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. A: normal lobular cells B: lobular cancer cells C: basement membrane
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 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