Pigmented mammary Paget’s disease: not a melanoma

Histopathology 2009, 54, 614–617

Lesson of the month Pigmented mammary Paget’s disease: not a melanoma

for an area of hyperpigmentation in the nipple region, which was completely excised following initial biopsy.

DOI: 10.1111/j.1365-2559.2009.03267.x

h i sto p a t h ol o g y case summary The patient was a hitherto fit and well 57-year-old Chinese woman with a history of a pigmented plaque over her nipple and areola for 12 months, which had been slowly increasing in size. Physical examination, including breast examination, was unremarkable except A

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The biopsy and resection specimens demonstrated similar histological features. Sections showed an intra-epidermal proliferation of large atypical tumour cells, with round or oval nuclei and prominent nucleoli arranged either as solitary units or as nests along and

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Figure 1. Pigmented variant of Paget’s disease of the nipple. Note large epithelioid cells, either clear or amphophilic cytoplasm appear singly or in clusters in the epidermis.  2009 The Authors. Journal compilation  2009 Blackwell Publishing Limited.

Lesson of the month

above the basal layer. These cells displayed clear and focally eosinophilic cytoplasm, sometimes with copious melanin (Figure 1). Extension of tumour cells into skin appendages was noted. Unequivocal dermal invasion was not identified, although assessment was hindered by the irregularity of the dermoepidermal junction and the presence of numerous melanophages and inflammatory cells in the dermis. immunohistochemistry The tumour cells were strongly positive for Cam5.2, cytokeratin (CK) 19 and epithelial membrane antigen (EMA). CK7 was positive in the neoplastic cells at the periphery of the lesion. Oestrogen receptor was weakly and very focally positive. Immunonegativity was seen for CD5, CD68, gross cystic disease fluid protein (GCDFP)-15, CD1a and cerb-B2. Interpretation of S100, Melan A and HMB45 was difficult due to the abundant melanin pigment present in tumour cells, although on balance these immunostains were considA

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ered to be negative (Figure 2). The diagnosis was pigmented mammary Paget’s disease (MPD). comment Paget’s disease of the nipple (MPD) was first described as a clinical entity by Paget in 1874.1 A comprehensive review by Treves2 drew attention to earlier reports of dermatitis of the nipple ⁄ areola that could precede cancer of the female breast (Velpeau in 1840) and even earlier reports of Paget’s disease in the nipple of a man by John of Arderne early in the 14th century. Extramammary Paget’s disease (EPD) histologically showing characteristic Paget cells was first described by Radcliffe Crooker in 1889 (according to Prose and Hyman).3 Pigmented MPD is a rare clinicopathological variant4–18 of Paget’s disease of the nipple. The diagnosis of this variant is difficult clinically, even with advanced non-invasive diagnostic techniques such as dermoscopy and in vivo reflectance-mode confocal microsB

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Figure 2. Immunohistochemistry of pigmented variant of Paget’s disease of the nipple. A, Cam 5.2. B, Melan A. C, Cytokeratin 7. D, Gross cystic disease fluid protein-15.  2009 The Authors. Journal compilation  2009 Blackwell Publishing Ltd, Histopathology, 54, 614–617.

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copy,11 which have been demonstrated to improve diagnostic accuracy in dermatological oncology.11,19–27 Clinically and histologically it can mimic melanoma.28 The final diagnosis is generally confirmed using immunohistochemistry, demonstrating the expression of cytokeratins, including CK7, by tumour cells. Rarely, Paget’s diseases of the nipple can be CK7).7 In this case, the lesion was histologically strongly pigmented, and there was prominent melanocytic hyperplasia. Most of the pigmentation can be attributed to melanocytic colonization of the tumour. Transfer of melanin to the tumour cells may explain positivity of some tumour cells for melanin-associated proteins such as HMB-45, similar to the phenomenon of melanophages sporadically expressing melanocyte-related markers due to phagocytosis of premelanosomes. Requena et al.18 reviewed three cases of the pigmented variant of MPD, all of which had associated intraductal carcinoma, emphasizing the importance of establishing the correct diagnosis of pigmented MPD versus melanoma in situ. In melanoma in situ, the nests (nests are defined as clusters of melanocytes, whereas pagetoid proliferation is defined as a discohesive singlecell growth throughout the entire epidermis) of neoplastic melanocytes and single melanocytes are typically present along the dermoepidermal junction and scattered throughout all levels of the epidermis, but almost always are in direct contact with the papillary dermis, whereas the neoplastic cells of MPD tend to be scattered throughout the suprabasal layers of the epidermis. Moreover, immunohistochemically intraepidermal pagetoid melanocytes in both primary and epidermotropic melanoma usually strongly express Melan-A, S100 protein, and HMB-45, whereas they do not typically express cytokeratins and ⁄ or EMA. Conventional dogma of today still teaches that mammary and extramammary Paget’s disease of the skin represent two separate diseases. MPD is said to emanate from the ‘migration’ of neoplastic cells into the epidermis from an underlying carcinoma, whereas EPD is thought to originate within the epidermis by the proliferation of primitive native stem (basal) cells with the potential for glandular differentiation.29,30 A somewhat iconoclastic and alternative view of the topic holds that both forms of pagetoid proliferation derive from the latter pathogenic mechanism, as cited traditionally only in connection with EPD, and that therefore MPD and EPD can be considered as a unified disorder. Although some support for this opinion comes from the observation that approximately 3–5% of MPD cases are not found to be associated with an underlying carcinoma, despite extensive sampling of the breast,31,32 this issue remains controversial. Both

MPD and EPD are typically of apocrine origin,33 with GCDFP-15 protein expression in the majority of cases. Occasionally, other cellular lineages are manifested in Paget’s disease, including sebaceous, eccrine, and visceral-enteric pathways. In summary, the pigmented variant of MPD is a wellknown mimic of melanoma, potentially leading to misdiagnosis. Clinically, hyperpigmentation is the most striking feature and the final pathological diagnosis is dependent on immunohistochemical expression of cytokeratins by tumour cells. Wael I Al-Daraji Anne Marie O’Shea Lai Meng Looi1 C H Yip2 Ian Ellis Histopathology Department, City Hospital, University of Nottingham, Nottingham, UK and Departments of 1Pathology, and 2Surgery, University of Mayala, Kuala Lumpur, Malaysia WIAD and AMO contributed equally to this work.

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 2009 The Authors. Journal compilation  2009 Blackwell Publishing Ltd, Histopathology, 54, 614–617.