Hepatocellular carcinoma (HCC) accounts for ~75% of primary liver cancer, with over 750000 cases annually. It ranks fifth among the most frequently seen malignant tumors and third among the factors leading to cancer-associated mortality worldwide (1–3). Surgery remains the cornerstone of treating patients with resectable HCC. Although only 20–30% of cases have resectable indications when diagnosed, surgical treatment is still the only potential choice for HCC treatment (4, 5). However, the early or late recurrence rate after surgery is high (6, 7), and according to some systematic reviews of large-scale data, the 5-year overall survival rate for patients with advanced HCC is still relatively low (8, 9).Therefore, research is needed to precisely estimate the long-time postoperative prognosis, thereby developing different classification systems and more appropriate risk stratification models. This will facilitate patient screening and improve long-time prognosis after HCC radical resection. In addition, this will help patients choose the most suitable treatment plan and conduct more targeted follow-up and post-surgery management to improve their survival rates and life quality.

In recent years, the American Joint Commission on Cancer (AJCC) and Barcelona Clinical Cancer Staging System are most commonly applied clinically (10). Previous research reports suggested multiple factors exerting adverse effects on the prognosis of patients with liver cancer, including morphological (i.e., maximum tumor size and number, collectively referred to as “tumor burden”) and pathological (such as microvascular infiltration, liver margin status, and liver capsule infiltration) features, and serum biomarkers (such as bilirubin, albumin, and alpha-fetoprotein (AFP)) (11, 12). Notably, tumor burden plays a critical role in predicting prognosis and stage determination (10). Recently, it has been considered a more accurate staging scheme than traditional Barcelona clinical liver cancer (BCLC) staging systems (13).

In 2018, the TBS was first proposed and proven useful in evaluating prognostic outcomes of cases receiving liver metastasis resection for colorectal cancer (14). In the past two years, Tsilimigras et al. proposed a method to calculate TBS using the Pythagoras theorem (α²+ β^{2 =} γ², of which α = Maximum tumor diameter, β = tumor number, γ = TBS). This method continuously combines tumor size with quantity and is used for evaluating how TBS affects the prognostic outcome of HCC resection cases, demonstrating good prognostic differentiation and determining efficient prognosis (15). The ability to identify and determine the prognosis of patients with liver cancer facilitates selecting surgical candidates, providing appropriate postoperative monitoring and rehabilitation plans, and setting realistic goals for patients and nursing staff. However, only a few studies have been conducted on how TBS affects prognostic outcomes of cases undergoing HCC radical resection. Therefore, the current work focused on determining the impact of TBS on the prognostic outcome of patients with HCC undergoing radical resection.

Currently, HCC displays poor treatment prognosis, and converse to the decrease in the mortality rate of other common cancers, the mortality rate of HCC increases by ~2–3% annually (22). Epidemiological data predict that it will continue to rise at least until 2030 (23). In China, the liver cancer mortality rate is higher in rural areas than in urban regions, and the western areas exhibit higher mortality rates compared to the eastern and central regions. This elevated mortality in rural and western areas is partly associated with the higher incidence of liver cancer (24). Among various treatment options, surgery remains the first choice for treating HCC among numerous treatment options. However, in several cases, owing to the lack of transplanted organs, hepatectomy takes precedence over liver transplantation (25). However, the recurrence and mortality rates of patients undergoing hepatectomy are still high (26). Traditionally, the survival of patients with HCC is usually assessed from the diagnosis or treatment of the disease, which often underestimates the prognostic outcome of the patients who have undergone surgery (27, 28). TBS integrates tumor size with quantity for evaluating overall tumor burden (15, 29). Because the method of calculating tumor burden is continuous rather than dichotomous, the prediction of results is more accurate than that possible using the current Milan standard (14), incorporating TBS allows for better risk stratification and identification of patients who require closer monitoring, thereby providing improved prognostic value (30). However, TBS was initially developed to evaluate the prognostic outcome of colorectal cancer following liver metastasis resection, but recently it has been extensively applied in evaluating the prognostic outcome of resectable HCC cases and demonstrates notable advantages (13, 14). This study aims to confirm whether the TBS score can become crucial in influencing the prognostic outcome of cases after radical resection of HCC to promote its clinical application. The observations of the current study revealed that TBS and other clinical pathological indicators have significant independent predictive value for the prognostic outcome of cases involving HCC radical surgery. For patients undergoing radical resection of HCC, high TBS is significantly related to shorter OS and RFS.

This retrospective cohort study used the X-Tile bioinformatics tool to determine the best threshold TBS of 10.77 so that all cases were classified into high (>10.77) or low TBS groups (≤10.77) (31). This is different from the cutoff value previously reported by Tsilimigras et al. (15), considering the differences arising from different patient characteristics. From the distribution of clinical characteristics of the patients, we observed that the operation being laparotomy, high preoperative AFP levels, BCLC stage of stage B, greater tumor diameter, multiple tumors with hepatic capsule invasion or the MVI, and higher TBS. Studies showed these factors are related to poor postoperative patient outcomes (32). In particular, patients with elevated AFP (33), MVI (34), or hepatic capsule invasion (35) have a higher risk of recurrence, and these factors are closely related to treatment outcome and poor prognosis. Notably, only some patients with high TBS have liver cirrhosis (32.4%), while patients with low TBS have a higher proportion of liver cirrhosis (40.9%). The possible reason for this is that patients with higher tumor burden must demonstrate better potential liver function before they are identified as candidates for surgical resection to minimize the risk of postoperative liver failure (36). Based on univariate and multivariate analyses, high TBS levels showed a higher risk of shortening OS and RFS, which independently predicted the prognosis of the patients with HCC receiving radical hepatectomy. Based on univariable/multivariable regression, higher TBS levels were positively correlated with shortened OS and RFS. High levels of TBS independently predicted the prognosis of the patients with HCC who underwent radical hepatectomy. In addition, preoperative high levels of AFP and MVI showed an independent relationship to OS and RFS. The Kaplan–Meier curve shows that compared with the high TBS group, the low TBS group demonstrated significantly extended OS and RFS. This finding agreed with the conclusion by Tsilimigras et al. The team used TBS combined with AFP levels to evaluate prognostic outcomes in cases undergoing radical liver cancer resection. The results showed that at low AFP levels, the high TBS group showed significantly decreased 5-year OS rates relative to the low and middle TBS groups (47.7% vs. 68.0% OS, P < 0.001) (15). Similarly, at higher AFP levels, the decreased TBS is related to superior OS (15). Another recently performed large retrospective study found that the peak risk of intrahepatic relapse in the high TBS score group approximately doubled than that of the low TBS group, which showed an independent relationship to a high risk of recurrence (27). This suggests that patients will experience a significantly increased early and extrahepatic relapse risk during surgery for HCC with high TBS scores. Therefore, higher relapse risk and more invasive relapse modes are recognized after the operation, and corresponding measures should be taken. In recent years, several articles confirmed the effective application of TBS in the prognosis prediction of cases receiving radical resection of HCC (37, 38). Such research regarding the prognostic significance of TBS in patients with HCC consistently shows that compared with low TBS, high TBS is closely related to poor clinicopathological features and adverse complications, suggesting poor prognosis after treatment.

Indeed, tumor morphology and the tumor microenvironment are critical factors that determine the biology and invasiveness of tumors. A high TBS indicates a larger tumor diameter, and as the tumor expands, the incidence of microvascular invasion continues to rise, particularly in tumors exceeding 10 centimeters (39). Furthermore, a growing body of evidence indicates that the tumor microenvironment—including cancer-associated fibroblasts, tumor-associated macrophages, oncogenic signaling pathways, tumor-associated extracellular matrix, activated tyrosine kinases, regulatory immune cells that support tumor progression, tumor-associated exosomes, inflammation-related cells, ligand-receptor interactions, immune escape mechanisms, and endothelial cell-mediated angiogenesis—plays a critical role in tumor progression. This creates a vicious cycle between cancer cells and the tumor microenvironment (40). The tumor microenvironment presents a promising target for therapy, as it plays a crucial role in regulating tumor-specific immune responses and enhancing the survival rates of liver cancer patients, particularly those with HCC (40).

However, the current study is somewhat different from others because its focus was to elucidate the role of TBS in the prognostic outcome of cases receiving radical resection of HCC. The subgroup analysis included age, sex, AFP level, MVI, mode of operation, HBV-DNA, liver cirrhosis, hepatic capsule involvement, and BCLC staging. Considering the group with TBS ≤ 10.77 as the control group, the significance of TBS in prognosis was confirmed and more intuitively explained. The results showed that TBS > 10.77 was the risk factor related to OS and RFS for all age groups, sex, BCLC stage, preoperative AFP level, no liver cirrhosis, HBV-DNA, mode of operation, MVI, and hepatic capsule involvement. TBS score demonstrates the advantages of simple acquisition, economy, and good repeatability, resulting in stability and intuitive nature of the results. This offers objective and valuable prognostic data for HCC cases receiving radical resection. Therefore, using the TBS score assists clinicians in the early detection of potentially poor prognostic outcomes in HCC cases and strengthens the dynamic monitoring of patients to adopt individualized adjuvant therapeutic measures. Furthermore, the etiology of liver cancer in China is closely linked to hepatitis B virus infection. This study indicates that HBV-DNA is a risk factor for OS and RFS. Implementing vaccination and antiviral treatments to reduce risk factors such as HBV and HCV can help decrease the TBS at diagnosis (41).

This study demonstrates the following merits: First, this study further analyzed the correlation between prognosis and TBS in liver cancer patients from the Guangxi region of China. Compared to previous studies in the same area, this research has a larger scale and longer follow-up time, making the conclusions more convincing. Additionally, it provides data support for the diagnosis and treatment prognosis of liver cancer in different countries and regions. Secondly, the cut-off value was optimized using X-Tile software. Thirdly, we excluded patients who had received antineoplastic therapies other than surgery to maintain the consistency of baseline data and minimize interference from other treatment methods. Finally, subgroup analysis confirmed that TBS possesses significant predictive value. Nonetheless, this study also has some limitations. First, although the study selected patients strictly according to the established criteria, an inevitable selection bias was present. Second, this study obtained data from one center, focusing on cases undergoing surgery. Third, the cutoff value of TBS needs to be verified from more prospective articles. Finally, the cases in this research are from China, and the major cause of the disease is associated with hepatitis B virus infection. Consequently, the current findings lack scientific guidance in HCC cases primarily resulting from alcoholic liver disease. Therefore, relevant research is needed, including data from multiple countries and populations worldwide. Despite these limitations, this study provides interesting data regarding how TBS affects HCC prognosis.

In summary, TBS is an important index for predicting prognostic outcomes in HCC cases. For cases undergoing radical resection of HCC, higher TBS is significantly associated with shorter OS and RFS. Tumor morphology (tumor burden) affects evaluating the prognostic outcome of cases undergoing hepatectomy.