It is generally believed that HCC is a common malignant tumor, most of which progressively develops from cirrhosis, atypical hyperplasia (precancerous lesions) and chronic inflammation (12). LNM is a major factor affecting the long-term survival of malignant tumors and plays an important role in the progression and recurrence of HCC. Increasing evidence has shown that the prognosis of patients with LNM is worse than that of patients without LNM (7). Even though studies have indicated that lymph node dissection and radiotherapy have a positive effect on the prognosis of HCC with LNM, the expected OS is only 8.0- 14.0 months and 7.0-13.0 months, respectively (13). Compared with lung cancer, esophageal cancer, gastric cancer, bladder cancer and other malignant tumors, HCC has a lower probability of distant metastasis (14). According to domestic and foreign research reports, the intraoperative detection rate of liver cancer LNM is only 0.75%~7.5%, while the detection rate in autopsy is as high as 30.3% (6), which shows that LNM is often ignored by clinicians in clinical work. However, the judgment of LNM in HCC through imaging is not effective, and it is necessary to explore other more sensitive auxiliary indicators to predict LNM risk in HCC patients.
Some previous studies have analyzed the risk factors for HCC complicated with LNM. Zhuang et al. found that CK19 expression and AJCC/UICC T classification were two independent risk factors for LNM in HCC (15). Xiang et al. identified 83 cancer genes that were differentially expressed in lymph node-positive and lymph node-negative HCC and found that intratumoral hypoxia-inducible factor (HIF) -1α, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) -2 were independent risk factors for LNM and can be used to identify high-risk patients with LNM in liver cancer (16). Abnormal expression of lncRNAs has been found to be involved in a variety of biological processes of cancer, including LNM (17-19). For example, Ma et al. suggested that a lncRNA-based nomogram can be used to predict LNM risk (20). Although related studies have revealed some risk factors for LNM in HCC, these indicators need additional testing, postoperative sample testing, and even clinical testing.
It is well known that HBV infection is one of the main causes of liver cancer. In Eastern countries, a large proportion of the HCC population has a liver background of HBsAg positivity (21). As one of the risk factors for chronic inflammation of the liver, HBV can activate the common pathway for the progression of all liver malignancies (22), which is related to the poor prognosis of HCC (23). Moreover, in intrahepatic cholangiocarcinoma, the incidence of LNM in patients with HBV infection is lower than that in patients without HBV infection, which has been confirmed in some studies (24). Recent studies have reported that HBsAg positivity is also associated with the incidence and progression of other malignancies, such as gastric, esophageal, and pancreatic cancers (25). The increase in serum globulin is associated with a variety of chronic inflammatory diseases, and the increase in inflammatory cytokines in serum globulin contributes to the increase in serum albumin and the inhibition of serum albumin biosynthesis (26). Considering the biological role of inflammation in tumors, some researchers have evaluated the prognosis of tumors by globulin levels and have demonstrated a correlation between globulin and LNM in malignant tumors (27). The lymphocyte-mediated immune response can eliminate abnormal cells and inhibit the production of cytokines for the proliferation and metastasis of various tumors (28). The increase in neutrophils in tumors can lead to an increase in angiogenic factors such as interleukin-8 (29) and vascular endothelial growth factor (VEGF) (30, 31) and promote tumor progression. Studies have confirmed that the preoperative NLR has diagnostic value for LNM of bladder cancer (32). Moreover, patients with a higher NLR are more likely to develop LNM in malignant tumors, such as gastric cancer (33), colorectal cancer (34), esophageal cancer (35), and small cell lung cancer (36). Cumulative studies have shown that among HCC patients, the larger the tumor diameter is, the higher the probability of LNM (37), which may be related to the biological invasive ability of the tumor; this conclusion has also been confirmed in studies of malignant tumors such as intrahepatic cholangiocarcinoma (38) and gastric cancer (39).
Nomograms are a common tool for evaluating tumors with high accuracy and applicability (40). In this study, we established a nomogram to predict the risk of preoperative LNM in HCC by including 4 clinical characteristic variables related to tumor LNM (HBsAg level, globulin level, NLR level, and tumor size). This nomogram demonstrated good consistency between predictions and observations and has great predictive value for LNM risk in HCC. Furthermore, DCA is a novel method for evaluating diagnostic tests, predictive models and molecular markers (41). In our research, we evaluated a nomogram through DCA. Fortunately, the model showed good clinical utility within an appropriate range. Although domestic and foreign guidelines for HCC management have not disclosed feasible and effective treatments for LNM in HCC, surgical dissection or radiotherapy of LNM was effective to improve patient survival and prognosis (8, 10). In this study, we have provided a simple and accurate predictive tool for preoperative LNM risk assessment of HCC patients, which not only preliminarily determines the clinical stage of the tumor before the operation but also affects the clinical treatment plan and surgical decisions to provide better consultation for patients.
Of course, there are some limitations in this study. First, due to the low probability of LNM occurring in HCC, it is necessary for us to further increase the sample size to verify our study in future studies. Second, this was a retrospective analysis, and inevitably, there were some biases in the selection of patients. Third, most of our research subjects were HBV-positive patients, and whether this research is applicable to groups in other regions and countries is not yet known. In addition, our data came from a single center, which requires some prospective studies to further confirm the reliability of the model. We are also currently working to collect data from multiple centers to build a database for external validation of this model. In the future, we may combine this model with other clinical characteristics, such as imaging information, to build a better LNM risk prediction model.