Apoptosis, proliferation, and Fas (APO-1, CD95)/Fas ligand expression in medullary carcinoma of the breast

Abstract

Medullary carcinoma (MC) of the breast is a unique subtype of infiltrating ductal carcinoma that is characterized by a prominent lymphoid infiltrate and improved prognosis. Activated granzyme B(+)/CD8(+) cytotoxic T-lymphocytes (CTLs) infiltrating tumour cell nests constitute a major subset within the lymphoid infiltrate. As CTLs destroy target tumour cells by triggering apoptosis, it would be of interest to determine whether the apoptotic rate in MC is increased. This study evaluates the extent of apoptosis in relation to Fas (APO-1, CD95)/Fas ligand (FasL) expression in MC. Fourteen cases of typical MC (TMC) and 15 cases of atypical MC (AMC) classified according to the Ridolfi criteria, as well as 19 cases of poorly differentiated infiltrating ductal carcinoma (PDC) were evaluated. The apoptotic index (AI) was assessed by the TUNEL method on paraffin-embedded tissue. Cell proliferation was evaluated immunohistochemically by PCNA staining. The level of Fas/FasL expression was determined semiquantitatively by immunohistochemistry using a four-grade scoring system. The AI was significantly increased in TMC and AMC as opposed to the PDC subgroup (2.2+/-0.8, 2.1+/-0.8, and 1.3+/-0.6, respectively; p<0.05). A significant proportion (31.8+/-7.9% in TMC and 25.8+/-9.7% in AMC) of the apoptotic tumour cells within tumour nests were in close contact with CD3(+) lymphocytes. Increased apoptosis was not accompanied by increased proliferation of tumour cells. The extent of Fas expression did not differ between the three subgroups. FasL was expressed both by tumour infiltrating lymphocytes in MC and by tumour epithelium in all three subgroups. The observation that the majority of MCs express Fas and are infiltrated by lymphocytes expressing FasL suggests that increased apoptosis in MC is mediated by Fas/FasL. However, our observation that the majority of MCs also express FasL and the fact that tumours co-expressing Fas and FasL did not show increased apoptosis suggest that there may be additional cytotoxic pathways that lead to tumour apoptosis in MC.