Co-expression of VEGF-C and survivin predicts poor prognosis in esophageal squamous cell carcinoma

Abstract

Background: Lymphatic metastasis is one of the main factors affecting prognosis in esophageal squamous cell carcinoma (ESCC). Vascular endothelial growth factor-C (VEGF-C) is an important factor that promotes lymphangiogenesis. Survivin also plays a significant role in lymphatic invasion. However, the role and mechanism of their co-expression are still unclear in ESCC. The purpose of this study was to investigate whether the co-expression of VEGF-C and survivin could be a potential marker to predict patient prognosis and survival in ESCC.

Methods: The levels of VEGF-C, vascular endothelial growth factor receptor 3 (VEGFR-3), survivin, and Ki-67 were determined by immunohistochemistry (IHC) in 97 ESCC patient tumors. The correlations of co-expression of VEGF-C and survivin with pathological features and survival results were also assessed.

Results: High VEGF-C expression was observed in 64.9% of the patients and significantly correlated with T stage (P=0.024), node status (P=0.038), and lymph node metastasis (P=0.015). High survivin expression was significantly associated with T stage (P=0.013), N stage (P=0.016), lymph node metastasis (P=0.005), and differentiation (P=0.044) in 67.0% of the patients. Co-expression of VEGF-C and survivin (V+S+) was significantly associated with T stage (P<0.001), N stage (P=0.015), lymph node metastasis (P=0.003), differentiation (P=0.0045), and Ki-67 levels (P=0.024). High expression of VEGF-C or survivin was associated significantly with worse disease-free survival (DFS) and overall survival (OS) (P<0.05). Moreover, the V+S+ group had a worse DFS (P<0.001) and OS (P=0.001) than any other group (i.e., V-S-, V+S-, V-S+). Furthermore, multivariate DFS analyses (95% CI: 1.147-2.220, P=0.006) and multivariate OS analyses (95% CI: 1.080-2.193, P=0.017) revealed that co-expression of VEGF-C and survivin was an independent prognostic factor in ESCC patients.

Conclusions: Co-expression of VEGF-C and survivin was predictive of poor prognosis in ESCC. Combined detection of VEGF-C and survivin could represent a feasible and effective marker to predict the prognosis and survival of ESCC patients.

Keywords: Vascular endothelial growth factor-C (VEGF-C); esophageal squamous cell carcinoma (ESCC); lymph node metastasis; prognosis; survivin.

Figure 1

Representative images of immunohistochemical staining for VEGF-C, VEGFR-3, survivin and Ki-67 in ESCC tumors (magnification: 200×). (A) VEGF-C negative expression; (B) VEGF-C positive staining (+), (C) (++), (D) (+++); (E) VEGFR-3 negative expression; (F) VEGFR-3 positive staining (+), (G) (++), (H) (+++); (I) survivin negative expression; (J) survivin positive staining (+), (K) (++), (L) (+++). VEGF-C, vascular endothelial growth factor-C; VEGFR-3, vascular endothelial growth factor receptor 3; ESCC, esophageal squamous cell carcinoma.

Figure 2

DFS and OS curves of VEGF-C and survivin expression in ESCC patients. (A) Over-expression of VEGF-C predicts worse DFS in patients with ESCC; (B) over-expression of survivin predicts worse DFS in patients with ESCC; (C) patients with co-expression of VEGC-C and survivin (V+S+) have worst DFS compared to patients with other groups; (D) over-expression of VEGF-C predicts worse OS in patients with ESCC; (E) over-expression of survivin predicts worse OS in patients with ESCC; (F) patients with co-expression of VEGC-C and survivin (V+S+) have worst OS compared to patients with other groups. DFS, disease-free survival; OS, overall survival; VEGF-C, vascular endothelial growth factor-C; ESCC, esophageal squamous cell carcinoma; V+S–, VEGF-C (+)/survivin (–); V–S+, VEGF-C (–)/survivin (+); V–S–, VEGF-C (–)/survivin (–); V+S+, VEGF-C (+)/survivin (+).