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Incidence and Risk Factors of Development of Lung Tumors After Liver Transplantation
Incidence and Risk Factors of Development of Lung Tumors After Liver Transplantation C. Jiménez, E. Marqués, A. Manrique, C. Loinaz, R. Gómez, J.C. Meneu, M. Abradelo, B. Pérez, A. Moreno, I. Garcı´a, and E. Moreno ABSTRACT Introduction. Lung tumors have been related to tobacco and alcohol. The incidence increases after orthotopic liver transplantation (OLT) especially when it is performed because of alcoholic cirrhosis. Patients and Methods. We analyzed the incidence and risk factors for de novo lung tumors among 701 patients who underwent OLT between April 1986 and July 2004, after exclusion of pediatric recipients and adults who died within 2 months after OLT. Results. The incidence of de novo lung tumors was 15 patients (2.1%), including 12 (4.3%) who underwent OLT for alcoholic cirrhosis and 3 (0.7%) for nonalcoholic diseases. There were 14 men and 1 woman of mean age at OLT of 50.8 ⫾ 9.6 years. Mean time from OLT to lung tumor was 83 ⫾ 43 months (range, 10 –184 months). Thirteen patients (86.6%) were heavy smokers before OLT and 8 (61.5%) continued after OLT; 12 patients (80%) were heavy drinkers before OLT. Ten patients were immunosuppressed with CyA and 5 with tacrolimus. Acute rejection episodes before tumor diagnosis occurred in 6 patients (40%). Two patients underwent thoracotomy, but only one was resected. The remaining 13 patients were unresectable because of locally advanced tumor or metastatic disease. Two unresectable patients received palliative chemotherapy. All patients died with a mean survival from tumor diagnosis, of 5.3 months (range, 3 days to 33 months). Conclusion. A significantly higher incidence of lung tumors was observed among patients who underwent OLT for alcoholic cirrhosis, usually diagnosed in advanced stages of poor prognosis and low survival.
S
MOKING is the etiology of more than 80% of lung tumors. Long-term alcohol intake can induce genetic alterations that potentiate those of tobacco smoke.1 In nontransplant patients it is difficult to separate the effects of alcohol and tobacco, because heavy drinkers tend to be heavy smokers and vice versa.2 Previous studies3– 8 have underlined a significantly higher incidence of upper aerodigestive and de novo lung tumors among patients who underwent orthotopic liver transplantation (OLT) for alcoholic cirrhosis, but we did not find any specific report about lung tumor incidence after OLT. Our intention was to analyze the incidence and outcome of recipients who developed de novo lung tumors after OLT. PATIENTS AND METHODS Between April 1986 and July 2004, we performed 1000 OLT among 883 patients. To analyze the true incidence of de novo lung tumors
in adults after OLT, we excluded 103 pediatric recipients and 79 adult recipients who died within 2 months post-OLT. Thus, this study included 701 recipients who underwent OLT: 276 (39.4%) for alcoholic cirrhosis and 425 (60.6%) for acute or chronic nonalcoholic diseases. The immunosuppressive regimens included CyA, prednisone, and azathioprine or mycophenolate mofetil (more recently), tacrolimus and prednisone. Acute rejection episodes were initially treated with three boluses of methylprednisolone (MP) and steroid recycling, and steroid-resistant rejection with From the Hospital Doce de Octubre, Servicio de Cirugı´a General, Aparato Digestivo, Trasplante de Organos Abdominales, Madrid, Spain. Address reprint requests to Carlos Jiménez Romero, Hospital Doce de Octubre, Servicio de Cirugı´a General, Aparato Digestivo, Trasplante de Organos Abdominales, 4a Planta, Ctra Andalucı´a, Km 5, 4, 28041 Madrid, Spain. E-mail: carlos.jimenez@ inforboe.es
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.10.041
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3970
Transplantation Proceedings, 37, 3970 –3972 (2005)
LUNG TUMORS AFTER LIVER TRANSPLANTATION antibodies, which have been rarely used in the last 8 years. Recipient follow-up after OLT ranged from 7 to 204 months. In this study we analyzed the incidence, histologic type, risk factors of alcohol and tobacco, immunosuppression and rejection rates, therapy, and survival. Data were expressed as mean values ⫾ SD. Differences between means and proportions were assessed by Student t test and chi-square test, respectively. P ⬍ .05 was considered significant.
RESULTS
The 97 de novo tumors observed among 701 recipients, represented an overall incidence of 13.8%: 62 tumors (22.4%) in the alcoholic group and 35 tumors (8.2%) in the nonalcoholic group (P ⬍ .001). Lung tumors were detected in 15 of these patients (2.1%), namely 14 men and 1 woman of mean age at OLT of 50.8 ⫾ 9.6 years (range, 32– 63 years). Mean time from OLT to lung tumor diagnosis was 83 ⫾ 43 months (range, 10 –184 months). The incidence of lung cancer in the alcoholic group was 4.3% (n ⫽ 12 patients), and 0.7% (n ⫽ 3) in the nonalcoholic group (P ⬍ .001). Histologic subtypes were: nine squamous cell carcinomas including two in heavy smokers of the nonalcoholic group, three large cell carcinomas, two adenocarcinomas, and one bronchoalveolar tumor in a nonsmoker patient of the nonalcoholic group. Thirteen patients (86.6%) were heavy smokers before OLT: 26 ⫾ 12 cigarettes/day (range, 15– 60) for 28 ⫾ 11 years (range, 10 – 45 years), and 8 patients (61.5%) continued after OLT with the same consumption. Additionally, 12 of these patients (80%) were heavy drinkers (⬎80 g/day of alcohol), and 3 (20%) were light drinkers (⬍50 g/day of alcohol). Eleven patients (73.3%) were both heavy smokers and drinkers. Mean alcohol consumption was 171 ⫾ 122 g/day (range, 20 –500 g/day) of mean duration 20.5 ⫾ 8.6 years (range, 6 – 40 years). Ten patients were immunosuppressed with CyA, and five with tacrolimus. Acute rejection episodes occurred before tumor diagnosis in six recipients (40%): four received three boluses of MP, and one received six boluses of MP and OKT3 therapy due to steroid-resistant rejection. Only two patients (13.3%) underwent thoracotomy: in one patient (7.1%) the tumor, a bronchoalveolar type, T3N0M0, stage IIB, was resected by lobectomy. In the other patient, a large cell carcinoma, T3N0M0, stage IIB, was unresectable. The remaining 13 patients (stage IIB: 1 patient; stage IIIB: 2 patients; stage IV: 10 patients) did not undergo exploratory thoracotomy due to chronic renal failure and sepsis (1 patient with stage IIB) or locally advanced tumor and/or metastatic disease (12 patients with stages IIIB, IV). Two of the unresectable patients (13.3%) received palliative chemotherapy. At present, all patients have died. The mean survival from tumor diagnosis was 5.3 months (range, 2 days to 33 months). DISCUSSION
The relative risk ratio of developing lung tumors in OLT patients was 3.7 times greater than the general population.6
3971
The reported incidence of de novo lung tumors has ranged from 0.2% to 2.2% among several reported series,3,8 –12 similar to our incidence of 2.1%. These tumors will increase upon long-term follow-up especially among patients who underwent OLT for alcoholic cirrhosis,3,8,10 a group who also has a longstanding history of cigarette smoking3,10 among at least 62.5%.3 In our series the incidence was higher: 86.6% were heavy smokers. The mean interval from OLT to tumor diagnosis in the literature was 48 months,3 but it was significantly larger (83 months) in our experience. All histological subtypes have been reported,3,9 although in our patients squamous cell carcinomas predominated, especially among smokers. Lung tumors are usually diagnosed in advanced stages. According to reported series3,9,10 and to our experience, lung tumor resection must be attempted in the early stages when the patient is in a general good condition, usually between 13.3% and 50% of patients. In unresectable patients palliative chemo- and/or radiotherapy is another option (0%– 66%), but more frequently (0%– 73%), at least in our experience, it is not possible to perform any treatment because of the poor condition of these patients.3,9,10 Prevention of de novo lung tumors by cessation of alcohol and tobacco consumption as soon as possible, reduction in immunosuppression for OLT patients due to alcoholic cirrhosis, and early tumor detection of by careful screening, may decrease the incidence and increase the resectability of these poor prognosis tumors.
REFERENCES 1. Castelli E, Hrelia P, Maffei F, et al: Indicators of genetic damage in alcoholics: reversibility after alcohol abstinence. Hepato-Gastroenterol 46:1664, 1999 2. Franceschi S, Talamini R, Barra S, et al: Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in Northern Italy. Cancer Res 50:6502, 1990 3. Jain AB, Yee LD, Nalesnik MA, et al: Comparative incidence of de novo nonlymphoid malignancies after liver transplantation under tacrolimus using surveillance epidemiologic and resultant data. Transplantation 66:1193, 1998 4. Duvoux C, Delacroix I, Richardet JP, et al: Increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis. Transplantation 67:418, 1999 5. Romano DR, Jiménez C, Rodriguez F, et al: Orthotopic liver transplantation in alcoholic cirrhosis. Transplant Proc 31:2491, 1999 6. Jain A, DiMartini A, Kashyap R, et al: Long-term follow-up after liver transplantation for alcoholic liver disease under tacrolimus. Transplantation 70:1335, 2000 7. Jiménez C, Marqués E, Loinaz C, et al: Upper aerodigestive tract and lung tumors after liver transplantation. Transplant Proc 35:1900, 2003 8. Benlloch S, Berenguer M, Prieto M, et al: De novo internal neoplasms after liver transplantation: increased risk and aggressive behavior in recent years? Am J Transplant 4:596, 2004 9. Jonas S, Rayes N, Neumann U, et al: De novo malignancies after liver transplantation using tacrolimus-based protocols or
3972 cyclosporine based quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin. Cancer 80:1141, 1997 10. Kelly DM, Emre S, Guy SR, et al: Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer 83:1237, 1998
JIMÉNEZ, MARQUÉS, MANRIQUE ET AL 11. Haagsma EB, Hagens VE, Schaapveld M, et al: Increased cancer risk after liver transplantation: a population-based study. J Hepatol 34:84, 2001 12. Xiol X, Guardiola J, Menendez S, et al: Risk factors for development of de novo neoplasia after liver transplantation. Liver Transplant 7:971, 2001
S
MOKING is the etiology of more than 80% of lung tumors. Long-term alcohol intake can induce genetic alterations that potentiate those of tobacco smoke.1 In nontransplant patients it is difficult to separate the effects of alcohol and tobacco, because heavy drinkers tend to be heavy smokers and vice versa.2 Previous studies3– 8 have underlined a significantly higher incidence of upper aerodigestive and de novo lung tumors among patients who underwent orthotopic liver transplantation (OLT) for alcoholic cirrhosis, but we did not find any specific report about lung tumor incidence after OLT. Our intention was to analyze the incidence and outcome of recipients who developed de novo lung tumors after OLT. PATIENTS AND METHODS Between April 1986 and July 2004, we performed 1000 OLT among 883 patients. To analyze the true incidence of de novo lung tumors
in adults after OLT, we excluded 103 pediatric recipients and 79 adult recipients who died within 2 months post-OLT. Thus, this study included 701 recipients who underwent OLT: 276 (39.4%) for alcoholic cirrhosis and 425 (60.6%) for acute or chronic nonalcoholic diseases. The immunosuppressive regimens included CyA, prednisone, and azathioprine or mycophenolate mofetil (more recently), tacrolimus and prednisone. Acute rejection episodes were initially treated with three boluses of methylprednisolone (MP) and steroid recycling, and steroid-resistant rejection with From the Hospital Doce de Octubre, Servicio de Cirugı´a General, Aparato Digestivo, Trasplante de Organos Abdominales, Madrid, Spain. Address reprint requests to Carlos Jiménez Romero, Hospital Doce de Octubre, Servicio de Cirugı´a General, Aparato Digestivo, Trasplante de Organos Abdominales, 4a Planta, Ctra Andalucı´a, Km 5, 4, 28041 Madrid, Spain. E-mail: carlos.jimenez@ inforboe.es
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.10.041
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3970
Transplantation Proceedings, 37, 3970 –3972 (2005)
LUNG TUMORS AFTER LIVER TRANSPLANTATION antibodies, which have been rarely used in the last 8 years. Recipient follow-up after OLT ranged from 7 to 204 months. In this study we analyzed the incidence, histologic type, risk factors of alcohol and tobacco, immunosuppression and rejection rates, therapy, and survival. Data were expressed as mean values ⫾ SD. Differences between means and proportions were assessed by Student t test and chi-square test, respectively. P ⬍ .05 was considered significant.
RESULTS
The 97 de novo tumors observed among 701 recipients, represented an overall incidence of 13.8%: 62 tumors (22.4%) in the alcoholic group and 35 tumors (8.2%) in the nonalcoholic group (P ⬍ .001). Lung tumors were detected in 15 of these patients (2.1%), namely 14 men and 1 woman of mean age at OLT of 50.8 ⫾ 9.6 years (range, 32– 63 years). Mean time from OLT to lung tumor diagnosis was 83 ⫾ 43 months (range, 10 –184 months). The incidence of lung cancer in the alcoholic group was 4.3% (n ⫽ 12 patients), and 0.7% (n ⫽ 3) in the nonalcoholic group (P ⬍ .001). Histologic subtypes were: nine squamous cell carcinomas including two in heavy smokers of the nonalcoholic group, three large cell carcinomas, two adenocarcinomas, and one bronchoalveolar tumor in a nonsmoker patient of the nonalcoholic group. Thirteen patients (86.6%) were heavy smokers before OLT: 26 ⫾ 12 cigarettes/day (range, 15– 60) for 28 ⫾ 11 years (range, 10 – 45 years), and 8 patients (61.5%) continued after OLT with the same consumption. Additionally, 12 of these patients (80%) were heavy drinkers (⬎80 g/day of alcohol), and 3 (20%) were light drinkers (⬍50 g/day of alcohol). Eleven patients (73.3%) were both heavy smokers and drinkers. Mean alcohol consumption was 171 ⫾ 122 g/day (range, 20 –500 g/day) of mean duration 20.5 ⫾ 8.6 years (range, 6 – 40 years). Ten patients were immunosuppressed with CyA, and five with tacrolimus. Acute rejection episodes occurred before tumor diagnosis in six recipients (40%): four received three boluses of MP, and one received six boluses of MP and OKT3 therapy due to steroid-resistant rejection. Only two patients (13.3%) underwent thoracotomy: in one patient (7.1%) the tumor, a bronchoalveolar type, T3N0M0, stage IIB, was resected by lobectomy. In the other patient, a large cell carcinoma, T3N0M0, stage IIB, was unresectable. The remaining 13 patients (stage IIB: 1 patient; stage IIIB: 2 patients; stage IV: 10 patients) did not undergo exploratory thoracotomy due to chronic renal failure and sepsis (1 patient with stage IIB) or locally advanced tumor and/or metastatic disease (12 patients with stages IIIB, IV). Two of the unresectable patients (13.3%) received palliative chemotherapy. At present, all patients have died. The mean survival from tumor diagnosis was 5.3 months (range, 2 days to 33 months). DISCUSSION
The relative risk ratio of developing lung tumors in OLT patients was 3.7 times greater than the general population.6
3971
The reported incidence of de novo lung tumors has ranged from 0.2% to 2.2% among several reported series,3,8 –12 similar to our incidence of 2.1%. These tumors will increase upon long-term follow-up especially among patients who underwent OLT for alcoholic cirrhosis,3,8,10 a group who also has a longstanding history of cigarette smoking3,10 among at least 62.5%.3 In our series the incidence was higher: 86.6% were heavy smokers. The mean interval from OLT to tumor diagnosis in the literature was 48 months,3 but it was significantly larger (83 months) in our experience. All histological subtypes have been reported,3,9 although in our patients squamous cell carcinomas predominated, especially among smokers. Lung tumors are usually diagnosed in advanced stages. According to reported series3,9,10 and to our experience, lung tumor resection must be attempted in the early stages when the patient is in a general good condition, usually between 13.3% and 50% of patients. In unresectable patients palliative chemo- and/or radiotherapy is another option (0%– 66%), but more frequently (0%– 73%), at least in our experience, it is not possible to perform any treatment because of the poor condition of these patients.3,9,10 Prevention of de novo lung tumors by cessation of alcohol and tobacco consumption as soon as possible, reduction in immunosuppression for OLT patients due to alcoholic cirrhosis, and early tumor detection of by careful screening, may decrease the incidence and increase the resectability of these poor prognosis tumors.
REFERENCES 1. Castelli E, Hrelia P, Maffei F, et al: Indicators of genetic damage in alcoholics: reversibility after alcohol abstinence. Hepato-Gastroenterol 46:1664, 1999 2. Franceschi S, Talamini R, Barra S, et al: Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in Northern Italy. Cancer Res 50:6502, 1990 3. Jain AB, Yee LD, Nalesnik MA, et al: Comparative incidence of de novo nonlymphoid malignancies after liver transplantation under tacrolimus using surveillance epidemiologic and resultant data. Transplantation 66:1193, 1998 4. Duvoux C, Delacroix I, Richardet JP, et al: Increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis. Transplantation 67:418, 1999 5. Romano DR, Jiménez C, Rodriguez F, et al: Orthotopic liver transplantation in alcoholic cirrhosis. Transplant Proc 31:2491, 1999 6. Jain A, DiMartini A, Kashyap R, et al: Long-term follow-up after liver transplantation for alcoholic liver disease under tacrolimus. Transplantation 70:1335, 2000 7. Jiménez C, Marqués E, Loinaz C, et al: Upper aerodigestive tract and lung tumors after liver transplantation. Transplant Proc 35:1900, 2003 8. Benlloch S, Berenguer M, Prieto M, et al: De novo internal neoplasms after liver transplantation: increased risk and aggressive behavior in recent years? Am J Transplant 4:596, 2004 9. Jonas S, Rayes N, Neumann U, et al: De novo malignancies after liver transplantation using tacrolimus-based protocols or
3972 cyclosporine based quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin. Cancer 80:1141, 1997 10. Kelly DM, Emre S, Guy SR, et al: Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer 83:1237, 1998
JIMÉNEZ, MARQUÉS, MANRIQUE ET AL 11. Haagsma EB, Hagens VE, Schaapveld M, et al: Increased cancer risk after liver transplantation: a population-based study. J Hepatol 34:84, 2001 12. Xiol X, Guardiola J, Menendez S, et al: Risk factors for development of de novo neoplasia after liver transplantation. Liver Transplant 7:971, 2001