Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third most common cause of cancer-related death worldwide [1]. Whereas effective treatment modalities exist to cure early-stage HCC, including surgical resection, radiofrequency ablation, and alcohol injection, late-stage HCC has few therapeutic options [2]. Furthermore, difficulty in early detection of HCC is related to poor prognosis, and more than two-thirds of patients are diagnosed at advanced stages [3].

In 1963, an antigen specific to human HCC was first reported by Yuri S. Tatarinov, and in 1970, it was given the name “α-fetoprotein” (AFP) [4]. This antigen has long been recognized as the first oncodevelopmental biomarker and has been used as a screening and diagnostic tool for HCC [4-6]. However, with the widespread use of advanced imaging techniques, the usefulness of the AFP assay in the diagnosis of HCC has decreased [7,8]. The sensitivity and specificity of AFP vary widely based on study design and patient characteristics [7,9-11]; recent guidelines do not recommend the use of AFP as a diagnostic test [8,12], focusing instead on the typical contrast enhancement imaging patterns of arterial hypervascularity with washout in the portal venous or delayed phases.

However, some debate still exists about the utility of AFP in the early diagnosis of HCC [13], and the role of AFP among different etiologic and ethnic groups remains to be established [14,15]. Moreover, other studies still highlight the diagnostic value of AFP [13,16].

As no well-designed studies in Koreans are available, the usefulness of AFP for HCC diagnosis in the Korean population remains unclear. We hypothesized that AFP may still have a role as a diagnostic test for HCC in the Korean population. Thus, we aimed to evaluate the feasibility of using AFP as a diagnostic tool for HCC and to determine the best cut-off value of serum AFP for discriminating HCC and cirrhosis.

We studied the role of AFP as a diagnostic tool for HCC in a Korean population with different HCC prevalence and risk factors compared to other ethnicities [18,19].

Previous reports have demonstrated a relationship between ethnicity and the level of AFP elevation in HCC patients. In Middle Eastern individuals, 20% of HCC patients had a normal serum AFP level [14], while 38% of HCC cases in Caucasian individuals did not show AFP elevation [20]. In HCC-related HCC patients, 43% of African-American and 18% of a mixed group of Asians, Hispanics, and Caucasians exhibited a normal AFP level [15]. In our cohort of Korean HCC patients, 28% had normal serum AFP levels. Biological and environmental factors may influence the differences in AFP levels among diverse ethnic groups.

In our study, the mean and median serum AFP levels in the HCC group, 3,315.6 and 20.45 ng/mL, respectively, were significantly higher than those in the cirrhosis group, 117.2 ng/mL and 3.95 ng/mL, respectively. In a Middle Eastern study, median AFP levels were significantly higher in the HCC group (median, 35.4 ng/mL [range, 0.5 to 805,795]) than the cirrhotic group (median, 6.4 ng/mL [range, 1 to 1,105]; p < 0.0001) [14]. Moreover, the median AFP levels in each cirrhosis group were within the laboratory upper limit of normal. In the early-stage group, the mean AFP level was higher than that in a previous study [21]. This is partially due to several early-stage HCC patients with very high AFP levels; thus, the median AFP value may be more appropriate for comparison.

For the optimal AFP cut-off level of early-stage HCC, nonviral etiology showed higher sensitivity (67.31% vs. 56.48%) but lower specificity (61.20% vs. 86.89%) compared with viral etiology. In one Italian study, a cut-off value of 20 ng/mL showed a sensitivity of 30.4% and a specificity of 100.0% [20]; the sensitivity was lower but the specificity was higher for nonviral etiologies compared with viral etiologies. The majority of nonviral HCC in these two studies were related to alcoholic liver disease, and the difference could be explained in part by ethnicity, environmental factors, and tumor staging. In contrast, a Middle Eastern study in which alcoholic liver disease did not serve as an etiologic factor of nonviral-related HCC, demonstrated that nonviral-related HCC showed the lowest sensitivity (60%), specificity (29%), and PPV (16%) compared with HCV- and HBV-infected groups [14].

The optimal cut-off point of AFP was 10.8 ng/mL (sensitivity 61.48% and specificity 79.23%) for the diagnosis of all HCC cases and 17.4 ng/mL (sensitivity 52.24% and specificity 86.89%) for diagnosis of early-stage HCC. Previous studies from the United States and Europe have identified a range of 20 to 30 ng/mL as the cut-off above which investigations for HCC are needed [7,15,20]. However, studies investigating Chinese and Middle Eastern populations found a range from 10 to 12 ng/mL as the best cut-off [13,14]. These latter results are more consistent with those of the current study; the difference may be due to ethnicity, distribution of risk factors, and environmental factors.

In a Chinese study, the optimal cut-off point of AFP for the diagnosis of HCC was 10 ng/mL, with a sensitivity of 82.6% and a specificity of 70.4%, and a level of 200 ng/mL was suggested to be a relevant cut-off for HCC diagnosis (sensitivity 47.7%, specificity 97.1%, and PPV 97.5%) [13]. In our study, an AFP value of 100 ng/mL showed higher sensitivity than one of 200 ng/mL, without compromising specificity or PPV. A cut-off of 20 ng/mL increased sensitivity at the expense of specificity and PPV, and that of 400 ng/mL had low sensitivity, limiting its clinical application.

Sanai et al. [14] conducted a multicenter, case-control study involving 206 HCC and 199 cirrhosis cases. The best cut-off point of AFP for the diagnosis of HCC was 11.7 ng/mL, with a sensitivity of 68.4% and a specificity of 75.4%. They compared AFP cut-off levels of 102, 200, and 400 ng/mL and concluded that an AFP level greater than 100 ng/mL had a high degree of specificity and could be used as a confirmatory test. The diagnosis of HCC was established on the basis of the published guideline [5] and included the presence of hepatic lesions with typical arterial hypervascularization and washout in the early or delayed venous phase as detected by liver CT and/or magnetic resonance imaging. They did not use AFP as one of the diagnostic criteria to exclude incorporation bias. However, in clinical practice, it is not uncommon to encounter suspicious malignant cases without typical imaging features. Therefore, in the current study, we included only tissue-confirmed patients to avoid diagnostic uncertainty and false positivity; this feature enabled the assessment of the performance of AFP in the diagnosis of HCC. The results of the two aforementioned studies that targeted Asian populations were similar to ours. This may reflect the distinct secretory function of AFP among racial groups.

The present study has several limitations. First, this was a retrospective study that may have been affected by selection bias. The authors tried to minimize this problem by matching underlying clinical characteristics of case and control patients. As previously reported, HCC patients were older and had a male predominance [14]; we matched age and sex as well as etiology and CPC by simple random sampling. Second, the correlation of AFP levels with contrast enhanced dynamic imaging could not be investigated, as radiologic information was not available in many subjects. However, we diagnosed HCC by histological evidence, which is objective and does not create bias by the attending physician. Third, although tumor size is a known independent factor of elevated AFP levels [22], we could not analyze the performance of AFP according to tumor size. Instead, we presented tumor staging, which included rough information about tumor size.

In conclusion, our study showed that the cut-off AFP value for early-stage HCC was 17.4 ng/mL. As a diagnostic tool for HCC, a cut-off value of 100 ng/mL is more sensitive than one of 200 ng/mL, with similar specificity and PPV. We cautiously suggest that AFP still has a role in the diagnosis of HCC, with an appropriate AFP value of 100 ng/mL rather than 200 ng/mL. This is the first large multicenter case-control study of Korean HCC patients. However, larger well-designed prospective studies are warranted to validate the optimal AFP value presented in the current study.