Clinical utility of tumor markers in early diagnosis of hepatocellular carcinoma

Abstract

Early diagnosis of hepatocellular carcinoma (HCC) is very important for a favorable prognosis. Some serologic tests including alpha-fetoprotein (AFP), protein induced by vitamin K absence-II (PIVKA-II), and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) have been studied as diagnostic markers of HCC; however, there is no consensus on which tumor markers are the most effective in detecting early HCC. In this study, we investigate the clinical utility of tumor markers in the early diagnosis of HCC. A total of 425 patients with liver cirrhosis (LC) (n =196) or HCC (n = 229) were studied from January 2012 to February 2013. Patients with LC had a mean age of 55.8 years and 58.7% were male, whereas the mean age of patients with HCC was 60.0 years and 76.0% were male. We analyzed the expression of tumor markers AFP, PIVKA-II, and AFP-L3 in these patients. All tumor markers were significantly elevated in HCC patients compared with LC patients (p <0.001). The area under the receiver operating characteristic curves (AUROC) of AFP, PIVKA-II, and AFP-L3 for distinguishing HCC from LC was 0.679 (95% confidence interval [CI], 0.626-0.732, p <0.001), 0.812 (95% CI, 0.770-0.854, p <0.001), and 0.690 (95% CI, 0.638-0.742, p <0.001), respectively. Moreover, PIVKA-II (AUROC = 0.705, 95% CI, 0.621-0.789, p <0.001) was superior to AFP (AUROC = 0.623, 95% CI, 0.527-0.719, p = 0.019) and AFP-L3 (AUROC = 0.561, 95% CI, 0.453-0.668, p = 0.245) for diagnosis of early HCC, defined as a single tumor less than 3 cm in size. The low sensitivity (25.6%) of PIVKA-II (cut-off 40 mAU/ml) can be overcome by combining it with AFP (48.7%). Furthermore, with combined AFP (cut-off 20 ng/ml), PIVKA-II (cut-off 40 mAU/ml), and AFP-L3 (cut-off 10%), the sensitivity was enhanced to 56.4%. In patients with AFP <20 ng/ml, the AUROC for PIVKA-II (0.743, 95% CI, 0.678-0.807; p = <0.001) was superior to that of AFP-L3 (0.576, 95% CI, 0.500-0.653; p = 0.052). AFP-L3 was able to differentiate HCC patients from AFP-false negative patients in the logistic regression analysis (odds ratio 1.076, 95% CI, 1.037-1.116, p = < 0.001). All tumor marker levels including AFP, PIVKA-II, and AFP-L3 correlated with the size and stage of HCC with statistical significance. In conclusion, combined AFP and PIVKA-II can used for good screening tool of early HCC. Furthermore, AFP-L3 may have an additional role to differentiate between true HCC in AFP false-positive patients.