# Confocal Laser Endomicroscopy for Bladder Cancer Detection: Where Do We Stand?
## 1 Introduction  
With the increasing augmentation of life expectancy and smoking habits, bladder cancer (BCa) represents the fourth most common neoplasm in men [1], occurring in 9 out of 100,000 men and in 2.2 out of as many women worldwide, representing the second most common malignant disease of the urinary system after prostate cancer [2]. As is well known, the first symptom is mostly the presence of gross hematuria, even if sometimes only urinary storage symptoms are present (i.e., pollakiuria) mimicking a urinary tract infection. The macroscopic aspects of the lesions at cystoscopy are variable, from sessile to flat ones, and sometimes BCa can manifest as hyperemic spots on bladder mucosa, mimicking cystitis; therefore, accurate diagnostic imaging is of outmost importance to discriminate the presence of BCa.  
At the first presentation, BCa is non-muscle-invasive in 70% of cases (NMIBC), with possible stages Ta, T1, or carcinoma in situ (CIS), and muscle-invasive in the remaining 30% of cases. The surgical approach consists in transurethral endoscopic resection of thebladder tumor (TURBT) for NMIBC and in radical cystectomy with eventual neoadjuvant chemotherapy for invasive forms [3].  
Thus, improving TURBT quality and completeness is of outmost importance to reduce the risk of disease recurrence and progression as this clinical step is crucial for the histologic determination of cancer lesions and can prevent the risk of disease recurrence or progression. Even with enhanced fiber optics and digital visualization technologies, several reports outline the persistence of remnant neoplastic tissue after TURBT, which arrives in the 33-76% of cases, usually located at the border of the resected tumor or hidden as a flat lesion [4; 5]. For this reason, current guidelines recommend a second procedure (re-TURBT) 4-6 weeks after the primary in cases of macroscopic incomplete cancer removal, pT1 stage or high-grade cancers, or in cases when muscular tissue is not present in the specimen [5].  
To reduce the likelihood of incomplete resection, new diagnostic tools have been purposed and validated, demonstrating a clear benefit in improving the outcome of the first TURBT. Those can be divided into \"macroscopic\" techniques, aiming to enhance the different features of the neoplastic tissue in comparison to the normal one (i.e., increased vascularization or increased cell metabolism), and \"microscopic\" techniques, which directly allow the clinician to evaluate in real time the cellular architecture of the examined area.  
Despite the current use and validation in clinical practice of contrast enhancement techniques like narrow-band imaging (NBI) and photodynamic detection (PDD) of bladder tumors using blue-light cystoscopy, there is still a quote of false-positive imaging related to those techniques, as they do not certainly discriminate between inflammatory and neoplastic \"flat\" areas [6]. To overcome this limit, an in vivo reading of microscopic cell architecture to directly discriminate between normal and neoplastic tissue has been advocated. Among them, confocal laser endomicroscopy (CLE) is the most promising tool that has already shown clinical benefit in clinical practice for gastrointestinal cancer detection (esophageal stomach, and colon cancer), facilitating the discrimination of tissue dysplasia and carcinoma in situ [7; 8]. Using a laser light source and fluorescent contrast dye, CLE has the potential property to allow a detailed and real-time understanding of tissue cell composition, allowing clinicians to postulate between areas with normal tissue and low-grade or high-grade tumors [9].  
Aim of this systematic review (SR) is to focus on the existing literature concerning CLE applications in BCA management, reporting the actual validation studies of this method, its limitations, and future potentials.