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Hypervascular hepatocellular carcinomas showing hyperintensity on hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging: a possible subtype with mature hepatocyte nature

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Japanese Journal of Radiology Aims and scope Submit manuscript

Abstract

Purpose

We evaluated molecular features of hypervascular hepatocellular carcinoma (HCC) that shows iso- or hyperintensity (hyperintense HCC) in the hepatobiliary phase (HB phase) of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI).

Materials and methods

We investigated 89 surgically resected cases. Patients were divided into two groups according to the signal intensity in the HB phase of EOB-MRI: hyperintense HCCs (n = 18) and hypointense HCCs (n = 71). We performed immunohistochemical staining for uptake transporter of gadoxetic acid: organic anion transporter polypeptides (OATP8); tumor markers: alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II); hepatic stem cell markers: epithelial cell adhesion molecule (EpCAM), cytokeratin 19 (CK19), and neural cell adhesion molecule (NCAM); biliary marker: CK7; hepatocyte marker: hepatocyte paraffin 1 (HepPar1); markers of HCC differentiation: glypican-3; signaling: beta-catenin, and the respective grade was semiquantitatively determined.

Results

Histopathologically, hyperintense HCCs showed significantly weaker expression of AFP (p < 0.05), PIVKA-II (p < 0.01), EpCAM (p < 0.005), glypican-3 (p < 0.005) relative to the hypointense HCCs, whereas OATP8 (p < 0.0001), HepPar1 (p < 0.05), and beta-catenin (p < 0.001) were overexpressed in hyperintense HCCs compared with hypointense HCCs.

Conclusion

Hyperintense HCC expressed OATP8 and showed a feature of mature hepatocytes with a weak expression of stem cell characteristics immunohistochemically. In addition, this type of HCC demonstrated a weaker expression of the poorer prognosis markers including, AFP, PIVKA-II, EpCAM, CK19, and glypican-3.

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Abbreviations

MR:

Magnetic resonance

EOB-MRI:

Gadoxetic acid-enhanced magnetic resonance imaging

HB phase:

Hepatobiliary phase

HCC:

Hepatocellular carcinoma

OATP:

Organic anion transporter polypeptides

HNF:

Hepatocyte nuclear factor

AFP:

Alpha-fetoprotein

PIVKA-II:

Protein induced by vitamin K absence or antagonist II

NCAM:

Neural cell adhesion molecule

HepPar1:

Hepatocyte paraffin 1

References

  1. Vogl T, Kümmel S, Hammerstingl R, Schellenbeck M, Schumacher G, Balzer T, et al. Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA. Radiology. 1996;200(1):59–67.

    PubMed  CAS  Google Scholar 

  2. Bluemke D, Sahani D, Amendola M, Balzer T, Breuer J, Brown J, et al. Efficacy and safety of MR imaging with liver-specific contrast agent: U.S. multicenter phase III study. Radiology. 2005;237(1):89–98.

    Article  PubMed  Google Scholar 

  3. Reimer P, Schneider G, Schima W. Hepatobiliary contrast agents for contrast-enhanced MRI of the liver: properties, clinical development and applications. Eur Radiol. 2004;14(4):559–78.

    Article  PubMed  Google Scholar 

  4. Schuhmann-Giampieri G, Schmitt-Willich H, Press W, Negishi C, Weinmann H, Speck U. Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system. Radiology. 1992;183(1):59–64.

    PubMed  CAS  Google Scholar 

  5. Reimer P, Rummeny E, Shamsi K, Balzer T, Daldrup H, Tombach B, et al. Phase II clinical evaluation of Gd-EOB-DTPA: dose, safety aspects, and pulse sequence. Radiology. 1996;199(1):177–83.

    PubMed  CAS  Google Scholar 

  6. Saito K, Kotake F, Ito N, Ozuki T, Mikami R, Abe K, et al. Gd-EOB-DTPA enhanced MRI for hepatocellular carcinoma: quantitative evaluation of tumor enhancement in hepatobiliary phase. Magn Reson Med Sci. 2005;4(1):1–9.

    Article  PubMed  Google Scholar 

  7. Huppertz A, Haraida S, Kraus A, Zech C, Scheidler J, Breuer J, et al. Enhancement of focal liver lesions at gadoxetic acid-enhanced MR imaging: correlation with histopathologic findings and spiral CT—initial observations. Radiology. 2005;234(2):468–78.

    Article  PubMed  Google Scholar 

  8. Kitao A, Zen Y, Matsui O, Gabata T, Kobayashi S, Koda W, Kozaka K, Yoneda N, et al. Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging—correlation with molecular transporters and histopathologic features. Radiology. 2010;256(3):817–26.

    Article  PubMed  Google Scholar 

  9. Narita M, Hatano E, Arizono S, Miyagawa-Hayashino A, Isoda H, Kitamura K, Taura K, Yasuchika K, et al. Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol. 2009;44(7):793–8.

    Article  PubMed  CAS  Google Scholar 

  10. Vavricka SR, Jung D, Fried M, Grutzner U, Meier PJ, Kullak-Ublick GA. The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. J Hepatol. 2004;40(2):212–8.

    Article  PubMed  CAS  Google Scholar 

  11. Jung D, Hagenbuch B, Gresh L, Pontoglio M, Meier PJ, Kullak-Ublick GA. Characterization of the human OATP-C (SLC21A6) gene promoter and regulation of liver-specific OATP genes by hepatocyte nuclear factor 1 alpha. J Biol Chem. 2001;276(40):37206–14.

    Article  PubMed  CAS  Google Scholar 

  12. Tsuboyama T, Onishi H, Kim T, Akita H, Hori M, Tatsumi M, et al. Hepatocellular carcinoma: hepatocyte-selective enhancement at gadoxetic acid-enhanced MR imaging—correlation with expression of sinusoidal and canalicular transporters and bile accumulation. Radiology. 2010;255(3):824–33.

    Article  PubMed  Google Scholar 

  13. Kitao A, Matsui O, Yoneda N, Kozaka K, Kobayashi S, Koda W, et al. Hypervascular hepatocellular carcinoma: correlation between biologic features and signal intensity on gadoxetic acid-enhanced MR images. Radiology. 2012;265(3):780–9.

    Article  PubMed  Google Scholar 

  14. Di Bisceglie AM. Issues in screening and surveillance for hepatocellular carcinoma. Gastroenterology. 2004;127(5 Suppl 1):S104–7.

    Article  PubMed  Google Scholar 

  15. Inoue S, Nakao A, Harada A, Nonami T, Takagi H. Clinical significance of abnormal prothrombin (DCP) in relation to postoperative survival and prognosis in patients with hepatocellular carcinoma. Am J Gastroenterol. 1994;89(12):2222–6.

    PubMed  CAS  Google Scholar 

  16. Okuda H, Nakanishi T, Takatsu K, Saito A, Hayashi N, Yamamoto M, et al. Clinicopathologic features of patients with hepatocellular carcinoma seropositive for alpha-fetoprotein-L3 and seronegative for des-gamma-carboxy prothrombin in comparison with those seropositive for des-gamma-carboxy prothrombin alone. J Gastroenterol Hepatol. 2002;17(7):772–8.

    Article  PubMed  CAS  Google Scholar 

  17. Miyaaki H, Nakashima O, Kurogi M, Eguchi K, Kojiro M. Lens culinaris agglutinin-reactive alpha-fetoprotein and protein induced by vitamin K absence II are potential indicators of a poor prognosis: a histopathological study of surgically resected hepatocellular carcinoma. J Gastroenterol. 2007;42(12):962–8.

    Article  PubMed  CAS  Google Scholar 

  18. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006;12(4):410–6.

    Article  PubMed  CAS  Google Scholar 

  19. Schmelzer E, Wauthier E, Reid LM. The phenotypes of pluripotent human hepatic progenitors. Stem Cells. 2006;24(8):1852–8.

    Article  PubMed  CAS  Google Scholar 

  20. Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL, et al. Human hepatic stem cells from fetal and postnatal donors. J Exp Med. 2007;204(8):1973–87.

    Article  PubMed  CAS  Google Scholar 

  21. Dan YY, Riehle KJ, Lazaro C, Teoh N, Haque J, Campbell JS, et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci U S A. 2006;103(26):9912–7.

    Article  PubMed  CAS  Google Scholar 

  22. Zhou H, Rogler LE, Teperman L, Morgan G, Rogler CE. Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver. Hepatology. 2007;45(3):716–24.

    Article  PubMed  Google Scholar 

  23. Filmus J. The contribution of in vivo manipulation of gene expression to the understanding of the function of glypicans. Glycoconj J. 2002;19(4-5): 319-323 5142016 [pii].

    Google Scholar 

  24. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843–50.

    Article  PubMed  CAS  Google Scholar 

  25. Heppner G. Tumor heterogeneity. Cancer Res. 1984;44(6):2259–65.

    PubMed  CAS  Google Scholar 

  26. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31(4):339–46.

    Article  PubMed  CAS  Google Scholar 

  27. Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res. 2007;67(22):10831–9.

    Article  PubMed  CAS  Google Scholar 

  28. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008;68(5):1451–61.

    Article  PubMed  CAS  Google Scholar 

  29. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136(3):1012–24.

    Article  PubMed  CAS  Google Scholar 

  30. Funayama N, Fagotto F, McCrea P, Gumbiner BM. Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling. J Cell Biol. 1995;128(5):959–68.

    Article  PubMed  CAS  Google Scholar 

  31. Suzuki T, Yano H, Nakashima Y, Nakashima O, Kojiro M. Beta-catenin expression in hepatocellular carcinoma: a possible participation of beta-catenin in the dedifferentiation process. J Gastroenterol Hepatol. 2002;17(9):994–1000.

    Article  PubMed  CAS  Google Scholar 

  32. Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999;155(3):703–10.

    Article  PubMed  CAS  Google Scholar 

  33. Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol. 2000;157(3):763–70.

    Article  PubMed  CAS  Google Scholar 

  34. Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC. Expression of mutant nuclear beta-catenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good prognosis. J Pathol. 2001;193(1):95–101.

    Article  PubMed  CAS  Google Scholar 

  35. Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 2001;120(7):1763–73.

    Article  PubMed  CAS  Google Scholar 

  36. Hailfinger S, Jaworski M, Braeuning A, Buchmann A, Schwarz M. Zonal gene expression in murine liver: lessons from tumors. Hepatology. 2006;43(3):407–14.

    Article  PubMed  CAS  Google Scholar 

  37. Vander Borght S, Libbrecht L, Blokzijl H, Faber KN, Moshage H, Aerts R, et al. Diagnostic and pathogenetic implications of the expression of hepatic transporters in focal lesions occurring in normal liver. J Pathol. 2005;207(4):471–82.

    Article  PubMed  CAS  Google Scholar 

  38. Rebouissou S, Couchy G, Libbrecht L, Balabaud C, Imbeaud S, Auffray C, et al. The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J Hepatol. 2008;49(1):61–71.

    Article  PubMed  CAS  Google Scholar 

  39. Sekine S, Ogawa R, Ojima H, Kanai Y. Expression of SLCO1B3 is associated with intratumoral cholestasis and CTNNB1 mutations in hepatocellular carcinoma. Cancer Sci. 2011;102(9):1742–7.

    Article  PubMed  CAS  Google Scholar 

  40. Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H, et al. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci. 2003;94(10):851–7.

    Article  PubMed  CAS  Google Scholar 

  41. Wu P, Fang J, Lau V, Lai C, Lo C, Lau J. Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am J Pathol. 1996;149(4):1167–75.

    PubMed  CAS  Google Scholar 

  42. Yang X, Xu Y, Shi G, Fan J, Zhou J, Ji Y, et al. Cytokeratin 10 and cytokeratin 19: predictive markers for poor prognosis in hepatocellular carcinoma patients after curative resection. Clin Cancer Res. 2008;14(12):3850–9.

    Article  PubMed  CAS  Google Scholar 

  43. Shirakawa H, Suzuki H, Shimomura M, Kojima M, Gotohda N, Takahashi S, et al. Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma. Cancer Sci. 2009;100(8):1403–7.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

No financial support was received for this study.

Conflict of interest

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Authors and Affiliations

  1. Department of Radiology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, 920-8640, Japan

    Norihide Yoneda, Osamu Matsui, Azusa Kitao, Kazuto Kozaka, Wataru Koda, Satoshi Kobayashi & Toshifumi Gabata

  2. Department of Diagnostic Pathology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, 920-8640, Japan

    Hiroko Ikeda

  3. Department of Human Pathology, Kanazawa University Graduate School of Medicine, 13-1 Takaramachi, Kanazawa, 920-8640, Japan

    Yasuni Nakanuma

  4. Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, 5-53 Fudegasaki-cho, Tennnoji-ku, Osaka, 543-8555, Japan

    Ryuichi Kita

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  1. Norihide Yoneda
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Correspondence to Norihide Yoneda.

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Yoneda, N., Matsui, O., Kitao, A. et al. Hypervascular hepatocellular carcinomas showing hyperintensity on hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging: a possible subtype with mature hepatocyte nature. Jpn J Radiol 31, 480–490 (2013). https://doi.org/10.1007/s11604-013-0224-6

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  • DOI: https://doi.org/10.1007/s11604-013-0224-6

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