Hepatocellular Carcinoma

Indications for Testing

Clinical symptoms in the presence of risk factors; elevated neoplastic markers

Laboratory Testing

Markers – alpha-fetoprotein L3 isoform (AFP-L3) with des-gamma-carboxy-prothrombin (DCP) in patient with risk factors (combined testing is superior to either marker alone)
- Recommend ultrasound and tissue diagnosis
- AFP ≥200 ng/mL – suspect HCC

Histology

Percutaneous biopsy – 90% sensitivity, 91% specificity for ultrasound guided; 92% sensitivity, 98% specificity for CT guided
Immunohistochemistry – alpha-1-fetoprotein (AFP); alpha-1-antichymotrypsin (A1ACT); beta-catenin-1; cytokeratin 8,18 low molecular weight (CAM 5.2); factor XIIIa; hepatocyte-specific antigen (HSA)

Imaging Studies

Ultrasound, CT, MRI
- Consider HCC if focal hepatic mass >2 cm (in cirrhotic patients) shows vascularity on 2 studies
  - No biopsy necessary
  - If lesion <2 cm, perform second study and look for hypervascularity
    - If no hypervascularity noted
      - AFP >400 ng/mL – malignancy likely
      - AFP ≤400 ng/mL – biopsy
- If AFP, AFP-L3% not elevated and ultrasound shows mass, consider variant HCC (eg, fibrolamellar)

Prognosis

AFP
- ≥400 ng/L associated with greater tumor size and invasiveness, lower rate of survival

Differential Diagnosis

Abdominal pain
- Acute cholecystitis
- Acute pancreatitis
- Infectious diarrhea
  - Parasitic
  - Viral
Hepatomegaly
- Other malignancy (biliary, pancreatic)
- Cirrhosis
- Metabolic disease
  - Hemochromatosis
  - Wilson disease
  - Metabolic syndrome (NASH)
  - AAT
Jaundice
- Other malignancy (biliary, pancreatic)
- Acute hepatitis
  - Toxins (eg, alcohol)
  - Infectious (HAV, HBV, HCV, HDV)
  - Metabolic
Autoimmune disease
- PBC
- AIH

No current guidelines demonstrating outcome change with routine screening
- Most liver centers use routine surveillance (every 6-12 months)
- Societies recommending surveillance
  - American Association for the Study of Liver Disease (AASLD)
  - European Association for the Study of Liver (EASL)
  - Japanese Society of Hepatology (JSH)
- Screening generally includes tumor markers and imaging (combination of AFP-L3%, DCP and ultrasound)

Surveillance recommendations for specific groups

AASLD (2005)	EASL (2001)	JSH (2007)
Chronic Hepatitis
Asian – males ≥40 years, females ≥50 years All cirrhotic patients Family history of HCC Africans >20 years	HCV with cirrhosis	Chronic HBV and HCV Alcoholism
Non-Hepatitis Cirrhosis
HBV, HCV carriers Alcoholic cirrhosis Hemochromatosis PBC AAT AIH	Child-Pugh A and no severe associated condition Child-Pugh C if liver transplant considered	HBV- or HCV-related cirrhosis Liver cirrhosis from other etiologies
El-Serag, 2008

Markers
- AFP-L3%
  - Specificity for HCC – >90%
  - May be predictive of tumor aggressiveness
  - Elevated AFP-L3% associated with a sevenfold increased risk of developing HCC within 21 months in patients with chronic liver disease but currently negative for HCC
  - Expect decrease in AFP-L3% with treatment
- AFP
  - Less specific than AFP-L3%
- DCP
  - Complements AFP or AFP-L3% markers in surveillance and risk assessment for HCC
  - Useful marker for following HCC patients post therapy if positive prior to therapy
  - Elevated DCP associated with increased risk of developing HCC
- TP53 mutations under investigation

Hepatocellular carcinoma (HCC) tumors are among the most common in the world, particularly in populations with chronic viral hepatitis and Asian or Sub-Saharan African ancestry.

Epidemiology

Incidence
- 4-11/100,000 (U.S. and Europe)
  - >24,000 cases in U.S. in 2010 (SEER estimate)
- Third most common cancer worldwide
Age – peaks in 60s in U.S.; 20s-40s in Asian countries
Sex – M>F 3:1 in populations with a high prevalence of HCC
Ethnicity – higher incidence in Asian and African populations

Risk Factors

Cirrhosis (90% of cases)
- Infectious – chronic hepatitis B (HBV), C (HCV) or D (HDV)
  - HBV accounts for majority of HCC in China and Africa
    - HBV antigen positivity increases risk 100-fold
  - HCV accounts for majority of HCC in Western hemisphere
- Heavy alcohol consumption
  - >80 gm/day for >10 years increases risk for HCC fivefold
  - Risk further increases two- to fourfold in the presence of chronic viral hepatitis
- Autoimmune diseases
  - Autoimmune hepatitis (AIH)
  - Primary biliary cirrhosis (PBC)
- Hereditary metabolic liver diseases
  - α-1-antitrypsin deficiency (AAT)
  - Hemochromatosis
  - Wilson disease
  - Hereditary tyrosinemia
  - Porphyria cutanea tarda
  - Glycogen storage diseases
- Nonalcoholic steatohepatitis (NASH)
- Highest risk in chronic hepatitis and alcohol-induced cirrhosis
Toxins
- Aflatoxin B1 – consumption of grains and nuts contaminated with Aspergillus spp (China and Africa)
- Long-term androgenic steroid therapy
- Vinyl chloride (occupational exposure)
- Tobacco use
Family history of HCC
Coexistent risk factors magnify risk

Pathophysiology

Usually hepatocyte malignancy
- Variants include pleomorphic cell, clear cell, sarcomatous, fibrolamellar or undifferentiated
- Other tumors (cholangiocarcinoma and angiosarcoma)
Three morphologic types
- Nodular – usually associated with cirrhosis
- Massive – usually associated with noncirrhotic liver
- Diffuse – less common

Clinical Presentation

Typically asymptomatic until late-stage tumor; often metastatic at presentation
Most patients have previous history of chronic liver disease or cirrhosis
Abdominal pain – usually right upper quadrant, friction rub or bruit over liver, abdominal mass, hepatomegaly, ascites
Constitutional manifestations – anorexia, malaise, weight loss
Jaundice
Unexplained decompensation in patients with underlying cirrhosis
Paraneoplastic syndromes (20%)
- Acquired porphyria
- Cryofibrinogenemia
- Diarrhea (vasoactive intestinal polypeptide)
- Erythrocytosis (erythropoietin-like activity)
- Hypercalcemia (parathyroid-like hormone)
- Hypercholesterolemia
- Hypoglycemia (insulin growth factor)
- Polymyositis

Prognosis

Four main parameters affect prognosis
- Tumor aggressiveness, growth rate
- Patient general health
- Liver function (degree of cirrhosis)
- Available treatment options (eg, resection, transplant)
Metastatic disease common
- Most often found in lung, abdominal lymph nodes, bone
General prognosis usually very poor (5-year survival <50%)
- Barcelona Clinic Liver Cancer System is the best at stratifying survival (Sala, 2005)

Prevention

HBV vaccination – markedly reduces HBV infection rate
Interferon-based therapies to reduce rate of hepatitis-induced cirrhosis for HBV and HCV infections
Effective iron depletion for patients with hemochromatosis
Liver transplantation in hereditary tyrosinemia
Eliminate hepatotoxin exposure (alcohol, aflatoxin, tobacco, occupational toxins)

Tests generally appear in the order most useful for common clinical situations

Test name: Hepatocellular Carcinoma Tumor Marker Panel

ARUP #: 0081326

Methodology: Quantitative Liquid-Phase Binding Immunoassay

Use:

Use in serial 6-month surveillance along with abdominal ultrasound for early detection of HPCC in high-risk groups (patients with chronic HBV, HCV or chronic liver disease) and in risk assessment for HCC

Monitor disease after surgery, transplantation or percutaneous therapy

Panel includes AFP total, AFP-L3%, and DCP

Use AFP-L3% measurement during and following treatment to predict adverse outcome, early recurrence and malignant potential

Limitations:

Not all liver cancers are AFP or AFP-L3% secreting

Not interpretable as a tumor marker in pregnant females

Test name: Alpha-1-Fetoprotein (AFP) by Immunohistochemistry

ARUP #: 2003436