Diagnosis and treatment options for CINs and CCa.

1. Cervical precancerous lesions and
Cervical cancer
Tevfik Yoldemir MD BSc MA PhD
tevfikyoldemir
profdrdrtevfikyoldemir

2. EPIDEMIOLOGY – RISK FACTORS
• Multipl sexual partners
• Early onset of sexual activity
• High-risk sexual partner
*Hx of multipl sexual partners
* Hx of HPV infection
* Hx of lower genital tract neoplasia
* Prior sexual exposure to someone with cervical neoplasia
• Hx of sexually-transmitted disease (STD)
• Cigarette smoking
• Immunodeficiency
• Multiparity
• Long-term oral contraceptive pill use

3. ETIOLOGY
• Human Papillomaviruses (HPVs) are a prime etiologic
factor
• Presence of HPV in CIN > 80%
• Presence of HPV in ICC > 90%
• Newborns in the US  1%
• Teenagers  20%
• 20-29 years of age  40%
• Age 50 or older  5%
* Condoms are not protective 
Labial-scrotal contact!

4. HPV SUBTYPES
• Low-risk HPV types  6,11,42,43,44
( Condylomata & Low-grade lesions- CIN I)
• Intermediate-risk HPV types 
33,35,51,52 ( Higher-grade
lesions- CIN II, CIN-III)
• High-risk HPV types  16,18,31,39,45,56,58,59,68
( High-grade lesions- CIN II, CIN III & Invasive Cancer)

5. ETIOLOGY- CIGARETTE SMOKING
• Cigarette smoking & HPV infection have synergistic
effects
• Cigarette smoking increases the risk  2-4 X
• Cigarette smoke carcinogens have been found to
accumulate locally in the cervical mucus
• The cumulative exposure as measured by pack-years
is related to the risk of developing CIN & CIS
• The mechanism is poorly understood

6. ETIOLOGY- IMMUNOSUPPRESSION
• The incidence in HIV-infected women 
20-30%
• With increasing immunosuppression
* Risk of de novo infection 
* Risk of persistent HPV infection 
* Progressive cervical neoplasia 
• Since 1993, invasive cervical cancer has been included
as an AIDS-defining illness

7. PATHOLOGY
Dysplastic cell- cytologic examination
• Anaplasia
• Increased nuclear:cytoplasmic ratio
• Hyperchromatism
• Changes in the nuclear chromatin
• Multinucleation
• Abnormalities in differentiation

8. SPECIAL EXAMINATIONS
• Visual inspection of the
cervix
• Repeat cytology
• HPV testing
• Staining with Lugol’s
solution (Schiller test)
• Toluidin blue test
• Colposcopy
• Directed biopsy
• Endocervical curettage
• Diagnostic conization

9. REPEAT CERVICAL CYTOLOGY
• The patient should be evaluated prior to repeat smear
• Treated for underlying conditions
* Antimicrobials for infection
* Hormones for atrophic vaginitis
• Smear should be repeated every 4-6 months until three to four
consecutive normal smears
• The false-negative rate of a single repeat smear is as high as
33% for biopsy-proven high-grade squamous intraepithelial
lesions ( CIN II/III)
• Second abnormal smear should be evaluated by colposcopy

10. SCHILLER TEST
• Normal mature epithelium of the cervix contains glycogen
• The combination with iodine produces a deep mahogany-
brown color
• Lugol’s solution is an aqueous iodine preparation
• Nonstaining ( Positive Schiller Test )
* Abnormal squamous (or columnar ) epithelium
* Scarring
* Cyst formation
* Immature metaplastic epithelium

11. SCHILLER TEST
• Normal mature epithelium of the cervix contains glycogen
• The combination with iodine produces a deep mahogany-
brown color
• Lugol’s solution is an aqueous iodine preparation
• Nonstaining ( Positive Schiller Test )
* Abnormal squamous (or columnar ) epithelium
* Scarring
* Cyst formation
* Immature metaplastic epithelium

12. COLPOSCOPY INDICATIONS
• Abnormal cervical cytology smear or HPV testing
• Clinically abnormal or suspicious-looking cervix
• Unexplained intermenstrual or postcoital bleeding
• Vulvar or vaginal neoplasia
• Hx of in utero DES exposure

13. COLPOSCOPY INDICATIONS
• Abnormal cervical cytology smear or HPV testing
• Clinically abnormal or suspicious-looking cervix
• Unexplained intermenstrual or postcoital bleeding
• Vulvar or vaginal neoplasia
• Hx of in utero DES exposure

14. ABNORMAL COLPOSCOPIC FINDINGS
• Leukoplakia or hyperkeratosis- an area of white, thickened
epithelium prior to the application of acetic acid and may
indicate underlying neoplasia
• Acetowhite epithelium- epithelium that stains after the
application of acetic acid
• Mosaicism or punctation- reflects abnormal vascular patterns
of surface capillaries
• Atypical vessels- bizarre capillaries with so- called corkscrew,
comma shaped, or spagetti-like configurations suggest early
stromal invasion

15. COLPOSCOPICALLYDIRECTED
BIOPSY

16. ENDOCERVICAL CANAL CURETTAGE
• Unsatisfactory colposcopy
• Lesions extended into the endocervical canal
• Cervical cytology inexplained by colposcopic impression

17. DIAGNOSTIC CONE BIOPSY
• Unsatisfactory colposcopy
• A high-grade cervical cytology smear
• Lesion extended into the cervical canal
• Significant discrepancy between the histologic
diagnosis of the directed biopsy specimen and the
cytologic examination
• Suspicion of adenocarcinoma in situ
• Suspicion of microinvasive carcinoma

19. NATURAL HISTORY
CIN I CINII CIN III
Regression to normal 60% 40% 30%
Persistence 30% 35% 48%
Progression to CIN III 10% 20% ---
Progression to cancer <1% 5% 22%

21. Smear Report

22. Cervical Cancer Screening

23. • The etiologic agent resulting in cervical cancer has been identified as
a sexually transmitted oncogenic virus, human papillomavirus (HPV).
• HPV is a circular, double-stranded DNA virus when in its’ infectious
state.
• Viral DNA integration into host DNA leads to a malignant phenotype.
Once integrated, HPV E6 codes for a protein that degrades p53 and
HPV E7 codes for a protein that complexes with pRB releasing
transcription factor E2F causing the cell to be immortal.
• Low risk strains of HPV (types 6 and 11) cause genital warts whereas
high risk strains (types 16, 18, 31, 45, and less commonly 33, 35, 39,
51, 54, 55, 56, 58, 59 66, and 68), if integrated into host DNA, cause
cervical dysplasia and cervical carcinoma.

24. • HPV is detectable in over 95 % of squamous cell carcinomas
and 30–40 % of adenocarcinomas.
• High-risk strains cause a mutation of cells in the
squamocolumnar junction leading to cervical dysplasia and
cancer.
• Incidence of progression without treatment:
– CIN1 (16 %), CIN2 (30 %), CIN3 (70 %).
– CIN3 → invasive disease: 0–20 years.

25. Dysplasia of cervical mucosa

26. • Risk factors:
– Lower socioeconomic status.
– Multiple sexual partners, early age of first intercourse,
promiscuous partners, co-infection with other sexually
transmitted diseases.
– Tobacco use.
– Immunocompromised conditions (HIV or pharmacologic).

27. HPV vaccines
Vaccine efficacy for preventing anogenital warts as well
as dysplasia or invasive disease associated with HPV
types 16 or 18 was 100 %.
Vaccine efficacy against HPV-16 and -18
CIN II–IIII was 92.9 %.
Efficacy against infection related to HPV-6, -11, -16, and -18
was 90.5 %.

28. • Abnormal pap smears may require further workup with colposcopy with
possible need for biopsy.
• Colposcopy involves use of 5 % acetic acid applied to the cervix and
inspection with a colposcope that magnifies the cervix and allows for
visualization with color filters.
– A satisfactory colposcopy requires that the entire squamocolumnar junction
(SCJ) be visualized.
– Concerning findings for which biopsy should be obtained:
○ Acetowhite changes.
○ Irregular contour.
○ Atypical vessels.
○ Coarse mosaicism or punctation.
○ Large multiquadrant lesions.
– An endocervical curettage (ECC) should be done as long as the patient is not
pregnant.
– Cervical dysplasia or early invasive cervical cancer (Stage IA1) can be treated
with loop electrosurgical excision procedure (LEEP) or cold knife cone (CKC).

29. ASCCP guidelines ( w ww.asccp.org ) used to
triage abnormal cytology and histology

30. ASCCP guidelines ( w ww.asccp.org ) used to
triage abnormal cytology and histology

31. ASCCP guidelines ( w ww.asccp.org ) used to
triage abnormal cytology and histology

32. ASCCP guidelines ( w ww.asccp.org ) used to
triage abnormal cytology and histology

33. Age at diagnosis

34. Estimated new gynecologic cancer cases and
deaths in the United States in 2008

35. Stage at presentation

36. Age at death

37. Average 5-year survival by stage

38. Expected cancers in the United States in 2008

39. Current cancer screening recommendations
for asymptomatic women

40. Common presenting syptoms of cervical
cancer

42. Four main routes of spread of cervical
carcinoma
– Direct spread into the vaginal mucosa.
– Spread into the myometrium, particularly with lesions
originating in the endocervix.
– Spread into the paracervical and parametrial lymphatics and
then further (primarily: obturator, hypogastric, external iliac, and
sacral nodes and secondarily: common iliac, inguinal, and para-
aortic nodes).
– Direct extension into adjacent structures (parametria, bladder,
bowel).

44. Staging
• Cervical cancer is clinically staged:
• Exam.
• Cold knife cone (CKC) or loop electrosurgical excision (LEEP).
• Imaging—CXR, IVP, CT urogram, Barium enema.
• Cystoscopy.
• Proctosigmoidoscopy