Exam I Flashcards
Female Histo: The ovary is an almond-shaped structure that produces the female gonads (oocytes). It is an endocrine organ that releases estrogen and progesterone.
It is attached to the uterus via the ____1___, and is a subdivision of the ___2____.
- ovarian ligament
2. broad ligament
Female Histo: There are two sources of blood supply to the ovary:
- _______, which arise from the abdominal aorta. They enter the ovary via the suspensory ligament and serve as the main arterial supply to the ovary and uterine tube.
- ______ arise from the internal iliac arteries and enter the ovary at the hilum. They become helicine/spiral arteries. These arteries anastamose with #1.
- Ovarian arteries
- Ovarian branches of uterine arteries
**uterine tube supplied by ovarian (lateral 1/3) and uterine (medial 2/3)
Female Histo: Venous drainage of ovaries and the uterine tube occur via the _________ in the broad ligament. The veins then merge to form a single ovarian vein.
Pampiniform plexus
- Rt. ovarian vein: IVC
- Left ovarian: Left renal vein
Female Histo: True/False - Venous drainage of the uterine tube is via
Ovarian veins (Lateral 1/3) and Uterine venous plexys
Female Histo: Innervation of the ovary and uterine tube is via
- Ovarian plexus
- Uterine plexus
These are mixed autonomic plexuses containing autonomic (PNS, SNS) and sensory stimuli. In addition, visceral afferent pain fibers follow PNS fibers to ______ spinal ganglia.
T11-L1
Female Histo: The ovaries are composed of cortex (outer region w/ ovarian follicles), and medulla (central region w/ loss CT, blood vessels, lymph, and nerves).
The ovaries are covered by a single layer of cuboidal to squamous cells known as ______ epithelium, which is continuous with mesothelium. Before puberty, this surface is smooth, but after puberty, it becomes scarred and irregular (repeated ovulations).
Germinal epithelium
NOTE: tunica albuginea - dense CT b/t germinal epithelium and cortex
Female Histo: True/False - post-menopause, the ovaries will decrease to 1/4th the size of ovaries in reproductive years
true
Female Histo: Ovaries have two inter-related functions:
- To produce gametes (oocytes)
- To produce steroids (steroidogenesis)
Sex steroids include estrogen and progesterone. _____ is responsible for promoting growth and maturation of the internal and external sex organs. It is responsible for female sex characteristics (@ puberty), and promotes breast development.
Estrogen
*breasts: ductal/stromal growth and inc. adipose
Female Histo: Sex steroids include estrogen and progesterone.
Progestogens have which of the following functions?
a. prep internal sex organs (uterus) for pregnancy (endometrial changes)
b. prep mammary gland for lactation (lobular proliferation)
c. enhance pubic hair development
d. promotes female characteristics at puberty
A and B
Female Histo: Ovarian follicles vary in size. DIfferent sizes indicate different stages of oocyte development, however, each follicle contains a single oocyte.
True/False - Early stages of oogenesis occur during fetal life, then arrest at first meiotic division.
True
~5 million in fetus
- 20% of oocytes remain at birth (due to atresia)
- 6-12 follicles begin developing each cycle
Female Histo: Ovarian follicles vary in size. DIfferent sizes indicate different stages of oocyte development, however, each follicle contains a single oocyte.
List the follicle stages
- Primordial
- Primary
- -unilaminar
- -multilaminar - Secondary (antral)
- Mature or Graafian
Female Histo: Oocytes arrest at ______, where they remain in arrest until puberty and the LH surge.
Prophase I
*Meiotic inhibotory factor (oocyte maturation inhibitor) keeps oocytes arrested
Female histo: _______ are the earliest developing follicles that appear in the ovaries during the 3rd month of fetal development.
Primordial follicles
Female histo: At birth, the newborn girl has about 2 million oocytes. At puberty, the girl has 400,00 oocytes.
How many are left at ovulation?
400-450
*all others atretic
Female histo: The germinal epithelium is simple cuboidal. Tumors that arise from this layer represent ~70% of ovarian cancers.
True/False - One theory for the development of these tumors is the repeated ovulations and repeated needs for repair.
True
Female histo: During development, follicular cells become granulosa cells which change from squamous epithelium to cuboidal epithelium.
The oocyte begins to secrete _____ which acts on granulosa cells to induce proliferation and promotes formation of multi-layered granulosa cells that surround the oocyte.
Activin
Female histo: Granulosa cells continue to secrete OMI (oocyte maturation inhibitor) to keep the oocyte frozen in prophase I.
During this time, the oocyte begins to secrete the components of the zona pellucida, which gets deposited between the oocyte and the granulosa cells.
What is the importance of the ZP?
*generates fertilization-competent sperm
Female histo: As granulosa proliferation continues, fluid filled spaces appear between these cells. These eventually fuse to form _____
antrum/vesicle
- follicles with antrums are dependent on FSH
- prior to this stage, follicle development does NOT depend on FSH
Female Histo: True/False- Factors required for later stages of growth (secondary follicle and oocyte) include FSH, EGF, IGF-1 and calcium.
True
Female Histo: As the antrum develops, CT cells outside of the follicle become organized.
The theca interna is the inner layer of cells next to the follicle. It is highly vascularized and expresses _____ receptors. These are important for the synthesis and secretion of androstenedione.
LH receptors
- synthesize and secrete androstendione
- taken up by granulosa cells – converted to testosterone and then E2
Female Histo: LH stimulates _____ cells to secrete androstenedione, which is transported to the sER of the granulosa cells.
In response to FSH, the granulosa cells then convert androstenedione to testosterone, and then 17B estradial.
Theca interna cells
*E2 - induces proliferation of granulosa cells (inc. follicular size)
Female histo: The late secondary follicle is formed as the antrum continues to increase.
Some granulosa cells maintain intimate contact with the oocyte, ultimately forming the ______ which is released with the oocyte during ovulation.
corona radiata
Female Histo: Inc. E2 leads to inc. sensitization of basophils to GnRH and Inc. release of FSH/LH (surge).
24 hours prior to ovulation, surge in release of FSH/LH occurs. In response to LH, granulosa cells downregulate LH receptors, and no longer produce estrogen. This triggers the first
meiotic division (1st polar body and secondary oocyte)
*secondary oocyte arrested at metaphase of meiosis II
Female Histo: Following ovulation, the granulosa and theca cells undergo luteinization and _______ is produced
progesterone
*Theca lutein, granulosa lutein
Female Histo: Ovulation is the release of secondary oocyte from the mature, graafian follicle. It occurs following the LH surge (signalled by inc. estrogen).
Prior to ovulation, the oocyte traverses the entire follicular wall and the germinal epithelium. This is due to hormonal changes and inc. enzyme activity. List these changes
- Inc. follicular fluid
- plasminogen digests the follicular wall
- GAGs deposit b/t granulosa and oocyte
- Prostaglandin induces contraction of SM in the theca externa
Female Histo: Prior to ovulation, blood flow stops to the area overlying the bulging follicle.
As a result, the ______ becomes elevated and ruptures, resulting in forceful expulsion of the oocyte, corona radiata and cumulus oophorus.
stigma
*corpus hemorrhagicum w/ central clot
Female Histo: _______ is the process of follicle degeneration and loss. It occurs at any stage of development. Most follicles are lost by atresia mediated by apoptosis of granulosa cells.
Ovarian follicular atresia
- collapse of follicle and CT invasion
- granulosa cells apoptose
- glassy membrane
Female Histo: The corpus luteum is the structure that remains following ovulation. It develops due to morphological changes in the cells and is viable for ~14 days in the absence of a viable pregnancy.
What are the morphological changes that occur?
- Inc. cell size
- accumulate lipid droplets/lipochrome
- resemble steroid secreting cells (sER/mito)
Female Histo: Following ovulation, the remaining follicle forms the corpus luteum. It develops via morphological changes in the cells and is viable for ~14 days. In the absence of a viable pregnancy it degrades to form the corpus albicans.
What are the morphological changes that occur?
- Inc. cell size
- accumulate lipid droplets/lipochrome
- resemble steroid secreting cells (sER/mito)
Female Histo: The corpus luteum of pregnancy forms in the presence of a viable pregnancy.
It requires paracrine and endocrine secretions (leutotropins) for maintenance. Which of the following is a paracrine leutotropin?
a. estrogen
b. IGF-I
c. hcG
d. LH
Estrogen and IGF I/II (ovary)
Endocrine:
- hcG (embryo)
- LH and prolactin (pituitary)
- insulin (pancreas)
*progesterone blocks cyclic development of follicles
Female Histo: Estrogen and Progesterone are produced in the corpus luteum in response to FSH and LH.
- In response to LH, ____ lutein cells secrete androstenedione, which is taken. up by granulosa letein cells.
- In response to FSH, _____ lutein cells convert androstenedione to estradiol. These cells also secrete progesterone in response to FSH.
- Theca lutein
- Granulosa lutein
E2 - stimulates granulosa lutein to uptake cholesterol for progesterone synthesis
Female Histo: The _____ is the degenerated corpus luteum that occurs from lack of viable pregnancy. Cells undergo involution, resulting in decreased size, involution and autolysis.
True/False - The absence of hcG, progesterone and estrogen ultimately lead to inc. FSH and initiation of follicle development.
True
Female Histo: Following ovultaion, the oocyte enters the uterine tube. The uterine tubes are paired tubes that extend from uterus to ovaries. They function in transport of the oocyte from the ovary to the tissues, and also act as the site of fertilization and embryo development.
What is the MC site of fertilization?
Ampulla of uterine tube
4 segments:
- infundibulum w/ fimbrae
- ampula (longest site)
- isthmus
- uterine/intramural
Female Histo: The uterine tube functions in oocyte transport and acts as site of fertilizatin. It is composed of 3 histologic layers:
- Mucosa
- Muscularis
- Serosa
________ is composed of simple columnar epithelium with ciliated or peg cells.
Mucosa
- muscularis
- serosa: mesothelium
Female Histo: The uterine tube is the site of bidirectional transport with the sperm moving up the tube via flagellar motility, and the oocyte moving down the tube toward the ampulla via ciliary motility and peristaltic contractions.
True
NOTE: developing zygote remains in uterine tube for ~3 days before entering uterus for implantation
Female Histo:
- _____ are ciliated cells within the mucose of the uterine tube. They beat the oocyte towards the uterus and inc. in # w/ E2 stimulation.
- ____ are non-ciliated cells the provide nutritive fluid for the oocyte/embryo. They are inc. by progesterone.
- Ciliated cells
- Peg cells
- hypertrophy during follicular
- atrophy during luteal
Female Histo: The _____ is a thick walled, pear shaped, hollow and muscular structure. Its shape is dynamic and changes with pregnancy.
It receives the morula from the uterine tube and acts as the site of all subsequent embryonic/fetal development. It consists of 2 main parts:
- Superior 2/3 (body)
- Inferior 1/3 (cervix)
uterus
Female Histo: The uterine arteries provide the main source of blood to the uterus. The are branches of the internal iliac.
What provides collateral supply?
Ovarian arteries (abdominal aorta)
Veins: uterine venous plexus into internal iliac
Female Histo: Sympathetic innervation of the uterus is derived from the _________, that originates from T12-L1.
Parasympathetic innervation comes from S2-S4.
inferior hypogastric plexus
Female Histo: The uterine wall is composed of the
- Endometrium
- Myometrium
- Perimetrium
________ undergoes monthly cyclic changes in the absence of pregnancy. Its thickness varies with the cycle
Endometrium
Female Histo: The uterine wall is composed of the
- Endometrium
- Myometrium
- Perimetrium (visceral peritoneal)
_____ us a SM layer that undergoes monthly cyclic changes in the absence of pregnancy. In pregnancy, cells undergo hypertrophy (10x increase).
Myometrium
- Inhibit contraction during pregnancy
- –relaxin (ovary/placenta) - Contraction during parturition
- –oxytocin (post. pituitary)
Female histo: Uterine blood supply originates in the myometrium and extends upwards towards the endometrium.
The uterine artery in the myometrium gives rise to ______ arteries that anastomose and form radial arteries. These radial arteries enter the basal layer of the endometrium.
arcuate arteries
Female histo: The radial arteries (derived from the arcuate arteries in the myometrium) enter the basal layer of the endometrium and become ______ which supply the stratum basale.
straight arteries
Female histo: The main branch of the radial artery continues upwarding and coiling, forming the ______ artery. These arteries form capillary beds and supply the endometrium.
Spiral arteries
*distal regions undergo degeneration and regeneration (dec. progesterone)
Female histo: Cyclic changes occur in the stratum functionale layer (endometrium) over a 28 day cycle. It is regulated by gonadotropins.
It occurs in 3 successive phases:
- Menstrual phase
- Proliferative phase
- Secretory phase
_______ occurs concurrently with follicle maturation and is influenced by ovarain secretion of estrogen.
proliferative phase
e. g. follicular/estrogenic phase
* thickened endometrium ~1 mm (by mitosis)
Female histo: Cyclic changes occur in the stratum functionale layer (endometrium) over a 28 day cycle. It is regulated by gonadotropins.
It occurs in 3 successive phases:
- Menstrual phase
- Proliferative phase
- Secretory phase
___ begins as ovarian hormone (E2 and progesterone) production is decreased and the corpus luteum degenerates. The low hormone levels also leads to subsequent contraction and relaxation of the spiral arteries, and ultimately, arterial rupture.
menstrual phase
- days 1-4
- lose 35-50 ml blood
- spiral artery constriction – ischemia and necrosis of functionale layer
- straight arteries supply basal layer (no necrosis)
Female histo: Cyclic changes occur in the stratum functionale layer (endometrium) over a 28 day cycle. It is regulated by gonadotropins.
It occurs in 3 successive phases:
- Menstrual phase
- Proliferative phase
- Secretory phase
_______ coincides with the functional activity of the corpus luteum. It is primarily influenced by progesterone
secretory phase
(i.e. luteal/progesterone phase)
- continued endometrial thickening (5-7 mm)
- corkscrew glands
- glycogen, mucous
Female Histo: The cervix is the lower region of the uteris. It consists of dense, CT and little SM.
True/False - the mucosa of the cervix differs from that of the uterine body. The endometrial layer does NOT undergo cyclic proliferation/shedding due to lack of spiral arteries.
True
- ectocervix
- endocervix
- transformation zone
Female histo: The cervix is composed of two types of epithelium:
- ________ projects into the vagina. It is stratified squamous wet w/ washed out cytoplasma and lots of glycogen.
- _____ is the cervical canal. It is made up of simple, columnar mucous secreting epithelium. It contains cervical glands.
These layers are separated by a transformation zone.
- Ectocervix
2. Endocervix
Female histo: The endocervix contains cervical glands, large branched mucous glands of the endometrium. These glands secrete mucous in different amounts, and the properties of the mucous differ based on their regulation by estrogen or progesterone.
- Estrogen leads to increased ______ mucous which aids in sperm transit.
- Progesterone inc. production of viscous mucous.
- Watery mucous
2. Viscous mucous
Female histo: The transformation zone separates the endocervix from the ectocervix. It is a common site of metaplastic change (cervical cancer) that is detectable via pap smear.
The transformation zone changes with age. Before puberty, is is located close to the external os. How does this differ from puberty and post-menopause?
- Puberty
- -outside of external os - Post-menopause
- -within cervical canal
*95% intraepithelail neoplasias originate in transformation zone
Female histo: The vagina is a fibromuscular sheath that extends from the cervix to the external reproductive organs. It does not contain glands.
- Blood supply to the superior region of the vagina comes from the: _____ arteries
- Supply to middle/inferior comes from _____
- Uterine arteries
- Vaginal and internal pudendal
*veins — vaginal venous plexuses continuous with uterine plexus – internal iliac veins
Female histo: The inferior 1/5 to 1/4 of the vagina has somatic innervation via the ______. It is a branch of the pudendeal nerve.
These fibers are sympathetic and visceral afferent fibers sensitive to touch and temperature.
deep perineal nerve
Female histo: The superior 3/4 - 4/5 of the vagina is innervated by the ______ (branch of inferior hypogastric plexus).
It provides sympathetic, parasympathetic and visceral afferent signals.
uterovaginal nerve plexus
Female histo: The vagina is lined by a stratified squamous wet epithelium with elastic fibers underneath. This epithelium undergoes cyclic changes.
SM is contained within the wall of the vagina, while striated muscle, the ________, is found at the vaginal opening.
bulbospongiosus muscle
- lymphocytes, neutrophils beneath epithelium
- especially menstrual phase
- mucous (cervical glands) lubricate the surface
Female histo: During the follicular phase, the epithelial cells of the vagina accumulate glycogen.
Glycogen is then converted to lactic acid via bacterial flora. This lactic acid causes dec. pH (follicular phase). What is the net result?
- dec. pH = inhibit pathogens
NOTE: alkaline pH inc. staph, trichomonas, candida (inc. vaginal transexudate/inflammation = pap smear
Vulva path: True/False - The vulva is part of the external part of the female genitalia. It is comprised of the pubis, the labia majora and minora, and the clitoris. It is prone to superficial infection due to constant exposure to secretions and moisture.
True
Vulva path: A 20 year old female presents with a superficial unilocular painless cystic lesion located in the posterolateral vaginal opening. It is palpable in the lower vestibule adjacent to the vaginal canal.
You suspect a Bartholin cyst due to her history of recent infection. What are methods of treatment?
- Usually asymptomatic – leave alone
- If symptomatic:
- -Incision/drainage (I and D) w/ catheter placement
- -marsupialization (excised or opened) to dec. recurrence
NOTE: cysts prevalence dec. w/ inc. age
Vulva path: A 20 year old female presents with a superficial unilocular painless cystic lesion located in the posterolateral vaginal opening. It is palpable in the lower vestibule adjacent to the vaginal canal.
You suspect Bartholin cyst due to her recent history of infection (N. gonorrhea, E. coli, Staph, Strep). What are potential complications of this cyst?
- May inc. in size gradually
- –persistent pain with intercourse (dysparenuria) - Abscess formation
- Recurrence after I & D (incision/drainage)
Vulva path: True/False - Bartholin cysts form from obstruction of the Bartholin duct due to inflammation (via infection, thickened mucous, or swelling).
The cyst may become secondarily infected and inflamed, leading to formation of an abscess
True
etiologies: Staph, Strep, N. gonorrhea, E. coli
Vulva path: A patient presents with a painless but itchy, wart-like vulvar growth that is moist, hypopigmented/gray, raised and firm. You note the growth is flat-topped.
You also note mucin-secreting pink to reddish papules that are malodorous and contain numerous spirochoetes. You suspect
Condylomata lata
- Syphilitic (T. pallidum)
- STI
- resembles acuminata, but less keratinization and no koilocytosis
Vulva path: A patient presents with a painless but itchy, wart-like vulvar growth that is moist, hypopigmented/gray, raised and firm. You note the growth is flat-topped. You also note mucin-secreting pink to reddish papules that are malodorous and contain numerous spirochoetes.
How do you diagnose?
- Dark field exam (spirochetes from active lesion)
- Immunohistochemistry
- Immunofluorescence or Warthin Starry stain
- PCR or serologic testing
*benign
Vulva path: A patient presents with benign, raised wart-like lesions on her vulva. You suspect condyloma.
True/False - Condyloma may be caused by infection or may be due to reactive conditions (unknown etiology). For example, fibroepithelial polyps are squamous papillomas of unknown etiology that are like skin tags.
True
Vulva path: A 21 year old female presents with painless vulvar lesions that spread, cauliflower like (or polypoid/verrucoid). Hypopigmented or skin-colored papules are present in varying sizes in the anogenital region.
Histology reveals:
- papillary, exophytic tree-like cores of stroma covered by thickened squamous epithelium
- cytologic atypia (koilocytosis and basal cell hyperplasia) with increases mitotic activity
- squamous maturation in the upper 2/3rds of the epithelium
You suspect
Condylomata acuminata
HPV 6, 11 (non-cancerous)
*HPV cytopathic effect: koilocytic atypia (nuclear enlargement, hyperchormoasia w/ irregular nuclear membrane (raisinoid change) and cytoplasmic perinuclear halo
Vulva path: Vulva path: A 21 year old female presents with painless vulvar lesions that spread, cauliflower like (or polypoid/verrucoid). Hypopigmented or skin-colored papules are present in varying sizes in the anogenital region.
True/False - Condylomata acuminata is frequently multi-focal and may be multicentric (involving vulva, perineal and perianal regions, vagina and maybe cervix)
True
Vulva path: Vulva path: A 21 year old female presents with painless vulvar lesions that spread, cauliflower like (or polypoid/verrucoid). Hypopigmented or skin-colored papules are present in varying sizes in the anogenital region.
Histology reveals:
- -papillary architecture (hyperkeratosis and unulating appearance of epidermis)
- -koilocytic atypia (nuclear enlargement, hyperchromasia w/ irregular nuclear membrane (raisinoid change) and a cytoplasmic perinuclear halo.
You suspect condylomata acuminata. How is it treated?
90% spontaneously clear within 2 years
Tx: topical podophyllin
–other: a-interferon, imiquimod
VUlva path: A 65 year old female presents with vulvar pruritis and pain that progressively worsens. Pelvic exam reveals red, white and skin colored raised nodules with possible ulceration.
You suspect vulvar carcinoma. 70% of vulvar cancers are not related to HPV. They develop from lichen sclerosus or squamous cell hyperplasia (differentiated VIN, dVIN). However, 30% ARE caused by high risk HPV infections. What HPV types are the most common causes?
HPV 16 (in situ lesion - classic VIN; usual VIN)
- uncommon
- most often asymptomatic
- condylomas, lichens can mimic VIN (biopsy DD)
Dx: biopsy
NOTE: VIN = vulvar intraepithelil neoplasia
Vulva path:
- ______ is NOT a precancerous lesion
- _____ is a non-invasive squamous lesion and precursor of vulvar squamous cell carcinoma
- condylomata acuminata
- -sometimes included with uVIN1 - usual type - VIN
- -non-invasive
- -Dx clinically, confirm via biopsy
types:
- -CLassic/Usual w/ HPV correlations
- -Differentiated w/ chronic inflammation
Vulva path: ______ begins at the basal layer and is partial or full thickness of the epithelium.
It is most often represented by koilocytosis and basal cell hyperplasia. Increased mitotic activity is seen and squamous maturation in upper 2/3 of epithelium.
uVIN
*UVIN1/vulvar LSIL: flat condylomata (koilocytic atypia; no dysplasia; uncommon and rarely diagnosed)
Vulva path: uVIN 2 and UVIN 3 are precancerous lesions exhibiting moderate, and severe/full thickness dysplasia respectively. There are two subtypes of vulvar high grade, vHSIL (UVIN 3):
- Warty (undulating, appears condylomatous)
- Basaloid (thickened epithelium, immature parabasal type cells)
True/False - Both forms are premalignant and treated the same.
True
Vulva path: It is unclear whether uVIN1 is related to benign condylomata, or if it is a precursor to uVIN2/3 (precancerous lesions).
Although vulva LSIL and condylomata acuminata are both caused by infection with low risk HPV (non-oncogenic types), they are classified separately by their morphologic appearance. Condylamata acuminata present with multifocal, ______ verrucoid lesions. In contrast, vulva LSIL/VIN! are typically ____ or macular papular.
Condylomata: exophytic verrucoid lesions
VIN1: flat, macular/papular
Vulva path: ______ is a separate category of vulvar intraepithelial neoplasia characterized by thickened epidermis, parakeratosis, and basal AND parabasal nuclear atypia. It tends to present with premature maturation of the basal layer. It can mistakenly be diagnosed as benign
dVIN (differentiated type VIN)
- confined to basal portion of rete pegs
- eosinophilic cytoplasm
Vulva path: Vulvar carcinoma arises from squamous epithelium lining the vulva. It is rare, and often is associated with 2 etiologies:
- HPV-related
- non-HPV related
HPV related is due to high risk HPV (16,18) and leads to development of vulvar intraepithelial neoplasia (dysplasia;VIN). This can eventually lead to the development of vulvar squamous cell carcinoma. How does this differ from non-HPV related?
due to long standing lichen sclerosis
- -chronic irritation/inflammation (paper thin skin)
- -elderly women
NOTE: VIN = precursor of SCC
Vulva path: True/False - Patients with vulvar squamous intraepithelial lesions (SIL’s/VIN/vulvar carcinoma) tend to have high frequency of co-occurrence with cervical or vaginal SIL’s. HPV is commonly the etiologic factor.
True
Vulva path: Vulvar intra-epithelial neoplasia (VIN) risk factors include:
- HPV type 16
- smoking
- immunodeficiency
- lichen sclerosus
- squamous cell hyperplasia
HPV is the most common risk factor as it integrates into the host genome and alters transcriptional regulation. It acts by inducing overexpression of ____ and _____ oncooproteins, leading to uncontrolled cell cycle progression.
E6/E7
- E6 binds p53
- E7 binds RB
- disable tumor suppressors
Vulva path: ______ VIN is the MC type of VIN. It is associated with warty and basaloid type carcinoma and with high risk HPV or HPV persistence factors (smoking/immunocompromised states).
True/False - RF’s for VIN also include the same risk factors seen in cervical squamous intra-epithelial lesions such as young age at 1st intercourse, multiple sexual partners or male partner with multiple sexual partners.
Classic (uVIN)
- MC 3-5th decade
- asymptomatic OR pruritis/dysuria
- multifocal white or erythematous macules/papules that coalesce
*spontaneous regression (younger females)
Vulva path: _____ usually occurs in post-menopausal women. They are often either asymptomatic or complain of pruritus or dysuria.
It is often associated with chronic inflammatory dermatosis (lichen sclerosus or squamous cell hyperplasia).
differentiated VIN (dVIN)
- unicentric (single center of origin)
- less bulky lesions (focal grey-white discoloration; white plaques; elevated nodules)
- adjacent to 80% of vulvar squamous cell carcinomas
Vulva path: The risk of cancer development in VIN is dependent on duration, extend of disease and immune status. Risk of progression in higher in women > 45 or in women who are immunosuppressed.
Once invasive cancer develops, the risk of metastasis is linked to tumor size, depth of invasion and lymph vessel involvement
True
- lesions < 2cm = 90% 5-year survival w/ Tx (vulvectomy)
- larger lesions w/ lymph node involvement = poor prognosis
Vulva path: Invasive carcinomas associated with lichen sclerosus, squamous cell hyperplasia, and dVIN may develop insidiously and may be misinterpreted as dermatitis or leukoplakia.
True/False - DVIN though less common than UVIN has a greater risk for malignant transformation to vulvar SCC w/ shorter time interval
True
NOTE: if untreated: LSIL - regress spontaneously (low risk progression); HISL progress to invasive SCC (~7yrs); dVIN leads to vulvar SCC most often (inc. w/ age)
Vulva path: Risk of cancer development depends on the type of VIN.
- ______ is equivalent to condylomata acuminata and is benign. It does not require Tx except for symptoms.
- _____ is associated with inc. risk occult and invasive disease. Excision is an effective diagnostic and Tx tool. Laser ablation and topical therapies are also treatment options
- Vulvar LSIL
2. Vulvar HSIL
Vulva path: Vulvar squamous cell carcinoma are divided into two groups:
- Keratinizing squamous cell carcinomas
- Invasive carcinomas
______ arise from dVIN. They contain invasive nests and tongues of malignant squamous epithelium + keratin pearls. This type of carcinoma is NOT associated with HPV infection. It is due to lichen sclerosus or squamous cell hyperplasia
Keratinizing squamous cell carcinomas
- MC elderly women (>60)
- chronic epithelial irritation = gradual evolution to malignancy
- GOF driver mutations in TP53 (oncogenes and tumor suppressors)
Vulva path: Vulvar squamous cell carcinoma are divided into two groups:
- Keratinizing squamous cell carcinomas
- Invasive carcinomas
_____ arise from an in-situ precursor lesion (uVIN) and are most often associated with high risk HPV’s (HPV 16). They may be exophytic or indurated with central ulceration.
Invasive carcinomas
- basaloid: nests, cords of small, tightly packed cells that lack maturation and resemble basal layer
- warty: exophytic, papillary architecture w/ koilocytic atypia
* younger ages (~60y/o)
Vulva path: _____ is a descriptive term that refers to white, plaque like epithelial thickening. This may produce pruritus (itching) and scaling.
It may be caused by a variety of benign and pre-malignant or malignant disorders including inflammatory dermatosis (psoriasis, chronic dermatitis)
Leukoplakia
- Non-neoplastic: lichen sclerosis, squamous cell hyperplasia
- Neoplastic w/ leukoplakia: VIN, Paget, Invasive carcinoma
Vulva path: A post-menopausal female presents with markedly thinned skin (epidermis). She complains of pruritus and pain during intercourse (dyspareunia). Physical exam reveals smooth, white plaques (collagenous thickening) overlaid by atrophic epithelium.
Her skin resembles white porcelain or parchment (leukoplakia). She exhibits labial shrinkage and introitus stenosis.
You suspect
Lichen sclerosus
- pathogenesis uncertain: possible autoimmune rxn (activated T cells in subepithelial infiltrate and inc. in autoimmunity)
- common dermatosis of the anogenital area
Vulva path: True/False - Lichen sclerosus is believed to be linked to _______ phenothype. It can affect any part of the skin (vulvar and elsewhere), causing whitish patches, but usually no discomfort.
Increased likelihood of developing lichen sclerosus is seen w/ previous skin damage.
HLA-DQ7
Vulva path: A patient presents with a chronic non-neoplastic inflammatory epithelial vulvar disorder. It is denoted histologically by thinning of the epidermis, sclerosis and edema of the superficial dermis, and presence of chronic inflammatory cells in the deeper dermis.
It is not pre-malignant, but does have inc. risk of squamous cell carcinoma of the vulva.
Lichen sclerosis
*deeneration of basal cells, bandlike lymphocytic infiltration in underlying dermis
Vulva path: A patient presents with leukoplakia.
Histology reveals:
- Thickening of the epidermis (acanthosis)
- Hyperkeratosis (non-specific)
She admits that she constantly rubs and scratches her skin to relieve her pruritis.
Squamous cell hyperplasia
(Lichen simplex chronicus)
*not pre-malignant, but can present at the margins of vulvar cancers
Vulvar path: The vulva contains modified apocrine sweat glands. These glands may produce tumors (similar to those in the breast tissue):
- Papillary hidradenoma
- Extramammary Paget disease
_____ is an uncommon, benign tumor of the apocrine gland. It presents as asymptomatic or painful, flesh colored/red sharply circumscribed nodule on the labia majora (or interlabial folds).
Papillary hidradenoma
- 30-49y/o
- DD carcinoma (ulcerations)
Histology:
–circumscribed nodule of papillary projections w/ 2 cell leyers (upper columnar covering flattened myoepithelial cells)
Vulvar path: A 63 year old female presents with a red (sometimes white leukoplakia), pruritic and crusted maplike region on the labia majora.
You suspect
Paget disease of the vulva
- pale, malignant mucin (mucopolysaccharide) filled cells infiltrate epidermis
- not associated w/ underlying cancer (unlike breast paget)
Tx: wide local excision; curable
Vulvar path: Paget is a distinctive intra-epithelial proliferation of malginant cells (adenocarcinoma) that is confined to the epidermis of the vulva.
True/False - Paget cells derive from primitive epithelial (multipotent) progenitor cells that arise within the mammary like gland ducts of the vulvar skin. These cells display aprocrine, eccrine and keratinocyte differentiation.
True
- 15% w/ underlying invasive Paget
- PAS stain, Alcian blue, Micicarmine
- cytokeratin 7 stain
Vulvar path: Paget cells spread laterally within the epidermis, and thus may be present beyond what is grossly visible. Thus, tumor cells may not be completely excised resulting in inc. risk recurrence.
Furthermore, these pay persist for years or decades without invasion. Invasion is rare, but if it occurs, prognosis is poor.
True
Vagina: The vagina is composed of 3 layers
- Mucosa (nonkeratinized, strat. squamous w/ no glands)
- Muscularis (SM)
- Adventitia
True/False - cells of the vaginal epithelium retain a high level of glycogen compared to other eepithelial tissue in the body. This is due to E2 inducesduptake of glycogen
True
Vagina: True/False - In adults, inflammation affects the vulva and can spread to the cervix without significant involvement in the vagina
True
Vagina: At menarche, ovarian estrogens stimulate vaginal and cervical squamous mucosa to mature and promote epithelial uptake of intracellular glycogen. When these cells are shed, the glycogen provides a substrate for endogenous vaginal aerobes and anerobes (lactobacilli) which produce lactic acid.
Why is this significant?
pH < 4.5 in vagina
- suppress growth of pathogenic organisms
- bacteriotoxic hydrogen peroxide
Vagina: A patient presents with red, granular areas within the pale-pink vaginal mucosa.
Histology reveals a bening, non-neoplastic lesion w/ persistence of small patches of Mullerian glandular epithelium (endocervical type).
You suspect
Vaginal adenosis
due to: DES exposure in utero synthetic/non-steroidal estrogen (agonist of E2-R’s); causes clear cell carcinoma
NOTE: during development, endocervical epithelium persists – replaced by squamous epithelium (normal).
Vagina: A patient presents for her annual pelvic exam and complains of dyspareunia (may be asymptomatic). During the exam, you discover a 1-2 cm submucosal, fluid-filled vaginal cyst located along the anterior (or lateral walls of the upper vagina).
Histology reveals:
1. Non-mucinous cuboidal or columnar epithelium
Gross reveals:
1. Benign vaginal cyst that originates from emryological remnant of the Wolffian duct (incomplete regression)
You suspect
Gartner duct cyst
- originates: Gartner’s duct (mesonephric/wolffian duct remnant; failure to regress)
- incidental finding
- No Tx unless symptoms (excise)
DD: Bartholin cyst - posterolateral vagina
Vagina: _______ occurs as a result of failure of the Mullerian duct to fuse. It is most often discovered incidentally (pelvic exam), but may present with dysmenorrhea, dyspareunia and/or reproductive problems.
It is important to pay attention to during pregnancy (may cause premature birth, miscarriage, IUGR, infertility, bleeding)
Septate/Double Vagina
- Dx: US or MRI
- etiologies: genetic syndromes, DES exposure, disturbance of reciprocal epithelial-stromal signalling (fetal dev.)
NOTE: MC presentation of mullerian duct non-fusion is septate uterus *
Vagina: Primary vaginal cancer is rare, however, metastatic disease/local extension to the vagina is not uncommon.
The most common malignant tumor to involve the vagina is ________, spreading from the cervix. The second MC is primary squamous cell carcinoma of the vagina
Carcinoma
*infants, young kids - embryonal rhabdomyosarcoma
Vagina: Squamous cell dysplasia that occurs within the vagina and is not metastatic/invading is known as VaIN. VaIN is typically asymptomatic, often presenting with abnormal cytology or post-coital spotting.
True/False - It is diagnosed histologically, based on colposcopic assessment and vaginal biopsy
True
- acetic acid = acetowhite epithelium (raised/flat white granular epithelium w/ punctuation and mosaic pattern)
- mean age ~50-60 (wide range 22-80)
Vagina: VaIN is classified similar to cervical intraepithlial neoplasia (CIN). It is based on the depth of epithelial involvement.
Distinguish between
- VaIN 1
- VaIN 2
- VaIN 3
Low grade:
- VaIN 1
- -mild dysplasia, superficial koilocytosis
- -minimal atypia of basal layers
- -lower 1/3
* low grade
High grade:
- VaIN 2
- -moderate dysplasia
- -lower 2/3 - VaIN 3
- -severe dysplasia
- -severe atypia, mitotic, full thickness
- -upper 2/3
Carcinoma in situ - full thickness dysplaisa
Vagina: True/False - Vaginal squamous cell carcinoma (SCC) is uncommon and arises from a pre-malignant lesion (high grade VaIN - precursor to invasion).
It is associated with high risk HPV’s (16 and 18) and most often affects the posterior wall of the upper vagina at the junction with the ectocervix.
True
Vagina: Lesions of the lower 2/3 of the vagina tend to metastasize to the ______ nodes, while lesions of the upper 2/3 (VaIN 3) tend to spread to _____ nodes
- inguinal
2. regional iliac
Vagina: What is the greatest risk factor for developing vagina squamous cell carcinoma (SCC)?
previous cervical or vulvar carcinoma
*VaIN - prior or concurrent neoplasia elsewhere in lower genital tract (cervical/vulvar; HPV cause)
Vagina: True/False - CIN has a higher incidence than VaIN in patients who test positive for HPV. This is believed to be due to the inc. susceptibility of the cervix, specifically the transformation zone, to oncogenic stimulation
True
*vaginal squamous epithelium is less vulnerable/sensitive to stimulation
Vagina: Treatment for patients with vaginal intraepithelial neoplasia 1 (VaIN1) primarily involves close surveillance over use of treatment (since they are associated w/ HPV and are self-limiting).
What is the most effective treatment for high grade VaIN?
Surgical excision w/ vaginal recunstruction
- Most effective: local excision, partial vaginectomy (safest)
- Rarely: total vaginectomy for extensive and persistent disease
- 3 standard: surgery, radiation, chemo
Vagina: True/False - Radical procedures like brachytherapy (radiation) and vaginectomy should be reserved for highly selective cases of VaIN.
True
Vagina: A 60 year old female presents with complaints of post-coital (or post-menopausal) vaginal bleeding.
You suspect primary vaginal carcinoma, which is rare. How do you diagnose?
Vaginal biopsy
- mostly asymptomatic
- most cases of vaginal cancer = HPV-mediated
- most vaginal tumors are SCC (may be melanoma, sarcoma, adeno)
- similar incidence as vulvar cancer
Vagina: A 60 year old female presents with complaints of post-coital (or post-menopausal) vaginal bleeding.
How do you treat primary vaginal carcinoma?
no definitive Tx
- surgical excision, radiation, chemo
- prognosis = stage-based (clinical)
Vagina: A 6 year old female presents with vaginal bleeding and/or vaginal polyp.
Gross finding reveal:
1. polypoid, rounded bulky masses that appear as grape-like clusters
Histology reveals:
- small tumor cells with spindle shaped nuclei, small protrusions (tennis-racket), and rare striations in the cytoplasm (SK muscle differentiation)
- Tumor cells are desmin positive
- Tumor cells are crowded (cambium layer) beneath the vaginal epithelium
You suspect
Embryonal rhabdomyosarcoma
- MC soft tissue sarcoma in childhood, young adulthood (< 8)
- MC sporadic, may have genetic
- death by local invasion
Tx: surgery w/ chemotherapy
Cervix: True/False - The cervix is composed of ectocervix (squ. epithelium continuous w/ the vagina) and endocervix (columnar, mucous secreting epithelium). In healthy people, the cervix should be moist, round, pink and centrally located. Secretions should be clear or whitish with no odor.
Its unique epithelial environment renders it highly susceptible to infections (HPV). The immature squamous metaplastic epithelial cells located in the transformation zone are most susceptible to development of precursor lesions and cancer.
True
Cervix: _______ is replacement of glandular epithelium by advancing squamous epithelium (change from columnar to squamous)
Squamous metaplasia
*transformation zone - b/t endo and ecto
Cervix: A patient presents with complaints of vaginal bleeding between her periods, abnormal discharge and pain during intercourse and with urination.
Pelvic exam reveals red and inflamed cervical os with thick, yellow mucopurulent exudate. Patient complains of discomfort during the exam.
Biopsy reveals: small, dark lymphocytes in submucosa and hemorrhage.
You suspect
Acute cervicitis
*due to infection (gonoccoci, chlamydia, mycoplasm, HSV - acute or chronic)
Complications:
- -upper genital tract issues
- -pregnancy issues
- -ascend and cause endometritis, PID
Cervix: True/False - Chronic cervicitis is NOT associated with infection, but rather gyn. procedures, foreign bodies (contraceptive devices, and/or chemicals - douches)
True
Cervix: True/False - Some cervical inflammation may be found in all women and is usually of little clinical significance.
However, marked inflammation can lead to epithelial reparative and reactive changes and shedding of atypical appearing squamous cells (detectable on Pap).
True
- benign histo: uniform nuclei, finely granular and evenly distributed chromatin, normal N/C ratio
- almost all cases have chronic inflammatory infiltrate
Cervix: A 43 year old, peri-menopausal female presents with complaints of vaginal spotting or bleeding (post-coital or contact) and abnormal vaginal discharge.
She admits to recent cervical infection which caused chronic inflammation.
Gross reveals benign exophytic growths within the endocervical canal that protrude through the os. They appear as small/large sessile, polypoid masses.
You suspect
Endocervical polyps
- perimenopausal w/ kids (rare in pre-menstrual/post-meno)
- incidental findings (MC asymptomatic)
Tx:
- currettage or surgical excision (cure)
- polypectomy and lab eval (symptomatic and > 3cm)
Cervix: The main significance of endocervical polyps is if a patient presents with irregular bleeding (menstrual periods abnormally frequent/polymenorrhea) arouses suspicion of a more ominous lesion.
True
*may harbor in situ or invasive squamous lesions
Cervix: Cytologic cancer screening has contributed drastically to the prevention and early detection of cervical neoplasms. It has helped reduce mortality, since most cancers arise from precursor lesions (over years) and shed abnormal cells.
The most effective screening method is the ______, which detects cervical intraepithelial neoplasias (CIN) and squamous intraepithelial neoplasias (SILs). It can also detect low-stage, highly curable cancers
Pap smear
*accessibility to pap testing, visual exam (colposcopy) and slow progression of precursor lesions to invasive carcinoma enables time for screening
Cervix: Pap test involves opening the vaginal canal with a speculum and collecting the cells at the transformation zone. Conventionally, the sample is rolled on a slide and fixed. However, it is cheaper to perform liquid based cytology, where cells are collected and put in a vial. HPV testing may be done using liquid based samples.
What is the next step if a pap test is abnormal?
colposcopic exam of cervix and vagina to ID lesion
- cervix and vagina swabbed w/ dilute acetic acid (vinegar) – highlights dysplasia (white)
- if abnormal swabbing = biopsy taken
Cervix: True/False - Testing for HPV DNA in cervical screening is a molecular method (high sensitivity, low specificity compared to Pap) that may be added to cervical cytology for screening of women > 30 y/o. It is not recommended in women younger than 30 (high incidence of infection and low specificity).
True
Cervix: What are the recommendations for Pap screening:
- 1st smear
- Following smears
- After age 30
- Over 65
- 1st smear at 21 years
- -or within 3 years of onset of sexual activity
- -every 3 years after - Over age 30
- -normal cytology + HPV screening every 5 years
* repeat if normal cytology, but + HPV - 6-12 months - > 65 years
- -none if negative before and no RF’s
Cervix: Vaccination against high risk oncogenic HPV is a new aspect of cervical cancer prevention. It is recommended for all girls and boys by age 11 to 12 and up to age 26.
It provides nearly complete protection against high risk oncogenic HPV types (16/18) which account for ~70% of cervical cancers.
True
- protect up to 10 years
- continue cervical cancer screen (doesn’t protect from all)
- can protect 6,11
Cervix: True/False - Almost are cervical precursor lesion and cervical carinomas are caused by high risk HPV- types (MC 16 - 60% of cervical cancer cases; 18 - ~10%).
In contrast, low oncogenic risk HPVs tend to cause sexually transmitted vuvular, perineal and perianal warts (e.g. condylomata acuminata).
True
Cervix: Genital HPV infections are common. Most are transient and asymptomatic and are eliminated by the immune response in months.
True/False - The duration of the infection is related to HPV type (high risk last longer than low risk). However, persistent infection increases the risk of developing cervical precursor lesions and developing carcinoma.
True
Cervix: A high percentage of young women are infected with one or more HPV types during their reproductive years. However, few develop cancer. Though HPV is a common cause for cancer development, it is not sufficient to cause cancer.
What are additional factors that influence HPV infection and progression to cancer?
- expsoure to co-carcinogens
- -smoking (dec. immunity and DNA damage in HPV infected cells) - host immune status
- -HPV regress or persist
Cervix: HPV infects immature _____ cells in epithelial breaks OR immature _______ cells at the transformation zone.
Immature basal cells OR Immature metaplastic squamous cells
*cannot infect mature cells (ectocervix, vagina, vulva) – must have damage to surface epithelium allowing access to immature cells
Cervix: Although HPV infects immature squamous cells, viral replication occurs in ______ cells. Highest viral load of HPV DNA is found in maturing keratinocytes of the upper half of the epithelium.
Maturing squamous cells
- more mature cells arrested in G1 phase, but progress w/ HPV infection
- viral E6/E7 protein action
Cervix: HPV (high risk) uses two viral oncoproteins proteins to regulate cell growth and survival within host cells:
- Viral E7
- Viral E6
_____ binds active RB, promoting its degradation. It also binds and inhibits p21 and 27 (CDK inhibitors) removing regulatory controls and enhancing cell cycle progression.
Protein E7
*impairs ability to repair DNA damage
Cervix: HPV (high risk) uses two viral proteins to regulate cell growth and survival within host cells:
- Viral E7
- Viral E6
_____ further exacerbates the defective DNA repair by binding p53, upregulating telomerase, and preventing apoptosis.
Viral E6
*inc. proliferation of cells that are prone to acquire additional mutations
Cervix: Low risk HPVs bind RB with lower affinity and faily to bind p53. They instead dysregulate growth and survival by interfering with ______
Notch
Cervix: The upper portion of the epithelium can express markers of actively dividing cells including ______ and ______. These are highly correlated with HPV infection and are useful in confirming diagnosis of squamous intra-epithelial lesions (SIL).
- Ki-67 (normally confined to basal layer)
- p16 overexpression
Cervix: Dx of SIL is based on histology. Features include koilocytic atypia, squamous epithelial cells with nuclear enlargement, coarse chromatin granules, irregular nuclear membranes, and perinuclear cavitation (perinuclear halo).
What contributes to the formation of the perinuclear halos (vacuoles)
cytopathic change from HPV-E5 protein localizing to Endoplasmic reticulum
Cervix: Grading of SIL (low or high) is based on expansion of immature cell layer from its normal, basal location.
A patient presents with suspected cervical lesion. You decide to obtain a histologic sample knowing the Dx of SIL is based on histology.
Histology reveals:
- immature squamous cells confined to the lower 1/3 of the epithelium
- koilocytes and atypia (below 1/3) epithelial thickness
You suspect
LSIL (CIN I)
*low grade squamous intraepithelial lesion
Cervix: Grading of SIL (low or high) is based on expansion of immature cell layer from its normal, basal location. You are given a histologic sample that reveals:
- Progressive atypia and expansion of the immature basal cells above the lower 1/3 epithelial thickness (up to 2/3). You suspect
HSIL (high grade squamous intra-epithelial lesion)
*CIN II
Cervis: Grading of SIL (low or high) is based on expansion of immature cell layer from its normal, basal location. You are given an histologic sample that reveals:
- Diffuse atypia, loss of maturation, and expansion of the immature basal cells to the epithelial surface. You suspect
HSIL (CIN III)
high grade squamous intra-eptithelial lesion (Cervical. intraepithelial III)
