Definition/General
Introduction:
Fibrocystic disease (fibrocystic changes) is the most common benign breast condition affecting 60-75% of women during their reproductive years
It represents a spectrum of benign histological changes including cysts, fibrosis, adenosis, epithelial proliferation, and apocrine metaplasia
FNAC shows characteristic diverse cytological features reflecting the underlying histological heterogeneity
The condition is hormonally mediated and shows cyclical variations.
Origin:
Fibrocystic changes originate from hormonal imbalance particularly estrogen dominance and relative progesterone deficiency
The changes primarily affect the terminal duct-lobular unit (TDLU) of the breast
Stromal fibrosis and ductal epithelial proliferation occur in response to cyclical hormonal stimulation
Cyst formation results from ductal obstruction and secretory activity
Apocrine metaplasia is a common accompaniment.
Classification:
Classified as C2 (Benign) in the Bethesda System for breast cytopathology
Subtypes include simple cysts (most common), complex fibrocystic changes with proliferative features, sclerosing adenosis, and apocrine metaplasia
Atypical epithelial proliferation may occasionally be present requiring correlation with histology
Papillary features may be seen in some cases.
Epidemiology:
Peak incidence in 3rd to 5th decades of life (20-50 years)
Affects 60-75% of women during reproductive years
Symptoms increase in the week before menstruation
Bilateral involvement is common (60-70%)
Regression occurs after menopause in most cases
HRT use may perpetuate symptoms in postmenopausal women.
Clinical Features
Presentation:
Breast pain and tenderness (mastalgia) especially premenstrual (80-90%)
Breast nodularity and lumpiness on palpation (70-80%)
Breast swelling and fullness during menstrual cycle
Multiple small cysts may be palpable
Nipple discharge (serous or green) in 10-15% of cases
Bilateral involvement with asymmetric presentation common.
Symptoms:
Cyclical breast pain (mastalgia) worsening before menstruation (80-90%)
Breast tenderness and sensitivity to touch
Feeling of breast fullness and heaviness
Nipple discharge may be spontaneous or expressible (10-15%)
Anxiety and concern about breast cancer (common psychological component)
Sleep disturbance due to breast discomfort in severe cases.
Risk Factors:
Reproductive age (20-50 years) is primary risk factor
Nulliparity or late first pregnancy (>30 years)
Early menarche (<12 years) and late menopause (>55 years)
Caffeine consumption may exacerbate symptoms
High-fat diet and obesity
Stress and hormonal imbalance
Family history of breast disease (genetic predisposition).
Screening:
Clinical breast examination reveals nodular, "lumpy-bumpy" breast texture
Breast ultrasound shows multiple small cysts and echogenic areas
Mammography demonstrates scattered fibroglandular densities and cysts
BI-RADS 2 (benign) categorization typically assigned
FNAC indicated for discrete palpable masses or dominant lesions
MRI rarely required unless high-risk features present.
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Gross Description
Appearance:
FNAC specimen shows variable cellularity depending on the predominant component sampled
Cystic fluid aspirate may be obtained from cystic areas (serous, greenish, or brownish)
Foamy, proteinaceous background common due to cyst contents
Hemorrhagic background may be present from vascular areas
Mucoid material may be seen in areas with apocrine metaplasia.
Characteristics:
Multiple slide preparations may show different cellular components from the same lesion
Cyst fluid may contain abundant proteinaceous material and debris
Thick, viscous aspirate from areas of fibrosis
Cellular yield variable ranging from paucicellular to moderately cellular
Background debris and inflammatory cells commonly present
Crystalline material may be identified in some cases.
Size Location:
Epithelial cells show size variation due to different components (ductal cells 15-20 μm, apocrine cells 20-30 μm)
Apocrine cells are distinctly larger with abundant eosinophilic cytoplasm
Foam cells (macrophages) measure 20-40 μm with foamy cytoplasm
Stromal fibroblasts are spindle-shaped measuring 20-30 μm in length
Inflammatory cells of various sizes depending on type.
Multifocality:
Multifocal involvement typical with different areas showing varying pathology
Cystic areas yield predominantly cyst macrophages and proteinaceous debris
Fibrotic areas show predominantly spindle stromal cells
Areas of epithelial proliferation yield increased ductal cells
Apocrine areas demonstrate characteristic apocrine cells
Sampling from multiple areas may be necessary for comprehensive diagnosis.
Microscopic Description
Histological Features:
Spectrum of benign changes including cyst macrophages, apocrine cells, and epithelial proliferation
Foamy macrophages (cyst macrophages) with abundant foamy cytoplasm and eccentric nuclei
Apocrine metaplastic cells with abundant eosinophilic, granular cytoplasm and prominent nucleoli
Ductal epithelial cells in sheets or clusters with mild proliferative changes
Stromal fibroblasts and inflammatory cells in background
Proteinaceous debris and cyst contents creating dirty background.
Cellular Characteristics:
Cyst macrophages with foamy, vacuolated cytoplasm and small, eccentric nuclei
Apocrine cells with abundant eosinophilic cytoplasm, prominent nucleoli, and occasionally binucleated forms
Ductal cells showing mild nuclear enlargement and prominent nucleoli
Myoepithelial cells may be present at periphery of epithelial clusters
Inflammatory cells including lymphocytes, plasma cells, and neutrophils
Hemosiderin-laden macrophages may be present.
Architectural Patterns:
Loosely cohesive epithelial sheets with mild overlapping and crowding
Apocrine cells singly dispersed or in loose clusters
Foam cells scattered individually throughout the background
Epithelial proliferation may show mild architectural complexity
Papillary fragments occasionally present
Calcifications may be seen as refractile crystalline material.
Grading Criteria:
Bethesda Category C2 (Benign) for typical fibrocystic changes
Adequacy assessment requires presence of characteristic cellular components
Atypia assessment important to exclude atypical ductal hyperplasia
Proliferative activity should remain within benign limits
Papillary features require careful evaluation and possible core biopsy
Clinical correlation essential for appropriate categorization.
Immunohistochemistry
Positive Markers:
Ductal epithelial cells: CK7, CK8/18, E-cadherin positive (95-100%)
Apocrine cells: GCDFP-15, androgen receptor (AR) positive (70-90%)
Cyst macrophages: CD68, CD163 positive (95-100%)
Myoepithelial cells: p63, calponin, smooth muscle actin positive
Epithelial cells: EMA, cytokeratin cocktail positive
Stromal fibroblasts: vimentin positive.
Negative Markers:
Ductal cells: CK5/6 typically negative (helps exclude squamous differentiation)
Apocrine cells: ER/PR typically negative (characteristic feature)
Macrophages: cytokeratins negative (excludes epithelial nature)
Epithelial cells: vimentin negative
All components: S-100 negative (excludes neural differentiation)
High-grade markers: p53, Ki-67 low.
Diagnostic Utility:
Immunohistochemistry rarely required for typical fibrocystic disease diagnosis
GCDFP-15 and AR confirm apocrine differentiation when morphology unclear
CD68 confirms macrophage nature of foam cells
p63 and calponin highlight myoepithelial cells in proliferative areas
Ki-67 may be useful in assessing proliferative activity
Research applications in studying hormonal effects on breast tissue.
Molecular Subtypes:
No specific molecular subtypes recognized for fibrocystic disease
Hormone-responsive subtype shows ER/PR expression in stromal and some epithelial cells
Apocrine-rich variant shows AR positivity and ER/PR negativity
Proliferative subtype shows increased Ki-67 but remains within benign limits
Inflammatory subtype shows increased inflammatory markers
Sclerotic subtype shows predominant fibroblastic markers.
Molecular/Genetic
Genetic Mutations:
No specific genetic mutations associated with fibrocystic disease
Hormonal pathway alterations may affect gene expression patterns
BRCA1/BRCA2 wild-type in typical cases
Proliferative forms may show low-level chromosomal instability
Complex fibrocystic changes may harbor minor genetic alterations
Age-related changes in DNA repair mechanisms may contribute.
Molecular Markers:
Low proliferation markers with Ki-67 typically <10%
p53 wild-type expression pattern in most cases
Hormone receptors variably expressed depending on menstrual cycle phase
Apoptosis regulators (BCL2, BAX) normally expressed
Cell cycle regulators (cyclin D1, p21) within normal limits
Growth factors (IGF-1, TGF-β) may be upregulated.
Prognostic Significance:
Excellent prognosis with no malignant potential in typical cases
Simple fibrocystic changes do not increase breast cancer risk
Complex fibrocystic changes with atypia may slightly increase cancer risk (1.5-2x)
Proliferative forms without atypia have minimal cancer risk increase
Sclerosing adenosis may be associated with slightly increased cancer risk
Regular surveillance recommended for complex lesions.
Therapeutic Targets:
Hormonal modulation primary therapeutic approach (oral contraceptives, progesterone)
Anti-inflammatory agents for symptomatic relief
Selective estrogen receptor modulators (SERMs) in severe cases
Aromatase inhibitors rarely used in postmenopausal women
Lifestyle modifications including dietary changes and caffeine reduction
Vitamin E supplementation may provide symptomatic relief.
Differential Diagnosis
Similar Entities:
Fibroadenoma shows biphasic pattern with epithelial and stromal cells
Phyllodes tumor demonstrates increased stromal cellularity and atypia
Papilloma shows complex papillary architecture
Atypical ductal hyperplasia demonstrates epithelial atypia and architectural complexity
Low-grade ductal carcinoma shows malignant cytological features
Inflammatory breast conditions show predominant inflammatory infiltrate.
Distinguishing Features:
Fibrocystic disease shows diverse benign changes with foam cells and apocrine cells
Fibroadenoma demonstrates uniform biphasic pattern with bland stromal cells
Phyllodes tumor shows increased stromal atypia and mitotic activity
Papilloma demonstrates complex papillary fragments with fibrovascular cores
ADH shows nuclear atypia and architectural distortion
Carcinoma demonstrates frankly malignant cytological features.
Diagnostic Challenges:
Atypical proliferative changes may be difficult to classify on FNAC alone
Papillary features require differentiation from papilloma and papillary carcinoma
Sampling adequacy issues due to cystic nature of many lesions
Hormonal variations cause cyclical changes in cellular morphology
Technical artifacts may obscure cellular details
Clinical correlation essential for accurate interpretation.
Rare Variants:
Sclerosing adenosis with increased stromal and epithelial proliferation
Complex fibrocystic changes with calcifications and atypical features
Apocrine adenosis with predominant apocrine cell proliferation
Microglandular adenosis with small glandular proliferation
Papillary apocrine change with papillary architecture
Pseudolactational change in pregnancy-related cases.
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 - representative cellular material obtained
Cytological Findings
Spectrum of benign changes including epithelial cells, apocrine cells, and foam cells consistent with fibrocystic disease
Cellular Components
Ductal epithelial cells, apocrine metaplastic cells, foam cells (cyst macrophages), scattered inflammatory cells
Epithelial Features
Benign ductal epithelial cells with mild proliferative changes. No high-grade atypia identified.
Background
Proteinaceous debris and cyst contents. Scattered inflammatory cells and foam cells.
Diagnosis
C2 - Benign: Consistent with fibrocystic disease
Bethesda Category
Category C2: Benign - fibrocystic disease
Clinical Correlation
Clinical and imaging findings consistent with benign fibrocystic changes
Recommendations
Clinical follow-up and symptomatic management as appropriate