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Flt-4–Positive Endothelial Cell Density and Its Clinical Significance in Non–Small Cell Lung Cancer

Departments of ¹ Thoracic Surgery, Faculty of Medicine, and ² Translational Clinical Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and ³ Department of Thoracic Surgery, Seishin-Iryo Center Hospital, Kobe, Japan

Purpose: Experimental studies have revealed that fms-like tyrosine kinase (Flt)-4 plays important roles in lymphangiogenesis in malignant tumors, but the clinical significance remains unclear. We assessed Flt-4 expression in tumor cells and in endothelial cells in correlation with clinical outcomes in non–small cell lung cancer (NSCLC).

Experimental Design: A total of 206 consecutive patients with resected pathological stage I-IIIA NSCLC were reviewed. Expression of Flt-4 was examined immunohistochemically, and Flt-4–positive microvessels were quantitatively evaluated (Flt-4–positive endothelial cell density).

Results: There was no significant correlation between Flt-4–positive endothelial cell density and any characteristic of patients including nodal metastases. A significant correlation between Flt-4–positive endothelial cell density and Flt-4 status in tumor cells was documented (P < 0.001), but there was no significant difference in the mean Flt-4–positive endothelial cell density according to vascular endothelial growth factor-C or -D status in tumor cells. The 5-year survival rate for higher Flt-4–positive endothelial cell density tumor (56.4%) was significantly lower than that of lower Flt-4–positive endothelial cell density tumor (69.0%, P = 0.046); the prognostic significance was enhanced in pIIIA-N2 patients (5-year survival rates, 18.8% for higher Flt-4–positive endothelial cell density tumor and 50.0% for lower Flt-4–positive endothelial cell density tumor, respectively; P = 0.012). A multivariate analysis confirmed that higher Flt-4–positive endothelial cell density was a significant and independent prognostic factor (P = 0.019). CD34-positive vessel density or Flt-4 status in tumor cells was not a significant prognostic factor.

Conclusions: Flt-4–positive endothelial cell density, not Flt-4 status in tumor cells, was a significant prognostic factor in NSCLC.