Breast

Question 1

• What does the breast consist of?

Answer 1

o ductal mammary gland tissue in F (M rare)
o Adipose, CT (collagen and elastin)
o Ligamentous tissue (Cooper’s ligs)
o Mamm:fat = 1:1 (non-lactating), 2+:1 (lactating)

Question 2

• What is ductal mammary gland tissue?

Answer 2

o modified sweat glands capable of producing and secreting milk during lactation
o lactiferous duct system (& lobules): 4-18 modified ducts, each has own opening at nipple
o cell lining: committed stem cell in terminal duct → myoepthelial cells and luminal cell types
o luminal: in lobules and terminal ducts make milk; no milk in large ducts
o myoepithelial cells: milk ejection, structure

Question 3

• where does lymph from breast flow to?

Answer 3

o 75% to axillary LNs (pectoral, sub-scapular, humeral)
o Rest to para-sternal, abdominal LNs, and to the other breast
o Also internal mammary nodes

Question 4

• What are the breast perimeter landmarks?

Answer 4

o Important in CBE!
o glandular tissue has 4 quadrants (upper outer, upper inner, lower outer, lower inner) and central sub-areolar
o Superior: clavicle
o Inferior: beyond infra-mammary crease
o Medial: sternal border
o Lateral: beyond the lateral breast fold (mid-axillary line), into axillary pectoral fascia and fat pad

Question 5

• Describe the development of breast tissue?

Answer 5

o pre-pubertal: ductal system ends in terminal ducts w minimal lobule formation, little stromal tissue
o after menarche: terminal ducts → lobules, ↑volume of interlobular stroma.
o → CT tends to wrap concentrically around ducts and lobules
o 3rd decade: lobules and CT normally begin to gradually involute
o After menopause: lobules almost totally disappear, interlobular stroma replaced by adipose, ↑ density of loose CT

Question 6

• How do mammograms look with age? Histology?

Answer 6

o When stroma is replaced by adipose tissue the breast more radiolucent.
o Younger: more radiopaque
o Older: adipse more radiolucent, so calcifications/tumors easier to detect
o Histo: younger has more CT stroma, older more adipose; pregnancy: much less stroma, mostly ductal

Question 7

• What effects do E and P have during menstrual cycle?

Answer 7

o E: epithelial cell proliferation, duct elongation and branching, ↑volume and elasticity of CT and ducts, ↑ deposition of adipose
o P: ↑lobule formation, ↑ size of acini, lumen and ducts

Question 8

• What are the breast tissue changes during the menstrual cycle (by day)?

Answer 8

o 3 - 7: ↑E → epithelial cell proliferation
o 8 - 14: E promotes differentiation of epithelial cells
o 15 - 20: ↑P → ↑size of acini, lumen, ducts
o 21 - 27: Intralobular stromal edema and venous congestion
o 27 - 30: ↓ E&P → ↓stromal edema and lumen size

Question 9

• What are the breast tissue changes with pregnancy?

Answer 9

o usu begin at time of first missed menstrual period (gestational week 4)
o dt P, E, prolactin and placental lactogen secretion in 3rd tri
o breast tissue reaches complete morphological maturation and full functional activity
o At full term, breast is composed almost entirely of lobules, separated by a little CT
o Montgomery tubercles ↑ in # size
o 1st tri: proliferation of acinar cells, minimal secretory changes. Involution of stroma
o 3rd tri: intense lobular proliferation. cells appear enlarged, ↑ cytoplasm, enlarged nuclei. dramatic stromal involution

Question 10

• What happens to breast tissue during lactation?

Answer 10

o Intralobular ducts form buds, secretory alveoli, grape-like clusters, scant stroma; glands have dilated lumina, lipid secretory vacuoles
o ↑ # lobules and acini in each lobule. ↓ inter/ intra-lobular stroma
o Myoepithelial cells are present but difficult to identify
o Luminal epithelial cells are secretory and have cytoplasmic vacuoles (to sustain lactation)
o Crying or suckling → hypothalamus → oxytocin → contraction of myoepithelial cells →expel milk
o Stop nursing: ↓ prolactin, ↓ milk; lobules involute over several months, infiltrated by lymphocytes and plasma cells

Question 11

• What are Montgomeryt ubercles?

Answer 11

o Visible bumps of Glands of Montgomery
o =sebaceous glands in the areola, and nipple itseld
o Keep nipple lubricated and protected
o more pronounced during pregnancy, more apparent as nipple is stimulated
o overlying skin is smoother than rest of areola

Question 12

• what are the terms for congenital breast conditions?

Answer 12

o Amastia= breast tissue, nipple, areola, absent; usu congenital or iatrogenic (drug or toxin induced)
o Amazia= mammary gland tissue absent, but nipple and areola present; congenital or iatrogenic
o Athelia= presence of breast glandular tissue but no nipple or areola; congenital, with progeria (premature aging)
o Poland Sequence: UL afflictions: athelia, defect pec mm, finger webbing
o Ectodermal dysplasia: BL athelia, abn skin, sweat glands, dry eyes, teeth

Question 13

• What is supernumerary nipple?

Answer 13

o = 1+ additional nipples
o 2-6% F, 1-3% M
o Location: mb on breast; MC along milk line (extends BL axillae to groin)

Question 14

• What is supernumerary breast tissue?

Answer 14

o Aka polymastia; presence of breast tissue in an ectopic location
o Established during development, but mb not apparent until puberty, or pregnancy and lactation
o Usu along milk line, rare elsewhere (foot)
o can undergo same pathologic changes as normal breasts- benign cystic changes, benign breast tumors (adenoma and fibroadenoma)
o consider polymastia if mass along milk line

Question 15

• what is an inverted nipple?

Answer 15

o retracted into breast tissue rather than protruding outward
o usu dt fibrous bands that tether nipple in inverted position
o st will protrude if stimulated, st remains inverted; can still breast feed
o st begins with pregnancy, may return to normal when stop lactating
o ~3% of all women, 90% BL; 50% familial
o Must r/o breast CA if no other known cause

Question 16

• What is galactorrhea?

Answer 16

o spontaneous flow of milky nipple d/c, in absence of childbirth or lactation
o mb dt local causes (excessive nipple stimulation); mc hormonal dysregulation
o LC (7%) presenting sx of underlying breast cancer in F < 60 (30% in > 60)
o Be concerned: UL, from 1 milk duct, serous-sanguineous (bloody), breast mass
o Assoc w ↑ prolactin (pituitary adenoma, med se, hypothyroid, endocrine anovulatory syndromes)
o Drugs: OCP’s, methyldopa, TCAs
o Also: solitary duct papilloma, breast cysts
o d/c w/o mass mb CA: 50% invasive carcinoma, 50% carcinoma in situ

Question 17

• what is mastitis? Acute?

Answer 17

o Aka recurrent sub-areolar abscess or squamous metaplasia of lactiferous ducts
o inflammation of parenchyma of mammary gland (usu non-infx)
o usu lactating F = puerperal mastitis; anyone else = non-puerperal mastitis
o acute: Usu sterile, non-infx inflam; If infx: usu Staph aureus or Strep epidermitis; via cracks, fissures in nipple

Question 18

• what is periductal mastitis? Micro appearance?

Answer 18

o usu painful mass in sub-areolar, w erythema
o st in M; > 90% are smokers; Nipple inversion mb sequelae
o micro: keratinizing squamous epithelium in duct system of nipple, extends to abn depth; chronic granulomatous inflammatory response; mb Dilation and rupture of involved ducts

Question 19

• what is mammary duct ectasia? Ssx? Cause? Micro?

Answer 19

o dilatation (widening) of sub-areolar (lactiferous) ducts; seen on US
o mc 5th-6th decade, usu multiparous F; incidence ↑ w age
o usu UL; st mistaken for carcinoma by palpation and mammography
o ssx: cyclic and non-cyclic breast pain; st erythema; Palp, poorly defined areolar or peri-areolar mass; Thick nipple d/c; nipple inversion 30-40% (dt fibrosis)
o Cause: mb peri-ductal inflam
o Micro: dilated lactiferous ducts filled w granular debris, foam cells, Peri-ductal and interductal inflammation w infiltrate Ls and M0s macrophages, ↑ plasma cells

Question 20

• What is Fibrocystic breast disease? Ssx?

Answer 20

o MC breast do, > 50% all breast surgeries
o fibrous lumps (cobblestone texture) and cords in breast tissue, non-cancerous
o 30-60% of F
o Lumps: smooth, defined edges, mobile; st obscured by assoc irregularities; mc upper outer quad
o Mb asx; or periodic pain/swelling dt hormones, menstrual cycle, life style

Question 21

• How is fibrocystic dz dx?

Answer 21

o Usu dx 20-40; uncommon before adolescence; rare after menopause
o Clinical, PE usu sufficient, st need bx: fibrosis, sclerosing ductal epithelial proliferation (inwards), adenosis (ducts enlarged, full of glands), apocrine metaplasia; cysts fluid filled
o Usu not mammo, tissue too dense
o Fine needle Aspiration to drain larger cysts

Question 22

• How is fibrocystic dz shown to be benign?

Answer 22

o Myoepithelial cells are present
o cytologic features of ductal cells vary depending on location within duct. ductal cells growing next to native myoepithelial/basal lamina zone

Question 23

• what is Fat necrosis of the breast?

Answer 23

o Usu F, especially if breast is heavy and pendulous
o Mc dt prior breast trauma (seat belt), surgery
o Dt rupture of adipocytes and hemorrhage
o → lipolysis, FAs, glycerol
o → fibrosis, ↑ vascularization may wall off area
o → Calcification, hemosiderin deposition

Question 24

• How does breast fat necrosis present?

Answer 24

o may appears as pnless breast mass, skin thickening, breast tissue retraction
o may look like malignant neoplasm
o mammo: central radiolucent area of fat, ↑density, calcifications at fat periphery
o typical: lucent-centered calcifications
o rule: do bx if CA possible from mammo

Question 25

• Histo of breast fat necrosis?

Answer 25

o irregular fatty spaces surrounded by foamy histiocytes and multinucleated giant cells

Question 26

• what is Lymphocytic mastopathy? Histo? Mammo?

Answer 26

o 1+ hard masses of collagenized stroma surrounding atrophic ducts and lobules
o MC in F with DM 1 or AI thyroiditis (thus mb AI dz)
o Histo: US-guided core needle bx; thickening and fibrosis of stroma, peri-ductal/ BV lymphocytic infiltrate (well-circumscribed); myofibroblasts
o Mam: diffuse heterogeneously fibroglandular pattern of breast parenchyma

Question 27

• What is Granulomatous mastopathy? Causes?

Answer 27

o Uncommon mastitis w granulomas of epithelioid cells and giant cells
o St assoc w breast CA, may involve draining lymph nodes
o Idiopathic, or dt TB, sarcoidosis, Wegener’s granulomatosis
o TB: caseating, acid-fast culture (mb PCR), usu solitary, ill-defined, UL hard lump in upper outer quad. curable with anti-TB drugs, surgery rarely required
o Mycobacterium/fungal: mc in immunocompromised, or nipple pierce, breast augment, breast prosthesis after mastectomy

Question 28

• What is adenosis of the breast?

Answer 28

o ↑ # glandular components, enlarged lobules, more organized

o Adenoma= entirely benign

Question 29

• What is a fibroadenoma of the breast?

Answer 29

o Mc benign tumor of the breast, minimal ↑ risk CA
o 1+ nodules
o Usu younger F, reproductive
o Firm, mobile, usu non-tender
o Hormonall responsive: ↑ size in pregnancy (lactating adenomas), and late luteal phase of menses → often regress after menopause.

Question 30

• What is histo appearance of fibroadenoma?

Answer 30

o well circumscribed, prominent fibrotic capsule, bi-layered tubular component
o Combines morphologic features of sclerosing adenosis and papilloma (w/o papillary structure)
o hyperplasia of intraductal epithelial cells (no atypia)
o mb discrete continuous within a ductal system
o Prominent hyalinizing fibrosis
o Frequently denser in center
o May form stellate scar but periphery still circumscribed

Question 31

• What is a lactating adenoma?

Answer 31

o localized focus of hyperplastic cells in breast tissue during pregnancy
o enlarged lobes, ↑ glands
o 1+ adenomas
o Micro: hyperplastic lobules, marked cytoplasmic vacuolization in secretory cells; some inflame and fibrosis; no neoplastic atypia
o Gross: mb enlarged breast, erythematous; necrotic core, necrotic skin; ↑ nipple-to-infra-mammary crease distance; 14cm

Question 32

• What are Intraductal papillomas? 2 types?

Answer 32

o Found in 1-3% of all breast bx
o Small malig potential
o solitary ductal papilloma (SDP): in large ducts, centrally beneath nipple
o multiple intraductal papilloma (MP): in terminal ducts at periphery of breast

Question 33

• histo of intraductal papilloma?

Answer 33

o myoepithelial cells (stain for actin)and multilayered ductal cells → flattened, heterochromatic nuclei on luminal surface
o Often the long axis of the multilayered ductal cells aligns in the same direction??
o Dilated ducts
o 7.5 x 5 cm
o often have only a tenuous connection with the wall of the duct
o Blood vessels and supporting fibroblasts extend from wall of duct to supply papilloma
o Multi-layering of ductal cells not always prominent in papillary lesions of breast

Question 34

• What is “breast cancer”?

Answer 34

o Most originate in glandular tissues of breast, called adenocarcinomas
o glandular tissues = Both lobular (milk) and ductal tissues (transfer milk to nipple)
o ?? veins resemble crab legs- ancient roman, curable wo surgery (small)

Question 35

• What are high rated risk factors for breast CA?

Answer 35

o F, ↑ age
o PMHx CA in one breast.
o FHx of both mother and a sister w breast CA
o Daily ETOH intake > 2 glasses
o ↑premenopausal blood insulin-like growth factor (IGF)–1
o ↑post-menopausal blood E

Question 36

• What are moderate rated risk factors for breast CA?

Answer 36

o	first full-term pregnancy > 30  
o	FHx Any first-degree relative w breast CA
o	Hx benign proliferative lesion, dysplastic mammographic changes, high dose ionizing radiation to chest
o	Tobacco use
o	Nulliparity
o	Early menarche, < 11
o	Late menopause, > 55
o	High-fat diet/saturated fat–rich diet
o	PM obesity
o	HRT
o	Residence in urban areas, northern U.S.
o	Caucasian, > 45
o	African American, < 45
o	Hx endometrial or ovarian cancer

Question 37

• What are Factors identified with a protective role against breast cancer?

Answer 37

o	Late Menarche, > 15 (also anovulation, lactation, early menopause dt ↓ E)
o	Breastfeeding > 1 year
o	Physical activity 
o	Minimal ETOH consumption
o	No tobacco use
o	Monounsaturated fat–rich diet

Question 38

• What causes breast CA?

Answer 38

o clonal line of malignant cells, usu dt multiple genetic changes or mutations.
o Early mutations mb inherited (i.e. mutations of breast stem cells) or acquired (i.e. somatic mutations due to ionizing radiation, chemical carcinogens or oxidative damage).
o Hereditary: 5-10% of all
o Acquired: usu E

Question 39

• What causes hereditary breast CA?

Answer 39

o Mutated BRCA1 and BRCA2 = 30-40% of all inherited
o BRCA1: 0.1% in general population, 20% in Ashkenazi Jews; 3% of general breast cancer population; ~70% of inherited early-onset
o Normal BRCA2 protein: binds to and regulates RAD51 to fix DNA breaks
o Hets: ↑ breast and ovarian CA rates
o 50-85% of F w mutated BRCA1 → breast cancer during their lifetime

Question 40

• What is the role of estrogen in breast CA?

Answer 40

o Binds estrogen receptors (ER, a and b)- over-expressed in 70% breast CA cases = “ER-positive”
o → disrupt normal growth cycle, apoptosis, DNA repair
o Has cell proliferating effect on breast epithelium, ↑ chance of DNA replication errors/ chance for mutations
o Unknown: pregnancy ↓ breast tissue susceptibility to somatic mutations.
o Thus, the earlier the first pregnancy, the shorter the susceptibility period that begins with menarche

Question 41

• What binds to the ERs?

Answer 41

o 17-beta-estradiol binds equally well to both receptors
o Estrone preferentially bind to alpha
o Estriol, Raloxifene,Genistein to beta

Question 42

• What are rates of breast CA in US?

Answer 42

o Highest in world, 12.5 % chance, 3% death

o Mc CA in women, 2nd CA death, 7% (after lung), 2% all death

Question 43

• What is done prophylactically for carriers of BRCA1/2?

Answer 43

o mastectomy and/or salpingo-oophorectomy, ↓ risk both breast and ovarian CA
o 40, BRCA1: oophorectomy → long term survival advantage. Earlier intervention actually adverse effects
o 40, BRCA2: oophorectomy only marginal effect on survival, better w mastectomy
o Overall, these procedures provide little effect

Question 44

• What is the HER2/neu gene?

Answer 44

o Aka ErbB-2, Human epidermal growth factor receptor 2
o Another genetic risk factor for breast CA; a known proto-oncogene; more aggressive, greater chemo resistance
o Breast tumors routinely checked for it
o ↑ in 30% of breast CA cases
o Overexpression in breast CA assoc w ↑ risk dz recurrence and worse px
o Also seen in ovarian CA, stomach, uterine
o Drug Trastuzumab: only effective in HER2 CA, ↑ p27 (halts proliferation)

Question 45

• What are some PE findings associated with breast cancer?

Answer 45

o	breast mass firm or hard
o	Painless mass (malignant masses painful in only 10-15%)
o	Irregular borders to mass
o	Mb fixed to skin or chest wall
o	Skin dimpling
o	Nipple retraction 
o	Bloody nipple d/c

Question 46

• What PE is found for benign breast masses? Cysts?

Answer 46

o	Firm, rubbery mass
o	Frequently painful
o	Regular margins
o	Mobile
o	No skin dimpling
o	No nipple retraction
o	No bloody d/c
o	Cysts: No reliable PE that consistently distinguish cysts from solid masses

Question 47

• What are the three main types of breast cancer?

Answer 47

o Ductal (aka Intraductal)
o Lobular
o Nipple (aka Paget’s dz of breast or nipple)
o Other: inflammatory breast cancer, etc

Question 48

• What are global stats for breast cancer?

Answer 48

o Worldwide: 10.4% of all CA in F = mc non-skin CA in F
o 5th mc cause CA death.
o 7% CA deaths, 1% all deaths
o F:M 100:1, but M usu worse px dt dx delay

Question 49

• What are hormone positive breast cancers?

Answer 49

o Some are sensitive to hormones, E and P
o May tx by blocking effects of E & P in target tissues
o E & P receptor positive tumors have better px, require less aggressive tx than hormone negative
o Tx more aggressively: w/o hormone receptors, spread to axilla LNs, or certain genetics = higher risk

Question 50

• What is carcinoma in situ? Invasive?

Answer 50

o Situ: low grade cancerous or precancerous cells in a particular tissue area such as mammary duct, w/o invasion of surrounding tissue
o Inv: invades surrounding tissue

Question 51

• What is the mc type of breast CA? gross?

Answer 51

o ductal carcinoma, aka infiltrating ductal carcinoma; 80%
o usu single hard mass, irregular borders, fixed
o gross: central white area very hard and gritty, dt desmoplastic rxn with lots of collagen. = “scirrhous” appearance. focal dystrophic calcification leading to the gritty areas.
o Adv: overlying skin may be invaded

Question 52

• What is micro appearance of ductal carcinoma?

Answer 52

o Papillary: Absent or scant stroma, bloody d/c common dt occurrence in central breast
o extends irregularly as cords and nests of neoplastic cells w intervening collagen
o micro-calcification, dystrophic, dt neoplastic cells undergoing necrosis
o pleomorphic cells haphazard throughout stroma.
o Heterogeneity of malignant ductal cells
o abundant pink collagen bands → tumor feels firmer than normal breast tissue

Question 53

• what is micro appearance of infiltrating ductal carcinoma in-situ?

Answer 53

o intact basement membrane surround ducts, confine neoplastic cells to duct
o profound nuclear atypia; enlarged round to oval nuclei with nucleoli
o duct may not be filled w cells, so look at lining cells
o loss of typical bi-layered epithelium
o loss of polarity towards lumen
o intraluminal microcalcifications

Question 54

• what are types of DCIS?

Answer 54

o papillary (delicate fibrovascular cores covered w atypical cells)
o cribriform (multiple lumens in a single duct)
o solid
o micropapillary (tiny epithelial papillae)
o comedo (around necrotic center; nuclear pleomorphism, hyperchromasia, large nucleoli and mitotic activity
o clinging: only 1-2 abn cell layers “cling” to basement membrane

Question 55

• what does “in situ” mean histologically?

Answer 55

o basement membrane remains intact, no signs of tumor infiltration into adjacent tissue
o can occur in ductal or lobular breast carcinoma

Question 56

• what is the 2nd mc type of breast carcinoma? Histo?

Answer 56

o Lobular carcinoma- 5-10%
o ↑ risk: mult loci, BL breasts
o small homogenous cells invade stroma, often “single file pattern”
o signet rings= worse px

Question 57

• what is Paget’s disease of the breast? Ssx?

Answer 57

o uncommon
o involves nipple and areolar area
o often assoc w underlying in-situ or invasive carcinoma (mb no mass)
o ssx: itching/burning in nipple-areolar area, w eczema (classic), ulceration/destruction (late)

Question 58

• What is histology of Paget’s dz of breast?

Answer 58

o Paget cells: large round, pale cytoplasm, pleomorphic nuclei, in epidermis
o derived from glandular epithelium, immunologically similar to the underlying cancer cells

Question 59

• what is Inflammatory breast cancer (IBC)? Tx?

Answer 59

o form of ductal carcinoma, breast appears markedly inflamed
o very aggressive
o no palpable lump
o tx: chemo, surgery, radiation= combo, better for IBC
o 30-45% 5yr survival; 25% 20 yr survival