Harvey's Garden

Breast cancer

6 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

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.

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)

Graph View

Backlinks