Splenectomy and risk of hepatocellular carcinoma

Table 1 Literature review on impact of splenectomy on hepatocellular carcinoma risk

Ref.	Publication year	Research type	Results	Conclusion
Increased incidence of HCC
Gao et al[10]	2024	Case-control study	A total of 178 patients with HBV-related portal hypertension underwent splenectomy, among whom 9 developed postoperative HCC. The incidence rate of HCC was significantly higher in IVAF-FIB-4-positive patients compared to IVAF-FIB-4-negative patients (138.1 vs 1.1 per 1000 person-years). Multivariate analysis identified IVAF-FIB-4 as an independent risk factor for postoperative HCC development (OR = 668, 95%CI: 53.895–8279.541)	IVAF-FIB-4 serves as an effective predictive biomarker for HCC following laparoscopic splenectomy in patients with HBV-related cirrhotic portal hypertension, enabling preoperative identification of high-risk individuals
Honmyo et al[13]	2023	Case-control study	A total of 65 patients with portal hypertension underwent splenectomy, among whom 36.9% developed HCC postoperatively. Univariate analysis revealed significant associations between HCC development and cirrhosis etiology (positive hepatitis C virus antibody: HR = 8.401; positive hepatitis B surface antigen: HR = 10.26), prior HCC history (HR = 5.137), and preoperative hemoglobin levels (HR = 1.353). Multivariate analysis identified prior HCC history (HR = 4.293) and preoperative hemoglobin levels (HR = 1.344) as independent risk factors for postoperative HCC	Preoperative hemoglobin levels serve as an independent predictive factor for HCC development following splenectomy, potentially associated with iron overload-induced oxidative stress and liver fibrosis. Patients with a history of HCC demonstrate significantly increased postoperative recurrence risk
Fan et al[58]	2022	Case-control study	The 5-year cancer-free survival rate was significantly lower in the splenectomy group (53.4%) compared to the non-splenectomy group (76.5%) (P = 0.003). Splenectomy emerged as an independent risk factor for HCC development (HR = 2.560, P < 0.05). Similarly, the 5-year OS rate was 68.1% in the splenectomy group vs 89.3% in the non-splenectomy group (P = 0.002), with splenectomy identified as an independent risk factor for mortality (HR = 2.791, P < 0.05)	Simultaneous splenectomy should be avoided during liver transplantation in HCC patients to reduce the risks of cancer recurrence and mortality
Du et al[81]	2018	Case-control study	Among 230 patients with HBV-related cirrhosis undergoing splenectomy, 38 (16.52%) developed HCC postoperatively. Cumulative 3-year, 5-year, and 10-year HCC incidence rates were 6.09%, 10.87%, and 17.39%, respectively. The 10-year HCC incidence in the high NLR group (NLR > 2.27) was significantly higher compared to that of the low NLR group (24.7% vs 10.6%, P = 0.006)	Preoperative high NLR > 2.27 can serve as an independent indicator for predicting HCC development. This biomarker may assist in identifying high-risk populations by reflecting the inflammatory microenvironment status
Higashijima et al[60]	2009	Animal study	In a mouse model of liver metastasis induced by intrasplenic injection of colorectal cancer cells, splenectomy resulted in significantly more hepatic metastatic foci compared to the spleen-preserved group. Splenectomized mice exhibited elevated hepatic Foxp3 mRNA levels and transiently increased NK cell counts that normalized by day 7 postoperatively	Splenectomy reduces regulatory T cells and NK cells in mesenteric lymph nodes, impairing local immune surveillance and upregulating hepatic Foxp3 expression. This process creates an immunosuppressive microenvironment that promotes tumor cell colonization and growth
Decreased incidence of HCC
Gao et al[15]	2023	Case-control study	The incidence density of HCC in the ET group was significantly higher than that of the LSD group (28.1 vs 9.6 per 1000 person-years). Patients in the LSD group demonstrated significantly higher 10-year survival rates compared to the ET group (P < 0.001). After IPTW adjustment, LSD emerged as an independent protective factor against HCC development (OR = 0.440, 95%CI: 0.316–0.612, P < 0.001)	LSD significantly reduces the risk of HCC development in patients with cirrhotic portal hypertension compared with ET
Gao et al[64]	2023	Case-control study	The incidence density of HCC in the laparoscopic LSD group was significantly lower than that of the ET group (8.0 vs 32.1 per 1000 person-years, HR = 3.998). After IPTW adjustment, the LSD group demonstrated a 484% reduction in HCC risk (OR = 0.516, P = 0.002) and significantly higher OS rates compared to the ET group (P < 0.001). Postoperative improvements in white blood cell count, lymphocyte count, and NLR were observed in the LSD group at 3-month follow-up	LSD reduces the risk of HCC by removing the pathological spleen, thereby decreasing pro-inflammatory cytokine secretion (e.g., IL-1, IL-6, transforming growth factor–beta) that promotes hepatic fibrosis. This intervention restores lymphocyte quantity and function, enhances anti-tumor immune responses, improves the portal hypertension-related immune microenvironment, and inhibits tumor angiogenesis and invasion
Zhang et al[67]	2022	Case-control study	For patients with T1-stage HCC, the 1-year and 2-year RFS rates in the HS group were significantly higher compared to those of the HA group (95% vs 81%, 81% vs 67%). However, no significant differences were observed in 3-year and 5-year RFS between the two groups. OS did not differ statistically between the HS and HA groups	HSS significantly improves early RFS in patients with T1-stage HCC and cirrhotic portal hypertension, particularly benefiting those with Child-Pugh A liver function. However, this intervention does not significantly improve OS
Zhang et al[11]	2021	Case-control study	The 1-year, 3-year, 5-year, and 7-year cumulative HCC incidence rates in the splenectomy group were 1%, 6%, 7%, and 15%, respectively, which were significantly lower than those of the non-splenectomy group (1%, 6%, 15%, and 23%) (HR = 0.53, 95%CI: 0.31–0.91, P = 0.028). Multivariate analysis confirmed splenectomy as an independent protective factor against HCC development (HR = 0.55, 95%CI: 0.32–0.95, P = 0.031)	Splenectomy may reduce the risk of HCC in patients with cirrhosis and portal hypertension by improving hepatic function, promoting liver regeneration, and enhancing anti-tumor immune function
Lv et al[24]	2016	Case-control study	In a cohort of 2678 patients with post-hepatitic cirrhosis and hypersplenism, abnormal liver function parameters (elevated alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, and prolonged prothrombin time) in non-splenectomized patients were significantly associated with an increased risk of HCC. Only 7.5% of patients in the HCC group had undergone splenectomy, compared to 16.1% in the non-HCC group (P < 0.001), indicating a significant inverse association between splenectomy and HCC incidence. Multivariate analysis confirmed splenectomy as an independent protective factor for reduced HCC risk	Splenectomy may reduce the risk of developing HCC in patients with cirrhosis by improving hypersplenism and hepatic function
Long et al[72]	2016	Animal study	The tumor volume of HCC in the splenectomy group (T + S) was significantly smaller than that of the non-splenectomy group (T). Specifically, splenectomy reduced tumor volume by 74% in the H22 model (P = 0.036) and 86% in the Hepa1-6 model (P = 0.0007). In the H22 model, splenectomy eliminated lung metastasis (0% vs 20%), diaphragmatic invasion (0% vs 20%), and reduced intrahepatic metastasis (40% vs 60%). Median survival was prolonged from 26 days to 34 days in the orthotopic transplantation model (P = 0.002) and from 26 days to 40.5 days in the tail vein injection model (P = 0.0007). HCC patients demonstrated splenomegaly and elevated splenic MDSCs (CD11b+Gr-1+ cells), which were significantly reduced in peripheral blood and tumor tissues after splenectomy	Splenectomy effectively inhibits the growth and metastasis of HCC by reducing the immunosuppressive effects of MDSCs
Chen et al[21]	2005	Case-control study	In patients with HCC and cirrhotic hypersplenism, the HS group demonstrated significantly higher leukocyte and platelet counts compared to the hepatic resection alone (H) group at postoperative day 14 (P = 0.043 and P = 0.037). At 2 months postoperatively, the HS group exhibited increased CD4+ T cell proportions, CD4/CD8 ratios, and Th1 type cytokines (IL-2, interferon-γ), along with decreased immunosuppressive cytokine IL-10. The 5-year DFS rate was significantly higher in the HS group (37% vs 27.3%, P = 0.003), although no significant difference was observed in OS between groups (56% vs 50.9%)	HSS safely improves postoperative immune status and chemotherapy tolerance in patients with HCC and hypersplenism, significantly prolonging DFS. This approach represents an effective therapeutic strategy for this patient population

DFS: Disease-free survival; HA: Hepatic ablation; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HS group: Hepatectomy and splenectomy group; HSS: Hepatic resection with synchronous splenectomy; ET: Endoscopic therapy; HR: Hazard ratio; IL: Interleukin; IPTW: Inverse probability of treatment weighting; IVAF-FIB-4: Type IV collagen-alpha fetoprotein-fibrosis-4 score; LSD: Laparoscopic splenectomy with devascularization; MDSCs: Myeloid-derived suppressor cells; NK: Natural killer; NLR: Neutrophil-to-lymphocyte ratio; OR: Odds ratio; OS: Overall survival; RFS: Recurrence-free survival.