Intraepidermal cytokeratin 7 expression is not restricted to Paget cells but is also seen in Toker cells and Merkel cells.

Histologically, extramammary Paget's disease and mammary Paget's disease (MPD) are characterized by large atypical cells distributed throughout the epidermis. Although classic examples of these disorders are easily diagnosed on morphologic grounds, some cases may cause differential diagnostic problems. Immunohistology with a wide variety of antibodies has been used as an aid for the identification of Paget cells, for their distinction from other entities, and for investigation of the origin or nature of the disorder. Recently, cytokeratin 7 has been proposed as a specific and 100% sensitive marker for Paget's disease. We studied 22 cases of mammary Paget's disease and 22 cases of extramammary Paget's disease with and without an underlying malignancy for their reactivity with monoclonal antibodies to cytokeratin 7 (CK7) and cytokeratin 20 (CK20). Our studies show that anti-CK7 is an effective but not 100% sensitive marker for Paget cells, staining 21 of 22 cases of mammary Paget's disease and 19 of 22 cases of extramammary Paget's disease, whereas CK20 stained 0 of 17 cases of mammary Paget's disease and 6 of 19 cases of extramammary Paget's disease. We also demonstrate that CK7, but not CK20, highlights intraepidermal clear cells with bland nuclear features (Toker cells) that have been reported in 11% of normal nipples. By using CK7 as a marker, however, we were able to identify Toker cells in most of the nipples we studied: 8 of 15 nipples from mastectomy patients without Paget's disease, and 15 of 18 autopsy cases (both male and female) with normal breasts and nipples. It also permitted us to perform more extensive phenotyping on them, showing that Toker cells share similar antigens with Paget cells and with cells lining the underlying normal lactiferous ducts. In 7 of 15 cases containing CK20-positive Merkel cells, CK7 was also seen to stain Merkel cells. In infrequent cases, Toker cells or Merkel cells may be so numerous focally that a CK7 stain may raise the possibility of involvement of the nipple by Paget's disease. An awareness of the CK7 reactivity of Toker cells and Merkel cells as well as attention to the cytologic features of the case should avoid this problem.