Paget disease of nipple

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Paget Disease of the Nipple

Definition and Historical Background

First described by Sir James Paget in 1874, who reported 15 women with chronic nipple ulcerations who developed breast cancer within 2 years. Paget disease of the nipple accounts for 1-3% of all new breast cancers in females.

Bailey and Love's Short Practice of Surgery, 28th Ed.
Mulholland and Greenfield's Surgery, 7th Ed., p. 3975

Pathogenesis

Paget disease is essentially a unique form of DCIS (ductal carcinoma in situ) arising in the nipple epidermis. There are two main theories:

Epidermotropic theory (favored): Malignant ductal cells migrate from underlying DCIS via the lactiferous ducts and invade upward into the epidermis of the nipple.
In-situ transformation theory: Keratinocytes of the nipple epidermis undergo malignant transformation independently.

The carcinoma cells spread into the lactiferous sinuses, invade across the junction of epidermal and ductal epithelial cells, and enter the epidermal layer. Paget cells do not invade through the dermal basement membrane, so they remain categorized as carcinoma in situ until invasion occurs.

Sabiston Textbook of Surgery, p. 3022-3031

Clinical Features

The hallmark is a scaly, raw, vesicular, or ulcerated lesion that begins on the nipple and spreads secondarily to the areola (unlike eczema, which typically begins on the areola).

Key features:

Chronic erythematous, scaling, eczematous eruption of the nipple
Progressive erosion/destruction of the nipple
Pruritus, burning, or pain (may precede visible disease)
Bloody nipple discharge
May progress to crusting, ulceration, and spread onto areola/breast skin
Usually unilateral

Important: Paget disease starts on the nipple, whereas most benign skin conditions (eczema, contact dermatitis) begin on the areola.

Nipple erosion in early Paget's disease - Bailey & Love's

Associated Malignancy

This is clinically very important:

Finding	Association
Overall association with underlying breast carcinoma	>95% of cases (Sabiston) / 85-88% (Mulholland)
Palpable mass present	>50% of patients
Palpable mass + mammographic abnormality	>90% have invasive carcinoma
No palpable mass, normal mammogram	More likely DCIS than invasive

Sabiston Textbook of Surgery, p. 3029

Pathology (Histology)

The pathognomonic finding is the Paget cell - a large, pale (vacuolated) cell with round or oval nuclei and large nucleoli, found between normal keratinocytes of the nipple epidermis (in the rete pegs of the epithelium).

Immunohistochemistry:

CK7 positive (low-molecular-weight cytokeratins) - characteristic
CEA (carcinoembryonic antigen) positive - distinguishes from melanoma
S-100 negative (positive in melanoma) - key differential
HER2 overexpression in 70-90% of cases
Hormone receptor (ER/PR) positive in approximately 50% of cases
Schwartz's Principles of Surgery, 11th Ed., p. 352
Mulholland and Greenfield's Surgery, 7th Ed., p. 3400

Differential Diagnosis

Condition	Distinguishing Feature
Eczema / Atopic dermatitis	Starts on areola, bilateral, responds to steroids
Contact dermatitis	Bilateral, history of irritant exposure
Post-radiation dermatitis	History of prior RT
Superficial spreading melanoma	S-100 positive, CEA negative on IHC
Erosive adenomatosis	Benign proliferation of lactiferous ducts

Sabiston Textbook of Surgery, Fitzpatrick's Dermatology

Investigations / Workup

Wedge or punch biopsy of nipple - confirms diagnosis by demonstrating Paget cells
Bilateral breast examination
Mammography - abnormal in ~50%; abnormalities can occur distant from the nipple-areolar complex
MRI - if mammography and breast imaging are normal (highly sensitive but not specific; detected lesions must be biopsied to confirm)
Triple assessment to exclude/characterize underlying malignancy

Treatment

Scenario	Treatment
Paget disease without underlying mass/malignancy	Central core excision (nipple + areola + cone of major ducts down to pectoralis major) + adjuvant radiotherapy
Paget disease with underlying malignancy	Mastectomy with axillary staging
Breast-conserving option	Wide local excision (nipple-areolar complex + underlying cancer to clear margins) + whole breast RT ± Grisotti flap reconstruction

For patients treated with breast-conserving surgery, nipple-areolar reconstruction can be performed 4-6 months after radiotherapy, or via 3D tattooing.
Axillary staging and adjuvant systemic therapy are determined by the nature of the underlying breast cancer.
Bailey and Love's, 28th Ed.; Sabiston, p. 3031; Mulholland, p. 3404

Extramammary Paget Disease (for comparison)

Paget disease can also occur outside the breast (most commonly anogenital skin, axillae, penis). It is classified into 3 types:

Primary intraepidermal adenocarcinoma (most common)
Associated with visceral malignancy (GI or genitourinary) - 25%
Associated with adjacent sweat gland carcinoma (least common)

Fitzpatrick's Dermatology, Vol. 1&2

Recent Literature

Recent reviews confirm the above framework. A 2026 systematic review of dermatologic mimickers (PMID: 40814164) highlights that Paget disease can be confused with several benign skin conditions, reinforcing the need for biopsy in any persistent unilateral nipple eruption. A 2024 review describes it as "an often-overlooked malignancy" (PMID: 42273835), emphasizing that delay in diagnosis is common due to its eczema-like appearance.

Key exam points to remember:

Starts on the nipple (not areola), spreads outward
Paget cells = large pale vacuolated cells in nipple epidermis (pathognomonic)
95% have underlying breast carcinoma
CEA positive, S-100 negative (distinguishes from melanoma)
HER2 overexpressed in 70-90%
Always biopsy any persistent unilateral nipple skin change

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