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6. HDS GI Repro > Breast Disorders > Flashcards

Breast Disorders Flashcards

1
Q

Breast Lumps

Differential Dx

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

Premenopausal Women

Breast Biopsy Outcomes

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
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3
Q

Acute Mastitis

A
  • Typically occurs during 1st month of breastfeeding
  • Breast is erythematous and painful
  • Usually due to S. aureus
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4
Q

Squamous Metaplasia of Lactiferous Ducts

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
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5
Q

Duct Ectasia

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
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6
Q

Fat Necrosis

A
  • May be very firm and mimic carcinoma
  • Grossly see chalky white deposits
  • Usu. triggered by tissue damage from injury, surgery, or radiation therapy
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7
Q

Lymphocytic Mastopathy

(Sclerosing Lymphocytic Lobulitis)

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
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8
Q

Fibroadenoma

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
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9
Q

Benign Cystosarcoma Phyllodes

(Phyllodes Tumor)

A

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

10% will recur

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10
Q

Intraductal Papilloma

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
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11
Q

Fibrocystic Disease

(Fibrocystic Changes)

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
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12
Q

Normal Breast Ducts

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
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13
Q

Proliferative Fibrocystic Change

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
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14
Q

Proliferative Breast Disease without Atypia

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
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15
Q

Proliferative Breast Disease with Atypia

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
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16
Q

Breast Carcinoma

Overview

A
  • Most common non-skin malignancy in women
  • 2nd 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
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17
Q

Ductal Carcinoma In Situ (DCIS)

Characteristics

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
18
Q

Ductal Carcinoma In Situ (DCIS)

Subtypes

A
  • Non-comedo DCIS
    • Cribriform
    • Solid
    • Micropapillary
  • Comedo DCIS
19
Q

Non-comedo

Ductal Carcinoma In Situ (DCIS)

A

Cribriform, Solid, and Micropapillary

Architectures

20
Q

Comedocarcinoma

Ductal Carcinoma In Situ (DCIS)

A

Pleomorphic high-grade nuclei and central necrosis

21
Q

Lobular Carcinoma In Situ (LCIS)

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)
22
Q

Invasive Breast Carcinoma

Overview

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
23
Q

Invasive Ductal Carcinoma

Subtypes

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
24
Q

Invasive Lobular Carcinoma

A

Cells often line up ⇒ ‘Indian Filing’

25
Q

Invasive Breast Carcinoma

Assessment / Prognostic Factors

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
26
Q

Invasive Breast CA

Extent of Carcinoma

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)
    • 2nd 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
27
Q

Invasive Breast CA

Tumor Biology

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
28
Q

Breast Carcinoma

Molecular Pathways

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
29
Q

ER-⊕ HER-⊖

Breast CA

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
30
Q

HER2-⊕

Breast CA

A
  • 10-20% of Breast CA
    • 2nd 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
31
Q

ER-⊖, HER2-⊖

Breast CA

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
32
Q

Breast CA

Subtypes Summary

A
33
Q

Sporadic Breast CA

Estrogen Exposure

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
34
Q

Familial Breast Cancer

Overview

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
35
Q

Familial Breast Cancer

Implicated Genes

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)
36
Q

Inflammatory Breast Carcinoma

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
37
Q

Paget Disease

Of the Breast

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
38
Q

Malignant Stromal Tumors

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
39
Q

Gynecomastia

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
40
Q

Male Breast Carcinoma

A

Rare

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

6. HDS GI Repro (30 decks)

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