Small tumors, big decisions: Rethinking resection and ablation in early hepatocellular carcinoma

Abstract

The management of small hepatocellular carcinoma (HCC) remains a matter of active debate. The recent study by Lei et al provides valuable evidence comparing laparoscopic hepatectomy (LH) and radiofrequency ablation (RFA) in patients with tumors ≤ 5 cm. In this retrospective analysis of 254 cases, LH achieved superior three-year overall and disease-free survival compared with RFA (85% vs 66% and 64% vs 45%, respectively), despite longer operative times and higher postoperative morbidity. These findings reinforce the oncologic advantage of anatomical resection in removing microscopic disease beyond radiologically visible margins. The biological rationale is compelling: While RFA induces local necrosis within a constrained ablation zone, LH allows complete excision of the tumor and surrounding parenchyma, thereby addressing microvascular invasion and satellite nodules that frequently accompany early HCC. Nonetheless, RFA retains an essential role for patients with limited hepatic reserve or comorbidities precluding surgery, offering a safe and repeatable alternative with minimal physiological impact. The results of Lei et al also prompt reappraisal of the Barcelona Clinic Liver Cancer framework, which may inadequately reflect advances in laparoscopic and ablative technologies. Modern treatment selection should move beyond stage-based algorithms toward individualized decision-making integrating liver function, tumor biology, and patient frailty. In appropriately selected candidates, LH should remain the reference curative option, while RFA continues to provide meaningful benefit in high-risk or inoperable patients. Together, they represent complementary strategies within the evolving continuum of curative therapies for small HCC.

Key Words: Hepatocellular carcinoma; Liver resection; Radiofrequency ablation; Therapeutic hierarchy; Barcelona Clinic Liver Cancer; Local ablation

Core Tip: Early hepatocellular carcinoma is typically managed with resection or local ablation, yet growing evidence shows that resection provides superior long-term oncologic outcomes whenever feasible. Modern ablative technologies, no-touch radiofrequency ablation, microwave ablation, and fusion-imaging guidance, have improved local control but do not surpass the curative potential of anatomical resection. The limitations of the Barcelona Clinic Liver Cancer staging system highlight the need for individualized decision-making. The therapeutic hierarchy, ranking treatments by intrinsic curative power, offers a dynamic, patient-centered framework better aligned with contemporary practice. Selecting the highest feasible therapy for each patient ensures the best outcomes in early-stage hepatocellular carcinoma.

INTRODUCTION

The management of small hepatocellular carcinoma (HCC) remains one of the most debated issues in modern hepatology, particularly as new technologies and improved surgical techniques continue to evolve[1-6]. For tumors typically classified as “early stage”, liver resection and local ablation represent the two most widely used curative options. Historically, the Barcelona Clinic Liver Cancer (BCLC) system has guided the assignment of these therapies through a stage-based algorithm linking tumor burden, liver function, and performance status. While BCLC provided structure and standardization for more than two decades, the rapid evolution of surgical capabilities, image-guided ablation, systemic therapy, and radiotherapy has progressively revealed the limits of a fixed stage-to-treatment model[7].

The recent study by Lei et al[8], which compared laparoscopic hepatectomy with radiofrequency ablation (RFA) for tumors ≤ 5 cm, adds to a growing body of evidence demonstrating that resection offers superior overall survival (OS) and disease-free survival (DFS), despite higher technical complexity. These findings are broadly consistent with numerous contemporary meta-analyses across various populations, ages, and clinical scenarios that firmly support the oncologic advantage of resection whenever it is technically and physiologically feasible. At the same time, modern ablation has rapidly improved through the introduction of no-touch RFA (NT-RFA), microwave ablation (MWA), and fusion-imaging guidance, suggesting a more nuanced therapeutic landscape than the one originally envisioned by BCLC[9-11].

This evolving evidence highlights a central issue: Treatment selection for early HCC cannot rely on stage alone. Instead, it requires an individualized and dynamic approach integrating tumor biology, liver function, anatomical feasibility, and patient-specific considerations. This is precisely the rationale of the therapeutic hierarchy, a conceptual framework developed by Vitale and colleagues[12,13], in which therapies are ranked by intrinsic curative potential, transplant, resection, ablation, and systemic therapy, allowing clinicians to select the highest achievable tier for each patient. In 2025, the therapeutic hierarchy more accurately reflects real-world clinical practice than rigid, stage-based algorithms.

LIMITATIONS OF BCLC IN THE MODERN ERA

BCLC remains the most widely used staging system worldwide, and its 2025 update makes an important conceptual contribution by recognizing the human complexity of decision-making through the CUSE model (Complexity, Uncertainty, Subjectivity, Emotion)[7]. Yet its core structure remains unchanged: Treatment is assigned based on stage rather than on a patient-specific assessment of feasibility, biology, and comorbidity.

Several limitations have become increasingly evident: (1) Stage heterogeneity. BCLC 0-A includes patients who are technically resectable, patients suitable for ablation, and patients who would benefit more from transplantation. However, the algorithm does not meaningfully differentiate among these options in relation to individual anatomy, portal hypertension, microvascular invasion risk, or institutional expertise; (2) Advances in surgical safety. Laparoscopic and robotic hepatectomy have dramatically reduced morbidity, length of stay, and postoperative liver dysfunction in selected patients[14,15]. As a result, many individuals traditionally assigned to ablation under BCLC may now safely undergo resection; (3) Lack of dynamic adaptability. Real-world management includes downstaging, conversion from unresectable to resectable disease, rehabilitation of liver function after abstinence or antiviral therapy, and continuous reassessment by multidisciplinary tumor boards. BCLC is fundamentally static and cannot account for this continuous evolution[12]; and (4) Insufficient representation of tumor biology. Early HCC is not biologically homogeneous. Microvascular invasion and satellite nodules occur even in tumors ≤ 3 cm, and their likelihood can be predicted through imaging, radiomics, and serum biomarkers. BCLC does not incorporate this dimension. Collectively, these limitations indicate that BCLC is best used as a prognostic framework, not as an exclusive allocative tool.

EVIDENCE SUPPORTING RESECTION OVER ABLATION: A CONSISTENT PATTERN

Across recent meta-analyses, the advantage of resection over RFA is remarkably consistent (Table 1). Xuan et al[16] analyzed over 15000 patients and showed significantly better OS and RFS with resection. Gani et al[17] demonstrated that resection provides superior OS and RFS across most tumor sizes (< 3 cm and > 5 cm), with near equivalence only in the 3-5 cm range. Shaaban et al[18] showed that laparoscopic liver resection yields better 5-year OS and DFS and dramatically lower recurrence rates compared with RFA, even after adjustment for confounders.

Table 1 Summary table of recent meta-analyses.

Ref.	Population/setting	Interventions	Main findings	Conclusion
[16]	Small HCC ≤ 5 cm	Resection vs RFA	Resection better OS/RFS	Surgery superior
[17]	HCC ≤ 5 cm stratified	Resection vs RFA	Benefit across sizes	Surgery > RFA
[18]	Early HCC	Laparoscopic liver resection vs RFA	Better OS/DFS; less recurrence	Laparoscopic liver resection preferred
[19]	Elderly ≥ 65	Resection vs RFA	Better OS/DFS	Age not exclusion for surgery
[20]	Recurrent HCC	Repeat resection vs RFA	Better OS	Resection preferred
[22]	Early-stage HCC (RCTs)	Resection vs RFA	OS similar; DFS trend favoring resection	Evidence inconclusive
[23]	Solitary HCC ≤ 3 cm	Resection vs RFA	LR better OS/DFS/RFS (PS-matched)	LR preferred
[24]	Early-stage HCC (RCTs)	Ablation vs resection	Non-inferiority not demonstrated	Resection favored
[25]	Solitary HCC ≤ 3 cm	LT vs LR vs ablation	LT > LR > ablation	Hierarchical efficacy
[11]	Ablation RCT NMA	RFA, microwave ablation, PEI, transcatheter arterial chemoembolization, stereotactic ablative body radiation therapy	RFA > PEI	Defines non-surgical hierarchy
[29]	Larger HCC	Hepatic arterial + transcatheter arterial chemoembolization vs mono	Improved OS/local control	Good alternative

HCC: Hepatocellular carcinoma; RCT: Randomized controlled trial; RFA: Radiofrequency ablation; LT: Liver transplantation; LR: Liver resection; PEI: Percutaneous ethanol injection; OS: Overall survival; RFS: Recurrence-free survival; DFS: Disease-free survival; PS: Propensity score.

Importantly, the superiority of resection extends to special populations: (1) Elderly patients. Yoo et al[19] found that resection produced significantly better OS and DFS than RFA in patients ≥ 65 years, with RFA showing much higher local recurrence; and (2) Recurrent HCC. Yang et al[20] reported that repeat resection yields better OS than RFA in recurrent disease. Additionally, anatomic resection provides better long-term outcomes than non-anatomic resection, likely due to more complete removal of potential micrometastatic spread within the portal territory[21]. These converging data support a clear principle: Whenever safely feasible, resection remains the curative modality offering the strongest long-term oncologic benefit[22-26].

MODERN ABLATION: IMPROVED BUT NOT EQUIVALENT

Ablation has undergone substantial refinement: NT-RFA shows exceptional local tumor progression-free survival (97%-99%), approaching surgical margins for very small tumors[9]. MWA offers faster heating, larger ablation volumes, and reduced heat-sink effects[11]. Fusion imaging guidance improves accuracy and reduces complications and local recurrence compared with conventional ultrasound[10].

Despite these technological advances and excellent local control, oncologic outcomes after ablation remain influenced by tumor biology beyond the ablation margin. Microscopic vascular invasion and satellite nodules cannot be reliably eradicated by heat-based techniques and may contribute to higher recurrence rates. Beyond oncologic completeness, a fundamental difference between resection and ablation lies in the availability of histological information. Surgical resection provides a full pathological specimen, allowing definitive assessment of microvascular invasion, tumor differentiation, satellite nodules, capsule invasion, and margin status, parameters that are strongly associated with recurrence risk, survival, and postoperative treatment stratification. In contrast, ablation inherently precludes histological evaluation, limiting biological characterization of the tumor and preventing refinement of prognostic assessment or eligibility for adjuvant strategies and clinical trials. While biopsy prior to ablation may partially mitigate this limitation, it does not provide the same comprehensive pathological information as an intact surgical specimen and is subject to sampling error. This limitation further supports the preferential role of resection whenever technically and physiologically feasible. Moreover, outcomes of advanced ablation are inherently operator- and technology-dependent, similarly to advanced laparoscopic liver resection, which is also subject to learning curves and institutional expertise. Accordingly, while modern ablation has substantially narrowed the therapeutic gap in carefully selected patients, it does not consistently achieve the same level of oncologic completeness as resection and therefore does not fundamentally modify the hierarchical relationship between the two modalities.

STEREOTACTIC RADIATION AND COMBINATION THERAPIES

Several non-surgical alternatives are gaining prominence: (1) Stereotactic body radiation therapy (SBRT)/stereotactic ablative body radiation therapy. Network meta-analyses show that SBRT provides DFS comparable to surgery but inferior OS at 3-5 years. Complication rates are lower, making this option valuable for patients unable to undergo invasive therapy. However, SBRT does not replace resection in fit patients[27,28]; and (2) Combination of locoregional therapies (e.g., hepatic arterial + transcatheter arterial chemoembolization): Meta-analytic evidence indicates improved OS and local control for tumors > 3 cm compared with monotherapy. These strategies are valuable for non-surgical candidates but still fall below resection in the therapeutic hierarchy of efficacy[29,30].

WHY THE THERAPEUTIC HIERARCHY OFFERS SUPERIOR GUIDANCE

In contrast to BCLC, the therapeutic hierarchy proposed by Vitale et al[12] views treatment as an independent predictor of survival, ranked according to intrinsic curative potential: Transplant 1, resection 2, local ablation 3, systemic therapy 4 (best supportive care outside the hierarchy)[12,13] (Figure 1). This model acknowledges that therapy choice should be determined by how high a patient can safely ascend, not by how they fit into a categorical stage. Factors guiding this assessment include liver function (albumin-bilirubin, model for end-stage liver disease, hepatic venous pressure gradient), technical feasibility of anatomical resection, predicted microvascular invasion, comorbidities and frailty, and institutional surgical and ablative expertise. Unlike BCLC, the therapeutic hierarchy is dynamic, patient-specific, compatible with modern surgical and ablative capabilities, reflective of real tumor biology, and aligned with multidisciplinary practice. It is particularly suited for early HCC, where multiple curative options coexist and must be ranked rather than assigned. Importantly, the application of a therapeutic hierarchy must be contextualized within resource-variable healthcare settings, where differences in cost, infrastructure, and procedural expertise may limit access to certain treatment modalities and influence which curative or disease-modifying option is realistically achievable for an individual patient.

Figure 1 The modern therapeutic cycle in hepatocellular carcinoma. The therapeutic cycle in hepatocellular carcinoma should be described today as a bidirectional pathway, enabling conversion and return to earlier treatment stages. BSC: Best supportive care.

CONCLUSION

The cumulative evidence from recent meta-analyses, observational studies, and technological advances makes one message clear: In early or small HCC, liver resection remains the most effective curative option when feasible. Ablation continues to improve, particularly through NT-RFA, MWA, and fusion imaging, and plays a critical role for patients with limited liver reserve or comorbidities. SBRT and combination therapies expand options for non-surgical candidates. However, none of these modalities surpass the oncologic reliability of resection.

The BCLC system remains a useful prognostic tool, but its prescriptive approach to treatment allocation is no longer adequate to navigate the complexity of modern HCC care. The therapeutic hierarchy, ranking treatments by their intrinsic curative power and integrating feasibility based on patient-specific factors, provides a more accurate, flexible, and clinically meaningful framework. In 2025, the real clinical question is not “resection or ablation?” nor “BCLC 0 or A?”, but rather: What is the highest-level curative therapy that this patient can safely receive, within a dynamic and individualized therapeutic hierarchy? This patient-centered approach will help ensure optimal outcomes in the contemporary management of early HCC.