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Evolving Concepts in the Management of Anal Dysplasia

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Edward Cachay, M.D., M.A.S, of UC San Diego Owen Clinic, presents "Evolving Concepts in the Management of Anal Dysplasia" at AIDS Clinical Rounds

Edward Cachay, M.D., M.A.S, of UC San Diego Owen Clinic, presents "Evolving Concepts in the Management of Anal Dysplasia" at AIDS Clinical Rounds

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  • 1. The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission. AIDS CLINICAL ROUNDS
  • 2. Evolving concepts in the management of anal dysplasia Edward Cachay, M.D., M.A.S. Associate Professor of Clinical Medicine UCSD Owen Clinic 8/14/2014 1Copyright © Edward Cachay MD, MAS.
  • 3. Incidence of invasive anal cancer on the HAART era 8/14/2014 2 Piketty et al. J Clin Oncol 2012, 30:4360-4366 Copyright © Edward Cachay MD, MAS.
  • 4. 8/14/2014 3Copyright © Edward Cachay MD, MAS. Clin Infect Dis. 2014 ;58(1):1-10. 1. Men who have sex with men 2. Anyone with a history of anogenital condylomas 3. Women with history of A. Cervical/vulvar dysplasia B. Anal receptive intercourse In whom is indicated to perform an anal PAP ?
  • 5. The outline for today 8/14/2014 4 Federico (26yo) Satish (40yo) Roger (45yo) Copyright © Edward Cachay MD, MAS.
  • 6. Federico is 24yo male and is studying to become a fashion designer. He came complaining of anal pain. • Following diagnosis of HIV infection in January 2014 he started Epzicom + dolutegravir. Recent CD4: 490 and VL was undetectable. • You performed a rectal GC/CT PCR and tested positive for chlamydia spp. His concurrent intake anal pap collected: ASCUS • He completed proper treatment for his proctitis but did not show for his recommended high resolution anoscopy (HRA) last month. 8/14/2014 5
  • 7. Today, Federico tells you that he was accepted for advances studies in Parsons The New School for Design in New York, starting in spring 2015. What is your recommendation for the management of his abnormal anal cytology? 1. Discuss with him that you need to perform a baseline digitorectal exam because the last time you did not perform one due to his anal pain. 2. Encourage to reschedule a new HRA appointment 3. Initiate HPV vaccine series 4. Only 1 & 2 5. All of the above 8/14/2014 6Copyright © Edward Cachay MD, MAS.
  • 8. 8/14/2014 7 Cachay et al AIDS Rev. 2013;15:122-33 Copyright © Edward Cachay MD, MAS.
  • 9. 2 Mathews ,Wm C. et al JAIDS 2014, 37:1610-1615. Yield of biopsy diagnosis of anal intraepithelial neoplasia 3 (HSIL) by concurrent cytology category. Copyright © Edward Cachay MD, MAS.
  • 10. Patients with an abnormal anal pap will benefit from a staging HRA evaluation. 8/14/2014 9Copyright © Edward Cachay MD, MAS.
  • 11. What is the goal of the anal cancer screening program of your institution? 8/14/2014 10Copyright © Edward Cachay MD, MAS. Early Diagnosis of Invasive anal cancer Prevention of Invasive anal cancer Minimalist Annual DRE ± anal cytology to identify higher risk patients Maximalist Annual DRE + anal cytology + HRA directed biopsy to identify microinvasive disease Annual DRE + anal cytology + HRA directly biopsy + Treatment of HSIL (unproven efficacy)
  • 12. IAC Outcomes: the importance of early diagnosis 8/14/2014 11 Bentzen et al. Int J Radiation Oncol Biol Phys, 2012, 83: e173-e180 Copyright © Edward Cachay MD, MAS. 0 12 24 36 48 60 72 0.0 0.2 0.4 0.6 0.8 1.0 Time (months) T1 T2 T3 T4 CumSurvival
  • 13. Early detection matters: • The most important predictor of survival of Invasive anal cancer is tumor size at diagnosis. • Annual DRE is an essential component of any annual physical exam. 8/14/2014 12Copyright © Edward Cachay MD, MAS.
  • 14. Federico complete a HRA evaluation 2 weeks later and findings are noted below 03 biopsies showed LSIL 8/14/2014 13 Cachay E. Owen anal dysplasia clinic Copyright © Edward Cachay MD, MAS.
  • 15. Federico ask whether he needs the HPV vaccine, he has a good PPO insurance. Is he a candidate for HPV vaccination? 1. Yes 2. No 8/14/2014 14Copyright © Edward Cachay MD, MAS.
  • 16. 8/14/2014 15 HPV vaccination is recommended for all: 1. Females ages 9-26years 2. Males ages 9-21years Males 22-26yo also if not vaccine at younger age Clin Infect Dis. 2014 ;58(1):1-10. Copyright © Edward Cachay MD, MAS.
  • 17. 8/14/2014 16 Critical steps for the development of HPV vaccine 2005 1991 1986 1983 Zhou et al demonstrated that using yeast media can generate Virus-like particles without infectious capacity HPV genome Harald zur Hausen Copyright © Edward Cachay MD, MAS.
  • 18. Papillomavirus Virion-related Structures Schiller JT, Lowy DR. Nat Rev Microbiol. 2012 Oct;10(10):681-92 17
  • 19. HPV infectivity 8/14/2014 18 Epithelium Epithelial disruption Basal membrane Copyright © Edward Cachay MD, MAS. HPV invasion
  • 20. Infectivity cycle: molecular level 8/14/2014 19 HPV virion Heparan Sulphate proteoglycan Conformational change exposing N terminus of L2 Furin mediated cleavage of L2 Exposure of cell-receptor- binding site on L1 Basement membrane Dermis Basal epithelial keratinocyte Several hours Cachay E. AIDS Rev. 2014; 16:90-100 Cell receptor
  • 21. 8/14/2014 20 Virus-like particle (VLP) HPV vaccines Cachay E. AIDS Rev. 2014; 16:90-100Copyright © Edward Cachay MD, MAS.
  • 22. Percentage seroconverting (anti-HPV) 4 weeks after vaccination in males, protocol per intention to treat 99.9 %ofseroconversion 20 40 60 80 100 HPV 6 9 -15 years 16 -26 years 99.4 100 98.9 99.9 99.2 100 99.4 98.4 99.6 HPV 11 99.8 100 99.2 98.8 99.3 97.9 HPV 16 99.8 97.4 99.2 100 98.2 96.3 HPV 18 Nº individuals contributing to analysis 884 1093 885 1093 882 1136 887 1175 Copyright © Edward Cachay MD, MAS.
  • 23. Per-protocol efficacy population(PPE): intraepithelial neoplasia associated with HPV 6,11,16 ó 18. 0 6 12 18 24 30 36 0 10 20 30 40 50 60 70 80 90 100 quadrivalent HPV vaccine Placebo Months after randomization Cumulativepercentageofpatientswithanal intraepitheliallesions Palefsky et al, NEJM 2011, 365;17 Specific efficacy: 77.5% (95% CI, 39.6 to 93.3) 8.9 per 100 person-years 4 per 100 person-years
  • 24. Intention to treat (ITT) efficacy population: intraepithelial neoplasia associated with HPV 6,11,16 ó 18 0 6 12 18 24 30 36 quadrivalent HPV vaccine Placebo Palefsky et al, NEJM 365;17, 2011 20 10 30 40 50 60 70 80 90 100 17.5 per/100 persons-years 13 per/100 person-years Specific efficacy: 50.3% (95% IC: 25.7 to 67.2) Cumulativepercentageofpatientswithanal intraepitheliallesions
  • 25. Be proactive about HPV vaccination in your HIV-infected patients who are 26 years-old or younger. 8/14/2014 24Copyright © Edward Cachay MD, MAS.
  • 26. Satish is a 40yo successful biotech engineer with CD4:580 and undetectable HIV Viral load who lives in Dallas. • He comes to discuss ‘more definitive ways’ to screen him for dysplasia. • Satish is aware of the new recommendations for cervical cancer screening where HPV DNA testing is preferred over cervical cytology. • Satish is willing to pay cash for anorectal HPV DNA testing if he could avoid a HRA. • His anal cytology performed 3 months ago showed ASCUS. 8/14/2014 25Copyright © Edward Cachay MD, MAS.
  • 27. Your laboratory has COBAS HPV DNA testing for cervical samples. Would you favor anorectal HPV DNA testing for Satish? 8/14/2014 26 1. Yes 2. No Copyright © Edward Cachay MD, MAS.
  • 28. Bio-markers investigated for the detection of anal precancerous lesions: - HPV genotyping - HPV mRNA detection - p16 INK4a/Ki-67 immunohistochemistry 8/14/2014 27Copyright © Edward Cachay MD, MAS.
  • 29. The one lesion, one virus concept 8/14/2014 28 1 clinical dysplastic lesion Contains 1 specific HPV Type in whole tissue analysis The same HPV type is found using in LCM in the dysplastic area within whole tissue section Most cervical cancers are caused for HPV type 16/18. Cervical swabs correlates ≥ 94% cases with isolated specific HPV type in dysplastic lesion.
  • 30. Selection of dysplastic regions for laser-capture microdissection (LCM). Richel O et al. J Infect Dis. 2014;210:111-120 Copyright © Edward Cachay MD, MAS.
  • 31. The suspicious clinical lesion under laser- captured microdisection 8/14/2014 30 Multiple HPV staining dysplastic lesions
  • 32. Results using anal swabs for HPV DNA showed that HIV-infected people have multiple types at any given time 8/14/2014 31 MSM Women Median Nº of HPV genotypes (IQR) 6 (4-8) 5 (2-7) is it possible to link a specific HPV type to the high grade AIN lesion in cases with multiple HPV genotypes in a swab? Adapted from Conley et al, JID 2010; 202: 1567-1576 Copyright © Edward Cachay MD, MAS.
  • 33. Flowchart with single versus multiple human papillomavirus (HPV) types in the 31 high-grade anal intraepithelial neoplasia (HGAIN) biopsy specimens. Richel O et al. J Infect Dis. 2014;210:111-120 Copyright © Edward Cachay MD, MAS.
  • 34. Whole-tissue section with a collision region. Richel O et al. J Infect Dis. 2014;210:111-120
  • 35. Two nondysplastic control lesions containing human papillomavirus type 74 (HPV74). Richel O et al. J Infect Dis. 2014;210:111-120
  • 36. 8/14/2014 35 Richel O et al. J Infect Dis. 2014;210:111-120 Multiple human papillomavirus (HPV) types in 2 regions.
  • 37. HPV Analysis of Anal Swabs • The median number of HPV types per swab was 4 (range, 1–13 genotypes). • The predominant HPV type was HPV16 , followed by HPV18, HPV39, HPV51, HPV52, and HPV70. • 50% of anal swab specimens did not contain all of the lesional HPV types found in the whole-tissue sections or LCM-selected areas. 8/14/2014 36Copyright © Edward Cachay MD, MAS.
  • 38. Larger studies illustrate the limit predictive value of HPV anal swabs DNA 8/14/2014 37 Test & HPV status Performance (%) of indicated test to detect AIN-2 or AIN-3 (n =68) Sensitivity Specificity PPV NPV LA (linear array) HPV 16 & 18 Any carcinogenic type 65.1 98.4 72.6 28.9 35.0 23.9 90.1 98.8 Cobas HPV 16 & 18 Any carcinogenic type 66.2 100.0 67.8 26.0 32.6 24.1 89.5 100.00 Anal cytology ≥ASCUS 83.6 51.1 28.9 92.9 HPV genotype & anal cytology ≥ASCUS or HPV16/18 95.5 40.1 27.7 95.2 Copyright © Edward Cachay MD, MAS. Wentzensen et al. J Clin Microbiol. 2014;52:2892-7
  • 39. HPV DNA anal swabs are not useful for detecting lesion-specific HPV types. 8/14/2014 38Copyright © Edward Cachay MD, MAS.
  • 40. Roger is a 45yo nurse who has had HIV for 15 years. Recently he transferred his care to the Owen clinic - Recent CD4; 430 and HIV VL undetectable - Roger reports than in 2001 he had surgical resection of anal warts. - Feb 2014: Anal cytology: HSIL - April 2014: HRA with 2 biopsies showing HSIL 8/14/2014 39Copyright © Edward Cachay MD, MAS.
  • 41. What is the best recommendation for management of Roger’s identified HSIL lesions? 1. Observation with annual cytology and DRE 2. Ablative therapy using infrared coagulation 3. Topical 5-fluoracilo 4. Quadrivalent HPV vaccine followed by ablation with IRC 8/14/2014 40Copyright © Edward Cachay MD, MAS.
  • 42. Current management options for anal dysplasia 8/14/2014 41 Expectant monitoring InterventionVS. Topical Ablation Immune modulation - 5% Fluorouracil cream - Imiquimod - Trichloroacetic acid - Photodynamic therapy - Topical lopinavir - Infrared coagulation - Electrosurgey - CO2 laser - Quadrivalent HPV vaccine Copyright © Edward Cachay MD, MAS.
  • 43. Challenges of ablative therapy 8/14/2014 42 Treatment is imperfect - No categorical proof of effectiveness: Ongoing randomized trials - Recurrence rate is high - Associate to personal discomfort
  • 44. Comparative efficacy 4 weeks after ablative or topical therapy in the only Randomized controlled study 8/14/2014 43 Richel et al. Lancet Oncol 2013; 14: 346–53 Copyright © Edward Cachay MD, MAS. Ablation (n=19) Fluorouracil (n=28) Imiquimod (n=24) Complete response Nº participants % (95% CI) 10 53% (32-73%) 6 21% (10-40) 5 21% (9-41) Partial response Nº participants % (95% CI) 3 16% (32-73) 6 21% (10-40) 6 25% (12-45) No response Nº participants % (95% CI) 6 32% (15-54) 16 57% (39-74) 13 54% (35-72) Difference between 3 groups on complete response p=0.010
  • 45. Rate of recurrences is high independently of the treatment modality 8/14/2014 44 Created using data from Richel et al. Lancet Oncol 2013; 14: 346–53 Copyright © Edward Cachay MD, MAS. 22% 38% 19% 46% 50% 47% 67% 58% 71% 0 10 20 30 40 50 60 70 80 Ablation Flurouracil Imiquimod 24 weeks 48 weeks 72 weeks Ablation Flurouracil Imiquimod
  • 46. What is the risk of progression to invasive anal cancer (IAC) 8/14/2014 45 HSIL IAC Cachay et al . HIV Medicine 2014. In press Historical surgical cohorts 9 -15% of patientsCumulative incidence 1.65 (95% CI 0.59 – 4.52)
  • 47. Why is the rate of progression to invasive anal cancer lower than initially reported? 8/14/2014 46
  • 48. Model for progression of anal dysplasia 8/14/2014 47 HSIL Invasive anal cancerLSIL Copyright © Edward Cachay MD, MAS. Regression Progression Cachay et al AIDS Rev. 2013;15:122-33
  • 49. The Australian SPANC study 8/14/2014 48 0 6m 1y 2y 3y 3 years - Anal PAP - HPVDNA - HRA HSIL = Cytology and/or Histology 1a Outcome
  • 50. 450 MSM by June 2014. 31% were HIV+, all were age ≥ 35yo, with a median age of 49 years. 8/14/2014 49 - Most observations consistent with literature Description of their HSIL clearance rate * 164 MSM HSIL HIV+ 64 (38%) HIV – 105 (62%) 20 HIV+ 41 HIV - 112 MSM HSIL Nº analyzed Nº patients downgrade Grulich AE, et al. 20th IAC. 2014. Melbourne. Abstract WEAB0102 41.7 41.8 Clearance of HSIL per 100PY
  • 51. The snapshot approach ignores anal canal is a dynamic process with multistate lesions Squamous columnar junction Anal verge Left Midcanal wall Dentate line Cachay E. Clin Infect Dis. 2014 ;58:906-7 8/14/2014 50Copyright © Edward Cachay MD, MAS.
  • 52. Model for progression of anal dysplasia 8/14/2014 51Copyright © Edward Cachay MD, MAS.
  • 53. 8/14/2014 52 The top part of figure presents Kaplan-Meier curves depicting infection clearance patterns for 3 of the most common HPV types. 4.4 new cases per 1000 person-months 4.0 new cases per 1000 person-months 10.8 new cases per 1000 person-months 12.2 cleared episodes per 1000 person-months 20.4 cleared episodes per 1000 person-months 26 cleared episodes per 1000 person-months The lower part of figure shows the cumulative incidence for 3 of the most common HPV types. Pokomandy et al. JID; 2009; 199:965–73 Dynamic process and reinfection is a frequent phenomena Copyright © Edward Cachay MD, MAS.
  • 54. Owen clinic contribution 8/14/2014 53 2804 patients with at least 1 anal cytology followed between 2001-2012 for median of ~ 5 years in a universal inception cohort. At baseline: - Median age:40yo, 62% white,78% MSM - 55% CD4 ≥ 350 - Three quarters were on ART 75% and 64% had HIV viral load undetectable
  • 55. Estimated 2 Year transition probabilities for progression and regression in 3-State Hidden Markov Model Adjusted for Cytology Misclassification Assumptions 8/14/2014 54Copyright © Edward Cachay MD, MAS. 0.07 – 0.12 < HSIL HSIL IAC 0.013 – 0.019 0.28 – 0.62 Mathews Wm C. et al. PLoS One. 2014;9:e104116 0.37 – 0.71
  • 56. Estimated 5 Year transition probabilities for progression and regression in 3-State Hidden Markov Model Adjusted for Cytology Misclassification Assumptions 8/14/2014 55Copyright © Edward Cachay MD, MAS. 0.13 – 0.15 < HSIL HSIL IAC 0.021 – 0.038 0.51 – 0.80 Mathews Wm C. et al. PLoS One. 2014;9:e104116 0.18 – 0.45
  • 57. How does it compare to cervical cancer? 64 studies, 274 carcinomas, 15,473 CIN cases, Follow-up <1-12 years 8/14/2014 56Copyright © Edward Cachay MD, MAS. 0.22 Invasive cervical CA CIN 3CIN 2 > 0.12 0.32 ~ 0.55 Ostör AG. Int J Gynecol Pathol. 1993;12:186-92
  • 58. Similar trends for anal dysplasia regression base on severity of HSIL lesions: AIN-2: 61 per 100 PY 8/14/2014 57 AIN-3: 36.9 per 100 PYVS P = 0.037 AIN-2 has greater chances of regression than AIN-3
  • 59. Are there any HIV-related factor that influence the progression of anal dysplasia 8/14/2014 58Copyright © Edward Cachay MD, MAS. ART: HR: 0.5 (0.4-0.8) < HSIL HSIL IAC Mathews Wm C. et al. PLoS One. 2014;9:e104116 HIV VL UD: HR: 0.5 (0.4-0.7) CD4 > 350: HR: 0.3 (0.2-0.5) Protective effect ART: HR: 0.9 (0.6-1.3) HIV VL UD: HR: 1.1 (0.8-1.5) CD4 > 350: HR: 0.8 (0.6-1.1)
  • 60. Molecular biology of invasive squamous anal cell carcinoma in HIV positive patients HPV infection HPV persistence HPVDNA integration 11q Microsatellite instability ?? Normal AIN 1-2 AIN -3 SCCA Gervaz. Br J Surg. 2006 May;93(5):531-8 8/14/2014 59Copyright © Edward Cachay MD, MAS.
  • 61. Effect of IRC 8/14/2014 60 < HSIL HSIL IAC HR 4.2 (2.0–8.5) HR 2.2 (0.6–7.9) 2.7 (0.6–11.7) Eight percent (n= 218) underwent one or more IRC ablations for HSIL lesions between 2007–2012.
  • 62. Conclusion Given the: A. The low short term (2-year) probabilities of progression to IAC B. Moderate to high probabilities of regression of HSIL to less than HSIL cytology C. Morbidity of HSIL ablative treatment D. High recurrence rates among HIV-infected patients 61
  • 63. Conclusion • After careful initial HRA evaluation and biopsy: “ It may be reasonable to defer routine immediate treatment for HSIL provided that close monitoring with HRA and DRE is available” 62
  • 64. 8/14/2014 63 Close up SCJ, left posterior quadrant Coarse punctation on background of severe acetowhitening and thickening Copyright © Edward Cachay MD, MAS. Perhaps, IRC should be reserved for patient with lesions with the highest risk to progress to invasive anal cancer
  • 65. Acknowledgements • Our patients • Christopher Mathews • Connie Languido • Bard Cosman • Wollelaw Agmas • Charles Hicks • Owen clinic colleagues 8/14/2014 64

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