Survival benefit of nephroureterectomy in systemic therapy exposed metastatic upper tract urinary urothelial carcinoma patients.

BACKGROUND: It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. METHODS: Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. RESULTS: Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20 months in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). CONCLUSIONS: In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).

Endoscopic intervention versus radical nephroureterectomy for the management of localized upper urinary tract urothelial carcinoma: a systematic review and meta-analysis of comparative studies.

OBJECTIVE: Localized Upper Urinary Tract Urothelial Carcinoma (UTUC) is an uncommon cancer typically detected at an advanced stage. Currently, radical nephroureterectomy (RNU) with bladder cuff excision is the standard treatment for high-risk UTUC. This meta-analysis aims to evaluate the 5-year overall and cancer-specific survival and bladder recurrence rates in studies comparing endoscopic kidney-sparing surgeries (E-KSS) with RNU in localized UTUC. EVIDENCE ACQUISITION: We performed a literature search on 20th April 2023 through PubMed, Web of Science, and Scopus. The PICOS model was used for study inclusion: P: adult patients with localized UTUC; I: E-KSS. C: RNU; O: primary: overall survival (OS); secondary: cancer-specific survival (CSS), bladder recurrence rate, and metastasis-free survival (MFS). S: retrospective, prospective, and randomized studies. EVIDENCE SYNTHESIS: Overall, 11 studies involving 2284 patients were eligible for this meta-analysis, 737 in the E-KSS group and 1547 in the RNU group. E-KSS showed a similar overall 5-year OS between E-KSS and RNU, and for low-grade tumors, while 5-year OS favored RNU for high-grade tumors (RR 1.84, 95% CI 1.26-2.69, p = 0.002). No difference emerged for 5-year CSS between the two groups, even when the results were stratified for low- and high grade tumors. Bladder recurrence rate and 5-year MFS were also similar between the two groups. CONCLUSIONS: Our review showed that E-KSS is a viable option for patients with localized UTUC with non-inferior oncological outcomes as compared with RNU, except for 5-year OS in high-grade tumors which favoured RNU.

Open versus minimally invasive nephroureterectomy in octogenarians: An analysis of surgical approach trends, outcomes, and survival analysis with propensity matching.

INTRODUCTION: Upper tract urothelial carcinoma (UTUC) is a rare disease accounting only for 5%-10% of urothelial carcinoma (UC). For localized high-risk disease, radical nephroureterectomy (RNU) is the standard of care. While minimally invasive (MIS) RNU has not been shown to decisively improve overall survival (OS) compared to open surgery, MIS RNU has been associated with reduced hospital length of stay (LOS), blood transfusion requirements and improved recovery, which are important considerations when treating older patients. The purpose of this study is to examine trends in surgical approach selection and outcomes of open vs. MIS RNU in patients aged ≥80 years. METHODS: Using the National Cancer Database (NCDB), patients aged ≥80 years who underwent open or MIS (either robotic or laparoscopic) RNU were identified from 2010 to 2019. Demographic, patient-related, and disease-specific factors associated with either open or MIS RNU were assessed using multivariate logistic regression models. Survival analysis was conducted using Kaplan-Meier plots and Cox-proportional hazard regression. Inverse probability of treatment weighting (IPTW) was utilized to adjust for confounding variables. Survival analysis was also conducted on the IPTW adjusted cohort using Kaplan-Meier plots and Cox-proportional hazard regression. RESULTS: 5,687 patients were identified, with 1,431 (25.2%) and 4,256 (74.8%) patients undergoing open and MIS RNU respectively. The proportion of RNU performed robotically has increased from 12.5% in 2010 to 50.4% in 2019. MIS was associated with a shorter hospital LOS (4.7 days versus 5.9 days, SMD 23.7%). Multivariate analysis revealed that MIS was associated with a significant reduction in 90-day mortality (OR: 0.571; 95%CI: 0.34-0.96, P = 0.033) and improved median OS (53.8 months [95%CI: 50.9-56.9] vs 42.35 months [95%CI: 38.6-46.8], P < 0.001) compared to open surgery. IPTW-adjusted survival analysis revealed improved median OS with MIS when compared to open surgery, with a survival benefit of 46.1 months (95%CI: 40.2-52.4 months) versus 37.7 months (95%CI: 32.6-46.5 months, P = 0.0034) respectively. IPTW-adjusted cox proportional hazard analysis demonstrated that MIS was significantly associated with reduced mortality (HR 0.76, 95%CI: 0.66-0.87, P < 0.001). CONCLUSION: In octogenarians undergoing RNU, MIS is associated with improved median OS and 90-day mortality.

Establishment and validation of a nomogram for predicting overall survival of upper-tract urothelial carcinoma with bone metastasis: a population-based study.

BACKGROUND: Bone metastasis (BM) carries a poor prognosis for patients with upper-tract urothelial carcinoma (UTUC). This study aims to identify survival predictors and develop a prognostic nomogram for overall survival (OS) in UTUC patients with BM. METHODS: The Surveillance, Epidemiology, and End Results database was used to select patients with UTUC between 2010 and 2019. The chi-square test was used to assess the baseline differences between the groups. Kaplan-Meier analysis was employed to assess OS. Univariate and multivariate analyses were conducted to identify prognostic factors for nomogram establishment. An independent cohort was used for external validation of the nomogram. The discrimination and calibration of the nomogram were evaluated using concordance index (C-index), area under receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). All statistical analyses were performed using SPSS 23.0 and R software 4.2.2. RESULTS: The mean OS for UTUC patients with BM was 10 months (95% CI: 8.17 to 11.84), with 6-month OS, 1-year OS, and 3-year OS rates of 41%, 21%, and 3%, respectively. Multi-organ metastases (HR = 2.21, 95% CI: 1.66 to 2.95, P < 0.001), surgery (HR = 0.72, 95% CI: 0.56 to 0.91, P = 0.007), and chemotherapy (HR = 0.37, 95% CI: 0.3 to 0.46, P < 0.001) were identified as independent prognostic factors. The C-index was 0.725 for the training cohort and 0.854 for the validation cohort, and all AUC values were > 0.679. The calibration curve and DCA curve showed the accuracy and practicality of the nomogram. CONCLUSIONS: The OS of UTUC patients with BM was poor. Multi-organ metastases was a risk factor for OS, while surgery and chemotherapy were protective factors. Our nomogram was developed and validated to assist clinicians in evaluating the OS of UTUC patients with BM.

Recent trends in incidence, mortality, survival, and treatment of upper tract urothelial carcinoma.

BACKGROUND: To examine the recent trends in incidence, incidence-based mortality, survival, and treatment of upper tract urothelial carcinoma (UTUC) from 2004 to 2019 and investigate whether patients would benefit from adjuvant chemotherapy. METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database, we identified 18,422 patients diagnosed with UTUC from 2004 to 2019. Joinpoint regression analyses were used to test the trends in annual percentage change (APC) for statistical significance. RESULTS: From 2004 to 2019, the incidence of all UTUC decreased from 1.46 to 1.27 per 100,000 person-years [APC: -1.11, P<0.001]. In subgroup analysis, the incidence decreased for localized, regional and stage I-II, but increased for distant. Over the study period, changes in trend for 5-year cancer specific survival [APC: -0.21, P=0.676] and 5-year overall survival [APC: 0.18, P=0.751] of all UTUC were not significant. The 5-year cancer specific survival and 5-year overall survival for regional and stage III cancer improved significantly from 2004 to 2014. Since 2004, rates of treatment with nephroureterectomy combined with chemotherapy increased significantly [APC: 7.38, P<0.001], while rates of treatment with nephroureterectomy alone decreased significantly [APC: -1.89, P<0.001]. CONCLUSION: The overall incidence of UTUC is reduced, with a significant reduction in the incidence of early stage UTUC but an increase in the incidence of late stage UTUC. No significant change in IBM was observed over the study period. No significant improvement in survival for early stage UTUC. Significant improvements in regional and stage III survival were observed with active adjuvant chemotherapy. There is also an excess of combination therapy. LEVEL OF EVIDENCE: 8.

Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.POUT was a phase III, randomized, open-label trial, including 261 patients with muscle-invasive or lymph node-positive, nonmetastatic upper tract urothelial cancer (UTUC) randomly assigned after radical nephroureterectomy to platinum-based chemotherapy (132) or surveillance (129). Primary outcome analysis demonstrated that chemotherapy improved disease-free survival (DFS). At that time, the planned secondary outcome analysis of overall survival (OS) was immature. By February 2022, 50 and 67 DFS events had occurred in the chemotherapy and surveillance groups, respectively, at a median follow-up of 65 months. The 5-year DFS was 62% versus 45%, univariable hazard ratio (HR), 0.55 (95% CI, 0.38 to 0.80, P = .001). The restricted mean survival time (RMST) was 18 months longer (95% CI, 6 to 30) in the chemotherapy arm. There were 46 and 60 deaths in the chemotherapy and control arms, respectively. The 5-year OS was 66% versus 57%, with univariable HR, 0.68 (95% CI, 0.46 to 1.00, P = .049) and RMST difference 11 months (95% CI, 1 to 21). Treatment effects were consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage. Toxicities were similar to those previously reported, and there were no clinically relevant differences in quality of life between arms. In summary, although OS was not the primary outcome measure, the updated results add further support for the use of adjuvant chemotherapy in patients with UTUC, suggesting long-term benefits.

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.

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.

Prognostic Analysis of Diagnostic Ureteroscopic Biopsy for Intravesical Recurrence of Upper Urinary Tract Urothelial Carcinoma.

OBJECTIVE: The aim of this study was to investigate whether diagnostic ureteroscopy (URS) biopsy is unfavourable for bladder tumour recurrence in upper urinary tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: We performed a retrospective analysis of 195 patients diagnosed with UTUC, who were divided into a diagnostic URS group (URS+) and a nondiagnostic URS group (URS-) according to whether diagnostic ureteroscopic biopsy was performed. A Cox regression model was used to analyse the risk factors for intravesical recurrence (IVR)-free survival (IRFS) and overall survival (OS) in UTUC after radical nephroureterectomy (RNU). Kaplan-Meier analysis was used to estimate the influence of factors on the incidence of IVR and the cumulative survival rate of UTUC. RESULTS: Patients with a maximum tumour diameter of less than 3.1 cm, low-stage tumours, and ureteral tumours were more likely to undergo diagnostic URS before radical surgery. Multivariate Cox regression analysis showed that tumour pathological stage and diagnostic ureteroscopic biopsy can be used as predictors of IVR after RNU (p = 0.019, 0.033). Kaplan-Meier survival analysis found that diagnostic ureteroscopic biopsy was a high-risk factor for IRFS (p = 0.034). Subcomponent analysis showed that pTa/Tis/T1, pT2, pT3/pT4 stage, and diagnostic ureteroscopic biopsy with pTa/Tis/T1 stage were unfavourable for IVR (p = 0.047). CONCLUSION: Diagnostic ureteroscopic biopsy before RNU should be carefully selected for patients with atypical preoperative UTUC. We believe that intravesical chemotherapy drug perfusion can be used after surgery to prevent IVR if biopsy is unavoidable, but this still requires further prospective studies.

Is bladder preservation safe? The oncology outcomes of patients after 2-sided radical nephroureterectomies due to bilateral upper urinary tract urothelial carcinomas.

PURPOSE: The prognosis of patients undergoing 2-sided radical nephroureterectomies (RNUs) with a residual bladder due to bilateral upper tract urothelial carcinoma (UTUC) is poorly understood. This study was aimed toward surveying the oncology outcomes and prognostic factors that may help in shared decision-making related to bladder preservation in patients preparing to receive 2-sided RNUs. METHODS: Patients with synchronous or metachronous bilateral UTUC who received bilateral RNUs with a residual bladder in our hospital were retrospectively reviewed. Clinical and pathological data were analyzed for potential variables affecting the oncology outcomes. RESULTS: A total of 50 patients were included. The average age at completion of the 2-sided RNU was 62.7 ± 12.4 years, with a mean follow-up of 88.4 ± 59.3 months after the 2-sided RNUs. The medium overall survival was 13.4 ± 1.8 years. Twenty-six patients (52%) had cancer recurrence in the residual bladder, but only 2 (8%) of the recurrences were muscle invasive. The highest UTUC stage was the only predictive factor for cancer-specific survival (CSS) rather than intravesical recurrence. The 5 year CSS rates in patients with the highest UTUC stage ≦ pT2 and ≧ pT3 were 90% and 51%, respectively (p = 0.007). CONCLUSIONS: Risk of cancer recurrence in the residual bladder is high, but does not affect survival outcomes. The highest UTUC stage plays a significant role in cancer-specific survival. With a careful patient surveillance, bladder preservation may be reasonable in patients with bilateral UTUC preparing for 2-sided RNUs.

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 role of surgery on primary site in metastatic upper urinary tract urothelial carcinoma and a nomogram for predicting the survival of patients with metastatic upper urinary tract urothelial carcinoma.

Metastatic upper urinary tract urothelial carcinoma (mUTUC) is a relatively rare urothelial carcinoma, and little attention has been given to it. Our study established a nomogram by analyzing the prognostic factors of mUTUC to predict the survival of patients and revealed that the role of surgery at the primary tumor site. We extracted our data (2010-2016) from the Surveillance, Epidemiology, and End Results (SEER) database, and 628 patients with distant metastasis were identified. Propensity score matching (PSM) was used to balance the clinical variable bias in a 1:1 ratio. After PSM, we enrolled 502 patients in our study cohort. Univariate and multivariate Cox regression analyses and Kaplan-Meier curves showed that T stage, N stage, hepatic metastasis, surgery, and chemotherapy were prognostic factors for mUTUC before and after PSM. Based on the findings, a nomogram was constructed to predict the 12-month survival of patients with distant metastasis. The analysis of subgroups of T stage, N stage, and different metastatic sites demonstrated that the survival of patients with T1/T2, N0/N1/N2/N3, metastasis including liver, and metastasis including bone could be improved by a combination of surgery and chemotherapy, while for the patients with T3/T4/TX, NX, metastasis including lung, and metastasis including distant lymph nodes, chemotherapy alone was a better choice to improve their overall survival. Radiotherapy has been proven to be useful for patients with N1/N2/N3 stage. We have provided more precise treatment strategies for stage IV patients. Our research fully affirms the role of surgery on primary site in UTUC patients with distant metastasis and the significance of classifying the patients into subgroups by integrating variables including T stage, N stage, and different metastatic sites to select the optimal treatment method.

A retrospective multicenter comparison of conditional cancer-specific survival between laparoscopic and open radical nephroureterectomy in locally advanced upper tract urothelial carcinoma.

BACKGROUND: Upper urinary tract urothelial carcinomas are relatively rare and have a cancer-specific survival rate of 20%-30%. The current gold standard treatment for nonmetastatic high-grade urinary tract urothelial carcinoma is radical nephroureterectomy with bladder cuff resection. OBJECTIVE: This study aimed to compare conditional cancer-specific survival between open radical nephroureterectomy and laparoscopic radical nephroureterectomy in patients with nonmetastatic stage pT3-4 or TxN(+) locally advanced urinary tract urothelial carcinoma from five tertiary centers. METHODS: The medical records of 723 patients were retrospectively reviewed. The patients had locally advanced and nodal staged tumors and had undergone open radical nephroureterectomy (n = 388) or laparoscopic radical nephroureterectomy (n = 260) at five tertiary Korean institutions from January 2000 and December 2012. To control for heterogenic baseline differences between the two modalities, propensity score matching and subgroup analysis were conducted. Conditional survival analysis was also conducted to determine survival outcome and to overcome differences in follow-up duration between the groups. RESULTS: During the median 50.8-month follow up, 255 deaths occurred. In univariate analysis, significant factors affecting cancer-specific survival (e.g., age, history of bladder cancer, American Society of Anesthesiologists score, pathological N stage, and presence of lymphovascular invasion and carcinoma in situ) differed in each subsequent year. The cancer-specific survival between patients treated with open radical nephroureterectomy and laparoscopic radical nephroureterectomy was not different between patients with and without a history of bladder cancer. After adjusting baseline differences between the two groups by using propensity score matching, both groups still had no significant differences in cancer-specific survival. CONCLUSION: The two surgical modalities showed no significant differences in the 5-year cancer-specific survival in patients with locally advanced urinary tract urothelial carcinoma.

Urinary Large Cell Neuroendocrine Carcinoma: A Clinicopathologic Analysis of 22 Cases.

Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a rare disease. We present a relatively large retrospective cohort of urinary LCNEC, 20 from the urinary bladder, and 2 from the ureter, from a single institution. The patients included 16 men and 6 women with a median age of 74.5 years. Most LCNEC presented at an advanced stage with tumors invading the muscularis propria and beyond (21/22). Eight cases were pure LCNEC, while 14 cases were mixed with other histologic types, including conventional urothelial carcinoma (n=9), carcinoma in situ (n=7), small cell carcinoma (n=6), and urothelial carcinoma with glandular (n=3) features. Most LCNEC expressed neuroendocrine markers synaptophysin (22/22), chromogranin (13/16), CD56 (7/7), TTF1 (8/8), and INSM1 (2/3). They were negative for common urothelial markers including HMWCK (0/3), p40/p63 (0/6), CK20 (0/10), and had variable GATA3 staining (4/8). Ki-67 stained 25% to nearly 100% tumor cell nuclei. Patient survival was associated with cancer stage, and pure LCNEC showed worse survival than mixed LCNEC. Compared with small cell carcinoma at similar stages from a prior study, LCNEC had a worse prognosis only when patients developed metastatic disease. For organ-confined LCNEC, neoadjuvant chemotherapy followed by radical resection is the treatment option to achieve long-term survival.

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma.

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.

Risk Factors for Intravesical Recurrence after Minimally Invasive Nephroureterectomy for Upper Tract Urothelial Cancer (ROBUUST Collaboration).

PURPOSE: Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence. RESULTS: A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031). CONCLUSIONS: IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.

Impact of cachexia on oncologic outcomes of sarcopenic patients with upper tract urothelial carcinoma after radical nephroureterectomy.

OBJECTIVES: To investigate the prognostic significance of sarcopenic cachexia compared to sarcopenia without cachexia in the outcomes of upper urinary tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: Between 2011 and 2016, 163 patients with UTUC who received RNU at a tertiary medical center were included. Pre-operatively clinical data, history, and abdominal computer tomography scans were analyzed retrospectively. The diagnosis of sarcopenia was based on abdominal computed tomography data on the patient's skeletal muscles. Outcomes of relapse-free, cancer-specific, and overall survival were analyzed by multivariate Cox regression. RESULTS: After adjusting for age, sex, pre-operatively estimated glomerular filtration rate, body mass index, underlying diseases, tumor grade, and tumor stage, cachexia was a significant poor prognostic factor for relapse-free survival (hazard ratio [HR]: 18.5, 95% confidence interval [CI]: 2.87-118, p = 0.002) and cancer-specific survival (HR: 26.6, 95% CI: 4.04-175, p = 0.001). In contrast, sarcopenia without cachexia was not a significant predictor of cancer outcomes. CONCLUSIONS: To date, this is the first study to investigate the effect of cachexia among sarcopenic patients with UTUC treated with RNU. We identified the prognostic significance of cachexia on outcomes. Indeed, when UTUC is treated with RNU, we should evaluate not only sarcopenia status but also cachexia. The low survival rate among patients with UTUC complicated with cachexia deserves attention.

The Consequences of Inadvertent Radical Nephrectomy in the Treatment of Upper Tract Urothelial Carcinoma.

OBJECTIVE: To determine factors associated with performing inadvertent radical nephrectomy (RN) for upper tract urothelial carcinoma (UTUC), and to assess the impact of radical nephrectomy on overall survival (OS) compared to radical nephroureterectomy (NU). METHODS: Using the National Cancer Database (NCDB), patients with UTUC of the renal pelvis who were diagnosed with renal cortical tumors and underwent RN (n = 820) with subsequent surgical pathology demonstrating urothelial carcinoma were identified. These patients were compared to those diagnosed with renal pelvis tumors who appropriately underwent NU (n = 16,464) between 2005 and 2015. Multivariable logistic regression was used to determine patient, facility and tumor-related factors associated with undergoing RN. The impact of surgery (RN vs NU) on OS was determined by Cox-regression after propensity score matching. RESULTS: A total of 4.7% patients with UTUC underwent inadvertent RN. Black race (adjusted odds ratio [aOR] 1.62, 95%CI 1.23-2.13), larger tumors, advanced tumor stage, and high-grade tumors (P < 0.0001) were associated with RN. However, surgery at a facility performing a higher volume of NU/year was associated with lower odds of having RN performed (aOR 0.85, 95%CI 0.75-0.97). After propensity score matching, the 5-year OS was 39.9% for those undergoing RN vs 49.9% for those undergoing NU (hazard ratio 1.45, 95%CI 1.30-1.62). CONCLUSION: Inadvertent RN is not uncommon, occurring in almost 5% of patients with UTUC in the NCDB. Patients who underwent RN had significantly worse OS as compared to those treated with NU. These data highlight that accurate diagnosis of UTUC is paramount and clinicians should not hesitate to perform further workup when imaging findings are equivocal.

Impact of high-intensity local treatment on overall survival in stage IV upper tract urothelial carcinoma.

OBJECTIVES: To investigate the impact of high-intensity local treatment (LT) on overall survival (OS) in patients with stage IV upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: Within the National Cancer Database, we identified 7,357 patients diagnosed with stage IV UTUC from 2004 to 2015. Patients who underwent high-intensity LT, defined as radical surgery of the primary tumor, were compared with those who did not. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. Weighted survival analyses were used to test the association between high-intensity LT and OS. Multivariable Cox model was used to assess for independent predictors of OS. Sensitivity analysis was used to account for possible biases. RESULTS: Among stage IV patients, 10.6% (n = 779) had locally advanced disease (T4), 32.6% (n = 2,399) had node-positive disease (N+) and 56.8% (N = 4,179) had distant metastases (M+). Fewer than half of the patients underwent high-intensity LT (n = 2,908, 39.5%) while the remainder did not. On IPTW-adjusted survival analysis, high-intensity LT was associated with a prolonged OS (11.17 months [IQR, 5.19 to 24.28] months vs. 6.18 months [IQR, 2.27 to 14.49], P ≤ 0.001). A similar benefit was seen on adjusted survival analyses for each stage IV subgroup, defined according to TNM characteristics. The survival benefit was confirmed at sensitivity analysis. CONCLUSION: High-intensity LT in balanced cohorts of patients with stage IV UTUC is associated with prolonged OS including those with locally advanced (T4), node-positive (N+) or distant metastases (M+).

Higher Cancer Mortality in Rural Upper Urinary Tract Urothelial Carcinoma Patients.

OBJECTIVE: The aim of the study was to investigate differences in the stage at presentation and cancer-specific mortality (CSM) between rural area (RA) and urban area (UA) residence status in nonmetastatic upper urinary tract urothelial carcinoma (UTUC) patients. METHODS: Newly diagnosed T1-3N0M0 UTUC patients with available residence status were abstracted from the Surveillance, Epidemiology, and End Results database (2004-2016). Propensity score (PS) matching (1 RA vs. 3 UA) accounted for age (interval ≤2 years), T stage (exact matching: T1, T2, and T3), and tumor grade (exact matching: high grade, low grade/unknown). Cumulative incidence plots and multivariable competing risk regression models focused on CSM, after adjustment for other-cause mortality. RESULTS: Of 6,012 patients, 125 (2.1%) resided in RAs and 5,887 (97.9%) in UAs. RA patients were younger than UA patients (median age 72 vs. 75 years, p = 0.03). No differences were recorded in tumor location, T stage, tumor grade, or surgical treatment between RA and UA patients. After 1:3 PS matching, 125 RA patients and 375 UA patients were assessable. At 5 years of follow-up, CSM rates were 26.7 versus 15.7% according to RA versus UA, respectively. After additional multivariable adjustment for age, sex, tumor location, and surgical treatment, RA remained an independent predictor of higher CSM (hazard ratio 1.75, p = 0.02). CONCLUSIONS: Despite no differences in cancer characteristics, UTUC patients in RA are at higher risk of CSM than their UA counterparts. This suggests suboptimal care delivery and compliance as possible causes. Complex and/or rare disease should be centralized to expert centers, which are often in UAs.