BREAST DISEASE

PATHOLOGYBenign changesFibrocystic changes: cyst formation, apocrine metaplasia, duct adenosis, sclerosing adenosis – in young females Epithelial hyperplasia: mild, moderate, florid (florid associated with potential progression to malignancy)Sclerosing lymphocytic lobulitis: perivascular and perilobular chronic inflammation associated with autoimmune disease (DM type 1) – presents as irregular mass – need a biopsy specimenHamartoma: growth of a benign lesion of a particular tissue type arranged abnormally – differential diagnosis of fibroadenomaDuct ectasia – abnormal dilatation of ducts – if acutely inflamed and presenting as a discharge or fistula (periductal mastitis)Radial scar (<1 cm) or complex sclerosing lesion (>1cm) – found incidentally or stellate lesion on mammography – can be associated with invasive or in situ carcinoma

Neoplastic breast diseaseAll patients identified through breast screening or symptomatic presentation – undergo TRIPLE ASSESSMENT

i. Clinical examination, ii. Radiology (mammography (>35yrs), Ultrasound + mammography (<35) – due to

dense breast tissue in young patients)iii. FNAC, Core Biopsy

Benign Fibroadenoma – well defined mobile mass in young women (biphasic lesion of epithelial and stromal component on histology)Intraduct papillomas comprise a frond-like epithelial proliferation within breast ducts, may be single or multiple – most common cause of bloody nipple discharge. Malignant carcinoma – Most common cancer in women, 2nd largest killer of all cancers (Lung: 1st)1 in 9 women and 1 in 300 menPaget’s disease: eczematous lesion of the breast – underlying DCIS or invasive carcinomaIn situ or invasive – lobular often missed on mammography – often need MRIPure ductal carcinoma in situ (DCIS): present as breast mass, nipple discharge, Paget’s disease of skin, skin dimpling, and peau d’orange. WLE: surgical resection margin of 2mm

Invasive carcinoma – breast mass, nipple discharge or breast pain (15%), asymptomatic on screening mammography; 75% ductal; conventionally invasive tubal carcinoma is better prognosis than DCISGrade: morphological description of tumour (differentiation and architectural changes)Stage: progression of tumour anatomically (depth of invasion (T), node involvement (N), metastasis (M))

Size (cm): <2 (T1), 2 – 5 (T2), >5 (T3), skin, chest wall involvement (T4)Determine prognosis using:Nottingham prognostic index (NPI): (0.2 x tumour size (cm)) + tumour grade + tumour stageStage 1 – no nodesStage 2 – three axillary lymph nodes OR single internal mammary nodeStage 3 - ≥4 axillary nodes OR an axillary lymph node + internal mammary node

Nodes: N0 No nodal metastasesN1 Mobile ipsilateral node(s) involvedN2 Fixed ipsilateral node(s) involvedN3 Ipsilateral internal mammary node(s) involved Immunohistochemistry:Determine oestrogen (ER) or progesterone (PR) receptor status – if positive (better prognosis than negative status)Determine c-erb-B2 (HER-2) gene over amplification or use FISH for gene overexpression: positive (poor prognosis); negative (better prognosis)If ER, PR negative and HER-2 positive (worse prognosis);

If no clinical or radiological (ultrasound) evidence of axillary node metastasis – do a Sentinel lymph node biopsy

Remember breast can be involved in unusual cancer and metastases.

Phyllodes tumours: biphasic but increased stromal component (increased stromal cellularity than fibroadenomas); tumour of young people (20-45yrs) – if benign: Wide local excision (WLE), if malignant (mastectomy); 30% benign, 30% malignant, 40% borderline; large; rare nodes (spread, if any, is haematogenous) – NO lymph nodes

Familial cancer: BRCA 1 (chromosome 17) and BRCA 2 (chromosome 13) and others Both BRCA mutations – autosomal dominant but VARIABLE penetranceBRCA 1: 80% risk breast cancer, 40% risk ovarian, Fallopian tubeBRCA 2: breast cancer, ovarian cancer – better prognosis than BRCA 1In males BRCA 2: breast, prostate, and both can get pancreatic and malignant melanomaCan offer Bilateral salpingo-oophorectomy (ablate ovarian cancer risk and decrease breast cancer risk by 50%) – (can give HRT to protect against osteoporosis and heart disease) or risk reducing mastectomy (RRM)Others: Li-Fraumeni syndrome (p53 mutation) – sarcomas, osteosarcomas, premenopausal breast cancer, brain cancerCowden Syndrome (PTEN mutation): autosmal dominant: hamartomas in breast, skin, thyroid, brain, endometrial, colorectal – malignant potential (most common: skin and brain)Peutz-Jehger’s syndrome: autosomal dominant – orofacial and palm mucocutaneous pigmentation with GI hamartomas – associated with a number of malignanciesConsider familial breast cancer in the following:

1. one first-degree relative with breast cancer diagnosed before age 40 years.

2. two first- or second-degree relatives with breast cancer diagnosed before age 60 years.

3. three or more first- or second-degree relatives with breast cancer at any age.4. a close relative with bilateral breast cancer.5. a close male relative with breast cancer

NHS BREAST SCREENING50-70 years 3 year mammography – if microcalcification or mass or stromal changes – undergo triple assessment.In familial screening – add MRI to mammography to increase sensitivityHigh risk women – start at age 30 -35 yearsModerate risk women – from 40 yearsMale breast cancer: invasive has worse prognosis than in situ (contrast to females) – can also present with gynaecomastia

Other risk factors: Anything to increase oestrogen exposure (endogenous or exogenous)

Increasing age Female Sex Use of combined oestrogen and progesterone > 4 years (OCP or HRT) Nulliparous women (no pregnancy) Early menarche Late menopause Pregnancy after 35 years (greater risk than nulliparous) Obesity Alcohol Ashkenazi Jewish Ancestry

Smoking does not increase risk nor decreases it

BREAST CANCERTRIPLE ASSESSMENTSuspect when: hard fixed lump with skin tethering, Paget’s disease, age >30 years with discrete lump that persists after period, unilateral skin/eczematous changes, recent nipple distortion, nipple discharge, male >50 years with firm unilateral mass

Radiology: Mammography: 90% sensitive in >50 years (2 views)Ultrasound: <35 years; axillary ultrasound and guiding aspiration or biopsyMRI: non-diagnostic mammography or young woman high risk

Core biopsy: local anaesthetic; invasive; can differentiate between in situ and invasive cancer and provide sample for immunohistochemistryFNAC: mostly for cyst aspiration; 20g needle to obtain cells – quick and limited in diagnosis – no immunohistochemistry – cannot differentiate between in situ and invasive carcinomaFailure of triple assessment mandates a surgical open biopsy: localize lesion using reidy wire under ultrasound/xray guidance

Punch biopsy: Paget’s disease, local recurrence, cutaneous lesions, nipple eczemaNo further tests indicated unless suspect metastasis or advanced disease at first presentation

MANAGEMENTCan be considered as initial; following local recurrence, and metastaticInitial Options:Neo-adjuvant chemotherapySurgeryAdjuvant radiotherapyAdjuvant chemotherapyAdjuvant hormonal therapy

NEO-ADJUVANT CHEMOTHERAPY: large, inflammatory, inoperable cancersInflammatory: oedematous and cardinal signs of inflammation but no systemic symptoms

SURGERYWide Local Excision (WLE): DCIS or invasive tumour <4cm – need a 2mm margin; if removing >15% breast volume – poor cosmetic result Mastectomy indications:

tumour >4cm multifocal breast cancer central breast cancers woman does not want radiotherapy high risk women (familial) male breast cancer local recurrence from previous WLE

Axillary node status is the single most important prognostic indicator in breast cancer

Axillary surgery: if no clinical, radiological or pathological evidence of lymph node involvement – offer sentinel (guardian) lymph node biopsy (SLNB) to ALL womenSLNB: based on principle that cancer drains into a chain of lymph nodes – if 1 st node not involved, then others are most likely negative – if hot/blue nodule detected – it’s positive – offer Axillary clearance; if negative no further axillary surgery or radiotherapy requiredAxillary clearance: removal of nodes (level I, II, III) around pectoralis minor – Most important complication: arm lymphoedema (30-40%)Breast reconstruction: immediate or late – depends on patient choice, availability of reconstructive surgeon, adjuvant radiotherapy; generally immediate is better as skin sparing mastectomy can be perfomed – skin provides good envelope to shape flap, is sensate and avoids colour mismatch between different muscle flaps (dorsal, abdominal)Nipple areolar reconstruction – late at nearly 6 months: challenging – use graft from opposite nipple

LOCAL ADJUVANT RADIOTHERAPY: Whole breast: all women with WLE; not usually in mastectomy unless inflammatory breast cancer, ≥4 axillary nodes involved, involvement of skin/chest wall

Chest wall: ≥ 4 axillary lymph nodes, tumour >5cm, involved resection margins (i.e. not cleared margins after resection)Supraclavicular fossa: ≥4 axillary lymph nodes metastasis AFTER axillary clearance

SYSTEMICADJUVANT CHEMOTHERAPY: anthracycline based – in intermediate or high risk womenDetermining risk:Low: Node negative AND ER/PR positive, tumour <2cm (T1), HER-2 negative, Age >35Intermediate: Node negative AND 1 of tumour >2cm (T2), ER/PR negative, HER-2 positive, Age < 35; OR Node positive (1-3) with ER/PR positive, HER-2 negativeHigh: Node positive (1-3) AND ER/PR negative, Age >50, HER-2 negative OR ≥4 axillary nodes

HORMONAL THERAPYER/PR positive: hormonal treatment for 5 yearsPre-menopausal: Tamoxifen (selective oestrogen receptor modulator) – if contraindicated ovarian suppression (oophorectomy, ovarian radiotherapy, GnRH agonists)Post-menopausal: Aromatase inhibitors (letrozole, anastrozole)Another option: Sequential therapy – aromatase inhibitor (2-3 years) to tamoxifen (2-3 years) (total 5 years)IF HER-2 positive: All women following surgery and adjuvant chemo/radiotherapy should get Trastuzumab (monoclonal antibody against HER-2 receptor)

Local Recurrence Options:Similar as above but different indicationsWhat is it: Recurrent malignancy in remaining breast tissue, skin or flaps; early recurrence (<5 years) has poor prognosisMost important factor in preventing recurrence: clear histological marginsDiagnose with triple assessment: clinical exam, radiology, ultrasound guided punch biopsyPrevious WLE and local recurrence: do a mastectomyPrevious mastectomy and local recurrence: if small: resect surgically; if large: chest wall radiotherapy and systemic therapyAxillary recurrence: If no previous axillary clearance (AXL) – offer AXL nowIf previous AXL: offer palliative radiotherapy/systemic therapy

Metastatic Disease: 18 – 24 months survivalSymptoms: systemic (weight loss, malaise, lethargy) and site specific (bone pain, change of personality, breathlessness, jaundice)Investigations: Tumour specific: grade, stage, receptor statusHaematological and biochemistry: FBC, U&Es, LFTs, ALP, Albumin, Phosphate, CalciumRadiology: CXR, CT Thorax, Abdomen, Pelvis (head if symptoms), Isotope bone scan, consider PET-CT if above non-diagnosticAspirate relevant sites: Ascites and Pleural effusion

Manage: Palliative (choose least toxic regime) 1st line: endocrine and chemotherapy

Managing complications: Bone metastases: bisphosphonates, surgical decompression (spinal cord involvement or long bones involved), and radiotherapy in spinal metastases following surgery unless surgery not indicated Brain metastases: surgery if fit patient, else radiotherapy and corticosteroidsPalliative care: address (1) pain; (2) nausea and vomiting; (3) dyspnoea; (4) constipation