1. Clinical Management / Natural History of Cervical Dysplasia (CIN) and Related Findings
Edward J. Wilkinson, MD, FACOG, FCAP
University of Florida College of Medicine
Department of Pathology
November 28, 2001

2. CERVICAL CANCER SCREENING IN THE USA
Approximately 50 million Pap tests done annually.+
Approximately 3.5 million ( 7%) interpreted as abnormal.+
Approximately 800,000 LSIL (1.6%); ~ 1600 women with LSIL have invasive cervical carcinoma (0.2 %)
Approximately 250,000 interpreted as HSIL; ~ 2500 women with HSIL have invasive cervical carcinoma ( %)
Jones HW, Cancer 1995:76:
Jones BA and Davey, Arch Pathol Lab Med 2000;124:672-81

3. THE CERVICAL TRANSFORMATION ZONE
The cervical transformation zone extends from the endocervical margin of the original squamous epithelium of the ectocervix to the identified squamo-columnar junction.
Over 95% of all cervical intraepithelial neoplasias (CIN) arise within the transformation zone of the cervix.

4. NORMAL AND NEOPLASTIC CELLULAR CHANGES WITHIN THE TRANSFORMATION ZONE
Normal Neoplastic Transforming Factors
Reserve Cell
l Cervical intraepithelial Neoplasia (CIN)
Reserve cell hyperplasia
l l l
immature atypical CIN 1_________
squamous immature : l
metaplasia metaplasia : regression
l l CIN 2
mature …………………. l ……..?………. CIN 3
squamous l
metaplasia Microinvasive
l Squamous carcinoma
stratified l
mature squamous Squamous carcinoma
epithelium
Wilkinson, 2001

5. CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN):
Mild Dysplasia / CIN 1: Dysplasia confined to the lowest third of the epithelium.
Moderate Dysplasia / CIN 2: Dysplasia involving the lower two thirds of the epithelium.
Severe Dysplasia / CIN 3: Dysplasia extending into the upper third of the epithelium, but not involving the full thickness.
Carcinoma In Situ / CIN 3: A squamous intraepithelial lesion in which nuclear abnormalities involve the full thickness of the epithelium.
Scully et al, WHO; Histological Typing of Female Genital Tract Tumors, 2nd ed,1994

6. The Bethesda 2001 System Major New Changes from Bethesda 1991:
* Negative for intraepithelial lesion or malignancy replaces “within normal limits”.
*Benign Cellular Changes Eliminated.
*ASCUS changed to ASC : either ASC-US or ASC-H
*AGUS changed to AGS

7. Bethesda 2001 Cervical Cytology Classification
Negative for squamous intraepithelial lesion or malignancy
Epithelial cell abnormalities: Squamous Cell
Atypical Squamous cells of undetermined significance (ASC-US)
Atypical Squamous Cells, cannot exclude HSIL (ASC-H)
Low-Grade Squamous Intraepithelial Lesion (LSIL)
encompassing: HPV / mild dysplasia / CIN 1
High-Grade Squamous Intraepithelial Lesion (HSIL)
encompassing: moderate and severe dysplasia, CIS / CIN 2 & CIN 3
-with features suspicious for invasion (if invasion is suspected)
Squamous cell carcinoma

8. Bethesda 2001 Cervical Cytology Classification
Epithelial cell abnormalities: Glandular Cell
Atypical Glandular Cells (AGC)
-endocervical cells (NOS)
-endometrial cells (NOS)
-glandular cells (NOS or specify in comments)
-endocervical cells, favor neoplastic
-glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
Adenocarcinoma
-endocervical endometrial
-extrauterine not otherwise specified (NOS)

9. COMPARISON OF THE WHO AND BETHESDA SYSTEM TERMINOLOGY
WHO histopathologic terms Bethesda Cytology Terms
CIN 1/ Mild Dysplasia LSIL
CIN 2 / Moderate Dysplasia HSIL
CIN 3 / Severe Dysplasia HSIL
CIN 3 / Carcinoma in Situ HSIL
*LSIL: low-grade squamous intraepithelial lesion
*HSIL: high-grade squamous intraepithelial lesion

10. CAUSES OF NON-CORRELATION BETWEEN CYTOLOGY AND COLPOSCOPY
* Cervical lesion is in the endocervical canal, or not in the cervix.
* Colposcopic findings are not apparent to the examiner, although the lesion is present. (eg. Severe atrophy obscures the colposcopic findings).
*The biopsies performed did not include the visualized lesion.
*The laboratory did not identify the lesion within the submitted
biopsies. (Orientation of the biopsy, initial sections of the
paraffin embedded tissue did not include the lesion.)
*The cervical cytologic sample was classified as HSIL, but only
contained immature metaplastic, or atrophic squamous
cells (interpretative cytology issue).
*Other issues.

11. Specimen Adequacy
Satisfactory for Evaluation (describe presence or absence of endocervical/ transformation zone component and any other quality indicators, e.g., partially obscuring blood, inflammation, etc)
Unsatisfactory for Evaluation
Specimen rejected (not processed) because …
Specimen processed and examined, but unsatisfactory for evaluation because of …

12. Other Non-Neoplastic Findings Optional to report; list not inclusive
Reactive cellular changes associated with
inflammation (includes typical repair)
radiation
intrauterine contraceptive device (IUD)
Glandular cells status post hysterectomy
Atrophy

13. Other Endometrial cells (in a woman >40 years of age)
exfoliated (not abraded) endometrial cells
not stromal cells or macrophages
Optional Comment: Endometrial cells after age 40, particularly out of phase or after menopause, may be associated with benign endometrium, hormonal alterations, and, less commonly, endometrial abnormality. Clinical correlation recommended.
Report in ALL women over 40; LMP not often given, information unreliable; HRT common
Not in women less than 40

14. Atypical Squamous Cells (ASC)
of undetermined significance (ASC-US)
cannot exclude HSIL (ASC-H)
ASCUS favor reactive low frequency of HPV+ and low detection of CIN2+
ASC-H: correlate cyto and histology if no CIN2+ to avoid overtreatment
higher PPV for CIN2+ but less than HSIL

15. ASC frequency and association with CIN
Average frequency of ASC: 4.4 %
Associated CIN 2 or CIN 3: %
ASC assoc. with cervical ca: %
Jones and Davey Arch Pathol lab Med 2000,124:672
Jones and Novis. Arch Pathol Lab Med 2000;124:665

16. Sensitivity of a single repeat Pap test for detection of CIN 2 or CIN 3
Sensitivity of repeat cervical cytology to detect
CIN 2 or CIN 3:
Manos, Kinney, Hurley et al. JAMA 1999;281:1605
Wright et al, Am J Obstet Gynecol 1998;178:962
Stoler and Shiffman JAMA 2001;285:1500
Shlay et al, Obstet Gynecol 2000;96:410

17. ALTS: ASCUS Cytology Review
ASCUS cases. On Review:
Concurred ASCUS 55%
Upgraded to LSIL 11%
Upgraded to HSIL % = 14% SIL
Downgraded to Negative 31%
Soloman D, et al, 2001 JNCI 93(4):293-99

18. Ancillary Testing
Provide a brief description of the test methods and report the result so that it is easily understood by the clinician
Encourage use of simultaneous/integrated reporting of cytology and HPV testing
Report test method (type specific vs cocktail)
Report result as positive or negative

19. HPV High Risk Types (N=13)
16, 18,
31, 33, 35, 39,
45,
51, 52, 56, 58, 59, 68
Solomon D, et al, 2001, JNCI 93(4):293-99

20. HPV Testing vs. Cervical Cytology / ASCUS and above
Sensitive Specificity* Referral for
colposcopy
HPV testing % % %
pg / mL
Cervical cytol
ASCUS  % % %
*specificity - defining HSIL or cancer
Schiffmann M, et al, JAMA 87-93, 2000

21. HPV Testing or Reflex to Colposcopy
ASCUS %
HPV positive %
HPV results missing %
Total referred to colposcopy %
ASCUS - CIN %
Sensitivity to detect CN1 or CIN 3:
HPV test %
Repeat cytology - HSIL %
Cyto. ASCUS or higher to
detect CIN %
Solomon D, et al, 2001, JNCI 93(4):293-99

22. Histology and Other Test Results for Women
Histology and Other Test Results for Women With an ASCUS Pap Test Result* N=973
Consensus No. of HPV ThinPrep Pap Repeat Pap
Histology Patients Positive Result Abnormal Result Abnormal
Normal (80.4) (30.5) (42.8) / 770 (31.8) LSIL (12.8) (69.6) (65.6) / 124 (63.1)
HSIL ( 6.7) (89.1) (84.4) / 62 (75.8)
Cancer (0.1) 1 (100) (100) 1 / 1 (100)
Total (100) (39.5) (48.6) / 957 (38.9)
Manos MM, et al, JAMA 281: , 1999

23. Management of women with ASCUS (ASC) with HPV testing
HPV DNA Testing Repeat Cytology
Author No. Pts. Sensitivity % Referred Sensitivity % Referred
Bergeron % %
Manos % %
Solomon* % %
Wright* % %
*HPV DNA testing was performed from liquid-based cytology specimens
Wright et al, 2001 Consensus Conference, submitted

24. Colposcopy predictive predictive % sensitivity % referral value value
Triage test performance of HC 2 and cytology at different thresholds for detection of histologically confirmed CIN3 and CIN2 in the combined human papillomavirus (HPV) triage and immediate colposcopy arms
Positive Negative
Colposcopy predictive predictive
% sensitivity % referral value value
CIN3+
HC2†
HSIL+ cytology
LSIL+ cytology
ASCUS + cytology
CIN2+ HC
HSIL+ cytology
LSIL+ cytology
ASCUS+ cytology
Solomon D, et al, 2001 JNCI 93(4):293-99

25. ASC-H (cannot exclude HSIL): association with CIN 2 or CIN 3
ASC overall:
Associated CIN 2 or CIN 3: %
ASC-H:
Associated with CIN 2 or 3: %
Jones and Davey Arch Pathol lab Med 2000,124:672
Jones and Novis. Arch Pathol Lab Med 2000;124:665
Malik, Wilkinson et al, Acta Cytol 1999;43:376

26. MANAGEMENT OF ASC-H * Refer directly to colposcopy
* Do not perform HPV testing
Wright et al, 2001 Consensus Conference, submitted

27. HPV Triage for ASC-US Pap test ________ | ____________ | |
| |
HPV positive HPV negative
| |
colposcopy or repeat pap 12 mos.
repeat pap at 6 & 12 mos.
Manos MM, et al, JAMA 281: , 1999
Solomon D, et al, 2001, JNCI 93(4):293-99
Wright et al, 2001 Consensus Conference, submitted

28. MANAGEMENT OF ASC-US Acceptable Options:
* Follow-up with repeat cervical cytology in 6 and
12 months; if ASC-US or more severe, refer to colposcopy.
* Perform HPV DNA testing for “high-risk” HPV types;
- if HPV negative: return to screening in 12 months
- if HPV positive: repeat cervical cytology in
6 & 12 months, if ASC-US or more severe, refer to
colposcopy. Use of HPV DNA testing in late follow-up.
Wright et al, 2001 Consensus Conference, submitted

29. LSIL frequency and association with CIN
Mean frequency of LSIL: %
Associated CIN 2 or CIN 3: %
LSIL assoc. with cervical ca: under 0.1 %
Jones and Davey Arch Pathol lab Med 2000,124:672
Jones and Novis. Arch Pathol Lab Med 2000;124:665

30. FOLLOW-UP: OBSERVATION VS. THERAPY
70% (of 972) of the patients with LSIL Pap
tests who had colposcopic follow-up and biopsy
had CIN diagnosed on colposcopic directed
cervical biopsies.
41.7% (of 405) had CIN 1
28.4% (of 276) having CIN 2 or CIN 3.
Takezawa et al, J Lower Gen. Tract Dis 1998;2:136-40

31. MANAGEMENT OF LSIL Recommend option: * Refer directly to colposcopy.
* If colposcopy and biopsies fail to identify CIN,
follow-up with repeat cytology at 6 and 12 months,
refer to colposcopy if repeat is ASC-US or
more severe.
* acceptable option to follow with Pap in 6 and 12 months with referral as above, in special circumstances.
Wright et al, 2001 Consensus Conference, submitted

32. HSIL frequency and association with CIN
Mean frequency of HSIL: %
Associated CIN 2 or CIN 3: %
HSIL assoc. with cervical ca: %
Jones and Davey Arch Pathol lab Med 2000,124:672
Jones and Novis. Arch Pathol Lab Med 2000;124:665
Massad et al, Gynecol Oncol 2001;82:516
Kinney et al, Obstet Gyncol 1998:91:973

33. MANAGEMENT OF HSIL Recommend option: * Refer directly to colposcopy.
* If colposcopy and biopsies fail to identify CIN,
review of the original cytology, biopsy and colposcopy
findings are recommended.
* If the above review confirms HSIL, a diagnostic
excisional procedure, such as electro-loop excision, of
the transformation zone is recommended in
non-pregnant patients.
Wright et al, 2001 Consensus Conference, submitted

34. HPV results by HC 2 Clinical Center Negative Positive TOTAL (N)
cytology (row %) (row %)
Missing (164)
Negative
ASCUS
LSIL
HSIL-CIN
HSIL-CIN
TOTAL
Solomon D, et al, 2001 JNCI 93(4):293-99

35. HIGH RISK HPV DETECTION
Group HPV detected
Women with CIN 2-3 disease 83.9%
Women with no disease %
Wright TC, et al, JAMA 283:81-86, 2000

36. Risk of high-grade CIN in relation to time since first exposure to HPV 16
Time since first exposure Relative hazards ratio
(months) (95% CI)*
Unexposed ·00
< ·98 (1·33-26·85)
·02 (5·50-59·03)
·22 (3·76-53·86)
> ·60 (0·75-8·99)
HPV=human papillomavirus; CIN=cervical intraepithelial neoplasia;
*Controlling for any other HPV exposure
Woodman CBJ, et al Lancet 2001;357:

37. Pap test Results Preceding the Identification of women with CIN 2 or CIN 3
Pap test Finding Percent with CIN 2,3
HSIL %
LSIL %
AGC (AGUS) %
ASC (ASCUS) %
Jones and Davey Arch Pathol lab Med 2000,124:672
Jones and Novis. Arch Pathol Lab Med 2000;124:665
Kinney et al, Obstet Gynecol 1998;91:973
Takezawa et al J Lower Gen. Tract Dis 1998;2:136

38. Mean frequency of AGC: 0.3 % Associated CIN 1, 2, or 3: 9 - 54 %
AGC frequency and association with CIN, Adenocarcinoma in situ (AIS) or Cervical or Endometrial Adenocarcinoma
Mean frequency of AGC: 0.3 %
Associated CIN 1, 2, or 3: %
AGC assoc. with AIS: %
AGC assoc. with carcinoma: %
Jones and Davey Arch Pathol lab Med 2000,124:672
Jones and Novis. Arch Pathol Lab Med 2000;124:665
Ronnett et al, Hum Pathol 1999;30:816
Veljovich et al, Am J Obstet Gynceol 1998;179:382
Soofer and Sidaway Cancer 2000;90:207

39. Glandular Cell Abnormalities
Atypical
endocervical cells (NOS or specify in comments)
endometrial cells (NOS or specify in comments)
glandular cells (NOS or specify in comments)
endocervical cells, favor neoplastic
glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ

40. Glandular Cell Abnormalities
Adenocarcinoma
endocervical
endometrial
extrauterine
not otherwise specified

41. AGC associated with CIN 2 or CIN 3
AGC, Not Otherwise specified:
CIN 2 or CIN 3 detected: %
AGC, favor neoplasia:
CIN 2 or CIN 3 detected: %
Jones and Novis. Arch Pathol Lab Med 2000;124: Ronnett et al, Hum Pathol 1999;30:816
Veljovich et al, Am J Obstet Gynceol 1998;179: Soofer and Sidaway Cancer 2000;90:207
Wright et al, 2001 Consensus Conference, in press

42. Cervical Adenocarcinoma Associated with HPV Types 16 and 18
Of 38 cases, 60.5% had HPV DNA detected
HPV 16 detected in 23.7% (9 of 38)
HPV 18 detected in 26.3% (10 of 38)
In patients 59 years of age or younger, 84.6% had HPV
Skyldberg et al Mod Pathol 1999;12(7):675-82

43. MANAGEMENT OF AGC Recommend option: * Refer directly to colposcopy.
* Colposcopy should include endocervical sampling.
*In symptomatic women, and women over 35 years
of age, endometrial sampling should also be performed.
* A diagnostic cervical cone biopsy may be needed,
and referral to a clinician experienced in management of
complex cervical cytologic situations is recommended.
Wright et al, 2001 Consensus Conference, submitted

44. Natural history of mild dysplasia (CIN 1)
Progress
n Regress Persist (to CIS)
Total , % % %
17 studies, N 12-1,269
Followup <1-18 yrs.
Östör AG, Int J Gyne Path 1993;12:

45. Natural history of moderate dysplasia (CIN 2)
Progress
n Regress Persist (to CIS)
Total , % % %
12 studies, N
Followup yrs
Östör AG, Int J Gyne Path 1993;12:

46. Natural history of CIS (CIN 3)
Progress n Regress Persist (to invasion)
Total % % %
21 studies: N5-109
Follow up yrs.
Östör AG, Int J Gyne Path 1993;12:

47. Natural history of CIN: summary
Progress Progress
Regress Persist to CIS to invasion
CIN 1 57% 32% 11% 1%
CIN 2 43% 35% 22% 5%
CIN 3 32% < 56% >12%
64 studies, 274 carcinomas, 15,473 CIN cases
Followup <1-12 years
Östör AG, Int J Gyne Path 1993;12:

48. Regression Low Grade SIL ASCUS + Low Grade SIL High Grade SIL ASCUS
Melnikow J et al. Obstet Gyne 1998;92:727-35

49. Progression Low Grade SIL ASCUS + Low Grade SIL ASCUS High Grade SIL
Melnikow J et al. Obstet Gyne 1998;92:727-35

50. Invasive Cancer Low Grade SIL ASCUS + Low Grade SIL ASCUS High Grade
Melnikow J et al. Obstet Gyne 1998;92:727-35

51. MANAGEMENT OF CIN 1 Risk of follow up of CIN 1 -
1. Invasive cancer already exists and was missed by Pap, colpo and biopsy.
2. Invasive cancer develops between follow up visits.
3. Patient lost to follow up and develops invasive cancer.

52. FOLLOW UP FOR CIN 1 Follow up Immediate 24 mo LLETZ 135 pts. 171 pts.
Atypia / LSIL Pap
Follow up Immediate
24 mo LLETZ
135 pts pts.
Histology
20% Negative < 1 %
55% CIN 1/HPV %
24% CIN %
l pt. Invasion
Shafi, BJOJ, 1997

53. FOLLOW-UP: OBSERVATION VS. THERAPY
Patients with Pap smears interpreted as LSIL may
have colposcopy directly
if reliable and have the ability to be followed, may be followed by
repeat smears at 4 to 6 months.
A meta-analysis of women with LSIL Pap tests had
a pooled rate of regression reported as 47.39%, with a very low
risk of invasive carcinoma, varying from 0.00% to
0.74% of the patients.
Melnikow J et al. Obstet Gyne 1998;92:727-35

54. FOLLOW-UP: OBSERVATION VS. THERAPY
Should the Pap return as ASCUS, LSIL or HSIL,
the patient should have colposcopy done, with
directed biopsies if needed. If colposcopy is
performed, and a lesion is identified, colposcopic
directed biopsies are indicated to establish the
diagnosis.
ACOG Committee Opinion, No 195, Nov. 1997;
Gold M et al, 1996; Ferris DG et al, 1996 ; ASCCP Practice Guidelines.

55. OBSERVATIONAL FOLLOW-UP, CIN 1
If the patient has a follow-up Pap smear that is
within normal, or benign cellular changes,
repeat follow-up at 4 to 6 month intervals
should continue. If the smears remain within
normal, or benign cellular changes, the patient
may return to annual yearly screening if four
consecutive smears remain unremarkable.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996

56. TREATMENT VS. OBSERVATION
The treatment decision on such patients is
dependent upon the pathologic findings.
Individuals that have CIN 2 and CIN 3, require
appropriate treatment for cervical intraepithelial
neoplasia. Patients with CIN 1 may have
observational follow-up by cytology if acceptable
to the patient and physician.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996

57. TREATMENT VS. OBSERVATION
Grossly visible lesions of the cervix require
cervical biopsy for pathologic evaluations.
Grossly visible CIN 2 and CIN 3 lesions may
be associated with invasive squamous cell
carcinoma, usually microinvasion, and rarely
adenocarcinoma, in situ, or invasive
adenocarcinoma.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996

58. The “see and treat” approach using electro-
loop excision of any visible lesion is generally
not recommended due to common treatment
of non CIN lesions, and the potential
unnecessary excision of part of the
cervix.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996.

59. TREATMENT OUTCOMES FOR CIN
A systemic review of controlled and
randomized trials in women with CIN 1 (low
grade lesions), or CIN 2 or CIN 3 (high grade
lesions) determined that the outcomes as far
as recurrence of CIN, or non-recurrence of CIN
between cone biopsy, cryotherapy, laser
ablation, or electro-loop excision demonstrated
“no substantive difference in outcomes”.
Nuovo et al. Int J Gynecol Obst 2000;68:25.

60. METHODS TO TREAT CIN There are a variety of accepted methods of
therapy to treat CIN, including:
cryosurgery ablation,
laser ablation or excision,
electro-loop excision,
cone biopsy
ACOG: 1997; Nuovo et al, 2000; Wright et al, 1995

61. RISK OF SIGNIFICANT HEMORRHAGE ASSOCIATED WITH TREATMENT FOR CIN
Treatment No. Hemorrhage
Cone biopsy %
Laser ablation %
Electro-loop %
Cryotherapy %
Total
Nuovo et al. Int J Gynol 2000;68:25

62. RESIDUAL CIN AFTER LEEP/CONE
ECC/MARGIN
-/ / / /+
Felix (1994) 1/ / / /12
Husseinzadeh
(1989) 3/ / / /30
Kobak (1995) 4/ / / /27
8/79 (10%) /70 (31%) /18 (39%) 45/69 (65%)
risk of residual if (+) Margin = 48% if (+) ECC = 59%
But, overall rate of residual = 45% and rate of (+) margin = 59%
Dunton, Obstet Gynecol Surv, 2000

63. MANAGEMENT OF CIN
Ablative therapy is not recommended if the SCJ and/or the limits of the lesion cannot be seen colposcopically.
A negative ECC prior to ablative therapy has been suggested by experts.
An ECC at the time of LEEP/cone may indicate an increased risk of residual disease but may not influence post-LEEP/cone management.
“See and treat” approach for low-grade lesions leads to a significant number of patients with negative histology.

64. CERVICAL CARCINOMA STAGING
Tis: Carcinoma in situ
T1a1: FIGO, IA1: Invasive carcinoma diagnosed by
microscopy with stromal invasion 3.0 mm or less in depth
and 7.0 mm or less in horizontal spread.
T1a2: FIGO, IA2: Invasive carcinoma diagnosed
by microscopy with stromal invasion
more than 3.0 mm and not more than 5.0 mm with
horizontal spread 7.0 mm or less.
T1b1 : FIGO, IB1: clinically visible lesion confined to the cervix
or microscopic lesion greater than T1a2
AJCC Cancer Staging Manual, 5th ed. 1997;190-1

65. Clinical Management / Natural History of Cervical Dysplasia (CIN) and Related Findings
Edward J. Wilkinson, MD, FACOG, FCAP
University of Florida College of Medicine
Department of Pathology