36. Breast carcinoma

1. Definition

• Breast carcinoma → malignant epithelial tumour of the terminal duct lobular unit (TDLU) of the breast
• In situ carcinoma → malignant cells confined by an intact basement membrane: ductal (DCIS) or lobular (LCIS)
• Invasive carcinoma → cells breach the basement membrane and infiltrate the stroma

2. Epidemiology

• Most common cancer in women in the UK and worldwide; 2.3 million new cases worldwide in 2020
• Lifetime risk → 1 in 7 to 1 in 9 women in the UK; about 55 000 women and 370 men a year
• Men → about 1% of cases
• Almost half diagnosed over 65 years; about three-quarters of women survive 10 years or more
• Presentation → about two-thirds symptomatic, one-third through screening

3. Aetiology and risk factors

Non-modifiable

• Female sex, increasing age
• Family history → one first-degree relative diagnosed at ≤ 50 years doubles the risk
• Genetic → about 5% of cancers:
  • BRCA1 → 60–80% lifetime breast cancer risk, 40–50% ovarian
  • BRCA2 → 40–85% breast, 10–25% ovarian; male breast, prostate and pancreatic cancer
  • TP53 (Li-Fraumeni), PTEN (Cowden), CDH1, PALB2, CHEK2
  • Under 30 years with breast cancer → 25% chance of a genetic cause
• Early menarche, late menopause → long oestrogen exposure
• Dense breasts
• Previous breast cancer, atypical hyperplasia (risk × 4), LCIS
• Chest radiotherapy in childhood or youth (Hodgkin's lymphoma)

Modifiable

• Nulliparity, first birth after 35 years
• Breastfeeding → risk falls 4% for every 12 months
• Combined hormone replacement therapy (HRT), oral contraceptive pill
• Postmenopausal obesity → aromatisation of androgens in fat
• Alcohol, physical inactivity

4. Pathogenesis

1. Normal TDLU epithelium
2. Hyperplasia → atypical hyperplasia
3. Carcinoma in situ (DCIS)
4. Invasive carcinoma
5. Spread:
   • Local → skin, nipple, pectoral fascia, chest wall
   • Lymphatic → axillary nodes (levels I–III), internal mammary, supraclavicular
   • Blood → bone (most common), lung, liver, brain
6. Skin dimpling → tumour shortens Cooper's ligaments
7. Peau d'orange → blocked dermal lymphatics, skin oedema

5. Classification

Histological

• In situ:
  • DCIS → 80% found on screening as microcalcifications; 10–50% become invasive if untreated; graded low, intermediate, high
  • LCIS → classical LCIS is a risk marker (risk × 7–8); pleomorphic LCIS treated as DCIS
• Invasive:
  • No special type (NST, formerly ductal) → 75–80%
  • Invasive lobular → 15%; multifocal, bilateral, poorly seen on mammography
  • Good prognosis special types → tubular, mucinous, cribriform
  • Poor prognosis → metaplastic, micropapillary
• Special presentations → Paget's disease of the nipple, inflammatory carcinoma

Grade

• Nottingham grade → gland formation + nuclear pleomorphism + mitoses, each scored 1–3
  1. Grade 1 → total 3–5
  2. Grade 2 → total 6–7
  3. Grade 3 → total 8–9

Molecular (receptor) subtypes

• Luminal A → oestrogen receptor (ER) positive, low Ki-67; about 40%; best prognosis
• Luminal B → ER positive, high Ki-67, HER2 normal or amplified
• HER2-enriched → human epidermal growth factor receptor 2 overexpressed in 15–20%; poorer outcome without anti-HER2 therapy
• Triple negative → ER, progesterone receptor (PR) and HER2 negative; basal-like; BRCA1; worst prognosis

TNM staging (key points)

• T1 ≤ 2 cm, T2 > 2–5 cm, T3 > 5 cm
• T4 → chest wall (T4a), skin ulceration, satellite nodules or peau d'orange (T4b), both (T4c), inflammatory carcinoma (T4d)
• N1 → mobile ipsilateral axillary nodes; N2 → fixed or matted axillary nodes, or internal mammary; N3 → infraclavicular or supraclavicular nodes
• M1 → distant metastases
• Stage I-II → early breast cancer; stage III → locally advanced; stage IV → metastatic

6. Clinical picture

Symptoms

• Breast lump → most common; painless unless inflammatory carcinoma
• Nipple change → retraction, inversion, eczema-like rash (Paget's disease)
• Bloody nipple discharge from one duct
• Change in breast shape or contour
• Axillary lump
• Metastatic → bone pain, breathlessness, jaundice, headache, weight loss

Signs

• Hard, irregular, ill-defined lump
• Immobile, tethered to skin or fixed to chest wall
• Skin → dimpling, puckering, peau d'orange, ulceration, fungation, satellite nodules
• Nipple → destroyed, inverted, deviated
• Axillary or supraclavicular nodes → hard, matted or fixed
• Inspection with arms raised and pectorals tensed → shows subtle dimpling

7. Diagnosis

Triple assessment

• Every lump or area of localised nodularity; each part scored 1–5 (P, M or U, B or C):
  1. Normal (or inadequate sample)
  2. Benign
  3. Indeterminate
  4. Suspicious, probably malignant
  5. Malignant
• Discordance between the three parts → further assessment

Imaging

• Mammography → women over 40 years; masses, distortion, microcalcifications
• Ultrasound → first choice under 40 years; all ages for a focal area; routine assessment of the axilla
• MRI → lobular carcinoma before breast conservation, dense breasts, high-risk screening, implants, discordant results
• Scoring → BI-RADS (Breast Imaging Reporting and Data System)

Pathology

• Core biopsy (14G, 3–6 cores) → invasive versus in situ, grade, ER, PR, HER2
• Vacuum-assisted biopsy → calcifications, B3 lesions
• Punch biopsy of skin → Paget's disease, inflammatory carcinoma
• Axillary node → ultrasound-guided core biopsy or fine-needle aspiration (FNA)
• Marker clip placed at the biopsy site

Staging

• Early, node-negative → staging scans not routine
• Node-positive, locally advanced or symptoms → CT chest, abdomen and pelvis + bone scan
• Bloods → liver function tests, calcium

Screening

• NHS Breast Screening Programme → women 50–70 years, two-view mammography every 3 years
• Per 1000 screened → about 5 lives saved, 17 overdiagnosed
• High risk → annual MRI from a younger age

8. Differential diagnosis

• Fibroadenoma, phyllodes tumour
• Cyst
• Fat necrosis → after trauma; hard, tethered, calcified
• Abscess, periductal mastitis, granulomatous mastitis
• Sclerosing adenosis, radial scar
• Duct ectasia → nipple retraction
• Eczema of the nipple → starts on the areola; Paget's starts on the nipple

9. Treatment

• Planned at a multidisciplinary team (MDT) meeting

Surgical: breast

• Breast-conserving surgery (wide local excision) → most cancers:
  • Margin → ≥ 1 mm clear on histology
  • Re-excision rate → about 20%
  • Always with whole-breast radiotherapy → survival equal to mastectomy
  • Impalpable lesion → wire, magnetic seed or radiofrequency tag localisation; specimen X-ray
  • Oncoplastic techniques → volume displacement or replacement
• Mastectomy:
  • Large tumour in a small breast, multifocal disease, central tumour, extensive DCIS
  • Previous chest radiotherapy
  • Patient preference
  • Reconstruction → immediate or delayed: implant, latissimus dorsi flap, deep inferior epigastric perforator (DIEP) flap

Surgical: axilla

• Clinically and ultrasound node-negative → sentinel lymph node biopsy (SLNB):
  • Radioisotope + Patent Blue dye (anaphylaxis 0.1%)
  • Less lymphoedema than clearance
• Biopsy-proven positive nodes → axillary node clearance (levels I–III) or axillary radiotherapy, per MDT
• Positive sentinel node → clearance, radiotherapy or no further treatment, depending on disease burden
• DCIS → no axillary surgery; SLNB only with mastectomy, mass-forming DCIS, microinvasion or DCIS > 4 cm

Conservative: radiotherapy and systemic therapy

• Radiotherapy:
  • After breast conservation → 26 Gy in 5 fractions over 1 week (FAST-Forward)
  • After mastectomy → T3–T4 or node-positive disease
  • Nodal fields → supraclavicular fossa, axilla
  • Omission → selected women ≥ 65 years with small, node-negative, ER-positive, low-grade tumours on endocrine therapy
• Endocrine therapy → ER-positive tumours, at least 5 years:
  • Premenopausal → tamoxifen (risk of endometrial cancer, venous thromboembolism)
  • Postmenopausal → aromatase inhibitor (anastrozole, letrozole, exemestane); bone loss
  • High-risk node-positive → add abemaciclib (CDK4/6 inhibitor)
• Anti-HER2 therapy → trastuzumab ± pertuzumab for 1 year; cardiotoxicity, monitor with echocardiography
• Chemotherapy → anthracycline and taxane; high grade, node-positive, HER2-positive, triple negative, young patients
• Neoadjuvant therapy → before surgery to downstage; HER2-positive, triple-negative, locally advanced, inflammatory
• Prognostic tools → Nottingham Prognostic Index (NPI) = 0.2 × size (cm) + grade (1–3) + node score (1–3); Oncotype DX for ER-positive, node-negative cancers with NPI ≥ 3.4; PREDICT
• Germline BRCA, high risk → olaparib

Special situations

• Inflammatory carcinoma → neoadjuvant chemotherapy, modified radical mastectomy, post-mastectomy radiotherapy
• Paget's disease → underlying carcinoma in 82–94%; central excision of nipple-areola or mastectomy
• Elderly, unfit, ER-positive → primary endocrine therapy
• Pregnancy → surgery in any trimester; chemotherapy from the 2nd trimester; no radiotherapy or tamoxifen in pregnancy
• Metastatic → palliative endocrine, chemotherapy, anti-HER2; radiotherapy for bone pain; toilet mastectomy for a fungating tumour

10. Complications

Of surgery

• Seroma, haematoma, wound infection
• Positive margins → re-excision
• Lymphoedema → mainly after axillary clearance or axillary radiotherapy
• Injury to the long thoracic nerve (winged scapula), thoracodorsal nerve, intercostobrachial nerve (numb inner arm)
• Flap necrosis, implant complications

Of disease and treatment

• Local and regional recurrence
• Metastases → spinal cord compression, hypercalcaemia, pathological fracture, malignant pleural effusion
• Radiotherapy → skin reaction, fibrosis, cardiac and lung damage
• Chemotherapy → neutropenic sepsis, cardiotoxicity (anthracyclines, trastuzumab), early menopause

11. Prognosis

• Prognostic factors → axillary node status (strongest), tumour size, grade, receptor status, lymphovascular invasion
• 5-year survival → stage I about 99%, stage IV about 25–30%
• NPI → < 3.4 good, 3.4–5.4 moderate, > 5.4 poor