- Research article
- Open Access
- Open Peer Review
Optimal staging system for predicting the prognosis of patients with hepatocellular carcinoma in China: a retrospective study
- Lihui Su†1,
- Tao Zhou†1,
- Zongli Zhang2,
- Xiuguo Zhang2,
- Xuting Zhi2,
- Caixia Li3,
- Qingliang Wang3,
- Chongqi Jia4,
- Wenna Shi1,
- Yanqiu Yue1,
- Yanjing Gao1Email author and
- Baoquan Cheng1Email author
© The Author(s). 2016
- Received: 14 December 2015
- Accepted: 27 June 2016
- Published: 7 July 2016
Several staging systems have been developed to evaluate patients with hepatocellular carcinoma (HCC), including the China Staging System (CS), the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system, and seventh edition; the Barcelona Clinic Liver Cancer (BCLC) staging system, and Cancer of the Liver Italian Program (CLIP) staging system. The optimal staging system for to evaluate patients in China with HCC has not been determined. This study was designed to determine the optimal staging system for predicting patient prognosis by comparing the performances of these four staging systems in a cohort of Chinese patients with HCC.
This study enrolled 307 consecutive Chinese patients with HCC in Shandong Province. The performances of the CS, TNM, BCLC, and CLIP staging systems were compared and ranked using a concordance index. Predictors of survival were identified using univariate and multivariate Cox model analyses.
The mean overall survival of the patient cohort was 12.08 ± 11.87 months. Independent predictors of survival included tumor size, number of lesions, tumor thromboses, cirrhosis, serum albumin level and serum total bilirubin level. Compared with the other three staging systems, the CS staging system showed optimal performance as an independent predictor of patient survival. The BCLC staging system showed the poorest performance; its treatment algorithm was not suitable for patients in this study.
CS was the most suitable staging system for predicting survival of patients with HCC in China.
- Hepatocellular carcinoma
- Staging system
- Independent predictors
- Overall survival
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer deaths worldwide . Approximately 55 % of patients with HCC live in China and the 5-year overall survival (OS) rate is only 7 % . Unlike other solid tumors, the prognosis and treatment options for patients with HCC depend not only on the tumor stage but also on residual liver function . Many staging systems that include both the liver cancer and residual liver function have been developed, including the Cancer of the Liver Italian Program (CLIP); the Barcelona Clinic Liver Cancer (BCLC), the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM), seventh edition and the China Staging (CS) systems [4–8].
Many clinical trials in western countries have evaluated the staging, natural history and prognosis of patients with HCC, with highly variable [9, 10]. Despite China having a greater disease burden than the rest of the world, few studies have been performed in China. Shandong Province, located in the east of China, has a high incidence of HCC. To date, the tumor staging system optimal for evaluating patients with HCC in Shandong province has not been determined. This retrospective study compared the performances of four staging systems, the CLIP, BCLC, AJCC TNM 7th edition, and CS staging systems, in patients with HCC in Shandong Province, China, who were treated at Qilu Hospital of Shandong University. This study also attempted to identify factors independently prognostic of survival in these patients.
This study was approved by the institutional ethical committee at Qilu Hospital of Shandong University. All patients or their family provided written informed consent for their clinical records to be stored in the hospital database and used for research.
Baseline information, including the results of clinical examinations, laboratory evaluations, imaging modalities (e.g. computed tomography [CT], magnetic resonance imaging [MRI] and/or ultrasonography), was collected at the time of diagnosis. OS was defined the time from the date of initial diagnosis of HCC to the date of death, last follow-up or the date of censoring (January 1, 2015), whichever came first.
HCC diagnosis was confirmed by histopathological examination of surgical samples or cytologic evaluation of needle biopsy samples (especially if mass less than 2 cm). Alternatively, a diagnosis of HCC was based on the radiologic criteria of the European Association for the Study of the Liver (EASL) [11, 12]. Based on collected data, all included patients were restaged retrospectively according to the CLIP, BCLC, AJCC TNM seventh edition, and CS staging systems.
All patients were followed up until death or January 1, 2015. Continuous variables were expressed as mean ± standard deviation (SD), and categorical as frequencies and percentage. Survival outcomes were estimated by the Kaplan–Meier method and compared by the log-rank test.
Staging systems were ranked using the concordance index (c-index), which measures the capacity of the different staging systems to stratify patients with different outcomes: the higher the c-index, the more informative the model was about patient outcomes.
Independent prognostic factors were identified through backward stepwise selection in a Cox regression model. Variables significant (p < 0.05) on univariate analysis were included in the multivariate Cox proportional hazards model. Adjusted hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) were calculated.
All statistical analyses were performed using STATA/SE version 13.1 software (Stata Corporation, College Station, TX, USA). All p-values were two-sided, and those less than 0.05 were considered statistically significant.
Mean ± SD
55.43 ± 10.69
ECOG PS, %
HBV + HCV
Child-Pugh Grade, %
Child-Pugh Score, %
Hepatic encephalopathy, %
Portal hypertension, %
Laboratory values, mean ± SD
Total bilirubin (μmol/l)
24.55 ± 50.93
38.53 ± 5.78
Prothrombin time (sec)
0.19 ± 0.80
AFP (ng/ml), %
Tumor size (mean ± SD, cm)
6.18 ± 4.04
Number of lesions, %
Lobar involvement, %
Tumor morphology, %
Vascular and/or organ invasion, %
Tumor thrombosis, %
Portal stem vein
Inferior vena cava
Hepatic vein branches
Portal vein branches
Inferior vena cava branches and Portal vein branches and/or Hepatic vein branches
Current outcomes, %
OS, mean ± SD, months
12.08 ± 11.87
Tumor staging information of the 307 patients with hepatocellular carcinoma
Baseline predictors of survival
Univariate analyses of factors independently prognostic of overall survival in the 307 patients with hepatocellular carcinoma
95 % CI
Number of lesions
hepatitis B virus
hepatitis C virus
Lymph node metastasis
Multivariate analysis of factors prognostic of overall survival in the 307 patients with hepatocellular carcinoma
95 % CI
Number of lesions
Survival comparisons among staging groups
Ranking of discriminatory ability of staging system
Ranking of staging systems by concordance indices in patients with hepatocellular carcinoma
95 % CI
The predominant etiology of HCC in patients in Shandong Province China was HBV infection. This study of factors independently prognostic of OS in this population found that tumor extent (e.g. tumor size, number of liver lesions, and tumor thromboses), hepatic function (serum total bilirubin concentration and serum albumin level), cirrhosis were independent baseline predictors of OS. Of this patient population, 68.4 % had underlying cirrhosis, which was strongly associated with OS, and 70–80 % showed histological evidence of liver cirrhosis. AFP was again of limited use in this study, because it was proven to be both not sensitive enough to identify early stage HCC and not specific enough to avoid unnecessary recall procedures, so AFP test has been dropped from the latest Western guideline for the clinical diagnosis of HCC [11–13]. We also founded that serum total bilirubin concentration, serum albumin level and greater tumor extent were related to poor prognosis variables, indicating that the long-term survival of patients with HCC was associated not only with the tumor but with liver function [3, 14–16].
The classification criteria of China staging system
Tumor size (cm) and location
single, ≤ 3
unilobar, ≤ 5
unilobar, ≤ 10; or bilobar, ≤ 5
unilobar, >10; or bilobar, > 5; any
absent; portal vein, or inferior vena cava, or biliary duct branches
A or B
portal vein, or inferior vena cava, or biliary duct stem;
A or B
This study had several potential limitations. First, it was retrospective in design. Moreover, 152 patients were lost to follow up and data were missing for 88. However, many Chinese people live in the countryside, making communication difficult. Thus, there may have been potential bias in patient selection. Secondly, this was a single-center study involving patients admitted consecutively to Qilu Hospital of Shandong University for treatment. However, our study had several strengths. Complete data were obtained from a large number of patients. Moreover, the follow-up period was relatively long, and the epidemiological characteristics of our cohort were consistent with those reported in other studies of Chinese patients with HCC [20, 21].
Of the four HCC staging systems evaluated, the CS staging system was the most informative in predicting survival for patients with HCC in Shandong Province. The poor performance of the BCLC staging system in this cohort suggests its unsuitability for evaluating Chinese patients with HCC. We also found that tumor size, number of lesions, tumor thromboses, serum total bilirubin level; albumin and cirrhosis were the accurate independent predictors of OS.
95 % CI, 95 % confidence interval; AFP, alpha-fetoprotein; AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer; c-index, concordance index; CLIP, Cancer of the Liver Italian Program; CS, China Staging System; CSLC, Chinese Society of Liver Cancer; CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; M, Distant metastasis; MRI, magnetic resonance imaging; N, Lymph node metastasis; OS, overall survival; SD, standard deviation; SE, standard error; TNM, tumor-node-metastasis
The authors thank the staff of Qilu Hospital of Shandong University for help with the clinical data. We thank nurses Min Zhang, Aifang Zhu, and Jianrong Bai for their contributions to care and referral of patients as well as data acquisition.
Tackling key problems in science and technology of Shandong province and the Fundamental Research Funds of Shandong University (Number: 2009GG20002039; 2014QLKY10) supported this research in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Availability of data and materials
All datasets on which the conclusions of the manuscript rely to be presented in additional supporting files in excel table format.
BQC, YJG, TZ and LHS conceived the trial concept and designed the protocol. LHS acquired data. CQJ is responsible for analysis and interpretation of data. LHS, BQC, ZT, WNS, and YQY are responsible for drafting of the manuscript. YJG, TZ, LHS, XGZ, XTZ, ZLZ, CXL, QLW, WNS and YQY are responsible for clinical work, and administrative and technical support. BQC is the principle investigator and responsible for trial conduct and critical revisions of the manuscript. All authors aided in drafting the manuscript. All authors have read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
All patients or their family provided written informed consent for their clinical records to be stored in the hospital database and used for research, and consent to publish.
Ethics approval and consent to participate
This study was approved by the institutional ethical committee at Qilu Hospital of Shandong University (Number: 2014042).
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- Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.View ArticlePubMedGoogle Scholar
- El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–50.View ArticlePubMedGoogle Scholar
- Abou-Alfa GK. Hepatocellular carcinoma: Molecular biology and therapy. Semin Oncol. 2006;33:S79–83.View ArticlePubMedPubMed CentralGoogle Scholar
- A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology.1998;28:751-5.Google Scholar
- Maida M, Orlando E, Cammà C, Cabibbo G. Staging systems of hepatocellular carcinoma: A review of literature. World J Gastroenterol. 2014;20:4141–50.View ArticlePubMedPubMed CentralGoogle Scholar
- Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–38.View ArticlePubMedGoogle Scholar
- Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
- Qu Q, Rui JA, Wang SB, Chen SG, Zhou L, Han K, et al. Comparison of different clinical staging systems for hepatocellular carcinoma. Zhonghua zhong liu za zhi [Chinese journal of oncology]. 2006;28:155–8.Google Scholar
- Cho YK, Chung JW, Kim JK, Ahn YS, Kim MY, Park YO, et al. Comparison of 7 staging systems for patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Cancer. 2008;112:352–61.View ArticlePubMedGoogle Scholar
- op den Winkel M, Nagel D, Sappl J, op den Winkel P, Lamerz R, Zech CJ, et al. Prognosis of patients with hepatocellular carcinoma. Validation and ranking of established staging-systems in a large western HCC-cohort. PLoS ONE. 2012;7:e45066.View ArticleGoogle Scholar
- Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. EASL Panel of Experts on HCC. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421–30.View ArticlePubMedGoogle Scholar
- Bruix J, Sherman M. Management of Hepatocellular Carcinoma. Hepatology. 2005;42:1208–35.View ArticlePubMedGoogle Scholar
- Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.View ArticlePubMedPubMed CentralGoogle Scholar
- Hsu CY, Hsia CY, Huang YH, Su CW, Lin HC, Pai JT, et al. Comparison of surgical resection and transarterial chemoembolization for hepatocellular carcinoma beyond the Milan criteria: a propensity score analysis. Ann Surg Oncol. 2012;19:842–9.View ArticlePubMedGoogle Scholar
- Zhou L, Rui JA, Wang SB, Chen SG, Qu Q. Risk factors of poor prognosis and portal vein tumor thrombosis after curative resection of solitary hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2013;12:68–73.View ArticlePubMedGoogle Scholar
- Huitzil-Melendez FD, Capanu M, O’Reilly EM, Duffy A, Gansukh B, Saltz LL, et al. Advanced hepatocellular carcinoma: which staging systems best predict prognosis? J Clin Oncol. 2010;28:2889–95.View ArticlePubMedPubMed CentralGoogle Scholar
- Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.View ArticlePubMedGoogle Scholar
- Cillo U, Vitale A, Grigoletto F, Farinati F, Brolese A, Zanus G, et al. Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol. 2006;44:723–31.View ArticlePubMedGoogle Scholar
- Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su GL, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology. 2005;41:707–16.View ArticlePubMedGoogle Scholar
- Chan SL, Mo FK, Johnson PJ, Liem GS, Chan TC, Poon MC, et al. Prospective validation of the Chinese University Prognostic Index and comparison with other staging systems for hepatocellular carcinoma in an Asian population. J Gastroenterol Hepatol. 2011;26:340–7.View ArticlePubMedGoogle Scholar
- Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL, et al. 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;94:1760–9.View ArticlePubMedGoogle Scholar