Mammography
Radiographic changes seen in mammary Paget disease (PD) include the following:
- Subareolar microcalcifications (helpful in evaluating and locating clinically occult, nonpalpable underlying breast carcinoma)
- Architectural distortion
- Thickening of the nipple and the areola (reflecting edema)
- Nipple changes (in a minority of patients)
About 50-70% of patients with biopsy-proven mammary PD show positive findings on mammography; image-guided biopsy is assisted by positive results on mammography.
Ninety-four percent of patients with biopsy-proven PD as the only physical finding had an underlying carcinoma, and nearly 60% had unifocal disease. However, negative preoperative mammography findings did not reliably exclude an underlying carcinoma. Statistical evidence suggests that in the setting of negative mammography findings, magnetic resonance imaging (MRI) of the involved breast can detect otherwise occult PD and thus facilitate treatment planning for patients with PD.[16]
Tissue Analysis
Scrape cytology
Scrape cytology has been suggested as a noninvasive and reliable, rapid diagnostic screening method for mammary PD. Scrape the affected area of the nipple with a glass slide or a wooden spatula and stain the smears with Papanicolaou or Giemsa stain. The presence of large cells with a high nuclear-to-cytoplasmic ratio, occasional acinar formation, and intracytoplasmic vacuoles is diagnostic for malignant Paget cells.
Using histochemical staining methods for the presence of epithelial mucin and immunoperoxidase stains (eg, anti-carcinoembryonic antigen [CEA]) enhances cytologic results and confirms the diagnosis of mammary PD. Drying artifact on the microscopic slides may produce both false-positive and false-negative results.
Biopsy
Punch, wedge, or excisional biopsy of the lesional skin of the nipple-areola complex to include the dermal and subcutaneous tissue for detailed microscopic examination provides an adequate sample for the accurate diagnosis of mammary PD.
Histologic Findings
Common histologic features of Paget disease
Several variants of PD of the breast show identical histopathologic features. The epidermis exhibits hyperkeratosis, parakeratosis, and acanthosis. Infiltration occurs by variable numbers of large, rounded or ovoid, signet-ring forms and sometimes mucin-positive, malignant-appearing tumor cells that are present in all layers of the epidermis. The tumor cells contain abundant pale-staining or sometimes eosinophilic cytoplasm and large vesicular-to-hyperchromatic nuclei with prominent nucleoli (see the images below).
Photomicrograph of mammary Paget disease lesion. Note nests of malignant Paget cells predominantly involving lower layers of epidermis. Cytoplasm of tumor cells contains abundant pale-staining, granular, mucinous material. Occasional small glandular structures can be seen within malignant cell nests (hematoxylin-eosin, ×100). 
Composite photomicrograph of mammary Paget disease depicting nests, islands, and individual tumor cells in epidermis (left; hematoxylin-eosin, ×250), along with tumor cells stained positive for carcinoembryonic antigen (CEA) (right; immunostain with anti-CEA, ×250). The malignant cells infiltrating the epidermis of the nipple are CK7 positive, exhibiting a typical invasive “shotgun” pattern. Epidermal keratinocytes are negative for CK7.
Mitotic figures are occasionally identified. The cytoplasm may contain periodic acid-Schiff (PAS)–positive, diastase-resistant granules, indicating the presence of neutral mucopolysaccharides. Less often, acid mucopolysaccharides (sialomucin) may be identified by Alcian blue reaction at pH 2.5, but not at lower pH (0.4) or by aldehyde Fuchsin.
Melaninlike pigment that is dihydroxyphenylalanine (DOPA)-negative is occasionally noted. Paget cells are devoid of intercellular bridges on hematoxylin and eosin (H&E)–stained sections. They often compress the basal keratinocytes that lie between the Paget cells and the papillary dermis. Paget cells are arranged singly or in a nested pattern, with occasional ductal formations.
Masses of large cells with numerous mitoses are observed in the advancing border of mammary PD. In the ulcerated lesions of mammary PD, the epidermis is totally replaced by Paget cells. Paget cells do not invade the dermis directly; however, they frequently extend along the follicular and sweat gland epithelia.
A large biopsy or excision may demonstrate the presence of epidermal Paget cells and an underlying infiltrating or intraductal carcinoma of the breast. The epidermal involvement by Paget cells is not always immediately adjacent to an underlying breast carcinoma.
Types and characteristics of Paget cells
The several histologic variants of PD are as follows:
- Adenocarcinomalike cell type - Cells are columnar similar to an adenocarcinoma metastasizing to the skin.
- Spindle cell type - Tumor cells are angular, elongated, arranged in a nested pattern, and grow in compact masses.
- Anaplastic cell type - Cells resemble those seen in Bowen disease. Pleomorphic tumor cells may be present in a full-thickness, distorted epidermis; a nested pattern is usually not present. Apoptotic (necrotic) tumor cells, mitotic figures, and multinucleated tumor cells are common. Acantholysis with cleft formation are helpful features. Positive immunoperoxidase staining for the presence of markers, such as CEA, epithelial membrane antigen (EMA), and c-erb B-2, favors a diagnosis of mammary PD and militates against a diagnosis of Bowen disease.
- Acantholytic cell type - This subtype may overlap with the anaplastic variant. Prominent acantholysis may lead to the misinterpretation of mammary PD as an acantholytic disorder involving the skin of the nipple and the areola.
- Pigmented cell type - Rare cases of pigmented mammary PD have been reported.[17] The pigmented Paget cells are DOPA negative. The melanin pigment is transferred from the melanocytes into the malignant Paget cells. The number of melanocytes is not increased in these lesions. A reticulated variant of pigmented PD has recently been described.[18]
Tumorous Paget cells are negative for estrogen and progesterone receptor sites, though one half of breast carcinomas are positive for these hormone receptors. In cases of positive estrogen and progesterone receptors in an underlying breast carcinoma, the overlying Paget disease is negative for these receptors. Paget cells are negative for mammary gland markers, such as lysozyme, k-casein, and alpha-lactalbumin.
The dermis contains a dense infiltrate of lymphocytes, histiocytes, plasma cells, and occasionally eosinophils.
The ultrastructural features of Paget cells are those of glandular epithelial cells. The pale cytoplasm of Paget cells lacks the dense CK filaments and keratohyalin granules of keratinocytes. Numerous free ribosomes, lysosomes, enlarged mitochondria, prominent smooth and rough endoplasmic reticulum, tonofilaments, Golgi membranes, and microvilli are present on the cell membrane (see the image below).
Low-power view of transmission electron micrograph displaying malignant Paget cells in lower layer of epidermis. Note large Paget cell containing ovoid nucleus (N), scanty nuclear chromatin, large nucleolus, and abundant pale-staining cytoplasm with smooth and rough endoplasmic reticulum (arrow), scattered enlarged mitochondria, free ribosomes, and lysosomes. No desmosomal attachments are seen between Paget cells and adjacent keratinocytes. Tonofilaments are seen in keratinocytes (uranyl acetate and lead citrate, ×5,500). Desmosomal attachments between Paget cells and adjacent keratinocytes are fewer and smaller than those between keratinocytes. Paget cells do not directly contact the basal lamina, and no gap junctions or tight junctions are present.
The cytoplasm of Paget cells contains numerous rounded, membrane-bound mucin granules of varying electron density (see the image below).
Cytoplasm of malignant Paget cell is packed with numerous rounded, membrane-bound mucin granules with various electron densities (uranyl acetate and lead citrate, ×12,000.) Histologic features distinguishing Paget disease
The intraductal carcinoma underlying mammary PD typically shows distended lactiferous ductal lumen by pleomorphic tumor cells with hyperchromatic nuclei, a high nuclear-to-cytoplasmic ratio, and a frequent gland-in-gland (cribriform) pattern (see the image below).
Photomicrograph of intraductal carcinoma of breast underneath Paget disease of nipple in 56-year-old woman. Note expansion of ductal lumen, which is filled with irregularly sized tumor cells of ductal epithelial origin. Nuclear hyperchromatism and gland-in-gland (cribriform) pattern are evident. Tumor was detected by positive mammogram result depicting focus of microcalcification beneath nipple. Both allergic contact dermatitis and irritant contact dermatitis and fixed drug eruption of the nipple-areola complex show histologic features of an inflammatory dermatosis. No Paget cells are seen in these conditions.
Nipple duct adenoma or erosive adenomatosis of the nipple may mimic mammary PD clinically; however, the histologic features of the former are those of a benign neoplasm of the major nipple ducts. The adenoma cells are negative for c-erb B-2, which is positive in 85% of cases of PD tested.
The following 2 histologic features differentiate Paget cells from melanoma cells:
- Paget cells are situated suprabasally above flattened basal keratinocytes with occasional ductal formation, whereas melanoma cells are located in the basal epidermis and all layers of the epidermis, the so-called intraepidermal pagetoid spread (see the image below)
- Paget cells are not present freely in the dermis, whereas melanoma cells are capable of invasion into the dermis. An intraductal or infiltrating ductal carcinoma of the breast can be seen in association with mammary Paget disease.
Photomicrograph of malignant melanoma in situ of skin displays prominent intraepidermal pagetoid spread. Note that melanoma cells are present in all layers of epidermis, mostly in single units. Cytoplasm of melanoma cells is vacuolated. Moderate upper dermal chronic inflammatory infiltrate is present (hematoxylin-eosin, original magnification ×250). S-100 protein and homatropine methylbromide immunostains are positive in melanoma cells, whereas carcinoembryonic antigen is negative. No epithelial mucin is seen in these tumor cells.
Immunohistochemistry
Immunohistochemistry allows definitive diagnosis of mammary PD. Paget cells can be demonstrated by immunohistochemical methods using several antibodies to cell surface and cytoplasmic markers (eg, low-molecular-weight keratins found in simple epithelia, EMA, c-erb B-2, polyclonal pCEA+).
Paget cells differ from melanoma cells by negative cytoplasmic epithelial phenotype markers (including pancytokeratin), positive homatropine methylbromide (HMB-45), and positive Melan-A (Mart-1) activity in the melanoma cells.[8] Paget cells show negative staining by anti-S-100 protein, which serves as a differentiating feature from malignant melanoma in situ. Most Paget cases are positive for cytokeratin 7 (CK7) and gross cystic disease fluid protein (GCDFP-15).
Toker (clear) cell hyperplasia of the nipple and the areola is a benign condition without well-defined clinical manifestations. Unlike the Paget cells, the large clear cells do not contain epithelial mucin, and no association with an underlying breast carcinoma exists. Benign Toker cells are positive for CK7[19] but negative for CEA and S-100 protein.
The similarity of the immunophenotypes suggests that Toker cells may be the origin of intraepithelial Paget cells.[4] In cases of florid papillomatosis of the nipple, some CK7-positive cells may be found in the epidermis, a pitfall to be aware of when diagnosing PD of the nipple. Furthermore, the intraepidermal portion of the nipple ducts can be a pitfall for intraepidermal CK7-positive cells.
Pagetoid squamous cell carcinoma in situ (Bowen disease) of the breast is rare, and it can be distinguished from Paget disease by negative CK7, positive K903, and positive p16 activity in the former and the reverse result for these antibodies in the latter. CEA is positive in Paget cells and negative in keratinocytes, thus differentiating Paget disease from Bowen disease.
Pseudo-Paget disease may, on occasion, be seen in the major nipple ducts. Large histiocytes infiltrate the epithelium and impart a histologic pattern mimicking Paget disease. The large cells are CK7 negative and strongly positive for CD68.
Staging
Mammary Paget disease has been classified into 4 clinical stages.
- Stage 0 - Lesion confined to the epidermis, without underlying in situ ductal carcinoma of the breast
- Stage 1 - Associated with in situ ductal carcinoma just beneath the nipple
- Stage 2 - Associated with extensive in situ ductal carcinoma
- Stage 3 - Associated with invasive ductal carcinoma
Of all patients with mammary PD, 40-50% have either stage 1 disease or stage 2 disease. These patients have no palpable breast tumor. A palpable breast tumor is a rule in stage 3; more than half of patients have coexisting axillary lymph node involvement. Patients with breast carcinoma previously treated by local excision and radiation therapy may present with PD of the nipple.
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