Splenectomy and risk of hepatocellular carcinoma

Abstract

Hypersplenism is a common complication of cirrhosis that is associated with significant impairment to patients' life quality. Splenectomy is often employed in clinical settings as a treatment for hypersplenism. While splenectomy is carried out for the purposes of alleviating hypersplenism-related adverse outcomes like thrombocytopenia or anaemia, studies have suggested alterations in the immune status, hemodynamics, and intestinal microbiota of patients following splenectomy, which may potentially influence the onset and progression of hepatocellular carcinoma (HCC). Additionally, patients have been found to face new health risks post-splenectomy, including infections and thrombosis, which could adversely impact their overall health and potentially increase the risk of HCC. Despite these findings, there is currently no consensus on whether splenectomy affects the risk of postoperative HCC in cirrhotic patients. This review synthesizes the pertinent literature on the incidence of HCC following splenectomy, with an emphasis on current evidence related to its physiology, pathophysiology, and epidemiology. Concepts such as immune status, hemodynamics changes, and intestinal microbiota in post-splenectomy patients are explored, in hopes that it can inform more individualized treatment approaches for patients.

Key Words: Splenectomy; Hepatocellular carcinoma; Immune status; Hemodynamics; Pathophysiology

Core Tip: Hypersplenism, a frequent complication of cirrhosis, often requires splenectomy to alleviate conditions like thrombocytopenia and anemia. However, splenectomy may alter immune status and hemodynamics, potentially influencing hepatocellular carcinoma (HCC) development. Post-splenectomy risks, including infections and thrombosis, further complicate outcomes. Current evidence on the splenectomy-HCC relationship remains inconclusive, necessitating further research into pathophysiology and epidemiology. This review examines immune, hemodynamic, and gut microbiota changes post-splenectomy to guide individualized treatment strategies for cirrhotic patients.

INTRODUCTION

Liver cirrhosis is a common chronic progressive liver disease characterized by diffuse hepatic damage caused by long-term or repeated actions of one or multiple etiologies[1]. Globally, cirrhosis remains a major health burden with high morbidity and mortality, placing patients at significant risk of hepatic decompensation, portal hypertension, and hepatocellular carcinoma (HCC). HCC, the most prevalent primary liver malignancy, is associated with aggressive progression and poor prognosis, severely compromising survival outcomes in cirrhotic patients. Epidemiological data indicate an annual HCC incidence of 3%-5% in cirrhotic populations, with this risk escalating alongside disease progression[2].

Splenectomy is a common intervention performed as part of the clinical management of liver cirrhosis. This procedure is typically indicated when cirrhotic patients develop hypersplenism-induced cytopenia, particularly severe thrombocytopenia that elevates bleeding risk. In this aspect, splenectomy demonstrates efficacy in symptom alleviation[3]. Furthermore, for cirrhotic patients complicated with portal hypertension, splenectomy combined with devascularization procedures or shunt surgeries has been shown to effectively reduce portal venous pressure, thereby preventing life-threatening complications such as esophageal/gastric variceal bleeding[4,5]. However, splenectomy is a major surgical intervention that substantially alters the anatomy and impacts the physiologic function of the hepatobiliary system, and its potential impact on postoperative HCC risk in cirrhotic patients remains undetermined.

Current studies on the oncological impact of splenectomy in cirrhotic patients have yielded conflicting conclusions regarding its association with postoperative HCC risk. Some investigations posit that splenectomy-induced immunosuppression may increase HCC susceptibility through attenuated immunosurveillance mechanisms, as the spleen's role in tumor cell recognition and elimination is compromised following resection[6]. Additionally, hemodynamic alterations within the portal venous system post-splenectomy may disrupt hepatic microcirculation, creating a local hypoxic microenvironment that promotes aberrant hepatocyte proliferation and malignant transformation[7]. Yet, conflicting evidence suggests that splenectomy might mitigate HCC risk by resolving hypersplenism-related immune hyperactivation, thereby improving homeostasis of the hepatic immune microenvironment[8]. Additionally, reductions in portal hypertension achieved through splenectomy could enhance hepatic perfusion, potentially alleviating hemodynamic stressors linked to hepatocyte injury and oncogenesis[9].

Given the inherent high risk of HCC in cirrhotic patients and the extensive clinical utilization of splenectomy, investigating the impact of splenectomy on postoperative HCC development holds significant clinical relevance. This inquiry not only aids in optimizing treatment decisions by enabling comprehensive risk stratification of cirrhotic patients but also enhances the precision of selecting appropriate candidates for surgical intervention. Additionally, it provides a theoretical foundation for developing adjunctive prophylactic strategies to mitigate HCC progression in this population. Ultimately, seeking an answer to this clinical question may contribute to reducing HCC incidence and improving long-term survival outcomes in cirrhotic patients.

INCIDENCE AND EPIDEMIOLOGY OF HCC AFTER SPLENECTOMY

The pathogenesis of HCC following splenectomy in patients with portal hypertension has been a focal point of interest among hepatobiliary surgeons. Existing literature reports significant variability in post-splenectomy HCC incidence ranging from 5.1% to 36.9% across different cohorts[10-13]. The disparity in HCC incidence can be attributed to differences in etiology of the chronic liver disease, geographical disparities, and patient age distribution, among other factors. Studies specifically evaluating cirrhotic patients with a history of viral hepatitis (e.g., chronic hepatitis B or C) undergoing splenectomy have demonstrated significantly higher HCC incidence compared to those with non-viral etiologies of portal hypertension, underscoring the critical role of hepatic injury patterns in oncogenesis[10,13-15]. Temporal analysis further reveals that the majority of HCC cases develop within 5 years post-splenectomy with a peak incidence occurring between 3–5 years postoperatively, although delayed presentations exceeding 10 years have also been documented, indicating a prolonged latency period influenced by complex interactions between residual hepatic dysfunction after surgical intervention and oncogenic pathways[13].

Sex differences also play a significant role, with male patients demonstrating a higher risk of post-splenectomy HCC compared to females, which may be attributed to lifestyle factors (e.g., higher prevalence of smoking and alcohol consumption) and androgenic effects on hepatocyte metabolism[10,16,17]. Age is another critical determinant, as HCC risk increases progressively with advancing age due to immunosenescence and impaired hepatic regenerative capacity in elderly patients[10,18]. Geographical disparities in post-splenectomy HCC incidence are also evident, with higher rates observed in Asia compared to Europe/North America due to regional differences in hepatitis B/C virus (HBV/HCV) prevalence and associated risk factors such as pickled food consumption containing hepatocarcinogenic nitrosamines[19,20]. Additionally, heterogeneous healthcare access and diagnostic capabilities across regions may influence HCC detection rates and reported incidence statistics.

IMPACT OF SPLENECTOMY ON PHYSIOLOGICAL STATES RELATED TO THE LIVER AND INTESTINES

Impact of splenectomy on the immunological environment within the liver

The spleen, a vital immune organ, plays a pivotal role in systemic immune regulation and hepatic immune homeostasis. Splenectomy induces significant alterations in immune cell quantity and functionality, thereby indirectly modulating the hepatic immune microenvironment. Studies demonstrate that cirrhotic patients with HCC and hypersplenism undergoing combined hepatectomy and splenectomy exhibit a significant elevation in CD4⁺ T cell counts and CD4⁺/CD8⁺ ratios at 2 months postoperatively, accompanied by increased levels of Th1 cytokines [interleukin (IL)-2 and interferon-γ (IFN-γ)] and reduced IL-10 expression[21]. These findings suggest that while hypersplenism may downregulate immune function, splenectomy restores immunosurveillance by eliminating cirrhotic hypersplenism-mediated immunosuppression. Next, the spleen contributes to tumor-induced immune tolerance through the release of immunosuppressive macrophages that disrupt T cell receptor-CD3 complexes and impair T cell functionality[22,23]. Splenectomy has been shown to restore lymphocyte function and induce tumor regression in preclinical models[24]. Post-splenectomy increases in natural killer (NK) cell activity facilitate direct tumor cell cytotoxicity[25,26], while concurrent enhancements in CD4⁺/CD8⁺ T cell-mediated anti-tumor immunity have been documented[8,27,28]. Lastly, splenectomy reduces hepatic transforming growth factor-beta 1 (TGF-β1) production, promoting cirrhotic liver regeneration and fibrosis resolution[29].

Yet, other studies have noted an opposite effect of imbalances in hepatic T lymphocyte subsets characterized by relative reductions in helper T cells and increased suppressor T cells post-splenectomy, which compromises cellular immunity and diminishes the liver's capacity for viral clearance and tumor immunosurveillance[30,31]. Concurrently, other studies have shown that splenectomy reduces B lymphocyte antibody production, further impairing humoral immunity and compromising hepatic defense mechanisms[32].

Through a separate mechanism of altering the cytokine profile and immunomodulatory factors within the liver, splenectomy has been shown to slow the progression of the characteristic progressive inflammatory injury and hepatic fibrosis in cirrhotic hypersplenism. Experimental models demonstrate that splenectomy attenuates histological severity scores and reduces serum aspartate aminotransferase, alanine aminotransferase, and tumor necrosis factor–alpha (TNF-α) levels in rats with hepatic ischemia-reperfusion injury, concomitantly alleviating renal and intestinal damage[33]. In cirrhotic contexts, splenectomy potentiates the therapeutic efficacy of adipose-derived mesenchymal stem cells in cirrhotic rat models by reducing serum TGF-β1 levels, ameliorating hepatic fibrosis, and enhancing hepatocyte regeneration[33]. Pathophysiological mechanisms underlying cirrhotic hypersplenism involve splenic macrophage hyperactivation driven by nuclear factor-kappa B signaling, which exacerbates hepatic inflammation and fibrosis through secretion of pro-inflammatory cytokines (IL-1β, IFN-γ, and TNF-α) and profibrotic mediators (TGF-β1)[29,34,35]. Splenectomy mitigates these effects by reducing hepatic macrophage infiltration and promoting C-C motif chemokine ligand 2 secretion via upregulation of the suppressors of cytokine signaling 3 signaling pathway in hepatic macrophages. In vivo studies further reveal that splenectomy decreases M1 macrophage polarization and hepatic fibrosis severity, effects partially reversed by adoptive transfer of splenocytes[36].

Influence of splenectomy on hepatic hemodynamics

Splenectomy induces significant hemodynamic alterations within the portal venous system. With the spleen no longer serving as a major shunt for portal blood flow, the sudden redirection of splenic venous blood into the liver results in an acute increase in portal venous blood flow. Studies indicate that portal venous blood flow may increase by 30%-50% in the early postoperative period following splenectomy[37]. This abrupt hemodynamic surge disrupts hepatic microcirculation, leading to elevated hepatic sinusoidal pressure. Additionally, the hepatic vasculature's short-term inability to adapt to such flow changes causes alterations in vascular resistance. Consequent increases in portal pressure not only compromise normal hepatic perfusion but also heighten risks for portal hypertension-related complications such as esophageal-gastric variceal hemorrhage.

To compensate for post-splenectomy hemodynamic changes, the liver initiates adaptive mechanisms involving vascular endothelial cell release of vasoactive substances. Splenectomy increases hepatic 5-hydroxytryptamine (5-HT) secretion, which mediates hepatic perfusion via vasodilatory effects[38]. Hepatic 5-HT further improves microcirculation and promotes hepatocyte regeneration by stimulating endothelial cell release of vascular endothelial growth factor[39]. Post-splenectomy reductions in portal blood flow, congestion index, and hepatic venous pressure gradient (HVPG) suggest that splenomegaly contributes to the pathogenesis of portal hypertension through augmented splanchnic blood flow. Research demonstrates that splenectomy reduces HVPG by 25% and intrahepatic portal venous resistance by 21%[37].

Intrahepatic portal vascular resistance is regulated by the balance between vasoconstrictors [e.g., endothelin-1 (ET-1)] and vasodilators [e.g., nitric oxide (NO)]. Cirrhotic patients exhibit elevated ET-1 levels in both splanchnic and systemic circulations[40]. Splenectomy significantly decreases peripheral ET-1 concentrations. ET-1 exerts dual vasoactive properties: Binding to endothelin A receptors on hepatic stellate cells (HSCs) mediates vasoconstriction, while binding to endothelin B receptors on sinusoidal endothelial cells promotes NO-dependent vasodilation[41]. In cirrhosis, elevated ET-1 and reduced NO contribute to HSC contraction and increased intrahepatic vascular resistance. Splenectomy reverses this imbalance by lowering hepatic venous ET-1 levels and augmenting NO bioavailability[37]. Hepatic extracellular matrix (ECM) remodeling further impacts hemodynamics. Excessive ECM deposition during fibrosis stiffens hepatic parenchyma, reduces vascular elasticity, and exacerbates circulatory impedance, creating a vicious cycle that progressively impairs hepatic metabolism and function[42,43].

Effect of splenectomy on intestinal dysbiosis

Splenectomy induces significant alterations in the intestinal ecosystem. As a major reservoir and activation site for lymphocytes, splenectomy impairs systemic immunity, particularly reducing host defense against intestinal pathogens. The immunodeficiency associated with splenectomy allows overgrowth of commensal bacteria, disrupting gut microbiota homeostasis. Previous studies have indicated that the spleen contributes to intestinal mucosal immune responses, and splenectomy disrupts the mucosal immune microenvironment required to maintain normal gut flora[44]. Zhu et al[45] reported significant compositional shifts in the gut microbiota following splenectomy, associated with elevated plasma endotoxin lipopolysaccharide (LPS) levels. Splenectomized patients exhibited altered abundances in 2 bacterial phyla, 7 families, and 15 genera, with significantly higher plasma LPS concentrations than healthy controls. Dysbiosis severity correlated with postoperative duration, and LPS biosynthesis pathway abundance positively correlated with plasma LPS levels[45]. Additionally, although intestine-spleen communication mechanisms remain unclear, splenectomy reduced beneficial bacteria species (e.g., Bifidobacterium and Lactobacillus) and increased pathogenic bacteria (e.g., Escherichia coli, Enterococcus, and Shigella)[46,47], causing reduced bacterial diversity and dysbiosis. Impairment to systemic immunity also means that post-splenectomy transient bacteremia may progress to severe infections[48].

Disruption of the gut microbiota exerts a profound impact on bile acid metabolism, facilitating the conversion of primary bile acids into secondary bile acids. This metabolic shift subsequently modulates the expression of CXC motif chemokine ligand 16 on liver sinusoidal endothelial cells, ultimately regulating the accumulation of NK T (NKT) cells within the hepatic microenvironment. Given the critical role of NKT cells in antitumor immunity, these alterations can significantly influence the liver's ability to mount an effective antitumor immune response, thereby elevating the risk of liver cancer development[49]. Simultaneously, gut microbiota dysbiosis is associated with significant changes in short-chain fatty acid (SCFA) levels. As essential metabolic byproducts of the gut microbiota, SCFAs are transported to the liver via the gut-liver axis, where they play a pivotal role in regulating hepatic metabolism and immune function. Imbalances in the gut microbiota can lead to a reduction in SCFA levels, weakening their regulatory effects on liver immune cells. This, in turn, impairs immune function and compromises the liver's capacity to eliminate abnormal cells, creating a permissive environment for HCC development. Moreover, abnormal SCFA levels can disrupt normal liver metabolic processes, triggering fat accumulation and promoting inflammatory responses, both of which contribute to the progression of HCC[50]. Notably, previous research has demonstrated that fluctuations in SCFA concentrations can modulate the expression of key cytokines in the liver, such as TNF, which are intricately linked to the initiation and progression of HCC[51].

Meanwhile, there exist mechanisms that link splenectomy to improvements in cirrhotic gut dysbiosis and metabolism[52]. Cirrhosis itself alters the gut microbiota, which correlates with decompensation and acute-on-chronic liver failure[53]. Host-microbiota co-metabolism of endogenous/exogenous substrates produces metabolites that translocate to the liver via the portal vein, influencing hepatic function[54]. In murine models, splenectomy modulates gut microbiota activation of HSCs, which reduces cirrhosis, decreasing Veillonella abundance and restoring intestinal barrier function via the hepatic Toll-like receptor 4/nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 inflammasome axis[33]. Thus, splenectomy’s impact on the gut microbiota is dual: Potential retardation of disease progression via microbiota regulation vs infection risk via barrier disruption and endotoxemia.

The spleen also secretes immunoglobulins and cytokines critical for intestinal mucosal immune barrier function. Splenectomy reduces immunoglobulin A secretion, weakening mucosal resistance to pathogen adhesion and exacerbating dysbiosis[55]. In animal models, splenectomized mice with dextran sulfate sodium-induced colitis exhibited severe bacteremia, increased mortality, and reduced serum pro-inflammatory cytokines (TNF-α and IL-6). Splenectomy impaired intestinal barrier function (e.g., reduced tight junction proteins) and increased Proteobacteria abundance, elevating endotoxemia and bacterial translocation risk[56]. Additionally, splenectomy may alter intestinal blood flow and neuroregulation, disrupting motility and secretion, allowing the creation of an aberrant microbial microenvironment[57].

IMPACT OF SPLENECTOMY ON HCC OCCURRENCE

Splenectomy increases the risk of HCC occurrence

Splenectomy, originally used for treating spleen-related disorders, certain hematological conditions, and portal hypertension, has recently become a key focus in studies exploring the risk of HCC development. A large body of clinical research and epidemiological investigations has firmly established that patients who have undergone splenectomy have a notably higher incidence of HCC compared to those who have not had the surgery[10,11,13,15]. A retrospective study that analyzed multi-center case data found that the risk of developing HCC in patients after splenectomy increases several-fold within 5-10 years[13]. In a study of liver transplantation with splenectomy, patients with HCC were found to have a significantly increased risk of tumor recurrence and mortality after splenectomy. Splenectomy is an independent risk factor for tumorigenesis and mortality[58].

At the mechanistic level, there are multiple reasons why splenectomy raises the risk of HCC. One significant factor is the impairment of immune function. As a vital immune organ in the human body, the spleen plays a crucial role in the storage and activation of immune cells, as well as the secretion of immunoglobulins and cytokines[34,59]. After splenectomy, the body's immune surveillance function is severely compromised. The activity of immune cells such as NK cells decreases, making it difficult for the immune system to effectively identify and eliminate abnormally proliferating hepatocytes. This creates favorable conditions for the escape and proliferation of tumor cells[60].

Changes in hemodynamics also plays a significant role. Splenectomy is often associated with portal hypertension, which disrupts the normal hemodynamics of the liver. This leads to disorders in the hepatic microcirculation and local tissue hypoxia[61,62]. In this hypoxic micro-environment, hepatocytes undergo compensatory hyperplasia to maintain their own metabolism. During this process, the probability of cellular gene mutations significantly increases, providing the conditions for the development of HCC. Furthermore, intestinal dysbiosis also plays a vital role. After splenectomy, the balance of the intestinal microbiota is disrupted, and pathogenic bacteria multiply in large numbers, producing harmful substances such as endotoxins. These substances enter the liver through the portal vein via the bloodstream, continuously triggering chronic inflammatory responses in the liver. Long-term inflammatory stimulation induces abnormal proliferation of hepatocytes, eventually leading to oncogenesis[63] (Figure 1).

Figure 1 Impact of splenectomy on occurrence and recurrence of hepatocellular carcinoma. ET-1: Endothelin-1; HCC: Hepatocellular carcinoma; IgA: Immunoglobulin A; LPS: Lipopolysaccharide; NK: Natural killer cell; NO: Nitric oxide; TGF-β: Transforming growth factor–beta.

Splenectomy reduces the risk of HCC occurrence

In recent years, some studies have put forward new viewpoints, suggesting that splenectomy may have the potential to reduce the risk of HCC development under specific circumstances. This discovery has paved the way for new research directions for the prevention and treatment of HCC.

Related clinical studies have observed that in patients with liver diseases caused by certain specific etiologies, the incidence of HCC has significantly decreased after they underwent splenectomy. Some research has shown that among patients with liver cirrhosis complicated by portal hypertension, after performing splenectomy combined with devascularization or shunt procedures, after several years of follow-up, compared with similar patients who did not receive splenectomy, their risk of developing HCC was significantly reduced[15,64]. This study found that the 10-year incidence of HCC in the endoscopic treatment group was significantly higher than that of the splenectomy group (28.1/1000 vs 9.6/1000). Compared with the endoscopic treatment group, the splenectomy group had a reduced risk of HCC by 56.0%. The likelihood of patients with liver cirrhosis complicated by portal hypertension who received endoscopic treatment developing HCC after the operation was 2.3 times that of patients who received splenectomy treatment[15]. Chen et al[21] demonstrated that the 5-year disease-free survival (DFS) rate of HCC patients who received hepatectomy combined with splenectomy was significantly higher than that of patients who received only hepatectomy. Zhang et al[65,66] also found that compared with patients who received only hepatectomy, the DFS rate and overall survival (OS) rate of HCC patients with hypersplenism who received hepatectomy combined with splenectomy were significantly improved. Zhang et al[67] reported that hepatic resection with synchronous splenectomy significantly improves early recurrence-free survival in patients with T1-stage HCC and cirrhotic portal hypertension, particularly benefiting those with Child-Pugh A liver function.

The role of splenectomy in improving oncological outcomes has also been reported in animal studies. Splenocytes release tumor-enhancing factors, and the activity that promotes tumor growth in vivo can be inhibited[68,69]. In addition to inhibiting tumor growth, it can also reduce tumor metastasis[70]. Furthermore, after splenectomy, liver fibrosis markers such as procollagen type III, hyaluronidase, laminin, and collagen type IV were significantly improved. Since liver cirrhosis is the main causative factor of HCC, splenectomy can, to a certain extent, prevent the occurrence of HCC[71]. Animal studies have shown that splenectomy can inhibit the progression of HCC and prolong the OS time of mice. Splenectomy inhibits the growth and metastasis of HCC by reducing myeloid-derived suppressor cells in the blood circulation and tumors, suggesting that splenectomy may be an adjuvant treatment for HCC[72,73].

Risk factors for HCC development after splenectomy

The occurrence of HCC following splenectomy is not stochastic but rather the result of interactions among multiple factors. Identifying these risk factors is vital for the early prevention and precision treatment of HCC. First, the underlying liver disease status is a critical determinant. Patients with pre-existing liver cirrhosis exhibit a significantly increased risk of HCC after splenectomy[2,74-76]. Cirrhosis leads to hepatic fibrosis and pseudolobule formation, disrupting normal hepatic architecture and function. Hepatocytes undergo continuous injury-repair cycles, drastically elevating the probability of oncogenic mutations. Even after splenectomy, this inherent carcinogenic tendency persists[77]. For instance, HBV X protein or HCV core protein directly interferes with hepatocyte cycle regulation, promoting malignant transformation[74,78]. Continuous hepatocyte regeneration in cirrhotic livers accumulates DNA replication errors, predisposing to mutations in genes such as tumor protein p53 and catenin beta 1 and eventual carcinogenesis[79]. Second, immune dysfunction plays a pivotal role. As a major immune organ, splenectomy impairs immunosurveillance and defense mechanisms. Reduced activity of NK cells and other immune cells compromises the ability to recognize and eliminate transformed hepatocytes, allowing tumor cells to evade immune attack and proliferate unchecked[80]. Furthermore, the persistent inflammatory microenvironment serves as a risk factor. Post-splenectomy intestinal dysbiosis leads to overgrowth of pathogenic bacteria, producing endotoxins and other harmful substances that translocate to the liver via the portal vein, triggering chronic hepatic inflammation[56]. Prolonged inflammatory stimulation disrupts the hepatic cytokine network, inducing abnormal hepatocyte proliferation and potentially driving carcinogenesis (Table 1)[10,11,13,15,21,24,58,60,64,67,72,81].

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.

Impact of concurrent splenectomy on HCC recurrence

In recent years, there has been an increasing number of studies on the impact of concurrent splenectomy in patients with HCC on the recurrence of HCC, which has attracted widespread attention among clinicians and scientists. Although some research achievements have been made, there is still no consensus on how this surgical approach exactly affects the recurrence of HCC. Studies have shown that concurrent hepatectomy combined with splenectomy can prolong the DFS of HCC patients with hypersplenism[21]. A case-control study by Zhang et al[67] found that the average recurrence time of HCC in the concurrent hepatectomy and splenectomy group (HS group) (21.11 months ± 12.04 months) was significantly longer than that of the simple hepatic ablation group (HA group). The 1-year, 3-year, 5-year, and 7-year DFS rates of the HS group were significantly higher than those of the HA group. Synchronous hepatectomy and splenectomy reduced tumor recurrence and prolonged the recurrence interval, but it did not benefit the OS of patients with HCC and hypersplenism[21]. Splenectomy may reduce the ability of HCC cells to escape immune defense and inhibit tumor metastasis by reducing the level of TGF-β and decreasing the recruitment of Treg cells[73,82,83].

INFLUENCE OF SPLENECTOMY ON THE USE OF IMMUNOTHERAPEUTIC AGENTS IN HCC PATIENTS

Recently, immunotherapy agents have emerged as promising therapeutic options for HCC, offering new hope for patients. However, splenectomy—a procedure often performed for specific clinical indications in HCC patients—may exert complex effects on the efficacy and safety of immunotherapy[84,85]. Regarding immunomodulation, the spleen serves as a vital immune organ containing abundant lymphocytes and bioactive immune substances, playing a critical role in maintaining systemic immune homeostasis. Following splenectomy, significant alterations occur in immune function, characterized by fluctuations in immune cell quantity and activity[48]. Dysregulation of T and B lymphocyte proportions, combined with reduced NK cell activity, may attenuate the immune activation and cytotoxicity of immunotherapy against tumor cells[32]. Immunotherapy agents typically rely on activating the host’s endogenous immune system to combat tumors; however, post-splenectomy changes in the immune microenvironment may blunt this activation, compromising treatment efficacy[86]. Additionally, impaired immunosurveillance following splenectomy may facilitate tumor cell evasion from immune recognition and attack, further undermining therapeutic outcomes[87]. Intestinal dysbiosis post-splenectomy contributes to overgrowth of pathogenic bacteria, leading to endotoxin translocation and systemic chronic inflammation. This inflammatory milieu may disrupt immunotherapy signaling pathways, interfering with tumor-targeting effects and potentially increasing the risk of immune-related adverse events[56].

While preliminary insights into the interplay between splenectomy and immunotherapy in HCC patients have been gained, numerous unresolved questions remain. Further exploration of the molecular mechanisms underlying post-splenectomy immune responses and inflammatory pathways, as well as identification of key signaling pathways and therapeutic targets, is essential to inform the development of tailored interventions. Additionally, optimizing immunotherapy selection and timing based on post-splenectomy immune status and tumor characteristics may mitigate adverse effects and improve prognoses for HCC patients.

CLINICAL DECISION-MAKING FOR PATIENTS WITH PORTAL HYPERTENSION COMPLICATED BY HCC

HCC complicated by portal hypertension presents a complex clinical scenario with significant therapeutic challenges, posing a severe threat to patient health. Globally, such cases are not uncommon, and the interplay between these two conditions exacerbates treatment complexity. On one hand, portal hypertension disrupts hepatic hemodynamics and impairs liver function, increasing procedural risks; on the other hand, the presence of HCC accelerates hepatic decompensation[88].

Clinical decision-making requires comprehensive consideration of multiple factors. First, hepatic reserve capacity is a critical determinant. The Child-Pugh classification and Model for End-Stage Liver Disease score are commonly used to assess hepatic function[89]. Cirrhotic hypersplenism, characterized by leukopenia and thrombocytopenia, has traditionally been considered a contraindication for hepatectomy[90]. However, selected patients with preserved hepatic reserve may tolerate combined hepatectomy and splenectomy. Splenic artery embolization can be employed to reduce splenic size in HCC patients with hypersplenism, enabling subsequent hepatectomy[91]. Laparoscopic splenectomy has also been reported as a feasible initial approach for staged hepatic resection[92]. Second, tumor characteristics are paramount. Tumor size, number, location, vascular invasion, and metastatic status directly influence treatment selection[93]. Surgical resection is often preferred for early-stage, solitary tumors without vascular invasion, whereas advanced cases with multifocality, vascular involvement, or metastasis may require multimodal therapy integrating interventional, targeted, and immunotherapeutic approaches. Additionally, the severity of portal hypertension and associated complications must be addressed. Severe portal hypertension increases the risk of esophageal-gastric variceal hemorrhage, necessitating priority interventions to reduce portal pressure (e.g., endoscopic therapy, transjugular intrahepatic portosystemic shunt, or pharmacotherapy) before definitive HCC treatment[88].

CLINICAL DECISION-MAKING FOR PATIENTS WITH HCC OCCURRING AFTER SPLENECTOMY

Post-splenectomy HCC patients present with unique clinical complexities. As a crucial immune and hematological filtration organ, splenic removal leads to a series of alterations including impaired immune function, hemodynamic changes, and intestinal microbiota dysbiosis. These changes not only affect normal hepatic physiological functions but also create a distinctive pathological microenvironment for HCC development and progression. The attenuation of immune surveillance facilitates tumor cells' evasion from immune recognition and elimination; at the same time, abnormal hemodynamic alterations may provide more favorable conditions for tumor cell proliferation and metastasis[6,94,95].

Currently, there is a lack of systematic and comprehensive guidelines for clinical decision-making in this special patient population. During clinical decision-making, patients' overall physical condition and immune status must be carefully considered. Following splenectomy, patients' immune function remains relatively compromised, necessitating thorough evaluation of their immunological tolerance to various treatment modalities when formulating therapeutic strategies. Concurrently, post-splenectomy reactive thrombocytosis may increase the risk of intraoperative and postoperative thrombosis[96]. Furthermore, for resectable HCC cases, special consideration must be given to patients' surgical tolerance, particularly regarding post-splenectomy anatomical changes and intra-abdominal adhesions. Patients meeting Milan criteria should be prioritized for liver transplantation evaluation[97].

CONCLUSION

Collectively, splenectomy—a common treatment for cirrhotic hypersplenism—ameliorates thrombocytopenia, anemia, and related complications. However, its impact on the immune system, hemodynamics, and intestinal microbiota may correlate with HCC development. Post-splenectomy patients face new health risks, including infections and thrombotic events, which may further elevate HCC susceptibility. Notably, no consensus has been reached regarding the precise role of splenectomy in HCC pathogenesis among cirrhotic patients. We believe that a comprehensive and individualized assessment is necessary to balance the benefits and risks of splenectomy. When considering splenectomy for patients at risk of liver cancer, clinicians need to carefully consider the type of underlying liver disease, liver function status, the presence of complications (such as variceal bleeding), and immune function. For patients with relatively good liver function and a high risk of bleeding, splenectomy can be cautiously considered, but close attention should be paid to immune regulation and prevention of infections after the operation. In contrast, for patients with severely impaired immune function or those with advanced stage of liver cancer, the risks of splenectomy may outweigh the benefits, and alternative treatment options should be explored. For patients with liver cancer complicated by portal hypertension who undergo combined hepatectomy and splenectomy simultaneously, the surgical risk is increased to a certain extent. Therefore, the surgical indications need to be strictly assessed, and perioperative preparation and postoperative nursing should be strengthened. At present, most scholars believe that for patients with portal hypertension, splenectomy can improve liver function, enhance the body's immunity, and inhibit the occurrence and progression of liver cancer. However, the specific mechanisms remain unclear. Future research should prioritize high-quality, large-sample, multicenter studies to clarify the mechanistic links between splenectomy and postoperative HCC risk. Such investigations will provide a robust evidence base for developing targeted treatment strategies that balance therapeutic benefits against oncological risks.