Based on the results of a large series of patients who underwent curative hepatectomy for HCC, we proposed a simple parametric model predicting the risk of EHR development. This model is straightforward and easy-to-use, consists of six easy-to-obtain variables that constitute not only the essentials of pre- and post-operative clinical parameters, but also the postoperative pathologic findings. Due to the lack of consensus on follow-up strategies for the detection of EHR after resection, our prediction models may aid in monitoring patients for individual risk and in appropriately assigning patients for participation in clinical trials for postoperative adjuvant therapy (e.g., patients would be categorized as intermediate or high risk, if they present with a predicted 5-year EHR rate as 50.5% or 100%, respectively).
Recent studies reported improved prognosis for recurrent HCC based on the pattern of IHR [5, 18]. However, these studies did not clarify the clinical features and pathological course of EHR, with the absence of models to predict EHR after curative treatment for HCC, limiting the early detection of EHR. In our study, we identified the risk factors of EHR after curative hepatectomy for HCC and used these factors to stratify the risk for EHR into four levels. Our findings highlight the necessity for a predictive score based on risk stratification to inform optimal surveillance for prompt detection of EHR to improve patient outcomes.
Current results of HCC recurrence and EHR development rates suggest some distinction from our previous study of HCC patients who underwent RFA [19]. In that study, the median time to first HCC recurrence and EHR after RFA was 1.75 years and 2.68 years, respectively, with 1-, 3-, 5-, 8-, and 10-year rates of EHR development of 1.0%, 2.9%, 8.1%, 15.7%, and 33.7%, respectively. These rates were comparably lower than those we now report after curative hepatectomy.
With regard to the pattern of HCC recurrence, the most common initial site of recurrence was within the intra-hepatic area, which was consistent with a previous report [20]. Another study identified IHR as being the most common initial site of recurrence, with EHR developing after several treatments for IHR [21]. Uchino et al. reported that 82.2% of HCC patients with EHR presented with IHR, a finding comparable to those of our previous study [19]. Therefore, multiple IHRs can be an indication of EHR risk in patients with HCC [22].
In our study cohort, the lungs were the most common site of EHR (42.6%). Thoracic metastases, which included the lungs and the vertebrae of the thoracic spine, were thus, relatively common as previously reported [23]. Thoracic metastases reflect a systemic involvement with poor prognosis as they are largely not curable. Of further concern is the fact that thoracic metastases may not be detected using conventional surveillance methods that rely on abdominal imaging. Therefore, the use of chest CT images should be included in the surveillance strategy for patients at risk for EHR after curative hepatectomy for HCC for the early detection of thoracic metastases. In addition, the rate of EHR at the time of the initial recurrence of HCC after hepatectomy was 34%, with 38.3% of these patients having no sign of IHR at the time of EHR diagnosis. Therefore, even if intra-hepatic HCC lesions are stable, close surveillance for possible development of EHR may be necessary.
Regarding the risk factors for EHR, bile duct invasion, necrotic HCC, large tumor size (sum > 7 cm), macrovascular invasion, first RFS < 12 months, and AFP level > 400 IU/mL at the time of first recurrence were associated with EHR after curative hepatectomy. Vascular invasion is a well-known prognostic indicator of HCC. Natsuizaka et al. showed that vascular invasion was more frequently observed in patients with EHR at the first diagnosis of HCC [1]. Senthilnathan et al. also reported a two-fold increase in EHR in the presence of portal vein invasion than without portal vein invasion (24% versus 12%) [24]. Yang et al. reported that EHR was more common among patients with vascular invasion, intrahepatic metastasis, and more advanced HCC stages [11]. However, whether bile duct invasion of HCC has a significant impact on its prognosis remains an issue of controversy. Two previous studies did not show any significant difference in the prognosis of patients with bile duct invasion after curative surgery than those without [25, 26]. However, Ikenaga et al. reported that the median survival of HCC patients with bile duct invasion after surgery was significantly shorter than that of patients without bile duct invasion (11.4 versus 56.1 months, p = 0.002) [27]. Moreover, Shao et al. reported that HCC patients with bile duct invasion developed early recurrence (< 1 year) after resection more frequently (recurrence rate, 70.3%) than those without bile duct invasion [28]. Our findings were consistent with those of these latter studies, with bile duct invasion being significantly associated with EHR after curative hepatectomy.
A recent study revealed that the presence of tumor necrosis is associated with an advanced tumor stage, HCC recurrence, and patient survival after curative hepatectomy for HCC [29]. In agreement with these findings, we also identified necrotic HCC to be associated with a high rate of EHR. HCC tumors > 6 cm in size were also predictive of EHR after curative resection for HCC [30], with the predictive cut-off in our study being close at > 7 cm. Similarly, our finding of a significant association between first recurrence free survival of < 12 months and EHR was consistent with the report by Kim et al. that reported EHR to develop more frequently among patients with early HCC recurrence [31]. They suggested that aggressive tumor pathology was, therefore, a risk factor of early HCC recurrence.
Recent studies have shown high AFP level to be an independent risk factor of HCC invasiveness [32–36]. However, only one previous study has reported an association between AFP level and EHR after curative HCC treatment [37]. In relation to the same, our previous study on RFA in EHR for HCC demonstrated an association between AFP levels and HCC recurrence when the AFP level was > 400 IU/mL. Similarly, this study also identified a serum AFP level > 400 IU/mL at the time of first recurrence to be predictive of high risk (OR: 2.409, 95% CI: 1.421–4.084). We stratified the risk for EHR into four levels based on the number of predictive factors present for EHR. We demonstrate that the cumulative rates of EHR and the median time to EHR correlated with these four risk levels. Therefore, our novel parametric model, albeit simple, could assist clinicians in identifying patients at high risk for EHR before surgery.
We identified involvement of the margin of resection as a significant risk factor of early EHR (OR: 4.035, 95% CI: 1.28-12.725), which is consistent with a previous study [38]. The frequency of diffuse steatosis in early HCCs peaks at a diameter of about 1.5 cm, decreasing as a function of increasing tumor size and grade [39]. Thus, diffuse fatty change is uncommon in HCCs > 3 cm and with progressing HCC disease status, and is also not usually observed in patients with poorly differentiated HCC [39, 40]. Therefore, the absence of fatty change in the liver with HCC is associated with the tumor aggressiveness. In our study, the proportion of patients with the absence of fatty change in the liver was higher for the early EHR than for the non-early EHR group.
We finally note that 54.8% in the early EHR group exhibited EHR at the time of first recurrence. This underlines the importance of identifying patients who are at high risk for early EHR, which may inform on the best strategy for surveillance after surgery for the rapid identification of EHR development.
The limitations of our study should be noted in the interpretation of results. First, the diagnosis of EHR was mostly based on medical imaging and, thus, the possibility of other primary cancers from an origin other than the liver could not be completely ruled out. However, in circumstances when the origin of the tumor was not certain, pathologic confirmation was performed at the discretion of the treating physician. Secondly, this was a retrospective study based on medical records from patients enrolled from two tertiary hospitals. Therefore, the effect of bias on results cannot be denied. Third, there was no uniform post-treatment or surveillance schedule, and the surveillance modality used for each patient was at the discretion of the treating physician. Moreover, patients underwent different treatment modalities for local HCC recurrence depending on the tumor and patient status. There may be diverse conditions in terms of tumor stage, liver reserve function, and patients’ physical performance status. However, we tried to overcome these limitations by using a considerable number of patients with a long-term follow-up duration in multiple tertiary centers. There is a need to conduct a well-organized prospective study to validate more effective methods of EHR prediction and management.
In conclusion, we present a simple parametric model to predict EHR after curative hepatectomy for HCC. This tailored approach may be useful for the early detection of EHR and permit a more refined estimation of risk on an individual basis.