Skip to main content

Advertisement

SpringerLink
Log in

Staging systems of hepatocellular carcinoma: A review

  • Review Article
  • Published:
Indian Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Staging of hepatocellular carcinoma (HCC) is necessary for guiding prognostication, management, and research purposes that further aid in the improvement of existing clinical and epidemiological health services. Though there are some new staging systems for HCC developed in different parts of the world, there is no globally accepted staging system that allows for comparison of current management protocols among heterogeneous populations. In this review, we discuss the evolution and applicability in clinical practice of different clinical staging systems of HCC—Okuda, CLIP (Cancer of the Liver Italian Program) score, MESIAH (Model to Estimate Survival In Ambulatory HCC patients) score, ITA.LI.CA (Italian Liver Cancer) score, BCLC (Barcelona Clinic Liver Cancer) staging, HKLC (Hong Kong Liver Cancer) staging, and the Alberta algorithm. This review aims to highlight the main criteria for assessing the prognosis of HCC that these different staging systems take into account, their strengths and limitations for use in modern clinical practice. Despite the limitations of the BCLC staging system, it remains the most validated and reliable system for prognostication. However, there is a need to update the BCLC staging system to include recent data on locoregional and systemic therapies for HCC, expanded criteria for transplantation, and systemic therapy for hepatitis C infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Article  CAS  PubMed  Google Scholar 

  2. El-Serag HB, Lau M, Eschbach K, Davila J, Goodwin J. Epidemiology of hepatocellular carcinoma in Hispanics in the United States. Arch Intern Med. 2007;167:1983–9.

    Article  PubMed  Google Scholar 

  3. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.

    Article  PubMed  Google Scholar 

  4. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127 5 Suppl 1:S5–16.

  5. Acharya SK. Epidemiology of hepatocellular carcinoma in India. J Clin Exp Hepatol. 2014;4 Suppl 3:S27–33.

  6. Bhala N, Angulo P, van der Poorten D, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011;54:1208–16.

  7. Mahady SE, George J. The future liver of the Asia pacific: fatter and firmer from more fructose and fortune? J Clin Exp Hepatol. 2013;3:106–13.

    Article  PubMed  Google Scholar 

  8. Das K, Das K, Mukherjee PS, et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology. 2010;51:1593–602.

  9. Amarapurkar D, Kamani P, Patel N, et al. Prevalence of non-alcoholic fatty liver disease: population based study. Ann Hepatol. 2007;6:161–3.

    Article  PubMed  Google Scholar 

  10. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.

    Article  CAS  PubMed  Google Scholar 

  11. Kumar A, Acharya SK, Singh SP, et al. The Indian National Association for Study of the Liver (INASL) consensus on prevention, diagnosis and management of hepatocellular carcinoma in India: the Puri recommendations. J Clin Exp Hepatol. 2014;4 Suppl 3:S3–26.

  12. Sherman M. Staging for hepatocellular carcinoma: an embarrassment of riches. J Hepatol. 2016;64:535–6.

    Article  PubMed  Google Scholar 

  13. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–9.

  14. Chan SC, Fan ST. Selection of patients of hepatocellular carcinoma beyond the Milan criteria for liver transplantation. Hepatobiliary Surg Nutr. 2013;2:84–8.

    PubMed  PubMed Central  Google Scholar 

  15. Shah SR. Living-related transplantation for hepatocellular carcinoma: how far do we travel beyond Milan? Indian J Gastroenterol. 2008;27:139–41.

    PubMed  Google Scholar 

  16. Gervais DA, Arellano RS. Percutaneous tumor ablation for hepatocellular carcinoma. AJR Am J Roentgenol. 2011;197:789–94.

    Article  PubMed  Google Scholar 

  17. Daher S, Massarwa M, Benson AA, Khoury T. Current and future treatment of hepatocellular carcinoma: an updated comprehensive review. J Clin Transl Hepatol. 2018;6:69–78.

    PubMed  Google Scholar 

  18. Sangro B, Iñarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J Hepatol. 2012;56:464–73.

    Article  PubMed  Google Scholar 

  19. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

  20. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.

  21. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.

  22. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.

  23. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kelley RK, Verslype C, Cohn AL, et al. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol. 2017;28:528–34.

  25. Zhu AX, Galle PR, Kudo M, et al. A study of ramucirumab (LY3009806) versus placebo in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein (REACH-2). J Clin Oncol. 2018;364 Suppl:TPS538.

  26. Papatheodoridis GV, Dalekos GN, Yurdaydin C, et al. Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir. J Hepatol. 2015;62:363–70.

  27. Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology. 2015;149:649–59.

  28. David D, Raghavendran A, Goel A, et al. Risk factors for non-alcoholic fatty liver disease are common in patients with non-B non-C hepatocellular carcinoma in India. Indian J Gastroenterol. 2017;36:373–9.

  29. Eshraghian A. Current and emerging pharmacological therapy for non-alcoholic fatty liver disease. World J Gastroenterol. 2017;23:7495–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–90.

    Article  CAS  PubMed  Google Scholar 

  31. Vauthey JN, Dixon E, Abdalla EK, et al. Pretreatment assessment of hepatocellular carcinoma: expert consensus statement. HPB (Oxford). 2010;12:289–99.

  32. Munene G, Vauthey J-N, Dixon E. Summary of the 2010 AHPBA/SSO/SSAT consensus conference on HCC. Int J Hepatol. 2011;2011:565060.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–38.

    Article  CAS  PubMed  Google Scholar 

  34. Llovet JM, Fuster J, Bruix J, Barcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004;102 Suppl 1:S115–20.

  35. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.

  36. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology. 1990;99:1401–7.

  37. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–17.

    Article  PubMed  Google Scholar 

  38. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150:835–53.

    Article  PubMed  Google Scholar 

  39. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.

    Article  PubMed  Google Scholar 

  40. Yang JD, Kim WR, Park KW, et al. Model to estimate survival in ambulatory patients with hepatocellular carcinoma. Hepatology. 2012;56:614–21.

    Article  PubMed  Google Scholar 

  41. European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.

    Article  Google Scholar 

  42. Llovet JM, Bruix J. Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology. 2000;32:679–80.

    Article  CAS  PubMed  Google Scholar 

  43. El-Fattah MA. Hepatocellular carcinoma biology predicts survival outcome after liver transplantation in the USA. Indian J Gastroenterol. 2017;36:117–25.

    Article  PubMed  Google Scholar 

  44. Kousik V, Promila P, Verma R, Gupta A. Role of yttrium-90 in the management of unresectable hepatocellular carcinoma and hepatic metastases. Indian J Gastroenterol. 2016;35:179–85.

    Article  PubMed  Google Scholar 

  45. McDevitt JL, Alian A, Kapoor B, et al. Single-center comparison of overall survival and toxicities in patients with infiltrative hepatocellular carcinoma treated with Yttrium-90 radioembolization or drug-eluting embolic transarterial chemoembolization. J Vasc Interv Radiol. 2017;28:1371–7.

    Article  PubMed  Google Scholar 

  46. Kim HY, Park JW. Clinical trials of combined molecular targeted therapy and locoregional therapy in hepatocellular carcinoma: past, present, and future. Liver Cancer. 2014;3:9–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim HY, Park JW, Joo J, et al. Severity and timing of progression predict refractoriness to transarterial chemoembolization in hepatocellular carcinoma. J Gastroenterol Hepatol. 2012;27:1051–6.

  48. Kalva SP, Pectasides M, Liu R, et al. Safety and effectiveness of chemoembolization with drug-eluting beads for advanced-stage hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2014;37:381–7.

    Article  PubMed  Google Scholar 

  49. Bolondi L, Burroughs A, Dufour JF, et al. Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis. 2012;32:348–59.

    CAS  PubMed  Google Scholar 

  50. Santambrogio R, Salceda J, Costa M, et al. External validation of a simplified BCLC staging system for early hepatocellular carcinoma. Eur J Surg Oncol. 2013;39:850–7.

    Article  CAS  PubMed  Google Scholar 

  51. Burak KW, Kneteman NM. An evidence-based multidisciplinary approach to the management of hepatocellular carcinoma (HCC): the Alberta HCC algorithm. Can J Gastroenterol. 2010;24:643–50.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology. 2014;146:1691–700.e1693.

    Article  PubMed  Google Scholar 

  53. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer. 1985;56:918–28.

  54. 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.

  55. Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg. 1964;1:1–85.

    CAS  PubMed  Google Scholar 

  56. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646–9.

    Article  CAS  PubMed  Google Scholar 

  57. Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) Investigators. Hepatology. 2000;31:840–5.

  58. Farinati F, Vitale A, Spolverato G, et al. Development and validation of a new prognostic system for patients with hepatocellular carcinoma. PLoS Med. 2016;13:e1002006.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Parikh ND, Singal AG. The ITA.LI.CA staging system: a novel staging system for hepatocellular carcinoma. PLoS Med. 2016;13:e1002005.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Cillo U, Bassanello M, Vitale A, et al. The critical issue of hepatocellular carcinoma prognostic classification: which is the best tool available? J Hepatol. 2004;40:124–31.

  61. Sirivatanauksorn Y, Tovikkai C. Comparison of staging systems of hepatocellular carcinoma. HPB Surg. 2011;2011:1–7.

    Article  Google Scholar 

  62. Memon K, Kulik LM, Lewandowski RJ, et al. Comparative study of staging systems for hepatocellular carcinoma in 428 patients treated with radioembolization. J Vasc Interv Radiol. 2014;25:1056–66.

  63. Liu PH, Hsu CY, Hsia CY. Prognosis of hepatocellular carcinoma: assessment of eleven staging systems. J Hepatol. 2016;64:601–8.

    Article  CAS  PubMed  Google Scholar 

  64. Su L, Zhou T, Zhang Z, et al. Optimal staging system for predicting the prognosis of patients with hepatocellular carcinoma in China: a retrospective study. BMC Cancer. 2016;16:424.

  65. Chen ZH, Hong YF, Lin J, et al. Validation and ranking of seven staging systems of hepatocellular carcinoma. Oncol Lett. 2017;14:705–14.

  66. Li JW, Goh BG, Chang PE, Tan CK. Barcelona Clinic Liver Cancer outperforms Hong Kong Liver Cancer staging of hepatocellular carcinoma in multiethnic Asians: real-world perspective. World J Gastroenterol. 2017;23:4054–63.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Zhou ZR, Liu M, Lu HR, Li YF, Liang SX, Zhang CY. Validation of different staging systems for hepatocellular carcinoma in a cohort of 249 patients undergoing radiotherapy. Oncotarget. 2017;8:46523–31.

    PubMed  PubMed Central  Google Scholar 

  68. Wallace MC, Huang Y, Preen DB, et al. HKLC triages more hepatocellular carcinoma patients to curative therapies compared to BCLC and is associated with better survival. Dig Dis Sci. 2017;62:2182–92.

  69. Sohn JH, Duran R, Zhao Y, et al. Validation of the Hong Kong Liver Cancer Staging System in determining prognosis of the North American patients following intra-arterial therapy. Clin Gastroenterol Hepatol. 2017;15:746–755 e744.

  70. Selby LK, Tay RX, Woon WW, et al. Validity of the Barcelona Clinic Liver Cancer and Hong Kong Liver Cancer staging systems for hepatocellular carcinoma in Singapore. J Hepatobiliary Pancreat Sci. 2017;24:143–52.

    Article  PubMed  Google Scholar 

  71. Parikh ND, Scaglione S, Li Y, et al. A comparison of staging systems for hepatocellular carcinoma in a multicenter US cohort. Clin Gastroenterol Hepatol. 2018;16:781–2.

  72. Chiba T, Suzuki E, Saito T, et al. Biological features and biomarkers in hepatocellular carcinoma. World J Hepatol. 2015;7:2020–8.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Chan SL, Yeo W. Targeted therapy of hepatocellular carcinoma: present and future. J Gastroenterol Hepatol. 2012;27:862–72.

    Article  CAS  PubMed  Google Scholar 

  74. Leary RJ, Sausen M, Kinde I, et al. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med. 2012;4:162ra154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Akai H, Yasaka K, Kunimatsu A, et al. Predicting prognosis of resected hepatocellular carcinoma by radiomics analysis with random survival forest. Diagn Interv Imaging. 2018;99:643–51.

Download references

Author information

Authors and Affiliations

  1. Division of Vascular and Interventional Radiology, Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Sreeshma Tellapuri, Patrick D. Sutphin & Sanjeeva P. Kalva

  2. Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Muhammad S. Beg

  3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Amit G. Singal

Authors
  1. Sreeshma Tellapuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick D. Sutphin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muhammad S. Beg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amit G. Singal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sanjeeva P. Kalva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sreeshma Tellapuri.

Ethics declarations

Conflict of interest

ST, PDS, MSB, AGS, and SPK declare that they have no conflict of interest.

Disclaimer

The authors are solely responsible for the data and the content of the paper. In no way the Honorary Editor-in-Chief, Editorial Board Members, or the printer/publishers are responsible for the results/findings and content of this article.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tellapuri, S., Sutphin, P.D., Beg, M.S. et al. Staging systems of hepatocellular carcinoma: A review. Indian J Gastroenterol 37, 481–491 (2018). https://doi.org/10.1007/s12664-018-0915-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12664-018-0915-0

Keywords

Search

Navigation