- Email: [email protected]
De novo tumors after liver transplantation: a single-center experience
De Novo Tumors After Liver Transplantation: A Single-Center Experience H. Schmilovitz-Weiss, E. Mor, J. Sulkes, N. Bar-Nathan, E. Shaharabani, E. Melzer, R. Tur-Kaspa, and Z. Ben-Ari
O
RGAN transplant recipients are considered to be at increased risk of malignancy because of prolonged immunosuppression therapy.1 Reported incidence rates range between 3% and 15%, twice that of the general population.2,3 De novo nonlymphoid solid tumors are an important cause of late allograft morbidity and patient mortality.1–7 The aim of the present study was to characterize the incidence and types of malignancies associated with liver transplantation in a single center. The analysis assessed the risk factors, clinical characteristics, and outcome of de novo malignancies particularly tumor-specific mortality.
azathioprine, or tacrolimus (55.1%) in combination with prednisone. Dosages were adjusted to achieve target trough levels in individual patients: tacrolimus, 5 to 15 ng/mL; cyclosporine 100 to 250 ng/mL. Episodes of severe, acute, steroid-resistant rejection were treated with OKT3. Statistical analysis was performed using Student’s t-test, chi-square test, and Fischer’s exact test when appropriate. Survival analysis was performed using the KaplanMeier method.
RESULTS
PATIENTS AND METHODS
Eight of the 98 patients (8.1%, 5 men) display a de novo malignancy during follow-up (Table 1). None of the patients were smokers or consumed alcohol. Indications for transplantation in these patients were hepatitis C cirrhosis
From 1992 to 2002, 98 adult patients underwent 102 liver transplantations at the Rabin Medical Center in Israel. We retrospectively identified all patients who developed de novo malignancies. The records of these patients were reviewed for sex, age at time of diagnosis, indication for transplantation, immunosuppressive regimen, rejection episodes, OKT3 use, retransplantation, interval from transplantation to diagnosis of malignancy, tumor type, treatment of malignancy, follow up, and overall survival. In no case was the tumor transmitted from the donor. The immunosuppressive regimen consisted of cyclosporine (43.9%) with or without
From the Gastroenterology Unit (H.S.-W., E.M.), Department of Transplantation, (E.M., N.B.-N., E.S.), Epidemiology Unit (J.S.), and Liver Institute and Department of Medicine D (R.T.-K., Z.B.-N.), Rabin Medical Center, Beilinson and Golda Campuses, Petah Tiqva and Sackler Faculty of Medicine (H.S.-W.), Tel Aviv University, Tel Aviv, Israel. Address reprint requests to Dr Z. Ben Ari, Liver Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. E-mail: [email protected]
Table 1. Clinical Characteristics and Outcome of Patients With De Novo Tumors
Patient
Tumor Type
Liver Disease
Sex/Age (y)
Time (mo) From OLT to Malignancy
IMS
Post-OLT Follow Up (mo)
Post-tumor Follow Up (mo)
Management
1 2 3
Lung cancer Pancreatic cancer Ovarian cancer
HBV PSC PBC
F/40 M/26 F/50
24 10 31
CyA FK FK
33 15 53
9 5 22
4
Breast cancer
HCV
F/52
24
FK
62
38
5
Kaposi’s sarcoma, cutaneous PTLD
Cryptogenic cirrhosis Fulminant/ unknown PSC
M/67
13
FK
78
65
Chemotherapy No treatment Chemotherapy, TAH ⫹ BOP Lumpectomy ⫹ tamoxifen ⫹ radiotherapy IMS reduction
M/42
4
FK
72
68
IMS withdrawal
M/47
24
CyA
28
4
Chemotherapy
HCV
M/65
24
FK
29
5
Surgical excision
6 7 8
Kaposi’s sarcoma, visceral BCC scalp
Outcome
Dead Dead Alive Alive
Alive Alive Retransplantation Dead Alive
Abbreviations: IMS, immunosuppression; HBV, hepatitis B virus; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; TAH ⫹ BOP, transabdominal hysterectomy ⫹ bilateral oophorectomy; HCV, hepatitis C virus; PTLD, posttransplant lymphoproliferative disorder; BCC, basal cell carcinoma.
© 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 665– 666 (2003)
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00089-7 665
666
(n ⫽ 2), primary sclerosing cholangitis (n ⫽ 2), and single cases of hepatitis B cirrhosis, cryptogenic cirrhosis, primary biliary cirrhosis, and fulminant hepatitis of unknown etiology. The two patients with primary sclerosing cholangitis also displayed ulcerative colitis. Median follow up after allografting was 44 months (range, 15 to 78 months). Mean age at diagnosis of malignancy was 46.3 ⫾ 12.3 years, and mean interval from transplantation to diagnosis of malignancy was 31.2 ⫾ 11.3 months. Five patients had a malignancy of epithelial origin (one each in skin, lung, ovary, breast, and pancreas), two had Kaposi sarcoma, and one had a lymphoproliferative disorder. There was no significant association between tumor development and the indication for or age at liver transplantation. Two patients (25%) received cyclosporine and prednisone as primary immunosuppression; one also azathioprine, and the other six (75%) a tacrolimus-based regimen. None of the patients displayed a severe acute rejection episode that required OKT3. One patient underwent retransplantation. No significant association was noted between tumor development, type of immunosuppression, OKT3 use, or graft rejection. The 3-year survival rate for the eight patients with de novo malignancy was 50%, significantly lower than the survival rate of the 90 patients without this complication (85%, P ⫽ .01). Three patients (37.5%) with epithelial tumors died as a direct consequence of the malignancy. The remaining five patients are still alive (median, 38 months). DISCUSSION
The incidence of de novo malignancy after solid organ transplantation varies in different studies (3% to 15%),
SCHMILOVITZ-WEISS, MOR, SULKES ET AL
although it is usually higher than the rate observed in the general population.2,3 In our single-center series, the incidence of de novo malignancy was 8.1%. The management of these malignancies was similar to that in the nontransplant setting, but the immunosuppression therapy was either reduced in dosage or, in two patients, completely withdrawn. One of the latter patients required retransplantation due to chronic rejection. The risk of malignancy has been found to be increased among patients with high levels and long exposure to calcineurin inhibitors. In our small study, we failed to observe a correlation between tumor development and the type of immunosuppression, the occurrence of rejection episodes, or OKT3 use. Our study supports the high reported mortality associated with de novo malignancy,4 –7 with a 3-year survival rate of 50% in the liver recipients, which was significantly lower than the 85% in recipients without malignancy (P ⫽ .01). In conclusion, the rate of malignancy is higher among liver recipients than in the general population, and significantly affects patient survival rates. REFERENCES 1. Penn I: Transplant Sci 4:23, 1994 2. Jonas S, Rayes N, Neumann U, et al: Cancer 80:1141, 1997 3. Penn I: Transplant Proc 23:1101, 1991 4. Levy M, Backman I, Husberg B, et al: Transplant Proc 25:1397, 1993 5. Peyregne V, Ducerf C, Adham M, et al: Transplant Proc 30:1484, 1998 6. Sheiner PA, Magliocca JF, Bodian CA, et al: Transplantation 69:781, 2000 7. Fung JJ, Jain A, Kwak EJ, et al: Liver Transpl 7(suppl):S109, 2001
O
RGAN transplant recipients are considered to be at increased risk of malignancy because of prolonged immunosuppression therapy.1 Reported incidence rates range between 3% and 15%, twice that of the general population.2,3 De novo nonlymphoid solid tumors are an important cause of late allograft morbidity and patient mortality.1–7 The aim of the present study was to characterize the incidence and types of malignancies associated with liver transplantation in a single center. The analysis assessed the risk factors, clinical characteristics, and outcome of de novo malignancies particularly tumor-specific mortality.
azathioprine, or tacrolimus (55.1%) in combination with prednisone. Dosages were adjusted to achieve target trough levels in individual patients: tacrolimus, 5 to 15 ng/mL; cyclosporine 100 to 250 ng/mL. Episodes of severe, acute, steroid-resistant rejection were treated with OKT3. Statistical analysis was performed using Student’s t-test, chi-square test, and Fischer’s exact test when appropriate. Survival analysis was performed using the KaplanMeier method.
RESULTS
PATIENTS AND METHODS
Eight of the 98 patients (8.1%, 5 men) display a de novo malignancy during follow-up (Table 1). None of the patients were smokers or consumed alcohol. Indications for transplantation in these patients were hepatitis C cirrhosis
From 1992 to 2002, 98 adult patients underwent 102 liver transplantations at the Rabin Medical Center in Israel. We retrospectively identified all patients who developed de novo malignancies. The records of these patients were reviewed for sex, age at time of diagnosis, indication for transplantation, immunosuppressive regimen, rejection episodes, OKT3 use, retransplantation, interval from transplantation to diagnosis of malignancy, tumor type, treatment of malignancy, follow up, and overall survival. In no case was the tumor transmitted from the donor. The immunosuppressive regimen consisted of cyclosporine (43.9%) with or without
From the Gastroenterology Unit (H.S.-W., E.M.), Department of Transplantation, (E.M., N.B.-N., E.S.), Epidemiology Unit (J.S.), and Liver Institute and Department of Medicine D (R.T.-K., Z.B.-N.), Rabin Medical Center, Beilinson and Golda Campuses, Petah Tiqva and Sackler Faculty of Medicine (H.S.-W.), Tel Aviv University, Tel Aviv, Israel. Address reprint requests to Dr Z. Ben Ari, Liver Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. E-mail: [email protected]
Table 1. Clinical Characteristics and Outcome of Patients With De Novo Tumors
Patient
Tumor Type
Liver Disease
Sex/Age (y)
Time (mo) From OLT to Malignancy
IMS
Post-OLT Follow Up (mo)
Post-tumor Follow Up (mo)
Management
1 2 3
Lung cancer Pancreatic cancer Ovarian cancer
HBV PSC PBC
F/40 M/26 F/50
24 10 31
CyA FK FK
33 15 53
9 5 22
4
Breast cancer
HCV
F/52
24
FK
62
38
5
Kaposi’s sarcoma, cutaneous PTLD
Cryptogenic cirrhosis Fulminant/ unknown PSC
M/67
13
FK
78
65
Chemotherapy No treatment Chemotherapy, TAH ⫹ BOP Lumpectomy ⫹ tamoxifen ⫹ radiotherapy IMS reduction
M/42
4
FK
72
68
IMS withdrawal
M/47
24
CyA
28
4
Chemotherapy
HCV
M/65
24
FK
29
5
Surgical excision
6 7 8
Kaposi’s sarcoma, visceral BCC scalp
Outcome
Dead Dead Alive Alive
Alive Alive Retransplantation Dead Alive
Abbreviations: IMS, immunosuppression; HBV, hepatitis B virus; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; TAH ⫹ BOP, transabdominal hysterectomy ⫹ bilateral oophorectomy; HCV, hepatitis C virus; PTLD, posttransplant lymphoproliferative disorder; BCC, basal cell carcinoma.
© 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 665– 666 (2003)
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00089-7 665
666
(n ⫽ 2), primary sclerosing cholangitis (n ⫽ 2), and single cases of hepatitis B cirrhosis, cryptogenic cirrhosis, primary biliary cirrhosis, and fulminant hepatitis of unknown etiology. The two patients with primary sclerosing cholangitis also displayed ulcerative colitis. Median follow up after allografting was 44 months (range, 15 to 78 months). Mean age at diagnosis of malignancy was 46.3 ⫾ 12.3 years, and mean interval from transplantation to diagnosis of malignancy was 31.2 ⫾ 11.3 months. Five patients had a malignancy of epithelial origin (one each in skin, lung, ovary, breast, and pancreas), two had Kaposi sarcoma, and one had a lymphoproliferative disorder. There was no significant association between tumor development and the indication for or age at liver transplantation. Two patients (25%) received cyclosporine and prednisone as primary immunosuppression; one also azathioprine, and the other six (75%) a tacrolimus-based regimen. None of the patients displayed a severe acute rejection episode that required OKT3. One patient underwent retransplantation. No significant association was noted between tumor development, type of immunosuppression, OKT3 use, or graft rejection. The 3-year survival rate for the eight patients with de novo malignancy was 50%, significantly lower than the survival rate of the 90 patients without this complication (85%, P ⫽ .01). Three patients (37.5%) with epithelial tumors died as a direct consequence of the malignancy. The remaining five patients are still alive (median, 38 months). DISCUSSION
The incidence of de novo malignancy after solid organ transplantation varies in different studies (3% to 15%),
SCHMILOVITZ-WEISS, MOR, SULKES ET AL
although it is usually higher than the rate observed in the general population.2,3 In our single-center series, the incidence of de novo malignancy was 8.1%. The management of these malignancies was similar to that in the nontransplant setting, but the immunosuppression therapy was either reduced in dosage or, in two patients, completely withdrawn. One of the latter patients required retransplantation due to chronic rejection. The risk of malignancy has been found to be increased among patients with high levels and long exposure to calcineurin inhibitors. In our small study, we failed to observe a correlation between tumor development and the type of immunosuppression, the occurrence of rejection episodes, or OKT3 use. Our study supports the high reported mortality associated with de novo malignancy,4 –7 with a 3-year survival rate of 50% in the liver recipients, which was significantly lower than the 85% in recipients without malignancy (P ⫽ .01). In conclusion, the rate of malignancy is higher among liver recipients than in the general population, and significantly affects patient survival rates. REFERENCES 1. Penn I: Transplant Sci 4:23, 1994 2. Jonas S, Rayes N, Neumann U, et al: Cancer 80:1141, 1997 3. Penn I: Transplant Proc 23:1101, 1991 4. Levy M, Backman I, Husberg B, et al: Transplant Proc 25:1397, 1993 5. Peyregne V, Ducerf C, Adham M, et al: Transplant Proc 30:1484, 1998 6. Sheiner PA, Magliocca JF, Bodian CA, et al: Transplantation 69:781, 2000 7. Fung JJ, Jain A, Kwak EJ, et al: Liver Transpl 7(suppl):S109, 2001