High LYVE-1–Positive Lymphatic Vessel Numbers Are Associated with Poor Outcome in Breast Cancer

Abstract

Purpose:The clinical significance of intratumoral or peritumoral lymph vessel density is not known. LYVE-1, a lymphatic endothelium-specific hyaluronan receptor, is a novel lymphatic vessel marker that is expressed on lymph vessel endothelial cells of both normal and neoplastic tissues.Experimental Design: We investigated expression of LYVE-1 by immunhistochemistry in 180 unilateral, invasive ductal breast carcinomas and assessed the presence and density of lymph vessels within the tumor and at the tumor periphery.Results: A minority (12%) of breast carcinomas had intratumoral lymph vessels, whereas peritumoral lymph vessels were identified in almost all cases (94%). No substantial association was found between the number of LYVE-1-positive vessels and the number of CD31 or vascular endothelial growth factor receptor-3-positive vessels, or vascular endothelial growth factor-C expression. The number of metastatic axillary lymph nodes increased in parallel with increasing lymph vessel counts (P ‫؍‬ 0.033). A higher than the median lymph vessel count at the tumor periphery was significantly associated with unfavorable distant disease-free survival and overall survival. Women with high peritumoral lymph vessel density had only 58% (95% confidence interval, 46 -70%) 5-year distant disease-free survival as compared with 74% (66 -83%) among those with a low peritumoral lymph vessel density (P ‫؍‬ 0.0088). In contrast, the presence of intratumoral lymph vessels was associated with neither axillary nodal status nor survival. Lymph vessel density was not an independent prognostic factor in a multivariate survival analysis.Conclusions: A high peritumoral lymph vessel density is associated with a poor outcome in ductal breast cancer.

Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications

“…Such associations were not found in other studies [18,39]. This may be due to different approaches used to assess LVD where it was assessed by counting the immunostained vessels in selected tumoural hot spots [16][17][18][19] or in randomly selected fields [39].…”

“…Opposing results have been reported by later studies where functional intratumoural lymphatics were detected in xenografted tumours [11]. With human breast cancer certain studies have reported an absence of both intratumoural lymphatics and of lymphangiogenesis [12][13][14] whereas others have detected lymphatics both inside and around the tumour [15][16][17]. The importance of the lymph vessel density (LVD) in promoting metastatic spread of breast cancer is questionable [18,19] and which vessels, newly formed lymphatics or pre-existing ones, play the more important role in the initial dissemination of tumour cells is uncertain.…”

“…With advances in imaging techniques, intratumoural lymphatics were detected and found to be functional, with tumour cells detected flowing within the vessels [11]. Controversy exists regarding lymphatics in human breast cancer, with some studies reported absence of intratumoural lymphatics [12][13][14] and others reporting their presence [17,19]. In the present study, lymphatics were detected in the peritumoural area in all specimens while 86 and 41% of specimens have additional lymphatics in the peripheral and in the inner 2/3 core of the tumour, respectively.…”

Prognostic significance of lymphatic invasion in lymph node-positive breast carcinoma: findings from a large case series with long-term follow-up using immunohistochemical endothelial marker

“…We and others had shown that intratumoral lymphatics with tumor emboli do exist; however, most of the LI lesions are located in peritumoral vessels. 8,[29][30][31] We have also examined whether the frequency of LI per tumor tissue affects outcome in LN-positive tumors. In our previous study assessing LI in 1000 LN-negative BC, number of LI foci ranged from 1 to 79 per tumor section.…”

Role of lymphangiogenesis in epithelial ovarian cancer

“…In melanoma, one large study with 202 samples demonstrated improved overall and recurrence free survival with increased LVD in both peritumoural and intratumoural areas (Straume et al, 2003) suggesting that vessel density may be a marker for an improved immune response whereas two smaller studies conclude the opposite with intratumoural lymphatics significantly higher in metastatic melanomas and correlating with poor survival (Dadras et al, 2003;Shields et al, 2004). Interestingly, in breast cancer intratumoral lymphatic vessels are absent and the significance of peritumoural vessels is unclear (Williams et al, 2003;Bono et al, 2004;Vleugel et al, 2004). Further studies in other tumour types investigating LVD and proliferation markers may clarify the role of new lymph vessel formation and the significance of LVD in cancer progression.…”