Inflammatory bowel diseases (IBD) including ulcerative colitis (UC) or Crohn’s disease (CD) are chronic relapsing immunemediated conditions of the gastrointestinal tract requiring lifelong treatment [1]. It is well known that long standing colitis can increase the risk of colon cancer, along with other risk factors such as histologically severe inflammation, disease extent, family history of colorectal cancer (CRC), and coexistent primary sclerosing cholangitis (PSC) [2-4]. As with sporadic colon cancer, dysplasia is considered to be the precursor of most IBDrelated CRC [5]. Based on this evidence, most guidelines recommend surveillance colonoscopy for the detection and treatment of dysplastic lesions with the goal of decreasing the morbidity and mortality from CRC [6-9].

Although most dysplasia in IBD is associated with endoscopically visible mucosal lesions, neoplastic lesions are often difficult to detect due to the flat morphology and surrounding chronic inflammation [10-12]. In an attempt to circumvent this issue, previous guidelines recommended obtaining random biopsies throughout the colon in order to increase the detection of “invisible dysplasia.” The yield of random biopsies is extremely low, the cost associated with the large number of tissue samples is high, and this strategy has not been shown to decrease the incidence of colon cancer [13]. Dye chromoendoscopy (CE), by using indigo carmine or methylene blue, is a promising technique used to increase the detection of neoplastic mucosal lesion by identifying subtle changes in the surface epithelium or pit pattern. Several randomized clinical trials and case control studies have shown that CE can detect significantly more neoplasia compared with white light endoscopy (WLE) with or without random biopsies [14-17]. In addition, a recent study showed that CE is more cost-effective than WLE for UC surveillance, regardless of the surveillance interval [18]. Based on these results, major society guidelines recommend using CE with targeted biopsies as the modality of choice for surveillance in IBD patients [6-8]. There are, however, several limitations to CE such as a long procedure time, additional cost for the dye and equipment, and the lack of systematic endoscopic training [19]. Given the lack of long-term outcomes with CE, several studies have raised doubts about the significance of the additional dysplasia detected by CE as most of these lesions may have low risk of progression to advanced neoplasia or cancer. In addition, recent studies have questioned the superiority of CE over high-definition WLE in detection neoplasia in patients with chronic colitis [20].

Compared with sporadic colon cancer, the transition from inflamed epithelium to low-grade dysplasia (LGD), high-grade dysplasia (HGD) and eventually invasive carcinoma may occur faster in patients with IBD. Thus, detecting advanced neoplastic lesions during surveillance in these patients may be a more relevant endpoint for decreasing the risk of CRC. Serrated lesions (sessile serrated polyps/adenoma and traditional serrated adenomas) have also been associated with an increased risk of metachronous multifocal dysplasia in patients with IBD thus being indirectly implicated in the pathogenesis of colitis associated CRC [21-23]. Whether CE has an increased detection ability for serrated lesions compared with WLE is unknown.

In this study, we aimed to compare the yield of CE and WLE for the detection of all neoplasia, advanced neoplasia, and serrated lesions and assess the utility of random versus targeted biopsies for the surveillance of neoplasia in patients with IBD.

A total of 106 patients underwent 315 surveillance colonoscopies (median 3/patient; range, 1-13) during a median followup period of 4 years (range, 0.5-12.5 years) for a total of 914 patient-years of follow-up. The median surveillance interval between colonoscopies was 15 months (range, 4-98 months). Eight patients were excluded based on disease limited to the rectum (n = 1), CD with exclusive small bowel involvement (n = 3), prior total colectomy (n = 2), and prior history of colon cancer (n = 2). A total of 290 surveillance colonoscopies from 98 patients were included in the final analysis, of which 7 procedures (2.4%) were performed using standard definition colonoscopes prior to 2008. Twenty-four patients had CD (24.5%), 68 UC (69.4%), and the other 6 had IBDU. The median disease duration was 16.5 years (range, 1-60 years) and median age at diagnosis was 30 years (range, 11-75 years). Among UC patients, 48 had extensive colitis (E3, 70.6%) and 20 left-sided colitis (E2, 29.4%). Coexistent PSC was present in 11.2% of patients.

Of the total of 290 procedures (episodes), 159 were performed using CE (54.8%). Demographic and baseline characteristics of the entire cohort are shown in Table 1. Family history of CRC was more prevalent in the WLE group, but active smoking and PSC were more common in the CE group. Follow-up duration and extent were not significantly different between the 2 groups. In 52.7% of procedures (150/290), the disease was in endoscopic remission (61.0% in CE and 40.5% in WLE) in 42.1% (122/290), there was mild or moderate activity (37.7 in CE and 47.3% in WLE) and in the remaining 18 procedures (5.2%) there was severe inflammation (1.3% in CE and 12.2% in WLE). The bowel preparation status was acceptable in 95.6% of CE and 91.6% of WLE procedure (P= 0.11). Withdrawal time was significantly longer in CE (25.0 ± 9.6 minutes vs. 18.9 ± 6.7 minutes, P< 0.001). EMR was performed in 29.6% of CE episodes versus 9.2% in the WLE group (P< 0.001). There were no serious adverse events during either CE or WLE including EMR cases.

In this study, we have shown that CE has a higher diagnostic yield for neoplasia and particularly advanced neoplasia, compared with high-definition WLE in patients with IBD. Per procedure, neoplasia detection rate was nearly double, and there were almost three times as many advanced neoplastic lesions detected by CE compared with WLE. Based on the available evidence regarding the superior yield for neoplasia, CE was recommended as the modality of choice for IBD surveillance by several major medical societies [6-8]. However, there are barriers to the implementation of CE in clinical practice. On a recent survey, only 30% of IBD specialists routinely use CE [27]. One of the reasons for the slow uptake of CE has been the lack of long-term data supporting an association between a higher neoplasia detection rate and a lower risk of cancer. While there is controversy as to the impact of non-advanced lesions detected by CE, the data seems more meaningful in regard to the advanced lesions (larger size or containing HGD). Choi et al. [28] showed that the rate of interval cancers was reduced in half following a negative CE compared with a normal WLE. The prevalence of dysplasia in our study (48.0%) was higher compared with other cohorts, but the incidence was similar [28,29]. This may be due to referral bias, a higher proportion of patients with major risk factors such as PSC, or the systematic use of high-definition endoscopy. In our institution, we also employed pan-chromoendoscopy as opposed to targeted dye spraying as was the case in some studies.

Most neoplastic lesions in our study were polypoid, which is consistent with previous publications [14,30-33]. Rutter et al. [31] and Rubin et al. [32] have shown that most neoplasia in patients with IBD is visible. In our study, CE detected significantly more elevated lesions leading to more targeted biopsies compared with WLE (213 vs. 89). Overall, our data confirms that CE has a higher sensitivity for neoplastic lesions compared with WLE. We have to acknowledge that our results are discordant to findings from other recent studies showing no superiority of CE over WLE [20,34,35]. However, these studies excluded patients at high-risk for neoplasia such as those with coexistent PSC which, again, may have biased the results.

An important finding from our study is the higher yield for advanced neoplasia. CE detected almost three times as many advanced neoplastic lesions compared with WLE, and per lesion advanced neoplasia yield was also significantly higher, although high-definition scopes were used in the vast majority of cases. The difference between the 2 methods remained robust even after excluding the 7 procedures performed with standard definition WLE colonoscopy prior to 2008. This is a very important finding again supporting the use of CE over WLE for IBD surveillance. The decreased incidence of interval cancer in the study of Choi et al. [28] may also be due in part to a higher detection rate for advanced neoplasia, although this was not specifically addressed.

The detection rate for serrated lesions was also higher with CE compared with WLE in this study. CE has been shown to have a higher detection rate for serrated lesions in patients without IBD [36,37]. Recent reports have suggested that IBD patients with serrated neoplasia at baseline have a higher risk of developing conventional dysplasia including advanced neoplasia in follow-up [21-23]. Therefore, detecting these often inconspicuous lesions may have an important impact in reducing the risk of interval cancers in IBD patients.

There were significantly more targeted biopsies and fewer random biopsies obtained during CE compared with WLE. Similar to previous studies, the yield of random biopsies for dysplasia was extremely low [14,16,38]. Thus, CE may represent a cost-saving method for IBD surveillance without compromising diagnostic accuracy. This is consistent with data from Konijeti et al. [18] showing that CE may be more cost-effective for IBD surveillance regardless of the surveillance interval.

Our study has several limitations resulting from its retrospective nature and the referral bias which likely led to the inclusion of patients with a higher risk for neoplasia compared with population-based studies. There was a slight imbalance between groups, particularly in regard to the distribution of patients with PSC and family history of colon cancer. In our retrospective review of medical and procedural records, we may have omitted other potential confounders that could have increased the imbalance between the groups and spuriously augmented the yield of CE over WCE. Such biases can only be mitigated in prospective randomized trials. All CEs were performed by a single experienced endoscopist, and it is unclear if this can be replicated in other clinical settings. However, the CE learning curve may not be steep; in a recent study, the yield of dysplasia during CE was not different between expert and novice endoscopists following a short training course [39]. We could not make a distinction between colitis-associated and sporadic neoplasms as most patients were in endoscopic remission and the histological disease extent was not adequately documented in all cases. However, our aim was to compare the yield of CE with WLE for IBD surveillance regardless of the disease extent and there is no reason to suspect that the inclusion of sporadic lesions has introduced a bias in favor of CE.

The relatively short follow-up duration and small number of patients also limit the generalizability of our results. Chronologically, CE procedures were performed during more recent years, so a calendar-year bias cannot be excluded. In addition, 7 exams before 2008 in WLE group were performed by standard definition. Although the proportion was relative low, it could influence on the result. All pathological specimens were internally reviewed, and observer bias may be a consideration, although this should be relatively balanced between CE and WLE.

In conclusion, we demonstrated that CE has a higher detection rate for all neoplasia and particularly advanced and serrated neoplasia compared with white light, high-definition colonoscopy. The yield of random biopsies performed during either CE or WLE was extremely low, which raises serious doubts about the utility of this method for neoplasia surveillance. Although further prospective studies are necessary, CE seems to be a useful technique for neoplasia surveillance in patients with IBD.