Malignant Breast Lesions

High-Level Content Map

  • Pre-malignant lesions

    • Ductal Carcinoma in Situ (DCIS)

    • Lobular Carcinoma in Situ (LCIS)

  • Invasive epithelial tumours (Carcinoma of the Breast)

  • Paget Disease of the nipple

  • Malignant stromal tumour – Phyllodes tumour

Types of Breast Carcinoma

  • Virtually all are adenocarcinomas that originate from the terminal duct–lobular unit (TDLU).

  • Historical “ductal” vs “lobular” labels now reflect tumour genetics/biology rather than cell of origin.

  • Broad groups (by ER / HER2 status):

    • Luminal = ER + / HER2 -

    • HER2-enriched = HER2 over-expressed, ER variable

    • Triple Negative = ER - / PR - / HER2 - (TNBC)

Premalignant Breast Lesions

Concept – Carcinoma in Situ

  • Malignant epithelial cells are confined by basement membrane → no metastatic access to lymphatics/blood.

  • Share many molecular events with invasive counterparts.

1. Ductal Carcinoma in Situ (DCIS)

Key Features

  • Clonal proliferation limited to ducts/lobules; myoepithelial layer preserved (often attenuated).

  • Can track widely through duct system → entire quadrant/sector involvement.

  • Detection: almost always on mammography –

    • Coarse/linear calcifications from necrotic debris or secretions.

    • Occasionally density or nipple discharge.

  • Architectural subtypes (usually mixed):

    1. Comedo – pleomorphic high-grade nuclei + central necrosis.

    2. Cribriform – round "cookie-cutter" spaces ± calcifications.

    3. Micropapillary – complex bulbous protrusions, no fibrovascular core.

    4. Papillary – true papillae with fibrovascular cores, absent myoepithelial layer.

  • Natural history:

    • Untreated low-grade DCIS → invasive cancer risk \approx 1\%\text{/year}.

    • High-grade/extensive lesions carry higher progression risk.

    • Breast-cancer death after DCIS diagnosis 1!–!3\% (often from later invasive foci).

Management

  • Mastectomy → cure >95\%.

  • Breast-conserving surgery ± radiotherapy acceptable but recurrence risk higher; of recurrences \approx 50\% are invasive.

  • Major recurrence predictors:

    1. High nuclear grade/necrosis

    2. Large extent

    3. Positive surgical margin.

  • Post-op radiation and/or tamoxifen for high-risk cases.

2. Lobular Carcinoma in Situ (LCIS)

Key Features

  • Dyscohesive, uniform cells fill ducts/lobules; loss of E-cadherin (CDH1) → lack of adhesion & signet-ring forms.

  • Incidental finding – rarely causes calcification/density ⇒ detection unchanged by screening.

  • Bilateral in 20!–!40\% (vs 10!–!20\% for DCIS).

  • Immunophenotype: ER+ / PR+ / HER2-.

Clinical Course & Management

  • Serves as a risk marker for invasive carcinoma in EITHER breast (rate \approx 1\%\text{/year}).

  • Subsequent invasive cancers are 3× more likely lobular.

  • Options: close surveillance, tamoxifen, or prophylactic bilateral mastectomy in selected high-risk patients.

DCIS vs LCIS – rapid comparison

  • Both non-palpable; DCIS often micro-calcifies, LCIS rarely.

  • Both lead to invasive cancer in about one-third of cases.

  • LCIS has greater contralateral-breast risk (20!–!40\%).

Invasive (Infiltrating) Breast Carcinoma

Incidence & Epidemiology

  • Most common malignant tumour of women worldwide; lifetime risk \approx 1:8\;(12\%).

  • Mean diagnostic age 64\;\text{yrs}; rare <25\;\text{yrs}; incidence climbs after 30\;\text{yrs}.

Major Risk Factors

  1. Female gender (99\% of cases).

  2. Age – risk rises with advancing age.

  3. Prolonged oestrogen exposure:

    • Early menarche, late menopause, nulliparity.

    • Post-menopausal obesity (↑ aromatisation → estrone).

    • Unopposed oestrogen HRT.

  4. Family / Genetics:

    • First-degree relative → risk doubled.

    • Germ-line high-penetrance genes <10\% of cases: BRCA1/2, TP53 (Li-Fraumeni), PTEN, CDH1, RB1, ERBB2.

  5. Environment – organochlorine pesticides, plastics (xeno-oestrogens).

  6. Lifestyle – post-menopausal obesity, alcohol, smoking, inactivity.

Risk-Reducing Factors

  • Pregnancy <20\;\text{yrs} & prolonged breastfeeding.

  • Chemoprevention with ER antagonists (↓ ER+ cancers).

  • Bilateral prophylactic mastectomy (risk ↓ \approx 90\%).

Pathogenesis Highlights

  • Multistep accumulation of driver mutations within a permissive hormonal milieu.

  • Familial pathway: germ-line BRCA1 → TNBC phenotype; BRCA2 → ER+ cancers.

  • Sporadic pathway: oestrogen-driven proliferation + mutagenesis (↑ TGF-α, PDGF, FGF).

  • Three molecular tracks:

    1. ER+ luminal (most common).

    2. HER2 amplification.

    3. ER/HER2 negative (TNBC, often p53-driven).

WHO / Histologic Classification (invasive)

  1. Invasive Ductal Carcinoma, NST 70!–!80\%.

  2. Invasive Lobular Carcinoma \approx 10\%.

  3. Special types – tubular/cribriform (\approx 6\%), mucinous (2\%), medullary (2\%), papillary (1\%), etc.

1. Invasive Ductal Carcinoma (IDC)

  • Presents as hard, irregular, radiodense mass ≥ 2!–!3\;\text{cm} with desmoplastic reaction (gritty cut surface).

  • May tether skin or pectoralis → dimpling / fixation / nipple inversion.

  • Modified Bloom–Richardson (Nottingham) Grade (each scored 1!–!3):

    1. Tubule formation

    2. Nuclear pleomorphism

    3. Mitotic count

    • Sum =3!–!5 → Grade 1; 6!–!7 → Grade 2; 8!–!9 → Grade 3.

2. Invasive Lobular Carcinoma (ILC)

  • Biallelic CDH1 loss → dyscohesive single-file ("Indian file") cells; scant desmoplasia → mammographic occult.

  • Often bilateral & exhibits unusual metastases: peritoneum, leptomeninges, GI tract, uterus/ovary.

  • Germ-line CDH1 carriers also predisposed to diffuse gastric signet-ring carcinoma.

Special Invasive Subtypes

  • Medullary pattern (IBC-NST with medullary features)

    • Age 45!–!54; >50\% of BRCA1 tumours.

    • Syncytial sheets >75\%, dense T-lymphocyte infiltrate, pushing border, no tubules.

    • ER/PR negative; prognosis better than grade suggests.

  • Tubular carcinoma – small angulated tubules, myoepithelium absent, excellent outcome; multifocal/bilateral.

  • Papillary carcinoma – fibrovascular cores, older women, dx requires lack of myoepithelium.

  • Mucinous (colloid) carcinoma – gelatinous pools of mucin, median age 71, slow-growing.

Patterns of Spread

  1. Direct – skin, underlying muscle.

  2. Lymphatic – axillary most common; internal mammary for medial tumours.

  3. Haematogenous – lungs, bone, liver, brain, adrenals.

  • Tumour topography: upper outer quadrant \approx 50\%; subareolar \approx 20\%.

Nipple / Cutaneous Manifestations

  • Retraction, distortion, bloody discharge, Paget eczema-like rash, skin dimpling, peau d’orange, ulceration/erythema.

Prognostic & Predictive Factors

  • Biology + stage drive outcome.

  • Fatal outlook when distant metastasis or inflammatory carcinoma present.

Major Prognostic Indicators

  1. Axillary lymph-node status – single best factor if M0.

    • Sentinel node biopsy guides need for full dissection.

  2. Distant metastasis – presence ⇒ cure unlikely; ER+ may achieve long remissions.

  3. Tumour size – node-negative <1\;\text{cm} → >90\% 10-yr survival; >2\;\text{cm} → 77\%.

  4. Local advancement – skin or muscle invasion.

  5. Lymphovascular invasion – correlates with node mets & local recurrence.

  6. Inflammatory subtype – 3-yr survival 3!–!10\%.

  7. Molecular subtype & grade – triple-negative poorest, special histologic types (e.g., tubular) very favourable.

  8. Gene-expression assays – help spare chemo in low-risk ER+ tumours.

  9. Pathologic complete response to neoadjuvant chemo – strong good-prognosis signal in TNBC/HER2 groups.

AJCC 8th Edition Staging (simplified)

  • Anatomic (T, N, M 0–IV) + Prognostic (adds Grade, ER, PR, HER2, multigene score).

  • Examples:

    • Stage 0 = DCIS; 10-yr survival 97\%.

    • Stage IV = any T/N with M1; 10-yr survival \approx 5\%.

Therapeutic Principles

  • Local control: breast-conserving surgery + radiation; mastectomy for large/multifocal or risk-reduction.

  • Systemic:

    • Endocrine therapy (tamoxifen, aromatase inhibitors, oophorectomy) for ER+ tumours.

    • HER2 antagonists (trastuzumab/pertuzumab) for HER2+.

    • Chemotherapy for high-grade, highly proliferative cancers (esp. TNBC).

  • Failure of local control may progress to carcinoma en cuirasse (diffuse chest-wall infiltration).

Male Breast Cancer

  • Incidence \approx 1\% of female rate.

  • Risk factors: age, BRCA2 (≈6\% carriers develop), Klinefelter, oestrogen exposure, obesity, radiation.

  • Usually luminal type; TNBC & HER2 rare.

  • Presents as sub-areolar mass 2!–!3\;\text{cm} and/or nipple discharge; early skin/chest-wall invasion.

  • Axillary nodes positive in \approx 50\% at dx; metastasis pattern mirrors women.

  • Treatment: mastectomy + node dissection; systemic therapy per female guidelines.

Paget Disease of the Nipple

  • Unilateral, eczematous, pruritic, erythematous nipple/areola lesion.

  • Paget cells migrate from underlying DCIS along lactiferous ducts into epidermis (do not breach basement membrane).

  • Lesion oozes as barrier disrupted → crust.

  • Palpable mass in 50!–!60\% → almost always invasive carcinoma (ER-, HER2+).

  • No mass → usually pure DCIS. Prognosis → features of underlying carcinoma.

Stromal (Mesenchymal) Tumours

Phyllodes Tumour

  • Origin: intralobular stroma (like fibroadenoma) but presents 10!–!20 yrs later (peak 6th decade).

  • Gross: large, lobulated, leaf-like clefts.

  • Histology criteria vs fibroadenoma: ↑ cellularity, mitoses, pleomorphism, stromal overgrowth, infiltrative margins.

  • Behaviour:

    • Low-grade (most) – local recurrence possible; no metastasis.

    • Borderline / High-grade – local recurrence common; \approx 1/3 haematogenous mets (only stromal component).

    • Lymph-node spread rare → axillary dissection contraindicated.

Malignant Interlobular Stroma – Angiosarcoma

  • Rare; may be sporadic (young women, mean 35 yrs, poor prognosis) or post-radiation/chronic oedema (latency 5!–!10 yrs, incidence 0.3\%).

Other Breast Malignancies

  • Primary/secondary lymphomas (mostly B-cell; rare implant-associated T-cell).

  • Cutaneous sarcomas identical to skin counterparts.

  • Metastases to breast uncommon; melanoma & ovarian most frequent.

Key Take-Away Connections & Clinical Pearls

  • Screening mammography excels at finding calcific DCIS; lobular lesions often invisible ⇒ pathologist awareness crucial.

  • E-cadherin loss is both morphologic clue (dyscohesive cells) and a genetic hallmark of lobular pathogenesis; same mutation links to gastric signet-ring carcinoma (precision medicine implication).

  • Host immune response (T-cell infiltrate) modulates prognosis in medullary-pattern cancers, foreshadowing current immunotherapy paradigms.

  • Sentinel-node biopsy exemplifies personalized surgery – balancing staging accuracy with morbidity avoidance.

  • ER / HER2 status are simultaneously prognostic and predictive, guiding endocrine or targeted therapies.

  • Inflammatory carcinoma represents clinical–pathologic synergy: dermal lymphatic tumour emboli produce redness/warmth akin to mastitis but signify dismal outlook.

  • Paget disease teaches the importance of full breast imaging when facing “eczema” limited to nipple.

  • For phyllodes tumours, remember “leaf-like but seldom lethal” – excise with margins, spare the axilla.

Quick-Reference Numerical Nuggets

  • Lifetime female risk \approx 12\% (1 in 8).

  • DCIS/LCIS → invasive risk \approx 1\%\text{/year}; one-third ultimately invade.

  • Bilaterality: LCIS 20!–!40\% vs DCIS 10!–!20\%.

  • BRCA1/2 carriers: lifetime breast risk 40!–!85\%; ovarian risk (BRCA1 higher, BRCA2 10!–!20\%).

  • Inflammatory ca 3-yr survival \le 10\%.

  • Axillary node negative, tumour <1\;\text{cm} → >90\% 10-yr survival.

  • Mastectomy cures >95\% of isolated DCIS.