1. CIN and mimics Dr Michael Coutts Consultant Gynaecological Pathologist
West Kent Gynae Oncology Centre, Maidstone, UK
and Centre Hospitalier Universitaire, Nice, France

2. Cervical intraepithelial neoplasia (CIN)
Abnormal proliferation, nuclear atypia and lack of maturation of squamous cells within the epithelium

3. Natural history of CIN Conflicting data from various studies, however:
90% of CIN 1 regresses in 2 years
50% of CIN 2 regresses in 2 years
Approx 10% of CIN 1 and 20% of CIN 2 will progress to CIN 3
Approx 30% of CIN 3 will regress but roughly 20% will progress to invasive squamous ca
Mean time for progression from CIN to invasive cancer approx 10 – 20 years

4. Human papillomavirus (HPV)
Present in 99.7% of cervical cancer
A causative agent for virtually all cervical cancer (and CIN and CGIN/ACIS)
55nm non-enveloped DNA virus

5. Human papillomavirus
Over 100 sub-types according to gene sequence of L1 capsid protein
Highest risk 16, 18, 31, 45
HPV 16 and 18 together cause 70% of cervical cancer
HPV infection starts at TZ (squamocolumnar junction)
Most HPV infection is cleared by the immune system but a minority progresses to CIN or invasive carcinoma
Factors influencing progression include HPV type, viral load, host immunity, parity, smoking, oral contraceptives

6. Elimination of virus Regression of lesions Infection with HPV Lesions
<10%
15-25 yrs
>90%
Lesions
Asymptomatic infection
Koilocytosis and CIN 1
Most
20%
CIN 2
Elimination of virus
Regression of lesions
20%
? Appx 30% regression of CIN2/3
Effective immune system
CIN 3
20% progression
If untreated
Invasive carcinoma
Normal cervix

7. CIN 1 (LSIL)
Nuclear atypia with mitoses and a high N:C ratio confined to the lower 1/3
Koilocytosis most obvious in the upper levels of epithelium

8. Koilocytosis Perinuclear clearing which is sharply defined
Eccentric, hyperchromatic nucleus with coarse chromatin
Nuclei may be multinucleate or raisin-shaped

9. Koilocytosis without CIN (LSIL)

10. Condyloma acuminatum Benign papilloma caused by HPV
Usually low risk 6, 11
More common on vulva
Cauliflower-like growth of fibrovascular cores lined by squamous mucosa with koilocytosis, parakeratosis
Essentially LSIL, but occasionally high grade CIN may occur in a condyloma

11. CIN 2 (HSIL)
Nuclear atypia with failure of maturation and mitoses in lower 2/3
Abnormal mitoses may be seen
Koilocytosis in upper layers

12. CIN 3 (HSIL) Nuclear atypia with failure of maturation in upper 1/3
Abnormal mitoses
Koilocytes hard to find
No invasion

13. CIN 3

14. CIN 3

15. CIN 3 in endocervical crypt

16. Keratinising CIN 3

17. Pleomorphic CIN 3

18. Immunohistochemistry in CIN 3
Ki67
p16

19. Mimics of CIN: Immature metaplasia
Stratified layers of cells with little maturation
(a high N:C ratio) which may extend into crypts
But:
Nuclei evenly spaced, without much crowding
Regular nuclear outline, without coarse chromatin
Low mitotic rate, without abnormal forms
Layer of residual endocervical epithelium may be present on the surface (rare over high grade CIN)

20. Mimics of CIN: Immature squamous metaplasia

21. Mimics of CIN: Immature metaplasia

22. Immunohistochemistry of immature squamous metaplasia
Ki67
p16

23. Mimics of CIN: Atrophy
Stratified layer of cells with little maturation (ie with a high N:C ratio)
But:
Epithelium is thin
Nuclei are evenly spaced, without crowding
Nuclear pleomorphism and mitoses are absent
Nuclei may be ovoid with longitudinal grooves (so-called ‘transitional metaplasia’, probably a variant of atrophy)

24. Mimics of CIN: Atrophy

25. Mimics of CIN: Atrophy and inflammation

26. Mimics of CIN: Reactive, inflammatory changes
Inflammation can cause nuclear enlargement, nucleolar prominence and scattered mitotic figures
But:
Pleomorphism is mild and N:C ratio generally normal
Mitoses are few and only in lower layers
Nucleolar prominence is not a typical feature of CIN
Acute and chronic inflammatory cells are present in the epithelium together with intercellular oedema
Mild perinuclear clearing of squamous cells may be seen as an inflammatory phenomenon

27. Mimics of CIN: Inflammation (with atrophy and tangential sectioning)

28. Mimics of CIN: inflammation

29. Inflamed CIN 3

30. Mimics of CIN: diathermy artefact
Artefact in surface epithelium adjacent to resection margins due to heat from the loop
Nuclear hyperchromasia and elongation
Changes most marked in the basal layers with the overlying surface epithelium often normal
Mitoses not identified
Adjacent epithelium often normal
Low immunohistochemical staining with Ki67

31. Mimics of CIN: Diathermy artefact

32. Mimics of CIN: tangential sectioning
Poor orientation of the biopsy during paraffin embedding so that the histological section is not 90° to the epithelial surface
The basal layer is sectioned obliquely so that it appears thicker than normal and gives a false impression of lack of maturation
However, cellular spacing is generally even, without crowding
Deeper levels cut from the block may clarify the overall architecture of the lesion

33. Mimics of CIN: tangential sectioning

34. Mimics of CIN: tangential sectioning

35. Tangential sectioning (deeper levels)

36. Conclusions
HPV infection is common but only a minority progresses to CIN or invasive carcinoma
This progression is slow and so CIN can be detected by screening before invasion occurs
CIN is graded 1 to 3
Mimics of CIN include immature squamous metaplasia, atrophy, inflammation, diathermy artefact, tangential sectioning