Purpose of This PDQ Summary
Summary of Evidence

Benefits Harms

Significance

Incidence, Mortality, and Risk Factors

Evidence of Benefit

Rationale for Screening Tumor Markers for the Detection of Hepatocellular Carcinoma         Alpha-fetoprotein Hepatic Ultrasound Computed Tomography Efficacy of Screening and Surveillance Programs

Evidence of Harms
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Changes To This Summary (04/03/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about hepatocellular cancer screening. This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board ¹.

Information about the following is included in this summary:

• Hepatocellular cancer incidence and mortality statistics and information about hepatocellular cancer risk factors.
• Hepatocellular cancer screening modalities.
• Benefits and harms of hepatocellular cancer screening.

This summary is intended as a resource to inform clinicians and other health professionals about currently available hepatocellular cancer screening modalities. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system ² in reporting the evidence of benefit and potential harms associated with each screening modality. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version ³, which is written in less technical language.

Summary of Evidence

Note: Separate PDQ summaries on Adult Primary Liver Cancer Treatment ⁴ and Childhood Liver Cancer Treatment ⁵ are also available.

Based on fair evidence, screening would not result in a decrease in mortality from hepatocellular cancer.

Magnitude of Effect: No reduction in mortality.

Study Design: Randomized controlled trials.

Internal Validity: Fair.

Consistency: Multiple studies, large number of participants.

External Validity: Fair.

Based on fair evidence, screening would result in rare but serious side effects associated with needle aspiration cytology such as needle-track seeding, particularly of lesions more than 2 cm in diameter, and hemorrhage, bile peritonitis, and pneumothorax. Transjugular liver biopsy is rarely associated with major complications such as perforation of the hepatic capsule or cholangitis.

Magnitude of Effect: Good evidence for uncommon but serious harms.

Study Design: Randomized controlled trials and observational studies.

Internal Validity: Fair.

Consistency: Multiple studies, large number of participants.

External Validity: Good.

Significance

Incidence, Mortality, and Risk Factors

Hepatocellular cancer (HCC) is the fourth most common cancer in the world.[1] Age-standardized incidence rates vary from 2.1 per 100,000 in North America [2] to 80 per 100,000 in China.[1] In the United States, it is estimated that there will be 21,370 new cases diagnosed in 2008 and 18,410 deaths due to this disease.[3] There is a distinct male preponderance among all ethnic groups in the United States, although this trend is most marked among Chinese Americans, in whom the annualized rate of HCC among men is 20.9 per 100,000 and among women is 8.0 per 100,000 population.[4] Chronic hepatitis B and C are recognized as the major factors worldwide increasing the risk of HCC, with risk being greater in the presence of coinfection with hepatitis B virus and hepatitis C virus.[5-7] The incidence of HCC in individuals with chronic hepatitis is as high as 0.46% per year. In the United States, chronic hepatitis B and C account for about 30% to 40% of HCC. Chronic hepatitis G infection is not associated with HCC in either hepatitis B surface antigen–positive carriers or noncarriers.[8]

Cirrhosis is also a risk factor for HCC, irrespective of the etiology of the cirrhosis. The annual risk of developing HCC among persons with cirrhosis is between 1% and 6%.[6] Other risk factors include alcoholic cirrhosis, hemochromatosis, alpha-l-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, tyrosinemia, and Wilson disease,[2] but rarely biliary cirrhosis.[9] A retrospective case-control study found that features suggestive of nonalcoholic steatohepatitis, including obesity, type 2 diabetes, dyslipidemia, and insulin resistance, were more frequently observed in patients with HCC associated with cryptogenic cirrhosis than in those with HCC of viral or alcohol etiology.[10,11] Aflatoxins, which are mycotoxins formed by certain Aspergillus species, are a frequent contaminant of improperly stored grains and nuts. In parts of Africa, the high incidence of HCC in humans may by related to ingestion of foods contaminated with aflatoxins. This association, however, is blurred by the frequent coexistence of hepatitis B infection in those population groups. The likely etiology of HCC is summarized in the following table.[12]

References

1. Parkin DM, Whelan SL, Ferlay J, et al., eds.: Cancer Incidence in Five Continents. Volume VII. Lyon, France: International Agency for Research on Cancer, 1997. 
   
   
2. Di Bisceglie AM, Carithers RL Jr, Gores GJ: Hepatocellular carcinoma. Hepatology 28 (4): 1161-5, 1998.  [PUBMED Abstract]
   
   
3. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ⁷ Last accessed October 1, 2008. 
   
   
4. Ries LAG, Harkins D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2003. Bethesda, Md: National Cancer Institute, 2006. Also available online ⁸. Last accessed October 07, 2008. 
   
   
5. Benvegnù L, Fattovich G, Noventa F, et al.: Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 74 (9): 2442-8, 1994.  [PUBMED Abstract]
   
   
6. Ikeda K, Saitoh S, Koida I, et al.: A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18 (1): 47-53, 1993.  [PUBMED Abstract]
   
   
7. Chiaramonte M, Stroffolini T, Vian A, et al.: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85 (10): 2132-7, 1999.  [PUBMED Abstract]
   
   
8. Yuan JM, Govindarajan S, Gao YT, et al.: Prospective evaluation of infection with hepatitis G virus in relation to hepatocellular carcinoma in Shanghai, China. J Infect Dis 182 (5): 1300-3, 2000.  [PUBMED Abstract]
   
   
9. Farinati F, Floreani A, De Maria N, et al.: Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 21 (3): 315-6, 1994.  [PUBMED Abstract]
   
   
10. Bugianesi E, Leone N, Vanni E, et al.: Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123 (1): 134-40, 2002.  [PUBMED Abstract]
    
    
11. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004.  [PUBMED Abstract]
    
    
12. Shiratori Y, Yoshida H, Omata M: Management of hepatocellular carcinoma: advances in diagnosis, treatment and prevention. Expert Rev Anticancer Ther 1 (2): 277-90, 2001.  [PUBMED Abstract]
    
    

Evidence of Benefit

Rationale for Screening

The rationale for screening for hepatocellular carcinoma (HCC) is based on the concept that populations at high risk for HCC, such as those with cirrhosis, can be identified. However, 20% to 50% of patients presenting with HCC have previously undiagnosed cirrhosis.[1,2] These patients would not be recruited into a surveillance program if the presence of cirrhosis is used to define a target population.[3] The modalities potentially available for screening include serum alpha-fetoprotein (AFP) and ultrasonography. Abnormal screening results may lead to liver biopsy for diagnosis. Complications of liver biopsy are reported in 0.06% to 0.32% of patients, and typically occur within the first few hours after the biopsy.

There are four categories of tumor markers that are currently being used or studied for the detection of hepatocellular carcinoma. These include oncofetal antigens and glycoprotein antigens; enzymes and isoenzymes; genes; and cytokines.[4]

Serum AFP, a fetal-specific glycoprotein antigen, is the most widely used tumor marker for detecting patients with HCC. The reported sensitivity of AFP for detecting HCC varies widely in both hepatitis B virus (HBV)-positive and HBV-negative populations, which is attributable to overlap between screening and diagnosis study designs.[3] When AFP is used for screening of high-risk populations, a sensitivity of 39% to 97%, specificity of 76% to 95%, and a positive predictive value (PPV) of 9% to 32% have been reported.[5-9] AFP is not specific for HCC. Titers also rise in acute or chronic hepatitis,[10] in pregnancy, and in the presence of germ cell tumors.

A prospective, 16-year, population-based, observational study of screening for hepatocellular cancer among 1,487 Alaska Natives chronically infected with HBV compared survival among screen-detected HCC patients with a historical comparison group of clinically diagnosed HCC patients.[8] The screening program’s target was AFP determination every 6 months. It achieved 97% sensitivity and 95% specificity (excluding pregnant women) for HCC. Such high sensitivity and specificity have not been found for other high-risk groups, such as individuals with cirrhosis.[11,12] Whether screening actually improved survival is not clear.

Limitations in the sensitivity and specificity of AFP in surveillance of high-risk populations led to the use of ultrasound as an additional method for detection of HCC.[3] Studies in both healthy hepatitis B surface antigen carriers [5] and in patients with cirrhosis [7] have defined the performance characteristics of ultrasound as a screening test for HCC. Sensitivity in the former was 71% and in the latter 78%, with 93% specificity. The PPVs were 14% and 73%, respectively. In a study of patients who were on a waiting list for liver transplantation, ultrasonography was found to have a sensitivity of 58%, a specificity of 94%, a negative predictive value of 91%, and a PPV of 68%.[13]

Limitations in the sensitivity and specificity of AFP and ultrasound in surveillance of high-risk populations, such as individuals with cirrhosis, led to the assessment of computed tomography (CT) as an additional method for detection of HCC. Studies in patients with cirrhosis suggest that CT may be a more sensitive test for HCC than ultrasound or AFP more than 20 μg/L.[11,12]

A controlled trial of 18,816 persons aged 35 to 59 years with hepatitis B in Shanghai randomly assigned patients to a screening group using AFP and ultrasound every 6 months versus a usual care group. HCC mortality was lower in the screened group (83.2 vs. 131.5 per 100,000; mortality rate ratio of 0.63 [95% confidence interval (CI), 0.41–0.98]). While these results are promising, the CI was near 1.0, intention-to-treat analysis was not used, assessment of outcome was not blinded, and generalizability to other populations is uncertain.[14]

A randomized controlled trial studied 5,581 men aged 30 to 69 years who were chronic carriers of HBV between 1989 and 1995 in Qidong County, China. Of these men, 3,712 were randomly assigned to a screening group and 1,869 to a control group. Screening entailed 6-monthly AFP assays, with follow-up of patients having an abnormal (≥20 μg/L) test result. All patients were followed up for liver cancer and/or death. The overall sensitivity and specificity of the program were 55.3% and 86.5%, respectively. In patients who complied with all scheduled screening tests, sensitivity was 80% and specificity was 80.9%. The mortality rate in the screening group (1,138 per 100,000 person-years) was not significantly different from that in the control group (1,114 per 100,000 person-years), although AFP screening resulted in an earlier diagnosis of liver cancer (i.e., percentage of cases in stage I was significantly higher in the screened group [29.0%] than in the control group [6%]).[15]

References

1. Zaman SN, Johnson PJ, Williams R: Silent cirrhosis in patients with hepatocellular carcinoma. Implications for screening in high-incidence and low-incidence areas. Cancer 65 (7): 1607-10, 1990.  [PUBMED Abstract]
   
   
2. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Liver Cancer Study Group of Japan. Ann Surg 211 (3): 277-87, 1990.  [PUBMED Abstract]
   
   
3. Collier J, Sherman M: Screening for hepatocellular carcinoma. Hepatology 27 (1): 273-8, 1998.  [PUBMED Abstract]
   
   
4. Zhou L, Liu J, Luo F: Serum tumor markers for detection of hepatocellular carcinoma. World J Gastroenterol 12 (8): 1175-81, 2006.  [PUBMED Abstract]
   
   
5. Sherman M, Peltekian KM, Lee C: Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 22 (2): 432-8, 1995.  [PUBMED Abstract]
   
   
6. Oka H, Tamori A, Kuroki T, et al.: Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 19 (1): 61-6, 1994.  [PUBMED Abstract]
   
   
7. Pateron D, Ganne N, Trinchet JC, et al.: Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 20 (1): 65-71, 1994.  [PUBMED Abstract]
   
   
8. McMahon BJ, Bulkow L, Harpster A, et al.: Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology 32 (4 Pt 1): 842-6, 2000.  [PUBMED Abstract]
   
   
9. Soresi M, Magliarisi C, Campagna P, et al.: Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res 23 (2C): 1747-53, 2003 Mar-Apr.  [PUBMED Abstract]
   
   
10. Di Bisceglie AM, Hoofnagle JH: Elevations in serum alpha-fetoprotein levels in patients with chronic hepatitis B. Cancer 64 (10): 2117-20, 1989.  [PUBMED Abstract]
    
    
11. Chalasani N, Horlander JC Sr, Said A, et al.: Screening for hepatocellular carcinoma in patients with advanced cirrhosis. Am J Gastroenterol 94 (10): 2988-93, 1999.  [PUBMED Abstract]
    
    
12. Peterson MS, Baron RL, Marsh JW Jr, et al.: Pretransplantation surveillance for possible hepatocellular carcinoma in patients with cirrhosis: epidemiology and CT-based tumor detection rate in 430 cases with surgical pathologic correlation. Radiology 217 (3): 743-9, 2000.  [PUBMED Abstract]
    
    
13. Dodd GD 3rd, Miller WJ, Baron RL, et al.: Detection of malignant tumors in end-stage cirrhotic livers: efficacy of sonography as a screening technique. AJR Am J Roentgenol 159 (4): 727-33, 1992.  [PUBMED Abstract]
    
    
14. Zhang BH, Yang BH, Tang ZY: Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 130 (7): 417-22, 2004.  [PUBMED Abstract]
    
    
15. Chen JG, Parkin DM, Chen QG, et al.: Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen 10 (4): 204-9, 2003.  [PUBMED Abstract]
    
    

Evidence of Harms

Two kinds of harms or complications may result from screening. Direct harms may result from complications of liver biopsy done as part of the diagnostic workup. Such complications are reported in 0.06% to 0.32% of patients, and typically occur within the first few hours after the biopsy. Complications include hemorrhage, bile peritonitis, penetration of viscera, and pneumothorax. Rarely, death occurs as a direct result of liver biopsy (0.009%–0.12%). About one third of patients experience pain at the site of entry, in the right upper quadrant, or in the right shoulder.[1] Needle aspiration cytology and liver biopsy are rarely associated with needle-track implantation of malignant cells. Lead-time bias (earlier diagnosis in the natural history of HCC rather than improved survival from earlier diagnosis and treatment), length bias (earlier detection of slower-growing and less aggressive tumors through screening), and/or overdiagnosis of HCC (detection of tumors that will not affect morbidity or mortality) may wholly or partially account for the improved 5-year and 10-year survival rates reported.

References

1. Tobkes AI, Nord HJ: Liver biopsy: review of methodology and complications. Dig Dis 13 (5): 267-74, 1995 Sep-Oct.  [PUBMED Abstract]
   
   

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Changes To This Summary (04/03/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance ¹²

Updated incidence and mortality estimates ¹³ for 2008 (cited American Cancer Society as reference 3).

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