Splenectomy and hepatocellular carcinoma: Cause or confounder?

Abstract

While splenectomy has been associated with hepatocellular carcinoma (HCC) in cirrhotic patients, its role as a direct carcinogenic factor remains controversial. This letter argues that the primary risk of HCC stems from the underlying liver disease rather than the surgical removal of the spleen itself. Current literature is based mostly on retrospective analyses lacking randomized controlled trials. Moreover, there is insufficient evidence to suggest that splenectomy in non-cirrhotic patients increases HCC risk. Prospective multicenter studies are needed to clarify the causal relationship.

Key Words: Splenectomy; Hepatocellular carcinoma; Liver cirrhosis; Hypersplenism; Portal hypertension

Core Tip: This letter challenges the notion that splenectomy itself increases hepatocellular carcinoma risk. This letter emphasize that the primary driver is underlying liver disease, not splenectomy. Current evidence is largely based on retrospective studies, and well-designed prospective or randomized trials are needed to determine any independent effect of splenectomy on hepatocarcinogenesis.

TO THE EDITOR

I read with great interest the article by Li et al[1]. Their review comprehensively explores the potential impact of splenectomy on hepatocellular carcinoma (HCC) risk in patients with cirrhosis and portal hypertension. The authors suggest a possible association between splenectomy and the development of HCC. While this hypothesis is thought-provoking, I believe the interpretation of the data deserves cautious consideration. So, I wish to offer a complementary viewpoint.

DISCUSSION AND PERSPECTIVE

HCC development is primarily driven by underlying etiology of liver disease, such as chronic viral hepatitis, alcoholic liver disease, or non-alcoholic steatohepatitis, rather than by splenectomy itself[2]. While splenectomy is usually performed to alleviate hypersplenism in cirrhotic patients and may alter portal hemodynamics and immune function, its role in hepatocarcinogenesis likely remains secondary and context-dependent.

To date, there is no clear evidence that splenectomy itself promotes hepatocarcinogenesis in patients without underlying liver disease. For instance, splenectomy performed during surgery for hematologic disorders or gastrointestinal malignancies without liver cirrhosis has not been associated with an increased incidence of HCC. Longterm followup studies in such populations demonstrate low complication rates and no elevated incidence of liver cancer[3]. This suggests that splenectomy alone is unlikely to be an independent carcinogenic factor.

The current evidence base, including the studies cited in the review by Li et al[1], is composed almost entirely of retrospective cohort or case-control studies, which are inherently limited by selection bias, confounding factors, and heterogeneity in surgical indications, patient selection, and baseline liver function. Furthermore, these studies often lack stratification by severity of liver fibrosis, portal hypertension, or viral control, which significantly influence HCC development.

While post-splenectomy changes in immune status, hemodynamics, or gut-liver axis may theoretically modulate liver carcinogenesis, these mechanisms remain speculative and require further elucidation. Without high-quality prospective data, drawing a causal link remains premature.

Therefore, the suggestion that splenectomy is a “risk factor” for HCC should be interpreted with caution. Prospective, multicenter studies and ideally randomized controlled trials are necessary to isolate the effect of splenectomy from that of the underlying liver pathology. Until then, the presence or absence of splenectomy should not be considered an independent predictor of HCC in clinical practice.

In summary, while the authors bring attention to this important and timely clinical question, I believe that the evidence supports etiological liver disease rather than splenectomy as the primary driver of HCC risk. While I may offer a different perspective, I sincerely appreciate their contribution to this complex topic and hope that this letter serves to foster further balanced and thoughtful discussion within the hepatology community.

CONCLUSION

While the review by Li et al[1] raises an important clinical question, the current evidence does not support a direct causal relationship between splenectomy and hepatocellular carcinoma. The development of HCC is more likely driven by the underlying liver disease rather than splenectomy itself. Given the limitations of retrospective analyses and potential confounding factors, prospective multicenter studies and randomized controlled trials are warranted to clarify this association.

ACKNOWLEDGEMENTS

I would like to express my sincere appreciation to all members of the Liver Surgery Team for their unwavering support and collaboration.