Liver Cancer (Hepatocellular Carcinoma): Causes, Diagnosis and Treatment

Liver Cancer (Hepatocellular Carcinoma): Causes, Diagnosis and Treatment

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer — cancer that originates in the liver cells themselves, as opposed to cancer that spreads to the liver from another organ. WHO/IARC estimated about 760,000 deaths from liver cancer overall in 2022, making liver cancer the third leading cause of cancer death worldwide. That total includes HCC and other liver cancer types.

Asia and sub-Saharan Africa carry the highest global burden of HCC. In China specifically, HCC is among the most prevalent cancers due to the high prevalence of chronic hepatitis B infection.

How Liver Cancer Develops

The liver has remarkable capacity for regeneration, but repeated cycles of injury and repair — from chronic viral infection, alcohol, or metabolic disease — promote inflammation, fibrosis, and ultimately cirrhosis (scarring that disrupts the liver's normal architecture). Cirrhosis is present in approximately 80% of HCC patients. Within the cirrhotic liver, accumulated DNA damage in repeatedly replicating cells leads to malignant transformation.

Risk Factors

Hepatitis B Virus (HBV) Infection

Chronic hepatitis B is the leading global cause of HCC, responsible for approximately 50–55% of cases worldwide. HBV raises HCC risk by more than 100-fold. Critically, HBV can cause HCC even without cirrhosis — a pattern also seen with other causes, including metabolic dysfunction-associated steatotic liver disease. The HBV vaccine is one of the most effective cancer prevention measures available.

Hepatitis C Virus (HCV) Infection

Chronic hepatitis C is the leading cause of HCC in Western countries and Japan. Unlike HBV, HCV virtually always causes HCC via cirrhosis. The advent of highly effective direct-acting antivirals (DAAs) that cure HCV in >95% of patients represents a major advance — but curing HCV in patients with cirrhosis does not eliminate HCC risk. Ongoing surveillance is generally recommended for those who remain eligible for HCC treatment, subject to the liver function, transplant eligibility and life-expectancy limits described below.

Cirrhosis from Other Causes

Any cause of cirrhosis increases HCC risk:

• Alcohol-related liver disease — a major risk factor globally
• Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD — increasingly important as obesity rates rise; MASH/NASH-related cirrhosis is now a leading cause of HCC in the US and Europe
• Primary biliary cholangitis (PBC) — lower risk than other cirrhosis causes
• Haemochromatosis — iron accumulation in the liver from this genetic disorder increases HCC risk substantially

Aflatoxin Exposure

Aflatoxins — carcinogens produced by moulds contaminating stored grains and peanuts — are a significant HCC risk factor in tropical regions (sub-Saharan Africa, Southeast Asia). Aflatoxin B1 causes a specific TP53 mutation (R249S) that drives HCC development.

Other Risk Factors

• Type 2 diabetes — independently raises HCC risk 2–3 fold
• Obesity — associated with MASLD and independent risk
• Anabolic steroid use

Symptoms

HCC typically remains asymptomatic in its early stages. Most early tumours are detected during surveillance programmes in patients with known cirrhosis or chronic HBV — before symptoms develop.

When symptoms occur, they may include:

• Right upper abdominal pain — the most common presenting symptom
• Unexplained weight loss and anorexia
• A palpable mass in the right upper abdomen (enlarged liver or discrete tumour)
• Worsening jaundice — yellowing of the skin and eyes as liver function deteriorates
• Abdominal swelling (ascites) — fluid accumulation from portal hypertension or peritoneal spread
• Sudden deterioration in previously stable cirrhosis
• Fever

A rare but dramatic presentation is acute haemoperitoneum — sudden abdominal pain and cardiovascular collapse from spontaneous tumour rupture and bleeding into the abdomen, requiring immediate emergency care and bleeding control, which may involve transarterial embolisation or surgery depending on clinical status.

Diagnosis

AFP (Alpha-Fetoprotein)

AFP is a blood protein marker elevated in approximately 50% of HCC patients. A rising AFP level in a patient with known cirrhosis is strongly suggestive of HCC, but AFP is neither sensitive nor specific enough to diagnose HCC alone — it can be elevated in other liver conditions and normal in many HCC cases. It is used alongside imaging and to monitor treatment response.

Imaging

For patients with cirrhosis, the diagnosis of HCC can often be established without biopsy based on characteristic imaging findings:

• Ultrasound — used for surveillance (every 6 months in high-risk patients); identifies new liver lesions requiring further investigation
• Contrast-enhanced CT or MRI — the diagnostic gold standard; HCC shows a characteristic "washout" pattern on imaging: avid contrast uptake in the arterial phase (arterial enhancement) followed by contrast washout in the venous/delayed phases. This pattern is highly specific for HCC in lesions >1 cm in cirrhotic livers.
• Hepatobiliary MRI with gadoxetate contrast — provides additional functional information; highly sensitive for HCC characterisation

Biopsy

Biopsy may be needed for indeterminate imaging or when non-invasive diagnostic criteria do not apply. Validated imaging criteria can establish HCC in at-risk patients, including selected people with chronic HBV without cirrhosis. Systemic treatment does not automatically require biopsy if HCC is already conclusively diagnosed; tissue sampling is decided by the multidisciplinary team. Biopsy carries small bleeding and tumour-seeding risks.

Staging

Several staging systems are used for HCC. The Barcelona Clinic Liver Cancer (BCLC) system is the most widely adopted, integrating:

• Tumour extent (number, size, vascular invasion)
• Liver function (Child-Pugh class)
• Performance status

BCLC Stage	Description	Recommended Treatment
0 (Very early)	Single ≤2 cm, Child-Pugh A	Resection or ablation
A (Early)	Single tumour or up to 3 nodules, each ≤3 cm; preserved liver function	Resection, transplant, or ablation
B (Intermediate)	Multinodular, no vascular invasion; preserved liver function	TACE for selected patients with adequate hepatic reserve and suitable tumour burden; specialist assessment is required
C (Advanced)	Portal invasion or extrahepatic spread	Systemic therapy for eligible patients with preserved liver function (Child-Pugh A or well-selected Child-Pugh B) and suitable performance status; specialist assessment is required
D (End-stage)	Severe liver dysfunction without a transplant option and/or poor performance status	Symptom-directed supportive care; Child-Pugh C alone does not exclude transplant assessment

Treatment

Surgical Resection

Surgical removal of the tumour-bearing liver segment offers the best chance of cure in patients with:

• A single tumour without vascular invasion
• Adequate residual liver function (Child-Pugh A with sufficient future liver remnant)
• No extrahepatic spread

After resection, HCC recurs in approximately 70% of patients within 5 years — emphasising ongoing surveillance. The initial recurrence-free survival benefit of adjuvant atezolizumab + bevacizumab in IMbrave050 was not sustained with longer follow-up; it should not be presented as established routine adjuvant treatment.

Liver Transplantation

Liver transplantation can treat both HCC and the underlying cirrhosis with curative intent in selected eligible patients. HCC can recur after transplantation, so cure is not assured.

Milan criteria (one tumour ≤5 cm or up to three tumours ≤3 cm, no vascular invasion, no extrahepatic spread) are the internationally accepted eligibility criteria. Five-year survival post-transplant within Milan criteria exceeds 70%.

China performs a significant number of liver transplants annually. Wait times and organ availability vary; locoregional therapy (ablation or TACE) is used to "bridge" patients while waiting — preventing tumour progression beyond transplant criteria.

Ablation

For small HCCs not suitable for surgery:

• Radiofrequency ablation (RFA) — delivers thermal energy through a needle electrode, destroying the tumour by heat; effective for tumours ≤3 cm with outcomes approaching resection
• Microwave ablation (MWA) — similar to RFA but faster and effective for larger tumours; increasingly preferred
• Cryoablation — freezes tumour tissue; less used
• The approach and anaesthesia vary by technique and patient. RFA, for example, can be percutaneous, laparoscopic or open and can use sedation or general anaesthesia.

Transarterial Chemoembolisation (TACE)

TACE exploits the fact that HCC derives its blood supply primarily from the hepatic artery (whereas normal liver tissue receives blood from both the portal vein and the hepatic artery). A catheter is passed through the groin artery to the hepatic artery, where chemotherapy (doxorubicin or cisplatin) is injected directly into the tumour's feeding vessels, followed by embolisation beads that cut off blood supply. This delivers high local drug concentrations while reducing systemic toxicity.

TACE is the standard treatment for intermediate-stage (BCLC-B) HCC and is also used to downstage tumours to transplant criteria.

Selective Internal Radiation Therapy (SIRT / Radioembolisation)

Tiny radioactive microspheres (yttrium-90) are injected via the hepatic artery, delivering targeted internal radiation to the tumour. SIRT has shown comparable or superior outcomes to TACE in some patient populations and is increasingly used in clinical practice.

Systemic Therapy

For advanced HCC (vascular invasion or extrahepatic spread):

First-line:

• Atezolizumab + bevacizumab — the current standard; combination of anti-PD-L1 immunotherapy and anti-VEGF agent; significantly superior to sorafenib in landmark IMbrave150 trial
• Tremelimumab + durvalumab — dual immunotherapy approved based on HIMALAYA trial
• Sorafenib — oral multikinase inhibitor; remains a first-line option for patients unsuitable for preferred immunotherapy-based combinations; it may also be used after these combinations according to clinical circumstances
• Lenvatinib — another first-line option, non-inferior to sorafenib

Second-line:

• Regorafenib, cabozantinib, ramucirumab (AFP ≥400 ng/mL; the FDA-labelled HCC indication is after prior sorafenib)

Surveillance and Prevention

Surveillance for High-Risk Patients

Surveillance is generally offered every 6 months to treatment-eligible patients with cirrhosis and to selected non-cirrhotic patients with chronic HBV whose risk warrants it. Eligibility considers liver function, transplant options, life expectancy and HBV-specific risk factors. AASLD recommends ultrasound plus AFP; patients with Child-Pugh C cirrhosis who are not transplant candidates generally should not undergo surveillance. The aim is detection at a potentially treatable stage.

Prevention

• Hepatitis B vaccination — prevents HBV infection and ultimately HCC; one of the most effective cancer vaccines available
• Antiviral treatment for chronic HBV and HCV — suppressing HBV replication and curing HCV substantially reduces (but does not eliminate) HCC risk in cirrhotic patients
• Alcohol cessation — prevents progression of alcohol-related liver disease
• Weight management — reduces MASLD progression and associated HCC risk

Liver Cancer Care in China

China's liver cancer centres are among the highest-volume HCC treatment centres in the world:

• Comprehensive HCC work-up: AFP, contrast-enhanced CT or gadoxetate MRI, and multidisciplinary tumour board review; availability and scheduling require confirmation with the receiving centre
• High-volume hepatic resection: experienced hepatobiliary surgeons performing complex resections including major hepatectomy and anatomical segmentectomy
• Liver transplantation: national organ allocation through COTRS; experienced transplant programmes in major centres
• Interventional oncology: TACE, SIRT, and percutaneous ablation (RFA and MWA) available in a single centre
• Systemic therapy access: atezolizumab + bevacizumab and other approved regimens available; biosimilars substantially reduce cost
• HBV management integration: antiviral therapy routinely combined with HCC treatment to protect residual liver function

Contact a PriumCare care navigator to arrange a liver cancer assessment or treatment consultation.

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External source attribution: the original article cites MSD Manuals, authored by Danielle Tholey MD (Sidney Kimmel Medical College, Thomas Jefferson University), reviewed by Minhhuyen Nguyen MD (Fox Chase Cancer Center), with a review/update date of March 2025. These names and dates credit the external source, not authorship or medical review of this PriumCare article.

Additional targeted source clarification

Editorial source check: 25 October 2026. This clarifies the specific claims linked below; it is not a whole-article medical review or a new clinical reviewer attribution. The original publication date is retained.

• AASLD: HCC diagnosis, risk-based surveillance and transplant eligibility
• NHC 2024 primary liver cancer guideline: emergency haemostasis
• AASLD critical update: IMbrave050
• FDA: ramucirumab indication

Further targeted source clarification

Editorial source check: 25 October 2026. This update checks only the specific residual claims linked below; it is not a whole-article medical review and does not add a named clinical reviewer. The original publication date is retained.

• WHO/IARC: global cancer estimates for 2022
• AASLD: surveillance, transplantation and systemic therapy
• BCLC strategy: the 2022 update
• NCI PDQ: primary liver cancer treatment
• NIH Clinical Center: RFA approach and anaesthesia

Targeted treatment-selection and blood-supply clarification

Editorial source check: 25 October 2026. This checks only the B/C-stage treatment-selection shorthand and the normal-liver blood-supply comparison clarified above; it is not a whole-article medical review and adds no named clinical reviewer. The original publication date is retained.

• AASLD: TACE suitability and systemic-therapy patient selection
• BSG: selection of patients for transarterial therapy
• NCI: liver blood supply and embolization