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Ovarian pathology, uterine pathology, cervical pathology
Terms in this set (264)
Histology of ovary: 3 tissue types
Ovarian surface epithelium
Fibrous stroma and specialized sex cord cells
- theca cells
- granulosa cells
Germ cells (oocytes)
Non neoplastic causes of ovarian enlargement
functional: follicle cyst/corpus luteum cyst,
cortical stromal hyperplasia/hyperthecosis
Mullerian: endometriotic cyst
Vascular: massive ovarian edema, ovarian torsion
reproductive aged women, >2 cm, clear fluid, multiple cell layers - pre-ovulatory follicle
Corpus luteum cyst
repro aged women, hemorrhagic, yellow wall due to luteinized cells
post ovulatory follicle
5-10% of women
inappropriate gonadotropin secretion, chronic anovulation, hyperandrogenism, sclerocystic ovaries
can diagnose in absence of polycystic ovaries (???0
What do PCO look like?
multiple small follicular cysts
thickened superficial cortex
anovulation, obesity, hirsutism, increased risk of endometrial adenocarcinoma
Ovarian stromal hyperplasia/hyperthecosis
Uniform bilateral ovarian enlargement
may be associated with excess androgen or estrogen production
Endometriosis: where + sxs
Presence of endometrial glands outside uterine cavity
primarily found on teh pelvic peritoneum and ovaries
chronic pelvic pain, pain during intercourse, infertility
association with chronic hemorrhage, adhesions and inflammation resulting in complex ovarian mass
potential misclassification as malignant tumor on ultrasound
association with malignancy
Ovarian cancer is _th most common cancer in women
Ovarian tumors can originate from where?
surface (mullerian) epithelium - serous tumor, mucinous tumor, endometrioid tumor, clear cell, brenner, cystadenofibroma
stroma including "sex cords" - fibroma, granulosa theca, sertoli leydig cell tumor
germ cells - teratoma, dysgerminoma, endodermal sinus tumor, choriocarcinoma
Which type is most likely malig?
SURFACE EPITHELIAL CELLS - 90% malignant
which types are most common for:
<20 years, 20-50 years, >50 years?
<20 : germ cell
Tumors of mullerian epithelium
most common type of tumor (65-70%)
90% of ovarian cancers
occur in adults, rare in kids
calssified by predominant cell type and degree of malig of epithelial component
Epithelial stromal tumors
Serous - fallopian tube
mucinous - endocervical
endometrioid - proliferative endometrium
clear cell - hypersecretory endometrium
brenner tumor - transitional
squamous and mixed epithelial and undifferentiated types
What are the three potential types of ovarian epithelial tumors?
Benign - cystadenoma, cystadenofibroma
Borderline - tmors of low malignant potential
Malignant - cystadenocarcinoma/adenocarcinoma
ovarian borderline tumors:
with epithelial atypicality but without obvious stromal invasion
small risk for recurrence and death
warrant close observation
Serous tumors (ie serous cystadenoma)
Composed of tubal like epithelium
30% of all ovarian tumors
60% benign, 30% malignant, 10% borderline
In 20-50 year old ppl - benign and borderline
low grade/high grade carcinomas - different tumor types
What is a histological finding in serous carcinoma?
Serous carcinomas have a dualistic model. What is the difference b/t low grade and high grade serous carcinoma?
low grade: associated with serous borderline component
BRAF and KRAS mutations present
Not associated with BRCA germline mutations
Do not respond to conventional chemotherapy
HIgh grade: BRCA 1/2 mutations
association with tubal intraepithelial carcinoma
Mucinous tumor - is the seoncd most common type of epithelial tumor. What % are benign? what are they like?
80% benign, 10% borderline
may have hormonal manifestations, estrogenic or androgenic.
tend to produce larger cystic masses
What are the genetic characterisitics of mucinous tumors?
mucinous adenocarcinomas are derived from benign or borderline precursors
genetically distinct from serous carcinoma
K ras mutations - early event
p53 mutations are rare
gross appearance of mucinous ascites
operative and gross description
not a specific histological diagnosis
can be on appendix
10% of ovarian carcinomas
most diagnosed as stage I or II
Frequently associated with endometriosis
mutations in PTEN tumor suppressor gene
Clear cell adenocarcinoma
10% of all ovarian carcinomas
present with stage 1 or 2
poor prognosis as compared with other low stage carcinomas
associated with endometriosis
Clnical presentation of epithelial tumors
most pts are 40-65.
non specific abdominal pain or distension, GI or urinary tract complaints - fluid in abdominal cavity
progressive weakness, weight loss, cachexia
How to diagnose?
mass on pelvic exam
characterize by ultrasound or CT - solid or cystic
evaluation of biomarkers like Ca125, HE4
exploratory laparotomy with intraoperative evaluation and removal debulking
Risks and protective factors
higher risk: early menarche, late menopause, nulliparity
Protective: increasing parity and oral contraceptives
Surgically induced protective factors
hysterectomy, tubal ligation, bilateral salpingo-oophorectomy
Familial (hereditary) ovarian ca
BRCA 1 and 2
hereditary non polyposis colorectal cancer syndrome (HNPCC) = lynch syndrome
Germ cell tumors
Recapitulate embryogenesis and human development
solid and cystic tumors
occur in children and young adults
benign and malignant types
analogous to testicular tumors
Germ cell tumors are malig/benign/both?
endodermal sinus tumor (yolk sac tumor)
- secretes alpha fetoprotein, grows rapidly and aggressively. has schiller duval body.
mature cystic teratoma (dermoid cyst) - very common
Sex cord stromal tumors
recapitulate stroma of ovary, testis or both
usually solid and unilateral
occur at any age
may secrete steroid hormones
benign and low grade malignant tumors
types of sex cord stromal tumors
granulosa - theca cell tumors
fibroma and thecoma
sertoli leydig cell tumors
steroid cell tumors
sertoli cell dumors
Granulosa cell tumor has what histologically
call exner bodies, positive immunostain with inhibin,
solid mass, fibroblasts and collagen, associated with meig's syndrome
Sertoli leydig cell tumor
cystic and solid
virilization in young women
FIGO surgical staging system
stage 1 - limited to ovaries
stage 2 - one or both ovaries with pelvic extension
stage 3 - peritoneal disease and/or retroperitoneal lymph node involvement
stage 4 - distant metastases (parenchymal liver disease or malignant pleural effusion)
may be initial presentation
most commonly derived from tumors of mullerian origin
non mullerian sources: colorectal, stomach (krukenberg tumor), pancreas and biliary tract, breast
Uterus consists of these three parts:
lower uterine segment
all three can give rise to a tumor
what are the three histologic components of the cervix?
squamous, glandular, stromal
three histologic components of corpus
endometrial glands, endometrial stroma, myometrium
what is the purpose of squamous epithelium
generate flat scales to protect cervix
layers of normal cervical stratified squamous epithelium
cervical stroma, basal layer, parabasal layer, intermediate layer, superficial layer
what is purpose of endocervical glandular epithelim?
generate muus for facilitating sperm transport and protecting developing fetus
whats often the first step in exposing cervix to virus invasion/cervical squamous metaplasia?
cervical eversion - part of the cervix gets pushed outwards, not covered by squamous cells - just glandular.
normal endocervical mucinous glands look like what histologically?
columnar glandular epithelium on a single layer of reserve cells.
whats the problem with exposing glandular epithelium?
its alkaline. vagina is acidic. you start to get squamous metaplasia at squamo columnar junction to protect exposed cells.
whats the first histological change in squamous metaplasia?
proliferation of reserve cells. reserve cells are immature squamous cells.
on gross observation, it now looks like pale, opaque villi at SCJ
What is the cervical transformation zone? and why is it iportant?zone
junction b/t exocervix and endocervix
endocervical glandular epithelium is transformed to squamous epithelium by squamous metaplasia
immature squamous metaplastic epithelium susceptible to lo and hi risk HPV infection
Oncogenic HPV infection --> precursor squamous intraepithelial lesions --> cervical cancer
Two possible outcomes:
NO HPV infectino - mature squamous metaplasia. fine.
HPV infetion - all of the metaplastic cells are malignant
What are risk factors for CIN and invasive cervical carcinoma?
Multiple sex partners
early age at first coitus
high risk males
sex partner more than two years older
more than three lifetime partners
a new sex partner in last six months
illegal drug use in last 12 months
intercourse while imparied by alcohol
what are the two cancer outcomes of HPV infection?
invasive squamous carcinoma
Low risk HPV: types and characteristics
6, 11 --> episomal in cell nucleus (not integrated into dna). produces condyloma and low grade sil/cin
can see capsids chillin in nucleus
high risk HPV: types and characterisitics:
16, 18. Integated into pt dna --> high grade SIL/CIN
Whats the invasive cell cycle?
HPV infects basal cell of squamous epithelium
early protein syntehsis
episomal dna replication
latent infection or condyloma or low grade lsion
integration into cellular genome ((high risk types
inactivation of suppressor genes
high grade intraepithelial lesion
how does HPV spread?
condyloma/low grade lesion - dna synthesis - late capsid protein synthesis - assembly of viral particles - desquamation of squamous cells and trasmission of virus
cell growth cycle interrupted at what regulators?
p53 telomerate, pR, regulation of virus gene expression and replication at URR.
what might affected nuclei loook like?
hyperchromatic, large, irregular
Different ways to classify cervical cancer precursors: CIN system vs bethesda (SIL) system
CIN 1 - mild dysplasia
CIN 2 - moderate dysplasia
CIN 3 - severe dysplasia / CIS
LSIL: CIN 1
HSIL = CIN 2 and 3
What do CIN/SIL/LSIL/HSIL mean?
cervical intraepithelial neoplasia = squamous intraepithelial lesions
low grade SIL, high grade SIL
What do you see on low grade SILs?
white flat condyloma, koilocytes (histo) - look like fried eggs with large, bumpy nucleus
normal squamous nucleus and clear cytoplasm with glycogen in superficial squamous epithelium
What do you see with high grade SILs?
Heterogenous lesion, very dysplastic cells. Still see koilocytes. STRONG p16 reactivity
What do you se in carcinoma in situ?
high nucleocytoplasmic ration, coarse chromatin
bethesda grading of cell abnormalities
low grade SIL
High grade SIL
atypical squaous cells
invasive squamous carcinoma
atypcial glandular cells
endocervical adenocarcinoma in situ
degene hybrid capture II HPV assay
detects 15 hpv types
distinguishes b/t low risk and high risk
low: 6 11 42 43 44
high: 16, 18, 31, 33, 45, 51
Glandular tumors arising from endocervix
adenocarcinoma in situ (non invasive adenoca)
invasive adeno squamous carcinoma
WHat do the different numbers usually do? 6 16 18
6 - always produces squamous lesions
16 - produces squamous or glandular lesions
18 - most common serotype in glandular lesions including small cell neuroendocrine carcinoma(BAD)
Microinvasive cervical carcinoma
Invasion equal to or less than three mm in depth
less than 7 mm in width
no vascular space invasion
risk of lymph node metastases directly related to depth of stromal invasion
.3% if 3 mm or less
14% if 3.1-5 mm
how could you treat microinvasive carcinoma to retain fertility?
cold cone biopsy
cut open and ink margins
How to treat intraepithelial (SILs and CINs)
follow up smears
large loop wire excision
cold kinife cone biopsy
how to treat invasive cancer
radical hysterectomy and lymph node dissection or pelvic exenteration
What is the most common cause of dysfucntional uterine bleeding?
anovulatory cycles - failure to ovulate, loss of progestational effect. unopposed estrogen stimulation.
Inadequate luteal phase
corpus luteum forms but poorly performs with low progesterone output. common in infertility patients
endometrial biopsy shows lagging/wimpy secretory endometrium
what is most common cause of DUB in postmenopausal women?
on histology see linear strips of atrophic endometrium. BENIGN
Ovarian dysfunctional cysts do what?
produce hormones! corpus luteum cyst with luteinized cells makes progesterone
ovarian theca lutein cyst makes estrogen
Leiomyomas cause bleeding how?
stretch endothelium and make it likely to shed. tend to infarct at the tip, too. Benign.
Endometrial polyp can contain...
Endometrial hyperplasia... whats the deal?
overgrowth of glands and stroma. caused by:
hormone producing tumors (granulosa cell tumors)
In other words... excess estrogen!!!
with endometrial hyperplasia what might you see?
increased endometrial stripe
Types of endometrial hyperplasia
simple (cystic), NOT pre cancerous. no atypia
atypical endometrial hyperplasia
complex - 25-33% pre cancerous
whats tricky about atypical hyperplasia?
you can get get cancer mixed in and not be able to tell it apart.
Two types and populations of endometrial cancer
type 1: younger women with good prognosis
most estrogen related
low stage (little spread)
minimal to no myometrial invasion
type 2: older women with poor prognosis
no association with estrogen
bad histology (serous or clear cell)
often deeply invasive of myometrium
What are the three types of endometrial carcinoma?
endometrioid adenocarcinoma +/- squamous differentiation - low grade, looks like endometrium
serous (papillary) carcinoma - mimics ovarian cancer
clear cell carcinoma - clear cells, hobnail cells. Bad news bears.
how do you grade endometrioid adenocarcinoma?
grade 1 - well diff
>95% glands, 5% solid growth
Grade 2 - mod diff >50% glands
grade 3 poorly dif <50% glands
staging of endometrioid carcinoma
stage 1 - no invasion of cervix, confined to endometrium
stage 2 - endocervical canal invasion
Mixed types of endometrial cancer
carcino sarcoma, homologous type
carcinosarcoma, heterologous type (malignatn mixed mullerian tumor)
other combos of malignant endometrial glands and strooma
mixed glandular and stormal tumors - double whammys
What has worm like vessel invasion?
endometrial stormal sarcoma. loos like endometrium.
smooth muscle tumors
most common uterine tumor
prseent in 1/4 of repro aged women
estrogens influence but dont cause
submucosal, intramural, subserosal
location influences sxs
histologically, leiomyomas look...
pink, spindly, boring.
like leiomyomas but invasive and malignant and bad
downward extension of endometrium into myometrium
island of endometrium in myometrium stimulate the immediately surrounding myometrium to hypertrophy
hypertropied muscle surrounding endometrial islands tries to simulate a mini uterus WOAH
aggregate of all the islands and muscle produce a globular symmetrically enlarged uterus
most pediatric tumors are ..._. what are common types?
benign. Melanocytic nevi of skin, vasc lesions, hematologic malig (leukemia and lymphoma) and brain tumors
Small blue cell tumors: high nuclear to cytoplasmic ratio: name five blast tumors
neuroblastoma, nephroblastoma, retinoblastoma, medulloblastoma, lymphoblastic leukemia/lymphoma
Neuroblastoma and neuroblastic tumors are what? what behavior do they exhibit?
tumors of sympathetic ganglia and adrenal medulla (derived from primordial neural crest cells)
neuroblastoma is 2nd most common solid malignancy of childhood after brain tumors - 50%% of malignancies diagnosed in infancy
spontaneous regression and spontaneous or therapy induced maturation
most sporadic. may be familial (ALK and PHOX genes) or in syndromes (BWS)
What is the morphology of neuroblastomas? where do they arise? What do they look like grossly?
40% arise in adrenal medulla, remainder occur anywhere along sympathetic chain
commonly in paravertebral region of abdomen and posterior mediastinum
Macroscopically they are composed of soft, gray-tan, brainlike tissue. Lobulated. Larger tumors have areas of necrossis, cystic softening and hemorrhage
what happens to neurblastoma after chemo?
fibrosis and cacification if more prominent
Histology of neuroblastoma
Histologically, classic neuroblastomas are composed of small primitive appearing cells with dark nuclei, scant cytoplasm, poorly dfined cell borders
mitotic activity adn nuclear breakdown (karyorrhexis) and pleomorphism may be prominent. background may be eosinophillic
can see rosettes where tumor cells are arranged around neuropil (eosinophilic fibrillary material)
neuroendocrine markers like NSE, CHR, SYN stain the tumor cells positively
neurodifferentiation of cells make them look like gangionic cells - evidence of more mature neuroblast
prognosis of neuroblast
age <1 year very good. >1 year worse
MYC N amplification
MYC N amplification
normally present on ch 2, becomes amplified, seen either as extrachromosomal double minutes or as chromosomally integrated, homogenous staining region.
affects cell motility and cell cell adhesions, determines spread.
seen on FISH
Clinical presentation in kids under 2
protuberant abdomen, fever, weight loss
in older kids?
unnoticed until metastases cause hepatomegaly, ascited, bone pain
can neuroblasts metastasize?
yes. to hematog, lymphatic systems, liver, lungs, bones, bone marrow
in neonates, disseminated neurblastomas may present with multiple cutaneous metastases with deep blue discoloration to skin = blueberry muffin baby
if ppl present with movement disordrs think brain tumor
outcome is good in babies even with metastases
all stages in infants and low stage in older kids. good.
high stage over age 1 is bad.
90% of neuroblastomas produce catecholamines, except for pretty immature ones
ganglioneuroblastoma - intermixed
more ganglionic differentiation
Ganglioneuroma - grossly and histologically
myxoid and whorled appearance. schwannian stroma dominates - gangion cells are distributed in nests. BENIGN.
Wha tis a ganglioneuroblastoma?
composit tumor of neurblastoma and either ganglioneuroblastoma intermixed or ganglioneuroma
Retino blastoma: avg age at diagnosis? sporadic or familil?
60-70% sporadic. many familial as well. ave age is 24 months, but can be over 5 years as well.
germline mutations of _ predispose to bilateral retinoblastoma and pinealobastoma?
RB 1 -
RB 1 is instrumental in ell cycle. if its hypophosphorylated, then there is transcriptional block. if its hyperpphosphorylated, then there is transcriptional activation
CYclins D and E hyperphosphorylate it
whats the difference in the mutation process b/t the sporadic form and the familial form?
in sporadic - you get double hit only in retina
in family, you get all cells with one hit on RB1, and then one hit in retina
gross appearance of retino blastoma?
white, soft, calcifications may be present, white chalky look
Clinical diagnosis of retinoblast
patients often have white pupil (leukoria), strabismus, decreased visual acuity, glaucoma, red or painful eye
diag by optho exam
tumors invade optic nerve and grow towards brain or tumor cells may reach CSF by penetrating subarachnoid space around optic nerve
treat with chemotherapy, laser treatment, cryoplexy.
used to treat with enucleation.
most common childhood malignant extracranial solid tumor
imitates embryonic histology of kidney
components of tumor, blastema, has features of small blue cell tumors - high nuclear to cytoplasmic ratio
peak incidence for wilms tumor is b/t _ and _ years
2 and 5. can involve both kidneys in 10%, at same time or one after the other.
bilateral tumors have median age of onset 10 months. may involve germline mutation
cure rates are low
wilms tumor is associated with several syndromes. waht are they?
1. WAGR syndome, characterized by aniridia, genital anomalies, mental retardation (deletion of 11p13) --> wilms tumor associated gene WT1 and contiguously deleted autosomal dominant gene for aniridia PAX 6
2. Higher risk (90) for wilms is DENYS DRASH syndrome - gonadal dysgenesis in men, early onset nephroathy and renal failure
3. beckwith wiedemann syndrome
enlargement of body organs, macroglossia, hemihypertrophy, omphalocele, abnormal large cells in drenal cortex (adrenal cytomegaly)
ch 11p15.5 (WT2) distal to WT1 locus
4. beta catenin in wilms tumor, belongs to developmentally important WNT (wingless) signaling pathway
Gross appearance of wilms tumor
large, solitary, well circumscribed mass. 10% are bilateral or multicentric at time of diagnosis.
on cut section, tumor is soft, homogenous, tan to gray with occasional hemorrhage, cyst formation, necrosis
renal vein can bulge. extension into perirenal fat can occur.
histologic appearance of wilms tumor
attempts to recapitulte different stages of nephrogenesis
classic triphasic combination of blastemal, stromal, epithelial cell types observed in vast majority of lesions
can see pseudo capsule
anaplasia in wilms tumor. what % have anaplasia
5%. presence of cells with large, hyperchromatic, pleomorphic nuclei, abnormal mitoses.
correlates with presence of p53 mutations and resistance to chemotherapy.
what are nephrogenic rests?
precursor lesions of wilms tumors. seen near tumors, esp in bilateral tumors.
hyperplastic rests - expansile, look like wilms tumors
sclerotic rests - consist of fibrous tissue and admixed immature tubules or glomeruli
increased risk of developing tumor in contralateral kidney if its seen in one kidney!!!
are either perilobar, or intralobar
clinical presentation of wilms tumor
large abdominal mass, may be unilateral or extend across midline.
hematuria, pain in abdomen, intestinal obstruction, appearance of HTN.
many of them will have pulmonary metastases at time of diagnosis
prognosis of wilms
most can expect to be cured.
anaplastic histology remains a critical determinant of adverse prognosis
loss of genetic material on ch 11 and 16, gain of chromosome 1 in tumor cells
may develop secondary tumors, however.
tumor derived from primitive mesenchyme and tends to do myogenesis
largest ategory of soft tissue sarcomas in kids
Embryonal rhabdomyosarcoma: where and in whom?
usually in head and neck, or GU tract.
under age 10
5 year survival varies from 70-95% depending on type and stage.
histology of rhabdomyosarcoma
spindle cells and blue cell component
desmin (not specific, often seen in other tumors) and myogen
Alveolar RMS: where? who?
occurs in older age 7 and 9 years old.
PAX FKHR translocation
50-55% 5 year survival
in solid variant of it, classic appearance is absent. IHC is crucial for diagnosis.
second most common sarcoma of bone and soft tissue
80% in less than 20 year olds
more in men
usually in bone - diaphysis of long bones, also pelvis and ribs. mostly in lower limb and central axis.
clinical presentation of ewing's
pain, mass, fever, leukocytosis, elevated ESR (erythrocyte sedimentation rate)
radiologically - multilayered periosteal reaction (onion skin)
what are the genetics of ewing?
translocaiton involving EWS gene on ch 22, and gene encoding ETS family transcription factor
most commonly involved gene is FLI1 as part of 11 22 translocation.
fusion genes generated by these translocations produce chimeric transcription factors that alter the xpression of a network of target genes, results in abnormal cell proflieration
Treatment of ewings
treatment includes chemo and surgical excision with or without irradiation.
75% 5 year survival with chemo
but chemotherapy induced necrosis is bad prognostic finding
malignant mesenchymal tumor in which cancerous cells produce bone matrix
most common primary tumor of bone, exclusive of myeloma and lymphoma
most occur in people under 20 years old
more in men
metaphyseal region of long bones
genetics of osteogenic sarcoma
frequent mutations that interfere with function of two genes: RB1 and p53 - affects DNA repair.
if you have a RB germline mutation you have a 1000 fold increased risk of osteosarcoma
in what syndrome do you ahve a greatly elevated incidence of osteogenic sarcoma?
li fraumeni - germline p53 mutations
gross appearance of osteogenic sarcoma
big, bulky tumors, gritty, grey white, hemorrhage, cystic degeneration
histo of osteogenic sarcoma
tumor cells vary in size /shape. formation of bone matrix is lace like pattern.
clnical presentation of OS
painful, progressively enlarging mass
x ray of primary tumor shows large, destructive, mixed lytic and blastic
when tumor breaks through cortex and lifts periosteum --> reactive periosteal bone formation --> triangular shadow between cortex and raised ends of periosteum (codman triangle)
10-20% of affected individuals also have demonstrable _ metastases
pulmonary. 5 year survival is 20% with metastases but 60-70% without.
overall, what are not mentioned that are very common in kids
leukemia, lymphoma (hodgkin, burkitt)
GET EVEN MORE EXCITED
what does the term mean?
hydrops - water
dropsy - excessive accumulation of serous fluid in interstitial tissue or body cavities
in older pts would be called anasarca - "generalized dropsy"
What are potential causes?
cardiovasc, chromosomal, fetal anemia, twin gestation, infectin, malformations, tumors, metabolic disorders
Cardiovascular causes HF how?
requires lesions that cause high pressure in right ventricle and atrium (ie tricuspid atresia, pulmonary valve atresia or premature closure of DA or FO
high output failure - overlap with fetal anemia --> massive congestion
Chromosomal causes of HF
esp turner syndrome and trisomy 21
maybe also trisomy 18
turner fetus do have hydrops but also may have nuchal cystic hygroma (different disorder caused by abnormal lymphatic drainage)
in survivors this is cause of webbed neck
Immune caused HF - how does RH incompatibility cause HF?
Rh negative mother develops IgG antibodies to D antigen on fetal cells.
these antibodies cross placental barrier and hemolyze fetal RBC's
Firstborn is spared
Fetus develops hemolytic anemia
Seldom seen now due to appropriate RhIg administration (Rhogam)
Kleihauer Betke test does what?
FMH test. determines % fetal cells in maternal circulation
If maternal BV 5000 mL, 1% 50 mL, 300 mcg RhIG covers 30 mL fetal blood
If you have 90 mL fetal blood, give three ampules of RhIg
inability of newborn to conjugate bilirubin - marked increase in circulating unconjugated bilirubin
this injures brain, esp brain stem and basal ganglia
one of many causes of cerebral palsy
occurs in infants with bad jaundice
in HF, extramedullary hematopoiesis will be present in various organs, esp liver
less severe - only a small % develops clinical problems
babies usually not hydropic.
limited to O type mothers with A or B fetus in which IgG anti A or anti B antibodies cross placenta
Usual response is production of IgM antibodies, which dont cross palcenta, but sometimes igg can be produced even in a uniparous owman.
what do you see histo with abo incompat?
large number of spherocytes
alpha thalassemia: who do you worry about?
women of southeast asian extraction
four gene deletion occurs only in southeast asians. does not occur in fetuses of mediterraneoan or african heritage - they always have at least one alpha gene or each allele.
RESULTS IN BAD ANEMIA - b/c they make abnl hemoglobin, which gets destoryed
if person has hg of 75ish, they may just have iron deficiency anemia, if its more like 60-70 its probably thallesemia.
one or two gene deletions - Hb Bart's. a tetramer of y chains - in cord blood but otherwise diagnosed only with molecular technology
HbH disease - three gene deletions - more anemic. Hb H is a tetramer of B chains, occuring after birth with switch from y to B chains.
See losts of lysed RBC's
INfections that cuase HF?
affects preschoolers and mothers
in kids it causes fifth disease, erythema infectiosum
pregnant woman can transmit it to fetus
fever, cough, sore throat in mother.
single stranded DNA virus
infects rapidly dividing cell lineslike bone marrow erythroid progennitor cells, which is fine in healthy ppl
aplastic crises in sicklers and other chronic hemolytic disorders
nuclear inclusion seen in RBC precursors . In hydrops, inclusions seen in any organ in which circulating NRBC's are seen
most frequently seen in liver lung and heart with some in placenta
Major link of these things to hydrops
ANEMIA --> HEart FAILURE --> EDEMA
DIABETES IN PREGNANCY
Maybe youre not so excited anymore
abnl glucose tolerance is present in 3-10% of pregnancies
must think in terms of preexisting diabetes and gestational diabetes
Pre existing diabetes - what can type 1 cause?
type 1 or 2
type 1 with vascular disease can cause IUGR
likely to have retinal or renal complciations
what percent with diabetes in preg have preexisting diabetes?
so 90% have Gestational Diabetes
when is onset for GDM
latter portion of gestation
screen at 24-28 weeks
Screening test for GDM
50 grams of glucose orally when fasting
Glucose at 1 hr
if >130 do GTT
if >195, GTT will almost certainly be positive
GTT for GDM
100 g of glucose to fasting patient
Upper level of reference range
1 hour 180
2 hrs 155
3 hrs 140
GDM if any two values above reference
Diabetic embryopathy: when? risk factors?
during period of embryogenesis (3-8 weeks developmental age)
poor control with hyperglycemia
20 year history
Diabetic embryopathy raises the rate of _ by 4-8 x?
major birth defects
if HbA1c is <8.5 rate of defects is 3.4
if its over, rate is 22.4%
Glycosylated hemoglobin can be used for what?
its the addition of glucose or glucose phosphate moieties on favline on one or both beta chains
rate of glycosylation is proportional to glucose concentration
reference range is 4-6%
higher levels reflect poor control of DM
What happens in diabetic embryopathy to fetus?
caudal regression syndrome
neural tube defects, holoprosencephaly
What are other defects that can occur?
transposition of great arteries, caudal regression, sirenomelia
Spontaneous abortion -increased or decreased?
increased, but not if there is meticulous control
diabetic embryopathy and or early spontaneous abortions usually only due to preexisting diabetes
fetopathy can ocur with either preexisting or gestational diabetes
Diabetic fetopathy - cause?
maternal glucose readily crosses placenta, but insulin does not.
fetal pancreas respoods to hyperglycemia
growth stimulus effect of insulin
infant or fetus exceeds 90th percentile in weight
some restrict to weight >4000 grams
accompanied by visceromegaly, brain spared
brain liver weight ratio may be <2/1 (normal is 3/1)
placenta also large
maternal obesity anotehr factor
Cardiomyopathy - where in the heart?
hypertrophic CM involves both ventricles
may show asymmetrical septal hypertrophy with left ventricular outflow obstruction
resolves if infant survives
Fetal hypoxia in diabetes - maternal and fetal causes
maternal causes include vasculopathy, ketoacidosis, alteration in HbO2 dissociation curve
uteroplacental blood flow decreased due to hyperglycemia, ketoacidosis or preeclampsia
fetal causes include
hyperglycemia, hyperinsulinemia, ketonemia
infant is pletoric due to polycythemia
macrosomia predisposes to complciations
erb's palsy due to brachial plexus injury
infant becomes hypoglycemic secondary to hyperinsulinism
in low birth weight infant: <20
in full sized: <30 in first 48 hours then <40-50
what effets on pancreas and calcium with postnatal hypoglycemia
pancreas shows enlarged islets, islet cell hypertrophy, pleomorphism and hyperchromatism of B cell nuclei, eosinophils in and around islets
hypocalcemia, cause unknown
lung development and surfactant production delayed
eletive delivery requires testing for pulmonary maturity through 38.5 weeks
hyaline membrane disease and bronchopulmonary dysplasia
unexplained stillbirth in late gestation more common in diabetes. do close fetal monitoring.
PATHOLOGY OF BREAST
Oh look, youre still not excited.
Branching duct system from nipple
normal breast consists of...
lobules - circumscribed groups of small acini
supporting fibroadipose tissue
two layers of cells line ducts/lobules
luminal epithelial - secrete milk in terminal duct and lobule
basal myoepithelial - assist in milk ejection during lactation lactation
stages in breast development
prepuberty - large duct system ends in terminal ducts with minimal lobule formation
beginning of menarche
terminal ducts give rise to lobuules
stroma increases in volume
lobules become atrophic
Changes in breast in menstrual cycle
cell proliferation increases
number of acini per lobule increases
intralobular stroma becomes edematous
b/c of estrogen and rising progesterone
creates sense of fullness during premenstrual phase
breast in pregnancy
lobules increase in number and size
secretory vacuoles form
milk secretio inhibited by high levels of progesterone until after birth
main causes of clinic visits
pain, palpable mass, nipple discharge or skin changes, lumpiness or other
fine needle aspiration cytology
core needle biopsy
fibrocystic changes (FCC) is what?
exaggeration and distortion of cyclic breast changes
arises during repro period but may persist into menopause
may be associated with cyclic pain of breasts
most common breast mass in women under 50, must distinguish from cancer
what do FCC feel like/look like on mamm, gross?
density, nodularity, calcification on mamm
fibrosis and cysts on gross
Two types of FCC and their three subtypes (each)
- no ductal or lobular hyperplasia
ductal or lobular hyperplasia with or without atypia
fibrosis and cysts
proliferation ofsmall ductules or acini
calponin immunostain highlight two layers of cells
Atypical hyperplasia - two types
atypical ductal hyperplasia - intraductal cellular proliferation approaches ductal carcinoma in situ
atypical lobular hyperplasia - cellular proliferation approaches lobular carcinoma in situ
clinical significance of FCC
may mimic cancer
increases cancer risk
risk of breast cancer in FCC
firboris and cysts: no increased risk
hyperplasia and sclerosing adenosis 1.5-2 x risk
atypical hyperplasia - 4-5 xx risk
most common breast mass in women under age 35
Benign and does not have to be excised
discrete movable nodule 1-10 cm, easily shelled out. can be larger.
histologically - fibroadenoma
mixed fibroblastic stroma and ducts/glands.
Intraductal papilloma is the most common cause of...
bloody nipple discharge in women younger than 50
arises in lactiferous duct or sinus
small subareolar tumor
Histology of intraductal papilloma
delicate, branching papillae, connective tissue core, lined by two layers of cells
Breast carcinoma is _ cause of cancer death in women,
second cause of cancer death
most common cancer in adult women
most common breast massin women over 50
Major risk factors for breast cancer
prolonged estrogen exposure (sporadic cancer)
What does estrogen do?
stimulates production of growth factors mediated by ER (abundant ER in breast and uterus)
Metabolites of estrogen damage DNA and cause gene mutations (abundant enzymes in breast and uterus)
initiates, promotes, progresses carcinogenesis
Hereditary breast cancer in _ of patients.
family history of breast cancer in a first degree relative
increased risk if multiple relatives are affected before menopause
different genes involved in hereditary breast ca (six)
BRCA 1 and 2
CHEK 2 (dna repair and BRCA 1 activation)
Li fraumeni syndrome (p53)
cowden syndrome (PTEN)
Peutz Jegher syndrome (LKB1)
Amount to one third of hereditary breast cas
BRCA 1 and 2
Mutations seen in 25% of hereditary breast ca's
carriers of mutations is .1% in population
life time risk is 60-85% of getting breast ca
BRCA 1 and 2 are involved in what?
cell cycle checkpoint activation
Where are BRCA 1 and 2? Which must be mutated before cancer develops?
two copies of BRCA 1 - one on each ch 17
two BRCA 2 - one on each ch 13
both must be mutated before cancer evelops but one mutated copy is enough to be susceptible
so you could inherit one and have the other hit by a somatic mutation - if in ovary - ovarian ca if i n breast breast ca develops
other familial cancers happen bc of the _ model
polygenic model - mostly are many weakly penetrant genes that act in combination
spectrum of risk
Types of breast carcinomas (2)
non invasive (carcinoma in situ)
no invasion through basement membrane into surroudning stroma
does not metastasize
invasion through basement membrane into surroudnign stroma
has capacity to matastasize to distant sites
Ductal carcinoma in situ - whats it like? can you palpate it?
usually wont form a mass
detected by mammography
often associated with calcifications
froliferation of malignant cells within duct lumen
what are the two types of ductal carcinoma in situ?
comedo type: high nuclear grade, central necrosis, microcalcifications
noncomedo type: lower nuclear grade or absence of necrosis
what are the implications of ductal carcinoma in situ?
8-10 x risk for invasive cancer in same area
1/3 of patients will develop it
primary treatment - surgical removal of lesion, good prognosis
Lobular carcinoma in situ - what are the characteristics
incidental finding, does not form a mass
usually no calcifications
uniform, loosely cohesive neoplastic cells expand acini
what are the implications of lobular carcinoma in situr?
if not treated, one third develop invasive cancer, equal risk of cancer in either breast, one third of invasive cancer is lobular type,
is both risk factor and a precuror of breast cancer.
Paget's disease of the nipple
extension of cancer cells up to main ducts and contiguous skin of nipple
underlying invasive carcinoma likely
single or groups of cancer cells within epidermis
prognosis depends on associated underlying tumor
Invasive carcinoma- what is it like on examinatio?
painless mass in breast, oten fixed to surrounding tissue, not freely movable
painless enlarged axillary lymph node
Five types of invasive carcinoma
invasive ductal carcinoma (carc of no special type)
invasive lobular carcinoma - diffuse and may not form a distinct mass
tubular carcinoma - usually small and may be incidental finding - good prognosis
invasive ductal carcinoma (carcinoma of no special type"
abnormal density on mammography, hard palpable, irregular mass, infiltrates glands,
invasive lobular carcinoma
diffusely infiltrative, single cell file, targetoid around a duct
invasive ductal carcinoma vs invasive lobular carcinoma
lobular are more diffuse and dont form masses
multicentric and bilateral
in older women
hormone receptor positive
nests of cancer cells of low nuclear grade float in pools of mucin
who gets mucinous carcinoma? do they have hormone receptors? whats the prognosis?
slightly higher in brca 1
majority have hormone receptors
prognosis better than carcinoma of no special type
mimics fibroadenoma clinically
sheets of large tumor cells are admixed with lymphocytes
no irregular invasion at tumor border
what mutations are in medullary carcinoma?
13% of cancers in women with BRCA1 mutations
ER and PR --> not expressed
HER2/neu over expression --> not observed
lymph node metastasis is infrequent
better prognosis than carcinoma of no special type
Tubular carcinoma - characteristics
well formed tubules, infiltrating pattern, single layer of ductal cells, no myoepithelial cell layer
usually hormone receptor positive
low risk of lymph node metastasis
may not need chemo if small
Inflammatory carcinoma - whats going on? whats it look like?
red swollen breast
tumor cells in distended dermal lymphatics
advanced stage usually
why's it get all inflammatory up in there?
blockage of lymphatics by tumor cells
hickened skin around exaggerated hair follicles
peau dorange (orange peel
what does immunohistochemistry show?
status of ER, PR, HER2/neu response
oncogene located on ch 17
belongs to epidermal growth factor receptor family
gene expression microarray
identify potentiallylarge group of susceptible genes
simulataneously detect and quanitfy the expressor of large numbers of genes in any tumor
basal like, basal keratins
her 2 positive
overexpression of her2
Luminal type cacner and Her2 + and - forms
Luminal a - HER2 negative, hormone receptor +
- most common type of breast cancer
luminal b - hormone receprot positive, HER2 positive
younger women than in luminal A
worse prognosis than luminal A
Basal like cancer (triple negative)
high grade carcinomas with central scar/necrosis and basaloid cells, more likely in younger, overweight , af am women, worse prognosis than other types
HER2 over expressing cancers prognosis
high grade carcinoma, worse prognosis than hormone receptor positive cancers
cancer response to therapy
need ER regulated gene expression for the cancer to respond to estrogen antagonist (tamoxifen)
ER postiive cancers that lack ER regulated genes
fail to respond to tamoxifen
Signs of advanced breast carcinoma
adherent to pectoral muscles or deep fascia of chest wall
adherent to overlying skin
retraction or dimpling of skin of nipple
lymph nodes, distant sites
t/f distant metastases may occur 10-15 years after treatment
surgery chemotherapy radiation
radiation and chemotherapy effects on normal tissue
atrophy of lobules
radiation induced angiosarcoma in breast
spindle cells with hyperchromatic nuclei
angiosarcoma in breast
can occur many years post treatment, usually high grade/agressive
median survival is 1-3 years
treating breast disorders
mammography involves two views
mlo (medial lateral)
and CC (cranial caudal)
MLO shows you axillary lymph nodes
start screening when?
above forty. maybe above fifty?
reduces rate of death by 15 %
may not be that useful over the age of 70
continue if woman in good health and cwould be candidate for teratment. like if life expectancy is at least 10 years
BIRADS rating system 0-6
0 requires further imaging
3 probably benign 1-2% chance of it being cancer. 6 mo follow up
4 suspicious - 30% chance of cancer.
5 highly suspicious - 80% chance of cancer
6 biopsy proven cancer
when is digital better than film?
very dense breasts
premenopausal or perimenopausal women
differene b/t radical mastectomy and modified radical mastectomy
radical is rare now - take underlying muscles and all axillary nodes
modified - breast tissue and axillary levels 1 and 2
standard of care for early breast cancer
combine with radiation, survival rates equivalent to mastectomy
Lymph node staging used for...
to determine need for chemo, need for regional radiation
do axillary node dissection on...
ppl with positive nodes!
gatekeeper lymph node
identify it with either blue dye or radioisotope
if its negative, then axillary disseaction has <5% chance of harboring positive node
decrease in lymphedema
oncotype dx score
expression of 21 genes measured in tumor tissue from pts diagnosed
assay evaluates whether patient will reur and predicts benefit from chemo and hormonal therapy
Risk assessment models
Gail and CLaus
BRCA 1-2 risks
10-20% by age 40
33-50% by age 50
56-87% by 70
16-44% brca 1
10-20% brca 2
what clinical features suggest brca mutation?
multiple cases of premenopausal breast cancer
personal history of serous ovarian, primary peritoneal or fallopian tube cancer
breast and ovaran in same women
ahkenazi with premen breast and or ovarian cancer
male breast prostate or pancreatic cancer
family member positive for genetic mutation
triple negative breast cancer
DCIS at a oung age witha family history of breast cancer
test affected family member first if possible. if they are positive then test others
full sequencing and 5 brca 1 rearrangement panel - sens is 90%
BART expanded large rearrangement panel is offered to high risk families
ashkenazi jews - test for three founder mutations
protection against genetic discrimination in health insurance and employment
surveilance for BRCA mutation carriers
monthly self exams and 2-3 clinical exams annually at age 25
annual mammograms starting at 25
annual breast MRI beginning at age 25 - can find cancer missed by mammography. space mamm and mri by three months
MRI vs MMG
MRI more sensitive
MRI lower specificity - 2-3 x as many unnecessary diagnostic exams
decision b/t the two unclar
High risk defined as:
BRCA 1 or 2 positive
first degree relative with BRCA
lifetime risk of breast ca estimates at greatern than 20-25%
history of radiation to chest prior to age 30
li fraumeni syndrome, cowden's syndrome, bannayan riley ruvalcaba syndrome
tamoxifen use in high risk ppl without cancer...
45% reduction in bresat cancer.
good for brca 2, less for brca 1
how about raloxifene vs tamoxifen?
as effective in preventing primary invasive breast ca
less effective than tamoxifen in preventing non invasive breast ca
fewer thromboembolic events
fewer endometrial cancers
surveillance for ovarian ca
but data on effectiveness is iffy
what lowers ovarian cancer in ppl with brca?
OCPs for 3-6 years.
OCPs unlikely to increase breast ca if used under ten years
reduces ovarian ca risk, also lowers risk of breast ca
SO in conclusion
mammography is standard
MRI for high risk
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