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Endoscopic evaluation for colon cancer and dysplasia in patients with inflammatory bowel disease
Author’s Accepted Manuscript Endoscopic Evaluation for Colon Cancer and Dysplasia in Patients with Inflammatory Bowel Disease Amandeep Shergill, Francis A. Farraye www.elsevier.com/locate/tgie
PII: DOI: Reference:
S1096-2883(16)30046-8 http://dx.doi.org/10.1016/j.tgie.2016.08.003 YTGIE50500
To appear in: Techniques in Gastrointestinal Endoscopy Received date: 25 May 2016 Accepted date: 19 August 2016 Cite this article as: Amandeep Shergill and Francis A. Farraye, Endoscopic Evaluation for Colon Cancer and Dysplasia in Patients with Inflammatory Bowel D i s e a s e , Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2016.08.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Techniques in Gastrointestinal Endoscopy Endoscopic Evaluation for Colon Cancer and Dysplasia in Patients with Inflammatory Bowel Disease
Amandeep Shergill, MD, MS San Francisco VA Medical Center; University of CA, San Francisco [email protected] Francis A. Farraye, MD, MSc Clinical Director, Section of Gastroenterology Boston Medical Center 85 East Concord Street Boston, MA 02118 [email protected]
ABSTRACT: Certain patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer, and surveillance is recommended to detect dysplasia and early neoplasia. Endoscopic techniques that screen large mucosal surface areas for potential areas of interest that have been studied in IBD surveillance include dye-based surface chromoendoscopy with methylene blue or indigo carmine, dye-less chromoendoscopy including narrow band imaging (NBI), i-scan, and Fujinon intelligent chromoendoscopy (FICE), and autofluorescence imaging. Literature to date supports the use of surface chromoendoscopy with either methylene blue or indigo carmine to maximize dysplasia detection. Characterization of detected lesions may be further enhanced with optical biopsy technology, including confocal laser endomicroscopy and endocystoscopy, that allow in vivo histological diagnosis that may guide both diagnosis and therapy of detected dysplastic lesions. Current and future endoscopic approaches for optimizing screening and surveillance of colon cancer and dysplasia in patients with IBD are reviewed. KEYWORDS: Inflammatory bowel disease, dysplasia, colon cancer, surveillance, image enhanced endoscopy, chromoendoscopy Request for reprints: Amandeep Shergill, MD
1. Introduction Inflammatory bowel disease (IBD) is associated with a 1.5 to 2 times increased risk of colorectal cancer (CRC).(1) Multiple societies endorse surveillance colonoscopy in patients with ulcerative colitis (UC) proximal to the rectosigmoid colon or Crohn’s disease (CD) involving more than one third of the colon, in an attempt to detect dysplasia and early neoplasia.(2-10) Case-control and cohort studies have demonstrated that surveillance colonoscopy is associated with a decreased incidence of CRC and an increased CRC-associated 5-year survival rate.(11-16) Risk for CRC is greatest in patients with primary sclerosing cholangitis (PSC), increased disease extent, severity and duration.(17-22) Herein we will review current and potential future endoscopic approaches for optimizing screening and surveillance of colon cancer and dysplasia in patients with IBD. 2. Techniques for Dysplasia Detection Surveillance should ideally be performed when in remission.(9, 10) Excellent bowel prep is required to identify subtle lesions.(23) “Red-flag” techniques are endoscopic techniques that screen large mucosal surface areas for potential “areas of interest”,(24) and many modalities have been studied in IBD surveillance colonoscopy. 2.1 Standard Definition White Light Endoscopy Historically, surveillance guidelines using standard white light endoscopy (WLE) endorsed a random biopsy protocol (4 biopsies obtained at every 10 cm intervals during withdrawal).(5) The recommendation for random biopsies stemmed from the belief that dysplasia in IBD was often endoscopically invisible. In an attempt to determine whether flow cytometric measurement of DNA content in colonic biopsies could identify UC patients at increased risk of progression to dysplasia, Rubin et al determined the prevalence and distribution of DNA aneuploidy.(25) Highrisk patients without cancer or dysplasia were subsequently enrolled in a prospective surveillance study. In the specimen procurement protocol, samples of flat mucosa were taken from 4 quadrants at 10 cm intervals from the cecum to the anus. Based on the percentage of biopsies with abnormal histology, the authors estimated that if dysplasia is present in 5% of the colonic mucosa, 33 biopsies are required for histologic detection of dysplasia with 90% confidence.(25) Multiple societies endorsed this 33 random biopsy protocol as the standard for IBD surveillance.(3, 5, 26)
Subsequent studies have demonstrated that most dysplasia is endoscopically visible, and there is a low yield of random biopsies as compared to targeted biopsies.(27-30) A single center experience of 1,010 surveillance colonoscopies in 475 UC patients during a 10-year period found that 94% of neoplastic lesions were macroscopically visible, with only a 0.2% yield from random biopsy. Random biopsies from normal appearing colon (no endoscopic features of prior severe inflammation) yielded no dysplasia.(30) Lesion detection is further enhanced with use of image-enhanced endoscopy (IEE).(27-30) Several but not all national and international consensus guidelines endorse the use of IEE over standard WLE, with the European Crohn’s and Colitis Organization stating that random biopsy is an inferior method of dysplasia detection.(6, 7, 9, 10, 31, 32) 2.2 High Definition White Light Endoscopy Standard definition (SD) endoscopes have image resolutions of approximately 367,000 pixels.(33) High-definition (HD) endoscopes display image resolutions that range from 850,000 pixels to more than 1 million pixels.(33) The higher pixel density and faster line scanning on the monitor produce sharper images.(34) One retrospective observational study of HD (N=209) vs. SD (N=160) found that the adjusted prevalence ratio of detecting any dysplastic lesion was 2.21 (95% confidence interval [CI] 1.1-4.5) in the HD group as compared to the SD group.(35) HD endoscopy is recommended rather than SD endoscopy to maximize dysplasia detection. (31)
2.3 Magnification Magnification refers to the ability to optically zoom or magnify images 150 fold, without affecting pixel density.(34, 36) Magnification endoscopy, coupled with other endoscopic modalities, can aid in the characterization of detected lesions. Further discussion of the role of magnification endoscopy in the endoscopic evaluation of dysplasia will be detailed in the sections below. 2.4 Chromoendoscopy Chromoendoscopy (CE) refers to enhanced imaging techniques that highlight mucosal architectural abnormalities and submucosal vascular patterns. Chromoendoscopy can involve the topical application of dyes (dye-based CE), or use optical or virtual enhancement tools (dyeless CE).(37)
2.4a Dye based CE Dilute indigo carmine (IC) (0.03-0.5%) or methylene blue (MB) (0.04-0.2%) is sprayed via a spray catheter or through the water-jet channel using an automated pump during dye based CE.(9, 10, 31, 38, 39) Indigo carmine is a contrast agent, while methylene blue is an absorptive agent that is variably absorbed or unabsorbed by inflamed or dysplastic mucosa.(40) The colonic mucosa is sprayed on withdrawal either segmentally or every 30cm, and excess fluid is aspirated.(10) Surface chromoendoscopy highlights the topography of the colonic mucosa,(40) aiding in the detection of subtle lesions that might have been missed with WLE alone.(39) (Figure 1a and 1b). Several organizations have recommended surface chromoendoscopy with IC or MB as the preferred surveillance technique for maximizing dysplasia detection during IBD colonoscopy(7, 9, 10, 32, 41) with a 2-3 fold increase in per patient dysplasia detection and 4-5 fold increase in per lesion dysplasia detection.(10) A meta-analysis of 8 trials (2 randomized controlled trials, 4 prospective tandem studies, and 2 retrospective studies) demonstrated a significant increase in dysplasia detection with chromoendoscopy compared to standard WLE (RR = 1.8 [95% CI 1.2-2.6]) and an absolute risk increase of 6% [95% CI 3-9%].(31) Chromoendoscopy is the recommended technique when compared to standard WLE. (31) There are few studies comparing CE to HD WLE. A prospective, tandem study of the implementation of CE with IC into practice utilizing HD colonoscopes demonstrated an increased yield of CE (21%) versus HD WLE (9%), resulting in a relative increase in yield of 129% per patient, p=0.007.(42) The increased yield was greatest for the detection of flat lesions: one flat lesion was detected with HD WLE versus 7 with CE, resulting in a relative increase in yield of 700% (p<0.001).(42) Preliminary results from a randomized trial of HD CE (50 patients) compared to HD WLE (53 patients) found a total of 14 dysplastic lesions (1 with high grade and 13 with low grade dysplasia) in 11 patients (22%) in the HD CE and 6 dysplastic lesions (all low grade dysplasia) in 5 patients (9.4%) in the HD WLE arm. HD CE was significantly better (p=0.04) than HD WLE on a per patient basis for the detection of endoscopically visible dysplastic lesions.(43) While we await more high quality studies comparing CE to HD WLE, during HD colonoscopy, CE is the suggested technique to maximize dysplasia detection.(31) The technique of CE has previously been described.(38, 39) SURFACE guidelines have been proposed to aid in standardization of the technique.(44) Picco et al demonstrated that CE can be successfully implemented into practice after a short training session using images from a
teaching file and general instruction on the IC CE technique.(42) Physicians with no prior experience in CE UC surveillance demonstrated a high yield using CE with acceptable withdrawal times (withdrawal time stabilized at a median of 19 minutes after more than 15 procedures had been performed).(42) In a meta-analysis, CE appears to increase procedure time by 11 min compared to WLE.(45) Magnification endoscopy can help characterize lesions detected by CE by differentiating neoplastic from non-neoplastic lesions. Routine application of Kudo pit patterns may not be applicable in colitis, as regenerative mucosa can have pit patterns that become elongated and irregular,(46) and can resemble Kudo type IV pit patterns without harboring dysplasia.(47) However, in a study by Hata et al, no neoplasia was seen in lesions with type I or II pit patterns.(47) Nishyama et al demonstrated in neoplastic lesions, pit density was greater (89% vs. 60%) and pit margins more frequently irregular (63% vs. 33%) when compared to nonneoplastic lesions.(48) Larger prospective studies are needed to validate these findings. Despite the endorsement by multiple societies and international consensus groups, adoption of CE as the standard for surveillance has been slow. Some critics call into question the natural history of CE-detected lesions, stating that the goal of surveillance should be to prevent lifethreatening colon cancer.(49) The longitudinal experience with standard WLE vs. CE supports CE as tool for cancer prevention. Over a 5-year period from 2006-2011, with a median of 27.8 months of follow-up for the cohort, Marion and colleagues found that CE was superior to targeted WLE (OR 2.4 [95% 1.4-4.0]) for dysplasia detection, and that a negative CE surveillance colonoscopy was the best indicator for a dysplasia-free outcome.(50) In addition, Choi and colleagues recently demonstrated in their St. Mark’s Hospital cohort of 1,375 patients undergoing 8,650 colonoscopies, 1,098 of which were performed with CE, that there was a twofold higher neoplasia detection rate in the CE group (n=92/1,098, 8.4%) compared to the WLE endoscopy group (n=175/4,373, 4.0%; p<0.001).(16) The incidence rate of CRC in patients with at least one CE surveillance colonoscopy was significantly lower (2.2 per 1,000 patient-years) than in those who had never had a CE exam (4.6 per 1,000 patient-years; p=0.02). Although not significantly different, there was also a trend towards a lower postcolonoscopy CRC rate in the CE group (1.2 per 1,000 patient-years) compared to WLE group (1.8 per 1,000 patient-years, p=0.6).(16) Others question the routine application of CE to all patients with IBD requiring surveillance without risk stratifying patients into high versus low risk groups. A prospective randomized study of 155 patients with long standing UC without PSC and/or history of IN compared CE-guided endomicroscopy (CGE, 72 patients) with conventional
WLE with random biopsies (73 patients).(51) While significantly fewer biopsies were obtained in the CGE group (4.7 +/- 4.9 vs. 36 +/- 6.2, p<0.001) and the per-biopsy yield of intraepithelial neoplasia (IN) was higher in the CGE group (1/48 vs. 1/438, p<0.001), there was no significant difference in dysplasia detection (7 IN in CGE and 6 in WLE, p>0.05) in UC patients without PSC or prior history of IN.(51) Lastly, the real-life effectiveness of CE has been questioned. While one prospective, tandem study demonstrated an increased yield with CE in routine practice,(42) a retrospective analysis over a 13 year period evaluating the implementation of HD CE in 440 colonoscopies compared to 1,802 WLE colonoscopies did not demonstrate significantly different dysplasia detection between these groups (11% CE vs. 10% WLE, p=0.80).(52) 2.4b Dye-less CE Dye-less CE includes narrow band imaging (NBI, Olympus, Tokyo, Japan), i-scan (Pentax, Tokyo, Japan), and Fujinon Intelligent Color Enhancement (FICE, Fujifilm, Tokyo, Japan).(37) Dye-less CE is attractive because these are “push-button” technologies that are integrated into the endoscopes, potentially leading to decreased time required for the application of the technology while, ideally, preserving dysplasia detection yield. Narrow Band Imaging NBI can be activated by the push of a button, and uses filters to restrict light to narrow bands of blue and green wavelengths which are strongly absorbed by hemoglobin, enhancing mucosal vasculature.(53) NBI has not demonstrated increased yield for dysplasia during surveillance examinations. NBI has been compared to WLE in three studies.(54-56) Two randomized, crossover studies comparing NBI to standard WLE (54) and to high definition WLE(56) failed to demonstrate improved dysplasia detection with NBI. A randomized, parallel group trial of NBI versus high definition WLE did not demonstrate a difference in dysplasia detection between the two groups. This study was powered to detect a three-fold increase in dysplasia detection with NBI, but was stopped after interim analysis of 112 patients demonstrated 9% dysplasia detection in both groups, with an adjusted OR of true-positive lesion detection of NBI vs. high definition WLE of 0.69 (95% CI 0.16-2.96, p=0.62), suggesting NBI was less likely to detect dysplasia than high definition WLE.(55) NBI has been compared to chromoendoscopy in two studies. A randomized, crossover study compared targeted biopsies by NBI to targeted biopsies by chromoendoscopy, and found no significant difference in dysplasia detection. However, a trend towards a higher missed neoplastic lesion rate was seen with NBI as
compared to CE (31.8% [95% CI 12.3-51.5%] vs. 13.6% [95% CI -0.7 to 27.9%], p=0.2), and a trend towards a higher missed neoplastic patient rate was seen with NBI as compared to CE (46.1% [95% CI 19-73.2] vs. 15.4% [95% CI -4.1 to 35], p=0.2).(57). Preliminary results from a second study of 93 patients with longstanding UC, published in abstract form only, suggested similar true neoplastic detection rates for NBI (11.8%) as compared to CE (17.9%, p=0.225) in endoscopically suspicious raised lesions.(58) It not surprising that in IBD, where inflammation can cause significant disruption of the underlying vascular pattern, NBI has not consistently demonstrated an increased dysplastic yield. The peer reviewed publication by Bisschops is eagerly awaited,(58) as there may be a patient population in which NBI may have a similar increased yield as CE, at least for raised lesions. Until this data are available, CE remains the gold standard for maximizing dysplasia detection. A potential niche for NBI, when combined with magnification endoscopy, may be in characterizing detected lesions. One of the first case reports exploring the role of NBI with magnification in UC surveillance discussed the role of vascular pattern intensity, with dysplastic lesion in one patient demonstrating a stronger (blacker) capillary vascular pattern as compared to normal mucosa.(59) In a pilot study evaluating magnifying colonoscopy with NBI in 46 patients with UC, a tortuous pattern seen on NBI may be a clue to identifying dysplasia during UC surveillance, although overall the number of dysplastic lesions detected in this study was low (5 lesions in 3 patients).(60) As discussed earlier, while the routine application of Kudo pit pattern may not be possible in colitis, integration of additional characteristics such as vascular pattern intensity or the presence of a tortuous pattern may be necessary to maximize differentiation of dysplastic from normal tissue. i-Scan i-Scan is a virtual CE technology that uses post-processing algorithms to enhance reflected light and reconstruct virtual images in real time.(53) i-Scan combines surface-enhancement , contrast-enhancement and tone-enhancement in three different modes: i-scan mode 1 (surfaceenhancement) is used for lesion detection, mode 2 (surface-enhancement plus tonal enhancement) for lesion characterization, and mode 3 (surface-, tone- and contrastenhancement) for lesion demarcation.(61) I-scan has yielded positive results in increased dysplastic yield in average risk patients undergoing colonoscopy as compared to WLE(62) and similar yield to CE.(63) University of Calgary is currently enrolling patients in a randomized
controlled trial comparing dysplasia detection during HD WLE, surface CE (0.2% indigo carmine) and i-scan in UC and CD patients with long standing colitis undergoing surveillance (NCT02098798). Fujinon Intelligent Chromoendoscopy FICE is another proprietary virtual CE technology utilizing post-processing algorithms to emphasize certain ranges of wavelengths.(53) While there appears to be ongoing clinical trials evaluating the role of FICE in IBD surveillance (NCT00816491), no published studies in IBD surveillance are available for review. Studies in average-risk patients have not demonstrated an increased dysplastic yield of FICE compared to standard WLE with targeted CE (64) or to HD WLE.(65) 2.5 Autofluorescence Imaging (AFI) Autofluorescence imaging utilizes short wavelength light to excite endogenous mucosal fluorophores, which then emit light of longer wavelengths.(66) Color differences in fluorescence emission are captured and integrated into a real-time pseudocolor image, with normal tissue appearing green and dysplastic tissue appearing purple/magenta. AFI can be activated by the push of a button on trimodal imaging video endoscopes (EVIS LUCERA SPECTRUM; Olympus Medical Systems Co, Tokyo, Japan).(66) Studies to date have demonstrated AFI is a sensitive tool for dysplasia detection. A study by van den Broek et al compared AFI against high resolution WLE for dysplasia detection followed by NBI for lesion classification (endoscopic trimodal imaging) in 50 UC patient with inactive pan-ulcerative colitis for ≥8 years duration; patients with active disease were excluded in this study.(67) In this randomized crossover study, the neoplasia miss rate for AFI was 0% and WLE 50% (P=0.036). For lesion characterization, the sensitivity and specificity of AFI was 100% and 42%, while NBI was 76% and 81%.(67) Matsumoto and colleagues prospectively studied 48 UC patients with clinically inactive disease undergoing UC surveillance, and lesions were characterized as flat or protruding, and low AFI (purple) or high AFI (green).(68) The positive rate of dysplasia in protruding lesions was significantly higher in low AF (purple, 45%) than in high AF (green, 13.3%, p=0.043). The positive rate of dysplasia in flat lesions was not significantly different in low AF (8.2%) vs. high AF (0%, p=0.3).(68) This study suggests there may be a role for AFI in detecting protruding lesions, and appears to have good sensitivity but poor specificity for detecting flat dysplasia.
The difficulty in detecting dysplasia in flat lesions may be due to an alteration in autofluorescence according to the grade of inflammation. One study of AFI in assessing UC activity demonstrated that active inflammation was associated with low AFI, likely due to an autofluorescence signal that is decreased by damaged submucosal layer or a thickened mucosal layer.(69) 3. CHARACTERIZATION OF DETECTED LESIONS: OPTICAL BIOPSY TECHNOLOGY Lesions detected by “red flag” technologies can be further characterized by new technology that allows in vivo histological analysis and for procurement of “smart” biopsies. 3.1 Confocal Laser Endomicroscopy (CLE) Confocal laser endomicroscopy requires the administration of a topical or systemic fluorescence agent followed by the use of a blue laser light, resulting in 1000-fold magnification of tissue and in vivo histological evaluation.(70) An endoscopy based CLE system (e-CLE) by Pentax is no longer commercially available (Pentax, Tokyo, Japan).(70) Currently, CLE is performed with a probe-based system (p-CLE, Cellvizio, Paris, France). P-CLE is best used in conjunction with other “red-flag” technologies to target CLE examination to focused “areas of interest”, since endomicroscopy has a limited field of view.(24) Criteria for classification of e-CLE(71) and pCLE(72) patterns have been proposed. Although these classification systems have been applied in colitis surveillance,(73) classifications for CLE images obtained during an exam within colitic mucosa have not been established. CLE, in conjunction with CE, can result in improved dysplasia characterization while reducing the number of biopsies required for diagnosis. Kiesslich et al demonstrated in a randomized controlled trial of 161 patients that CE guided CLE increased the diagnostic yield 4.75 fold as compared to standard WLE with random biopsy (p=0.005), predicting dysplasia with a sensitivity of 94.7%, and specificity of 98.3% in a total of 134 lesions.(74) Per-patient biopsies could be decreased from 42.2 biopsies in the conventional colonoscopy group to 3.9 biopsies in the CECLE targeted group if biopsies were limited to the detected lesions. CLE images were classified as normal mucosa, regenerative mucosa, neoplasia, or inflammation by using crypt and vessel architecture and cellular infiltration. CLE had a negative predictive value of 99.1% if mucosa appeared normal on CLE imaging.(74) A retrospective cohort study by Gunther et al evaluated the yield of random versus targeted biopsy protocols in three cohorts of 50 patients each: HD (Olympus CF-180AI)/ high-resolution endoscopy targeted, HD chromoendoscopy (Olympus CF-
180AI) targeted, and confocal endomicroscopy (Pentax EC-3870CIFK) targeted biopsy protocols (endoscope type, personal communication with author).(75) Targeted biopsies with CE and CLE yielded significantly greater dysplasia detection rates (HD 0, CE 4%, CLE 8%, p<0.05).(75) In the previously mentioned study of a single endoscopist performing CE-guided endomicroscopy (CGE), CGE decreased the number of biopsies performed while significantly improving the per-biopsy yield of dysplasia, although the overall dysplastic yield was similar to WLE in UC patients without PSC or prior history of dysplasia.(51) In contrast, a study by Hlavaty et al of 30 patients with 100 suspicious lesions evaluated with WLE, CE and e-CLE found that eCLE did not improve the sensitivity and specificity of CE for dysplasia detection, and one-third of lesions, especially if pedunculated, could not be evaluated by CLE.(76) In addition to differentiating dysplastic from non-dysplastic tissue, CLE may allow for real-time evaluation of endoscopic resectability. Hurlstone et al evaluated the use of e-CLE on 36 lesions to determine endoscopic resectability of detected lesions (previously termed adenoma-like mass (ALM) if endoscopically resectable, and dysplasia associated lesional mass if endoscopically unresectable (DALM)). E-CLE and histopathology demonstrated a kappa coefficient of agreement of 0.91, reporting an overall CLE predictive accuracy of 97% (95% confidence interval 86%–99%).(73) Interestingly, in the 6 lesions determined to be dysplastic lesions that were not endoscopically resectable, 4 (66%) were ultimately diagnosed with a colitis-associated CRC localized to the detected lesion, while 2 (35%) had CRC remote to the detected lesion that was not seen on the index colonoscopy.(73) P-CLE has also been utilized for lesion characterization for endoscopic resectability.(77) 3.2 Endocystoscopy After topical application of an absorptive contrast agent (methylene blue, toluidine blue, crystal violet), endocytoscopy (Olympus, Tokyo, Japan) allows a 1400 fold magnification of the mucosa via a contact light microscope that enables real time visualization of the very superficial epithelial cellular structures.(78) Endocystoscopy can be performed via a probe-based system (pEC) or an integrated endoscope system (iEC).(79) Literature evaluating the role of endocystoscopy in IBD is limited. Two studies have evaluated the yield of endocytoscopy in the determination of histopathological activity in UC.(80, 81) Emerging data suggest endocytoscopy may have a role in differentiating neoplastic from nonneoplastic tissue in the colon,(82) and application in IBD surveillance is awaited.
4. Current and Future Prospects Studies in IBD surveillance clearly support the notion that the era of random biopsies for dysplasia detection has passed. The optimal “red-flag” technique and smart biopsy protocol will be a balance of increased dysplasia yield and ease of use, which will need to take into account both training and practical implementation. CE is currently the established technique to maximize dysplasia detection, and should be the standard against which all other technology is compared. Endoscopists employing CE will need to determine if the data is sufficient to warrant CE surveillance in all patients, or selectively use it in the highest risk patients. While we agree that more prospective data are needed to understand how best to utilize CE in the era of HD WLE and other IEE, we believe that the current data support the use of CE with targeted biopsies to maximize dysplasia detection over other endoscopic methods. CE can be readily applied in most endoscopic units, since specialized equipment is not required beyond the CE agent (MB/IC), and a spray catheter or water jet pump, which are available in most endoscopy units today. Published data support successful implementation of a CE surveillance program after a short tutorial, which are readily available on-line.(38) CE surveillance will lead to increased dysplasia detection with fewer biopsies, and with acceptable withdrawal times. Further studies need to address if intervals between colonoscopic examinations can be lengthened after a negative CE examination. While some may continue to argue that the natural history of CE-guided lesions in not known, there is a robust body of literature that demonstrates increased adenoma detection is inversely correlated with interval cancer risk in screening colonoscopies.(83) The interval cancer risk in IBD can be substantial.(84) Ideally, longer-term data will confirm the findings of Marion et al that a negative CE exam is the best indicator for a dysplasia free outcome, which can hopefully lead to a lengthening of the surveillance intervals. Perhaps HD WLE with targeted biopsies will yield similar dysplasia detection rates to CE, especially in the hands of trained endoscopists.(51) Until that is proven in other high quality prospective studies and in general practice settings, we cannot ignore the body of literature supporting the superior dysplasia detection with CE, even in the hands of novice CE endoscopists. NBI, especially the newer generation scopes which yield brighter images, has promise as an easy to use push button technology. Since the technology relies on enhancement of mucosal vasculature, future studies should clarify the role background inflammation has on the yield of NBI exam. In addition, the learning curve for NBI and real-time lesion detection and
characterization during IBD surveillance has not been defined. At present, NBI cannot be considered comparable to CE for dysplasia detection. i-scan, FICE and AFI are other push-button technologies that require the use of dedicated equipment and expertise in image interpretation. Studies are ongoing and will help clarify their role in IBD surveillance. P-CLE is available in specialized endoscopy units and requires additional training for in vivo histologic assessment and the use of dedicated equipment. A short learning curve has been established for p-CLE using offline video sequences,(85) but the learning curve for dysplasia evaluation in potentially inflamed mucosa is unknown. Thus, while the role of CLE in “smart biopsy” protocols is promising, additional studies are needed to better understand its application to routine IBD surveillance colonoscopy. In conclusion, HD CE is currently the preferred method of IBD surveillance to maximize dysplasia detection. While other "red flag” techniques are promising, they will need to demonstrate equivalent dysplasia detection before they can be adopted in place of CE. IEE enables the use of targeted biopsies, and new technology such as CLE and endocytoscopy may allow in vivo histological diagnosis that will not only guide diagnosis but therapy of these lesions.
Conflicts of Interest: Shergill: NONE Farraye: NONE
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Figure 1. Surface chromoendoscopy highlights the topography of the colonic mucosa, aiding in the detection of subtle lesions. a. High definition white light endoscopy
b. Surface chromoendoscopy with indigo carmine enhances detection of a depressed lesion with a distinct border; pathology yields low-grade dysplasia.
PII: DOI: Reference:
S1096-2883(16)30046-8 http://dx.doi.org/10.1016/j.tgie.2016.08.003 YTGIE50500
To appear in: Techniques in Gastrointestinal Endoscopy Received date: 25 May 2016 Accepted date: 19 August 2016 Cite this article as: Amandeep Shergill and Francis A. Farraye, Endoscopic Evaluation for Colon Cancer and Dysplasia in Patients with Inflammatory Bowel D i s e a s e , Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2016.08.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Techniques in Gastrointestinal Endoscopy Endoscopic Evaluation for Colon Cancer and Dysplasia in Patients with Inflammatory Bowel Disease
Amandeep Shergill, MD, MS San Francisco VA Medical Center; University of CA, San Francisco [email protected] Francis A. Farraye, MD, MSc Clinical Director, Section of Gastroenterology Boston Medical Center 85 East Concord Street Boston, MA 02118 [email protected]
ABSTRACT: Certain patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer, and surveillance is recommended to detect dysplasia and early neoplasia. Endoscopic techniques that screen large mucosal surface areas for potential areas of interest that have been studied in IBD surveillance include dye-based surface chromoendoscopy with methylene blue or indigo carmine, dye-less chromoendoscopy including narrow band imaging (NBI), i-scan, and Fujinon intelligent chromoendoscopy (FICE), and autofluorescence imaging. Literature to date supports the use of surface chromoendoscopy with either methylene blue or indigo carmine to maximize dysplasia detection. Characterization of detected lesions may be further enhanced with optical biopsy technology, including confocal laser endomicroscopy and endocystoscopy, that allow in vivo histological diagnosis that may guide both diagnosis and therapy of detected dysplastic lesions. Current and future endoscopic approaches for optimizing screening and surveillance of colon cancer and dysplasia in patients with IBD are reviewed. KEYWORDS: Inflammatory bowel disease, dysplasia, colon cancer, surveillance, image enhanced endoscopy, chromoendoscopy Request for reprints: Amandeep Shergill, MD
1. Introduction Inflammatory bowel disease (IBD) is associated with a 1.5 to 2 times increased risk of colorectal cancer (CRC).(1) Multiple societies endorse surveillance colonoscopy in patients with ulcerative colitis (UC) proximal to the rectosigmoid colon or Crohn’s disease (CD) involving more than one third of the colon, in an attempt to detect dysplasia and early neoplasia.(2-10) Case-control and cohort studies have demonstrated that surveillance colonoscopy is associated with a decreased incidence of CRC and an increased CRC-associated 5-year survival rate.(11-16) Risk for CRC is greatest in patients with primary sclerosing cholangitis (PSC), increased disease extent, severity and duration.(17-22) Herein we will review current and potential future endoscopic approaches for optimizing screening and surveillance of colon cancer and dysplasia in patients with IBD. 2. Techniques for Dysplasia Detection Surveillance should ideally be performed when in remission.(9, 10) Excellent bowel prep is required to identify subtle lesions.(23) “Red-flag” techniques are endoscopic techniques that screen large mucosal surface areas for potential “areas of interest”,(24) and many modalities have been studied in IBD surveillance colonoscopy. 2.1 Standard Definition White Light Endoscopy Historically, surveillance guidelines using standard white light endoscopy (WLE) endorsed a random biopsy protocol (4 biopsies obtained at every 10 cm intervals during withdrawal).(5) The recommendation for random biopsies stemmed from the belief that dysplasia in IBD was often endoscopically invisible. In an attempt to determine whether flow cytometric measurement of DNA content in colonic biopsies could identify UC patients at increased risk of progression to dysplasia, Rubin et al determined the prevalence and distribution of DNA aneuploidy.(25) Highrisk patients without cancer or dysplasia were subsequently enrolled in a prospective surveillance study. In the specimen procurement protocol, samples of flat mucosa were taken from 4 quadrants at 10 cm intervals from the cecum to the anus. Based on the percentage of biopsies with abnormal histology, the authors estimated that if dysplasia is present in 5% of the colonic mucosa, 33 biopsies are required for histologic detection of dysplasia with 90% confidence.(25) Multiple societies endorsed this 33 random biopsy protocol as the standard for IBD surveillance.(3, 5, 26)
Subsequent studies have demonstrated that most dysplasia is endoscopically visible, and there is a low yield of random biopsies as compared to targeted biopsies.(27-30) A single center experience of 1,010 surveillance colonoscopies in 475 UC patients during a 10-year period found that 94% of neoplastic lesions were macroscopically visible, with only a 0.2% yield from random biopsy. Random biopsies from normal appearing colon (no endoscopic features of prior severe inflammation) yielded no dysplasia.(30) Lesion detection is further enhanced with use of image-enhanced endoscopy (IEE).(27-30) Several but not all national and international consensus guidelines endorse the use of IEE over standard WLE, with the European Crohn’s and Colitis Organization stating that random biopsy is an inferior method of dysplasia detection.(6, 7, 9, 10, 31, 32) 2.2 High Definition White Light Endoscopy Standard definition (SD) endoscopes have image resolutions of approximately 367,000 pixels.(33) High-definition (HD) endoscopes display image resolutions that range from 850,000 pixels to more than 1 million pixels.(33) The higher pixel density and faster line scanning on the monitor produce sharper images.(34) One retrospective observational study of HD (N=209) vs. SD (N=160) found that the adjusted prevalence ratio of detecting any dysplastic lesion was 2.21 (95% confidence interval [CI] 1.1-4.5) in the HD group as compared to the SD group.(35) HD endoscopy is recommended rather than SD endoscopy to maximize dysplasia detection. (31)
2.3 Magnification Magnification refers to the ability to optically zoom or magnify images 150 fold, without affecting pixel density.(34, 36) Magnification endoscopy, coupled with other endoscopic modalities, can aid in the characterization of detected lesions. Further discussion of the role of magnification endoscopy in the endoscopic evaluation of dysplasia will be detailed in the sections below. 2.4 Chromoendoscopy Chromoendoscopy (CE) refers to enhanced imaging techniques that highlight mucosal architectural abnormalities and submucosal vascular patterns. Chromoendoscopy can involve the topical application of dyes (dye-based CE), or use optical or virtual enhancement tools (dyeless CE).(37)
2.4a Dye based CE Dilute indigo carmine (IC) (0.03-0.5%) or methylene blue (MB) (0.04-0.2%) is sprayed via a spray catheter or through the water-jet channel using an automated pump during dye based CE.(9, 10, 31, 38, 39) Indigo carmine is a contrast agent, while methylene blue is an absorptive agent that is variably absorbed or unabsorbed by inflamed or dysplastic mucosa.(40) The colonic mucosa is sprayed on withdrawal either segmentally or every 30cm, and excess fluid is aspirated.(10) Surface chromoendoscopy highlights the topography of the colonic mucosa,(40) aiding in the detection of subtle lesions that might have been missed with WLE alone.(39) (Figure 1a and 1b). Several organizations have recommended surface chromoendoscopy with IC or MB as the preferred surveillance technique for maximizing dysplasia detection during IBD colonoscopy(7, 9, 10, 32, 41) with a 2-3 fold increase in per patient dysplasia detection and 4-5 fold increase in per lesion dysplasia detection.(10) A meta-analysis of 8 trials (2 randomized controlled trials, 4 prospective tandem studies, and 2 retrospective studies) demonstrated a significant increase in dysplasia detection with chromoendoscopy compared to standard WLE (RR = 1.8 [95% CI 1.2-2.6]) and an absolute risk increase of 6% [95% CI 3-9%].(31) Chromoendoscopy is the recommended technique when compared to standard WLE. (31) There are few studies comparing CE to HD WLE. A prospective, tandem study of the implementation of CE with IC into practice utilizing HD colonoscopes demonstrated an increased yield of CE (21%) versus HD WLE (9%), resulting in a relative increase in yield of 129% per patient, p=0.007.(42) The increased yield was greatest for the detection of flat lesions: one flat lesion was detected with HD WLE versus 7 with CE, resulting in a relative increase in yield of 700% (p<0.001).(42) Preliminary results from a randomized trial of HD CE (50 patients) compared to HD WLE (53 patients) found a total of 14 dysplastic lesions (1 with high grade and 13 with low grade dysplasia) in 11 patients (22%) in the HD CE and 6 dysplastic lesions (all low grade dysplasia) in 5 patients (9.4%) in the HD WLE arm. HD CE was significantly better (p=0.04) than HD WLE on a per patient basis for the detection of endoscopically visible dysplastic lesions.(43) While we await more high quality studies comparing CE to HD WLE, during HD colonoscopy, CE is the suggested technique to maximize dysplasia detection.(31) The technique of CE has previously been described.(38, 39) SURFACE guidelines have been proposed to aid in standardization of the technique.(44) Picco et al demonstrated that CE can be successfully implemented into practice after a short training session using images from a
teaching file and general instruction on the IC CE technique.(42) Physicians with no prior experience in CE UC surveillance demonstrated a high yield using CE with acceptable withdrawal times (withdrawal time stabilized at a median of 19 minutes after more than 15 procedures had been performed).(42) In a meta-analysis, CE appears to increase procedure time by 11 min compared to WLE.(45) Magnification endoscopy can help characterize lesions detected by CE by differentiating neoplastic from non-neoplastic lesions. Routine application of Kudo pit patterns may not be applicable in colitis, as regenerative mucosa can have pit patterns that become elongated and irregular,(46) and can resemble Kudo type IV pit patterns without harboring dysplasia.(47) However, in a study by Hata et al, no neoplasia was seen in lesions with type I or II pit patterns.(47) Nishyama et al demonstrated in neoplastic lesions, pit density was greater (89% vs. 60%) and pit margins more frequently irregular (63% vs. 33%) when compared to nonneoplastic lesions.(48) Larger prospective studies are needed to validate these findings. Despite the endorsement by multiple societies and international consensus groups, adoption of CE as the standard for surveillance has been slow. Some critics call into question the natural history of CE-detected lesions, stating that the goal of surveillance should be to prevent lifethreatening colon cancer.(49) The longitudinal experience with standard WLE vs. CE supports CE as tool for cancer prevention. Over a 5-year period from 2006-2011, with a median of 27.8 months of follow-up for the cohort, Marion and colleagues found that CE was superior to targeted WLE (OR 2.4 [95% 1.4-4.0]) for dysplasia detection, and that a negative CE surveillance colonoscopy was the best indicator for a dysplasia-free outcome.(50) In addition, Choi and colleagues recently demonstrated in their St. Mark’s Hospital cohort of 1,375 patients undergoing 8,650 colonoscopies, 1,098 of which were performed with CE, that there was a twofold higher neoplasia detection rate in the CE group (n=92/1,098, 8.4%) compared to the WLE endoscopy group (n=175/4,373, 4.0%; p<0.001).(16) The incidence rate of CRC in patients with at least one CE surveillance colonoscopy was significantly lower (2.2 per 1,000 patient-years) than in those who had never had a CE exam (4.6 per 1,000 patient-years; p=0.02). Although not significantly different, there was also a trend towards a lower postcolonoscopy CRC rate in the CE group (1.2 per 1,000 patient-years) compared to WLE group (1.8 per 1,000 patient-years, p=0.6).(16) Others question the routine application of CE to all patients with IBD requiring surveillance without risk stratifying patients into high versus low risk groups. A prospective randomized study of 155 patients with long standing UC without PSC and/or history of IN compared CE-guided endomicroscopy (CGE, 72 patients) with conventional
WLE with random biopsies (73 patients).(51) While significantly fewer biopsies were obtained in the CGE group (4.7 +/- 4.9 vs. 36 +/- 6.2, p<0.001) and the per-biopsy yield of intraepithelial neoplasia (IN) was higher in the CGE group (1/48 vs. 1/438, p<0.001), there was no significant difference in dysplasia detection (7 IN in CGE and 6 in WLE, p>0.05) in UC patients without PSC or prior history of IN.(51) Lastly, the real-life effectiveness of CE has been questioned. While one prospective, tandem study demonstrated an increased yield with CE in routine practice,(42) a retrospective analysis over a 13 year period evaluating the implementation of HD CE in 440 colonoscopies compared to 1,802 WLE colonoscopies did not demonstrate significantly different dysplasia detection between these groups (11% CE vs. 10% WLE, p=0.80).(52) 2.4b Dye-less CE Dye-less CE includes narrow band imaging (NBI, Olympus, Tokyo, Japan), i-scan (Pentax, Tokyo, Japan), and Fujinon Intelligent Color Enhancement (FICE, Fujifilm, Tokyo, Japan).(37) Dye-less CE is attractive because these are “push-button” technologies that are integrated into the endoscopes, potentially leading to decreased time required for the application of the technology while, ideally, preserving dysplasia detection yield. Narrow Band Imaging NBI can be activated by the push of a button, and uses filters to restrict light to narrow bands of blue and green wavelengths which are strongly absorbed by hemoglobin, enhancing mucosal vasculature.(53) NBI has not demonstrated increased yield for dysplasia during surveillance examinations. NBI has been compared to WLE in three studies.(54-56) Two randomized, crossover studies comparing NBI to standard WLE (54) and to high definition WLE(56) failed to demonstrate improved dysplasia detection with NBI. A randomized, parallel group trial of NBI versus high definition WLE did not demonstrate a difference in dysplasia detection between the two groups. This study was powered to detect a three-fold increase in dysplasia detection with NBI, but was stopped after interim analysis of 112 patients demonstrated 9% dysplasia detection in both groups, with an adjusted OR of true-positive lesion detection of NBI vs. high definition WLE of 0.69 (95% CI 0.16-2.96, p=0.62), suggesting NBI was less likely to detect dysplasia than high definition WLE.(55) NBI has been compared to chromoendoscopy in two studies. A randomized, crossover study compared targeted biopsies by NBI to targeted biopsies by chromoendoscopy, and found no significant difference in dysplasia detection. However, a trend towards a higher missed neoplastic lesion rate was seen with NBI as
compared to CE (31.8% [95% CI 12.3-51.5%] vs. 13.6% [95% CI -0.7 to 27.9%], p=0.2), and a trend towards a higher missed neoplastic patient rate was seen with NBI as compared to CE (46.1% [95% CI 19-73.2] vs. 15.4% [95% CI -4.1 to 35], p=0.2).(57). Preliminary results from a second study of 93 patients with longstanding UC, published in abstract form only, suggested similar true neoplastic detection rates for NBI (11.8%) as compared to CE (17.9%, p=0.225) in endoscopically suspicious raised lesions.(58) It not surprising that in IBD, where inflammation can cause significant disruption of the underlying vascular pattern, NBI has not consistently demonstrated an increased dysplastic yield. The peer reviewed publication by Bisschops is eagerly awaited,(58) as there may be a patient population in which NBI may have a similar increased yield as CE, at least for raised lesions. Until this data are available, CE remains the gold standard for maximizing dysplasia detection. A potential niche for NBI, when combined with magnification endoscopy, may be in characterizing detected lesions. One of the first case reports exploring the role of NBI with magnification in UC surveillance discussed the role of vascular pattern intensity, with dysplastic lesion in one patient demonstrating a stronger (blacker) capillary vascular pattern as compared to normal mucosa.(59) In a pilot study evaluating magnifying colonoscopy with NBI in 46 patients with UC, a tortuous pattern seen on NBI may be a clue to identifying dysplasia during UC surveillance, although overall the number of dysplastic lesions detected in this study was low (5 lesions in 3 patients).(60) As discussed earlier, while the routine application of Kudo pit pattern may not be possible in colitis, integration of additional characteristics such as vascular pattern intensity or the presence of a tortuous pattern may be necessary to maximize differentiation of dysplastic from normal tissue. i-Scan i-Scan is a virtual CE technology that uses post-processing algorithms to enhance reflected light and reconstruct virtual images in real time.(53) i-Scan combines surface-enhancement , contrast-enhancement and tone-enhancement in three different modes: i-scan mode 1 (surfaceenhancement) is used for lesion detection, mode 2 (surface-enhancement plus tonal enhancement) for lesion characterization, and mode 3 (surface-, tone- and contrastenhancement) for lesion demarcation.(61) I-scan has yielded positive results in increased dysplastic yield in average risk patients undergoing colonoscopy as compared to WLE(62) and similar yield to CE.(63) University of Calgary is currently enrolling patients in a randomized
controlled trial comparing dysplasia detection during HD WLE, surface CE (0.2% indigo carmine) and i-scan in UC and CD patients with long standing colitis undergoing surveillance (NCT02098798). Fujinon Intelligent Chromoendoscopy FICE is another proprietary virtual CE technology utilizing post-processing algorithms to emphasize certain ranges of wavelengths.(53) While there appears to be ongoing clinical trials evaluating the role of FICE in IBD surveillance (NCT00816491), no published studies in IBD surveillance are available for review. Studies in average-risk patients have not demonstrated an increased dysplastic yield of FICE compared to standard WLE with targeted CE (64) or to HD WLE.(65) 2.5 Autofluorescence Imaging (AFI) Autofluorescence imaging utilizes short wavelength light to excite endogenous mucosal fluorophores, which then emit light of longer wavelengths.(66) Color differences in fluorescence emission are captured and integrated into a real-time pseudocolor image, with normal tissue appearing green and dysplastic tissue appearing purple/magenta. AFI can be activated by the push of a button on trimodal imaging video endoscopes (EVIS LUCERA SPECTRUM; Olympus Medical Systems Co, Tokyo, Japan).(66) Studies to date have demonstrated AFI is a sensitive tool for dysplasia detection. A study by van den Broek et al compared AFI against high resolution WLE for dysplasia detection followed by NBI for lesion classification (endoscopic trimodal imaging) in 50 UC patient with inactive pan-ulcerative colitis for ≥8 years duration; patients with active disease were excluded in this study.(67) In this randomized crossover study, the neoplasia miss rate for AFI was 0% and WLE 50% (P=0.036). For lesion characterization, the sensitivity and specificity of AFI was 100% and 42%, while NBI was 76% and 81%.(67) Matsumoto and colleagues prospectively studied 48 UC patients with clinically inactive disease undergoing UC surveillance, and lesions were characterized as flat or protruding, and low AFI (purple) or high AFI (green).(68) The positive rate of dysplasia in protruding lesions was significantly higher in low AF (purple, 45%) than in high AF (green, 13.3%, p=0.043). The positive rate of dysplasia in flat lesions was not significantly different in low AF (8.2%) vs. high AF (0%, p=0.3).(68) This study suggests there may be a role for AFI in detecting protruding lesions, and appears to have good sensitivity but poor specificity for detecting flat dysplasia.
The difficulty in detecting dysplasia in flat lesions may be due to an alteration in autofluorescence according to the grade of inflammation. One study of AFI in assessing UC activity demonstrated that active inflammation was associated with low AFI, likely due to an autofluorescence signal that is decreased by damaged submucosal layer or a thickened mucosal layer.(69) 3. CHARACTERIZATION OF DETECTED LESIONS: OPTICAL BIOPSY TECHNOLOGY Lesions detected by “red flag” technologies can be further characterized by new technology that allows in vivo histological analysis and for procurement of “smart” biopsies. 3.1 Confocal Laser Endomicroscopy (CLE) Confocal laser endomicroscopy requires the administration of a topical or systemic fluorescence agent followed by the use of a blue laser light, resulting in 1000-fold magnification of tissue and in vivo histological evaluation.(70) An endoscopy based CLE system (e-CLE) by Pentax is no longer commercially available (Pentax, Tokyo, Japan).(70) Currently, CLE is performed with a probe-based system (p-CLE, Cellvizio, Paris, France). P-CLE is best used in conjunction with other “red-flag” technologies to target CLE examination to focused “areas of interest”, since endomicroscopy has a limited field of view.(24) Criteria for classification of e-CLE(71) and pCLE(72) patterns have been proposed. Although these classification systems have been applied in colitis surveillance,(73) classifications for CLE images obtained during an exam within colitic mucosa have not been established. CLE, in conjunction with CE, can result in improved dysplasia characterization while reducing the number of biopsies required for diagnosis. Kiesslich et al demonstrated in a randomized controlled trial of 161 patients that CE guided CLE increased the diagnostic yield 4.75 fold as compared to standard WLE with random biopsy (p=0.005), predicting dysplasia with a sensitivity of 94.7%, and specificity of 98.3% in a total of 134 lesions.(74) Per-patient biopsies could be decreased from 42.2 biopsies in the conventional colonoscopy group to 3.9 biopsies in the CECLE targeted group if biopsies were limited to the detected lesions. CLE images were classified as normal mucosa, regenerative mucosa, neoplasia, or inflammation by using crypt and vessel architecture and cellular infiltration. CLE had a negative predictive value of 99.1% if mucosa appeared normal on CLE imaging.(74) A retrospective cohort study by Gunther et al evaluated the yield of random versus targeted biopsy protocols in three cohorts of 50 patients each: HD (Olympus CF-180AI)/ high-resolution endoscopy targeted, HD chromoendoscopy (Olympus CF-
180AI) targeted, and confocal endomicroscopy (Pentax EC-3870CIFK) targeted biopsy protocols (endoscope type, personal communication with author).(75) Targeted biopsies with CE and CLE yielded significantly greater dysplasia detection rates (HD 0, CE 4%, CLE 8%, p<0.05).(75) In the previously mentioned study of a single endoscopist performing CE-guided endomicroscopy (CGE), CGE decreased the number of biopsies performed while significantly improving the per-biopsy yield of dysplasia, although the overall dysplastic yield was similar to WLE in UC patients without PSC or prior history of dysplasia.(51) In contrast, a study by Hlavaty et al of 30 patients with 100 suspicious lesions evaluated with WLE, CE and e-CLE found that eCLE did not improve the sensitivity and specificity of CE for dysplasia detection, and one-third of lesions, especially if pedunculated, could not be evaluated by CLE.(76) In addition to differentiating dysplastic from non-dysplastic tissue, CLE may allow for real-time evaluation of endoscopic resectability. Hurlstone et al evaluated the use of e-CLE on 36 lesions to determine endoscopic resectability of detected lesions (previously termed adenoma-like mass (ALM) if endoscopically resectable, and dysplasia associated lesional mass if endoscopically unresectable (DALM)). E-CLE and histopathology demonstrated a kappa coefficient of agreement of 0.91, reporting an overall CLE predictive accuracy of 97% (95% confidence interval 86%–99%).(73) Interestingly, in the 6 lesions determined to be dysplastic lesions that were not endoscopically resectable, 4 (66%) were ultimately diagnosed with a colitis-associated CRC localized to the detected lesion, while 2 (35%) had CRC remote to the detected lesion that was not seen on the index colonoscopy.(73) P-CLE has also been utilized for lesion characterization for endoscopic resectability.(77) 3.2 Endocystoscopy After topical application of an absorptive contrast agent (methylene blue, toluidine blue, crystal violet), endocytoscopy (Olympus, Tokyo, Japan) allows a 1400 fold magnification of the mucosa via a contact light microscope that enables real time visualization of the very superficial epithelial cellular structures.(78) Endocystoscopy can be performed via a probe-based system (pEC) or an integrated endoscope system (iEC).(79) Literature evaluating the role of endocystoscopy in IBD is limited. Two studies have evaluated the yield of endocytoscopy in the determination of histopathological activity in UC.(80, 81) Emerging data suggest endocytoscopy may have a role in differentiating neoplastic from nonneoplastic tissue in the colon,(82) and application in IBD surveillance is awaited.
4. Current and Future Prospects Studies in IBD surveillance clearly support the notion that the era of random biopsies for dysplasia detection has passed. The optimal “red-flag” technique and smart biopsy protocol will be a balance of increased dysplasia yield and ease of use, which will need to take into account both training and practical implementation. CE is currently the established technique to maximize dysplasia detection, and should be the standard against which all other technology is compared. Endoscopists employing CE will need to determine if the data is sufficient to warrant CE surveillance in all patients, or selectively use it in the highest risk patients. While we agree that more prospective data are needed to understand how best to utilize CE in the era of HD WLE and other IEE, we believe that the current data support the use of CE with targeted biopsies to maximize dysplasia detection over other endoscopic methods. CE can be readily applied in most endoscopic units, since specialized equipment is not required beyond the CE agent (MB/IC), and a spray catheter or water jet pump, which are available in most endoscopy units today. Published data support successful implementation of a CE surveillance program after a short tutorial, which are readily available on-line.(38) CE surveillance will lead to increased dysplasia detection with fewer biopsies, and with acceptable withdrawal times. Further studies need to address if intervals between colonoscopic examinations can be lengthened after a negative CE examination. While some may continue to argue that the natural history of CE-guided lesions in not known, there is a robust body of literature that demonstrates increased adenoma detection is inversely correlated with interval cancer risk in screening colonoscopies.(83) The interval cancer risk in IBD can be substantial.(84) Ideally, longer-term data will confirm the findings of Marion et al that a negative CE exam is the best indicator for a dysplasia free outcome, which can hopefully lead to a lengthening of the surveillance intervals. Perhaps HD WLE with targeted biopsies will yield similar dysplasia detection rates to CE, especially in the hands of trained endoscopists.(51) Until that is proven in other high quality prospective studies and in general practice settings, we cannot ignore the body of literature supporting the superior dysplasia detection with CE, even in the hands of novice CE endoscopists. NBI, especially the newer generation scopes which yield brighter images, has promise as an easy to use push button technology. Since the technology relies on enhancement of mucosal vasculature, future studies should clarify the role background inflammation has on the yield of NBI exam. In addition, the learning curve for NBI and real-time lesion detection and
characterization during IBD surveillance has not been defined. At present, NBI cannot be considered comparable to CE for dysplasia detection. i-scan, FICE and AFI are other push-button technologies that require the use of dedicated equipment and expertise in image interpretation. Studies are ongoing and will help clarify their role in IBD surveillance. P-CLE is available in specialized endoscopy units and requires additional training for in vivo histologic assessment and the use of dedicated equipment. A short learning curve has been established for p-CLE using offline video sequences,(85) but the learning curve for dysplasia evaluation in potentially inflamed mucosa is unknown. Thus, while the role of CLE in “smart biopsy” protocols is promising, additional studies are needed to better understand its application to routine IBD surveillance colonoscopy. In conclusion, HD CE is currently the preferred method of IBD surveillance to maximize dysplasia detection. While other "red flag” techniques are promising, they will need to demonstrate equivalent dysplasia detection before they can be adopted in place of CE. IEE enables the use of targeted biopsies, and new technology such as CLE and endocytoscopy may allow in vivo histological diagnosis that will not only guide diagnosis but therapy of these lesions.
Conflicts of Interest: Shergill: NONE Farraye: NONE
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Figure 1. Surface chromoendoscopy highlights the topography of the colonic mucosa, aiding in the detection of subtle lesions. a. High definition white light endoscopy
b. Surface chromoendoscopy with indigo carmine enhances detection of a depressed lesion with a distinct border; pathology yields low-grade dysplasia.