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. 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

11. 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

13. 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

14. 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

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

16. 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

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

19. 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

20. 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

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. central necrosis and calcification DCIS with cribriform pattern
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 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

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

40. 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

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 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

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
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
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.