DSA16 - Pathology of the Cervix, Vulva, and Vagina

Transformation Zone (TZ)

Where might you find immature squamous metaplasia/95% of cancers in the Cervix?

HPV/Cervical Dysplasia

Define Cervical Condition:

Caused by non-enveloped circular dsDNA virus

-Hx/Path: Very Common infex - usually from intimate skin-to-skin contact

> May be d/t vaginal, anal, oral sex w/ someone who has virus

> RARELY vertical transmission (mother to baby)

> MC LOW RISK = Types 6 & 11

> MC HIGH RISK (Cancer) = Types 16 & 18, 31, 33

-Path (Infex): Virus enters immature basal epithelial cells (trauma, immature squamous metaplasia at TZ) --> Replication in MATURING Squamous cells (G1 phase) ==> Persistent Infex = Risk of Precursor Lesions (Cervical Dysplasia) and Carcinoma))

-Tx: Usually Transient Infex (cleared by immune system)

-Prog:

> Duration of Infex depends on Type (HIGH > LOW)

> Causes 99.7% of cervical cancer

> Other cancers = Vaginal, Vulvar, Anal, Penile, Oropharyngeal SCC (mouth, throat)

-Viral E6 protein binds/degrades p53 (high-risk HPV ↑affinity)

> p53 protein: controls cell cycle G1 to S phase progression

> Inhibited p53 -> uncontrolled growth

There are 2 key HPV viral proteins, E6 & E7 - what is the pathology behind E6 in HPV Oncogenesis?

-Viral E7 protein binds/inhibits RB protein (high-risk HPV ↑affinity)

> RB protein inactivates E2F transcription factor

> Inhibited RB -> E2F activation -> uncontrolled growth

There are 2 key HPV viral proteins, E6 & E7 - what is the pathology behind E7 in HPV Oncogenesis?

MILD DYSPLASIA in LOWER 1/3 of EPITHELIUM:

-60% regress; few progress to malignancy

-HIGH VIRAL REPLICATION, mild alterations in host cells

-Much more common than HSIL

Define Low Grade Squamous Intraepithelial Lesions/Cervical Intraepithelial Neoplasia 1 (LSIL/CIN1)

Observation

What is the Tx for LSIL/CIN1?

Koilocytic atypia = dysplastic nuclei (enlarged, hyperchromatic, nuclei with irregular nuclei membranes (“raisinoid”)) + perinuclear halos

How do cervical cells appear d/t HPV infex?

MOD to SEVERE DYSPLASIA (in Lower 2/3 to FULL LAYER of EPITHELIUM)

-DYSPLASTIC CELLS HAVE HIGH N:C RATIO

-↑risk of progression to malignancy

-↑deregulation of cell cycle, ↓cell maturation -> ↓viral replication

-Most develop from LSIL (20% develop de novo)

Define High Grade Squamous Intraepithelial Lesions/Cervical Intraepithelial Neoplasia 2-3 (HSIL/CIN2-3)

higher

CIN 2 has a (higher/lower) regression rate than CIN 3

Cone biopsy, loop electrosurgical excision procedure (LEEP), cryotherapy

What is the Tx for HSIL/CIN2-3?

Better for fertility

What is a benefit of LEEP/Cone Biopsy?

Preterm Delivery

What is a risk of LEEP/Cone Biopsy?

Cervical Squamous Cell Carcinoma

Define Cervical Condition:

Malignant tumor arising from cervical squamous epithelium

-Hx:

> Usually in Women in 40s-50s

> D/t High Risk HPV Type 16 (60%) or HPV Type 18 (10%)

-Path: 70-80%

> HPV-related = Early sexual activity, multiple partners, Hx of STDs

> Non-HPV related = Immunosuppression, Cigarette smoking, Lower socioeconomic status

-Sx/PE:

> Most Asx

> Postcoital Bleeding

-Dx:

> Gross = Fungating (Exophytic), ulcerated, or infiltrating mass

> Micro = Keratinizing/Nonkeratinizing invasive squamous cells

-Prog: Depends on TUMOR STAGE

> Advanced tumor may invade anterior uterine wall into bladder (blocks uterus) --> Hydronephrosis w/ postrenal failure = Common Cause of Death if Advanced

-Tx/Screen:

> Pap Smear (GOLD Standard for Screen) = brush exfoliates cells at the cervical TZ and are evaluated for cytologic atypia -> detect early/precursor lesions

> HPV DNA on Pap Smear Test

> HPV Vaccines

Endocervical Adenocarcinoma

Define Cervical Condition:

Malignant proliferation of endocervical glands

-Hx:

> D/t High Risk HPV Type 18 (50%)

> Precursor = AIS

-Path: 15-25%

> HPV-related = Early sexual activity, multiple partners, Hx of STDs

> Non-HPV related = Immunosuppression, Cigarette smoking, Lower socioeconomic status

-Sx/PE: Usually Asx

-Dx:

> Gross = Exophytic, ulcerated, flat, barrel cervix

> Micro = Invasive malignant glands

-Prog: Depends on TUMOR STAGE

-Tx/Screen:

> Pap Smear (GOLD Standard for Screen) = brush exfoliates cells at the cervical TZ and are evaluated for cytologic atypia -> detect early/precursor lesions

> HPV DNA on Pap Smear Test

> HPV Vaccines

Vaginal Adenosis

Define Vaginal Condition:

Focal persistence of columnar epithelium; BENIGN/NON-NEOPLASTIC Lesion

-Hx: A/w in utero diethylstilbestrol (DES) exposure)

> Exposed to Hormones

> Trauma

> Inflammation

-Path: During development, squamous epithelium from the lower 1/3 of the vagina (derived from the urogenital sinus) grows UPWARD to replace the columnar epithelium lining of the upper 2/3 of the vagina (derived from the Müllerian ducts)

-Sx/PE:

> MC Found in UPPER VAGINA

> Usually Asx

> Vaginal Discharge

> Postcoital bleeding

> Dyspareunia

-Dx:

> Gross: Vaginal mucosa displays red granular spots or patches

> Histo: cluster of benign glands in vaginal stroma

-Prog: Clear Cell Carcinoma!

Vaginal Clear Cell Adenocarcinoma

Define Vaginal Condition:

Malignant proliferation of glands with clear cytoplasm

-Hx: Rare, complication of DES-associated vaginal adenosis

-Dx: Histo: Tumor cells have distinct cell membranes, are large with moderate to abundant clear cytoplasm

Vaginal Embryonal Rhabdomyosarcoma

Define Vaginal Condition:

Rare, malignant mesenchymal proliferation of immature skeletal muscle

Sarcoma Botyroides

Define Vaginal Condition:

Rhabdomyosarcoma variant

-Hx: Infants or children < 5 y/o

-Dx:

> Gross: Clear, polypoid grape-like mass growing from vagina

> Histo: Tumor consists of small round blue cells and rhabdomyoblasts (pink spindled cells with cytoplasmic cross-striations) and positive immunohistochemical staining for desmin and myogenin (muscle cell markers)

-Prog: May invade peritoneum --> Obstruct bladder

Vaginal Squamous Cell Carcinoma

Define Vaginal Condition:

Malignant tumor arising from squamous epithelium

-Hx: Usually involves high-risk HPV; MC Secondary to extension of cervical SCC

> Usually in Women in 40s-50s

> D/t High Risk HPV Type 16 (60%) or HPV Type 18 (10%)

-Path:

> Primary tumor RARE

> Precursor = Vaginal Intraepithelial Neoplasia (VaIN), LSIL, HSIL

> LN metastasis

>> Inguinal Nodes = cancer from lower 1/3 vagina (from urogenital)

>> Regional Iliac Nodes = cancer from upper 2/3 vagina (from Mullerian ducts)

Bartholin Cyst/Abscess

Define Vulvar Condition:

Inflammation and obstruction of Bartholin gland duct (normally secretes mucus-like fluid draining into lower vestibule to lubricate vagina) -> accumulation of fluid -> cystic dilation of Bartholin gland ==> Infex = ABSCESS

-Hx: Reproductive females

-Sx/PE: Tender/painful bump at a 4- or 8-o’clock position on the vulva

Lichen Sclerosus (LS)

Define Vulvar Condition:

Chronic inflammatory skin disorder that most often affects genital and perianal areas

-Hx: Any age, but MC in Peri/Postmenopausal females

-Path: A/w Other Autoimmune disorders

-Sx/PE: INTENSE PRURITUS

-Dx:

> Gross: white patch (leukoplakia) with parchment-like vulvar skin

> Histo: Epithelial thinning/Atrophic epidermis, dermal fibrosis (aka SCLEROSIS), and a band of chronic inflammation

-Prog: Benign, but slight risk of SCC

Lichen Simplex Chronicus

Define Vulvar Condition:

Chronic, itchy skin disorder

-Hx: (These CAUSE it)

> Chronic Irritation

> Scratching

-Dx:

> Gross: Leukoplakia with thick, leathery vulvar skin

> Histo: squamous hyperplasia of the vulvar epithelium, hyperkeratosis

-Prog: Benign, but NO RISK OF SCC

Condyloma Acuminatum (Genital Warts)

Define Vulvar Condition:

Warty neoplasm of vulvar skin, often large

-Hx/Path: Most commonly due to Low-risk HPV types 6 & 11

-Dx:

> Gross: exophytic lesion, “cauliflower-like”

> Histo: exophytic lesion covered with thickened squamous epithelium and viral cytopathic changes (koilocytic atypia or LSIL)

>> Koilocytes - squamous cells with enlarged, hyperchromatic, wrinkled nuclei with perinuclear halos

-Prog: Low risk of carcinoma

HPV-Related Vulvar Squamous Cell Carcinoma

Define Vulvar Condition:

Carcinoma arising from the vulvar epithelium

-Hx: RARE

> HPV exposure

> Multiple Sexual Partners

> Early Intercourse

> Women of Reproductive age

-Path: Due to high-risk HPV (type 16)

> Arises from HPV-associated vulvar intraepithelial neoplasia (VIN), a dysplastic precursor lesion characterized by koilocytic change, disordered cellular maturation, nuclear atypia, and increased mitotic activity

-Sx/PE: Leukoplakia

-Dx: Biopsy = nests and sheets of pleomorphic squamous cells +/- keratinization

HPV-Independent Vulvar Squamous Cell Carcinoma

Define Vulvar Condition:

Carcinoma arising from the vulvar epithelium

-Hx: RARE

> Elderly Women (> 70)

-Path: Arises, most often, from long-standing lichen sclerosus

> Chronic Inflammation & Irritation --> Carcinoma

> Precursor lesion is differentiated vulvar intraepithelial neoplasia (dVIN) - can be seen adjacent -Sx/PE: Leukoplakia

-Dx: Biopsy = nests and sheets of pleomorphic squamous cells +/- keratinization

Extramammary Paget Disease

Define Vulvar Condition:

Malignant epithelial cells in the epidermis of the vulva

-Path: Represents adenocarcinoma in situ, usually with NO underlying carcinoma

-Sx/PE: Erythematous, pruritic, ulcerated vulvar skin

-Dx:

> Biopsy = Paget cells: enlarged, polygonal epithelial cells with abundant pale cytoplasm, large nuclei; frequently has intracytoplasmic mucin (clusters and single pale vacuolated cells/mucin in the epidermis)

> Markers

>> Paget = PAS+ (mucin), Cytokeratin+ (Epithelial), S-100-

>> Melanoma = PAS-, Keratin-, S-100+