OVERALL DIAGNOSIS CONSIDERATIONS

Liver function affects HCC management, influencing prognosis and treatment decisions.4 Most patients with HCC have underlying cirrhosis and may experience complications such as portal hypertension, ascites, encephalopathy, and bleeding from gastro-esophageal varices.4 It is crucial a patient’s liver function is assessed before and during treatment, to allow for accurate disease staging and personalized care.4,5

Tumor characteristics such as size, molecular alterations, and histologic subtypes are crucial in HCC management because they may impact prognosis and response to treatment.6,7 HCC exhibits wide variability in aggressiveness due to diverse pathological and molecular features, so understanding these characteristics is an important component of overall diagnosis.8

Serum biomarkers such as AFP, AFP-L3, ctDNA, and DCP may offer diagnostic and prognostic insights for HCC, but further validation through large-scale studies is needed to develop robust predictors of disease progression and ensure that serum biomarkers are actionable in clinical practice.1,8–11

Serum biomarkers such as alpha feto-protein (AFP), AFP-L3, circulating tumor DNA (ctDNA), and des-y-carboxyprothrombin (DCP) offer diagnostic and prognostic insights for HCC, but further validation through large-scale studies is needed to develop robust predictors of disease progression and ensure that serum biomarkers are actionable in clinical practice.1,8,10,11

The ECOG PS, a standardized scale ranging from 0 (asymptomatic) to 4 (confined to bed), is a prognostic factor used to help guide treatment decisions.12 It is used to assess the impact of cancer on a patient's daily life and functioning; in HCC, higher scores are associated with a worse prognosis, larger tumor burden and a more advanced stage.12–14

The Eastern Cooperative Oncology Group (ECOG) performance status (PS), a standardized scale ranging from 0 (asymptomatic) to 4 (confined to bed), is a significant prognostic factor used to guide treatment decisions.12 It is used to assess the impact of cancer on a patient's daily life and functioning; in HCC, higher scores are associated with a worse prognosis, larger tumor burden and a more advanced stage.12–14

Imaging plays a central role at every stage of disease assessment, including diagnosis and staging of HCC.15 Patients may receive one or more of the following imaging modalities during their diagnosis:

CEUS Icon

CEUS detects HCC based on appearance, which varies depending on the size and degree of differentiation15

Contrast-enhanced ultrasound (CEUS) detects HCC based on appearance, which varies depending on the size and degree of differentiation15

  • Advantages: safe; cost-effective; provides real-time imaging15,16
  • Disadvantages: accuracy is operator dependent; limited detection capability in patients with high body mass index15,17
Dynamic CT Icon

Dynamic CT detects hemodynamic changes indicative of HCC development15

Dynamic computed tomography (CT) detects hemodynamic changes indicative of HCC development15

  • Advantages: widely available; rapid; less prone to motion artifacts in patients who are unable to hold their breath15
  • Disadvantages: exposes patient to radiation and has lower sensitivity and specificity compared to MRI, meaning small tumors may not be identified15
MRI Icon

MRI detects HCC with detailed images of liver tissue characteristics15

  • Advantages: higher sensitivity for identifying small lesions compared with CT, allowing for detection of early-stage HCC15
  • Disadvantages: potential for artifacts due to patient movement; inconsistent image quality18
Liver Imaging Icon

LI-RADS®

To reduce variability and mistakes in image interpretation and promote communication with referring clinicians, the standardized LI-RADS is used for imaging interpretation, reporting, and data collection during HCC diagnosis.16

LI-RADS is endorsed by AASLD guidelines for at-risk patients requiring HCC surveillance, as well as for diagnosis.1

LI-RADS scoring classifies observations according to clinical significance15,16:

Diagnostic categories Clinical significance Recommendation
LR-1 Definitely benign Return for 6-month follow-up
LR-2 Probably benign Return for 6-month follow-up
LR-3 Intermediate potential of malignancy Second modality ≤6 months
LR-4 Probably HCC Biopsy or treatment; if none are planned, repeat routine/alternative imaging in ≤3 months
LR-5 Definitely HCC Biopsy or treatment
LR-M Probably or definitely malignant, not necessarily HCC Alternative or repeat imaging, biopsy, or treatment
LR-TIV Tumor in vein Biopsy or biomarker correlation to determine etiology

To reduce variability and mistakes in image interpretation and promote communication with referring clinicians, the standardized LI-RADS is used for imaging interpretation, reporting, and data collection during HCC diagnosis.16

LI-RADS is endorsed by AASLD guidelines for at-risk patients requiring HCC surveillance, as well as for diagnosis.1

LI-RADS scoring classifies observations according to clinical significance15,16:

Diagnostic category

LR-1

Clinical significance

Definitely benign

Recommendation

Return for 6-month follow-up

Diagnostic category

LR-2

Clinical significance

Probably benign

Recommendation

Return for 6-month follow-up

Diagnostic category

LR-3

Clinical significance

Intermediate potential of malignancy

Recommendation

Second modality ≤6 months

Diagnostic category

LR-4

Clinical significance

Probably HCC

Recommendation

Biopsy or treatment; if none are planned, repeat routine/alternative imaging in ≤3 months

Diagnostic category

LR-5

Clinical significance

Definitely HCC

Recommendation

Biopsy or treatment

Diagnostic category

LR-M

Clinical significance

Probably or definitely malignant, not
necessarily HCC

Recommendation

Alternative or repeat imaging, biopsy, or treatment

Diagnostic category

LR-TIV

Clinical significance

Tumor in vein

Recommendation

Biopsy or biomarker correlation to determine etiology

In contrast to most solid tumors, HCC can be diagnosed using radiologic imaging without biopsy confirmation; although it may be used when imaging or other diagnostic markers are inconsistent.2,19 Nonetheless, biopsy at the point of diagnosis is beneficial to help to enable better characterization of disease and prognosis.10

The limited use of diagnostic biopsies in HCC poses challenges for biomarker research and disease characterization, and leads to a lack of potential prognostic data.10

The integration of an MDT is crucial in the complex process of diagnosis and staging, evaluating a wide array of clinical factors and developing tailored treatment plans.3,20

The integration of a multidisciplinary team (MDT) is crucial in the complex process of diagnosis and staging, evaluating a wide array of clinical factors and developing tailored treatment plans.3,20

CLINICAL GUIDELINES FOR DIAGNOSIS AND STAGING

AASLD, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), and BCLC guidelines share similar recommendations for HCC diagnosis.1–3

BCLC is the most prevalent and widely cited staging system globally for prognostic prediction and treatment allocation.10,20,21 Its use is recommended by the AASLD due to its incorporation of liver dysfunction and ECOG PS, external validation in multiple cohorts, and ease of use in clinical practice.1

Treatment choices are guided by prognostic variables and disease stage within the BCLC system3:

Bclc staging system Bclc staging system
Treatment Choices for HCC chartTreatment Choices for HCC chart

Figure adapted from Reig M, et al. 2025.3

The current treatment landscape for patients with HCC has shifted over the past several decades.

DELVE DEEPER

Let HORIZONS HCC be your compass in navigating the complexities and latest developments in HCC patient care.

Abbreviations:

AASLD=American Association for the Study of Liver Diseases; AFP=alpha-fetoprotein; AFP-L3=lens culinaris agglutinin-reactive alpha-fetoprotein; ALBI=albumin-bilirubin; BCLC=Barcelona Clinic Liver Cancer; CEUS=contrast-enhanced ultrasound; CT=computed tomography; ctDNA=circulating tumor DNA; CUSE=complexity, uncertainty, subjectivity, and emotions; DCP=des-y-carboxyprothrombin; EBRT=external beam radiotherapy; ECOG=Eastern Cooperative Oncology Group; HCC=hepatocellular carcinoma; LI-RADS=Liver Imaging Reporting and Data System; MDT=multidisciplinary team; MELD=model for end-stage liver disease; MRI=magnetic resonance imaging; MW=microwave ablation; NCCN=National Comprehensive Cancer Network; PS=performance status; RFA=radiofrequency ablation; TACE=transarterial chemoembolization; TARE=transarterial radioembolization.

References:

1. Singal AG, Llovet JM, Yarchoan M, et al. Hepatology. 2023;78(6):1922–1965; 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatocellular Carcinoma V.2.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed December 11, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way; 3. Reig M, Sanduzzi-Zamparelli M, Forner A, et al. J Hepatol. 2025:S0168-8278(25)02571-1. 4. Pinter M, Trauner M, Peck-Radosavljevic M, Sieghart W. ESMO Open. 2016;1(2):e000042; 5. Tsoris A, Marlar CA. StatPearls [Internet]. Accessed October 2025. https://www.ncbi.nlm.nih.gov/books/NBK542308/; 6. Vij M and Caldedaro J. World J Hepatol. 2021;13(4):393–410; 7. Wu G, Wu J, Wang B, Zhu X, Shi X, Ding Y. Cancer Manag Res. 2018;10:4401–4410; 8. Fowler KJ, Burgoyne A, Fraum TJ, et al. Radiographics. 2021;41(6):1611–1631; 9. Schlosser S, Tümen D, Volz B, et al. Front Oncol. 2022;12:1016952; 10. Ducreux M, Abou-Alfa GK, Bekaii-Saab T, et al. ESMO Open. 2023;8(3):101567; 11. Lapitan LDS, Pietrzak M, Krawczyk M, Malinowska E. Sens and Actuators B Chem. 2023;393:134209; 12. Nishikawa H, Kita R, Kimura T, et al. J Cancer. 2015;6(4):394–402; 13. Llovet JM, Kelley RM, Villanueva A, et al. Nat Rev Dis Primers. 2021;7(1):6; 14. Cancer Research UK. Updated March 25, 2025. Accessed September 30, 2025. https://www.cancerresearchuk.org/about-cancer/liver-cancer/stages/bclc-staging-system-child-pugh-system; 15. Chartampilas E, Rafailidis V, Georgopoulou V, et al. Cancers (Basel). 2022;14(16):3997; 16. Bartolotta TV, Terranova MC, Gagliardo C, Taibbi A. Insights into Imaging. 2020;11(9):1–13; 17. Esfeh JM, Hajifathalian K, Ansari-Gilani K. Clin Mol Hepatol. 2020;26(1):54–59; 18. Roberts LR, Sirlin CB, Zaiem F, et al. Hepatology. 2018;67(1):401–421; 19. Rho YS, Pagano I, Wong LL, Kwee SA, Acoba JD. HPB (Oxford). 2020;23:1054–1060; 20. Vogel A, Chan SL, Dawson LA, et al. Ann Oncol. 2025;36(5):491–506; 21. Han K, Kin JH. World J Gastroenterol. 2015;21(36):10327–10335.

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