Pigmented Paget's disease of nipple: A diagnostic challenge on cytology.

Paget's disease is a rare form of breast cancer often associated with an underlying ductal carcinoma in situ or invasive cancer. A 47-year-old female patient presented with bleeding from the left nipple since 4 months. Imprint smears from the lesion showed pleomorphic malignant epithelial cells in singles and in small clusters, many of them containing dark brown cytoplasmic pigment granules. There was no palpable breast lump or axillary lymph node enlargement. Based on the physical examination and cytological features, a diagnosis of malignant melanoma with a differential of Paget's disease of the nipple was made. Biopsy showed features of Paget's disease and immunohistochemistry was positive for HER-2/neu, negative for HMB-45 and S-100, thus confirming the diagnosis. This case has been reported to emphasize the fact that Paget's cells can contain imbibed brown cytoplasmic pigment and should not be mistaken for melanoma cells on cytology smears.

Introduction

Paget's disease of nipple is an uncommon form of breast cancer characterized by infiltration of nipple epidermis by adenocarcinoma cells. It accounts for 1-4% of breast cancer and is most often associated with an underlying invasive or in situ ductal carcinoma.[1] The lesion is often mistaken for eczema clinically. Early and accurate diagnosis of Paget's disease by means of cytology enables organ conserving surgery, especially when the lesion is confined to the epidermis of nipple.[2]

Case Report

A 47-year-old female presented with a pigmented plaque over left nipple since 4 months. There was associated bleeding and pruritus. On examination, there was no palpable mass in the underlying breast parenchyma or axillary lymph node enlargement. A clinical diagnosis of eczema was made and cytological study was requested to rule out melanoma. Imprint smears from the eczematous plaque were prepared. The smears showed clusters and singly scattered, pleomorphic malignant epithelial cells exhibiting, hyperchromatic nuclei, with moderate amount of eosinophilic, vacuolated cytoplasm, with dark brown pigment [Figure 1a]. Extracellular deposits of such pigment granules were also noted in a hemorrhagic background. A cytological diagnosis of malignancy, possibly malignant melanoma of the nipple with a differential diagnosis of pigmented Paget's disease was made.

Figure 1

(a) Cytology showing neoplastic cells containing cytoplasmic brown pigment (H and E, ×400). (b) Vacuolated tumor cells containing brown pigment on histopathology (H and E, ×400). (c) Immunohistochemical stain showing strong membrane positivity of tumor cells for HER-2/neu(IHC, ×400)

Mammography and magnetic resonance imaging (MRI) were performed to rule out any breast mass. Both investigations were negative.

Following this, excision biopsy of the lesion was carried out and subjected for histopathological examination. The gross specimen was an elliptical bit of skin with a blackish elevated lesion measuring 1 × 0.5 × 0.2 cm. The microscopic sections showed epidermal expansion with clusters of large round to ovoid cells with clear to eosinophilic cytoplasm, pleomorphic nuclei, and prominent nucleoli devoid of intercellular bridges [Figure 1b]. Such cells were also seen singly within the malpighian layer. Intracytoplasmic melanin pigment granules were noted in many cells and the melanin nature was confirmed by Masson's Fontana stain. Sub-epithelial tissue exhibited lymphocytic infiltration with pigment incontinence; however, tumor infiltration was not seen in the sub-epithelium. A periodic acid-Schiff (PAS) stain was done which was also negative.

Immunohistochemistry was carried out and showed strong membrane positivity of tumor cells for HER-2/neu and negative for both S-100 and HMB-45 [Figure 1c], thus excluding melanoma. A final diagnosis of Paget's disease of nipple was made. No recurrence was reported after 1-year follow-up.

Discussion

Paget's disease of nipple was named after Sir James Paget, who described eczematous eruption of nipple and areola, progressing to cancer of the mammary gland in 1874. It is an uncommon presentation of breast cancer, accounting for 1-3% of all new breast cancer diagnosis.[3] The presenting age ranges from 24 to 84 years with a mean age at diagnosis being 55 years.[4]

Common clinical manifestations include erythema and scaling or eczematous changes in the nipple which may later progress to ulceration, erosion, and frank destruction. There may be associated bloody discharge, pruritus, nipple retraction, or a palpable mass. Uncommonly, patients may present with only a hyperpigmented plaque over the nipple, causing a clinical diagnostic dilemma between Paget's disease and melanoma,[56] as in our case. Melanoma of the nipple is very rare, with only few cases being reported.[6]

Paget's disease most commonly occurs in conjunction with an underlying invasive or intraductal carcinoma, the pathogenesis is explained by epidermotropic theory of migration of malignant cells of invasive ductal carcinoma to the epidermis. Very rarely, Paget's disease can occur in the absence of intraductal or invasive carcinoma, as a result of in situ malignant transformation or degeneration of existing cells of nipple epidermis[7] (as in our case).

Hence, it is essential to carefully look for in situ or invasive carcinomas in such cases where the lump is not palpable by means of mammography[2] or MRI.

On cytology, Paget's cells are large with abundant pale cytoplasm, irregular nuclei, prominent nucleoli, and occur in singles or in small clusters in a background of inflammatory cells and debris.[8] Melanoma cells, on the other hand, contain highly atypical hyperchromatic nuclei with macronucleoli. They may be spindle shaped, bi- or multinucleated. The melanin nature of the cytoplasmic pigments can be confirmed by Masson Fontana's staining. However, Paget's cells may also very rarely exhibit intracytoplasmic melanin granules transferred from neighboring melanocytes by the process of cytocrinia,[9] making its diagnosis difficult. Characteristic histology in Paget's disease is the presence of malignant epithelial cells occurring as clusters in basal portion of the epidermis and infiltrating as single cells in the upper layers. Histochemical stains for mucin, if positive, are useful in diagnosis of Paget's disease. However, a negative result does not exclude mammary Paget's disease. In the present case, Paget's cells were PAS negative.

Immunohistochemistry of Paget's disease is positive for CK7, EMA, CEA, and mucin, whereas Melan A, HMB45, and S100 are negative in Paget's disease but positive for melanoma.[6] Paget's cells express HER2/neu receptors and c-erb B-2 oncogene indicating common histological and biological origin with breast carcinoma.[2]

Paget's disease, if left untreated, spreads to areola and other regions of breast. Hence, an early and prompt diagnosis using immunocytochemical techniques can enable organ conserving surgery.[10] Treatment with cone excision of nipple–areola complex results in survival rates similar to those with mastectomy.[11]

The present case highlights the cytological challenges in interpreting an innocuous hyperpigmented eczematous lesion of nipple in the presence of cytoplasmic pigmentation.