# Presentation: 205710

## 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**

## 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 (1.0-2.0%)
**Jones HW, Cancer 1995:76:1914-18**
**Jones BA and Davey, Arch Pathol Lab**** ****Med 2000;124:672-81**

**CERVICAL CANCER SCREENING IN THE USA**

## Over 95% of all cervical intraepithelial neoplasias (CIN) arise within the transformation zone of the cervix.

- Over 95% of all cervical intraepithelial neoplasias (CIN) arise within the transformation zone of the cervix.

**THE CERVICAL TRANSFORMATION ZONE**

## 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**_
**    ****l****	****	****	**** l ****	****	****	****	****   l**
**mature****	****...................... l ........?..........****	****	****	**_**CIN 3**_
**squamous****	****	****	****	****	****	****   l**
**metaplasia****	****	****	****	****	****	****Microinvasive**
**   ****l****	****	****	****	****	****	****	**_**Squamous carcinoma**_
**stratified****	****	****	****	****	****	****   l**
**mature squamous****	****	****	****	****	****Squamous carcinoma**
**epithelium**

**Wilkinson, 2001**

## 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**

## 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**

## 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**

## 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)**
**Atypical Glandular Cells (AGC****)**
**	****-endocervical cells, favor neoplastic**
**	****-glandular  cells, favor neoplastic**
**Endocervical adenocarcinoma in situ**
**Adenocarcinoma**
**	****-endocervical         -endometrial**
**	****-extrauterine          -not otherwise specified (NOS)**

## 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**

## 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.**

## 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 ...

## 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

## 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.

**Notes:**
Report in ALL women over 40; LMP not often given, information unreliable; HRT common
Not in women less than 40

## Atypical Squamous Cells (ASC)

**Atypical squamous cells**
**of undetermined significance** (ASC-US)
**cannot exclude HSIL** (ASC-H)

**Notes:**
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

## ASC frequency and association with CIN

**Average frequency of ASC:****	****	****4.4 %**
**Associated CIN 2 or CIN 3:****	****	****5 - 17 %**
**ASC assoc. with cervical ca:       0.1 - 0.2 %**

**Jones and Davey Arch Pathol lab Med 2000,124:672**
**Jones and Novis. Arch Pathol Lab Med 2000;124:665**

## 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:     0.67 - 0.76**

**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**

## ALTS: ASCUS Cytology Review

**	****ASCUS  3379 cases. On Review:****	****	****	**
**	****Concurred ASCUS**		**55%**
**	****Upgraded to LSIL****	****	****11%**
**	****Upgraded to HSIL                     3%      =****	****14% SIL**
**	****Downgraded to Negative****	****31%**
**                                                                            **
**	****	****	****	****	****Soloman D, et al, 2001 *****JNCI***** 93(4):293-99**

## 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

## 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**

## HPV Testing vs. Cervical Cytology / ASCUS and above

**	****	****	****Sensitive****	****Specificity*****	****Referral for **
**	****                                                                    ****colposcopy**
**HPV testing 1.0-****	****   88.4%                  89%            12.3%**
**	****pg / mL**
**Cervical cytol**
**	****ASCUS ********	****    77.7%****	****         94.2%            6.9%****	**
***specificity - defining HSIL or cancer**
**	****	****	****	****Schiffmann M, et al, *****JAMA***** 87-93, 2000****	****	****	**

## HPV Testing or Reflex to Colposcopy

- 	**ASCUS ****	****	****	****	****	****3488       %**
**	****HPV positive****	****	****	****	****1766   50.6%**
**	****HPV results missing****	****	****	****  164****	****   4.7%****	**
**	****Total referred to colposcopy****	****           ****	****   5.3% **
**	****ASCUS - CIN 3****	****	****	****	****             5.1%**
**	****Sensitivity to detect CN1 or CIN 3:**
**	****	****HPV test ****	****	****	**** ****	****	**** 96.3%**
**	****	****Repeat cytology - HSIL-****	****	**** 44.1%**
**	****	****Cyto. ASCUS or higher to **
**	****	****detect CIN 2****	****	****	****	**** 85.3%**
- 	                             **Solomon D, et al, 2001, JNCI 93(4):293-99**

## 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****	****          783 (80.4)        239 (30.5)      335 (42.8)             245 / 770 (31.8) LSIL****	****          125 (12.8)          87 (69.6)        82 (65.6) ****	****          79 / 124 (63.1)**
**HSIL                 54  ( 6.7)          57 (89.1)        54 (84.4)                47 / 62 (75.8)**
**Cancer****	****              1  (0.1) ****	****1 (100)          1 (100)****	****	****1 / 1 (100) **
**Total              973 (100)****	****        384 (39.5)****	****   472 (48.6)               372 / 957 (38.9)**
**	****	****	****	****	****Manos MM, et al,  *****JAMA 281:1605-10, 1999***

## Management of women with ASCUS (ASC) with HPV testing

- 			      **HPV DNA Testing****	****	****Repeat Cytology**
**Author        No. Pts.     Sensitivity   % Referred     Sensitivity   % Referred****	**

**Bergeron****	**** 111****	****       0.83                  43%                0.67                  32%**
**Manos****	****	**** 995****	****       0.89****	****        40%                0.76                  39%**
**Solomon*      2324            0.96                   56% ****	****        0.85                  58%**
**Wright*****	****144             0.78                   54%               0.67                  63%**
**	*****HPV DNA testing was performed from liquid-based cytology specimens**** **
**	****	****	****Wright et al, 2001 Consensus Conference, submitted****                  ****	**

## 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†****	****	****	****96.3****	****    56.1****	****       10.0****	****99.5****	**
**	****HSIL+ cytology****	****	****44.1****	****      6.9****	****       37.5****	****96.5**
**	****LSIL+ cytology****	****	****64.0****	****    26.2****	****       14.3****	****97.1**
**	****ASCUS + cytology****	****85.3****	****     58.6****	****         8.5****	****97.9**
**	****CIN2+**
**	****HC2****	****	****	****95.9****	****     56.1****	****	****19.6****	****98.9**
**	****HSIL+ cytology****	****	****34.8****	****       6.9****	****	****58.1****	****92.0**
**	****LSIL+ cytology ****	****59.2****	****     26.2****	****	****25.9****	****93.6**
**	****ASCUS+ cytology****	****85.0****	****     58.6****	****	****16.7****	****95.8**

**	****	****	****	****	****Solomon D, et al, 2001 *****JNCI***** 93(4):293-99**

## ASC-H (cannot exclude  HSIL):     association with CIN 2 or CIN 3

**ASC overall:**
**Associated CIN 2 or CIN 3:****	****	****5 - 17 %**
**ASC-H:**
**Associated with CIN 2 or 3:       24 - 94 %**

**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**

## MANAGEMENT OF ASC-H

**	***** Refer directly to colposcopy**
**	*****  Do not perform HPV testing**
**	****	****	**
**	****	****	****Wright et al, 2001 Consensus Conference, submitted **

## 	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 281:1605-10, 1999** **
**	****	****	****Solomon D, et al, 2001, JNCI 93(4):293-99**
**	****	****	****Wright et al, 2001 Consensus Conference, submitted ****	**

## 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**

## LSIL frequency and association with CIN

**Mean frequency of LSIL:****	****	****  1.6 %**
**Associated CIN 2 or CIN 3:****	****	****15 - 30 %**
**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**

## 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**

## 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**

## HSIL frequency and association with CIN

**Mean frequency of HSIL:****	****	****  0.45 %**
**Associated CIN 2 or CIN 3:****	****	****70 - 75 %**
**HSIL assoc. with cervical ca:    ****	****  1 - 2 % **

**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**

## 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**

## HPV results by HC 2

**     ****Clinical Center****	****    Negative****	****    Positive****	****     TOTAL (N)**
_**      **__**cytology                    (row %)         (row %)                           **_**	**

**	****Missing (164)****	****50****	****	****33.3****	****	**** 18**
**	****Negative****	****	****64****	****	****31.0****	****          1460****	**
**	****ASCUS****	****	****47.7****	****	****48.9****	****          1134****	**
**	****LSIL****	****	****	****10.6****	****	****83.3****	****            630**
**	****HSIL-CIN2****	****	****  3.4****	****	****92.3****	****            207**
**	****HSIL-CIN3****	****	**** 0****	****	****92.3****	****	**** 39**
**	****TOTAL****	****	**** 44.7****	****	****50.6****	****          3488**
**      ****	****	****	****	****	****Solomon D, et al, 2001 *****JNCI***** 93(4):293-99**

## HIGH RISK HPV DETECTION

**         ****Group****	****	****	****	****	****	****  HPV****	****	****	****	****	****	****	****     detected****	**
**Women with CIN 2-3 disease****	****	****83.9%**
**	****Women with no disease****	****	****	****15.5%**
**Wright TC, et al,  *****JAMA***** 283:81-86, 2000**

## 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****	****	****	****	****  1·00**
**<6****	****	****	****	**	  **5·98 (1·33-26·85)**
**6-12****	****	****	****	****	****18·02 (5·50-59·03)**
**12-18****	****	****	****	****	****14·22 (3·76-53·86)**
**>18****	****	****	****	****	****  2·60 (0·75-8·99)****	****	**
**HPV=human papillomavirus; CIN=cervical intraepithelial neoplasia;**
***Controlling for any other HPV exposure**
**	**			      **Woodman CBJ, et al *****Lancet***** 2001;357:1831-36**

## Pap test Results Preceding the Identification of women with CIN 2 or CIN 3

**Pap test Finding****	****	****	****Percent with CIN 2,3**
**HSIL****	****	****	****	****	****	****31 %**
**LSIL****	****	****	****	****	****	****15 - 30 %**
**AGC (AGUS)****	****	****	****	****30 - 40 %**
**ASC (ASCUS)****	****	****	****	****10 %**

**Kinney et al, Obstet Gynecol 1998;91:973**
**Takezawa et al J Lower Gen. Tract Dis 1998;2:136**

**Jones and Davey Arch Pathol lab Med 2000,124:672**
**Jones and Novis. Arch Pathol Lab Med 2000;124:665**

## 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:****	****	****9 - 54 %**
**AGC assoc. with AIS:   ****	****	****0  -  8 %**
**AGC assoc. with carcinoma:       1  -  9 %**

**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**

## 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)**
**Atypical **
**endocervical cells, favor neoplastic**
**glandular cells, favor neoplastic**
**Endocervical adenocarcinoma *****in situ***

## Glandular Cell Abnormalities

**Adenocarcinoma **
- endocervical
- endometrial
- extrauterine
- not otherwise specified

## AGC associated with CIN 2 or CIN 3 

**AGC, Not Otherwise specified:**
**  ****CIN 2 or CIN 3 detected:         9 - 41 %**
**AGC, favor neoplasia:****	****	**
**  ****CIN  2 or CIN 3 detected:****	****   27 - 96 %**

**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**
**Wright et al, 2001 Consensus Conference, in press**

## 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**

## 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**

## Natural history of mild dysplasia (CIN 1)

- 		**	****	****	****	****	****    ****Progress****	**
**	****	****n****	****    Regress          Persist      (to CIS)**
**Total          4,504****	****        57%            32%            11%**

**17 studies, N 12-1,269**
**Followup <1-18 yrs.****         **
**	****	****	****	****         **
**	****	****	****	****        ****Östör AG, Int J Gyne Path 1993;12:186-192**

## Natural history of moderate dysplasia (CIN 2)

- 							    **Progress****	**
**	****	****n****	****    Regress          Persist      (to CIS)**
**Total          2,247           43%              35%            22%**

** ****12 studies, N 12-894**
**Followup 0.3-18 yrs**
**	****	****	****	****	****Östör AG, Int J Gyne Path 1993;12:186-192**

## Natural history of CIS (CIN 3)

- 							   **Progress****	****	****          ****	****	****n****	**** Regress****	****     Persist  ****	**** (to invasion)****	****	****	****	****	**
**Total          767           32%              56%            12%**

**21 studies: N5-109**
**Follow up  0.5-20 yrs.****	**
**	****	****	****	****	**** ****Östör AG, Int J Gyne Path 1993;12:186-192**

## Natural history of CIN: summary

**CIN 1****	****57%****	****	****32%****	****	****11%****	****	****  1%**
**CIN 2****	****43%****	****	****35%****	****	****22%****	****	****  5%**
**CIN 3****	****32%       < 56%            --            >12%**

- 				   **Progress    Progress**
**      ****Regress     Persist       to CIS     to invasion**

**64 studies, 274 carcinomas, ****	****15,473 CIN cases**
**Followup <1-12 years****	****	**
- 				        **Östör AG, Int J Gyne Path 1993;12:186-192**

## Regression

**ASCUS**

**Low**
**Grade**
**SIL**

**ASCUS**
**+ Low**
**Grade**
**SIL**

**High**
**Grade**
**SIL**

**Melnikow J et al. Obstet Gyne 1998;92:727-35**

## Progression

**ASCUS**

**Low**
**Grade**
**SIL**

**ASCUS **
**+ Low**
**Grade**
**SIL**

**High**
**Grade**
** ****SIL**

**	****Melnikow J et al. Obstet Gyne 1998;92:727-35**

## Invasive Cancer

-  ** ****ASCUS**

**Low**
**Grade**
**SIL**

**ASCUS**
**+ Low**
**Grade**
**SIL**

**High**
**Grade**
**SIL**

**Melnikow J et al. Obstet Gyne 1998;92:727-35**

## 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.

## FOLLOW  UP  FOR  CIN  1

- 		       **Atypia / LSIL Pap**
** ****	****Follow up****	****	****	****     Immediate**
**	****  ****24 mo****	****	****	****      LLETZ**
**	****   ****135 pts.****	****	****	****      171 pts.**
**	****	****	****Histology**
**	****20%****	****	****Negative****	****     < 1 %**
**	****55%****	****	****CIN 1/HPV****	****      76%**
**	****24%****	****	****CIN 2-3****	****      23%**
**	****   ****l pt.****	****	****Invasion****	****         --**
**	****	****	****	****	****	**** ****Shafi, BJOJ, 1997**

## 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**

## 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.**

## 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**

## 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**

## 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**

## 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.**

## 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.****  **

## 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**

## RISK OF SIGNIFICANT HEMORRHAGE ASSOCIATED WITH TREATMENT FOR CIN

**Treatment****	****	****	****	****No.****	****	****Hemorrhage**
**Cone biopsy****	****	****	****627****	****	****4.6%**
**Laser ablation****	****	****       1419****	****	****1.75%**
**Electro-loop****	****	****	****635****	****	****1.35%**
**Cryotherapy****	****                1130****	****	****0.00%**
**Total****	****	****	****	****       3811****	****	****	**
**	****	****	****	****	**
**	****	****	****	****	****Nuovo et al. Int J Gynol 2000;68:25 **

## RESIDUAL  CIN  AFTER  LEEP/CONE

- 			**ECC/MARGIN**
**	****	**_**-/-**_**	****        **_**-/+**_**	****	****         **_**+/-**_**	****             **_**+/+**_
**Felix (1994)****	****1/38****	****        2/4****	****	****         1/3****	****             9/12**
**Husseinzadeh **
**(1989)****	****	****3/19****	****       9/29****	****	****         2/5****	****           24/30**
**Kobak (1995)****     **_**4/22**_**	****      **_**11/37**_**	****        **_**4/10**_**          **_**12/27**_
_**	**_**         ****8/79 (10%)       22/70 (31%)      7/18 (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**

## 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.

## 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**

## 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**