Advances and Challenges in Hepatocellular Carcinoma: A Comprehensive Review
DOI:
https://doi.org/10.12775/JEHS.2023.49.01.002Keywords
hepatocellular carcinoma, cirrhosis, non-alcoholic steatohepatitis, transartransarterial chemoembolizationAbstract
Hepatocellular carcinoma (HCC) stands as a pressing global health concern. It is the predominant form of liver cancer and ranks among the leading causes of cancer-related death globally. Hepatitis B virus infection and hepatitis C infection remain the primary risk factors for the development of HCC. However, recently other factors such as cirrhosis due to chronic alcohol intake and non-alcoholic steatohepatitis have been becoming an increasingly common risk factor. The advancement and refinement of diagnostic methods play a crucial role in early diagnosis and surveillance, especially in high-risk populations. Patients diagnosed with hepatocellular carcinoma face a challenging prognosis, despite advancements in surgical techniques and other therapeutic interventions. This underscores the importance of sustained attention to this issue. Continuous research into systemic therapies and refining diagnostic strategies is imperative to address the dynamic landscape of HCC. Efforts to reduce risk factors, coupled with improved surveillance, may contribute to a decline in HCC incidence in the future. This comprehensive review delves into current research on HCC, focusing on risk factors, symptoms, diagnosis, and treatment options.
References
Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018. Published 2016 Apr 14. doi:10.1038/nrdp.2016.18
Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380(15):1450-1462. doi:10.1056/NEJMra1713263
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660
International Agency for Research on Cancer. GLOBOCAN 2018. IARC
Park W, Chung YH, Kim JA, et al. Recurrences of hepatocellular carcinoma following complete remission by transarterial chemoembolization or radiofrequency therapy: focused on the recurrence patterns. Hepatol Res. 2013;43:1304–1312. doi: 10.1111/hepr.12083.
European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).
Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723-750. doi:10.1002/hep.29913
Scartozzi M, Faloppi L, Bianconi M, et al. The role of LDH serum levels in predicting global outcome in HCC patients undergoing TACE: implications for clinical management. PLoS One. 2012;7(3):e32653. doi:10.1371/journal.pone.0032653
Marengo A, Rosso C, Bugianesi E. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis. Annu Rev Med. 2016;67:103-117. doi:10.1146/annurev-med-090514-013832
Gurtsevitch VE. Human oncogenic viruses: hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis. Biochemistry (Mosc). 2008;73(5):504-513. doi:10.1134/s0006297908050039
WHO. Department of Communable Diseases, Surveillance and Response: WHO. Hepatitis B. 2002
Szabó E, Páska C, Kaposi Novák P, Schaff Z, Kiss A. Similarities and differences in hepatitis B and C virus induced hepatocarcinogenesis. Pathol Oncol Res. 2004;10(1):5-11. doi:10.1007/BF02893401
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012;30(12):2212-2219. doi:10.1016/j.vaccine.2011.12.116
Crissien AM, Frenette C. Current management of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2014;10(3):153-161.
McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49(5 Suppl):S45-S55. doi:10.1002/hep.22898
Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health. 2016;4(9):e609-e616. doi:10.1016/S2214-109X(16)30143-7
Michielsen PP, Francque SM, van Dongen JL. Viral hepatitis and hepatocellular carcinoma. World J Surg Oncol. 2005;3:27. Published 2005 May 20. doi:10.1186/1477-7819-3-27
Liaw YF, Tai DI, Chu CM, et al. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study. Gastroenterology. 1986;90(2):263-267. doi:10.1016/0016-5085(86)90919-4
Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 1981;2(8256):1129-1133. doi:10.1016/s0140-6736(81)90585-7
World Health Organization (WHO). Hepatitis B 3rd dose (HepB3) immunization coverage. Accessed October 28, 2020.
World Health Organization (WHO). Immunization coverage. WHO; 2020. Accessed October 20, 2020.
Puigvehí M, Moctezuma-Velázquez C, Villanueva A, Llovet JM. The oncogenic role of hepatitis delta virus in hepatocellular carcinoma. JHEP Rep. 2019;1(2):120-130. Published 2019 May 16. doi:10.1016/j.jhepr.2019.05.001
Choo QL, Richman KH, Han JH, et al. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci U S A. 1991;88(6):2451-2455. doi:10.1073/pnas.88.6.2451
Bostan N, Mahmood T. An overview about hepatitis C: a devastating virus. Crit Rev Microbiol. 2010;36(2):91-133. doi:10.3109/10408410903357455
Alan D, Herbst BA, Reddy KR. Risk Factors for Hepatocellular Carcinoma. Clinical Liver Disease. 2012;1(6)
Ferenci P, Fried M, Labrecque D, Bruix J, Sherman M, Omata M, et al. World Gastroenterology Organisation guideline. Hepatocellular carcinoma (HCC): a global perspective. J Gastrointestin Liver Dis. 2010;19:311–317.
Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol. 2002;155(4):323-331. doi:10.1093/aje/155.4.323
Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. Published 2021 Jan 21. doi:10.1038/s41572-020-00240-3
Lanini S, Easterbrook PJ, Zumla A, Ippolito G. Hepatitis C: global epidemiology and strategies for control. Clin Microbiol Infect. 2016;22(10):833-838. doi:10.1016/j.cmi.2016.07.035
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection [published correction appears in N Engl J Med. 2014 Apr 10;370(15):1469]. N Engl J Med. 2014;370(3):211-221. doi:10.1056/NEJMoa1306218
Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology. 2017;153(4):996-1005.e1. doi:10.1053/j.gastro.2017.06.012
Cooke GS, Andrieux-Meyer I, Applegate TL, et al. Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission [published correction appears in Lancet Gastroenterol Hepatol. 2019 May;4(5):e4]. Lancet Gastroenterol Hepatol. 2019;4(2):135-184. doi:10.1016/S2468-1253(18)30270-X
El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol. 2006;4(3):369-380. doi:10.1016/j.cgh.2005.12.007
Jepsen P, Ott P, Andersen PK, Sørensen HT, Vilstrup H. Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a Danish nationwide cohort study. Ann Intern Med. 2012;156(12):841-W295. doi:10.7326/0003-4819-156-12-201206190-00004
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-133. doi:10.1002/hep.29466
Kanwal F, Kramer JR, Mapakshi S, et al. Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease. Gastroenterology. 2018;155(6):1828-1837.e2. doi:10.1053/j.gastro.2018.08.024
Waly Raphael S, Yangde Z, Yuxiang C. Hepatocellular carcinoma: focus on different aspects of management. ISRN Oncol. 2012;2012:421673. doi:10.5402/2012/421673
Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci. 2002;963:13-20. doi:10.1111/j.1749-6632.2002.tb04090.x
Groopman JD, Scholl P, Wang JS. Epidemiology of human aflatoxin exposures and their relationship to liver cancer. Prog Clin Biol Res. 1996;395:211-222.
Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421–430. doi: 10.1016/S0168-8278(01)00130-1.
El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology. 2008;134:1752–1763. doi: 10.1053/j.gastro.2008.02.090.
Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J Hepatol. 2020;72(2):250-261. doi:10.1016/j.jhep.2019.08.025
Papatheodoridis G, Dalekos G, Sypsa V, et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol. 2016;64(4):800-806. doi:10.1016/j.jhep.2015.11.035
El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118-1127. doi:10.1056/NEJMra1001683
Omata M, Lesmana LA, Tateishi R, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int. 2010;4:439–474. doi: 10.1007/s12072-010-9165-7.
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 [published correction appears in J Hepatol. 2012 Jun;56(6):1430]. J Hepatol. 2012;56(4):908-943. doi:10.1016/j.jhep.2011.12.001
Bruix J, Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022. doi: 10.1002/hep.24199.
Leoni S, Piscaglia F, Golfieri R, et al. The impact of vascular and nonvascular findings on the noninvasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria. Am J Gastroenterol. 2010;105(3):599-609. doi:10.1038/ajg.2009.654.
Bolondi L. Screening for hepatocellular carcinoma in cirrhosis. J Hepatol. 2003;39(6):1076-1084. doi:10.1016/s0168-8278(03)00349-0
Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther. 2009;30(1):37-47. doi:10.1111/j.1365-2036.2009.04014.x
Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist. 2010;15 Suppl 4:14-22. doi:10.1634/theoncologist.2010-S4-14
Ryder SD; British Society of Gastroenterology. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut. 2003;52 Suppl 3(Suppl 3):iii1-iii8. doi:10.1136/gut.52.suppl_3.iii1
Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF. Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality. N Engl J Med. 2020;382(11):1018-1028. doi:10.1056/NEJMoa1912035
Shinmura R, Matsui O, Kobayashi S, et al. Cirrhotic nodules: association between MR imaging signal intensity and intranodular blood supply. Radiology. 2005;237(2):512-519. doi:10.1148/radiol.2372041389
van der Pol CB, Lim CS, Sirlin CB, et al. Accuracy of the Liver Imaging Reporting and Data System in Computed Tomography and Magnetic Resonance Image Analysis of Hepatocellular Carcinoma or Overall Malignancy-A Systematic Review. Gastroenterology. 2019;156(4):976-986. doi:10.1053/j.gastro.2018.11.020
Paisant A, Vilgrain V, Riou J, et al. Comparison of extracellular and hepatobiliary MR contrast agents for the diagnosis of small HCCs. J Hepatol. 2020;72(5):937-945. doi:10.1016/j.jhep.2019.12.011
Atiq O, Tiro J, Yopp AC, et al. An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis. Hepatology. 2017;65(4):1196-1205. doi:10.1002/hep.28895
Willatt JM, Hussain HK, Adusumilli S, Marrero JA. MR imaging of hepatocellular carcinoma in the cirrhotic liver: challenges and controversies. Radiology. 2008;247:311–330. doi: 10.1148/radiol.2472061331. .
Andersson KL, Salomon JA, Goldie SJ, Chung RT. Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2008;6:1418–1424. doi: 10.1016/j.cgh.2008.08.005.
Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonography as a screening test for primary liver cancer. J Med Screen. 1999;6(2):108-110. doi:10.1136/jms.6.2.108
Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 2010;138:493–502. doi: 10.1053/j.gastro.2009.10.031.
Somi MH. Hepatocellular Carcinoma. Hepatitis Monthly. 2005;5(3):65–76
Pons F, Varela M, Llovet JM. Staging systems in hepatocellular carcinoma. HPB (Oxford). 2005;7(1):35-41. doi:10.1080/13651820410024058
Llovet, J. M. et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology https://doi.org/10.1002/hep.31327 (2020).
Raza A, Sood GK. Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World J Gastroenterol. 2014;20(15):4115-4127. doi:10.3748/wjg.v20.i15.4115
Cabrera R, Nelson DR. Review article: the management of hepatocellular carcinoma. Aliment Pharmacol Ther. 2010;31(4):461-476. doi:10.1111/j.1365-2036.2009.04200.x
Forner A, Hessheimer AJ, Isabel Real M, Bruix J. Treatment of hepatocellular carcinoma. Crit Rev Oncol Hematol. 2006;60:89–98. doi: 10.1016/j.critrevonc.2006.06.001.
Yu SJ. A concise review of updated guidelines regarding the management of hepatocellular carcinoma around the world: 2010–2016. Clin Mol Hepatol. 2016;22:7–17. doi: 10.3350/cmh.2016.22.1.7.
Kohles N, Nagel D, Jüngst D, Durner J, Stieber P, Holdenrieder S. Prognostic relevance of oncological serum biomarkers in liver cancer patients undergoing transarterial chemoembolization therapy. Tumour Biol. 2012;33:33–40. doi: 10.1007/s13277-011-0237-7.
Shrager B, Jibara G, Schwartz M, Roayaie S. Resection of hepatocellular carcinoma without cirrhosis. Ann Surg. 2012;255(6):1135-1143. doi:10.1097/SLA.0b013e31823e70a3
Roayaie S, Obeidat K, Sposito C, et al. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology. 2013;57(4):1426-1435. doi:10.1002/hep.25832
Franssen B, Jibara G, Tabrizian P, Schwartz ME, Roayaie S. Actual 10-year survival following hepatectomy for hepatocellular carcinoma. HPB (Oxford). 2014;16(9):830-835. doi:10.1111/hpb.12206
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(11):693-699. doi:10.1056/NEJM199603143341104
Tabrizian, P. et al. A US multicenter analysis of 2529 HCC patients undergoing liver transplantation: 10-year outcome assessing the role of down-staging to within Milan criteria. Hepatology 70, 10–11 (2019).
Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358-380. doi:10.1002/hep.29086
Lencioni R, Cioni D, Crocetti L, Franchini C, Pina CD, Lera J, Bartolozzi C. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology. 2005;234:961–967. doi:10.1148/radiol.2343040350
Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: Ethanol injection therapy and radiofrequency ablation. Gastroenterology. 2004;127:S159–S166. doi:10.1053/j.gastro.2004.09.030
Llovet JM, De Baere T, Kulik L, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18(5):293-313. doi:10.1038/s41575-020-00395-0
Yu J, Yu XL, Han ZY, et al. Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial. Gut. 2017;66(6):1172-1173. doi:10.1136/gutjnl-2016-312629
Hu J, Chen S, Wang X, Lin N, Yang J, Wu S. Image-Guided Percutaneous Microwave Ablation Versus Cryoablation For Hepatocellular Carcinoma In High-Risk Locations: Intermediate-Term Results. Cancer Manag Res. 2019;11:9801-9811. Published 2019 Nov 18. doi:10.2147/CMAR.S227961
Cheng RG, Bhattacharya R, Yeh MM, Padia SA. Irreversible Electroporation Can Effectively Ablate Hepatocellular Carcinoma to Complete Pathologic Necrosis. J Vasc Interv Radiol. 2015;26(8):1184-1188. doi:10.1016/j.jvir.2015.05.014
Wang P, Sheng L, Wang G, et al. Association of transarterial chemoembolization with survival in patients with unresectable hepatocellular carcinoma. Mol Clin Oncol. 2014;2(2):203-206. doi:10.3892/mco.2014.239
Poyanli A, Rozaneş I, Acunaş B, Sencer S. Palliative treatment of hepatocellular carcinoma by chemoembolization. Acta Radiol. 2001;42(6):602-607. doi:10.1080/028418501127347278
Greten TF, Papendorf F, Bleck JS, et al. Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients. Br J Cancer. 2005;92(10):1862-1868. doi:10.1038/sj.bjc.6602590
Janevska D, Chaloska-Ivanova V, Janevski V. Hepatocellular Carcinoma: Risk Factors, Diagnosis and Treatment. Open Access Maced J Med Sci. 2015;3(4):732-736. doi:10.3889/oamjms.2015.111
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