Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers

Background: Clinical relevance of tumor infiltrating lymphocytes (TILs) in breast cancer is controversial. Here, we used a tumor microarray including a large series of ductal and lobular breast cancers with long term follow up data, to analyze clinical impact of TIL expressing specific phenotypes and distribution of TILs within different tumor compartments and in different histological subtypes. Methods: A tissue microarray (TMA) including 894 ductal and 164 lobular breast cancers was stained with antibodies recognizing CD4, FOXP3, and IL-17 by standard immunohistochemical techniques. Lymphocyte counts were correlated with clinico-pathological parameters and survival. Results: CD4(+) lymphocytes were more prevalent than FOXP3(+) TILs whereas IL-17(+) TILs were rare. Increased numbers of total CD4(+) and FOXP3(+) TIL were observed in ductal, as compared with lobular carcinomas. High grade (G3) and estrogen receptor (ER) negative ductal carcinomas displayed significantly (p < 0.001) higher CD4(+) and FOXP3(+) lymphocyte infiltration while her2/neu over-expression in ductal carcinomas was significantly (p < 0.001) associated with higher FOXP3(+) TIL counts. In contrast, lymphocyte infiltration was not linked to any clinicopathological parameters in lobular cancers. In univariate but not in multivariate analysis CD4(+) infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers. However, a FOXP3(+)/CD4(+) ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033). Conclusions: Ductal and lobular breast cancers appear to be infiltrated by different lymphocyte subpopulations. In ductal cancers increased CD4(+) and FOXP3(+) TIL numbers are associated with more aggressive tumor features. In survival analysis, absolute numbers of TILs do not represent major prognostic indicators in ductal and lobular breast cancer. Remarkably however, a ratio > 1 of total FOXP3(+)/CD4(+) TILs in ductal carcinoma appears to represent an independent favorable prognostic factor.