hepatocellular carcinoma
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Etiology
- risk factors
- hepatic cirrhosis
- 80% of hepatocellular carcinomas occur in patients with cirrhosis[1]
- 30% lifetime risk with cirrhosis & hemochromatosis
- uncommon with primary biliary cirrhosis
- uncommon with hepatolenticular degeneration (Wilson's disease)
- diabetes further increases risk
- obesity further increases risk
- hepatitis B virus
- hepatitis C virus
- non-alcoholic fatty liver disease (NAFLD)
- non-alcoholic steatohepatitis (NASH)
- aflatoxin
- anabolic steroids
- hepatic cirrhosis
Epidemiology
- more common in Asia & Africa than in North America & Europe
- 3rd[1] or 4th[23] leading cause of cancer death world-wide
Pathology
- often dysplastic hepatocytes develop in setting of chronic hepatitis or cirrhosis
Genetics
- no genetic predisposition discernable
- overexpression of SMYD3, YY1AP1 common, PLXNB1
- underexpression of StARD13
- lack of HTATIP2 expression in 33% of hepatocellular carcinomas
- PPAPDC1B may suppress metastases
- defects in MET are a cause of hepatocellular carcinoma
- other implicated genes
Clinical manifestations
- abdominal pain
- malaise
- palpable liver mass
- stigmata of underlying cirrhosis or hepatitis
- may present as rapid deterioration in a patient with previously stable liver disease
Laboratory
- serum alpha-fetoprotein generally elevated (> 20 ng/mL)
- may be used with ultrasound for survelliance[14]
- not for use alone for screening or survelliance[1]
- molecular diagnostic testing
- hepatocellular carcinoma genotyping
- mRNA expression analysis of peripheral blood for genes expressed by circulating hepatocellular carcinoma cells[12]
- autoantibodies: IGF2BP2, PHF20
- see ARUP consult[5]
- liver biopsy (gadolinium-enhanced MRI makes biopsy unnecessary) Special labooratory:
- liver biopsy
- lesions > 1 cm on ultrasound with serum AFP > 20 ng/mL
- required for diagnosis in patients without cirrhosis[14]
- liver biopsy
Radiology
- hepatobiliary ultrasound
- all patients with cirrhosis every 6 months[1][14]
- discontinue ultrasound surveillance in patients with HCV infection or nonalcoholic fatty liver disease without cirrhosis[14]
- contrast-enhanced abdominal computed tomography (CT)
- indications
- serum alpha-fetoprotein > 20 ng/mL
- abnormal abdominal ultrasound
- lesions > 1 cm in patients with cirrhosis that enhance in the arterial phase with washout in the venous phase make the diagnosis; liver biopsy not needed[1]
- indications
- magnetic resonance imaging
- differentiation of regenerating nodules in cirrhosis from hepatocellular carcinoma
- gadolinium-contrast MRI suffcient for diagnosis of hepatocellular carcinoma; biopsy not needed[1]
Staging
- Barcelona Clinic Liver Cancer (BCLC) staging classification
- A asymptomatic early tumors suitable for resection*, transplantation or percutaneous therapy
- B asymptomatic multinodular disease
- C symptomatic tumors &/or an invasive tumors pattern (vascular invasion/extrahepatic spread) candidates for palliative treatment, clinical trials
- D advanced disease, grim prognosis palliatative treatment only[3]
* eligibility for resection, consider liver transplantation for others
- no significant portal hypertension or jaundice
- single lesion <= 5 cm
Differential diagnosis
- hepatic adenoma
- heterogenous in appearance due to hemorrhage & necrosis
- associated with oral contraceptives, discontinue, resect
- focal nodular hyperplasia, regenerating liver nodule
- metastatic tumors
- single or multiple hypoechoic lesions on ultrasound
- hypovascular on contrast-enhanced CT
- isolated lesions may be amenable to resection
- single or multiple hypoechoic lesions on ultrasound
Management
- surgical resection or liver transplantation as primary therapy[1]
- early identification & surgical resection
- after surgery, overall median survival is 45 months, 5-year survival is 39%[4]
- tumor size >2 cm, tumor multifocality, & presence of microvascular invasion predict poor prognosis[4]
- risk for recurrence of hepatocellular carcinoma
- liver transplantation is generally associated with recurrence of tumor
- Milan criteria to assess 5 year prognosis after liver transplantation[1]
- therapies with limited efficacy
- chemotherapy[1]
- sorafenib (Nexavar)[13]
- cabozantinib[15]
- tremelimumab + first-line durvalumab[21]
- a single 300-mg priming dose of tremelimumab with 1,500 mg durvalumab followed by durvalumab every 4 weeks[21]
- arterial embolization
- radiotherapy
- neoadjuvant intensity-modulated radiotherapy is effective & well-tolerated for centrally located hepatocellular carcinoma[22]
- intra-arterial & intratumoral injections
- transarterial chemoembolization + radiotherapy superior to sorafenib (Nexavar) for unresectable hepatocellular carcinoma[13]
- supportive care & hospice for metastatic disease in debilitated patients[1]
- chemotherapy[1]
- progression to death within months is usual;
- overall survival at 3 years is only 5%
- antidepressant use after diagnosis of hepatocellular carcinoma may lower mortality, overall & cancer-specific mortality
- screening of patients with cirrhosis
- periodic abdominal ultrasonography
- serum alpha-fetoprotein
- little evidence to support screening, even in high-risk patients[8]
- prevention
- hepatitis B vaccination is the most important preventive measure[1]
- daily aspirin is associated with a reduced risk of hepatocellular carcinoma (RR = 0.59)[6][16][19]
More general terms
More specific terms
Additional terms
- aflatoxin B1
- alpha-fetoprotein; alpha-1-fetoprotein; alpha-fetoglobulin (AFP HPAFP)
- androgen or anabolic steroid
- cirrhosis
- hemochromatosis
- hepatitis B virus (HBV)
- hepatitis C virus
- hepatocellular carcinoma genotyping
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2012, 2015, 2018, 2021.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ N'Kontchou G et al, Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis Clin Gastroenterol Hepatol 2006, 4:1062 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16844421
- ↑ 3.0 3.1 Llovet JM et al Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329-38. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10518312
- ↑ 4.0 4.1 4.2 Nathan H et al Predictors of survival after resection of early hepatocellular carcinoma. Ann Surg 2009 May; 249:799. PMID: https://www.ncbi.nlm.nih.gov/pubmed/193873
- ↑ 5.0 5.1 ARUP Consult: Hepatocellular Carcinoma The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/hepatocellular-carcinoma
- ↑ 6.0 6.1 Sahasrabuddhe VV et al Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma JNCI J Natl Cancer Inst (2012) November 28 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/3197492 <Internet> http://jnci.oxfordjournals.org/content/early/2012/11/28/jnci.djs452.abstract
Levy IG and Pim CP An Aspirin a Day: The Allure (and Distraction) of Chemoprevention JNCI J Natl Cancer Inst (2012) November 28 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23197493 <Internet> http://jnci.oxfordjournals.org/content/early/2012/11/28/jnci.djs462.full - ↑ Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005 Nov;42(5):1208-36. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16250051 (corresponding NGC guideline withdrawn Nov 2015)
- ↑ 8.0 8.1 Kansagara D et al Screening for Hepatocellular Carcinoma in Chronic Liver Disease: A Systematic Review. Ann Intern Med. Published online 17 June 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24934699 <Internet> http://annals.org/article.aspx?articleid=1882141
- ↑ Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011 Mar;53(3):1020-2. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21374666
- ↑ El-Serag HB Hepatocellular carcinoma. N Engl J Med. 2011 Sep 22;365(12):1118-27 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21992124
- ↑ 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 Mar 14;334(11):693-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8594428
- ↑ 12.0 12.1 Kalinich M, Bhan I, Kwan TT et al. An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. Proc Natl Acad Sci U S A 2017 Jan 31; 114:1123 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28096363 Free PMC Article
- ↑ 13.0 13.1 13.2 Bankhead Combo Therapy Doubles PFS in Unresectable HCC. Chemoembolization plus sorafenib tops embolization alone MedPage Today. January 23, 2018 https://www.medpagetoday.com/meetingcoverage/mgics/70705
Yoon SM, et al Effect of transarterial chemoembolization plus external beam radiotherapy on survival of aptients with hepatocellular carcinoma showing macroscopic vascular invasion compared with sorafenib: A randomized trial. Gastrointestinal Cancers Symposium (GICS) 2018; Abstract 210.
Yoon SM, Ryoo BY, Lee SJ et al Efficacy and Safety of Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma With Macroscopic Vascular Invasion: A Randomized Clinical Trial. JAMA Oncol. 2018 Mar 15. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29543938
Farsad K, Costentin CE, Zhu AX. Hepatocellular Carcinoma With Portal Venous Invasion: Radiating New Hope? JAMA Oncol. 2018 Mar 15. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29543953 - ↑ 14.0 14.1 14.2 14.3 14.4 Marrero JA, Kulik LM, Sirlin C et al. Diagnosis, staging and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2018 Apr 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29624699 https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.29913
- ↑ 15.0 15.1 Abou-Alfa GK, Meyer T, Cheng AL et al Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med 2018; 379:54-63. July 5, 2018 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29972759 https://www.nejm.org/doi/full/10.1056/NEJMoa1717002
- ↑ 16.0 16.1 Simon TG, Ma Y, Ludvigsson JF et al Association Between Aspirin Use and Risk of Hepatocellular Carcinoma. JAMA Oncol. Published online October 4, 2018. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30286235 https://jamanetwork.com/journals/jamaoncology/fullarticle/2704212
- ↑ Heimbach JK, Kulik LM, Finn RS et al AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018 Jan;67(1):358-380. PMID: https://www.ncbi.nlm.nih.gov/pubmed/28130846
- ↑ Villanueva A. Hepatocellular Carcinoma N Engl J Med 2019; 380:1450-1462. April 11. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30970190 https://www.nejm.org/doi/full/10.1056/NEJMra1713263
- ↑ 19.0 19.1 Simon TG, Duberg AS, Aleman S et al. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med 2020 Mar 12; 382:1018 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32160663 https://www.nejm.org/doi/10.1056/NEJMoa1912035
- ↑ Fox E, Patel NT, Patel AD A Farmer With Diffuse Pruritus and a Suntan That Won't Fade Medscape - Jun 08, 2021. https://reference.medscape.com/viewarticle/952272_6
- ↑ 21.0 21.1 21.2 Leiser M FDA approves tremelimumab with durvalumab for advanced liver cancer. Helio. Oct 24, 2022 https://www.healio.com/news/hematology-oncology/20221024/fda-approves-tremelimumab-with-durvalumab-for-advanced-liver-cancer
- ↑ 22.0 22.1 Wu F, Chen B, Dong D et al Phase 2 Evaluation of Neoadjuvant Intensity-Modulated Radiotherapy in Centrally Located Hepatocellular Carcinoma. A Nonrandomized Controlled Trial. JAMA Surg. 2022;157(12):1089-1096 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36197682 PMCID: PMC9535533 (available on 2023-10-05) https://jamanetwork.com/journals/jamasurgery/fullarticle/2797090
- ↑ 23.0 23.1 Brown ZJ, Tsilimigras DI, Ruff SM et al Management of Hepatocellular Carcinoma. A Review. JAMA Surg. Published online February 15, 2023 https://jamanetwork.com/journals/jamasurgery/fullarticle/2801509
- ↑ Cappuyns S, Corbett V, Yarchoan M et al Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma. A Review. JAMA Oncol. Published online August 3, 2023 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37535375 https://jamanetwork.com/journals/jamaoncology/fullarticle/2808069
- ↑ Huang KL, Chen YL, Stewart R et al Antidepressant Use and Mortality Among Patients With Hepatocellular Carcinoma. JAMA Netw Open. 2023;6(9):e2332579 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37672269 PMCID: PMC10483320 Free PMC article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808957
- ↑ National Cancer Institute Adult Primary Liver Cancer Treatment (PDQ) - Health Professional Version https://www.cancer.gov/types/liver/hp/adult-liver-treatment-pdq
Patient information
hepatocellular carcinoma patient information