Hepatocellular Carcinoma (Liver Cancer): Causes, Staging and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, accounting for 75–85% of primary liver cancers. It is the sixth most common cancer globally and the third leading cause of cancer mortality, with approximately 900,000 new cases and 830,000 deaths annually (GLOBOCAN 2020). HCC develops almost exclusively (80–90%) in the setting of chronic liver disease — particularly cirrhosis — driven by chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcoholic liver disease, or non-alcoholic fatty liver disease/metabolic-associated steatohepatitis (MASLD/MASH). The Barcelona Clinic Liver Cancer (BCLC) staging system — integrating tumor burden, liver function (Child-Pugh score), and performance status — is the standard framework for treatment allocation. Prognosis depends critically on liver functional reserve: Child-Pugh A patients with resectable disease have 5-year survival exceeding 70%, whereas advanced HCC carries a median overall survival of 12–14 months with modern systemic therapy. Surveillance of cirrhotic patients with 6-monthly liver ultrasound and AFP enables early detection and curative treatment.

Chronic HBV infection is the dominant global cause of HCC, particularly in East Asia and sub-Saharan Africa, where perinatal HBV transmission is prevalent. HBV integrates into the host genome and can cause HCC even without cirrhosis — the only common viral hepatitis to do so. Chronic HCV infection, more prevalent in Western countries, causes cirrhosis in 20–30% of infected individuals; the risk of HCC is 1–4% per year in HCV cirrhosis. Sustained virological response (SVR) with direct-acting antiviral therapy (DAA) reduces HCC risk by 70–80%, though residual risk persists in established cirrhosis. Alcoholic cirrhosis confers an annual HCC incidence of 1–2%. MASLD-related HCC is a rapidly rising etiology, unique in that 15–30% of cases arise in non-cirrhotic livers. Aflatoxin B1 exposure (from Aspergillus-contaminated grain storage) is a carcinogen in sub-Saharan Africa and Southeast Asia, acting synergistically with HBV. Hereditary hemochromatosis, primary biliary cholangitis, and autoimmune hepatitis cause cirrhosis and secondary HCC risk. Obesity, diabetes, and metabolic syndrome are increasingly recognized independent risk factors.

Early-stage HCC is typically asymptomatic and detected by surveillance. Symptomatic presentation indicates locally advanced or metastatic disease and carries a poor prognosis. Right upper quadrant pain or a dull ache is the most common presenting symptom; it may reflect capsular stretching from tumor growth or portal vein invasion. Unexplained weight loss, anorexia, and fatigue are constitutional symptoms. Decompensation of previously compensated cirrhosis — new onset ascites, jaundice, hepatic encephalopathy, or variceal hemorrhage — may be the presenting feature of HCC. Paraneoplastic syndromes include hypoglycaemia (due to IGF-II secretion), erythrocytosis (ectopic EPO), hypercalcaemia, and gynecomastia. Rarely, HCC presents with haemoperitoneum from spontaneous tumor rupture — an emergency associated with sudden-onset severe abdominal pain and hypovolaemic shock. Pulmonary (dry cough, dyspnoea) and bone metastases (pain) occur in advanced disease.

Liver ultrasound every 6 months is the standard surveillance tool for cirrhotic patients and HBV carriers per AASLD and EASL guidelines. AFP is used as a co-surveillance marker but is insufficient alone (low sensitivity for small tumors). Diagnosis of HCC by imaging (non-invasive criteria) is accepted per AASLD/EASL for hepatic nodules ≥1 cm on multiphasic CT or MRI demonstrating 'arterial phase hyperenhancement' (APHE) followed by 'portal venous phase washout' — the hallmark HCC imaging pattern (LI-RADS 5; EASL criteria). Biopsy is required for atypical imaging features, non-cirrhotic liver, or if diagnosis is uncertain. Alpha-fetoprotein (AFP) over 400 ng/mL in a cirrhotic patient with a compatible liver lesion is near-diagnostic. BCLC staging (0–D: very early, early, intermediate, advanced, terminal) integrates tumor number/size, vascular invasion, extrahepatic spread, Child-Pugh class, and ECOG performance status to assign treatment modality.

BCLC 0/A (very early/early): Surgical resection is the preferred treatment for solitary HCC in non-cirrhotic or compensated cirrhotic (Child-Pugh A) patients with preserved portal pressure; 5-year OS of 60–80%. Liver transplantation (Milan criteria: solitary tumor ≤5 cm or up to 3 tumors ≤3 cm each, no vascular invasion, no extrahepatic disease) offers 5-year OS of 70–80% and treats the underlying cirrhosis. Radiofrequency ablation (RFA) or microwave ablation is curative for BCLC 0/A tumors ≤3 cm in patients not candidates for resection. BCLC B (intermediate): Transarterial chemoembolization (TACE) — selective hepatic arterial injection of chemotherapy (doxorubicin) plus Lipiodol followed by arterial embolization — is the standard of care; median OS of 20–26 months. Drug-eluting bead TACE (DEB-TACE) reduces systemic toxicity. BCLC C (advanced): Atezolizumab + bevacizumab (IMbrave150 trial) is the first-line standard, achieving median OS of 19.2 months vs 13.4 months with sorafenib. Durvalumab + tremelimumab (HIMALAYA) is an alternative first-line option. Lenvatinib is non-inferior to sorafenib. Second-line therapies include regorafenib, ramucirumab, and cabozantinib. Selective internal radiotherapy (SIRT) with yttrium-90 microspheres and stereotactic body radiation therapy (SBRT) are locoregional options.

Prognosis in HCC is critically determined by tumor burden, liver functional reserve (Child-Pugh status), and treatment modality received. BCLC 0/A (very early/early) HCC treated with resection achieves 5-year survival of 60–80%; liver transplantation within Milan criteria achieves 5-year survival of 70–80% with excellent long-term outcomes. Ablation (RFA) for tumors ≤3 cm achieves 5-year survival of 50–70%, with recurrence rates of 50–70% at 5 years. BCLC B (intermediate) treated with TACE achieves median overall survival of 20–26 months. BCLC C (advanced) with modern atezolizumab-bevacizumab (IMbrave150) achieves median OS of 19.2 months versus 13.4 months with sorafenib. Prognostic factors include Child-Pugh class (A vs B), presence and extent of vascular invasion (portal vein thrombosis markedly worsens prognosis), AFP level (>400 ng/mL is adverse), tumor multiplicity, and ECOG performance status. HCC surveillance in cirrhotic patients is the most important population-level determinant of prognosis — surveillance-detected HCC is diagnosed at early stage in 50–70% of cases versus less than 20% in symptomatic patients, translating into dramatically better survival. Post-treatment surveillance includes multiphasic CT or MRI every 3 months for the first 2 years to detect early intrahepatic recurrence amenable to repeat treatment, then 6-monthly thereafter.

HBV vaccination — universally offered to neonates — is the most effective HCC prevention measure and is projected to eliminate HBV-associated HCC in vaccinated cohorts. HBsAg-positive patients should receive antiviral therapy (tenofovir or entecavir) to suppress HBV replication, reducing HCC risk by 50–70%. HCV eradication with DAAs (sofosbuvir-based regimens) reduces HCC risk by ~70–80% post-SVR. Alcohol abstinence in alcoholic liver disease and weight loss/metabolic syndrome control in MASLD reduce progression to cirrhosis and HCC risk. Six-monthly liver ultrasound surveillance in all cirrhotic patients — regardless of etiology — and in HBV carriers with risk factors (family history, African ethnicity, age >40 in males or >50 in females) enables early-stage diagnosis when curative treatment is possible. AFP monitoring alongside ultrasound improves detection of AFP-secreting tumors.

Patients with known cirrhosis must not miss their 6-monthly ultrasound surveillance appointments — this is the only way to detect HCC at a curative stage. Any cirrhotic patient with new decompensation (ascites, jaundice, encephalopathy) should have urgent liver imaging to exclude HCC as a precipitant. Sudden-onset severe right upper quadrant pain in a cirrhotic patient with hemodynamic instability requires emergency evaluation for HCC rupture. A liver nodule of any size detected on surveillance imaging requires urgent diagnostic work-up with multiphasic CT or MRI within 1 month. Patients with chronic HBV or HCV who have not been tested for underlying liver fibrosis or cirrhosis should have fibroscan or biopsy performed and, if cirrhotic, enrolled in a surveillance program. Referral to a liver transplant center should occur early for cirrhotic patients with early-stage HCC meeting transplant criteria.