RAPID COMMUNICATION Preexisting malignancy is considered a relative contrain- dication to orthotopic liver transplantation (OLT) be-

Transcription

1 RAPID COMMUNICATION Successful Outcome of Orthotopic Liver Transplantation in s With Preexisting Malignant States Sanjiv Saigal, Suzanne Norris, Parthi Srinivasan, Paolo Muiesan, Mohamed Rela, Nigel Heaton, and John O Grady Preexisting malignancy is considered a relative contraindication to orthotopic liver transplantation (OLT) because of the risk of tumor recurrence. The purpose of this study is to assess the outcome of OLT in patients with a preexistent malignant state. Of 1,097 OLTs performed between 1989 and 1999 at King s College Hospital (London, UK), 18 patients had a pretransplantation malignant state, including 6 cases of myeloproliferative disorder (MPD) presenting as Budd-Chiari syndrome. Those patients with solid-organ malignancies had their tumor detected at an early stage and underwent curative treatment before or during OLT. s were followed up for a median of 71 months (range, 1 to 119 months) post-olt, and the rates of rejection and malignancy were compared with those of transplant recipients without preexisting malignancy during the same period. One patient had a recurrence of his primary malignancy (non-hodgkin s lymphoma) after 27 months, whereas another patient developed a de novo posttransplant lymphoproliferative disorder after 57 months. One patient with MPD developed acute leukemia 72 months after OLT. In comparison, of 1,079 OLTs performed in patients without preexisting malignancy during the same period, there were 34 cases of de novo malignancies. The rate of rejection in patients with and without preexisting malignancy was similar. Successful medium-term outcome after OLT can be achieved in carefully selected patients with preexisting malignancy providing the malignancy is amenable to curative treatment before or at OLT. Primary MPDs responsible for Budd-Chiari syndrome should not be considered a contraindication to OLT. (Liver Transpl 2001;7:11-15.) Orthotopic liver transplantation (OLT) has become the definitive therapy for patients with endstage liver disease. Because increasing numbers of older patients are considered for OLT, some will inevitably present with malignancy or have a history of antecedent malignancy. Potential liver transplant candidates with a preexisting malignancy pose special problems. Because of the long-term immunosuppression that accompanies OLT, there is concern about the risk for recurrent or de novo tumors in such patients. 1 In addition, it is not clear whether such patients have a different profile of rejection-related complications compared with transplant recipients without a history of malignancy. The presence of preexisting malignancy is often considered a relative contraindication to OLT. 2 The purpose of this study is to examine retrospectively the outcome of OLT in patients with a preexistent malignant state and compare it with the outcome in liver transplant recipients without a preexisting malignancy. An additional aim is to determine whether liver transplant recipients with a preexistent malignant state had a different pattern of rejection than those without a preexisting malignancy. Finally, we examined the propensity of liver transplant recipients with a preexistent malignant state to develop posttransplantation recurrent or de novo neoplasia. s and Methods Of 1,097 adult OLTs performed between 1989 and 1999 at the King s College Hospital (London, UK), 18 patients had a preexisting malignant state at the time of OLT. This included colon (4 patients), renal (2 patients), malignant melanoma (1 patient), bladder (1 patient), breast (1 patient), thyroid (1 patient), endometrial (1 patient), non- Hodgkin s lymphoma (NHL; 1 patient), and myeloproliferative disorders (MPDs) presenting as Budd-Chiari syndrome (6 patients). characteristics are listed in Tables 1, 2, and 3. s with a history of malignancy were considered for OLT provided the malignancy appeared clinically, radiologically, biochemically, and serologically to have been eradicated and the stage of the neoplasm did not predict a poor prognosis. Although cases were assessed on an individual basis, the decision was heavily influenced by the data generated by the From the Institute of Liver Studies, King s College Hospital, London, UK. Address reprint requests to John O Grady, MD, Institute of Liver Studies, King s College Hospital, Denmark Hill, London SE5 9RS, England, UK. Telephone: ; FAX: ; john.o grady@kcl.ac.uk Copyright 2001 by the American Association for the Study of Liver Diseases /01/ $3.00/0 doi: /jlts Liver Transplantation, Vol 7, No 1 ( January), 2001: pp

2 12 Saigal et al Table 1. Clinical Characteristics of Liver Transplant Recipients With Preexisting Malignant Tumors No. Sex Age (yr) CLD Malignancy Age at Malignancy (yr) Malignancy to OLT (mo) Post-OLT Follow-Up (mo) Tumor Recurrence Outcome 1 M 52 PSC Colon No Alive 2 F 55 AIH (1) Colon No* Dead (2) Basal cell No 3 F 63 PBC Renal cell No Alive 4 M 54 PSC Colon No Alive 5 F 56 PBC Malignant No Alive melanoma 6 M 37 PH Bladder No Alive 7 F 70 PBC Renal cell No Dead 8 F 60 PBC Breast No Alive 9 F 46 PBC Thyroid No Alive 10 F 50 PBC Colon No Alive 11 F 57 AC Endometrial No Alive 12 M 46 HBV NHL Yes Alive Abbreviations: CLD, chronic liver disease; PSC, primary sclerosing cholangitis; AC, alcoholic cirrhosis; HBV, hepatitis B cirrhosis; PH, primary hyperoxaluria; AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis. * Developed PTLD after 57 months. Combined liver-kidney transplantation. Recurrence of NHL after 27 months. Cincinnati Transplant Tumor Registry (CTTR). 1 The initial immunosuppression regimen used for these patients was similar to that of all other liver transplant recipients and consisted of cyclosporine, azathioprine, and prednisolone. Tacrolimusbased immunosuppression was introduced in 1993 in combination with steroids, with or without azathioprine. Immunosuppressive dosages were modified in individual patients to maintain the desired blood levels (tacrolimus, 5 to 15 ng/ml; cyclosporine, 100 to 250 ng/ml) during follow-up. s charts were reviewed, and the incidence of rejection was determined in each case. All rejection episodes were histologically confirmed. Episodes of acute cellular rejection were treated with 1 g of methylprednisolone administered intravenously for 3 days. Resistant acute cellular rejection was treated with tacrolimus as rescue therapy or monoclonal antibody OKT3. None of the patients with a history of malignancy required OKT3. During follow-up assessment, recurrent and de novo malignancy was determined in all patients. Twelve patients (4 men, 8 women) had solid-organ or skin malignancies, with a median age at OLT of 54.5 years (range, 37 to 70 years). The cause of the underlying liver disease was as follows: primary biliary cirrhosis (6 patients), primary sclerosing cholangitis (2 patients), autoimmune hepatitis (1 patient), alcoholic cirrhosis (1 patient), and hepatitis B related cirrhosis (1 patient). One patient underwent combined liverkidney transplantation for primary hyperoxaluria. Of these 12 patients, 4 patients had an incidental malignancy detected at the time of OLT; in 3 patients, the malignancy was resected at the time of OLT, whereas 1 patient underwent resection 3 months after OLT. In the remaining 8 patients, the median interval from diagnosis of malignancy to OLT was 25 months (range, 2 to 240 months). The median post-olt follow-up in these 12 patients was 58.5 months (range, 1 to 115 months). Six patients (1 man, 5 women) who underwent OLT for Budd-Chiari syndrome had an identifiable underlying overt myeloproliferative state. These patients are considered to have a preexistent malignant state that can transform into acute leukemia. 3 Their median age at OLT was 35.5 years (range, 23 to 49 years). In 5 patients, the MPD was diagnosed in the pre-olt period, whereas in 1 patient presenting with acute Budd-Chiari syndrome, the MPD was diagnosed in the immediate post-olt period. The median duration from diagnosis of MPD to OLT was 33 months (range, 7 to 96 months). Of these 6 patients, 3 patients had polycythemia rubra vera (PRV), 1 patient had essential thrombocythemia, and the myeloproliferative state could not be categorized further in the remaining 2 patients. The median post-olt fol-

3 Liver Transplantation and Preexisting Malignancy 13 Table 2. Management of Preexisting Tumors in Liver Transplant Recipients No. Malignancy Tumor Stage Treatment 1 Colon Duke B* Subtotal colectomy with ileostomy at OLT 2 (1) Colon Carcinoma in situ (1) Sigmoid colectomy and defunctioning colostomy 5 months after OLT for Duke s A sigmoid tumor (2) Basal cell (2) Radiotherapy before OLT 3 Renal cell Stage I* Right nephrectomy 3 months after OLT 4 Colon Duke B Subtotal colectomy with ileostomy at OLT 5 Malignant melanoma IIA, Breslow score; Tumor resection 84 months before OLT 2.2 mm 6 Bladder Stage I* Tumor resection at OLT 7 Renal cell Stage I* Left nephrectomy at OLT 8 Breast Intraductal Mastectomy 12 months before OLT, followed by tamoxifen therapy 9 Thyroid NA Thyroidectomy 20 years before OLT 10 Colon Duke C Subtotal colectomy 34 months before OLT, followed by adjuvant chemotherapy 11 Endometrial Stage I Total abdominal hysterectomy with bilateral salpingooophorectomy 27 months before OLT 12 NHL Stage IIB Chemotherapy 23 months before OLT Abbreviation: NA, not available. * Tumor detected incidentally at OLT. Villous adenoma in sigmoid colon showing severe dysplasia detected 2 months before OLT. low-up in these 6 patients was 83.5 months (range, 38 to 119 months). In 4 of these 6 patients, a mesoatrial shunt had been placed before OLT. All patients were administered standard anticoagulation in the post-olt period. Three patients were administered pretransplantation chemotherapy that included hydroxyurea and busulfan. Four patients were administered chemotherapy with hydroxyurea in the post-olt period. Results Of the 12 patients with solid-organ or skin malignancy, 1 patient (8.3 %) had recurrence of his primary malignancy during the post-olt period. This patient initially underwent mantle radiotherapy for Hodgkin s lymphoma 120 months before OLT for hepatitis B cirrhosis, and subsequently chemotherapy for NHL (stage IIB) 23 months before OLT. After OLT, he had a relapse of NHL (stage IVB) after 27 months, which presented as cutaneous lymphomatous deposits and inguinal lymphadenopathy. Another patient developed de novo posttransplant lymphoproliferative disease (PTLD) 57 months after OLT that regressed after immunosuppression reduction alone. Table 3. Clinical Characteristics of Liver Transplant Recipients With Budd-Chiari Syndrome and Preexistent MPD No. Sex Age at OLT (yr) Myeloproliferative State Age at MPD Diagnosis (yr) MPD to OLT (mo) Post-OLT Follow-Up (mo) Recurrence of Budd-Chiari Transformation Into Acute Leukemia Outcome 1 M 42 PRV No No Alive 2 F 37 PRV No Yes Dead 3 F 46 PRV Yes No Alive 4 F 30 ET No No Alive 5 F 23 MPD* No No Alive 6 F 49 MPD* No No Alive Abbreviation: ET, essential thrombocythemia. * MPD not further classified.

4 14 Saigal et al Five of 6 patients with an MPD are currently between 38 and 119 months (median, 79 months) of follow-up post-olt without a transformation to leukemic state. However, 1 patient developed acute leukemia 72 months post-olt and died 93 months post- OLT. There was no case of de novo malignancy in patients with a preexisting myeloproliferative state. Conversely, of 1,079 OLTs performed during the same period in patients without a preexisting malignancy, there were 34 cases (3.1%) of de novo malignancy after OLT, including 7 cases of PTLD. Among patients with a history of preexisting malignancy, 9 patients (50%) developed acute rejection, whereas 2 patients (11%) developed chronic rejection. The incidences of acute and chronic rejection in liver transplant recipients without a preexisting malignant state during the same period were 62% and 5%, which were not significantly different from those in liver transplant recipients with a history of preexisting malignancy. The immunosuppression regimen in these 18 patients was not tailored because of the history of malignancy and was identical to the standard immunosuppression used in our unit for all patients. Discussion There is limited published experience on the outcome of OLT in the presence of a preexistent malignant state, and most data originated from renal transplant recipients. The data collected by the CTTR from 823 renal transplant recipients with preexisting malignancy reported an overall tumor recurrence rate of 22%. Fifty percent of these post-olt tumor recurrences were in those who underwent antitumor therapy less than 2 years before OLT. 1 Subsequently, the same registry reviewed the data from 41 liver transplant recipients who had a history of preexisting malignancy and reported a recurrence of neoplasms in 24% at 1.5 to 42.5 months (mean, 14 months; median, 7.5 months) after OLT. 4 In a more recent study, Kelly et al 5 reported tumor recurrence in 13.8% of liver transplant recipients who had a history of malignancy before OLT. A lower rate (8.3%) of tumor recurrence in the current study may relate to less aggressive immunosuppression used in the United Kingdom, including less use of monoclonal antibody OKT3 compared with that in the United States. Also, the majority of our patients had early-stage malignancy, whereas in the CTTR data, some patients had more advanced malignancy before OLT, evidenced by 1 patient with hepatic metastasis secondary to colonic pre-olt and 1 patient with a perforated colonic resected 36.5 months before OLT. Of the 4 patients with malignancy detected incidentally at OLT, 2 patients had renal (patients 3 and 7) and 1 patient each had colon (patient 1) and bladder (patient 6). Three of these 4 patients had a successful outcome without tumor recurrence. However, 1 patient (no. 7) who underwent resection of a renal cell during OLT died of uncontrollable sepsis and multiple organ failure in the early post-olt period. Two patients with primary sclerosing cholangitis had colon resected at OLT. In 1 patient (no. 4), the malignancy was diagnosed 4 months before OLT, whereas in the other patient (no. 1), it was detected incidentally at OLT. This patient had a colonoscopic evaluation at the referral center 6 months before OLT that failed to detect a mucosal abnormality, and his pretransplantation carcinoembryonic antigen levels were normal. In another patient (no. 2; Tables 1 and 2), a villous adenoma showing severe dysplasia that could not be snared was detected in the sigmoid colon 2 months before OLT. At OLT, there were no palpable colonic lesions, but colonoscopic evaluation at 2-month intervals after OLT showed increasing size of the polyp, and a sigmoid colectomy was subsequently performed at 5 months for Duke s A sigmoid. Encouraging data also have been reported after cardiac transplantation. Dillon et al 6 reported a 2-year survival rate of 100% after cardiac transplantation in 7 patients with preexistent malignancies. CTTR data recommend a 2-year waiting period between treatment of cancer and renal transplantation, except for cases of incidentally discovered renal s, in situ s of most organs, focal neoplasms (a small single focus), and nonmelanoma skin cancers. The same center has recently recommended a modification of these guidelines for liver transplantation because it is highly unlikely that the majority of patients awaiting OLT can be kept alive for a 2-year waiting period. 4 From our limited experience, we suggest that OLT can be performed in patients with preexisting malignancy provided that the malignancy is amenable to curative treatment before or at OLT and the stage of the malignancy does not have a poor prognosis. PTLD is an important complication in organ transplant recipients, with an incidence of 2% in renal transplantation and up to 10% in heart and lung transplantation. 7,8 Its incidence after OLT has varied from 1.8% to 4%. 9,10 Predisposing factors include the use of immunosuppressive antibody OKT3 11 and primary Ep-

5 Liver Transplantation and Preexisting Malignancy 15 stein-barr virus infection in the post-olt period. 12 No particular predisposing factor could be recognized in our patient with PTLD, and it is unclear whether a preexistent malignant state would increase its incidence in the post-olt period. Primary MPDs are a leading cause of Budd-Chiari syndrome, which frequently results in end-stage liver failure necessitating OLT. The course of MPD is characterized by transformation into acute leukemia, which in PRV is up to 10%. 3 There is concern that immunosuppression after OLT may increase this risk. Dousset et al 13 reported 2 patients with MPD with Budd-Chiari syndrome who underwent transplantation and did not develop leukemia at up to 29 and 31 months followup. One of our patients developed acute leukemia 6 years after OLT. This leukemic transformation occurred 14 years after her primary diagnosis of PRV, which very much favors the natural history of the disease rather than an effect of immunosuppression. The overall rate of rejection in these 18 patients was similar to that observed in our liver transplant recipients who did not have a preexistent malignant state. A similar observation has been made in patients undergoing cardiac transplantation who have a history of preexisting malignancy. 6 Therefore, in liver transplant recipients with a history of preexisting malignancy, standard immunosuppression regimens should be used to prevent rejection episodes, rather than using reduced immunosuppression to prevent tumor recurrence. In conclusion, OLT can be performed successfully in carefully selected patients with preexisting malignancy provided that the malignancy is amenable to curative treatment before or at OLT and the stage of the malignancy does not have a poor prognosis. Primary MPDs responsible for Budd-Chiari syndrome should not be considered a contraindication to OLT. References 1. Penn I. Effect of immunosuppression on pre-existing cancers. Transplantation 1993;55: Neuberger J, Shorrock CS. General considerations. In: Neuberger J, Lucey MR (eds). Liver transplantation Practice and management. Great Britain: BMJ, 1994: Henderson ES. Acute leukemia: General considerations. In: Williams WJ, Beutler E, Erslev AJ, Lichtman MA (eds). Hematology (ed 4). New York: McGraw-Hill, 1990: Penn I. Evaluation of the candidate with a previous malignancy. Liver Transpl Surg 1996;2(suppl 1): Kelly DM, Emre S, Guy SR, Miller CM, Schwartz ME, Sheiner PA. Liver transplant recipients are not at an increased risk for nonlymphoid solid organ tumors. Cancer 1998;83: Dillon TA, Sullivan M, Schatzlein MH, Peterson AC, Scheeringa RH, Clark WR Jr, et al. Cardiac transplantation in patients with pre-existing malignancies. Transplantation 1991;52: Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc 1969; 1: Penn I. The changing pattern of post transplant malignancies. Transplant Proc 1991;23: Reyes J, Tzakis A, Green M, Nour B, Nalesnik M, Van Thiel D, et al. Post transplant lymphoproliferative disorder during primary FK506 immunosuppression. Transplant Proc 1991;23: Starzl T, Porter K, Iwatsuki S, Rosenthal J, Nalesnik MA, Ho M, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1984;1: Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O Sullivan EJ, Johnson MR, Heroux AL, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with monoclonal antibody OKT3 in cardiac-transplant patients. N Engl J Med 1990;323: Ho M, Jaffe R, Miller G, Breining MK, Dummer JS, Makowka L, et al. The frequency of Epstein-Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation 1988;45: Dousset B, Boudet MJ, Soubrane O, Calmus Y, Bernard O, Houssin D. Liver transplantation in patients with preexisting malignancy. Transplant Proc 1995;27: