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Page 6 of 8 Chen et al. Hepatoma Res 2019;5:25 I http://dx.doi.org/10.20517/2394-5079.2019.12

Figure 3. Cumulative hepatocellular carcinoma (HCC) development in men and women. The annual HCC incidence was 0.53% in men
and 0.04% in women

were patients who returned with HCC and 53 (22.3%) were patients who had been completely lost to follow-
up. This suggests that ongoing surveillance at 3-12-month intervals was difficult to maintain for nearly
half of the patients. The results from our single hospital with 15,235 cases are similar to a meta-analysis
of 22 reports covering 19,511 cases . In that study, Wang et al. found that the adherence rate to HCC
[21]
[21]
surveillance was only 52%.
The regular follow-up group had a higher survival (43.8% vs. 30.9%) and smaller mean tumor size (2.72 vs.
4.59 cm) than the out-of-schedule group (Table 2; P < 0.001). These results are in agreement with a randomized
control study that included 18,816 participants . Zhang et al. found that regular surveillance leads to
[22]
[22]
early detection of HCC, resulting in better survival than in those without surveillance. A recent extensive
review confirms surveillance improved survival . There is therefore no doubt that surveillance should be
[23]
carried out in high-risk HBsAg carriers. The current Asian Pacific Association for Study of the Liver (APASL)
guideline specifies that male HBsAg carriers aged greater than 40 years and females aged greater than 50
years are high-risk groups . In our previous analysis, which used a subset of patients from this cohort, we
[7]
found that the incidence of HCC was relatively low if the initial ALT level was lower than 2 × ULN or if
the patients maintained persistent normal ALT [23,24] . In this study, 72.6% of chronic HBsAg carriers without
HCC had initial ALT levels lower than 2 × ULN, and 69.3% had maximal ALT levels lower than 5 × ULN. In
contrast, 63.5% HCC patients had initial ALT levels greater than or equal to 2 × ULN and 71.5% had maximal
ALT levels greater than or equal to 5 × ULN. Therefore, we might not encourage patients with persistent
ALT levels lower than 2 × ULN, no cirrhosis, female gender, or age under 40 years to receive early full
surveillance. Repeated negative findings during regular follow-up visits may cause the patient to feel it is less
necessary to continue surveillance. For such patients, we may continue with simple ALT and AFP surveys.
Full surveillance, including HBV viral load, US, elastography, or new markers may then be started once a
risk factor is identified. Active call-back mechanisms focusing on these high-risk patients will be mandatory.

The prevalence of liver cirrhosis was relatively high (70.2%) in patients with HCC. In addition, lesions
resembling liver regeneration nodules were found in 47 (36.2%) patients preceding HCC diagnosis. Of these,
16 (12.3%) had three or more nodules. These preexisting findings decreased the likelihood of early diagnosis
of HCC. Indeed, cirrhotic nodules have been reported as a problem in the diagnosis of small HCC . New
[25]
parameters to allow the discrimination of HCC from regeneration nodules will therefore be needed [26-28] .