Breast

Question 1

Most common bacteria associated with lactational mastitis?

Answer 1

Staph aureus (leads to single or multiple abscesses)

Question 2

Second most common bacteria associated with lactational mastitis?

Answer 2

Streptococci (less likely to form abscesses, infection spreads in the form of cellulitis)

Question 3

Older woman, smoker, presents with a painful erythematous subareolar mass. Biopsy demonstrates keratinising squamous metaplasia and extensive chronic inflammation within the periductal tissues. What is the diagnosis?

Answer 3

Squamous metaplasia of lactiferous ducts (aka non-lactational (periductal) mastitis).

90% are smokers.
Older women

Question 4

Describe the pathogenesis of squamous metaplasia of lactiferous ducts?

Answer 4

1. Keratinising squamous metaplasia extends into the nipple duct beyond the usual point of transition from squamous to glandular epithelium.
2. Keratin sheds and is trapped within the ducts forming a keratin plug causing progressive diltation and eventual rupture of the duct.
3. Spillage of keratin into the periductal tissues forms an intense chronic granulomatous inflammatory response, resulting in a painful subareolar mass.
4. Recurrent inflammation may lead to the formation of a sinus tract opening on to the edge of the areolar or fibrosis and scarring leading to nipple retraction.
5. Secondary bacterial infection may occur causing acute inflammation.

Vitamin A deficiency from smoking, affects differentiation of ductal epithelium

Question 5

What is the expected histology of fat necrosis?

Answer 5

Focal disruption of adipocytes leads to haemorrhage and liquefactive fat necrosis with lipid-laden macrophages and acute inflammatory cells initially, then later mutlinucleated giant cells.

Over time, fibrosis peripherally encloses the necrotic fat. Peripheral calcification may progressively develop (giving the characteristic oil cyst appearance on imaging).

Eventually the area may be entirely replaced with a fibrotic scar.

Question 6

Older woman, non-smoker presents with a palpable periareolar mass, thick white nipple discharge and skin retraction. Biopsy demonstrates ectatic periareolar dilated ducts filled with inspissated secretions and lipid-laden macrophages, as well as periductal and interstitial chronic inflammation and granulomas. What is the diagnosis?

Answer 6

Duct ectasia. In multiparous women, 5th-6th decade.

Not associated with smoking (unlike squamous metaplasia of the lactiferous ducts) or pregnancy

Duct rupture leads to periductal and interstitial chronic inflammation (lymphocytes, macrophages and plasma cells)
Granulomas may form
Subsequent fibrosis can lead to skin and nipple retraction

Question 7

Three types of non-proliferative morphological changes in the breast?

Answer 7

1. Cystic change - small cysts form due to dilation of lobules, may coaelsce to form larger cysts.
2. Fibrosis - ruptured cysts lead to chronic inflammation in the adjacent stroma
3. Adenosis - increase in the number of acini per lobule.

Question 8

Younger women presents with multiple well-circumscribed masses and diffuse tea in cup calcifications on mammogram. What is the diagnosis?

Answer 8

Fibrocystic change

Question 9

Apocrine metaplasia can be seen in what two benign epithelial lesions?

Answer 9

Fibrocystic change and papilloma

Question 10

Four morphological patterns of proliferative breast disease without atypia?

Answer 10

1. Epithelial hyperplasia (usual ductal hyperplasia) - increased numbers of luminal and myoepithelial cells fill and distend ducts/lobules.
2. Sclerosing adenosis - increased number of acini that are compressed and distorted in the centre of the lesion with surrounding stromal fibrosis
3. Complex sclerosing lesions (including radial scar) - have components of all 3 other proliferative epithelial lesions without atypia. Radial scar has an irregular shape and closely mimics invasive carcinoma on imaging and pathology.
4. Papilloma - growth within a dilated duct made of branching fibrovascular cores

Question 11

Histology of a radial scar

Answer 11

Central fibroelastotic stromal core with radiating extensions of entrapped ducts and lobules (can mimic the spicules of an infiltrating carcinoma)

Question 12

Relative risk of developing invasive carcinoma for the following lesions:
1. Non-proliferative changes
2. Proliferative breast disease without atypia
3. Proliferative disease with atypia
4. Carcinoma in situ

Answer 12

Ascending order of risk.

1. Non-proliferative changes - 1x relative risk
2. Proliferative breast disease without atypia - 1.5 - 2x relative risk
3. Proliferative disease with atypia - 4 - 5x relative risk
4. Carcinoma in situ - 8 - 10x relative risk

Question 13

What is the full name of a breast hamartoma?

Answer 13

Fibroadenolipoma

Disorganised mass of cells indigenous to the involved tissue

Question 14

Multiple breast hamartomas are associated with what syndrome?

Answer 14

Cowden syndrome (PTEN mutation)

Question 15

Histological appearance of a breast hamartoma

Answer 15

Overgrowth of normal mature stromal and epithelial components of breast tissue surrounded by a thin pseudocapsule with pushing borders (compressed normal breast).

“Breast within a breast”

Question 16

Two benign interlobular stromal tumours?

Answer 16

Myofibroblastoma - consists of myofibroblasts.
Lipoma

Question 17

Only breast tumour that is equally common in males?

Answer 17

Myofibroblastoma

Question 18

Most common malignant interlobular stromal tumour?

Answer 18

Angiosarcoma
- very rare, less than 0.05% of breast malignancies.
- can be sporadic (typically in young women) or post treatment for breast cancer , associated with radiotherapy and chronic oedema (in older women, 5-10 years post treatment).

Sporadic angiosarcoma have a poor prognosis.

Question 19

Most common cancers to metastasise to breast?

Answer 19

Melanoma and ovarian cancer

Question 20

A women 2 years post partum presents with mastitis which is not responding to antibiotics. Histology shows granulomatous inflammation, no evidence of malignancy. What is the cause?

Answer 20

Idiopathic granulomatous mastitis

• Consider systemic granulomatous disese (sarcoid, TB, GPA)
• Infection such as Cornebacterium
• Usually within 6 years of pregnancy
• Antibiotics and steroids

Question 21

Typical demographic of mammary duct ectasia

Answer 21

50-60s, multiparous

Not related to pregnancy or smoking.
Usually bilateral

Question 22

Typical conditions which are related with lymphocytic mastopathy

Answer 22

Long-standing type 1 diabetes or autoimmune thyroid disease

Question 23

Typical age group of patients with complex sclerosing lesion / radial scar? Is this abnormality usually palpable? Should this be excised?

Answer 23

40-60

Not usually palpable. Often found on screening.

Yes it is rarely associated with low grade DCIS and invasive (often tubular) malignancy, thus it is surgically excised

Question 24

What is the main difference between complex sclerosing lesion and radial scar?

Answer 24

Complex sclerosing lesion > 1cm
Radial scar < 1 cm

Question 25

What are the steps to becoming invasive lobular carcinoma and what is a common mutation?

Answer 25

Atypical lobular hyperplasia -> lobular carcinoma in situ -> invasive lobular carcinoma once broken through basement membrane Loss of E-cadherin (CDH1) - dyscohesive cells are a histological hallmark.

Question 26

How much of the terminal duct lobular units is filled by atypical cells in atypical lobular hyperplasia?

Answer 26

<50% 50-75% (plus more atypia) in lobular carcinoma in situ. - ALH increases both breasts risk of cancer by 4-5x - Highly ER +. Low proliferation rate. - 16p or 17q deletions. 1q gains.

Question 27

What are the two subtypes of lobular carcinoma in situ?

Answer 27

1. Classic - rarely calcifies 2. Pleomorphic - more aggressive, calcifies, treated like DCIS - Usually ER/PR + and HER2- - Bilateral in 20-40% (more than DCIS) - Dyscohesive growth, mucin positive signet ring cells, pagetoid cells - Increased risk of breast cancer in both breasts by 8-10x

Question 28

What cell layer is lost when lobular carcinoma in situ becomes invasive lobular carcinoma?

Answer 28

Myoepithelial cell layer as it crosses the basement membrane

Question 29

A 45 year old female presents with multi-focal breast masses, with minimal desmoplastic reaction and CDH1 mutation. What is the mass?

Answer 29

Invasive lobular carcinoma - Bilateral 10-20%, multicentric/multifocal 10-20% - CDH1 mutation - Single row/sheets of tumour growth - Minimal desmoplastic reaction thus hard to detect on mammography - Classic or pleomorphic type (latter more aggressive) - Metastases: leptomeninges, peritoneum, retroperitoneum, GI tract, ovaries, uterus

Question 30

What is usual ductal hyperplasia?

Answer 30

It is more than the normal 2 layers (myoepithelial and luminal epithelial) lining the glandular tissue of the breast. No cellular atypia. No change in the number of acini.

Question 31

What are the common age groups and risk factors for gynaecomastia?

Answer 31

Neonates (maternal oestrogen) Adolescent boys (high estradiol) Older men (declining testosterone) RF: cirrhosis, alcohol, marijuana, heroin, antiretroviral, anabolic steroids, Klinefelter syndrome (XXY) and functioning testicular neoplasms (Leydig/Sertoli cell tumours)

Question 32

What are two intralobular stromal tumours?

Answer 32

Fibroadenoma Phyllodes tumour

Question 33

What are some important features about fibroadenoma?

Answer 33

- Most common benign tumour of the female breast - Women 20-30s - Biphasic - contains neoplastic stromal and non-neoplastic glandular tissue - Hormonally responsive - Frequently multiple and bilateral - 2/3 have a driver mutation in MED12 - Slight increased risk of carcinoma if complex features (sclerosing adenosis, epithelial calcification, papillary apocrine change, cysts > 0.3cm) - 50% of those on cyclosporin A after renal transplant develop fibroadnoma

Question 34

What are some important features about phyllodes tumour?

Answer 34

- Women, 60s - Large and rapidly growing - Biphasic - contains neoplastic stromal and non-neoplastic glandular tissue - Low grade (75%) are benign, appear similar to fibroadenomas, have MED 12 mutations, slight propensity to recur. - High grade lesions are malignant, appear similar to sarcoma. Associated with TERT mutations. Lymphatic spread is rare, 1/3 have haematogenous spread of the **stromal component only**

Question 35

What are some differences between fibroadenoma and phyllodes tumour?

Answer 35

Phyllodes: - Usually older - Less common - Higher cellularity, mitotic rate, nuclear pleomorphism, stromal overgrowth - Can have infiltrative borders - Can metastasize (stromal component only)

Question 36

Is pseudoangiomatous stromal hyperplasia a precursor lesion or associated with malignancy?

Answer 36

No for both. It is benign mesenchymal proliferation of stromal myofibroblasts in women of reproductive age. It is hormonally responsive.

Question 37

How does Paget disease of the nipple occur?

Answer 37

Malignant cells from DCIS spread along ductal system, via lactiferous sinuses into the epidermis of the nipple. It does not cross the basement membrane. - Unilateral erythematous eruption with scaliness of the nipple/areola. Can have pruritis - Older women - 50-60% associated palpable mass (almost always prove to be invasive carcinoma, usually ER- HER2+)

Question 38

How is atypical ductal hyperplasia different to DCIS?

Answer 38

It is limited in: - extent (<2 ducts) - size (<2 mm) - cells only partially fills ducts

Question 39

What is the increased relative risk of breast cancer in atypical ductal hyperplasia, and what are common histopathological findings associated with ADH?

Answer 39

4-5x increased risk Can be a precursor to DCIS High levels of ER, low rate of proliferation, 16p or 17q deletions, 1q gains

Question 40

What are the 4 traditional classifications of DCIS? What mutations are frequently involved in DCIS?

Answer 40

- Comedo: intraluminal necrosis surrounded by high grade malignant cells. More aggressive. - Cribriform - Micropapillary - Papillary Now classified as low, intermediate or high grade based on nuclear morphology. Mutations in chromosome 17 + 11. Tp53 and HER2 mutations

Question 41

What is the typical age group for intraductal papilloma and what is its relative risk of breast cancer?

Answer 41

40-50 Proliferative disease without atypia, therefore relative risk of breast cancer is 1.5-2x.

Question 42

What are the four main groups and their receptor status of invasive carcinoma?

Answer 42

1. Luminal A ER+, PR+, HER2- 2. Luminal B ER+, PR+, HER2- (30% HER2+) 3. HER2 enriched ER-, PR-, HER2+ (some are ER+) 4. Triple negative / basal type ER-, PR-, HER2-

Question 43

What are the differences between luminal A and B invasive carcinoma?

Answer 43

Luminal B has - higher Ki-67 - higher grade - more TP53 and less PIK3CA mutations - 30% are HER2+ - worse prognosis - younger population - More BRCA 2 germline mutations - Special subtypes: Grade 3 lobular tumours

Question 44

What types of breast cancer are Li-Fraumeni, BRCA1 and BRCA2 associated with.

Answer 44

Li-Fraumeni - HER2 enriched BRCA1 - triple negative BRCA2 - Majority are ER positive

Question 45

What factors decrease your risk of breast cancer?

Answer 45

- Early pregnancy (<20 years) - Prolonged breastfeeding - Bilateral prophylactic mastectomy - reduces risk 90% - Chemoprevention (ER antagonists)

Question 46

What are common syndromes/mutations associated with breast cancer?

Answer 46

BRCA1 BRCA2 Cowden syndrome - PTEN Li-Fraumeni syndrome - TP53 Peutz-Jeghers syndrome - STK11 Hereditary diffuse gastric Ca - CDH1 PALPB2 ATM CHEK2

Question 47

What are important features of BRCA1 and BRCA2?

Answer 47

BRCA1: - 40-90% breast cancer risk by 70 - 17q21 - Markedly increased risk of ovarian serous carcinoma (20-40%) - Usually triple negative BRCA2: - 30-60% risk of breast cancer by 70 - 13q12.3 - Smaller risk for ovarian 10-20% - More associated with male breast cancer - More often ER positive BRCA1 + BRCA2: - Poorly differentiated cancers - Increased prostate and pancreatic cancer - Ashkenazi Jewish population have a 1/40 chance of carrying 3 specific BRCA mutations

Question 48

What are some subtypes of invasive carcinoma within the luminal group (ER positive and HER2 negative) and what is the most common?

Answer 48

No special type is the most common (75% of all adenocarcinoma). Others: - Tubular (6%) - often associated with a radial scar. Consists exclusively of well-formed tubules. - Mucinous (1-5%) - Papillary (2%)

Question 49

What differentiates carcinoma in situ and invasive carcinoma?

Answer 49

Loss of myoepithelial layer and invasion through the basement membrane

Question 50

What type of invasive ductal carcinoma is the best prognosis? What are other good prognosis types?

Answer 50

Encapsulated papillary carcinoma Tubular, papillary

Question 51

What is a poor prognosis special type of invasive breast carcinoma?

Answer 51

Metaplastic - often triple negative, less nodal metastasis, more haemotogenous metastasis

Question 52

What specific type of BRCA1 associated breast cancer has a better prognosis?

Answer 52

Medullary pattern subtype. - 50% of BRCA1 associated carcinomas have this appearance - Large amount of infiltrating T lymphocytes

Question 53

What is the definition of DCIS?

Answer 53

Clonal proliferation of malignant epithelial cells originating from the TDLU. The myoepithelial cell layer is preserved and there is no invasion of the basement membrane. DCIS can spread through the ductal system and produce extensive lesions. E-cadherin positive.

Question 54

How is DCIS typically diagnosed and how should it be managed?

Answer 54

Most are identified as calcifications on mammography. Less commonly, periductal fibrosis may create a palpable mass. 1% per year can develop into invasive cancer if untreated. DCIS is typically treated locally but this has a higher rate of recurrence. Mastectomy is curative for 95% of women. (major risks for recurrence are higher grade and necrosis, extent of disease and positive surgical margins).

Question 55

Is prognosis affected by the presence of Paget's disease of the nipple?

Answer 55

No! Prognosis depends of the grade and stage of the underlying carcinoma

Question 56

Women in her 40s - 50s presents with bloody nipple discharge and no palpable mass? What is the likely diagnosis and how should it be managed?

Answer 56

Papilloma = benign epithelial neoplasm made of branching fibrovascular cores, typically seen within a dilated duct. Most (80%) are located in the periareolar region. - 80% of large, central papillomas present with nipple discharge which may be bloody due to torsion of the vascular stalk leading to infarction. Small (peripheral) duct papillomas - more often multiple and deeper in ductal system, harder to detect clinically. Usually excised as often associated with atypia.

Question 57

What are some important features of triple negative breast cancer?

Answer 57

- 15% of breast cancers - ER -ve, PR -ve, HER2 - negative - Express basal cytokeratin - "basal-like", - Younger patients - More likely to present with a palpable mass than luminal cancers. - TP53 mutations (70-80%) - Common in BRCA 1 (shares from histological features with serous ovarian carcinoma) - Bone, viscera and brain mets are all common. - 30% have complete response to chemo - Cancers that recur usually recur within 8 years.

Question 58

What is the grading system for invasive breast carcinoma and what are carcinomas scored for?

Answer 58

Nottingham histological score Scored 1-3 for each of the following: tubule formation, nuclear pleiomorphism and mitotic figures. Maximum score of 9 Grade 1 = well-differentiated, tubular growth formation, small uniform nuclei, low proliferative rate (score of 3-5). Grade 2 = moderately differentiated (score 6-7) Grade 3 = poorly differentiated (score 8-9)

Question 59

Key differences between invasive ductal carcinoma and invasive lobular carcinoma

Answer 59

- Ductal carcinoma makes up 90% of breast cancer. - Lobular carcinoma makes up 10% of breast cancer. - Ductal presents as a hard, irregular, radiodense mass associated with strong desmoplastic reaction. - Lobular carcinoma may fail to produce a desmoplastic response, more difficult to detect by palpation and imaging. However, spiculated mass is still the most common imaging finding. - Ductal carcinoma is E-cadherin positive. - Lobular carcinoma is E-cadherin negative (Males and females with CDH1 mutation are at increased risk).

Question 60

What are some special subtypes of invasive carcinoma that overexpress HER2?

Answer 60

- Apocrine carcinoma - resembles sweat glands - Micropapillary carcinoma - misnomer, actually pseudopapillary, hollow balls of cells float within fluid, create structures that mimic papillae

Question 61

What are some special subtypes of invasive carcinoma that are triple negative?

Answer 61

- Medullary - Over half of BRCA1 associated carcinomas have this appearance. Histological features include: pushing/non-infiltrative borders, marked lyphoplasmacytic infiltrate with large amount of T cells. Better prognosis than poorly differentiated carcinomas. - Secretory - Low-grade adenosquamous carcinoma - Adenoid cystic carcinoma - Metaplastic (rare) - Rapidly growing with poor prognosis, less nodal metastasis and more risk of haematogenous spread.

Question 62

Prognostic factors for breast cancer and which is the most important?

Answer 62

Metastasis beyond regional lymph nodes is the most important prognostic factor. The next most important prognostic factor (and the most important in the absence of distant mets) is axillary lymph nodes metastasis, including how many nodes are involved. Other important prognostic factors include: - Tumour size - Locally advanced disease (including involvement of skin and invasion of chest wall) - Lymphovascular invasion - Inflammatory carcinoma - characterised by extensive invasion of dermal lymphovascular channels - Histologic grade - Expression of ER, PR and HER (high ER most favourable, triple negative least favourable)

Question 63

Most important familial germline mutation for male breast cancer?

Answer 63

BRCA 2

Question 64

What somatic mutation is associated with both fibroadenoma and phyllodes tumours in the breast, as well as uterine leiomyomas?

Answer 64

MED12

Question 65

Which lymphomas can arise in the breast?

Answer 65

- Non-Hodgkin lymphoma may arise primarily in the breast or the breasts may be secondarily involved. - Most primary breast lymphomas are B cell type, rare T cell type can be associated with breast implants. - Young women with Burkitt lymphoma may present with massive bilateral breast involvement, often while pregnant or lactating.