Hepatocellular Carcinoma

Diagnosis

Indications for Testing

• Clinical symptoms in the presence of risk factors; elevated neoplastic markers

Laboratory Testing

• Markers – alpha-fetoprotein L3 isoform (AFP-L3) with des-gamma-carboxy-prothrombin (DCP) in patient with risk factors (combined testing is superior to either marker alone)
  • Recommend ultrasound and tissue diagnosis
  • AFP ≥200 ng/mL – suspect HCC

Histology

• Percutaneous biopsy – 90% sensitivity, 91% specificity for ultrasound guided; 92% sensitivity, 98% specificity for CT guided
• Immunohistochemistry – alpha-1-fetoprotein (AFP); alpha-1-antichymotrypsin (A1ACT); beta-catenin-1; cytokeratin 8,18 low molecular weight (CAM 5.2); factor XIIIa; hepatocyte-specific antigen (HSA)

Imaging Studies

• Ultrasound, CT, MRI
  • Consider HCC if focal hepatic mass >2 cm (in cirrhotic patients) shows vascularity on 2 studies
    • No biopsy necessary
    • If lesion <2 cm, perform second study and look for hypervascularity
      • If no hypervascularity noted
        • AFP >400 ng/mL – malignancy likely
        • AFP ≤400 ng/mL – biopsy
  • If AFP, AFP-L3% not elevated and ultrasound shows mass, consider variant HCC (eg, fibrolamellar)

Prognosis

• AFP 
  • ≥400 ng/L associated with greater tumor size and invasiveness, lower rate of survival

Differential Diagnosis

• Abdominal pain
  • Acute cholecystitis
  • Acute pancreatitis 
  • Infectious diarrhea
    • Parasitic
    • Viral
• Hepatomegaly
  • Other malignancy (biliary, pancreatic)
  • Cirrhosis
  • Metabolic disease
    • Hemochromatosis 
    • Wilson disease
    • Metabolic syndrome (NASH)
    • AAT
• Jaundice
  • Other malignancy (biliary, pancreatic)
  • Acute hepatitis
    • Toxins (eg, alcohol)
    • Infectious (HAV, HBV, HCV, HDV)
    • Metabolic
      • Hemochromatosis
      • Wilson disease
      • AAT
• Autoimmune disease
  • PBC
  • AIH

Screening

Monitoring

Clinical Background

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

Epidemiology

• Incidence
  • 4-11/100,000 (U.S. and Europe)
    • >24,000 cases in U.S. in 2010 (SEER estimate)
  • Third most common cancer worldwide
• Age – peaks in 60s in U.S.; 20s-40s in Asian countries
• Sex – M>F 3:1 in populations with a high prevalence of HCC
• Ethnicity – higher incidence in Asian and 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
      • HBV antigen positivity increases risk 100-fold
    • HCV accounts for majority of HCC in Western hemisphere
  • Heavy alcohol consumption
    • >80 gm/day for >10 years increases risk for HCC fivefold
    • Risk further increases two- to fourfold in the presence of chronic viral hepatitis
  • Autoimmune diseases
    • Autoimmune hepatitis (AIH)
    • Primary biliary cirrhosis (PBC)
  • Hereditary metabolic liver diseases
    • α-1-antitrypsin deficiency (AAT)
    • Hemochromatosis
    • Wilson disease
    • Hereditary tyrosinemia
    • Porphyria cutanea tarda
    • Glycogen storage diseases
  • Nonalcoholic steatohepatitis (NASH)
  • Highest risk in chronic hepatitis and alcohol-induced cirrhosis
• Toxins
  • Aflatoxin B1 – consumption of grains and nuts contaminated with Aspergillus spp (China and Africa)
  • Long-term androgenic steroid therapy
  • Vinyl chloride (occupational exposure)
  • Tobacco use
• Family history of HCC
• Coexistent risk factors magnify risk

Pathophysiology

• Usually hepatocyte malignancy
  • Variants include pleomorphic cell, clear cell, sarcomatous, fibrolamellar or undifferentiated
  • Other tumors (cholangiocarcinoma and angiosarcoma)
• Three morphologic types
  • Nodular – usually associated with cirrhosis
  • Massive – usually associated with noncirrhotic liver
  • Diffuse – less common

Clinical Presentation

• Typically asymptomatic until late-stage tumor; often metastatic at presentation
• Most patients have previous 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
• Unexplained decompensation in patients with underlying cirrhosis
• Paraneoplastic syndromes (20%)
  • Acquired porphyria
  • Cryofibrinogenemia
  • Diarrhea (vasoactive intestinal polypeptide)
  • Erythrocytosis (erythropoietin-like activity)
  • Hypercalcemia (parathyroid-like hormone)
  • Hypercholesterolemia
  • Hypoglycemia (insulin growth factor)
  • Polymyositis

Prognosis

• Four main parameters affect prognosis
  • Tumor aggressiveness, growth rate
  • Patient general health
  • Liver function (degree of cirrhosis)
  • Available treatment options (eg, resection, transplant)
• Metastatic disease common
  • Most often found in lung, abdominal lymph nodes, bone
• General prognosis usually very poor (5-year survival <50%)
  • Barcelona Clinic Liver Cancer System is the best at stratifying survival (Sala, 2005)

Prevention

• HBV vaccination – markedly reduces HBV infection rate
• Interferon-based therapies to reduce rate of hepatitis-induced cirrhosis for HBV and HCV infections
• Effective iron depletion for patients with hemochromatosis
• Liver transplantation in hereditary tyrosinemia
• Eliminate hepatotoxin exposure (alcohol, aflatoxin, tobacco, occupational toxins)

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Alpha Fetoprotein, Serum (Tumor Marker) 0080428 Method: Quantitative Chemiluminescent Immunoassay	Not all liver cancers are AFP secreting Other liver diseases may elevate AFP Use with DCP, AFP-L3% during and following treatment to predict adverse outcome, early recurrent and malignant potential
Alpha Fetoprotein, Total and L3 Percent 0081208 Method: Quantitative Liquid-Phase Binding Immunoassay	Predicts more malignant stage and poor outcome Post-treatment monitoring (where pre-treatment AFP-L3% elevated) as an adjunct to imaging Monitor disease after surgery, transplantation or percutaneous therapy Not all liver cancers are AFP-L3 secreting Not interpretable as a tumor marker in pregnant females
Des-gamma-carboxy Prothrombin 0081312 Method: Quantitative Liquid-Phase Binding Immunoassay	Not all liver cancers secrete DCP 25-50% of patients with HCC will have negative results for DCP Sensitivity – 86% when combined with AFP and AFP-L3% Useful marker for monitoring patients with HCC after therapy (if positive prior to therapy)
Hepatitis B Virus Surface Antigen with Reflex to Confirmation 0020089 Method: Qualitative Chemiluminescent Immunoassay	Presence of this marker indicates increased risk for HCC