Week 2:pathology of the breast

Question 1

fibrocystic change

Answer 1

• non-neoplastic, benign
• multiple areas of breasts bilaterally
• lumpy bumpy nodular masses
• changes with menstrual cycle
• morphology: ductal hyperplasia, sclerosing adenosis, terminal duct cysts, fibrosis of storma, increased lymphocytic infiltrate
• proliferative change has increased risk of carcinoma

Question 2

Acute mastitis

Answer 2

-Bacterial infection of the breast, most frequently occurs in postpartum lactation
-Secondary to nipple cracking/fissuring
-Staphy/ Strept organisms typical
Staphylococcal infections may progress to abscess formation
-Cardinal signs of acute inflammation grossly, PMNs microscopically
-granulomatous mastitis is rare: assoc. with TB, fungal, silicone breast implant leakage

Question 3

Fat necrosis

Answer 3

• trauma or surgery assoc.
• small palpable mass with or without pain
• histology: necrotic fat cells, lipid laden macs, lymphocytic infiltration, PMNs, fibroblastic proliferation to wall off area
• dystrophic calcification common, must be distinguised from malignancy

Question 4

Neoplastic benign breast disease

Answer 4

1. fibroadenoma: benign proliferation of stromal and glandular elements
   - most common breast mass in young women. Multiple, freely movable.
2. papilloma: arising in duct
   - branches into multiple projections
   - presents with bloody or serous nipple discharge

Question 5

Increased risk of developing breast cancer

Answer 5

Early menarche 
Late menopause 
Nulliparous 
Lack of breast feeding 
Lack of physical exercise (<4 hrs/wk) 
Family history: Li-fraumeni syndrome, BRCA1, BRCA2 mutations

Question 6

Model for major pathways of breast cancer development

Answer 6

1. BRCA2 mutations–> flat epithelial atypia –> (PK3CA mutations) atypical ductal hyperplasia –> DCIS –> ER+/HER2 -
2. Germline TP53 mutations, HER2 amplication –>atypical apocrine adenosis –>DCIS –> HER2 +
3. germline BRCA1 mutations –> ? –> DCIS –> ER neg

Question 7

Ductal carcinoma in situ (DCIS)

Answer 7

-non invasive, limited to ducts and lobules. intact BM.
Morphological Patterns
-comedo: extensive central necrosis often with micro calcifications
-solid: cells completely fill space
-cribiform: cookie like
-micropapillary

Question 8

Paget Disease of the Breast

Answer 8

Paget disease of the nipple. DCIS arising within the ductal system of the breast can extend up the lactiferous ducts into nipple skin without crossing the basement membrane. The malignant cells disrupt the normally tight squamous epithelial cell barrier, allowing extracellular fluid to seep out and form an oozing scaly crust over the nipple skin.

Question 9

Lobular Carcinoma in Situ (LCIS)

Answer 9

• incidental finding on biopsy
• loosely cohesive, small cells, with round or oval nuclei
• often bilateral and multifocal
• increased risk of invasive carcinoma

Question 10

Invasive ductal carcinoma

Answer 10

• 80% of invasive breast CA
• heterogenous microscopic appearance: well differentiated, irregular nests, solid sheets, poorly differentiated
• Well-differentiated tumors typically express hormone receptors and do not overexpress HER2/neu; reverse is true for poorly differentiated tumors
• Most breast carcinomas incite a strong desmoplastic response, giving rise to a hard, fixed mass on palpation

Question 11

Lobular carcinoma

Answer 11

• 10% of invasive breast CA
• Cells morphologically similar to those in LCIS; diffuse widespread invasion pattern; classic finding is short, single-file chain or strands of cells (“single file”) infiltrating between collagen fibers; mucin-producing ‘signet ring’ appearance
• 75% present similarly to ductal CA; remaining 25% have diffuse disease with no/minimal desmoplastic changes – may result in occult disease

Question 12

Prognostic markers of breast cancer (anatomical/path)

Answer 12

-predicts clinical outcome independent of treatment
MAJOR markers (poor)
-invasive vs. in situ
-presence of metastatic disease
-axillary lymph node involvement 
-larger tumor size
-inflammatory breast CA
MINOR
-favorable: tubular, medullary, mucinous, adenoid cystic CA
-not favorable: inflammatory CA
-grade, DNA ploidy, S phase fraction

Question 13

Staging of breast cancer

Answer 13

0: CA in situ (92% 5 yr survival)
1: T1 (<3 axillary nodes), M0 (75%)
3: (46%)
4: distant metastasis (13%)

Question 14

Predictive molecular markers in Breast cancer

Answer 14

• predictive markers: predicts responsiveness to therapy
  1. ER+ and PR+
• 75% of breast cancers. more favorable disease free survival. Responds to tamoxifen and other anti estrogen therapies
  2. HER2+
• HER2/neu encodes membrane receptor in epidermal growth factor receptor family
• amplification and overexertion of HER2 correlated with poor clinical outcome
• Rx: Trastuzumab/herceptin (anti HER2 antibody), Iapatinib/Tykerb (tyrosine kinase inhibitors)

Question 15

BRCA1

Answer 15

• Mendelian dominant inheritance, chrom 17
• gene function: tumor suppressor, transcriptional regulation, role in DNA repair
• breast cancer <30 yo
• bilateral breast cancer
• increased risk of ovarian cancer too
• most mutations result in truncated protein

Question 16

BRCA2

Answer 16

• mendelian dominant inheritance, chrom 13
• gene function: tumor suppressor, transcriptional regulation, role in DNA repair
• breast cancer <30, bilateral breast Ca
• male breast ca (and pancreatic Ca)

Question 17

BRCA mutation mechanisms

Answer 17

• loss of BRCA affects choice of DNA double strand break repair pathway
• In the absence of BRCA1 or BRCA2, alternative repair pathways, such as nonhomologous end-joining (NHEJ) and single-strand annealing (SSA), are used, leading to cell death or survival with genomic damage.