1. Literature Review Peter R. McNally, DO, FACP, FACG
University Colorado School of Medicine
Center for Human Simulation
Aurora, Colorado 80045

2. Sunanda Kane, MD,1 Bahar Khatibi B Sc2 & Deepa Reddy, MD1
Higher Incidence of Abnormal Pap Smears in Women
With Inflammatory Bowel Disease. AM J Gastroenterol. 2008;103:
1Mayo Clinic, Rochester, Minnesota, and 2University of Chicago, Chicago, Illinois

3. Kane S, et al. AM J Gastroenterol. 2008;103;631-636
Introduction
Cervical cancer is one of the leading causes of cancer death among women world wide. 1
Human Papilloma Virus (HPV) infection has been linked to cervical cancer. 2
American College of Obstetricians and Gynecologists (ACOG) recommend yearly Pap smears for women younger than 30 yrs and screenings every 2-3 yrs for older women who have has three consecutive negative Pap smears.3
immunosuppression
1. Wright TC, et al. AJOG. 2007; Ellerbrock, et al. JAMA 2000;283: ACOG. Obstet Gynecol 2003;102:

4. Introduction Risk Factors for evolution of Cervical cancer4,5
Kane S, et al. AM J Gastroenterol. 2008;103;
Introduction
Risk Factors for evolution of Cervical cancer4,5
HPV (Human Papilloma Virus) infection of cervix
HIV
Immune suppression
Smoking
Serial Pap smear has been show to effectively detect HPV infection and dysplastic changes of the cervix.
A Meta-Analysis of the Yield of Capsule Endoscopy Compared to Other Diagnostic Modalities in Patients with Non-Stricturing Small Bowel Crohn's Disease. Triester S, Leighton JA, Leontiadis GI, et al. Am J Gastroenterol 2006;101:954-64
4. Edelman M, et al. Cancer. 1999;87; Bernatsky S, et al. Rheumatol. 2004;43:1386-9

5. Kane S, et al. AM J Gastroenterol. 2008;103;631-636
Aim
To determine if there is increased risk for abnormal Pap among patients with IBD compared to a like control population.
To determine if immune suppression medication among IBD patients increased the risk for abnormal Pap.

6. Study Design: Study Population
Kane S, et al. AM J Gastroenterol. 2008;103;
Study Design:
Study Population
Prospectively enrolled IBD patients over a 2 yr period of January 2004 through December 2005.
Demographics
N=40 (8 UC and 32 CD)
Baseline normal Pap smear prior to diagnosis of IBD & at least 2 Pap smears after Dx IBD
All had at least 3 Pap smears available for review
Exclusion Criteria
Pap smears unavailable for review
History of total hysterectomy

7. Study Design: Control Population
Kane S, et al. AM J Gastroenterol. 2008;103;
Study Design:
Control Population
Women receiving routine Pap smears in the University of Chicago Gynecology Clinic
All women without diagnosis of IBD or history of immune suppressant use
Each IBD patient was control matched to 3 ♀
Age within 2 yrs
Race
Parity
Smoking

8. Study Evaluations Definition of Immune Suppressant Rx (I-Rx)
Kane S, et al. AM J Gastroenterol. 2008;103;
Study Evaluations
Definition of Immune Suppressant Rx (I-Rx)
Azathioprine/6MP for 3 months
Prednisone > 15 mg/day for > 8 consecutive weeks
Methotrexate > 100 mg
Infliximab within 8 wk of Pap smear

9. Kane S, et al. AM J Gastroenterol. 2008;103;631-636
Study Evaluations
Pap Smears were conducted at University of Chicago Gynecology Clinics
Cytopapthology using Bethesda Criteria
All Pap smears tested using Digent Hybrid Capture II HPV-DNA test.

10. Study Evaluations Definition of Pap Smear Abnormalities
Kane S, et al. AM J Gastroenterol. 2008;103;
Study Evaluations
Definition of Pap Smear Abnormalities
ASC: atypical squamous cells of unknown significance
ASC-US: atypical squamous cells cannot r/o high grade lesion
ASG-H: atypical glandular cells
AGC: atypical glandular cells unknown significance
AGS-US: glandular or squamous carcinoma
SILs: atypical squamous cells with high grade intra- epithelial cells

11. Study Evaluations Bethesda Criteria for Pap Smear Classification
Kane S, et al. AM J Gastroenterol. 2008;103;
Study Evaluations
Bethesda Criteria for Pap Smear Classification
Pap Smear “High Grade”
ASG-H
SILs (low and high grade)
Pap Smear “Low Grade”
ASC
ASC-US
AGC
AGC-US

12. Kane S, et al. AM J Gastroenterol. 2008;103;631-636
Normal squamous cells
Illustrations Courtesy of: Mattu Rubina, MD, AFIP, Washington, DC

13. Normal endocervical cells
Kane S, et al. AM J Gastroenterol. 2008;103;
Normal endocervical cells
Illustrations Courtesy of: Mattu Rubina, MD, AFIP, Washington, DC

14. Low grade squamous intraepithelial lesion (LSIL) with koilocytes
Kane S, et al. AM J Gastroenterol. 2008;103;
Low grade squamous intraepithelial lesion (LSIL) with koilocytes
Illustrations Courtesy of: Mattu Rubina, MD, AFIP, Washington, DC

15. High Grade Squamous Intraepithelial lesion (HSIL)
Kane S, et al. AM J Gastroenterol. 2008;103;
High Grade Squamous Intraepithelial lesion (HSIL)
Illustrations Courtesy of: Mattu Rubina, MD, AFIP, Washington, DC

16. High Grade Squamous Intraepithelial lesion (HSIL)

17. Demographics: IBD vs. Controls
Kane S, et al. AM J Gastroenterol. 2008;103;
Demographics: IBD vs. Controls
Variable
IBD
N=40
Controls
N=120
P value
(+) I-Rx 23 NA
Age 1st abn Pap
24 +/- 4 yr
25+/- 3 yr NS
Oral contraceptive
58%
70%
P=0.04
Sexually Active
97%
96%
Smoking
37%
34%

18. Results: No. of women with history of abn Pap smear.
Kane S, et al. AM J Gastroenterol. 2008;103;
Results: No. of women with history of abn Pap smear.
Variable
IBD
(+) I-Rx
(-) I-Rx
Control
Total 40 23 17
120
Normal Pap 11 12
112
Low Risk Pap 7 9 4 6
High Risk Pap 10 3 1 2 OR
4.3( )
4.5 (
1.9 ( NA

19. Results: No abnormal Pap smears among all pts for 2 yr.
Kane S, et al. AM J Gastroenterol. 2008;103;
Results: No abnormal Pap smears among all pts for 2 yr.
Variable
IBD (+)
I-Rx
IBD (-)
Controls
P value
Normal Pap 47 35
298
Low Risk Pap 20 15
<0.001
High Risk Pap 2 7

20. Results: IBD (+) I-Rx, IBD (-) I-Rx, vs. Controls
Kane S, et al. AM J Gastroenterol. 2008;103;
Results: IBD (+) I-Rx, IBD (-) I-Rx, vs. Controls
50%
30% 7%
IBD
(+) I-Rx
IBD
(-) I-Rx
Control
Percentage of women with any history of abnormal Pap smear.

21. Results: HPV-DNA testing
Kane S, et al. AM J Gastroenterol. 2008;103;
Results: HPV-DNA testing
All “high risk” Pap smears were positive for HPV-DNA
Either serotype 16 or 18
50% of “low risk” Pap smears were (+) for HPV-DNA
Percentage of women with any history of abnormal Pap smear.

22. Results: Influence of I-Rx on Pap
Kane S, et al. AM J Gastroenterol. 2008;103;
Results: Influence of I-Rx on Pap
♀ on multiple I-Rx more likely to have abnormal Pap smear (p < 0.04)
♀ on I-Rx > 6 mo had a trend for abnormal pap (p=0.048)
♀ with “low grade” pap on I-Rx, lesions regressed with 6 mo of stopping I-Rx

23. Kane S, et al. AM J Gastroenterol. 2008;103;631-636
Conclusions:
Abnormal Pap smears were more common among IBD pts (17/40) vs. matched controls (8/120) 42% vs. 7%, respectively, p <
Both “low risk” and “high risk” Pap smears were more common in IBD group, P < for both Pap smear groups.
Stratification by IBD (+) I-Rx further increased risk over IBD (-) I-Rx for abnormal Pap smear, p <

24. Reviewer Comments Kane, et al, have clearly shown the following:
Kane S, et al. AM J Gastroenterol. 2008;103;
Reviewer Comments
Kane, et al, have clearly shown the following:
IBD pts have greater risk for abnormal Pap smear than matched controls, p <
IBD pts on I-Rx have greater risk for abnormal Pap smears that IBD pts not on I-Rx, p <
All ♀ with IBD and more importantly those on I-Rx should be considered for inclusion among the ACOG guidelines for more frequent cancer screening for immune compromised pts.

25. Reviewer Comments Kane, et al, do not answer the following questions?
Kane S, et al. AM J Gastroenterol. 2008;103;
Reviewer Comments
Kane, et al, do not answer the following questions?
What is the efficacy of quadrivalent HPV vaccine (Gardasil, Merck) among IBD pts?
Is vaccine protection of Gardasil (Merck) against HPV 16, 18 and 6, 11 as effective in IBD patients, especially those on I-Rx?
Should IBD pts still be undergo Pap smears after Gardasil (Merck) vaccination and how often?

26. Kane S, et al. AM J Gastroenterol. 2008;103;631-636
Reviewer Comments
Dr. Kane and colleagues are commended for demonstrating that IBD patients clearly have an increased risk for abnormal Pap smears in the decade prior to Gardasil vaccination against HPV 16 & 18.
We, as gastroenterologists should actively recommend Gardasil to ALL of our sexually active ♀ IBD pts. and caution that the vaccine is only 70% protective against cervical cancer. Hence, periodic gynecologic evaluation IS still advisable even after Gardasil in this high risk group.