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Surgical Pathology Criteria
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Paget Disease of the Breast

Definition

  • Intraepithelial involvement of the nipple by breast carcinoma cells

Alternate/Historical Names

  • Mammary Paget disease
  • Paget disease of the nipple

Diagnostic Criteria

  • Intraepithelial population of large atypical cells (Paget cells) distinct from surrounding normal epithelial cells
    • Large nuclei, prominent nucleoli
    • Abundant pale to amphophilic cytoplasm
    • Scattered individually and in clusters
      • May form small acini
  • Epidermal hyperplasia and hyperkeratosis and parakeratosis frequently present
    • May result in pseudoepitheliomatous hyperplasia
    • Underlying chronic inflammation common
  • Phenotype is similar to breast carcinoma
    • Mucin stain occasionally positive
    • CK7 highlights Paget cells
    • Melanin is detectable in Paget cells in rare cases
  • Underlying in situ or invasive breast carcinoma is found in nearly every case
    • May require extensive examination of breast tissue
    • Nearly always ductal type

Sabine Kohler MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting:: May 1, 2006

Supplemental studies

Immunohistology

  • CK7 is the most useful marker as it is not expressed by the surrounding epidermal cells
    • Normal Toker cells and Merkel cells are positive for CK7 and must be distinguished morphologically
    • CAM5.2 may be useful as a substitute as it is nearly as specific
  • Other anti-keratins and EMA will stain most Paget cells but are not as specific
  • High molecular weight cytokeratin (HMWCK) and p63 are useful complementary markers
    • Squamous carcinoma in situ is nearly always positive while Paget cells are nearly always negative
  • S100 may be expressed by Paget cells so it is not a perfect marker to rule out melanoma
  • ER and PR are variably expressed
  Paget Cells
CK7 >95%
CK20 0%
GCDFP15 50%
S100 0-26%
HMB45 0%
HMWCK rare

Differential Diagnosis

Pagetoid Squamous Cell Carcinoma In Situ Mammary Paget Disease
Atypical cells usually merge with surrounding keratinocytes Discrete population of atypical cells
Atypical cells may keratinize Atypical cells may form lumens or be mucin positive
Desmosomes and keratohyaline granules may be visible in atypical cells Desmosomes and keratohyaline granules not present
HMWCK+, p63+, CK7 negative CK7 >95%+, p63 negative, HMWCK rare
GCDFP15 negative GCDFP15 50%+

 

Melanoma In Situ Mammary Paget Disease
Substantial proportion of atypical cells sit directly on the epidermal basement membrane Atypical cells at all levels but frequently have at least one layer of normal cells separating them from the basement membrane
No lumen formation or mucin positivity Atypical cells may form lumens or be mucin positive
CK7 and other keratins negative CK7 and other broad spectrum antikeratins >95%+
S100 nearly 100%+ S100 0-26%+
HMB45 and MelanA 60-95%+ HMB45 and MelanA negative
Rare cases of Paget disease are pigmented

 

Toker Cells Mammary Paget Disease
Small-medium sized bland cells Large atypical cells
No epidermal reaction Epidermis generally shows reactive changes

  • Both are CK7+
  • Both may show small lumens (less frequently with Toker cells)
  • Both have pale cytoplasm
  • Toker cells are normal inhabitants of the nipple epidermis (see Lundquist 1999)
  • Merkel cells may also be CK7+
  • Clinical

    • Nearly all cases of mammary Paget disease are associated with underlying in situ or infiltrating breast carcinoma
      • Demonstration of underlying lesion may require extensive examination of the breast
    • Of females with known breast carcinoma, 1-4% may have Paget disease
      • Higher incidence of 1-10% reported for males
      • No clinical significance to the finding of Paget disease in a patient already known to have underlying carcinoma
    • Typical presentation is as an eczematous eruption of the nipple
      • May involve surrounding skin
      • 10-28% of Paget disease cases have no abnormality of the nipple on clinical examination

    Grading / Staging / Report

    Grading

    • Underlying carcinoma should be graded

    Staging

    • If underlying carcinoma is identified, staging is based on it's features
      • The presence of Paget disease does not influence staging
    • If no underlying carcinoma is identified, stage is Tis (Paget's)

    Report

    • Include results of stains performed

    Lists

    Processes That May Have a Prominent Pagetoid Pattern

    • Clear cell papulosis
    • Cutaneous T cell lymphoma
    • Eccrine poroma
    • Epidermotropic metastasis
    • Extramammary Paget disease
    • Langerhans cell histiocytosis
    • Langerhans cell microabscess
    • Merkel cell carcinoma
    • Paget disease of the breast
    • Pagetoid dyskeratosis
    • Sebaceous carcinoma
    • Spitz nevus
    • Squamous cell carcinoma in situ
    • Superficial spreading melanoma
    • Toker cells

    Lesions Preferentially Localized to the Nipple and Subareola

    Bibliography

    • Fu W, Mittel VK, Young SC. Paget disease of the breast: analysis of 41 patients. Am J Clin Oncol. 2001 Aug;24(4):397-400.
    • Bijker N, Rutgers EJ, Duchateau L, Peterse JL, Julien JP, Cataliotti L; EORTC Breast Cancer Cooperative Group. Breast-conserving therapy for Paget disease of the nipple: a prospective European Organization for Research and Treatment of Cancer study of 61 patients. Cancer. 2001 Feb 1;91(3):472-7.
    • Lundquist K, Kohler S, Rouse RV. Intraepidermal cytokeratin 7 expression is not restricted to Paget cells but is also seen in Toker cells and Merkel cells. Am J Surg Pathol. 1999 Feb;23(2):212-9.
    • Kohler S, Rouse RV, Smoller BR. The differential diagnosis of pagetoid cells in the epidermis. Mod Pathol. 1998 Jan;11(1):79-92.
    • Lau J, Kohler S. Keratin profile of intraepidermal cells in Paget's disease, extramammary Paget's disease, and pagetoid squamous cell carcinoma in situ. J Cutan Pathol. 2003 Aug;30(7):449-54.
    • Hitchcock A, Topham S, Bell J, Gullick W, Elston CW, Ellis IO. Routine diagnosis of mammary Paget's disease. A modern approach. Am J Surg Pathol. 1992 Jan;16(1):58-61.
    • Requena L, Sangueza M, Sangueza OP, Kutzner H. Pigmented mammary Paget disease and pigmented epidermotropic metastases from breast carcinoma. Am J Dermatopathol. 2002 Jun;24(3):189-98.
    • Sahoo S, Green I, Rosen PP. Bilateral paget disease of the nipple associated with lobular carcinoma in situ. Arch Pathol Lab Med. 2002 Jan;126(1):90-2.
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