Gastroenterology Research and Practice

Gastroenterology Research and Practice / 2016 / Article

Review Article | Open Access

Volume 2016 |Article ID 1632439 | https://doi.org/10.1155/2016/1632439

Chelle L. Wheat, Kindra Clark-Snustad, Beth Devine, David Grembowski, Timothy A. Thornton, Cynthia W. Ko, "Worldwide Incidence of Colorectal Cancer, Leukemia, and Lymphoma in Inflammatory Bowel Disease: An Updated Systematic Review and Meta-Analysis", Gastroenterology Research and Practice, vol. 2016, Article ID 1632439, 18 pages, 2016. https://doi.org/10.1155/2016/1632439

Worldwide Incidence of Colorectal Cancer, Leukemia, and Lymphoma in Inflammatory Bowel Disease: An Updated Systematic Review and Meta-Analysis

Academic Editor: Bjørn Moum
Received08 Feb 2016
Accepted21 Mar 2016
Published16 May 2016

Abstract

Background/Aims. Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC). In addition, there may be an association between leukemia and lymphoma and IBD. We conducted a systematic review and meta-analysis of the IBD literature to estimate the incidence of CRC, leukemia, and lymphoma in adult IBD patients. Methods. Studies were identified by a literature search of PubMed, Cochrane Library, Medline, Web of Science, Scopus, EMBASE, and ProQuest Dissertations and Theses. Pooled incidence rates (per 100,000 person-years [py]) were calculated through use of a random effects model, unless substantial heterogeneity prevented pooling of estimates. Several stratified analyses and metaregression were performed to explore potential study heterogeneity and bias. Results. Thirty-six articles fulfilled the inclusion criteria. For CRC, the pooled incidence rate in CD was 53.3/100,000 py (95% CI 46.3–60.3/100,000). The incidence of leukemia was 1.5/100,000 py (95% CI −0.06–3.0/100,000) in IBD, 0.3/100,000 py (95% CI −1.0–1.6/100,000) in CD, and 13.0/100,000 py (95% CI 5.8–20.3/100,000) in UC. For lymphoma, the pooled incidence rate in CD was 0.8/100,000 py (95% CI −0.4–2.1/100,000). Substantial heterogeneity prevented the pooling of other incidence estimates. Conclusion. The incidence of CRC, leukemia, and lymphoma in IBD is low.

1. Introduction

Colorectal cancer (CRC) incidence is higher in inflammatory bowel disease (IBD) patients than in the general population, and CRC accounts for an estimated 10–15% of deaths in patients with IBD [1]. The risk conferred by IBD may be due to chronic inflammation combined with genetic factors [13]. Patients with extensive inflammation, a younger age at diagnosis, long disease duration, comorbid primary sclerosing cholangitis (PSC), and pseudopolyposis are at the highest risk [414].

IBD patients receiving immunomodulators may or may not also be at higher risk of lymphoproliferative disorders such as lymphoma and leukemia [1519]. The risk of lymphoma in IBD patients is low but appears to be higher than in the general population [6, 8, 14, 2022]. The risk of leukemia in IBD is less clear [6, 8, 14, 23, 24].

Understanding the risk of development of these malignancies inherent to IBD is crucial for cancer surveillance strategies. In addition, determination of the absolute increase in risk of these malignancies from IBD pharmacotherapy is a crucial consideration for providers and patients. The aims of this study are to estimate the incidence of CRC, leukemia, and lymphoma in adult IBD patients through a systematic review and meta-analysis. Unique to this study, we attempt to evaluate the underlying risk of these cancers in IBD overall and separately Crohn’s Disease (CD) and ulcerative colitis (UC) and exclude the effects of IBD pharmacotherapy (specifically immunomodulators and biologics), given the evidence that these medications may increase cancer risk.

2. Materials and Methods

2.1. Literature Search

A detailed literature search was conducted to identify all published and unpublished studies examining the incidence of CRC, leukemia, and lymphoma in adult IBD patients. We searched the PubMed, Cochrane Library, Medline, Web of Science, Scopus, EMBASE, and ProQuest Dissertations and Theses databases. Reference lists of published articles were hand searched for secondary sources and experts in the field contacted for unpublished data. Furthermore, https://clinicaltrials.gov/, the WHO International Clinical Trial Registry, and scientific information packets of approved IBD pharmacotherapies were scrutinized for additional information sources. No restrictions on language, country of origin, or publication date were used. Figure 1 outlines the literature search and Supplementary Table  1 (in Supplementary Material available online at http://dx.doi.org/10.1155/2016/1632439) details the search strategy employed.

2.2. Inclusion and Exclusion Criteria

All studies that reported incidence or provided information sufficient to accurately calculate incidence for the three cancers of interest in adult IBD patients were included. Studies focusing on pediatric populations, not reporting person-years of follow-up, of duration less than one year, and not written in English and unable to be translated to English were excluded. If publications reported duplicate data on a population, only the publication with the longest follow-up period was included.

2.3. Data Collection and Quality Assessment

Two independent reviewers (CW and KCS) examined each article for inclusion according to the eligibility criteria. Any disagreement was resolved through discussion and consensus. Thirty-six articles fulfilled the inclusion criteria. Twenty-five articles reported incidence estimates for CRC [7, 10, 11, 13, 14, 18, 19, 21, 22, 2439], ten for leukemia [8, 14, 18, 19, 2124, 33, 39], and twenty-one for lymphoma [8, 10, 14, 18, 19, 21, 22, 24, 26, 33, 34, 3948] (some articles reported incidence estimates for multiple cancers). Figure 1 outlines the search flowchart.

We retrieved demographic (where possible) and outcome data for each included article using standardized forms. Individual studies were assigned a bias risk rating using the Cochrane Collaboration’s Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions (ACROBAT-NRSI) [49]. The strength of evidence for each cancer was assessed utilizing the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach [50].

2.4. Statistical Analysis

Individual study unadjusted incidence rates (per 100,000 person-years [py]) were calculated from the reported number of cancer cases and person-years of follow-up for each outcome separately. Standard errors and 95% confidence intervals (CIs) were estimated assuming a Poisson distribution [51]. In situations with zero observed cases, the value of 3.7 was used to calculate incidence rates and the confidence interval upper limit [51].

As our interest is in quantifying the incidence rate of CRC, leukemia, and lymphoma in IBD patients not treated with immunomodulators or biologic agents (and treatment information is often unreported), two stratification variables were created using study publication year as an estimate of when each medication class became widely used. 1995 was used as the dividing year for widespread immunomodulator use and 2000 for biologic use. Pooled incidence rates with 95% CIs were then calculated for (1) each cancer overall, (2) each cancer in CD and UC separately, (3) each cancer stratified by year of publication, and (4) each cancer stratified by country of origin (to determine if incidence varied by geographic region). A random effects model was used to account for potential between-study variations. The statistic was used to quantify the percentage of heterogeneity for all pooled estimates from between-study variation, with ≥75% indicating substantial heterogeneity [52]. Publication bias and the presence of other small study effects were measured through visual assessment of funnel plot symmetry and Egger’s test [52]. Sensitivity analyses were undertaken to explore potential sources of heterogeneity. Metaregression was used to further test the effects of study- and subject-level covariates on cancer risk, as well as the degree of between-study heterogeneity explained by the covariates through calculation of the adjusted . The adjusted measures the relative reduction in the between-study variance explained by the covariates in the model and is presented as a percentage [52]. Statistical analysis was performed using Stata (StataCorp, College Station, TX). values ≤0.05 were considered statistically significant.

3. Results and Discussion

3.1. Results
3.1.1. Colorectal Cancer

Reported incidence rates of CRC in IBD ranged from 41.5/100,000 py (95% CI 24.5–58.5/100,000) to 543.5/100,000 py (95% CI 316.4–770.6/100,000) (Table 1). Substantial heterogeneity prevented pooling of estimates using a random effects model (heterogeneity test, chi2 = 174.65; ; ). Therefore, we present unpooled incidence estimates. Separate sensitivity analyses excluding the studies with the highest individual incidence estimate [31] and the study with the greatest weight on the pooled estimate [7] did not significantly change the degree of heterogeneity present.

(a)

AuthorJournalPublication yearStudy designStudy populationRegion of originNumber of sitesStudy duration (yrs)Person-yearsNumber of patientsDiagnosisMean age (yrs)Female (%)Mean disease duration (yrs)Surgery (%)

Askling  et  al.  [25]    Gastroenterology 2001 Cohort National registry Europe (Western) Countrywide 54 169,332 
91,833  
77,499
19,459 
8,810
10,649
IBD
CD
UC
48.6
53.0
45.0

Bernstein  et  al.  [24]Cancer2001Case-controlAdministrative claimsCanadaRegionwide1441,005 
21,340
19,665
5,529 
2,857
2,672
IBD
CD
UC
39.0
36.3
41.7
54.5
59.0
50.0

Farrell  et  al.  [26]Gut2000CohortReferral centerEurope (Western)19 6,256 782 IBD44.152.010.0

Fraser  et  al.  [18]Aliment Pharmacol Ther2002CohortReferral centerEurope (Western)Countywide35 55,388 
20,494
34,894
1,578 
584
994
IBD
CD
UC
35.053.0

Gillen  et  al.  [27]    Gut 1994 Cohort Referral center Europe (Western) Countrywide 30 12,324 
2,320
10,004
611 
125
486
IBD
CD
UC

Herrinton  et  al.  [28]Gastroenterology2012CohortAdministrative claimsUnited StatesCountywide1261,793 
28,469
33,324
14,875 
5,053
9,822
IBD
CD
UC
61.8
62.4
61.1

Hou  et  al. [29]Inflamm Bowel Dis2012CohortNational registryUnited StatesCountrywide11 112,243 20,949 UC61.65.05.0

Jess  et  al. [7]Gastroenterology2012CohortNational registryEurope (Western)Countywide29385,608 
130,391
255,217
47,374 
14,463
32,911
IBD
CD
UC
40.3
35.7
44.9
55.0
57.0
53.0

Jess  et  al. [39]Aliment Pharmacol Ther2004CohortRegional registryEurope (Western)Regionwide356,569374CD58.0

Jussila  et  al. [10]    Scand J Gastroenterol 2013 Cohort National registry Europe (Western) Countrywide 23 232,536 
51,876
180,660
20,970 
4,983
15,987
IBD
CD
UC

Lakatos  et  al. [38]Inflamm Bowel Dis2006CohortProvincial registryEurope (Eastern)711 8,564 723 UC49.047.010.0

Lakatos  et  al. [30]J Crohn’s Colitis2011CohortProvincial registryEurope (Eastern)731 5,758 506 CD31.550.431.0

Lennard-Jones  et  al. [31]Gut1990CohortSurveillanceEurope (Western)121 4,048 401 UC42.6

Lovasz  et  al.  [32]J Gastroenterol Liver Dis2013CohortProvincial registryEurope (Eastern)Regionwide34 7,759 640 CD28.049.811.038.4

Manninen  et  al.  [11]J Crohn’s Colitis2013CohortReferral centerEurope (Western)12122,900 
7,265
15,635
1,804 
551
1,253
IBD
CD
UC
33.0
30.0
34.0
47.0
51.0
45.0
13.5
13.0
13.1
46.0

Mellemkjær  et  al.  [33]Cancer Causes Control2000CohortNational registryEurope (Western)Countrywide16 22,875 2,645 CD50.0

Mizushima  et  al.  [21]Digestion2010CohortReferral centerAsia120 4,248 294 CD39.030.6

Palli  et  al.  [22]Gastroenterology2000CohortRegional registryEurope (Western)11910,592 
2,716
7,877
920 
231
689
IBD
CD
UC

Pasternak  et  al.    [34]Am J Epidemiology2013CohortNational registryEurope (Western)Countrywide11 304,992 38,772 IBD47.055.04.0

Selinger  et  al. [13]Clin Gastroenterol Hepatol2014CohortReferral centerAustralia/New Zealand21513,423 
5,417
8,006
881 
377
504
IBD
CD
UC
31.5
29.0
34.0
53.1
59.1
47.1

van  Schaik    et  al. [35]Gut2012CohortNational registryEurope (Western)Countrywide8 4,864 835 IBD43.057.02.9

Venkataraman  et  al.    [36]Australian J Gastroenterol Hepatol2005CohortReferral centerAsia1254,901532UC36.86.08.8

Wandall  et  al.   [37]Scand J Gastroenterol2000CohortRegional registryEurope (Western)Regionwide258,101801UC41.044.810.115.9

Winther  et  al.    [19]Clin Gastroenterol Hepatol2004CohortRegional registryEurope (Western)Regionwide3522,2901,160UC53.4

Yano  et  al.  [14]J Gastroenterol Hepatol2013CohortReferral centerAsia12510,552770CD25.131.313.1

Did not report separate incidence estimates for CD and UC.
(b)

AuthorJournalPublication yearPSC (%)Pancolitis (%)Immunomodulator use (%)Biologic use (%)Observed number of CRCsIncidence rate (per 100,000 persons)Standard error95% CI lower bound95% CI upper boundBias rating

Askling et al. [25] Gastroenterology 2001 10.3
17.0
4.8
143
40
103
84.4
43.6
132.9
7.1
6.9
13.1
70.6
30.1
107.2
98.2
57.1
158.6
Moderate

Bernstein et al. [24]Cancer20010.0
0.0
0.0
0.0
0.0
0.0
60
24
36
146.3
112.5
183.1
18.9
23.0
30.5
109.3
67.5
123.3
183.3
157.5
242.9
Moderate

Farrell et al. [26]Gut200026.030.0348.027.7−6.3102.3Moderate

Fraser et al. [18]Aliment Pharmacol Ther200230.00.0
0.0
0.0
0.0
0.0
0.0
23
4
19
41.5
19.5
54.5
8.7
9.8
12.5
24.5
0.4
30.0
58.5
38.6
79.0
Moderate

Gillen et al. [27] Gut 1994 37
8
29
300.2
344.9
289.9
49.4
121.9
53.8
203.5
105.9
184.4
396.9
583.9
395.4
Moderate

Herrinton et al. [28]Gastroenterology201282
29
53
132.7
101.9
159.0
14.7
18.9
21.8
104.0
64.8
116.2
161.4
139.0
201.8
Moderate

Hou et al. [29]Inflamm Bowel Dis2012183163.012.0139.4186.6Moderate

Jess et al. [7]Gastroenterology2012338
70
268
87.7
53.7
105.0
4.8
6.4
6.4
78.4
41.1
92.4
97.0
66.3
117.6
Moderate

Jess et al. [39]Aliment Pharmacol Ther2004460.930.41.2120.6Moderate

Jussila et al. [10] Scand J Gastroenterol 2013 189
32
157
81.3
61.7
86.9
5.9
10.9
6.9
69.7
40.3
73.3
92.9
83.1
100.5
Moderate

Lakatos et al. [38]Inflamm Bowel Dis20062.925.813151.842.169.3234.3Moderate

Lakatos et al. [30]J Crohn’s Colitis20111.8586.838.810.7162.9Moderate

Lennard-Jones et al. [31]Gut199022543.5115.9316.4770.6Moderate

Lovasz et al. [32]J Gastroenterol Liver Dis20130.934.547.27.7677.331.615.4139.2Moderate

Manninen et al. [11]J Crohn’s Colitis20132.5
1.1
3.2
43.2
37.7
49.4
21
5
16
91.7
68.8
102.3
20.0
30.8
25.6
52.5
8.5
52.2
130.9
129.1
152.4
Moderate

Mellemkjær et al. [33]Cancer Causes Control20001565.616.932.498.8Moderate

Mizushima et al. [21]Digestion201012.46141.257.628.2254.2Moderate

Palli et al. [22]Gastroenterology200012
2
10
113.0
73.6
127.0
32.6
52.0
40.2
49.1
−28.4
48.3
176.9
175.6
205.7
Moderate

Pasternak et al. [34]Am J Epidemiology20130.00.0380124.66.4112.1137.1Moderate

Selinger et al. [13]Clin Gastroenterol Hepatol201438.4
37.4
39.1
29
5
24
216.0
92.3
299.8
40.1
41.3
61.2
137.4
11.4
179.9
294.6
173.2
419.7
Moderate

van Schaik et al. [35]Gut201229.00.00.09185.061.764.1305.9Moderate

Venkataraman et al. [36]Australian J Gastroenterol Hepatol200544.05102.045.612.6191.4Moderate

Wandall et al. [37]Scand J Gastroenterol200018.0674.130.314.8133.4Moderate

Winther et al. [19]Clin Gastroenterol Hepatol200454.01358.316.226.690.0Moderate

Yano et al. [14]J Gastroenterol Hepatol201314.7985.328.429.6141.0Moderate

Reported CRC incidence rates in CD ranged from 19.5/100,000 py (95% CI 0.4–38.6/100,000) to 344.9/100,000 py (95% CI 105.9–583.9/100,000) (Table 1). Using a random effects model, an estimated incidence of CRC in CD of 53.3/100,000 py (95% CI 46.3–60.3/100,000) was obtained. Figure 2 displays the Forest plot for the pooled estimates. In UC, the reported incidence rates ranged from 54.5/100,000 py (95% CI 30.0–79.0/100,000) to 543.5/100,000 py (95% CI 316.4–770.6/100,000). Substantial heterogeneity was again present when pooling using a random effects model (heterogeneity test, chi2 = 110.7; ; ), and thus the results in UC were not pooled.

Analyses stratified by publication year and region of origin did not reveal any significant differences in results. We also conducted metaregression analyses to evaluate the potential impact of age, gender, race, Montreal Classification, disease duration, surgical history, smoking status, comorbid primary sclerosing cholangitis, presence of extraintestinal manifestations, and concomitant treatment with immunosuppressants and/or biologics on the CRC incidence in IBD. Due to the limited sample size and incomplete reporting of demographic characteristics in many studies, these analyses were underpowered. Together, age, gender, and disease duration explained a significant proportion of the between-study variability (adjusted ); however we could not make any further conclusions regarding the impact of these covariates on CRC incidence in IBD. Evaluation of funnel plots and Egger’s test showed evidence of small study effects and/or publication bias for IBD overall () and weak evidence of small study effects in CD and UC ( CD;  UC). However, the power of these tests may be compromised due to small sample sizes and significant heterogeneity between studies. Given the observational nature of the included studies and the probability of bias from small study effects, the overall quality of the CRC body of evidence per the GRADE approach is low.

3.1.2. Leukemia

Reported incidence rates of leukemia in IBD ranged from 0.0/100,000 py (95% CI 0.0–3.7/100,000) to 28.4/100,000 py (95% CI −3.7–60.5/100,000) (Table 2). Using a random effects model, the pooled estimated incidence of leukemia in IBD of 1.5/100,000 py was obtained (95% CI −0.02–3.0/100,000). Figure 3 illustrates the Forest plot for the pooled estimates. Moderate between-study heterogeneity was seen (heterogeneity test chi2 = 23.8, ; ); however this is likely influenced by the small number of available studies. In CD, the range of reported incidence rates was identical to that of IBD (Table 2). In UC, reported incidence rates ranged from 8.97/100,000 py (95% CI 0.2–17.8/100,000) to 25.4/100,000 py (95% CI −9.8–60.6/100,000) (Table 2). The pooled incidence estimate was 0.3/100,000 py for CD (95% CI −1.0–1.6/100,000) and 13.0/100,000 py for UC (95% CI 5.8–20.3/100,000). The statistics are 44.3% (heterogeneity test, chi2 = 10.8, ) and 0.0% (heterogeneity test, chi2 = 2.65, ), respectively, indicating low levels of heterogeneity; however the power of this analysis is severely limited due to the small number of included studies.

(a)

AuthorJournalPublication yearStudy designStudy populationRegion of originNumber of sitesStudy duration (yrs)Person-yearsNumber of patientsDiagnosisMean age (yrs)Female (%)Mean disease duration (yrs)Surgery (%)

Bernstein et al. [24]Cancer2001Case-controlAdministrative claimsCanadaRegionwide14 41,005  
21,340
19,665
5,529  
2,857
2,672
IBD 
CD
UC
39.0 
36.3
41.7
54.5 
59.0
50.0

Fraser et al. [18]Aliment Pharmacol Ther2002CohortReferral centerEurope (Western)Countrywide3555,3881,578IBD35.053.0

Jess et al. [8]Am J Gastroenterol2013CohortRegional registryEurope (Western)13233,843 
11,261
22,582
2,211 
774
1,437
IBD 
CD
UC
53.0 
57.0
49.0

Jess et al. [39]Aliment Pharmacol Ther2004CohortRegional registryEurope (Western)Regionwide356,569374CD58.0

Lopez et al. [23]Clin Gastroenterol Hepatol2014CohortNational registryEurope (Western)Countrywide323,45710,810IBD40.053.0

Mellemkjær et al. [33]Cancer Causes Control2000CohortNational registryEurope (Western)Countrywide1622,8752,645CD50.0

Mizushima et al. [21]Digestion2010CohortReferral centerAsia1204,248294CD39.030.6

Palli et al. [22]Gastroenterology2000CohortRegional registryEurope (Western)11910,592 
2,716
7,877
920 
231
689
IBD 
CD
UC

Winther et al. [19]Clin Gastroenterol Hepatol2004CohortRegional registryEurope (Western)Regionwide3522,2901,160UC53.4

Yano et al. [14]J Gastroenterol Hepatol2013CohortReferral centerAsia12510,552770CD25.131.313.1

(b)

AuthorJournalPublication yearPSC (%)Pancolitis (%)Immunomodulator use (%)Biologic use (%)Observed number of leukemia casesIncidence rate (per 100,000 persons)Standard error95% CI lower bound95% CI upper boundBias rating

Bernstein et al. [24]Cancer20010.0 
0.0
0.0
0.0 
0.0
0.0
7 
3
4
17.1 
14.1
20.3
6.5 
8.1
10.2
4.4 
−1.9
0.4
29.8 
30.1
40.2
Moderate

Fraser et al. [18]Aliment Pharmacol Ther200230.00.00.011.811.8−1.75.4Moderate

Jess et al. [8]Am J Gastroenterol201326.7 
41.0
19.0
27.2 
45.0
18.0
6 
1
5
17.7 
8.9
22.1
7.2 
8.9
9.9
3.5 
−8.5
2.7
31.9 
26.3
41.5
Moderate

Jess et al. [39]Aliment Pharmacol Ther2004115.215.2−14.645.1Moderate

Lopez et al. [23]Clin Gastroenterol Hepatol20140.00.00.52.133.0−3.88.0Moderate

Mellemkjær et al. [33]Cancer Causes Control2000313.17.6−1.727.9Moderate

Mizushima et al. [21]Digestion201012.400.00.03.7Moderate

Palli et al. [22]Gastroenterology20002 
0
2
19.0 
0.0
25.4
13.4 

18.0
−7.3 
0.0
−9.8
45.3 
3.7
60.6
Moderate

Winther et al. [19]Clin Gastroenterol Hepatol200454.048.974.50.217.8Moderate

Yano et al. [14]J Gastroenterol Hepatol201314.7328.416.4−3.760.5Moderate

Did not report separate incidence measures for CD and UC.

Stratification by publication year and region did not impact the incidence estimates for IBD or for CD and UC separately. Furthermore, no significant effects of any study- or subject-level covariates on incidence estimates were discovered in metaregression analyses; however the small sample size again restricted the power of these tests.

As less than 10 studies were included, the interpretation of funnel plot symmetry and Egger’s test to assess the presence of small study effects and/or publication bias are not recommended [52]. The overall quality of the leukemia body of evidence, per the GRADE approach, is low due to study designs and small sample size.

3.1.3. Lymphoma

Reported incidence rates for lymphoma in IBD ranged from 0.0/100,000 py (95% CI 0.0–3.7/100,000) to 81.7/100,000 py (95% CI 21.2–142.2/100,000) (Table 3). Substantial heterogeneity between studies prevented pooling of estimates (heterogeneity test, chi2 = 591.1; ; ). Thus, the included studies are presented as unpooled estimates. A sensitivity analysis excluding the two studies with the lowest individual incidence estimates and highest weights on the pooled estimates was conducted, with no significant corresponding decrease in heterogeneity [14, 21].

(a)

AuthorJournalPublication yearStudy designStudy populationRegion of originNumber of sitesStudy duration (yrs)Person-yearsNumber of patientsDiagnosisMean age (yrs)Female (%)Mean disease duration (yrs)Surgery (%)

Abbas et al. [40]Am J Gastroenterol2012CohortNational registryUnited StatesCountrywide11.0 352,429 32,039 UC60.07.0

Beaugerie et al. [41]Lancet2009CohortNational registryEurope (Western)Countrywide3.0 22,706  
10,899
11,807
10,810  
5,153
5,657
IBD 
CD
UC
53.0

Bernstein et al. [24]Cancer2001Case-controlAdministrative claimsCanadaRegionwide14.0 41,005  
21,340
19,665
5,529  
2,857
2,672
IBD 
CD
UC
39.0 
36.3
41.7
54.5 
59.0
50.0

Chiorean et al. [42]Dig Dis Sci2011Case-controlReferral centerUnited States18.4 30,121  
19,127
10,994
3,585  
2,277
1,308
IBD 
CD
UC

Farrell et al. [26]Gut2000CohortReferral centerEurope (Western)19.0 6,256 782 IBD44.152.010.0

Fraser et al. [18]Aliment Pharmacol Ther2002CohortReferral centerEurope (Western)Countrywide35.0 55,388  
20,494
34,894
1,578  
584
994
IBD 
CD
UC
35.053.0

Herrinton et al. [43]Am J Gastroenterol2011CohortAdministrative claimsUnited StatesRegionwide13.0 67,867 16,023 IBD53.0

Jess et al. [8]Am J Gastroenterol2013CohortRegional registryEurope (Western)132.0 33,843  
11,261
22,582
2,211  
774
1,437
IBD 
CD
UC
53.0 
57.0
49.0

Jess et al. [39]Aliment Pharmacol Ther2004CohortRegional registryEurope (Western)Regionwide35.06,569374CD58.0

Jussila et al. [10]Scand J Gastroenterol2013CohortNational registryEurope (Western)Countrywide23.0232,536 
51,876
180,660
20,970  
4,983
15,987
IBD 
CD
UC

Khan et al. [44]Gastroenterology2013CohortNational registryUnited StatesCountrywide10.0 199,046 36,891 UC60.07.0

Lakatos et al. [45]J Crohn’s Colitis 2012CohortProvincial registryEurope (Eastern)731.0 19,293  
7,093
12,830
1,420  
506
914
IBD 
CD
UC
32.5 
28.5
36.5
48.8 
50.0
47.6
22.8 
41.3
4.2

Lewis et al. [46]Gastroenterology2001CohortNational registryEurope (Western)Countrywide9.0 64,239  
24,221
40,018
16,996  
6,605
10,391
IBD 
CD
UC
47.3 
44.3
50.3
54.0 
58.0
50.0

Loftus Jr. et al. [47]Am J Gastroenterol2000CohortRegional registryUnited States253.0 6,662  
3,150
3,512
454  
216
238
IBD 
CD
UC
24.014.9

Mellemkjær et al. [33]Cancer Causes Control2000CohortNational registryEurope (Western)Countrywide16.0 22,875 2,645 CD50.0

Mizushima et al. [21]Digestion2010CohortReferral centerAsia120.0 4,248 294 CD39.030.6

Palli et al. [22]Gastroenterology2000CohortRegional registryEurope (Western)119.0 10,592  
2,716
7,877
920  
231
689
IBD 
CD
UC

Pasternak et al. [34]Am J Epidemiology2013CohortNational registryEurope (Western)Countrywide11.0 304,992 38,772 IBD47.055.04.0

Van Domselaar et al. [48]J Gastroenterol Hepatol2010CohortReferral centerEurope (Western)1 8,563 911 IBD53.028.64.8

Winther et al. [19]Clin Gastroenterol Hepatol2004CohortRegional registryEurope (Western)Regionwide35.0 22,290 1,160 UC53.4

Yano et al. [14]J Gastroenterol Hepatol2013CohortReferral centerAsia125.0 10,552 770 CD25.131.313.1

(b)

AuthorJournalPublication yearPSC (%)Pancolitis (%)Immunomodulator use (%)Biologic use (%)Observed number of lymphomasIncidence rate (per 100,000 persons)Standard error95% CI lower bound95% CI upper boundBias rating

Abbas et al. [40]Am J Gastroenterol20120.00.028280.04.870.789.3Moderate

Beaugerie et al. [41]Lancet200929.6 
13.0
16.0
0.0 
0.0
0.0
0.0 
0.0
0.0
6 
3
3
26.4 
27.5
25.4
10.8 
15.9
14.7
5.3 
−3.6
−3.3
47.5 
58.6
54.1
Moderate

Bernstein et al. [24]Cancer20010.0 
0.0
0.0
0.0 
0.0
0.0
16 
9
7
39.0 
42.2
35.6
9.8 
14.1
13.5
19.9 
14.6
9.2
58.1 
69.8
62.0
Moderate

Chiorean et al. [42]Dig Dis Sci20118 
5
3
26.6 
26.1
27.3
9.4 
11.7
15.8
8.2 
3.2
−3.6
45.0 
49.0
58.2
Moderate

Farrell et al. [26]Gut200026.030.0464.032.01.3126.7Moderate

Fraser et al. [18]Aliment Pharmacol Ther200230.00.0 
0.0
0.0
0.0 
0.0
0.0
5 
1
4
9.0 
4.87
11.5
4.0 
4.9
5.8
1.1 
−4.7
0.2
16.9 
14.4
22.8
Moderate

Herrinton et al. [43]Am J Gastroenterol20110.00.03348.68.532.065.2Moderate

Jess et al. [8]Am J Gastroenterol201326.7 
41.0
19.0
27.2 
45.0
18.0
15 
7
8
44.3 
62.2
35.4
11.4 
23.5
12.5
21.9 
16.1
10.9
66.7 
108.3
59.9
Moderate

Jess et al. [39]Aliment Pharmacol Ther200400.00.03.7Moderate

Jussila et al. [10]Scand J Gastroenterol201372 
14
58
31.0 
27.0
32.1
3.7 
7.2
4.2
23.8 
12.9
23.8
38.2 
41.1
40.4
Moderate

Khan et al. [44]Gastroenterology20130.00.011960.05.549.270.8Moderate

Lakatos et al. [45]J Crohn’s Colitis20122.3 
1.8
2.7
30.2 
35.9
24.4
0.0 
0.0
0.0
0.0 
0.0
0.0
3 
1
2
15.5 
14.1
15.6
8.9 
14.1
11.0
−2.0 
−13.5
−6.0
33.0 
41.7
37.2
Moderate

Lewis et al. [46]Gastroenterology20019.5 
13.0
6.0
18 
7
11
28.0 
28.9
27.5
6.6 
10.9
8.3
15.1 
7.5
11.2
40.9 
50.3
43.8
Moderate

Loftus Jr. et al. [47]Am J Gastroenterol20001 
1
0
15.0 
32.0
0.0
15.0 
32.0
−14.4 
−30.7
0.0
44.4 
94.7
3.7
Moderate

Mellemkjær et al. [33]Cancer Causes Control2000417.58.80.434.7Moderate

Mizushima et al. [21]Digestion201012.400.00.03.7Moderate

Palli et al. [22]Gastroenterology20007 
1
6
66.0 
36.8
76.2
24.9 
36.8
31.1
17.1 
−35.3
15.2
114.9 
108.9
137.2
Moderate

Pasternak et al. [34]Am J Epidemiology20130.00.04615.12.210.719.5Moderate

Van Domselaar et al. [48]J Gastroenterol Hepatol2010781.730.921.2142.2Moderate

Winther et al. [19]Clin Gastroenterol Hepatol200454.0217.912.7−6.942.8Moderate

Yano et al. [14]J Gastroenterol Hepatol201314.700.00.03.7Moderate

Did not report separate incidence estimates for CD and UC.

Reported incidence rates of lymphoma in CD ranged from 0.0/100,000 py (95% CI 0.0–3.7/100,000) to 62.2/100,000 py (95% CI 16.1–108.3/100,000) (Table 3). For UC, the incidence rates ranged from 0.0/100,000 py (95% CI 0.0–3.7/100,000) to 76.2/100,000 py (95% CI 15.2–137.2/100,000) (Table 3). A pooled incidence rate of 0.6/100,000 py (95% CI −0.5–1.6/100,000) for CD was obtained. Substantial heterogeneity prevented pooling of estimates for UC (heterogeneity test, chi2 = 199.5; ; ). A sensitivity analysis excluding the study with the largest impact on the pooled estimate in UC [47] decreased the heterogeneity (heterogeneity test, chi2 = 44.79; ; ). However, substantial heterogeneity remained, and results for UC are presented as unpooled estimates (Figure 4).

Incidence estimates stratified by publication year and region did not differ. Metaregression analysis revealed a statistically significant effect of age on lymphoma incidence in IBD. For each mean year increase in age, the incidence of lymphoma increased by approximately 2.1/100,000 py (95% CI 0.74–3.4/100,000), explaining approximately 65.8% of the between-study heterogeneity (adjusted ). No other covariate effects were found in metaregression analyses.

There was weak evidence of publication bias and/or small study effects in the IBD analysis () and in the UC analysis (). The number of included studies for CD is less than 10; thus analyses of funnel plots and Egger’s test are not recommended [52]. The overall quality of the lymphoma body of evidence, per the GRADE approach, is low due to the observational designs of available studies.

3.2. Discussion

This meta-analysis was performed in order to produce updated and reliable incidence rates for CRC, leukemia, and lymphoma in IBD patients and in CD and UC separately. We aimed to quantify cancer incidence associated with underlying IBD, without the effects of immunomodulator and biologic pharmacotherapy, but this was difficult without reliable reporting of treatment information in the available studies. Although we could not pool estimates of the incidence of CRC in IBD and UC specifically, a pooled incidence rate of 53.3/100,000 py (95% CI 46.3–60.3/100,000) in CD was obtained. The estimated worldwide CRC incidence rate is 19.3/100,000 py [53]. In more developed regions of the world, which compares to the regions of origin of the included studies, the incidence rate is higher at 59.2/100,000 py [53]. As such, CRC incidence in CD does not appear to be higher than that of the general population in similar areas of origin. Of note, these incidence estimates are crude (not age-adjusted) and therefore may not reflect differences in the age of the underlying populations.

For leukemia, pooled incidence rates of 1.5/100,000 py (95% CI −0.06–3.0/100,000), 0.3/100,000 py (95% CI −1.0–1.6/100,000), and 13.0/100,000 py (95% CI 5.8–20.3/100,000) were obtained for IBD, CD, and UC, respectively. The estimated worldwide leukemia incidence is 5.0/100,000 py and 11.3/100,000 py in developed regions [53]. Thus, the incidence of leukemia in IBD and CD is lower than that of the general population in developed regions but is slightly higher in UC. For lymphoma, substantial heterogeneity prevented the pooling of estimates for IBD and UC; however a pooled incidence rate of 0.6/100,000 py (95% CI −0.4–2.1/100,000) in CD was obtained. Estimated worldwide lymphoma incidence is 6.4/100,000 py and 17.6/100,000 py in more developed areas [53]. Thus, the incidence of lymphoma in CD is lower than estimated both worldwide and in developed regions.

Due to incomplete reporting of use of immunomodulators and biologics in the published literature, we could not calculate incidence rates of CRC, leukemia, and lymphoma specifically in persons not treated with these medications; however incidence estimates stratified by publication year before and after widespread use of these medications were not significantly different. This suggests that the impact of immunomodulators and biologics on the incidence of these cancers may be negligible. Metaregression did not reveal any significant subject- or study-level covariate effects in the majority of analyses, with the exception of the effect of mean age on the incidence of lymphoma in IBD. The power of these tests was limited by incomplete reporting of these variables and the small number of included studies.

The strength of the present study is the comprehensiveness of the literature search and evaluation of data for inclusion. Despite the exhaustiveness of the search, we could include only a small number of studies, limiting the power of the pooled analyses and ultimate confidence in incidence estimates. In addition, substantial heterogeneity prevented pooling of estimates in some cases. The heterogeneity of the included studies may reflect differences in follow-up time, cohort size, geographic differences in patient care, or other factors that we were unable to assess due to incomplete reporting in the published literature. Although these limitations may lead to bias in our incidence estimates, the direction of which is indeterminable, our estimates are based on the best available evidence.

4. Conclusions

This meta-analysis presents updated estimates of the incidence of CRC, leukemia, and lymphoma in adults with IBD. Overall, the incidence of these malignancies does not appear to be higher than in the general population. Further research is needed to explore patient characteristics that may modify the risk of malignancy. Specifically, we need large population based cohort studies in IBD patients that report complete demographic and outcome data. Detailed information on immunomodulator and biologic use is limited in the published literature, and if we are to be able to truly understand the potential increased risk of malignancy associated with IBD pharmacotherapy, this information is required.

Abbreviations

CRC:Colorectal cancer
IBD:Inflammatory bowel disease
PSC:Primary sclerosing cholangitis
LD:Lymphoproliferative disorders
CD:Crohn’s Disease
UC:Ulcerative colitis
CI:Confidence interval
py:Person-years.

Competing Interests

The authors declare that they have no competing interests.

Supplementary Materials

Supplementary Table 1 details the search algorithms used for the systematic review. The search algorithm specific to each source are listed along with the number of results returned.

  1. Supplementary Material

References

  1. J. K. Dyson and M. D. Rutter, “Colorectal cancer in inflammatory bowel disease: what is the real magnitude of the risk?” World Journal of Gastroenterology, vol. 18, no. 29, pp. 3839–3848, 2012. View at: Publisher Site | Google Scholar
  2. E. R. Kim and D. K. Chang, “Colorectal cancer in inflammatory bowel disease: the risk, pathogenesis, prevention and diagnosis,” World Journal of Gastroenterology, vol. 20, no. 29, pp. 9872–9881, 2014. View at: Publisher Site | Google Scholar
  3. J. K. Triantafillidis, G. Nasioulas, and P. A. Kosmidis, “Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies,” Anticancer Research, vol. 29, no. 7, pp. 2727–2737, 2009. View at: Google Scholar
  4. J. E. Baars, E. J. Kuipers, M. van Haastert, J. J. Nicolaï, A. C. Poen, and C. J. van der Woude, “Age at diagnosis of inflammatory bowel disease influences early development of colorectal cancer in inflammatory bowel disease patients: a nationwide, long-term survey,” Journal of Gastroenterology, vol. 47, no. 12, pp. 1308–1322, 2012. View at: Publisher Site | Google Scholar
  5. V. Bergeron, A. Vienne, H. Sokol et al., “Risk factors for neoplasia in inflammatory bowel disease patients with pancolitis,” American Journal of Gastroenterology, vol. 105, no. 11, pp. 2405–2411, 2010. View at: Publisher Site | Google Scholar
  6. F. G. Campos, M. G. Teixeira, A. Scanavini, M. G. D. Almeida, S. C. Nahas, and I. Cecconello, “Intestinal and extraintestinal neoplasia in patients with inflammatory bowel disease in a tertiary care hospital,” Arquivos de Gastroenterologia, vol. 50, no. 2, pp. 123–129, 2013. View at: Publisher Site | Google Scholar
  7. T. Jess, J. Simonsen, K. T. Jorgensen, B. V. Pedersen, N. M. Nielsen, and M. Frisch, “Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years,” Gastroenterology, vol. 143, no. 2, pp. 375–381, 2012. View at: Publisher Site | Google Scholar
  8. T. Jess, E. Horváth-Puhó, J. Fallingborg, H. H. Rasmussen, and B. A. Jacobsen, “Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a danish population-based cohort study,” American Journal of Gastroenterology, vol. 108, no. 12, pp. 1869–1876, 2013. View at: Publisher Site | Google Scholar
  9. C. M. Johnson, C. Wei, J. E. Ensor et al., “Meta-analyses of colorectal cancer risk factors,” Cancer Causes and Control, vol. 24, no. 6, pp. 1207–1222, 2013. View at: Publisher Site | Google Scholar
  10. A. Jussila, L. J. Virta, E. Pukkala, and M. A. Färkkilä, “Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland,” Scandinavian Journal of Gastroenterology, vol. 48, no. 12, pp. 1405–1413, 2013. View at: Publisher Site | Google Scholar
  11. P. Manninen, A.-L. Karvonen, H. Huhtala et al., “The risk of colorectal cancer in patients with inflammatory bowel diseases in Finland: a follow-up of 20 years,” Journal of Crohn's and Colitis, vol. 7, no. 11, pp. e551–e557, 2013. View at: Publisher Site | Google Scholar
  12. M. H. Imam, E. W. Thackeray, and K. D. Lindor, “Colonic neoplasia in young patients with inflammatory bowel disease and primary sclerosing cholangitis,” Colorectal Disease, vol. 15, no. 2, pp. 198–203, 2013. View at: Publisher Site | Google Scholar
  13. C. P. Selinger, J. M. Andrews, A. Titman et al., “Long-term follow-up reveals low incidence of colorectal cancer, but frequent need for resection, among Australian patients with inflammatory bowel disease,” Clinical Gastroenterology and Hepatology, vol. 12, no. 4, pp. 644–650, 2014. View at: Publisher Site | Google Scholar
  14. Y. Yano, T. Matsui, F. Hirai et al., “Cancer risk in Japanese Crohn's disease patients: investigation of the standardized incidence ratio,” Journal of Gastroenterology and Hepatology, vol. 28, no. 8, pp. 1300–1305, 2013. View at: Publisher Site | Google Scholar
  15. F. Magro, L. Peyrin-Biroulet, H. Sokol et al., “Extra-intestinal malignancies in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (III),” Journal of Crohn's and Colitis, vol. 8, no. 1, pp. 31–44, 2014. View at: Publisher Site | Google Scholar
  16. M. Mason and C. A. Siegel, “Do inflammatory bowel disease therapies cause cancer?” Inflammatory Bowel Diseases, vol. 19, no. 6, pp. 1306–1321, 2013. View at: Publisher Site | Google Scholar
  17. H. Sokol and L. Beaugerie, “Inflammatory bowel disease and lymphoproliferative disorders: the dust is starting to settle,” Gut, vol. 58, no. 10, pp. 1427–1436, 2009. View at: Publisher Site | Google Scholar
  18. A. G. Fraser, T. R. Orchard, E. M. Robinson, and D. P. Jewell, “Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine,” Alimentary Pharmacology and Therapeutics, vol. 16, no. 7, pp. 1225–1232, 2002. View at: Publisher Site | Google Scholar
  19. K. V. Winther, T. Jess, E. Langholz, P. Munkholm, and V. Binder, “Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County,” Clinical Gastroenterology and Hepatology, vol. 2, no. 12, pp. 1088–1095, 2004. View at: Publisher Site | Google Scholar
  20. N. Pedersen, D. Duricova, M. Elkjaer, M. Gamborg, P. Munkholm, and T. Jess, “Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies,” American Journal of Gastroenterology, vol. 105, no. 7, pp. 1480–1487, 2010. View at: Publisher Site | Google Scholar
  21. T. Mizushima, Y. Ohno, K. Nakajima et al., “Malignancy in Crohn's disease: incidence and clinical characteristics in Japan,” Digestion, vol. 81, no. 4, pp. 265–270, 2010. View at: Publisher Site | Google Scholar
  22. D. Palli, G. Trallori, S. Bagnoli et al., “Hodgkin's disease risk is increased in patients with ulcerative colitis,” Gastroenterology, vol. 119, no. 3, pp. 647–653, 2000. View at: Publisher Site | Google Scholar
  23. A. Lopez, M. Mounier, A.-M. Bouvier et al., “Increased risk of acute myeloid leukemias and myelodysplastic syndromes in patients who received thiopurine treatment for inflammatory bowel disease,” Clinical Gastroenterology and Hepatology, vol. 12, no. 8, pp. 1324–1329, 2014. View at: Publisher Site | Google Scholar
  24. C. N. Bernstein, J. F. Blanchard, E. Kliewer, and A. Wajda, “Cancer risk in patients with inflammatory bowel disease: a population-based study,” Cancer, vol. 91, no. 4, pp. 854–862, 2001. View at: Google Scholar
  25. J. Askling, P. W. Dickman, P. Karlén et al., “Family history as a risk factor for colorectal cancer in inflammatory bowel disease,” Gastroenterology, vol. 120, no. 6, pp. 1356–1362, 2001. View at: Publisher Site | Google Scholar
  26. R. J. Farrell, Y. Ang, P. Kileen et al., “Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low,” Gut, vol. 47, no. 4, pp. 514–519, 2000. View at: Publisher Site | Google Scholar
  27. C. D. Gillen, R. S. Walmsley, P. Prior, H. A. Andrews, and R. N. Allan, “Ulcerative colitis and Crohn's disease: a comparison of the colorectal cancer risk in extensive colitis,” Gut, vol. 35, no. 11, pp. 1590–1592, 1994. View at: Publisher Site | Google Scholar
  28. L. J. Herrinton, L. Liu, T. R. Levin, J. E. Allison, J. D. Lewis, and F. Velayos, “Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010,” Gastroenterology, vol. 143, no. 2, pp. 382–389, 2012. View at: Publisher Site | Google Scholar
  29. J. K. Hou, J. R. Kramer, P. Richardson, M. Mei, and H. B. El-Serag, “Risk of colorectal cancer among Caucasian and African American veterans with ulcerative colitis,” Inflammatory Bowel Diseases, vol. 18, no. 6, pp. 1011–1017, 2012. View at: Publisher Site | Google Scholar
  30. P. L. Lakatos, G. David, T. Pandur et al., “Risk of colorectal cancer and small bowel adenocarcinoma in Crohn's disease: a population-based study from western Hungary 1977–2008,” Journal of Crohn's and Colitis, vol. 5, no. 2, pp. 122–128, 2011. View at: Publisher Site | Google Scholar
  31. J. E. Lennard-Jones, D. M. Melville, B. C. Morson, J. K. Ritchie, and C. B. Williams, “Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years,” Gut, vol. 31, no. 7, pp. 800–806, 1990. View at: Publisher Site | Google Scholar
  32. B. D. Lovasz, L. Lakatos, P. A. Golovics et al., “Risk of colorectal cancer in Crohn's disease patients with colonic involvement and stenosing disease in a population-based cohort from Hungary,” Journal of Gastrointestinal and Liver Diseases, vol. 22, no. 3, pp. 265–268, 2013. View at: Google Scholar
  33. L. Mellemkjær, C. Johansen, G. Gridley, M. S. Linet, S. K. Kjær, and J. H. Olsen, “Crohn's disease and cancer risk (Denmark),” Cancer Causes and Control, vol. 11, no. 2, pp. 145–150, 2000. View at: Publisher Site | Google Scholar
  34. B. Pasternak, H. Svanström, K. Schmiegelow, T. Jess, and A. Hviid, “Use of azathioprine and the risk of cancer in inflammatory bowel disease,” American Journal of Epidemiology, vol. 177, no. 11, pp. 1296–1305, 2013. View at: Publisher Site | Google Scholar
  35. F. D. M. van Schaik, M. G. H. van Oijen, H. M. Smeets, G. J. M. G. van der Heijden, P. D. Siersema, and B. Oldenburg, “Thiopurines prevent advanced colorectal neoplasia in patients with inflammatory bowel disease,” Gut, vol. 61, no. 2, pp. 235–240, 2012. View at: Publisher Site | Google Scholar
  36. S. Venkataraman, V. Mohan, B. S. Ramakrishna et al., “Risk of colorectal cancer in ulcerative colitis in India,” Journal of Gastroenterology and Hepatology (Australia), vol. 20, no. 5, pp. 705–709, 2005. View at: Publisher Site | Google Scholar
  37. E. P. Wandall, P. Damkier, F. Møller Pedersen, B. Wilson, and O. B. Schaffalitzky De Muckadell, “Survival and incidence of colorectal cancer in patients with ulcerative colitis in funen county diagnosed between 1973 and 1993,” Scandinavian Journal of Gastroenterology, vol. 35, no. 3, pp. 312–317, 2000. View at: Google Scholar
  38. L. Lakatos, G. Mester, Z. Erdelyi et al., “Risk factors for ulcerative colitis-associated colorectal cancer in a Hungarian cohort of patients with ulcerative colitis: results of a population-based study,” Inflammatory Bowel Diseases, vol. 12, no. 3, pp. 205–211, 2006. View at: Publisher Site | Google Scholar
  39. T. Jess, K. V. Winther, P. Munkholm, E. Langholz, and V. Binder, “Intestinal and extra-intestinal cancer in Crohn's disease: follow-up of a population-based cohort in Copenhagen County, Denmark,” Alimentary Pharmacology and Therapeutics, vol. 19, no. 3, pp. 287–293, 2004. View at: Publisher Site | Google Scholar
  40. A. Abbas, Y. Koleva, and N. Khan, “Lymphoproliferative disorders in patients receiving thiopurines for ulcerative colitis: a nationwide 10-year retrospective cohort from the veterans affairs healthcare system,” The American Journal of Gastroenterology, vol. 107, article S693, 2012. View at: Google Scholar
  41. L. Beaugerie, N. Brousse, A. M. Bouvier et al., “Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study,” The Lancet, vol. 374, no. 9701, pp. 1617–1625, 2009. View at: Publisher Site | Google Scholar
  42. M. V. Chiorean, B. Pokhrel, J. Adabala, D. J. Helper, C. S. Johnson, and B. Juliar, “Incidence and risk factors for lymphoma in a single-center inflammatory bowel disease population,” Digestive Diseases and Sciences, vol. 56, no. 5, pp. 1489–1495, 2011. View at: Publisher Site | Google Scholar
  43. L. J. Herrinton, L. Liu, X. Weng, J. D. Lewis, S. Hutfless, and J. E. Allison, “Role of thiopurine and anti-TNF therapy in lymphoma in inflammatory bowel disease,” American Journal of Gastroenterology, vol. 106, no. 12, pp. 2146–2153, 2011. View at: Publisher Site | Google Scholar
  44. N. Khan, A. M. Abbas, G. R. Lichtenstein, E. V. Loftus Jr., and L. A. Bazzano, “Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a nationwide retrospective cohort study,” Gastroenterology, vol. 145, no. 5, pp. 1007.e3–1015.e3, 2013. View at: Publisher Site | Google Scholar
  45. L. Lakatos, P. A. Golovics, B. D. Lovasz et al., “Sa1247 Low risk of lymphoma in inflammatory bowel diseases in Western Hungary. Results from a population-based incident cohort,” Gastroenterology, vol. 142, no. 5, supplement 1, p. S-253, 2012. View at: Publisher Site | Google Scholar
  46. J. D. Lewis, W. B. Bilker, C. Brensinger, J. J. Deren, D. J. Vaughn, and B. L. Strom, “Inflammatory bowel disease is not associated with an increased risk of lymphoma,” Gastroenterology, vol. 121, no. 5, pp. 1080–1087, 2001. View at: Publisher Site | Google Scholar
  47. E. V. Loftus Jr., W. J. Tremaine, T. M. Habermann, W. S. Harmsen, A. R. Zinsmeister, and W. J. Sandborn, “Risk of lymphoma in inflammatory bowel disease,” The American Journal of Gastroenterology, vol. 95, no. 9, pp. 2308–2312, 2000. View at: Publisher Site | Google Scholar
  48. M. Van Domselaar, A. López San Román, M. Bastos Oreiro, and E. Garrido Gómez, “Lymphoproliferative disorders in an inflammatory bowel disease unit,” Gastroenterologia y Hepatologia, vol. 33, no. 1, pp. 12–16, 2010. View at: Publisher Site | Google Scholar
  49. J. Sterne, J. Higgins, and B. Reeves, A Cochrane Risk of Bias Assessment Tool: For Non-Randomized Studies of Interventions (ACROBAT-NRSI), Version 1.0.0, 2014.
  50. J. P. T. Higgins and S. Green, Cochrane Handbook for Systematic Reviews of Interventions, John Wiley & Sons, 2011.
  51. J. Higgins, J. Deeks, and D. Altman, Special Topics in Statistics, The Cochrane Book, chapter 16, John Wiley & Sons, London, UK, 2008.
  52. T. M. Palmer and J. A. C. Sterne, Eds., Meta-Analysis in Stata: An Updated Collection from the Stata Journal, Stata Press, Station, Tex, USA, 2009.
  53. J. Ferlay, I. Soerjomataram, M. Ervik et al., “GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide,” IARC Cancer Base 11, International Agency for Research on Cancer, Lyon, France, 2013. View at: Google Scholar

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