Breast Cancer

1. Breast Cancer

2. 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

3. 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.

5. Low power Terminal duct lobular unit

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

7. 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.

8. 52 year old woman post menopausal comes into GP clinic with a mass in her right breast, in the upper right quadrant DDx???

9. 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

10. A spectrum/variety of benign changes in the breast Fibrocystic change HISTOLOGICAL CHANGES • Adenosis • SclerosingAdenosis • Epithelial hyperplasia • Cysts • Apocrinemetaplasia • 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 • SclerosingAdenosis • There is a proliferation of the lobules • The acini are distorted • Looks like calcification and mimic carcinomas

11. Epithelial Hyperplasia • epithelial cells get massive and feel like solid masses, they close the lumen, mimic carcinoma (later read table) • Cysts/ Apocrinemetaplasia • Acini grow to become cysts which can burst and cause inflammation • Apocrinemetaplasia 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

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

14. Epithelial Proliferation Disordered orientation of cells Nuclear pleopmorphism Mitotic figures

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

16. Stromalneoplasms • Fibroadenoma • 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 • PhylloidesTumor • Localled invasive variant (5% metastasis) • Increased stromalcellularity; Usually much bigger

17. Fibroadenoma Phyllodes tumour with exaggerated leaf-like pattern

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

20. Breast carcinoma • “Ductal” vs “lobular” • 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

21. 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.

22. 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

23. Paget’s disease of Nipple

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

25. 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.

26. Lobular carcinoma in situ

27. 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

28. 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

29. Invasive ductal carcinoma

30. 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

31. Invasive ductal carcinoma

32. 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.

33. Invasive lobular carcinoma

34. 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

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

37. DDX Sx

38. Dx - Triple Test • Clinical Examination • Imaging • 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, ashkenazijews

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

40. 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

41. 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

42. Prognostic Factors • Smaller Lesions = Better px • Type of tumour • The grade of tumour • Presence of lymphovascularinvasion = 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

43. Questions • What are the key aspects of describing a lump?

44. 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

45. 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.

46. 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.

47. 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.

48. 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.

49. 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.