Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma

BACKGROUND Vascular endothelial growth factor C (VEGF‐C) plays an important role in lymphangiogenesis and activates VEGF receptor 3 (VEGFR‐3). By contrast, lymphatic spread is an important prognostic factor in patients with nonsmall cell lung carcinoma (NSCLC). The objective of the current study was to determine whether the expression of VEGF‐C and VEGFR‐3 correlates with clinicopathologic factors and prognosis in patients with primary NSCLC. METHODS The authors conducted a retrospective review of 180 consecutive patients who underwent complete resection for NSCLC and who did not receive any chemotherapy or radiotherapy prior to surgery. Immunohistochemical staining for VEGF‐C and VEGFR‐3 was performed. The clinicopathologic implications of VEGF‐C and VEGFR‐3 expression were analyzed statistically. RESULTS Of 180 patients with NSCLC, 137 patients (76.1%) were positive for VEGF‐C, and 40 patients (22.2%) were positive for VEGFR‐3. VEGF‐C expression was observed frequently in patients with adenocarcinoma (P = 0.026). For VEGFR‐3 expression, significant correlations were demonstrated with age (P = 0.02), gender (P = 0.008), and histologic differentiation in patients with squamous cell carcinoma (P = 0.03). Patients who had positive staining for VEGF‐C showed significantly less favorable survival rates compared with patients who had negative staining for VEGF‐C (P = 0.003). The survival rates of patients who had positive staining for VEGFR‐3 also were significantly lower compared with patients who had negative staining for VEGFR‐3 (P < 0.001). Patients who had positive staining for both VEGF‐C and VEGFR‐3 exhibited the most unfavorable prognoses. Univariate analysis revealed the following prognostic factors: gender (P = 0.03), tumor status (T1,T2 vs. T3; P < 0.01), lymph node status (negative vs. positive; P < 0.01), tumor size (≤ 35 mm vs. > 35 mm; P < 0.01), disease stage (Stage I vs. Stages II and III; P < 0.01), VEGF‐C expression (negative vs. positive; P < 0.01), VEGFR‐3 expression (negative vs. positive; P < 0.01) and combined VEGF‐C and/or VEGFR‐3 expression (both positive vs. VEGF‐C or VEGFR‐3 positive; P < 0.01). Multivariate analysis demonstrated that VEGFR‐3 expression was the only independent negative prognostic factor (P < 0.01). CONCLUSIONS VEGF‐C and VEGFR‐3 expression may be indicative of survival rates for patients with NSCLC. Cancer 2003;97:457–64. © 2003 American Cancer Society. DOI 10.1002/cncr.11073 Patients who showed positive staining fo