Definition/General
Introduction:
Invasive lobular carcinoma (ILC) is the second most common invasive breast cancer, accounting for 5-15% of all breast cancers
It is characterized by single-file growth pattern and loss of E-cadherin expression
FNAC diagnosis is challenging due to low cellularity and bland cytological features
The cells grow in a non-cohesive pattern infiltrating between normal breast elements
Clinical and imaging correlation is essential for accurate diagnosis.
Origin:
Lobular carcinoma originates from the terminal duct-lobular unit (TDLU) of the breast, specifically from lobular epithelium
It develops through progression from atypical lobular hyperplasia (ALH) to lobular carcinoma in situ (LCIS) to invasive lobular carcinoma
Loss of E-cadherin is the key molecular event enabling single-cell infiltrative growth
Hormonal stimulation plays a significant role in pathogenesis
Genetic alterations accumulate during progression to invasive disease.
Classification:
Classified as C4 (Suspicious) or C5 (Malignant) in Bethesda System depending on cytological features
Histological subtypes include classic lobular carcinoma (Grade 1-2), pleomorphic lobular carcinoma (Grade 3), signet ring variant, and tubulolobular variant
Mixed ductal-lobular carcinomas contain both growth patterns
Molecular subtypes are typically luminal (ER+/PR+).
Epidemiology:
Peak incidence in 6th decade of life (50-60 years)
Accounts for 5-15% of invasive breast cancers
More common in postmenopausal women
Bilateral occurrence higher than ductal carcinoma (20-30% vs 5%)
Multicentric disease present in 40-50% of cases
Indian population shows similar age distribution but lower overall incidence compared to ductal carcinoma.
Clinical Features
Presentation:
Subtle clinical presentation with ill-defined thickening rather than discrete mass (60-70%)
Often mammographically occult or shows subtle architectural distortion
Palpable mass may be absent despite significant tumor burden
Larger size at presentation compared to ductal carcinoma (average 3-4 cm)
Multifocal/multicentric disease common (40-50%)
Bilateral involvement more frequent than ductal carcinoma.
Symptoms:
Painless breast thickening or fullness (most common presentation)
Subtle skin changes including dimpling or thickening
Nipple retraction may occur with central lesions
Usually asymptomatic in early stages
Advanced cases may present with skin involvement
Axillary lymphadenopathy may be the presenting feature.
Risk Factors:
Age >50 years (postmenopausal status)
Family history of breast or ovarian cancer
Previous LCIS or atypical lobular hyperplasia
Hormone replacement therapy use
Late menopause (>55 years)
Nulliparity or late first pregnancy
BRCA2 mutations (higher association than BRCA1)
Dense breast tissue on mammography.
Screening:
Mammography may show subtle architectural distortion or asymmetry
Breast MRI superior for detection and extent assessment (90% sensitivity)
Ultrasound may show ill-defined hypoechoic area
Clinical examination often reveals subtle thickening
BI-RADS 4 or 5 categorization when suspicious features present
Tissue sampling essential for definitive diagnosis.
Master Lobular Carcinoma FNAC Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
FNAC specimen typically shows low to moderate cellularity due to single-cell infiltrative pattern
Less cellular compared to ductal carcinoma aspirates
Predominantly single cells with occasional small clusters
Clean background without significant necrosis or inflammation
May appear deceptively benign due to bland cytological features
Multiple passes often required to obtain adequate material.
Characteristics:
Individual dispersed cells rather than cohesive clusters characteristic of ductal carcinoma
Uniform, small cells with high nuclear-to-cytoplasmic ratio
Minimal background debris due to lack of central necrosis
Preservation of cell morphology better in alcohol-fixed preparations
Giemsa staining may highlight intracytoplasmic lumina
Cell block preparation helpful for immunohistochemical studies.
Size Location:
Tumor cells measure 12-18 micrometers in diameter, smaller than typical ductal carcinoma cells
Uniform cell size with minimal pleomorphism in classic type
Pleomorphic variant shows larger cells (20-25 μm) with more variation
Intracytoplasmic lumina may be present as characteristic feature
Nuclear size slightly larger than normal breast epithelial cells
Signet ring cells may be present in specific variants.
Multifocality:
Multifocal sampling often necessary due to infiltrative growth pattern
Variable cellularity from different areas of the same tumor
Areas of in situ carcinoma may show higher cellularity
Edge of tumor may show single dispersed cells only
Central areas may be more cellular with small clusters
Clinical correlation essential for adequate sampling.
Microscopic Description
Histological Features:
Single dispersed malignant cells with occasional small loose clusters
Uniform small to medium-sized cells with increased nuclear-to-cytoplasmic ratio
Round to oval nuclei with fine to moderately coarse chromatin
Small prominent nucleoli in most cells
Scant to moderate cytoplasm which may be eosinophilic or amphophilic
Intracytoplasmic lumina (targetoid appearance) may be present
Signet ring morphology in some variants.
Cellular Characteristics:
Monotonous population of malignant epithelial cells with uniform morphology
Nuclear features: round to oval with fine chromatin and small nucleoli
Nuclear-to-cytoplasmic ratio increased (approximately 1:1 to 1:2)
Cytoplasm scant to moderate, eosinophilic or amphophilic
Intracytoplasmic lumina containing eosinophilic secretions (pathognomonic feature)
Mitotic figures infrequent in classic type
Pleomorphic variant shows higher-grade nuclear features.
Architectural Patterns:
Predominantly single cell pattern (70-80% of cells) with loss of cell cohesion
Small loose clusters (2-10 cells) without overlapping
Absence of large cohesive sheets typical of ductal carcinoma
Linear arrangement may occasionally be seen
Targetoid pattern due to intracytoplasmic lumina
Indian file pattern may be represented in linear cell arrangements
Absence of papillary or complex architecture.
Grading Criteria:
Cytological grading based on nuclear features and pleomorphism
Grade 1-2 (classic type): uniform nuclei, fine chromatin, small nucleoli
Grade 3 (pleomorphic type): marked nuclear pleomorphism, coarse chromatin, prominent nucleoli
Mitotic activity generally low except in pleomorphic variant
Necrosis uncommon in cytological preparations
Assessment challenging due to bland morphology in classic type.
Immunohistochemistry
Positive Markers:
Cytokeratin cocktail (AE1/AE3, CAM5.2) positive in malignant cells (95-100%)
CK8/18 positive (characteristic of glandular epithelium)
Mammaglobin positive (breast-specific marker)
GCDFP-15 positive (gross cystic disease fluid protein)
ER (Estrogen Receptor) positive in 90-95% of cases
PR (Progesterone Receptor) positive in 70-80% of cases.
Negative Markers:
E-cadherin negative or markedly reduced (diagnostic feature - 95% of cases)
HER2 typically negative (90-95% of cases)
CK5/6 negative (excludes basal-like phenotype)
CK14 negative
p63 negative (excludes myoepithelial differentiation)
S-100 negative (excludes neural differentiation)
Vimentin negative (excludes mesenchymal origin).
Diagnostic Utility:
E-cadherin negativity is pathognomonic for lobular carcinoma (key diagnostic marker)
ER/PR positivity supports luminal phenotype and guides therapy
HER2 testing usually negative but required for treatment decisions
Ki-67 proliferation index typically low (5-15%) except in pleomorphic variant
Cytokeratin positivity confirms epithelial nature
Mammaglobin supports breast primary origin.
Molecular Subtypes:
Luminal A subtype (ER+, PR+, HER2-, low Ki-67) - most common (70-80%)
Luminal B subtype (ER+, PR+, HER2-, high Ki-67) - less common (15-20%)
HER2-positive subtype - rare in lobular carcinoma (5%)
Triple-negative subtype - very rare in classic lobular carcinoma (1-2%)
Pleomorphic lobular carcinoma may show non-luminal phenotypes more commonly.
Molecular/Genetic
Genetic Mutations:
CDH1 gene mutations (E-cadherin gene) in 50-60% of cases - key driver mutation
PIK3CA mutations (25-45%) - activating phosphatidylinositol 3-kinase pathway
TP53 mutations (10-15% in classic type, higher in pleomorphic variant)
GATA3 mutations (5-10%) - transcription factor important in breast development
TBX3 mutations (5-10%) - T-box transcription factor
FOXA1 mutations (5-10%) - pioneer transcription factor.
Molecular Markers:
E-cadherin protein loss (immunohistochemical hallmark - 95% of cases)
β-catenin redistribution from membrane to cytoplasm/nucleus
ER/PR expression (luminal gene signature)
Low proliferation markers (Ki-67 typically <15%)
Cyclin D1 amplification (20-30% of cases)
CCND1 gene amplification (chromosome 11q13)
Low-grade molecular signature in classic type.
Prognostic Significance:
Generally good prognosis when matched for stage and hormone receptor status
Luminal A subtype has excellent prognosis with appropriate endocrine therapy
Late recurrence risk similar to ductal carcinoma (5-10 years post-treatment)
Pleomorphic lobular carcinoma has worse prognosis than classic type
Bilateral breast cancer risk higher than ductal carcinoma (20-30% vs 5%)
Bone and soft tissue metastases more common than visceral metastases.
Therapeutic Targets:
Estrogen Receptor - target for endocrine therapy (tamoxifen, aromatase inhibitors)
CDK4/6 pathway - target for CDK4/6 inhibitors (palbociclib, ribociclib)
PI3K/AKT/mTOR pathway - potential target (everolimus, alpelisib)
HER2 - rarely amplified, not typical therapeutic target
Immunotherapy - limited role due to low mutation burden
PARP inhibitors - potential in cases with DNA repair deficiency.
Differential Diagnosis
Similar Entities:
Invasive ductal carcinoma shows cohesive cell clusters with ductal architecture
Metaplastic carcinoma demonstrates spindle cell features and may be E-cadherin negative
Lymphoma shows monotonous population but lymphoid morphology
Metastatic carcinoma may show single cell pattern but different immunoprofile
Lobular carcinoma in situ shows similar morphology but lacks stromal invasion
Atypical lobular hyperplasia shows bland cytology but lesser degree of atypia.
Distinguishing Features:
Lobular carcinoma shows single cell pattern with E-cadherin negativity and intracytoplasmic lumina
Ductal carcinoma demonstrates cohesive clusters with E-cadherin positivity
Lymphoma shows lymphoid morphology with negative epithelial markers
Metastatic carcinoma shows organ-specific markers (TTF-1 for lung, CDX2 for GI)
LCIS shows bland cytology without significant atypia
ALH shows minimal atypia and lower cellularity.
Diagnostic Challenges:
Low cellularity may result in false-negative diagnosis on FNAC
Bland cytological features may be mistaken for benign lesions
Sampling adequacy difficult to assess due to infiltrative growth
Pleomorphic variant may mimic high-grade ductal carcinoma
Mixed ductal-lobular features create diagnostic confusion
Clinical and imaging correlation essential for accurate diagnosis
Core needle biopsy preferred over FNAC for definitive diagnosis.
Rare Variants:
Pleomorphic lobular carcinoma shows high-grade nuclear features and increased mitotic activity
Signet ring cell variant demonstrates prominent intracytoplasmic mucin
Tubulolobular carcinoma shows mixed tubular and lobular growth patterns
Solid lobular carcinoma demonstrates solid growth with lobular cytology
Alveolar lobular carcinoma shows rounded clusters
Mixed ductal-lobular carcinoma contains both architectural patterns.
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
Fine needle aspiration cytology from [breast location], [number] of slides examined
Adequacy
Adequate for evaluation with caveats - low cellularity noted (typical for lobular lesions)
Cytological Findings
Predominantly single dispersed epithelial cells with uniform morphology and increased nuclear-cytoplasmic ratio
Cellular Pattern
Single cell pattern (>70% of cells) with minimal clustering. Loss of cellular cohesion noted.
Nuclear Features
Uniform round to oval nuclei with fine to moderate chromatin and small prominent nucleoli
Special Features
Intracytoplasmic lumina (targetoid appearance) identified in scattered cells
Background
Clean background without significant necrosis or inflammation
Diagnosis
C5 - Malignant: Features consistent with lobular carcinoma
Bethesda Category
Category C5: Malignant - lobular carcinoma
Recommendations
Core needle biopsy recommended for histological confirmation and receptor studies. E-cadherin immunostaining suggested.