Synchronous Paget disease of the breast and axilla
Authors: Keiju Kobayashi, Yasuyuki Sumikawa, Yumiko Kikuchi, Yuji Kan, Junji Kato, Fukino Satomi, Hiroaki Shima, Goro Kutomi, Toshiharu Yamashita
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: Mammary Paget disease (MPD) and extramammary Paget disease (EMPD) are rare acquired skin disorders having clinical features that are similar to those of inflammatory or infectious skin disorders. MPD is mostly associated with high-grade ductal carcinoma in situ, whereas EMPD arises in areas rich in apocrine glands. EMPD is classified into primary and secondary EMPD; the latter is associated with underlying malignancy and may arise as a result of epidermal invasion of malignant adenocarcinoma cells. We report a rare case of synchronous Paget disease. A 63-year-old woman presented concomitantly with crusting and erosion of the right nipple, with brown plaques on the left axilla. Breast lesion biopsy specimen indicated underlying foci of ductal carcinoma in situ, which required total mastectomy and sentinel lymph node biopsy. Axilla biopsy specimen indicated EMPD, which required simple resection of the left axilla lesion. Both tumors were located in the epithelium (Fig 1, Fig 2), and axillary sentinel lymph node biopsy specimen yielded negative results. Because the operative margins were negative and both tumors were staged as TisN0M0, the treatment was deemed adequate. Gross cystic disease fluid protein-15 and estrogen receptor were expressed in the breast, but not in the axilla tumor cells. Immunohistochemical and pathological analyses indicated that neither of these were secondary metastatic lesions, but suggested that they arose from independent tumorigenic events.Fig 2In the axilla, atypical large cells with prominent nuclei and pale cytoplasm are present diffusely within the epidermis. (Hematoxylin-eosin stain; original magnification: ×200.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Cases of synchronous MPD and EMPD are extremely rare; to our knowledge, only 2 other cases have been reported. This report is the first to our knowledge that describes the simultaneous diagnosis of synchronous Paget disease of the breast and axilla. The origin of MPD and EMPD is controversial; it may reportedly involve the intraepithelial epidermotropic migration of carcinoma cells to the epidermis, followed by in situ neoplastic transformation of multipotential cells located in the basallayer of the lactiferous duct and epidermis.1Eusebi V. Mai K.T. Taranger-Charpin A. Tumors of the nipple.in: Tavassoli F.A. Devilee P. Pathology and genetics, tumors of the breast and female genital organs. IARC Press, Lyon2003: 104-106Google Scholar Schelfhout et al2Schelfhout V. Coene E. Delaey B. Thys S. Page D.L. De Potter C.R. Pathogenesis of Paget's disease: epidermal heregulin-α, motility factor, and the HER receptor family.J Natl Cancer Inst. 2000; 92: 622-628Crossref PubMed Scopus (85) Google Scholar reported that heregulin-α, a motility factor released by nipple keratinocytes, plays a key role in the spread of Paget cells throughout the nipple epidermis. A recent study hypothesized that Toker cells, which are intraepithelial cells with a paler cytoplasm than surrounding keratinocytes, are precursors of MPD3Marucci G. Betts C. Golouh R. Peterse J.L. Foschini M.P. Eusebi V. Toker cells are probably precursors of Paget cell carcinoma: a morphological and ultrastructural description.Virchows Arch. 2002; 441: 117-123Crossref PubMed Scopus (80) Google Scholar and EMPD.4Willman J. Golitz L. Fitzpatrick J. Vulvar clear cells of Toker: precursors of extramammary Paget's disease.Am J Dermatopathol. 2005; 27: 185-188Crossref PubMed Scopus (92) Google Scholar In our case, the development of synchronous Paget disease can be explained by the pathogenetic multicentric theory5Montgomery H. Dermatopathology. Vol 1 & 2. New York: Hoeber Medical Division, Harper & Row. 1967. pp 1007-1016.Google Scholar–a unified explanation of synchronous lesions in the vulva and axilla, and multiple lesions within a single aspect, occurring by the same mechanism. In frequently affected sites of Paget disease (eg, vulva, anus, axilla), the entire aspect assumes a “cancer readiness state.” However, it is more easily explained as some oncogenic stimulus that results in synchronous, heterochronic, and multicentric oncogenesis. First, an oncogenic stimulus elicits in situ transformation of Toker cells, after which heregulin-α induces chemotaxis of carcinoma cells; these carcinoma cells eventually migrate via the lactipherous ducts into the right nipple epidermis. A similar process may explain the initiation and spread of cutaneous EMPD in the axilla. However, based on the immunohistochemical differences, we infer that each lesion arose from distinct types of as-yet-uncharacterized Toker cells. Further study can help develop effective therapeutic strategies, particularly in patients with recurrent EMPD.