Hepatocellular carcinoma (HCC) is characterized by abnormal angiogenesis, and vascular endothelial growth factor-B (VEGF-B) has emerged as a potential contributor to its pathophysiology. This retrospective study aimed to explore the significance of VEGF-B in HCC. A total of 180 HCC patients who underwent surgical resection at our institution between 2016 and 2021 were included. VEGF-B expression in tumor and adjacent non-tumor tissues was evaluated by immunohistochemistry. Associations with clinicopathological features, overall survival (OS), and recurrence-free survival (RFS) were analyzed. High VEGF-B expression in tumor tissues was significantly associated with tumor multiplicity (p = 0.03), microvascular invasion (p = 0.01), and higher AFP levels (p = 0.02). Multivariate analysis indicated that high tumor VEGF-B expression was an independent predictor of poor OS (hazard ratio [HR] = 1.9, 95% confidence interval [CI]: 1.2 - 3.0, p = 0.008) and RFS (HR = 1.7, 95% CI: 1.1 - 2.6, p = 0.02). These findings suggest that VEGF-B may play a critical role in HCC progression and could serve as a novel prognostic biomarker and therapeutic target.

Hepatocellular carcinoma (HCC) remains a major global health burden, with limited treatment options for advanced - stage patients [1, 2]. Angiogenesis is a hallmark of HCC, enabling tumor growth, invasion, and metastasis [3]. While vascular endothelial growth factor-A (VEGF-A) has been extensively studied as a key regulator of angiogenesis in HCC, the role of its homologue, VEGF-B, has received less attention [4]. VEGF-B binds to the VEGFR-1 receptor, promoting non-canonical angiogenic pathways and enhancing tumor cell survival [5]. Recent studies have suggested that VEGF-B may contribute to tumor progression in various malignancies [6 - 8], but its role in HCC is still poorly understood. This retrospective study aimed to investigate the expression pattern of VEGF-B in HCC, its association with clinicopathological features, and its prognostic value.

2.1 Patient Selection
A total of 180 patients who underwent surgical resection for HCC at our tertiary - care hospital from January 2016 to December 2021 were retrospectively enrolled. Inclusion criteria were: (1) histologically confirmed HCC; (2) availability of both tumor and adjacent non-tumor tissue samples; (3) complete clinical and follow - up data. Exclusion criteria included prior anti - cancer treatment before surgery and incomplete pathological data.
2.2 VEGF-B Expression Analysis
Immunohistochemistry (IHC) was performed on formalin - fixed, paraffin - embedded tissue sections using a specific anti - VEGF-B antibody (Abcam, Cambridge, UK). The staining intensity was scored as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong). High VEGF-B expression was defined as a score of 2+ or 3+ in tumor tissues.
2.3 Data Collection
Clinicopathological data, including age, gender, tumor size, tumor number, TNM stage, histological grade, microvascular invasion, alpha - fetoprotein (AFP) levels, and cirrhosis status, were collected from medical records. Follow - up data, including OS and RFS, were also recorded.
2.4 Statistical Analysis
Statistical analyses were conducted using SPSS software (version 26.0, IBM). Categorical variables were compared using the chi - square test or Fisher's exact test, and continuous variables were compared using the t - test or Mann - Whitney U test. Survival curves were plotted using the Kaplan - Meier method, and differences were evaluated by the log - rank test. Multivariate Cox regression analysis was performed to identify independent prognostic factors. A p - value < 0>

3.1 Patient Characteristics
The baseline characteristics of the 180 patients are shown in Table 1. The mean age was 57.8 ± 9.5 years, and 135 (75%) were male. Cirrhosis was present in 100 (55.6%) patients. The median tumor size was 5.2 cm (range: 1.5 - 13.0 cm), and 70 (38.9%) patients had multiple tumors. According to the TNM staging system, 35 (19.4%) patients were in stage I, 60 (33.3%) in stage II, 50 (27.8%) in stage III, and 35 (19.4%) in stage IV.

3.2 VEGF-B Expression and Clinicopathological Features
VEGF-B expression was detected in 120 (66.7%) of the 180 tumor samples, with high expression observed in 50 (27.8%) samples. High VEGF-B expression in tumor tissues was significantly associated with tumor multiplicity (p = 0.03), microvascular invasion (p = 0.01), and higher AFP levels (p = 0.02) (Table 2). There was no significant association with age, gender, tumor size, TNM stage, or histological grade.
 

3.3 Prognostic Significance of VEGF-B Expression
The Kaplan - Meier analysis showed that patients with high VEGF-B expression in tumor tissues had significantly shorter OS (Figure 1A, p < 0 xss=removed xss=removed xss=removed xss=removed xss=removed>

In this retrospective study, we demonstrated that high VEGF-B expression in HCC tumor tissues is significantly associated with tumor multiplicity, microvascular invasion, and higher AFP levels, and serves as an independent predictor of poor OS and RFS.VEGF-B has been reported to play a role in tumor angiogenesis and progression in several cancers [6 - 8]. In HCC, our findings suggest that VEGF-B may contribute to tumor heterogeneity and aggressiveness. The association with tumor multiplicity indicates that VEGF-B could promote the development of multiple tumor foci, potentially through its role in facilitating the migration and invasion of cancer cells [9]. The link with microvascular invasion further supports the notion that VEGF-B may enhance the formation of tumor - associated blood vessels, providing a pathway for tumor cell dissemination [10]. The positive correlation with AFP levels may reflect the involvement of VEGF-B in the dysregulated signaling pathways that drive HCC progression [11]. Previous studies on VEGF-B in HCC have been limited. A recent study by Li et al. [12] showed that VEGF-B promoted HCC cell proliferation and migration in vitro, which is consistent with our clinical findings. Another study by Wang et al. [13] suggested that VEGF-B could modulate the tumor microenvironment, contributing to immune evasion in HCC. Our study extends these findings by demonstrating the prognostic significance of VEGF-B in a large - scale clinical cohort.The identification of VEGF-B as a prognostic biomarker in HCC has important clinical implications. It could help in the risk stratification of patients, guiding personalized treatment decisions. Moreover, targeting VEGF-B may represent a novel therapeutic strategy for HCC. Given its role in non-canonical angiogenic pathways, VEGF-B - specific inhibitors may offer an alternative approach to traditional anti - VEGF therapies, potentially overcoming resistance mechanisms associated with VEGF-A - targeted agents [14].However, our study has several limitations. First, it is a single - center study, which may limit the generalizability of the results. Second, the mechanism by which VEGF-B promotes HCC progression remains unclear, and further in - depth molecular studies are needed. Third, we did not explore the potential interaction between VEGF-B and other angiogenic factors in HCC. In conclusion, our study provides evidence for the critical role of VEGF-B in HCC progression and prognosis. VEGF-B may serve as a promising prognostic biomarker and a potential therapeutic target for HCC. Future studies should focus on elucidating the underlying mechanisms and developing effective VEGF-B - targeted therapies.

This retrospective analysis of 180 HCC patients revealed that high VEGF-B expression in tumor tissues is associated with adverse clinicopathological features and poor prognosis. VEGF-B could be a novel prognostic biomarker and a potential therapeutic target for HCC. Further research is required to understand its molecular mechanisms and to develop specific anti - VEGF-B therapies.