Hepatocellular carcinoma (HCC) is the most common primary malignant tumour of the liver, arising from hepatocytes. It represents a major cause of cancer-related morbidity and mortality worldwide, particularly in regions with a high prevalence of chronic viral hepatitis infection.

HCC commonly develops in the setting of chronic liver disease and cirrhosis. The major associated causes include chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). Other contributing conditions include alcohol-related liver disease, non-alcoholic fatty liver disease, and metabolic liver disorders.

The disease often presents at an advanced stage due to delayed symptom development. Clinical presentation may include right upper abdominal pain, abdominal swelling, weight loss, fever, jaundice, ascites, and signs of hepatic dysfunction.

Management depends on tumour stage, liver function reserve, and patient performance status. Treatment options include surgical resection, liver transplantation, locoregional therapy, systemic therapy, radiotherapy, and supportive palliative care.

Assessment of liver function is essential in treatment planning and is commonly performed using the Child–Pugh scoring system.

Epidemiology

Hepatocellular carcinoma is the predominant form of primary liver cancer, accounting for approximately 75–85% of primary hepatic malignancies.

Epidemiological characteristics include:

• More common in males than females.

• Incidence is highest in regions with high prevalence of chronic HBV infection.

• Occurs commonly in individuals with underlying cirrhosis.

• Increasing incidence is associated with metabolic liver disease worldwide.

In Tanzania and other sub-Saharan African countries, HCC represents a significant cancer burden due to:

• High prevalence of chronic hepatitis B infection.

• Limited access to early screening and diagnosis.

• Late presentation with advanced disease.

Risk factors

Major risk factors for hepatocellular carcinoma include:

1. Chronic hepatitis B infection

HBV is one of the strongest risk factors for HCC.

Risk occurs through:

• Persistent viral replication.

• Chronic hepatic inflammation.

• Direct viral integration into hepatocyte DNA.

HCC may occur in HBV infection even without cirrhosis.

2. Chronic hepatitis C infection

HCV increases HCC risk mainly through:

• Chronic inflammation.

• Progressive fibrosis.

• Development of cirrhosis.

3. Liver cirrhosis

Major causes include:

• Chronic viral hepatitis.

• Alcohol-related liver disease.

• Non-alcoholic steatohepatitis (NASH).

4. Alcohol consumption

Chronic heavy alcohol use causes:

• Hepatic inflammation.

• Fibrosis.

• Cirrhosis.

• Increased HCC risk.

5. Metabolic disorders

Including:

• Obesity.

• Diabetes mellitus.

• Metabolic syndrome.

• Non-alcoholic fatty liver disease.

6. Aflatoxin exposure

Exposure to aflatoxin-contaminated foods increases risk, particularly in individuals with chronic HBV infection.

7. Genetic and inherited conditions

Associated conditions include:

• Hemochromatosis.

• Alpha-1 antitrypsin deficiency.

• Wilson disease.

Pathophysiology

Hepatocellular carcinoma develops through progressive genetic and cellular changes occurring in chronically injured liver tissue.

The typical pathway involves:

1. Chronic liver injury.

2. Persistent inflammation.

3. Fibrosis formation.

4. Cirrhosis development.

5. Malignant transformation of hepatocytes.

HBV contributes through:

• Viral DNA integration into hepatocyte genomes.

• Alteration of cellular growth pathways.

HCV contributes mainly through:

• Chronic immune-mediated hepatocyte injury.

• Oxidative stress.

• Fibrosis progression.

Tumour progression occurs through:

• Local hepatic invasion.

• Portal vein invasion.

• Lymphatic spread.

• Hematogenous metastasis.

Common metastatic sites include:

• Lung.

• Bone.

• Brain.

Clinical presentation

Hepatocellular carcinoma may remain asymptomatic in early stages and is often detected during surveillance of high-risk patients.

Clinical manifestations depend on:

• Tumour size.

• Number of lesions.

• Liver function status.

• Presence of metastases.

Symptoms

Local hepatic symptoms

• Right upper abdominal pain.

• Right upper abdominal swelling.

• Abdominal fullness.

• Reduced appetite.

Constitutional symptoms

• Unintentional weight loss.

• Fever.

• Fatigue.

• General weakness.

Symptoms due to liver dysfunction

• Jaundice.

• Abdominal distension due to ascites.

• Easy bruising or bleeding.

Symptoms due to advanced disease

• Bone pain due to skeletal metastases.

• Shortness of breath due to lung metastases.

• Neurological symptoms due to brain metastases.

Clinical signs

Clinical examination may reveal:

Liver-related findings

• Hepatomegaly.

• Right upper abdominal mass.

• Liver tenderness.

Vascular and portal hypertension signs

• Ascites.

• Splenomegaly.

• Peripheral oedema.

Tumour-related signs

• Arterial bruit over the liver.

• Abdominal swelling.

Signs of advanced disease

• Jaundice.

• Cachexia.

• Reduced performance status.

Differential diagnosis

Differential diagnoses of hepatocellular carcinoma include:

• Liver metastases from other cancers.

• Hepatic adenoma.

• Liver abscess.

• Hepatic cyst.

• Cholangiocarcinoma.

• Liver lymphoma.

• Regenerative nodules in cirrhosis.

• Focal nodular hyperplasia.

Diagnostic criteria

Diagnosis should be suspected in patients with:

• Chronic hepatitis B or C infection.

• Known liver cirrhosis.

• Right upper abdominal swelling or pain.

• Weight loss with liver enlargement.

• Jaundice or ascites.

Diagnostic confirmation is based on:

• Characteristic imaging findings on multiphasic liver CT/MRI.

• Elevated alpha-fetoprotein (AFP) levels.

• Histological confirmation where required.

Investigations

Laboratory investigations

Full blood count (FBC)

Assessment of:

• Anaemia.

• Platelet count.

• General health status.

Liver function tests (LFTs)

Assess:

• Hepatic reserve.

• Baseline liver dysfunction.

Includes:

• Bilirubin.

• Albumin.

• Transaminases.

Renal function tests (RFTs)

Includes:

• Urea.

• Creatinine.

Important before contrast imaging and systemic therapy.

Serum alpha-fetoprotein (AFP)

• Tumour marker associated with HCC.

• Useful for diagnosis support and monitoring response.

Viral hepatitis markers

Include:

• Hepatitis B surface antigen (HBsAg).

• Hepatitis B core antibody.

Coagulation profile

Includes:

• Partial thromboplastin time (PTT).

• Prothrombin time assessment.

Important because liver dysfunction affects coagulation.

Imaging investigations

Chest X-ray (CXR)

Used for:

• Baseline assessment.

• Detection of pulmonary metastases.

Abdominal and pelvic ultrasound scan

Used for:

• Detection of liver lesions.

• Surveillance in high-risk patients.

Three-phase liver protocol CT scan with intravenous contrast

Provides assessment of:

• Tumour vascular characteristics.

• Tumour extent.

• Portal vein involvement.

• Resectability.

MRI liver with contrast

Used when CT findings are inconclusive or further tumour characterization is required.

PET/CT

May be used for:

• Assessment of metastatic disease.

• Selected cases requiring staging clarification.

Tissue diagnosis

Liver biopsy or FNAC

Indicated when:

• Imaging findings are not diagnostic.

• Histological confirmation is required.

Staging

Hepatocellular carcinoma is staged using the TNM staging system:

T – Primary tumour

Assessment includes:

• Tumour size.

• Number of lesions.

• Vascular invasion.

• Local extension.

N – Regional lymph nodes

Assessment of regional nodal involvement.

M – Distant metastasis

Assessment of spread to:

• Lung.

• Bone.

• Brain.

• Other organs.

Assessment of liver function: Child–Pugh score

The Child–Pugh score evaluates hepatic reserve and guides treatment decisions.

(For primary biliary cirrhosis: bilirubin thresholds differ: 1–4, 4–10, >10 mg/dL.)

Management

Management depends on:

• Tumour stage.

• Resectability.

• Liver function reserve.

• Child–Pugh classification.

• Patient performance status.

Management pathway:

1. Confirm diagnosis and stage disease.

2. Assess hepatic reserve.

3. Determine resectability.

4. Provide curative or palliative treatment.

Non-pharmacological treatment

Surgical treatment

Partial hepatectomy

Indicated for:

• Resectable tumours.

• Adequate remaining liver function.

• Absence of extensive vascular invasion.

Liver transplantation

Indicated for:

• Unresectable tumours.

• Medically operable patients meeting transplant criteria.

• Significant underlying liver dysfunction.

Radiotherapy

Radiotherapy may be used for:

• Unresectable disease.

• Patients unsuitable for surgery.

• Palliation of metastatic lesions.

Palliative radiotherapy indications

• Bone metastases.

• Brain metastases.

Supportive care

Includes:

• Pain control.

• Nutritional support.

• Management of ascites.

• Symptom relief.

• Psychosocial support.

Pharmacological treatment

Systemic therapy for advanced disease

Sorafenib

Drug: SorafenibDose: 400 mgRoute: OralFrequency: Once dailyDuration: Until disease progression or unacceptable toxicity.

Indication:

• Advanced unresectable HCC.

• Patients unsuitable for curative therapy.

Palliative chemotherapy

Doxorubicin

Drug: DoxorubicinDose: 60 mg/m²Route: Intravenous infusion over 30 minutesFrequency: Day 1 every 3 weeksDuration: 4–6 cycles.

Management according to underlying cause

Hepatitis B-associated HCC

Management includes:

• Tumour-directed therapy according to stage.

• Antiviral management of chronic HBV infection according to hepatitis treatment guidelines.

• Regular surveillance of high-risk patients.

Hepatitis C-associated HCC

Management includes:

• Cancer treatment according to stage.

• Assessment and treatment of chronic HCV infection.

• Monitoring for liver disease progression.

Cirrhosis-associated HCC

Management requires:

• Assessment of Child–Pugh score.

• Management of portal hypertension.

• Control of ascites and hepatic complications.

Referral

All patients with suspected or confirmed HCC should be referred to specialized hepatobiliary oncology centres.

Referral should involve:

• Hepatology.

• Surgical oncology.

• Medical oncology.

• Interventional radiology.

• Palliative care.

Urgent referral indications

• Rapidly enlarging liver mass.

• Severe jaundice.

• Refractory ascites.

• Hepatic failure.

• Evidence of metastatic disease.

• Severe abdominal pain.

Complications

Disease-related complications

• Liver failure.

• Portal vein thrombosis.

• Ascites.

• Variceal bleeding.

• Metastatic disease.

• Cachexia.

Treatment-related complications

Surgery

• Bleeding.

• Liver failure.

• Infection.

Systemic therapy

• Hand-foot syndrome (sorafenib).

• Hypertension.

• Fatigue.

• Myelosuppression.

Radiotherapy

• Fatigue.

• Radiation-induced liver injury.

Prognosis

Prognosis depends on:

• Tumour stage.

• Liver function reserve.

• Presence of vascular invasion.

• Performance status.

• Response to treatment.

Patients with early-stage disease who undergo curative therapy have better outcomes.

Advanced HCC associated with poor liver function or metastatic disease has limited survival.

Prevention

Preventive strategies include:

Hepatitis B prevention

• Universal hepatitis B vaccination.

• Screening and management of chronic HBV infection.

Hepatitis C prevention

• Prevention of blood-borne transmission.

• Screening of high-risk populations.

• Treatment of chronic HCV infection.

Liver disease prevention

• Avoid excessive alcohol consumption.

• Maintain healthy body weight.

• Control diabetes and metabolic syndrome.

• Reduce exposure to aflatoxin-contaminated foods.

Surveillance

High-risk individuals should undergo regular monitoring with:

• Liver ultrasound.

• AFP measurement where appropriate.