1. Preinvasive Cervical Neoplasia
Meral Aban MD.
Professor of OBS&GYN

2. Cervical Intraepithelial Neoplasia (CIN)
CIN I: Mild dysplasia
CIN II: Moderate dysplasia
CIN III:Severe dysplasia - CIS
Precursor lesions for cervical cancer

3. Dysplasia Lack of normal maturation of cell
They move from basal layer to superficial layer
*Large nuclei more variable in size &shape
*more actively dividing nuclei.
Dysplasia are now referred to as cervical intraepithelial neoplasia ( CIN)

4. Cervical Intraepithelial Neoplasia
CIN1
CIN2
CIN3
İnvaziv Canser

5. of cervical cancer cases
Etiology
HPV DNA is (+) in
99.7 %
of cervical cancer cases

6. Human Papilloma Virus Family: Papillomaviridae
Genus: Papillomavirus
Morphology:
Naked, icasohedral
55nm
72 capsomer
2 capsid protein, 1 major protein (L1) and 1 minor protein (L2)
Circular, dsDNA, 8Kb
Episomal able to integrate to host genome

7. HPV HPV Types 16-18 high cancer risk
HPV Types is responsible of % of cancer cases
Low risk :6,11
Moderate risk :33, 35, 39, 40, 43, 45, 51-56, 58
High risk: 16, 18, 31

9. The HPV Life Cycle
JA Kahn, NEJM, 2009;361:271

10. HPV-carcinogenesis HPV DNA integration E6 and E7 oncogene activation
They make complexes with tm supressor genes P53-pRB
Inactivation
CIN I-II-III
Cancer

11. HPV ve Onkogenez Malignite E6 Oncoprotein E7 Onkoprotein
p53 inhibistion
pRb – E7 komplex
Repair of Demaged
DNA
Transcription
Aktivation in cell
Increase of
Cell proliferation
Block repair
of DNA
Block of Apoptozis
Mutant cell
Malignite
Moodley M, Int J Gynecol Cancer 2003;13:103-10

12. HPV Related Disease Genital warts CINCervical Cancer
VIN  Vulvar Cancer
VaIN  Vaginal Cancer
AIN  Anal Cancer
PIN  Penile Cancer
Recurrent Laryngeal Papillomatosis
Head&Neck Cancers
1. Walboomers JM et al. J Pathol. 1999
2. WHO 1999
3. Herrero R et al. J Natl Cancer Inst. 2003;95:1772–1783.

13. Cervix Epithelium Exocervix – stratified squamous epithelium
Endocervix – cylindrical epithelium,
Squamocolumnar junction connect Exocervix with endocervix epithelium

14. Origine of CIN
80-85 % Transformation zone
15-20 % Ectocervical region

16. Transformation zone Most active zone of squamous metaplasia
Prone to carcinogenic effects

20. Most active zone of squamous metaplasia

21. Precursor lesions for cervical cancer

23. Natural history of HPV infection to Cervical cancer
0–1yrs
0–5yrs
1–20yrs
High Grade
Precancers (CIN 2/3)
HPV infection
Persistent
infection
Cervical Cancer
Low Grade
Precancers (CIN 1)
Recovery: HPV clearance…90%
Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43:352–362.

24. Natural History of Preinvazive Disease
About 15% of low- grade dysplasias will progress within 2 years
About 1/3 of high- grade dysplasias will progress within 10 years if not treated.
High- grade dysplasia is detected up to 10 years before invazive carcinoma develops.
Low- grade dysplasia and genital warts have a pick incidence in the 20s
High-grade dysplasia peks in the mid- 30s
Invaziv cervical carcinoma is most often sees after age 40.

25. Diagnosis
Cytology ( pap smear)
Colposcopy
Biopsy

26. History of the Conventional Pap Smear
Developed by Dr. George N. Papanicolaou in 1940’s
Most common cancer screening test
Key part of annual gynecologic examination
Primary cervical cancer screening essentially began with the introduction of the Pap Smear.
Introduced in the 1940’s, by Dr. George N. Papanicolaou, the pap smear eventually became the standard screening test for cervical cancer and pre-malignant lesions.
The Pap test is based on a relatively simple principle. Cells from squamous epithelium exfoliate over time. Thus, the cells removed for cytologic examination represent epithelial cells, normal or abnormal, found at the surface.
Widespread use of the pap smear has decreased cervical cancer deaths by 70%.
Reference: Ferris et al. Modern Colposcopy. 2004: 2-4, 49.
Ferris et al. Modern Colposcopy. 2004: 2-4, 49.
Photo accessed from

27. Cell collection enstrumants for Paptest
Cytobruch, dacron swab, broom instruments, sponges and tampon.
Rotate 360 degrees
Don’t use too much force (bleeding, pain)
Don’t use too little force (inadequate sample)

28. Convantional
Liquıd base

29. Bethesda (2001) reporting of Pap Smear
Specimen type – conventional or Liquıd base
Specimen adequacy – satisfactory, unsatisfactory
General Categorisation: Negative for intra-epithelial lesion
Epithelial cell abnormality, Glandular cell abnormality

31. Abnormal Cytology Squamous Abnormalities ASC-US ASC-H
LSIL HPV effect, CIN I
HSIL CIN II, CIN III
Invasive cancer

32. Bethesda System Squamous Cell Atipical squamous cells:
Undetermined significance (ASC-US)
Can not exclude High Grade (ASC-H)
HPV- LSIL
LSIL(CIN I, Mild Dysplasia)
HSIL(CIN2 Moderate Dysplasia, CIN3 Severe Dysplasia)
CIS
Squamous Cell Carcinoma
Glandular Cells
Atypical Glandular Cells (AGC)
AGC - Favor Neoplasia
ACI
Adenocarcinoma

33. Colposcope illuminates the cervix for biopsy
COLPOSCOPY
Colposcope illuminates the cervix for biopsy

36. Colposcopy Stereoscopic binocular microscope X 8 – X 12 - X 20
For vascular pattern; green filter is used

37. Colposcopy Direct vision Acetic acid, 3-5%
Acetowhite epithelium: acetic acid coagulates protein of the nucleus and cytoplasm; make protein opaque and white
Lugol test

38. Abnormal colposcopic findings
Keratosis
Aceto-white epithelium
Punctation CIN
Mosaic pattern
Atypic vasculature İNV. CA
Biopsy from suspicious areas must be done

40. Guidelines for colposcopy
ASC-H, LSIL, HSIL – colposcopy and biopsy
AGC – colposcopy, endocervical and endometrial evaluation
AIS – excision biopsy

41. Lugol ( 1 %) Schiller Test
During colposcopic assessment,
Beneficial during conization !
Colposcopic lesion must match with Lugol (-) area

42. Natural History of CIN

43. ASC HPV DNA test or repeat smear 6 months later
If HPV DNA (+) directly colpocopy or Repeat smear after 6 month
If second smear is again ASC: Colposcopy

44. ASC-H LSIL HSIL ASC that high grade lesions cannot be ruled out
Directly colposcopy+ECC
LSIL
Colposcopy or smear after 6 months
Second time LGSIL: Colposcopy+ ECC + Biopsy +
HPV DNA
HSIL
Colposcopy
Colposcopic biopsy
Endo Cervical Curretage(ECC)

45. AGC
< age 35 Colposcopy + ECC
> age 35, Colposcopy+ECC+D&C

46. Treatment after Histopathologic Diagnosis
CIN 1
Pap smear: HSIL, AGC-NOS
CIN 1
Pap Smear: ASCUS, LSIL
Yearly HPV test or pap 6-12 months
HPV 2 yr persistance: Observation or treatment( ablative or excisional)
Unsatisfactory colposcopy or ECC (+) diagnostic excision
LEEP excision or colposcopy after 6 months
If colposcopy unsatisfactory LEEP
CIN 1 in Adolescant and pregnant
Follow-up

47. Treatment after Histopathologic Diagnosis
CIN 2-3
Ablative or excisional therapy
(Folow-up annual for 5 year, overall 20 years)
Adolescant CIN 2-3: follow-up

48. LEEP and Conization

49. Treatment of CIN Destructive Cryotherapy Excisional
Electrocautery
LaserVaporisation
Excisional
-Cold knife conization
-LEEP
-Laser cone
FOR ABLATIF TREATMENT
Smear-colposcopy-Bx-ECC
Lesion should be completely visualized
SCJ complete destruction
No glandular lesion

50. Efficiency & Cochrane Review
Kriyoterapi %77-93
Laser ablasyon %94-95
LEEP %91-98
Laser konizasyon %93-96
Soğuk konizasyon %90-97

51. Management of Abnormal Cytology
Therefore, in 2012 the American Society for Colposcopy and Cervical Pathology (ASCCP), together with its 24 partner professional societies, Federal agencies, and international organizations, began the process of revising the 2006 management guidelines.

52. HPV(+)

53. ASC-US

54. ASC-US and LSIL: Age 21-24

55. LSIL

56. Pregnant Women& LSIL

57. ASC-H

60. Atypical Glandular Cell(AGC)