In this prospective cohort study to evaluate the effectiveness of ALA-PDD for UT-UC diagnosis using the VISERA ELITE® video system, the sensitivity and specificity were 62.5% and 67.3%, respectively. Of the 38 specimens that were randomly biopsied without any abnormality under examination by both white light and ALA-PDD, 11 specimens (28.9%) from 5 patients were diagnosed with high grade UC. On the other hand, four biopsy specimens that had abnormal findings with ALA-PDD but not with normal white light observation were diagnosed with CIS.
ALA-PDD was approved only for bladder cancer by Japanese national health insurance in 2017. This approach is expected to have value not only for bladder cancer diagnosis but also for treatment, namely complete resection at TURBT [1, 13–16]. On the other hand, studies describing photodynamic treatment using ALA (ALA-PDT)  and some pilot studies [18, 19] involving ALA-PDD for UT-UC reported that ALA-PDT and ALA-PDD could be effective and useful even for UT-UC (Table 3). Among studies concerning ALA-PDT and -PDD conducted since 2012, most used ureteroscopes with a video system produced by Karl Storz SE & Co. KG (Tuttlingen, Germany) to diagnose ALA-PDD and this technique was shown to have higher accuracy for UT-UC diagnosis than methods involving white light [10, 20–22] and CT urography . Thus, before carrying out the present study, we confirmed that PpIX fluorescence could be observed using a ureteroscope with the VISERA ELITE® video system . Our present study revealed that sensitivity and specificity values for ALA-PDD for UT-UC were lower than other studies for UT-UC and slightly lower than those for bladder cancer. These outcomes could be due to differences in: i) cystoscopes and ureteroscopes; ii) image quality; and iii) video system quality. First, images obtained using ureteroscopy are dark and small because ureteroscopes are longer and thinner than cystoscopes. Second, image processing software that optimizes gradations of collected images has not been available yet. Third, neither the VISERA ELITE® nor camera head are designated for ALA-PDD, and thus surgeons must insert a special filter between the camera head and the endoscope. Use of the newest video system such as the VISERA ELITE II® could produce a higher sensitivity and specificity since we did perform additional ex vivo experiments to evaluate which video system was better for ALA-PDD using ureteroscopy, and found that images produced by the VISERA ELITE II® were superior to those obtained using VISERA ELITE® (Fig. 1).
Interestingly, 11 of the 38 (28.9%) specimens that exhibited no abnormalities in either white light or ALA-PDD examinations were pathologically diagnosed with high grade UC. The reasons for this result are unclear, but some abovementioned factors may have contributed to this outcome. To our knowledge there are no studies that examined random biopsy samples taken from the upper urinary tract, and additional investigations are needed.
According to European guidelines , diagnostic ureteroscopy is strongly recommended to diagnose UT-UC tumor type and tumor grade. Furthermore, endoscopic management for UT-UC is the primary treatment option as a kidney-sparing surgery for patients with low-risk tumors (unifocal tumor; tumor size < 2 cm; low-grade cytology; low-grade URS biopsy; no invasive aspect on CT urography). Although in our study 2 specimens from one patient with low grade UC were ALA-PDD negative, low grade UC can be positive even in normal white light observation. In addition, 4 specimens diagnosed with CIS were negative in normal observation but positive in ALA-PDD. Hence, our results indicate that ALA-PDD might be an effective method for detection of CIS in the upper urinary tract.
Adverse events of ALA-PDD have been reported as liver toxicity, allergic episode, cardiovascular complications, photosensitivity, hypotension, nausea and vomiting [9, 25]. In our study, no severe adverse events were observed outside of hypotension in one patient because of some preventative measures such as oral intake before the procedure, shading for 48 hours to avoid photosensitivity, and other factors. However, one patient who had vomited 2 hours after administration of 5-ALA was diagnosed with high grade UC while any abnormality could not be observed under examination by both white light and PDD. The fact suggests the possibility that vomiting had some effect on ALA-PDD.
The present study has several limitations. Although this pilot study was prospective, it was performed at a single center, was non-randomized and included small number of patients (n = 20). Second, there were 2 patients who underwent protocol URS after endoscopic laser ablation and cognitive bias could be associated with the previous procedure. Third, we evaluated the usefulness of ALA-PDD only in the diagnostic process and not the treatment process. Fourth, we did not compare endoscopic devices including semirigid/flexible ureteroscopes, light cables, and video systems, and did not evaluate their compatibility with ALA-PDD. Despite these limitation, the ureteroscopy with ALA-PDD might be more useful for diagnosis in patients with UT-UC, particularly with CIS.