Hepatocellular carcinoma (HCC) is one of the most common tumors in the world, particularly in populations with chronic viral hepatitis and Asian or Sub-Saharan African ancestry.

Epidemiology

• Incidence
  • 2.4/100,000
  • 18,000 cases each year in the U.S.
  • 5th most common cancer worldwide
• Age - peaks in 50-60 year olds in U.S. (in Asian countries, 20-50 year olds)
• Sex - M>F (3:1 in populations with a high prevalence of HCC)
• Ethnicity - higher incidence in Asian or African populations

Risk Factors

• Cirrhosis (90% of cases)
  • Infectious - chronic hepatitis B (HBV), C (HCV) or D (HDV)
    • HBV accounts for majority of HCC in China and Africa
    • HCV accounts for majority of HCC in Western hemisphere
  • Heavy alcohol consumption
    • >80 gm/day for >10 years increases risk for HCC 5-fold
  • Autoimmune diseases
    • Autoimmune hepatitis
    • Primary biliary cirrhosis
  • Hereditary metabolic liver diseases
    • Alpha-1-antitrypsin deficiency
    • Hemochromatosis
    • Hereditary tyrosinemia
    • Porphyria cutanea tarda
    • Glycogen storage diseases
  • Non-alcoholic steatohepatitis (NASH)
  • Highest risk in chronic hepatitis and alcohol-induced cirrhosis
• Toxins
  • Aflatoxin B1 - produced by Aspergillus species that contaminate grains and nuts in China and Africa
  • Long term androgenic steroid administration
  • Vinyl chloride exposure
  • Tobacco
• Coexistence of risk factors increases the risk of HCC

Pathophysiology

• Usually hepatocyte malignancy
  • Variants include pleomorphic cell, clear cell, sarcomatous, fibrolamellar or undifferentiated
  • Other tumors (cholangiocarcinoma and angiosarcoma)

Clinical Presentation

• Most patients have a past history of chronic liver disease or cirrhosis
• Abdominal pain - usually right upper quadrant, friction rub or bruit over liver, abdominal mass, hepatomegaly, ascites
• Constitutional manifestations - anorexia, malaise, weight loss
• Jaundice
• Paraneoplastic syndromes (20%)
  • Acquired porphyria
  • Cryofibrinogenemia
  • Diarrhea (vasoactive intestinal polypeptide)
  • Erythrocytosis (erythropoietin-like activity)  
  • Hypercalcemia (parathyroid-like hormone)
  • Hypercholesterolemia
  • Hypoglycemia (insulin growth factor)
  • Polymyositis
• Degree of underlying cirrhosis impacts survival; general prognosis is very poor (5 year survival <50%)
  • Barcelona Clinic Liver Cancer System is the best at stratifying for survival (for more information, refer to Sala, 2005)

Prevention

• Hepatitis B vaccination markedly reduces infection rate
• Interferon-based therapies to reduce rate of hepatitis-induced cirrhosis for hepatitis B and C
• Effective iron depletion for patients with hemochromatosis
• Liver transplantation in hereditary tyrosinemia
• Elimination of hepatotoxin exposure (alcohol, aflatoxin)

Diagnosis

• Indications for testing - clinical symptoms in the presence of risk factors; elevated markers
• Biopsy - histopathology of tissue sample is diagnostic
• Imaging - ultrasound, CT/MRI

Disease Monitoring

• Markers
  • Alpha fetoprotein (AFP)-L3%
    • Specificity for HCC is >90%
    • May be predictive of tumor aggressiveness
    • Elevated AFP-L3% is associated with a seven-fold increase in the risk of developing HCC within the next 21 months in a patient who does not currently have HCC but has chronic liver disease
  • Alpha fetoprotein (AFP)
    • Less specific than AFP-L3%
  • Des-gamma-carboxy prothrombin (DCP)
    • Complements hepatocellular carcinoma markers AFP or AFP-L3% in surveillance and risk assessment for hepatocellular carcinoma
    • Useful marker for following patients with HCC after therapy if they were positive prior to therapy
    • Elevated DCP is associated with an increased risk for developing hepatocellular carcinoma
  • TP53 mutations are under investigation at this time

Disease Screening

• No guidelines exist which demonstrate routine screening changes outcome
  • Most liver centers use routine surveillance (every 6 months)
  • Screening generally includes tumor markers and imaging (combination of AFP-L3%, des-gamma-carboxy prothrombin, ultrasound)