Key Facts

HCC is increasing in incidence globally and in the UK, driven by NAFLD/MASLD and residual HCV burden. Surveillance in cirrhotic patients enables early detection and curative treatment.

Epidemiology

• ~6,000 new cases/year in the UK; incidence rising
• Male:female ratio 3:1
• Fifth most common cancer worldwide; third most common cause of cancer death
• 5-year survival: approximately 15% overall (stage-dependent)

Aetiology

• Cirrhosis (any cause): 80-90% of HCC arises in cirrhotic livers
• Alcohol-related liver disease: most common cause of cirrhosis in UK
• NAFLD/MASLD: fastest rising cause (can cause HCC without cirrhosis in 10-20%)
• Hepatitis B: major cause globally; can cause HCC without cirrhosis
• Hepatitis C: major cause in UK/US; risk reduced but not eliminated with SVR
• Haemochromatosis, alpha-1 antitrypsin deficiency, autoimmune hepatitis, PBC
• Aflatoxin B1 exposure: Aspergillus contamination of grains/nuts (sub-Saharan Africa, Asia)

Pathophysiology

• Chronic liver injury → inflammation → regeneration → fibrosis → cirrhosis → dysplastic nodules → HCC
• Key molecular pathways: Wnt/β-catenin, PI3K/AKT/mTOR, RAS/MAPK, VEGF
• HBV: direct oncogenic effect (HBx protein disrupts p53); can cause HCC without cirrhosis
• HCC is highly vascular (arterial supply) — basis for imaging diagnosis and TACE treatment
• AFP produced by HCC cells (not all tumours produce AFP)

Early HCC (screen-detected)

• Often asymptomatic
• Detected on surveillance USS/AFP

Symptomatic HCC

• Right upper quadrant pain
• Weight loss
• Hepatomegaly (may be palpable mass)
• Worsening of previously stable liver disease (decompensation)
• Ascites
• Jaundice (if advanced/decompensated)

Complications

• Hepatic decompensation (new ascites, variceal bleeding, encephalopathy)
• Rupture with intraperitoneal haemorrhage (rare, surgical emergency)
• Budd-Chiari syndrome (hepatic vein invasion)
• Portal vein thrombosis (tumour thrombus)

Red Flags

• New decompensation in a previously stable cirrhotic patient
• Rapidly rising AFP
• New hepatomegaly or liver mass on examination
• Budd-Chiari features (ascites, hepatomegaly, RUQ pain)
• Paraneoplastic: hypoglycaemia, erythrocytosis, hypercalcaemia

Bedside

• Abdominal examination (hepatomegaly, ascites, splenomegaly)
• Signs of chronic liver disease (spider naevi, palmar erythema, gynaecomastia)

Bloods

• AFP: screening and monitoring marker; >400 ng/mL highly suggestive
• FBC, U&Es, LFTs, coagulation (INR)
• Hepatitis serology: HBsAg, anti-HCV, HBV DNA, HCV RNA
• Child-Pugh score and MELD score (assess liver function/transplant eligibility)

Imaging

• Surveillance: 6-monthly USS ± AFP
• Diagnostic: CT or MRI with contrast (arterial phase hyperenhancement + portal venous/delayed phase washout = diagnostic of HCC in cirrhotic liver — LI-RADS classification)
  • MRI with Primovist (hepatocyte-specific contrast): superior for small lesions and differentiation from dysplastic nodules
• CT chest: staging (lung metastases)
• Bone scan: if suspected bone metastases

Special Tests

• Biopsy: NOT routinely required if typical imaging features in cirrhotic liver (risk of seeding 2-5%)
  • Required if: atypical imaging, non-cirrhotic liver, or diagnosis uncertain
• Child-Pugh score: guides treatment eligibility
• BCLC staging: integrates tumour stage, liver function, and performance status

Non-pharmacological

• MDT discussion mandatory (hepatologist, HPB surgeon, radiologist, oncologist, transplant team)
• Alcohol cessation
• Antiviral therapy for HBV/HCV (reduces recurrence risk)
• Nutritional support

Pharmacological

• Advanced HCC (BCLC C) — first-line: atezolizumab 1,200mg + bevacizumab 15mg/kg IV every 3 weeks (IMbrave150 trial)
  • Contraindication to bevacizumab: durvalumab + tremelimumab (HIMALAYA trial)
• Second-line: sorafenib 400mg BD or lenvatinib 8-12mg OD
• Third-line: regorafenib, cabozantinib, ramucirumab (if AFP ≥400)

Surgical/Interventional

• BCLC 0-A (very early/early):
  • Surgical resection: for single HCC in non-cirrhotic liver or compensated cirrhosis (Child-Pugh A)
  • Liver transplantation: within Milan criteria (single ≤5cm or up to 3 lesions each ≤3cm, no vascular invasion, no extrahepatic disease); curative for both cancer and cirrhosis
  • Ablation (RFA, microwave): for tumours <3cm, especially if not surgical candidates
• BCLC B (intermediate):
  • Transarterial chemoembolisation (TACE): delivers chemotherapy directly + embolic agent into tumour arterial supply
• BCLC D (end-stage): best supportive care/palliative

Referral Criteria

• All HCC: hepato-pancreato-biliary/liver cancer MDT
• Within Milan criteria: transplant assessment
• Cirrhosis surveillance: 6-monthly in hepatology/gastroenterology clinic

• BCLC 0 (very early): 5-year survival >70% with resection or ablation
• BCLC A (early): 5-year survival 50-70% (transplant achieves best outcomes)
• BCLC B (intermediate): median survival 20-26 months with TACE
• BCLC C (advanced): median survival 12-19 months with atezolizumab + bevacizumab
• BCLC D (end-stage): median survival 3 months
• Overall 5-year survival: approximately 15%
• Liver transplant within Milan criteria: 5-year survival >70%; recurrence rate <15%
• Post-resection recurrence: 50-70% at 5 years (new tumours and intrahepatic metastases)

BCLC Staging and Treatment

Milan Criteria for Liver Transplantation