Staging and prognostic factors in hepatocellular carcinoma
- Steven A Curley, MD, FACS
Steven A Curley, MD, FACS
- Professor of Surgery
- Baylor College of Medicine
- Carlton C Barnett, Jr, MD
Carlton C Barnett, Jr, MD
- Professor of Surgery
- University of Colorado at Denver
- Eddie K Abdalla, MD
Eddie K Abdalla, MD
- Professor of Surgery
- The Lebanese American University
Hepatocellular carcinoma (HCC) is an aggressive tumor that frequently occurs in the setting of chronic liver disease and cirrhosis. (See "Epidemiology and etiologic associations of hepatocellular carcinoma".) It is typically diagnosed late in the course of these diseases, and the median survival following diagnosis ranges from approximately 6 to 20 months . Available therapeutic options for HCC are dictated by the complex interplay of tumor stage and the extent of underlying liver disease.
This topic review will provide an overview of staging and prognostic scoring systems for HCC. Surgical and nonsurgical treatments for HCC are discussed separately. (See "Overview of treatment approaches for hepatocellular carcinoma".)
STAGING AND PROGNOSTIC SCORING SYSTEMS
A number of systems have been proposed to predict the prognosis for hepatocellular carcinoma (HCC), none of which has been universally adopted [2-8]. These schema variably incorporate four features that have been recognized as being important determinants of survival: the severity of underlying liver disease, the size of the tumor, extension of the tumor into adjacent structures, and the presence of metastases [2,3,9-11]; some (eg, the Hong Kong and French prognostic staging systems) also incorporate performance status [5,8]. The four most commonly used systems are the tumor, node, metastasis (TNM), Okuda and Barcelona Clinic Liver Cancer (BCLC) systems, and the Cancer of the Liver Italian Program (CLIP) score. A new, evidence-based score – the ALBI (albumin-bilirubin) grade – if independently validated, may allow more objective assessment of the severity of liver dysfunction in patients with HCC across a wide spectrum of treatments. (See 'ALBI score' below.)
Tumor, node, metastasis (TNM) staging — The current combined TNM staging classification of the American Joint Committee on Cancer (AJCC)/Union for international Cancer Control (UICC) was revised in 2010 (table 1) . Like the 2002 classification, this system recognizes the most important predictors of prognosis: the number of tumors, and the presence and extent of vascular invasion within the tumor [13,14]. However, compared with the 2002 staging system, there are some reclassification changes, primarily surrounding the better prognosis for multiple HCC versus HCC with major vascular invasion.
Five-year survival rates after complete resection for HCC, based upon the 2010 TNM staging system, are as follows :
- 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.
- 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.
- 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.
- Farinati F, Rinaldi M, Gianni S, Naccarato R. How should patients with hepatocellular carcinoma be staged? Validation of a new prognostic system. Cancer 2000; 89:2266.
- Chevret S, Trinchet JC, Mathieu D, et al. 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.
- Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19:329.
- Yang JD, Kim WR, Park KW, et al. Model to estimate survival in ambulatory patients with hepatocellular carcinoma. Hepatology 2012; 56:614.
- Yau T, Tang VY, Yao TJ, et al. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014; 146:1691.
- Tang ZY. Liver cancer. In: Manual of Clinical Oncology, Pollock RE (Ed), Wiley-Liss, Inc, New York 1999. p.407.
- Primack A, Vogel CL, Kyalwazi SK, et al. A staging system for hepatocellular carcinoma: prognostic factors in Ugandan patients. Cancer 1975; 35:1357.
- Lai CL, Lam KC, Wong KP, et al. Clinical features of hepatocellular carcinoma: review of 211 patients in Hong Kong. Cancer 1981; 47:2746.
- American Joint Committee on Cancer. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.175.
- Ikai I, Yamaoka Y, Yamamoto Y, et al. Surgical intervention for patients with stage IV-A hepatocellular carcinoma without lymph node metastasis: proposal as a standard therapy. Ann Surg 1998; 227:433.
- Vauthey JN, Lauwers GY, Esnaola NF, et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002; 20:1527.
- Abou-Alfa GK, Pawlik, Shindoh J, and Vauthey J-N.. Liver. In: AJCC Cancer Staging Manual, 8th, Amin MB (Ed), AJCC, Chicago 2017. p.287.
- Shindoh J, Andreou A, Aloia TA, et al. Microvascular invasion does not predict long-term survival in hepatocellular carcinoma up to 2 cm: reappraisal of the staging system for solitary tumors. Ann Surg Oncol 2013; 20:1223.
- Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22:696.
- Nzeako UC, Goodman ZD, Ishak KG. Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients. Am J Clin Pathol 1996; 105:65.
- Kosuge T, Makuuchi M, Takayama T, et al. Long-term results after resection of hepatocellular carcinoma: experience of 480 cases. Hepatogastroenterology 1993; 40:328.
- Bilimoria MM, Lauwers GY, Doherty DA, et al. Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg 2001; 136:528.
- Vauthey JN, Ribero D, Abdalla EK, et al. Outcomes of liver transplantation in 490 patients with hepatocellular carcinoma: validation of a uniform staging after surgical treatment. J Am Coll Surg 2007; 204:1016.
- Poon RT, Fan ST, Lo CM, et al. Long-term prognosis after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol 2000; 18:1094.
- Levy I, Sherman M, Liver Cancer Study Group of the University of Toronto. Staging of hepatocellular carcinoma: assessment of the CLIP, Okuda, and Child-Pugh staging systems in a cohort of 257 patients in Toronto. Gut 2002; 50:881.
- Ueno S, Tanabe G, Sako K, et al. Discrimination value of the new western prognostic system (CLIP score) for hepatocellular carcinoma in 662 Japanese patients. Cancer of the Liver Italian Program. Hepatology 2001; 34:529.
- Villa E, Colantoni A, Cammà C, et al. Estrogen receptor classification for hepatocellular carcinoma: comparison with clinical staging systems. J Clin Oncol 2003; 21:441.
- Cho YK, Chung JW, Kim JK, et al. Comparison of 7 staging systems for patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Cancer 2008; 112:352.
- Huo TI, Huang YH, Lin HC, et al. Proposal of a modified Cancer of the Liver Italian Program staging system based on the model for end-stage liver disease for patients with hepatocellular carcinoma undergoing loco-regional therapy. Am J Gastroenterol 2006; 101:975.
- Yu SJ. A concise review of updated guidelines regarding the management of hepatocellular carcinoma around the world: 2010-2016. Clin Mol Hepatol 2016; 22:7.
- Torzilli G, Belghiti J, Kokudo N, et al. A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group. Ann Surg 2013; 257:929.
- Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005; 41:707.
- Cillo U, Vitale A, Grigoletto F, et al. Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol 2006; 44:723.
- 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.
- Vitale A, Morales RR, Zanus G, et al. Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study. Lancet Oncol 2011; 12:654.
- Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol 2015; 33:550.
- Mehta N, Heimbach J, Harnois DM, et al. Validation of a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score for Hepatocellular Carcinoma Recurrence After Liver Transplant. JAMA Oncol 2017; 3:493.
- Lee JH, Cho Y, Kim HY, et al. Serum Tumor Markers Provide Refined Prognostication in Selecting Liver Transplantation Candidate for Hepatocellular Carcinoma Patients Beyond the Milan Criteria. Ann Surg 2016; 263:842.
- Sherman M. Staging for hepatocellular carcinoma: complex and confusing. Gastroenterology 2014; 146:1599.
- Liu PH, Hsu CY, Hsia CY, et al. Prognosis of hepatocellular carcinoma: Assessment of eleven staging systems. J Hepatol 2016; 64:601.
- Vauthey JN, Dixon E, Abdalla EK, et al. Pretreatment assessment of hepatocellular carcinoma: expert consensus statement. HPB (Oxford) 2010; 12:289.
- Lee YT. Primary carcinoma of the liver: diagnosis, prognosis, and management. J Surg Oncol 1983; 22:17.
- Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer 1996; 77:2217.
- Rustgi VK. Epidemiology of hepatocellular carcinoma. Gastroenterol Clin North Am 1987; 16:545.
- Rolfes DB. Fibrolamellar carcinoma of the liver. In: Neoplasms of the Liver, Okuda K, Shak KG (Eds), Springer-Verlag, Tokyo 1987. p.137.
- Okuda K, Musha H, Nakajima Y, et al. Clinicopathologic features of encapsulated hepatocellular carcinoma: a study of 26 cases. Cancer 1977; 40:1240.
- Cillo U, Vitale A, Bassanello M, et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004; 239:150.
- Tangkijvanich P, Anukulkarnkusol N, Suwangool P, et al. Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J Clin Gastroenterol 2000; 31:302.
- Ebara M, Ohto M, Shinagawa T, et al. Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology 1986; 90:289.
- Matsumoto Y, Suzuki T, Asada I, et al. Clinical classification of hepatoma in Japan according to serial changes in serum alpha-fetoprotein levels. Cancer 1982; 49:354.
- Hanazaki K, Kajikawa S, Koide N, et al. Prognostic factors after hepatic resection for hepatocellular carcinoma with hepatitis C viral infection: univariate and multivariate analysis. Am J Gastroenterol 2001; 96:1243.
- Tyson GL, Duan Z, Kramer JR, et al. Level of α-fetoprotein predicts mortality among patients with hepatitis C-related hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011; 9:989.
- Santambrogio R, Opocher E, Costa M, et al. Hepatic resection for "BCLC stage A" hepatocellular carcinoma. The prognostic role of alpha-fetoprotein. Ann Surg Oncol 2012; 19:426.
- Yamamoto K, Imamura H, Matsuyama Y, et al. Significance of alpha-fetoprotein and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy. Ann Surg Oncol 2009; 16:2795.
- Shim JH, Yoon DL, Han S, et al. Is serum alpha-fetoprotein useful for predicting recurrence and mortality specific to hepatocellular carcinoma after hepatectomy? A test based on propensity scores and competing risks analysis. Ann Surg Oncol 2012; 19:3687.
- Kiriyama S, Uchiyama K, Ueno M, et al. Triple positive tumor markers for hepatocellular carcinoma are useful predictors of poor survival. Ann Surg 2011; 254:984.
- Toyoda H, Kumada T, Kaneoka Y, et al. Prognostic value of pretreatment levels of tumor markers for hepatocellular carcinoma on survival after curative treatment of patients with HCC. J Hepatol 2008; 49:223.
- Kim HS, Park JW, Jang JS, et al. Prognostic values of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II in hepatitis B virus-related hepatocellular carcinoma: a prospective study. J Clin Gastroenterol 2009; 43:482.
- Villa E, Camellini L, Dugani A, et al. Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma. Cancer Res 1995; 55:498.
- Cescon M, Cucchetti A, Grazi GL, et al. Role of hepatitis B virus infection in the prognosis after hepatectomy for hepatocellular carcinoma in patients with cirrhosis: a Western dual-center experience. Arch Surg 2009; 144:906.
- Chen JH, Chau GY, Lui WY, et al. Surgical results in patients with hepatitis B-related hepatocellular carcinoma and positive hepatitis B early antigen. World J Surg 2000; 24:383.
- Sun HC, Zhang W, Qin LX, et al. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol 2007; 47:684.
- Kubo S, Hirohashi K, Yamazaki O, et al. Effect of the presence of hepatitis B e antigen on prognosis after liver resection for hepatocellular carcinoma in patients with chronic hepatitis B. World J Surg 2002; 26:555.
- Li J, Zhou J, Yang PH, et al. Nomograms for survival prediction in patients undergoing liver resection for hepatitis B virus related early stage hepatocellular carcinoma. Eur J Cancer 2016; 62:86.
- Sasaki Y, Yamada T, Tanaka H, et al. Risk of recurrence in a long-term follow-up after surgery in 417 patients with hepatitis B- or hepatitis C-related hepatocellular carcinoma. Ann Surg 2006; 244:771.
- Roayaie S, Haim MB, Emre S, et al. Comparison of surgical outcomes for hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: a western experience. Ann Surg Oncol 2000; 7:764.
- Utsunomiya T, Shimada M, Kudo M, et al. A comparison of the surgical outcomes among patients with HBV-positive, HCV-positive, and non-B non-C hepatocellular carcinoma: a nationwide study of 11,950 patients. Ann Surg 2015; 261:513.
- Kim BK, Park JY, Kim DY, et al. Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection. Liver Int 2008; 28:393.
- Wu JC, Huang YH, Chau GY, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009; 51:890.
- Wang YG, Wang P, Wang B, et al. Diabetes mellitus and poorer prognosis in hepatocellular carcinoma: a systematic review and meta-analysis. PLoS One 2014; 9:e95485.
- Kaseb AO, Hassan MM, Lin E, et al. V-CLIP: Integrating plasma vascular endothelial growth factor into a new scoring system to stratify patients with advanced hepatocellular carcinoma for clinical trials. Cancer 2011; 117:2478.
- Kaseb AO, Morris JS, Hassan MM, et al. Clinical and prognostic implications of plasma insulin-like growth factor-1 and vascular endothelial growth factor in patients with hepatocellular carcinoma. J Clin Oncol 2011; 29:3892.
- Kaseb AO, Abbruzzese JL, Vauthey JN, et al. I-CLIP: improved stratification of advanced hepatocellular carcinoma patients by integrating plasma IGF-1 into CLIP score. Oncology 2011; 80:373.
- Sun H, Teng M, Liu J, et al. FOXM1 expression predicts the prognosis in hepatocellular carcinoma patients after orthotopic liver transplantation combined with the Milan criteria. Cancer Lett 2011; 306:214.
- Schmitz KJ, Sotiropoulos GC, Baba HA, et al. AKR1B10 expression is associated with less aggressive hepatocellular carcinoma: a clinicopathological study of 168 cases. Liver Int 2011; 31:810.
- Nault JC, De Reyniès A, Villanueva A, et al. A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection. Gastroenterology 2013; 145:176.
- Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359:1995.
- Tsuchiya M, Parker JS, Kono H, et al. Gene expression in nontumoral liver tissue and recurrence-free survival in hepatitis C virus-positive hepatocellular carcinoma. Mol Cancer 2010; 9:74.
- Qiu J, Peng B, Tang Y, et al. CpG Methylation Signature Predicts Recurrence in Early-Stage Hepatocellular Carcinoma: Results From a Multicenter Study. J Clin Oncol 2017; 35:734.
- Kornberg A, Küpper B, Tannapfel A, et al. Patients with non-[18 F]fludeoxyglucose-avid advanced hepatocellular carcinoma on clinical staging may achieve long-term recurrence-free survival after liver transplantation. Liver Transpl 2012; 18:53.
- Cascales Campos P, Ramirez P, Gonzalez R, et al. Value of 18-FDG-positron emission tomography/computed tomography before and after transarterial chemoembolization in patients with hepatocellular carcinoma undergoing liver transplantation: initial results. Transplant Proc 2011; 43:2213.
- Lee JH, Park JY, Kim DY, et al. Prognostic value of 18F-FDG PET for hepatocellular carcinoma patients treated with sorafenib. Liver Int 2011; 31:1144.
- Kim JW, Seong J, Yun M, et al. Usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose in predicting treatment response in unresectable hepatocellular carcinoma patients treated with external beam radiotherapy. Int J Radiat Oncol Biol Phys 2012; 82:1172.
- Cheung TT, Chan SC, Ho CL, et al. Can positron emission tomography with the dual tracers [11 C]acetate and [18 F]fludeoxyglucose predict microvascular invasion in hepatocellular carcinoma? Liver Transpl 2011; 17:1218.
- Minagawa M, Makuuchi M. Treatment of hepatocellular carcinoma accompanied by portal vein tumor thrombus. World J Gastroenterol 2006; 12:7561.
- Roayaie S, Jibara G, Taouli B, Schwartz M. Resection of hepatocellular carcinoma with macroscopic vascular invasion. Ann Surg Oncol 2013; 20:3754.
- Poon RT, Fan ST. Evaluation of the new AJCC/UICC staging system for hepatocellular carcinoma after hepatic resection in Chinese patients. Surg Oncol Clin N Am 2003; 12:35.
- Lei HJ, Chau GY, Lui WY, et al. Prognostic value and clinical relevance of the 6th Edition 2002 American Joint Committee on Cancer staging system in patients with resectable hepatocellular carcinoma. J Am Coll Surg 2006; 203:426.
- STAGING AND PROGNOSTIC SCORING SYSTEMS
- Tumor, node, metastasis (TNM) staging
- Okuda system
- CLIP score
- The Barcelona staging classification
- ALBI score
- RETREAT and MoRAL scores
- Choice of staging system
- OTHER FACTORS INFLUENCING SURVIVAL
- High versus low-incidence regions
- Tumor histology
- Serum alpha-fetoprotein level
- Variant estrogen receptors
- Hepatitis B and C
- - Antiviral therapy for HBV-related HCC
- Diabetes mellitus
- New prognostic markers under investigation
- Clinical implications