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Purpose: Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene, whose role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC., Methods: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy for high-grade UTUC from 1990 to 2008. Immunohistochemistry for EZH2 was performed on tissue microarrays. Percentage of staining was evaluated, and the discriminative value of EZH2 was tested, with EZH2 positivity defined as>20% staining present. Clinicopathologic characteristics and oncologic outcomes (recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)) were compared, stratified by EZH2 positivity. The prognostic role of EZH2 was assessed using Kaplan-Meier, univariate (UVA), and multivariate (MVA) Cox regression analyses. Significance was defined for P<0.05., Results: A total of 376 patients were included for analysis, with median follow-up 36.0 months. Overall, 78 (20.7%) were EZH2-positive. EZH2 expression was more often associated with ureteral location, lymphovascular invasion, sessile architecture, necrosis, and concomitant carcinoma in situ. On UVA, increased EZH2 expression was a significant predictor for inferior RFS (HR 1.63, P = 0.033), CSS (HR 2.03, P = 0.003), and OS (HR 2.11, P<0.001). On MVA EZH2 remained a significant predictor of worse CSS (HR 1.99 [95% CI: 1.21-3.27], P = 0.007) and OS (HR 1.54 [95% CI: 1.06-2.24], P = 0.024), while significance was lost for RFS., Conclusion: Increased EZH2 expression is associated with adverse pathologic features and inferior oncologic outcomes in patients with high-grade UTUC. The role of EZH2 biology in UTUC pathogenesis remains to be further elucidated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: We developed a prognostic nomogram for patients with high grade urothelial carcinoma of the upper urinary tract after extirpative surgery., Materials and Methods: Clinical data were available for 2,926 patients diagnosed with high grade urothelial carcinoma of the upper urinary tract who underwent extirpative surgery. Cox proportional hazard regression models identified independent prognosticators of relapse in the development cohort (838). A backward step-down selection process was applied to achieve the most informative nomogram with the least number of variables. The L2-regularized logistic regression was applied to generate the novel nomogram. Harrell's concordance indices were calculated to estimate the discriminative accuracy of the model. Internal validation processes were performed using bootstrapping, random sampling, tenfold cross-validation, LOOCV, Brier score, information score and F1 score. External validation was performed on an external cohort (2,088). Decision tree analysis was used to develop a risk classification model. Kaplan-Meier curves were applied to estimate the relapse rate for each category., Results: Overall 35.3% and 30.7% of patients experienced relapse in the development and external validation cohort. The final nomogram included age, pT stage, pN stage and architecture. It achieved a discriminative accuracy of 0.71 and 0.76, and the AUC was 0.78 and 0.77 in the development and external validation cohort, respectively. Rigorous testing showed constant results. The 5-year relapse-free survival rates were 88.6%, 68.1%, 40.2% and 12.5% for the patients with low risk, intermediate risk, high risk and very high risk disease, respectively., Conclusions: The current nomogram, consisting of only 4 variables, shows high prognostic accuracy and risk stratification for patients with high grade urothelial carcinoma of the upper urinary tract following extirpative surgery, thereby adding meaningful information for clinical decision making., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We created a prognostic tool for the prediction of oncologic outcomes after radical nephroureterectomy (RNU) for high-grade non-metastatic upper tract urothelial carcinoma (UTUC)., Methods: UTUC collaboration was utilized to include 586 patients who underwent RNU for non-metastatic high-grade UTUC. Survival outcomes were compared according to a score defined based on the sum of the independent prognostic variables., Results: The study included 382 males with a median age 70 years (range 28-97). Independent prognostic factors included: T (t stage), A (architecture), LVI (lympho-vascular invasion) and L (lymphadenectomy). TALL score (1-7) was the sum of T (≤T1 = 1, T2 = 2, T3 = 3 and T4 = 4), A (papillary = 0 and sessile = 1), LVI (absent = 0 and present = 1) and L (lymphadenectomy = 0 and no lymphadenectomy = 1). Five-year disease-free survival (DFS) and cancer-specific survival (CSS) were stratified into four risk categories according to the TALL score: low (TALL 0-2; 86 % DFS and 90 % CSS), intermediate (TALL = 3; 71 % DFS and 75 % CSS), high (TALL = 4; 57 % DFS and 58 % CSS) and very high risk (TALL ≥ 5; 34 % DFS and 38 % CSS) using Kaplan-Meier survival analyses. TALL score was externally validated in a single-center cohort of 85 UTUC patients., Conclusions: We developed a multivariable prognostic tool for the prediction of oncological outcomes after RNU for high-grade UTUC. The score can be used for patient counseling, selection for adjuvant systemic therapies and design of clinical trials.

Objective: Several small single-center studies have reported conflicting results on the prognostic value of survivin expression in upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy. We attempted to validate the prognostic utility of survivin using a large multi-institutional cohort., Material and Methods: Survivin expression was evaluated by immunohistochemistry in tumor tissue from 732 patients with unilateral, sporadic UTUC treated with radical nephroureterectomy between 1990 and 2008 at 7 centers. Survivin expression was considered altered when at least 10% of the tumor cells stained positive. Associations of altered survivin expression with recurrence-free survival (RFS) and cancer-specific survival (CSS) were evaluated using Cox proportional hazards regression models., Results: Altered survivin expression was observed in 288 (39.3%) tumors and was associated with more advanced pathological tumor stages (P<0.001), lymph node metastases (P<0.001), lymphovascular invasion (P<0.001), tumor necrosis (P = 0.027), and tumor architecture (P<0.001). Median follow-up was 35 (16-64) months. There were 191 (25.4%) patients who experienced disease recurrence, and 165 patients (21.9%) died of the disease. In the univariable analysis, altered survivin expression was significantly associated with worse RFS and CSS (each P<0.001); however, altered survivin expression did not achieve independent predictive status on multivariable models (P = 0.24 and P = 0.53). Similarly, survivin was not independently associated with outcomes in subgroup analyses, including patients with high-grade tumors., Conclusions: In UTUC, altered survivin expression is associated with worse clinicopathological features and worse RFS and CSS. However, it does not appear to be independently associated with cancer outcomes when considering standard prognostic factors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC)., Materials and Methods: We performed a multi-institutional review of clinical and pathologic information on patients receiving extirpative surgery for UTUC from 1990 to 2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, phosphorylated-4EBP1, phosphorylated-AKT, PTEN, HIF-1a, raptor, and cyclin D was performed on tissue microarrays from radical nephroureterectomy (RNU) specimens. Prognostic markers were identified and the significance of altered markers was assessed with the Kaplan-Meier analysis and the Cox regression analysis., Results: Six hundred twenty patients were included. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariate analysis, PI3K (odds ratio, 1.28; P = .001) and cyclin D (odds ratio, 3.45; P = .05) were significant predictors of clinical outcomes. Cumulative marker score was defined as low risk (no altered markers or 1 altered marker) or high risk (cyclin D and PI3K altered). Patients with high-risk marker score had a significantly higher proportion of high-grade disease (91% vs 71%; P <.001), non-organ-confined disease (61% vs 33%; P <.001), and lymphovascular invasion (35% vs 20%; P = .001). The Kaplan-Meier analysis demonstrated a significant difference in cancer-specific mortality (CSM) based on the risk groups. On Cox regression multivariate analysis for CSM incorporating non-organ-confined disease, grade, lymphovascular invasion, tumor architecture, and marker score, high-risk biomarker score was an independent predictor of CSM (hazard ratio, 1.5; 95% confidence interval, 1.04-2.3; P = .03)., Conclusion: Alterations in mTOR pathway correlate with established adverse pathologic features and independently predict inferior oncologic outcomes. Incorporation of mTOR-based marker profiles may allow for enhanced patient counseling, risk stratification, and individualized treatment regimens., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with uniformly poor survival. Neoadjuvant chemotherapy may offer a way to improve clinical outcomes. The authors compared the survival rates of patients with UTUC who received neoadjuvant chemotherapy before surgery with the rates among patients who did not., Methods: A retrospective review was conducted of patients with high-risk UTUC who received neoadjuvant chemotherapy followed by surgery from 2004 to 2008 (study group) compared with a matched cohort who underwent initial surgery from 1993 to 2003 (control group). Fisher exact tests, Wilcoxon rank-sum tests, and Kaplan-Meier methods were used. The log-rank test and Cox proportional-hazards models were used to evaluate the association of the 2 outcomes with patient, treatment, and tumor characteristics in univariate and multivariate models., Results: Of 112 patients, there were 31 in the study group and 81 in the control group. Patients who received neoadjuvant chemotherapy had improved overall survival (OS) and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year OS rate of 80.2% versus DSS and OS rates of 57.6% for those who underwent initial surgery (P = .0204 and P = .0015, respectively). In multivariate analyses, the neoadjuvant group had a lower risk of mortality (OS: hazard ratio, 0.42 [P = .035]; DSS: hazard ratio, 0.19 [P = .006])., Conclusions: Neoadjuvant chemotherapy improved the survival of patients with UTUC compared with a matched historic cohort of patients who underwent initial surgery. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy in view of the limited opportunity to administer effective cisplatin-based chemotherapy after nephroureterectomy., (© 2014 American Cancer Society.)

Purpose: To report the outcomes of patients with pathologic T4 UTUC and investigate the potential impact of peri-operative chemotherapy combined with radical nephroureterectomy (RNU) and regional lymph node dissection (LND) on oncologic outcomes., Materials and Methods: Patients with pathologic T4 UTUC were identified from the cohort of 1464 patients treated with RNU at 13 academic centers between 1987 and 2007. Oncologic outcomes were stratified according to utilization of perioperative systemic chemotherapy and regional LND as an adjunct to RNU., Results: The study included 69 patients, 42 males (61%) with median age 73 (range 43-98). Median follow-up was 17 months (range: 6-88). Lymphovascular invasion was found in 47 (68%) and regional lymph node metastases were found in 31 (45%). Peri-operative chemotherapy was utilized in 29 (42%) patients. Patients treated with peri-operative chemotherapy and RNU with LND demonstrated superior oncologic outcomes compared to those not treated by chemotherapy and/or LND during RNU (3Y-DFS: 35% vs. 10%; P = 0.02 and 3Y-CSS: 28% vs. 14%; P = 0.08). In multivariate Cox regression analysis, administration of peri-operative chemotherapy and utilization of LND during RNU was associated with lower probability of recurrence (HR: 0.4, P = 0.01), and cancer specific mortality (HR: 0.5, P = 0.06)., Conclusions: Pathological T4 UTUC is associated with poor prognosis. Peri-operative chemotherapy combined with aggressive surgery, including lymph node dissection, may improve oncological outcomes. Our findings support the use of aggressive multimodal treatment in patients with advanced UTUC.

Objective: The natural history of urothelial carcinoma arising at the uretero-enteric junction (UEJ) is poorly defined, and the data guiding clinical management of these patients is limited. Therefore, we evaluated oncologic outcomes of patients treated for urothelial carcinoma at the UEJ., Methods: Utilizing a multi-institutional database of patients treated with radical nephroureterectomy (RNU), we assessed the clinicopathologic parameters and oncologic outcomes of UEJ tumors compared with other upper tract urothelial carcinomas (UTUC). Survival analyses were performed to determine independent predictors of disease recurrence and cancer-specific mortality after RNU., Results: The study included 1,363 patients, 921 men and 442 women with 36 months median follow-up after RNU. Compared with UTUC in the kidney or ureter, UEJ tumors (n = 22) were more likely to demonstrate features of advanced disease, which were proved to be independent predictors of disease recurrence and cancer-specific mortality after RNU. The 5 year disease-free survival (DFS) and cancer-specific survival (CSS) rates were 25% and 39% in those with UEJ tumors vs. 69% and 73% in those with UTUC in the kidney or ureter (P = 0.001 and P = 0.008, respectively)., Conclusions: UEJ tumors harbor features of locally advanced disease associated with high risk of systemic recurrence and death from cancer after RNU. Our findings suggest the need for integration of systemic therapy into the management paradigm of these patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Context: The heterogeneity of upper tract urothelial carcinoma (UTUC) biology and prognosis, as well as the presence of different treatment options, makes the clinical decision-making process extremely challenging., Objective: Provide an overview of the currently available prognostic factors for UTUC, focusing on clinical and pathologic characteristics, as well as on molecular markers., Evidence Acquisition: A systematic literature search was conducted using the PubMed, Scopus, and Embase databases to identify original articles, review articles, and editorials regarding prognostic factors in patients with UTUC. Keywords included urothelial carcinoma, renal pelvis, ureter, upper urinary tract urothelial carcinoma, upper urinary tract transitional cell carcinoma, prognosis, prognostic factors, markers, and survival. Articles published between 2000 and 2011 were reviewed and selected with the consensus of all the authors., Evidence Synthesis: Prognostic factors can be divided into four different categories: preoperative/clinical factors, intraoperative/surgical factors, postoperative/pathologic factors, and molecular markers. Because of the rarity of the disease, only a small amount of level 1 evidence information from prospective randomized trials is available. Conversely, several single-institutional and multi-institutional studies have been published providing level 3 evidence information on various prognostic factors. Tumor stage and grade represent the best-established predictors of prognosis in patients with UTUC, but controversies still exist regarding the prognostic impact of tumor location and tumor necrosis. Several promising biomarkers have also been evaluated, but further studies evaluating their prognostic role are still needed. Finally, few prognostic models have been developed to provide clinicians with accurate estimates of the outcome of interest., Conclusions: In the past few years, several prognostic factors have been identified to help clinicians dealing with patients with UTUC in the decision-making process. However, well-designed multi-institutional studies are still needed to provide stronger evidence and to promote the use of these prognostic factors in clinical practice., (Copyright © 2012 European Association of Urology. All rights reserved.)

Background: Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described., Objective: We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU., Design, Setting, and Participants: Our study included 2244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant carcinoma in situ (CIS). The cohort was randomly split for development (12 centers, n=1273) and external validation (11 centers, n=971)., Interventions: All patients underwent RNU., Measurements: Univariable and multivariable models addressed RFS, CSS, and comparison of discrimination and calibration with American Joint Committee on Cancer (AJCC) stage grouping., Results and Limitations: At a median follow-up of 45 mo, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p for trend <0.001), lymph node metastasis (hazard ratio [HR]: 1.98; p=0.002), lymphovascular invasion (HR: 1.66; p<0.001), sessile tumor architecture (HR: 1.76; p<0.001), and concomitant CIS (HR: 1.33; p=0.035) were associated with disease recurrence. Similarly, T classification (p for trend<0.001), lymph node metastasis (HR: 2.23; p=0.001), lymphovascular invasion (HR: 1.81; p<0.001), and sessile tumor architecture (HR: 1.72; p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination., Conclusions: Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be used for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: • To describe a multicentre experience with preoperative platinum-based chemotherapy before radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) with loco-regional nodal metastases., Patients and Methods: • We identified 313 patients from the UTUC Collaboration (over 1200 patients), who underwent RNU with concomitant retroperitoneal lymph node dissection between 1990 and 2007 and met the inclusion criteria for one of three groups. • Group 1 comprised patients who received chemotherapy before RNU because of biopsy-proven loco-regional nodal metastases. • Group 2 consisted of patients who underwent primary RNU and were found to have metastatic nodal disease on final pathological review (node-positive). • Group 3 comprised a comparative cohort of patients treated with primary RNU for invasive or locally advanced (pT2/pT4) node-negative (N0) UTUC., Results: • Groups 1, 2 and 3 included 18, 120 and 175 patients, respectively. The 5-year disease-free survival rates were 49%, 30% and 64%, whereas the 5-year cancer-specific survival rates were 44%, 36% and 69% in groups 1, 2 and 3, respectively. • In group 1, on final pathological evaluation, nine patients were pN0, six patients were pT0 and five patients had pT0N0 disease. Kaplan-Meier survival analyses showed similar recurrence and survival rates in group 1 compared with group 3 (P= 0.14 and P= 0.06, respectively). • Meanwhile, group 2 had significantly lower disease-free and cancer-specific survival rates compared with group 3 (P < 0.001 and P < 0.001, respectively) and compared with group 1 (P= 0.04 and P= 0.06, respectively)., Conclusions: • Preoperative chemotherapy followed by aggressive surgical consolidation may yield favourable oncological outcomes in patients with UTUC with loco-regional nodal metastases. • These data support further evaluation of neoadjuvant systemic therapy in patients at risk for locally advanced UTUC., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Abstract We investigated whether a history of endoscopic tumor ablation impacts oncologic outcomes after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). Using a multi-institutional database that contained patients who were treated with RNU, oncologic outcomes were assessed according to history of ureteroscopic tumor ablation. Disease-free survival (DFS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier survival analysis. Multivariate Cox regression analyses were performed to determine independent predictors of disease recurrence and cancer-specific mortality after RNU. The study included 1268 patients, 853 men and 415 women, with a mean age of 67.5 years (range 32-94 y) and 52.8 months median follow-up after RNU. A total of 175 (13%) patients underwent RNU after endoscopic tumor ablation and 1093 (87%) patients underwent RNU without a history of endoscopic ablation. The 5-year DFS and CSS rates were 72% and 77% in those with a history of tumor ablation vs 69% and 73% in those without a history of ablation (P = 0.171 and P = 0.365, respectively). In multivariate Cox regression analysis, history of ablation therapy was not associated with disease recurrence or cancer-specific mortality (hazard ratio [HR]: 0.79, P = 0.185 and HR: 0.7, P = 0.078, respectively). Our collaborative international efforts suggest that in selected patients, endoscopic tumor ablation does not adversely affect the recurrence and survival after subsequent RNU for UTUC. Our data support the continued role of ureteroscopic ablation of UTUC in appropriately selected patients.

Objectives: To evaluate the effect of a history of bladder carcinoma in situ (CIS) on relapse and survival after surgical management of metachronous upper tract urothelial carcinoma (UTUC). Urinary bladder CIS was previously reported to be among the independent risk factors for the development of UTUC., Methods: Using a multi-institutional database of patients treated with radical nephroureterectomy (RNU) for UTUC, we compared the clinicopathologic parameters and clinical outcomes of patients with and without a history of bladder CIS. Multivariate Cox regression analysis was performed to determine the independent predictors of disease recurrence and cancer-specific mortality after RNU., Results: The study included 1316 patients, 884 men and 432 women, with median follow-up of 36 months after RNU. The patients with a history of bladder CIS (n = 91) were more likely to have high-grade and sessile UTUC (P < .05). The 5 year disease-free survival and cancer-specific survival rate was 53% and 59% in those with a history of bladder CIS and 71% and 75% in those without a history of bladder CIS, respectively (P = .031 and P = .045, respectively). On multivariate Cox regression analysis, a history of bladder CIS was an independent predictor of disease recurrence and cancer-specific mortality after RNU (P = .006 and P = .045, respectively)., Conclusions: The results of our study have shown that patients with a history of bladder CIS are more likely to develop aggressive UTUC and demonstrate a greater risk of recurrence and death from cancer after RNU. Our findings suggest the need for aggressive surveillance regimens and multimodal management strategies for patients who develop UTUC in the setting of previous bladder CIS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To assess the impact of patient age on outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC)., Patients and Methods: Data were collected on 1453 patients treated with RNU at 13 centres. Pathological slides were reviewed by dedicated genitourinary pathologists according to standardized criteria. Age at RNU was analysed both as a continuous and categorical variable (<50, n = 85; 50-59.9, n = 229; 60-69.9, n = 416; 70-79.9, n = 523; > or =80 years, n = 200). RESULTS Patients aged <50 years were less likely to have undergone previous ureteroscopy and to have a history of bladder cancer (P < or = 0.026). Advanced age was associated with infiltrative architecture and female gender (P < or = 0.003). Patients aged >70 years were less likely to undergo lymphadenectomy and to receive adjuvant chemotherapy (P < or = 0.026). In multivariable analyses, being older was associated with decreased all-cause (AC) survival (>60 years) and cancer-specific survival (CSS; >80 years) after controlling for the effects of standard pathological features (P < or = 0.006). However, addition of age did not improve the predictive accuracy of a base model that included standard pathological features for prediction of either disease recurrence, AC survival or CSS., Conclusions: Being older at the time of RNU was associated with decreased survival. This finding could be due to a change in the biological potential of the tumour cell, a decrease in the host's defence mechanisms, or differences in care patterns. Further work is needed to improve our understanding of UTUC outcomes in this growing segment of the population and to develop strategies to improve cancer control in the elderly.

Background: The literature on upper tract urothelial carcinoma (UTUC) has been limited to small, single center studies. A large series of patients treated with radical nephroureterectomy for UTUC were studied, and variables associated with poor prognosis were identified., Methods: Data on 1363 patients treated with radical nephroureterectomy at 12 academic centers were collected. All pathologic slides were re-reviewed by genitourinary pathologists according to strict criteria., Results: Pathologic review revealed renal pelvis location (64%), necrosis (21.6%), lymphovascular invasion (LVI) (24.8%), concomitant carcinoma in situ (28.7%), and high-grade disease (63.7%). A total of 590 patients (43.3%) underwent concurrent, lymphadenectomy and 135 (9.9%) were lymph node (LN) -positive. Over a mean follow-up of 51 months, 379 (28%) patients experienced disease recurrence outside of the bladder and 313 (23%) died of UTUC. The 5-year recurrence-free and cancer-specific survival probabilities (+/-SD) were 69%+/-1% and 73%+/-1%, respectively. On multivariate analysis, high tumor grade (hazards ratio [HR]: 2.0, P<.001), advancing pathologic T stage (P-for-trend<.001), LN metastases (HR: 1.8, P<.001), infiltrative growth pattern (HR: 1.5, P<.001), and LVI (HR: 1.2, P=.041) were associated with disease recurrence. Similarly, patient age (HR: 1.1, P=.001), high tumor grade (HR: 1.7, P=.001), increasing pathologic T stage (P-for-trend<.001), LN metastases (HR: 1.7, P<.001), sessile architecture (HR: 1.5, P=.002), and LVI (HR: 1.4, P=.02) were independently associated with cancer-specific survival., Conclusions: Radical nephroureterectomy provided durable local control and cancer-specific survival in patients with localized UTUC. Pathologic tumor grade, T stage, LN status, tumor architecture, and LVI were important prognostic variables associated with oncologic outcomes, which could potentially be used to select patients for adjuvant systemic therapy., (Copyright (c) 2009 American Cancer Society.)

Purpose: To assess the association of lymphovascular invasion (LVI) with cancer recurrence and survival in a large international series of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC)., Patients and Methods: Data were collected on 1,453 patients treated with RNU at 13 academic centers and combined into a relational database. Pathologic slides were rereviewed by genitourinary pathologists according to strict criteria. LVI was defined as presence of tumor cells within an endothelium-lined space., Results: LVI was observed in 349 patients (24%). Proportion of LVI increased with advancing tumor stage, high tumor grade, presence of tumor necrosis, sessile tumor architecture, and presence of lymph node metastasis (all P < .001). LVI was an independent predictor of disease recurrence and survival (P < .001 for both). Addition of LVI to the base model (comprising pathologic stage, grade, and lymph node status) marginally improved its predictive accuracy for both disease recurrence and survival (1.1%, P = .03; and 1.7%, P < .001, respectively). In patients with negative lymph nodes and those in whom a lymphadenectomy was not performed (n = 1,313), addition of LVI to the base model improved the predictive accuracy of the base model for both disease recurrence and survival by 3% (P < .001 for both). In contrast, LVI was not associated with disease recurrence or survival in node-positive patients (n = 140)., Conclusion: LVI was an independent predictor of clinical outcomes in nonmetastatic patients who underwent RNU for UTUC. Assessment of LVI may help identify patients who could benefit from multimodal therapy after RNU. After confirmation, LVI should be included in staging of UTUC.

Objective: To assess whether tumour architecture can help to refine the prognosis of patients treated with nephroureterectomy (NU) for urothelial carcinoma (UC) of the upper urinary tract (UT), as the prognostic value of tumour architecture (papillary vs sessile) in UTUC remains elusive., Patients and Methods: The study included 1363 patients with UTUC and treated with radical NU at 12 centres worldwide. All slides were re-reviewed according to strict criteria by genitourinary pathologists who were unaware of the findings of the original pathology slides and clinical outcomes. Gross tumour architecture was categorized as sessile vs papillary., Results: Papillary growth was identified in 983 patients (72.2%) and sessile growth in 380 (27.8%). The sessile growth pattern was associated with higher tumour grade, more advanced stage, lymphovascular invasion, and metastasis to lymph nodes (all P < 0.001). In multivariable Cox regression analyses that adjusted for the effects of pathological stage, grade and lymph node status, tumour architecture (sessile or papillary) was an independent predictor of cancer recurrence (hazard ratio 1.5, P = 0.002) and cancer-specific mortality (1.6, P = 0.001). Adding tumour architecture increased the predictive accuracy of a model that comprised pathological stage, grade and lymph node status for predicting cancer recurrence and cancer-specific death by a minimal but statistically significant margin (gain in predictive accuracy 1% and 0.5%, both P < 0.001)., Conclusion: The tumour architecture of UTUC is associated with established features of biologically aggressive disease, and more importantly, with prognosis after radical NU. Including tumour architecture in predictive models for disease progression should be considered, aiming to identify patients who might benefit from early systemic therapeutic intervention.

Objective: To determine the risk factors associated with clinical outcome in patients with lymph node (LN)-positive urothelial carcinoma of the upper urinary tract (UTUC) treated with radical nephroureterectomy (RNU) and lymphadenectomy, focusing on the concept of LN density (LND)., Patients and Methods: Patients undergoing RNU with regional lymphadenectomy were identified through multi-institutional databases. All pathology slides were re-evaluated by genitourinary pathologists unaware of the clinical data. The exposure variable used was LND (continuously coded and that of all possible thresholds) with recurrence-free and disease-specific survival (DSS) serving as the outcome measures., Results: Of 432 patients undergoing RNU with lymphadenectomy, 135 (31%) had LN metastases. Within a median follow-up of 4.1 years, 90 of the 135 patients with LN metastases (68%) had disease recurrence and 76 (58%) died from UTUC. The mean (sem) 5-year recurrence-free and DSS probabilities were 27 (4)% and 33 (5)%, respectively. The median (range) LND was 50 (3-100)%. The most informative threshold for LND in relation to outcome was 30%. In multivariable analyses that adjusted for the effects of tumour stage and grade, patients with a LND of > or =30% were at greater risk of both cancer recurrence, with 5-year rates of 25 (5)% vs 38 (8)% (hazard ratio 1.8, P = 0.021) and mortality, with 5-year rates of 30 (6)% vs 48 (9)% (1.7, P = 0.032) compared to those with a LND of <30%. Our results are primarily limited by a lack of standardization in the lymphadenectomy template., Conclusion: We evaluated the concept of LND for the first time in UTUC. LND provides additional prognostic information in patients with node-positive disease after RNU. The use of LND in clinical trials might provide an additional insight into the value of LN dissection in patients undergoing RNU.

We report two cases of transitional cell carcinoma of the urinary tract that consist of optically clear cells rich in glycogen. We propose that transitional cell carcinoma may exhibit a clear cell morphologic variant that should be distinguished from clear cell adenocarcinoma.