BM4007 & PM3017 Breast Pathology PDF

BM4007 & PM3017 Breast Pathology Dr Collette Hand UCC Department of Pathology [email protected] September 2024 BM4007&PM3017 Dr C.Hand Textbooks BM4007&PM3017 Dr C.Hand  Breast Pathology Lecture Outline FEMALE Breast...

BM4007 & PM3017 Breast Pathology Dr Collette Hand UCC Department of Pathology [email protected] September 2024 BM4007&PM3017 Dr C.Hand Textbooks BM4007&PM3017 Dr C.Hand  Breast Pathology Lecture Outline FEMALE Breast MALE Breast Normal structure and function Gynaecomastia Clinical presentation of breast lesions Carcinoma Diagnostic methods Developmental Abnormalities Inflammatory conditions Benign Epithelial Lesions – Non-Proliferative conditions – Proliferative conditions Neoplasia BM4007&PM3017 Dr C.Hand Breast: normal structure & function 1 Function: U6/U7: – Production and expression of milk Fig 18.2 Structure: – Lobules and Ducts U6/U7: Fig 18.1 BM4007&PM3017 Dr C.Hand  Breast: normal structure & function 2 A3: Fig 14.3 Right: larger duct. Left: lobular units. Collagenous stroma between structures U6/U7: Fig 18.3 A breast lobule showing BM4007&PM3017 Dr C.Hand different components.  Normal Breast- histology A3: Fig 14.4 The appearance of a normal breast acinus is shown at high magnification. The epithelial cells lining the lumen show apocrine secretion with snouting, or cytoplasmic extrusions (▲) into the lumen. A layer of myoepithelial cells (▼), some of which are slightly vacuolated, is seen just around the outside of the acinus. BM4007&PM3017 Dr C.Hand  Normal variation Minor changes in each menstrual cycle – -> exam of pre-menopausal breast in first half of cycle is preferable Pregnancy & lactation – Lobules proliferate and enlarge – Epithelial cells differentiate: synthesis & secretion of milk / components – When feeding ceases: involution of differentiated lobules Lobules regress and atrophy, remain larger than pre-pregnancy Involution – Breast changes with age May be uneven rate: lumps Connective tissue of lobules: dense -> loose ↑ Adipose tissue BM4007&PM3017 Dr C.Hand Life cycle changes in the breast R9: Fig 23.2 A) Mammograms in young women are radiodense/white –>less useful B) Density of young breast is due to fibrous interlobular stroma, little adipose tissue C) Pregnancy: branching of terminal ducts -> more numerous, larger lobules D) Aging: lobules decrease in size and number and interlobular stroma is replaced by adipose tissue E) Mammograms more useful with age as tissue becomes more radiolucent BM4007&PM3017 Dr C.Hand  Clinical features of breast lesions Physiological v Pathological changes Lump(s) – Well circumscribed or ill-defined, single or multiple, soft or firm, mobile or attached to skin/muscle Palpable mass – ≥ 2 cm size – Likelihood of mass being malignant ↑ with age Malignant in 10 % masses < 40 years; 60 % masses > 50 years Pain R9: Fig 23.3; R10: Fig 23.2; RBP10: Fig 19.23 Nipple discharge BM4007&PM3017 Dr C.Hand  Diagnostic methods Mammography – Detects small, non-palpable asymptomatic carcinomas – Densities, Calcification (areas of cell injury and necrosis) Ultrasonography – Solid v cystic lesion Biopsy – Fine needle aspirate biopsy (FNAB) – Core biopsy Screening – Early detection, mammography – Ireland: every 2y for women 50-69y – > 50 years, tissue is less dense; ↑ risk malignancy BM4007&PM3017 Dr C.Hand  Developmental abnormalities Failure of development – Rare: ovarian agenesis, eg Turner Syndrome Juvenile hypertrophy – Rapid, disproportionate development during puberty – Surgery Milkline Remnants – Supernumerary nipples, hormone responsive Nipple Inversion – Congenital: usually revert during pregnancy – Acquired: concerning BM4007&PM3017 Dr C.Hand  Inflammation Infection Mammary duct ectasia Fat necrosis Significance is possible confusion with breast cancer Does not increase risk Mastitis = inflammation of breast BM4007&PM3017 Dr C.Hand  Inflammation of the Breast Acute Mastitis – Lactation, cracks, fissures, Staphylococcus aureus, swelling, erythema, antibiotics, +/- drainage, abscess Squamous metaplasia of lactiferous ducts (SMoLD) – Women, men, smokers (90%), not associated with lactation – Painful erythematous subareolar mass – Keratin plugs, block ducts -> dilation, rupture – Chronic inflammation +/-acute – Drainage, re-occurrence, Surgical duct removal R9: Fig 23.4; R10: Fig 23.3 BM4007&PM3017 Dr C.Hand  Duct ectasia Post-menopausal, parous women Periareolar palpable mass, painless – *Mimic carcinoma, but no ↑ risk Duct dilation, rupture Thick nipple discharge Inflammation: – Lymphocytes, macrophages, plasma cells Fibrosis -> nipple retraction No association with smoking (v SMoLD) R9: Fig 23.5; R10: Fig 23.4 Ectasia = swelling / dilation Chronic inflammation & fibrosis surround an ectatic duct BM4007&PM3017 Dr C.Hand  Fat necrosis Inflammatory reaction to damaged adipose tissue Common. Trauma or surgery – Car seat belt injury, implants, biopsy May present as painless palpable mass – *Mimic carcinoma but no ↑ risk Obese post-menopausal women, more adipose tissue Necrotic tissue-> inflammation, Macrophages, giant cells, fibrosis Wheater’s BM4007&PM3017 Dr C.Hand  Benign Epithelial Lesions Clinically detected – Mammogram – Incidental findings surgical specimens Types -> risk of subsequent breast ca. 1. Non proliferating breast changes 2. Proliferative breast disease without atypia 3. Proliferative breast disease with atypia Atypical hyperplasia BM4007&PM3017 Dr C.Hand  Non proliferating breast changes Most common breast lesion in pre-menopausal women Normal but exaggerated response to hormones Also called Fibrocystic changes – Exam: Lumps on palpation* – Radiology: Dense tissue – Pathology: Benign histological findings 1. Cystic change – Cysts form by dilation and unfolding of lobules – Lined by flat atrophic epithelium +/- apocrine metaplasia – Calcification common 2. Fibrosis – Cysts rupture-> inflammation -> fibrosis -> firmness 3. Adenosis – Increase number of acini per lobule; normal in pregnancy – Calcifications in lumen – Acini lined with columnar cells BM4007&PM3017 Dr C.Hand  Proliferative breast disease: no atypia Without atypia Atypia: departure from typical normal appearance, usually histological, either reactive (reversible), or sometimes denoting pre-neoplastic changes (ie dysplasia) Detection: mammographic densities, calcifications, incidental Proliferation of ductal epithelium and/or stroma without cytological or architectural features suggestive of carcinoma in situ. 1. Epithelial hyperplasia 2. Sclerosing Adenosis 3. Complex sclerosing lesion 4. Papilloma BM4007&PM3017 Dr C.Hand  Epithelial Hyperplasia > 2 layers of myoepithelial and luminal cells Additional cells fill & distend ducts & lobules B R9:Fig 23.7; R10:Fig 23.6 RBP9:Fig 18.25, RBP10: Fig 19.25; U6:Fig 18.9 Epithelial Hyperplasia A. Normal duct: single layer of myoepithelial (dark compact nuclei, scant cytoplasm) and a single luminal cell layer (larger open nuclei, more abundant cytoplasm). B. Epithelial hyperplasia: lumen filled with mix of luminal and myoepithelial cells. No atypia. BM4007&PM3017 Dr C.Hand  Sclerosing Adenosis ≥ double number of acini in terminal ducts – normal in pregnancy Normal lobular arrangement Palpable mass, radiologic density, calcification – mimic carcinoma Adenosis = glandular proliferation R9: Fig 23.8; R10: Fig 23.7; RBP9/10:Fig18.26, U6/U7:Fig 18.8 Terminal duct lobular unit enlarged Acini are compressed & distorted by dense stroma Calcifications present in some lumens (these would be visible on mammography) BM4007&PM3017 Dr C.Hand  Papillomas Multiple branching fibrovascular cores with connective tissue axis lined with luminal and myoepithelial cells Growth within a dilated duct – Large, solitary within sinus of duct – Small, multiple : deeper in ducts Often nipple discharge, may be bloody – Infarct or torsion R9: Fig 23.10; R10: Fig 23.9 Intraductal papilloma Central fibrovascular core BM4007&PM3017 Dr C.Hand  Complex sclerosing lesion Components of all 3 epithelial hyperplasia, sclerosing adenosis papillomas Radial Sclerosing lesion (radial scar) the only commonly occurring benign lesion that forms irregular masses and can mimic invasive ca. mammographically, grossly and histologically R9: Fig 23.9; R10: Fig 23.8 A. Radiograph: irregular central mass with radiodense projections B. Gross: lesion is solid, irregular borders C. Densely fibrotic stroma, projections containing epithelium and varying degrees of cyst formation and hyperplasia BM4007&PM3017 Dr C.Hand Proliferative breast disease: + atypia With atypia Atypical hyperplasia – Clonal proliferation having some, but not all, of the histological features that are required for the diagnosis of carcinoma in situ. – Harbour genetic change R9: Fig 23.12; R10: Fig 23.11 Atypical ductal hyperplasia (ADH) Atypical lobular hyperplasia Duct filled with cells (ALH) Spaces: some round, regular, some slit like Population of cells partially fill lobule Atypical but not DCIS Some intracellular lumens - limited extent- doesn’t fill ducts Atypical but not LCIS Seen in biopsies for calcifications - limited extent ( 260,000 invasive br ca – > 40,000 deaths (second only to lung ca) Mortality ↓ in past 30 years; 30% → 20% Heterogenous disease, cluster in 3 main groups – Based on oestrogen receptor (ER) and HER2 expression 1) ER pos, HER2 neg (50-65%) luminal 2) HER2 pos (~20%), may be ER pos or neg HER2 3) ER neg, HER2 neg (~15%) basal / triple negative Triple as Progesterone receptor (PR) negative also BM4007&PM3017 Dr C.Hand  HER2 ERBB2: epidermal growth factor receptor 2, proto-oncogene on chr17q Amplified / Overexpressed (> 2 copies) in 25-30% cancers Most respond to Trastuzumab (Herceptin) – monoclonal antibody against HER2 R9: Fig 23.21; R10: Fig 23.16 HER2 protein overexpression generally results from amplification of chr17q region that contains HER2 gene. Copy number can be determined by FISH using HER2 probe and chr17 centromeric probe (control). HER2 overexpression detected by immuno staining using HER2 antibodies Dr C.Hand BM4007&PM3017  Breast cancer subtypes RBP10: Fig 19.26 Age and the incidence of breast cancer subtypes BM4007&PM3017 Dr C.Hand  Risk Factors #1 Gender – 1% breast cancer occurs in men Age – ↑ with age, peak 75 – 80 yrs, – 75% br ca are in women > 50 yr, Oestrogen exposure – early menarche; late menopause, HRT, age at first live birth Genetics / Geography – First degree relatives with breast cancer; race/ethnicity Breast – Atypical hyperplasia; breast density, ca other breast or endometrium Lifestyle – Diet, obesity, exercise, toxins, RBP9: Table 18.5; RBP10: Table 19.6; tobacco, radiation R10: Table 23.2 BM4007&PM3017 Dr C.Hand  Aetiology and Pathogenesis Hereditary Breast Cancer (12% cases) BRCA1 gene – 50% hereditary br. ca. cases, 2% all br. ca. cases – lifetime risk of br. ca. = 65% – ↑ risk of ovarian, male breast, prostate, pancreas, + BRCA2 gene – 30% hereditary br. ca. cases, 1% all br. ca. cases – lifetime risk of br. ca. = 45% – ↑ risk of ovarian, male breast, prostate, pancreas ,+ Sporadic Breast Cancer Main risk is hormone exposure – Gender, menarche, menopause, pregnancies, breastfeeding, exogenous oestrogen Mostly postmenopausal, ER+ Hormone exposure – stimulate growth, ↑ # potential target cells, ↑ risk DNA damage BM4007&PM3017 Dr C.Hand  Pathways for breast cancer development R9: Fig 23.16; R10: Fig 23.14; RPB10: Fig 19.27: Major pathways for breast cancer development. Three main pathways 1) Most common pathway (yellow arrow) leads to ER+ cancers. Precursor lesions include flat epithelial atypia, ADH, and DCIS. Gene expression profiling: “luminal.” Most common breast ca seen with germline BRCA2 mutations. 2) Less common are cancers that overexpress HER2 by gene amplification (green arrow). These cancers may be ER + or -, often with germline TP53 mutations. 3) The least common type of breast cancer is negative for ER and HER2 (“triple negative”; blue arrow). Loss of BRCA1 & TP53 function; genomically unstable. BM4007&PM3017 Dr C.Hand  Classification 1 Lobular and ductal – Though all breast cancers arise from cells in terminal duct lobular unit Current convention – Lobular = ca of a specific type, related to LCIS – Ductal = more generally used for adenocarcinoma without another designation BM4007&PM3017 Dr C.Hand  Classification 2 95% breast malignancies: adenocarcinoma – Remaining stromal – Carcinoma in Situ (BM intact) Ductal Carcinoma in Situ (DCIS) Lobular Carcinoma in Situ (LCIS) – Invasive (Infiltrating) Carcinoma Invasive Carcinoma, No Special Type (NST) Invasive Lobular Carcinoma Other types BM4007&PM3017 Dr C.Hand  Ductal Carcinoma in Situ (DCIS) A malignant clonal proliferation of epithelial cells limited to ducts and lobules by the basement membrane 15-30% carcinomas in well screened populations Detection / Presentation – 50% of mammography detected ca (*calcifications) – nipple discharge (rarely) Can spread through ducts and lobules Treatment – Current practice: surgery + irradiation, tamoxifen (if ER+) Excellent prognosis: 97% long term survival – Untreated: DCIS->invasive cancer in about 1/3 cases, usually same breast / quadrant – Risk factors for recurrence: grade, size and margins BM4007&PM3017 Dr C.Hand  Paget disease of the nipple Rare (1-4%) manifestation of breast cancer Unilateral erythematous eruption with scale crust – Mistaken for eczema Malignant cells extend from DCIS via lactiferous sinuses into R9/R10: Fig 23.18 nipple skin without breaching basement membrane Palpable mass in 50-60% – most are underlying invasive ca. – usually ER-, HER2+ No palpable mass – usually only DCIS Prognosis based on features of carcinoma, not affected by presence of Paget disease BM4007&PM3017 Dr C.Hand  Lobular Carcinoma in Situ (LCIS) A clonal proliferation of cells within ducts and lobules that grow in a discohesive fashion, usually due to acquired loss of e-cadherin Incidental biopsy finding – No calcs or densities -> not seen on mammography Histology – Loosely cohesive clusters within lobules – Mucin-positive signet ring cells common – ER+, HER2/neu -, E-cadherin loss Approx 1/3 of women with LCIS eventually develop invasive ca. – Invasive ca. following LCIS may arise in either breast 2/3 in same breast, 1/3 in contralateral breast – ** LCIS is a marker of increased risk of bilateral carcinoma Treatment – Close clinical and radiologic follow-up, chemoprevention with tamoxifen, bilateral prophylactic mastectomy (less common) BM4007&PM3017 Dr C.Hand  LCIS R10: Fig 23.19 A. Population of small round loosely cohesive cells fills and expands the acinus. Underlying architecture is still recognisable B. Immunoperoxidase: E-cadherin pos. normal luminal cells undermined by E-cadherin neg. LCIS cells spreading along BM BM4007&PM3017 Dr C.Hand  Invasive (Infiltrating) Carcinoma Malignant epithelial tumours which infiltrate within the breast and have the capacity to spread to distant sites Palpable mass (if not detected by mammography) – Axillary lymph node metastases in 50% Nipple retraction may develop – centre of breast involved Blocked lymphatics – lymphoedema, skin thickening: peau d’orange Mammography: radiodense mass – ½ size of palpable mass < 20% lymph mets BM4007&PM3017 Dr C.Hand  Invasive Carcinoma, No Special Type NST; Invasive ductal carcinoma Majority (70-80%) carcinomas Firm, irregular border – Grating sound when cut (like water chestnut) – Chalky areas of stroma – Foci of calcification A2: Fig 14.35 Small nests and infiltrating strands of neoplastic cells Bands of collagen Infiltrate surrounding stroma BM4007&PM3017 Dr C.Hand  Infiltrating Lobular Carcinoma 10% carcinomas Most: palpable mass or mammographic density Often poorly defined- irregular border Diffuse: dyscohesive infiltrating tumour cells – single file or loose clusters/sheets – invade dense fibrous stroma – some signet-ring shape – absence E-cadherin (adhesion molecule) U6/U7: Fig 18.22 BM4007&PM3017 Dr C.Hand  Molecular classification R9: Fig 23.20; R10: Fig 23.12 Characteristic changes: DNA, mRNA, protein, morphology Chromosomal rearrangements – Green loops: intrachr. – Red loops: interchr. Gene expression – Red : relative ↑ – Green relative ↓ Immunohistochemistry – Detect protein levels Ki-67: assess proliferation Morphology – Characteristic of group basal / BM4007&PM3017 Dr C.Hand Luminal triple neg  Spread of breast cancer Directly -> skin, muscle Lymphatics -> Axillary and local lymph nodes Vascular -> Lung, bone, liver, brain May be delay before spread U6/U7: Fig 18.27 BM4007&PM3017 Dr C.Hand  Presentation Distribution R8 Most common locations R8: Fig 23-4 50% upper outer quadrant 20% central portion 10% each other quadrant BM4007&PM3017 Dr C.Hand Prognostic factors Provide information on clinical outcome at time of diagnosis 1. **Lymph node status, Biopsy necessary No nodes, 10 yr survival = 70-80% 1-3 nodes, 10 yr survival = 35-40% > 10 nodes, 10 yr survival = 10-15% 2. Tumour size, Risk of mets ↑ with size No nodes, < 1 cm 10 yr survival ≥ 90% No nodes, > 2 cm 10 yr survival = 77% Invasive v in situ: > 50% invasive have mets at diagnosis Distant mets: Once present, cure is less likely, ER+ treatments useful Locally advanced disease: Difficult to treat, now less common Histologic subtype Histologic grade, proliferative rate BM4007&PM3017 Dr C.Hand Targeted treatments of breast cancer Target Treatment Assay Comments Estrogen deprivation (oophorectomy, Effective cytostatic (but not ER aromatase inhibitors) IHC for nuclear ER cytotoxic) therapy for ER+ Blockage of ER (tamoxifen) cancer Antibodies to HER2 eg herceptin IHC for membrane Cytotoxic therapy linked to HER2 HER2 Effective for HER2+ HER2 antibody ISH for HER2 gene cancers Tyrosine kinase inhibitors amplification Susceptibility to May be effective for Chemotherapy with agents causing DNA DNA damage carcinomas arising in damage that requires HRR (e.g., Sequencing `to resulting from patients with platinum agents) identify BRCA1 and germline BRCA1 or 2 Inhibition of alternative DNA repair BRCA1 and BRCA2 BRCA2 mutations mutations or cancers with pathway (poly-ADP ribose polymerase or mutations that cause somatic loss of BRCA PARP inhibitors) defects in HRR function >80% of breast cancers Activating mutations have alterations in this PI3K/AKT or pathway Inhibition of proteins in the pathway pathway. Effectiveness of pathway activation—not yet treatment not yet validated demonstrated Immune IHC for immune Under investigation in Blocking antibodies to PD-L1, PD-1, and checkpoint checkpoint proteins— patients with triple- other immune checkpoint proteins proteins not yet validated negative breast cancer ER, Estrogen receptor; HRR, homologous recombination R10: Table 23.7; RBP10: Table 19.8 repair; IHC, immunohistochemistry; ISH, in situ hybridization. BM4007&PM3017 Dr C.Hand  Stromal tumours Fibroadenoma Most common benign tumour in young women (20-30 yr) Detection: – younger: mobile palpable mass – older: mammographic density Intralobular stroma Grossly: Spherical, well circumscribed, rubbery, freely moveable, ‘breast mouse’ Size: 10-40 mm Excision R9: Fig 23.27; R10: Fig 23.23 Fibroadenoma A. Radiograph: characteristically well circumscribed mass B. Gross: rubbery, white, clearly demarcated from surrounding adipose tissue C. Proliferation of intralobular stroma pushes,distorts epithelium. Sharp border BM4007&PM3017 Dr C.Hand  Male Breast Male breast: nipple and ducts- no lobules Gynaecomastia – Benign enlargement of male breast Dilated ducts; epithelial proliferation – Causes Hormonal (hyperestrinism) Liver cirrhosis (metabolism of oestrogen) Klinefelter syndrome (47, XXY) Carcinoma – Rare, lifetime risk 0.1% (v 13% for woman) – Palpable mass, discharge common, infiltrates rapidly – BRCA2, BRCA1, 47XXY BM4007&PM3017 Dr C.Hand Findings in women being evaluated for ‘lumps’ RBP9: Fig 18.22 BM4007&PM3017 Dr C.Hand  Origins of breast disorders R10: Fig 23.1; RPB10 Fig19.22: Origins of breast disorders. The normal cells and structures of the breast, including epithelial cells and myoepithelial cells, intralobular stromal cells and interlobular stromal cells, and large ducts and terminal lobular duct unit can give rise to both benign and malignant tumours. BM4007&PM3017 Dr C.Hand R9: Fig 23.1 Anatomic origins of common breast lesions BM4007&PM3017 Dr C.Hand Probably pathological causes - ages BM4007&PM3017 Dr C.Hand  Breast Cancer Summary Lifetime risk is 1:8. Majority (75%) breast cancers are diagnosed after the age of 50 years. Major risk factors are hormonal exposure and inherited susceptibility. About 12% all breast cancers are caused by inherited germline mutations; BRCA1 and BRCA2 account for 50% cases with single gene mutations. DCIS is a precursor to invasive ductal carcinoma. When a carcinoma develops in a woman with a previous DCIS, it is usually invasive ductal ca of same breast. When a carcinoma develops in a woman with a previous LCIS, 2/3 are in the same breast and 1/3 in other breast. Invasive carcinomas are classified according to histological and biological type: ER+/HER2-, HER2+ and ER/PR/HER2-. Prognosis is dependent on type of tumour, stage and available treatments. BM4007&PM3017 Dr C.Hand  Learning objectives Outline the common presenting complaints of breast disease Discuss the many benign conditions in breast; inflammatory, non-proliferative or proliferative disease (with or without atypia) and the subsequent risk of developing an invasive cancer Classify variants of breast cancer, need to know the 2 most common (ductal and lobular) including their in-situ component Describe the risk factors for breast cancer Discuss the main prognostic factors Describe the molecular markers used in diagnosis, prognosis and treatment selection. BM4007&PM3017 Dr C.Hand