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

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Presentation on theme: "Clinical Management / Natural History of Cervical Dysplasia (CIN) and Related Findings Edward J. Wilkinson, MD, FACOG, FCAP University of Florida College."— Presentation transcript:

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 *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: CERVICAL CANCER SCREENING IN THE USA

3 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. THE CERVICAL TRANSFORMATION ZONE

4 NORMAL AND NEOPLASTIC CELLULAR CHANGES WITHIN THE TRANSFORMATION ZONE NormalNeoplastic Transforming Factors Reserve Cell lCervical intraepithelial Neoplasia (CIN) Reserve cell hyperplasia l l l immatureatypical CIN 1_________ squamousimmature :l metaplasiametaplasia : regression l lCIN 2 l l l mature…………………. l ……..?……….CIN 3 squamous l metaplasiaMicroinvasive lSquamous carcinoma stratified l mature squamousSquamous 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) Atypical Glandular Cells (AGC ) -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 DysplasiaLSIL CIN 2 / Moderate DysplasiaHSIL CIN 3 / Severe DysplasiaHSIL CIN 3 / Carcinoma in SituHSIL * 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 EvaluationSatisfactory 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 EvaluationUnsatisfactory for Evaluation  Specimen rejected (not processed) because …  Specimen processed and examined, but unsatisfactory for evaluation because of …

12 Other Non-Neoplastic Findings 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.

14 Atypical Squamous Cells (ASC) Atypical squamous cells –of undetermined significance (ASC-US) –cannot exclude HSIL (ASC-H)

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 3379 cases. On Review: Concurred ASCUS55% Upgraded to LSIL11% Upgraded to HSIL 3% =14% SIL Downgraded to Negative31% 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 SensitiveSpecificity*Referral for colposcopy HPV testing % 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

21 HPV Testing or Reflex to Colposcopy ASCUS 3488 % HPV positive % HPV results missing % 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 % Solomon D, et al, 2001, JNCI 93(4):293-99

22 Histology and Other Test Results for Women With an ASCUS Pap Test Result* N=973 ConsensusNo. of HPVThinPrep 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: , 1999

23 Management of women with ASCUS (ASC) with HPV testing HPV DNA TestingRepeat 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 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 PositiveNegative Colposcopypredictivepredictive % sensitivity % referralvalue 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): 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: 1.6 % 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 % (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: 0.45 % 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 disease83.9% Women with no disease15.5% 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 exposureRelative hazards ratio (months)(95% CI)* Unexposed 1·00 <6 5·98 (1·33-26·85) ·02 (5·50-59·03) ·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:

37 Pap test Results Preceding the Identification of women with CIN 2 or CIN 3 Pap test FindingPercent with CIN 2,3 HSIL31 % LSIL % AGC (AGUS) % 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

38 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) Atypical –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;124:665 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

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 4,504 57% 32% 11% 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 2,247 43% 35% 22% 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 % 56% 12% 21 studies: N5-109 Follow up yrs. Östör AG, Int J Gyne Path 1993;12:

47 Natural history of CIN: summary CIN 157%32%11% 1% CIN 243%35%22% 5% CIN 332% 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:

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

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

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

51 MANAGEMENT OF CIN 1 Risk of follow up of CIN 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 Atypia / LSIL Pap Follow up Immediate Follow up Immediate 24 mo LLETZ 24 mo LLETZ 135 pts. 171 pts. 135 pts. 171 pts.Histology 20%Negative < 1 % 55%CIN 1/HPV 76% 24%CIN % l pt.Invasion -- l pt.Invasion -- Shafi, BJOJ, 1997 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 TreatmentNo.Hemorrhage Cone biopsy6274.6% Laser ablation % Electro-loop % Cryotherapy % Total 3811 Nuovo et al. Int J Gynol 2000;68:25

62 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%) 8/79 (10%) 22/70 (31%) 7/18 (39%) 45/69 (65%) risk of residual if (+) Margin = 48% if (+) ECC = 59% 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 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


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