Screening for Anal Dysplasia in HIV-infected Men and Women

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Evidence Based Evaluation of Anal Dysplasia
Screening Ready for Prime Time?
Wm. Christopher Mathews, MD
San Diego AETC, UCSD Owen Clinic
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Clinical Case

• 50 year old asymptomatic physician with HIV
  infection presented for routine care in May 1999
• CD4350, HIV viral load 35,000
• Physical exam normal except for 3 cm irregular
  hard anal mass
• Biopsy invasive squamous cell carcinoma

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Clinical Case -2

• Resection had positive margins
• He was treated with radiotherapy and mitomycin C
  5FU
• Severe disabling radiation proctitis
• Biopsy at end of treatment showed residual tumor
• Abdominal perineal resection in 11/99
• Small bowel obstruction?ileocolic anastasmosis
  (3/00)
• Bilateral hydronephrosis and renal failure
• Declined intervention
• Viral load lt50 prior to withdrawal of therapy

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Audience Response Questions

• Is anal dysplasia screening with Pap smears being
  routinely done in your primary clinical site?
• Yes
• No
• Is high resolution anoscopy (HRA) available to
  patients receiving care at your primary clinical
  site
• Yes, on site
• Yes, by outside referral
• Not available

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Evidence-based screening What kind of evidence
is needed?

• How important is the health condition to be
  sought in terms of frequency, morbidity, and
  mortality?
• How good is the screening test in terms of
  accuracy, safety, simplicity, acceptability (to
  patients and providers), labeling effects, and
  financial costs?
• How strong is the evidence that the outcome will
  improve if treatment is given after screening
  rather than at the time the patient presents with
  symptoms?

(Fletcher, S. ACP Journal Club. 1998 128A12)
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Lead-time Bias in Screening
(http//bmj.com/epidem/epid.a.html)
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How important is the health condition to be
sought in terms of frequency, morbidity, and
mortality?
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Epidemiology

• US Incidence of cervical cancer 8 / 100,000 (1)
• Incidence of anal carcinoma in men with history
  of anal receptive intercourse 35 / 100,000 (2)
• Current incidence of anal carcinoma similar to
  that of cervical CA prior to routine PAP
  screening
• Anal CA among HIV MSM about twice the incidence
  among HIV MSM (3)

(1) Qaulters et al, 1992. (2) Daling et al,
1987. (3)Goedert et al, 1998
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Cervical CA as Model for Anal CA

• Similar histology
• Frequently arise in transformation zone (4)
• Both strongly associated with oncogenic strains
  of HPV (5)
• Both associated with squamous intraepithelial
  lesions (SIL)
• Cervical HSIL? Cervical CA
• Anal HSIL suspected ? Anal CA

(4) Palefsky, AIDS, 1994. (5) Frisch et al,
NEJM, 1997
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HPV Types and Anal Dysplasia

• HPV is double stranded DNA virus (gt100 subtypes)
• Low risk types (6, 11) associated with condyloma
  and LSIL
• Intermediate risk types (31, 33, 35,45, 51, 52,
  56)
• High risk types (16, 18)
• Present in 64 of invasive cervical CA (6)

(6) Bosch et al, JNCI, 1995
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Frisch et al. J Natl Cancer Inst 200092150010
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Relative risks (RRs) of developing cervical
cancer (invasive or in situ), anal cancer
(invasive or in situ, males only), Kaposi's
sarcoma, or non-Hodgkin's lymphoma in the 4-27
months after the AIDS period, according to the
CD4 T-lymphocyte count within /-1 month of
AIDS onset
Frisch, M. et al. J Natl Cancer Inst
2000921500-1510
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Four-year incidence of anal HSIL
Year
Chin-Hong et al. CID 2002351127-34
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Chin-Hong et al. CID 2002351127-34
Immune suppression
Genetic changes
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HAART HIV-associated Anal Cancer

• Cohort of 8640 HIV seropositive patients
• Overall incidence anal CA 60/100,000 p-yrs
• 120 times higher than age and gender matched
  controls
• Incidence by time period
• Pre-HAART 35/100,000 (95 CI 15-72)
• Post-HAART 92/100,000 (95 CI 52-149)

Bower et al. JAIDS 2004371563-1565
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Palefsky et al. AIDS 2005191407-1414
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24-Month Survival and Adjusted Death Hazards (vs.
persons having anal cancer without AIDS)
AIDS AIDS Survival (SE) Death Hazard
AIDS Onset 1980-1989 32 (12) 4.6
1990-1995 54 (8) 2.4
1996-2000 76 (11) 0.9
No AIDS 1996-2000 78 (lt1)
Biggar et al. JAIDS 200539293-299
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Audience Response Questions

• How strong is the evidence that invasive anal
  cancer is an important enough health condition to
  justify routine screening of HIV infected MSM?
• Very strong
• Moderately strong
• Neither strong nor weak
• Moderately weak
• Very weak

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Audience Response Questions

• How strong is the evidence that invasive anal
  cancer is an important enough health condition to
  justify routine screening of HIV infected women?
• Very strong
• Moderately strong
• Neither strong nor weak
• Moderately weak
• Very weak

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I. How good is the screening test in terms of
accuracy, safety, simplicity, acceptability (to
patients and providers), labeling effects, and
financial costs?
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Bethesda Staging System(2001) CIN/AIN

• Atypical squamous cells
• Of undetermined significance (ASCUS-US)
• Cannot exclude HSIL (ASC-H)
• Squamous intraepithelial lesion (SIL)
• Low grade SIL (LSIL)
• Mild dysplasia/CIN 1 (HPV cellular changes)
• High grade SIL (HSIL)
• Moderate dysplasia/CIN2
• Severe dysplasia/ CIS / CIN 3
• Squamous cell carcinoma

(Wright et al. JAMA 20022872120-2129)
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Chin-Hong et al. CID 2002351127-34
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Who to screen?

• HIV and HIV- MSM
• HIV women with history of
• Anal receptive intercourse
• Anogenital warts or HPV infection
• Cervical dysplasia
• Consider screening all HIV men and women

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ASIL Screening Procedures

• Ascertain risk ractors for ASIL
• HIV status and degree of immune suppression
• History of
• Anogenital warts
• Anal receptive intercourse
• Prior ASIL or CSIL
• Symptoms discharge, pain, bleeding
• Tobacco use
• Ascertain anal STD risk

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ASIL Screening Procedures

• Examine perianal area, perineum, and genitalia,
  including inguinal nodes
• Obtain PAP smear
• before digital rectal exam
• No prior douching or enemas
• Use dacron, not cotton swab, moistened in tap
  water
• Insert swab 1.5-2 inches
• Rotate against anal wall in spiral fashion for 10
  seconds while slowly withdrawing
• Roll swab across labeled slide and dip in
  fixative
• Perform digital rectal exam

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High Resolution Anoscopy

• Procedure
• Informed consent with patient education materials
• History and risk factor assessment
• Examination of perianal, perineal, and genital
  regions
• Obtain PAP and cultures (if indicated)
• Digital rectal exam with lidocaine/water based
  lubricant mixture
• Insert anoscope and through it insert 4X4 gauze
  soaked in 3 vinegar rolled around a cotton
  swab for 1-2 minutes
• Reinsert anoscope and examine with coloposcope

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High Resolution Anoscopy

• Lesions first examined after 3 acetic acid
  application
• Suspicious lesions (acetowhite, punctation,
  atypical vessels, ulcerations) should be biopsied
  (baby Tischler forceps)
• Lugols iodine can be applied
• Dysplastic lesions turn mustard or light yellow
  instead of mahogany brown
• Counsel regarding bleeding, pain, signs of
  infection
• Follow-up appointment in 1-2 weeks

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Monitoring after HRA

• If PAP HSIL but biopsy not concordant
• Repeat PAP and HRA in 3 months
• If biopsy HSIL/severe dysplasia or CIS and
  patient remains untreated
• Repeat HRA every 3-4 months
• If PAP and HRA concordant LSIL/mild-moderate
  dysplasia
• Repeat HRA in 6-12 months

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Anal Canal before 3 Acetic Acid
(Jay N et al. Dis Colon Rectum 199740923)
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Anal Transition Zone after Acetic Acid (x40)
(Jay N et al. Dis Colon Rectum 199740923)
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After 3 Acetic Acid (25x)
? indicates HGSIL area on biopsy
(Jay N et al. Dis Colon Rectum 199740923)
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HGSIL with Punctation (X40)
(Jay N et al. Dis Colon Rectum 199740923)
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Coarse Mosaicism Punctation (x40)
(Jay N et al. Dis Colon Rectum 199740923)
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Wart-like HGSIL (x16)
(Jay N et al. Dis Colon Rectum 199740923)
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Flat LGSIL (x16)
? Indicates granular surface
(Jay N et al. Dis Colon Rectum 199740923)
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Anal Colposcopic View after Acetic Acid and
Lugols Iodine
(1) Healthy Lugols (2) LSIL Lugols (3)
HSIL Lugols -
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UCSD Owen Clinic
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Slippage in Anal Cytology Technique
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Measures of Agreement

• Absolute agreement
• Cohens kappa
• Measure of chance-corrected agreement
• How to interpret
• 0.93-1.00 Excellent agreement
• 0.81-0.92 Very good agreement
• 0.61-0.80 Good agreement
• 0.41-0.60 Fair agreement
• 0.21-0.40 Slight agreement
• 0.01-0.20 Poor agreement
• 0.00 No agreement

(Byrt T. Epidemiology 19967561)
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Overall Reproducibility of Cytologic Diagnosis
Agreement Expected Agreement Kappa Std Err p-value
75.8 62.4 0.36 0.03 lt0.00001
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Variability in Cyto-Histopathologic Agreement
among Examiners
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Practice Effect for HRA Cyto-Histopathologic
Agreement
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The Fuzzy Gold Standard Issue

• Because of sampling variability, a
  histopathologic diagnosis based on biopsy at HRA
  is not necessarily a criterion or gold standard
  diagnosis
• No equivalent of the cervical LEEP in HRA
• Consider patients with HSIL PAPs and biopsies
  showing lower grade disease
• Is the PAP wrong?
• Was the high grade lesion missed at HRA?

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Agreement between PAP and Concurrent Biopsy
Agreement Expected Agreement Kappa Std Err p-value
74.7 60.5 0.36 0.06 lt0.00001
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Agreement between Colposcopic Visual Impression
and Biopsy
BIOPSY
Colpo Impression
lt AIN II ? AIN II
ltHSIL 60 43 103
? HSIL 21 62 83
81 105 186
Agreement Expected Agreement Kappa Std Err p
65.6 49.3 0.32 0.07 lt0.00001
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Prevalence of AIN III or CIS at Biopsy by
Simultaneous Cytologic Diagnosis (n154)
PAP diagnosis Prevalence of AIN III or CIS 95 CI (exact)
Normal 0 (0/7) 0 41
ASCUS 21 (5/24) 7 42
LSIL 27 (17/64) 16 39
HSIL 54 (32/59) 41 67
Overall 35 (54/154) 27 43
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Yield of Routine Cultures at Time of HRA in HIV
Clinic
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Cost-Effectiveness of ASIL CSIL Screening
(Goldie, 1999 2000)
Preventive Intervention Months Gained / Year of Life Saved
Cervical cytology screening Cervical cytology screening Cervical cytology screening
HIV- (q 3 yrs) 3.1 180,000
HIV (annual) 2.9 13,100
Anal cytology screening Anal cytology screening Anal cytology screening
HIV men (annual) 2.4 11,000
HIV- men (q 3y) 7,800
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Audience Response Question

• How good is anal dysplasia screening (Pap
  followed by HRA) in terms of accuracy, safety,
  simplicity, acceptability (to patients and
  providers), labeling effects, and financial
  costs?
• Very good
• Somewhat good
• Neither good nor bad
• Somewhat bad
• Very bad

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III. How strong is the evidence that the outcome
will improve if treatment is given after
screening rather than at the time the patient
presents with symptoms?
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Treatment Related Questions

• Will treatment of AIN prevent progression to
  invasive cancer?
• Will monitoring of high risk patients (those with
  HSIL cytology) lead to detection of invasive
  carcinoma at such an early stage that treatment
  with chemo-radiation can be avoided?

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Treatment of ASIL

• No accepted standard of treatment for ASIL
• Only patients with HSIL should be routinely
  recommended for treatment
• Treatments limited by morbidity high recurrence
  rates (50-85)
• Treatment options include
• Excision with fulguration
• Topical Rx with 80 TCA, cryotherapy, ?
  Imiquimod, ? Podophyllotoxin, ? 5FU cream,
  cidofovir
• Laser ablation
• Thermocoagulation/infrared photocoagulation
• Intralesional interferon

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Chin Hong et al. CID 2002351127-34
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Chin Hong et al. CID 2002351127-34
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Infrared Photocoagulation Treatment of Anal
Dysplasia in HIV-infected Males

• Goldstone et al. Dis Colon Rectum. 2005
  481042-54.

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Goldstone et al. Dis Col Rectum
2005481042-1054
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Recurrence Rates after IRC Treatment (n68
patients)
Treatment Recurrence (n/N) Median time to recurrence Median Baseline CD4
1 65 (44/68) 203 d 390
2 58 (21/36) 217 d 300
3 40 (6/15) 91 d 450
Goldstone et al. Dis Col Rectum 2005481042-1054
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Vaccine Approaches to HPV, Warts, and Dysplasia
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Franco et al. Vaccine 2005232388-2394
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Franco et al. Vaccine 2005232388-2394
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CSL HPV Immunotherapeutic

• Fusion product of HPV E6 and E7 proteins combined
  with novel adjuvant (ISCOMATRIX)
• Both E6 and E7 are expressed in HPV-associated
  dysplastic and malignant cells
• HPV E6 and E7 block activity of tumor suppressor
  genes p53 (E6) and RB (E7)
• Immunisation with E6 E7 proteins has potential
  to eliminate HPV-transformed cells

Frazer et al. Vaccine 200423172-81
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Antiviral Approaches
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Cidofovir

• Acyclic nucleoside phosphonate analog with
  activity against DNA viruses (herpes, CMV,
  adenovirus, polyomavirus, papilloma virus, pox
  virus)
• Not dependent on virally encoded thymidine kinase
• May act by antiviral and antiproliferative
  mechanisms (inducing apoptosis)1

1. Andrei et al. Oncol Res. 200012(9-10)397-408
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Topical Cidofovir for Oral Warts
Husak et al. Brit J Derm 2005152590-1
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Cidofovir Treatment of CIN III

• 15 women with biopsy proven CIN III
• Treated with Cidofovir gel 1 three times every
  other day
• Cervix removed within 1 month of start of
  treatment
• Complete response in 7/15
• Partial response 5/15
• Not toxic to normal epithelium as assessed at
  colposcopy

Snoeck et al. J Med Virol 200060205-209
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Snoeck et al. J Med Virol 200060205-209
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Audience Response Question

• How strong is the evidence that the outcome will
  improve if treatment is given after screening
  rather than at the time the patient presents with
  symptoms?
• Very strong
• Somewhat strong
• Neither strong nor weak
• Somewhat weak
• Very weak

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Audience Response Question

• How likely are to you recommend anal dysplasia
  screening as part of routine HIV care?
• Very likely
• Somewhat likely
• Not sure
• Somewhat unlikely
• Very unlikely

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