Female Genital Tract Flashcards
Embryology female genital tract
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
Chlamydia trachomatis
Pelvic inflammatory disease; serous discharge
Neisseria gonorrhea
pelvic inflammatory disease (most serious complication of gonorrhea in women); purulent discharge; gram negative diplococci within neutrophils (PMNs
Trichomonas vaginalis
large, flagellated ovoid protozoan; yellow, frothy vaginal discharge; “strawberry cervix
Gardnerella vaginalis
gram negative bacillus; main cause of bacterial vaginosis; thin, grey-green malodorous (fishy) vaginal discharge; premature labor
Ureaplasma urealyticum, mycoplasma hominis
Pre term deliveries
Plasma cell morphology
Nucleus placed off to one side
Clearing around the nucleus
HSV
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
HSV 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
HSV lesion
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 HSV
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 HSV
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 HSV
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
HSV-2 infection enhances HIV-1 acquisition and transmission
Vertical transmission (mom to baby) warrants C-section if infection is (1° and) active
Diagnosis and complications HSV
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 HSV
There is no treatment, but some antivirals (acyclovir) can shorten the active phase
Molluscum contagiosum (poxvirus)
Skin or mucosal poxvirus with 4 subtypes
MCV1: most prevalent
MCV2: most often sexually transmitted
6 week incubation period
Viral characteristics molluscum contagiosum
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 molluscum contagiosum
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
Clincial appearance molluscum contagiosum (poxvirus)
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 molluscum contagiosum (poxvirus)
1-5mm papules
Pearly, dome shaped with dimpled/umbilicated center
Central waxy core with cytoplasmic viral inclusions
Candida (moniliasis)
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
Dimorphic: mold in the heat, yeast in the cold
Forms pseudohyphae and budding yeast at 20˚C and germ tubes
Presentation candida
Intense vulvovaginal pruritis, erythema, and swelling
Thick white vulvovaginal discharge “curd-like or cottage cheese-like”
If severe → mucosal ulceration
Diagnosis candida
Pseudospores or filamentous fungal hyphae in wet KOH mounts of discharge or on Pap smear
Not considered an STI
Trichmonas vaginalis
Definition and transmission Large, flagellated ovoid protozoan Sexual transmission 4-14 days to develop Most common curable STI
Presentation trichmonas vaginalis
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
Diagnose trichmonas vaginalis
Motile trophozoites in methylene blue wet mount, present with corkscrew motility
Gardnerella vaginalis
Gram -ve bacillus
Main cause of vaginitis (Bacterial vaginosis)
Found normally in the reproductive tract, but lactobacillus keeps it in check
Presentation gardnerella vaginalis
Present with thin, green-gray, malodorous (fishy) discharge
Pregnant patients: may cause premature labor
Gardnerella vaginalis 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 and mycoplasma hominis
May cause some cases of vaginitis and cervicitis
Implicated in chorioamnionitis and premature delivery in pregnant patients
Ureaplasma: urease positive
Mycoplasma: no cell wall
Look for the fried egg appearance
Chlamydia trachomatis
Most common STI in the world
One of the main causes of pelvic inflammatory disease
Bacterial characteristics chlamydia
Small gram - obligate intracellular bacteria
Two forms of chlamydia
Elementary bodyL metabolically inactive, infectious form in endosome
Reticulate body: metabolically active form
Presentation chlamydia
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
Diagnose chlamydia
Diagnose with Nucleic Acid Amplification Test (NAAT
PID
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
Most infections travel via the lymph or venous systems rather than the mucosal route (except Neisseria gonorrhea
Causes PID
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 PID
Peritonitis & bacteremia
Endocarditis, meningitis and suppurative arthritis
Chronic sequelae PID
hronic 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
Lymphogranuloma venereum
From Chlamydia 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 and blindness
Treponema pallidus (syphilis)
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 treponema
Sexually or across placenta
Pathogenesis treponema
Disease is characterized by endarteritis resulting in lesions; strong tendency to chronicity
Diagnosis treponema pallidus (syphilis)
Visualized by immunofluorescence or dark-field microscopy
Warthin-Starry stain or steiner silver stain
Can also use VDRL or RPR
Jarisch-herxheimer reaction
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 treponema pallidus
Non-tender chancre (wart); clean, indurated edge; contagious; heals spontaneously 3-6 weeks but progresses because painless and is typically left untreated
Secondary stage treponema pallidus
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 treponema
No symptoms
Tertiary syphilis
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 and 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
Treat symphysis
Penicillin G
Puerperal infection
Infection after spontaneous or induced abortion and normal or abnormal deliveries
Polymicrobial with Staph, Strep, coliforms, Clostridium perfringens
Neisseria gonorrhea
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
Characteristics of neisseria gonorrhea
Phagocytosed gram -ve diplococci within neutrophils/PMNs (intracellular)
Will have pili on electron microscopy
Presentation gonorrhea
Females: Often asymptomatic; scarring of tubal lumen and fimbriae can → infertility or ectopic pregnancy
Males: Urethral discharge
Can lead to Fitz-Hugh Curtis syndrome
Morphology gonorrhea
Marked acute inflammation of involved mucosal surfaces
Acute suppurative salpingitis
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
Diagnosis gonorrhea
Definitive diagnosis
Detection of DNA or RNA
Culture or NAATS
Thayer-Martin agar
Treat gonorrhea
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 presentation
Presentation:
Multiple warty lesions on the perineum and around the anus in low-risk types 6 and 11
HPV VIRAL CHARCTERISTICS
ral characteristics
Non-enveloped, double-stranded, circular DNA virus with an icosahedral capsid.
Composed
Transmission HPV
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 sysem HPV
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
High risk HPV
16,18,31,45
Oncogenic effect HPV
oncogenic potential of HPV can be explained by the activities of the two viral genes encoding E6 and E7
E6
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
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
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
Acute ulcerative infection that leads to painful chancroid (soft chancre)
The chancre is tender and erythematous on the external genitalia (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
Untreated cases lead to excessive scarring –> lymphatic obstruction and lymphedema == elephantiasis
Look for encapsulated coccobacilli in macrophages (Donovan bodies) on Giemsa stain
STI with ulcers
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 and squamous cell hyperplasia
Neoplasia: vulvar intraepithelial neoplasia (VIN), Paget disease, and invasive carcinoma
Lichen sclerosis
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 lichen sclerosis
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 lichen sclerosis
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 hyperplastic dystrophy or lichen simplex chronicles
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 squamous cell hyperplasia
Thickening of the epidermis + hyperkeratosis
Hyperplastic epithelium may show mitotic activity but lacks cellular atypia
Lymphocytic infiltration of the dermis may occur
Condyloma acuminata (benign genital wart)-HPV
inition
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 condyloma acuminata
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 Latium
Condyloma latum: benign raised lesion due to syphilis == treponema pallidum
Fibroepithial polyp
al 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
Vulva carcinoma
Most common (still uncommon) 2/3 occur in females > 60 years
Two types of vulvar carcinoma
Basaloid & warty carcinoma related to HPV 16 (younger age, 50’s)
Keratinizing SCC not related to HPV (older age
Basaloid carcinoma
Exophytic or indurated and ulcerated
Small tightly caked basaloid cells
Foci of central necrosis
Warty carcinoma
Exophytic, papillary architecture
Prominent koilocytic atypia
Classic vulvar intraepithelial neoplasia (VIN) carcinoma in situ, bowen disease
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
Young age at first intercourse
Multiple sexual partners
Male partner with multiple sexual partners
Presentation VIN
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 VIN
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
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 differentiated VIN
phology
Marked atypia of the basal layer of the squamous epithelium
Normal differentiation of the superficial layers
Invasive keratinizing squamous cell carcinomas
Nests and tongues of malignant squamous epithelium
Prominent central keratin pearls
Progression to carcinoma differentiated VIN
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 differentiated VIN
Prognosis
Lesions < 2cm = 90% 5 year survival after treatment with vulvectomy + ladectomy
Larger lesions with involved lymph nodes have worse prognosis
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
Ok
Glandular neoplastic lesions
Ok
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
Extramammary Paget Disease == typically not associated with underlying cancer and is confined to the epidermis of vulvar skin
Morphology extramammary paget disease
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
Extramammary paget disease location of tumor
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
Extramammary paget disease metastasis
Metastasis
May remain intraepidermal for years and not invade or metastasize
Invasion = poor prognosis
Vagina
_________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 vagina
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
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
Gardner 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
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
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 embryonal rhabdomyosarcoma
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)
Grow as polypoid, rounded, bulky masses
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 embryonal rhabdomyosarcoma
Conservative surgery + chemotherapy
Best if diagnosed early
Cervix external vaginal portion
External vaginal portion (ectocervix)
Visible on vaginal exam
Covered with mature squamous epithelium continuous with the vaginal wall that converges at the external os
Cervix 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
Lactobacilli in 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
Treat endocervical polyps
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 HPV on cancer
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
Low risk HPV 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
V 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
Prognosis HPV infections
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
HPV infection
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 increased risk
↑ risk == Cervix and Anus (homosexual men
Epithelial susceptibility to HPV decreased risk
↓ 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
E7
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
this allows E2F to dissociate and ???
viral E7 binds & inhibiting p21 & p27 (cyclin dependent kinase inhibitors, CKIs
E6
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
E6 and E7
↑ 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
Squamous intraepithelial lesions
Classification
Classified into a two tier system, all are most commonly caused by HPV16
Low grade squamous intraepithelial lesion
Previously CIN I (mild cervical intraepithelial neoplasia)
80% of LSILs are associated with high-risk HPV types
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
LSIL
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
HSIL
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 considered to be at high risk for progression to carcinoma
Diagnose SIL
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 SIL
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 (where it shouldn’t be)
Overexpression of p16 (increased CDK4) [cyclin dependent kinase inhibitor]
“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 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
LSIL
60% regress
30% persist
10% progress to HSIL
HSIL
30% regress
60% persist
10% progress to carcinoma within 2-10 years
Most develop from LSIL, though 20% develop de novo
Cervical carcinoma
Average Age: 45 years
due to high risk HPVs (16, 18, 31, 33, and 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
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
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, and 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
Stage 0
Staged as carcinoma in situ (CIS) = CIN III, HSIL
Stage I
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
Stage II
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
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
Stage IV: Carcinoma has extended beyond the true pelvis or involves the mucosa of the bladder or rectum
Also includes cancers with metastatic dissemination
Treat
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
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
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
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
Gardasil: 6, 11, 16, 18
Myometrium
myometrium == tightly interwoven bundles of smooth muscle that form the wall of the uterus
hormonally responsive to oxytocin during parturition
Endometrium
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
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
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
Tortuous and serrated or saw toothed
Stromal changes during the late secretory phase are important for dating the endometrium
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 (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
Day 21-22
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
Day 23-24: Stromal cell hypertrophy, ↑ cytoplasmic eosinophilia (predecidual change), resurgence of stromal mitoses
Day 24-28
Days 24-28: Pre-decidual changes occur + a normal, sparse infiltrate of neutrophils + lymphocytes
Decidualized cells high in glycogen and lipid
Dissolution of corpus luteum
Leads to ↓ progesterone
Functionalis degeneration + bleeding into the stroma occurs
Stromal breakdown → onset of the next menstrual cycle
Estrogen
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
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
Functional endometrial disorders
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 of functional endometrial disorders
Most commonly due to hormonal disturbances
May also be due to pathologies such as chronic endometritis, endometrial polyps, submucosal leiomyomas, endometrial neoplasms
Anovulatory cycle
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 anovulatory cycle
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 anovulatory phase
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 leutal 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
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 endometriosis
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 endometriosis
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
What is chronic endometriosis associated with
PID (mostly chlamydia)
Retained gestational tissue, post-partum or post-abortion
IUD
TB (miliary or from drainage of TB salpingitis) [rare in Western countries]
Chlamydia
No identified cause (15%)
Presentation chronic endometriosis
Abnormal bleeding
Pain
Discharge
Infertility
Pelvic TB
Both fallopian tubes are involved
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 pelvic TB
Multinucleated giant cells
Histiocytes
Can see the bugs with a Kinyoun or Ziehl-Neelsen acid fast stain
Endometriosis
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 endometriosis
Ovaries Uterine ligaments Rectovaginal septum Cul de sac Pelvic peritoneum Large & small bowel, appendix, Mucosa of cervix, vagina, fallopian tubes Laparotomy scars
Pathogenesis endometriosis
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 endometriosis
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
↓ responsiveness to progesterone
Risk of carcinoma from endometriosis
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
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 similar to complex atypical endometrial hyperplasia
Clincial endometriosis
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
Diagnose endometriosis
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
Treat endometriosis
Aromatase inhibitors or surgical
Adeno Yoshi’s
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
Endometrial polyps
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 endometrial polyps
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 endometrial polyps
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
↑ 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
What is endometrial hyperplasia 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
Genetics endometrial hyperplasia
PTEN inactivating mutation
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
not predictive of progression to carcinoma
germline mutation == Cowden syndrome
Cowden patients have an ↑ incidence of endometrial + breast cancer
Classification endometrial hyperplasia
Nonatypical hyperplasia
Atypical hyperplasia (endometrial intraepithelial neoplasia)
Differ in appearance and their propensity to progress to carcinoma
Nonatypical 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 morphology (endometrial intraepithelial neoplasia )
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
Treat endometrial hyperplasia
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
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
two types: Type 1 (endometrioid) and Type II (serous)
Type I (endometrioid) == low-grade, indolent, preceded by atypical hyperplasia
Type II (serous) == high-grade, aggressive, poor prognosis, preceded by serous endometrial intraepithelial carcinoma
Type I (endometriod) carcinoma of endometrium
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
Type I arise in setting of endometrial hyperplasia and associated with
Arise in the setting of endometrial hyperplasia & associated with: Obesity Diabetes HTN Infertility Unopposed estrogen stimulation
Mutations type I
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
Type I DNA mismatch repair genes
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 type I
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
Grade 1
Grade 1: Well differentiated, well-formed glands
distinguished from hyperplasias by lack of intervening stroma
Grade 2
Grade 2: Moderately differentiated, well-formed glands mixed with solid sheets of cells (50% or less or tumor mass
Grade 3
Grade 3: Poorly differentiated greater than 50% solid growth
Grading
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
Stage I: carcinoma is confined to the corpus uteri (body of the uterus
Stage II
Stage II: carcinoma involves the copus + cervix
Stage III
Stage III: carcinoma extends outside the uterus but not out of the true pelvis
Stage IV
Stage IV: carcinoma extends outside the true pelvis or involves the mucosa of the bladder or rectum
Type II carcinoma of the endometrium (serous )
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 of type II
Subtypes Serous (most common), clear cell carcinoma, malignant mixed mullerian tumor
Pathogenesis type II
90% have TP53 missense mutations == accumulation of altered protein
Precursor lesion: serous endometrial intraepithelial carcinoma (also has altered TP53)
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 type II
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 type II
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 type II
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 type II 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
Endometrial adenocarcinomas with a 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 malignant mixed mullerian tumors (carcinosarcomas)
Mutations
PTEN, TP53, PIK3CA (similar to endometrial carcinoma)
Alterations typical of those in sarcomas are absent
mechanism of sarcomatous transformation is unknown
Morphology malignant mixed mullerian tumros
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 malignant mixed mullerian tumors
Seen in postmenopausal women
Present with bleeding
resemble endometrial carcinoma genetically
poor outcomes with current therapies
Prognosis malignant mixed mullerian tumors
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
Tumors of the endometrial stroma are __-
Rare
Adenosarcoma
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 adenosarcoma
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 sarcoma
JAZF1 (transcription repressor)/SUZ12 (polycomb gene family)
High grade endometrial tumor sarcoma
“other gene fusions,” function of which is currently unknown
Uterine leiomyoma
Most common tumor in women
Benign, smooth muscle neoplasms
Multiple > single
Genetics uterine leiomyoma
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 uterine leiomyoma
Found in the myometrium of the corpus
Infrequently involve uterine ligaments, lower uterine segment or cervix
Morphology uterine leiomyoma
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 uterine leiomyoma (fibroids)
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
Pregnancy and uterine leiomyoma
↑ 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
Most commonly the lung
Disseminated peritoneal leiomyomatosis
Multiple, small peritoneal nodules
Benign
Leiomyosasrcoma
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 leiomyosarcoma
Complex, highly variable karyotypes, often with deletions
MED12 mutations – virtually unique to uterine smooth muscle tumors
Morphology leiomyosarcoma
Bulky, fleshy masses that invade the uterine wall
OR
Polypoid masses that project into the uterine lumen
Spread and prognosis leiomyosarcoma
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
Diagnose leiomyosarcoma
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
Inflammation Fallopian tubes
60% of suppurative salpingitis == neisseria gonorrhea
many of the remaining cases == chlamydia trachomatis
Paratubal cysts Fallopian tubes
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
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.
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
Ovarian 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
very common in the ovary
Originate from unruptured graafian follicles or in follicles that ruptured and then immediately sealed
Morphology cystic ovarian follicles
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)
Cystic ovarian follicles hyperthecosis==pronounced leutinization
Hyperthecosis == pronounced leutinization
Often associated with ↑ estrogen production and endometrial abnormalities
Lateral 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
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?)
What is PCOS associated with
underlying metabolic disorder
Obesity (altered adipose tissue metabolism)
T2DM (insulin resistance, Acanthosis Nigricans)
Premature atherosclerosis
Dysregulation of enzymes for androgen biosynthesis (excess androgen production)
Endometrial hyperplasia and carcinoma due to ↑ free estrone (E1) levels
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 (cortisol 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
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 ovarian tumros
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 ovarian tumors
Abdominal pain and distention
Urinary and GI tract symptoms due to compression or invasion
Vaginal bleeding
Ovarian epithelial tumors
Most primary ovarian neoplasms arise from the Müllerian epithelium
Types of epithelial ovarian tumros
Serous
Mucinous
Endometrioid
Classification of epithelial tumors of ovary
Cystic or fibrous, and may be:
Benign (classified by tumor components)
Borderline
Malignant (cystadenocarcinomas
Clinical epithelial tumors or ovary
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
Type I epithelial ovarian tumor
Type I: Low-grade with variable histology, often associated with borderline tumors or endometriosis
Type II
Type II: High-grade, most often serous, arise from serous intraepithelial carcinoma
Mullerian epithelium: serous tumors
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 of 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
Low grade pathogenesis mullerian epithelial serous tumors
Arise in serous borderline tumors
KRAS, BRAF, ERBB2 mutations
Wildtype TP53
Responds better to chemotherapy
High grade pathogenesis mullerian epithelium: serous tumors
↑ 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 mullerian epithelium serous tumour
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
What is mullerian epithelium serous tumors associated with
Larger areas of solid or papillary tumor mass, irregularity, and fixation/nodularity of the capsule are features associated with malignancy
Associated features with malignancy serous tumors of mullerian epithelium
Larger areas of solid or papillary tumor mass, irregularity, and fixation/nodularity of the capsule are features associated with malignancy
Benign morphology serous of mullerian
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 mullerian serous
↑ # 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 mullerian serous morphology
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
Cells identical to high grade, but there is no invasion
“But there is also an invasive type? WTF is going on in this section?” - SD/OMM Fellow Marc Larsen-Hallock
Marked epithelial atypia in the fallopian tubes
Indicates a fallopian tube origin for high grade serous carcinomas
females are BRCA1/2
Germline mutations
Often seen at the time of prophylactic salpingo-oophorectomy
Associated with sporadic, high grade serous ovarian cancer
Tumor spread mullerian serous
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 mullerian serous
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
Borderline tumors may recur and 5-year survival is not synonymous with cure
Mullerian epithelium: mucinous tumor
20-25% of all ovarian neoplasms
Most are benign or borderline tumors
Common in middle adult life, rare before puberty or after menopause
Pathogenesis mullerian mucinous
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 mullerian mucinous
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 mullerian epithelium
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 mullerian mucinous
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
Endometrial tumors
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 of endometriod tumors
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 endometrioid tumors
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 endometrioid tumors
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
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 clear cell carcinoma
PIK3CA, ARID1A, KRAS, PTEN, TP53 mutations
Morphology CCC solid and cystic
Solid: cells are arranged in sheets or tubules
Cystic: cells line the spaces
Prognosis CCC
90% 5 year survival if confined to the ovaries
Poor outcome if advanced
Cystadenofibroma
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
Clincial 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
Clincila nature of malignant tumors
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)
Monodermal/highly specialized
Mature teratoma benign
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
Mature teratoma benign 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
Stroma 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 eratomas
Tumor tissue resembles embryonal and immature fetal tissue
Seen in prepubertal patients and young women (average age: 18 at presentation)
Morphology immature malignant teratoma
Solid, bulky tumors with a smooth external surface
May see hair, sebaceous material, cartilage, bone, calcification
+/- necrosis & hemorrhage
Growth and spread immature malignant teratomas
Grow rapidly, frequently penetrate the capsule, and spread locally or distantly
Risk of spread is proportional to amount of tissue containing immature neuroepithelium
Prognosis immature malignant teratomas
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
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 dysgerminoma
OCT3, OCT4, NANOG (as seen in seminomas) which maintain pluripotency
33% have mutations of KIT (may target for therapy
Morphology dysgerminoma
Unilateral tumors that vary in size
Large vesicular cells with clear cytoplasm (like seminoma)
Well defined borders
Central nuclei
Grow in sheets or cords
Scant fibrous stroma infiltrated by mature lymphocytes +/- granulomas
Treatment and prognosis dysgerminoma
all are malignant only ∼ 1/3 are aggressive unilateral, non-invasive, no metastasis == 96% cure rate (excellent prognosis) after salpingo-oophorectomy responsive to chemotherapy overall survival is >80%
Yolk sac tumor
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 yolk sac tumor
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
Clinical yolk sac tumor
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 and often fatal
In 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 celll tumors
germ cell tumors containing various combinations of dysgerminoma, teratoma, yolk sac tumor, and choriocarcinoma
Sex cord stroma 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
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 granulosa cell tumors
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
Occasionally there is a predominant thecoma component (clusters/sheets of cuboidal/polygonal cells
Clincial granulosa
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 granulosa
↑ 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 granulosa
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
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
benign
Fibrothecoma
Fibrothecoma
Tumor arising in the ovarian stroma composed of both fibroblasts & plump spindle cells with lipid droplets
benign
Meigs syndrome
Meigs Syndrome == ovarian tumor, hydrothorax, and ascites
(Fibroma, Thecoma, Fibrothecoma) == benign
Ovarian tumor present as a pelvic mass +/- pain
Ascites if the tumor > 6cm
Hydrothorax, usually only on the right side
Sertoli leydig cell tumors
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 Sertoli leydig cell tumor
DICER1 mutation in > 50%
Endonuclease essential for micro-RNA processing
Morphology sertoli leydig cell tumors
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
Hilo’s cell tumors (pure leydig cell tumors)
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 hilum cell tumors
unilateral tumors with large, lipid laden Leydig cells
Distinct borders
Reinke crystalloids: characteristic cytoplasmic structures
Clincial Hilus cell tumors
Present with evidence of masculinization: hirsutism, voice changes, clitoral enlargement
Mild vs. Sertoli-Leydig cell tumors
Treatment Hilus cell tumor
Surgery
Almost always benign
Pregnancy luteoma
Ovarian tumor of sex cord or stromal origin
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
Kurek Berg 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
Children – congenitally malformed or long fallopian tubes, or absent mesosalpinx
Pregnancy (20%) – enlarged corpus luteum, laxity in ligaments
Pregnancy induction – multiple enlarging follicles
Ovarian tumors – benign and malignant, dermoid most common
Etiology ovarian torsion
Children
Congenitally malformed or long fallopian tubes, or absent mesosalpinx
Pregnancy (20%)
Enlarged corpus luteum, laxity in ligaments
Pregnancy induction
Multiple enlarging follicles
Ovarian tumors
Benign and malignant, dermoid most common
Spontaneous abortion
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
Maternal endocrine factors spontaneous abortion
Luteal phase defect, poorly controlled diabetes, thyroid dysfunction
Systemic disorders affecting maternal vasculature spontaneous abortion
Systemic disorders affecting maternal vasculature
Antiphospholipid antibody syndrome, coagulopathy, HTN
APS gives a false positive test for syphilis
Infections spontaneous abortion
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
Fetal implantation outside the normal intrauterine location
Most common: fallopian tube (90%)
2% of confirmed pregnancies and for 4-10% of pregnancy related deaths
Who has increased risk of ectopic pregnancy
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
Diagnose tubal pregnancy
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
Twin placenta
Dizygotic: fertilization of two ova Monozygotic: division of one fertilized ovum three 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 prevails
a – “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 accretion
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
Placenta infection
Develop via
Ascending infection through the birth canal (most common, usually bacterial)
Hematogenous (transplacental) infection
Placenta 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
TORCH infection
Affect the placenta and can cause chronic villitis
Toxoplasmosis
Others (To Light Passing hovering Zambonis: TB, listeria, parvovirus, HIV, Zika)
Rubella
CMV
Herpes simplex virus
Syphilis
Gestational HTN
Develops during pregnancy
No proteinuria
Must be distinguished from preeclampsia
Preeclampsia
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 preeclampsia
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 preeclampsia
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 preeclampsia
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 preeclampsia
Hypercoagulable state
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 preeclampsia
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 preeclampsia
Liver: irregular, focal, subcapsular + intraparenchymal hemorrhages
Variable kidney lesions
Brain and heart morphology preeclampsia
Brain: foci of hemorrhage +/- thromboses
Similar changes in heart & anterior pituitary
When preeclampsia presents
Usually occurs > 34 weeks of gestation
Earlier in women with hydatidiform mole, pre-existing kidney disease, HTN or coagulopathy
Risk factors preeclampsia
Risk factors age> 40 African American renal disease HTN DM clotting disorders first pregnancy family history
Clincial preeclampsia
Insidious onset of HTN, edema, and proteinuria in several days
headache + visual disturbances indicate severe manifestations that may require delivery
eclampsia == seizures –> coma
Treat preeclampsia 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 preeclampsia
20% of patients develop HTN and microalbuminuria within 7 years of a pregnancy complicated by this disease
2x ↑ risk of vascular disease of the heart and brain
Hydatidiform mole
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
Risk for hydatidiform mole
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
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 hydatidiform mole
Delicate, friable mass of thin walled, translucent, cystic, grapelike structures with swollen, edematous (hydropic) villi
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 morphology
Only a fraction/partial of the villi are enlarged and edematous
Trophoblastic hyperplasia is focal and less marked than in complete moles
Clinical partial mole
Partial or early complete
Spontaneous miscarriage or curettage due to abnormal villous findings on ultrasound (will see snowstorm pattern on ultrasound
Clincial complete mole
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 invasive moles
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 invasive moles
Presents as vaginal bleeding + irregular uterine enlargement
Persistently ↑ HCG
Treat invasive mole
responds well to chemotherapy
may result in uterine rupture requiring hysterectomy
Choriocarcinoma
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 choriocarcinoma
Complete hydatidiform mole (50%) Previous abortion (25%) Normal pregnancy (22%) Ectopic pregnancy (3%) Germ cells of the ovaries or mediastinum (rare
Morphology choriocarcinoma
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 and cytotrophoblasts
Clincial choriocarcinoma
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
Treat choriocarcinom
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 size trophoblastic tumor
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
