Malignant Breast Diseases Lecture

Malignant Breast Diseases Dr Ben Dessauvagie UWA Senior Lecturer PathWest Anatomical Pathologist Todays lectures 10:00am 11:00am Benign breast diseases Malignant Breast Diseases Development, anatomy and...

Malignant Breast Diseases Dr Ben Dessauvagie UWA Senior Lecturer PathWest Anatomical Pathologist Todays lectures 10:00am 11:00am Benign breast diseases Malignant Breast Diseases Development, anatomy and Proliferative breast disease with histology atypia Clinical presentations of breast In situ disease disease Breast Cancer Inflammatory conditions Benign and proliferative breast diseases without atypia Learning Objectives 1. Give an overview of breast cancer incidence and risk factors. 2. Give an account of the range of proliferative breast conditions including atypical proliferative lesions. 3. Give a classification of malignant diseases of the breast. 4. Describe the various types of in situ breast cancer. 5. Give an account of the various types of invasive breast cancer including ‘special’ types. 6. Give an account of methods of predicting prognosis in breast cancer including special pathological techniques used to guide management. The scope of Breast Cancer Overview Invasive breast carcinoma (BC) the most common cancer in women (excluding non-melanoma skin cancer) 31% vs colorectal 10%, melanoma 10% and lung 9% Est >18,000 new cases in Australia in 2017; approx 1 in 10 women BC the second most common cause of cancer related death in women Lung 19%, breast 15%, colorectal 9%, pancreas 6% Est >2,800 deaths in Australia in 2017; approx. 1 in 76 women 5 year survival 95%; improvement from 72% (1988) and 90% (2013) Breast cancer statistics, Cancer Australia website, 2018 Risk Factors Gender (> 99% occur in women) Age (77% over 50) Previous breast carcinoma and other benign proliferative breast disease Oestrogen exposure: Young age at menarche Older age at menopause Obesity OCP/HRT Nulliparity and older age at first pregnancy Family Hx/Genetics Breast density Radiation Estimating Risk Breast Cancer Risk Assessment Tool developed by US National Cancer institute Estimates risk of developing BC in next 5 years Applicable to women over 35 Without diagnosis of LCIS or DCIS Without family Hx suggesting single gene mutation https://www.cancer.gov/bcrisktool/ Genetics and Risk (Hereditary Breast Cancer) Accounts for 5-10% of all BC Present at younger age, bilateral BRCA1/BRCA2 mutation Tumour suppressor genes, function to maintain DNA integrity Most common; 47% of heritable BC syndromes Highly penetrant, autosomal dominant pattern Lifetime risk of BC 50-85% Increased risk of other cancers (BRCA1- ovarian Ca, colon, prostate; BRCA2 – ovary, pancreas, prostate, oesophagus, male breast cancer) Mutations rare in pathogenesis of sporadic BC Genetics and Risk (Hereditary Breast Cancer) Accounts for 5-10% of all BC Present at younger age, bilateral Other well characterised heritable mutations: TP53 (Li-Fraumeni), ATM (Ataxia Telangectasia), PTEN (Cowden), STK11 (Peutz–Jeghers), CHEK2, PALB2 Collectively account for 8% 45% involve unidentified or multiple genes For all syndromes – risk is modified by environmental interactions Benign Lesions and Risk Benign breast disease is much more common than breast cancer Non-proliferative and many proliferative breast disease have no increased risk Inflammatory conditions, fibrocystic change Adenosis, PASH, fibroadenoma Some proliferative conditions do have increased risk Usual hyperplasia, complex sclerosing lesion/radial scar, papilloma Magnitude of risk is related to degree of histological atypia Proliferative breast disease Proliferative Breast Disease without Atypia Associated with mild increased risk of BC 1.5-2x above general population Includes: epithelial hyperplasia Columnar cell change intraductal papilloma complex sclerosing lesion/radial scar Proliferative Breast Disease with Atypia Associated with moderate increased risk of BC 4-5x above general population Proliferative breast disease, but with addition of histological atypia Includes: Atypical papilloma Columnar cell change with atypia (‘flat epithelial atypia’) Atypical hyperplasia (‘Atypical ductal hyperplasia’ or ‘atypical lobular hyperplasia’) Exist toward the ‘benign’ end of a biologic continuum with low grade in situ and low grade invasive BC Degree of morphologic overlap Shared genetic alterations Atypical ductal hyperplasia Atypical lobular hyperplasia Flat epithelial atypia Breast carcinoma in situ Breast Carcinoma in situ (CIS) Malignant BC cells confined to the ductal-lobular system without invasion through the basement membrane into stroma Cells are morphologically identical and genetically similar to invasive BC 20 - 25% of newly diagnosed BC Associated with high increased risk of invasive BC 10x above general population Classification: Ductal (DCIS) Lobular (LCIS) Different biology, clinical presentation, pathology and management DCIS BC cells confined within duct spaces, occasionally lobular spaces Exist toward the ‘malignant’ end of a biologic continuum with ductal type BC ‘Premalignant’ lesion Identical morphologic features Very similar genetic alterations Theoretically curable: no invasion = no metastatic potential Clinical: calcifications on MMG, background finding in biopsy for invasive DCIS Histopath: Malignant cells, variable growth pattern (solid, cribriform, micropapillary etc), necrosis, calcifications Classified by grade of nuclear atypia: low, intermediate, high Mx: Surgical excision with clear margins +/- radiotherapy Prognosis (time to recurrence, invasive recurrence, metastasis): Grade Extent of lesion Completeness of excision  Low grade DCIS Intermediate grade DCIS High grade DCIS Cribriform pattern with calcifications Solid pattern Solid pattern with necrosis Paget’s Disease of the Nipple BC cells within epidermis of nipple Almost always associated with underlying high grade DCIS, cells spread up lactiferous ducts Clinical: Red, weeping, “eczematous” nipple Histopath: BC cells admixed with keratinocytes in epidermis, DCIS in lactiferous ducts Mx: Surgical excision with clear margins including associated DCIS (+/- invasive) Prognosis dependant on features of associated DCIS (+/- invasive) LCIS BC cells confined within lobular spaces, occasionally duct spaces The biologic nature and potential of classical LCIS is less clear cut than for DCIS Exist toward the ‘malignant’ end of a biologic continuum with lobular type BC ‘Premalignant’ lesion; high risk of lobular type BC at same site Identical morphologic features Very similar genetic alterations when IBC arises in same area as LCIS it is typically of lobular type invasive However, risk of subsequent BC is bilateral And the invasive BC may or may not be lobular type Theoretically curable: no invasion = no metastatic potential LCIS Clinical: Usually an incidental finding (i.e. seldom symptomatic or seen on MMG) 20-40% bilateral, often multifocal Histopath: Expansion of lobules by discohesive, uniform neoplastic cells, loss of E-cadherin expression Mx: Isolated in core biopsy – increased surveillance Associated with mod-high risk lesion – dictated by the mod-high risk lesion In surgical margins in excision – no action required Consider anti-oestrogen risk reducing medication Bilateral mastectomy no longer recommended LCIS Negative E-cadherin stain Invasive Breast Cancer Breast Cancer Invasion of malignant epithelial cells beyond myoepithelial layer/ basement membrane into stroma Access to vessels and lymphatics  potential to metastasise Most deaths results from metastasis to distant organs with impairment of function Clinical discrete mass (lump)/ Lumpiness pain nipple changes/discharge skin changes (tethering, peau d’orange, ulceration etc) other (including distant manifestations) Workup Examination – breast, axilla, general Pathology – Fine needle aspiration or core biopsy Radiology – MMG, US, MRI Breast Cancer Pathology: Malignant cells, invasive into stroma, classified in terms of type, grade, stage (degree of spread), biomarker expression, +/- molecular profile These classifiers constitute important BC prognostic and predictive factors Prognostic = predictors of disease free and/or overall survival Predictive = predictors of response to particular treatments Histological type >80% of cases are invasive ductal carcinoma (IDC) of ‘no special type’ (NST) About 10% are invasive lobular carcinoma (ILC) Remainder are relatively uncommon ‘special’ types of carcinoma, most considered variants of IDC WHO Classification of Breast Carcinoma Invasive duct carcinoma Invasive lobular carcinoma Breast carcinoma – ‘special’ types with good prognosis Mucinous carcinoma Tubular carcinoma Breast carcinoma – ‘special’ types with bad prognosis Micropapillary carcinoma Basal-like carcinoma Histological Grade Grading is by the modified Bloom and Richardson method (often referred to as Nottingham grade) Score out of 3 for each of following: Tubule formation nuclear atypia Mitotic rate The sum is split into grade 1 (3,4,5) grade 2 (6,7) and grade 3 (8,9 points) with increasingly worse prognosis Grade 1 Grade 2 Grade 3 Stage Staging is by the AJCC system, latest revision 2017 (8th edition) All cancer types scored for each of the following: Primary tumour – size, local invasiveness Nodal burden – number and size of deposits in draining nodes Metastases – present/absent Stage BC spread via lymphatics will usually manifest as axillary node deposit BC nodal status determined by axillary surgery axillary dissection – high risk of lymphoedema, or sentinel node biopsy (SNB) – evaluation of first draining lymph node with a view to avoiding axillary dissection if negative, less lymphoedema Stage N0 N1 N2 N3 M1 T1 I IIA IIIA IIIC IV T2 IIA IIB IIIA IIIC IV T3 IIB IIIA IIIA IIIC IV T4 IIIB IIIB IIIB IIIC IV Biomarkers Biomarker – measurable biological characteristic, indicator of normal/pathologic process, prognosis or predictor of response to treatment Huge number of candidate biomarkers Three in routine use in BC – ER, PR, HER2 Assessed by immunohistochemistry or in situ hybridisation  Hormone receptor status Oestrogen and progesterone bind to ER/PR in cytoplasm, migrate to nucleus, transcribe DNA to protein  exert physiological effects Promote growth and differentiation in normal breast tissue Promotes a growth advantage for overexpressing malignant cells Hormone receptor status ER in ~80% invasive BC PR in ~65% invasive BC Assessed by immunohistochemistry (IHC) which detects ER/PR protein expression ER positive Prognostic: ER+/PR+ BC improved survival vs ER-/PR- Predictive: Strong predictors of response to anti-oestrogen therapy (e.g. tamoxifen) ER+/PR+ 80% response ER-/PR- 10% response ER negative  Her2 Transmembrane tyrosine kinase (TK) protein Binds ligand (growth factors), forms heterodimers with other HER family proteins, activates intracellular signals Upregulates the RAS-MAPK pathway  proliferation and invasiveness Upregulates the PI3K pathway  inhibits cell death Promote growth and differentiation in normal breast tissue Promotes a growth and survival advantage for overexpressing malignant cells Her2 IHC negative IHC positive HER2 gene amplification and receptor overexpression in ~15-30% BCs Assessed by IHC to detect Her2 protein expression and/or silver in situ hybridisation (SISH) to detect gene amplification Prognostic: Her2 positive BC poor survival vs Her2 negative BC Predictive: strong predictor of response to anti-HER2 therapies (e.g. Trastuzumab) SISH negative SISH positive Molecular Profiling Luminal A Luminal B Early gene expression profiling studies examined gene up and down regulation across genome Identified four distinct BC subsets Luminal A, Luminal B, HER2 enriched, Basal-like Prognostic and predictive significance But… Upregulation Downregulation  Molecular Profiling Impractical to perform routine genome wide expression profiling Subsequent studies examined smaller subsets of genes Esp ER, Her2, basal differentiation and proliferation genes Cost-effective…well sort of ($4000 per test) Recapitulate molecular subtypes And/or stand alone prognostic/predictive tests Some panels now accepted in clinical use E.g. Oncotype DX, Prosigna, Mammaprint) Breast Cancer Mx: Surgical excision with clear margins – Mastectomy or wide local excision (WLE) +/- axillary surgery – SLN biopsy, with axillary clearance if SLN positive +/- radiotherapy – to the chest wall – if WLE, ‘locally advanced disease’ or positive margins on mastectomy to the axilla or supraclavicular nodes – if high nodal burden (>4 involved) +/- chemotherapy – if high risk clinicopathological features Learning Objectives 1. Give an overview of breast cancer incidence and risk factors. 2. Give an account of the range of proliferative breast conditions including atypical proliferative lesions. 3. Give a classification of malignant diseases of the breast. 4. Describe the various types of in situ breast cancer. 5. Give an account of the various types of invasive breast cancer including ‘special’ types. 6. Give an account of methods of predicting prognosis in breast cancer including special pathological techniques used to guide management.