What primary care providers need to know about hepatocellular carcinoma


  • Parul Dureja Agarwal M.D.

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
    • Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, 4245 MFMB, Madison, WI 53792-5124. E-mail: pagarwal@medicine.wisc.edu.

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  • Potential conflict of interest: Nothing to report.


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American Association for the Study of Liver Diseases




computed tomography


hepatitis B virus


hepatocellular carcinoma


hepatitis C virus


multidetector computed tomography


magnetic resonance


magnetic resonance imaging



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?

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?

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?

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?

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]

Figure 1.

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

How Is HCC Best Managed?

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.


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.