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The Breast - Sabiston Textbook of Surgery (Chapter 68)

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ANATOMY

1. Glandular epithelium
2. Fibrous stroma
3. Adipose tissue

• In adolescents: epithelium + stroma predominate
• Postmenopause: glandular structures involute, replaced by adipose tissue

• Branching ducts in a radial pattern from the nipple-areolar complex (NAC)
• 15-20 lobes, each ending in a lactiferous duct opening at the nipple
• Each duct has a dilated lactiferous sinus below the NAC
• Terminal branching ends in terminal ductules (acini) = the milk-forming glands
• Acini + efferent ductules = Terminal Duct Lobular Units (TDLUs) - the functional unit
• TDLUs are invested in specialized loose connective tissue (intralobular stroma - distinct from denser interlobular stroma)

• Axillary nodes: ~75% of breast lymph drains here (level I, II, III)
• Internal mammary nodes
• Supraclavicular nodes

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BREAST DEVELOPMENT AND PHYSIOLOGY

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CLINICAL APPROACH TO THE BREAST PATIENT

Patient History

• Pain (cyclical vs. noncyclical)
• Nipple discharge (color, single vs. multiple ducts, unilateral vs. bilateral)
• Masses (duration, change with menstrual cycle)
• Skin changes
• Risk factors (family history, prior biopsies, hormone use, radiation history)

Physical Examination

• Asymmetry, skin changes, nipple retraction, peau d'orange, Paget disease
• Performed with arms at side, then raised, then hands pressed on hips

• Axilla, supraclavicular and infraclavicular spaces for lymphadenopathy (seated)
• Breast palpation: patient supine, arm above head, compression toward chest wall
• Systematic palpation of each quadrant + tissue under NAC
• Characterize masses: size, shape, consistency, location (clock position + cm from nipple), fixation to skin/muscle

• Peau d'orange: edema/dimpling from dermal lymphatic blockage - most feared cause is inflammatory carcinoma
• Nipple discharge from single duct: may signify underlying pathology (e.g., papilloma)
• Paget disease of nipple: psoriatic rash starting at nipple, spreading to areola - malignant ductal cells invading epidermis
• Skin dimpling: traction on Cooper ligaments by scirrhous tumor, best seen with angled indirect lighting during arm abduction

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BREAST IMAGING AND DIAGNOSTIC BIOPSY

Screening Mammography

• Performed in asymptomatic females to detect occult cancer
• Average-risk = no personal history, no strong family history, no BRCA mutation, no chest RT before age 30

Imaging Modalities

• Primary screening tool; can detect microcalcifications, masses, architectural distortion
• BI-RADS classification (0-6): 0 = incomplete, 1 = negative, 2 = benign, 3 = probably benign (6-month follow-up), 4 = suspicious (biopsy), 5 = highly suggestive of malignancy, 6 = known malignancy
• Sensitivity ~85%; reduced in dense breasts

• Differentiates cystic from solid masses
• Useful in dense breasts, pregnant/lactating females
• Not a standalone screening tool; used as extension of physical exam
• Simple cysts: anechoic, posterior acoustic enhancement, thin smooth walls - no further workup needed

• Most sensitive modality (~90-95%)
• Indications: screening in high-risk patients (BRCA+), extent of disease for newly diagnosed cancer, response to neoadjuvant therapy, occult primary breast cancer, implant evaluation
• Lower specificity than mammography; high false-positive rate

Biopsy Techniques

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IDENTIFICATION AND CARE OF HIGH-RISK PATIENTS

Risk Factors for Breast Cancer (Box 68.1)

• Increased age (peaks in 8th decade)
• Female sex
• Shift work (nighttime)
• Obesity, smoking, alcohol, physical inactivity
• High-fat/low-fiber diet

• Early menarche (before age 11)
• Late menopause (after age 55)
• Nulliparity / fewer live births
• First full-term pregnancy after age 30
• Lack of breastfeeding
• HRT, OCP use

• Family history of breast/ovarian cancer
• BRCA1 (chr 17q): 60-80% lifetime risk; associated with triple-negative cancers
• BRCA2 (chr 13q): 40-70% lifetime risk; associated with ER+ cancers; also male breast cancer
• Other: TP53 (Li-Fraumeni), PTEN (Cowden), CDH1 (lobular), PALB2, ATM, CHEK2

• Proliferative disease without atypia (sclerosing adenosis, papillomatosis, moderate hyperplasia): RR 1.3-1.9
• Proliferative disease with atypia (ADH, ALH): RR 3.7-4.2
• LCIS: RR >7

Risk Assessment Models

• Gail Model: age, race, menarche, first live birth, prior biopsies, atypia, family history; best for average-risk women
• Tyrer-Cuzick (IBIS): incorporates BRCA probability; preferred for high-risk assessment
• ≥20% lifetime risk = high-risk category (qualifies for MRI screening + chemoprevention discussion)

Care of High-Risk Patients

• Reduces breast cancer risk by ~90-95% in BRCA carriers
• Bilateral prophylactic salpingo-oophorectomy (BPSO) reduces risk further and addresses ovarian cancer risk
• Genetic counseling and multidisciplinary discussion essential before proceeding

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BENIGN BREAST DISEASES

Fibrocystic Changes and Mastalgia

• Common in 4th-5th decades; exaggerated response to hormones/growth factors
• Cyclic mastalgia: premenstrual, bilateral, resolves with menopause
• Noncyclic mastalgia: idiopathic, harder to treat; require breast imaging in women ≥30
• Scapulothoracic bursitis: referred pain along intercostal nerves mimicking breast pain; trigger-point injections diagnostic + therapeutic
• Histology: macrocysts, microcysts, adenosis, sclerosis, apocrine metaplasia, stromal fibrosis, epithelial hyperplasia
• Simple cysts: confirmed on US; no further workup needed; aspiration if symptomatic; vacuum-assisted excision for large recurrent cysts
• Treatment of mastalgia: danazol, Lupron, tamoxifen (significant side effects); NSAIDs for noncyclical

Fibroadenomas

• Most common breast tumor in young females (teens to 30s)
• Arise from TDLUs; estrogen-sensitive - grow in pregnancy, regress after menopause
• Well-circumscribed, rubbery, mobile ("breast mouse")
• US: homogeneous, hypoechoic, well-defined
• Giant fibroadenoma (>5 cm): may require excision
• Management: CNB confirmation + observation if classic features; excise if enlarging, >3 cm, or patient preference

Breast Infections and Abscess

• Lactational mastitis: S. aureus most common; treat with antibiotics + continued breastfeeding; progress to abscess in ~10%
• Periductal (non-lactational) mastitis: associated with smoking, subareolar; mixed flora; recurrent; fistula formation common
• Abscess: US-guided aspiration or incision and drainage; must exclude inflammatory carcinoma

Idiopathic Granulomatous Mastitis

• Rare; mimics carcinoma clinically
• Diagnosis by core biopsy; rule out TB, fungal infections
• Treatment: steroids ± methotrexate; surgery for resistant cases

Nipple Discharge

• Physiologic (bilateral, multiple ducts, non-spontaneous, non-bloody): reassurance
• Pathologic (unilateral, single duct, spontaneous, bloody/serous): requires workup
• Most common causes: intraductal papilloma (most common cause of bloody discharge), duct ectasia, carcinoma
• Workup: cytology, ductography/galactography, duct excision (microdochectomy)

Papillomas and Papillomatosis

• Solitary papilloma: most common cause of bloody nipple discharge; low malignant potential; treated by duct excision
• Multiple peripheral papillomas (papillomatosis): higher risk of atypia and subsequent carcinoma

Fat Necrosis

• Post-traumatic or post-surgical; mimics carcinoma on imaging (oil cyst, calcifications, spiculated mass)
• Biopsy if imaging uncertain; no treatment if confirmed

Gynecomastia

• Benign glandular proliferation in males; due to estrogen-androgen imbalance
• Causes: puberty, liver disease, renal failure, hypogonadism, drugs (spironolactone, cimetidine, marijuana, anabolic steroids), tumors (HCG-secreting)
• Management: treat underlying cause; tamoxifen/anastrozole pharmacologically; subcutaneous mastectomy for cosmetically unacceptable cases

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EPIDEMIOLOGY OF BREAST CANCER

• 297,790 cases of invasive + 55,720 in situ breast cancer diagnosed in the US (2023)
• Second leading cause of cancer death in females (after lung); ~43,700 deaths in 2023
• Most prevalent cancer worldwide: >2 million cases, ~685,000 deaths/year
• 5-year survival improved: 63% (1960s) → 91% (2012-2018)
• Highest incidence in White females (133.7/100,000); highest mortality in Black females (40% higher than White) - due to higher TNBC incidence, later-stage diagnosis, and disparate access to care

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PATHOLOGY OF BREAST CANCER

Noninvasive (In Situ) Breast Cancer

• Malignant epithelial cells confined within ductal system, basement membrane intact
• Classified by architecture (comedo, cribriform, micropapillary, papillary, solid) and nuclear grade (low, intermediate, high)
• Comedo DCIS (high-grade, central necrosis with calcifications): more aggressive, higher local recurrence risk
• Treatment: BCS + radiation; mastectomy for extensive/multicentric DCIS; endocrine therapy (tamoxifen) to reduce contralateral risk in ER+ DCIS

• No longer classified as carcinoma in AJCC 8th edition - recognized as a risk marker
• Bilateral, multicentric; most detected incidentally
• Marker for subsequent invasive cancer (bilateral risk, either ductal or lobular)
• Management: surveillance or chemoprevention; bilateral prophylactic mastectomy in select high-risk cases

Invasive Breast Cancer

Molecular Markers (Intrinsic Subtypes)

• Oncotype DX (21-gene): predicts recurrence score (RS) and benefit from chemotherapy in ER+/HER2-/N0 or N1 disease
  • RS <18: endocrine therapy alone; RS ≥18 (node-negative, postmenopausal) or ≥26: benefit from chemotherapy
• MammaPrint (70-gene): risk stratification for distant recurrence

Other Breast Tumors

• Stromal/epithelial mixed tumor; classified benign, borderline, malignant
• Present as rapidly enlarging mass (bulky, firm); leaf-like architecture on histology
• Treatment: wide local excision with 1-cm margins; mastectomy for large/malignant
• Malignant phyllodes: sarcomatous stroma; hematogenous spread (not lymphatic - no axillary dissection needed)

• Rare; primary (young women) or secondary (post-radiation, post-lymphedema - Stewart-Treves syndrome)
• Purple/blue skin discoloration; aggressive; poor prognosis
• Treatment: wide surgical resection; chemotherapy (anthracycline-based)

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STAGING (AJCC 8th Edition)

• Tumor grade (histologic)
• Biologic markers: ER, PR, HER2 status
• Genomic assays (Oncotype DX RS, where applicable)
• Response to neoadjuvant therapy

• y prefix: after neoadjuvant therapy (ypTNM)
• r prefix: recurrent tumor
• m suffix: multiple primary tumors
• c = clinical staging; p = pathologic staging

• History + physical + bilateral breast imaging for all patients
• CT, bone scan reserved for: clinically positive nodes, abnormal labs/CXR, locally advanced/inflammatory cancer, or symptomatic patients

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SURGICAL TREATMENT OF BREAST CANCER

Historical Perspective

• Halsted radical mastectomy (1894): en bloc removal of breast, both pectoral muscles, axillary contents - reduced local recurrence but no survival benefit vs. less aggressive surgery
• Modified radical mastectomy (MRM): removes breast + pectoralis fascia + axillary dissection; preserves pectoralis muscles (Patey/Auchincloss procedures) - became standard
• NSABP B-06 trial: proved BCS + RT equivalent to total mastectomy in OS and DFS for tumors ≤4 cm

Selection of Surgical Therapy

• Prior breast or chest wall radiation
• Active connective tissue disease involving skin (scleroderma, lupus)
• Pregnancy (1st/2nd trimester)
• Multicentric disease
• Diffuse malignant-appearing microcalcifications

• Large tumor-to-breast ratio
• Involved margins after reexcision
• Certain collagen vascular diseases

Breast-Conserving Surgery (BCS) - Technical Aspects

• Also called: lumpectomy, partial mastectomy, segmentectomy, wide local excision
• Excise tumor with surrounding rim of grossly normal parenchyma
• Specimen oriented + inked before sectioning
• Specimen radiography for all nonpalpable lesions or lesions with microcalcifications
• Cavity shave margins (level I evidence): reduce positive margins and need for re-excision
• Clips placed in cavity for radiation planning

• Invasive cancer: "no ink on tumor" = adequate negative margin (SSO/ASTRO consensus)
• DCIS: ≥2 mm = adequate negative margin (SSO/ASTRO/ASCO consensus)

Localization of Nonpalpable Lesions

• Wire-localization (traditional)
• Radioactive seed localization
• Magnetic seed (Magseed)
• Radar reflector (SAVI SCOUT)
• Radioactive tracer injection (SCOUT)

Mastectomy Types

Axillary Surgery

• Standard for clinically node-negative breast cancer
• Dual tracer (blue dye + radioisotope) maximizes identification rate and minimizes false-negative rate (FNR)
• If SLN negative: no further axillary surgery needed
• ACOSOG Z0011 trial: patients with 1-2 positive SLNs undergoing BCS + whole breast irradiation (WBI) - ALND can be omitted without difference in OS or DFS
• AMAROS trial: axillary RT equivalent to ALND for 1-2 positive SLNs

• Level I-III dissection (relative to pectoralis minor)
• Standard for: locally advanced/inflammatory breast cancer, >3 positive nodes, mastectomy without WBI, clinically positive nodes after neoadjuvant therapy
• Complications: lymphedema (~20%), paresthesias (intercostobrachial nerve), seroma, shoulder dysfunction

• Initially cN+ patients: SLNB accuracy improved with ≥2 SLNs retrieved, dual tracer, and clipping the biopsy-proven node
• Targeted Axillary Dissection (TAD) = SLNB + retrieval of clipped biopsy-proven node: FNR as low as 1.4%

• Identifies arm lymphatics (blue dye in arm) vs. breast lymphatics (isotope in breast)
• Preserves arm lymphatics during ALND, reducing lymphedema
• Alliance 221702 is ongoing to validate

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RADIATION THERAPY

After Breast-Conserving Surgery

• Whole breast irradiation (WBI): standard after BCS; reduces local recurrence by ~50-70%
• Hypofractionated WBI (FAST-Forward trial): 26 Gy/5 fractions (vs. standard 50 Gy/25 fractions) - equivalent outcomes; preferred for most patients
• Accelerated Partial Breast Irradiation (APBI): radiation to lumpectomy cavity only; suitable for select patients (see ASTRO guidelines - age ≥50, tumor ≤2 cm, pN0, negative margins ≥2 mm, ER+, no LVI)
• Radiation boost to lumpectomy cavity reduces local recurrence further, especially in young patients (<40)

Post-Mastectomy Radiation Therapy (PMRT)

• Indicated for: ≥4 positive lymph nodes, T3/T4 tumors, positive margins
• Consider for: 1-3 positive nodes (supported by Danish trials, EBCTCG meta-analysis)
• Danish Breast Cancer Cooperative Group Trials (82b/82c): PMRT + chemotherapy or tamoxifen significantly improved locoregional control and OS in stage II/III disease
• Radiation fields: chest wall + axillary, infraclavicular, supraclavicular, and internal mammary nodal basins

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SYSTEMIC THERAPY

Goals and Assessment

• Adjuvant therapy reduces risk of distant recurrence and death
• Tools to assess benefit: ER/PR/HER2 status, grade, Oncotype DX, MammaPrint, Ki-67
• For ER+/HER2-/N0: TAILORx trial - Oncotype RS 0-10: endocrine therapy alone; RS 11-25 (postmenopausal): endocrine therapy alone; RS 26-100: add chemotherapy
• RxPONDER trial: in N1 (1-3 nodes) ER+/HER2- postmenopausal patients with RS ≤25: no benefit from adding chemotherapy

Chemotherapy

• Anthracyclines (doxorubicin/cyclophosphamide = AC) + Taxanes (paclitaxel/docetaxel) = backbone
• Regimens: TC (taxane + cyclophosphamide); AC-T; dose-dense AC-T
• Capecitabine: adjuvant in TNBC with residual disease after neoadjuvant chemo (CREATE-X trial)
• Olaparib/niraparib: PARP inhibitors for BRCA-mutated HER2-negative early breast cancer with residual disease (OlympiA trial)

HER2-Targeted Therapy

• Trastuzumab (Herceptin): anti-HER2 monoclonal antibody; ~50% reduction in recurrence; 1 year adjuvant
• Pertuzumab + trastuzumab: dual HER2 blockade; APHINITY trial: benefit in node-positive disease
• T-DM1 (ado-trastuzumab emtansine): for residual disease after neoadjuvant therapy (KATHERINE trial): reduces recurrence by 50%
• Lapatinib: oral TKI, dual EGFR/HER2 inhibitor; used in metastatic HER2+ disease
• Cardiotoxicity monitoring required for all HER2-targeted agents

Endocrine Therapy

• SERM; competitive ER antagonist in breast (agonist in bone, endometrium)
• Standard for premenopausal ER+ breast cancer; also used postmenopausal
• 5 years: standard; ATLAS trial - 10 years reduces distant recurrence and mortality further
• Risks: endometrial cancer, thromboembolic events (DVT/PE), hot flashes

• Anastrozole, letrozole (non-steroidal); exemestane (steroidal)
• Block peripheral aromatization of androgens to estrogen
• Postmenopausal only (ovarian estrogen production not suppressed)
• Superior to tamoxifen in postmenopausal ER+ disease (ATAC, BIG 1-98 trials)
• Risks: arthralgia, bone loss (osteoporosis), fractures - monitor bone density + bisphosphonates

• GnRH agonists (goserelin, leuprolide): medical castration
• Combined with AI (SOFT/TEXT trials): superior to tamoxifen alone in high-risk premenopausal patients
• Surgical oophorectomy: permanent

• Abemaciclib (monarchE trial): adjuvant in high-risk ER+/HER2- patients with ≥4 nodes or 1-3 nodes + high-grade/large tumor/high Ki-67; added to endocrine therapy

Neoadjuvant Systemic Therapy

• Converts inoperable to operable disease; allows BCS in previously mastectomy-only candidates
• Provides in vivo chemosensitivity data; pathologic complete response (pCR) = prognostic marker
• pCR (no residual invasive disease in breast + nodes) correlates with improved survival, especially in TNBC and HER2+
• Residual disease after neoadjuvant: escalate therapy (T-DM1 for HER2+; capecitabine for TNBC; olaparib for BRCA-mutated)

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TREATMENT OF SPECIAL CONDITIONS

Locally Advanced and Inflammatory Breast Cancer (LABC/IBC)

• Includes: tumors >5 cm, chest wall involvement, skin involvement, bulky/fixed axillary nodes, internal mammary/supraclavicular involvement
• Current approach: neoadjuvant chemotherapy → surgery (MRM preferred) → RT ± further systemic therapy
• Surgery alone: 30-50% local recurrence; RT alone: similar; trimodality required

• 1-5% of all breast cancers; most aggressive subtype
• Hallmark: dermal lymphatic involvement (pathologic) causing erythema, edema, warmth, peau d'orange
• Rapid onset: progression over weeks to 3 months
• Clinical diagnosis - palpable mass not required; pathologic confirmation of dermal lymphatics helpful but not prerequisite
• Staging: always T4d = stage IIIB minimum
• Treatment: neoadjuvant chemotherapy → modified radical mastectomy (no immediate reconstruction) → PMRT → adjuvant systemic therapy
• SLNB has high FNR in IBC - always perform ALND
• 5-year outcomes: locoregional recurrence ~6.9%; distant recurrence ~35.1% with trimodal treatment

Breast Cancer in Older Adults

• CALGB 9343 / PRIME-II trials: in women ≥65-70 with ER+, HER2-, small tumors (≤2-3 cm), clinically node-negative - lumpectomy + endocrine therapy without radiation: no OS difference at 10 years (inferior local control but clinically acceptable)
• SLNB may be safely omitted in older patients with early ER+ disease (SOUND, INSEMA trials evaluating this)

Breast Cancer in Males

• Rare (~1% of breast cancers)
• Risk factors: BRCA2 mutation (RR ~7), Klinefelter syndrome, gynecomastia, exogenous estrogens
• Usually ER+ (>90%); presents at more advanced stage due to delayed diagnosis
• Treatment: same principles as female breast cancer; MRM preferred (less breast tissue)
• Tamoxifen is the endocrine therapy of choice (AIs less effective due to intact gonadal estrogen production in premenopausal males)

Breast Cancer During Pregnancy (Pregnancy-Associated Breast Cancer)

• Defined as breast cancer diagnosed during pregnancy or within 1 year postpartum
• Most common cancer in pregnancy; ~1 in 3000 pregnancies
• Delayed diagnosis common due to physiologic breast changes
• Diagnosis: US safe at all trimesters; mammography (with shielding); MRI without gadolinium preferred in 2nd/3rd trimester; CNB safe
• Surgery: safe at any trimester; MRM if BCS would require radiation in 1st/2nd trimester
• Chemotherapy: safe after 1st trimester (AC regimen); taxanes in 2nd/3rd trimester
• Radiation: contraindicated during pregnancy
• HER2-targeted therapy: contraindicated (fetal harm - oligohydramnios)
• Endocrine therapy: contraindicated (teratogenic)
• Prognosis: stage for stage, similar to non-pregnant females; delayed diagnosis leads to worse outcomes

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BREAST RECONSTRUCTION

• Immediate: done at time of mastectomy; preferred for psychological wellbeing; requires coordination with oncologic surgery and radiation planning
• Delayed: after completion of all oncologic treatments; safer in high-risk radiation candidates

1. Implant-based: tissue expander → permanent implant; most common; simpler; may be affected by radiation
2. Autologous flaps:
   • TRAM flap (transverse rectus abdominis myocutaneous): pedicled or free; abdominal donor site
   • DIEP flap (deep inferior epigastric perforator): microsurgical; spares rectus muscle; preferred when available
   • Latissimus dorsi flap: with or without implant; used when abdominal tissue unavailable
   • SIEA flap (superficial inferior epigastric artery): alternative microsurgical; limited pedicle
3. Nipple reconstruction: after breast mound achieved; tattooing for areola

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