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Diseases of the Breast: Benign & Malignant, HPE, TNM Staging

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1. Normal Breast Histology - Foundation for Understanding Disease

• Inner luminal epithelial cells - produce milk during lactation
• Basally located myoepithelial cells - contractile (aid milk ejection); support the basement membrane

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2. Clinical Presentations of Breast Disease

• Most lesions (>90%) are benign
• ~45% of cancers have symptoms; remainder detected by screening mammography
• Sensitivity/specificity of mammography increases with age; likelihood of malignancy rises from ~10% at age 40 to >25% after age 50

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3. Benign Breast Lesions

A. Inflammatory Processes

• Acute mastitis / Lactational abscess: Staphylococcus aureus (most common) or streptococci; occurs within the first month of breastfeeding; treated with antibiotics + continued milk expression; rarely requires I&D
• Non-lactational abscess: Mixed anaerobic organisms; less common

B. Benign Epithelial Lesions (Classified by Cancer Risk)

• Nonproliferative changes: Single layers of epithelial cells; cysts lined by luminal cells with apocrine metaplasia; secretions may calcify (mammographic calcifications); ruptured cysts cause chronic inflammation and palpable nodularity ("fibrocystic changes"); adenosis = increased acini per lobule
• ADH: Uniform cells forming sharply marginated spaces or rigid bridges - closely resembles DCIS but limited in extent
• ALH: Monomorphic cells with bland, round nuclei - closely resembles LCIS but limited in extent

C. Stromal Neoplasms (Intralobular Stroma)

• Most common benign tumor of the breast
• Composed of neoplastic stromal cells + reactive proliferation of epithelial cells
• As fibroblasts proliferate, they push/distort epithelial cells into elongated, slit-like structures
• HPE: Circumscribed mass, low cellularity, biphasic (epithelial + stromal) - expansile growth with pushing borders
• Does NOT increase risk of breast cancer development
• Management: If diagnosed by core biopsy and ≤3 cm, observation is appropriate

• Stromal cells outgrow epithelial cells; bulbous nodules of proliferating stroma covered by epithelium
• Characteristic "phyllodes" (leaf-like) growth pattern on HPE
• High-grade forms: epithelium may be scant or absent (sarcomatous appearance)
• May recur following excision; rarely malignant
• Share driver mutations with fibroadenomas - they are part of a related neoplasm spectrum

• Myofibroblastoma: Only breast tumor equally common in males
• Lipoma: Palpable; fat-containing on mammography
• Fibromatosis: Clonal fibroblast/myofibroblast proliferation; locally aggressive but does NOT metastasize; associated with FAP/Gardner syndrome; some post-traumatic

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4. Malignant Breast Diseases

A. Carcinoma In Situ

• Malignant cells confined within the duct-lobular system; no invasion through basement membrane
• HPE: Ductlike spaces distort the lobule; calcified secretory material common
• Comedo type DCIS: High-grade proliferation with large central zones of necrosis + calcifications ("comedonecrosis"); linear/branching calcifications on mammogram
• Paget disease of the nipple: Tumor cells within the squamous epithelium of the nipple (large cells with clear halo = Paget cells); presents as unilateral crusting exudate; almost always associated with underlying invasive carcinoma or high-grade DCIS
• Treatment: Surgical excision + radiation → >95% survival at 20 years
• Progression: ~1% per year to invasive cancer in the same quadrant; same grade/ER/HER2 as associated DCIS

• Monomorphic cells fill the breast lobule
• Almost always an incidental finding (rarely associated with calcifications or stromal reactions)
• Risk factor for invasive carcinoma in either breast (~1% per year; one-third ultimately develop invasive cancer)
• Unlike DCIS, surgical removal of the identified lesion may not lower risk
• Management: Close clinical/radiologic follow-up ± antiestrogen risk reduction (tamoxifen)

B. Invasive (Infiltrating) Carcinomas

• Most common invasive breast cancer (~70-80%)
• HPE: Tubule formation; desmoplastic stromal reaction (reactive fibrosis); irregular spicular margins on mammography (invasion of adjacent radiolucent tissue)
• Spreads to axillary lymph nodes (most important prognostic factor)

• Sheets of tightly cohesive cells (or "Indian file" single-cell pattern)
• May appear as well-circumscribed masses on mammography mimicking benign lesions
• Loss of E-cadherin (CDH1 mutation) - key molecular feature

C. Malignant Stromal Tumors

• Angiosarcoma: Most common interlobular stromal malignancy (<0.05% of breast malignancies); sporadic (young females, mean age 35, poor prognosis) or secondary (post-radiation or chronic lymphedema = Stewart-Treves syndrome); molecular hallmark = high-level MYC amplification
• Primary breast lymphoma: Usually diffuse large B-cell lymphoma; breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is T-cell type

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5. Histopathological Examination (HPE) of Breast Tissue

What HPE Assesses:

1. Architecture: Ductal vs lobular pattern; in situ vs invasive; margins
2. Nuclear grade: Low (1), intermediate (2), high (3)
3. Tubule formation: Used for Nottingham grade (% tubule formation score)
4. Mitotic rate: Mitoses per 10 HPF
5. Nottingham Grading System (Elston-Ellis): Tubule formation + nuclear pleomorphism + mitotic count → Grade 1 (well), 2 (moderate), 3 (poorly differentiated)
6. Special stains: ER, PR (hormone receptors), HER2/neu (IHC ± FISH)
7. Ki-67 proliferative index
8. Lymphovascular invasion (LVI)
9. Sentinel lymph node biopsy analysis: Isolated tumor cells (ITCs ≤0.2 mm), micrometastases (0.2-2 mm), macrometastases (>2 mm)

Molecular Subtypes (HPE-based biomarkers):

Predictive Genomic Tests:

• Oncotype DX (21-gene assay): Node-negative, ER-positive; generates recurrence score to guide chemotherapy decision
• Other: Nottingham Prognostic Index, PREDICT

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6. TNM Staging for Breast Cancer (AJCC 8th Edition)

T - Primary Tumor

Size should be measured to the nearest mm. If slightly less/greater than a cutoff, round to the nearest mm.

N - Regional Lymph Nodes (Pathologic pN)

M - Distant Metastasis

Anatomic Stage Groups

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7. Prognostic & Predictive Factors for Invasive Breast Cancer

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Key Concepts Summary

• All breast cancers arise from the terminal duct lobular unit (TDLU) - the "ductal" and "lobular" designations are histomorphologic, not anatomic
• Myoepithelial cells are the key marker of in situ vs. invasive disease - intact myoepithelial layer = in situ; absent = invasive (IHC: p63, smooth muscle actin, calponin)
• E-cadherin loss distinguishes lobular (negative) from ductal (positive) carcinoma
• Nottingham grade (tubule formation + nuclear pleomorphism + mitotic count) is the standard grading system used in HPE reports
• DCIS risk for invasion: ~1%/year; treatment is excision + radiation; >95% survival at 20 years
• LCIS is a bilateral risk marker (not a direct precursor), not treated with excision alone
• Inflammatory carcinoma (T4d) is a clinical diagnosis (erythema, peau d'orange, rapid onset), NOT defined by the presence of tumor in dermal lymphatics on biopsy alone