Tumor Invasiveness, Not Lymphangiogenesis, Is Correlated with Lymph Node Metastasis and Unfavorable Prognosis in Young Breast Cancer Patients (≤35 Years).

Zhi-Qiang Zhang,Gang Chen,Shu-Qing Cui,Qing Nian,Xing-Yong Wang,Yu-Zhen Han,William B Coleman

doi:10.1371/journal.pone.0144376

Abstract

The morbidity rate of breast cancer is on the rise, and the age of onset appears to be trending toward a young age. Breast cancer in young women (BCYW) has a number of distinctive features that differ from breast cancer in middle-aged or elderly women (BCMEW). Lymphatic metastasis plays an important role in the spread of BCYW; however, the mechanisms of lymph node metastasis (LNM) in BCYW are not clear. This study aimed to investigate the mechanism of lymphatic metastasis in BCYW and to evaluate the relationships between lymphangiogenesis, the expression of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor C (VEGF-C) expression, clinicopathological characteristics, and prognosis. Using immunohistochemistry, MMP-9, VEGF-C and the level of lymphatic microvessel density (LMVD) were analyzed in 106 cases of breast invasive ductal carcinoma and 20 cases of breast proliferative lesions. Compared with BCMEW, BCYW had higher MMP-9 expression, higher LNM, and more adverse prognoses. In BCYW, high MMP-9 expression was positively correlated with LNM and impaired survival time. However, in BCMEW, MMP-9 expression was not correlated with LNM or survival time. In addition, high VEGF-C expression was positively correlated with a high level of LMVD in both BCYW and BCMEW. Nevertheless, a high level of LMVD was not correlated with LNM or survival time in the two groups. More importantly, univariate and multivariate survival analysis showed that MMP-9 expression and LNM were independent prognostic factors in BCYW. Our present study indicates that lymphangiogenesis induced by VEGF-C is augmented in breast cancer; however, a higher level of lymphangiogenesis has no significant impact on LNM or survival time. We suggest that tumor invasiveness, rather than lymphangiogenesis, plays an important role in LNM among BCYW. Moreover, MMP-9 and LNM were independent prognostic factors for BCYW.

Highlights

Breast cancer is one of the most common malignancies and the leading cause of cancer deaths in women worldwide
Data analysis indicated that the rate of lymph node metastasis (LNM) was higher in Breast cancer in young women (BCYW) compared to breast cancer in middle-aged or elderly women (BCMEW)
There were no significant differences in tumor size, histological grade, molecular subtype, and TNM staging between BCYW and BCMEW group

Summary

Introduction

Breast cancer is one of the most common malignancies and the leading cause of cancer deaths in women worldwide. The study of lymphatic vessel characteristics in malignant tumors has lagged behind the study of blood vessels, largely due to the lack of availability of lymphatic-specific markers. In recent years, these types of specific markers, such as LYVE-1, Prox-1, and D2-40, have been characterized and have become commercially available. Tumor cells can invade the lymphatic vessels and metastasize to lymph nodes or distant sites. These findings suggest that lymphatic vessel characteristics may be an applicable indicator to predict the metastatic ability of breast tumor cells

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