Advanced Colposcopy Conflict of Interest Disclosure Anita L. Nelson, MD Anita L. Nelson, MD Professor OB-GYN David Geffen School of Medicine at UCLA CFHC s 2014 Women s Health Update Berkeley, CA May 20, 2014 Grants/ Research Honoraria/ Speakers Bureau Consultant/ Advisory Board Bayer, Merck, Pfizer, Teva Actavis, Bayer, Merck, Pfizer, Teva Agile, Bayer, ContraMed, Medicus, Merck, Teva Anita L. Nelson, MD 2 Learning Objectives At the end of this presentation, the participant will be able to: Outline routine screening recommendations for women of different ages. Explain the principles underlying the differences between younger and older women in recommendations for management of biopsy-proven dysplasia. Describe the upcoming new terminology that is expected to replace the current CIN nomenclature. Outline the evaluation needed for abnormal cytologic test results and for dysplasia. Anita L. Nelson, MD 3 Principles Underlying Screening Recommendations Virtually every sexually active person will be exposed to HPV Most HPV infections are transient High risk-hpv infections take longer (> 24 months) than low risk HPV Significant cervical dysplasia is caused by persistent HPV infection Anita L. Nelson, MD 4 Cervical Cancer Anita L. Nelson, MD 5 U.S. Incidence of Cervical Cancer In US in 2014: 12,360 new cases 4,020 deaths 70% reduction due to Pap smear screening Cervical cancer is disease of economically disadvantaged--elderly, minorities and low socioeconomic status Types of cervical carcinoma: Squamous 85% Adenocarcinoma 15% Anita L. Nelson, MD 6 1
Risk Factors For Cervical Dysplasia and Cancer: Multiple Sexual Partners Natural Course of HPV Infection Number of Sexual Partners Relative Risk Without Smoking 0-1 1.00 Relative Risk With Smoking 2 2.37 4.7 3-5 5.41 10.8 6+ 6.07 12.1 Anita L. Nelson, MD 7 I N F E C T I O N Incubation (1-8 Mo.) First Lesion Immune Response About 9 mo Active Growth (3-6 Mo.) Host Late Stage Containment (3-6 Mo.) Sustained clinical remission Persistent or recurrent disease Anita L. Nelson, MD 8 Prevalence of Minor Precursors, Major Precursors, and Invasive Cancer Screening Recommendations Age/Condition < 21 21 29 30 65 > 65 After hysterectomy No Screening Screening Cytology alone Q 3 years HPV and cytology co-testing Q 5 years OR No screening following adequate prior negative screening No screening if no prior CIN 2 in prior 20 years Anita L. Nelson, MD 9 ACOG Bulletin no. 140. Obstet Gynecol. 2013;122(6):1338-66. Anita L. Nelson, MD 10 Cervical Cancer: Impact of Screening: Remaining Gaps About 50% of US cervical cancers occur in: Women never screened Another 10% US cervical cancers Women not screened in past 5 years Screening fails Low resource, medically underserved regions rates 7 times higher Socioeconomic, geographic and/or racial disparities Saslow D, et al. Am J Clin Pathol. 2012;137:516-32. Anita L. Nelson, MD 11 Accuracy of Colposcopically-Directed Punch Biopsies: Meta-analysis 7,873 pairs of punch biopsy and excisional biopsies when excisional biopsy done immediately following punch biopsy 1 Sensitivity 81.4% Specificity 63.3% Norwegian study 24% with negative biopsies found to have CIN 2 on follow-up biopsy 2 Single punch biopsy/leep pairs in colposcopically diagnosed CIN 1 failed to detect 71.4% of CIN 2 1. Underwood M, et al. BJOG. 2012;119(11):1293-1301. 2. Moss EL, et al. J Low Genit Tract Dis. 2012;16(4):421-6. Anita L. Nelson, MD 12 2
Contributions of ECC 13,115 colposcopic examinations with guided biopsy ECC increased diagnosis of CIN2+ by 1.01% 99 ECC procedures needed to identify one new case of CIN2+ ECC most valuable in: Women 46 years old High grade CIN, HSIL Most of these women need excisional biopsy regardless of ECC Gage JC, et al. Am J Obstet Gynecol. 2010;203(5):481.e1-9. Anita L. Nelson, MD 13 Random Cervical Biopsy and ECC in Low Risk Populations 4 quadrant random biopsies and ECC routinely added to colposcopically directed biopsies 4,677 women had colposcopy 295 CIN 3 61 (20.7%) diagnosed on random biopsy ± ECC Random biopsies increase yield ECC not helpful in women < 25 years Pretorius RG, et al. J Low Genit Tract Dis. 2012;16(4):333-8. Anita L. Nelson, MD 14 Revised Terminology for Cervical Histopathology Consensus conference: Lower Anogenital Squamous Terminology (LAST) 35 organizations Uniform 2-tier terminology for all HPV-related squamous diseases Vulva, vagina, cervix, penis, perianus, and anus 2-tier classification similar to cytology results Low-grade SIL (IN) High-grade SIL (IN) Replaces CIN 1, CIN 2, CIN 3 Waxman AG, et al. Obstet & Gynecol. 2012;120(6):1465-71. Anita L. Nelson, MD 15 Revised Terminology for Cervical Histopathology Problems with prior CIN 2 Poor reproducibility Agreement in only 13-43% of cases Not clear clinical meaning Usually combined with CIN 3 Many represent mixture of cells Intermediate diagnosis of CIN 2 now resolved into either high or low grade SIL Waxman AG, et al. Obstet & Gynecol. 2012;120(6):1465-71. Anita L. Nelson, MD 16 Use of Adjunctive Tests to Sort CIN 2 Use of p16 INK4a (p16) immunohistochemical stain to determine if high or low grade lesion Overexpression of P16 occurs in squamous cells Cell cycle regulator (retinoblastoma protein)(prb) inactivated by E7 oncoprotein of high-risk HPV Positive p16 immunostaining of squamous cells throughout epithelium correlates well with HSIL If CIN 2 lesion seen on hematoxylin and eosin dyes P16 HSIL (histology) P16 LSIL (histology) Waxman AG, et al. Obstet & Gynecol. 2012;120(6):1465-71. Anita L. Nelson, MD 17 Lost to Follow-Up Low-Income Colposcopy Clinic Compliance was defined as 1 return visit within 3-14 months 54% appropriately timed repeat testing 46% failed to return within 14 months 45% of women with CIN 2 or 3 did not return Risk factors: Referral from outside clinic, self or government funds, Spanish speaking, unmarried Chase DM, et al. J Low Genit Tract Dis. 2012;16(4):345-51. Anita L. Nelson, MD 18 3
Recurrence Rates After Treatment for CIN 1, 2, 3 37,142 women treated for CIN 1, 2, or 3 diagnosed in 1986-2000 Recurrence rates depend on grade of CIN, treatment used and woman s age In first 6 year after treatment, rate of CIN 2,3 5.6% for original CIN 1 9.3% for original CIN 2 14.0% for original CIN 3 After 6 years, annual recurrence rates were <1% Melnikov J, et al. J Natl Cancer Inst. 2009;20(101):721-8. Anita L. Nelson, MD 19 Alternative Screening Methods High risk HPV testing of urine sample 1 Concordance with cervical cytology 80% Sensitivity for HSIL 100% Specificity for HSIL 80% Positive predictive value 91% Blind vaginal swabs for HR-HPV 2 Acceptable yield of endocervical cells Self swabbing for cytology and HR-HPV samples 1. Alameda F, et al. J Low Genit Tract Dis. 2007;11(1):5-7. 2. Kavoussi SK, et al. J Womens Health. 2009;18(1):115-8. Anita L. Nelson, MD 20 Future Developments: Cervical Adenocarcinoma HPV 16, 18 account for: 70% squamous cell carcinoma 80% adenocarcinoma HPV test-based screening may be more effective than cytology-based screening for adenocarcinoma HPV 77.8% vs. PAP 17.4% HPV-related adenocarcinoma detected earlier by HPV-tests Adegple O, et al. J Womens Health. 2012;21(10):1031-7. Anita L. Nelson, MD 21 Vaccine for Cervical Dysplasia Cancer Treatment: Early Promise 10-25% of women with high grade dysplasia clear themselves Tend to have higher levels of T cells against HPV genes E6 and E7 New vaccine designed to trigger production of these T cells 14 of 18 women responded for 2 years T cells functional Inserts specific DNA into patient s cells using electroporation www.reuters.com/assets/pring?aid=usbre8991js20121010 Anita L. Nelson, MD 22 Treatment CIN 2-3 Topical Imiquimod: 16 Week Trial Randomized, double-blind, placebo-controlled phase 2 trial self-applied vaginal imiquimod vs. placebo: Imiquimod Placebo Reduced to CIN 1 73% 39% Complete remission 47% 14% HPV clearance 60% 14% Complete remission HPV-16 47% 0 Microinvasive 0 5% Erythema 37% Erosion 30% Severe edema 13% Grimm C, et al. Obstet & Gynecol. 2012;120(1):152-9. Anita L. Nelson, MD 23 Value of ECC and Random Biopsy Retrospective analysis of 550 patients undergoing colposcopy Women with CIN 2 on colposcopy 42.1% single 1-quadrant lesion 101 patients with no visible lesion; CIN 2 found 26 patients on ECC only 11 patients ECC + random biopsy 63% of ASC-US on pap and no colposcopic lesion had on CIN 2 on random biopsy Patients with no visible lesions were 4 times more likely to have CIN 2 Diedrich JT, et al. J Low Genit Tract Dis. 2012;S11. Anita L. Nelson, MD 24 4
ECC in Low Grade Cytology (LSIL or ASC-US + HPV) Improves Detection High Grade Disease 374 patients; 75 women CIN 2 16 ECC with high grade dysplasia 12 high grade had ectocervical dysplasia 4 on ECC alone 4 in 374 = 1 in 93.5 Screen 93-94 to find 1 case 4 in 16-25% of cases Rose JD, et al. Am J Obstet Gynecol. 2012;doi:10.1016 Anita L. Nelson, MD 25 ECC in Low Grade Cytology Improve Detection High Grade Disease Conclusion: Routine ECC at time of satisfactory colposcopy for low grade abnormality with a visible lesion does not significantly improve the diagnosis of high grade dysplasia Rose JD, et al. Am J Obstet Gynecol. 2012;doi:10.1016 Anita L. Nelson, MD 26 Pain Control (VAS) with Cervical Biopsy Forced Coughing vs 1% Lidocaine Injection Speculum Insertion Local Anesthetic Injection 1.4 (0-6) Cervical Biopsy Forced Coughing P Value 95% CI for Difference 1.7 (0-7.5) 1.4 (0-6.9).97-0.8 to 0.8 1.5 (0-7.1) 1.9 (0-8.5).47-0.4 to 1.3 Overall Score 2.3 (0-9) 3.0 (0-8.5).30-0.5 to 1.5 Time needed (min) 7.0 (5-15) 5.0 (3-8) <.001-2.8 to -1.6 Schmid BC, et al. Am J Obstet Gynecol. 2008;199(6):641.e1-3. Anita L. Nelson, MD 27 Role Of Primary LLETZ Therapy Look and LEEP Reserved for HSIL in Adults Pap smear Histology No dysplasia CIN 1 CIN 2/3 Microinvasive All grades 32.5% 26.5% 40.5% 0.5% CIN 1 40.7% CIN 2,3 63.9% Alvarez: Gynecol Oncology. 1994. Anita L. Nelson, MD 28 Photodynamic Therapy http://www.obgynnews.com/index.php?id=11192&tx_ttnews[tt_news]=1429 19&cHash=742ddca6d83d090bfeb4b64383ba1678 Anita L. Nelson, MD 29 Anita L. Nelson, MD 30 5
Anita L. Nelson, MD 31 Anita L. Nelson, MD 33 35 year old, obese G 5 P 4 Ab woman referred in for abnormal pap smear. After challenging placement of the speculum, this is what you can see. Anita L. Nelson, MD 34 Anita L. Nelson, MD 35 What tricks do you have to improve visualization of her cervix? Anita L. Nelson, MD 36 Anita L. Nelson, MD 37 6
CN is a 21 year old G 3 P 0 Ab 3 woman whose pap smear returns ASC-US. She had coarche at age 13 and has had 6 lifetime partners. At age 14, she had EGW that required multiple treatments with TCA and cryotherapy to eradicate. She wants you to test to see if she has HPV. How do you manage her? Anita L. Nelson, MD 38 Anita L. Nelson, MD 39 ASC-US or LSIL Age 21-24 Anita L. Nelson, MD 40 Anita L. Nelson, MD 41 Anita L. Nelson, MD 42 Anita L. Nelson, MD 43 7
So young, but so worrisome, 21 year old with history of sexual debut 2 years ago has HSIL on her first pap. Anita L. Nelson, MD 44 Anita L. Nelson, MD 45 More Worrisome? Would you be more worried if you learned that she had been sexually abused at age 12 and has not been able to have sexual relations since then? Anita L. Nelson, MD 46 Anita L. Nelson, MD 47 A 67 year old G 7 P 7 woman who has never had a pap smear test is referred for well woman care. She denies any recent abnormal bleeding, vaginal discharge or sexual contact for last 12 years. She has never smoked tobacco or consumed alcohol. What examinations and tests should she have to evaluate for pelvic organ carcinoma? A. No tests B. Cytology test C. Cytology test + HP-HPV test D. Colposcopy Conditions for Discontinuation for Cervical Cytology Discontinuation 3 consecutive normal pap smears with satisfactory samples in last 10 years No abnormal tests in that time frame No CIN2 in last 20 years Anita L. Nelson, MD 48 Anita L. Nelson, MD 49 8
What would you do if your examination revealed a 5 mm cervical polyp? What would you do if you found an exophytic lesion on the anterior lip of her cervix? Anita L. Nelson, MD 50 Anita L. Nelson, MD 51 A 29 year old woman with LSIL on pap smear. No previously abnormal pap smears. New sex partner 9 months ago. No HPV test was done. What should we do next. Management of Women with Low-Grade LSIL A. HPV testing B. Colposcopy C. Repeat testing in 12 months Anita L. Nelson, MD 52 Anita L. Nelson, MD 53 Anita L. Nelson, MD 54 Anita L. Nelson, MD 55 9
Anita L. Nelson, MD 56 Anita L. Nelson, MD 57 If colposcopy failed to identify any suspicious lesions and her ECC is negative, which of the following is recommended? No Lesion or CIN 1 Proceeded by Lesser Abnormalities A. Repeat colposcopy with blind biopsies B. Repeat pap every 6 months X 2 C. Cotesting at 12 months D. Look and LEEP Anita L. Nelson, MD 58 Anita L. Nelson, MD 59 39 year old woman with pap smear with ASC-H underwent colposcopy. No lesions were seen on inspection of the cervix and ECC showed no dysplasia. Would you do A. Repeat pap in 6 and 12 months B. Co-testing at 6 and 12 months C. Repeat colposcopy, on cervix and vagina with blind cervical biopsies D. Other Anita L. Nelson, MD 60 Anita L. Nelson, MD 61 10
No Lesions or CIN 1 Preceded by ASC-H or HSIL What if Leukoplakia Found? Anita L. Nelson, MD 62 Anita L. Nelson, MD 63 What if Noncervical Lesions Were Seen? Anita L. Nelson, MD 64 Anita L. Nelson, MD 65 Now What? A 23 year old woman with repeat pap smear with LSIL. At age 21 she had LSIL on pap smear. Her colposcopy exam at the time was reported as being satisfactory and a cervical biopsy showed CIN1. Last year her pap smear was ASC-US, so repeat pap was done this year. Now what do we do? Anita L. Nelson, MD 66 Anita L. Nelson, MD 67 11
Women Age 21-24 With No Lesions Or CIN 1 Anita L. Nelson, MD 68 Anita L. Nelson, MD 69 What if... Her next biopsy returns as CIN1 again? How long can this watch and wait process go on? Why? Anita L. Nelson, MD 70 Anita L. Nelson, MD 71 Climbing Higher, Higher A 52 year old woman with HSIL after years without any screening. Colposcopic exam was unsatisfactory. Biopsy was CIN1 and ECC was negative. What are your treatment options? Choose all the apply A. Cytology at 6 and 12 months B. Co-testing at 12 and 24 months C. Diagnostic excision procedure D. Review cytology, histological and colposcopic findings Anita L. Nelson, MD 72 Anita L. Nelson, MD 73 12
No Lesions or CIN 1 Preceded by ASC-H or HSIL Climbing Higher, Higher What if her ECC were inadequate? What would your options be then? Check all the apply: A. Cytology at 6 and 12 months B. Co-testing at 12 and 24 months C. Diagnostic excision procedure D. Review cytology, histological and colposcopic findings Anita L. Nelson, MD 74 Anita L. Nelson, MD 75 More About ECCs A 22 year old with ASC-H has CIN1 biopsy and ECC with CIN1. What are her treatment options? Check all that apply. A. Cytology at 6 and 12 months B. Cytology and colposcopy every 6 months x 4 a. Biopsy if high grade lesion persists for > 1 year C. Cytology, colposcopy and ECC every 6 months x 4 a. Biopsy if high grade lesion persists for > 1 year Anita L. Nelson, MD 76 Anita L. Nelson, MD 77 Young Woman Again: Border Cases A 24 year old woman has a pap smear with LSIL. The following year, her pap smear is LSIL again. Now what do you do? Management of Women with Atypical Squamous Cells A. Repeat cytology in 1 year B. Colposcopy Anita L. Nelson, MD 78 Anita L. Nelson, MD 79 13
Management of Women with Low-Grade LSIL Oops! A 47 year old woman presents with HSIL. Her colposcopy was not satisfactory. A diagnostic LEEP cone was performed as was an ECC above the LEEP site. Hemostasis was challenging. Her remaining cervical length is 2.5 cm. Her ECC was unsatisfactory. What are your treatment options? Check all that apply: A. Cytology at 6 and 12 months B. Co-testing at 12 and 24 months C. Cytology and ECC at 4-6 months D. Repeat diagnostic excisional procedure E. Hysterectomy Anita L. Nelson, MD 80 Anita L. Nelson, MD 81 Anita L. Nelson, MD 82 Anita L. Nelson, MD 83 A 32 year old woman G3P2 at 8 weeks gestational age reports she has missed her paps since her last pregnancy 4 years ago. She says she was told her pap was not normal, but they would look into the problem after she delivered. She figured it probably was not very serious because they never got back to her. Her pap is now HSIL. A. What are your options? B. What is the purpose of your evaluation? C. What are your challenges? D. What tests are you allowed to perform? Anita L. Nelson, MD 84 Anita L. Nelson, MD 85 14
Colposcopic Principles in Pregnancy Limit biopsy to lesions suspicious for CIN2, 3 or cancer Biopsy not linked to fetal loss or preterm labor ECC is contraindicated in pregnancy CIN2 or CIN3 on biopsy rarely progress to invasive cancer during first months of pregnancy Re-evaluation during pregnancy may prompt needless intervention Observation until postpartum period safe and reasonable provided cancer has been ruled out Anita L. Nelson, MD 86 Management of ASC-US Pregnant women > 20 years Reflex HR-HPV testing Repeat cytology Colposcopy may be deferred until at least 6 weeks postpartum If colposcopy done, biopsy only lesions suspicious for invasive carcinoma Wright TC Jr, et al. Am J Obstet Gynecol. 2007;197(4):346-55. Anita L. Nelson, MD 87 Anita L. Nelson, MD 88 Anita L. Nelson, MD 89 Anita L. Nelson, MD 90 Anita L. Nelson, MD 91 15
Management of LSIL in Pregnant Woman > 20 Years Colposcopy is preferred Biopsy only lesions suspicious for invasive disease ECC unacceptable If no high grade lesions seen, repeat evaluation 6 weeks postpartum If high grade lesion seen, repeating colposcopy periodically until delivery may be helpful Deferring colposcopy until 6 weeks postpartum is acceptable Wright TC Jr, et al. Am J Obstet Gynecol. 2007;197(4):346-55. Anita L. Nelson, MD 92 Anita L. Nelson, MD 93 Anita L. Nelson, MD 94 Anita L. Nelson, MD 95 Anita L. Nelson, MD 96 Anita L. Nelson, MD 97 16
Management of HSIL in Pregnancy Colposcopy necessary to rule out invasive disease Biopsy lesions with features that can not confidentially exclude invasive disease Endocervical curettage not acceptable If colposcopy satisfactory and no invasive disease Repeat colposcopy and cytology in 8-12 weeks Anticipate vaginal delivery Repeat full evaluation at 8-12 weeks postpartum If lesion resolved, repeat 2 tests Q 6 months for 2 years Anita L. Nelson, MD 98 Anita L. Nelson, MD 99 Anita L. Nelson, MD 100 Anita L. Nelson, MD 101 Management of HSIL in Pregnancy If colposcopy not satisfactory Repeat colposcopy periodically until Satisfactory or GA of 28 weeks, when can consider cone biopsy Anita L. Nelson, MD 102 Details of Management of Abnormal Cytology Tests During Pregnancy AGC and AIS Colposcopy recommended Cervical biopsy of suspicious lesions HR-HPV testing preferred at time of colposcopy for AGC-NOS Endocervical cuttage and endometrial biopsy are unacceptable Postpartum re-evaluation at 6 weeks Wright TC Jr, et al. Am J Obstet Gynecol. 2007;197(4):346-55. Anita L. Nelson, MD 103 17
Physiologic Effects of Pregnancy Colposcopic Challenges Cervical mucus obscures visualization Cervical hyperemia Gland prominence Eversion of columnar epithelium SCJ difficult to visualize early Everts later Fleury AC, et al. Minerca Ginecol. 2012;64(2):137-48. Anita L. Nelson, MD 104 Management of CIN or AIS During Pregnancy: Considerations Risk of progression of CIN 2,3 to invasive cancer during pregnancy is minimal Rate of regression postpartum is relatively high Treatment of CIN during pregnancy is associated with Complications-bleeding, infection, abortion High rate of recurrence/persistence CIN and AIS should not affect route of delivery Wright TC, et al. Am J Obstet Gynecol. 2007;197(4):340-345. Anita L. Nelson, MD 105 Natural History Dysplasia in Pregnancy 65 women followed postpartum Remission 40.0% Partial remission 4.6% Persistence 26.2% Progression 3.0% 4.4% miscarried 71.1% Delivered vaginally Henes M, et al. Anticancer Res. 2013;3(2):711-5. Anita L. Nelson, MD 106 Anita L. Nelson, MD 107 Anita L. Nelson, MD 108 Anita L. Nelson, MD 109 18
Anita L. Nelson, MD 110 Anita L. Nelson, MD 111 Anita L. Nelson, MD 112 Anita L. Nelson, MD 113 Anita L. Nelson, MD 114 Anita L. Nelson, MD 115 19
Colposcopy Indicated For... Ablation or Excision for... ASC-US + HPV women over 25 LSIL women over 25 ASC-H women all ages HSIL women all ages AGC (with ECC +/- EMB) AIS (with ECC +/- EMB) Histology of CIN2, CIN3, CIN2, 3 with adequate colposcopy Anita L. Nelson, MD 116 Anita L. Nelson, MD 117 Repeat Co-Testing for: HPV and cytology in 30 years Negative colposcopy in HPV ASC-US CIN1 in women < 25 years with lesser abnormalcies pap Repeat co-testing in 3 years ASC-US with HPV Follow-up negative co-testing, negative colposcopy in HPV, ASC-US Treatment CIN1 Unacceptable Pregnant women Women 21-24 years Anita L. Nelson, MD 118 Anita L. Nelson, MD 119 Repeat Cytology Only Diagnostic Excision Procedure Repeat cytology in 12 months Women 21-24 ASC-US LSIL HSIL with inadequate colposcopy Except in pregnancy Except in women 21-24 Anita L. Nelson, MD 120 Anita L. Nelson, MD 121 20
Anita L. Nelson, MD 122 Anita L. Nelson, MD 123 Anita L. Nelson, MD 124 21