Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide [12]. Although various treatment strategies have been developed for HCC, hepatic resection (HR) is considered the initial curative treatment strategy for HCC, along with liver transplantation (LT) in especially early HCC [3]. However, HCC recurrence after HR is the primary limitation reducing the effectiveness of HCC treatment because of its high incidence [4]. In particular, early recurrence leads to a worse survival rate among patients [56].

Traditionally, serum tumor markers including α-FP and protein induced by vitamin K absence-II (PIVKA-II) have been considered monitoring factors or potential predictors of poor prognosis after multimodal treatments for HCC as they are indirect indicators of tumor aggressiveness [78910].

A tumor recurrence prediction model based on a combination of PIVKA-II and α-FP for HCC patients after living donor LT (LDLT) beyond the Milan criteria was previously introduced for predicting HCC recurrence [11]. The models for tumor recurrence after liver transplantation (MoRAL) score ($11\times \sqrt{\text{PIVKA}-\mathrm{II}}+2\times \sqrt{\mathrm{\alpha }-\mathrm{F}\mathrm{P}}$) employs 2 tumor markers [11]. A previous study reported that a low MoRAL score (<314.8 points) was closely associated with better recurrence-free survival and overall survival after LDLT compared with a high MoRAL score because MoRAL score reflects tumor aggressiveness and biology [11].

However, no study employing the MoRAL score in HR in HCC patients has been reported. On the basis of the usefulness of the MoRAL score in predicting tumor aggressiveness, we hypothesized that the MoRAL score can predict patient prognosis following HR for treatment-naïve solitary HCC. The purpose of this study is to validate the predictability of MoRAL for HCC recurrence or patient death and to evaluate the predictors of early HCC recurrence after HR in patients with treatment-naïve solitary HCC.

The present study revealed that a preoperative MoRAL score greater than 314.8 points is closely associated with worse DFS and PS and can predict early recurrence. The time from first HCC recurrence to second HCC recurrence and the time from first HCC recurrence to patient death were correlated with a preoperative MoRAL score greater than 314.8 points.

Preoperative serum α-FP level is a prognostic factor correlated with oncological outcomes [11]. The expression of α-FP in HCC tissues was shown to be closely associated with biological aggressiveness and tumor differentiation of HCC because the serum α-FP level reflects tumor necrosis and tumor cell proliferation or regeneration of the underlying liver [1415].

PIVKA-II level for detection or diagnosis of HCC has been demonstrated and widely used in Asian countries, but experiences using PIVKA-II as a screening diagnostic tool in European countries remain limited in number [14]. PIVKA-II has been proven to act not only as a diagnostic biomarker but also as an independent prognostic factor in HCC patients [8910]. Also, PIVKA-II has been reported to be another independently predisposing factor of intrahepatic recurrence; a high serum PIVKA-II level was closely associated with tumor recurrence by intrahepatic metastasis of tumor cells via the portal vein because of the increased biological invasiveness to the vessel [16]. Thus, serum PIVKA-II has been demonstrated to be strongly associated with extrahepatic metastasis and microvascular invasion, even in early HCC [1718].

These observations suggest that serum α-FP and PIVKA levels have a significant association with a high rate of HCC recurrence after surgery [8910]. Our study also demonstrated that the early recurrence group presented significantly higher preoperative α-FP and PIVKA-II levels than the late recurrence group. Early recurrence of HCC is known to shorten the survival time after HR [6], which implies that early recurrent HCC cases are biologically more aggressive than late recurrent HCC cases [14].

The MoRAL score is a model that involves PIVKA-II and α-FP as components. Accordingly, MoRAL scores in the early recurrence group were significantly higher than those in the late recurrence group. The MoRAL score was developed for predicting early recurrence after LDLT in HCC patients [11]. Clinicians could use this approach to identify patients beyond the Milan criteria who are at low risk of tumor recurrence after LDLT. Higher MoRAL scores are associated with cytokeratin 19 expression, which is a stemness-related marker and indicates tumor aggressiveness or tumor invasiveness [15]. A previous study reported that a low MoRAL score (<314.8 points) was closely associated with a significantly lower risk of both tumor recurrence and overall death than was a high MoRAL score (>314.8 points) [19]. Therefore, the predictability and statistical usefulness of the MoRAL score were demonstrated in an LT setting [20]. Recently, another study validated use of the MoRAL score in RFA patients [21]. However, LDLT is not always an option in solitary HCC patients [12]. If liver function is preserved and adequate living liver donors are not available, HR is more highly recommended than LDLT in patients with solitary HCC. In our study, the MoRAL score was significantly associated with DFS and PS after HR. Our study also demonstrated that high MoRAL scores were consistent with the findings of previous studies [111921]. The cut-off value of 314.8 points was statistically useful in the case of HR as was true in the case of LDLT. The MoRAL score was statistically meaningful not only in univariate analysis but also in multivariate analysis. Interestingly, the MoRAL score can predict the development of early HCC recurrence within 2 years after HR. In addition, a high MoRAL score predicted early recurrence within 2 years after HR and the chance for the second recurrence after the first recurrence.

The biggest factor that impacts survival after treatment of HCC is early recurrence, based on the present study. Appropriate treatments for early recurrence improve the survival rate of patients [5]. Using the MoRAL score model, we can discern patients in the early recurrence risk group in the preoperative stage. Therefore, we cautiously suggest that regular or frequent surveillance for the development of early recurrence by liver radiologic images might be necessary among patients with high MoRAL scores. The risk of developing early recurrence after HR for treatment-naïve solitary HCC seemed to be quite high among patients with high MoRAL scores. Early detection of early recurrent HCC improves the survival rate by facilitating the earlier introduction of appropriate treatments such as PEI, RFA, TACE, re-resection, and LDLT [5].

Our study has several limitations. First, there is a potential risk for selection bias because of its retrospective design. In addition, our study included only recurrent hepatectomy patients with HCC. Second, as our study population reflects the epidemiology of HCC in South Korea, most of our patients had chronic hepatitis B. Third, it was not easy to gather detailed information from 2 hospitals. The type of liver resection, intraoperative blood loss and transfusion during the surgical procedure, and postoperative complications were not investigated. Further studies validating the prognostic role of the MoRAL score in HCC patients with different etiologies in Western countries are warranted to generalize our results.

In conclusion, we validated the MoRAL score for prediction of oncological outcome after HR in patients with treatment-naïve solitary HCC. Patients with MoRAL scores of 314.8 points or less demonstrated better outcomes in comparison with patients with high MoRAL scores. Patients with high MoRAL scores (>314.8 points) might require frequent regular surveillance regarding the development of early tumor recurrence, and MoRAL scoring is an easily performed, widely available, objective, and reproducible means by which to identify patients at greater potential risk of recurrence.