Evidence Based Evaluation of Anal Dysplasia Screening
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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. Clinical Case. 50 year old asymptomatic physician with HIV infection presented for routine care in May 1999 CD4=350, HIV viral load 35,000

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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


Clinical case
Clinical Case

  • 50 year old asymptomatic physician with HIV infection presented for routine care in May 1999

  • CD4=350, HIV viral load 35,000

  • Physical exam normal except for 3 cm irregular hard anal mass

  • Biopsy: invasive squamous cell carcinoma


Clinical case 2
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 <50 prior to withdrawal of therapy


Audience response questions
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


Evidence based screening what kind of evidence is needed
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; 128:A12)


Lead time bias in screening
Lead-time Bias in Screening

(http://bmj.com/epidem/epid.a.html)


How important is the health condition to be sought in terms of frequency morbidity and mortality
How important is the health condition to be sought in terms of frequency, morbidity, and mortality?


Epidemiology
Epidemiology of frequency, morbidity, and mortality?

  • 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


Cervical ca as model for anal ca
Cervical CA as Model for Anal CA of frequency, morbidity, and mortality?

  • 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


Hpv types and anal dysplasia
HPV Types and Anal Dysplasia of frequency, morbidity, and mortality?

  • HPV is double stranded DNA virus (>100 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


Frisch et al. of frequency, morbidity, and mortality?J Natl Cancer Inst 2000;92:1500–10


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 2000;92:1500-1510


Four year incidence of anal hsil
Four-year incidence of anal HSIL 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

Year

Chin-Hong et al. CID 2002;35:1127-34


Chin-Hong et al. 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

CID 2002;35:1127-34

Immune suppression

Genetic changes


Haart hiv associated anal cancer
HAART & HIV-associated Anal Cancer 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

  • 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 2004;37:1563-1565


Palefsky et al. AIDS 2005;19:1407-1414 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


24 month survival and adjusted death hazards vs persons having anal cancer without aids
24-Month Survival and Adjusted Death Hazards (vs. persons having anal cancer without AIDS)

Biggar et al. JAIDS 2005;39:293-299


Audience response questions1
Audience Response Questions having anal cancer without AIDS)

  • 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


Audience response questions2
Audience Response Questions having anal cancer without AIDS)

  • 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


I. How good is the screening test in terms of accuracy, safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?


Bethesda staging system 2001 cin ain
Bethesda Staging System(2001): CIN/AIN safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

  • 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 2002;287:2120-2129)


Chin-Hong et al. CID 2002:35:1127-34 safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?


Who to screen
Who to screen? safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

  • 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


Asil screening procedures
ASIL Screening Procedures safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

  • 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


Asil screening procedures1
ASIL Screening Procedures safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

  • 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


High resolution anoscopy
High Resolution Anoscopy safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

  • 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


High resolution anoscopy1
High Resolution Anoscopy safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

  • Lesions first examined after 3% acetic acid application

  • Suspicious lesions (acetowhite, punctation, atypical vessels, ulcerations) should be biopsied (baby Tischler forceps)

  • Lugol’s 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


Monitoring after hra
Monitoring after HRA safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

  • 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


Anal canal before 3 acetic acid
Anal Canal before 3% Acetic Acid safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

(Jay N et al. Dis Colon Rectum 1997;40:923)


Anal transition zone after acetic acid x40
Anal Transition Zone after Acetic Acid (x40) safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

(Jay N et al. Dis Colon Rectum 1997;40:923)


After 3 acetic acid 25x
After 3% Acetic Acid (25x) safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

 indicates HGSIL area on biopsy

(Jay N et al. Dis Colon Rectum 1997;40:923)


Hgsil with punctation x40
HGSIL with Punctation (X40) safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

(Jay N et al. Dis Colon Rectum 1997;40:923)


Coarse mosaicism punctation x40
Coarse Mosaicism & Punctation (x40) safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

(Jay N et al. Dis Colon Rectum 1997;40:923)


Wart like hgsil x16
Wart-like HGSIL (x16) safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

(Jay N et al. Dis Colon Rectum 1997;40:923)


Flat lgsil x16
Flat LGSIL (x16) safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

 Indicates granular surface

(Jay N et al. Dis Colon Rectum 1997;40:923)


Anal Colposcopic View after Acetic Acid and Lugol’s Iodine safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

(1) Healthy Lugol’s +; (2) LSIL Lugol’s +; (3) HSIL Lugol’s -


UCSD Owen Clinic safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?


Slippage in anal cytology technique
Slippage in Anal Cytology Technique safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?


Measures of agreement
Measures of Agreement safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?

  • Absolute agreement

  • Cohen’s 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 1996;7:561)


Overall reproducibility of cytologic diagnosis
Overall Reproducibility of Cytologic Diagnosis safety, simplicity, acceptability (to patients and providers), labeling effects, and financial costs?




The fuzzy gold standard issue
The Fuzzy Gold Standard Issue Examiners

  • 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?




Prevalence of ain iii or cis at biopsy by simultaneous cytologic diagnosis n 154
Prevalence of AIN III or CIS at Biopsy Examinersby Simultaneous Cytologic Diagnosis (n=154)



Cost effectiveness of asil csil screening goldie 1999 2000
Cost-Effectiveness of ASIL & CSIL Screening Examiners(Goldie, 1999 & 2000)


Audience response question
Audience Response Question Examiners

  • 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


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?


Treatment related questions
Treatment Related Questions improve if treatment is given after screening rather than at the time the patient presents with symptoms?

  • 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?


Treatment of asil
Treatment of ASIL improve if treatment is given after screening rather than at the time the patient presents with symptoms?

  • 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


Chin Hong et al. CID 2002;35:1127-34 improve if treatment is given after screening rather than at the time the patient presents with symptoms?


Chin Hong et al. CID 2002;35:1127-34 improve if treatment is given after screening rather than at the time the patient presents with symptoms?


Infrared photocoagulation treatment of anal dysplasia in hiv infected males

Infrared Photocoagulation Treatment of Anal Dysplasia in HIV-infected Males

Goldstone et al. Dis Colon Rectum. 2005 48:1042-54.



Recurrence rates after irc treatment n 68 patients
Recurrence Rates after IRC Treatment (n=68 patients) HIV-infected Males

Goldstone et al. Dis Col Rectum 2005;48:1042-1054





Csl hpv immunotherapeutic
CSL HPV Immunotherapeutic HIV-infected Males

  • 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 2004;23:172-81


Antiviral approaches
Antiviral Approaches HIV-infected Males


Cidofovir
Cidofovir HIV-infected Males

  • 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. 2000;12(9-10):397-408


Topical cidofovir for oral warts
Topical Cidofovir for Oral Warts HIV-infected Males

Husak et al. Brit J

Derm 2005;152:590-1


Cidofovir treatment of cin iii
Cidofovir Treatment of CIN III HIV-infected Males

  • 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 2000;60:205-209



Audience response question1
Audience Response Question HIV-infected Males

  • 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


Audience response question2
Audience Response Question HIV-infected Males

  • 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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