Prognostic factors affecting postoperative survival of patients with solitary small hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide [1]. HCC has a high prevalence in Southeast Asia and Africa [2], and the incidence has been steadily increasing in both Europe and the United States [3]. Liver cirrhosis, particularly as a consequence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, is the most common risk factor for the development of HCC [4]. Due to the high prevalence of HBV infection among Chinese populations, there are a significant number of deaths due to HBV-related HCC in China [5]. Surveillance and recent advances in imaging techniques have resulted in improved identification and diagnosis of small HCC (sHCC, ≤3 cm in diameter) [6, 7].

Early detection of HCC allows for curative or palliative treatment with surgical resection or transcatheter arterial chemoembolization [8]. Currently, surgical resection offers the greatest chance for cure; however, many patients still suffer from disease recurrence after primary treatment [9, 10]. It is imperative to identify patients at high risk for optimal follow-up or postoperative adjuvant therapies in these patients [11, 12]. The known risk factors for sHCC enable the identification and screening of patients at high risk for HCC; however, prognosis-related factors are yet to know, which would enable stratification of sHCC patients into treatment groups following hepatectomy [13–15]. Clinicopathologic features are the main factors affecting postoperative survival of patients with sHCC. The current study was to identify clinicopathologic factors that predict survival of sHCC patients who underwent hepatectomy.

In the present study, we have investigated the prognostic predictors in a large cohort of patients from an area of high prevalence of HBV infection and who underwent liver resection for sHCC. Importantly, tumor size and vascular invasion were independent prognostic factors determining the outcome of these patients, and a prognostic scoring model derived according to these two variables was shown to accurately predict survival in patients with sHCC.

Tumor size is a well-known risk factor for survival after hepatectomy for HCC [17–19]. However, the appropriate tumor size cutoff for prognosis predicting has been debated at length. Several studies have indicated that a tumor size >5 cm is of prognostic significance only in patients with multifocal tumors [19]. In contrast, Minagawa et al. [17] showed a significant difference in survival between patients with tumors <2 cm and those with tumors measuring 2–5 cm, irrespective of multifocality or vascular invasion. Moreover, Zhou et al. [20] reported that tumor size significantly associated with decreased OS; the 5-year OS rates for patients with sHCC tumors measuring ≤2.0, 2.1–3.0, and 3.1–5.0 cm were 82.5%, 66.3%, and 61.2%, respectively. Similarly, we found that tumor size >2.5 cm was associated with a short OS or RFS, even within a cohort of patients with tumors ≤3 cm. However, Nanashima et al. [21] reported no significant difference in OS between patients with solitary sHCC tumors <2 cm and those with tumors measuring 2–3 cm in size. Lu et al. [22] observed no significant difference in OS and RFS between patients with tumors measuring 1.1–2.0 and 2.1–3.0 cm. Taken together, differences in the clinicopathologic characteristics among cohorts, geographic backgrounds, tumor size cutoff, patient heterogeneity, small sample sizes, and different definitions of end points (OS or RFS) may contribute to the conflicting results. In our study, the findings of a significant association between tumor size and clinical outcome in sHCC patients may be strengthened by the consistent resection procedure and large sample size. Moreover, the rate of liver cirrhosis was 40% in the present study, which is much lower than that observed in previous studies of Chinese populations [23, 24]. Only patients with sHCC (≤3 cm) were included in our study, and this group is generally considered to have early stage HCC. This is one potential explanation for the low incidence of liver cirrhosis observed in the present study.

HCC is characterized by a propensity for vascular invasion [23], and vascular invasion is a clinicopathologic feature related to aggressive biological behavior of HCC. Over the past several decades, multiple studies have shown that vascular invasion is a strong predictor of outcome following hepatic resection and liver transplantation for HCC. Nevertheless, the relative prognostic importance of vascular invasion in sHCC remains controversial, and there is significant inter-study and intra-study variability in assessing vascular invasion. Shindoh et al. [25] reported that vascular invasion did not affect survival of patient with sHCC (≤2 cm), whereas others maintain the opposing view that vascular invasion is an independent prognostic factor for sHCC (≤3 cm) [26]. Our data showed that vascular invasion had an adverse effect on long-term survival in patients with sHCC. The presence of vascular invasion was associated with a significant decrease in both 5-year OS and RFS rates. However, a crossover exists in RFS curves between patients with and without vascular invasion. We thought that the individual differences of cohorts and the different effects of vascular invasion on short-term and long-term survival would have contributed to this crossover. Based on a meta-analysis of our results as well as those of other studies, the presence of vascular invasion is associated with an adverse prognosis in HCC [27]. An international consensus on precisely what is meant by vascular invasion in HCC could provide a more consistent assessment and therefore a more reliable prediction of prognosis and a better understanding of the pathophysiology of HCC angioinvasion.

The reported OS rates for patients with HCC following resection varies widely in the literature, with 5-year OS rates ranging from 35% to 70% [28–30]. Patients with sHCC are generally thought to have a good outcome and are often considered a relatively homogeneous group. Data from our study revealed that even patients with early-stage HCC could be stratified into subgroups with distinct long-term prognoses. An improved understanding of the factors that affect outcome in this group of patients may impact choice of follow-up strategies and salvage therapy as well as guiding future studies [13]. In this study, we analyzed data from a large, population-based cohort of patients with pathologically proven sHCC. The apparent homogeneity of this cohort with respect to extent of disease (≤3 cm in size, solitary tumor, and no nodal involvement or metastases) and surgical resection was notable. Despite this, we found that the 5-year OS rate in this group ranged from 59.2% to 83.2%. In the current study, we found that the proposed prognostic model containing both tumor size and vascular invasion could reflect the aggressive phenotype of sHCC. Thus, this combined model may be a useful prognostic indicator for sHCC. There are also intense ongoing efforts to integrate biomarkers into established clinicopathologic models to further improve their predictive ability.

Tumor size and vascular invasion are feasible and useful prognostic factors for solitary sHCC (≤3 cm). The proposed prognostic model, based on tumor size and vascular invasion, is informative to predict the survival in sHCC patients undergoing hepatectomy.