Review Article

Confocal Laser Endomicroscopy in Gastrointestinal and Pancreatobiliary Diseases: A Systematic Review and Meta-Analysis

Table 3

Summary of the studies evaluating CLE in lower gastrointestinal disease screening and diagnosis (“per patient” and “per lesion” analysis).

Author and yearCountryMean age or range Sensitivity (%)Specificity (%)PPV (%)NPV (%)Accuracy (%)Main findings

Inflammatory bowel disease
Watanabe et al. 2008 [63]Japan31 patientsn/an/an/an/an/an/aImages obtained with CLE provide equivalent information to conventional histology.
Trovato et al. 2009 [64]Italy18 patients
253 lesions
70n/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]China73 patients50.4n/an/an/an/an/aCLE 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 patients46.6n/an/an/an/an/aEpithelial gap density visualized by CLE is significantly increased in patients with IBD compared with controls.
Moussata et al. 2011 [67]France, Germany, and UK21 patients
26 lesions
n/an/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 China58 patientsn/a62.591.2n/an/a79 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]Germany146 patients34.9n/an/an/an/an/aCLE 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]Germany72 patients39n/an/an/an/an/aCLE has the potential to significantly improve diagnosis of CD compared with standard endoscopy.
Turcotte et al. 2012 [71]Canada, USA41 patients41.1n/an/an/an/an/aIncreased 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, USA16 patients35.5n/an/an/an/an/aCLE allows quantitative analysis of colonic pit structure in healthy and CD patients.
Atreya et al. 2014 [73]Germany25 patients41.6n/an/an/an/an/aMolecular 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 UK38 patients52n/an/an/an/an/aIn vivo intramucosal changes detected by CLE in UC remittent patients can predict disease relapse.
Li et al. 2014 [75]China43 patients4495.785n/an/a90.7CLE is comparable to conventional histology in predicting relapse in patients with UC.

Dysplasia/neoplasia in inflammatory bowel disease
Hurlstone et al. 2007 [76]UK36 patients56n/an/an/an/a97Adenoma 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]Germany153 patients
134 lesions
44n/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]Germany150 patients48.3n/an/an/an/an/aCLE targeted biopsies led to higher detection rates of intraepithelial neoplasia in patients with long-standing UC.
Hlavaty et al. 2011 [79]Slovakia30 patients
68 lesions
n/an/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]Netherlands22 patients
87 lesions
54n/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] Italy51 patients
14 biopsies
52n/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]Germany42 patients
390 lesions
64.2n/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]Japan45 patients63n/an/an/an/an/aCEM 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]USA54 patientsn/a9187n/an/a89CLE provides in vivo real time pathological interpretation of tissue.
Buchner et al. 2010 [85]USA75 patients
119 lesions
73n/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]Italy20 patients
32 lesions
62.5n/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 Germany53 patients
75 lesions
n/an/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]Netherlands72 patients
116 lesions
72n/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]China115 patients
115 lesions
51.6n/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, France71 patients
135 lesions
75n/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]Romania4 patientsn/an/an/an/an/an/aImaging 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
62n/an/an/an/an/aStandard 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]Netherlands64 patients
154 lesions
59n/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]Italy22 patients61.6n/an/an/an/an/aBy 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]USA74 patients
154 lesions
69n/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]USA65 patients
130 lesions
69n/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, Netherlands92 patients
129 lesions
70n/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]USA85 patients
127 lesions
72n/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]China71 patients
166 lesions
57.6n/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]China37 patients
37 lesions
70n/an/an/an/an/aCLE could be used in molecular imaging with specific targeting of EGFR in colorectal neoplasia.
Ciocâlteu et al. 2014 [101] Romania5 patientsn/an/an/an/an/an/aDifferences in vessels morphology with CLE are useful for identifying patients who might benefit from neoadjuvant angiogenetic therapy.
Yuan et al. 2014 [102]China39 patients
50 lesions
52n/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]Germany35 patientsn/a74100n/an/an/aCLE provides rapid diagnosis of acute intestinal GVHD with high accuracy while performing endoscopy.

Infectious colitis
Neumann et al. 2013 [104]Germany10 patients72.588.997.28098.696.25CLE 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]Canada34 patients45.162898373n/aAs 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 patients44.6n/an/an/an/an/aBased 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.