Flt-4-positive vessel density correlates with vascular endothelial growth factor-d expression, nodal status, and prognosis in breast cancer.
OBJECTIVE
Metastasis to the regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer and an important prognostic factor in many types of cancer. Recent evidence suggests that tumor lymphangiogenesis promotes lymphatic metastasis, and that the presence of Flt-4 on tumor blood and lymphatic vessels may play a important role in mediating lymphangiogenic factor-induced neovascularization. We assessed flt-4-positive vessel density (FVD) in breast cancer, and examined whether FVD associates with lymph node metastasis, VEGF-D expression, or prognosis.


METHODS
One hundred three invasive breast carcinomas with long-term follow-up were included in our study. Flt-4 was assessed using immunohistochemistry, then we analyzed the relationship between FVD and lymph node status, as well as VEGF-D expression and other established clinicopathological parameters. The relationship between FVD and prognosis was also investigated.


RESULTS
Mean FVD of "hot spot" was 29.3 +/- 22.5 for each case. FVD was correlated significantly with lymph node metastasis (P < 0.0001), VEGF-D expression (P = 0.0019), tumor size (P = 0.0015), estrogen receptor (P = 0.0211), progesterone receptor (P = 0.0462), and c-erbB-2 (P = 0.0326). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that high FVD was associated with both worse disease-free survival (P = 0.0035) and overall survival (P = 0.0336).


CONCLUSIONS
Increased FVD was correlated with lymph node metastasis and VEGF-D expression. High FVD may be a significant unfavorable prognostic factor for long-term survival in breast cancer. It is possible that Flt-4 becomes a target for antiangiogenic therapy to breast cancer.
Nakamura
Yasushi
Y
Second Department of Pathology, Wakayama Medical University, 641-8509 Wakayama City, Japan. ynakamur@mail.wakayama-med.ac.jp
Yasuoka
Hironao
H
Tsujimoto
Masahiko
M
Yang
Qifeng
Q
Imabun
Shigeru
S
Nakahara
Masaaki
M
Nakao
Kazuyasu
K
Nakamura
Misa
M
Mori
Ichiro
I
Kakudo
Kennichi
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3