any de novo neoplasia and skin cancer (Table 2). However, in multivariate analysis, age was the only independent predictor for any cancer (Table 4). Independent risk factors for skin cancer were age and hepatocarcinoma in the explanted liver (Table 4). We did not identify risk factors for solid-organ cancer or lymphoproliferative disorder. Discussion Our results confirm the high incidence of neoplasia in liver transplant recipients after several years of followup, 4-8 particularly skin cancer. 9 Nonmelanoma skin cancer occurs most commonly after excessive sun exposure in susceptible individuals, 11 and long-term immunosuppression increases individual susceptibility. 9 Exposure to the sun is intense in Spain, and a high incidence of skin cancer is reported in Spanish heart Table 3. De Novo Neoplasms Diagnosed During Follow-Up Neoplasm No. of Patients Skin cancer 14 Basal cell carcinoma 16 Squamous carcinoma 5 Solid-organ cancer 6 Lung carcinoma 3 Colon carcinoma 2 Carcinoma of the cervix 1 Lymphoproliferative disease 3 Non-Hodgkin s lymphoma 2 Acute leukemia 1 Total neoplasias 30 Figure 1. Cumulative incidence of de novo neoplasia and skin cancer after OLT. The two curves correspond to the same patients. transplant recipients. 12 Our cumulative incidence at 8 years post-olt (17%) is less than that reported in renal or heart transplant recipients in Australia ( 30%), but greater than that described in Dutch renal or liver transplant recipients (7% to 13%), 8,13,14 which may reflect differences in latitude and sun exposure of these countries and perhaps differences in immunosuppressive schedules. However, the posttransplantation tumor rate has been reported to be similar for three- or fourdrug regimens, 15,16 suggesting that geographic factors, rather than the immunosuppressive schedule, are the main determinants of our high rate of de novo skin cancer. Squamous carcinoma is the most frequent skin cancer reported in transplant recipients. 11 However, in our series, we found a ratio of four basal cell carcinomas to every squamous carcinoma, the same distribution observed in the general population, 17 perhaps because our follow-up is short. This short follow-up and the limited number of patients are the main limitations of our study. Although the incidence of skin neoplasias can be underestimated because the study was retrospective and patients can be treated outside our hospital, liver transplant recipients are exhaustively controlled in the hospital. The age of the transplant recipient was the only factor associated with any kind of de novo neoplasia and one of the factors associated with nonmelanoma skin cancer. This result was expected because the incidence of all neoplasias, including skin cancer, increases with age. 17 In the previously mentioned Dutch study, 8 greater age was the only risk factor associated with post- OLT cancer. In that study, most of the patients who developed a neoplasia were aged older than 40 years. In our series, the best discriminant age cutoff value for the

4 974 Xiol et al Table 4. Independent Prognostic Variables Associated With Any Neoplasm or Skin Cancer in the Cox Proportional Hazards Model Procedure Variable SE Wald Chi-Squared P Hazard Ratio 95% CI Any Neoplasm Age 51 yr Skin Cancer Age 51 yr Hepatocarcinoma Abbreviation: CI, confidence interval. risk for cancer was 51 years. Hepatocarcinoma in the explanted liver was found to be a risk factor for skin cancer. This unexpected association has not been previously reported. 18 The high survival rate found by our group in patients with hepatocarcinoma treated with OLT 19 could explain why we were able to detect this association. The association of neoplasia before transplantation and skin cancer has not been previously reported, probably because renal neoplasias are not an indication for renal transplantation. Several hypotheses can explain the association of pretransplantation and posttransplantation neoplasias in the same patient. First, both tumors may share common risk factors; second, the later neoplasm may be secondary to treatment of the former; and last, the patient may be intrinsically susceptible to both neoplasias. In the case of hepatocarcinoma and skin cancer, common risk factors can be excluded because none of the conditions related with hepatocarcinoma, such as cirrhosis, hepatitis B or C virus infection, alcohol, hemochromatosis, or aflatoxin exposure, 20 are associated with nonmelanoma skin neoplasm. In turn, UV exposure, fair skin type, male sex, older age, and tendency to sunburn easily 9,17,21 predispose to skin cancer, but not hepatocarcinoma. Immunosuppression contributes to the development of skin cancer. 11,17 Thus, this neoplasia could be considered a secondary effect of the treatment of hepatocarcinoma with OLT. However, the incidence of skin cancer is greater in patients on long-term immunosuppression therapy regardless of its indication. A variety of arguments support the hypothesis of individual susceptibility to both neoplasias. Patients with a history of nonmelanoma skin cancer have a greater risk for developing a second cancer ; therefore, it is conceivable that the opposite is also true. Retinoids have been successful in the prevention of both skin cancer 11 and second primary hepatocarcinoma. 26 In addition, p53 mutations and glutathione S-transferase (GST) genes have been implicated in the genesis of both tumors We hypothesize that hepatocarcinoma appears in cirrhotic patients with some genetic predisposition. This predisposition, along with immunosuppression and sun exposure, favors skin cancer after OLT. The underlying genetic disorder may be located at p53 or GST genes, although new studies focused on this field are needed to confirm this hypothesis. References 1. Hiesse C, Rieu P, Kriaa F, Larue JR, Goupy C, Neyrat N, et al. Malignancy after renal transplantation: Analysis of incidence and risk factors in 1700 patients followed during a 25-year period. Transplant Proc 1997;29: Kolb HJ, Socié G, Duell T, Van Lint MT, Tichelli A, Apperley JF, et al. Malignant neoplasms in long-term survivors of bone marrow transplantation. Ann Intern Med 1999;131: Goldstein DJ, Williams DL, Oz MC, Weinberg AD, Rose EA, Michler RE. De novo solid malignancies after cardiac transplantation. Ann Thorac Surg 1995;60: Penn I. Posttransplantation de novo tumors in liver allograft recipients. Liver Transpl Surg 1996;2: Tan-Shalaby J, Tempero M. Malignancies after liver transplantation: A comparative review. Semin Liver Dis 1995;15: Kelly DM, Emre S, Guy SR, Miller CM, Schwartz ME, Sheiner PA. Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer 1998;83: Frezza EE, Fung JJ, Van Thiel DH. Non-lymphoid cancer after liver transplantation. Hepatogastroenterology 1997;44: Haagsma EB, Hagens VE, Schaapveld M, van den Berg AP, de Vries EGE, Klompmaker IJ, et al. Increased cancer risk after liver transplantation: A population study. J Hepatol 2001;34: Otley CC, Pittelkow MR. Skin cancer in liver transplant patients. Liver Transpl 2000;6: Guardiola J, Xiol X, Sallie R, Nolla JM, Roig Escofet D, Jaurrieta E, et al. Influence of the vitamin D receptor gene polymorphism on bone loss in man after liver transplantation. Ann Intern Med 1999;131: DiGiovana JJ. Posttransplantation skin cancer: Scope of the

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