The evolving role of contrast-enhanced ultrasound in hepatocellular carcinoma: from diagnosis to therapeutic monitoring

Abstract

Hepatocellular carcinoma (HCC) remains a significant global health issue, linked to chronic liver diseases such as viral hepatitis, cirrhosis, and metabolic dysfunction-related steatohepatitis. Early, accurate diagnosis is vital for treatment, but many cases are diagnosed at advanced stage. Contrast-enhanced ultrasound (CEUS) is a valuable, radiation-free tool for real-time liver lesion assessment with high accuracy. This review examines the growing role of ultrasound and CEUS in diagnosing, monitoring, and post-treatment care of HCC. CEUS has sensitivity and specificity similar to computed tomography and magnetic resonance imaging, especially for nodules ≥ 1 cm, and helps clarify uncertain Liver Imaging Reporting and Data System findings. Dynamic CEUS improves diagnosis by allowing microvascular perfusion measurement. Artificial intelligence (AI) and machine learning integration promises automated lesion classification and better consistency. CEUS is especially useful in outpatient and resource-limited settings, enabling quick decision-making and reducing delays. Meta-analyses and studies support CEUS for initial detection and post-treatment follow-up. As advanced ultrasound becomes more accessible, CEUS can be more widely used in hepatology. Future steps include standard protocols, clinician training, and AI integration. Overall, CEUS complements other imaging methods and aids precision medicine in liver cancer management.

Keywords

Imaging / diagnosis / treatment / artificial intelligence / liver cancer

References

[1] Sung H,Siegel RL.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin.2021;71:209-49

[2] Scarlata GGM,Spagnuolo R.Impact of diet and gut microbiota changes in the development of hepatocellular carcinoma.Hepatoma Res.2024;10:19

[3] Kim TH,Tang A.Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma: 2018 update.Clin Mol Hepatol.2019;25:245-63 PMCID:PMC6759428

[4] Kim TK.Contrast-enhanced ultrasound in the diagnosis of nodules in liver cirrhosis.World J Gastroenterol.2014;20:3590-6 PMCID:PMC3974526

[5] Ciocalteu A,Cazacu SM.Role of contrast-enhanced ultrasonography in hepatocellular carcinoma by using LI-RADS and ancillary features: a single tertiary centre experience.Diagnostics.2021;11:2232 PMCID:PMC8700695

[6] Duparc F,Bonnel F,Douard R.Liver anatomy: from Couinaud to the transplantation.Surg Radiol Anat.2020;42:1405

[7] Fasel JHD.Human liver territories: think beyond the 8-segments scheme.Clin Anat.2017;30:974-7

[8] Mathew RP.Liver vascular anatomy: a refresher.Abdom Radiol.2018;43:1886-95

[9] Tyagi G.Portal vein variations, clinical correlation, and embryological explanation: a review article.Cureus.2023;15:e36400 PMCID:PMC10115697

[10] Mao W,Cao Y.A practical study of the hepatic vascular system anatomy of the caudate lobe.Quant Imaging Med Surg.2021;11:1313-21 PMCID:PMC7930664

[11] D’Souza JC,Hunt SJ.B-mode ultrasound for the assessment of hepatic fibrosis: a quantitative multiparametric analysis for a radiomics approach.Sci Rep.2019;9:8708 PMCID:PMC6581954

[12] Hirooka M,Sunago K.Efficacy of B-mode ultrasound-based attenuation for the diagnosis of hepatic steatosis: a systematic review/meta-analysis.J Med Ultraso.2022;49:199-210

[13] Uggowitzer M,Machan L.Power Doppler imaging and evaluation of the resistive index in focal nodular hyperplasia of the liver.Abdom Imaging.1997;22:268-73

[14] Cannella R,Pellegrinelli A.Color Doppler ultrasound in portal hypertension: a closer look at left gastric vein hemodynamics.J Ultrasound Med.2021;40:7-14

[15] Iranpour P,Houshyar R.Altered Doppler flow patterns in cirrhosis patients: an overview.Ultrasonography.2016;35:3-12 PMCID:PMC4701371

[16] Chawla Y,Dhiman RK,Dilawari JB.Duplex Doppler sonography in patients with Budd-Chiari syndrome.J Gastroenterol Hepatol.1999;14:904-7

[17] Lee DH,Han JK.Superb microvascular imaging technology for ultrasound examinations: Initial experiences for hepatic tumors.Eur J Radiol.2016;85:2090-5

[18] Shankar N,Krugliak Cleveland N.Point-of-care ultrasound in gastroenterology and hepatology.Clin Gastroenterol Hepatol.2025;23:1277-90

[19] Ying X,Zhao Y,Jiang J.Research progress on contrast-enhanced ultrasound (CEUS) assisted diagnosis and treatment in liver-related diseases.Int J Med Sci.2025;22:1092-108 PMCID:PMC11866529

[20] Friedrich-Rust M,Nierhoff J.Contrast-enhanced ultrasound for the differentiation of benign and malignant focal liver lesions: a meta-analysis.Liver Int.2013;33:739-55

[21] Goto E,Tateishi R.Value of post-vascular phase (Kupffer imaging) by contrast-enhanced ultrasonography using Sonazoid in the detection of hepatocellular carcinoma.J Gastroenterol.2012;47:477-85

[22] Huang J,Li J.Head-to-head comparison of Sonazoid and SonoVue in the diagnosis of hepatocellular carcinoma for patients at high risk.Front Oncol.2023;13:1140277 PMCID:PMC10050587

[23] Westwood M,Grutters J.Contrast-enhanced ultrasound using SonoVue® (sulphur hexafluoride microbubbles) compared with contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging for the characterisation of focal liver lesions and detection of liver metastases: a systematic review and cost-effectiveness analysis.Health Technol Assess.2013;17:1-243 PMCID:PMC4781376

[24] Ren J,Fei X.Assessment of arterial-phase hyperenhancement and late-phase washout of hepatocellular carcinoma-a meta-analysis of contrast-enhanced ultrasound (CEUS) with SonoVue® and Sonazoid®.Eur Radiol.2024;34:3795-812

[25] Kang HJ,Yoo J.Diagnostic criteria of perfluorobutane-enhanced ultrasonography for diagnosing hepatocellular carcinoma in high-risk individuals: how is late washout determined?.Ultrasonography.2022;41:530-42 PMCID:PMC9262666

[26] D’Onofrio M,De Robertis R,Mucelli RP.Contrast-enhanced ultrasound of focal liver lesions.AJR Am J Roentgenol.2015;205:W56-66

[27] Sawatzki M,Brand S.Contrast-enhanced ultrasound (CEUS) has excellent diagnostic accuracy in differentiating focal liver lesions: results from a Swiss tertiary gastroenterological centre.Swiss Med Wkly.2019;149:w20087

[28] Schwarze V,Völckers W.Diagnostic value of contrast-enhanced ultrasound versus computed tomography for hepatocellular carcinoma: a retrospective, single-center evaluation of 234 patients.J Int Med Res.2020;48:300060520930151 PMCID:PMC7294502

[29] Ghazanfar H,Qasim A.Metabolic dysfunction-associated steatohepatitis and progression to hepatocellular carcinoma: a literature review.Cancers.2024;16:1214 PMCID:PMC10969013

[30] Chen HJ,Jiang YX,Wang AF.Multifunctional roles of inflammation and its causative factors in primary liver cancer: a literature review.World J Hepatol.2023;15:1258-71 PMCID:PMC10784815

[31] Hansmann J.Overview of staging systems for hepatocellular carcinoma and implications for interventional radiology.Semin Intervent Radiol.2017;34:213-9 PMCID:PMC5453774

[32] Beudeker BJB,Balderramo D.Validation and optimization of AFP-based biomarker panels for early HCC detection in Latin America and Europe.Hepatol Commun.2023;7:e0264 PMCID:10503685

[33] Cao J,Xu X.LI-RADS CEUS nonradiation TRA version 2024: application on HCC patients treated with ablation treatment.Ultrasound Med Biol.2025;51:1308-15

[34] Han K.Transarterial chemoembolization in hepatocellular carcinoma treatment: Barcelona clinic liver cancer staging system.World J Gastroenterol.2015;21:10327-35 PMCID:PMC4579879

[35] Zhang Y,Li L.Diagnostic performance of modified contrast-enhanced ultrasound liver imaging reporting and data system in patients without risk factors for hepatocellular carcinoma: comparison with world federation for ultrasound in medicine and biology guideline.Ultrasound Med Biol.2024;50:243-50

[36] Piscaglia F,Lyshchik A.American college of radiology contrast enhanced ultrasound liver imaging reporting and data system (CEUS LI-RADS) for the diagnosis of hepatocellular carcinoma: a pictorial essay.Ultraschall Med.2017;38:320-4

[37] Terzi E, Iavarone M, Pompili M, et al.; CEUS LI-RADS Italy study group collaborators. Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter restropective study of 1,006 nodules. J Hepatol. 2018;68:485-92.

[38] Quaia E,Baratella E.Effect of observer experience in the differentiation between benign and malignant liver tumors after ultrasound contrast agent injection.J Ultrasound Med.2010;29:25-36

[39] Park HJ.Imaging modalities for hepatocellular carcinoma surveillance: expanding horizons beyond ultrasound.J Liver Cancer.2020;20:99-105 PMCID:PMC10035675

[40] Melendez-Torres J.Early detection of hepatocellular carcinoma: roadmap for improvement.Expert Rev Anticancer Ther.2022;22:621-32 PMCID:PMC9845108

[41] Tzartzeva K,Rich NE.Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.Gastroenterology.2018;154:1706-18.e1 PMCID:PMC5927818

[42] Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol.2018;69:182-236

[43] Tarao K,Komatsu H.Comparison of unenhanced magnetic resonance imaging and ultrasound in detecting very small hepatocellular carcinoma.World J Hepatol.2021;13:699-708 PMCID:PMC8239491

[44] Mei Q,Chen Q.Clinical value of contrast-enhanced ultrasound in early diagnosis of small hepatocellular carcinoma (≤ 2 cm).World J Clin Cases.2022;10:8525-34 PMCID:PMC9453369

[45] Claudon M,Choi BI.Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver-update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.Ultraschall Med.2013;34:11-29

[46] Marrero JA,Sirlin CB.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases.Hepatology.2018;68:723-50 PMCID:12460225

[47] Sidhu PS,Dietrich CF.The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: update 2017 (long version).Ultraschall Med.2018;39:e2-44

[48] Wang DC,Kim TK.Characterization of indeterminate liver lesions on CT and MRI with contrast-enhanced ultrasound: what is the evidence?.AJR Am J Roentgenol.2020;214:1295-304

[49] Seitz K,Bernatik T.Contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions - prospective comparison in clinical practice: CEUS vs. CT (DEGUM multicenter trial). Parts of this manuscript were presented at the ultrasound Dreiländertreffen 2008, Davos.Ultraschall Med.2009;30:383-9

[50] Lanka B,Kim TK,Wilson SR.Impact of contrast-enhanced ultrasonography in a tertiary clinical practice.J Ultrasound Med.2007;26:1703-14

[51] Enders J,Rief M.Reduction of claustrophobia during magnetic resonance imaging: methods and design of the “CLAUSTRO” randomized controlled trial.BMC Med Imaging.2011;11:4 PMCID:3045881

[52] Zhang Z,Luo Y.Diagnostic value of liver contrast-enhanced ultrasound in early hepatocellular carcinoma: a systematic review and meta-analysis.J Gastrointest Oncol.2023;14:626-35 PMCID:PMC10186536

[53] Candita G,Cwiklinska K.Imaging diagnosis of hepatocellular carcinoma: a state-of-the-art review.Diagnostics.2023;13:625 PMCID:PMC9955560

[54] Wang H,Fan H,Zhang H.Compared with CT/MRI LI-RADS, whether CEUS LI-RADS is worth popularizing in diagnosis of hepatocellular carcinoma?.Quant Imaging Med Surg.2023;13:4919-32 PMCID:10423374

[55] Wilson SR.Microbubble-enhanced US in body imaging: what role?.Radiology.2010;257:24-39

[56] Zhang J,Li Y.Diagnostic value of contrast-enhanced ultrasound in hepatocellular carcinoma: a meta-analysis with evidence from 1998 to 2016.Oncotarget.2017;8:75418-26 PMCID:PMC5650432

[57] Hai Y,Chong W,Lyshchik A.Meta-analysis and systematic review of contrast-enhanced ultrasound in evaluating the treatment response after locoregional therapy of hepatocellular carcinoma.Abdom Radiol.2021;46:5162-79 PMCID:PMC8569603

[58] Dietrich CF,Barr RG.Guidelines and good clinical practice recommendations for contrast-enhanced ultrasound (CEUS) in the liver-update 2020 WFUMB in cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS.Ultrasound Med Biol.2020;46:2579-604

[59] Bartolotta TV,Midiri M.Contrast-enhanced ultrasound of hepatocellular carcinoma: where do we stand?.Ultrasonography.2019;38:200-14 PMCID:PMC6595127

[60] Nakai M,Sahara S.Radiofrequency ablation assisted by real-time virtual sonography and CT for hepatocellular carcinoma undetectable by conventional sonography.Cardiovasc Intervent Radiol.2009;32:62-9

[61] Huang J,Yao S.Assessing diagnostic value of contrast-enhanced ultrasound and contrast-enhanced computed tomography in detecting small hepatocellular carcinoma: a meta-analysis.Medicine.2017;96:e7555 PMCID:5627828

[62] Ramesh H.Resection for hepatocellular carcinoma.J Clin Exp Hepatol.2014;4:S90-6 PMCID:PMC4284204

[63] Wicks JS,Ruffolo L.Comparable and complimentary modalities for treatment of small-sized HCC: surgical resection, radiofrequency ablation, and microwave ablation.J Clin Med.2023;12:5006 PMCID:PMC10419984

[64] Dong Y,Yang D.Potential application of dynamic contrast enhanced ultrasound in predicting microvascular invasion of hepatocellular carcinoma.Clin Hemorheol Microcirc.2021;77:461-9

[65] Chernyak V,Do RKG.LI-RADS: looking back, looking forward.Radiology.2023;307:e222801 PMCID:PMC10068888

[66] Cai WJ,Zheng RQ.Contrast-enhanced ultrasound liver imaging reporting and data system in hepatocellular carcinoma ≤ 5 cm: biological characteristics and patient outcomes.Liver Cancer.2023;12:356-71 PMCID:PMC10561321

[67] Lyshchik A,Dietrich CF.Contrast-enhanced ultrasound of the liver: technical and lexicon recommendations from the ACR CEUS LI-RADS working group.Abdom Radiol.2018;43:861-79 PMCID:PMC5886815

[68] Tong J,Ouyang W.Targeting immune checkpoints in hepatocellular carcinoma therapy: toward combination strategies with curative potential.Exp Hematol Oncol.2025;14:65 PMCID:PMC12046748

[69] Brooks JA,Radu IP.Artificial intelligence for contrast-enhanced ultrasound of the liver: a systematic review.Digestion.2025;106:227-44 PMCID:PMC12129427

[70] Abenavoli L,Gambardella ML.Combined model for the diagnosis of hepatocellular carcinoma: a pilot study comparing the liver to spleen volume ratio and liver vein to cava attenuation.J Clin Med.2025;14:4306 PMCID:PMC12194391

[71] Scarpellini E,Santori V,Kobyliak N.Gut microbiota, deranged immunity, and hepatocellular carcinoma.Biomedicines.2024;12:1797 PMCID:PMC11351762