Lecture 7.1: Vulva, Vagina, and Cervix Flashcards
Which descriptive clinical term refers to opaque, white, plaquelike epithelial thickening that may produce pruritus and scaling?
Leukoplakia
Which cause of leukoplakia presents as smooth, white plaques of macules on the vulva that in time may enlarge and coalesce, producing a surface that resembles porcelain or parchment?
Lichen Sclerosus
What is seen histologically with Lichen Sclerosus?
- Marked thinning of epidermis (parchment paper) + fibrosis/sclerosis of superficial dermis
- Excessive keratinization (hyperkeratosis)
- Chronic inflammatory cells in deeper dermis = band-like infiltrate
Who is lichen sclerosus most commonly seen in; what are the risks of cancer?
- All ages, but most common in post-menopausal women
- NOT a premalignant lesion
- Slightly ↑ risk of developing SCC of the vuvlva
Pathogenesis of Lichen Sclerosus is uncertain, but there is a higher frequency in association with what?
Autoimmune disorders
Squamous cell hyperplasia (aka lichen simplex chronicus) results from what and how does it present?
- Presents as leukoplakia w/ leathery, THICK vulvar skin w/ enhanced skin markings
- Due to chronic rubbing or scratching
Histological examination of Squamous cell hyperplasia (aka lichen simplex chronicus) will show what?
Thickening of the epidermis (acanthosis) and hyperkeratosis
Is squamous cell hyperplasia (aka lichen simplex chronicus) pre-malignant?
Not premalignant; sometimes present at the margins of vulvar cancer
Condyloma acuminatum are benign genital warts caused by what; are they pre-malignant?
- LOW oncogenic risk HPV, mainly types 6 and 11
- NOT pre-malignant
What is seen on histological examination of condyloma acuminatum; which characteristic cytopathic change is seen in the surface epithelium?
- Papillary, exophytic, tree-like cores of stroma covered by thickened squamous epithelium
- Surface epi. shows koilocytic atypia = nuclear enlargement + hyperchromasia and a cytoplasmic perinuclear halo
What are the 2 groups of SCC of the vuvla; which is related to HPV and what age group is more commonly affected by each?
- Basaloid and warty carcinomas related to HPV-16; less common and occur in younger women (peak in 50’s)
- Keratinizing SCC unrelated to HPV; more common; occur in older women (peak in 70’s)
Basaloid and warty carcinomas and keratinizing SCC of the vulva arise from what precursor lesions?
- Basaloid and warty = classic vulvar intraepithelial neoplasia (VIN)
- Keratinizing = differentiated vulvar intraepithelial neoplasia (aka VIN simplex)
The risk of progression from VIN to invasive basaloid and warty carcinomas is higher in whom?
- Women older than 45 y/o
- Immunosuppressed
Keratinizing SCC of the vulva occurs most often in women with what underlying condition?
Older women w/ long-standing lichen sclerosus or SCC hyperplasia
Higher frequency of what type of mutations are seen in differentiated VIN leading to keratinizing SCC of the vulva?
TP53
What is the morphology upon presentation of classic VIN; what is seen microscopically?
- Presents as a discrete white (hyperkeratotic) or slightly raised, pigmented lesion
- Microscopically, shows epidermal thickening, nuclear atypia + ↑ mitoses and lack of cellular maturation
Which carcinoma of the vulva is characterized by nests and cords of small, tightly packed cells that lack maturation often with a foci of central necrosis?
Basaloid carcinoma (HPV-16 assoc.)
Which vulvar carcinoma is exophytic w/ papillary architectureand prominent koilocytic atypia?
Warty carcinoma
Which carcinoma of the vulva is characterized by nests and tongues of malignant squamous epithelium w/ prominent central keratin pearls?
Keratinizing SCC
Which type of VIN is characterized by marked atypia of the basal layer of the squamous epithelium and normal-appearing differentiation of the more superficial layers?
Differentiated VIN
Which lesions of invasive carcinoma of the vulva are associated with an excellent prognosis (90% at 5-years)?
Lesions <2 cm
What sharply circumscribed nodule most commonly presents on the labia majora or interlabial folds, and is often confused clinically w/ carcinoma due to its tendency to ulcerate?
Papillary Hidradenoma
Papillary hidradenomas are histologically identical to what other tumor; what are the 2 layers of cells seen on the papillary projections?
- Identical to intraductal papilloma of the breast
- Upper layer = columnar secretory cells covering
- Deeper layer = flattened myoepithelial cells
How does extramammary paget disease of the vulva typically present?
Itchy, red, crusted, maplike area usually on labia majora
What do the cell of Paget disease of the vulva express which allows for immunostaining?
Cytokeratin 7
Paget cells have pale cytoplasm containing mucopolysaccharide that can be stained with what 3 stains?
PAS, Alcian blue, or macicarimine stains
How does Paget disease of the nipple differ from extramammary Paget disease in terms of underlying cancer association?
- Paget of the nipple = 100% of pt’s have underlying ductal breast carcinoma
- Extramammary = typically not associated w/ underlying cancer and is confined to the epidermis of vulvar skin
Septate, or double, vagina is accompanied by a double uterus (uterus didelphys) and is due to failure of what?
Failure of müllerian duct fusion
What is vaginal adenosis and who is it most commonly seen in?
- Small patches of residual glandular epithelium from the developing vagina which persist into adult life and are seen as red, granular areas
- Women exposed to DES in utero
Where are gartner duct cysts found and what are they derived from?
- Lateral walls of the vagina and derived from wolffian (mesonephric) duct rests
- Fluid-filled cysts occurring in submucosal location
In rare instances DES-related vaginal adenosis has been associated with what type of cancer?
Clear cell carcinoma
What is the greatest risk factor for SCC of the vagina?
Previous carcinoma of the cervix or vulva; associated w/ high-risk HPVs
List 3 benign tumors of the vagina that most often occur in women of reproductive-age.
- Stromal tumors (stromal polyps)
- Leiomyomas
- Hemangiomas
In which location of the vagina are invasive tumors most often seen?
Upper vagina along the posterior wall at the junction with the ectocervix
Embryonal rhabdomyosarcoma (aka sarcoma botryoides) arises where in the female genital tract and most often in what age group?
- Rare vaginal tumor
- Most often in infants and children <4 y/o
How do embryonal rhabdomyosarcoma (aka sarcoma botryoides) appear on presenation?
Clear, polypoid, round, grape-like mass emerging from vagina
How do the tumor cells of embryonal rhabdomyosarcoma (aka sarcoma botryoides) and tumor appear histologically?
- Small and have oval nuclei, w/ small protrusions of cytoplasm from one end, resembling a tennis racket
- Tumor cells beneath vaginal epi. = crowded in a cambium layer
- Deep regions lie in loose fibromyxomatous stroma that is edematous
What is the prognosis and complications associated with embryonal rhabdomyosarcoma (aka sarcoma botryoides)?
- Tend to invade locally = death by penetration into peritoneal cavity or by obstruction of the urinary tract
- Surgery + chemotherapy offer best hope in cases diagnosed early
What is the “transformation zone” of the cervix and why is this area clinically significant?
- Area where columnar epithelium (endocervix) meets the squamous epithelium (ectocervix) = Squamocolumnar Jct.
- Contains area of immature squamous metaplatic epithelial cells which are highly susceptible to infections with HPV
In which location do cervical precursor lesions and cancer develop?
“Transformation zone” = Squamocolumnar Junction
What is the dominant microbial species found in the normal vagina and what is its function?
- Lactobacilli
- Produce lactic acid, which maintain vaginal pH <4.5
- Produce bacteriotoxic hydrogen peroxide (H2O2)
What are endocervical polyps, where do they arise and how do they appear?
- Common benign exophytic growths arising within endocervical canal
- Vary from small, sessile “bumps” to large polypoid masses that may protrude through cervical os
What is the clinical significance of endocervical polyps?
May be source of irregular vaginal “spotting” (bleeding) that arouses suspicion of some more ominous lesion
What is the most important risk factor for the development of cervical cancer?
HPV especially type 16 (60% of cases) and (10% of cases)
Which viral protein of high-risk HPV impairs the ability of cells to repair DNA and which up-regulates expression of telomerase leading to cellular immortalization?
- E6 inhibits p53 and ↑ regulates expression of telomerase
- E7 inhibits RB + p21 and p27 = impairs ability of cell to repair DNA damage
How do the E6 and E7 proteins of low-risk HPV impact cellular growth and survival?
- E7 proteins bind RB with lower affinity; E6 proteins fail to bind p53
- Dysregulate growth and survival by interfering w/ Notch signaling pathway
What is the position of HPV DNA in precursor lesions assoc. w/ high-risk HPVs and in condylomata assoc. w/ low-risk HPVs?
DNA is extrachromosomal (episomal)
How does the squamous cell that HPV infects differ from the cell that HPV replicates in?
- Infects immature squamous cells; cannot infect mature cells
- Viral replication occurs in maturing squamous cells
How does the position of the viral DNA of HPV change with malignant transformation?
Viral DNA is integrated INTO the host cell genome –> ↑ expression of E6 and E7
How does the viral replication and cellular proliferation differ between low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL)?
- LSIL have high levels of viral replication and only mild alterations in the growth of host cells –> NOT treated as pre-malignant
- HSIL = lower rate of viral replication w/ ↑ cellular proliferation and ↓ or arrested epithelial maturation –> high risk for progression to carcinoma
Diagnosis of squamous intraepithelial lesions (pre-cursor lesions) is based on identification of what characteristics of nuclear atypia?
- Nuclear enlargement
- Hyperchromasia (dark staining)
- Coarse chromatin granules
- Variation in nuclear size and shape
Nuclear changes seen in squamous intraepithelial lesions often accompanied by what cytoplasmic finding?
Cytoplasmic “halos” + nuclear alterations = koilocytic atypia
How does expansion of the immature cell layer in the normal basal location dictate the grading of a low vs. high-grade squamous intraepithelial lesion?
- LSIL = immature cells confined to the lower 1/3 of the epithelium
- HSIL = expansion to the upper 2/3 of the epithelial thickness
Staining for what cell markers highly associated with HPV infection is useful for confirmation of the diagnosis in equivocal cases of SIL?
Ki-67 (marker of actively dividing cells) and p16 (characterized high-risk infections)
After SCC what is the second most common tumor type (15%) of the cervix and which 2 types represent only 5% of cases?
- Adenocarcinoma (15%)
- Adenosquamous and neuroendocrine carcinomas (5%)
Advanced cervical carcinoma spreads how and to where?
Direct extension to contiguous tissues:
- Paracervical soft tissue
- Urinary bladder
- Ureters –> hydronephrosis
- Rectum
- Vagina
Lymphovascular invasion by advanced cervical carcinoma may cause distant metastases to what organs?
Liver + Lungs + Bone marrow
Which cancer of the cervix is associated with a very poor prognosis?
Small-cell neuroendocrine tumors
Most patients with advanced cervical cancer die due to what?
Local tumor invasion –> ureteral obstruction, pyelonephritis, and uremia
An abnormal Pap test should be followed up with what?
Colposcopic exam of the cervix and vagina to identify lesion
What % of cervical cancer arise in women who were not in a regular screening program?
50%
What is the significance of persistent HPV infections?
Persistent infection ↑↑↑ risk for cancer
What % of LSIL regress, persist, and progress to HSIL within 2-year follow-up?
- 60% regress
- 30% persist
- 10% progress to HSIL
