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.
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
|
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
Dynamic CT scan/MRI (only super high risk or in those whom US was suboptimal)
|
Every 6 mos | Every 6 mos |
At-Risk Patients to Screen | Cirrhosis
Without cirrhosis – chronic viral hepatitis B and carriers |
Super high-risk population
High-risk population
|
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)
- As a panel or separately
- Prothrombin time (PT)/international normalized ratio (INR)
- Kidney function testing – evaluate severity of cirrhosis
- Blood urea nitrogen (BUN)
- Creatinine
- CBC with platelets
- Viral hepatitis testing if etiology of liver disease is unclear
- 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
- Abdominal pain
- Acute cholecystitis
- Acute pancreatitis
- Infectious diarrhea
- Parasitic
- Viral
- Hepatomegaly
- Other malignancy (eg, biliary, pancreatic)
- Cirrhosis
- Metabolic disease
- Hemochromatosis
- Wilson disease
- Metabolic syndrome (eg, nonalcoholic steatohepatitis)
- Alpha-1 antitrypsin deficiency (AAT)
- Jaundice
- Other malignancy (eg, biliary, pancreatic)
- Acute hepatitis
- Toxins (eg, alcohol)
- Infectious (hepatitis A, B, C, D)
- Metabolic
- Autoimmune disease
- Hepatic lesion
- Infection/abscess (hydatid cyst)
- Metastatic disease
- Hemangioma
- Focal nodular hyperplasia
- Hepatic adenoma
- Cholangiocarcinoma
- Focal nodular hyperplasia
- Simple cyst
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
- 8.6/100,000 new cases per year (liver and intrahepatic bile duct cancer combined) (SEER, 2017)
- 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
- 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 fivefold
- Risk further increases two- to fourfold in the presence of chronic viral hepatitis
- Autoimmune diseases
- Hereditary metabolic liver diseases
- AAT
- Hemochromatosis
- Wilson disease
- Hereditary tyrosinemia
- Porphyria cutanea tarda
- 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
- Acquired porphyria
- Cryofibrinogenemia
- Diarrhea – vasoactive intestinal polypeptide
- Erythrocytosis – erythropoietin-like activity
- Hypercalcemia – parathyroid-like hormone
- Hypercholesterolemia
- Hypoglycemia – insulin growth factor
- Polymyositis
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
- Child-Pugh score – assessment of surgical risk in patients with cirrhosis
ARUP Laboratory 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)
Quantitative Liquid Chromatography/Immunoassay
Aid in histological diagnosis of HCC
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
Immunohistochemistry
Aid in histological diagnosis of HCC versus metastatic carcinoma
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
Aid in the histological diagnosis of HCC, depending on differential diagnosis
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
Aid in the diagnosis of HCC versus hepatic adenoma
Special Stain
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
Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Initial screening for hepatobiliary inflammation
Immunohistochemistry
May be useful as an indirect marker of alcohol abuse, NAFLD, drug intoxication, or other liver diseases
Quantitative Enzymatic Assay
Use to evaluate for a viral etiology in symptomatic patients with acute hepatitis
Qualitative Chemiluminescent Immunoassay (CLIA)/Quantitative Transcription-Mediated Amplification (TMA)
Surveillance and monitoring of HCC
Less specific than test that includes AFP-L3 isoform
Quantitative Chemiluminescent Immunoassay
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
Quantitative Liquid Chromatography/Immunoassay
Refer to aruplab.com/bodyfluids for clinical indications and interpretive information
Quantitative Chemiluminescent Immunoassay
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)
Quantitative Liquid Chromatography/Immunoassay
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
Qualitative Chemiluminescent Immunoassay
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)
Electromagnetic Mechanical Clot Detection
Screening test to evaluate kidney function
Quantitative Enzymatic Assay
Spectrophotometry
References
27895416
Cong WM, Bu H, Chen J, et al. Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update. World J Gastroenterol. 2016;22(42):9279-9287.
18538135
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.
21992124
El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118-1127.
29628281
European Association for the Study of the Liver (EASL). EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182-236.
21689614
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.
28130846
Heimbach J, Kulik LM, Finn R, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358-380
26280007
Kudo M, Matsui O, Izumi N, et al. 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):458-468.
14762851
Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004;10(2 Suppl 1):S115-120.
19852963
Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 2010;138(2):493-502.
25135008
Marrero JA, Ahn J, Reddy R, et al. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014;109(9):1328-1347;quiz 1348.
22846860
Masuzaki R, Karp SJ, Omata M. New serum markers of hepatocellular carcinoma. Semin Oncol. 2012;39(4):434-439.
NCI - Adult Primary Liver Cancer Treatement (PDQ)--Health Professional Version
National Cancer Institute. Adult Primary Liver Cancer Treatement (PDQ)--Health Professional Version. [Updated: Feb 2018; Accessed: Feb 2018]
NCCN - Clinical Practice Guidelines in Oncology, Hepatobiliary Cancers Version 2.2018
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary cancers. Version 2.2018. [Update: Jun 2018; Accessed: Sep 2018]
25260308
Sherman M. Surveillance for hepatocellular carcinoma. Best Pract Res Clin Gastroenterol. 2014;28(5):783-793.
24759379
Shoreibah MG, Bloomer JR, McGuire BM, et al. Surveillance for hepatocellular carcinoma: evidence, guidelines and utilization. Am J Med Sci. 2014;347(5):415-419.
20679622
Thomas MB, Jaffe D, Choti MM, et al. Hepatocellular carcinoma: consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol. 2010;28(25):3994-4005.
22997453
Verslype C, Rosmorduc O, Rougier P, et al. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii41-vii48.
WHO - Guidelines - HBV
World Health Organization. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva, Switzerland. [ Accessed: Mar 2018]
Panel includes albumin; ALP; AST; ALT; bilirubin, direct; protein, total; and bilirubin, total