Definition/General
Introduction:
Medullary carcinoma of the breast is a rare special type of invasive ductal carcinoma characterized by syncytial growth pattern, high-grade nuclear features, and prominent lymphoplasmacytic infiltrate
On FNAC, it presents with highly cellular smears showing large pleomorphic cells in syncytial clusters with abundant lymphoid background
This accounts for <5% of all breast carcinomas and paradoxically has better prognosis than grade-matched ductal carcinoma NOS.
Origin:
Arises from ductal epithelium and shows circumscribed growth pattern
Characterized by pushing rather than infiltrative borders
Associated with BRCA1 mutations in hereditary breast cancer syndrome
Triple-negative phenotype is typical.
Classification:
WHO recognizes typical medullary carcinoma (strict criteria) and atypical medullary carcinoma (partial criteria)
Strict criteria include >75% syncytial pattern, moderate to marked lymphoplasmacytic infiltrate, complete histological circumscription, nuclear pleomorphism, and lack of tubule formation.
Epidemiology:
Represents 3-5% of all breast carcinomas
Mean age 45-52 years, younger than ductal carcinoma NOS
Higher prevalence in BRCA1 mutation carriers (13% vs 2%)
More common in premenopausal women
Associated with dense breast tissue.
Clinical Features
Presentation:
Well-circumscribed, mobile breast mass
Rapid growth may be reported
Often large at presentation (mean size 3-5 cm)
May feel softer than typical breast cancer due to cellular composition.
Symptoms:
Palpable breast lump in younger women
Mass may be tender due to inflammatory infiltrate
Skin changes uncommon despite large size
Nipple discharge rare.
Risk Factors:
BRCA1 germline mutations (10-15% of medullary carcinomas)
Young age <50 years
Dense breast tissue
Family history of breast/ovarian cancer
Jewish ancestry (Ashkenazi).
Screening:
Regular clinical examination in high-risk women
Mammography shows circumscribed mass without spiculation
Ultrasound demonstrates hypoechoic lesion with well-defined borders
MRI shows rapid enhancement pattern.
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Gross Description
Appearance:
Well-circumscribed mass with smooth, pushing borders
Cut surface shows gray-tan to pink coloration
Soft, fleshy consistency
May show areas of hemorrhage or necrosis in large tumors.
Characteristics:
Encapsulated or pseudo-encapsulated appearance
Bulging cut surface
No significant desmoplastic reaction
Absence of chalky white appearance typical of ductal carcinoma.
Size Location:
Usually 2-6 cm diameter at diagnosis
Any quadrant may be involved
Tends to be larger than other breast cancers at presentation
Multifocality uncommon.
Multifocality:
Unifocal disease in majority of cases
Bilateral occurrence rare
Associated DCIS component uncommon
Lymph node involvement less frequent than grade-matched ductal carcinoma.
Microscopic Description
Histological Features:
Syncytial sheets of large pleomorphic cells with vesicular nuclei and prominent nucleoli
>75% syncytial pattern required for diagnosis
Minimal tubule formation (<25%)
Prominent lymphoplasmacytic infiltrate at periphery and within tumor.
Cellular Characteristics:
Large epithelial cells with abundant eosinophilic cytoplasm
High-grade nuclear features (grade 3)
Vesicular chromatin with prominent nucleoli
Frequent mitotic figures
Multinucleated giant cells may be present.
Architectural Patterns:
Syncytial growth pattern predominant
Sheets and trabeculae of cells without gland formation
Pushing borders rather than infiltrative pattern
Absence of single file growth
Minimal stromal desmoplasia.
Grading Criteria:
Nuclear grade 3 by definition
Architectural score 3 (no tubule formation)
Mitotic count typically high (>20 per 10 HPF)
Overall histological grade III despite better prognosis.
Immunohistochemistry
Positive Markers:
CK7 positive
CK8/18 positive
E-cadherin positive
p53 commonly overexpressed (60-80%)
Ki-67 high proliferation index (>30%)
Vimentin may be positive.
Negative Markers:
ER negative (90-95% cases)
PR negative (90-95% cases)
HER2/neu negative (>95% cases)
CK5/6 variable
GCDFP-15 negative
Mammaglobin variable.
Diagnostic Utility:
Triple-negative phenotype (ER-/PR-/HER2-) typical
p53 overexpression supports diagnosis
High Ki-67 reflects proliferative activity
Cytokeratin positivity confirms epithelial origin.
Molecular Subtypes:
Predominantly basal-like subtype of triple-negative breast cancer
p53 pathway alterations common
EGFR expression in subset of cases
High-grade features typical.
Molecular/Genetic
Genetic Mutations:
BRCA1 mutations in 10-15% sporadic cases
TP53 mutations in 60-80% cases
PIK3CA mutations less common
Homologous recombination deficiency signature.
Molecular Markers:
p53 pathway alterations predominant
RB pathway alterations common
DNA damage response pathway defects
High tumor mutational burden in subset.
Prognostic Significance:
Better prognosis than grade-matched triple-negative ductal carcinoma
10-year survival 60-80% vs 40-50% for TNBC
Lower propensity for nodal metastasis.
Therapeutic Targets:
DNA damage response pathway inhibitors (PARP inhibitors)
Immunotherapy candidates due to tumor-infiltrating lymphocytes
Platinum-based chemotherapy responsive.
Differential Diagnosis
Similar Entities:
High-grade ductal carcinoma NOS
Inflammatory carcinoma
Lymphoma of breast
Metaplastic carcinoma
Atypical medullary carcinoma
Lymphoepithelial-like carcinoma.
Distinguishing Features:
Ductal carcinoma NOS: infiltrative borders, desmoplastic stroma, variable ER/PR status
Lymphoma: hematologic markers positive, epithelial markers negative
Inflammatory carcinoma: dermal lymphatic invasion.
Diagnostic Challenges:
Distinction from high-grade ductal carcinoma requires assessment of growth pattern
Lymphoma exclusion important in lymphocyte-rich cases
Metaplastic carcinoma may have overlapping features.
Rare Variants:
Atypical medullary carcinoma with partial criteria
Lymphoepithelial-like carcinoma with prominent lymphoid stroma
Medullary carcinoma with neuroendocrine differentiation rare.
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.
Site and Procedure
Site: [breast location], Procedure: Fine needle aspiration cytology
Adequacy
Adequate for evaluation - highly cellular specimen
Cellularity
High cellularity with cohesive epithelial cell clusters
Cellular Pattern
Syncytial sheets and large clusters of epithelial cells
Nuclear Features
High-grade nuclei with marked pleomorphism, vesicular chromatin, prominent nucleoli
Cytoplasmic Features
Abundant eosinophilic cytoplasm with indistinct cell borders
Background
Prominent lymphoplasmacytic infiltrate, occasional histiocytes
Special Features
Absence of myoepithelial cells, minimal stromal fragments
Cytological Diagnosis
Highly suspicious for high-grade carcinoma, consistent with medullary carcinoma (Category V)
Recommendation
Histopathological confirmation recommended for definitive diagnosis and assessment of growth pattern