Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix.
OBJECTIVE
Lymphatic invasion and nodal metastasis plays a major role in the spread of cervical cancer; however, little is known about the mechanisms whereby tumor cells enter the lymphatic system.


METHODS
We examined the intra- and peritumoral lymphatic vessel density (LVD) using D2-40 immunohistochemistry in 111 cervical squamous cell carcinomas and correlated them with vascular endothelial growth factor (VEGF)-C expression, clinicopathologic tumor features, and outcome.


RESULTS
Compared with benign cervix, intratumoral and peritumoral LVD was significantly increased (P < 0.0001). Peritumoral LVD was significantly higher than intratumoral LVD (P = 0.009). High peritumoral, but not intratumoral, LVD showed significant correlation with high tumor stage, lymphatic invasion, and nodal metastasis. VEGF-C showed increased expression at the invasive edge compared with the center of tumors (P < 0.0001) and correlated with high peritumoral LVD, lymphatic invasion, and nodal metastasis. High peritumoral LVD and VEGF-C expression at the invasive edge of tumors were associated with poor overall and recurrence-free survival in univariate analysis. In multivariate analysis, peritumoral LVD was the only independent term predictive of overall survival.


CONCLUSIONS
Our findings suggest a potential role for VEGF-C in tumor-induced lymphangiogenesis represented by high peritumoral LVD, which may be one of the mechanisms leading to lymphatic invasion and metastatic spread. High peritumoral LVD may be an independent prognostic factor in early-stage cervical cancer.
Gombos
Zoltan
Z
Department of Pathology and Laboratory Medicine and Division of Gynecologic Oncology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Xu
Xiaowei
X
Chu
Christina S
CS
Zhang
Paul J
PJ
Acs
Geza
G
D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
D042582:Vascular Endothelial Growth Factor C