Approximately 1%–3% of women with adenocarcinoma of the breast have Paget disease. Clinically-Paget disease has common dermatitis-like appearance, as originally described in 1874, when Sir James Paget recorded that such lesions may resemble “ordinary chronic eczema” or present as nipple erosion or ulceration. Paget disease often has a deceptively banal clinical morphology but should lead the list of differential diagnoses when evaluating unilateral lesions of the nipple–areola complex in adults.
Paget disease presenting with nipple erosion.
Most women with the histopathologic finding of Paget disease have a clinical abnormality of the nipple. However, in at least 10% of affected patients, Paget disease is found incidentally, during microscopic examination of mastectomy specimens.
Underlying invasive ductal carcinoma or DCIS, detected in more than 90% of patients with Paget disease, is multifocal in about 50% of cases and does not necessarily occur near or contiguous with the nipple–areola complex.
In addition, because of the practice shift from mastectomy to breast-conserving surgery, a patient whose nipple–areola complex was spared during surgery may present with Paget disease or epidermotropic metastatic breast cancer to the nipple after diagnosis and treatment of primary breast cancer.
Paget disease is characterized by intraepidermal infiltration with large cells that have abundant pale cytoplasm and hyperchromatic nuclei often with prominent nucleoli.
Potential histopathologic pitfalls include pronounced epidermal hyperplasia or denuded epithelium, sometimes mandating additional biopsy. The latter is particularly problematic when Paget cells completely separate from surrounding keratinocytes. Although this phenomenon has been described as acantholysis, Paget disease cells do not have intercellular connections with keratinocytes; they instead are tucked individually or in clusters between normal epithelial cells.
When the appearance of acantholysis is pronounced, pemphigus may be included in the differential diagnosis. Large acantholytic-like Paget disease cells may mimic the cytopathic effect of herpes simplex or varicella-zoster infection, particularly when their nucleoli are inconspicuous.
Large, rounded, “acantholytic” cells in Paget disease of the nipple
Intraepidermal clefting and stromal inflammation in Paget disease of the nipple
Infiltration of epithelium by pale cells and stromal inflammation in Paget disease involving the areola
Immunohistochemical stains often are necessary to confirm the diagnosis of Paget disease because the differential diagnosis may include SCC in situ, malignant melanoma in situ, and rarely other entities such as Langerhans cell histiocytosis.
Pigmented Paget disease and pigmented epidermotropic metastatic breast cancer have been reported. In contrast with melanoma, pigmented Paget disease usually is negative for S100, Melan A, and HMB-45.
In contrast with SCC in situ, Paget disease cells typically express low–molecular-weight keratins 7 and CAM 5.2 but not keratin 20 or high–molecular-weight keratins.
Paget disease tends to be estrogen- and progesterone-receptor negative and androgen-receptor positive, especially in patients with high-grade underlying ductal carcinoma.
HER2 overexpression often is a feature of cases associated with underlying ductal carcinoma.
Immunohistochemical stain for keratin 7 highlights epithelial infiltration with Paget disease cells
Immunohistochemical stain for Cam 5.2 highlights epithelial infiltration with Paget disease cells.
HER2 expression in Paget disease.
The histopathologic differential diagnosis also should include benign conditions characterized by pale-clear intraepidermal cells; these include pagetoid dyskeratosis, thought to be due to chronic irritation of the nipples, and clear-cell papulosis, a rare eruption affecting children that manifests as hypopigmented macules, mainly along milk lines.
These 2 disorders of large pale cells usually are distinguishable from Paget disease morphologically. Both are characterized by pale cells with limited (if any) pleomorphism; these cells tend to be larger than surrounding keratinocytes and are distributed singly or in small clusters set neatly in an otherwise normal-appearing epidermis, without discohesion. The clear cells of pagetoid dyskeratosis are positive for high–molecular-weight keratins, rather than low–molecular-weight keratins. Clear-cell papulosis typically has a profile similar to that of Paget disease, including expression of keratin 7, CAM5.2, and lack of staining for estrogen receptor, but appears to be negative for HER2.
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