Definition/General

Introduction:
-Invasive lobular carcinoma (ILC) represents the second most common type of breast cancer after ductal carcinoma
-It constitutes 10-15% of all invasive breast cancers
-It arises from the terminal duct-lobular unit (TDLU) and demonstrates characteristic single-file infiltration pattern with loss of E-cadherin expression.
Origin:
-Originates from the epithelial cells lining the mammary lobules
-Specifically from the terminal duct-lobular unit (TDLU)
-The neoplastic transformation involves loss of E-cadherin expression
-It leads to loss of cellular cohesion
-It results in characteristic single-file infiltration pattern.
Classification:
-Classified as in situ (LCIS) or invasive (ILC)
-LCIS shows malignant cells confined within basement membrane
-ILC demonstrates stromal invasion
-Grading follows Nottingham system
-Grade I (well-differentiated)
-Grade II (moderately differentiated)
-Grade III (poorly differentiated).
Epidemiology:
-Peak incidence in 6th-7th decades
-Risk factors include age
-Family history
-BRCA1/2 mutations
-Early menarche
-Late menopause
-Nulliparity
-Hormone replacement therapy
-Obesity
-Indian population shows increasing incidence with westernization of lifestyle.

Clinical Features

Presentation:
-Palpable mass (less common than ductal)
-Nipple discharge (rare)
-Skin changes (peau d'orange, dimpling)
-Nipple retraction
-Axillary lymphadenopathy
-Bilateral involvement (more common than ductal)
-Multicentric disease (frequent).
Symptoms:
-Pain (20% cases)
-Nipple discharge (5-10%)
-Skin ulceration
-Weight loss (advanced cases)
-Bone pain (metastatic disease)
-Respiratory symptoms (pulmonary metastases)
-Neurological symptoms (brain metastases).
Risk Factors:
-Age >50 years
-Family history (especially first-degree relative)
-BRCA1/2 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:
-Firm, irregular mass with ill-defined margins
-Gray-white cut surface with areas of necrosis and hemorrhage
-Size varies from microscopic to >10 cm
-Cut surface shows gritty consistency due to calcifications.
Characteristics:
-Gray-white to yellow-tan cut surface with areas of necrosis
-Hemorrhage and cystic degeneration
-Calcifications may be visible as gritty areas
-Margins are typically irregular and infiltrative.
Size Location:
-Variable size (0.5-15 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 30-40% cases
-Multicentric in 15-20%
-Contralateral breast involvement in 10-15% cases
-Lymph node involvement correlates with tumor size and grade.

Microscopic Description

Histological Features:
-Malignant epithelial cells forming single-file infiltration pattern
-Cells show nuclear pleomorphism
-Prominent nucleoli
-Increased nuclear-cytoplasmic ratio
-Mitotic activity
-Targetoid appearance around ducts and lobules.
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:
-Single-file infiltration pattern with targetoid appearance
-Variants include alveolar pattern
-Solid pattern
-Tubulolobular pattern
-Pleomorphic pattern
-Signet ring cell pattern
-LCIS 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 (80-90%)
-PR (70-80%)
-HER2 (5-10%)
-CK7
-CK8/18
-EMA
-GCDFP-15
-Mammaglobin
-Triple-negative: ER-
-PR-
-HER2-
-Luminal A: ER+
-PR+
-HER2-
-Luminal B: ER+
-PR+
-HER2+.
Negative Markers:
-E-cadherin (characteristically negative)
-CK5/6
-CK14
-CK17
-p63
-Calponin
-S-100
-Smooth muscle actin
-These markers help distinguish from ductal carcinoma.
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:
-Luminal A (ER+, PR+, HER2-, low Ki-67)
-Luminal B (ER+, PR+, HER2+, high Ki-67)
-HER2-enriched (ER-, PR-, HER2+)
-Triple-negative (ER-, PR-, HER2-)
-Normal-like (ER+, PR+, HER2-, low Ki-67).

Molecular/Genetic

Genetic Mutations:
-CDH1 mutations (60-80%)
-TP53 mutations (20-30%)
-PIK3CA mutations (30-40%)
-GATA3 mutations (15-20%)
-MAP3K1 mutations (10%)
-BRCA1/2 mutations (5-10% hereditary cases).
Molecular Markers:
-HER2 amplification (5-10%)
-ER/PR expression (80-90%)
-Ki-67 proliferation index (variable)
-p53 overexpression
-Cyclin D1 amplification
-EGFR overexpression (triple-negative cases).
Prognostic Significance:
-Molecular subtypes determine prognosis
-Luminal A (best prognosis)
-Luminal B (intermediate prognosis)
-HER2-enriched (poor prognosis, but treatable)
-Triple-negative (worst prognosis)
-CDH1 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 (E-cadherin positive, ductal architecture)
-Metaplastic carcinoma (spindle cell component, p63 positive)
-Medullary carcinoma (lymphocytic infiltrate, pushing margins)
-Mucinous carcinoma (abundant mucin)
-Tubular carcinoma (well-formed tubules).
Distinguishing Features:
-Lobular carcinoma: E-cadherin negative
-Lobular carcinoma: Single file pattern
-Lobular carcinoma: Targetoid appearance
-Ductal: E-cadherin positive
-Ductal: Ductal architecture
-Ductal: Desmoplastic stroma
-Metaplastic: Spindle cell component
-Metaplastic: p63 positive
-Medullary: Pushing margins
-Medullary: Lymphocytic infiltrate.
Diagnostic Challenges:
-Distinguishing LCIS from ALH (extent, architecture, nuclear grade)
-Invasive from in situ disease (basement membrane integrity)
-Low-grade lobular from tubular carcinoma
-High-grade lobular from metaplastic carcinoma
-Immunohistochemistry crucial for accurate classification.
Rare Variants:
-Pleomorphic lobular carcinoma (high-grade nuclei)
-Apocrine lobular carcinoma (apocrine features, AR positive)
-Secretory lobular carcinoma (young patients, t(12;15))
-Adenoid cystic lobular carcinoma (basaloid pattern, MYB rearrangement)
-Neuroendocrine lobular 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

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Classification

Classification: [classification system] [grade/type]

Histological Features

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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

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Final Diagnosis

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