The majority of patients with Paget’s disease present with eczema or ulceration of the nipple and many have a prolonged period of symptoms before diagnosis. It is, therefore, important to have a high index of suspicion for Paget’s when a patient presents with nipple complaints. The most common initial presentation is erythema and mild eczematous scaling which progresses to crusting, skin erosion, and ulceration, with exudation or frank discharge (Figs. 63-3, 63-4 and 63-5).

The clinical differential diagnosis of scaling skin and erythema of the nipple-areola complex in addition to Paget’s includes eczema, contact dermatitis, and post radiation dermatitis. Although bilateral Paget’s has been reported, bilateral symptoms are most consistent with eczema or contact dermatitis. Skin changes that are confined to the areola and spare the nipple are typically attributed to eczema, although they can occur rarely in Paget’s disease. The clinical
differential diagnosis has prompted initial topical steroid treatment, often with transient improvement of symptoms (3). Other patients have been treated with antibiotics. In patients who have been previously treated with breast conservation, Paget’s disease may mimic post radiation scaling. Given the infrequency of Paget’s disease in this setting, the diagnosis of Paget’s disease may be delayed. Symptom duration preceding the diagnosis of Paget’s disease is variable and averages 91/2 weeks to 27 months, with a range of 1 week to 20 years (18). In a study from the MAYO clinic, the median duration of symptoms was 6 days with a range of 1 to 80 days, clearly a unique patient population (14).

Less common diagnoses in the clinical differential of mammary Paget’s disease include nipple adenoma, papillomatosis, melanoma, Bowen’s disease, and, rarely, basal cell carcinoma, squamous carcinoma, sebaceous carcinoma, Merkel cell carcinoma, infiltrating lobular carcinoma, cutaneous T-cell lymphoma, Spitz nevus, epidermotropic metastases, alteration of keratinocytes present in 10% of normal nipples. Toker cells can be distinguished from Paget cells by their lack of nuclear pleomorphism or cytologic atypia and their absence of mucin (19).

Although most patients with Paget’s present with nipple changes, up to 50% will present with a palpable mass. The majority of patients who present with a palpable mass have an underlying invasive cancer and thus have a worse prognosis. Patients who present with a palpable mass also have a higher rate of nodal positivity (3, 20). It has also been shown that HER2-neu overexpression has been found in both DCIS and invasive disease associated with Paget’s and this may, in part, account for the poorer prognosis associated with Paget’s.

The diagnosis can be obtained by scrape cytology, a superficial epidermal shave biopsy, a punch biopsy, a wedge incision biopsy, or nipple excision (19). The ideal specimen contains adequate epidermis to provide Paget cells and a lactiferous duct. Paget cells may be distributed in a patchy fashion throughout the nipple, so additional specimen sampling may be required to secure the diagnosis.

The histologic differential diagnosis of Paget’s disease includes superficial spreading melanoma, squamous cell carcinoma in situ (Bowen’s disease) and clear-cell changes of squamous cells of the epidermis (Toker cells). The cell type can be determined by immunohistochemical studies including low-molecular-weight keratins (CK7, cellular adhesion molecule 5.2[CAM-5.2]), broad-spectrum keratins, melanoma antibodies, and mucin stains (19).

Paget cells are immunoreactive for keratins (CK7, CAM-5.2, and AE1/AE3), occasionally are immunoreactive to S100 (21), and are not immunoreactive for HMB45 or high-molecular-weight keratins (22). In one study, mucin was present in 55% of 20 patients and, thus, was not informative in 45% of patients (22). Paget cells can phagocytose melanin from adjacent epidermal melanocytes and may be mistaken for melanoma if immunohistochemistry is not performed (22). Melanomas are immunoreactive for S100, are often immunoreactive for HMB45 and are only very rarely immunoreactive for low-molecular-weight (CAM-5.2), broad-spectrum keratins (AE1/AE3), or mucin stains (22). Squamous cells are immunoreactive for low-molecular-weight keratins and broad-spectrum keratins (AE1/AE3) are infrequently immunoreactive for S100 and are not immunoreactive for CAM-5.2, HMB45, or mucin stains (50). Toker cells, or clear-cell changes of the epidermal squamous cells, are a non-neoplastic DCIS, and 1% had Paget’s disease only. Toker cells are concentrated within the basal layer or arranged into glandular structures growing up to the spinous layer. These clear cells of the nipple were first described by Cyril Toker in 1970 (7). On occasion these cells can be numerous and atypical and can be difficult to distinguish from malignant cells of Paget’s disease. In a study by Di Tommaso et al. (7), Toker cells were identified in 10.2% of patients who underwent mastectomy. In the majority of cases the Toker cells were cytologically bland and benign, while in 27.5% of cases the Toker cells were more numerous and persistent on serial sections and referred to as hyperplastic Toker cells. In 12.5% of cases the Toker cells were hyperplastic and atypical. On immunohistochemistry Toker cells were positive for estrogen receptor and progesterone receptor and negative for CD138 and p53. In comparison Paget’s cells were negative for ER and PR and positive for HER2/neu. Both Toker and Paget’s cells stained positive for cytokeratin 7 and epithelial membrane antigen and negative for p63 (7).