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Management of Abnormal Pap Smears and Cervical Dysplasia

Management of Abnormal Pap Smears and Cervical Dysplasia. Jennifer L. Ragazzo, M.D. Department of Obstetrics and Gynecology Division of Women’s Primary Healthcare April 1, 2009. Objectives. Review of cervical cancer and risk factors Outline screening guidelines

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Management of Abnormal Pap Smears and Cervical Dysplasia

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

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

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

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

  5. Twenty-seven times higher risk!

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

  7. Human Papilloma Virus • HPV is sexually transmitted • But it is so common • NEJM 1998 – 43% of 608 college age women • JAMA 2001 – 46% of 467 college age women • Estimate lifetime risk of 80% • Transmission decreased with condom use • N Engl J Med. 2006 Jun 22;354(25):2645-54 • 37.8 per 100 patient-years using 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

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

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

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

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

  13. Pap Smear • Sample of ecto- and endo-cervix

  14. Squamous epithelium Columnar epithelium

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

  16. Look at the cervix under a microscope Apply Acetic Acid or Lugol’s solution to see dysplastic changes Take colposcopic directed biopsies +/- endocervical currettage (ECC) Colposcopy

  17. 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 Colposcopy:Anatomy of the Cervix

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

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

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

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

  22. 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

  23. 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

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

  25. 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

  26. Natural History of Cervical Cancer CIN 1,2 Avg. 6-24 mo Avg. 10 yrs HPV infection CIN 2,3 Invasive CA Avg. 6-9 mo. HPV disappearance 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  43. Combined Phase II/III Efficacy Data:Mean 20 month after vaccine regimen * Subjects are counted once per row

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

  45. Any questions?

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