FINAL DIAGNOSIS: PAGET'S DISEASE OF THE BREAST
Paget's disease (PD) of the breast is rare, with a reported incidence of 0.5-2% of all patients with breast cancer. However, this disorder should be considered in the differential diagnosis of all the patients presenting with lesions of the nipple. The characteristic erythema and eczematous changes of the nipple with this disease were first described by Velpeau in 1856, but the association of nipple-areolar changes with underlying carcinoma of the breast was not reported until 1874 by Paget (1). Ulceration, crusting and serous or bloody discharge characterize more advanced cases. Exfoliative cytology with demonstration of Paget's cells may be useful, but a negative finding does not exclude PD. Surgical biopsy is the diagnostic standard. The histogenesis of PD continues to be debated. The epidermotropic theory holds that Paget's cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma. According to the in situ transformation theory, the Paget's cells arise as malignant cells in the nipple epidermis independent from any other pathologic process within the breast parenchyma (2). Paget's cell movement within the epidermis is a fascinating phenomenon. Paget's cells express heregulin receptors, including HER2/Neu, which exert a chemotactic effect resulting in migration into the epidermis. Fifty to sixty percent of patients have a palpable tumor in the breast. An invasive carcinoma was detected in 75-90% of women who had PD accompanied by a tumor.
The gross pathologic changes on the surface duplicate those observed clinically. Occasionally, enlarged lactiferous ducts can be detected. Intraductal carcinoma usually can be found in at least one lactiferous duct. An invasive tumor, if present, tends to be central.
Microscopically, the characteristic feature is the presence of adenocarcinoma cells (Paget's cells) in the keratinizing epithelium of the epidermis. These cells occur singly in superficial epidermal layers. They are more likely to form clusters in the basal portions of the epidermis. Isolated Paget's cells appear to lie in vacuoles. The cytoplasm is pale or clear, and it may contain mucin secretion vacuoles. Nuclei tend to have prominent nucleoli. Hyperplasia and hyperkeratosis of the epidermis occur to some degree. The superficial dermal stroma usually infiltrated by a moderate to marked lymphocytic reaction.
Histologic differential diagnosis includes inflammatory conditions of the skin, clear cell change in epidermal cells, Toker cells, florid papillomatosis of nipple ducts or nipple adenoma. The most common differential diagnoses are malignant melanoma and squamous or basal cell carcinoma (3).
The extramammary forms of PD occur predominantly as vulvar or perianal disease. Primary vulvar PD (Figs. 7 and 8) is a localized carcinoma of sweat duct origin. The extravulvar form presents in the perianal areas as metastatic disease from sites that may include the rectum or urinary bladder (4).
Mammary PD: CK7+, GCDFP-15+, CEA+
Primary vulvar PD: CK7+ (Fig. 9), GCDFP-15+ (Fig. 10), CEA mostly + (Fig. 11)
Metastatic from rectum: CK7 negative, CK20+, CEA+, GCDFP-15 negative
Metastatic from urinary blabber: CK7+, CK20+, GCDFP-15 negative, CEA mostly negative
PD of the breast often is estrogen- and progesterone-receptor negative, because the underlying carcinoma tend to be poorly differentiated. In one study Paget's cells were positive for S-100 in 18% of lesions. PD is HMB45 negative. Paget's cells are positive for EMA and low-molecular-weight cytokeratin. Immunoreactivity for p21 and HER2/Neu has been detected (5). In one study, tumors from patients with PD of the breast were positive for c-erbB-2, Cyclin D1, and Ki-67, molecular markers commonly associated with more aggressive tumor behavior (6). Another study showed P53 may have a prognostic role in progression of PD of the vulva. Neither p53 nor Ki67 appeared to have prognostic role in PD of the breast (7).
The prognosis of patients is determined by the extent of the associated carcinoma. Treatment is mastectomy. Some patients without a palpable mass may be candidates for breast-conservation therapy.
Contributed by Franklin Sedarat, MD, Rovena L Kessinger, MD, David J. Dabbs, MD