Hepatocellular Carcinoma

Primary Author: Grenache, David G., PhD.

  • Key Points
  • Diagnosis
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Topics

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, 2014

NCCN, 2016


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

Abdominal US

AFP not recommended

Recommended Interval for Screening Every 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 months Every 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


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 (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

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


  • 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)


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

Differential Diagnosis

  • Refer to Key Points for surveillance guidelines

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.


  • Incidence
    • 4-11/100,000 (U.S. and Europe)
      • >33,000 cases and ~23,000 deaths in U.S. in 2014 (NCCN, 2016)
    • 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

  • Highest risk in U.S. associated with chronic infectious hepatitis and alcohol-induced cirrhosis
    • Coexistent risk factors magnify risk
  • 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)
  • 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


  • 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 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)
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


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

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

Beta-Catenin-1 by Immunohistochemistry 2003454
Method: Immunohistochemistry

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

Factor XIIIa by Immunohistochemistry 2003878
Method: Immunohistochemistry

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

Arginase 1 by Immunohistochemistry 2011890
Method: Immunohistochemistry

Glypican 3 by Immunohistochemistry 2011925
Method: Immunohistochemistry


Bruix J, Sherman M. AASLD Practice Guideline: Management of hepatocellular carcinoma: An update. American Association for the Study of Liver Diseases. Alexandria, VA [Accessed: Jun 2015]

Chou R, Cuevas C, Fu R, Devine B, Wasson N, Ginsburg A, Zakher B, Pappas M, Graham E, Sullivan SD. Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. Ann Intern Med. 2015; 162(10): 697-711. 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

Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, Kojiro M, Makuuchi M, HCC Expert Panel of Japan Society of Hepatology. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis. 2011; 29(3): 339-64. 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

NCCN Clinical Practice Guidelines in Oncology, Hepatobiliary Cancers. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Apr 2016]

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 [Accessed: Jun 2015]

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

Last Update: August 2016