Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines

Published:February 03, 2018DOI:


      • Surveillance based on biannual ultrasonography allows early detection of Hepatocellular Carcinoma (HCC) in patients at risk.
      • Only patients at risk that could be treated if diagnosed of HCC should be included in surveillance programs.
      • Diagnosis of HCC in early stages is key to apply effective therapy and expand life expectancy.
      • Typical vascular profile of HCC on imaging allows non-invasive diagnosis of HCC in patients at risk with sensitivity and specificity rates of 60% and 96–100% respectively.
      • The added benefit of new diagnostic tools for HCC based on MRI and PET in the decision making process is pending on robust data on specificity rates.
      • Treatment should be indicated only when the diagnosis of HCC is secure to avoid overtreatment of suspicious lesions.


      One of the key strategies to improve the prognosis of HCC, beside prevention, is to diagnose the tumor in early stages, when the patient is asymptomatic and the liver function is preserved, because in this clinical situation effective therapies with survival benefit can be applied. Imaging techniques are a key tool in the surveillance and diagnosis of HCC. Screening should be based in US every 6 months and non-invasive diagnostic criteria of HCC based on imaging findings on dynamic-MR and/or dynamic-CT have been validated and thus, accepted in clinical guidelines. The typical vascular pattern depicted by HCC on CT and or MRI consists on arterial enhancement, stronger than the surrounding liver (wash-in), and hypodensity or hyposignal intensity compared to the surrounding liver (wash-out) in the venous phase. This has a sensitivity of around 60% with a 96–100% specificity. Major improvements on liver imaging have been introduced in the latest years, adding functional information that can be quantified: the use of hepatobiliary contrast media for liver MRI, the inclusion of diffusion-weighted sequences in the standard protocols for liver MRI studies and new radiotracers for positron-emission tomography (PET). However, all them are still a matter of research prior to be incorporated in evidence based clinical decision making. This review summarizes the current knowledge about imaging techniques for the early diagnosis and staging of HCC, and it discusses the most relevant open questions.


      To read this article in full you will need to make a payment


        • Ferlay J.
        • Soerjomataram I.
        • Dikshit R.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int. J. Cancer. 2015; 136: E359-E386
        • El-Serag H.B.
        • Davila J.A.
        • Petersen N.J.
        • et al.
        The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update.
        Ann. Intern. Med. 2003; 139: 817-823
        • Prorok P.C.
        Epidemiologic approach for cancer screening: problems in design and analysis of trials.
        Am. J. Pediatr. Hematol. Oncol. 1992; 14: 117-128
        • Kramer B.S.
        • Croswell J.M.
        Cancer screening: the clash of science and intuition.
        Annu. Rev. Med. 2009; 60: 125-137
        • Chen J.-G.
        • Parkin D.M.
        • Chen Q.-G.
        • et al.
        Screening for liver cancer: results of a randomised controlled trial in Qidong, China.
        J. Med. Screen. 2003; 10: 204-209
        • Zhang B.-H.
        • Yang B.-H.
        • Tang Z.-Y.
        Randomized controlled trial of screening for hepatocellular carcinoma.
        J. Cancer Res. Clin. Oncol. 2004; 130: 417-422
        • Yeh Y.-P.
        • Hu T.-H.
        • Cho P.-Y.
        • et al.
        Evaluation of abdominal ultrasonography mass screening for hepatocellular carcinoma in Taiwan.
        Hepatology. 2014; 59: 1840-1849
        • Singal A.
        • Volk M.L.
        • Waljee A.
        • et al.
        Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis.
        Aliment Pharmacol. Ther. 2009; 30: 37-47
        • Poustchi H.
        • Farrell G.C.
        • Strasser S.I.
        • et al.
        Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.
        Hepatology. 2011; 54: 1998-2004
        • European Association for the Study of the Liver
        • European Organisation for Research and Treatment of Cancer
        EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma.
        J. Hepatol. 2012; 56: 908-943
        • Bruix J.
        • Sherman M.
        Management of hepatocellular carcinoma: an update.
        Hepatology. 2011; 53: 1020-1022
        • Bruix J.
        • Sherman M.
        Management of hepatocellular carcinoma.
        Hepatology. 2005; 42: 1208-1236
        • Jepsen P.
        • Ott P.
        • Andersen P.K.
        • et al.
        Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a Danish nationwide cohort study.
        Ann. Intern. Med. 2012; 156 (W295): 841-847
        • Mancebo A.
        • González-Diéguez M.L.
        • Cadahía V.
        • et al.
        Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups.
        Clin. Gastroenterol. Hepatol. 2013; 11: 95-101
        • Nahon P.
        • Sutton A.
        • Rufat P.
        • et al.
        Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis.
        Hepatology. 2009; 50: 1484-1493
        • Verslype C.
        • Rosmorduc O.
        • Rougier P.
        Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann. Oncol. 2012; 23 (vii): 41-48
        • Marrero J.A.
        • Feng Z.
        • Wang Y.
        • et al.
        Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.
        Gastroenterology. 2009; 137: 110-118
        • Singal A.G.
        • Conjeevaram H.S.
        • Volk M.L.
        • et al.
        Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis.
        Cancer Epidemiol. Biomark. Prev. 2012; 21: 793-799
        • Pocha C.
        • Dieperink E.
        • McMaken K.A.
        • et al.
        Surveillance for hepatocellular cancer with ultrasonography vs: computed tomography – a randomised study.
        Aliment Pharmacol. Ther. 2013; 38: 303-312
        • Giorgio A.
        • Montesarchio L.
        • Gatti P.
        • et al.
        Contrast-enhanced ultrasound: a simple and effective tool in defining a rapid diagnostic work-up for small nodules detected in cirrhotic patients during surveillance.
        J. Gastrointest. Liver Dis. 2016; 25: 205-211
        • Forner A.
        • Vilana R.
        • Bianchi L.
        • et al.
        Lack of arterial hypervascularity at contrast-enhanced ultrasound should not define the priority for diagnostic work-up of nodules <2 cm.
        J. Hepatol. 2015; 62: 150-155
        • Atiq O.
        • Tiro J.
        • Yopp A.C.
        • et al.
        An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis.
        Hepatology. 2016; (Epub ahead of print)
        • Sutherland T.
        • Watts J.
        • Ryan M.
        • et al.
        Diffusion-weighted MRI for hepatocellular carcinoma screening in chronic liver disease: direct comparison with ultrasound screening.
        J. Med. Imaging Radiat. Oncol. 2016; (Epub ahead of print)
        • Besa C.
        • Lewis S.
        • Pandharipande P.V.
        • et al.
        Hepatocellular carcinoma detection: diagnostic performance of a simulated abbreviated MRI protocol combining diffusion-weighted and T1-weighted imaging at the delayed phase post gadoxetic acid.
        Abdom. Radiol. (NY). 2016; (Epub ahead of print)
        • Bizollon T.
        • Rode A.
        • Bancel B.
        • Gueripel V.
        • Ducerf C.
        • Baulieux J.
        • et al.
        Diagnostic value and tolerance of Lipiodol-computed tomography for the detection of small hepatocellular carcinoma: correlation with pathologic examination of explanted livers.
        J. Hepatol. 1998; 28: 491-496
        • Vilana R.
        • Forner A.
        • Bianchi L.
        • et al.
        Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.
        Hepatology. 2010; 51: 2020-2029
        • Galassi M.
        • Iavarone M.
        • Rossi S.
        • et al.
        Patterns of appearance and risk of misdiagnosis of intrahepatic cholangiocarcinoma in cirrhosis at contrast enhanced ultrasound.
        Liver Int. 2013; 33: 771-779
        • Huang B.
        • Wu L.
        • Lu X.Y.
        • et al.
        Small intrahepatic cholangiocarcinoma and hepatocellular carcinoma in cirrhotic livers may share similar enhancement patterns at multiphase dynamic MR imaging.
        Radiology. 2016; 281: 150-157
        • Ciresa M.
        • de Gaetano A.M.
        • Pompili M.
        • et al.
        Enhancement patterns of intrahepatic mass-forming cholangiocarcinoma at multiphasic computed tomography and magnetic resonance imaging and correlation with clinicopathologic features.
        Eur. Rev. Med. Pharmacol. Sci. 2015; 19: 2786-2797
        • Bruix J.
        • Reig M.
        • Sherman M.
        Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma.
        Gastroenterology. 2016; 150: 835-853
        • Kojiro M.
        • Roskams T.
        Early hepatocellular carcinoma and dysplastic nodules.
        Semin. Liver Dis. 2005; 25: 133-142
        • Forner A.
        • Vilana R.
        • Ayuso C.
        • et al.
        Diagnosis of hepatic nodules 20 mm or smallerin cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.
        Hepatology. 2008; 47: 97-104
        • Sangiovanni A.
        • Manini M.A.
        • Iavarone M.
        • et al.
        The diagnostic and economic impact of contrast imaging technique in the diagnosis of small hepatocellular carcinoma in cirrhosis.
        Gut. 2010; 59: 638-644
        • Khalili K.T.
        • Kim T.K.
        • Jang H.J.
        • et al.
        Optimization of imaging diagnosisof 1–2 cm hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization.
        J. Hepatol. 2011; 54: 723-728
        • Torbenson M.
        • Schirmacher P.
        Liver cancer biopsy–back to the future?.
        Hepatology. 2015; 61: 431-433
        • Schirmacher P.
        • Bedossa P.
        • Roskams T.
        • et al.
        Fighting the bushfire in HCC trials.
        J. Hepatol. 2011; 55: 276-277
        • Sherman M.
        • Bruix J.
        Biopsy for Liver Cancer: how to balance research needs with evidence-based clinical practice.
        Hepatology. 2011; 53: 1020-1022
        • Mitchell D.G.
        • Bruix J.
        • Sherman M.
        • et al.
        LI-RADS (Liver imaging reporting and data system): summary, discussion, consensus of the LI-RADS management working group and future directions.
        Hepatology. 2015; 61: 1056-1065
        • Darnell A.
        • Forner A.
        • Rimola J.
        • et al.
        Liver imaging reporting and data system with MR imaging: evaluation in nodules 20 mm or smaller detected in cirrhosis at screening US.
        Radiology. 2015; 275: 698-707
        • Sirlin C.B.
        • Hussain H.K.
        • Jonas E.
        • et al.
        Consensus report from the 6th international forum for liver MRI using gadoxetic acid.
        J. Magn. Reson. Imaging. 2014; 40: 516-529
        • Hope T.A.
        • Fowler K.J.
        • Sirlin C.B.
        • et al.
        Hepatobiliary agents and their role in LI-RADS.
        Abdom. Imaging. 2015; 40: 613-625
        • Neri E.
        • Bali M.A.
        • Ba-Ssalamah A.
        • et al.
        ESGAR consensus statement on liver MR imaging and clinical use of liver-specific contrast agents.
        Eur. Radiol. 2016; 26 (Epub 2015 Jul 21): 921-931
        • Gschwend S.
        • Ebert W.
        • Schultze-Mosgau M.
        • et al.
        Pharmacokinetics and imaging properties of Gd-EOB-DTPA in patients with hepatic and renal impairment.
        Invest. Radiol. 2011; 46: 556-566
        • Okada M.
        • Murakami T.
        • Kuwatsuru R.
        • et al.
        Biochemical and clinical predictive approach and time point analysis of hepatobiliary phase liver enhancement on Gd-EOB-DTPA–enhanced MR images: a multicenter study.
        Radiology. 2016; 281: 474-483
        • Van Beers B.E.
        • Pastor C.M.
        • Hussain H.K.
        Primovist, Eovist: what to expect?.
        J. Hepatol. 2012; 57: 421-429
        • Kitao A.
        • Matsui O.
        • Yoneda N.
        • et al.
        The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging.
        Eur. Radiol. 2011; 21: 2056-2066
        • Joo I.
        • Lee J.M.
        • Lee D.H.
        • et al.
        Noninvasive diagnosis of hepatocellular carcinoma on gadoxético acid-enhanced MRI: can hypointensity on the hepatobiliary phase be used as an alternative to washout.
        Eur. Radiol. 2015; 25: 2859-2868
        • Yu M.H.
        • Kim J.H.
        • Yoon J.H.
        • et al.
        Small (≤1-cm) Hepatocellular carcinoma: diagnostic performance and imaging features at gadoxetic acid–enhanced MR imaging.
        Radiology. 2014; 271: 748-760
        • Sano K.
        • Ichikawa T.
        • Motosugi U.
        • et al.
        Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid–enhanced MR imaging.
        Radiology. 2011; 261: 834-844
        • Ichikawa T.
        • Saito K.
        • Yoshioka N.
        • et al.
        Detection and characterization of focal liver lesions. A japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.
        Invest. Radiol. 2010; 45: 133-141
        • Kim J.E.
        • Kim S.H.
        • Lee S.J.
        • et al.
        Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver disease: characterization with gadoxetic acid–enhanced MRI that includes diffusion-weighted imaging.
        AJR. 2011; 196: W758-W765
        • Granito A.
        • Galassi M.
        • Piscaglia F.
        • et al.
        Impact of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance on the non-invasive diagnosis of small hepatocellular carcinoma: a prospective study.
        Aliment Pharmacol. Ther. 2013; 37: 355-363
        • Bartolozzi C.
        • Battaglia V.
        • Bargellini I.
        • et al.
        Contrast-enhanced magnetic resonance imaging of 102 nodules in cirrhosis: correlation with histological findings on explanted livers.
        Abdom. Imaging. 2013; 38: 290-296
        • Choi J.W.
        • Lee J.M.
        • Kim S.J.
        • et al.
        Hepatocellular carcinoma: imaging patterns on gadoxetic acid–enhanced MR images and their value as an imaging biomarker.
        Radiology. 2013; 267: 776-786
        • Golfieri R.
        • Grazioli L.
        • Orlando E.
        • et al.
        Which is the best MRI marker of malignancy for atypical cirrhotic nodules: hypointensity in hepatobiliary phase alone or combined with other features? Classification after Gd-EOB-DTPA administration.
        J. Magn. Reson. Imaging. 2012; 36: 648-657
        • Faletti R.
        • Cassinis M.C.
        • Paolo Fonio P.
        • et al.
        Multiparametric Gd-EOB-DTPA magnetic resonance in diagnosis of HCC: dynamic study, hepatobiliary phase, and diffusion weighted imaging compared to histology after orthotopic liver transplantation.
        Abdom. Imaging. 2015; 40: 46-55
        • Golfieri R.
        • Garzillo G.
        • Ascanio S.
        • et al.
        Focal lesions in the cirrhotic liver: their pivotal role in gadoxetic acid-enhanced MRI and recognition by the western guidelines.
        Dig. Dis. 2014; 32: 696-704
        • Choi S.H.
        • Byun J.H.
        • Lim Y.S.
        • et al.
        Diagnostic criteria for hepatocellular carcinoma 3 cm with hepatocyte-specific contrast-enhanced magnetic resonance imaging.
        Radiology. 2016; 64: 1099-1107
        • Piana G.
        • Trinquart L.
        • Nawel Meskine N.
        • et al.
        New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases.
        J. Hepatol. 2011; 55: 126-132
        • Taouli B.
        Diffusion-weighted MR imaging for liver lesion characterization: a critical look.
        Radiology. 2012; 262: 378-380
        • Bieze M.
        • Klümpen H.J.
        • Verheij J.
        • et al.
        Diagnostic accuracy of (18) F-methylcholine positron emissiontomography/computed tomography for intra- and extrahepatic hepatocellular carcinoma.
        Hepatology. 2014; 59: 996-1006
        • Castilla-Lièvre M.A.
        • Franco D.
        • Gervais P.
        • et al.
        Diagnostic value of combining 11C-choline and 18F-FDG PET/CT in hepatocellular carcinoma.
        Eur. J. Nucl. Med. Mol. Imaging. 2016; 43: 852-859
        • Llovet J.M.
        • Bru C.
        • Bruix J.
        Prognosis of hepatocellular carcinoma: the BCLC staging classifi cation.
        Semin. Liver Dis. 1999; 19: 329-338
      1. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators, [No authors listed] Hepatology, 28 (September (3)) 1998:751–5.

        • Bolondi L.
        • Burroughs A.
        • Dufour J.-F.
        • et al.
        Het-erogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma:proposal for a subclassification to facilitate treatment decisions.
        Semin. Liver Dis. 2012; 32: 348-359
        • Yau T.
        • Tang V.Y.
        • Yao T.J.
        • Fan S.T.
        • et al.
        Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocelular carcinoma.
        Gastroenterology. 2014; 146: 1691-1700
        • Bruix J.
        • Qin S.
        • Merle P.
        • et al.
        Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet. 2016; (pii: S0140-6736(16)32453-9 [Epub ahead of print])
        • Ferrer-Fabrega J.
        • Forner A.
        • Liccioni A.
        • et al.
        Prospective validation of ab initio liver transplantation in hepatocellular carcinoma upon detection of risk factors for recurrence after resection.
        Hepatology. 2016; 63: 839-849
        • Forner A.
        • Reig M.
        • Varela M.
        • et al.
        Diagnosis and treatment of hepatocelular carcinoma Update consensus from the AEEH, SEOM, SERAM, SERVEI and SETH.
        Med. Clin. 2016; 146 ([Article in Spanish] (e1-511. e22)): 511
        • Renzulli M.
        • Brocchi S.
        • Cucchetti A.
        • et al.
        Can current preoperative imaging be used to detect microvascular invasion of hepatocellular carcinoma.
        Radiology. 2016; 279: 432-442
        • Lei Z.
        • Li J.
        • Wu D.
        • et al.
        Nomogram for preoperative estimation of microvascular invasión risk in hepatitis B virus-related hepatocellular carcinoma within the milan criteria.
        JAMA Surg. 2016; 151: 356-363

      Linked Article