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Surveillance and management of colorectal dysplasia and cancer in inflammatory bowel disease: Current practice and future perspectives

  • Anouk M. Wijnands
    Affiliations
    Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands
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  • Remi Mahmoud
    Affiliations
    Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands
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  • Maurice W.M.D. Lutgens
    Affiliations
    Department of Gastroenterology and Hepatology, Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands
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  • Bas Oldenburg
    Correspondence
    Corresponding author at: Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, P.O. Box 85500, internal mail no F02.618, Heidelberglaan, 100 3584 CX Utrecht, the Netherlands.
    Affiliations
    Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands
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Open AccessPublished:September 01, 2021DOI:https://doi.org/10.1016/j.ejim.2021.08.010

      Highlights

      • Chronic inflammation predisposes patients with colonic IBD to develop CRC.
      • Surveillance enables early detection of dysplastic lesions and CRC.
      • Improved risk-stratification of IBD patients is required to optimise surveillance.
      • Dysplastic lesions are increasingly treated with endoscopic resection techniques.
      • Long-term follow-up studies after endoscopic resections of dysplasia are needed.

      Abstract

      Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). Current guidelines recommend frequent surveillance colonoscopies for patients with at least left-sided ulcerative colitis, or Crohn's disease involving more than 30% of the colon. Surveillance allows for early detection and treatment of colorectal dysplasia and cancer. The first colonoscopy should be performed 8 to 10 years after onset of disease symptoms. European and British guidelines employ a risk-stratification algorithm that assigns patients to surveillance intervals of one, three or five years, whereas American guidelines recommend to perform surveillance every 1 to 3 years based on the (combined) presence of risk factors. Patients with concomitant primary sclerosing cholangitis are at an additionally increased risk, and should undergo annual surveillance starting immediately after the diagnosis. The current practice of surveillance is based on limited evidence, is resource intensive and cannot preclude the occurrence of interval carcinomas. Fortunately, advances in endoscopic techniques for mucosal visualisation, along with better control of inflammation, have resulted in a declining incidence of CRC in patients with IBD. Furthermore, advanced endoscopic resection techniques can be expected to result in a shift from surgical to endoscopic management of dysplastic lesions. In this review, we provide an up-to-date overview of colitis-associated CRC pathophysiology, epidemiology, surveillance practices, and management of dysplasia.

      Keywords

      Abbreviations:

      5-ASA (5-aminosalicilyc acid), CD (Crohn's disease), CRC (Colorectal cancer), EMR (Endoscopic mucosal resection), ESD (Endoscopic submucosal dissection), HD (High-definition), HGD (High-grade dysplasia), IBD (Inflammatory bowel disease), LGD (Low-grade dysplasia), pks (polyketide nonribosomal peptide synthase operon), PSC (Primary sclerosing cholangitis), RCT (Randomised controlled trial), TNF-alpha (Tumour necrosis factor-alpha), UC (Ulcerative colitis), UDCA (Ursodeoxycholic acid)

      1. Introduction

      Almost a century ago, Crohn and Rosenberg described the first case of ulcerative colitis (UC) complicated by colorectal carcinoma (CRC). [
      • Crohn B
      • Rosenberg H.
      The sigmoidoscopic picture of chronic ulcerative colitis (non- specific).
      ] Nowadays, it is widely recognised that patients with colonic inflammatory bowel disease (IBD), including UC and Crohn's disease (CD), are at increased risk of CRC and therefore these patients are enrolled in surveillance programs. [
      • Jess T
      • Simonsen J
      • Jorgensen KT
      • et al.
      Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years.
      ,
      • Lutgens MW
      • van Oijen MG
      • van der Heijden GJ
      • et al.
      Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
      ,
      • Maaser C
      • Sturm A
      • Vavricka SR
      • et al.
      ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications.
      ,
      • Lamb CA
      • Kennedy NA
      • Raine T
      • et al.
      British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
      ,
      • Rubin DT
      • Ananthakrishnan AN
      • Siegel CA
      • et al.
      ACG clinical guideline: ulcerative colitis in adults.
      ,
      • Lichtenstein GR
      • Loftus EV
      • Isaacs KL
      • et al.
      ACG clinical guideline: management of Crohn's disease in adults.
      ,
      • Farraye FA
      • Odze RD
      • Eaden J
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      ] Endoscopic surveillance aims to detect and remove precursor lesions or early-stage CRC, and has been linked to a decreased risk of CRC and corresponding mortality based on retrospective data. [
      • Bye WA
      • Ma C
      • Nguyen TM
      • et al.
      Strategies for detecting colorectal cancer in patients with inflammatory bowel disease: a cochrane systematic review and meta-analysis.
      ]
      The development of novel endoscopic technologies has had an enormous impact on endoscopy practices. High-definition endoscopes allow for detailed visualisation of the colonic mucosa, and novel resection techniques enable endoscopic treatment of lesions that previously had to be removed surgically. [
      • Manta R
      • Zullo A
      • Telesca DA
      • et al.
      Endoscopic submucosal dissection for visible dysplasia treatment in ulcerative colitis patients: cases series and systematic review of literature.
      ] This technological progress, along with the expanding therapeutic armamentarium to control inflammation, [
      • Katsanos KH
      • Papamichael K
      • Feuerstein JD
      • et al.
      Biological therapies in inflammatory bowel disease: beyond anti-TNF therapies.
      ,
      • Olivera P
      • Danese S
      • Peyrin-Biroulet L.
      Next generation of small molecules in inflammatory bowel disease.
      ] likely explains why the incidence of colitis-associated CRC has declined over time. [
      • Lutgens MW
      • van Oijen MG
      • van der Heijden GJ
      • et al.
      Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
      ]
      In the light of these developments, this review aims to provide an up-to-date overview on the pathophysiology, epidemiology, surveillance strategies and management of colitis-associated dysplasia and cancer. Furthermore, we will highlight several areas of interest for further research.

      2. Pathophysiology

      According to the widely accepted adenoma-carcinoma sequence paradigm, most cases of sporadic CRC develop from adenomatous polyps over a long period of time. [
      • Fearon ER
      • Vogelstein B.
      A genetic model for colorectal tumorigenesis.
      ] Colitis-associated CRC is thought to develop through several stages of precursor lesions as well, from inflamed but non-dysplastic epithelium to low-grade dysplasia (LGD), high-grade dysplasia (HGD) and finally CRC. [
      • Itzkowitz SH.
      Molecular biology of dysplasia and cancer in inflammatory bowel disease.
      ,
      • Riddell RH
      • Goldman H
      • Ransohoff DF
      • et al.
      Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications.
      ] Here, chronic inflammation is thought to be the main driver of tumourigenesis. [
      • Itzkowitz SH.
      Molecular biology of dysplasia and cancer in inflammatory bowel disease.
      ] Indeed, endoscopic or histologic inflammation, and extensive disease are well-known independent risk factors for colorectal dysplasia and cancer in IBD. [
      • Choi CR
      • Al Bakir I
      • Ding NJ
      • et al.
      Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study.
      ,
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.
      ]
      A unique feature of the pathogenesis of colitis-associated CRC is that chronic inflammation leads to a ‘field defect’ of damaged DNA in colonic epithelial cells, rather than unifocal aberrant clones. [
      • Itzkowitz SH.
      Molecular biology of dysplasia and cancer in inflammatory bowel disease.
      ] Small genomic alterations may be present throughout the (entire) colon affected by colitis in normally appearing, non-dysplastic mucosa. [
      • Lai LA
      • Risques RA
      • Bronner MP
      • et al.
      Pan-colonic field defects are detected by CGH in the colons of UC patients with dysplasia/cancer.
      ] From these areas, dysplastic lesions arise, which are usually endoscopically visible, using current high-definition endoscopes. [
      • Ten Hove JR
      • Mooiweer E
      • van der Meulen de Jong AE
      • et al.
      Clinical implications of low grade dysplasia found during inflammatory bowel disease surveillance: a retrospective study comparing chromoendoscopy and white-light endoscopy.
      ] This field defect or ‘field cancerisation’ explains why dysplasia in IBD is often multifocal. [
      • Ten Hove JR
      • Mooiweer E
      • van der Meulen de Jong AE
      • et al.
      Clinical implications of low grade dysplasia found during inflammatory bowel disease surveillance: a retrospective study comparing chromoendoscopy and white-light endoscopy.
      ,
      • Mahmoud R
      • Shah SC
      • Torres J
      • et al.
      Association between indefinite dysplasia and advanced neoplasia in patients with inflammatory bowel diseases undergoing surveillance.
      ,
      • Choi CH
      • Ignjatovic-Wilson A
      • Askari A
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      ]
      At a genetic level, in line with sporadic CRC, most colitis-associated CRCs develop through the chromosomal instability pathway as opposed to the microsatellite instability pathway (i.e. malfunctioning of DNA mismatch repair genes, involved in Lynch syndrome). [
      • Itzkowitz SH.
      Molecular biology of dysplasia and cancer in inflammatory bowel disease.
      ,
      • Hirsch D
      • Hardt J
      • Sauer C
      • et al.
      Molecular characterization of ulcerative colitis-associated colorectal carcinomas.
      ,
      • Wanders LK
      • Cordes M
      • Voorham Q
      • et al.
      IBD-Associated Dysplastic Lesions Show More Chromosomal Instability Than Sporadic Adenomas.
      ] The chromosomal instability pathway manifests by copy number alterations of chromosomes or parts of chromosomes (i.e. aneuploidy) and includes changes to the APC, TP53 and K-RAS genes, [
      • Itzkowitz SH.
      Molecular biology of dysplasia and cancer in inflammatory bowel disease.
      ] among others. It is thought that these changes occur in a different sequence in colitis-associated versus sporadic CRC. For example, APC mutations are more frequent in precursors lesions of sporadic CRC (sporadic adenomas), [
      • Wanders LK
      • Cordes M
      • Voorham Q
      • et al.
      IBD-Associated Dysplastic Lesions Show More Chromosomal Instability Than Sporadic Adenomas.
      ] while colitis-associated precursor lesions usually harbour TP53 mutations. [
      • Xie H
      • Xiao SY
      • Pai R
      • et al.
      Diagnostic utility of TP53 and cytokeratin 7 immunohistochemistry in idiopathic inflammatory bowel disease-associated neoplasia.
      ,
      • Horvath B
      • Liu G
      • Wu X
      • et al.
      Overexpression of p53 predicts colorectal neoplasia risk in patients with inflammatory bowel disease and mucosa changes indefinite for dysplasia.
      ] This differential sequence may explain why colitis-associated dysplasia can be morphologically distinct from sporadic adenomas, as it is often non-polypoid. [
      • Mahmoud R
      • Shah SC
      • Torres J
      • et al.
      Association between indefinite dysplasia and advanced neoplasia in patients with inflammatory bowel diseases undergoing surveillance.
      ,
      • Choi CH
      • Ignjatovic-Wilson A
      • Askari A
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      ]
      The gut microbiome differs between IBD patients and healthy individuals, [
      • Pittayanon R
      • Lau JT
      • Leontiadis GI
      • et al.
      Differences in gut microbiota in patients with vs without inflammatory bowel diseases: a systematic review.
      ] and this has recently been linked to the increased CRC risk in patients with IBD. [
      • Arthur JC
      • Perez-Chanona E
      • Muhlbauer M
      • et al.
      Intestinal inflammation targets cancer-inducing activity of the microbiota.
      ] A specific strain of Escherichia Coli (polyketide non-ribosomal peptide synthase operon [pks] positive strain) has a twofold higher prevalence in IBD patients as compared to healthy individuals. [
      • Arthur JC
      • Perez-Chanona E
      • Muhlbauer M
      • et al.
      Intestinal inflammation targets cancer-inducing activity of the microbiota.
      ] This pks-positive Escherichia Coli strain produces a toxin (colibactin) that damages DNA and induces a specific signature of mutations (including mutations in the APC gene and genes involved in the TP53-axis, among others) in intestinal organoids. [
      • Pleguezuelos-Manzano C
      • Puschhof J
      • Rosendahl Huber A
      • et al.
      Mutational signature in colorectal cancer caused by genotoxic pks(+) E. coli.
      ,
      • Iftekhar A
      • Berger H
      • Bouznad N
      • et al.
      Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells.
      ] These preliminary findings might, in the future, lead to new targets for preventive strategies.
      Finally, it should be noted that patients with IBD may also develop sporadic adenomas. Since the prognosis differs for colitis-associated dysplasia versus sporadic adenoma in IBD patients, [
      • Choi CH
      • Rutter MD
      • Askari A
      • et al.
      Forty-year analysis of colonoscopic surveillance program for neoplasia in ulcerative colitis: an updated overview.
      ] various efforts have been made to identify endoscopic or histopathological characteristics that can help making this distinction. Currently, the distinction is based on lesion morphology, presence of multifocal dysplasia, and whether the lesion is located in an area previously affected by inflammation.

      3. Epidemiology

      3.1 Excess risk of CRC in patients with IBD

      Patients with IBD are at an 1.4 to 2.2 fold increased risk of CRC compared with the general population. [
      • Lutgens MW
      • van Oijen MG
      • van der Heijden GJ
      • et al.
      Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
      ,
      • Beaugerie L
      • Svrcek M
      • Seksik P
      • et al.
      Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease.
      ,
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study.
      ,
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in Crohn's disease: a Scandinavian population-based cohort study.
      ] Furthermore, CRC-related survival is lower among patients with IBD, even after adjustment for tumour stage at diagnosis. [
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study.
      ,
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in Crohn's disease: a Scandinavian population-based cohort study.
      ,
      • Ou B
      • Zhao J
      • Guan S
      • et al.
      Survival of colorectal cancer in patients with or without inflammatory bowel disease: a meta-analysis.
      ] Thus, both a higher incidence of CRC as well as worse clinical outcomes of colitis-associated CRC contribute to an overall increased rate of CRC-related mortality in patients with IBD. [
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study.
      ,
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in Crohn's disease: a Scandinavian population-based cohort study.
      ]
      The incidence of IBD-CRC is considerably higher in hospital-based studies as compared to population-based studies (1.7-3.0 per 1,000 patient-years and 0.8-1.3 per 1,000 patient-years, respectively). [
      • Beaugerie L
      • Svrcek M
      • Seksik P
      • et al.
      Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease.
      ,
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study.
      ,
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in Crohn's disease: a Scandinavian population-based cohort study.
      ,
      • Gordon C
      • Chee D
      • Hamilton B
      • et al.
      Root-cause analyses of missed opportunities for the diagnosis of colorectal cancer in patients with inflammatory bowel disease.
      ,
      • Selinger CP
      • Andrews JM
      • Titman A
      • et al.
      Long-term follow-up reveals low incidence of colorectal cancer, but frequent need for resection, among Australian patients with inflammatory bowel disease.
      ,
      • Wintjens DSJ
      • Bogie RMM
      • van den Heuvel TRA
      • et al.
      Incidence and classification of postcolonoscopy colorectal cancers in inflammatory bowel disease: a dutch population-based cohort study.
      ] Cohort studies of patients undergoing surveillance report the highest IBD-CRC incidences (3.1-4.7 per 1,000 patient-years). [
      • Choi CH
      • Rutter MD
      • Askari A
      • et al.
      Forty-year analysis of colonoscopic surveillance program for neoplasia in ulcerative colitis: an updated overview.
      ,
      • Shah SC
      • Ten Hove JR
      • Castaneda D
      • et al.
      High risk of advanced colorectal neoplasia in patients with primary sclerosing cholangitis associated with inflammatory bowel disease.
      ] Beaugerie's landmark study showed that IBD patients with a disease duration of more than ten years and involvement of more than half of the colonic mucosa are at a 5.2-fold (UC) and 9.0-fold (CD) increased risk of CRC compared with the general population. In contrast, patients in whom such long-standing, extensive colitis was not present had a similar CRC risk as non-IBD controls. [
      • Beaugerie L
      • Svrcek M
      • Seksik P
      • et al.
      Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease.
      ]
      Interestingly, the excess risk of CRC in patients with IBD has been found to decline over time in most regions where this has been examined, [
      • Lutgens MW
      • van Oijen MG
      • van der Heijden GJ
      • et al.
      Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
      ,
      • Olen O
      • Erichsen R
      • Sachs MC
      • et al.
      Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study.
      ] but not all. [
      • Lutgens MW
      • van Oijen MG
      • van der Heijden GJ
      • et al.
      Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
      ,
      • Gordon C
      • Chee D
      • Hamilton B
      • et al.
      Root-cause analyses of missed opportunities for the diagnosis of colorectal cancer in patients with inflammatory bowel disease.
      ] This decline may be explained by advances in surveillance techniques and improved management of inflammation. [
      • Jess T
      • Simonsen J
      • Jorgensen KT
      • et al.
      Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years.
      ,
      • Lutgens MW
      • van Oijen MG
      • van der Heijden GJ
      • et al.
      Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
      ] Of note, results from the longest-running surveillance cohort in patients with UC initially indicated a decreasing CRC incidence, but subsequently reported an increase in early CRC. The authors attributed this phenomenon to a shift from managing dysplasia surgically (i.e. colectomy) to endoscopic resection. [
      • Choi CH
      • Rutter MD
      • Askari A
      • et al.
      Forty-year analysis of colonoscopic surveillance program for neoplasia in ulcerative colitis: an updated overview.
      ] Reassuringly, the incidence of advanced CRC had continued to decline in the last decade.

      3.2 Risk factors

      Risk factors for HGD and CRC combined (‘advanced colorectal neoplasia’, a commonly used composite endpoint in studies) in patients with IBD include extensive colonic disease, presence of post-inflammatory polyps, colonic strictures and severity of histologic inflammation. [
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.
      ] These factors are all closely related to the cumulative inflammatory burden, [
      • Choi CR
      • Al Bakir I
      • Ding NJ
      • et al.
      Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study.
      ] and underpin the central role of inflammation in the pathogenesis of colitis-associated CRC. The main challenge therefore, is to create a pragmatic score for cumulative inflammation (either based on histology or endoscopy), that can be readily implemented in routine practice.
      In addition to the abovementioned phenotypic features related to inflammation, primary sclerosing cholangitis (PSC) is a very strong risk factor for HGD and CRC in patients with IBD as well. [
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.
      ,
      • Lazaridis KN
      • LaRusso NF.
      Primary sclerosing cholangitis.
      ] PSC is a chronic progressive cholestatic liver disease leading to biliary inflammation and fibrosis, [
      • Lazaridis KN
      • LaRusso NF.
      Primary sclerosing cholangitis.
      ] that is exceedingly rare in the general population, but is present in 3-5% of patients with IBD (mainly UC patients). [
      • Choi CH
      • Rutter MD
      • Askari A
      • et al.
      Forty-year analysis of colonoscopic surveillance program for neoplasia in ulcerative colitis: an updated overview.
      ,
      • Olsson R
      • Danielsson A
      • Jarnerot G
      • et al.
      Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis.
      ] Similar to sporadic CRC, older age, a positive family history of CRC and male sex also increase the risk of colitis-associated HGD and CRC. [
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.
      ] Moreover, IBD patients with prior indefinite dysplasia or LGD are also at increased risk of HGD and CRC. [
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.
      ] The latter may be explained by various factors, including local recurrence (inadequate resections), missed synchronous lesions, or the aforementioned “field defect” of damaged DNA that extends beyond the dysplastic lesion. Notably, aneuploidy in biopsies from normally appearing mucosa may indicate a field defect and is indeed associated with a more than fivefold increased risk of HGD or CRC. [
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.
      ]

      4. Surveillance

      4.1 Surveillance strategies

      Leading guidelines recommend to perform surveillance in patients with colonic IBD. A first surveillance colonoscopy should be scheduled in all patients with colonic IBD either 8 to 10 years after onset of symptoms. [
      • Maaser C
      • Sturm A
      • Vavricka SR
      • et al.
      ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications.
      ,
      • Lamb CA
      • Kennedy NA
      • Raine T
      • et al.
      British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
      ,
      • Rubin DT
      • Ananthakrishnan AN
      • Siegel CA
      • et al.
      ACG clinical guideline: ulcerative colitis in adults.
      ,
      • Lichtenstein GR
      • Loftus EV
      • Isaacs KL
      • et al.
      ACG clinical guideline: management of Crohn's disease in adults.
      ,
      • Farraye FA
      • Odze RD
      • Eaden J
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      ] Continued surveillance is recommended if the colonic involvement exceeds proctitis (UC) or is more than 30% (CD). European and British guidelines stratify patients in one of three risk categories (high, intermediate, or low risk group) with surveillance intervals ranging from annually to every five years (Fig. 1). [
      • Maaser C
      • Sturm A
      • Vavricka SR
      • et al.
      ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications.
      ,
      • Lamb CA
      • Kennedy NA
      • Raine T
      • et al.
      British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
      ] American guidelines recommend to perform surveillance every 1 to 3 years and to consider the (combined) presence of risk factors when determining the next surveillance interval. [
      • Rubin DT
      • Ananthakrishnan AN
      • Siegel CA
      • et al.
      ACG clinical guideline: ulcerative colitis in adults.
      ,
      • Lichtenstein GR
      • Loftus EV
      • Isaacs KL
      • et al.
      ACG clinical guideline: management of Crohn's disease in adults.
      ,
      • Farraye FA
      • Odze RD
      • Eaden J
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      ] Importantly, IBD patients with concomitant PSC are a distinct category. For these patients, all guidelines recommend annual surveillance, starting immediately after the diagnosis because of the strongly increased CRC risk in patients with PSC. [
      • Maaser C
      • Sturm A
      • Vavricka SR
      • et al.
      ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications.
      ,
      • Lamb CA
      • Kennedy NA
      • Raine T
      • et al.
      British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
      ,
      • Rubin DT
      • Ananthakrishnan AN
      • Siegel CA
      • et al.
      ACG clinical guideline: ulcerative colitis in adults.
      ,
      • Lichtenstein GR
      • Loftus EV
      • Isaacs KL
      • et al.
      ACG clinical guideline: management of Crohn's disease in adults.
      ,
      • Farraye FA
      • Odze RD
      • Eaden J
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      ,
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.
      ]
      Fig 1
      Fig. 1Surveillance strategy of the European Crohn's and Colitis Organisation (ECCO)
      [
      • Maaser C
      • Sturm A
      • Vavricka SR
      • et al.
      ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications.
      ]
      * Presence of inflammation is based on endoscopic or histologic inflammation. CRC=colorectal cancer, PSC=primary sclerosing cholangitis.
      The (cost)effectiveness of the algorithms recommended in current guidelines has never been investigated prospectively and the available evidence is insufficient to objectively define optimal, individualised surveillance intervals. As a result, current surveillance regimens undoubtedly lead to overutilisation of health care resources, as most IBD patients will never develop CRC. This is underscored by a previous cost-effectiveness modelling study that found a risk-stratification approach for surveillance to be more cost-effective than annual or biannual surveillance. [
      • Lutgens M
      • van Oijen M
      • Mooiweer E
      • et al.
      A risk-profiling approach for surveillance of inflammatory bowel disease-colorectal carcinoma is more cost-effective: a comparative cost-effectiveness analysis between international guidelines.
      ] Meanwhile, 30% of CRC cases in IBD are missed during surveillance and can therefore be classified as interval carcinomas. [
      • Mooiweer E
      • van der Meulen-de Jong AE
      • Ponsioen CY
      • et al.
      Incidence of interval colorectal cancer among inflammatory bowel disease patients undergoing regular colonoscopic surveillance.
      ] Furthermore, half of the CRCs diagnosed in patients with IBD who underwent a colonoscopy in the past five years, can be attributed to a previously missed lesion, despite adequate procedural quality measures. [
      • Wintjens DSJ
      • Bogie RMM
      • van den Heuvel TRA
      • et al.
      Incidence and classification of postcolonoscopy colorectal cancers in inflammatory bowel disease: a dutch population-based cohort study.
      ] These findings highlight the need for an evidence-based systematic approach to identify patients with IBD in whom surveillance is indicated, [
      • Gordon C
      • Chee D
      • Hamilton B
      • et al.
      Root-cause analyses of missed opportunities for the diagnosis of colorectal cancer in patients with inflammatory bowel disease.
      ,
      • Prentice RE
      • Hollingsworth L
      • Middleton C
      • et al.
      Letter: colorectal cancer surveillance in inflammatory bowel disease-a call for systematic reform.
      ,
      • Mahmoud R
      • Itzkowitz SH.
      Editorial: missed opportunities to detect colorectal cancer in inflammatory bowel disease-getting to the root.
      ] as well as the importance of optimising surveillance techniques to reduce the risk of missed lesions.

      4.2 Surveillance technique

      Colonoscopy is the gold standard for CRC surveillance in IBD patients. Optimal bowel preparation and disease remission are absolute requirements for adequate surveillance. [
      • Mooiweer E
      • van der Meulen-de Jong AE
      • Ponsioen CY
      • et al.
      Incidence of interval colorectal cancer among inflammatory bowel disease patients undergoing regular colonoscopic surveillance.
      ,
      • Clark BT
      • Protiva P
      • Nagar A
      • et al.
      Quantification of adequate bowel preparation for screening or surveillance colonoscopy in men.
      ] Present guidelines recommend to perform surveillance colonoscopies employing chromoendoscopy. [
      • Maaser C
      • Sturm A
      • Vavricka SR
      • et al.
      ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications.
      ,
      • Lamb CA
      • Kennedy NA
      • Raine T
      • et al.
      British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
      ,
      • Rubin DT
      • Ananthakrishnan AN
      • Siegel CA
      • et al.
      ACG clinical guideline: ulcerative colitis in adults.
      ,
      • Farraye FA
      • Odze RD
      • Eaden J
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      ,
      • Laine L
      • Kaltenbach T
      • Barkun A
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      ] Chromoendoscopy creates enhanced images by directly spraying dye on the colonic mucosa during endoscopy (Fig. 2). Lichtenstein et. al. published an educational video that illustrates this technique. [
      • Lichtenstein GR
      • Picco MF
      • Solomon S
      • et al.
      The use of chromoendoscopy for surveillance of inflammatory bowel disease.
      ] Downsides of chromoendoscopy are that this technique prolongs procedure time, requires additional training, and may be perceived as impractical by endoscopists. [
      • Iannone A
      • Ruospo M
      • Wong G
      • et al.
      Chromoendoscopy for surveillance in ulcerative colitis and crohn's disease: a systematic review of randomized trials.
      ] It can be questioned whether the advent of high definition (HD) endoscopy has made chromoendoscopy redundant. Previous meta-analyses including only randomised controlled trials (RCT) reported similar dysplasia detection rates with and without chromoendoscopy in patients with IBD. [
      • Iannone A
      • Ruospo M
      • Wong G
      • et al.
      Chromoendoscopy for surveillance in ulcerative colitis and crohn's disease: a systematic review of randomized trials.
      ,
      • Feuerstein JD
      • Rakowsky S
      • Sattler L
      • et al.
      Meta-analysis of dye-based chromoendoscopy compared with standard- and high-definition white-light endoscopy in patients with inflammatory bowel disease at increased risk of colon cancer.
      ,
      • Resende RH
      • Ribeiro IB
      • de Moura DTH
      • et al.
      Surveillance in inflammatory bowel disease: is chromoendoscopy the only way to go? A systematic review and meta-analysis of randomized clinical trials.
      ] In contrast, superiority of surveillance using chromoendoscopy was reported in a recent well-conducted RCT from Sweden (Supplementary Table 1 provides summary data of these RCTs). [
      • Alexandersson B
      • Hamad Y
      • Andreasson A
      • et al.
      High-definition chromoendoscopy superior to high-definition white-light endoscopy in surveillance of inflammatory bowel diseases in a randomized trial.
      ] Nowadays, most guidelines still recommend chromoendoscopy, but also state that white light endoscopy using HD endoscopes is a good alternative.
      Fig 2
      Fig. 2Examples of endoscopy images. A: Moderate disease (the colonic mucosa shows marked erythema, absent vascular pattern, and erosions); B: Normal colonic mucosa (the colonic mucosa shows a normal vascular pattern, no erythema); C: Normal colonic mucosa (chromoendoscopy); D: Flat colitis-associated neoplasia; E: Colitis-associated neoplasia (methylene blue is rapidly absorbed by normal mucosa, but the absorption in neoplastic mucosa is impaired); F: Large colitis-associated neoplastic lesion (chromoendoscopy).
      The role of random biopsies, four biopsies every ten centimetres, in surveillance colonoscopies, using HD endoscopes, has also become unclear. [
      • Laine L
      • Kaltenbach T
      • Barkun A
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      ] The rationale for random biopsies is that they may detect dysplastic lesions that cannot be identified endoscopically. As with chromoendoscopy, taking random biopsies prolongs procedure time and additionally adds costs of histopathologic evaluation. In this era of HD endoscopes, the neoplastic yield of only random biopsies in IBD patients in the setting of surveillance is quite low, 1.2-3.0% per-colonoscopy and 0.09-0.2% per biopsy. [
      • Alexandersson B
      • Hamad Y
      • Andreasson A
      • et al.
      High-definition chromoendoscopy superior to high-definition white-light endoscopy in surveillance of inflammatory bowel diseases in a randomized trial.
      ,
      • Moussata D
      • Allez M
      • Cazals-Hatem D
      • et al.
      Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy?.
      ] Non-inferiority in neoplasia detection was reported for surveillance with only targeted biopsies versus target and random biopsies in a RCT study, although no data on long-term outcomes were reported. [
      • Watanabe T
      • Ajioka Y
      • Mitsuyama K
      • et al.
      Comparison of targeted vs random biopsies for surveillance of ulcerative colitis-associated colorectal cancer.
      ] The yield of random biopsies is higher in patients with concomitant PSC (3.7% per-colonoscopy and 0.3% per biopsy), [
      • Alexandersson B
      • Hamad Y
      • Andreasson A
      • et al.
      High-definition chromoendoscopy superior to high-definition white-light endoscopy in surveillance of inflammatory bowel diseases in a randomized trial.
      ,
      • Moussata D
      • Allez M
      • Cazals-Hatem D
      • et al.
      Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy?.
      ,
      • Coelho-Prabhu N
      • Bruining DH
      • Faubion WA
      • et al.
      A 1-year cross-sectional inflammatory bowel disease surveillance colonoscopy cohort comparing high-definition white light endoscopy and chromoendoscopy.
      ,
      • Navaneethan U
      • Kochhar G
      • Venkatesh PG
      • et al.
      Random biopsies during surveillance colonoscopy increase dysplasia detection in patients with primary sclerosing cholangitis and ulcerative colitis.
      ] prior dysplasia, or a tubular colon. [
      • Moussata D
      • Allez M
      • Cazals-Hatem D
      • et al.
      Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy?.
      ] The added value of random biopsies in these high-risk patients should be balanced against additional costs and potential risks, e.g. of surgical procedures. In a retrospective cohort study including 71 UC patients with concomitant PSC, the diagnosis of invisible (without visible) dysplasia in random biopsies, detected in eight patients, impacted clinical outcomes. [
      • Navaneethan U
      • Kochhar G
      • Venkatesh PG
      • et al.
      Random biopsies during surveillance colonoscopy increase dysplasia detection in patients with primary sclerosing cholangitis and ulcerative colitis.
      ] As high-risk patients already receive frequent surveillance, the additional impact of detecting invisible dysplasia might be overestimated, however.
      Thus, to define the optimal surveillance technique when using HD endoscopes, more research is needed to determine the (cost)effectiveness of HD-endoscopy with versus without chromoendoscopy and/or random biopsies.

      4.3 Unmet needs

      To further improve surveillance strategies in IBD patients, we believe a novel prediction model is warranted. Such a model should be easy to implement in clinical practice, while accounting for the presence of multiple risk factors and their effect sizes. The potential place of biomarkers (e.g. aneuploidy) as prognostic factors should also be evaluated. Additionally, exit strategies for surveillance should be explored. One study indicated that after two consecutive surveillance colonoscopies without abnormalities (defined as no post-inflammatory polyps, strictures, dysplasia or CRC, or endoscopic disease activity), the subsequent risk of HGD or CRC is negligible. [
      • Ten Hove JR
      • Shah SC
      • Shaffer SR
      • et al.
      Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long-standing colitis: results of a 15-year multicentre, multinational cohort study.
      ] Discontinuation of surveillance in patients at lowest risk of CRC, as is recommended in the Dutch guideline, [

      Nederlandse Vereniging van Maag-, Darm- en Leverartsen, Handleiding behandeling IBD - 2014-2015. (Accessed April 8, 2021, at https://www.mdl.nl/sites/www.mdl.nl/files/richlijnen/Document_volledig_Handleiding_met_literatuur_def.pdf).

      ] will reduce the burden for patients and the healthcare system considerably. It is presently not clear what strategy should be adopted in IBD patients in whom surveillance is discontinued. Enrolment in a nationwide, faecal occult blood test (FOBT)-based, screening program seems practical, but the accuracy of FOBT is diminished by mucosal inflammation, [
      • Mooiweer E
      • Fidder HH
      • Siersema PD
      • et al.
      Fecal hemoglobin and calprotectin are equally effective in identifying patients with inflammatory bowel disease with active endoscopic inflammation.
      ] rendering this type of surveillance less effective.

      5. Management of dysplasia

      Until recently, guidelines recommended to perform a proctocolectomy in case of colorectal dysplasia in patients with IBD, based on a high perceived risk of synchronous dysplasia in this setting. Nowadays, treatment of these lesions is increasingly moving towards endoscopic options, where interventions are tailored based on patient and lesion characteristics.
      It must be emphasized that a diagnosis of colorectal dysplasia or cancer in IBD patients should be confirmed by a second pathologist with expertise in this field. [
      • Maaser C
      • Sturm A
      • Vavricka SR
      • et al.
      ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications.
      ,
      • Rubin DT
      • Ananthakrishnan AN
      • Siegel CA
      • et al.
      ACG clinical guideline: ulcerative colitis in adults.
      ,
      • Farraye FA
      • Odze RD
      • Eaden J
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      ,
      • Laine L
      • Kaltenbach T
      • Barkun A
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      ,
      • Magro F
      • Langner C
      • Driessen A
      • et al.
      European consensus on the histopathology of inflammatory bowel disease.
      ] This recommendation is based on the high level of interobserver variability (especially for LGD and indefinite dysplasia) [
      • Odze RD
      • Goldblum J
      • Noffsinger A
      • et al.
      Interobserver variability in the diagnosis of ulcerative colitis-associated dysplasia by telepathology.
      ,
      • van Schaik FD
      • ten Kate FJ
      • Offerhaus GJ
      • et al.
      Misclassification of dysplasia in patients with inflammatory bowel disease: consequences for progression rates to advanced neoplasia.
      ] which, at least partly, can be attributed to the presence of histologic inflammation. [
      • van Schaik FD
      • ten Kate FJ
      • Offerhaus GJ
      • et al.
      Misclassification of dysplasia in patients with inflammatory bowel disease: consequences for progression rates to advanced neoplasia.
      ,
      • DeRoche TC
      • Xiao SY
      • Liu X.
      Histological evaluation in ulcerative colitis.
      ]
      First, a distinction between endoscopically visible and invisible dysplasia has to be made. [
      • Laine L
      • Kaltenbach T
      • Barkun A
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      ] If invisible dysplasia is detected in random biopsies, present guidelines advise to consider strict continued surveillance, reassessment by an IBD expert, or surgical treatment. [
      • Laine L
      • Kaltenbach T
      • Barkun A
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      ] This choice is based on the grade of dysplasia, presence of unifocal versus multifocal invisible dysplasia, synchronous visible dysplasia as well as patient characteristics (e.g. age, comorbidity) and preferences. In case of a visible lesion, the first step is to determine whether the lesion can be resected endoscopically, and if so, which technique should be used. This depends on lesion size, shape, site (colitis-associated area or not), surface, and surrounding area (together known as Five “s” characteristics), risk of invasion (amongst others based on Five “s” criteria) and endoscopic accessibility. [
      • Laine L
      • Kaltenbach T
      • Barkun A
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      ,
      • Adamina M
      • Feakins R
      • Iacucci M
      • et al.
      ECCO topical review optimising reporting in surgery, endoscopy, and histopathology.
      ] Small polypoid and non-polypoid lesions can be removed with a simple endoscopic resection technique using snares. [
      • Farraye FA
      • Odze RD
      • Eaden J
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      ] For larger lesions endoscopic mucosal resection (EMR) is used, a technique that involves lifting of the lesion from the muscularis propria using a submucosal injection with saline to permit safe removal of the lesion with a snare. Endoscopic submucosal dissection (ESD) should be considered for large (>20mm) lesions, especially if these are non-polypoid or display high-risk features. In ESD the lesion is lifted from the muscularis propria, followed by dissection of the lesion from deeper layers using an endo-knife. ESD has the advantage of high en bloc resection rates (even in case of submucosal fibrosis which is frequently encountered in colitis-associated lesions), high numbers of radical (R0) resections at histopathologic examination, and is associated with low risk of adverse events such as bleeding or perforation. [
      • Manta R
      • Zullo A
      • Telesca DA
      • et al.
      Endoscopic submucosal dissection for visible dysplasia treatment in ulcerative colitis patients: cases series and systematic review of literature.
      ] Furthermore, previous studies on ESD in IBD patients report low local recurrence rates and small numbers of metachronous lesions, although these studies have relatively short follow-up periods and small sample sizes. [
      • Manta R
      • Zullo A
      • Telesca DA
      • et al.
      Endoscopic submucosal dissection for visible dysplasia treatment in ulcerative colitis patients: cases series and systematic review of literature.
      ] Table 1 summarises the main advantages and disadvantages of endoscopic resections using an EMR or ESD technique. Educational videos on these techniques were previously published. [
      • Lichtenstein GR
      • Picco MF
      • Solomon S
      • et al.
      The use of chromoendoscopy for surveillance of inflammatory bowel disease.
      ,
      • Iacopini F
      • Saito Y
      • Yamada M
      • et al.
      Curative endoscopic submucosal dissection of large nonpolypoid superficial neoplasms in ulcerative colitis (with videos).
      ,
      • Draganov PV
      • Wang AY
      • Othman MO
      • et al.
      AGA institute clinical practice update: endoscopic submucosal dissection in the United States.
      ] Importantly, when a lesion is successfully resected endoscopically, strict endoscopic follow-up is needed. [
      • Laine L
      • Kaltenbach T
      • Barkun A
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      ]
      Table 1Advantages and disadvantages of EMR and ESD.
      Endoscopic mucosal resection (EMR)Endoscopic submucosal dissection (ESD)
      Resection plane+ Submucosa+ Submucosa
      Suitable lesions- Smaller polypoid and non-polypoid lesions+ Large (>20mm), high-risk lesions
      and non-polypoid lesions
      Procedure time+ Relatively short- Long
      Learning curve+ Relatively short- Relatively long
      Adverse events+ Low+/- Low, but higher than EMR
      Histopathological examination- Difficult, due to frequent piecemeal resections
      ) i.e. fragmented resections, especially when treating larger lesions with EMR.
      + Good, due to high rate of en bloc resections
      Radical (R0) resections rate- Relatively low+ High
      EMR=Endoscopic mucosal resection, ESD=Endoscopic submucosal dissection.
      1 ) i.e. fragmented resections, especially when treating larger lesions with EMR.
      Surgery is the treatment of choice for endoscopically non-resectable lesions, invisible dysplasia (especially in case of HGD), and/or ‘high risk’ colons. [
      • Laine L
      • Kaltenbach T
      • Barkun A
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      ,
      • Oresland T
      • Bemelman WA
      • Sampietro GM
      • et al.
      European evidence based consensus on surgery for ulcerative colitis.
      ] A total proctocolectomy is recommended in case of HGD or CRC, in order to also reduce the future risk of dysplasia and cancer. [
      • Farraye FA
      • Odze RD
      • Eaden J
      • et al.
      AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
      ,
      • Bemelman WA
      • Warusavitarne J
      • Sampietro GM
      • et al.
      ECCO-ESCP consensus on surgery for Crohn's disease.
      ] After a total proctocolectomy, a pouch (reservoir) can be constructed from the terminal ileum with an anastomosis to the anal canal, as an alternative to a permanent ileostomy. Guidelines state that in patients diagnosed with LGD not involving the rectum, or in presence of comorbidities, a subtotal colectomy with ileorectal anastomosis or ileostomy, or segment resection can be considered. [
      • Bemelman WA
      • Warusavitarne J
      • Sampietro GM
      • et al.
      ECCO-ESCP consensus on surgery for Crohn's disease.
      ] Importantly, after a subtotal colectomy (or even segmental colonic resection), the remaining colonic mucosa remains at risk for dysplasia and cancer. [
      • Ten Hove JR
      • Bogaerts JMK
      • Bak MTJ
      • et al.
      Malignant and nonmalignant complications of the rectal stump in patients with inflammatory bowel disease.
      ] Also, colectomy is associated with a 1% risk of perioperative mortality, risk of long-term complications (e.g. faecal incontinence or leakage, ileus or small bowel obstruction, fistulae) and reduced quality of life. [
      • Peyrin-Biroulet L
      • Germain A
      • Patel AS
      • et al.
      Systematic review: outcomes and post-operative complications following colectomy for ulcerative colitis.
      ,
      • Woehl A
      • Hawthorne A
      • McEwan P.
      The relation between disease activity, quality of life and health utility in patients with ulcerative colitis.
      ]
      To further improve the management of dysplasia, future studies should examine the long-term oncological safety and efficacy of both advanced endoscopic resection techniques and limited surgical resections (segment resections or subtotal colectomy for endoscopically non-resectable lesions).

      6. Chemoprevention

      In theory, every therapeutic agent that effectively induces and maintains remission in IBD will decrease the risk of CRC, because inflammation is the main driver behind tumourigenesis in colitis-associated CRC. However, the role of maintenance therapy in the prevention of colitis-associated dysplasia and cancer is currently unclear. Most evidence for chemoprevention is based on retrospective studies with varying definitions of medication use. Moreover, most studies did not adjust for (cumulative) inflammation and should therefore be interpreted with caution.
      Previous meta-analyses report a negative association of 5-aminosalicylic acid (5-ASA) use and development of dysplasia and CRC in IBD (mostly UC patients). [
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.
      ,
      • Bonovas S
      • Fiorino G
      • Lytras T
      • et al.
      Systematic review with meta-analysis: use of 5-aminosalicylates and risk of colorectal neoplasia in patients with inflammatory bowel disease.
      ,
      • Qiu X
      • Ma J
      • Wang K
      • et al.
      Chemopreventive effects of 5-aminosalicylic acid on inflammatory bowel disease-associated colorectal cancer and dysplasia: a systematic review with meta-analysis.
      ] This finding might be explained by anti-inflammatory effects, direct chemoprotective properties of 5-ASA at a molecular level, or a milder phenotype of patients on 5-ASA (mono)therapy. [
      • Lopez A
      Peyrin-Biroulet L. 5-Aminosalicylic acid and chemoprevention: does it work?.
      ] The protective effect of 5-ASA on the risk of dysplasia and CRC seems to be dose-related, which additionally supports its role in this setting. [
      • Bonovas S
      • Fiorino G
      • Lytras T
      • et al.
      Systematic review with meta-analysis: use of 5-aminosalicylates and risk of colorectal neoplasia in patients with inflammatory bowel disease.
      ]
      Thiopurine use has also been found to prevent the development of dysplasia and CRC. [
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic factors for advanced colorectal neoplasia in inflammatory bowel disease: systematic review and meta-analysis.
      ,
      • Zhu Z
      • Mei Z
      • Guo Y
      • et al.
      Reduced risk of inflammatory bowel disease-associated colorectal neoplasia with use of thiopurines: a systematic review and meta-analysis.
      ,
      • Lu MJ
      • Qiu XY
      • Mao XQ
      • et al.
      Systematic review with meta-analysis: thiopurines decrease the risk of colorectal neoplasia in patients with inflammatory bowel disease.
      ] A recent meta-analysis did not show a protective effect of TNF-alpha inhibitors on HGD and CRC. Of note, TNF-alpha inhibitors are usually prescribed in patients with more severe disease, which might have confounded the results considerably. [
      • Wijnands AM
      • de Jong ME
      • Lutgens M
      • et al.
      Prognostic factors for advanced colorectal neoplasia in inflammatory bowel disease: systematic review and meta-analysis.
      ] Theoretically, both thiopurines and TNF-alpha inhibitors could either decrease the risk of CRC by reducing colonic inflammation, but also increase the risk of CRC through their immunosuppressive effects.
      In patients with IBD and concomitant PSC, a meta-analysis reported no overall reduction in the risk of dysplasia and CRC in patients using ursodeoxycholic acid (UDCA). However, the risk of dysplasia and CRC was lower in a subgroup of patients using low-dose UDCA (8-15 mg/kg) (OR 0.19, 95% CI 0.08-0.49). [
      • Singh S
      • Khanna S
      • Pardi DS
      • et al.
      Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis.
      ] In contrast, the use of high-dose UDCA (15-30 mg/kg) is reportedly associated with a trend towards an increased risk of colorectal dysplasia or cancer in pooled analysis (OR 2.03, 95% CI 0.53-7.73), [
      • Singh S
      • Khanna S
      • Pardi DS
      • et al.
      Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis.
      ] and other adverse outcomes such as mortality and liver transplantation. [
      • Lindor KD
      • Kowdley KV
      • Luketic VA
      • et al.
      High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.
      ,
      • Eaton JE
      • Silveira MG
      • Pardi DS
      • et al.
      High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.
      ] Current British guidelines recommend against the use of ursodeoxycholic acid for the sole purpose of preventing CRC. [
      • Chapman MH
      • Thorburn D
      • Hirschfield GM
      • et al.
      British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.
      ]
      Overall, guidelines are not consistent with respect to prescribing specific drugs solely for chemopreventive purposes in patients not requiring maintenance therapy.

      7. Conclusion

      In conclusion, the risk of CRC in patients with colonic IBD is increased, especially among those with a high (prior) inflammatory burden, concomitant PSC, or a history of dysplasia. The current practice of colonoscopic surveillance aims to detect and remove precursor lesions of CRC and thereby mitigate the excess CRC risk in patients with IBD. Some studies, but not all, indicate that the CRC risk in IBD has declined over the last decades, which has been ascribed to the wide implementation of surveillance colonoscopies, advanced endoscopic techniques for mucosal visualisation and lesion resection, and improved management of inflammation.
      The mainstay in the management of these patients remains colonoscopic surveillance. This resource-intensive procedure imposes a significant burden on patients, while interval CRCs still occur too frequently. In this review, we have highlighted several areas of interest for future research (Fig. 3). More research is needed to develop a prediction model to determine individualised surveillance intervals, to assess the necessity of taking random biopsies and/or using chromoendoscopy with modern HD endoscopes, and to establish the long-term efficacy and safety of advanced resection techniques such as ESD in patients with IBD.
      Fig 3
      Fig. 3Current practice and future perspectives
      CRC=colorectal cancer, HD=high-definition.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Authors’ contributions

      AW, RM: conception of the work, drafting of manuscript. BO: conception of the work. ML, BO: revising the work critically for intellectual content. All authors approved the final version of the manuscript.

      Declarations of Competing Interest

      None.

      Appendix. Supplementary materials

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