Hepatocellular carcinoma (HCC)

Summary

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, arising from hepatocytes. It typically develops in the setting of chronic liver disease and cirrhosis, with hepatitis B, hepatitis C, and alcohol-related liver disease being the leading causes worldwide. In Jordan and the Middle East, chronic hepatitis B infection remains a significant risk factor. The majority of patients (80-90%) have underlying cirrhosis at diagnosis.

Clinical presentation is often insidious, with symptoms including right upper quadrant pain, weight loss, and signs of decompensated liver disease. Diagnosis involves a combination of imaging studies showing characteristic arterial enhancement with rapid washout, and elevated alpha-fetoprotein (AFP) levels. The Barcelona Clinic Liver Cancer (BCLC) staging system guides treatment decisions, which range from potentially curative options (resection, transplantation, ablation) for early-stage disease to systemic therapy for advanced cases. Prognosis depends on tumor burden, liver function, and performance status.

Overview

• Hepatocellular carcinoma (HCC) is a primary liver malignancy arising from hepatocytes
• Third leading cause of cancer-related death worldwide
• Incidence is highest in regions with endemic hepatitis B (Asia, sub-Saharan Africa)
• Male-to-female ratio is approximately 3:1
• Most cases (>80%) occur in patients with underlying cirrhosis
• Surveillance with ultrasound every 6 months is recommended for high-risk patients
• The only definitive cure is surgical resection or liver transplantation in selected patients

Risk Factors & Etiology

• Major risk factors (80-90% of cases have cirrhosis):
  • Chronic hepatitis B infection (HBV)
    • Can cause HCC even without cirrhosis
    • Integration of HBV DNA into host genome
    • Higher risk with high viral load and HBeAg positivity
  • Chronic hepatitis C infection (HCV)
    • Usually requires cirrhosis for HCC development
    • Risk persists even after viral clearance
  • Alcoholic liver disease
    • Synergistic effect with viral hepatitis
  • Non-alcoholic fatty liver disease (NAFLD)/NASH
    • Increasing cause in developed countries
    • Associated with metabolic syndrome
• Other risk factors:
  • Aflatoxin exposure (Aspergillus contamination of grains/nuts)
    • Synergistic with HBV infection
    • Causes p53 mutation (codon 249)
  • Hereditary hemochromatosis
  • α1-antitrypsin deficiency
  • Primary biliary cholangitis
  • Wilson disease
  • Glycogen storage diseases
  • Tyrosinemia
  • Porphyria cutanea tarda

Clinical Features

• Early stage (often asymptomatic):
  • May be detected incidentally on surveillance imaging
  • No specific symptoms
• Advanced stage symptoms:
  • Right upper quadrant pain or fullness
  • Weight loss and anorexia
  • Early satiety
  • Malaise and weakness
  • Abdominal distension (ascites)
• Physical examination findings:
  • Hepatomegaly (irregular, hard, sometimes nodular)
  • Arterial bruit over liver (rare but specific)
  • Ascites
  • Splenomegaly
  • Jaundice (late finding, poor prognosis)
  • Signs of chronic liver disease:
    • Spider angiomas
    • Palmar erythema
    • Gynecomastia
    • Testicular atrophy
    • Caput medusae
• Acute presentations (uncommon):
  • Tumor rupture → hemoperitoneum → shock
  • Acute Budd-Chiari syndrome (hepatic vein thrombosis)
  • Obstructive jaundice (bile duct invasion)

Diagnosis

• Laboratory tests:
  • Alpha-fetoprotein (AFP)
    • Elevated (>400-500 ng/mL) highly suggestive of HCC
    • Normal in 30-40% of HCC cases
    • Can be mildly elevated in chronic hepatitis/cirrhosis
    • Not recommended as sole diagnostic test
  • Liver function tests:
    • May show signs of underlying liver disease
    • Elevated transaminases, bilirubin
    • Decreased albumin, prolonged PT/INR
  • CBC: thrombocytopenia (portal hypertension)
  • Other tumor markers (less commonly used):
    • Des-gamma-carboxy prothrombin (DCP)
    • AFP-L3 fraction
• Imaging studies:
  • Ultrasound
    • Screening tool for surveillance (every 6 months)
    • Hypoechoic or hyperechoic mass
    • Sensitivity: 60-80% for early HCC
  • Multi-phase CT or MRI (diagnostic gold standard)
    • Characteristic pattern:
      • Arterial phase: hyperenhancement (tumor supplied by hepatic artery)
      • Portal venous/delayed phase: rapid washout
    • LI-RADS classification system for standardized reporting
    • Can detect lesions ≥1 cm
• Diagnostic criteria (AASLD/EASL guidelines):
  • Lesions ≥1 cm with typical imaging features (arterial enhancement + washout) in cirrhotic liver → diagnosis without biopsy
  • Lesions <1 cm → follow-up imaging in 3-6 months
  • Atypical lesions → consider biopsy (but risk of tumor seeding)
• Biopsy:
  • Not always required if imaging is typical
  • Indicated for:
    • Atypical imaging findings
    • Non-cirrhotic liver
    • Before systemic therapy (molecular profiling)
  • Risk of tumor seeding along needle tract (1-2%)

Treatment

• Curative treatments:
  • Surgical resection
    • Best for non-cirrhotic patients or Child-Pugh A cirrhosis
    • Adequate liver remnant required (≥40% in cirrhosis)
    • No portal hypertension (portal pressure gradient <10 mmHg)
    • 5-year survival: 60-70%
  • Liver transplantation
    • Treatment of choice for HCC within Milan criteria
    • Treats both tumor and underlying liver disease
    • 5-year survival: 70-80%
    • Limited by organ availability
  • Local ablation (microwave, cryoablation)
    • For tumors ≤3 cm, up to 3 lesions
    • Contraindicated near major vessels/bile ducts
    • Similar outcomes to resection for small tumors
• Palliative treatments

Summary Table