Upper tract urothelial cancer (UTUC) is a rare disease whose standard treatment has traditionally been represented by radical nephroureterectomy (RNU). In recent years, advances in the endourological technology armamentarium have led to the selection of some patients with low-risk disease, namely low-grade single tumor <2 cm, who may benefit from ablative ureteroscopy (URS).¹ On the other hand, ureterectomy has been proven to be a feasible and safe treatment in patients with high-risk disease of the distal ureter.² Moreover, patients with high-risk UTUC might be directed to endoscopic treatment due to imperative indications (ie, solitary kidney, chronic kidney disease, panurothelial tumors).

Regardless, the correct risk stratification of UTUC remains a challenge. Computed tomography has shown a high accuracy to detect UTUC but a low performance in UTUC risk stratification.³ Urinary cytology has limited sensitivity (64%) for UTUC. URS has been proven to be the best technique to diagnose UTUC, providing important information on tumor characteristics such as tumor grading and in situ cytology, and potentially ablating the lesion in a single session. However, it is not considered a key step in the diagnostic workflow of UTUC due to the relatively high percentage of nondiagnostic biopsies and the risk of bladder recurrence after endoscopic tumor manipulation.⁴

In this regard, the application of ureteral systematic biopsies (USBs) has never been considered. We postulated that, similarly to bladder cancer, USB might be useful in specific populations of patients affected by UTUC and candidates for kidney-sparing treatment (KSS). Thus, this technique has been implemented in our institutional protocol.

USB was performed via a semirigid URS and consisted of at least two 3F biopsies in each of the upper tract portions: pelvis, proximal, mid, and distal ureter.

The indications were as follows: (1) suspicion of upper tract carcinoma in situ, (2) follow-up after upper tract bacillus Calmette-Guérin instillations for high-risk disease, (3) high-risk tumors, candidate for KSS, (4) recurrent low-risk UTUCs.

A total of 300 USBs was performed in 91 patients. This technique proved to be safe, since postoperative complications and readmissions were comparable to those of patients who were not submitted to USB. Notably, bladder recurrence-free survival was similar between those submitted to URS for UTUC suspicion with or without USB (77% vs 73%).

A significant number of USBs were positive (47%), while 19% were nondiagnostic. Furthermore, in 31% of negative/nondiagnostic URS, USB was positive. Therefore, USB provided a significantly higher number of tumor diagnoses in the setting of negative or nondiagnostic URS.

A biopsy of a target lesion was performed in 40% of cases. In 19% of these cases, USB outperformed the biopsy of the lesion in detecting UTUC. Conversely, 73% of patients with positive target biopsies had positive USB. This underlines that a nonnegligible portion of patients with a lesion detected during the URS might harbor disease in other portions of the upper urinary tract.

In 45% (5/11) of patients diagnosed with a distal ureteral tumor, USB detected UTUC in other upper tract portions. Thus, notably almost half of patients who were candidates for KSS, either endoscopic management or distal ureterectomy, had UTUCs in other portions of the upper urinary. This could lead to a change in treatment algorithm, from KSS to RNU.

The higher number of tumor diagnoses and multifocal tumor detection has a clinical impact that is demonstrated by the 2-year RNU-free survival rates, which were 87% (95CI%: 78.1-98.5) vs 53% (95% CI: 39.4-71.2; P = .001) for negative vs positive USB patients. At Cox regression model accounting for predefined variables, patients with positive USB had a higher risk of being treated with RNU (HR: 3.38, 95% CI: 1.46-7.80; P = .004).

In view of this, we concluded that USBs for UTUC were safe and could provide significant improvements in the selection of patients who may benefit from a KSS. A refined risk stratification of UTUC could also facilitate the expansion of the criteria for endoscopic treatment, which are actually reserved to a small percentage of patients affected by the disease. In the pursuit of shedding light on this rare disease, we believe that the implementation of USBs could represent a small but significant step toward the optimization of the diagnostic pathway, and thus treatment indication, of UTUC.