Breast Cancer

Case OPbjectives On completion of this case and associated learning activities you should be able to: Consider the different causes of a breast lump Describe the handling of lumpectomy specimens by pathologists Discuss the various prognostic factors in breast carcinoma Evaluate a pathology report for prognostic factors of breast carcinoma

Specimen The pathologist orientates the specimen according to the information by the surgeon. If no information is available, the short stitch is taken as superior, the medium stitch as medial and the long stitch is taken as lateral. The siding of the specimen must be known (i.e left or right side) for accurate orientation. The correct siding and the orientating sutures of an excision specimen of breast are important  indicates where the tumour is in the specimen and the extent of tumour. If tumour is present at the margins of his resection, he may choose to re- excise the area.

Low power Terminal duct lobular unit

The entire duct system is lined by: Epithelial cell layer (milk) Myoepithelial cell layer (luminal fn) Basement membrane

Breast Tissue Normal adult female breast tissue consists of fat and many terminal duct lobular units covered with surface skin Terminal duct lobular units (TDLU) contain a central duct and acini (green part of spinach) or glands of breast tissue. Glands are lined by bi-layered epithelium: (i) inner one - epithelial cell: in pregnancy cells enlarge and produce milk (ii) outer one - myoepithelial layer: contain filaments that cause contraction of the epithelial cells so milk enters the central ducts and beyond. The ducts from multiple TDLUs join  lactiferous duct  lactiferous sinus  nipple surface.

52 year old woman post menopausal comes into GP clinic with a mass in her right breast, in the upper right quadrant DDx???

Congenital and inflammatory disorders Acute mastitis/abscess Usually associated with lactation, cracks in nipple Staph aureus Mammary duct ectasia /Periductal mastitis Painful, erythematous, subareolar mass Dilated ducts with foamy macrophages in lumen Mistaken for Ca due to nipple discharge (sometimes blood stained) Fat necrosis Localised mass – simulates carcinoma Trauma /surgery/ radiotherapy Macroscopically – tissue is yellow and haemorrhagic

Fibrocystic change HISTOLOGICAL CHANGES Adenosis Sclerosing Adenosis A spectrum/variety of benign changes in the breast Fibrocystic change HISTOLOGICAL CHANGES Adenosis Sclerosing Adenosis Epithelial hyperplasia Cysts Apocrine metaplasia fibrosis Adenosis: When lobules enlarge and have more cells The epithelial cells actually enlarge but lumen is there still Fine nodules felt clinically Macroscopically grey-pink nodules There is a proliferation of the lobules The acini are distorted Looks like calcification and mimic carcinomas

Epithelial Hyperplasia epithelial cells get massive and feel like solid masses, they close the lumen, mimic carcinoma (later read table)   Cysts/ Apocrine metaplasia Acini grow to become cysts which can burst and cause inflammation Apocrine metaplasia is cysts which are made of sweat gland cells Fibrosis Associated with a hormone imbalance Can be associated with proliferative lesions or by itself Its rubbery mixed with connective tissue

Radial scar (next slides) Sclerosing adenosis Radial scar (next slides) Increase in glandular elements plus stromal proliferation that distorts and compresses glands; Lobular architecture maintained. Stellate lesion with appearance of carcinoma grossly Flower head pattern on low power; radiation of compressed tubular structures with 2 cell layers and fibroelastotic stroma

Epithelial Proliferation Lesion Features Risk of carcinoma vs normal (relative risk) Epithelial hyperplasia (EH) Epithelium >4 cells thick 1.5 – 2x(slight) Atypical ductal hyperplasia (ADH) As for EH plus cytologic atypia 5x Sclerosing adenosis (SA) Increased numbers of acini, distorted by fibrosis – microscopically resembles carcinoma. 1.5 – 2x Radial scar (<1cm) Complex sclerosing lesion (>1cm) As for SA, forming a stellate scar – macroscopically resembles carcinoma. 2x Multiple intraduct papillomas Fibrovascular core lined by benign epithelium Disordered orientation of cells Nuclear pleopmorphism Mitotic figures

Neoplasms Epithelial Stromal Ductal adenoma Papilloma Carcinoma In situ vs invasive Ductal vs lobular Stromal Fibroadenoma Phyllodes tumour Sarcoma

Stromal neoplasms Fibroadenoma Phylloides Tumor Most common benign tumour of breast Benign neoplasm of intra-lobular stroma Epithelial component is not neoplastic Young women – typically 30 years or less Rounded, smooth, mobile mass “breast mouse” May: Enlarge with phases of menstrual cycle Calcify Regress after menopause Phylloides Tumor Localled invasive variant (5% metastasis) Increased stromal cellularity; Usually much bigger

Phyllodes tumour with exaggerated leaf-like pattern Fibroadenoma Phyllodes tumour with exaggerated leaf-like pattern

Epithelial neoplasms Papillomas Ductal adenoma Intraductal proliferation of epithelial and myoepithelial cells overlying fibrovascular stalks 70% associated with nipple discharge (may be bloody) Mass felt; Multiple with cytologic atypia - associated risk of carcinoma Ductal adenoma Uncommon; usually 60+ Well circumscribed, benign glandular proliferation in part within a duct lumen

Breast carcinoma “Ductal” vs “lobular” In situ vs Invasive Descriptive terms only – both types arise from the epithelium of the terminal duct lobular unit In situ vs Invasive DUCTAL CARCINOMA IN SITU LOBULAR CARCINOMA IN SITU INVASIVE DUCTAL CARCINOMA INVASIVE LOBULAR CARCINOMA

In situ carcinoma 30% of breast carcinomas. A proliferation of malignant cells which has not invaded through the basement membrane. Myoepithelial cell layer is intact. May spread along ducts to involve an entire breast segment/lobule. Ductal and lobular subtypes.

Ductal carcinoma in situ (DCIS) Usually detected as calcification on mammogram. Ducts distended by malignant cells (bm and myoepithelium present) Growth patterns: Solid (ducts completely filled with cells) Cribriform Comedo type with central necrosis +/- Calcification Malignant cells may spread to nipple “Paget’s disease of the nipple” 8-10x relative risk of developing invasive carcinoma Variable tendency to progress to invasive carcinoma - based on nuclear grade

Paget’s disease of Nipple

central necrosis and calcification DCIS with cribriform pattern Comedo- type DCIS with central necrosis and calcification DCIS with cribriform pattern

Lobular carcinoma in situ Usually incidental microscopic finding since no distinguishing features on gross examination and usually not associated with microcalcifications Lobules (clusters of acini) distended by malignant cells Malignant cells are monomorphic. 50-70% bilateral cf DCIS (10%); Risk of developing invasive carcinoma ~20-30%, but equally likely in either breast.

Lobular carcinoma in situ

Invasive Breast Carcinoma 70% of breast carcinomas are invasive. Malignant cell have invaded beyond basement membrane / Myoepithelial cells absent. Metastasis to: Lymph nodes, usually axillary Brain, bone, lungs, other organs. Ductal and lobular subtypes most commonly

Invasive Ductal carcinoma Most common type of invasive breast carcinoma (75-80%) Lacks features of any other subtypes. Variable tubule formation. Grossly hard, gritty, stellate, poorly circumscribed mass

Invasive ductal carcinoma

Invasive Ductal Carcinoma Microscopy Irregular infiltrating cords and nests of malignant cells. Absent myoepithelial cell layer. Grade 1-3 based on nuclear atypia, mitotic activity and degree of tubule formation. Immunohistochemistry stains are performed to test for oestrogen and progesterone receptors, and HER-2

Invasive ductal carcinoma

Invasive Lobular Carcinoma 10% of invasive carcinomas. 10-20% bilateral. Ill-defined macroscopically. Tumour forms single files (“Indian file”) or targetoid arrangement encircling ducts. Monomorphic, uniform cells with minimal nuclear pleomorphism. Metastasis more common than other subtypes of breast carcinoma. Long term prognosis may be similar to ductal carcinoma.

Invasive lobular carcinoma

Breast carcinoma Women have ~1 in 10 lifetime risk Risk factors – genetic, hormonal and enviromental Sex – Women 100x risk compared with men Genes – mutations in BRCA1 and 2 (5%) Family history – first degree relatives Epithelial proliferations (ADH) Older age Exogenous oestrogen (HRT, ?OCP) Nulliparity Long reproductive life (early menarche, late menopause) Age at first child (>30 years) Obesity Oestrogen producing ovarian tumours Radiation exposure

Signs and Symptoms Lump Often Painless, if present then non-cyclic Nipple discharge Skin and nipple tethering Ulceration Oedema and Erythema

DDX Sx

Dx - Triple Test Clinical Examination Imaging Cytological Pathology Mammography Recommended biannually for 50-90yo; look for speculated mass or micro calcification U/S Cytological Pathology FNA – Cytology rather than histology Cannot differentiate b/w DCIS and Ca Core Biopsy Genetic testing – bilateral tumour, concurrent ovarian ca, male breast ca, ashkenazi jews

Ix for metastasis Lymph, Axilla, Skin, Bones Liver Lung CXR CT Bone Scan (xray not so apparent) High metabolic uptake

Management – Radiotherapy Management – Surgical Breast Conserving surgery: Wide local excision + clearance + radiotherapy Mastectomy Management – Radiotherapy Breast Conserving Pt: Wide local excision + clearance + radiotherapy Minimises recurrence (otherwise 80% in 2 yrs) Management – Chemo Used for >stage 2 breast ca (LN involvement) Eg: Cyclophosphamide + methotrexate + 5FU given in 6 cycles over 24 weeks

Management - Hormonal Tamoxifen Blocks tumour oestrogen receptors Not routinely recommended: flushing, vag bleeds, dec bone density, Selective oestrogen receptor modulators (Serms) – Raloxifene Less SE and as effective GnRh Analogues – Goserelin Dec endogenous oestrogen via pituitary downreg Can be as effective as tamoxifen Trastzumad – Herceptin Blocks HER-2 Receptors (only for +ve HER-2) $60000 per course; Inc 5 year survival by 10% SE: Cardiomyopathy

Prognostic Factors Smaller Lesions = Better px Type of tumour The grade of tumour Presence of lymphovascular invasion = Bad If the tumour is not completely excised local recurrence may occur If lymph nodes have been resected the presence of nodal metastases is a poor prognostic factor

Questions What are the key aspects of describing a lump?

What are some differentials for discharges of the nipple Where does breast ca usually metastasis too? Lungs, Bone, Liver, brain and local LYMPH What other cancers are associated with breast ca Ovarian, endometrium, thyroid and colon What cancers metastasis to breast Lung, endometrium, leukemia, lymphoma, melanoma

Describe I thought id put the ones from the path case first for recap The tissue seen comprises fat and a central area of poorly circumscribed dense white and focally cream tissue that extends onto the painted surface over an area of approximately 15mm. Some adjacent white tissue extends as streaks into the surrounding fat. The diagnosis favoured is a primary neoplasm of the breast - breast carcinoma.

Figure 2A highlights the infiltrative nature of the lesion Figure 2A highlights the infiltrative nature of the lesion. Look at the periphery of the lesion see how the edges extend into the surrounding tissue. Fig 2B is at high power and shows that the lesion is composed of nested cells that are infiltrating into the surrounding tissue. Cells have a high nuclear to cytoplasmic ratio and small nucleoli are seen. The cells are a little bit pleomorphic. There is a hint of gland formation. No mitoses are seen in this field. Given the macroscopic and microscopic appearance the diagnosis is a primary breast carcinoma.

Here is another area of the same lesion Here is another area of the same lesion. Note the dense (pink) collagenous connective tissue component. In this area of the lesion, the connective tissue component is more prominent than the cells of the lesion. The infiltrating cells elicit this fibrous tissue reaction called a desmoplastic reaction. The desmoplastic tissue is firm. The corresponding clinical feature is a firm breast mass. It can be of varying size but often with an ill-defined margin, and if large can be palpated as being tethered to the pectoralis muscle if it invades into the chest.

The first specimen shows a fatty lump of tissue within which there are many streaks of white tissue slightly centred around a local area over 20mm but extending well into the adjacent tissues over an area of 80mm. The second specimen shows a more localised area of grey yellow tissue with an ill defined margin over 10mm with the strands of grey tissue extending into the surrounding fatty tissue and appearing to extend into the overlying skin. More likley that the second specimen is a tumour macroscopically. The first specimen lacks a definitive localised area but the white tissue does not appear to be typical for contracted white fibrous tissue of ageing breast. I would need to take sections and further examine the specimen to confirm my suspicion of this being a breast tumour. Comment – both specimens are breast carcinoma on section.

Describe Dx Ddx Benign Lumps There appears to be several areas within the breast tissue where there are streaks of white tissue. No localised lesion is identified. Very careful observation of the white tissue shows small cystic spaces within it. Benign lumps are frequent and are due to a number of causes. The frequency of some of these lesions depends a bit on the age of the patient. Other symptoms or signs and the nature of the beast lesion are also important in assessing the lesion. The following is a list of some of the more common causes; • A fibroadenoma • An abscess • An ectactic duct • Fat necrosis secondary to trauma • Fibrocystic change of the breast.