Recurrence and timing of conversion to radical nephroureterectomy after endoscopic laser ablation for upper tract urothelial carcinoma: a multicenter Japanese study

Introduction

Upper urinary tract urothelial carcinoma (UTUC) accounts for approximately 5–10% of all urothelial carcinomas (UCs), and remains a relatively rare and heterogeneous disease (1,2). Due to its low incidence, high-level evidence guiding optimal management is limited. The European Association of Urology (EAU) classifies low- and high-risk categories to assist in selecting candidates for nephron-sparing surgery (NSS) (2); however, radical nephroureterectomy (RNU) with bladder cuff excision remains the standard treatment regardless of risk classification.

RNU is associated with substantial renal function deterioration. Patients with UTUC frequently present with impaired renal function at diagnosis, which is further exacerbated by the removal of the affected renal unit. In a previous large cohort study, we demonstrated a decrease in the proportion of patients with preserved renal function after RNU, highlighting the clinical importance of renal preservation strategies (3).

According to the current EAU guidelines, NSS is strongly recommended for low-risk UTUC and may be considered in selected patients with high-risk disease under specific circumstances. However, its oncological safety in high-risk UTUC remains controversial, as existing evidence is largely derived from retrospective studies with limited sample sizes (4-6). Consequently, the effectiveness and limitations of NSS in high-risk UTUC have not been clarified.

Strict application of the EAU risk criteria often complicates clinical decision-making regarding endoscopic ablation for high-risk UTUC. Given the high incidence of urinary tract (UT) recurrence after ablation, intensive surveillance with repeat ureteroscopy is frequently required. However, detailed clinical courses and oncological outcomes of Japanese patients with high-risk UTUC treated with laser ablation remain poorly characterised. We conducted a multicentre retrospective study to evaluate the clinical course and oncological outcomes of patients with UTUC who underwent endoscopic laser ablation, focusing on high-risk disease. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0082/rc).

Methods

Patient characteristics

We retrospectively analysed 34 patients who underwent endoscopic laser ablation for UTUC between September 2018 and October 2025. Patients were treated at seven Japanese institutions participating in the Thulium Laser Collaborative Group: Jikei University Hospital (n=18), Koga Hospital 21 (n=5), Kawasaki Municipal Tama Hospital (n=4), Japan Community Healthcare Organization (JCHO) Hokkaido Hospital (n=3), Yokohama Minami Kyousai Hospital (n=2), Ama Municipal Hospital (n=1), and Osaka Gyoumeikan Hospital (n=1). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of The Jikei University School of Medicine {No. 35-144 [11772]} and individual consent for this retrospective analysis was waived. All participating hospitals were informed and agreed to the study.

All patients were classified as low- or high-risk UTUC according to the EAU criteria. Low-risk UTUC was defined as unifocal disease, tumour size <2.0 cm, negative high-grade cytology, low-grade histology on ureteroscopic biopsy, and absence of invasive features on computed tomography. Laser ablation indications were determined based on EAU recommendations; in high-risk patients, endoscopic ablation was considered only in those with a solitary kidney or contraindications to or refusal of RNU.

Surgical procedure and follow-up

Retrograde pyelography was performed before laser ablation, and selective urine samples were obtained for cytological evaluation. The ureter was assessed using rigid ureteroscopy, followed by the inspection of the renal pelvis and calyces using flexible ureteroscopy. Tumour biopsies were performed using 3-Fr cup biopsy forceps. Laser ablation of ureteral tumours was performed using a rigid ureteroscope; tumours in the renal pelvis or calyces were treated using a flexible ureteroscope with an access sheath, the diameter of which was selected based on intraoperative findings.

White light and narrowband imaging were used to enhance detection of small or flat lesions. Ablation was performed using a thulium:YAG laser (Cyber TM200W, Quanta System S.p.A, Milan, Italy) with fibre diameters ranging from 200 to 272 µm. Laser settings were applied in pulsed mode (15 ms, 20 Hz), with power adjustments made at the surgeon’s discretion. Afterward, a double-J ureteral stent was placed. There was no standard protocol for adjuvant instillation therapy. Complete ablation was assigned when the basement membrane of all tumours was visibly ablated. Ureteroscopic surveillance and UT urine collection for cytology were performed every 3 months postoperatively for the first 2 years, and then every 6 months until 5 years. After 5 years, annual ureteroscopic surveillance was recommended. To distinguish residual tumors resulting from incomplete ablation from UT recurrence at the first surveillance ureteroscopy, residual tumors were defined as lesions detected at the same sites as the initial ablation in cases where incomplete ablation was suspected by the operating surgeon. Computed tomography with contrast (when renal function allowed) was performed according to the same schedule as ureteroscopic surveillance.

Data collection and outcome measures

Data on patient demographics, clinicopathological characteristics, surgical details, treatment management, and follow-up outcomes were collected retrospectively. UT recurrence-free survival (RFS) was defined as the interval from initial ablation to UT recurrence detection on ureteroscopy surveillance. Distant metastasis-free survival was defined as the interval from initial ablation to detection of lymph node or visceral metastasis. The primary outcomes were UT-RFS after laser ablation stratified by EAU risk, as well as identification of factors associated with UT-RFS and the impact of preoperative variables on UT-RFS. The secondary outcome was the identification of factors associated with advanced pathological findings at RNU after disease recurrence following ablation.

Decisions regarding repeat laser ablation or conversion to RNU at the time of recurrence were made at the discretion of the treating physician. The extent of lymph node dissection (LND) was determined at the surgeon’s discretion, rather than applying an LND template. Pathological evaluation of RNU specimens was performed according to standardised criteria: tumour staging was assigned based on the American Joint Committee on Cancer Tumor-Node-Metastasis (TNM) classification, 8th edition [2017] (7), and tumour grading was determined in accordance with the 2016 World Health Organization and International Society of Urological Pathology consensus classification (8). Papanicolaou classification system was used for cytology assessment (9).

Statistical analysis

Patient demographics were compared using Chi-squared and t-tests. The association between EAU risk with UT-RFS and distant metastasis-free survival rates were estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival outcomes. Univariate and multivariate Cox regression analyses were performed to identify independent factors impacting UT-RFS. All data were analysed using STATA 18 (Stata Corp., College Station, TX, USA), with two-sided P<0.05 considered significant.

Results

Patient characteristics

Baseline clinical and pathological characteristics of the 34 patients with UTUC are summarised in Table 1. The median age was 76 years [interquartile range (IQR), 69–81 years], and 25 patients (73.5%) were male. Overall, 23 (67.6%) patients had a history of UC. According to the EAU risk stratification, 25 patients (73.5%) were classified as having high-risk UTUC, whereas 9 (26.5%) were classified as having low-risk disease. The most common high‑risk factor was the presence of multiple tumors (n=10), followed by high-grade histology (n=8) and tumor size >20 mm (n=5).

Twelve high-risk patients (48.0%) had a solitary kidney, compared with two low-risk patients (22.2%). Tumours were more frequently located in the renal pelvis or calyces in the high-risk group (60.0%, 15/25), whereas ureteral tumours were more common in the low-risk group (22.2%, 2/9). The median tumour size in the entire cohort was 10 mm (IQR, 7.0–19.8 mm). Positive urinary cytology (≥ class 4) was observed in 20.0% of the high-risk group, and high-grade disease was identified in 36.0% of cases based on ureteroscopic biopsy findings.

Oncological outcomes after laser ablation

The oncological outcomes are summarised in Table 2. Incomplete ablation after initial laser ablation was observed in 10/34 patients (29.4%). The rate of incomplete ablation tended to be higher in high-risk patients than low-risk patients (36.0% vs. 11.1%, respectively); however, this difference was not statistically significant (P=0.16). Larger tumor (n=6) or multiple tumors (n=3) were the most common reasons for incomplete ablation. Re-ablation was subsequently performed in four of the 9 high-risk patients (44.5%); no patients in the low-risk group required repeat ablation. UT recurrence was significantly higher in high-risk patients than in low-risk patients (77.3% vs. 11.1%, P<0.01) (Table 2). Laser ablation for recurrent tumours was performed in 15/18 patients (83.3%).

Kaplan-Meier curves for UT-RFS in the entire cohort and stratified by EAU risk classification are shown in Figure 1A,1B, respectively. UT-RFS was significantly worse in high-risk patients than in low-risk patients (P<0.01; Figure 1B). Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors associated with UT-RFS (Table 3). In the univariate analysis, tumour location in the renal pelvis or calyces (reference: ureter) and EAU high-risk classification were significantly associated with UT-RFS; EAU high-risk classification remained an independent predictor in multivariate analysis (hazard ratio: 9.02; 95% confidence interval: 1.18–68.8; P=0.03). During follow-up, distant metastasis developed in four of the 34 patients. The lungs (75%) were the most frequent metastatic sites, followed by the liver (50%) and lymph nodes (25%). All patients received at least one regimen of platinum-based chemotherapy or enfortumab vedotin plus pembrolizumab. One patient died owing to cancer progression. Kaplan-Meier curves for distant metastasis-free survival in the overall cohort and according to EAU risk classification are presented in Figure S1A,S1B, respectively.

Figure 1 Kaplan-Meier curves for upper tract recurrence-free survival in all cases (A) and according to EAU risk classification (B). EAU, European Association of Urology.

Evaluation of patients who underwent RNU

During the follow-up period, 13/34 patients with UTUC (38.2%) underwent RNU. Among patients with high-risk UTUC, 12/25 (48.0%) progressed to RNU; of these, 6 (50.0%) had advanced pathological features at RNU [defined as pathological stage ≥ pT3 and/or lymph node metastasis (pN1)] (Table 4).

Detailed clinicopathological characteristics of patients who underwent laser ablation followed by RNU are summarised in Table S1. Baseline characteristics were compared between patients with advanced and non-advanced pathologies at RNU, excluding three patients who underwent immediate RNU due to incomplete initial laser ablation (patients #1, #7 and #13 in Table S1) and three patients who underwent RNU without LND (patients #4, #9 and #11 in Table S1), leaving a total of seven patients for analysis. Patients with ureteral tumours exhibited a higher rate of advanced pathology at RNU than those with tumours located in the renal pelvis or calyces. Additionally, the median interval from the initial recurrence to RNU tended to be longer in patients with advanced pathology at RNU (17.5 months) than in those with non-advanced pathology (9 months) (Table 5), suggesting that delayed conversion to RNU after recurrence may be associated with pathological upstaging.

Discussion

In this multicentre retrospective study, we evaluated the association between EAU risk classification and oncological outcomes in Japanese patients with non-metastatic UTUC treated with endoscopic laser ablation. Consistent with previous reports (4,10), the EAU high-risk classification was significantly associated with worse UT-RFS and was an independent predictor of UT-RFS. Nearly half of high-risk patients ultimately required RNU, with advanced pathological features (≥ pT3 and/or pN1) identified in 50% of this group. These findings highlight the limited oncological durability of laser ablation in high-risk UTUC and underscore the importance of close surveillance and timely consideration of definitive surgery when recurrence occurs.

The oncological role of NSS in UTUC has been extensively debated, largely owing to the heterogeneity of disease biology and the lack of high-quality comparative data. In 2016, the EAU guidelines panel on non-muscle-invasive bladder cancer conducted a meta-analysis of 22 non-randomised retrospective studies, reporting that the cancer-specific survival (CSS) and overall survival (OS) outcomes in patients with low-risk UTUC treated with nephron-sparing approaches were comparable to those in patients treated with RNU (4). However, only two of these studies included patients with high-grade UTUC undergoing ureteroscopic laser ablation, collectively comprising a limited sample size of 35 patients, and both demonstrated inferior OS and CSS compared to RNU-treated cohorts (4). Based on this, current EAU guidelines strongly recommend NSS as an alternative to RNU for low-risk UTUC; the use of laser ablation in high-risk disease is restricted to highly selected circumstances, such as a solitary kidney or RNU contraindications (4).

More recently, a larger systematic review of 32 studies reported no significant difference in 5-year OS or CSS between kidney-sparing surgery and RNU (5). Nevertheless, multivariate subgroup analyses revealed that endoscopic surgery was independently associated with worse OS than RNU, despite a higher prevalence of low-grade tumours in the endoscopic cohort (5). Additional systematic reviews focusing specifically on endoscopic management of high-grade UTUC have similarly reported inferior survival outcomes compared with RNU (10). Although some Japanese retrospective cohort studies have suggested comparable survival rates between ureteroscopic management and RNU (6,11), these findings should be interpreted cautiously given the limited sample sizes and inherent selection bias. In line with these prior observations, low-risk patients with UTUC in our cohort experienced low rates of UT recurrence and disease progression following laser ablation, supporting its role as a safe and effective alternative to RNU in this population. In contrast, the high incidence of UT recurrence and pathological upstaging observed among high-risk patients highlights the need for thorough shared decision-making and careful patient selection when considering laser ablation in this setting.

Current EAU guidelines define appropriate candidates for laser ablation and recommend strict ureteroscopic surveillance (4); however, no consensus exists regarding the optimal timing or indications for conversion to RNU. In this multicentre cohort, 77.3% of high-risk patients with UTUC treated with laser ablation developed UT recurrence, and 48.0% ultimately required RNU. An important observation in the present study is the potential association between the timing of conversion to RNU and pathological upstaging. Among patients who ultimately underwent RNU after recurrence, those with advanced pathological findings tended to have a longer interval between recurrence and definitive surgery. Although the sample size is limited, this pattern suggests that prolonged endoscopic management after recurrence may allow disease progression before radical surgery is performed. Therefore, particularly in high-risk UTUC patients, early consideration of conversion to RNU after recurrence may be important to avoid pathological upstaging and maintain oncological control. In addition, the development of preoperative prognostic biomarkers, such as the modified Glasgow Prognostic Score (12), neutrophil-to-lymphocyte ratio (13), and albumin-to-globulin ratio (14), as well as emerging liquid biopsy approaches including circulating and urinary tumour deoxyribonucleic acid (DNA) (15), may help identify patients at high risk of disease progression. However, large-scale, multi-institutional studies are required to validate their clinical utility in this setting.

Ureteral tumour location tended to be more common among patients with advanced pathology at RNU, despite showing a trend toward a lower risk of UT-RFS in Cox regression analyses. This apparent discrepancy may reflect anatomical differences between the renal pelvis and ureter that influence endoscopic assessment and pathological staging differences (16,17). Since laser ablation in ureteral lesions is technically more challenging than in renal pelvic lesions—due to the narrower lumen, limited manoeuvrability, and higher risk of thermal injury—this technical difficulty may have influenced oncological outcomes. Indeed, the laser fiber can be introduced from the top of the rigid ureteroscope, which may be one of the reasons for the technical difficulty in ablating ureteral tumors. In contrast, for renal pelvic tumors, a flexible ureteroscope allows adjustment of the laser fiber’s direction. Complex pelvic anatomy may predispose patients to residual disease, whereas the tubular ureter allows more complete visualisation but may conceal deeper invasive components. These findings suggest that anatomical tumour location should be carefully considered when managing UTUC using nephron-sparing strategies.

This study had several limitations. First, its multicentre retrospective design and relatively small sample size may have introduced selection bias and affected the statistical analyses. Endoscopic laser ablation therapy was offered only to high-risk patients with a solitary kidney, contraindications to RNU, or refusal of RNU. This selective use introduces a potential selection bias, and the findings of this study may not be generalizable to all patients with high-risk UTUC. Additionally, the limited follow-up duration may have affected the robustness of long-term survival analyses. Ambiguous histological grading resulting from insufficient tissue obtained by cold biopsy influenced the EAU risk classification. Pathological assessments were also performed at individual institutions without a centralised genitourinary pathology review, which may have resulted in interobserver variability. Additionally, ureteroscopic and laser ablation techniques, as well as RNU with LND were not fully standardised across the participating centres, potentially influencing oncological outcomes. Finally, this cohort included patients with distal ureteral (U3) tumours for whom segmental ureterectomy may have been an alternative treatment option. Despite these limitations, this study provides clinically relevant insights into the real-world outcomes of laser ablation for UTUC, particularly by detailing the disease course in high-risk patients. These findings may help inform clinical decision-making in the management of non-metastatic UTUC in routine practice.

Conclusions

This multicentre study comprising a relatively large cohort of reports on NSS for UTUC demonstrated that patients with high-risk UTUC treated with laser ablation experience a substantially higher risk of UT-RFS. Approximately half of high-risk patients ultimately required conversion to RNU; among these, advanced pathological features were identified in a considerable proportion, often after a prolonged interval following recurrence. These findings suggest that when NSS is considered for high-risk UTUC, careful patient selection and timely conversion to RNU after recurrence may be essential to optimize oncological outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0082/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0082/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0082/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0082/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of The Jikei University School of Medicine {No. 35-144 [11772]} and individual consent for this retrospective analysis was waived. All participating hospitals were informed and agreed to the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin 2025;75:10-45. [Crossref] [PubMed]
2. Masson-Lecomte A, Birtle A, Pradere B, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: Summary of the 2025 Update. Eur Urol 2025;87:697-716. [Crossref] [PubMed]
3. Muramoto K, Urabe F, Koike Y, et al. Perioperative renal function change and oncological outcomes of radical nephroureterectomy in patients with upper tract urothelial carcinoma: A multicenter retrospective study. Urol Oncol 2024;42:332.e21-32.
4. Seisen T, Peyronnet B, Dominguez-Escrig JL, et al. Oncologic Outcomes of Kidney-sparing Surgery Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the EAU Non-muscle Invasive Bladder Cancer Guidelines Panel. Eur Urol 2016;70:1052-68. [Crossref] [PubMed]
5. Zhou L, Huang C, Sun S, et al. Kidney sparing surgery versus radical nephroureterectomy in upper tract urothelial carcinoma: a meta-analysis and systematic review. Front Oncol 2025;15:1448079. [Crossref] [PubMed]
6. Tsujino T, Komura K, Inamoto T, et al. Nephron-sparing ureteroscopic surgery vs. radical nephroureterectomy: comparable survival-outcomes in upper tract urothelial carcinoma. World J Urol 2023;41:3585-91.
7. Paner GP, Stadler WM, Hansel DE, et al. Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers. Eur Urol 2018;73:560-9.
8. Humphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol 2016;70:106-19. [Crossref] [PubMed]
9. Owens CL, Vandenbussche CJ, Burroughs FH, et al. A review of reporting systems and terminology for urine cytology. Cancer Cytopathol 2013;121:9-14. [Crossref] [PubMed]
10. Giulioni C, Brocca C, Tramanzoli P, et al. Endoscopic intervention versus radical nephroureterectomy for the management of localized upper urinary tract urothelial carcinoma: a systematic review and meta-analysis of comparative studies. World J Urol 2024;42:318. [Crossref] [PubMed]
11. Yoshida T, Murota T, Matsuzaki T, et al. Photodynamic Diagnosis-guided Dual Laser Ablation for Upper Urinary Tract Carcinoma: Preoperative Preparation, Surgical Technique, and Clinical Outcomes. Eur Urol Open Sci 2021;28:17-25. [Crossref] [PubMed]
12. Tsuzuki S, Kimura S, Fukuokaya W, et al. Modified Glasgow prognostic score is a pre-surgical prognostic marker of disease mortality in upper urinary tract urothelial carcinoma. Jpn J Clin Oncol 2021;51:138-44. [Crossref] [PubMed]
13. Tanaka N, Kikuchi E, Kanao K, et al. A multi-institutional validation of the prognostic value of the neutrophil-to-lymphocyte ratio for upper tract urothelial carcinoma treated with radical nephroureterectomy. Ann Surg Oncol 2014;21:4041-8. [Crossref] [PubMed]
14. Fukushima H, Kobayashi M, Kawano K, et al. Prognostic Value of Albumin/Globulin Ratio in Patients with Upper Tract Urothelial Carcinoma Patients Treated with Radical Nephroureterectomy. Anticancer Res 2018;38:2329-34. [Crossref] [PubMed]
15. Huelster HL, Gould B, Schiftan EA, et al. Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non-organ-confined Upper Tract Urothelial Carcinoma. Eur Urol 2024;85:283-92. [Crossref] [PubMed]
16. Nakano J, Urabe F, Kiuchi Y, et al. The clinical impact of ureteroscopy for upper tract urothelial carcinoma: A multicenter study. Int J Urol 2024;31:394-401. [Crossref] [PubMed]
17. Suhara Y, Urabe F, Yoshihara K, et al. Prognostic significance of subclassifying pathological T3 upper tract urothelial carcinoma: Results from a multicenter cohort study. Int J Urol 2024;31:125-32. [Crossref] [PubMed]