Breast anatomy

• Terminal ductal lobular units (TDLU)
  • Basic histopathological units of the mammary gland
  • Consist of:
    • Lobule of the mammary gland: (functional unit of the breast)
      • Intralobular stroma: loose, cell-rich connective tissue
      • Intralobular terminal (milk) duct with multiple outpouchings called acini or ductules (site of milk production)
        • Structure: tubulo-alveolar with two-layered glandular epithelium
          • Outer layer: myoepithelial cells (contractile, route the milk to the ducts in lactating breasts)
          • Inner layer: cubic, apocrine glandular epithelial cells (can produce milk)
    • Extralobular terminal duct

Overview

I. Benign Breast Diseases

• Fibrocystic Changes:
  • General: Premenopausal; bilateral, often painful, lumpy breasts, symptoms vary with menstrual cycle. Cysts may have a "blue dome" appearance.
  • Nonproliferative lesions: No increased cancer risk.
  • Sclerosing Adenosis: Proliferative; acini, stromal fibrosis, often calcifications (can mimic cancer). Slight �?cancer risk.
  • Epithelial Hyperplasia (with atypia - ADH, ALH): Proliferative; significantly �?cancer risk (4-5x).
• Inflammatory Processes:
  • Fat Necrosis: History of trauma/surgery; firm mass, mammographic calcifications (oil cyst), or skin changes mimicking cancer. Biopsy: necrotic fat, lipid-laden macrophages, giant cells.
  • Lactational Mastitis: Breastfeeding woman; localized erythema, pain, fever. Usually S. aureus. Key: Continue breastfeeding/pumping + antibiotics.
  • Mammary Duct Ectasia: Perimenopausal women, smokers common; periareolar mass, nipple retraction, thick, multicolored (often green-brown) nipple discharge. Plasma cells on histology.
• Benign Tumors:
  • Fibroadenoma: Most common in women < 35 yrs; well-defined, mobile ("breast mouse"), rubbery, painless mass. Estrogen sensitive. Usually no increased cancer risk.
  • Intraductal Papilloma: Most common cause of bloody or serosanguineous nipple discharge. Small tumor in lactiferous duct. Slight �?cancer risk.
  • Phyllodes Tumor: Large, bulky mass with "leaf-like" projections on histology. More common in 5th decade. Can be benign, borderline, or malignant.
• Gynecomastia: Benign male breast enlargement due to �?estrogen relative to androgens. Causes: physiologic (newborn, puberty, elderly), cirrhosis, testicular tumors, Klinefelter syndrome, drugs (e.g., Spironolactone, Ketoconazole, Cimetidine).

II. Malignant Breast Diseases (Breast Cancer)

• Key Risk Factors: �?Age, BRCA1/BRCA2, family history, atypical hyperplasia, unopposed estrogen exposure.
• Noninvasive Carcinomas:
  • Ductal Carcinoma In Situ (DCIS): Malignant cells in duct without basement membrane invasion. Often seen as microcalcifications on mammography. Precursor to invasive ductal carcinoma.
  • Lobular Carcinoma In Situ (LCIS): Abnormal cells in lobules without basement membrane invasion. Loss of E-cadherin is characteristic. Often incidental finding. Increased risk of invasive cancer in either breast.
  • Paget Disease of the Nipple: Eczematous, crusted lesion of nipple/areola. Due to intraepithelial spread of adenocarcinoma cells (Paget cells) from underlying DCIS or invasive cancer.
• Invasive Carcinomas:
  • Invasive Ductal Carcinoma (IDC), No Special Type (NST): Most common type. Firm, "rock-hard" mass with irregular borders, gritty texture. Small, glandular, ductlike cells in desmoplastic stroma.
  • Invasive Lobular Carcinoma (ILC): Loss of E-cadherin leads to cells infiltrating in a single-file ("Indian file") pattern. Often multifocal and bilateral. May present as subtle thickening rather than a discrete mass.
  • Inflammatory Breast Cancer (IBC): Aggressive. Diffuse breast erythema, warmth, swelling, and peau d'orange (orange peel skin) due to dermal lymphatic invasion. Often lacks a palpable mass. Poor prognosis.

Benign cancer

Intraductal papilloma

• BIoody nipple discharge in pre-menopausal women (vs. Papillary Carcinoma)
• FibrovascuIar projections lined by luminal myoepithelial cells (vs. Papillary Carcinoma)

Fibroadenoma

• Refers to a marble-like, rubbery mobile, stromal/glandular benign tumor
• Estrogen sensitive (will enlarge during pregnancy/menstrual cycle)
• Typically occurs in 15-35 y/o women
• Biopsy: fibrous and glandular tissue

Phyllodes tumor

• Refers to a fibroepithelial tumor that ranges from benign (mostly) to malignant (rarely)
• Characteristic leaf-like projections into epithelium-lined stroma & dilated lumen
• Typically occurs in 40-50 y/o women

Malignant cancer

Noninvasive carcinomas

Ductal carcinoma in situ (DCIS)

• Characteristics
  • No penetration of the basement membrane
  • Preceded by ductal atypia
  • Frequently appears as a pattern of grouped microcalcifications on mammography
    • Abnormal cell growth and death will leave calcium deposits
    • Because DCIS often doesn't cause noticeable symptoms like a lump, these microcalcifications serve as an important visual indicator.
  • Higher risk of subsequent ipsilateral invasive carcinoma
• Comedocarcinoma
  • Characteristics: subtype of DCIS characterized by central necrosis

Lobular carcinoma in situ (LCIS)

• Refers to proliferation of lobular cells but has not yet invaded basement membrane
• Lacks E-Cadherin

Invasive carcinomas

Invasive ductal carcinoma (IDC)

• Characteristics
  • Most common type of invasive breast cancer (�?80%)
  • Aggressive formation of metastases
• Localization
  • Unilateral
  • Mostly unifocal

Medullary breast cancer

• Characteristics
  • Rare subtype of invasive ductal carcinoma
  • Most common tumor associated with the BRCA1 mutation
  • Well-circumscribed soft tumor with smooth borders (may appear benign)
  • Usually triple-negative
  • Lymphadenopathy
• Differential diagnosis: fibroadenoma

Invasive lobular carcinoma (ILC)

• Characteristics
  • �?10% of all invasive breast carcinomas
  • Less aggressive than ductal carcinoma
  • Monomorphic cells in a single file pattern due to a decrease in E-cadherin expression
• Localization
  • Bilateral in �?20% of cases
  • Frequently multifocal

Clinical features

Locally advanced disease

• Skin
  • Retractions or dimpling (due to fixation to the pectoral muscles, deep fascia, Cooper ligaments, and/or overlying skin)
  • Peau d'orange (see below)

Subtypes and variants

Inflammatory conditions (DDx)

• Mastitis
• Mammary duct ectasia
• Fat necrosis of the breast

Paget disease of the breast

• Definition: a rare type of breast cancer that affects the lactiferous ducts and the skin of the nipple and areola
• Pathogenesis: migratory/epidermotropic theory: neoplastic ductal epithelial cells from an underlying DCIS or IDC move through the lactiferous ducts and invade the surrounding epidermis of the nipple.
• Clinical features
  • Erythematous, scaly, or vesicular rash affecting the nipple and areola
  • Pruritus; burning sensation
  • Nipple retraction
  • Ulceration that causes blood-tinged nipple discharge
• Diagnostics
  • Punch/wedge or surface biopsy of nipple tissue: Paget cells confirm disease.

Inflammatory breast cancer (IBC)

• Definition: a rare form of advanced, aggressive invasive carcinoma characterized by dermal lymphatic invasion of tumor cells
• Clinical features
  • Peau d'orange
    • Erythematous, warm, and edematous skin plaques with prominent hair follicles that resemble orange peel
    • Caused by obstruction of the lymphatic channels due to tumor growth
  • Tenderness, burning sensation
  • Blood-tinged nipple discharge
  • Signs of metastatic disease (e.g., axillary lymphadenopathy)
  • Usually no palpable mass
• Differential diagnosis
  • Mastitis
    • Fever
    • No Peau d'orange
    • Good response to antibiotics
  • Paget disease of the breast
  • Breast abscess

Diagnostics

Receptor testing

• Hormone receptors (HR) positive
  • Estrogen receptor
  • Progestogen receptor
• Human epidermal growth factor receptor 2 (HER2/neu, c-erbB2) positive
• Triple negative
• Ranking
  • Aggressive: TN > HER2+ > HR+
  • Prognosis: HR+/HER2- > HR+/HER2+ > HR-/HER2+ > TN

Treatment

Systemic therapy

ERBB2-targeted therapy (ERBB2 = HER2)

ERBB2-targeted therapy includes ERBB2 antibodies (e.g., trastuzumab, pertuzumab) and tyrosine kinase inhibitors (e.g., lapatinib, neratinib).

• Indication: all ERBB2+ tumors
• First-line agent: trastuzumab
  • A humanized monoclonal antibody against the ERBB2 tyrosine kinase receptor; used in the treatment of ERBB2+ breast and gastric cancer
  • Mechanism of action: targets c-erbB2 tyrosine kinase receptor �?�?of ERBB2-initiated cellular signaling and �?antibody-dependent cytotoxicity �?�?tumor growth
  • Adverse effects: cardiotoxicity (e.g., dilated cardiomyopathy with systolic CHF)