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• Embryology
• Unfused upper portions of the müllerian ducts--> Fallopian tubes
• Fused lower portions of the müllerian ducts --> Uterus, cervix, and upper vagina
• Endometriosis is a müllerian-derived lesion
• may occur in the vagina and clinically simulate a neoplasm
• Urogenital sinus --> lower vagina
• Mesonephric ducts --> normally regress
• Gartner duct cysts: when remnants of the mesonephric ducts persist into adult life as epithelial inclusions
adjacent to the ovaries, tubes, and uterus; in the cervix and vagina these rests may be cystic and are termed
Gartner duct cysts
• coelomic epithelium (mesothelium) --> lining of the female genital tract as well as the ovarian surface
• morphologically similar lesions arise in various sites within the female genital tract and the adjacent
peritoneal surfaces
Gardnerella gram negative bacillus; main cause of bacterial vaginosis; thin, grey-
vaginalis green malodorous (fishy) vaginal discharge; premature labor
1
• Plasma cell morphology
• Nucleus placed off to one side
• Clearing around the nucleus
• Presentation
• 1/3 of newly infected females show painful lesions 3-7 days
post-infection with fever, malaise, and tender inguinal lymph nodes
• Red papules that progress to vesicles and then to painful coalescent ulcers
• Cervical or vaginal lesions present with purulent discharge and pelvic pain
• Lesions around the urethra may cause painful urination and urinary retention
• ALL MALES are symptomatic
• Viral characteristics
• Herpesvirus family; large linear dsDNA, enveloped, icosahedral, derives
envelope from nuclear membrane, contains intranuclear inclusion
bodies AKA Cowdry bodies
• Lesions
• Lesions are red papules that progress to vesicles and the coalesce to ulcers that are easily visible on the
vulva, but lesions on the cervix or vagina are associated with purulent discharge and pain
• Vesicles & ulcers contain viral particles causing ↑ transmission rate with active infection
• Lesions heal spontaneously in 1-3 weeks
• Easily visible on vulvar skin and mucosa
• Near urethra = painful urination (dysuria)
• Latency
• Infection remains latent in lumbosacral nervous ganglia
• Reactivation due to stress, trauma, UV light,
hormonal changes (skin & mucosal lesions)
• Immunocompromised → meningitis,
hepatitis, pneumonitis
• Detection of anti-HSV antibodies in the serum is indicative
of recurrent/latent infection
• Morphology
• Usually biopsy the ulcer phase
• Desquamated epithelium with acute inflammation at the ulcer bed
• Multinucleated squamous cells with eosinophilic to basophilic viral inclusions with a "ground glass"
appearance (viral cytopathic effect)
• Transmission
• Transmitted during active infection
• May occur during latent phase due to subclinical viral shedding
• ↓ risk with condoms and antiviral therapy
• Never completely prevented!
• Females have higher susceptibility
• Previous infection with HSV-1 ↓ risk of infection with HSV-2
2
• HSV-2 infection enhances HIV-1 acquisition and transmission
• Vertical transmission (mom to baby) warrants C-section if infection is (1° and) active
• Deadly to neonates – high mortality rate
• Treatment
• There is no treatment, but some antivirals (acyclovir) can shorten the active phase
• Definition
• Skin or mucosal poxvirus with 4 subtypes
• MCV1: most prevalent
• MCV2: most often sexually transmitted
• 6 week incubation period
• Viral characteristics
• dsDNA , can make its own envelope, has complex morphology, only DNA virus that replicates in the
cytoplasm and has own RNA polymerase and everything it needs to replicate outside the nucleus
• Guarnieri bodies, or inclusion bodies, which are sites of viral replication in the cytoplasm and a dumbbell
shaped core
• Transmission
• Children (2-12 years old): spread via direct contact or shared items (towels) and is most common on the
trunk, arms & legs. Think of sexual abuse if seen in genitals in kids.
• Adults: sexually transmitted and seen on genitals, lower abdomen,
buttocks, inner thighs
• Clinical appearance
• Pearly, dome-shaped papules with a dimpled center
• The papules measure 1 to 5 mm in diameter, dimpled umbilicated
center, and their central waxy core contains cells with cytoplasmic
viral inclusion bodies
• Diagnosis
• 1-5mm papules
• Pearly, dome shaped with dimpled/umbilicated center
• Central waxy core with cytoplasmic viral inclusions
• Candida (Moniliasis)
• Definition
• Yeast are part of many females’ normal vaginal microflora
• Opportunistic yeast infection with disturbance of the microbial ecosystem
• Increased incidence: DM, antibiotics, pregnancy, burn patients, indwelling catheter, immunosuppression
(compromise neutrophils or Th17 cells)
• Most common cause of opportunistic mycosis
• Yeast characteristics
3
• Dimorphic: mold in the heat, yeast in the cold
• Forms pseudohyphae and budding yeast at 20˚C and germ tubes-hyphae molds at 37˚C
• Presentation
• Intense vulvovaginal pruritis, erythema, and swelling
• Thick white vulvovaginal discharge “curd-like or cottage cheese-like”
• If severe → mucosal ulceration
• Diagnosis
• Pseudospores or filamentous fungal hyphae in wet KOH mounts of discharge or on Pap smear
• Not considered an STI
• Trichomonas vaginalis
• Definition and transmission
• Large, flagellated ovoid protozoan
• Sexual transmission
• 4-14 days to develop
• Most common curable STI
• Presentation
• Yellow, frothy vaginal discharge, vulvovaginal discomfort, dysuria, dyspareunia
• Fiery red mucosa of the vagina and cervix
• Marked dilation of cervical mucosal vessels → 'strawberry cervix' (colposcopic appearance)
• Diagnosis
• Motile trophozoites in methylene blue wet mount, present with corkscrew motility
• Gardnerella vaginalis
• Definition
• Gram -ve bacillus
• Main cause of vaginitis (Bacterial vaginosis)
• Found normally in the reproductive tract, but lactobacillus keeps it in check
• Presentation
• Present with thin, green-gray, malodorous (fishy)
discharge
• Pregnant patients: may cause premature labor.
• Diagnosis
• Pap smear: superficial, intermediate squamous cells covered by a shaggy coating of coccobacilli (clue cells)
• Cultures: also contain anaerobic pepto-streptococci and aerobic α-hemolytic streptococci
• Need to differentiate it from candida and trichomonas by examining a slide to look for clue cells
• Whiff Test: there is a fishy amine odor when KOH is added to it
4
• Implicated in chorioamnionitis and premature delivery in
pregnant patients
• Ureaplasma: urease positive
• Mycoplasma: no cell wall
• Look for the fried egg appearance
• Chlamydia trachomatis
• Definition
• Most common STI in the world
• One of the main causes of pelvic inflammatory disease
• Bacterial characteristics
• Small gram -ve obligate intracellular bacteria
• Two forms
• Elementary body: metabolically inactive, infectious form in endosome - infectious
• Reticulate body: metabolically active form - Replicating
• Presentation
• Usually asymptomatic or presents similar to gonorrhea: primary infection is characterized by a
mucopurulent discharge containing a predominance of neutrophils
• Chlamydia == mucopurulent ("pus-sy")
• Gonorrhea == serous, thin, watery
• Diagnosis
• Diagnose with Nucleic Acid Amplification Test (NAAT)
In lecture
• Granuloma inguinale – uncommon in US and europ – but common in rural areas of
developing countries
• Chancroid is uncommon in US – but most common in Africa and Southeast Asia
• L serotypes of C. trachomati causes lymphogranuloima venerum – chronic ulcerative
disease – Lymphogrannuloma venerum – sporadic disease in US and Europ – Endemic in
Asia, Affrica, Caribbean region, South America
• Granuloma Inguinale - Klebsiella granulomatous giesma stain – Donovan bodies – macrophages with encapsulated
coccobaciliary organisms – 20 year old female on OCP – uncommon in US and Europe be endemic in rural areas and
developing countries
• Acute complications
• Peritonitis & bacteremia
• Endocarditis, meningitis and suppurative arthritis
• Chronic sequelae
• Infertility, tubal obstruction, ectopic pregnancy, pelvic pain, intestinal
obstruction due to adhesion between bowel and pelvic organs
• Fitz-Hugh Curtis syndrome: rare complication involving liver capsule
inflammation leading to the creation of adhesions (especially from
Neisseria gonorrhea) – violin string
• Lymphogranuloma venereum
• From Chlamydia Trachomatis serotypes L1-L3
• Prevalent in Africa, Asia, and South America
• Presents first with a painless ulcer at the site of contact then progresses to swollen lymph nodes leading to genital
elephantiasis in late stage
• Tertiary stage presents with ulcers, fistulas, and genital elephantiasis
• Trachoma
• From Chlamydia serotypes A, B, Ba, and C – is the leading cause of preventable infectious blindness
• Follicular conjunctivitis leading to conjunctival scarring; in-turned eyelashes leading to corneal scarring &
blindness
• Transmission
• Sexually or across the placenta
• Pathogenesis
• Disease is characterized by endarteritis resulting in lesions; strong tendency to chronicity
• Diagnosis
• Visualized by immunofluorescence or dark-field microscopy
• Warthin-Starry stain or steiner silver stain
• Can also use VDRL or RPR
• Jarisch-Herxheimer reaction
6
• Starts generally during the first 24 hours of antibiotic treatment and presents with increase in temperature,
decrease in blood pressure, rigors, and leukopenia
• Primary stage
• Non-tender chancre (wart); clean, indurated edge; contagious; heals spontaneously 3-6 weeks but
progresses because painless and is typically left untreated
• Secondary stage
• Maculopapular (copper-colored) rash that is diffuse, and includes palms and soles, patchy alopecia;
condyloma lata: flat wart like perianal and mucous membrane lesions; highly infectious
• Latent stage
• No clinical symptoms.
• Tertiary Stage
• Gummas or syphilitic granulomas that are soft growths with firm necrotic centers
• Aortitis and aneurysm of ascending aorta with tree-barking appearance; destroys the vasa vasorum that
supplies the aorta with blood
• CNS inflammation: damage to the posterior column of the spinal cord and ocular defect of Argyll Robertson
("prostitutes") pupils which react to accommodation but has no reaction to light
• Congenital
• Desquamating Maculopapular rash & Tabes dorsalis
• Can have Saber-shins or anterior bowing of the tibia; saddle nose; Hutchinson’s notched teeth and
Mulberry molars with enamel outgrowths; deafness
• Treatment
• Penicillin G
• Puerperal Infection
• Infection after spontaneous or induced abortion and normal or abnormal deliveries
• Polymicrobial with Staph, Strep, coliforms, Clostridium perfringens
• Bacterial characteristics
• Phagocytosed gram -ve diplococci within neutrophils/PMNs (intracellular)
• Will have pili on electron microscopy
• Presentation
• Females: Often asymptomatic; scarring of tubal lumen and fimbriae can → infertility or ectopic pregnancy
• Can lead to Fitz-Hugh Curtis syndrome
• Males: Urethral discharge
• Morphology
• Marked acute inflammation of involved mucosal surfaces
• Acute suppurative salpingitis
7
• Infection of the fallopian tubes
• Diffusely infiltrated → epithelial injury & sloughing of plicae
• Salpingo-oophoritis: exudate leaks from fimbriae of the tubal lumen to cause infection of the ovary
• Tubo-ovarian abscesses: Collections of pus in the ovary and fallopian tube or in the tubal lumen (pyosalpinx)
• Chronic salpingitis: Scarring of denuded tubal plicae causing gland-like spaces and blind pouches
• Hydrosalpinx: due to fusion of fimbriae and the accumulation of tubal secretions and tubal distension.
• Definitive diagnosis
• Detection of DNA or RNA
• Culture or NAATS
• Thayer-Martin agar
• Treatment
• antibiotics
• Penicillin resistant strains have emerged
• Tubo-ovarian abscesses may require surgical removal as antibiotics may not penetrate
• Post abortion/postpartum are much more difficult to control due to broad spectrum of potential pathogens
• Viral characteristics
• Non-enveloped, double-stranded, circular DNA virus with an
icosahedral capsid.
• Composed of early proteins (E1, E2, E4, E5, E6*, E7*) and late proteins (L1, L2)
• Transmission
• HPV enters the target cells by binding to its cellular receptor. This binding is dependent only on capsid protein
L1 and does not require the other capsid protein L2. HPVs are generally internalized via a clathrin-dependent
endocytic mechanism.
• After getting internalized, the viral coat is disassembled which allow viral genomes access to the cellular
transcription and replication machinery.
• The virus infects the stem cells basal keratinocytes of the mucosal (genital) epithelium and delivers the
genome to the nucleus.
• Infected epithelial cells are called koliocytes -- have a krinkled nucleus that looks like a raisin
8
• High risk types: 16, 18, 31, 33, 45
• Oncogenic effects
• oncogenic potential of HPV can be explained by the activities of the two viral genes encoding E6 and E7
• 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
• 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
9
• Untreated cases lead to excessive scarring --> lymphatic obstruction
and lymphedema == elephantiasis
• Look for encapsulated coccobacilli in macrophages (Donovan bodies) on
Giemsa stain
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
• Leukoplakia
• Descriptive clinical term for opaque, white, plaque-like epithelial thickening that may produce pruritus and scaling
• May be due to:
• Inflammatory dermatoses (psoriases, chronic dermatitis)
• Lichen sclerosis & squamous cell hyperplasia
• Neoplasia: vulvar intraepithelial neoplasia (VIN), Paget disease, invasive carcinoma
10
• Lichen Sclerosis
• Definition
• Smooth, white plaques or macules seen on the vulva
• May enlarge and coalesce → 'porcelain/parchment'
surface
• paper-thin plaque -- very, very thin
• Autoimmune likely
• presence of activated T cells in the subepithelial
inflammatory infiltrate
• increased frequency of autoimmune disorders in
affected women
• Cancer risk
• Not a premalignant lesion
• women with symptomatic lichen sclerosis have a slightly increased risk of developing squamous cell
carcinoma of the vulva
• Patients have an ↑ incidence of autoimmune disorders
• Morphology
• Marked thinning of the epidermis (parchment paper)
• Degeneration of the basal cells
• Excessive keratinization (hyperkeratosis)
• Sclerotic changes of the superficial dermis
• Activated T cells are seen in the subepithelial inflammatory infiltrate (band-like infiltrate)
11
• Benign genital warts due to low oncogenic risk HPV (6 & 11)
• Usually multifocal
• Involve vulvar, perineal and perianal areas +/- cervix and
vagina
• Not precancerous lesions
• Morphology
• Papillary, exophytic, tree-like cores of stroma covered by thickened
squamous epithelium (no mucous inside of them)
• Surface epithelium: viral cytopathic changes (koilocytic atypia)
• Nuclear enlargement, hyperchromasia, and a cytoplasmic nuclear halo -- nucleus looks like a raisin
• Fibroepithelial Polyp: skin tag of the vulva similar to other places on the body
12
• Classic Vulvar Intraepithelial Neoplasia (VIN) (carcinoma in situ, Bowen disease) – see
photo below
• Definition
• Precursor lesion to basaloid & warty carcinoma of the vulva
• Most common in females of reproductive age
• HPV16 related
• Presentation
• Multi-centric around the vulva
• 10-30% also have vaginal or cervical HPV related lesions
• Progression to carcinoma
• Spontaneous regression may occur
• More likely to progresses to invasive
carcinoma in females > 45 years old or
immunocompromised
• Morphology
• Discrete white (hyperkeratotic) or slightly raised,
pigmented lesion
• Epidermal thickening, nuclear atypia, increased
mitoses and lack of cellular maturation
• May progress to invasive carcinoma that are exophytic or indurated with central ulceration
• Histology: nests and cords of small, tightly packed cells that lack maturation and resemble the basal layer of
the normal epithelium
• Morphology
• Marked atypia of the basal layer of the squamous epithelium
• Normal differentiation of the superficial layers
13
• Invasive keratinizing squamous cell
carcinomas
• Nests and tongues of malignant squamous
epithelium
• Prominent central keratin pearls
• Prognosis
• Lesions < 2cm = 90% 5 year survival after treatment with vulvectomy + ladectomy
• Larger lesions with involved lymph nodes have worse prognosis
• Lower 1/3 of vagina = inguinal LN
• Upper 1/3 of vagina = internal iliac
Key CONCEPTS
• 30% of vulvar cancers are caused by infection with high-risk HPVs (HPV-16, 18, 31, and 33)
• Develop from an in situ lesion termed classic VIN
• 70% of vulvar cancers are not related to HPV and develop in a background of lichen sclerosus or squamous cell
hyperplasia
• Premalignant lesion == differentiated VIN
GLANDULAR NEOPLASTIC LESIONS – modified apocrine sweat glands – breast like features – the vulva may be involved by 2
tumors with counter parts in the breast
• Papillary Hidradenoma
• Sharply circumscribed nodule
• Most common on the labia majora or inter-labial folds
• Tends to ulcerate = clinically confused with carcinoma
• Morphology
• histology is identical to intraductal papilloma of the breast
• Not associated with underlying cancer (unlike the counterpart in the breast)
• Paget disease of the nipple == 100% of patients have underlying ductal breast carcinoma
14
• Extramammary Paget Disease == typically not associated with underlying cancer and is confined to the
epidermis of vulvar skin
• Morphology
• Intraepithelial proliferation of malignant cells
• Cells are larger than surrounding keratinocytes
• May be single or in small clusters within the epidermis
• Express apocrine, eccrine and keratinocyte differentiation
• Express cytokeratin 7
• likely arise from multipotent cells in the mammary-like
gland ducts of the vulvar skin
• Have pale cytoplasm with mucopolysaccharide that stains with PAS, Alcian blue, or mucicarmine stains
• Location of tumor
• Intraepithelial malignancy
• Confined to the epidermis of vulvar skin
• Cells spread laterally within the epidermis and may be present beyond the borders of the visible lesion
• treatment is wide local excision
• Metastasis
• May remain intraepidermal for years and not invade or metastasize
• Invasion = poor prognosis
VAGINA
• Remarkably free from primary disease
• Squamous cell carcinoma is the most serious primary disease
• In adults, inflammation often affects the vulva and perivulvar structures and spreads to the cervix without significant
involvement of the vagina
• Developmental Anomalies
• Septate (double) Vagina
• due to failure of Müllerian duct fusion and is accompanied by a double uterus (uterus didelphys)
• Causes:
• Genetic syndromes
• In utero exposure to DES (diethylstilbestrol)
• used to prevent threatened abortions (vaginal bleeding during the first 20 weeks)
• Disturbed epistromal signaling during fetal development
15
• Vaginal Adenosis
• Embryonal epithelium: columnar, endocervical type epithelium
• Replaced with squamous epithelium ascending from the
urogenital sinus
• small patches of residual glandular epithelium which persists
into adult life == vaginal adenosis
• Red, granular areas that stand out from a normal, pale-pink
vaginal mucosa
• Micro: columnar mucinous epithelium indistinguishable from endocervical epithelium
• Most common in females exposed to DES in utero
• Rarely: clear cell carcinoma can arise from DES-related adenosis
• stopped using DES in the 1980s
• Morphology
• Cells are small with oval nuclei and cytoplasmic protrusions
(tennis racket shape)
• Striations may be seen in the cytoplasm
• Tumor cells may be crowded in a cambium layer beneath vaginal
epithelium
• Or the tumor cells can be within an edematous, loose fibromyxomatous stroma in the deep
regions with inflammatory cells (often mistaken for inflammatory polyps)
16
• Grow as polypoid, rounded, bulky masses
• Bortyoides = Appear as grapelike clusters
• Tend to invade locally and cause death by penetration into the peritoneal cavity or by
obstruction of the urinary tract
• Treatment
• Conservative surgery + chemotherapy
• Best if diagnosed early
CERVIX
• Cervix
• External vaginal portion (ectocervix)
• Visible on vaginal exam
• Covered with mature squamous epithelium continuous with the vaginal wall that converges at the external os
• Endocervical canal
• Columnar, mucus secreting epithelium that converges at the external os
• Ectocervix and endocervical come together at the squamocolumnar junction
• The unique epithelium of the cervix makes it highly susceptible to HPV infections
• HPV == leading cause of cervical cancer so this matters
17
INFLAMMATIONS
• Important to identify because of associations with upper genital tract disease, pregnancy complications, sexual
transmission, and pelvic inflammatory disease (PID) --> Fitz-Hugh-Curtis Syndrome (violin string adhesions)
• Marked cervical inflammation can cause reparative and reactive changes of the epithelium + shedding of atypical
squamous cells → abnormal Pap smear
• due to infection, not neoplasm -- don't want to do a hysterectomy because of an infection, give antibiotics
• Endocervical Polyps
• Common, benign exophytic growths within the endocervical canal
• Loose, fibromyxomatous stroma covered by mucus secreting endocervical
glands +/- inflammation
• Vary from small, sessile 'bumps' to large, polypoid masses that protrude
through the cervical os
• may be the source of irregular vaginal "spotting" (bleeding) that
arouses suspicion for ominous disease
• Treatment: curettage or surgical excision = curative
• Cervical Carcinoma
• 3rd most common cause of cancer in women worldwide
• Typically progresses slowly, allowing screening, detection and treatment
• 50% are fatal
• Significant benefits from early diagnosis & curative treatment
• Pap smears detects precursor lesions and low-stage, highly curable cancers
• Strong association with HPV
• HPV Infections
• genital HPV infections are extremely common; most of them are asymptomatic, do not cause any tissue changes,
and therefore are not detected on Pap test
• 50% of HPV infections are cleared within 8 months, and 90% of infections are cleared within 2 years
• high-risk type infections last longer --> more time to develop a precursor lesion --> increased risk
• May infect immature basal cells of the squamous epithelium in areas of epithelial breaks or immature metaplastic
squamous cells at the squamocolumnar junction
• Cannot infect mature superficial squamous cells covering the ectocervix, vagina or vulva unless there is damage to
the surface epithelium allowing access to immature cells in the basal layer of the epithelium
• cervix = large area of immature squamous metaplastic epithelium = particularly vulnerable to HPV infection
• **Infects immature squamous cells
• **Replicates in mature squamous cells
• HPV: E7 Protein
• Enhanced cell cycle progression and impaired ability to repair DNA damage due to:
• viral E7 binds the hypophosphorylated (active) from of RB and promotes its degradation via proteasomes
• viral E7 binds & inhibiting p21 & p27 (cyclin dependent kinase inhibitors, CKIs)
• HPV: E6 Protein
• net effect: increased proliferation of cells that are prone to acquire additional mutations
• viral E6 exacerbates the defective DNA repair via binding to p53 (tumor suppressor) and promoting
proteasomal degradation of p53
• viral E6 upregulates telomerase expression via TERT → cellular immortalization
• Classification
• Classified into a two tier system, all are most commonly
caused by HPV16
• LSIL: low grade squamous intraepithelial lesion
• Previously CIN I (mild cervical intraepithelial neoplasia)
• 80% of LSILs are associated with high-risk HPV types
• Diagnosis
• Diagnosed based on identification of nuclear atypia with:
• Nuclear enlargement & Hyperchromasia (dark staining)
• Coarse chromatin granules
• Variation in nuclear size & shape
• May be accompanied with cytoplasmic 'halos'
• Halos: perinuclear vacuoles due to E5 protein localization to the endoplasmic reticulum= koilocytic
atypia
• Aids in diagnosis
• Highest viral loads in upper ½ of the epithelium
• Ki-67 (marker of actively dividing cells) usually restricted to basal layer
• viral E6 and E7 prevent cell cycle arrest --> Ki-67 seen in upper levels (CIN II/III) (where it shouldn't be)
20
• "Both Ki-67 and p16 staining are highly correlated with HPV infection and are useful for confirmation
of the diagnosis in equivocal cases of SIL."
• Grading
• Based on expansion of immature cell layer from its normal, basal
location
• Confined to lower 1/3 = LSIL
• Expansion into upper 2/3 = HSIL
This is tested fo sho’
• LSIL progression
• 60% regress
• 30% persist
• 10% progress to HSIL
• HSIL progression –
• 30% regress
• 60% persist
• 10% progress to carcinoma within 2-10 years
• Most develop from LSIL, though 20% develop de novo
• Cervical Carcinoma
• Definition
• Average Age: 45 years
• due to high risk HPVs (16, 18, 31, 33, 45)
• 80% of cervical carcinomas are squamous cell carcinomas
• 15% of cervical carcinomas are adenocarcinoma (precursor lesion
== adenocarcinoma in situ)
• 5% of cervical carcinomas are adenosquamos or neuroendocrine
carcinomas
• have a shorter progression time than squamous cell carcinoma
21
• patients often present with advanced disease and less favorable prognosis
• Adenocarcinoma Morphology
• Proliferation of glandular epithelium composed of malignant
endocervical cells with large, hyperchromatic nuclei and mucin
depleted cytoplasm = dark appearance of glands (vs. normal
endocervical epithelium)
• Adenosquamous Morphology
• Intermixed malignant glandular and squamous epithelium
• Neuroendocrine Morphology
• Appears similar to small cell carcinoma of the lung but is +ve for
high risk HPV (16, 18, 31, 33, 45)
• Very poor prognosis
• Staging
• Stage 0: Staged as carcinoma in situ (CIS) = CIN III, HSIL
• Stage I: Carcinoma confined to the cervix
• I-A: preclinical carcinoma (diagnosed only with microscopy)
• I-A1: stromal invasion < 3mm deep & < 7mm wide (microinvasive carcinoma)
• I-A2: 3mm < max stromal invasion < 5mm from the base of the epi; horizontal < 7mm
• I-B: Confined to the cervix and > stage Ia2
• Stage II: Carcinoma extends beyond the cervix but not to the pelvic wall
• Involves the upper 2/3 of the vagina
• No involvement of the lower 1/3
• Stage III: Carcinoma is extended beyond the pelvic wall
• Rectal exam: no cancer free space between the tumor and pelvic wall
• Involvement of the lower 1/3 of the vagina
• Stage IV: Carcinoma has extended beyond the true pelvis or involves the mucosa of the bladder or rectum
• Also includes cancers with metastatic dissemination
• Treatment
• Early invasive: cervical cone excision
• Invasive cancer: hysterectomy + lymph node dissection
• Advanced cancer: + radiation + chemotherapy
• Prognosis
• patients tend to die from consequences of local tumor invasion (ureteral obstruction, pyelonephritis, uremia)
• 100% 5 year survival for microinvasive carcinomas
• < 50% 5 year survival for tumors extending beyond the pelvis
22
• 50% are detected in females without regular screenings
• most patients with advanced cervical cancer die of the consequences of local tumor invasion (e.g. ureteral
obstruction, pyelonephritis, and uremia) rather than distant metastases
• 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
• HPV Vaccine
• Recommended for all girls and boys 11-12 years old, up to age 26
• Provide nearly complete protection vs strains 16 & 18
• One also provides protection vs 6 & 11 (genital warts)
• Protects up to 10 years
• Cervical screenings should still continue as not all strains are protected against
23
• Gardasil: 6, 11, 16, 18
• 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)
• Ovulation
• Endometrial proliferation ceases
24
• Differentiation occurs in response to progesterone produced by the corpus luteum in the ovary
• Post-ovulation
• Marked appearance of secretory vacuoles beneath the nuclei in the glandular epithelium
• Week 3: prominent secretory activity
• Basal vacuoles move towards apical surface
• Glands are dilated between days 18-24 due to max secretion
• Week 4: Tortuous glands with a serrated/sawtooth (secretory phase) appearance accentuated by secretory
exhaustion and shrinkage of the glands
• Secretory Phase
• Progesterone down regulates the expression of estrogen receptors in
the glands and stroma
• Endometrial proliferation is suppressed
• promotes the differentiation of the glands and causes
functional changes in the stromal cells
• 3rd week of cycle: vacuoles become supranuclear and are most prominent
25
FUNCTIONAL ENDOMETRIAL DISORDERS (DYSFUNCTIONAL UTERINE BLEEDING)
• Definition
• Uterine bleeding that lacks an underlying (structural) abnormality
• Most commonly due to hormonal disturbances
• Any alteration of the hypothalamic-pituitary-ovarian system can alter release (timing or amount) of
hormones
• Causes
• Most commonly due to hormonal disturbances
• May also be due to pathologies such as chronic endometritis, endometrial polyps, submucosal leiomyomas,
endometrial neoplasms
• Anovulatory Cycle
• Definition
• Most frequent cause of dysfunctional bleeding is anovulation (failure to ovulate)
• due to subtle hormonal imbalances
• Most common at menarche and perimenopausal periods
• failure of ovulation --> excessive endometrial stimulation by estrogens that is unopposed by
progesterone
• Causes
• most commonly due to subtle hormonal imbalances
• Endocrine disorders: thyroid, adrenal, or pituitary tumors/etiology
• Ovarian lesions: granulosa cell tumors or polycystic ovaries
• Generalized metabolic disturbances: obesity, malnutrition or chronic systemic disease
• Morphology
• Repeated anovulation may result in bleeding that may prompt endometrial biopsy (sometimes)
• Stromal condensation
• Eosinophilic epithelial metaplasia similar to menstrual epithelium BUT lacks progesterone dependent
morphologic features (glandular secretory changes, stromal predecidualization) because the source of
progesterone (corpus luteum) does not develop without ovulation
• Endometrium exhibits pseudostratified glands with scattered mitotic figures
26
INFLAMMATORY DISORDERS
• Chronic inflammation of the endometrium (not associated with menstrual phase) is of concern
• Acute Endometritis
• Uncommon; limited to bacterial infections that arise after delivery or miscarriage
• Predisposed by retained products of conception
• due to group A hemolytic streptoocci, staphylococci, etc.
• Nonspecific inflammation of the stroma
• Treatment: curettage of fragments and antibiotics (beta-lactams for strep and staph) == curative
• Chronic Endometritis
• Definition
• Most common form of endometritis
• Typically caused by an ascending infection (especially chlamydia), sometimes idiopathic
• if organisms are not detected on culture, proceed with antibiotic therapy to prevent sequelae
• If you see one plasma cell on biopsy then it is chronic endometritis until proven otherwise
• diagnosis is made on the identification of plasma cells in the stroma
• plasma cells not normally seen in the normal endometrium
• Pelvic TB
• Both fallopian tubes are involved
27
• Infects the endometrium 50% of the time
• Rarely infects the cervix, vagina, or vulva
• If the ovaries are infected, then there is only surface infection
• Mucosa of the tube may not be involved
• 1/3 of patients will have had TB somewhere else in the body before
• Morphology
• Multinucleated giant cells
• Histiocytes
• Can see the bugs with a Kinyoun or Ziehl-Neelsen acid fast stain
• Endometriosis
• Definition
• Ectopic endometrial tissue seen outside of the
uterus
• Tissue typically includes stroma + endometrial
glands (which may be absent)
• Causes infertility, dysmenorrhea, and pelvic
pain
• Complications can occur if invasion/spread
occurs
• Most common in females 3-4th decade
• Pathogenesis Theories
• Regurgitation theory: endometrial tissue implants at ectopic sites
via retrograde flow of menstrual endometrium through the
fallopian tubes
• this occurs regularly even in normal women
• Most likely theory to explain endometriosis; though not
perfect
• Molecular Analyses
• Release of proinflammatory & other factors: VEGF (need blood
supply), PGE2, IL1β, TNFα, IL6, IL8, NGF, MCP1, MMPS, TIMP
• ↑ estrogen production by endometriotic stromal cells (↑ aromatase, which is absent in normal
stroma)
• inhibitors of aromatase are beneficial in the treatment of endometriosis
• These contribute to invasion and establishment of neurovascular networks + decreased immune clearance
= survival of ectopic tissue
• ↑ responsiveness to estrogen
28
• ↓ responsiveness to progesterone
• Risk of carcinoma
• Patients have a 3x ↑ risk of ovarian cancer of the
endometrioid and clear cell types
• PTEN, ARID1A mutations
• Mutations are also found in endometriotic cysts, atypical
endometriosis & associated carcinomas
• Clinical
• Active reproductive/childbearing years, 3-4th decade, 6-10% of women affected
• Severe dysmenorrhea, Dyspareunia, and Pelvic pain due to intrapelvic bleeding & periuterine adhesions
• Menstrual irregularities
• Infertility == presenting complaint in 30-40% of patients
• pain with defecation if rectal wall is involved
• dysuria if bladder serosa involvement
• Diagnosis
• Diagnosis via presence of endometrial glands and stroma +/-
hemosiderin
• May be obscured by secondary fibrosis
• Rarely only stroma is identified
• Treatment
• Aromatase inhibitors or surgical
• Adenomyosis
• Related to endometriosis
• Presence of endometrial tissue within the uterine wall (myometrium)
• Down growth of endometrial tissue into & between smooth muscle fascicles of the myometrium
• Occurs in 20% of females (uteri)
• Irregular nests of endometrial stroma +/- glands
• Separated from basalis by 2-3mm
• menometrorrhagia, colicky dysmenorrhea, dyspareunia, pelvic pain (premenstrual)
• May coexist with endometriosis
29
• Endometrial Polyps
• Definition
• Exophytic masses of variable sizes that project into the endometrial cavity
• Single or multiple, sessile polyps
• Occasionally: large and pedunculated (attached by a stalk)
• May be asymptomatic or cause abnormal bleeding
• Seen in reproductive age, peri and postmenopausal females
May (rarely) give rise to adenocarcinoma
• Morphology
• Possess chromosomal rearrangements seen in other benign mesenchymal tumors
• Stroma appear neoplastic, while the glands appear reactive
• Glands may be hyperplastic, atrophic or functional (demonstrate secretory changes)
• May become hyperplastic with generalized endometrial hyperplasia
• Hormone sensitivity
• Responsive to estrogen
• Little to no response to progesterone
• Associated with tamoxifen therapy (for estrogen receptor positive breast cancer)
• tamoxifen has weak pro-estrogenic effects in the endometrium (anti-estrogenic effects in breast)
• Atrophic Polyps
• Remnants of previously hyperplastic polyps
• Seen mostly in postmenopausal females
• 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
30
• not predictive of progression to carcinoma
• Germline mutation == Cowden syndrome – (multiple hamartoma syndrome – germline PTEN mutation and
high incidence of endometrial and breast cancer
• Cowden patients have an ↑ incidence of endometrial + breast cancer
• Classified as
• Nonatypical hyperplasia
• Atypical hyperplasia (endometrial intraepithelial neoplasia)
• Differ in appearance and their propensity to progress to carcinoma
• Treatment
• Hysterectomy
• Up to half of patients are found to have carcinoma after hysterectomy
• In patients who wish to remain fertile, progesterone therapy and close follow up may be trialed
• Lack of regression usually prompts hysterectomy (hopefully after successful pregnancy)
31
• Carcinoma of the Endometrium
• Most common invasive cancer of the female’s genital tract
• earlier detection and eradication of the precursor lesions of cervical carcinoma
• 7% of all invasive cancer in women, excluding skin cancer
• Bleeding is an early sign
• Mutations
• Most common (hallmark) == ↑ signaling via PI3K/AKT pathway via multiple mutations
• increasing sensitivity to estrogen as more mutations occur
32
• Defects of DNA mismatch repair genes are prevalent in carcinomas in females from families with HNPCC
(hereditary nonpolyposis colorectal carcinoma). This is
Lynch syndrome
• Often due to epigenetic silencing (hypermethylation)
• Spread
• Localized polypoid tumor or diffuse infiltration of the
endometrial lining
• Spread via myometrial invasion, then direct
extension
• Grading
• Grade 1: Well differentiated, well-formed glands
• distinguished from hyperplasias by lack of intervening stroma
• Grade 2: Moderately differentiated, well-formed glands mixed with solid sheets of cells (50% or less or
tumor mass)
• Grade 3: Poorly differentiated greater than 50% solid growth
• Lack of intervening stroma will differentiate well differentiated tumors from hyperplasia
• There can be squamous elements too, but these are ignored in the grading
• Staging
• Also applies to Malignant Mixed Mullerian Tumors
• Stage I: carcinoma is confined to the corpus uteri (body of the uterus)
• Stage II: carcinoma involves the copus + cervix
• Stage III: carcinoma extends outside the uterus but not out of the true pelvis
• Stage IV: carcinoma extends outside the true pelvis or involves the mucosa of the bladder or rectum
• Subtypes
• Serous (most common), clear cell carcinoma, malignant mixed mullerian tumor
• Pathogenesis
• 90% have TP53 missense mutations == accumulation of altered protein
• Precursor lesion: serous endometrial intraepithelial carcinoma (also has altered TP53)
33
• Identical cells, but lack stromal invasion (i.e. are not malignant; confined to epithelial surfaces)
• Likely begins as a surface epithelial neoplasm that extends to adjacent glands, then invades stroma
• Other mutations: PI3K, PP2A which are also seen in the precursor lesions (early events)
• Morphology: serous
• Seen in small, atrophic uteri
• Tumors are large and bulky or invasive into the myometrium
• Papillary growth pattern
• ↑ nuclear: cytoplasmic ratio, atypical mitotic figures, hyperchromasia, prominent nucleoli
• May also have a glandular growth pattern, but can differentiate by looking for the nuclear atypia
• Clinical
• No screening test available
• Asymptomatic or with irregular or post-menopausal bleeding with excessive leukorrhea
• No uterine enlargement in early stages
• Diagnosis requires histological exam of tissue from biopsy or curettage
• Most patients are cured if there is postmenopausal bleeding as this leads to early detection
• Prognosis, general
• Prognosis is based on stage at presentation
• Most (in USA) are stage I and well-moderately
differentiated
• Stage I (grade 1 or 2): 90% 5 year
survival
• treatment with surgery +/-
irradiation
• Stage I (grade 3): 75% 5 year survival
• Stage II or III: < 50% 5 year survival
• Mutations
• PTEN, TP53, PIK3CA (similar to endometrial carcinoma)
• Alterations typical of those in sarcomas are absent
• mechanism of sarcomatous transformation is unknown
34
• Morphology
• Bulky, polypoid, and may protrude through the cervical os
• Usually consist of adenocarcinoma (glandular) mixed with malignant mesenchymal elements (sarcomatous)
• The metastases typically only have the epithelial components
• Clinical
• Seen in postmenopausal women
• Present with bleeding
• resemble endometrial carcinoma genetically
• poor outcomes with current therapies
• Prognosis
• Prognosis based on depth of invasion and stage
• Also based on differentiation of the mesenchymal component
• patients with tumors that have a heterologous mesenchymal component do worse than those who do not
• 25-30% 5 year survival for high-stage disease
Figure 3: Heterologous elements - (Seen with muscle, cartilage, adipose tissue, bone)
• Adenosarcomas
• Definition
• Stromal neoplasm admixed with benign glands
• Large, broad based endometrial polypoid growths
• May prolapse through the cervical os
• Females in 4-5th decade
• Low grade malignancy
• 25% recur and are confined to the pelvis
• Diagnosis:
• Based on malignant appearing stroma and coexistent benign but abnormally shaped endometrial glands
• need to distinguish adenosarcomas from large benign polyps
• adenosarcomas are estrogen-sensitive and responds to oophorectomy
• Stromal Tumors
• Stromal nodules == benign, well-circumscribed tumors
• Low-grade endometrial tumor sarcoma == infiltrate into the surrounding myometrium
• High-grade endometrial tumor sarcoma == marked atypia
• associated with chromosomal translocations that create fusion genes
Low-grade endometrial tumor JAZF1 (transcription repressor)/SUZ12 (polycomb
sarcoma gene family)
35
High-grade endometrial tumor "other gene fusions," function of which is currently
sarcoma unknown
• Genetics
• Commonly have normal karyotypes
• 40% have a simple chromosome abnormality
• T(12q14;6p): HMGIC, HMGIY -- genes that regulate chromatin structure
• ^^ also implicated in a variety of other benign neoplasms
• MED12 mutations seen in 70% of tumors
• Morphology
• Sharply circumscribed, discrete, round, firm, gray-white tumors that vary
in size
• Characteristic whorled pattern of smooth muscle bundles resembling
the uninvolved myometrium
• Individual muscle cells are uniform in size and shape
• Characteristic oval nucleus & long, slender bipolar cytoplasmic
processes
• Scarce mitotic figures (helps to differentiate from
leiomyosarcoma)
• Large: develop yellow-brown-red areas of softening
• Clinical
• Often asymptomatic, but may have:
• Abnormal bleeding
• Urinary frequency (bladder compression)
• Sudden pain due to infarction of a large or pedunculated tumor
• Impaired fertility
• Malignant transformation → leiomyosarcoma is extremely rare
• Clinical in pregnancy
• ↑ frequency of:
• Spontaneous abortion
• Fetal malpresentation
• Uterine inertia (failure to contract with sufficient force)
• Postpartum hemorrhage
• Leiomyosarcoma
• Definition
• Uncommon, malignant neoplasm
• Arise from myometrium or endometrial stromal precursor cells, rarely from leiomyomas (i.e. de novo)
• Peak 40-60 years (before & after menopause)
• Genetics
• Complex, highly variable karyotypes, often with deletions
• MED12 mutations -- virtually unique to uterine smooth muscle tumors
• Grow as:
• Bulky, fleshy masses that invade the uterine wall OR Polypoid masses that project into the uterine lumen
• Diagnosis
• Distinguished from benign counterpart via nuclear atypia, mitotic index, zonal necrosis; malignant if:
• 10 mitoses per high powered field
• 5 mitoses per high powered field with nuclear atypia or large cells
FALLOPIAN TUBES
• Inflammations
• 60% of suppurative salpingitis == neisseria gonorrhea
• many of the remaining cases == chlamydia trachomatis
• Paratubal Cysts
• Most common primary lesion of the fallopian tubes, excluding endometriosis
• Small translucent cysts filled with clear, serous fluid
• Hydatids of Morgagni: Larger cysts near the fimbriated end of the tube or in the broad ligaments that arise from
remnants of the mullerian duct and are lined with benign, serous (tubal type) epithelium
• Relatively insignificant Figure 4: adnex - parts adjoining an organ
37
• Others may come to attention due to abnormal discharge, bleeding, or abnormal cells on Pap smear
• ~ 50% are stage 1 at diagnosis, but only have a 60% 5 year survival
• Higher grade tumors are more aggressive
• Treatment: ovarian cancer chemotherapy protocols
• at least a subset of "serous ovarian cancers" actually arise from the epithelium of the fallopian tube
OVARIES
• Functional or Benign Ovarian Cysts
• Most common lesion encountered in the ovary
• Morphology
• Multiple cysts < 2cm in diameter
• Larger may cause pelvic pain or be palpable, if >2cm then called Follicle Cyst
• Filled with a clear, serous fluid
• Lined by gray, glistening membrane
• Granulosa cells if not atrophied due to intraluminal
pressure
• Conspicuous outer theca cells due to ↑ amounts of pale
cytoplasm (leutinization)
• Associated with
• Underlying metabolic disorder
• Obesity (altered adipose tissue metabolism)
• T2DM (insulin resistance, Acanthosis Nigricans)
38
• Premature atherosclerosis
• Dysregulation of enzymes for androgen biosynthesis (excess androgen production)
• Endometrial hyperplasia and carcinoma due to ↑ free estrone (E1) levels
• E1= Esterone
• Menopausal estrogen produced by aromatization of andrestenedion
in peripheral fatty tissue
• Less potent estrogen than E2
• E2 = Estradiol
• Predominates in reproductive years
• Most potent estrogen produced by aromatization of
testosterone in Graafian follicle
• E3 = Estriol
• Placental estrogen that originates in fetal adrenal gland as DHEA
and converted in placenta
• Least potent
OVARIAN TUMORS
• Definition
• 80% are benign; occur mostly in females 20-45 years old
• Borderline tumors appear at a slightly older age
• Tissue sources
• Surface/fallopian tube epithelium and endometriosis
• Pluripotent germ cells that migrate to the ovary from the yolk sac
• Stromal cells (including sex cords) which are forerunners of the endocrine apparatus of the postnatal ovary
39
• Urinary and GI tract symptoms due to compression or invasion &
vaginal bleeding
• Epithelial Tumors
• Most primary ovarian neoplasms arise from the Müllerian epithelium
• Types
• Serous
• Mucinous
• Endometrioid
• Classification
• Cystic or fibrous, and may be:
• Benign (classified by tumor components)
• Borderline
• Malignant (cystadenocarcinomas)
• Clinical
• Type I: Low-grade with variable histology, often associated with borderline tumors or endometriosis
• Type II: High-grade, most often serous, arise from serous
intraepithelial carcinoma
• ↓ risk = 40-59 year old that took oral contraceptive therapy or had tubal ligation
40
• Low Grade Pathogenesis
• Arise in serous borderline tumors
• KRAS, BRAF, ERBB2 mutations
• Wildtype TP53
• Responds better to chemotherapy
• Genetics
• low-grade tumors arising in serous borderline tumors have mutations in the KRAS, BRAF, or ERBB2
oncogenes, and usually have a wild-type tp53
• high-grade tumors have a high frequency of tp53 mutations and lack mutations in either KRAS or BRAF
• Benign Morphology
• Smooth glistening cyst wall with no epithelial thickening or with small papillary projections
• 20% are bilateral
• Cysts are lined with columnar epithelium with lots of cilia
41
• Complex patterns of growth
• Widespread infiltration of underlying stroma
• Marked nuclear atypia, pleomorphism, and
multinucleation
• Increased mitotic activity with atypical
mitosis
• Cysts are lined with columnar epithelium
• 66% are bilateral
• Often involve the surface of the ovary
• Tumor spread
• Propensity to spread to the peritoneal surfaces & omentum
• Tumors are more likely to spread to the peritoneum if they are not encapsulated
• Borderline tumors can arise or extend to the peritoneum and remain fixed or spread leading to
intestinal obstruction after many years
• Low grade may spread in this manner but survival is still good
• High grade are often highly metastatic throughout the abdomen at presentation and are commonly
associated with ascites
• Extent of spread outside the ovaries determines the staging
42
• Borderline tumors may recur and 5-year survival is not
synonymous with cure
• Pathogenesis
• Most have KRAS mutation, more likely if the tumor is malignant
• General morphology
• Multi-loculated tumors willed with sticky, gelatinous fluid rich in glycoproteins
• May grow very large (up to 25kg)
• Lined by tall, columnar epithelium with apical mucin, lacking cilia
• Most show gastric or intestinal type differentiation
• Pseudomyxoma Peritonei
• Extensive mucinous ascites, cystic epithelium implants on
peritoneal surfaces, adhesions, and frequent involvement of the
ovaries
• May result in intestinal obstruction and death
• Source most commonly extraovarian (appendiceal) as
most ovarian tumors do not spread away from the ovary
• bilateral presentation requires exclusion of nonovarian origin
• most primary mucinous ovarian tumors are unilateral
43
• Endometrioid Tumors
• Definition
• Endometrioid carcinomas comprise 10-15% of all ovarian cancers
• Benign endometrioid (adenofibromas) and borderline tumors
may occur but are rare
• Relatively good prognosis
• May arise in the setting of endometriosis and borderline
tumors
• 15-20% of cases with endometrioid carcinoma coexist with
endometriosis
• Associations
• Can be associated with ovarian endometriosis or uterine endometrial carcinoma
• Pathogenesis
• When associated with endometriosis, occurs in patients, on average, 10 years younger
• Shared features with endometrial counterpart
• mutations that increase PI3K/AKT signaling pathway (PTEN, PIK3CA, ARID1A, and KRAS)
• Mutations of mismatch DNA repair and CTNNB1 (β-catenin)
• TP53 mutations seen in poorly differentiated tumors
• Morphology
• Solid + cystic areas of growth
• Epithelium consists of tubular glands resembling endometrium
• 40% are bilateral, implies extension beyond the genital tract
• Low grade tumors
• 75% 5 year survival (stage I)
• Mutations
• PIK3CA, ARID1A, KRAS, PTEN, TP53 mutations
• Cystadenofibroma
44
• Small, multilocular tumors with simple papillary processes
• Epithelium is variable
• more pronounced proliferation of the fibrous stroma under the columnar epithelium
• Benign
• Borderline tumors or carcinoma rarely occur and metastatic spread is extremely uncommon
• Teratoma types
• Mature (benign): majority
• Immature (malignant)
45
• Monodermal/highly specialized
• 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
• Struma Ovarii
• Composed entirely of mature thyroid tissue that may by functional →
hyperthyroidism
• Always unilateral
• Ovarian Carcinoid
• Arises from intestinal tissue in teratomas and may be functional
• >7cm = 5HT (5-HIAA) production --> carcinoid syndrome
• Even in absence of hepatic metastases because ovarian veins
are connected directly to systemic circulation
• always unilateral (metastatic intestinal carcinoid is virtually always
bilateral)
• Morphology
• Solid, bulky tumors with a smooth external surface
• May see hair, sebaceous material, cartilage, bone, calcification
• +/- necrosis & hemorrhage
46
• Growth and spread
• Grow rapidly, frequently penetrate the capsule, and spread locally
or distantly
• Risk of spread is proportional to amount of tissue containing
immature neuroepithelium
• Prognosis
• Stage I, grade 1 = excellent prognosis
• Prophylactic chemotherapy if higher grade yet confined to
the ovary
• Recurrences occur in first two years
• absence of disease beyond two years == excellent chance of cure
• Dysgerminoma
• Definition
• 50% of all malignant ovarian germ cell tumors
• Ovarian counterpart of testicular seminoma (which is the most
common male germ cell tumor).
• 2% of all ovarian cancers
• Most have no endocrine function, but may produce hCG (if
syncytiotrophoblasts are present)
• 75% in patients in 2nd-3rd decade, but may occur in childhood
• May occur in patients with gonadal dysgenesis
(Pseudohermaphroditism)
• all dysgerminomas are malignant
• Mutations
• OCT3, OCT4, NANOG (as seen in seminomas) which maintain pluripotency
• 33% have mutations of KIT (may target for therapy)
• Morphology
• Glomerulus-like structure with a central blood vessel enveloped
by tumor cells in a space lined by tumor cells (Schiller-Duval body) -- characteristic histologic feature
47
• Clinical
• Seen in children or young females
• Abdominal pain and rapidly growing pelvic mass (usually involving a single ovary)
• 80% survival with chemotherapy regardless of disease stage
• Choriocarcinoma
• Extraembryonic differentiation of malignant germ cells of placental origin
• germ cell origin can only be confirmed in prepubertal females
• after puberty, ovarian ectopic pregnancy cannot be excluded
• Embryonal Carcinoma: highly malignant germ cell tumor of primitive embryonal elements
• histologically similar to embryonal carcinoma in the testes
• Mixed Germ Cell Tumors: germ cell tumors containing various combinations of dysgerminoma, teratoma, yolk sac
tumor, choriocarcinoma
• Morphology
• Typically unilateral and vary from microscopic foci to large, solid, and cystic encapsulated masses
• If they are hormonally active, they are yellow from stored lipids
• often are hormonally active and associated with endometrial hyperplasia/cancer
• The small cuboidal/polygonal cells may grow in anastomosing cords, sheets, or strands
• Call-Exner bodies: small, distinct, gland-like structures filled with acidophilic material
48
• Occasionally there is a predominant thecoma component (clusters/sheets of cuboidal/polygonal cells)
• Clinical
• Precocious puberty if the tumor is functionally active in a juvenile patient
• Adult females may have proliferative breast disease, endometrial hyperplasia, and endometrial
carcinoma, and/or bleeding
• Masculinization or Pseudohermaphroditism if androgens are produced (most only produce estrogen though)
• Some tumors elaborating hormone can lead to endometrial carcinoma
• Diagnosis
• ↑ serum inhibin (produced by granulosa cells) that inhibits FSH
• Allows diagnosis and monitoring treatment
• Most of the adult type have FOXL2 mutations (important in granulosa cell development)
• Prognosis
• All are potentially malignant
• tumors composed predominantly of theca cells are unlikely to be malignant
• Malignant tumors are usually indolent and local recurrences are treated with surgery
• can recur in the pelvis or abdomen 2=10-20 years after resection of the primary tumor
• Fibroma
• Tumor arising in the ovarian stroma composed of
well differentiated fibroblasts with scant
interspersed collagenous stroma
• by definition, hormonally inactive
• 90% are unilateral
• Solid, spherical or slightly lobulated,
encapsulated masses covered with a
glistening, intact ovarian serosa
• Benign
• Mitotic activity + ↑ nuclear:cytoplasmic ratio = Fibrosarcoma and a malignant course
• Thecoma - benign
• Tumor arising in the ovarian stroma composed of plump spindle cells with lipid droplets
• Pure = rare
• If the predominant cell in a tumor, may be hormonally active
• Fibrothecoma
• Tumor arising in the ovarian stroma composed of both fibroblasts & plump spindle cells with lipid droplets
• benign
49
• Hydrothorax, usually only on the right side
• Mutation
• DICER1 mutation in > 50%
• Endonuclease essential for micro-RNA processing
• Morphology
• Unilateral tumors & Solid grey to golden brown
• Grossly resemble granulosa cell tumors
• Well-differentiated: Sertoli or Leydig cells interspersed with stroma
• Poorly-differentiated: sarcomatous pattern with disorderly disposition of epithelial cell cords; Leydig
cells may be absent
• There may be heterologous elements in some tumors (mucinous glands, bone, cartilage)
• Morphology
• Unilateral tumors with large, lipid laden Leydig cells
• Distinct borders
• Reinke crystalloids: characteristic cytoplasmic structures
• Clinical
• Present with evidence of masculinization: hirsutism, voice changes, clitoral enlargement
• Mild vs. Sertoli-Leydig cell tumors
• Treatment
• Surgical excision
• almost always benign
• Pregnancy Luteoma
• Ovarian tumor of sex cord or stromal origin
50
• Rare tumor that closely resembles the corpus luteum of pregnancy
• Produce virilization in pregnant patients and their female infants/progeny
• Gonadoblastoma
• Uncommon ovarian tumor of sex cord or stromal origin
• Resembles immature Sertoli & granulosa cells
• Seen in patients with abnormal sexual development and in patients with indeterminate gonads
• 80% are phenotypic females
• 20% are phenotypic males with undescended testicles and female internal secondary organs
• coexistent dysgerminoma occurs in 50% of the cases
• Excellent prognosis if tumor is completely excised
• Metastatic Tumors
• Derived from tumors of mullerian origin (most common)
• Uterus
• Fallopian tube
• Contralateral ovary
• Pelvic peritoneum
• Extra-mullerian: carcinoma of the breast or GI tract
• Pseudomyxoma peritonei (appendiceal tumor)
• Krukenberg Tumor
• Metastatic GI tumor involving the ovaries -- when gastric carcinoma metastasizes to the ovaries
• bilateral metastases composed of mucin producing, signet ring cancer cells usually of gastric origin
• Ovarian Torsion
• Causes • Etiology
• Children – congenitally malformed or long • Children Congenitally malformed or long
fallopian tubes, or absent mesosalpinx fallopian tubes, or absent mesosalpinx
• Pregnancy (20%) – enlarged corpus • Pregnancy (20%)
luteum, laxity in ligaments • Enlarged corpus luteum, laxity in
• Pregnancy induction – multiple enlarging ligaments
follicles • Pregnancy induction
• Ovarian tumors – benign and malignant, • Multiple enlarging follicles
dermoid most common • Ovarian tumors
• Benign and malignant, dermoid most
common
51
• Luteal phase defect, poorly controlled diabetes, thyroid dysfunction
• Infections
• Protozoa (toxoplasma), bacterial (mycoplasma, listeria), viral (CMV, HSV2, Parvovirus, Rubella)
• Ascending infection is particularly common in second trimester losses
• CMV: common, intranuclear inclusions
• Ectopic Pregnancy
• Definition
• Fetal implantation outside the normal intrauterine location
• Most common: fallopian tube (90%)
• 2% of confirmed pregnancies and for 4-10% of pregnancy related
deaths
• Increased risk
• PID → chronic salpingitis
• Peritubal scarring and adhesions (due to appendicitis,
endometriosis, prior surgery)
• use of an IUD is associated with a twofold increase of ectopic pregnancy
• if you get pregnant with an IUD, it's most likely a tubal pregnancy
• Smoking
• Diagnosis
• hCG titers (should show that you are pregnant)
• Pelvic sonography (look for donut sign) -- nothing in the uterus (uh oh moment)
• Endometrial biopsy: decidua without chorionic villi or implantation site
• Laparoscopy to take a look
52
• disorders occurring in the third trimester of pregnancy are related to the complex anatomy of the maturing placenta
• Twin Placentas
• Dizygotic: fertilization of two ova
• Monozygotic: division of one fertilized ovum
• 3 types
• Diamnionic dichorionic: May be fused
• Diamnionic monochorionic
• Monoamnionic monochorionic
• Placental infection
• Develop via
• Ascending infection through the birth canal (most common, usually bacterial)
• Hematogenous (transplacental) infection
• Placental infection
• Can cause premature rupture of membranes → preterm delivery
• Amniotic fluid: cloudy with purulent exudate
• Chorionamnion: infiltrate of neutrophils + edema & congestion of vessels
• Fetal 'vasculitis' of umbilical and fetal chorionic plate vessels may occur
• Acute villitis due to hematogenous spread is uncommon
• TORCHS infection
• Affect the placenta and can cause chronic villitis
• Toxoplasmosis
• Others (To Light Passing hovering Zambonis: TB, listeria, parvovirus, HIV,
Zika)
• Rubella
• CMV
53
• Herpes simplex virus
• Syphilis
• Gestational HTN
• Develops during pregnancy
• No proteinuria
• Must be distinguished from preeclampsia
• Preeclampsia
• Definition
• Systemic syndrome with widespread maternal endothelial
dysfunction
• Presents during pregnancy with HTN, edema, proteinuria
(nephrotic range?)
• Most common in the 3rd trimester & primiparas (first
pregnancies)
• Can lead to eclampsia
• Eclampsia
• Severe manifestation of eclampsia.
• Women are very ill.
• Convulsions occur (seizures)
• Can progress to coma
• HELLP Syndrome
• Occurs in 10% of women with severe preeclampsia
• Microangiopathic hemolytic anemia
• Elevated liver enzymes
• Low platelets
• Pathogenesis
• Placenta plays a central role in pathogenesis
• Symptoms rapidly disappear after delivery of the placenta
• Potentially due to factors released from the placenta into maternal circulation
• Diffuse endothelial dysfunction
• Vasoconstriction → HTN
• ↑ vascular permeability = proteinura + edema
• Endothelial Dysfunction
• Imbalance of Angiogenic/Anti-angiogenic Factors
• Ischemic placenta → factors that antagonize VEGF & TGFβ released into maternal circulation
• FMS-like tyrosine kinase (sFltl) antagonizes VEGF
• Endoglin antagonizes TGFβ
• Factors are higher in women with this condition and cause defective placental vascular development
and vasoconstriction (due to TGFβ inhibition of NO)
• Maternal vessels remain small caliber high resistance vessels that leads to HTN and tissue hypoperfusion
• Coagulation Abnormalities
• Hypercoagulable state
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• Likely due to ↓ PGI2 which is normally stimulated by VEGF (which these women lack)
• Normally PGI2 is a potent antithrombotic factor and the deficiency leads to formation of thrombi in arterioles
and capillaries especially in the Liver, kidneys, brain, and pituitary
• Placenta morphology
• Placental infarcts that are larger and more numerous
• Exaggerated ischemic changes of chorionic villi & trophoblasts
→ syncytial knots
• Frequent retroplacental hematomas
• Abnormal decidual vessels
• When it presents
• Usually occurs > 34 weeks of gestation
• Earlier in women with hydatidiform mole, pre-existing kidney disease, HTN or coagulopathy
• Risk factors • DM
• age> 40 • clotting disorders
• African American • first pregnancy
• renal disease • family history
• HTN
• Clinical
• Insidious onset of HTN, edema, and proteinuria in several days
• headache + visual disturbances indicate severe manifestations that may require delivery
• eclampsia == seizures --> coma
• Treatment
• Preterm:
• Mild: close monitoring of mom + baby.
• Delivery is indicated with end organ damage, eclampsia, fetal compromise or HELLP syndrome
regardless of age
• Term: Delivery (regardless of severity)
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• 2x ↑ risk of vascular disease of the heart and brain
• Hydatidiform Mole
• Definition
• Cystic swelling of the chorionic villi and trophoblastic proliferation
• Diagnosed at ~ 9 weeks via sonogram
• increased risk of persistent trophoblastic disease (invasive
mole) or choriocarcinoma
• patients at risk
• Bimodal distribution: teenagers or females > 40
• 2X more likely in southeast Asia
• General Morphology
• Delicate, friable mass of thin walled, translucent, cystic, grapelike structures with swollen, edematous
(hydropic) villi
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• Trophoblastic hyperplasia is focal and less marked than in
complete moles
• Clinical
• Partial or early complete
• Spontaneous miscarriage or curettage due to abnormal
villous findings on ultrasound (will see snowstorm pattern
on ultrasound)
• Complete
• HCG rate of rise is markedly increased and rises more than in normal single or multiple pregnancies
• Removed via curettage
• patients are monitored for 6-12m to ensure HCG levels return to normal
• persistent/invasive moles = when HCG levels remain high; happens in 15% of molar pregnancies
• Invasive Mole
• Mole that penetrates or perforates the uterine wall (i.e. it invades)
• there is invasion of the myometrium by hydropic chorionic villi, accompanied by proliferation of both
cytotrophoblasts and syncytiotrophoblasts (produce β-hCG)
• Pathogenesis
• Hydropic chorionic villi penetrate the myometrium
• May embolize to lungs or brain but do not grow at these sites (will regress without chemotherapy)
• Cytotrophoblasts & syncytiotrophoblasts proliferate
• Tumor is locally destructive
• Invasion of parametrial tissue or blood vessels
• Presentation
• Presents as vaginal bleeding + irregular uterine enlargement
• Persistently ↑ HCG
• Treatment
• Responds well to chemotherapy
• may result in uterine rupture requiring hysterectomy
• Choriocarcinoma
• Definition
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• Uncommon malignant neoplasm of trophoblastic
cells derived from a previously normal or
abnormal pregnancy (e.g. extrauterine ectopic
pregnancy)
• Rapidly invasive, metastasizes widely == very
aggressive
• Responds well to chemotherapy
• Preceding factors
• Complete hydatidiform mole (50%)
• Previous abortion (25%)
• Normal pregnancy (22%)
• Ectopic pregnancy (3%)
• Germ cells of the ovaries or mediastinum (rare) – does not respond well to chemotherapy
• Morphology
• Soft, fleshy, yellow-white tumor
• Large, pale areas of necrosis + extensive hemorrhage
• Invades underlying myometrium, often penetrating blood vessels
• Abundant (possibly abnormal) mitoses
• May extend to uterine serosa and adjacent structures
• Does not produce chorionic villi, comprised only of proliferating syncytiotrophoblasts & cytotrophoblasts
• Clinical
• Irregular vaginal spotting of a bloody, brown fluid
• May occur months after pregnancy, abortion, etc
• Larger than expected uterus
• high propensity for hematogenous spread (widespread):
• Lungs (50%)
• vagina (30-40%)
• brain
• liver
• bones
• kidney
• ↑ HCG, but may be low in some tumors (especially if tumor is necrotic)
• Treatment
• Evacuation of uterine contents + chemotherapy
• chemotherapy results in nearly 100% remission and a high rate of cures
• Cured patients can have normal subsequent pregnancies and deliveries
• Non-gestational tumors that arise outside the uterus are more resistant to therapy
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