Hepatocellular Carcinoma - HCC

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. Most occur in individuals with chronic liver disease.

Key Points

HCC Surveillance Guidelines

The incidence of 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, 2016 JSH, 2014 NCCN, 2018 EASL, 2018
Recommended Screening Abdominal US with or without AFP Abdominal US and combination of ≥2 markers including AFP, PIVKA-II, AFP-L3
  • Combination of ≥2 markers increases sensitivity
Abdominal US and AFP

Multiphasic CT or MRI recommended in setting of positive AFP or liver mass on US

Abdominal US

AFP not recommended

Recommended Interval for Screening Every 6 mos (can range from 4-8 mos) Markers plus US
  • Super high risk – every 3-4 mos
  • High risk – every 6 mos

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

  • Every 6-12 mos
Every 6 mos Every 6 mos
At-Risk Patients to Screen Cirrhosis

Without cirrhosis – chronic viral hepatitis B and carriers

Super high-risk population
  • Hepatitis B- or C-related cirrhosis

High-risk population

  • Chronic hepatitis B or C
  • Cirrhosis
Cirrhosis

Without cirrhosis – hepatitis B carriers

Cirrhosis (Child-Pugh stage A or B)

Cirrhosis (Child-Pugh stage C awaiting transplant)

Patient with hepatitis B at intermediate or high risk of HCC according to PAGE-B

Noncirrhotic patients with severe fibrosis, regardless of etiology

All patients awaiting transplant

AASLD, American Association for the Study of Liver Disease; AFP, alpha-fetoprotein; AFP-L3, alpha-fetoprotein L3 isoform; CT, computed tomography; EASL, European Association for the Study of the Liver; EORTC, European Organisation for Research and Treatment of Cancer; JSH, Japanese Society of Hepatology; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PAGE-B, platelet, age, gender, and hepatitis B status; PIVKA-II, protein induced by vitamin K absence-II; US, ultrasound

Diagnosis

Indications for Testing

  • Clinical symptoms in the presence of risk factors for HCC
  • Elevated neoplastic markers
  • Intrahepatic mass
  • Nonspecific symptoms such as 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, perform viral load testing
    • Hepatic function testing
      • As a panel or separately
        • Albumin
        • Alkaline phosphatase (ALP)
        • Aspartate transaminase (AST)
        • Alanine transaminase (ALT)
        • Bilirubin
      • Gamma-glutamyl transferase (GGT)
    • Prothrombin time (PT)/international normalized ratio (INR)
    • Kidney function testing – evaluate severity of cirrhosis
      • Blood urea nitrogen (BUN)
      • Creatinine
    • CBC with platelets
  • Hepatic mass
    • CEA, CA 19-9, liver markers (below)
  • Liver tumor markers may be useful in patients with risk factors; however, further studies are needed to confirm role
    • AFP
    • AFP-L3 – more specific than AFP
    • Des-gamma-carboxy-prothrombin (DCP) – more specific than AFP
    • Combined testing – superior to single marker alone
    • No marker is optimal in early-stage disease
      • AFP frequently not elevated in early-stage disease

Histology

  • Gold standard for diagnosis of HCC – definitive diagnosis requires biopsy and pathologist examination
  • US- or CT-guided percutaneous biopsy

Imaging Studies

  • Most surveillance and treatment algorithms currently rely heavily on imaging studies
  • MRI or abdominal multiphasic CT – for diagnosis and staging
  • Contrast-enhanced US – not recommended as a first-line imaging test (EASL, 2018)
    • Lower sensitivity than MRI or multiphasic CT
    • Can be used when CT and MRI results are inconclusive
  • For confirmed HCC
    • Chest CT – evaluate for extrahepatic metastases
    • Bone scan – when skeletal symptoms present

Differential Diagnosis

Screening

Refer to Key Points for surveillance guidelines.

Background

Epidemiology

  • Incidence
    • 8.6/100,000 new cases per year (liver and intrahepatic bile duct cancer combined) (SEER, 2017)
      • Estimated >40,000 cases and ~28,000 deaths in U.S. in 2017 (SEER, 2017)
    • Fifth most common cancer for men worldwide; ninth for women
    • Second most common cause of cancer-related death
  • Age – peaks in 60s in U.S.; 20s-40s in Asian countries
  • Sex – M:F >2:1
  • Ethnicity – higher incidence in Asian, Hispanic, American Indian/Alaska Native, and African American populations (SEER, 2017)

Risk Factors

  • Highest risk in U.S. associated with nonalcoholic fatty liver disease (NAFLD), chronic infectious hepatitis, and alcohol-induced cirrhosis
    • Coexistent risk factors magnify risk
  • Cirrhosis – most cases of HCC arise in cirrhotic liver
  • 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

Pathophysiology

  • HCCs arise from
    • Parenchymal cells of the liver
    • Dysplastic nodules (controversial)
  • DNA damage leads to activation of proto-oncogenes and deactivation of tumor suppressors
  •  80% associated with chronic liver disease and cirrhosis
    • Individuals with HBV may develop HCC without presence of cirrhosis

Clinical Presentation

  • Typically asymptomatic until late-stage tumor – often metastatic at presentation
  • Most patients have 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 size and location (resectability)
    • 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 scoring systems
    • Child-Pugh score – assessment of surgical risk in patients with cirrhosis
      • Uses bilirubin, albumin, PT, and presence of ascites and encephalopathy
    • Model for End-Stage Liver Disease (MELD) – determines eligibility for transplant
    • Barcelona Clinic Liver Cancer System – best at stratifying survival (Llovet, 2004)
      • Prognosis poor – 5-year survival <50%
      • Uses tumor extent, liver function, and general condition

ARUP Lab Tests

Acceptable panel for surveillance and monitoring of HCC

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

Monitoring posttreatment

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)

Aid in histological diagnosis of HCC

Stained and returned to client pathologist; consultation available if needed

Aid in histological diagnosis of HCC versus metastatic carcinoma

Stained and returned to client pathologist; consultation available if needed

Aid in the histological diagnosis of HCC, depending on differential diagnosis

Stained and returned to client pathologist; consultation available if needed

Aid in the diagnosis of HCC versus hepatic adenoma

Aid in histological diagnosis of HCC versus hepatic adenoma; typically used in combination with Hsp70 and glutamine synthetase

Stained and returned to client pathologist; consultation available if needed

Panel includes albumin; ALP; AST; ALT; bilirubin, direct; protein, total; and bilirubin, total

Related Tests

Initial screening for hepatobiliary inflammation

May be useful as an indirect marker of alcohol abuse, NAFLD, drug intoxication, or other liver diseases

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 (HBsAg), HCV antibody

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

Surveillance and monitoring of HCC

Less specific than test that includes AFP-L3 isoform

Surveillance and monitoring of HCC

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

Refer to aruplab.com/bodyfluids for clinical indications and interpretive information

Surveillance and monitoring of 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)

Can be ordered as part of the acute hepatitis panel which includes HAV IgM, HBV core antibody IgM, HBsAg, 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 test will be added

Initial test for evaluating bleeding disorders and monitoring oral anticoagulation therapy (warfarin/Coumadin)

Screening test to evaluate kidney function

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory and Farmington Health Center Clinical Laboratory, ARUP Laboratories
Contributor

References

Additional Resources