Week 5 Flashcards
Malignant Breast Neoplasms: (5 major groups)
1) Metastatic Tumors (to breast)
2) Epithelial Tumors
- Carcinoma in situ
- Invasive Epithelial Carcinoma
- Metaplastic carcinoma
3) Stromal Tumors:
- Invasive stromal carcinoma
4) Mixed stroma and epithelium:
- Phyllodes Tumor
5) Lymphoid tumors:
- Lymphoma
Carcinoma in situ (2 kinds)
Limited by basement membrane of ducts and lobules → cannot metastasize
Ductal Carcinoma in situ → Paget’s
Lobular Carcinoma in situ (LCIS)
Invasive Epithelial Carcinoma (6 types)
1) Invasive ductal carcinoma
2) Invasive lobular carcinoma
3) Tubular carcinoma
4) Mucinous (colloid) carcinoma
5) Medullary carcinoma
6) Inflammatory carcinoma
Metaplastic carcinoma
Any carcinoma with NON GLANDULAR growth (squamous, spindle cell, or heterologous differentiation)
Arise in association with poorly differentiated ductal carcinoma most commonly
Usually ER/PR negative
Can grow fast
Angiosarcoma
can be de novo or post radiation (common)
Proliferation of cells forming vasculature
Invasive stromal carcinoma
Phyllodes Tumor
basically all stroma + some glands
Looks like a leaf = “Phyllodes”
Can be mistaken for benign fibroadenoma
Mixed stroma and epithelium
Ductal Carcinoma in situ (DCIS)
clonal proliferation of epithelial cells within ducts leaving myoepithelial layer and BM intact
Present as calcifications on mammography
Asymptomatic, nonpalpable
INCREASED RISK for developing invasive carcinoma in ipsilateral breast BUT excision is often curative (may get recurrence)
Ductal Carcinoma in situ (DCIS)
Low grade vs. high grade?
Positive ________
*POSITIVE E-CADHERIN
Five histologic patterns: comedo, solid, cribriform, papillary, micropapillary
**High grade DCIS often overexpresses Her2/neu protein
**Low grade DCIS often express hormonal receptors (ER, PR)
Ductal Carcinoma in situ (DCIS)
Progression?
usual ductal hyperplasia → atypical ductal hyperplasia (ductal or lobular) → DCIS → Invasive carcinoma
Paget’s Disease of the Nipple
neoplastic DCIS cells grow from ducts onto adjacent skin without invading through the BM of ducts or skin
Presents as scaly rash on nipple +/- pruritus
May or may not have underlying invasive carcinoma
Can be mistaken for melanoma
Lobular Carcinoma in situ (LCIS)
Typically incidental finding, often multicentric and bilateral
SIGNIFICANT increased risk for invasive carcinoma in BOTH breasts
Lobular Carcinoma in situ (LCIS)
Histology
small, uniform cells with cound nuclei filling lobules, and poorly adhering to adjacent cells
*LACKS E-CADHERIN
Invasive Epithelial Carcinoma:
Presentation:
palpable mass or on mammography
Can also present as enlarged erythematous breast (“inflammatory carcinoma”) or metastatic disease to axillary nodes
Advanced lesions fix mass to chest wall → dimpling of overlying skin
Where does invasive epithelial carcinoma typically present? where does it spread?
Typically in UPPER OUTER quadrant → spread first to axillary nodes
If in inner quadrant → spread to internal mammary nodes
1) Invasive Ductal Carcinoma
- ER/PR?
- Her2/neu?
- differentiation?
- precursor lesion?
Associated with DCIS
Expresses estrogen and progesterone receptors when it is a WELL-DIFFERENTIATED lesion
Her2/neu expressed in POORLY DIFFERENTIATED lesion
Most common histologic subtype
2) Invasive lobular carcinoma (ILC)
- precursor lesion?
- ER/PR?
- Her2/neu?
- where does it metastasize
Second most common histologic subtype
Tumor cells similar to LCIS cells
LOSE function or expression of E-CADHERIN
Express HORMONE RECEPTORS
DO NOT overexpress HER2/Neu
Patterns of metastases: more frequently will go to CSF, GI tract, ovaries, uterus, and peritoneum
3) Tubular carcinoma
- presents at what age?
- prognosis?
- ER/PR, Her2/neu?
- Subtype of what other cancer?
Presents in 50’s
Subtype of ductal carcinoma BUT is very well differentiated tumor composed of well-formed tubules and bland appearing cells
Almost all express hormone receptors and do NOT express HER2/neu
Excellent prognosis
Mucinous (colloid) carcinoma
- presentation? age?
- prognosis?
- ER/PR, Her2/neu?
Presents as well-circumscribed mass (mimics benign lesions)
Older age groups
Relatively favorable prognosis
Usually expresses HORMONE receptors, NOT HER2/Neu
Frequent in patients with BRCA1 mutation
5) Medullary carcinoma
- presentation?
- prognosis?
- ER/PR, Her2/neu?
Presents as well-circumscribed mass
Negative for hormone receptors and HER2/Neu = TRIPLE NEGATIVE
More frequent in patients with BRCA1 mutation
Do slightly better than typical IDC
6) Inflammatory carcinoma
presents with breast erythema and swelling of breast
Diffuse involvement of dermal lymphatics
Poor prognosis - underlying carcinoma usually high grade
Prognosis in breast cancer (6 main factors)
1) Lymph node metastasis
2) Tumor size
3) Presence of invasion
4) Distant metastases
5) Locally advanced disease
6) Inflammatory carcinoma
Prognosis in breast cancer
minor factors for prognosis (6)
1) Hormone receptor expression
2) HER2/neu overexpression
3) Histologic type
4) Lymphovascular invasion
5) Proliferative rate
6) Histologic grade
Breast Cancer Risk Factors (6)
1) Hormonal exposure
2) Post-menopausal, Age
3) Family history
4) Age at menarche and first live birth
5) Breastfeeding duration
6) Environmental factors (ionizing radiation)
BRCA1 and BRCA2
tumor suppressor genes and facilitate DNA damage repair
BRCA1 → ovarian cancer, breast carcinomas (that are ER, PR and Her2/neu negative)
BRCA2 → increased risk of ovarian cancer (but smaller than BRCA1), male breast cancer
Accounts for 3% of all breast cancers
CHEK2 gene
tumor suppressor gene → cellular proliferation
Responsible for progression to carcinoma
5% of familial breast cancer
Li-Fraumeni Syndrome
TP53 gene mutation
5% of familial breast cancer
Cowden Syndrome
PTEN gene mutation
<1% of familial breast cancer
Peutz-Jeghers Syndrome
STK11/LKB1 gene mutation
< 1% of familial breast cancer
Pathogenesis of Breast Cancer:
Molecular pathways: (3)
1) ER positive, HER2 negative cancers arise via the dominant pathway
2) HER2 Positive cancer
3) ER negative, HER2 negative = TRIPLE NEGATIVE
Molecular pathways:
ER positive, HER2 negative cancers arise via the dominant pathway
Majority of cases (50-65%)
Seen in ADH, flat epithelial atypia, and low grade DCIS
Molecular pathways:
HER2 Positive cancer
20% of breast cancers
Most common subtype in Li-Fraumeni syndrome
Associated with amplification of HER2 gene (Chr17)
Seen in high grade DCIS - worse prognosis
Molecular pathways:
ER negative, HER2 negative = TRIPLE NEGATIVE
15% of all breast cancers
Most common subtype with BRCA1
Precursor lesion unknown
male breast cancer
Klinefelter’s, BRCA2 mutations
Associated with subareolar mass
Nucleus contains _____
highly condensed chromatin
Protamines
specialized basic histone tightly held together by disulfide bond cross-linking keeps chromatin compact
Shape of sperm head is species dependent
Acrosome
anterior ½ or ⅔ of sperm head
Thin, double-layered membrane sac
Contains hydrolytic enzymes, critical for fertilization
Tail of sperm
: contains 9 axoneme doublets arranged circumferentially around a pair of microtubules → doublets surrounded by mitochondrial sheath
→ sperm motility
Normal values of semen analysis:
- Volume
- Concentration
- Motility
- Morphology
Volume > 1.5 ml
Concentrations: > 15 x 10^6 /ml
Motility: > 32%
Morphology: 4% normal
Female evaluation of fertility
How many eggs are available:
- Blood tests: FSH, E2, AMH
- Ultrasound
Euploid embryos decrease with maternal age
Women have a peak number of oocytes when?
20 weeks gestation
Primary oocyte is arrested when?
Prophase I of meiosis I
Primary oocyte finishes 1st meiotic division when?
after LH surge → secondary oocyte + 1st polar body
Secondary oocyte → finishes meiosis II after ____
fertilization
Zona Pellucida
shell-like structure that surrounds oocytes
Glycoprotein sheet of Zona pellucida
70% protein, 20% hexose, 3% sialic acid, 2% sulfate
Composed of 3 glycoproteins: ZP1, ZP2, ZP3
Mutant/inactivated zone proteins → infertility
Fertilization:
process involving union of male and female germ cells that results in formation of a pronuclear zygote
9 steps of fertilization
1) Ovulation and collection of oocyte in oviduct
2) Deposition of sufficient # of sperm with normal form and motility
3) Sperm capacitation
4) Sperm traversal of cumulus oophorus
5) Sperm interaction with zona pellucida
6) Acrosome reaction
7) Sperm-oocyte plasma membrane fusion
8) Oocyte activation
9) Male pronuclei formation
Sperm capacitation
Process by which spermatozoa acquire capacity to undergo acrosome reaction and fertilize eggs
Acquired in distal genital tract of male
Sperm interaction with zona pellucida
Sperm binding to zona pellucida: ZP3 glycoprotein = sperm receptor
Acrosome reaction
(digest zona): occurs when outer membrane of acrosome region fuses with plasma membrane of sperm
Fusion of membranes → release of hyaluronidase and acrosin → complete fusion of sperm with oocyte
Sperm-oocyte plasma membrane fusion
Fertilin = protein responsible for sperm-oocyte fusion
Oocyte activation
Zona (cortical) reaction: occurs as soon as first sperm fuses
First sperm fuses → release cortical granules → form new glycoprotein ZP3-F which is incapable of binding sperm
Prevents polyspermy
Oocyte finishes meiosis
Male pronuclei formation
Protamines unwinds, disulfide bonds reduced by action of oocyte-derived glutathione
Sperm nuclei decondense
Forms male/female pronuclei
Preimplantation embryo development:
Day 1 = 2 cells, Day 2 = 2 → 4 cells, Day 3 = 4 → 8 cells
Day 4 = Morula stage
Day 5 = Blastocyst stage
Trophectoderm develops → will become placenta
Biopsied if looking for preimplantation genetic diagnosis
I
nner cell mass → becomes fetus
Implantation
attachment of fertilized egg to uterine lining - occurs 6-7 days after conception
Requires interaction between blastocyst outer trophectoderm layer and hormonally primed lining of uterine cavity
Most common sites of implantation:
Posterior wall in midsagittal plane
Blastocyst Hatching
g: process when blastocyst “escapes” from zona pellucide (day 6-7)
Once hatched, the trophectoderm can come into direct contact with endometrial epithelium
Unfertilized eggs do NOT hatch
Implantation fails if hatching does not take place
Decidualization:
process where by endometrial stromal cells, fibroblasts, are transformed into round decidual cells
Critical for trophoblast invasion and formation of placenta
Dependent on progesterone and cAMP → accumulation of glycogen and lipids, change in nature of ECM
Process begins in secretory phase of menstrual cycle (around day 23)
If implantation takes place, process expands and includes remaining stromal cells
Window of implantation
finite period of time that epithelium lining of uterus is prepared to accept implantation of blastocyst (day 20-24)
Small finger-like projection from apical surface of endometrial epithelium
Dependent on progesterone (secreted by corpus luteum - maintained by hCG produced by trophectoderm of blastocyst)
3 stages of implantation
- Apposition
- Adhesion
- Invasion
Appostion
loose, unstable connection between trophectoderm and endometrial lining - microvilli of trophoblast interdigitate with pinopodes
Adhesion
stronger connection, created by ligand-receptor interactions
Trophoblastic cells rapidly proliferate → syncytiotrophoblasts (outer) and cytotrophoblasts (inner)
Syncytiotrophoblasts → secrete TNF-a, proteases→ helps dislodge epithelial cells (down regulate cadherins and B-catenin) and invade through BM and endometrial stroma (decidua)
Molecules that facilitate adhesion
Integrins: cell surface receptors that bind ECM (laminin and fibronectin)
Heparan sulfate proteoglycans
L-selectin
Invasion
completely buries into endometrium, no longer in direct contact with uterine cavity (occurs by day 10)
→ Placentation process begins
Inner cell mass of blastocyst positioned on side of endometrium → first to invade
Placenta previa
implantation near cervix
Placenta accreta
implantation at site of a prior uterine sca
Ectopic pregnancies:
pregnancy outside uterine cavity
TX = methotrexate or surgery
Desirable attributes of screening tests
Screening advances time of diagnosis of cancers destined to cause trouble
Early treatment is superior to treatment started after patient already has symptoms
Compared to unscreened populations, screening ALWAYS increases survival even if death is not delayed by early detection. Why? (3)
Lead time: earlier diagnosis → patients appear to live longer
Length time bias: more likely to find slower growing tumors → better prognosis
Overdiagnosis bias: benign natural history → best prognosis
Sensitivity
SNOUT - high sensitivity → rule out
TP / TP + FN
Specificity
SPIN - high specificity → rule in
TN / TN + FP
As prevalence increases –> _______ false negatives, _______ PPV, and _______ NPV
*As prevalence increases → INCREASE FALSE NEGATIVES
Increase PPV, decrease NPV
As prevalence decreases –> _______ false negatives, _______ PPV, and _______ NPV
*As prevalence decreases → INCREASES FALSE POSITIVES
Decrease PPV, increase NPV
PPV and NPV formulas
PPV = TP/TP+FP
NPV = TN/TN+FN
Likelihood ratios
probability of a test result in person WITH disease/probability of same test result in person WITHOUT disease
Likelihood ratios
LR > 1 –> ?
LR < 1 –> ?
LR < 0.1 –> ?
LR > 10 –> ?
LR > 1 = disease more likely
LR < 1 = disease less likely
LR < 0.1 → rule OUT
LR > 10 → rule IN
Likelihood ratios formulas for LR- and LR+?
LR+ = sensitivity /(1-specificity)
LR- = (1-sensitivity) / specificity
Relative risk
chance of outcome in group of interest / chance of outcome in comparison group
How to calculate relative risk reduction?
1-RR = RRR (Relative risk reduction)
Absolute risk reduction (%)
difference in risk between groups
NNS or NNT (number needed to screen / treat)
formula?
what happens as prevalence increases?
NNS or NNT = 100/ARR
Development of placenta
1) Implantation
1) Implantation of BLASTOCYST occurs day 6-8 → TROPHOBLAST LAYER multiplies and differentiates into inner cytotrophoblast and outer syncytiotrophoblasts
Development of placenta
2) Chorionic Villi
Develop weeks 2-3 –> primary, secondary, and tertiary vili made up of syncytiotrophoblasts and cytotrophoblasts that invade maternal blood supply
Primary Villi
cytotrophoblast core surrounded by syncytiotrophoblast - develop in week 2
Secondary Villi
xtraembryonic mesoderm core surrounded by cytotrophoblast and syncytiotrophoblast - develop in week 3
Tertiary Villi
formation of arterio capillary network
Core of villous (fetal) capillaries surrounded by cytotrophoblasts and syncytiotrophoblasts
Syncytiotrophoblasts contact
blood, while cytotrophoblasts to the invading
Develop at end of week 3
Will become VILLOUS CHORION (fetal component of placenta)
Floating Villi
majority of placental mass
Site of nutrient and waste exchange
Anchoring Villi
attachment to uterus
Site for invasive cytotrophoblast development
Development of placenta:
3) Cytotrophoblast endovascular invasion
invade spiral arteries of uterus → modify lining so arterioles relax to become low resistance, high flow arteries
-Interstitial invasion and endovascular invasion
Interstitial invasion
cytotrophoblasts invade the entire endometrium and the first third of the myometrium
Endovascular invasion
cytotrophoblasts invade uterine spiral arterioles through superficial myometrial segments
Only termini of veins are breached
Amniotic fluid
Composed of ultrafiltrate of maternal plasma, fetal urine, and fetal lung secretions
Ranges from 250 ml at 16 weeks to 1 L at 32 weeks
Critical for lung development and proper MSK function
Causes of decreased amniotic fluid: oligohydramnios (4)
Rupture of membranes
Congenital anomalies (GU system)
Nephrotoxic drugs (ACEIs, NSAIDs)
Poor placental perfusion
Causes of increased amniotic fluid: polyhydramnios (2)
Congenital anomalies (neural tube defects, esophageal atresia)
Gestational diabetes
Function of placenta: (7)
1) Support growth and development of fetus
2) Transport
3) Respiratory
4) Endocrine
5) Immune system
6) Skin
7) Hepatic/Metabolism
Function of placenta:
Types of transport (3)
1 )Diffusion: concentration dependent
-Gases, H2O
2) Facilitated diffusion: driven by gradient + specific carrier
- Glucose
3) Active transport: Transport against gradient, requires energy
- Amino acids
Global impaired transport
can result in intrauterine growth restriction (IUGR)
Diffusion limited transport
Flow-limited transport
Flow-limited transport
cross the placenta rapidly
-Most affected by uterine blood flow (maternal BP, Aortic stenosis)
Diffusion limited transport
cross the placenta slowly
-Most affected by syncytiotrophoblast membrane
Function of placenta: Respiratory functions
fetal O2 dissociation curve shifted to left
- Decreased affinity for 2,3 DPG
- Increased pH
Function of placenta: Endocrine function - secretes what?
CRH, GnRH, TRH, SRIF, ACTH, hCG (human chorionic gonadotropin), hCT (human chorionic thyrotropin), hPL (human placental lactogen)
hCG (human chorionic gonadotropin)
One of earliest markers of pregnancy
Peaks around week 10, then declines
Maintains corpus luteum and progesterone production until week 8 when placenta makes enough progesterone
Regulates cytotrophoblast differentiation into syncytiotrophoblasts
*Elevated in pregnancies with trisomy 21
hPL (human placental lactogen)
produced by SCTB
Directs maternal system to shift to more fatty acid metabolism, making carbohydrates more available to fetus
Creates insulin resistance
Partly responsible for gestational diabetes
Placental growth hormone
Similar to pituitary growth hormone
Increases from 12 wks to term → gradually replaces pituitary GH
Controls maternal IGF-1 levels
Secretion regulated by glucose
Lower levels observed in IUGR
Trophoblasts secrete what?
what is the function of that?
Trophoblasts → secrete estrogen/progesterone at high levels
Progesterone suppresses uterine contractions, necessary for pregnancy maintenance
Estrogen production requires maternal-fetal-placental unit - baby has what mom doesn’t and vice versa
Placenta Immune function
Protective barrier → physical barrier to pathogens, Hofbauer cells in villous core
Transports maternal IgG to fetal circulation (receptor mediated endocytosis)
Fetal immune system makes IgM
IgM does NOT cross placenta
Clinical implications of maternal IgG crossing placenta? (4)
Isoimmunization/immune hydrops (IgG anti RH)
Flu vaccination in pregnancy → baby protected with flu IgG
Tdap vaccine in pregnancy → baby protected by IgG
Maternal autoimmune diseases → can cross placenta and affect the baby as well
Placenta function as skin?
temperature regulation (women feel warmer during pregnancy), and protective barrier to pathogens
Placental hepatic/metabolism function?
Produces glycogen, cholesterol, and fatty acids
Drug metabolism
Excretion of waste products
Dizygotic
“Fraternal”
2 ova fertilized by 2 sperm
Not genetically identical
70% of spontaneous twins, 95% of ART twins
Monozygotic
“Identical”
1 ovum fertilized by 1 sperm → fertilized oocyte divides
Genetically identical
30% of spontaneous twins
3-5/1000 births
Chorionicity types
1) Dichorionic/Diamniotic
2) Monochorionic diamniotic
3) Monochorionic, Monoamniotic
4) Monochorionic monoamniotic conjoined twins
Dichorionic, Diamniotic
2 cell stage → cell splits at morula stage (day 0-4)→ develops own trophoblast and inner cell mass → SEPARATE chorionic cavities, SEPARATE amnion, and SEPARATE placenta
**Cleavage at day 0-4
**Can be monozygotic or dizygotic
20-30% of monozygotic twins
Monochorionic diamniotic
2 cell stage →single morula → shared chorion, separate amnions = one placenta, but two separate sacs divided by an amnion
**Cleavage at day 4-8
**Can only be monozygotic - 70% of monozygotic twins
Monochorionic, Monoamniotic
2 cell stage → Morula → cell splits at day 8-12 → shared amnion and shared chorion = one chorion, one amnion, one placenta
ONLY monozygotic
Only 1% of monozygotic twins
Increased risk of having cord entanglement → high perinatal mortality
Monochorionic monoamniotic conjoined twins
2 cell stage → morula → cell splits after 13 days → end up with conjoined twins sharing one amnion, placenta, and chorion
How to determine chorionicity?
Di/Di → “Thick dividing membrane” + “twin peak” or “lambda” sign
Mono/Di → Thin dividing membrane + “T sign”
Mono/Mono → no dividing membrane
Complications with twins:
Miscarriage Hyperemesis (due to increased hCG) Increased risk of aneuploidy Prenatal screening tests less sensitive and diagnostic procedures more difficult Maternal anemia Gestational diabetes (increased hPL) Gestational hypertension / preeclampsia Intrauterine growth restriction Preterm birth (37 weeks = full term, average twin is 36 weeks) Cesarean delivery Postpartum hemorrhage Perinatal mortality increased
Twin-Twin Transfusion Syndrome (TTTS)
ONLY in monochorionic-diamniotic twins
15-20% of monochorionic-diamniotic twins have unbalanced flow through connected vessels (connection between artery/vein)
Classification based on US findings - intertwin weight discordance of 15-20% is diagnostic, or amniotic fluid difference
More severe → more risk of complications
Twin-Twin Transfusion Syndrome (TTTS) - what happens to the RECIPIENT TWIN
Recipient twin (receiving blood flow) → gets larger → increases urine production to reduce blood volume → large bladder on ultrasound, polyhydramnios
Twin-Twin Transfusion Syndrome (TTTS) - what happens to the DONOR TWIN
Donor twin (giving away blood) → gets smaller → reduces urine production to retain blood volume → oligohydramnios
Implications of TTTS:
Untreated TTTS prior to 24 weeks gestational age → mortality of one or both twins in 80-90% of cases
After death of one twin, other twin at increased risk for brain damage in ⅓ of cases
Severe TTTS prior to 16 weeks has dismal prognosis
Donor twin most likely to die from
decreased blood volume, oligohydramnios, small placental volume, not enough nutrients to support fetal growth
Recipient twin most likely to die from
too much blood volume → polyhydramnios, early delivery, fetal hydrops due to diffuse edema
Treatment of TTTS (3)
1) Reduction amniocentesis
2) Micro Septostomy
3) Laser ablation
Reduction amniocentesis
Removal of excess fluid from recipient twin sac using needle through mom’s abdomen
→ risk of early delivery
Micro Septostomy
create hole between babies’ sacs
Laser ablation
direct visualization of communicating vessels and ablation with laser
High complication rate, but better survival of babies
3 types of decidua
1) Decidua basalis
2) Decidua capsularis
3) Decidua parietalis
Decidua basalis
under the implanting embryo
Region of endometrium deep to developing embryo and superficial to underlying myometrium
Maternal component of placenta
Decidua capsularis
overlies embryo
Region of endometrium that covers the blastocyst, separating it from the uterine cavity
Decidua parietalis
covers remainder of uterine surface
Every portion of endometrium other than site of implantation
Oxygen diffuses from maternal → fetal circulation in this order: (4)
Maternal arterial blood within intervillous space →
Syncytiotrophoblastic layer →
cytotrophoblastic layer →
fetal endothelial cells of L umbilical vein
