- Email: [email protected]
Development of Lymphoproliferative Disease After Liver Transplantation
Neoplastic
Development of Lymphoproliferative Disease After Liver Transplantation E. Marqués, C. Jiménez, A. Manrique, G.H. Vallejo, M. Clemares, P. Ortega, and E. Moreno ABSTRACT Introduction. Malignancies are a serious long-term complication among liver transplant recipients, with an overall incidence of 4.5%–15%. Posttransplantation lymphoproliferative disease (PTLD) is one of the leading causes of late death. Its development is related to complex interactions between immunosuppressive drugs and environmental agents. The aim of this study was to analyze risk factors for PTLD and survival after orthotopic liver transplantation (OLT) compared with solid tumors. Patients and Methods. We undertook a retrospective review of the clinical histories of adult patients who underwent OLT between July 1986 and February 2001, and who had been followed until 2005. This study comprised 528 adult recipients who survived more than 2 months after OLT. We excluded pediatric, partial-organ, and multiorgan recipients. Results. No differences were observed concerning gender, viral etiology of hepatitis, calcineurin inhibitor regimen, or steroid maintenance period. Treated acute rejection episodes accounted for 53.3% of patients who developed PTLD compared with 47.3% in the control group (P ⫽ .787). Patients with solid tumors were older at the time of diagnosis than those with PTLD (57.5 ⫾ 8.13 years vs 48.8 ⫾ 13.9; P ⫽ .002). The overall mortality rate for PTLD was 55.5%, which did not differ significantly from solid tumors. Conclusions. PTLD develops in younger patients after OLT. Various immunosuppressive regimens do not seem to influence the incidence of PTLD or other solid tumors.
L
ONG-term results in liver recipients show that de novo malignancy is becoming a leading cause of late mortality. Susceptibility depends on complex interactions between pharmacological immunosuppression, smoking, alcohol consumption, viral infection, and genetic predisposition.1 The overall incidence ranges from 4.5%–15%.2,3 Posttransplantation lymphoproliferative disease (PTLD) comprises a heterogeneous spectrum of diseases affecting up to 4% of solid organ recipients, leading to death in 50% of cases.4
From the Servicio de Cirugá General, Ap. Digestivo y Trasplante de Órganos Abdominales, Hospital Doce de Octubre, Madrid, Spain. Address reprint requests to Elia Marqués Medina, Hospital Doce de Octubre, Servicio de Cirugía General, Ap. Digestivo y Trasplante de Órganos Abdominales, Ctra de Andalucía Km 5,4, 28041 Madrid, Spain. E-mail: [email protected]
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.09.008
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2988
Transplantation Proceedings, 40, 2988 –2989 (2008)
LYMPHOPROLIFERATIVE DISEASE
2989
Table 1. Immunosuppressive Regimens in Patients With PTLD and Solid Malignancies Immunosuppression Regimen
PTLD % Solid-organ tumors %
Acute Rejection Episodes
CyA
Tacrolimus
Yes
No
Months to Steroid Withdrawal
76.5% 17.6% P ⫽ .36 (2)
58.5% 35.4%
53.3% 41% P ⫽ .387 (2)
46.7% 69%
32.0 ⫾ 22.0 29.3 ⫾ 26.9 P ⫽ .704 (t test)
PATIENTS AND METHODS We retrospectively reviewed the clinical history of adult patients who underwent orthotopic liver transplantation (OLT) between July 1986 and February 2001, and were followed until 2005. We excluded patients receiving a multiorgan transplant. This study comprised 528 adult recipients who survived more than 2 months after OLT. The influence of various factors on the development of de novo tumors (DNT) was examined in a univariate Cox proportional hazards model. All predictors with a P ⬍ .2 were entered into a multivariate Cox hazards model. P ⬍ .05 was considered significant. Patients were treated with immunosuppression as previously described.5 Until 1992 immunosuppression was based on cyclosporine (CyA) protocols (cyclosporine, azathioprine, and steroids). From 1993 it was based on tacrolimus combined with steroids. More recently, some patients received mycophenolate mofetil. Treatment of acute rejection episodes consisted of up to 3 boluses (1 g) of methylprednisolone. Steroid-resistant rejection was treated with antibodies (OKT3 or antithymocyte globulins).
RESULTS
We analyzed a sample of 528 patients with a mean follow-up of 80.1 ⫾ 41.3 months. A total of 99 DNT developed in 87 patients. The overall frequency of DNT was 16.5%, or 13.8% if skin cancer was excluded. The mean time from OLT to tumor diagnosis was 59.3 months (range, 2–192). Cutaneous cancer was diagnosed in 22 patients who had 26 skin tumors. PTLD occurred in 18 patients. Thirty were squamous cell carcinomas and their locations were as follows: 13, lung; 7, oropharynx; 5, larynx; and 5, esophagus. The average time between transplantation and tumor diagnosis was lower in the PTLD group when compared with solid-organ malignancies (44.28 ⫾ 41.77 months vs 62.64 ⫾ 45.14; P ⫽ .07). No differences were found in relation to gender, viral etiology of the hepatitis, use of calcineurin inhibitors, or time of steroid use. Treated acute rejection episodes occurred in 53.3% of the patients who developed PTLD compared with 47.3% in the control group (P ⫽ .787) and 41% in the solid tumor group (P ⫽ .387) (Table 1). Patients with solid tumors were older at the time of diagnosis than those with PTLD (57.5 ⫾ 8.1 years vs 48.8 ⫾ 13.9; P ⫽ .002).
Treatment of PTLD consisted of reduction or withdrawal of immunosuppression. Chemotherapy was also used. In some cases surgery was performed either for diagnosis or treatment (2 patients with hilar involvement of the graft). The 10 patients with PTLD died because of the malignancy or due to complications of immunosuppression withdrawal. Thus, the overall mortality rate for PTLD was 55.5%, an average of 7.8 ⫾ 6.6 months after diagnosis (range, 1–19), with survival rates at 3, 5, and 10 years after OLT of 77.7%, 66.6%, and 38%, respectively. Results did not differ from the survival rates of the group that developed solid tumors (56 ⫾ 13 months; 95% confidence interval [CI], 31– 81 vs 69 ⫾ 7 months; 95% CI, 55– 83, respectively; P ⫽ .67). DISCUSSION
The 3.4% overall incidence of PTLD was similar to that previously reported from other groups. Nevertheless, we found no association between different immunosuppressive regimens, steroid administration for acute rejection, or treatment with antibodies for steroid-resistant rejection. Only younger age was associated with PTLD development. Although the behavior of PTLD was aggressive with an overall mortality rate ⬎50%, it did not differ significantly from the outcome of solid-organ tumors. REFERENCES 1. Reyes J, Tzakis A, Green M, et al: Posttransplant lymphoproliferative disorders occuring under primary FK 506 immunosuppression. Transplant Proc 23:3044, 1991 2. Kelly DM, Emre S, Guy SR, et al: Liver transplant recipients are not at increased risk for non lymphoid organ tumors. Cancer 83:1237, 1998 3. Xiol X, Guardiola J, Menéndez S, et al: Risk factors for development of de novo neoplasia after liver transplantation. Liver Transplant 7:971, 2001 4. Duvoux C, Pageaux GP, Vanlemmens C, et al: Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis or 480 patients. Transplantation 74:1103, 2002 5. Jiménez-Romero C, Manrique Municio A, Marqués Medina E, et al: Incidence of de novo nonmelanoma skin tumors after liver transplantation for alcoholic and nonalcoholic liver diseases. Transplant Proc 38:2505, 2006
Development of Lymphoproliferative Disease After Liver Transplantation E. Marqués, C. Jiménez, A. Manrique, G.H. Vallejo, M. Clemares, P. Ortega, and E. Moreno ABSTRACT Introduction. Malignancies are a serious long-term complication among liver transplant recipients, with an overall incidence of 4.5%–15%. Posttransplantation lymphoproliferative disease (PTLD) is one of the leading causes of late death. Its development is related to complex interactions between immunosuppressive drugs and environmental agents. The aim of this study was to analyze risk factors for PTLD and survival after orthotopic liver transplantation (OLT) compared with solid tumors. Patients and Methods. We undertook a retrospective review of the clinical histories of adult patients who underwent OLT between July 1986 and February 2001, and who had been followed until 2005. This study comprised 528 adult recipients who survived more than 2 months after OLT. We excluded pediatric, partial-organ, and multiorgan recipients. Results. No differences were observed concerning gender, viral etiology of hepatitis, calcineurin inhibitor regimen, or steroid maintenance period. Treated acute rejection episodes accounted for 53.3% of patients who developed PTLD compared with 47.3% in the control group (P ⫽ .787). Patients with solid tumors were older at the time of diagnosis than those with PTLD (57.5 ⫾ 8.13 years vs 48.8 ⫾ 13.9; P ⫽ .002). The overall mortality rate for PTLD was 55.5%, which did not differ significantly from solid tumors. Conclusions. PTLD develops in younger patients after OLT. Various immunosuppressive regimens do not seem to influence the incidence of PTLD or other solid tumors.
L
ONG-term results in liver recipients show that de novo malignancy is becoming a leading cause of late mortality. Susceptibility depends on complex interactions between pharmacological immunosuppression, smoking, alcohol consumption, viral infection, and genetic predisposition.1 The overall incidence ranges from 4.5%–15%.2,3 Posttransplantation lymphoproliferative disease (PTLD) comprises a heterogeneous spectrum of diseases affecting up to 4% of solid organ recipients, leading to death in 50% of cases.4
From the Servicio de Cirugá General, Ap. Digestivo y Trasplante de Órganos Abdominales, Hospital Doce de Octubre, Madrid, Spain. Address reprint requests to Elia Marqués Medina, Hospital Doce de Octubre, Servicio de Cirugía General, Ap. Digestivo y Trasplante de Órganos Abdominales, Ctra de Andalucía Km 5,4, 28041 Madrid, Spain. E-mail: [email protected]
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.09.008
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2988
Transplantation Proceedings, 40, 2988 –2989 (2008)
LYMPHOPROLIFERATIVE DISEASE
2989
Table 1. Immunosuppressive Regimens in Patients With PTLD and Solid Malignancies Immunosuppression Regimen
PTLD % Solid-organ tumors %
Acute Rejection Episodes
CyA
Tacrolimus
Yes
No
Months to Steroid Withdrawal
76.5% 17.6% P ⫽ .36 (2)
58.5% 35.4%
53.3% 41% P ⫽ .387 (2)
46.7% 69%
32.0 ⫾ 22.0 29.3 ⫾ 26.9 P ⫽ .704 (t test)
PATIENTS AND METHODS We retrospectively reviewed the clinical history of adult patients who underwent orthotopic liver transplantation (OLT) between July 1986 and February 2001, and were followed until 2005. We excluded patients receiving a multiorgan transplant. This study comprised 528 adult recipients who survived more than 2 months after OLT. The influence of various factors on the development of de novo tumors (DNT) was examined in a univariate Cox proportional hazards model. All predictors with a P ⬍ .2 were entered into a multivariate Cox hazards model. P ⬍ .05 was considered significant. Patients were treated with immunosuppression as previously described.5 Until 1992 immunosuppression was based on cyclosporine (CyA) protocols (cyclosporine, azathioprine, and steroids). From 1993 it was based on tacrolimus combined with steroids. More recently, some patients received mycophenolate mofetil. Treatment of acute rejection episodes consisted of up to 3 boluses (1 g) of methylprednisolone. Steroid-resistant rejection was treated with antibodies (OKT3 or antithymocyte globulins).
RESULTS
We analyzed a sample of 528 patients with a mean follow-up of 80.1 ⫾ 41.3 months. A total of 99 DNT developed in 87 patients. The overall frequency of DNT was 16.5%, or 13.8% if skin cancer was excluded. The mean time from OLT to tumor diagnosis was 59.3 months (range, 2–192). Cutaneous cancer was diagnosed in 22 patients who had 26 skin tumors. PTLD occurred in 18 patients. Thirty were squamous cell carcinomas and their locations were as follows: 13, lung; 7, oropharynx; 5, larynx; and 5, esophagus. The average time between transplantation and tumor diagnosis was lower in the PTLD group when compared with solid-organ malignancies (44.28 ⫾ 41.77 months vs 62.64 ⫾ 45.14; P ⫽ .07). No differences were found in relation to gender, viral etiology of the hepatitis, use of calcineurin inhibitors, or time of steroid use. Treated acute rejection episodes occurred in 53.3% of the patients who developed PTLD compared with 47.3% in the control group (P ⫽ .787) and 41% in the solid tumor group (P ⫽ .387) (Table 1). Patients with solid tumors were older at the time of diagnosis than those with PTLD (57.5 ⫾ 8.1 years vs 48.8 ⫾ 13.9; P ⫽ .002).
Treatment of PTLD consisted of reduction or withdrawal of immunosuppression. Chemotherapy was also used. In some cases surgery was performed either for diagnosis or treatment (2 patients with hilar involvement of the graft). The 10 patients with PTLD died because of the malignancy or due to complications of immunosuppression withdrawal. Thus, the overall mortality rate for PTLD was 55.5%, an average of 7.8 ⫾ 6.6 months after diagnosis (range, 1–19), with survival rates at 3, 5, and 10 years after OLT of 77.7%, 66.6%, and 38%, respectively. Results did not differ from the survival rates of the group that developed solid tumors (56 ⫾ 13 months; 95% confidence interval [CI], 31– 81 vs 69 ⫾ 7 months; 95% CI, 55– 83, respectively; P ⫽ .67). DISCUSSION
The 3.4% overall incidence of PTLD was similar to that previously reported from other groups. Nevertheless, we found no association between different immunosuppressive regimens, steroid administration for acute rejection, or treatment with antibodies for steroid-resistant rejection. Only younger age was associated with PTLD development. Although the behavior of PTLD was aggressive with an overall mortality rate ⬎50%, it did not differ significantly from the outcome of solid-organ tumors. REFERENCES 1. Reyes J, Tzakis A, Green M, et al: Posttransplant lymphoproliferative disorders occuring under primary FK 506 immunosuppression. Transplant Proc 23:3044, 1991 2. Kelly DM, Emre S, Guy SR, et al: Liver transplant recipients are not at increased risk for non lymphoid organ tumors. Cancer 83:1237, 1998 3. Xiol X, Guardiola J, Menéndez S, et al: Risk factors for development of de novo neoplasia after liver transplantation. Liver Transplant 7:971, 2001 4. Duvoux C, Pageaux GP, Vanlemmens C, et al: Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis or 480 patients. Transplantation 74:1103, 2002 5. Jiménez-Romero C, Manrique Municio A, Marqués Medina E, et al: Incidence of de novo nonmelanoma skin tumors after liver transplantation for alcoholic and nonalcoholic liver diseases. Transplant Proc 38:2505, 2006