# Confocal Laser Endomicroscopy for Bladder Cancer Detection: Where Do We Stand?
## 4 Discussion
### CLE Feasibility  
The first reported studies investigated the safety and technical feasibility of CLE for BCa detection. The technique appeared completely safe, without any reported adverse events among all studies.  
Since the first report by [PERSON] et al. [15], CLE showed a definite image reporting of normal and neoplastic tissue, with macroscopic distinction between low-grade and high-grade cellular differentiation. In this study, the authors compared the results obtained by intravenous fluorescein administration and bladder instillation, showing the potential advantages of fluorescein instillation as being capable to detect bladder tissue and vascularization similar to the intravenous technique but with longer duration and with the possibility to modulate contrast intensity with the control of bladder irrigation. The subsequent five prospective studies reported a substantial similar percentage of inter-observer agreement for CLE image interpretation, which becomes more similar between experienced readers. [PERSON] et al. [16] performed an inter-observer comparison study between experienced CLErologists, non-experienced CLE urologists, a pathologist, and researchers. After two hours of computer-based training, in which participants were instructed to identify microarchitectural (flat vs. papillary, and tissue organization and vascularity) and cellular features (morphology, cohesiveness, and cellular borders) of benign and pathologic urothel, they had to classify a series of 31 CLE video sequences consisting of 12 benign, 9 LG, and 10 HG images. The percentage of agreement was 81.6% for both microarchitectural and cellular features, showing that non-experienced readers were also able to interpretate CLE images with proper teaching. The diagnostic accuracy and agreement improved with experience (i.e., 75% sensitivity and 64% specificity for experienced readers versus 46% sensitivity and 74% specificity for non-experienced ones). [PERSON] et al. [20] then validated and improved the imaging interpretation criteria in 2018, giving as the main differential features for the definition of lesions and tumor grade the organization of cells, cellular morphology, and definition of cell borders. [PERSON] et al. [17] demonstrated the elevated accuracy of computer-based classification of CLE images, with an accuracy of 79% in discriminating benign from malignant lesions and 82% for low-grade versus high-grade tumors. [PERSON] et al. [20] reported optimistic results regarding the association of WLC + CLE, with a high level of sensitivity and specificity for low-grade UC (79% vs. 78%) and similar for HG ones with a slightly higher specificity (67% vs. 79%). From the experience of previous works, the authors outlined the predominant CLE feature to discriminate between LG and HG lesions, namely papillary configuration, organization of cells, cellular morphology, and definition of cell borders. Those characteristics appear easily identifiable and assure a moderate to substantial interobserver agreement, which is mandatory for large-scale CLE application. However, the reported concordance of CLE evaluation by three observers and histopathology was only 63.6%.