Liver Cancer (Hepatocellular Carcinoma)

Types of Liver Cancer

Primary Liver Cancers

These cancers start in the liver:

• Hepatocellular carcinoma (HCC) (75-85% of primary liver cancers)
  • Starts in hepatocytes (main liver cells)
  • Usually develops in people with cirrhosis
  • Most common type worldwide
• Intrahepatic cholangiocarcinoma (10-15%)
  • Starts in bile duct cells within the liver
  • Different risk factors and treatment than HCC
  • Less common but increasing in incidence
• Hepatoblastoma (rare)
  • Occurs almost exclusively in children under 3 years
  • Usually curable with surgery and chemotherapy
• Angiosarcoma (very rare)
  • Starts in blood vessel cells
  • Aggressive, poor prognosis

Risk Factors

Most HCC develops in the setting of chronic liver disease. Major risk factors include:

Chronic Viral Hepatitis

• Hepatitis B (HBV) - most important risk factor worldwide
  • Increases risk 100-fold
  • Can cause HCC even without cirrhosis
  • Preventable with vaccination
  • 2 billion people infected worldwide
• Hepatitis C (HCV) - leading cause in Western countries
  • Increases risk 15-20 fold
  • Usually requires cirrhosis first
  • Now curable with direct-acting antivirals (DAAs)
  • Risk reduced but not eliminated after cure

Cirrhosis (Any Cause)

Cirrhosis is present in 80-90% of HCC cases. Causes include:

• Alcohol use - heavy drinking over many years (>3 drinks/day for women, >4 for men)
• Non-alcoholic fatty liver disease (NAFLD) - linked to obesity, diabetes, metabolic syndrome
  • Fastest-growing cause of HCC in developed countries
  • Can progress to NASH (non-alcoholic steatohepatitis) and cirrhosis
• Hemochromatosis - genetic iron overload disorder
• Primary biliary cholangitis
• Autoimmune hepatitis

Other Risk Factors

• Aflatoxin exposure - toxin from mold on stored grains/nuts (common in sub-Saharan Africa, Asia)
• Diabetes - 2-3 times higher risk
• Obesity - increases risk through NAFLD
• Smoking - modest increase in risk
• Age - risk increases with age, peak incidence 60-70 years
• Male sex - 2-3 times more common in men

Signs and Symptoms

Early HCC usually has no symptoms. Symptoms typically appear with more advanced disease:

Common Symptoms

• Abdominal pain - especially upper right side, may be dull or sharp
• Unintentional weight loss
• Loss of appetite, early satiety (feeling full quickly)
• Abdominal swelling or mass - enlarged liver or fluid (ascites)
• Weakness and fatigue
• Nausea and vomiting

Signs of Advanced Disease

• Jaundice - yellowing of skin and eyes (indicates bile duct blockage or liver failure)
• Ascites - fluid buildup in abdomen
• Easy bruising or bleeding - liver produces clotting factors
• Confusion or drowsiness - hepatic encephalopathy (toxin buildup)
• Itching - from bile salt accumulation
• Enlarged veins on abdomen - portal hypertension

Screening and Surveillance

Regular screening is recommended for high-risk individuals:

Who Should Be Screened?

• Cirrhosis (any cause) - Child-Pugh class A or B
• Hepatitis B carriers without cirrhosis if:
  • Asian males ≥40 years
  • Asian females ≥50 years
  • Family history of HCC
  • African descent ≥20 years
• Hepatitis C with advanced fibrosis (F3)

Screening Protocol

• Ultrasound every 6 months - standard screening test
  • Non-invasive, no radiation
  • Detects 60-80% of early HCC
  • Less sensitive in obese patients or fatty liver
• AFP (alpha-fetoprotein) blood test - often added to ultrasound
  • Tumor marker elevated in 50-70% of HCC
  • Can be falsely elevated in active hepatitis
  • Combined with ultrasound improves detection

Diagnosis

Imaging

HCC has characteristic features on imaging that allow non-invasive diagnosis in cirrhotic patients:

• Multiphase CT scan or MRI with contrast
  • Classic pattern: arterial phase hyperenhancement + delayed washout
  • Lesions ≥1 cm with this pattern are diagnostic of HCC (no biopsy needed)
  • MRI slightly more sensitive than CT
• Contrast-enhanced ultrasound - emerging alternative in some centers

Biopsy

• Not always needed if imaging is characteristic
• Required when:
  • Imaging is indeterminate
  • No cirrhosis present
  • Considering specific targeted therapy (to test biomarkers)
• Small risk of tumor seeding along needle tract (1-3%)

Blood Tests

• AFP (alpha-fetoprotein) - elevated >400 ng/mL is highly suggestive
• Liver function tests - assess severity of underlying liver disease (bilirubin, albumin, INR)
• Complete blood count
• Hepatitis B and C testing

Staging

HCC staging is unique because both tumor characteristics and liver function determine treatment and prognosis.

Barcelona Clinic Liver Cancer (BCLC) Staging

Most widely used system, links stage to treatment recommendations:

TNM Staging (AJCC 8th Edition)

Also used, especially for surgical planning:

• T - tumor size and number, vascular invasion
• N - lymph node involvement (uncommon in HCC)
• M - distant metastasis (lung, bone most common sites)

Child-Pugh Score

Assesses liver function severity (critical for treatment planning):

• Class A (5-6 points) - well-compensated, can tolerate most treatments
• Class B (7-9 points) - significant liver dysfunction, limited treatment options
• Class C (10-15 points) - decompensated cirrhosis, transplant or supportive care only

Treatment Options

Treatment depends on tumor stage, liver function, and overall health. HCC is one of the few cancers where treatment is based as much on underlying organ function as tumor extent.

Curative Treatments (BCLC 0-A)

1. Surgical Resection

• Removing part of the liver containing the tumor
• Best for:
  • Single tumor, any size
  • Good liver function (Child-Pugh A)
  • No cirrhosis or well-compensated cirrhosis
  • Adequate future liver remnant (FLR)
• Liver can regenerate after resection
• 5-year survival: 50-70% if early stage
• Recurrence risk 70% at 5 years (new tumors often develop in diseased liver)

2. Liver Transplantation

• Removes entire diseased liver and replaces with donor liver
• Milan criteria (standard for transplant eligibility):
  • Single tumor ≤5 cm, OR
  • Up to 3 tumors, each ≤3 cm
  • No vascular invasion
  • No extrahepatic spread
• Treats both cancer and underlying cirrhosis
• Best long-term outcomes: 70-80% 5-year survival
• Lowest recurrence rate (10-15% at 5 years)
• Limited by organ availability (long wait times)
• Bridging therapy (TACE, ablation) used while waiting

3. Ablation

Destroying tumor in place without surgery:

• Radiofrequency ablation (RFA)
  • Heat destroys tumor (using high-frequency electrical current)
  • Best for tumors <3 cm
  • 5-year survival similar to resection for small tumors
• Microwave ablation (MWA)
  • Similar to RFA, may handle larger tumors better
  • Faster treatment time
• Percutaneous ethanol injection (PEI)
  • Alcohol injected directly into tumor
  • Less commonly used now (RFA/MWA more effective)
• Done through skin (minimally invasive)
• Can be repeated if tumor recurs
• Lower risk than surgery, outpatient or short hospital stay

Loco-Regional Therapies (BCLC B)

Transarterial Chemoembolization (TACE)

• Standard treatment for intermediate-stage HCC
• How it works:
  • Chemotherapy injected directly into artery feeding tumor
  • Artery then blocked (embolized), trapping chemo in tumor
  • Tumor deprived of blood supply
• Two main types:
  • Conventional TACE (cTACE) - chemotherapy with lipiodol
  • Drug-eluting beads TACE (DEB-TACE) - chemo loaded onto beads for sustained release
• Usually requires multiple treatments (every 1-3 months)
• Median survival 20-30 months
• Not suitable if portal vein thrombosis or poor liver function

Transarterial Radioembolization (TARE/Y90)

• Radioactive microspheres (yttrium-90) injected into tumor's blood supply
• Delivers high-dose radiation directly to tumor
• Alternative to TACE, may be better tolerated
• Can treat larger tumors and portal vein thrombosis
• Typically one-time treatment

Stereotactic Body Radiation Therapy (SBRT)

• High-dose focused external beam radiation
• 3-5 treatments
• Good for tumors unsuitable for other local therapies
• Increasing use, especially in combination with systemic therapy

Systemic Therapies (BCLC C)

For advanced HCC with vascular invasion, metastases, or progression after loco-regional therapy:

First-Line Options

• Atezolizumab + Bevacizumab (Tecentriq + Avastin)
  • NEW standard of care (FDA approved 2020)
  • Checkpoint inhibitor + anti-VEGF antibody
  • Median survival 19.2 months (vs 13.4 with sorafenib)
  • Requires adequate liver function (Child-Pugh A)
  • Not for patients with bleeding risk or untreated varices
• Sorafenib (Nexavar)
  • Multi-kinase inhibitor (TKI)
  • First systemic therapy approved for HCC (2007)
  • Median survival 10.7 months (vs 7.9 with placebo)
  • Oral medication, twice daily
  • Side effects: hand-foot syndrome, diarrhea, fatigue, hypertension
• Lenvatinib (Lenvima)
  • Multi-kinase inhibitor
  • Non-inferior to sorafenib in first-line
  • Median survival 13.6 months
  • Once-daily oral
  • Alternative to sorafenib (patient/doctor preference)

Second-Line Options (After Sorafenib)

• Regorafenib (Stivarga) - TKI, median survival 10.6 months
• Cabozantinib (Cabometyx) - TKI, median survival 10.2 months
• Ramucirumab (Cyramza) - anti-VEGF antibody (for AFP ≥400 ng/mL)
• Nivolumab (Opdivo) or Pembrolizumab (Keytruda) - checkpoint inhibitors

Prognosis and Survival

Prognosis depends heavily on stage at diagnosis and liver function:

5-Year Survival Rates by BCLC Stage

• BCLC 0 (Very Early): 80-90% (with curative treatment)
• BCLC A (Early): 50-70% (with curative treatment)
• BCLC B (Intermediate): 20-30%
• BCLC C (Advanced): <10%
• BCLC D (Terminal): <5%

Factors Affecting Prognosis

• Tumor factors: size, number, vascular invasion, AFP level
• Liver function: Child-Pugh class, MELD score, presence of ascites/encephalopathy
• Performance status: overall health and ability to function
• Treatment received: curative vs palliative
• Etiology: HBV-related HCC may have better response to some treatments

Living with Liver Cancer

During Treatment

• Liver-healthy diet
  • Adequate protein (unless hepatic encephalopathy present)
  • Limit salt if ascites or fluid retention
  • Avoid alcohol completely
  • Small, frequent meals if early satiety
• Monitor for complications
  • Ascites (fluid buildup) - may need diuretics or drainage
  • Varices (enlarged veins) - screening endoscopy if cirrhosis
  • Hepatic encephalopathy - confusion from toxin buildup
• Medication safety
  • Avoid NSAIDs (ibuprofen, naproxen) - can worsen liver/kidney function
  • Check with doctor before taking any new medications/supplements
  • Acetaminophen (Tylenol) - use cautiously, low doses only if needed

Follow-up After Curative Treatment

• Imaging (CT/MRI) every 3 months for first 2 years, then every 6 months
• AFP blood test at each visit
• Liver function tests
• Long-term surveillance for recurrence or new tumors

Managing Advanced Disease

• Palliative care team involvement for symptom management
• Pain management
• Nutritional support
• Treatment of liver-related complications
• Psychosocial support for patients and families

Prevention

Primary Prevention (Preventing HCC Development)

• Hepatitis B vaccination
  • Routine childhood vaccination in most countries
  • Catch-up vaccination for adults
  • Has reduced HCC incidence by 70-80% in vaccinated populations
• Hepatitis C treatment
  • Direct-acting antivirals (DAAs) cure >95% of HCV
  • Reduces but doesn't eliminate HCC risk (continued screening needed if cirrhosis)
• Limit alcohol
  • No more than 1 drink/day for women, 2 for men
  • Less is better for liver health
• Maintain healthy weight
  • Prevents NAFLD/NASH
  • Exercise regularly
  • Balanced diet
• Diabetes management - good glucose control reduces risk
• Avoid aflatoxin - proper food storage, especially in high-risk regions

Secondary Prevention (Early Detection)

• Surveillance for high-risk individuals
  • Ultrasound ± AFP every 6 months
  • Detects tumors when curative treatment possible
• Antiviral therapy for chronic hepatitis B (even if not cured, reduces HCC risk)
• Treat underlying liver disease to slow progression to cirrhosis

Current Research

• Combination immunotherapy - checkpoint inhibitors + other agents
• Biomarker-directed therapy - targeting specific genetic alterations
• Combination loco-regional + systemic therapy - TACE/Y90 with immunotherapy
• Novel targeted agents - FGFR inhibitors, MET inhibitors
• Liquid biopsy - blood tests to detect HCC earlier or monitor treatment
• Expanding transplant criteria - beyond Milan criteria with downstaging
• Adjuvant therapy - treatment after surgery to prevent recurrence

Frequently Asked Questions

Can I get liver cancer without cirrhosis?

Yes, but it's less common. About 80-90% of HCC develops in cirrhotic livers. Hepatitis B can cause HCC even without cirrhosis (unlike hepatitis C, which usually requires cirrhosis first). NAFLD-related HCC can occasionally occur without cirrhosis, especially in diabetics.

What's the difference between primary and metastatic liver cancer?

Primary liver cancer (HCC) starts in the liver. Metastatic liver cancer starts elsewhere (like colon, breast, lung) and spreads to the liver. Metastatic liver cancer is actually more common. Treatment depends on the original cancer type, not the fact that it's in the liver.

Is liver cancer curable?

Yes, if caught early. Curative options include surgery, liver transplant, and ablation. Transplant offers the best long-term cure rates (70-80% 5-year survival). However, most HCC is diagnosed at advanced stages where cure is not possible, making screening crucial for high-risk individuals.

Why can't all HCC be treated with surgery?

Surgery requires adequate liver function and enough healthy liver tissue to remain after removing the tumor. Many HCC patients have cirrhosis, limiting the amount of liver that can be safely removed. Also, the liver may not regenerate well in cirrhotic patients. Tumor location near major blood vessels may also make surgery too risky.

What is AFP and why is it important?

Alpha-fetoprotein (AFP) is a protein normally produced by the fetal liver. Elevated AFP levels (>400 ng/mL) in adults can indicate HCC. However, only 50-70% of HCC patients have elevated AFP, so normal AFP doesn't rule out HCC. AFP is used for screening (with ultrasound), diagnosis support, and monitoring treatment response.

How long can someone live with liver cancer?

It varies widely. With curative treatment (transplant, resection, ablation), 5-year survival is 50-80%. Intermediate-stage HCC treated with TACE: median survival 20-30 months. Advanced HCC with modern systemic therapy (atezolizumab + bevacizumab): median survival ~19 months. Without treatment, advanced HCC has median survival of 3-6 months.

Can liver cancer come back after treatment?

Yes, recurrence is common (50-70% at 5 years after resection). This can be true recurrence (same tumor returns) or new tumors developing in the still-diseased liver. Transplant has the lowest recurrence rate (10-15%) because the entire diseased liver is removed. Continued surveillance is essential after any curative treatment.

Should I get the hepatitis B vaccine?

Yes! The hepatitis B vaccine is one of the first "cancer prevention vaccines." It's routine for children in most countries and recommended for all unvaccinated adults, especially those at higher risk (healthcare workers, people with multiple sexual partners, injection drug users, travelers to endemic areas). The vaccine is safe and highly effective.

What should I avoid if I have liver disease or HCC?

Avoid alcohol completely (even small amounts harm the liver). Avoid NSAIDs like ibuprofen (can worsen liver/kidney function and increase bleeding risk). Limit acetaminophen (Tylenol) - use only if necessary and at low doses. Check with your doctor before taking ANY new medications, supplements, or herbal products, as many are metabolized by the liver.

Is immunotherapy effective for liver cancer?

Yes! Atezolizumab + bevacizumab is now the preferred first-line treatment for advanced HCC (Child-Pugh A), offering median survival of 19 months compared to 13 months with sorafenib. However, not all patients are candidates (need good liver function, no bleeding risk). Single-agent checkpoint inhibitors (nivolumab, pembrolizumab) also have activity and are used in later lines.