- Email: [email protected]
Advanced endoscopic imaging techniques in Crohn's disease
Journal of Crohn's and Colitis (2014) 8, 261–269
Available online at www.sciencedirect.com
ScienceDirect
REVIEW ARTICLE
Advanced endoscopic imaging techniques in Crohn's disease Gian Eugenio Tontinia,b,⁎, Maurizio Vecchib,c , Markus F. Neuratha , Helmut Neumann a,⁎⁎ a
Department of Medicine I, University of Erlangen-Nuremberg, Germany Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy c Department of Medical Science for Health, University of Milan, Italy b
Received 4 August 2013; received in revised form 5 September 2013; accepted 5 September 2013 KEYWORDS Inflammatory Bowel Disease; Crohn's disease; Confocal laser endomicroscopy; Chromoendoscopy; Small-bowel capsule endoscopy; Device-assisted enteroscopy
Abstract Background: Endoscopy is of pivotal importance in Crohn's disease (CD) patients for diagnosis, surveillance and assessment of disease activity and extent. Device-assisted enteroscopy (DAE) and small-bowel capsule endoscopy (SBCE) have recently changed our endoscopic approach to small-bowel imaging. Furthermore, new advanced endoscopic imaging techniques have been implemented into clinical practice to improve both characterization of mucosal inflammation and detection of dysplastic lesions. Aim: To provide readers with a review about the concept of advanced endoscopic imaging for the diagnosis and characterization of CD. Methods: A literature search on the use of advanced endoscopy techniques in IBD patients was performed. Results: DAE and SBCE allow for deep enteroscopy with high diagnostic yields and low complication's rate but their collocation in the diagnostic algorithm is still not clearly defined. Dye-based chromoendoscopy (DBC) and magnification chromoendoscopy improved dysplasia's detection in long standing colitis and prediction of inflammatory activity and extent. Dye-less chromoendoscopy (DLC) might offer the potential to replace conventional DBC for surveillance. However, both narrow band imaging and i-scan have already shown to significantly improve activity and extent assessment in comparison to white-light endoscopy. Confocal laser endomicroscopy (CLE) can detect more dysplastic lesions in surveillance colonoscopy and predict neoplastic and inflammatory changes with high accuracy compared to histology. Moreover, CLE-based molecular imaging may anticipate the therapeutic responses to biological therapy. Endocytoscopy can identify in vivo inflammatory mucosal cells harboring a new method to assess the mucosal activity.
⁎ Correspondence to: G.E. Tontini, Department of Medicine I, University of Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany. Tel.: + 49 9131 85 35000; fax: + 49 9131 85 35209. ⁎⁎ Corresponding author. Tel.: + 49 9131 85 35000; fax: + 49 9131 85 35209. E-mail addresses: [email protected] (G.E. Tontini), [email protected] (H. Neumann). 1873-9946/$ - see front matter © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.crohns.2013.09.004
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G.E. Tontini et al. Conclusions: Recent progresses in small-bowel enteroscopy offer several potential benefits to improve both diagnosis and characterization of CD. New advanced endoscopic imaging techniques can improve detection of dysplasia and refine mucosal healing assessment, even looking beyond the morphological parameters revealed by conventional endoscopic imaging. © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Deep small-bowel enteroscopy for Crohn's disease . . . . 2.1. Device-assisted enteroscopy . . . . . . . . . . . . . 2.2. Capsule endoscopy . . . . . . . . . . . . . . . . . . . 3. Advanced endoscopic imaging techniques in patients with
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3.1. Magnification endoscopy and dye-based chromoendoscopy 3.2. Dye-less chromoendoscopy . . . . . . . . . . . . . . . . . . 3.3. Confocal Laser endomicroscopy . . . . . . . . . . . . . . . 3.4. Endocytoscopy . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Inflammatory Bowel Disease (IBD) encompasses ulcerative colitis (UC), Crohn's disease (CD) and IBD type unclassified (IBDU).1 These three entities have several aspects in common but their peculiarities are critical for a correct and tailored clinical management.2,3 The differential diagnosis between IBD and other gastrointestinal disorders is based on clinical evaluation and combination of endoscopic, histological, radiologic and biochemical investigations.3–8 Patients with IBD associated colitis may present with clinical and endoscopic unspecific features, often requiring additional diagnostic work-up. It is well accepted that chronic inflammation involving the large bowel of patients with IBD represents a major risk factor for the development of colitis-associated cancer (CAC).9–12 While all patients with IBD suffer from an increased risk for developing CAC, it was shown that the duration and anatomical extent of disease are well-established risk factors for cancer development.13,14 In addition, one retrospective case–control study assessed the severity of inflammation as a risk factor for CAC in UC and found that inflammation measured by endoscopy, which was significant at univariate analysis, was not a significant determinant of cancer risk in a multivariate model.11 Only the degree of inflammation over time as assessed by histopathology was considered to be an independent risk factor for CAC development.11 This finding was confirmed by Mathy and co-workers, who demonstrated that histological, rather than endoscopic assessment of inflammation, serve as a better determinant for CAC risk.10 Moreover, in a recent a prospective case– control study, Rubin et al. have reported a positive association between histological activity and CAC in patients with UC.12
. . . . . . . . . . . . IBD
CAC may occur in elevated protruded lesions but may also develop in normal-appearing mucosa (i.e. “flat”). Data from the literature indicate that in 50%–80% of cases with colitis-associated neoplasms, the lesions are overlooked upon pan-colonoscopy.15 This aspect limits the usefulness of colonoscopic visualization and mandates the need for multiple random biopsies, which is a time consuming, costly and ineffective endeavor.16–22 Therefore, most guidelines recommend surveillance colonoscopy with multiple random biopsies every 10 cm as the reference standard for diagnosis of intraepithelial neoplasia and cancer in either UC or CD with long standing and extensive involvement.5,23–27 Nevertheless, to date, no randomized controlled study could show a reduced risk of CAC development by surveillance colonoscopy in IBD.14,28 Thus, it becomes obvious that there is a need for new and more advanced endoscopic imaging techniques for surveillance in IBD.16 In recent years new emerging endoscopic imaging techniques were introduced, allowing a detailed analysis of subtle endoscopic findings and revealing microscopic features. Furthermore, recent introduced endoscopic imaging techniques have enriched the available equipment for deep small-bowel imaging, offering a more tailored approach for patients with suspected or established CD. This review describes the concept of advanced endoscopic imaging for the diagnosis and characterization of Crohn's disease.
2. Deep small-bowel enteroscopy for Crohn's disease 2.1. Device-assisted enteroscopy Although standard small-bowel endoscopy plays a pivotal role in the management of patients with IBD, its collocation
Endoscopic diagnosis in Crohn’s disease in the diagnosis and treatment algorithm is still not clearly defined.29 Accordingly, small-bowel cross-sectional imaging should generally precede enteroscopic examination and the decision on whether small-bowel capsule endoscopy, rather than whether device-assisted enteroscopy should be performed depends on the nature and location of the smallbowel lesion, as well as local availability and expertise of the examiners.29–32 The term “balloon-assisted enteroscopy” (BAE) was first proposed by Mönkemüller and co-workers and summarizes three different endoscopic methods for small-bowel imaging: (I) double-balloon enteroscopy (DBE; Fujinon, Tokyo, Japan); (II) single-balloon endoscopy (SBE; Olympus, Tokyo, Japan); and (III) NaviAid (Pentax, Tokyo, Japan).16 All systems allow deep intubation of the small-bowel for diagnostic and therapeutic interventions (e.g. for hemostasis, dilation or biopsy acquisition). Combination of oral and anal insertion routes are used to achieve deep or complete examination of the small-bowel.33 Up to now, few studies have reported a 30–48% diagnostic yield of DBE when evaluating patients with suspected Crohn's disease.34–37 Complications are rare and occur in b 1% of cases, while balloon dilation of strictures has a reported perforation risk of up to 3%.35 Nevertheless, BAE should not be considered as the first-line procedure in the evaluation of suspected small-bowel CD, as the procedure is somehow invasive, time and cost-expensive and mostly limited to specialized centers.29 Therefore, in patients with suspected or established small-bowel CD without fistulating or stenosing behavior, capsule endoscopy should be considered as the first choice.29 However, BAE allows for the retrieval of tissue for analysis and permits therapeutic interventions such as stricture dilation (Table 1). Besides BAE, spiral enteroscopy was introduced, as a new imaging modality enabling deep smallbowel enteroscopy. One recent multicenter study compared double-balloon enteroscopy and spiral enteroscopy and found that spiral enteroscopy appears as safe as double-balloon enteroscopy for small-bowel exploration with a similar diagnostic and therapeutic yield. Comparison between the two procedures in terms of duration and length of small-bowel explored was slightly in favor of spiral enteroscopy but this was not statistically significant.38 Despite these promising results, no data of spiral enteroscopy in patients with IBD is yet available.
2.2. Capsule endoscopy Capsule endoscopy (CE) was introduced in 2002. Currently, various capsule systems from different companies are available for examination of the esophagus, small-bowel (SBCE) and colon.30–32,39 The capsule movement is passively propelled through the intestine by peristalsis while transmitting color images of the intestine. Multiple studies have shown the impact of CE for diagnosis of CD associated changes including ulcers, erosions, erythema, aphthae and strictures as to evaluate response to therapy.40–42 In addition, recent data has shown that SBCE is able to identify mucosal lesions according to CD even in patients with negative small-bowel radiographic imaging.29 In the study by Dubcenco et al., CE yielded a sensitivity and specificity of 90% and 100%, respectively, and a positive
263 Table 1
Diagnosis of suspected small-bowel Crohn’s disease.
predictive value and a negative predictive value of 100% and 77%, respectively, for diagnosis of active small-bowel CD.41 One disadvantage may be that the coecum could not be reached in between 8% and 40% of cases and inadequate bowel preparation could additionally hamper the SBCE accuracy.29 Moreover, none of the above-mentioned studies used unequivocal gold-standards and the diagnosis of CD was always supported by the clinical presentation.16 As with other imaging modalities, the diagnosis of CD should not be based on the appearances at CE alone. In subjects suspected for CD, a positive SBCE requires a further endoscopic approach for biopsy sampling (i.e. by using DAE as depicted in Table 1). In established Crohn's disease, SBCE findings should be counted against lesions of unknown clinical significance, which are also present in up to 13% of asymptomatic patients.29 The main contraindication for capsule endoscopy is related to the risk of retention. In patients with suspected CD the capsule retention's rate is low and comparable to that when the indication for SBCE is bleeding. Conversely, in established CD the risk is increased, particularly in those with known or suspected intestinal stenosis.29 Thus small-bowel strictures should be excluded by a thorough clinical workup and radiographic imaging before performing SBCE. However, conventional radiographic studies cannot entirely rule out the potential for capsule retention, thereby suggesting the use of the so called “Agile Patency Capsule” (biodegradable analogous) to prevent the risk of retention.29,43
• In case of suspected small-bowel Crohn's disease without strictures or stenosis capsule endoscopy should be preferred to device-assisted enteroscopy. • Device-assisted enteroscopy offers the potential to perform interventions within the small-bowel and is associated with low complication rate.
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3. Advanced endoscopic imaging techniques in patients with IBD 3.1. Magnification chromoendoscopy
endoscopy
and
dye-based
Magnification endoscopy utilizes a movable lens to vary the degree of magnification up to 150-fold, thereby allowing a detailed characterization of the mucosal surface and pit pattern.44 Hurlstone and co-workers prospectively analyzed indigo carmine-assisted high-magnification endoscopy for detection and characterization of neoplasia in UC.45 Significantly more neoplastic lesions were detected in the magnification chromoendoscopy group as compared to controls, particularly due to the enhanced detection of non-polypoid (i.e. flat) lesions. In addition, the same group reported the results of a large prospective study on the value of high-magnification chromoendoscopy guided colonoscopy (HMCC) for in vivo prediction of histopathological inflammatory changes associated with IBD.46 In 300 consecutive patients with a known history of UC, white-light colonoscopy was used followed by HMCC with indigo carmine dye-spraying. Magnification imaging was significantly better than conventional colonoscopy for predicting disease extent in vivo (P b 0.0001).46 Chromoendoscopy is divided into dye-based chromoendoscopy (DBC) and dye-less chromoendoscopy (DLC). The basic principle of chromoendoscopy is to enhance the mucosal detail and the mucosal vascular pattern with the use of various dyes (DBC) or optical and computer-based color programs (DLC). DLC further comprised optical chromoendoscopy and digital chromoendoscopy techniques. The contrast enhancement of the mucosal surface results in an improved detection of subtle mucosal details, thereby improving the characterization of superficial patterns and the mucosal vascular network.16 DBC uses different dye agents which are divided in absorptive agents (e.g. Lugol solution, methylene blue, toludine blue, and cresyl violet), contrast agents (e.g. indigo carmine, and acetic acid) and reactive staining agents (e.g. congo red, phenol red).16 Dye agents are mostly applied via standard spraying catheters or plain biliary ERCP catheters.47 Various studies have shown the potential of DBC to enhance detection of pre-neoplastic and neoplastic lesions in IBD.48–52 In this setting, the available data are mostly based on UC patients. Nonetheless, one would suspect similar efficacy to improve surveillance strategies in long standing colitis related to CD. One randomized, controlled trial evaluated whether 0.1% methylene blue-aided chromoendoscopy might facilitate early detection of intraepithelial neoplasia and CAC in UC.48 DBC permitted more accurate diagnosis of extent and severity of inflammatory activity in UC compared with conventional white-light endoscopy and improved significantly the early detection of intraepithelial neoplasia and CAC in patients with UC.48 Another back-to-back colonoscopy trial evaluated pan-colonic chromoendoscopy with 0.1% indigo carmine for detection of dysplasia in UC.49 Non-targeted biopsies detected no dysplasia in 2904 biopsies while the targeted biopsy protocol with pan-colonic chromoendoscopy required fewer
biopsies (157) and detected nine dysplastic lesions.49 A recent introduced meta-analysis of six randomized controlled trials evaluated the diagnostic accuracy of chromoendoscopy for dysplasia detection in UC.52 The results demonstrated a pooled sensitivity of 83%, specificity of 91%, and diagnostic odds ratio of 17.5. It was concluded that DBC has a medium to high sensitivity and a high diagnostic accuracy for detection of dysplastic lesions in UC.52
• Pan-colonic chromoendoscopy and targeted biopsies of suspicious lesions represent a more effective surveillance method in IBD than taking only multiple non-targeted biopsies. • Magnification chromoendoscopy improves the detection of pre-neoplastic and neoplastic colorectal lesions in IBD.
3.2. Dye-less chromoendoscopy DLC is divided into optical chromoendoscopy, including Narrow Band Imaging (NBI; Olympus, Tokyo, Japan) or Compound Band Imaging (CBI; Aohua, Shanghai, China), and digital chromoendoscopy including i-scan (Pentax, Tokyo, Japan) and Fujinon intelligent color enhancement (FICE; Fujinon, Tokyo, Japan).16 Optical chromoendoscopy is based on optical filters within the light source of the endoscope, which narrow the bandwidth of spectral transmittance, thereby enhancing blood vessels. Otherwise, i-scan and FICE use digital post-processing for computed spectral estimation for enhanced tissue contrast.16,53 Various studies have addressed the potential of NBI for diagnosis and characterization of pre-neoplastic and neoplastic changes in IBD. Recently, van den Broek and co-workers performed a crossover trial in which patients with UC underwent both NBI and high-definition (HD) white-light colonoscopy in a randomized order. It was shown that NBI does not improve the detection of neoplasia in patients with UC compared to HD white-light endoscopy. In addition, NBI proved suboptimal accuracy (73%) for differentiating neoplastic from non-neoplastic colorectal lesions.54 The same group assessed the value of endoscopic tri-modal imaging for surveillance in UC. Fifty patients underwent surveillance colonoscopy and each colonic segment was inspected twice, once with auto-fluorescence imaging (AFI) and once with high-resolution white-light endoscopy, in a random order. In addition, all detected lesions were inspected by NBI according to Kudo pit pattern followed by random biopsies. AFI improved the detection of neoplasia and decreased the yield of random biopsies compared to white-light endoscopy. Pit pattern analysis by NBI had a moderate accuracy for the prediction of histology (80%). However, all neoplasia was colored purple on AFI (sensitivity 100%), thereby suggesting a valuable effect of AFI color for exclusion of neoplasia.55 In a pilot study, magnification colonoscopy with NBI was used to assess diagnosis of dysplasia in UC. The surface pattern was determined to be either “honeycomb-like”, “villous” or “tortuous-like”. By taking the surface pattern into account, the rate of positive dysplasia was higher in the
Endoscopic diagnosis in Crohn’s disease “tortuous” pattern than in the “honeycomb-like” or “villous” pattern group. Therefore, the “tortuous” pattern determined by NBI colonoscopy may be a clue for the identification of dysplasia during surveillance in UC.56 Very recently, it was also shown that NBI is less time consuming and equally effective alternative to DBC for the detection of intraepithelial neoplasia. In this prospective, randomized, crossover study, NBI resulted in a significantly inferior false-positive biopsy rate providing a similar true-positive rate. However, given the lower NBI neoplastic lesion and neoplastic patient miss rates (P = 0.2), the authors did not recommend NBI as standard surveillance technique in IBD.57 To the best of our knowledge, there is no published data regarding the use of digital chromoendoscopy techniques for detection and characterization of intraepithelial neoplasia in IBD. The potential of DLC has been also studied to improve the characterization of disease extent and activity in IBD. One recent published article reviewed endoscopic findings under NBI in long standing UC. NBI strongly correlated with histological findings including crypt distortion, goblet cell depletion and basal plasmacytosis, therefore harboring the potential to better assess histologic severity in only mild and inactive disease.58 Another pilot study addressed the question if NBI could successfully assess mucosal angiogenesis in UC and CD. In mucosal areas that were endoscopically normal but positive on NBI, there was a significant increase in mucosal angiogenesis. Therefore, the authors suggested that NBI might allow in vivo imaging of intestinal neo-angiogenesis in IBD patients.59 One additional study evaluated FICE in the IBD setting, showing that the system could not improve the detection or delineation of evident lesions such as ulcers and erosions in CD.60 Recently, our group successfully studied the impact of i-scan for prediction of mucosal inflammation in IBD.61 Patients underwent total colonoscopy and were examined using both HD white-light (group A) and HD plus i-scan colonoscopy (group B). Agreement between endoscopic prediction of disease severity and histological findings was 54% in group A and 90% in group B (P = .066). Moreover, using histology as reference standard the endoscopic prediction of the inflammatory activity's extent was 49% in group A and 92% in group B (P = .001). Compared with histological results, i-scan enabled a more precise diagnosis of mucosal inflammation than the conventional colonoscopy.61
• Dye-less chromoendoscopy might offer the potential to replace conventional dye-based chromoendoscopy for lesion detection and assessment of disease severity in IBD. • i-scan has the potential to improve diagnosis of severity and extent of mucosal inflammation in patients with IBD.
3.3. Confocal Laser endomicroscopy Confocal laser endomicroscopy (CLE) was introduced in 2004 and has rapidly emerged as a promising approach to
265 obtain real time in vivo histology during ongoing endoscopy.62 The technique is based on tissue illumination with a blue laser light after topical or systemic application of fluorescence agents. Currently, two FDA approved and CE certified devices are available. One is integrated into the distal tip of a high-resolution endoscope (“integrated”, iCLE; Pentax, Tokyo, Japan), one represents a stand-alone confocal probe which is capable of passage through the working channel of most standard endoscopes (“probe-based”, pCLE; Cellvizio, Mauna Kea Technologies, Paris, France).62,63 The literature reports several different potential applications of CLE in IBD.18,64–74 Kiesslich and co-workers demonstrated that the combination of methylene blue-aided chromoendoscopy and CLE could detect 4.75-fold more neoplasia in surveillance colonoscopies compared to standard white-light endoscopy. Moreover, 50% less biopsy specimens were required and CLE could predict neoplastic changes with a sensitivity, specificity and accuracy of 95%, 98%, and 98% respectively.18 In another study, CLE was also feasible to differentiate dysplasia-associated lesion or mass (DALM) from sporadic adenoma (adenoma-like mass; ALM) with a high accuracy of 97% and an excellent agreement between CLE and histology (кappa = 0.91).72 Moreover, it has been established that CLE allows for a clear characterization of several microscopic changes, conventionally used as histopathological hallmarks for diagnosis of IBD.64–70 Our group has recently evaluated the use of CLE for in vivo microscopic diagnosis and severity assessment in Crohn's disease using histology as the reference standard.67 CLE was able to detect microscopic changes associated with active CD with high accuracy. Furthermore, in quiescent CD, endomicroscopy could detect a significant increase in crypt and goblet cell number compared with healthy controls.69 Another study by Kiesslich and co-workers correlated the presence of inflammatory-induced endomicroscopic findings in quiescent IBD patients, such as cell shedding and barrier loss, with subsequent relapse within 12 months (P b 0.001) harboring the use of this technique to drive IBD clinical management.70 CLE has been recently implemented in a new field of interest for luminal digestive endoscopy, enabling the in vivo evaluation of pathogenetic IBD-related pathways. In a pilot study, Atreya and co-workers assessed the use of CLE-based molecular imaging with monoclonal anti-TNF antibodies to evaluate whether in CD patients the therapeutic responses to Adalimumab correlate with the amount of mucosal membrane TNF receptor.74 Therefore, a newly developed fluorescent anti-TNF antibody (FITC-Adalimumab) was topically applied via a spraying catheter onto the inflamed mucosa of CD patients during a colonoscopy prior to anti-TNF therapy. Fluorescein expression on a cellular level as identified and quantified by CLE, indicated mucosal membrane-bound TNF + (mTNF +) cells. Patients with high amounts of mTNF + cells showed significantly higher short-term response rates at week 12 (92%) upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF + cells (15%). This clinical response in the former patients was sustained over a follow-up period of one year. Therefore, these data indicate for the first time that molecular imaging with fluorescent antibodies in vivo has the potential to predict therapeutic responses to biological treatment and opens new
266 avenues for personalized medicine by using fluorescent labeled antibodies.74
• CLE can detect more dysplastic lesions in surveillance colonoscopy for IBD and predict neoplastic changes with high accuracy compared to histology. • CLE can reliably identify microscopic features of CD distinguishing among active disease, quiescent disease with macroscopically uneventful mucosa and healthy controls. • CLE may predict clinical relapse within 12 months in quiescent IBD patients. • CLE-based molecular imaging with fluorescent monoclonal anti-TNF may predict therapeutic responses to biological therapy.
G.E. Tontini et al. Table 2 Potential uses of advanced endoscopic imaging techniques in Crohn's disease.
Dye-based chromoendoscopy48–52 Magnified chromoendoscopy45,46 Narrow band Imaging54–59 i-scan61 Confocal Laser Endomiscroscopy18’64–74 Endocytoscopy80
Adenoma detection rate
Disease Microscopic severity changes and extent
+++
++
+
+
++
++
+ ++ Not applicable Not applicable
++ ++ +++
++ ++ +++
++
++
4. Conclusion 3.4. Endocytoscopy Endocytoscopy (EC) enables in vivo microscopic imaging at a magnification up to 1390-fold, thereby allowing the analysis of mucosal structures at the cellular level.75 EC is based on the principle of contact light microscopy, therefore allowing the visualization of the very superficial mucosal layer.76 The technique was shown to be reliable for the examination of gastrointestinal mucosal surfaces.76–78 In addition, EC could predict neoplasia in aberrant crypt foci and could distinguish neoplastic from non-neoplasic colorectal lesions.78,79 Our group has recently assessed the value of EC to determine single inflammatory cells in patients with IBD.80 EC enabled clear visualization of different cellular structures within the intestinal mucosa, including size, arrangement and density of cells. Furthermore, size and shape of nuclei and the nucleus-to-cytoplasm ratio were visualized. Based on these specifications, it was possible to reliably distinguish single inflammatory cells by EC with the following respective sensitivities and specificities: neutrophilic (60% and 95%), basophilic (74% and 94%), eosinophilic granulocytes (75% and 91%), and lymphocytes (89% and 93%).80 The interobserver agreement between two investigators was substantial (kappa = 0.61–0.78), while the intraobserver agreement was substantial to almost perfect (kappa = 0.76–0.88). Concordance between EC and histopathology for grading intestinal disease activity was 100%.80
Advanced endoscopic imaging in IBD has experienced a major revolution during the last 10 years. By using capsule endoscopy or device-assisted enteroscopy the endoscopist is now able to evaluate the entire small-bowel, thereby improving both diagnosis and differential diagnosis among patients with IBD (Table 1). Magnification and dye-less chromoendoscopy enhance mucosal characterization of subtle details, harboring the potential of a more accurate detection and characterization of dysplastic lesions and of a refined assessment of mucosal severity compared to conventional white-light endoscopy. Moreover, recent advances in endoscopic imaging now enable the endoscopist to obtain real time in vivo histology during ongoing endoscopy by using endomicroscopy or endocytoscopy (Table 2). Nowadays, growing efforts are made to develop molecular imaging in the field of IBD.74 This innovative imaging technique can indeed look beyond the conventional morphological parameters and quantify those specific receptors that underlie both disease-related inflammatory pathways and pharmacological response, thereby opening a new avenue to improve the clinical management of IBD.
Conflict of interest statement None of the authors has any conflicts of interest related to this article/work to declare.
Acknowledgment Gian Eugenio Tontini has gained a grant from the Italian Group for the study of IBD (IG-IBD) supporting his research works at the Department of Medicine I, University of Erlangen-Nuremberg. • EC harbors the potential to identify various inflammatory mucosal cells during ongoing endoscopy in IBD, thereby enabling a new method to assess the severity of mucosal inflammation.
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268 38. Rahmi G, Samaha E, Vahedi K, Ponchon T, Fumex F, Filoche B, et al. Multicenter comparison of double-balloon enteroscopy and spiral enteroscopy. J Gastroenterol Hepatol 2013;28:992–8. 39. Mishkin DS, Chuttani R, Croffie J, Disario J, Liu J, Shah R, et al. Petersen BT; Technology Assessment Committee, American Society for Gastrointestinal Endoscopy. ASGE technology status evaluation report: wireless capsule endoscopy. Gastrointest Endosc 2006;63:539–45. 40. Eliakim R, Suissa A, Yassin K, Katz D, Fischer D. Wireless capsule video endoscopy compared to barium follow-through and computerised tomography in patients with suspected Crohn's disease—final report. Dig Liver Dis 2004;36:519–22. 41. Dubcenco E, Jeejeebhoy KN, Petroniene R, Tang SJ, Zalev AH, Gardiner GW, et al. Capsule endoscopy findings in patients with established and suspected small-bowel Crohn's disease: correlation with radiologic, endoscopic, and histologic findings. Gastrointest Endosc 2005;62:538–44. 42. Hara AK, Leighton JA, Heigh RI, Sharma VK, Silva AC, De Petris G, et al. Crohn disease of the small bowel: preliminary comparison among CT enterography, capsule endoscopy, small-bowel followthrough, and ileoscopy. Radiology 2006;238:128–34. 43. Spada C, Riccioni ME, Costamagna G. Patients with known small bowel stricture or with symptoms of small bowel obstruction secondary to Crohn’s disease should not perform video capsule endoscopy without being previously tested for small bowel patency. Am J Gastroenterol 2007;102(7):1542–3. 44. Kudo S, Tamura S, Nakajima T, Yamano H, Kusaka H, Watanabe H. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc 1996;44:8–14. 45. Hurlstone DP, Sanders DS, Lobo AJ, McAlindon ME, Cross SS. Indigo carmine-assisted high-magnification chromoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation. Endoscopy 2005;37:1186–92. 46. Hurlstone DP, Sanders DS, McAlindon ME, Thomson M, Cross SS. High-magnification chromoscopic colonoscopy in ulcerative colitis: a valid tool for in vivo optical biopsy and assessment of disease extent. Endoscopy 2006;38:1213–7. 47. Mönkemüller K, Fry LC, Zimmermann L, Mania A, Zabielski M, Jovanovic I. Advanced endoscopic imaging methods for colon neoplasia. Dig Dis 2010;28:629–40. 48. Kiesslich R, Fritsch J, Holtmann M, Koehler HH, Stolte M, Kanzler S, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;124:880–8. 49. Rutter MD, Saunders BP, Schofield G, Forbes A, Price AB, Talbot IC. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 2004;53:256–60. 50. Marion JF, Waye JD, Present DH, Israel Y, Bodian C, Harpaz N, et al. Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial. Am J Gastroenterol 2008;103:2342–9. 51. Technology Committee ASGE, Wong Kee Song LM, Adler DG, Chand B, Conway JD, Croffie JM, et al. Chromoendoscopy. Gastrointest Endosc 2007;66:639–49. 52. Wu L, Li P, Wu J, Cao Y, Gao F. The diagnostic accuracy of chromoendoscopy for dysplasia in ulcerative colitis: meta-analysis of six randomized controlled trials. Colorectal Dis 2012;14(4):416–20. 53. Neumann H, Neurath MF, Mudter J. New endoscopic approaches in IBD. World J Gastroenterol 2011;17:63–8. 54. van den Broek FJ, Fockens P, van Eeden S, Stokkers PC, Ponsioen CY, Reitsma JB, et al. Narrow-band imaging versus high-definition endoscopy for the diagnosis of neoplasia in ulcerative colitis. Endoscopy 2011;43:108–15. 55. van den Broek FJ, Fockens P, van Eeden S, van Eeden S, Reitsma JB, Hardwick JC, et al. Endoscopic tri-modal imaging for surveillance in ulcerative colitis: randomised comparison of
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269 features in adult patients with celiac sprue: a prospective, blinded endocytoscopy-conventional histology correlation study. Gastrointest Endosc 2009;70:933–41. 78. Cipolletta L, Bianco MA, Rotondano G, Piscopo R, Meucci C, Prisco A, et al. Endocytoscopy can identify dysplasia in aberrant crypt foci of the colorectum: a prospective in vivo study. Endoscopy 2009;41(2):129–32. 79. Neumann H, Vieth M, Neurath MF. Image of the month. Endocytoscopy-based detection of focal high-grade intraepithelial neoplasia in colonic polyps. Clin Gastroenterol Hepatol 2011;9(2): e13. 80. Neumann H, Vieth M, Neurath MF, Atreya R. Endocytoscopy allows accurate in vivo differentiation of mucosal inflammatory cells in IBD: a pilot study. Inflamm Bowel Dis 2013;19: 356–62.
Available online at www.sciencedirect.com
ScienceDirect
REVIEW ARTICLE
Advanced endoscopic imaging techniques in Crohn's disease Gian Eugenio Tontinia,b,⁎, Maurizio Vecchib,c , Markus F. Neuratha , Helmut Neumann a,⁎⁎ a
Department of Medicine I, University of Erlangen-Nuremberg, Germany Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy c Department of Medical Science for Health, University of Milan, Italy b
Received 4 August 2013; received in revised form 5 September 2013; accepted 5 September 2013 KEYWORDS Inflammatory Bowel Disease; Crohn's disease; Confocal laser endomicroscopy; Chromoendoscopy; Small-bowel capsule endoscopy; Device-assisted enteroscopy
Abstract Background: Endoscopy is of pivotal importance in Crohn's disease (CD) patients for diagnosis, surveillance and assessment of disease activity and extent. Device-assisted enteroscopy (DAE) and small-bowel capsule endoscopy (SBCE) have recently changed our endoscopic approach to small-bowel imaging. Furthermore, new advanced endoscopic imaging techniques have been implemented into clinical practice to improve both characterization of mucosal inflammation and detection of dysplastic lesions. Aim: To provide readers with a review about the concept of advanced endoscopic imaging for the diagnosis and characterization of CD. Methods: A literature search on the use of advanced endoscopy techniques in IBD patients was performed. Results: DAE and SBCE allow for deep enteroscopy with high diagnostic yields and low complication's rate but their collocation in the diagnostic algorithm is still not clearly defined. Dye-based chromoendoscopy (DBC) and magnification chromoendoscopy improved dysplasia's detection in long standing colitis and prediction of inflammatory activity and extent. Dye-less chromoendoscopy (DLC) might offer the potential to replace conventional DBC for surveillance. However, both narrow band imaging and i-scan have already shown to significantly improve activity and extent assessment in comparison to white-light endoscopy. Confocal laser endomicroscopy (CLE) can detect more dysplastic lesions in surveillance colonoscopy and predict neoplastic and inflammatory changes with high accuracy compared to histology. Moreover, CLE-based molecular imaging may anticipate the therapeutic responses to biological therapy. Endocytoscopy can identify in vivo inflammatory mucosal cells harboring a new method to assess the mucosal activity.
⁎ Correspondence to: G.E. Tontini, Department of Medicine I, University of Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany. Tel.: + 49 9131 85 35000; fax: + 49 9131 85 35209. ⁎⁎ Corresponding author. Tel.: + 49 9131 85 35000; fax: + 49 9131 85 35209. E-mail addresses: [email protected] (G.E. Tontini), [email protected] (H. Neumann). 1873-9946/$ - see front matter © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.crohns.2013.09.004
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G.E. Tontini et al. Conclusions: Recent progresses in small-bowel enteroscopy offer several potential benefits to improve both diagnosis and characterization of CD. New advanced endoscopic imaging techniques can improve detection of dysplasia and refine mucosal healing assessment, even looking beyond the morphological parameters revealed by conventional endoscopic imaging. © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Deep small-bowel enteroscopy for Crohn's disease . . . . 2.1. Device-assisted enteroscopy . . . . . . . . . . . . . 2.2. Capsule endoscopy . . . . . . . . . . . . . . . . . . . 3. Advanced endoscopic imaging techniques in patients with
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3.1. Magnification endoscopy and dye-based chromoendoscopy 3.2. Dye-less chromoendoscopy . . . . . . . . . . . . . . . . . . 3.3. Confocal Laser endomicroscopy . . . . . . . . . . . . . . . 3.4. Endocytoscopy . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Inflammatory Bowel Disease (IBD) encompasses ulcerative colitis (UC), Crohn's disease (CD) and IBD type unclassified (IBDU).1 These three entities have several aspects in common but their peculiarities are critical for a correct and tailored clinical management.2,3 The differential diagnosis between IBD and other gastrointestinal disorders is based on clinical evaluation and combination of endoscopic, histological, radiologic and biochemical investigations.3–8 Patients with IBD associated colitis may present with clinical and endoscopic unspecific features, often requiring additional diagnostic work-up. It is well accepted that chronic inflammation involving the large bowel of patients with IBD represents a major risk factor for the development of colitis-associated cancer (CAC).9–12 While all patients with IBD suffer from an increased risk for developing CAC, it was shown that the duration and anatomical extent of disease are well-established risk factors for cancer development.13,14 In addition, one retrospective case–control study assessed the severity of inflammation as a risk factor for CAC in UC and found that inflammation measured by endoscopy, which was significant at univariate analysis, was not a significant determinant of cancer risk in a multivariate model.11 Only the degree of inflammation over time as assessed by histopathology was considered to be an independent risk factor for CAC development.11 This finding was confirmed by Mathy and co-workers, who demonstrated that histological, rather than endoscopic assessment of inflammation, serve as a better determinant for CAC risk.10 Moreover, in a recent a prospective case– control study, Rubin et al. have reported a positive association between histological activity and CAC in patients with UC.12
. . . . . . . . . . . . IBD
CAC may occur in elevated protruded lesions but may also develop in normal-appearing mucosa (i.e. “flat”). Data from the literature indicate that in 50%–80% of cases with colitis-associated neoplasms, the lesions are overlooked upon pan-colonoscopy.15 This aspect limits the usefulness of colonoscopic visualization and mandates the need for multiple random biopsies, which is a time consuming, costly and ineffective endeavor.16–22 Therefore, most guidelines recommend surveillance colonoscopy with multiple random biopsies every 10 cm as the reference standard for diagnosis of intraepithelial neoplasia and cancer in either UC or CD with long standing and extensive involvement.5,23–27 Nevertheless, to date, no randomized controlled study could show a reduced risk of CAC development by surveillance colonoscopy in IBD.14,28 Thus, it becomes obvious that there is a need for new and more advanced endoscopic imaging techniques for surveillance in IBD.16 In recent years new emerging endoscopic imaging techniques were introduced, allowing a detailed analysis of subtle endoscopic findings and revealing microscopic features. Furthermore, recent introduced endoscopic imaging techniques have enriched the available equipment for deep small-bowel imaging, offering a more tailored approach for patients with suspected or established CD. This review describes the concept of advanced endoscopic imaging for the diagnosis and characterization of Crohn's disease.
2. Deep small-bowel enteroscopy for Crohn's disease 2.1. Device-assisted enteroscopy Although standard small-bowel endoscopy plays a pivotal role in the management of patients with IBD, its collocation
Endoscopic diagnosis in Crohn’s disease in the diagnosis and treatment algorithm is still not clearly defined.29 Accordingly, small-bowel cross-sectional imaging should generally precede enteroscopic examination and the decision on whether small-bowel capsule endoscopy, rather than whether device-assisted enteroscopy should be performed depends on the nature and location of the smallbowel lesion, as well as local availability and expertise of the examiners.29–32 The term “balloon-assisted enteroscopy” (BAE) was first proposed by Mönkemüller and co-workers and summarizes three different endoscopic methods for small-bowel imaging: (I) double-balloon enteroscopy (DBE; Fujinon, Tokyo, Japan); (II) single-balloon endoscopy (SBE; Olympus, Tokyo, Japan); and (III) NaviAid (Pentax, Tokyo, Japan).16 All systems allow deep intubation of the small-bowel for diagnostic and therapeutic interventions (e.g. for hemostasis, dilation or biopsy acquisition). Combination of oral and anal insertion routes are used to achieve deep or complete examination of the small-bowel.33 Up to now, few studies have reported a 30–48% diagnostic yield of DBE when evaluating patients with suspected Crohn's disease.34–37 Complications are rare and occur in b 1% of cases, while balloon dilation of strictures has a reported perforation risk of up to 3%.35 Nevertheless, BAE should not be considered as the first-line procedure in the evaluation of suspected small-bowel CD, as the procedure is somehow invasive, time and cost-expensive and mostly limited to specialized centers.29 Therefore, in patients with suspected or established small-bowel CD without fistulating or stenosing behavior, capsule endoscopy should be considered as the first choice.29 However, BAE allows for the retrieval of tissue for analysis and permits therapeutic interventions such as stricture dilation (Table 1). Besides BAE, spiral enteroscopy was introduced, as a new imaging modality enabling deep smallbowel enteroscopy. One recent multicenter study compared double-balloon enteroscopy and spiral enteroscopy and found that spiral enteroscopy appears as safe as double-balloon enteroscopy for small-bowel exploration with a similar diagnostic and therapeutic yield. Comparison between the two procedures in terms of duration and length of small-bowel explored was slightly in favor of spiral enteroscopy but this was not statistically significant.38 Despite these promising results, no data of spiral enteroscopy in patients with IBD is yet available.
2.2. Capsule endoscopy Capsule endoscopy (CE) was introduced in 2002. Currently, various capsule systems from different companies are available for examination of the esophagus, small-bowel (SBCE) and colon.30–32,39 The capsule movement is passively propelled through the intestine by peristalsis while transmitting color images of the intestine. Multiple studies have shown the impact of CE for diagnosis of CD associated changes including ulcers, erosions, erythema, aphthae and strictures as to evaluate response to therapy.40–42 In addition, recent data has shown that SBCE is able to identify mucosal lesions according to CD even in patients with negative small-bowel radiographic imaging.29 In the study by Dubcenco et al., CE yielded a sensitivity and specificity of 90% and 100%, respectively, and a positive
263 Table 1
Diagnosis of suspected small-bowel Crohn’s disease.
predictive value and a negative predictive value of 100% and 77%, respectively, for diagnosis of active small-bowel CD.41 One disadvantage may be that the coecum could not be reached in between 8% and 40% of cases and inadequate bowel preparation could additionally hamper the SBCE accuracy.29 Moreover, none of the above-mentioned studies used unequivocal gold-standards and the diagnosis of CD was always supported by the clinical presentation.16 As with other imaging modalities, the diagnosis of CD should not be based on the appearances at CE alone. In subjects suspected for CD, a positive SBCE requires a further endoscopic approach for biopsy sampling (i.e. by using DAE as depicted in Table 1). In established Crohn's disease, SBCE findings should be counted against lesions of unknown clinical significance, which are also present in up to 13% of asymptomatic patients.29 The main contraindication for capsule endoscopy is related to the risk of retention. In patients with suspected CD the capsule retention's rate is low and comparable to that when the indication for SBCE is bleeding. Conversely, in established CD the risk is increased, particularly in those with known or suspected intestinal stenosis.29 Thus small-bowel strictures should be excluded by a thorough clinical workup and radiographic imaging before performing SBCE. However, conventional radiographic studies cannot entirely rule out the potential for capsule retention, thereby suggesting the use of the so called “Agile Patency Capsule” (biodegradable analogous) to prevent the risk of retention.29,43
• In case of suspected small-bowel Crohn's disease without strictures or stenosis capsule endoscopy should be preferred to device-assisted enteroscopy. • Device-assisted enteroscopy offers the potential to perform interventions within the small-bowel and is associated with low complication rate.
264
G.E. Tontini et al.
3. Advanced endoscopic imaging techniques in patients with IBD 3.1. Magnification chromoendoscopy
endoscopy
and
dye-based
Magnification endoscopy utilizes a movable lens to vary the degree of magnification up to 150-fold, thereby allowing a detailed characterization of the mucosal surface and pit pattern.44 Hurlstone and co-workers prospectively analyzed indigo carmine-assisted high-magnification endoscopy for detection and characterization of neoplasia in UC.45 Significantly more neoplastic lesions were detected in the magnification chromoendoscopy group as compared to controls, particularly due to the enhanced detection of non-polypoid (i.e. flat) lesions. In addition, the same group reported the results of a large prospective study on the value of high-magnification chromoendoscopy guided colonoscopy (HMCC) for in vivo prediction of histopathological inflammatory changes associated with IBD.46 In 300 consecutive patients with a known history of UC, white-light colonoscopy was used followed by HMCC with indigo carmine dye-spraying. Magnification imaging was significantly better than conventional colonoscopy for predicting disease extent in vivo (P b 0.0001).46 Chromoendoscopy is divided into dye-based chromoendoscopy (DBC) and dye-less chromoendoscopy (DLC). The basic principle of chromoendoscopy is to enhance the mucosal detail and the mucosal vascular pattern with the use of various dyes (DBC) or optical and computer-based color programs (DLC). DLC further comprised optical chromoendoscopy and digital chromoendoscopy techniques. The contrast enhancement of the mucosal surface results in an improved detection of subtle mucosal details, thereby improving the characterization of superficial patterns and the mucosal vascular network.16 DBC uses different dye agents which are divided in absorptive agents (e.g. Lugol solution, methylene blue, toludine blue, and cresyl violet), contrast agents (e.g. indigo carmine, and acetic acid) and reactive staining agents (e.g. congo red, phenol red).16 Dye agents are mostly applied via standard spraying catheters or plain biliary ERCP catheters.47 Various studies have shown the potential of DBC to enhance detection of pre-neoplastic and neoplastic lesions in IBD.48–52 In this setting, the available data are mostly based on UC patients. Nonetheless, one would suspect similar efficacy to improve surveillance strategies in long standing colitis related to CD. One randomized, controlled trial evaluated whether 0.1% methylene blue-aided chromoendoscopy might facilitate early detection of intraepithelial neoplasia and CAC in UC.48 DBC permitted more accurate diagnosis of extent and severity of inflammatory activity in UC compared with conventional white-light endoscopy and improved significantly the early detection of intraepithelial neoplasia and CAC in patients with UC.48 Another back-to-back colonoscopy trial evaluated pan-colonic chromoendoscopy with 0.1% indigo carmine for detection of dysplasia in UC.49 Non-targeted biopsies detected no dysplasia in 2904 biopsies while the targeted biopsy protocol with pan-colonic chromoendoscopy required fewer
biopsies (157) and detected nine dysplastic lesions.49 A recent introduced meta-analysis of six randomized controlled trials evaluated the diagnostic accuracy of chromoendoscopy for dysplasia detection in UC.52 The results demonstrated a pooled sensitivity of 83%, specificity of 91%, and diagnostic odds ratio of 17.5. It was concluded that DBC has a medium to high sensitivity and a high diagnostic accuracy for detection of dysplastic lesions in UC.52
• Pan-colonic chromoendoscopy and targeted biopsies of suspicious lesions represent a more effective surveillance method in IBD than taking only multiple non-targeted biopsies. • Magnification chromoendoscopy improves the detection of pre-neoplastic and neoplastic colorectal lesions in IBD.
3.2. Dye-less chromoendoscopy DLC is divided into optical chromoendoscopy, including Narrow Band Imaging (NBI; Olympus, Tokyo, Japan) or Compound Band Imaging (CBI; Aohua, Shanghai, China), and digital chromoendoscopy including i-scan (Pentax, Tokyo, Japan) and Fujinon intelligent color enhancement (FICE; Fujinon, Tokyo, Japan).16 Optical chromoendoscopy is based on optical filters within the light source of the endoscope, which narrow the bandwidth of spectral transmittance, thereby enhancing blood vessels. Otherwise, i-scan and FICE use digital post-processing for computed spectral estimation for enhanced tissue contrast.16,53 Various studies have addressed the potential of NBI for diagnosis and characterization of pre-neoplastic and neoplastic changes in IBD. Recently, van den Broek and co-workers performed a crossover trial in which patients with UC underwent both NBI and high-definition (HD) white-light colonoscopy in a randomized order. It was shown that NBI does not improve the detection of neoplasia in patients with UC compared to HD white-light endoscopy. In addition, NBI proved suboptimal accuracy (73%) for differentiating neoplastic from non-neoplastic colorectal lesions.54 The same group assessed the value of endoscopic tri-modal imaging for surveillance in UC. Fifty patients underwent surveillance colonoscopy and each colonic segment was inspected twice, once with auto-fluorescence imaging (AFI) and once with high-resolution white-light endoscopy, in a random order. In addition, all detected lesions were inspected by NBI according to Kudo pit pattern followed by random biopsies. AFI improved the detection of neoplasia and decreased the yield of random biopsies compared to white-light endoscopy. Pit pattern analysis by NBI had a moderate accuracy for the prediction of histology (80%). However, all neoplasia was colored purple on AFI (sensitivity 100%), thereby suggesting a valuable effect of AFI color for exclusion of neoplasia.55 In a pilot study, magnification colonoscopy with NBI was used to assess diagnosis of dysplasia in UC. The surface pattern was determined to be either “honeycomb-like”, “villous” or “tortuous-like”. By taking the surface pattern into account, the rate of positive dysplasia was higher in the
Endoscopic diagnosis in Crohn’s disease “tortuous” pattern than in the “honeycomb-like” or “villous” pattern group. Therefore, the “tortuous” pattern determined by NBI colonoscopy may be a clue for the identification of dysplasia during surveillance in UC.56 Very recently, it was also shown that NBI is less time consuming and equally effective alternative to DBC for the detection of intraepithelial neoplasia. In this prospective, randomized, crossover study, NBI resulted in a significantly inferior false-positive biopsy rate providing a similar true-positive rate. However, given the lower NBI neoplastic lesion and neoplastic patient miss rates (P = 0.2), the authors did not recommend NBI as standard surveillance technique in IBD.57 To the best of our knowledge, there is no published data regarding the use of digital chromoendoscopy techniques for detection and characterization of intraepithelial neoplasia in IBD. The potential of DLC has been also studied to improve the characterization of disease extent and activity in IBD. One recent published article reviewed endoscopic findings under NBI in long standing UC. NBI strongly correlated with histological findings including crypt distortion, goblet cell depletion and basal plasmacytosis, therefore harboring the potential to better assess histologic severity in only mild and inactive disease.58 Another pilot study addressed the question if NBI could successfully assess mucosal angiogenesis in UC and CD. In mucosal areas that were endoscopically normal but positive on NBI, there was a significant increase in mucosal angiogenesis. Therefore, the authors suggested that NBI might allow in vivo imaging of intestinal neo-angiogenesis in IBD patients.59 One additional study evaluated FICE in the IBD setting, showing that the system could not improve the detection or delineation of evident lesions such as ulcers and erosions in CD.60 Recently, our group successfully studied the impact of i-scan for prediction of mucosal inflammation in IBD.61 Patients underwent total colonoscopy and were examined using both HD white-light (group A) and HD plus i-scan colonoscopy (group B). Agreement between endoscopic prediction of disease severity and histological findings was 54% in group A and 90% in group B (P = .066). Moreover, using histology as reference standard the endoscopic prediction of the inflammatory activity's extent was 49% in group A and 92% in group B (P = .001). Compared with histological results, i-scan enabled a more precise diagnosis of mucosal inflammation than the conventional colonoscopy.61
• Dye-less chromoendoscopy might offer the potential to replace conventional dye-based chromoendoscopy for lesion detection and assessment of disease severity in IBD. • i-scan has the potential to improve diagnosis of severity and extent of mucosal inflammation in patients with IBD.
3.3. Confocal Laser endomicroscopy Confocal laser endomicroscopy (CLE) was introduced in 2004 and has rapidly emerged as a promising approach to
265 obtain real time in vivo histology during ongoing endoscopy.62 The technique is based on tissue illumination with a blue laser light after topical or systemic application of fluorescence agents. Currently, two FDA approved and CE certified devices are available. One is integrated into the distal tip of a high-resolution endoscope (“integrated”, iCLE; Pentax, Tokyo, Japan), one represents a stand-alone confocal probe which is capable of passage through the working channel of most standard endoscopes (“probe-based”, pCLE; Cellvizio, Mauna Kea Technologies, Paris, France).62,63 The literature reports several different potential applications of CLE in IBD.18,64–74 Kiesslich and co-workers demonstrated that the combination of methylene blue-aided chromoendoscopy and CLE could detect 4.75-fold more neoplasia in surveillance colonoscopies compared to standard white-light endoscopy. Moreover, 50% less biopsy specimens were required and CLE could predict neoplastic changes with a sensitivity, specificity and accuracy of 95%, 98%, and 98% respectively.18 In another study, CLE was also feasible to differentiate dysplasia-associated lesion or mass (DALM) from sporadic adenoma (adenoma-like mass; ALM) with a high accuracy of 97% and an excellent agreement between CLE and histology (кappa = 0.91).72 Moreover, it has been established that CLE allows for a clear characterization of several microscopic changes, conventionally used as histopathological hallmarks for diagnosis of IBD.64–70 Our group has recently evaluated the use of CLE for in vivo microscopic diagnosis and severity assessment in Crohn's disease using histology as the reference standard.67 CLE was able to detect microscopic changes associated with active CD with high accuracy. Furthermore, in quiescent CD, endomicroscopy could detect a significant increase in crypt and goblet cell number compared with healthy controls.69 Another study by Kiesslich and co-workers correlated the presence of inflammatory-induced endomicroscopic findings in quiescent IBD patients, such as cell shedding and barrier loss, with subsequent relapse within 12 months (P b 0.001) harboring the use of this technique to drive IBD clinical management.70 CLE has been recently implemented in a new field of interest for luminal digestive endoscopy, enabling the in vivo evaluation of pathogenetic IBD-related pathways. In a pilot study, Atreya and co-workers assessed the use of CLE-based molecular imaging with monoclonal anti-TNF antibodies to evaluate whether in CD patients the therapeutic responses to Adalimumab correlate with the amount of mucosal membrane TNF receptor.74 Therefore, a newly developed fluorescent anti-TNF antibody (FITC-Adalimumab) was topically applied via a spraying catheter onto the inflamed mucosa of CD patients during a colonoscopy prior to anti-TNF therapy. Fluorescein expression on a cellular level as identified and quantified by CLE, indicated mucosal membrane-bound TNF + (mTNF +) cells. Patients with high amounts of mTNF + cells showed significantly higher short-term response rates at week 12 (92%) upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF + cells (15%). This clinical response in the former patients was sustained over a follow-up period of one year. Therefore, these data indicate for the first time that molecular imaging with fluorescent antibodies in vivo has the potential to predict therapeutic responses to biological treatment and opens new
266 avenues for personalized medicine by using fluorescent labeled antibodies.74
• CLE can detect more dysplastic lesions in surveillance colonoscopy for IBD and predict neoplastic changes with high accuracy compared to histology. • CLE can reliably identify microscopic features of CD distinguishing among active disease, quiescent disease with macroscopically uneventful mucosa and healthy controls. • CLE may predict clinical relapse within 12 months in quiescent IBD patients. • CLE-based molecular imaging with fluorescent monoclonal anti-TNF may predict therapeutic responses to biological therapy.
G.E. Tontini et al. Table 2 Potential uses of advanced endoscopic imaging techniques in Crohn's disease.
Dye-based chromoendoscopy48–52 Magnified chromoendoscopy45,46 Narrow band Imaging54–59 i-scan61 Confocal Laser Endomiscroscopy18’64–74 Endocytoscopy80
Adenoma detection rate
Disease Microscopic severity changes and extent
+++
++
+
+
++
++
+ ++ Not applicable Not applicable
++ ++ +++
++ ++ +++
++
++
4. Conclusion 3.4. Endocytoscopy Endocytoscopy (EC) enables in vivo microscopic imaging at a magnification up to 1390-fold, thereby allowing the analysis of mucosal structures at the cellular level.75 EC is based on the principle of contact light microscopy, therefore allowing the visualization of the very superficial mucosal layer.76 The technique was shown to be reliable for the examination of gastrointestinal mucosal surfaces.76–78 In addition, EC could predict neoplasia in aberrant crypt foci and could distinguish neoplastic from non-neoplasic colorectal lesions.78,79 Our group has recently assessed the value of EC to determine single inflammatory cells in patients with IBD.80 EC enabled clear visualization of different cellular structures within the intestinal mucosa, including size, arrangement and density of cells. Furthermore, size and shape of nuclei and the nucleus-to-cytoplasm ratio were visualized. Based on these specifications, it was possible to reliably distinguish single inflammatory cells by EC with the following respective sensitivities and specificities: neutrophilic (60% and 95%), basophilic (74% and 94%), eosinophilic granulocytes (75% and 91%), and lymphocytes (89% and 93%).80 The interobserver agreement between two investigators was substantial (kappa = 0.61–0.78), while the intraobserver agreement was substantial to almost perfect (kappa = 0.76–0.88). Concordance between EC and histopathology for grading intestinal disease activity was 100%.80
Advanced endoscopic imaging in IBD has experienced a major revolution during the last 10 years. By using capsule endoscopy or device-assisted enteroscopy the endoscopist is now able to evaluate the entire small-bowel, thereby improving both diagnosis and differential diagnosis among patients with IBD (Table 1). Magnification and dye-less chromoendoscopy enhance mucosal characterization of subtle details, harboring the potential of a more accurate detection and characterization of dysplastic lesions and of a refined assessment of mucosal severity compared to conventional white-light endoscopy. Moreover, recent advances in endoscopic imaging now enable the endoscopist to obtain real time in vivo histology during ongoing endoscopy by using endomicroscopy or endocytoscopy (Table 2). Nowadays, growing efforts are made to develop molecular imaging in the field of IBD.74 This innovative imaging technique can indeed look beyond the conventional morphological parameters and quantify those specific receptors that underlie both disease-related inflammatory pathways and pharmacological response, thereby opening a new avenue to improve the clinical management of IBD.
Conflict of interest statement None of the authors has any conflicts of interest related to this article/work to declare.
Acknowledgment Gian Eugenio Tontini has gained a grant from the Italian Group for the study of IBD (IG-IBD) supporting his research works at the Department of Medicine I, University of Erlangen-Nuremberg. • EC harbors the potential to identify various inflammatory mucosal cells during ongoing endoscopy in IBD, thereby enabling a new method to assess the severity of mucosal inflammation.
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