Liver transplantation in patients with hepatocellular carcinoma:
factors implicated in tumor relapse

D. Martínez Ares, F. J. Suárez López, J. Souto Ruzo, A. Otero Ferreiro, M. Gómez Gutiérrez,
B. González Conde, C. Fernández Sellés, B. Gala López, F. Arnal Monreal and J. L. Vázquez Iglesias

Service of Digestive Diseases and Unit of Liver Transplantation. Complejo Hospitalario Universitario Juan Canalejo. A Coruña, Spain

 

ABSTRACT

Introduction: liver segmental resection and liver transplantation are both treatments intended for healing liver cancer. An adequate selection of patients eligible for transplantation is crucial, since organs available for transplants are usually scarce. For this reason, awareness of the prognostic factors of relapse is of great importance. We present a comprehensive review of our series in order to better understand these prognostic factors.
Material and methods: we revised the cases of patients with hepatocellular carcinoma who underwent liver transplantation during the period 1994-2000, and present a detailed analysis of a series of variables which may be probably implicated in the appear-ance of relapse and which have an effect on survival.
Results: after a mean follow-up of 33 months, the mortality rate was 27.5% and relapse occurred in 18.75% of cases. No history of alcohol abuse, the number and size of the nodules, the presence of macro and microscopic vascular invasion, and pTNM stage T4 were all factors associated with a significantly increased risk of relapse (p<0.05). These factors and positive HCV were associated to decreased survival. After a multivariate analysis, the size of the nodules and the presence of macroscopic vascular invasion were considered the only independent risk factors for tumor relapse and post-transplantation relapse and mortality, respectively.
Conclusions: macroscopic vascular invasion and tumor nodules larger than 5 cm are both independent risk factors of tumor relapse after transplantation. Nevertheless, only macroscopic vascular invasion seems to have a significant effect on survival.

Key words: Hepatocellular carcinoma. Liver transplantation. Prognostic factors. Tumor relapse. Survival.

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Martínez Ares D, Suárez López FJ, Souto Ruzo J, Otero Ferreiro A, Gómez Gutiérrez M, González Conde B, Fernández Sellés C, Gala López B, Arnal Monreal F, Vázquez Iglesias JL. Liver transplantation in patients with hepatocellular carcinoma: factors implicated in tumor relapse. Rev Esp Enferm Dig 2004; 96: 22-31.

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Recibido: 29-01-03.
Aceptado: 03-09-03.

Correspondencia: D. Martínez  Ares. Servicio de Aparato Digestivo y Unidad de Trasplante Hepático. Complejo Hospitalario Universitario Juan Canalejo. C/ As Xubias de Arriba, 84. 15006 A Coruña. Tel.: 981 128914 - 619 983701. e-mail: martinezares@eresmas.com

 

INTRODUCTION

Hepatocellular carcinoma is the commonest malignant tumor of the liver (1). It is clearly associated with cirrhosis of the liver, especially in geographical areas where viral hepatitis has a low incidence. In developing countries, where infection with hepatotrope viruses is endemic, up to 40% of all cases of liver carcinoma may appear in non-cirrhotic livers. Chronic liver pathology due to alcohol abuse and liver pathology associated with chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) are the usual substrate of hepatocellular carcinoma (2).

Several factors, such as increased survival of patients with liver cirrhosis, developments in diagnosis, follow-up programs, etc., have all contributed to a significant increase in the prevalence of this condition in recent years. Now, there are more efficient therapeutic modalities, and diagnosis is more often achieved in the early stages of the disease, when treatment targeted to cure the disease may be applied. Liver segmental resection and liver transplantation may help achieve a survival rate of 60-70% at five years in selected patients. In patients undergoing transplantation survival is similar to that expected in patients without liver carcinoma who undergo transplantation for end-stage liver disease (3).

According to the most recent trends (4), patients with a single nodule smaller than 5 cm who do not have portal hypertension and who have normal bilirubin are the ideal candidates for resection. In such cases, and although relapse is more frequent at five years, survival is similar to that observed when transplantation is the treatment of choice. In patients with several nodules (smaller than 3 cm, and with a maximum of 3 nodules) and with a more advanced liver pathology, liver transplantation is considered the ideal approach, which will besides help cure the underlying hepatic disease (5).

The process of selecting patients eligible for healing treatment, and especially for liver transplantation, is now a commonly debated topic. This involves a discussion on the prognostic factors that may offer a better prognosis for mortality and tumor relapse after treatment. For this reason, we decided to revise the results in our series and assess those factors that, as regards tumor relapse and survival, may provide a better prognosis regarding the outcome of patients with hepatocellular carcinoma who undergo liver transplantation.

MATERIAL AND METHODS

Patient selection

We revised all the cases of patients who underwent liver transplantation at our center during the period 1944-2000. Of these, we selected the cases in which a hepatocellular carcinoma was detected in the explant, whether detection was the result of the intervention or an incidental finding.

Variables studied

We made a comprehensive study of the demographic variables and further analyzed over thirty variables, evaluating their potential prognostic influence. Of all these variables, we mention those considered of relevance or with clinical significance in previous studies. Thus, the level of serum alpha-fetoprotein, the number and size of nodules, the presence of an incidental tumor or tumor capsule, tumor growth pattern and tumor differentiation, gross and microscopic vascular invasion, tumor stage in the explant (pTNM), and etiology of the underlying liver condition (HCV or alcohol abuse) were all included in the statistical analysis.

Statistical analysis

The statistical analysis was performed using SPSS 11.5. Survival and tumor relapse rates were calculated by constructing Kaplan-Meier survival curves. Statistical significance was calculated by log-rank and Chi squared tests. Cox regression method was used for the multivariate analysis.

RESULTS

Three hundred and forty liver transplantations were performed in out center during this period. In 80 of these (23.5%), the presence of hepatocellular carcinoma was the indication for transplantation in some cases, and an incidental finding in the explant in other. Of these 80 patients, 65 were males (81.25%) and 15 were females (18.75%). Patients’ mean age was 52.6 years, similar to that of patients who underwent liver transplantation for other reasons. A follow-up period of 12 months was required as an inclusion criterion in the study. Mean follow-up was 33 months. A summary of these data can be seen in table I.

Twenty-two patients (27.5%) died during follow-up. Kaplan-Meier curves (Fig. 1) were constructed, showing a survival probability of 63% at 60 months. Tumor relapse was the main cause of death (54.5%), followed by viral relapse (18.2%). Tumor relapse was seen in 15 cases, most of which were cases of systemic relapse (66.7%). Regional relapse (20%) and local relapse (13.3%) were less frequent. Systemic relapse appeared in the form of bone (6 cases, 60%), lung (3 cases, 30%), and esophageal metastasis (one case, 10%).

The hepatocellular carcinoma recurrence curve (Fig. 2) shows that the probability of relapse of the disease is 4% at one year, 15% at three years, and 18% at five years. Both curves show that most tumor relapses and deaths occurred within the first 24-36 months.

As regards tumor relapse after liver transplantation, a series of variables were analyzed (Table II). Of all the variables studied, only a non-alcohol abuse-related cause, number (multinodular) and size (larger than 5 cm) of nodules, gross and microscopic vascular invasion, and pTNM stage T4 were associated with a significantly increased risk of relapse (p<0.05). Expansive growth pattern (p = 0.086) and lack of tumor capsule (p = 0.055) seemed to be associated with an increased risk of relapse, although these factors did not achieve statistical significance. Statistical significance might have been achieved if the series had included more cases, since we had only ten patients with infiltrative growth recorded. Data of CLIP (6) and BCLC7 stages, two staging methods which may help in the management of hepatocellular carcinoma and in the construction of decision trees (7) and algorithms to manage the disease, were included in the study. No statistically significant results were obtained in either case. In some groups this was due to the small number of patients included.

After the multivariate analysis, the size of nodules and presence of macroscopic vascular invasion were considered the only independent risk factors of tumor relapse. Their relative risk is 9,421; 95% CI (1,080-82,206) for the former and 9,743 for the latter; 95% CI (1,847-26,562).

Regarding survival, an etiology different from a history of alcohol abuse, the number and size of tumor nodules, the presence of macroscopic vascular invasion,  pTNM stage T4, and positive HCV were the factors associated with significantly decreased survival (p < 0.05) (Table III). Although lacking statistical significance (p = 0.08), microscopic vascular invasion was apparently associated with decreased survival rate. In the multivariate analysis, macroscopic vascular invasion was the only independent factor associated with increased mortality, with a relative risk of 23,351 and a CI 95% (3,503, 155,673).

DISCUSSION

In recent years many attempts have been made to identify those factors that most accurately may predict risk of relapse for an hepatocellular carcinoma after liver transplantation (8,9). As the number of candidates for this procedure increases, and organ availability decreases, an adequate selection of patients eligible for transplantation is even more important. Liver transplantation has been the usual treatment indicated for patients with only one tumor nodule of 5 cm or smaller, and patients with a maximum of three nodules (the biggest of which should not be larger than 3 cm) of late. These restrictive criteria (known as Milan criteria) proved useful in identifying a group of patients with a low probability of recurrence (5). Notwithstanding, other authors have achieved similarly good results when patients with a size of up to 6.5 cm in the case of single tumors, and with a size of up to 4.5 cm when three tumor nodules were present, provided overall tumor diameter did not exceed 8 cm (these are the inclusion criteria known as San Francisco criteria) (10), were also included in their studies. In our country, Herrero et al. used similar criteria and achieved a free-of-disease survival of 70% at five years after transplantation (11). Thus, controversy arises when a subgroup of patients with a low probability of tumor recurrence are excluded due to very restrictive criteria (12).

There is a general agreement that standard TNM stag-ing is not useful, since it does not allow a good prognosis for risk of relapse or survival in patients who have undergone liver transplantation. Moreover, a preoperat-ive and postoperative comparison of pTNM staging shows that there is not much correlation in most cases (11,13-15). In our series, patients with pT1, pT2 or pT3 stages did not show significant differences as for the risk of relapse and mean survival. Only pT4 proved to entail a significantly higher risk of mortality and of tumor relapse. However, given the level of knowledge on this condition nowadays, patients with a different prognosis are included in this stage: a patient with a single nodule of 4 cm in size and with macroscopic vascular invasion will have a poorer prognosis when compared to a patient with two nodules of 2 cm each, one in the LHL, the other in the RHL, and both of them showing no vascular invasion.

In most studies, macroscopic vascular invasion is considered the most important prognostic factor for relapse and survival (16,17). The results in our study correlate with the results of previously published studies. However, the fact that this type of invasion is usually identified by the pathologist after an examination of the explant, where he can see a macroscopically visible vessel (usually larger than 2 mm) infiltrated by the tumor, implies a certain limitation. Thus, the objective should be the preoperative identification of this type of infiltration.

Unlike other authors, we think there is no relation be-tween level of alpha-fetoprotein and risk of tumor recurrence (10,18). We found no significant differences regarding risk of relapse and influence on survival. However, authors who consider that this has prognostic value reached statistical significance only when alpha-fetoprotein levels were over 300 and even up to 1,000 ng/mL. In our study, however, 100 ng/mL was considered the acceptable limit, and only 8 patients had AFP > 300 ng/mL.

In our study, the presence of a tumor nodule larger than 5 cm was accompanied by a significantly increased risk of relapse, although this fact does not have a signi-ficant effect on survival. This has also been noticed by other authors (19,20), who also found significant differences in survival and risk of relapse in relation to the number of nodules and their unilobular o bilobular distribution. In our case, these factors achieved statistical significance in the univariate analysis, but were not considered independent risk factors after the multivariate analysis.

A significantly increased mortality rate in the group of HCV-positive patients was a finding not seen in other series. After a detailed study of these cases (Table IV), we saw that most patients had died as a consequence of tumor relapse, which also happened in the group of patients with transplantation for hepatocellular carcinoma. Al-though there were no statistically significant differences, we found out that diagnosis was reached in more advanced stages of the disease in the case of HCV-positive patients, although follow-up had been the same in all groups (and all cases correlated with the current consensus) (21,22). At least half of HCV-positive patients are diagnosed when the disease is in stage pT4, while in 48.7% of HCV-negative patients a diagnosis is reached in stage pT1 or pT2 (p = 0.087).

From our results we conclude that the degree of tumor differentiation, and the fact that hepatocellular carcinoma is an incidental finding in the explant (and not an indication for transplantation), are variables that lack prognostic value. The low number of patients with poorly differentiated tumors (15%) may be a reason that statistical significance was not reached. Nevertheless, statistical significance has been achieved in wider series, including approximately 800 cases of transplantation for hepatocellular carcinoma registered in the International Tumor Registry (23-26). On the other hand, other authors (27) have mentioned that these incidental tumors are of little value, since they found up to 30% cases of vascular invasion in them. An expansive growth pattern and the lack of tumor capsule are factors that, despite not having statistical significance, are usually accompanied by an increased risk of tumor relapse that may be related to the fact that vascular invasion and a more remarkable tumor growth are more probable in this situation.

To conclude, our opinion is that standard TNM staging is a poorly useful and anachronical technique. We also believe that gross and microscopic vascular invasion, and nodules larger than 5 cm allow better prediction for increased risk of relapse, although only macroscopic vascular invasion significantly reduces survival. Finally, patients with chronic liver pathology for HCV and hepatocellular carcinoma who have undergone transplantation have a decreased long-term survival, probably due to the fact that tumors are in a more advanced stage at diagnosis in their case.

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