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SCENIC update 2021: Is chromoendoscopy still standard of care for inflammatory bowel disease surveillance?

Published:November 17, 2021DOI:https://doi.org/10.1016/j.gie.2021.10.009

      Abbreviations:

      IBD (inflammatory bowel disease), NBI (narrow-band imaging), PSC (primary sclerosing cholangitis)
      Patients with inflammatory bowel diseases (IBDs) face an increased risk for colon cancer development. Recent guidelines recommend surveillance colonoscopies for patients with longstanding left-sided colitis or pancolitis and for patients with primary sclerosing cholangitis (PSC).

      Wijnands AM, Mahmoud R, Lutgens MWMD, et al. Surveillance and management of colorectal dysplasia and cancer in inflammatory bowel disease: current practice and future perspectives. Eur J Intern Med. Epub 2021 Sep 1.

      Colitis-associated neoplasia is difficult to detect during surveillance colonoscopy. The lesions are often flat and subtle and difficult to differentiate from the surrounding inflamed mucosa. Studies have shown that postcolonoscopy cancer is more common in patients with IBD than in the normal screening population.
      • Schønfeldt Troelsen F.
      • Sørensen H.T.
      • Pedersen L.
      • et al.
      Risk of a post-colonoscopy colorectal cancer diagnosis in patients with inflammatory bowel disease: a population-based cohort study.
      Chromoendoscopy was first introduced in 2003; dye staining of the entire colon with methylene blue led to a significant diagnostic increase of colitis-associated dysplasia.
      • Kiesslich R.
      • Fritsch J.
      • Holtmann M.
      • et al.
      Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.
      The technique of chromoendoscopy is quite simple. The dyes indigo carmine (0.4%) or methylene blue (0.1%) are applied onto the colonic surface with a spraying catheter. Chromoendoscopy unmasks flat lesions and the borders; in addition, the surface architecture becomes better visible. The yield of targeted biopsy specimens can be subsequently increased.
      The SCENIC guidelines, which were published in 2015, strongly recommend the use of chromoendoscopy in the performance of surveillance with standard-definition colonoscopes.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      The role of conventional chromoendoscopy with high-definition colonoscopes, the value of virtual chromoendoscopy, and the value of untargeted biopsies remained unclear.
      The current article by Rabinowitz et al
      • Rabinowitz L.G.
      • Kumta N.A.
      • Marion J.F.
      Beyond the SCENIC route: updates in chromoendoscopy and dysplasia screening in patients with inflammatory bowel disease.
      presents recent developments based on randomized trials and meta-analyses. The authors give guidance on how to update the SCENIC guideline from 2015.
      Adherence to the SCENIC guideline seems to be very low, and chromoendoscopy is not widely accepted.
      • Laine L.
      • Kaltenbach T.
      • Barkun A.
      • et al.
      SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.
      In a study by Santi et al,
      • Santi G.
      • Michetti P.
      • Froehlich F.
      • et al.
      Adherence to recommendations and quality of endoscopic colorectal cancer surveillance in long-standing ulcerative colitis.
      the guideline using chromoendoscopy was followed in only 7.4% of cases in 8 Swiss centers.
      In Japan, 541 physicians received a questionnaire about the guideline of surveillance colonoscopy in ulcerative colitis. The use of chromoendoscopy, the number of biopsy specimens, and the time intervals of surveillance were followed in <50% of received answers.
      • Shinozaki M.
      • Kobayashi K.
      • Kunisaki R.
      • et al.
      Surveillance for dysplasia in patients with ulcerative colitis: discrepancy between guidelines and practice.
      Both studies showed that chromoendoscopy is not well accepted. There are uncertainties about the technique, its clinical value, and the length of procedure.

      Value of targeted biopsies

      Targeted and untargeted biopsies are recommended for surveillance colonoscopy in ulcerative colitis. Random biopsies were proposed on the basis of old studies to reduce the number of missed colitis-associated dysplasia during colonoscopy. However, the value of random biopsies is questioned, and recommendations for its use are not based on prospective trials.
      An excellent study was carried out in 2016 in Japan.
      • Watanabe T.
      • Ajioka Y.
      • Mitsuyama K.
      • et al.
      Comparison of targeted vs random biopsies for surveillance of ulcerative colitis-associated colorectal cancer.
      First, a prospective comparison was made between targeted versus random biopsies for surveillance of colitis-associated cancer. Two hundred forty-six patients with ulcerative colitis with indication for surveillance, seen at 52 institutions in Japan, were randomly assigned to the random group (4 random biopsies performed every 10 cm in addition to targeted biopsies) or the target group (biopsy specimens collected from locations of suspected neoplasia). The primary endpoint was the number of neoplastic lesions detected in a single surveillance colonoscopy (endpoint: noninferiority).
      Significantly fewer biopsies and significantly shorter examination times in the target group led to similar numbers of colitis-associated dysplasia (11.4%) as in the random group (9.3%). In the random group, all neoplastic tissues found in random biopsy specimens were collected from areas of the mucosa with a history or presence of inflammation.
      Moussata et al
      • Moussata D.
      • Allez M.
      • Cazals-Hatem D.
      • et al.
      Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy?.
      performed 1000 surveillance colonoscopies with chromoendoscopy in patients with IBD. Targeted and untargeted biopsies were performed. Eighty-two patients with dysplasia were identified with targeted biopsies and 7 with random biopsies only. The study confirmed a low yield of random biopsy specimens. Risk factors for dysplasia in random biopsies were personal history of neoplasia, concomitant PSC, or a tubular colon during colonoscopy. Another more recent study confirmed these findings.
      • Hu A.B.
      • Burke K.E.
      • Kochar B.
      • et al.
      Yield of random biopsies during colonoscopies in inflammatory bowel disease patients undergoing dysplasia surveillance.
      Longer disease duration, active inflammation, and concomitant PSC were associated with the detection of dysplasia on random biopsy specimens.
      Rabinowitz et al
      • Rabinowitz L.G.
      • Kumta N.A.
      • Marion J.F.
      Beyond the SCENIC route: updates in chromoendoscopy and dysplasia screening in patients with inflammatory bowel disease.
      clearly make this statement, calling it SCENIC update 1: Random biopsies (in addition to targeted biopsies) should be used only in the highest-risk patients, including those with PSC, previous neoplasia, active inflammation, or a tubular, scarred colon.

      Value of conventional chromoendoscopy with high-definition colonoscopes

      The diagnostic yield of conventional chromoendoscopy was mainly investigated in studies using standard-definition colonoscopes. Three new studies have addressed the value of chromoendoscopy by using high-definition colonoscopes.

      Study 1 (2019): chromoendoscopy with targeted biopsies compared with high-definition colonoscopy with targeted and random biopsies

      Yang et al
      • Yang D.H.
      • Park S.J.
      • Kim H.S.
      • et al.
      High-definition chromoendoscopy versus high-definition white light colonoscopy for neoplasia surveillance in ulcerative colitis: a randomized controlled trial.
      performed a multicenter, prospective randomized controlled trial involving 9 tertiary teaching hospitals in South Korea. A total of 210 patients with longstanding ulcerative colitis were randomized to undergo either high-definition white-light colonoscopy with targeted or additional random biopsies or chromoendoscopy with targeted biopsies. The detection rates of colitis-associated dysplasia or all colorectal neoplasia from each trial arm were compared. Chromoendoscopy showed improved colorectal neoplasia detection compared with high-definition colonoscopy (20.6% vs 12.0%). However, this trend was not statistically significant.

      Conclusions

      The study showed a clinical meaningful higher diagnostic yield for chromoendoscopy, but the power of the study was not sufficient to show a significant difference.

      Study 2 (2020): chromoendoscopy versus high-definition colonoscopy with random and targeted biopsies in both groups

      Alexandersson et al
      • Alexandersson B.
      • Hamad Y.
      • Andreasson A.
      • et al.
      High-definition chromoendoscopy superior to high-definition white-light endoscopy in surveillance of inflammatory bowel diseases in a randomized trial.
      performed a prospective study of 305 patients with ulcerative colitis or Crohn's colitis referred for surveillance colonoscopy at a university hospital in Sweden. Patients were randomly assigned to receive high-definition chromoendoscopy with indigo carmine (chromoendoscopy) with targeted and random biopsies or high-definition colonoscopy with targeted and random biopsies. The primary endpoint was the number of patients with dysplastic lesions. Chromoendoscopy identified significantly more patients with dysplasia (11.1%) than did high-definition with light colonoscopy (4.5%).

      Conclusions

      The study showed a clear benefit for chromoendoscopy; even the total numbers of patients with colitis-associated dysplasia seemed to be low in both groups.

      Study 3 (2020): chromoendoscopy with targeted biopsies compared with high-definition colonoscopy with targeted and random biopsies and long-term follow-up

      A recent study used high-definition colonoscopes, and long-term follow-up was performed.
      • Wan J.
      • Zhang Q.
      • Liang S.H.
      • et al.
      Chromoendoscopy with targeted biopsies is superior to white-light endoscopy for the long-term follow-up detection of dysplasia in ulcerative colitis patients: a multicenter randomized-controlled trial.
      Patients were randomly assigned to 3 groups, either to high-definition colonoscopy with targeted biopsies, to targeted and random biopsies, or to chromoendoscopy with targeted biopsies only. Eleven centers in China participated in the trial, and the median follow-up time was 55 months. Annual follow-up colonoscopies were performed, always by use of the same surveillance method based on initial randomization.

      Conclusions

      Chromoendoscopy was able to identify significantly more patients with colitis-associated dysplasia. This advantage became even more prominent during the second half of follow-up time.
      The 3 studies taken together show a benefit of adding chromoendoscopy to the use of high-definition colonoscopes. All 3 studies showed higher detection rates of lesions with colitis-associated dysplasia. The Chinese study clearly highlighted the use of chromoendoscopy for subsequent follow-up colonoscopies.
      • Alexandersson B.
      • Hamad Y.
      • Andreasson A.
      • et al.
      High-definition chromoendoscopy superior to high-definition white-light endoscopy in surveillance of inflammatory bowel diseases in a randomized trial.

      Diagnostic yield of virtual chromoendoscopy

      Virtual chromoendoscopy is a simple technology wherein different light filters or postprocessing algorithms are applied by pressing a button on the colonoscope.
      • Rabbenou W.
      • Ullman T.A.
      Risk of colon cancer and recommended surveillance strategies in patients with ulcerative colitis.
      Surface and vessel architecture can be highlighted. All main endoscopic manufacturers provide virtual chromoendoscopy in conjunction with high-definition imaging. Most recently, virtual chromoendoscopy was improved by the application of filters with brighter contrast compared with first-generation virtual chromoendoscopy. First-generation virtual chromoendoscopy showed no benefit for diagnosing colitis-associated dysplasia compared with white-light endoscopy. Three more recent randomized trials have investigated the value of last-generation virtual chromoendoscopy.

      Study 1 (2018): direct comparison between virtual and conventional chromoendoscopy

      Bisshops et al
      • Bisschops R.
      • Bessissow T.
      • Joseph J.A.
      • et al.
      Chromoendoscopy versus narrow band imaging in UC: a prospective randomised controlled trial.
      performed a multicenter prospective randomized controlled trial in which 131 patients with longstanding ulcerative colitis were randomized to undergo chromoendoscopy with methylene blue 0.1% (n = 66) or virtual chromoendoscopy with narrow-band imaging (NBI) (n = 65). Biopsy specimens were taken from visible lesions and the surrounding mucosa. No random biopsies were performed. The primary outcome was the difference in total number of neoplastic lesions detected in each group. The neoplasia detection rate was not different between chromoendoscopy (21.2%) and NBI (21.5%). The total procedural time on average was 7 minutes shorter in the NBI group.

      Conclusions

      Virtual chromoendoscopy showed shorter examination times and similar diagnostic yields for colitis-associated dysplasia compared with chromoendoscopy.

      Study 2 (2018): comparison among high-definition colonoscopy, virtual chromoendoscopy, and conventional chromoendoscopy

      Iacucci et al
      • Iacucci M.
      • Kaplan G.G.
      • Panaccione R.
      • et al.
      A randomized trial comparing high definition colonoscopy alone with high definition dye spraying and electronic virtual chromoendoscopy for detection of colonic neoplastic lesions during IBD surveillance colonoscopy.
      performed a prospective randomized controlled noninferiority trial comparing high-definition colonoscopy, conventional chromoendoscopy, and virtual chromoendoscopy. The study included 270 patients. High-definition colonoscopy identified dysplasia in 25.6% of patients, conventional chromoendoscopy in 24.4%, and virtual chromoendoscopy in only 15.6%. However, virtual chromoendoscopy was not inferior to the other 2 techniques in the diagnosis of colitis-associated dysplasia.

      Conclusions

      High-definition colonoscopy and high-definition chromoendoscopy showed similar detection rates of colitis-associated dysplasia. Virtual chromoendoscopy performed less effectively, but the diagnostic yield was still within the range of this noninferiority trial.

      Study 3 (2021): virtual chromoendoscopy versus high-definition colonoscopy with random and targeted biopsies in both groups

      Kandiah et al
      • Kandiah K.
      • Subramaniam S.
      • Thayalasekaran S.
      • et al.
      Multicentre randomised controlled trial on virtual chromoendoscopy in the detection of neoplasia during colitis surveillance high-definition colonoscopy (the VIRTUOSO trial).
      performed a multioperator randomized controlled trial at 2 centers in the United Kingdom. A total of 188 patients with ulcerative or Crohn’s colitis were randomized to undergo virtual chromoendoscopy or high-definition white-light colonoscopy. Targeted and random biopsy specimens were taken in both arms of the study. The primary outcome was the difference in neoplasia detection rate between the 2 techniques. High-definition colonoscopy (24.2%) and virtual chromoendoscopy (14.9%) showed no significant difference in dysplasia detection; even so, high-definition white-light colonoscopy showed higher numbers of patients with dysplasia.

      Conclusions

      Virtual chromoendoscopy showed a clinically meaningful lower dysplasia detection rate and cannot be recommended on the basis of this trial.
      The 3 trials could not show any difference between high-definition virtual chromoendoscopy and high-definition colonoscopy alone. The combination of virtual chromoendoscopy with high-definition colonoscopy showed no increased detection rates of colitis-associated dysplasia.
      Rabinowitz et al
      • Rabinowitz L.G.
      • Kumta N.A.
      • Marion J.F.
      Beyond the SCENIC route: updates in chromoendoscopy and dysplasia screening in patients with inflammatory bowel disease.
      clearly state that white-light endoscopy, chromoendoscopy, and virtual chromoendoscopy with targeted biopsies are all acceptable modalities for surveillance when a high-definition colonoscope is used; the endoscopist should have training or expertise in dysplasia detection while using the method of choice.

      Meta-analysis

      Three meta-analyses have assessed the value of chromoendoscopy, virtual chromoendoscopy, standard-definition colonoscopy, and high-definition colonoscopy.

      Meta-analysis 1

      Nonrandomized controlled trials by Feuerstein et al
      • Feuerstein J.D.
      • Rakowsky S.
      • Sattler L.
      • et al.
      Meta-analysis of dye-based chromoendoscopy compared with standard- and high-definition white-light endoscopy in patients with inflammatory bowel disease at increased risk of colon cancer.
      demonstrated a benefit of chromoendoscopy over standard-definition and high-definition colonoscopy, whereas randomized controlled trials showed only a small benefit of chromoendoscopy over standard-definition colonoscopy but not over high-definition colonoscopy.

      Meta-analysis 2

      Gondal et al
      • Gondal B.
      • Haider H.
      • Komaki Y.
      • et al.
      Efficacy of various endoscopic modalities in detecting dysplasia in ulcerative colitis: a systematic review and network meta-analysis.
      found only small differences in the diagnostic yield between high-definition colonoscopy and high-definition chromoendoscopy, whereas standard-definition colonoscopy was inferior in detecting dysplasia in ulcerative colitis.

      Meta-analysis 3

      Resende et al
      • Resende R.H.
      • Ribeiro I.B.
      • de Moura D.T.H.
      • et al.
      Surveillance in inflammatory bowel disease: is chromoendoscopy the only way to go? A systematic review and meta-analysis of randomized clinical trials.
      determined that chromoendoscopy can detect more patients and dysplastic lesions than does standard white-light colonoscopy. Although no difference was observed between chromoendoscopy and high-definition colonoscopy or virtual chromoendoscopy, the main outcomes numerically favored dye-spraying chromoendoscopy, except in regard to procedure time.

      Summary

      There is an ongoing debate about the best technique for surveillance colonoscopy in patients with ulcerative or Crohn’s colitis. There is clear evidence for chromoendoscopy when only standard-definition colonoscopes are available. However, in recent times, high-definition endoscopy and virtual chromoendoscopy have become broadly available. Rabinowitz et al
      • Rabinowitz L.G.
      • Kumta N.A.
      • Marion J.F.
      Beyond the SCENIC route: updates in chromoendoscopy and dysplasia screening in patients with inflammatory bowel disease.
      clearly describe how new endoscopic techniques should be included.
      Conventional chromoendoscopy in conjunction with high-definition colonoscopy can still be performed. There is a clear trend for diagnosing more colitis-associated dysplasia. However, more examination time is needed, and high-definition colonoscopy with targeted biopsies seems to be the only current technique of choice according to most recent trials. Random biopsies should be added for patients with PSC, a history of colonic neoplasia, or tubular colon.
      Virtual chromoendoscopy has no added value for surveillance colonoscopy. No randomized study showed a benefit of virtual chromoendoscopy over with high-definition colonoscopy alone or high-definition chromoendoscopy.
      Better visualization leads to better demarcation of colitis-associated dysplasia. New resection techniques like endoscopic submucosal dissection offer new options for IBD patients. It is clearly recommended that dysplastic lesions be completely removed and that no synchronous dysplastic lesion be left in place.
      • Rabinowitz L.G.
      • Kumta N.A.
      • Marion J.F.
      Beyond the SCENIC route: updates in chromoendoscopy and dysplasia screening in patients with inflammatory bowel disease.
      There is not enough evidence to clearly specify the best interval for surveillance in these high-risk patients, especially those with high-grade or multifocal dysplasia. However, these patients are at increased cancer risk and need the highest-quality surveillance in centers with high experience in advanced imaging techniques.

      Disclosure

      The author disclosed no financial relationships.

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      Linked Article

      • Beyond the SCENIC route: updates in chromoendoscopy and dysplasia screening in patients with inflammatory bowel disease
        Gastrointestinal EndoscopyVol. 95Issue 1
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          Patients with Crohn’s disease affecting the colon and ulcerative colitis are known to be at increased risk for the development of dysplasia and colorectal cancer (CRC).1,2 Unlike patients with sporadic CRC, patients with longstanding inflammatory bowel disease (IBD) who develop malignancy do so through different pathophysiologic mechanisms and with foreshortened time frames.3,4 Furthermore, the gross appearance of dysplasia exhibits greater morphologic range in IBD patients, with subtler, flat lesions being commonplace.
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