Breast Pathology
Pathology · Neoplasia · lean revision notes
Breast Pathology
Breast disease spans benign reactive change, benign neoplasms, in-situ carcinoma and invasive carcinoma. NEET PG loves the receptor triad (ER/PR/HER2), Paget disease histology, the "most common" tags, and the malignant-mimic differentials. This note maps the whole landscape from clinical lump to molecular subtype.
Orientation: the diagnostic approach to a breast lump
A palpable breast lump is worked up by the triple assessment:
Clinical exam → Imaging (USG <35 yr / mammography ≥35 yr) → Tissue (core-needle biopsy preferred over FNAC)
High-yield: Core-needle biopsy is the investigation of choice for a breast lump because it preserves architecture and allows ER/PR/HER2 testing; FNAC gives cytology only and cannot distinguish in-situ from invasive disease.
Mammographic red flags: spiculated mass, architectural distortion, and clustered pleomorphic microcalcifications. Microcalcifications are the classic mammographic signature of DCIS (comedo type).
Classification overview
| Category | Lesions | Key point |
|---|---|---|
| Inflammatory | Acute mastitis, fat necrosis, duct ectasia | Mimic cancer clinically/radiologically |
| Fibrocystic change | Non-proliferative & proliferative | Commonest benign disorder; risk depends on atypia |
| Benign neoplasms | Fibroadenoma, phyllodes, intraductal papilloma | Fibroadenoma = commonest benign tumour |
| In-situ carcinoma | DCIS, LCIS | Confined within basement membrane |
| Invasive carcinoma | IDC (NST), ILC, special types | IDC = commonest malignant tumour |
| Nipple lesions | Paget disease | Always implies underlying carcinoma |
Inflammatory & reactive lesions
Acute mastitis — usually during lactation; cracked nipple allows Staphylococcus aureus entry; presents as a red tender breast, may abscess. Treatment: continue feeding/expression + antistaphylococcal antibiotics (cloxacillin); drain if abscess.
Fat necrosis — follows trauma or surgery; presents as a firm, sometimes tethered, painless mass that mimics carcinoma clinically and on mammography (may show calcification/spiculation). Histology: necrotic fat, foamy macrophages, foreign-body giant cells, later fibrosis. Benign and self-limiting.
Duct ectasia (plasma cell mastitis) — dilated subareolar ducts in older multiparous women; thick green/cheesy nipple discharge, slit-like nipple retraction, periductal plasma-cell inflammation. Differential for nipple retraction (the other being carcinoma).
High-yield: Fat necrosis and duct ectasia are the classic benign mimics of carcinoma (retraction + mass).
Fibrocystic change
The commonest benign breast condition, peak 25–45 yr, oestrogen-driven. Presents as cyclical pain and lumpy ("nodular") breasts, often bilateral and multifocal. The crucial NEET PG point is whether the change is non-proliferative (no increased risk) or proliferative (mild risk), and whether atypia is present.
| Pattern | Histology | Relative risk of carcinoma |
|---|---|---|
| Non-proliferative | Cysts, apocrine metaplasia, fibrosis, mild adenosis | No increased risk (1.0) |
| Proliferative without atypia | Epithelial hyperplasia, sclerosing adenosis, papilloma | Mild (1.5–2×) |
| Proliferative with atypia | Atypical ductal/lobular hyperplasia (ADH/ALH) | Moderate (4–5×) |
Sclerosing adenosis — increased acini with stromal fibrosis distorting glands; can mimic cancer on mammography (calcification) and histology, but myoepithelial layer is preserved (highlighted by p63, calponin, SMA). The intact myoepithelial layer is the key feature separating benign proliferations from invasive carcinoma.
High-yield: Atypical hyperplasia (ADH/ALH) raises carcinoma risk ~4–5× and is bilateral risk; presence of atypia is what matters, not "lumpiness."
Benign neoplasms
Fibroadenoma — the commonest benign tumour
Young women (15–35 yr). A firm, mobile, painless, well-circumscribed "breast mouse" that slips under the palpating finger. It is a biphasic tumour (epithelial + stromal proliferation), oestrogen-sensitive (may enlarge in pregnancy, regress after menopause).
- Histology: two growth patterns — pericanalicular (glands round, stroma around them) and intracanalicular (stroma compresses ducts into slits). Stroma is the neoplastic clonal element (driven by MED12 mutation).
- Giant fibroadenoma: >5 cm, especially in adolescents.
- Management: observe if small/young and typical; excise if large, growing or symptomatic.
Phyllodes tumour — the malignant mimic of fibroadenoma
Older women (40–50 yr), larger, rapidly growing mass. Histology shows a leaf-like (foliated) architecture with hypercellular stroma — the stroma is what determines behaviour.
| Feature | Fibroadenoma | Phyllodes tumour |
|---|---|---|
| Age | 15–35 yr | 40–50 yr |
| Growth | Slow | Rapid, can be huge |
| Stroma | Scanty, bland | Hypercellular, "leaf-like" |
| Behaviour | Benign | Benign → borderline → malignant |
| Metastasis | Never | Malignant type → haematogenous to lung (not nodes) |
| Treatment | Excision/observe | Wide local excision with ≥1 cm margin |
High-yield: Phyllodes recurs locally if excised inadequately; the malignant variant metastasises haematogenously (lungs), NOT to axillary lymph nodes. Treatment is wide excision, not just enucleation.
Intraductal papilloma
Solitary lesion in a large lactiferous duct near the nipple; commonest cause of bloody nipple discharge in a woman without a palpable mass. Has a fibrovascular core lined by epithelium with preserved myoepithelium (benign). Multiple peripheral papillomas (papillomatosis) carry higher malignant risk.
High-yield: Solitary intraductal papilloma = #1 cause of serosanguinous/bloody nipple discharge; investigate to exclude papillary carcinoma.
Breast carcinoma — risk factors
Mnemonic for oestrogen-exposure risk — "Early periods, late menopause": early menarche, late menopause, nulliparity or first child after 30, no/short breastfeeding, obesity (postmenopausal), HRT, alcohol.
Genetic: BRCA1 (chromosome 17q; also high-grade triple-negative/medullary-like cancers and ovarian cancer) and BRCA2 (chromosome 13q; male breast cancer association). Strong family history, prior atypical hyperplasia or LCIS, ionising radiation to chest (e.g., mantle radiotherapy for Hodgkin).
High-yield: BRCA1 → triple-negative, high-grade, ovarian cancer. BRCA2 → male breast cancer. Both are tumour-suppressor genes (autosomal dominant, DNA repair).
In-situ carcinoma — DCIS vs LCIS
Malignant cells confined within the basement membrane (myoepithelium intact, no stromal invasion). The distinction below is heavily tested.
| Feature | DCIS | LCIS |
|---|---|---|
| Origin | Ducts | Lobules/terminal ducts |
| Detection | Mammographic microcalcification | Incidental (no calcification, no mass) |
| Laterality | Usually unilateral | Often bilateral & multicentric |
| E-cadherin | Positive (retained) | Negative (lost) |
| Significance | Direct precursor → same breast IDC | Marker of risk in both breasts |
| Comedo subtype | Central necrosis + calcification, high grade | — |
| Paget disease | Arises from underlying DCIS | — |
| Management | Excision ± radiotherapy ± endocrine | Surveillance / chemoprevention (tamoxifen) |
High-yield: Loss of E-cadherin is the hallmark of all lobular neoplasia (LCIS and invasive lobular carcinoma) — this membrane adhesion molecule is encoded by CDH1. DCIS retains E-cadherin.
High-yield: Comedocarcinoma = high-grade DCIS with central necrosis that calcifies → the classic mammographic microcalcifications.
Invasive carcinoma
Invasive ductal carcinoma, NST (no special type) — commonest malignancy
Accounts for ~70–80% of all breast cancers. Classically the scirrhous carcinoma: a hard, gritty, irreversibly fixed mass that produces a desmoplastic (fibrous) reaction — cut surface shows chalky white streaks (elastosis) with a gritty "unripe pear" feel. Histology: infiltrating duct-like glands/cords in dense fibrous stroma.
Clinical signs of advanced disease: skin tethering (Cooper ligament involvement), peau d'orange (dermal lymphatic blockage → orange-peel skin), nipple retraction, fixation to chest wall.
Invasive lobular carcinoma
~10%. Cells infiltrate in a single-file (Indian-file) linear pattern around ducts, often with a targetoid arrangement; signet-ring cells may be seen. E-cadherin negative. Tends to be multifocal/bilateral and presents as diffuse thickening rather than a discrete lump (so it can be mammographically occult). Higher tendency to metastasise to unusual sites — peritoneum, GI tract, ovary, meninges.
High-yield: ILC = Indian-file pattern + loss of E-cadherin; often bilateral; metastasises to serosal surfaces, GI tract and ovary.
Special types (generally better prognosis except inflammatory)
- Medullary carcinoma — soft, well-circumscribed; syncytial sheets of pleomorphic cells with lymphoplasmacytic infiltrate and pushing margins; associated with BRCA1; often triple-negative yet relatively better prognosis than its grade suggests.
- Mucinous (colloid) carcinoma — elderly women; abundant extracellular mucin "islands of tumour in mucin lakes"; excellent prognosis.
- Tubular carcinoma — well-formed angulated tubules, low grade, excellent prognosis.
- Inflammatory carcinoma — NOT a histological type but a clinical entity: erythematous, warm, swollen breast with peau d'orange from dermal lymphatic invasion; worst prognosis; T4d by staging.
Paget disease of the nipple
Eczematous, crusting, ulcerated, weeping lesion of the nipple/areola that, unlike eczema, starts at the nipple and spreads to the areola and does not respond to topical steroids. It almost always signals an underlying DCIS or invasive ductal carcinoma.
- Histology: large cells with abundant pale cytoplasm, prominent nucleoli, sitting singly or in clusters within the epidermis = Paget cells.
- IHC: Paget cells are CK7 +, HER2 +, CEA +, mucin +, and (unlike melanoma) S100/HMB-45 negative.
High-yield: Paget disease of the nipple = CK7 positive, HER2 positive Paget cells; always implies an underlying carcinoma — investigate the whole breast, not just the nipple. Differential: nipple eczema (areola → nipple, responds to steroids) and superficial spreading melanoma (S100/HMB-45 +).
The receptor triad: ER / PR / HER2
This is the single most tested molecular topic in breast pathology and drives both prognosis and therapy.
| Marker | Method | Therapeutic implication |
|---|---|---|
| ER (oestrogen receptor) | IHC (nuclear) | ER+ → endocrine therapy (tamoxifen premenopausal; aromatase inhibitors postmenopausal); good prognosis |
| PR (progesterone receptor) | IHC (nuclear) | Confirms a functional ER pathway; PR+ predicts better endocrine response |
| HER2/neu (ERBB2) | IHC (membranous); FISH if 2+ equivocal | HER2+ → trastuzumab (anti-HER2 mAb); otherwise aggressive |
HER2 IHC scoring: 0/1+ = negative; 2+ = equivocal → confirm with FISH (gene amplification); 3+ = positive.
Molecular (intrinsic) subtypes
- Luminal A — ER+/PR+, HER2−, low Ki-67 → best prognosis, endocrine-responsive.
- Luminal B — ER+, HER2±, high Ki-67 → worse than A.
- HER2-enriched — ER−/PR−, HER2+ → aggressive but targetable with trastuzumab.
- Triple-negative (basal-like) — ER−/PR−/HER2− → worst prognosis, no targeted hormonal/HER2 therapy, chemotherapy mainstay; associated with BRCA1 and younger/Afro-Caribbean women.
High-yield: Triple-negative breast cancer (ER−, PR−, HER2−) has the worst prognosis and no endocrine/HER2 target. Trastuzumab cardiotoxicity is typically reversible (contrast with irreversible anthracycline/doxorubicin cardiotoxicity).
High-yield: The single best prognostic factor overall in breast cancer is axillary lymph node status; tumour size is next. ER/PR/HER2 are predictive (therapy-guiding) more than purely prognostic.
Staging, spread & sentinel node
- Spread: lymphatic to axillary nodes (most), internal mammary nodes (medial/deep tumours); haematogenous to bone (commonest distant site, typically osteolytic), lung, liver, brain.
- Sentinel lymph node biopsy (SLNB) is the standard for axillary staging in clinically node-negative disease — uses blue dye + radioactive colloid to find the first draining node, avoiding full axillary clearance and its lymphoedema risk.
- TNM: peau d'orange/skin nodules/inflammatory cancer = T4; supraclavicular node = N3.
Management overview (concept-level)
Surgery (BCS + radiotherapy, or mastectomy) + axillary staging → systemic therapy guided by receptors:
- ER/PR positive → endocrine therapy (tamoxifen / aromatase inhibitor like anastrozole).
- HER2 positive → trastuzumab ± chemotherapy.
- Triple-negative or high-risk → chemotherapy (anthracycline + taxane); PARP inhibitors if BRCA-mutated.
- Tamoxifen is a SERM — antagonist in breast but agonist in endometrium (→ endometrial carcinoma risk) and bone/clotting (→ VTE risk).
Key differentials to keep straight
- Lump that mimics cancer but is benign: fat necrosis, sclerosing adenosis, duct ectasia, granulomatous mastitis.
- Bloody nipple discharge: intraductal papilloma (commonest) vs papillary/intraductal carcinoma.
- Nipple skin change: Paget disease (nipple→areola, no steroid response, CK7+) vs eczema (areola→nipple, steroid-responsive) vs melanoma (S100/HMB-45+).
- Stromal/biphasic mass: fibroadenoma (young, slow) vs phyllodes (older, rapid, leaf-like hypercellular stroma).
- In-situ: DCIS (calcification, E-cadherin+) vs LCIS (incidental, bilateral, E-cadherin−).
Recently asked / exam angle
- E-cadherin loss identifying lobular neoplasia (LCIS / invasive lobular) — repeatedly asked image/IHC question.
- Paget cells: CK7 + and HER2 + — match-the-IHC question; remember S100 negative excludes melanoma.
- HER2 2+ → next step is FISH for gene amplification — sequencing question.
- Triple-negative = worst prognosis / BRCA1 association — single best answer.
- Phyllodes tumour metastasises haematogenously to lung, not nodes; treat with wide excision — frequently confused with fibroadenoma.
- Comedo DCIS → microcalcification on mammography — clinicopathological correlation.
- Scirrhous carcinoma = invasive ductal NST, gritty chalky-white cut surface — gross/histology recall.
- Best prognostic factor = axillary node status.
- Indian-file pattern image → invasive lobular carcinoma.
- Tamoxifen → endometrial carcinoma & VTE; trastuzumab → reversible cardiotoxicity.
Rapid revision
- Investigation of choice for a breast lump = core-needle biopsy (allows ER/PR/HER2); FNAC cannot distinguish in-situ from invasive.
- Fibroadenoma = commonest benign tumour, young women, mobile "breast mouse," biphasic, MED12 mutation in stroma.
- Phyllodes = leaf-like hypercellular stroma, older women; malignant type spreads haematogenously to lung; treat with wide excision.
- Intraductal papilloma = commonest cause of bloody nipple discharge.
- Invasive ductal carcinoma (NST) = commonest malignancy = scirrhous, gritty chalky-white desmoplastic mass.
- Invasive lobular carcinoma = Indian-file pattern + E-cadherin loss, bilateral, metastasises to GI tract/ovary/peritoneum.
- DCIS = E-cadherin positive, microcalcification (comedo); LCIS = E-cadherin negative, bilateral, incidental.
- Paget disease = nipple eczema + underlying carcinoma; Paget cells CK7+, HER2+, S100−.
- Triple-negative (ER−/PR−/HER2−) = worst prognosis, BRCA1, chemotherapy mainstay.
- HER2 IHC 2+ → confirm with FISH; HER2+ → trastuzumab (reversible cardiotoxicity).
- Best prognostic factor = axillary lymph node status; commonest distant met = bone (osteolytic).
- BRCA1 (chr 17) → triple-negative/ovarian; BRCA2 (chr 13) → male breast cancer; tamoxifen → endometrial Ca + VTE.