This study focused on evaluating the prognostic value of age in patients with HCC receiving radical resection. X-tile, a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization, was used to stratified age, and 46 was identified as the optimal cutoff value. Younger patients (age ≤ 46) have a statistically significant worse DFS (38.1% vs. 47.6%, p = 0.046) than elder patients. Multivariate analysis showed that age was neither an independent prognostic factor for DFS nor for OS [DFS: HR = 1.3 (0.9–1.7), p = 0.126; OS: HR = 1.1 (0.7–1.5), p = 0.734].
The previous research didn’t propose an optimized method to determine the cutoff value of age. Some studies determined the cutoff value as 40 based on the European or American guidelines’ recommendation.[8–10] However, hepatocellular carcinoma in non-hepatitis B virus endemic areas, including Europe and America, is rare in patients younger than 40 years of age. This classification is not suitable for the hepatitis B virus endemic areas such as East Asia and sub-Saharan Africa. The imbalance in number of cases between each age group limited the impact of this cutoff value. Others selected the cuf-off value of 55 based on the median of the sample data. Selection bias may exist in these studies. We use the X-tile software to evaluate the robustness of the relationship between age and DFS by the construction of a two-dimensional projection of every possible division, which theoretically can produce a cutoff that will optimally divide the cohort.
The previous studies had inconsistent results about the relation between age and the long-term prognosis of hepatocellular carcinoma. Some studies reported that the overall survival of younger patients with HCC and received radical resection is worse than that of elderly patients,[8,12−15] while others got the opposite conclusion.[11,16−17] The difference may be caused by their choice of cutoff value. Besides, with the age increasing, more and more lethal factors would occur except for HCC, so the evaluation of overall survival of HCC would be more difficult. Therefore, we chose disease-free survival as the primary endpoints and overall survival as the second endpoint.
Wang JH et al, Liu et al, and Yang, G et al found that although ablation performed less intraoperative blood loss, shorter operative time, lower incidence of complications and shorter length of stay, radical resection offered a lower incidence of recurrence. Combining our study, to reduce the frequency of hospitalizations caused by recurrence, the first choice for young patients with resectable HCC should recommend surgical resection. 46 years of age may be an appropriate cutoff value. Meanwhile, most patients with intrahepatic recurrence have the opportunity to receive repeated ablation.[18, 20] Ablation may be an effective and safe alternative for intrahepatic recurrence or liver metastases. Besides, clinical doctors should pay more attention to the education of regular follow-up to younger patients.
Some studies proposed age was an independent prognostic factor. But more studies disagreed with this.[5, 12, 14] The results of our study did not support that age was an independent prognostic factor. The seemingly worse prognosis of young age may be a “dilution” caused by the negligence of important counfounding factors. WXiao H et al also found similar phenomenon. In our stue found that a higher proportion of young patients had microvascular invasion (p = 0.016) than elder patients, which was one of the independent factors for DFS (HR = 1.6, p = 0.002). dy, analysis of patients subgroup with microvascular invasion showed the difference in DFS between the two age groups were insignificant, which support the hypothesis that microvascular invasion was a potential confounding factor.
In our study, we found that the YG got a significantly higher proportion of hepatitis B virus infection, and worse tumor condition ( higher proportion of microvascular invasion), but better liver function than the EG. It`s consistent with the previous published study.[8–10, 12] Ha SY et al conducted a gene expression analysis and found 69 differentially expressed genes between the young and old patients. Most of the genes were relative to the cell cycle or cell division, and the mitotic rate was significantly higher in HCC of young patients, which means more aggressive tumor biology. Further exploration from the cellular and molecular levels is necessary to determine whether there are mechanism differences related to the occurrence of HCC in different age groups.
Fidler MM et al pointed out that the global incidence of cancer in 20–39 years old in 2012 was 43.3 per 100 000 people per year, and the corresponding mortality was 15.9 per 100 000 people per year. Although the data was not as terrifying as in the elder group, it’s of great importance to increase awareness and resources for this neglected sub-population. Currently, risk stratification and treatment protocols are not clear for younger patients because lack of corresponding clinical trials. Screening and early detection programs might have a significant effect at a limited cost.
There are some limitations to the study. First, the study was single-center research and the sample size was relatively small, selection bias may exist. Larger sample validation is needed. Second, this study did not fully adjust for potentially unknown confounding factors that may affect the results. Third, the study lacked the exploration of the molecular level. Lastly, cox regression could not statistically prove that age was an independent risk factor for either DFS or OS, indicating that the problem needs further study.