Screening for Hepatocellular Carcinoma

Rowen K. Zetterman, MD


November 03, 2015

In This Article

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide.[1] The incidence of HCC is increasing in the United States, with a rate in men that is three times higher than the rate in women the rate in women.[2] The risk for HCC in developed countries is increasing, owing to its associations with hepatitis C virus (HCV), alcoholic liver disease, and nonalcoholic fatty liver disease.[1] Underlying cirrhosis of any cause also increases the risk for HCC.

Finding HCC early is crucial; the prognosis correlates with delays in diagnosis, and small, localized, early-stage tumors are amenable to better treatment options.[3,4,5]

Primary care physicians play an important role in identifying patients who are at risk for HCC and ensuring that they receive proper screening. Most patients with cirrhosis in the United States receive their healthcare from primary care physicians, but only one half of primary care physicians routinely screen their at-risk patients for HCC.[6] Some patients will develop HCC before cirrhosis is clinically recognized by their physician.[7]

Patient selection, frequency of screening, and reevaluation of patients with small hepatic nodules are crucial to early diagnosis. The use of automated electronic medical record reminders for screening can significantly improve HCC screening.[8]

Screening Algorithms

Screening for HCC is important to identify tumors that are amenable to hepatic resection or liver transplantation. Early detection improves 5-year survival rates to > 60% with tumor resection or liver transplantation, compared with only 32% when advanced tumors are detected.[9]

Three major screening algorithms for HCC have been published, as well as a global perspective on HCC surveillance by the World Gastroenterology Organization.[4,10,11,12] HCC is more common in eastern Asian countries owing to the prevalence of chronic hepatitis B virus (HBV) and HCV infections. The 2010 Asian Pacific Association for the Study of the Liver (APASL) guideline[11] recommends screening high-risk patients with alpha-fetoprotein and hepatic ultrasound every 6 months.

The 2011 American Association for the Study of Liver Diseases (AASLD) guideline[10] recommends surveillance with non–contrast-enhanced hepatic ultrasound when the HCC risk is > 1.5% per year for HCV patients and > 0.2% per year for HBV patients. The 2012 guidelines[4] from the European Association for the Study of the Liver and the European Organization for Research and Treatment of Cancer (EASL-EORTC) recommend surveillance for patients with cirrhosis who have a > 1.5% annual risk for HCC and surveillance for HBV patients when the annual risk is > 0.2% per year.

A cost-effectiveness model shows a ≥ 3-month gain in life expectancy at a cost of < $50,000 per life-year gained.[13] They do not recommend screening patients with advanced liver disease who are not amenable to potentially curative therapy, except for patients on transplant lists for whom transplantation would be curative.

Timing and Frequency of Screening

Surveillance of patients who are at risk for HCC balances the timing of screening initiation and the frequency of screening with the objective of reducing mortality in those screened.[14] Unfortunately, few studies have adequately assessed the timing and frequency of screening of at-risk patients.

Two community-based trials from China compared screening vs no screening and determined the effect of screening on overall mortality. The first study used alpha-fetoprotein plus ultrasound every 6 months compared with a population of patients who were not regularly screened.[15] Despite only 60% compliance with the protocol in actively screened patients, fewer deaths from HCC were observed in those who were screened.

In the second study,[16] HBV surface antigen carriers were screened every 6 months with alpha-fetoprotein levels, followed by hepatic ultrasound if an elevated alpha-fetoprotein level was found, and were compared with a population of unscreened hepatitis B carriers. Fewer patients with advanced HCC were identified in the screened group, although no difference in all-cause mortality or mortality from HCC was seen in either group.

The interval between screenings for HCC by ultrasound has been based on accepted tumor growth doubling time and the cost-effectiveness of frequent screening.[17] A randomized trial from Taiwan compared 4-month vs 12-month screening intervals and determined that more patients in the 4-month group were identified with early disease.[18] In a cohort of 52,823 patients found to have HCC in Taiwan, patient groups were segregated by the interval between ultrasound screenings.[19] The study confirmed that patients with a shorter interval between screenings had a better likelihood of survival of HBV-associated HCC.

Are We Screening Adequately?

But how well is screening used? Less than 20% of patients with cirrhosis in the United States are screened for HCC, and only 2% get twice-annual screening.[20] Factors that reduce screening include patient age older than 65 years or younger than 50 years, male sex, non-Hispanic white ethnicity, and low income.

A safety-net hospital study also confirmed that fewer than 2% of at-risk patients had biannual screening, 13% had annual screening, and 67% had surveillance at least once every 3 years.[21] Reasons for the inconsistent screening included failure to recognize cirrhosis, patient insurance status, African-American race, cirrhosis due to nonalcoholic fatty liver disease, and the presence of extrahepatic cancer. Patients who received better screening had more than one primary care or hepatology visit annually.

Do we need to better educate physicians on screening for HCC? The answer appears to be "yes." A survey of primary care physicians found that although 65% reported using annual screening, only 15% performed biannual screening of patients who are at risk for HCC.[22] The reported barriers to adequate screening included lack of being up to date on screening guidelines, poor patient communication, and the need to care for bigger clinical issues during office hours than screening for HCC.


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