Pathology of uterine corpus:

Endometrium
mucosal lining of uterine cavity
hormonally sensitive
Estrogen --> proliferation
progesterone --> preparation for implantation (secretory phase)
loss of progesterone --> menses
Myometrium
smooth muscle

proliferative secretory


http://missinglink.ucsf.edu/lm/IDS_107_Cervix_Ovary_Uterus/homepage.htm

Asherman syndrome:
secondary amenorrhea due to loss of basalis + scarring
secondary of overaggressive D+C

Abnormal Uterine Bleeding: Anovulatory cycle


polymenorrhea: bleeding occurs in intervals <21 days
menorrhagia: prolonged >7 days)/ excessive (>80mL) bleeding - at regular intervas
oligomenorrhea: > 35 day cycle
Metorrhagia: frequent / irregular intervals
Menometrorrhagia: prolonged/excessive, frequent, irregular
dysfunctional uterine bleeding: anovulatory vs ovulatory

excessive / prolonged estrogen stimulation WITHOUT counteractive effect of progestational phase
Estrogen -- builds up endometrium
built up endometrium (due to E) will breakdown/shed --> irregular bleeding
progesterone -- stabilize endometrium (withdrawal of progesterone --> menses)
most common in menarche + perimenopausal women
Causes:
usually subtle hormone imbalance - no obvious cause
endocrine: thyroid, adrenal, pituitary disorders
functioning ovarian tumor or polycystic ovaries
metabolic disturbance --- obesity
Histology:
proliferative glands - secondary to estrogen exposure
no secretory changes
breakdown of stroma (stromal condensation) when estrogen levels diminish
estrogen withdrawal
glandular + stromal breakdown


Changes induced by exogenous progesterone
seen in women on OCP + in women attempting to control bleeding
undeveloped glands with stromal cells showing enlargement + abundant
eosinophilic cytoplasm (Decidualized stroma)

enlarged stromal cells with more abundant pink cytoplasm (Decidualized)
with inactive glands



Chronic endometritis:

may cause pelvic pain, infertility, bleeding
May be due to:
retained products of conception
retained IUDs
previous instrumentation
chronic PID
often cause unknown
Histology
**plasma cells**
Rx: AB







Endometrial polyps:

proliferation of endometrial glands + stroma
benign -- may contain hyperplasia or carcinoma
increased in patients taking tamoxifen
tomaxifen:
antiestrogenic effect on the breast but a weak pro-estrogenic effect on the
endometrium


Endometriosis

https://secure.health.utas.edu.au/intranet/cds/pathprac/Files/Cases/Female/Case58/Case58.htm
presence of endometrial glands or stroma in abnormal extra-uterine locations
reproductive age F (10%)
symptoms:
infertility - 30-40%
scarring increases risk of ectopic (fallopian tube mucosa)
dysmenorrhea (painful menstruation)
cycles with the normal endometrium
Pain:
pelvic pain: uterine ligament
pain w/ urination: bladder wall
pain w/ defecation: pouch of douglas
Sites of involvement:
ovaries, uterine ligaments, rectovaginal septum, cul de sac, pelvic peritoneum, GI, cervix,
vagina. fallopian tubes, laparotomy scars

Theories for development:
Metastatic theory:
retrograde menstruation through the fallopian tubes
arises directly from the coelomic epithelium
mesothelium of pelvis or abdomen

Gross:
white, tan nodule in
cul-de-sac,
rectovaginal space,
peritoneum
ovary bleeding =
chocolate cyst


Complications:
scarring --> infertility
malignancy can develop
ovary and gynecologic tract
rare cases in the intestine


Adenomyosis:

endometrial glands and stroma in the myometrium
20% of uteri removed
symptom = pelvic pain


Endometrial carcinoma
most common invasive cancer of the female genital tract in US
post-menopausal (55-65)
presents as post-menopausal bleeding (must do an endometrial biopsy)
endometrial biopsy & curettage
two types
type I: hyperplasia
type II: sporadic pathway


preneoplastic / neoplastic lesions
precursor
simple hyperplasia
complex hyperplasia
simple atypical hyperplasia (rare)
complex atypical hyperplasia
alternative endometrial intraepithelial neoplasia (EIN) for precursor lesions
Endometrial carcinoma
type I/II carcinoma

Type 1 -75% type 2
increase in the gland: stroma ratio
associated with prolonged estrogen
stimulation of the endometrium
obesity
late menopause
polycytic ovarian disease
functioning ovarian tumors
prolonged estrogen administration
Genetic alterations:
inactivation of the PTEN (TSG)





Histologic types:
serous:

high cytologic atypia/ mitosis/
papillary
clear cells

carcinosarcoma (malignant mixed
mullerian tumor - MMMT)

http://www.webpathology.com/image.asp?n=15&Case=56
9

combined sarcoma
cartilage / bone/
rhabdomyoblasts
+ carcinoma (metaplastic)
aggressive 5yr 25-30% survival
F > 60
high grade
generally > aggressive than type 1
55-65 65-75
unopposed estrogen
obesity
HTN
DM
atrophy
thin
endometriod morphology serous, clear cell, carcinosarcoma, MMMT
hyperplasia endometrial intraepithelial carcinoma (rare)
PTEN, PIK3CA, KRAS, MSI, B-catenin P53, aneuploidy, PIK3CA
less aggressive -- spread via lymphatics aggressive -- intraperitoneal / lymphatic spread
incidence = 85% incidence = 15%

Histologic grade:
grade 1: well differentiated (< 5% solid)
grade 2: moderately differentiated (5-50% solid)
grade 3: poorly differentiated (>50% solid)

Prognosis:
most are stage 1 (confined to the uterus) > 90% survival
grade III - stage I ~75% 5yr survival
survival drops to 50% for stage II/III






Mesenchymal tumors- uterus

smooth muscle tumor endometrial stromal tumor
leiomyoma
leiomyosarcoma
endometrial stromal nodule
endometrial stromal sarcoma



Leiomyoma - fibroid



very common (increased incidence in AA)
75% are reproductive age F
Symptoms:
abnormal bleeding / urinary fq
fq cause of spontaneous abortion + infertility
Malignant change = very rare
not regarded as a precursor to leiomyosarcoma
Rx:
myomectomy
hysterectomy
uterine artery embolization
GnRH agonists: continuous stimulation = inhibitory --> hypoestrogen state
used to shrink fibroid prior to Sx
Pathology

well circumscribed, white, tan, firm mass
size: range - microscopic --> 20 cm
often multiple
enlarged during pregnancy / shrink post menopause (E sensitive)
location:
intramural
submucosal
subserosal
+/- broad ligamanet / cervix
Histology:
smooth muscle cells
no significant cytologic atypia - few/no mitoses


leiomyosarcoma:

malignant smooth muscle tumor
peak incidence 40-60
aggressive malignancy with frequent lung mets
gross:
bulky, fleshy mass, not well circumscribed, hemorrhage
Histologic criteria:
mitotic activity
cytology (nuclear) atypia
necrosis/hemorrhage


Gestational + Placental disorders
spontaneous abortions
ectopic pregnancy
abnormalities in placental implantation
placent previa
placental accreta/incretia/percretia
placental infections
pre-eclampsia / eclampsia
gestational trophoblastic disease









Ectopic Pregnancy:

implantation of the products of gestation in any site outside the normal intrauterine location
occurrence:
1/150 pregnancies
symptoms
severe abdominal pain about 6 wks after last menstrual period
Predisposing conditions:
prior peritubal scarring(chronic salpingitis)
adhesions (appendicitis, endometriosis, prior surgery)
location
fallopian tube (90%)
abdominal cavity, intrauterine portion of the fallopian tube, ovary (rare)
histologic:
chorionic villi + trophoblastic cells
may see only trophoblastic cells only











abnormalities in placental implantation:


Placental previa Placenta Accreta placenta increta
placental implants in the lower uterine
segment or cervix and may result in
bleeding

3rd trimester painless
bleeding
often requires C-section
partial or complete absence of decidua
with adherence of the placental villous
tissue directly to the myometrium

failure of the placenta to separate from
the myometrium is a cause of
postpartum bleeding (life-threatening)

often rq hysterectomy
placenta dissecting
through the
myometrium



Placental infections:


bacterial:
acute chorioamnionitis + acute villitis
opaque membrane (normal = translucent)
acute inflammation in the chorionic membrane extending --> amnion

TORCH + syphilis + TB + rubella + CMV + HSV --> chronic villitis


Gestational trophoblastic disease:
tumor/ tumor-like conditions characterized by a proliferation of placental tissue
hydatiform mole: complete/ partial / invasive
choriocarcinoma
placental site trophoblastic tumor

Hydatidiform Molar Pregnancies

US incidence is 1 / 1000 2000 pregnancies.
7-10 times higher in Asia than in North America and Europe.
Patients with > four pregnancies and increased number of abortions are at high risk
>50% are complete moles.
25-43% partial moles.


complete partial
genetics empty ovum + 2 sperm (46) normal ovum + 2 sperm (69)
fetal tissue none present
villous edema most some
trophoblastic proliferation diffuse, circumfrential
proliferation around hydrophic
villi
focal proliferation around
hydrophic villi
choriocarcinoma risk 2-3% minimal

Clinical symptoms:
Uterus larger than expected for date of gestation
passage of grape-like masses
High HCG level that expected for date of gestation
Often diagnosed in the first trimester today
Fetal heart sounds absent
Snow storm appearance on ultrasound

Complete Mole


Histologic Features
Enlarged and dilated villi with central cistern formation (cavitations)
Circumferential trophoblastic proliferation
atypia
Early complete mole can be a diagnostic challenge as the proliferation is not as well
developed

Partial mole

karyotype: triploid 69, XXY or tetraploid 92, XXXY
+/- fetal parts
some villi are edematous
trophoblastic proliferation - not as marked as that of a complete mole
Rx:
D&C + BHCG monitoring
Px: molar pregnancies have ~10% chance of persistent moles/invasive mole
complete molar pregnancies have 2.5% risk of subsequent choriocarcinoma
***note:
choriocarcinomas arising from gestational pathway - respond to chemo
ones that arise from germ cell pathway do not!
partial moles
increased risk of persistent molar disease/minimal risk of subsequent choriocarcinoma







post ovulation: corpus luteum secretes progesterone --> prepares endometrium for possible implantation
(secretory phase)





PCOS: (Stein-leventhal syndrome)

3-6% reproductive aged F
obese young infertile
oligomenorrhea
hirsutism
+/- DM (insulin R)
numerous cystic follicles
oligomenorrhea
persistent anovulation, hirsutism, obseity
Pathophys: unclear
increased secretion of LH --> excessive androgen production (theca cells) --(Aromatase)->
estrone
estrone negative feedback on FSH --> cystic degeneration of follicles
high estrone levels --> risk of endometrial carcinoma
LH:FSH > 2


Ovarian cancer:

3% of all cancers US- F
1/70 american women lifetime incidence
risk increases with age
3/100,000 F <30
54/100,000 F 75-79
rates higher in developed countries
pariety + OCP = protective
more deaths than cervical/endometrial cancer
clinical:
abdominal distention, ascites, pan
complications --> rupture / torsion
urinary or GI symptoms
No well-validated screening
Genetic risk factors:
About 5-10% patients have a first degree relative with ovarian cancer
Compared to a 1-2% risk for the general population
women who have relative with ovarian cancer have a 9.4% risk
Women who inherit the BRCA1 or BRCA2 have a 15-40% absolute risk
estimated risk by age 70 -- 20-60%
BRCA still explain < 1/3 familial ovarian cancers
Usually serous carcinoma and display p53 dysregulation.
Histologic classification of primary ovarian surface epithelial tumors / site of origin
serous: fallopian tube / surface epithelial lining
cystadenoma/adenofibroma 70%
borderline 10%
CA 20-25%
endometrioid: endometriosis
clear cell: endometriosis
mucinous: unclear primary
About 10-15% of ovarian tumors; May be combined with other types
tumors (serous tumor), teratoma, sex cord stromal tumors.
Mean age 51-54
transitional (Urothelial) - possible walthard nests

benign - cystadenoma

single cyst w/ simple
flat lining (30-40)
borderline: low malignant potential,
atypical proliferating
*proliferation - no stromal invasion*
malignant:
stromal invasion
serous - 70% Serous Borderline Tumor - 15%

Histology: Proliferation of epithelial
cells, but no invasion
Synonyms:
Serous borderline tumor (SBT)
Serous tumor of low malignant
potential (SLMP)
Atypical proliferating serous tumor
(APST)

low metastatic potential if
confined to the ovary, may progress
over many years

Serous Carcinoma: 5%
40-50% of all ovarian malignancies
Mean age 56 (45-65)
67% Bilateral
Stage distribution:
I: 14% confined to the ovary
II: 7% confined to the pelvis
III: 63% in the peritoneum
IV: 16% distant metastasis

Size-microscopic to over 20 cm
Solid and cystic confluent areas

BRCA1: increased risk serous
carcinoma ovary/fallopian tube

Microscopic

Destructive stromal invasion

Mucinous
cystadenoma 80%

benign: 2-5% bilat
largest ovarian tumors
multi/uni-cystic

single layer of
columnar cells w/ lots
of intracellular mucin
(endocervical or GI)
Mucinous borderline 15%
increases epithelial
proliferation w/o destructive
stromal invasion

Mucinous Carcinoma 5-10%

5% present stage II+
5% bilateral
gross: large tumors
(15-30cm), multiloculated
cysts w/ mucin
hemorrhage, necrosis, solid
+/- papillary areas
http://www.webpathology.com/image.asp?n=14&Case=526

Ovary: Endometrioid Carcinoma

Often (15%-20% of cases) co-exist with endometriosis.
Frequent mutations in the PTEN tumor suppressor gene and in the KRAS and -catenin
oncogenes.
40% are bilateral.
About 15%-30% are accompanied by a synchronous carcinoma in the endometrium
Microscopic:
Resemble endometrioid carcinoma of the uterine corpus
glands and nests of cells invading the ovarian stroma
Grade identical to endometrial carcinoma
May find adjacent endometriosis

Clear Cell Tumors of the Ovary

Benign and borderline variants are rare, most are carcinomas
Similar histology to clear cell carcinomas of the endometrium
clear cytoplasm
Frequently arise in endometriosis
Frequently admixed with endometrioid carcinomas



Transitional Cell Tumors


Epithelial elements histologically resembling urothelium
May arise from benign Walthards Nests

Vast Majority are benign Brenner tumor
uncommon borderline and malignant Brenner tumors
Benign Brenner Tumor

Common incidental finding (microscopic size to several cm) about 4-5% of all benign ovarian
tumors.
7-8% Bilateral
Microscopically:
Mature urothelial-like cells arranged in solid or cystic within a fibromatous stroma
Associations:
mucinous cystic tumors
serous cystadenoma
dermoid cyst



Metastatic Tumors to the Ovary
~5% of ovarian tumors
Non-ovarian primary may present after ovarian met
Metastatic mucinous carcinomas are more common than primary ovarian mucinous carcinomas
Krukenburg tumor
metastatic mucin-produing signet-ring cell carcinoma
typically gastric origin


Common tumors metastasizing --> ovary
GYN tract: Tube, endometrium, cervix.
GI tract: Colon, appendix, stomach, pancreas,
hepatobilliary tree.
Breast.
Lung.
Melanoma.
GU tract: Bladder and kidney.
Sarcoma.


Pseudomyxoma Peritonei

Clinical term indicating the presence of mucinous material in the peritoneum (jelly belly)
surrounded by fibrous tissue.
almost all are metastatic tumors rather than primary tumors (GI tract, appendix)
Generally regarded as malignant, but may have a protracted clinical course.



Germ Cell Tumors
Teratoma, seminoma, yolk sac, choriocarcinoma, embryonal, mixed type

mature cystic teratomas:

46 xx -- usually reproductive years (but seen all ages 2-80)
27-40% of all ovarian tumors
58% of all benign tumors (almost all benign)
most form a mass
Variety of cells from all three germ cell layers: endoderm, mesoderm, ectoderm.
Skin and sebaceous glands, hair shafts, bone, cartilage, gastrointestinal epithelium,
bronchial epithelium, thyroid, neural tissue.

Skin only dermoid cyst
Monodermal teratoma- composed of only one cell type such as thyroid

Teratoma with Secondary Malignant Transformation
~1.5%.
usually post-menopausal women,
Squamous cell carcinoma, melanoma, thyroid, adenocarcinoma, carcinoid, skin adnexal
tumors, basal cell carcinoma, thyroid carcinoma, chondrosarcoma, etc

Immature Teratoma
contains a variable amount of immature, embryonal-type (generally immature neuroectodermal) tissue.
1-2 weeks of gestation-germ cell tumor.
2-8 weeks embryonal.
>8 weeks fetal.
Generally seen in patients less than 40, peak incidence of 14-19 years.
Raised HCG and AFP levels.
Treatment
Rapidly growing tumor - graded by amount of immature elements
grade I, stage I surgery.
> stage I , or higher histologic grade or very large tumors are given chemotherapy

Mature cystic teratoma- majority and are benign
young adult to middle age
Multiple different types of cells.

Malignancy
Malignant transformation older patients, rare.
Immature teratoma younger patients, immature neuroepithelium.

Dysgerminoma

primitive germ cell tumor.
+/- elevated Serum LDH
Histology:
Proliferation of primitive germ cells
large cells w/ clear cytoplasm and central nuclei
Lymphocytes and macrophages.
Identical to a testicular seminoma.
Respond to chemotherapy and radiation therapy.
Stage - significant factor.
yolk sac

#2 malignant tumor of germ cell origin
Derived from differentiation of malignant germ cells along the extra-embryonic yolk sac lineage.
rich in -fetoprotein.
Characteristic feature
glomeruloid-like structure composed of central blood vessel enveloped by germ cells within a
space lined by germ cells (Schiller-Duval body).
Identical morphology to testicular counterpart.

choriocarcinoma
Non-gestational
Trophoblastic differentiation within a germ cell tumor.
Strict definition of combination of cytotrophoblast and syncytiotrophoblasts (NO villi)
Secrete -HCG
Less favorable outcome than gestational choriocarcinoma- which is chemo sensitive.
Rx: Cytoreductive surgery followed by chemotherapy.

embryonal


Least differentiated form with large, highly atypical cells
Highly malignant aggressive malignancy
Treated with chemotherapy


Sex cord stromal tumors

granulosa cell tumor


call-exner bodies


Adult Granulosa Cell Tumors
>95% of granulosa cell tumors
Middle aged to postmenopausal women
Average size 12.5 cm - Commonly encapsulated.
Sectioned surface is yellow to tan with
various amounts of solid and cystic
areas.
Hemorrhage is common
Generally regarded as malignant but low risk for
metastasis
May show metastasis years after
diagnosis
10-year survival is about 85%
may have late > 10 year recurrences and
metastasis

Histopathology
Small round cells with scant cytoplasm, and
round to oval nucleus (coffee bean) with
longitudinal grooves.
Variety of patterns
microfollicular insular,
moire silk (water silk),
trabecular, diffuse.
Call-Exner body gland-like structure filled with
eosinophilic material.
Mitotic rate rarely exceeds 1-2 per 10 hpf.

Call-Exner bodies and grooved, coffee bean nuclei
Secrete estrogen-may be associated with
endometrial hyperplasia.
Inhibin product of granulosa cells.




Juvenile type granulosa cell tumor
5% of all granulosa cell tumors
First 30 yrs
Almost always stage I
Less than 5% bilateral
2% have extraovarian spread.
Vast majority are benign.
Associated with precocious puberty.

fibromas, trhecoma, fibrothecoma




Composed of plump spindle cells (fibroma) with
lipid droplets cells within the cells (thecoma).
Unilateral: 90%.
Hormonally inactive
Grossly:
White tan mass.
Histology:
Well-differentiated fibroblasts with
interspersed collagen.

Thecoma-fibroma group
Generally have a favorable prognosis
Association with Meigs syndrome
Ovarian tumor
Hydrothorax right side.
Ascites

sertoli-leydig cell tumor
androblastoma


Composed of Sertoli cells tubules that resemble testis
Leydig cells and primitive gonadal stroma
May see Reinke crystals
<0.5% of all ovarian neoplasms.
2-75 years of age, but mean 23-25.
1/3 of patients androgenic manifestations, some
may have estrogenic manifestations.

pure leydig cell tumor