Pathology

Pathology/C/78

Malignant tumors of the breast

乳腺の悪性腫瘍

1. Overview

  • Breast carcinoma = #2 cause of cancer death in women (after lung).
  • 75 % of cases in women > 50 yr; only 5 % < 40 yr.

2. Risk Factors

  • Age: ↑ risk after 30.
  • Genetic:
    • Hereditary (5–10 %): BRCA1 (50 %), BRCA2 (1/3) — tumor suppressors involved in DNA repair (two-hit theory).
    • Sporadic: HER2/NEU overexpression (EGF receptor family).
  • Benign breast disease: atypical hyperplasia, LCIS.
  • Exogenous estrogens (HRT short-term).
  • Geographic: ↑ in North America + Northern Europe.
  • Late age at first pregnancy, nulliparity.
  • Obesity + high-fat diet.
  • Early menarche, late menopause.

3. Pathogenesis

Genetic changes

  • Best characterized: HER2/NEU overexpression (EGF receptor family).
  • p53 + RB mutations.
  • ER inactivated by hypermethylation of promoter.

Hormonal influences

  • Estrogens stimulate GF production in normal + cancer cells → interact with ER + PR → autocrine tumor growth.
  • Functioning ovarian tumors (PCOS) ↑ estrogen → ↑ breast cancer in postmenopausal women.

4. Morphology

  • Left breast > right slightly.
  • Upper outer quadrant = favored location.
  • Classified into non-invasive (in situ) vs invasive based on BM penetration.

A) Non-invasive (In Situ) Carcinoma

Ductal carcinoma in situ (DCIS / intraductal carcinoma)

  • Tumor confined to duct.
  • Unilateral; pre- and postmenopausal.
  • Comedo carcinoma: creamy necrotic material exudes from cut surface.
  • Frequently associated with calcifications (detected by mammography).
  • Large duct involvement → nipple discharge or Paget disease of the nipple.

Paget disease of the nipple

  • Erosion of nipple resembling eczema (roughening, reddening, slight ulceration).
  • Associated with underlying DCIS or invasive carcinoma.
  • Tumor cells extend into and disrupt epidermal barrier → ECF extruded onto surface.

Lobular carcinoma in situ (LCIS)

  • Tumor confined to acini.
  • Pre-menopausal women.
  • No clinical features — incidental finding.
  • Often bilateral + multifocal.
  • ~1/3 develop invasive carcinoma.
  • Loss of E-cadherin (no cohesion).

B) Invasive Carcinoma

  1. Invasive ductal carcinoma (NOS)
  • Most common type; cannot be subclassified.
  • Usually associated with DCIS.
  • Produces desmoplastic response → hard palpable mass.
  • Histology: variable — well-differentiated to anaplastic.
  1. Invasive lobular carcinoma
  • 2/3 associated with adjacent LCIS.
  • Multicentric + bilateral.
  • Almost all express hormone receptors (ER/PR+).
  • Cells uniform, arranged in strands/chains (single-file due to E-cadherin loss).
  • Surround normal cells creating a bull’s-eye pattern.
  • Metastasis: CSF, serosal surfaces, GI, ovary, uterus, BM (unusual sites).
  1. Medullary carcinoma
  • Circumscribed, often large with necrosis.
  • Histology: large cells + little stroma + lymphocytic infiltrate.
  • Marked polymorphism + mitoses; no gland formation (poorly differentiated).
  • Better prognosis than IDC despite aggressiveness — attributed to lymphocytic infiltrate.
  1. Colloid (mucinous) carcinoma
  • Postmenopausal women.
  • Well-circumscribed, soft / gelatinous.
  • Histology: small nests + cords in large amount of mucin; little pleomorphism.
  • Better prognosis.
  1. Tubular carcinoma
  • Well-differentiated; cells arranged as tubules.
  • Small, firm, irregular outline.
  • Dense stroma with elastosis; ER/PR+.
  • Excellent prognosis, metastasis rare.

5. Signs of Invasive Carcinoma

  • Adherence to pectoral muscle / fascia → fixation.
  • Adherence to overlying skin → skin / nipple retraction.
  • Lymphatic involvement → lymphedema → peau d’orange (orange-peel skin).

6. Spread of Breast Cancer

Lymphatic

  • Outer + central quadrants → axillary nodes.
  • Inner quadrants → internal mammary nodes.

Hematogenous

  • Distant metastasis to almost any organ.
  • Favored: lungs, skeleton, liver, adrenals, brain.

7. Clinical Features + Prognostic Factors

  • Usually: discrete, solitary, painless, movable mass (2–3 cm + axillary node involvement).
  • Mammographic screening detects pre-palpable tumors.

Prognostic factors

  1. Size of primary (< 1 cm = better).
  2. Lymph node involvement + number.
  3. Distant metastases (rarely curable if present).
  4. Grade (tubule formation + nuclear grade + mitotic rate; well-differentiated = better).
  5. Histological type — specialized types (tubular, medullary, mucinous) = better prognosis.
  6. Hormone receptors (ER + PR) = better prognosis (responds to therapy).
  7. Aneuploidy = poor prognosis.
  8. HER2/NEU overexpression = poor prognosis (but treatable with trastuzumab).

8. TNM Staging

Stage Tumor Nodes Metastasis
T0/Tis No primary / in situ only — —
T1 ≤ 2 cm N1 = 1–3 axillary M0 = none
T2 2–5 cm N2 = 4–9 axillary M1 = distant
T3 > 5 cm N3 = infra/supraclav or ≥10 axillary
T4 Any size + chest wall/skin extension

💡 High-yield: #2 cancer death in women. Hereditary = BRCA1/BRCA2 (DNA repair). Sporadic = HER2/NEU overexpression. Upper outer quadrant + left > right. DCIS = ductal, calcifications, comedo type; → Paget disease of nipple (eczema-like nipple lesion). LCIS = bilateral + multifocal, E-cadherin loss, 1/3 → invasive. Invasive ductal (NOS) = #1, desmoplastic hard mass. Invasive lobular = single-file/bull’s-eye, multicentric/bilateral, ER+, unusual mets (ovary, uterus, BM). Medullary = lymphocytic infiltrate, better prognosis. Tubular + mucinous = best prognosis. Peau d’orange = lymphatic obstruction. Spread: outer → axillary, inner → internal mammary; hematogenous → lung/bone/liver/adrenal/brain. Prognosis: size + nodes + mets + grade + type + ER/PR+ (better) + HER2 (worse, but treatable).