Hepatocellular Carcinoma

Key Points

Hepatocellular Carcinoma Surveillance Guidelines

The incidence of hepatocellular carcinoma (HCC) is rising in many countries. HCC is associated with a low 5-year survival rate due to the often advanced state of the disease when it is detected. Early lesion detection improves survival and may allow liver transplantation in selected individuals. Given that there are several known risk factors for the development of HCC, surveillance screening is recommended by many societies for high-risk individuals. However, only one study to date has demonstrated improved survival; therefore, surveillance screening must be limited to those at risk and should be a physician-patient based choice.

• Guideline recommendations for HCC surveillance (see table below)

Diagnosis

Indications for Testing

• Clinical symptoms in the presence of risk factors for hepatocellular carcinoma (HCC)
• Elevated neoplastic markers
• Nonspecific symptoms include jaundice, anorexia, weight loss, malaise, upper abdominal pain

Laboratory Testing

• Initial testing
  • Hepatitis panel if etiology of liver disease is not clear
    • If viral disease confirmed – viral load testing
      • Positive – refer to hepatologist
• Serum markers may be useful in patients with risk factors – alpha-fetoprotein L3 isoform (AFP-L3%) and des-gamma-carboxy-prothrombin (DCP) are more specific than AFP
  • Combined testing – superior to either marker alone
  • No marker is optimal in early stage disease
    • AFP frequently not elevated in early stage disease
  • AFP ≥200 ng/mL – suspect HCC; proceed to imaging studies
  • AFP ≥400 ng/mL – strongly suggests HCC
    • Elevated AFP can occur in the absence of HCC
  • If AFP-L3% is not elevated and ultrasound shows mass – consider variant HCC (eg, fibrolamellar) and follow patient with AFP and liver imaging every 3 months

Histology

• Gold standard for diagnosis of HCC
• Percutaneous biopsy
  • 90% sensitivity, 91% specificity for ultrasound guided specimen
  • 92% sensitivity, 98% specificity for CT guided specimen
• Immunohistochemistry – 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/MRI/CT
  • Liver nodule <1 cm on imaging – follow-up with CT (at least 3-phase)/MRI or ultrasound every 3-6 months
    • Stable nodule – continue imaging every 3-6 months with technique that identified nodule
    • Enlarging nodule – proceed according to nodule size
  • Liver nodule 1-2 cm (in cirrhotic patients) with classic arterial enhancement – diagnostic for HCC; biopsy often unnecessary
    • Noncirrhotic patients – biopsy should be strongly considered
    • 2 classic enhancements – HCC confirmed
    • 0 or 1 classic enhancement – imaging (at least 3-phase CT or MRI), biopsy
  • Liver nodule >2 cm – perform core biopsy (preferred) or FNA

Prognosis

• AFP – ≥400 ng/mL
  • 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 (eg, biliary, pancreatic)
  • Cirrhosis
  • Metabolic disease
    • Hemochromatosis 
    • Wilson disease
    • Metabolic syndrome (eg, nonalcoholic steatohepatitis)
    • α-1 antitrypsin deficiency (AAT)
• Jaundice
  • Other malignancy (eg, biliary, pancreatic)
  • Acute hepatitis
    • Toxins (eg, alcohol)
    • Infectious (HAV, HBV, HCV, HDV)
    • Metabolic
      • Hemochromatosis
      • Wilson disease
      • AAT
• Autoimmune disease
  • Primary biliary cirrhosis
  • Autoimmune hepatitis

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)
    • >26,190 cases and ~3,300 deaths in U.S. in 2011 (NCCN 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)
  • Chronic infections – hepatitis B (HBV), C (HCV), or D (HDV)
    • HBV – majority of HCC in Asia and Africa
      • HBV antigen positivity increases risk 100-fold
    • HCV – risk factor for majority of HCC in Europe, Japan, and North America
      • ~5% of patients have markers of both HBV and HCV
  • 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 infectious 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 (eg, cholangiocarcinoma and angiosarcoma)
• Three morphologic types
  • Nodular – usually associated with cirrhosis
  • Massive – usually associated with noncirrhotic liver disease
  • 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% of cases
  • 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 and growth rate
  • Patient general health
  • Liver function – degree of cirrhosis
  • Available treatment options (eg, resection, transplant)
• Metastatic disease common
  • Common sites – 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 (Vitale, 2011)

Prevention

• HBV
  • Vaccination – markedly reduces HBV infection rate
  • Interferon-based therapies to reduce rate of hepatitis-induced cirrhosis for HBV and HCV infections
• HCV
  • Hemochromatosis – effective iron depletion
  • Hereditary tyrosinemia – liver transplantation
  • Toxin induced – eliminate hepatotoxin exposure (eg, 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 secrete AFP Not interpretable as a tumor marker in pregnant females Use with DCP and AFP-L3% during and following treatment to predict adverse outcome, early recurrence, and malignant potential
Des-gamma-carboxy Prothrombin 0081312 Method: Quantitative Liquid Chromatography/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