Breast Disorders Flashcards

Question 1

Q

Breast Lumps

Differential Dx

Answer

A

Differentials:
Fibrocystic change, lactational change
Mastitis
Fat Necrosis
Fibroadenoma
Carcinoma
Most breast masses are benign
- However, breast CA is the 2^nd most common cause of CA death for women
- All breast masses have to be taken seriously and worked up

Question 2

Q

Premenopausal Women

Breast Biopsy Outcomes

Answer

A

40% dx as fibrocystic change
30% will show no disease
7% dx as fibroadenoma
13% will be miscellaneous benign lesions (mastitis, etc.)
10% will be carcinoma

Question 3

Q

Acute Mastitis

Answer

A

Typically occurs during 1^st month of breastfeeding
Breast is erythematous and painful
Usually due to S. aureus

Question 4

Q

Squamous Metaplasia of Lactiferous Ducts

Answer

A

“Recurrent sub-areolar abscess”

Keratinizing squamous metaplasia
- Keratin plugs the duct system
- Dilates and ruptures ⇒ chronic granulomatous inflammation
Can become secondarily infected w/ bacteria
May be due to relative deficiency of Vit A
Associated w/ smoking or toxins in tobacco smoke

Question 5

Q

Duct Ectasia

Answer

A

Palpable periareolar mass w/ thick, white nipple secretions
Usually seen in multiparous women in their 40s and 50s
Ectatic ducts fill w/ inspissated secretions and lipid-laden MΦ
Duct can rupture ⇒ granulomatous inflammation

Question 6

Q

Fat Necrosis

Answer

A

May be very firm and mimic carcinoma
Grossly see chalky white deposits
Usu. triggered by tissue damage from injury, surgery, or radiation therapy

Question 7

Q

Lymphocytic Mastopathy

(Sclerosing Lymphocytic Lobulitis)

Answer

A

Firm masses
Atrophic ducts and lobules
Thickened BM surrounded by dense lymphocytic infiltrate
Most common in pts w/ Type I DM and autoimmune thyroid disease

Question 8

Q

Fibroadenoma

Answer

A

Usu. between 20-35 y/o
Usu. grow slowly, except during pregnancy
Rarely become malignant
If they do, malignancy arises from the epithelial cells
Gross:
- Single lesion, usually 1-3 cm. in greatest dimension
- Well-circumscribed, rubbery, easily movable on exam, solid, greyish-white
- No necrosis
Micro: Epithelial and stromal elements involved
- Stroma: loose connective tissue
- Epithelial elements: round or elongated glands, distorted by growth of stromal cells
- If the stroma is very cellular, might be a phyllodes tumor

Question 9

Q

Benign Cystosarcoma Phyllodes

(Phyllodes Tumor)

Answer

A

Similar to fibroadenoma, but less well-delineated and stroma is more cellular

10% will recur

Question 10

Q

Intraductal Papilloma

Answer

A

Most common cause of nipple discharge
- Can be serous, serosanguinous, or sanguineous
Subareolar location, arising from large collecting ducts
Usually small, < 1 cm. in diameter
Gross:
- Pedunculated, greyish tan, soft, easily friable
- Located within a dilated duct
Micro:
- Complex papillary configuration w/ fibrovascular core upon which lie two layers of cells
- Hemorrhage and fibrosis w/ entrapment of epithelial cells are common
Adenoma of nipple is a similar lesion

Question 11

Q

Fibrocystic Disease

(Fibrocystic Changes)

Answer

A

Fibrosis + cysts w/ tenderness beyond usual monthly changes
Non-proliferative changes: no ↑ cancer risk
Common
Most pts are 25-45 y/o
Often bilateral, but one side may be more severely involved
Three main morphologic changes:
- Cystic change, often w/ apocrine metaplasia
  - Formed by dilation of lobules, can coalesce
  - Gross: Blue-dome cyst ⇒ contain turbid fluid
  - Micro: Lined by atropic epithelium or apocrine metaplastic cells w/ lots of eosinophilic cytoplasm
  - May see calcifications
  - Can do FNA and lesion disappears
- Fibrosis
  - Chronic inflammatory reaction to rupture of cysts
- Adenosis
  - ↑ # of acini per lobule
  - Columnar cells line the acini
  - May be normal or show nuclear atypia
  - Flat epithelial atypia: clonal proliferation ass. w/ deletion of chromosome 16q
  - Earliest recognizable precursor of low-grade breast CA but doesn’t ↑ risk

Question 12

Q

Normal Breast Ducts

Answer

A

Lined by two cell layers: myoepithelial cells and epithelial cells
Normal breast ducts have an empty lumen
- Where the milk would be secreted if lactation were taking place
In fibrocystic change, cells lining the ducts can proliferate in some cases

Question 13

Q

Proliferative Fibrocystic Change

Answer

A

Fibrocystic change can show proliferation of epithelial cells lining the duct
Duct can begin to be filled up by the proliferating cells ⇒ hyperplasia
- If hyperplasia involves cells w/o atypia ⇒ minimal risk of developing carcinoma
- If atypia is seen ⇒ atypical ductal hyperplasia ⇒ ↑ risk of breast CA
Atypical ductal hyperplasia → ductal carcinoma in situ → invasive carcinoma
Both breasts at ↑ risk
- To ↓ risk: bilateral prophylactic mastectomy or tx w/ estrogen antagonists
- < 20% of women w/ atypical hyperplasia ever get breast cancer

Question 14

Q

Proliferative Breast Disease without Atypia

Answer

A

1.5-2x ↑ risk of subsequent carcinoma in either breast
Can be seen as mammographic densities, calcifications, or incidental findings
Not clonal lesions, no genetic changes
Types of lesions:
Epithelial hyperplasia
↑ # of luminal and myoepithelial cell types
Fill and distend ducts and lobules
Can see irregular lumens at periphery of cellular masses
Sclerosing Adenosis
↑ # of acini compressed and distorted in central portion of the lesion
Can also see stromal fibrosis
Can look concerning for cancer
Complex Sclerosing Lesion
Components of sclerosing adenosis, papilloma and epithelial hyperplasia
Can mimic carcinoma, particularly ‘radial scar’ type

Question 15

Q

Proliferative Breast Disease with Atypia

Answer

A

4-5x ↑ risk for carcinoma
Types:
- Atypical Ductal Hyperplasia (ADH)
  - Seen in 5-17% of biopsy specimens performed for calcifications
  - Looks like DCIS but only partially fills involved ducts
    - Monomorphic proliferation of regularly spaced cells
- Atypical Lobular Hyperplasia (ALH)
  - Looks like LCIS but cells don’t distend or fill > 50% of acini within a lobule
ADH and ALH
- May have acquired chromosomal aberrations like loss of 16q or gain of 17p
  - Also see changes in CIS
ALH only
- Loss of E-cadherin expression
  - Similar to LCIS

Question 16

Q

Breast Carcinoma

Overview

Answer

A

Most common non-skin malignancy in women
2^nd only to lung CA as cause of cancer death
Living to age 90: ⅛ chance of getting breast CA
2012: 226k dx w/ invasive breast CA, 63k dx w/ CIS, 40k died

Question 17

Q

Ductal Carcinoma In Situ (DCIS)

Characteristics

Answer

A

DCIS = Intraductal carcinoma = In Situ Carcinoma

Expanded acini look like small ducts
Myoepithelial cells still present
May detect on imaging d/t calcifications, periductal fibrosis
If untreated, small low-grade DCIS develops invasive CA at 1% per year
- Mostly in same quadrant
- Similar grade and expression pattern of ER and HER2 as the associated DCIS
Mastectomy cures 95% of DCIS
- Need to see that all DCIS comes out

Question 18

Q

Ductal Carcinoma In Situ (DCIS)

Subtypes

Answer

A

Non-comedo DCIS
- Cribriform
- Solid
- Micropapillary
Comedo DCIS

Question 19

Q

Non-comedo

Ductal Carcinoma In Situ (DCIS)

Answer

A

Cribriform, Solid, and Micropapillary

Architectures

Question 20

Q

Comedocarcinoma

Ductal Carcinoma In Situ (DCIS)

Answer

A

Pleomorphic high-grade nuclei and central necrosis

Question 21

Q

Lobular Carcinoma In Situ (LCIS)

Answer

A

Involved spaces resembles normal lobules
DCIS & LCIS both originate from the same cells in the terminal duct lobular unit
- Proliferation of cells in ducts and lobules
- Grows in incohesive fashion
- Lose tumor suppressive adhesion protein ⇒ E-cadherin
Usu. incidental findings
If biopsy both breasts, LCIS will be bilateral in 20-40%
Can see signet-ring cell phenotype
Usually expresses estrogen receptor (ER) and progesterone receptor (PR)
Risk factor for invasive CA
- 25-35% of women over 20-30 years
- 1% per year (risk is for both breasts)

Question 22

Q

Invasive Breast Carcinoma

Overview

Answer

A

Carcinoma w/ stromal invasion
- Cells have broken through BM
Most commonly dx type of breast CA
Further classified according to special features such as:
- Secretion of mucin (as in mucinous carcinoma)
- Architectural features (as in papillary carcinoma and tubular carcinoma)
- Pattern of spread (as in inflammatory carcinoma)
Gross lesion is very firm w/ gritty (scirrhous) texture
- Likened to a pear or water chestnut

Question 23

Q

Invasive Ductal Carcinoma

Subtypes

Answer

A

Classical (NOS)
- Not otherwise specified
Tubular Carcinoma
- Well-formed tubular structures with open lumina
- Lined by one layer of epithelial cells
- Good prognosis compared to NOS
Mucinous Carcinoma
- Soft, islands of tumor cells afloat in a sea of mucus
- Good prognosis compared to NOS
Medullary Carcinoma
- Soft, sheets of tumor cells mixed with lymphocytes
- Good prognosis compared to NOS

Question 24

Q

Invasive Lobular Carcinoma

Answer

A

Cells often line up ⇒ ‘Indian Filing’

Question 25

Q

Invasive Breast Carcinoma

Assessment / Prognostic Factors

Answer

A

Two important groups of factors:

Extent of Disease
- Grading and staging
Tumor Biology: markers that play a role in determining prognosis and tx
- Estrogen Receptor (ER)
- Progesterone Receptor (PR)
- HER-2 protein overexpression
- Proliferation marker (Ki-67) status
- BRCA-1 or BRCA-2 gene status

Question 26

Q

Invasive Breast CA

Extent of Carcinoma

Answer

A

TMN staging:

Distant metastasis (M)
- Most important ⊖ factor
- Metz mostly seen in bone marrow, lung and pleura, liver, adrenal glands, CNS
Axillary lymph node status (N)
- 2^nd most important prognostic factor
- Most common site for breast CA is upper outer quadrant ⇒ spreads to axillary nodes
- Tumor in inner quadrant of breast ⇒ can metastasize to internal mammary chain
- Sentinel node sampling is an important tool
  - No nodes: 10-yr disease-free survival 70-80%
  - 1-3+ nodes: 10-yr disease-free survival 35-40%
  - More than 10+ nodes: 10-yr disease-free survival 10-15%
Tumor size (T)
- More important prognostically for ER ⊕ HER2 ⊖ cancers
- Others can metastasize even though small
- Lymphovascular invasion
  - Often associated with node metz

Question 27

Q

Invasive Breast CA

Tumor Biology

Answer

A

Molecular subtype
- Determined by expression of ER and HER2 & proliferation
Special histologic types of invasive carcinoma
- Better survival rate for tubular, mucinous, lobular, papillary
Histologic grade
- Use the Nottingham Histologic Score
- Assesses Nuclear Grade, tubule (gland) formation, mitotic rate
- Add up points for grade I, II, III
Proliferative Rate
- Can use Ki-67
ER/PR receptors
- ⊕ ⇒ likely to respond to hormonal therapy, but not chemotherapy
- ⊖ ⇒ vice versa
HER2 overexpression
- Poorer survival
- Status predicts response to agents that target the receptor

Question 28

Q

Breast Carcinoma

Molecular Pathways

Answer

A

ER-⊕ pathway
- Most common
- Recognizable precursor lesions include flat epithelial atypia and atypical hyperplasia
- Luminal gene expression profile
HER2-⊕ pathway
- May be ER-⊕ or ER-⊖
- Amplification of HER2 gene also present in a subset of atypical apocrine lesions
  - May represent a precursor lesion
- HER2-enriched gene expression profile
ER-⊖ and HER2-⊖ pathway
- Less common
- No precursor lesion identified
- Basal-like gene expression profile

Question 29

Q

ER-⊕ HER-⊖

Breast CA

Answer

A

“Luminal Breast CA”

50-65% of Breast CA
Most similar to nl breast luminal cells in mRNA expression pattern
Dominated by genes regulated by estrogen
Flat epithelial atypia and ADH precursor lesions
Two major molecular subtypes ⇒ differ in proliferation rate and response to therapy
- ER-⊕, HER2-⊖, low proliferation (45-55%)
  - Majority of cancers in older women
  - Most common type detected by mammographic screening and in women on HRT
  - Gene expression dominated by genes directly regulated by ER
  - Prognosis:
    - Often detected early, low rate of recurrence
    - If metastasize, do it after many years and go to bone
    - Respond well to hormonal treatment,
      - Long survival even with metastases
    - Chemotherapy doesn’t add much therapeutic value
- ER-⊕, HER2-⊖, high proliferation (10%)
  - Most common type ass. w/ BRCA2 germline mutation
  - mRNA like other ER-⊕ cancers but higher expression of genes related to proliferation
  - More chromosomal aberrations than low-grade
  - 10% show complete response to chemo

Question 30

Q

HER2-⊕

Breast CA

Answer

A

10-20% of Breast CA
- 2^nd most common molecular subtype of invasive breast CA
- Seen more in young and non-white women
- Most common subtype in pts with germline TP53 mutation (Li-Fraumeni)
Can be ER-⊕ or ER-⊖
Atypical Apocrine Adenosis ⇒ suspected precursor
Complex chromosomal translocations
- Arise via pathway strongly ass. w/ high-level amplification of HER2 on chromosome 17q
Mostly poorly differentiated, no specific pattern
50% of apocrine CA and 40% of micropapillary are in this group
Often show extensive DCIS
Assay: HER2 protein overexpression or HER2 gene amplification
Tumor can metastasize early and when small → viscera and brain
Before HER-2 targeted tx, these were bad
Trastuzumab (Herceptin)
- ≥ ⅓ respond completely to Ab that block HER2 activity
- Now have excellent prognosis
- Some are non-responders and some become resistant

Question 31

Q

ER-⊖, HER2-⊖

Breast CA

Answer

A

10-20% of Breast CA
Young premenopausal women, AA, Hispanic
Characteristics:
- Palpable mass, circumscribed pushing borders
- Poorly differentiated, high proliferation fraction, rapid growth
- Central fibrotic or necrotic center
- ± Medullary features
- ± Spindle, squamous, etc.
- Not much DCIS
Least understood pathway
No precursor lesion described
Most common type w/ germline BRCA1 mutations
- ↑ Frequency in African Americans
Basal-like pattern of mRNA expression
- Includes many genes expressed in normal myoepithelial cells
- Has some similarities to serous ovarian CA
Can metastasize when still small
30% completely respond to chemo
Recur in first 5 years

Question 32

Q

Breast CA

Subtypes Summary

Question 33

Q

Sporadic Breast CA

Estrogen Exposure

Answer

A

Estrogen promotes breast CA
- Stimulates breast growth
- Proliferate during menstrual cycle
  - More cycles = more risk
↑ Estrogen exposure ⇒ ↑ risk
- Menopausal HRT, esp. if estrogen and progestin for many yrs
- Early menarche, late menopause
- Nulliparity or first birth after age 35
↓ Estrogen exposure ⇒ ↓ risk
- Oophorectomy ⇒ ↓ endogenous estrogen
  - ↓ Breast CA risk by up to 75%
- Tamoxifen (⊗ estrogenic effects) and Aromatase inhibitors (⊗ formation of estrogen)
  - ↓ Risk of ER-⊕ breast CA
- Full term pregnancy before 20 halves risk

Question 34

Q

Familial Breast Cancer

Overview

Answer

A

12% of breast CA
Autosomal dominant
Inherit defective copy of tumor suppressor gene
- Sporadic mutation in remaining nl allele ⇒ lose tumor suppressor function ⇒ initiating driver mutation
Creates a ‘mutator’ phenotype
- ↑ Propensity to genetic damage
- Speeds cancer development
Major known susceptibility genes are BRCA1, BRCA2, TP53, CHEK2
- All tumor suppressor genes w/ roles in DNA repair and maintenance of genomic integrity

Question 35

Q

Familial Breast Cancer

Implicated Genes

Answer

A

BRCA1 and BRCA2 ⇒ 80-90% of single gene familial breast CA (3% of all breast CA)
- Penetrance varies 30-90%
- Involved in homologous recombination for repair of DS DNA breaks
- BRCA1 ⇒ Chromosome 17q21
  - 20-40% ↑ risk of ovarian CA
- BRCA2 ⇒ Chromosome 13q12.3
  - 10-20% ↑ risk for ovarian CA
- Restrict genetic testing to pts w/ strong FHx and certain groups
  - Ashkenazi Jews
    - 1/40 carry 1 of 3 specific mutations
    - Once carriers ID’d ⇒ surveillance, mastectomy, BSO
< 10% of familial breast CA
- TP53 (Li-Fraumeni syndrome) [3%)
- CHEK2 = 8% of single gene breast CA [5%]
< 1% of familial breast CA
- PTEN (Cowden Syndrome)
- STK11 (Peutz-Jeghers)
- ATM (ataxia-telangiectasia)

Question 36

Q

Inflammatory Breast Carcinoma

Answer

A

Tumors present w/ breast swelling, erythema and skin thickening
- ± Palpable mass, can be confused w/ infection
Very poor prognosis
- 3-year survival rate 3-10%
Most pts have distant metastases at presentation
Dermal lymphatics filled w/ metastatic carcinoma ⇒ blocks lymphatic drainage
Edematous skin tethered to the breast by Cooper ligaments
Skin surface mimics surface of an orange peel ⇒ peau d’orange
60% ER-⊖
40-50% overexpress HER2

Question 37

Q

Paget Disease

Of the Breast

Answer

A

Presents w/ excoriated nipple lesion
- May need to biopsy to differentiate from skin lesion
Large, pale Paget cells
- Extend from DCIS in ductal system → nipple skin via lactiferous sinuses w/o crossing BM
- Tumor cells disrupt normal epithelial barrier ⇒ ECF seeps out onto nipple surface
- Causes eruption w/ a scale crust
50-60% w/ Paget have palpable mass
- Almost all of these pts have underlying invasive CA
  - Usu. poorly differentiated, ER-⊖, HER2-⊕
Paget w/o palpable mass usually have DCIS

Question 38

Q

Malignant Stromal Tumors

Answer

A

Most important is angiosarcoma
< 0.05% of breast malignancies
Can be sporadic or arise as a complication of therapy
- Sporadic
  - Young women (mean age 35)
  - High grade
  - Poor prognosis
- Treatment related
  - Arise secondary to radiation or edema
  - After radiation therapy, ~0.3% of women develop angiosarcomas in breast skin
  - Most cases are dx 5-10 years after tx

Question 39

Q

Gynecomastia

Answer

A

Enlargement of male breast d/t hypertrophy and hyperplasia of both glandular and stromal components
Most cases related to relative ↑ estrogenic activity; ↓ in androgenic activity, or both
Many are idiopathic

Question 40

Q

Male Breast Carcinoma

Answer

A

Rare

< 1% of all breast CA in the U.S. population