Mammary Paget Disease (MPD) - Dermatology Notes

Definition: An uncommon intraepidermal adenocarcinoma characterized by the presence of Paget cells within the nipple and areolar epithelium, almost always associated with an underlying ductal carcinoma in situ (DCIS) or invasive breast carcinoma.

Key Clinical Features:

• Demographics: Mean age 50–60 years; unilateral in >95%.

• Nipple–areolar complex: Eczematous, well-demarcated, erythematous plaque with scale, crust, erosion, or ulceration.

• Symptoms: Pruritus, burning, or pain (often mild, leading to delayed diagnosis).

• Classic description: "Eczema that does not respond to topical steroids" – persistent, often with serous or bloody discharge, nipple retraction or destruction.

• Palpable mass: Present in 50–70% (indicates invasive component).

• Areola only (without nipple involvement): Rare; should still prompt evaluation for underlying breast malignancy.

Associated Conditions/Diseases:

• Underlying breast carcinoma: Present in 85–100% of cases.

  • DCIS alone: ~60–70%.

  • Invasive ductal carcinoma (IDC): ~30–40%.

• Extramammary Paget disease (EMPD): Different entity (vulva, perianal, axilla); associated with underlying apocrine adenocarcinoma or internal malignancy (colorectal, urothelial).

• Occult breast carcinoma: MPD can be the first and only sign.

Types:

• Type 1 (most common): Paget cells arise from migration of malignant cells from an underlying DCIS through lactiferous ducts into nipple epidermis.

• Type 2 (rare): In situ transformation of epidermal stem cells or Toker cells to Paget cells (no underlying DCIS – but still high risk for subsequent malignancy).

Prognosis:

• Depends entirely on underlying breast carcinoma (stage, grade, receptor status).

• MPD alone (without palpable mass or invasive disease) – better prognosis.

• MPD with palpable mass – worse prognosis (higher risk of invasive disease, nodal metastases).

• Overall 5-year survival: 80–90% for DCIS alone; 30–60% for invasive cancer with nodes.

Differential Diagnosis:

• Chronic eczema/atopic dermatitis: Bilateral, responds to steroids, no nipple destruction.

• Psoriasis: Typically bilateral, other body sites involved.

• Contact dermatitis: History of exposure, acute onset.

• Bowen disease (squamous cell carcinoma in situ): No underlying breast malignancy, histology shows atypical keratinocytes (not Paget cells).

• Melanoma (in situ): Pagetoid spread of melanocytes (S100+, SOX10+, HMB45+).

• Nipple adenoma: Benign, no Paget cells, no underlying carcinoma.

Management with Rationale:

1. Diagnostic biopsy of nipple lesion (shave or punch including epidermis) → confirms Paget cells.

2. Imaging: Mammogram + breast ultrasound + MRI → identify underlying mass, extent of DCIS/invasive disease.

3. Core needle biopsy of any radiologic abnormality → histology of underlying carcinoma.

4. Surgical excision:

   • Central lumpectomy (nipple–areolar complex excision) + whole breast irradiation → breast-conserving option (if margins clear, no invasive disease).

   • Total mastectomy → for extensive DCIS, invasive carcinoma, or patient preference.

5. Sentinel lymph node biopsy → if invasive component present.

6. Adjuvant therapy (hormonal, chemotherapy, HER2-targeted) → based on underlying tumor receptor profile.

7. Topical therapy (imiquimod or 5-FU) → only for very select, non-surgical candidates with confirmed no underlying invasive disease (rare, not standard).

Histopathology

1. FOUNDATIONS (First Principles)

• Normal nipple epidermis: Stratified squamous epithelium with rete ridges; contains scattered clear cells (Toker cells) – benign, cytokeratin 7+ cells considered precursors or normal variants.

• Lactiferous ducts: Open at nipple surface; lined by bilayered epithelium (inner luminal cytokeratin 7+/8+/18+, outer myoepithelial p63+/CK5/6+).

• Epidermal–ductal junction: Continuity between ductal and epidermal keratinocytes.

• Basement membrane: Intact in MPD (Paget cells are intraepidermal).

2. INITIATING EVENT

• Type 1 (majority): Malignant transformation in a terminal duct lobular unit (TDLU) → DCIS → malignant cells migrate upward through lactiferous ducts → reach nipple epidermis.

• Type 2 (minority): Malignant transformation of a Toker cell or epidermal stem cell in situ (no ductal component at diagnosis, but subsequent risk).

3. PATHOGENESIS

• Loss of E-cadherin-mediated adhesion (Paget cells are dyscohesive) → cells detach from ductal epithelium.

• Chemotactic gradient (possibly SDF-1/CXCR4) → Paget cells migrate through ductal basement membrane? No – they remain within ductal epithelium and then enter epidermis.

• In epidermis, Paget cells spread pagetoid (single cells or small clusters) – preferentially along the basal layer but extend upward.

• Paget cells displace and compress adjacent keratinocytes → spongiosis and epidermal thickening clinically mimicking eczema.

• Underlying DCIS progresses or remains indolent – variable.

• Why nipple skin is preferentially involved? Continuous epithelium between lactiferous sinus and nipple surface allows direct migration.

4. HISTOPATHOLOGY

• Low power: Hyperplastic epidermis with scattered large, pale, round cells singly or in clusters – Paget cells. Often spared the stratum corneum.

• High power – Paget cells:

  • Large (2–3x keratinocyte), round to oval.

  • Abundant pale to clear cytoplasm (due to intracytoplasmic mucin – glycogen or sialomucin).

  • Hyperchromatic, pleomorphic nucleus with prominent nucleoli.

  • Frequent mitotic figures.

• Arrangement: Pagetoid spread – single cells scattered throughout all epidermal layers, often with a halo (retraction artifact around the cell).

• Nesting: Occasionally form small gland-like structures or acini.

• Background epidermis: Acanthosis, spongiosis, parakeratosis. May see ulceration.

• Dermis: Often a chronic lymphohistiocytic infiltrate (secondary to epidermal disruption). No dermal invasion of Paget cells unless invasive component from underlying carcinoma.

• Lactiferous ducts: May show in situ Paget cells within ductal epithelium (continuity with nipple surface).

Why this appearance:

• Clear cytoplasm → Intracytoplasmic mucin (PAS-positive, diastase-labile) and glycogen; mucin pushes organelles to periphery.

• Pagetoid spread → Loss of desmosomal adhesion (E-cadherin downregulation) → cells do not stick to keratinocytes.

• Halo artifact → Formalin fixation shrinks mucin-rich Paget cells away from surrounding keratinocytes.

5. NAMING LOGIC & TERMINOLOGY

• "Paget" – Named after Sir James Paget (1874) who described "eczema of the nipple" preceding breast cancer.

• "Pagetoid spread" – Resembles the upward, single-cell pattern of melanocytes in pagetoid melanoma (but different cell type).

• "Clear cell" – Pale cytoplasm due to mucin.

• "Intraepidermal adenocarcinoma" – Malignant glandular cells confined to epidermis.

6. STAINING & MARKERS

H&E: As above – Paget cells are distinctive but can mimic melanoma or Bowen disease.

Special stains:

• PAS with diastase: Positive (cytoplasmic mucin is PAS-positive, diastase-labile).

• Mucicarmine: Positive (epithelial mucin).

Why CK7 is critical: Paget cells are glandular (CK7+) – distinguishes from melanoma (S100+) and Bowen (CK5/6+, p63+).

7. TEMPORAL EVOLUTION

• Early lesion: Rare Paget cells in basal layer of nipple epidermis, minimal epidermal change. Easily missed.

• Established lesion: Paget cells extend to all epidermal layers, acanthosis, spongiosis, chronic dermal inflammation.

• Late lesion: Ulceration, full-thickness epidermal involvement, possible dermal invasion (from underlying invasive carcinoma, not Paget cells themselves). Nipple destruction.

• Underlying DCIS: May progress to invasive carcinoma over time.

8. PATTERN RECOGNITION & DIAGNOSTIC LOGIC

• Pattern: Pagetoid intraepidermal large clear cells with pleomorphic nuclei.

• Diagnostic pathway:

  • Intraepidermal pagetoid large cells + CK7+ GCDFP-15+ → Mammary Paget disease (look for underlying breast carcinoma).

  • Intraepidermal pagetoid large cells + CK7+ but GCDFP-15– → consider EMPD (needs CK20, CDX2, uroplakin for origin).

  • Intraepidermal pagetoid large cells + S100+ HMB45+ → Melanoma in situ.

  • Intraepidermal large atypical keratinocytes + CK5/6+ p63+ → Bowen disease.

  • Intraepidermal pagetoid cells + CK7+ HER2+ but no underlying breast mass after full imaging → consider primary MPD without DCIS (type 2) but monitor closely.

9. CLINICO-PATHOLOGICAL CORRELATION

• Eczematous, scaling plaque → Paget cells in epidermis induce acanthosis, spongiosis, parakeratosis (mimics eczema).

• Failure to heal with topical steroids → Paget cells are neoplastic, not inflammatory.

• Nipple erosion/ulceration → Paget cells replace and disrupt the epidermis.

• Serous/bloody discharge → Underlying DCIS in lactiferous ducts produces secretions.

• Palpable mass → Indicates invasive component or large DCIS.

• Unilateral nature → Underlying breast malignancy is almost always unilateral.

10. EXAM-FOCUSED INSIGHTS

• "Eczema of the nipple that does not respond to steroids" = Paget disease until proven otherwise – Board classic.

• CK7 is the single most useful IHC marker – Paget cells are glandular; keratinocytes and melanocytes are not.

• HER2/neu overexpression in 80–90% – Potential therapeutic target (trastuzumab for invasive component).

• No palpable mass does NOT mean no underlying cancer – 30–40% of MPD without palpable mass still have DCIS or invasive disease on imaging.

• Extramammary Paget disease is a different entity – Associated with apocrine or visceral (colorectal, bladder) malignancies, not breast.

• Toker cells are benign mimics – Scattered CK7+ clear cells in normal nipple; they are smaller, less pleomorphic, no mitoses, no nesting.

• Biopsy technique – Full-thickness punch (including dermis) to assess invasion; shave may miss invasive component.

Must-Know Board Exam Questions & Answers

Q1: A 58-year-old woman presents with a 6-month history of unilateral nipple eczema that has failed to improve with topical hydrocortisone. On examination, the nipple is crusted and slightly eroded. What is the most likely diagnosis?

A: Mammary Paget disease.

Q2: What is the most useful immunohistochemical marker to confirm the diagnosis of mammary Paget disease?

A: CK7 (strongly positive in Paget cells; negative in keratinocytes and melanocytes).

Q3: A biopsy of a nipple lesion shows large, pale cells with pleomorphic nuclei scattered throughout the epidermis. The underlying dermis has a chronic inflammatory infiltrate. What two conditions are in the differential diagnosis, and how do you distinguish them?

A: Melanoma in situ (pagetoid spread) and Bowen disease (SCC in situ). Distinguish with IHC: CK7+ GCDFP-15+ HER2+ = Paget; S100+ HMB45+ = melanoma; CK5/6+ p63+ = Bowen.

Q4: What percentage of mammary Paget disease cases are associated with an underlying breast carcinoma?

A: 85–100% (most commonly DCIS, then invasive ductal carcinoma).

Q5: A patient with mammary Paget disease has no palpable breast mass. Does this exclude underlying malignancy?

A: No. 30–40% of patients without a palpable mass still have DCIS or invasive carcinoma on imaging (mammogram/ultrasound/MRI).

Q6: What is the difference between mammary Paget disease and extramammary Paget disease?

A: MPD is almost always associated with underlying breast DCIS/invasive carcinoma. EMPD involves vulva, perianal, or axilla; may be primary intraepidermal or associated with underlying apocrine adenocarcinoma or visceral malignancy (colorectal, bladder, prostate).

Q7: What is the prognostic factor in mammary Paget disease?

A: The stage, grade, and receptor status of the underlying breast carcinoma, not the presence of Paget cells themselves.

Q8: What is the HER2/neu status in most cases of mammary Paget disease?

A: Overexpressed in 80–90% (strong, diffuse membranous staining).

Q9: A 65-year-old man presents with unilateral nipple crusting and erosion. Biopsy shows Paget cells. What is the management?

A: Same as in women – mammogram, ultrasound, core biopsy of any radiologic abnormality, then surgical excision (mastectomy or central lumpectomy). Underlying breast carcinoma is present in most male cases.

Q10: What are Toker cells, and why are they relevant?

A: Benign CK7+ clear cells normally present in nipple epidermis. They can mimic Paget cells but are smaller, lack atypia, no mitoses, and do not nest. Rarely, they can undergo malignant transformation (type 2 Paget disease).