Pagets Disease


Extramammary Paget's disease, mammary Paget's disease


Ductular extension of carcinoma from breast

genitourinary, gastrointestinal, or apocrine glands


Underlying adenocarcinoma of breast (mammary)

or genitourinary or gastrointestinal carcinoma

(extramammary) or primary appendageal



Scaly, erythematous patch on nipple (mammary)

or anogenital region (extramammary Paget's)


Large, atypical cells at all levels of epidermis

IHC repertoire:

Cytokeratins 7, CEA, EMA


Essential to workup for underlying adenocarcinoma


Excellent if no underlying carcinoma; poor if internal

carcinoma present

Adverse variables:

Dermal invasion by neoplastic cells; association with

underlying malignancy


Surgery, (topical chemotherapy, radiation)

Mammary and extramammary Paget's disease represent two clinical conditions with potentially serious consequences for the patient. Mammary Paget's disease is associated with underlying carcinoma of the breast in virtually all cases. Exact incidence numbers vary, but with meticulous serial sections of major ducts entering into the nipple, foci of ductular carcinoma are identified in most cases (1). The disease has the same epidemiologic characteristics as breast carcinoma, independent of the presence of Paget's disease. It is most frequently encountered in middle-aged to elderly women and it may be unilateral or bilateral. Mammary Paget's disease presents as an erythematous, scaling patch on the nipple (Figure 9.1).

The clinical differential diagnosis usually includes squamous cell carcinoma in situ, and most commonly, eczematous processes.

Extramammary Paget's disease has an identical appearance, but is located in areas with abundant apocrine glands (Figure 9.2).

The most frequently involved site is the anogenital region, though cases have been reported in the axillae and within the external auditory canal. Extramammary Paget's disease is slightly more common in women and is more frequent in elderly patients (2). The relationship between underlying carcinoma is less strong with extramammary

Paget's disease. Incidence estimates range from 0% to 54% of cases, depending upon series (3). In approximately 25% of these cases, the underlying tumor appears to arise from apocrine or (less commonly) eccrine glands (4). Another 10%-15% of these cases have underlying tumors of the genitourinary or gastrointestinal tracts (2). Cases of extramammary Paget's disease involving the anogenital region seem to have a higher association with underlying carcinoma.

The histologic features of Paget's disease of the nipple and extramammary Paget's disease are identical except for site-specific anatomic variations. Large cells with abundant pale cytoplasm are present at all levels of the affected epidermis (Figure 9.3).

The atypical cells may display vesicular nuclei, and nucleoli are often visible, though not usually as prominent as those seen in melanoma cells (Figure 9.4).

There is no tendency for nest formation by the atypical cells. In some cases, intracytoplasmic vacuoles may be present, suggesting early ductular differentiation. This finding can be accentuated with the use of a periodic acid-Schiff stain that demonstrates cytoplasmic acidic mucopolysaccharides. The background epidermis is often acanthotic and spongiotic, with overlying parakeratosis.

Spongiotic Dermatitis
Figure 9.1. Scaly eruption centered on the nipple in Paget's disease.

The histologic differential diagnosis includes entities characterized by individual, atypical intraepidermal cells. The major differential possibilities include malignant melanoma and squamous cell carcinoma in situ. In most cases, it is useful to make this distinction with the use of immunostains. Melanoma cells strongly express S100 protein, an antigen that is occasionally expressed weakly and focally by Paget's disease cells (especially when they are ductular breast carcinoma cells). Squamous cell carcinoma cells express some pan-cytokeratin markers, as do the cells in Paget's disease. The most useful distinguishing markers are cytokeratin 7 (Figure 9.5), which is expressed

Ductular Adenocarcinoma
Figure 9.2. The anogenital region is a frequent site of involvement with extramammary paget's disease.

by neither the cells in malignant melanoma nor those in squamous cell carcinoma in situ, and epithelial membrane antigen, which has a similar staining profile (Figure 9.6).

CAM5.2 and carcinoembryonic antigen have also been used with good success in establishing the diagnosis. The use of an antibody panel using the reagents suggested makes the distinction between these entities very straightforward in most cases. It should be noted, however, that

Histology Paget
Figure 9.3. Medium power photomicrograph depicting scattered atypical clear cells, Paget's cells occupying all levels of the epithelium.

Figure 9.4. The neoplastic cells in Paget's disease have vesicular nuclei with prominent nucleoli.

Figure 9.4. The neoplastic cells in Paget's disease have vesicular nuclei with prominent nucleoli.

Paget Disease Teeth

melanoma is not usually in the clinical differential diagnosis of this process.

In cases of extramammary Paget's disease, the neo-plastic cells within the epidermis may represent upward extension of malignant transformation of cutaneous appendages (i.e., apocrine or eccrine structures). In these cases, similar-appearing tumor cells are apparent within the glandular apparatus. In more advanced cases, the same tumor cells may violate the basement membrane, invading the dermis. Lymphatic involvement has also been reported. This portends a significantly worse prognosis (5). In other cases of extramammary Paget's disease, the tumor cells represent upward extension of underlying tumors arising within the genitourinary system (most commonly, bladder), or gastrointestinal tract (most commonly, colon). In these cases, invasion of the dermis

Figure 9.5. Cytokeratin 7 is strongly expressed by intraepithe-lial neoplastic cells , but not by the background keratinocytes within the epidermis.

Figure 9.5. Cytokeratin 7 is strongly expressed by intraepithe-lial neoplastic cells , but not by the background keratinocytes within the epidermis.

Cytokeratin Paget Skin

Figure9.6. Epithelial membrane antigen is expressed by tumor cells in Paget's disease, but not by the background kera-tinoeytes within the epithelium.

denotes a more aggressive neoplasm, but careful histologic evaluation of the primary tumor is necessary for determining accurate prognostic data.

Paget's disease (mammary and extramammary) is treated with locally destructive therapy. Complete surgical excision is usually the first line of treatment for suitable candidates. Prior to excision, a staging workup is performed in order to isolate any underlying malignancies. In Paget's disease of the nipple, the underlying duct-ular tissue is removed, as a minimum, in most cases in order to identify any associated breast carcinoma. In extramammary Paget's disease, screening procedures are initiated prior to the surgical procedure. For patients who are not candidates for surgery, radiation and topical chemotherapeutic agents have been used with some success.

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