Liver cancer showed the second highest mortality rate among major cancers in 2022 [1]. In Korea, hepatocellular carcinoma (HCC) was added to the National Cancer Screening Program (NCSP) in 2003. Surveillance tests for HCC target high-risk groups, defined as individuals over 40 years of age with chronic hepatitis B or C, or liver cirrhosis. Both liver ultrasonography (US) and serum alpha-fetoprotein (AFP) testing are performed for these highrisk groups [2].

Until 2017, in the NCSP, a finding of a lesion on US resulted in a conclusion of ‘HCC suspected,’ regardless of the AFP results. In 2018, the NCSP results were further subdivided to include ‘HCC suspected’ and ‘3-month follow-up required,’ based on joint considerations of AFP levels and US findings. ‘HCC suspected’ is reported when AFP levels exceed the normal range and there is a solid mass smaller than 1 cm on US or when there is a solid mass larger than 1 cm, portal or hepatic vein thrombosis, or bile duct dilation, regardless of AFP levels. ‘3-Month follow-up required’ is reported when the AFP level is normal but a new solid mass is detected in liver US, or when the AFP level is elevated but no specific lesions are found on liver US [3]. The importance of AFP testing has increased, as it now influences comprehensive determination of NCSP. Therefore, it is important to adopt standardized reporting methods based on accurate AFP results.

When the NCSP for HCC was initially introduced in Korea, reporting of AFP testing results was not standardized. Although the quantitative method was generally recommended, the qualitative method was also allowed because the quantitative method typically required large instruments and was difficult to perform in remote area such as on islands and in mountainous regions at that time [4]. Using the quantitative method, results could be reported using one of two types of units (ng/mL and IU/mL), and the cutoff values varied depending on the medical institutions [4]. Therefore, assessing the diagnostic performance of AFP testing used in Korea’s NCSP for HCC is difficult. Furthermore, there is no information available on the type of AFP test (quantitative or qualitative), units used for reporting, or commonly used cutoff values.

We investigated the AFP reporting status of the medical institutions participating in NCSP for HCC from 2018 to 2020. Data were obtained from the National Health Insurance Service’s health screening database (NHIS study no: NHIS-2024-1-414). We categorized the medical institutions into general hospitals, hospitals, and clinics because the type of institutions might lead to differences in the quality management of laboratory tests [5]. In Korea, a “hospital” refers to a medical facility with an inpatient capacity of 30 to 99 beds. The number of medical institutions was analyzed separately by counting those using qualitative methods and quantitative methods for AFP testing. Among those determined using quantitative methods, we assessed the ratio of institutions choosing each unit (ng/mL vs. IU/mL). We investigated the cutoff values when ng/mL was used, without separating the medical institutions. The data on cutoff values, which included both integers and decimals, were organized using the rounding down method. This study was approved by the Institutional Review Board of Konkuk University (study number: 7001355-202401-E-755).

The results showed that over 99% of general hospitals used quantitative methods from 2018 to 2020 (Table 1). Hospitals and clinics chose quantitative methods over 90% of the time, with the ratio increasing from 2018 to 2020. When using quantitative methods, over 92% of medical institutions preferred using units of ng/mL. A cutoff of 7 was the most commonly used value, followed by cutoffs of 8 and 9 (Fig. 1). Although we found that some hospitals used a value of up to 21, these hospitals represent a small portion.

Several guidelines are used for HCC surveillance. The American Association for the Study of Liver Disease recommends HCC surveillance with liver US and AFP testing for at-risk populations at six-month intervals. Surveillance results are determined based on a combination of the presence of liver lesions in liver US and AFP levels. It suggests an AFP cutoff value of 20 ng/mL; by checking the longitudinal change in AFP levels; doubling of the AFP level is considered an indication for dynamic computed tomography/magnetic resonance imaging (CT/MRI) [6]. The clinical practice guidelines of the Japan Society of Hepatology recommend a surveillance protocol with liver US and tumor markers (AFP, AFPL3 fraction, and proteins induced by vitamin K absence or antagonist-II) for high-risk groups at 3–6 months intervals. When new nodules are found on liver US, or when there are no lesions on liver US but AFP levels show persistent elevation exceeding 200 ng/mL, the use of CT/MRI is considered [7]. The Asia-Pacific Association for the Study of the Liver guideline recommends that AFP testing should not be used alone for surveillance. When surveillance is conducted with both AFP testing and liver US, an optimal AFP cutoff value 200 ng/mL is suggested [8]. As with the guidelines mentioned above, recommended AFP testing varies by country depending on the prevalence of HCC and screening protocols.

The primary reason why the AFP cutoff used in Korea’s NCSP differs from those recommended in international guidelines appears to be a lack of understanding of the differences between reference intervals and cutoff values. A reference interval reflects the typical range in a healthy population, whereas a cutoff value is used for clinical decision-making. For example, when using Roche reagents for AFP testing, the reference interval is approximately 7 ng/mL in the instructions. However, two cutoff values (20 or 200 ng/mL) are also provided depending on the clinical context. In Korea, many laboratories appear to report AFP results alongside reference intervals rather than cutoff values, which have likely led to the reference interval being mistakenly entered in the AFP cutoff field in NCSP programs.

AFP levels can vary in different clinical situations such as chronic liver disease and cholangiocarcinoma. Using quantitative methods allows for the comparison of trends in AFP level, which can aid in diagnosis [9]. AFP testing methods are not standardized, and there is no reference test method, which can result in discrepancies in test outcomes among medical institutions. Therefore, quality control is crucial, and it is necessary to not only implement internal quality programs, but also participate in external quality control programs [4]. Lee et al. [10] reported the reliability of qualitative AFP tests across medical institutions participating in NCSP. Among the AFP qualitative test reagents, only one reagent demonstrated suitable performance in all cases when considering the cutoff values of the qualitative test kits used with several instrument platforms [10]. In some cases, a level 2 material (70.9±9.0 ng/mL) received negative results, even though the cutoff value of the qualitative test reagent was 10 or 20 ng/mL. These medical institutions had a lower participation rate of internal and external quality control programs compared to those using quantitative methods [10]. Furthermore, the Korean Association of External Quality Assessment addresses exclusively the quantitative method of AFP testing. Even in our study, most medical institutions are already using the quantitative method. We recommend discontinuing the use of the qualitative method, which is no longer widely used and is often associated with low quality and inadequate management.

We found that the AFP value is mostly expressed in ng/mL. The conventional unit of AFP is mg/dL, and the international system of units uses g/L. The Korean Association of External Quality Assessment Service, College of American Pathologists, and several textbooks (Tietz 6th edition and Henry 24th edition) use a unit of ng/mL [11]. The ng/mL unit is also commonly used according to the results of a domestic questionnaire survey [11]. Standardizing the unit to ng/mL, which is widely used by most institutions and literature, would simplify comparisons of AFP values between medical institutions.

According to the Internal Consortium for Harmonization of Clinical Laboratory results, AFP appears to have a harmonized status [12]. In research, AFP is considered sufficiently harmonized with the acceptable bias standard [13, 14]. The major manufacturers’ (Abbott, Roche, and Siemens) reagents have traceability to the 1st IRP WHO Reference Standard 72/225. It is reasonable to unify the cutoff value of AFP. The appropriate cutoff value for the NCSP requires further discussion, as guidelines for HCC and various studies suggest different thresholds for HCC surveillance based on varying clinical situations and surveillance protocols. Zhang et al. [15] suggests an optimal threshold of 400 ng/mL AFP based on a systematic review and meta-analysis. Marrero et al. [16] suggests using 10.9 ng/mL and Gopal et al. [9] suggests using 11 and 59 ng/mL for patients who are HCV-negative and HCV-positive, respectively. In our study, most medical institutions chose a cutoff value of 7, but this was only based on survey results and cannot be considered the optimal cutoff. Therefore, further research is needed to establish an optimal AFP cutoff value tailored to the Korean population based on large-scale NCSP data.

It is imperative to discontinue the use of the qualitative method for AFP testing and adopt the quantitative method with a unified unit and optimal cutoff value. This change will ensure more accurate and reliable surveillance of HCC in Korea.