Definition/General

Introduction:
-Medullary carcinoma represents a rare subtype of breast cancer characterized by pushing margins and prominent lymphocytic infiltrate
-It constitutes 1-7% of all invasive breast cancers
-It demonstrates high-grade morphology with paradoxically favorable prognosis compared to other high-grade breast cancers.
Origin:
-Originates from the epithelial cells lining the mammary ducts
-Specifically from the terminal duct-lobular unit (TDLU)
-The neoplastic transformation involves immune response activation
-It leads to prominent lymphocytic infiltrate
-It results in characteristic pushing margins.
Classification:
-Classified as typical medullary carcinoma (meeting all criteria) or atypical medullary carcinoma (meeting some criteria)
-Grading follows Nottingham system
-Grade III (poorly differentiated)
-High nuclear grade
-High mitotic rate.
Epidemiology:
-Peak incidence in 4th-5th decades
-Risk factors include age
-Family history
-BRCA1 mutations
-Early menarche
-Late menopause
-Nulliparity
-Hormone replacement therapy
-Obesity
-Indian population shows increasing incidence with westernization of lifestyle.

Clinical Features

Presentation:
-Palpable mass (most common)
-Nipple discharge (rare)
-Skin changes (peau d'orange, dimpling)
-Nipple retraction
-Axillary lymphadenopathy
-Well-circumscribed mass on imaging
-Soft consistency on palpation.
Symptoms:
-Pain (25% cases)
-Nipple discharge (5%)
-Skin ulceration
-Weight loss (advanced cases)
-Bone pain (metastatic disease)
-Respiratory symptoms (pulmonary metastases)
-Neurological symptoms (brain metastases).
Risk Factors:
-Age >40 years
-Family history (especially first-degree relative)
-BRCA1 mutations
-Early menarche (<12 years)
-Late menopause (>55 years)
-Nulliparity
-First pregnancy >30 years
-Hormone replacement therapy
-Obesity
-Alcohol consumption
-Radiation exposure.
Screening:
-Mammography (40+ years)
-Clinical breast examination
-Self-breast examination
-High-risk patients: MRI screening
-Genetic counseling
-Prophylactic measures.

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Gross Description

Appearance:
-Well-circumscribed, soft mass with pushing margins
-Gray-white to tan cut surface with areas of necrosis
-Size varies from 1-15 cm
-Cut surface shows soft consistency
-Hemorrhagic areas may be present.
Characteristics:
-Gray-white to tan cut surface with areas of necrosis
-Soft consistency
-Well-circumscribed margins
-Pushing borders
-Hemorrhagic areas
-Cystic degeneration may be present
-Calcifications may be visible as gritty areas.
Size Location:
-Variable size (1-15 cm)
-Commonly in upper outer quadrant (50-60%)
-Followed by upper inner quadrant (15%)
-Lower outer quadrant (10%)
-Lower inner quadrant (5%)
-Central/subareolar (10%).
Multifocality:
-Multifocal disease in 5-10% cases
-Multicentric in 3-5%
-Contralateral breast involvement in 5-10% cases
-Lymph node involvement correlates with tumor size and grade.

Microscopic Description

Histological Features:
-Malignant epithelial cells with pushing margins and prominent lymphocytic infiltrate
-Cells show nuclear pleomorphism
-Prominent nucleoli
-Increased nuclear-cytoplasmic ratio
-Mitotic activity
-Syncytial growth pattern.
Cellular Characteristics:
-Epithelial cells with pleomorphic nuclei
-Prominent nucleoli
-Increased nuclear-cytoplasmic ratio
-Mitotic figures
-Cytoplasm varies from eosinophilic to clear
-Intracytoplasmic lumina may be present.
Architectural Patterns:
-Syncytial growth pattern with pushing margins
-Variants include typical medullary pattern
-Atypical medullary pattern
-Mixed medullary pattern
-Lymphoepithelioma-like pattern
-DCIS component often present at periphery.
Grading Criteria:
-Nottingham grading system: Tubule formation (1-3 points)
-Nuclear pleomorphism (1-3 points)
-Mitotic count (1-3 points)
-Total score: Grade I (3-5 points)
-Grade II (6-7 points)
-Grade III (8-9 points).

Immunohistochemistry

Positive Markers:
-ER (10-20%)
-PR (10-20%)
-HER2 (10-20%)
-CK7
-CK8/18
-EMA
-GCDFP-15
-Mammaglobin
-Triple-negative: ER-
-PR-
-HER2-
-Luminal A: ER+
-PR+
-HER2-
-Luminal B: ER+
-PR+
-HER2+.
Negative Markers:
-CK5/6
-CK14
-CK17
-p63
-Calponin
-S-100
-Smooth muscle actin
-These markers help distinguish from metaplastic carcinoma and myoepithelial lesions.
Diagnostic Utility:
-Essential for molecular classification
-Essential for treatment decisions
-Essential for prognosis
-ER/PR positivity indicates hormone therapy benefit
-HER2 amplification indicates trastuzumab therapy
-Ki-67 proliferation index guides chemotherapy decisions.
Molecular Subtypes:
-Triple-negative (ER-, PR-, HER2-)
-Luminal A (ER+, PR+, HER2-, low Ki-67)
-Luminal B (ER+, PR+, HER2+, high Ki-67)
-HER2-enriched (ER-, PR-, HER2+)
-Normal-like (ER+, PR+, HER2-, low Ki-67).

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (60-80%)
-PIK3CA mutations (20-30%)
-GATA3 mutations (10-15%)
-MAP3K1 mutations (10%)
-CDH1 mutations (5-10%)
-BRCA1 mutations (10-20% hereditary cases).
Molecular Markers:
-HER2 amplification (10-20%)
-ER/PR expression (10-20%)
-Ki-67 proliferation index (high)
-p53 overexpression
-Cyclin D1 amplification
-EGFR overexpression (triple-negative cases).
Prognostic Significance:
-Molecular subtypes determine prognosis
-Triple-negative (intermediate prognosis)
-Luminal A (best prognosis)
-Luminal B (intermediate prognosis)
-HER2-enriched (poor prognosis, but treatable)
-BRCA1 mutations indicate hereditary risk.
Therapeutic Targets:
-ER/PR: Endocrine therapy (tamoxifen, aromatase inhibitors)
-HER2: Trastuzumab
-HER2: Pertuzumab
-HER2: Lapatinib
-PARP inhibitors: BRCA-mutated cases
-Immunotherapy: Triple-negative cases
-CDK4/6 inhibitors: ER+ cases.

Differential Diagnosis

Similar Entities:
-Ductal carcinoma (infiltrative margins, desmoplastic stroma)
-Lobular carcinoma (single file pattern, no lymphocytic infiltrate)
-Metaplastic carcinoma (spindle cell component, p63 positive)
-Mucinous carcinoma (abundant mucin, no lymphocytic infiltrate)
-Tubular carcinoma (well-formed tubules, no lymphocytic infiltrate).
Distinguishing Features:
-Medullary carcinoma: Pushing margins
-Medullary carcinoma: Prominent lymphocytic infiltrate
-Medullary carcinoma: Syncytial growth pattern
-Ductal: Infiltrative margins
-Ductal: Desmoplastic stroma
-Lobular: Single file pattern
-Lobular: No lymphocytic infiltrate
-Metaplastic: Spindle cell component
-Metaplastic: p63 positive
-Mucinous: Abundant mucin
-Mucinous: No lymphocytic infiltrate.
Diagnostic Challenges:
-Distinguishing typical from atypical medullary carcinoma (criteria fulfillment)
-Invasive from in situ disease (basement membrane integrity)
-Low-grade medullary from benign lymphocytic infiltrate
-High-grade medullary from metaplastic carcinoma
-Immunohistochemistry crucial for accurate classification.
Rare Variants:
-Lymphoepithelioma-like medullary carcinoma (prominent lymphocytic infiltrate)
-Apocrine medullary carcinoma (apocrine features, AR positive)
-Secretory medullary carcinoma (young patients, t(12;15))
-Adenoid cystic medullary carcinoma (basaloid pattern, MYB rearrangement)
-Neuroendocrine medullary carcinoma (neuroendocrine markers).

Sample Pathology Report

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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]

Prognostic Factors

Prognostic factors: [list factors]

Final Diagnosis

Final diagnosis: [complete diagnosis]