Definition/General
Introduction:
Paget disease of the nipple is a rare form of breast cancer characterized by the infiltration of the epidermis of the nipple and areola by malignant glandular epithelial cells (Paget cells)
It is almost always associated with an underlying in situ or invasive carcinoma of the breast.
Origin:
The Paget cells are believed to originate from an underlying ductal carcinoma (usually DCIS) and migrate along the lactiferous ducts to the nipple epidermis
This is known as the epidermotropic theory.
Classification:
It is considered a form of intraepidermal adenocarcinoma
The clinical presentation is key to the diagnosis
The underlying carcinoma determines the stage and prognosis.
Epidemiology:
It accounts for 1-3% of all breast cancers
It typically affects women over the age of 50
It can also occur in men, but this is very rare.
Clinical Features
Presentation:
Presents as a chronic, eczematous-like lesion of the nipple and areola
The lesion may be crusted, scaly, or ulcerated
Itching, burning, and nipple discharge (often bloody) are common symptoms.
Symptoms:
The lesion is often mistaken for benign dermatological conditions like eczema or psoriasis, leading to a delay in diagnosis
A palpable breast mass is present in about 50-60% of cases.
Risk Factors:
The risk factors are those of the underlying breast carcinoma
These include age, family history, and hormonal factors.
Screening:
The diagnosis is often delayed because of its resemblance to benign skin conditions
A high index of suspicion is needed for any persistent nipple lesion
Mammography and ultrasound are used to evaluate for an underlying mass.
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Gross Description
Appearance:
The nipple and areola appear erythematous, scaly, and crusted
Ulceration and nipple retraction may be present
An underlying breast mass may or may not be palpable or visible.
Characteristics:
The skin changes can be subtle initially and progress over time
The extent of the skin involvement is variable.
Size Location:
The lesion is confined to the nipple-areolar complex
The size of the underlying carcinoma is variable.
Multifocality:
The underlying carcinoma can be multifocal.
Microscopic Description
Histological Features:
The hallmark is the presence of Paget cells within the epidermis of the nipple
These are large, atypical cells with abundant pale cytoplasm and large, pleomorphic nuclei with prominent nucleoli
They are typically arranged singly or in small clusters.
Cellular Characteristics:
Paget cells are round or oval with clear or eosinophilic cytoplasm that is rich in mucin (PAS-positive, diastase-resistant)
The nuclei are hyperchromatic and irregular.
Architectural Patterns:
The Paget cells are found scattered throughout the epidermis, particularly in the basal layer
They can form small nests or glandular structures
An underlying DCIS or invasive carcinoma is present in over 95% of cases.
Grading Criteria:
The grade is determined by the underlying invasive carcinoma, if present.
Immunohistochemistry
Positive Markers:
Paget cells are positive for Cytokeratin 7 (CK7), EMA, and CEA
They are also positive for HER2 in a high percentage of cases
GATA3 is a sensitive marker
ER and PR status depends on the underlying carcinoma.
Negative Markers:
Paget cells are negative for Cytokeratin 20 (CK20) and S100 protein
This helps distinguish them from melanoma cells and Toker cells (benign intraepidermal clear cells).
Diagnostic Utility:
IHC is crucial for diagnosis and differentiating from other conditions
CK7+/CK20- profile is characteristic
HER2 status is important for therapy.
Molecular Subtypes:
The molecular subtype is determined by the underlying carcinoma
HER2-positive and luminal subtypes are common.
Molecular/Genetic
Genetic Mutations:
The genetic alterations are those of the associated underlying breast carcinoma, such as TP53 mutations and PIK3CA mutations.
Molecular Markers:
HER2 amplification is a common finding
The molecular profile of the Paget cells is identical to that of the underlying carcinoma.
Prognostic Significance:
The prognosis is determined by the stage of the underlying breast cancer (size, grade, node status)
If no underlying mass is palpable and no invasive cancer is found, the prognosis is excellent
The presence of an invasive carcinoma worsens the prognosis.
Therapeutic Targets:
Treatment is directed at the underlying breast cancer
This usually involves surgery (mastectomy or breast-conserving surgery with removal of the nipple-areolar complex), radiation, and systemic therapy based on the hormone receptor and HER2 status.
Differential Diagnosis
Similar Entities:
Eczema of the nipple
Psoriasis
Bowen's disease (squamous cell carcinoma in situ)
Malignant melanoma
Toker cell hyperplasia.
Distinguishing Features:
Eczema and psoriasis do not have malignant cells on biopsy
Bowen's disease is positive for p63 and high molecular weight cytokeratins
Melanoma is S100 and Melan-A positive
Toker cell hyperplasia consists of benign clear cells that are CK7 positive but lack the atypia of Paget cells.
Diagnostic Challenges:
The clinical appearance can be very similar to benign inflammatory conditions
A biopsy is essential for diagnosis
Distinguishing Paget cells from melanoma cells or Toker cells requires IHC.
Rare Variants:
Paget disease can rarely be associated with an underlying invasive lobular carcinoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[specimen type], measuring [size] cm in greatest dimension
Diagnosis
[diagnosis name]
Classification
Classification: [classification system] [grade/type]
Histological Features
Shows [architectural pattern] with [nuclear features] and [mitotic activity]
Size and Extent
Size: [X] cm, extent: [local/regional/metastatic]
Margins
Margins are [involved/uninvolved] with closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined
Special Studies
IHC: [marker]: [result]
Molecular: [test]: [result]
[other study]: [result]
Final Diagnosis
Final diagnosis: [complete diagnosis]