COMMENTARIES The SCENIC Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease: Praise and Words of Caution See Laine L et al on page 639.
N
early a century after Rosenberg and Crohn recognized the occurrence of colorectal cancer (CRC) in ulcerative colitis,1 our understanding of how best to prevent this lethal complication of inflammatory bowel disease (IBD) continues to confound practitioners and disconcert patients. A profusion of recommendations about the best means to perform surveillance for dysplasia, and how best to manage it once found, has led to considerable discord and confusion. Published simultaneously in this month’s issues of Gastroenterology2 and Gastrointestinal Endoscopy,3 the SCENIC consensus statement (Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations) hopes to bring some order to this chaotic scene. SCENIC covers a range of topics in screening and surveillance for dysplasia in colitis and addresses, head on, several areas of contention with a deliberate thoroughness and an excellent summary of the available data. Central to the statements contained in SCENIC is the placement of chromoendoscopy (CE) as the preferred technique for surveillance for dysplasia in IBD. SCENIC provides a comprehensive summary of the available data underlying this core recommendation, and may have an important impact on the field. However, it is our belief that many practical issues and the lack of longitudinal data on CE as Gastroenterology 2015;148:462–467
the basis of colon cancer surveillance in IBD limit the acceptability of SCENIC as the standard of care at this time.
A Brief History of Surveillance Colonoscopy for IBD The progression of molecular events causing sporadic CRC has been well elucidated, and informs, to some degree, our knowledge of CRC complicating IBD. In sporadic CRC, the progression begins with mutation of APC and the accumulation of b-catenin to induce hyperplastic epithelium, followed by K-ras mutation and adenoma formation, and finally culminating in CRC with mutation of p53 or Deleted in Colorectal Carcinoma (DCC) proteins.4 This predictable adenoma–carcinoma sequence, occurring over a 7- to 10year timeframe, and the polypoid nature of the majority of dysplasia, have been the basis of colonoscopic screening for sporadic CRC, with identification and removal of adenomas leading to a reduction in CRC incidence and mortality.5 The pathogenesis of CRC in IBD is less certain, but it is believed that lowand high-grade dysplasia and cancer are a consequence of the cytokine milieu and free radicals associated with inflammation creating, or being superimposed upon, molecular alterations.6 Although many of the causative genetic alterations are the same as in sporadic CRC, they seem to occur in a different sequence, with p53 mutated early and APC and GSK3b mutations occurring late and over a shorter timeframe.4 Consequently, the morphologic features of CRC in IBD are also more varied; more often serrated or flatter, and often multifocal, perhaps because the ongoing stimulus of inflammation affects broad swaths of mucosa. Such temporal and morphologic considerations have led to the accepted practice of surveillance colonoscopy with numerous (33) random biopsies every 1–2 years in IBD patients at increased risk for CRC as the cornerstone of cancer prevention in IBD. The goal of such a surveillance program is to
identify patients with dysplasia, for whom colectomy would avoid cancer (Figure 1). Data gathered retrospectively in the 1990s found that highgrade dysplasia was associated with a very high risk of synchronous CRC, and even flat, low-grade dysplasia found on random biopsies had a risk of concurrent advanced neoplasia (high-grade dysplasia or cancer) as high as 23.5%.8 IBD patients over the last few decades have been subjected to countless colonoscopies and random biopsies in the name of CRC prevention. This labor and resource-intensive effort notwithstanding, the efficacy of surveillance colonoscopy in IBD is difficult to demonstrate. Some population-based studies, such as a recent report from Copenhagen County, Denmark, demonstrate a decreasing incidence of CRC in IBD patients over the last few decades,9 but a recent study in a closed health maintenance organization (HMO) in Northern California continued to find excess CRC incidence and mortality in patients with IBD,10 in concordance with findings from Olmsted County, Minnesota.11 Notably, data from the same HMO in Northern California found adoption of surveillance colonoscopy in at-risk IBD patients to be low,12 although it is uncertain to what degree this deficit is driven by patient preferences or physician practices. However, even with robust adoption of a program of surveillance colonoscopy in IBD patients, cancer prevention is imperfect. At 1 tertiary medical center where such a program has been in place for 3 decades, the cumulative incidence of CRC at 30 years of disease was 7.6%.13 Disturbingly, 16 of 30 cancers found were interval cancers, albeit using lower resolution colonoscopic technology available in the 1970s and 1980s.13 Such findings highlight the limitations of surveillance programs for CRC in IBD. Resignation among gastroenterologists about random biopsy owing to low yields and poor evidence has grown into cynicism about the value of the American Gastroenterological Association guidelines as the technique continues to be touted as the standard of good practice.14,15 At the same time,
COMMENTARIES
Figure 1.Natural history of dysplasia in inflammatory bowel disease (IBD) and endoscopic screening by low- and highresolution methods. Adapted with permission from Egger M et al.7
463
COMMENTARIES our patients have grown increasingly fearful over our uncertainty in this area.16 The basic tenet of surveillance for dysplasia by random biopsy—that dysplasia is often not accompanied by visible mucosal abnormalities—has been increasingly disputed.17,18 This tenet was likely true at the inception of surveillance programs, when fiberoptic colonoscopy was performed, but endoscopic technology has progressed considerably over the last 3 decades. Standard definition colonoscopy using CCD video chips improved the sensitivity of colonoscopy for visual identification of dysplasia, likely further enhanced by the adoption of highdefinition colonoscopy. The growing recognition that colonic dysplasia and neoplasia can be visualized most often has also led to the recommendation that if complete endoscopic resection of the dysplastic focus can be achieved, intensified surveillance may continue to avoid colectomy.14,19,20 This management strategy is consistent with patient preferences. Available evidence suggests that patients do not wish to consider colectomy until there is a relatively high certainty of cancer.21 At the same time, the adjunctive technique of CE was introduced over the last decade as a means of more sensitive detection of dysplasia in the setting of colitis.22,23 The technique had originally been introduced to the United States by Japanese investigators for the detection of smaller, flatter lesions in noncolitis patients 30 years ago. The importance of these lesions is still being debated in the noncolitis setting as well, and CE has not caught on, despite evidence showing that detection of these lesions was enhanced.24,25 Multiple cross-sectional studies have shown CE to be more sensitive than standard definition white-light examination in detection of colonic dysplasia in IBD, with fewer biopsies.26 Despite this robust evidence, CE has not yet been widely adopted in the United States, but has gained some acceptance in the UK and Europe. Several reasons for lack of adoption in the United States include initial confusion about whether new, higher resolution or zoom lens equipment used in the European trials was required. Several of the studies 464
paired CE with endomicroscopy, which left many wondering if they should wait for the next technological advance. Simultaneous to these early CE reports, virtually every American endoscopy suite transitioned to higher definition and narrow-band imaging capable equipment, so many awaited confirmation that these technologies would work as well as CE. Furthermore, the first American study demonstrating the efficacy of CE using standard equipment was not published until 200827 and, unlike the UK and European GI societies, more recent US-based position statements continued to champion random biopsy technique.14 Finally, other barriers, such as concerns about the mess related to dye use, the cost and lack of confidence about interpreting the blue landscape, led many gastroenterologists to simply refer the patients in whom they had found dysplasia to academic centers where a “chromo expert” could confirm their finding. The SCENIC consensus statement notes correctly that CE is the most sensitive modality for detection of dysplasia in colitis, and the data support their contention that CE should be considered the preferred method of detecting dysplasia in IBD. However, optimizing a cancer surveillance program is not solely about choosing the most sensitive technology. A wellconceived, effective surveillance program should incorporate appropriate definitions of the population at risk, and
risk stratification that takes into account clinical factors and prior surveillance findings; should address the accuracy of detection, which includes not only the limitations of the technique and technology but of operatordependent factors, including the skill of the endoscopist in accurately recognizing abnormalities and the ability of the pathologist to correctly identify and grade dysplasia; should address the operational aspects of implementation in real-world practice; and should consider the outcomes, both positive and negative, of the response to the detection of dysplasia, which may include intensified surveillance, endoscopic resection, or colectomy. In addition, a successful program will account for the patient’s willingness to undergo repeated, timely examinations and to comply fully with a bowel preparation. Unfortunately, the current state of practice and deficits in the evidence base make the broader aspirational aspects of SCENIC impractical and unproven as a standard of care in 2015, with many challenges remaining (Table 1). Consolidation of the progress made in this area will be needed to achieve that standard. The nature of dysplasia found by CE is different than in the historical studies of dysplasia with white light endoscopy: more numerous, smaller, flatter. Although multiple studies confirm the heightened sensitivity of CE in detecting dysplastic foci, the natural history of
Table 1.Challenges in Chromoendoscopy for Colitis Surveillance Operator barriers Training of fellows, gastroenterologists, nurses, and staff Unknown learning curve Identifying clinically relevant lesions Pathologist interobserver variability in identifying and grading dysplasia Varying endoscopists’ skill in managing or resecting found dysplasia Operational barriers Availability of dye, equipment Billing and reimbursement Time requirement Prep quality Confounding of findings by inflammation Patients’ willingness to undergo repeated, timely exams Knowledge barriers Uncertain natural history of dysplasia detected by CE Lack of well-defined population at risk Lack of risk stratification Uncertain implications of prior surveillance findings for management Uncertainty of appropriate surveillance intervals
COMMENTARIES these lesions is poorly understood. The benefits of clearing the colon of dysplasia by CE may be real, but only limited longitudinal data have been reported.28 It is important to keep in mind, however, that screening data (ability to detect dysplasia in an index colonoscopy) is not the same as longitudinal surveillance data. The belief is that this more sensitive test will identify important lesions: If more dysplasia and earlier stages of cancer are detected during surveillance, then one assumes that additional colons and lives will be spared. Proving this belief will be challenging. Randomized, controlled trials to prove the efficacy of CE in preventing cancer seem impractical. In addition, future longitudinal cohorts assessing the efficacy of CE-based cancer surveillance in IBD may be subject to a number of biases that will make outcomes difficult to interpret. These include possible contributions of healthy screener bias (wherein healthier patients are more likely to be screened), lead time bias (in which the more sensitive test of CE detects dysplasia much earlier than a less sensitive test, but may have no real effect on survival time, but instead lengthens the time of follow-up), and length time bias (an effect of more sensitive screening detecting more slowly progressing dysplasia, with less sensitive screening tending to find more rapidly progressing tumors, conferring the appearance that more sensitive screening picks up dysplasia when it is less dangerous, whereas actually it is simply that less dangerous dysplasia is more likely to be detected by the more sensitive method.) These considerations raise the possibility that CE surveillance in IBD may find itself in a situation similar to breast and prostate cancer screenings, where overdiagnosis has become a real issue.29 Surveillance by CE should be shown to improve outcomes, not just provide earlier detection. Anecdotally, our experience is that, when colectomy is done because of increased dysplasia detection using CE (as opposed to white light endoscopy), cancers do not seem to be found. The issue for the gastroenterologist remains the same as 30 years
ago: What does a positive result truly portend and how do we advise our patients to act on them? Other issues are of a more practical nature. If we are to incorporate formally, for the first time, a dye spray protocol as standard of care into our endoscopy suites, we must face the challenges it will impose upon our physicians, staff, and patients. Of course, spraying dye is not difficult and staff can be easily trained on preparation of dye spray, but a sense of increasing time pressure on the part of endoscopists might discourage adoption. In addition, many technical aspects that are emphasized by clinical studies of CE are addressed only briefly in SCENIC. How precisely should CE be performed? Two passes of the scope or one? White light endoscopy plus CE or CE alone? If the blue dye method is superior, then why bother with a white-light examination? Should nontargeted, random biopsies be taken in addition to targeted biopsies directed by CE? The utility of nontargeted biopsies is questioned in the introduction to SCENIC, but the consensus statement does not recommend abandoning this cumbersome technique. Nevertheless, a subtype of low-grade dysplasia called “incomplete goblet cell maturation” has been recognized recently, in which crypt architecture and white light endoscopy appearance are normal, but there is cellular dysplasia.29 It is not known if this type of dysplasia is visible with CE, and the natural history is yet unknown. Most important, lesion characterization by CE requires visual training. Data suggest such training is also not difficult, but requires broad implementation if it is to be adopted widely. For both fellowship and postfellowship training, and as with all new methods, standards for competence need to be established. It is also our experience that learning CE provides unexpected benefits for the endoscopist. Once the endoscopist’s eye has been trained by CE to see subtle lesions, such lesions are more readily noticed during white light endoscopy. A similar learning effect for adenoma detection has been reported with narrow band imaging in screening for sporadic CRC.30
Clinical Implications of Finding Dysplasia on CE As noted, multiple lines of evidence suggest that finding dysplasia no longer necessitates surgery in all patients. SCENIC correctly focuses on endoscopic resectability of the dysplastic focus. Implicit as well is the ability to survey sensitively for new/ additional foci after an index occurrence of dysplasia in the high-risk patient. Because the published data are limited to index screening, however, surveillance examination intervals cannot be extrapolated easily using current evidence. Once elucidated, it may be possible and safe to prevent unnecessary colectomy in the setting of dysplasia. Here, the skill of the endoscopist will play an enormous role. If dysplasia identified using CE can be safely managed endoscopically using polypectomy, endoscopic mucosal resection, or ablation, then colectomy might be delayed or avoided in some patients. The greater sensitivity of CE may move us toward a model similar to Barrett’s surveillance, with preservation of the esophagus made possible by new modes of ablation/resection of dysplasia and even cancer. However, studies of these endoscopically managed patients, despite being hampered by lack of long-term follow-up, already indicate a markedly increased risk of future cancer.20 Until better data are available to guide us on the long-term follow-up of dysplasia discovered by CE, controversy on this aspect of chromoendoscopic surveillance will likely persist. The SCENIC consensus panel was convened and supported by an informed group of patient advocates out of concern that the current surveillance guidelines were not protecting patients with colitis from dying of CRC. The SCENIC panel is correct: The current surveillance recommendations are onerous and imperfect. The need for progress in managing dysplasia in colitis is unmistakable. There are few more noble motivations in medicine than preventing cancer and saving lives. Many of these recommendations seem reasonable enough, but seeming reasonable is simply not enough to guide us and our patients in clinical 465
COMMENTARIES decisions. Will these recommendations accomplish the goals of keeping our patients safe from cancer or unnecessary surveillance (and its potential complications) or surgery?
4.
Future Directions
5.
The SCENIC consensus statement is best viewed as a springboard for further understanding of the natural history of dysplasia in colitis. If the SCENIC recommendations are put into widespread practice, we must mobilize to track dysplasia on a much larger scale. Over time, much will be learned with regard to the clinical implications of dysplasia found by CE and many of the gaps in the SCENIC guidelines can eventually be closed. It will be critical to learn how to risk-stratify patients, how to manage dysplasia once it has been found, and how to set appropriate screening intervals. In addition, new and potentially more sensitive detection modalities, which may even be personalized based on familial genetic risks, are likely to be forthcoming. Eventually, stool DNA testing or other technology may either enhance or supplant endoscopy-based screening and surveillance for CRC in IBD.31 Until then, longitudinal studies exploring not only outcomes, but also variations in follow-up and management, are needed. JAMES F. MARION BRUCE E. SANDS Dr Henry D. Janowitz Division of Gastroenterology Icahn School of Medicine at Mount Sinai New York, New York
6.
7.
8.
9.
10.
11.
References 1. Crohn BB, Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis (non-specific). Am J Med Sci 1925;170:220–227. 2. 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. 3. Laine L, Kaltenbach T, Barkun A, et al. SCENIC International consensus statement on surveillance and management of dysplasia in
466
12.
13.
14.
inflammatory bowel disease. Gastrointest Endosc 2015;64:489–501. Foersch S, Neurath MF. Colitisassociated neoplasia: molecular basis and clinical translation. Cell Mol Life Sci 2014;71:3523–3535. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012;366:687–696. Cooks T, Pateras IS, Tarcic O, et al. Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammationassociated colorectal cancer. Cancer Cell 2013;23:634–646. Egger M, Zwahlen M, Cerny T. [Cancer screening - principles, evaluation and implementation]. Ther Umsch 2013;70:195–203. Ullman T, Croog V, Harpaz N, et al. Progression of flat lowgrade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003; 125:1311–1319. Jess T, Simonsen J, Jorgensen KT, et al. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology 2012;143:375–381 e371; quiz e313–374. Herrinton LJ, Liu L, Levin TR, et al. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology 2012;143:382–389. Jess T, Loftus EV Jr, Velayos FS, et al. Incidence and prognosis of colorectal dysplasia in inflammatory bowel disease: a populationbased study from Olmsted County, Minnesota. Inflamm Bowel Dis 2006;12:669–676. Velayos FS, Liu L, Lewis JD, et al. Prevalence of colorectal cancer surveillance for ulcerative colitis in an integrated health care delivery system. Gastroenterology 2010; 139:1511–1518. Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030–1038. Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010;138:738–745. van den Broek FJ, Stokkers PC, Reitsma JB, et al. Random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis: low yield and absence of clinical consequences. Am J Gastroenterol 2014;109: 715–722. Zarrow R, Zarrow A, Zarrow H. “That was me” a patient’s perspective on flat lesion in inflammatory bowel disease. Gastrointest Endosc Clin N Am 2014; 24:349–351. Rubin DT, Rothe JA, Hetzel JT, et al. Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis? Gastrointest Endosc 2007;65:998–1004. Rutter MD, Saunders BP, Wilkinson KH, et al. Most dysplasia in ulcerative colitis is visible at colonoscopy. Gastrointest Endosc 2004;60:334–339. Rubin PH, Friedman S, Harpaz N, et al. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps. Gastroenterology 1999;117:1295–1300. Wanders LK, Dekker E, Pullens B, et al. Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis. Clin Gastroenterol Hepatol 2014;12:756–764. Siegel CA, Schwartz LM, 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. Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;124:880–888. Rutter MD, Saunders BP, Schofield G, et al. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 2004;53:256–260. Li D, Terdiman JP. “Did you check my colon for flat polyps?” Should
COMMENTARIES patients and colonoscopists really be concerned? Gastroenterology 2008;135:315–317. 25. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027–1035. 26. Wu L, Li P, Wu J, et al. The diagnostic accuracy of chromoendoscopy for dysplasia in ulcerative colitis: meta-analysis of six randomized controlled trials. Colorectal Dis 2012;14:416–420. 27. Marion JF, Waye JD, Present DH, et al. Chromoendoscopy-targeted biopsies are superior to standard
colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial. Am J Gastroenterol 2008;103:2342–2349. 28. Marion JF, Waye JD, Present DH, et al. Follow-up chromoendoscopy continues to be superior to standard colonoscopic surveillance for managing dysplasia in patients with IBD: A long-term, prospective, endoscopic trial. Gastroenterology 2008;134:A34–A34. 29. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010;102:605–613. 30. Adler A, Pohl H, Papanikolaou IS, et al. A prospective randomised
study on narrow-band imaging versus conventional colonoscopy for adenoma detection: does narrow-band imaging induce a learning effect? Gut 2008;57:59–64. 31. Kisiel JB, Yab TC, Nazer Hussain FT, et al. Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;37:546–554.
Conflicts of interest The authors disclose no conflicts. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.01.029
467
N
early a century after Rosenberg and Crohn recognized the occurrence of colorectal cancer (CRC) in ulcerative colitis,1 our understanding of how best to prevent this lethal complication of inflammatory bowel disease (IBD) continues to confound practitioners and disconcert patients. A profusion of recommendations about the best means to perform surveillance for dysplasia, and how best to manage it once found, has led to considerable discord and confusion. Published simultaneously in this month’s issues of Gastroenterology2 and Gastrointestinal Endoscopy,3 the SCENIC consensus statement (Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations) hopes to bring some order to this chaotic scene. SCENIC covers a range of topics in screening and surveillance for dysplasia in colitis and addresses, head on, several areas of contention with a deliberate thoroughness and an excellent summary of the available data. Central to the statements contained in SCENIC is the placement of chromoendoscopy (CE) as the preferred technique for surveillance for dysplasia in IBD. SCENIC provides a comprehensive summary of the available data underlying this core recommendation, and may have an important impact on the field. However, it is our belief that many practical issues and the lack of longitudinal data on CE as Gastroenterology 2015;148:462–467
the basis of colon cancer surveillance in IBD limit the acceptability of SCENIC as the standard of care at this time.
A Brief History of Surveillance Colonoscopy for IBD The progression of molecular events causing sporadic CRC has been well elucidated, and informs, to some degree, our knowledge of CRC complicating IBD. In sporadic CRC, the progression begins with mutation of APC and the accumulation of b-catenin to induce hyperplastic epithelium, followed by K-ras mutation and adenoma formation, and finally culminating in CRC with mutation of p53 or Deleted in Colorectal Carcinoma (DCC) proteins.4 This predictable adenoma–carcinoma sequence, occurring over a 7- to 10year timeframe, and the polypoid nature of the majority of dysplasia, have been the basis of colonoscopic screening for sporadic CRC, with identification and removal of adenomas leading to a reduction in CRC incidence and mortality.5 The pathogenesis of CRC in IBD is less certain, but it is believed that lowand high-grade dysplasia and cancer are a consequence of the cytokine milieu and free radicals associated with inflammation creating, or being superimposed upon, molecular alterations.6 Although many of the causative genetic alterations are the same as in sporadic CRC, they seem to occur in a different sequence, with p53 mutated early and APC and GSK3b mutations occurring late and over a shorter timeframe.4 Consequently, the morphologic features of CRC in IBD are also more varied; more often serrated or flatter, and often multifocal, perhaps because the ongoing stimulus of inflammation affects broad swaths of mucosa. Such temporal and morphologic considerations have led to the accepted practice of surveillance colonoscopy with numerous (33) random biopsies every 1–2 years in IBD patients at increased risk for CRC as the cornerstone of cancer prevention in IBD. The goal of such a surveillance program is to
identify patients with dysplasia, for whom colectomy would avoid cancer (Figure 1). Data gathered retrospectively in the 1990s found that highgrade dysplasia was associated with a very high risk of synchronous CRC, and even flat, low-grade dysplasia found on random biopsies had a risk of concurrent advanced neoplasia (high-grade dysplasia or cancer) as high as 23.5%.8 IBD patients over the last few decades have been subjected to countless colonoscopies and random biopsies in the name of CRC prevention. This labor and resource-intensive effort notwithstanding, the efficacy of surveillance colonoscopy in IBD is difficult to demonstrate. Some population-based studies, such as a recent report from Copenhagen County, Denmark, demonstrate a decreasing incidence of CRC in IBD patients over the last few decades,9 but a recent study in a closed health maintenance organization (HMO) in Northern California continued to find excess CRC incidence and mortality in patients with IBD,10 in concordance with findings from Olmsted County, Minnesota.11 Notably, data from the same HMO in Northern California found adoption of surveillance colonoscopy in at-risk IBD patients to be low,12 although it is uncertain to what degree this deficit is driven by patient preferences or physician practices. However, even with robust adoption of a program of surveillance colonoscopy in IBD patients, cancer prevention is imperfect. At 1 tertiary medical center where such a program has been in place for 3 decades, the cumulative incidence of CRC at 30 years of disease was 7.6%.13 Disturbingly, 16 of 30 cancers found were interval cancers, albeit using lower resolution colonoscopic technology available in the 1970s and 1980s.13 Such findings highlight the limitations of surveillance programs for CRC in IBD. Resignation among gastroenterologists about random biopsy owing to low yields and poor evidence has grown into cynicism about the value of the American Gastroenterological Association guidelines as the technique continues to be touted as the standard of good practice.14,15 At the same time,
COMMENTARIES
Figure 1.Natural history of dysplasia in inflammatory bowel disease (IBD) and endoscopic screening by low- and highresolution methods. Adapted with permission from Egger M et al.7
463
COMMENTARIES our patients have grown increasingly fearful over our uncertainty in this area.16 The basic tenet of surveillance for dysplasia by random biopsy—that dysplasia is often not accompanied by visible mucosal abnormalities—has been increasingly disputed.17,18 This tenet was likely true at the inception of surveillance programs, when fiberoptic colonoscopy was performed, but endoscopic technology has progressed considerably over the last 3 decades. Standard definition colonoscopy using CCD video chips improved the sensitivity of colonoscopy for visual identification of dysplasia, likely further enhanced by the adoption of highdefinition colonoscopy. The growing recognition that colonic dysplasia and neoplasia can be visualized most often has also led to the recommendation that if complete endoscopic resection of the dysplastic focus can be achieved, intensified surveillance may continue to avoid colectomy.14,19,20 This management strategy is consistent with patient preferences. Available evidence suggests that patients do not wish to consider colectomy until there is a relatively high certainty of cancer.21 At the same time, the adjunctive technique of CE was introduced over the last decade as a means of more sensitive detection of dysplasia in the setting of colitis.22,23 The technique had originally been introduced to the United States by Japanese investigators for the detection of smaller, flatter lesions in noncolitis patients 30 years ago. The importance of these lesions is still being debated in the noncolitis setting as well, and CE has not caught on, despite evidence showing that detection of these lesions was enhanced.24,25 Multiple cross-sectional studies have shown CE to be more sensitive than standard definition white-light examination in detection of colonic dysplasia in IBD, with fewer biopsies.26 Despite this robust evidence, CE has not yet been widely adopted in the United States, but has gained some acceptance in the UK and Europe. Several reasons for lack of adoption in the United States include initial confusion about whether new, higher resolution or zoom lens equipment used in the European trials was required. Several of the studies 464
paired CE with endomicroscopy, which left many wondering if they should wait for the next technological advance. Simultaneous to these early CE reports, virtually every American endoscopy suite transitioned to higher definition and narrow-band imaging capable equipment, so many awaited confirmation that these technologies would work as well as CE. Furthermore, the first American study demonstrating the efficacy of CE using standard equipment was not published until 200827 and, unlike the UK and European GI societies, more recent US-based position statements continued to champion random biopsy technique.14 Finally, other barriers, such as concerns about the mess related to dye use, the cost and lack of confidence about interpreting the blue landscape, led many gastroenterologists to simply refer the patients in whom they had found dysplasia to academic centers where a “chromo expert” could confirm their finding. The SCENIC consensus statement notes correctly that CE is the most sensitive modality for detection of dysplasia in colitis, and the data support their contention that CE should be considered the preferred method of detecting dysplasia in IBD. However, optimizing a cancer surveillance program is not solely about choosing the most sensitive technology. A wellconceived, effective surveillance program should incorporate appropriate definitions of the population at risk, and
risk stratification that takes into account clinical factors and prior surveillance findings; should address the accuracy of detection, which includes not only the limitations of the technique and technology but of operatordependent factors, including the skill of the endoscopist in accurately recognizing abnormalities and the ability of the pathologist to correctly identify and grade dysplasia; should address the operational aspects of implementation in real-world practice; and should consider the outcomes, both positive and negative, of the response to the detection of dysplasia, which may include intensified surveillance, endoscopic resection, or colectomy. In addition, a successful program will account for the patient’s willingness to undergo repeated, timely examinations and to comply fully with a bowel preparation. Unfortunately, the current state of practice and deficits in the evidence base make the broader aspirational aspects of SCENIC impractical and unproven as a standard of care in 2015, with many challenges remaining (Table 1). Consolidation of the progress made in this area will be needed to achieve that standard. The nature of dysplasia found by CE is different than in the historical studies of dysplasia with white light endoscopy: more numerous, smaller, flatter. Although multiple studies confirm the heightened sensitivity of CE in detecting dysplastic foci, the natural history of
Table 1.Challenges in Chromoendoscopy for Colitis Surveillance Operator barriers Training of fellows, gastroenterologists, nurses, and staff Unknown learning curve Identifying clinically relevant lesions Pathologist interobserver variability in identifying and grading dysplasia Varying endoscopists’ skill in managing or resecting found dysplasia Operational barriers Availability of dye, equipment Billing and reimbursement Time requirement Prep quality Confounding of findings by inflammation Patients’ willingness to undergo repeated, timely exams Knowledge barriers Uncertain natural history of dysplasia detected by CE Lack of well-defined population at risk Lack of risk stratification Uncertain implications of prior surveillance findings for management Uncertainty of appropriate surveillance intervals
COMMENTARIES these lesions is poorly understood. The benefits of clearing the colon of dysplasia by CE may be real, but only limited longitudinal data have been reported.28 It is important to keep in mind, however, that screening data (ability to detect dysplasia in an index colonoscopy) is not the same as longitudinal surveillance data. The belief is that this more sensitive test will identify important lesions: If more dysplasia and earlier stages of cancer are detected during surveillance, then one assumes that additional colons and lives will be spared. Proving this belief will be challenging. Randomized, controlled trials to prove the efficacy of CE in preventing cancer seem impractical. In addition, future longitudinal cohorts assessing the efficacy of CE-based cancer surveillance in IBD may be subject to a number of biases that will make outcomes difficult to interpret. These include possible contributions of healthy screener bias (wherein healthier patients are more likely to be screened), lead time bias (in which the more sensitive test of CE detects dysplasia much earlier than a less sensitive test, but may have no real effect on survival time, but instead lengthens the time of follow-up), and length time bias (an effect of more sensitive screening detecting more slowly progressing dysplasia, with less sensitive screening tending to find more rapidly progressing tumors, conferring the appearance that more sensitive screening picks up dysplasia when it is less dangerous, whereas actually it is simply that less dangerous dysplasia is more likely to be detected by the more sensitive method.) These considerations raise the possibility that CE surveillance in IBD may find itself in a situation similar to breast and prostate cancer screenings, where overdiagnosis has become a real issue.29 Surveillance by CE should be shown to improve outcomes, not just provide earlier detection. Anecdotally, our experience is that, when colectomy is done because of increased dysplasia detection using CE (as opposed to white light endoscopy), cancers do not seem to be found. The issue for the gastroenterologist remains the same as 30 years
ago: What does a positive result truly portend and how do we advise our patients to act on them? Other issues are of a more practical nature. If we are to incorporate formally, for the first time, a dye spray protocol as standard of care into our endoscopy suites, we must face the challenges it will impose upon our physicians, staff, and patients. Of course, spraying dye is not difficult and staff can be easily trained on preparation of dye spray, but a sense of increasing time pressure on the part of endoscopists might discourage adoption. In addition, many technical aspects that are emphasized by clinical studies of CE are addressed only briefly in SCENIC. How precisely should CE be performed? Two passes of the scope or one? White light endoscopy plus CE or CE alone? If the blue dye method is superior, then why bother with a white-light examination? Should nontargeted, random biopsies be taken in addition to targeted biopsies directed by CE? The utility of nontargeted biopsies is questioned in the introduction to SCENIC, but the consensus statement does not recommend abandoning this cumbersome technique. Nevertheless, a subtype of low-grade dysplasia called “incomplete goblet cell maturation” has been recognized recently, in which crypt architecture and white light endoscopy appearance are normal, but there is cellular dysplasia.29 It is not known if this type of dysplasia is visible with CE, and the natural history is yet unknown. Most important, lesion characterization by CE requires visual training. Data suggest such training is also not difficult, but requires broad implementation if it is to be adopted widely. For both fellowship and postfellowship training, and as with all new methods, standards for competence need to be established. It is also our experience that learning CE provides unexpected benefits for the endoscopist. Once the endoscopist’s eye has been trained by CE to see subtle lesions, such lesions are more readily noticed during white light endoscopy. A similar learning effect for adenoma detection has been reported with narrow band imaging in screening for sporadic CRC.30
Clinical Implications of Finding Dysplasia on CE As noted, multiple lines of evidence suggest that finding dysplasia no longer necessitates surgery in all patients. SCENIC correctly focuses on endoscopic resectability of the dysplastic focus. Implicit as well is the ability to survey sensitively for new/ additional foci after an index occurrence of dysplasia in the high-risk patient. Because the published data are limited to index screening, however, surveillance examination intervals cannot be extrapolated easily using current evidence. Once elucidated, it may be possible and safe to prevent unnecessary colectomy in the setting of dysplasia. Here, the skill of the endoscopist will play an enormous role. If dysplasia identified using CE can be safely managed endoscopically using polypectomy, endoscopic mucosal resection, or ablation, then colectomy might be delayed or avoided in some patients. The greater sensitivity of CE may move us toward a model similar to Barrett’s surveillance, with preservation of the esophagus made possible by new modes of ablation/resection of dysplasia and even cancer. However, studies of these endoscopically managed patients, despite being hampered by lack of long-term follow-up, already indicate a markedly increased risk of future cancer.20 Until better data are available to guide us on the long-term follow-up of dysplasia discovered by CE, controversy on this aspect of chromoendoscopic surveillance will likely persist. The SCENIC consensus panel was convened and supported by an informed group of patient advocates out of concern that the current surveillance guidelines were not protecting patients with colitis from dying of CRC. The SCENIC panel is correct: The current surveillance recommendations are onerous and imperfect. The need for progress in managing dysplasia in colitis is unmistakable. There are few more noble motivations in medicine than preventing cancer and saving lives. Many of these recommendations seem reasonable enough, but seeming reasonable is simply not enough to guide us and our patients in clinical 465
COMMENTARIES decisions. Will these recommendations accomplish the goals of keeping our patients safe from cancer or unnecessary surveillance (and its potential complications) or surgery?
4.
Future Directions
5.
The SCENIC consensus statement is best viewed as a springboard for further understanding of the natural history of dysplasia in colitis. If the SCENIC recommendations are put into widespread practice, we must mobilize to track dysplasia on a much larger scale. Over time, much will be learned with regard to the clinical implications of dysplasia found by CE and many of the gaps in the SCENIC guidelines can eventually be closed. It will be critical to learn how to risk-stratify patients, how to manage dysplasia once it has been found, and how to set appropriate screening intervals. In addition, new and potentially more sensitive detection modalities, which may even be personalized based on familial genetic risks, are likely to be forthcoming. Eventually, stool DNA testing or other technology may either enhance or supplant endoscopy-based screening and surveillance for CRC in IBD.31 Until then, longitudinal studies exploring not only outcomes, but also variations in follow-up and management, are needed. JAMES F. MARION BRUCE E. SANDS Dr Henry D. Janowitz Division of Gastroenterology Icahn School of Medicine at Mount Sinai New York, New York
6.
7.
8.
9.
10.
11.
References 1. Crohn BB, Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis (non-specific). Am J Med Sci 1925;170:220–227. 2. 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. 3. Laine L, Kaltenbach T, Barkun A, et al. SCENIC International consensus statement on surveillance and management of dysplasia in
466
12.
13.
14.
inflammatory bowel disease. Gastrointest Endosc 2015;64:489–501. Foersch S, Neurath MF. Colitisassociated neoplasia: molecular basis and clinical translation. Cell Mol Life Sci 2014;71:3523–3535. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012;366:687–696. Cooks T, Pateras IS, Tarcic O, et al. Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammationassociated colorectal cancer. Cancer Cell 2013;23:634–646. Egger M, Zwahlen M, Cerny T. [Cancer screening - principles, evaluation and implementation]. Ther Umsch 2013;70:195–203. Ullman T, Croog V, Harpaz N, et al. Progression of flat lowgrade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003; 125:1311–1319. Jess T, Simonsen J, Jorgensen KT, et al. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology 2012;143:375–381 e371; quiz e313–374. Herrinton LJ, Liu L, Levin TR, et al. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology 2012;143:382–389. Jess T, Loftus EV Jr, Velayos FS, et al. Incidence and prognosis of colorectal dysplasia in inflammatory bowel disease: a populationbased study from Olmsted County, Minnesota. Inflamm Bowel Dis 2006;12:669–676. Velayos FS, Liu L, Lewis JD, et al. Prevalence of colorectal cancer surveillance for ulcerative colitis in an integrated health care delivery system. Gastroenterology 2010; 139:1511–1518. Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030–1038. Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010;138:738–745. van den Broek FJ, Stokkers PC, Reitsma JB, et al. Random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis: low yield and absence of clinical consequences. Am J Gastroenterol 2014;109: 715–722. Zarrow R, Zarrow A, Zarrow H. “That was me” a patient’s perspective on flat lesion in inflammatory bowel disease. Gastrointest Endosc Clin N Am 2014; 24:349–351. Rubin DT, Rothe JA, Hetzel JT, et al. Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis? Gastrointest Endosc 2007;65:998–1004. Rutter MD, Saunders BP, Wilkinson KH, et al. Most dysplasia in ulcerative colitis is visible at colonoscopy. Gastrointest Endosc 2004;60:334–339. Rubin PH, Friedman S, Harpaz N, et al. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps. Gastroenterology 1999;117:1295–1300. Wanders LK, Dekker E, Pullens B, et al. Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis. Clin Gastroenterol Hepatol 2014;12:756–764. Siegel CA, Schwartz LM, 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. Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;124:880–888. Rutter MD, Saunders BP, Schofield G, et al. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 2004;53:256–260. Li D, Terdiman JP. “Did you check my colon for flat polyps?” Should
COMMENTARIES patients and colonoscopists really be concerned? Gastroenterology 2008;135:315–317. 25. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027–1035. 26. Wu L, Li P, Wu J, et al. The diagnostic accuracy of chromoendoscopy for dysplasia in ulcerative colitis: meta-analysis of six randomized controlled trials. Colorectal Dis 2012;14:416–420. 27. Marion JF, Waye JD, Present DH, et al. Chromoendoscopy-targeted biopsies are superior to standard
colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial. Am J Gastroenterol 2008;103:2342–2349. 28. Marion JF, Waye JD, Present DH, et al. Follow-up chromoendoscopy continues to be superior to standard colonoscopic surveillance for managing dysplasia in patients with IBD: A long-term, prospective, endoscopic trial. Gastroenterology 2008;134:A34–A34. 29. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010;102:605–613. 30. Adler A, Pohl H, Papanikolaou IS, et al. A prospective randomised
study on narrow-band imaging versus conventional colonoscopy for adenoma detection: does narrow-band imaging induce a learning effect? Gut 2008;57:59–64. 31. Kisiel JB, Yab TC, Nazer Hussain FT, et al. Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013;37:546–554.
Conflicts of interest The authors disclose no conflicts. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.01.029
467
