Increased Sentinel Lymph Node Lymphangiogenesis is Associated with Nonsentinel Axillary Lymph Node Involvement in Breast Cancer Patients with a Positive Sentinel Node

Abstract

Purpose: Lymph node (LN) lymphangiogenesis has recently been shown to be important in the premetastatic niche of sentinel LNs. To study its role in the further metastatic spread of human breast cancer, we investigated the association of angiogenesis and lymphangiogenesis in sentinel LN metastases with the presence of nonsentinel LN metastases in breast cancer patients with a positive sentinel LN. Experimental Design: Angiogenesis and lymphangiogenesisöquantified as endothelial cell proliferation fraction (ECP%) and lymphatic ECP fraction (LECP%)öwere assessed in sentinel LN metastases of 65 T 1 /T 2 patients with breast cancer using CD34/Ki67 and D2-40/Ki67 immunohistochemical double stains. Correlations were analyzed between nonsentinel LN status, LECP%, and other clinicopathologic variables (number of involved sentinel LNs, size of the primary tumor and LN metastasis, presence of lymphovascular invasion in the primary tumor, and of extracapsular growth in the sentinel LN metastasis). Results: Thirty seven out of 65 patients (56.9%) had at least one involved nonsentinel LN. Size of the sentinel LN metastasis (P = 0.001), lymphovascular invasion (P = 0.02), extracapsular growth (P = 0.02), and LECP% (P = 0.01) were correlated with a positive nonsentinel LN status. The multivariate logistic regression model retained high LECP% (odds ratios = 4.2, P = 0.01) and the presence of extracapsular growth (odds ratios = 3.38, P = 0.04) as independently associated with the presence of nonsentinel LN metastases. Conclusions: Increased sentinel LN metastasis lymphangiogenesis is associated with metastatic involvement of nonsentinel axillary LNs. These are the first data sustaining the hypothesis that sentinel LN lymphangiogenesis is involved in further metastatic spread of human breast cancer. Primary breast tumors can metastasize in two different ways:tumor cells can leave the primary tumor and spread by the lymphatic or by the hematogenous route leading to the formation of locoregional lymph node (LN) and distant metastases, respectively (1). In the lymphatic pathway, the sentinel LN is the first metastatic station and a sentinel LN free of carcinoma has a very high negative predictive value for further lymphatic dissemination in patients with breast cancer.Axillary LN dissection and associated morbidity could therefore be avoided in 65% to 70% of patients with breast cancer (2). Even in cases of metastatic involvement of the sentinel LN, metastases in further axillary LNs will only be present in 30% to 60% of the patients. Several authors studied the features of sentinel LN metastasis and of the primary tumor that can predict axillary nonsentinel LN involvement. The size of the sentinel LN metastasis has emerged as a most powerful independent predictor in several studies (3 -15). Furthermore, the number of involved sentinel LNs (3,4,7,10,11,16), extracapsular growth of the sentinel LN metastasis (3,6,15), the size of the primary tumor (7,9,10,13,14), and the presence of lymphovascular invasion (4,7,9,14,15) have ...

Lymphangiogenesis in breast carcinoma is present but insufficient for metastatic spread

“…Active lymphangiogenesis was also detected in positive sentinel LN (22,23) that displayed a signifi cantly higher median LECP% (p < 0.001) than uninvolved LN (23). Moreover, high frequency of Ki-67-labeled lymphatics in positive sLN was strongly associated (p = 0.01) with axillary metastasis (22), supporting the contention that tumor-induced lymphangiogenesis promotes dissemination from both the primary tumor and secondary metastatic sites. Nevertheless, with the exception of very active lymphangiogenesis in infl ammatory breast cancer (20,21), a relatively low fraction of dividing lymphatic endothelial cells (2-6%) and some discrepancy between high %LVI and low %LECP in other breast cancer types suggest that both new and existing lymphatic vessels partake in lymphatic metastasis (24).…”

“…Studies that compared LECP% in infl ammatory and noninfl ammatory breast cancers found that the former have both a higher incidence of Ki-67 positive lymphatics (80% vs. 50%) and an increased median LECP% (20,21). Active lymphangiogenesis was also detected in positive sentinel LN (22,23) that displayed a signifi cantly higher median LECP% (p < 0.001) than uninvolved LN (23). Moreover, high frequency of Ki-67-labeled lymphatics in positive sLN was strongly associated (p = 0.01) with axillary metastasis (22), supporting the contention that tumor-induced lymphangiogenesis promotes dissemination from both the primary tumor and secondary metastatic sites.…”

Molecular Regulation of Lymphangiogenesis in Development and Tumor Microenvironment

“…Another contributing factor for lymphatic metastasis is the increased lymphangiogenesis in sentinel lymph nodes draining a tumor (Hirakawa et al 2005;Van den Eynden et al 2007;Rinderknecht and Detmar 2008;Ruddell et al 2008). Besides the lymphangiogenic factors transported with lymph from tumor, lymphocytes in lymph nodes also actively participate in the regulation of lymph nodeassociated lymphatic vessel growth.…”

Erythropoietin Induces Lymph Node Lymphangiogenesis and Lymph Node Tumor Metastasis

“…Lymph node lymphangiogenesis has also been shown to be associated with lymphatic metastases in animal models (16,17). It has been shown that the lymphangiogenesis in the sentinel lymph node is initiated before tumor metastasis in the lymph nodes (18,19). Thus, lymph node lymphangiogenesis can be an important factor in lymph node tumor metastasis.…”

“…VEGF-C is an angiogenic factor mainly involved in lymphatic endothelial cell (LEC) growth. Macrophages produce and secrete VEGF-C and play a critical role in lymphangiogenesis (19). VEGF-C from macrophages induces lymphangiogenesis in advanced ovarian cancer (20).…”