Endoscopic Management of Low-Grade Upper Tract Urothelial Carcinoma: Characterizing the Long-term Burden of Care in Comparison to Radical Nephroureterectomy.

OBJECTIVE: To compare procedure burden, oncologic, surgical and renal-function outcomes between patients with low-grade upper urothelial cancer (UTUC) who were referred for either radical management (RM) or kidney-sparing endoscopic management (EM). PATIENTS AND METHODS: We retrospectively reviewed data of all patients treated for UTUC at our tertiary medical center between 2000 and 2018 and selected patients diagnosed with unilateral low-grade UTUC. RESULTS: Twenty-four patients were treated with EM and 37 with RM. Surgical and oncologic risk factors were similar between the arms except for tumor size. Mean follow-up was 4.9 ± 3.4 years. The 5-year overall-survival rate was 85% with EM and 84% with RM (P = .707). Metastasis-free and cancer-specific survival were also similar (P = .994, P = .960). End-of-follow-up average glomerular filtration rates were 58.7 ± 21.5 and 49.2 ± 22.1 mL/min/1.73 m2, respectively (P = .12). Ninety-two percent of patients managed endoscopically had local recurrences, with an average of 3.2 recurrences per patient. Four (17%) patients underwent salvage radical nephroureterectomy. Procedure burden was higher with EM, having 6.5 ± 4.4 operations and 344 ± 272 minutes under anesthesia compared with 1.9 ± 0.4 operations (P <.0001) and 213 ± 84 minutes under anesthesia (P = .031) with RM. Cost-of-care analysis revealed higher costs for EM in both private and publicly funded medical insurance plans. CONCLUSION: Patients undergoing endoscopic management had an 83% chance of preserving their kidney and an 81% chance of 5-year metastasis-free survival at a cost of 6.5 ± 4.4 operations during a mean follow-up of 4.9 ± 3.4 years. Our findings support EM for low-grade UTUC as a valid option from oncological aspects but highlight the associated costs.

Treatment Patterns, Outcomes, and Costs Associated With Localized Upper Tract Urothelial Carcinoma.

Background: Upper tract urothelial carcinoma (UTUC) is a heterogeneous disease that presents a clinical management challenge for the urologic surgeon. We assessed treatment patterns, costs, and survival outcomes among patients with nonmetastatic UTUC. Methods: We identified 4114 patients diagnosed with nonmetastatic UTUC from 2004 to 2013 in the Survival Epidemiology, and End Results-Medicare population-based database. Patients were stratified into low- or high-risk disease groups. Median total costs from 30 days prior to diagnosis through 365 days after diagnosis were compared between groups. Overall and cancer-specific survival were evaluated using Cox proportional hazards regression. All statistical tests were 2-sided. Results: After risk stratification, 1027 (24.9%) and 3087 (75.0%) patients were classified into low- vs high-risk UTUC groups. Most patients underwent at least 1 surgical intervention (95.1%); 68.4% underwent at least 1 endoscopic intervention. Patients diagnosed with high- vs low-risk UTUC were more likely to undergo nephroureterectomy (83.6% vs 72.0%; P < .001); few patients with low-risk disease were exclusively managed endoscopically (16.9%). At 365 days after diagnosis, costs of care for high- vs low-risk UTUC were statistically significantly higher ($108 520 vs $91 233; median difference $16 704, 95% confidence interval [CI] = $11 619 to $21 778; P < .001). Those with high-risk UTUC had worse cancer-specific and overall survival compared with patients with low-risk UTUC (cancer-specific survival hazard ratio [HR] = 4.14, 95% CI = 3.19 to 5.37; overall survival HR = 1.78, 95% CI = 1.62 to 1.96). Conclusions: UTUC continues to be managed primarily with nephroureterectomy, regardless of risk stratification, and patients with high-risk UTUC have worse overall and cancer-specific survival. Substantial costs are associated with management of low- and high-risk UTUC, with the latter being more costly up to 1 year from diagnosis.

The Impact of Hospital Volume on Short-term and Long-term Outcomes for Patients Undergoing Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

OBJECTIVES: To examine the effect of hospital volume on short and long-term outcomes for radical nephroureterectomy (RNUx). Upper tract urothelial carcinoma is a rare malignancy that few surgeons have experience with. The hospital volume-outcome relationship has been well established for other cancers but not RNUx. METHODS: The National Cancer Database was queried for all cases of upper tract urothelial carcinoma that underwent RNUx from 2004 to 2016. Average annual hospital volume for radical nephroureterectomy was stratified into tertiles. The upper tertile, defined as 6 or more RNUx per year, was considered high volume while low volume was less than 6 RNUx per year. Kaplan-Meier and Cox proportional hazards regression were used to identify independent predictors of overall survival, and logistic regression was used to identify predictors of perioperative outcomes. RESULTS: We identified 37,479 RNUx performed across 1290 hospitals. There were no differences in baseline health or cancer staging between patients who presented at low- versus high-volume centers. Both peri-operative survival (30- and 90-day mortality) and long-term overall survival were improved in patients treated at high-volume centers. On multivariable survival analysis, treatment at a high-volume center was associated with improved hazards of survival. This relationship for long-term survival remained consistent on landmark analysis where patients who died within 90 days of surgery were removed. CONCLUSIONS: Treatment at a high-volume hospital was associated not only with improved short-term perioperative outcomes but also with improved overall long-term survival. The mechanism behind this is likely multifactorial with surgeon volume, and ancillary support services all playing critical roles.

Single-port Robotic Surgery Allows Same-day Discharge in Majority of Cases.

OBJECTIVE: To assess the influence of single-port (SP) robotic surgery on length of stay (LOS) in our initial experience using the da Vinci SP robot as compared with traditional, multiport procedures. METHODS: We evaluated our single surgeon (RA) prospective database for the initial 100 SP procedures performed between January 2019 and January 2020. Patient LOS was compared with standard multiport robotic surgery patients since we began routinely offering same-day discharge (SDD) in September 2016. RESULTS: Among the initial 100 SP robotic surgeries, there were 59 prostatectomies, 18 partial nephrectomies, 12 pyeloplasties, 4 nephrectomies, 4 adrenalectomies, 2 partial cystectomies, and 1 nephroureterectomy. The rate of SDD in SP procedures was higher compared to our historical SDD for multiport robotic surgeries despite uniformly offering SDD to all patients in both groups (88% vs 51%, P < .0001). Among prostatectomies, 88% of SP patients were discharged the same day versus 55% (P < .001). Among partial nephrectomies, 83% of SP patients went home the same day versus 17% (P < .001) as well as 83% of pyeloplasty patients versus 52% (P = .064). For SP adrenalectomy, nephrectomy, partial cystectomy, and nephroureterectomy, all were discharged the same day. CONCLUSION: Our initial experience with SP robotic surgery suggests earlier discharge is possible with the large majority (88%) so far opting to go home the same day as surgery. Further experience will be necessary to allow analysis of pain scores and analgesic usage as potential causative factors.

Preoperative frailty predicts adverse short-term postoperative outcomes in patients treated with radical nephroureterectomy.

BACKGROUND: To investigate the effect of frailty on short-term postoperative outcomes and total hospital charges (THCs) in patients with non-metastatic upper urinary tract carcinoma, treated with radical nephroureterectomy (RNU). METHODS: Within the National Inpatient Sample (NIS) database we identified 11 258 RNU patients (2000-2015). We used the Johns Hopkins frailty-indicator to stratify patients according to frailty status. Time trends and multivariable logistic, Poisson and linear regression models were applied. RESULTS: Overall, 1801 (16.0%) patients were frail, 4664 (41.4%) were older than 75 years and 1530 (13.6%) had Charlson comorbidity index ≥2. Rates of frail patients increased over time, from 7.3% to 24.9% (P < .001). Frail patients exhibited higher rates (all P < .05) of overall complications (62.6% vs 50.9%), in-hospital mortality (1.6% vs 1.0%), non-home-based discharge (22.7% vs 12.1%), longer length of stay (LOS) (6 vs 1 day) and higher THCs ($49 539 vs $39 644). Moreover, frailty independently predicted (all P < .05) overall complications (OR, 1.46), in-hospital mortality (OR, 1.52), non-home-based discharge (OR, 1.36), longer LOS (RR, 1.30) and higher THCs (RR, +$11 806). CONCLUSION: Preoperative frailty is important in RNU patients. One of four RNU patients is frail. Moreover, frailty predicts short-term postoperative complications, as well as longer LOS and higher THCs after RNU.

Urothelial Carcinoma of the Renal Pelvis and Ureter: Does Location Make a Difference?

BACKGROUND: There is a paucity of data on outcomes of upper tract urothelial carcinoma (UTUC) arising from the renal pelvis (RPUC) versus UTUC arising from the ureter (UUC). The published literature is conflicting, and there is no consensus on patient prognosis based on disease location. The aim of this study is to compare clinical and survival outcomes based on location of primary tumor using a large national registry. MATERIALS AND METHODS: The National Cancer Database was queried from 2010 to 2016 for patients with localized (cN0M0) UTUC. Patients were stratified based on location of tumor. Survival analysis was performed using Cox proportional hazard regression and inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves. We also performed exploratory analyses based on tumor stage. RESULTS: We identified 11,922 patients who underwent surgical treatment. The median follow-up was 32.1 months. Patients with RPUC presented with higher tumor stage and grade. Patients with UUC were treated with less radical nephroureterectomy (56.4% vs. 84.3%; P < .01). IPTW-adjusted Kaplan-Meier curves demonstrated higher median overall survival for RPUC versus UUC (71.1 vs. 66.8 months, respectively; P = .01). This benefit was consistent across tumor stage subgroups, reaching statistical significance in patients with T1 disease. On multivariable analysis, ureteral location of tumor was a predictor of worse survival. CONCLUSION: Patients with UUC were found to be treated with less radical surgery and to have worse survival than those with RPUC. These patients may suffer from poor initial staging and suboptimal treatments. Further studies are needed to evaluate potential biological differences of UTUC based on tumor location.

Incidence and survival outcomes in patients with upper urinary tract urothelial carcinoma diagnosed with variant histology and treated with nephroureterectomy.

OBJECTIVE: To evaluate the incidence and survival outcomes of histological variants of upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively analysed data from 1610 patients treated with RNU for clinically non-metastatic UTUC between 1990 and 2016 in several centres participating in the UTUC Collaboration. Histological variants were classified as micropapillary, squamous, sarcomatoid and other, including other rare variants (<10 cases for each). Multivariable competing risk analyses were conducted to assess the effect of variant histology on overall recurrence and cancer-specific mortality (CSM). RESULTS: Overall, 1460 patients (91%) had pure urothelial carcinoma (PUC), whereas 150 (9%) were diagnosed with a variant histology, including 89 (5.0%), 41 (2.0%), 10 (1.0%) and 10 (1.0%) cases of micropapillary, squamous, sarcomatoid and other tumours, respectively. Variant histology was associated with the presence of adverse pathological features compared with PUC, including non-organ-confined disease (59% vs 38%; P < 0.001), lymph node invasion (28% vs 24%; P = 0.02), high-grade disease (88% vs 71%; P < 0.001), tumour necrosis (28% vs 16%; P = 0.001) and positive surgical margins (15% vs 8%; P = 0.01). In competing risk analysis, micropapillary variant was the only factor associated with worse recurrence (sub-hazard ratio [SHR] 2.27, 95% confidence interval [CI] 1.25-4.79; P = 0.02) whereas sarcomatoid variant was associated with worse CSM (SHR 16.8, 95% CI 6.86-41.17; P < 0.001). CONCLUSION: We found that one out of 10 patients with UTUC treated with RNU had variant histology. Only micropapillary and sarcomatoid variants were associated with poorer oncological outcomes after adjusting for available confounding factors.

8-armed octopus: Evaluation of clinicopathologic prognostic factors of urothelial carcinoma of the upper urinary system

Background/aim: This study was designed to determine the characteristic features of upper urinary system urothelial carcinomas (UUSUCs) and to evaluate the clinicopathological parameters associated with prognosis. Materials and methods: A total of 74 cases of UUSUC were included, from three different centers. Demographic data and histopathological features such as tumor localization, concomitant tumor in the urinary system, distant metastasis with overall survival and disease-free survival obtained from the hospital records were evaluated retrospectively. Histopathologic prognostic features such as grade, perineural invasion, lymphovascular invasion, tumor necrosis, and surgical margin status were also evaluated. Results: Seventy cases (94.6%) underwent open nephroureterectomy whereas 4 cases (5.4%) had laparoscopic nefroureterectomy. Thirty-eight (51.4%) cases were located in the pelvis, 7 (9.5%) in the ureter, 29 (39.2%) both in the pelvis and ureter. Fifty-six (75.7%) cases were alive; however, 18 (24.3%) patients were found to be dead. pTa, pT1, pT2, pT3, and pT4 tumors were reported in 16 (21.6%), 13 (17.6%), 4 (5.4%), 28 (37.8%), and 13 (17.6%) patients, respectively. Histopathologically, 17 cases (23%) were low-grade, 57 cases (77%) were high-grade. Statistically significant correlation was observed between overall survival and lymph node metastasis, distant metastasis, tumor necrosis, and differentiation by univariate analysis. Only distant metastasis was statistically associated with overall survival by multivariate analysis. We found no significant relationship between disease-free survival and all parameters. Conclusion: Differentiation and necrosis of tumor, lymph node involvement, and presence of distant metastasis is associated with the overall survival of urothelial carcinoma of the upper urinary system.

Coincidental Bladder Cuff Transitional Cell Carcinoma in Nephroureterectomy Specimens: Risk Factors, Prognosis and Clinical Implementation.

PURPOSE: There is a lack of reporting of the bladder cuff pathology in the literature and ongoing debate regarding the role of bladder cuff excision (BCE) in the prognosis in patients with upper tract urothelial carcinoma (UTUC). We aimed to know the risk factors, the survival, and the clinical course of such pathology. MATERIALS AND METHODS: The study was retrospective, from 1983-2013 on 305 patients who had diagnosed with UTUC. Patients were managed by radical open/ laparoscopic nephroureterectomy with bladder cuff excision. The tumor was staged using 1997 TNM classification and the 3-tiered WHO grading system was used for grading. Patients who found to have a malignant bladder cuff on the final pathology were further analyzed for the risk factors for such disease and its effect on survivaltheir outcomes. RESULTS: 13/ 281 (4.6%) cases were found to have malignant bladder cuff. Regarding tumor stage; one case was diagnosed with Tis, eight had T1 and four cases had T2 malignant bladder cuff. All cases were with pure ureteric or multifocalcentric tumors, and none had pure pelvicalyceal tumors (p = .001).Local recurrence at the surgical site and distant metastasis were significantly higher among patients with malignant bladder cuff (p = .001 and .002 respectively), and the last sustained its significance in multivariate analysis. Those patients had a poor prognosis when compared to non-malignant bladder cuff cases (Log Rank test, p = .001)Conclusion: Ureteric tumor is the only independent risk factor for malignant bladder cuff at the final pathology and is associated with increased risks for invasive bladder tumor, distant metastasis and poor survival in comparison with non-malignant bladder cuff. In a clinical implementation, BCE is considered as a mandatory step in management of ureteric tumors, while it could be omitted in pure and low grade renal pelvis tumors.

Thulium Laser Treatment of Upper Urinary Tract Carcinoma: A Multi-Institutional Analysis of Surgical and Oncological Outcomes.

INTRODUCTION: To evaluate the efficacy and safety of ureteroscopic thulium laser (TL) treatment of upper urinary tract carcinoma (UTUC). MATERIALS AND METHODS: Forty-two consecutive patients underwent conservative TL treatment for UTUC at two referral institutions. All patients underwent preliminary biopsy and then laser vaporization. A 272 µm and 365 µm laser fibers were used with a flexible and semirigid scope, respectively. Ablation was carried out with a 10 to 20 W power. RESULTS: Mean age at surgery was 68 years (SD 10.7). Mean tumor size was 14.3 mm (range 2-30 mm). Preliminary biopsy revealed the presence of low-grade disease in 29 (69.1%) patients, high-grade disease in 4 (9.5%) and 1 carcinoma in situ 1 (2.4%), whereas it was not conclusive in 8 (19%) cases. Final stage was pTa and pTis in 41 (97.6%) and 1 (2.4%) patients, respectively. Thirty eight percent (16) experienced Clavien-Dindo grade I complication, 47.6% (20) grade II, and 2.4% (1) grade III. Five (12%) patients underwent a second-look procedure due to residual disease. Eight (19%) patients experienced clinical recurrence. The median estimated recurrence-free survival was 44 months (SE 3.68). Four patients (9.5%) underwent a nephroureterectomy. Final pathological stage was pTis, pT3 high grade, pTa low grade, and pT0. Median follow-up was 26.3 months (range 2-54 months), and no progression or upstaging of disease occurred. CONCLUSIONS: TL management of UTUC is a safe and efficacious conservative treatment. Our experience shows optimal vaporization and hemostatic control in the absence of major complications.

Timing of blood transfusion and oncologic outcomes in patients treated with radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate the impact of timing of blood transfusion in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). METHODS: Outcomes of consecutive patients with UTUC treated with RNU were analyzed. Clinicopathologic factors were compared using Fisher's exact test or the Wilcoxon rank-sum test between patients who received any transfusion and no transfusion, and between patients receiving intraoperative transfusion only and patients receiving no transfusion. Cancer-specific and overall survival were estimated and multivariable analyses were performed to assess the impact of timing of transfusion on clinical outcomes. RESULTS: Among 402 patients included in this study, 71 (17.6%) patients received a transfusion at any point and 27 (6.7%) patients received an intraoperative blood transfusion. Transfusion at any time, patient comorbidity, high grade, advanced stage, positive surgical margins, low preoperative hemoglobin, longer operative duration, and increased blood loss were significantly associated with cancer-specific survival (DSS) on univariable analysis (HR 1.85, 95% CI 1.20-2.85, p < 0.005). In the multivariable analysis, transfusion at any point was not a prognostic factor (HR 1.00, 95% CI 0.60-1.68, p = 0.99). When examining intraoperatively transfusion only, transfusion was significantly associated with DSS (HR 1.91, 95% CI 1.01-3.59, p = 0.045) but no longer significant in multivariable analysis (HR 0.72, 95% CI 0.32-1.65, p = 0.440). CONCLUSIONS: Our study indicates that the administration of blood transfusion either intraoperatively or postoperatively is not associated with clinical or oncological outcomes in patients with upper tract urothelial carcinoma when adjusted for other factors in multivariable analysis. Further study is required.

Trends of lymphadenectomy in upper tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy.

INTRODUCTION: To evaluate temporal trends in the delivery and extent of lymphadenectomy (LND) in radical nephroureterectomy (RNU) performed in upper tract urothelial carcinoma (UTUC) patients. METHODS: We evaluated a multi institutional collaborative database composed by 1512 consecutive patients diagnosed with UTUC treated with RNU between 1990 and 2016. Year of surgery were grouped in five periods: 1990-1996, 1997-2002, 2003-2007, 2008-2012 and 2013-2016. Data about LND were available for all patients and numbers of nodes removed and positive were reported by dedicate uropathologists. The Mann-Whitney and Chi square tests were used to compare the statistical significance of differences in medians and proportions, respectively. RESULTS: Five hundred forty-five patients (36.0%) received a concomitant LND while 967 (64.0%) did not; 41.9% of open RNU patients received a concomitant LND compared to 24.4% of laparoscopic RNU patients. The rate of concomitant LND increased with time in the overall, laparoscopic and open RNU patients (all p < 0.03). Patients treated with open RNU also had an increasing likelihood to receive an adequate concomitant LND (p < 0.001) while those undergoing a laparoscopic approach did not (p = 0.1). Patients treated with concomitant LND had a median longer operative time of 20 min (p = 0.01). There were no differences in perioperative outcomes and complications between patients who received a concomitant LND and those who did not (p > 0.1). CONCLUSION: Although an increased trend was observed, most patients treated with RNU did not receive LND. Surgeons using a laparoscopic RNU were less likely to perform a concomitant LND, and when done, they remove less nodes.

Prognostic role of expression of N-cadherin in patients with upper tract urothelial carcinoma: a multi-institutional study.

PURPOSE: To assess the role of N-cadherin as prognostic biomarker in patients with upper tract urothelial carcinoma (UTUC) in a large multi-institutional cohort of patients. PATIENTS AND METHODS: Immunohistochemistry was used to evaluate the status of N-cadherin expression in 678 patients with unilateral sporadic UTUC treated with radical nephroureterectomy. N-cadherin was considered positive if any immunoreactivity with membranous staining was detected. The Kaplan-Meier method was used to estimate recurrence-free survival, overall survival and cancer-specific survival. Disease recurrence, overall mortality and cancer-specific mortality probabilities were tested in Cox regression models. RESULTS: Expression of N-cadherin was observed in 292 (43.1%) of patients, and it was associated with advanced tumour stage (p < 0.04), lymph node metastases (p = 0.04) and sessile architecture (p < 0.02). Within a median follow-up of 37.5 months (IQR 20-66), 171 patients (25.2%) experienced disease recurrence and 150 (22.1%) died from UTUC. In univariable analyses, N-cadherin expression was significantly associated with higher probability of recurrence (p = 0.01), but not overall (p = 0.9) or cancer-specific mortality (p = 0.06). When adjusted for the effects of all available confounders, N-cadherin was not associated with any of the survival outcomes. CONCLUSION: N-cadherin is expressed in approximately 2/5 of UTUs. It is associated with adverse pathologic factors but not with survival outcomes. Its clinical value remains limited.

Increased nucleophosmin expression is a strong predictor of recurrence and prognosis in patients with N0M0 upper tract urothelial carcinoma undergoing radical nephroureterectomy.

PURPOSE: We aimed to evaluate whether increased nucleophosmin expression predicts recurrence and survival in upper tract urothelial carcinoma (UTUC). METHODS: Specimens from 101 patients with N0M0 UTUC undergoing radical nephroureterectomy were evaluated. Nucleophosmin expression was determined immunohistochemically and categorized into two groups according to nucleophosmin staining intensity. The association between nucleophosmin expression and various clinicopathological factors including Ki-67 expression was analyzed. Multivariate analyses were performed to identify the independent predictors of extraurothelial recurrence and cancer-specific survival. RESULTS: High nucleophosmin expression was significantly correlated with tumor location, pT ≥3, lymphovascular invasion, lymph node metastasis, and high Ki-67 expression. Patients whose tumors demonstrated high nucleophosmin expression had a significantly higher rate of extraurothelial recurrence and a lower survival rate than those with low nucleophosmin expression. Multivariate analysis showed that pT ≥3, lymph node metastasis, high nucleophosmin expression, and high Ki-67 expression were independent predictors of extraurothelial recurrence. When patients were stratified into three groups according to the number of risk factors, the 2-year extraurothelial recurrence-free survival rates were 92.9% in patients with 0 or 1 risk factor, 76.5% in patients with 2 risk factors, and 9.1% in patients with 3 or 4 risk factors. Regarding cancer-specific survival, lymphovascular invasion and high nucleophosmin expression were independent predictors. CONCLUSIONS: Increased nucleophosmin expression was a strong predictor of extraurothelial recurrence and cancer-specific survival in patients with N0M0 UTUC undergoing radical nephroureterectomy. Our risk stratification models integrating nucleophosmin expression may provide valuable information on disease recurrence and prognosis.