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]