Hepatocellular carcinoma in the setting of liver transplantation

Abstract

Hepatocellular carcinoma (HCC) is a frequent complication and leading cause of mortality among patients with cirrhosis. In the setting of advanced liver disease, many patients with HCC are not candidates for hepatic resection due to inadequate functional hepatic reserve and the risk of postoperative decompensation. In these patients, liver transplantation (LT) offers curative therapy, as well as amelioration of their underlying chronic liver disease. Among appropriately selected candidates, LT for HCC provides excellent technical results with 5-yr overall survival rates exceeding 70%, similar to patients undergoing LT for other indications.1-4 The size and number of tumors plays an important role in determining an individual patient's candidacy for LT. However, patients on the LT waiting list are at risk for tumor progression leading to ineligibility for LT and death. Given the significant impact of HCC on patients with cirrhosis, healthcare providers caring for this patient population need to be familiar with the diagnostic criteria, pretransplantation management, transplantation criteria, and organ allocation policies associated with LT for HCC. HCC, hepatocellular carcinoma; LT, liver transplantation; HCV, hepatitis C virus; AFP, alpha fetoprotein; CT, computerized tomography; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; TACE, transarterial chemoembolization; RFA, radiofrequency ablation; UNOS, United Network for Organ Sharing; MRI, magnetic resonance imaging. With the exception of patients from areas of the world with endemic hepatitis B virus infection, an estimated 95% of HCCs arise in the setting of cirrhosis. Reported estimates of the annual incidence of HCC among cirrhotic patients ranges from 2-9%.5-9 Data from a cohort of European patients with hepatitis B virus-related cirrhosis reported that 6% of patients developed HCC within 5 yr of diagnosis.10 Among Asian patients with cirrhosis secondary to chronic hepatitis B virus, the reported incidence of HCC is 2.5% per yr.11, 12 The observed incidence of HCC among patients with cirrhosis secondary to hepatitis C (HCV) ranges from 2 to 8% per yr.12-15 Patients with hereditary hemochromatosis have a reported incidence of HCC approaching 3 to 4% per yr.12, 16 Globally, HCC is the third leading cause of cancer-related death and accounts for as many as 500,000 deaths annually.16 The prevalence of HCC is especially high in Asia, where HCC is the second most common cause of cancer death. In Japan, primary liver malignancies (95% of which are HCC) are the third and fifth leading cause of cancer death among men and women, respectively. In Western nations, both the incidence and mortality rate from HCC are increasing.5, 17 Data from European centers suggests that HCC causes 50 to 70% of liver-related mortality among patients with cirrhosis.5 In the United States, where approximately 50% of cases are secondary to chronic HCV infection, the incidence of HCC has dramatically increased over the past 2 decades. An estimated 8,500 to 11,500 new cases of HCC occur in the United States each year. Data from the National Cancer Institute Surveillance Epidemiology and End Results registry demonstrates that the age-adjusted U.S. incidence of HCC has doubled between 1985 and 1998.17 Associated with the rising incidence of HCC, healthcare expenditures for HCC have also significantly increased. Hospital charges for HCC-related treatments doubled from 1988 to 2000 to exceed $500 million.18 Furthermore, the incidence of HCC in the United States is projected to continue rising due to epidemiologic factors such as the aging of the population and the rising frequency of cirrhosis in patients with chronic HCV infection. Additionally, the obesity epidemic in the United States associated with nonalcoholic fatty liver disease will also likely contribute to the prevalence of HCC.19-21 Practice guidelines recommend that patients with cirrhotic stage liver disease be enrolled in surveillance programs with the aim of identifying HCC at an early stage.12 Surveillance programs are typically based on ultrasonography of the liver at 6-month intervals. Serum alpha fetoprotein (AFP) is also frequently measured, although it has not been found to be sensitive and efficient as a screening tool, and current guidelines from the American Association for the Study of Liver Diseases do not recommend serum AFP determinations for HCC surveillance.12 Since HCC develops at a relatively high frequency among patients with cirrhosis, any new liver mass identified in a cirrhotic patient should be considered to be HCC until proven otherwise. The detection of a lesion suspicious for HCC in the setting of a surveillance program should prompt further diagnostic and therapeutic evaluation.7 In contrast to other malignant tumors in which biopsy is required to guide management decisions, the diagnosis of HCC can usually be established by noninvasive means. HCC is characterized by a specific vascular pattern that in dynamic imaging studies results in contrast enhancement during the arterial phase (Fig. 1) followed by a contrast washout in the delayed venous phase. This pattern of contrast enhancement is seldom observed in minute nodules measuring less than 1 cm as they are not yet fully vascularized. This pathologic feature explains why mass lesions <1 cm cannot be confidently diagnosed by imaging studies; their small size also often makes a biopsy technically challenging, further confounding the diagnosis of these small nodules. Hence, many clinicians follow nodules <1 cm with interval imaging studies. When the detected nodule exceeds 1 cm but is still less than 2 cm, a biopsy is technically more feasible and can be considered if the dynamic imaging studies are indeterminate.12 HCC can be confidently diagnosed in most instances if a nodule >2 cm within a cirrhotic liver demonstrates the characteristic imaging pattern (rapid arterial contrast enhancement with washout during the delayed venous phase imaging studies) in a well-done imaging study by computerized tomography (CT) or magnetic resonance imaging (MRI). In nodules between 1 and 2 cm, a noninvasive diagnosis requires that 2 distinct imaging studies (CT and MRI) both demonstrate these features. This double confirmation helps avoid a false positive diagnosis in nodules of this size which may display difficult to interpret subtle findings on cross sectional imaging studies. It has to be stressed that almost one-half of the HCC between 1 and 2 cm will not exhibit the specific contrast enhancement pattern on CT or MRI, and, thus, a biopsy may be necessary to establish the diagnosis. Also, occasionally even large lesions may not have arterial phase contrast enhancement and will require a biopsy for the diagnosis. It should be noted, however, that a negative biopsy does not exclude the diagnosis of HCC, and hence, if the biopsy report is equivocal, repeated biopsies may be necessary to confidently establish a diagnosis. The role of serum AFP determinations are of limited usefulness.22 In patients with an increased AFP in whom a liver mass shows a nonspecific vascular pattern, a biopsy should be obtained, as cholangiocarcinoma and some digestive metastases may also present with an increased serum AFP value. If the mass has a diagnostic imaging pattern for HCC, the diagnosis is already established irrespective of serum AFP concentrations. Nonetheless, studies have reported that a mass in a cirrhotic liver with a serum AFP >200 ng/mL can be confidently diagnosed as HCC with a specificity of 99.4%.23 Because noninvasive criteria may have only moderately specificity in diagnosing HCC ≤2 cm and these small lesions do not rapidly progress even if they are HCC, the United Network for Organ Sharing (UNOS) does not allocate additional priority to patients awaiting LT with lesions smaller than 2 cm. This policy was developed to avoid transplantation in patients with a false-positive HCC diagnosis. While several recently published practice guidelines exist with regard to diagnostic criteria for HCC, recommendations for small lesions differ somewhat. The recent guidelines from the American Association for the Study of Liver Diseases only recommend a biopsy for lesions that lack characteristic radiographic features (Fig. 2).12 However, a biopsy of small lesions is technically more difficult and a negative biopsy from a suspicious lesion result should be regarded with caution (i.e., is the lesion benign or was the lesion missed by the biopsy needle). For lesions smaller than 1 cm in diameter, where the risk of HCC is lower, continued observation with serial imaging has been recommended.12 The risk of seeding from a biopsy could argue against performing this procedure. However, in a large multicenter series of 2,320 patients undergoing repeated tumor puncture for radiofrequency ablation (RFA), the reported seeding rate was only 0.5%.24 Therefore, it is likely that tumor seeding is an uncommon event and needle biopsy should be performed when necessary. Alternatively, small lesions suspicious for HCC can be followed with serial imaging studies; an enlarging lesion demonstrating characteristic features of HCC can be considered diagnostic. Gadolinium-enhanced MRI reveals a single HCC of 43 mm in diameter located in the caudal part of the right hepatic lobe (arrows). Suggested algorithm for evaluation of a liver mass in a cirrhotic patient detected during HCC surveillance according to the American Association for the Study of Liver Diseases (AASLD) guidelines. [Reproduced with permission from Bruix and Sherman,12 Hepatology, 2005]. Treatment options for HCC include those therapies with curative intent such as LT, hepatic resection, and ablation, as well as palliative therapies such as transarterial chemoembolization (TACE). Systemic chemotherapy and radiation therapy are of limited utility due to a high incidence of side effects, dose-limiting hepatotoxicity, and poor efficacy.12 There are no randomized controlled trials comparing LT to other therapies for the management of HCC. While early experience with LT for HCC was disappointing with 5-yr survival rates of approximately 25%, outcomes have significantly improved over time.25 In part, improved outcomes have been due to the application of stringent eligibility criteria for patients undergoing LT for HCC. Currently, patients undergoing LT for HCC have a 5 yr survival rate exceeding 70%, which is similar to survival for other indications for LT.1 The observed tumor recurrence rates are less than 15% at 5 yr.2-4 Chronic infection with HCV is the most common indication for LT in the United States. Among U.S. LT recipients, patients with HCV-related liver disease have a 23% increased mortality rate and a 30% increased allograft failure rate.26 These data obtained from the management of UNOS databases are in discrepancy with those obtained from the NIH LT Database,27 in which long-term patient and graft survival following LT for end-stage liver disease secondary to HCV infection are comparable with that observed for other indications. These differences may relate to donor age in the 2 databases. Older donors are associated accelerated fibrosis in HCV recipients. Since the universal use of hepatitis B immunoglobulin and oral antiviral drugs posttransplantation, the outcome of hepatitis B virus transplanted patients infection has become similar to those transplanted by other than virus-related causes.28, 29 Patients with well-compensated liver disease (Child-Turcotte-Pugh class A) and localized HCC may be managed with hepatic resection. Among carefully selected patients, outcomes for hepatic resection for HCC are satisfactory with reported 5 yr survival rates of over 50%.3, 30, 31 In an European study performed years ago, the multivariate analysis of risk factors for cirrhotic patients undergoing hepatic resection for HCC identified a serum bilirubin greater than 1.1 mg/dL and portal hypertension ≥10 mmHg (as measured by hepatic venous pressure gradient) as predictive of postoperative hepatic decompensation.32 For that reason, surgical resection should, therefore, be restricted to patients without portal hypertension. The applicability of hepatic resection in this circumstances is low (less than 5% of patients with HCC are candidates for hepatic resection), and the main drawback of this therapeutic option is the development of tumor recurrence in the remaining liver, as high as 50% at 3 yr and 70% at 5 yr.3, 30, 31, 33-35 Unfortunately, effective strategies for prevention of HCC recurrence following hepatic resection are lacking. Recurrence related to dissemination appear early during follow-up and are usually multifocal, thus excluding patients from subsequent LT. If such patients (patients with recurrence following hepatic resection) do undergo LT the results are disappointing with high postoperative tumor recurrence and mortality rates compared to initial LT.36 For that reason, some groups have recommended immediate transplantation for resected patients in whom pathological examination of the surgical specimen demonstrates features placing the patient at high risk for recurrence such as satellite lesions or However, in the United States, is no to these patients for LT although a analysis a waiting list for LT a for patients undergoing LT similar to those undergoing primary LT Patients for hepatic resection due to liver disease have small lesions may undergo randomized controlled trials comparing outcomes from therapies to hepatic resection or LT There are a of and The is by and ablation is limited by the number of tumors that may be in large tumors and technical for tumors in the liver to the or other survival rates of 50% have been reported for in tumors less than 2 cm in diameter, tumor rates of over for tumors to 3 cm in hepatic resection, do not the underlying chronic liver disease and patients be for tumor Liver have a to the use of donor Among cirrhotic patients with HCC, those with advanced liver disease to 3 nodules HCC the most from disease and vascular are considered criteria for LT due to the high rate of tumor for metastases with CT and with is with LT for other patients with HCC also undergo evaluation of their overall and as In the candidates for LT are those with the risk of tumor experience that tumor size was an important for patients undergoing LT for HCC. The metastases cancer has not been found to have for small experience with patients tumors on that they a survival comparable to patients undergoing LT for Therefore, tumor size has to as a noninvasive for other important factors such as and tumor In their that survival LT for HCC was similar to LT for other indications among patients have a limited of disease. In is to as the patients undergoing LT with a single tumor less than or to 5 cm in diameter or to 3 tumors each 3 cm or less in diameter have overall and of and respectively. it has been that the criteria could be based on demonstrating that patients with tumors exceeding these criteria satisfactory However, radiographic to tumor size and data that size with vascular Hence, an in size at the of for LT as by radiographic criteria should an increased risk of tumor recurrence following LT. This was by the experience at In their cohort of patients with HCC, the criteria, the of at criteria but not the criteria, and patients In those patients the criteria, the survival was patients with advanced HCC and a early survival as compared to end-stage patients with cirrhosis. However, recurrence was increased and long-term outcome was not Therefore, of size criteria likely will not result in satisfactory In exceeding the number of 3 with small which are likely should be further Nonetheless, the to patients with tumors exceeding established criteria be carefully against the use of donor Therefore, large trials demonstrating satisfactory long-term outcomes are Currently, data the use of criteria in LT are not and patients exceeding the criteria should be considered for LT only as part of are data to establish new it is important that the healthcare to LT candidates with HCC that tumor progression on the organ waiting list can occur and may exclude from LT In to a to the Model for End-Stage Liver was for organ allocation in patients by UNOS in While the has been to 3 survival in patients with end-stage liver disease of it has not been to survival in cirrhotic patients with HCC. cirrhotic patients with HCC have relatively hepatic and, therefore, are at low risk for death from liver These patients, however, are at a significantly of tumor progression leading to ineligibility for LT, which is not by their progression is significantly by the of waiting necessary for a donor organ to become demonstrate that outcomes for LT are by the of on the organ waiting when to patients with HCC limited to the criteria tumor cm or to 3 tumors the risk of from the waiting list at is approximately of 12 or greater is associated with a of due to tumor If the criteria are the rate exceeds The need to this event is the of priority policies and on the waiting list as the of In to the risk of death from tumor an to the UNOS was necessary for patients awaiting LT for HCC. the of the for organ patients with small HCCs a priority to a mortality rate of 15% tumors a priority to a mortality rate of 30% These to a in the number of patients undergoing LT for HCC during the yr was Furthermore, over of patients undergoing LT for HCC transplanted within of on the waiting This of patients with HCC to a significantly smaller number of patients with HCC from the waiting list compared to patients with chronic liver In UNOS several to the priority for HCC. UNOS has restricted the of additional priority to patients with a HCC or to 3 tumors each the for these patients is to a 15% of death within 3 biopsy is not but the lesion the following imaging an of the liver, a CT or MRI of the that the and a CT of the a that disease. In the have at 1 of the a vascular to the of on the imaging an AFP of >200 an a a biopsy HCC, chemoembolization of the and RFA, or ablation of the with chronic liver disease have a rising AFP ng/mL may be with a to an 8% mortality risk without even is no of a tumor based on imaging studies. will additional to a in mortality 3 until LT or due to tumor Currently, an HCC lesion greater than 2 cm is a of with tumors less than 2 cm in diameter no additional 3 the is increased to for an additional in mortality risk for patients remaining on the waiting 50 the increased of patients undergoing LT for HCC during the early was that patients with tumor (i.e., those most likely to progress and exclude a patient from transplanted without an to their the survival of patients undergoing LT for HCC during the early is not significantly than survival during the 50 a significant of patients undergoing LT for small HCCs during the early found to have been with no of HCC identified in the criteria for the noninvasive diagnosis of HCC not tumors smaller than 2 cm no additional priority for The of transplantation priority for patients with HCC the will continue to be and as by outcomes related to the allocation Patients with HCC waiting for LT are at significant risk for tumor the between the number of patients awaiting LT and the number of donor the waiting for patients for LT will become to UNOS in United States the of candidates waiting 2 yr or more has increased from 15% in to in with a in the number of patients on the waiting to the number of donor such as the use of criteria liver and are to the donor and however, also patients with HCC to LT with the aim of tumor progression and have that the of LT over hepatic resection with waiting Therefore, most centers chemoembolization is performed by the hepatic the HCC lesion and a that the is well and has been in a of randomized trials to a survival in patients with While is a risk of further hepatic does not appear to impact the of the Because of these is frequently to patients awaiting LT for In a study of patients with to the of the observed that patients from the LT waiting list during a waiting of of due to tumor progression 2 not considered to be candidates due to other was by a liver in 1 but no individual patient developed significant hepatic decompensation. This rate is than that reported by in a cohort of patients where no therapy was In a of TACE, reported a rate of from the LT waiting with a to LT of selected a cohort of patients the of to liver With a waiting of at the of the study on the waiting list and liver 1 of these patients with HCC recurrence and to survival rates and at and 5 respectively. In this HCC patients, of with more than 50% in size 3 developed tumor progression and from the and LT. these HCC patients, 3 patients developed HCC. in the patients, survival rates and at and 5 on these limited it appear that patients to the criteria results in to the use of in the pretransplantation are no randomized controlled studies the utility of The most frequent therapies are and In a patients for LT with a waiting of 3 patients due to tumor of transplantation and have developed HCC on CT or MRI, radiographic tumor was in of tumors with However, was a between the of to based on pathologic analysis radiographic of tumor nodules In a HCC in 50 patients with to LT interval of initial to LT of of the patients from LT due to tumor to the of at CT 70% obtained a but pathologic examination of the liver that only of HCCs a ablation was most effective in patients with lesions 3 cm in diameter or a of on the satisfactory with patient survival rates of 3 yr following it has been that initial to ablation is associated with an improved survival in both class and B patients, although the of failure initial is as high as to at 1 to at 3 and to at 5 ablation is also an to LT. living donor LT is a to transplantation rates and on the waiting but this important only if the waiting for liver transplantation is to exceed offers the of early to LT for patients with HCC, the risk of tumor progression awaiting a donor for HCC is in where outcomes are similar to In the United States, offers curative therapy to patients with tumor exceeding the criteria do not additional priority current UNOS In the criteria for for HCC include tumors to cm in diameter, 3 tumors each to 5 cm in diameter, or 5 tumors each to 3 cm in diameter, but outcome data from application will be necessary application of these criteria can be with the use of for other the to the be against the risk to the which a mortality rate of as well as a significant postoperative outcomes have been reported for patients with HCV-related liver disease as compared to donor and some centers this when patients for HCC has become a indication for LT. When appropriately patients undergoing LT for HCC have excellent outcomes that are similar to those undergoing LT for disease. Given epidemiologic HCC will continue to be an important indication for LT in the However, are many to be in the of LT for HCC. the of tumor size criteria for LT may this therapy to be to more In an of organ large trials of pretransplantation therapies and the development of to progression of HCC are necessary among patients awaiting LT. is the and of Hepatology, of of