df Flashcards
The __________ can be affected by psoriasis, eczema, allergic dermatitis and is more prone to superficial infections because it is constantly exposed to secretions
Vulva
What vulvar disorders do we discuss?
- Bartholin cyst
- Non-neoplastic epithelial disorders (Leukoplakia, lichen sclerosis, squamous cell hyperplasia = lichen simplex chronicus)
- Benign exophytic lesions (condyloma acuminatum/condylomas latum)
What is a Bartholin Cyst?
Obstruction of the Bartholin gland causes infection and inflammation (adenitis), forming a painful cyst that can get large (3-5cm)
Bartholin Cyst
- What lines the cyst?
- Most often seen when?
- Treatment?
- Lined with transitional or squamous epithelium
- All ages
- Excised or opened permanently (marsupialization)
What non-neoplastic epithelial disorders can cause leukoplakia on the vulva?
- Lichen sclerosis
- Squamous cell hyperplasia (lichen simplex chronicus)
What is leukoplakia?
Opaque-white, plaquelike epithelial thickening that can cause pruritus and scaling.
Leukoplakia can also be caused by what?
- Vulvar intraepithelial neoplasia (VIN)
- Paget disease
- Invasive carcinoma
Lichen Sclerosis
- Presentation:
- Occurs in who?:
- Risk of cancer:
- Presentation: Smooth, white plaques macules on the vulva that can enlarge, coalesce and have porcelain/parchment surface.
- Occurs when: Any age, MC in post-menopausal W.
- Risk of cancer: Not a premalignant lesion, but have an increase risk of developing vulvar carcinoma
What is seen histologically with Lichen Sclerosus?
- Thinning of epidermis (parchment paper) + fibrosis/sclerosis of superficial dermis
- Excessive keratinization(hyper-keratosis)
- Chronic inflammatory cells in deeper dermis = band-like infiltrate
Pathogenesis of Lichen Sclerosus is uncertain, but there is a higher frequency in association with what?
Autoimmune disorders
Lichin Simplex Chronicus
- Other names:
- Presentation:
- Occurs in who?:
- Risk of cancer:
- Squamous cell hyperplasia/hyperplastic dystrophy
- Presentation: leukoplakia w/ thick, leathery skin on vulva w/ enhanced skin markings due to chronic rubbing or scratching
- Occurs in who: chronic rubbers or scratchers
- Risk of cancer: Not premaligant, but can be on the margins of vulvular cancer
What is seen histologically with Lichen Simplex Chronicus?
- Hyperkeratosis
- Thick epidermis (acanthosis) = squamous cell hyperplasoa
- Lymphocytes in dermis
What are benign exophytic lesions?
Benign raised (exophytic) lesions = wart-like lesions
- Condyloma Acuminatum (genital warts) due to HPV
- Condyloma Latum due to syphilis
Condyloma Acuminatum
- Presentation:
- Cancer risk:
- Presentation: Benign genital warts, which can be multiple, due to low oncogenic risk HPV (6 & 11).
- Cancer risk: Not a precancerous lesion
What is seen histologically with Condyloma Acuminatum (genital wart)?
- Exophytic papillas, tree-like cores of stroma covered by thick squamous epithelium
- Surface epithelium has koilocytic atypia = large nuclei + hyperchromasia + cytoplasmic perinuclear halo
Squamous neoplastic lesions of the vulva: VIN and vulvar carcinoma
2 groups of squamous cell carcinoma of the vuvla?
- How are they different
-
Basaloid & warty carcinoma related to HPV 16
- (younger age, 50’s)
-
Keratinizing SCC not related to HPV
- (older age; 70’s )
Precursor lesions in:
- Basaloid and warty carcinomas of the vulva
- Keratinizing SCC of the vulva
- Basaloid & warty carcinoma of the vulva: Classic vulvar intraepithelial neoplasia (VIN)
- Keratinizing = Differentiated vulvar intraepithelial neoplasia (aka VIN simplex)
What is VIN?
Who is it most commonly seen in?
- Precursor lesion that progresses to [Basaloid & warty cancers] of the vulva, often caused by HPV 16.
- Pre-menopausal F
Presentation & Histology of VIN
- Presents: discrete white (hyperkeratotic) or slightly raised, pigmented lesion
- Histologically:
- Epidermal thickening,
- Nuclear atypia + ↑ mitoses
- Lack of cellular maturation
Presentation and Histology of Basaloid Carcinoma
-
Presentation:
- Exophytic or indurated/ulcerated
-
Histology
- Small, tightly packed basaloid cells that lack maturation (look like basal layer of NL epithlelium
- Central necrosis
Presentation and Histology of Warty Carcinoma of the Vulva
- Presentation: Exophytic and papillary
- Prominent koilocytic atypia
Progression from [VIN => invasive basaloid and warty carcinomas] is higher in whom?
- Women older than 45YO
- Immunosuppressed
Keratinizing Squamous Cell Carcinoma
- Occurs more in?
- Precursor lesion?
- Older women (70s) with long-standing lichen sclerosus or squamous cell hyperplasia
- VIN simplex/differentiated VIN
Histology of Keratinzing Squamous Cell Carcinoma
Malignant squamous epithelium with keratin pearls
Histology of Diffentiated VIN/ VIN simplex
- Basal layer atypia
- Normal-appearing differentiation of superficial layers
- Hyperkeratatosis
Which precursor lesion has a higher frequency of TP53 mutations?
Differentiated VIN
When Differeniated VIN becomes invasive, where does it spread?
- LN: Inguinal, pelvic, iliac and periaortic lymph nodes
- Lympho-hematogenously: lungs, liver and other organs
How many vulvular cancers are caused by high-risk HPV?
What are the others caused by?
- 30% = HPV 16 and 18; VIN
- 70% = not HPV-related and develop in background of lichen sclerosus or squamous cell hyperplasia; Differentiated VIN
What glandular neoplastic lesions occur in the vulva (has apocrine sweat glands)?
- Papillary Hildradenoma
- Extramammary Paget Disease
Which lesions of invasive carcinoma of the vulva have an excellent prognosis (90% at 5-years)?
Lesions <2 cm
Papillary Hidradenoma
- Presentation:
- Often confused with:
- Histology:
- Presentation: Sharply, circumscribed nodule of the apocrine sweat gland, most often on labia major or interlabial folds that tends to ulcerate
- Often confused with: Invasive carcinoma bc ulcerates
-
Histology:
- Same as intraductal papilloma of the breast:
- Papilloma covered by 2 cells: columnar and flat myoepthial cells of sweat glands.
- Same as intraductal papilloma of the breast:
Extramammary Paget Disease
- Presentation
- Associated with cancer?
- Cell of Paget disease of the vulva express _______, which allows for immunostaining
- Itchy, red, crusty, maplike area confined to the epidermis of vulva (mainly labia majora)
- No
- Cytokeratin 7
Histology of Extramammary Paget Disease
- Epidermis: Large cells with pale-pink cytoplasm (mucopolysaccharide) with apocrine, eccrine and keratinocyte differentiation
- Dermis: inflammation
Paget cells have pale cytoplasm containing mucopolysaccharide that can be stained with what 3 stains?
- PAS
- Alcian blue
- 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
Treatment of Extramammary Paget Disease
Wide local excision because cells spread laterally within the epidermis and can be present beyond the borders of the visible lesion
What part of the female genital tract is a RARE site of primary disease?
Vagina
Most vaginal cancers are what kind?
Squamous cell carcinomas due to high-risk HPV
What developmental anomalies occur in the vagina?
- Septate (double) vagina
- Vaginal adenosis
- Gartner duct cyst
Septate, or double, vagina is accompanied by a double uterus (uterus didelphys) and is due to failure of what?
Failure of müllerian duct to fuse
What can cause septate (double) vagina?
Exposure to DES (diethylstilbestrol) in utero.
- Used to prevent threatened abortions (vaginal bleeding during the first 20 weeks)
What is vaginal adenosis and who is it most commonly seen in?
- Persistance of small patches of residual glandular epithelium from the developing vagina => create red, granular areas
- Women exposed to DES in utero
What was a RARE complication seen in vaginal adenosis?
Clear cell carcinoma can arise from DES-related adenosis
Where are gartner duct cysts found and what are they derived from?
Fluid-filled cysts in the submucosa of lateral walls of vagina, derived from wolffian (mesonephric) duct rests
What is the greatest risk factor for SCC of the vagina?
Cervical or vulvular carcinoma due to high-risk HPV
List 3 benign tumors of the vagina that most often occur in women of reproductive-age.
- Stromal tumors (stromal polyps)
- Leiomyomas
- Hemangiomas
Vaginal Squamous Cell Carcinoma
- Premalignant lesion:
- What part of the vagina is most commonly affected?
- What LN does it metasasize?
- VaIN
- Posterior wall of the upper vagina, at the junction of the ectocervix
- Metastasize
- Upper 1/3 of vagina: iliac LN
- Lower 2/3 of vaina: inguinal LN
*
What is embryonal rhabdomyosarcoma (sarcoma bortyoides)?
- Rare, malignant 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
Histology of Embryonal Rhabdomyosarcoma (aka sarcoma botryoides)
- Tumor cells are small, oval nuclei, w/ smallcytoplasmic protrusions from one end, resembling a tennis racket
- Tumor cells beneath vaginal epi. = crowded in a cambium layer
- Tumor cells in deep regions = lie in loose, edematous fibromyxomatous stroma
Risk of metatsis of the invasive VULVAR cancer depends on what?
- 1. Size of the tumor (<2cm => 90% chance of survival in 5 years)
- 2. Depth of invasion
- 3. Lymphatic involvement
What is the prognosis and complications associated with embryonal rhabdomyosarcoma (aka sarcoma botryoides)?
- Tend to invade locally = death by penetrating into peritoneal cavity or by obstructing urinary tract
- Surgery + chemotherapy offer best hope in cases diagnosed early
Describe the anatomy of the cervix (& cell type)
-
Ectocervix (external vaginal part) = part seen on vaginal exam
- Squamous epithelium
- Converges at the external os
-
Endocervix (endocervical canal)
- Columnar, mucus secreting epithelium that begins at the external os
- Squamocolumnar junction (transformation zone) = where both meet
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)
- Area has immature squamous metaplatic epithelial cells, which are highly susceptible to HPV.
Where do cervical precursor lesions and cancer develop?
Transformation zone
How does the transformation zone of the cervix change over time?
Location depends on age and hormones.
Overtime, moves upward into the endocervical canal.
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 hydrogen peroxide (H2O2), which is bacteriotoxic when pH gets too low.
Physiologically, what causes cervicitis or vaginitis?
- Vaginal pH becomes alkaline (> 7) due to bleeding, sex, ABX*, douching
- Decreases H2O2 production
- Overgrowth of other microorganisms
What can cause cervicitis or vaginitis?
- Gonorrhea
- Chlamydia
- Mycoplasma
- HSV
Why is it important to ID the causes of cervicitis or vaginitis?
They can be associated with a upper genital tract disease, pregnany complication, STI, PID (=> Fitz-Hugh Curtis Syndrome).
Cervicitis can lead to what complication of the cervix?
- Reparative and reactive changes of the epithelium + shedding of atypical squamous cells → abnormal Pap smear
What is the most common benign exophytic growth in the endocervical canal?
Endocervical polyps = Range from [small, sessile “bumps” => large polpys] that may protrude through cervical os.
Endocervical Polyps
- Histology
- Symptoms
- Treatment
- Loose fibromyxomatous stroma covered by mucus secreting endocervical glands that can inflammed
- Vaginal “spotting” (bleeding), makes us things something else
- Curretege and excise via surgery
Cervical cancer is the ___ most common cancer in women in the WORLD.
3rd
What is the most important risk factor for the development of cervical cancer?
High-risk HPV16 (60% of cases) and HPV18 (10% of cases)
What kind of cells can HPV NOT infect?
Mature superficial squamous cells that cover the cervix, vagina or vulva.
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 => cell immortilization
- E7 inhibits RB + p21 and p27 = cell cannot 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 do not bind to p53
- Dysregulate growth and survival by interfering w/ Notch signaling pathway
- High risk HPV strains cause =>
- Low risk HPV stains cause = >
- Cervical cancer
- Conduloma acuminta in the vulva, perineal and perianal area
Alone, HPV is not enough to cause cervical cancer. What else influences the progression?
- Carcinogens
- Host immune status
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
Genital HPV infections are extremely _____; most of them are symptomatic/asymptomatic, do/do not cause any tissue changes, and therefore ______ detected on Pap test
- common
- asymptomatic
- no tissue changes => not detected on Pap smear
What makes high-risk HPV infections more likely to become cancer?
- 50% of HPV infections are cleared within 8 months, and 90% of infections are cleared within 2 years
- High-risk HPV infections last longer => more time develop precursor lesion
- Epithelial cells in the ________ => ↑ risk of HPV
- Epithelial cells in the ________ => ↓ risk of HPV
- Cervix and anus (homosexual men)
- Vulva and penis (except for epithelial breaks)
HPV causes 80% of ____ and 100% of ____ precursor lesions
HPV causes:
- 80% of LSIL (low grade squamous intraepithelial lesions)
- 100% of HSIL (high grade SIL)
_LSIL** (more common) & HSIL:_
Differentiate the two based on
- viral replication
- cellular proliferation
- progression to invasive carcinoma
-
LSIL:
- high rate of viral replication;
- mild alterations in growth of host cells =>
- not pre-malignant and does directly become invasive carcinoma (60% regress; 10% => HSIL)
-
HSIL
- lower rate of viral replication
- ↑ cellular proliferation and ↓ arrested epithelial maturation
- ALL are high risk for progression to carcinoma
Diagnosis of squamous intraepithelial lesions (pre-cursor lesions) is based on identification of what?
- Atypical nuclei
- Nuclear enlargement
- Hyperchromasia (dark staining)
- Coarse chromatin granules
- Variation in nuclear size & shape
- Cytoplasmic halos due to E5 protein localization to the ER = koilocytic atypia
How do we assign low-grade/high-grade to cervical precusor lesions?
Based on expansion of immature cells from its normal, basal location. If,
- Confined to the lower 1/3 => LSIL
- Expands to upper 2/3 => HSIL
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), usually restricted to basal layer. But seen in upper levels when E6 and E7 prevent arrest of cell-cycle.
- p16 (characterized high-risk infections) => increase CDK4
Most (80%) HSIL develop from _____.
How many progress to invasive cancer?
- LSIL
- 10%
After SCC what is the second most common cancer (15%) of the cervix and which 2 types represent only 5% of cases?
- Adenocarcinoma (15%)
- Adenosquamous and neuroendocrine carcinomas (5%) = progress quicker and pt presents with advanced disease and worse prognosis
Average age of cerical cancer?
45 YO
How does advanced cervical cancer spread?
Directly extends into 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
- Uremia
An abnormal pap test should be followed up with what?
Colposcopic exam of the cervix and vagina to ID 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
- Histology of cervical intraepithelial neoplasia
- LSIL (CIN I) =
- HSIL (CIN II) =
- HSIL (CIN III) =
- HSIL (CN IV) =
- LSIL (CIN I) = mild cervical intraepithelial neoplasia = koilocytic atypia in basal layer
- HSIL (CIN II) = moderate dysplasia = progressive atypia and expansion of immature basal cells above lower 1/3 of the epithelium
- HSIL (CIN III) = severe dysplasia = diffuse atypia, loss of maturation and expansion of the immature basal cells to the surface
- HSIL (CN IV) = CIS
What % of LSIL regress, persist, and progress to HSIL within 2-year follow-up?
- 60% regress
- 30% persist
- 10% progress to HSIL
Describe the staging of cervical cancer
- Stage 0 = CIS (HSIL CN III)
- Stage 1 = confined to cervix
- Stage 2 = cancer goes beyond cervix, but NOT pelvic wall (involves only upper 2/3 of vagina)
- Stage 3= : cancer extends beyond pelvic wall (lower 1/3 of vagina is involved)
- Stage 4 = cancer extends beyond pelvis or involves bladder/rectum mucosa.
Treatment of: early invasive, invasive cancer or advanced cervical carcinoma
- Early invasive: cervical cone excision
- Invasive cancer: hysterectomy + lymph node dissection
- Advanced cancer: + radiation + chemotherapy
What is a pap smear?
How does it affect mortality of cervical cancer?
Pap Smear: transformation zone is scraped and smeared onto a slide, fixed and stained with Papanicolaou method
- ↓ mortality of cervical cancer because most cancers arise from precursor lesions over many years
HPV vaccine
- Recommended for who?
- Gardasil protects agains?
- should cervical screens still be done?
- All girls and boys 11-12 years old, up to age 26
- 6, 11, 16, 18
- Yes bc does not protect against all strains
Describe the precursor lesions
- A = NL
- B = LSIL bc koilocytes
- C = HSIL (II)
- D = HSIL (III)
Increase in nucleus to cytplasm ratio which occurs as the grade of the lesion increases. Indicates progressive loss of cellular differentiation on the surface of the lesion.
