Cervical and Anal Dysplasia in HIV Infected Individuals

1. Cervical and Anal Dysplasia in HIV Infected Individuals Jeff Logan, PA-C

2. Anogenital Human Papilloma Virus

3. The Role of HPV in the Development of Cervical and Anal Dysplasia HPV infection is causally associated with cervical cancer and probably other anogenital squamous cell cancers (e.g., anal, penile, vulvar, vaginal) Over 99% of cervical cancers have HPV DNA detected within the tumor Persistent infection with a high-risk HPV type is necessary but not sufficient for the development of cervical cancer

4. HPV Papillomaviridae Double-stranded DNA virus that belongs to the Papovaviridae family No envelope, icosahedral capsid 55 nm Anogenital HPV is the most common STD Most anogenital HPV infections are transient, asymptomatic, and have no clinical consequences

5. HPV Types HPV types identified by nucleic acid sequence homology (not by serology) Over 100 HPV types identified Anogenital types have specific tropism (affinity) for anogenital skin and mucosa More than 30 types affect the anogenital area

6. HPV Types (cont) Anogenital HPV types are divided into 2 groups based on their association with cervical cancer Low-risk types associated with anogenital warts and mild Pap test abnormalities High-risk types associated with mild to severe Pap test abnormalities and cervical cancer, and possibly other anogenital cancers (anus, penis, vulva, etc.)

7. HPV Types (cont) Most visible anogenital warts caused by HPV types 6 and 11 Recurrent respiratory papillomatosis associated with HPV types 6 and 11 HPV types 16 and 18 found in up to 70% of anogenital cancers

8. Anogenital HPV Types

9. Clinical Manifestations of HPV In most cases, anogenital HPV infection is transient and has no clinical manifestations or sequelae Clinical manifestations of genital HPV infection include: Anogenital warts Anogenital dysplasia Squamous cell cancers Others

10. Penile Warts

11. Vulvar Warts

12. Perianal Warts

13. Oral Warts

14. Cervical Warts

15. Intrameatal Wart

16. Transmission of HPV Predominantly associated with sexual activity Can occur from asymptomatic and subclinical patients Probably requires microtrauma to skin/mucous membranes Role of fomite transmission never documented

17. Transmission of HPV (cont) Incubation period unclear, probably 3 weeks to 20 months Prior HPV infection at other sites does not appear to offer protection Autoinnoculation can occur Vertical transmission may very rarely result in recurrent respiratory papillomatosis in infants and young children Infectivity after treatment of anogenital warts or cervical cell abnormalities is unknown

18. Transmission of HPV Recurrences usually are not re-infection. Transmission risk to current and future partners is unclear Current partners likely infected at time of diagnosis Value of disclosing a past diagnosis of genital HPV infection to future partners is unclear, although candid discussions about past STD should be encouraged

19. Natural History of HPV HPV infects stratified squamous epithelium and stimulates cellular proliferation Affected cells display a broad spectrum of changes ranging from benign hyperplasia to dysplasia to invasive carcinoma The median duration of new cervical infections is 8 months but varies by type Gradual development of an effective immune response is the likely mechanism for HPV DNA clearance

20. Natural History of HPV (cont) Infection with multiple types is common HPV infection is usually benign Clinical manifestations of HPV infection can spontaneously regress Most women infected with high-risk HPV types have no Pap test abnormalities and do not develop cervical cancer

21. Natural History of HPV (cont) Persistent infection is infection that is not cleared by the immune system and is characterized by persistently detectable HPV DNA HPV infection that persists is the most important factor for precancerous cervical cell changes and cervical cancer The rate of persistent infection is higher in HIV+ individuals

22. Epidemiology of HPV True incidence/prevalence difficult to define Incidence estimated to be 6.2 million/year for genital HPV infection in U.S. Estimated 20 million people currently have a detectable genital HPV infection in U.S. Estimated $1.6 billion spent annually in direct medical costs to treat symptoms of anogenital HPV infection

23. Question What is the estimated lifetime risk of genital HPV infection for a sexually active adult? 10% 25% 40% 50%

24. Question What is the estimated lifetime risk of genital HPV infection for a sexually active adult? 10% 25% 40% 50% (correct answer)

25. Epidemiology of HPV (cont) 50% of sexually active people in the U.S. will acquire anogenital HPV at some point in their lives Greater than 75% of sexually active people age 15-45 will acquire HPV Estimated 1.4 million are affected with anogenital warts at any one time

26. Epidemiology of HPV (cont) Incidence of cervical cancer is estimated at 8.3/100,000 Rates of cervical cancer have fallen by approximately 75% since the introduction of Pap screening programs

27. Risk Factors for Women Young age Sexual history Sexual history of male sex partners HIV infection

28. Risk Factors for Men Greater lifetime number of sex partners Greater number of recent sex partners Being uncircumcised HIV infection

29. Question How is the diagnosis of external genital warts usually made? Visual inspection Biopsy Acetic acid evaluation HPV DNA test

30. Question How is the diagnosis of external genital warts usually made? Visual inspection (correct answer) Biopsy Acetic acid evaluation HPV DNA test

31. Diagnosis of HPV Genital warts usually diagnosed by visual inspection Biopsy for atypical cases No feasible system for viral culture or serologic testing

32. Diagnosis of HPV (cont) Cervical or anal lesions detected by Pap smear Acetic acid evaluation may be used with Pap smears or more often with colposcopy or anoscopy HPV DNA detection commercially available

33. Prevention of HPV ABC While the effect of condoms in preventing HPV infection is unknown, condom use has been associated with lower rates of genital warts and cervical cancer, both HPV-associated diseases HPV infections can occur in male and female genital areas that are not covered by a latex condom, as well as in areas that are covered

35. HPV Vaccine Gardasil vaccine approved by FDA in June 2006 Targets HPV types 6, 11, 16 and 18 Approved for use in females aged 9-26 Administered in 3 injections over six months Cost is $360 for all three doses

36. HPV Vaccine (cont) Does not eliminate the need for pap tests Does not prevent disease in individuals already infected Not approved for use in males Cervarix targets HPV types 16 and 18 only

37. Squamous Intraepithelial Neoplasia (SIL)

38. Squamous Intraepithelial Neoplasia A synonym for dysplasia/CIN (cervical intraepithelial neoplasia) Categorized as low-grade SIL (LSIL)--HPV-associated changes, CIN 1 high-grade SIL (HSIL)--CIN 2/3, CIS Can involve anus (AIN), vulva (VIN), vagina (VaIN), penis (PIN) as well as cervix

41. Cervical Cell Abnormalities Usually subclinical Detected by Pap test, colposcopy, or biopsy Usually caused by high-risk HPV types Most of the time high-risk HPV types do not cause any abnormalities Most women infected with high-risk HPV types have normal Pap test results Often regress spontaneously without treatment

42. Classification of Pap Abnormalities 2001 Bethesda System Atypical squamous cells (ASC) are cells that do not appear to be completely normal ASC–US—atypical squamous cells of undetermined significance. Sometimes the changes are related to HPV infection. ASC–US changes are usually mild abnormalities. ASC–H—atypical squamous cells cannot exclude a high-grade squamous intraepithelial lesion. ASC–H changes are more likely to be precancerous abnormalities.

43. Classification of Cervical Cell Abnormalities (cont) Low-grade squamous intraepithelial lesion (LSIL)--generally a transient infection with a high-risk HPV type High-grade squamous intraepithelial lesion (HSIL)--generally a persistent infection with a high-risk HPV type with a higher risk for progression to cervical cancer

44. Cervical Dysplasia

45. Cervical Dysplasia

46. Diagnosis of Cervical Cell Abnormalities Cytology (Pap test) Useful screening test to detect cervical dysplasia (not HPV per se) Provides indirect evidence of HPV because it detects squamous epithelial cell changes that are almost always due to HPV

47. Liquid-Based Cytology More expensive than conventional Pap Improves detection of pre-invasive lesions Reduces # of unsatisfactory Paps due to inflammation, poor fixation, etc. May be more cost effective because fewer repeat Paps needed HPV typing can be done on the same sample if indicated Separate swab must be sent to do typing with conventional Pap

48. Diagnosis of Cervical Cell Abnormalities (cont) Nucleic acid testing FDA-approved for two optional uses: To triage women with atypical cells of undetermined significance (ASC-US) Pap test results As an adjunct to the Pap test to screen for cervical cancer in women 30 years or older Use of HPV DNA testing for women with SIL Pap test results is unnecessary because the vast majority of women with SIL are infected with HPV

49. Diagnosis of Cervical Cell Abnormalities (cont) Indication for colposcopy is guided by physical exam or Pap test findings with or without HPV DNA test findings Indications for cervical biopsy include: Visible exophytic lesions on the cervix Pap test with HSIL Pap test with ASC-H or LSIL with colposcopic abnormalities

50. Triage For Cervical Pap Results

51. Cervical Cancer Screening The key strategy to prevent cervical cancer is regular Pap test screening for all sexually active women New technologies may offer potential advantages over conventional Pap testing Several organizations provide guidelines for cervical cancer screening, including: The American Cancer Society The American College of Obstetricians and Gynecologists The U.S. Preventive Services Task Force

52. Delay Adjusted Incidence and U.S. Death Rates of Cervical Cancer by Year of Diagnosis and Race: 1973-2001

53. Cervical Cancer Screening Guidelines

54. Cervical Cancer Screening Guidelines

55. Cervical Cancer Screening Guidelines

56. Cervical Cancer Screening Guidelines

57. Pap Test Screening in Immunodeficient Patients Immunodeficiency appears to accelerate intraepithelial neoplasia and invasive cancer Provide cervical Pap test screening every 6 months for 1 year, then annually for all HIV-infected women with or without genital warts Anal pap tests and anoscopy: value in absence of symptoms not established, but is under investigation

58. Treatment of Cervical Cellular Abnormalities For more information on managing women with cervical cell abnormalities, refer to: CDC National Breast and Cervical Cancer Early Detection Program http://www.cdc.gov/cancer/nbccedp/index.htm 2001 Consensus Guidelines for the Management of Women with Cervical Cytologic Abnormalities http://www.asccp.org/consensus/cytological.shtml

59. Resources National HPV and Cervical Cancer Prevention Resource Center, created by the American Social Health Association http://www.ashastd.org/hpvccrc/ CDC Cervical Cancer Screening Fact Sheet http://www.cdc.gov/cancer/nbccedp/cc_basic.htm National Cancer Institute Cervical Cancer Screening Information For Patients http://www.nci.nih.gov/cancerinfo/pdq/screening/cervical/patient/ American Society of Colposcopy and Cervical Cancer Pathology http://www.asccp.org/pdfs/patient_edu/women_should_know.pdf

60. Anal HPV Infection

61. Overcoming Anophobia Dr. Seymore Butts

62. Anal Problems Benign anal conditions highly prevalent in the general population 1.5 million anorectal preparations dispensed by prescription each year in US 80% of US population with anal symptoms self-medicate Janicke 1996, Nagle 1996, Nelson 1995

63. Common Anal Conditions Fissure Fistula Erosions Hemorrhoids Hypertrophic papillae Bacterial infection Herpes, herpes, herpes

64. Manifestations of Anal HPV No sequellae Warts Friable tissue Anal dysplasia (AIN) Anal cancer

65. Anal and Perianal Warts Cosmetic concerns Hygiene problems Impact sexual function Pain, bleeding, itch Incontinence of stool

66. Differential Diagnosis of Anal Papules and Nodules Fibroepitheliomas Redundant tissue Cysts Comedones Hemorrhoids Nodular herpes Condylomata lata

78. Incidence of Anal Cancer, All Men and Women Aged 40-64,San Francisco County 1973-1999

79. Relative Risk of Anal Cancer in U.S. AIDS-Cancer Registry Match Study

81. Anal and Cervical HPV Infection in Women

83. Baseline Anal Cytology Among HIV-Positive and HIV-Negative Women

84. Four-Year Incidence of Anal HSIL

85. Effect of HAART on HPV-Related Disease Modest or no effect on cervical pathology No effect on anal pathology Risk of anal cancer is likely to increase over time

86. Anal SIL No study has proven that anal HSIL leads to anal cancer, but … Anal cancer is often found with overlying HSIL Cervical HSIL is a known precursor to cervical cancer It is not clear if HIV+ men/women with anal SIL progress to anal cancer faster than HIV- men/women with anal SIL

87. Cervical and Anal Cancer Incidence Cervical cancer prior to cervical cytology screening: 40-50/100,000 Cervical cancer currently: 8/100,000 Anal cancer currently: 1/100,000 Anal cancer among HIV- MSM: 13-35/100,000 Martin, Bower. Sex Trans Inf 77 (2001) 237-31 Anal cancer may be twice as high among HIV+ MSM vs. HIV- MSM: (?70/100,000) Frisch, Biggar, Goedert. J Natl Cancer Inst 92 (2000) 1500-10

88. Anal Cancer Anal cancer is a growingclinical problem in the HIV+ population It is not known if screening by anal Pap and HRA decrease the incidence of anal cancer and prolong survival Smoking is a known risk factor for anal cancer

90. Anal Cancer in ID/AIDS Clinic at Denver Public Health New diagnoses of invasive anal cancer increased from 0/year 1995-7 to 1/year 1998-2000 and 3.3/year 2001-3 in this HIV-positive population Because of this an anal Pap screening program was instituted To date 121 (119 men and 2 women) screened, with 117 (97%) satisfactory for evaluation

91. Invasive Anal Cancer Rates in Denver Health ID Clinic Patients 0 Cases per year from 1995-7 1 Cases per year from 1998-2000 3.3 Cases per year from 2001-3

92. Readings on Anal Paps 15% normal (n = 17) 4% ASC-US (n = 5) 69% LSIL (n = 81) 12% HSIL (n = 14) Total of 85% abnormal (n = 100)

93. Anal Cytology (Pap Smear) Atypical squamous cells – undetermined significance (ASC-US) Atypical squamous cells – cannot rule out HSIL (ASC-H) Low-grade squamous intraepithelial lesions (LSIL) Mild dysplasia and condyloma High-grade squamous intraepithelial lesions (HSIL) Moderate and severe dysplasia Anal Cancer

94. Some Notes on Anal Pap Smears Conventional pap smears may be as reliable as the liquid-fixative technique Grade of dysplasia found on anal pap smear does not correlate as well with grade of dysplasia found on biopsy ASCUS should be followed up with biopsy, unlike with ASCUS found on cervical pap smear

95. Anal Pap Screening Guidelines All MSM (men who have sex with men), regardless of HIV status (? women with history of anal intercourse) Women with cervical cancer or high-grade vulvar disease All HIV-positive men and women, regardless of route of transmission Transplant recipients (immunocompromised)

96. High Resolution AnoscopyHRA Disposable plastic anoscope with plunger Colposcope (light source, magnification, image capture) such as Zeiss FC 150 (with built-in digital camera) Lubricant, 3% acetic acid, Lugol’s iodine Baby Tischler or other small forceps (eg, laryngeal biopsy forceps), formalin

97. HRA Procedure Identify transformation zone [epithelial columnar junction] Identify areas of aceto-whitening If needed, identify areas that are Lugol’s NEGATIVE (light yellow to white) Biopsy suspicious areas

98. Anal Histopathology Atypical/HPV changes Anal Intraepithelial Neoplasia (AIN) AIN I/mild dysplasia AIN II/moderate dysplasia AIN III/severe dysplasia Squamous Cell Carcinoma In-Situ (SCCIC) Microinvasive SCC (anal cancer)

99. Anal Histopathology (cont) There is no clinical distinction between AIN-III and squamous cell carcinoma in-situ (SCCIS) Don’t tell patients with SCCIS they have cancer The rate of SCCIS progression to invasive SCC is uncertain (<1%-5% per year in HIV+ patients with HSIL)

106. Normal Anorectal Transformation Zone 1

107. Condyloma / LSIL 1

108. HRA: Applying 3% Acetic Acid 1 Normal epithelium 2 Condylomas 3 Thick acetowhite flat HSIL plaque in transition zone

109. HRA: Applying Lugol’s Iodine Mahogany/black (strongly Lugol’s positive): Normal tissue Dark yellow (weakly Lugol’s positive): LSIL Light yellow/white (Lugol’s negative): HSIL

111. HRA Results 61/100 abnormal anal Paps have gone to anoscopy so far 18% no AIN (n = 11) 29% AIN 1 (n = 18) 28% AIN 2 (n = 17) 25% AIN 3 (n = 15)

112. Anal Dysplasia in ID/AIDS Clinic High grade dysplasia (AIN II or III) was found in 52% of those evaluated with anoscopy to date Best treatment is unclear at this time, as destructive modalities less well tolerated in the anal canal than on the cervix

117. Treatment Options for Anal SCC Surgical excision Radiation Chemotherapy