+

The Female Genital Tract

Dr. Aileen Ong-Sy, M.D., DPSP

ANATOMY

+
Uterus
Vary
50

in size depends on the age and parity

gms and 8.0x6.0x3.0cm nulliparous

in size following pregnancies (70 gms); in half

the size after menopause

anatomic and functional regions:

Cervix
Lower uterine segment
Corpus

 Cervix
+

ecto/exocervix or
portio vagina (WDSSE);
visible to naked eye
and continuous with the
vaginal vault
external os
Endocervix
(SCE;mucin-secreting)
invaginates forming
endocervical glands
Squamocolumnar
junction/transformation
zone SQUAMOUS
METAPLASIA
susceptible to HPV
CA

+
Corpus
Consists

of
endometrium
surrounded by
myometrium

LUS

Fallopian

tube

+ Ovaries

4x2.5x1.5

cm active
reproductive life
Divided into cortex
and medulla
Cortex closely
packed stromal cells;
Follicle ovulation
Graafian Follicle
Corpus Luteum
senescence
Corpus albicans
Medulla loose
mesenchymal
tissues, vessels,
nerves

INFECTIONS

INFECTIONS
Candida, Gardnerella

and Trichomonas common;

significant discomfort; NO serious sequelae

N. gonorrhae

and C. Trachomatis infertility

Ureaplasma

urealyticum and Mycoplasma hominis

preterm deliveries

Viruses

e.g. HSV and HPV (tumors of cervix, vulva

and vagina)

Most

common ROT: Sexually transmitted

Herpes Simplex Virus

HSV

type 2 cervix, vagina and vulva

DNA

virus

Clinical

sns and sxs: 3-7 days after sex red

papules vesicles painful coalescent ulcers in
vulvar skin and mucosa; pelvic pain and
tenderness and purulent discharges in cervical or
vaginal lesions; dysuria and urine retention
(urethra)

Systemic

nodes

Active

sxs: fever, malaise and tender inguinal

infection most infectious phase; numerous

viral particles within vesicles and ulcers

Latent

infection after 1-3 wks; virus migrates to

lumbosacral nerve ganglia

Transmission

may occur in both active and latent

phase; however, more so in active phase

Reactivation:

immune system, stress, trauma, UV

radiation and hormonal changes

C/S

done in pregnant women

Dx: clinical

findings; tissue culture from purulent

exudates; PCR and direct immunofluorescent Ab
test

Tx: no

effective treatment for latent HSV infection;

Acyclovir or Famciclovir may shorten

Herpes Simplex type 2

Molluscum Contagiosum
DNA

Poxvirus; infection of the skin and mucous

membranes

MCV1

- Common in young children (2-12 y.o.);

transmitted through direct contact or shared
articles; trunk, arms and legs

In

adults MCV2; sexually transmitted; genitals,

lower abdomen, buttocks and inner thigh

1-5mm

papules; central waxy core

intracytoplasmic viral inclusions

Molluscum Contagiosum

+ Candida albicans
m.c.;part

of normal

flora
Disturbance in vaginal
microbial ecosystem
DM, Abx, Pregnancy,
Immunocompromised
CMI

Trichomonas

vaginalis
Flagellated protozoan
Sexually transmitted;
4days to 4 weeks
Frothy yellow vaginal
discharges
Dysuria, dyspareunia
PE: red and inflamed
cervical mucosa
(strawberry cervix)

Gardnerella

vaginalis
Gm (-) bacillus
mc cause of bacterial
vaginosis
Green-gray,
malodorous (fishy)
discharge
Clue cells

U. urealyticum

M. hominis
Vaginitis and
cervicitis

and

Pelvic Inflammatory Disease

Ascending

infection fr vulva or vagina spreads

upwards to involve most structures in the female
genital system

Pelvic

pain, adnexal tenderness, fever and vaginal

discharges

Gonococcus
Chlamydia

mc cause of PID

2nd mc

Polymicrobial

(staph, strep, Cl. Perfringens);

usually after spontaneous or induced abortions;
normal to abnormal deliveries (puerperal
infections)

Gonococcal infection
2-7

days after inoculation; involves usually

endocervical mucosa

May

spread upwards to involve the fallopian tubes

and tubo-ovarian region

Mx: marked

acute inflammation confined to the

superficial mucosa

Inflammatory

exudates intracellular gm (-)

diplococci
Def. Dx: Culture

or PCR

+
Acute

suppurative salpingitis tubal mucosa becomes

congested and infiltrated with neutrophils, lymphocytes
and plasma cells tubal lumen fills with purulent
exudate leaks out to the fimbriated end spillage into
ovary salpingo-oophoritis

Tubo-ovarian
Pyosalpinx

abscess pus within ovary and tube

pus within tubal lumen

Hydrosalpinx

dilated fluid-filled tubal lumen

Acute

Cx: peritonitis, bacteremia endocarditis,

meningitis, suppurative arthritis

Chronic

sequelae: tubal adhesions and obstruction

infertility, ectopic pregnancy, intestinal
obstruction

Tx: early

can be treated with penicillin; later

stage - difficult

Vulva

+ Bartholin Cyst
Infection

of Bartholin
gland abscess

Bartholin

duct cysts
secondary to obstruction
of the duct by
inflammation

Lining

epithelium
squamous metaplastic
epithelium

3-5cm; pain

and

discomfort
Tx: excised

or
marsupialization

+ Non-neoplastic Epithelial Disorders

Lichen

Sclerosus

White plaques or papules

may coalesce over time
Entire vulvar involvement
parchment-like
Labia becomes atrophic and
stiffened with constriction of
the vaginal orifice
Postmenopausal women
Hx: thinning of epidermis with
disappearance of the rete
pegs, hydropic degeneration
of the basal cells, superficial
hyperkeratosis; dermal
fibrosis/sclerosis; dermal
chronic inflammation

+ Squamous cell

hyperplasia
Formerly called as
Lichen simplex
chronicus
Nonspecific condition
resulting from
scratching or rubbing
the skin to relieve
pruritus
Hx: marked epithelial
thickening; expansion
of the S. granulosum
and significant
hyperkeratosis;
dermal infiltrates is
pronounced

Benign Exophytic Lesions

Condyloma

Acuminatum
Sexually

transmitted
Verrucous warty growth
HPV 6 and 11
Koilocytes
NOT a precancerous
lesion

+
Squamous Neoplastic Lesions
Uncommon; 3%; >60

Squamous
2

y.o.

cell carcinoma mc

groups:
Basaloid and Warty CA 30%; assoc with
oncogenic HPV
Keratinizing SQCA 70%; NOT assoc with
oncogenic HPV

+
Basaloid/Warty
Results

CAs

from an in-situ precursor lesion - Classic VIN;

formerly called Bowen disease; similar to CIN III;
nuclear dysplasia, full thickness involvement without
breaching the bm, increase mitoses and loss of
polarity
Risk factors: young age on 1st intercourse, multiple
partners
HPV-related HPV 16; multicentric
Peak age 6th decade
***exophytic, papillary architecture and prominent
koilocytic atypia

+
Keratinizing

SQCA

Etiology: unknown; Long-standing

lichen sclerosus or
squamous cell hyperplasia (Chronic irritation) with
TP53 mutation
Peak age: 8th decade
Premalignant lesion: Differentiated VIN or VIN simplex
(marked atypia of the basal squamous layer with normal
superficial epithelial maturation
Gx: nodules in a background of vulvar inflammation
Sn/Sxs: Non-specific (local discomfort, itchiness or (+)
exudates with secondary bacterial infection)

Invasive

SQCA initial spread is to inguinal, pelvic,

iliac and periaortic LN

<2cm

lesions: 60-80% 5 yr survival rate

Larger

lesions with LN involvement - <10%

survival rate

Tx: Vulvectomy

and lymphadenectomy

Classic VIN

Basaloid/Warty Carcinoma

+ VIN simplex

KeratinizingSQCA

Vagina

Developmental Anomalies
Septate/Double

vagina failure of fusion of the

mullerian ducts accompanies Double Uterus
(Uterine Didelphys)
DES exposure

Gartner

duct cyst
Common; lateral walls of the vagina derived from
the Wolffian (mesonephric) duct rests
1-2 cm fluid-filled cysts

Premalignant and Malignant

Neoplasms
Stromal

polyps, Leiomyoma and

Hemangiomas

VAIN

: Vaginal Intraepithelial Neoplasm

Similar to classic VIN; rare; 1%- primary
Assoc with oncogenic HPVs
mc location: upper posterior portion

Invasive

SQCA

+ Embryonal Rhabdomyosarcoma
aka

Sarcoma botryoides

mc

in infants and children

younger than 5 y.o.

Consists

of embryonal
rhabdomyoblasts

Gx: polypoid, grape-like,

bulky masses projecting

out
Hx: tc

are small with oval

nuclei with small
protusions of cytoplasm
from one end; tennis
racket appearance

Cervix

Inflammations Acute and Chronic

Cervicitis

intracellular glycogen vacuoles in squamous cells

cells shed glycogen provides a substrate for
endogenous vaginal aerobes and anaerobes (
strep, enterococci, E. coli and Staph)

Some

degree of inflammation is found in all women

Exceptions: Chlamydia, Gonorrhea, HSV, HPV,

mycoplasma
spread to upper portion (upper genital tract dse)
Complications during pregnancy
Abnormal PAP test result

Endocervical Polyp
Benign

exophytic growth

2-5%
Irregular
Arise

vaginal spotting and bleeding

from endocervical canal

Vary

from small sessile to large 5 cm mass

protuding out the cervical os

Soft

to mucoid lesions with loose edematous

fibromyxoid stroma and several dilated mucinsecreting endocervical glands; (+) inflammation

Surgical

excision or simple curettage

Premalignant and Malignant

Neoplasms
3rd

mc cancer in women

Previously

leading cause of death (50 years ago);

rank 13th cause of mortality

Early

detection by PAP (Papanicolaou) and

colposcopy (visual exam) potentially curable

HPV

DNA virus; single most impt factor in

cervical oncogenesis
15 high oncogenic risk HPVs identified
HPV 16 (60%) and HPV 18 (10%) most impt
5% - rest of oncogenic HPV

+
Risk

Factors:
Multiple sexual partners
A male partner with multiple previous or current
sexual partners
Young age at 1st intercourse
Low parity
Persistent HPV 16 or 18 infection
Immunosuppression
Certain HLA subtypes
Use of oral contraceptives
Use of nicotine

 On average, 50% of HPV

+

infections are cleared

within 8 mos and 90%,
within 2 years

Duration

of HPV is related
to HPV type

HPVs

infect immature
basal cells in areas of
epithelial breaks or
immature metaplastic
squamous cells at the
squamocolumnar junction

HPV

requires damage the

surface epithelium; cervix
more susceptible

HPV
Act

as a carcinogen E6 and E7 interfere with

tumor suppressor proteins (TSP) regulating cell
growth and survival

Infects

the immature epith BUT replicates in

maturing squamous cells (N arrested in G1 cycle)

Viral

E7 protein
binds the hypophosphorylated (active) form of RB
Binds and inhibits p21 and p27 CDK inhibitors
***enhances cell cycle progression, impairs the
ability of the cells to repair DNA damage

HPV
Viral

E6 protein
Exacerbates damage of DNA repair
Binds to TSP p53
Upregulates telomerase expression

Physical

state of HPV viral DNA is integrated into

host cell genome

HPV

infection alone - NOT sufficient to cause CA

exposure to co-carcinogens
Host immune status

Cervical Intraepithelial Neoplasia

(Squamous Intraepithelial Lesions)

+
Two-tiered

management: Observation and surgery

LSIL

high level of viral replication; BUT does NOT

progress directly to INVASIVE CA; most cases
regress spontaneously

HSIL

progressive deregulation of the cell cycle

cellular proliferation, or arrest epithelial
maturation
***low rate of viral replication

LSIL

is 10X more common than HSIL

Morphology of SIL

Nuclear

atypia
(enlargement,
hyperchromasia, coarse
chromatin granules,
pleomorphism)

Cytoplasmic Halos

E5

protein (localizes to
membranes of ER)
perinuclear halo
Koilocytic

atypia nuclear
atypia with perinuclear
halo

+
>80%

of LSIL and
100% of HSIL assoc
with high-risk HPV
(more with HPV16)

Majority

of HSILs arise
from LSILs

20%

novo

HSIL arise de-

Cervical Carcinoma
45

y.o. average age

SQCA

mc subtype

AdenoCA

2nd mc; 15%; adenoCA-in-situ

(precursor lesions)

Rare

types: Adenosquamous CA and

Neuroendocrine CA
5%; high-risk HPVs
Shorter progression from in-situ to invasive
Aggressive; poorer prognosis

+
Fungating

(exophytic) or infiltrative masses

Types:
SQCA

- Composed of nests and tongues of malignant

squamous epithelium; keratinizing to non-keratinizing;
invade the underlying cervical stroma
AdenoCA - Proliferation of glandular epithelium
composed of malignant endocervical cells with large,
hyperchromatic nuclei and mucin-depleted cytoplasm
hyperchromasia

Adenosquamous

CA - Intermixed malignant
glandular and squamous epithelium
Neuroendocrine CAs - Uniform small round cells
resembling Small cell CA of the lung
Advanced

dse direct extension (paracervical

tissues, vagina, UB, rectum; LVI distant mets (liver,
lungs, bone, BM, etc)

Adenosquamous
CA

Neuroendocrine
tumor

Clinical Features
Microinvasive

CAs may be treated by cervical

cone excision alone

Invasive

CAs hysterectomy with LND

Advanced

dse plus radiation and chemoTX

Prognosis: 100%

5 yr. SR - Microinvasive CAs

<50% - advanced dse

COD: consequence

of tumor invasion rather than

distant mets
Ureteral obstruction
PN
Uremia

Cervical CA screening and Prevention

PAP

(Papanicolaou) method
Circumferential scraping with a spatula or brush
partic on the transformation zone
Smeared into slides fixation and staining

Molecular

Method HPV DNA in cervical scrapes

High sensitivity but low specificity

Combined
ROT: 1st

method women over 30 y.o.

21 y.o. or within 3 yrs after onset of sexual

activity every 3 yrs thereafter
After 30 y.o. w/ (-)cytology and (-) HPV DNA every 5
yrs
(-) cytology with positive HPV DNA cytology every
6-12 mos

+ Cytology (PAP) test (+)

Colposcopic

exam of cervix and vagina is done

Using a magnifying glass acetic acid application
white spots (acetowhite areas) in abnormal epithelium
Bx
(+) LSIL conservative tx; local ablation (cryotherapy)
(+) HSIL conization (superficial excision)
PREVENTION
Vaccine

recommended for all girls and boys by age

11 to 12 y.o. up to age 26 y.o.
2 vaccines are FDA-licensed; HPV16 and HPV18; HPV 6
and 11
Current studies: offer 10 years protection
Does NOT protect against ALL high-risk HPV types

Body of Uterus
and
Endometrium

+ 2 major components:
Myometrium
Composed

of tightly
interwoven bundles
of smooth muscle
Form the walls of the
uterus
Endometrium
Lined the internal
cavity of the uterus
Composed of glands
embedded in a
cellular stroma
Affected

by endocrine
imbalances, Cx of
pregnancy and
neoplasms

+ Endometrial Histology in the

Menstrual Cycle
affected

during the menstrual cycle

2 layers: Functional and Basal Layer
Phases: Proliferative, Secretory Phase and Menstrual
Phase

Menstrual

phase superficial portion (Functionalis) is

shed
Proliferative

phase rapid growth of glands and

stroma arising from the basal layer (preovulation)
Glands are straight to tubular lined by PSCC
Mitotic figures are numerous
NO evidence of secretion and vacuolation

+
Secretory

phase post ovulation

Presence of vacuoles ( subnuclear to supranuclear )
Tortuous to serrated glands saw-toothed
Early secretory phase
Subnuclear vacuoles
Late secretory phase progesterone
Supranuclear vacuoles
Prominent spiral arterioles and edema (days 21 to
22)
Stromal cell hypertrophy with edema (predecidual
change) days 24-28
Dissolution of Corpus luteum and drop in
progesterone levels stromal breakdown

Dysfunctional Uterine Bleeding

(DUB)
mc

cause: hormonal imbalance

Other

causes with structural abn:

Chronic endometritis
Endometrial polyps
Submucosal leiomyoma
Endometrial neoplasms

+ Anovulatory Cycle
Most

frequent cause of DUB

Failure

to ovulate

mc

hormonal imbalance; common in menarche and

in perimenopausal pd

Less

common causes:
Endocrine d.o. thyroid, adrenal or pituitary d.o.
Ovarian lesions ovarian tumor or polycystic ovaries
General metabolic disturbances obesity,
malnutrition or other chronic systemic diseases

Excessive

endometrial stimulation by estrogen with

unopposed by progesterone

Inflammatory Disorders
Acute Endometritis
Uncommon; bacterial

infections arising after

delivery or miscarriage

Retained
Gp

POC usual predisposing factor

A hemolytic strep, staph and other bacteria

Inflammation
Tx: Removal

Abx Tx

usually limited to stroma

of retained POC by curettage and

Chronic Endometritis
Associated

with the ffg. d.o.:

PID
Retained

POC, postpartum or post-abortion

Intrauterine contraceptive devices
TB miliary TB or TB salpingitis
15%

- cause is unknown
Abn bleeding, pain, discharge and infertility
Chlamydia can cause acute or chr dse

Hx: (+)

plasma cells in the stroma

Tx: Abx

if EA is known

+ Endometriosis and Adenomyosis

ENDOMETRIOSIS
Presence

of ectopic endometrial tissue at a site outside

the uterus

Contains
May

mostly both endometrial glands and stroma

occur in the ff sites (in descending order):

Ovaries
Uterine ligaments
Rectovaginal septum
Cul de sac
Pelvic peritoneum
Small and large bowel, appendix
Mucosa of the cervix, vagina, and FT
Laparotomy scars

+ Cause infertility, dysmenorrhea, pelvic pain

Mainly

in 6-10% of reproductive women (3th-4th decade)

Pathogenesis:
Regurgitation Theory

implants at ectopic sites via

retrograde flow of menstruation; common in FT
peritoneal cavity
Benign Metastases Theory spread to distant sites
(bone, lungs and liver) via lymphatics and bv
Metaplastic Theory endometrium arises directly fr
coelomic epithelium (mesothelium of pelvis and
abdomen) from mullerian ducts during embryonic
devt; Mesonephric remnants
Extrauterine stem/Progenitor cell Theory stem
cells fr the bm endometrial tissue

+
Regurgitation Theory
Molecular

in vast majority of cases

analyses:
Release of proinflammtory and other factors e.g.
PGE2, IL-1, TNF, IL6 or 8, NGF, VEGF, MCP-1,
MMPs and TIMPs
estrogen production by endometriotic stromal
cells due to high levels of enzyme aromatase
(absent in normal endometrial stroma);
an association between endometriosis and
ovarian CA (endometrioid and clear cell type);
genes PTEN and ARIDIA

Endometriotic

lesions bleed secondary to both

extrinsic cystic (ovarian) and intrinsic hormonal
stimulation

Red-blue

to yellow-brown appearance on either

mucosal or serosal surfaces

Ovary

cystic; aka Chocolate cysts

Aggressive

forms can invade adjacent tissues causing

fibrosis and adhesions

Hx: (+)

endometrial glands and stroma; hemosiderinladen macrophages; sometimes, one or the other is seen

Atypical

Endometriosis precursor to endometriosisrelated CA

+
Clinical

Features: (secondary to intrapelvic

bleeding and periuterine adhesions)
Severe dysmenorrhea
Dyspareunia
Pelvic pain
Pain on defecation rectal wall
involvement
Dysuria bladder serosal involvement
Menstrual irregularities
Infertility 30-40% of women

+ ADENOMYOSIS

defined as the (+) of endometrial tissue within the

uterine wall (myometrium)

Signify a downgrowth of endometrial tissue in

between smooth muscle fascicles of the
myometrium

Mx: (+)

irregular nests of endometrial stroma, w/

or w/out glands; separated fr the basal layer by 23mm

Sxs: Menometrorrhagia

(irreg and heavy menses)

Colicky dysmenorrhea
Dyspareunia
Pelvic pain

Can

co-exists with endometriosis

Endometrial Polyps
Exophytic

masses of variable size projecting into

the endometrial cavity

May

be single or multiple; usually sessile; 0.5 to 3

cm; occasionally pedunculated

May

be asymptomatic or abnormal bleeding

Cytogenetic

studies:
Chromosomal arrangements

Tamoxifen
Functional, Hyperplastic

and Atrophic polyp

Endometrial Hyperplasia
Impt

cause of abn bleeding; frequent precursor to

the mc type of Endometrial CA
proliferation of endometrial glds relative to the
stroma gland-to-stroma ratio

Molecular

studies: EH and CA share specific

acquired genetic alterations in genes linked to
oncogenesis

Prolonged

estrogenic stimulation secondary to

anovulation, estrogen production from
endogenous or exogenous sources

+
Associated

conditions include:
Obesity (peripheral conversion of androgens to
estrogens)
Menopause
Polycystic ovarian syndrome
Functioning Granulosa cell tumors of the ovary
Excessive ovarian cortical function (Cortical
stromal hyperplasia)
Prolonged admin of estrogenic substances
(Estrogen Replacement Tx)
***same influences to be of pathogenic significance
in some endometrial carcinomas

+
Molecular

Basis:
Inactivation of PTEN TSG (negative regulator of
phosphotidylinositol 3-kinase (P13K)/AKT
growth-regulatory pathway) OVERACTIVE
P13K/AKT pathway
PTEN 20% of EH; 30-80% of CAs

WHO
a.
b.

Classification:
Non-atypical Hyperplasia
Atypical Hyperplasia (aka Endometrial
intraepithelial neoplasia)

+
Non-atypical

Hyperplasia
gland-to-stroma ratio
Glands show variation
insize and shape
Few are cystically
dilated
Crowded glandular
structures, however,
retention of stroma
Rare (1-3%) CA
Withholding estrogen
cystic atrophy

+
Atypical Hyperplasia
Complex

pattern of
proliferating glands w/
nuclear atypia
Back-to-back glands
Cells are rounded with
loss of perpendicular
orientation to bm
Nuclei have vesicular
chromatin and
conspicuous nucleoli
May overlap a well-diff
adenoCA
23 -48% - may have CA
when hysterectomy is
done

+
Malignant tumors of the Endometrium
mc

invasive cancer of the female genital tract; 7%

Type I Endometrial CA

mc

type; 80%; resemble more proliferative endometrial

glds

Called
May

as ENDOMETRIOID CARCINOMA

arise in the setting of EH

Associated

with obesity, diabetes, HPN, infertility and

unopposed estrogen stimulation

mc

mutation: signaling through the P13K/AKT pathway

TP53

mutation is found in 50% of poorly-diff CAs; (-) in

well-diff or late events involved in tumor progression

+ Morphology:
Polypoid

or diffuse
Composed of glandular growth patterns
3 grades:
1. Well-differentiated AdenoCA
composed almost entirely of well-formed
glands
2. Moderately-differentiated AdenoCA
well-formed glds admixed with 50% or less
solid sheets of cells
3. Poorly-differentiated AdenoCA
>50% solid growth pattern
20% - may contain squamous elements
(Endometrioid CA with squamous differentiation)

+ Type II (Serous) Carcinoma

gen

10 yrs older than women with type I; 15% of

endometrial CAs

Usually

arise in the setting of endometrial atrophy

Usually

poorly-diff (grade 3) tumors

mc

subtype: Serous carcinoma

Less

common subtype: Clear cell CA and MMMT

(Malignant Mixed Mullerian Tumor)

TP53
Poor

mutation 90% of Serous CA

prognosis: propensity to exfoliate , travel through

FT implant on peritoneal surfaces; often spread
outside the uterus at the time of Dx

+
Morphology:
Large

bulky tumors; deeply invasive to

myometrium
Precursor lesion: Serous endometrial
intraepithelial CA
Papillary or glandular pattern
High-grade nuclei (Marked cytologic atypia)
High N:C ratio
Atypical MF
Marked hyperchromasia
Prominent nucleoli
Grade

3 - irrespective of histologic pattern

Uncommon

in women younger than 40 y.o; NO current

available screening test

Postmenopausal

leukorrhea

Uterine

stages

vaginal bleeding with excessive

enlargement usually not present in early

Prognosis

depends on the clinical stage at Dx as well

as the Hx grade and subtype

Tx: surgery

alone or combine with irradiation 90% 5

yr SR in stage I (grade1-2) in Endometrioid CA

Serous

CA 18-27% 5 yr SR; more common in women

of African-American descent; 80% recurrence rate;
Surgery with chemoTx

+ MMMT
aka

Carcinosarcomas

Endometrial

component

adenoCA with a malignant mesenchymal

Stromal

malignancy:
Homologous leiomyosarcoma
Heterologous chondroSA, RhabdoSA, OsteoSA

Molecular

studies: similar to the prev-mentioned

Endometrial CAs (PTEN, TP53)

Mx: Bulky

and polypoid; protude through the cervical os

Postmenopausal

Heterologous
Overall

women; bleeding

cpt has worse Px than homologous

poor Px: 25-30% 5 yr SR

Homologous

Heterologous

Tumors of Endometrial Stroma

Uncommon; <5%

ADENOSARCOMAS
Large

broad-based endometrial polypoid

growths may prolapse through the cervical os
Malignant-appearing stroma with benign but
abnormally shaped endometrial glands
4th-5th decade
Low-grade malignancy
Estrogen-receptive responds to oophorectomy

+
STROMAL TUMORS
2

categories:
Benign stromal nodules
Endometrial stromal sarcomas (ESS)

ESS

- aberrant chromosomal translocations

fusion gene (JAZF1)
Relapse rates relatively common
Px: poor; 50% 5 yr SR with Low-grade ESS; lower
in High-grade ESS

Adenosarcoma

ESS

+ Tumors of the Myometrium

Leiomyoma
prev

called as Fibroids; mc tumor in women

Benign sm tumor; can occur anywhere in the uterus
3 common type: Subserous (beneath serosa),
Submucosal (beneath endometrium); Intramural (within
the myometrium)
Gx: May be single or multiple; well-circumscribed; grayw; nodules to masses
Mx: Whorled pattern of sm bundles
40% - cytogenetic abn
Rearrangement of chr 12q14
MED12 gene mutation

+
Asxmatic, abn

bleeding, urinary
frequency
frequency of
spontaneous abortion,
fetal malpresentation,
uterine inertia (failure
to contract with
sufficient force),
postpartum HgE
Rare malignant
transformation

+ Leiomyosarcoma
Uncommon
Arise

fr myometrium or endometrial stromal

precursor cells, rather than leiomyomas
Cytogenetics: more complex; deletions; also have
MED12 mutations
Gx: 1. bulky, fleshy masses invading the uterine wall
2. polypoid masses that project into the uterine
lumen
Mx: well to highly anaplastic; criteria for malignancy
nuclear atypia, mitotic index, zonal necrosis
Mitotic index - >10/10hpf; high grade nuclear
atypia (>5/10hpf is enough)
***Mitotically-active benign leiomyoma in young
or pregnant women

+
Peak

age incidence:
40-60 y.o.

Hematogenous

spread
lungs, bone, brain

Dissemination

througout the
peritoneal cavity
40%

5 yr SR

Anaplastic

lesions
10-15% 5 yr SR

Fallopian Tubes

Inflammations
Suppurative

Salpingitis

Any

pyogenic org; more than one org may be

involved
Gonococcus 60% of cases
Chlamydia
Tuberculous
Rare

Salpingitis

in western countries
Common in countries where TB is prevalent
Can cause infertility

+ Tumors and Cysts

Endometriosis
mc

primary lesions

Paratubal

Cyst
0.1-2cm translucent cysts filled with clear serous fluid

Hydatids

of Morgagni
Larger cysts located usually at the fimbriated end
Arise from mullerian ducts; no clinical significance

Adenomatoid

tumors
Subserosal location; small nodules with benign glands

+
Ectopic

pregnancy
Mc in ampulla

AdenoCA
Rare; usually

metastatic; aggressive

course
poor Px; abN discharge, bleeding or abN
PAP smear

Ovaries

+
mc

lesions: functional, benign cyts and tumors

Neoplastic

disorders gp accdg to origin

Mullerian epithelium
Germ cells
Sex-cord stromal cells

Primary

inflammations - uncommon

Nonneoplastic and Functional Cysts

Follicle

1.

Cysts

Cystic follicles
very common; originate from an unruptured
graafian follicle or ruptured follicles but
immediately sealed
Usually multiple; up to 2cm; filled with clear
serous fluid
Gray glistening membrane

2. Follicle cysts
>2cm; may cause pelvic pain
Granulosa-thecal cell lining; assoc with
estrogen

Luteal

Cysts
aka corpora lutea; present in the normal ovaries
of women of reproductive age
Lined by a rim of bright yellow containing
luteinized granulosa cells
Occasionally rupture peritoneal reaction

+ Polycystic Ovaries and Stromal

Hyperthecosis
POLYCYSTIC OVARIAN SYNDROME (PCOS)

is a complex endocrine d.o. charac by:

Hyperandrogenism
Menstrual abN
Polycystic ovaries
Chronic anovulation
Decreased fertility

Formerly
Affects

called Stein Leventhal syndrome

6-10% of reproductive age women

+
Assoc

with obesity, type 2 DM and premature AS

Etiology: NOT

completely understood

Marked

dysregulation of enzymes involved in

androgen biosynthesis and excessive androgen
production (central feature of this d.o.)

Insulin

resistance and altered adipose tissue

metabolism diabetes and obesity

Hx: Numerous

cystic follicles or follicle cysts that

enlarge the ovaries (only in 20-30% of women)
estrone levels risk for EH and CA

+
STROMAL HYPERTHECOSIS
aka

cortical stromal hyperplasia

d.o. of ovarian stroma in postmenopausal women
May overlap with PCOS in younger women
Gx: uniform enlargement of the ovary (up to
7cm); white to tan; usually bilateral
Mx: hypercellular stroma and luteinization of the
stromal cells forming discrete nests of cells with
vacuolated cytoplasm
Clinical features: similar to PCOS but virilization
more striking

Ovarian Tumors
80%

are benign; bet 20-45 y.o.; borderline tumors

at slightly older age

Malignant

tumor in older women (45-65 y.o.)

3%

of all cancers in females; 5th mc COD; spread at

the time of Dx

WHO

classification
Surface epithelium/FT epithelium and
endometriosis
Germ cells fr yolk sac; pluripotent
Stromal cells, sex cords

Epithelial Tumors
Most

arise from Mullerian epithelium

Classification

- based on differentiation and extent

of proliferation of the epithelium

major histologic types: Serous, Mucinous and

Endometrioid tumors

epithelial proliferation are benign, borderline,

malignant

Benign

cystic areas - cystadenomas

Cyst and fibrous areas cystadenofibromas
Predominantly fibrous adenofibromas

+
Borderline

and malignant tumors with

cystic cpt cystadenofibromas

different types with regards to

clinicopathologic and molecular studies:
Type 1 low-grade tumors; in assoc with
borderline tumors or endometriosis
Type II high-grade tumors; high-grade
serous CAs

SEROUS TUMORS
mc

malignant ovarian tumors of the ovary

30%

of all ovarian tumors: 70% (benign or borderline)

and 30% (malignant)

Benign

and Borderline Tumors unknown etiology

Malignant

incompletely understood: nulliparity, family

history and heritable mutations; BRCA1 and BRCA2
mutations

Serous

ovarian carcinomas
Low-grade (WD) CA may arise from borderline
tumors
High-grade (Mod to poorly diff) CA may arise from
in-situ lesions if FT fimbriae or fr serous inclusion cysts

Mutations:
Low-grade

tumors KRAS, BRAF, ERBB2, TP53

High-grade TP53; (-)KRAS or BRAF
Gene amplification of PIK3CA
Deletion of RB gene
BRCA1/2
Gx: Multicystic

lesions; Intracystic or outside ovary

Benign smooth glistening cyst wall
Borderline (+) papillary projections
Malignant papillary outgrowths or polypoid
projections; larger solid areas with fixation or
nodularities to the capsule

+
Mx:
Benign

SCE with cilia

Borderline - complexity of the stromal
papillae;epithelial stratification and mild nuclear
atypia; NO stromal invasion
LG and HG CAs complexity of growth pattern,
infiltrative involvement; stromal involvement;
nuclear stypia, (+) atypical MF; multinucleation
Psammoma bodies concentric Ca++ characteristic of serous tumors but not indicative
of malignancy only
LG to HG serous tumors involves peritoneal
surface and omentum ascites

+
Bilaterality

is common:
20% in benign
30% in Borderline
66% in malignant

Px:
100%

5 yr SR borderline; confined within ovary

70% 5 yr SR malignant; confined within ovary
90% - borderline with peritoneal involvement
25% - malignant with peritoneal involvement

MUCINOUS TUMORS
20-25%

of all ovarian neoplasms

Middle

adult life (rare b4 puberty and postmenopause)

Classification:
Benign
Borderline
Malignant
Mutation

3% of all ovarian tumors

of KRAS proto-oncogene
58% in benign
75-86% in Borderline
85% - malignant

+
Gx:
Surface

of ovary rarely involved

Bilaterality uncommon; 5%
Larger cystic masses, >25kg; usually multiloculated
filled with sticky, gelatinous fluid rich in
glycoCHONs
Mx:

Benign

lined by tall columnar cells with apical

mucin that lacks cilia (endocervical type or
Intestinal type)
Borderline epithelial stratification, tufting and/or
papillary intraglandular growth
Malignant confluent glandular growth (expansile);
marked epithelial atypia

ENDOMETRIOID OVARIAN TUMORS

10-15%

of all ovarian CAs

(+)

tubular glds; may arise in the setting of

endometriosis; 15-20% may coexist with
endometriosis

Similar

genetic alterations with endometrial CA,

endometrioid type

Gx:
Solid

and cystic areas of growth

Bilaterality is common 40%
Mx: Glandular

patterns resembling endometrial origin

CLEAR CELL CARCINOMA

Extremely

rare; composed of large epithelial cells with

abundanr clear cytoplasm

Stage

3; 90% 5 yr SR rate for tumors confined within

ovary; very poor outcome if spread has occured

TRANSITIONAL CELL TUMORS

Usually

benign

BRENNER TUMOR
May

be solid or cystic; unilateral (90%)

Small

(<1cm) to massive tumors (20-30cm)

Fibrous

stroma is sharply demarcated nests of

epithelial cells resembling the epithelium of the
urinary tract

Most

are benign; small cases: borderline and

malignant

+ SUMMARY of ovarian epithelial tumors:

Sn/Sx: lower

abdml pain and abdml enlargement

GI complaints
Urinary frequency
Dysuria
Pelvic pressure
For MALIGNANT: progressive weakness, weight loss,
cachexia; ascites (seeding into peritoneal cavity);
tumor exfoliation and seeding is common
Regional nodes usually involved
Distant mets: lungs, liver, GIT
***most women with ovarian CA present with high stage
dse
***NO specific specific tumor marker; CA-125 (use more
for dse recurrence/progression)

Germ Cell Tumors

15-20%

of all ovarian tumors

TERATOMAS
3

categories: Mature (Benign), Immature

(Malignant) and Monodermal or highly
specialized
A. Mature (Benign) Teratomas
Most are cystic; aka Dermoid Cysts
Almost always lined by skin structures
In young women of active reproductive years

+
Gx:
Bilateral

in 10-15% of cases; unilocular cysts

containing hair and sebaceous material
Common to find tooth structures and areas of Ca++
Mx:
Thin walled lined by epidermis (SSE) with hair
follicles, sebaceous glds, and other skin adnexal
elements
Structures originating fr other germ cell layers:
cartilage, bone, thyroid and neural tissue
1% undergo malignant transformation (mc: SQCA,
others are thyroid CA and melanoma)

+
B. Monodermal or Specialized Teratoma
Rare gp of tumors
mc: Struma ovarii and Carcinoid; usua unilateral
Struma ovarii composed entirely of mature
throid tissue; may be fxnal hyperthyroidism
Ovarian carcinoid may arise from intestinal
tiss; may be fxnal (esp >7cm) produce 5hydroxytryptamine; metastatic intestinal
carcinoid usually bilateral

+
C. Immature Malignant Teratomas
rare tumors; (+) embryonal or immature fetal
tissue
Found in prepubertal adolescents and young
women; mean age: 18 y.o.
Gx: Bulky tumors; still see components of the
mature counterpart
Mx: (+) immature neuroepithelium, cartilage,
bone, muscle and other elements
Grow rapidly; penetrate capsule local or distant
spread
Good prognosis

+
DYSGERMINOMA
2%

of ovarian CAs; 50% of malignant germ cell

tumors

Female

May
NO

counterpart of testicular seminoma

occur in childhood; 75% - 20-30 y.o.

endocrine fxn

expresses

OCT3, OCT4 and NANOG (transcription

factors); KIT gene mutations

+ Gx: 80-90% - unilateral tumors; size range: barely

visible nodules to masses filling virtually entire
abdomen
Solid yellow-white to gray pink surface
Often soft and fleshy appearance
Mx: composed

of large vesicular cells with clear

cytoplasm and centrally placed nuclei
t.c. grow in sheets and cords separated by scant
fibrous stroma (infiltrated by mature lymphocytes)

All

are malignant tumors; only 1/3rd is aggressive

96%

cure rate when limited to ovary; highly responsive

to chemoTX even for tumors extending beyond
ovary; overall survival is high (80%)

YOLK SAC TUMOR

aka

Endodermal Sinus tumor

2nd mc malignant tumor of germ cell origin
Derived fr malignant germ cells differentiating along
the extraembryonic yolk sac lineage
Elaborate -fetoprotein
Charac feature: glomerulus-like structure composed
of a central bv enveloped by tc within a space also
lined by tumor cells
Intracellular and extracellular hyaline droplets are
seen; stained (+) for -fetoprotein by peroxidase
Mostly in children and young women; abdml pain
and rapidly growing pelvic mass; unilateral
Tx: surgery + chemoTx 80% SR

CHORIOCARCINOMA
Similar

to yolk sac tumor; extraembryonic

differentiation of malignant germ cells
Usually in assoc with other germ cell tumors; pure
chorioCA is extremely rare
Aggressive; hematogenous spread lungs, liver,
bone and other sites (at the time of Dx)
Secrete levels of HCG
Unresponsive to chemoTx fatal

OTHER GERM CELL TUMORS

Embryonal

CA highly malignant
Polyembryoma embryoid bodies
Mixed Germ cell tumors

ChorioCA

Embryonal CA

Sex Cord-Stromal Tumors

Derived

fr ovarian stroma (derived fr the sex cords

of the embryonic gonads)

Undiff

gonads males (Sertoli and Leydig) and

females (Granulosa and Theca)

Secrete

estrogen (granulosa and theca)

feminizing

Secrete

androgens (sertoli and leydig)

masculinizing

+
GRANULOSA CELL TUMOR
Composed

of cells resembling granulosa cells of a

developing ovarian follicle
Divided into: Juvenile and adult GCT (based on Pxs
age)
5% of all ovarian tumors; 95% - adult type granulosa
cell tumor (postmenopausal women)
Gx: usually unilateral; size vary from small to large,
solid and cystic encapsulated masses
Yellow hue hormonally-active; due to intracellular
lipids
Mx: small cuboidal cells growing in anastomosing
cord, sheets and strands
Small, distinctive gland-like structures filled with
acidophilic material (Call-Exner bodies)

clinical importance:
May elaborate large amts of estrogen
May behave like low-grade malignancy

In

prepubertal age precocious sexual devt

In

adult women proliferative breast dses, EH,

endometrial CA

Occasionally, GCT

secrete androgens musculinizing

the Px
All

GCT are potentially malignant; indolent course;

recurrences are not uncommon; 10 yr SR 85%
and serum inhibin, product of granulosa cells;
used as biomarker

tissue

Assoc

with FOXL2 gene mutation 97% of cases

+
FIBROMAS, THECOMAS and FIBROTHECOMAS
Fibromas

arise fr fibroblast; hormonally inactive

Usually unilateral (90%)
Gx: Solid, round or slightly lobulated, encapsulated,
hard, gray to white masses
Mx: well-diff fibroblasts and scant interspersed
collagenous stroma

Thecomas

composed of plump spindle cells with

lipid droplets; pure thecomas rare; hormonally active
Fibrothecomas mixture of both

Clin

snx/sxs:
Pelvic mass, occasionally with pain
Ascites 40% (esp with tumors >6cm)
Hydrothorax R side
*** Meigs syndrome: ascites, hydrothorax and
ovarian tumor

SERTOLI-LEYDIG TUMORS
Fxnal; masculinization
Peak

or defeminization

age: 20-30 y.o.

Mutations of DICER1
Gx: same as GCT
Mx: sertoli or leydig cells interspersed with stroma

+
METASTATIC TUMORS
mc

is from mullerian origins, ft, contralateral ovary,

pelvic peritoneum

mc

extramullerian tumors: breast and GOT

Rare

case: Pseudomyxoma peritonei from

appendiceal tumors

Krukenberg

tumor metastatic from gastric

adenoCA; bilateral involvement; charac by mucinsecreting, signet-ring cancer cells

Pseudomyxoma Krukenberg tumor

peritonei

Gestational and
Placental Disorders

+ Impt cause of IU or perinatal death, congenital

malformations, IUGR, maternal death

Disorders of Early Pregnancy

Spontaneous

Abortion
miscarriage; pregnancy loss before 20 wks of
gestation
Most occure at 12 weeks
Most cases: unknown cause
Fetal chromosomal anomalies aneuploidy and
translocations; 50%
Maternal endocrine factors poorly controlled DM
Physical defects of the uterus leiomyomas
Systemic d.o. affecting maternal vasculature HPN
Infections - toxoplasma

+
Ectopic

Pregnancy
Implantation of the fetus other than normal
intrauterine location
m.c.: FT in 90% of cases; others: ovary (trapping of the
fertilized ovum within the follicle), abdml cavity
(fertilized ovum fails to enter or drops out of the
fimbriated end of FT), intrauterine portion of the FT
(cornual pregnancy)
Most impt predisposing condition: PID; other cause of
peritubal scarring and adhesions: AP, Endometriosis,
prev surgery; use of IU contraceptive device

+
m.c. cause

of
hematosalpinx (bldfilled FT) growth of
gestational sac
rupture massive
intraperitoneal he
Medical emergency;
onset of moderate to
severe abdml pain
and vaginal bleeding
Hemorrhagic shock

Disorders of Late Pregnancy

3rd

trimester; related to the complex anatomy of the

maturing placenta
Twin placentas arteriovenous shunts
preferential blood flow to one twin at the expense of
the other
Abnormalities of placental implantation
Placenta previa placenta implants at the LUS or
cervix
Placenta accreta partial or complete absence of
decidua; chorionic villi adheres directly to the
myometrium failure of placental separation at
birth

Placental Infections
2 pathways:
1. ascending infection through the birth canal
- mc; almost always bacterial; may cause
PROM and preterm delivery
- amniotic fluid is cloudy with purulent
exudate; (+) neutrophils in C-A membrane
2. hematogenous (transplacental) infection
- classic cpts of the TORCH gp
(toxoplasmosis, rubella, CMV, HSV)
- chronic inflammation in C-A membrane

Preeclampsia and eclampsia

Systemic syndrome charac by widespread
maternal endothelial dysfunction that presents
during pregnancy with HPN, edema and
proteinuria
3-5% in last trimester; mc in primigravida
Starts after 34 wks of gestation
Mx:
Infarcts
Exaggerated ischemic changes in cv (syncytial
knots)
Retroplacental hematoma
abN placental vessels thrombi, fibrinoid
necrosis

Gestational Trophoblastic Disease

Hydatidiform Mole
Cystic

swelling of the cv
Variable trophoblastic proliferation
Usually dx during early pregnancy (average 9 wks)
by sonogram
Can occur at any age BUT common during the 2 ends
of reproductive life (teenagers and between 40-50
y.o.)
2 types:
Complete Mole
Fertilization of an egg that has lost its female
chromosome genetic material is paternally
derived

+
90%

have a karyotype 46XX

Embryo dies very early in devt
2.5% risk of subsequent chorioCA and 15% to
invasive mole
Partial Mole
Fertilization of an egg with 2 sperm
Karyotype is triploid (69XXY)
Fetal tissues are (+)
NOT assoc with chorioCA
Gx: delicate, friable

mass of thin walled,

translucent, cystic, grapelike structures consisting
of edematous (hydropic) villi

+
Complete

Mole involve most villous structures;

cv are enlarged with scalloped shape with
central cavitation (cisterns)
Extensive trophoblastic proliferation involving
the entire circumference of the villi

Partial

Mole only a fraction of the villi are

enlarged and edematous
Trophoblastic hyperplasia is focal

+
Clinical

Features:
Most women present with spontaneous
miscarriage or undergo D&C due to sonogram
findings
HCG markedly increase
Most moles are successfully removed by D&C
Pxs subsequently monitored for 6 mos to a yr to
ensure HCG levels decrease to non-pregnant
levels
Continuous of HCG indicative of a
persistent or invasive mole

Invasive Mole
Mole

that penetrates or even perforates the uterine

wall
Invasion of the myometrium by hydropic cv with
proliferation of both cyto and syncytiotrophoblasts
Locally destructive tumor; may invade parametrial
tissue and bv
cv may embolize to distant sites e.g. lung and brain
(BUT do not grow as true metastases); regress
spontaneously
Sn/Sxs: vaginal bleeding
Irregular uterine enlargement
Persistent elevated serum HCG
Responsive to chemoTx; however, uterine rupture
may necessitate hysterectomy

+
Choriocarcinoma
Malignant

neoplasm of trophoblastic cells derived

from a previous normal or abnormal pregnancy e.g.
extrauterine ectopic pregnancy
Rapidly invasive and metastasize widely
Responds well to chemoTx
Uncommon; 50% may arise fr complete H mole,
25% from previous abortions, 22% ffg normal
pregnancies, remainder in ectopic pregnancy
Gx: soft and fleshy, yellow-white tumor with large
pale areas of necrosis and extensive he
Mx: proliferation ofcyto and syncytiotrophoblasts
within the myometrial wall, bv, serosa; (-) for cv

+
Clinical

features:
Irregular vaginal spotting of bloody, brown fluid
High propensity for hematogenous spread
HCG: variable; maybe be high like in H mole;
necrotic tumors may have low HCG
Metastases: 50% - lungs, 30-40% - vagina, brain,
liver, bone and kidney
Tx: depends on stage; usually involves surgery +
chemoTx
Responsive to chemoTx 100% remission with
high rate of cures

Placental Site Trophoblastic Tumor (PSTT)

<2%; neoplastic

proliferations of extravillous
trophoblasts k.a. Intermediate trophoblasts
(polygonal mononuclear cells with abundant
cytoplasm
Produce human placental lactogen
Presents with a uterine mass, abN uterine bleeding
or amenorrhea with moderately elevated HCG
Mx: malignant trophoblastic cells infiltrating
endomyometrium
May follow normal pregnancy (50%), spontaneous
abortion or H mole
Localized dse excellent Px; Disseminated dse
very poor