Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP

Abstract

Aim: To evaluate diagnostic value of α-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-II (PIVKA-II) in hepatocellular carcinoma (HCC).

Methods: One hundred and sixty-eight patients during routine HCC surveillance were included in this study. Of the 168 patients, 90 (53.6%) had HCC including newly developed HCC (n = 82) or recurrent HCC after treatment (n = 8). Sera were obtained during their first evaluation for HCC development and at the time of HCC diagnosis before commencing HCC treatment. HCC was diagnosed by histological examination, appropriate imaging characteristics-computed tomography or magnetic resonance imaging. Control sera were collected from 78 patients with benign liver disease (BLD), which were obtained during routine surveillance with a suspicion of HCC. AFP, AFP-L3 and PIVKA-II were measured in the same serum by microchip capillary electrophoresis and liquid-phase binding assay on a micro-total analysis system Wako i30 auto analyzer. The performance characteristics of three tests and combined tests for the diagnosis of HCC were obtained using receiver operating characteristic curves in all populations and subgroups with AFP < 20 ng/mL.

Results: Of 90 HCC patients, 38 (42.2%) patients had AFP < 20 ng/mL, 20 (22.2%) patients had AFP 20-200 ng/mL and 32 (35.6%) patients had AFP > 200 ng/mL. Of the 78 BLD patients, 74 (94.9%) patients had AFP < 20 ng/mL. After adjustment for age and HBV infection status, AFP-L3 levels were higher in HCC than in BLD among patients with low AFP levels (< 20 ng/mL) (P < 0.001). In a total of 168 patients, areas under the curve (AUC) for HCC were 0.879, 0.887, 0.801 and 0.939 for AFP, AFP-L3, PIVKA-II and the combined markers, respectively. The combined AUC for three markers showed higher value than the AUCs of individual marker (P < 0.05). AFP-L3 had higher AUC value than PIVKA-II for HCC detection in entire patients (P = 0.043). With combination of AFP-L3 (cut-off > 5%) and PIVKA-II (cut-off > 40 AU/L), the sensitivity were 94.4% and specificity were 75.6% in all patients. In 112 patients with low AFP levels (< 20 ng/mL), AUCs of AFP-L3, PIVKA-II and combine AFP-L3 and PIVKA-II tests were 0.824, 0.774 and 0.939, respectively. AFP-L3 with a cut-off value of 5% showed sensitivity of 71.1% and specificity of 83.8%, and PIVKA-II with a cut-off value of 40 AU/L had sensitivity of 57.9% and specificity of 95.9% in patients with low AFP levels. The combination of AFP-L3 and PIVKA-II increased the sensitivity and specificity up to 92.1% and 79.7%, respectively, in low AFP group. Combined markers detected 81.8% of early stage HCC (Union for International Cancer Control stage I), 86.7% of small sized tumor (< 2 cm) and 91.7% of single tumor of HCC in the low AFP group. In multivariate analysis, AFP-L3 was correlated with AFP and tumor size, and PIVKA-II was correlated with laboratory tests including serum aspartate aminotransferase, total bilirubin, platelets and albumin levels. PIVKA-II had no correlation with AFP, AFP-L3 or tumor characteristics.

Conclusion: Combined determination of AFP-L3 and PIVKA-II could improve the diagnostic value for HCC detection in patients with or without increased AFP levels.

Keywords: Diagnosis; Hepatocellular carcinoma; Prothrombin induced by vitamin K absence-II; Tumor marker; α-fetoprotein.

Figures

Figure 1

α-fetoprotein (A), α-fetoprotein-L3 (B) and prothrombin induced by vitamin K absence-II (C) values in benign liver disease and hepatocellular carcinoma patients. α-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence (PIVKA)-II levels are plotted by AFP concentrations (AFP 200 ng/mL). In patients with AFP P < 0.001) (B). In patients with AFP 20-200 ng/mL, PIVKA-II showed higher levels in HCC (P = 0.010) (C). The horizontal dotted lines are cut-off values used for performance analysis in this study. BLD: Benign liver disease.

Figure 2

Receiver operating characteristic curves of total α-fetoprotein, α-fetoprotein-L3, prothrombin induced by vitamin K absence-II and three combined markers for the diagnosis of hepatocellular carcinoma in all patients. The area under the curve values were 0.879 for total α-fetoprotein (AFP), 0.887 for AFP-L3, 0.801 for prothrombin induced by vitamin K absence (PIVKA)-II and 0.959 for the three combined markers.

Figure 3

Receiver operating characteristic curves of α-fetoprotein-L3 and prothrombin induced by vitamin K absence-II for the diagnosis of hepatocellular carcinoma in patients with total α-fetoprotein