Harvey's Garden

Breast cancer

5 min read

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

Benign Breast Disease

  • Fibrocystic Changes: Premenopausal. Cyclical, bilateral pain and lumps. No ↑ cancer risk.
  • Fibroadenoma: Women <35. Firm, mobile, painless “breast mouse.” Estrogen sensitive. Benign.
  • Intraductal Papilloma: Most common cause of unilateral bloody/serosanguineous nipple discharge.
  • Atypical Hyperplasia: Highest risk factor among benign diseases for developing invasive carcinoma.
  • Fat Necrosis: Hx of trauma. Can present as a fixed mass with calcifications, mimicking cancer.
  • Acute Mastitis: During breastfeeding. S. aureus. Presents as a warm, erythematous, painful breast. Tx: Dicloxacillin, continue breastfeeding.

Malignant Breast Disease

  • Ductal Carcinoma In Situ (DCIS)
    • Non-invasive. Basement membrane intact.
    • Often detected as microcalcifications on mammography.
  • Paget Disease of the Breast
    • Eczematous rash and ulceration of the nipple.
    • Associated with underlying DCIS or invasive cancer.
  • Invasive Ductal Carcinoma (IDC)
    • Most common type of breast cancer (~80%).
    • Presents as a hard, fixed, irregular mass.
  • Invasive Lobular Carcinoma (ILC)
    • Cells arranged in a single-file “Indian file” pattern.
    • Due to loss of E-cadherin. Often bilateral.
  • Inflammatory Breast Cancer
    • Red, swollen, warm breast (“peau d’orange”).
    • Caused by cancer cells in dermal lymphatics. Very aggressive.

Tip

Nipple discharge happens in duct-related diseases, or diseases affecting the nipple skin. It doesn’t happen in lobule-related diseases, or stromal cancer.

Benign cancer

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
FeatureFibroadenomaPhyllodes Tumor
Typical AgeYounger (15-35 yrs)Older (40-50 yrs)
PrevalenceVery common, most common benign breast tumorRare, <1%
GrowthSlow, often hormone-sensitiveCan be rapid
SizeUsually <3 cmOften larger
HistologyBenign stroma & epithelium, well-circumscribedIncreased STROMAL CELLULARITY, atypia, mitoses define grade (Benign, Borderline, Malignant). LEAF-LIKE projections.
BehaviorBenignCan be benign, borderline, or malignant (hematogenous spread)
RecurrenceRare after excisionHigher risk, especially if margins inadequate or higher grade
ManagementObservation or simple excisionWIDE LOCAL EXCISION (with clear margins) is crucial for all types.

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

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

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)

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

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)

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