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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Cutan Pathol. Author manuscript; available in PMC 2010 September 7.
Published in final edited form as:
PMCID: PMC2935254
NIHMSID: NIHMS226282

Pigmented extramammary Paget’s disease of the axilla mimicking melanoma: case report and review of the literature

Abstract

Pigmented Paget’s disease is a rare variant which is often confused clinically and histologically with melanoma in situ. Herein, we describe a case of pigmented extramammary Paget’s disease involving the axilla of a 79 year old white male thought initially to represent malignant melanoma clinically and histologically. Review of the literature reveals that pigmented variant of Paget’s disease, either mammary or extramammary, could be initially misdiagnosed as melanoma unless this entity is considered in the differential diagnosis and additional confirmatory studies are performed.

Paget’s disease was initially reported in 1874 by Sir James Paget 1. He described eczema-like lesions involving the breast of 15 women who subsequently developed breast carcinoma. In 1889, Darier established the link between the intraepidermal Paget cell and the underlying breast adenocarcinoma 2. Paget’s disease of the nipple or mammary Paget’s disease (MPD) occurs in approximately 1–5% of all mammary carcinomas 3, 4 and rarely represents the initial presentation of an underlying breast adenocarcinoma 35. MPD occurs from an underlying intraductal breast carcinoma with intraepidermal extension without destruction of the epidermal basement membrane. Epidermotropic metastases of breast carcinoma, in contrast, are characterized by direct infiltration of the epidermis by an underlying breast adenocarcinoma via breaching the basement membrane of the epidermis with colonizing intraepithelial tumor nests. These cases also demonstrate an underlying desmoplastic dermis secondary to infiltrating tumor.

The first case of extramammary Paget’s disease (EMPD) involving the male genitalia was reported by Crocker et al in 1889 6. EMPD is an uncommon entity which may arise as a manifestation of an underlying adnexal apocrine carcinoma 79, prostatic carcinoma 1012, rectal/anal carcinoma 1315 or as a seemingly primary epidermal neoplasm without an associated carcinoma 1619.

Pigmented MPD is an uncommon variant described clinically by Cuberson et al. 20. Since then, only 34 cases of this entity have been reported in the literature 2133. The difficulty in distinguishing this entity both clinically and histopathologically from a melanocytic neoplasm has been first described by Ho et al 21. Pigmented MPD is characterized by Paget cells within the epidermis showing dusty melanin pigment and intervening dendritic melanocytes. Paget cells endocytose melanin pigment 21 making distinction from malignant melanoma in situ very difficult without the aid of immunohistochemistry. Pigmented epidermotropic metastases from a known underlying breast carcinoma may also occur rarely 21, 22, 3444, however, these cases pose less diagnostic challenges due to previous clinical history. Similar to its mammary counterpart, pigmented EMPD is characterized by intraepidermal Paget cells containing melanin pigment, surrounded by dendritic melanocytes. Pigmented EMPD is an extremely rare neoplasm with only three well documented cases published so far 45, 46.

CASE REPORT

A 79 year old white male presented to the Mohs surgery department for excision of a 6x4 cm pigmented plaque in the right axilla. Clinically the lesion was thought to represent a melanoma. The patient had no clinical evidence of an underlying neoplasm in the axilla or either breasts on palpation and there was no lymphadenopathy. A right axillary excision was undertaken and the specimen measuring 5.3 x 2.6 cm was entirely submitted for histopathological examination. The excision was characterized by a broad intraepidermal proliferation of pagetoid tumor cells with abundant pale cytoplasm and large pleomorphic nuclei (Fig 1). The pale pagetoid cells displayed small amounts of fine melanin granules within the cytoplasm (Fig 2). Interdigitating between the pagetoid cells were numerous benign, dendritic melanocytes (Fig 2). In some areas the epidermis was atrophic and the superficial dermis was remarkable for an increased number of melanophages, fibrosis and a chronic lymphocytic inflammatory infiltrate resembling dermal regression of a melanoma (Fig 3, ,4).4). Based on the histology alone, a diagnosis of melanoma in situ with prominent regression was initially considered. Further immunoperoxidase studies revealed the pagetoid cells to be positive for pancytokeratin, CK7 (Fig 6), CAM 5.2, EMA, and CEA. GCDFP15 and mucicarmine were weakly positive in the pagetoid cells. These cells were negative for CK903 (Fig 5), CK20, S100, MART1, HMB45 (Fig 7), and MITF. The populations of non-neoplastic intraepidermal dendritic melanocytes were highlighted by melanocytic markers (S100, MART1, HMB45 (Fig 7), and MITF). There was no invasive carcinoma identified on multiple levels within the dermis or subcutis and the underlying apocrine sweat glands were normal.

Fig 1
Extramammary pigmented Paget’s disease (H&E 100X) showing dendritic melanocytes and malignant Paget cells with endocytosed melanin pigment. Note the lymphocytic infiltrate in the papillary dermis simulating regression of a melanoma.
Fig 2
Extramammary pigmented Paget’s disease (H&E 400X) with brown arrows highlighting dendritic melanocytes and red arrows highlighting the malignant Paget adenocarcinoma cells with endocytosed melanin pigment.
Fig 3
Extramammary pigmented Paget’s disease (H&E 100X) showing epidermal atrophy, dermal fibrosis, inflammation and melanophages resembling regression of a melanoma.
Fig 4
Extramammary pigmented Paget’s disease (H&E 200X) showing epidermal atrophy, intraepidermal apoptotic cells, dermal fibrosis, inflammation and melanophages resembling regression of a melanoma.
Fig 5
Immunoperoxidase staining (cytokeratin CK903 (34βE12), a high molecular weight keratin; 400X), which highlights normal keratinocytes and produces a negative image of the Paget’s disease.
Fig 6
Immunoperoxidase staining (cytokeratin CK7, a low molecular weight keratin; 400X) which highlights the malignant Paget adenocarcinoma cells.
Fig 7
Immunoperoxidase staining (HMB45, a melanocytic marker; 200X) which highlights the dendritic melanocytes. Note the melanin pigment within Paget adenocarcinoma cells forming a granular cytoplasmic blush.

Integrating the histological findings and immunohistochemical profile, the diagnosis of pigmented EMPD was rendered. Based on clinical and histopathological examination, which failed to detect invasive carcinoma, this case, most likely represents an example of primary EMPD. No further treatment was given post excision with negative margins. The patient was alive and free of disease 9 months after the primary excision.

DISCUSSION

Compared to the MPD, EMPD is relatively uncommon with most cases occurring in the genital or perianal region 47. Axillary location of EMPD is very rare. A review of the literature revealed only 23 cases reported so far, the majority in Japanese population 4864 (Table 1). Out of these, 10 cases had isolated axillary involvement while 13 demonstrated simultaneous axillary and genital disease (so called triple EMPD). An additional number of 22 cases of triple EMPD were described exclusively in the Japanese literature for a total of 45 cases of reported axillary EMPD 54, 55. The cases of triple EMPD show a striking male predominance (94.3% of cases) in contrast to the cases with isolated axillary involvement which are more prevalent in females (70% of cases). Presence of an underlying carcinoma in axillary EMPD has been reported in 8 of the 23 cases (35%).

Table 1
Extramammary Paget’s Disease of the axilla

Pigmented variant of mammary or extramammary Paget’s disease is very uncommon 2033, 45, 46, 65. Out of the 34 cases reported of pigmented MPD, 5 cases (15%) were males which is unusual considering the overwhelming predominance of MPD in females (95–99%) 66, 67. The pigmented variant of EMPD is an extremely rare entity with only 3 well documented cases previously reported in the literature (Table 2) 45, 46. The 3 cases of pigmented EMPD have all occurred in females with an average age of 62 years (range 52–70 years), and have involved the vulvar or perineal region (Table 2). We present here the first, to our knowledge, histologically confirmed case of a pigmented EMPD occurring in a male patient and in an axillary location. Only one previous report by Ohno et al. describes 2 cases of axillary EMPD which had a brownish appearance on clinical examination however, there is no histologic description of pigmented Paget cells or increased number of intraepidermal dendritic melanocytes 56. All cases (including the current one) demonstrated intraepidermal Paget cells with abundant cytoplasm containing conspicuous melanin pigment. In addition, a reactive population of dendritic melanocytes was also noted in the epidermis, enveloping the tumor cells. One explanation for the pigmentation of Paget cells could be the transfer of melanin pigment from the surrounding melanocytes. Interestingly, increased uptake of melanin pigment was not observed in to the surrounding epidermal keratinocytes. In pigmented epidermotropic breast carcinoma it has been shown that basic fibroblastic growth factor (bFGF) and other chemotactic factors may aid in the transfer of pigment to the carcinoma cells from the surrounding dendritic melanocytes 38, 42. It is possible that these factors could play a role in pigmented Paget’s disease as well.

Table 2
Pigmented Extramammary Paget’s Disease in the Literature

The clinical relevance of this variant of EMPD (or MPD) resides in its potential to be misdiagnosed as malignant melanoma. The clinical differential diagnosis often includes an atypical melanocytic neoplasm or a pigmented Bowen’s disease. In this context, the presence of intraepidermal pagetoid cells containing cytoplasmic melanin pigment, in the absence of an underlying carcinoma may prompt the histological diagnosis of melanoma unless pigmented variant of Paget’s disease is considered in the differential diagnosis and additional confirmatory studies are performed. Adding to the confusion is the presence of increased number of bonafide intraepidermal melanocytes associated with the Paget cells and of dermal melanophages, inflammation and fibrosis mimicking regression of a dermal melanocytic component. With the advent of immunohistochemical studies, pigmented variant of Paget’s disease is easily diagnosed. Similar to non-pigmented counterparts, Paget cells in the pigmented variant stain positively for CK7, CAM 5.2, EMA, CEA, Her2neu, BCA-225 (BRST1), mammoglobin, and variably with GCDFP15 (BRST2) and mucicarmine. They are almost uniformly negative for melanocytic markers: S100, HMB45, MART1, and MITF.

Presence of reactive melanocytes within an epithelial neoplasm has been described in other cutaneous tumors. Melanoacanthomas represent rare benign tumors of the skin characterized by an epithelial component with the resemblance of seborrheic keratosis populated by numerous dendritic melanocytes 68, 69. Similarly, basal cell carcinomas are commonly colonized by benign reactive melanocytes 70 and rarely a bonafide melanoma is found within a basal cell carcinoma 71, 72. Melanocytic matricoma is another example of a benign adnexal neoplasm with pilar differentiation and prominent dendritic melanocytes 73.

In summary, we described the first case of pigmented extramammary Paget’s disease in a male patient and axillary location and the fourth patient in the literature with this uncommon neoplasm. We also intended to raise awareness to the potential pitfall of misdiagnosing pigmented Paget’s disease both clinically and histologically as melanoma unless this variant of Paget’s disease is considered in the differential diagnosis.

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