This document outlines a plan for discussing cervical intraepithelial neoplasia (CIN) and cervical cancer screening. It covers the incidence, pathogenesis and prevention of CIN, describing how persistent high-risk HPV infection can lead to precancerous lesions and cancer. It then discusses cervical screening guidelines, procedures for Pap tests and HPV tests, and approaches for diagnosing and treating abnormal screening results, including excision or ablation depending on factors like lesion size and margins. Follow-up testing and surveillance is recommended based on screening and treatment outcomes.

1. CIN & Cervical Screening

2. Plan
• Part 1: Incidence, pathogenesis, and
prevention
• Part 2: Cervical Screening
• Part 3: Grading, treatment, and Follow up

3. Part 1: Incidence, pathogenesis,
and prevention

4. Introduction
• Premalignant condition of uterine cervix
• Ectocervix is covered by squamous epitheiam
• Endocervix including cervical canal covered by
glandular epithelium
– CIN refers to squamous abnormality
• Adenocarcinoma in situ, and adenocarcinoma
• CIN can be low grade or high grade.
– Women with low grade CIN have minimal
potential for developing cervical malignancy

5. Incidence
• 4 % in US for CIN 1, 5% for CIN2, 3
• High grade lesion are typically diagnosed in
women 25-35 years old
• Invasive cancer is commonly after age of 40
– Typically 8-13 years afer a diagnosis of a high
grade lesion

6. Premalignant disease of the cervix
HPV
infection
CIN I
CIN II
CIN III
Cervical
cancer
Normal cervix

7. Pathogenesis
• Role of human papillomavirus (HPV)
– Major etiologic agent
– Strong association
– Necessary for development of neoplasia
– Not sufficient alone to cause such disorders cause
many HPV infected women do not develop it
– HPV subtype, and persistence of virus
• Enviromental (eg, cigarette smoking)
• Immunlogic influences

8. HPV Subtype
• Over 100 subtype
– 40 types specific for anogenital epithelium
– Distribution varies by geographic region
– Infection with more than one subtype is common
– Acquisition of one subtype and clearance of
another are independent events
• Subtype determines manifestation of infection
and oncogenic potential of virus

9. Oncogenic HPV

10. Low Risk & High Risk Subtypes
• Low risk – e.g., HPV 6 and 11
– do not integrate into host genome
– Only cause CIN 1 (10%)
– benign condylomatous genital warts (90%)
• High risk – e.g., HPV 16 and 18
– Associated with CIN 2, 3, persistence, and invasive
cancer, can also cause low grade
– Low grade (25%), high grade (50-60%)Cancer(70%)

11. Persistence
• HPV is transient and occur in young women
– Persistency is a key factor for development of high
grade
– Unknown why it persists
– The likelihood of persistence
• Older age - > 55 years of age (50%)
• Duration of infection – long infection = long clearance
• High oncogenic HPV subtype – the longer it persists

12. Sexual transmission
• HPV transmitted sexually
• Endemic amongst sexually experienced
individuals
• At least 75-85% of sexually active women will
have acquired genital HPV by age 50

13. Cervical Transformation Zone
• Transformation Zone vs SCJ
– SCJ – where the squamous epithelium meets the
cervical of ectocervix meets columnar epithelium of
endocervix.
– Transformation zone is dynamic entity of metaplasia
throughout a women’s life, which is the area of
glandular epithelium has been replaced by squamous
epithelium
– Transformation zone comprises SCJ + larger area
• Primary site of carcinogenic HPV-related CIN& CN
– Cuboidal cells at Squamouscolumnar Junction

15. Molecular Mechanism
• Epitheliotropic, once epithelium is infected, the virus
can either persist in cytoplasm or integrate into the
host genome
– Remains episomal nonintegrated state
• Low-grade cervical lesion
– Becomes integrate into human genome
• High grade lesion and cancer may develop
• Integration into host cell – disruptions of viral
regulatory oncoproteins, where E6 binds to p53, and
E7 binds to Retinoblastoma, and suppress their
function, the latter activates IL5&IL6 which are
important in progression of CN 2,3 to over malignancy..

16. Co-factor in Pathogenesis
• Immunosupression – cervical cancer is one of
AIDS related malignancy in women
• Cigarette smoking – with HPV have synergistic
effects on development of CIN and CN
– Breakdown products of nicotine cotinine and NNK are
concentrated in cervical mucus and cause cellular
abnormalities
• HSV and Chlamydia – surrogate marker for
exposure of HPV rather than a causal factor
• OCP – long term use, as a surrogate marker

17. Prevention
• Primary – HPV vaccination
• Secondary – for cervical cancer rather than
CIN, through appropriate treatment and
prevent progression to malignant disease

18. Part 2
Cervical Screening

19. Cervical screening
• Prevention of cervical cancer
• Early detection by:
– Pap smear
– HPV test

20. Pap Smear
• George Papanicolaou (1883-1962)
• The Pap test aims to identify abnormal cells
sampled from the transformation zone, the
junction of the ecto- and endocervix, where
cervical dysplasia and cancers arise.

21. Guidelines
• ACOG
• Start at 21 years
• 21-29: Pap smear every 3 years
• 30-65: Pap smear every 3 years OR HPV co-test
every 5 years
• Stop at 65 years
• Annual screening not recommended

22. How to prepare?
• Before the pap test, patient should avoid:
– Having intercourse
– Using tampon
– Douching
• Preferably not during menstruation

23. Speculum
• Insert lubricated speculum

24. Methods Of Interpretation
• For conventional Pap smears, cervical samples
obtained by brush and spatula are plated on a
microscope slide and preserved with fixative.
• Thin layer (or liquid-based) cytology, an
alternative to conventional cytologic sampling,
has been widely implemented in the US.
– Testing involves transferring samples from the brush
and spatula into a liquid fixative solution; the cytology
lab subsequently traps the loose cells onto a filter
from which they are plated in a monolayer onto a
glass slide

25. Spatula
• Insert spatula and rotate
• Smear on a slide

26. Cytobrush
• Insert brush and rotate
• Smear on slide

27. Fixation
• Alcohol

29. Liquid Media

31. Bethesda
• Specimen type (conventional, liquid-based, etc)
• Specimen adequacy
– Satisfactory for evaluation (note presence/absence of
endocervical/transformation zone component)
– Unsatisfactory for evaluation (specify reason)
• Specimen rejected/not processed (specify reason)
• Specimen processed and examined, but unsatisfactory
for evaluation of epithelial abnormality because of
(specify reason)

32. Bethesda
• General Categorization (Optional)
– Negative for intraepithelial lesion or malignancy
– Epithelial cell abnormality
– Other
• Interpretation/result
– Negative for intraepithelial lesion or malignancy
• Organisms (e.g. trichomonasvaginalis)
• Reactive cellular changes associated with inflammation,
radiation, intrauterine contraceptive device
• Atrophy

33. Bethesda
• Epithelial cell abnormalities
– Squamous
• Atypical squamous cells
– ASC-US (undetermined significance)
– ASC-H (cannot exclude HSIL)
• Low grade squamous intraepithelial lesion (LSIL) - mild
dysplasia/CIN I
• High grade squamous intraepithelial lesion (HSIL) –
moderate and severe dysplasia/CIN II/III
• Squamous cell carcinoma

34. Bethesda
• Epithelial cell abnormalities
– Glandular
• Atypical
– Endocervical
– Endometrial
– NOS
• Atypical favor neoplastic
– Endocervical
– NOS
• Endocervical adenocarcinoma in situ (AIS)
• Adenocarcinoma

36. Part 3
Classification and Treatment

37. CIN Classification
• Low-grade squamous intraepithelial lesion
(LSIL)
– CIN I (Mild dysplasia) 50%, 30%, 20%, 1-5%
• High-grade squamous intraepithelial lesion
(HSIL
– CIN II (Moderate dysplasia)
– CIN III (Severe dysplasia) 33%, 60-74%

38. CIN Classification

39. Diagnosis:
• Pap tests
• Colposcopy
• Endocervical curettage
• Cone biopsy or loop electrosurgical excision
procedure (LEEP) which are performed to rule
out invasive cancer

41. Adequacy of Colposcopy
• Must evaluate the entirety of the lesion
• Must evaluate the entirety of the SCJ
Failure of either criteria is an inadequate
colposcopy and leads to changes

42. TREATMENT
• Mainstays of treatment of high-grade cervical
intraepithelial neoplasia (CIN) are excision or
ablation
• Excisional treatments are:
– referred to as cone biopsies or cervical conization
• Ablative treatments
– use an energy source (eg, cryotherapy, laser) to
destroy the transformation zone

43. Laser
TREATMENT

44. What to choose
• Factors affect:
– Efficacy: the efficacy rate for both ablation and excision is
approximately 90 to 95 percent
– Diagnostic specimen: no specimen is removed in ablative. For
this reason, an excisional procedure is required for diagnostic
purposes in the following situations:
• High risk of invasive disease
• Glandular disease is present
• Diagnostic uncertainty
– Future obstetric risks — Excision has been associated with an
increased risk of adverse obstetric outcomes
– Morbidity — Excisional methods are typically thought to be
associated with greater morbidity than ablative therapy.
However, the meta-analysis of randomized trials found no
significant difference in adverse effects

45. What to choose?
• For women with CIN 2,3 and an adequate
colposcopy, either an excisional treatment or
an ablative treatment is appropriate.
• For women with an inadequate colposcopy,
recurrent CIN 2,3, an excisional procedure is
preferred

46. What to choose?
• For young women with CIN 2,3 and an
adequate colposcopy, either observation or
treatment is acceptable. If treatment is
performed, either excision or ablation may be
used.

47. What to choose?
• Women with CIN 1 — Most women with CIN 1
are managed with follow-up testing, and
treatment is only indicated if CIN 1 persists for
longer than two years.

48. Hysterectomy for:
1. CIN 2,3 with a positive conization margin
2. who have completed childbearing
3. who would benefit from a definitive
procedure
4. women who are not willing or able to comply
with long-term follow-up

49. Outcome:
• The rate of recurrent or persistent CIN is 5 to 17 percent
despite therapy with any of the excisional or ablative
techniques
• Higher rates of persistent disease are associated with:
– Large lesion size (eg, greater than two thirds of the surface of the
cervix)
– Endocervical gland involvement
– Positive margin status
– Continuing human papillomavirus (HPV) DNA positivity (especially
with HPV 16) six months or more post-treatment
• The prognosis after treatment of CIN differs based upon the
presence of CIN at the margin of a conization specime

50. FOLLOW-UP AFTER TREATMENT:
• After treatment with excision or ablation, women with
CIN 2,3 should be followed with:
– Human papillomavirus (HPV)/cervical cytology co-testing in
12 and 24 months.
• If both co-tests are negative, co-testing should be repeated in
three years.
• If there is abnormal cytology or a positive HPV test during follow-up,
colposcopy with endocervical sampling should be performed.
• If CIN 2,3 is identified at the margins of an excisional
procedure or post-procedure endocervical curettage
(ECC), cytology and ECC at four to six months is
preferred.