evidence based evaluation of anal dysplasia screening : ready for prime time? wm. christopher...

Evidence Based Evaluation of Anal Dysplasia Screening:

Ready for Prime Time?

Evidence Based Evaluation of Anal Dysplasia Screening:

Ready for Prime Time?Wm. Christopher Mathews, MD

San Diego AETC, UCSD Owen Clinic

Slide #2

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

Slide #3

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 obstructionileocolic anastasmosis (3/00)• Bilateral hydronephrosis and renal failure• Declined intervention• Viral load <50 prior to withdrawal of therapy

Slide #4

Audience Response Questions

1. Is anal dysplasia screening with Pap smears being routinely done in your primary clinical site?

a) Yesb) No

2. Is high resolution anoscopy (HRA) available to patients receiving care at your primary clinical site

a) Yes, on siteb) Yes, by outside referralc) Not available

Slide #5

Evidence-based screening: What kind of evidence is needed?

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

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

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?

(Fletcher, S. ACP Journal Club. 1998; 128:A12)

Slide #6

Lead-time Bias in Screening

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

Slide #7

How important is the health condition to be sought in terms of

frequency, morbidity, and mortality?

Slide #8

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

Slide #9

150

200

250

300

Rat

e pe

r 10

0,00

0 p-

yrs

0 21995-2005

Average Incidence Rate Invasive Anal CAOwen Clinic, 28 cases, 13411 years-at risk

Slide #10

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

Slide #11

HPV Types and Anal Dysplasia

• 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

Slide #12

Frisch et al. J Natl Cancer Inst 2000;92:1500–10

01

002

003

004

00R

elat

ive

Ris

k

<30 30-39 40-49 >=50 OverallAge Group

Women Men

Sex

Relative Risk is ratio of observed/expected

Frisch (2000), AIDS-Cancer Match Registry (1978-1996)Relative Risk of Invasive Anal Cancer (by age at onset of AIDS)

Slide #13

Frisch, M. et al. J Natl Cancer Inst 2000;92:1500-1510

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

Slide #14

Four-year incidence of anal HSILFour-year incidence of anal HSIL

0

0.1

0.2

0.3

0.4

0.5

0.6

0 1 2 3 4

HIV+, CD4<200HIV+, CD4:200-500HIV+, CD4>500HIV-

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

Slide #15

Immune suppression

Genetic changes

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

Slide #16

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 2004;37:1563-1565

Slide #17

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

Slide #18

24-Month Survival and Adjusted Death Hazards

(vs. persons having anal cancer without 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% (<1%)

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

Slide #19


I. How strong is the evidence that invasive anal cancer is an important enough health condition to justify routine screening of HIV infected MSM?

a) Very strong

b) Moderately strong

c) Neither strong nor weak

d) Moderately weak

e) Very weak

Slide #20


I. How strong is the evidence that invasive anal cancer is an important enough health condition to justify routine screening of HIV infected women?

a) Very strong

b) Moderately strong


d) Moderately weak

e) Very weak

Slide #21

I. How good is the screening test in terms of accuracy, safety, simplicity,

acceptability (to patients and providers), labeling effects, and

financial costs?

Slide #22

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 2002;287:2120-2129)

Slide #23

Slide #24

Slide #25

Slide #26

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

Slide #27

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

Slide #28

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

Slide #29

ASIL Screening Procedures

1. Examine perianal area, perineum, and genitalia, including inguinal nodes

2. Obtain PAP smeara) before digital rectal examb) No prior douching or enemasc) Use dacron, not cotton swab, moistened in tap waterd) Insert swab 1.5-2 inchese) Rotate against anal wall in spiral fashion for 10 seconds while

slowly withdrawing f) Roll swab across labeled slide and dip in fixative

3. Perform digital rectal exam

Slide #30

High Resolution Anoscopy

• Procedure1) Informed consent with patient education materials2) History and risk factor assessment3) Examination of perianal, perineal, and genital regions4) Obtain PAP and cultures (if indicated)5) Digital rectal exam with lidocaine/water based lubricant

mixture6) Insert anoscope and through it insert 4X4 gauze soaked in

3% vinegar & rolled around a cotton swab for 1-2 minutes7) Reinsert anoscope and examine with coloposcope

Slide #31

High Resolution Anoscopy

• 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

Slide #32

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

Slide #33

Anal Canal before 3% Acetic Acid

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

Slide #34

Anal Transition Zone after Acetic Acid (x40)


Slide #35

After 3% Acetic Acid (25x)


indicates HGSIL area on biopsy

Slide #36

HGSIL with Punctation (X40)


Slide #37

Coarse Mosaicism & Punctation (x40)


Slide #38

Wart-like HGSIL (x16)


Slide #39

Flat LGSIL (x16)


Indicates granular surface

Slide #40

Anal Colposcopic View after Acetic Acid and Lugol’s Iodine

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

Slide #41

43.62

34

15.04

7.327

010

20

30

40

Perc

ent

Normal ASCUS LSIL HSILAnal Cytology Diagnostic Category

(n=1864 patients)Distribution of Initial Anal Cytology Results

UCSD Owen Clinic

Slide #42

Slippage in Anal Cytology Technique.2

.4.6

.81

Pro

port

ion U

nsatisfa

cto

ry

1 2 3 4 5 6 7 8 9 10 11 12 13 14

by Submitting Provider (overall 0.27)Proportion Unsatisfactory Anal Cytology

Slide #43

Measures of Agreement

• 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)

Slide #44

Overall Reproducibility of Cytologic Diagnosis

Time 2 Normal ASCUS LSIL HSIL

Normal 102 91 27 14 234 ASCUS 44 97 51 31 223

LSIL 6 31 50 23 110 HSIL 2 17 17 39 75

Time 1

154 236 145 107 642

AgreementExpected

AgreementKappa Std Err p-value

75.8% 62.4% 0.36 0.03 <0.00001

Slide #45

n=16n=23

n=82n=269

n=487n=886

-.4

-.2

0.2

.4.6

Ka

pp

a

Overall One Two Three Four FiveOperator

Number of Procedures nKappa Agreement +/- 1 SE, Overall and by Operator

Variability in Cyto-Histopathologic Agreement among Examiners

Slide #46

Practice Effect for HRA Cyto-Histopathologic Agreement

.1.1

5.2

.25

.3.3

5K

app

a

0 100 200 300 400 500Number of Procedures

Kappa Fitted values

R^2 = 0.85

Kappa Agreement for 5 HRA Operators by Procedure VolumeCyto-Histopathologic Agreement is Related to Experience

Slide #47

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?

Slide #48

Agreement between PAP and Concurrent Biopsy

Concurrent Biopsy ≤ ASCUS LSIL HSIL

≤ ASCUS 10 14 7 31 LSIL 6 27 31 64 HSIL 3 7 49 59

PAP

19 48 87 154

Agreement Expected Agreement

Kappa Std Err p-value

74.7% 60.5% 0.36 0.06 <0.00001

Slide #49

Agreement between Colposcopic Visual Impression and Biopsy

< AIN II AIN II

<HSIL 60 43 103

HSIL 21 62 83

81 105 186

BIOPSY

Colpo

Impression

Agreement Expected Agreement

Kappa Std Err p

65.6% 49.3% 0.32 0.07 <0.00001

Slide #50

Prevalence of AIN III or CIS at Biopsy by Simultaneous Cytologic Diagnosis (n=154)

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%

Slide #51

Yield of Routine Cultures at Time of HRA in HIV Clinic

02

46

81

0P

erc

en

t of e

xam

s

GC Chlamydia Herpes EntericPathogenGCorCT AnyPathogen

637 exams on 455 patientsPrevalence of Anal STI at HRA

Slide #52

Cost-Effectiveness of ASIL & CSIL Screening (Goldie, 1999 & 2000)

Preventive Intervention

Months Gained $ / Year of Life Saved

Cervical cytology screening

HIV- (q 3 yrs) 3.1 ~180,000

HIV+ (annual) 2.9 ~13,100

Anal cytology screening

HIV+ men (annual)

2.4 ~11,000

HIV- men (q 3y) ~7,800

Slide #53

• 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?

a) Very goodb) Somewhat goodc) Neither good nor badd) Somewhat bade) Very bad

Audience Response Question

Slide #54

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?

Slide #55

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?

Slide #56

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

Slide #57

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

Slide #58

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

Slide #59

Infrared Photocoagulation Treatment of Anal Dysplasia in HIV-infected Males

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

Slide #60

Slide #61

Slide #62

Slide #63

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

Slide #64

Recurrence Rates after IRC Treatment (n=68 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 2005;48:1042-1054

Slide #65

Vaccine Approaches to HPV, Warts, and Dysplasia

Slide #66

Franco et al. Vaccine 2005;23:2388-2394

Slide #67

Franco et al. Vaccine 2005;23:2388-2394

Slide #68

Slide #69

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 2004;23:172-81

Slide #70

Antiviral Approaches

Slide #71

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. 2000;12(9-10):397-408

Slide #72

Topical Cidofovir for Oral Warts

Husak et al. Brit JDerm 2005;152:590-1

Slide #73

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 2000;60:205-209

Slide #74

Snoeck et al. J Med Virol 2000;60:205-209

Slide #75


• 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?

a) Very strong

b) Somewhat strong


d) Somewhat weak

e) Very weak

Slide #76


• How likely are to you recommend anal dysplasia screening as part of routine HIV care?

a) Very likelyb) Somewhat likelyc) Not sured) Somewhat unlikelye) Very unlikely

Slide #77

02

46

810

Fre

quen

cy

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005Year

Owen Clinic, 1995-2005Frequency of Invasive Squamous CA of Anal Canal

Slide #78

02

46

8R

ate

per

1000

p-y

rs

1996 1998 2000 2002 2004Year

Incidence Rate of Invasive Anal Cancer, by YearOwen Clinic, 22 cases, 13512 years-at-risk

evidence based evaluation of anal dysplasia screening : ready for prime time? wm. christopher...

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