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Abbreviations
AASLD

American Association for the Study of Liver Diseases

AFP

α-fetoprotein

CT

computed tomography

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

MDCT

multidetector computed tomography

MR

magnetic resonance

MRI

magnetic resonance imaging

US

ultrasound

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and is a major global health problem. Most cases of HCC (85%) arise in eastern Asia and sub-Saharan Africa, and they are associated with chronic hepatitis B virus (HBV) infection. In contrast, the dominant risk factor in the United States, Europe, and Japan is chronic hepatitis C virus (HCV) infection. In the United States, the age-adjusted incidence rates for HCC have tripled since the early 1980s, with the greatest proportional increases occurring among whites and younger patients (45-60 years old).[1]

What Are the Risk Factors for Developing HCC?

  1. Top of page
  2. Abstract
  3. What Are the Risk Factors for Developing HCC?
  4. Is Surveillance Effective?
  5. Who Should Receive Surveillance?
  6. How Should Surveillance Be Performed?
  7. How Is HCC Best Managed?
  8. Summary
  9. References

Most cases of HCC (approximately 90%) are associated with a known risk factor. More than half of HCC cases worldwide can be attributed to chronic HBV infection, and the risk is increased in patients with a high viral load and a longer period of infection. Cirrhosis of any cause is an important risk factor for the development of HCC. The incidence of HCC in individuals with cirrhosis varies from 1% to 8% per year, with the greatest risk (estimated to be 3%-8% per year) among those with viral hepatitis (particularly HCV).[2] Obesity and diabetes, often contributing to fatty liver disease, are also independent risk factors for the development of HCC and may act synergistically with other risk factors such as viral hepatitis.[3, 4] Coinfection with HIV is also an additive risk factor for HCC in patients with chronic viral hepatitis.[5] Smokers have a higher risk than nonsmokers.[6] In all populations, HCC has a strong male preponderance, with the male-to-female ratio estimated to be 2.4.[7]

Is Surveillance Effective?

  1. Top of page
  2. Abstract
  3. What Are the Risk Factors for Developing HCC?
  4. Is Surveillance Effective?
  5. Who Should Receive Surveillance?
  6. How Should Surveillance Be Performed?
  7. How Is HCC Best Managed?
  8. Summary
  9. References

Surveillance is the repeated application of a screening test to an at-risk population with the aim of detecting disease at an earlier stage when potential curative options are available and thus reducing disease-related mortality. HCC is a condition that readily lends itself to surveillance because the at-risk population can be identified on the basis of the presence of chronic viral hepatitis and/or cirrhosis. Uncontrolled studies and one randomized control trial in China [which involved 18,816 patients with chronic HBV infections who were randomized to biannual surveillance with ultrasonography and serum α-fetoprotein (AFP) or no surveillance] strongly suggest that surveillance reduces patient mortality because of the increased applicability of curative measures (e.g., resection) to HCC-detected patients.[8-10]

Who Should Receive Surveillance?

  1. Top of page
  2. Abstract
  3. What Are the Risk Factors for Developing HCC?
  4. Is Surveillance Effective?
  5. Who Should Receive Surveillance?
  6. How Should Surveillance Be Performed?
  7. How Is HCC Best Managed?
  8. Summary
  9. References

The guidelines of the American Association for the Study of Liver Diseases (AASLD) recommend HCC surveillance for all patients with cirrhosis who could be treated if they were diagnosed with HCC as well as some patients with chronic HBV infections even in the absence of cirrhosis. Patients with advanced cirrhosis should be evaluated for liver transplantation. Patients who are not transplant candidates should not undergo continued surveillance, whereas patients with cirrhosis awaiting liver transplantation should receive surveillance.[11]

How Should Surveillance Be Performed?

  1. Top of page
  2. Abstract
  3. What Are the Risk Factors for Developing HCC?
  4. Is Surveillance Effective?
  5. Who Should Receive Surveillance?
  6. How Should Surveillance Be Performed?
  7. How Is HCC Best Managed?
  8. Summary
  9. References

The AASLD guidelines recommend abdominal ultrasound (US) as the imaging test of choice for HCC surveillance. It has a sensitivity of 60% to 80% and a specificity > 90% for the detection of HCC.[11] US is well tolerated and without risk, has a relatively moderate cost, and improves in sensitivity with serial testing. Abdominal computed tomography (CT) scanning has fallen out of favor on account of its cost and the radiation risk with repeated use. Magnetic resonance (MR) scanning is more expensive than US, is demanding of the patient, and potentially has a high false-positive rate. Suspicious lesions found on US should be further evaluated with one-time multiphase CT or MR. Serum AFP is the most common serological test used for surveillance of HCC, although it has mainly been studied as a diagnostic tool. The diagnostic sensitivity of AFP is only approximately 60%, and its performance as a surveillance tool is worse still. AFP levels often fluctuate, especially in patients with chronic viral HCV (false positives), whereas only 10% to 20% of tumors at an early stage present with abnormal AFP levels (false negatives). Combining AFP with US increases costs but improves detection by only 6% to 8% and is, therefore, not recommended by the AASLD. The surveillance interval is based on the tumor doubling time as well as the tumor incidence in the at-risk population. On the basis of these factors, a 6-month interval is considered optimal.[12]

In patients with cirrhosis, nodules less than 1 cm in size that are detected on US should be followed with repeat US every 3 months to assess for interval changes (Fig. 1). For lesions that are enlarging or nodules greater than 1 cm in size, diagnostic imaging with 4-phase multidetector computed tomography (MDCT) or dynamic MR should be obtained. The diagnosis of HCC for nodules greater than 1 cm in size can be made with noninvasive criteria based on imaging and laboratory findings, and this often obviates the need for biopsy. The radiological hallmark of HCC is intense contrast uptake in the arterial phase followed by contrast washout in the venous/late phase; these features have a specificity and a positive predictive value of almost 100%. Biopsy is recommended for all nodules occurring in noncirrhotic livers or for cases in which a nodule has an inconclusive or atypical appearance against the background of cirrhosis. Negative biopsy findings do not exclude HCC because the false-negative rate for biopsying can reach 30%. For a pathological diagnosis, an immunohistochemistry staining panel consisting of glypican 3, heat shock protein 70, and glutamine synthetase can provide 100% specificity for HCC, albeit with lesser sensitivity (72%).[13]

image

Figure 1. Diagnostic algorithm for suspected HCC. Reprinted with permission from Hepatology.[11] Copyright 2011, American Association for the Study of Liver Diseases.

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How Is HCC Best Managed?

  1. Top of page
  2. Abstract
  3. What Are the Risk Factors for Developing HCC?
  4. Is Surveillance Effective?
  5. Who Should Receive Surveillance?
  6. How Should Surveillance Be Performed?
  7. How Is HCC Best Managed?
  8. Summary
  9. References

Given the complexity of HCC and cirrhosis and the plethora of treatment options, I believe that patients with possible or likely HCC are best served by referral to centers of expertise with multidisciplinary teams (or tumor boards) that include hepatologists, oncologists, radiologists, surgeons, and pathologists. Potential curative options for early-stage disease include ablation, surgical resection, and liver transplantation. For intermediate- or advanced-stage disease, the only therapies that have been shown to prolong life include liver-directed therapy with transarterial chemoembolization and systemic chemotherapy with sorafenib.

Summary

  1. Top of page
  2. Abstract
  3. What Are the Risk Factors for Developing HCC?
  4. Is Surveillance Effective?
  5. Who Should Receive Surveillance?
  6. How Should Surveillance Be Performed?
  7. How Is HCC Best Managed?
  8. Summary
  9. References

HCC is a global health problem with a rising incidence in the United States. Until recently, HCC was universally fatal. The 21st century has seen a significant change in the management of HCC, and it is now a potentially curable cancer if it is detected early. To minimize disease-related mortality, it is imperative for providers caring for at-risk patients to employ consistent surveillance, rigorously investigate screen-detected lesions, and make provisions for appropriate therapy based on the stage of disease.

References

  1. Top of page
  2. Abstract
  3. What Are the Risk Factors for Developing HCC?
  4. Is Surveillance Effective?
  5. Who Should Receive Surveillance?
  6. How Should Surveillance Be Performed?
  7. How Is HCC Best Managed?
  8. Summary
  9. References
  • 1
    El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012;142:12641273.e1.
  • 2
    Ioannou GN, Splan MF, Weiss NS, McDonald GB, Beretta L, Lee SP. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2007;5:938945.
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    El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States veterans. Am J Gastroenterol 2001;96:24622467.
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    Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol 2005;42:218224.
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    Marcellin P, Pequignot F, Delarocque-Astagneau E, Zarski JP, Ganne N, Hillon P, et al. Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption. J Hepatol 2008;48:200207.
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    Trichopoulos D, Bamia C, Lagiou P, Fedirko V, Trepo E, Jenab M, et al. Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested case-control study. J Natl Cancer Inst 2011;103:16861695.
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    International Agency for Research on Cancer. Liver cancer incidence and mortality worldwide in 2008 summary. http://globocan.iarc.fr/factsheets/cancers/liver.asp. Accessed October2012.
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    Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417422.
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    Trevisani F, Santi V, Gramenzi A, Di Nolfo MA, Del Poggio P, Benvegnù L, et al.;for Italian Liver Cancer Group. Surveillance for early diagnosis of hepatocellular carcinoma: is it effective in intermediate/advanced cirrhosis?Am J Gastroenterol 2007;102:24482457.
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  • 10
    Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009;30:3747.
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    Bruix J, Sherman M; for American Association for the Study of Liver Diseases.Management of hepatocellular carcinoma: an update. Hepatology 2011;53:10201022.
  • 12
    Santi V, Trevisani F, Gramenzi A, Grignaschi A, Mirici-Cappa F, Del Poggio P, et al.;for Italian Liver Cancer (ITA.LI.CA) Group. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol 2010;53:291297.
  • 13
    Di Tommaso L, Franchi G, Park YN, Fiamengo B, Destro A, Morenghi E, et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 2007;45:725734.