Objectives: Liver transplantation has become one of the best treatment options for early hepatocellular carcinoma in cirrhosis. We sought to study the results of liver transplantation in patients with hepatocellular carcinoma and to evaluate the outcome of the patients.
Materials and Methods: The medical records of 256 recipients who underwent a liver transplantation from April 2001 to January 2010 were reviewed. One hundred seventy-six patients received their livers from deceased donors, and 80 received their livers from living donors. Fifty-two patients underwent liver transplantation for hepatocellular carcinoma.
Results: From April 2001 until now, 52 patients (20.3%) underwent liver transplantation for hepatocellular carcinoma. Eighteen patients (34.6%) were performed from living-related donors, and 34 (65.4%) were from deceased donors. The patients were 37 males and 15 females (median, 55 years old; age range, 5 through 68 years). Model for end-stage liver disease score ranged from 6 to 40 with a median of 14. All patients were within the Milan criteria by the preoperative evaluation. Hospital stay ranged from 6 to 338 days with a median 14 days. Operating time ranged from 4 to 15 hours with a median 7.5 hours. Blood transfusion ranged from 0 to 19 units median 5 units. Thirty-four complications occurred in 23 patients (44.2%). Recurrence of hepatocellular carcinoma in 7 patients (13.5%), of which recurrent cholangiocarcinoma was diagnosed in 3 (5.7%), accidentally discovered in the explant. One deceased donor had hepatitis B core antibody positive. One explant showed macrovascular invasion. Sixteen patients died, 7 of 52 (13.5%) from hepatocellular carcinoma recurrence, including the 3 cases of accidental discovery of cholangiocarcinoma (5.7%).
Conclusions: Apart from the common complications that can occur with any transplantation, liver transplantation remains the most-promising solution for patients with hepatocellular carcinoma among the available ones, and represents a cornerstone in managing hepatocellular carcinoma. It is the only acceptable option for complete eradication of both the disease and the predisposing factor.
Key words : Liver transplantation, Hepatocellular carcinoma, Milan criteria, Alphafetoprotien
Over a quarter century, orthotopic liver transplantation has been established as a durable therapy for all forms of end-stage liver disease.1, 2 Orthotopic liver transplantation appears ideally suited for hepatocellular carcinoma, as it provides complete oncologic resection and correction of the underlying liver dysfunction. Early experience with orthotopic liver transplantion for hepatocellular carcinoma had poor results with a high recurrence rate.3-6 In 1996, Mazzaferro and associates reported improved results with orthotopic liver transplantation in patients with single tumor ≤ 5 cm or no more than 3 tumors, each up to 3 cm.7 These Milan criteria were adopted by the United Network for Organ Sharing (UNOS) and by most transplant centers as selection guidelines for orthotopic liver transplantation in patients with hepatocellular carcinoma. Recent data suggest that Milan criteria may be too conservative. Yao and associates reported their results with a moderate expansion of these criteria.8 Patients selected with these expanded criteria had disease-free survival that was comparable to survival of patients selected with Milan criteria.8 We sought to study the results of liver transplantation in patients with hepatocellular carcinoma and to evaluate the outcome of the patients.
Materials and Methods
A total of 256 recipients underwent liver transplantation from April 2001 to January 2010. One hundred and seventy-six patients underwent deceased-donor liver transplantation and 80 living-donor liver transplantation. Prior to the study, the protocol was approved by our local institutional ethics committee.
The data was collected and entered into a personal computer. Statistical analyses were performed with SPSS software for Windows (Statistical Product and Service Solutions, version 17.0, SSPS Inc, Chicago, IL, USA). Arithmetic mean, standard deviation, numbers and percentages were measured for categorized parameters, the chi-square test was used, while for numerical data, the t test were used to compare groups. The level of significance was set at .05. For both mortality and recurrence, a Kaplan-Meier curve was estimated to calculate the survival for all patients during follow-up.
Fifty-two patients (20.3%) underwent liver transplantation for hepatocellular carcinoma. All were within the Milan criteria by preoperative assessment. Eighteen of 52 patients (34.6%) from living-related donors; 34 of 52 (65.4%) were from deceased donors. Thirty seven were males (71%) and 15 were females (29%). Ages ranged from 5 to 68 years, with a median 56 years. Model for end-stage liver disease score ranged from 6-40, with a median 14. Hospital stay ranged from 6 to 338 days, with a median 14 days. Operating time ranged from 4 to 15 hours, with median 7.5 hours. Blood transfusion ranged from 0 to 19 units, with a median of 5 units. Follow-up ranged from 1 to 101 months, with a median 32 months. Thirty-four complications occurred in 23 of 52 patients (44.2%). Recurrence of hepatocellular carcinoma and cholangiocarcinoma, accidentally discovered in the explanted liver, in 7 of 34 patients (20.5%), hepatic artery thrombosis in 1 patient (2.8%), bile leak and biloma in 5 patients (14.6%), biliary stricture in 1 patient (2.8%), primary nonfunction in 2 patients (5.7%), bleeding in 2 patients (5.7%), acute tubular necrosis in 1 patient (2.8%), portal vein thrombosis in 1 patient (2.8%), small for a size graft in 1 patient (2.8%), recurrent hepatitus C virus in 2 patients (5.7%), initial poor function in 1 patient (2.8%), heart failure in 1 patient (2.8%), graft-versus-host disease in 1 patient (2.8%), incisional hernia in 1 patient (2.8%), abdominal collection in 1 patient (2.8%), fracture neck femur in 1 patient (2.8%), rectal bleeding in 1 patient (2.8%), and severe sepsis in 4 patients (11.5%).
Predictive factors of tumor recurrence and patient survival
Multiple factors were studied by univariate analysis for their effect on hepatocellular carcinoma recurrences after liver transplantation (Table). It was found that female sex, pretransplant tumor control therapy, pretransplant alpha fetoprotein ≥ 400 ng/mL, presence of cholangiocarcinoma, poorly differentiated hepatocellular carcinoma, presence of microvascular invasion in the explant and presence of macrovascular invasion in the explant were all significant risk factors for tumor recurrence. All patients who had tumor recurrence died.
During the follow-up, 16 of 52 patients (30.8%) died. Hepatocellular carcinoma recurred in 7 of 52 patients (13.5%) surviving during a median follow-up of 32 months. All of them received various antitumor treatments; however, they all died including the 3 cases with accidental discovery of cholangiocarcinoma, from dissemination of the tumor, and this resulted in a median survival after detection of the tumor recurrence of 24 months. Nine of 52 patients died from liver transplantation related complications (various causes other than tumor recurrence and this resulted in perioperative mortality of [17.3%]). The causes of death were 2 from primary nonfunction (died within 1 week posttransplant), 1 from hepatic artery thrombosis (after retransplantation by 14 days), 1 from graft-versus-host disease (in ABO incompatible blood group recipient), 1 from small-for-size graft, portal vein thrombosis, and multiple organ failure; and 4 from severe sepsis.
The overall recurrence-free patient survival rate and the patient survival rate for 5 years follow-up are shown in Figures 1 and 2. These curves were put for the patients who died from hepatocellular carcinoma recurrence, which was 7 of 52 (13.5%) after liver transplantation. Patients who died in the perioperative period 9 of 52 (17.3%) from causes other than tumor recurrence were excluded. No perioperative mortality occurred owing to tumor recurrence.
Most of the early results for orthotopic liver transplantation with hepatocellular carcinoma were disappointing, largely because of poor patient selection.3-6 In 1991, Ringe reported 3 and 5 years’ survival of 15% after transplantation in 61 of patients in whom 80% had a tumor > 5 cm.4 Iwatsuki5 and Bismuth1 found 3- and 5-year survival rates below 50% after transplantation of advanced-stage tumors. In their series, 17% to 35% of the patients had portal vein invasion, and nearly 50% were symptomatic from their tumors.3-5 Reports of orthotopic liver transplantation for hepatocellular carcinoma after 1996 confirm superior results to the Milan criteria.7 For tumors within the Milan criteria compared with tumors exceeding them, 5-year survival was significantly better.9 Although restrictive, results of patients with hepatocellular carcinoma selected within Milan criteria were better until now, and it is the way adopted at our center to select patients with hepatocellular carcinoma for transplantation.
In the present study, it was found that recurrence occurred in 7 of 52 patients (13.5%). The rate was similar to the rates found in other studies.7, 10-14 Female sex, absence of pretransplant tumor control therapy, pretransplant alpha-fetoprotein ≥ 400 ng/mL, presence of combined hepatocellular carcinoma and cholangiocarcinoma, poorly differentiated hepatocellular carcinoma, presence of macrovascular invasion, or microvascular invasion in the explanted liver were all significant risk factors for tumor recurrence, while the number and the size of the lesions were not significant factors for tumor recurrence.
Recent studies have shown the importance of microvascular invasion and a poor differentiation degree as independent prognostic factor for hepatocellular carcinoma recurrence in patients undergoing resection or transplantation,15-20 but these histopathologic variables cannot be used for preoperative selection because they can be only accessible by histopathology on an explanted liver. Some studies have shown that the main predictor of microvascular invasion is the histologic grade of hepatocellular carcinoma, which can be determined preoperatively by a percutaneous needle biopsy.15, 16, 21-23 Also, the principle challenge is to identify and use preoperative criteria to select tumors with favorable biology and patients whose 5-year survival will meet or exceed 50%, as advocated by the Barcelona group.24-26 However, the critical role of tumor biology, especially regarding histologic grade and lymphovascular invasion, suggests that tumor staging before orthotopic liver transplantation should include biopsy and histologic examination in all cases.27 Although there are real concerns regarding patient acceptance, sampling error, and technical complications in cirrhotic patients (especially those with coagulopathy), the risk of tumor dissemination is minimal with proper patient selection and meticulous attention to biopsy technique.11 Therefore, the behavior of hepatocellular carcinoma is the final deciding factor for patient outcome. So, staging criteria for hepatocellular carcinoma did not take into account the tumor morphology but only the number and size of the tumors. The development of noninvasive alternatives to identify tumors with aggressive biology is fertile area for research.28 Despite being a useful approach, further studies are required for validation.
All our patients’ preoperative selections were within the Milan criteria, but postoperatively, we found that 13 patients exceeded these criteria with only 1 recurrence (7.7%), and 36 patients were within the Milan criteria with 3 recurrences (8.3%) which put the Milan criteria, per se, are not prognostic factors in tumor recurrence, but the presence of cholangiocarcinoma in the explanted liver gives 100% tumor recurrence. This put the presence of cholangiocarcinoma as a highly significant factor for tumor recurrence. The number and the size of tumors in the explanted liver were not significant factors in tumor recurrence. So, dependence on Milan criteria is restrictive and prevents many patients from taking the full chances in the transplantation. This was also approved by many authors who concluded that the Milan criteria limits liver transplantation for hepatocellular carcinoma and that they had encouraging results with expanded criteria.29 In recent years, with the development of living-donor liver transplantation, many liver transplantation centers explored the feasibility of expanding the criteria and they concluded that even patients with a tumor > 8 cm may benefit from the operation as long as the histologic grade is favorable without gross microvascular invasion and serum alpha-fetoprotein is less than 400 ng/mL.11, 30-32
Patients who received pretransplant tumor control therapy as an adjuvant therapy before transplant showed a significantly lower recurrence rate of malignancies. Yao and colleagues demonstrated improved posttransplant survival for patients with selected tumors treated loco-regionally before orthotopic liver transplantation,8 but the design of the present study was not adequate to conclude the efficacy of these therapies and further prospective analyses are necessary to assess their value.
According to the principle that, the main challenge is to identify patients with tumors with favorable biology based on preoperative features, a pretransplant alpha-fetoprotein level of ≥ 400 ng/mL was found to be an important independent preorthotopic liver transplantation variable affecting tumor recurrence. Alpha-fetoprotein has been reported to be an important predictor factor of hepatocellular carcinoma recurrence.33 The pretransplant alpha-fetoprotein level was proved to associate with tumor recurrence and prognosis,34 and the adjuvant treatments often fail to prevent tumor progression in patients with high alpha-fetoprotein level.35 Ochiai and associates36 investigated 95 patients with hepatocellular carcinoma undergoing hepatectomy and found that serum alpha-fetoprotein concentration above 400 ng/L was one of the preoperative risk factors associated with postoperative prognosis. Furthermore, studies from De Carlis and associates,37 and Del Gaudio and associates,38 who retrospectively analyzed 121 and 87 hepatocellular carcinoma patients who received liver transplantation, verified that a serum alpha-fetoprotein level was not only significantly related to the development of tumor recurrence but also, a significant independent risk factor for patient overall-survival after transplantation.
In the present study, orthotopic liver transplantation proved to be an effective treatment for hepatocellular carcinoma in cirrhotic patients, with a 5-year survival rate of 86%, which may be high because of the high selection criteria with low number of patients. Perhaps this high survival rates will encourage us to widen the criteria of hepatocellular carcinoma patients’ acceptance for orthotopic liver transplantation. The overall 5-year survival rate for all causes of death in patients with hepatocellular carcinoma including hepatocellular carcinoma recurrence and other causes of death was 70%. In other reports, patient survival at 1, 3, and 5 years after orthotopic liver transplantation was 92%, 79%, and 69% for patients selected with hepatocellular carcinoma within Milan criteria and were 83%, 69%, and 63% for patients selected with hepatocellular carcinoma outside Milan criteria.10
Apart from the common complications that can occur with any transplantation, liver transplantation remains the most-promising solution for patients with hepatocellular carcinoma among all those available and represents a cornerstone in managing hepatocellular carcinoma. It is the only acceptable option for complete eradication of both the disease and the predisposing factor (cirrhosis). Trails to expand Milan criteria are mandatory to cope with the increasing number of patients with hepatocellular carcinoma, and to decrease the wait-list time and mortality. Given the shortage of available organs for liver transplantation and lack of the predictive power of currently used staging system, pretransplant evaluations must be refined to include more-precise assessments of tumor biology.
Volume : 9
Issue : 5
Pages : 323 - 328
From the Liver Transplantation and Hepatobiliary-Pancreatic Surgery Department,
King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Address reprint requests to: Dr. Ayman Zaki Azzam, King Faisal Specialist Hospital And Research Center, mbc: 72, PO Box 3354 Riyaddh 11211, Saudi Arabia
Phone: +966 1 464 7272 ext 39474
Fax: +966 1 442 4817
Table. Studied factors and their effect on hepatocellular carcinoma recurrence.
Figure 1. Kaplan-Meier for recurrence-free patient survival rate for 5 years’ follow-up.
Figure 2. Kaplan-Meier for patient survival rate over 5 years’ follow-up.