Hepatocellular Carcinoma - HCC

Key Points

HCC Surveillance Guidelines

The incidence of HCC is rising in many countries. HCC is associated with a low 5-year survival rate due to late-stage detection when disease is often advanced. Early lesion detection improves survival and may allow liver transplantation in selected individuals. Surveillance screening for high-risk individuals is recommended by many societies. 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.

Diagnosis

Indications for Testing

• Clinical symptoms in the presence of risk factors for HCC
• Elevated neoplastic markers
• Intrahepatic mass
• Nonspecific symptoms such as jaundice, anorexia, weight loss, malaise, upper abdominal pain

Laboratory Testing

• Initial testing
  • Viral hepatitis testing if etiology of liver disease is unclear
    • If viral disease confirmed, perform viral load testing
  • Hepatic function testing
    • As a panel or separately
      • Albumin
      • Alkaline phosphatase (ALP)
      • Aspartate transaminase (AST)
      • Alanine transaminase (ALT)
      • Bilirubin
    • Gamma-glutamyl transferase (GGT)
  • Prothrombin time (PT)/international normalized ratio (INR)
  • Kidney function testing – evaluate severity of cirrhosis
    • Blood urea nitrogen (BUN)
    • Creatinine
  • CBC with platelets
• Hepatic mass
  • CEA, CA 19-9, liver markers (below)
• Liver tumor markers may be useful in patients with risk factors; however, further studies are needed to confirm role
  • AFP
  • AFP-L3 – more specific than AFP
  • Des-gamma-carboxy-prothrombin (DCP) – more specific than AFP
  • Combined testing – superior to single marker alone
  • No marker is optimal in early-stage disease
    • AFP frequently not elevated in early-stage disease

Histology

• Gold standard for diagnosis of HCC – definitive diagnosis requires biopsy and pathologist examination
• US- or CT-guided percutaneous biopsy

Imaging Studies

• Most surveillance and treatment algorithms currently rely heavily on imaging studies
• MRI or abdominal multiphasic CT – for diagnosis and staging
• Contrast-enhanced US – not recommended as a first-line imaging test (EASL, 2018)
  • Lower sensitivity than MRI or multiphasic CT
  • Can be used when CT and MRI results are inconclusive
• For confirmed HCC
  • Chest CT – evaluate for extrahepatic metastases
  • Bone scan – when skeletal symptoms present

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)
    • Alpha-1 antitrypsin deficiency (AAT)
• Jaundice
  • Other malignancy (eg, biliary, pancreatic)
  • Acute hepatitis
    • Toxins (eg, alcohol)
    • Infectious (hepatitis A, B, C, D)
    • Metabolic
      • Hemochromatosis
      • Wilson disease
      • AAT
• Autoimmune disease
  • Primary biliary cholangitis
  • Autoimmune hepatitis
• Hepatic lesion
  • Infection/abscess (hydatid cyst)
  • Metastatic disease
  • Hemangioma
  • Focal nodular hyperplasia
  • Hepatic adenoma
  • Cholangiocarcinoma
  • Focal nodular hyperplasia
  • Simple cyst

Screening

Refer to Key Points for surveillance guidelines.

Background

Epidemiology

• Incidence
  • 8.6/100,000 new cases per year (liver and intrahepatic bile duct cancer combined) (SEER, 2017)
    • Estimated >40,000 cases and ~28,000 deaths in U.S. in 2017 (SEER, 2017)
  • Fifth most common cancer for men worldwide; ninth for women
  • Second most common cause of cancer-related death
• Age – peaks in 60s in U.S.; 20s-40s in Asian countries
• Sex – M:F >2:1
• Ethnicity – higher incidence in Asian, Hispanic, American Indian/Alaska Native, and African American populations (SEER, 2017)

Risk Factors

• Highest risk in U.S. associated with nonalcoholic fatty liver disease (NAFLD), chronic infectious hepatitis, and alcohol-induced cirrhosis
  • Coexistent risk factors magnify risk
• Cirrhosis – most cases of HCC arise in cirrhotic liver
  • NAFLD/nonalcoholic​​​ steatohepatitis (NASH) – major risk factor leading to cirrhosis and HCC due to high prevalence of diabetes and metabolic syndrome in the U.S.
  • Chronic infections – hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV)
    • HCV – risk factor for HCC in North America
    • HBV – majority of HCC in Asian Americans and African Americans
  • Heavy alcohol consumption – alcoholic cirrhosis
    • >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 cholangitis (PBC)
  • Hereditary metabolic liver diseases
    • AAT
    • Hemochromatosis
    • Wilson disease
    • Hereditary tyrosinemia
    • Porphyria cutanea tarda
  • Glycogen storage diseases
• 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

Pathophysiology

• HCCs arise from
  • Parenchymal cells of the liver
  • Dysplastic nodules (controversial)
• DNA damage leads to activation of proto-oncogenes and deactivation of tumor suppressors
•  80% associated with chronic liver disease and cirrhosis
  • Individuals with HBV may develop HCC without presence of cirrhosis

Clinical Presentation

• Typically asymptomatic until late-stage tumor – often metastatic at presentation
• Most patients have chronic liver disease or cirrhosis
• Constitutional manifestations – anorexia, malaise, weight loss
• Abdominal pain – usually right upper quadrant
  • Friction rub or bruit over liver
  • Abdominal mass
  • Hepatomegaly
  • Ascites
• 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

• Prognosis based on
  • Tumor size and location (resectability)
  • 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
• Prognosis scoring systems
  • Child-Pugh score – assessment of surgical risk in patients with cirrhosis
    • Uses bilirubin, albumin, PT, and presence of ascites and encephalopathy
  • Model for End-Stage Liver Disease (MELD) – determines eligibility for transplant
  • Barcelona Clinic Liver Cancer System – best at stratifying survival (Llovet, 2004)
    • Prognosis poor – 5-year survival <50%
    • Uses tumor extent, liver function, and general condition