There have been a few widely known predictive factors for survival and tumor progression in HCC patients with LT, such as cumulative tumor size [5], histological grade of differentiation [6], vascular invasion [7], lymph node involvement [8], higher TNM stages [9], and high dosage of cyclosporine [10]. In particular, microvascular invasion, macrovascular invasion, tumor number, and total tumor diameter were among the strongest prognostic factors in Chinese patients [11]. In the aspect of postoperative monitoring, different hematological indices have also been investigated (e.g. platelet counts [12], CD133 and CD90 [3]). Moreover, some preventing treatments (e.g. Licartin administration, Sorafenib treatment) may be helpful for blocking HCC recurrence or metastasis [13]. Theoretically, CTCs may serve as a liquid biopsy for metastatic tumors, with adequate and unique advantages: collection of peripheral blood is easy, rapid, lowly invasive, cost-effective, and feasible for serial real-time monitoring. Extensive studies have demonstrated that CTCs are useful prognostic biomarkers. Currently, the index CTC (especially mCTC) has seldom used in monitoring metastasis or recurrence after LT. We here for the first time found that combination of CTC/AFP/PIVKA-Ⅱ can effectively indicate the later metastasis.
However, we failed to find clear links between post-LT metastasis and traditional factors, such as Milan criteria, Child-Pugh-Turcotte classification, lymph node involvement, cirrhosis background or age [14]. Also, postoperative preventing treatment did not show significant benefit in our work. This may be due to a limited sample size. Overall, the positive results we discovered are consistent with most published research. Similar to the study of Zavaglia [6], we also noticed microvascular invasion classification influenced the postoperative metastasis, which is as theoretically expected. Nevertheless, this variable has a relatively lower association (p = 0.045) in comparison with postoperative hematological indices. Adler et al reported that AFP above 100 ng/mL and vascular involvement of the tumor on the explant were predictors of recurrence [15]. Zhang et al pointed out that AFP can be an independent predictor of OS and AFP above 200 ng/ml indicates poorer outcomes. This was repeatedly reported by other independent studies [16]. We also noticed that AFP monitoring helps reflect the postoperative progression of HCC. Especially, the 4th month time point is more valuable. PIVKA-II is an important biomarker for HCC surveillance in conjunction with AFP [17]. AFP and PIVKA-II are associate with giant lymph node metastasis in hepatoid gastric cancer [18]. Another study showed AFP level, PIVKA-II level, portal vein invasion were the most important prognostic factors for HCC patients [19]. Ultra-high PIVKA-II level is correlated with hepatic portal lymph node metastasis [20]. Our work firstly demonstrated that the PIVKA-II level at postoperative 3 month is elevated in the metastasis group, which emphasizes its value of metastasis monitoring.
Still, there are some limitations in this study. For the scarcity of HCC patients with LT treatment, the sample size was small, and no significant results were found regarding the progression free survival and overall survival. Besides, also for the limited sample size, we did not observe a regular trend of changes in hematological indices. Some indices were significantly changed at one time point (e.g. 3rd month) but turned negative at another (e.g. the 4th month). Although it may be due to a key stage of post-LT metastasis (e.g. at round day 45), the clear trend, changing curves, and burst-out time point of metastasis are still to be explored through larger sample size.