A 58-Year-Old Woman Develops a Pruritic, Erythematous Plaque Involving the Areola
A 58-year-old woman, previously in excellent health, noted the insidious development of a unilateral, irregularly annular, modestly pruritic, erythematous patch/plaque involving the edge of the areola and extending onto the contiguous skin. By history, the affected skin occasionally wept clear fluid that formed a superficial crust. Periodic application of over-the-counter 1% hydrocortisone relieved itching and weeping, but the lesion itself persisted and expanded. Past medical and social histories were unremarkable. Family history disclosed that one of two sisters died of complications from breast cancer. Despite this history, the patient had not obtained a mammogram in over five years. Her primary care physician referred her for dermatologic consultation due to “intractable eczema.”
E. > 90%
This patient suffers from Paget disease of the breast.
The term “pagetoid” refers to a histological phenomenon, namely the upward spread of cells within the skin. This term was coined in honor of Sir James Paget, a 19th-century British physician-scientist who described the phenomenon. He also delineated several other disease processes, including the degenerative disease of the bone and malignant disease of the breast that bear his name.
Paget disease of the breast is an uncommon disease, accounting for about 1% to 4% of all breast malignancies. [1,2] It occurs most commonly in postmenopausal females, with a mean age of onset at 57 years.  It is worthwhile noting, however, that this phenomenon can be observed on occasion in adolescent and very elderly women, as well as in men. [4,5] The disease presents as a solitary erythematous, slightly infiltrated patch on the breast; specifically, the lesion most often begins on the nipple, and then extends sequentially to the areola and finally to surrounding skin. As evidenced by this case, the nipple does not have to be involved. Serous drainage, crust, and scab formation and complaints of pain or itching are all frequent. Advanced lesions present as deeper red, polycyclic plaques. In short, Paget disease of the breast closely mimics eczema. In long-standing lesions , erosion or ulceration, and/or retraction of the nipple may occur. Paget disease of the breast is nearly always unilateral.
Mammary Paget disease is associated with either an in situ or an invasive ductal carcinoma in some 92% to 100% of cases. [6,7] An associated palpable breast mass is appreciable in approximately 50% of the patients with underlying carcinoma. [1-3] When a palpable mass is present, invasive carcinoma is more likely to be found; conversely, patients without a palpable mass more likely have an associated in situ ductal carcinoma. The underlying breast cancer is most typically located centrally, but the tumor is multifocal in nature 40% to 60% of the time.[6-8] Once the diagnosis of Paget disease of the breast has been established, imaging should be performed in an attempt to precisely delineate any underlying cancer. Radiologic findings are also crucial factors that help guide future management measures. Standard mammography, ultrasound evaluation, and magnetic resonance imaging may all be utilized. Mammograms are limited in their ability to detect in situ ductal carcinoma, and the sensitivity of mammography is best when there is an underlying palpable mass. 
From a histological perspective, Paget disease of the breast is characterized by epidermal invasion by mucin-rich, clear cells with pleomorphic and hyperchromatic nuclei. The number of such characteristic cells varies from a few isolated cells to complete replacement of the epidermis. Paget cells express low molecular weight keratin (eg, CK7) and carcinoembryonic antigen (CEA). Expression can be determined by immunohistochemistry. Paget cells are frequently negative for both estrogen and progesterone receptors, mimicking the situation in the underlying, poorly differentiated ductal tumors. However, the cells found in Paget disease are frequently HER2-positive.  The exact origin of these cells remains uncertain and controversial. They may be modified ductal carcinoma cells that have migrated upward due to intrinsic epidermotropism. Alternatively, they may represent a malignant degeneration or transformation of cutaneous keratinocytes that has occurred independent of any underlying breast tissue pathology.
The clinical differential diagnosis of Paget disease of the breast is diverse, and includes: eczema, contact dermatitis, parapsoriasis, psoriasis, squamous cell carcinoma in situ, superficial basal cell carcinoma, erosive adenomatosis of the nipple, and hyperplasia of mammary gland-related cells. A biopsy, coupled with immunocytochemistry studies and imaging results, should establish the proper diagnosis.
Without treatment, the skin lesion will spread progressively, invasive breast cancer will appear, and lymph node and visceral metastases will eventuate. Patients with a palpable mass at the time of initial diagnosis have a high rate of axillary lymph node metastasis and a 10-year disease-specific survival of 47%; conversely, patients without a palpable breast mass at the time of initial diagnosis have a low rate of axillary lymph node metastasis and a 10-year disease-specific survival of 93%.[7,11] All other factors being equal, men have a worse prognosis than women, with an overall 5-year survival rate of only 20% to 30%. Mastectomy (with or without axillary lymph node dissection) has long been regarded as the standard therapeutic choice for Paget disease of the breast, even in the absence of any additional signs of underlying pathology. However, in recent years, various breast-conserving surgical techniques have been advocated for Paget disease, either without demonstrable underlying breast carcinoma or with breast carcinoma clinically confined to the central segment of the breast. Such techniques, which must be individualized, include: nipple excision, central segmentectomy alone, either of the foregoing surgeries combined with radiotherapy, or radiotherapy as monotherapy. Several long-term follow-up studies do suggest that breast-conserving surgery plus irradiation is equivalent to mastectomy with regards to overall and disease-free survival, and this may well become the future standard approach in selected patients with Paget disease.[11,12] Adjuvant chemotherapy or hormonal therapy is dictated by the stage and nature of any underlying tumor.
Breast radiation, when given as monotherapy, has only been reported in a limited number of patients and with mixed results. Perhaps the most logical approach would be to recommend this modality only when Paget disease is confined to the nipple-areolar complex, without clinical or radiologic evidence of an underlying associated breast tumor.