European Radiology

, Volume 21, Issue 6, pp 1233–1242 | Cite as

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

  • Rita Golfieri
  • Matteo Renzulli
  • Vincenzo Lucidi
  • Beniamino Corcioni
  • Franco Trevisani
  • Luigi Bolondi
Magnetic Resonance



To prospectively assess the additional value of the hepatobiliary (HB) phase of Gd-EOB-DTPA-MRI in identifying and characterising small (≤2 cm) hepatocellular carcinomas (HCCs) undetermined in dynamic phases alone because of their atypical features, according to the AASLD criteria.


127 cirrhotic patients were evaluated with Gd-EOB-DTPA-MRI in two sets: unenhanced and dynamic phases; unenhanced, dynamic and HB phases. Sixty-two out of 215 nodules (29%) were atypical in 42 patients (33%).


62 atypical nodules were reported at histology: high-grade dysplastic nodules (HGDN)/early HCC (n = 20), low-grade DN (LGDN) (n = 21), regenerative nodules (n = 17) and nodular regenerative hyperplasia (n = 4). The sensitivity, specificity, accuracy, positive and negative predictive value (PPV, NPV) were increased by the addition of the HB phase: 88.4–99.4%, 88–95%, 88–98.5%, 97–99%, and 65–97.5%, respectively. Twenty atypical nodules were malignant (32%), 19 of which were characterised only during the HB phase.


The HB phase is 11% more sensitive in the classification of HGDN/early HCC than dynamic MRI, with an added value of 32.5% in the NPV. The high incidence (33%) of atypical nodules and their frequent malignancy (32%) suggest the widespread employment of Gd-EOB-DTPA-MRI in the follow-up of small nodules (≤2 cm) in cirrhosis.


Hypovascular HCC Atypical small liver nodules Cirrhosis Gd-EOB-DTPA-enhanced MR imaging Magnetic resonance imaging 



Antonio Di Micoli M.D., Division of Internal Medicine, Department of Digestive Diseases and Internal Medicine; Sant’ Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy for the support in the statistical analysis


  1. 1.
    Sherman M (2010) Epidemiology of hepatocellular carcinoma. Oncology 78(Suppl 1):7–10PubMedCrossRefGoogle Scholar
  2. 2.
    Roayaie S, Llovet JM (2005) Liver transplantation for hepatocellular carcinoma: is expansion of criteria justified? Clin Liver Dis 9:315–28PubMedCrossRefGoogle Scholar
  3. 3.
    Shibuya K, Yano E (2005) Regression analysis of trends in mortality from hepatocellular carcinoma in Japan, 1972–2001. Int J Epidemiol 34:397–402PubMedCrossRefGoogle Scholar
  4. 4.
    El-Serag HB (2004) Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 127:S27–34PubMedCrossRefGoogle Scholar
  5. 5.
    El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 11:745–750CrossRefGoogle Scholar
  6. 6.
    Hayashi M, Matsui O, Ueda K, Kawamori Y, Gabata T, Kadoya M (2002) Progression to hypervascular hepatocellular carcinoma: correlation with intranodular blood supply evaluated with CT during intrarterial injection of contrast material. Radiology 225:143–149PubMedCrossRefGoogle Scholar
  7. 7.
    Hayashi M, Matsui O, Ueda K, Kawamori Y, Kadoya M, Yoshikawa J, Gabata T, Takashima T, Nonomura A, Nakanuma Y (1999) Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium. AJR Am J Roentgenol 172:969–976PubMedGoogle Scholar
  8. 8.
    Leoni S, Piscaglia F, Golfieri R, Camaggi V, Vidili G, Pini P, Bolondi L (2010) The impact of vascular and non vascular findings on the non invasive diagnosis of small hepatocellular carcinoma based on EASL and AASLD criteria. Am J Gastroenterol 105:599–609PubMedCrossRefGoogle Scholar
  9. 9.
    Colli A, Fraquelli M, Casazza G, Massironi S, Colucci A, Conte D, Duca P (2006) Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol 101:513–523PubMedCrossRefGoogle Scholar
  10. 10.
    Hecht EM, Holland AE, Israel GM, Hahn WY, Kim DC, West AB, Babb JS, Taouli B, Lee VS, Krinsky GA (2006) Hepatocellular carcinoma in the cirrhotic liver: gadolinium-enhanced 3D T1-weighted MR imaging as a stand-alone sequence for diagnosis. Radiology 239:438–447PubMedCrossRefGoogle Scholar
  11. 11.
    Rode A, Bancel B, Douek P, Chevallier M, Vilgrain V, Picaud G, Henry L, Berger F, Bizollon T, Gaudin JL, Ducerf C (2001) Small nodule detection in cirrhotic livers: evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver. J Comput Assist Tomogr 25:327–336PubMedCrossRefGoogle Scholar
  12. 12.
    Snowberger N, Chinnakotla S, Lepe RM, Peattie J, Goldstein R, Klintmalm GB, Davis GL (2007) Alpha fetoprotein, ultrasound, computerized tomography and magnetic resonance imaging for detection of hepatocellular carcinoma in patients with advanced cirrhosis. Aliment Pharmacol Ther 26:1187–1194PubMedCrossRefGoogle Scholar
  13. 13.
    Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. AASLD PRACTICE GUIDELINE. Hepatology 42:1208–1235PubMedCrossRefGoogle Scholar
  14. 14.
    Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ, Lok AS (2005) Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl 11:281–289PubMedCrossRefGoogle Scholar
  15. 15.
    Bruix J, Sherman M (2010) Management of hepatocellular carcinoma: an update. AASLD PRACTICE GUIDELINE. Hepatology July, published online by American Association for the Study of Liver Diseases.
  16. 16.
    Mion F, Grozel L, Boillot O, Paliard P, Berger F (1996) Adult cirrhotic liver explants: precancerous lesions and undetected small hepatocellular carcinomas. Gastroenterology 111:1587–1592PubMedCrossRefGoogle Scholar
  17. 17.
    Bolondi L, Gaiani S, Celli N, Golfieri R, Grigioni WF, Leoni S, Venturi AM, Piscaglia F (2005) Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma. Hepatology 42:27–34PubMedCrossRefGoogle Scholar
  18. 18.
    International Consensus Group for Hepatocellular Neoplasia (2009) Pathologic diagnosis of early hepatocellular carcinoma: a report of the International Consensus Group for Hepatocellular Neoplasia. Hepatology 49:658–664CrossRefGoogle Scholar
  19. 19.
    Spinazzi A, Lorusso V, Pirovano G, Kirchin M (1999) Safety, tolerance, biodistribution, and MR imaging enhancement of the liver with gadobenate dimeglumine: results of clinical pharmacologic and pilot imaging studies in nonpatient and patient volunteers. Acad Radiol 6:282–291PubMedCrossRefGoogle Scholar
  20. 20.
    Kirchin MA, Pirovano GP, Spinazzi A (1998) Gadobenate dimeglumine (Gd-BOPTA). An overview. Invest Radiol 33:798–809PubMedCrossRefGoogle Scholar
  21. 21.
    Seale MK, Catalano OA, Saini S, Hahn PF, Sahani DV (2009) Hepatobiliary-specific MR contrast agents: role in imaging the liver and biliary tree. RadioGraphics 29:1725–1748PubMedCrossRefGoogle Scholar
  22. 22.
    Reimer P, Rummeny EJ, Shamsi K, Balzer T, Daldrup HE, Tombach B, Hesse T, Berns T, Peters PE (1996) Phase II clinical evaluation of Gd-EOB-DTPA: dose, safety aspects, and pulse sequence. Radiology 199:177–183PubMedGoogle Scholar
  23. 23.
    Vogl TJ, Kümmel S, Hammerstingl R, Schellenbeck M, Schumacher G, Balzer T, Schwarz W, Müller PK, Bechstein WO, Mack MG, Söllner O, Felix R (1996) Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA. Radiology 200:59–67PubMedGoogle Scholar
  24. 24.
    Saito K, Kotake F, Ito N, Ozuki T, Mikami R, Abe K, Shimazaki Y (2005) Gd-EOB-DTPA enhanced MRI for hepatocellular carcinoma: quantitative evaluation of tumor enhancement in hepatobiliary phase. Magn Reson Med Sci 4:1–9PubMedCrossRefGoogle Scholar
  25. 25.
    Kim JI, Lee JM, Choi JY, Kim YK, Kim SH, Lee JY, Han JK, Choi BI (2008) The value of gadobenate dimeglumine-enhanced delayed phase MR imaging for characterization of hepatocellular nodules in the cirrhotic liver. Invest Radiol 43:202–210PubMedCrossRefGoogle Scholar
  26. 26.
    Kogita S, Imai Y, Okada M, Kim T, Onishi H, Takamura M, Fukuda K, Igura T, Sawai Y, Morimoto O, Hori M, Nagano H, Wakasa K, Hayashi N, Murakami T (2010) Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow. Eur Radiol 20:2405–2413PubMedCrossRefGoogle Scholar
  27. 27.
    Ahn SS, Kim MJ, Lim JS, Hong HS, Chung YE, Choi JY (2010) Added value of gadoxetic acid-enhanced hepatobiliary phase MR imaging in the diagnosis of hepatocellular carcinoma. Radiology 255:459–466PubMedCrossRefGoogle Scholar
  28. 28.
    Forty-first World Medical Assembly (1990) Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. Bull Pan Am Health Organ 24:606–609Google Scholar
  29. 29.
    International Working Party (1995) Terminology of nodular hepatocellular lesions. Hepatology 22:983–993Google Scholar
  30. 30.
    Stevens WR, Gulino SP, Batts KP, Stephens DH, Johnson CD (1996) Mosaic pattern of hepatocellular carcinoma: histologic basis for a characteristic CT appearance. J Comput Assist Tomogr 20:337–342PubMedCrossRefGoogle Scholar
  31. 31.
    Choi SH, Lee JM, Yu NC, Suh KS, Jang JJ, Kim SH, Choi BI (2008) Hepatocellular carcinoma in liver transplantation candidates: detection with gadobenate dimeglumine-enhanced MRI. AJR Am J Roentgenol 191:529–536PubMedCrossRefGoogle Scholar
  32. 32.
    Kim YK, Kwak HS, Han YM, Kim CS (2007) Usefulness of combining sequentially acquired gadobenate dimeglumine-enhanced magnetic resonance imaging and Resovist enhanced magnetic resonance imaging for the detection of hepatocellular carcinoma: comparison with computed tomography hepatic arteriography and computed tomography arterioportography using 16-slice multidetector computed tomography. J Comput Assist Tomogr 31:702–711PubMedCrossRefGoogle Scholar
  33. 33.
    Willatt JM, Hussain HK, Adusumilli S, Marrero JA (2008) MR Imaging of hepatocellular carcinoma in the cirrhotic liver: challenges and controversies. Radiology 247:311–330PubMedCrossRefGoogle Scholar
  34. 34.
    Brancatelli G, Federle MP, Grazioli L, Golfieri R, Lencioni R (2002) Large regenerative nodules in Budd-Chiari Syndrome and other vascular disorders of the liver: CT and MR imaging findings with clinicopathologic correlation. AJR Am J Roentgenol 178:877–883PubMedGoogle Scholar
  35. 35.
    Amesa JT, Federle MP, Chopra K (2009) Distinguishing clinical and imaging features of nodular regenerative hyperplasia and large regenerative nodules of the liver. Clin Radiol 64:1190–1195CrossRefGoogle Scholar
  36. 36.
    Kitao A, Zen Y, Matsui O, Gabata T, Kobayashi S, Koda W, Kozaka K, Yoneda N, Yamashita T, Kaneko S, Nakanuma Y (2010) Hepatocellular carcinoma: signal intensity at gadoxetic acid–enhanced MR imaging—correlation with molecular transporters and histopathologic features. Radiology 256:817–826PubMedCrossRefGoogle Scholar
  37. 37.
    Narita M, Hatano E, Arizono S, Miyagawa-Hayashino A, Isoda H, Kitamura K, Taura K, Yasuchika K, Nitta T, Ikai I, Uemoto S (2009) Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 44:793–798PubMedCrossRefGoogle Scholar
  38. 38.
    Pascolo L, Petrovic S, Cupelli F, Bruschi CV, Anelli PL, Lorusso V, Visigalli M, Uggeri F, Tiribelli C (2001) Abc protein transport of MRI contrast agents in canalicular rat liver plasma vesicles and yeast vacuoles. Biochem Biophys Res Commun 282:60–66PubMedCrossRefGoogle Scholar
  39. 39.
    Hamm B, Staks T, Mühler A, Bollow M, Taupitz M, Frenzel T, Wolf KJ, Weinmann HJ, Lange L (1995) Phase I clinical evaluation of Gd-EOB-DTPA as a hepatobiliary MR contrast agent: safety, pharmacokinetics, and MR imaging. Radiology 195:785–792PubMedGoogle Scholar
  40. 40.
    Kudo M (2008) Hepatocellular carcinoma 2009 and beyond: from the surveillance to molecular targeted therapy. Oncology 75(suppl 1):1–12. doi: 10.1159/000181865 PubMedCrossRefGoogle Scholar
  41. 41.
    Hammerstingl R, Huppertz A, Breuer J, Balzer T, Blakeborough A, Carter R, Fusté LC, Heinz-Peer G, Judmaier W, Laniado M, Manfredi RM, Mathieu DG, Müller D, Mortelè K, Reimer P, Reiser MF, Robinson PJ, Shamsi K, Strotzer M, Taupitz M, Tombach B, Valeri G, van Beers BE, Vogl TJ, European EOB-study group (2008) Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions. Eur Radiol 18(3):457–467. doi: 10.1007/s00330-007-0716-9 PubMedCrossRefGoogle Scholar
  42. 42.
    Tajima T, Honda H, Taguchi K, Asayama Y, Kuroiwa T, Yoshimitsu K, Irie H, Aibe H, Shimada M, Masuda K (2002) Sequential hemodynamic change in hepatocellular carcinoma and dysplastic nodules: CT angiography and pathologic correlation. AJR Am J Roentgenol 178:885–897PubMedGoogle Scholar
  43. 43.
    Kojiro M (2007) Diagnostic discrepancy of early hepatocellular carcinoma between Japan and West. Hepatology Res 37:S249–S252CrossRefGoogle Scholar
  44. 44.
    Gabata T, Matsui O, Kadoya M, Yoshikawa J, Ueda K, Kawamori Y, Takashima T, Nonomura A (1998) Delayed MR imaging of the liver: correlation of delayed enhancement of hepatic tumors and pathologic appearance. Abdom Imaging 23:309–313PubMedCrossRefGoogle Scholar
  45. 45.
    Grazioli L, Morana G, Caudana R, Benetti A, Portolani N, Talamini G, Colombari R, Pirovano G, Kirchin MA, Spinazzi A (2000) Hepatocellular carcinoma: correlation between gadobenate dimeglumine-enhanced MRI and pathologic findings. Invest Radiol 35:25–34PubMedCrossRefGoogle Scholar
  46. 46.
    Manfredi R, Maresca G, Baron RL, Cotroneo AR, De Gaetano AM, De Franco A, Pirovano G, Spinazzi A, Marano P (1999) Delayed MR imaging of hepatocellular carcinoma enhanced by gadobenate dimeglumine (Gd-BOPTA). J Magn Reson Imaging 9:704–710PubMedCrossRefGoogle Scholar
  47. 47.
    Nakashima Y, Nakashima O, Hsia CC, Kojiro M, Tabor E (1999) Vascularization of small hepatocellular carcinomas: correlation with differentiation. Liver 19:12–18PubMedCrossRefGoogle Scholar
  48. 48.
    Takayasu K, Furukawa H, Wakao F, Muramatsu Y, Abe H, Terauchi T, Winter TC 3rd, Sakamoto M, Hirohashi S (1995) CT diagnosis of early hepatocellular carcinoma: sensitivity, findings, and CT-pathologic correlation. AJR Am J Roentgenol 164:885–890PubMedGoogle Scholar
  49. 49.
    Lim JH, Choi D, Kim SH, Lee SJ, Lee WJ, Lim HK, Kim S (2002) Detection of hepatocellular carcinoma: value of adding delayed phase imaging to dual-phase helical CT. AJR Am J Roentgenol 179:67–73PubMedGoogle Scholar
  50. 50.
    Marin D, Di Martino M, Guerrisi A, De Filippis G, Rossi M, Ginanni Corradini S, Masciangelo R, Catalano C, Passariello R (2009) Hepatocellular carcinoma in patients with cirrhosis: qualitative comparison of gadobenate dimeglumine-enhanced MR imaging and multiphasic 64-section CT. Radiology 251:85–95PubMedCrossRefGoogle Scholar
  51. 51.
    Kim SH, Kim SH, Lee J, Kim MJ, Jeon YH, Park Y, Choi D, Lee WJ, Lim HK (2009) Gadoxetic acid-enhanced MRI versus triple-phase MDCT for the preoperative detection of hepatocellular carcinoma. AJR Am J Roentgenol 192:1675–1681PubMedCrossRefGoogle Scholar
  52. 52.
    Ransohoff DF, Feinstein AR (1978) Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 299:926–930PubMedCrossRefGoogle Scholar
  53. 53.
    Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, Moher D, Rennie D, de Vet HC, Lijmer JG (2003) Standards for reporting of diagnostic accuracy. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Ann Intern Med 138:W1–12PubMedGoogle Scholar
  54. 54.
    Kojiro M (2004) Focus on dysplastic nodules and early hepatocellular carcinoma: an Eastern point of view. Liver Transpl 10:S3–S8PubMedCrossRefGoogle Scholar
  55. 55.
    Kojiro M, Roskams T (2005) Early hepatocellular carcinoma and dysplastic nodules. Semin Liver Dis 25:133–142PubMedCrossRefGoogle Scholar
  56. 56.
    Kudo M (2009) Multistep human hepatocarcinogenesis: correlation of imaging with pathology. J Gastroenterol 44:112–118PubMedCrossRefGoogle Scholar
  57. 57.
    Inoue K, Takayama T, Higaki T, Watanabe Y, Makuuchi M (2004) Clinical significance of early hepatocellular carcinoma. Liver Transpl 10:S16–S19PubMedCrossRefGoogle Scholar
  58. 58.
    Yamamoto M, Takasaki K, Otsubo T, Katsuragawa H, Katagiri S, Yoshitoshi K, Ariizumi S, Saito A, Nakano M (2004) Favorable surgical outcomes in patients with early hepatocellular carcinoma. Ann Surg 239:395–399PubMedCrossRefGoogle Scholar

Copyright information

© European Society of Radiology 2011

Authors and Affiliations

  • Rita Golfieri
    • 1
  • Matteo Renzulli
    • 1
  • Vincenzo Lucidi
    • 1
  • Beniamino Corcioni
    • 1
  • Franco Trevisani
    • 2
  • Luigi Bolondi
    • 3
  1. 1.Radiology Unit, Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi HospitalUniversity of BolognaBolognaItaly
  2. 2.Unit of Semeiotica, Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi HospitalUniversity of BolognaBolognaItaly
  3. 3.Unit of Internal Medicine, Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi HospitalUniversity of BolognaBolognaItaly

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