Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hepatocellular carcinoma

Abstract

Liver cancer is the second leading cause of cancer-related deaths globally and has an incidence of approximately 850,000 new cases per year. Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer. The main risk factors for developing HCC are well known and include hepatitis B and C virus infection, alcohol intake and ingestion of the fungal metabolite aflatoxin B1. Additional risk factors such as non-alcoholic steatohepatitis are also emerging. Advances in the understanding of the molecular pathogenesis of HCC have led to identification of critical driver mutations; however, the most prevalent of these are not yet druggable targets. The molecular classification of HCC is not established, and the Barcelona Clinic Liver Cancer staging classification is the main clinical algorithm for the stratification of patients according to prognosis and treatment allocation. Surveillance programmes enable the detection of early-stage tumours that are amenable to curative therapies — resection, liver transplantation or local ablation. At more developed stages, only chemoembolization (for intermediate HCC) and sorafenib (for advanced HCC) have shown survival benefits. There are major unmet needs in HCC management that might be addressed through the discovery of new therapies and their combinations for use in the adjuvant setting and for intermediate- and advanced-stage disease. Moreover, biomarkers for therapy stratification, patient-tailored strategies targeting driver mutations and/or activating signalling cascades, and validated measurements of quality of life are needed. Recent failures in the testing of systemic drugs for intermediate and advanced stages have indicated a need to refine trial designs and to define novel approaches.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The global burden of HCC.
Figure 2: Liver cancer incidence according to region and sex.
Figure 3: Cancer progression and driver genes.
Figure 4: BCLC staging system and therapeutic strategy.
Figure 5: Molecular targeted therapies for HCC and their target signalling pathways.

References

  1. Torre, L. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

    Article  PubMed  Google Scholar 

  2. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385, 117–171 (2014).

    PubMed Central  Google Scholar 

  3. 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. 56, 908–943 (2012). This article outlines the European consensus guidelines for the management of HCC, including the definition of treatment allocation criteria according to evidence.

    Article  Google Scholar 

  4. Liu, J. & Fan, D. Hepatitis B in China. Lancet 369, 1582–1583 (2007).

    Article  PubMed  Google Scholar 

  5. Mohd Hanafiah, K., Groeger, J., Flaxman, A. D. & Wiersma, S. T. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 57, 1333–1342 (2013).

    Article  PubMed  Google Scholar 

  6. Mohamoud, Y. A., Mumtaz, G. R., Riome, S., Miller, D. & Abu-Raddad, L. J. The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infect. Dis. 13, 288 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  7. El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. National Center for Health Statistics. Health, United States, 2014: With Special Feature on Adults Aged 55–64 (National Center for Health Statistics, 2015).

  9. Omer, R. E. et al. Population-attributable risk of dietary aflatoxins and hepatitis B virus infection with respect to hepatocellular carcinoma. Nutr. Cancer 48, 15–21 (2004).

    Article  PubMed  Google Scholar 

  10. Laursen, L. A preventable cancer. Nature 516, S2–S3 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Sartorius, K., Sartorius, B., Aldous, C., Govender, P. S. & Madiba, T. E. Global and country underestimation of hepatocellular carcinoma (HCC) in 2012 and its implications. Cancer Epidemiol. 39, 284–290 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Nault, J.-C. et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 10, 1187–1193 (2015).

    Article  CAS  Google Scholar 

  14. Zucman-Rossi, J., Villanueva, A., Nault, J.-C. & Llovet, J. M. The genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 5, 1226–1239 (2015).

    Article  CAS  Google Scholar 

  15. Bruix, J. & Sherman, M. Management of hepatocellular carcinoma: an update. Hepatology 53, 1020–1022 (2011).

    Article  PubMed  Google Scholar 

  16. Forner, A., Llovet, J. M. & Bruix, J. Hepatocellular carcinoma. Lancet 379, 1245–1255 (2012).

    Article  PubMed  Google Scholar 

  17. Llovet, J. M. et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359, 1734–1739 (2002). This paper reports a positive RCT supporting the use of TACE in intermediate-stage HCC.

    Article  PubMed  Google Scholar 

  18. Llovet, J. M. & Bruix, J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37, 429–442 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008). This paper details a positive RCT supporting the use of sorafenib in advanced-stage HCC. It was the first RCT to demonstrate survival benefits for a systemic drug in HCC and provided the rationale for approval of this drug in the management of HCC.

    Article  CAS  PubMed  Google Scholar 

  20. Yang, J. D. et al. Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 9, 64–70 (2011).

    Article  PubMed  Google Scholar 

  21. Lok, A. S. et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 136, 138–148 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Hsu, I. C. et al. Mutational hotspot in the P53 gene in human hepatocellular carcinomas. Nature 350, 427–428 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Bruix, J. & Sherman, M. Management of hepatocellular carcinoma. Hepatology 42, 1208–1236 (2005).

    Article  PubMed  Google Scholar 

  24. Yang, D. et al. Impact of sex on the survival of patients with hepatocellular carcinoma: a surveillance, epidemiology, and end results analysis. Cancer 120, 3707–3716 (2014).

    Article  PubMed  Google Scholar 

  25. Mittal, S. et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin. Gastroenterol. Hepatol. 13, 594–601.e1 (2015).

    Article  PubMed  Google Scholar 

  26. Chang, M. H. et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J. Natl Cancer Inst. 101, 1348–1355 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Wong, G. L. et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology 58, 1537–1547 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Singal, A. G., Volk, M. L., Jensen, D., Di Bisceglie, A. M. & Schoenfeld, P. S. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin. Gastroenterol. Hepatol. 8, 280–288.e1 (2010).

    Article  PubMed  Google Scholar 

  29. Singh, S., Singh, P. P., Singh, A. G., Murad, M. H. & Sanchez, W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144, 323–332 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Marquardt, J. U., Andersen, J. B. & Thorgeirsson, S. S. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat. Rev. Cancer 15, 653–667 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Alizadeh, A. A. et al. Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21, 846–853 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Guichard, C. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44, 694–698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 44, 505–511 (2015). This paper reports the largest whole-exome sequencing study in a cohort of HCC patients from western countries (Europe and North America).

    Article  CAS  Google Scholar 

  34. Nault, J. C. et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 4, 2218 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Ahn, S.-M. et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 60, 1972–1982 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Nault, J. C. et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 60, 1983–1992 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Pilati, C. et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 25, 428–441 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Totoki, Y. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 46, 1267–1273 (2014). This paper reports the largest whole-exome sequencing study in a cohort of HCC patients from Asia.

    Article  CAS  PubMed  Google Scholar 

  39. Di Tommaso, L. et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 45, 725–734 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Di Tommaso, L. et al. The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma. J. Hepatol. 50, 746–754 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Llovet, J. M. et al. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 131, 1758–1767 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Wurmbach, E. et al. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 45, 938–947 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Paradis, V. et al. Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale real-time RT-PCR approach: determination of a molecular diagnostic index. Am. J. Pathol. 163, 733–741 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Günes, C. & Rudolph, K. L. The role of telomeres in stem cells and cancer. Cell 152, 390–393 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Satyanarayana, A. et al. Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol. Cell. Biol. 24, 5459–5474 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Farazi, P. A. et al. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 63, 5021–5027 (2003).

    CAS  PubMed  Google Scholar 

  47. Hartmann, D. et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology 53, 1608–1617 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Calado, R. T. et al. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology 53, 1600–1607 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N. & DePinho, R. A. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 287, 1253–1258 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Lechel, A. et al. Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology 132, 1465–1475 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Kotoula, V. et al. Expression of human telomerase reverse transcriptase in regenerative and precancerous lesions of cirrhotic livers. Liver 22, 57–69 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Bartosch, B., Thimme, R., Blum, H. E. & Zoulim, F. Hepatitis C virus-induced hepatocarcinogenesis. J. Hepatol. 51, 810–820 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Neuveut, C., Wei, Y. & Buendia, M. A. Mechanisms of HBV-related hepatocarcinogenesis. J. Hepatol. 52, 594–604 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Wang, J., Chenivesse, X., Henglein, B. & Bréchot, C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343, 555–557 (1990).

    Article  CAS  PubMed  Google Scholar 

  55. Sung, W.-K. et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 44, 765–769 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. De La Coste, A. et al. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc. Natl Acad. Sci. USA 95, 8847–8851 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Audard, V. et al. Cholestasis is a marker for hepatocellular carcinomas displaying β-catenin mutations. J. Pathol. 212, 345–352 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Bressac, B., Kew, M., Wands, J. & Ozturk, M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429–431 (1991).

    Article  CAS  PubMed  Google Scholar 

  59. Amaddeo, G. et al. Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas. Gut 64, 820–829 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Fei, Q. et al. Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53. Nat. Commun. 6, 8651 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wong, C.-M. et al. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis. Hepatology 63, 474–487 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Villanueva, A. et al. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology 61, 1945–1956 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Herceg, Z. & Paliwal, A. Epigenetic mechanisms in hepatocellular carcinoma: how environmental factors influence the epigenome. Mutat. Res. 727, 55–61 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Sporn, M. B. & Liby, K. T. NRF2 and cancer: the good, the bad and the importance of context. Nat. Rev. Cancer 12, 564–571 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 68, 6779–6788 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sawey, E. T. et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 19, 347–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Horwitz, E. et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 4, 730–743 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Rudalska, R. et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med. 20, 1138–1146 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Weber, J. et al. CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice. Proc. Natl Acad. Sci. USA 112, 13982–13987 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hoshida, Y. et al. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin. Liver Dis. 30, 35–51 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Boyault, S. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45, 42–52 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Lee, J.-S. et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 40, 667–676 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Lee, J.-S. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat. Med. 12, 410–416 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Hoshida, Y. et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 69, 7385–7392 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lachenmayer, A. et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin. Cancer Res. 18, 4997–5007 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  79. Hernandez-Gea, V., Toffanin, S., Friedman, S. L. & Llovet, J. M. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144, 512–527 (2013).

    Article  PubMed  Google Scholar 

  80. Wada, Y., Nakashima, O., Kutami, R., Yamamoto, O. & Kojiro, M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 27, 407–414 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Hoshida, Y. et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359, 1995–2004 (2008). This manuscript is the first to define the importance of the ‘cancer field effect’ in the prognosis of patients with HCC after resection.

  82. Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Thomson, A. W. & Knolle, P. A. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10, 753–766 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Bauer, J. et al. Lymphotoxin, NF-κB, and cancer: the dark side of cytokines. Dig. Dis. 30, 453–468 (2012).

    Article  PubMed  Google Scholar 

  87. Taniguchi, K. & Karin, M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin. Immunol. 26, 54–74 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. LeCouter, J. et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299, 890–893 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Hussain, S. P., Hofseth, L. J. & Harris, C. C. Radical causes of cancer. Nat. Rev. Cancer 3, 276–285 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Kiraly, O., Gong, G., Olipitz, W., Muthupalani, S. & Engelward, B. P. Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo. PLoS Genet. 11, e1004901 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang, D. Y. et al. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Guthttp://dx.doi.org/10.1136/gutjnl-2015-309655 (2015).

  92. Campbell, J. S. et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc. Natl Acad. Sci. USA 102, 3389–3394 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Dapito, D. H. & Schwabe, R. F. Hepatic Stellate Cells and Liver Cancer. Stellate Cells in Health and Disease (Elsevier, 2015).

    Google Scholar 

  94. Lee, Y. A., Wallace, M. C. & Friedman, S. L. Pathobiology of liver fibrosis: a translational success story. Gut 64, 830–841 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Chang, M. H. et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N. Engl. J. Med. 336, 1855–1859 (1997). A study demonstrating the effect of universal HBV vaccination in decreasing the incidence of HCC in Taiwan.

    Article  CAS  PubMed  Google Scholar 

  96. Yuen, M.-F. et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J. Hepatol. 50, 80–88 (2009).

    Article  PubMed  Google Scholar 

  97. Wong, V. W.-S. et al. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J. Clin. Oncol. 28, 1660–1665 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Wong, G. L.-H. et al. Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B. J. Hepatol. 60, 339–345 (2014).

    Article  PubMed  Google Scholar 

  99. Chen, C.-J. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295, 65–73 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Yang, H.-I. et al. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J. Clin. Oncol. 28, 2437–2444 (2010).

    Article  PubMed  Google Scholar 

  101. Yang, H.-I. et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol. 12, 568–574 (2011).

    Article  PubMed  Google Scholar 

  102. Lee, M.-H. et al. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles. Hepatology 58, 546–554 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Wong, G. L.-H. et al. Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment. Gastroenterology 144, 933–944 (2013).

    Article  PubMed  Google Scholar 

  104. Arends, P. et al. Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. Gut 64, 1289–1295 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Liaw, Y.-F. et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N. Engl. J. Med. 351, 1521–1531 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Papatheodoridis, G. V. et al. Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir. J. Hepatol. 62, 363–370 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Ogawa, E. et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: a prospective, multicenter study. J. Hepatol. 58, 495–501 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Harada, N. et al. Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin. J. Viral Hepat. 21, 357–365 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Dohmen, K. et al. The incidence and risk factors for the development of hepatocellular carcinoma after peginterferon plus ribavirin therapy for chronic hepatitis C. Hepatogastroenterology 60, 2034–2038 (2013).

    CAS  PubMed  Google Scholar 

  110. Van der Meer, A. J. et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 308, 2584–2593 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Morgan, R. L. et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann. Intern. Med. 158, 329–337 (2013).

    Article  PubMed  Google Scholar 

  112. Foster, G. R. et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N. Engl. J. Med. 373, 2608–2617 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Singal, A. G. & El-Serag, H. B. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin. Gastroenterol. Hepatol. 13, 2140–2151 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Younossi, Z. M. et al. The impact of hepatitis C burden: an evidence-based approach. Aliment. Pharmacol. Ther. 39, 518–531 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Bosch, J. & Forns, X. Therapy. Statins and liver disease: from concern to ‘wonder’ drugs? Nat. Rev. Gastroenterol. Hepatol. 12, 320–321 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Zhang, H., Gao, C., Fang, L., Zhao, H.-C. & Yao, S.-K. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis. Scand. J. Gastroenterol. 48, 78–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Zhang, X. et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology 60, 2008–2016 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, B.-H., Yang, B.-H. & Tang, Z.-Y. Randomized controlled trial of screening for hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 130, 417–422 (2004).

    PubMed  Google Scholar 

  119. Yeh, Y.-P. et al. Evaluation of abdominal ultrasonography mass screening for hepatocellular carcinoma in Taiwan. Hepatology 59, 1840–1849 (2014).

    Article  PubMed  Google Scholar 

  120. Tong, M. J., Sun, H.-E., Hsien, C. & Lu, D. S. K. Surveillance for hepatocellular carcinoma improves survival in Asian–American patients with hepatitis B: results from a community-based clinic. Dig. Dis. Sci. 55, 826–835 (2010).

    Article  PubMed  Google Scholar 

  121. Tanaka, H. et al. Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival. Liver Int. 26, 543–551 (2006).

    Article  PubMed  Google Scholar 

  122. Wong, G. L.-H. et al. Surveillance programme for hepatocellular carcinoma improves the survival of patients with chronic viral hepatitis. Liver Int. 28, 79–87 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Taura, N. et al. Clinical benefits of hepatocellular carcinoma surveillance: a single-center, hospital-based study. Oncol. Rep. 14, 999–1003 (2005).

    PubMed  Google Scholar 

  124. Chan, A. C. Y. et al. Changing paradigm in the management of hepatocellular carcinoma improves the survival benefit of early detection by screening. Ann. Surg. 247, 666–673 (2008).

    Article  PubMed  Google Scholar 

  125. Nouso, K. et al. Cost-effectiveness of the surveillance program of hepatocellular carcinoma depends on the medical circumstances. J. Gastroenterol. Hepatol. 23, 437–444 (2008).

    Article  PubMed  Google Scholar 

  126. Lin, O. S., Keeffe, E. B., Sanders, G. D. & Owens, D. K. Cost-effectiveness of screening for hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C. Aliment. Pharmacol. Ther. 19, 1159–1172 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Arguedas, M. R., Chen, V. K., Eloubeidi, M. A. & Fallon, M. B. Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis. Am. J. Gastroenterol. 98, 679–690 (2003).

    Article  PubMed  Google Scholar 

  128. Andersson, K. L., Salomon, J. A., Goldie, S. J. & Chung, R. T. Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 6, 1418–1424 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Cucchetti, A. et al. Cost-effectiveness of semi-annual surveillance for hepatocellular carcinoma in cirrhotic patients of the Italian liver cancer population. J. Hepatol. 56, 1089–1096 (2012).

    Article  PubMed  Google Scholar 

  130. Sarasin, F. P., Giostra, E. & Hadengue, A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child–Pugh class A cirrhosis. Am. J. Med. 101, 422–434 (1996).

    Article  CAS  PubMed  Google Scholar 

  131. Thompson Coon, J. et al. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis. Health Technol. Assess. 11, 1–206 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Saab, S. et al. Hepatocellular carcinoma screening in patients waiting for liver transplantation: a decision analytic model. Liver Transpl. 9, 672–681 (2003).

    Article  PubMed  Google Scholar 

  133. Naugler, W. E. & Sonnenberg, A. Survival and cost-effectiveness analysis of competing strategies in the management of small hepatocellular carcinoma. Liver Transpl. 16, 1186–1194 (2010).

    Article  PubMed  Google Scholar 

  134. Thompson Coon, J. et al. Surveillance of cirrhosis for hepatocellular carcinoma: a cost-utility analysis. Br. J. Cancer 98, 1166–1175 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Patel, D., Terrault, N. A., Yao, F. Y., Bass, N. M. & Ladabaum, U. Cost-effectiveness of hepatocellular carcinoma surveillance in patients with hepatitis C virus-related cirrhosis. Clin. Gastroenterol. Hepatol. 3, 75–84 (2005).

    Article  PubMed  Google Scholar 

  136. Kang, J. Y., Lee, T. P., Yap, I. & Lun, K. C. Analysis of cost-effectiveness of different strategies for hepatocellular carcinoma screening in hepatitis B virus carriers. J. Gastroenterol. Hepatol. 7, 463–468 (1992).

    Article  CAS  PubMed  Google Scholar 

  137. Shih, S. T.-F., Crowley, S. & Sheu, J.-C. Cost-effectiveness analysis of a two-stage screening intervention for hepatocellular carcinoma in Taiwan. J. Formos. Med. Assoc. 109, 39–55 (2010).

    Article  PubMed  Google Scholar 

  138. Marrero, J. A. et al. α-Fetoprotein, des-γ carboxyprothrombin, and lectin-bound α-fetoprotein in early hepatocellular carcinoma. Gastroenterology 137, 110–118 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Asaoka, Y. et al. Frequency of and predictive factors for vascular invasion after radiofrequency ablation for hepatocellular carcinoma. PLoS ONE 9, e111662 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kudo, A. et al. Does the preoperative α-fetoprotein predict the recurrence and mortality after hepatectomy for hepatocellular carcinoma without macrovascular invasion in patients with normal liver function? Hepatol. Res. 44, E437–E446 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. Shirabe, K. et al. New scoring system for prediction of microvascular invasion in patients with hepatocellular carcinoma. Liver Int. 34, 937–941 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Park, H. et al. Clinical usefulness of double biomarkers AFP and PIVKA-II for subdividing prognostic groups in locally advanced hepatocellular carcinoma. Liver Int. 34, 313–321 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. Nakazawa, T. et al. Early increase in α-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib. Eur. J. Gastroenterol. Hepatol. 25, 683–689 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Park, W.-H. et al. Clinical utility of des-γ-carboxyprothrombin kinetics as a complement to radiologic response in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. J. Vasc. Interv. Radiol. 23, 927–936 (2012).

    Article  PubMed  Google Scholar 

  145. Han, K.-H. et al. Survival of hepatocellular carcinoma patients may be improved in surveillance interval not more than 6 months compared with more than 6 months: a 15-year prospective study. J. Clin. Gastroenterol. 47, 538–544 (2013).

    Article  PubMed  Google Scholar 

  146. Trinchet, J.-C. et al. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology 54, 1987–1997 (2011).

    Article  PubMed  Google Scholar 

  147. Santi, V. et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J. Hepatol. 53, 291–297 (2010).

    Article  PubMed  Google Scholar 

  148. Wang, J.-H. et al. Hepatocellular carcinoma surveillance at 4- versus 12-month intervals for patients with chronic viral hepatitis: a randomized study in community. Am. J. Gastroenterol. 108, 416–424 (2013).

    Article  PubMed  Google Scholar 

  149. Mitchell, D. G., Bruix, J., Sherman, M. & Sirlin, C. B. LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions. Hepatology 61, 1056–1065 (2015).

    Article  PubMed  Google Scholar 

  150. Khalili, K. et al. Optimization of imaging diagnosis of 1–2 cm hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization. J. Hepatol. 54, 723–728 (2011).

    Article  PubMed  Google Scholar 

  151. Sangiovanni, A. et al. The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 59, 638–644 (2010).

    Article  PubMed  Google Scholar 

  152. Lencioni, R., Cioni, D., Della Pina, C., Crocetti, L. & Bartolozzi, C. Imaging diagnosis. Semin. Liver Dis. 25, 162–170 (2005).

    Article  PubMed  Google Scholar 

  153. Silva, M. A. et al. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut 57, 1592–1596 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. The International Consensus Group of Hepatocellular Neoplasia. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49, 658–664 (2009).

    Article  Google Scholar 

  155. Libbrecht, L. et al. Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Am. J. Surg. Pathol. 30, 1405–1411 (2006).

    Article  PubMed  Google Scholar 

  156. Tremosini, S. et al. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut 61, 1481–1487 (2012).

    Article  PubMed  Google Scholar 

  157. Di Tommaso, L. et al. Diagnostic accuracy of clathrin heavy chain staining in a marker panel for the diagnosis of small hepatocellular carcinoma. Hepatology 53, 1549–1557 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. Llovet, J. M., Brú, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19, 329–338 (1999). A seminal study proposing the BCLC staging system, now accepted by European and American guidelines of management of HCC.

    Article  CAS  PubMed  Google Scholar 

  159. Bruix, J., Han, K., Gores, G., Llovet, J. M. & Mazzaferro, V. Liver cancer: approaching a personalized care. J. Hepatol. 62, S144–156 (2015).

    Article  Google Scholar 

  160. Yau, T. et al. Development of Hong Kong liver cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 146, 1691–1700.e3 (2014).

    Article  PubMed  Google Scholar 

  161. The Cancer of the Liver Italian Program (CLIP) Investigators A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 28, 751–755 (1998).

  162. Sobin, L. H. & Compton, C. C. TNM seventh edition: what's new, what's changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer 116, 5336–5339 (2010).

    Article  PubMed  Google Scholar 

  163. 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. 38, 207–215 (2003).

    Article  PubMed  Google Scholar 

  164. Bruix, J. et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 111, 1018–1022 (1996).

    Article  CAS  PubMed  Google Scholar 

  165. Llovet, J. M., Schwartz, M. & Mazzaferro, V. Resection and liver transplantation for hepatocellular carcinoma. Semin. Liver Dis. 25, 181–200 (2005).

    Article  PubMed  Google Scholar 

  166. Llovet, J. M., Fuster, J. & Bruix, J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30, 1434–1440 (1999).

    Article  CAS  PubMed  Google Scholar 

  167. Imamura, H. et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J. Hepatol. 38, 200–207 (2003).

    Article  PubMed  Google Scholar 

  168. Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a Phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. Takayama, T. et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356, 802–807 (2000).

    Article  CAS  PubMed  Google Scholar 

  170. Muto, Y. et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N. Engl. J. Med. 334, 1561–1567 (1996).

    Article  CAS  PubMed  Google Scholar 

  171. Mazzaferro, V. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 334, 693–699 (1996). This paper defines the Milan criteria for selecting candidates for liver transplantation; these criteria are currently adopted by most transplant units globally.

    Article  CAS  PubMed  Google Scholar 

  172. Mazzaferro, V. et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 10, 35–43 (2009).

    Article  PubMed  Google Scholar 

  173. Toso, C. et al. Total tumor volume and α-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: a prospective validation. Hepatology 62, 158–165 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. Miltiadous, O. et al. Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. J. Hepatol. 63, 1368–1377 (2015).

    Article  PubMed  Google Scholar 

  175. Livraghi, T. et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology 47, 82–89 (2008).

    Article  PubMed  Google Scholar 

  176. Lo, C.-M. et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35, 1164–1171 (2002). This RCT demonstrates the efficacy of TACE in patients with intermediate-stage HCC.

    Article  CAS  PubMed  Google Scholar 

  177. Kudo, M. et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized Phase III trial. Hepatology 60, 1697–1707 (2014).

    Article  CAS  PubMed  Google Scholar 

  178. Burrel, M. et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using drug eluting beads. Implications for clinical practice and trial design. J. Hepatol. 56, 1330–1335 (2012).

    Article  PubMed  Google Scholar 

  179. Salem, R. et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 140, 497–507.e2 (2011).

    Article  PubMed  Google Scholar 

  180. Cheng, A.-L. 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. 10, 25–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  181. Yeo, W. et al. A randomized Phase III study of doxorubicin versus cisplatin/interferon α-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J. Natl Cancer Inst. 97, 1532–1538 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. D'Amico, G., Garcia-Tsao, G. & Pagliaro, L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J. Hepatol. 44, 217–231 (2006).

    Article  PubMed  Google Scholar 

  183. Eguchi, S. et al. Comparison of the outcomes between an anatomical subsegmentectomy and a non-anatomical minor hepatectomy for single hepatocellular carcinomas based on a Japanese nationwide survey. Surgery 143, 469–475 (2008).

    Article  PubMed  Google Scholar 

  184. Palavecino, M. et al. Major hepatic resection for hepatocellular carcinoma with or without portal vein embolization: perioperative outcome and survival. Surgery 145, 399–405 (2009).

    Article  PubMed  Google Scholar 

  185. Vouche, M. et al. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J. Hepatol. 59, 1029–1036 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Cherqui, D. Laparoscopic liver resection: a new paradigm in the management of hepatocellular carcinoma? J. Hepatol. 63, 540–542 (2015).

    Article  PubMed  Google Scholar 

  187. Ishizawa, T. et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 134, 1908–1916 (2008).

    Article  PubMed  Google Scholar 

  188. Franssen, B. et al. Differences in surgical outcomes between hepatitis B- and hepatitis C-related hepatocellular carcinoma: a retrospective analysis of a single North American center. Ann. Surg. 260, 650–656 (2014).

    Article  PubMed  Google Scholar 

  189. Roayaie, S., Bassi, D., Tarchi, P., Labow, D. & Schwartz, M. Second hepatic resection for recurrent hepatocellular cancer: a western experience. J. Hepatol. 55, 346–350 (2011).

    Article  PubMed  Google Scholar 

  190. Fuks, D. et al. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology 55, 132–140 (2012).

    Article  PubMed  Google Scholar 

  191. Lau, W. Y. et al. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 353, 797–801 (1999).

    Article  CAS  PubMed  Google Scholar 

  192. Clavien, P.-A. et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 13, e11–e22 (2012). This publication outlines consensus guidelines for the management of HCC with liver transplantation.

    Article  PubMed  Google Scholar 

  193. Lesurtel, M., Mü llhaupt, B., Pestalozzi, B. C., Pfammatter, T. & Clavien, P.-A. Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular carcinoma: an evidence-based analysis. Am. J. Transplant. 6, 2644–2650 (2006).

    Article  CAS  PubMed  Google Scholar 

  194. Kulik, L. M. et al. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am. J. Transplant. 12, 2997–3007 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Toso, C., Merani, S., Bigam, D. L., Shapiro, A. M. J. & Kneteman, N. M. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 51, 1237–1243 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. Schnitzbauer, A. A. et al. A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 10, 190 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label Phase 3 trial. Transplantation 100, 116–125 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  198. Vitale, A. et al. Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study. Lancet Oncol. 12, 654–662 (2011).

    Article  PubMed  Google Scholar 

  199. Menon, K. V., Hakeem, A. R. & Heaton, N. D. Review article: liver transplantation for hepatocellular carcinoma — a critical appraisal of the current worldwide listing criteria. Aliment. Pharmacol. Ther. 40, 893–902 (2014).

    Article  CAS  PubMed  Google Scholar 

  200. Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 33, 1394–1403 (2001).

    Article  CAS  PubMed  Google Scholar 

  201. Yao, F. Y. et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 48, 819–827 (2008).

    Article  PubMed  Google Scholar 

  202. Kowdley, K. V. et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N. Engl. J. Med. 370, 1879–1888 (2014).

    Article  CAS  PubMed  Google Scholar 

  203. Ahmed, M. et al. Image-guided tumor ablation: standardization of terminology and reporting criteria — a 10-year update. Radiology 273, 241–260 (2014).

    Article  PubMed  Google Scholar 

  204. Lencioni, R. & Crocetti, L. Image-guided ablation for hepatocellular carcinoma. Recent Results Cancer Res. 190, 181–194 (2013).

    Article  PubMed  Google Scholar 

  205. Cho, Y. K. et al. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 49, 453–459 (2009).

    Article  PubMed  Google Scholar 

  206. Orlando, A., Leandro, G., Olivo, M., Andriulli, A. & Cottone, M. Radiofrequency thermal ablation versus percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am. J. Gastroenterol. 104, 514–524 (2009).

    Article  PubMed  Google Scholar 

  207. Shiina, S. et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am. J. Gastroenterol. 107, 569–577 (2012).

    Article  CAS  PubMed  Google Scholar 

  208. Salem, R. et al. Research reporting standards for radioembolization of hepatic malignancies. J. Vasc. Interv. Radiol. 22, 265–278 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Bruix, J., Sala, M. & Llovet, J. M. Chemoembolization for hepatocellular carcinoma. Gastroenterology 127, S179–S188 (2004).

    Article  CAS  PubMed  Google Scholar 

  210. Raoul, J.-L. et al. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat. Rev. 37, 212–220 (2011).

    Article  PubMed  Google Scholar 

  211. Golfieri, R. et al. Randomised controlled trial of doxorubicin-eluting beads versus conventional chemoembolisation for hepatocellular carcinoma. Br. J. Cancer 111, 255–264 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Sangro, B. & Salem, R. Transarterial chemoembolization and radioembolization. Semin. Liver Dis. 34, 435–443 (2014).

    Article  PubMed  Google Scholar 

  213. Lencioni, R. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J. Hepatol.http://dx.doi.org/10.1016/j.jhep.2016.01.012 (2016).

  214. Oliveri, R. S., Wetterslev, J. & Gluud, C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst. Rev. 3, CD004787 (2011).

    Google Scholar 

  215. Sangro, B., Iñarrairaegui, M. & Bilbao, J. I. Radioembolization for hepatocellular carcinoma. J. Hepatol. 56, 464–473 (2012).

    Article  PubMed  Google Scholar 

  216. Sangro, B. et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 54, 868–878 (2011).

    Article  PubMed  Google Scholar 

  217. Meyer, T. et al. A randomised Phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation versus embolisation alone for hepatocellular carcinoma. Br. J. Cancer 108, 1252–1259 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Llovet, J. M., Villanueva, A., Lachenmayer, A. & Finn, R. S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol. 12, 408–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  219. Qin, S. et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J. Clin. Oncol. 31, 3501–3508 (2013).

    Article  CAS  PubMed  Google Scholar 

  220. Bruix, J. et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a Phase III trial. J. Hepatol. 57, 821–829 (2012).

    Article  CAS  PubMed  Google Scholar 

  221. Llovet, J. M. et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 18, 2290–2300 (2012).

    Article  CAS  PubMed  Google Scholar 

  222. Wilhelm, S. M. et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 7, 3129–3140 (2008).

    Article  CAS  PubMed  Google Scholar 

  223. Llovet, J. M. et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J. Natl Cancer Inst. 100, 698–711 (2008). This paper describes consensus guidelines for the design of clinical trials in HCC.

    Article  PubMed  Google Scholar 

  224. Johnson, P. J. et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized Phase III BRISK-FL study. J. Clin. Oncol. 31, 3517–3524 (2013).

    Article  CAS  PubMed  Google Scholar 

  225. Cheng, A.-L. et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized Phase III trial. J. Clin. Oncol. 31, 4067–4075 (2013).

    Article  CAS  PubMed  Google Scholar 

  226. Cainap, C. et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized Phase III trial. J. Clin. Oncol. 33, 172–179 (2015).

    Article  CAS  PubMed  Google Scholar 

  227. Zhu, A. X. et al. SEARCH: a Phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 33, 559–566 (2015).

    Article  CAS  PubMed  Google Scholar 

  228. Llovet, J. M. et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized Phase III BRISK-PS study. J. Clin. Oncol. 31, 3509–3516 (2013).

    Article  CAS  PubMed  Google Scholar 

  229. Zhu, A. X. et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 312, 57–67 (2014).

    Article  CAS  PubMed  Google Scholar 

  230. Zhu, A. X. et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, Phase 3 trial. Lancet Oncol. 20, 859–870 (2015).

    Article  CAS  Google Scholar 

  231. Llovet, J. M. & Hernandez-Gea, V. Hepatocellular carcinoma: reasons for Phase III failure and novel perspectives on trial design. Clin. Cancer Res. 20, 2072–2079 (2014).

    Article  CAS  PubMed  Google Scholar 

  232. Lencioni, R. & Llovet, J. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).

    Article  CAS  PubMed  Google Scholar 

  233. Coulouarn, C., Factor, V. M. & Thorgeirsson, S. S. Transforming growth factor-β gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 47, 2059–2067 (2008).

    Article  CAS  PubMed  Google Scholar 

  234. Faivre, S. J., Santoro, A. & Kelley, R. K. A Phase 2 study of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. Abstr. 32, LBA173 (2014).

    Article  Google Scholar 

  235. Finn, R. S. Gains in FGF19 are predictive of response to the fibroblast growth factor receptor (FGFR) small molecule tyrosine kinase inhibitor BGJ 398 in vitro. Cancer Res. Abstr. 72, 3858 (2012).

    Article  Google Scholar 

  236. Hagel, M. et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 5, 424–437 (2015).

    Article  CAS  PubMed  Google Scholar 

  237. Calvisi, D. F. et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130, 1117–1128 (2006).

    Article  CAS  PubMed  Google Scholar 

  238. O'Neil, B. H. et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 29, 2350–2356 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Lim, H. Y. et al. A Phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86–9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clin. Cancer Res. 20, 5976–5985 (2014).

    Article  CAS  PubMed  Google Scholar 

  240. Goyal, L., Muzumdar, M. D. & Zhu, A. X. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin. Cancer Res. 19, 2310–2318 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Xiang, Q. et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin. Cancer Res. 20, 2959–2970 (2014).

    Article  CAS  PubMed  Google Scholar 

  242. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2014).

    Article  CAS  PubMed  Google Scholar 

  243. Butterfield, L. H. et al. A Phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four α-fetoprotein peptides. Clin. Cancer Res. 12, 2817–2825 (2006).

    Article  CAS  PubMed  Google Scholar 

  244. Palmer, D. H. et al. A Phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49, 124–132 (2009).

    Article  PubMed  Google Scholar 

  245. Sangro, B. et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 59, 81–88 (2013).

    Article  CAS  PubMed  Google Scholar 

  246. El-Khoueiry, A. et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J. Clin Oncol. Abstr. 33, LBA101 (2015).

    Article  Google Scholar 

  247. Yeo, W. et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter Phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J. Clin. Oncol. 30, 3361–3367 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Bitzer, M. et al. Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study. J. Clin Oncol. Abstr. 30, 4115 (2012).

    Google Scholar 

  249. US National Library of Science. A study of RO5137382 (GC33) in patients with advanced or metastatic hepatocellular carcinoma. ClinicalTrials.gov[online], (2015).

  250. Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Van Allen, E. M. et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4, 94–109 (2014).

    Article  CAS  PubMed  Google Scholar 

  252. Tovar, V. et al. Tumor initiating cells and IGF/FGF signaling contribute to sorafenib resistance in hepatocellular carcinoma. Guthttp://dx.doi.org/10.1136/gutjnl-2015-309501 (2015).

  253. Chie, W.-C. et al. International cross-cultural field validation of an European Organization for Research and Treatment of Cancer questionnaire module for patients with primary liver cancer, the European Organization for Research and Treatment of Cancer quality-of-life ques. Hepatology 55, 1122–1129 (2012).

    Article  PubMed  Google Scholar 

  254. Blazeby, J. M. et al. Development of a questionnaire module to supplement the EORTC QLQ-C30 to assess quality of life in patients with hepatocellular carcinoma, the EORTC QLQ-HCC18. Eur. J. Cancer 40, 2439–2444 (2004).

    Article  PubMed  Google Scholar 

  255. Huang, G. et al. Quality of life after surgical resection compared with radiofrequency ablation for small hepatocellular carcinomas. Br. J. Surg. 101, 1006–1015 (2014).

    Article  CAS  PubMed  Google Scholar 

  256. Salem, R. et al. Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. Clin. Gastroenterol. Hepatol. 11, 1358–1365.e1 (2013).

    Article  PubMed  Google Scholar 

  257. Afdhal, N. et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N. Engl. J. Med. 370, 1889–1898 (2014).

    Article  CAS  PubMed  Google Scholar 

  258. Kahn, M. Can we safely target the WNT pathway? Nat. Rev. Drug Discov. 13, 513–532 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Roayaie, S. et al. The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology 62, 440–451 (2015).

    Article  CAS  PubMed  Google Scholar 

  260. Park, J.-W. et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 35, 2155–2166 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  261. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    Article  CAS  PubMed  Google Scholar 

  262. Weinstein, I. B. Cancer. Addiction to oncogenes — the Achilles heal of cancer. Science 297, 63–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  263. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).

    Article  CAS  PubMed  Google Scholar 

  264. Nault, J.-C. & Villanueva, A. Intratumor molecular and phenotypic diversity in hepatocellular carcinoma. Clin. Cancer Res. 21, 1786–1788 (2015).

    Article  CAS  PubMed  Google Scholar 

  265. McGranahan, N. & Swanton, C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27, 15–26 (2015).

    Article  CAS  PubMed  Google Scholar 

  266. Gridelli, C. et al. Non-small-cell lung cancer. Nat. Rev. Dis. Primers 1, 1–16 (2015).

    Article  Google Scholar 

  267. Tabernero, J. et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 16, 937–948 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Crowley, E., Di Nicolantonio, F., Loupakis, F. & Bardelli, A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 10, 472–484 (2013).

    Article  CAS  PubMed  Google Scholar 

  269. Thierry, A. R. et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat. Med. 20, 430–435 (2014).

    Article  CAS  PubMed  Google Scholar 

  270. Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

J.M.L. has grants from the US National Cancer Institute (NCI) (P30CA165979), the European Commission Horizon 2020 (HEP-CAR, proposal number 667273–2), the Samuel Waxman Cancer Research Foundation, the Grant I+D Program (SAF2013-41027) and the Asociación Española Contra el Cáncer (AECC). J.Z.-R. has received funding from INSERM, the French National Cancer Institute (INCa) and The Ligue Contre le Cancer (équipe Labellisée). E.P. receives funding from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the European Research Council and the Israel Science Foundation. The authors thank R. Montal, S. Torrecilla, A. Farré and M. Boteller (Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS — Hospital Clinic, Barcelona, Spain) for their support in editing references, figures and tables for this manuscript.

Author information

Authors and Affiliations

Authors

Contributions

Introduction (J.M.L.); Epidemiology (G.G.); Mechanisms/pathophysiology (J.Z.-R. and E.P.); Diagnosis, screening and prevention (M.Sh. and G.G.); Management (M.Sc., B.S. and J.M.L.); Quality of life (M.Sh.); Outlook (J.M.L., G.G. and E.P.); overview of Primer (J.M.L.).

Corresponding author

Correspondence to Josep M. Llovet.

Ethics declarations

Competing interests

J.M.L. receives research support and grants from Bayer Pharmaceuticals, Blueprint Medicines, Bristol-Myers Squibb and Boehringer Ingelheim, and is a consultant for Bayer Pharmaceuticals, Bristol-Myers Squibb, Blueprint Medicines, Eli Lilly and Company, Celsion, Biocompatibles, Boehringer Ingelheim, Novartis and GlaxoSmithKline. M.Sh. is a consultant for Bayer Pharmaceuticals, Celsion, ArQule, H3 Biomedicine and Merck. J.Z.-R. is a consultant for IntegraGen. B.S. has received lecturing and consulting fees from Bayer Healthcare and Sirtex Medical. G.G. is in the Data Safety and Monitoring committee for a Bayer Pharmaceuticals trial in hepatocellular carcinoma. M.Sc. and E.P. have nothing to disclose.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Llovet, J., Zucman-Rossi, J., Pikarsky, E. et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2, 16018 (2016). https://doi.org/10.1038/nrdp.2016.18

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/nrdp.2016.18

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing