The extent of retraction clefts correlates with lymphatic vessel density and VEGF-C expression and predicts nodal metastasis and poor prognosis in early-stage breast carcinoma

Abstract

Although the earliest feature of disseminated disease in breast cancer is regional lymph node involvement, little is known about the mechanisms whereby cancer cells interact with lymphatic endothelial cells and enter the lymphatic system. We have previously reported that the extensive presence of retraction clefts in breast carcinomas highly significantly correlates with lymphatic tumor spread and predicts poor outcome, suggesting that retraction clefts are not just fixation artifacts, but real potential spaces that are exaggerated by tissue processing and may reflect an early stage of lymphatic invasion. In this study, we examined the correlation between the extent of retraction clefts and lymphangiogenesis, as assessed by lymphatic vessel density and vascular endothelial growth factor-C (VEGF-C) expression in a series of 256 early-stage breast carcinomas. The presence and extent of retraction clefts around tumor cell nests was determined by review of all hematoxylinand eosin-stained tumor sections. Lymphatic vessels were detected by podoplanin immunohistochemistry and lymphatic vessel density was measured using the hot-spot method. The expression of VEGF-C in the tumor cells was determined by immunohistochemistry and analyzed semiquantitatively on a four-tiered scale. High levels of retraction clefts, peritumor lymphatic vessel density and VEGF-C expression at the invasive edge in breast carcinomas significantly correlated with tumor size, histological grade, lymphatic invasion and nodal metastasis. Breast carcinomas showing extensive retraction clefts (420% of tumor volume) were found to have significantly higher lymphatic vessel density and VEGF-C expression levels compared to tumors without this feature. High retraction clefts, peritumor lymphatic vessel density and VEGF-C expression predicted poor outcome in breast carcinomas. Our results support the hypothesis that retraction clefts are real potential spaces that may represent 'pre-lymphatic spaces' facilitating initial lymphatic invasion and that growth factors secreted by the tumor cells may stimulate tumor-associated lymphangiogenesis by promoting the endothelialization of these 'pre-lymphatic channels'.

Expression of cluster of differentiation 34 and vascular endothelial growth factor in breast cancer, and their prognostic significance

“…The majority of previous studies have identified that VEGF expression is significantly increased in metastatic breast ductal carcinoma and is correlated with the poor clinical outcomes in patients with early-stage breast cancer (12,(17)(18)(19). Furthermore, VEGF may be an independent prognostic factor for the disease-free survival and OS of breast cancer patients (20). Thus, anti-VEGF therapy may have potential in the treatment of patients with breast cancer.…”

Sulfatase 2 facilitates lymphangiogenesis in breast cancer by regulating VEGF-D

“…The basement membranes of new lymphatic vessels are incomplete, and the endothelial cells do not connect tightly. These factors allow tumor cells to easily invade new lymphatic vessels and metastasize to regional lymph nodes or distant organs (15–18). In recent years more research oncologists are becoming interested in the mechanisms of tumor-induced lymphangiogenesis in various tumors (19,20).…”

“…Breast cancer is one of the most common types of cancer among women worldwide (21,22). Over 50% of early-stage breast cancer patients have local lymph node metastasis (18). Moreover, regional lymph node metastasis in breast cancer is also one of the main factors that leads to breast cancer metastasis and poor prognosis (23,24).…”

Invasive Micropapillary Carcinoma of the Breast: An Update

“…25 Some studies have shown that a retraction artifact is correlated with lymphatic invasion and nodal metastasis and predicts a poorer outcome in early stage breast carcinoma. 26,27 The retraction artifact may be an early stage in the development of micropapillary architecture. These studies suggest that IDC with any well-defined micropapillary carcinoma component is diagnostic of IMPC.…”