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INTRODUCTION
Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer-associated deaths worldwide, with more than 750,000 deaths reported annually.1 However, the overall prognosis remains poor, with a median survival of 6-24 months,2,3 despite significant advancements in treatment over the past decade.4,5 Numerous international hepatology societies have evaluated HCC management and treatment strategies and released corresponding guidelines.6-12 Clinical practice guidelines are defined as statements that include recommendations intended to optimize patient care, informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options.13 Proper implementation of these guidelines can help achieve key objectives, including supporting medical practitioners in making informed decisions, enhancing healthcare quality and patient outcomes, and providing guidance to local or national authorities regarding resource allocation.
Many HCC guidelines have been published globally, demonstrating overall consistency while being tailored to regional and epidemiological characteristics. In this study, we performed a systematic review of guidelines and expert consensus statements for HCC that were published or updated between 2017 and 2024, building on a review article published in 2016.14 References meeting the following criteria were included: 1) credibility, determined by the extent to which the guidelines were widely cited in subsequent publications or guidelines on HCC management after their original publication; and 2) influence, reflected in the guidelines being supported by governmental, academic, or medical organizations and their ability to gain national recognition for application and standardized HCC management.
EVALUATION OF CURRENT GUIDELINES AND EXPERT CONSENSUS STATEMENTS FOR HCC
After screening, as shown in Table 1, we selected 13 current guidelines for HCC from around the world, comprising five guidelines from Asia (the Korean Liver Cancer Association [KLCA] and the National Cancer Center of Korea [NCC],9 the Japan Society of Hepatology [JSH],15,16 the Taiwan Liver Cancer Association [TLCA], and the Gastroenterological Society of Taiwan [GEST],17 the Asian Pacific Association for the Study of the Liver [APASL],6,18 and the Asia-Pacific Primary Liver Cancer Expert [APPLE]19), four from Europe (the British Society of Gastroenterology [BSG],20 the European Association for the Study of the Liver [EASL],7 the European Society for Medical Oncology [ESMO],8 and the Barcelona Clinic Liver Cancer [BCLC]21), and four from the United States (the American Association for the Study of Liver Disease [AASLD],11 the National Comprehensive Cancer Network [NCCN],12 the American Gastroenterological Association [AGA],10 and the American Society of Clinical Oncology [ASCO]22).
SURVEILLANCE STRATEGY
Target population
Surveillance refers to the periodic use of a sensitive diagnostic test to detect early disease in a specific high-risk population.23,24 Most HCC management guidelines consider patients with chronic hepatitis B (CHB) virus infection, hepatitis C virus infection, or cirrhosis as high-risk populations (Table 2). The EASL suggests that surveillance is cost-effective for populations with a predicted HCC incidence of ≥1.5% per year among patients with cirrhosis. However, the AASLD recommends surveillance for at-risk populations with cirrhosis of any etiology if their predicted HCC incidence is ≥1.0% per year, which is lower than the traditional threshold.25 For individuals with noncirrhotic CHB, a predicted HCC incidence of ≥0.2% per year is considered sufficient risk to justify surveillance. Notably, both guidelines integrate risk prediction models, such as PAGE-B, to estimate HCC risk in patients with CHB.26 In contrast, most patients with non-cirrhotic nonalcoholic fatty liver disease or metabolic dysfunction-associated steatotic liver disease are estimated to have an HCC incidence of <0.2% per year.27 Consequently, risk stratification is essential to determine whether these individuals should be included in surveillance programs.
Tests
Ultrasonography (US) has long been the cornerstone for HCC surveillance,28,29 with recent meta-analyses reporting a sensitivity of 84% for detecting HCC at all stages and 47% for detecting it at an early stage, along with a specificity of 94-96% when used alone.30,31 Serum α-fetoprotein (AFP), a traditional tumor marker for HCC diagnosis and recurrence monitoring,32,33 has a sensitivity of 60-65% and a specificity of 80-84% when using a cut-off point of 20 ng/mL.31 Combining US with AFP enhances both sensitivity and specificity, providing additional diagnostic value.34 However, because AFP levels can be elevated in various clinical conditions,35-37 whether to incorporate AFP into surveillance programs varies across guidelines. The EASL and ESMO advocate for US-only surveillance, whereas more recent guidelines, including those from the BSG, recommend a combination of US and AFP for surveillance.
Computed tomography (CT)- and magnetic resonance imaging (MRI)-based surveillance are generally not recommended. However, the KLCA-NCC guidelines suggest that dynamic contrast-enhanced CT or MRI can be considered an alternative when liver US cannot be performed adequately. Similarly, the JSH and TLCA optionally recommend dynamic CT or MRI for patients who are at an extremely high risk of developing HCC.
Abbreviated MRI (aMRI) protocols have been introduced in several recent guidelines. The aMRI uses a limited set of sequences from a full diagnostic protocol, significantly reducing examination time while maintaining promising sensitivity (80-90%) and specificity (91-98%). This approach has the potential to enhance cost-effectiveness and patient acceptance.38,39
Several promising biomarkers aside from AFP are currently being evaluated for HCC surveillance, although most require further validation. Two notable blood-based biomarkers are desgamma carboxyprothrombin (DCP), also known as protein induced by vitamin K absence/antagonist-II (PIVKA-II), and the lens culinaris lectin-binding sub-fraction of AFP (AFP-L3%). These biomarkers are each produced at high levels by a specific subset of HCC. However, AFP, AFP-L3%, and DCP each exhibit insufficient sensitivity when used individually. To address these limitations, the TLCA has recommended complementing AFP with PIVKA-II for surveillance, and the JSH has not restricted the use of tumor markers combined with US to AFP alone. In addition, liquid biopsy approaches, including circulating tumor DNA, tumor cells, and extracellular vesicles, have recently been extensively studied as promising methods to overcome the limitations of current surveillance and diagnostic tools.40
Interval
The ideal interval for HCC surveillance should be determined from a cost-effectiveness perspective. Most guidelines recommend semiannual intervals, supported by the reported tumor doubling time of HCC, which ranges from 4 to 7 months, providing a rationale for this recommendation.41,42 Further analyses have shown that semiannual surveillance is associated with detection of tumors at earlier stages and improved survival compared to annual surveillance.43 However, a multicenter randomized controlled trial indicated that quarterly surveillance did not enhance the detection of small HCCs or improve survival outcomes, compared to semiannual surveillance.44 Nevertheless, some guidelines recommend shorter surveillance intervals for patients at extremely high risk.45,46
Recall policies
Recall policies are procedures established to address abnormal screening test results and are closely linked to the diagnostic process. Significant differences in recall policies exist among international guidelines, primarily concerning the management of lesions <1 cm. The EASL recommends follow-up at intervals of less than 4 months, considering the high proportion of nonmalignant lesions in patients without cirrhosis and the excellent outcomes achievable for lesions up to 2 cm, where a complete response to therapy is almost always possible.47,48 Similarly, the AASLD recommends follow-up every 3-6 month. For small HCC cases with elevated (≥20 ng/mL) or rising AFP levels, diagnostic multiphasic CT or MRI is recommended. The AASLD also suggests shorter follow-up intervals for patients with suboptimal US visualization.49,50 The KLCA-NCC recommends follow-up surveillance within a 6-month interval, while the TLCA recommends repeating US, AFP, and/or PIVKA-II every 3-6 month. The JSH offers more specific approaches based on imaging characteristics. For lesions <1 cm in size with arterial phase hyperenhancement (APHE) but no portal or equilibrium phase washout, follow-up US every 3 months is recommended. Similarly, for lesions <1.5 cm without APHE, US follow-up every 3 month is advised.
DIAGNOSIS
Most guidelines recommend that the diagnosis of HCC should be established using non-invasive imaging criteria and/or pathology. However, the EASL and BSG specifically recommend confirming the diagnosis of HCC in patients without cirrhosis by pathology. In contrast, the APASL allows for the diagnosis of typical HCC based solely on imaging, regardless of tumor size, and provides a typical vascular pattern (i.e., arterial enhancement with portal venous washout).
Non-invasive diagnosis
Most current guidelines recommend multiphasic CT, multiphasic MRI with extracellular contrast agents, or multiphasic MRI with hepatocyte-specific contrast agents as the primary diagnostic modality for HCC.51 Previously observed differences in diagnostic preferences, often due to regional variations in HCC prevalence and liver transplantation allocation policies, have significantly narrowed. However, some guidelines highlight the importance of caution regarding the pseudo-washout effect that can occur when using MRI with hepatocyte-specific contrast agents.52
The Liver Imaging Reporting and Data System is widely recommended for HCC diagnosis in at-risk patients with cirrhosis or CHB. A definitive imaging diagnosis of HCC can be made for nodules ≥1 cm identified through surveillance in high-risk patients if they exhibit the following radiological hallmarks: APHE with washout appearance in the portal venous or delayed phases on multiphasic CT or MRI with extracellular contrast agents, or APHE with washout appearance in the portal venous, delayed, or hepatobiliary phases on multiphasic MRI with hepatocyte-specific contrast agents. These criteria should be applied only to lesions that do not demonstrate marked T2 hyperintensity or a targetoid appearance on diffusion-weighted or contrast-enhanced imaging. For nodules ≥1 cm that do not fulfill the noninvasive diagnostic criteria, a diagnosis of probable HCC can be made by considering ancillary imaging features such as the presence of an enhancing capsule, nonperipheral washout, or threshold growth.53
Few guidelines recommend the use of Kupffer phase contrast-enhanced US (CEUS) for the diagnosis of HCC. The APASL and TLCA endorse CEUS as equivalent to multiphase CT or MRI for diagnostic purposes, whereas the EASL and AASLD recommend CEUS as a second-line modality in cases where CT or MRI results are inconclusive, unavailable, or contraindicated, particularly when a tumor biopsy cannot be performed. The AFP level, previously recommended as a diagnostic criterion for HCC at a threshold of 400 ng/mL, is no longer recommended because of its insufficient diagnostic accuracy. Meanwhile, several circulating tumor DNA (ctDNA)-based tests have been approved by the United States Food and Drug Administration (FDA) in oncology, and alterations in ctDNA and ctDNA methylation profiles have shown promise in case-control studies for the early detection and diagnosis of HCC.40,54 However, these findings require validation in phase III-IV biomarker cohort studies.
Pathological diagnosis
According to all the guidelines, the pathological diagnosis of HCC should adhere to the international consensus recommendations and incorporate the necessary histological and immunohistological analyses. Pathological diagnosis is consistently recommended when imaging does not reveal the characteristic features of HCC. In cases of probable HCC, the KLCA-NCC guidelines recommend repeated imaging or biopsies for pathological confirmation. The AASLD further suggests that biopsy should be included in the diagnostic process, even in cases where imaging strongly indicates definite HCC. Similarly, European guidelines emphasize that HCC diagnosis in patients without cirrhosis should be confirmed through pathology because of the lower specificity of imaging hallmarks in this population, where alternative diagnoses are more frequent.
Staging
Staging systems for clinical decision-making in HCC should account for tumor burden, liver function, and performance status (Table 2). The BCLC staging system is the most widely validated and utilized framework for guiding treatment allocation, as endorsed by many guidelines, including those of the AASLD and EASL. The 2022 revised version of the BCLC staging system emphasizes on treatment stage migration through clinical decision-making, highlighting its adaptability in clinical practice. In contrast, the KLCA-NCC primarily uses the modified International Union for Cancer Control (UICC) staging system, while incorporating the BCLC and American Joint Committee on Cancer (AJCC)/UICC TNM staging systems as complementary tools. Other Asian guidelines do not primarily adopt the BCLC staging system; however, some use it as a reference for treatment planning. The NCCN, on the other hand, does not follow a specific staging system. Instead, it classifies HCC as operable, unresectable, or inoperable based on factors such as performance status and comorbidities.
The AASLD recommends that patients with HCC at BCLC early stage or beyond undergo non-contrast chest CT to assess metastatic disease. However, it advises against the routine use of positron emission tomography (PET) and bone scans for staging, citing their low sensitivity for detecting HCC.55 In contrast, the KLCA-NCC suggests that PET, chest CT, and bone scans may be used for staging in specific scenarios, such as prior to treatment with curative intent or when extrahepatic metastasis of HCC is suspected.
TREATMENT
Although the BCLC staging system has long been the dominant framework for treatment-guided staging of HCC, many Asia-Pacific experts do not fully agree with its principles (Fig. 1). The BCLC system, particularly in its recommendations for surgical resection, transarterial treatment, and other locoregional therapies, is often viewed as more conservative than Asian guidelines such as the KLCA-NCC, APASL, JSH, and TLCA. Asian guidelines generally adopt a more aggressive approach, favoring surgical resection, transarterial chemoembolization (TACE), and TACE-based combined treatments even for more advanced tumors.
Resection and transplantation
Surgical resection is recommended as the first-line treatment for patients with localized HCC lesions but without cirrhosis. However, guidelines vary in defining the optimal candidates for surgery. For example, guidelines adhering to the BCLC staging system recommend resection only for patients with solitary tumors but no evidence of portal hypertension. In contrast, the KLCA-NCC guidelines recommend resection for patients with up to three intrahepatic tumors without vascular invasion, provided that liver function is well preserved. Moreover, resection is conditionally permitted even for small single HCC with vascular invasion. Similarly, the JSH guidelines recommend resection for patients with HCC, regardless of tumor size, provided they have up to three tumors and Child-Pugh class A liver function. In addition, under the same tumor conditions, resection is more selectively permitted in patients with Child-Pugh class B liver function.
Resection has been demonstrated to provide the greatest benefit for single HCC in patients without cirrhosis, accounting for approximately 5% of cases in Western countries and 40% in Asia.56,57 Recent studies have reported that postoperative mortality after HCC resection is low (less than 1-3%). Moreover, the 5-year overall survival and disease-free survival rates range from 46.0-69.5% and 23.0-56.3%, respectively.58,59 Advances in surgical techniques, perioperative care, and patient selection have further enhanced outcomes for surgical resection in patients with cirrhosis.60 The latest AASLD guidelines underscore the role of surgical resection in select patients with multifocal HCC beyond BCLC stage A criteria, supported by findings from recent studies in Western countries.61,62 Similarly, the KLCA-NCC guidelines suggest that hepatic resection may be considered for HCC cases with invasion into the portal vein, hepatic vein, or bile duct, provided that the main portal trunk is not involved and liver function is preserved. This recommendation is based on evidence from several retrospective studies.63-66
Liver transplantation (LT) is consistently recommended across international guidelines as the preferred treatment for HCC within the Milan criteria, defined as a single tumor ≤5 cm or up to three nodules, each ≤3 cm, when resection is not feasible.67,68 Owing to the excellent outcomes observed in patients meeting these criteria, many guidelines also suggest considering expanded criteria for patients with a large tumor burden. The expanded criteria include the University of California, San Francisco criteria with an 81% 5-year survival rate, the up-to-seven criteria with a 71% 5-year survival rate, and the Kyoto criteria with a 65% 5-year survival rate.69-71
Notable regional differences exist regarding the availability of allografts and allocation protocols for LT. In Korea, patients with HCC represent only 2-5% of all deceased donor LT cases. An European study found that prolonged waiting times for transplantation lead to up to 20% of patients being delisted because of tumor progression.71 To mitigate this issue, bridging therapies (aimed at reducing waiting list dropout rates) and downstaging therapies (targeting patients initially beyond standard transplant criteria but potentially eligible for LT) have been extensively studied and require global consensus.72 In the United States, patients within Milan criteria or those downstaged to within Milan criteria using the United Network for Organ Sharing downstaging criteria are eligible for an exception score after a mandatory 6-month waiting period.73 The KLCA-NCC recommends LT for patients whose tumor stage has been successfully downstaged to meet Milan criteria through locoregional therapies such as TACE or radiofrequency ablation (RFA), as these patients demonstrate outcomes comparable to those originally within the Milan criteria. However, other Asian guidelines do not universally adopt downstaging strategies or expanded criteria for LT, reflecting the variability in regional approaches to transplantation.
The AASLD and BSG currently suggest considering adjuvant therapy with atezolizumab plus bevacizumab for patients at high risk of recurrence after liver resection or local ablation. However, these recommendations are expected to be revised because of the recent inability of the IMbrave050 trial to demonstrate clear superiority in immunotherapy groups.73 In contrast, the APASL has stated that recommending adjuvant therapy with atezolizumab plus bevacizumab at this stage is premature. Meanwhile, the KLCA-NCC suggests that adjuvant immunotherapy with cytokine-induced killer cells should be considered following curative treatment, although further multinational validation studies are needed.74
Locoregional therapies
RFA is recommended as an alternative to surgical resection for patients with a solitary tumor and good hepatic function. Most guidelines indicate that RFA provides comparable outcomes to resection in patients with single-nodular HCC ≤3 cm. However, the AASLD has expanded its recommendations to include local ablative therapies, such as RFA, for patients with single-nodular HCC ≤5 cm who are either ineligible for or decline surgical treatment. The EASL further highlights microwave ablation as a promising modality for local tumor control and improved survival. In addition, the EASL presents studies demonstrating that combining RFA with TACE improves survival outcomes compared with RFA alone in patients with 3-5 cm sized HCCs when surgical resection is not an option.74
TACE is the primary treatment option for patients with multinodular HCC without vascular invasion, exploiting the arterial blood supply of the HCC in contrast to the portal venous blood flow of the surrounding normal liver. It can be performed using either lipiodol (conventional TACE, cTACE) or drug-eluting beads (DEB-TACE). The KLCA-NCC additionally recommends TACE for patients with portal vein invasion, with or without the addition of external beam radiation therapy (EBRT).75,76 Both the EASL and KLCA-NCC suggest DEB-TACE as an alternative to cTACE for intermediate-stage HCC. Transarterial radioembolization (TARE), also known as selective internal radiation therapy, has been increasingly adopted, leading to significant updates to several guidelines. The BCLC now includes TARE as a treatment option for single HCCs ≤8 cm after the failure of initial treatment for BCLC stage 0/A HCC.74 The AASLD also recommends TARE as an alternative to TACE for treatment of patients with BCLC stage B HCC. The APASL has further expanded the indications for TARE as a locoregional therapy for unresectable HCC. The KLCA-NCC highlights that TARE provides a better quality of life and a lower incidence of post-embolization syndrome than TACE.77 Meanwhile, the TLCA suggests considering TACE alone or in combination with sorafenib or lenvatinib for unresectable intermediate-stage HCC in patients meeting the up to 11 criteria for BCLC stage B disease.78,79
The EASL recommends a conservative approach for EBRT, reserving it for selected cases. In contrast, the BSG considers EBRT a viable option for tumor ablation in patients who are unsuitable for surgery or conventional ablative techniques. The KLCA-NCC provides the broadest guidance and recommends EBRT as an alternative for patients with HCC who are not candidates for hepatic resection, transplantation, local ablation, or TACE. The AASLD highlights findings from a Korean clinical trial comparing proton beam therapy (PBT) and RFA in patients with recurrent or residual HCC, suggesting that PBT may be considered an alternative to RFA in specific cases.80,81
Systemic therapies
Systemic therapy is primarily reserved for patients with unresectable HCC who are not candidates for locoregional treatment, including those with advanced-stage disease. With the development of several new agents, recent guidelines from various regions have either provided more detailed recommendations for systemic therapy or issued separate updates on this topic.82,83 Recent studies on first-line systemic therapies demonstrating significant survival benefits have led to the inclusion of combinations such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab in the updated guidelines.84 In contrast, older guidelines primarily listed tyrosine kinase inhibitors as firstline options, despite emerging evidence suggesting that treatment efficacy may vary based on HCC etiology.
Most guidelines recommend atezolizumab plus bevacizumab and durvalumab plus tremelimumab as the preferred first-line therapies for HCC. The APASL additionally includes nivolumab plus ipilimumab, sintilimab plus IBI305, and camrelizumab plus rivoceranib (apatinib) as preferred first-line options, depending on tolerance to adverse events.18,85,86 However, guidelines such as the BSG highlight that sintilimab plus IBI305 and camrelizumab plus rivoceranib have not been extensively evaluated in non-hepatitis B virus populations outside Asia, limiting their use as first-line therapies globally. Owing to the high risk of gastrointestinal bleeding, the AASLD recommends that patients considered for atezolizumab plus bevacizumab treatment undergo esophagogastroduodenoscopy (EGD) to screen for high-risk stigmata of variceal or other gastrointestinal bleeding. Similarly, the KLCA-NCC advises evaluating patients at high risk of bleeding for gastroesophageal varices through EGD and managing these risks before initiating atezolizumab plus bevacizumab treatment. All guidelines also propose alternative first-line regimens such as lenvatinib or sorafenib for patients ineligible for atezolizumab plus bevacizumab or durvalumab plus tremelimumab treatment. In the second-line setting, following progression to first-line atezolizumab plus bevacizumab, lenvatinib has shown better outcomes than sorafenib. However, further prospective studies are required to validate these findings.87,88
The concept of TACE refractoriness has been proposed to address insufficient responses to TACE due to tumor biology. The KLCA-NCC defines TACE refractoriness as the absence of an objective response after two or more sessions of on-demand cTACE within 6 months, the development of vascular invasion, or the occurrence of extrahepatic metastasis. The AASLD and most Asian guidelines have addressed the concept of TACE refractoriness and recommend transitioning to systemic therapy for patients with intermediate-stage HCC that is either refractory to TACE or deemed unsuitable for further TACE. The JSH provides detailed descriptions of TACE unsuitability and refractoriness while presenting various treatment strategies, including combined therapies such as TACE plus systemic treatment. However, other guidelines have not yet addressed the concept of TACE refractoriness.89,90
The ASCO and AGA have also highlighted concerns regarding health equity and disparities. The ASCO has emphasized the importance of considering the low rates of treatment with systemic therapy, disparities in access to care and clinical trials, and differences in outcomes within the context of this clinical practice guideline.
CONCLUSION
The current guidelines for HCC management are broadly similar, although some discrepancies persist in surveillance and treatment allocation recommendations. Recommendations from the three main regions (Asia, Europe, and the United States) are influenced by geographic variations in disease prevalence and biology (e.g., the higher prevalence of hepatitis B in some regions and differing rates of steatotic liver disease across regions) as well as differences in resources, such as treatment accessibility, financial constraints, and organ availability, for LT. While these regional differences pose challenges in establishing a global consensus, the gap between Eastern and Western approaches has narrowed in recent years. Efforts to understand and bridge these regional disparities are crucial to foster international collaboration and advance HCC management. Physicians and policymakers must consider these factors when managing patients with HCC and developing policies and guidelines to ensure optimal and equitable care.
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