Aim: To clarify whether hepatocellular carcinoma (HCC) originates from hepatic progenitor cells and whether there is any correlation with the clinicopathologic factors of HCC, we reviewed 217 resected HCC specimens. Methods: Immunohistochemical examination of cytokeratin (CK) 7, CK19, CD34, and CD117 (c-KIT) was performed. Overexpression of CK7 and CK19 indicates differentiation from cholangiocellular and hepatic progenitor cells, while overexpression of CD34 and CD117 indicates hepatic stem cells. Fresh specimens were obtained from 20 HCC patients for mutation of the c-KIT gene. Results: CK7, CK19, and CD117 were positive in 41, 9.7, and 0.9% of the HCC specimens, respectively, and CD34 was never positive. None of the fresh HCC specimens demonstrated a c-KIT mutation. CK19 positivity was significantly correlated with a positive hepatitis B core antibody, and with poor survival outcome, and tended to correlate with poor histologic differentiation. Conclusion: These results suggest that: (i) about 10% of HCCs with typical histologic features originate from an intermediate hepatic progenitor cell, such as the canal of Hering and oval cells in the rat, or acquire the characteristics of cholangiocellular epithelium by metaplasia; (ii) HCC with typical histologic features rarely originates from hepatic stem cells, and (iii) patients with CK19-positive HCC have a poor prognosis.

Keywords:
Hepatocellular carcinoma, c-KIT, Cytokeratin, Hepatic stem cell, Hepatic progenitor cell
1.
Desmet VJ: Organizational principles; in Arias IM, Boyer JL, Chisari FV (eds): The Liver, Biology and Pathology. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 3–15.
2.
Shiojiri N, Lemire JM, Fausto N: Cell lineages and oval cell progenitors in rat liver development. Cancer Res 1991;51:2611–2620.
3.
Suzuki K, Hayashi N, Miyamoto Y, Yamamoto M, Ohkawa K, Ito Y, Sasaki Y, Yamaguchi Y, Nakase H, Noda K, Enomoto N, Arai K, Yamada Y, Yoshihara H, Tujimura T, Kawano K, Yoshikawa K, Kamada T: Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res 1996;56:3004–3009.
4.
Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, Kumar A, Crawford JM: The canals of Hering and hepatic stem cells in humans. Hepatology 1999;30:1425–1433.
5.
Blakolmer K, Jaskiewicz K, Dunsford HA, Robson SC: Hematopoietic stem cell markers are expressed by ductal plate and bile duct cells in developing human liver. Hepatology 1995;21:1510–1516.
6.
Haque S, Haruna Y, Saito K, Nalesnik MA, Atillasoy E, Thung SN, Gerber MA: Identification of bipotential progenitor cells in human liver regeneration. Lab Invest 1996;75:699–705.
7.
Haratake J, Horie A. An immunohistochemical study of sarcomatoid liver carcinomas. Cancer 1991;68:93–97.
8.
Uenishi T, Kubo S, Hirohashi K, Yamamoto T, Ogawa M, Tanaka H, Shuto T, Kinoshita H: Expression of bile duct-type cytokeratin in hepatocellular carcinoma in patients with hepatitis C virus and prior hepatitis B virus infection. Cancer Lett 2002;178:107–112.
9.
Eyken VP, Sciot R, Paterson A, Callea F, Kew MC, Desmet VJ: Cytokeratin expression in hepatocellular carcinoma: an immunohistochemical study. Hum Pathol 1988;19:562–568.
10.
Wu PC, Fang JW, Lau VK, Lai CL, Lo CK, Lau JY: Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am J Pathol 1996;149:1167–1175.
11.
Dhar DK, Ono T, Yamanoi A, Soda Y, Yamaguchi E, Rahman MA, Kohno H, Nagasue N: Serum endostatin predicts tumor vascularity in hepatocellular carcinoma. Cancer 2002;95:2188–2195.
12.
Egger JF, Coindre JM, Benhattar J, Coucke P, Guillou L: Radiation-associated synovial sarcoma: clinicopathologic and molecular analysis of two cases. Mod Pathol 2002;15:998–1004.
13.
Iwahashi N, Nagasaka T, Tezel G, Iwashita T, Asai N, Murakumo Y, Kiuchi K, Sakata K, Nimura Y, Takahashi M: Expression of glial cell line-derived neurotrophic factor correlates with perineural invasion of bile duct carcinoma. Cancer 2002;94:167–174.
14.
Kitamura Y, Hirota S, Nishida T: Gastrointestinal stromal tumors (GIST): A model for molecule-based diagnosis and treatment of solid tumors. Cancer Sci 2003;94:315–320.
15.
Kumada T, Nakano S, Takeda I, Kiriyama S, Sone Y, Hayashi K, Katoh H, Endoh T, Sassa T, Satomura S: Clinical utility of lens culinaris agglutinin-reactive alpha-fetoprotein in small hepatocellular carcinoma: special reference to imaging diagnosis. Am J Pathol 1999;30:125–130.
16.
Uenishi T, Kubo S, Hirohashi K, Tanaka H, Shuto T, Yamamoto T, Nishiguchi S: Cytokeratin-19 fragments in serum (CYFRA 21-1) as a marker in primary liver cancer. Br J Cancer 2003;88:1894–1899.
17.
Abelev GI, Eraiser TL: Cellular aspects of alpha-fetoprotein reexpression in tumors. Semin Cancer Biol 1999;9:95–107.
18.
Oka H, Tamori A, Kuroki T, Kobayashi K, Yamamoto S: Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 1994;19:61–66.
19.
Rogler LE: Selective bipotential differentiation of mouse embryonic hepatoblasts in vitro. Am J Pathol 1997;150:591–602.
20.
Evans DB, Catalano P, Charnsangavej C, Castillo CF, Fong Y, Lauwers G, MacDonald J, O’Reilly EM, Pater SE, Rich T, Vauthey JN, Washington MK, Willet CG, Wittekind C, Yeo CJ: Digestive system; in Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M (eds): AJCC Cancer Staging Handbook, ed 6. New York, Springer, 2002, pp 99–188.
21.
Desmet VJ, Gerber M, Hoofnagle HJ, Manns M, Scheuer JP: Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–1520.
22.
Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessin-ger J, Francke U, Ullrich A: Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 1987;6:3341–3351.
23.
Uenishi T, Hirohashi K, Shuto T, Tsukamoto T, Yamamoto T, Ogawa M, Kubo S, Tanaka H, Kinoshita H: Primary liver cancer with dual expression of hepatocyte and bile duct epithelial markers. Hepatogastroenterology 2002;49:1092–1094.
24.
Yamashita F, Tanaka M, Satomura S, Tanikawa K: Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinomas. Gastroenterology 1996;111:996–1001.
25.
Omori M, Evarts RP, Omori N, Hu Z, Marsden ER, Thorgeirsson SS: Expression of alpha-fetoprotein and stem cell factor/c-kit system in bile duct ligated young rats. Hepatology 1997;25:1115–1122.
26.
Roskams T, Vos RD, Von Eyken PV, Myazaki H, Van Damme B, Desmet V: Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. J Hepatol 1998;29:455–463.
27.
Tee LB, Kirilak Y, Huang WH, Smith PG, Morgan RH, Yeoh GC: Dual phenotypic expression of hepatocytes and bile ductular markers in developing and preneoplastic rat liver. Carcinogenesis 1996;17:251–259.
28.
Lemmer ER, Shepard EG, Blakolmer K, Kirsch RE, Robson SC: Isolation from human fetal liver of cells co-expressing CD34 haematopoietic stem cell and CAM 5.2 pancytokeratin markers. J Hepatol 1998;29:450–454.
29.
Libbrecht L, Desmet V, Van Damme B, Roskams T: The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol 2000;33:76–84.
30.
Hsia CC, Evarts RP, Nakatsukasa H, Marsden ER, Thorgeirsson SS: Occurrence of oval-type cells in hepatitis B virus-associated human hepatocarcinogenesis. Hepatology 1992;16:1327–1333.
31.
Tamori A, Nishiguchi S, Kubo S, Koh N, Moriyama Y, Fujimoto S, Takeda T, Shiomi S, Hirohashi K, Kinoshita H, Otani S, Kuroki T: Possible contribution to hepatocarcinogenesis of X transcript of hepatitis B virus in Japanese patients with hepatitis C virus. Hepatology 1999;29:1429–1434.
32.
Ding SJ, Li Y, Tan YX, Jiang MR, Tian B, Liu YK, Shao XX, Ye SL, Wu JR, Zeng R, Wang HY, Tang ZY, Xia QC: From proteomic analysis to clinical significance: overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics 2004;3:73–81.
33.
Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H, Tanaka S, Kaneda K, Hirohashi K: Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci 2003;94:851–857.
34.
Matsusaka S, Tsujimura T, Toyosaka A, Nakasho K, Sugihara A, Okamoto E, Uematsu K, Terada N: Role of c-kit receptor tyrosine kinase in development of oval cells in the rat 2-acetylaminofluorene/partial hepatectomy model. Hepatology 1999;29:670–676.
35.
Hornick JL , Fletcher CD: Validating immunohistochemical staining for KIT (CD117). Am J Clin Pathol 2003;119:325–327.
36.
Potti A, Ganti AK, Tendulkar K, Chitajallu S, Sholes K, Koch M, Kargas S: HER-2/neu and CD117 (C-kit) overexpression in hepatocellular and pancreatic carcinoma. Anticancer Res 2003;23:2671–2674.
37.
Chung CY, Yeh KT, Hsu NC, Chang JH, Lin JT, Horng HC, Chang CS: Expression of c-kit protooncogene in human hepatocellular carcinoma. Cancer Lett 2005;217:231–236.
© 2005 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.