IBD-Associated Dysplastic Lesions Show More Chromosomal Instability Than Sporadic Adenomas.

BACKGROUND: Patients with longstanding inflammatory bowel disease (IBD; ie, ulcerative colitis and Crohn's disease) have an increased risk of colorectal cancer (CRC). Due to ongoing inflammation, IBD-associated dysplastic lesions can develop. These lesions have an increased risk to progress to cancer compared with sporadic adenomas, which are also found in these patients. Differentiating between these 2 types of dysplasia remains challenging, both clinically and histologically, while treatment strategies may differ. Therefore, the aim of this study was to investigate molecular alterations associated with colorectal dysplasia to cancer progression in IBD and evaluate to what extent these alterations differ from sporadic adenomas. METHODS: DNA copy number aberrations and mutation analyses of 48 genes were performed by next-generation sequencing in 43 IBD-associated dysplastic lesions, 30 of which were dysplastic and 13 of which were cancers. Results were compared with existing DNA copy number and mutation data from 118 sporadic adenomas and 24 sporadic cancers. RESULTS: Inflammatory bowel disease-associated dysplastic lesions harbor patterns of DNA copy number aberrations comparable to carcinomas, which are rare in sporadic adenomas. TP53 mutation was the most frequent mutation observed in IBD-associated dysplastic lesions and in cancers. FBXW7 was mutated significantly more often in IBD-associated dysplastic lesions than in sporadic adenomas. CONCLUSIONS: Inflammatory bowel disease-associated dysplastic lesions show more DNA copy number aberrations than sporadic adenomas. TP53 and FBXW7 mutations appear to be involved in the development of IBD-associated dysplastic lesions and cancer. These findings indicate that IBD-associated dysplastic lesions are more genomically unstable, possibly reflecting a faster progression toward cancer.

CD31-positive microvessel density within adenomas of Lynch Syndrome patients is similar compared to adenomas of non-Lynch patients.

Background and study aims Microsatellite instability accelerates colorectal cancer development in patients with Lynch syndrome (LS). Previous research showed that virtual chromoendoscopy increases detection of adenomas during colonoscopy surveillance of patients with LS. Because previous research revealed that Lynch patients have an increased vascular network in the oral mucosa, we hypothesized that increased vascularization of LS-associated adenomas is the cause of better detection with virtual chromoendoscopy. Patients and methods In this pilot study, patients with LS having a proven germline mutation were selected from two tertiary referral hospitals and non-LS patients from an outpatient colonoscopy center. Adenomas from patients with LS were exactly matched in size and histology with adenomas from non-LS patients. Initial adenoma diagnosis was confirmed by a specialist pathologist. All adenomas were stained with CD31 and adenomatous tissue was annotated by the specialist pathologist. Image analysis of CD31-positive microvessel density was conducted using FIJI software. Results Colonoscopy of 63 patients with LS and 24 non-LS patients provided 40 adenomas that could be exactly matched in size and histology. In image-analysis, the CD31-positive microvessel density (2.49 % vs. 2.47 %, P  = 0.96), the average size of CD31-positive structures (514 µm 2 vs. 523 µm 2 , P  = 0.26) nor the amount of vascular structures per mm 2 (183 vs. 176, P  = 0.50) differed between adenomas of LS patients and non-Lynch patients. Conclusion The outcomes of this pilot case-control study did not provide further insights into the mechanism of increased adenoma detection in LS patients using virtual chromoendoscopy techniques.

Diagnostic Accuracy of Endoscopic Trimodal Imaging and Chromoendoscopy for Lesion Characterization in Ulcerative Colitis.

BACKGROUND: During surveillance colonoscopy of patients with long-standing ulcerative colitis [UC], a variety of dysplastic and non-dysplastic lesions are detected. The aim of this study was to address the diagnostic accuracy of endoscopic characterization of endoscopic trimodal imaging [ETMI] and chromoendoscopy [CE]. ETMI includes the combination of autofluorescence imaging [AFI], narrow band imaging [NBI] and white light endoscopy [WLE]. METHODS: This is a pre-specified additional analysis of a multi-centre, randomized controlled trial that compared AFI with CE for dysplasia detection in 210 patients with long-standing UC [FIND-UC trial]. In the AFI arm, endoscopists used the ETMI system to record AFI colour, Kudo pit pattern using NBI and WLE for lesion characterization. For AFI, purple colour and ambiguous colour combined with pit pattern type III-V on NBI was considered dysplastic. Kudo pit pattern was described in the CE arm. For pit pattern description using NBI and CE, type III-V was considered dysplastic. Histology was the reference standard. RESULTS: In total, 52 dysplastic and 255 non-dysplastic lesions were detected. Overall sensitivity for real-time prediction of dysplasia was 76.9% (95% confidence interval [CI] 46.2-95.0) for ETMI, and 81.6% [95% CI 65.7-92.3] for CE. Overall negative predictive value [NPV] for ETMI was 96.9% [95% CI 92.0-98.8] and 94.7% [90.2-97.2] for CE. CONCLUSIONS: Sensitivity for endoscopic differentiation of dysplastic lesions detected during surveillance of patients with long-standing UC seems limited using ETMI and CE. Future research is warranted as the high NPV indicates that these techniques are valuable for the exclusion of dysplastic lesions [NTR4062].

Chromoendoscopy versus autofluorescence imaging for neoplasia detection in patients with longstanding ulcerative colitis (FIND-UC): an international, multicentre, randomised controlled trial.

BACKGROUND: Patients with longstanding ulcerative colitis undergo regular dysplasia surveillance because they have an increased colorectal cancer risk. Autofluorescence imaging and chromoendoscopy improve dysplasia detection. The aim of this study was to determine whether autofluorescence imaging should be further studied as an alternative method for dysplasia surveillance in patients with longstanding ulcerative colitis. METHODS: This prospective, international, randomised controlled trial included patients from an ulcerative colitis-dysplasia surveillance cohort from five centres in the Netherlands and the UK. Eligible patients were aged 18 years or older who were undergoing dysplasia surveillance after being diagnosed with extensive colitis (Montreal E3) at least 8 years before study start or with left-sided colitis (Montreal E2) at least 15 years before study start. Randomisation (1:1) was minimised for a previous personal history of histologically proven dysplasia and concomitant primary sclerosing cholangitis. The coprimary outcomes were the proportion of patients in whom at least one dysplastic lesion was detected and the mean number of dysplastic lesions per patient. The relative dysplasia detection rate, calculated as the ratio of the detection rates by autofluorescence imaging and chromoendoscopy, needed to be more than 0·67 (using an 80% CI) for both primary outcomes to support a subsequent large non-inferiority trial. Outcomes were analysed on a per-protocol basis. The trial is registered at the Netherlands Trial Register, number NTR4062. FINDINGS: Between Aug 1, 2013, and March 10, 2017, 210 patients undergoing colonoscopy surveillance for longstanding ulcerative colitis were randomised for inspection with either autofluorescence imaging (n=105) or chromoendoscopy (n=105). Dysplasia was detected in 13 (12%) patients by autofluorescence imaging and in 20 patients (19%) by chromoendoscopy. The relative dysplasia detection rate of autofluorescence imaging versus chromoendoscopy for the proportion of patients with ulcerative colitis with at least one dysplastic lesion was 0·65 (80% CI 0·43-0·99). The mean number of detected dysplastic lesions per patient was 0·13 (SD 0·37) for autofluorescence imaging and 0·37 (1·02) for chromoendoscopy (relative dysplasia detection rate 0·36, 80% CI 0·21-0·61). Adverse events were reported for two patients in the autofluorescence imaging group (one patient had intraprocedural mild bleeding, and one patient had abdominal pain) and for three patients in the chromoendoscopy group (two patients had intraprocedural mild bleeding, and one patient had perforation). INTERPRETATION: Autofluorescence imaging did not meet criteria for proceeding to a large non-inferiority trial. Therefore, existing autofluorescence imaging technology should not be further investigated as an alternative dysplasia surveillance method. FUNDING: Olympus Europe and Olympus Keymed.

Effects of Training and Feedback on Accuracy of Predicting Rectosigmoid Neoplastic Lesions and Selection of Surveillance Intervals by Endoscopists Performing Optical Diagnosis of Diminutive Polyps.

BACKGROUND & AIMS: Real-time differentiation of diminutive polyps (1-5 mm) during endoscopy could replace histopathology analysis. According to guidelines, implementation of optical diagnosis into routine practice would require it to identify rectosigmoid neoplastic lesions with a negative predictive value (NPV) of more than 90%, using histologic findings as a reference, and agreement with histology-based surveillance intervals for more than 90% of cases. METHODS: We performed a prospective study with 39 endoscopists accredited to perform colonoscopies on participants with positive results from fecal immunochemical tests in the Bowel Cancer Screening Program at 13 centers in the Netherlands. Endoscopists were trained in optical diagnosis using a validated module (Workgroup serrAted polypS and Polyposis). After meeting predefined performance thresholds in the training program, the endoscopists started a 1-year program (continuation phase) in which they performed narrow band imaging analyses during colonoscopies of participants in the screening program and predicted histological findings with confidence levels. The endoscopists were randomly assigned to groups that received feedback or no feedback on the accuracy of their predictions. Primary outcome measures were endoscopists' abilities to identify rectosigmoid neoplastic lesions (using histology as a reference) with NPVs of 90% or more, and selecting surveillance intervals that agreed with those determined by histology for at least 90% of cases. RESULTS: Of 39 endoscopists initially trained, 27 (69%) completed the training program. During the continuation phase, these 27 endoscopists performed 3144 colonoscopies in which 4504 diminutive polyps were removed. The endoscopists identified neoplastic lesions with a pooled NPV of 90.8% (95% confidence interval 88.6-92.6); their proposed surveillance intervals agreed with those determined by histologic analysis for 95.4% of cases (95% confidence interval 94.0-96.6). Findings did not differ between the group that did vs did not receive feedback. Sixteen endoscopists (59%) identified rectosigmoid neoplastic lesions with NPVs greater than 90% and selected surveillance intervals in agreement with those determined from histology for more than 90% of patients. CONCLUSIONS: In a prospective study following a validated training module, we found that a selected group of endoscopists identified rectosigmoid neoplastic lesions with pooled NPVs greater than 90% and accurately selected surveillance intervals for more than 90% of patients over the course of 1 year. Providing regular interim feedback on the accuracy of neoplastic lesion prediction and surveillance interval selection did not lead to differences in those endpoints. Monitoring is suggested, as individual performance varied. ClinicalTrials.gov no: NCT02516748; Netherland Trial Register: NTR4635.

Limited applicability of chromoendoscopy-guided confocal laser endomicroscopy as daily-practice surveillance strategy in Crohn's disease.

BACKGROUND AND AIMS: Patients with longstanding ulcerative colitis have an increased risk for developing colorectal cancer (CRC). Although the risk for ulcerative colitis is well-established, for Crohn's disease data are contradictory. This study aimed to determine the number of patients with Crohn's disease with dysplasia who are undergoing surveillance and to assess the diagnostic accuracy of chromoendoscopy (CE) combined with integrated confocal laser endomicroscopy (iCLE) for differentiating dysplastic versus nondysplastic lesions. METHODS: Patients with longstanding Crohn's colitis undergoing surveillance colonoscopy were included in this multicenter, prospective, cohort study. Surveillance was performed with CE, and lesions were assessed with iCLE for differentiation. All lesions were removed and sent for pathology as the reference standard. RESULTS: Between 2010 and 2014, a total of 61 patients with Crohn's colitis were included in 5 centers. Seventy-two lesions, of which 7 were dysplastic, were detected in 6 patients (dysplasia detection rate 9.8%); none included high-grade dysplasia or cancer. Combined CE with iCLE for differentiating neoplastic from nonneoplastic lesions had accuracy of 86.7% (95% confidence interval [CI], 78.1-95.3), sensitivity of 42.9% (95% CI, 11.8-79.8), and specificity of 92.4% (95% CI, 80.9-97.6). For CE alone, this was 80.3% (95% CI, 70.7-89.9), 28.6% (95% CI, 5.1-69.7), and 86.4% (95% CI, 80.9-97.6). The study terminated early because of frequent failure of the endoscopic equipment. CONCLUSIONS: This study shows a low incidence of dysplastic lesions found during surveillance colonoscopy in patients with longstanding extensive Crohn's colitis. The accuracy of both CE alone and CE in combination with iCLE was relatively good, although the sensitivity for both was poor. Because of frequent equipment failure, iCLE has limited applicability in daily practice as a surveillance strategy.

Low interobserver agreement among endoscopists in differentiating dysplastic from non-dysplastic lesions during inflammatory bowel disease colitis surveillance.

OBJECTIVES: During endoscopic surveillance in patients with longstanding colitis, a variety of lesions can be encountered. Differentiation between dysplastic and non-dysplastic lesions can be challenging. The accuracy of visual endoscopic differentiation and interobserver agreement (IOA) has never been objectified. MATERIAL AND METHODS: We assessed the accuracy of expert and nonexpert endoscopists in differentiating (low-grade) dysplastic from non-dysplastic lesions and the IOA among and between them. An online questionnaire was constructed containing 30 cases including a short medical history and an endoscopic image of a lesion found during surveillance employing chromoendoscopy. RESULTS: A total of 17 endoscopists, 8 experts, and 9 nonexperts assessed all 30 cases. The overall sensitivity and specificity for correctly identifying dysplasia were 73.8% (95% confidence interval (CI) 62.1-85.4) and 53.8% (95% CI 42.6-64.7), respectively. Experts showed a sensitivity of 76.0% (95% CI 63.3-88.6) versus 71.8% (95% CI 58.5-85.1, p = 0.434) for nonexperts, the specificity 61.0% (95% CI 49.3-72.7) versus 47.1% (95% CI 34.6-59.5, p = 0.008). The overall IOA in differentiating between dysplastic and non-dysplastic lesions was fair 0.24 (95% CI 0.21-0.27); for experts 0.28 (95% CI 0.21-0.35) and for nonexperts 0.22 (95% CI 0.17-0.28). The overall IOA for differentiating between subtypes was fair 0.21 (95% CI 0.20-0.22); for experts 0.19 (95% CI 0.16-0.22) and nonexpert 0.23 (95% CI 0.20-0.26). CONCLUSION: In this image-based study, both expert and nonexpert endoscopists cannot reliably differentiate between dysplastic and non-dysplastic lesions. This emphasizes that all lesions encountered during colitis surveillance with a slight suspicion of containing dysplasia should be removed and sent for pathological assessment.

Quality of colonoscopy and advances in detection of colorectal lesions: a current overview.

Colonoscopy is the gold standard for the detection of colorectal cancer and its precursors. Nevertheless multiple studies have demonstrated a significant miss-rate for polyps and, more importantly, demonstrated the occurrence of interval cancers in the years after colonoscopy. This imperfect protection against colorectal cancer can be explained by multiple factors related to both the endoscopist and the equipment. To ensure the quality of colonoscopy, several quality indicators have been described. These include bowel preparation, cecal intubation rate, withdrawal time, adenoma detection rate and complication rate. Measurement of these quality indicators, followed by awareness, benchmarking and additional training will hopefully optimize daily practice. If these basic quality parameters are well taken care of, advanced colonoscopic techniques will aim at further increasing the detection and differentiation of colonic lesions. In this review, the authors discuss the literature on quality indicators for colonoscopy and give a comprehensive overview of the advanced colonoscopic techniques currently available.

Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis.

BACKGROUND & AIMS: American and European guidelines propose complete endoscopic resection of polypoid dysplasia (adenomas or adenoma-like masses) in patients with longstanding colitis, with close endoscopic follow-up. The incidence of cancer after detection of flat low-grade dysplasia or dysplasia-associated lesion or mass is estimated at 14 cases/1000 years of patient follow-up. However, the risk for polypoid dysplasia has not been determined with precision. We investigated the risk of cancer after endoscopic resection of polypoid dysplasia in patients with ulcerative colitis. METHODS: MEDLINE, EMBASE, PubMed, and the Cochrane library were searched for studies of patients with colitis and resected polypoid dysplasia, with reports of colonoscopic follow-up and data on cancers detected. Outcomes from included articles were pooled to provide a single combined estimate of outcomes by using Poisson regression. RESULTS: Of 425 articles retrieved, we analyzed data from 10 studies, comprising 376 patients with colitis and polypoid dysplasia with a combined 1704 years of follow-up. A mean of 2.8 colonoscopies were performed for each patient after the index procedure (range, 0-15 colonoscopies). The pooled incidence of cancer was 5.3 cases (95% confidence interval, 2.7-10.1 cases)/1000 years of patient follow-up. There was no evidence of heterogeneity or publication bias. The pooled rate of any dysplasia was 65 cases (95% confidence interval, 54-78 cases)/1000 patient years. CONCLUSION: Patients with colitis have a low risk of colorectal cancer after resection of polypoid dysplasia; these findings support the current strategy of resection and surveillance. However, these patients have a 10-fold greater risk of developing any dysplasia than colorectal cancer and should undergo close endoscopic follow-up.

Diagnostic performance of narrowed spectrum endoscopy, autofluorescence imaging, and confocal laser endomicroscopy for optical diagnosis of colonic polyps: a meta-analysis.

BACKGROUND: Novel endoscopic technologies could allow optical diagnosis and resection of colonic polyps without histopathological testing. Our aim was to establish the sensitivity, specificity, and real-time negative predictive value of three types of narrowed spectrum endoscopy (narrow-band imaging [NBI], image-enhanced endoscopy [i-scan], and Fujinon intelligent chromoendoscopy [FICE]), confocal laser endomicroscopy (CLE), and autofluorescence imaging for differentiation between neoplastic and non-neoplastic colonic lesions. METHODS: We identified relevant studies through a search of Medline, Embase, PubMed, and the Cochrane Library. Clinical trials and observational studies were eligible for inclusion when the diagnostic performance of NBI, i-scan, FICE, autofluorescence imaging, or CLE had been assessed for differentiation, with histopathology as the reference standard, and for which a 2 × 2 contingency table of lesion diagnosis could be constructed. We did a random-effects bivariate meta-analysis using a non-linear mixed model approach to calculate summary estimates of sensitivity and specificity, and plotted estimates in a summary receiver-operating characteristic curve. FINDINGS: We included 91 studies in our analysis: 56 were of NBI, ten of i-scan, 14 of FICE, 11 of CLE, and 11 of autofluorescence imaging (more than one of the investigated modalities assessed in eight studies). For NBI, overall sensitivity was 91·0% (95% CI 88·6-93·0), specificity 85·6% (81·3-89·0), and real-time negative predictive value 82·5% (75·4-87·9). For i-scan, overall sensitivity was 89·3% (83·3-93·3), specificity 88·2% (80·3-93·2), and real-time negative predictive value 86·5% (78·0-92·1). For FICE, overall sensitivity was 91·8% (87·1-94·9), specificity 83·5% (77·2-88·3), and real-time negative predictive value 83·7% (77·5-88·4). For autofluorescence imaging, overall sensitivity was 86·7% (79·5-91·6), specificity 65·9% (50·9-78·2), and real-time negative predictive value 81·5% (54·0-94·3). For CLE, overall sensitivity was 93·3% (88·4-96·2), specificity 89·9% (81·8-94·6), and real-time negative predictive value 94·8% (86·6-98·1). INTERPRETATION: All endoscopic imaging techniques other than autofluorescence imaging could be used by appropriately trained endoscopists to make a reliable optical diagnosis for colonic lesions in daily practice. Further research should be focused on whether training could help to improve negative predictive values. FUNDING: None.