Paget's disease of the breast

To the Editor -With regard to a recent report by Sahoo et al1 suggesting bilateral Paget disease of the nipple associated with lobular carcinoma in situ, the remarkable resemblance of the photographic and descriptive histologic findings with a relatively obscure look-alike is rather striking. Approximately 30 years ago, Cyril Toker2 described benign clear cell infiltrates of the nipple epidermis occurring in 31 of 340 nipples from cancerous breasts and 23 of 190 nipples examined at autopsy. As illustrated in the case of Sahoo et al, relatively bland cells larger than adjacent keratinocytes with pale to clear cytoplasm are arranged as single, clustered, or tubular aggregates primarily within the lower half of the epidermis. Upward transmigration toward the stratum corneum may be occasionally observed. These cells do not stain with mucicarmine or periodic acid-Schiff stains, although these stains were apparently not applied in this case. As Sahoo et al convincingly show, there is strong immunohistochemical reactivity for cytokeratin 7; however, since cytokeratin 7 expression has been found in both Paget and Toker cells, its utility as a distinguishing marker for either condition is doubtful.3 Sahoo et al also describe a surprising lack of reactivity with antibodies to carcinoembryonic antigen and HER-2/ neu, both of which regularly react with Paget cells.4 Finally, although the clear cells were purportedly estrogen receptor positive, this finding would neither establish Paget disease nor exclude Toker cells since Paget cells are typically estrogen receptor negative,5 and expression in Toker cells, to my knowledge, has not been studied. I believe that the epidermal lesions in the case presented by Sahoo et al represent a lesser known pitfall in the differential diagnosis of "pagetoid" epidermal proliferations, that is to say, the clear cells of Toker. Conventional mucin stains seem to remain the most reliable adjunct technique in their differentiation.

KEVAGHN P. FAIR, DO Department of Pathology Riverside Regional Medical Center

Newport News, VA 23601-1976

1. Sahoo S, Green I, Rosen PP. Bilateral Paget disease of the nipple associated with lobular carcinoma in situ. Arch Pathol Lab Med. 2002;126:90-92.

2. Toker C. Clear cells of the nipple epidermis. Cancer. 1970;25:601-610.

3. Lundquist K, Kohler S, Rouse RV. Intraepidermal cytokeratin 7 expression is not restricted to Paget cells but is also seen in Toker cells and Merkel cells. Am J Surg Pathol. 1999;23:212-219.

4. Lloyd J, Flanagan AM. Mammary and extramammary Paget's disease. J Clin PathoL 2000;53: 742-749.

5. Cohen C, Guarner J, DeRose PB. Mammary Paget's disease and associated carcinoma: an immunohistochemical study. Arch Pathol Lab Med. 1993;117:291-294.

In Reply.-I am pleased that Dr Kevaghn Fair read our article describing an instance of bilateral Paget disease of the nipple that was associated with lobular carcinoma in situ.1 Evidently, the information we presented needs further clarification because Dr Fair has misperceived the message, and others may be in the same quandary.

My coauthors and I are fully conversant with the "lesser known pitfall," to use Dr Fair's term, of the socalled Toker cell in the differential diagnosis of mammary Paget disease. In fact, the phenomenon is so well known to us that I discuss it in my textbook,2 and I recently coauthored a report that documents the probable histogenetic origin of benign intraepithelial glandular cells that may correspond to the so-called Toker cell.3

Paget disease typically originates from intraductal carcinoma, most often of a high-grade type. The immunoprofile of Paget cells reflects this ancestry in being hormone receptor negative and HER-2/neu positive. Lobular carcinoma in situ has a different immunophenotype that was displayed by the Paget cells in our case report. A diagnosis of Paget disease arising from lobular carcinoma in situ would be very doubtful if the Paget cells fulfilled Dr Fair's requirement to be HER-2/neu positive and hormone receptor negative.

Perhaps the most convincing evidence in support of our conclusion that Paget disease arose from lobular carcinoma in situ in the case reported was the lack of E-cadherin reactivity in the Paget cells. Strong E-cadherin reactivity occurs in intraductal carcinoma and in normal ductal epithelium. This would also be expected in Paget cells arising from intraductal carcinoma and in so-called Toker cells but not in Paget disease derived from lobular carcinoma in situ.

Dr Fair also refers to our failure to report the results of periodic acidSchiff and mucicarmine stains. We did not do these tests because we preferred to use the limited material available for immunohistochemistry, and they are presently regarded as having limited usefulness for the diagnosis of Paget disease.2

PAUL PETER ROSEN, MD Department of Surgical Pathology

New York Presbyterian Hospital

Weill Medical College of Cornell University

New York, NY 10021

1. Sahoo S, Green I, Rosen PP. Bilateral Paget's disease of the nipple associated with lobular carcinoma in situ: application of immunohistochemistry to a rare finding. Arch Pathol Lab Med. 2002;126: 90-92.

2. Rosen PP. Paget's disease of the nipple. In: Rosen's Breast Pathology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:571-574.

3. Yao DX, Hoda SA, Chiu A, Ying L, Rosen PP. Intraepidermal cytokeratin 7 immunoreactive cells in the non-neoplastic nipple may represent interepithelial extension of lactiferous duct cells. Histopathology. 2002;40:230-236.

Copyright College of American Pathologists Oct 2002
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