Definition/General
Introduction:
Fibroadenoma is the most common benign breast tumor in young women, representing 50% of all breast biopsies
It is a biphasic tumor composed of both epithelial and stromal components
FNAC of fibroadenoma shows characteristic dual cell population with epithelial cells and spindle stromal cells
The cytological diagnosis has high sensitivity and specificity (85-95%) when adequate material is obtained.
Origin:
Fibroadenoma originates from the terminal duct-lobular unit (TDLU) of the breast
It represents a benign proliferation of both epithelial and stromal elements
The stromal component shows varying degrees of cellularity and myxoid change
Hormonal influence plays a significant role in development and growth
Estrogen and progesterone receptors are often present in the stromal component.
Classification:
Classified as C2 (Benign) in the Bethesda System for breast cytopathology
Subtypes include simple fibroadenoma (most common), complex fibroadenoma (with additional features), giant fibroadenoma (>5 cm), and juvenile fibroadenoma (in adolescents)
Phyllodes tumor represents the malignant counterpart with similar biphasic pattern but different biological behavior.
Epidemiology:
Peak incidence in 2nd and 3rd decades of life (15-35 years)
Accounts for 50% of breast biopsies in women under 25 years
Multiple fibroadenomas occur in 10-15% of cases
Bilateral occurrence in 5-10% of patients
Recurrence rate after excision is less than 5%
Malignant transformation is extremely rare (<1%).
Clinical Features
Presentation:
Painless, mobile breast mass is the most common presentation (90%)
Well-defined, rubbery consistency on palpation
Rapid growth may occur during pregnancy and adolescence
Size typically 1-3 cm but can be larger in giant fibroadenomas
Multiple masses may be present in some patients
Usually unilateral but bilateral occurrence possible.
Symptoms:
Asymptomatic in most cases except for presence of palpable mass
Mild breast discomfort may be present (20-30% cases)
No nipple discharge typically associated
Cyclical changes in size may occur with menstrual cycle
Rapid enlargement during pregnancy or hormone therapy
No skin changes or nipple retraction observed.
Risk Factors:
Young age (15-35 years) is the primary risk factor
African ancestry shows higher prevalence
Early menarche may be associated
Nulliparity or late first pregnancy
High-fat diet may contribute to development
Hormonal contraceptive use may influence growth
Family history of breast disease in some cases.
Screening:
Clinical breast examination reveals mobile, well-defined mass
Breast ultrasound shows characteristic hypoechoic mass with smooth margins
Mammography demonstrates well-circumscribed mass (in older patients)
BI-RADS 2 or 3 categorization typically assigned
FNAC recommended for tissue diagnosis and patient reassurance
Core needle biopsy may be preferred in some cases for histological confirmation.
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Gross Description
Appearance:
FNAC specimen shows abundant cellular material with both epithelial and stromal components
Slightly hemorrhagic aspirate due to vascular stromal tissue
Mucoid background may be present from myxoid stromal component
Good cellularity usually obtained due to high cellular content
Multiple passes may yield different cellular compositions depending on sampling area.
Characteristics:
Air-dried smears show excellent stromal cell morphology with Giemsa staining
Alcohol-fixed smears demonstrate epithelial cell details with Papanicolaou stain
Biphasic pattern evident with both cell types present
Variable cellularity depending on stromal-to-epithelial ratio in sampled area
Cell block preparation helpful for architectural assessment and ancillary studies.
Size Location:
Epithelial cells measure 15-20 micrometers in diameter arranged in cohesive clusters
Stromal cells are spindle-shaped measuring 20-30 micrometers in length
Cell size variation minimal within each cell type
Stromal cells may show mild pleomorphism but remain bland
Giant cells may occasionally be present but are benign.
Multifocality:
Sampling from different areas may show varying epithelial-to-stromal ratios
Central areas may be more stromal-rich while periphery shows more epithelial cells
Myxoid areas yield predominantly stromal cells with mucoid background
Fibrotic areas may show predominantly spindle cells
Consistent biphasic pattern should be identifiable throughout the lesion.
Microscopic Description
Histological Features:
Biphasic cell population with epithelial and mesenchymal components is diagnostic
Cohesive epithelial cell clusters showing ductal differentiation with bland nuclear features
Abundant spindle stromal cells with elongated nuclei and wispy cytoplasm
Clean background with minimal inflammatory cells
Myxoid material may be present from stromal component
Capillary fragments may be seen due to vascular stroma.
Cellular Characteristics:
Epithelial cells with uniform round to oval nuclei, fine chromatin, and moderate cytoplasm
Honeycomb arrangement of epithelial cells in clusters
Stromal cells with spindle-shaped nuclei, fine chromatin, and scant to moderate cytoplasm
Nuclear-to-cytoplasmic ratio normal in both cell types
Minimal atypia may be present in stromal cells but remains within benign limits
Mitotic activity rare in both components.
Architectural Patterns:
Cohesive epithelial clusters with maintained polarity and cell-to-cell adhesion
Staghorn configuration may be seen in epithelial clusters
Loose aggregates of spindle stromal cells without specific architecture
Single dispersed stromal cells scattered throughout smears
Epithelial-stromal interface may be identifiable in some areas
Myoepithelial cells may be present at periphery of epithelial clusters.
Grading Criteria:
Bethesda Category C2 (Benign) assigned to typical fibroadenoma
Adequacy criteria require presence of both epithelial and stromal components
Stromal cellularity should be adequate to make confident diagnosis
Epithelial component should show benign cytological features
Absence of high-grade atypia in either component
Clinical and imaging correlation essential for final diagnosis.
Immunohistochemistry
Positive Markers:
Epithelial markers: CK7, CK8/18, E-cadherin positive in ductal cells (95-100%)
Stromal markers: Vimentin strongly positive in stromal cells
CD34 positive in stromal cells (60-80%)
Smooth muscle actin may be focally positive in stromal cells
Estrogen and progesterone receptors positive in stromal cells (70-90%)
BCL2 positive in stromal component.
Negative Markers:
S-100 typically negative in stromal cells (differentiating from neural tumors)
Desmin negative in stromal cells (differentiating from smooth muscle tumors)
CD68 negative in stromal cells (differentiating from histiocytes)
Myogenin negative (differentiating from rhabdomyosarcoma)
CK5/6 typically negative in ductal cells
p63 negative in stromal cells.
Diagnostic Utility:
Immunohistochemistry rarely required for diagnosis of typical fibroadenoma on FNAC
May be helpful in distinguishing from phyllodes tumor (similar IHC profile)
Useful in cell block preparations when morphology is unclear
CD34 positivity supports diagnosis of fibroepithelial lesion
Hormone receptor status may predict response to anti-estrogen therapy
Research applications in studying fibroadenoma pathogenesis.
Molecular Subtypes:
No specific molecular subtypes recognized for fibroadenoma
Hormone receptor-positive subtype responds to anti-estrogen therapy
CD34-positive stromal cells are characteristic feature
Low Ki-67 proliferation index in both epithelial and stromal components
Normal p53 expression pattern
Absence of HER2 amplification in epithelial component.
Molecular/Genetic
Genetic Mutations:
No specific genetic mutations identified in typical fibroadenoma
Chromosomal rearrangements occasionally reported but not diagnostic
PLAG1 rearrangements described in some cases
HMGA2 rearrangements may be present
Complex fibroadenomas may show additional genetic alterations
Malignant transformation associated with acquisition of oncogenic mutations (very rare).
Molecular Markers:
Normal gene expression profile with low proliferation markers
MIB1 (Ki-67) proliferation index typically low (<5%)
p53 wild-type in vast majority of cases
BRCA1/BRCA2 wild-type unless part of hereditary syndrome
Hormone receptor genes (ESR1, PGR) expressed in stromal component
Growth factor signaling pathways may be upregulated.
Prognostic Significance:
Excellent prognosis with no malignant potential in typical cases
Low recurrence rate after complete excision (<5%)
No increased risk of breast cancer development
Complex fibroadenomas may have slightly higher cancer risk (1.5-2x)
Giant fibroadenomas may cause cosmetic problems but remain benign
Pregnancy-associated growth resolves after delivery.
Therapeutic Targets:
No specific therapeutic targets required for typical fibroadenoma
Hormone receptor-positive cases may respond to anti-estrogen therapy
Observation approach appropriate for small, typical lesions
Surgical excision for large or growing lesions
Vacuum-assisted biopsy may be used for removal of small lesions
Patient reassurance important component of management.
Differential Diagnosis
Similar Entities:
Phyllodes tumor shows similar biphasic pattern but with increased stromal cellularity and atypia
Fibrocystic changes may show stromal proliferation but lacks typical biphasic pattern
Invasive ductal carcinoma may have stromal reaction but shows malignant epithelial features
Metaplastic carcinoma shows malignant spindle cells with epithelial differentiation
Primary breast sarcoma shows purely mesenchymal proliferation
Papilloma shows complex epithelial proliferation without typical stromal component.
Distinguishing Features:
Fibroadenoma shows bland biphasic pattern with benign features in both components
Phyllodes tumor demonstrates increased stromal cellularity, atypia, and mitotic activity
Fibrocystic changes show apocrine metaplasia, foam cells, and inflammatory background
Invasive carcinoma demonstrates malignant epithelial cells with loss of cohesion
Metaplastic carcinoma shows malignant spindle cells with keratin expression
Sarcoma lacks epithelial component and shows high-grade atypia.
Diagnostic Challenges:
Sampling bias may lead to predominantly epithelial or stromal representation
Phyllodes tumor differentiation may be impossible on FNAC alone
Juvenile fibroadenoma may show increased cellularity mimicking phyllodes tumor
Pregnancy-related changes cause increased cellularity and mitotic activity
Fibroadenoma with atypia may require core biopsy for definitive diagnosis
Technical factors may affect cellular morphology and interpretation.
Rare Variants:
Complex fibroadenoma contains additional elements like sclerosing adenosis or calcifications
Giant fibroadenoma (>5 cm) may show areas of infarction and inflammation
Juvenile fibroadenoma in adolescents shows increased stromal cellularity
Cellular fibroadenoma demonstrates increased stromal cellularity without atypia
Myxoid fibroadenoma shows prominent myxoid stromal component
Hyalinized fibroadenoma in elderly patients may be paucicellular.
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 - biphasic pattern with epithelial and stromal components present
Cytological Findings
Biphasic pattern with cohesive epithelial cell clusters and abundant spindle stromal cells
Epithelial Component
Cohesive clusters of benign ductal epithelial cells with uniform morphology and maintained polarity
Stromal Component
Abundant spindle stromal cells with bland nuclear features and wispy cytoplasm
Background
Clean background with myxoid material. Minimal inflammatory cells or debris.
Diagnosis
C2 - Benign: Consistent with fibroadenoma
Bethesda Category
Category C2: Benign - fibroadenoma
Clinical Correlation
Clinical and imaging correlation recommended. Typical imaging features support diagnosis.
Recommendations
Observation appropriate for typical cases. Surgical consultation if discordant with imaging.