Ductal Carcinoma In Situ, Paget Disease

Ductal Carcinoma In Situ, Paget Disease

This is a typical clinical appearance of a nipple involved by mammary Paget disease. There is evidence of erythema, crusting, and scaling image as well as a suggestion of focal ulceration.

The clinical appearance of MPD is due to hyperkeratosis image and loss of intercellular fluid image via the disrupted skin barrier. DCIS is typically present in the lactiferous sinuses image.



  • Ductal carcinoma in situ (DCIS)

  • Mammary Paget disease (MPD)


  • Paget disease of nipple

  • DCIS involving nipple skin


  • Uncommon clinical presentation of breast cancer involving nipple

  • MPD described by Sir James Paget (1874)

    • “An eruption on the nipple and areola … with characteristics of ordinary chronic eczema”

      • Paget linked skin changes with later development of cancer in underlying breast

  • MPD was later shown to be due to spread of carcinoma cells into nipple epidermis from lactiferous sinuses

  • Pagetoid spread is presence of tumor cells between basement membrane and overlying layer of normal cells

    • In nipple skin, pagetoid spread is almost always due to DCIS with overlying squamous cells

    • In ducts and lobules, pagetoid spread is most commonly seen with LCIS with overlying luminal cells

      • Unlike LCIS, DCIS typically overgrows or pushes aside overlying luminal cells and fills ducts and lobules


Pathogenesis of Paget Disease

  • Remains debatable

    • In most cases, Paget cells likely originate from DCIS involving lactiferous sinuses of nipple

      • Supported by finding of DCIS deeper in breast identical to Paget cells in almost all cases

    • Very rarely, Paget cells may be derived from precursor cells (Toker cells) present within nipple epidermis

      • In such cases, cancer may not be present in underlying breast

  • Motility factor (heregulin-a) secreted by epidermal keratinocytes may attract Paget cells within nipple epidermis

    • Heregulin-a binds to HER2 family receptors that are overexpressed by Paget cells

  • Tumor cells disrupt normal tight junctions between keratinocytes

    • Extracellular fluid can escape through skin, and this produces characteristic scale crust

      • Diagnosis can sometimes be made using cytologic preparations of skin scrapings



  • Skin lesions

    • Occur in 1-2% of women with breast cancer

    • May be limited to nipple or extend to areola

    • Scaling and redness in affected area

    • Pain and itching are frequent symptoms

    • Ulceration or serosanguineous/bloody discharge may be present in more advanced cases

    • Delay in diagnosis of MPD may be related to initial diagnosis of eczema or inflammatory skin disorder

  • Underlying breast cancer found in > 95% of cases (invasive &/or DCIS)

    • No age predilection seen

    • No clinical or epidemiologic factors have been described that predispose to development of MPD

    • Up to 1/2 of patients have palpable tumor on affected side

      • Most of these patients have associated invasive carcinoma

      • In very rare cases, invasion occurs directly from nipple skin into dermis

  • Majority of cases of MPD diagnosed microscopically are not detected clinically

    • Focal nipple involvement is insufficient to produce clinically detected symptoms


  • Surgical approaches

    • Determined by presence and extent of underlying breast cancer

      • Due to nipple involvement, mastectomy is often performed

  • Adjuvant therapy

    • Features of associated breast cancer, including grade and extent, dictate need for and type of adjuvant therapy


  • Determined by presence and extent of underlying breast cancer

    • For MPD associated with underlying DCIS only, survival approaches 100% at 10 years after mastectomy

    • 10-year survival for node-negative patients with palpable invasive carcinoma is 70%


Mammographic Findings

  • In early cases, imaging findings may be absent

  • Skin thickening is typical finding in advanced cases

    • MPD associated with mammographic density or nipple retraction is more likely to have areas of invasion

    • Calcifications may be associated with underlying DCIS

MR Findings

  • Typically shows abnormal nipple enhancement &/or ill-defined, thickened nipple-areolar complex

  • MR may be useful in detection of occult neoplastic disease in underlying breast tissue

    • In setting of negative mammography, MR can facilitate treatment planning for patients with MPD


General Features

  • Gross changes reflect features seen clinically

    • Frequently, erythematous appearance with crusting of skin

    • Skin may show ulceration

      • However, skin preparation prior to surgery often removes gross scaling crust in surgical specimens

  • Palpable mass lesion may be present in underlying breast parenchyma


Histologic Features

  • Adenocarcinoma cells, single and in clusters, present within keratinizing epidermis of nipple

    • Clusters of Paget cells more common in basal portion of epidermis

    • Tumor cells extend from lactiferous sinuses to overlying skin without crossing basement membrane

      • Therefore, Paget disease can occur in absence of stromal invasion

  • Paget cells are large and atypical in appearance, stand out from surrounding keratinocytes

    • Enlarged pleomorphic nuclei, which tend to show prominent nucleoli

    • Abundant pale or eosinophilic cytoplasm

    • Cytoplasm may contain diastase-resistant PAS positive globules consistent with mucin

  • Moderate to intense lichenoid lymphocytic infiltrates typically seen in underlying superficial dermis

    • May obscure diagnosis, should not be mistaken for dermatitis

  • Varying degrees of hyperplasia and hyperkeratosis of associated epidermis

    • Inflammation, hyperplasia, and hyperkeratosis responsible for clinical appearance of lesion

    • May be associated with ulceration of epidermis

  • Associated ductal carcinoma (with or without invasion) usually found in underlying breast

    • Associated DCIS is typically high grade with solid or comedo pattern



  • Panel of immunohistochemistry stains is helpful in establishing glandular origin of Paget cells


Carcinoma Directly Invading Nipple Skin

  • Subareolar tumor with infiltration of superficial dermal collagen and overlying epidermis

    • Skin ulceration is usually present

  • Invasive carcinomas may involve dermis in horizontal pattern for 1-2 mm

Toker Cells and Toker Cell Hyperplasia

  • Epidermally located breast ductal epithelium

    • Most common near duct orifices

    • Present in at least 70% of normal nipples when detected with immunohistochemical studies

  • Benign appearance, bland nuclei, inconspicuous nucleoli

  • Toker cells share some IHC features with Paget cells

    • Cells are positive for CK7, CAM5.2, and EMA but are usually negative for mucin, CEA, and HER2

  • In Toker cell hyperplasia, cells are numerous and may show some nuclear atypia

    • Usually incidental finding; it would be highly unusual to be associated with clinical findings

Squamous Cell Carcinoma In Situ/Bowen Disease

  • Extensive replacement of nipple epidermis by Paget cells can mimic squamous cell carcinoma in situ

  • Squamous cell carcinoma in situ is not associated with underlying breast cancer

  • Usually positive for high molecular weight cytokeratins (CK5/6, CK20) and negative for mucin and HER2


  • Melanoma cells show nesting at dermo-epidermal junction

  • “Buck shot” spread in overlying epidermis

  • Paget cells may take up melanin pigment released by epidermal cells or melanocytes, simulating melanoma

  • Immunohistochemical staining pattern is helpful for confirming diagnosis

Clear Cell Change in Keratinocytes

  • Clear cell change, benign cytology, bland nuclei

  • More frequently seen in basal and mid layers of epidermis


1. Lester T et al: Different panels of markers should be used to predict mammary Paget’s disease associated with in situ or invasive ductal carcinoma of the breast. Ann Clin Lab Sci. 39(1):17-24, 2009

2. Park S et al: Useful immunohistochemical markers for distinguishing Paget cells from Toker cells. Pathology. 41(7):640-4, 2009

3. Di Tommaso L et al: Toker cells of the breast. Morphological and immunohistochemical characterization of 40 cases. Hum Pathol. 39(9):1295-300, 2008

4. Liegl B et al: Mammary and extramammary Paget’s disease: an immunohistochemical study of 83 cases. Histopathology. 50(4):439-47, 2007

Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Ductal Carcinoma In Situ, Paget Disease

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