Histol Histopathol (2009) 24: 367-376 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review An overview of the pale and clear cells of the nipple epidermis M.F. Garijo, D. Val and J.F. Val-Bernal Department of Anatomical Pathology, Marqués de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain Summary. The stratified squamous epithelium of the exterior. In the non-lactating breast these duct openings nipple-areola complex may contain pale or clear cells are usually filled with plugs of keratin. The nipple and including: Paget’s disease cells (PDCs), Toker cells areola are covered by keratinizing stratified squamous (TCs), and so-called clear cells (CCs). Paget’s disease is epithelium similar to that seen in the epidermis an uncommon presentation of breast carcinoma. PDCs elsewhere in the body. The collecting ducts show a are large, atypical, have abundant, pale-staining double epithelial and myoepithelial lining. The cytoplasm that may contain mucin secretion vacuoles epithelium is columnar and the myoepithelial cells lie and bulky heterochromatic nuclei. They are commonly between the epithelial layer and the basal lamina. A concentrated along the basal layer and stain for EMA, cross section of the major ducts shows an irregular, CAM5.2, cytokeratin 7, and HER2/neu oncoprotein. TCs pleated or serrated outline and an investment with are bland cells with roundish and scant chromatin nuclei. muscular tissue. The areola dermis contains numerous They are found incidentally and are reactive for EMA, sebaceous glands. Some of them open directly onto the CAM5.2, and cytokeratin 7, but show negativity for surface, whereas others drain into a collecting duct or HER2/neu oncoprotein. So-called CCs show varied share a common ostium with a lactiferous duct. morphology, are found incidentally, and have been Diverse types of pale or clear cells are reported in variably interpreted by different authors. The majority of the epidermis of the nipple-areolar complex. Most cells that have been called epidermal CCs fit the features common cells include the following: (1) Paget’s disease of pagetoid dyskeratosis. These cells are reactive for cells; (2) Toker cells; and (3) so-called epidermal clear high molecular weight cytokeratin. Other CCs showing cells or epidermal clear cell change, terms which have signet-ring morphology present negativity for mucins been used and made popular by numerous authors (Page and correspond to a fixation artefact. and Anderson, 1987; Rosen and Oberman, 1993; Rosen, 1997; Tavassoli, 1999; Manavi et al., 2002; Bane et al., Key words: Nipple, Pagetoid dyskeratosis, Paget’s 2007; Li and Urmacher, 2007; Collins and Schnitt, 2007; disease, Toker cells, Clear cells, Signet-ring cells, Breast Rosen, 2009). These clear keratinocytes have been carcinoma, Immunohistochemistry analyzed and subjected to a thorough study by our group (Garijo et al., 2008). In this review, we briefly summarize the main Introduction features of the pale and clear cells of the epidermis of the nipple with special reference to the so-called The nipple-areolar complex forms a disc of epidermal clear cells and their differential diagnosis. mammary skin showing increased melanic pigmentation. The nipple is centrally placed surrounded by the areola, Paget’s disease cells and variably elevated above it. In the tip of the nipple there are 15-20 orifices which lead into the collecting Alfred Velpeau (1854) was the first acknowledged ducts and lactiferous sinuses which deliver milk to the author to write on an intriguing crusting lesion, located on the nipple of two patients, that now bears the name of Offprint requests to: Dr. J. Fernando Val-Bernal, Departamento de Paget’s disease. However, the distinguished French Anatomía Patológica, Hospital Universitario Marqués de Valdecilla, surgeon did not follow-up his patients and he did not Avda. Valdecilla s/n, ES-39008 Santander, Spain. e-mail: establish any relationship between the nipple lesion and [email protected] the development of breast carcinoma. Sir James Paget 368 Pale and clear cells of the nipple epidermis (Paget, 1874) reported an eruption on the nipple and acantholysis. The epidermis commonly exhibits areola, with features of “ordinary chronic eczema” or hyperkeratosis and acanthosis. The underlying “psoriasis,” that was followed by cancer of the breast lactiferous ducts contain carcinoma cells cytologically within at the most two years. The superficial lesion of similar to the cells invading the epidermis. The the nipple induced the underlying mammary cancer. superficial dermis is usually infiltrated by a moderate-to- However, Paget did not describe the histopathology of intense lymphocytic reaction. the disease, so the use of the term Paget’s cells for An anaplastic form of Paget’s disease has been describing the malignant cells of the nipple epidermis is reported (Rayne and Santa Cruz, 1992). Pigmented inappropriate. mammary Paget’s disease is another form that must be George Thin (1881) who had early recourse to differentiated from melanoma of the nipple (Requena et microscopy, is credited to be the first in illustrating the al., 2002; Mitchell et al., 2006). Local production of malignant cells of the nipple epidermis after studying melanocytic chemotactic factor by neoplastic cells of the four specimens exhibited in the pathological museum of breast carcinoma when they reach the epidermis has the British Medical Association at Cambridge. Thin been postulated as the cause of pigmentation. Another suggested that the disease should be called “malignant possibility is the phagocytosis or transfer of melanin papillary dermatitis of the nipple” and concluded that the from melanocytes (Requena et al., 2002). malignant dermatitis had neither the symptoms nor the The underlying carcinoma, in situ or infiltrating, is pathological anatomy of any known skin disease. He present in more than 95% of the cases and it is in most believed that the secretions emerging from the mammary cases of ductal type. Intraductal carcinoma ducts injured the epidermis and that this process induced caracteristically has a comedo or solid growth pattern. the underlying carcinoma (Thin, 1881). The concept that Very rarely, lobular intraepithelial neoplasia or Paget’s disease represents the spread of carcinoma cells infiltrating lobular carcinoma is encountered (Sahoo et into the epidermis from an underlying breast carcinoma, al., 2002). through the duct system, was first advanced in 1904 by In the rare cases of Paget’s disease without an the Stockholm internist Jacobaeus (Jacobaeus, 1904) underlying carcinoma, it is suggested that the disease is a based on histological study of three cases. Muir (1927) carcinoma in situ arising from intraepidermal duct cells confirmed these observations and also described the (Toker cells) or from basal multipotential cells with Paget’s disease secondary to an infiltrating primary capacity of glandular differentiation (Eusebi et al., carcinoma of the breast extending directly into the 2003). epidermis and accompanied by the intraepidermal spread Special stains often, but not invariably, detect mucin of the malignant cells (Fig. 1A). in the cytoplasm of intraepidermal cells. PAS after Paget’s disease is an uncommon presentation of diastase, Alcian blue, and mucicarmin may all be in use. breast carcinoma that accounts for 1-4,3% of all breast Immunohistochemically, Paget’s disease cells show carcinomas (Bane et al., 2007). The disease can be reactivity for epithelial membrana antigen (EMA), low observed in 1 of 3 ways: (a) in conjunction with an molecular weight cytokeratin (LMWCK), cytokeratin 7 underlying ductal carcinoma in situ (DCIS), (b) in (CK7), carcinoembryonic antigen (CEA) polyclonal and conjunction with an underlying invasive carcinoma, or HER2/neu oncoprotein (Fig. 1D), and they are negative (c) alone without any underlying carcinoma. The tumor for high molecular weight cytokeratin (HMWCK), is usually centrally located, within 2 cm of the areola, estrogen receptor, progesterone receptor, HMB-45 and but occasionally can be more peripherally sited. In our Melan-A (Garijo et al., 2008). series, the mean age of the patients was 61 years (range, At present the origin of Paget’s disease cells is 38 to 84 years). Clinically, the lesion is centred on the controversial although there is a widespread opinion that nipple and may extend to the areola. In advanced cases these cells result from an epidermotropic migration of the lesion involves the skin surrounding the areola. The neoplastic elements from an underlying ductal nipple may appear normal, thickened, erythematous, carcinoma. De Potter et al. (1994) concluded that Paget’s eczematoid, hemorrhagic, pigmented, erosive, ulcerated, disease cells spread through the epidermis due to the weeping or crusted. The lesion may be associated with motility induced by a chemotactic factor, which is pruritus, burning sensation, tingling or pain. released by epidermal keratinocytes and whose influence Microscopically, cells invading epidermis are large, and is mediated by the HER2/neu oncoprotein. The motility they have abundant, pale-staining cytoplasm (Fig. 1B) can be inhibited in vitro using monoclonal antibodies that may contain mucin secretion vacuoles. Nuclei are against the extracellular domain of the HER2/neu bulky, atypical sometimes with prominent nucleoli (Fig. oncoprotein. However, Morandi et al. (2003) using 1C). These cells occur singly, but more commonly form methods