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 ...