Incidence, Risk Factors, and Outcomes of Colorectal Cancer in Patients With Ulcerative Colitis With Low-Grade Dysplasia: A Systematic Review and Meta-analysis

Published:December 02, 2016DOI:https://doi.org/10.1016/j.cgh.2016.11.025

      Background & Aims

      Little is known about outcomes of patients with ulcerative colitis with low-grade dysplasia (UC-LGD). We estimated the incidence of and risk factors for progression to colorectal cancer (CRC) in cohorts of patients with UC-LGD who underwent surveillance (surveillance cohort), and the prevalence of dysplasia-related findings among patients who underwent colectomy for UC-LGD (surgical cohort).

      Methods

      We performed a systematic literature review through June 1, 2016, to identify cohort studies of adults with UC-LGD. We estimated pooled incidence rates of CRC and risk factors associated with dysplasia progression in surveillance cohorts, and prevalence of synchronous advanced neoplasia (CRC and/or high-grade dysplasia) in surgical cohorts.

      Results

      In 14 surveillance cohort studies of 671 patients with UC-LGD (52 developed CRC), the pooled annual incidence of CRC was 0.8% (95% confidence interval [CI], 0.4–1.3); the pooled annual incidence of advanced neoplasia was 1.8% (95% CI, 0.9–2.7). Risk of CRC was higher when LGD was diagnosed by expert gastrointestinal pathologist (1.5%) than by community pathologists (0.2%). Factors significantly associated with dysplasia progression were concomitant primary sclerosing cholangitis (odds ratio [OR], 3.4; 95% CI, 1.5–7.8), invisible dysplasia (vs visible dysplasia; OR, 1.9; 95% CI, 1.0–3.4), distal location (vs proximal location; OR, 2.0; 95% CI, 1.1–3.7), and multifocal dysplasia (vs unifocal dysplasia; OR, 3.5; 95% CI, 1.5–8.5). In 12 surgical cohort studies of 450 patients who underwent colectomy for UC-LGD, 34 patients had synchronous CRC (pooled prevalence, 17%; 95% CI, 8–33).

      Conclusion

      In a systematic review of the literature, we found that among patients with UC-LGD under surveillance, the annual incidence of progression to CRC was 0.8%; differences in rates of LGD diagnosis varied with pathologists’ level of expertise. Concomitant primary sclerosing cholangitis, invisible dysplasia, distal location, and multifocal LGD are high-risk features associated with dysplasia progression.

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), CRC (colorectal cancer), HGD (high-grade dysplasia), IBD (inflammatory bowel disease), IR (incidence rate), LGD (low-grade dysplasia), OR (odds ratio), PSC (primary sclerosing cholangitis), UC (ulcerative colitis)
      The risk of colorectal cancer (CRC) is 2–5 times higher in patients with ulcerative colitis (UC) than the general population, and it is a major cause of morbidity and mortality among these individuals.
      • Bewtra M.
      • Kaiser L.M.
      • TenHave T.
      • et al.
      Crohn's disease and ulcerative colitis are associated with elevated standardized mortality ratios: a meta-analysis.
      • Jess T.
      • Rungoe C.
      • Peyrin-Biroulet L.
      Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies.
      • Beaugerie L.
      • Itzkowitz S.H.
      Cancers complicating inflammatory bowel disease.
      • Bernstein C.N.
      • Nugent Z.
      • Targownik L.E.
      • et al.
      Predictors and risks for death in a population-based study of persons with IBD in Manitoba.
      In contrast to sporadic CRC, which arises from 1–2 foci of dysplastic changes and follows a well-recognized adenoma-carcinoma sequence, colitis-associated CRC results from a field change effect with multifocal genetic alterations that do not follow the typical adenoma-carcinoma sequence of events.
      • Ullman T.A.
      • Itzkowitz S.H.
      Intestinal inflammation and cancer.
      Neoplasia development in long-standing UC progresses from nondysplastic mucosa, to visible or invisible low-grade dysplasia (LGD), high-grade dysplasia (HGD), to carcinoma. Periodic surveillance for colorectal neoplasia is recommended for patients with long-standing UC (or those with associated primary sclerosing cholangitis [PSC]), and during surveillance, pooled prevalence of LGD is 9.4%.
      • Thomas T.
      • Abrams K.A.
      • Robinson R.J.
      • et al.
      Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis.
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      Although management of nondysplastic UC (continued periodic surveillance) or UC-HGD (colectomy or endoscopic resection with intensive surveillance) is well accepted, management of UC-LGD is controversial. It is unclear whether these patients should continue surveillance or proceed to surgery, especially in case of nonvisible or nonendoscopically resectable dysplasia.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      • Bernstein C.N.
      Ulcerative colitis with low-grade dysplasia.
      • Van Assche G.
      • Dignass A.
      • Bokemeyer B.
      • et al.
      Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations.
      • Bernstein C.N.
      • Weinstein W.M.
      • Levine D.S.
      • et al.
      Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis.
      This is, in part, caused by limited understanding of the natural history of UC-LGD, with regard to rate and risk factors for progression to HGD and/or CRC and presence of synchronous CRC. In a systematic review of 7 studies in patients with UC-LGD published over a decade ago, the estimated annual incidence of progression to CRC was 1.4% and to advanced neoplasia (CRC and/or HGD) was 3.0%.
      • Thomas T.
      • Abrams K.A.
      • Robinson R.J.
      • et al.
      Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis.
      However, there was no synthesis of risk factors associated with dysplasia progression (which may help risk stratify patients to avoid potential oversurveillance in a subset of low-risk patients, and undersurveillance in a subset of high-risk patients), and no assessment of dysplastic findings at colectomy specimens in patients with UC-LGD who opted to undergo surgery (and hence, no assessment of possibility of synchronous, potentially missed, CRC).
      In this updated systematic review and meta-analysis, we estimated the incidence and risk factors for progression to CRC and/or HGD in patients who continued surveillance after UC-LGD diagnosis (surveillance cohorts); and prevalence and degree of dysplasia in the surgical specimen among patients who underwent colectomy for UC-LGD (surgical cohorts). With the increasing uptake of advanced dysplasia detection techniques, such as chromoendoscopy with higher rates of detecting LGD, these data would enable a more personalized approach to management of UC-LGD and aid shared-decision making for these patients.

      Methods

      We followed an a priori protocol registered at the International Prospective Register of Systematic Reviews (PROSPERO CRD42016033500), and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

       Study Selection

      To address the 2 primary aims of this review, 2 sets of inclusion criteria were used. To estimate rate and risk factors associated with progression of LGD, we included cohort studies in (1) adults with UC-LGD identified during colonoscopy (visible or nonvisible, resectable or nonresectable), (2) who continued periodic colonoscopic surveillance (had at least 1 follow-up colonoscopy after the initial LGD diagnosis), and (3) specified number of patients with UC-LGD who developed CRC and/or HGD, along with the total person-years or mean/median follow-up for the subset of patients with UC-LGD. These studies formed the surveillance cohort. We excluded (1) case-control studies, cross-sectional studies, and case series; (2) studies that did not specify the number of patients with UC-LGD who developed CRC and/or HGD; (3) studies that did not report follow-up duration; and (4) studies that selectively reported only outcome after adenoma-like or polypoid lesion.
      To assess dysplasia-related findings on colectomy in patients with UC-LGD, we included cohort studies or case series (>1 patient) in (1) adults with UC-LGD identified during colonoscopy (visible or nonvisible, resectable or nonresectable); (2) who underwent colectomy at time of first diagnosis of UC-LGD (without any subsequent colonoscopy); and (3) specified number of patients who were diagnosed with no dysplasia, LGD, HGD, and CRC in the surgical specimen (worst finding), with at least 75% follow-up (ie, dysplasia-related findings reported for at least 75% of patients who underwent surgery for UC-LGD). These studies formed the surgical cohort. Studies in which dysplasia-related findings were reported for <75% of cohort, and where findings for HGD and CRC were not separately reported (ie, where HGD and CRC were grouped as advanced neoplasia) were excluded. In case of multiple publications from the same cohort, data from the most recent comprehensive report were included.

       Search Strategy

      A systematic literature search of multiple electronic databases was conducted from inception to November 30, 2015, in adults with no language restrictions; this search was updated on June 1, 2016. The databases included Ovid Medline, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus. The search strategy was designed and conducted by an experienced medical librarian with input from the study’s investigators, using controlled vocabulary supplemented with keywords, for studies on dysplasia in UC. The details of the search strategy are reported in the Supplementary Appendix. In addition, conference abstracts (Digestive Disease Week, United European Gastroenterology Week, American College of Gastroenterology annual meeting, Advances in Inflammatory Bowel Diseases meeting organized by the Crohn’s and Colitis Foundation of America, and European Crohn’s and Colitis Organization annual meeting) from 2012 to 2015, and bibliography of the selected articles and review articles on the topic were manually searched for additional studies, with no language restrictions. Two reviewers (MF and PSD) independently assessed the title and abstract of studies identified in the primary search for inclusion, and the full text of remaining articles were examined to determine whether they met inclusion criteria. Any discrepancy in article selection was resolved by consensus, and in discussion with a third reviewer (SS). A reviewer (MF) contacted the primary study authors as needed for additional data or missing information.

       Data Abstraction and Definition

      Two authors (MF and PSD) independently abstracted data on (1) study characteristics of primary author, time period of study/year of publication, country of origin, and study setting (population-based or referral center); (2) UC-related characteristics of total number patients with UC (if unavailable, total number of patients with inflammatory disease [IBD]) and UC-LGD, duration of follow-up (total person-years of follow-up after diagnosis of UC-LGD), and number of biopsy specimens taken during surveillance; (3) demographic characteristics of age at UC diagnosis/LGD diagnosis, disease duration, sex, familial history of colorectal neoplasia, extent of UC, concomitant PSC, smoking status, and use of UC-related medications; (4) dysplasia-related characteristics of visible versus nonvisible dysplasia, unifocal versus multifocal, size and location (distal vs proximal) of dysplastic lesion, associated stricture, and pathologic confirmation of LGD (single or consensus of pathologists, expert vs community); and (5) outcomes of number of patients with UC-LGD who developed HGD and/or CRC (and associated clinical and dysplasia-related characteristics).
      For the surgical cohort, dysplasia-related findings on pathologic specimens were abstracted. For analysis, “indefinite for dysplasia” was considered equivalent to no dysplasia. Nonvisible dysplasia was defined by an absence of documented endoscopic abnormalities. Visible dysplasia was defined as dysplasia-associated lesion or mass, adenoma-like mass, or raised or endoscopically visible flat dysplasia.

       Quality Assessment

      The quality of included studies was assessed using a scale derived from the Newcastle-Ottawa scale for cohort studies, and has been used in a similar study on risk of progression of Barrett’s esophagus with LGD.
      • Singh S.
      • Manickam P.
      • Amin A.V.
      • et al.
      Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta-analysis.
      This quality score consisted of 7 questions: representative of the average adult in the community, large cohort size, definite histologic confirmation of LGD, adequate follow-up of cohort for outcome to occur, clear information on duration of follow-up of patients with UC-LGD, attrition rate, definite information on progression of UC-LGD (Supplementary Appendix). A score of ≥6, 4–5, and ≤3 was considered suggestive of high-, medium-, and low-quality study.

       Outcomes Assessed

      For the surveillance cohort, the primary outcome was the incidence rate (IR) of CRC, and the secondary outcome was incidence of composite outcome of advanced neoplasia (CRC and/or HGD). A priori hypotheses to explain potential heterogeneity in the incidence of CRC among different observational studies included location of study (North America vs Europe), and whether diagnosis of LGD was confirmed by single versus consensus of pathologists. Sensitivity analyses were performed to assess stability of findings after excluding low-quality studies, and studies in which >50% patients had concomitant PSC was also performed.
      To identify risk factors associated with progression of UC-LGD to advanced neoplasia, we systematically reviewed UC-related (age at UC diagnosis, sex, disease duration, presence of concomitant PSC) and dysplasia-related factors (age at LGD diagnosis, invisible vs visible dysplasia, unifocal vs multifocal dysplasia, one-time vs persistent LGD, location of dysplasia) associated with progression of UC-LGD to advanced neoplasia. We also qualitatively reviewed the prognosis of CRC diagnosed during surveillance of patients with UC-LGD.
      For the surgical cohort, the primary outcome of interest was the proportion of patients with no dysplasia (or indefinite for dysplasia), LGD, HGD, and CRC in the surgical specimen after colectomy for UC-LGD.

       Statistical Analysis

      The summary measure for the surveillance cohort was pooled IR (and 95% confidence interval [CI]), and was estimated using the random effects model proposed by DerSimonian and Laird.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      To identify risk factors associated with progression of dysplasia, we pooled maximally adjusted odds ratio (OR; to account for confounding variables), where reported, using random-effects model. For the surgical cohort, the summary measure was the pooled and weighted prevalence of different dysplasia-related findings. We assessed heterogeneity using the I2 statistic. Values of <30%, 30%–59%, 60%–75%, and >75% were classified as low, moderate, substantial, and considerable heterogeneity, respectively.
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines: 7. Rating the quality of evidence–inconsistency.
      Between-study sources of heterogeneity were assessed using subgroup analyses defined previously. A P value for differences between subgroups of < .10 was considered statistically significant. Publication bias was assessed quantitatively using Egger regression test (publication bias considered present if P ≤ .10), and qualitatively, by visual inspection of funnel plots.
      • Egger M.
      • Smith G.D.
      • Phillips A.N.
      Meta-analysis: principles and procedures.
      • Easterbrook P.J.
      • Berlin J.A.
      • Gopalan R.
      • Matthews D.R.
      Publication bias in clinical research.
      All analyses were performed using Comprehensive Meta-Analysis software, version 2 (Biostat, Englewood, NJ).

      Results

      Of 3609 unique studies identified using our search strategy, 14 surveillance cohorts and 12 surgical cohorts were included. Forty-four studies were excluded, primarily because of insufficient data to calculate IR of progression of dysplasia in patients with UC-LGD (Figure 1).

       Surveillance Cohorts

       Characteristics and Quality of Included Studies

      Fourteen studies reporting on 671 individuals with UC-LGD with total 4238 patient years of follow-up formed the surveillance cohort.
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      • Eaton J.E.
      • Smyrk T.C.
      • Imam M.
      • et al.
      The fate of indefinite and low-grade dysplasia in ulcerative colitis and primary sclerosing cholangitis colitis before and after liver transplantation.
      • Goldstone R.
      • Itzkowitz S.
      • Harpaz N.
      • et al.
      Progression of low-grade dysplasia in ulcerative colitis: effect of colonic location.
      • Navaneethan U.
      • Jegadeesan R.
      • Gutierrez N.G.
      • et al.
      Progression of low-grade dysplasia to advanced neoplasia based on the location and morphology of dysplasia in ulcerative colitis patients with extensive colitis under colonoscopic surveillance.
      • Venkatesh P.G.
      • Jegadeesan R.
      • Gutierrez N.G.
      • et al.
      Natural history of low grade dysplasia in patients with primary sclerosing cholangitis and ulcerative colitis.
      • Zisman T.L.
      • Bronner M.P.
      • Rulyak S.
      • et al.
      Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines.
      • van Schaik F.D.
      • Oldenburg B.
      • Offerhaus G.J.
      • et al.
      Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.
      • Pekow J.R.
      • Hetzel J.T.
      • Rothe J.A.
      • et al.
      Outcome after surveillance of low-grade and indefinite dysplasia in patients with ulcerative colitis.
      • Jess T.
      • Loftus Jr., E.V.
      • Velayos F.S.
      • et al.
      Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county, Denmark and Olmsted county, Minnesota.
      • Lim C.H.
      • Dixon M.F.
      • Vail A.
      • et al.
      Ten year follow up of ulcerative colitis patients with and without low grade dysplasia.
      • Fusco V.
      • Ebert B.
      • Weber-Eibel J.
      • et al.
      Cancer prevention in ulcerative colitis: long-term outcome following fluorescence-guided colonoscopy.
      • Lynch D.A.
      • Lobo A.J.
      • Sobala G.M.
      • et al.
      Failure of colonoscopic surveillance in ulcerative colitis.
      • Rozen P.
      • Baratz M.
      • Fefer F.
      • et al.
      Low incidence of significant dysplasia in a successful endoscopic surveillance program of patients with ulcerative colitis.
      • Befrits R.
      • Ljung T.
      • Jaramillo E.
      • et al.
      Low-grade dysplasia in extensive, long-standing inflammatory bowel disease: a follow-up study.
      The characteristics of these studies are summarized in Table 1. Seven studies were performed in Europe, and 7 in North America. All studies, except 1, were single, referral-center studies. An expert pathologist in 11 cohorts confirmed LGD, and for 3 studies, a community pathologist alone diagnosed LGD. Associated factors with progression from LGD to advanced neoplasia were available in 6 studies.
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      • Eaton J.E.
      • Smyrk T.C.
      • Imam M.
      • et al.
      The fate of indefinite and low-grade dysplasia in ulcerative colitis and primary sclerosing cholangitis colitis before and after liver transplantation.
      • Goldstone R.
      • Itzkowitz S.
      • Harpaz N.
      • et al.
      Progression of low-grade dysplasia in ulcerative colitis: effect of colonic location.
      • Navaneethan U.
      • Jegadeesan R.
      • Gutierrez N.G.
      • et al.
      Progression of low-grade dysplasia to advanced neoplasia based on the location and morphology of dysplasia in ulcerative colitis patients with extensive colitis under colonoscopic surveillance.
      • van Schaik F.D.
      • Oldenburg B.
      • Offerhaus G.J.
      • et al.
      Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.
      • Jess T.
      • Loftus Jr., E.V.
      • Velayos F.S.
      • et al.
      Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county, Denmark and Olmsted county, Minnesota.
      The quality of the included studies is shown in Supplementary Table 1. There was no high-quality study; 4 studies were classified as low-quality.
      Table 1Characteristics of Included Studies on Risk of Dysplasia Progression in Surveillance Cohorts of Patients With UC With LGD
      First authorCountry, cityStudy periodPathology confirmationPatients with UC-LGDMedian follow-up (y)Duration of UC, mean (y)PSC (n)Median colonoscopy per patient (n)Incident HGD (n)Incident CRC (n)
      Choi, 2015UK, London1993–20122 expert pathologists1724231031320
      Eaton, 2013USA, Rochester1993–20112 expert pathologists261232604
      Goldstone, 2011USA, New York City1994–20062 expert pathologists1213.119.40487
      Navaneethan, 2013USA, Cleveland1998–20112 expert pathologists1023120532
      Venkatesh, 2013USA, Cleveland1996–20112 expert pathologists102.811.510512
      Zisman, 2012USA, Seattle1987–20022 expert pathologists423.917.91162
      van Schaik, 2011Netherlands1990–20062 expert pathologists25
      Includes both patients with UC and CD.
      247
      Pekow, 2010USA, Chicago1994–20082 expert pathologists284.220.83311
      Jess, 2007USA, Rochester1940–20011 expert pathologist617.82300
      Lim, 2003UK, Leeds1978–2000Community pathologist only291703
      Fusco, 2012Germany, Grünheide1999–20022 expert pathologists25.75,501
      Lynch, 1994UK, Leeds1978–1990Community pathologist only405.617.7501
      Rozen, 1995Israel, Tel Aviv1976–19941 expert pathologist839.5211
      Befrits, 2002Sweden, Stockholm1976–1998Community pathologist only49 UC, 11 CD1010321
      CD, Crohn’s disease.
      a Includes both patients with UC and CD.

       Incidence of Colorectal Cancer and Advanced Neoplasia

      On meta-analysis of 14 studies in 671 patients with UC-LGD under surveillance, 52 patients developed CRC. The pooled IR of CRC was 0.8 per 100 patient-year follow-up (95% CI, 0.4–1.3), with substantial heterogeneity across studies (I2 = 65%) (Figure 2). Similarly, the pooled incidence of advanced neoplasia was 1.8 per 100 patient-year (95% CI, 0.9–2.7), with considerable heterogeneity (I2 = 82%) (Figure 3). Five studies reported rates of progression to advanced neoplasia in patients with nonvisible (flat) LGD and endoscopically visible dysplasia (dysplasia-associated lesion or mass/adenoma-like lesion), separately.
      • Goldstone R.
      • Itzkowitz S.
      • Harpaz N.
      • et al.
      Progression of low-grade dysplasia in ulcerative colitis: effect of colonic location.
      • Navaneethan U.
      • Jegadeesan R.
      • Gutierrez N.G.
      • et al.
      Progression of low-grade dysplasia to advanced neoplasia based on the location and morphology of dysplasia in ulcerative colitis patients with extensive colitis under colonoscopic surveillance.
      • Venkatesh P.G.
      • Jegadeesan R.
      • Gutierrez N.G.
      • et al.
      Natural history of low grade dysplasia in patients with primary sclerosing cholangitis and ulcerative colitis.
      • van Schaik F.D.
      • Oldenburg B.
      • Offerhaus G.J.
      • et al.
      Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.
      • Pekow J.R.
      • Hetzel J.T.
      • Rothe J.A.
      • et al.
      Outcome after surveillance of low-grade and indefinite dysplasia in patients with ulcerative colitis.
      On meta-analysis, pooled IR of advanced neoplasia in patients with nonvisible LGD was 6.1 per 100 patient-year follow-up (95% CI, 0.9–11.4), and with endoscopically visible dysplasia was 1.0 per 100 patient-year follow-up (95% CI, 0–2.1).
      Figure thumbnail gr2
      Figure 2Pooled incidence rate (and 95% confidence interval) of progression to colorectal cancer in patients with ulcerative colitis with low-grade dysplasia.
      Figure thumbnail gr3
      Figure 3Pooled incidence rate (and 95% confidence interval) of progression to advanced neoplasia (colorectal cancer or high-grade dysplasia) in patients with ulcerative colitis with low-grade dysplasia.
      In exploring potential sources of heterogeneity, the risk of progression to CRC was significantly lower in studies in which LGD was diagnosed by community pathologists without expert confirmation (IR, 0.2 per 100 patient-years; 95% CI, 0.0–0.4; 3 studies); the corresponding incidence in studies with confirmation by expert pathologists was 1.5% (95% CI, 0.6–2.4; 10 studies; P interaction = .006). There were no significant differences in IR of CRC between studies conducted in Europe (IR, 0.7; 95% CI, 0.1–1.4; 7 studies) versus North America (IR, 1.0; 95% CI, 0.3–1.7; 7 studies; P interaction = .54). Only 1 study reported a potential beneficial effect between receipt of chromoendoscopy and lower risk of progression to advanced neoplasia in patients with LGD (hazard ratio, 0.5; 95% CI, 0.3–1.0).
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      On sensitivity analysis, the incidence of CRC was similar to the primary estimate after excluding low-quality studies (IR, 1.0; 95% CI, 0.3–1.6; 10 studies) and after excluding studies with high proportion of patients with concomitant PSC (IR, 0.8; 95% CI, 0.3–1.3; 12 studies). After excluding 2 studies with very high observed rate of progression, including 1 study performed exclusively in patients with flat LGD,
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      • van Schaik F.D.
      • Oldenburg B.
      • Offerhaus G.J.
      • et al.
      Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.
      a more conservative IR of progression to CRC was 0.4 per 100 patient-years (95% CI, 0.1–0.8) and advanced neoplasia was 1.2 per 100 patient-years (95% CI, 0.5–1.9). Because of considerable heterogeneity, assessment of publication bias was unreliable.

       Risk Factors Associated with Progression to Advanced Neoplasia

      Six studies reported various UC- and dysplasia-related factors associated with progression of UC-LGD to advanced neoplasia.
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      • Eaton J.E.
      • Smyrk T.C.
      • Imam M.
      • et al.
      The fate of indefinite and low-grade dysplasia in ulcerative colitis and primary sclerosing cholangitis colitis before and after liver transplantation.
      • Goldstone R.
      • Itzkowitz S.
      • Harpaz N.
      • et al.
      Progression of low-grade dysplasia in ulcerative colitis: effect of colonic location.
      • Navaneethan U.
      • Jegadeesan R.
      • Gutierrez N.G.
      • et al.
      Progression of low-grade dysplasia to advanced neoplasia based on the location and morphology of dysplasia in ulcerative colitis patients with extensive colitis under colonoscopic surveillance.
      • van Schaik F.D.
      • Oldenburg B.
      • Offerhaus G.J.
      • et al.
      Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.
      • Jess T.
      • Loftus Jr., E.V.
      • Velayos F.S.
      • et al.
      Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county, Denmark and Olmsted county, Minnesota.
      Where ≥2 studies reported on same risk factor, meta-analysis was performed and is summarized in Table 2. Concomitant PSC (OR, 3.4; 95% CI, 1.5–7.8), invisible dysplasia (vs visible dysplasia; OR, 1.9; 95% CI, 1.0–3.4), distal dysplasia location (vs proximal to splenic flexure; OR, 2.0; 95% CI, 1.1–3.7), and multifocal dysplasia (vs unifocal dysplasia; OR, 3.5; 95% CI, 1.5–8.5) were significantly associated with progression to advanced neoplasia. There was no significant association between age at diagnosis of UC or LGD, sex, and disease duration. Persistent or metachronous LGD (vs incident LGD) was also not independently associated with increased risk of progression to advanced neoplasia (OR, 1.4; 95% CI, 0.6–3.3). In 1 study, dysplastic lesion >1 cm (hazard ratio, 3.8; 95% CI, 1.5–13.4) and previous history of “indefinite for dysplasia” (hazard ratio, 2.8; 95% CI, 1.2–6.5) was associated with increased risk of progression to advanced neoplasia.
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      Table 2UC and Dysplasia-Related Risk Factors Associated With Progression of Dysplasia in Patients With LGD
      OutcomeNumber of studiesPooled OR with 95% CIP value
      UC-related characteristics
      Age at LGD diagnosis (per unit)30.99 (0.96–1.02).53
      Age at UC diagnosis (per unit)21.00 (0.96–1.03).86
      Disease duration (per unit)30.99 (0.96–1.02).42
      Male sex21.10 (0.57–2.12).77
      Concomitant PSC33.42 (1.51–7.78)< .01
      Dysplasia-related characteristics
      Invisible dysplasia (vs visible dysplasia)61.87 (1.04–3.36).04
      Distal location (vs proximal)42.01 (1.10–3.65).02
      Multifocal dysplasia33.54 (1.47–8.52)< .01
      Persistent dysplasia (vs incident LGD)21.36 (0.56–3.31).50

       Surgical Cohorts

       Advanced Neoplasia in Patients Undergoing Colectomy for Ulcerative Colitis With Low-Grade Dysplasia

      We identified 12 surgical cohort studies of 450 patients who underwent colectomy for LGD (Table 3).
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      • Venkatesh P.G.
      • Jegadeesan R.
      • Gutierrez N.G.
      • et al.
      Natural history of low grade dysplasia in patients with primary sclerosing cholangitis and ulcerative colitis.
      • Zisman T.L.
      • Bronner M.P.
      • Rulyak S.
      • et al.
      Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines.
      • Lynch D.A.
      • Lobo A.J.
      • Sobala G.M.
      • et al.
      Failure of colonoscopic surveillance in ulcerative colitis.
      • Murphy J.
      • Kalkbrenner K.A.
      • Pemberton J.H.
      • et al.
      Dysplasia in ulcerative colitis as a predictor of unsuspected synchronous colorectal cancer.
      • Kiran R.P.
      • Ahmed Ali U.
      • Nisar P.J.
      • et al.
      Risk and location of cancer in patients with preoperative colitis-associated dysplasia undergoing proctocolectomy.
      • Hata K.
      • Watanabe T.
      • Kazama S.
      • et al.
      Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population.
      • Löfberg R.
      • Broström O.
      • Karlén P.
      • et al.
      Colonoscopic surveillance in long-standing total ulcerative colitis–a 15-year follow-up study.
      • Nugent F.W.
      • Haggitt R.C.
      • Gilpin P.A.
      Cancer surveillance in ulcerative colitis.
      • Lindberg B.
      • Persson B.
      • Veress B.
      • Ingelman-Sundberg H.
      • Granqvist S.
      Twenty years' colonoscopic surveillance of patients with ulcerative colitis. Detection of dysplastic and malignant transformation.
      • Connell W.R.
      • Lennard-Jones J.E.
      • Williams C.B.
      • et al.
      Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis.
      Overall, findings at time of surgery were no dysplasia, 37% (95% CI, 29–47; 197 of 450; I2 = 42%); LGD, 34% (95% CI, 30–39; 153 of 450; I2 = 0%); or advanced neoplasia, 30% (95% CI, 21–41; 97 of 450; I2 = 59%).
      Table 3Surgical Cohort: Characteristics of Studies Reporting Dysplasia-Related Findings in Patients With UC-LGD Undergoing Colectomy
      Authors, year of publicationCountry, cityStudy periodPathology diagnosisColectomy for UC-LGDDefinitive pathology on colectomy
      No dysplasia or indefinite for dysplasia, n (%)LGD, n (%)HGD, n (%)CRC, n (%)Advanced neoplasia (HGD or CRC), n (%)
      Murphy, 2014USA, multicentric1993–20122 expert pathologists220105 (48)74 (34)36 (16)5 (2)41 (18)
      Kiran, 2014USA, Cleveland1984–20072 expert pathologists13670 (51)46 (34)16 (12)4 (3)20 (15)
      Hata, 2003Japan, Tokyo1979–2001Community pathologist only31 (33)01 (33)1 (33)2 (66)
      Löfberg, 1990Sweden, Stockholm1973–19881 expert pathologist41 (25)3 (75)000
      Nugent, 1991USA, Burlington1974–19861 expert pathologist41 (25)1 (25)02 (50)2 (50)
      Woolrich, 1992USA, New York1977–19872 expert pathologists202 (100)000
      Lindberg, 1996Sweden, Hundinge1974–19932 expert pathologists164 (25)4 (25)05 (31)5 (31)
      Connell, 1994UK, London1971–19902 expert pathologists134 (30)2 (15)2 (15)5 (38)7 (54)
      Choi, 2015UK, London1993–20122 expert pathologists369 (25)13 (36)5 (14)9 (25)14 (39)
      Venkatesh, 2013USA, Cleveland1996–20112 expert pathologists21 (50)1 (50)000
      Zisman, 2012USA, Seattle1987–20022 expert pathologists61 (16)2 (33)2 (33)1 (16)3 (50)
      Fusco, 2012Germany, Grünheide1999–20022 expert pathologists805 (62)1 (12)2 (24)3 (37)
      CD, Crohn’s disease.
      At surgery, synchronous CRC was identified in 34 patients (17%; 95% CI, 8–33; I2 = 77%). In studies published before 2000, rate of synchronous CRC at time of surgery was significantly higher (33%; 95% CI, 20–50) as compared with studies published after 2000 (11%; 95% CI, 4–29; P interaction = .04).

       Outcome after Colorectal Cancer Diagnosis

      Eight studies reported outcome after diagnosis of 12 CRC.
      • Venkatesh P.G.
      • Jegadeesan R.
      • Gutierrez N.G.
      • et al.
      Natural history of low grade dysplasia in patients with primary sclerosing cholangitis and ulcerative colitis.
      • Zisman T.L.
      • Bronner M.P.
      • Rulyak S.
      • et al.
      Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines.
      • van Schaik F.D.
      • Oldenburg B.
      • Offerhaus G.J.
      • et al.
      Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.
      • Fusco V.
      • Ebert B.
      • Weber-Eibel J.
      • et al.
      Cancer prevention in ulcerative colitis: long-term outcome following fluorescence-guided colonoscopy.
      • Lynch D.A.
      • Lobo A.J.
      • Sobala G.M.
      • et al.
      Failure of colonoscopic surveillance in ulcerative colitis.
      • Rozen P.
      • Baratz M.
      • Fefer F.
      • et al.
      Low incidence of significant dysplasia in a successful endoscopic surveillance program of patients with ulcerative colitis.
      • Befrits R.
      • Ljung T.
      • Jaramillo E.
      • et al.
      Low-grade dysplasia in extensive, long-standing inflammatory bowel disease: a follow-up study.
      • Murphy J.
      • Kalkbrenner K.A.
      • Pemberton J.H.
      • et al.
      Dysplasia in ulcerative colitis as a predictor of unsuspected synchronous colorectal cancer.
      Among these, 11 patients underwent surgery with curative intent. Overall, 2 patients died during follow-up, both related to CRC: 1 patient died because of metastatic CRC, and another following recurrence of CRC after initial curative surgery.

      Discussion

      The management of UC-LGD is challenging because of a limited understanding of its natural history with regard to rate of metachronous or synchronous CRC, and risk factors associated with progression of dysplasia. In this systematic review of 14 surveillance cohorts and 12 surgical cohorts, we made several important observations. First, among patients with UC-LGD undergoing surveillance, the annual incidence of CRC is approximately 0.8% (95% CI, 0.4–1.3); rates of progression to CRC were higher when LGD was diagnosed by at least 1 expert gastrointestinal pathologist (IR, 1.5%; 95% CI, 0.6–2.4) as compared with a community pathologist without expert confirmation (IR, 0.2%; 95% CI, 0.0–0.4). Second, dysplastic lesions that were multifocal, invisible, located in the distal colon, or those detected in patients with concomitant PSC had the higher risk of progression to advanced neoplasia, and variable distribution of these risk factors in included surveillance cohorts may also explain observed heterogeneity. In particular, in patients with invisible dysplasia, annual incidence of progression to advanced neoplasia was 6.1% (95% CI, 0.9–11.4), and with endoscopically visible dysplasia was 1.0% (95% CI, 0–2.1).
      Finally, we observed that among patients with UC-LGD undergoing colectomy, advanced neoplasia is observed in approximately 30% of patients, whereas in 70% patients, either no dysplasia, “indefinite for dysplasia,” or LGD is identified; the risk of identifying synchronous CRC was significantly higher in older studies (published in 1990s, 33%) as compared with more contemporary cohorts (published in 2000s, 11%). Together, these findings comprehensively inform clinical practice on the natural history of UC-LGD and will facilitate shared decision-making regarding intensive endoscopic surveillance versus early colectomy in patients with UC-LGD.
      The observed annual incidence of CRC (0.8%; 95% CI, 0.4–1.3) and advanced neoplasia (1.8%; 95% CI, 0.9–2.7) was lower than observed in the previous systematic review (1.4% and 3.0%, respectively); the previous review included only 7 studies, primarily conducted in the 1990s before widespread uptake of surveillance for CRC, and predated advanced dysplasia detection techniques.
      • Thomas T.
      • Abrams K.A.
      • Robinson R.J.
      • et al.
      Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis.
      We identified 8 additional studies since the publication of the last review, and observed lower rates of progression to CRC and advanced neoplasia in our meta-analysis. This might be a true finding with an actual decrease in rate of dysplasia progression with widespread use of disease-modifying therapy that control inflammation better and hence, decrease risk of dysplasia progression, lead-time bias with higher rates of LGD detection at low-risk of progression with surveillance examinations, and advanced dysplasia detection techniques, or may be attributed to publication bias (with unreported studies) in the earlier meta-analysis. In contrast to UC-LGD, estimated annual incidence of CRC in unselected patients with nondysplastic UC is 0.3%,
      • Eaden J.A.
      • Abrams K.R.
      • Mayberry J.F.
      The risk of colorectal cancer in ulcerative colitis: a meta-analysis.
      and between 0.017% and 0.041% in the general CRC screening population.

      National Cancer Institute. Surveillance, Epidemiology, and Ends results program. Available at: http://seer.cancer.gov/statfacts/html/colorect.html. Accessed August 2016.

      International Agency for Research in Cancer. World Health Organization. Available at: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed August 2016.

      We observed wide variability in rates of progression to CRC across studies. This could be explained by 2 potential reasons. First, the studies were conducted in diverse clinical practices with wide variability in interpretation of LGD diagnosis. In studies where LGD was diagnosed only by a community pathologist, rates of progression to CRC were lower, as compared with studies with expert pathologic confirmation. Analogous to LGD in patients with Barrett’s esophagus, UC-LGD may be overcalled by community pathologists, such that these patients are intrinsically at lower risk of progression to CRC.
      • Singh S.
      • Manickam P.
      • Amin A.V.
      • et al.
      Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta-analysis.
      • Dixon M.F.
      • Brown L.J.R.
      • Gilmour H.M.
      • et al.
      Observer variation in the assessment of dysplasia in ulcerative colitis.
      • Eaden J.
      • Abrams K.
      • McKay H.
      • et al.
      Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis.
      In a Dutch pathology registry study, on re-review of 70 patients initially diagnosed as having flat LGD by 3 expert pathologists, the diagnosis of flat LGD was confirmed in only 21 patients (30%); in 29 patients (41%), the diagnosis was downgraded to indefinite for dysplasia, in 17 patients (24%) to no dysplasia, and in 3 patients (5%) to non-IBD-related dysplasia.
      • van Schaik F.D.
      • Oldenburg B.
      • Offerhaus G.J.
      • et al.
      Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.
      Although the rate of progression to advanced neoplasia in patients originally classified as having flat LGD was 19%, this rate increased to 44% on restricting to patients confirmed as having LGD by 3 expert pathologists. Second, there may be referral bias wherein expert centers may be more likely providing care to patients at highest risk of dysplasia progression.
      An apparent discrepancy was observed in rates of metachronous CRC (from surveillance cohorts; annual IR, 0.8%) and synchronous CRC (from surgical cohorts; 17%). We hypothesize that these differences may be caused by (1) differences in patient population (systematic difference in patients with LGD who undergo surveillance, and those who undergo surgery, where physicians may be intuitively referring patients deemed to be at high risk of progression to surgery, and selectively including low-risk LGD patients in surveillance), (2) differences in time period (most surgical cohorts were published before 2000 and most surveillance cohorts were published after 2000, and with regular use of surveillance colonoscopies and advanced dysplasia detection techniques in recent times may enable early identification of LGD at low risk of harboring synchronous advanced neoplasia), or by (3) potential missed or interval CRCs. In surveillance cohorts, we assumed that risk of CRC increases linearly with time. It is possible that most patients who are diagnosed with CRC after a diagnosis of LGD develop CRC within 1–2 years of LGD diagnosis, and that these cancers were probably missed at the original colonoscopy, rather than truly being incident cancers, akin to observations in patients with Barrett’s esophagus, in which we estimated that about 25% of esophageal cancers in patients with Barrett’s esophagus develop within 2 years of initial Barrett’s esophagus diagnosis.
      • Visrodia K.
      • Singh S.
      • Krishnamoorthi R.
      • et al.
      Magnitude of missed esophageal adenocarcinoma after Barrett's esophagus diagnosis: a systematic review and meta-analysis.
      In a study from the Netherlands on magnitude of interval CRCs in patients with IBD, the investigators observed that whereas the annual incidence of LGD in patients with IBD is 5.2%, about 1.3% patients developed interval CRC, possibly caused by inadequate colonoscopy, inadequate surveillance intervals, inadequate dysplasia management, or true biologic interval CRC.
      • Mooiweer E.
      • van der Meulen-de Jong A.E.
      • Ponsioen C.Y.
      • et al.
      Incidence of interval colorectal cancer among inflammatory bowel disease patients undergoing regular colonoscopic surveillance.
      The strengths of this systematic review include (1) comprehensive and systematic literature search with well-defined inclusion criteria; (2) quantitatively and qualitatively studying all aspects of dysplasia progression in patients with UC-LGD including incidence, risk factors and outcomes of metachronous CRC and advanced neoplasia, and risk of synchronous CRC and advanced neoplasia; (3) subgroup and sensitivity analyses to evaluate the stability of findings and identify potential factors responsible for inconsistencies; and (4) rigorous quality assessment of studies.
      Our study has several limitations. First, significant heterogeneity was observed in the pooled estimate of incidence of dysplasia progression. We explored and identified potential explicit study-related (study setting, location, time period, whether diagnosis was confirmed by expert gastrointestinal pathologist) and implicit patient-related factors (UC- and dysplasia-related potential risk factors) that may be contributing to this heterogeneity. Second, studies did not consistently report the frequency of endoscopic surveillance, use of advanced dysplasia detection techniques as chromoendoscopy, and numbers of random and/or targeted biopsies taken in the surveillance cohorts.
      • Awais D.
      • Siegel C.A.
      • Higgins P.D.
      Modelling dysplasia detection in ulcerative colitis: clinical implications of surveillance intensity.
      Similarly, for surgical cohorts, there was incomplete reporting in terms of all dysplastic findings, resulting in exclusion of some studies with incomplete information. In assessing risk factors, several studies only provided univariate analysis because of limited number of events. Some potentially important risk factors, such as disease extent, associated stricture, familial history of CRC, or impact of IBD therapies and associated endoscopic and/or histologic remission on dysplasia progression, could not be evaluated because of insufficient data. Third, there was variability in study quality especially with regard to duration of follow-up, attrition rate, and specific reporting of follow-up in a subset of patients with UC-LGD. Moreover, most of the included studies were performed in referral centers, and these tend to overestimate CRC risk as compared with population-based studies.
      • Lutgens M.W.
      • van Oijen M.G.
      • van der Heijden G.J.
      • et al.
      Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
      In fact, we did not identify any high-quality study on this topic because of the aforementioned factors in this review. Finally, the analyses were done assuming that IR is constant over time, which may not be accurate.

       Implications for Clinical Practice

      Recently, the SCENIC consensus statements have proposed an individualized approach to surveillance in patients with UC-LGD.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      Based on our observations, we recommend early repeat colonoscopy (within 6m), preferably with chromoendoscopy, in patients diagnosed with LGD, particularly invisible dysplasia, because of potential missed CRCs in these patients. Given low rates of progression to advanced neoplasia in patients with endoscopically visible lesions, we agree with the SCENIC consensus statements, that in patients with visible nonpolypoid dysplastic lesions that are amenable to endoscopic resection, surveillance colonoscopy may be suggested rather than colectomy. Finally, in patients with invisible dysplasia, we propose risk-stratification to identify patients at low and high risk of dysplasia progression, based on presence of absence of risk factors associated with dysplasia progression (concomitant PSC, multifocal LGD, previous indefinite for dysplasia, and distal location). Choi et al
      • Choi C.H.
      • Ignjatovic-Wilson A.
      • Askari A.
      • et al.
      Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
      estimated risk of dysplasia progression based on number of risk factors, and observed a significant increase in risk if multiple risk factors were present. Hence, in patients with multiple high-risk features, particularly those who may be difficult to survey (multiple pseudopolyps, poor compliance, ongoing active disease, and so forth), early colectomy may be advisable. However, there are significant differences in patients’ and physicians’ willingness to undergo colectomy for dysplasia risk, and hence, shared decision-making is recommended.
      • Siegel C.A.
      • Schwartz L.M.
      • Woloshin S.
      • et al.
      When should ulcerative colitis patients undergo colectomy for dysplasia? Mismatch between patient preferences and physician recommendations.
      In conclusion, we estimate that the annual rate of progression to CRC or to advanced neoplasia in patients with UC-LGD under surveillance is approximately 0.8% (95% CI, 0.4–1.3) and 1.8% (95% CI, 0.9–2.7), respectively, and this rate may be variable depending on whether or not diagnosis of LGD was confirmed by an expert gastrointestinal pathologist. Concomitant PSC, invisible dysplasia, distal colonic location, and multifocal LGD are potential high-risk features associated with progression to advanced neoplasia. Among patients undergoing colectomy for UC-LGD, about 17% may have synchronous CRC, and this rate seems to have decreased over time potentially because of regular surveillance and advanced dysplasia detection techniques that enable early LGD diagnosis. Prospective, population-based observational cohort studies in patients with an expert pathologist-confirmed LGD are warranted to better understand the natural history of UC-LGD.

      Supplementary Appendix

       Literature Search

       Ovid

      Database(s): Embase 1988 to 2015 Week 50, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present, EBM Reviews - Cochrane Database of Systematic Reviews 2005 to December 2015 Search Strategy:
      Tabled 1
      #SearchesResults
      1exp Colitis, Ulcerative/73739
      2(“colitis gravis” or “chronic colon ulcer*” or ((ulcer* or mucosal or distal or “left-sided” or idiopathic) adj2 (colitis or colorectitis or “procto-colitis” or proctocolitis or proctosigmoiditis or “procto-sigmoiditis” or proctitis))).mp.89089
      31 or 289089
      4exp gastrointestinal dysplasia/664
      5((“adenoma-like” adj3 (dysplasia* or mass or masses or lesion*)) or ((“low-grade” or “high-grade” or indefinite or indeterminate or “low-flat” or flat or raised) adj3 dysplasia*) or fLGD or HGD or LGD).mp.12632
      6Colonic Polyps/14270
      7exp Colonic Neoplasms/283531
      8colorectal neoplasms/81542
      9adenomatous polyposis coli/9069
      10colorectal neoplasms, hereditary nonpolyposis/5858
      11((colon* or colorect* or colonic) adj3 (adenocarcinoma* or adenoma* or cancer* or carcinoma* or malignan* or neoplas* or polyp* or tumor* or tumour*)).mp.425419
      12exp Population Surveillance/227762
      13Surveillance.mp.345876
      14or/4-13921798
      153 and 1412961
      16exp meta analysis/165627
      17exp Meta-Analysis as Topic/39031
      18exp “systematic review”/99527
      19exp Guideline/ or exp Practice Guideline/382234
      20exp Cohort Studies/1744357
      21exp longitudinal study/180418
      22exp retrospective study/999324
      23exp prospective study/723633
      24exp population research/73878
      25exp observational study/98996
      26exp correlational study/17050
      27exp proportional hazards model/111405
      28review.pt.4038501
      29exp review/3985727
      30((meta adj analys*) or (systematic* adj3 review*) or guideline* or cohort* or “longitudinal study” or “longitudinal survey” or “longitudinal analysis” or “longitudinal evaluation” or longitudinal* or ((retrospective or “ex post facto”) adj3 (study or survey or analysis or design)) or retrospectiv* or “prospective study” or “prospective survey” or “prospective analysis” or prospectiv* or (population adj3 (stud* or survey* or analys* or research)) or “incidence study” or “incidence survey” or “incidence analysis” or ((“follow-up” or followup) adj (stud* or survey or analysis)) or ((observation or observational) adj (study or survey or analysis)) or ((correlation* adj2 study) or (correlation* adj2 analys*)) or (hazard* adj (model or analys* or regression or ratio or ratios)) or “Cox model” or “Cox multivariate analyses” or “Cox multivariate analysis” or “Cox regression” or “Cox survival analyses” or “Cox survival analysis” or “Cox survival model” or review).mp,pt.9856013
      31or/16-309917336
      3215 and 316097
      33from 15 keep 7544-129285385
      34limit 33 to (guideline or practice guideline or meta analysis or observational study or systematic reviews) [Limit not valid in Embase,CDSR; records were retained]137
      3532 or 346104
      36(exp animals/ or exp nonhuman/) not exp humans/8237238
      37((alpaca or alpacas or amphibian or amphibians or animal or animals or antelope or armadillo or armadillos or avian or baboon or baboons or beagle or beagles or bee or bees or bird or birds or bison or bovine or buffalo or buffaloes or buffalos or “c elegans” or “Caenorhabditis elegans” or camel or camels or canine or canines or carp or cats or cattle or chick or chicken or chickens or chicks or chimp or chimpanze or chimpanzees or chimps or cow or cows or “D melanogaster” or “dairy calf” or “dairy calves” or deer or dog or dogs or donkey or donkeys or drosophila or “Drosophila melanogaster” or duck or duckling or ducklings or ducks or equid or equids or equine or equines or feline or felines or ferret or ferrets or finch or finches or fish or flatworm or flatworms or fox or foxes or frog or frogs or “fruit flies” or “fruit fly” or “G mellonella” or “Galleria mellonella” or geese or gerbil or gerbils or goat or goats or goose or gorilla or gorillas or hamster or hamsters or hare or hares or heifer or heifers or horse or horses or insect or insects or jellyfish or kangaroo or kangaroos or kitten or kittens or lagomorph or lagomorphs or lamb or lambs or llama or llamas or macaque or macaques or macaw or macaws or marmoset or marmosets or mice or minipig or minipigs or mink or minks or monkey or monkeys or mouse or mule or mules or nematode or nematodes or octopus or octopuses or orangutan or “orang-utan” or orangutans or “orang-utans” or oxen or parrot or parrots or pig or pigeon or pigeons or piglet or piglets or pigs or porcine or primate or primates or quail or rabbit or rabbits or rat or rats or reptile or reptiles or rodent or rodents or ruminant or ruminants or salmon or sheep or shrimp or slug or slugs or swine or tamarin or tamarins or toad or toads or trout or urchin or urchins or vole or voles or waxworm or waxworms or worm or worms or xenopus or “zebra fish” or zebrafish) not (human or humans)).mp.7257234
      3835 not (36 or 37)6060
      39limit 38 to (editorial or erratum or letter or note or addresses or autobiography or bibliography or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in Embase,Ovid MEDLINE(R),Ovid MEDLINE(R) In-Process,CDSR; records were retained]163
      4038 not 395897
      41from 15 keep 12929-1296133
      4240 or 415930
      43limit 42 to English language [Limit not valid in CDSR; records were retained]5263
      44limit 43 to yr=“2005 -Current”3609
      45remove duplicates from 442816

       Scopus

      • 1
        TITLE-ABS-KEY(“colitis gravis” or “chronic colon ulcer*” or ((ulcer* or mucosal or distal or “left-sided” or idiopathic) W/2 (colitis or colorectitis or “procto-colitis” or proctocolitis or proctosigmoiditis or “procto-sigmoiditis” or proctitis)))
      • 2
        TITLE-ABS-KEY((“adenoma-like” W/3 (dysplasia* or mass or masses or lesion*)) OR ((“low-grade” or “high-grade” or indefinite or indeterminate or “low-flat” or flat or raised) W/3 dysplasia*) OR ((colon* or colorect* or colonic) W/3 (adenocarcinoma* or adenoma* or cancer* or carcinoma* or malignan* or neoplas* or polyp* or tumor* or tumour*)) OR fLGD OR HGD OR LGD OR Surveillance)
      • 3
        TITLE-ABS-KEY((meta W/1 analys*) OR (systematic* W/3 review*) OR guideline* OR cohort* OR longitudinal* OR retrospectiv* OR prospectiv* OR (population W/3 stud*) OR “incidence study” OR “incidence survey” OR “incidence analysis” OR “follow-up” OR followup OR “observational study” OR (correlation* W/2 study) OR (correlation* W/2 analys*) OR (hazard* W/1 model) OR “Cox model” OR “Cox multivariate analyses” OR “Cox multivariate analysis” OR “Cox regression” OR “Cox survival analyses” OR “Cox survival analysis” OR “Cox survival model” OR review)
      • 4
        PUBYEAR AFT 2004 AND LANGUAGE(english)
      • 5
        1 and 2 and 3 and 4
      • 6
        TITLE-ABS-KEY((alpaca OR alpacas OR amphibian OR amphibians OR animal OR animals OR antelope OR armadillo OR armadillos OR avian OR baboon OR baboons OR beagle OR beagles OR bee OR bees OR bird OR birds OR bison OR bovine OR buffalo OR buffaloes OR buffalos OR “c elegans” OR “Caenorhabditis elegans” OR camel OR camels OR canine OR canines OR carp OR cats OR cattle OR chick OR chicken OR chickens OR chicks OR chimp OR chimpanze OR chimpanzees OR chimps OR cow OR cows OR “D melanogaster” OR “dairy calf” OR “dairy calves” OR deer OR dog OR dogs OR donkey OR donkeys OR drosophila OR “Drosophila melanogaster” OR duck OR duckling OR ducklings OR ducks OR equid OR equids OR equine OR equines OR feline OR felines OR ferret OR ferrets OR finch OR finches OR fish OR flatworm OR flatworms OR fox OR foxes OR frog OR frogs OR “fruit flies” OR “fruit fly” OR “G mellonella” OR “Galleria mellonella” OR geese OR gerbil OR gerbils OR goat OR goats OR goose OR gorilla OR gorillas OR hamster OR hamsters OR hare OR hares OR heifer OR heifers OR horse OR horses OR insect OR insects OR jellyfish OR kangaroo OR kangaroos OR kitten OR kittens OR lagomorph OR lagomorphs OR lamb OR lambs OR llama OR llamas OR macaque OR macaques OR macaw OR macaws OR marmoset OR marmosets OR mice OR minipig OR minipigs OR mink OR minks OR monkey OR monkeys OR mouse OR mule OR mules OR nematode OR nematodes OR octopus OR octopuses OR orangutan OR “orang-utan” OR orangutans OR “orang-utans” OR oxen OR parrot OR parrots OR pig OR pigeon OR pigeons OR piglet OR piglets OR pigs OR porcine OR primate OR primates OR quail OR rabbit OR rabbits OR rat OR rats OR reptile OR reptiles OR rodent OR rodents OR ruminant OR ruminants OR salmon OR sheep OR shrimp OR slug OR slugs OR swine OR tamarin OR tamarins OR toad OR toads OR trout OR urchin OR urchins OR vole OR voles OR waxworm OR waxworms OR worm OR worms OR xenopus OR “zebra fish” OR zebrafish) AND NOT (human OR humans))
      • 7
        5 and not 6
      • 8
        DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR DOCTYPE(sh)
      • 9
        7 and not 8
      • 10
        PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR PMID(7*) OR PMID(8*) OR PMID(9*)
      • 11
        9 and not 10

       Web of Science

      • 1
        TOPIC: ((“colitis gravis” or “chronic colon ulcer*” or ((ulcer* or mucosal or distal or “left-sided” or idiopathic) NEAR/2 (colitis or colorectitis or “procto-colitis” or proctocolitis or proctosigmoiditis or “procto-sigmoiditis” or proctitis)))) AND TOPIC: (((“adenoma-like” NEAR/3 (dysplasia* or mass or masses or lesion*)) OR ((“low-grade” or “high-grade” or indefinite or indeterminate or “low-flat” or flat or raised) NEAR/3 dysplasia*) OR ((colon* or colorect* or colonic) NEAR/3 (adenocarcinoma* or adenoma* or cancer* or carcinoma* or malignan* or neoplas* or polyp* or tumor* or tumour*)) OR fLGD OR HGD OR LGD OR Surveillance)) AND TOPIC: (((meta NEAR/1 analys*) OR (systematic* NEAR/3 review*) OR guideline* OR cohort* OR “longitudinal study” OR “longitudinal survey” OR “longitudinal analysis” OR “longitudinal evaluation” OR longitudinal* OR ((retrospective OR “ex post facto”) NEAR/3 (study OR survey OR analysis OR design)) OR retrospectiv* OR “prospective study” OR “prospective survey” OR “prospective analysis” OR prospectiv* OR (population NEAR/3 (stud* or survey* or analys* or research)) OR “incidence study” OR “incidence survey” OR “incidence analysis” OR ((“follow-up” or followup) NEAR/1 (stud* or survey or analysis)) OR ((observation or observational) NEAR/1 (study or survey or analysis)) OR ((correlation* NEAR/2 study) OR (correlation* NEAR/2 analys*)) OR (hazard* NEAR/1 (model OR analys* OR regression or ratio or ratios)) OR “Cox model” OR “Cox multivariate analyses” OR “Cox multivariate analysis” OR “Cox regression” OR “Cox survival analyses” OR “Cox survival analysis” OR “Cox survival model” or review)) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Abstract of Published Item OR Meeting Abstract OR Proceedings Paper OR Review) Indexes=SCI-EXPANDED Timespan=2005-2015
      • 2
        TS=((alpaca OR alpacas OR amphibian OR amphibians OR animal OR animals OR antelope OR armadillo OR armadillos OR avian OR baboon OR baboons OR beagle OR beagles OR bee OR bees OR bird OR birds OR bison OR bovine OR buffalo OR buffaloes OR buffalos OR “c elegans” OR “Caenorhabditis elegans” OR camel OR camels OR canine OR canines OR carp OR cats OR cattle OR chick OR chicken OR chickens OR chicks OR chimp OR chimpanze OR chimpanzees OR chimps OR cow OR cows OR “D melanogaster” OR “dairy calf” OR “dairy calves” OR deer OR dog OR dogs OR donkey OR donkeys OR drosophila OR “Drosophila melanogaster” OR duck OR duckling OR ducklings OR ducks OR equid OR equids OR equine OR equines OR feline OR felines OR ferret OR ferrets OR finch OR finches OR fish OR flatworm OR flatworms OR fox OR foxes OR frog OR frogs OR “fruit flies” OR “fruit fly” OR “G mellonella” OR “Galleria mellonella” OR geese OR gerbil OR gerbils OR goat OR goats OR goose OR gorilla OR gorillas OR hamster OR hamsters OR hare OR hares OR heifer OR heifers OR horse OR horses OR insect OR insects OR jellyfish OR kangaroo OR kangaroos OR kitten OR kittens OR lagomorph OR lagomorphs OR lamb OR lambs OR llama OR llamas OR macaque OR macaques OR macaw OR macaws OR marmoset OR marmosets OR mice OR minipig OR minipigs OR mink OR minks OR monkey OR monkeys OR mouse OR mule OR mules OR nematode OR nematodes OR octopus OR octopuses OR orangutan OR “orang-utan” OR orangutans OR “orang-utans” OR oxen OR parrot OR parrots OR pig OR pigeon OR pigeons OR piglet OR piglets OR pigs OR porcine OR primate OR primates OR quail OR rabbit OR rabbits OR rat OR rats OR reptile OR reptiles OR rodent OR rodents OR ruminant OR ruminants OR salmon OR sheep OR shrimp OR slug OR slugs OR swine OR tamarin OR tamarins OR toad OR toads OR trout OR urchin OR urchins OR vole OR voles OR waxworm OR waxworms OR worm OR worms OR xenopus OR “zebra fish” OR zebrafish) NOT (human OR humans)) Indexes=SCI-EXPANDED Timespan=2005-2015
      • 3
        1 NOT 2
      • 4
        PMID=(0* or 1* or 2* or 3* or 4* or 5* or 6* or 7* or 8* or 9*) Indexes=SCI-EXPANDED Timespan=2005-2015
      • 5
        3 NOT 4

       Quality assessment

      The quality of included studies was assessed using a scale derived from the Newcastle-Ottawa scale for cohort studies, and has been used in a similar study on risk of progression of Barrett’s esophagus with LGD.
      • Singh S.
      • Manickam P.
      • Amin A.V.
      • et al.
      Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta-analysis.
      This quality score consisted of 7 questions: representative of the average adult in the community (1 point for population-based studies, 0.5 points for multicenter studies, 0 points for a single-center hospital-based study); large cohort size (1 point if cohort size >200 patients with LGD, 0.5 points if cohort size between 100 and 200 patients, 0 points if cohort size of <100 patients with LGD); definite histologic confirmation of LGD (1 point if confirmed by consensus of 2 expert pathologists, 0.5 points if reviewed by 1 expert gastrointestinal pathologist, 0 points if reviewed only by community pathologist or not reported in study); adequate follow-up of cohort for outcome to occur (1 point if mean follow-up of entire cohort >5 years, 0.5 points if cohort follow-up between 3 and 5 years, 0 points if mean follow-up of cohort <3 years); clear information on duration of follow-up of patients with UC-LGD (1 point if reported in study in total person-years, 0.5 point if reported as mean follow-up of UC-LGD cohort, 0 points if imputed from entire UC cohort); attrition rate (1 point if >80% of cohort followed-up, 0.5 points if 60%–80% cohort followed-up, 0 points if >40% lost to follow-up); definite information on progression of UC-LGD (1 point if adequate information on rate of progression from UC-LGD to UC-HGD and CRC separately, 0.5 points if only information on rate of progression to CRC, without information on UC-HGD). A score of ≥6, 4–5, and ≤3 was considered suggestive of high-, medium-, and low-quality study.
      Supplementary Table 1Quality of Included Studies Based on a Modification of the Newcastle-Ottawa Scale for Cohort Studies
      Representative of the average adult in the community 1 pt: population-based studies 0.5 pt: multicenter studies 0 pt: single-center hospital-based studyLarge cohort size 1 pt: cohort size >200 patients 0.5 pt: cohort size 100–200 patients 0 pt: cohort size of <100 patientsDefinite histologic confirmation of LGD 1 pt: confirmed by consensus of 2 expert pathologists 0.5 pt: reviewed by 1 expert pathologist 0 pt: reviewed by community pathologist only or not reported in studyAdequate follow-up of cohort 1 pt: mean follow-up of entire cohort >5 y 0.5 pt: cohort follow-up 2–5 y 0 pt: mean follow-up of cohort <2 yClear information on duration of follow-up 1 pt: reported in study in total person years 0.5 pt: reported as mean follow-up of UC-LGD cohort 0 pt: imputed from entire UC cohortAttrition rate 1 pt: >80% of cohort followed-up 0.5 pt: 60%–80% of cohort followed-up 0 pt: <40% lost to follow-upDefinite information on progression of UC-LGD 1 pt: adequate information on rate of progression from UC-LGD to UC-HGD and AN separately 0.5 pt: only information on rate of progression to advanced neoplasiaTotal high quality >5; medium quality 4–5; low quality <4
      Choi et al00.510.51115
      Eaton et al00100.5113.5
      Goldstone et al00.510.50.5114
      Navaneethan et al00.510.50.5114.5
      Venkatesh et al00101114
      Zisman et al0010.50.5114
      van Schaik et al0.50100.5113.5
      Pekow et al0010.51114.5
      Jess et al100.510.5115
      Lim et al00010.5113.5
      Fusco et al00110.5114.5
      Lynch et al00011114
      Rozen et al000.50.50.5113.5
      Befrits et al00110.5114.5

      References

        • Bewtra M.
        • Kaiser L.M.
        • TenHave T.
        • et al.
        Crohn's disease and ulcerative colitis are associated with elevated standardized mortality ratios: a meta-analysis.
        Inflamm Bowel Dis. 2013; 19: 599-613
        • Jess T.
        • Rungoe C.
        • Peyrin-Biroulet L.
        Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies.
        Clin Gastroenterol Hepatol. 2012; 10: 639-645
        • Beaugerie L.
        • Itzkowitz S.H.
        Cancers complicating inflammatory bowel disease.
        N Engl J Med. 2015; 373: 195
        • Bernstein C.N.
        • Nugent Z.
        • Targownik L.E.
        • et al.
        Predictors and risks for death in a population-based study of persons with IBD in Manitoba.
        Gut. 2015; 64: 1403-1411
        • Ullman T.A.
        • Itzkowitz S.H.
        Intestinal inflammation and cancer.
        Gastroenterology. 2011; 140: 1807-1816
        • Thomas T.
        • Abrams K.A.
        • Robinson R.J.
        • et al.
        Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis.
        Aliment Pharmacol Ther. 2007; 25: 657-668
        • Choi C.H.
        • Ignjatovic-Wilson A.
        • Askari A.
        • et al.
        Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.
        Am J Gastroenterol. 2015; 110: 1461-1471
        • Laine L.
        • Kaltenbach T.
        • Barkun A.
        • et al.
        SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
        Gastroenterology. 2015; 148: 639-651
        • Bernstein C.N.
        Ulcerative colitis with low-grade dysplasia.
        Gastroenterology. 2004; 127: 950-956
        • Van Assche G.
        • Dignass A.
        • Bokemeyer B.
        • et al.
        Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations.
        J Crohns Colitis. 2013; 7: 1-33
        • Bernstein C.N.
        • Weinstein W.M.
        • Levine D.S.
        • et al.
        Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis.
        Am J Gastroenterol. 1995; 90: 2106-2114
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ. 2009; 339: b2535
        • Singh S.
        • Manickam P.
        • Amin A.V.
        • et al.
        Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta-analysis.
        Gastrointest Endosc. 2014; 79: 897-909
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Guyatt G.H.
        • Oxman A.D.
        • Kunz R.
        • et al.
        GRADE guidelines: 7. Rating the quality of evidence–inconsistency.
        J Clin Epidemiol. 2011; 64: 1294-1302
        • Egger M.
        • Smith G.D.
        • Phillips A.N.
        Meta-analysis: principles and procedures.
        BMJ. 1997; 315: 1533-1537
        • Easterbrook P.J.
        • Berlin J.A.
        • Gopalan R.
        • Matthews D.R.
        Publication bias in clinical research.
        Lancet. 1991; 337: 867-872
        • Eaton J.E.
        • Smyrk T.C.
        • Imam M.
        • et al.
        The fate of indefinite and low-grade dysplasia in ulcerative colitis and primary sclerosing cholangitis colitis before and after liver transplantation.
        Aliment Pharmacol Ther. 2013; 38: 977-987
        • Goldstone R.
        • Itzkowitz S.
        • Harpaz N.
        • et al.
        Progression of low-grade dysplasia in ulcerative colitis: effect of colonic location.
        Gastrointest Endosc. 2011; 74: 1087-1093
        • Navaneethan U.
        • Jegadeesan R.
        • Gutierrez N.G.
        • et al.
        Progression of low-grade dysplasia to advanced neoplasia based on the location and morphology of dysplasia in ulcerative colitis patients with extensive colitis under colonoscopic surveillance.
        J Crohns Colitis. 2013; 7: e684-e691
        • Venkatesh P.G.
        • Jegadeesan R.
        • Gutierrez N.G.
        • et al.
        Natural history of low grade dysplasia in patients with primary sclerosing cholangitis and ulcerative colitis.
        J Crohns Colitis. 2013; 7: 968-973
        • Zisman T.L.
        • Bronner M.P.
        • Rulyak S.
        • et al.
        Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines.
        Inflamm Bowel Dis. 2012; 18: 2240-2246
        • van Schaik F.D.
        • Oldenburg B.
        • Offerhaus G.J.
        • et al.
        Role of immunohistochemical markers in predicting progression of dysplasia to advanced neoplasia in patients with ulcerative colitis.
        Inflamm Bowel Dis. 2012; 18: 480-488
        • Pekow J.R.
        • Hetzel J.T.
        • Rothe J.A.
        • et al.
        Outcome after surveillance of low-grade and indefinite dysplasia in patients with ulcerative colitis.
        Inflamm Bowel Dis. 2010; 16: 1352-1356
        • Jess T.
        • Loftus Jr., E.V.
        • Velayos F.S.
        • et al.
        Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county, Denmark and Olmsted county, Minnesota.
        Am J Gastroenterol. 2007; 102: 829-836
        • Lim C.H.
        • Dixon M.F.
        • Vail A.
        • et al.
        Ten year follow up of ulcerative colitis patients with and without low grade dysplasia.
        Gut. 2003; 52: 1127-1132
        • Fusco V.
        • Ebert B.
        • Weber-Eibel J.
        • et al.
        Cancer prevention in ulcerative colitis: long-term outcome following fluorescence-guided colonoscopy.
        Inflamm Bowel Dis. 2012; 18: 489-495
        • Lynch D.A.
        • Lobo A.J.
        • Sobala G.M.
        • et al.
        Failure of colonoscopic surveillance in ulcerative colitis.
        Gut. 1993; 34: 1075-1080
        • Rozen P.
        • Baratz M.
        • Fefer F.
        • et al.
        Low incidence of significant dysplasia in a successful endoscopic surveillance program of patients with ulcerative colitis.
        Gastroenterology. 1995; 108: 1361-1370
        • Befrits R.
        • Ljung T.
        • Jaramillo E.
        • et al.
        Low-grade dysplasia in extensive, long-standing inflammatory bowel disease: a follow-up study.
        Dis Colon Rectum. 2002; 45: 615-620
        • Murphy J.
        • Kalkbrenner K.A.
        • Pemberton J.H.
        • et al.
        Dysplasia in ulcerative colitis as a predictor of unsuspected synchronous colorectal cancer.
        Dis Colon Rectum. 2014; 57: 993-998
        • Kiran R.P.
        • Ahmed Ali U.
        • Nisar P.J.
        • et al.
        Risk and location of cancer in patients with preoperative colitis-associated dysplasia undergoing proctocolectomy.
        Ann Surg. 2014; 259: 302-309
        • Hata K.
        • Watanabe T.
        • Kazama S.
        • et al.
        Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population.
        Br J Cancer. 2003; 89: 1232-1236
        • Löfberg R.
        • Broström O.
        • Karlén P.
        • et al.
        Colonoscopic surveillance in long-standing total ulcerative colitis–a 15-year follow-up study.
        Gastroenterology. 1990; 99: 1021-1031
        • Nugent F.W.
        • Haggitt R.C.
        • Gilpin P.A.
        Cancer surveillance in ulcerative colitis.
        Gastroenterology. 1991; 100: 1241-1248
        • Lindberg B.
        • Persson B.
        • Veress B.
        • Ingelman-Sundberg H.
        • Granqvist S.
        Twenty years' colonoscopic surveillance of patients with ulcerative colitis. Detection of dysplastic and malignant transformation.
        Scand J Gastroenterol. 1996; 3: 1195-1204
        • Connell W.R.
        • Lennard-Jones J.E.
        • Williams C.B.
        • et al.
        Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis.
        Gastroenterology. 1994; 107: 934-944
        • Eaden J.A.
        • Abrams K.R.
        • Mayberry J.F.
        The risk of colorectal cancer in ulcerative colitis: a meta-analysis.
        Gut. 2001; 48: 526-535
      1. National Cancer Institute. Surveillance, Epidemiology, and Ends results program. Available at: http://seer.cancer.gov/statfacts/html/colorect.html. Accessed August 2016.

      2. International Agency for Research in Cancer. World Health Organization. Available at: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed August 2016.

        • Dixon M.F.
        • Brown L.J.R.
        • Gilmour H.M.
        • et al.
        Observer variation in the assessment of dysplasia in ulcerative colitis.
        Histopathology. 1988; 13: 385-397
        • Eaden J.
        • Abrams K.
        • McKay H.
        • et al.
        Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis.
        J Pathol. 2001; 194: 152-157
        • Visrodia K.
        • Singh S.
        • Krishnamoorthi R.
        • et al.
        Magnitude of missed esophageal adenocarcinoma after Barrett's esophagus diagnosis: a systematic review and meta-analysis.
        Gastroenterology. 2016; 150: 599-607
        • Mooiweer E.
        • van der Meulen-de Jong A.E.
        • Ponsioen C.Y.
        • et al.
        Incidence of interval colorectal cancer among inflammatory bowel disease patients undergoing regular colonoscopic surveillance.
        Clin Gastroenterol Hepatol. 2015; 13: 1656-1661
        • Awais D.
        • Siegel C.A.
        • Higgins P.D.
        Modelling dysplasia detection in ulcerative colitis: clinical implications of surveillance intensity.
        Gut. 2009; 58: 1498-1503
        • Lutgens M.W.
        • van Oijen M.G.
        • van der Heijden G.J.
        • et al.
        Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
        Inflamm Bowel Dis. 2013; 19: 789-799
        • Siegel C.A.
        • Schwartz L.M.
        • Woloshin S.
        • et al.
        When should ulcerative colitis patients undergo colectomy for dysplasia? Mismatch between patient preferences and physician recommendations.
        Inflamm Bowel Dis. 2010; 16: 1658-1662

      Linked Article