Plasma Level Of Macrophage Migration Inhibitory Factor (MIF) Plays A Role In Prognosis Of The Patients With Hepatocellular Carcinoma (HCC) After Curative Resection

Objective:We measured the plasma levels of MIF and microvessel density(MVD) of tumor tissue in 44 patients with hepatocellular carcinoma(HCC) after curative resection to investigate its relationship with HCC angiogenesis and roles in predicting prognosis of the overall survival and disease-free survival.Material and methods:Forty-four consecutive Chinese patients who underwent curative resection of HCC in the Department of Hepatic Surgery(Zhongshan Hospital,Fudan University) between January 2005 and December 2005 were recruited randomly into this study after informed consent.As negative control,twenty patients with liver benign lesions (including 8 patients with haemangioma,2 patients with focal nodular hyperplasia,10 patients with cyst) were enlisted as well.Enzyme-linked immunosorbentassay (ELISA) was used to detect the concentrations of MIF,vascular endothelial growth factor(VEGF) and interleukin-8(IL-8) in preoperative plasma of 44 patients with curative resection of HCC and 20 negative subjects.Immunohistochemistry was used to measure microvessel density(MVD) stained by anti-CD34 antibody.The relationship between MIF and angiogenesis was evaluated by comparing plasma MIF level and MVD of HCC.The relationship between plasma MIF level of HCC with clinicopathological feature(gender,age,HBsAg status,tumor size,tumor number, tumor capsule,venous invasion,tumor differentiation,TNM stage),disease-free survival and overall survival of patients after curative resection were analyzed.The prognosis value of plasma MIF level was evaluated by survival analysis and Cox regression. Results:The preoperative plasma MIF levels of 44 patients with resection of HCC ranged from 1.42 to 78.8 ng/ml,with a median of 9.09 ng/ml(interquartile range, 4.54-20.45ng/ml).The average level of plasma MIF in these 44 patients with HCC was significantly higher than that of healthy controls(median,4.80 ng/ml; interquartile range,2.39-6.80ng/ml;P=0.002).The plasma VEGF levels of HCC patients ranged from 10.57 to 654.78 pg/ml,with a median of 76.13 pg/ml (interquartile range,22.42-148.01 pg/ml),the average level of plasma VEGF in HCC patients was significantly higher than that of healthy control(median,25.40 pg/ml; interquartile range,20.16-37.58 pg/ml;P=0.002).To our interest,all but one plasma samples were undetectable for IL-8.Analyzed by the Pearson correlation coefficient, plasma MIF levels correlated positively with VEGF(r=0.547,P＜0.001).The intratumoral MVD ranged from 20.3/HPF to 96.2/HPF,with a median of 33.7/HPF (interquartile range,28.0-41.9/HPF).The MVD was significantly higher in tumors with high plasma MIF level than in tumors with low plasma MIF level.Plasma MIF level positively correlated with MVD(r=0.747,P＜0.001).There was no significant correlation between plasma MIF concentration and patients' gender(P=0.166),age (P=0.558),hepatitis B surface antigen status(P=0.370) and Edmonson grade (P=0.421).whereas high plasma MIF levels were significantly associated with large tumors＞5cm(P=0.039),multiple tumor(P＜0.001),absence or unintegrity of tumor capsule(P=0.044),presence of venous invasion(P=0.041) and an advanced disease stage(P＜0.001).The plasma MIF levels in patients with stageⅢorⅣdisease were significantly higher than those of patients with stageⅠorⅡdisease.The median overall survival of patients in low MIF group was significantly better than that of patients in high MIF group(median overall survival,26.9 months versus 20.3 months; P=0.0069).The median disease-free survival of patients in low MIF group was also significantly better than that patients in high MIF group(median disease-free survival, 24.5 months versus 12.3 months;P=0.0023).A high plasma MIF level was significantly associated with a poorer overall survival(P=0.0069) as well as disease-free survival(P=0.0023),and was one of the leading independent prognostic factors for both overall survival(hazard ratio=3.279;95%confidence interval 2.095-8.821;P=0.02) and disease-free survival(hazard ratio--2.256;95%confidence interval 2.100-7.652;P=0.004) in multivariate COX model analyses.Conclusions:The plasma MIF level of HCC positively correlated with MVD and plasma VEGF level,it is maybe enhancing VEGF level by which MIF stimulates angiogenesis of HCC.There are significant relationships between plasma MIF level and clinicopathological features,disease-free survival and overall survival,so the evaluation of preoperative plasma MIF level may be helpful to predict the recurrence and prognosis of HCC patients in advance.