Epithelial dysplasia and cancer in IBD strictures

Journal : ECCOJC Article Doi

: 10.1093/ecco-jcc/jjv108

Article Title

: Epithelial dysplasia and cancer in IBD strictures

First Author

: Amnon Sonnenberg

Corr. Author

: Amnon Sonnenberg

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AUTHOR QUERY FORM Journal

: ECCOJC

Article Doi

: 10.1093/ecco-jcc/jjv108

Article Title : Epithelial dysplasia and cancer in IBD strictures First Author : Amnon Sonnenberg Corr. Author : Amnon Sonnenberg AUTHOR QUERIES - TO BE ANSWERED BY THE CORRESPONDING AUTHOR The following queries have arisen during the typesetting of your manuscript. Please click on each query number and respond by indicating the change required within the text of the article. If no change is needed please add a note saying “No change.” AQ1 AQ2

‘Portland, OR, USA’ has been added. OK?

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This has been reworded because in the original sentence it did not seem clear what was the risk factor and what was possibly affected by or associated with the risk factor (‘the risk of A’ in UK English means the risk of A occurring). Is this change correct or do you mean e.g. ‘colonic stricture and epithelial dysplasia as risk factors for the occurrence of colonic adenocarcinoma.’ or ‘the associations among colonic stricture, epithelial dysplasia and colonic adenocarcinoma’?

AQ4


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Please clarify what ‘its’ refers to.


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Journal of Crohn's and Colitis, 2015, 1–7 doi:10.1093/ecco-jcc/jjv108 Original Article

Original Article

Epithelial dysplasia and cancer in IBD strictures Amnon Sonnenberg1,2, Robert M. Genta1,3 AQ1

Miraca Life Sciences, Irving, TX, USA 2Oregon Health & Science University, Portland, OR, USA 3University of Texas Southwestern Medical Center, Dallas, TX, USA

1

Corresponding author: Amnon Sonnenberg, Portland VA Medical Center P3-GI, Portland, OR 97239, USA. Tel: +1-503-220-8262; Email: [email protected]

Abstract

AQ2

Background: Colonic strictures and epithelial dysplasia are both known risk factors for the occurrence of colorectal cancer in inflammatory bowel disease (IBD) patients. The aim of the present work was to study colonic stricture as a risk factor for the occurrence of epithelial dysplasia and colonic adenocarcinoma. Methods: In a case–control study among 53 568 IBD patients undergoing colonoscopy, we compared the prevalence of strictures among cases with dysplasia or adenocarcinoma and controls without such complications by calculating odds ratios (ORs) and their 95% confidence intervals (CIs). Multivariate logistic regressions were used to assess the joint influence of multiple predictor variables (age, sex, IBD type and stricture) on the occurrence of colonic dysplasia or adenocarcinoma. Results: The prevalence of strictures was 1.06% in ulcerative colitis (UC) and 8.71% in Crohn’s disease (CD, OR 11.09, 95% CI 9.72–12.70). The prevalence of dysplasia was 3.22% in UC and 2.08% in CD (OR 0.75, 95% CI 0.65–0.86). The prevalence of dysplasia was similar in IBD patients with and without stricture: 2.82 and 2.41%, respectively. The prevalence of cancer was higher in IBD patients with than without stricture: 0.78 and 0.11%, respectively (OR 6.87, 95% CI 3.30–12.89). In the multivariate analysis, old age, male sex and UC, but not stricture, were all significantly and independently associated with dysplasia. Old age, dysplasia and stricture were significantly and independently associated with cancer. Conclusion: The prevalence of epithelial dysplasia is not generally increased in IBD patients with strictures. Key Words: Colon cancer; dysplasia; epidemiology; histopathology of inflammatory bowel disease; intestinal strictures

1. Introduction AQ3

The incidence of colorectal cancer is considerably higher in patients with inflammatory bowel disease (IBD) than in the general population.1 The incidence rises exponentially with increasing duration of the disease.2 Regular surveillance colonoscopies serve to detect epithelial dysplasia as precursor lesions before invasive cancer develops.3 Colonic strictures detected during colonoscopy are frequently associated with the occurrence of cancer.4 The interaction between colonic strictures and epithelial dysplasia and their joint influence on the occurrence of colorectal cancer in IBD patients are unknown. The aim of the present work was to study colonic stricture

as a risk factor for the occurrence of epithelial dysplasia and colonic adenocarcinoma.

2. Materials and methods 2.1. Data source The Miraca Life Sciences Database is an electronic repository of histopathological patient records. Biopsy specimens are submitted to Miraca Life Sciences by ~1500 gastroenterologists from private practices distributed throughout the USA. In general, Miraca Life Sciences does not serve academic institutions or federal hospitals.

Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation (ECCO) 2015. This work is written by US Government employee and is in the public domain in the US

1

Copyedited by: OUP

A. Sonnenberg and R. M. Genta

2 The database contains demographic information, a detailed list of all results of surgical pathology reports (current and past, coded in a predefined, standardized and searchable fashion), a summary of the endoscopic report and a synopsis of the clinical indications that led to the endoscopic procedure. Medication history, serology and results of other laboratory tests are rarely provided with the pathology specimen. Therefore, they were not extracted for the performance of this study. In the recent past, this database has been utilized for a variety of histo-epidemiological studies.4–10 For the purpose of the present study, the database was searched for all records of IBD patients who underwent a colonoscopy between January 2008 and December 2014. Colonoscopies among IBD patients were searched irrespective of their primary indication, e.g. initial diagnosis, surveillance or onset of new symptoms. The analysis was restricted to biopsy specimens obtained during colonoscopy; surgical resection specimens were not included in the analysis. All data were derived from pre-existing records. No direct contact with either patients or providers was made and no individual patient information was revealed. All patient records were de-identified before being analysed. For these reasons, the study protocol was exempted from the need for informed consent from its participants.

2.2. Histopathological diagnoses All biopsy specimens were read by board-certified gastrointestinal pathologists. The diagnosis of inflammatory bowel disease rested on the clinical diagnosis provided by the endoscopist and the histopathological assessment by the pathologist. The pathologist looked for presence of increased lymphoplasmocytic lamina propria cellularity, active cryptitis, crypt abscesses, distorted crypt architecture and Paneth cell metaplasia in the distal colon.11 Crohn’s disease was diagnosed in the presence of chronic ileitis, rectal sparing, normal mucosa interspersed with inflamed areas (‘skip lesions’) and/or nonnecrotizing granulomas. In instances when patients could not be differentiated into ulcerative colitis or Crohn’s disease, we used the term ‘indeterminate colitis’. Areas of dysplasia were detected by the combination of characteristic architectural and cytological abnormalities.12–14 Depending on the severity of intra-epithelial nuclear aberration and stratification, dysplasia was classified into low- and high-grade dysplasia. Adenocarcinomas were diagnosed when invasion of or beyond the muscularis mucosae was present. All cases of suspected dysplasia (low or high grade) and carcinoma detected in specimens from patients with IBD were reviewed in documented intradepartmental consultations or at consensus conferences, according to Miraca Life Sciences policy. Polyps that occurred proximal to the inflammation (in ulcerative colitis) or in areas unaffected by the inflammation were assumed to be sporadic adenomas unrelated to IBD. Such lesions were not included in the overall counts of dysplasia. The diagnosis of colonic stricture was made by the endoscopist based on endoscopic appearance.

2.3. Statistical analyses The statistical analyses compared cases (IBD patients with dysplasia or adenocarcinoma) and controls (IBD patients without such lesions). The study was focused on testing the influence of stricture (as the primary predictor variable) on the occurrence of dysplasia or cancer as two separate outcome variables. Varying gender distributions between case and control subjects were compared by calculating odds ratios (ORs) and their 95% confidence intervals (CIs). The prevalences of strictures, dysplasia and adenocarcinoma were compared between patients with ulcerative colitis and Crohn’s disease

by calculating ORs and their 95% CIs, using multivariate logistic regression analyses to adjust for the confounding influences of gender and age. Multivariate logistic regressions were used to assess the joint influence of multiple predictor variables (age, sex, IBD type and stricture) on the occurrence of colonic dysplasia or adenocarcinoma.

3. Results The database contained a total of 53 568 IBD patients. The largest fraction consisted of patients with ulcerative colitis followed by patients with Crohn’s disease and indeterminate colitis. Of all patients, 2.4% were found to harbour strictures during colonoscopy. Similarly, 2.8% of all patients were found to have mucosal changes consistent with any type of dysplasia, the majority being low-grade dysplasia (Table 1). In ulcerative colitis and Crohn’s disease alike, the age-specific prevalence of dysplasia showed a marked age-specific rise (Figure 1). In ulcerative colitis, the age-dependent rise in colon cancer followed a pattern similar to that of dysplasia. Patients with colon cancers in Crohn’s disease were too infrequent to discern an obvious pattern. In ulcerative colitis, the prevalence of strictures also showed an age-dependent rise, albeit less pronounced than that of dysplasia. In Crohn’s disease, the occurrence of strictures started to rise at a much younger age than in ulcerative colitis and then appeared to level off after the age of 40 years. Figure 2 contains the stratification of stricture, dysplasia and colon cancer by sex. In ulcerative colitis, dysplasia and colon cancer were both more common in men than women. In Crohn’s disease, dysplasia was more common and colon cancer less common in men than women. Table 2 shows the prevalence of stricture and dysplasia, stratified by type of IBD. Colonic strictures were about 11-fold more common in Crohn’s disease than in ulcerative colitis. Dysplasia occurred significantly less often in Crohn’s disease than in ulcerative colitis. No significant difference between the two types of IBD was found with respect to their prevalence of high-grade dysplasia or adenocarcinoma. A total of 31 patients were found to harbour both stricture and dysplasia. In 10 of 31 patients, the dysplasia was found within the stricture itself. In the remainder of this patient group with strictures and dysplasia, the strictures were located remotely from the area of dysplasia. Their tissue samples from the strictures showed only epithelial changes indicative of acute or chronic inflammation. In 10 patients with stricture and cancers, 8/10 cancers were located within Table 1. Patient characteristics. Patient characteristics All inflammatory bowel disease Ulcerative colitis Crohn’s disease Indeterminate colitis Mean age (years, SD) Males* Females Strictures Any type of dysplasia Low-grade dysplasia High-grade dysplasia Colonic adenocarcinoma *17 patients with unknown sex.

n

%

53 568 37 043 11 700 4825 49.6 (16.5) 26 449 27 102 1285 1507 1478 29 69

100.00 69.15 21.84 9.01 49.37 50.59 2.40 2.81 2.76 0.05 0.13

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Dysplasia and cancer in IBD strictures

3

8.0%

0.4%

6.0%

0.3%

4.0%

0.2%

2.0%

0.1%

0.0%

0.0% 0-9

10-19 20-29 30-39 40-49 50-59 60-69 70-79 Age group

80+

0.5%

UC 8.0%

0.4%

Dysplasia

6.0%

0.3%

4.0%

0.2%

Cancer

2.0%

0.1% Stricture

0.0%

Adenocarcinoma prevalence

Stricture or dysplasia prevalence

10.0%

0.0% 0-9

10-19 20-29 30-39 40-49 50-59 60-69 70-79 Age group

80+

10.0% Stricture or dysplasia prevalence


0.5%

IBD

0.5%

CD 8.0%

0.4%

6.0%

0.3%

4.0%

0.2%

2.0%

0.1%

0.0%



10.0%

0.0% 0-9

10-19 20-29 30-39 40-49 50-59 60-69 70-79 Age group

80+

Figure 1. Age-dependent rise in the prevalence of stricture, any dysplasia or adenocarcinoma among patients with inflammatory bowel disease (IBD, upper panel), ulcerative colitis (UC, middle panel) or Crohn’s disease (CD, lower panel).

the stricture itself. Table 3 lists stricture and dysplasia or adenocarcinoma by site and IBD type in the 41 patients with coincidence of these lesions. Table 4 shows the interplay between the occurrence of stricture and dysplasia or colon cancer. The occurrence of stricture was not associated with a generally increased prevalence of any dysplasia. There was a trend, however, for stricture to be associated with an increased prevalence of high-grade dysplasia or adenocarcinoma. Polyps in areas unaffected by the inflammation were assumed to be sporadic adenomas and excluded from the analysis. Table 5 contains a comparison of patients with and without colonic strictures with respect to the presence of adenomatous polyps. Adenomatous polyps with high-grade dysplasia were generally

rare. Their prevalence was not increased among IBD patients with strictures. In two multivariate logistic regressions, the presence of any type of dysplasia or colon adenocarcinoma served as two separate outcome variables. Age (old vs young), sex (female vs male), IBD type (Crohn’s disease or indeterminate colitis vs ulcerative colitis) and stricture (vs no stricture) served as predictor variables (Table 6). In general, the results of the multivariate analyses confirmed the observations of the prior univariate analysis. Stricture was a strong and independent risk factor for the occurrence of colonic adenocarcinoma, but not for the occurrence of dysplasia. Besides stricture, old age and dysplasia (as predictor variable) both exerted a statistically significant influence on the presence of colonic adenocarcinoma. With respect to dysplasia,

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IBD

4.0%

*

3.0%

1.0% 0.0%

0.0% Male

5.0% *

4.0%

UC

0.5% 0.4% 0.3%

3.0% *

2.0%

0.2% 0.1%

1.0% 0.0%



0.1%

* 2.0%

Female

Stricture LHG Dysplasia Adenocarcinoma

0.0% Female


0.2% Adenocarcinoma prevalence

5.0%

Male

10%

CD

5%

0.2%

0.1% *

*

0%

Prevalence of adenoca


4

0.0% Female

Male

Figure 2. Sex-dependent variations in the prevalence of stricture, any dysplasia or adenocarcinoma among patients with inflammatory bowel disease (IBD, upper panel), ulcerative colitis (UC, middle panel) or Crohn’s disease (CD, lower panel).

Table 2. Comparison of patients with ulcerative colitis (UC) and Crohn’s disease (CD). Number of patients

All patients Stricture Any type of dysplasia High-grade dysplasia Colonic adenocarcinoma

Prevalence in patients

UC

CD

UC

CD

37 043 295 1,194 23 54

11 700 933 244 6 13

1.06% 3.22% 0.06% 0.15%

8.71% 2.08% 0.05% 0.11%

OR*

95% CI

11.09 0.75 0.93 0.89

9.72–12.70 0.65–0.86 0.34–2.16 0.46–1.58

*Adjusted for age and sex.

old age, female sex and IBD type exerted statistically significant influences similar to those in the univariate analyses.

4. Discussion The present case–control study was undertaken to study colonic stricture as a risk factor for the occurrence of epithelial dysplasia and colonic adenocarcinoma. Stricture was found to be a significant risk factor for the occurrence of colonic adenocarcinoma, but not

epithelial dysplasia. Besides strictures, older age and the presence of any dysplasia also exerted statistically significant influences on the occurrence of adenocarcinoma in the colon of IBD patients. Epithelial dysplasia was most commonly found in older patients, male patients and patients with ulcerative colitis. Using X-ray imaging, the National Cooperative Crohn’s Disease Study reported colonic strictures in 10% of patients with Crohn’s disease.15 Based on the Vienna classification, 11% of patients with Crohn’s disease were found to harbour ileal or colonic strictures.16

AQ4

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Dysplasia and cancer in IBD strictures

5

Table 3. Coincidence of stricture with dysplasia or adenocarcinoma by site and type of inflammatory bowel disease. Dysplasia location

Stricture location

Dysplasia

Rectum

Sigmoid

Descending

Transverse

Asc + caecum

Rectum Sigmoid Descending Transverse Asc + caecum IC valve

1, 3

0, 1 2, 2

1, 1

0, 1 0, 2

1, 0

0, 1

0, 1 0, 1 1, 0 2, 0

Asc + caecum

1, 0

2, 0

2, 0

1, 0 1, 0 3, 0

Sigmoid

Descending

Transverse

IC valve

Adenocarcinoma location

Stricture location

Cancer

Rectum

Rectum Sigmoid Descending Transverse Asc + caecum IC valve

0, 3

IC valve

0,1 0, 2 1, 0

1, 0 2, 0

The upper part shows the relationship between the location of stricture and dysplasia, the lower part the relationship between the location of stricture and adenocarcinoma. In each cell, the first number represents patients with Crohn’s disease and the second number patients with ulcerative colitis. IC, ileocaecal; Asc, ascending colon.

Table 4. Comparison of patients with and without colonic stricture with respect to presence of dysplasia or cancer. Number of patients

All inflammatory bowel disease Any type of dysplasia High-grade dysplasia Colonic adenocarcinoma Ulcerative colitis Any type of dysplasia High-grade dysplasia Colonic adenocarcinoma Crohn’s disease Any type of dysplasia High-grade dysplasia Colonic adenocarcinoma

Prevalence in patients

w/o strictures

w strictures

52 283 1476 27 59 36 748 1181 23 47 10 767 227 4 10

1285 31 2 10 295 13 0 7 933 17 2 3

OR*

95% CI

w/o strictures

w strictures

2.82% 0.05% 0.11%

2.41% 0.16% 0.78%

0.84 3.03 6.87

0.57–1.19 0.49–10.13 3.30–12.89

3.21% 0.06% 0.13%

4.41% 0.00% 2.37%

1.02 0.00 14.27

0.55–1.73

2.11% 0.04% 0.09%

1.82% 0.21% 0.32%

0.86 5.73 3.28

0.50–1.37 0.79–29.49 0.73–10.75

5.79–30.23

*Adjusted for age and sex.

Table 5. Comparison of patients with and without colonic strictures with respect to presence of adenomatous polyps. Number of patients None

OR

95% CI

0.56

0.38–0.82

1.31

0.18–9.62

Adenoma

Adenoma without high-grade dysplasia No stricture 50 352 1931 Stricture 1258 27 Adenoma with high-grade dysplasia No stricture 52 252 31 Stricture 1284 1

These prevalence rates are similar to the one found in the present study, which was limited to colonic lesions. Because of its smaller diameter, strictures are prone to occur more frequently in the small bowel than in the large bowel.17 Whereas the inflammation

associated with ulcerative colitis tends to be restricted to the mucosa, in Crohn’s disease it involves deeper layers of the intestinal wall. Accordingly, strictures occur less frequently in ulcerative colitis than in Crohn’s disease,18 as also evidenced by the present study. Patients with IBD harbour an increased risk of developing colorectal cancer. Various clinical characteristics contribute to this risk, such as young age at disease onset, disease duration, old age at the time of endoscopic screening, extent of colonic involvement, and comorbidity with primary sclerosing cholangitis.1,2,4,19 Among the endoscopic findings, the presence of colonic strictures and the presence of low- or high-grade dysplasia on colonic biopsies from mucosal irregularities are associated with the most significant risk of imminent colorectal cancer. Previous studies have suggested that malignancy might affect 29% of strictures in ulcerative colitis and 7% of strictures in Crohn’s disease.20,21 However, these previous studies might have been prone to a selection bias, including more severe cases of longstanding disease with fibrostenotic presentation. In general, more recent studies have

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6 Table 6. Results of multivariate analyses. Term

Estimate

Standard error

χ2

Logistic fit for presence of any dysplasia (χ2 = 812.3616, df = 5, p