Modern immunochemistry has turned PDB inside out. Today, PDB is believed to begin within the breast and then to spread “upward” to the NAC, called the epidermotrophic theory. This theory is supported by the fact that Paget’s cells share several molecular markers with their respective parenchymal tumors. Some researchers now propose that there is a single Paget’s progenitor cell with a motility factor that allows it to traverse the ductal system, resulting in nipple and skin changes that have come to be recognized as PDB.6-8
The invasive cancers that are associated with PDB are most likely to be both estrogen- and progesterone-receptor–negative and of a high histologic grade.3,7 Estrogen- and progesterone-sensitive tumors respond to hormonal manipulation therapy. Tumors that are receptor-negative and that have a more aggressive grade are more difficult to treat.
Differential Diagnosis
PDB may be confused with the early stages of inflammatory breast cancer (IBC), an aggressive malignant disease (see Table 1). Both conditions may present with erythema and skin thickening and may be mistaken for mastitis. However, IBC spreads rapidly through the entire breast, and clinical features may include tenderness, a feeling of heat or heaviness, breast enlargement, and significant lymphadenopathy. Current recommendations call for a biopsy of any area of breast inflammation that does not respond to antibiotics within seven days.9
PDB is not the only cutaneous manifestation of breast cancer. Others include carcinoma erysipeloides (inflammatory changes that resemble cellulitis), carcinoma telangiectaticum (vascularized plaques), and/or inflammatory papules or nodules appearing on the breast, back, neck, or scalp. Each of these non–Paget’s conditions involves lymphatic (versus ductal) spread and signifies advanced malignancy.10
Diagnosis and Staging
After biopsy of the nipple lesion(s), diagnosis proceeds to the assessment of the breast itself and ultimately to cancer staging. PDB may occur (in order of incidence):
• In conjunction with an invasive cancer
• With underlying ductal carcinoma in situ (DCIS)
• Without any underlying disease.7
Mammography is used to determine the extent and location of the underlying lesion(s), which is more likely to be peripheral and/or multicentric. However, in some cases, there are no mammographic changes, which is now recognized as an indication for performing a breast MRI.11 Once the lesion is located, direct or image-guided biopsy confirms whether it is invasive cancer or DCIS. Palpable masses that occur with PDB are usually invasive and signal advanced disease.2,6,12,13 Sentinel lymph node biopsy (SLNB), which is usually performed at the time of surgery, plays a critical role in cancer staging and treatment planning. SLNB reliably diagnoses axillary metastasis in approximately 98% of patients.14
Like other breast cancers, PDB is also categorized by the expression of molecular markers, including HER2 (human epidermal growth factor receptor 2). Cancer cells in which HER2 gene is overexpressed tend to proliferate more rapidly than others. HER-status can also provide a clue as to which chemotherapy agents are likely to be most effective.2
Treatment and Management
The primary treatment for breast cancer is surgery, which serves both diagnostic and therapeutic purposes. To be effective, surgical treatment of PDB requires excision of the NAC, also called central lumpectomy. This may be sufficient treatment in those rare cases in which the disease is confined to the NAC.11,12
For underlying tumors, partial mastectomy is an option when the tumor is small (< 2 cm) and located close enough to the NAC to achieve negative margins, while leaving a cosmetically acceptable breast. Partial mastectomy is usually followed by whole breast irradiation. A few centers offer intraoperative radiation therapy (IORT)—performed before the surgeon closes the incision—for patients who wish to avoid or limit the duration of postoperative radiation treatment.15-17
Complete mastectomy (including excision of the NAC) should be considered when:
• The distance between the NAC and the underlying tumor is significant
• Multicentric disease and/or diffuse calcifications exist
• Achieving negative margins would remove too much tissue to leave a cosmetically acceptable breast.
Evaluation of the axillary nodes is the same in PDB as with other breast cancers. Patients with disease localized to the NAC and no underlying carcinoma may choose to forego lymph node biopsy. The same is true for patients who have PDB with a single underlying DCIS. However, lymph node biopsy is always recommended in cases of multicentric DCIS or invasive disease, or if a mastectomy is planned.18,19
Sentinel node biopsy results determine whether the mastectomy should be simple (excision of the breast alone) or modified radical (breast and axillary nodes). Today, complete radical mastectomy (excision of the breast, axillary nodes, and pectoral muscle) is reserved for cases in which disease invades the chest wall.18,19