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Prevalence of Anal Dysplasia in Patients With Inflammatory Bowel Disease Q22

Shamita B. Shah,*,a Danielle Pickham,‡,a Hiwot Araya,* Ahmad Kamal,§ Carlos E. Pineda,‡ Saif Ghole,‡ Lauren Shih,‡ Christina Kong,k Reet Pai,k and Mark Welton¶ *Division of Gastroenterology, ‡Division of Colorectal Surgery, kDepartment of Pathology, ¶Surgery-Colorectal Surgery, Stanford University School of Medicine, Stanford, California; §Division of Gastroenterology, Santa Clara Valley Medical Center, San Jose, California

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BACKGROUND & AIMS:

Although the prevalence of anal dysplasia is higher in some immunosuppressed populations, the prevalence in patients with inflammatory bowel disease (IBD) is unknown. We examined the prevalence of abnormal anal cytology among IBD patients, and its relation to the human papilloma virus (HPV).

METHODS:

Adults with IBD and age-matched healthy controls (HC) were recruited. IBD patients were categorized as nonimmunosuppressed (IBD-N) or immunosuppressed (IBD-I). Anal Papanicolaou tests were performed for HPV testing and classification by a cytopathologist as follows: negative, atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, cancer, or unsatisfactory.

RESULTS:

A total of 270 subjects (100 IBD-I, 94 IBD-N, and 76 HC) were recruited. ASC-US were detected in 19 subjects, with a trend toward a higher prevalence among IBD subjects compared with HC (8.8% vs 2.6%; P [ .10). The prevalence did not differ with respect to immunosuppression. Crohn’s disease (CD) subjects had a higher prevalence of ASC-US compared with others with IBD (P [ .02). Among those with CD, female sex and disease duration longer than 10 years were risk factors. There were no cases of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, or anal cancer in the cohort. HPV was present in 5.3% and 1.5% of subjects with and without ASC-US, respectively (P [ .26).

CONCLUSIONS:

Although there was a trend toward abnormal anal Papanicolaou tests in IBD subjects compared with HC, there was no difference based on immunosuppression. The presence of HPV did not correlate with abnormal anal cytology. Risk factors associated with this increased trend include female CD subjects and those with a longer duration of CD. ClinicalTrials.gov number: NCT01860963; https://clinicaltrials.gov/ct2/show/NCT01860963.

Keywords: Inflammatory Bowel Disease (IBD); Crohn’s Disease; Ulcerative Colitis; Human Papilloma Virus (HPV); Anal Pap Test; Anal Cancer; Anal Dysplasia; Atypical Squamous Cells of Undetermined Significance (ASC-US); Low-Grade Squamous Intraepithelial Lesion (LSIL); High-Grade Squamous Intraepithelial Lesion (HSIL); Immunosuppression.

Q7 Q8 Q9

nal dysplasia, also referred to as anal intraepithelial neoplasia (AIN) or squamous intraepithelial lesion (SIL), is a precursor for anal cancer. Similar to cervical dysplasia, AIN can be diagnosed by cytology obtained through an anal Papanicolaou (Pap) test. The natural history of the disease is not well understood, but early detection of dysplasia and treatment through targeted destruction of dysplastic cells may prevent malignant transformation.1 Current screening for anal dysplasia is limited to human immunodeficiency virus (HIV)-positive men who have sex with men.2 Guidelines have not been established for other potential at-risk patient populations.

A

Both cervical and anal cancers are highly associated with HPV, specifically types 16 and 18.3,4 Risk factors for anal dysplasia include smoking, receptive anal

a

Authors share co-first authorship.

Abbreviations used in this paper: AIN, anal intraepithelial neoplasia; ASCUS, atypical squamous cells of undetermined significance; CD, Crohn’s disease; HC, healthy control; HIV, human immunodeficiency virus; HRA, high-resolution anoscopy; IBD, inflammatory bowel disease; IBD-I, immunosuppressed inflammatory bowel disease; IBD-N, nonimmunosuppressed inflammatory bowel disease; Pap, Papanicolaou; SIL, squamous intraepithelial lesion; UC, ulcerative colitis. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.05.031

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intercourse, sexual promiscuity, and the presence of genital intraepithelial neoplasia.5,6 Furthermore, anal cancer also has been shown to occur at increased rates in certain immunosuppressed patient populations, such as patients with HIV or solid-organ transplantation.7–10 Inflammatory bowel disease (IBD) relies on the use of immunosuppressant therapy to control disease activity and symptoms. These immunosuppressant treatments impair cell-mediated immunity, leading to a greater chance of opportunistic infections and neoplasia. Some investigators have shown an increased risk of cervical dysplasia among female, immunosuppressed IBD patients.11 The risk of anal dysplasia and cancer in this cohort has not been well studied. We performed a prospective single-center, crosssectional study to evaluate the prevalence of anal dysplasia and HPV in patients with and without inflammatory bowel disease compared with healthy controls. We also explored risk factors associated with the development of anal dysplasia and the effect of immunosuppression. We hypothesized that immunosuppressed IBD patients have a higher prevalence of anal dysplasia compared with nonimmunosuppressed IBD patients or healthy controls.

Methods Study Design and Patients This single-center, cross-sectional study recruited patients from a single physician’s tertiary referral IBD practice from 2010 to 2013. Eligible patients were at least 18 years of age with an established diagnosis of IBD. We excluded patients who were immunosuppressed owing to other diseases (ie, systemic lupus erythematosus, cancer, rheumatoid arthritis, HIV, transplant) or who did not meet immunosuppression criteria (see protocol later). Pregnant women and patients with a previous diagnosis of AIN or anal/rectal squamous cell carcinoma, or history of HPV vaccination also were excluded. The institutional review board at Stanford University approved the protocol, and all patients provided written informed consent.

Controls Age-matched healthy controls were recruited at the time of screening or surveillance colonoscopy, upper endoscopy among patients with no lower-gastrointestinal symptoms, or during outpatient gastroenterology clinic visits. Other healthy controls were recruited from the general public by flyers and online advertisements. A complete medical history was obtained from all healthy volunteers. Patients were excluded if they had any underlying lower gastrointestinal symptoms, small-bowel or colonic pathology, or underlying immunosuppression.

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Protocol The study cohort comprised 3 groups: immunosuppressed IBD (IBD-I) patients, nonimmunosuppressed IBD (IBD-N) patients, and healthy controls (HCs). Immunosuppression was defined as use of azathioprine or 6-mercaptopurine for 3 months or more, prednisone 15 mg/day or more for 8 consecutive weeks, methotrexate cumulative dose of 100 mg or more, at least 3 infliximab infusions before the anal Pap test, at least 6 weeks of adalimumab treatment (3 doses) before the anal Pap test, or at least 6 weeks of certolizumab treatment (3 doses) before the anal Pap test. IBD patients who were off immunosuppressants were either on mesalamine, antibiotics, or no treatment for IBD. Informed consent was obtained from all participants. Participants completed an anonymous self-administered questionnaire assessing risk factors for HPV and AIN/ cancer at the time of the anal Pap test. The questionnaire was used to gather data relating to participants’ demographics, medical history, and social history including comprehensive sexual history. Disease severity scores also were obtained for all patients using simple the colitis index for ulcerative colitis patients and the Harvey–Bradshaw index for Crohn’s disease patients. All study patients underwent anal Pap sampling, performed at the time of a clinic visit or at the time of a scheduled endoscopy. The samples were collected using standard swabs, which then were suspended in Thin Prep (Hologic, Inc, Marlborough, MA) liquid medium before being sent to our internal pathology laboratory. All anal Pap slides were screened by cytotechnologists blinded to the patient status (IBD vs control) and IBD medications, and interpreted by board-certified cytopathologists who also were blinded to patient status. The diagnoses were reported as follows: (1) negative for intraepithelial lesion or malignancy, (2) atypical squamous cells of undetermined significance (ASC-US), (3) low grade SIL (AIN1), (4) high-grade SIL (AIN2-AIN3), (5) squamous cell carcinoma, or (6) unsatisfactory specimen. Repeat anal Pap tests were performed for participants with unsatisfactory specimens. Digene HC2 (Qiagen, Inc, Valencia, CA) was used to detect the presence of high-risk HPV DNA. Study participants with AIN were referred to a colorectal surgeon for further recommendations and treatment. High-resolution anoscopy (HRA) with possible directed cautery ablation was offered to all participants with abnormal anal cytology. Subjects who tested positive for HPV with normal or insufficient cytology were advised to undergo follow-up anal Pap sampling within 12 months.

Statistical Analysis Study results and data obtained using the selfadministered questionnaire were entered in a secure

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Table 1. Baseline Characteristics Pa

Variable

IBD-I

IBD-N

HC

N Age, mean, y (range) Female Race/ethnicity White Asian Black Hispanic Other Unknown Smoking history Current Former Never Marital status Married Single Divorced/separated Sexually active History of STD Previous abnormal cervical PAP test Multiple sexual partners No. of partners, mean (range) History of receptive anal sex IBD type Crohn’s disease Ulcerative colitis IBD-unspecified Mean age at diagnosis, y (range) Mean duration of IBD, y (range)

100 41 (19–77) 44%

94 43 (19–83) 52%

76 47 (22–76) 62%

71% 11% 5% 10% 2% 1%

67% 20% 1% 6% 3% 2%

59% 21% 5% 11% 4% 0%

2% 27% 71%

3% 19% 78%

0% 19% 81%

55% 42% 3% 94% 22% 31%

60% 34% 6% 97% 29% 24%

49% 37% 13% 97% 25% 26%

.95 .25 .90

44% 6.8 (0–20)

37% 6.0 (0–20)

46% 6.3 (0–20)

.21 .67

23%

14%

.08

67% 25% 8% 29 (10–65)

46% 47% 7% 33 (14–82)

-

.03

11.2 (1–58)

9.9 (1–59)

-

.44

.03 .25 .32

.41

.78

8%

.01

STD, sexually transmitted disease. a Mantel–Hanzel chi-square test or analysis of variance.

Q11

online database. SAS version 9.3 (Cary, NC) was used to perform data analysis. Based on studies in HIV and transplant patients,7–10 we estimated a prevalence of AIN of 5% in HC and 20% in IBD-I patients. For this, a sample size of 100 patients in each group was necessary to detect a difference with 85% power and a 5% a error. Baseline and demographic characteristics of the 3 groups were compared with the Mantel–Hanzel chisquare test (for categoric data) or analysis of variance (for continuous data, implemented in SAS using the GLM procedure). Chi-square tests and binary logistic regression were used to compare the prevalence of AIN with respect to the various putative risk factors. Those risk factors found to be significant in a univariate analysis were used in a multivariate logistic regression to determine independent risk factors for anal dysplasia in our population. All odds ratio were reported with a 95% confidence interval. A P value of less than .05 was considered significant for all comparisons. Study data,

3 Q1

analysis, and results were reviewed by authors and approved for publication.

Q12

Results A total of 290 patients were recruited over a 3-year period (January 2010 to June 2013). Thirty-two subjects with unsatisfactory specimens were asked to undergo a second anal Pap test. Seventeen agreed, yielding an additional 12 samples. leaving 20 subjects who were excluded because of unsatisfactory specimens. Table 1 shows enrollment by group. The final study cohort consisted of 270 subjects: 100 in the IBD-I group, 94 in the IBD-N group, and 76 in the HC group. Baseline characteristics are shown in Table 1. Although we attempted to age-match controls, the HC group was older than both IBD groups. The groups were otherwise similar with respect to sex, race, and ethnicity. The prevalence of smoking and sexual activity was similar among all 3 groups. In regard to sexual practices, multiple sexual partners was defined as more than 5 sexual partners. The HC group had a slightly higher rate of multiple sexual partners (46%), and immunosuppressed IBD subjects had a lower rate of receptive anal intercourse (8%). However, these differences did not reach statistical significance. Fifty-seven percent of IBD subjects had Crohn’s disease (CD), 36% had ulcerative colitis (UC), and 8% had IBD-unspecified. The mean duration of disease was approximately 10 years in both the IBD-I and IBD-N groups. Patients with CD were more likely to be immunosuppressed than those with UC. ASC-US were detected in 19 subjects, with a trend toward a higher prevalence of ASC-US among IBD subjects (both IBD-I and IBD-N) compared with healthy controls (8.8% vs 2.6%; P ¼ .10). However, the prevalence of ASC-US did not differ among IBD subjects with respect to immunosuppression status (Figure 2). HPV was present in 1 of the 19 subjects with ASC-US (5.3%) and in 4 of 251 subjects without ASC-US (1.5%; P ¼ .26). Of the 19 subjects with ASC-US, 6 subjects underwent HRA to confirm. Secondary analysis showed that the prevalence of ASC-US was higher among subjects with CD (P ¼ .02), but not for subjects with UC or IBDunspecified. Among patients with CD, female sex and disease duration of 10 years or more was linked to a higher prevalence of ASC-US (Table 2). Clinical characteristics of all subjects with ASC-US are listed in Supplementary Table 1. Risk factors for anal dysplasia in univariate analysis were female sex, positive HPV status, presence of CD, and longer duration of CD (Table 3). Only female sex and longer duration of CD (10 year) remained significant in multivariate analysis (Table 4). Of 19 subjects with ASC-US, 6 subjects had a followup HRA, 6 patients were lost to follow-up evaluation, 4 subjects agreed to repeat anal Pap cytology before undergoing HRA, and 3 subjects deferred the procedure. Of

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Table 2. Prevalence of ASC-US in Subgroups of Crohn’s Disease Subjects Variable Sex Male Female Duration of Crohn’s disease, y 0–4 5–9 10–14 15þ Disease score (Harvey–Bradshaw index) 0 1–2 3–4 5–6 7–8 9–10 Age, y 0) vs inactive Crohn’s disease (score ¼ 0) Crohn’s disease score  5 vs Crohn’s disease score < 5 Ulcerative colitis Ulcerative colitis vs healthy controls only UC for  10 years vs UC for < 10 years

3.8 1.1 1.3 0.7 0.6 3.4 2.5 3.6 3.7 1.1

1.2–11.7 0.4–2.9 0.3–4.6 0.2–2.6 0.4–4.5 0.4–32.0 1.0–6.6 0.8–15.7 0.8–17.5 0.4–2.9

.02 .84 .73 .62 .55 .29 Q21 .06 .10 .10 .90

3.4 5.0 2.7 0.8

1.3–9.4 1.1–22.6 0.8–8.5 0.2–2.3

.02 .04 .10 .58

4.2

1.2–14.5

.03

1.2

0.3–4.3

.77

0.4

0.1–1.5

.19

1.2

0.3–4.0

.84

0.3 1.1 1.7

0.1–1.4 0.2–8.1 0.1–28.0

.14 .92 .72

CI, confidence interval; OR, odds ratio; STD, sexually transmitted disease. a Binary logistic regression.

years.12,13 These rates are similar to cervical HPV rates of 26.8% reported by the National Health and Nutrition Examination Survey. In heterosexual men, the anal HPV rate has been reported as 16.6%.14 The presence of highrisk HPV is associated highly with SIL and the low rate in our population is consistent with the low rate of ASC-US and anal dysplasia. In our cohort, the overall prevalence of ASC-US was 7% (8.8% in the IBD group vs 2.6% in healthy controls). This is similar to the prevalence in other low-risk populations (3.9%–10%),15–17 but lower than the prevalence of AIN reported in other high-risk populations (19.6%– 28%), such as those with genital dysplasia or a history of transplant.16,18,19 However, the trend toward a higher prevalence of ASC-US in IBD patients is in keeping with the cervical dysplasia literature. Kane et al11 studied 40 patients with

Table 4. Independent Predictors of ASC-US Predictor

OR

95% CI

Pa

Female sex Crohn’s disease for  10 y

3.3 5.1

1.03–10.3 1.9–13.6

.047 .001

CI, confidence interval; OR, odds ratio. a Multiple logistic regression.

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465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522

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Anal Dysplasia in IBD Patients

IBD and compared with matched controls found the prevalence of cervical dysplasia to be higher in patients with IBD vs those without (42.5% vs 7%; P < .001). A larger study of 116 women with IBD by Bhatia et al20 found that the prevalence of cervical dysplasia was 3-fold higher in subjects with IBD vs healthy controls (18% vs 5%; P ¼ .004). Although the pathogenesis is not fully understood, the risk of dysplasia is greater in IBD patients. Additional risk factors for ASC-US from our study were as follows: female sex, HPV, Crohn’s disease, and a duration of Crohn’s disease of 10 year or longer. After multivariate modeling, female sex and long-standing Crohn’s disease remained as risk factors. In combination, women with long-standing Crohn’s disease (10 y) were 4.8 times more likely to have abnormal anal Pap cytology compared with other subjects (P ¼ .0038). One proposed mechanism for this was a reduction in human defensins in Crohn’s disease patients. Human defensins are proteins found within cells of the immune system that aid in the body’s defense against viruses. Human a-defensins 1, 2, 3, and 5 have been shown to inhibit both cutaneous and mucosal HPV.21 Human defensin 5 is present in the genital mucosa of women and is thought to act as a natural barrier against HPV. Defensins are produced by Paneth cells in the intestine and can be decreased in Crohn’s patients.22 Furthermore, patients with Crohn’s disease also may possess a genetic mutation in nucleotide-binding oligomerization domain 2, which is responsible for bacterial recognition and immune activation, which further decreases a-defensin levels.23 Although more research is needed in this area, the hindered ability for an IBD patient to defend against viral illness may be responsible for their susceptibility to HPV-related cervical and anal neoplasia. Another proposed mechanism for an increase of dysplasia in IBD patients is the use of immunosuppression. The study by Kane et al,11 for example, showed that more than 6 months of exposure to an immunosuppressant resulted in an increased risk of cervical dysplasia (odds ratio, 1.51; P ¼ .021). However, our study did not support this theory. There was a lack of association between immunosuppression and AIN. A careful review of other studies supports our findings. The case–control study by Bhatia et al20 found that although patients with IBD were at risk for cervical dysplasia, there was no influence of immunosuppression. In addition, Lee et al compared cervical dysplasia rates in 411 women with IBD with 1:4 age-matched, healthy controls and found no impact of immunosuppression on risk of dysplasia (12.4% vs 16.2%; odds ratio, 0.72; P ¼ .35). Most recently, in a population-based large Danish cohort study, women with CD showed a significantly increased risk of developing a low-grade and high-grade SIL and cervical cancer whereas UC patients showed a slightly increased risk of developing both low-grade and

5

high-grade squamous intraepithelial lesions but no increased risk of cervical cancer.24 This was similar to another IBD cohort study from Denmark, which suggested an increased risk of carcinoma in site and cervical cancer among patients with CD but not UC.25 This reason for this increased risk in Crohn’s disease patients is unknown. The paucity of studies and lack of powered data make it difficult to make any firm conclusions, especially when multiple prior studies in HIV, transplant, and lupus populations have suggested a clear association between HPV-related neoplasia and immunosuppression. One concern that our study did not shed light on, is whether the true influence of immunosuppression may be in fostering malignant transformation. Transformation of anal dysplasia to cancer is estimated at 6% compared with up to 13% to 50% of immunocompromised patients.26,27 There also have been reports of squamous cell carcinoma proximal to the transition zone in IBD patients.28 These findings are clinically significant because patients with IBD are at increased risk for dysplasia. Exposure to immunosuppressants may increase the risk that undetected, untreated dysplasia may progress to cancer. This highlights the need for additional studies in this area, and consideration of screening guidelines for anal Pap tests, as already established by the American College of Obstetrics and Gynecology for cervical dysplasia screening. There were some limitations of our study. The use of cytology to diagnose AIN may have influenced our results. High-resolution anoscopy, rather than cytology, is the gold standard for the diagnosis of AIN. Although cytology is a common screening modality, the sensitivity has been reported to be as low as 11.9%, and therefore may underestimate the prevalence of AIN.18 Also, our studied was slightly underpowered because of unsatisfactory samples. A majority of the unsatisfactory samples were from patients with ileoanal pouch anastomosis. These patients were not excluded from our study initially because, despite removal of their rectum, these patients still theoretically are at equal risk for anal dysplasia because their anal canal is intact. Furthermore, a questionnaire was used to obtain both medical and sexual history and may have resulted in reporting bias. We did not validate positive or negative patient-reported genital dysplasia history in women. This may explain why we did not find an association between a history of abnormal cervical cytology and the presence of AIN; a finding that has been well documented in a number of other studies.12,15,17 More recent data also have shown that vulvar, not cervical, dysplasia may be associated more strongly with AIN.18,19 Finally, although anonymous, the questions within the sexual history portion of the questionnaire were very sensitive in nature and may have resulted in reporting bias. Twenty-four percent of women reported a history

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of receptive anal intercourse. This was low compared with other studies in which 32% to 47% reported receptive anal intercourse.18,19 Receptive anal intercourse is a well-established risk factor for AIN15,16,18 and low reporting rates may explain why our study could not verify this as a risk factor. This study determined the prevalence of AIN and anal HPV, and evaluated associated risk factors in this population. The strengths of this study included the prospective nature of this study with 3 equal study groups including age-matched controls. Anal Pap samples were obtained by a limited number of study personnel who underwent training in performing anal Pap sampling before the study. Unsatisfactory anal cytology samples were excluded from the study. Two pathologists, who are experts in diagnosing anal dysplasia, were blinded to the patient’s group. AIN represents a spectrum of disease that, if left untreated, can progress to malignancy. Immunosuppressed patients are known to be at risk for AIN and cancer, and this study shows that IBD patients, especially women, and those with long-standing CD, are at higher risk. Although our study suggested that immunosuppression may not play a role in the risk of dysplasia, a question remains as to whether it contributes to malignant transformation in patients with dysplasia. More research needs to be performed to identify the utility of wider anal dysplasia screening programs in high-risk populations, and the role of HPV vaccine in prevention.

Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2015.05.031.

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8. Holly EA, Ralston ML, Darragh TM, et al. Prevalence and risk factors for anal squamous intraepithelial lesions in women. Q18 J Natl Cancer Inst 2001;93:843–849. 9. Kessler M, Jay N, Molle R, et al. Excess risk of cancer in renal transplant patients. Transpl Int 2006;19:908–914. 10. Ogilvie JW Jr, Park IU, Downs LS, et al. Anal dysplasia in kidney transplant recipients. J Am Coll Surg 2008;207:914–921. 11. Kane S, Khatibi B, Reddy D. Higher incidence of abnormal Pap smears in women with inflammatory bowel disease. Am J Gastroenterol 2008;103:631–636. 12. Hernandez BY, McDuffie K, Zhu X, et al. Anal human papillomavirus infection in women and its relationship with cervical infection. Cancer Epidemiol Biomarkers Prev 2005; 14:2550–2556. 13. Goodman MT, Shvetsov YB, McDuffie K, et al. Acquisition of anal human papillomavirus (HPV infection in women: the Hawaii HPV cohort study. J Infect Dis 2008;197: 957–966. 14. Nitray A, Nielson CM, Harris RB, et al. Prevalence of and risk factors for anal human papillomavirus infection in heterosexual men. J Infect Dis 2008;197:1676–1684. 15. Moscicki A, Hills NK, Shiboski S, et al. Risk factors for abnormal anal cytology in young heterosexual women. Cancer Epidemiol Biomarkers Prev 1999;8:173–178. 16. Holly EA, Ralston ML, Darragh TM, et al. Prevalence and risk factors for anal squamous intraepithelial lesions in women. J Natl Cancer Inst 2001;93:843–849. 17. Veo C, Saad S, Nicolau SM, et al. Study on the prevalence of human papillomavirus in the anal canal od women with cervical intraepithelial neoplasia grade III. Eur J Obstetr Gynecol Reprod Biol 2008;140:103–107. 18. El Naggar AC, Santoso JT. Risk factors for anal intraepithelial neoplasia in women with genital dysplasia. Obstet Gynecol 2013;122:219–223. 19. Tatti S, Suzuki V, Fleider L, et al. Anal intraepithelial lesions in women with human papillomavirus-related disease. Am Soc Q19 Colposcopy Cervical Pathol 2012. 20. Bhatia J, Bratcher J, Korelitz B, et al. Abnormalities of uterine cervix in women with inflammatory bowel disease. World J Gastroenterol 2006;12:6167–6171. 21. Buck CB, Day OM, Thompson CD, et al. Human a-defensins block papillomavirus infection. Proc Natl Acad Sci U S A 2006; 105:1516–1521. 22. Wehkamp J, Salzman NH, Porter E, et al. Reduced paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci U S A 2005;102:18129–18134. 23. Savoye G, Lerebours E. Abnormal pap smears in women with Q20 Crohn’s disease: is there a role for defensin deficiency. 24. Rungoe C, Simonsen J, Riis L, et al. Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study. Clin Gastroenterol Hepatol 2015;13:693–700. 25. Jess T, Horvath-Puho E, Falingborg J, et al. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study. Am J Gastroenterol 2013;108:1869–1876. 26. Devaraj B, Cosman BC. Expectant management of anal squamous cell dysplasia in patients with HIV. Dis Colon Rectum 2006;49:36–40. 27. Scholefield JH, Castle MT, Watson NF. Malignant transformation of high-grade anal intraepithelial neoplasia. Br J Surg 2005;92:1133–1136.

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Anal Dysplasia in IBD Patients

28. Kulaylat MN, Doerr R, Butler B, et al. Squamous cell carcinoma complicating idiopathic inflammatory bowel disease. J Surg Oncol 1995;59:48–55.

Reprint requests Address requests for reprints to: Shamita B. Shah, MD, Division of Gastroenterology, Stanford University School of Medicine, 300 Pasteur Drive, Room

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M211, MC 5187, Stanford, California 94305. e-mail: shamita.shah@stanford. edu; fax: (xxx) xxx-xxxx. Acknowledgments The authors thank Hologic, Inc (Marlborough, MA), for providing the Thin Prep PAP test at no charge. Conflicts of interest The authors disclose no conflicts.

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Clinical Gastroenterology and Hepatology Vol.

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Supplementary Table 1. Details of Patients With ASC-US Age, y Sex Race/ ethnicity

IBD

IBD location Colon Colon Colon, perianal Colon, perianal Ileocolonic Ileocolonic Ileocolonic Ileocolonic Ileocolonic Ileocolonic, perianal Ileocolonic, perianal Ileum Upper GI, colon Extensive (beyond splenic flexure) Left sided (to splenic flexure) Chronic pouchitis Rectum N/A N/A

60 62 37 27 32 55 38 43 49 41 76 36 27 56

F M F F F F F F F M M F F F

White White Asian Hispanic White White White Hispanic White Asian White White White White

CD CD CD CD CD CD CD CD CD CD CD CD CD IBD-U

30

F

Hispanic

IBD-U

31 29 60 62

F M F F

White Black White White

J pouch UC N/A (control) N/A (control)

IBD duration, y Smoke Immunosuppression HPV status 1 14 7 1 3 28 1 13 21 13 57 20 16 3

Former No No No No Former No No Former No No Former Former No

No No Yes No Yes Yes No No No Yes Yes Yes Yes Yes

Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Positive Negative

10

Former

Yes

Negative

15 2 N/A N/A

No No Former Former

No No No No

Negative Negative Negative Negative

GI, gastrointestinal; IBD-U, IBD-unspecified.

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Prevalence of Anal Dysplasia in Patients With Inflammatory Bowel Disease.

Although the prevalence of anal dysplasia is higher in some immunosuppressed populations, the prevalence in patients with inflammatory bowel disease (...
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