Table 3.
Summary of the studies evaluating CLE in lower gastrointestinal disease screening and diagnosis (“per patient” and “per lesion” analysis).
| Author and year | Country | N | Mean age or range | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | Accuracy (%) | Main findings |
|---|---|---|---|---|---|---|---|---|---|
| Inflammatory bowel disease | |||||||||
| Watanabe et al. 2008 [63] | Japan | 31 patients | n/a | n/a | n/a | n/a | n/a | n/a | Images obtained with CLE provide equivalent information to conventional histology. |
| Trovato et al. 2009 [64] | Italy | 18 patients 253 lesions |
70 | n/a 94.1 |
n/a 100 |
n/a n/a |
n/a n/a |
n/a 94.4 |
Endomicroscopy may be helpful in the evaluation of morphologic changes in ileal pouch. |
| Li et al. 2010 [65] | China | 73 patients | 50.4 | n/a | n/a | n/a | n/a | n/a | CLE is reliable for real-time assessment of inflammation activity in UC by evaluation of crypt architecture, microvascular alterations, and fluorescein leakage. |
| Liu et al. 2011 [66] | Canada USA |
57 patients | 46.6 | n/a | n/a | n/a | n/a | n/a | Epithelial gap density visualized by CLE is significantly increased in patients with IBD compared with controls. |
| Moussata et al. 2011 [67] | France, Germany, and UK | 21 patients 26 lesions |
n/a | n/a 89 |
n/a 100 |
n/a 100 |
n/a 80 |
n/a 92.3 |
CLE is a new tool that can image intramucosal bacteria in vivo in patients with IBD. |
| Kiesslich et al. 2012 [68] | Germany, France, UK, and China | 58 patients | n/a | 62.5 | 91.2 | n/a | n/a | 79 | Cell shedding and barrier loss detected by CLE predict relapse of IBD and have potential as a diagnostic tool for the management of the disease. |
| Krauss et al. 2012 [69] | Germany | 146 patients | 34.9 | n/a | n/a | n/a | n/a | n/a | CLE allows the analysis of the subsurface structure of lymphoid follicles, those surrounded by a red ring may represent an early marker of CD. |
| Neumann et al. 2012 [70] | Germany | 72 patients | 39 | n/a | n/a | n/a | n/a | n/a | CLE has the potential to significantly improve diagnosis of CD compared with standard endoscopy. |
| Turcotte et al. 2012 [71] | Canada, USA | 41 patients | 41.1 | n/a | n/a | n/a | n/a | n/a | Increased epithelial gaps in the small intestine as determined by pCLE are a predictor for future hospitalization or surgery in IBD patients. |
| Musquer et al. 2013 [72] | France, USA | 16 patients | 35.5 | n/a | n/a | n/a | n/a | n/a | CLE allows quantitative analysis of colonic pit structure in healthy and CD patients. |
| Atreya et al. 2014 [73] | Germany | 25 patients | 41.6 | n/a | n/a | n/a | n/a | n/a | Molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment in CD and autoimmune or inflammatory disorders. |
| Buda et al. 2014 [74] | Italy, Germany, and UK | 38 patients | 52 | n/a | n/a | n/a | n/a | n/a | In vivo intramucosal changes detected by CLE in UC remittent patients can predict disease relapse. |
| Li et al. 2014 [75] | China | 43 patients | 44 | 95.7 | 85 | n/a | n/a | 90.7 | CLE is comparable to conventional histology in predicting relapse in patients with UC. |
|
| |||||||||
| Dysplasia/neoplasia in inflammatory bowel disease | |||||||||
| Hurlstone et al. 2007 [76] | UK | 36 patients | 56 | n/a | n/a | n/a | n/a | 97 | Adenoma Like Masses and Displasia Associated Lesional Masses can be differentiated by CLE with a high overall accuracy in patients with Ulcerative Colitis. |
| Kiesslich et al. 2007 [77] | Germany | 153 patients 134 lesions |
44 | n/a 94.7 |
n/a 98.3 |
n/a 90 |
n/a 99.1 |
n/a 97.8 |
Chromoscopy-guided endomicroscopy can determine if Ulcerative Colitis should undergo biopsy examination, increasing the diagnostic yield and reducing the need for biopsy examinations. |
| Günther et al. 2011 [78] | Germany | 150 patients | 48.3 | n/a | n/a | n/a | n/a | n/a | CLE targeted biopsies led to higher detection rates of intraepithelial neoplasia in patients with long-standing UC. |
| Hlavaty et al. 2011 [79] | Slovakia | 30 patients 68 lesions |
n/a | n/a 100 |
n/a 98.4 |
n/a 66.7 |
n/a 100 |
n/a n/a |
CLE targeted biopsies are superior to random biopsies in the screening of intraepithelial neoplasia in patients with inflammatory bowel disease. |
| van den Broek et al. 2011 [80] | Netherlands | 22 patients 87 lesions |
54 | n/a 65 |
n/a 82 |
n/a n/a |
n/a n/a |
n/a 81 |
pCLE for UC surveillance is feasible with reasonable diagnostic accuracy. |
| Rispo et al. 2012 [81] | Italy | 51 patients 14 biopsies |
52 | n/a 100 |
n/a 90 |
n/a 83 |
n/a 100 |
n/a n/a |
CLE is an accurate tool for the detection of dysplasia in long-standing Ulcerative Colitis, limiting the need of biopsies. |
|
| |||||||||
| Colorectal neoplasms and polyps | |||||||||
| Kiesslich et al. 2004 [82] | Germany | 42 patients 390 lesions |
64.2 | n/a 97.4 |
n/a 99.4 |
n/a n/a |
n/a n/a |
n/a 99.2 |
CLE enables virtual histology of neoplastic changes with high accuracy, optimizing diagnosis during colonoscopy. |
| Odagi et al. 2007 [83] | Japan | 45 patients | 63 | n/a | n/a | n/a | n/a | n/a | CEM provides endoscopists with a valuable new diagnostic tool, for observing tissue in situ at the histopathological level, allowing evaluation of physiological function during endoscopic examination. |
| Wang et al. 2007 [84] | USA | 54 patients | n/a | 91 | 87 | n/a | n/a | 89 | CLE provides in vivo real time pathological interpretation of tissue. |
| Buchner et al. 2010 [85] | USA | 75 patients 119 lesions |
73 | n/a 88 |
n/a 76 |
n/a n/a |
n/a n/a |
n/a n/a |
CLE demonstrates higher sensitivity than chromoendoscopy with similar specificity in differentiating colorectal polyps. |
| De Palma et al. 2010 [86] | Italy | 20 patients 32 lesions |
62.5 | n/a 100 |
n/a 84.6 |
n/a 90.5 |
n/a 100 |
n/a 92.3 |
pCLE permits high-quality imaging enabling prediction of intraepithelial neoplasia with high level of accuracy. |
| Gómez et al. 2010 [87] | USA, Netherlands, and Germany | 53 patients 75 lesions |
n/a | n/a 76 |
n/a 72 |
n/a n/a |
n/a n/a |
n/a 75 |
An international collaboration group had moderate to good interobserver agreement using a pCLE system to predict neoplasia. |
| Sanduleanu et al. 2010 [88] | Netherlands | 72 patients 116 lesions |
72 | n/a 97.3 |
n/a 92.8 |
n/a n/a |
n/a n/a |
n/a 95.7 |
C-CLE accurately discriminates adenomatous from nonadenomatous colorectal polyps and enables evaluation of degree of dysplasia during ongoing endoscopy. |
| Xie et al. 2011 [89] | China | 115 patients 115 lesions |
51.6 | n/a 93.9 |
n/a 95.9 |
n/a 96.9 |
n/a 92.2 |
n/a n/a |
Endoscope integrated CLE with fluorescein staining may reliably assist in the real-time identification of colonic adenomas. |
| André et al. 2012 [90] | USA, France | 71 patients 135 lesions |
75 | n/a 91.4 |
n/a 85.7 |
n/a n/a |
n/a n/a |
n/a 89.6 |
The proposed software for automated classification of pCLE videos of colonic polyps achieves high performance, comparable to that of offline diagnosis of pCLE videos established by expert endoscopists. |
| Cârţână et al. 2012 [91] | Romania | 4 patients | n/a | n/a | n/a | n/a | n/a | n/a | Imaging of blood vessels with CLE is feasible in normal and tumor colorectal tissue by using fluorescently labeled antibodies targeted against an endothelial marker. The method could be translated into the clinical setting for monitoring of antiangiogenic therapy. |
| Coron et al. 2012 [92] | France USA |
16 patients 13 lesions |
62 | n/a | n/a | n/a | n/a | n/a | Standard colonic biopsies obtained during CLE retain fluorescein, show excellent delineation of mucosal structures without additional staining, allow the evaluation of mucosal microvasculature and vascular permeability, and are suitable for immunostaining. |
| Kuiper et al. 2012 [93] | Netherlands | 64 patients 154 lesions |
59 | n/a 57.1 |
n/a 71 |
n/a n/a |
n/a n/a |
n/a 66.7 |
The majority of p-CLE videos demonstrated insufficient quality in more than half of the time recorded. Post hoc accuracy of p-CLE was significantly lower in comparison with real-time accuracy of CLE and NBI. |
| Mascolo et al. 2012 [94] | Italy | 22 patients | 61.6 | n/a | n/a | n/a | n/a | n/a | By p-CLE, it is possible to identify specific crypt architecture modifications associated with changes in cellular infiltration and vessels architecture, highlighting a good correspondence between p-CLE features and histology. |
| Shahid et al. 2012 [95] | USA | 74 patients 154 lesions |
69 | n/a 81 |
n/a 76 |
n/a 78 |
n/a 79 |
n/a 79 |
Real-time and offline interpretations of p-CLE images are moderately accurate. Real-time interpretation is slightly less accurate than offline diagnosis. |
| Shahid et al. 2012 [96] | USA | 65 patients 130 lesions |
69 | n/a 86 |
n/a 78 |
n/a n/a |
n/a n/a |
n/a 82 |
p-CLE demonstrated higher sensitivity in predicting histology of small polyps compared with NBI, whereas NBI had higher specificity. When used in combination, the accuracy of pCLE and NBI was extremely high, approaching the accuracy of histopathology. |
| Shahid et al. 2012 [97] | USA, Netherlands | 92 patients 129 lesions |
70 | n/a 97 |
n/a 77 |
n/a 55 |
n/a 99 |
n/a 81 |
Confocal endomicroscopy increases the sensitivity for detecting residual neoplasia after colorectal EMR compared with endoscopy alone. In combination with virtual chromoendoscopy, the accuracy is extremely high, and sensitivity approaches that of histopathology. |
| Gómez et al. 2013 [98] | USA | 85 patients 127 lesions |
72 | n/a 43.4 |
n/a 70.6 |
n/a 18.6 |
n/a 89 |
n/a n/a |
The attempt at creating classification criteria for probe-based CLE did not consistently distinguish advanced from nonadvanced adenomas and, therefore, is not useful in applying a “diagnose, resect, and discard” strategy. |
| Liu et al. 2013 [99] | China | 71 patients 166 lesions |
57.6 | n/a 97.1 |
n/a 96.9 |
n/a n/a |
n/a n/a |
n/a 97.6 |
CLE has the potential to enable an immediate diagnosis of CRC and the degree of differentiation of CRC during ongoing endoscopy in vivo. |
| Liu et al. 2013 [100] | China | 37 patients 37 lesions |
70 | n/a | n/a | n/a | n/a | n/a | CLE could be used in molecular imaging with specific targeting of EGFR in colorectal neoplasia. |
| Ciocâlteu et al. 2014 [101] | Romania | 5 patients | n/a | n/a | n/a | n/a | n/a | n/a | Differences in vessels morphology with CLE are useful for identifying patients who might benefit from neoadjuvant angiogenetic therapy. |
| Yuan et al. 2014 [102] | China | 39 patients 50 lesions |
52 | n/a 79 |
n/a 83 |
n/a n/a |
n/a n/a |
n/a 81 |
Three different confocal laser endomicroscopy (CLE) diagnostic systems including Maiz, Sanduleanu, and Qilu for the prediction of colorectal hyperplastic polyp or adenoma have a high accuracy, sensitivity, and specificity. |
|
| |||||||||
| Graft versus Host Disease | |||||||||
| Bojarski et al. 2009 [103] | Germany | 35 patients | n/a | 74 | 100 | n/a | n/a | n/a | CLE provides rapid diagnosis of acute intestinal GVHD with high accuracy while performing endoscopy. |
|
| |||||||||
| Infectious colitis | |||||||||
| Neumann et al. 2013 [104] | Germany | 10 patients | 72.5 | 88.9 | 97.2 | 80 | 98.6 | 96.25 | CLE has the potential for in vivo diagnosis of CDI associated colitis. In addition, CLE allowed the detection of intramucosal bacteria in vivo. |
|
| |||||||||
| Irritable bowel syndrome | |||||||||
| Turcotte et al. 2013 [105] | Canada | 34 patients | 45.1 | 62 | 89 | 83 | 73 | n/a | As a result of CLE analysis, IBS patients have significantly more epithelial gaps in their small intestine compared with healthy controls, which may be a cause of altered intestinal permeability observed in IBS. |
| Fritscher-Ravens et al. 2014 [106] | Germany USA UK |
36 patients | 44.6 | n/a | n/a | n/a | n/a | n/a | Based on CLE analysis of IBS patients with a suspected food intolerance, exposure to candidate food antigens caused immediate breaks, increased intervillous spaces, and increased IELs in the intestinal mucosa. |
CLE stands for confocal laser endomicroscopy; p-CLE, probe-based confocal laser endomicroscopy; c-CLE, colon probe-based confocal laser endomicroscopy; UC, Ulcerative Colitis; IBD, inflammatory bowel disease; CD, Crohn's disease; NBI, narrow binding imaging; GVHD, Graft versus Host Disease; PPV, positive predictive value; NPV, negative predictive value; and BE, Barrett's esophagus.