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
  • Diagnosis
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Topics
Primary Author: Grenache, David G., PhD.

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, 2016

JSH, 2014

NCCN, 2017

EASL-EORTC, 2012

Recommended Screening

Abdominal ultrasound (US) with or without AFPa

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

  • Combination of ≥2 markers increases sensitivity

Abdominal US and AFP

3-phase CT or MRI recommended in setting of rising 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 6-12 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)

Hepatitis B carrier with active hepatitis or family history of HCC

Chronic hepatitis C and advanced liver fibrosis

All patients awaiting transplant

aAFP – alpha-fetoprotein

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

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
  • Intrahepatic mass

Laboratory Testing

  • Initial testing
    • Viral hepatitis testing if etiology of liver disease is unclear
      • If viral disease confirmed – 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/international normalized ratio (PT/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
    • Alpha-fetoprotein (AFP)
    • Alpha-fetoprotein L3 isoform (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
  • Ultrasound- or CT-guided percutaneous biopsy

Imaging Studies

  • Most surveillance and treatment algorithms currently rely heavily on imaging studies
    • Ultrasound – safe, low cost
      • Does not have performance characteristics of CT and MRI
    • MRI or abdominal multiphasic CT – for diagnosis and staging
    • For confirmed HCC
      • Chest CT – evaluate for extrahepatic metastases
      • Bone scan – when skeletal symptoms present

Differential Diagnosis

Refer to Key Points for surveillance guidelines

Epidemiology

  • Incidence
    • 4-11/100,000 (U.S. and Europe)
      • 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 and African populations

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
    • NAFLD/nonalcoholic​​​ steatohepatitis (NASH) – major risk factor leading to cirrhosis and HCC due to high prevalence of diabetes and metabolic syndrome in the U.S.
    • Chronic infections – hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV)
      • HCV – risk factor for HCC in North America
      • HBV – majority of HCC in Asian Americans and African Americans
    • Heavy alcohol consumption – alcoholic cirrhosis
      • >80 gm/day for >10 years increases risk for HCC 5-fold
      • Risk further increases 2- to 4-fold in the presence of chronic viral hepatitis
    • Autoimmune diseases
    • Hereditary metabolic liver diseases
    • Glycogen storage diseases
  • 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, prothrombin time, 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
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.

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

Limitations 

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)

Beta-Catenin-1 by Immunohistochemistry 2003454
Method: Immunohistochemistry

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

Arginase 1 by Immunohistochemistry 2011890
Method: Immunohistochemistry

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

Special Stain, Reticulin 2005996
Method: Special Stain

Glypican 3 by Immunohistochemistry 2011925
Method: Immunohistochemistry

Guidelines

Cong W, Bu H, Chen J, Dong H, Zhu Y, Feng L, Chen J, Committee G. Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update. World J Gastroenterol. 2016; 22(42): 9279-9287. PubMed

European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012; 56(4): 908-43. PubMed

Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. World Health Organization. Geneva, Switzerland [Accessed: May 2017]

Heimbach J, Kulik LM, Finn R, Sirlin CB, Abecassis M, Roberts LR, Zhu A, Murad H, Marrero J. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2017; PubMed

Kudo M, Matsui O, Izumi N, Iijima H, Kadoya M, Imai Y, Okusaka T, Miyayama S, Tsuchiya K, Ueshima K, Hiraoka A, Ikeda M, Ogasawara S, Yamashita T, Minami T, Yamakado K, Liver Cancer Study Group of Japan. JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan Liver Cancer. 2014; 3(3-4): 458-68. PubMed

Marrero JA, Ahn J, Reddy R, Americal College of Gastroenterology. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014; 109(9): 1328-47; quiz 1348. PubMed

NCCN Clinical Practice Guidelines in Oncology, Hepatobiliary Cancers. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: May 2017]

Protocol for the Examination of Specimens from Patients with Hepatocellular Carcinoma. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Feb 2011. College of American Pathologists (CAP). Northfield, IL [Revised: Feb 2012; Accessed: May 2017]

Thomas MB, Jaffe D, Choti MM, Belghiti J, Curley S, Fong Y, Gores G, Kerlan R, Merle P, O'Neil B, Poon R, Schwartz L, Tepper J, Yao F, Haller D, Mooney M, Venook A. Hepatocellular carcinoma: consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol. 2010; 28(25): 3994-4005. PubMed

Verslype C, Rosmorduc O, Rougier P, ESMO Guidelines Working Group. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol. 2012; 23 Suppl 7: vii41-8. PubMed

General References

Debruyne EN, Delanghe JR. Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications. Clin Chim Acta. 2008; 395(1-2): 19-26. PubMed

El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011; 365(12): 1118-27. PubMed

Gonzalez SA, Keeffe EB. Diagnosis of hepatocellular carcinoma: role of tumor markers and liver biopsy. Clin Liver Dis. 2011; 15(2): 297-306, vii-x. PubMed

Llovet JM, Fuster J, Bruix J, Barcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004; 10(2 Suppl 1): S115-20. PubMed

Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, Morgan TR, Kim H, Lee WM, Bonkovsky HL, Dienstag JL, HALT-C Trial Group. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 2010; 138(2): 493-502. PubMed

Masuzaki R, Karp SJ, Omata M. New serum markers of hepatocellular carcinoma. Semin Oncol. 2012; 39(4): 434-9. PubMed

Sherman M. Surveillance for hepatocellular carcinoma. Best Pract Res Clin Gastroenterol. 2014; 28(5): 783-93. PubMed

Shoreibah MG, Bloomer JR, McGuire BM, Massoud OI. Surveillance for hepatocellular carcinoma: evidence, guidelines and utilization. Am J Med Sci. 2014; 347(5): 415-9. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Owen WE, Roberts RF, Roberts WL. Performance characteristics of the LiBASys des-gamma-carboxy prothrombin assay. Clin Chim Acta. 2008; 389(1-2): 183-5. PubMed

Rowe LR, Mulvihill SJ, Emerson L, Gopez EV. Subcutaneous tumor seeding following needle core biopsy of hepatocellular carcinoma. Diagn Cytopathol. 2007; 35(11): 717-21. PubMed

Medical Reviewers

Grenache, David G., PhD, Medical Director, Special Chemistry; Co-Director, Electrophoresis and Manual Endocrinology; Chief Medical Director, Clinical Chemistry at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Salama, Mohamed E., MD, Laboratory Section Chief, Hematopathology, at ARUP Laboratories; Professor of Clinical Pathology, Chief of Hematopathology, and Director of the Hematopathology Fellowship Program, University of Utah

Content Reviewed: 
May 2017

Last Update: October 2017