Management of the Abnormal Pap Smear, Cervical Dysplasia, and Cervical Cancer

1. Management of the Abnormal Pap Smear, Cervical Dysplasia, and Cervical Cancer Todd D. Tillmanns MD Assistant Professor Department of Obstetrics & Gynecology Division of Gynecologic Oncology University of Tennessee and West Clinic E-mail: ttillmanns@westclinic.com

2. CREOG OBJECTIVES • Pre-invasive cervical disease: • 1. describe the epidemiology of cervical dysplasia • 2. elicit a pertinent history in a woman with an abnl pap • 3. interpret pap test reports using bethesda classification system and • determine appropriate follow-up. • 4.perform and interpret the results of diagnostic procedures for cerivical • dysplasia • 5. treat cervical dysplasia with modalities, such as: cryosurgery, laser • ablation, leep, ckc • 6. manage the complications resulting in the treatment of cervical dysplasia 7. establish an appropriate follow-up plan for a woman who has been treated • for cervical dysplasia • 8. describe the structural changes in the cervix that are characteristic of • in-utero des exposure • Invasive cervical cancer: • 1. describe the epidemiology of cervical ca • 2. describe the typical clinical manifestations of cervical ca 3. describe the differential diagnosis of cervical ca 4. perform appropriate biopsies to diagnose invasive cervical ca 5. describe the figo staging of cervical ca--maybe throw in your bulls-eye • here. • 6. in consultation with a gyn onc, counsel the patient about the evaluation • and treatment (indications, complications) of cervical ca • 7. describe the prognosis • 8. describe the impact of treatment of cervical ca on sexual function and • manage/refer the patient appropriately • 9. provide psychosocial support and long-term follow up for patients with • cervical ca.

3. Natural History of Dysplasia • Human Papilloma Virus is etiologic in the development of invasive cervical cancer. • 99% of cervical cancers worldwide are HPV positive1 • 96% of HSIL is HPV positive2 • 30% of HPV 16 CIN III will progress to cancer • Infection with a high-risk or carcinogenic HPV type is associated w/ 100-fold or greater risk of developing cervical cancer compared to someone who is not infected 1Bosch FX, et al. J Natl Cancer Inst 1995; 87:796-802 2Matsukura M, et al. Int J Cancer 1995; 61:13-22

4. Relative Risk of Cervical Cancerby HPV Type

5. Electron Micrograph of HPV

6. Cervical Histology Showing HPV & Koilocytes

7. Cervical Cytology Showing HPV & Koilocytes

8. Risk of Progression to Cancer

9. Conventional Cervical Cytology (Papanicolaou Smear) • Introduced in 1939 • Substantially unchanged in 50 years • Responsible for a 76.6% reduction in the incidence of invasive cervical cancer & 74.5% reduction in mortality in the United States since 19501 • No randomized controlled trials have evaluated efficacy Herrero R. Monogr Natl Cancer Inst 1996; 21:1-6

10. Conventional Cervical Cytology (Papanicolaou Smear) • Good screening test • Inexpensive • High sensitivity & specificity • Easy to perform, noninvasive, nonmorbid • Reproducible

11. Screening Guidelines Early Detection of Cervical Cancer American Cancer Society 2003 • Screening should begin approximately three years after a woman begins having vaginal intercourse, but no later than 21 years of age • Screening should be done every year with regular Pap tests or every two years using liquid-based tests • At or after age 30, women who have had three normal test results in a row may get screened every 2-3 years. However, doctors may suggest a woman get screened more if she has certain risk factors, such as HIV infection or a weakened immune system • Women 70 and older who have had three or more consecutive Pap tests in the last ten years may choose to stop cervical cancer screening • Screening after a total hysterectomy (with removal of the cervix) is not necessary unless the surgery was done as a treatment for cervical cancer Wright et al: ASCCP Cytol

12. Atypical Squamous Cells • ASC: • Atypical Squamous Cells of Undetermined Significance (ASC-US) • Atypical Squamous Cells cannot exclude HSIL (ASC- • ASC is poorly reproducible • ASC has a 5-17% chance of having CIN II-III • CIN III is diagnosed in 24-94% of those with ASC-H • Risk of invasive caner with ASC is low (0.1-0.2 %) Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

13. Managing ASC • Sensitivity of a single repeat test for detecting CIN II-III after ASC is low (0.67-0.85) • Colposcopy; mean sensitivity for distinguishing normal from abnormal was 0.96 and weighted specificity was 0.48 • Sensitivity of HPV testing to detect CIN II-III in women with ASC is (0.83-1.0) better than a single Pap. The (-) predictive value for high risk HPV is 0.98 • Between 31% and 60% of all women with ASC will have high risk HPV, but this decreases with age • Reflex HPV: 40-60% of women will be spared colposcopy and (-) testing assures women that they do not have a lesion Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

14. ASCCP Management Guidelines ASC-US: HPV Testing HPV DNA Testing Repeat Cytology @ 4 - 6 mos Preferred if liquid-based cytology or co-collection available Colposcopy “When liquid-based cytology is used, or when co-collection for HPV DNA testing can be done, "reflex" HPV DNA testing is the preferred approach” Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for 2001 ASCCP-Sponsored Consensus Conference. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

15. Patient Management Using HPV Triage ASCUS HPV TEST Low Risk + or HPV– HPV + COLPOSCOPY BIOPSY/ABLATION Repeat Pap and/or HPV Test in 12 mo. or return to routine screening at discretion of clinician

16. ASC Special Circumstances • Postmenopausal Women • Using intravaginal estrogen followed one week later with Pap If (-) then repeat 6 months later • Immunosuppressed Women • Referral colposcopy is recommended • Pregnant Women • Same as non-pregnant Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

17. Atypical Glandular Cells and AIS • AGC : Atypical Glandular Cells (endocervical, endometrial, or glandular cells not otherwise specified) • AGC: Favor Neoplasia • AIS: Adenocarcinoma in situ Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

18. AGC Category • 9-54% of women with AGC have biopsy confirmed CIN • 0-8% have AIS • 1-9% have invasive cancer • Biopsy confirmed CIN II-III, AIS, or invasive cancer have been found in 9-41% of women with AGC NOS compared to 27-96% of women with AGC “favor neoplasia” Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

19. AIS Category • The cytologic interpretation of AIS is associated with a very high risk of women having either AIS (48-69%) or invasive cervical adenocarcinoma (38%). Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

20. Managing AGC and AIS • Screening cervical cytology has a sensitivity of only 50%-72% for identifying glandular neoplasia • CIN is the most common neoplasia identified in women with the cytologic result of AGC • Repeat cervical cytology is less sensitive than colposcopy for identifying CIN II-III • This supports using colposcopy • There is a higher risk of CIN II-III, and AIS in premenopausal women compared to menopausal women • ½ of the women with AIS have a coexisting squamous lesion Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

21. AGC and AIS Management • Colposcopy and ECC is recommended for women with all subcategories of AGC with the caveat that women with atypical endometrial cells should have an EMBX • EMBX should be performed in conjunction with colposcopy in women older than 35 with AGC and in younger women with AGC with unexplained bleeding or AIS • There is insufficient data to allow an assessment of HPV DNA testing in the management of women with AGC or AIS Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

22. AGC favor dysplasia • AGC favor dysplasia or AIS with (-) colpo should receive a diagnostic excisional procedure CKC • If no neoplasia identified at initial workup, then repeat cytology q 4-6 months until normal x 4 • Acceptable options include referral Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

23. LSIL • Median rate of LSIL in the USA is 1.6%, but high risk populations have reported LSIL rates as high as 7.7%. • 15-30% of women with LSIL on cervical cytology will have CIN II-III identified on subsequent cervical biopsy. Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

24. Managing LSIL • 53-76% likelihood of abnormal Pap on follow up cytology • 83% of women referred for the evaluation of an LSIL cytology result tested positive for high risk HPV types. • HPV DNA and LEEP do not appear to be useful for the initial management of women with LSIL • Colposcopy with directed biopsies is the initial best option. Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

25. Managing LSIL with Satisfactory and Unsatisfactory Colposcopy • Satisfactory Colposcopy • ECC is an acceptable option with follow up in 6 months if normal • Unsatisfactory Colposcopy: • ECC in non pregnant with follow up in 6 months if normal –vs- LEEP Cone • Pregnancy • Colposcopy with biopsy only if high grade lesion or cancer is suspected • Adolescents • Acceptable option is follow up in 6 months without colposcopy Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

26. Transformation Zone

27. Cryotherapy • Nitrous oxide or CO2 refrigerant • Lesion covered by probe, lubricant • Freeze 4-6 mm beyond probe • Freeze - Thaw - Freeze Technique • Failure in 7% of 422 CIN III patients1 1(Bryson. Am J Ob Gyn 1985; 151:201-6)

28. LEEP • Transformation zone excised to depth of 7-8 mm • Provides tissue diagnosis • Easy to perform • Well tolerated by patients • Can be performed in outpatient setting • Success rates 90-96%

29. Cone Biopsy Indications • (+) ECC • Cytologic abnormality not consistent w/ tissue diagnosis • Unsatisfactory colposcopy • Microinvasion on biopsy, r/o invasive cancer • Adenocarcinoma in situ or invasive adenocarcinoma

30. Cone Biopsy 2 Methods: • Cold Knife Cone Biopsy • LEEP Cone Biopsy or Laser Cone Biopsy • Equivalent results for most indications • Exceptions include: • Microinvasion on biopsy, r/o invasive cancer • Adenocarcinoma in situ or invasive adenocarcinoma

31. Cervical Conization

33. In Utero Exposure to DES • In women exposed to DES in utero, the normal migration of the squamous epithelium is prematurely halted. • The original SCJ is often located in the vagina rather than on the exocervix. • In these women the entire cervical portio can be covered with endocervical columnar epithelium. Kurman, RJ. Blaustein’s Pathology of the Female Genital Tract 5th edition. 2002 Springer-Verlag. New York. pp.216

34. Cervical Cancer • 2nd most important cancer in women worldwide • Most important cancer in developing countries1 • Approximately 10,370 new cases/yr in U.S.2 Approximately 3,710 deaths/yr in U.S.2 • 1991-1995 Tennessee ranked 7th in mortality from Cervical Cancer • Overall 5-year survival is approximately 70%2 1Int J Cancer 1993; 54:594-606 2Cancer Facts and Figures -2005, ACS 2005

35. Age-adjusted* Death Rates and Rank from Cervical Cancer United States 1996-2000 49 44 31 30 29 19 40 51 42 41 43 39 47 16 26 32 37 35 45 25 36 20 21 2 23 17 Age-adjusted Death Rate (Rank) 12 50 3 48 1 24 27 28 38 22 5 15 2.3-1.8 (41-51) 7 34 11 9 33 8 2.6-2.3 (31-40) 18 14 4 3.1-2.6 (22-30) 46 10 6 3.4-3.1 (11-21) 3.8-4.8 (1-10) 13 *Age-adjusted to 2000 population -Rank 1 is worst; 51 is best. -Rates are per 100,000

36. Lifetime Probability of Developing Cancer, by Site, Women, US, 1997-1999 Site Risk All sites 1 in 3 Breast 1 in 8 Lung & bronchus 1 in 17 Colon & rectum 1 in 18 Uterine corpus 1 in 37 Non-Hodgkin lymphoma 1 in 56 Ovary 1 in 58 Pancreas 1 in 80 Melanoma 1 in 81 Urinary bladder 1 in 88 Uterine cervix 1 in 123 Source: Surveillance, Epidemiology, and End Results Program, 1973-1999, Division of Cancer Control and Population Sciences, National Cancer Institute, 2002.

37. Test Trends in Recent* Pap Prevalence (%), by Educational Attainment, Women 25 and Older, US, 1992-2000 Some college or greater All women 18 and older High School graduate Less than High School Prevalence (%) * A Pap test within the past three years. **Includes fewer than 50 states and District of Columbia Source: Behavior Risk Factor Surveillance System, 1992-1995, 1996-1997, 1998, 1999, 2000, National Center for Chronic Disease Prevention and Health Promotion, Center for Disease Control and Prevention,1997, 1999, 2000, 2000, 2001

38. Incidence and Mortality Rates 1997-2001 by Race/Ethnicity Mortality rates per 100,000 based on 2000 US standard population American Cancer Society 2005

39. Cancer Survival*(%) by Site and Race,1992-1998 African Site White % Difference American All Sites 64 53 11 Breast (female) 88 73 15 Colon & rectum 63 53 10 Esophagus 15 8 7 Leukemia 47 38 9 Non-Hodgkin lymphoma 56 46 10 Oral cavity 59 35 24 Prostate 98 93 5 Urinary bladder 82 65 17 Uterine cervix 72 60 12 Uterine corpus 86 61 25 *5-year relative survival rates based on follow up of patients through 1999. Source: Surveillance, Epidemiology, and End Results Program, 1973-1999, Division of Cancer Control and Population Sciences, National Cancer Institute, 2002.

40. Cervical Cancer: Improved Mortality & Morbidity with Early Identification FIGO Stage% Cases5-Year Survival I 46% 83% II 28% 64% III 21% 38% IV 4% 14% FIGO Annual Report. J Epi & Biostat 1998; 3(1)

41. Risk Factors • HPV infection (plus cofactors)1 • Subtypes 16, 18, 31, 35, 39 • Sexual behavior1-3 • Sex at young age; multiple partners • High parity; race; low socioeconomic status • History of smoking1-3 • Oral contraceptives (?)3 • controversial • 1. Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550. 2. ACS. Cancer Facts & Figures 2004. • 3. Janicek et al. CA Cancer J 2001;51:92-114.

42. Presenting Symptoms • Pre-invasive disease • no symptoms • Invasive cervical cancer • abnormal vaginal bleeding • pelvic pain (locoregional disease) • flank pain (hydronephrosis) • triad (siatic pain, leg edema, hydronephrosis) • Extensive pelvic wall involvement • hematuria, incontinence (bladder involvement) • constipation (external compression of rectum) • not common at early diagnosis • Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550.

43. Cervical Cancer Differential Diagnosis • Cervical condyloma or dysplasia • Uterine cancer extending to cervix • Metastatic disease to cervix • Cervical or endometrial polyp

44. Diagnostic Modalities • Clinical staging (FIGO) • EUA, Cystoscopy, Proctoscopy, appropriate biopsies • CKC only for microscopic disease • Review Bulls Eye and treatment based on stage

45. FIGO Staging • Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550.

46. Cervical Cancer: Improved Mortality & Morbidity with Early Identification FIGO Stage% Cases5-Year Survival I 46% 83% II 28% 64% III 21% 38% IV 4% 14% FIGO Annual Report. J Epi & Biostat 1998; 3(1)

47. Counseling Patient After Diagnosis of Cervical Cancer • Treatment modalities based on stage • Side effects and toxicities of whole pelvic radiation and brachytherapy with chemotherapy • Sexual side effects of different treatment • Vaginal shortening • Vaginal coaptation with radiation therapy • Radiation necrosis • Loss of ovarian function • Decreased lubrication

48. Follow Up After First Line Therapy • Every 3 months for the first 2 years • Every 6 months for the following 3 years • Pap smear at each visit • 85% of patients that recur will recur in 2 years

49. Chemotherapy • Advanced/recurrent disease • Agents with > 15% response cyclophosphamide ifosfamide melphalan cisplatin carboplatin doxorubicin topotecan irinotecanmethotrexate vincristine vindesine vinorelbine paclitaxel/docetaxel 5-FU • Platinum regimens commonly used • Combination regimens • Previously • Higher ORR but no survival advantage vs single-agents • Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550. • PDQ®. Cervical Cancer Treatment. http://cancer.gov/cancer_information/PDQ. Lastmodified 6/03. Rein DT, et al. Anti-Cancer Drugs 2001;12:787-795.

50. Advanced Cervical Cancer EB=external beam, ICRT=intracavitary radiation therapy, P=platinum, F=5-FU, HU=hydroxyurea