Advertisement

European Radiology

, Volume 28, Issue 10, pp 4243–4253 | Cite as

Quantitative correlation between uptake of Gd-BOPTA on hepatobiliary phase and tumor molecular features in patients with benign hepatocellular lesions

  • Edouard Reizine
  • Giuliana Amaddeo
  • Frederic Pigneur
  • Laurence Baranes
  • François Legou
  • Sebastien Mulé
  • Benhalima Zegai
  • Vincent Roche
  • Alexis Laurent
  • Alain Rahmouni
  • Julien Calderaro
  • Alain Luciani
Gastrointestinal

Abstract

Purpose

The purpose of our study was to correlate the quantitative analysis of benign hepatocellular tumor uptake on delayed hepatobiliary phase (HBP) imaging with the quantitative level of OATP expression.

Methods

This single-center retrospective study, which took place between September 2009 and March 2015, included 20 consecutive patients with a proven pathologic and immunohistochemical (IHC) diagnosis of FNH or HCA, including quantification of the OATP expression. The patients underwent Gd-BOPTA-enhancement MRI, including an HBP. The analysis of HBP uptake was performed using the liver-to-lesion contrast enhancement ratio (LLCER). Mean LLCER and OATP expressions were compared between FNH and HCA, and the expression of OATP was correlated with the LLCER value.

Results

Of the 23 benign hepatocellular tumors, 9 (39%) were FNH and 14 (61%) were HCA, including 6 inflammatory, 2 HNF1a inactivated, 3 β-catenin-mutated and 3 unclassified HCAs. On HBP, 100% of the FNH appeared hyper- or isointense, and 79% of the adenomas appeared hypointense. The mean OATP expression of FNH (46.67 ± 26.58%) was significantly higher than that of HCA (22.14 ± 30.74%) (p = 0.0273), and the mean LLCER of FNH (10.66 ± 7.403%) was significantly higher than that of HCA (-13.5 ± 12.25%) (p < 0.0001). The mean LLCER of β-catenin-mutated HCA was significantly higher than that of other HCAs (p = 0.011). Significant correlation was found between the OATP expression and LLCER values (r = 0.661; p = 0.001).

Conclusion

In benign hepatocellular tumors, the quantitative analysis of hepatobiliary contrast agent uptake on HBP is correlated with the level of OATP expression and could be used as an imaging biomarker of the molecular background of HCA and FNH.

Key Points

• Gd-BOPTA uptake on HBP correlates with the OATP level in benign hepatocellular tumors

• FNH and β-catenin-mutated HCA showed an increased lesion-to-liver contrast enhancement ratio (LLCER)

• Increased LLCER may be explained by activation of the Wnt β-catenin pathway

Keywords

Focal nodular hyperplasia Adenoma Liver neoplasms Organic anion transporters Contrast media 

Abbreviations

CRP

C-reactive protein

FNH

Focal nodular hyperplasia

GS

Glutamine synthetase

HBP

Hepatobiliary phase

HCA

Hepatocellular adenoma

IHC

Immunohistochemistry

LFABP

Liver fatty acid binding protein

LLCER

Liver-to-lesion contrast enhancement ratio

OATP

Organic anion transporting polypeptide

SAA

Serum amyloid A

SI

Signal intensity

VIBE

Volumetric interpolated breath-hold examination

Notes

Funding

The authors state that this work has not received any funding.

Compliance with ethical standards

Guarantor

The scientific guarantor of this publication is Prof. Alain Luciani.

Conflict of interest

The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

Written informed consent was waived by the Institutional Review Board.

Ethical approval

Institutional Review Board approval was obtained.

Study subjects or cohorts overlap

Some study subjects or cohorts have been previously reported in the Journal of Magnetic Resonance Imaging by Roux et al. (J MRI, Apr 2015) focusing on imaging analysis of HBP-MRI using a quantitative approach.

Methodology

• retrospective

• cross-sectional study

• performed at one institution

References

  1. 1.
    Cherqui D, Rahmouni A, Charlotte F et al (1995) Management of focal nodular hyperplasia and hepatocellular adenoma in young women: A series of 41 patients with clinical, radiological, and pathological correlations. Hepatology 22:1674–1681.  https://doi.org/10.1016/0270-9139(95)90190-6 CrossRefPubMedGoogle Scholar
  2. 2.
    De Carlis L, Pirotta V, Rondinara GF et al (1997) Hepatic adenoma and focal nodular hyperplasia: diagnosis and criteria for treatment. Liver Transpl Surg 3:160–165CrossRefGoogle Scholar
  3. 3.
    Charny CK, Jarnagin WR, Schwartz LH et al (2001) Management of 155 patients with benign liver tumours. Br J Surg 88:808–813.  https://doi.org/10.1046/j.0007-1323.2001.01771.x CrossRefPubMedGoogle Scholar
  4. 4.
    Cherqui D (2008) Clinical management of benign liver cell tumors. Gastroenterol Clin Biol 32(310-313):314.  https://doi.org/10.1016/j.gcb.2008.02.012 CrossRefGoogle Scholar
  5. 5.
    Weimann A, Ringe B, Klempnauer J et al (1997) Benign liver tumors: differential diagnosis and indications for surgery. World J Surg 21:983–991CrossRefGoogle Scholar
  6. 6.
    Nault J-C, Bioulac-Sage P, Zucman-Rossi J (2013) Hepatocellular benign tumors-from molecular classification to personalized clinical care. Gastroenterology 144:888–902.  https://doi.org/10.1053/j.gastro.2013.02.032 CrossRefPubMedGoogle Scholar
  7. 7.
    Nault J-C, Paradis V, Cherqui D et al (2017) Molecular classification of hepatocellular adenoma in clinical practice. J Hepatol 67:1074–1083.  https://doi.org/10.1016/j.jhep.2017.07.009 CrossRefPubMedGoogle Scholar
  8. 8.
    Cadoret A, Ovejero C, Terris B et al (2002) New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene 21:8293–8301.  https://doi.org/10.1038/sj.onc.1206118 CrossRefPubMedGoogle Scholar
  9. 9.
    Millet P, Moulin M, Stieger B et al (2011) How organic anions accumulate in hepatocytes lacking Mrp2: evidence in rat liver. J Pharmacol Exp Ther 336:624–632.  https://doi.org/10.1124/jpet.110.175406 CrossRefPubMedGoogle Scholar
  10. 10.
    Pascolo L, Cupelli F, Anelli PL et al (1999) Molecular mechanisms for the hepatic uptake of magnetic resonance imaging contrast agents. Biochem Biophys Res Commun 257:746–752.  https://doi.org/10.1006/bbrc.1999.0454 CrossRefPubMedGoogle Scholar
  11. 11.
    Pastor CM (2010) Gadoxetic acid-enhanced hepatobiliary phase MR imaging: cellular insight. Radiology 257:589.  https://doi.org/10.1148/radiol.101172 CrossRefPubMedGoogle Scholar
  12. 12.
    Planchamp C, Hadengue A, Stieger B et al (2007) Function of both sinusoidal and canalicular transporters controls the concentration of organic anions within hepatocytes. Mol Pharmacol 71:1089–1097.  https://doi.org/10.1124/mol.106.030759 CrossRefPubMedGoogle Scholar
  13. 13.
    Ba-Ssalamah A, Antunes C, Feier D et al (2015) Morphologic and molecular features of hepatocellular adenoma with gadoxetic acid-enhanced MR imaging. Radiology 277:104–113.  https://doi.org/10.1148/radiol.2015142366 CrossRefPubMedGoogle Scholar
  14. 14.
    Yoneda N, Matsui O, Kitao A et al (2016) Benign hepatocellular nodules: hepatobiliary phase of gadoxetic acid-enhanced MR imaging based on molecular background. Radiographics 36:2010–2027.  https://doi.org/10.1148/rg.2016160037 CrossRefPubMedGoogle Scholar
  15. 15.
    Ueno A, Masugi Y, Yamazaki K et al (2014) OATP1B3 expression is strongly associated with Wnt/β-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma. J Hepatol 61:1080–1087.  https://doi.org/10.1016/j.jhep.2014.06.008 CrossRefPubMedGoogle Scholar
  16. 16.
    Mathieu D, Rahmouni A, Anglade MC et al (1991) Focal nodular hyperplasia of the liver: assessment with contrast-enhanced TurboFLASH MR imaging. Radiology 180:25–30.  https://doi.org/10.1148/radiology.180.1.2052704 CrossRefPubMedGoogle Scholar
  17. 17.
    Vilgrain V, Fléjou JF, Arrivé L et al (1992) Focal nodular hyperplasia of the liver: MR imaging and pathologic correlation in 37 patients. Radiology 184:699–703.  https://doi.org/10.1148/radiology.184.3.1509052 CrossRefPubMedGoogle Scholar
  18. 18.
    Vilgrain V (2006) Focal nodular hyperplasia. Eur J Radiol 58:236–245.  https://doi.org/10.1016/j.ejrad.2005.11.043 CrossRefPubMedGoogle Scholar
  19. 19.
    Bieze M, van den Esschert JW, Nio CY et al (2012) Diagnostic accuracy of MRI in differentiating hepatocellular adenoma from focal nodular hyperplasia: prospective study of the additional value of gadoxetate disodium. AJR Am J Roentgenol 199:26–34.  https://doi.org/10.2214/AJR.11.7750 CrossRefPubMedGoogle Scholar
  20. 20.
    Suh CH, Kim KW, Kim GY et al (2015) The diagnostic value of Gd-EOB-DTPA-MRI for the diagnosis of focal nodular hyperplasia: a systematic review and meta-analysis. Eur Radiol 25:950–960.  https://doi.org/10.1007/s00330-014-3499-9 CrossRefPubMedGoogle Scholar
  21. 21.
    Ronot M, Vilgrain V (2014) Imaging of benign hepatocellular lesions: current concepts and recent updates. Clin Res Hepatol Gastroenterol 38:681–688.  https://doi.org/10.1016/j.clinre.2014.01.014 CrossRefPubMedGoogle Scholar
  22. 22.
    Neri E, Bali MA, Ba-Ssalamah A et al (2016) ESGAR consensus statement on liver MR imaging and clinical use of liver-specific contrast agents. Eur Radiol 26:921–931.  https://doi.org/10.1007/s00330-015-3900-3 CrossRefPubMedGoogle Scholar
  23. 23.
    Merkle EM, Zech CJ, Bartolozzi C et al (2016) Consensus report from the 7th international forum for liver magnetic resonance imaging. Eur Radiol 26:674–682.  https://doi.org/10.1007/s00330-015-3873-2 CrossRefPubMedGoogle Scholar
  24. 24.
    Kreft BP, Baba Y, Tanimoto A et al (1993) Orally administered manganese chloride: enhanced detection of hepatic tumors in rats. Radiology 186:543–548.  https://doi.org/10.1148/radiology.186.2.8421762 CrossRefPubMedGoogle Scholar
  25. 25.
    Ni Y, Marchal G, Yu J et al (1994) Prolonged positive contrast enhancement with Gd-EOB-DTPA in experimental liver tumors: potential value in tissue characterization. J Magn Reson Imaging 4:355–363CrossRefGoogle Scholar
  26. 26.
    Ni Y, Marchal G (1998) Enhanced magnetic resonance imaging for tissue characterization of liver abnormalities with hepatobiliary contrast agents: an overview of preclinical animal experiments. Top Magn Reson Imaging 9:183–195CrossRefGoogle Scholar
  27. 27.
    Grazioli L, Morana G, Kirchin MA, Schneider G (2005) Accurate differentiation of focal nodular hyperplasia from hepatic adenoma at gadobenate dimeglumine-enhanced MR imaging: prospective study. Radiology 236:166–177.  https://doi.org/10.1148/radiol.2361040338 CrossRefPubMedGoogle Scholar
  28. 28.
    Grazioli L, Bondioni MP, Haradome H et al (2012) Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis. Radiology 262:520–529.  https://doi.org/10.1148/radiol.11101742 CrossRefPubMedGoogle Scholar
  29. 29.
    Thomeer MG, Willemssen FE, Biermann KK et al (2014) MRI features of inflammatory hepatocellular adenomas on hepatocyte phase imaging with liver-specific contrast agents. J Magn Reson Imaging 39:1259–1264.  https://doi.org/10.1002/jmri.24281 CrossRefPubMedGoogle Scholar
  30. 30.
    Agarwal S, Fuentes-Orrego JM, Arnason T et al (2014) Inflammatory hepatocellular adenomas can mimic focal nodular hyperplasia on gadoxetic acid-enhanced MRI. AJR Am J Roentgenol 203:W408–W414.  https://doi.org/10.2214/AJR.13.12251 CrossRefPubMedGoogle Scholar
  31. 31.
    Tse JR, Naini BV, Lu DSK, Raman SS (2016) Qualitative and quantitative gadoxetic acid-enhanced MR imaging helps subtype hepatocellular adenomas. Radiology 279:118–127.  https://doi.org/10.1148/radiol.2015142449 CrossRefPubMedGoogle Scholar
  32. 32.
    Glockner JF, Lee CU, Mounajjed T (2017) Inflammatory hepatic adenomas: characterization with hepatobiliary MRI contrast agents. Magn Reson Imaging 47:103–110.  https://doi.org/10.1016/j.mri.2017.12.006 CrossRefPubMedGoogle Scholar
  33. 33.
    Roux M, Pigneur F, Calderaro J et al (2015) Differentiation of focal nodular hyperplasia from hepatocellular adenoma: role of the quantitative analysis of gadobenate dimeglumine-enhanced hepatobiliary phase MRI. J Magn Reson Imaging 42:1249–1258.  https://doi.org/10.1002/jmri.24897 CrossRefPubMedGoogle Scholar
  34. 34.
    Cassidy FH, Yokoo T, Aganovic L et al (2009) Fatty liver disease: MR imaging techniques for the detection and quantification of liver steatosis. Radiographics 29:231–260.  https://doi.org/10.1148/rg.291075123 CrossRefPubMedGoogle Scholar
  35. 35.
    Fléjou J-F (2011) WHO Classification of digestive tumors: the fourth edition. Ann Pathol 31:S27–S31.  https://doi.org/10.1016/j.annpat.2011.08.001 CrossRefPubMedGoogle Scholar
  36. 36.
    Zucman-Rossi J, Jeannot E, Nhieu JTV et al (2006) Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatol Baltim Md 43:515–524.  https://doi.org/10.1002/hep.21068 CrossRefGoogle Scholar
  37. 37.
    Bioulac-Sage P, Laumonier H, Couchy G et al (2009) Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatol Baltim Md 50:481–489.  https://doi.org/10.1002/hep.22995 CrossRefGoogle Scholar
  38. 38.
    van Kessel CS, de Boer E, ten Kate FJW et al (2013) Focal nodular hyperplasia: hepatobiliary enhancement patterns on gadoxetic-acid contrast-enhanced MRI. Abdom Imaging 38:490–501.  https://doi.org/10.1007/s00261-012-9916-0 CrossRefPubMedGoogle Scholar
  39. 39.
    van Aalten SM, Verheij J, Terkivatan T et al (2011) Validation of a liver adenoma classification system in a tertiary referral centre: implications for clinical practice. J Hepatol 55:120–125.  https://doi.org/10.1016/j.jhep.2010.10.030 CrossRefPubMedGoogle Scholar
  40. 40.
    Kitao A, Matsui O, Yoneda N et al (2015) Hepatocellular carcinoma with β-catenin mutation: imaging and pathologic characteristics. Radiology 275:708–717.  https://doi.org/10.1148/radiol.14141315 CrossRefPubMedGoogle Scholar
  41. 41.
    Vilgrain V, Van Beers BE, Pastor CM (2016) Insights into the diagnosis of hepatocellular carcinomas with hepatobiliary MRI. J Hepatol 64:708–716.  https://doi.org/10.1016/j.jhep.2015.11.016 CrossRefPubMedGoogle Scholar
  42. 42.
    Kitao A, Matsui O, Yoneda N et al (2017) Gadoxetic acid-enhanced magnetic resonance imaging reflects co-activation of β-catenin and hepatocyte nuclear factor 4α in hepatocellular carcinoma. Hepatol Res.  https://doi.org/10.1111/hepr.12911 CrossRefGoogle Scholar
  43. 43.
    Kanda T, Osawa M, Oba H et al (2015) High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 275:803–809.  https://doi.org/10.1148/radiol.14140364 CrossRefPubMedGoogle Scholar
  44. 44.
    Kahn J, Posch H, Steffen IG et al (2017) Is there long-term signal intensity increase in the central nervous system on T1-weighted images after MR imaging with the hepatospecific contrast agent agdoxetic acid? A cross-sectional study in 91 patients. Radiology 282:708–716.  https://doi.org/10.1148/radiol.2016162535 CrossRefPubMedGoogle Scholar

Copyright information

© European Society of Radiology 2018

Authors and Affiliations

  • Edouard Reizine
    • 1
  • Giuliana Amaddeo
    • 2
    • 3
    • 4
  • Frederic Pigneur
    • 1
  • Laurence Baranes
    • 1
  • François Legou
    • 1
  • Sebastien Mulé
    • 1
  • Benhalima Zegai
    • 1
  • Vincent Roche
    • 1
  • Alexis Laurent
    • 3
    • 4
    • 5
  • Alain Rahmouni
    • 1
    • 3
  • Julien Calderaro
    • 3
    • 4
    • 6
  • Alain Luciani
    • 1
    • 3
    • 4
  1. 1.Imagerie MedicaleAP-HP, Groupe Henri Mondor Albert ChenevierCréteilFrance
  2. 2.Hepatology DepartmentAP-HP, Groupe Henri Mondor Albert ChenevierCreteilFrance
  3. 3.Faculté de MédecineUniversite Paris Est CreteilCreteilFrance
  4. 4.INSERM Unit U 955CreteilFrance
  5. 5.Liver SurgeryAP-HP, Groupe Henri Mondor Albert ChenevierCreteilFrance
  6. 6.PathologyAP-HP, Groupe Henri Mondor Albert ChenevierCreteilFrance

Personalised recommendations