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hepatocellular carcinoma

Etiology: - risk factors a) hepatic cirrhosis 1] 80% of hepatocellular carcinomas occur in patients with cirrhosis [1] - alcoholism 2] 30% lifetime risk with cirrhosis & hemochromatosis 3] uncommon with primary biliary cirrhosis 4] uncommon with hepatolenticular degeneration (Wilson's disease) 5] diabetes further increases risk 6] obesity further increases risk b) hepatitis B virus c) hepatitis C virus d) non-alcoholic fatty liver disease (NAFLD) e) non-alcoholic steatohepatitis (NASH) f) aflatoxin g) anabolic steroids Epidemiology: 1) more common in Asia & Africa than in North America & Europe 2) 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: 1) no genetic predisposition discernable 2) overexpression of SMYD3, YY1AP1 common, PLXNB1 3) underexpression of StARD13 4) lack of HTATIP2 expression in 33% of hepatocellular carcinomas 5) PPAPDC1B may suppress metastases 6) defects in MET are a cause of hepatocellular carcinoma 7) other implicated genes - GBA3, WDR16, HDMCP, RNF43, SULF1, DDEFL1, ANLN, HCC1, TBRG1, KIAA1524, GLOD4, HEPACAM, OIT3, PRAP1, MTUS1, PGCP, HEPN1, PHF19, PSMG2, PTPRH, CTNNB1, CCNDBP1, PEG10, DNCL2A, DYNLRB2, URG4, MICB, CDKN3, AXIN1 Clinical manifestations: 1) abdominal pain 2) malaise 3) palpable liver mass 4) stigmata of underlying cirrhosis or hepatitis 5) may present as rapid deterioration in a patient with previously stable liver disease Laboratory: 1) 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] 2) molecular diagnostic testing a) hepatocellular carcinoma genotyping b) mRNA expression analysis of peripheral blood for genes expressed by circulating hepatocellular carcinoma cells [12] 3) autoantibodies: IGF2BP2, PHF20 4) see ARUP consult [5] 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] Radiology: 1) 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] 2) contrast-enhanced abdominal computed tomography (CT) a) indications - serum alpha-fetoprotein > 20 ng/mL - abnormal abdominal ultrasound b) 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] 3) magnetic resonance imaging a) differentiation of regenerating nodules in cirrhosis from hepatocellular carcinoma b) 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 - larger lesions may have a central stellate scar, no therapy - metastatic tumors - single or multiple hypoechoic lesions on ultrasound - hypovascular on contrast-enhanced CT - isolated lesions may be amenable to resection Management: 1) surgical resection or liver transplantation as primary therapy [1] 2) early identification & surgical resection a) after surgery, overall median survival is 45 months, 5-year survival is 39% [4] b) tumor size >2 cm, tumor multifocality, & presence of microvascular invasion predict poor prognosis [4] c) risk for recurrence of hepatocellular carcinoma - continue surveillance after resection [1] 3) liver transplantation is generally associated with recurrence of tumor - Milan criteria to assess 5 year prognosis after liver transplantation [1] 4) therapies with limited efficacy a) 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] b) arterial embolization c) radiotherapy - neoadjuvant intensity-modulated radiotherapy is effective & well-tolerated for centrally located hepatocellular carcinoma [22] d) intra-arterial & intratumoral injections e) transarterial chemoembolization + radiotherapy superior to sorafenib (Nexavar) for unresectable hepatocellular carcinoma [13] f) supportive care & hospice for metastatic disease in debilitated patients [1] 5) 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 6) screening of patients with cirrhosis a) periodic abdominal ultrasonography b) serum alpha-fetoprotein c) little evidence to support screening, even in high-risk patients [8] 7) 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]

Interactions

disease interactions

Related

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

Specific

hepatocellular carcinoma [TP53/ARG249SER] hepatocellular carcinoma [TP53/VAL157PHE]

General

adenocarcinoma liver cancer; hepatobiliary carcinoma

Database Correlations

OMIM 114550

References

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