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
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
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.
