Path Chapter 22: The Female Genital Tract (pages 1006-1024)
Primordial germ cells arise int eh wall of the yolk sac by the 4th week of gestation, and the 5th-6th week
they migrate into the urogenital ridge (page 1007 – embryo visual)
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The mesoderm epithelium of the urogenital ridge then proliferates, to form the epithelium and
stroma of the gonad
Dividing germs cells come from endoderm, and are incorporated into the proliferating
mesodermal epithelium, to form the ovary
At the 6th week, coelomic lining epithelium invaginates and fuses to form the lateral mullerian (aka
paramesonephric) ducts
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Mullerian ducts grow caudally then into the pelvis, and fuse with the urogenital sinus at the
mullerian tubercle
Normally, the unfused parts mature into the fallopian tubes, the fused caudal parts develop into
the uterus and upper vagina, and the urogenital sinus forms the lower vagina and vestibule
So the entire lining of the uterus and tubes and ovarian surface is derived from coelomic
epithelium (mesothelium)
o This is important in benign lesions (endometriosis) and malignant (endometrioid and
serous tumors) lesions on the surface of the ovaries or peritoneum
o This is also why tumors at different parts of the female genital tract look
morphologically similar
The epithelium of the vagina, cervix, and urinary tract is formed by induction of basal cells from the
underlying stroma, which then undergo squamous and urothelial differentiation
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Some of them remain uncommitted, forming the reserve cells of the cervix, which can do both
squamous and columnar cell differentiation
In males, mullerian inhibitory substance from the developing testis causes regression of the mullerian
ducts
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The paired wolffian (mesonephric) ducts form the epididymis and vas deferens
Normally the mesonephric duct regresses in the female, but remnants can persist into adult life
as epithelial inclusions next to the ovaries, tubes, and uterus
o In the cervix and vagina, the remnants are called Gartner duct cysts
The ovary is divided into a cortex and a medulla
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The cortex – has a layer of closely packed stromal cells, and thin covering of collagen connective
tissue
o Follicles are found in the outer cortex
o With each menstrual cycle, one follicle develops into a graafian follicle, which is
transformed inot a corpus luteum after ovulation
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The corpus luteum and its later corpus albicans can be found int eh
cortex
The medulla has loosely arranged mesenchymal tissue that has remnants of the mesonephric
duct (called rete ovarii) and small clusters of eiptheliod cells (hilus cells) around vessels & nerves
o Hilus cells are remnants from when the gonads weren’t committed to guy or girl yet,
so they look like interstitial cells of the testis, and can make steroids
 Rarely, hilar cells can cause masculinizing tumors
The fallopian tube mucosa is made of many papillary folds (plica) made of 3 cell types: ciliated-columnar
cells, nonciliated columnar secretory cells, and intercalated cells
The uterus varies in size based on age and whether you’re pregnant or not
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It gets bigger during pregnancy & after, & gets smaller to 1/2 nulliparous size after menopause
The uterus is divided into the cervix, lower uterus, corpus (body), vaginal portio (ectocervix), and
endocervix (page 1008)
o The portio (ectocervix) is visible to the naked eye on vaginal exam, and covered with
stratified nonkeratinizing squamous epithelium continuous with the vaginal vault
 This squamous epithelium converges at a small opening called the external os
 In nulliparous women, the os is basically closed
o Just above the os is the endocervix, which is lined by columnar mucus-secreting
epithelium that dips into the underlying stroma to make endocervical glands
o The point where the squamous and endocervical mucinous columnar epithelium meet is
called the squamocolumnar junction (page 1008)
o The area of the cervix where the columnar epithelium switches to squamous is called
the transformation zone
 Metaplasia of the glandular (columnar) epithelium to squamous at the
squamocolumnar junction produces multilayered, squamous epithelium called
squamous metaplasia
 These immature squamous cells are susceptible to human
papillomavirus (HPV) infection
 So precancerous lesions and cervical carcninomas develop at the
squamocolumnar junction
The corpus (body) consists of the endometrium surrounded by the myometrium
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Changes in the endometrium from the menstrual cycle are due to the rise and fall of ovarian
hormones
Candida, trichomonas, and gardnerella are very common infections of the female genital tract
Neisseria gonorrhoae and chlamydia infections are major causes of female infertility
Ureaplasma urealyticum and mycoplasma hominis infections are common causes of preterm deliveries
Infections of the lower female genital tract:
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Genital herpes – common, most often infects the cervix, then vagina and vulva in frequency
o HSV’s are DNA viruses that can by 2 types: HSV-1 or HSV-2
o HSV-1 – usually causes oropharyngeal infection
o HSV-2 – usually causes infection of the genital mucosa and skin
o Depending on sexual practices though, both can be in both areas
o By age 20, 1/5 of women test positive for antibodies to HSV-2
o 1/3 of infected people actually show symptoms
o The initial lesion shows up 3-7 days after sex, and looks like red papules that progress to
blisters (vesicles), and then to painful ulcers
o Cervical or vaginal lesions that you can’t see on the external genitalia, show severe
purulent discharge and pelvic pain
o Lesions around the urethra can cause painful urination and urine retention
o The initial HSV infection shows systemic symptoms like fever, malaise, and tender
inguinal lymph nodes
o The blisters and ulcers have tons of viral particles, making HSV easy to spread
o The lesions will heal spontaneously in 1-3 weeks, but the virus migrates to the regional
lumbosacral nerve ganglia to establish a latent infection
 So HSV infections persist indefinitely, and any decrease in the immune system,
like in stress, trauma, UV radiation, hormonal change, can trigger reactivation
of the virus
 Reoccurrences are much more common in immunosuppressed people
 HSV-2 is more likely to recur than HSV-1
o HSV can be transmitted in both the active or latent phase, but is much less likely in
asymptomatic carriers
o Condoms offer only limited protection, since a large genital area can be infected
o Like other STI’s, women are more susceptible to transmission than men
o Previous infection with HSV-1 decreases susceptibility to getting HSV-2
o Active HSV can be passed on to neonates during delivery, especially during primary
(initial) infection of the mom, so you have to do a C-section to avoid this
o People with primary, acute-phase HSV infection don’t have serum anti-HSV antibodies
 Finding anti-HSV antibodies in the serum indicates a recurrent/latent infection
o No treatment for latent HSV, but antivirals like acyclovir or famciclovir can shorten the
length of initial and recurrent symptomatic phases
Molluscum contagiosum (MCV) – poxvirus infection of the skin and mucous membranes
o 4 types of MCVs: MCV-1 to -4
o MCV-1 is most common, MCV-2 is the one most spread by sex
o MCV is common in young kids age 2-12, and transmitted through direct contact or
shared infected stuff
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MCV can affect any area of the skin, but is most common on the trunk, arms, & legs
In adults molluscum infections are usually STI’s that affect the genitals, lower abs, butt,
and inner thighs
o Has an incubation period of 6 weeks
o Diagnose based on characteristic pearly, dome-shaped papules with a dimpled center
 The core of MCV papules have viral inclusions in the cytoplasm (page 1009)
Fungal infections of the lower female genital tract are common, especially candida
o Fungi are part of a woman’s normal vaginal flora
o Diabetes, antibiotics, pregnancy, and being immunocompromised allow yeast
infections to develop
o Yeast infections show strong itching, erythema, swelling, & a curdlike vaginal
discharge
o Diagnose by finding pseudospores or fungal hyphae in discharge placed on wet mount
or pap smear
Trichomonas vaginalis – large oval protoazoa with flagella transmitted by sex within 4 days to 4
weeks
o Can be asymptomatic, or show yellow, frothy vaginal discharge, vulvovaginal
discomfort, dysuria (painful urination), and dyspareunia (painful intercourse)
o The vaginal & cervical mucosa usually has a fiery-red appearance with marked dilation
of cervical mucosal vessels that causes characteristic “strawberry cervix” on colposcopy
Gardnerella vaginallis – gram negative bacilli that is the main cause of bacterial vaginosis
(vaginitis)
o Shows thin, green/gray, fishy smelling discharge
o Pap smear shows superficial and imtermediate squamous cells covered by a shaggy coat
of many coccobaccili
o Gardnerella vaginallis can cause premature delivery in pregnancy
Ureaplasma urealyticum and mycoplasma hominis can cause vaginitis and cervicitis, and can
cause chorioamnionitis and premature delivery
Most chlamydia trachomatic infections affect the cervix, but some can get to the uterus and
fallopian tubes causing endometritis and salpingitis, causing pelvic inflammatory disease
Pelvic inflammatory disease – an ascending infection that starts itn eh vulva or vagina, and spreads up to
involve most of the female genital system
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This causes pelvic pain, adnexal tenderness, fever, and vaginal discharge
Gonococcus and chlamydia can cause PID, and infections after abortions and delivery can also
cause PID
o Usually after delivery or abortion, infection involves many microbes, often staph, strep,
coliform, and clostridium perfringens
In gonococcus, inflammatory changes start 2-7 days after infection, most often at the
endocervix mucosa
o Can also start in the bartholin gland or other glands
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o It then spreads up to the fallopian tubes and tubo-ovarian area
Non-gonococcal infections after delivery, dilation, or surgery, spread from the uterus upward
through lymph or veins instead of mucosal surfaces, so they affect the mucosa less and deep
tissues more
Gonococcal disease is characterized by marked acute inflammation in the superficial mucosa
o Smears show gram-negative diplococcic, and you diagnose with culture or detection of
gonococcal RNA or DNA
o Spread often spares the endometrium
o Once infection reaches the tubes it causes acute suppurative salpingitis
o The tubal mucosa gets congested and infiltrated by WBCs
o Gonococcal LPS and inflammatory mediators cause epithelial injury and sloughing of
plicae
o The tubal lumen fills with purulent exudate
o Infection can then spill over into the ovary, causing salpingo-oophoritis
 Collections of pus in the ovary and tube (tubo-ovarin abscesses) or tubal lumen
(pyosalpinx) can happen
o Over time the infecting organisms disappear, leaving behind chronic follicular salpingitis
(fallopian inflammation) and hydrosalpinx (dilated, fluid-filled fallopian tubes)
o The tubal plicae, which have lost their epithelium, adhere to one another and fuse in a
reparative scarring process, that forms glandlike spaces and blind pouches, called
chronic follicular salpingitis
 The lumen of these tubes may be impenetrable for the oocyte, causing
infertility or ectopic pregnancy
o Hydrosalpinx develops from fusion of fimbriae and accumulation of tube secretions and
distention, and can cause post-PID infertility, since the tubual fimbriae aren’t flexible
anymore and can’t take up the oocyte after ovulation
PID from non-gonococcal stuff has less exudate in the tube lumen, and less involvement of the
mucosa, but a greater inflammatory response in the deep tissues
o These infections often spread throughout the wall to involve the serosa and broad
ligaments, pelvic structures, and peritoneum
o Spread is more common in this type
Acute symptoms of PID include peritonitis and bacteremia, leading to possible endocarditis,
meningitis, and suppurative arthritis (gonorrhea)
More chronic conditions are infertility and tube obstruction, increased risk for ectopic
pregnancy, pelvic pain, and intestinal obstruction from adhesions between bowel & pelvic stuff
In early stages, gonococcal infection is easily controlled with antibiotics, but when it walls off
into tubo-ovarian abscesses, it’s hard to get high enough antibiotic levels to the infection, and
sometimes requires surgery
Vulva (external genitalia) diseases are only a minority of gynecological problems
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Other skin stuff, like psoriasis, eczema, and allergic dermatitis, can also happen at the vulva
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The vulva is more prone to skin infections, because it is constantly exposed to secretions and
moisture
Nonspecific vulvitis is especially likely to happen in immunosuppression
Bartholin cysts – infection of the Bartholin gland causes acute inflammation in the gland
(adenitis) and can cause an abscess
o Bartholin duct cysts are common, happen at all ages, and happen from obstruction of
the duct by inflammation
 The resulting cysts are lined by duct squamous and metaplastic epithelium
 They can get large and cause pain or discomfort
Non-cancerous epithelial disorders of the vulva:
o Leukoplakia – term for opaque, white, plaque-like mucosal thickenings of the vulva
that cause itching and scaling
 White plaques though can represent a variety of benign, pre-malignant, or
malignant lesions from inflammatory dermatitis, vulva cancers, or other
epithelial problems
o Non-cancerous epithelial problems of unknown etiology are classified as either lichen
sclerosus, or squamous cell hyperplasia
o Lichen sclerosus – lesion characterized by thinning of the epidermis and disappearance
of rete pegs, hydropic degeneration of the basal cells, superficial hyperkeratosis, and
dermal fibrosis with scant perivascular WBC infiltrate (page 1011)
 The lesions look like smooth white plaques or papules that can extend or
combine
 The surface is smooth and can “resemble parchment”
 When the whole vulva is affected, the labia gets atrophic and stiff, and the
vaginal orifice constricts
 Happens in all age groups, but most common in postmenopausal women
 The lesion isn’t premalignant, but women with this have an increased chance
of getting squamous cell carcinoma
o Squamous cell hyperplasia (aka lichen simplex chronicus) – an area of leukoplakia from
rubbing or scratching of the skin
 Shows epithelial thickening, expansion of the stratum granulosum, and surface
hyperkeratosis
 The epithelium may show increased mitotic activity
 WBCs infiltrate
 There is no increased risk for cancer, but it’s often seen at the margins of
established cancers
Benign raised (exophytic) or wart-like lesions of the vulva can be caused by an infection, or other
causes
o Condyloma acuminatum – name for the genital wart (page 1012)
 It’s caused by human papillomavirus (HPV), which is an STI
 Most often there’s multiple warts
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They have branching, tree-like cores of stroma covered by squamous
epithelium with characteristic viral cytopathic changes called koilocytic atypia
 Koilocytic atypia – enlarged nucleus and nucleus atypia, and a
cytoplasmic perinuclear halo
 Condyloma are not considered precancerous
Squamous cancerous lesions of the vulva – includes vulvar intraepithelial neoplasia and vulvar
carcinoma
o Carcinoma of the vulva is uncommon, and most happen in women older than 60
o Squamous cell carcinoma is the most common type of vulvar cancer
o Vulvar squamous cell carcinomas are divided into 2 groups: basaloid and warty
carciomas with high risk for cancer causing HPV (1/3 of cases), and keratinizing
squamous cell carcinomas not related to HPV (2/3 of cases)
o Invasive basaloid and warty carcniomas develop from a precancerous lesion called
classic vulvar intraepithelial neoplasia (classic VIN) (page 1013 top and bottom pics)
 Classic VIN is characterized by nuclear atypia of the squamous cells, increased
mitoses, and lack of cell maturation
 Most commonly happens in reproductive age-women (HPV)
 Risk factors are young age at first intercourse, multiple sex partners, and male
partner with multiple sex partners
 Up to 1/3 of classic VIN cases also have vaginal or cervical HPV related lesions
 Most cases of classic VIN are positive for HPV 16
 The risk for progression to invasive carcinoma is higher in women older than 45,
or those with immunosuppression
 HPV caused vulvar squamous cell carciomas start as classic VIN lesions, which
show white, hyperkeratotic, flesh-colored or pigmented, slighty raised lesions
 Basaloid carcinoma shows an infiltrating tumor characterized by nests and
cords of small tightly packed malignant squamous cells that are immature, and
resemble the basal layer of the normal epithelium
 Warty carcinoma is characterized by exophytic (raised) papillary structure with
koilocytic atypia
o Non-HPV related keratinizing squamous cell carcinomas arise in people with longstanding lichen sclerosus or squamous cell hyperplasia
 Average age of onset is 76 years old
 The immediate premalignant lesion is called differentiated vulvar
intraepithelial neoplasia (differentiated VIN aka VIN simplex) – page 1014
 These carcinomas can develop as nodules in vulvar inflammation, that cause
local discomfort, itching, and exudation because of superficial infection
 Histo shows infiltrating tumor characterized by nests and tongues of malignant
squamous epithelium with prominent central keratin pearls
 Risk for cancer in VIN depends on age, extent, and immune status
 Once malignant, it can spread to regional lymph nodes, and eventually the
lungs, liver, or other organs
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 Small lesions have a good survival rate, while larger ones it’s bad
Vulva sweat gland cancerous lesions – papillary hidradenoma and extramammary paget disease
o Papillary hidradenoma – sharply circumscribed nodules usually in the labia majora or
interlabial folds, with papillary projections covered with 2 layers of cells: a top
columnar secretory layer, & an underlying flattened myoepithelial layer (myoepithelial
cells are characteristic of sweat gland tumors) - page 1015 top pic
o Paget disease of the vulva – rare vulva lesion similar to Paget disease in the breast
 Shows itchy red, crusted, sharply demarcated, map-like area usually in the
labia majora – page 1015 bottom pic
 Paget disease – intraepithelial proliferation of malignant cells, diagnosed by
large tumor cells lying singly or in small clusters in the epidermis
 The cells are distinguished by a clear separation (“halo”) from the
surrounding epithelial cells, and granular cytoplasm with proteoglycans
(aka mucopolysaccharides)
 Paget cells can come from apocrine, eccrine, and keratinocyte
differentitation, and arise from primitive germ cells of the vulva
 Unlike in the nipple, vulva Paget disease is usually confined to the epidermis of
the skin and adjacent hair follicles and sweat glands
 Has a high recurrence rate, but rarely invades
Malignant melanoma of the vulva – rare, similar to other melanomas with a low survival rate
o Most common in your 60’s-70’s
o Can tell that it’s melanoma by finding uniform reactivity with antibodies to S100
proteins, absence of reactivity to antibodies to cytokeratin, and lack of
mucopolysaccharides (Ig to cytokeratin and mucopolysaccharides are seen in Paget’s)
The vagina is usually free of primary disease, and primary lesions of the vagina are rare
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Inflammations of the vulva and stuff around it usually spread to the cervix and avoid the vagina
Septate (aka double) vagina – uncommon anomaly from failure of total fusion of the mullerian
ducts, that accompanies double uterus (uterus didelphys)
o Can be a manifestation of genetic stuff, or in uteruo exposure to diethylstilbestrol (DES),
a drug used in the past to prevent abortions
Vaginal adenosis – remnant of columnar endocervical epithelium that extends from the
endocervix and covers the ectocervix and upper vagina in embryo, and then usually replaced by
squamous epithelium
o So small patches of unreplaced glandular epithelium can persist into adult life
o Shows red, granular areas that look different from the surrounding pale/pink vaginal
mucosa
Gartner duct cysts – common fluid-filled cysts in the lateral walls of the vagina, derived from
wolffian (mesonephric) duct rests
Most benign tumors of the vagina happen in reproductive-age women, and include stromal
polyps, leiomyomas, and hemangiomas
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The most common malignant tumor of the vagina is carcinoma that spread from the cervix,
followed by primary squamous cell carcinoma of the vagina
o Primary carincoma of the vagina is extremely rare
o All primary carcinomas of the vagina are squamous cell carcinomas from HPV
o The greatest risk factor is a previous carcinoma of the cervix or vulva
 Only 1-2% of women with one of those carcinomas get a vaginal carcinoma
o Squamous cell carcinoma of the vagina arises from a premalignant lesion called vaginal
intraepithelial neoplasia (page 1016)
o Lower vagina lesions tend to spread to inguinal nodes, while upper vagina lesions spread
to regional iliac nodes
Embryonal rhabdomyosarcoma (aka sarcoma botryoides) – uncommon vaginal tumor in infants
and kids under 5, made of mostly embryonal rhabdomyoblasts
o They grow as polypoid, rounded, bulky masses that sometimes fill and project out of
the vagina, and look like “grape clusters” (botryoides means grapelike) (page 1017)
o The tumor cells are small and have oval nuclei, with small protrusions of cytoplasm at
one end, so that they look like a “tennis racket”
o They tend to invade locally and cause death by penetrating the peritoneal cavity or
obstructing the urinary tract
The cervix is a main target for infections, viruses, and carcinogens that can lead to invasive carcinoma
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Cervical cancer is the second most common cancer in women, and half are fatal
Cervicitis – cervix inflammation
o At the onset of menarche, the making of estrogens by the ovary stimulates maturation
of the cervical and vaginal squamous mucosa, and making of intracellular glycogen
vacuoles in the squamous cells
o As these cells are shed, the glycogen is used by vaginal bacteria
 The most numerous bacteria is lactobacilli, which make lactic acid that keeps
the vaginal pH below 4.5, which can suppress growth of other organisms
 The low pH also causes lactobacilli to make hydrogen peroxide
 Vaginal pH can be increased by bleeding, sex, douching, and antibiotics, causing
lactobacilli to make less hydrogen peroxide, allowing other stuff to grow and
cause vaginitis or cervicitis
o Some degree of cervical inflammation is seen in most women, and is usually not
clinically important
o Marked cervical inflammation from infections causes reparative and reactive changes of
the epithelium, & shedding of atypical-appearing squamous cells, that can cause
abnormal Pap smears
Endocervical polyps – benign raised (exophytic) growths seen in up to 5% of women (page 1018)
o They can cause irregular vaginal “spotting” or bleeding
o They’re soft, almost mucoid, and made of loose fibromyxomatous stroma with dilated
mucus secreting endocervical glands
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o Often accompanied by inflammation
Cervical cancer used to be the leading cause of cancer deaths in women, but now we screen for
it well and catch it more often
o Pap testing is awesome at detecting cervical cancers,a dn colposcopy lets you actually
see the cervix with a magnifying glass
o HPV can cause cervical cancer
 High oncogenic risk HPVs are the single most important factor in cervical cancer
 Low oncogenic risk HPVs cause sexually transmitted vulvar, perineal, and
perianal condyloma acuminatum
 HPV 16 and HPV 18 are the most important cancer causing HPVs
 HPV 16 causes over half of cervical cancers
o Risk factors for cervical cancer include:
 Multiple sex partners, male partner whose had lots of partners, young age of
first intercourse, high parity (births), persistent infection with HPV 16 or 18,
immunosuppression, HLA subtypes, oral contraceptives, and use of nicotine
o Genital HPV infections are extremely common, but most are asymptomatic and so
aren’t caught by Pap smears
o HPV peaks in occurrence in 20 year olds, and then decreases in risk as you get older
from establishment of immunity and monogamous relationships
o Most HPV infections are temporary and eliminated by the immune system in months
 Half are cleared within 8 months, and most are cleared within 2 years
 High oncogenic risk HPVs last longer
 Persistent infection increases the risk for developing cervical cancers
o HPVs infect immature basal cells of the squamous epithelium in areas of epithelial
breaks, or immature metaplastic squamous cells at the squamocolumnar junction
o HPVs can’t infect the mature superficial squamous cells that cover the ecotcervix,
vagina, or vulva, and infection here only happens if the surface epithelium gets
damaged
o The cervix has a large area of immature squamous metaplastic epithelium, so it’s very
vulnerable to HPV, compared to the vulva which is covered by mature squamous cells
 This is why HPV often infects the cervix & anus, but not often the vulva or penis
o Infection can only happen in immature squamous cells, but replication of HPV happens
in maturing squamous cells (when they turn into keratinocytes), causing a cytopathic
effect called koilocytic atypia, which shows nuclear atypia & a cytoplasmic perinuclear
halo
o To replicate, HPV has to induce DNA synthesis in the host cells
 Since it replicates in maturing nonproliferating squamous cells, it must
reactivate the mitotic cycle in these cells
 Can do this by interfering with rb and p53 tumor suppressor genes
o Viral E6 and E7 proteins are critical for the oncogenic effects of HPV
 They can promote cell growth by binding to RB and up-regulating cyclin E (E7),
interrupting cell death pathways by binding p53 (E6), induce centrosome
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duplication and genomic instability (both), and prevent replicative senescence
by up-regulating telomerase (E6)
 HPV E6 induces rapid degradation of p53 through ubiquitin proteasomes,
decreasing p53 levels
 E7 complexes with active forms of RB, promoting its breakdown by proteasomes
 So they promote DNA synthesis while interrupting p53 causes growth-arrest and
apoptosis, making them critical in extending the life of the epithelial cell
o HPV is integrated into host DNA in cancers, & has free viral DNA in condylomatas and
precancerous lesions
o In HPV, immune status, other carcinogens, and hormones can also determine if the
infection turns cancerous
o HPVs can also infect glandular cells or neuroendocrine cells in the cervix, causing
adenocarcinomas, but this is less common since these tissues don’t support HPV
replication
Cervical intraepithelial cancers (CIN) (page 1020)
o Low grade squamous intraepithelial lesion (LSIL) – shows mild dysplasia (CIN1)
 Involved with HPV, but shows no disruption or changes of the host cell cycle
 Most LSILs regress spontaneously, with very few progressing to HSIL
o High grade squamous intraepithelial lesion (HSIL) – moderate (CIN2) to severe (CIN3)
dysplasia
 HSIL shows dysruegulation of the cell cycle by HPV, which causes increased cell
proliferation, decreased or arrested epithelial maturation, and a lower rate of
viral replication
 Less common than LSILs
o You diagnose squamous intraepithelial lesions (SIL) by characteristic nuclear atypia with
nuclear enlargement, hyperchromasia (dark staining), presence of coarse chromatin
granules, and variation of nucleus size and shape
 Nucleus changes can be accompanied by halos in the cytoplasm which indicate
disruption of the cytoskeleton before release of virus into the environement
 Nucleus changes and perinuclear halos are called koilocytic atypia
o You grade the squamous intraepithelial lesions by how far the immature cell layer
expands
 If the immature squamous cells are confined to the lower 1/3 of the epithelium,
it’s LSIL
 If the expand to 2/3 of the epithelial thickness, it’s HSIL
o The in situ hybridization test will stain for HPV DNA
 The staining will be most intense in the superficial layers of the epithelium
(keratinocytes), which have the highest viral load
o Can stain with Ki-67, which is a marker for cell proliferation
 In normal squamous mucosa, Ki-67 will only stain the basal layer of the
epithelium
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In SILs, Ki-67 positivity is seen throughout the entire thickness of the epithelium,
which indicates abnormal expansion of the epithelial proliferative zone
o So these tests look for staining in the upper nondividing layers of the epithelium,
where the HPV starts replicating
o P16 is overexpressed in cancers from HPV
 P16 is a cyclin kinase inhibitor that inhibits the cell cycle by preventing
phosphorylation of RB
 You still get proliferation in SIL though, cause HPV E7 protein then inactivates RB
o Most LSILs, and all HSILs are associated with HPV, most often HPV 16
o Most HSILs form from progression from a LSIL, but most LSILs won’t progress to HSIL
o HSIL can then progress to carcinoma
Cervical squamous cell carcinoma – most common type of cervical cancer (80% of cases)
o HSIL is an immediate precursor of cervical squamous cell carcinoma
o Cervical adenocarcinoma can less often progress to cervical carcinoma
o These are all caused by high oncogenic risk HPVs
o Pap screening is less effective at detecting adenocarcinomas
o Cervical carcinoma is most common at age 45
o Invasive cervical carcinoma can be fungating (exophytic, raised) or infiltrative
o Squamous cell carciomas are made of nests and tongues of malignant squamous
epithelium that invades the underlying cervical stroma (page 1022 top pic)
o Adenocarcinomas are characterized by proliferation of glandular eiphteilum made of
malignant endocervical cells (page 1022 bottom pic)
 They’ll look darker than a normal gland from large hyperchromatic nuclei and
little mucin in the cytoplasm
o Adenosquamous carciomas are tumors made of a mix malignant glandular and
malignant squamous epithelium
o Neuroendocrine cervical carcinomas look like small cell carciomas of the lungs
o Advanced cervical carcinoma can spread to the tissues nearby, bladder, ureters, rectum,
and vagina
o Stages of cervical cancer:
 Stage 0 – carcinoma in situ (CIN 3, HSIL)
 Stage 1 – carcinoma confined to the cervix
 1a – preclinical carcinoma, diagnosed only by microscopy
o 1a1 – stromal invasion no deeper than 3 mm, & no wider than 7
mm, called a microinvasive carcinoma (page 1022 top right)
o 1a2 –max depth of invasion of stroma deeper than 3mm but
less than 5 mm, and horizontal invasion less than 7 mm
 1b – invasive carcinoma confined to the cervix, & greater than stage 1a2
 Stage 2 – carcinoma extends beyond the cervix, but not to the pelvic wall
 It involves the vagina, but not the lower 1/3 of it
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Stage 3 – carcinoma has extended to the pelvic wall, involves the lower 1/3 of
the vagina, & there is no space between the tumor & pelvic wall on rectal exam
 Stage 4 – carcinoma has extended beyond the true pelvis, or has involved the
mucosa of the bladder or rectum
 Stage 4 includes cancers with metastatic dissemination
Early invasive cervix cancers (microinvasive carcinomas) can be treated by cone biopsy
Most invasive cervical cancers need a hysterectomy
Most people stage 1 and 2 survive, while stage 3 and 4 it goes down to half
Cervical cancer screening and prevention:
 Cytologic screening for cervical cancer is awesome, because most of them are
preceded by a long-standing precancerous lesion
 Pap tests are cytologic preparations of exfoliated cells from the cervical
transformation zone, that are stained with the Pap method
 You use a brush to scrape the transformation zone and put it on a slide
 In staining, the higher the stage of cancer, the less cytoplasm there is
and the bigger the nucleus seems
 Page 1023 – stages on pap smear from normal, LSIL, CIN 2, and CIN 3
 Your first pap smear should be gotten at 21 years old, or within 3 years of onset
of sexual activity, and then you get one annually after
 If at age 30 you’ve had 3 consecutive normal results, you can be screened every
2-3 years
 Can also check for HPV with Pap smears, and normal results means you can
screened every 3 years
 Women at high risk though need it every 6-12 months
 HPV testing in women under 30 isn’t recommended because so many
have HPV, so positives won’t tell you much
 When a pap test is abnormal, a colposcopy of the cervix and vagina is done to
see the extent of the lesion
 LSILs you treat conservatively, HSILs you remove, and then they get follow up
smears for life since they’re considered at increased risk
 HPV vaccine is against types 6, 11, 16, and 18, and is made to reduce the
chances of getting cervical cancer from HPV 16 and 18, and vulvar condylomas
from HPV 6 and 11
 It’s made from noninfectious DNA free virus-like particles that induces
high levels of serum antibodies
 It protects from HPV infection for up to 5 years after vaccination
 Since other HPV types can also cause cervical cancer, there’s still risk for
cervical cancer and they still need check ups
Path Chapter 22: The Female Genital Tract (pages 1052-1061)
The placenta is made of chorionic villi that sprout from the chorion, to provide a large contact area
between mom and fetal circulation – page 1053 and page 1054!
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In the mature placenta, mom blood enters the intervillous space through endometrial arteries
(spiral arteries), and circulates around the villi to allow for gas and nutrient exchange
The deoxygenated blood flows back from the intervillous space to the decidua and enters the
endometrial veins
Deoxygenated fetal blood enters the placenta through 2 umbilical arteries that branch to form
chorionic arteries
Chorionic arteries also branch as they enter the villi
o In the chorionic villi, they form a big capillary system, bringing fetal blood close to
maternal blood
The gas and nutrient diffusion happens through the villous capillary endothelial cells and
thinned-out syncytiotrophoblast and cytotrophoblast
Normally, there is no mixing between the fetal and mom blood
Blood oxygenated in the placenta returns to the fetus through the single umbilical vein
Early pregnancy problems:
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Spontaneous abortion (aka “miscarriage”) – pregnancy loss before 20 weeks gestation
o Most happen before 3 months
o 10-15% of pregnancies end in spontaneous abortion
o In about half of spontaneous abortions, there are chromosome problems, like
aneuploidy, polyploidy, and translocations
o Mom things that can cause abortions are luteal-phase defects and poorly controlled
diabetes
 Uterine defects, like polyps or malformations, can prevent an implantation
good enough to support fetal development
 Systemic stuff affecting mom blood, like clotting problems, hypertension, and
antiphospholipid antibody syndrome, can predispose to miscarriage
o Infections can cause abortion
Ectopic pregnancy – implantation of the fetus anywhere other than the normal uterus site
o The most common site by far for ectopic pregnancy is in the fallopian tubes (90%)
 Other sites could the ovary, abdominal cavity, or where the fallopian tubes meet
the ovary (corneal pregnancy)
o The most important predisposing risk factor for ectopic pregnancy seen up to half of
cases is pelvic inflammatory disease (PID) that causes fallopian tube scarring, called
chronic follicular salpingitis
 Other things that lead to fallopian tube scarring and adhesions are appendicitis,
endometriosis, and previous surgery
 Intrauterine contraceptives devices (IUDs) also increase the risk
o Ovarian pregnancy – happens from rare fertilization and trapping of the ovum within
the follicle right when it ruptures
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o
o
o
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Abdominal pregnancies – happen when the fertilized ovum doesn’t enter the fimbriated
end of the fallopian tube
So the ectopic pregnancy develops placental tissue, amniotic sac, and a fetus
Ectopic pregnancy of the fallopian tubes is the most common cause of hematosalpinx
(blood-filled fallopian tube)
Proper decidualization (getting ready for implantation) is lacking in the fallopian tube, so
growth fo the gestational sac distends the fallopian tube, causing thinning and rupture
 Fallopian tube rupture causes massive intraperitoneal hemorrhage
With time, trophoblastic cells and chorionic villi start to invade the site just like the
would the uterus in normal pregnancy
Ectopic pregnancy shows onset of severe abdominal pain, usually about 6 weeks after
the last menstrual period
 This is when rupture of the fallopian tube leads to pelvic hemorrhage, which is
a medical emergency that can lead to rapid hemorrhagic shock
Late pregnancy problems – in the 3rd trimester
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Complete interruption of blood flow through the umbilical cord from any cause can be lethal to
the fetus
Ascending infections of the chorioamnionic membranes can lead to premature rupture and
delivery
Retroplacental hemorrhage where the placenta meets the myometrium, called abruption
placenta, will threaten both the mom and the fetus
Disruption of the fetal vessels in terminal villi can cause loss of fetal blood that leads to fetal
injury or death
Abnormal placental implantation or development can cause malperfusion
Twin placenta:
o Twin pregnancies happens from fertilization of 2 ova (dizygotic) or from division of one
fertilized ovum (monozygotic)
o 3 types of twin placentas – page 1055
 Diamnionic dichorionic (can sometimes be fused), diamnionic monochorionic,
and monoamnionic monochorionic (monozygotic (identical) twins)
o Monochorionic twin pregnancy can cause twin-twin transfusion syndrome
 Monochorionic twin placentas have vascular anastomoses that connect the
circulations of the twins
 Sometimes, there is abnormal sharing of fetal ciruclaitons through an
arteriovenous shunt
 If an imbalance in blood flow happens, one twin gets more blood than the
other, which can lead to death of one or both fetuses
Abnormal placenta implantation:
o Placenta previa – the placenta implants in the lower uterine part of the cervix, causing
serious 3rd trimester bleeding
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It covers the internal cervical os, so you have to do a cesarean section to avoid
rupturing the placenta and causing fatal mom hemorrhage during delivery
o Placenta accrete – partial or complete absence of the decidua, so placenta villi adhere
directly to the myometrium, making it so that the placenta won’t separate from it
 Causes postpartum bleeding, which can be life threatening to mom
 Risk factors are placenta previa (most cases) and history of C section
Infection of the placenta can either be hematogenous transplacental spread through blood, or
ascending from up the birth canal
o Ascending infections are way more common and almost always bacterial
o Often results in premature rupture of membranes, causing preterm delivery
o The amniotic fluid will be cloudy with purulent exudate and neutrophils
o Also see edema and congestion of chorion-amnion vessels
o The infection causes fetal vasculitis of umbilical and fetal chorionic plate vessels
o Spread thorugh blood through the plaecnta will show acute inflammatory cells, called
acute villitus
o Infection causes inflammatory infiltrates in the chorionic villi, causing chronic villitus
Preeclampsia – systemic syndrome characterized by widespread mom endothelial dysfunction
that shows hypertension, edema, and proteinuria during pregnancy
o Happens in up to 5% of pregnancies, usually in the last trimester, and usually in first
pregnancies
o When it gets more serious and causes convulsions, it’s called ecclampsia
o Other problems from systemic endothelial dysfunction include hypercoagulability, acute
renal failure, and pulmonary edema
o About 1/10 women with preeclampsia develop HELLP syndrome (Hemolysis, Elevated
Liver enzymes, and Low Platelets)
o The placenta is key in causing preeclampsia, and symptoms go away once the placenta is
lost in birth
o The main problems in preeclampsia are diffuse endothelial dysfunction, vasoconstriction
leading to hypertension, and increased vascular permeability that cause proteinuria and
edema
 These are caused by the placenta releasing stuff into mom circulation
o The main problems of preeclampsia:
 Abnormal placental vasculature – pic of all this on page 1056
 The initial event in causing preeclampsia is abnormal trophoblastic
implantation, and mom’s vessels don’t do the normal changes needed
to perfuse the placenta
 In normal pregnancy, fetal extravillous trophoblasts at the implantation
site invade the maternal decidua and decidual vessels, destroy the
vascular smooth muscle, and replace the mom endothelial cells with
fetal trophoblastic cells, forming hybrid fetal-mom blood vessels
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o
This converts the decidual spiral arteries from small vessels to large
capacity uteroplacental vessels lacking a smooth muscle coat
 In preeclampsia, this remodeling doesn’t happen, leaving the placenta
poorly equipped to meet the increased circulatory demands of late
gestation, which can cause placental ischemia
 Endothelial dysfunction and imbalance of angiogenic and anti-angiogenic factors
 In response to hypoxia, the ischemic placenta releases factors into mom
circulation that cause an imbalance in circulating angiogenic/antiangiogenic factors
 This leads to systemic mom endothelial dysfunction and symptoms
 Blood levels of soluble fms-like tyrosine kinase (sFltl) and endoglin, both
anti-angiogenesis factors, is increased in women with preeclampsia
 Placental hypoxia causes overmaking of sFlt1 from the villous
trophoblast
o sFltl is a smaller form of VEGF receptor that acts as a decoy
receptor that binds VEGF and placental growth factor to
neutralize and prevent angiogenesis
 Endoglin is a circulating form of the TGF-β receptor that can bind TGF-β
and inhibit signaling
 Normally in late gestation, sFltl and endoglin levels increase in the
blood, while placental growth factor and VEGF decrese, leading to a
decrease in angiogenesis
 In preeclampsia, high sFLt1 and endoglin cause a decrease in
angiogenesis way earlier than normal, causing defective vascular
development in the placenta
 Clotting problems – preeclampsia causes a hypercoagulable state
 Thrombosis of arterioles and capillaries can happen throughout the
body, especially int eh lvier, kidneys, brain, and pituitary
 This is due to decreased endothelial making of prostacyclin (PGI2), and
increased release of procoagulants
o Making of prostacyclin is stimulated by VEGF and TGF-β
The placenta in preeclampsia will show many changes from malperfusion, ischemia,
and vascular injury:
 Placental infarcts – somewhat common in normal pregnancy, but they’re way
bigger and numerous in preeclampsia
 Shows increased syncytial knots and accelerated villous maturity
 Increased frequency of retroplacental hematomas from bleeding and instability
of uteroplacental vessels
 The decidual vessels show abnormal implantation – most characteristic finding
 Seen as thrombosis, lack of physiologic conversion, fibirnoid necrosis, or
lipid deposition in the vessel (acute atherosis)
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The liver can show hemorrhages and thrombi
The kidney shows diffuses glomerular lesions
Preeclampsia most often starts after 34 weeks gestation
 Will start earlier in women with hydatiform mole or preexisting kidney disease,
hypertension, or clotting problems
 Onset is marked by insidious hypertension and edema, with proteinuria showing
up days after
 Headaches and visual distrubances indicate it’s severe preeclampsia, which
often requires delivery
Ecclampsia is when the CNS gets involved, causing convulsions and coma
You treat ecclampsia by inducing delivery in those who are at term
 If preterm, you manage best you can to avoid having to do early delivery
 Anithypertensives won’t affect preeclampsia at all
Preeclampsia symptoms clear up after delivery
Having preeclampsia may increase the risk for hypertension, heart disease, or brain
disease later in life
Gestational trophoblastic disease – tumors characterized by proliferation of placental tissue, either
villous or trophoblastic
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Includes hydatiform mole, invasive mole, malignant choriocarcinoma, and placental-site
trophoblastic tumor (page 1058-1059)
Hydatiform mole – characterized by cystic swelling of the chorionic villi, with trophoblastic
proliferation
o Moles increase the risk of persistent trophoblastic disease (invasive mole) or
choriocarcinoma
o Molar pregnancy can happen at any age, but risk is higher in teens or at the end of
reproductive life
o Hydatiform mole is rare in the US, but common in the Eastern world
o Two types of benign noninvasive moles – complete and partial moles
 Complete moles – happens from fertilization of an egg that has lost its
chromosomes, and the genetic material comes entirely from dad
 Most have a 46, XX diploid pattern, all gotten from the duplication of
the genetic material of one sperm, a process called androgenesis
 A minority are from fertilization of an empty egg by 2 sperm (46, XX and
46, XY)
 Complete moles are enlarged and edematous, with lots of trophoblast
hyperplasia
 The embryo dies early in development, so there’s rarely ever fetal parts
in the mole
 Have increased risk for choriocarcinoma
 Show abnormalities that involve all or most of the villous tissue
o
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Chorionic villi are enlarged and scalloped shaped with central
cavitation (cisterns), and will lack adequately developed vessels
o They show extensive trophoblast proliferation that involves the
whole circumference of the villi
 Complete moles show increased human chorionic gonadotropin (hCG),
at levels way higher than a pregnancy would show at that point
 Partial mole – happens from fertilization of an egg by 2 sperm
 They’re triploid (69 XXY) and sometimes tetraploid (92 XXXY)
 Fetal parts are more common in partial moles than in complete
 Some villi are edematous and others have only minor changes
 Trophoblastic proliferation is focal and less intense
 Not involved with any risk for choriocarcinoma
o Hydatiform moles look like a group of translucent cystic grapelike structures full of
swollen edematous villi
o P57KIP2 gene can be used to tell the difference between a complete or partial mole
 P57KIP2 is expressed in moles w/ mom tissue only, so it’s found only in partial
moles & not complete moles, since in complete both XX’s come from dad
o Most women with partial and early complete moles have a spontaneous pregnancy
loss, or undergo curettage because of diffuse villi enlargement
o Need to monitor hCG levels, which will be very high
Invasive mole – mole that penetrates the uterine wall (page 1060)
o Chorionic villi invades the myometrium, along with proliferation of cytotrophoblast and
syncytiotrophoblat
o The tumor is locally destructive, and can invade parametrial tissue and blood vessels
o They can spread to other organs, but don’t grow in them like a true metastases
o Invasive moles show vaginal bleeding and irregular uterine enlargement
o It always shows persistently elevated serum HCG
o Bad moles cause uterine rupture, requiring a hysterectomy
Choriocarcinoma –rare malignant tumor of trophoblast cells derived from a previously normal
or abnormal pregnancy (page 1060)
o It’s rapidly invasive and metastasizes widely
o More common in Africa
o Half are preceded by hydatidiform moles, ¼ by previous abortions, and 1/5 from
normal pregnancies
o Choriocarcinoma is a soft, fleshy yellow white tumor that really tends to form large pale
areas of ischemic necrosis, cystic softening, and extensive hemorrhage
o It’s made entirely of a mixed proliferation of syncytiotrophoblasts and
cytotrophoblasts
o Mitoses are abundant
o Due to rapid growth, it’s subject to hemorrhage, ischemic necrosis, and inflammation
o Uterine choriocarcinoma is seen as irregular vaginal spotting of a bloody, brown fluid
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This happens during an apparently normal pregnancy, after a miscarriage, or
after curettage
 Can take months to appear sometimes
 Usually by the time you notice symptoms, it’s already spread, most often to the
lungs and vagina
 HCG is even higher than it was with moles
o Every choriocarcinoma can be cured by chemo
Placental site trophoblastic tumor – rare tumor of proliferation of extravillous trophoblast aka
intermediate trophoblast