Does hypointense HCC in the Hepatobiliary Phase at Gadoxetate-Enhanced MRI Predict Recurrence After Surgery? A Systematic Review and Meta-analysis

Published:October 15, 2022DOI:

      Rationale and Objectives

      The aim of the current study was to investigate whether hypointense hepatocellular carcinoma (HCC) in the hepatobiliary phase (HBP) on gadoxetic acid-enhanced MRI at pretreatment is a potential prognostic marker for tumor recurrence within 3 years after surgery conducted for a curative purpose (resection or liver transplantation).

      Materials and Methods

      Systematic review was performed in the PubMed, Embase, Cochrane Library, and LILACS databases. Original articles focused on evaluating HCC signal intensity (SI) in HBP, as well as recurrence at least 3 years after surgery were included in the study. Odds ratio (OR) was measured based on the inverse variance method and the random-effects model. The Quality in Prognosis Studies (QUIPS) tool was used to assess the quality of the included articles.


      Five studies with 718 patients, in total, were analyzed. The odds ratio of disease recurrence in patients with hypointense HCC in the HBP, within 3 years after surgery, was 3.12 times higher than that observed in patients with hyperintense HCC in the HBP (OR 3.12; 95% CI 1.27-7.68; p = 0.01). Heterogeneity was classified as intermediate (I2 = 52%). Articles included in the review overall presented a low risk of bias.


      Hypointense HCC in the HBP on gadoxetic acid-enhanced MRI at pretreatment has increased the likelihood of tumor recurrence in patients subjected to resection or liver transplantation. HCC SI in the HBP is a potential non-invasive imaging biomarker associated with patient prognosis.

      Key Words


      AASLD (American Association for the Study of Liver Diseases), ADC (Apparent Diffusion Coefficient), HCC (Hepatocellular Carcinoma), HBP (Hepatobiliary Phase), CI (Confidence Interval), SI (Signal Intensity), OATP8 (Organic Anion Transporting Polypeptide 8), OR (Odds Ratio), PICOS (Patient, Index test, Comparator, Outcome and Study design), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), QUIPS (Quality in Prognostic Studies), MRI (Magnetic Resonance Imaging)
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        • Llovet JM
        • Burroughs A
        • Bruix J.
        Hepatocellular carcinoma.
        The Lancet. 2003; 362: 1907-1917
        • Singal AG
        • Lampertico P
        • Nahon P.
        Epidemiology and surveillance for hepatocellular carcinoma: new trends.
        J Hepatol. 2020; 72: 250-261
      1. American College of Radiology Committee on LI-RADS®. LI-RADS® CT/MRI v2018. Available at: Accessed on August 22, 2022 n.d.

        • El-Serag HB
        • Marrero JA
        • Rudolph L
        • Reddy KR.
        Diagnosis and Treatment of Hepatocellular Carcinoma.
        Gastroenterology. 2008; 134: 1752-1763
        • Bruix J
        • Sherman M.
        Management of hepatocellular carcinoma.
        Hepatol. 2005; 42: 1208-1236
        • Bruix J
        • Sherman M.
        Management of hepatocellular carcinoma: An update.
        Hepatol. 2011; 53: 1020-1022
        • Marrero JA
        • Kulik LM
        • Sirlin CB
        • et al.
        Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases.
        Hepatol. 2018; 68: 723-750
        • Vogl TJ
        • Kümmel S
        • Hammerstingl R
        • et al.
        Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA.
        Radiology. 1996; 200: 59-67
        • Huppertz A
        • Balzer T
        • Blakeborough A
        • et al.
        Improved Detection of Focal liver lesions at MR Imaging: multicenter comparison of gadoxetic acid-enhanced MR images with intraoperative findings.
        Radiology. 2004; 230: 266-275
        • Sung SA
        • Kim MJ
        • Joon SL
        • et al.
        Added value of gadoxetic acid-enhanced hepatobiliary phase MR imaging in the diagnosis of hepatocellular carcinoma.
        Radiology. 2010; 255: 459-466
        • Ichikawa T
        • Saito K
        • Yoshioka N
        • Tanimoto A
        • Gokan T
        • Takehara Y
        • et al.
        Detection and Characterization of Focal Liver Lesions.
        Invest Radiol. 2010; 45: 133-141
        • Golfieri R
        • Renzulli M
        • Lucidi V
        • et al.
        Contribution of the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to dynamic MRI in the detection of hypovascular small (≥2 cm) HCC in cirrhosis.
        Eur Radiol. 2011; 21: 1233-1242
        • 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
        • Choi JW
        • Lee JM
        • Kim SJ
        • et al.
        Hepatocellular carcinoma: Imaging patterns on gadoxetic acid-enhanced MR images and their value as an imaging biomarker.
        Radiology. 2013; 267: 776-786
        • Kitao A
        • Zen Y
        • Matsui O
        • et al.
        Hepatocellular carcinoma: Signal intensity at gadoxetic acid - Enhanced MR imaging - Correlation with molecular transporters and histopathologic features.
        Radiology. 2010; 256: 817-826
        • Narita M
        • Hatano E
        • Arizono S
        • et al.
        Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma.
        J Gastroenterol. 2009; 44: 793-798
        • 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
        • Kitao A
        • Matsui O
        • Yoneda N
        • et al.
        Hypervascular hepatocellular carcinoma: correlation between biologic features and signal intensity on gadoxetic acid - Enhanced MR images.
        Radiology. 2012; 265: 780-789
        • An C
        • Kim MJ.
        Imaging features related with prognosis of hepatocellular carcinoma.
        Abdom Radiol. 2019; 44: 509-516
        • Cho ES
        • Choi JY.
        MRI features of hepatocellular carcinoma related to biologic behavior.
        Korean J Radiol. 2015; 16: 449-464
        • Lee BC
        • Jeong YY
        • Heo SH
        • et al.
        Gadoxetic acid-enhanced MRI features for predicting treatment outcomes of early hepatocellular carcinoma (< 3 cm) after transarterial chemoembolization.
        Acad Radiol. 2022;
        • Miura T
        • Ban D
        • Tanaka S
        • et al.
        Distinct clinicopathological phenotype of hepatocellular carcinoma with ethoxybenzyl-magnetic resonance imaging hyperintensity: Association with gene expression signature.
        Am J Surg. 2015; 210: 561-569
        • Yamashita T
        • Kitao A
        • Matsui O
        • et al.
        Gd-EOB-DTPA-enhanced magnetic resonance imaging and alpha-fetoprotein predict prognosis of early-stage hepatocellular carcinoma.
        Hepatology. 2014; 60: 1674-1685
        • Moher D
        • Liberati A
        • Tetzlaff J
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
        PLoS Med. 2009; 6
        • Ouzzani M
        • Hammady H
        • Fedorowicz Z
        • Elmagarmid A.
        Rayyan—a web and mobile app for systematic reviews.
        Syst Rev. 2016; 5: 210
        • Hayden JA
        • van der Windt DA
        • Cartwright JL
        • Co P.
        Research and Reporting Methods Annals of Internal Medicine Assessing Bias in Studies of Prognostic Factors.
        Ann Intern Med. 2013; 158: 280-286
        • Higgins JPT
        • Thompson SG.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Ariizumi SI
        • Ban D
        • Abe Y
        • et al.
        High-signal-intensity MR image in the hepatobiliary phase predicts long-term survival in patients with hepatocellular carcinoma.
        Anticancer Res. 2019; 39: 4219-4225
        • Fujita N
        • Nishie A
        • Kubo Y
        • et al.
        Hepatocellular carcinoma: clinical significance of signal heterogeneity in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging.
        Eur Radiol. 2015; 25: 211-220
        • Chen J
        • Wu M
        • Liu R
        • et al.
        Preoperative evaluation of the histological grade of hepatocellular carcinoma with diffusion-weighted imaging: a meta-analysis.
        PLoS ONE. 2015; 10: 1-16
        • Reginelli A
        • Vacca G
        • Segreto T
        • et al.
        Can microvascular invasion in hepatocellular carcinoma be predicted by diagnostic imaging? A critical review.
        Future Oncol. 2018; 14: 2985-2994
        • Hu HT
        • Shen SL
        • Wang Z
        • et al.
        Peritumoral tissue on preoperative imaging reveals microvascular invasion in hepatocellular carcinoma: A systematic review and meta-analysis.
        Abdom Radiol. 2018; 43: 3324-3330
        • Song L
        • Li J
        • Luo Y.
        The importance of a nonsmooth tumor margin and incomplete tumor capsule in predicting HCC microvascular invasion on preoperative imaging examination: a systematic review and meta-analysis.
        Clin Imaging. 2021; 76: 77-82
        • Nordenstedt H
        • White DL
        • El-Serag HB.
        The changing pattern of epidemiology in hepatocellular carcinoma.
        Dig Liver Dis. 2010; 42: S206-S214
        • Omata M
        • Cheng AL
        • Kokudo N
        • et al.
        Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
        Hepatol Int. 2017; 11: 317-370
        • Galle PR
        • Forner A
        • Llovet JM
        • et al.
        EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Asayama Y
        • Tajima T
        • Nishie A
        • et al.
        Uptake of Gd-EOB-DTPA by hepatocellular carcinoma: Radiologic-pathologic correlation with special reference to bile production.
        Eur J Radiol. 2011; 80: e243-e248
        • Mulé S
        • Chalaye J
        • Legou F
        • et al.
        Hepatobiliary MR contrast agent uptake as a predictive biomarker of aggressive features on pathology and reduced recurrence-free survival in resectable hepatocellular carcinoma: comparison with dual-tracer 18F-FDG and 18F-FCH PET/CT.
        Eur Radiol. 2020; 30: 5348-5357
        • Fowler KJ
        • Burgoyne A
        • Fraum TJ
        • et al.
        Pathologic, Molecular, and Prognostic Radiologic Features of Hepatocellular Carcinoma.
        Radiographics. 2021; 41: 1611-1631
        • Harding-Theobald E
        • Louissaint J
        • Maraj B
        • et al.
        Systematic review: radiomics for the diagnosis and prognosis of hepatocellular carcinoma.
        Aliment Pharmacol Ther. 2021; 54: 890-901
        • Higgins JPT.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560