Hepatocellular Carcinoma

Key Points

Hepatocellular Carcinoma Surveillance Guidelines

The incidence of hepatocellular carcinoma (HCC) is rising in many countries. HCC is associated with a low 5-year survival rate due to late stage detection when disease is often advanced. Early lesion detection improves survival and may allow liver transplantation in selected individuals. Surveillance screening for high-risk individuals is recommended by many societies. Only one study to date has demonstrated improved survival; therefore, surveillance screening must be limited to those at risk and should be a physician/patient-based choice.

Guideline Recommendations for HCC Surveillance

 

AASLD, 2011

JSH, 2010

NCCN, 2015

EASL-EORTC, 2012

Recommended Screening

Abdominal ultrasound (US)

AFP*/PIVKA-II** not recommended

Abdominal US and combination of ≥2 markers including AFP, PIVKA-II, AFP-L3

  • Combination of ≥2 markers increases sensitivity

Abdominal US and AFP

Additional imaging (eg, 3-phase CT or MRI); recommended in setting of rising AFP

Recommended in setting of rising AFP

Abdominal US

AFP not recommended

Recommended Interval for ScreeningEvery 6 months

Markers plus US

  • Super-high risk – every 3-4 months
  • High-risk – every 6 months

Dynamic CT scan/MRI (only super-high risk or in those whom US was suboptimal)

  • Every 6-12 months
Every 6-12 monthsEvery 6 months
At-Risk Patients to Screen

Hepatitis B carrier

  • Asian male >40 yrs or Asian female >50 yrs
  • Family history of HCC

African/North American Blacks with hepatitis B

Cirrhosis

All patients awaiting transplant

Super-high-risk population

  • Hepatitis B- or C-related cirrhosis

High-risk population

  • Chronic hepatitis B or C
  • Cirrhosis

Hepatitis B or C carrier

  • Asian male ≥40 yrs or Asian female ≥50 yrs
  • Family history of HCC

African/North American Blacks with hepatitis B

Cirrhosis

Cirrhosis (Child-Pugh stage A or B)

Cirrhosis (Child-Pugh stage C awaiting transplant)

Hepatitis B carrier with active hepatitis or family history of HCC

Chronic hepatitis C and advanced liver fibrosis

All patients awaiting transplant

*AFP – alpha-fetoprotein

**PIVKA-II – protein induced by vitamin K absence/antagonist-II or des-gamma carboxy-prothrombin (DCP)

AASLD – American Association for the Study of Liver Disease; JSH – Japanese Society of Hepatology; NCCN – National Comprehensive Cancer Network; EASL – European Association for the Study of the Liver; EORTC – European Organisation for Research and Treatment of Cancer

Diagnosis

Indications for Testing

  • Clinical symptoms in the presence of risk factors for hepatocellular carcinoma (HCC)
  • Elevated neoplastic markers
  • Nonspecific symptoms include jaundice, anorexia, weight loss, malaise, upper abdominal pain

Laboratory Testing

  • Initial testing
    • Viral hepatitis testing if etiology of liver disease is unclear
      • If viral disease confirmed – viral load testing with referral to hepatologist
  • Serum markers may be useful in patients with risk factors – alpha-fetoprotein L3 isoform (AFP-L3) and des-gamma-carboxy-prothrombin (DCP) are more specific than AFP
    • AASLD no longer recommends AFP testing as part of diagnostic evaluation (Bruix, 2011)
    • Combined testing – superior to either marker alone
    • No marker is optimal in early stage disease
      • AFP frequently not elevated in early stage disease
    • AFP results
      • AFP ≥200 ng/mL – suspect HCC; proceed to imaging studies
      • AFP ≥400 ng/mL – strongly suggests HCC
      • Elevated AFP can occur in the absence of HCC
    • If AFP-L3 is not elevated and ultrasound shows mass – consider variant HCC (eg, fibrolamellar) and follow patient with AFP and liver imaging every 3 months

Histology

  • Gold standard for diagnosis of HCC
  • Percutaneous biopsy
    • High sensitivity/specificity for ultrasound-guided or CT-guided specimen
      • CT guided slightly more sensitive and specific
  • Immunohistochemistry – AFP; alpha-1-antichymotrypsin (A1ACT); beta-catenin-1; cytokeratin 8,18 low molecular weight (CAM 5.2); factor XIIIa; hepatocyte-specific antigen (HSA); arginase 1; glypican 3

Imaging Studies

  • Ultrasound/MRI/CT
    • For detection of HCC – CT and MRI are higher sensitivity than US (Chou, 2015)
    • For evaluation of focal lesions CT/MRI or ultrasound have similar sensitivity
    • Recommendations based on nodule size
      • Liver nodule <1 cm on imaging – follow up with CT (at least 3-phase)/MRI or ultrasound every 3-6 months
        • Stable nodule – continue imaging every 3-6 months with technique that identified nodule
        • Enlarging nodule – proceed according to nodule size
      • Liver nodule 1-2 cm (in cirrhotic patients) with classic arterial enhancement – diagnostic for HCC
        • Biopsy often unnecessary
        • Noncirrhotic patients – biopsy should be strongly considered
        • 2 classic enhancements – HCC confirmed
        • 0 or 1 classic enhancement – imaging (at least 3-phase CT or MRI), biopsy
      • Liver nodule >2 cm – perform core biopsy (preferred) or fine-needle aspiration (FNA)

Prognosis

  • AFP – ≥400 ng/mL
    • Associated with greater tumor size and invasiveness – lower rate of survival

Differential Diagnosis

Screening

  • Refer to Key Points for surveillance guidelines

Clinical Background

Hepatocellular carcinoma (HCC) tumors are among the most common in the world, particularly in populations with chronic viral hepatitis such as those of Asian or sub-Saharan African ancestry.

Epidemiology

  • Incidence
    • 4-11/100,000 (U.S. and Europe)
      • >33,000 cases and ~23,000 deaths in U.S. in 2014 (NCCN, 2015)
    • 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 – majority of cases in U.S.
    • Chronic infections – hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV)
      • HBV – majority of HCC in Asia and Africa
      • HCV – risk factor for majority of HCC in Europe, Japan, and North America
        • ~5% of patients have markers of both HBV and HCV
    • Heavy alcohol consumption
      • >80 gm/day for >10 years increases risk for HCC five-fold
      • Risk further increases two- to four-fold in the presence of chronic viral hepatitis
    • Autoimmune diseases
    • Hereditary metabolic liver diseases
    • Nonalcoholic steatohepatitis (NASH)
    • Highest risk associated with chronic infectious 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 (eg, cholangiocarcinoma and angiosarcoma)
  • Morphological types
    • Nodular – usually associated with cirrhosis
    • Massive – usually associated with noncirrhotic liver disease
    • 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
  • Constitutional manifestations – anorexia, malaise, weight loss
  • Abdominal pain – usually right upper quadrant, friction rub or bruit over liver, abdominal mass, hepatomegaly, ascites
  • Jaundice
  • Unexplained decompensation in patients with underlying cirrhosis
  • Paraneoplastic syndromes – 20% of cases

Prognosis

  • Prognosis based on
    • Tumor aggressiveness and growth rate
    • Patient general health
    • Liver function – degree of cirrhosis
    • Available treatment options (eg, resection, transplant)
  • Metastatic disease common
    • Common sites – lung, abdominal lymph nodes, bone
  • Prognosis poor – 5-year survival <50%
    • Barcelona Clinic Liver Cancer System is the best at stratifying survival (Llovet, 2004)

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Alpha Fetoprotein, Total and L3 Percent 0081208
Method: Quantitative Liquid Chromatography/Immunoassay

Surveillance and monitoring of hepatocellular carcinoma

Clinical sensitivity/specificity

AFP-L3%

  • L3% ≥10% – relative risk (RR) 43.3% (95% CI: 31.4-55%)
  • L3% <10% – RR 4.1% (95% CI: 1.6-6.6%)

Analytical sensitivity – 0.1 ng/mL

Analytical specificity – unknown

Not all HCCs secrete AFP

Test not useful for monitoring if pretreatment levels were not elevated

False-positive result may occur in the following clinical contexts – pregnancy, age <1 year, acute fulminant hepatitis, cirrhosis

 
Hepatocellular Carcinoma Tumor Marker Panel 0081326
Method: Quantitative Liquid Chromatography/Immunoassay

Acceptable panel for surveillance in high-risk groups

Panel includes alpha fetoprotein (AFP) total, AFP-L3%, and des-gamma-carboxy-prothrombin (DCP)

Clinical sensitivity/specificity

AFP-L3%

  • L3% ≥10% – relative risk (RR) 43.3% (95% CI: 31.4-55%)
  • L3% <10% – RR 4.1% (95% CI: 1.6-6.6%)

DCP

  • DCP ≥7.5 – RR 36.5% (95% CI: 23.5-49.6%)
  • DCP <7.5 – RR 7.6% (95% CI: 4.4-10.8%)

Analytical sensitivity – AFP and DCP 0.1 ng/mL

Analytical specificity – unknown

Not all HCCs secrete AFP and/or DCP

Test is not useful for monitoring if pretreatment levels were not elevated

False-positive result may occur in the following clinical contexts

AFP-L3% – pregnancy, age <1 year, acute fulminant hepatitis, cirrhosis

DCP – obstructive jaundice, intrahepatic cholestasis, drugs (eg, warfarin)

 
Alpha-1-Fetoprotein (AFP) by Immunohistochemistry 2003436
Method: Immunohistochemistry

Aid in histological diagnosis of HCC

Stained and returned to client pathologist; consultation available if needed

   
Alpha-1-Antichymotrypsin (A1ACT) by Immunohistochemistry 2003418
Method: Immunohistochemistry

Aid in histological diagnosis of HCC

Stained and returned to client pathologist; consultation available if needed

   
Beta-Catenin-1 by Immunohistochemistry 2003454
Method: Immunohistochemistry

Aid in histological diagnosis of HCC

Stained and returned to client pathologist; consultation available if needed

   
Cytokeratin 8,18 Low Molecular Weight (CAM 5.2) by Immunohistochemistry 2003493
Method: Immunohistochemistry

Aid in histological diagnosis of HCC

Stained and returned to client pathologist; consultation available if needed

   
Factor XIIIa by Immunohistochemistry 2003878
Method: Immunohistochemistry

Aid in histological diagnosis of HCC

Stained and returned to client pathologist; consultation available if needed

   
Hepatocyte Specific Antigen (HSA) by Immunohistochemistry 2003923
Method: Immunohistochemistry

Aid in histological diagnosis of HCC

Stained and returned to client pathologist; consultation available if needed

   
Arginase 1 by Immunohistochemistry 2011890
Method: Immunohistochemistry

Aid in histological diagnosis of HCC versus metastatic carcinoma

Stained and returned to client pathologist; consultation available if needed

   
Glypican 3 by Immunohistochemistry 2011925
Method: Immunohistochemistry

Aid in histological diagnosis of HCC versus versus hepatic adenoma

Stained and returned to client pathologist; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457
Method: Qualitative Chemiluminescent Immunoassay

Order to evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen, HCV antibody

Reflex pattern – if results for HBsAg are repeatedly reactive with an index value between 1.00 and 50.00, then HBsAg Confirmation will be added

Alpha Fetoprotein, Serum (Tumor Marker) 0080428
Method: Quantitative Chemiluminescent Immunoassay

Surveillance and monitoring in HCC

Less specific than test that includes AFP-L3 isoform

Des-gamma-carboxy Prothrombin 0081312
Method: Quantitative Liquid Chromatography/Immunoassay

Surveillance and monitoring in HCC

Test is not useful for monitoring if pretreatment levels were not elevated

Not all HCCs secrete DCP  

False-positive result may occur in the following clinical contexts – obstructive jaundice, intrahepatic cholestasis, drugs (eg, warfarin)

Clinical sensitivity/specificity

  • DCP ≥7.5 – relative risk (RR) 36.5% (95% CI: 23.5-49.6%)
  • DCP <7.5 – RR 7.6% (95% CI: 4.4-10.8%)

Analytical sensitivity – 0.1 ng/mL

Analytical specificity – unknown

Hepatitis B Virus Surface Antigen with Reflex to Confirmation 0020089
Method: Qualitative Chemiluminescent Immunoassay 

Can be ordered as part of the acute hepatitis panel which includes HAV IgM, HBV core antibody IgM, HBV surface antigen, and HCV antibody

Refer to hepatitis panel, acute with reflex to HBsAg confirmation

Reflex pattern – if results for HBsAg screen are repeatedly reactive with an index value between 1.00 and 50.00, then HBsAg Confirmation will be added