1. 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

2. 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)

3. PART – 1 Infections of lower female genital tract

4. 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)

5. Morphological diagnosis of infectious pathogens: Chlamydia
Follicular Cervicitis
Invasive Carcinoma

6. Morphological diagnosis of infectious pathogens: TB

7. Morphological diagnosis of infectious pathogens: Candida

8. Morphological diagnosis of infectious pathogens: Trichomonas

9. Morphological diagnosis of infectious pathogens: CMV

10. Morphological diagnosis of infectious pathogens: Herpes

11. Morphological diagnosis of infectious pathogens: HPV

12. Morphological diagnosis of infectious pathogens: Actinomycosis

13. 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

14. 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

15. PART – 2 HPV related pre-malignant and malignant lesions

16. 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

17. HPV Infection and oncogenesis:

18. 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

19. 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)

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

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

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

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

24. Invasive squamous carcinoma: Gross
Ulcerative invasive carcinoma

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

26. Staging of Carcinoma of Uterine Cervix
Clinical Extent 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 %
beyond the pelvis

27. Stage T1a (1a1 and 1a2): Recurrence

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

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

30. Invasive Cervical Adenocarcinoma
Infiltrating irregular malignant glands

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

32. Vulva Lesions

33. 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.

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

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

36. 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)

37. “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

38. Vaginal Lesions

39. 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

40. 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)

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

42. Cervical Lesions

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

44. 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.

45. CORRECT ANSWER: E
Follicular cervicitis: Chlamydia infection

46. 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.

47. CORRECT ANSWER: E
Persistent HPV infection indicates progression of neoplasia

48. 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.

49. 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.

50. 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 yo who did not get vaccine before
- Men yo who did not get vaccine before

51. THANK YOU