Hepatocellular Carcinoma: Epidemiology, Causes, Pathogenesis, Symptoms, Diagnosis, Staging, Treatment and Prevention

Hepatocellular Carcinoma

~Introduction

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, accounting for nearly 75–85% of all liver cancer cases worldwide. It typically arises in the background of chronic liver disease and cirrhosis, making it one of the most lethal cancers globally. Today, HCC ranks as the sixth most common cancer and the third leading cause of cancer-related deaths, with particularly high prevalence in regions burdened by chronic hepatitis B and hepatitis C infections.

HCC is a complex disease influenced by viral, metabolic, environmental, and genetic factors. Recent decades have seen advances in diagnostic imaging, biomarker development, locoregional therapies, surgical techniques, and systemic treatments such as targeted therapies and immunotherapy. Understanding its epidemiology, pathogenesis, diagnostic pathways, and management strategies is crucial for improving survival and reducing global burden.

~Epidemiology

HCC demonstrates striking geographic variations:

• High incidence regions: East Asia, Southeast Asia, and sub-Saharan Africa

• Intermediate incidence: Mediterranean countries

• Low incidence: North America and Northern Europe

Globally, HCC predominantly affects males, with a male-to-female ratio of approximately 3:1. Age of onset varies with etiology—HBV-associated HCC may occur earlier, while HCV and alcohol-related cases appear later in life.

~Etiology and Risk Factors

HCC arises from various chronic liver injuries. Major risk factors include:

1. Viral Hepatitis

Hepatitis B Virus (HBV)

• The strongest etiologic factor in endemic regions

• HCC can develop even in non-cirrhotic HBV carriers due to direct viral oncogenesis

Hepatitis C Virus (HCV)

• Indirect carcinogenic effect through chronic inflammation

• Most cases develop in cirrhotic livers

2. Alcoholic Liver Disease

Chronic and heavy alcohol consumption leads to:

• Steatohepatitis

• Progressive fibrosis

• Cirrhosis—creating a high-risk environment for HCC development

3. Non-alcoholic Fatty Liver Disease (NAFLD)

An increasingly important cause due to:

• Obesity

• Diabetes

• Metabolic syndrome

Notably, HCC may occur even in non-cirrhotic NAFLD patients.

4. Aflatoxin Exposure

Common in regions with poor food storage practices.
Aflatoxin B1 induces a characteristic mutation in the TP53 gene.

5. Genetic Diseases

• Hemochromatosis

• Wilson’s disease

• Alpha-1 antitrypsin deficiency

6. Other Factors

• Male gender

• Smoking

• Chronic liver damage from autoimmune hepatitis

• Cirrhosis of any cause (major underlying condition)

~Pathogenesis

HCC develops through several steps:

1. Chronic inflammation due to persistent liver injury

2. Hepatocyte regeneration and fibrosis

3. Progression to cirrhosis with nodular transformation

4. Emergence of dysplastic nodules

5. Malignant transformation into early HCC

6. Growth into advanced, vascular-invasive tumor

Molecular alterations include:

• Activation of oncogenic pathways (Wnt/β-catenin, PI3K/AKT)

• Telomerase reactivation

• Tumor suppressor gene mutations (TP53)

• Angiogenesis driven by VEGF

Hepatitis B can directly integrate its DNA into the host genome, promoting carcinogenesis even without cirrhosis.

~Clinical Presentation

HCC symptoms vary widely, depending on tumor size, liver function, and stage.

Early stages

Often asymptomatic; detected during surveillance.

Later stages

• Right upper quadrant pain

• Abdominal fullness or mass

• Weight loss, anorexia

• Fatigue

• Jaundice

• Ascites

• Gastrointestinal bleeding (portal hypertension)

Some patients experience paraneoplastic syndromes such as hypercalcemia or erythrocytosis.

~Diagnostic Evaluation

1. Surveillance

High-risk groups (HBV, HCV, cirrhosis, NAFLD with fibrosis) undergo:

• Ultrasound every 6 months

• Alpha-fetoprotein (AFP) monitoring

2. Imaging

Dynamic Imaging is central to diagnosis.
Typical HCC characteristics:

• Arterial phase hyperenhancement (APHE)

• Washout in portal venous or delayed phase

Common modalities:

• Contrast-enhanced CT

• Contrast-enhanced MRI

• Contrast-enhanced ultrasound (CEUS)

3. Laboratory Tests

• AFP: Elevated in ~50–70% of cases

• Liver function tests

• Virology markers (HBV DNA, HCV RNA)

4. Liver Biopsy

Reserved for atypical lesions or when imaging is inconclusive.

~Staging Systems

Several staging systems exist, but Barcelona Clinic Liver Cancer (BCLC) is most widely used because it links stage to treatment:

BCLC Stages

• Stage 0 (Very early): Single tumor <2 cm, preserved liver function

• Stage A (Early): Up to 3 tumors <3 cm, good liver function

• Stage B (Intermediate): Multinodular, preserved liver function

• Stage C (Advanced): Vascular invasion or extrahepatic spread

• Stage D (Terminal): End-stage liver disease or poor performance status

Other systems: TNM, CLIP score, Child-Pugh classification (for liver function).

~Treatment Modalities

Management depends on tumor burden, liver function, and patient performance status.

1. Surgical Resection

Best option for non-cirrhotic patients or early-stage cirrhotics with good liver reserve.

Advantages:

• Potentially curative

• Good outcomes in selected patients

Limitations:

• High recurrence rate

• Not suitable for advanced cirrhosis

2. Liver Transplantation

Ideal for early-stage HCC within Milan criteria:

• Single tumor ≤5 cm OR

• Up to 3 tumors, each ≤3 cm

• No vascular invasion or metastasis

Benefits:

• Treats both tumor and underlying liver disease

• Best long-term survival

Challenges:

• Organ shortage

• Waiting list drop-outs

3. Locoregional Therapies

Used in early or intermediate stages.

Ablation Therapies

• Radiofrequency Ablation (RFA)

• Microwave Ablation (MWA)

• Percutaneous ethanol injection (PEI)

Best for tumors ≤3 cm.

Transarterial Therapies

Since HCC is highly vascular:

• TACE (Transarterial Chemoembolization)

  • First-line for intermediate-stage HCC

• TARE (Transarterial Radioembolization)

  • Using Yttrium-90 microspheres

  • Useful for portal vein thrombosis

4. Systemic Therapies

Targeted Therapies

• Sorafenib

• Lenvatinib

• Regorafenib

• Cabozantinib

These agents inhibit tumor angiogenesis and growth pathways.

Immunotherapy

Revolutionary advancement in HCC:

• Atezolizumab + Bevacizumab (first-line standard now)

• Nivolumab

• Pembrolizumab

• Durvalumab + Tremelimumab

Particularly effective in selected patient populations.

5. Palliative and Supportive Care

For end-stage disease:

• Pain management

• Nutritional support

• Ascites and encephalopathy control

~Complications

Disease-Related

• Portal vein invasion

• Metastasis (lungs, bones, lymph nodes)

• Portal hypertension complications

• Liver failure

Treatment-Related

• Post-resection liver insufficiency

• Radiation-induced liver disease

• Hand-foot syndrome (TKI therapies)

• Immune-related adverse events

~Prognosis

Survival depends on stage and underlying liver disease:

• Early-stage treated: 5-year survival 50–75%

• Intermediate-stage: 2–3 years median survival

• Advanced-stage: <1 year without treatment, improved to 12–19 months with modern therapies

Prognostic factors:

• Tumor size and number

• AFP level

• Vascular invasion

• Liver function (Child-Pugh class)

• Performance status

~Prevention

1. Hepatitis B Vaccination

World’s first cancer-preventing vaccine; drastically reduces HCC incidence in vaccinated populations.

2. Treatment of Viral Hepatitis

• Antiviral therapy for chronic HBV

• Direct-acting antivirals (DAAs) cure HCV

3. Lifestyle Modifications

• Alcohol cessation

• Weight management

• Control of diabetes and metabolic syndrome

4. Screening and Surveillance

High-risk individuals must undergo:

• Ultrasound ± AFP every 6 months

Early detection dramatically increases survival.

~Conclusion

Hepatocellular carcinoma remains one of the most challenging malignancies due to its association with chronic liver disease, late diagnosis, and complexity of management. However, substantial advancements in screening, imaging, surgical techniques, locoregional therapies, targeted drugs, and immunotherapy have significantly improved outcomes in recent years.

Prevention through vaccination, antiviral therapy, and metabolic disease management represents the most powerful strategy for reducing global incidence. Early detection through rigorous surveillance remains the key to effective treatment. With continued research and public health efforts, the global burden of HCC can be greatly reduced in the future.