Prognostic and diagnostic effects of high serum midkine levels in patients with hepatocellular carcinoma

Abstract

Midkine (MK) is a soluble cytokine, and its serum levels strongly correspond to protein expression levels in tumors. The present study aimed to clarify the clinicopathological and prognostic significance of serum MK (s-MK) in patients with hepatocellular carcinoma (HCC). Serum samples were obtained before surgery from 123 patients with HCC who had undergone surgery between January 2012 and December 2020. The receiver operating characteristic curve revealed that the best cut-off value for s-MK in differentiating HCC from healthy cases was 426 pg/ml. The clinicopathological variables and overall survival of patients were compared between the s-MK-positive group and s-MK-negative group. The sensitivity, specificity and accuracy of s-MK were 82.1, 97.4 and 88.0%, respectively. An s-MK-positive status was significantly associated with the number of tumors (≥2). The positivity rate of s-MK was significantly higher compared with that of α-fetoprotein and protein-induced by vitamin K absence-II. In total, only 28% of the patients were positive for s-MK. The s-MK-positive group showed significantly worse overall survival compared with the s-MK-negative group. Moreover, multivariate analysis revealed that an s-MK-positive status was independently associated with poor prognosis. s-MK was useful in detecting early HCC. The findings of this study indicated that the s-MK-positive status is associated with the number of tumors and can act as an independent prognostic risk factor.

Keywords: diagnosis; hepatocellular carcinoma; midkine; prognosis; tumor marker.

Figure 1.

Receiver operating curve and a box-and-whisker plot for serum midkine. (A) Receiver operating characteristic curve showing the diagnostic performance of serum midkine for discriminating the hepatocellular carcinoma group from the healthy group. (B) Serum midkine expression is upregulated in the hepatocellular carcinoma group compared with the healthy group. Data are shown in a box-and-whisker plot (median, 25th, and 75th percentile, range, and extreme values outside the range). *P<0.05. AUC, area under the curve; HCC, hepatocellular carcinoma; SD, standard deviation.

Figure 2.

Relationship between positive serum tumor marker findings in patients with hepatocellular carcinoma. (A) All patients, (B) stage I/II patients and (C) stage III/IV patients. AFP, α-fetoprotein; PIVKA-II, protein-induced by vitamin K absence-II.

Figure 3.

Positivity rates of serum tumor markers in hepatocellular carcinoma. (A) Comparison of the positivity rates of serum tumor markers. (B) Comparison of the positivity rates between AFP/PIVKA-II and AFP/PIVKA-II/Midkine. *P<0.05. AFP, α-fetoprotein; PIVKA, protein induced by vitamin K absence I.

Figure 4.

Overall survival for midkine, AFP and PIVKA-II. Comparison of overall survival between the (A) positive and negative midkine groups, (B) AFP groups and (C) PIVKA-II groups. AFP, α-fetoprotein; PIVKA, protein induced by vitamin K absence.

Figure 5.

Overall survival for midkine, AFP and PIVKA-II at stages I/II and III/IV. Comparison of overall survival between the positive and negative midkine groups for (A) stage I/II, (B) midkine for stage III/IV, (C) AFP for stage I/II, (D) AFP for stage III/IV, (E) PIVKA-II for stage I/II and (F) PIVKA-II for stage III/IV. AFP, α-fetoprotein; PIVKA, protein-induced by vitamin K absence.

Figure 6.

Recurrence-free survival for midkine at stages I/II and III/IV. Comparison of recurrence-free survival between the (A) positive and negative midkine groups for (B) stage I/II and (C) stage III/IV.