Ultrasound-guided ablation of hepatocellular carcinoma: a review of its past, present, and future
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Abstract
Ultrasound (US)-guided ablation has evolved from early ethanol injection into a cornerstone curative strategy for hepatocellular carcinoma. This review traces the technological advancement of US guidance from early pioneering efforts to present standardized techniques and future innovations. It discusses how modern tools—fusion imaging, contrast-enhanced US, and artificial fluid techniques—overcome challenges in tumor visibility and accessibility, emphasizing technique optimization rather than energy modality selection. The review also explores future horizons, including artificial intelligence–driven planning, histotripsy, and immuno-ablation. Ultimately, the authors advocate for a philosophy of “optimized ablation,” prioritizing technical mastery of evolving US technologies to maximize therapeutic efficacy and patient safety beyond simple expansion of treatment territory.
Introduction
The treatment paradigm for hepatocellular carcinoma (HCC) has fundamentally transformed over the past four decades, as minimally invasive therapies—radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation—have been established as standard curative options for early-stage disease. These parenchyma-preserving techniques are particularly important for patients with compromised hepatic function or significant comorbidities, as endorsed by international guidelines such as those from the American Association for the Study of Liver Diseases (AASLD) [1–5]. Beyond HCC, thermal ablation is increasingly recognized for the treatment of liver metastases and has demonstrated oncologic non-inferiority to surgical resection with fewer complications in a recent randomized trial [6].
The efficacy and safety of percutaneous ablation depend fundamentally on the precision of image guidance. Although computed tomography (CT)–guided ablation remains clinically useful—particularly because of its high spatial resolution and ability to overcome poor sonic windows—this review focuses on the unique advantages of ultrasound (US) guidance. These include real-time imaging, safety, cost-effectiveness, and broad availability, positioning US as a sophisticated platform for therapeutic guidance rather than merely a diagnostic modality.
This review provides a comprehensive overview of technological advancements in US-guided liver ablation within a “past, present, and future” framework. While incorporating extensive experience from the Asia-Pacific region, driven by the high prevalence of HCC, these insights are presented in the context of universal clinical practice. The review first traces the historical development of US-guided liver ablation and acknowledges key contributions to modern techniques. It then examines current standards of care, focusing on how advanced US techniques address challenges related to tumor conspicuity and accessibility. Finally, it explores future directions—including artificial intelligence (AI), histotripsy, and immuno-ablation—and advocates for an approach of optimized ablation, emphasizing mastery of existing techniques to achieve superior clinical outcomes.
Past: The Evolution of Image-Guided Intervention
Early Development (1950s–1970s): From Blind Biopsy to US-Guided Targeting
The foundations of US-guided liver intervention trace back to the transition from blind to image-guided procedures. Percutaneous liver biopsy, first reported in the 1920s using a percussion-based “blind” approach [7], remained standard practice for decades despite limitations in accuracy and safety. Although Menghini’s “one-second needle biopsy” in 1958 standardized the technique [8], a major advance occurred in the 1970s with the introduction of US-guided aspiration biopsy [9]. This pioneering work established US as a viable modality for percutaneous procedures, prioritizing precision over empirical localization. Concurrently, the development of real-time B-mode scanning and improvements in transducer technology enabled visualization of liver anatomy and focal lesions with unprecedented clarity, laying the groundwork for interventional applications [10].
The Beginnings of Local Therapy (1980s–1990s): Chemical and Thermal Ablation
US-guided local therapy began in 1983 with Sugiura et al.’s description of percutaneous ethanol injection therapy (PEIT) [11]. Although subsequently refined and validated in Japan and Italy [12–14], PEIT was largely limited to very small tumors (≤2 cm) and was hindered by technical unpredictability related to intratumoral septa. A major advance occurred in the early 1990s with the introduction of RFA by McGahan et al. [15] and Rossi et al. [16], marking a transition from chemical to thermal ablation and enabling the creation of larger, more predictable coagulation zones. Following promising clinical results reported by Rossi et al. in 1996 [17], the therapeutic armamentarium expanded further with the development of MWA and cryoablation. Fig. 1 summarizes key technological advancements in US-guided liver tumor ablation.
Timeline of ultrasound-guided liver ablation.
US, ultrasound; PEIT, percutaneous ethanol injection therapy; RFA, radiofrequency ablation; CEUS, contrast-enhanced US.
The Pioneering Role of Asia
Asian countries, particularly Korea, Japan, and China, played a pivotal role in accumulating clinical evidence for liver tumor ablation, largely driven by the high prevalence of hepatitis B and C. Japanese investigators made seminal contributions to establishing the efficacy of PEIT and RFA through long-term outcome studies [18,19], while Korean researchers advanced the field through innovations in US-guided techniques [20–23]. This accumulated experience led to the development of regional guidelines and professional societies, including the Asian Conference on Tumor Ablation (ACTA) in 2014. Throughout these developments, US remained the primary guidance modality, and refinement of US-guided RFA in Asia contributed substantially to modern ablation practice.
Present: Standardization and Precision in US Guidance
The present era is characterized by technical standardization and increasingly sophisticated US guidance to address clinical challenges. This section outlines strategies for overcoming technical difficulties in US-guided ablation and discusses the advantages and limitations of specific methods. As contemporary guidelines do not prescribe a single “one-size-fits-all” approach, the diversity of available energy sources and techniques is highlighted, with emphasis on tailoring strategies to specific procedural obstacles.
Clinical Positioning in Current Guidelines
Thermal ablation is globally endorsed as a standard curative modality by major guidelines, including those of the European Association for the Study of the Liver and the AASLD [1,5]. For small HCCs (<2 cm), RFA achieves excellent long-term survival, with reported 5-year overall survival rates of 65%–70% [19,24,25]. High-quality evidence indicates that RFA provides survival outcomes comparable to hepatic resection for single nodules <3 cm, with fewer complications despite higher rates of local tumor progression [26–31]. Consistent with these findings, Asian guidelines—including those of the Korean Liver Cancer Association–National Cancer Center, ACTA, and the Japanese Society of Hepatology—recommend RFA as a primary treatment option for small HCCs (<3 cm), advocate combined transarterial chemoembolization (TACE) and ablation for tumors measuring 3–5 cm, and recognize MWA and cryoablation as comparable alternatives [2,3,32].
Selection of Energy Source
As thermal ablation has become firmly established as a cornerstone of curative treatment, both RFA and MWA are widely used under US guidance. Mechanistically, MWA employs dielectric heating to achieve higher temperatures more rapidly, thereby reducing susceptibility to the heat-sink effect. In contrast, RFA offers highly predictable ablation zone geometry supported by well-established protocols [19,33,34]. These complementary physical characteristics likely explain why comparable clinical outcomes are reported across studies despite inherent technical differences. Although MWA offers advantages such as faster heating, larger ablation zones, and reduced heat-sink effects [35], often making it preferable for tumors ≥2 cm [32], RFA remains a robust option supported by extensive long-term survival data. Comparative studies of RFA and MWA for HCCs <5 cm have demonstrated similar oncologic outcomes and complication rates [35–39]. Accordingly, current guidelines emphasize tailoring energy source selection to anatomical factors, procedural context, and tumor characteristics rather than asserting modality superiority.
Cryoablation is increasingly recognized as an alternative to heat-based ablation. Recent studies suggest that cryoablation achieves survival and recurrence outcomes comparable to those of RFA [38,40]; however, large-scale randomized controlled trials remain limited. Further investigation is required to define its optimal clinical role, particularly in scenarios where advantages such as reduced procedure-related pain and lower risk of collateral thermal injury may offer benefits. Long-term validation of therapeutic efficacy also remains necessary.
Advanced US Guidance Techniques
Although conventional B-mode US remains the primary guidance modality, its effectiveness is limited in a substantial proportion of cases. Approximately 30% of small HCCs are considered inconspicuous or invisible on B-mode US due to coarse liver echotexture or deep lesion location [20]. To address these limitations, several advanced guidance techniques have been developed to enhance procedural precision and feasibility, as summarized in Table 1.
Overview of advanced ultrasound guidance techniques for liver ablation
Fusion imaging
Real-time fusion imaging (FI), which co-registers live US with pre-acquired CT, magnetic resonance imaging (MRI), or US datasets, is increasingly adopted in modern ablation practice. Its utility can be divided into pre-procedural targeting and intra-procedural margin assessment.
For targeting, FI overcomes limitations of B-mode US by allowing direct reference to pre-acquired CT or MRI, facilitating localization of inconspicuous tumors. In a Korean prospective study, FI enabled visualization of nearly 40% (30/216) of HCCs not visible on B-mode US and allowed successful ablation in approximately 30% (60/216) of patients initially considered untreatable, with a technical success rate of 97.1% [20].
For assessment, US-US overlay fusion mitigates visibility challenges caused by ablation-induced gas bubbles [41]. These bubbles often obscure tumor boundaries, complicating margin assessment. Overlay techniques enable side-by-side or superimposed (“overlay”) comparisons to verify whether the hyperechoic ablation zone fully encompasses the tumor with an adequate safety margin (e.g., >5 mm). Clinical data indicate significant improvements in achieving sufficient margins (89.3% vs. 47.0%) and reductions in local tumor progression compared with conventional guidance [41].
Artificial ascites and pleural effusion
Creation of artificial fluid collections serves dual purposes: establishing a sonic window for tumors obscured by the lung or ribs and providing hydrodissection to physically displace adjacent organs from the thermal field (Fig. 2) [42]. This approach offers thermal protection, reduces procedure-related pain, and improves visualization by enhancing acoustic transmission to both tumor and surrounding structures. However, prior upper abdominal surgery may limit feasibility because of adhesions.
Recurrent hepatocellular carcinoma (HCC) treated with advanced ultrasound guidance techniques in a 60-year-old man.
A. Axial gadoxetic acid-enhanced magnetic resonance imaging (MRI) shows a 1-cm enhancing nodule in liver segment 7 (arrow), indicating recurrent HCC. B. On B-mode ultrasonography with fusion MRI guidance, the recurrent tumor (arrow on MRI) is not clearly visible. C. A subtle hypoechoic lesion is revealed in liver segment 7 (arrow) after the administration of artificial pleural effusion. D. In the portal venous phase after Kupffer phase agent injection, the tumor is visualized as a hypoechoic nodule between the echogenic active metal tips of two radiofrequency electrodes (arrows) inserted using the no-touch technique. E. Immediate post-ablation computed tomography demonstrates the ablation zone fully covering the entire tumor (arrow) with a sufficient ablative margin, indicating technical success.
Contrast-enhanced US
Contrast-enhanced US (CEUS) employs gas-filled microbubbles to provide sensitive information on blood flow and tissue perfusion, enhancing contrast between tumors and surrounding liver parenchyma [43,44]. Contrast agents are broadly classified as pure blood-pool agents or Kupffer-phase agents. While blood-pool agents enable dynamic vascular imaging, Kupffer-phase agents accumulate within Kupffer cells, providing prolonged parenchymal enhancement during the post-vascular phase and a stable imaging window lasting up to one hour.
CEUS plays key roles in both pre-procedural detection and intra-procedural margin verification. For detection, CEUS improves visualization of inconspicuous tumors. A study evaluating Kupffer-phase agents demonstrated significantly higher HCC detection rates compared with B-mode US (93.2% vs. 83.5%, P=0.04) [45]. This enhanced conspicuity facilitates precise targeting and translates into improved therapeutic outcomes. In a prospective randomized trial of poorly visualized lesions, CEUS guidance significantly increased the complete ablation rate after a single session (94.7% vs. 65.0%, P=0.04) and reduced the number of treatment sessions compared with conventional guidance [46].
CEUS is also valuable for intra-procedural and immediate post-ablation assessment by enabling the detection of residual viable tumor tissue and permitting immediate re-ablation when necessary. A retrospective study reported a significantly lower residual tumor rate with immediate post-procedural CEUS compared with standard protocols (0% vs. 16.7%, P=0.02) [47].
Integration of CEUS with CT/MRI FI further enhances targeting precision. A recent prospective study demonstrated improved tumor visibility and procedural feasibility in 85.5% of cases involving small lesions inconspicuous on B-mode US [48]. Improvements were consistent across contrast agent types, with visibility scores of grade 3 or higher achieved in 87.7% of cases using blood-pool agents and 90% using Kupffer-phase agents, resulting in a technical success rate of 99.6%.
Technical Strategies for Complete Ablation
Single-electrode strategy
For small, well-defined tumors (<2 cm), a single-electrode approach with central targeting is often sufficient. Achieving a circumferential ablative margin >5 mm, however, typically requires an ablation zone with a short-axis diameter of approximately 3 cm. Unlike modern MWA systems, single-needle RFA frequently cannot achieve this dimension in a single application, which has been associated with higher local tumor progression rates compared with MWA (30.4% vs. 16.4%) in a recent randomized trial [49]. Consequently, overlapping ablations are often required to ensure adequate safety margins.
Multiple electrodes and no-touch technique
To reduce local recurrence and address microscopic satellite nodules in tumors >2 cm, the no-touch RFA technique using multiple electrodes has been developed [21–23,50]. Rather than directly puncturing the tumor, electrodes are placed in surrounding normal liver parenchyma under US guidance (Fig. 3). Energy delivery may occur in monopolar, bipolar, or switching modes [51,52]. Monopolar mode directs current from active electrodes to a dispersive grounding pad, whereas bipolar mode concentrates current between paired electrodes without a grounding pad. Switching algorithms further optimize large ablations: single-switching monopolar mode alternates energy delivery based on impedance, while dual-switching monopolar mode delivers synchronous energy to electrode pairs. Fig. 4 illustrates a case using three electrodes with both dual-switching monopolar and sequential-switching bipolar modes. This strategy aims to achieve wider ablative margins (≥1 cm) encompassing the primary tumor and potential microsatellites while minimizing tumor seeding along the needle tract. Immediately after ablation, hyperechoic gas bubbles may obscure tumor boundaries; allowing an appropriate waiting period facilitates bubble dissipation and improves margin assessment confidence [53].
Schematic illustration of ablation zones created by a single electrode versus multiple electrodes using the no-touch technique.
RFA, radiofrequency ablation.
Radiofrequency ablation (RFA) using the no-touch technique in a 67-year-old man.
A. Arterial phase gadoxetic acid-enhanced magnetic resonance image shows a 2.5-cm hypervascular hepatocellular carcinoma nodule in liver segment 3 (arrow). B. On B-mode ultrasound, the tumor appears as a 2.4-cm hypoechoic ovoid nodule located at the capsule of liver segment 3 (arrow). C. Three radiofrequency electrodes were inserted along the deeper margin of the tumor for the no-touch technique. The echogenic spots (arrows) represent the active tips of the electrodes. D. Immediate post-RFA computed tomography demonstrates the technical success of RFA with a sufficient ablative margin around the ablated tumor (arrow).
Perivascular tumors and alternative modalities
Tumors in contact with vessels ≥3 mm in diameter may be less amenable to thermal ablation because of the heat-sink effect, whereby blood flow dissipates thermal energy [54,55]. In such cases, cryoablation may be considered. Under US guidance, the ice ball produced during cryoablation appears as a clearly delineated hyperechoic margin with posterior acoustic shadowing, enabling real-time monitoring [56]. Retrospective studies suggest that cryoablation can be safely performed for selected perivascular tumors, with potentially fewer complications than RFA in some series [57], although high-quality randomized evidence remains limited. Cryoablation is also subject to flow-related limitations, including a cold-sink effect when tumors abut large vessels, which may impair iceball formation and reduce treatment efficacy. Therefore, while cryoablation can be considered an alternative in specific high-risk scenarios, its benefits should be weighed against these limitations and the current strength of available evidence.
Combined TACE and ablation for larger tumors
For HCCs >3 cm, local recurrence rates after ablation alone range from 30% to 50% [58], prompting development of combined treatment strategies. Combining TACE with RFA or MWA significantly improves local control and survival compared with ablation alone for tumors measuring 3–5 cm [59–61]. Accordingly, current guidelines recommend combined TACE and ablation for patients with 3–5 cm HCCs who are not candidates for surgical resection [32].
Future: Digital Transformation and New Horizons
The future of US-guided ablation lies in increased precision, automation, novel energy sources, and integration with systemic therapies. Rather than indiscriminately adopting new technologies, emphasis should remain on refining current techniques—a philosophy termed optimized ablation.
AI and Digital Solutions in Ultrasonography
AI algorithms are being developed to enhance multiple aspects of US-guided ablation procedures.
Planning
AI-based systems are under development for automated tumor segmentation, patient selection, and outcome prediction using US imaging. Machine learning algorithms can analyze pre-procedural imaging to guide personalized treatment planning by predicting responses to locoregional therapy [62], potentially reducing operator dependence and improving standardization across institutions.
Guidance
Augmented reality platforms are emerging for real-time navigation during ablation procedures. These systems project three-dimensional representations of vascular structures and tumor locations onto the operative field, potentially enhancing electrode placement accuracy. AI-enhanced FI and robotic-assisted ablation tools represent promising innovations that may overcome current technical limitations [63].
Assessment
Beyond visual inspection, three-dimensional quantitative margin assessment software is increasingly needed. Technologies such as the Food and Drug Administration (FDA)–approved BioTraceIO platform provide real-time visualization of ablation extent through AI-driven analysis of standard US images [64]. This technology addresses the challenge of poor visibility and control of the tissue destruction zone. The development of US-based assessment tools, rather than reliance on CT-based evaluation, represents an important future direction.
Emerging Energy Sources
Irreversible electroporation
Irreversible electroporation (IRE) is gaining attention as a non-thermal ablation technique for liver tumors near major vessels and bile ducts because it does not rely on thermal injury [65]. Under US guidance, IRE produces a characteristic hypoechoic region with gradual echogenicity changes during ablation [66], although US monitoring is less intuitive than the well-demarcated ice ball in cryoablation. Despite theoretical advantages, IRE remains limited by procedural complexity (often requiring general anesthesia and neuromuscular blockade), procedure duration, and cost. Future research should define optimal selection criteria and standardize protocols to validate its clinical role.
Histotripsy
Histotripsy is a non-invasive, non-thermal, purely mechanical method of tissue destruction that is guided and monitored by US. Pulsed acoustic energy induces cavitation bubble clouds from gases naturally present in tissue; rapid bubble formation and collapse generate mechanical forces sufficient to disrupt tissue at cellular and subcellular levels. The U.S. FDA granted marketing authorization for the Edison Histotripsy System in October 2023 based on the HOPE4LIVER trials, which reported a 95% technical success rate and a 7% complication rate comparable to other local therapies [67]. As a US-guided and US-monitored modality, histotripsy represents a natural evolution of US-based interventional oncology. Preliminary studies suggest that histotripsy may trigger immune responses in which untreated tumors are recognized and attacked, potentially providing systemic effects beyond local tumor destruction [68]. Real-world experience reported in 2024 suggests that histotripsy can be performed safely across multiple tumor types, with serious complications occurring rarely [69]. Table 2 summarizes the local ablation modalities for HCC reviewed above.
Comparison of US-guided modalities used in liver ablation
Immuno-Ablation: Expanding the Role
A promising frontier is combining local ablation with systemic immunotherapy. With recent advances in immunotherapy-based systemic treatments, the role of ablative therapy may extend beyond traditional indications. Rather than being replaced by systemic options, ablative therapy may serve as a complementary partner in combination strategies to enhance outcomes compared with either approach alone [70,71].
Mechanistically, ablation can induce immunogenic cell death, releasing tumor antigens and creating an in situ vaccine effect. Local treatment of HCC may enhance antitumor immunity through the release of inflammatory factors and tumor-specific neoantigens from dying tumor cells [72,73]. In combination with immune checkpoint inhibitors, local treatment may contribute to systemic antitumor responses (the “abscopal effect”).
Clinical evidence supporting this rationale is emerging through two approaches. First, concurrent combination therapy—administering immunotherapy simultaneously with ablation—was evaluated in a phase 1/2 study of tremelimumab (anti–cytotoxic T-lymphocyte–associated protein 4 [anti–CTLA-4]) combined with ablation for unresectable HCC, demonstrating safety and feasibility [72]. Second, sequential adjuvant therapy—administering immunotherapy after curative-intent ablation—was evaluated in the IMbrave050 trial, which assessed atezolizumab plus bevacizumab following resection or ablation in high-risk patients and reported an initial improvement in recurrence-free survival compared with surveillance; however, updated analyses indicated that the benefit was not sustained with longer follow-up [74,75]. Although these strategies differ in timing and target populations, both support the rationale for integrating immunotherapy with local treatment.
Multiple ongoing clinical trials (Table 3) are investigating the efficacy and safety of combining locoregional therapies with immune checkpoint inhibitors. As US-guided ablation becomes incorporated into combination protocols, the role of US in response assessment and guidance of subsequent interventions will become increasingly important. Clinical validation remains in early stages, and definitive survival benefits await larger randomized trial results.
Ongoing major clinical trials investigating combination of ablation and immunotherapy for HCC
Conclusion: Optimized ablation
US-guided local ablation therapy has evolved from a simple approach for small tumors into a sophisticated, highly technical, and indispensable component of contemporary HCC management. Progress has been driven by continuous innovation in ablation energy sources and, critically, in the US guidance systems used to deploy them.
The philosophy of optimized ablation emphasizes that, rather than simply expanding treatment territory, priority should be placed on mastering current technologies—FI, advanced US guidance techniques, and understanding of tumor biology—to achieve superior clinical outcomes. Current standard-of-care techniques, including FI, contrast-enhanced US, and artificial fluid creation, enable the safe and effective treatment of complex tumors that would otherwise be difficult or impossible to approach using conventional B-mode US guidance.
Future advances, including AI-enhanced procedural planning, novel US-guided modalities such as histotripsy, and integration with systemic immunotherapy, are expected to further improve safety, efficacy, and scope. Even as AI capabilities advance, the role of the expert interventional oncologist, who performs and evaluates the accuracy of the procedure, will remain essential.
The message is clear: while embracing future technologies built on past innovations, optimized practice of current techniques will be a key determinant of patient outcomes. As these technologies continue to evolve, the role of US in guiding liver ablation is expected to become further consolidated, maintaining its position as a cornerstone of image-guided tumor ablation.
Notes
Author Contributions
Conceptualization: Rhim H. Data acquisition: Gu K, Rhim H. Data analysis or interpretation: Gu K, Lee MW, Han S. Drafting of the manuscript: Gu K, Rhim H. Critical revision of the manuscript: Rhim H, Lee MW, Han S. Approval of the final version of the manuscript: all authors.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
References
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Notes
Key points
Ultrasound (US) guidance has been fundamental to the evolution of local ablation therapy for hepatocellular carcinoma, accompanying the shift from early ethanol injection to modern thermal and non-thermal techniques. Advanced US techniques, including fusion imaging, contrast-enhanced US, and artificial fluid techniques, enable treatment of challenging tumors by emphasizing technique optimization over energy modality selection. Future innovations in artificial intelligence, histotripsy, and immuno-ablation will expand the role of US-guided ablation while upholding the philosophy of "optimized ablation."