Hepatocellular Carcinoma (HCC) and Liver Metastases

Epidemiology and Etiology

Epidemiology

• Hepatocellular carcinoma (HCC) accounts for 80% of primary liver cancers in adults.
• Mortality-to-incidence ratio (MIR): 0.95 (2nd-worst survival rate after pancreatic cancer) 
• Worldwide:
  • 5.4% of all cancers
  • 4th most common cause of all cancer deaths
  • 85% of cases occur in Asia and Sub-Saharan Africa:
    • Associated with a high rate of maternal-fetal transmission of hepatitis B virus (HBV)
    • Incidence rates have decreased in areas with increased rates of HBV vaccination.
    • Age at diagnosis: 20–40 years 
    • Male-to-female ratio: 8:1
• United States:
  • < 2.5% of all cancers
  • 5th most common cause of all cancer deaths
  • Incidence is increasing (mostly due to non-alcoholic fatty liver disease (NAFLD)).
  • Ethnic variations: Asians/Pacific Islanders > Blacks > Native Americans/Alaska Natives > Whites
  • Median age at diagnosis: 65 years
  • Male-to-female ratio: 3:1

Risk factors

Cirrhosis:

One-third of patients with cirrhosis will develop HCC during their lifetime, including those caused by:

• Chronic HBV
• Chronic hepatitis C virus (HCV) infection
• NAFLD (increased risk even without cirrhosis)
• Alcoholic liver disease
• Hemochromatosis
• α-1 antitrypsin (AAT) deficiency

Other:

• Aflatoxin B1:
  • Toxin from Aspergillus flavus and A. parasiticus fungi
  • Contaminates stored food products (e.g., peanuts, corn) 
  • Acts synergistically with HBV infection and alcohol ingestion
• Smoking
• Alcohol
• Obesity
• Wilson disease
• Chronic biliary disease
• Autoimmune hepatitis

Pathogenesis and Pathology

Pathogenesis

• HCC arising in chronic liver disease with cirrhosis (80% of cases):
  • Chronic injury → inflammation → hepatocyte regeneration → driver mutations of HCC 
  • Driver mutations and frequencies: 
    • β-catenin gene (40%)
    • TERT gene promoter → upregulates telomerase activity (50-60%) 
    • TP53: inactivation mutations (60%)
• HCC arising in noncirrhotic livers with preexisting chronic liver disease:
  • Aflatoxin B1 → converted to toxic epoxide → damage to DNA (including p53)
  • Hepatocellular adenoma with β-catenin–activating mutations
  • Fibrolamellar type of HCC: fusion gene forms → aberrant activity of protein kinase A (PKA)→ abnormal activity of cAMP

Precursor (premalignant) lesions

Hepatocytes show “large-cell change” and “small-cell change” with abnormal architecture (thick trabeculae) microscopically.

• Large-cell change: enlarged hepatocytes with large, multinucleated and pleomorphic nuclei
• Small-cell change: hepatocytes with a high nuclear-to-cytoplasmic ratio, but mild nuclear change
• Dysplastic nodules: often associated with small-cell change

Hepatocellular carcinoma (HCC)

Gross appearance:

• Usually in a cirrhotic liver
• Single or multiple masses (discrete or infiltrative)
• Extensive intrahepatic metastases are common.
• Color:
  • White
  • Yellow (due to fatty change)
  • Green (presence of cholestasis)
• Portal vein invasion: common with extension to the inferior vena cava and right side of the heart 
• Vena cava invasion: HCC and renal cell carcinoma are the 2 carcinomas with a propensity to invade the vena cava as a growing thrombus.

Microscopic appearance:

• Well-differentiated tumors:
  • Resemble normal hepatocytes
  • Thickened trabeculae
  • Dilated and irregular canaliculi
  • Pseudoglandular spaces
• Poorly-differentiated tumors:
  • Composed of undifferentiated sheets of cells with marked cytologic atypia
  • Necrosis and hemorrhage 

Clinical Presentation

Four possible clinical presentations for HCC:

1. Asymptomatic: HCC liver mass is found incidentally on imaging.
2. Cirrhosis 1st:
   • Symptoms and signs of cirrhosis appear 1st
   • The discovery of HCC follows
3. Decompensated cirrhosis in the presence of known cirrhosis:
   • Variceal bleeding
   • Ascites
   • Extension of HCC into the hepatic or portal veins
4. HCC 1st:
   • Symptoms and signs of HCC appear 1st
   • Abdominal pain/RUQ discomfort
   • Malaise, fatigue, weight loss
   • Hepatomegaly, splenomegaly, palpable mass
   • Tumor rupture with intraperitoneal hemorrhage (life-threatening event)
   • Fever due to tumor necrosis
   • Obstructive jaundice
   • Extrahepatic metastases (10%–15% of cases): lung > regional lymph nodes > peritoneum > bone > adrenal gland

Diagnosis

Ultrasound

Surveillance screening by ultrasound every 6 months is recommended for patients in the following high-risk groups:

• Patients with cirrhosis (annual incidence of HCC > 1.5%):
  • Least severe and moderately severe (Child-Pugh classification A and B)
  • Most severe (Child-Pugh classification C) if awaiting liver transplantation
• Patients without cirrhosis (annual incidence of HCC > 0.2%) with HBV infection, occurring in any of the following settings or patient types:
  • Active hepatitis (elevated serum alanine aminotransferase and/or high viral load)
  • Family history of HCC
  • Africans and African-Americans
  • Asian men > 40 years of age
  • Asian women > 50 years of age
• Chronic HCV and advanced liver fibrosis (not included for surveillance screening by all experts)
• Ultrasound findings:
  • Irregular mass borders
  • Echogenicity ranging from homogeneous to inhomogeneous and from hypoechoic to hyperechoic (indicating different densities)

CT or MRI

If ultrasound shows a lesion > 1 cm, dynamic contrast imaging by CT or MRI is performed.

• Abdominal triphasic CT: confirmatory test showing enhancement in the arterial phase and washout during the portal venous phase with possible local invasion
• MRI (with contrast): hypodense, irregular lesions

Biopsy

If imaging results are unequivocal, a biopsy is not always needed. 

• Perform if the lesion is > 1 cm and tissue confirmation would change management.
• Risk of bleeding and tumor spread (< 3% cases)

Serum markers

• Not used as stand-alone tests
• Serum alpha-fetoprotein (AFP): insufficient sensitivity and specificity
• Plasma microRNA (miRNA): shows promise as diagnostic and prognostic tools, but not sufficiently studied yet

Management and Complications

Nonsurgical options

• Radiofrequency ablation (RFA), microwave ablation, and cryoablation
• Irreversible electroporation (electropermeabilization with high-current electrical pulses)
• Transarterial chemoembolization (TACE) and bland embolization
• Transarterial radioembolization (TARE)
• Percutaneous ethanol or acetic acid ablation
• Stereotactic radiation therapy
• Systemic chemotherapy and radiotherapy
• Immunotherapy (studies in progress)

Surgical tumor resection

• Only 10% of patients have resectable tumors. 
• Eligibility limited by:
  • Cirrhosis due to decreased hepatic reserve (limits resection)
  • Extensive tumor present within the liver

Liver transplantation

• Absolute contraindications: extrahepatic disease, vascular invasion
• Bridging methods (usually with RFA or TACE) to prevent tumor progression while awaiting a donor, and to downsize the tumor to fit into eligibility criteria 

Complications

• Paraneoplastic syndromes (20%):
  • Hypoglycemia: due to high metabolism of the tumor, or tumor secretion of insulin-like growth factor-2
  • Hypercalcemia: due to osteolytic lesions, or tumor secretion of parathyroid hormone-related protein
  • Erythrocytosis: likely due to tumor secretion of erythropoietin 
  • Diarrhea (may be intractable): likely due to secretion of peptides causing intestinal secretion (e.g., vasoactive intestinal polypeptide, gastrin, prostaglandin-like eicosanoids)
  • Skin lesions (rare): dermatomyositis, pemphigus foliaceus, Leser-Trélat sign (sudden appearance of multiple seborrheic keratoses, skin tags, and acanthosis nigricans)
• Tumor rupture with intraperitoneal hemorrhage (an emergent, life-threatening event)
• Budd-Chiari syndrome: tumor compresses and obstructs the hepatic veins

Prognosis and Prevention

Prognosis

• 4 important determinants of survival:
  • The severity of the underlying liver disease
  • Tumor size
  • Extension of the tumor into adjacent structures
  • Presence or absence of metastases
• Treatment must be individualized: Some patients with poor prognostic determinants do well with aggressive therapy (including liver transplantation).
• Survival: 
  • Due to late-stage presentation, the 5-year survival rate is poor (10%–12%).
  • The 2nd-worst survival rate after pancreatic cancer
  • 5-year survival by determinants:
    • Patients with liver transplantation: 70%–75%
    • Tumor limited to the liver: 30%
    • Regional extension of tumor: 12%
    • Distant metastases: 2.5%
  • Median survival:
    • < 3 months in parts of Africa
    • > 3 years in Taiwan and Japan

Prevention

• HBV vaccination
• Treatment for viral hepatitis: 
  • HBV: Relative risk is reduced by 50%–60% with interferon or nucleoside derivatives.
  • HCV: Antiviral therapy decreases, but does not eliminate, risk.
• Medications:
  • Statins (HMGR inhibitors):
    • Most profound effect in East Asian men with chronic hepatitis
    • Statins may indirectly reduce HCC by slowing the progression of cirrhosis.
  • Aspirin: Long-term, regular use lowers the risk of HCC.
  • Metformin: associated with lower overall cancer risk, including HCC
• Lifestyle factors:
  • Physical activity: associated with lower risk of liver cancer compared with a sedentary lifestyle
  • Diet consumption: White meat, fish, omega-3 fatty acids, vegetables, and vitamin E are protective.
  • Coffee consumption: protective factor against HCC (contains abundant amounts of antioxidants)

Liver metastases

• 30x more common than primary liver cancers
• 40%–50% of people with death from malignancy have a metastatic tumor in the liver.
• The most common types of cancer to spread to the liver are:
  • Colorectal
  • Lung
  • Breast
  • Pancreatic
  • Stomach
  • Melanoma
  • Neuroendocrine
• Diagnosis:
  • CT/PET scan while staging the primary tumor
  • Imaging usually shows multiple tumors with well-defined (noninfiltrative) borders.
  • Often with central umbilication due to central necrosis
• Management: 
  • Depends on the primary cancer site
  • Common treatment modalities:
    • Chemotherapy
    • Targeted therapy with monoclonal antibodies
    • Immunotherapy 
  • Metastasectomy:
    • May be appropriate for some cancers:
      • For curative attempts
      • To reduce tumor burden and prolong survival in select tumors
    • Colorectal cancer: The standard of care in select patients is resection or ablation of colorectal liver metastases (CRLM).
    • The 5-year survival rate for patients with resectable CRLM has doubled from 30% to 60% in the last 2 decades.

Differential Diagnosis

The following are important differential diagnoses of a solid mass in the liver:

Benign lesions:

• Hepatic hemangioma (also known as “cavernous hemangioma”): the most common benign liver lesion. Incidence is higher in women than men. Presentation is usually asymptomatic and the prognosis is excellent.
• Focal nodular hyperplasia (FNH): a proliferation of hyperplastic hepatocytes surrounding a central stellate scar. Incidence is higher in women than men.
• Hepatocellular adenoma (hepatic adenoma): solitary lesions developing in the normal liver of young women using estrogen medications, and patients with glycogen storage disease or metabolic syndrome.
• Regenerative nodules: proliferations of hepatocytes and stroma usually seen in cirrhosis as a response to liver injury.

Malignant lesions:

Cholangiocarcinoma (bile duct cancer): arises from epithelial cells of the intrahepatic and extrahepatic bile ducts. Risk factors in the United States include primary sclerosing cholangitis and fibropolycystic liver disease (e.g., choledochal cysts). Hepatolithiasis (recurrent pyogenic cholangitis) is the biggest risk factor for cholangiocarcinoma in Asia.