1. Management of Abnormal Pap Smears and Cervical Dysplasia Jennifer L. Ragazzo, M.D. Department of Obstetrics and Gynecology Division of Womens Primary Healthcare April 1, 2009

2. ObjectivesObjectives Review of cervical cancer and risk factors Review of cervical cancer and risk factors Outline screening guidelines Outline screening guidelines Overview of Pap smear results and colposcopy Overview of Pap smear results and colposcopy Summarize recommendations for patients with CIN and AIS Summarize recommendations for patients with CIN and AIS Brief overview of the HPV vaccine Brief overview of the HPV vaccine Review of cervical cancer and risk factors Review of cervical cancer and risk factors Outline screening guidelines Outline screening guidelines Overview of Pap smear results and colposcopy Overview of Pap smear results and colposcopy Summarize recommendations for patients with CIN and AIS Summarize recommendations for patients with CIN and AIS Brief overview of the HPV vaccine Brief overview of the HPV vaccine

3. Cervical Cancer Cervical cancer is the third most common gynecological cancer in the U.S. Cervical cancer is the third most common gynecological cancer in the U.S. Caused by HPV – high risk types Caused by HPV – high risk types Annual pap smear testing potentially reduces a womans chance of dying of cervical cancer by almost 90% Annual pap smear testing potentially reduces a womans chance of dying of cervical cancer by almost 90% Cervical cancer is the third most common gynecological cancer in the U.S. Cervical cancer is the third most common gynecological cancer in the U.S. Caused by HPV – high risk types Caused by HPV – high risk types Annual pap smear testing potentially reduces a womans chance of dying of cervical cancer by almost 90% Annual pap smear testing potentially reduces a womans chance of dying of cervical cancer by almost 90%

4. Risk factors for Cervical Cancer Early age of first intercourse Early age of first intercourse Multiple sexual partners Multiple sexual partners Cigarette smoking Cigarette smoking Immunosuppresion Immunosuppresion HIV: Cervical Cancer is an AIDS-defining illness HIV: Cervical Cancer is an AIDS-defining illness Chronic steroid use Chronic steroid use DES exposure DES exposure Early age of first intercourse Early age of first intercourse Multiple sexual partners Multiple sexual partners Cigarette smoking Cigarette smoking Immunosuppresion Immunosuppresion HIV: Cervical Cancer is an AIDS-defining illness HIV: Cervical Cancer is an AIDS-defining illness Chronic steroid use Chronic steroid use DES exposure DES exposure

5. Twenty-seven times higher risk!

6. Human Papilloma Virus Double-stranded DNA virus that induces epithelial cell proliferation or Papillomas Double-stranded DNA virus that induces epithelial cell proliferation or Papillomas At least 35 of over 100 different types can infect the genital tract At least 35 of over 100 different types can infect the genital tract Divided into low and high risk types Divided into low and high risk types Low Risk – 6, 11 Low Risk – 6, 11 may cause genital warts may cause genital warts High Risk – 16, 18, 31, 33, 39, 45, etc. High Risk – 16, 18, 31, 33, 39, 45, etc. may cause cervical dysplasia and cervical cancer may cause cervical dysplasia and cervical cancer Double-stranded DNA virus that induces epithelial cell proliferation or Papillomas Double-stranded DNA virus that induces epithelial cell proliferation or Papillomas At least 35 of over 100 different types can infect the genital tract At least 35 of over 100 different types can infect the genital tract Divided into low and high risk types Divided into low and high risk types Low Risk – 6, 11 Low Risk – 6, 11 may cause genital warts may cause genital warts High Risk – 16, 18, 31, 33, 39, 45, etc. High Risk – 16, 18, 31, 33, 39, 45, etc. may cause cervical dysplasia and cervical cancer may cause cervical dysplasia and cervical cancer

7. Human Papilloma Virus HPV is sexually transmitted HPV is sexually transmitted But it is so common But it is so common NEJM 1998 – 43% of 608 college age women NEJM 1998 – 43% of 608 college age women JAMA 2001 – 46% of 467 college age women JAMA 2001 – 46% of 467 college age women Estimate lifetime risk of 80% Estimate lifetime risk of 80% Transmission decreased with condom use Transmission decreased with condom use N Engl J Med. 2006 Jun 22;354(25):2645-54 N Engl J Med. 2006 Jun 22;354(25):2645-54 37.8 per 100 patient-years using condoms 37.8 per 100 patient-years using condoms 89.3 per 100 patient-years without condoms 89.3 per 100 patient-years without condoms HPV is sexually transmitted HPV is sexually transmitted But it is so common But it is so common NEJM 1998 – 43% of 608 college age women NEJM 1998 – 43% of 608 college age women JAMA 2001 – 46% of 467 college age women JAMA 2001 – 46% of 467 college age women Estimate lifetime risk of 80% Estimate lifetime risk of 80% Transmission decreased with condom use Transmission decreased with condom use N Engl J Med. 2006 Jun 22;354(25):2645-54 N Engl J Med. 2006 Jun 22;354(25):2645-54 37.8 per 100 patient-years using condoms 37.8 per 100 patient-years using condoms 89.3 per 100 patient-years without condoms 89.3 per 100 patient-years without condoms

8. Human Papilloma Virus In pre-cancer lesions, HPV DNA has extra- chromosomal replication In cancers, the DNA is integrated in the human genome Seven early genes (E1-7), two late genes (L1-2) E6 and E7 genes express oncoproteins that form complexes with host regulatory proteins such as p53 and pRB In pre-cancer lesions, HPV DNA has extra- chromosomal replication In cancers, the DNA is integrated in the human genome Seven early genes (E1-7), two late genes (L1-2) E6 and E7 genes express oncoproteins that form complexes with host regulatory proteins such as p53 and pRB

9. Cervical Cancer Screening Begin Pap smears at age 21 Begin Pap smears at age 21 OR 3 years after first sexual encounter OR 3 years after first sexual encounter Women up to age 30 Women up to age 30 Should undergo annual cervical cytology Should undergo annual cervical cytology Begin Pap smears at age 21 Begin Pap smears at age 21 OR 3 years after first sexual encounter OR 3 years after first sexual encounter Women up to age 30 Women up to age 30 Should undergo annual cervical cytology Should undergo annual cervical cytology

10. Women age 30 and older First option - Cervical cytology alone First option - Cervical cytology alone Negative results on 3 consecutive annual Pap smears Negative results on 3 consecutive annual Pap smears May be re-screened with cervical cytology alone every 2 to 3 years May be re-screened with cervical cytology alone every 2 to 3 years Second option - Combined cervical cytology and testing for high risk HPV Second option - Combined cervical cytology and testing for high risk HPV Both tests negative may repeat every 3 years Both tests negative may repeat every 3 years If only one of the tests are negative more frequent testing indicated If only one of the tests are negative more frequent testing indicated First option - Cervical cytology alone First option - Cervical cytology alone Negative results on 3 consecutive annual Pap smears Negative results on 3 consecutive annual Pap smears May be re-screened with cervical cytology alone every 2 to 3 years May be re-screened with cervical cytology alone every 2 to 3 years Second option - Combined cervical cytology and testing for high risk HPV Second option - Combined cervical cytology and testing for high risk HPV Both tests negative may repeat every 3 years Both tests negative may repeat every 3 years If only one of the tests are negative more frequent testing indicated If only one of the tests are negative more frequent testing indicated

11. Women age 30 and older When to stop screening When to stop screening After hysterectomy – for benign indications After hysterectomy – for benign indications ACS recommendations: After age 70, if history of 3 consecutive negative Pap smears ACS recommendations: After age 70, if history of 3 consecutive negative Pap smears When to stop screening When to stop screening After hysterectomy – for benign indications After hysterectomy – for benign indications ACS recommendations: After age 70, if history of 3 consecutive negative Pap smears ACS recommendations: After age 70, if history of 3 consecutive negative Pap smears

12. New Terminology and Consensus Guidelines The Bethesda System 2001 - JAMA April 2002 The Bethesda System 2001 - JAMA April 2002 American Society of Colposcopy and Cervical Cytology 2001 (Cytological Abnormalities) - JAMA April 2002 American Society of Colposcopy and Cervical Cytology 2001 (Cytological Abnormalities) - JAMA April 2002 American Society of Colposcopy and Cervical Cytology 2001 (Histological Abnormalities) - AJOG July 2003 American Society of Colposcopy and Cervical Cytology 2001 (Histological Abnormalities) - AJOG July 2003 American Cancer Society, CA Ca J Clinic - Dec 2002 American Cancer Society, CA Ca J Clinic - Dec 2002 ACOG Cervical Cytology Screening - Obstet Gynecol, Aug 2003 ACOG Cervical Cytology Screening - Obstet Gynecol, Aug 2003 Interim guidance for the use of HPV DNA testing as an adjunct to cervical cytology for screening, Obstet Gynecol, Feb 2004 Interim guidance for the use of HPV DNA testing as an adjunct to cervical cytology for screening, Obstet Gynecol, Feb 2004 ACOG – Human Papillomavirus, Obstet Gynecol, April 2005 ACOG – Human Papillomavirus, Obstet Gynecol, April 2005 American Society of Colposcopy and Cervical Cytology - 2006 Consensus Guidelines for management of abnormal cytology and CIN/AIS, just released October 2007 American Society of Colposcopy and Cervical Cytology - 2006 Consensus Guidelines for management of abnormal cytology and CIN/AIS, just released October 2007 The Bethesda System 2001 - JAMA April 2002 The Bethesda System 2001 - JAMA April 2002 American Society of Colposcopy and Cervical Cytology 2001 (Cytological Abnormalities) - JAMA April 2002 American Society of Colposcopy and Cervical Cytology 2001 (Cytological Abnormalities) - JAMA April 2002 American Society of Colposcopy and Cervical Cytology 2001 (Histological Abnormalities) - AJOG July 2003 American Society of Colposcopy and Cervical Cytology 2001 (Histological Abnormalities) - AJOG July 2003 American Cancer Society, CA Ca J Clinic - Dec 2002 American Cancer Society, CA Ca J Clinic - Dec 2002 ACOG Cervical Cytology Screening - Obstet Gynecol, Aug 2003 ACOG Cervical Cytology Screening - Obstet Gynecol, Aug 2003 Interim guidance for the use of HPV DNA testing as an adjunct to cervical cytology for screening, Obstet Gynecol, Feb 2004 Interim guidance for the use of HPV DNA testing as an adjunct to cervical cytology for screening, Obstet Gynecol, Feb 2004 ACOG – Human Papillomavirus, Obstet Gynecol, April 2005 ACOG – Human Papillomavirus, Obstet Gynecol, April 2005 American Society of Colposcopy and Cervical Cytology - 2006 Consensus Guidelines for management of abnormal cytology and CIN/AIS, just released October 2007 American Society of Colposcopy and Cervical Cytology - 2006 Consensus Guidelines for management of abnormal cytology and CIN/AIS, just released October 2007

13. Pap Smear Introduced in 1939 Most common cancer screening test Most common cancer screening test Virtually unchanged in 50 years Virtually unchanged in 50 years George N. Papanicolaou 1883-1962

14. Pap Smear Sample of ecto- and endo-cervix

15. Squamous epitheliumColumnar epithelium

16. Pap Smear Results No dysplasia No dysplasia ASC-US (atypical squamous cells of undetermined significance) ASC-US (atypical squamous cells of undetermined significance) +/- High Risk HPV +/- High Risk HPV ASC – H (favor high grade) ASC – H (favor high grade) LSIL (low grade squamous intraepithelial lesion) LSIL (low grade squamous intraepithelial lesion) HSIL (high grade SIL) HSIL (high grade SIL) AGC (atypical glandular cells) AGC (atypical glandular cells) NOS NOS Favor Neoplasia Favor Neoplasia No dysplasia No dysplasia ASC-US (atypical squamous cells of undetermined significance) ASC-US (atypical squamous cells of undetermined significance) +/- High Risk HPV +/- High Risk HPV ASC – H (favor high grade) ASC – H (favor high grade) LSIL (low grade squamous intraepithelial lesion) LSIL (low grade squamous intraepithelial lesion) HSIL (high grade SIL) HSIL (high grade SIL) AGC (atypical glandular cells) AGC (atypical glandular cells) NOS NOS Favor Neoplasia Favor Neoplasia

17. ColposcopyColposcopy Look at the cervix under a microscope Apply Acetic Acid or Lugols solution to see dysplastic changes Take colposcopic directed biopsies +/- endocervical currettage (ECC) Look at the cervix under a microscope Apply Acetic Acid or Lugols solution to see dysplastic changes Take colposcopic directed biopsies +/- endocervical currettage (ECC)

18. Colposcopy: Anatomy of the Cervix Transformation Zone: area that was initially covered by columnar epithelium, replaced by squamous epithelium through metaplasia Squamo-columnar junction: where they two cell types are visible Transformation Zone: area that was initially covered by columnar epithelium, replaced by squamous epithelium through metaplasia Squamo-columnar junction: where they two cell types are visible

19. Colposcopy Acetic Acid Dehydrates cells Abnormal areas appear white (aceto-white) because of decreased glycogen Acetic Acid Dehydrates cells Abnormal areas appear white (aceto-white) because of decreased glycogen Lugols Solution Iodine is taken up by normal cells with high glycogen content Non-staining is abnormal

20. Colposcopy - Grading Lesions Less Severe >> More Severe Less Severe >> More Severe Mild acetowhite epithelium > Intensely acetowhite Mild acetowhite epithelium > Intensely acetowhite No blood vessels > Punctation > Mosaicism No blood vessels > Punctation > Mosaicism Diffuse vague borders > Sharp demarcation Diffuse vague borders > Sharp demarcation Along normal cervical contours > humped up Along normal cervical contours > humped up Normal iodine reaction (dark) > Iodine-negative epithelium (yellow) Normal iodine reaction (dark) > Iodine-negative epithelium (yellow) Leukoplakia - usually a very good (condyloma) or very bad (SCC) sign Leukoplakia - usually a very good (condyloma) or very bad (SCC) sign Less Severe >> More Severe Less Severe >> More Severe Mild acetowhite epithelium > Intensely acetowhite Mild acetowhite epithelium > Intensely acetowhite No blood vessels > Punctation > Mosaicism No blood vessels > Punctation > Mosaicism Diffuse vague borders > Sharp demarcation Diffuse vague borders > Sharp demarcation Along normal cervical contours > humped up Along normal cervical contours > humped up Normal iodine reaction (dark) > Iodine-negative epithelium (yellow) Normal iodine reaction (dark) > Iodine-negative epithelium (yellow) Leukoplakia - usually a very good (condyloma) or very bad (SCC) sign Leukoplakia - usually a very good (condyloma) or very bad (SCC) sign

21. ColposcopyColposcopy Biopsy Results Normal Normal Condyloma Condyloma Cervical Intraepithelial Neoplasia (1-3) Cervical Intraepithelial Neoplasia (1-3) Adenocarcinoma in situ Adenocarcinoma in situ Cancer Cancer

22. Colposcopy – Biopsy Results Normal HPV Changes/ Koilocytes CIN 2CIN 3

23. Natural History of CIN Depends upon age and health status CIN1 – about 90% regression, 10% progression CIN2 – about 50% regression, 20% persistence, 30% progression CIN3 – about 10% regression, 90% persistence/progression Depends upon age and health status CIN1 – about 90% regression, 10% progression CIN2 – about 50% regression, 20% persistence, 30% progression CIN3 – about 10% regression, 90% persistence/progression

24. Treatment of CIN Observation Ablation of abnormal cells Cryotherapy – freezes to a depth of up to 8mm CO2 Laser Therapy – dessicates tissue Diagnostic excisional procedures LEEP – Loop electro-diathermy excisional procedure Cold Knife Cone biopsy (CKC) Hysterectomy Observation Ablation of abnormal cells Cryotherapy – freezes to a depth of up to 8mm CO2 Laser Therapy – dessicates tissue Diagnostic excisional procedures LEEP – Loop electro-diathermy excisional procedure Cold Knife Cone biopsy (CKC) Hysterectomy

25. Diagnostic Excisional Procedures LEEP Office procedure – convenient, quick, cost- effective Margins difficult to assess LEEP Office procedure – convenient, quick, cost- effective Margins difficult to assess CKC OR procedure Larger specimen possible Non-cauterized margins Always for AIS

26. Treatment vs. Observation Age Parity Non-compliant patient Unsatisfactory colposcopy Discrepancy between Pap smear and biopsy results CIN2 treat most of the time, CIN3 always treat Adenocarcinoma in situ +ECC – with CIN2 or 3 Age Parity Non-compliant patient Unsatisfactory colposcopy Discrepancy between Pap smear and biopsy results CIN2 treat most of the time, CIN3 always treat Adenocarcinoma in situ +ECC – with CIN2 or 3

27. Natural History of Cervical Cancer HPV infection CIN 1,2 CIN 2,3 HPV disappearance Invasive CA Avg. 10 yrs Avg. 6- 24 mo Avg. 6-9 mo. Ho GY, et al. New England Journal of Medicine. 1998,338:423-428. Bory JP, et al. Int J Cancer, 2002;102:519-525. Nobbenhuis MAE, et al. Lancet. 1999;354:20-25.

29. Changes to Management Algorithms Using HPV triage Using HPV triage Age 20 years or less Age 20 years or less Pregnancy Pregnancy Using HPV triage Using HPV triage Age 20 years or less Age 20 years or less Pregnancy Pregnancy

30. Normal Pap test Repeat in 1 year Repeat in 1 year If age >30 and history of 3 normals repeat in 3 yrs If age >30 and history of 3 normals repeat in 3 yrs HPV triage HPV triage -HR HPV repeat in 1 yr for age 30 -HR HPV repeat in 1 yr for age 30 +HR HPV repeat in 1 yr +HR HPV repeat in 1 yr Repeat in 1 year Repeat in 1 year If age >30 and history of 3 normals repeat in 3 yrs If age >30 and history of 3 normals repeat in 3 yrs HPV triage HPV triage -HR HPV repeat in 1 yr for age 30 -HR HPV repeat in 1 yr for age 30 +HR HPV repeat in 1 yr +HR HPV repeat in 1 yr

31. Management of Abnormal Cytology ASC-US ASC-US * If age 20 or less repeat in 1 year * If age 20 or less repeat in 1 year If <HSIL repeat in 1 yr if abnomal, colpo If <HSIL repeat in 1 yr if abnomal, colpo HPV triage HPV triage -HR HPV repeat in 1 year -HR HPV repeat in 1 year +HR HPV colposcopy +HR HPV colposcopy LSIL LSIL *If age 20 or less repeat in 1 year *If age 20 or less repeat in 1 year No need for HPV triage straight to colpo No need for HPV triage straight to colpo ASC-US ASC-US * If age 20 or less repeat in 1 year * If age 20 or less repeat in 1 year If <HSIL repeat in 1 yr if abnomal, colpo If <HSIL repeat in 1 yr if abnomal, colpo HPV triage HPV triage -HR HPV repeat in 1 year -HR HPV repeat in 1 year +HR HPV colposcopy +HR HPV colposcopy LSIL LSIL *If age 20 or less repeat in 1 year *If age 20 or less repeat in 1 year No need for HPV triage straight to colpo No need for HPV triage straight to colpo www.asccp.org

32. Management of Abnormal Cytology ASC-H ASC-H No need for HPV triage straight to colpo No need for HPV triage straight to colpo Treat just like LSIL Treat just like LSIL Exception age group <20 still needs colpo Exception age group <20 still needs colpo HSIL HSIL No need for HPV triage No need for HPV triage See and treat if age > 20 years LEEP See and treat if age > 20 years LEEP Or colposcopy with ECC Or colposcopy with ECC ASC-H ASC-H No need for HPV triage straight to colpo No need for HPV triage straight to colpo Treat just like LSIL Treat just like LSIL Exception age group <20 still needs colpo Exception age group <20 still needs colpo HSIL HSIL No need for HPV triage No need for HPV triage See and treat if age > 20 years LEEP See and treat if age > 20 years LEEP Or colposcopy with ECC Or colposcopy with ECC www.asccp.org

33. Management of Abnormal Cytology AGC - initial evaluation If atypical endometrial cells EMB, ECC if no endometrial abnormality colpo If atypical endometrial cells EMB, ECC if no endometrial abnormality colpo Otherwise HPV typing if not already done, colpo, ECC, EMB Otherwise HPV typing if not already done, colpo, ECC, EMB AGC - initial evaluation If atypical endometrial cells EMB, ECC if no endometrial abnormality colpo If atypical endometrial cells EMB, ECC if no endometrial abnormality colpo Otherwise HPV typing if not already done, colpo, ECC, EMB Otherwise HPV typing if not already done, colpo, ECC, EMB www.asccp.org

34. Management of Abnormal Cytology AGC - further evaluation If AGC-NOS and work-up negative, use HPV If AGC-NOS and work-up negative, use HPV If HPV unknown repeat cytology q6mos x 4 If HPV unknown repeat cytology q6mos x 4 If -HR HPV repeat cytology/HPV at 12 mos If -HR HPV repeat cytology/HPV at 12 mos If +HR HPV repeat cytology/HPV at 6 mos If +HR HPV repeat cytology/HPV at 6 mos If AGC-NOS and cervical or glandular neoplasia present routine management protocols If AGC-NOS and cervical or glandular neoplasia present routine management protocols If AGC-favor neoplasia and work-up negative CKC If AGC-favor neoplasia and work-up negative CKC AGC - further evaluation If AGC-NOS and work-up negative, use HPV If AGC-NOS and work-up negative, use HPV If HPV unknown repeat cytology q6mos x 4 If HPV unknown repeat cytology q6mos x 4 If -HR HPV repeat cytology/HPV at 12 mos If -HR HPV repeat cytology/HPV at 12 mos If +HR HPV repeat cytology/HPV at 6 mos If +HR HPV repeat cytology/HPV at 6 mos If AGC-NOS and cervical or glandular neoplasia present routine management protocols If AGC-NOS and cervical or glandular neoplasia present routine management protocols If AGC-favor neoplasia and work-up negative CKC If AGC-favor neoplasia and work-up negative CKC www.asccp.org

35. Abnormal Cytology in Pregnancy LSIL LSIL Colposcopy Colposcopy OR defer colposcopy until 6 wks postpartum OR defer colposcopy until 6 wks postpartum HSIL HSIL Colposcopy Colposcopy LSIL LSIL Colposcopy Colposcopy OR defer colposcopy until 6 wks postpartum OR defer colposcopy until 6 wks postpartum HSIL HSIL Colposcopy Colposcopy www.asccp.org

36. Management of Cervical Intraepithelial Neoplasia CIN 1 If < age 20 repeat cytology at 12 months If < age 20 repeat cytology at 12 months If <HSIL, repeat cytology in 12 mos If <HSIL, repeat cytology in 12 mos If >HSIL colposcopy If >HSIL colposcopy If preceded by ASCUS, ASC-H, LSIL Pap q6mos x 2 or HPV testing in 1 year If preceded by ASCUS, ASC-H, LSIL Pap q6mos x 2 or HPV testing in 1 year re-colpo if abnormal cytology persists re-colpo if abnormal cytology persists CIN 1 If < age 20 repeat cytology at 12 months If < age 20 repeat cytology at 12 months If <HSIL, repeat cytology in 12 mos If <HSIL, repeat cytology in 12 mos If >HSIL colposcopy If >HSIL colposcopy If preceded by ASCUS, ASC-H, LSIL Pap q6mos x 2 or HPV testing in 1 year If preceded by ASCUS, ASC-H, LSIL Pap q6mos x 2 or HPV testing in 1 year re-colpo if abnormal cytology persists re-colpo if abnormal cytology persists

37. Management of Cervical Intraepithelial Neoplasia CIN 1 If preceded by HSIL, AGC-NOS If preceded by HSIL, AGC-NOS Diagnositc excisional procedure Diagnositc excisional procedure Review all pathologic specimens Review all pathologic specimens *OR Repeat Colpo/Cytology at 6 month intervals *OR Repeat Colpo/Cytology at 6 month intervals Excisional procedure if HSIL persists Excisional procedure if HSIL persists CIN 1 If preceded by HSIL, AGC-NOS If preceded by HSIL, AGC-NOS Diagnositc excisional procedure Diagnositc excisional procedure Review all pathologic specimens Review all pathologic specimens *OR Repeat Colpo/Cytology at 6 month intervals *OR Repeat Colpo/Cytology at 6 month intervals Excisional procedure if HSIL persists Excisional procedure if HSIL persists

38. Management of Cervical Intraepithelial Neoplasia CIN 2,3 If satisfactory colpo ablation vs excision If satisfactory colpo ablation vs excision If unsatisfactory colpo excision If unsatisfactory colpo excision In age 20 or less In age 20 or less If satisfactory colpo, can watch closely with cytology/colposcopy q6mos for up to 24 mos If satisfactory colpo, can watch closely with cytology/colposcopy q6mos for up to 24 mos If unsatisfactory or CIN3 ablation or excision is recommended If unsatisfactory or CIN3 ablation or excision is recommended CIN 2,3 If satisfactory colpo ablation vs excision If satisfactory colpo ablation vs excision If unsatisfactory colpo excision If unsatisfactory colpo excision In age 20 or less In age 20 or less If satisfactory colpo, can watch closely with cytology/colposcopy q6mos for up to 24 mos If satisfactory colpo, can watch closely with cytology/colposcopy q6mos for up to 24 mos If unsatisfactory or CIN3 ablation or excision is recommended If unsatisfactory or CIN3 ablation or excision is recommended

39. Management of Cervical Intraepithelial Neoplasia CIN 2,3 - after treatment Cytology and/or Colposcopy at 6 month intervals Cytology and/or Colposcopy at 6 month intervals If negative results x2 annual screening If negative results x2 annual screening OR HPV typing at 6 or 12 month intervals OR HPV typing at 6 or 12 month intervals Repeat colpo if abnormal Pap or +HR HPV Repeat colpo if abnormal Pap or +HR HPV CIN 2,3 - after treatment Cytology and/or Colposcopy at 6 month intervals Cytology and/or Colposcopy at 6 month intervals If negative results x2 annual screening If negative results x2 annual screening OR HPV typing at 6 or 12 month intervals OR HPV typing at 6 or 12 month intervals Repeat colpo if abnormal Pap or +HR HPV Repeat colpo if abnormal Pap or +HR HPV

40. HPV Vaccines : Will they Make Cervical Screening Obsolete?

41. HPV Vaccines ProphylacticProphylactic –target extracellular virus –epitopes of native proteins – viral-like particles (VLP) –produce antibodies Humoral Immunity CD4+/MHC II TherapeuticTherapeutic –target viral-infected cells –epitopes of MHC processed peptides –produce CTLs Cellular Immunity CD8+/MHC I

42. HPV L1 VLP Vaccine Synthesis Yeast Cell (or Yeast Cell (or Baculovirus Expression System) L1 gene on HPV DNA L1 gene inserted into genome of yeast cell Yeast cell DNA mRNA tRNA rRNA Transcription Translation Capsid proteins Empty viral capsids Elicits immune response in host

45. Prophylactic HPV Vaccines Merck – now available Merck – now available Gardasil Gardasil Recombinant L1 proteins using yeast Recombinant L1 proteins using yeast 100% effective in preventing persistent HPV infection 100% effective in preventing persistent HPV infection Phase III Study concluded! Phase III Study concluded! HPV L1 Types 6, 11, 16 and 18 vs. adjuvant HPV L1 Types 6, 11, 16 and 18 vs. adjuvant Endpoint CIN2+ Endpoint CIN2+ Merck – now available Merck – now available Gardasil Gardasil Recombinant L1 proteins using yeast Recombinant L1 proteins using yeast 100% effective in preventing persistent HPV infection 100% effective in preventing persistent HPV infection Phase III Study concluded! Phase III Study concluded! HPV L1 Types 6, 11, 16 and 18 vs. adjuvant HPV L1 Types 6, 11, 16 and 18 vs. adjuvant Endpoint CIN2+ Endpoint CIN2+ GSK GSK Recombinant L1 proteins using baculovirus Recombinant L1 proteins using baculovirus 100% effective in preventing persistent HPV infection 100% effective in preventing persistent HPV infection Phase III study ongoing Phase III study ongoing HPV L1 Types 16 and 18 vs. Hepatitis A HPV L1 Types 16 and 18 vs. Hepatitis A Endpoint CIN 2+ Endpoint CIN 2+

46. Merck Phase III Study: GARDASIL TM Oct 6, 2005 Infectious Disease Society of America San Francisco, California www.merck.com/newsroom/press_releases_and development/2005_1006 12,167 women age 16 to 26 Vaccine: Day 1, Month 2, Month 6Placebo: Day 1, Month 2, Month 6

47. Combined Phase II/III Efficacy Data: Mean 20 month after vaccine regimen Endpoint Vaccine Cases (8,487) Placebo Cases (8,460) Vaccine Efficacy (%) 95% CIP Value HPV 16/18 CIN 2/3+* 05310093, 100<0.001 HPV 16 CIN 2/3+ 04410092,100<0.001 HPV 18 CIN 2/3+ 01410070,100<0.001 HPV 16/18 CIN 2 03610089,100<0.001 HPV 16/18 CIN 3+ 03210088,100<0.001 * Subjects are counted once per row

48. Recommendations for Gardasil For girls and women ages 9 to 26 For girls and women ages 9 to 26 Exact recommended age varies Exact recommended age varies CDCs ACIP - ages 11-12 CDCs ACIP - ages 11-12 ACOG - ages 9-26 ACOG - ages 9-26 Three doses Three doses 1st dose, 2nd at 2 months, 3rd at 6 months 1st dose, 2nd at 2 months, 3rd at 6 months Not indicated for males or women over age 26 Not indicated for males or women over age 26 For girls and women ages 9 to 26 For girls and women ages 9 to 26 Exact recommended age varies Exact recommended age varies CDCs ACIP - ages 11-12 CDCs ACIP - ages 11-12 ACOG - ages 9-26 ACOG - ages 9-26 Three doses Three doses 1st dose, 2nd at 2 months, 3rd at 6 months 1st dose, 2nd at 2 months, 3rd at 6 months Not indicated for males or women over age 26 Not indicated for males or women over age 26

49. Any questions?