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Chen et al. Hepatoma Res 2019;5:12 I http://dx.doi.org/10.20517/2394-5079.2019.03 Page 5 of 17

[19]
specificity were 55.3% and 86.5%, respectively . A systematic review evaluating AFP in cirrhotic patients
with HCV infection showed sensitivities and specificities of 41%-65% and 80%-94%, respectively, for HCC
[63]
diagnosis . In a Taiwan study, screening with AFP was reported to be feasible screening marker of risk
[64]
identification, and could result in good prognosis in an aged population . A recent report in a South
[65]
East Scotland HCC Surveillance Study (January 2009 and December 2014) showed that AFP as an HCC
surveillance tool detects a significant number of treatable HCC in patients with satisfactory outcomes. They
also found that the use of serum AFP in HCC surveillance has facilitated the early diagnosis of HCC in a
large proportion of the patients undergoing HCC surveillance in whom the HCC was otherwise not detected
[66]
by ultrasound (US) alone, and that AFP should be included in the liver cancer surveillance .
US could be used for early detection
The application of US and other imaging modalities facilitate localized diagnosis for liver cancer. In the
1980s, US examination began to be used widely in the clinical detection of liver diseases in China. The
advantages of US are manyfold. It is non-invasive, produces no radioactive damage, is easy to repeat,
has high sensitivity and at a relatively low cost. US is considered as the preferred method for liver cancer
localization in screening [6,67,68] . US has a sensitivity of 60%-80% and a specificity of over 90% when it is done
[70]
[69]
expertly . An early prospective study reported in the United States in 1985 showed that in the initial
screening for 528 patients, 17 liver cancer patients were found after an average follow-up of 1.4 years. In
tumors < 5 cm, AFP levels were normal in 46.2%, 20-400 μg/L in another 46.2%, and only 7.6% were over
400 μg/L. Another 7 patients were found by further follow-up to have cancer varying from 1.6 to 4.7 cm,
with normal serum AFP levels in 3 cases. Hence the authors concluded that real-time ultrasonography is
more sensitive than AFP assay for the early detection of HCC, and that high-risk subjects should receive this
[71]
procedure at regular intervals. A randomized trial compared two US periodicities: 3 months vs 6 months,
in a surveillance of HCC in cirrhotic patients. The results showed that 3-month US detection may find more
small focal lesions than 6-months US detection, but does not improve detection rate of small HCC, nor
improve the 5-year survival. The efficacy of US screening every 6 months for HCC or CC in a selective high
risk group in endemic areas of hepatitis B such as in Thailand, Taiwan have been reported [72-74] .

The combined application of AfP and Us
AFP or US detection have their limitations. It is a common practice to combine these two methods for HCC
surveillance. Many studies using a combined AFP and US surveillance/screening have proven survival
benefit to patients by detecting smaller and curable liver cancers [20,55,61,75-78] , US combined with AFP for
screening for liver cancer is believed to be superior to AFP alone, but periodic US examination would be
expensive, while AFP testing is relatively inexpensive [79,80] . At present, computed tomography (CT) and
dynamic magnetic resonance imaging (MRI) as robust imaging location techniques for the diagnosis of liver
cancer are used widely in clinical practice [81,82] . A prospective randomized study comparing two different
HCC screening procedures (biannual ultrasonography vs. annual triphasic CT) with biannual AFP has
[83]
suggested that biannual US is comparable to annual CT in detecting early-stage HCC, with lower costs .
So there is no evidence to support the use of CT or MRI for routine liver cancer surveillance/screening;
while its disadvantages are obvious: significant cost and radiation exposure [81,82,84] . Furthermore, findings
[85]
are frequently discordant even on both CT and MRI . In an Alaskan Native screening cohort study
during 1983-2012, the cost-effectiveness of two HCC screening methods (by US-alone, or screening by AFP
[86]
initially and switching to US) was evaluated . The sensitivity analysis demonstrated that AFP→US was
more cost-effective than US-alone over a broad range of differences in sensitivity between the two HCC
screening methods. It was also pointed out that for many of the patients in rural Alaska, AFP is the only
locally available option for HCC screening, and it could potentially identify patients at high risk for HCC
who could benefit from referral for a liver US or CT. Thus, public health officials should evaluate the cost-
effectiveness of AFP→US to increase access to HCC screening for persons living in remote communities