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Chapter 22: The Female Genital Tract

Thursday, January 14, 2019


7:13 PM - BobSteele

• Embryology
• Unfused upper portions of the müllerian ducts--> Fallopian tubes
• Fused lower portions of the müllerian ducts --> Uterus, cervix, and upper vagina
• Endometriosis is a müllerian-derived lesion
• may occur in the vagina and clinically simulate a neoplasm
• Urogenital sinus --> lower vagina
• Mesonephric ducts --> normally regress
• Gartner duct cysts: when remnants of the mesonephric ducts persist into adult life as epithelial inclusions
adjacent to the ovaries, tubes, and uterus; in the cervix and vagina these rests may be cystic and are termed
Gartner duct cysts
• coelomic epithelium (mesothelium) --> lining of the female genital tract as well as the ovarian surface
• morphologically similar lesions arise in various sites within the female genital tract and the adjacent
peritoneal surfaces

• Common curable STIs


Buzzwords

Chlamydia pelvic inflammatory disease; serous discharge


trachomatis

Neisseria pelvic inflammatory disease (most serious complication of gonorrhea in


gonorrhea women); purulent discharge; gram negative diplococci within
neutrophils (PMNs)

Trichomonas large, flagellated ovoid protozoan; yellow, frothy vaginal discharge;


vaginalis "strawberry cervix"

Treponema 1º - painless chancer, 2º - maculopapule rash, conyloma latum 3º -


pallidum Gummas, tabes dorsalis, saber shins Hutchinson teeth

Gardnerella gram negative bacillus; main cause of bacterial vaginosis; thin, grey-
vaginalis green malodorous (fishy) vaginal discharge; premature labor

Ureaplasma pre-term deliveries


urealyticum,
mycoplasma
hominis

1
• Plasma cell morphology
• Nucleus placed off to one side
• Clearing around the nucleus

• Herpes Simplex Virus (HSV)


• Definition
• Common and involves the cervix > vagina > vulva
• By age 40, 30% of females present with antibodies to
type 2
• HSV-1 → oropharyngeal infection
• HSV-2 → genital mucosa + skin infection

• Presentation
• 1/3 of newly infected females show painful lesions 3-7 days
post-infection with fever, malaise, and tender inguinal lymph nodes
• Red papules that progress to vesicles and then to painful coalescent ulcers
• Cervical or vaginal lesions present with purulent discharge and pelvic pain
• Lesions around the urethra may cause painful urination and urinary retention
• ALL MALES are symptomatic

• Viral characteristics
• Herpesvirus family; large linear dsDNA, enveloped, icosahedral, derives
envelope from nuclear membrane, contains intranuclear inclusion
bodies AKA Cowdry bodies

• Lesions
• Lesions are red papules that progress to vesicles and the coalesce to ulcers that are easily visible on the
vulva, but lesions on the cervix or vagina are associated with purulent discharge and pain
• Vesicles & ulcers contain viral particles causing ↑ transmission rate with active infection
• Lesions heal spontaneously in 1-3 weeks
• Easily visible on vulvar skin and mucosa
• Near urethra = painful urination (dysuria)

• Latency
• Infection remains latent in lumbosacral nervous ganglia
• Reactivation due to stress, trauma, UV light,
hormonal changes (skin & mucosal lesions)
• Immunocompromised → meningitis,
hepatitis, pneumonitis
• Detection of anti-HSV antibodies in the serum is indicative
of recurrent/latent infection

• Morphology
• Usually biopsy the ulcer phase
• Desquamated epithelium with acute inflammation at the ulcer bed
• Multinucleated squamous cells with eosinophilic to basophilic viral inclusions with a "ground glass"
appearance (viral cytopathic effect)

• Transmission
• Transmitted during active infection
• May occur during latent phase due to subclinical viral shedding
• ↓ risk with condoms and antiviral therapy
• Never completely prevented!
• Females have higher susceptibility
• Previous infection with HSV-1 ↓ risk of infection with HSV-2
2
• HSV-2 infection enhances HIV-1 acquisition and transmission
• Vertical transmission (mom to baby) warrants C-section if infection is (1° and) active
• Deadly to neonates – high mortality rate

• Diagnosis & Complications


• Diagnosed clinically
• Associated with a high mortality rate (2% US women)
• Aspiration of exudate shows viral cytopathic effect after 48-72 hrs, and allows serotyping
• Primary, acute infections do not have established antibodies in the serum
• Antibody (Smith antigen) detection = recurrent/latent infection
• Use the Tzanck smear

• Treatment
• There is no treatment, but some antivirals (acyclovir) can shorten the active phase

• Molluscum contagiosum (poxvirus)

• Definition
• Skin or mucosal poxvirus with 4 subtypes
• MCV1: most prevalent
• MCV2: most often sexually transmitted
• 6 week incubation period

• Viral characteristics
• dsDNA , can make its own envelope, has complex morphology, only DNA virus that replicates in the
cytoplasm and has own RNA polymerase and everything it needs to replicate outside the nucleus
• Guarnieri bodies, or inclusion bodies, which are sites of viral replication in the cytoplasm and a dumbbell
shaped core

• Transmission
• Children (2-12 years old): spread via direct contact or shared items (towels) and is most common on the
trunk, arms & legs. Think of sexual abuse if seen in genitals in kids.
• Adults: sexually transmitted and seen on genitals, lower abdomen,
buttocks, inner thighs

• Clinical appearance
• Pearly, dome-shaped papules with a dimpled center
• The papules measure 1 to 5 mm in diameter, dimpled umbilicated
center, and their central waxy core contains cells with cytoplasmic
viral inclusion bodies

• Diagnosis
• 1-5mm papules
• Pearly, dome shaped with dimpled/umbilicated center
• Central waxy core with cytoplasmic viral inclusions

• Candida (Moniliasis)
• Definition
• Yeast are part of many females’ normal vaginal microflora
• Opportunistic yeast infection with disturbance of the microbial ecosystem
• Increased incidence: DM, antibiotics, pregnancy, burn patients, indwelling catheter, immunosuppression
(compromise neutrophils or Th17 cells)
• Most common cause of opportunistic mycosis

• Yeast characteristics
3
• Dimorphic: mold in the heat, yeast in the cold
• Forms pseudohyphae and budding yeast at 20˚C and germ tubes-hyphae molds at 37˚C

• Presentation
• Intense vulvovaginal pruritis, erythema, and swelling
• Thick white vulvovaginal discharge “curd-like or cottage cheese-like”
• If severe → mucosal ulceration

• Diagnosis
• Pseudospores or filamentous fungal hyphae in wet KOH mounts of discharge or on Pap smear
• Not considered an STI

• Trichomonas vaginalis
• Definition and transmission
• Large, flagellated ovoid protozoan
• Sexual transmission
• 4-14 days to develop
• Most common curable STI

• Presentation
• Yellow, frothy vaginal discharge, vulvovaginal discomfort, dysuria, dyspareunia
• Fiery red mucosa of the vagina and cervix
• Marked dilation of cervical mucosal vessels → 'strawberry cervix' (colposcopic appearance)

• Diagnosis
• Motile trophozoites in methylene blue wet mount, present with corkscrew motility

• Gardnerella vaginalis
• Definition
• Gram -ve bacillus
• Main cause of vaginitis (Bacterial vaginosis)
• Found normally in the reproductive tract, but lactobacillus keeps it in check

• Presentation
• Present with thin, green-gray, malodorous (fishy)
discharge
• Pregnant patients: may cause premature labor.

• Diagnosis
• Pap smear: superficial, intermediate squamous cells covered by a shaggy coating of coccobacilli (clue cells)
• Cultures: also contain anaerobic pepto-streptococci and aerobic α-hemolytic streptococci
• Need to differentiate it from candida and trichomonas by examining a slide to look for clue cells
• Whiff Test: there is a fishy amine odor when KOH is added to it

• Ureaplasma urealyticum & Mycoplasma hominis


• May cause some cases of vaginitis & cervicitis

4
• Implicated in chorioamnionitis and premature delivery in
pregnant patients
• Ureaplasma: urease positive
• Mycoplasma: no cell wall
• Look for the fried egg appearance

• Chlamydia trachomatis
• Definition
• Most common STI in the world
• One of the main causes of pelvic inflammatory disease

• Bacterial characteristics
• Small gram -ve obligate intracellular bacteria

• Two forms
• Elementary body: metabolically inactive, infectious form in endosome - infectious
• Reticulate body: metabolically active form - Replicating

• Presentation
• Usually asymptomatic or presents similar to gonorrhea: primary infection is characterized by a
mucopurulent discharge containing a predominance of neutrophils
• Chlamydia == mucopurulent ("pus-sy")
• Gonorrhea == serous, thin, watery

• Most infections cause cervicitis


• In some patients it may ascend to
the uterus and fallopian tubes →
endometritis and salpingitis
• Infection of non-ciliated columnar or
cuboidal epithelial cells of mucosal
surfaces leads to granulomatous
response and damage

• Diagnosis
• Diagnose with Nucleic Acid Amplification Test (NAAT)

In lecture
• Granuloma inguinale – uncommon in US and europ – but common in rural areas of
developing countries
• Chancroid is uncommon in US – but most common in Africa and Southeast Asia
• L serotypes of C. trachomati causes lymphogranuloima venerum – chronic ulcerative
disease – Lymphogrannuloma venerum – sporadic disease in US and Europ – Endemic in
Asia, Affrica, Caribbean region, South America

• Granuloma Inguinale - Klebsiella granulomatous giesma stain – Donovan bodies – macrophages with encapsulated
coccobaciliary organisms – 20 year old female on OCP – uncommon in US and Europe be endemic in rural areas and
developing countries

• Pelvic Inflammatory Disease (PID)


• Definition
• Infection that begins in the vulva or vagina and spreads upward to involve most of the structures of the
female genital system
• Causes pelvic pain, adnexal tenderness, fever, and vaginal discharge
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• Most infections travel via the lymph or venous systems rather than the mucosal route (except Neisseria
gonorrhea)
• Causes
• Neisseria gonorrhea
• Chlamydia trachomatis (serotypes D-K)
• Puerperal infections: infections after spontaneous or induced abortions and normal or abnormal deliveries
• Polymicrobial: may be caused by staphylococci, streptococci, coliforms, and Clostridium perfringens
• PID caused by these microbes tends to show less involvement of the mucosa and the tube
lumen, and more inflammation within the deeper tissue layers
• Bacteremia is a more frequent complication of streptococcal or staphylococcal PID than gonococcal

• Acute complications
• Peritonitis & bacteremia
• Endocarditis, meningitis and suppurative arthritis
• Chronic sequelae
• Infertility, tubal obstruction, ectopic pregnancy, pelvic pain, intestinal
obstruction due to adhesion between bowel and pelvic organs
• Fitz-Hugh Curtis syndrome: rare complication involving liver capsule
inflammation leading to the creation of adhesions (especially from
Neisseria gonorrhea) – violin string

• Lymphogranuloma venereum
• From Chlamydia Trachomatis serotypes L1-L3
• Prevalent in Africa, Asia, and South America
• Presents first with a painless ulcer at the site of contact then progresses to swollen lymph nodes leading to genital
elephantiasis in late stage
• Tertiary stage presents with ulcers, fistulas, and genital elephantiasis

• Trachoma
• From Chlamydia serotypes A, B, Ba, and C – is the leading cause of preventable infectious blindness
• Follicular conjunctivitis leading to conjunctival scarring; in-turned eyelashes leading to corneal scarring &
blindness

• Treponema pallidum (syphilis)


• Bacterial characteristics
• Thin spirochete, poorly visible on gram stain but has thin gram (-) envelope
• Outer membrane has endotoxin-like lipids, axial filaments = endoflagella = periplasmic flagella allows for
motility, cannot culture in clinical lab so serodiagnosis
• Obligate pathogen, but not intracellular

• Transmission
• Sexually or across the placenta

• Pathogenesis
• Disease is characterized by endarteritis resulting in lesions; strong tendency to chronicity

• Diagnosis
• Visualized by immunofluorescence or dark-field microscopy
• Warthin-Starry stain or steiner silver stain
• Can also use VDRL or RPR

• Jarisch-Herxheimer reaction
6
• Starts generally during the first 24 hours of antibiotic treatment and presents with increase in temperature,
decrease in blood pressure, rigors, and leukopenia

• Primary stage
• Non-tender chancre (wart); clean, indurated edge; contagious; heals spontaneously 3-6 weeks but
progresses because painless and is typically left untreated

• Secondary stage
• Maculopapular (copper-colored) rash that is diffuse, and includes palms and soles, patchy alopecia;
condyloma lata: flat wart like perianal and mucous membrane lesions; highly infectious

• Latent stage
• No clinical symptoms.

• Tertiary Stage
• Gummas or syphilitic granulomas that are soft growths with firm necrotic centers
• Aortitis and aneurysm of ascending aorta with tree-barking appearance; destroys the vasa vasorum that
supplies the aorta with blood
• CNS inflammation: damage to the posterior column of the spinal cord and ocular defect of Argyll Robertson
("prostitutes") pupils which react to accommodation but has no reaction to light

• Congenital
• Desquamating Maculopapular rash & Tabes dorsalis
• Can have Saber-shins or anterior bowing of the tibia; saddle nose; Hutchinson’s notched teeth and
Mulberry molars with enamel outgrowths; deafness
• Treatment
• Penicillin G

• Puerperal Infection
• Infection after spontaneous or induced abortion and normal or abnormal deliveries
• Polymicrobial with Staph, Strep, coliforms, Clostridium perfringens

• Neisseria gonorrhea – gram – diplococci intracellular


• Definition
• Most common cause of PID
• Inflammatory changes appear 2-7 days after inoculation
• Involves endocervical mucosa (or Bartholin gland, other vestibular or periurethral glands)
• Spreads cephalad (ascending infection) to fallopian tubes and tuboovarian region via mucosal surfaces;
endometrium is usually spared
• May become disseminated

• Bacterial characteristics
• Phagocytosed gram -ve diplococci within neutrophils/PMNs (intracellular)
• Will have pili on electron microscopy

• Presentation
• Females: Often asymptomatic; scarring of tubal lumen and fimbriae can → infertility or ectopic pregnancy
• Can lead to Fitz-Hugh Curtis syndrome
• Males: Urethral discharge

• Morphology
• Marked acute inflammation of involved mucosal surfaces
• Acute suppurative salpingitis
7
• Infection of the fallopian tubes
• Diffusely infiltrated → epithelial injury & sloughing of plicae

• Salpingo-oophoritis: exudate leaks from fimbriae of the tubal lumen to cause infection of the ovary

• Tubo-ovarian abscesses: Collections of pus in the ovary and fallopian tube or in the tubal lumen (pyosalpinx)

• Chronic salpingitis: Scarring of denuded tubal plicae causing gland-like spaces and blind pouches

• Hydrosalpinx: due to fusion of fimbriae and the accumulation of tubal secretions and tubal distension.

• Definitive diagnosis
• Detection of DNA or RNA
• Culture or NAATS
• Thayer-Martin agar

• Treatment
• antibiotics
• Penicillin resistant strains have emerged
• Tubo-ovarian abscesses may require surgical removal as antibiotics may not penetrate
• Post abortion/postpartum are much more difficult to control due to broad spectrum of potential pathogens

• Human Papillomavirus - HPV


• Presentation:
• Multiple warty lesions on the perineum and around the anus
in low-risk types 6 and 11
• VIN – vulvar
• VaIN – vagina
• Cervix - CIN

• Viral characteristics
• Non-enveloped, double-stranded, circular DNA virus with an
icosahedral capsid.
• Composed of early proteins (E1, E2, E4, E5, E6*, E7*) and late proteins (L1, L2)

• Transmission
• HPV enters the target cells by binding to its cellular receptor. This binding is dependent only on capsid protein
L1 and does not require the other capsid protein L2. HPVs are generally internalized via a clathrin-dependent
endocytic mechanism.
• After getting internalized, the viral coat is disassembled which allow viral genomes access to the cellular
transcription and replication machinery.
• The virus infects the stem cells basal keratinocytes of the mucosal (genital) epithelium and delivers the
genome to the nucleus.
• Infected epithelial cells are called koliocytes -- have a krinkled nucleus that looks like a raisin

• Interaction with the immune system


• The complete virus cycle takes place above the basal layer and without directly triggering cell lysis, limits
the interaction of viral antigens (which do not spill out) with the immune cells of the host that keep an active
surveillance for pathogens of the basal membrane.
• Thus the immune system remains largely unaware of the infection that has taken place in the
epithelium
• Together these events help attain a sort of immune anergy that explains the general lack of local
inflammation, the poor immune response to the virus, and the long persistence of HPVs even in healthy
immunocompetent individuals.

8
• High risk types: 16, 18, 31, 33, 45

• Oncogenic effects
• oncogenic potential of HPV can be explained by the activities of the two viral genes encoding E6 and E7

• E6 == “Cutting the breaks”


• E6 protein binds to and mediates the degradation of p53
• E6 stimulates the expression of TERT, the catalytic subunit of telomerase
• contributes to the immortalization of cells
• E6 from high-risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types

• E7 == “Foot on the gas pedal”


• The E7 protein has effects that complement those of E6, all of which are centered on speeding cells through
the G- S cell cycle checkpoint
• It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB
• promoting progression through the cell cycle.
• E7 proteins from high-risk HPV types have a higher affinity for RB than E7 proteins from low-risk HPV types
• E7 inactivates the CDK inhibitors p21 and p27
• E7 proteins from high-risk HPVs (types 16, 18, and 31) also bind and activate cyclins E and A

• Listeriosis
• Listeria monocytogenes can cause stillbirth, neonatal sepsis, or abortion
• In infants it can lead to widespread disease (granulomatosis
infantiseptica) and exudative meningitis
• Facultative intracellular bacillus
• Look for gram +ve intracellular bacilli in the CSF
• Can also look for the bacillus if there are abscesses with alternating greyish
or yellow nodules

• Haemophilus ducreyi - Chancroid


• Acute ulcerative infection that leads to painful chancroid (soft chancre)
• The chancre is tender and erythematous on the external genitalia Figure 1: chancroid
(penis, vagina/periurethral area) that erodes over a few days to make
an irregular non-indurated painful ulcer. There may be multiple ulcers.
• Regional lymph nodes are enlarged 1-2 weeks later (buboes) and may lead to ulceration of the overlying skin
• Especially prevalent in tropical areas in Africa and southeast Asia
• Cofactor in HIV transmission
• Coccobacci are sometimes found on silver stain

• Klebsiella granulomatous
• Can cause granuloma inguinale (donovanosis): raised papular lesion
on the moist stratified squamous epithelium of the genitalia or the
pharynx/oral mucosa
• There is eventual ulceration and lots of granulation tissue

• Active lesions have epithelial hyperplasia at the borders of the


ulcer

• Bacterial characteristics: minute encapsulated coccobacillus


• Endemic in rural developing countries

9
• Untreated cases lead to excessive scarring --> lymphatic obstruction
and lymphedema == elephantiasis
• Look for encapsulated coccobacilli in macrophages (Donovan bodies) on
Giemsa stain

• STIs with ulcers


• HSV
• Syphilis
• Chancroid (haemophilus ducreyi)
• LGV lymphogranuloma venereum (Chlamydia trachomatis (L1-3)
• Klebsiella granulomatis

VULVA
• Many diseases of the skin elsewhere on the body can also affect this area including psoriasis, eczema, allergic dermatitis
• Prone to superficial infections due to constant exposure to secretions
• Immunosuppression: vulvitis
• Contains modified apocrine sweat glands

• Bartholin Cyst
• Acute inflammation (adenitis) than can create an abscess
• Occur at all ages
• due to obstruction of the duct by an inflammatory process

• Lined with transitional or squamous epithelium


• 3-5 cm in diameter
• Pain + local discomfort
• Treatment: excised or opened permanently (marsupialization)

• Leukoplakia
• Descriptive clinical term for opaque, white, plaque-like epithelial thickening that may produce pruritus and scaling
• May be due to:
• Inflammatory dermatoses (psoriases, chronic dermatitis)
• Lichen sclerosis & squamous cell hyperplasia
• Neoplasia: vulvar intraepithelial neoplasia (VIN), Paget disease, invasive carcinoma

10
• Lichen Sclerosis
• Definition
• Smooth, white plaques or macules seen on the vulva
• May enlarge and coalesce → 'porcelain/parchment'
surface
• paper-thin plaque -- very, very thin

• Occurs at any age, most common in post-menopausal


females
• labia become atrophic and agglutinated & the
vaginal orifice constricts when the entire vulva is
involved

• Autoimmune likely
• presence of activated T cells in the subepithelial
inflammatory infiltrate
• increased frequency of autoimmune disorders in
affected women

• Cancer risk
• Not a premalignant lesion
• women with symptomatic lichen sclerosis have a slightly increased risk of developing squamous cell
carcinoma of the vulva
• Patients have an ↑ incidence of autoimmune disorders

• Morphology
• Marked thinning of the epidermis (parchment paper)
• Degeneration of the basal cells
• Excessive keratinization (hyperkeratosis)
• Sclerotic changes of the superficial dermis
• Activated T cells are seen in the subepithelial inflammatory infiltrate (band-like infiltrate)

• Squamous Cell Hyperplasia (nee Hyperplastic dystrophy or lichen simplex chronicus)


• Definition
• Nonspecific condition resulting from rubbing or scratching of the skin to
relieve pruritus
• Presents as leukoplakia; histology reveals acanthosis (thickening of the
epidermis) and hyperkeratosis
• Not considered premalignant
• sometimes present at the margins of vulvar cancers
• Morphology
• Thickening of the epidermis + hyperkeratosis
• Hyperplastic epithelium may show mitotic activity but lacks cellular
atypia
• Lymphocytic infiltration of the dermis may occur

BENIGN EXOPHYTIC LESIONS

• Condyloma Acuminatum (genital wart) == HPV


• Definition

11
• Benign genital warts due to low oncogenic risk HPV (6 & 11)
• Usually multifocal
• Involve vulvar, perineal and perianal areas +/- cervix and
vagina
• Not precancerous lesions
• Morphology
• Papillary, exophytic, tree-like cores of stroma covered by thickened
squamous epithelium (no mucous inside of them)
• Surface epithelium: viral cytopathic changes (koilocytic atypia)
• Nuclear enlargement, hyperchromasia, and a cytoplasmic nuclear halo -- nucleus looks like a raisin

• Condyloma latum: benign raised lesion due to syphilis == treponema pallidum

• Fibroepithelial Polyp: skin tag of the vulva similar to other places on the body

• Vulvar Squamous Papilloma


• Benign exophytic proliferations covered by nonkeratinized squamous epithelium
• Develop on vulvar surfaces
• Single or numerous

SQUAMOUS NEOPLASTIC LESIONS

• Carcinoma of the Vulva


• Definition
• Most common (still uncommon malignant neoplasm – SCC most common type)
• 2/3 occur in females > 60 years
Basaloid Carcinoma Morphology Warty Carcinoma
• Two types Morphology
• Basaloid & warty carcinoma related to
Exophytic or indurated and ulcerated Exophytic, papillary
HPV 16 (younger age, 50’s)
architecture
• Keratinizing SCC not related to HPV Small tightly packed basaloid cells Prominent koilocytic
(older age) atypia

Foci of central necrosis

12
• Classic Vulvar Intraepithelial Neoplasia (VIN) (carcinoma in situ, Bowen disease) – see
photo below

• Definition
• Precursor lesion to basaloid & warty carcinoma of the vulva
• Most common in females of reproductive age
• HPV16 related

• Increased risk with increased risk of HPV-16 infection


• Young age at first intercourse
• Multiple sexual partners
• Male partner with multiple sexual partners

• Presentation
• Multi-centric around the vulva
• 10-30% also have vaginal or cervical HPV related lesions

• Progression to carcinoma
• Spontaneous regression may occur
• More likely to progresses to invasive
carcinoma in females > 45 years old or
immunocompromised

• Morphology
• Discrete white (hyperkeratotic) or slightly raised,
pigmented lesion
• Epidermal thickening, nuclear atypia, increased
mitoses and lack of cellular maturation
• May progress to invasive carcinoma that are exophytic or indurated with central ulceration
• Histology: nests and cords of small, tightly packed cells that lack maturation and resemble the basal layer of
the normal epithelium

• Keratinizing Squamous Cell Carcinoma


• Occurs in older women with long standing lichen sclerosus or squamous cell hyperplasia
• Not related to HPV infection
• Precursor lesion is differentiated vulvar intraepithelial neoplasia (differentiated VIN, or VIN simplex)

• Differentiated VIN (VIN simplex)


• Pathogenesis
• Gradual acquisition may be due to acquisition of driver mutations in oncogenes and tumor suppressors
• ↑ frequency of TP53 mutations
• May be associated with chronic epithelial irritation (lichen sclerosus or squamous cell hyperplasia)

• Morphology
• Marked atypia of the basal layer of the squamous epithelium
• Normal differentiation of the superficial layers

13
• Invasive keratinizing squamous cell
carcinomas
• Nests and tongues of malignant squamous
epithelium
• Prominent central keratin pearls

• Progression to carcinoma and spread


• Once invasive lesions develop the
prognosis and risk of metastases is related
to tumor size, depth of invasion and
involvement of lymphatic vessels
• Initially spreads to inguinal, pelvic, iliac and periaortic lymph nodes
• Can spread lympho-hematogenously to lungs, liver and other organs

• Prognosis
• Lesions < 2cm = 90% 5 year survival after treatment with vulvectomy + ladectomy
• Larger lesions with involved lymph nodes have worse prognosis
• Lower 1/3 of vagina = inguinal LN
• Upper 1/3 of vagina = internal iliac

Key CONCEPTS
• 30% of vulvar cancers are caused by infection with high-risk HPVs (HPV-16, 18, 31, and 33)
• Develop from an in situ lesion termed classic VIN

• 70% of vulvar cancers are not related to HPV and develop in a background of lichen sclerosus or squamous cell
hyperplasia
• Premalignant lesion == differentiated VIN

GLANDULAR NEOPLASTIC LESIONS – modified apocrine sweat glands – breast like features – the vulva may be involved by 2
tumors with counter parts in the breast

• Papillary Hidradenoma
• Sharply circumscribed nodule
• Most common on the labia majora or inter-labial folds
• Tends to ulcerate = clinically confused with carcinoma

• Morphology
• histology is identical to intraductal papilloma of the breast

• Papillary projections covered with two layers of cells


• Upper layer: columnar secretory cells
• Deep layer: flattened myoepithelial cells (characteristic of
sweat glands and sweat gland tumors)

• Extramammary Paget Disease


• Pruritic, red, crusted, map-like area, usually on the labia majora

• Not associated with underlying cancer (unlike the counterpart in the breast)
• Paget disease of the nipple == 100% of patients have underlying ductal breast carcinoma

14
• Extramammary Paget Disease == typically not associated with underlying cancer and is confined to the
epidermis of vulvar skin

• Morphology
• Intraepithelial proliferation of malignant cells
• Cells are larger than surrounding keratinocytes
• May be single or in small clusters within the epidermis
• Express apocrine, eccrine and keratinocyte differentiation
• Express cytokeratin 7
• likely arise from multipotent cells in the mammary-like
gland ducts of the vulvar skin
• Have pale cytoplasm with mucopolysaccharide that stains with PAS, Alcian blue, or mucicarmine stains

• Location of tumor
• Intraepithelial malignancy
• Confined to the epidermis of vulvar skin
• Cells spread laterally within the epidermis and may be present beyond the borders of the visible lesion
• treatment is wide local excision

• Metastasis
• May remain intraepidermal for years and not invade or metastasize
• Invasion = poor prognosis

VAGINA
• Remarkably free from primary disease
• Squamous cell carcinoma is the most serious primary disease
• In adults, inflammation often affects the vulva and perivulvar structures and spreads to the cervix without significant
involvement of the vagina

• Developmental Anomalies
• Septate (double) Vagina
• due to failure of Müllerian duct fusion and is accompanied by a double uterus (uterus didelphys)
• Causes:
• Genetic syndromes
• In utero exposure to DES (diethylstilbestrol)
• used to prevent threatened abortions (vaginal bleeding during the first 20 weeks)
• Disturbed epistromal signaling during fetal development

15
• Vaginal Adenosis
• Embryonal epithelium: columnar, endocervical type epithelium
• Replaced with squamous epithelium ascending from the
urogenital sinus
• small patches of residual glandular epithelium which persists
into adult life == vaginal adenosis
• Red, granular areas that stand out from a normal, pale-pink
vaginal mucosa
• Micro: columnar mucinous epithelium indistinguishable from endocervical epithelium
• Most common in females exposed to DES in utero
• Rarely: clear cell carcinoma can arise from DES-related adenosis
• stopped using DES in the 1980s

• Gartner Duct Cyst


• Common lesions found along the lateral vaginal walls
• Derived from Wolffian (mesonephric) duct rests
• cysts In the proximal vagina are derived from müllerian epithelium
• 1-2cm fluid filled cysts found in the submucosa

• Premalignant & Malignant Neoplasms of the Vagina


• Benign Vaginal Tumors
• Occur in females of reproductive age
• Stromal tumors (stromal polyps)
• Leiomyomas
• Hemangiomas

• Squamous Cell Carcinoma of the vagina


• Virtually all primary carcinomas of the vagina are squamous cell carcinomas associated with high-risk HPVs
(16, 18, 31, and 33)
• ↑ risk: previous carcinoma of the cervix or vulva
• Arises in 1-2% of females with previous invasive cervical carcinoma
• Premalignant lesion == vaginal intraepithelial neoplasia (VIN)
• Analogous to cervical squamous intraepithelial lesions
• Most invasive tumors affect the posterior wall of the upper vagina at the junction of the ectocervix
• Lesions of the upper 1/3 metastasize to iliac lymph nodes
• Lesions in the lower 2/3 metastasize to inguinal lymph nodes

• Embryonal Rhabdomyosarcoma (sarcoma bortyoides)


• Definition
• Rare tumor of malignant embryonal rhabdomyoblasts
• Infants and children < 5 years
• Tumors invade locally and cause death via penetration
into the peritoneal cavity or obstruction of the urinary
tract.

• Morphology
• Cells are small with oval nuclei and cytoplasmic protrusions
(tennis racket shape)
• Striations may be seen in the cytoplasm
• Tumor cells may be crowded in a cambium layer beneath vaginal
epithelium
• Or the tumor cells can be within an edematous, loose fibromyxomatous stroma in the deep
regions with inflammatory cells (often mistaken for inflammatory polyps)

16
• Grow as polypoid, rounded, bulky masses
• Bortyoides = Appear as grapelike clusters
• Tend to invade locally and cause death by penetration into the peritoneal cavity or by
obstruction of the urinary tract

• Treatment
• Conservative surgery + chemotherapy
• Best if diagnosed early

CERVIX

• Cervix
• External vaginal portion (ectocervix)
• Visible on vaginal exam
• Covered with mature squamous epithelium continuous with the vaginal wall that converges at the external os

• Endocervical canal
• Columnar, mucus secreting epithelium that converges at the external os
• Ectocervix and endocervical come together at the squamocolumnar junction

• Squamocolumnar Junction == transformation zone


• Location where squamous and columnar epithelium meet
• Variable position based on age and hormonal influence
• Typically moves upward into the endocervical canal with time
• squamous metaplasia == the replacement of the glandular epithelium by advancing squamous
epithelium

• Transformation Zone -- this matters


• Area of the cervix where the columnar epithelium abuts the squamous epithelium
• Immature squamous metaplastic epithelial cells in this zone are the most susceptible to HPV infection

• The unique epithelium of the cervix makes it highly susceptible to HPV infections
• HPV == leading cause of cervical cancer so this matters

• MOST susceptible area


• this is where cervical precursor lesions and cancers will develop

17
INFLAMMATIONS

• Lactobacilli in the vagina


• Gram +ve non-spore forming bacillus
• Dominant microbial species of the normal vagina
• Produces lactic acid --> maintains pH < 4.5 that suppresses growth of other saprophytic and pathogenic
organisms
• At low pH they produce H2O2, which is bacteriotoxic
• pH becomes alkaline (> 7) due to bleeding, sexual intercourse, antibiotics, or vaginal douching
• Leads to ↓ H2O2 production by lactobacilli
• Promotes overgrowth of other microorganisms that can lead to cervicitis or vaginitis
• Receives nutrients from intracellular glycogen vacuoles of squamous cells which start being shed at puberty
• Cervicitis or vaginitis
• (acute or chronic)
• May be due to gonococci, chlamydia, mycoplasmas, HSV

• Important to identify because of associations with upper genital tract disease, pregnancy complications, sexual
transmission, and pelvic inflammatory disease (PID) --> Fitz-Hugh-Curtis Syndrome (violin string adhesions)

• Marked cervical inflammation can cause reparative and reactive changes of the epithelium + shedding of atypical
squamous cells → abnormal Pap smear
• due to infection, not neoplasm -- don't want to do a hysterectomy because of an infection, give antibiotics

• Endocervical Polyps
• Common, benign exophytic growths within the endocervical canal
• Loose, fibromyxomatous stroma covered by mucus secreting endocervical
glands +/- inflammation
• Vary from small, sessile 'bumps' to large, polypoid masses that protrude
through the cervical os
• may be the source of irregular vaginal "spotting" (bleeding) that
arouses suspicion for ominous disease
• Treatment: curettage or surgical excision = curative

• Cervical Carcinoma
• 3rd most common cause of cancer in women worldwide
• Typically progresses slowly, allowing screening, detection and treatment
• 50% are fatal
• Significant benefits from early diagnosis & curative treatment
• Pap smears detects precursor lesions and low-stage, highly curable cancers
• Strong association with HPV

• High risk HPV strains


• 15 high risk HPVs, but HPV-16 accounts for 60% of cervical cancer cases (the most high-risk/prevalent == HPV-16)
• HPV18 accounts for 10%

• High Risk HPVs on cancer


• Most important factor in the development of cervical cancer
• Also implicated in squamous cell carcinoma at other sites (vagina, vulva, penis, anus, tonsils, oropharynx)

• HPV is a DNA virus


• Viral DNA remains extrachromosomal (episomal)
• Alone, it is not sufficient to cause cervical cancer
• Progression to carcinoma is influenced by exposure to cocarcinogens and host immune status
• Cause 80% of LSIL and 100% of HSIL
• LSIL – low grade squamous intraepithelial lesion
18
• HSIL – high grade squamous intraepithelial lesion

• Low Risk HPVs on cancer


• Cause of condyloma acuminata
• Sexually transmitted infections of the vulvar, perineal and perianal regions
• E6: Fails to bind p53, but dysregulates growth & survival via the Notch pathway
• E7: Bind RB with low affinity
• Viral DNA remains extrachromosomal (episomal)

• HPV Infections
• genital HPV infections are extremely common; most of them are asymptomatic, do not cause any tissue changes,
and therefore are not detected on Pap test
• 50% of HPV infections are cleared within 8 months, and 90% of infections are cleared within 2 years
• high-risk type infections last longer --> more time to develop a precursor lesion --> increased risk
• May infect immature basal cells of the squamous epithelium in areas of epithelial breaks or immature metaplastic
squamous cells at the squamocolumnar junction
• Cannot infect mature superficial squamous cells covering the ectocervix, vagina or vulva unless there is damage to
the surface epithelium allowing access to immature cells in the basal layer of the epithelium
• cervix = large area of immature squamous metaplastic epithelium = particularly vulnerable to HPV infection
• **Infects immature squamous cells
• **Replicates in mature squamous cells

• Epithelial Susceptibility to HPV


• ↑ risk == Cervix and Anus (homosexual men)
• ↓ risk == Vulva and Penis (barring any epithelial breaks)

• Mature Squamous Cells and HPV


• Cannot be infected by HPV, but are the site of HPV replication
• Normally arrested in G1 phase of cell cycle -- "senescent"
• If infected, actively progress through the cell cycle as the virus uses the host cell DNA synthesis machinery to
replicate its genome

• HPV: E7 Protein
• Enhanced cell cycle progression and impaired ability to repair DNA damage due to:
• viral E7 binds the hypophosphorylated (active) from of RB and promotes its degradation via proteasomes
• viral E7 binds & inhibiting p21 & p27 (cyclin dependent kinase inhibitors, CKIs)

• HPV: E6 Protein
• net effect: increased proliferation of cells that are prone to acquire additional mutations
• viral E6 exacerbates the defective DNA repair via binding to p53 (tumor suppressor) and promoting
proteasomal degradation of p53
• viral E6 upregulates telomerase expression via TERT → cellular immortalization

• HPV: E6 & E7 Proteins


• ↑ proliferation of cells that are prone to acquire new mutations that can lead to cancer development
• Expression is increased via integration into the host genome
• Oncogenes near viral insertion may be dysregulated
• These oncogenic proteins inactivate tumor suppressors, activate cyclins, inhibit, apoptosis, and combat
cellular senescence

• E6 and E7 proteins from low-risk HPV types


• E7: binds to RB with lower affinity
• E6: does not bind to p53 at all
• dysregulates growth and survival by interfering with the Notch signaling pathway instead
19
• Squamous intraepithelial lesions (SIL)

• Classification
• Classified into a two tier system, all are most commonly
caused by HPV16
• LSIL: low grade squamous intraepithelial lesion
• Previously CIN I (mild cervical intraepithelial neoplasia)
• 80% of LSILs are associated with high-risk HPV types

• HSIL: high grade squamous intraepithelial lesion


• Previously CIN II (moderate dysplasia), CIN III (severe dysplasia) & CIS (carcinoma in situ)
• 100% of HSILs are associated with high risk HPV types

• Low Grade Squamous Intraepithelial Lesions (LSIL) – 80% are HPV16


• Associated with a productive HPV infection
• High level of viral replication
• only mild alteration in growth of host cells
• Does NOT progress directly to invasive carcinoma
• Most (60%) regress spontaneously, small portion (10%) → HSIL
• Not treated as a premalignant lesion
• 10x more common than HSIL

• High Grade Squamous Intraepithelial Lesions (HSIL) – 100% are HPV16


• Progressive deregulation of the cell cycle by HPV -->
• increased cellular proliferation
• decreased/arrested epithelial maturation
• lower rate of viral replication
• Derangement of the cell cycle in HSIL may become irreversible and lead to a fully transformed malignant
phenotype
• 80% of HSILs develop from LSILs; 20% of HSILs develop de novo
• all HSILs are at high risk for progression to carcinoma

• Diagnosis
• Diagnosed based on identification of nuclear atypia with:
• Nuclear enlargement & Hyperchromasia (dark staining)
• Coarse chromatin granules
• Variation in nuclear size & shape
• May be accompanied with cytoplasmic 'halos'
• Halos: perinuclear vacuoles due to E5 protein localization to the endoplasmic reticulum= koilocytic
atypia

• Aids in diagnosis
• Highest viral loads in upper ½ of the epithelium
• Ki-67 (marker of actively dividing cells) usually restricted to basal layer
• viral E6 and E7 prevent cell cycle arrest --> Ki-67 seen in upper levels (CIN II/III) (where it shouldn't be)

• Overexpression of p16 (increased CDK4) [cyclin dependent kinase inhibitor]

20
• "Both Ki-67 and p16 staining are highly correlated with HPV infection and are useful for confirmation
of the diagnosis in equivocal cases of SIL."

• Grading
• Based on expansion of immature cell layer from its normal, basal
location
• Confined to lower 1/3 = LSIL
• Expansion into upper 2/3 = HSIL
This is tested fo sho’
• LSIL progression
• 60% regress
• 30% persist
• 10% progress to HSIL

• HSIL progression –
• 30% regress
• 60% persist
• 10% progress to carcinoma within 2-10 years
• Most develop from LSIL, though 20% develop de novo

Figure 2: A) LSIL B) highest viral loads in upper 1/2 C) Ki-67 proliferation


marker usually restricted to basal layer but E6/E7 prevent cell cycle arrest so
unseen in upper levels D) over expression of P16 = increased CDK4

• Cervical Carcinoma
• Definition
• Average Age: 45 years
• due to high risk HPVs (16, 18, 31, 33, 45)
• 80% of cervical carcinomas are squamous cell carcinomas
• 15% of cervical carcinomas are adenocarcinoma (precursor lesion
== adenocarcinoma in situ)
• 5% of cervical carcinomas are adenosquamos or neuroendocrine
carcinomas
• have a shorter progression time than squamous cell carcinoma

21
• patients often present with advanced disease and less favorable prognosis

• Squamous Cell Carcinoma Morphology -


• Nests and tongues of malignant squamous epithelium
• Keratinizing or nonkeratinizing
• Invade the underlying cervical stroma -- makes it a carcinoma (i.e.
malignant)

• Adenocarcinoma Morphology
• Proliferation of glandular epithelium composed of malignant
endocervical cells with large, hyperchromatic nuclei and mucin
depleted cytoplasm = dark appearance of glands (vs. normal
endocervical epithelium)

• Adenosquamous Morphology
• Intermixed malignant glandular and squamous epithelium

• Neuroendocrine Morphology
• Appears similar to small cell carcinoma of the lung but is +ve for
high risk HPV (16, 18, 31, 33, 45)
• Very poor prognosis

• Advanced Cervical Carcinoma Morphology


• Spreads via direct extension to contiguous tissues
• Paracervical soft tissue
• Urinary bladder
• Ureters (→ hydronephrosis)
• Rectum
• Vagina
• Lymphovascular invasion --> local and distant lymph node metastases (liver, lungs, bone marrow)

• Staging
• Stage 0: Staged as carcinoma in situ (CIS) = CIN III, HSIL
• Stage I: Carcinoma confined to the cervix
• I-A: preclinical carcinoma (diagnosed only with microscopy)
• I-A1: stromal invasion < 3mm deep & < 7mm wide (microinvasive carcinoma)
• I-A2: 3mm < max stromal invasion < 5mm from the base of the epi; horizontal < 7mm
• I-B: Confined to the cervix and > stage Ia2
• Stage II: Carcinoma extends beyond the cervix but not to the pelvic wall
• Involves the upper 2/3 of the vagina
• No involvement of the lower 1/3
• Stage III: Carcinoma is extended beyond the pelvic wall
• Rectal exam: no cancer free space between the tumor and pelvic wall
• Involvement of the lower 1/3 of the vagina
• Stage IV: Carcinoma has extended beyond the true pelvis or involves the mucosa of the bladder or rectum
• Also includes cancers with metastatic dissemination
• Treatment
• Early invasive: cervical cone excision
• Invasive cancer: hysterectomy + lymph node dissection
• Advanced cancer: + radiation + chemotherapy
• Prognosis
• patients tend to die from consequences of local tumor invasion (ureteral obstruction, pyelonephritis, uremia)
• 100% 5 year survival for microinvasive carcinomas
• < 50% 5 year survival for tumors extending beyond the pelvis
22
• 50% are detected in females without regular screenings
• most patients with advanced cervical cancer die of the consequences of local tumor invasion (e.g. ureteral
obstruction, pyelonephritis, and uremia) rather than distant metastases

• Cytologic Cancer Screening


• Pap Smear: transformation zone is scraped and smeared onto a slide, fixed and stained with Papanicolaou method
• Significantly ↓ mortality of cervical cancer because most cancers arise from precursor lesions over many
years
• Lesions shed abnormal cells

• HPV DNA testing (↑ sensitivity, ↓ specificity) can also be added for females < 30 years
• > 30 not recommended due to ↑ incidence of infection and low specificity of test results

• Pap Smear recommendations


• Recommended at age 21 or within 3 years of the onset of sexual activity, then every three years
• After age 30
• Normal cytology, (-) for HPV, every 5 years
• Normal cytology, (+) for high risk HPV, every 6-12 months

• Abnormal Pap Test


• Follow up should include colposcopic exam of the cervix and vagina to identify the lesion
• Examine mucosa after application of acetic acid, and abnormal epithelium = white spots
• Abnormal areas should be biopsied

• LSIL: followed in conservative fashion


• can do a local ablation if there is concern about the reliability of
patient follow-up

• HSIL: cervical conization

• HPV Vaccine
• Recommended for all girls and boys 11-12 years old, up to age 26
• Provide nearly complete protection vs strains 16 & 18
• One also provides protection vs 6 & 11 (genital warts)
• Protects up to 10 years
• Cervical screenings should still continue as not all strains are protected against

23
• Gardasil: 6, 11, 16, 18

BODY OF UTERUS AND ENDOMETRIUM

• myometrium == tightly interwoven bundles of smooth muscle that form


the wall of the uterus
• hormonally responsive to oxytocin during parturition

• endometrium == lining of the internal cavity of the uterus; composed of glands embedded in a cellular stroma
• hormonally responsive to sex steroid hormones

• Menses
• Beginning of the menstrual cycle
• this is Day 0
• Shedding of the functionalis (superficial portion of the endometrium)

• Day 15: Corpus luteum involutes if no fertilized egg


• Progesterone drops → functionalis layer degenerates/sheds
• Normal stroma breakdown (bleeding into stroma with fibrin, RBCs, and
inflammatory cells)
• Stem cells in basal layer regenerate after menses

• Proliferative Phase (estrogen dependent)


• rapid growth of glands & stroma from the basalis (deeper portion of the endometrium) → new functionalis
• Glands are straight, tubular structures lined with regular, tall, pseudostratified columnar cells

• Numerous mitotic figures


• No evidence of mucus secretion or vacuolization

• Endometrial stroma: actively proliferating spindle cells with scant cytoplasm


• Phase ceases at ovulation
• estrogen drives the proliferation of both glands and stroma

• Ovulation
• Endometrial proliferation ceases
24
• Differentiation occurs in response to progesterone produced by the corpus luteum in the ovary

• Post-ovulation
• Marked appearance of secretory vacuoles beneath the nuclei in the glandular epithelium
• Week 3: prominent secretory activity
• Basal vacuoles move towards apical surface
• Glands are dilated between days 18-24 due to max secretion
• Week 4: Tortuous glands with a serrated/sawtooth (secretory phase) appearance accentuated by secretory
exhaustion and shrinkage of the glands

• Secretory Phase
• Progesterone down regulates the expression of estrogen receptors in
the glands and stroma
• Endometrial proliferation is suppressed
• promotes the differentiation of the glands and causes
functional changes in the stromal cells

• Early secretory: secretory subnuclear vacuoles with glycogen (day 16-


17)

• 3rd week of cycle: vacuoles become supranuclear and are most prominent

• Tortuous and serrated or saw toothed


• Stromal changes during the Late Secretory Phase are important for dating the endometrium
• Day 21-22: Appearance of prominent spiral arterioles + ↑ in ground substance & edema
between stromal cells
§ normal placenta: maternal blood enters the intervillous space through endometrial
arteries (spiral arteries) and circulates around the villi to allow gas and nutrient
exchange
• Day 23-24: Stromal cell hypertrophy, ↑ cytoplasmic eosinophilia (predecidual change),
resurgence of stromal mitoses
• Days 24-28: Pre-decidual changes occur + a normal, sparse infiltrate of neutrophils +
lymphocytes
§ Decidualized cells high in glycogen and lipid

• Dissolution of the Corpus Luteum


• Leads to ↓ progesterone
• Functionalis degeneration + bleeding into the
stroma occurs
• Stromal breakdown → onset of the next
menstrual cycle

• Estrogen == drives proliferation of glands & stroma


during the proliferative phase
• "Crosstalk" between the cells may occur
• Hormonal effects on glandular proliferation
occur via stromal cells
• Stromal cells → growth factors (IGF1,
epidermal GF) that bind to receptors on
epithelial cells

• Endometrial Stem Cells


• Play a central role in the regeneration of endometrium after menses
• May contribute to the development of ectopic endometrial tissue and endometrial cancer

25
FUNCTIONAL ENDOMETRIAL DISORDERS (DYSFUNCTIONAL UTERINE BLEEDING)

• Definition
• Uterine bleeding that lacks an underlying (structural) abnormality
• Most commonly due to hormonal disturbances
• Any alteration of the hypothalamic-pituitary-ovarian system can alter release (timing or amount) of
hormones

• Causes
• Most commonly due to hormonal disturbances
• May also be due to pathologies such as chronic endometritis, endometrial polyps, submucosal leiomyomas,
endometrial neoplasms

• Anovulatory Cycle
• Definition
• Most frequent cause of dysfunctional bleeding is anovulation (failure to ovulate)
• due to subtle hormonal imbalances
• Most common at menarche and perimenopausal periods
• failure of ovulation --> excessive endometrial stimulation by estrogens that is unopposed by
progesterone

• Causes
• most commonly due to subtle hormonal imbalances
• Endocrine disorders: thyroid, adrenal, or pituitary tumors/etiology
• Ovarian lesions: granulosa cell tumors or polycystic ovaries
• Generalized metabolic disturbances: obesity, malnutrition or chronic systemic disease

• Morphology
• Repeated anovulation may result in bleeding that may prompt endometrial biopsy (sometimes)
• Stromal condensation
• Eosinophilic epithelial metaplasia similar to menstrual epithelium BUT lacks progesterone dependent
morphologic features (glandular secretory changes, stromal predecidualization) because the source of
progesterone (corpus luteum) does not develop without ovulation
• Endometrium exhibits pseudostratified glands with scattered mitotic figures

• Inadequate Luteal Phase


• Manifests clinically as infertility and increased bleeding or amenorrhea
• Due to inadequate progesterone production during postovulatory period
• Secretory endometrium with features lagging behind those expected for the estimated date

26
INFLAMMATORY DISORDERS

• Endometrium & myometrium are relatively resistant to infection


• endocervix forms a barrier to ascending infection

• Chronic inflammation of the endometrium (not associated with menstrual phase) is of concern

• Acute Endometritis
• Uncommon; limited to bacterial infections that arise after delivery or miscarriage
• Predisposed by retained products of conception
• due to group A hemolytic streptoocci, staphylococci, etc.
• Nonspecific inflammation of the stroma
• Treatment: curettage of fragments and antibiotics (beta-lactams for strep and staph) == curative

• Chronic Endometritis
• Definition
• Most common form of endometritis
• Typically caused by an ascending infection (especially chlamydia), sometimes idiopathic
• if organisms are not detected on culture, proceed with antibiotic therapy to prevent sequelae
• If you see one plasma cell on biopsy then it is chronic endometritis until proven otherwise
• diagnosis is made on the identification of plasma cells in the stroma
• plasma cells not normally seen in the normal endometrium

• Associated with • No identified cause (15%)


• PID (mostly chlamydia)
• Retained gestational tissue, post-partum • Presentation
or post-abortion • Abnormal bleeding
• IUD • Pain
• TB (miliary or from drainage of TB • Discharge
salpingitis) [rare in Western countries] • Infertility
• Chlamydia

• Pelvic TB
• Both fallopian tubes are involved
27
• Infects the endometrium 50% of the time
• Rarely infects the cervix, vagina, or vulva
• If the ovaries are infected, then there is only surface infection
• Mucosa of the tube may not be involved
• 1/3 of patients will have had TB somewhere else in the body before

• Morphology
• Multinucleated giant cells
• Histiocytes
• Can see the bugs with a Kinyoun or Ziehl-Neelsen acid fast stain

• Endometriosis
• Definition
• Ectopic endometrial tissue seen outside of the
uterus
• Tissue typically includes stroma + endometrial
glands (which may be absent)
• Causes infertility, dysmenorrhea, and pelvic
pain
• Complications can occur if invasion/spread
occurs
• Most common in females 3-4th decade

• Locations (descending order of frequency)


• Ovaries
• Uterine ligaments
• Rectovaginal septum
• Cul de sac
• Pelvic peritoneum
• Large & small bowel, appendix,
• Mucosa of cervix, vagina, fallopian tubes
• Laparotomy scars

• Pathogenesis Theories
• Regurgitation theory: endometrial tissue implants at ectopic sites
via retrograde flow of menstrual endometrium through the
fallopian tubes
• this occurs regularly even in normal women
• Most likely theory to explain endometriosis; though not
perfect

• Molecular Analyses
• Release of proinflammatory & other factors: VEGF (need blood
supply), PGE2, IL1β, TNFα, IL6, IL8, NGF, MCP1, MMPS, TIMP
• ↑ estrogen production by endometriotic stromal cells (↑ aromatase, which is absent in normal
stroma)
• inhibitors of aromatase are beneficial in the treatment of endometriosis

• These contribute to invasion and establishment of neurovascular networks + decreased immune clearance
= survival of ectopic tissue
• ↑ responsiveness to estrogen

28
• ↓ responsiveness to progesterone

• Risk of carcinoma
• Patients have a 3x ↑ risk of ovarian cancer of the
endometrioid and clear cell types
• PTEN, ARID1A mutations
• Mutations are also found in endometriotic cysts, atypical
endometriosis & associated carcinomas

• Endometriotic Lesions Morphology


• Bleed in response to extrinsic (cyclic) & intrinsic hormonal stimulation → red/blue to yellow/brown nodules
on or beneath the mucosa and/or serosal surfaces – powder burn
• Extensive lesions with hemorrhage → extensive fibrous adhesions between structures = obliteration of
rectouterine pouch of Douglas
• Formation of chocolate cysts/endometriomas: 3-5cm cystic masses filled with brown fluid (hemosiderin
deposits) from previous hemorrhage

Conditions that increase estrogen à pic


• Anovulation, obesity, menopause, prolonged administration of estrogenic
substance.
• PCOS – increased estrone, excess ovarian cortical function, functioning
ovarian tumors (Granulosa cell)

• Atypical Endometriosis Morphology


• Precursor to endometriosis-related ovarian carcinoma
• Cytologic atypia of epithelium lining the endometriotic cyst without major architectural changes
• OR
• Glandular crowding due to excess epithelial proliferation +/- cytologic atypia → appearance like complex
atypical endometrial hyperplasia

• Clinical
• Active reproductive/childbearing years, 3-4th decade, 6-10% of women affected
• Severe dysmenorrhea, Dyspareunia, and Pelvic pain due to intrapelvic bleeding & periuterine adhesions
• Menstrual irregularities
• Infertility == presenting complaint in 30-40% of patients
• pain with defecation if rectal wall is involved
• dysuria if bladder serosa involvement
• Diagnosis
• Diagnosis via presence of endometrial glands and stroma +/-
hemosiderin
• May be obscured by secondary fibrosis
• Rarely only stroma is identified
• Treatment
• Aromatase inhibitors or surgical

• Adenomyosis
• Related to endometriosis
• Presence of endometrial tissue within the uterine wall (myometrium)
• Down growth of endometrial tissue into & between smooth muscle fascicles of the myometrium
• Occurs in 20% of females (uteri)
• Irregular nests of endometrial stroma +/- glands
• Separated from basalis by 2-3mm
• menometrorrhagia, colicky dysmenorrhea, dyspareunia, pelvic pain (premenstrual)
• May coexist with endometriosis
29
• Endometrial Polyps
• Definition
• Exophytic masses of variable sizes that project into the endometrial cavity
• Single or multiple, sessile polyps
• Occasionally: large and pedunculated (attached by a stalk)
• May be asymptomatic or cause abnormal bleeding
• Seen in reproductive age, peri and postmenopausal females
May (rarely) give rise to adenocarcinoma

• Morphology
• Possess chromosomal rearrangements seen in other benign mesenchymal tumors
• Stroma appear neoplastic, while the glands appear reactive
• Glands may be hyperplastic, atrophic or functional (demonstrate secretory changes)
• May become hyperplastic with generalized endometrial hyperplasia

• Hormone sensitivity
• Responsive to estrogen
• Little to no response to progesterone
• Associated with tamoxifen therapy (for estrogen receptor positive breast cancer)
• tamoxifen has weak pro-estrogenic effects in the endometrium (anti-estrogenic effects in breast)

• Atrophic Polyps
• Remnants of previously hyperplastic polyps
• Seen mostly in postmenopausal females

• Endometrial Hyperplasia (a precursor lesion)


• Definition
• ↑ proliferation of the endometrial glands relative to the stroma that leads to ↑ gland:stroma ratio
• Associated with prolonged estrogenic stimulation of the endometrium
• anovulation
• increased estrogen production from endogenous sources
• exogenous sources of estrogen (hormone replacement therapy)
• Important cause of abnormal bleeding
• Frequent precursor to the most common type of endometrial carcinoma

• Associated with
• Obesity (peripheral conversion of androgens → estrogens)
• Menopause
• Poly-Cystic Ovarian Syndrome (PCOS)
• Functioning granulosa cell tumors of the ovary
• Excessive ovarian cortical function (cortical stromal hyperplasia)
• Prolonged administration of estrogenic substances

• PTEN Inactivating Mutation


• Tumor suppressor gene
• seen in both endometrial hyperplasia (20%) and endometrial
carcinomas (30-80%)

• Causes overactive PI3K/AKT growth regulatory pathway which enhances


ability of estrogen to stimulate gene expression (i.e. endometrial and
mammary epithelial cells)
• loss of PTEN function --> overactive estrogen dependent gene expression

30
• not predictive of progression to carcinoma

• Germline mutation == Cowden syndrome – (multiple hamartoma syndrome – germline PTEN mutation and
high incidence of endometrial and breast cancer
• Cowden patients have an ↑ incidence of endometrial + breast cancer

• Classified as
• Nonatypical hyperplasia
• Atypical hyperplasia (endometrial intraepithelial neoplasia)
• Differ in appearance and their propensity to progress to carcinoma

• Non-atypical Hyperplasia Morphology


• ↑ gland:stroma ratio
• Glands vary in size & shape
• May be dilated
• May be back-to-back, but some intervening stroma is
typically retained
• due to endometrial response to persistent estrogen
stimulation
• may evolve to cystic atrophy if estrogen is withdrawn
• Rarely progresses to adenocarcinoma

• Atypical Hyperplasia (endometrial intraepithelial


neoplasia (EIN) Morphology
• Complex patterns of proliferating glands with
nuclear atypia
• Nuclei have open/vesicular chromatin +
conspicuous nucleoli
• Glands are back-to-back and branch
• Cells: rounded, losing perpendicular
orientation to basement membrane
• Overlaps with well-differentiated
endometrioid adenocarcinoma

• Differentiation may require hysterectomy

• Treatment
• Hysterectomy
• Up to half of patients are found to have carcinoma after hysterectomy
• In patients who wish to remain fertile, progesterone therapy and close follow up may be trialed
• Lack of regression usually prompts hysterectomy (hopefully after successful pregnancy)

MALIGNANT TUMORS OF THE ENDOMETRIUM

31
• Carcinoma of the Endometrium
• Most common invasive cancer of the female’s genital tract
• earlier detection and eradication of the precursor lesions of cervical carcinoma
• 7% of all invasive cancer in women, excluding skin cancer
• Bleeding is an early sign

• 2 types of Endometrial Carcinoma


• Type I (endometrioid) == low-grade, indolent, preceded by atypical hyperplasia
• Type II (serous) == high-grade, aggressive, poor prognosis, preceded by serous endometrial intraepithelial
carcinoma

• Carcinoma of the Endometrium: Type I (Endometrioid)


• Definition
• most common type accounting for 80% of all
endometrial carcinomas
• Most are well differentiated & mimic
proliferative endometrial glands
(endometrioid morphology)
• Age 55-65 ---- Comes from hyperplasia

• Arise in the setting of endometrial hyperplasia &


associated with:
• Obesity
• Diabetes
• HTN
• Infertility
• Unopposed estrogen stimulation

• Mutations
• Most common (hallmark) == ↑ signaling via PI3K/AKT pathway via multiple mutations
• increasing sensitivity to estrogen as more mutations occur

• PTEN, PIK3CA, KRAS


• PIK3CA mutations rarely occur in atypical hyperplasias (mutations in PIK3CA have a role in invasion)

• loss-of-function mutations of ARID1A


enhances PI3K/AKT signaling
• seen in ovarian endometrioid and
clear cell carcinomas that arise within
endometriosis

• Other mutations include: @MLH1,


CTNNB1, FGFR2 & DNA mismatch repair defects

• TP53 mutations are seen in 50% of the poorly differentiated carcinomas


• thought to be a late event in tumor progression

• DNA mismatch repair genes

32
• Defects of DNA mismatch repair genes are prevalent in carcinomas in females from families with HNPCC
(hereditary nonpolyposis colorectal carcinoma). This is
Lynch syndrome
• Often due to epigenetic silencing (hypermethylation)

• Spread
• Localized polypoid tumor or diffuse infiltration of the
endometrial lining
• Spread via myometrial invasion, then direct
extension

• Invasion of broad ligament → palpable mass


• Late metastases via lymphatics to lungs, liver, bone,
etc
• Chemotherapy is given to these patients if the cancer
has spread beyond the uterus

• Grading
• Grade 1: Well differentiated, well-formed glands
• distinguished from hyperplasias by lack of intervening stroma
• Grade 2: Moderately differentiated, well-formed glands mixed with solid sheets of cells (50% or less or
tumor mass)
• Grade 3: Poorly differentiated greater than 50% solid growth

• Lack of intervening stroma will differentiate well differentiated tumors from hyperplasia

• There can be squamous elements too, but these are ignored in the grading

• Staging
• Also applies to Malignant Mixed Mullerian Tumors
• Stage I: carcinoma is confined to the corpus uteri (body of the uterus)
• Stage II: carcinoma involves the copus + cervix
• Stage III: carcinoma extends outside the uterus but not out of the true pelvis
• Stage IV: carcinoma extends outside the true pelvis or involves the mucosa of the bladder or rectum

• Carcinoma of the Endometrium: Type II (Serous)


• Definition
• Arise in the setting of endometrial atrophy in women 10
years older than type I (age 65-75)
• uncommon <40 years olds
• More common in African Americans
• Poorly differentiated (grade 3) tumors with poor prognosis
due to cell exfoliation, travel through fallopian tubes &
implantation on peritoneal surfaces
• Often already spread out of the uterus at
presentation

• Subtypes
• Serous (most common), clear cell carcinoma, malignant mixed mullerian tumor

• Pathogenesis
• 90% have TP53 missense mutations == accumulation of altered protein

• Precursor lesion: serous endometrial intraepithelial carcinoma (also has altered TP53)

33
• Identical cells, but lack stromal invasion (i.e. are not malignant; confined to epithelial surfaces)

• Likely begins as a surface epithelial neoplasm that extends to adjacent glands, then invades stroma
• Other mutations: PI3K, PP2A which are also seen in the precursor lesions (early events)

• Morphology: serous
• Seen in small, atrophic uteri
• Tumors are large and bulky or invasive into the myometrium
• Papillary growth pattern
• ↑ nuclear: cytoplasmic ratio, atypical mitotic figures, hyperchromasia, prominent nucleoli
• May also have a glandular growth pattern, but can differentiate by looking for the nuclear atypia

• Clinical
• No screening test available
• Asymptomatic or with irregular or post-menopausal bleeding with excessive leukorrhea
• No uterine enlargement in early stages
• Diagnosis requires histological exam of tissue from biopsy or curettage
• Most patients are cured if there is postmenopausal bleeding as this leads to early detection

• Prognosis, general
• Prognosis is based on stage at presentation
• Most (in USA) are stage I and well-moderately
differentiated
• Stage I (grade 1 or 2): 90% 5 year
survival
• treatment with surgery +/-
irradiation
• Stage I (grade 3): 75% 5 year survival
• Stage II or III: < 50% 5 year survival

• Prognosis for the serous subtype


• Propensity for extrauterine spread
• More frequent in African American females
• 2x mortality for African Americans
• 18-27% 5 year survival even if confined to the uterus, 80% recurrence
• Adjuvant radiation may reduce local recurrence
• Chemotherapy may be given, even in the absence of detectable extrauterine spread

• Malignant Mixed Mullerian Tumors (MMMTS) (carcinosarcomas)


• Definition
• Endometrial adenocarcinomas & malignant mesenchymal component
• Mesenchymal component may be tumor cells resembling uterine mesenchymal elements (stromal sarcoma,
leiomyosarcoma) or contain heterologous malignant cell types (rhabdomyosarcoma, chondrosarcoma).
• Epithelial & stromal components are from the same founding cell
• Majority are carcinomas with sarcomatous differentiation

• Mutations
• PTEN, TP53, PIK3CA (similar to endometrial carcinoma)
• Alterations typical of those in sarcomas are absent
• mechanism of sarcomatous transformation is unknown

34
• Morphology
• Bulky, polypoid, and may protrude through the cervical os
• Usually consist of adenocarcinoma (glandular) mixed with malignant mesenchymal elements (sarcomatous)
• The metastases typically only have the epithelial components

• Clinical
• Seen in postmenopausal women
• Present with bleeding
• resemble endometrial carcinoma genetically
• poor outcomes with current therapies

• Prognosis
• Prognosis based on depth of invasion and stage
• Also based on differentiation of the mesenchymal component
• patients with tumors that have a heterologous mesenchymal component do worse than those who do not
• 25-30% 5 year survival for high-stage disease
Figure 3: Heterologous elements - (Seen with muscle, cartilage, adipose tissue, bone)

TUMORS OF THE ENDOMETRIAL STROMA


• These tumors are rare (< 5% of endometrial cancers)

• Adenosarcomas
• Definition
• Stromal neoplasm admixed with benign glands
• Large, broad based endometrial polypoid growths
• May prolapse through the cervical os
• Females in 4-5th decade
• Low grade malignancy
• 25% recur and are confined to the pelvis

• Diagnosis:
• Based on malignant appearing stroma and coexistent benign but abnormally shaped endometrial glands
• need to distinguish adenosarcomas from large benign polyps
• adenosarcomas are estrogen-sensitive and responds to oophorectomy

• Stromal Tumors
• Stromal nodules == benign, well-circumscribed tumors
• Low-grade endometrial tumor sarcoma == infiltrate into the surrounding myometrium
• High-grade endometrial tumor sarcoma == marked atypia
• associated with chromosomal translocations that create fusion genes
Low-grade endometrial tumor JAZF1 (transcription repressor)/SUZ12 (polycomb
sarcoma gene family)

35
High-grade endometrial tumor "other gene fusions," function of which is currently
sarcoma unknown

TUMORS OF THE MYOMETRIUM

• Uterine Leiomyoma (fibroids)


• Definition
• Most common tumor in women
• Benign, smooth muscle neoplasms
• Multiple > single

• Genetics
• Commonly have normal karyotypes
• 40% have a simple chromosome abnormality
• T(12q14;6p): HMGIC, HMGIY -- genes that regulate chromatin structure
• ^^ also implicated in a variety of other benign neoplasms
• MED12 mutations seen in 70% of tumors

• Location of the tumor


• Found in the myometrium of the corpus
• Infrequently involve uterine ligaments, lower uterine segment or cervix

• Morphology
• Sharply circumscribed, discrete, round, firm, gray-white tumors that vary
in size
• Characteristic whorled pattern of smooth muscle bundles resembling
the uninvolved myometrium
• Individual muscle cells are uniform in size and shape
• Characteristic oval nucleus & long, slender bipolar cytoplasmic
processes
• Scarce mitotic figures (helps to differentiate from
leiomyosarcoma)
• Large: develop yellow-brown-red areas of softening

• Clinical
• Often asymptomatic, but may have:
• Abnormal bleeding
• Urinary frequency (bladder compression)
• Sudden pain due to infarction of a large or pedunculated tumor
• Impaired fertility
• Malignant transformation → leiomyosarcoma is extremely rare

• Clinical in pregnancy
• ↑ frequency of:
• Spontaneous abortion
• Fetal malpresentation
• Uterine inertia (failure to contract with sufficient force)
• Postpartum hemorrhage

• Benign Metastasizing Leiomyoma • Uterine leiomyoma that extends into


vessels and spreads hematogenously to
other sites
36
• Most commonly the lung • Multiple, small peritoneal nodules
• Benign
• Disseminated Peritoneal Leiomyomatosis

• Leiomyosarcoma
• Definition
• Uncommon, malignant neoplasm
• Arise from myometrium or endometrial stromal precursor cells, rarely from leiomyomas (i.e. de novo)
• Peak 40-60 years (before & after menopause)
• Genetics
• Complex, highly variable karyotypes, often with deletions
• MED12 mutations -- virtually unique to uterine smooth muscle tumors

• Grow as:
• Bulky, fleshy masses that invade the uterine wall OR Polypoid masses that project into the uterine lumen

• Spread and prognosis


• 50% metastasize hematogenously to lungs, bone, and brain
• Local spread to abdominal cavity can also happen
• 40% 5 year survival
• Anaplastic lesions: 10-15% 5 year survival
• Often recur after surgery

• Diagnosis
• Distinguished from benign counterpart via nuclear atypia, mitotic index, zonal necrosis; malignant if:
• 10 mitoses per high powered field
• 5 mitoses per high powered field with nuclear atypia or large cells

FALLOPIAN TUBES

• Formed from upper unfused Mullerian duct


• Most commonly affected by infections and associated inflammatory
conditions
• Also affected by ectopic (tubal) pregnancy and endometriosis

• Inflammations
• 60% of suppurative salpingitis == neisseria gonorrhea
• many of the remaining cases == chlamydia trachomatis

• Paratubal Cysts
• Most common primary lesion of the fallopian tubes, excluding endometriosis
• Small translucent cysts filled with clear, serous fluid
• Hydatids of Morgagni: Larger cysts near the fimbriated end of the tube or in the broad ligaments that arise from
remnants of the mullerian duct and are lined with benign, serous (tubal type) epithelium
• Relatively insignificant Figure 4: adnex - parts adjoining an organ

• Adenomatoid Tumors of the Fallopian Tubes (mesotheliomas)


• benign, uncommon
• Occur sub-serosally on the tube or in the mesosalpinx
• Counterpart to the same tumor of the testes or epididymis

• Primary Adenocarcinoma of the Fallopian Tubes


• Rare tubal mass that may be detected by pelvic exam.

37
• Others may come to attention due to abnormal discharge, bleeding, or abnormal cells on Pap smear
• ~ 50% are stage 1 at diagnosis, but only have a 60% 5 year survival
• Higher grade tumors are more aggressive
• Treatment: ovarian cancer chemotherapy protocols
• at least a subset of "serous ovarian cancers" actually arise from the epithelium of the fallopian tube

OVARIES
• Functional or Benign Ovarian Cysts
• Most common lesion encountered in the ovary

• Neoplastic Disorders can be grouped according to their origin


• müllerian epithelium
• germ cells
• sex cord-stromal cells

• Primary inflammations of the ovary (oophoritis) are uncommon


• may have an autoimmune component --> autoimmune oophoritis --> may lead to infertility

• Cystic Ovarian Follicles


• Definition
• very common in the ovary
• Originate from unruptured graafian follicles or in follicles that ruptured and then immediately sealed

• Morphology
• Multiple cysts < 2cm in diameter
• Larger may cause pelvic pain or be palpable, if >2cm then called Follicle Cyst
• Filled with a clear, serous fluid
• Lined by gray, glistening membrane
• Granulosa cells if not atrophied due to intraluminal
pressure
• Conspicuous outer theca cells due to ↑ amounts of pale
cytoplasm (leutinization)

• Hyperthecosis == pronounced leutinization


• Often associated with ↑ estrogen production and
endometrial abnormalities

• Luteal Cysts (corpora lutea)


• Seen in the normal ovaries of reproductive age females
• Lined with a rim of bright yellow tissue containing leutinizing granulosa cells
• May rupture → peritoneal reaction
• May be mistaken for endometriotic cysts due to old hemorrhage and fibrosis

• Polycystic Ovarian Syndrome (PCOS)


• Definition
• Complex endocrine disorder characterized by hyperandrogenism (hirsutism, acne, deep voice), menstrual
abnormalities (amenorrhea), polycystic ovaries, chronic anovulation,
and decreased fertility
• affects 6-10% of reproductive age women worldwide (common?)

• Associated with
• Underlying metabolic disorder
• Obesity (altered adipose tissue metabolism)
• T2DM (insulin resistance, Acanthosis Nigricans)

38
• Premature atherosclerosis
• Dysregulation of enzymes for androgen biosynthesis (excess androgen production)
• Endometrial hyperplasia and carcinoma due to ↑ free estrone (E1) levels
• E1= Esterone
• Menopausal estrogen produced by aromatization of andrestenedion
in peripheral fatty tissue
• Less potent estrogen than E2

• E2 = Estradiol
• Predominates in reproductive years
• Most potent estrogen produced by aromatization of
testosterone in Graafian follicle

• E3 = Estriol
• Placental estrogen that originates in fetal adrenal gland as DHEA
and converted in placenta
• Least potent

• Stromal Hyperthecosis (cortical stromal hyperplasia);


• Uniform enlargement of the ovary; usually bilateral
• White-tan appearance
• Hypercellular stroma & leutinization of stromal cells
• Seen as nests of cells with vacuolated cytoplasm

• Most common in post-menopausal females; overlaps with PCOS in younger


females
• similar presentation to PCOS
• virilization may be even more striking

• Theca Lutein Hyperplasia of Pregnancy


• Theca cells proliferate and the perifollicular zone expands in response to
gonadotropins released during pregnancy
• Concentric theca-lutein hyperplasia
• Regression of follicles → nodular appearance
• Do not confuse with true luteomas of pregnancy

OVARIAN TUMORS
• Definition
• 80% are benign; occur mostly in females 20-45 years old
• Borderline tumors appear at a slightly older age

• Malignant tumors are more common in older females 45-65


• Most have spread beyond the ovary by the time of diagnosis --
> disproportionate number of deaths from cancers of the
female genital tract

• Tissue sources
• Surface/fallopian tube epithelium and endometriosis
• Pluripotent germ cells that migrate to the ovary from the yolk sac
• Stromal cells (including sex cords) which are forerunners of the endocrine apparatus of the postnatal ovary

• Signs and symptoms


• Abdominal pain and distention

39
• Urinary and GI tract symptoms due to compression or invasion &
vaginal bleeding
• Epithelial Tumors
• Most primary ovarian neoplasms arise from the Müllerian epithelium

• Types
• Serous
• Mucinous
• Endometrioid

• Classification
• Cystic or fibrous, and may be:
• Benign (classified by tumor components)
• Borderline
• Malignant (cystadenocarcinomas)
• Clinical
• Type I: Low-grade with variable histology, often associated with borderline tumors or endometriosis
• Type II: High-grade, most often serous, arise from serous
intraepithelial carcinoma

• Mullerian Epithelium: Serous Tumors


• Definition
• Cystic, with tubal-like epithelium
• most common malignant ovarian tumor; ~40% of all
cancers of the ovary
• 70% are benign or borderline that happen 20-45
years old
• 30% are malignant, occur later in life (early if
familial)
• All serous tumors have psammoma bodies (concentric
calcifications)

• Risk factors for MALIGNANT serous tumors


• Nullparity --- Family history of breast/ovarian cancer

• Heritable mutations in BRCA1, BRCA2


• 20-60% risk of cancer by age 70

• ↓ risk = 40-59 year old that took oral contraceptive therapy or had tubal ligation

• Serous ovarian carcinoma is divided into two major groups

40
• Low Grade Pathogenesis
• Arise in serous borderline tumors
• KRAS, BRAF, ERBB2 mutations
• Wildtype TP53
• Responds better to chemotherapy

• High Grade Pathogenesis


• ↑ frequency of TP53 mutations
• BRCA1/2 mutations are rare (but if present always result
in this class of tumor)
• No KRAS, BRAF mutations

• Mutations: TP53, amplification in PIK3CA, RB deletions


• ↑ frequency of genomic imbalances
• Amplification of oncogenes

• Deletion of tumor suppressors

• Genetics
• low-grade tumors arising in serous borderline tumors have mutations in the KRAS, BRAF, or ERBB2
oncogenes, and usually have a wild-type tp53

• high-grade tumors have a high frequency of tp53 mutations and lack mutations in either KRAS or BRAF

• Associated features with malignancy


• Larger areas of solid or papillary tumor mass, irregularity, and fixation/nodularity of the capsule are features
associated with malignancy

• Benign Morphology
• Smooth glistening cyst wall with no epithelial thickening or with small papillary projections
• 20% are bilateral
• Cysts are lined with columnar epithelium with lots of cilia

• Borderline Tumor Morphology


• ↑ # of papillary projections
• 30% are bilateral
• Often involve the surface of the ovary
• Increased complexity of the stromal papillae, stratification of the epithelium, and mild nuclear atypia, but
stromal invasion is not seen
• Epithelial proliferation occurs in a 'micropapillary carcinoma' pattern that is a precursor to low grade serous
carcinoma

• High Grade Morphology

41
• Complex patterns of growth
• Widespread infiltration of underlying stroma
• Marked nuclear atypia, pleomorphism, and
multinucleation
• Increased mitotic activity with atypical
mitosis
• Cysts are lined with columnar epithelium
• 66% are bilateral
• Often involve the surface of the ovary

• Serous Tubal Intraepithelial Carcinoma (STIC)


• Cells identical to high grade, but there is no
invasion

• Marked epithelial atypia in the fallopian tubes


• Indicates a fallopian tube origin for high grade serous carcinomas
• females are BRCA1/2
Figure 5: Serous tumors have Psammoma Bodies
• Germline mutations
• Often seen at the time of prophylactic salpingo-oophorectomy
• Associated with sporadic, high grade serous ovarian cancer

• Tumor spread
• Propensity to spread to the peritoneal surfaces & omentum
• Tumors are more likely to spread to the peritoneum if they are not encapsulated
• Borderline tumors can arise or extend to the peritoneum and remain fixed or spread leading to
intestinal obstruction after many years
• Low grade may spread in this manner but survival is still good
• High grade are often highly metastatic throughout the abdomen at presentation and are commonly
associated with ascites
• Extent of spread outside the ovaries determines the staging

• Prognosis and treatment


• Prognosis and treatment depend on pathologic classification as both low & high grade may extend to the
peritoneum
• Borderline & malignant, confined to the ovary: 100% & 70% 5-year survival
• Borderline & malignant, spread to the peritoneum: 90%, 25% 5-year survival

42
• Borderline tumors may recur and 5-year survival is not
synonymous with cure

• Mullerian Epithelium: Mucinous Tumors


• Definition
• 20-25% of all ovarian neoplasms
• Most are benign or borderline tumors
• Common in middle adult life, rare before puberty or after
menopause

• Pathogenesis
• Most have KRAS mutation, more likely if the tumor is malignant

• Main differences between mucinous and serous


• Rarely involve the surface of the ovary
• Rarely bilateral, if bilateral, think non-ovarian origin (appendix) --- Produce larger cystic masses

• General morphology
• Multi-loculated tumors willed with sticky, gelatinous fluid rich in glycoproteins
• May grow very large (up to 25kg)
• Lined by tall, columnar epithelium with apical mucin, lacking cilia
• Most show gastric or intestinal type differentiation

• Borderline tumor Morphology


• Epithelial stratification, tufting +/- papillary growth (vs.
Cystadenomas)
• Papillary growth looks very similar to tubular adenomas or
villous adenomas of the intestine

• Mucinous Carcinoma Morphology/prognosis


• Confluent glandular growth “expansile” invasion
• 95% 5 year survival for stage I, noninvasive.
• 90% 5 year survival for invasive malignant tumors.
• Fatal if spread beyond the ovary
• Distinguish from metastatic mucinous adenocarcinoma

• Pseudomyxoma Peritonei
• Extensive mucinous ascites, cystic epithelium implants on
peritoneal surfaces, adhesions, and frequent involvement of the
ovaries
• May result in intestinal obstruction and death
• Source most commonly extraovarian (appendiceal) as
most ovarian tumors do not spread away from the ovary
• bilateral presentation requires exclusion of nonovarian origin
• most primary mucinous ovarian tumors are unilateral

43
• Endometrioid Tumors
• Definition
• Endometrioid carcinomas comprise 10-15% of all ovarian cancers
• Benign endometrioid (adenofibromas) and borderline tumors
may occur but are rare
• Relatively good prognosis
• May arise in the setting of endometriosis and borderline
tumors
• 15-20% of cases with endometrioid carcinoma coexist with
endometriosis

• Associations
• Can be associated with ovarian endometriosis or uterine endometrial carcinoma

• Main difference of endometrioid vs serous/mucinous


• Presence of tubular glands resembling benign or malignant endometrium

• Pathogenesis
• When associated with endometriosis, occurs in patients, on average, 10 years younger
• Shared features with endometrial counterpart
• mutations that increase PI3K/AKT signaling pathway (PTEN, PIK3CA, ARID1A, and KRAS)
• Mutations of mismatch DNA repair and CTNNB1 (β-catenin)
• TP53 mutations seen in poorly differentiated tumors
• Morphology
• Solid + cystic areas of growth
• Epithelium consists of tubular glands resembling endometrium
• 40% are bilateral, implies extension beyond the genital tract
• Low grade tumors
• 75% 5 year survival (stage I)

• Clear Cell Carcinoma


• Definition
• Benign and borderline types are very rare and the
carcinoma subtype is still uncommon.
• Large epithelial cells with abundant clear cell
cytoplasm -- (resembles hypersecretory
gestational endometrium)
• Variant of endometrioid adenocarcinoma

• Mutations
• PIK3CA, ARID1A, KRAS, PTEN, TP53 mutations

• Morphology (solid vs cystic) • Prognosis


• Solid: cells are arranged in sheets or • 90% 5 year survival if confined to the
tubules ovaries
• Cystic: cells line the spaces • Poor outcome if advanc

• Cystadenofibroma
44
• Small, multilocular tumors with simple papillary processes
• Epithelium is variable
• more pronounced proliferation of the fibrous stroma under the columnar epithelium
• Benign
• Borderline tumors or carcinoma rarely occur and metastatic spread is extremely uncommon

• Transitional Cell Tumors (Brenner Tumors)


• Can be solid or cystic, typically unilateral
• Normal stroma with nests of neoplastic epithelial cells resemble urothelium with mucinous glands in the
center
• Usually benign, even when large
• Incidental detection
• Most brenner tumors are benign – but boarderline atypical proliferative brenner tumor and malignant
counterparts are reported
• Tumors with benign brenner nests admixed with malignant tumor cells are referered to as malignant brenner
tumors
• Transitional cells resemble urothelium
Clinical course, detection ,prevention of ovarian epithelial
tumors
• Clinical nature of benign tumors
• Lower abdominal pain + abdominal enlargement
• GI complaints, urinary frequency, dysuria, pelvic
pressure may occur
• Benign tumors are easily resected and cured

• Clinical nature of malignant tumors of ovary


• Progressive weakness, weight loss, cachexia
• Massive ascites (exfoliated tumor cells) if extending through the tumor capsule to seed the peritoneal cavity
• Serosal surfaces seeded with small nodules that rarely invade the parenchyma
• Regional lymph nodes involved; liver, lung, GI, etc. involvement
• 50% cross midline to opposite ovary and indicate downhill course with death in
months-years
• most women with ovarian carcinoma present with high stage disease
• relatively poor 5- and 10-year survival rates when compared to cervical or
endometrial carcinomas
• CA-125 or HE4 are biomarkers that can be used to monitor disease recurrence &
progression

GERM CELL TUMORS


• 15-20% of all ovarian tumors; majority are benign cystic (mature) teratomas
(aka dermoid cysts)
• Some may have malignant behavior
• Similar to germ cell tumors in the male testis

• Teratoma types
• Mature (benign): majority
• Immature (malignant)

45
• Monodermal/highly specialized

• Mature Teratoma (benign)


• Definition
• Most are cystic (referred to as dermoid cysts) and almost always
lined with skin-like structures
• Young women during active reproductive years
• Discovered incidentally or associated with paraneoplastic
syndromes (inflammatory limbic encephalitis)
• Almost all are 46,XX
• majority arise from an ovum after first meiotic division
• minority arise from an ovum before first meiotic division

• Morphology
• 10-15% are bilateral - Unilocular cysts with hair + sebaceous material
• Tooth structures (Rokitansky tubercle) + calcification within the walls (& other germ layers: cartilage,
thyroid, neural tissue, etc.)
• Walls = stratified squamous epithelium
• 1% undergo malignant transformation (usually the skin component) → squamous cell carcinoma

• Monodermal or Specialized Teratoma


• struma ovarii and carcinoid tumors
• Rare: strumal carcinoid, a combo of the previously mentioned tumors
in the same ovary
• always unilateral
• May see a contralateral teratoma
• Only 2% metastasize

• Struma Ovarii
• Composed entirely of mature thyroid tissue that may by functional →
hyperthyroidism
• Always unilateral

• Ovarian Carcinoid
• Arises from intestinal tissue in teratomas and may be functional
• >7cm = 5HT (5-HIAA) production --> carcinoid syndrome
• Even in absence of hepatic metastases because ovarian veins
are connected directly to systemic circulation
• always unilateral (metastatic intestinal carcinoid is virtually always
bilateral)

• Immature Malignant Teratomas


• Definition
• Tumor tissue resembles embryonal and immature fetal tissue
• Seen in prepubertal patients and young women (average age:
18 at presentation)

• Morphology
• Solid, bulky tumors with a smooth external surface
• May see hair, sebaceous material, cartilage, bone, calcification
• +/- necrosis & hemorrhage

46
• Growth and spread
• Grow rapidly, frequently penetrate the capsule, and spread locally
or distantly
• Risk of spread is proportional to amount of tissue containing
immature neuroepithelium

• Prognosis
• Stage I, grade 1 = excellent prognosis
• Prophylactic chemotherapy if higher grade yet confined to
the ovary
• Recurrences occur in first two years
• absence of disease beyond two years == excellent chance of cure

• Dysgerminoma
• Definition
• 50% of all malignant ovarian germ cell tumors
• Ovarian counterpart of testicular seminoma (which is the most
common male germ cell tumor).
• 2% of all ovarian cancers
• Most have no endocrine function, but may produce hCG (if
syncytiotrophoblasts are present)
• 75% in patients in 2nd-3rd decade, but may occur in childhood
• May occur in patients with gonadal dysgenesis
(Pseudohermaphroditism)
• all dysgerminomas are malignant

• Mutations
• OCT3, OCT4, NANOG (as seen in seminomas) which maintain pluripotency
• 33% have mutations of KIT (may target for therapy)

• Morphology • Treatment & prognosis


• Unilateral tumors that vary in size • All are malignant - only ∼ 1/3 are
• Large vesicular cells with clear cytoplasm aggressive
(like seminoma) • unilateral, non-invasive, no metastasis ==
• Well defined borders 96% cure rate (excellent prognosis) after
• Central nuclei salpingo-oophorectomy
• Grow in sheets or cords • responsive to chemotherapy
• Scant fibrous stroma infiltrated by mature • overall survival is >80%
lymphocytes +/- granulomas

• Yolk Sac Tumor (endodermal sinus tumor)


• Definition
• Rare tumor derived from malignant germ cells differentiating
along the extraembryonic yolk sac lineage
• rare, but the second most common malignant tumor of
germ cell origin
• Produce α-fetoprotein (AFP) that can be stained for in hyaline
droplets

• Morphology
• Glomerulus-like structure with a central blood vessel enveloped
by tumor cells in a space lined by tumor cells (Schiller-Duval body) -- characteristic histologic feature

47
• Clinical
• Seen in children or young females
• Abdominal pain and rapidly growing pelvic mass (usually involving a single ovary)
• 80% survival with chemotherapy regardless of disease stage

• Choriocarcinoma
• Extraembryonic differentiation of malignant germ cells of placental origin
• germ cell origin can only be confirmed in prepubertal females
• after puberty, ovarian ectopic pregnancy cannot be excluded

• Exist in combination with other tumors (pure choriocarcinoma is extremely rare)


• ovarian tumors are aggressive and have usually metastasized by presentation (lungs, liver, bone)
• Elaborate high levels of chorionic gonadotropins (β-hCG) which is used for diagnosis and detecting
recurrence

• When found in the:


• ovary: unresponsive to chemotherapy & often fatal
• placental tissue: responsive

• Embryonal Carcinoma: highly malignant germ cell tumor of primitive embryonal elements
• histologically similar to embryonal carcinoma in the testes

• Polyembryoma: malignant germ cell tumor containing so-called 'embryoid bodies'

• Mixed Germ Cell Tumors: germ cell tumors containing various combinations of dysgerminoma, teratoma, yolk sac
tumor, choriocarcinoma

• Sex cord-stromal Tumors


• Ovarian neoplasms are derived from ovarian stroma which came from the sex cords of embryonic gonad
• Undifferentiated gonadal mesenchyme:
• Males: Sertoli + Leydig cells (+ fibroblasts)
• Females: granulosa + theca cells (+ fibroblasts)
• Tumors of all these cell types may secrete estrogens or androgens and may be feminizing or masculinizing
• granulosa/theca cell tumors secrete estrogen and are feminizing
• Leydig and Sertoli cells secrete androgens and are masculinizing

• Granulosa Cell Tumors


• Definition
• Composed of cells that look like granulosa cells
of a developing ovarian follicle
• 5% of all ovarian tumors and most are
adult granulosa cell tumors
• 2/3 occur in post-menopausal females
• May elaborate large amounts of estrogen (some
produce androgens)
• May behave like low grade malignancies

• Morphology
• Typically unilateral and vary from microscopic foci to large, solid, and cystic encapsulated masses
• If they are hormonally active, they are yellow from stored lipids
• often are hormonally active and associated with endometrial hyperplasia/cancer
• The small cuboidal/polygonal cells may grow in anastomosing cords, sheets, or strands
• Call-Exner bodies: small, distinct, gland-like structures filled with acidophilic material
48
• Occasionally there is a predominant thecoma component (clusters/sheets of cuboidal/polygonal cells)

• Clinical
• Precocious puberty if the tumor is functionally active in a juvenile patient
• Adult females may have proliferative breast disease, endometrial hyperplasia, and endometrial
carcinoma, and/or bleeding
• Masculinization or Pseudohermaphroditism if androgens are produced (most only produce estrogen though)
• Some tumors elaborating hormone can lead to endometrial carcinoma

• Diagnosis
• ↑ serum inhibin (produced by granulosa cells) that inhibits FSH
• Allows diagnosis and monitoring treatment
• Most of the adult type have FOXL2 mutations (important in granulosa cell development)

• Prognosis
• All are potentially malignant
• tumors composed predominantly of theca cells are unlikely to be malignant

• Malignant tumors are usually indolent and local recurrences are treated with surgery
• can recur in the pelvis or abdomen 2=10-20 years after resection of the primary tumor

• Histology does not predict tumor behavior


• 85% 10 year survival

• Fibroma
• Tumor arising in the ovarian stroma composed of
well differentiated fibroblasts with scant
interspersed collagenous stroma
• by definition, hormonally inactive
• 90% are unilateral
• Solid, spherical or slightly lobulated,
encapsulated masses covered with a
glistening, intact ovarian serosa
• Benign
• Mitotic activity + ↑ nuclear:cytoplasmic ratio = Fibrosarcoma and a malignant course

• Thecoma - benign
• Tumor arising in the ovarian stroma composed of plump spindle cells with lipid droplets
• Pure = rare
• If the predominant cell in a tumor, may be hormonally active

• Fibrothecoma
• Tumor arising in the ovarian stroma composed of both fibroblasts & plump spindle cells with lipid droplets
• benign

• Meigs Syndrome == ovarian tumor, hydrothorax, & ascites


• (Fibroma, Thecoma, Fibrothecoma) == benign
• Ovarian tumor present as a pelvic mass +/- pain
• Ascites if the tumor > 6cm

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• Hydrothorax, usually only on the right side

• Sertoli-Leydig Cell Tumors


• Definition
• Functional tumors that often lead to
masculinization or defeminization
• Some may have estrogenic effects
• Cells are in various stages of
development
• Females of all ages, peak in 2nd-3rd
decade

• Mutation
• DICER1 mutation in > 50%
• Endonuclease essential for micro-RNA processing

• Morphology
• Unilateral tumors & Solid grey to golden brown
• Grossly resemble granulosa cell tumors
• Well-differentiated: Sertoli or Leydig cells interspersed with stroma
• Poorly-differentiated: sarcomatous pattern with disorderly disposition of epithelial cell cords; Leydig
cells may be absent
• There may be heterologous elements in some tumors (mucinous glands, bone, cartilage)

• Sertoli-Leydig Cell Tumors


• Functional and commonly produce masculinization or defeminization
• a few have estrogenic effects
• Neoplasms can block normal female sexual development in children
• In adults there may be atrophy of breasts amenorrhea, sterility, loss of hair
• May progress to virilization with male distribution of hair (hirsutism), hypertrophy of the clitoris, voice changes
• < 5% recur or metastasize

• Hilus Cell tumors (pure Leydig cell tumors)


• Definition
• Rare, unilateral, (predominantly) testosterone producing
tumors
• Ovarian tumor of sex cord or stromal origin
• Benign tumor with clusters of polygonal cells around hilar
vessels

• Morphology
• Unilateral tumors with large, lipid laden Leydig cells
• Distinct borders
• Reinke crystalloids: characteristic cytoplasmic structures

• Clinical
• Present with evidence of masculinization: hirsutism, voice changes, clitoral enlargement
• Mild vs. Sertoli-Leydig cell tumors

• Treatment
• Surgical excision
• almost always benign

• Pregnancy Luteoma
• Ovarian tumor of sex cord or stromal origin
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• Rare tumor that closely resembles the corpus luteum of pregnancy
• Produce virilization in pregnant patients and their female infants/progeny

• Gonadoblastoma
• Uncommon ovarian tumor of sex cord or stromal origin
• Resembles immature Sertoli & granulosa cells
• Seen in patients with abnormal sexual development and in patients with indeterminate gonads
• 80% are phenotypic females
• 20% are phenotypic males with undescended testicles and female internal secondary organs
• coexistent dysgerminoma occurs in 50% of the cases
• Excellent prognosis if tumor is completely excised

• Metastatic Tumors
• Derived from tumors of mullerian origin (most common)
• Uterus
• Fallopian tube
• Contralateral ovary
• Pelvic peritoneum
• Extra-mullerian: carcinoma of the breast or GI tract
• Pseudomyxoma peritonei (appendiceal tumor)

• Krukenberg Tumor
• Metastatic GI tumor involving the ovaries -- when gastric carcinoma metastasizes to the ovaries
• bilateral metastases composed of mucin producing, signet ring cancer cells usually of gastric origin
• Ovarian Torsion
• Causes • Etiology
• Children – congenitally malformed or long • Children Congenitally malformed or long
fallopian tubes, or absent mesosalpinx fallopian tubes, or absent mesosalpinx
• Pregnancy (20%) – enlarged corpus • Pregnancy (20%)
luteum, laxity in ligaments • Enlarged corpus luteum, laxity in
• Pregnancy induction – multiple enlarging ligaments
follicles • Pregnancy induction
• Ovarian tumors – benign and malignant, • Multiple enlarging follicles
dermoid most common • Ovarian tumors
• Benign and malignant, dermoid most
common

GESTATIONAL & PLACENTAL DISORDERS


• Spontaneous Abortion (miscarriage)
• Definition
• Pregnancy loss before 20 weeks gestation,
usually before 12 weeks
• Occurs in 10-15% of recognized pregnancies,
occurs in another 20% which are not
recognized by women
• 70% of pregnancies terminate within 14 days
of fertilization with passage of some
abnormal tissue

• Fetal chromosomal abnormalities


• Aneuploid, polyploid, translocation
• 45xo & trisomy 16

• Maternal endocrine factors

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• Luteal phase defect, poorly controlled diabetes, thyroid dysfunction

• Physical defects of the uterus


• Submucosal leiomyomas, or uterine polyps
• Uterine malformations (septum, didelphys)

• Systemic disorders affecting maternal vasculature


• Antiphospholipid antibody syndrome, coagulopathy, HTN
• APS gives a false positive test for syphilis

• Infections
• Protozoa (toxoplasma), bacterial (mycoplasma, listeria), viral (CMV, HSV2, Parvovirus, Rubella)
• Ascending infection is particularly common in second trimester losses
• CMV: common, intranuclear inclusions

• Ectopic Pregnancy
• Definition
• Fetal implantation outside the normal intrauterine location
• Most common: fallopian tube (90%)
• 2% of confirmed pregnancies and for 4-10% of pregnancy related
deaths

• Increased risk
• PID → chronic salpingitis
• Peritubal scarring and adhesions (due to appendicitis,
endometriosis, prior surgery)
• use of an IUD is associated with a twofold increase of ectopic pregnancy
• if you get pregnant with an IUD, it's most likely a tubal pregnancy
• Smoking

• Tubal pregnancy pathogenesis


• Embryonal sac implants in the lumen and is surrounded by immature chorionic villi
• Chorionic villi + trophoblastic cells invade the wall
• Eventually produced distention → thinning of the wall and rupture
• Rupture → massive intraperitoneal hemorrhage that can be fatal, which is a medical emergency
• Tubal abortion == when the conceptus is extruded through the fimbriated end of the tube into the abdominal
cavity

• Tubal pregnancy clinical


• tubal pregnancy is the most common cause of hematosalpinx (blood filled fallopian tube), should always be
suspected when a tubal hematoma is present
• Moderate to severe abdominal pain + bleeding
• 6-8 weeks after the last normal menstrual period
• this is when the conceptus is large enough to rupture the fallopian tube
• Hemorrhagic shock and acute abdomen (sudden severe pain of less than 24hrs) if there is rupture

• Diagnosis
• hCG titers (should show that you are pregnant)
• Pelvic sonography (look for donut sign) -- nothing in the uterus (uh oh moment)
• Endometrial biopsy: decidua without chorionic villi or implantation site
• Laparoscopy to take a look

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• disorders occurring in the third trimester of pregnancy are related to the complex anatomy of the maturing placenta

• Twin Placentas
• Dizygotic: fertilization of two ova
• Monozygotic: division of one fertilized ovum
• 3 types
• Diamnionic dichorionic: May be fused
• Diamnionic monochorionic
• Monoamnionic monochorionic

• Monochorionic = monozygotic (identical)

• Dichorionic = nonspecific (may be mono/di zygotic)

• Twin-twin Transfusion Syndrome


• Complication of monochorionic/monozygotic/identical twin pregnancy
• Vascular anastomoses connect the circulations and may include 1 or more AV shunts
• Can lead to fluid overload for one & under perfusion for the other
• May lead to death of one or both fetuses

• Placenta Previa -- "get a preview of the placenta"


• Placenta implants in the lower uterine segment or cervix → serious 3rd trimester bleeding
• Complete: covers the internal cervical os and requires c-section to avoid placental rupture and fatal maternal
hemorrhage

• Placenta Accreta -- "abnormal attachment of the placenta"


• Partial or complete absence of the decidua, thus direct attachment to myometrium
• Placental villous tissue adheres directly to the myometrium = failure of placental separation at birth
• Severe, life threatening postpartum bleeding can occur
• Predisposed by placenta previa or history of cesarean
section
• Can be placenta increta or percreta too depending on the
depth of invasion

• Placental infection
• Develop via
• Ascending infection through the birth canal (most common, usually bacterial)
• Hematogenous (transplacental) infection

• Placental infection
• Can cause premature rupture of membranes → preterm delivery
• Amniotic fluid: cloudy with purulent exudate
• Chorionamnion: infiltrate of neutrophils + edema & congestion of vessels
• Fetal 'vasculitis' of umbilical and fetal chorionic plate vessels may occur
• Acute villitis due to hematogenous spread is uncommon

• TORCHS infection
• Affect the placenta and can cause chronic villitis
• Toxoplasmosis
• Others (To Light Passing hovering Zambonis: TB, listeria, parvovirus, HIV,
Zika)
• Rubella
• CMV
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• Herpes simplex virus
• Syphilis

• Gestational HTN
• Develops during pregnancy
• No proteinuria
• Must be distinguished from preeclampsia

• Preeclampsia
• Definition
• Systemic syndrome with widespread maternal endothelial
dysfunction
• Presents during pregnancy with HTN, edema, proteinuria
(nephrotic range?)
• Most common in the 3rd trimester & primiparas (first
pregnancies)
• Can lead to eclampsia

• Eclampsia
• Severe manifestation of eclampsia.
• Women are very ill.
• Convulsions occur (seizures)
• Can progress to coma

• HELLP Syndrome
• Occurs in 10% of women with severe preeclampsia
• Microangiopathic hemolytic anemia
• Elevated liver enzymes
• Low platelets

• Pathogenesis
• Placenta plays a central role in pathogenesis
• Symptoms rapidly disappear after delivery of the placenta
• Potentially due to factors released from the placenta into maternal circulation
• Diffuse endothelial dysfunction
• Vasoconstriction → HTN
• ↑ vascular permeability = proteinura + edema

• Abnormal Placental Vasculature


• Abnormal trophoblastic implantation + lack of physiologic remodeling of maternal vessels
• Failure leaves the placenta ill equipped to meet the ↑ circulatory demands of late gestation
• Placental ischemia may occur

• Endothelial Dysfunction
• Imbalance of Angiogenic/Anti-angiogenic Factors
• Ischemic placenta → factors that antagonize VEGF & TGFβ released into maternal circulation
• FMS-like tyrosine kinase (sFltl) antagonizes VEGF
• Endoglin antagonizes TGFβ
• Factors are higher in women with this condition and cause defective placental vascular development
and vasoconstriction (due to TGFβ inhibition of NO)
• Maternal vessels remain small caliber high resistance vessels that leads to HTN and tissue hypoperfusion

• Coagulation Abnormalities
• Hypercoagulable state
54
• Likely due to ↓ PGI2 which is normally stimulated by VEGF (which these women lack)
• Normally PGI2 is a potent antithrombotic factor and the deficiency leads to formation of thrombi in arterioles
and capillaries especially in the Liver, kidneys, brain, and pituitary

• Placenta morphology
• Placental infarcts that are larger and more numerous
• Exaggerated ischemic changes of chorionic villi & trophoblasts
→ syncytial knots
• Frequent retroplacental hematomas
• Abnormal decidual vessels

• Kidney and liver morphology


• Liver: irregular, focal, subcapsular + intraparenchymal
hemorrhages
• Variable kidney lesions

• Brain and heart morphology


• Brain: foci of hemorrhage +/- thromboses
• Similar changes in heart & anterior pituitary

• When it presents
• Usually occurs > 34 weeks of gestation
• Earlier in women with hydatidiform mole, pre-existing kidney disease, HTN or coagulopathy

• Risk factors • DM
• age> 40 • clotting disorders
• African American • first pregnancy
• renal disease • family history
• HTN

• Clinical
• Insidious onset of HTN, edema, and proteinuria in several days
• headache + visual disturbances indicate severe manifestations that may require delivery
• eclampsia == seizures --> coma
• Treatment
• Preterm:
• Mild: close monitoring of mom + baby.
• Delivery is indicated with end organ damage, eclampsia, fetal compromise or HELLP syndrome
regardless of age
• Term: Delivery (regardless of severity)

• HTN is not amenable to antihypertensive therapy


• HTN & proteinuria disappear 12 weeks after delivery (unless they were present prior to pregnancy)
• Complications
• 20% of patients develop HTN and microalbuminuria within 7 years of a pregnancy complicated by this
disease

55
• 2x ↑ risk of vascular disease of the heart and brain

• Hydatidiform Mole
• Definition
• Cystic swelling of the chorionic villi and trophoblastic proliferation
• Diagnosed at ~ 9 weeks via sonogram
• increased risk of persistent trophoblastic disease (invasive
mole) or choriocarcinoma

• patients at risk
• Bimodal distribution: teenagers or females > 40
• 2X more likely in southeast Asia

• Complete Mole Genetics


• Fertilization of an egg that has lost its females chromosomes and
genetic material is completely paternal
• 90% are 46,XX: One sperm duplicates its genetic material
(androgenesis)
• 10% are 46,XX or 46,XY: Empty egg is fertilized by two sperm
• Embryo dies early and is not identified
• NO fetal tissue -- complete absence of fetal tissue
• 2.5% risk of choriocarcinoma 15% risk of persistent or invasive mole

• Complete Mole morphology


• All/most chorionic villi are enlarged
• Scalloped in shape with central cavitation (cisterns)
• Covered by extensive trophoblastic proliferation of the
entire/complete villi circumference

• Partial Mole Genetics


• due to fertilization of an egg by two sperm -- polyspermy
• 69,XXY (usually triploid); 92,XXXY (can be tetraploid)
• Fetal tissue IS present
• ↑ risk of persistent molar disease
• Not associated with choriocarcinoma
• Only some villi are enlarged and edematous
• Trophoblastic hyperplasia is focal and less marked

• General Morphology
• Delicate, friable mass of thin walled, translucent, cystic, grapelike structures with swollen, edematous
(hydropic) villi

• Partial Mole Morphology


• Only a fraction/partial of the villi are enlarged and edematous

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• Trophoblastic hyperplasia is focal and less marked than in
complete moles

• Clinical
• Partial or early complete
• Spontaneous miscarriage or curettage due to abnormal
villous findings on ultrasound (will see snowstorm pattern
on ultrasound)

• Complete
• HCG rate of rise is markedly increased and rises more than in normal single or multiple pregnancies
• Removed via curettage
• patients are monitored for 6-12m to ensure HCG levels return to normal
• persistent/invasive moles = when HCG levels remain high; happens in 15% of molar pregnancies

• Invasive Mole
• Mole that penetrates or perforates the uterine wall (i.e. it invades)
• there is invasion of the myometrium by hydropic chorionic villi, accompanied by proliferation of both
cytotrophoblasts and syncytiotrophoblasts (produce β-hCG)

• Pathogenesis
• Hydropic chorionic villi penetrate the myometrium
• May embolize to lungs or brain but do not grow at these sites (will regress without chemotherapy)
• Cytotrophoblasts & syncytiotrophoblasts proliferate
• Tumor is locally destructive
• Invasion of parametrial tissue or blood vessels

• Presentation
• Presents as vaginal bleeding + irregular uterine enlargement
• Persistently ↑ HCG

• Treatment
• Responds well to chemotherapy
• may result in uterine rupture requiring hysterectomy

• Choriocarcinoma
• Definition

57
• Uncommon malignant neoplasm of trophoblastic
cells derived from a previously normal or
abnormal pregnancy (e.g. extrauterine ectopic
pregnancy)
• Rapidly invasive, metastasizes widely == very
aggressive
• Responds well to chemotherapy

• Preceding factors
• Complete hydatidiform mole (50%)
• Previous abortion (25%)
• Normal pregnancy (22%)
• Ectopic pregnancy (3%)
• Germ cells of the ovaries or mediastinum (rare) – does not respond well to chemotherapy

• Morphology
• Soft, fleshy, yellow-white tumor
• Large, pale areas of necrosis + extensive hemorrhage
• Invades underlying myometrium, often penetrating blood vessels
• Abundant (possibly abnormal) mitoses
• May extend to uterine serosa and adjacent structures
• Does not produce chorionic villi, comprised only of proliferating syncytiotrophoblasts & cytotrophoblasts

• Clinical
• Irregular vaginal spotting of a bloody, brown fluid
• May occur months after pregnancy, abortion, etc
• Larger than expected uterus
• high propensity for hematogenous spread (widespread):
• Lungs (50%)
• vagina (30-40%)
• brain
• liver
• bones
• kidney
• ↑ HCG, but may be low in some tumors (especially if tumor is necrotic)

• Treatment
• Evacuation of uterine contents + chemotherapy
• chemotherapy results in nearly 100% remission and a high rate of cures
• Cured patients can have normal subsequent pregnancies and deliveries
• Non-gestational tumors that arise outside the uterus are more resistant to therapy

• Placental Site Trophoblastic Tumor (PSTT)


• Neoplastic proliferation of extra-villous trophoblasts (intermediate trophoblasts)
• Normal to be found in non-villous sites like the placental parenchyma and placental membranes
• Polygonal mononuclear cells with abundant cytoplasm
• Produce increased human placental lactogen (hPL)
• Malignant trophoblastic cells diffusely infiltrating the endomyometrium
• Presentation: uterine mass and abnormal uterine bleeding/amenorrhea, moderately ↑ HCG
• May follow normal pregnancy (50%), spontaneous abortion, or hydatidiform mole
• Localized disease = excellent prognosis
• Disseminated disease = 10-15% mortality

Lecture = Mayer-Rokitansky-Kuster-Hauser Syndrome


• Absent periods – No uterus –
58
• Noticed around age 16 – 1º amenorrhea
• 46XX – normal ovaries – normal external female genetalia
• Kidney malformation – unilateral renal agenesis
• Vertebrae are defective, hearing loss, heart defect

59