Skip to main content

Advertisement

SpringerLink
Log in

Hepatocarcinoma: from pathogenic mechanisms to target therapy

  • Review
  • Published:
Oncology Reviews

Abstract

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. It is currently estimated that there are 14,000–18,000 new cases of hepatocellular carcinoma in the United States each year. It is often difficult to identify individuals at risk for HCC. The main associated diseases are chronic hepatitis B and chronic hepatitis C viral infections. While a significant number of potential mutations have been generated including p53 and Insulin-like Growth Factor, our understanding of the molecular mechanisms driving the genesis and progression of HCC remain limited. HCC screening is recommended in high-risk patients. High-risk patients include virtually all patients with cirrhosis and some HBV-infected patients irrespective of cirrhosis (>40 years in men and >50 years in women). A diagnostic approach to HCC has been developed incorporating serology, cytohistology, and radiological characteristics. A precise staging of the disease may help decide on prognosis as well as choice of therapy with the greatest survival potential. Liver transplantation, in theory, is the optimal therapeutic option for HCC; it simultaneously removes the tumor and underlying cirrhosis thus minimizing the risk of HCC recurrence. When it is impossible for this to be performed, percutaneous ablation, chemoembolization, chemotherapy and the newer molecular therapies can be used. Sorafenib is the only drug registered today for the treatment of advanced HCC.

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

Similar content being viewed by others

References

  1. Gish RG (2006) Risk factors and treatment for hepatocellular carcinoma Gastroenterology & Hepatology 2:477–478

    Google Scholar 

  2. Bosch FX, Ribes J, Borras J (1999) Epidemiology of primary liver cancer. Semin Liv Dis 19:271–285

    Article  CAS  Google Scholar 

  3. Stocker JT (1990) Hepatic tumors. In Balistreri WF, Stocker JT, Pediatric hepatology New York: Hemisphere 399–488

    Google Scholar 

  4. Farazi PA, Glickman J, Horner J et al (2006) cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res 66:4766–4773

    Article  PubMed  CAS  Google Scholar 

  5. Breuhahn K, Longerich T, Schirmacher P (2006) Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 25:3787–3800

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  7. Chen JG, Parkin DM, Chen QG et al (2003) Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen 10:204–209

    Article  PubMed  Google Scholar 

  8. El-Bassiouni A, Nosseir M, Zoheiry M et al (2006) Immunohistochemical expression of CD95 (Fas), c-myc and epidermal growth factor receptor in hepatitis C virus infection, cirrhotic liver disease and hepa tocellular carcinoma. APMIS 114:420–427

    Article  PubMed  CAS  Google Scholar 

  9. Romano PR, McCallus DE, Pachuk CJ (2006) RNA interferencemediated prevention and therapy for hepatocellular carcinoma. Oncogene 25:3857–3865

    Article  PubMed  CAS  Google Scholar 

  10. Trevisani F, De NS, Rapaccini G et al (2002) Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience). Am J Gastroenterol 97:734–744

    Article  PubMed  Google Scholar 

  11. Yuan RH, Jeng YM, Chen HL et al (2006) Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. J Pathol May 31 epub

  12. Zhang BH, Yang BH, Tang ZY (2004) Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 130:417–422

    PubMed  Google Scholar 

  13. Zhang B, Yang B (1999) Combined Alpha-fetoprotein testing and ultra-sonography as a screening test for primary liver cancer. J Med Screen 6:108–110

    PubMed  CAS  Google Scholar 

  14. Bolondi L, Sofia S, Siringo S et al (2001) Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut 48: 251–259

    Article  PubMed  CAS  Google Scholar 

  15. Collier J, Sherman M (1998) Screening for hepatocellular carcinoma. Hepatology 27:273–278

    Article  PubMed  CAS  Google Scholar 

  16. Kim CK, Lim JH, Lee WJ (2001) Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver: accuracy of ultrasonography in transplant patients. J Ultrasound Med 20:99–104

    PubMed  CAS  Google Scholar 

  17. Trevisani F, D’Intino PE, Morselli-Labate AM et al (2001) Serum Alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCVstatus. J Hepatol 34:570–575

    Article  PubMed  CAS  Google Scholar 

  18. Sherman M, Peltekian KM, Lee C (1995) Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 22:432–438

    PubMed  CAS  Google Scholar 

  19. Trevisani F, D’Intino PE, Caraceni P et al (1995) Etiologic factors and clinical presentation of hepatocellular carcinoma. Differences between cirrhotic and noncirrhotic Italian patients. Cancer 75:2220–2232

    Article  PubMed  CAS  Google Scholar 

  20. Bayati N, Silverman AL, Gordon SC (1998) Serum a-fetoprotein levels and liver histology in patients with chronic hepatitis C. Am J Gastroenterol 93:2452–2456

    Article  PubMed  CAS  Google Scholar 

  21. Franca AV, Elias JJ, Lima BL, et al (2004) Diagnosis, staging and treatment of hepatocellular carcinoma. Braz J Med Biol Res 37:1689–1705

    Article  PubMed  CAS  Google Scholar 

  22. Patel D, Terrault NA, Yao FY, et al (2005) Cost-effectiveness of hepatocellular carcinoma surveillance in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol 3:75–84

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  24. Choi D, Kim SH, Lim JH et al (2001) Detection of hepatocellular carcinoma: combined T2-weighted and dynamic gadoliniumenhanced MRI versus combined CT during arterial portography and CT hepatic arteriography. J Comput Assist Tomogr 25:777–785

    Article  PubMed  CAS  Google Scholar 

  25. Arguedas MR, Chen VK, Eloubeidi MA et al (2003) Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis. Am J Gastroenterol 98:679–690

    Article  PubMed  Google Scholar 

  26. Marrero JA, Hussain HK, Nghiem HV et al (2005) Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially enhancing liver mass. Liver Transpl 11:281–289

    Article  PubMed  Google Scholar 

  27. Burrel M, Llovet JM, Ayuso C et al (2003) MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation. Hepatology 38:1034–1042

    PubMed  Google Scholar 

  28. De Ledinghen V, Laharie D, Lecesne R et al (2002) Detection of nodules in liver cirrhosis: spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients. Eur J Gastroenterol Hepatol 14:159–165

    Article  PubMed  Google Scholar 

  29. Libbrecht L, Bielen D, Verslype C et al (2002) Focal lesions in cirrhotic explant livers: pathological evaluation and accuracy of pretransplantation imaging examinations. Liver Transpl 8:749–761

    Article  PubMed  Google Scholar 

  30. Rode A, Bancel B, Douek P et al (2001) Small nodule detection in cirrhotic livers: evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver. J Comput Assist Tomogr 25:327–336

    Article  PubMed  CAS  Google Scholar 

  31. Ebara M, Ohto M, Watanabe Y et al (1986) Diagnosis of small hepatocellular carcinoma: correlation of MR imaging and tumor histologic studies. Radiology 159:371–377

    PubMed  CAS  Google Scholar 

  32. Ebara M, Ohto M, Kondo F (1989) Strategy for early diagnosis of hepatocellular carcinoma (HCC). Ann Acad Med Singapore 18:83–89

    PubMed  CAS  Google Scholar 

  33. Torzilli G, Minagawa M, Takayama T et al (1999) Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy. Hepatology 30:889–893

    Article  PubMed  CAS  Google Scholar 

  34. Bruix J, Sherman M, Llovet JM et al (2001) Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35:421–430

    Article  PubMed  CAS  Google Scholar 

  35. Byrnes V, Shi H, Kiryu S et al (2007) The clinical outcome of small (<20 mm) arterially enhancing nodules on MRI in the cirrhotic liver. Am J Gastroenterol 102:1654–1659

    Article  PubMed  Google Scholar 

  36. Durand F, Regimbeau JM, Belghiti J et al (2001) Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma. J Hepatol 35:254–258

    Article  PubMed  CAS  Google Scholar 

  37. Llovet JM, Bru C, Bruix J (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19:329–338

    Article  PubMed  CAS  Google Scholar 

  38. Zhou XD, Tang ZY, Yang BH et al (2001) Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer 91:1479–1486

    Article  PubMed  CAS  Google Scholar 

  39. Ikai I, Arii S, Kojiro M et al (2004) Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey. Cancer 101:796–802

    Article  PubMed  Google Scholar 

  40. Shi M, Guo RP, Lin XJ et al (2007) Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: a prospective randomized trial. Ann Surg 245:36–43

    Article  PubMed  Google Scholar 

  41. Bruix J, Hessheimer AJ, Forner A, et al (2006) New aspects of diagnosis and therapy of hepatocellular carcinoma. Oncogene 25:3848–3856

    Article  PubMed  CAS  Google Scholar 

  42. Sala M, Varela M, Bruix J (2004) Selection of candidates with HCC for transplantation in the MELD era. Liver Transpl 10[Suppl 2]:S4–S9

    Article  PubMed  Google Scholar 

  43. 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;334:693–699

    Article  PubMed  CAS  Google Scholar 

  44. Shetty K, Timmins K, Brensinger C et al (2004) Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 10:911–918

    Article  PubMed  Google Scholar 

  45. Yao FY, Ferrell L, Bass NM et al (2001) Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 33:1394–1403

    Article  PubMed  CAS  Google Scholar 

  46. Margarit C, Escartin A, Castells L et al (2005) Resection for hepatocellular carcinoma is a good option in Child-Turcotte-Pugh class Apatients with cirrhosis who are eligible for liver transplantation. Liver Transpl 11:1242–1251

    Article  PubMed  Google Scholar 

  47. Yao FY, Hirose R, LaBerge JM et al (2005) A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl 11:1505–1514

    Article  PubMed  Google Scholar 

  48. Adam R, Azoulay D, Castaing D et al (2003) Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg 238:508–518

    Article  PubMed  Google Scholar 

  49. Lo CM, Fan ST, Liu CL et al (2004) The role and limitation of living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 10:440–447

    Article  PubMed  Google Scholar 

  50. Trotter JF, Wachs M, Everson GT et al (2002) Adult-to-adult transplantation of the right hepatic lobe from a living donor. N Engl J Med 346:1074–1082

    Article  PubMed  Google Scholar 

  51. Fisher RA, Kulik LM, Freise CE et al (2007) Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transplant 7:1601–1608

    Article  PubMed  CAS  Google Scholar 

  52. Ringe B, Pichlmayr R, Wittekind C et al (1991) Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg 15:270–285

    Article  PubMed  CAS  Google Scholar 

  53. Ishii H, Okada S, Nose H et al (1996) Local recurrence of hepatocellular carcinoma after percutaneous ethanol injection. Cancer 77:1792–1796

    Article  PubMed  CAS  Google Scholar 

  54. Livraghi T, Bolondi L, Lazzaroni S et al (1992) Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis. A study on 207 patients. Cancer 69:925–929

    Article  PubMed  CAS  Google Scholar 

  55. Vilana R, Bruix J, Bru C et al (1992) Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. Hepatology 16:353–357

    Article  PubMed  CAS  Google Scholar 

  56. Livraghi T, Bolondi L, Buscarini L et al (1995) No treatment, resection and ethanol injection in hepatocellular carcinoma: a retrospective analysis of survival in 391 patients with cirrhosis. Italian Cooperative HCC Study Group. J Hepatol 22:522–526

    Article  PubMed  CAS  Google Scholar 

  57. Yamamoto J, Okada S, Shimada K et al (2001) Treatment strategy for small hepatocellular carcinoma: comparison of longterm results after percutaneous ethanol injection therapy and surgical resection. Hepatology 34:707–713

    Article  PubMed  CAS  Google Scholar 

  58. Ryu M, Shimamura Y, Kinoshita T et al (1997) Therapeutic results of resection, transcatheter arterial embolization and percutaneous transhepatic ethanol injection in 3225 patients with hepatocellular carcinoma: a retrospective multicenter study. Jpn J Clin Oncol 27:251–257

    Article  PubMed  CAS  Google Scholar 

  59. Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 1999;210:655–661

    PubMed  CAS  Google Scholar 

  60. Shiina S, Teratani T, Obi S et al (2005) A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129:122–130

    Article  PubMed  Google Scholar 

  61. Lin SM, Lin CJ, Lin CC et al (2004) Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma ≤4 cm. Gastroenterology 127:1714–1723

    Article  PubMed  Google Scholar 

  62. Lencioni RA, Allgaier HP, Cioni D et al (2003) Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection. Radiology 228:235–240

    Article  PubMed  Google Scholar 

  63. Teratani T, Yoshida H, Shiina S et al (2006) Radiofrequency ablation for hepatocellular carcinoma in so-called high-risk locations. Hepatology 43:1101–1108

    Article  PubMed  Google Scholar 

  64. Liu DQ, Lu MD, Tan JF et al (2006) Microwave coagulation at different temperatures for hepatocellular carcinoma management: efficacy evaluation by enzyme histochemical staining. Nan Fang Yi Ke Da Xue Xue Bao 26:1149–1151

    PubMed  CAS  Google Scholar 

  65. Chen MS, Li JQ, Zheng Y et al (2006) Aprospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 243:321–328

    Article  PubMed  Google Scholar 

  66. Livraghi T, Meloni F, Di SM et al (2008) 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

    Article  PubMed  Google Scholar 

  67. Llovet JM, Real MI, Montana X et al (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739

    Article  PubMed  Google Scholar 

  68. Bruix J, Sala M, Llovet JM (2004) Chemoembolization for hepatocellular carcinoma. Gastroenterology 127[Suppl 1]: S179–S188

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  70. Kulik LM, Atassi B, van Holsbeek L et al (2006) Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellu hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol 94:572–586

    Article  PubMed  CAS  Google Scholar 

  71. Wong LL, Limm WM, Severino R et al (2000) Improved survival with screening for hepatocellular carcinoma. Liver Transpl 6: 320–325

    Article  PubMed  CAS  Google Scholar 

  72. Leung TW, Patt YZ, Lau WY et al (1999) Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 5:1676–1681

    PubMed  CAS  Google Scholar 

  73. Lee J, Park JO, Kim WS et al (2004) Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma. Cancer Chemother Pharmacol 54:385–390

    Article  PubMed  CAS  Google Scholar 

  74. Yeo W, Mok TS, Zee B et al (2005) A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 97:1532–1538

    Article  PubMed  CAS  Google Scholar 

  75. Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–109

    Article  PubMed  CAS  Google Scholar 

  76. Adnane L, Trail PA, Taylor I, Wilhelm SM (2005) Sorafenib (BAY 43-9006, Nexavar), a dual-actioninhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 407:597–612

    Google Scholar 

  77. Chang YS, Adnane J, Trail PA et al (2007) Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59:561–574

    Article  PubMed  CAS  Google Scholar 

  78. Llovet JM, Ricci S et al (2008) Sorafenib in Advanced Hepatocellular Carcinoma. N Engl J Med 359:3:78–90

    Google Scholar 

  79. Schwartz JD, Schwartz M, Lehrer D et al (2006) Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein. J Clin Oncol 24:[Suppl]:213s. abstract

    Google Scholar 

  80. Terstriep S, Grothey A (2006) First-and second-line therapy of metastatic colorectal cancer. Expert Rev Anticancer Ther 6:921–930

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Oncology, A.O. S. Carlo, Potenza, Italy

    Luigi Manzione, Antonio Maria Grimaldi, Rosangela Romano, Domenica Ferrara & Angelo Dinota

Authors
  1. Luigi Manzione
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Maria Grimaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosangela Romano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Domenica Ferrara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angelo Dinota
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonio Maria Grimaldi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Manzione, L., Grimaldi, A.M., Romano, R. et al. Hepatocarcinoma: from pathogenic mechanisms to target therapy. Oncol Rev 2, 214–222 (2008). https://doi.org/10.1007/s12156-008-0077-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12156-008-0077-x

Keywords

Search

Navigation