Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer

Abstract

Objective: The aim of this study was to investigate the prognostic relevance of lymphangiogenesis and lymphovascular invasion in a large cohort of breast cancer patients.

Introduction: Invasion of tumor cells into blood and lymphatic vessels is one of the critical steps for metastasis. The presence or absence of lymph node metastasis is one of the main decision criteria for further therapy. One shortcoming of previous morphologic studies was the lack of specific markers that could exact discriminate between blood and lymphatic vessels. The aim of this study was to evaluate the prognostic relevance of lymphangiogenesis and lymphovascular invasion in breast cancer patients.

Methods: We investigated 374 tissue specimens of patients suffering from invasive breast cancer by immunostaining for the lymphatic endothelial specific marker podoplanin. Lymphangiogenesis, quantified by evaluating the lymphatic microvessels density (LMVD), and lymphovascular invasion (LVI) were correlated with various clinical parameters and prognostic relevance.

Results: LMVD correlated significantly with LVI (P = 0.001). LVI was associated significantly with a higher risk for developing lymph-node metastasis (P = 0.004). Calculating the prognostic relevance, LVI presented as an independent prognostic parameter for disease free as well as overall survival (P = 0.001, and P = 0.001, respectively).

Conclusion: Our data provide evidence that the biologic system of lymphangiogenesis constitutes a potential new target for development of anti-breast cancer therapeutic concepts. Our results further suggest that young, premenopausal patients with low differentiated breast tumors and high LMVD and LVI would, in particular, benefit from lymphangiogenesis-associated therapeutic strategies.

FIGURE 1. A: Breast cancer specimen with a high peritumoral LMVD (some of the lymphatic vessels stained for podoplanin are marked with arrows). Note the absence of lymphatic vessels in the tumor (T) (immunoperoxidase, original magnification ×200). B: Podoplanin-stained lymphatic vessel (arrows) with tumor cells (T) inside (LVI). Note the absence of endothelial podoplanin staining in a venous blood vessel (BV) with typical smooth muscle cells within its wall (immunoperoxidase, original magnification ×400). Line below shows immunofluorescence on lymphatic vessel for podoplanin and lyve-1, revealing perfect overlap (merge). Immunofluorescence, nuclear counterstaining with propidium iodide.

FIGURE 2. A: Overall survival in 374 breast cancer patients with (LVI+) or without (LVI-) lymphovascular invasion. B: Disease-free survival in 374 breast cancer patients with (LVI+) or without (LVI-) lymphovascular invasion.