Paget Disease of the Breast

Paget disease of the breast is an eczematous, scaly or ulcerated change of the nipple and areola caused by intraepidermal adenocarcinoma cells (Paget cells). It is almost always associated with an underlying in situ or invasive breast carcinoma.

It makes up 0.7% to 4.3% of breast cancers. Most patients are in their 50s to 60s, and it is rare in men.

Over 90% of cases have an underlying DCIS or invasive carcinoma on full breast examination, often remote from the nipple. The underlying lesion is invasive in most patients who have a palpable mass and in fewer who do not.

Pathophysiology. Two theories explain it. Epidermotropism proposes that cells from an underlying duct cancer migrate to the epidermis along the lactiferous ducts, driven by HER2-related heregulin signalling. In situ transformation proposes that nipple epidermal cells become malignant in situ.

Immunoprofile. Paget cells are CK7 positive and usually CK20 negative, and HER2 is overexpressed in 80% to 90%. ER and PR are often negative. GCDFP-15 and androgen receptor are often positive. Melanocytic markers (S100, SOX10, HMB-45) are negative.

Subtypes. Paget disease with an underlying invasive cancer, with an underlying DCIS, and isolated Paget disease with no underlying lesion on imaging or histology (5% to 10%).

Outcome. Prognosis follows the stage of the underlying cancer. Outcomes for isolated Paget disease and Paget disease with DCIS are excellent.

• Unilateral, scaly, erythematous, eczematous plaque beginning on the nipple and spreading to the areola, with itching, burning or pain. Weeping, crusting, ulceration, nipple retraction or flattening, and bloodstained discharge occur.
• A palpable breast mass is present in a minority and suggests invasive disease.
• The lesion does not respond to topical corticosteroids, and does not heal.
• Nipple involvement is first, and bilateral disease is rare.

• Full thickness punch or wedge biopsy of the nipple, or an excisional biopsy of the nipple skin. Skin scrapings and cytology are inadequate.
• Immunohistochemistry: CK7, HER2 and GCDFP-15 positive supports Paget disease. S100, SOX10 and HMB-45 exclude melanoma. p63 and CK7 negativity favour squamous Bowen disease.
• Bilateral mammography, ultrasound and MRI of the breast to identify the underlying lesion. MRI detects extent and underlying disease that mammography misses.
• Core biopsy of any underlying mass or suspicious calcification, with ER, PR and HER2 testing.
• Axillary ultrasound with sampling of suspicious nodes. Staging imaging only for invasive cancer of higher stage.

Differential diagnosis.

• Nipple eczema (often bilateral and spares the nipple core)
• Psoriasis and contact dermatitis
• Bowen disease (squamous carcinoma in situ)
• Superficial spreading melanoma
• Adenoma of the nipple (florid papillomatosis)
• Nipple candidiasis and herpes infection
• Toker cell hyperplasia (benign)

Management depends on the underlying disease.

Surgery.

• Mastectomy for extensive underlying disease, multifocal disease, or when central excision gives a poor shape.
• Central excision of the nipple areola complex with clear margins plus whole breast radiotherapy when imaging shows no extensive underlying disease. Central excision alone has high recurrence and radiotherapy is added.
• Sentinel node biopsy for underlying invasive cancer, and with mastectomy for DCIS. Omit it for isolated Paget disease treated by central excision.

Radiotherapy. Whole breast 40 Gy in 15 fractions over 3 weeks after central excision, with a boost of about 10 to 16 Gy in higher risk cases. Radiotherapy to the chest wall and nodes after mastectomy is by the stage of the underlying cancer.

Systemic therapy. By the stage and receptor status of the underlying invasive cancer. This includes adjuvant endocrine therapy for ER-positive cancers and anti-HER2 therapy with chemotherapy for HER2-positive invasive disease, as the HER2 overexpression of Paget cells does not itself indicate systemic therapy. Systemic therapy is not given for DCIS or isolated Paget disease beyond endocrine risk reduction in ER-positive disease.

Monitoring. Bilateral mammography annually and clinical examination every 6 to 12 months for 5 years. Examine the nipple areola scar and chest wall.

Referral and escalation.

• Breast clinic review of any nipple eczema that persists beyond 2 to 3 weeks of topical therapy, or any unilateral nipple change.
• Urgent multidisciplinary review when a mass, bloodstained discharge or ulceration is present.

Special groups.

• Men: same approach, with mastectomy more usual because of small breast volume.
• Pregnancy: defer radiotherapy and endocrine therapy until after delivery.
• Pathogenic variant carriers: bilateral risk reducing mastectomy is discussed.