OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy

A. Sciarra, S. Schmidt, A. Pellegrinelli, M. Maggioni, D. Dondossola, J. Pasquier, C. Cigala, D. Tosi, N. Halkic, G. Bulfamante, G. Viale, S. Bosari, C. Balabaud, P. Bioulac-Sage, C. Sempoux

Research output: Contribution to journalArticle

Abstract

Background and Aims: Hepatobiliary phase (HBP) Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) has increased the accuracy in differentiating focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). However, the ability of this technique to distinguish HCA subtypes remains controversial. The aim of this study was to investigate the expression of hepatocyte transporters (OATPB1/B3, MRP2, MRP3) in HCA subtypes, hence to understand their MRI signal intensity on HBP Gd-EOB-DTPA-enhanced MRI. Methods: By means of immunohistochemistry (IHC), we scored the expression of OATPB1/B3, MRP2 and MRP3, in resected specimens of FNH (n = 40), subtyped HCA (n = 58) and HCA with focal malignant transformation (HCA-HCC, n = 4). Results were validated on a supplementary set of FNH (n = 6), subtyped HCA (n = 17) and HCA-HCC (n = 1) with Gd-EOB-DTPA MR images. Results: All FNH showed a preserved expression of hepatocytes transporters. Beta-catenin-activated HCA (at highest risk of malignant transformation) and HCA-HCC were characterized by preserved/increased OATPB1/B3 expression (predictor of hyperintensity on HBP), as opposed to other HCA subtypes (P 
Original languageEnglish
Pages (from-to)158-167
Number of pages10
JournalLiver International
Volume39
Issue number1
DOIs
Publication statusPublished - 2019

Fingerprint

Liver Cell Adenoma
Focal Nodular Hyperplasia
Neoplasms
Magnetic Resonance Imaging
Hepatocytes
gadolinium ethoxybenzyl DTPA
beta Catenin
Adenocarcinoma

Keywords

  • hepatocellular adenoma
  • hepatocyte transporters
  • hepatospecific magnetic resonance imaging
  • radio-pathological correlation
  • b3 protein
  • beta catenin
  • gadolinium
  • multidrug resistance associated protein 2
  • multidrug resistance associated protein 3
  • oatpb1 protein
  • pentetic acid
  • protein
  • unclassified drug
  • adult
  • Article
  • chronic liver disease
  • fatty liver
  • female
  • human
  • human tissue
  • immunohistochemistry
  • liver adenoma
  • liver cirrhosis
  • liver fibrosis
  • major clinical study
  • male
  • malignant transformation
  • medical history
  • nuclear magnetic resonance imaging
  • oral contraception
  • protein expression
  • sensitivity and specificity

Cite this

OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy. / Sciarra, A.; Schmidt, S.; Pellegrinelli, A.; Maggioni, M.; Dondossola, D.; Pasquier, J.; Cigala, C.; Tosi, D.; Halkic, N.; Bulfamante, G.; Viale, G.; Bosari, S.; Balabaud, C.; Bioulac-Sage, P.; Sempoux, C.

In: Liver International, Vol. 39, No. 1, 2019, p. 158-167.

Research output: Contribution to journalArticle

Sciarra, A, Schmidt, S, Pellegrinelli, A, Maggioni, M, Dondossola, D, Pasquier, J, Cigala, C, Tosi, D, Halkic, N, Bulfamante, G, Viale, G, Bosari, S, Balabaud, C, Bioulac-Sage, P & Sempoux, C 2019, 'OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy', Liver International, vol. 39, no. 1, pp. 158-167. https://doi.org/10.1111/liv.13964
Sciarra, A. ; Schmidt, S. ; Pellegrinelli, A. ; Maggioni, M. ; Dondossola, D. ; Pasquier, J. ; Cigala, C. ; Tosi, D. ; Halkic, N. ; Bulfamante, G. ; Viale, G. ; Bosari, S. ; Balabaud, C. ; Bioulac-Sage, P. ; Sempoux, C. / OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy. In: Liver International. 2019 ; Vol. 39, No. 1. pp. 158-167.
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title = "OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy",
abstract = "Background and Aims: Hepatobiliary phase (HBP) Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) has increased the accuracy in differentiating focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). However, the ability of this technique to distinguish HCA subtypes remains controversial. The aim of this study was to investigate the expression of hepatocyte transporters (OATPB1/B3, MRP2, MRP3) in HCA subtypes, hence to understand their MRI signal intensity on HBP Gd-EOB-DTPA-enhanced MRI. Methods: By means of immunohistochemistry (IHC), we scored the expression of OATPB1/B3, MRP2 and MRP3, in resected specimens of FNH (n = 40), subtyped HCA (n = 58) and HCA with focal malignant transformation (HCA-HCC, n = 4). Results were validated on a supplementary set of FNH (n = 6), subtyped HCA (n = 17) and HCA-HCC (n = 1) with Gd-EOB-DTPA MR images. Results: All FNH showed a preserved expression of hepatocytes transporters. Beta-catenin-activated HCA (at highest risk of malignant transformation) and HCA-HCC were characterized by preserved/increased OATPB1/B3 expression (predictor of hyperintensity on HBP), as opposed to other HCA subtypes (P ",
keywords = "hepatocellular adenoma, hepatocyte transporters, hepatospecific magnetic resonance imaging, radio-pathological correlation, b3 protein, beta catenin, gadolinium, multidrug resistance associated protein 2, multidrug resistance associated protein 3, oatpb1 protein, pentetic acid, protein, unclassified drug, adult, Article, chronic liver disease, fatty liver, female, human, human tissue, immunohistochemistry, liver adenoma, liver cirrhosis, liver fibrosis, major clinical study, male, malignant transformation, medical history, nuclear magnetic resonance imaging, oral contraception, protein expression, sensitivity and specificity",
author = "A. Sciarra and S. Schmidt and A. Pellegrinelli and M. Maggioni and D. Dondossola and J. Pasquier and C. Cigala and D. Tosi and N. Halkic and G. Bulfamante and G. Viale and S. Bosari and C. Balabaud and P. Bioulac-Sage and C. Sempoux",
note = "Export Date: 6 February 2019 CODEN: LIINC Correspondence Address: Sempoux, C.; Service of Clinical Pathology, Institute of Pathology, Lausanne University HospitalSwitzerland; email: christine.sempoux@chuv.ch Chemicals/CAS: gadolinium, 7440-54-2; multidrug resistance associated protein 2, 256503-65-8; pentetic acid, 14047-41-7, 67-43-6; protein, 67254-75-5 References: Roncalli, M., Sciarra, A., Tommaso, L.D., Benign hepatocellular nodules of healthy liver: focal nodular hyperplasia and hepatocellular adenoma (2016) Clin Mol Hepatol, 22 (2), pp. 199-211; Sempoux, C., Paradis, V., Komuta, M., Hepatocellular nodules expressing markers of hepatocellular adenomas in Budd-Chiari syndrome and other rare hepatic vascular disorders (2015) J Hepatol, 63 (5), pp. 1173-1180; Dokmak, S., Paradis, V., Vilgrain, V., A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas (2009) Gastroenterology, 137 (5), pp. 1698-1705; Chang, C.Y., Hernandez-Prera, J.C., Roayaie, S., Schwartz, M., Thung, S.N., Changing epidemiology of hepatocellular adenoma in the United States: review of the literature (2013) Int J Hepatol, 2013, p. 604860; Paradis, V., Laurent, A., Flejou, J.F., Vidaud, M., Bedossa, P., Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation (1997) Hepatology, 26 (4), pp. 891-895; Chen, Y.J., Chen, P.J., Lee, M.C., Yeh, S.H., Hsu, M.T., Lin, C.H., Chromosomal analysis of hepatic adenoma and focal nodular hyperplasia by comparative genomic hybridization (2002) Genes Chromosomes Cancer, 35 (2), pp. 138-143; Zucman-Rossi, J., Jeannot, E., Nhieu, J.T., Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC (2006) Hepatology, 43 (3), pp. 515-524; Bioulac-Sage, P., Rebouissou, S., Thomas, C., Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry (2007) Hepatology, 46 (3), pp. 740-748; Sasaki, M., Yoneda, N., Kitamura, S., Sato, Y., Nakanuma, Y., Characterization of hepatocellular adenoma based on the phenotypic classification: The Kanazawa experience (2011) Hepatol Res, 41 (10), pp. 982-988; Bellamy, C.O., Maxwell, R.S., Prost, S., Azodo, I.A., Powell, J.J., Manning, J.R., The value of immunophenotyping hepatocellular adenomas: consecutive resections at one UK centre (2013) Histopathology, 62 (3), pp. 431-445; Bioulac-Sage, P., Balabaud, C., Bedossa, P., Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update (2007) J Hepatol, 46 (3), pp. 521-527; Nault, J.C., Couchy, G., Balabaud, C., Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation (2017) Gastroenterology, 152 (4), pp. 880-894.e886; Henriet, E., Abou Hammoud, A., Dupuy, J.W., Argininosuccinate synthase 1 (ASS1): A marker of unclassified hepatocellular adenoma and high bleeding risk (2017) Hepatology, 66 (6), pp. 2016-2028; Bioulac-Sage, P., Laumonier, H., Couchy, G., Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience (2009) Hepatology, 50 (2), pp. 481-489; Cho, S.W., Marsh, J.W., Steel, J., Surgical management of hepatocellular adenoma: take it or leave it? (2008) Ann Surg Oncol, 15 (10), pp. 2795-2803; Cherqui, D., Rahmouni, A., Charlotte, F., Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations (1995) Hepatology, 22 (6), pp. 1674-1681; Ronot, M., Bahrami, S., Calderaro, J., Hepatocellular adenomas: accuracy of magnetic resonance imaging and liver biopsy in subtype classification (2011) Hepatology, 53 (4), pp. 1182-1191; Agnello, F., Ronot, M., Valla, D.C., Sinkus, R., Van Beers, B.E., Vilgrain, V., High-b-value diffusion-weighted MR imaging of benign hepatocellular lesions: quantitative and qualitative analysis (2012) Radiology, 262 (2), pp. 511-519; Laumonier, H., Bioulac-Sage, P., Laurent, C., Zucman-Rossi, J., Balabaud, C., Trillaud, H., Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification (2008) Hepatology, 48 (3), pp. 808-818; EASL Clinical Practice Guidelines on the management of benign liver tumours (2016) J Hepatol, 65 (2), pp. 386-398; Nault, J.C., Bioulac-Sage, P., Zucman-Rossi, J., Hepatocellular benign tumors-from molecular classification to personalized clinical care (2013) Gastroenterology, 144 (5), pp. 888-902; Grazioli, L., Bondioni, M.P., Haradome, H., Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis (2012) Radiology, 262 (2), pp. 520-529; McInnes, M.D., Hibbert, R.M., Inacio, J.R., Schieda, N., Focal nodular hyperplasia and hepatocellular adenoma: accuracy of gadoxetic acid-enhanced mr imaging–a systematic review (2015) Radiology, 277 (2), pp. 413-423; Tselikas, L., Pigneur, F., Roux, M., Impact of hepatobiliary phase liver MRI versus Contrast-Enhanced Ultrasound after an inconclusive extracellular gadolinium-based contrast-enhanced MRI for the diagnosis of benign hepatocellular tumors (2017) Abdom Radiol (NY), 42 (3), pp. 825-832; Roux, M., Pigneur, F., Baranes, L., Differentiating focal nodular hyperplasia from hepatocellular adenoma: Is hepatobiliary phase MRI (HBP-MRI) using linear gadolinium chelates always useful? (2017) Abdom Radiol (NY); Boyer, J.L., Bile formation and secretion (2013) Comprehensive Physiology, 3 (3), pp. 1035-1078; Van Beers, B.E., Pastor, C.M., Hussain, H.K., Primovist, Eovist: what to expect? (2012) J Hepatol, 57 (2), pp. 421-429; Leporq, B., Daire, J.L., Pastor, C.M., Quantification of hepatic perfusion and hepatocyte function with dynamic gadoxetic acid-enhanced MRI in patients with chronic liver disease (2018) Clin Sci, 132 (7), pp. 813-824; Denecke, T., Steffen, I.G., Agarwal, S., Appearance of hepatocellular adenomas on gadoxetic acid-enhanced MRI (2012) Eur Radiol, 22 (8), pp. 1769-1775; Grieser, C., Steffen, I.G., Kramme, I.B., Gadoxetic acid enhanced MRI for differentiation of FNH and HCA: a single centre experience (2014) Eur Radiol, 24 (6), pp. 1339-1348; Vander Borght, S., Libbrecht, L., Blokzijl, H., Diagnostic and pathogenetic implications of the expression of hepatic transporters in focal lesions occurring in normal liver (2005) J Pathol, 207 (4), pp. 471-482; Guo, Y., Li, W., Cai, W., Zhang, Y., Fang, Y., Hong, G., Diagnostic value of gadoxetic acid-enhanced MR imaging to distinguish HCA and its subtype from FNH: a systematic review (2017) Int J Med Sci, 14 (7), pp. 668-674; Ba-Ssalamah, A., Antunes, C., Feier, D., Morphologic and molecular features of hepatocellular adenoma with gadoxetic acid-enhanced MR imaging (2015) Radiology, 277 (1), pp. 104-113; Grieser, C., Steffen, I.G., Seehofer, D., Histopathologically confirmed focal nodular hyperplasia of the liver: gadoxetic acid-enhanced MRI characteristics (2013) Magn Reson Imaging, 31 (5), pp. 755-760; Thomeer, M.G., Broker, M., Lussanet, Q., Biermann, K., Dwarkasing, R.S., Genotype-phenotype correlations in hepatocellular adenoma: an update of MRI findings (2014) Diagn Interv Radiol, 20 (3), pp. 193-199; Suh, C.H., Kim, K.W., Kim, G.Y., Shin, Y.M., Kim, P.N., Park, S.H., The diagnostic value of Gd-EOB-DTPA-MRI for the diagnosis of focal nodular hyperplasia: a systematic review and meta-analysis (2015) Eur Radiol, 25 (4), pp. 950-960; Fukusato, T., Soejima, Y., Kondo, F., Preserved or enhanced OATP1B3 expression in hepatocellular adenoma subtypes with nuclear accumulation of beta-catenin (2015) Hepatol Res, 45 (10), pp. E32-E42; Paradis, V., Benzekri, A., Dargere, D., Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma (2004) Gastroenterology, 126 (5), pp. 1323-1329; Reizine, E., Amaddeo, G., Pigneur, F., Quantitative correlation between uptake of Gd-BOPTA on hepatobiliary phase and tumor molecular features in patients with benign hepatocellular lesions (2018) Eur Radiol; Yoneda, N., Matsui, O., Kitao, A., Benign hepatocellular nodules: hepatobiliary phase of gadoxetic acid-enhanced MR imaging based on molecular background (2016) Radiographics, 36 (7), pp. 2010-2027; Colletti, M., Cicchini, C., Conigliaro, A., Convergence of Wnt signaling on the HNF4alpha-driven transcription in controlling liver zonation (2009) Gastroenterology, 137 (2), pp. 660-672; Lu, H., Gonzalez, F.J., Klaassen, C., Alterations in hepatic mRNA expression of phase II enzymes and xenobiotic transporters after targeted disruption of hepatocyte nuclear factor 4 alpha (2010) Toxicol Sci, 118 (2), pp. 380-390; Kitao, A., Zen, Y., Matsui, O., Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging–correlation with molecular transporters and histopathologic features (2010) Radiology, 256 (3), pp. 817-826; Kitao, A., Matsui, O., Yoneda, N., The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging (2011) Eur Radiol, 21 (10), pp. 2056-2066; Zollner, G., Fickert, P., Zenz, R., Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases (2001) Hepatology, 33 (3), pp. 633-646; Lemberger, U.J., Fuchs, C.D., Karer, M., Hepatocyte specific expression of an oncogenic variant of beta-catenin results in cholestatic liver disease (2016) Oncotarget, 7 (52), pp. 86985-86998; Yeh, T.H., Krauland, L., Singh, V., Liver-specific beta-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis (2010) Hepatology, 52 (4), pp. 1410-1419",
year = "2019",
doi = "10.1111/liv.13964",
language = "English",
volume = "39",
pages = "158--167",
journal = "Liver International",
issn = "1478-3223",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "1",

}

TY - JOUR

T1 - OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy

AU - Sciarra, A.

AU - Schmidt, S.

AU - Pellegrinelli, A.

AU - Maggioni, M.

AU - Dondossola, D.

AU - Pasquier, J.

AU - Cigala, C.

AU - Tosi, D.

AU - Halkic, N.

AU - Bulfamante, G.

AU - Viale, G.

AU - Bosari, S.

AU - Balabaud, C.

AU - Bioulac-Sage, P.

AU - Sempoux, C.

N1 - Export Date: 6 February 2019 CODEN: LIINC Correspondence Address: Sempoux, C.; Service of Clinical Pathology, Institute of Pathology, Lausanne University HospitalSwitzerland; email: christine.sempoux@chuv.ch Chemicals/CAS: gadolinium, 7440-54-2; multidrug resistance associated protein 2, 256503-65-8; pentetic acid, 14047-41-7, 67-43-6; protein, 67254-75-5 References: Roncalli, M., Sciarra, A., Tommaso, L.D., Benign hepatocellular nodules of healthy liver: focal nodular hyperplasia and hepatocellular adenoma (2016) Clin Mol Hepatol, 22 (2), pp. 199-211; Sempoux, C., Paradis, V., Komuta, M., Hepatocellular nodules expressing markers of hepatocellular adenomas in Budd-Chiari syndrome and other rare hepatic vascular disorders (2015) J Hepatol, 63 (5), pp. 1173-1180; Dokmak, S., Paradis, V., Vilgrain, V., A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas (2009) Gastroenterology, 137 (5), pp. 1698-1705; Chang, C.Y., Hernandez-Prera, J.C., Roayaie, S., Schwartz, M., Thung, S.N., Changing epidemiology of hepatocellular adenoma in the United States: review of the literature (2013) Int J Hepatol, 2013, p. 604860; Paradis, V., Laurent, A., Flejou, J.F., Vidaud, M., Bedossa, P., Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation (1997) Hepatology, 26 (4), pp. 891-895; Chen, Y.J., Chen, P.J., Lee, M.C., Yeh, S.H., Hsu, M.T., Lin, C.H., Chromosomal analysis of hepatic adenoma and focal nodular hyperplasia by comparative genomic hybridization (2002) Genes Chromosomes Cancer, 35 (2), pp. 138-143; Zucman-Rossi, J., Jeannot, E., Nhieu, J.T., Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC (2006) Hepatology, 43 (3), pp. 515-524; Bioulac-Sage, P., Rebouissou, S., Thomas, C., Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry (2007) Hepatology, 46 (3), pp. 740-748; Sasaki, M., Yoneda, N., Kitamura, S., Sato, Y., Nakanuma, Y., Characterization of hepatocellular adenoma based on the phenotypic classification: The Kanazawa experience (2011) Hepatol Res, 41 (10), pp. 982-988; Bellamy, C.O., Maxwell, R.S., Prost, S., Azodo, I.A., Powell, J.J., Manning, J.R., The value of immunophenotyping hepatocellular adenomas: consecutive resections at one UK centre (2013) Histopathology, 62 (3), pp. 431-445; Bioulac-Sage, P., Balabaud, C., Bedossa, P., Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update (2007) J Hepatol, 46 (3), pp. 521-527; Nault, J.C., Couchy, G., Balabaud, C., Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation (2017) Gastroenterology, 152 (4), pp. 880-894.e886; Henriet, E., Abou Hammoud, A., Dupuy, J.W., Argininosuccinate synthase 1 (ASS1): A marker of unclassified hepatocellular adenoma and high bleeding risk (2017) Hepatology, 66 (6), pp. 2016-2028; Bioulac-Sage, P., Laumonier, H., Couchy, G., Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience (2009) Hepatology, 50 (2), pp. 481-489; Cho, S.W., Marsh, J.W., Steel, J., Surgical management of hepatocellular adenoma: take it or leave it? (2008) Ann Surg Oncol, 15 (10), pp. 2795-2803; Cherqui, D., Rahmouni, A., Charlotte, F., Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations (1995) Hepatology, 22 (6), pp. 1674-1681; Ronot, M., Bahrami, S., Calderaro, J., Hepatocellular adenomas: accuracy of magnetic resonance imaging and liver biopsy in subtype classification (2011) Hepatology, 53 (4), pp. 1182-1191; Agnello, F., Ronot, M., Valla, D.C., Sinkus, R., Van Beers, B.E., Vilgrain, V., High-b-value diffusion-weighted MR imaging of benign hepatocellular lesions: quantitative and qualitative analysis (2012) Radiology, 262 (2), pp. 511-519; Laumonier, H., Bioulac-Sage, P., Laurent, C., Zucman-Rossi, J., Balabaud, C., Trillaud, H., Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification (2008) Hepatology, 48 (3), pp. 808-818; EASL Clinical Practice Guidelines on the management of benign liver tumours (2016) J Hepatol, 65 (2), pp. 386-398; Nault, J.C., Bioulac-Sage, P., Zucman-Rossi, J., Hepatocellular benign tumors-from molecular classification to personalized clinical care (2013) Gastroenterology, 144 (5), pp. 888-902; Grazioli, L., Bondioni, M.P., Haradome, H., Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis (2012) Radiology, 262 (2), pp. 520-529; McInnes, M.D., Hibbert, R.M., Inacio, J.R., Schieda, N., Focal nodular hyperplasia and hepatocellular adenoma: accuracy of gadoxetic acid-enhanced mr imaging–a systematic review (2015) Radiology, 277 (2), pp. 413-423; Tselikas, L., Pigneur, F., Roux, M., Impact of hepatobiliary phase liver MRI versus Contrast-Enhanced Ultrasound after an inconclusive extracellular gadolinium-based contrast-enhanced MRI for the diagnosis of benign hepatocellular tumors (2017) Abdom Radiol (NY), 42 (3), pp. 825-832; Roux, M., Pigneur, F., Baranes, L., Differentiating focal nodular hyperplasia from hepatocellular adenoma: Is hepatobiliary phase MRI (HBP-MRI) using linear gadolinium chelates always useful? (2017) Abdom Radiol (NY); Boyer, J.L., Bile formation and secretion (2013) Comprehensive Physiology, 3 (3), pp. 1035-1078; Van Beers, B.E., Pastor, C.M., Hussain, H.K., Primovist, Eovist: what to expect? (2012) J Hepatol, 57 (2), pp. 421-429; Leporq, B., Daire, J.L., Pastor, C.M., Quantification of hepatic perfusion and hepatocyte function with dynamic gadoxetic acid-enhanced MRI in patients with chronic liver disease (2018) Clin Sci, 132 (7), pp. 813-824; Denecke, T., Steffen, I.G., Agarwal, S., Appearance of hepatocellular adenomas on gadoxetic acid-enhanced MRI (2012) Eur Radiol, 22 (8), pp. 1769-1775; Grieser, C., Steffen, I.G., Kramme, I.B., Gadoxetic acid enhanced MRI for differentiation of FNH and HCA: a single centre experience (2014) Eur Radiol, 24 (6), pp. 1339-1348; Vander Borght, S., Libbrecht, L., Blokzijl, H., Diagnostic and pathogenetic implications of the expression of hepatic transporters in focal lesions occurring in normal liver (2005) J Pathol, 207 (4), pp. 471-482; Guo, Y., Li, W., Cai, W., Zhang, Y., Fang, Y., Hong, G., Diagnostic value of gadoxetic acid-enhanced MR imaging to distinguish HCA and its subtype from FNH: a systematic review (2017) Int J Med Sci, 14 (7), pp. 668-674; Ba-Ssalamah, A., Antunes, C., Feier, D., Morphologic and molecular features of hepatocellular adenoma with gadoxetic acid-enhanced MR imaging (2015) Radiology, 277 (1), pp. 104-113; Grieser, C., Steffen, I.G., Seehofer, D., Histopathologically confirmed focal nodular hyperplasia of the liver: gadoxetic acid-enhanced MRI characteristics (2013) Magn Reson Imaging, 31 (5), pp. 755-760; Thomeer, M.G., Broker, M., Lussanet, Q., Biermann, K., Dwarkasing, R.S., Genotype-phenotype correlations in hepatocellular adenoma: an update of MRI findings (2014) Diagn Interv Radiol, 20 (3), pp. 193-199; Suh, C.H., Kim, K.W., Kim, G.Y., Shin, Y.M., Kim, P.N., Park, S.H., The diagnostic value of Gd-EOB-DTPA-MRI for the diagnosis of focal nodular hyperplasia: a systematic review and meta-analysis (2015) Eur Radiol, 25 (4), pp. 950-960; Fukusato, T., Soejima, Y., Kondo, F., Preserved or enhanced OATP1B3 expression in hepatocellular adenoma subtypes with nuclear accumulation of beta-catenin (2015) Hepatol Res, 45 (10), pp. E32-E42; Paradis, V., Benzekri, A., Dargere, D., Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma (2004) Gastroenterology, 126 (5), pp. 1323-1329; Reizine, E., Amaddeo, G., Pigneur, F., Quantitative correlation between uptake of Gd-BOPTA on hepatobiliary phase and tumor molecular features in patients with benign hepatocellular lesions (2018) Eur Radiol; Yoneda, N., Matsui, O., Kitao, A., Benign hepatocellular nodules: hepatobiliary phase of gadoxetic acid-enhanced MR imaging based on molecular background (2016) Radiographics, 36 (7), pp. 2010-2027; Colletti, M., Cicchini, C., Conigliaro, A., Convergence of Wnt signaling on the HNF4alpha-driven transcription in controlling liver zonation (2009) Gastroenterology, 137 (2), pp. 660-672; Lu, H., Gonzalez, F.J., Klaassen, C., Alterations in hepatic mRNA expression of phase II enzymes and xenobiotic transporters after targeted disruption of hepatocyte nuclear factor 4 alpha (2010) Toxicol Sci, 118 (2), pp. 380-390; Kitao, A., Zen, Y., Matsui, O., Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging–correlation with molecular transporters and histopathologic features (2010) Radiology, 256 (3), pp. 817-826; Kitao, A., Matsui, O., Yoneda, N., The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging (2011) Eur Radiol, 21 (10), pp. 2056-2066; Zollner, G., Fickert, P., Zenz, R., Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases (2001) Hepatology, 33 (3), pp. 633-646; Lemberger, U.J., Fuchs, C.D., Karer, M., Hepatocyte specific expression of an oncogenic variant of beta-catenin results in cholestatic liver disease (2016) Oncotarget, 7 (52), pp. 86985-86998; Yeh, T.H., Krauland, L., Singh, V., Liver-specific beta-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis (2010) Hepatology, 52 (4), pp. 1410-1419

PY - 2019

Y1 - 2019

N2 - Background and Aims: Hepatobiliary phase (HBP) Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) has increased the accuracy in differentiating focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). However, the ability of this technique to distinguish HCA subtypes remains controversial. The aim of this study was to investigate the expression of hepatocyte transporters (OATPB1/B3, MRP2, MRP3) in HCA subtypes, hence to understand their MRI signal intensity on HBP Gd-EOB-DTPA-enhanced MRI. Methods: By means of immunohistochemistry (IHC), we scored the expression of OATPB1/B3, MRP2 and MRP3, in resected specimens of FNH (n = 40), subtyped HCA (n = 58) and HCA with focal malignant transformation (HCA-HCC, n = 4). Results were validated on a supplementary set of FNH (n = 6), subtyped HCA (n = 17) and HCA-HCC (n = 1) with Gd-EOB-DTPA MR images. Results: All FNH showed a preserved expression of hepatocytes transporters. Beta-catenin-activated HCA (at highest risk of malignant transformation) and HCA-HCC were characterized by preserved/increased OATPB1/B3 expression (predictor of hyperintensity on HBP), as opposed to other HCA subtypes (P 

AB - Background and Aims: Hepatobiliary phase (HBP) Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) has increased the accuracy in differentiating focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). However, the ability of this technique to distinguish HCA subtypes remains controversial. The aim of this study was to investigate the expression of hepatocyte transporters (OATPB1/B3, MRP2, MRP3) in HCA subtypes, hence to understand their MRI signal intensity on HBP Gd-EOB-DTPA-enhanced MRI. Methods: By means of immunohistochemistry (IHC), we scored the expression of OATPB1/B3, MRP2 and MRP3, in resected specimens of FNH (n = 40), subtyped HCA (n = 58) and HCA with focal malignant transformation (HCA-HCC, n = 4). Results were validated on a supplementary set of FNH (n = 6), subtyped HCA (n = 17) and HCA-HCC (n = 1) with Gd-EOB-DTPA MR images. Results: All FNH showed a preserved expression of hepatocytes transporters. Beta-catenin-activated HCA (at highest risk of malignant transformation) and HCA-HCC were characterized by preserved/increased OATPB1/B3 expression (predictor of hyperintensity on HBP), as opposed to other HCA subtypes (P 

KW - hepatocellular adenoma

KW - hepatocyte transporters

KW - hepatospecific magnetic resonance imaging

KW - radio-pathological correlation

KW - b3 protein

KW - beta catenin

KW - gadolinium

KW - multidrug resistance associated protein 2

KW - multidrug resistance associated protein 3

KW - oatpb1 protein

KW - pentetic acid

KW - protein

KW - unclassified drug

KW - adult

KW - Article

KW - chronic liver disease

KW - fatty liver

KW - female

KW - human

KW - human tissue

KW - immunohistochemistry

KW - liver adenoma

KW - liver cirrhosis

KW - liver fibrosis

KW - major clinical study

KW - male

KW - malignant transformation

KW - medical history

KW - nuclear magnetic resonance imaging

KW - oral contraception

KW - protein expression

KW - sensitivity and specificity

U2 - 10.1111/liv.13964

DO - 10.1111/liv.13964

M3 - Article

VL - 39

SP - 158

EP - 167

JO - Liver International

JF - Liver International

SN - 1478-3223

IS - 1

ER -