In this mini-review, Audenet et al.  describe the potential application of photodynamic diagnosis, narrow-band imaging and molecular markers to clinical practice for patients with upper urinary tract urothelial carcinoma (UUT-UCC). Many of these techniques have been developed, preliminarily validated, and even brought into clinical practice for other disease processes, including urothelial carcinoma of the bladder (UCB). Although technological advances, such as improvements in rigid and flexible ureteroscopes, have facilitated access to the upper urinary tract with improved visualization and the ability to biopsy or ablate tissue, the current armamentarium for the diagnosis and treatment of patients with UUT-UCC remains limited in comparison to that for UCB. Nevertheless, technologies developed and tested for UCB have the potential to improve urologists' abilities to endoscopically diagnose and stage UUT-UCC, as well as manage low-grade and low-stage UUT-UCC.
The utility of photodynamic diagnosis for enhancing visualization, and thereby the completeness of resection, of non-muscle invasive UCB has been reported in multiple studies . Unfortunately, similar to intravesical therapies such as BCG, existing protocols for intravesical administration of 5-aminolevulinic acid and hexaminolevulinate are not immediately translatable for use in the upper urinary tract. Consequently, oral administration of 5-aminolevulinic acid for photodynamic diagnosis and therapy of UUT-UCC has been described in pilot case series [3,4]. Additional studies and novel strategies for the application of photodynamic diagnosis in UUT-UCC are needed.
One such alternative strategy for photodynamic diagnosis is harnessing the potential of target tissues for autofluorescence. Currently at our centre, we are exploring applications of multiphoton microscopy for UCB and prostate cancer [5,6]. Multiphoton microscopy uses two-photon excitation, harnessing tissue autofluorescence and second-harmonic generation. This enables high-resolution, high-contrast imaging of unprocessed and unstained fresh tissue. Efforts are focused on miniaturization of the components for potential use during laparoscopic/robotic surgery and endoscopic procedures. Obviously, further studies on the safety and efficacy of miniaturized multiphoton microscopy will be needed before its widespread clinical application.
Narrow-band imaging is another option for improving the visualization and detection of UUT-UCC. The potential of this technology, which uses optical interference filters during endoscopy, has been shown in several studies of non-muscle-invasive UCB . Preliminary studies evaluating the use of narrow-band imaging during ureteroscopy have been reported . Although these imaging techniques may improve the visualization of UUT-UCC, technological advances to improve our abilities to fully resect and ablate tumours through the small working channels of ureteroscopes are also necessary to make significant strides in the endoscopic management of this potentially lethal disease.
UUT-UCC is an especially complex and heterogeneous disease with a broad spectrum of biological and clinical behaviours [9,10]. Molecular medicine, including imaging and biomarkers, holds the promise that clinical outcomes will be improved by accurate diagnosis, staging, prognosis and prediction of response to standard and targeted therapies. The advent of sophisticated technologies enables comprehensive identification of molecular targets and markers specific for UUT-UCC. Molecular profiling may provide a better understanding of the biology associated with tumorigenesis and tumour progression. Indeed, the emergence of new therapeutic approaches for UUT-UCC cannot flourish without a set of imaging tools and biomarkers to serve as prognosticators, therapeutic targets, and surrogate endpoints . However, further research is warranted and the challenge remains to optimize research strategies and collaborations, evaluate novel targets for therapeutic drug development, and translate imaging tools and molecular markers into improved clinical management of UUT-UCC patients.