Hepatocellular Carcinoma (HCC)
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for 75-85% of liver cancers. It typically arises in the context of chronic liver disease, especially cirrhosis. The major risk factors are hepatitis B and C, alcohol-related liver disease, and increasingly non-alcoholic steatohepatitis (NASH/MASLD). HCC can be diagnosed non-invasively using characteristic imaging patterns on multiphasic CT or MRI (arterial enhancement with venous/delayed washout). Treatment depends on tumour stage, liver function (Child-Pugh), and performance status, ranging from curative options (resection, transplantation, ablation) to locoregional therapies (TACE, TARE) and systemic therapy (atezolizumab-bevacizumab).
Key Facts
- Incidence: 6th most common cancer, 3rd leading cause of cancer death globally
- Risk Factors: Cirrhosis (any cause), HBV, HCV, Alcohol, NASH
- Screening: 6-monthly USS ± AFP in cirrhotics
- Diagnosis: Multiphasic CT/MRI (arterial enhancement, venous washout)
- Curative Options: Resection, Transplant (Milan criteria), Ablation
- Palliative Options: TACE, TARE, Sorafenib, Lenvatinib, Atezolizumab-Bevacizumab
Clinical Pearls
"Cirrhosis is the Biggest Risk Factor": 80-90% of HCC occurs in cirrhotic livers. Screen ALL cirrhotics with 6-monthly USS.
"No Biopsy Needed for Typical HCC": If multiphasic CT/MRI shows arterial enhancement + portal venous washout in a cirrhotic liver, diagnosis is confirmed. Biopsy risks seeding.
"Milan Criteria for Transplant": Single tumour ≤5cm OR up to 3 tumours ≤3cm each. No macrovascular invasion or extrahepatic spread.
"HBV Can Cause HCC Without Cirrhosis": Unlike other causes, HBV is directly oncogenic. Screen HBV carriers even without cirrhosis.
Incidence
- 6th most common malignancy worldwide
- 3rd leading cause of cancer death
- ~10,000 new cases/year in UK
- Incidence rising globally (NASH epidemic)
Demographics
- M:F = 3:1
- Peak incidence: 50-70 years
- Geographic variation: Highest in East Asia and sub-Saharan Africa (HBV endemic)
Risk Factors
| Factor | Relative Risk |
|---|---|
| Cirrhosis (any cause) | 20-40x |
| Hepatitis B (with cirrhosis) | 100x |
| Hepatitis B (without cirrhosis) | 15-20x |
| Hepatitis C (with cirrhosis) | 20-30x |
| Alcohol-related liver disease | 10x |
| NASH/MASLD | 3-5x |
| Haemochromatosis | 20x |
| Aflatoxin exposure | Synergistic with HBV |
Preventable Causes
- HBV vaccination (primary prevention)
- HCV treatment (SVR reduces risk by 70-80%)
- Alcohol cessation
- NASH management
Carcinogenesis
- Chronic hepatocyte injury → Inflammation → Fibrosis → Cirrhosis
- Regenerative nodules → Dysplastic nodules → HCC
- Duration: Typically 20-30 years from injury to HCC
Molecular Pathways
- p53 mutations
- WNT/β-catenin pathway activation
- Telomere shortening and TERT activation
- RAS/MAPK signalling dysregulation
HBV-Specific Oncogenesis
- HBV integrates into host genome
- HBx protein has direct oncogenic effects
- Can cause HCC WITHOUT cirrhosis
Tumour Biology
- Hypervascular (arterialised blood supply)
- Portal vein invasion common
- Alpha-fetoprotein (AFP) produced by 70%
Symptoms
| Feature | Notes |
|---|---|
| Often asymptomatic | Found on surveillance |
| Abdominal pain | RUQ discomfort, dull ache |
| Weight loss | Non-specific |
| Hepatic decompensation | Ascites, encephalopathy, jaundice |
| Acute presentation | Rupture → Haemoperitoneum (rare but dramatic) |
Signs
Paraneoplastic Syndromes
Assessment
- Performance status (ECOG)
- Signs of liver disease: Jaundice, ascites, encephalopathy, spider naevi
- Hepatomegaly: May be nodular
- Splenomegaly (portal hypertension)
- Peripheral oedema
Child-Pugh Score (Liver Function)
| Parameter | 1 Point | 2 Points | 3 Points |
|---|---|---|---|
| Bilirubin (μmol/L) | <34 | 34-50 | >0 |
| Albumin (g/L) | >5 | 28-35 | <28 |
| INR | <1.7 | 1.7-2.3 | >.3 |
| Ascites | None | Mild | Moderate-severe |
| Encephalopathy | None | Grade 1-2 | Grade 3-4 |
- Class A: 5-6 points (good function)
- Class B: 7-9 points (moderate impairment)
- Class C: 10-15 points (severe impairment)
Surveillance (At-Risk Patients)
- 6-monthly abdominal ultrasound
- ± AFP (variable guidelines; may improve sensitivity)
- Who to screen: All cirrhotics, HBV carriers (especially Asian males >40, African >20)
Diagnostic Imaging
| Modality | Features |
|---|---|
| Multiphasic CT/MRI | DIAGNOSTIC if: Arterial phase enhancement + Venous/delayed washout |
| LI-RADS Classification | Standardised reporting for HCC probability |
Tumour Markers
- AFP: Elevated in 70%; >400 ng/mL highly suggestive
- AFP <20 = normal; 20-400 = non-specific; >400 = suggestive of HCC
- AFP-L3, DCP: Additional markers (not routine)
Biopsy
- NOT required if classic imaging features in cirrhotic liver
- Consider if: Atypical imaging, non-cirrhotic liver, therapeutic implications
- Risk: Needle tract seeding (1-3%)
Staging Investigations
- CT chest/abdomen/pelvis
- Bone scan if symptoms
- MRI liver with hepatocyte-specific contrast (Primovist)
Staging: BCLC (Barcelona Clinic Liver Cancer)
| Stage | Criteria | Treatment |
|---|---|---|
| 0 (Very early) | Single <2cm, PS 0, Child-Pugh A | Resection/Ablation |
| A (Early) | Single or ≤3 nodules ≤3cm, PS 0, Child-Pugh A-B | Resection/Transplant/Ablation |
| B (Intermediate) | Multinodular, PS 0, Child-Pugh A-B | TACE |
| C (Advanced) | Portal invasion/extrahepatic, PS 1-2 | Systemic therapy |
| D (Terminal) | Child-Pugh C, PS 3-4 | Best supportive care |
Curative Treatments
Surgical Resection
- Suitable for: Non-cirrhotic or Child-Pugh A with adequate remnant
- 5-year survival: 50-70%
Liver Transplantation
- Milan Criteria: Single ≤5cm OR up to 3 nodules each ≤3cm
- No macrovascular invasion, no extrahepatic spread
- Cures BOTH cancer and underlying liver disease
- 5-year survival: 70-80%
Ablation (RFA/MWA)
- For tumours ≤3cm (equivalent to resection)
- Can be percutaneous or laparoscopic
- Complete ablation in >90% for small tumours
Locoregional Therapy
TACE (Transarterial Chemoembolisation)
- Delivers chemotherapy + embolisation via hepatic artery
- For intermediate stage (BCLC B)
- Median survival: 26-40 months
TARE (Transarterial Radioembolisation)
- Y-90 microspheres
- Alternative to TACE; may have role in portal vein invasion
Systemic Therapy
| Line | Regimen | Notes |
|---|---|---|
| First-line | Atezolizumab + Bevacizumab | Now standard; supersedes sorafenib |
| Second-line | Sorafenib, Lenvatinib | TKIs with OS benefit |
| Subsequent | Cabozantinib, Regorafenib, Ramucirumab | After TKI failure |
Of HCC
- Portal vein thrombosis
- Hepatic decompensation
- Tumour rupture → Haemoperitoneum
- Metastases (lung, bone, lymph nodes)
- Paraneoplastic syndromes
Of Treatment
- Post-hepatectomy liver failure
- Transplant rejection/immunosuppression complications
- Post-ablation: Abscess, haemorrhage
- TACE: Post-embolisation syndrome
- Systemic therapy: Hypertension, proteinuria, bleeding (bevacizumab)
Survival by Stage
| Stage | Median Survival |
|---|---|
| BCLC 0 | > years |
| BCLC A | 2-5 years |
| BCLC B | 1-2 years |
| BCLC C | 6-12 months |
| BCLC D | <3 months |
Post-Treatment Survival
| Treatment | 5-Year Survival |
|---|---|
| Transplant (Milan) | 70-80% |
| Resection | 50-70% |
| Ablation (≤3cm) | 50-70% |
| TACE | 20-30% |
| Systemic (advanced) | <5% |
Recurrence
- 70% recurrence at 5 years post-resection
- Lower with transplantation (cures underlying disease)
Key Guidelines
- EASL Clinical Practice Guidelines: HCC (2018)
- AASLD Guidelines for HCC (2018)
- ESMO Guidelines (2021)
- NICE NG85: Cirrhosis in Over 16s (Surveillance)
Key Evidence
IMbrave150 Trial (2020)
- Atezolizumab + Bevacizumab vs Sorafenib
- Superior OS (19.2 vs 13.4 months) and PFS
- Now first-line standard of care
Milan Criteria (1996)
- Landmark study defining transplant criteria
- Validated 4-year survival 75%
Surveillance Meta-Analysis
- 6-monthly USS surveillance reduces HCC mortality
- Improves early detection and curative treatment rates
What is Hepatocellular Carcinoma?
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer - meaning the cancer starts in the liver itself. It usually develops in people who have an underlying liver condition, particularly cirrhosis (scarring of the liver).
What Causes It?
The main risk factors are:
- Hepatitis B or C infection
- Alcohol-related liver disease
- Fatty liver disease (NASH/MASLD)
- Cirrhosis from any cause
- Haemochromatosis (iron overload)
What Are the Symptoms?
In early stages, HCC often causes no symptoms. As it grows, you might notice:
- Pain or discomfort in the upper right abdomen
- Weight loss and poor appetite
- Yellowing of the skin or eyes (jaundice)
- Swelling in the abdomen (ascites)
- Feeling very tired
How is it Found?
If you have cirrhosis, you should have regular screening (ultrasound scan every 6 months). HCC can also be diagnosed with special CT or MRI scans that show a typical pattern.
How is it Treated?
Treatment depends on how advanced the cancer is and how well your liver is working:
- Early stage: Surgery to remove the tumour, liver transplant, or destruction of the tumour with heat (ablation)
- Intermediate stage: Targeted treatment delivered through blood vessels (TACE)
- Advanced stage: Immunotherapy and targeted medicines
Can HCC Be Prevented?
Yes, many cases are preventable:
- Hepatitis B vaccination
- Treatment of hepatitis C (highly effective)
- Reducing alcohol intake
- Maintaining a healthy weight
Primary Guidelines
- EASL. Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. J Hepatol. 2018;69(1):182-236.
- Marrero JA, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the AASLD. Hepatology. 2018;68(2):723-750. PMID: 29624699
Key Studies
- Finn RS, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma (IMbrave150). N Engl J Med. 2020;382(20):1894-1905. PMID: 32402160
- Mazzaferro V, et al. Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis (Milan Criteria). N Engl J Med. 1996;334(11):693-699. PMID: 8594428