• 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

Benign cancer

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Intraductal papilloma

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

Mnemonic

• Intraductal = Myoepithelium Included
• Papillary = Myoepithelium Popped

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

Mnemonic

fibROadenoma = estROgen sensitive

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

Feature	Phyllodes Tumor	Fibroadenoma
Prevalence	Rare (less than 1% of all breast tumors)	Common (especially in women under 30)
Age	Typically 40-50 years old, about 10-15 years later than fibroadenomas	Most common in women aged 15-35, but can occur at any age.
Growth Rate	Can grow rapidly	Usually slow-growing, but can be variable.
Size	Often larger (average 4-7 cm, can be >10cm)	Typically smaller (1-3 cm), but can grow larger (“giant fibroadenoma” if >5 cm)
Malignancy Potential	Can be benign, borderline, or malignant (though most are benign)	Benign. Very rarely associated with malignancy (complex fibroadenomas or those with associated proliferative changes may have a slightly increased risk)
Symptoms	Usually painless, firm and mobile mass, rapid growth. The skin can appear thin, translucent, ulcerated, shiny, or with distended veins	Well-defined, mobile, rubbery, and usually painless lump. May change with the menstrual cycle.
Imaging	Mammography: Well-circumscribed, round, oval, or lobulated mass. Ultrasound: Solid mass, may have cystic spaces or clefts, internal heterogeneity, and posterior acoustic enhancement.	Mammography: Well-defined, round, oval, or lobulated mass, may have coarse calcifications (“popcorn” calcifications). Ultrasound: Solid, well-circumscribed, homogeneous mass.
Histology	Increased stromal cellularity, leaf-like architecture (clefts lined by epithelium), stromal overgrowth. Mitotic activity is important for grading.	Stromal and epithelial components, but stroma does not dominate. Pericanalicular (stroma surrounds ducts) and intracanalicular (stroma compresses ducts into slits) patterns.
Treatment	Wide local excision with wide margins (at least 1 cm) to prevent recurrence. Mastectomy may be considered for large or recurrent tumors.	Observation, Excisional biopsy, or cryoablation.
Recurrence	Higher risk of local recurrence, even for benign types.	Low risk of recurrence after complete excision. New fibroadenomas can develop.

Malignant cancer

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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

Tip

Noninvasive carcinomas are characterized by the absence of stromal invasion.

Lobular carcinoma in situ (LCIS)

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

Mnemonic

Lobular Carcinoma Lacks 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

Mnemonic

ILC = Individual Line Carcinoma

Clinical features

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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

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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

Tip

It is called inflammatory breast cancer because its appearance resembles inflammation, but there is actually no inflammation!

Diagnostics

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Receptor testing

• Hormone receptors (HR) positive
  • Estrogen receptor
  • Progestogen receptor
• Human epidermal growth factor receptor 2 (HER2/neu, c-erbB2) positive
• Triple negative

Prognosis

• Hormone-negative breast cancer has a poorer prognosis than hormone-positive breast cancer.
• HER2-positive tumors show aggressive growth and metastasize quickly compared to HER2-negative tumors.
• Triple-negative disease is associated with a poor prognosis.

Treatment

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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)