Longitudinal Assessment of Three Serum Biomarkers to Detect Very Early‐Stage Hepatocellular Carcinoma

We aimed to determine the surveillance performance of alpha‐fetoprotein (AFP), lectin‐reactive AFP (AFP‐L3), des‐gamma‐carboxy prothrombin (DCP), and their combinations for the early detection of hepatocellular carcinoma (HCC) by using prospectively collected longitudinal samples in patients at risk. Among 689 patients with cirrhosis and/or chronic hepatitis B who participated in four prospective studies, 42 HCC cases were diagnosed, selected, and matched with 168 controls for age, sex, etiology, cirrhosis, and duration of follow‐up in a 1:4 ratio. Levels of AFP, AFP‐L3, and DCP at the time of HCC diagnosis, month −6, and month −12 were compared between cases and controls. Of 42 HCC cases, 39 (93%) had cirrhosis, 36 (85.7%) had normal alanine aminotransferase levels, and 31 (73.8%) had very early‐stage HCC (single <2 cm). AFP and AFP‐L3 began to increase from 6 months before diagnosis of HCC in cases (P < 0.05), while they remained unchanged in controls. At HCC diagnosis, the area under the receiver operator characteristic curves (AUROCs) for AFP, AFP‐L3, and DCP were 0.77, 0.73, and 0.71, respectively. Combining AFP and AFP‐L3 showed a higher AUROC (0.83), while adding DCP did not further improve the AUROC (0.86). With the optimal cutoff values (AFP, 5 ng/mL; AFP‐L3, 4%), the sensitivity and specificity of AFP and AFP‐L3 combination were 79% and 87%, respectively. The sensitivity of ultrasonography was 48.6%, which was increased to 88.6% and 94.3% by adding AFP and AFP + AFP‐L3, respectively. Conclusion: Among three biomarkers, AFP showed the best performance in discriminating HCC cases from controls; the AFP and AFP‐L3 combination, adopting cutoff values (5 ng/mL and 4%, respectively), significantly improved the sensitivity for detecting HCC at a very early stage.