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Anais Brasileiros de Dermatologia

Print version ISSN 0365-0596On-line version ISSN 1806-4841

An. Bras. Dermatol. vol.81 no.5 Rio de Janeiro Sept./Oct. 2006 



Pigmented Paget's disease of the nipple mimicking cutaneous melanoma: importance of the immunohistochemical profile to differentiate between these diseases*



Tatiana Villas Boas GabbiI; Neusa Yuriko Sakai ValenteII; Luiz Guilherme Martins CastroIII

IAttending Physician of Dermatology at Hospital das Clínicas da Universidade de São Paulo (HC-FMUSP) - São Paulo (SP), Brazil
IIPhysiscian, Researcher at the Laboratory of Medical Investigation 53 at Hospital das Clínicas da Universidade de São Paulo (HC-FMUSP) - São Paulo (SP), Brazil
IIIPhD, Physician, Supervisor of the Department of Dermatology at Hospital das Clínicas da Universidade de São Paulo (HC-FMUSP) - São Paulo (SP), Brazil

Mailing address




Pigmented mammary Paget's disease is a rare dermatosis, with approximately 12 reported cases in the literature, which can mimic cutaneous melanoma both clinically and histologically. As for classical mammary Paget's disease, the pigmented variant is associated with neoplasia of the breast, originating mainly from intraductal mammary carcinoma that extends to the epidermis of the nipple and areola through a lactiferous duct. Physiopathology of hyperpigmentation remains unknown. We present a 49-year-old female patient who presented with a pigmented lesion of the nipple suspected of melanoma. Histological examination was not sufficient to confirm diagnosis. Immunohistochemical examination confirmed the diagnosis of Paget's disease. Although uncommon, pigmented Paget's disease must be reminded as a differential diagnosis of melanoma in pigmented lesions of the nipple, in both genders.

Keywords: Immunohistochemistry; Melanoma; Paget's disease, mammary




Mammary Paget's disease (MPD) presents as an eczema-like lesion in nipple and areola skin, usually associated to intraductal mammary carcinoma, which extends to the epidermis through a lactiferous duct, or to invasive carcinoma, which affects the epidermis by continuity through the dermis.1 Pigmented variant of MPD is rare, having been described in patients of both genders, with little more than 10 described cases in the literature.1-10 The presence of a pigment makes MPD a likely mimicker of cutaneous melanoma (CM), both clinically and histologically.1-10 Performance of an immunohistochemical (IH) study is often necessary for establishing the correct diagnosis.11,12 Below, we present the case of patient who presented a pigmented lesion in the nipple, whose initial diagnostic hypothesis of CM could only be discarded after an IH study, which allowed diagnosing pigmented MPD.



PForty-nine-year old white female patient, born in and coming from São Paulo, was seen in 1994 at the Dermatology Outpatient Clinic at University of São Paulo Medical School Hospital, complaining of a hyperpigmented, non-painful lesion located in the left nipple that had appeared six months before, with gradual growth ever since. Upon dermatological examination, a slight increase in nipple volume could be noted, along with a well-delimited brownish-darkened spot, with irregular borders and erythematiccrustous center, measuring 0.5 x 0.5 cm (Figure 1). On palpation, no breast masses or axillary lymph node enlargements could be noted. Hypothesis of CM was considered, and the patient was submitted to nipple excision, and material was sent for histological studies, which revealed proliferation of large atypical clear cells, isolated or grouped, sometimes with melanin- rich cytoplasm, located between squamous cells, in all levels of the epidermis. In upper dermis, there was a band-like lymphocyte and plasma cell infiltrate (Figures 2 and 3). Since these findings may be present both in Paget-like melanoma and pigmented Paget's disease, and clear differentiation between the two was not possible, we proceed to IH study. Assessed antigens were: AE1 + AE3, CEA, EMA and S100. The first three had positive results in intra-epidermal neoplasic cells, and S100 was negative (Table 1). It was thereby possible to establish diagnosis of Paget's disease and discard the possibility of CM. A later investigation revealed the presence of intraductal mammary carcinoma, and the patient decided to have her oncological treatment elsewhere, were she underwent quadrantectomy and axillary emptying, followed by radiation therapy.










Numerous melanocytic and non-melanocytic lesions may present with clinical patterns that mimic CM, thus being crucial differential diagnoses for a proper treatment. Among them, are included congenital and acquired nevi, Spitz's nevus, Reed's nevus, basocellular carcinoma, seborrheic keratosis, simple and solar lentigo and tinea nigra.

Pigmented MPD is an uncommon clinicopathological variant of intraductal mammary carcinoma or of invasive mammary carcinoma, which extends up to nipple and areola epidermis. Because of the presence of melanic pigment, such lesions can mimic CM, both clinically and histologically.13 For this reason, despite is rarity, it should be included in the list of CM differential diagnoses, especially those lesions located in the nipple and mammary areola.

Requena et al.1 reviewed and reclassified cases of pigmented MPD, describing three others. The also reported six cases of pigmented metastases of epidermotropic carcinoma. Among the 12 reports of MPD found in the literature,1-10 six occurred in males and six in females. Women age ranged from 42 to 84 years, with an average of 62 years, and men ranged from 47 to 83 years of age, averaging 67 years. IH was performed in order to differentiate from CM in most of these cases, and histological findings were very similar, with the observation of affection of the dermoepidermal junction in all of them. Eight of them presented proliferation of dendritic melanocytes among Paget cells; in two of them melanin was found within neoplasic cells. Two presented both melanocyte proliferation and melanin within Paget cells.

Some theories seek explanations for the origin of the pigment in PD, namely: a) proliferation of dendritic melanocytes containing abundant melanin, stistimulated by some chemotactic factor produced by neoplasic cells; b) Paget cells phagocyted melanin from melanocytes, in association to a blockage of pigment transference from melanocytes to keratinocytes. However, its exact physiopathology remains unknown to the present date.1

Differential diagnosis between Paget-like CM and pigmented MPD can be difficult, and demands a correct application of histological and immunohistochemical criteria.11,12

There are subtle differences between histological findings from the two lesions.1,11,13 In in situ CM, melanocytes spread through all levels of the epidermis and isolated at the dermoepidermal junction are observed. On the other hand, in pigmented MPD, isolated cells or Paget cell nests are seen in the suprabasal layers, without the junctional component. In in situ CM, dermal component is not noted, whereas in pigmented MPD, often an invasive or intraductal mammary carcinoma can be observed in the underlying dermis.13 Special staining techniques also allow for the differentiation. Paget cells are PAS-positive, diastase-labile, and contain acid mucine, which does not hold for CM. In the present case, upon review of the slides, a ductal carcinoma was noted, which reinforced the diagnosis of pigmented MPD. Nevertheless, since CM may exceptionally exist in the areola,14 and since a collision between CM and ductal mammary carcinoma has been described,15 an IH is imperative for establishing a definite diagnosis. When performing IH studies is not possible, special stains for glycogen and acid mucine, as seen previously, may be clarifying.

IH profile will favor either CM or MPD.12 In the present case, were assessed cytokeratins AE1 + AE3, carcinoembrionary antigen (CEA), epithelial membrane antigen (EMA) and protein S100.

Intra-epidermal Paget-like melanocytes present in CM usually express strong positivity for protein S100, HMB45, melan-A and MITF, unlike for cytokeratins, CEA and EMA. Protein S100 has a high sensitivity for CM, albeit with low specificity, thus, when it is negative, there is no need in assessing HMB-45 or melan-A, which are more specific.

Intra-epithelial cells present in mammary carcinoma, on the other hand, are generally negative for protein S100, and, in the rare positive cases, simultaneous expression of cytokeratins, CEA and EMA would still allow distinction from CM.

In the present IH study, antigens AE1 + AE3 were positive in intra-epidermal neoplasic cells, as well as antigens CEA and EMA, and S100 was negative (Chart 1). This IH profile seals the diagnosis of pigmented MPD.



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Mailing address:
Tatiana Villas Boas Gabbi
Divisão de Clínica Dermatológica do Hospital das Clínicas da FMUSP
Av. Enéias de Carvalho
Aguiar, 255 - 3º andar
05403-000 - São Paulo - SP
Tel/Fax: +55 11 5044-1008 / 3069-6450

Received on March 26, 2004.
Approved by the Consultive Council and accepted for publication on June 01, 2005.



Conflict of interests: None
* Work done at Department of Dermatology at Hospital das Clínicas da Universidade de São Paulo (HC-FMUSP) - São Paulo (SP), Brazil.

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