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The Oncologist, Vol. 10, No. 4, 269-281, April 2005; doi:10.1634/theoncologist.10-4-269
© 2005 AlphaMed Press

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Liver Transplantation for Malignancy

Martin Hertl, A. Benedict Cosimi

Massachusetts General Hospital Transplant Unit, Boston, Massachusetts, USA

Correspondence: Martin Hertl, M.D., Transplant Unit, 55 Fruit Street, Blake 655, Boston, Massachusetts 02114, USA. Telephone: 617-724-3730; Fax: 617-724-8634; e-mail: mhertl{at}partners.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 
After completing this course, the reader will be able to:

  1. List the indications for liver transplantation in patients with hepatobiliary malignancies.
  2. Describe the MELD and PELD system.
  3. Discuss the management and treatment algorithm of a patient with hepatobiliary malignancy.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 
Liver transplantation for hepatic malignancies has emerged from an exotic and desperate approach to a well-documented and proven treatment modality for these unfortunate patients. However, early unsatisfactory results emphasized that only a highly selected patient population would benefit from transplantation. Currently, <10% of all liver transplants performed are for hepatocellular cancer (HCC). There is no controversy that hepatoblastoma is an excellent indication in pediatric patients with unresectable tumors. Similarly, liver transplantation for HCC in the adult population yields good results for patients whose tumor masses do not exceed the Milan criteria. It remains to be determined whether patients with more extensive tumors can be reliably selected to benefit from the procedure. Adjunctive procedures like radiofrequency ablation, chemoembolization, or cryotherapy might be indicated to limit tumor progression for patients on waiting lists. Epitheloid hemangioendothelioma is also an appropriate indication for liver transplantation, unlike angiosarcoma. Metastatic liver disease is not an indication for liver transplantation, with the exception of cases in which the primary is a neuroendocrine tumor, for which liver transplantation can result in long-term survival and even cure in a number of patients. And finally, while gallbladder cancers are never an indication for liver transplantation, rare cases of cholangiocellular cancer might qualify if aggressive combination therapies, including chemotherapy and radiotherapy followed by OLT, are carried through. Survival in these selected patients can approach that for patients with cholestatic liver disease.

Key Words. Hepatic malignancy • Liver transplantation • HCC • MELD


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 
Malignancy of the liver includes neoplastic lesions that either originate in the liver or are metastatic from other tissues. The incidence of metastatic liver disease (e.g., from gastrointestinal cancer) by far outweighs that of primary liver tumors in Western countries. However, for the scope of this review, we focus mainly on liver transplantation for hepatobiliary carcinoma. Additionally, we discuss liver transplantation for the different histologic types of neuroendocrine metastases. Treatment with hepatectomy and transplantation for all other types of unresectable metastatic disease has typically failed due to early tumor recurrence and, therefore, is not performed in the U.S.

Survival rates for patients following conventional therapy for hepatic malignancies are still discouraging. The 5-year survival rate for U.S. patients with gallbladder cancer is 15.2%; for liver cancer, it is 8.9%; for intrahepatic bile duct tumors, it is 4.8%; and for extrahepatic bile duct tumors, it is 20.2% (Table 1Go). Only neoplasms of the pancreas have a worse 5-year survival rate at 4.4% [1]. In recent years, progress has been made in certain areas, for example, liver transplantation for hepatocellular cancer (HCC) in patients with viral hepatitis and cirrhosis, but the typically advanced stage of disease at the time of initial diagnosis continues to preclude effective therapy in the majority of patients.


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  		Table 1. Five-year survival rates in the U.S. from 1995–2000 following conventional therapy for selected types of hepatobiliary malignancies. Several other cancers are included for comparison.
 
Table 2Go summarizes incidences of the different primary hepatobiliary lesions. Overwhelming in number is HCC, with gallbladder cancer, cholangiocellular cancer (CCC), and fibrolamellar cancer following at some distance. In children, hepatoblastoma is the most common hepatobiliary tumor. HCC generally occurs only in young children with hepatitis B virus (HBV) infection.


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  		Table 2. Incidence of primary malignant tumors of the liver
 

   HCC
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 
Numerous reports have documented an increasing incidence of and mortality from HCC in the U.S. over the past three decades. In the period from 1976–1980, the incidence was 1.4 per 100,000 population; for the period from 1991–1995, the incidence rose to 2.4 per 100,000 population. HCC typically presents in association with cirrhotic liver disease or in patients with chronic viral hepatitis. Cirrhosis due to HBV infection carries an eightfold greater risk for HCC. With hepatitis C virus (HCV) infection, there is a fourfold greater risk [2]. African Americans are at a higher risk for HCV and HBV infection than Caucasians, and indeed, the rate of HCC from 1991–1995 was 6.1 per 100,000 in the African-American population, again emphasizing the close relationship between viral hepatitis and the occurrence of HCC [3]. Exceptions exist, but patients with HCC in a noncirrhotic liver either have resectable disease or are usually too advanced to be eligible for liver transplantation. In the U.S., HCC in absolute numbers is now most commonly associated with HCV infection, which is the cause of 40% of chronic liver disease cases. Some estimates suggest that approximately 3.9 million people in the U.S. (1.8%) are currently infected with HCV [4]; however, the Center for Disease Control suggests the number approximates 6 million. The usual estimate is that approximately 20% of initially infected individuals will progress to fibrosis and cirrhosis, and that 20% of that group will progress to HCC [4]. Eight to ten thousand deaths are attributed to HCV-related disease every year [5]. Whether individual HCV genotypes play an important role in disease progression remains controversial. Genotypes 1a and 1b, as well as genotype 4, seem to be associated with more aggressive recurrence, leading to fibrosis and cirrhosis after liver transplantation [6–8]. While in the mid-1980s HCV infection was largely due to contaminated blood transfusion products, this has become a rare event after routine testing of donors for HCV infection was instituted in May 1990. This has reduced the risk of transfusing a unit of HCV-positive blood to about 1:100,000 [9]. As a result, i.v. drug abuse has become the leading cause of acute infection with HCV. Most chronically infected patients acquired their disease 20–30 years earlier, typically as a result of past parenteral drug administration. Alcoholic liver disease in conjunction with viral hepatitis is an augmenting factor for the development of HCC [3, 10].

Two prerequisites are needed for the development of HCC in association with HCV infection [11]: a high viral replication rate, depicted by HCV-RNA levels, and progression of the chronic hepatitis to fibrosis and cirrhosis. HCC usually develops 3–4 decades after initial HCV infection [4]. In a large, North-Italian center, 447 patients with Child class A cirrhosis (of known viral origin in 62%) were followed from 1985–1990. In 30 patients, HCC was found at the baseline examination, and another 29 patients developed HCC during a median follow-up of 33 months. In that population, interestingly, and in contrast to large epidemiologic studies [2], HCV infection, rather than HBV infection, was more commonly associated with the risk for developing HCC. At study entry, 12 of 201 patients (5%) with HCV-related cirrhosis had HCC versus only 1 of 47 patients (2%) with HBV cirrhosis. If multiple causes for cirrhosis were present (alcohol, HCV infection, and HBV infection simultaneously), 11 of 82 patients (12%) had HCC at study entry. These numbers did not change significantly during the follow-up period [12]. In contrast to the experience reported in Japanese studies [13], close follow-up with serial ultrasound and {alpha}-fetoprotein (AFP) determinations did not improve outcome in the Italian series. In another study, by Koike et al. [14], the recurrence rate of HCC following alcohol injection or microwave coagulation therapy as initial therapy was compared in patients with nonviral and those with viral cirrhosis. Those with nonviral cirrhosis had a significantly lower intrahepatic recurrence rate at a site different from the primary lesion at 3 years than patients with HBV or HCV infection (28% versus 56% and 51%, respectively), again emphasizing the greater risk for HCC in livers with viral hepatitis.

A number of treatment options, including resection, chemoembolization, alcohol injection, thermoablation, and orthotopic liver transplantation, are available for patients presenting with HCC in a cirrhotic liver. The best treatment for each patient with HCC is dependent upon numerous factors: size and number of lesions, tumor grade, hepatic reserve, patient age, patient’s overall medical condition, and, most importantly, availability of organs for transplantation. The optimal treatment options are complete resection in patients with non- or minimally cirrhotic livers and liver transplantation in patients with more advanced cirrhosis; but this is rarely possible due to either advanced disease and/or lack of donor organs.

In a more than 12,000-patient Japanese study investigating the outcome of either hepatic resection, chemoembolization, or alcohol injection, it was found that resection was superior to the other treatment modalities in patients with solitary tumors [15]. Yamamoto et al. [16] conducted a similar study in 97 patients undergoing either resection or alcohol injection. While differences in overall 5-year survival rates did not achieve statistical significance in that study, there was again a trend toward a longer tumor-free survival time in the resection group. A French group compared chemoembolization with conservative treatment in patients with unresectable HCC and found no significant difference in survival [17].

Surgical Approach
For patients with anatomically resectable HCC and adequate hepatic reserve to tolerate the surgical procedure, resection remains the standard to which alternative treatment methods must be compared. In a large Japanese study of liver resection for patients suffering from HCC on the basis of HBV and HCV disease (with cirrhosis in about 58% of patients), tumor recurrence was observed in 372 of 423 patients within 5 years (88%). Nevertheless, the 1-, 3-, and 5-year survival rates of patients, even after recurrence, were 88.6%, 64.8%, and 35.5%, respectively, in patients with only intrahepatic disease and 62.3%, 30.2%, and 7.3%, respectively, in patients with intra- and extrahepatic recurrences [18]. Other authors have reported similar results [19]. In the same edition of Surgery, liver transplantation in the Japanese population was reported. Only 21 of a total of 308 patients undergoing living-donor right-lobe transplantation in Japan had HCC, reflecting their practice that the availability of liver transplantation is limited in general and that only patients with HCCs <2 cm in diameter are eligible for it. Survival in these patients was similar to that achieved in liver-allograft recipients not having HCC [20, 21].

There are three reasons postulated for the high rate of tumor recurrence in the remnant liver: A) dissemination of tumor cells through surgical manipulation; B) undetected intrahepatic metastases at the time of resection; and C) the likelihood of new primary tumors occurring in cirrhotic livers, especially in patients with HCV infections ("field defect"). Because of the high rate of development of new lesions following partial liver resection for HCC, treatment with total hepatectomy and transplantation, therefore, appears to be an attractive alternative.

In an early evaluation of transplantation, 192 patients encountered from 1974–1988 underwent either resection or liver transplantation for hepatic tumors. The histologic grading was more advanced in the liver transplantation group, 75% of whom had T4 tumors versus only 38% with T4 tumors in the liver resection group. This was reflective of the treatment strategy at that time in which liver transplantation was offered for unresectable disease, regardless of tumor stage. As a consequence, the 5-year survival rate following transplantation was only 17.2% [22].

In a subsequent study comparing liver resection with transplantation in 120 patients with cirrhosis, Bismuth et al. found significant advantages of transplantation. The patient groups were comparable with regard to underlying disease, age, and tumor size. However, as expected, patients in the resection group were more often Child class A and B cirrhotics. Despite the apparent advantage for the resection candidates, even patients with small (<3 cm) tumors and unifocal or bifocal disease had only a 17% 3-year recurrence-free survival rate, versus an 83% rate in the transplanted group [23]. These findings confirmed those presented by Bismuth et al. in their earlier, similarly sobering experience [24]. Transplantation was also reported to provide better survival than resection in the experience of the Pittsburgh group [25]. The 3-year survival rate in their patients was only 5.9% after resection versus 42.9% after transplantation. Otto et al. also found a benefit of liver transplantation in patients with early-stage tumors and end-stage liver disease that precluded resection. The 3-year survival rate after liver resection in patients with cirrhosis was only 23% compared with a 48% rate after liver transplantation. Also, in tumors <3 cm, liver resection yielded a 3-year survival rate of 33%, versus 76% after transplantation. However, the authors of that study did not find any benefit of liver transplantation in patients with HCC without cirrhosis (45% survival rate after resection, 30% after liver transplantation [26]).

Perioperative nutritional support has been suggested to improve outcome in patients with HCC who undergo major liver resection. For example, 124 patients were randomized to receive either parenteral therapy consisting of branched-chain amino acids, dextrose, and lipid emulsion given for 14 days perioperatively or no special preoperative nutritional support. Patients receiving i.v. nutritional support had fewer septic complications, less need for diuretics to control postoperative ascites, less weight loss, and better recovery of liver function [27].

In patients with extrahepatic spread of the HCC, liver transplantation is not a treatment option. The same holds true for patients with positive lymph nodes at the time of transplantation. Early experience revealed that rapid tumor recurrence develops in these allograft recipients in association with the required immunosuppressive therapy.

Organ Procurement and Transplantation Network/United Network for Organ Sharing Guidelines
Recognizing the relative urgency of proceeding to transplantation in patients with malignancy, the Organ Procurement and Transplantation Network (OPTN) as well as the United Network for Organ Sharing (UNOS) established special rules for liver allocation to patients with liver cancer (Table 3Go). Current UNOS policies, which have been revised several times over the past 5 years, direct liver allocation from deceased donors to all patients with end-stage liver disease according to the Model of End-stage Liver Disease/Pediatric End-stage Liver Disease (MELD/PELD) system. In adults, the International Normalized Ratio (INR), creatinine level, and bilirubin level are incorporated into a formula (Table 4Go) and a MELD score is calculated. In children, a modified formula that also includes age and growth failure as criteria is used for determining the PELD score. This allocation policy was implemented in February of 2002 in an attempt to address the conclusion that the previously used waiting time had proved to be a poor criterion on which to prioritize transplant candidates. In contrast, the MELD system had proved to be a reliable measure of short-term liver disease mortality [28]. Since patients with HCC usually have minimal liver dysfunction until late in the disease process, compared with patients suffering from cholestatic liver disease or viral hepatitis without cancer [28], a separate point system had to be implemented that would provide these candidates access to an allograft before their HCC progressed beyond the Milan criteria (see below). The Milan criteria were accepted by UNOS as a basis for organ allocation for patients with HCC: patients meeting the criteria can have one tumor <5 cm in diameter or up to three HCCs, the biggest not exceeding 3 cm. Therefore, additional MELD points were awarded to patients with HCC according to tumor size and number (Table 5Go), predicated upon the natural outcome of the disease [29].


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  		Table 3. Simplified TNM classification of HCC [45]
 

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  		Table 4. MELD/PELD calculator [32]
 

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  		Table 5. Initial and extension (every 3 months until transplantation is accomplished) MELD/PELD scores assigned for patients with HCC
 
Clearly, the policies initially implemented with this new allocation system overestimated the risk of HCC, as additional MELD score points were provided for both stage I and stage II lesions. As a result, according to the Scientific Registry of Transplant Recipients [30], 9,651 potential liver allograft recipients were added to the waiting list in 2002, resulting in a total of 17,332 patients on the list at the end of the year. Of the patients listed for orthotopic liver transplant (OLT) during 2002, 2.6% had malignancies, but at the end of the year only 0.9% of the patients waiting had hepatobiliary cancer. This translated to the observation by Freeman [28] that 21.5% of transplant recipients listed with the diagnosis of HCC in 2002 received a liver transplant, versus only 8% in the pre-MELD era. The reduction in HCC patients waiting for a liver transplant was comparable only with that observed for acute hepatic necrosis (7.6% of patients listed but only 4.9% of the total list at the end of the year). In contrast, for patients with cholestatic or noncholestatic cirrhosis, 8.4% and 59.3%, respectively, of patients listed were in these categories, but at year’s end, 10.3% and 66.4% were still waiting for an organ. These data prompted a change in MELD/PELD score calculations beginning on February 27, 2003. The MELD score at that point for patients with stage I HCC was lowered to 20 from 24; for stage II HCC it was lowered to 24 from 27 [31]. Further modifications occurred as of November 1, 2003, at which time all additional MELD points were removed for stage I HCC. At this point, the stage II MELD score exemption remained unchanged.

For listing a potential recipient with metastatic neuroendocrine tumors, or for patients with primary hepatobiliary malignancies that do not meet current UNOS criteria, individual patient approval must be obtained from a local board of appeal (regional review board [RRB]) that has been established for each region of the country. RRB approval is not necessary for HCC that meets UNOS criteria, which are essentially derived from the Milan criteria [32]. Pretransplant tumor documentation is based upon established imaging criteria plus either a positive biopsy, AFP level >200 mg/ml, or previous chemoembolization or other therapy. Patients with elevated AFP levels of >500 mg/ml can be listed even if there is no evidence of tumor on imaging studies since, occasionally, diffusely growing HCC might be diagnosed only by this marker. The MELD score allocation for these patients is that previously assigned to stage I HCC (Table 5Go).

Liver Transplantation
The early experience comparing resection with liver transplantation for patients with HCC emphasized that the most important objective is to accurately define the patient population for whom liver transplantation provides a survival rate that is both significantly better than that without transplantation and comparable with the survival rate following liver transplantation for other indications [33] (Fig. 1Go). The publication by Mazzaferro et al. [32] presented a landmark study that clarified the application of liver transplantation for HCC. In their study, liver transplantation was evaluated in 48 patients with HCC, apparently meeting the preset criteria of either one tumor <5 cm or up to three tumors <3 cm, the now called Milan criteria. In 35 patients, adherence to these criteria was confirmed upon pathological review of the explanted liver. The overall and recurrence-free survival rates over a median of 26 months of follow-up for these patients were 92% and 85%, respectively. In contrast, in the 13 patients whose disease in the explanted liver exceeded the criteria upon pathological review, overall and recurrence-free survival rates of only 59% and 50%, respectively, were achieved (p = .01 for overall survival and p = .002 for recurrence-free survival). Klintmalm subsequently emphasized the additional importance of histological grading of the tumor. In an analysis of 422 patients undergoing liver transplantation for HCC, he reported 1-, 2-, 4-, and 5-year survival rates of 72.2%, 63.4%, 47.4%, and 44.4%, respectively. Five factors were identified as having an impact on disease recurrence and mortality: tumor size >5 cm, vascular invasion, positive nodes, bilobar spread, and histological grade [34, 35]. Haug et al. came to the same conclusion, emphasizing that patients with tumors >3 cm in diameter had a worse prognosis [36].



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  		Figure 1. Treatment algorithm for patients with HCC. Patients with neuroendocrine tumors and liver metastases are considered as a separate group. They are treated according to the same algorithm except that the total tumor burden exceeding stage II does not contraindicate transplantation. Abbreviations: HCC = hepatocellular cancer; RFA = radiofrequency thermoablation.

 
More recently, Yao et al. [37, 38] have questioned whether the Milan criteria might be safely extended. They developed the so-called University of California, San Francisco (UCSF) criteria from an analysis of their own patient population over 12 years. Seventy patients with HCC initially meeting UNOS (Milan) criteria were followed prospectively. The average waiting time for a donor liver at that time (before MELD/PELD) was about 20 months for patients with HCC. Eleven patients dropped out because of tumor progression beyond the Milan criteria while waiting. The incidence of dropout was estimated to be only 2.5% for up to 9 months, but rose rapidly to 25% after a waiting time of 15 months. Not surprisingly, patients with initially borderline size or number of lesions were at highest risk to exceed the UNOS stage II limits while waiting. Survival after liver transplantation in 14 patients whose tumor burden fell within the proposed UCSF criteria (one tumor ≤6.5 cm, three or fewer nodules with the largest lesion ≤4.5 cm and total diameter ≤8 cm) was comparable with that in the patients undergoing transplantation based on the Milan criteria. They therefore concluded that the Milan criteria are too stringent and may be excluding some patients who might benefit from the procedure from consideration for transplantation.

These observations emphasize that current organ allocation policies for patients with HCC are being continually reassessed and will likely be further modified in the future. Currently achieved results in adult and pediatric transplant recipients are summarized in Table 6Go.


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  		Table 6. Experience with liver transplantation for hepatic malignancies in the U.S. in adult and pediatric (hepatoblastoma) transplant recipients
 
Imaging for HCC
In an attempt to ensure that the preoperative assessment of HCC status is as accurate as possible, the UNOS Liver and Intestinal Organ Transplantation Committee has provided specific requirements for listing [31]: A) The patient must undergo a "thorough" assessment to evaluate the number and size of tumors and rule out any extrahepatic spread and/or macrovascular involvement. This is accomplished by ultrasound, computerized tomography (CT) or magnetic resonance imaging (MRI) scans, and chest CT. The patient must have one of the following: a tumor >1 cm in size with a blush, an AFP level >200 mg/ml, an arteriogram confirming a tumor, or chemoembolization, radiofrequency thermoablation (RFA), cryoablation, or chemical ablation of the tumor. A prelisting biopsy is not mandatory. An HCC exception may be approved for patients with elevated AFP levels of >500 mg/ml but no sign of tumor on imaging with points being assigned equal to an HCC stage I tumor. B) The patient must not be a resection candidate. C) Continued documentation of the tumor is required every 3 months by CT or MRI scan.

These guidelines help to ensure uniform listing criteria. Unfortunately, even the most advanced techniques (multidetection CT scan and MRI scan) are known to have low sensitivities and specificities. In a study by Libbrecht et al. [39], CT scanning was found to provide a sensitivity of 50% and a specificity of 79%, while MRI scans had a sensitivity of 70% and a specificity of 82%, observations that are comparable with other reports [40, 41].

LDLT for HCC
Detection of HCC in the cirrhotic liver provides a seemingly highly appropriate indication for LDLT. Since hepatic dysfunction in these individuals is typically modest, the transplant can be planned as a semielective procedure, yet more expeditiously than is usually possible with deceased-donor transplantation. Most centers have observed, in fact, that relatives are typically quite aggressive in seeking immediate access to transplantation for the patient with cancer, even if it requires living donation. In an evaluation by Cheng at al. [42], LDLT appeared to provide a distinct advantage over deceased-donor liver transplantation. Survival rates for patients undergoing LDLT versus deceased-donor liver transplantation were 86% and 71% (at 1 year) and 68% and 42% (at 5 years), respectively. The estimated average survival time after LDLT was 12.2 years, versus 7.8 years after deceased-donor OLT. A similar experience was reported by researchers at the Mount Sinai Hospital. Their average waiting time for a deceased-donor liver transplant in 1998–2001 was 414 days, versus only 83 days for an LDLT. The authors emphasized that an aggressive LDLT strategy not only shortened the waiting time but also provided access to liver transplantation for patients with HCC that exceeded UNOS criteria [43]. This strategy, however, has been criticized because of the possibility that such previously ineligible transplant candidates could compete subsequently for a deceased-donor allograft if the living-donor liver failed, and would thereby deprive other patients on the waiting list from receiving an organ. As noted above, the current UNOS allocation system, employing MELD/PELD scoring, continues to evolve in an attempt to address the unique needs of the HCC patient population. At least initially, this policy has greatly reduced the waiting period for these recipients (Table 7Go). Over the first year following its activation, patients with stage I HCC in our region received allografts within 6–9 months, and those with stage II disease received allografts within 3–6 months. No comparable data are yet available to assess the effects of the modifications introduced in 2003.


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  		Table 7. Waiting times for deceased-donor livers for patients with hepatic malignancies in the U.S. in 2000–2002. For comparison, waiting times for common indications for liver transplantation are added.
 
Nevertheless, these, and the more complete UNOS data, confirmed that this practice has resulted in a shift in the U.S. from LDLT to deceased-donor OLT for adult patients with HCC. While, in 2000, only 100 deceased-donor OLTs were performed for patients with HCC (with or without cirrhosis), this number rose to 236 in 2002 following implementation of the MELD/PELD allocation rules. At the same time, the number of LDLTs for HCC decreased: from 22 in 2000 to 11 in 2002. As noted earlier, the overall consequence has been a marked increase in the total number of patients receiving liver transplants, increasing from the previous annual volume of 122 to 247 in 2002 (+102%).

Results after Transplantation for HCC
According to the OPTN [44], early survival after liver transplantation for HCC performed between 1996 and 2001 was quite satisfactory. However, longer-term follow-up revealed a more rapid attrition than that observed in patients with cholestatic liver disease or even noncholestatic cirrhosis (viral hepatitis). One-year survival rates for liver cancer (n = 464) and cholestatic liver disease (n = 1,213) transplant recipients were 82.2% and 91.9%, respectively. Three-year survival rates for liver cancer (n = 305) and cholestatic liver disease (n = 1,474) transplant recipients were 66.3% and 84.4%, respectively. The 5-year survival rate was only 57.0% for liver cancer transplant recipients (n = 212) but 80.2% for cholestatic liver disease transplant recipients (n = 1,417). How the new allocation system, which provides for earlier transplantation of patients with HCC, will impact these long-term survival rates remains to be determined.

Some authors have suggested that, in addition to more advanced disease, including tumors exceeding the Milan criteria or the finding of vascular invasion in the explanted liver, other factors, such as intensity or type of immunosuppression administered, may influence outcome following transplantation for HCC. Vivarelli et al. [45] suggested a correlation between the cumulative dose of cyclosporine A (CSA) and the risk for recurrence. They followed 82 patients over a 15-year period. Patients with HCC recurrence were found to have received a significantly higher first-year cumulative CSA dose than those without recurrence (135 g versus 106 g, p < .05). Possible limitations of this retrospective review were the findings that 70% of all recurrences were seen within the first year after transplantation and that the CSA dose was not significantly different between the two groups during the first 3 months (46 g in the tumor group and 39.5 g in the tumor-free group, respectively). One would have to postulate, therefore, that the additional CSA doses given to the recurrence-group patients during the second half of the first year immediately translated into rapid tumor growth.

More recently, there has been some interest in the possible efficacy of adding rapamycin immunosuppression to the antirejection regimen following transplantation for HCC. Because of its antiproliferative effects, it is postulated that this drug could potentially inhibit growth of any residual tumor cells. A pilot clinical trial assessing this hypothesis is now beginning.

The efficacy of adjuvant chemotherapy as prophylaxis for tumor recurrence has not been systematically evaluated. Since we had observed disappointingly high recurrence rates in our initial experience, we subsequently routinely added low-dose doxorubicin (Adriamycin®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) chemotherapy to our management regimen beginning in 1996. All subsequently treated patients meeting specific criteria have received post-transplantation doxorubicin (10 mg/m2) weekly for 20 weeks. This drug is generally well tolerated, except for bone marrow and cardiac toxicities. The explanted liver tumor burden in all liver allograft recipients enrolled in the study met the Milan criteria. Other inclusion criteria were stable liver function within 6–8 weeks following OLT, normal hematologic profiles, normal cardiac function (ejection fraction >50%), and no evidence of occult infection. During the observation period, a total of 23 patients had HCC with cirrhosis as their indication for OLT. Sixteen were enrolled into the study. Seven patients were excluded because they received multidrug regimens (two patients), had early complications precluding adjuvant chemotherapy (four patients), or had left the region (one patient). All patients completed the treatment course with only occasional interruptions for reversible myelosuppression. Of the patients enrolled, one died from unrelated causes and two developed recurrent HCC within 4 years. Thirteen were alive with excellent liver function and no evidence of recurrent disease with a median follow-up of 31.5 months. These observations were compared with those from a cohort of 103 patients receiving liver allografts for HCC at other centers in our UNOS region during the same time period. The overall survival rates for that cohort were 76%, 59%, and 45% at 1, 3, and 5 years, respectively, which are similar to national data. In contrast, the survival rates for our cohort receiving post-OLT chemotherapy were 93.8%, 93.8%, and 81.3% at 1, 3, and 5 years, respectively (unpublished data). Similarly encouraging observations have been reported by other groups [46], but no controlled studies of adjuvant chemotherapy have been completed.


   OTHER HEPATIC MALIGNANCIES
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 
Fibrolamellar Hepatocellular Carcinoma
Fibrolamellar carcinoma is a rare, less-aggressive form of HCC. This tumor does not appear to be related to underlying viral disease or cirrhosis. The malignant hepatocytes are large and polygonal in shape, and calcifications are not uncommon. In an excellent review, El-Serag and Davila [47] investigated the outcomes of fibrolamellar carcinoma patients compared with those of HCC patients in a population-based study. They identified 68 patients with fibrolamellar carcinoma and 7,896 patients with HCC during the years 1986–2000. The mean patient age at diagnosis of fibrolamellar carcinoma was 39 years; that of HCC was 65 years. The survival rate was significantly better for patients with fibrolamellar carcinoma, most notably at 1 year, at 72.8% versus 25.2% for HCC patients (Table 8Go). Ringe et al. published their data comparing resection with transplantation in 20 patients with fibrolamellar carcinoma. Fourteen patients underwent radical and complete resections and six patients underwent hepatectomies and liver transplantations. The 5-year survival rates were 44.5% and 28.5% for the two patient populations, respectively. The resection-alone group, as expected, had an overall lower tumor stage, which undoubtedly accounted for their superior outcome over those treated by transplantation [48]. The largest single-center series was reported by investigators at the University of Pittsburgh. In that study, 41 patients were treated with either resection (n = 28) or transplantation (n = 13). The 10-year survival rates were 70% after resection and 28% after transplantation; but again, the patients with more advanced tumors had been directed to the transplantation arm. One-third of the patients undergoing transplantation required concomitant resection of adjacent organs, the vast majority having stage IVa and IVb tumors [49]. Appropriate staging studies are the same as for HCC; extrahepatic disease is a contraindication for liver transplantation.


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  		Table 8. Comparison of fibrolamellar carcinoma and HCC based on the SEER program of the NCI [47]
 

   CHOLANGIOCELLULAR CARCINOMA
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 
In the early days of liver transplantation, CCC was considered an appropriate indication for transplantation, since survival after resection for CCC was so poor and these patients were generally in good overall condition without the complications of cirrhosis and portal hypertension. However, the initially treated allograft recipients quickly established that CCC was not an acceptable indication for liver transplantation due to early disease recurrence and poor long-term survival. The 3-year survival rate was about 20% and the 5-year survival rate was only 5%–15% [50]. This observation was confirmed by the Cincinnati Transplant Tumor Registry. From 1968–1997, 207 patients were registered after undergoing a liver transplantation for CCC. Seventy-one patients (34%) were still alive after a median follow-up of 23 months. At the time of writing of this report, only 11 patients (5%) had survived for more than 5 years. Of those who died, the median survival time was only 8.4 months [51]. This view is also supported by the publication by Goss et al. [52], in which a diagnosis of CCC in patients originally diagnosed with primary sclerosing cholangitis (n = 4) led to tumor recurrence and death in all patients within 3 years. These data have led to a general consensus that, in light of limited donor organ availability, liver transplantation is not a suitable therapeutic approach for patients with CCC.

Recently, the Mayo Clinic group suggested that this practice should be re-evaluated. They have designed a protocol that includes pretransplant external-beam irradiation followed by transcatheter irradiation and 5-fluorouracil (5-FU) infusion. An exploratory laparotomy is then performed to exclude extrahilar lymph node disease, following which the patient is activated on the waiting list. 5-FU therapy continues to the time of transplantation. In their initial report, 19 patients had been treated under this protocol, 11 of whom proved to be eligible for liver transplantation. All 11 patients were alive 17–83 months after the OLT. Only one patient, who had unrecognized stage IV disease at the time of transplantation, manifested disease recurrence in mediastinal lymph nodes but was alive 40 months after the transplantation [53, 54]. Those investigators concluded that liver transplantation after pretransplant conditioning with radiation and chemotherapy provides effective therapy for patients with CCC with disease limited to stage I or stage II. Under these stringent criteria, liver transplantation could be an option in very selected cases.


   EPITHELOID HEMANGIOENDOTHELIOMA
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 
Epitheloid hemangioendothelioma is a disease that was first described in 1982, affecting mainly younger females and resulting from a malignant transformation of vascular endothelium. An association with oral contraceptives has been suggested but not completely established. Clinical presentation may be with abdominal pain, but more frequently the lesion is an incidental finding. Since the tumor is often widespread within the parenchyma, complete resection may not be possible, even in the noncirrhotic liver. The results after liver transplantation are quite acceptable, being comparable with those after OLT for viral-induced cirrhosis. The largest single-center report comes from the Pittsburgh Transplant Center. In 16 patients with a median follow-up of 4.5 years, survival rates were 100%, 87.5%, and 73.3% at 1, 3, and 5 years, respectively. The disease-free survival rates were 81.3%, 68.8%, and 60.2%, respectively [55]. Penn’s tumor registry contains 21 patients (9 male, 12 female), with an average age of 34 years. Seven of those 21 patients had tumor recurrences (33%); the 2-year survival rate was 82% [56].

In contrast, angiosarcoma also originates from the endothelium; but unlike epitheloid hemangioendothelioma, this tumor is very aggressive, typically filling the hepatic sinusoids and causing hepatocyte atrophy. Surgical resection is complicated by a high early recurrence rate, and there is clearly no role for liver transplantation for this endothelial cell tumor. Diagnosis and staging of both vascular tumors are done by biopsy and imaging.


   HEPATOBLASTOMA
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 
Hepatoblastoma is the most common malignant tumor of the liver in the pediatric population, affecting mostly young boys age <3 years and accounting for 75% of primary liver tumors in childhood. Diagnosis is usually at a late stage. Nevertheless, the introduction of chemotherapy with cisplatin (Platinol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and doxorubicin has changed the treatment success of hepatoblastoma substantially, and despite a large tumor mass at presentation, a combined surgical and chemotherapeutic approach has yielded a 5-year survival rate of approximately 80%. Liver transplantation plays a role only in those patients whose tumors cannot be completely resected after appropriate chemotherapy. The most complete report of liver transplantation was published by Otte et al. [57], who reviewed the results of 147 patients from several European pediatric centers. The overall survival rate at 6 years post-transplantation was 82% in patients who had not undergone pretransplant-attempted liver resections, versus 30% at 6 years for patients who underwent liver transplantations after failed resections. A multivariate analysis showed that the only variable adversely impacting outcome was the presence of macroscopic venous invasion. Additional encouraging results were published by the London group at Kings College Hospital: 13 children (11 boys, two girls) were alive after liver transplantation at a mean follow-up of 33 months. One child was alive with tumor recurrence. Most remarkably, some of these long-term remissions were achieved in children who had received pretransplant chemotherapy for pulmonary metastases and extrahepatic intra-abdominal tumor growth [58]. A similar experience was reported by the Birmingham group. Thirty-four children with hepatoblastomas were treated over a period of 10 years. If a resection was not feasible or if the tumor recurred after resection, then liver transplantation (n = 12) proved to be effective rescue therapy, leading to recurrence-free survival in all seven patients with chemosensitive tumors after a mean follow-up of 3.5 years. Three of the five patients whose tumors were not chemosensitive were alive with no evidence of recurrent disease. Two patients died, one of recurrence (23 months after transplantation) and the second of unrelated causes [59].


   METASTATIC LESIONS
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
Summary
 Disclosure of Potential...
 References
 
As already noted, metastatic disease is a contraindication for liver transplantation except when the primary disease is a neuroendocrine tumor. Neuroendocrine tumors are also referred to as apudomas (amine precursor uptake and decarboxylation). These tumors are usually hormone producing (serotonin, insulin, gastrin, glucagon, etc.), but also may present as a nonfunctioning mass lesion. The clinical presentation is diverse, depending upon the hormone secreted. These tumors typically metastasize to the liver, and some patients note pain, resulting from capsule distention, as a first symptom. Even after metastasizing, these tumors often remain slow growing so that approximately one-third of the patients survives for 5 years after the development of liver metastases. Because of the somewhat indolent nature of their liver metastases, these patients are considered appropriate candidates for liver transplantation. In the French experience [60], 31 patients diagnosed with neuroendocrine tumors underwent liver transplantations. In 14 patients, the primary tumors were also removed at the time of transplantation. Patients with hormone-producing neuroendocrine tumors (n = 15) had a 5-year survival rate of 69%, while the survival rate for patients with noncarcinoid apudomas (n = 16) was only 8% at 4 years. Two reasons were proposed for this difference: postoperative mortality was lower in the patients with carcinoid tumors (1/15 of patients with carcinoid tumors versus 5/16 of patients with noncarcinoid apudomas dying within 30 days) and recurrence of carcinoid tumors is not as aggressive as that of noncarcinoid apudomas. Other authors support this view. The Milan group compared resection with liver transplantation for patients with neuroendocrine tumors of comparable sizes and histology. Liver resection resulted in a 5-year survival rate of 67%, but a disease-free survival rate of only 29%. Liver transplantation resulted in a 5-year survival rate of 70% and recurrence-free survival rate of 53% [61]. The conclusion of that study was that OLT can be proposed for young patients with carcinoid tumors confirmed by histology, with primary tumors originating in the gastrointestinal tract, previously removed surgically, controlled for at least 6 months after the resection, and without signs of extrahepatic metastases. The importance of removing the primary tumor before the liver transplantation was confirmed by Lang et al. [62]. Three of four patients who were free of recurrence 2, 57, 58, and 103 months after transplantation did not have extrahepatic tumor manifestations at the time of transplantation. In contrast, 5 of 12 patients with recurrences had extrahepatic disease, including four patients with unknown primaries. In their series, the tumor burden was impressive; about 50%–60% of the liver was replaced by tumor. These advanced disease states explain the high rate of palliation and the low rate of "cure" in this series and support the aforementioned guidelines for liver transplantation in patients with neuroendocrine tumors.


   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
Disclosure of Potential...
 References
 
Liver transplantation for hepatic malignancies has emerged from an exotic and desperate approach to a well-documented and proven treatment modality for these unfortunate patients. However, early unsatisfactory results emphasized that only a highly selected patient population would benefit from transplantation. Currently, <10% of all liver transplants performed are for HCC. There is no controversy that hepatoblastoma is an excellent indication in pediatric patients with unresectable tumors. Similarly, liver transplantation for HCC in the adult population yields good results for patients whose tumor masses do not exceed the Milan criteria. It remains to be determined whether patients with more extensive tumors can be reliably selected to benefit from the procedure. Adjunctive procedures like RFA, chemoembolization, or cryotherapy might be indicated to limit tumor progression for patients on waiting lists. Epitheloid hemangioendothelioma is also an appropriate indication for liver transplantation, unlike angiosarcoma. Metastatic liver disease is not an indication for liver transplantation, with the exception of cases in which the primary is a neuroendocrine tumor, for which liver transplantation can result in long-term survival and even cure in a number of patients. And finally, while gallbladder cancers are never an indication for liver transplantation, rare cases of CCC might qualify if aggressive combination therapies, including chemotherapy and radiotherapy followed by OLT, are carried through. Survival in these selected patients can approach that for patients with cholestatic liver disease.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
References
 
The authors indicated no potential conflicts of interest.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 HCC
 Other Hepatic Malignancies
 Cholangiocellular Carcinoma
 Epitheloid Hemangioendothelioma
 Hepatoblastoma
 Metastatic Lesions
 Summary
 Disclosure of Potential...
 References
 

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Received August 2, 2004; accepted for publication January 14, 2005.




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