In the present study, we developed and validated a practical nomogram model, based on clinicopathological characteristics of HCC patients who underwent LH, to predict the 1-, 2-, and 3-year RFS. It demonstrated superior prognostication performance compared with the 8th AJCC TNM classification and the BCLC staging system (C-index, 0.786 vs. 0.698 vs. 0.632, respectively).
It is widely believed that poor liver function and heavy tumor burden are significant prognostic factors that are associated with tumor recurrence after hepatectomy in HCC patients [15,16,17]. Compared to non-resection treatment, such as radiofrequency ablation, interventional therapy, and radiotherapy, establishing staging systems that are based on postoperative pathology combined with clinical factors seems more reliable for the prediction of recurrence, as it possesses more accurate and reliable information on tumor profiles as to that provided solely by postoperative pathology. However, almost all previously established staging systems are based on conventional hepatectomy which is much invasive to patients, and predictive model based per-patient is limited [18, 19]. Traditional opinions suggest that the evaluation of conventional hepatectomy is more depended on liver profiles that contribute more for long-term survival [18], whereas laparoscopic hepatectomy has comparable clinical outcomes to conventional hepatectomy and is less invasive, thereby reducing the injury to liver function for patients who are subjected to hepatectomy [20]. Simultaneously, this change of surgical selection increases the role of tumor burden in the prediction of recurrence for patients who are treated with LH. As a result, LH has different intrinsic properties from that of open procedure, and their long-term outcomes need to be separately mapped.
Several studies have emphasized the critical roles of tumor burden, gender, liver function, and performance status in the prognosis of HCC, but few have actually shown the role of detailed information of pathology in prognosis prediction [12, 21]. It is commonly supposed that the 8th AJCC TNM classification is one of the most prevalent staging systems of HCC, which is composed of TNM stage. However, this only classifies tumor burden and is limited in the power of prediction for HCC patients who are subjected to LH [22]. HCC patients who undergo surgical resection rarely suffer from lymph node metastases or distant metastases, and this classification thereby influences the accurate evaluation of RFS. The BCLC staging system takes both the liver function and tumor characteristics into account, including tumor extension, reserved liver function, physical status, and cancer-related symptoms [23]. The notable feature that distinguishes the BCLC staging system from other systems is the treatment recommendations for each stage based on the best treatment options currently available [24]. However, the BCLC class B (intermediate stage) covers a considerable heterogeneous population of HCC patients with varying degree of tumor extension, reserved liver function, and disease etiology, thus resulting in prognostic heterogeneity and preventing the decision of optimal treatment regimen selection. Meanwhile, the guidelines mentioned above are mainly based on preoperative clinical data or pathological information. Moreover, no guideline tailors for resectable HCC patients who were subjected to LH. Therefore, it is urgent to introduce a reliable, practicable, and individualized predictive model for patients who are candidates for surgical hepatectomy, especially LH.
The present nomogram integrates five independent risk factors for RFS, including HBsAg, tumor thrombus, tumor number, cancer cell differentiation, and MVI. Many studies have indicated that HBV infection, tumor thrombus, and MVI were significant risk factors for recurrence in patients with HCC [25,26,27]. The underlying hepatitis background was significantly associated with late recurrence and multicentric carcinogenesis. Tang et al. [27] reported that HBV infection might accelerate hepatocarcinogenesis via the integration of HBV DNA into the host genome, and continuous expression of viral proteins such as HBx might be involved in hepatocarcinogenesis. However, the major source of early recurrence is generally thought as metastasis, which is mainly derived from vascular invasion. Hirokawa et al. [25] indicated that circulating tumor cells were closely related to epithelial–mesenchymal transition and mesenchymal–epithelial transition which are the significant property of cancer stem cells. Given the early diagnosis of HCC, tumor thrombus is rare. Alternately, MVI is another potent parameter indicating vascular invasion for the prediction of recurrence [28]. Additionally, the present study demonstrated that tumor number predicted HCC recurrence, which was consistent with the results of other studies [29, 30]. However, tumor size could not be included in the nomogram proposed for HCC recurrence prediction in the present study, although other studies have indicated its insightful role in prognostic prediction [31, 32]. The possible explanation is that vascular invasion plays a more critical role in recurrence than tumor size, especially for patients with tumor size > 2 cm, according to 8th AJCC TNM classification [14, 33]. Besides, surgical margin was also not included in the nomogram, and it could be explained in the way that the patients included in the present study all had a minimal surgical margin of 1 cm, which indicated better RFS [13]. Interestingly, cancer cell differentiation was found to be a significant prognostic factor, and this was rarely mentioned in other studies. Low cancer cell differentiation has been reported to be the property of cancer progenitor or cancer stem cells which has high malignant biological behavior [34].
As the clinical and pathological factors mentioned in the present study have been validated separately in previous conventional hepatectomy studies, and the present study is the first to combine them together to assess patients who are subjected to laparoscopic hepatectomy. Hence, the proposed nomogram can be used to better guide routine follow-up for patients who have undergone LH as initial therapy. Patients characterized with a high recurrence score on our nomogram could be counseled to receive more high-end imaging examinations and close follow-up. In addition, more aggressive adjuvant therapy might be proposed, even if the results of the latest postoperative examinations indicated no evidence of recurrence. Conversely, the follow-up period for low-risk patients should refer to the clinical guideline [3].
Although our nomogram demonstrated satisfactory performance compared with existing systems used clinically, its related limitations need to be described. First, the nomogram was derived from data collected at a single institution, and the follow-up duration was relatively short for prognosticating long-term survival outcomes. Second, as this is a retrospective study for predicting the anticipated result, our nomogram needs to be confirmed in a prospective cohort. Third, our nomogram is mainly based on pathological outcomes, therefore, it is inapplicable to evaluate non-surgical patients.