TYPES OF BRCA

1. TYPES OF BRCA • David A

2. Histopathologic Types • Pre/non-Invasive • Ductal Carcinoma In Situ (DCIS) • Lobular Carcinoma In Situ (LCIS) • Invasive • Invasive Ductal Carcinoma • Invasive Lobular Carcinoma • Medullary Carcinoma • Mucinous (colloid) carcinoma • Tubular carcinoma • Papillary carcinoma • Other - • Paget’s Disease • Inflammatory BRCA

3. Pre/non-invasive BRCA • Malignant cells are confined to either the ducts or acini of the lobules. • No evidence of penetration of the tumour cells through the basement membrane. • Strongly associated with the concurrent or subsequent development of invasive breast cancer

4. DCIS • Can occur in both pre and post-menopausal women, usually in the 40 to 60 year-old age group. • Generally unifocal, being confined within one quadrant of the breast; bilateral disease is uncommon. • Majority of cases cannot be detected by either palpation or visual inspection. • Frequently presents as mammographic calcifications. • Morphology; • Changes within small and medium-sized ducts, although can be large ducts in older women. • Cells show cytoplasmic and nuclear pleomorphism to varying degrees. • Mitotic figures used to classify into high grade and non-high grade. • Divided into five architectural subtypes: • Comedo: characterized by solid sheets of pleomorphic cells with high-grade nuclei and central necrosis; necrotic cell membranes commonly calcify. • Solid: completely fills the involved spaces. • Cribiform: intraepithelial spaces are evenly distributed and regular in shape (cookie cutter-like). • Papillary: grows into spaces and lines fibrovascular cores typically lacking the normal myoepithelial cells layer. • Micropapillary: recognized by bulbous protrusions without a fibrovascular core, often forming complex intraductal patterns. • Capable of spreading into the lobules.

5. Comedo architecture • A: living cancer cells • B: dying cancer cells • C: cell debris (necrosis) • D: basement membrane

6. Solid architecture • A: cancer cells • B: basement membrane

7. Cribiform architecture • A: cancer cells • B: basement membrane • C: lumen (centre of duct)

8. Papillary architecture • A: cancer cells • B: basement membrane • C: lumen (centre of duct)

9. DCIS Ductal carcinoma in situ. Both ducts are expanded. One has (A) a central necrotic area which has calcified and would show on a mammogram. The basement membrane (B) is intact.

10. LCIS • Occurs predominately in pre-menopausal women. • Does not present as a palpable lump; usually an incidental finding in a biopsy performed for another reason. • Often multifocal within the one breast and is frequently bilateral. • Been suggested that LCIS is not a true neoplasm but rather a marker of breast cancer risk. • About one third of all patients with LCIS who are treated with biopsy alone will go on to develop invasive carcinoma. • Almost always expresses oestrogen and progesterone receptors. • Morphology; • Abnormal cells of atypical lobular hyperplasia (ALH), LCIS and invasive lobular carcinoma are identical. • Consist of small cells that have oval or round nuclei with small nucleoli that do not adhere to one another. • Signet-ring cells containing mucin are present commonly. • Rarely distorts the underlying architecture and the involved acini remain recognizable as lobules. • May extend into extralobular ducts and replace ductal epithelium. • Necrosis is unusual. Normal breast with lobular carcinoma in situ (LCIS) in an enlarged cross–section of the lobule. Breast profile: A: ducts B: lobules C: dilated section of duct to hold milk D: nipple E: fat F: pectoralis major muscle G: chest wall/ rib cage Enlargement: A: normal lobular cells B: lobular cancer cells C: basement membrane

11. LCIS Lobular carcinoma in situ. A breast lobule in which the acini are expanded. There is complete loss of the lumen and of the two-cell layer.

12. Invasive BRCA • Tumour cells have broken through the basement membrane around the breast structure in which they have arisen and spread into the surrounding tissue. • Firm on palpation and may show evidence of tethering to the overlying skin. • Skin can show peau d’ orange (dimpling due to lymphatic permeation). • Nipple may be retracted due to tethering and contraction of the intramammary ligaments. • Macroscopic appearance of tumours depends on the amount of type of stroma present; this gave rise to the terms previously applied to breast carcinomas: • Scirrhous: implies there is a prominent fibrous tissue reaction; dense white appearance and may have yellow streaks; usually has irregular edges, extending into the adjacent fat or other structures. • Medullary: very cellular with little stroma; edges are more rounded and discrete; necrosis is common, tumour feel softer on palpation. • Mucinous (colloid): predominance of mucin or jelly-like material; often have a well-defined edge.

13. Invasive Ductal Carcinoma • Comprise the majority of infiltrating breast carcinomas. • Can occur in both pre and post-menopausal women. • Morphology; • Usually have a scirrhous consistency. • Most carcinomas are firm to hard with an irregular border. • Within the centre there are small pinpoint foci or streaks of chalky white elastotic stroma and occasionally small foci of calcification. • Amount of stroma between the tumour cells can vary, but in those in which it is prominent it is most marked at the centre, with the periphery being more cellular. • Marked variations are seen between different carcinomas: • Well-differentiated tumours consist of tubules lined by minimally atypical cells and typically express hormone receptors and do not over express HER2. • Others are composed of anastomosing sheets of pleomorphic cells and are less likely to express hormone receptors and more likely to over express HER2. • Generally accompanied by varying amounts of DCIS; grade of DCIS usually correlates with the grade of the invasive carcinoma. Normal breast with invasive ductal carcinoma (IDC) in an enlarged cross–section of the duct. Breast profile: A: ducts B: lobules C: dilated section of duct to hold milk D: nipple E: fat F: pectoralis major muscle G: chest wall/ rib cage Enlargement: A: normal duct cells B: ductal cancer cells breaking through the basement membrane C: basement membrane

14. Invasive Ductal Carcinoma Infiltrating ductal carcinoma. The lesion is composed of irregular solid groups of cells in a dense fibrous stroma, with an associated lymphocytic infiltrate.

15. Invasive Lobular Carcinoma • Usually occurs in pre-menopausal women, however incidence in post-menopausal women is reported to be increasing. • Constitute about 10% of invasive breast carcinomas. • Generally form at one focus within the breast, but can be multifocal. • Different pattern of metastasis compared to other breast cancers; metastases to the peritoneum, retroperitoneum, leptomeninges, gastrointestinal tract, ovaries and uterus are more frequently involved. • Morphology; • Abundant fibrous stroma, thus always scirrhous. • Elastosis can be present. • Cells are small and uniform; dispersed singly or in columns one cell wide (Indian files). • Cells infiltrate around pre-existing breast ducts and acini, rather than destroying them. • Cells have the same cytological features as LCIS and lack cohesion, without formation of tubules or papillae. • Signet-ring cells are common. • Well/moderately differentiated carcinomas usually express hormone receptors and HER2 over expression is very rare. • Poorly differentiated often lack hormone receptors and may over express HER2. Normal breast with invasive lobular carcinoma (ILC) in an enlarged cross–section of the lobule. Breast profile: A: ducts B: lobules C: dilated section of duct to hold milk D: nipple E: fat F: pectoralis major muscle G: chest wall/ rib cage Enlargement: A: normal cells B: lobular cancer cells breaking through the basement membrane C: basement membrane

16. Invasive Lobular Carcinoma Infiltrating lobular carcinoma. Strands of single cells (Indian file) invade fibrous stroma.

17. Medullary carcinoma • May be mistaken clinically and radiologically for a fibroadenoma. • Greater incidence in post-menopausal women. • Well-circumscribed and often large. • Tumour has a soft, fleshy consistency. • Lymphatic or vascular invasion is hardly ever seen. • Patients have a significantly better 10-year survival than women with invasive duct carcinoma. • Morphology: • Characterised by: • Solid, syncytium-like sheets (occupying more than 75% of the tumour) of large cells with vesicular, pleomorphic nuclei, containing prominent nucleoli and frequent mitoses. • Moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumour. • Pushing (noninfiltrative) border. • HER2 over expression is not observed. • Around the islands of tumour cells there is a prominent lymphocytic infiltrate, predominately T-lymphocytes, with macrophages.

18. Mucinous (colloid) carcinoma • Also known as colloid, mucoid and gelatinous carcinomas. • Generally arise in post-menopausal women; may grow slowly during the course of many years. • Comprise two to three percent of invasive carcinomas. • Well-circumscribed and have a soft, grey, gelatinous cut surface. • Do not cause retraction of the nipple or tethering of the skin. • Overall prognosis is slightly better than that of carcinomas of no special type. • Morphology: • Small nests and cords of tumour cells, which show little pleomorphism, embedded in large amounts of mucin. • Mucin is composed of neutral or weakly acidic glycoproteins, which are secreted by the tumour cells.

19. Tubular Carcinoma • Typically detected as irregular mammographic densities. • Women usually present in their late forties. • Make up one to two percent of invasive carcinomas. • Firm, gritty tumours with irregular outlines. • Morphology: • Consist exclusively of well-formed tubules and are sometimes mistaken for benign sclerosing lesions. • Myoepithelial cell layer is absent, and tumour cells are in direct contact with stroma. • Cribriform spaces may also be present. • Apocrine snouts are typical, and calcifications may be present within the lumens

20. Papillary Carcinoma • Rare (represent one percent or fewer of invasive cancers). • Occur in post-menopausal women. • Prognosis is better than that of the infiltrating ductal carcinomas. • Usually circumscribed and can be focally necrotic, with little stromal reaction. • Morphology: • In the form of papillary structures and areas of intraductal papillary growths are usually found.

21. OTHER • Paget’s Disease • Rare • Erosion of the nipple clinically resembling eczema. • Associated with underlying ductal carcinoma in situ or invasive carcinoma

22. OTHER • Inflammatory Breast Cancer (IBC) • accounts for approx. 3-5% of all BRCA • A form of rapidly progressive locally advanced BRCA characterised by symptoms arising over weeks/months (not yrs) • Associated with: discolouration ranging from red to purple and affecting at least 1/3 of breast, thickening and/or fine dimpling, warmth, a palpable ridge present at the margin of induration • Often mistaken for breast infection • Biopsy of affected skin often shows dermal lymphatic invasion by tumour cells - tumour cells interfere with lymphatic drainage thereby contributing to symptoms and presumably to its high rate of lymph node metastases • Almost all pt with IBC have lymph node involvement and about 1/3 will have distant mets at the time of Dx • IBC tends to have a younger age of onset, a worse prognosis and tends to be ER- • IBC is the most aggressive form of BRCA (median survival 18-24 months)

23. OTHER • Adenoid cystic carcinomas. • Secretory carcinomas. • Apocrine carcinomas. • Carcinomas showing metaplasia

24. INTRINSIC SUBTYPES/RECEPTOR PROFILES • Luminal A • Luminal B • Basal • HER2+ • NOTE: ER = estrogen receptor, PR = progesterone receptor, HER2 = human epidermal growth factor receptor 2, EGFR = epidermal growth factor receptor

25. Luminal A • ER+ &/or PR+, HER2- • Most common subtype • Less aggressive • Lower histological grade • Good prognosis • Hormone responsive • Associated with increasing age

26. Luminal B • ER+ &/or PR+, HER2+ • Similar to Luminal A • More frequently ER+/PR- • Worse outcome than Luminal A

27. HER2+ • ER- • Less common, highly aggressive subtype • High grade histology • Risk at younger age (<40yo) greater than Luminal subtypes • Outcome improved with HER2

28. Basal • Triple negative (ER, PR, HER2) • Cytokeratin (proteins of keratin-containing intermediate filaments found in the intracytoplasmic cytoskeleton of epithelial tissue) 5/6+ &/or EGFR+ • Aggressive subtype • high grade histology • high grade mitotic rate • Risk at younger age (<40yo) • More likely premenopausal