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

Medullary carcinoma (MC) of the breast is a unique subtype of infiltrating ductal carcinoma that is characterized by a prominent lymphoid infiltrate a nd 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 apo ptosis, it mould be of interest to determine whether the apoptotic rate in MC is increased. This study evaluates the extent of apoptosis in relation t o Fas (APO-1, CD95)/Fas ligand (FasL) expression in MC. Fourteen cases of t ypical MC (TMC) and 15 cases of atypical MC (AMC) classified according to t he Ridolfi criteria, as well as 19 cases of poorly differentiated infiltrat ing ductal carcinoma (PDC) were evaluated. The apoptotic index (AI) was ass essed by the TUNEL method on paraffin-embedded tissue. Cell proliferation w as 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 nest s mere in close contact with CD3(+) lymphocytes. Increased apoptosis was no t 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 a ll three subgroups. The observation that the majority of MCs express Fas an d are infiltrated by lymphocytes expressing FasL suggests that increased ap optosis in MC is mediated by Fas/FasL. However, our observation that the ma jority of MCs also express Fast and the fact that tumours co-expressing Fas and FasL did not show increased apoptosis suggest that there may be additi onal cytotoxic pathways that lead to tumour apoptosis in MC. Copyright (C) 2000 John Wiley & Sons, Ltd.