Unveiling the challenges of UTUC biopsies and cytology: insights from a global real-world practice study.

PURPOSE: Diagnostic ureteroscopy (dURS) is optional in the assessment of patients with upper tract urothelial carcinoma (UTUC) and provides the possibility of obtaining histology. METHODS: To evaluate endoscopic biopsy techniques and outcomes, we assessed data from patients from the CROES-UTUC registry. The registry includes multicenter prospective collected data on diagnosis and management of patients suspected having UTUC. RESULTS: We assessed 2380 patients from 101 centers. dURS with biopsy was performed in 31.6% of patients. The quality of samples was sufficient for diagnosis in 83.5% of cases. There was no significant association between biopsy techniques and quality (p = 0.458). High-grade biopsy accurately predicted high-grade disease in 95.7% and high-risk stage disease in 86%. In ureteroscopic low-grade tumours, the prediction of subsequent low-grade disease was 66.9% and low-risk stage Ta-disease 35.8%. Ureteroscopic staging correctly predicted non-invasive Ta-disease and ≥ T1 disease in 48.9% and 47.9% of patients, respectively. Cytology outcomes did not provide additional value in predicting tumour grade. CONCLUSION: Biopsy results adequately predict high-grade and high-risk disease, but approximately one-third of patients are under-staged. Two-thirds of patients with low-grade URS-biopsy have high-risk stage disease, highlighting the need for improved diagnostics to better assess patient risk and guide treatment decisions. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (ClinicalTrials.gov NCT02281188; https://clinicaltrials.gov/ct2/show/NCT02281188 ).

Comparison of Oncological Outcomes between Transperitoneal and Retroperitoneal Approaches in Laparoscopic Nephroureterectomies for Upper Tract Urothelial Carcinoma.

Background and Objectives: Our aim was to clarify the oncological outcomes of the two different approaches to laparoscopic nephroureterectomies (LNUs) in Japan, and to examine whether there were any significant differences between the transperitoneal approach and the retroperitoneal approach. Materials and Methods: We retrospectively evaluated patients who underwent an LNU for upper tract urothelial carcinoma (UTUC) from January 2013 to December 2022. We identified 52 patients who underwent a transperitoneal LNU (tLNU) and 93 who underwent a retroperitoneal LNU (rLNU). We adopted age, smoking, and pT-stage matching, and 43 patients were classified in each group. We investigated the time from surgery to recurrence (RFS: recurrence-free survival), the time to death (OS: overall survival), and the time to non-urothelial-tract recurrence-free survival (NUTRFS). A Cox regression analysis was performed to evaluate the risk factors that influenced recurrence. Results: There were no significant differences in the RFS, OS, and NUTRFS between the two matched groups. In the multivariate Cox regression analysis, the pT stage (pT3≥ vs. pT2≤) had an HR = 2.09 and a p = 0.01, and was an independent prognostic risk factor regarding cancer recurrence. Conclusions: There were no significant differences in the oncological outcomes between the tLNU and rLNU groups. It is suggested that the transperitoneal approach should be selected for LNUs.

Regional differences in upper tract urothelial carcinoma patients across the United States.

BACKGROUND: It is unknown whether regional differences in patient, tumor, and treatment characteristics of upper tract urothelial carcinoma (UTUC) patients exist and may potentially result in regional overall mortality (OM) differences. We tested for inter-regional differences, according to Surveillance, Epidemiology, and End Results (SEER) registries. METHODS: Using SEER database 2000 to 2016, patient (age, sex, race/ethnicity), tumor (location, grade) and treatment (nephroureterectomy, systemic therapy [ST]) characteristics of UTUC patients of all-stages were tabulated and graphically depicted in a stage-specific fashion (T1-2N0M0 vs. T3-4N0M0 vs. TanyN1-2M0/TanyNanyM1). Multivariable Cox regression (MCR) models tested for inter-regional differences in OM. RESULTS: Regarding T1-2N0M0 patients, statistically significant differences existed for race/ethnicity (Caucasian 71 vs. 98%), location (renal pelvis: 55 vs. 67%), grade (high 60 vs. 83%) and ST (5.5 vs. 13.9%). In MCR models, registries 3 (Hazard ratio [HR]:1.39; P < 0.001) and 4 (HR:1.31; P = 0.01) independently predicted higher OM and Registry 8 (HR:0.64; P = 0.001) lower OM. Regarding T3-4N0M0 patients, statistically significant differences existed for race/ethnicity (Caucasian 70 vs. 98%), location (renal pelvis: 67 vs. 76%), grade (high 84 vs. 94%) and ST (18.7 vs. 29.5%). In MCR models, registries 3 (HR:1.42; P < 0.001) and 4 (HR:1.31; P = 0.009) independently predicted higher OM. Regarding TanyN1-2M0/TanyNanyM1 patients, statistically significant differences existed for location (renal pelvis: 63 vs. 82%), grade (high 92 vs. 98%) and ST (53.4 vs. 58.8%). In MCR models, Registry 3 (HR:1.37; P = 0.004) independently predicted higher OM and Registry 2, (HR:0.78; P = 0.02) lower OM. CONCLUSIONS: Inter-regional differences were recorded in patients, tumor, and treatment characteristics. Even after adjustment for these characteristics, OM differences persisted which may be indicative of regional differences in quality of care or expertise in UTUC management.

The impact of squamous cell transformation on the prognosis of patients treated with radical nephroureterectomy.

BACKGROUND: Limited information is available for guiding the management of upper urinary tract (UUT) urothelial carcinoma with squamous differentiation (UC-SqD). We did not even know about the difference between pure urothelial carcinoma (UC) and UC-SqD in the UUT regardless of treatment policy and prognosis. Instead of direct comparisons against each other, we included the third UUT malignancy, squamous cell carcinoma (SCC). This three-way-race model allows us to more clearly demonstrate the impact of squamous cell transformation on patient outcomes in UUT malignancy. METHODS: We retrospectively analysed 327 patients with UC, UC-SqD, or SCC who underwent radical nephroureterectomy with bladder cuff excision (RNU) at Taichung Veterans General Hospital, Taichung, Taiwan, between January 2006 and December 2013. A Kaplan-Meier survival analysis was used to evaluate the relationship between patient outcomes and histology. Multivariate Cox proportional hazards modelling was also used to predict patient prognoses. RESULTS: The five-year postoperative cancer-specific survival (CSS) rates were 83.6% (UC), 74.4% (UC-SqD), and 55.6% (SCC), and the 5-year recurrence-free survival (RFS) rates were 87.7% (UC), 61.5% (UC-SqD), and 51.9% (SCC). UC patients had significantly better 5-year RFS than UC-SqD and SCC patients (P = 0.001 and P < 0.0001, respectively). Patients with pure UC had significantly better 5-year CSS than SCC patients (P = 0.0045). SCC or UC-SqD did not independently predict disease-specific mortality (HR 0.999, p = 0.999; HR 0.775, p = 0.632, respectively) or disease recurrence compared to pure UC (HR 2.934, p = 0.239; HR 1.422, p = 0.525, respectively). Age, lymphovascular invasion (LVI), and lymph node (LN) status independently predicted CSS, while pathological tumour stage, LN status, and LVI predicted RFS. CONCLUSIONS: SCC and UC-SqD are not independent predictors of survival outcomes in patients with UUT tumours. However, they are associated with other worse prognostic factors. Hence, different treatments are needed for these two conditions, especially for SCC.

Association of Androgen Receptor and PD-L1 Expression in Upper Urinary Tract Urothelial Carcinoma.

BACKGROUND/AIM: The response to immune checkpoint inhibitors (ICIs) or enfortumab vedotin is limited in patients with upper urinary tract urothelial carcinoma (UTUC), and the development of new targeted therapy for UTUC is eagerly needed. Several biomarkers, including programmed cell death-ligand 1 (PD-L1), have already been reported as predictors of response to ICIs therapy for UTUC. Recently, several studies have shown that steroid hormone receptors, including the androgen receptor (AR), are associated with progression of urothelial carcinoma. MATERIALS AND METHODS: We prepared tissue microarrays (TMA) from paraffin blocks of UTUC specimens in 99 non-metastatic UTUC patients who underwent radical nephroureterectomy. With these TMA sections, we performed immunohistochemical staining for PD-L1 and AR and examined PD-L1 and AR expression levels in tumor cells. In addition, we analyzed the correlation between these markers and clinical prognosis in UTUC cases. RESULTS: PD-L1 was positive in 24 (24%) of the 99 samples, whereas AR was positive in 20 (20%) patients. AR-negative samples had significantly higher PD-L1 expression level than that the AR-positive samples (mean value 4.70% versus 2.55%, p=0.0324). Among AR-positive cases, patients with absence of PD-L1 expression had significantly lower cancer-specific survival (CSS) than that in PD-L1 expression-positive cases (p=0.049), although PD-L1 expression had no significant impact on CSS in AR-negative cases (p=0.920). CONCLUSION: Our findings suggest that AR is the promising target for UTUC treatment, especially in PD-L1-negative cases.

Variant histology is associated with more non-urothelial tract recurrence but less intravesical recurrence for upper tract urothelial carcinoma after radical nephroureterectomy.

PURPOSE: To investigate the prognostic impact of variant histology (VH) on oncological outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) who had undergone radical nephroureterectomy (RNU). PATIENTS AND METHODS: A total of 1239 patients with clinically localized UTUC who underwent RNU at a single institution between January 2005 and June 2020 were included. The VH was reviewed by a uro-pathologist at our institution. The Cox regression model was used to perform multivariate analysis, including VH and other established prognostic factors for post-RNU oncological outcomes (intravesical recurrence [IVR], non-urothelial recurrence, and cancer-specific death). RESULTS: Of the 1239 patients with UTUC, 384 patients (31%) were found to have VH. Advanced tumor stage, lymph node metastasis, high tumor grade, lymphovascular invasion, open surgery, and renal pelvis had a significantly larger proportion of UTUC with VH compared to pure UTUC (all p < 0.05). VH was an independent prognostic factor associated with less IVR identified by multivariate analysis, more non-urothelial recurrence, and more cancer-specific mortality. CONCLUSION: Patients with VH account for 31% with UTUC treated with RNU in this cohort. VH was an independent prognostic factor associated with more non-urothelial recurrence and cancer-specific mortality but less IVR.

Multiple Fluorescences in Situ Hybridization Status in Excreted Urine Improve Diagnostic Efficacy for Upper Urinary Tract Urothelial Carcinomas.

PURPOSE: To evaluate the diagnostic accuracy of single and multiple fluorescence in situ hybridization (FISH) tests for upper urinary tract cancer (UTUC), we analyzed the diagnostic efficacy of FISH in patients with UTUC and the difference between it and the Tumor Node Metastasis (TNM) stage and grade of the tumor. MATERIALS AND METHODS: Patients treated for UTUC at our institution between 2011 and 2021 who had not been previously diagnosed with UTUC were included. Patients were divided into single, two, and multiple (three times or four times) FISH groups based on the number of FISH tests performed on different samples from the same patient, and the diagnostic efficiency of single, two, and multiple FISH tests for muscle-invasive tumors and highgrade tumors were assessed. RESULTS: We included a total of 207 patients with UTUC, and when compared to single FISH, the sensitivity of multiple and double FISH for the diagnosis of UTUC increased from 62% to 76% and 78%, respectively. It went from 67% to 78% and 80% for muscle-invasive UTUC (> = pT2) and from 71% to 79% and 81% for the highest- grade UTUC. CONCLUSION: Multiple FISH improves the diagnostic efficacy of UTUC and helps to differentiate aggressive tumors.

Diagnostic pathways and treatment strategies in upper tract urothelial carcinoma in Sweden between 2015 and 2021: a population-based survey.

OBJECTIVE: To report national data on diagnostics and treatment of upper tract urothelial carcinoma (UTUC) from the Swedish National Registry of Urinary Bladder Cancer (SNRUBC). PATIENTS AND METHODS: Data from 2015 to 2021 were retrieved, and descriptive analyses were performed regarding incidence, diagnostic modalities, preoperative tumor staging, quality indicators for treatment including the use of standardized care pathways (SCP) and multidisciplinary tumor boards (MDTB). Time trends were explored for the study period. RESULTS: Registrations included 1,213 patients with renal pelvic cancer and 911 patients with ureteric cancer with a median age of 74 (interquartile range [IQR] 70-77) and 75 (IQR 71-78) years, respectively. Incidence rates of UTUC were stable, as were proportions of curative treatment intent. Median number of days from referral to treatment was 76 (IQR 57-99) and 90 (IQR 72-118) days, respectively, for tumors of the renal pelvis and ureter, which remained unchanged after introduction of SCP in 2016. Noticeable trends included stable use of kidney-sparing surgery and increased use of MDTB. For radical nephroureterectomy (RNU), robot-assisted technique usage increased even for non-organ-confined tumors (cT3-4) and in one out of three patients undergoing RNU a bladder cuff excision was not registered. CONCLUSIONS: The population-based SNRUBC with high coverage contributes to the knowledge about UTUC with granular and generalizable data. The present study reveals a high proportion of patients not subjected to curatively intended treatment and suggests unmet needs to shorten lead times to treatment and use of bladder cuff excision when performing radical surgery for UTUC in Sweden.

Oncologic outcomes of patients treated with kidney-sparing surgery or radical nephroureterectomy for upper urinary tract urothelial cancer: a population-based study.

PURPOSE: Although kidney-sparing surgery (KSS) is a nonminor option for low-risk upper urinary tract urothelial cancer (UTUC), its oncological benefits in high-risk UTUC remain unclear when compared to radical nephroureterectomy (RNU). This study aimed to compare the oncological outcomes of RNU and KSS in patients with UTUC. METHODS: We searched the SEER database for patients treated for primary non-metastatic UTUC with either RNU or a kidney-sparing approach (segmental ureterectomy (SU) or local tumor excision (LTE)) between 2004 and 2018. RESULTS: The study included 6,659 patients with primary non-metastatic UTUC treated with surgery; 2,888 (43.4%) and 3,771 (56.6%) patients presented with ureteral and renal pelvicalyceal tumors, respectively. Finally, 5,479 (82.3%) patients underwent RNU, 799 (12.0%) were treated with SU, and 381 (5.7%) patients received LTE. For confounder control, propensity score matching (PSM) of patients treated with SU and RNU was performed to adjust for T stage, grade, age, gender, tumor size, and lymphadenectomy performance. PSM analysis included 694 patients treated with RNU and 694 individuals who underwent SU. In multivariable Cox regression and Kaplan-Meier analyses, we found no difference in either CSS or OS between RNU and SU, even in the subgroup of high-grade and/or muscle-invasive UTUC including pT3-T4 tumors (all p > 0.05). CONCLUSION: In this population-based study, SU provides equivalent CSS and OS compared to RNU, even in high-risk and locally advanced ureteral cancer. Due to the unavoidable risk of selection bias, further prospective studies are expected to overcome the limitations of this study and support the wider implementation of KSS.

Clinicopathological characteristics, surgical treatments, and oncological outcomes of localized primary unifocal urothelial carcinoma involving the ureterovesical junction.

OBJECTIVE: To investigate clinicopathological characteristics, surgical treatments, and oncological outcomes of patients with localized primary unifocal urothelial carcinoma involving the ureterovesical junction (UC-UVJ). PATIENTS AND METHODS: Localized primary unifocal UC-UVJ cases in patients admitted to our hospital from March 2013 to August 2021 were reviewed. Clinicopathological parameters, perioperative data, and oncological outcomes were compared between patients grouped by tumor location and surgical treatment. RESULTS: A total of 130 patients with localized primary unifocal UC-UVJ were enrolled in this study. These included 72 cases of bladder cancer (BC) involving the ureteral orifice, and 58 cases of upper urinary tract urothelial carcinoma (UTUC) involving the intramural ureter. The proportion of male patients, hydronephrosis, flank pain/abdominal pain, and tumor size differed significantly between the BC and UTUC groups (all P < 0.05). During the median follow-up period of 32.9 months, 49 cases (37.7%) recurred and 29 (22.3%) died from urothelial carcinoma (UC), though no statistical difference in recurrence (P = 0.436) or cancer-specific mortality (P = 0.653) was observed between the BC and UTUC groups. Cox proportional hazards regression analysis identified age, tumor grade, and lymphovascular invasion (LVI) as independent predictors of cancer-specific survival (CSS), and sex, T stage, tumor grade, and LVI as independent predictors of recurrence-free survival (RFS). CONCLUSION: Owing to positional properties, patients with localized primary unifocal UC-UVJ exhibited significant heterogeneity, leading to varied treatment strategies. No statistically significant differences in CSS or RFS were observed between the BC and UTUC groups. Furthermore, age, sex, T stage, tumor grade, and LVI should be carefully considered in clinical practice because of their associations with CSS and RFS.

A SEER-Medicare Based Quality Score for Patients With Metastatic Upper Tract Urothelial Carcinoma.

BACKGROUND: Population-based studies evaluating outcomes for metastatic upper tract urothelial carcinoma (mUTUC) are sparse and rarely capture both patients with de novo (synchronous) metastases and those who progress to metastatic disease (metachronous). Herein we evaluated the outcomes and costs associated with synchronous and metachronous mUTUC, utilizing a novel Methodology. Additionally, we created a guideline-based quality score to improve care in this space. PATIENTS AND METHODS: We identified all patients with mUTUC aged 66 years and older included in the SEER-Medicare linked database between 2004 and 2012. Achievement of 3 quality criteria was assessed: (1) cancer-specific survival (CSS)>12 months; (2) receipt of systemic therapy; (3) receipt of hospice/palliative care. Total healthcare and out-of-pocket costs were evaluated. Regression analyses were performed to assess characteristics associated with quality criteria and total healthcare costs. RESULTS: Of the 1223 patients identified, at least one quality criterion was met in just 40.2% and only 54 patients (4.4%) received palliative care. In multivariable analysis, patients with synchronous mUTUC (OR:0.55, 95%CI:0.41-0.72), and at least 3 comorbidities (OR:0.68, 95%CI:0.47-0.98) were less likely to achieve at least 1 quality criterion. Meeting at least 1 quality criterion was associated with increased costs ($94,677, 95%CI:87,702-101,652 versus $63,575, 95%CI:59,598-67,552). CONCLUSIONS: Less than half of patients with mUTUC met at least 1 quality criterion. Quality score achievement was associated with a modest increase in total healthcare spending. These findings not only provide guidance for future study of rare diseases using secondary data, but also highlight inadequacies in the current management of mUTUC.

Sequential endoluminal gemcitabine and docetaxel for the treatment of clinically non-invasive high-grade upper tract urothelial carcinoma.

PURPOSE: There is an unmet need for effective renal sparing treatments for upper tract urothelial carcinoma (UTUC). Gemcitabine/Docetaxel (Gem/Doce) has shown favorable efficacy in nonmuscle invasive bladder cancer. We report the outcomes of patients treated with endoluminal Gem/Doce for noninvasive high-grade UTUC. METHODS: A retrospective review of patients treated with Gem/Doce for clinically noninvasive high-grade UTUC with no radiographic or endoscopically visible disease, either at diagnosis or following ablation, was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. Induction instillations were performed weekly for 6 weeks, followed by 6 monthly instillations if disease-free. Recurrence was defined as biopsy-proven disease or high-grade (HG) cytology. Progression was defined by development of muscle invasion, metastases, or death due to cancer. Survival was assessed with the Kaplan-Meier method. RESULTS: The final cohort included 31 patients with 41 upper tract units, 51% of which would have been dialysis dependent with nephroureterectomy. Median (IQR) age was 74 years (68-81). Median follow-up was 29 months (IQR 20-58). Prior to treatment, 37 (90%) units presented with a localizing HG cytology (presumed occult CIS), and 4 (9.8%) with HG biopsy-proven disease. Sixteen (52%) patients reported any side effects; 5 were Grade 3 and 1 was Grade 5. Recurrence-free survival was 76%, 54%, and 40% at 1, 2, and 3 years, respectively. Five patients died from urothelial carcinoma. The 3-year progression-free and overall survival were 75% and 75%, respectively. CONCLUSIONS: Gem/Doce demonstrates promising safety and efficacy as a renal-sparing treatment option for high-grade UTUC in appropriately selected patients.

The clinical impact of ureteroscopy for upper tract urothelial carcinoma: A multicenter study.

BACKGROUND: With the development of kidney-sparing surgery and neoadjuvant chemotherapy, ureteroscopic biopsy (URSBx) has become important for the management of upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively analyzed data from 744 patients with UTUC who underwent radical nephroureterectomy (RNU), stratified into no ureteroscopy (URS), URS alone, and URSBx groups. Intravesical recurrence-free survival (IVRFS) was examined using the Kaplan-Meier method. We conducted Cox regression analyses to identify risk factors for IVR. We investigated differences between clinical and pathological staging to assess the ability to predict the pathological tumor stage and grade of RNU specimens. RESULTS: Kaplan-Meier curves and multivariate Cox regression revealed significantly more IVR and inferior IVRFS in patients who underwent URS and URSBx. Superficial, but not invasive, bladder cancer recurrence was more frequent in the URS and URSBx groups than in the no URS group. Clinical and pathological staging agreed for 55 (32.4%) patients. Downstaging occurred for 48 (28.2%) patients and clinical understaging occurred for 67 (39.4%) patients. Upstaging to muscle-invasive disease occurred for 39 (35.8%) of 109 patients with ≤cT1 disease. Clinical and pathological grading were similar for 72 (42.3%) patients. Downgrading occurred for 5 (2.9%) patients, and clinical undergrading occurred for 93 (54.7%) patients. CONCLUSION: URS and URSBx instrumentation will be risk factors for superficial, but not invasive, bladder cancer recurrence. Clinical understaging/undergrading and upstaging to muscle-invasive disease occurred for a large proportion of patients with UTUC who underwent RNU. These data emphasize the challenges involved in accurate UTUC staging and grading.

Impact of lymphovascular invasion on survival in surgically treated upper tract urothelial carcinoma: a nationwide analysis.

OBJECTIVES: To assess the prognostic ability of lymphovascular invasion (LVI) in upper tract urothelial carcinoma (UTUC) as a predictor of overall survival (OS) using a large North American cohort. PATIENTS AND METHODS: Our cohort included 5940 patients with clinical M0 UTUC who underwent a radical nephroureterectomy (RNU), between 2010 and 2016, within the National Cancer Database. The main variable of interest was LVI status, and its interaction with pathological nodal (pN) status. Kaplan-Meier curves were used to depict the OS also stratifying patients on LVI status. Cox regression analysis tested the impact of LVI status on OS after accounting for the available covariates. RESULTS: The median (interquartile range [IQR]) age at diagnosis was 71 (63-78) years and most patients had pathological T1 stage disease (48.6%). Nodal status was pN0, pN1 and pNx in 45.8%, 6.3% and 47.9%, respectively. Overall, 22.1% had LVI. The median (IQR) follow-up time was 32.6 (16.0-53.3) months. At the 5-year postoperative follow-up, the estimated OS rate was 28% in patients with LVI vs 66% in those without LVI (P < 0.001). When patients were stratified based on nodal status those rates were 32% vs 68% in pN0 patients (P < 0.001), 23% vs 30% in pN1 patients (P = 0.8), and 28% vs 65% in pNx patients (P < 0.001). On multivariable analysis, the presence of LVI was associated with less favourable OS (hazard ratio 1.79, 95% confidence interval 1.60-1.99; P < 0.001). CONCLUSION: Our study assessed the impact of LVI on OS in patients with UTUC in a large North American nationwide cohort. Our series, as the largest to date, indicate that LVI is associated with less favourable survival outcomes in patients with UTUC after RNU, and this variable could be used in counselling patients about their prognosis and might be a useful tool for future trials to risk-stratify patients.