Uterus and endometrium path Flashcards
a disorder that occurs in females and mainly affects the reproductive system. causes the vagina and uterus to be underdeveloped or absent. usually no periods. Primary amenorrhea. may also have abnormalities in other parts. kidneys may be abnormally formed or positioned. skeletal: . . vertebrae. may have hearing loss or heart defects
Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH)
what is the endometrium of the uterus composed of
glands and stroma
Describe the menstrual phase of the menstrual cycle
- days 1-5
- initiated when corpus luteum involutes if no fertilized egg
- progesterone drops –> functionalis layer degenerates/sheds
- bleeding into stroma (fibrin, RBC’s, inflammatory cells)
- stromal breakdown
- endometrial “stem cells” in basal layer regenerate after menses
Describe the proliferative (estrogenic) phase of the menstrual cycle
- Rapid growth of glands and stroma arising from deeper basalis layer –> new functionalis
- GLANDS ARE STRAIGHT, TUBULAR Structures
- lined by regular tall, psuedostratified columnar cells with basal nuclei
- NO MUCUS SECRETION OR VACUOLIZATION
- Stromal cells proliferating (releaseing growth factors)
- numberous mitotic figures in glands and stromal cells
- THIS PHASE CEASES AT OVULATION (day 14)
Describe the early secretory phase (progesterone or luteal phase)
- (day 16-17) marked by secretory SUBNUCLEAR vacuoles
- Most prominent during 3rd week of cycle when vacuoles become SUPRANUCLEAR
- glands dilate days 18-24
- glands are Tortuous and serrated or “SAW_TOOTHED”
Describe the late secretory phase of the menstrual cycle
- stromal changes
- PROMINENT SPIRAL ARTERIES
- increased ground substance and edema
- Stromal “PREDECIDUAL CHANGE” about day 23-24
- increase in stromal mitoses
- These changes spread over entire functionalis to day 28 and accompaenied by neutrophils and lymphocytes
- decidualized cells high in glycogen and lipid
what is the most common cause of abnormal uterine bleeding
hormonal disturbance that produce dysfunctional uterine bleeding
What is the most frequent cause of dysfunctional uterine bleeding
anovulation (failure to ovulate)
Anovulatory cycles result from subtle hormonal imbalances and are most common when?
at menarche and in the perimenopausal period
what are the less common causes of anovulation
- Endocrine disorders: thyroid, adrenal, pituitary disease
- Ovarian lesions: functioning ovarian tumor (granulosa cell tumors) or polycystic ovaries
- Generalized metabolic disturbances: obesity, malnutrition
Failure of ovulation results in what hormonally?
This causes what architectural changes?
excessive endometrial stimulation by estrogens that is UNOPPOSED by progesterone
-cystic dilation
pneumonic for classification of AUB
PALM (structural) COEIN (non structural)
- P: polyps
- A: Adenomyosis
- L: Leiomyoma
- M: Malignancy and hyperplasia
- C: coagulopathy
- O: ovulatory dysfunction
- E: endometrial
- I: iatrogenic
- N: not yet classified
how do you tell an endometrium from anovulation from those of a menstrual cycle
- lacks progesterone dependent morphologic features like glandular secretory changes and stromal pre-decidualization
- the source of progesterone, the corpus luteum does not develop without ovulation
- most commonly comprosed of psuedostratified glands that contains scattered mitotic figures
This term refers to a condition that manifests clinically as infertility associated with either increased bleeding or amenorrhea.
Inadequate Luteal phase
Inadequate luteal phase is believed to be caused by what
inadequate progesterone production during the post ovulatory period
what does an endometrial biopsy show in inadequate luteal phase
secretory endometrium with features that lag behind those expected for the estimated date
Acute endomtreitis is uncommon and limited to bacterial infections that arise when?
after delivery or miscarriage
What are the usual predisposing influences of acute endometritis
retained products of conception
What are the causative agents of acute endometritis
- group A hemolytic strep
- staph
The inflammatory response in acute endometritis is limited to where
stroma
Chronic endometritis occurs in association with what disorders
- PID
- Retained gestational tissue, postpartum or post abortion
- intrauterine contraceptive devices
- tuberculosis
The diagnosis of chronic endometritis rests on identification of what?
PLASMA CELLS in the stroma which are not seen in normal endometrium
some complaints of women with nonspecific (15% of cases with no apparent cause) chronic endometritis
- ABNORMAL BLEEDING
- pain
- discharge
- infertility
What may be the causative agent of chronic endometritis
chlamydia associated with both acute (neutrophils) and chronic (lymphocytes and plasma cells)
defined by the presence of “ectopic” endometrial tissue at a site outside the uterus
Endometriosis
The presence of endometrial tissue WITHIN the myometrium 2-3 mm below the basalis layer
Adenomyosis
sites of endometriosis in decreasing order of frequency
- OVARIES
- uterine ligaments
- rectovaginal septum
- Cul de sac (pouch of Douglas)
- pelvic peritoneum
- Large and small bowel and appendix
- mucosa of cervix, vagina, and fallopian tubes
- Laparotomy scars
what is the most likely theory on the cause of endometriosis
regurgitation theory - retrograde flow of menstrual endometrium through the fallopian tubes
Pathogenesis of endometriosis
- Release of proinflammatory and other factors (IL’s, VEGF, metalloproteinases etc)
- increased estrogen production by endometriotic stromal cells due to high levels of AROMATASE
- Epigenetic alterations increase response to estrogen and decrease response to progesterone
endometriosis is associated with increase in what type of cancer? . . genes involved
clear cell ovarian cancer
-PTEN and ARID1A
Symptoms of endometriosis
- bleeding PERIODICALLY produces red/blue to yellow/brown nodules on or beneath the mucosa or serosa (powder burn marks )
- depends on site of involvement
- pelvic pain
- Dysmenorrhea (“colicky”) or menometrorrhagia
- Infertility (30-40%)
- Dyspareunia (pain with intercourse)
- Painful defacation with rectal wall involvement
- Dysuria
When endometriosis is extensive what can it cause
-organizing hemorrhage can cause FIBROUS ADHESIONS between tubes, ovaries, and other structures
Explain a chocolate cyst
when an ovary in endometriosis becomes markedly distorted by large cystic masses filled with brown fluid from previous hemorrhage . . also called endometrioma
diagnosis of endometriosis is readily made when?
when both endometrial glands and stroma are present
Explain Atypical endometriosis
- likely a precursor to endometriosis-related ovarian carcinoma
- 2 morphological appearances
- one is cytologic atypia of epithelium lining endometriotic cyst without major architectural changes
- other is marked by glandular crowding due to excessive epithelial proliferation
symptoms of Adenomyosis
similar to endometriosis
endometrial polyps . . what 3 age groups
- Reproductive age
- Perimenopausal
- Postmenopausal
symptoms of endometrial polyps
- may be asymptomatic
- or abnormal bleeding
structural characteristics of endemetrial polyps
-sessile or pedunculated exophytic masses (can be small or large) single or multiple
Endometrial polyps have been observed in association with administration of what?
tamoxifen which is often used in therapy of breast cancer
Atrophic endometrial polyps mainly occur in who?
they represent what?
- postmenopausal women
- atrophic remnants of previously hyperplastic polyps
Endometrial polyps and malignancy?
can be malignant
This is an important cause of abnormal bleeding and a frequent precursor to the most common type of endometrial carcinoma
endometrial hyperplasia
defined as an increased proliferation of the endometrial glands relative to the stroma . . increased gland to stroma ratio
Endometrial hyperplasia
Endometrial hyperplasia is due to what
prolonged estrogenic stimulation of the endometrium
What conditions cause increased estrogen and therefore can cause endometrial hyperplasia
- Anovulation
- obesity (peripheral conversion of androgen to estrogens)
- menopause
- polycystic ovarian syndrome
- Functioning granulosa cell tumors of the ovary
- excessive ovarian cortical function
- Prolnged administration of estrogenic substances
Genetic associations with endometrial hyperplasia
- inactivation of PTEN tumor suppressor gene . . 20% of hyperplasias and 30-80% of endometrial cancer
- PTEN encodes a lipid phophatase . . negative regulator of PI3K/AKT
Explain what Cowden syndrome is
- multiple hamartoma syndrome
- germline PTEN mutation
- high incidence of endometrial and breast cancer
Loss of PTEN leads to overactivation of what
PI3K/AKT pathway
2 major WHO categories of endometrial hyperplasia
- Non atypical hyperplasia
- Atypical hyperplasia (endometrial intraepithalial hyperplasia-EIN)
each has different morphology and risk of progression to cancer
Cardinal feature of non atypical hyperplasia
increase in gland to stroma ratio
Describe non atypical hyperplasia
- Variation in size and shape (dilated glands)
- can be back to back glands but USUALLY INTERVENING STROMA REMAINS
- RARELY progress to cancer (1-3%)
- after menopause may become cystic atrophy
Describe Atypical hyperplasia or EIN
- COMPLEX PATTERNS of proliferating glands displaying NUCLEAR ATYPIA
- GLANDS BACK TO BACK AND BRANCHING
- loss of orientation of nuclei to basement membrane
- NUCLEAR CHROMATIN OPEN (vesicular)
- conspicuous NUCLEOLI
- overlap with well differentiated cancer (23-48% of biopsies for EIN will show cancer on hysterectomy)
How is atypical hyperplasia managed
hysterectomy or in young women who desire fertility, a trial of pregestin therapy and close follow up
what is the most common invasive cancer of the female genital tract
endometrial carcinoma
2 broad categories of endometrial carcinoma
Type I (most common) and type II
Peak age for endometrial carcinoma
55-65 (postmenopausal) . . uncommon under 40
what is an early sign of endometrial carcinoma
bleeding . . there is no screening test like cervical cancer
What is another term for type 1 endometrial carcinoma
endometroid carcinoma because most are well differentiated and mimic proliferative endometrial glands
Type I endometrial carcinom arise in a setting of what
endometrial hyperplasia
type I endometrial carcinoma is associated with what conditions
- obesity
- diabetes
- HTN
- infertility
- unopposed estrogen stimulation
what is the genetic hallmark for type I endometrial carcinoma
increased signaling through PI3K/AKT pathway
-may have multiple mutations that increase this
Main genetic mutations for type I endometrial carcinoma?
type II?
- PTEN
- TP53
Age: type I endometrial carcinoma?
type II
- 55-65
- 65-75
Clinical setting: type I endometrial carcinoma?
type II?
- unopposed estrogen, obesity, HTN, diabetes
- atrophy, thin physicque
Morphology: type I endometrial carcinoma?
type II?
- Endometroid
- Serous, clear cell, mixed mullerian
Precursor: type I endometrial carcinoma?
type II?
- hyperplasia
- Serous endometrial intraepithelial carcinoma
Behavior: type I endometrial carcinoma?
type II?
- Indolent, spreads via lymphatics
- Aggressive, intraperitoneal and lymphatic spread
Grading of type I endometrial carcinoma
Based on GLANDULAR differentiation
Grade 1: well differentiated
Grade 2: moderately
Grade 3: poorly
pathologic staging of both types of endometrial carcinomas
Stage I: confined to corpus uteri itself
Stage II: involves corpus and the cervix
Stage III: extends outside the uterus but not outside the true pelvis
Stage IV: outside true pelvis or involves the mucosa of bladder or rectum
Describe the grading for type II (serous) endometrial carcinoma
by definitions poorly differentiated so grade 3
what ethnicity gets type II serous endometrial carcinoma more often
African american
The poorer prognosis of type II serous endometrial carcinoma is thought to be a consequence of what?
a propensity to exfoliate, travel through the fallopian tubes, and implant on peritoneal surfaces like their ovarian counterparts . . they have often spread outside of the uterus at the time of diagnosis
Morphology box of type I endometrial carcinoma
- localized polypoid tumor or DIFFUSE INFILTRATION of the endometrial lining
- spread by invasion of myometrium with direct extension to surrounding organs/structures
- eventual lymph node dissemination
Symptoms for endometrial carcinoma
usually produces irregular or postmenopausal vaginal bleeding with excessive leukorrhea
Survivial and prognosis of endometrial carcinoma depends on what?
clinical stage at diagnosis
treatment for endometrial carcinoma
surgery +/- radiation
5 year survival rate for stage 1 (grade 1 and 2) endometrial carcinoma?
stage 1 grade 3?
stage II and III?
- 90%
- 75%
- 50% or less
morphology of type II serous endometrial carcinoma
- Large bulky tumor that deeply infiltrates myometrium and arises in small atrophic uterus
- propensity for extrauterine spread via lymphatics or tumes
5 year survival for type II serous endometrial carcinoma
18-27% even when confined to the uterus
mortality for type II endometrial carcinoma is 2x greater in who
African American women
recurrence rate for type II serous endometrial carcinoma
80%
Treatment for type II serous endometrial carcinoma
- surgery, radiation, chemo
- PI3K inhibitor clinical trials
endometrial adenocarcinomas with a malignant mesenchymal component
Malignant mixed mullerian tumors (MMMTs)
What is another name for MMMTs
carcinosarcomas
genetic mutations for MMMTs (carcinosarcomas)
similar to endometrial carcinomas
- TP53
- PTEN
- PIK3CA
presentation of MMMTs (carcinosarcomas)
postmenopausal women with bleeding
the outcome of MMMTs (carcinosarcomas) depends on what?
depth of invasion and stage
-only other prognostic factor is the differentiation of the mesenchymal component . . . Heterologous elements=worse outcome
Morphology box for MMMTs (carcinosarcomas)
- often bulky and polypoid and may protrude through cervical os
- adenocarcinoma mixed with malignant mesenchyme
The metastasis of MMMTs usually contains what?
only the epithelial component
What are the 2 types of endometrial stromal tumors (only 5% of endometrial cancers)
- Adenosarcoma
- pure stromal tumor
The diagnosis of Adenosarcoma is based on presence of what
malignant appearing stroma with benign but abnormally shaped endometrial glands
Adenosarcoma presents most commonly as what
large broad based endometrial polypoid growths that may prolapse through the cervical os
Adenosarcomas predominate in who
women b/t the fourth and fifth decades and are generally considers low grade
recurrences and adenosarcomas
1/4 of cases and nearly always confined to the pelvis
How do you distinguish adenosarcoma from a large benign polyp
adenosarcoma is estrogen sensitive and responds to oophorectomy
Endometrial stromal neoplasms are divided into what two categories
- benign
- endometrial stromal sarcomas . . further divided into low and high grade
chromosomal translocation for low grade stromal sarcomas
JAZF1-SUZ12
Benign smooth muscle neoplasm of the myometrium that perhaps may be the most common tumor in women
Uterine leiomyoma
what is another name for uterine leiomyoma
fibroids
what are the 2 tumors of the myometrium
- leiomyoma
- leiomyosarcoma
leiomyoma and karotyping
40% are abnormal
chromosome rearrangement for leiomyomas
HMGIC and HMHIY (chromosomes 12q14p and 6p
What mutation is found in 70% of uterine leiomyomas
MED12 . . component of Mediator which allows cells to divide in an uncontrolled way
Gross features of Leiomyoma
- sharply circumscribed
- single or multiple
- small or large
- Firm grey-white masses
- subserosal, myometrial (intramural), submucosal
- Rarely involves uterine ligaments, LUS, or cervix
microscopic features of leiomyoma
- bundles of smooth muscle cells (WHORLED APPEARANCE)
- uniform in size and shape, oval nucleus, long bipolar processes
- RARE mitosis
- can degenerate
Clinical presentation of leiomyoma
- may be asymptomatic
- abnormal bleeding
- urinary frequency due to compression of bladder
- sudden pain from infarction of a large pedunculated tumor
- impaired fertility
Describe leiomyomas in pregnancy
- increase in spontaneous abortion
- fetal malpresentation
- uterine inertia (failure to contract with sufficient force)
- postpartum hemorrhage
Age for leiomyosarcoma
uncommon but peak at 40-60
Leiomyosarcoma arise from what
stromal precursor cell (de novo)
karyotypes in leiomyosarcoma
complex that include deletions (also the MED12)
recurrence and leiomyosarcoma
common
metastasis and leiomyosarcoma
more than 1/2
Gross features of leiomyosarcomas
2 patterns
- bulky fleshy invasive masses
- polypoid intraluminal masses
key microscopic features of leiomyosarcoma
- nuclear atypia
- Mitotic index of 10 per 10 hpf = malignancy
- zonal necrosis
explain the high power field mitosis requirement for malignancy in lieomyosarcoma with nuclear atypyia or “epithelioid” cells
if 5 mitosis per 10 hpf then malignant
Describe the spead of leiomyosarcoma
- local to abdominal cavity
- distant to lung
5 year survival for leiomyosarcoma
- 40%
- high grade only 10-15%
