Objectives: The conventional Japan Integrated Staging (c-JIS) score has been reported to effectively stratify patients with hepatocellular carcinoma (HCC). Recently, two new staging systems, the biomarker-combined JIS (bm-JIS) score and the BALAD score, have been proposed. Both staging systems include three tumor markers: α-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP and des-γ-carboxy prothrombin specific for HCC. The aim of this study is to evaluate the performance of these three staging systems. Methods: A total of 1,173 HCC patients were included in this study. The stratification ability and prognostic predictive power were compared between these three staging systems. Results: These three staging systems effectively predicted the patient survival. When accounting for the best prognostic subgroup of each staging systems (i.e. score of 0), there were significant differences between the bm-JIS score and the BALAD score and, likewise, between the c-JIS score and the BALAD score. The likelihood ratio χ2 test showed the highest value and the Akaike information criterion value was lowest in the bm-JIS score. Conclusions: The bm-JIS score showed good stratification ability and was thus demonstrated to be a better predictor of the prognosis than the c-JIS score and the BALAD score, especially for the patients with a good prognosis.

Keywords:
Japan Integrated Staging score, Biomarker-combined Japan Integrated Staging score, BALAD score, α-Fetoprotein, Lens culinaris agglutinin-reactive α-fetoprotein fraction, Des-γ-carboxy prothrombin
1.
Oka H, Tamori A, Kuroki T, et al: Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 1994;19:61–66.
2.
Ikeda K, Saitoh S, Koida I, et al: A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993;18:47–53.
3.
Tsukuma H, Hiyama T, Tanaka S, et al: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797–1801
4.
Aoyagi Y, Isokawa O, Suda T, Watanabe M, Suzuki Y, Asakura H: Fucosylation index of alpha-fetoprotein as a possible prognostic indicator in patients with hepatocellular carcinoma. Cancer 1998;83:2076–2082.
5.
Santon C, Taylor R, Wallin R: Processing of prothrombin in the secretory pathway. Biochem J 1991;277:59–65.
6.
Taketa K, Sekiya C, Namiki N, et al: Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions. Gastroenterology 1990;99:508–518.
7.
Liebman HA, Furie BC, Tong MJ, et al: Des-gamma-carboxy (abnormal) prothrombin as a serum marker of patients with hepatocellular carcinoma. N Engl J Med 1984;310:1427–1431.
8.
Fujiyama S, Tanaka M, Maeda S, et al: Tumor markers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma. Oncology 2002;62:S57–S63.
9.
Kudo M, Okanoue T: Management of hepatocellular carcinoma in Japan: consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology 2007;72:S2–S15.
10.
Di Bisceglie AM, Hoofnagle JH: Elevations in serum alpha-fetoprotein levels in patients with chronic hepatitis B. Cancer 1989;64:2117–2120.
11.
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.
12.
Kobayashi M, Kuroiwa T, Suda T, Tamura Y, Kawai H, Igarashi M, Fukuhara Y, Aoyagi Y: Fucosylated fraction of alpha-fetoprotein, L3, as a useful prognostic factor in patients with hepatocellular carcinoma with special reference to low concentrations of serum alpha-fetoprotein. Hepatol Res 2007;37:914–922.
13.
Suehiro T, Sugimachi K, Matsumata T, et al: Protein induced by vitamin K absence or antagonist II as a prognostic marker in hepatocellular carcinoma. Comparison with alpha-fetoprotein. Cancer 1994;73:2464–2471.
14.
Koike Y, Shiratori Y, Sato S, et al: Des-gamma-carboxy prothrombin as a useful predisposing factor for the development of portal venous invasion in patients with hepatocellular carcinoma: a prospective analysis of 227 patients. Cancer 2001;91:561–569.
15.
Toyoda H, Kumada T, Kiriyama S, Sone Y, Tanikawa M, Hisanaga Y, Yamaguchi A, Isogai M, Kaneoka Y, Washizu J: Prognostic significance of simultaneous measurement of three tumor markers in patients with hepatocellular carcinoma. Clin Gastroenterol Hepatol 2006;4:111–117.
16.
Tateishi R, Shiina S, Yoshida H, Teratani T, Obi S, Yamasaki N, Yoshida H, Akamatsu M, Kawabe T, Omata M: Prediction of recurrence of hepatocellular carcinoma after curative ablation using three tumor markers. Hepatology 2006;44:1518–1527.
17.
Kudo M, Chung H, Osaki Y: Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol 2003;38:207–215.
18.
Liver Cancer Study Group of Japan: The General Rules for the Clinical and Pathological Study of Primary Liver Cancer (in Japanese), ed 4. Tokyo, Kanehara, 2000.
19.
Liver Cancer Study Group of Japan: The General Rules for the Clinical and Pathological Study of Primary Liver Cancer, ed 2. Tokyo, Kanehara, 2003.
20.
Kudo M, Chung H, Haji S, Osaki Y, Oka H, Seki T, Kasugai H, Sasaki Y, Matsunaga T: Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score. Hepatology 2004;40:1396–1405.
21.
Toyoda H, Kumada T, Kiriyama S, et al: Comparison of usefulness of three staging systems for hepatocellular carcinoma (CLIP, BCLC, JIS) in Japan. Am J Gastroenterol 2005;100:1764–1771.
22.
Chung H, Kudo M, Takahashi S, Hagiwara S, Sakaguchi Y, Inoue T, Minami Y, Ueshima K, Fukunaga T, Matsunaga T: Comparison of three current staging systems for hepatocellular carcinoma: Japan integrated staging score, new Barcelona Clinic Liver Cancer staging classification, and Tokyo score. J Gastroenterol Hepatol 2008;23:445–452.
23.
A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751–755.
24.
Chevret S, Trinchet JC, Mathieu D, Rached AA, Beaugrand M, Chastang C: A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire. J Hepatol 1999;31:133–141.
25.
Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL, Lau JT, Yu SC, Johnson PJ: Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 2002;94:1760–1769.
26.
Toyoda H, Kumada T, Osaki Y, Oka H, Urano F, Kudo M, Matsunaga T: Staging hepatocellular carcinoma by a novel scoring system (BALAD score) based on serum markers. Clin Gastroenterol Hepatol 2006;4:1528–1536.
27.
Kitai S, Kudo M, Minami Y, Ueshima K, Chung H, Hagiwara S, Inoue T, Ishikawa E, Takahashi S, Asakuma Y, Haji S, Osaki Y, Oka H, Seki T, Kasugai H, Sasaki Y, Matsunaga T: A new prognostic staging system for hepatocellular carcinoma: value of the biomarker combined Japan integrated staging score. Intervirology 2008;51(suppl 1):86–94.
28.
Torzilli G, Minagawa M, Takayama T, Inoue K, Hui AM, Kubota K, et al: Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy. Hepatology 1999;30:889–893.
29.
Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.
30.
Kaplan EL, Meier P: Nonparametric estimation for incomplete observation. J Am Stat Assoc 1958;53:457–481.
31.
Petro R, Pike MC: Conservation of the approximation for (0-E2)/E in the log rank test for survival data on tumor incidence data. Biometrics 1973;29:579–584.
32.
Akaike H: A new look at statistical model identification. IEEE Trans Autom Control 1974;AC-19:716–722.
33.
Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: BCLC staging classification. Semin Liver Dis 1999;19:329–337.
34.
Llovet JM, Bruix J, Fuster J, Castells A, Garcia-Valdecasas JC, Grande L, Franca A, et al: Liver transplantation for small hepatocellular carcinoma: the tumor-node metastasis classification does not have prognostic power. Hepatology 1998;27:1572–1577.
35.
Lui WY, Chiu ST, Chiu JH, Loong CC, Chau GY, King KL, Hsia CY, et al: Evaluation of a simplified staging system for prognosis of hepatocellular carcinoma. J Formos Med Assoc 1999;4:248–253.
36.
Calvet X, Bruix J, Bru C, Gines P, Vilana R, Sole M, Ayuso MC, et al: Natural history of hepatocellular carcinoma in Spain. Five years’ experience in 249 cases. J Hepatol 1990;10:311–317.
37.
Yamanaka N, Okamoto E, Toyosaka A, Mitunobu M, Fujihara S, Kato T, Fujimoto J, et al: Prognostic factors after hepatectomy for hepatocellular carcinomas. Cancer 1990;65:1104–1110.
38.
Kasahara A, Hayashi N, Fusamoto H, et al: Clinical evaluation of plasma des-gamma-carboxy prothrombin as a marker protein of hepatocellular carcinoma in patients with tumors of various sizes. Dig Dis Sci 1993;38:2170–2176.
39.
Hamamura K, Shiratori Y, Shiina S, et al: Unique clinical characteristics of patients with hepatocellular carcinoma who present with high plasma des-gamma-carboxy prothrombin and low serum alpha-fetoprotein. Cancer 2000;88:1557–1564.
40.
Kudo M: New sonographic techniques for the diagnosis and treatment of hepatocellular carcinoma. Hepatol Res 2007;37:S193–S199.
41.
Hatanaka K, Kudo M, Minami Y, Ueda T, Tatsumi C, Kitai S, Takahashi S, Inoue T, Hagiwara S, Chung H, Ueshima K, Maekawa K: Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid. Intervirology 2008;51:S61–S69.
© 2008 S. Karger AG, Basel
2008
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.