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Liver Transplantation as a Primary Indication for Intrahepatic Cholangiocarcinoma: A Single-Center Experience
Liver Transplantation as a Primary Indication for Intrahepatic Cholangiocarcinoma: A Single-Center Experience G.C. Sotiropoulos, G.M. Kaiser, H. Lang, E.P. Molmenti, S. Beckebaum, I. Fouzas, G. Sgourakis, A. Radtke, M. Bockhorn, S. Nadalin, J. Treckmann, W. Niebel, H.A. Baba, C.E. Broelsch, and A. Paul ABSTRACT Background. Intrahepatic cholangiocarcinoma (ICC) is not a widely accepted indication for orthotopic liver transplantation (OLT). The present study describes our institutional experience with patients who underwent transplantation for ICC as well as those with ICC who underwent transplantation with the incorrect diagnosis of hepatocellular carcinoma (HCC). Patients and Methods. Data corresponding to ICC patients were reviewed for the purposes of this study. Patients with hilar cholangiocarcinoma and incidentally found ICC after OLT for benign diseases were excluded from further consideration. Results. Among the 10 patients, 6 underwent transplantation before 1996 and 4 after 2001. Those who underwent transplantation in the early period had a preoperative diagnosis of inoperable ICC (n ⫽ 4) and ICC in the setting of primary sclerosing cholangitis (n ⫽ 2). In the latter period the subjects had a diagnosis of HCC in cirrhosis (n ⫽ 3) or recurrent ICC after an extended right hepatectomy (n ⫽ 1). Median survival was 25.3 months for the whole series and 32.2 months (range, 18 –130 months) when hospital mortality was excluded (n ⫽ 3). Four patients are currently alive after 30, 35, 42, and 130 months post-OLT, respectively. Two patients died of tumor recurrence at 18 and 21 months post-OLT, respectively. One-, 3-, and 5-year survival rates were 70%, 50%, and 33%, respectively. Conclusions. The role of OLT in the setting of ICC may be re-evaluated in the future under strict selection criteria and with prospective multicenter randomized studies. Potential candidates to be included are those with liver cirrhosis and no hilar involvement who meet the Milan criteria for HCC.
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HOLANGIOCARCINOMA, and especially hilar cholangiocarcinoma, was thought to be a good indication in the early days of orthotopic liver transplantation (OLT), due in part to the fact that patients with irresectable hepatobiliary malignancies were in relatively satisfactory physical condition, and operative technical problems were diminished in the absence of severe portal hypertension and end- stage liver disease. The good early postoperative clinical outcomes, however, were usually followed by high recurrence rates of the tumors; most patients died within 1 to 2 years after transplantation.1–3 Although there is currently a reconsideration of the effectiveness of OLT for hilar cholangiocarcinomas, such is not the case for intrahepatic cholangiocarcinomas (ICC). The present study reports our historical institutional experience with OLT for ICC, as well as for ICC patients who underwent transplantation with a presumed diagnosis of hepatocellular carcinoma (HCC). 0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.053 3194
PATIENTS AND METHODS We reviewed prospectively collected data corresponding to patients with ICC who underwent OLT at our institution. Patients with hilar cholangiocarcinoma and with incidentally found ICC after performance of OLT for benign indications were excluded. Data analysis From the Department of General, Visceral, and Transplantation Surgery (G.C.S., G.M.K., H.L., E.P.M., S.B., I.F., G.S., A.R., M.B., S.N., J.T., W.N., C.E.B., A.P.); and Institute of Pathology and Neuropathology (H.A.B.), University Hospital Essen, Essen; Department of General and Abdominal Surgery (G.C.S., H.L., G.S., A.R.), Johannes Gutenberg University Hospital, Mainz, Germany; and Organ Transplant Unit (I.F.), Hippocration University Hospital, Thessaloniki, Greece. Address reprint requests to Dr. Georgios C. Sotiropoulos, MD, Department of General and Abdominal Surgery, Johannes Gutenberg University Hospital, Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. E-mail: [email protected]
Crown Copyright © 2008 Published by Elseiver Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 40, 3194 –3195 (2008)
INTRAHEPATIC CHOLANGIOCARCINOMA was performed according to time periods and to the primary indication for OLT. Survival analysis was calculated according to the Kaplan-Meier method and the log-rank test.
RESULTS
There were 10 patients with a median age of 50 years (range, 29 – 62 years). Six patients underwent transplantation before 1996 (historical series) with a diagnosis of inoperable ICC (n ⫽ 4) or ICC in the setting of primary sclerosing cholangitis (n ⫽ 2). Four (n ⫽ 4) underwent transplantation after 2001. Three (n ⫽ 3) of them had a preoperative diagnosis of cirrhosis and HCC fulfilling the Milan criteria. The fourth (n ⫽ 1) had recurrent ICC after an extended right hepatectomy in the past. All patients received deceased donor grafts, except for the last 1 described who underwent a live donor OLT 25 months after the initial resection. Careful study of the explanted livers excluded hilar cholangiocarcinomas in all cases. ICC was solitary in 2 cases (both from the second period of study) and multifocal in the rest. Three patients (all from the first period) died shortly after OLT as a result of technical and septic complications. Median survival was 25.3 months for the whole series, 32.2 months (range, 18 –130 months) when hospital mortality was excluded, and 17.8 months when only the first time period of study was considered. Four patients are currently alive at 30, 35, 42, and 130 months post-OLT, respectively. Two patients died on tumor recurrence at 18 and 21 months post-OLT, respectively (the former from the first period of study, the latter one who underwent the live donor OLT). One patient developed ischemic biliary complications and is currently relisted 35 months post-OLT. The longest survivor is now 40 years old, and has recurrent primary sclerosing cholangitis with no evidence of tumor. Survival rate at 1, 3, and 5 years was 70%, 50%, and 33%, respectively. All patients who were discharged from the hospital reached at least 1-year survival. DISCUSSION
Liver resection with curative intent is presently considered to be the best therapy for ICC.4,5 Technical innovations in liver surgery, computed assisted operative planning, as well as other improvements have allowed for more “sophisticated” liver resections.6,7 They have also allowed for reoperations in cases of intrahepatic tumor recurrence.8 Although at the present time consideration of a transplant
3195
indication for ICC is elusive because of the dramatic organ shortage, our small series provides an encouraging message for the future. This could be the rare category of patients with liver cirrhosis and with ICC and no involvement of the hilar bifurcation who may benefit from liver replacement. The last 3 patients in our series, who “falsely” fulfilled the Milan criteria (a single tumor ⱕ5 cm in diameter or 2–3 tumors all ⱕ3 cm in diameter),9 are currently alive and with no tumor recurrence 30, 35, and 42 months post-OLT, respectively. The indications for OLT in the setting of a diagnosis of ICC may be re-examined within prospective multicentric randomized trials. Live donor OLT may represent an alternative to be considered in selected patients,10 as long as a thorough informed consent of both donors and recipients is obtained. REFERENCES 1. Goldstein RM, Stone M, Tillery GW, et al: Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 166:768, 1993 2. Meyer CG, Penn I, James L: Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 69:1633, 2000 3. Shimoda M, Farmer DG, Colquhoun SD, et al: Liver transplantation for cholangiocellular carcinoma: analysis of a singlecenter experience and review of the literature. Liver Transpl 7:1023, 2001 4. Lang H, Sotiropoulos GC, Frühauf NR, et al: Extended hepatectomy for intrahepatic cholangiocellular carcinoma (ICC): when is it worthwhile? Single center experience with 27 resections in 50 patients over a 5-year period. Ann Surg 241:134, 2005 5. Lang H, Sotiropoulos GC, Brokalaki E, et al: Surgical therapy of intrahepatic cholangiocellular carcinoma. Chirurg 77:53, 2006 6. Lang H, Sotiropoulos GC, Brokalaki EI, et al: Left hepatic trisectionectomy for hepatobiliary malignancies. J Am Coll Surg 203:311, 2006 7. Lang H, Radtke A, Hindennach M, et al: Impact of virtual tumor resection and computer- assisted risk analysis on operation planning and intraoperative strategy in major hepatic resection. Impact of virtual tumor resection and computer-assisted risk analysis on operation planning and intraoperative strategy in major hepatic resection. Arch Surg 140:629, 2005 8. Sotiropoulos GC, Lang H, Broelsch CE: Surgical management of recurrent intrahepatic cholangiocellular carcinoma after liver resection. Surgery 137:669, 2005 9. Sotiropoulos GC, Brokalaki EI, Molmenti EP, et al: Liver transplantation for small solitary cholangiocellular carcinoma in cirrhosis: a medical mistake or a new indication? Transplantation 80:1356, 2005 10. Jonas S, Mittler J, Pascher A, et al: Extended indications in living-donor liver transplantation: bile duct cancer. Transplantation 80:S101, 2005
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HOLANGIOCARCINOMA, and especially hilar cholangiocarcinoma, was thought to be a good indication in the early days of orthotopic liver transplantation (OLT), due in part to the fact that patients with irresectable hepatobiliary malignancies were in relatively satisfactory physical condition, and operative technical problems were diminished in the absence of severe portal hypertension and end- stage liver disease. The good early postoperative clinical outcomes, however, were usually followed by high recurrence rates of the tumors; most patients died within 1 to 2 years after transplantation.1–3 Although there is currently a reconsideration of the effectiveness of OLT for hilar cholangiocarcinomas, such is not the case for intrahepatic cholangiocarcinomas (ICC). The present study reports our historical institutional experience with OLT for ICC, as well as for ICC patients who underwent transplantation with a presumed diagnosis of hepatocellular carcinoma (HCC). 0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.053 3194
PATIENTS AND METHODS We reviewed prospectively collected data corresponding to patients with ICC who underwent OLT at our institution. Patients with hilar cholangiocarcinoma and with incidentally found ICC after performance of OLT for benign indications were excluded. Data analysis From the Department of General, Visceral, and Transplantation Surgery (G.C.S., G.M.K., H.L., E.P.M., S.B., I.F., G.S., A.R., M.B., S.N., J.T., W.N., C.E.B., A.P.); and Institute of Pathology and Neuropathology (H.A.B.), University Hospital Essen, Essen; Department of General and Abdominal Surgery (G.C.S., H.L., G.S., A.R.), Johannes Gutenberg University Hospital, Mainz, Germany; and Organ Transplant Unit (I.F.), Hippocration University Hospital, Thessaloniki, Greece. Address reprint requests to Dr. Georgios C. Sotiropoulos, MD, Department of General and Abdominal Surgery, Johannes Gutenberg University Hospital, Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. E-mail: [email protected]
Crown Copyright © 2008 Published by Elseiver Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 40, 3194 –3195 (2008)
INTRAHEPATIC CHOLANGIOCARCINOMA was performed according to time periods and to the primary indication for OLT. Survival analysis was calculated according to the Kaplan-Meier method and the log-rank test.
RESULTS
There were 10 patients with a median age of 50 years (range, 29 – 62 years). Six patients underwent transplantation before 1996 (historical series) with a diagnosis of inoperable ICC (n ⫽ 4) or ICC in the setting of primary sclerosing cholangitis (n ⫽ 2). Four (n ⫽ 4) underwent transplantation after 2001. Three (n ⫽ 3) of them had a preoperative diagnosis of cirrhosis and HCC fulfilling the Milan criteria. The fourth (n ⫽ 1) had recurrent ICC after an extended right hepatectomy in the past. All patients received deceased donor grafts, except for the last 1 described who underwent a live donor OLT 25 months after the initial resection. Careful study of the explanted livers excluded hilar cholangiocarcinomas in all cases. ICC was solitary in 2 cases (both from the second period of study) and multifocal in the rest. Three patients (all from the first period) died shortly after OLT as a result of technical and septic complications. Median survival was 25.3 months for the whole series, 32.2 months (range, 18 –130 months) when hospital mortality was excluded, and 17.8 months when only the first time period of study was considered. Four patients are currently alive at 30, 35, 42, and 130 months post-OLT, respectively. Two patients died on tumor recurrence at 18 and 21 months post-OLT, respectively (the former from the first period of study, the latter one who underwent the live donor OLT). One patient developed ischemic biliary complications and is currently relisted 35 months post-OLT. The longest survivor is now 40 years old, and has recurrent primary sclerosing cholangitis with no evidence of tumor. Survival rate at 1, 3, and 5 years was 70%, 50%, and 33%, respectively. All patients who were discharged from the hospital reached at least 1-year survival. DISCUSSION
Liver resection with curative intent is presently considered to be the best therapy for ICC.4,5 Technical innovations in liver surgery, computed assisted operative planning, as well as other improvements have allowed for more “sophisticated” liver resections.6,7 They have also allowed for reoperations in cases of intrahepatic tumor recurrence.8 Although at the present time consideration of a transplant
3195
indication for ICC is elusive because of the dramatic organ shortage, our small series provides an encouraging message for the future. This could be the rare category of patients with liver cirrhosis and with ICC and no involvement of the hilar bifurcation who may benefit from liver replacement. The last 3 patients in our series, who “falsely” fulfilled the Milan criteria (a single tumor ⱕ5 cm in diameter or 2–3 tumors all ⱕ3 cm in diameter),9 are currently alive and with no tumor recurrence 30, 35, and 42 months post-OLT, respectively. The indications for OLT in the setting of a diagnosis of ICC may be re-examined within prospective multicentric randomized trials. Live donor OLT may represent an alternative to be considered in selected patients,10 as long as a thorough informed consent of both donors and recipients is obtained. REFERENCES 1. Goldstein RM, Stone M, Tillery GW, et al: Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 166:768, 1993 2. Meyer CG, Penn I, James L: Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 69:1633, 2000 3. Shimoda M, Farmer DG, Colquhoun SD, et al: Liver transplantation for cholangiocellular carcinoma: analysis of a singlecenter experience and review of the literature. Liver Transpl 7:1023, 2001 4. Lang H, Sotiropoulos GC, Frühauf NR, et al: Extended hepatectomy for intrahepatic cholangiocellular carcinoma (ICC): when is it worthwhile? Single center experience with 27 resections in 50 patients over a 5-year period. Ann Surg 241:134, 2005 5. Lang H, Sotiropoulos GC, Brokalaki E, et al: Surgical therapy of intrahepatic cholangiocellular carcinoma. Chirurg 77:53, 2006 6. Lang H, Sotiropoulos GC, Brokalaki EI, et al: Left hepatic trisectionectomy for hepatobiliary malignancies. J Am Coll Surg 203:311, 2006 7. Lang H, Radtke A, Hindennach M, et al: Impact of virtual tumor resection and computer- assisted risk analysis on operation planning and intraoperative strategy in major hepatic resection. Impact of virtual tumor resection and computer-assisted risk analysis on operation planning and intraoperative strategy in major hepatic resection. Arch Surg 140:629, 2005 8. Sotiropoulos GC, Lang H, Broelsch CE: Surgical management of recurrent intrahepatic cholangiocellular carcinoma after liver resection. Surgery 137:669, 2005 9. Sotiropoulos GC, Brokalaki EI, Molmenti EP, et al: Liver transplantation for small solitary cholangiocellular carcinoma in cirrhosis: a medical mistake or a new indication? Transplantation 80:1356, 2005 10. Jonas S, Mittler J, Pascher A, et al: Extended indications in living-donor liver transplantation: bile duct cancer. Transplantation 80:S101, 2005