Screening strategy for primary hepatocellular carcinoma based on different combinations of protein induced by vitamin K absence or antagonist-Ⅱ, alpha-fetoprotein, and alpha-fetoprotein-L3

Objective To investigate the sensitivities and specificities of different combinations of serum protein induced by vitamin K absence or antagonist-Ⅱ ( PIVKA-Ⅱ) , alpha-fetoprotein ( AFP) , and alpha-fetoprotein-L3 ( AFP-L3) in the screening for primary hepatocellular carcinoma ( HCC) . Methods Serum samples were collected from 118 patients with HCC and 76 patients with hepatitis or liver cirrhosis who were hospitalized in Liver Disease Center of PLA, General Hospital of Eastern Theater Command, from January 2017 to July 2018, and the serum levels of PIVKA-Ⅱ, AFP, and AFP-L3 were measured. The sensitivities and specificities of each individual indicator and their different combinations in HCC screening were calculated and compared. The Mann-Whitney U test was used for comparison of continuous data with skewed distribution between groups, and the chi-square test was used for comparison of categorical data between groups. The efficiency of PIVKA-Ⅱ, AFP, and AFP-L3 in HCC screening was analyzed, their sensitivities and specificities were calculated, and receiver operating characteristic ( ROC) curves were plotted. Results The HCC group had significantly higher levels of PIVKA-Ⅱ and AFP than the hepatitis/liver cirrhosis group ( Z = 7. 80 and 3. 80, both P < 0. 001) . Compared with the hepatitis/liver cirrhosis group, the HCC group had a significantly higher proportion of patients with positive PIVKA-Ⅱ, AFP, or AFP-L3 ( χ2= 153. 36, 83. 97, and 168. 82, all P < 0. 001) . There was no significant difference between the positive rates of PIVKA-Ⅱ and AFP in the HCC group ( 68. 6% vs 67. 8%, χ2= 0. 02, P > 0. 05) , while a significant difference was observed in the hepatitis/liver cirrhosis group ( 14. 5%vs 51. 3%, χ2= 23. 37, P < 0. 001) . There was a significant difference between the positive rates of PIVKA-Ⅱ and AFP-L3 in the HCC group ( 68. 6% vs 35. 6%, χ2= 25. 83, P < 0. 001) , while no significant difference was observed in the hepatitis/liver cirrhosis group ( 14. 5% vs 9. 2%, χ2= 1. 01, P > 0. 05) . There was a significant difference between the positive rates of AFP and AFP-L3 in the HCC group ( 67. 8% vs 35. 6%, χ2= 24. 50, P < 0. 001) and the hepatitis/liver cirrhosis group ( 51. 3% vs 9. 2%, χ2= 31. 92, P < 0. 001) . In HCC screening, PIVKA-Ⅱ had a significantly larger area under the ROC curve than AFP ( 0. 832 vs 0. 662, P < 0. 01) and AFP-L3 ( 0. 832 vs 0. 656, P < 0. 01) . With PIVKA-Ⅱ > 40 mA U/ml, AFP > 10 ng/ml, and AFP-L3 > 10% as the positive cut-off values for the possibility of HCC, both PIVKA-Ⅱ and AFP had a sensitivity of 67. 8% in the ROC curve, which was significantly higher than the sensitivity of AFP-L3 ( 55%) . PIVKA-Ⅱ had a significantly higher specificity than AFP ( 85. 5% vs 48. 7%) and AFP-L3 ( 85. 5%vs 60%) . In HCC screening, positive PIVKA-Ⅱ, AFP, and AFP-L3 had a sensitivity of 29. 7% and a specificity of 98. 7%; positive PIVKA-Ⅱ and AFP had a sensitivity of 55. 9% and a specificity of 90. 8%; positive PIVKA-Ⅱ and AFP-L3 had a sensitivity of 30. 5%and a specificity of 98. 7%; positive AFP and AFP-L3 had a sensitivity of 34. 7% and a specificity of 93. 4%. Conclusion In the context of no influence from the factors including anticoagulants and cholestasis, elevated serum PIVKA-Ⅱ alone has a better value in HCC screening than elevated AFP or AFP-L3. The increase in PIVKA-Ⅱ or AFP significantly improves the sensitivity in HCC screening, and the increases in all or any two of PIVKA-Ⅱ, AFP-and AFP-L3 can significantly improve the specificity in HCC screening.