Liver transplantation (LT) is regarded as the best treatment for both primary and recurrent hepatocellular carcinoma (HCC). Post-transplant HCC recurrence rate is relatively low but significant, ranging from 10%-30% according to different series. When recurrence happens, it is usually extrahepatic and associated with poor prognosis. A predictive model that allows patient stratification according to recurrence risk can help to individualize post-transplant surveillance protocol and guidance of the use of anti-tumor immunosuppressive agents.

To develop a scoring system to predict HCC recurrence after LT in an Asian population.

Consecutive patients having LT for HCC from 1995 to 2016 at our hospital were recruited. They were randomized into the training set and the validation set in a 60:40 ratio. Multivariable Cox regression model was used to identity factors associated with HCC recurrence. A risk score was assigned to each factor according to the odds ratio. Accuracy of the score was assessed by the area under the receiver operating characteristic curve.

In total, 330 patients were eligible for analysis (183 in training and 147 in validation). Recurrent HCC developed in 14.2% of them. The median follow-up duration was 65.6 mo. The 5-year disease-free and overall survival rates were 78% and 80%, respectively. On multivariate analysis, alpha-fetoprotein > 400 ng/mL [P = 0.012, hazard ratio (HR) 2.92], sum of maximum tumor size and number (P = 0.013, HR 1.15), and salvage LT (P = 0.033, HR 2.08) were found to be independent factors for disease-free survival. A risk score was calculated for each patient with good discriminatory power (c-stat 0.748 and 0.85, respectively, in the training and validation sets). With the derived scores, patients were classified into low- (0–9), moderate- (> 9–14), and high-risk groups (> 14), and the risk of HCC recurrence in the training and validation sets was 10%, 20%, 54% (c-stat 0.67) and 4%, 22%, 62% (c-stat 0.811), accordingly. The risk stratification model was validated with chi-squared goodness-of-fit test (P = 0.425).

A validated predictive model featuring alpha-fetoprotein, salvage LT, and the sum of largest tumor diameter and total number of tumor nodule provides simple and reliable guidance for individualizing postoperative surveillance strategy.

Regardless of which selection criteria are used, post-LT hepatocellular carcinoma (HCC) recurrence happens in around 15%-20% of the cases, and it remains an important cause of death for HCC patients after liver transplantation (LT). A number of factors have been found to be associated with post-LT HCC recurrence, including alpha-fetoprotein (AFP)[1,2], PIVKA-II[3], lympho-vascular permeation[4,5], tumor differentiation[6], response to down-staging or bridging therapies[7-10], etc. However, studies focusing on the development of a risk prediction model for HCC recurrence had been limited, and this set the stage for research of predictive scoring model at different centers[11-14]. One of the scoring systems known as Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score was proposed by a group at the University of California at San Francisco (UCSF)[12]. It is composed of three parameters, namely serum AFP level, presence of microvascular invasion, and the sum of largest tumor diameter and total number of tumor nodules. Such predictive scores were shown to have a high concordance index in relation to HCC recurrence. Nonetheless, characteristics of the population from which the RETREAT score was derived were quite different from those of Asian regions. For example, only 20% of the population from which the RETREAT score derived was hepatitis B virus (HBV) carriers. In contrast, 80% of our population was HBV carriers. There is a need to develop a scoring system that is readily generalizable to Asian HCC patients. In this study, we derive and validate a new scoring system, aiming to delineate better the post-LT HCC recurrence risk so that future surveillance strategies can be more individualized and immunosuppressive therapy with anti-tumor properties can be commenced in a timely manner.

This study illustrated the development of a new scoring system featuring pre-LT AFP, salvage LT, and the sum of largest tumor size and number of tumor nodule on explant examination. In the validation process, this scoring system exhibited a high concordance index (c-index 0.85) in relation to HCC recurrence and demonstrated performance at least comparable to the AFP model (c-stat 0.77) and the RETREAT score (c-index 0.82). The proposed risk stratification model showed satisfactory goodness-of-fit between the expected and observed HCC recurrence rates, with high discrimination ability as exemplified by the Kaplan-Meier curve separation for the disease-free survival in patients from three different risk groups.

Since the introduction of the RETREAT score in 2017, it was widely accepted in Europe and North America as one of the most useful tools in predicting HCC recurrence after transplantation. RETREAT score was derived and externally validated using multicenter data of over 1000 patients. The good study design, scientific analyses, and encouraging results accounted for its success and popularity. In contrast, our current model was developed and internally validated based on a single center data with sample size of roughly one third to that of the RETREAT score. These facts do not negate the value of our current model, as the RETREAT score might not be readily generalizable to Asian populations (19.1% were Asian in the RETREAT score population), where prevalence of HBV carrier state is up to 80%. In addition, we are the first to incorporate quantitatively and qualitatively salvage transplantation, which is a common strategy for HCC in many centers, as one of the variables in the predictive model. We believe that the current model should work complementarily with RETREAT score in predicting HCC recurrence in particularly for patients of Asian ethnicity.

In this study, a number of preoperative and pathological factors were put into multivariate analysis. The influence of tumor size and multiplicity on post-LT HCC recurrence had been well recognized since the introduction of Milan criteria and its subsequent variants from other series. The effect of the sum of largest tumor diameter and total tumor number was illustrated by the “Metro-ticket” concept introduced by Mazzaferro et al[25]. The tumor size and number used in the current analyses were from explant measurement rather than preoperative imaging. The authors considered this a more objective and accurate assessment of tumor metrics when compared to preoperative imaging measurement. This is because the discrepancy between different imaging modalities (computed tomography, magnetic resonance imaging, or positron emission tomography), contrast injection protocols, and presence of inter-observer variability during reporting could lead to substantial errors, such as over- or under-reporting of tumor size and number. Using explant measurements should be theoretically more objective and accurate. Pathological tumor size and number should be inferable to pre-LT imaging during patient selection and counselling process.

Pre-LT serum AFP over 400 ng/mL was shown to be the most influential factor associated with disease-free survival. The role of AFP in HCC recurrence after LT has been demonstrated in the literature[26-28]. Moreover, it has been suggested that AFP over 1000 ng/mL should be a contraindication to LT even if Milan criteria are met[29]. The fact that AFP is frequently included as a parameter in other published scoring systems suggests that it is an important recurrence predictor[11,12,30,31]. In addition, there is a growing body of evidence that suggests that AFP level response to bridging loco-regional therapy has a significant prognostic effect in terms of post-LT HCC recurrence[32,33]. Although AFP response to pre-LT therapy was not investigated in our current series, future study should look into the effect of incorporating this variable into the existing risk prediction models.

Since its introduction by Majno et al[34], the approach of salvage LT has been a topic of debate. Theoretically, by delaying (resection first, transplant when recurrence occurs) or negating (curative hepatectomy in some HCC patients) LT, this “salvage” policy should be able to relieve the donor pool burden[35]. However, there are worries about the development of un-transplantable HCC recurrence after initial resection and inferior oncological outcomes[36-38]. In an intention-to-treat analysis by Fuks et al[36], half of the patients with recurrent HCC did not receive salvage LT because of disease beyond Milan criteria and deteriorated physical conditions. Patients who received salvage LT were also shown to have inferior disease-free survival[37,38]. In our current analysis, salvage LT, regardless of the previous treatment modality and number of tumor recurrence, was a significant predisposing factor for HCC recurrence.

Microvascular invasion has been shown to be an important factor in post-LT HCC recurrence in the literature. Failure to demonstrate this relationship in our series could be explained by the low prevalence of HCC recurrence (14.2%) and microvascular invasion (29.4%) in this study population. In our multivariate analysis, AFP over 400 ng/mL, salvage LT, and the sum of tumor size and number in explant were the more influential factors in this group of good risk HCC population. AFP over 400 ng/mL before LT represented a remarkable risk of post-LT HCC recurrence as suggested by the risk score of 7 for this predictor.

There were some limitations of the current study. Firstly, confounders associated with retrospective study, such as missing data and selection bias, could not be totally avoided. Secondly, the fact that some of the HCC patients in this analysis were transplanted with MELD bonus scores might have led to data contamination as patients from pre- and post-MELD-bonus eras had different tumor characteristics and prognosis; the random allocation of patients to the training and validation sets could have alleviated this problem. Thirdly, parameters such as neutrophil/platelet to lymphocyte ratio, total tumor volume, and other newer biomarkers were not investigated. Last but not least, despite good performance of our proposed scoring system demonstrated in the independent, randomly allocated validation population, the relatively small patient number (n = 147) might have limited its validating power, stressing the importance of multicenter patient recruitment in a future external validation study. Nonetheless, this new predictive model provides a simple and reliable way to stratify patients into different recurrence risk groups. For patients who belong to the high HCC recurrence risk group, close surveillance and early commencement of m-TOR inhibitor are strongly recommended, as the predicted recurrence risk is over 50%. To extrapolate further the application of our study, when a patient has a high pre-LT AFP level (i.e., over 400 ng/mL) and tumor metrics unequivocally approaching the “up-to-7” Metro-ticket limit value on pre-LT imaging, his/her baseline risk score is expected to be close to 14. Salvage LT in such a scenario should be rejected or at least deferred until the AFP level and tumor metrics could be brought down to a “safer” level by bridging loco-regional therapy.

In conclusion, a scoring system featuring pre-LT AFP level, salvage LT, and the sum of tumor largest diameter and total number of tumor nodule was developed and validated. This scoring system helps to stratify patients into different HCC recurrence risk groups, and thus an individualized surveillance strategy and immuno-suppressive protocol can be implemented.

The authors would like to thank Ms. Lam Ka Yiu Banny (BSc) and Mr. Yuen Kim [BSc (Hons), Stat and Comp] for data and statistical support.