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Breast Disease: Pathology Reference Guide

• Robbins, Cotran & Kumar - Pathologic Basis of Disease (10th Ed.)
• Robbins & Kumar Basic Pathology (10th Ed.)
• Schwartz's Principles of Surgery (11th Ed.) - AJCC 8th Edition TNM

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1. Clinical Presentations of Breast Disease

Greater than 90% of symptomatic breast lesions are benign. Of females with cancer, about 45% have symptomatic disease, while the remainder come to attention through mammographic screening.

1.1 Lumpiness (Diffuse Nodularity)

• Usually a manifestation of normal glandular tissue or fibrocystic changes
• When pronounced, imaging studies may be needed to exclude a discrete mass
• This is the most common presenting symptom, but only 1% of such cases represent cancers

1.2 Pain (Mastalgia / Mastodynia)

• Very common; may be cyclic (with menses - due to premenstrual edema) or noncyclic
• Noncyclic pain is usually localized and may be caused by: ruptured cyst, physical injury, infection, or fat necrosis
• Often no specific lesion is identified
• Important: in approximately 5% of cases, the underlying cause is breast cancer

1.3 Palpable Mass

• Detected when 2-3 cm in size
• About 95% of palpable masses are benign
• Benign features: discrete, round or oval, rubbery, mobile (e.g., fibroadenoma, cyst)
• Malignant features: irregular (spiculated), hard (scirrhous), nonmobile - because malignant tumors invade across tissue planes
• Likelihood of malignancy increases with age:
  • Under age 40: ~10% chance of malignancy
  • Over age 50: ~60% chance of malignancy
• Distribution of carcinomas by quadrant:
  • Upper outer quadrant: ~50%
  • Each remaining quadrant: ~10%
  • Central/subareolar region: ~20%

1.4 Nipple Discharge

• Normal in small quantities if bilateral
• Milky discharge (galactorrhea): associated with elevated prolactin (pituitary adenoma), hypothyroidism, anovulatory syndromes, oral contraceptives, tricyclic antidepressants, methyldopa, phenothiazines - not a feature of malignancy
• Bloody or serous discharge: most commonly due to large duct papillomas and cysts
• Discharge of greatest concern for malignancy: spontaneous, unilateral, bloody, in an older patient
• Discharge associated with malignancy (most commonly DCIS) accounts for 7% of cases in women under 60, and 30% in women 60 years or older

1.5 Inflammatory Changes

• Erythema and edema involving all or part of a breast
• Most often caused by infections, usually in the setting of lactation/breastfeeding (acute bacterial mastitis)
• Critical mimic: "Inflammatory" breast carcinoma - must always be considered when evaluating breast inflammation

1.6 Mammographic Abnormalities (Asymptomatic)

• Most cancers in women over 50 are now detected by mammography
• Principal mammographic signs of breast carcinoma: densities and calcifications
• Sensitivity and specificity of mammography increase with age
• Likelihood that an abnormal mammographic finding is malignant:
  • Age 40: ~10%
  • Over age 50: >25%

1.7 Gynecomastia (Males)

• The only common breast symptom in males
• Increase in both stroma and epithelial cells due to an imbalance between estrogens (stimulatory) and androgens (inhibitory)

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2. Types of Epithelial Lesions of the Breast

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Group 1: Nonproliferative Breast Changes (Fibrocystic Changes)

• Most common between ages 30-50 years, possibly due to cyclic hormonal changes

• Small cysts form by dilation of lobules and terminal ducts, lined by flattened atrophic epithelium
• Large cysts (>3 mm) have a blue-dome appearance grossly (tension cysts)
• Apocrine metaplasia is common - cells with abundant granular eosinophilic cytoplasm resembling apocrine sweat gland cells

• Cyst rupture releases secretions into stroma, causing chronic inflammation and fibrosis
• Dense fibrous tissue replaces normal breast stroma

• Increase in the number of acini per lobule
• Regular form is normal during pregnancy; in pathological adenosis, acini may be enlarged
• Sclerosing adenosis: a specific variant - enlarged terminal duct lobular unit with compressed and distorted acini in dense fibrotic stroma; can mimic carcinoma clinically and radiologically; calcifications may be present

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Group 2: Proliferative Breast Disease Without Atypia

• Increase in the number of cells in acini and ducts relative to the basement membrane
• Cells fill and distend the lumen; irregular "streaming" pattern of cells with overlapping nuclei
• Variable cell morphology

• Florid form associated with slightly increased cancer risk

• Central nidus of small tubules entrapped in a densely fibrotic stroma with long radiating projections
• Radiographically mimics carcinoma (irregular central mass with spiculated projections)
• Microscopically: epithelium shows varying degrees of cyst formation, hyperplasia, and adenosis in projections

• Papillary growth within a large duct, with a central fibrovascular core lined by myoepithelial and luminal cells
• Presents as spontaneous, often bloody nipple discharge
• Usually solitary (central), located in the large ducts below the nipple
• Multiple peripheral papillomas carry a slightly higher cancer risk

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Group 3: Proliferative Breast Disease With Atypia (Atypical Hyperplasia)

• Monomorphic proliferation that partially fills ducts
• Has some but not all histologic features of low-grade ductal carcinoma in situ (DCIS)
• Differs from DCIS: smaller in extent, incompletely fills duct spaces, or lacks high-grade nuclear features
• Found in ~10% of biopsies performed to evaluate calcifications

• Clonal proliferation of cells with features similar to lobular carcinoma in situ (LCIS), but incompletely fills or distends fewer than 50% of the acini in a lobule
• Incidental finding; found in <5% of biopsies
• Identical cytology to LCIS (small, uniform, discohesive cells lacking E-cadherin expression)

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Group 4: Carcinoma In Situ (High Risk / Precursor Lesions)

• Malignant epithelial cells confined within the basement membrane
• Most common form of noninvasive carcinoma (~80% of carcinoma in situ)
• Classified by architectural pattern (comedo, cribriform, solid, papillary, micropapillary) and nuclear grade (low, intermediate, high)
• Comedo DCIS: high-grade cells with central necrosis; calcifications are common (detected on mammography)
• Without treatment, ~50% will progress to invasive carcinoma within 10 years

• Clonal proliferation of cells with lobular cytology that fills and distends acini
• Generally incidental finding; not usually detectable on mammography
• Cells are small, uniform, round/discohesive, with intracytoplasmic mucin vacuoles
• Lack E-cadherin (diagnostic immunohistochemical marker)
• Removed from TNM staging in AJCC 8th edition - classified as a benign entity / risk indicator
• Bilateral in ~20-40% of patients

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Columnar Cell Lesions and Flat Epithelial Atypia

• Thought to be the earliest morphologically recognizable precursors in the low-grade breast neoplasia pathway
• Present as calcifications on mammographic screening
• Columnar cell lesions: variably dilated acini lined by columnar epithelial cells, often with apical snouts, with microcalcifications
• Flat epithelial atypia (FEA): columnar cell lesion with cytologic atypia but without architectural complexity (distinguishes it from ADH)

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3. TNM Staging of Breast Cancer (AJCC 8th Edition)

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T - Primary Tumor

Note: LCIS is removed from TNM staging in the AJCC 8th edition - classified as a benign entity.

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N - Regional Lymph Nodes

Clinical N (cN)

Pathologic N (pN)

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M - Distant Metastasis

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Anatomic Stage Groups (AJCC 8th Edition)

Special notations:

• "c" or "p" prefix denotes clinical vs. pathologic staging (pathologic takes precedence for T)
• "sn" suffix = sentinel node biopsy confirmation
• "f" suffix = FNA/core needle biopsy confirmation (no further node resection)
• Staging after neoadjuvant therapy uses "yc" or "yp" prefix
• No anatomic stage group is assigned for complete pathological response (pCR): ypT0ypN0cM0

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Key Concepts Summary

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• Robbins, Cotran & Kumar. Pathologic Basis of Disease, 10th Ed. Chapter 23: The Breast, pp. 961-966
• Kumar, Abbas & Aster. Robbins & Kumar Basic Pathology, 10th Ed. Chapter 17, pp. 705-706
• Schwartz. Principles of Surgery, 11th Ed. Table 17-10 (AJCC Cancer Staging Manual, 8th Ed., 2017)