Prognostic role of lymphatic vessel density and lymphovascular invasion in chemotherapy-naive and chemotherapy-treated patients with invasive breast cancer.

It is assumed that the spread of breast cancer cells via the lymphatic system might be influenced by inflammatory reactions and/or the application of chemotherapy or molecularly targeted therapy. Therefore, we analysed survival according to lymphatic vessel density (LVD), lymphovascular invasion (LVI) (both assessed using podoplanin as immunohistochemical marker of lymphatic endothelium) and well-established clinico-pathological features in a group of 358 patients with invasive ductal breast cancer: 139 chemotherapy-naïve (pT1-2/pN0/M0) and 219 treated with chemotherapy (pT1-4/pN1-3/M0). Univariate analysis revealed that high LVD was related to unfavourable disease-free survival (DFS) in pN0/chemotherapy/trastuzumab-naïve patients (P = 0.028). Conversely, in pN+/chemotherapy-treated individuals high LVD was related to favourable DFS (P = 0.019). LVI was a significant indicator of survival (P = 0.005) only in pN0/chemotherapy/trastuzumab-naïve patients. The following parameters were significant independent adverse prognostic factors for DFS: (i) in pN0/chemotherapy/trastuzumab-naïve patients: high LVD (LVD > 7 vessels/mm2; RR = 2.7, P = 0.039), LVI (RR = 3.3, P = 0.046) and high tumor grade (G3 vs. G1 + G2; RR = 2.6, P = 0.030); (ii) in pN+/chemotherapy/trastuzumab-treated patients: low LVD (RR = 1.8, P = 0.042), the number of involved lymph nodes (pN3 vs. pN1-2; RR = 2.3, P = 0.012) and the breast cancer subtype (expression of steroid receptors together with HER2 immunonegativity and high proliferation index vs. other breast cancer immunophenotypes; RR = 3.0, P < 0.001). High LVD may identify high progression risk in pN0/chemotherapy/trastuzumab-naïve patients, and low progression risk in pN+/chemotherapy-treated patients. This phenomenon might be explained by potential involvement of lymphangiogenesis in two processes related to cancer eradication: a chemotherapy-stimulated activity of the immune system against cancer cells, or increased tumour drainage influencing the efficacy of cytotoxic drugs.