Curr Treat Options Gastro (2016) 14:103–114 DOI 10.1007/s11938-016-0072-4
Colon (C Kahi, Section Editor)
Colonoscopy Surveillance and Management of Dysplasia in Inflammatory Bowel Disease Tonya Kaltenbach, MD, MS1,* Gisele Leite, MD2 Roy Soetikno, MD, MS3 Address *,1 Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, 3801 Miranda Ave, GI111, Palo Alto, CA, 94304, USA Email: [email protected] 2 Hospital Sírio-Libanês, Rua Dona Adma Jafet, 91, Bela Vista, 01308050, São Paulo, SP, Brazil 3 Duke-NUS, National Cancer Center, Singapore General Hospital, Outram Rd, Singapore, 169608, Singapore
Published online: 1 February 2016 * Springer Science+Business Media, LLC (outside the USA) 2016
This article is part of the Topical Collection on Colon Keywords Dysplasia I Endoscopy I Inflammatory bowel disease I Surveillance I Endoscopic resection I Chromoendoscopy
Opinion statement Patients with long-standing ulcerative colitis (UC) and extensive Crohn’s disease (CD) colitis have a high risk of colorectal cancer (CRC) and are recommended to undergo surveillance with colonoscopy. Recent data highlights their increased risk of CRC compared to the general population despite colonoscopy surveillance. The proportion of IBD patients diagnosed with interval CRC within 6 to 36 months following a clearing colonoscopy was 15 %. Optimizing colonoscopy surveillance methods is important. Studies have demonstrated that the best endoscopic surveillance strategy to detect dysplasia is chromoendoscopy with surface application of dyes to enhance the mucosal visualization and that visible dysplasia should be endoscopically resected. In this chapter we will summarize the optimal surveillance and management techniques for colorectal dysplasia in IBD patients.
Introduction Patients with inflammatory bowel disease (IBD), specifically with long-standing ulcerative colitis (UC) and extensive Crohn’s disease (CD) colitis, have an increased risk of colorectal cancer (CRC), approximately twofold
greater than that in the general population [1–3]. Most IBD CRC is believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended [4]. High-quality surveillance colonoscopy for the
104
Colon (C Kahi, Section Editor)
detection of colorectal dysplasia in the IBD population can be challenging [5, 6]. Colitic dysplastic lesions are predominantly flat, nonpolypoid in shape with indistinct borders from the surrounding tissue [7••]. Active colonic inflammation confounds both the endoscopic and pathologic interpretation. Similarly, chronic mucosal changes—erythema, loss of vascular pattern, scars, and uneven mucosal surface—can also make the identification of dysplasia difficult. Thus, surveillance should be undertaken when colitis is in remission, when the bowel preparation quality is excellent, and using evidence-based techniques to detect dysplasia. Most dysplasia detected at surveillance colonoscopy today is visible [8, 9]. Progress in endoscopic technology and technique has invalidated the prior belief that most dysplasia is Binvisible^ and best detected on random biopsies. Using high-resolution videoendoscopy and chromoendoscopy, targeted biopsies of visible lesions now account for approximately 90 % of cases, whereas random biopsy accounts for only 10 % of cases of identified dysplasia.
In order to update and unify the guidelines for the surveillance and management of dysplasia in IBD, in 2014, an international multidisciplinary group, Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus (SCENIC), synthesized the literature and suggested a new guideline [10, 11••]. The SCENIC statements have since been endorsed by numerous societies worldwide (The American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy (ASGE), Asian Pacific Association of Gastroenterology, British Society for Gastroenterology, Canadian Association of Gastroenterology, European Society of Gastrointestinal Endoscopy, and Japan Gastroenterological Endoscopy Society). Uniformity of guidelines across gastrointestinal societies will provide the foundation to standardize the practice of IBD surveillance colonoscopy. The purpose of this article is to describe the latest recommendations for the surveillance and management of dysplasia in IBD.
Detection of dysplasia Chromoendoscopy is the superior surveillance method The robust process of SCENIC determined that colonoscopy using chromoendoscopy is the optimal endoscopic surveillance strategy to detect dysplasia. Chromoendoscopy uses a dye solution of either methylene blue or indigo carmine applied onto the colonic mucosa to enhance contrast during surveillance colonoscopy. In a meta-analysis of eight clinical trials of surveillance colonoscopy, chromoendoscopy detected a significantly greater proportion of patients with dysplasia in comparison with white light colonoscopy (relative risk (RR), 1.8 [95 %CI, 1.2–2.6] and absolute risk increase, 6 % [95 %CI, 3–9 %]) (Table 1) [10, 11••]. In the four tandem studies of the meta-analysis, in which each patient had both a chromoendoscopy and white light examination, the number of visible dysplastic areas almost doubled (RR, 1.9; 95 %CI, 1.4–2.7) with chromoendoscopy. Following the SCENIC statements, several studies of chromoendoscopy in IBD surveillance have been published [12–16]. Overall, the findings are consistent. Chromoendoscopy with targeted biopsy is the optimal surveillance technique for dysplasia detection.
Chromoendoscopy technique As previously described [17], the chromoendoscopy technique involves the topical application of dye during surveillance colonoscopy in patients with IBD who are in remission and have a good quality bowel preparation (Table 2). The dye is sprayed onto the colon mucosa in order to enhance dysplasia detection by highlighting surface abnormalities, e.g., areas that
Randomized parallel-group Randomized parallel-group Prospective tandem Prospective tandem Prospective tandem Prospective tandem and additional cohort Retrospective two-group Prospective tandem
Kiesslich [20] Kiesslich [21] Marion [24] Rutter [23] Matsumoto [25] Hlvaty [26] 2/50 No per-patient data given (N = 63)
Patients with dysplasia/all patients Chromoendoscopy 13/84 11/80 22/102 7/100 12/57 4/30 0/50
White light 6/81 4/73 12/102 2/100 12/57 2/45
1.8 (1.2–2.6)
5.0 (0.3–101.6)
2.1 (0.8–5.2) 2.5 (0.8–7.5) 1.8 (0.96–3.5) 3.5 (0.8–16.4) 1.0 (0.5–2.0) 3.0 (0.6–15.4)
RR (95 % CI)
6 % (3 to 9 %)
4 % (−3 to 11 %)
8 % (−2 to 18 %) 8 % (−1 to 17 %) 10 % (0 to 20 %) 5 % (−1 to 11 %) 0 % (−2 to 2 %) 9 % (−5 to 23 %)
Absolute risk increase (95 % CI)
2 41
Chromoendoscopy 32 19 35 9 18 6
0 18
White-light 10 2 13 2 8 2
No. of visible dysplastic lesions
Reprinted from Gastrointestinal Endoscopy (81) and Gastroenterology (148), Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, and Soetikno R. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Copyright (2015), with permission from Elsevier RR Relative risk; CI confidence interval; SCENIC Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations
SCENIC meta-analysis
Gunther [27] Chiorean [22]
Study type
Study
Table 1. Proportion of patients with dysplasia and number of visible dysplastic lesions identified in studies comparing chromoendoscopy versus white-light colonoscopy Colonoscopy Surveillance and Management of Dysplasia Kaltenbach et al. 105
106
Colon (C Kahi, Section Editor)
Table 2. Suggested steps for implementation of chromoendoscopy into endoscopic practice Equipment Colonoscope Accessories
Contrast agent Procedure and protocol Time allotment Standard operating procedure
High-definition colonoscope, monitor, and cables Apply dye via the following: Water jet channel by using water pump attached to the endoscope activated via foot pedal or spray catheter: length 240 cm, endoscope accessory channel 2.8 mm Indigo carmine, 5-mL ampule (0.8 %) Consider doubling colonoscopy time slot initially during the learning curve period. Complete colonoscopy to cecum. Lavage with water and suction during intubation. Prepare dye solution during insertion for application via the foot pump or spray. Indigo carmine (0.03 %): mix 2 5-mL ampules of 0.8 % indigo carmine with 250 mL water. Methylene blue (0.04 %): mix one 10-mL ampule of 1 % methylene blue with 240 mL water. If using a foot pump: once the cecum is intubated, the water irrigation can be exchanged with the contrast solution. Apply the dye solution in a circumferential technique while withdrawing the colonoscope. Direct spray to the antigravity side. If using a spray catheter: the dye spray catheter is inserted into the biopsy channel; the catheter tip should protrude 2–3 cm from the endoscope. Apply dye solution segmentally by using a rotational technique while withdrawing the colonoscope to cover the surface mucosa with dye. Suction any excess solution after approximately 1 min to aid mucosal visualization. Focus on 20–30-cm segments sequentially with insertion of the endoscope to the proximal extent of each segment before slow withdrawal and mucosal visualization. Targeted dye spray for suspicious lesions: Prepare more concentrated dye solution for application. Indigo carmine (0.13 %): mix one 5-mL ampule of 0.8 % indigo carmine with 25 mL water. Methylene blue (0.2 %): mix one 10-mL ampule of 1 % methylene blue with 40 mL water. Spray about 30 mL directly from a 60-mL syringe through the biopsy channel. Remove endoscopically resectable suspicious lesions by using polypectomy or endoscopic mucosal resection. Do targeted biopsies of any unresectable abnormality visualized through chromoendoscopy to diagnose dysplasia. Do biopsies of flat area surrounding lesions to assess for dysplasia. Consider tattoo of suspicious dysplastic lesions arising from flat mucosa or not amendable to complete removal. Recommendations regarding the need to perform random, non-targeted biopsies for detection of dysplasia vary. If biopsies for dysplasia are not done, two random biopsies in every bowel segment are commonly recommended to document microscopic disease activity.
Reprinted from Gastrointestinal Endoscopy (81) and Gastroenterology (148), Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, and Soetikno R. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Copyright (2015), with permission from Elsevier
are slightly elevated or depressed, friable, obscure in vascular pattern, and villous or nodular in appearance (Fig. 1). Interfering anatomy, such as pseudopolyposis and strictures, can limit the yield of the panchromoendoscopy technique [18]. Prior to the start of the procedure, a total of approximately 250 mL of diluted dye (methylene blue, 0.04 to 0.1 %; or indigo carmine, 0.03 to 0.1 %) is prepared (Fig. 2). For 0.04 % methylene blue, one 10-mL ampule of 1 % methylene blue is mixed with 240-mL water. For 0.03 % indigo carmine, two 5-mL ampules of 0.8 % indigo carmine are mixed with 250mL water. Solutions can be prepared in containers compatible with the forward wash jet.
Colonoscopy Surveillance and Management of Dysplasia
Kaltenbach et al.
107
Fig. 1. a Three-centimeter, nonpolypoid, superficial, elevated colon lesion after indigo carmine chromoendoscopy. b The area of the lesion before dye spray. c The same lesion had likely been photographed approximately a year earlier (on fold to left of ulcer), but it was not recognized to be dysplastic. Histologic examination showed low-grade dysplasia. Reprinted from Gastrointestinal Endoscopy (81) and Gastroenterology (148), Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, and Soetikno R. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Copyright (2015), with permission from Elsevier.
During insertion, the mucosa should be washed and suctioned to free it of residual stool or debris. We use standard water jet for washing. After intubation of the cecum, the examination with pan-chromoendoscopy begins. The prepared chromoendoscopy solution container is directly exchanged with the water container. Methylene blue or indigo carmine is directly applied to the colon mucosa through the water jet channel (or a spray catheter). For efficient application, the dye is sprayed using the foot wash pump, and is targeted to the antigravity wall of the colon. The dye then pools to the gravity side and provides a circumferential coating of the
Fig. 2. Chromoendoscopy Technique. Reprinted from Gastrointestinal Endoscopy (81) and Gastroenterology (148), Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, and Soetikno R. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Copyright (2015), with permission from Elsevier.
108
Colon (C Kahi, Section Editor) mucosa. Expansion of the lumen with carbon dioxide insufflation can expand the mucosal surface to decrease large pools of dye. Chromoendoscopy can be performed segmentally during withdrawal whereby each colon segment is sprayed, any excess pools of dye are suctioned, and the mucosa with a thin layer of dye is carefully inspected for any suspicious areas that appear to be different from the surrounding background in color, pattern, or level. When chromoendoscopy is used for IBD surveillance, random biopsies for dysplasia detection are unnecessary [19, 20]. If biopsies for dysplasia are not done, two random biopsies in every bowel segment are commonly recommended to document microscopic disease activity.
Alternative surveillance methods to chromoendoscopy, such as high definition or equipmentbased image enhancement, are not superior in the detection of dysplasia The value of chromoendoscopy in the detection of dysplasia beyond high-definition colonoscopy has been a point of contention. Highdefinition endoscopy provides image signals of higher pixel density than standard-definition. Based on a prospective trial that showed the significant benefit in dysplasia detection using chromoendoscopy (21 %) compared to high definition white light alone (9 %), p = 0.007, the SCENIC guideline suggested the use of chromoendoscopy even when using high definition white light colonoscopy [21]. Since the SCENIC publication, a prospective randomized controlled trial further supports the significant value of chromoendoscopy in IBD surveillance colonoscopy to detect more dysplasia compared to white light highdefinition colonoscopy [22]. Currently available equipment-based image enhancement technologies include narrow band imaging (NBI) (Olympus, Tokyo, Japan), i-scan (Pentax, Tokyo, Japan), and Fuji Intelligent Chromo Endoscopy (FICE) (Fujinon, Tokyo, Japan) [23]. NBI has been the one studied in IBD surveillance. While alternative techniques continue to be studied, their routine use for surveillance is not supported by available evidence, and the SCENIC guidelines suggested against the use of NBI over that of white light colonoscopy or chromoendoscopy.
Characterization of visible dysplasia Any suspicious areas of abnormal mucosa should be further inspected. Using a syringe, a concentrated solution of dye can be sprayed directly onto the mucosa through the working channel. The more concentrated dye provides contrast to mucosal pattern and contour and can delineate borders of dysplastic lesions. Visible dysplasia should be described according to the Paris classification [24], polypoid (pedunculated, 0-Ip or sessile, 0-Is) or nonpolypoid (superficially elevated, 0-IIa; completely flat, 0-IIb; or depressed, 0-IIc), with qualifiers for ulceration and border of the lesion, as well as description of the location as within or outside an area of known colitis [10, 11••]. In addition, visible dysplasia should be characterized as Bendoscopically resectable^ or Bendoscopically unresectable.^ Endoscopically resectable features of visible dysplasia include (1) distinct margins, (2) complete removal based on endoscopic and
Colonoscopy Surveillance and Management of Dysplasia
Kaltenbach et al.
109
histologic assessment, and (3) the adjacent mucosa is free of dysplasia on histologic examination. Terms including dysplasia-associated lesion or mass (DALM), adenoma-like, and non-adenoma-like are not useful. After characterizing the lesion, biopsies should be targeted to the most concerning area of the lesion as well as the mucosa adjacent to the lesion to exclude invisible dysplasia.
Management Management decisions on endoscopic versus surgical resection of colorectal dysplasia in IBD patients are guided by both endoscopic and histologic findings, as well as patient-related factors such as age, comorbidities, patient preference, and risk tolerance.
Endoscopically visible dysplasia The SCENIC guidelines describe the role of endoscopic removal with surveillance for endoscopically resectable visible dysplasia. They recommend complete endoscopic removal of polypoid dysplasia over colectomy and suggest complete endoscopic resection of nonpolypoid dysplastic over colectomy. Most patients prefer endoscopic alternatives to colectomy until there is a relatively high certainty of cancer [25]. Endoscopic techniques for complete removal of flat dysplasia in IBD often require more than the simple polypectomy performed for polypoid ones [26]. If the visible dysplastic lesion is characterized as endoscopically resectable, en bloc endoscopic mucosal resection (EMR) is preferred. Hybrid EMR and endoscopic submucosal dissection are other options dependent upon the lesion characteristics and endoscopist’s skill. After endoscopic resection is complete, biopsies of the flat mucosa surrounding the resection site should be done to ensure that the lateral margins are free of dysplasia. Tattooing and photodocumentation of the area should also be performed to facilitate future surveillance or treatment. Recent ASGE guidelines provide an algorithm for the surveillance recommendations of endoscopically resectable lesions [19]. For example, patients with IBD who have large lesions that are endoscopically removed should have surveillance at approximately 3 to 6 months, with longer subsequent intervals (e.g., yearly) if the initial repeat colonoscopy result is negative. Patients with smaller polypoid lesions resected en bloc may return at 1-year intervals.
Endoscopically invisible dysplasia Colorectal dysplasia that is detected by random biopsies alone (i.e., endoscopically invisible) should be verified by another gastrointestinal (GI) pathologist. Interobserver agreement on the histologic diagnosis of dysplasia, low-grade dysplasia, or high-grade dysplasia in IBD has been shown to be fair even by expert GI pathologist review [27, 28]. Confirmed dysplasia warrants reevaluation with chromoendoscopy. Upon repeat colonoscopy by an endoscopist experienced with chromoendoscopy, if a visible dysplastic lesion can be localized in the same region of the colon as the previous random biopsy that showed invisible dysplasia, then the lesion should be characterized, determined to be endoscopically resectable or endoscopically unresectable and managed accordingly. Alternatively, if dysplasia is not visible, such patients
110
Colon (C Kahi, Section Editor) should have individualized management approach that considers the risks and benefits of continued intensive surveillance colonoscopy and colectomy. For example, patients with invisible low-grade dysplasia may remain in intensive surveillance while those with invisible high-grade dysplasia may more strongly consider colectomy. A recent retrospective observational study highlights the value of referring patients with endoscopically invisible dysplasia to an endoscopist with expertise in IBD surveillance using chromoendoscopy with high-definition colonoscopy [13]. The authors demonstrated the impact of performing chromoendoscopy in IBD patients whom had a diagnosis colorectal dysplasia from a white light high-definition examination. On subsequent chromoendoscopy examination, 30 % of the patients had dysplasia seen—dysplasia that was likely initially missed on the white light examination and classified as invisible. Importantly, these now visible lesions were often amenable to endoscopic resection.
Implications Improving the endoscopic recognition and management of dysplastic colorectal lesions in IBD patients could have important clinical practice implications. Namely, it may shift the current onerous and flawed surveillance approach of random biopsy that samples less than 0.1 % of the colonic mucosal surface area in a blind search for what is thought to be invisible dysplasia, to a targeted biopsy strategy whereby the colon surface is meticulously surveyed for dysplasia that is known to be predominantly visible. Furthermore, it may redirect the current treatment away from colectomy for invisible dysplasia to an individualized approach to locally remove a discrete dysplastic lesion. Most cases of CRC in IBD are believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended. The SCENIC process consented that surveillance to detect neoplasia is a shared recommendation and practice worldwide. From that starting point, the goal was to determine the optimal approach for detection and management of neoplasia when surveillance is performed. Arguments that chromoendoscopy should only be considered in high-risk IBD cohorts, such as those with a family history of CRC, concomitant primary sclerosing cholangitis, or prior history of dysplasia, are unfounded based on available literature [29–31]. The IBD populations surveyed with chromoendoscopy compared to white light in all of the studies were heterogeneous and did not stratify specific high-risk IBD groups. Furthermore, US guidelines (unlike British or European) do not directly address risk stratification and optimal surveillance interval [19, 32–34]. The key point is that when a patient is undergoing surveillance for dysplasia, the optimal method should be used. An economic analysis showed that surveillance colonoscopy using chromoendoscopy with targeted biopsies was less costly and more effective than conventional white light surveillance colonoscopy with random biopsies, at every surveillance interval [35•]. The study used endoscopic test characteristics, stage-specific CRC mortality rates, and Medicare reimbursement costs. Despite the robust prospective evidence base for chromoendoscopy with targeted biopsy, its uptake into routine IBD surveillance has been
Colonoscopy Surveillance and Management of Dysplasia
Kaltenbach et al.
111
challenged. Perceptions of its high complexity and long procedure time and frustrations with the limited supply of indigo carmine in the USA in the past year coupled with rising methylene blue costs and lack of reimbursement for the procedure have stalled widespread implementation of the optimal surveillance method. Furthermore, some authorities have questioned the significance and natural history of dysplasia detected using chromoendoscopy and pointed to lower quality evidence to defer the value and adoption of a universal chromoendoscopy approach. It is important to note that the SCENIC consensus ultimately made recommendations following a rigorous guideline development process as prescribed by the Institute of Medicine. A recent prospective follow-up evaluation of patients in an IBD surveillance program by Marion and colleagues demonstrates for the first time the superiority of chromoendoscopy over conventional white light examination with random biopsy technique in detecting dysplasia in patients who underwent colonoscopy surveillance over a 5-year period [16]. No adverse dysplasiarelated events, such as unnecessary surgery or interval carcinoma were observed in the follow-up period. By transitioning IBD surveillance to targeted sampling and resection of visible dysplastic lesions, we may positively impact the quality of colonoscopy, and increasing the dysplasia detection rates is a necessary stepping stone. Colonoscopy quality metrics in non-colitic patients, such as adenoma detection rate (ADR), can be a model [36]. ADR has the strongest association to interval or Bmissed^ CRC after screening colonoscopy. A landmark study of 314,872 exams performed by 136 gastroenterologists showed that each 1.0 % increase in the ADR had a 3.0 % decrease in the risk of CRC [37•]. Among patients of physicians with ADRs in the highest quintile, as compared with those in the lowest, the adjusted hazard ratio for any interval cancer was 0.52 (95 %CI, 0.39– 0.69). A longitudinal study of 1375 UC patients suggests that the adoption of a surveillance colonoscopy strategy using chromoendoscopy to detect visible dysplasia can influence similar quality outcomes. Over a four-decade period, the authors observed significant reductions in the risk of interval CRC, advanced stage CRC, and proportion of colectomies for dysplasia. A benchmark of excellence today for physicians and endoscopy centers is measuring and reporting quality; IBD surveillance should be held to the same standards. In summary, chromoendoscopy with targeted biopsies can improve the endoscopic detection and management of visible dysplastic colorectal lesions in IBD patients, compared with conventional white light colonoscopy with random biopsy. This strategy has been rigorously studied, synthesized, and summarized by SCENIC. Efforts and resources should now focus on its implementation into clinical practice, such as through training courses, photographic atlases [7••], and video repositories [38••]. A recent article provides a roadmap to navigate the barriers for the implementation of chromoendoscopy in IBD colonoscopy surveillance practice [39••]. It describes standardization of terminology, clinical protocols, training, and reporting and proposes mechanisms to measure quality and pursue reimbursement. Future research should explore alternative chromoendoscopy agents, should risk stratifying patients in order
112
Colon (C Kahi, Section Editor) to clarify optimal surveillance intervals using chromoendoscopy, should evaluate dysplasia and CRC incidence following chromoendoscopy examination as well as following endoscopic or surgical resection, and should measure quality of life.
Compliance with ethical standards Conflict of interest Gisele Leite declares no conflict of interest. Tonya Kaltenbach reports grants and personal fees from Olympus, Inc., outside the submitted work. Two non-profit charitable foundations, the Maxine and Jack Zarrow Family Foundation and the William K. Warren Foundation, provided unrestricted gifts supporting the SCENIC guideline development process. The funding sources had no involvement at any stage of the development process, no representation at the consensus meeting, and no role in the drafting or approval of the manuscript. Roy Soetikno reports grants and personal fees from Olympus, Inc, outside the submitted work. Human and animal rights and informed consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2.
3. 4. 5.
6.
7.••
Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35. Friedman S, Rubin PH, Bodian C, et al. Screening and surveillance colonoscopy in chronic Crohn’s colitis: results of a surveillance program spanning 25 years. Clin Gastroenterol Hepatol. 2008;6:993–8. quiz 953–4. Friedman S, Rubin PH, Bodian C, et al. Screening and surveillance colonoscopy in chronic Crohn’s colitis. Gastroenterology. 2001;120:820–6. Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel disease. N Engl J Med. 2015;373:195. Wang YR, Cangemi JR, Loftus Jr EV, et al. Rate of early/ missed colorectal cancers after colonoscopy in older patients with or without inflammatory bowel disease in the United States. Am J Gastroenterol. 2013;108:444–9. Sanduleanu S, Rutter MD. Interval colorectal cancers in inflammatory bowel disease: the grim statistics and true stories. Gastrointest Endosc Clin N Am. 2014;24:337–48. Soetikno R, Sanduleanu S, Kaltenbach T. An atlas of the nonpolypoid colorectal neoplasms in inflammatory
bowel disease. Gastrointest Endosc Clin N Am. 2014;24:483–520. Comprehensive atlas of endoscopic images, algorithms and tools to provide examples and guidance for detection of visible non-polypoid dysplasia in inflammatory bowel disease patients. 8. Rutter M, Bernstein C, Matsumoto T, et al. Endoscopic appearance of dysplasia in ulcerative colitis and the role of staining. Endoscopy. 2004;36:1109–14. 9. 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. 10. Laine L, Kaltenbach T, Barkun A, et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastrointest Endosc. 2015;81:489–501. e26. 11.•• 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 e28. Statements on optimal surveillance and management strategies for patients with inflammatory bowel disease following a rigorous guideline development process, including meta-analyses
Colonoscopy Surveillance and Management of Dysplasia and synthesis of data. The publication and recommendations have been endorsed by numerous international societies. 12. Choi CH, Rutter MD, Askari A, et al. Forty-year analysis of colonoscopic surveillance program for neoplasia in ulcerative colitis: an updated overview. Am J Gastroenterol. 2015;110:1022–34. 13. Deepak P, Hanson GJ, Fletcher JG, et al. Incremental diagnostic yield of chromoendoscopy and outcomes in inflammatory bowel disease patients with a history of colorectal dysplasia on white-light endoscopy. Gastrointest Endosc 2015. 14. Choi CH, Ignjatovic-Wilson A, Askari A, et al. Lowgrade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer. Am J Gastroenterol. 2015;110:1461–71. 15. Mooiweer E, van der Meulen-de Jong AE, Ponsioen CY, et al. Chromoendoscopy for surveillance in inflammatory bowel disease does not increase neoplasia detection compared with conventional colonoscopy with random biopsies: results from a large retrospective study. Am J Gastroenterol. 2015;110:1014–21. 16. Marion JF, Waye JD, Israel Y, et al. Chromoendoscopy is more effective than standard colonoscopy in detecting dysplasia during long-term surveillance of patients with colitis. Clin Gastroenterol Hepatol 2015. 17. Soetikno R, Subramanian V, Kaltenbach T, et al. The detection of nonpolypoid Dflat and depressed] colorectal neoplasms in patients with inflammatory bowel disease. Gastroenterology. 2013;144:1349–52. 1352 e1-6. 18. Fumery M, de Pineton CG, Stefanescu C, et al. Detection of dysplasia or cancer in 3.5% of patients with inflammatory bowel disease and colonic strictures. Clin Gastroenterol Hepatol. 2015;13:1770–5. 19. Committee ASoP, Shergill AK, Lightdale JR, et al. The role of endoscopy in inflammatory bowel disease. Gastrointest Endosc. 2015;81:1101–21. e1-13. 20. 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;109:715–22. 21. Picco MF, Pasha S, Leighton JA, et al. Procedure time and the determination of polypoid abnormalities with experience: implementation of a chromoendoscopy program for surveillance colonoscopy for ulcerative colitis. Inflamm Bowel Dis. 2013;19:1913–20. 22. Mohammed N, Kant P, Abid F. High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial. Gastrointest Endosc. 2015;81:AB148. 23. Subramanian V, Ragunath K. Advanced endoscopic imaging: a review of commercially available technologies. Clin Gastroenterol Hepatol. 2014;12:368–76. e1. 24. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003;58:S3-43.
25.
Kaltenbach et al.
113
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;16:1658–62. 26. 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 2013. 27. Eaden J, Abrams K, McKay H, et al. Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis. J Pathol. 2001;194:152–7. 28. Odze RD, Goldblum J, Noffsinger A, et al. Interobserver variability in the diagnosis of ulcerative colitisassociated dysplasia by telepathology. Mod Pathol. 2002;15:379–86. 29. Marion JF, Sands BE. The SCENIC consensus statement on surveillance and management of dysplasia in inflammatory bowel disease: praise and words of caution. Gastroenterology. 2015;148:462–7. 30. Ananthakrishnan AN. Chromoendoscopy is better: so why am I not (yet) using it for routine inflammatory bowel disease surveillance? Clin Gastroenterol Hepatol 2015. 31. Higgins PD. Miles to go on the SCENIC route: should chromoendoscopy become the standard of care in IBD surveillance? Am J Gastroenterol. 2015;110:1035–7. Farraye FA, Odze RD, Eaden J, et al. AGA technical 32. review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010;138:746–74. 774 e1-4; quiz e12-3. 33. Kornbluth A, Sachar DB. Practice parameters committee of the American College of G. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, practice parameters committee. Am J Gastroenterol. 2010;105:501–23. quiz 524. 34. Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. 2010;59:666–89. 35.• Konijeti GG, Shrime MG, Ananthakrishnan AN, et al. Cost-effectiveness analysis of chromoendoscopy for colorectal cancer surveillance in patients with ulcerative colitis. Gastrointest Endosc 2013. Economic analysis of surveillance strategies for dypslasia showing chromoendoscopy as dominant surveillance strategy, irrespective of surveillance interval. 36. Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81:31–53. 37.• Corley DA, Jensen CD, Marks AR, et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014;370:1298–306. Landmark study to show strong inverse association of adenoma detection rates with incident colorectal cancer and mortality. 38.•• Kaltenbach T, McQuaid K, Sanchez-Yague A, et al. Chromoendoscopy with Targeted Biopsy to Detect
114
Colon (C Kahi, Section Editor)
Nonpolypoid Colorectal Neoplasms in Inflammatory Bowel Disease http://www.youtube.com/watch?v= OARkbgwlObI. ASGE Eductational Products and CME Program Audiovisual Award, 2014. Audio-visual instruction on the chromoendoscopy with targeted biopsy technique to detect visible nonpolypoid dysplasia in inflammatory bowel disease, including numerous video examples of lesion detection, characterization and removal, as well as the necessary tools.
39.•• Sanduleanu S, Kaltenbach T, Barkun A, et al. A roadmap to the implementation of chromoendoscopy in inflammatory bowel disease colonoscopy surveillance practice. Gastrointest Endosc. 2016;83:213–22. This article provides a framework for practitioners and centers to adopt chromendoscopy into inflammatory bowel disease colonoscopy surveillance practice.
Colon (C Kahi, Section Editor)
Colonoscopy Surveillance and Management of Dysplasia in Inflammatory Bowel Disease Tonya Kaltenbach, MD, MS1,* Gisele Leite, MD2 Roy Soetikno, MD, MS3 Address *,1 Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, 3801 Miranda Ave, GI111, Palo Alto, CA, 94304, USA Email: [email protected] 2 Hospital Sírio-Libanês, Rua Dona Adma Jafet, 91, Bela Vista, 01308050, São Paulo, SP, Brazil 3 Duke-NUS, National Cancer Center, Singapore General Hospital, Outram Rd, Singapore, 169608, Singapore
Published online: 1 February 2016 * Springer Science+Business Media, LLC (outside the USA) 2016
This article is part of the Topical Collection on Colon Keywords Dysplasia I Endoscopy I Inflammatory bowel disease I Surveillance I Endoscopic resection I Chromoendoscopy
Opinion statement Patients with long-standing ulcerative colitis (UC) and extensive Crohn’s disease (CD) colitis have a high risk of colorectal cancer (CRC) and are recommended to undergo surveillance with colonoscopy. Recent data highlights their increased risk of CRC compared to the general population despite colonoscopy surveillance. The proportion of IBD patients diagnosed with interval CRC within 6 to 36 months following a clearing colonoscopy was 15 %. Optimizing colonoscopy surveillance methods is important. Studies have demonstrated that the best endoscopic surveillance strategy to detect dysplasia is chromoendoscopy with surface application of dyes to enhance the mucosal visualization and that visible dysplasia should be endoscopically resected. In this chapter we will summarize the optimal surveillance and management techniques for colorectal dysplasia in IBD patients.
Introduction Patients with inflammatory bowel disease (IBD), specifically with long-standing ulcerative colitis (UC) and extensive Crohn’s disease (CD) colitis, have an increased risk of colorectal cancer (CRC), approximately twofold
greater than that in the general population [1–3]. Most IBD CRC is believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended [4]. High-quality surveillance colonoscopy for the
104
Colon (C Kahi, Section Editor)
detection of colorectal dysplasia in the IBD population can be challenging [5, 6]. Colitic dysplastic lesions are predominantly flat, nonpolypoid in shape with indistinct borders from the surrounding tissue [7••]. Active colonic inflammation confounds both the endoscopic and pathologic interpretation. Similarly, chronic mucosal changes—erythema, loss of vascular pattern, scars, and uneven mucosal surface—can also make the identification of dysplasia difficult. Thus, surveillance should be undertaken when colitis is in remission, when the bowel preparation quality is excellent, and using evidence-based techniques to detect dysplasia. Most dysplasia detected at surveillance colonoscopy today is visible [8, 9]. Progress in endoscopic technology and technique has invalidated the prior belief that most dysplasia is Binvisible^ and best detected on random biopsies. Using high-resolution videoendoscopy and chromoendoscopy, targeted biopsies of visible lesions now account for approximately 90 % of cases, whereas random biopsy accounts for only 10 % of cases of identified dysplasia.
In order to update and unify the guidelines for the surveillance and management of dysplasia in IBD, in 2014, an international multidisciplinary group, Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus (SCENIC), synthesized the literature and suggested a new guideline [10, 11••]. The SCENIC statements have since been endorsed by numerous societies worldwide (The American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy (ASGE), Asian Pacific Association of Gastroenterology, British Society for Gastroenterology, Canadian Association of Gastroenterology, European Society of Gastrointestinal Endoscopy, and Japan Gastroenterological Endoscopy Society). Uniformity of guidelines across gastrointestinal societies will provide the foundation to standardize the practice of IBD surveillance colonoscopy. The purpose of this article is to describe the latest recommendations for the surveillance and management of dysplasia in IBD.
Detection of dysplasia Chromoendoscopy is the superior surveillance method The robust process of SCENIC determined that colonoscopy using chromoendoscopy is the optimal endoscopic surveillance strategy to detect dysplasia. Chromoendoscopy uses a dye solution of either methylene blue or indigo carmine applied onto the colonic mucosa to enhance contrast during surveillance colonoscopy. In a meta-analysis of eight clinical trials of surveillance colonoscopy, chromoendoscopy detected a significantly greater proportion of patients with dysplasia in comparison with white light colonoscopy (relative risk (RR), 1.8 [95 %CI, 1.2–2.6] and absolute risk increase, 6 % [95 %CI, 3–9 %]) (Table 1) [10, 11••]. In the four tandem studies of the meta-analysis, in which each patient had both a chromoendoscopy and white light examination, the number of visible dysplastic areas almost doubled (RR, 1.9; 95 %CI, 1.4–2.7) with chromoendoscopy. Following the SCENIC statements, several studies of chromoendoscopy in IBD surveillance have been published [12–16]. Overall, the findings are consistent. Chromoendoscopy with targeted biopsy is the optimal surveillance technique for dysplasia detection.
Chromoendoscopy technique As previously described [17], the chromoendoscopy technique involves the topical application of dye during surveillance colonoscopy in patients with IBD who are in remission and have a good quality bowel preparation (Table 2). The dye is sprayed onto the colon mucosa in order to enhance dysplasia detection by highlighting surface abnormalities, e.g., areas that
Randomized parallel-group Randomized parallel-group Prospective tandem Prospective tandem Prospective tandem Prospective tandem and additional cohort Retrospective two-group Prospective tandem
Kiesslich [20] Kiesslich [21] Marion [24] Rutter [23] Matsumoto [25] Hlvaty [26] 2/50 No per-patient data given (N = 63)
Patients with dysplasia/all patients Chromoendoscopy 13/84 11/80 22/102 7/100 12/57 4/30 0/50
White light 6/81 4/73 12/102 2/100 12/57 2/45
1.8 (1.2–2.6)
5.0 (0.3–101.6)
2.1 (0.8–5.2) 2.5 (0.8–7.5) 1.8 (0.96–3.5) 3.5 (0.8–16.4) 1.0 (0.5–2.0) 3.0 (0.6–15.4)
RR (95 % CI)
6 % (3 to 9 %)
4 % (−3 to 11 %)
8 % (−2 to 18 %) 8 % (−1 to 17 %) 10 % (0 to 20 %) 5 % (−1 to 11 %) 0 % (−2 to 2 %) 9 % (−5 to 23 %)
Absolute risk increase (95 % CI)
2 41
Chromoendoscopy 32 19 35 9 18 6
0 18
White-light 10 2 13 2 8 2
No. of visible dysplastic lesions
Reprinted from Gastrointestinal Endoscopy (81) and Gastroenterology (148), Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, and Soetikno R. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Copyright (2015), with permission from Elsevier RR Relative risk; CI confidence interval; SCENIC Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations
SCENIC meta-analysis
Gunther [27] Chiorean [22]
Study type
Study
Table 1. Proportion of patients with dysplasia and number of visible dysplastic lesions identified in studies comparing chromoendoscopy versus white-light colonoscopy Colonoscopy Surveillance and Management of Dysplasia Kaltenbach et al. 105
106
Colon (C Kahi, Section Editor)
Table 2. Suggested steps for implementation of chromoendoscopy into endoscopic practice Equipment Colonoscope Accessories
Contrast agent Procedure and protocol Time allotment Standard operating procedure
High-definition colonoscope, monitor, and cables Apply dye via the following: Water jet channel by using water pump attached to the endoscope activated via foot pedal or spray catheter: length 240 cm, endoscope accessory channel 2.8 mm Indigo carmine, 5-mL ampule (0.8 %) Consider doubling colonoscopy time slot initially during the learning curve period. Complete colonoscopy to cecum. Lavage with water and suction during intubation. Prepare dye solution during insertion for application via the foot pump or spray. Indigo carmine (0.03 %): mix 2 5-mL ampules of 0.8 % indigo carmine with 250 mL water. Methylene blue (0.04 %): mix one 10-mL ampule of 1 % methylene blue with 240 mL water. If using a foot pump: once the cecum is intubated, the water irrigation can be exchanged with the contrast solution. Apply the dye solution in a circumferential technique while withdrawing the colonoscope. Direct spray to the antigravity side. If using a spray catheter: the dye spray catheter is inserted into the biopsy channel; the catheter tip should protrude 2–3 cm from the endoscope. Apply dye solution segmentally by using a rotational technique while withdrawing the colonoscope to cover the surface mucosa with dye. Suction any excess solution after approximately 1 min to aid mucosal visualization. Focus on 20–30-cm segments sequentially with insertion of the endoscope to the proximal extent of each segment before slow withdrawal and mucosal visualization. Targeted dye spray for suspicious lesions: Prepare more concentrated dye solution for application. Indigo carmine (0.13 %): mix one 5-mL ampule of 0.8 % indigo carmine with 25 mL water. Methylene blue (0.2 %): mix one 10-mL ampule of 1 % methylene blue with 40 mL water. Spray about 30 mL directly from a 60-mL syringe through the biopsy channel. Remove endoscopically resectable suspicious lesions by using polypectomy or endoscopic mucosal resection. Do targeted biopsies of any unresectable abnormality visualized through chromoendoscopy to diagnose dysplasia. Do biopsies of flat area surrounding lesions to assess for dysplasia. Consider tattoo of suspicious dysplastic lesions arising from flat mucosa or not amendable to complete removal. Recommendations regarding the need to perform random, non-targeted biopsies for detection of dysplasia vary. If biopsies for dysplasia are not done, two random biopsies in every bowel segment are commonly recommended to document microscopic disease activity.
Reprinted from Gastrointestinal Endoscopy (81) and Gastroenterology (148), Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, and Soetikno R. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Copyright (2015), with permission from Elsevier
are slightly elevated or depressed, friable, obscure in vascular pattern, and villous or nodular in appearance (Fig. 1). Interfering anatomy, such as pseudopolyposis and strictures, can limit the yield of the panchromoendoscopy technique [18]. Prior to the start of the procedure, a total of approximately 250 mL of diluted dye (methylene blue, 0.04 to 0.1 %; or indigo carmine, 0.03 to 0.1 %) is prepared (Fig. 2). For 0.04 % methylene blue, one 10-mL ampule of 1 % methylene blue is mixed with 240-mL water. For 0.03 % indigo carmine, two 5-mL ampules of 0.8 % indigo carmine are mixed with 250mL water. Solutions can be prepared in containers compatible with the forward wash jet.
Colonoscopy Surveillance and Management of Dysplasia
Kaltenbach et al.
107
Fig. 1. a Three-centimeter, nonpolypoid, superficial, elevated colon lesion after indigo carmine chromoendoscopy. b The area of the lesion before dye spray. c The same lesion had likely been photographed approximately a year earlier (on fold to left of ulcer), but it was not recognized to be dysplastic. Histologic examination showed low-grade dysplasia. Reprinted from Gastrointestinal Endoscopy (81) and Gastroenterology (148), Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, and Soetikno R. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Copyright (2015), with permission from Elsevier.
During insertion, the mucosa should be washed and suctioned to free it of residual stool or debris. We use standard water jet for washing. After intubation of the cecum, the examination with pan-chromoendoscopy begins. The prepared chromoendoscopy solution container is directly exchanged with the water container. Methylene blue or indigo carmine is directly applied to the colon mucosa through the water jet channel (or a spray catheter). For efficient application, the dye is sprayed using the foot wash pump, and is targeted to the antigravity wall of the colon. The dye then pools to the gravity side and provides a circumferential coating of the
Fig. 2. Chromoendoscopy Technique. Reprinted from Gastrointestinal Endoscopy (81) and Gastroenterology (148), Laine L, Kaltenbach T, Barkun A, McQuaid KR, Subramanian V, and Soetikno R. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Copyright (2015), with permission from Elsevier.
108
Colon (C Kahi, Section Editor) mucosa. Expansion of the lumen with carbon dioxide insufflation can expand the mucosal surface to decrease large pools of dye. Chromoendoscopy can be performed segmentally during withdrawal whereby each colon segment is sprayed, any excess pools of dye are suctioned, and the mucosa with a thin layer of dye is carefully inspected for any suspicious areas that appear to be different from the surrounding background in color, pattern, or level. When chromoendoscopy is used for IBD surveillance, random biopsies for dysplasia detection are unnecessary [19, 20]. If biopsies for dysplasia are not done, two random biopsies in every bowel segment are commonly recommended to document microscopic disease activity.
Alternative surveillance methods to chromoendoscopy, such as high definition or equipmentbased image enhancement, are not superior in the detection of dysplasia The value of chromoendoscopy in the detection of dysplasia beyond high-definition colonoscopy has been a point of contention. Highdefinition endoscopy provides image signals of higher pixel density than standard-definition. Based on a prospective trial that showed the significant benefit in dysplasia detection using chromoendoscopy (21 %) compared to high definition white light alone (9 %), p = 0.007, the SCENIC guideline suggested the use of chromoendoscopy even when using high definition white light colonoscopy [21]. Since the SCENIC publication, a prospective randomized controlled trial further supports the significant value of chromoendoscopy in IBD surveillance colonoscopy to detect more dysplasia compared to white light highdefinition colonoscopy [22]. Currently available equipment-based image enhancement technologies include narrow band imaging (NBI) (Olympus, Tokyo, Japan), i-scan (Pentax, Tokyo, Japan), and Fuji Intelligent Chromo Endoscopy (FICE) (Fujinon, Tokyo, Japan) [23]. NBI has been the one studied in IBD surveillance. While alternative techniques continue to be studied, their routine use for surveillance is not supported by available evidence, and the SCENIC guidelines suggested against the use of NBI over that of white light colonoscopy or chromoendoscopy.
Characterization of visible dysplasia Any suspicious areas of abnormal mucosa should be further inspected. Using a syringe, a concentrated solution of dye can be sprayed directly onto the mucosa through the working channel. The more concentrated dye provides contrast to mucosal pattern and contour and can delineate borders of dysplastic lesions. Visible dysplasia should be described according to the Paris classification [24], polypoid (pedunculated, 0-Ip or sessile, 0-Is) or nonpolypoid (superficially elevated, 0-IIa; completely flat, 0-IIb; or depressed, 0-IIc), with qualifiers for ulceration and border of the lesion, as well as description of the location as within or outside an area of known colitis [10, 11••]. In addition, visible dysplasia should be characterized as Bendoscopically resectable^ or Bendoscopically unresectable.^ Endoscopically resectable features of visible dysplasia include (1) distinct margins, (2) complete removal based on endoscopic and
Colonoscopy Surveillance and Management of Dysplasia
Kaltenbach et al.
109
histologic assessment, and (3) the adjacent mucosa is free of dysplasia on histologic examination. Terms including dysplasia-associated lesion or mass (DALM), adenoma-like, and non-adenoma-like are not useful. After characterizing the lesion, biopsies should be targeted to the most concerning area of the lesion as well as the mucosa adjacent to the lesion to exclude invisible dysplasia.
Management Management decisions on endoscopic versus surgical resection of colorectal dysplasia in IBD patients are guided by both endoscopic and histologic findings, as well as patient-related factors such as age, comorbidities, patient preference, and risk tolerance.
Endoscopically visible dysplasia The SCENIC guidelines describe the role of endoscopic removal with surveillance for endoscopically resectable visible dysplasia. They recommend complete endoscopic removal of polypoid dysplasia over colectomy and suggest complete endoscopic resection of nonpolypoid dysplastic over colectomy. Most patients prefer endoscopic alternatives to colectomy until there is a relatively high certainty of cancer [25]. Endoscopic techniques for complete removal of flat dysplasia in IBD often require more than the simple polypectomy performed for polypoid ones [26]. If the visible dysplastic lesion is characterized as endoscopically resectable, en bloc endoscopic mucosal resection (EMR) is preferred. Hybrid EMR and endoscopic submucosal dissection are other options dependent upon the lesion characteristics and endoscopist’s skill. After endoscopic resection is complete, biopsies of the flat mucosa surrounding the resection site should be done to ensure that the lateral margins are free of dysplasia. Tattooing and photodocumentation of the area should also be performed to facilitate future surveillance or treatment. Recent ASGE guidelines provide an algorithm for the surveillance recommendations of endoscopically resectable lesions [19]. For example, patients with IBD who have large lesions that are endoscopically removed should have surveillance at approximately 3 to 6 months, with longer subsequent intervals (e.g., yearly) if the initial repeat colonoscopy result is negative. Patients with smaller polypoid lesions resected en bloc may return at 1-year intervals.
Endoscopically invisible dysplasia Colorectal dysplasia that is detected by random biopsies alone (i.e., endoscopically invisible) should be verified by another gastrointestinal (GI) pathologist. Interobserver agreement on the histologic diagnosis of dysplasia, low-grade dysplasia, or high-grade dysplasia in IBD has been shown to be fair even by expert GI pathologist review [27, 28]. Confirmed dysplasia warrants reevaluation with chromoendoscopy. Upon repeat colonoscopy by an endoscopist experienced with chromoendoscopy, if a visible dysplastic lesion can be localized in the same region of the colon as the previous random biopsy that showed invisible dysplasia, then the lesion should be characterized, determined to be endoscopically resectable or endoscopically unresectable and managed accordingly. Alternatively, if dysplasia is not visible, such patients
110
Colon (C Kahi, Section Editor) should have individualized management approach that considers the risks and benefits of continued intensive surveillance colonoscopy and colectomy. For example, patients with invisible low-grade dysplasia may remain in intensive surveillance while those with invisible high-grade dysplasia may more strongly consider colectomy. A recent retrospective observational study highlights the value of referring patients with endoscopically invisible dysplasia to an endoscopist with expertise in IBD surveillance using chromoendoscopy with high-definition colonoscopy [13]. The authors demonstrated the impact of performing chromoendoscopy in IBD patients whom had a diagnosis colorectal dysplasia from a white light high-definition examination. On subsequent chromoendoscopy examination, 30 % of the patients had dysplasia seen—dysplasia that was likely initially missed on the white light examination and classified as invisible. Importantly, these now visible lesions were often amenable to endoscopic resection.
Implications Improving the endoscopic recognition and management of dysplastic colorectal lesions in IBD patients could have important clinical practice implications. Namely, it may shift the current onerous and flawed surveillance approach of random biopsy that samples less than 0.1 % of the colonic mucosal surface area in a blind search for what is thought to be invisible dysplasia, to a targeted biopsy strategy whereby the colon surface is meticulously surveyed for dysplasia that is known to be predominantly visible. Furthermore, it may redirect the current treatment away from colectomy for invisible dysplasia to an individualized approach to locally remove a discrete dysplastic lesion. Most cases of CRC in IBD are believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended. The SCENIC process consented that surveillance to detect neoplasia is a shared recommendation and practice worldwide. From that starting point, the goal was to determine the optimal approach for detection and management of neoplasia when surveillance is performed. Arguments that chromoendoscopy should only be considered in high-risk IBD cohorts, such as those with a family history of CRC, concomitant primary sclerosing cholangitis, or prior history of dysplasia, are unfounded based on available literature [29–31]. The IBD populations surveyed with chromoendoscopy compared to white light in all of the studies were heterogeneous and did not stratify specific high-risk IBD groups. Furthermore, US guidelines (unlike British or European) do not directly address risk stratification and optimal surveillance interval [19, 32–34]. The key point is that when a patient is undergoing surveillance for dysplasia, the optimal method should be used. An economic analysis showed that surveillance colonoscopy using chromoendoscopy with targeted biopsies was less costly and more effective than conventional white light surveillance colonoscopy with random biopsies, at every surveillance interval [35•]. The study used endoscopic test characteristics, stage-specific CRC mortality rates, and Medicare reimbursement costs. Despite the robust prospective evidence base for chromoendoscopy with targeted biopsy, its uptake into routine IBD surveillance has been
Colonoscopy Surveillance and Management of Dysplasia
Kaltenbach et al.
111
challenged. Perceptions of its high complexity and long procedure time and frustrations with the limited supply of indigo carmine in the USA in the past year coupled with rising methylene blue costs and lack of reimbursement for the procedure have stalled widespread implementation of the optimal surveillance method. Furthermore, some authorities have questioned the significance and natural history of dysplasia detected using chromoendoscopy and pointed to lower quality evidence to defer the value and adoption of a universal chromoendoscopy approach. It is important to note that the SCENIC consensus ultimately made recommendations following a rigorous guideline development process as prescribed by the Institute of Medicine. A recent prospective follow-up evaluation of patients in an IBD surveillance program by Marion and colleagues demonstrates for the first time the superiority of chromoendoscopy over conventional white light examination with random biopsy technique in detecting dysplasia in patients who underwent colonoscopy surveillance over a 5-year period [16]. No adverse dysplasiarelated events, such as unnecessary surgery or interval carcinoma were observed in the follow-up period. By transitioning IBD surveillance to targeted sampling and resection of visible dysplastic lesions, we may positively impact the quality of colonoscopy, and increasing the dysplasia detection rates is a necessary stepping stone. Colonoscopy quality metrics in non-colitic patients, such as adenoma detection rate (ADR), can be a model [36]. ADR has the strongest association to interval or Bmissed^ CRC after screening colonoscopy. A landmark study of 314,872 exams performed by 136 gastroenterologists showed that each 1.0 % increase in the ADR had a 3.0 % decrease in the risk of CRC [37•]. Among patients of physicians with ADRs in the highest quintile, as compared with those in the lowest, the adjusted hazard ratio for any interval cancer was 0.52 (95 %CI, 0.39– 0.69). A longitudinal study of 1375 UC patients suggests that the adoption of a surveillance colonoscopy strategy using chromoendoscopy to detect visible dysplasia can influence similar quality outcomes. Over a four-decade period, the authors observed significant reductions in the risk of interval CRC, advanced stage CRC, and proportion of colectomies for dysplasia. A benchmark of excellence today for physicians and endoscopy centers is measuring and reporting quality; IBD surveillance should be held to the same standards. In summary, chromoendoscopy with targeted biopsies can improve the endoscopic detection and management of visible dysplastic colorectal lesions in IBD patients, compared with conventional white light colonoscopy with random biopsy. This strategy has been rigorously studied, synthesized, and summarized by SCENIC. Efforts and resources should now focus on its implementation into clinical practice, such as through training courses, photographic atlases [7••], and video repositories [38••]. A recent article provides a roadmap to navigate the barriers for the implementation of chromoendoscopy in IBD colonoscopy surveillance practice [39••]. It describes standardization of terminology, clinical protocols, training, and reporting and proposes mechanisms to measure quality and pursue reimbursement. Future research should explore alternative chromoendoscopy agents, should risk stratifying patients in order
112
Colon (C Kahi, Section Editor) to clarify optimal surveillance intervals using chromoendoscopy, should evaluate dysplasia and CRC incidence following chromoendoscopy examination as well as following endoscopic or surgical resection, and should measure quality of life.
Compliance with ethical standards Conflict of interest Gisele Leite declares no conflict of interest. Tonya Kaltenbach reports grants and personal fees from Olympus, Inc., outside the submitted work. Two non-profit charitable foundations, the Maxine and Jack Zarrow Family Foundation and the William K. Warren Foundation, provided unrestricted gifts supporting the SCENIC guideline development process. The funding sources had no involvement at any stage of the development process, no representation at the consensus meeting, and no role in the drafting or approval of the manuscript. Roy Soetikno reports grants and personal fees from Olympus, Inc, outside the submitted work. Human and animal rights and informed consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2.
3. 4. 5.
6.
7.••
Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35. Friedman S, Rubin PH, Bodian C, et al. Screening and surveillance colonoscopy in chronic Crohn’s colitis: results of a surveillance program spanning 25 years. Clin Gastroenterol Hepatol. 2008;6:993–8. quiz 953–4. Friedman S, Rubin PH, Bodian C, et al. Screening and surveillance colonoscopy in chronic Crohn’s colitis. Gastroenterology. 2001;120:820–6. Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel disease. N Engl J Med. 2015;373:195. Wang YR, Cangemi JR, Loftus Jr EV, et al. Rate of early/ missed colorectal cancers after colonoscopy in older patients with or without inflammatory bowel disease in the United States. Am J Gastroenterol. 2013;108:444–9. Sanduleanu S, Rutter MD. Interval colorectal cancers in inflammatory bowel disease: the grim statistics and true stories. Gastrointest Endosc Clin N Am. 2014;24:337–48. Soetikno R, Sanduleanu S, Kaltenbach T. An atlas of the nonpolypoid colorectal neoplasms in inflammatory
bowel disease. Gastrointest Endosc Clin N Am. 2014;24:483–520. Comprehensive atlas of endoscopic images, algorithms and tools to provide examples and guidance for detection of visible non-polypoid dysplasia in inflammatory bowel disease patients. 8. Rutter M, Bernstein C, Matsumoto T, et al. Endoscopic appearance of dysplasia in ulcerative colitis and the role of staining. Endoscopy. 2004;36:1109–14. 9. 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. 10. Laine L, Kaltenbach T, Barkun A, et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastrointest Endosc. 2015;81:489–501. e26. 11.•• 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 e28. Statements on optimal surveillance and management strategies for patients with inflammatory bowel disease following a rigorous guideline development process, including meta-analyses
Colonoscopy Surveillance and Management of Dysplasia and synthesis of data. The publication and recommendations have been endorsed by numerous international societies. 12. Choi CH, Rutter MD, Askari A, et al. Forty-year analysis of colonoscopic surveillance program for neoplasia in ulcerative colitis: an updated overview. Am J Gastroenterol. 2015;110:1022–34. 13. Deepak P, Hanson GJ, Fletcher JG, et al. Incremental diagnostic yield of chromoendoscopy and outcomes in inflammatory bowel disease patients with a history of colorectal dysplasia on white-light endoscopy. Gastrointest Endosc 2015. 14. Choi CH, Ignjatovic-Wilson A, Askari A, et al. Lowgrade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer. Am J Gastroenterol. 2015;110:1461–71. 15. Mooiweer E, van der Meulen-de Jong AE, Ponsioen CY, et al. Chromoendoscopy for surveillance in inflammatory bowel disease does not increase neoplasia detection compared with conventional colonoscopy with random biopsies: results from a large retrospective study. Am J Gastroenterol. 2015;110:1014–21. 16. Marion JF, Waye JD, Israel Y, et al. Chromoendoscopy is more effective than standard colonoscopy in detecting dysplasia during long-term surveillance of patients with colitis. Clin Gastroenterol Hepatol 2015. 17. Soetikno R, Subramanian V, Kaltenbach T, et al. The detection of nonpolypoid Dflat and depressed] colorectal neoplasms in patients with inflammatory bowel disease. Gastroenterology. 2013;144:1349–52. 1352 e1-6. 18. Fumery M, de Pineton CG, Stefanescu C, et al. Detection of dysplasia or cancer in 3.5% of patients with inflammatory bowel disease and colonic strictures. Clin Gastroenterol Hepatol. 2015;13:1770–5. 19. Committee ASoP, Shergill AK, Lightdale JR, et al. The role of endoscopy in inflammatory bowel disease. Gastrointest Endosc. 2015;81:1101–21. e1-13. 20. 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;109:715–22. 21. Picco MF, Pasha S, Leighton JA, et al. Procedure time and the determination of polypoid abnormalities with experience: implementation of a chromoendoscopy program for surveillance colonoscopy for ulcerative colitis. Inflamm Bowel Dis. 2013;19:1913–20. 22. Mohammed N, Kant P, Abid F. High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomized controlled trial. Gastrointest Endosc. 2015;81:AB148. 23. Subramanian V, Ragunath K. Advanced endoscopic imaging: a review of commercially available technologies. Clin Gastroenterol Hepatol. 2014;12:368–76. e1. 24. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003;58:S3-43.
25.
Kaltenbach et al.
113
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;16:1658–62. 26. 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 2013. 27. Eaden J, Abrams K, McKay H, et al. Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis. J Pathol. 2001;194:152–7. 28. Odze RD, Goldblum J, Noffsinger A, et al. Interobserver variability in the diagnosis of ulcerative colitisassociated dysplasia by telepathology. Mod Pathol. 2002;15:379–86. 29. Marion JF, Sands BE. The SCENIC consensus statement on surveillance and management of dysplasia in inflammatory bowel disease: praise and words of caution. Gastroenterology. 2015;148:462–7. 30. Ananthakrishnan AN. Chromoendoscopy is better: so why am I not (yet) using it for routine inflammatory bowel disease surveillance? Clin Gastroenterol Hepatol 2015. 31. Higgins PD. Miles to go on the SCENIC route: should chromoendoscopy become the standard of care in IBD surveillance? Am J Gastroenterol. 2015;110:1035–7. Farraye FA, Odze RD, Eaden J, et al. AGA technical 32. review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010;138:746–74. 774 e1-4; quiz e12-3. 33. Kornbluth A, Sachar DB. Practice parameters committee of the American College of G. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, practice parameters committee. Am J Gastroenterol. 2010;105:501–23. quiz 524. 34. Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. 2010;59:666–89. 35.• Konijeti GG, Shrime MG, Ananthakrishnan AN, et al. Cost-effectiveness analysis of chromoendoscopy for colorectal cancer surveillance in patients with ulcerative colitis. Gastrointest Endosc 2013. Economic analysis of surveillance strategies for dypslasia showing chromoendoscopy as dominant surveillance strategy, irrespective of surveillance interval. 36. Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81:31–53. 37.• Corley DA, Jensen CD, Marks AR, et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014;370:1298–306. Landmark study to show strong inverse association of adenoma detection rates with incident colorectal cancer and mortality. 38.•• Kaltenbach T, McQuaid K, Sanchez-Yague A, et al. Chromoendoscopy with Targeted Biopsy to Detect
114
Colon (C Kahi, Section Editor)
Nonpolypoid Colorectal Neoplasms in Inflammatory Bowel Disease http://www.youtube.com/watch?v= OARkbgwlObI. ASGE Eductational Products and CME Program Audiovisual Award, 2014. Audio-visual instruction on the chromoendoscopy with targeted biopsy technique to detect visible nonpolypoid dysplasia in inflammatory bowel disease, including numerous video examples of lesion detection, characterization and removal, as well as the necessary tools.
39.•• Sanduleanu S, Kaltenbach T, Barkun A, et al. A roadmap to the implementation of chromoendoscopy in inflammatory bowel disease colonoscopy surveillance practice. Gastrointest Endosc. 2016;83:213–22. This article provides a framework for practitioners and centers to adopt chromendoscopy into inflammatory bowel disease colonoscopy surveillance practice.
