Overexpression of the receptor tyrosine kinase EphA2 in choroidal melanoma: correlation with vesculogenic mimicry and prognosis

Abstract

To study the correlation of EphA2 protein expression with vesculogenic mimicry (VM), clinicopathological characteristics and prognosis in choroidal melanoma (CM). It was a retrospective case series study. Between January 1992 and December 2005, 56 cases of human CM with clinicopathologic data from the Second Hospital of Tianjin Medical University were studied. HE stainings were performed to observe the microcirculation patterns in tumor tissue specimens. VM was found in 26 of the 56 cases using CD31/periodic acid-Schiff (PAS) double staining and transelectron microscopy. All cases were divided into two groups: VM-positive and VM-negative. Immunohistochemical staining was performed on paraffin sections of the 56 cases of CM specimens to investigate the expression of EphA2. According to tumor cells positive rate and staining intensity of the results of evaluation, the specimens were divided into low expression and high expression groups.χ(2)-test and t-test were used to analyzed the enumeration data and measurement data, respectively. Survival analysis was used to further elucidate its correlation with clinicopathological characteristics, VM and prognosis. Cox proportional hazard model was used to analyzed the influence factors of prognosis. VM channels were found in 26 of the 56 CM cases and VM-negative 30 cases. VM-positivity was related to cell type, tumor size and recurrence and metastasis, and the differences were statistically significant (χ(2) = 4.612, 5.346, 5.213; P = 0.036, 0.021, 0.027). The results showed that EphA2 was up-regulated in the VM-positive group compared with the group of VM-negative group. The positive rates of EphA2 expression in the VM-positive group and VM-negative group were 92.3% (25/26) and 70.0% (21/30), respectively, with a significant difference between the two groups (t = 2.247, P = 0.009). The EphA2 protein was expressed in epithelioid (10/12), mixed (11/15) and spindle (41.40%) cell types, with a significant difference among these histological types (χ(2) = 6.513, P = 0.010). The expression rate of EphA2 protein were significantly higher in large (54.55%, 18/33) than small (45.45%, 15/33) tumors, and the expression of EphA2 in metastatic and recurrence patients (10/11) were significantly higher compared with controls (31.11%, 14/45) (χ(2) = 4.556, 8.211;P = 0.016, 0.005). Kaplan-Meier survival analysis showed the presence of VM resulted in a poor prognosis (t = 9.263, P = 0.000). The Cox proportional hazards model indicated that the EphA2 overexpression and the presence of VM were independent predictors of a poor prognosis (χ(2) = 12.041, P = 0.001). Moreover, there was a significant positive correlation between them (r = 0.412, P < 0.05). The results of this study demonstrate that EphA2 may play a critical role in the formation process of VM in CM, implicating EphA2 as a valuable marker for the prediction of recurrence, metastasis and prognosis in CM patients.