Key Facts

HCC is the commonest primary liver cancer and the fastest-rising cause of cancer death in the UK. Surveillance of at-risk populations enables detection at a stage amenable to curative treatment.

Epidemiology

~6,200 new cases per year in the UK. Male predominance (3:1). Incidence has trebled over the past 30 years. Globally, HCC is the 3rd leading cause of cancer death. In the UK, NAFLD-related HCC is increasing while HCV-related HCC is declining with DAA treatment.

Aetiology

• Cirrhosis (any cause): ~80-90% of HCC arises in cirrhotic livers
• Chronic HBV: can cause HCC even WITHOUT cirrhosis (HBV integrates into genome)
• Chronic HCV: mainly through cirrhosis pathway
• Alcohol/NAFLD: increasingly common causes in UK
• Aflatoxin B1: food contaminant (Sub-Saharan Africa, Southeast Asia) — synergistic with HBV
• Haemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency

Pathophysiology

Chronic liver inflammation → repetitive hepatocyte death and regeneration → accumulation of genetic/epigenetic alterations → dysplastic nodules → HCC. Key molecular pathways: WNT/β-catenin, TP53, PI3K/mTOR, TERT promoter mutations. HBV directly contributes through insertional mutagenesis. NAFLD-related HCC may arise without significant fibrosis in some cases. HCC is characteristically hypervascular (arterial neovascularisation) — the basis for diagnostic imaging criteria.

Early Disease (Screen-Detected)

• Often asymptomatic
• Rising AFP on surveillance
• Nodule detected on surveillance USS

Symptomatic Disease

• RUQ pain/discomfort
• Weight loss, anorexia
• Hepatomegaly (often irregular/nodular)
• Worsening liver function in known cirrhotic (decompensation)
• Paraneoplastic: polycythaemia (EPO), hypoglycaemia, hypercalcaemia

Advanced Disease

• Ascites (portal vein invasion, peritoneal carcinomatosis)
• Variceal bleeding (portal vein tumour thrombosis)
• Jaundice
• Bone pain (metastases)

Red Flags

• New hepatic mass in cirrhotic patient
• Rapidly rising AFP (>200 ng/mL strongly suggestive)
• Sudden hepatic decompensation without other explanation
• Portal vein thrombosis (tumour invasion vs bland thrombus)
• Haemoperitoneum (HCC rupture — surgical emergency)

Bedside

• History: underlying liver disease, surveillance compliance

Bloods

• AFP (alpha-fetoprotein): >200 ng/mL strongly suggestive of HCC in cirrhotic; >400 virtually diagnostic; normal AFP does not exclude HCC (~40% are AFP-negative)
• LFTs, albumin, INR, FBC: assess liver function (Child-Pugh/MELD)
• HBV/HCV status: treatment implications

Imaging

• Contrast-enhanced CT or MRI (multiphase): diagnostic in cirrhotic liver if lesion shows:
  • Arterial phase hyperenhancement AND portal venous/delayed phase washout — this pattern is pathognomonic for HCC ≥1 cm in cirrhotic liver (LI-RADS 5)
  • No biopsy needed if imaging is characteristic
• MRI with hepatobiliary contrast (gadoxetate/Primovist): superior for detecting small HCC (<2 cm) and distinguishing from dysplastic nodules
• CT chest: staging for lung metastases
• Bone scan: if bone pain or elevated ALP

Special Tests

• Liver biopsy: only if imaging inconclusive (atypical enhancement) in lesions 1-2 cm; risk of tumour seeding (~2%) and bleeding
• BCLC staging (Barcelona Clinic Liver Cancer): integrates tumour burden, liver function, and performance status to guide treatment

Non-pharmacological

• HCC MDT discussion: all cases — hepatologist, HPB surgeon, transplant surgeon, radiologist, oncologist, CNS
• Treat underlying liver disease: antiviral therapy, alcohol abstinence

Pharmacological

• Advanced/unresectable HCC — first-line: atezolizumab 1200 mg + bevacizumab 15 mg/kg IV every 3 weeks (IMbrave150 trial — superior to sorafenib; NICE TA816)
• Second-line: sorafenib 400 mg BD or lenvatinib 12 mg OD (if ≥60 kg) — for those who progress/are ineligible for atezolizumab-bevacizumab
• Other systemic options: cabozantinib, ramucirumab (if AFP ≥400), regorafenib
• Transarterial chemoembolisation (TACE): doxorubicin-loaded beads delivered via hepatic artery; for intermediate stage (BCLC B)

Surgical/Interventional

• Surgical resection: for single HCC with preserved liver function (Child-Pugh A, no portal hypertension); 5-year survival ~60-70%
• Liver transplantation: curative for HCC AND underlying cirrhosis; Milan criteria (single ≤5 cm or ≤3 lesions each ≤3 cm); 5-year post-transplant survival ~70%
• Ablation (RFA, microwave): for early HCC ≤3 cm not suitable for resection; equivalent to resection for lesions <2 cm
• TACE: for intermediate stage HCC (multinodular, Child-Pugh A-B)
• Selective internal radiation therapy (SIRT/Y-90): alternative to TACE in selected patients
• Bridging/downstaging therapy: TACE or ablation while awaiting transplant, or to bring tumour within Milan criteria

Referral Criteria

• All HCC to specialist MDT (hepatology + HPB surgery)
• Transplant assessment if within Milan criteria
• Palliative care: advanced HCC not amenable to active treatment

Prognosis depends on BCLC stage. Very early/early (BCLC 0-A): 5-year survival 50-70% with curative treatment (resection, transplant, ablation). Intermediate (BCLC B): median survival 20 months with TACE. Advanced (BCLC C): median survival ~12-14 months with atezolizumab-bevacizumab. Terminal (BCLC D): median survival <3 months. Screen-detected HCC has significantly better outcomes than symptomatic presentation. Recurrence after resection is ~70% at 5 years (high rate driven by underlying cirrhosis creating new tumours).

BCLC Staging and Treatment

Milan Criteria for Transplant