LC Unit 2 Flashcards
tissue, cellular, and functional organization of breast tissue in non-lactating state
breast is composed of glandular lobes
- composed of multiple lobules containing alveoli (milk producing units) that are connected by ductal network that empties into a single milk duct
- milk ducts from multiple lobes feed into the nipple
alveolar structures:
- composed of myoepithelial and secretory epithelial cells
- at tips of ducts
- responsible for synthesis/secretion of like
- lobuloaveolar unit also called terminal ductal lobular unit (TDLU)
breast is mainly composed of ligaments and inter glandular fat
- glandular components are very proximal to nipple and don’t radiate out very far
- glands of ducts are superficial and easily damaged, esp during surgery
- number of ducts ranges from 4-14 ducts; avg 9
relative distribution of breast tissue in lactating state vs non-lactating
lactating breast:
glandular component 64%
intraglandular fat 6%
non lactating breast:
glandular component 20%
intraglandular fat 49%
stages of breast development and key hormones
embryogenesis:
- establishment of rudimentary gland
- ectoderm invades mesenchyme; develops secondary buds and a fat pad
hormonal control of nipple morphogenesis:
PTH related protein PTHrP
-interacts w/ mesenchymal cells to induce differentiation into fat pad, which is required for further elaboration of duct and formation of mammary gland
–absence of PTHrP: Blomstrands achondroplasia (amastia)
neonatal breast morphology: maternal hormone influence
- presence of secretory product in ducts (elevated PRL and low Progesterone at parturition can induce temporary milk sectretion- witches milk)
- simple ductal network ending with TEB structures
- branching ductal network with lobules (progesterone receptors present for up to 3mo; thought to be driven by temporary GnRH-driven spike in progesterone to stimulate branching and lobule formation)
Puberty:
-elaboration/growth of ducts and alveoli
-macroscopic development due to increase in fat accumulation in mammary adipose tissue
-driven by estrogen and progesterone
-associated with Tanner scale, but not a hard indicator of functional development
-menstrual cycle drives developmental changes
(increase in estrogen in combo w/ GH is primary driver of ductal elongation by increasing IGF-1 production by stromal cells; progesterone secretion during luteal phase acts to elaborate the side branches of the ducts and lobuloaveolar TDLU development; these 2 together are responsible for arborization; no further elaboration of ducts at end of puberty because there’s no more GH, even though there’s estrogen present)
changes that occur during pregnancy:
- glandular morphogenesis
- secretory differentiation
- –lactogenesis-1 initiation of milk protein expression and development of secretory capacity
- –lactogenesis-2 copious milk production
-features: increased lobules, differentiation of alveolar cells, inhibition of milk secretion
- hormones during pregnancy:
- —ovaries and placenta: estrogen, progesterone, placental lactogen
- —pituitary: prolactin
- progesterone is required for alveolar formation during pregnancy
- both progesterone and PRL are required for full alveolar maturation
- milk protein expression is initiated during pregnancy by PRL or placental lactogen but milk secretion is held in check by Progesterone levels
hormonal basis of breast abnormalities in males
ratio of T/estrogen during puberty, esp initially, can cause temporary gynecomastia
–disappears as M gains more T
neural and hormonal mechanisms that regulate lactation
initiation of lactation:
- milk secretion initiated by the fall in progesterone at parturition (removal of placenta)
- elevated prolactin levels maintain synthesis and secretion of milk
lactation requires PRL and oxytocin-regulated by neuroendocrine feedback
2 components of lactation:
- milk secretion (prolactin and milk removal)
- milk ejection (oxytocin and suckling; requires alveoli to be squeezed)
Prolactin:
- is released in pulses
- pulse size/frequency are regulated by suckling stimulus
- suckling is required to maintain PRL levels
- failure to initiate breastfeeding shortly after parturition leads to loss of PRL and impaired ability to maintain lactation (problem w/ preterm infants)
Oxytocin:
- required for milk ejection
- stimulates contraction of myoepithelial cells that form basket-like network around alveoli
feedback loop that controls lactation
Anterior pituitary:
- releases prolactin
- causes milk secretion
baby:
- Dopamine inhibits prolactin release
- suckling inhibits dopamine release from posterior pituitary
- suckling frees up the release of prolactin
Neuroendocrine reflex:
oxytocin:
-produced/released by posterior pituitary
-suckling, conditioning can stimulate oxytocin
-stress can inhibit oxytocin
sources and actions of specific hormones that control lactation
prolactin is required for milk synthesis and secretion
oxytocin is required for milk ejection
factors that influence neuroendocrine reflex can negatively impact lactation
cellular pathways involved in milk secretion
water and proteins are released via classical secretion proteins
cytoplasmic lipid droplets are enveloped by membrane and released
during lactation- transepithelial tight junctions are closed
prior/shortly after lactation- the junctions are open and allows circulatory system to get into milk
-sIgA, lactoferrin (antiinflammatory/immunity agensts) are elevated in milk
progression of lactation
-physiological changes and composition of milk
time course of lactogenesis in women:
- milk volume increase
- tight junction closure
- transcytosis of sIgA
- coordinated increase in secretory activity
human milk (vs bovine): -high amounts of oligosaccharides (prevent infantile infection)
individual milk volumes vary considerably but the timing of milk production is very similar
- timing is related to closure of tight junctions
- immunity portion w/ open tight junctions (sIgA secretion and leukocytes)
- when tight junctures finally close by ~3days postpartum, the milk volume increases substantially and transitions to nutrition (vs immunity)
physiological factors that affect lactation
Factors affecting lactation:
- anxiety/stress
- delayed lactation initiation
- pituitary disorders or damage
- excessive weight/obesity (inhibit PRL secretion)
removal of milk is required to maintain glandular integrity
a prior pregnancy primes the breast for milk production
nutritional composition of breast milk
breast milk:
- dynamic fluid secreted from mammary glands
- changes throughout the day
colostrum milk:
- yellow in color
- high in IgA and lactoferrin (anti-infection properties)
- higher protein, lower fat and lactose
- facilitates: est of lactobacillus and passage of meconium
transitional milk:
- 2-14 days
- imunoglobulins and protein decrease
- lactose and fat increase
- increase in calories
- vitamin changes
mature milk:
- water (maintains infant hydration; largest constituent)
- lipids (50% of calories; variety; varies during feeding)
- proteins (WHEY and casein, lactoferrin- inhibits growth of Fe-dependent bacteria in GI tract)
- immunoglobulin s(sIgA- offers mucosal protection)
- other antimicrobial factors
- Carbs (lactose mainly)
- trace elements (Fe, Zn)
- Vitamins (Vit D- inadequate due to lack of infant production from sunlight)
- foremilk: milk at beginning of feeding (blue-ish)
- hindmilk: milk at end of feeding (yellow/creamy)
elements change:
- fat, carbs, proteins, cells
- osmolarity, pH
volume increases:
- 1st month: 22oz/day
- 6 months: 30oz/day
- 12 months: 25 oz/day
impact of maternal diet on breast milk
malnourished mothers have same proportions of macros as a nourished mother, but they produce less milk
water intake is important
-dehydrated mothers will decrease urine output before diminishing breastmilk output
fat intake influences lipid content
-not linked to infant health at this point
advantages of breast milk over infant formula
mother:
- convenient- always available at right temp
- free
- suckling causes uterine contraction–> oxytocin release; prevention of postpartum hemorrhage
- lactational amenorrhea decreases maternal Re loss
- more rapid return to postpartum weight loss
- decreased breast and ovarian cancer risks
- decrease osteoporosis risk
- improved CV outcomes
- bonding/stress reduction
- monetary savings (vs formula; decreased infant illnesses/hospitalizations)
- less expense per child on healthcare
- less missed days of work
infant:
- bonding
- benefits that can’t be duplicated (nutrients, immunology)
- immune support for immature immune system (macrophages, lymphocytes, antibodies/IgA, probiotics, lactoferrin)
- protection against infections (gastroenteritis, resp infections, acute otitis media)
- protection against (atopy, asthma, SIDS, diabetes, death, neurodevelopmental)
hospital practices that support and undermine successful breastfeeding
Support breastfeeding:
Baby Friendly Hospital Initiative:
- written breastfeeding policy
- train all hospital care staff
- inform all pregnant women of its benefits
- help mothers initiate breastfeeding w/in 30 min
- show mothers how to breastfeed
- only give infants breastmilk
- practice rooming-in
- encourage breastfeeding on demand
- no artificial pacifiers
- foster breastfeeding support groups
- breastfeeding in 1st hour
- skin/skin contact
- rooming in
- lactation consultants
- peer role modeling
- ad lib nursing/feeding
Inhibit successful breastfeeding:
- disruptive hospital practices
- inappropriate interruption/cessation of breast feeding
- availability and proportion of formula
- lack of training
- not encouraging breastfeeding as the norm
- separation of infant/mom
- mother discouraged BF/limited time suckling
- covert formula feeding
- D/C packs with formula
- lack of support
- pacifier use
published recommendations for infant feeding practices from delivery through 2 years of life
WHO:
- exclusive breastfeeding for 6 mo
- continue to at least 2 yrs
American Academy of Pediatrics:
- Exclusive breastfeeding for 6 mo
- continue to at least 1 yr
US Healthy People 2020 Goals:
- 82% ever breastfeed
- 61% at 6 mo
- 34% at 12 mo
- exclusive BF for 3 mo (46%)
- exclusive BF for 6 mo (25%)
- system level goals: increase worksite lactation support groups; decrease BF infants who receive formula supplementation within 1st 2 days of life; increase births in facilities that provide recommended care for BF mother/infants
AAP and WHO recommend infants be nursed skin/skin within the first hour after birth (before sleep)
- thermoregulation
- better BF outcomes at 4 mo
- breastfeeding crawl
newborn’s adaptation to extra-uterine life
first 3 days:
- colostrum (high fat, protein, Ig’s, low vol)
- practice breast feeding
- E source (12 hr store of glycogen; glucose drop –> gluconeogenesis; stress —> glycerol and fatty acids)
lactogenesis stage 2- occurs about 3-4 days after life- “milk comes in”
-subsequent milk production based on supply and demand
frequency of breast feeding:
- on demand
- variable time between feeds (30min-4 hrs)
- 8-12 times/day in beginning
- thorough emptying of breast is important (hind milk; also good for lactogenesis)
- duration varies (10-30min?)
early patterns of weight loss and regain by the infant
normal:
- infants expected to lose 5-7% of their birth weight
- typically stop losing weight by 5 days (breast milk comes in)
- start gaining 15-30g/day
- regain of Birth weight BW by 7-14 days
formula fed babies don’t go through the dip/regain
common issues:
- poor feeding/poor weight gain (requires immediate medical attention- dehydration/hypernatremia, jaundice)
- can lead to poor milk production
prevention:
- in-hosital observation of feeding/weight gain
- outpatient F/U (within 1-4 days)
WHO growth standards with the US/CDC growth references for infants through the age of 2
CDC growth charts:
difference in growth of breastfed vs formula fed infants:
-first 3 months similar weight gain
-after: formula-fed gains more weight
-12mo: formula fed 0.65kg more
-until 2010, growth charts were based on sample of formula-fed infants (Breastfed infants looked “growth faltering”)
recommend to use WHO growth charts in children 0-2yo:
- biggest differences (vs CDC) in growth after 6 months
- for high weights, earlier “overweight” (earlier recognition)
- for low weighs, less “underweight” (fewer dx’s of growth faltering)
characterize the terminal duct lobular unit
TDLU:
- functional unit in breast
- large duct differentiates into smaller ducts, eventually a terminal duct w/ small tubules/acini = terminal duct lobule unit
- the area where most changes occur
entire ductal system is lined by 2-cell layer:
- past the nipple squamous epithelium
- 2 cell layers must be present for normal histology
- luminal epithelial layer (functional milk production; single layer)
- myoepithelial cell layer (outer; contractile properties; supporting inner layer; absent in malignancies)
compare/contrast breast histology in different states: resting, pregnancy, lactation, postmenopausal involution
Resting:
- puberty: stimulation by E and P
- forms acini and terminal ducts
- 2nd half of menstruation: larger lobules and increased acini; involution at end of menses
Pregnancy:
- increase in acini
- entire lobule increases in size
- epi vacuolization–> produces secretions into lumen
Lactation:
- very little stroma left
- mostly lobules composed of back-to-back tubules
- involution after lactation 2-3 months
Postmenopausal Involution:
- Involuted TDLUs
- ductal system remains
- lobules become small/atrophic
- comparatively more stroma and less glandular tissue
- more fat and less fibrous tissue
Common congenital breast anomalies, incl supernumerary nipple/breasts, accessory breast tissue, and congenital inversion of nipples
Supernumerary nipple/breast:
- accessory breasts
- along milk line, present during fetal development
- most common site for ectopic breast tissue = axilla
- may feel lump in axilla during menses/pregnancy
- prophylactic mastectomies may leave some breast tissue behind
Accessory Breast tissue:
-additional breast tissues along milk line
Congenital Inversion of Nipples:
- can occur and correct itself over time
- some advanced breast cancers can also have retraction (from fibrosis retracting skin)
Key histologic characteristics of lesions: apocrine metaplasia blue-dome cysts sclerosing adenosis acute mastitis and abscess chronic mastitis mammary duct ecstasies plasma cell mastitis granulomatous mastitis fact necrosis of breast fibroadenoma lactating adenoma intraductal papilloma phyllodes tumor gynecomasti
apocrine metaplasia:
- cystic changes
- epithelial cells undergo change that makes them look like apocrine glands
- protruding appearance into lumen; AKA apocrine snouts
blue-dome cysts:
-non-proliferative fibrocystic change w/ epithelial cells undergoing apocrine metaplasia –> fluid-filled blue dome cysts
sclerosing adenosis:
- fibrous tissue and adenosis, but NO cyst formation
- micro: adenosis, marked fibrosis which may compress/distort the lumens of acini and ducts; giving the appearance of solid cords of cells
- myoepithelial cells are still present (vs cancer)
acute mastitis:
- occurs in young F during lactation
- swollen, red, painful breast (inflammatory)
- cracked or inflamed skin and milk stasis permits entry and proliferation of organisms (Staph, ex)
- acute inflammation- neutrophils
- acute abscess formation
- tx w/ antibiotics; surgical drainage of pus
- DDx: inflammatory carcinoma (malignant; not a true inflammation)
chronic mastitis:
- postmenopausal F
- duct obstruction by inspissated secretion or cell debris
- dilation of ducts (duct ectasia)
- stasis of secretion and epithelial debris
- can go on to plasma cell mastitis or granulomatous mastitis
- –> irregular fibrosis
- painless, irregular, fixed mass mimicking carcinoma (absence of signs of acute inflammation)
plasma cell mastitis:
- stasis of secretion and epithelial debris
- infiltration by lymphocytes and plasma cells
granulomatous mastitis:
- stasis of secretion and epithelial debris
- duct rupture w/ release of lipid contents
- infiltration by foamy histiocytes
Recurrent subareolar abscess AKA periductal mastitis:
- clinically appears like infection (abscess)
- related to smoking
- metaplastic change of luminal epithelium; and squamous epithelium continues deep into duct
- squamous cells tend to mature and fall off into lumen; induce inflammatory response and abscess formation
- can cause fistula w/ oozing pus on skin surface
- tx w/ surgical excision
fact necrosis of breast:
- benign
- necrosis of fatty tissue in stroma
- Hx of trauma or surgery, ischemia?
- ill-defined mass (Can mimic carcinoma)
- early phase: necrotic fat cells, neutrophils
- late phase: macrophages, giant cells, fibrosis, Calcifications, fibrous tissue
- clinicially and on mammogram very suspicious for cancer (irregular, calcified, hard mass)
fibroadenoma:
- most common benign neoplasm of breast
- discrete, capsulated mass 2-4cm
- firm and mobile, but not irregular
- arises from TDLU (made of stroma/fibrous and glandular tissue)
- can occur in any age group
- can be proliferative (Epithelial hyperplasia- >2 cell layers)
lactating adenoma:
- arises from TDLU (occurs in lactating F breasts), but mostly glandular proliferation
- mass is not as firm as fibroadenoma
- discrete, well-circumscribed, rounded mass
- can sometimes now rapidly
phyllodes tumor:
- can be benign, borderline, or malignant
- benign: “leaf life growth” into cystic spaces; mostly stroma proliferation
- large >4cm, pushing margin
- low grade: can recur
- high grade: can metastasize to lungs, bones
- atypical fibrobastic cells in stroma and a lot of mitoses = malignant phyllodes tumor
intraductal papilloma:
- occurs in larger ducts closer to nipple area
- ~1cm size
- proliferation of epithelium w/ finger-like processes –> dilation of duct
- delicate papillae, fibrovascular core, 2 cell epi layer
- bloody nipple discharge
- can become malignant
gynecomastia:
- M breast (common in young and elderly)
- assoc w/ changes in estrogen levels
- unilateral or bilateral
- can use FNA for biopsy
- increased ducts and fibrous stroma proliferation
- no lobules in M breast
differentiate between non-proliferative and proliferative fibrocystic changes
Fibrocystic change:
- fibrosis and cystic change; and sometimes proliferation of epithelium
- gross exam= cystic structures and white fibrosis
- can be multiple cysts or one large cyst filled w/ fluid arising from TDLU; and fibroplasia and epithelium increasing; may be a prominent lump or diffuse
- seen in 60-80% of autopsies
- asymptomatic, or pain/nodularity
- ranges from innocuous to pre-malignant
- due to hormonal changes of body
Non-proliferative fibrocystic change:
- cysts/fibrosis
- epithelial hyperplasia ABSENT
- some epithelial cells may undergo apocrine metaplasia –> blue domed cysts
- only 2 cell layers
Proliferative fibrocystic change:
- cysts/fibrosis
- epithelial hyperplasia
- lobular hyperplasia (acinar epithelium):
- –atypical lobular hyperplasia
- –LCIS
- ductal hyperplasia (terminal duct):
- –usual hyperplasia (mild, moderate, florid)
- –atypical ductal hyperplasia
- –DCIS
Sclerosing adenosis:
- fibrous tissue and adenosis, but no cyst formation (vs the other 2)
- gross: hard, rubbery, looks a lot like cancer
- micro: adenosis, marked fibrosis which may compress/distort the lumens of acini and ducts; giving the appearance of solid cords of cells
- myoepithelial cells are still present (vs cancer)
compare/contrast usual ductal hyperplasia and atypical ductal hyperplasia
Usual ductal hyperplasia:
- can be mild, moderate, or florid
- mild:
- –some heaping up of endothelial cells
- –more than 2 cell layers
- –focally involving the ducts
- –proliferative change associated w/ mild hyperplasia
- moderate:
- –more proliferation
- –some bridges of connected epithelial layers
- –lumen is at periphery w/ irregular slits
- florid:
- –duct is completely filled
- –very few luminal slits at periphery
- –cells overlap/crowd; cell bodies are not clear
Atypical ductal hyperplasia:
- proliferation of epithelium
- cell bodies are more visible- no overlapping
- luminal holes left behind, but more discrete and punched out (vs slits)
- assoc w/ higher risk of developing cancer
DCIS:
- more atypia
- mitoses
- may see necrosis within ducts
- basement membrane is intact
- myoepithelial layer is intact
describe atypical lobular hyperplasia
Atypical lobular hyperplasia:
- some lobules look normal (2 cell epithelium, lumen, normal size)
- acini are filled w/ more cells than normal
- > 2 cell layers; look filled
- involving <50% of lobules = atypical lobular hyperplasia
- > 50% of lobules= LCIS
- risk of malignancy is bilateral
counsel pts about cancer risk assoc w/ various forms of hyperplasia
risk of breast carcinoma in FCC:
minimal/no risk:
-duct ectasia, cysts, apocrine met adenosis, mild hyperplasia, fibroadenoma w/o complex features
slight risk: 1.5-2x
-moderate- florid hyperplasia, papilloma, Serous adenoma, fibroadenoma w/ complex features
moderate risk: 4-5x
- atypical hyperplasia
- atypical ductal hyperplasia
- atypical lobular hyperplasia
significant risk: 8-10x
- DCIS: risk of invasive ductal carcinoma
- LCIS: risk of both ductal and lobular carcinoma and can be ipsilateral or other side
FHx of breast cancer increases risk in all groups
classify malignant neoplasms of breast
Metastatic: rare
- melanoma (most common)
- renal cell carcinoma
- papillary thyroid carcinoma
Primary breast tumors:
- epithelial (by far most common; incl DCIS and LCIS)
- stromal (stromal mesenchymal, vascular, fibroblastic, etc)
- mixed (epithelial + stromal)
- lymphoid tumors
clinical features and histology of in-situ breast carcinomas
Carcinoma in situ general:
- one particular cell that has made an entire clonal process; expanded duct/lobule; caused havoc
- has NOT invaded through basement membrane
Squamous cell CIS:
- acanthosis (increased epithelial thickness)
- huge/ugly cells (increased N/C ratio, size, mitotic activity)
- tongues of tumor coming down
Bladder CIS: (normally transitional/urothelial epithelium)
- urothelial CIS- increased mitoses; going above the basal layer of the tissue
- cells are increased, big, N/C ratios, lighter chromatin (open chromatin pattern- denotes active proliferating cell) and discrete nucleoli
Breast CIS:
- DCIS:
- LCIS:
basic features of Paget’s disease
Paget’s disease = special DCIS
- starts as crusty/infectious looking process of nipple
- often misconceived as eczema
- need to biopsy
- proliferation of monotonous cells; increased N/C ratio, increased size; cleared-out cells; acanthosis, abnormal cell proliferation within the epidermal layer
- doesn’t break through basement membrane
- often mistaken morphologically for melanoma
compare/contrast histology of different types of CIS
DCIS:
- an epithelial CIS
- increasing size of proliferation within ducts
- numerous cells (all coming from same clone)
- cribiform variant (looks like sieve)
- papillary variant (fingerlike projections w/ fibrovascular core)
- solid variant (duct is filled w/ cells)
- micropapillary variant (do not have fibrovascular core; little tufts of cells coming out into lumen; hobnail looking cells)
- camedo type (high-grade; very magenta-pink center; camedo-type necrosis like a zit)
- risk of invasive carcinoma (mostly ipsilateral breast)
- excision is often curative (no invasion through basement membrane/ into blood vessels)
- risk factors for recurrence: histo grade, extent of breast involvement, and positive surgical margins
- tend to be difficult to treat (vs invasive carcinoma…?)
- low grade DCIS often expresses HORMONE RECEPTORS (ER, PR) but HER2 negative
- high grade DCIS often over expresses HER2/NEU protein
LCIS:
- epithelial CIS
- looks very monotonous- 1 solid type of morphologic appearance
- look like discrete/evenly placed ants
- expand and fill lobules
- lobules and acini lose the dual cell layer
- no crossing of basement membrane
- can look similar to DCIS; use immunohistochemical staining to differentiate
- does not typically form masses or calcifications
- often multi centric and bilateral (hard to chase surgically)
- increased risk for invasive carcinoma in BOTH breasts
E-cadherin:
- cell-cell adhesion marker
- LCIS is defined by its LACK of E-cadherin expression (via IHC stain)
- DCIS DOES have E-cadherin expression
Invasive breast carcinomas
INVASIVE epithelial carcinoma:
-most commonly in UOQ (spread first to axillary lymph nodes)
2 main clinical presentations:
- Palpable mass
- mammographic abnormality
uncommon presentations:
- enlarged erythematous breast (“inflammatory carcinoma”; diffuse involvement of dermal lymphatics; very poor prognosis)
- metastatic disease (usually in an axillary lymph node)
signs of locally advanced disease:
- fixation/pinning of tissue to underlying chest wall
- dimpling of the overlying skin (carcinoma is more adherent and invading into skin- retracting skin)
- numerous histologic subtypes, but we focus most on Invasive ductal carcinoma, not otherwise specified (NOS) and invasive lobular, and tubular carcinoma, metaplastic carcinoma, medullary carcinoma, and mucinous carcinoma
Invasive Ductal Carcinoma (NOS)
- 3 different degrees of differentiation help determine histo and clinical prognosis
- well-differentiated degree: forms glands; cells aren’t terribly ugly but still monotonous; glands aren’t forming discrete lobules like usual
- poorly differentiated: individual cells, lack of gland formation, infiltrated, large cells, high mitotic activity, big/ugly cells; have apoptotic debris; discrete nucleoli; open chromatin (high proliferation); not forming luminal/glandular structures
- tends to metastasize to lungs and pleura
Invasive Lobular Carcinoma:
- 2nd most common histo type
- tumor cells lose E-cadherin
- tend to express hormone receptors but do not overexpress HER2/Neu
- frequently assoc w/ LCIS
- same prognosis as invasive ductal carcinoma
- metastasizes more to CSF, GI, ovaries
- very monotonous appearance; cells are large; increased N/C ratio, but they infiltrate; “Indian filing”- individual cells stacked and infiltrating through the glands
Tubular carcinoma:
- subtype of ductal carcinoma
- very GOOD prognosis (has to have strict criteria for it- entire tumor has to be well-differenitaed)
- 1 cell layer (lost myoepithelial layer), but forming nice tubules
- cells are bigger, but not crazy ugly
Mucinous carcinoma:
- well-circumscribed mass
- older aged groups
- relatively favorable prognosis
- usually express hormone receptors ER, PR (do not overexposes HER2/neu)
- more frequent in pts w/ BRCA1 mutation
- a lot of mucin; very few epithelial cells floating in pools of mucin; pale/white/grey
Medullary carcinoma
- often presents as well circumscribed mass
- typically negative for hormone receptors
- does NOT overexposes HER2/Neu (triple negative)
- more frequent in pts w/ BRCA1 mutation
- do slightly better than typical IDC
- 3 main features:
- –indistinct cell borders (AKA syncytial growth)
- –prominent lymphoplasmacytic infiltrate at periphery (T cells and IgA plasma cells)
- –pushing borders/ well circumscribed
- not encapsulated, but well defined; brisk proliferation of lymphocytes around the tumor cells
Metaplastic carcinoma:
- any carcinoma w/ non-glandular growth
- usually restricted to carcinomas demonstrating squamous, spindle cell, or heterologous (pseudo sarcomatous) differentiation
- arise in assoc w/ poorly differentiated ductal carcinoma most commonly
- usually ER/PR negative
- Clinical: age range is similar in other types of breast carcinoma; seem to grow FASTER than other types; no specific mammography features (may have circumscribed contours)
- no differentiation, except ugly/high mitotic rate cells; pleomorphic; can have squamoid appearance; very different than the others we’ve looked at
INVASIVE STROMAL CARCINOMA:
Angiosarcoma:
- can be de novo or post radiation (more common)
- often show up close to surface
- proliferation of vascular cells
- ugly spindle cells; extravasation of RBCs in stromal components; well delineated blood cells
MIXED:
- Phyllodes tumor:
- –can be mistaken for benign fibroadenoma (more glandular proliferation and some stromal proliferation)
- pretty much all stromal proliferation
- leaf-like projections
LYMPHOID:
- can arise because there’s lymph cells in beast (like other places in body)
- can get mantle cell, marginal, CLL-associated, diffuse large B cell lymphoma, small lymphocytic lymphoma, etc
factors which impact breast cancer prognosis, incl staging
Hormone receptor expression = better prognosis
HER2/neu expression = worse prognosis
Prognostic factors:
- lesion characteristics
- regional lymph node involvement
- examination for metastatic disease
- not to be confused w/ risk factors (likelihood of developing vs progressing cancer)
Major prognostic factors:
- lymph node metastasis
- tumor size
- presence of invasion
- distant metastasis
- locally advanced disease
- inflammatory carcinoma
Used in the staging systems: TNM system
- Tumor size and local growth characteristics
- Node involvement extent
- Metastasis presence of distant metastasis
- used to separate pts into 5 categories, stage 0 up to stage 4
Minor prognostic factors:
- tumor biology (hormone receptor or HER2 expression; histologic the; lymphovascular invasion, proliferative rate)
- histologic grade (degree of differentiation- well differentiated = better prognosis)
- amount of tubule formation
- mitotic rate
- degree of nuclear atypia
- add points to give a combined score/GRADE (well differentiated - poorly differentiated)
Biomarkers (ER, PR, Her2) are prognostic and have strong predictive value (how well pt will fare, and how well pt will respond)
epidemiology of breast cancer
- most common incidence of F cancer
- 2nd most common death of F cancer
- incidence rapidly increased in 1980 w/ screenings
- slightly decreased recently
risk factors and hereditary causes of developing breast cancer
Risk factors: assoc/ w/ MORE estrogen exposure
- age
- age at menarche
- age at menopause
- age at first live birth
- 1st degree FHx
- prior biopsy results
- race
- exogenous estrogen exposure
- radiation exposure
- cancer of opposite breast or endometrial cancer
- obesity
- breast-feeding (protective)
70-80% sporadic 10-15% Hereditary (BRCA1/2 mutation) 20-25% Familial (FHx, but neg for BRCA) -CHEK2 gene mutation -Tumor suppressor gene mutation (LOF) -Li-Fraumeni Syndrome (TP53 mutation) -Cowden Syndrome (PTEN mutation) -Peutz-Jeghers Syndrome (STK11/LKB1 mutation)
pathogenesis of breast cancer
Carcinoma sequence:
-Hyperplasia –> dysplasia –> CIS –> invasive cancer
Molecular pathway of pathogenesis:
-acquired mutations will eventually lead into the invasive carcinomas to some degree
ER positive, HER2 negative cancers arise via dominant pathway (>50%)
- same genetics found in: Atypical Ductal Hyperplasia, flat epithelial atypia, low grade DCIS
- assoc w/ better prognosis of tumors
HER2 positive (Chr 17q) cancer pathway:
- 20% of all breast cancers
- most common subtype of Li-Fraumeni syndrome
- same genetics found in: DCIS (assumed precursor lesion)
- assoc w/ worse prognosis
ER negative, HER2 negative (triple negative):
- 15% of all breast cancers
- most common subtype assoc w/ BRCA1 mutation
- precursor lesion is still unknown
basic features of male breast cancer and differentiate it from female breast cancer
rare disease in males
risk factors are similar to F (incl hereditary and hormonal)
BRCA2 mutations significantly increase the risk for males
also assoc w/ Klinefelter’s syndrome, likely related to altered testicular hormonal function
often present as a subareolar mass
often involve chest wall and skin
expression of ER is more common
tend to present at higher stage, but prognosis is same stage for stage
key parts of sperm, intracellular structures, and functions
Sperm head:
- haploid
- nucleus contains highly condensed chromatin
- protamines –> specialized basic histone tightly held together by disulfide bond cross-linking
- shape of the sperm head is species-dependent
- contains DNA and acrosome
Sperm tail:
- designed for maximum transport through fluid
- narrow flagellum w/ tons of of mitochondrial content
- microtubules 9+2 axoneme structure for motility
Failure of sperm motility: Kartagener’s (primary ciliary dyskinesia)
components of a semen analysis w/ normal values
color viscosity volume >1.5mL pH concentration >15 million /mL motility >32% rate of progression morphology 4%
roles of zona pellucida and its glycoproteins, ZP1, ZP2, and ZP3, in the process of fertilization
Zona pellucida:
- shell; barrier to most diffusion surrounding oocyte
- glycoprotein sheet w/ several microns thick
- composed of 3 glycoproteins: ZP1, ZP2, ZP3
- glycoproteins play a role in fertilization (mutant/inactive zona proteins = infertility; clinically could be used as contraception)
sperm-oocyte fusion process and oocyte activation
Oocyte quantity and quality both determine reproductive potential
-DNA damage, radiation, infection, chemical exposure, polyglandular endocrine failure, etc can affect the oocytes
sperm capacitation, acrosome reaction, and zona reaction
Fertilization:
-the process involving union of male and female germ cells that result in formation of a pronuclear zygote or once-cell embryo
Fertilization requirements:
- ovulation and oviductal collection of oocytes
- deposition of sperm with sufficient number and motility
- sperm capacitation
- sperm traversal of cumulus oophorus
- sperm interaction w/ zona pellucida and acrosome rxn
- sperm penetration into zona pellucida
- sperm-oocyte fusion
- oocyte activation
- male pronuclei formation
Sperm capacitation:
- spermatozoa acquire the capacity to undergo the acrosome reaction and fertilize eggs
- capacitated sperm display hyperactive motility (increased flagellar beat frequency and amplitude; decrease in progressive movement), bind to zona pellucida, and area able to undergo acrosome rxn
Acrosome reaction:
- ZP3 receptor on tip of it
- process of exocytosis
Zona reaction:
- prevents polysperm fertilization
- as soon as first sperm binds, it alters cortical lumen and forms a barrier
- 1st sign of fertilization: 2 pronuclei
Sperm-egg interaction:
- sperm activated by F reproductive tract
- sperm goes through Cumulus layer and binds zona pellucida
- acrosomal rxn
- sperm lyses hole in zona
- sperm and egg membranes fuse
Sperm-oocyte fusion:
- occurs between sperm’s plasma membrane in the postacrosomal region and the oolemma
- Fertilin: sperm protein responsible for sperm-oocyte fusion
- lack of species specificity (sperm penetration assay SPA: zona-free hamster oocyte fusing w/ human sperm)
development of human zygote and pre-embryo through earliest stages
oocyte activation:
- reawakening of the oocyte in regard to 2nd meiotic division
- morphological indicator: exocytosis of cortical granules
preimplantation:
- 2 pronuclei w/ 2 polar bodies
- 24 hours to get to 4 cell stage
- good embryo morphology= 2 blastomeres w/ ground glass appearance (not lumpy bumpy)
- 3 days after fertilization to get to 4-cell
- variable quality of embryos- look for uniform/similarity in size and granulation of cells
- rough correlation between quality and implant ability
- day 4: morulae (cluster of grapes)
- early blastocyst formation; zona thinning; cells move to one pole
- a lab can look at polar body to get some chromosomal abnormality help (less invasive to the eggs)
timeline of implantation
within first 6 days after conception/fertilization, implantation of the blastocyst occurs
(“blastocyst sticks at day 6”)
-hCG secretion begins around this time
- implantation requires a direct and coordinated interaction between blastocyst, (outer trophectoderm) and the hormonally primed lining of the uterine cavity
- primary processes for the preparations for implantation are blastocyst hatching and decidualization
process of hatching and decidualization
-primary processes for the preparations for implantation are blastocyst hatching and decidualization
Blastocyst hatching:
-process when blastocyst “escapes” from zona pellucida
-occurs around day 6-7 after ovulation (20-21 from LMP)
-zona pellucida has been serving as a protective shell for the developing zygote
-products of blastocyst likely activate the lytic factor(s) in the uterine fluid, as an unfertilized egg does not hatch
(egg can be hatched in vitro via mechanical disruption or enzymatic digestion)
-once hatched, the trophectoderm can come into direct contact w/ the endometrial epithelium
Decidualization:
- process where the endometrial stromal cells (fibroblasts) are transformed into round decimal cells
- process is dependent on progesterone and cAMP
- process begins in the secretory phase of the menstrual cycle
- pre-decidualization takes place where stromal cells immediately adjacent to the spiral arteries begin to transform into rounded decimal cells
- if fertilization takes place, then this process expands and includes the remaining stromal cells
- depending upon the location of the decidua, it has different names
- decidua basalis: resides under implanting embryo
- decidua capsularis: overlies embryo
- decidua parietalis: covers the remainder of the uterine surface
stages of implantation
prep:
- fertizlied egg will be in fallopian tube for 3 days; undergoes cell division
- corpus luteum begins to secrete estrogen and P soon after fertilization
- P and E start deciddualization of stroma
- by the time it arrives in uterine cavity = morula
- very quickly after uterine cavity = blastocyst
window of implantation:
- only a finite period of time that the epithelium lining of uterus is prepared to accept a blastocyst implantation
- occurs day 20-24 during cycle
- pinopodes (small finger-like projections) form on the apical surface of the endometrium
- this is dependent on progesterone, and can be suppressed by estrogen
- endometrium is becoming more vascular and edematous
- endometrial glands have enhanced secretory activity
Stages of implantation:
- Apposition: 1st stage
- –loose unstable connection between the trophectoderm and the endometrial lining
- –trophoblast microvilli interdigitate w/ the pinopodes
- Adhesion: 2nd stage
- –stronger connection created by ligand-receptor interactions
- –integrins (cell surface receptors) and intracellular cytoskeleton and L-selectin expression likely play a role
- –heparin or heparin sulfate proteoglycans and their receptors are also important for implantation
- –thought to dislodge and allow access of trophoblast to the basal lamina (asymmetric blastocyst positioned such that inner cell mass is embedded first)
- Invasion: 3rd stage
- –trophoblastic cells rapidly proliferation once the blastocyst adheres to epithelium
- –cells differentiate into syncytiotrophoblasts and cytotrophoblasts
- syncytiotrophoblasts: extend long protrusions and secrete TNF-alpha, which interferes w/ expression of cadherins and beta-catenin (assisting in dislodgment of the epithelial cells); secrete autocrine factors and proteases that promote invasion through the basement membrane and the endometrial stroma (decidua)
- –other sub’s: prostaglandins, CSF-1, LIF, IL-1
- blastocyst invades and is completely buried into the endometrium
- no longer in direct contact w/ uterine cavity
- occurred by the 10th day after fertilization
types of abnormal implantation and clinical implication
some infertility may be the result of defects in the ability to transform the endometrial lining or impaired decidualization
- progesterone (via corpus luteum) is a critical player for both of these
- the trophectoderm of the blastocyst produces hCG, which maintains the corpus luteum, and therefore progesterone
- hCG is closely related to LH, and has immunosuppressive properties and growth-promoting properties likely critical for implantation
implantation most frequently occurs in upper posterior wall in the midsagittal plane, but it can occur anywhere
- implant near cervix = placenta previa
- implant over site of prior uterine scar = placenta accreta
- viable pregnancy can still occur, and are still considered intrauterine pregnancies
Abnormal implantation leading to ectopic pregnancies:
- ectopic = pregnancy outside uterine cavity
- MOST common site = fallopian tube (mostly ampulla)
- others: ovary, cervix, within abdominal cavity
- not a viable fetus; life-threatening to mother
- main risk: rupture and hemorrhage
- present: vaginal bleeding, abdominal pain, hypotension, lack of US confirmation of intrauterine pregnancy
- 2nd leading cause of maternal mortality
Tx:
- medical: methotrexate
- surgical: laparotomy vs laparoscopy (salpingectomy, salpingostomy)
- expectant
desirable attributes of screening tests
Screening test:
-no symptoms allowed
(symptoms = diagnostic testing)
-screening advances time of dx of cancers destined to cause trouble
-early tx is superior to tx initiated after pt already has symptoms
-an effective screening program: increase the dx of early-stage cancer and decrease the amount of ate-stage cancer
-hope to find bear cancers- detect it early enough to catch it before it gets too bad (length time bias)- slower growing–> better prognosis
perils of screening tests, incl issues related to lead time and over diagnosis bias
lead time bias:
- early detection is confused w/ increased survival
- “screening always increases survival- even if death is not delayed by early detection”
over diagnosis bias:
-benign natural history –> best prognosis
commonly used screening tests for breast cancer and how to optimize their use by quantifying benefits and harms applied to a pt
BRCA1 mutation screening
breast MRI
ideal candidate for prophylactic tamoxifen:
-high risk pt w/ no personal or family hx of endometrial cancer or VTE’s
biostatistics commonly used to describe screening tests incl sensitivity, specificity, predictive values, likelihood ratios, relative risk, absolute risk, risk difference, number needed to screen, and number needed to harm
2x2 table:
- “the truth is on top”- disease or no disease
- screening pos/neg is on the side- true or false
Sensitivity:
TP/(TP+FN)
-about pts w/ the disease; how often is this test right?
-how often a metal detector beeps when you have metal
-test for the guilty; to rule something out
-SNOUT- Negative rules it out (high sensitivity = low false negatives)
Specificity:
TN/(TN+FP)
-about the pts without the disease; how often is this test right?
-how often a metal detector doesn’t beep when you don’t have metal
-SPIN- positive rules it in (high specificity = low false positives)
Likelihood ratio:
LR= probability a test result in pt w/ disease / probability of the same test result in a pt without disease
-disease is always in numerator
-without disease is always in denominator
-moves us from a pretest to a posttest predictive value
-LR moves towards infinity- more likely pt has disease; LR >10 rules in (rapid strep test pos)
-LR=1; test has no impact
-LR moves towards 0- more likely pt does not have disease; LR <0.1 rules out (neg HIV test)
-use Fagan’s nomogram:
-start w/ prevalence on pretest probability; draw a line through the LR in the center; then you get post-test probability
-LR + = sensitivity / (1-specificity)
-LR - = (1-sensitiivty) / specificity
Relative risk:
RR = (a/(a+b)) / (c/(c+d))
1-RR = RRR
Absolute risk:
AR = (a/(a+b)) - (c/(c+d))
Risk difference: AKA absolute risk reduction ARR
-ARR = difference (decrease) in risk between groups- risk of death in screened pop’s vs unscreened pop’s
RRR les than avg risk
8% less (RR 0.92) than 0.35% = 0.32%
ARR = (0.35% - 0.32%) = 0.03%
NNS: AKA NNT
NNS = 100 / ARR (where ARR is expressed as %)
or NNS = 1 / ARR (where ARR is expressed as a decimal)
-number needed to screen in order to prevent one death
-NNS decreases as the prevalence increases: RRR increases with age; and ARR further increases since risk of breast cancer mortality increases w/ age
NNH:
NNH = 1/AR
assess pt’s risk of developing breast cancer, and implement an appropriate preventative regimen incl screening and chemoprevention
Positive and Negative Predictive Values-
PPV= TP/(TP+FP)- chance you have dz when test is positive NPV= TN/(TN+FN)- chance you do not have dz when test is negative
to fill in 2x2 box:
- need prevalence: total number of all 4 boxes
- need sensitivity: TP/FN
- need specificity: TN/FP
False negatives are more common with increased prevalence
- NPV’s vary inversely w/ prevalence or pretest probability
- –high Pretest probability = low NPV
Prevalence goes up: PPV goes up; NPV goes down
Prevalence goes down: PPV goes down; NPV goes up
assess pt’s risk of being a BRCA mutation carrier, and when to refer for additional testing and counseling
Use the online Breast Cancer Screening Tool to determine if you should screen for BRCA
additional testing and counseling when BRCA+
likely no more testing or counseling is
differences in breast cancer screening guidelines from professional societies, and recognize the origins of the differences
higher false positives and treating pts who don’t need it- cancer under a microscope but is unlikely to cause harm
- unnecessary surgery, radiation, or chemo (over diagnosis)
- increasing the breast cancer screening has a very small effect on avoiding death from cancer
