The Risk of Extraintestinal Cancer in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis of Population-based Cohort Studies

Published:August 12, 2020DOI:https://doi.org/10.1016/j.cgh.2020.08.015

      Background & Aims

      Patients with Crohn’s disease (CD) and ulcerative colitis (UC) are at increased risk of developing intestinal cancer. However, less is known about the risk of extraintestinal cancers (EICs). The aim of this study was to conduct a systematic review and meta-analysis of population-based cohorts assessing the risk of EICs in inflammatory bowel disease (IBD) patients.

      Methods

      Only population-based studies reporting on the prevalence or incidence of EICs were included. In total, 884 studies were screened and those included were assessed for quality. Eligible studies were pooled for length of follow-up evaluation, events in the IBD population, and events or expected events in a control population for the meta-analyses.

      Results

      In total, 40 studies were included in the systematic review and 15 studies were included in the meta-analysis. The overall risk of EICs was found to be increased in both CD (incidence rate ratio [IRR]: 1.43 [CI, 1.26, 1.63]) and UC (IRR: 1.15 [1.02, 1.31]) patients. Both CD and UC patients presented with an increased risk of skin (IRR: CD, 2.22 [1.41–3.48]; UC, 1.38 [1.12–1.71]) and hepatobiliary (IRR: CD, 2.31 [1.25–4.28]; UC, 2.05 [1.52–2.76]) malignancies. Furthermore, CD patients showed an increased risk of hematologic (IRR, 2.40 [1.81–3.18]) and lung (IRR, 1.53 [1.23–1.91]) cancers. These increased risks were present despite treatment with immunosuppressives.

      Conclusions

      This systematic review and meta-analysis shows that both CD and UC patients are at an increased risk of developing EICs, both overall and at specific sites. However, additional studies with longer follow-up evaluation are needed to assess the true risk of EICs posed by IBD.

      Keywords

      Abbreviations used in this paper:

      CD (Crohn’s disease), EIC (extraintestinal cancer), IBD (inflammatory bowel disease), IR (incidence rate), IRD (incidence rate difference), IRR (incidence rate ratio), PY (patient-year), SIR (standardized incidence ratio), TNF (tumor necrosis factor), UC (ulcerative colitis)

       Background

      Inflammatory bowel disease increases the risk of intestinal and hepatobiliary cancers.

       Findings

      Crohn’s disease and ulcerative colitis are associated with an overall increased risk of developing extraintestinal cancers. A baseline risk for developing extraintestinal cancers seems to be present despite immunosuppressive treatments.

       Implications for patient care

      These results should encourage physicians to be more aware of cancers outside of the digestive tract in patients with inflammatory bowel disease.
      Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBDs) of unknown origin. Several studies have shown that patients with IBD are at increased risk of intestinal cancer compared with the general population.
      • Jess T.
      • Gamborg M.
      • Matzen P.
      • et al.
      Increased risk of intestinal cancer in Crohn’s disease: a meta-analysis of population-based cohort studies.
      ,
      • Castaño-Milla C.
      • Chaparro M.
      • Gisbert J.P.
      Systematic review with meta-analysis: the declining risk of colorectal cancer in ulcerative colitis.
      The pathogenetic link between IBD and intestinal cancer is not completely understood, however, chronic inflammation in the gut is thought to underlie the cause of colorectal and small-intestinal cancer in IBD patients.
      • Solinas G.
      • Marchesi F.
      • Garlanda C.
      • et al.
      Inflammation-mediated promotion of invasion and metastasis.
      • Danese S.
      • Mantovani A.
      Inflammatory bowel disease and intestinal cancer: a paradigm of the yin-yang interplay between inflammation and cancer.
      • Mantovani A.
      • Allavena P.
      • Sica A.
      • et al.
      Cancer-related inflammation.
      • Kundu J.K.
      • Surh Y.-J.
      Inflammation: gearing the journey to cancer.
      Less is known about the risk of extraintestinal cancers (EICs). Most data come from selected cohorts or trials, and few studies have investigated the risk of EIC in an unselected population-based setting with sufficiently long follow-up evaluation. A previous meta-analysis of the risk of EICs in population-based studies from 2009 found that the overall risk of EIC was not increased among patients with IBD, but that the risk of individual cancer types differed from that of the general population.
      • Pedersen N.
      • Duricova D.
      • Elkjaer M.
      • et al.
      Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies.
      However, the meta-analysis was limited by the scarcity of available studies and the short length of follow-up evaluation in those cohorts.
      We therefore aimed to perform an updated systematic review and meta-analysis of the risk of EIC among IBD patients in population-based cohorts.

      Methods

      This study, including its design and aims, was registered at the International Prospective Register of Systematic Reviews, before conducting the literature search (ID: CRD42019145585). The review question (Population, Intervention, Comparator and Outcomes [PICO]) is provided in Supplementary Figure 1. Identification and retrieval of studies were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

       Literature Search

      A comprehensive search strategy, which included both subject headings and keywords, initially was performed on August 2, 2019, and again on June 11, 2020. The specific search strategy is provided in Supplementary Figure 1. In short, PubMed, Embase, Medline, and the Cochrane Library were searched for studies investigating any kind of cancer in patients with IBD in a population-based or nationwide cohort. In addition, we searched the reference lists of relevant studies, as well as review articles, for studies eligible for inclusion in this systematic review.

       Inclusion Criteria

      We included only population-based studies reporting the prevalence or incidence of EIC. A population-based or nationwide study was defined as a study involving all residents in a defined geographic area or nation. Studies published as abstracts were excluded.
      The meta-analysis only included studies that provided data on the following: (1) the number of patient-years (PY) followed up or the mean number of PYs and the number of patients, (2) the number of events in the IBD population, and (3) the number of either events in a matched control population or expected events calculated according to the incidence rates in the general population; this was to allow for the possibility of weighing studies rather than, for example, compiling standardized incidence ratios (SIRs), which would distort the true risk of events. Authors were contacted if their data were published in a format that did not strictly follow the inclusion criteria and were requested to provide data in a format appropriate to the present study.

       Data Collection

      Search results were assessed using Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Available at www.covidence.org).
      Veritas Health Innovation
      Covidence systematic review software. 2019.
      After removing duplicates, the title and abstract were screened for inclusion and exclusion criteria and eligible studies were included in the full-text screening. All included studies were quality assessed according to the Newcastle–Ottawa scale for cohort studies. A minimum of 10 years of follow-up evaluation was deemed adequate.
      At each step of the process, 2 investigators (B.L. and M.Z.) assessed the studies separately. Any discrepancy was discussed, and a consensus was reached; if this proved elusive, a senior researcher (J.B.) made the final decision.
      The author, year of study, origin of the cohort, year of the cohort, number of each EIC within the cohort, estimated numbers of EICs in the general population or true numbers of EICs in the control population, data acquisition method, outcome measures, definition of controls, and risk factors associated with the development of cancer across all sites besides the diagnosis of either UC or CD, were collected.

       Statistical Analysis

      Analyses were performed in R (R Core Team (2020). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org)
      R Core Team (2019)
      R: A language and environment for statistical computing. 2019.
      using the metafor package.
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor.
      Studies eligible for the meta-analysis were pooled for events, expected events or events in a control population, and the length of follow-up evaluation in PY. If the latter was not specified, the number of patients was multiplied by the mean years of follow-up evaluation to yield an estimate of PY followed up. For the gender-specific analyses, if PY followed up was not specified, PY for the specific sex were calculated by multiplying the total PY with the percentage of that gender. Studies reporting all observed EICs were included in the analysis of the overall risk of EICs.
      We planned a priori to report the results of our analyses based on random-effects meta-analyses. The fixed-effect meta-analysis therefore only was reported if the larger studies were conducted with greater methodologic rigidity or conducted in circumstances more representative of the general IBD population. A significance level of 5% was chosen. The results were reported as incidence rates (IRs), incidence rate differences (IRDs), incidence rate ratios (IRRs) using the Mantel–Haenszel method, and 95% CIs. We calculated the I2 to express the heterogeneity using the following thresholds: 0% to 40% (unimportant), 40% to 60% (moderate), 60% to 80% (substantial), and more than 80% (considerable). Publication bias was assessed using the Egger test, the Begg test, and funnel plots for visual assessment. If 2 cohorts were overlapping and/or of the same origin and assessing the same outcome, the cohort with the most PY available was used in the meta-analyses of the specific outcome. However, if the 2 cohorts had more than 10 years of nonoverlapping follow-up evaluation, both cohorts were included in the analysis of the specific outcome.
      Meta-analyses of the overall and site-specific risk of cancers was performed for CD and UC patients separately. The site-specific risk of cancers included the following: hepatobiliary, pancreatic, hematologic, skin, lung, kidney, urologic, breast, and male/female reproductive organ cancers. Furthermore, a stratified analysis of cohorts, with patients diagnosed before or after the year 2000 for overall risk of cancers, was performed for CD and UC separately. Subgroup analyses of adult vs pediatric, male vs female, and Eastern vs Western countries were performed where possible.

      Results

      Results from the literature search are shown in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart (Figure 1). In total, 40 studies were included in the review
      • Nyboe Andersen N.
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      • Basit S.
      • et al.
      Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease.
      • Armstrong R.G.
      • West J.
      • Card T.R.
      Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study.
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      • Burisch J.
      • Kiudelis G.
      • Kupcinskas L.
      • et al.
      Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      • Jess T.
      • Winther K.V.
      • Munkholm P.
      • et al.
      Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      • Kappelman M.D.
      • Farkas D.K.
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      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      • Karlén P.
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      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
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      Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.
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      The risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: results from a population-based cohort in Eastern Europe.
      • Lemaitre M.
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      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
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      Risk of lymphoma in inflammatory bowel disease.
      • Malham M.
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      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
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      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      • So J.
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      • Leung W.K.
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      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      • Olén O.
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      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      • Peneau A.
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      • et al.
      Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study.
      • Persson P.G.
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      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      • Rungoe C.
      • Simonsen J.
      • Riis L.
      • et al.
      Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study.
      • Tsai M.S.
      • Chen H.P.
      • Hung C.M.
      • et al.
      Hospitalization for inflammatory bowel disease is associated with increased risk of breast cancer: a nationwide cohort study of an Asian population.
      • van den Heuvel T.R.
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      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      • Mak J.W.Y.
      • So J.
      • Tang W.
      • et al.
      Cancer risk and chemoprevention in Chinese inflammatory bowel disease patients: a population-based cohort study.
      • Lin W.-C.
      • Weng M.-T.
      • Tung C.-C.
      • et al.
      Trends and risk factors of mortality analysis in patients with inflammatory bowel disease: a Taiwanese nationwide population-based study.
      • Trivedi P.J.
      • Crothers H.
      • Mytton J.
      • et al.
      Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Diseases, Based on Sex, Race, and Age.
      • Fumery M.
      • Pariente B.
      • Sarter H.
      • et al.
      Long-term outcome of pediatric-onset Crohn’s disease: a population-based cohort study.
      • Ng S.C.
      • Zeng Z.
      • Niewiadomski O.
      • et al.
      Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia.
      • Pasternak B.
      • Svanström H.
      • Schmiegelow K.
      • et al.
      Use of azathioprine and the risk of cancer in inflammatory bowel disease.
      (n = 882,622 IBD patients with 5.1 million PY [7 studies did not specify the number of PY]) and 15 studies were included in the meta-analysis
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Jess T.
      • Winther K.V.
      • Munkholm P.
      • et al.
      Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      ,
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      ,
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      ,
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      (Table 1). No studies investigating pediatric IBD patients were included in the meta-analysis. The results from the quality assessment are shown in Table 1. Only 4 studies were rated as being of poor quality because of their incomparability. In the studies that did not receive a maximum score for selection and outcome, the reason was missing information regarding “Demonstration that outcome of interest was not present at start of study” and an inadequate length of follow-up evaluation (ie, 10 y), respectively (Table 2). Overall, we found no significant publication bias except for those pertaining to skin cancers (Egger, P = .9; Begg, P = .03) and lung cancers (Egger, P = .01; Begg, P = .02) in UC patients (funnel plots shown in Supplementary Figures 2 and 3).
      Figure thumbnail gr1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.
      Table 1Study Characteristics
      StudyCountryCohort yearMean/median age CD patients at inclusionMean/median age UC patients at inclusionMean/median age IBD patients at inclusionUC phenotypeCD phenotypen = CD/UCPerson-yearsPatients, nStudy design and outcomes
      Armstrong 2010
      • Armstrong R.G.
      • West J.
      • Card T.R.
      Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study.
      United Kingdom1897–2001NANANANANANA15,441Risk of cancer in patients treated with AZA, nested case-control

      Data acquisition: use of recorded diagnostic codes

      Outcome measure: OR
      Askling 2005
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      Sweden1965–1983

      UC: 1954–1984 CD: 1954–1990

      1973–1996

      1964–1987
      NANAE1, 33%

      E2, 25%

      E3, 35%

      Ex, 6%
      L1, 37%

      L2, 27%

      L3, 31%

      Lx, 6%
      20,120/27,559NA47,679Risk of hematopoietic cancer from 4 cohorts

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: combination of recorded diagnostic codes and manual assessment

      Outcome measure: SIR, RR
      Bernstein 2001
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      Canada1984–199736.341.7NANA2857/267241,0055529Risk of cancer

      1:10 age-, sex-, resident-matched controls

      Data acquisition: combination of recorded diagnostic codes and manual assessment

      Outcome measure: IRR
      Burisch 2018
      • Burisch J.
      • Kiudelis G.
      • Kupcinskas L.
      • et al.
      Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.
      Europe201033L1, 27%

      L2, 28%

      L3, 23%

      L4, 6%

      L4+ (L1–L3), 16%

      B1, 71%

      B2, 21%

      B3, 8%

      Perianal, 9%
      2442499476Disease course of CD from 22 european countries and Israel

      Controls = none

      Data acquisition: manual assessment

      Outcome measure: only n (%)
      Cheddani 2016
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      France1988–20067069E1, 29%

      E2, 45%

      E3, 26%
      L1, 10%

      L2, 65%

      L3, 25%

      B1, 78%

      B2, 17%

      B3, 5%

      Perianal, 8%
      370/4745598844Risk of cancer in elderly-onset patients

      Controls = expected cancer based on sex, age

      Data acquisition: manual assessment

      Outcome measures: IR, SIR
      Ekbom 1991
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      Sweden1965–1983NANAE1, 37%

      E3, 63%
      NA1655/3121NA4776Risk of extracolonic cancer

      Controls = expected cancer based on sex, age group, calendar year

      Data acquisition: recorded diagnostic codes

      Outcome measure: SIR
      Erichsen 2009
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      Denmark1978–200340.240.2NANA10,430/26,552

      unspecified, 4298
      NA41,280Risk of cholangiocarcinoma

      1:10 age-, sex-matched controls

      Data acquisition: combination of recorded diagnostic codes and manual search

      Outcome measures: IR, AR, IRR
      Fumery 2019
      • Fumery M.
      • Pariente B.
      • Sarter H.
      • et al.
      Long-term outcome of pediatric-onset Crohn’s disease: a population-based cohort study.
      France1988–200414.5L1, 13%

      L2, 20%

      L3, 67%

      L4, 31%

      B1, 73%

      B2, 24%

      B3, 3%

      Perianal, 10%
      5355938.5535Long-term outcome in pediatric CD patients

      Controls = none

      Data acquisition: manual search

      Outcome measures: CP, HR, SIR, SMR
      Jess 2004
      • Jess T.
      • Winther K.V.
      • Munkholm P.
      • et al.
      Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
      Denmark1962–198732.5L1, 30%

      L2, 31%

      L3, 36%

      Lx, 3%

      Perianal, 4%

      L4 + (L1–L3), 6%
      3746569374Risk of cancer

      Controls = expected cancer based on sex, age

      Data acquisition: combination of recorded diagnostic codes and manual search

      Outcome measure: SMR
      Jess 2013
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      Denmark1978–2002NANAE1, 54%

      E2, 23%

      E3, 19%

      Ex, 4%
      L1, 29%

      L2, 41%

      L3, 26%

      Lx, 4%
      774/143733,8432211Risk of cancer

      Controls = expected cancer based on sex, age

      Data acquisition: combination of recorded diagnostic codes and manual search

      Outcome measure: SIR
      Jung 2017
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      Korea2011–201431.942.3NANA5506/978532,62615,219Risk of cancer

      Controls = expected cancer based on sex, age

      Data acquisition: recorded diagnostic codes

      Outcome measures: SIR, OR
      Jussila 2013
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      Finland1987–1993 and 2000–2007NANANANA5315/16,649236,12921,964Risk of cancer

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: recorded diagnostic codes

      Outcome measure: SIR
      Kappelman 2014
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      Denmark1978–201040.646.5NANA13,756/35,152378,731.248,908Risk of cancer

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: recorded diagnostic codes

      Outcome measures: SIR, AR
      Karlén 1999
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      Sweden1955–1984NAE1, 26%

      E2, 38%

      E3, 35%

      Ex, 1%
      154725,4641547Risk of cancer

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: recorded diagnostic codes

      Outcome measure: SIR
      Katsanos 2007
      • Katsanos K.H.
      • Vermeire S.
      • Christodoulou D.K.
      • et al.
      Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.
      Europe1991–199337.837.8NANA365/77611,752.31141Risk of cancer

      Controls = estimated numbers based on national cancer incidence

      Data acquisition: manual search

      Outcome measure: RR
      Katsanos 2011
      • Katsanos K.H.
      • Tatsioni A.
      • Pedersen N.
      • et al.
      Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study.
      Europe1991–1993NANANANA263/445NA681Risk of cancer

      Controls = estimated numbers based on national cancer incidence

      Data acquisition: manual search

      Outcome measure: RR
      Kuo 2015
      • Kuo C.J.
      • Yu K.H.
      • See L.C.
      • et al.
      The trend of inflammatory bowel diseases in Taiwan: a population-based study.
      Taiwan2000–2010NANANANA526/212510,296.142651Trends in IBD including cancer

      Controls = none

      Data acquisition: recorded diagnostic codes

      Outcome measure: IR
      Lakatos 2013
      • Lakatos P.L.
      • Lovasz B.D.
      • David G.
      • et al.
      The risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: results from a population-based cohort in Eastern Europe.
      Hungary1977–200828.536.5E1, 25%

      E2, 50%

      E3, 24%
      L1, 33%

      L2, 36%

      L3, 31%

      L4 only, 1%

      B1, 57%

      B2, 20%

      B3, 23%

      Perianal, 26%
      506/91419,2931420Risk of lymphoma

      Controls = expected cancer based on sex, age

      Data acquisition: manual search

      Outcome measures: SIR, RR, HR
      Lemaitre 2017
      • Lemaitre M.
      • Kirchgesner J.
      • Rudnichi A.
      • et al.
      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
      France2008–2013NANA43NANA95,537/93,7521,268,236189,289Risk of lymphoma in a nested case-control

      Data acquisition: recorded diagnostic codes

      Outcome measures: HR, IR, ARD
      Lin 2019
      • Lin W.-C.
      • Weng M.-T.
      • Tung C.-C.
      • et al.
      Trends and risk factors of mortality analysis in patients with inflammatory bowel disease: a Taiwanese nationwide population-based study.
      Taiwan2001–2015NANANANANA919/2887NA3806Risk of mortality

      Controls = none

      Data acquisition: recorded diagnostic codes

      Outcome measures: HR, SMR
      Loftus 2000
      • Loftus E.V.
      • Tremaine W.J.
      • Habermann T.M.
      • et al.
      Risk of lymphoma in inflammatory bowel disease.
      United States1950–1993NANA43.8NANA216/2386662454Risk of lymphoma

      Controls = expected cancer based on sex, age

      Data acquisition: recorded diagnostic codes

      Outcome measures: IR, SIR, RR, AR
      Mak 2020
      • Mak J.W.Y.
      • So J.
      • Tang W.
      • et al.
      Cancer risk and chemoprevention in Chinese inflammatory bowel disease patients: a population-based cohort study.
      Hong Kong2000–2016NANA40E1, 35%

      E2, 30%

      E3, 35%
      L1, 25%

      L2, 31%

      L3, 44%

      L4, 9%

      B1, 69%

      B2, 22%

      B3, 14%

      Perianal, 25%
      857/124615,982.82103Risk of cancer

      Controls = none

      Data acquisition: recorded diagnostic codes

      Outcome measure: HR
      Malham 2019
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      Denmark and Finland1992–2014NANA14NANA2921/374171,6756689Risk of cancer and mortality in children

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: recorded diagnostic codes

      Outcome measures: SIR, SMR
      Mellemkjaer 1995
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      Denmark1977–198940NANA554632,9685546Risk of cancer

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: recorded diagnostic codes

      Outcome measure: RR
      Ng 2016
      • Ng S.C.
      • Zeng Z.
      • Niewiadomski O.
      • et al.
      Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia.
      Asia and Australia2011–2013NANA37E1, 37%

      E2, 31%

      E3, 33%
      L1, 29%

      L2, 24%

      L3, 50%

      L4, 8%

      B1, 99%

      B2, 16%

      B3, 12%

      Perianal, 21%

      Not exclusive
      181/222

      unspecified, 10
      627.25413Disease course in IBD patients

      Controls = none

      Data acquisition: manual search

      Outcome measure: only number and percentage
      Nyboe Andersen 2014
      • Nyboe Andersen N.
      • Pasternak B.
      • Basit S.
      • et al.
      Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease.
      Denmark1999–2012NANA43.6NANA17,849/38,297489,43356,146Risk of cancer in IBD patients treated with anti-TNF-α

      Nested case-control

      Data acquisition: recorded diagnostic codes

      Outcome measure: RR
      Olén 2017
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      Sweden1964–2001 and 2002–20141414End of follow-up period

      E1, 5%

      E2, 9%

      E3, 66%

      Ex, 21%
      End of follow-up period

      L1, 27%

      L2, 44%

      L3Lx, 28%

      B1, 79%

      B2, 9%

      B3, 8%

      B2 and B3, 3%

      Perianal, 19%
      3768/4648

      unspecified, 989
      148,6829405Risk of cancer in children

      1:10 age-, sex-, resident-matched controls

      Data acquisition: recorded diagnostic codes

      Outcome measures: IR, HR, AIR
      Palli 2000
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      Italy1978–1992NANANANA231/68910,593920Risk of cancer

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: manual search

      Outcome measure: SIR
      Pasternak 2013
      • Pasternak B.
      • Svanström H.
      • Schmiegelow K.
      • et al.
      Use of azathioprine and the risk of cancer in inflammatory bowel disease.
      Denmark1997–200845.9NANA129,547/31,015337,61245,986Risk of cancer in patients treated with AZA

      Nested case-control

      Adjusted by propensity score

      Data acquisition: recorded diagnostic codes

      Outcome measure: RR
      Peneau 2013
      • Peneau A.
      • Savoye G.
      • Turck D.
      • et al.
      Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study.
      France1988–200414.614.5E1, 14%

      E2, 26%

      E3, 60%
      L1, 14%

      L2, 16%

      L3, 70%

      L4, 37%

      B1, 73%

      B2, 23%

      B3, 4%

      Perianal, 9%
      531/1607881.6698Risk of cancer and mortality

      Controls = expected cancer based on sex, age

      Data acquisition: manual search

      Outcome measures: SMR, SIR
      Persson 1994
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      Sweden1955–1984NAL1, 36%

      L2, 18%

      L3, 45%

      Lx, 0.4%
      1251NA1251Risk of cancer

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: combination of recorded diagnostic codes and manual search

      Outcome measure: SMR
      Rungoe 2015
      • Rungoe C.
      • Simonsen J.
      • Riis L.
      • et al.
      Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study.
      Denmark1979–201140.446.4NANA8717/18,6917753.927,408Risk of cervical neoplasia

      1:50 matched controls

      Data acquisition: recorded diagnostic codes

      Outcome measures: IRR, OR
      So 2017
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      Hong Kong1990–20162941E1, 35%

      E2, 31%

      E3, 34%
      L1, 25%

      L2, 32%

      L3, 44%

      L4, 8%

      B1, 66%

      B2, 24%

      B3, 16%

      Perianal, 25%
      1018/160326,2342621Risk of cancer

      Controls = expected cancer based on sex, age

      Data acquisition: recorded diagnostic codes

      Outcome measures: SIR, HR
      Tsai 2015
      • Tsai M.S.
      • Chen H.P.
      • Hung C.M.
      • et al.
      Hospitalization for inflammatory bowel disease is associated with increased risk of breast cancer: a nationwide cohort study of an Asian population.
      Taiwan1998–200859.3NANANA34,380.484856Risk of breast cancer

      1:4 controls matched by index date, age

      Data acquisition: recorded diagnostic codes

      Outcome measures: HR; IR
      Trivedi 2020
      • Trivedi P.J.
      • Crothers H.
      • Mytton J.
      • et al.
      Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Diseases, Based on Sex, Race, and Age.
      United Kingdom2006–2016NANANANANA93,100/153,640

      unspecified, 37,820
      1,994,441284,560PSC on risk of cancer and death

      Controls = none

      Data acquisition: recorded diagnostic codes

      Outcome measures: IR, IRR, YLL
      van den Heuvel 2016
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      The Netherlands1991–201134.345E1, 34%

      E2, 48%

      E3, 18%
      L1, 43%

      L2, 32%

      L3, 23%

      L4, 11%
      1157/164426,898.52801Risk of cancer

      Controls = expected cancer based on sex, age, calendar period

      Data acquisition: combination of recorded diagnostic codes and manual search

      Outcome measure: SIR
      Wang 2016
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      Taiwan1995–201234.943.1NANA685/266323,557.63348Risk of cancer

      Controls = expected cancer based on sex, age

      Data acquisition: recorded diagnostic codes

      Outcome measure: SIR
      Wilson 2016
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      United Kingdom1995–2012NANANANA7850/11,797251,70919,647Risk of cancer

      1:1 controls matched by index date, age, sex, general practice, year before index date

      Data acquisition: recorded diagnostic codes

      Outcome measures: OR, HR
      Winther 2004
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      Denmark1962–1987NAProctitis, 45%

      Extensive, 36%

      Pancolitis, 18%

      Unspecified, 1%
      116022,2901160Risk of cancer

      Controls = expected cancer based on sex, age

      Data acquisition: recorded diagnostic codes

      Outcome measure: SMR
      Yadav 2015
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      United States1940–20043035NANA377/46217,309839Risk of cancer

      Controls = expected cancer based on sex, age

      Data acquisition: recorded diagnostic codes

      Outcome measures: SIR, IRR
      AZA, Azathiopurine; CD, Crohn’s disease; CP, cumulative probabilities; HR, hazard ratio; IBD, inflammatory bowel disease; IRR, incidence rate ratio; OR, odds ratio; PSC, primary sclerosing cholangitis; RR, rate ratio; SIR, standardized incidence ratio; SMR, standardized morbidity ratio; TNF-α, tumor necrosis factor-α; UC, ulcerative colitis; YLL, years of life lost.
      Table 2Quality Assessment of Studies Included Using the Newcastle–Ottawa Scale for Cohort Studies
      StudySelectionComparabilityOutcomeQuality
      Armstrong 2010
      • Armstrong R.G.
      • West J.
      • Card T.R.
      Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study.
      ★★★★★★★★Good
      Askling 2005
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      ★★★★★★★★Good
      Bernstein 2001
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ★★★★★★★★Good
      Burisch 2018
      • Burisch J.
      • Kiudelis G.
      • Kupcinskas L.
      • et al.
      Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.
      ★★★%★★Poor
      Cheddani 2016
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      ★★★★★★Good
      Ekbom 1991
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      ★★★★★★Good
      Erichsen 2009
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      ★★★★★★★★Good
      Fumery 2019
      • Fumery M.
      • Pariente B.
      • Sarter H.
      • et al.
      Long-term outcome of pediatric-onset Crohn’s disease: a population-based cohort study.
      ★★★★★★★★★Good
      Jess 2004
      • Jess T.
      • Winther K.V.
      • Munkholm P.
      • et al.
      Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
      ★★★★★★Good
      Jess 2013
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ★★★★★★★Good
      Jung 2017
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ★★★★★★Good
      Jussila 2013
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      ★★★★★★★★Good
      Kappelman 2014
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      ★★★★★★★★Good
      Karlén 1999
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ★★★★★★★★Good
      Katsanos 2007
      • Katsanos K.H.
      • Vermeire S.
      • Christodoulou D.K.
      • et al.
      Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.
      ★★★%★★Poor
      Katsanos 2011
      • Katsanos K.H.
      • Tatsioni A.
      • Pedersen N.
      • et al.
      Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study.
      ★★★%★★Poor
      Kuo 2015
      • Kuo C.J.
      • Yu K.H.
      • See L.C.
      • et al.
      The trend of inflammatory bowel diseases in Taiwan: a population-based study.
      ★★★%★★Poor
      Lakatos 2013
      • Lakatos P.L.
      • Lovasz B.D.
      • David G.
      • et al.
      The risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: results from a population-based cohort in Eastern Europe.
      ★★★★★★Good
      Lemaitre 2017
      • Lemaitre M.
      • Kirchgesner J.
      • Rudnichi A.
      • et al.
      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
      ★★★★★★★★★Good
      Lin 2019
      • Lin W.-C.
      • Weng M.-T.
      • Tung C.-C.
      • et al.
      Trends and risk factors of mortality analysis in patients with inflammatory bowel disease: a Taiwanese nationwide population-based study.
      ★★★★★★★★Good
      Loftus 2000
      • Loftus E.V.
      • Tremaine W.J.
      • Habermann T.M.
      • et al.
      Risk of lymphoma in inflammatory bowel disease.
      ★★★★★★Good
      Mak 2020
      • Mak J.W.Y.
      • So J.
      • Tang W.
      • et al.
      Cancer risk and chemoprevention in Chinese inflammatory bowel disease patients: a population-based cohort study.
      ★★★★★★★★Good
      Malham 2019
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      ★★★★★★★Good
      Mellemkjaer 1995
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      ★★★★★★★★Good
      Ng 2016
      • Ng S.C.
      • Zeng Z.
      • Niewiadomski O.
      • et al.
      Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia.
      ★★%★★Poor
      Nyboe Andersen 2014
      • Nyboe Andersen N.
      • Pasternak B.
      • Basit S.
      • et al.
      Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease.
      ★★★★★★★★Good
      Olén 2017
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      ★★★★★★★★★Good
      Palli 2000
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      ★★★★★★★Good
      Pasternak 2013
      • Pasternak B.
      • Svanström H.
      • Schmiegelow K.
      • et al.
      Use of azathioprine and the risk of cancer in inflammatory bowel disease.
      ★★★★★★★★Good
      Peneau 2013
      • Peneau A.
      • Savoye G.
      • Turck D.
      • et al.
      Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study.
      ★★★★★★★Good
      Persson 1994
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      ★★★★★★★Good
      Rungoe 2015
      • Rungoe C.
      • Simonsen J.
      • Riis L.
      • et al.
      Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study.
      ★★★★★★★Good
      So 2017
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      ★★★★★★★Good
      Trivedi 2020
      • Trivedi P.J.
      • Crothers H.
      • Mytton J.
      • et al.
      Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Diseases, Based on Sex, Race, and Age.
      ★★★★★★★★Good
      Tsai 2015
      • Tsai M.S.
      • Chen H.P.
      • Hung C.M.
      • et al.
      Hospitalization for inflammatory bowel disease is associated with increased risk of breast cancer: a nationwide cohort study of an Asian population.
      ★★★★★★★★Good
      van den Heuvel 2016
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      ★★★★★★★Good
      Wang 2016
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      ★★★★★★Good
      Wilson 2016
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      ★★★★★★★★Good
      Winther 2004
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      ★★★★★★Good
      Yadav 2015
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      ★★★★★★★Good
      NOTE. Good quality: 3 or 4 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain. Fair quality: 2 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain. Poor quality: 0 or 1 star in selection domain OR 0 stars in comparability domain OR 0 or 1 stars in outcome/exposure domain.
      The overall and site-specific IRRs are provided in Figures 2 and 3. The IR and IRD for each specific cancer site can be found in their respective Supplementary Figure, as described later.
      Figure thumbnail gr2
      Figure 2Forest plot of overall and site-specific cancers in Crohn's disease patients. IRR, incidence rate ratio; n, number of studies included in the analysis; pval, P value.
      Figure thumbnail gr3
      Figure 3Forest plot of overall and site-specific cancers in ulcerative colitis patients. IRR, incidence rate ratio; n, number of studies included in the analysis; pval, P value.

       Overall Risk of Extraintestinal Cancers

      The majority of studies assessing all cancers in their respective cohorts reported no significantly increased risk compared with either a control population or what was expected in the general population.
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      ,
      • Jess T.
      • Winther K.V.
      • Munkholm P.
      • et al.
      Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
      ,
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      • Katsanos K.H.
      • Vermeire S.
      • Christodoulou D.K.
      • et al.
      Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.
      • Katsanos K.H.
      • Tatsioni A.
      • Pedersen N.
      • et al.
      Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study.
      ,
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      ,
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      ,
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      ,
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      ,
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      ,
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      Increased risk was found mainly in CD patients,
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ,
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      ,
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      including those with ileocolonic disease location,
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Peneau A.
      • Savoye G.
      • Turck D.
      • et al.
      Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study.
      ,
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      pediatric onset
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      ,
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      ,
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      ,
      • Peneau A.
      • Savoye G.
      • Turck D.
      • et al.
      Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study.
      of IBD, as well as UC patients with disease extending past the rectum.
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      ,
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • Peneau A.
      • Savoye G.
      • Turck D.
      • et al.
      Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study.
      In a cross European cohort, there was a higher-than-expected incidence of EICs found in Southern countries, but not in Northern countries.
      • Katsanos K.H.
      • Vermeire S.
      • Christodoulou D.K.
      • et al.
      Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.
      ,
      • Katsanos K.H.
      • Tatsioni A.
      • Pedersen N.
      • et al.
      Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study.
      Two studies
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ,
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      found that the use of mesalamine had a protective role against the development of EICs. One population-based, nested, case-control study found a relative risk of 1.41 (95% CI, 1.15–1.74) in patients using azathioprine.
      • Pasternak B.
      • Svanström H.
      • Schmiegelow K.
      • et al.
      Use of azathioprine and the risk of cancer in inflammatory bowel disease.
      One study did not find any protective role of mesalamine or any increased risk in using immunosuppressives.
      • Mak J.W.Y.
      • So J.
      • Tang W.
      • et al.
      Cancer risk and chemoprevention in Chinese inflammatory bowel disease patients: a population-based cohort study.
      In the meta-analysis, 11 studies were included for CD and 12 studies for UC. When pooling all data, an increased risk of EIC was found for both CD (IRR, 1.43 [95% CI, 1.26–1.63]; IR, 5.29 [95% CI, 3.85–6.72] per 1000 PY; IRD, 1.68 [95% CI, 0.79–2.56]) and UC (IRR, 1.15 [95% CI, 1.02–1.31]; IR, 5.61 [95% CI, 4.07–7.16] per 1000 PY; IRD, 0.78 [95% CI, 0.07–1.49]) patients (Supplementary Figures 4 and 5).
      When stratifying according to when the cohort populations were diagnosed (ie, before or after the year 2000), a significantly increased risk was found among CD patients in both groups, but not among UC patients (Supplementary Figures 6 and 7). A subgroup meta-analysis of adult vs pediatric patients was not performed because no pediatric studies were eligible. However, studies of pediatric patients found an increased overall risk compared with the general population (pediatric SIR range, 2.2–3.3; adult SIR range, 0.9–2.2).
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ,
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      ,
      • Jess T.
      • Winther K.V.
      • Munkholm P.
      • et al.
      Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
      ,
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      ,
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      ,
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      ,
      • Fumery M.
      • Pariente B.
      • Sarter H.
      • et al.
      Long-term outcome of pediatric-onset Crohn’s disease: a population-based cohort study.
      In the subgroup analysis of men vs women, CD patients of both sexes had a similarly increased risk, whereas UC patients, regardless of sex, had no increased risk. As noted in the meta-analysis (Supplementary Figures 8 and 9), some studies included intestinal cancers that could not be differentiated from EICs and not all studies included in the overall analysis could be used in this subgroup analysis. Regarding the subanalysis of Eastern vs Western countries, the significantly increased risk of EIC persisted in both regions except among UC patients in Eastern countries (Supplementary Figures 10 and 11).
      Risk factors associated with specific cancers from each study are shown in Table 3. In general, a pattern in the use of immunosuppressants and the development of various cancers was observed, particularly for hematologic and skin cancers. In addition, being male seemed to be a risk factor for developing various cancers.
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      ,
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ,
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      ,
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ,
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      ,
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • Lemaitre M.
      • Kirchgesner J.
      • Rudnichi A.
      • et al.
      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
      ,
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      ,
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      Table 3Risk Factors Associated With Various Cancers, Listed by Population-Based Studies Included
      StudyRisk factor CDRisk factor UC
      Armstrong 2010
      • Armstrong R.G.
      • West J.
      • Card T.R.
      Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study.
      Lymphoma = immunosuppressants vs never usersNone
      Askling 2005
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      Lymphomas = 1–5 years of follow-up evaluationMyeloid leukemia = men, diagnosed in 1990s, >5 years follow-up evaluation Lymphomas = 1–5 years of follow-up evaluation
      Bernstein 2001
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      Lymphomas = menNone
      Burisch 2018
      • Burisch J.
      • Kiudelis G.
      • Kupcinskas L.
      • et al.
      Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.
      Not reported
      Cheddani 2016
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      Lymphomas = men

      Pancreatic cancer = immunosuppressants
      Lymphomas = men

      Pancreatic cancer = immunosuppressants
      Ekbom 1991
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      None reportedOverall = proctitis

      Brain = extensive

      Breast = ↓ extensive
      Erichsen 2009
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      CC = men, diagnosed 1978–1987, ages 60–69, <1 year of follow-up evaluationCC = men, diagnosed 1978–1987, ages 60–69, <1 year of follow-up evaluation
      Fumery 2019
      • Fumery M.
      • Pariente B.
      • Sarter H.
      • et al.
      Long-term outcome of pediatric-onset Crohn’s disease: a population-based cohort study.
      None reported
      Jess 2004
      • Jess T.
      • Winther K.V.
      • Munkholm P.
      • et al.
      Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
      None
      Jess 2013
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      Lung = women, ages 50–59, L1, smoking, mesalamine

      Cervical = ages 0–19, smoking, mesalamine, immunosuppressants

      Non-Hodgkin = ages 20–39, L3, never user of mesalamine
      Prostate = mesalamine, never user of immunosuppressants
      Jung 2017
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      Women = liver, pancreas, hematologic, non-Hodgkin, leukemia

      Men = hematologic

      Overall cancer = ↓ mesalamine
      Women = liver, cervix, hematologic, non-Hodgkin

      Men = prostate, brain/CNS, thyroid
      Jussila 2013
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      Non-Hodgkin = men, age >75 with >3 years of follow-up evaluation

      Myeloma = men

      Kidney = men

      BCC = men ages 30–44 with >3 years of follow-up evaluation, women ages 45–59 with >3 years of follow-up evaluation

      Melanoma = men ages 30–44 with >3 years of follow-up evaluation
      CC = men

      Hodgkin = men

      BCC = ages 30–44 with >3 years of follow-up evaluation

      Tracheal, lung, prostate = ↓ men
      Kappelman 2014
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      Overall = diagnosis age <20Overall = diagnosis age <20

      Liver and gallbladder = cholangitis
      Karlén 1999
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      Liver and biliary tract = men
      Katsanos 2007
      • Katsanos K.H.
      • Vermeire S.
      • Christodoulou D.K.
      • et al.
      Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.
      None reportedNone reported
      Katsanos 2011
      • Katsanos K.H.
      • Tatsioni A.
      • Pedersen N.
      • et al.
      Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study.
      Overall = Southern European CountriesOverall = Southern European countries
      Kuo 2015
      • Kuo C.J.
      • Yu K.H.
      • See L.C.
      • et al.
      The trend of inflammatory bowel diseases in Taiwan: a population-based study.
      None reportedNone reported
      Lakatos 2013
      • Lakatos P.L.
      • Lovasz B.D.
      • David G.
      • et al.
      The risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: results from a population-based cohort in Eastern Europe.
      None reportedNone reported
      Lemaitre 2017
      • Lemaitre M.
      • Kirchgesner J.
      • Rudnichi A.
      • et al.
      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
      Lymphoma = Immunosuppressants monotherapy, anti–TNF-α monotherapy, combination therapy, older age, men, smoking-related conditionLymphoma = immunosuppressants monotherapy, anti–TNF-α monotherapy, Combination therapy, older age, men, smoking-related condition
      Lin 2019
      • Lin W.-C.
      • Weng M.-T.
      • Tung C.-C.
      • et al.
      Trends and risk factors of mortality analysis in patients with inflammatory bowel disease: a Taiwanese nationwide population-based study.
      None reportedNone reported
      Loftus 2000
      • Loftus E.V.
      • Tremaine W.J.
      • Habermann T.M.
      • et al.
      Risk of lymphoma in inflammatory bowel disease.
      None reportedNone reported
      Mak 2020
      • Mak J.W.Y.
      • So J.
      • Tang W.
      • et al.
      Cancer risk and chemoprevention in Chinese inflammatory bowel disease patients: a population-based cohort study.
      Overall = increasing ageOverall = increasing age
      Malham 2019
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      None reportedNone reported
      Mellemkjaer 1995
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      Hepatobiliary = ↓older age, ages 20–39
      Ng 2016
      • Ng S.C.
      • Zeng Z.
      • Niewiadomski O.
      • et al.
      Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia.
      None reportedNone reported
      Nyboe Andersen 2014
      • Nyboe Andersen N.
      • Pasternak B.
      • Basit S.
      • et al.
      Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease.
      None reportedNone reported
      Olén 2017
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      Overall = young age, PSC, colitis >10 yOverall = young age, PSC, colitis >10 y, relatives with cancer age <50
      Palli 2000
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      None reportedNone reported
      Pasternak 2013
      • Pasternak B.
      • Svanström H.
      • Schmiegelow K.
      • et al.
      Use of azathioprine and the risk of cancer in inflammatory bowel disease.
      Overall = immunosuppressants vs nonusers

      Lymphoid = immunosuppressants vs nonusers

      Urinary tract = immunosuppressants vs nonusers
      Lymphoid = immunosuppressants vs nonusers

      Urinary tract = immunosuppressants vs nonusers
      Peneau 2013
      • Peneau A.
      • Savoye G.
      • Turck D.
      • et al.
      Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study.
      None reportedNone reported
      Persson 1994
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      Overall = L3 location
      Rungoe 2015
      • Rungoe C.
      • Simonsen J.
      • Riis L.
      • et al.
      Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study.
      HSIL = diagnosis between ages 0–25 and 26–39, anti–TNF-α vs never users, redemption of immunosuppressant prescription, redemption of >20 Immunosuppressant prescription

      Cervical = diagnosis between ages 0–25
      HSIL = diagnosis between ages 26–39
      So 2017
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      Overall = age at diagnosis (not specified further)Overall = ↓diagnosis between ages 60–79, age at diagnosis (not specified further)
      Trivedi 2020
      • Trivedi P.J.
      • Crothers H.
      • Mytton J.
      • et al.
      Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Diseases, Based on Sex, Race, and Age.
      Hepatobiliary/pancreatic = PSC vs non-PSCHepatobiliary/pancreatic = PSC vs non-PSC
      Tsai 2015
      • Tsai M.S.
      • Chen H.P.
      • Hung C.M.
      • et al.
      Hospitalization for inflammatory bowel disease is associated with increased risk of breast cancer: a nationwide cohort study of an Asian population.
      Breast = >2 hospitalizations per year (especially those age <65)Breast = >2 hospitalizations per year (especially those age <65)
      van den Heuvel 2016
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      Hematologic = age >40 at diagnosis, first 10 years of follow-up evaluation, diagnosed between 2001–2011, immunosuppressants, immunosuppressants + anti–TNF-α

      Skin = L1 at diagnosis, first 10 years of follow-up evaluation, immunosuppressants + anti–TNF-α

      SCC = men, age >40 at diagnosis, L1 at diagnosis, first 10 years of follow-up evaluation, diagnosed between 2001–2011, immunosuppressants, immunosuppressants + anti–TNF-α

      Non-Hodgkin = immunosuppressants, immunosuppressants + anti–TNF-α
      Hematologic = immunosuppressants, immunosuppressants + anti–TNF-α

      Skin = immunosuppressants + anti–TNF-α

      SCC = immunosuppressants, immunosuppressants + anti–TNF-α

      Non-Hodgkin = immunosuppressants, immunosuppressants + anti–TNF-α
      Wang 2016
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      Hematologic = first year of follow-up evaluationHematologic = first year of follow-up evaluation
      Wilson 2016
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      Overall = >3 IBD-related symptoms, current smokers, former drinker, ↓ BMI 25–39.9, ↓ diabetes, corticosteroids, ↓ mesalamine

      Prostate = ↓ mesalamine
      Overall = other autoimmune disorder, diabetes

      Prostate = ↓ mesalamine
      Winther 2004
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      Melanoma = men

      Overall ↓women with E3
      Yadav 2015
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      Overall = women

      Melanoma = corticosteroids, immunosuppressives
      Overall = women

      Melanoma = corticosteroids, immunosuppressives
      NOTE. Empty cells, the study did not investigate this patient group. ↓ = Reduces the risk.
      Overall = Across all cancers
      BMI, body mass index; CC, cholangiocarcinoma; CNS, central nervous system; HSIL, high-grade squamous intraepithelial lesion; IBD, inflammatory bowel disease; PSC, primary sclerosing cholangitis; SCC, squamous cell carcinoma; TNF-α, tumor necrosis factor-α.

       Risk of Cancer in the Bile Duct, Liver, and Pancreas

      The majority of studies showed an increased risk of cancer, especially in the bile duct and liver, for both CD and UC patients.
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ,
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      ,
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      ,
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      ,
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      ,
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      ,
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      UC patients consistently were found to have an increased risk compared with CD patients.
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ,
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      ,
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      ,
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      ,
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      ,
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      The risk of cholangiocarcinoma was reported to be increased in patients diagnosed at a young age,
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      ,
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      in men,
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      ,
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      women,
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      patients with a long-standing diagnosis,
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      and with primary sclerosing cholangitis.
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      ,
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      However, the absolute risk of developing cancer in the hepatobiliary system was low (7.6–76 per 100,000 PY).
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ,
      • Erichsen R.
      • Jepsen P.
      • Vilstrup H.
      • et al.
      Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978-2003.
      ,
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      ,
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      ,
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      ,
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      One study found that the risk was higher among patients with primary sclerosing cholangitis (200–1200 per 100,000 PY).
      • Trivedi P.J.
      • Crothers H.
      • Mytton J.
      • et al.
      Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Diseases, Based on Sex, Race, and Age.
      Only 1 study showed an increased risk of pancreatic cancer among female CD patients.
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      Another study observed a correlation between thiopurine use and the development of pancreatic cancer among UC patients,
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      while a different study did not find any correlation between the development of cancer in the digestive organ (noncolorectal) and use of thiopurine.
      • Pasternak B.
      • Svanström H.
      • Schmiegelow K.
      • et al.
      Use of azathioprine and the risk of cancer in inflammatory bowel disease.
      The meta-analysis found an increased risk of malignancy in the bile duct among UC and CD patients (IRR, 2.93 [95% CI, 1.73–4.98] and 2.93 [95% CI, 1.16–7.41], respectively), although only UC patients were at increased risk of hepatobiliary (and pancreatic) malignancies (IRR, 2.05 [95% CI, 1.52–2.76]) (Supplementary Figures 12 and 13).

       Risk of Hematologic Cancers

      The majority of studies observed an increased risk of hematologic malignancies in both CD and UC patients.
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      ,
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ,
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ,
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      ,
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      ,
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      ,
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      ,
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      ,
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      The risk of non-Hodgkin lymphomas was found to be especially higher in IBD patients, particularly those with CD.
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      ,
      • Bernstein C.N.
      • Blanchard J.F.
      • Kliewer E.
      • et al.
      Cancer risk in patients with inflammatory bowel disease: a population-based study.
      ,
      • Cheddani H.
      • Dauchet L.
      • Fumery M.
      • et al.
      Cancer in elderly onset inflammatory bowel disease: a population-based study.
      ,
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ,
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      ,
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      ,
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      ,
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      ,
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      • Wilson J.C.
      • Furlano R.I.
      • Jick S.S.
      • et al.
      A population-based study examining the risk of malignancy in patients diagnosed with inflammatory bowel disease.
      ,
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      Four studies found that the increased incidence of non-Hodgkin lymphomas was associated with the use of immunosuppressives.
      • Armstrong R.G.
      • West J.
      • Card T.R.
      Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study.
      ,
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      ,
      • Lemaitre M.
      • Kirchgesner J.
      • Rudnichi A.
      • et al.
      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
      ,
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      One study found that the combination of immunosuppressives and anti–TNF-α inhibitors further increased the risk (adjusted hazard ratio, 6.11 [95% CI, 3.46–10.8]) compared with patients who were unexposed or on monotherapy.
      • Lemaitre M.
      • Kirchgesner J.
      • Rudnichi A.
      • et al.
      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
      Two studies found that the risk of Hodgkin lymphoma was higher in UC patients,
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      ,
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      whereas 2 other studies found it to be higher in CD patients.
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      Immunosuppressives were found to increase the risk further.
      • Armstrong R.G.
      • West J.
      • Card T.R.
      Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study.
      ,
      • Lemaitre M.
      • Kirchgesner J.
      • Rudnichi A.
      • et al.
      Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.
      Three studies found an increased risk of leukemia in CD patients
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      ,
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ,
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      and 1 study observed an increased risk in UC patients.
      • Askling J.
      • Brandt L.
      • Lapidus A.
      • et al.
      Risk of haematopoietic cancer in patients with inflammatory bowel disease.
      In the meta-analysis, a significantly increased risk of hematologic malignancies in general, and of lymphomas in particular, was found among CD patients (IRR, 2.40 [95% CI, 1.81–3.18] and 1.86 [95% CI, 1.04–3.32], respectively). There was no significantly increased risk of any specific hematologic malignancies in either CD or UC patients (Supplementary Figures 14 and 15). However, borderline significance was found for both non-Hodgkin lymphoma and leukemia in CD patients.

       Risk of Skin Cancers

      Nonmelanoma skin cancers were found to be more common in both CD and UC patients in 8 of the 14 studies, especially in CD patients
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      ,
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      ,
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • Malham M.
      • Jakobsen C.
      • Paerregaard A.
      • et al.
      The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.
      • Mellemkjaer L.
      • Olsen J.H.
      • Frisch M.
      • et al.
      Cancer in patients with ulcerative colitis.
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      ,
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      ; however, 6 studies found no such increased risk.
      • Jess T.
      • Winther K.V.
      • Munkholm P.
      • et al.
      Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark.
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ,
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      ,
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      ,
      • Winther K.V.
      • Jess T.
      • Langholz E.
      • et al.
      Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.
      Two studies found that the use of immunosuppressives increased the risk,
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      ,
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      while 1 did not.
      • Pasternak B.
      • Svanström H.
      • Schmiegelow K.
      • et al.
      Use of azathioprine and the risk of cancer in inflammatory bowel disease.
      For example, van den Heuvel et al
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      found a SIR of 1.95 (95% CI, 1.22–2.96) among CD patients after being exposed to immunosuppressives vs patients who were not exposed.
      Regarding the risk of melanoma, study findings were inconsistent. One study found a significantly increased risk of melanoma in IBD patients,
      • Olén O.
      • Askling J.
      • Sachs M.C.
      • et al.
      Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014.
      while 2 other studies found an increased risk specific to CD patients.
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      ,
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      Jussila et al
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      found that male CD patients had an increased risk of melanoma with a SIR of 2.33 (95% CI, 1.12–4.28). Yadav et al
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      found that IBD patients undergoing treatment with either corticosteroids (IRR, 8.23 [95% CI, 1.38–49.25]) or immunosuppressives (IRR, 5.26 [95% CI, 1.12–24.77]) were at increased risk of developing melanoma.
      These results were supported by the meta-analysis, showing an increased risk for nonmelanoma skin cancers among both CD and UC patients (IRR, 2.28 [95% CI, 1.36–3.81] and 1.36 [95% CI, 1.05–1.77], respectively), while the risk of melanoma only was increased significantly among CD patients (IRR, 1.52 [95% CI, 1.03–2.23]) (Supplementary Figures 16 and 17).

       Risk of Lung Cancers

      Only 2 of 16 studies found an increased risk of lung cancers in CD patients.
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      In UC patients, no significant risk of lung cancers was found in any study. Moreover, 4 studies found that UC patients had a significantly lower risk of lung cancers.
      • Karlén P.
      • Löfberg R.
      • Broström O.
      • et al.
      Increased risk of cancer in ulcerative colitis: a population-based cohort study.
      ,
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      ,
      • Palli D.
      • Trallori G.
      • Bagnoli S.
      • et al.
      Hodgkin’s disease risk is increased in patients with ulcerative colitis.
      ,
      • Yadav S.
      • Singh S.
      • Harmsen W.S.
      • et al.
      Effect of medications on risk of cancer in patients with inflammatory bowel diseases: a population-based cohort study from Olmsted County, Minnesota.
      When pooling the available data, the meta-analysis showed an increased risk of lung cancers in CD patients (IRR, 1.53 [95% CI, 1.23-1.91]), while a borderline significantly lower risk was found in UC patients (Supplementary Figures 18 and 19).

       Risk of Urologic and Nephrologic Cancers

      Only 4
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      ,
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      ,
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      ,
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      of 16 studies found an increased risk of urologic or nephrologic cancers. One study found an increased risk of bladder cancer among CD patients (standardized morbidity ratio, 2.68 [95% CI, 1.08–5.53])
      • Persson P.G.
      • Karlén P.
      • Bernell O.
      • et al.
      Crohn’s disease and cancer: a population-based cohort study.
      and 1 study found an increased risk of cancer in the urinary tract among UC patients (SIR, 2.05 [95% CI, 1.0–3.7]).
      • Wang L.H.
      • Yang Y.J.
      • Cheng W.C.
      • et al.
      Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan.
      Furthermore, 2 studies found a significantly increased risk of malignancies in the kidney among male CD patients and in CD patients in general.
      • Jussila A.
      • Virta L.J.
      • Pukkala E.
      • et al.
      Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland.
      ,
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      One study found that the use of azathioprine increased the risk of cancer in the urinary tract.
      • Pasternak B.
      • Svanström H.
      • Schmiegelow K.
      • et al.
      Use of azathioprine and the risk of cancer in inflammatory bowel disease.
      The nonsignificant findings were supported by the meta-analysis (Supplementary Figures 20 and 21).

       Risk of Cancers in the Reproductive Organs

      Only 3
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ,
      • Rungoe C.
      • Simonsen J.
      • Riis L.
      • et al.
      Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study.
      of 21 studies found a significant risk of cancer in the female reproductive organs (cervix, uterus, ovaries, and breasts).
      Rungoe et al
      • Rungoe C.
      • Simonsen J.
      • Riis L.
      • et al.
      Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study.
      found an increased risk of both low- and high-grade squamous intraepithelial lesions in patients with CD (IRR, 1.26 [95% CI, 1.07–1.48] and 1.28 [95% CI, 1.13–1.45], respectively) and UC (IRR, 1.15 [95% CI, 1.00–1.32] and 1.12 [95% CI, 1.01–1.25], respectively). Furthermore, the same study found an increased risk of cervical cancer in CD patients (IRR, 1.53 [95% CI, 1.04–2.27]), despite the same screening frequencies in a nationwide study. Jung et al
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      found an increased risk of malignancies in the cervix uteri among UC patients (SIR, 5.65 [95% CI, 2.44–11.13]).
      Concerning breast cancer, van den Heuvel et al
      • van den Heuvel T.R.
      • Wintjens D.S.
      • Jeuring S.F.
      • et al.
      Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort.
      found a significantly lower risk among CD patients (SIR, 0.11 [95% CI, 0.00–0.64]), while Ekbom et al
      • Ekbom A.
      • Helmick C.
      • Zack M.
      • et al.
      Extracolonic malignancies in inflammatory bowel disease.
      found a lower risk among patients with extensive UC (SIR, 0.4 [95% CI, 0.1–1.0]).
      Four of 21 studies found an increased risk of cancers in the male reproductive organs (testes, prostate, penis).
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
      ,
      • Jung Y.S.
      • Han M.
      • Park S.
      • et al.
      Cancer risk in the early stages of inflammatory bowel disease in Korean patients: a nationwide population-based study.
      ,
      • Kappelman M.D.
      • Farkas D.K.
      • Long M.D.
      • et al.
      Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
      ,
      • So J.
      • Tang W.
      • Leung W.K.
      • et al.
      Cancer risk in 2621 Chinese patients with inflammatory bowel disease: a population-based cohort study.
      Jess et al
      • Jess T.
      • Horváth-Puhó E.
      • Fallingborg J.
      • et al.
      Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.