GYNECOLOGY I: Diseases of the Lower Female Genital Tract (Vulva, Vagina, and Uterine Cervix) Di Lu, MD Clinical Professor Department of Pathology & Laboratory Medicine University of California Irvine

Contents of the lecture Diseases involves entire lower female genital tract Pathology of infectious diseases (Part – 1) Pathology of HPV-related pre-malignant and malignant lesions (Part – 2) Diseases unique to each organ of lower female genital tract (Part – 3)

PART – 1 Infections of lower female genital tract

Infections of lower female genital tract: pathogens and morphology Chlamydia: follicular cervicitis. Tuberculosis: caseating granulomas; acid-fast bacilli (AFB) staining. Fungal infection: pseudohyphae and yeast (Candida albican). Trichomonas vaginalis: pear-shaped organism. CMV: large basophilic intranuclear inclusion. Herpes: multinucleation; ground-glass intranuclear inclusion. HPV: koilocytes; koilocytosis. Actinomycosis tangled filamentous organism (IUD)

Morphological diagnosis of infectious pathogens: Chlamydia Follicular Cervicitis Invasive Carcinoma

Morphological diagnosis of infectious pathogens: TB

Morphological diagnosis of infectious pathogens: Candida

Morphological diagnosis of infectious pathogens: Trichomonas

Morphological diagnosis of infectious pathogens: CMV

Morphological diagnosis of infectious pathogens: Herpes

Morphological diagnosis of infectious pathogens: HPV

Morphological diagnosis of infectious pathogens: Actinomycosis

Infections of lower female genital tract: Pelvic Inflammatory Diseases (PID) Infections involving both lower and upper FGT Clinical presentation: pelvic pain, adnexal tenderness, fever, vaginal discharge Pathogens: gonococcus, chlamydia, bacteria, etc. Pathology: Bartholin’s abscess Cervicitis Endometritis Salpingitis Tubo-ovarian abscess Peritonitis

Infections of lower female genital tract: Pelvic Inflammatory Diseases (PID) Complications: Chronic salpingitis: infertility, ectopic pregnancy Peritonitis: intestinal obstruction Torsion of ovary Bacteremia: endocarditis, meningitis, suppruative arthritis Mistaken for ovarian cancer

PART – 2 HPV related pre-malignant and malignant lesions

HPV infection and oncogenesis Requires micro- trauma to infect basal cells of the squamous epithelium HPV replicates along with squamous cell maturation HPV E7 binds to RB to up-regulate cyclin E and promote cell cycle; HPV E6 binds p53 to interrupt death pathway Outcomes following infection: transient, cleared within a year, or persistent infection with integration of its genome into host DNA

HPV Infection and oncogenesis:

Pre-malignancy Terminologies --------------------------------------------------------------------------------------------- WHO/ISGYP Bethesda System Mild dysplasia (CIN/VAIN/VIN-1) Low-grade squamous intraepithelial lesion (Low-SIL) Moderate dysplasia (CIN/VAIN/VIN-2) High-grade squamous intraepithelial lesion (High-SIL) Severe dysplasia (CIN/VAIN/VIN-3) Carcinoma in-situ (CIS) WHO: World Health Organization ISGYP: International Society of Gynecological Pathologists CIN: Cervical Intraepithelial Neoplasia VAIN: Vaginal Intraepithelial Neoplasia VIN: Vulvar Intraepithelial Neoplasia

HPV induced dysplasia Responsible for essentially all cervical, vaginal, and1/3 of vulva dysplasias Histological types, warty (mostly in vulvar) or basal types are typical (vs. differentiated VIN of vulva)

Schematic representation of dysplasias Grade of dysplasia is based on the involvement of squamous epithelium by immature dysplastic cells

Histology of mild, moderate severe dysplasia mild dysplasia moderate dysplasia severe dysplasia/CIS

Invasive squamous cell carcinomas All carcinomas arise from dysplasia; eliminating dysplasia prevents invasive carcinoma Natural history of cervical dysplasia:

Invasive Squamous Carcinoma: Gross Cervical Squamous Carcinoma Three gross pattern: Fungating. Ulcerative. Infiltrative.

Invasive squamous carcinoma: Gross Ulcerative invasive carcinoma

Invasive Squamous Carcinoma: Microscopic Three patterns / grading: Well-differentiated (keratinizing) Moderately-differentiated Poorly differentiated

Staging of Carcinoma of Uterine Cervix Clinical Extent 5-Year Survival Stage 0 Carcinoma in situ 100% Stage I Carcinoma is confined 80-90% to the cervix Stage II Carcinoma extends 75% beyond cervix, but not to pelvic wall Stage III Carcinoma extends to 35% pelvic wall Stage IV Carcinoma extends 10-15% beyond the pelvis

Stage T1a (1a1 and 1a2): Recurrence

Stage 1a (1a1 and 1a2): nodal metastasis

Pre-malignant lesions of Cervical Adenocarcinoma Atypical Glandular Lesion Glandular Dysplasia Adenocarcinoma in-situ - Nuclear stratification - Nuclear atypia - Mitosis Normal Endocervix

Invasive Cervical Adenocarcinoma Infiltrating irregular malignant glands

PART – 3 Lesions unique to each part of lower female genital tract

Vulva Lesions

Bartholin gland lesions Bartholin Cyst: Cysts formed as a result of obstruction of the duct following acute infection or abscess formation Bartholin gland carcinoma: usually HPV associated squamous cell carcinoma (Bartholin ducts are lined by squamous epithelium; adenocarcinoma and other tumor occur as well.

Lichen sclerosus Autoimmune reaction; T-cell related Chronic dermal inflammation resulting epithelial atrophy and subepithelial sclerosis Atrophic skin resembles cigarette paper (crinkly atrophy)

Squamous hyperplasia Chronic mechanical irritation Acanthosis, hyperkeratosis and elongation of rete ridges

Differentiated VIN and invasive keratinizing squamous carcinoma Lichen sclerosus, squamous cell hyperplasia give rise to differentiated VIN, and further the keratinizing squamous cell carcinoma Older patient; in contrast to HPV related lesions (70 vs. 40 years old)

“Ectopic” breast lesions Papillary hidradenoma (intraductal papilloma of breast) Mammary carcinoma Extra-mammary Paget disease: large pale, with finely granular amphophilic to basophilic cytoplasm and round to oval nuclei

Vaginal Lesions

Cysts Epidermal (squamous) inclusion cyst Gardner’s duct (mesonephric) cyst: Wolffian duct remnants in anteriolateral wall: lined by non-mucin secreting cuboidal or low-columnar epithelium

Adenosis A rarity: columnar epithelium present in vaginal mucosa 30% to 90% of offsprings having history of diethylstilbestrol (DES) exposure in utero Adenocarcinoma rarely arises from adenosis (vast majority if adenocarcinoma identified in vagina are metastatic)

Embryonal rhabdomyosarcoma Grape-like lesion Infants and children Small blue cell tumor

Cervical Lesions

Endocervical polyp 2% to 5% of adult women Cause spotting or bleeding

Quiz A 32-year-old woman has been on oral contraceptives for many years. She has noted vaginal discharge and bleeding for the past 5 weeks. Now, sexual intercourse has become painful. In her history, the patient was diagnosed with severe cervical dysplasia and treated by cervical LEEP a year ago. During examination, you find the cervix is friable. A biopsy is taken and shown in the image. The patient: has developed recurrence of severe dysplasia. has developed invasive squamous cell carcinoma. has herpes infection. has non-specific cervicitis. should receive antibiotic (azithromycin or erythromycin) treatment.

CORRECT ANSWER: E Follicular cervicitis: Chlamydia infection

Quiz A 32-year-old female patient of yours has had continued ASCUS (atypical squamous cell of unknown significance) diagnosis on Pap smears. Each Pap smear had reflex HPV testing and were all positive. Cervical biopsies were performed. Pathology report is negative for dysplasia. Which of the following statements is correct? A. The patient does not have dysplasia as the biopsy proves. B. The pathologist made misdiagnosis on the biopsy. C. Since HPV testing is positive, the patient must have dysplasia. D. Repeated ASCUS by Pap smear is equivalent to a dysplasia diagnosis. E. Continued HPV positivity is worrisome for a high-grade dysplasia.

CORRECT ANSWER: E Persistent HPV infection indicates progression of neoplasia

Quiz A 32-year-old female patient of yours, who has not had primary care for many years, comes to your clinic complaining of vaginal discharge tinged with blood. Recently she has avoided sexual intercourse because it became painful. During examination, you find an ulcerated lesion on the posterior cervix, which bleeds on contact. A Pap smear is performed and HPV testing is requested. The cytology report states: Poorly differentiated carcinoma. HPV testing however is negative. Which of the following statements is correct? A. The patient’s carcinoma is not related to HPV infection. B. The HPV test is falsely negative. C. The carcinoma is not cervical in origin (e.g., metastasis). D. HPV is only involved in dysplasia, not carcinoma. E. Poorly differentiated carcinoma commonly loses HPV replication.

CORRECT ANSWER: E HPV replication requires squamous cell maturation. Poorly differentiated carcinoma loses ability of maturation, as well as HPV replication. Tumor cell genome however contains integrated HPV genes, which can be detected by isolating tumor cell DNA and HPV PCR test.

Additional learning: HPV vaccine Two vaccines are available: Cervarix, Gardasil Cervarix – bivalent (HPV types 16, 18) Gardasil – quadrivalent (HPV types 6, 11, 16, 18) Both vaccines are very effective against diseases caused by HPV 16/18 Both vaccines have been shown to prevent cervical precancers in women Only Gardasil has been tested and licensed to use in male Both vaccines are given as shots and requires 3 doses Both vaccines are safe and effective through 9 to 26 years of age HPV vaccines will not treat or get rid of existing HPV infections and medical problems (wart precancer, or cancer) caused by HPV infections occurred before vaccines CDC recommendations: - All 11 and 12 year old girls and boys - Women 13-26 yo who did not get vaccine before - Men 13-21 yo who did not get vaccine before

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