Concomitant carcinoma in situ as a prognostic factor in the upper tract urothelial carcinoma after radical nephroureterectomy: A systematic review and meta-analysis

PurposeSome excised specimens of upper tract urothelial carcinoma (UTUC) are concomitant carcinoma in situ (CIS). However, whether concomitant CIS affects the prognosis of UTUC is controversial. The objective of this study was to provide a comprehensive association between CIS and the prognosis of UTUC.Materials and methodsWeb of Science, PubMed, and Embase were searched to identify clinical studies about CIS and UTUC before July 2019. Newcastle Ottawa Scale was used to evaluate the quality of the literature. We calculated hazard ratios (HRs) and 95% CIs to evaluate the relationship between concomitant CIS and survival outcomes. Z test was used to pooled HRs, if P < 0.05, the difference was considered statistically significant.ResultsTotal of 7,852 patients with UTUC were included, of which 1,004 (12.79%) concomitant CIS. In univariate analysis, our meta-analysis shows that concomitant CIS is associated with worse cancer-specific survival (HR: 1.54; P < 0.00001), worse recurrence-free survival (RFS) (HR: 1.42; P < 0.00001) and worse overall survival (OS; HR: 1.41; P = 0.04). In multivariate analysis, concomitant CIS is associated with worse cancer-specific survival (HR: 1.25; P = 0.004), worse recurrence-free survival (HR: 1.24; P = 0.006), and worse OS (HR: 1.12; P = 0.25), however, there was no statistical difference in the effect of CIS on OS (P > 0.05).ConclusionsOur meta-analysis shows that concomitant CIS is associated with worse survival outcomes in UTUC after radical nephroureterectomy. CIS is an independent prognostic risk factor in UTUC.     

Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients

Purpose

The purpose of this study is to assess the association of concomitant carcinoma in situ (CIS) with disease recurrence and cancer-related death in a multi-institutional series of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

Methods

We collected retrospectively the data of 772 patients treated with RNU and ipsilateral bladder cuff excision at 9 international institutions in Asia, Europe, and Northern America from 1987 to 2008. Surgical specimens were processed according to standard pathologic procedures at each institution. Univariable and multivariable Cox regression models addressed time to recurrence and cancer-specific mortality.

Results

Concomitant CIS was present in 88 patients (11.4%); it was associated with more advanced pathologic stage, higher tumor grade, and presence of lymphovascular invasion (all P-values?P-values?P?=?0.007) and CSS (HR: 1.7, P?=?0.048). Similar findings were reconfirmed in subgroups analyses limited to T2, organ confined, and N0/Nx UTUC, or patients who did not receive adjuvant chemotherapy.

Conclusions

Presence of concomitant CIS is an independent predictor of both RFS and CSS in patients treated with RNU for UTUC. This information may be useful in risk stratification of UTUC patients for follow-up and additional therapy.     

Influence of late-stage chronic kidney disease on overall survival in patients with upper tract urothelial carcinoma following radical nephroureterectomy

ObjectivesThe prevalence of both chronic kidney disease (CKD) and upper tract urothelial carcinoma (UTUC) in Taiwan is unusually high, and we aimed to investigate the impact of preoperative renal function on UTUC after radical nephroureterectomy.Materials and methodsBetween 2000 and 2013, 248 UTUC patients were enrolled in this retrospective study after excluding patients who had concomitant muscle-invasive bladder cancer, whose tumor metastasized at initial presentation, and who received perioperative chemotherapy or radiotherapy. The significance of CKD on overall survival (OS), cancer-specific survival (CSS), and bladder recurrence-free survival (BRFS) was evaluated by Cox proportional hazard model.ResultsThe median follow-up time was 45.41 months. Overall 5-year OS, CSS, and BRFS rates were 78.27%, 87.81%, and 70.42%, respectively. Aging, late-stage CKD, and nonorgan-confined primary tumor stage were independent predictors for OS after adjustment. Nonorgan-confined primary tumor stage and lymph node involvement were two independent predictors for CSS after adjustment. Concomitant bladder tumor was the only significant predictor for BRFS after adjustment.ConclusionPatients with late-stage CKD had a higher risk of having poor OS. Patients with concomitant bladder tumor had a greater risk of having bladder cancer recurrence despite primary tumor stage. Concomitant bladder tumor, however, had no effect on OS and CSS in this study.     

Prognostic significance of non-muscle-invasive bladder tumor history in patients with upper urinary tract urothelial carcinoma

ObjectiveTo evaluate the prognostic factors for survival and disease recurrence in patients treated surgically for upper tract urothelial carcinoma (UTUC), focusing especially on the impact of history of non-muscle-invasive bladder cancer.Patients and methodsA single-center series of 221 consecutive patients who were treated surgically for UTUC between January 1999 and December 2010 was evaluated. Patients who had a history of bladder tumor at a higher stage than the upper tract disease, preoperative chemotherapy, or previous contralateral UTUC were excluded. None of the patients included in this study had distant metastasis at diagnosis of UTUC. In total, 183 patients (mean age 66 years, range 36–88) were then available for evaluation. Tumor multifocality was defined as the synchronous presence of 2 or more pathologically confirmed tumors in any upper urinary tract location (renal pelvis or ureter). All patients were treated with either open radical nephroureterectomy (RNU) or open conservative surgery. Recurrence-free probabilities and cancer-specific survival were estimated using the Kaplan-Meier method and Cox regression analyses.ResultsFifty-one patients (28%) had previous carcinoma not invading bladder muscle. Previous history of non-muscle-invasive bladder cancer was significantly associated with tumor multifocality (P < 0.001), concomitant bladder cancer (P < 0.001), higher tumor stage (P = 0.020), and lymphovascular invasion (P = 0.026). Using univariate analyses, history of non-muscle-invasive bladder cancer was significantly associated with an increased risk of both any recurrence (HR = 2.17; P = 0.003) and bladder-only recurrence (HR = 3.17; P = 0.001). Previous carcinoma not invading bladder muscle (HR = 2.58; P = 0.042) was an independent predictor of bladder-only recurrence. Overall 5-year disease recurrence-free (any recurrence and bladder-only recurrence) survival rates were 66.7% and 77%, respectively. Previous history of non-muscle-invasive bladder cancer was not associated with cancer-specific survival. Our results are subject to the inherent biases associated with high-volume tertiary care centers.ConclusionsPatients with previous history of non-muscle-invasive bladder cancer had a higher risk of having multifocal and UTUC with higher tumor stages (pT3 or greater). History of bladder tumor was an independent predictor of bladder cancer recurrence but had no effect on non-bladder recurrence, and cancer-specific survival in patients who underwent surgical treatment of UTUC.     

Degree of hydronephrosis predicts adverse pathological features and worse oncologic outcomes in patients with high-grade urothelial carcinoma of the upper urinary tract

ObjectiveTo evaluate degree of hydronephrosis (HN) as a surrogate for adverse pathological features and oncologic outcomes in patients with high-grade (HG) and low-grade (LG) upper tract urothelial carcinomas (UTUCs).MethodsWe retrospectively reviewed 141 patients with localized UTUCs that underwent extirpative surgery at a tertiary referral center. Preoperative imaging was used to evaluate presence and degree of ipsilateral HN. We evaluated degree of HN (none/mild vs. moderate/severe), pathological findings, and oncologic outcomes.ResultsHG UTUC was present in 113 (80%) patients, muscle-invasive disease (≥pT2) in 49 (35%), and non–organ-confined disease (≥pT3) in 41 (29%). At a median follow-up of 34 months, 49 (35%) patients experienced intravesical recurrence, 28 (20%) developed local/systemic recurrence, and 24 (17%) died of UTUC. HN was graded as none/mild in 77 (55%) patients and moderate/severe in 64 (45%). In patients with HG UTUC, but not LG, degree of HN was associated with advanced pathological stage (P<0.001), positive lymph nodes (P = 0.01), local/systemic recurrence-free survival (hazard ratio [HR] = 5.5, P = 0.02), and cancer-specific survival (HR = 5.2, P = 0.02). On multivariable analysis of preoperative factors, degree of HN in patients with HG UTUC was associated with muscle invasion (HR = 9.3; 95% CI: 3.08–28.32; P<0.001), non–organ-confined disease (HR = 4.5; 95% CI: 1.66–12.06; P = 0.003), local/systemic recurrence-free survival (HR = 2.5; 95% CI: 1.07–5.64; P = 0.04), and cancer-specific survival (HR = 2.6; 95% CI: 1.05–6.22; P = 0.04).ConclusionsDegree of HN can serve as a surrogate for advanced disease and predict worse oncologic outcomes in HG UTUC. Degree of HN was not predictive of intravesical or local/systemic recurrence in LG UTUC.     

Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma

Purpose

Women have been associated with adverse outcomes after radical cystectomy for lower tract urothelial carcinoma. We evaluated the prognostic value of gender in an international cohort of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

Methods

We retrospectively studied 754 patients treated with RNU for UTUC without neoadjuvant chemotherapy at nine centers located in Asia, Canada, and Europe. Univariable and multivariable Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. Median follow-up was 40?months (interquartile range: 18?C75).

Results

The majority of patients was of men (516, 68.4%). Women were older than men at the time of RNU (median: 69.2 vs. 66.5?years; P?=?0.0003). Women were less likely to have high-grade disease, undergo lymph node dissection, and to receive adjuvant chemotherapy. Gender was not associated with pathologic stage, lymph node metastasis, lymphovascular invasion, concomitant CIS, tumor architecture, or tumor necrosis. On univariable Cox regression analyses, there was no association between gender and cancer recurrence (P?=?0.76) or cancer-specific mortality (P?=?0.30). On multivariable Cox regression analyses that adjusted for the effects of clinicopathologic features, gender was not associated with disease recurrence (P?=?0.47) or cancer-specific survival (P?=?0.15).

Conclusions

We found no difference in histopathologic features and outcomes between men and women treated with RNU for UTUC. Nevertheless, epidemiologic and mechanistic molecular studies should be encouraged to design, analyze, and report gender-specific associations to aid in our understanding of gender impact on UTUC incidence, progression, and metastasis.     

Effect of concomitant variant histology on the prognosis of patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy

ObjectiveTo evaluate the prognostic effect of concomitant variant histology (CVH) on survival outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) after radical nephroureterectomy.Materials and methodsData on 417 patients with UTUC treated with radical nephroureterectomy without preoperative adjuvant therapy were retrospectively reviewed with a focus on CVH. Clinicopathological features and prognostic factors were compared between patients with pure UTUC and patients with UTUC with CVH. The primary end points were cancer-specific survival (CSS), disease recurrence-free survival (DFS), and overall survival (OS).ResultsUTUC with CVH was present in 90 (21.6%) of 417 patients. At a median follow-up of 26 months, 153 (36.7%) had died of UTUC, 161 (38.6%) had experienced a relapse, and 176 (42.2%) had died of other causes. UTUC with CVH was significantly associated with advanced tumor stage, high tumor grade, tumor diameter, lymphovascular invasion, lymph node metastasis, positive surgical margins, and tumor architecture compared with pure UTUC (all P<0.01). The estimated 5-year CSS, DFS, and OS rates were 64.9%, 61.1%, and 62.1%, respectively, in the pure UTUC group, compared with 36.3%, 34.3%, and 26.5%, respectively, in the UTUC with CVH group (P<0.001). Multivariate analysis demonstrated that CVH was an independent predictor of CSS (hazard ratio [HR] = 1.594; 95% CI: 1.125–2.259; P = 0.009), DFS (HR = 1.549; 95% CI: 1.077–2.152; P = 0.017), and OS (HR = 1.685; 95% CI: 1.212–2.343; P = 0.002).ConclusionsApproximately one-fifth of the specimens of patients with UTUC were observed to exhibit CVH. CVH was an independent prognostic factor for CSS, DFS, and OS in patients with UTUC on both univariate and multivariate analyses. Genitourinary pathologists should look for potential CVH components in UTUC specimens and report this in routine pathological practice. The presence of CVH should identify patients as candidates for consultation regarding early adjuvant therapy and intensive surveillance protocols.     

C-reactive protein: A biomarker of survival in patients with localized upper tract urothelial carcinoma treated with radical nephroureterectomy

Background and objectiveSerum C-reactive protein (CRP) is one particular marker of systemic inflammation, and an elevated CRP level is associated with poor outcome in various malignancies. While the clinical value of CRP levels in upper tract urothelial carcinoma (UTUC) has not yet been fully evaluated, we investigated the impact of CRP elevation as a biomarker of patient prognosis in UTUC.Materials and methodsA total of 183 patients who underwent radical nephroureterectomy (RNU) for localized UTUC (pTa-4N0M0) were identified between 1993 and 2009. The associations between the levels of serum CRP and patient outcome were analyzed.ResultsThirty-three patients experienced disease recurrence, and 28 died of the disease during the median follow-up period of 39 months. Using the defined cutoff level of CRP >0.5 mg/dl as elevated, preoperative CRP (pre-CRP) levels were elevated in 42 patients (23.0%). Kaplan-Meier curves revealed that subsequent tumor recurrences and worse cancer-specific survival could be significantly predicted in the elevated pre-CRP group. The 5-year recurrence-free survival rate was 63.6% in the elevated pre-CRP group and 83.4% in their counterparts (P < 0.001), and the 5-year cancer-specific survival rate was 64.7% in the elevated pre-CRP group and 84.3% in their counterparts (P = 0.001). Multivariate analysis revealed that elevated pre-CRP, in addition to pathologic T stage, was an independent risk factor for subsequent disease recurrence (P = 0.003, hazard ration (HR) = 2.83), and the decrease in cancer-specific survival (P = 0.012, HR = 2.65). In subgroup analysis using patients with pT3 tumors or greater, multivariate analysis also showed that elevated pre-CRP was an independent risk factor for a decrease in both recurrence-free and cancer-specific survival.ConclusionsPre-CRP level was an independent predictor of patient survival in localized advanced UTUC. Patients with pre-CRP >0.5 mg/dl were strongly predicted to have worse prognostic outcomes following RNU. Due to its low cost and easy accessibility, CRP may be a useful biomarker for localized UTUC.     

Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma

ObjectiveMacroscopic sessile tumor architecture was associated with adverse outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Before inclusion in daily clinical decision-making, the prognostic value of tumor architecture needs to be validated in an independent, external dataset. We tested whether macroscopic tumor architecture improves outcome prediction in an international cohort of patients.Material and methodsWe retrospectively studied 754 patients treated with RNU for UTUC without neoadjuvant chemotherapy at 9 centers located in Asia, Canada, and Europe. Tumor architecture was macroscopically categorized as either papillary or sessile. Univariable and multivariable Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates.ResultsMacroscopic sessile architecture was present in 20% of the patients. Its prevalence increased with advancing pathologic stage and it was significantly associated with established features of biologically aggressive UTUC, such as tumor grade, lymph node metastasis, lymphovascular invasion, and concomitant CIS (all P values < 0.02). The median follow-up for patients who were alive at last follow-up was 40 months (IQR: 18–75 months, range: 1–271 months). Two-year RFS and CSS for tumors with papillary architecture were 85% and 90%, compared with 58% and 66% for those with macroscopic sessile architecture, respectively (P values < 0.0001). On multivariable Cox regression analyses, macroscopic sessile architecture was an independent predictor of both RFS (hazard ratio {HR}: 1.5; P = 0.036) and CSS (HR: 1.5; P = 0.03).ConclusionWe confirmed the independent prognostic value of macroscopic tumor architecture in a large, independent, multicenter UTUC cohort. It should be reported in every pathology report and included in post-RNU predictive models in order to refine current clinical decision making regarding follow-up protocol and adjuvant therapy.     

Does preoperative symptom classification impact prognosis in patients with clinically localized upper-tract urothelial carcinoma managed by radical nephroureterectomy?

ObjectivesTo evaluate if preoperative symptom classification could refine prediction of outcomes for patients with clinically localized upper-tract urothelial carcinoma (UTUC) managed by radical nephroureterectomy (RNU).MethodsData on 654 patients with localized UTUC who underwent RNU were reviewed. Preoperative symptoms were classified as incidental (S1), local (S2), and systemic (S3). Clinical and pathologic data were compared between the cohorts. Kaplan-Meier analyses and Cox proportional hazard modeling were used to determine recurrence-free and cancer-specific survival amongst the symptom cohorts.ResultsSymptom classification was S1 in 213 (33%) patients, S2 in 402 (61%), and S3 in 39 (6%). S3 symptoms were associated with advanced pathology, including higher stage, grade, and lymph node (LN) positivity. Five and 10-year recurrence-free and cancer-specific survival estimates were similar for patients with S1 and S2 symptoms (P = 0.75 and 0.58, respectively), but was worse for patients with S3 symptoms (P < 0.001 for both). On multivariate analysis adjusting for final pathologic stage, grade, and LN status, S3 symptoms were not an independent predictor of recurrence (HR 1.44, P = 0.19) or death due to disease (HR 1.66, P = 0.07). Addition of symptom classification, however, increased the accuracy of a model consisting of stage, grade, and LNs for prediction of recurrence-free and cancer-specific survival by 1.4% and 1.3%, respectively (P < 0.001 for both).ConclusionsLocal symptoms do not confer worse prognosis compared with patients with incidentally detected UTUC. However, systemic symptoms are associated with worse outcomes despite apparently effective RNU. Patients with systemic symptoms may harbor micrometastatic disease and could potentially benefit from a more rigorous metastatic evaluation or perioperative chemotherapy regimens.     

The expression of urokinase-type plasminogen activator system in upper tract urothelial carcinoma and its prognostic value after radical nephroureterectomy

BackgroundTo evaluate the expression pattern and prognostic role of the urokinase-type plasminogen activator (uPA) system in patients who underwent radical nephroureterectomy (RNU) for nonmetastatic upper tract urothelial carcinoma (UTUC).MethodsA total of 732 patients who were treated with RNU for clinically nonmetastatic UTUC comprised our analytical cohort. Immunohistochemical staining of uPA, uPA receptor (uPAR) and uPA inhibitor (PAI-1) was performed using Murine IgG1 monoclonal antibodies. Outcomes of interest were recurrence-free survival, cancer-specific survival, and overall survival.ResultsThe median age of the patients was 69.8 years and 56.6% of them were males. Overall, overexpression of uPA, uPAR, and PAI-1 was observed in 292 (39.9%), 346 (47.3%), and 345 (47.1%) patients, respectively. The uPA system components showed a statistically significant association with adverse clinicopathologic features such as lymphovascular invasion, multifocality, sessile tumors, and advanced pathologic stage (P < 0.01). On multivariable models, higher pathologic tumor stage, multifocality, and lymph node involvement were associated with RFS, OS, and CSS, but not the overexpression of uPA, uPAR, or PAR-1. In patients with organ-confined disease (≤pT2N0), however, uPA was significantly associated with RFS (hazard ratio [HR]: 2.04, 95% confidence interval [CI]: 1.21–3.43), OS (HR: 1.59, 95% CI:1.08–2.24) and CSS (HR: 2.55, 95% CI:1.44–4.52). uPA improved the predictive accuracy of a standard post-RNU model for all 3 endpoints, in organ-confined disease, by a prognostically significant margin.ConclusionsOverexpression of uPA system components was associated with adverse clinicopathologic characteristics and survival outcomes on the univariable, but not multivariable analyses. uPA expression was an independent predictor of survival outcomes in patients with organ-confined disease. While the clinical value of the uPA system remains limited in this cohort, further studies are needed to identify a marker or constellation of markers of high predictive value to help in counseling and treatment planning of UTUC patients.     

Urothelial carcinoma at the uretero-enteric junction: Multi-center evaluation of oncologic outcomes after radical nephroureterectomy

ObjectiveThe 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.MethodsUtilizing 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.ResultsThe 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).ConclusionsUEJ 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.     

Incidence,characteristics, treatment strategies,and oncologic outcomes of synchronous bilateral upper tract urothelial carcinoma in the Chinese population

ObjectivesTo investigate the incidence and treatment strategies for bilateral upper tract urothelial carcinoma (UTUC) and to compare the characteristic and oncologic outcomes of bilateral UTUC with those of unilateral tumors.Methods and materialsThe study included 892 consecutive patients with UTUC. Bilateral UTUC was defined as synchronous bilateral carcinoma on preoperative imaging before confirmation by pathology or positive urine cytology result plus direct visualization. Radical nephroureterectomy (RNU) or nephron-sparing surgery (NSS) or both were carried out.ResultsA total of 39 patients (4.37%) suffered from bilateral disease. Discordant histological grade of bilateral tumor was found in 39.3% cases. Bilateral tumors were associated with female sex (P<0.001), preoperative renal insufficiency (P<0.001), previous or concomitant bladder tumors (P = 0.013), lower tumor stages (P = 0.020), papillary architecture (P = 0.001), and smaller-sized tumors (P = 0.020). Patients with worse renal function (P<0.001) or large-sized tumors (P = 0.039) tended to be treated with bilateral RNU. Most patients (67.6%) were treated with unilateral RNU plus unilateral NSS, with NSS being performed on tumors that only extended to the ureter (P = 0.003) and had a smaller size (P = 0.005). The median follow-up duration was 56 months. The 5-year cancer-specific survival and bladder recurrence-free survival rates were 81.2% and 64.5%, respectively, similar to those of unilateral tumors. Male sex (hazard ratio = 11.535) and higher tumor stage (hazard ratio = 3.386) were independent worse prognostic factors.ConclusionsThe prevalence of bilateral UTUC is rare. Female patients, patients with renal insufficiency, and those with bladder tumor tended to suffer from bilateral disease and were less likely to present with worse pathological outcomes in the Chinese population. The tumor characteristics and renal function were informative in treatment selection. The oncologic outcomes were similar to those in unilateral UTUC, and male sex and a higher tumor stage were poor prognostic factors for these patients.     

Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ-confined TCC at radical cystectomy

OBJECTIVES: Carcinoma in situ (CIS) is a nonpapillary, high-grade, potentially aggressive, and unpredictable manifestation of transitional cell carcinoma (TCC) of the bladder. The aim of this study was to assess whether presence of concomitant CIS has a detrimental effect on cancer control after radical cystectomy. METHODS: The records of 812 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for bladder TCC at three US academic centres were reviewed. Ninety-nine of 812 (12%) patients had CIS only at radical cystectomy and were excluded from the analyses. RESULTS: Three hundred thirty of the 713 (46.3%) patients had concomitant CIS at radical cystectomy. Patients with TCC involvement of the urethra were more likely to have concomitant CIS than not (61% vs. 40%, p=0.018). Concomitant CIS was significantly more common in patients with lower cystectomy stages and higher tumour grades. In univariate, but not multivariate, analysis, patients with concomitant CIS versus those without were at increased risk of disease recurrence (p=0.0371). In patients with organ-confined disease, concomitant CIS was an independent predictor of disease recurrence (p=0.048 and p=0.012, respectively) but not bladder cancer-specific mortality (p=0.160 and p=0.408, respectively) after adjusting for the effects of standard postoperative features. CONCLUSIONS: Concomitant CIS in the cystectomy specimen is common, and patients with concomitant CIS are at increased risk of urethral TCC involvement. The presence of concomitant CIS appears to confer a worse prognosis in patients with non-muscle-invasive TCC treated with radical cystectomy.     

Effect of tumor size on recurrence-free survival of upper tract urothelial carcinoma following surgical resection

ObjectiveTo identify predictors of recurrence-free survival (RFS) based on the clinicopathological features of patients with upper tract urothelial carcinoma (UTUC) who have undergone radical nephroureterectomy (RNU) with bladder cuff resection.Materials and methodsWe retrospectively reviewed the records of patients from October 1998 to July 2012 at our tertiary institution and identified 120 patients with sufficient data who underwent RNU for UTUC. We recorded various clinical and histopathological parameters as potential predictors of outcome. Recurrence was defined as any occurrence of urothelial carcinoma after RNU either intravesically, local/regionally, or at distant sites. Univariate, multivariate, and RFS analyses were conducted using the Cox regression and Kaplan-Meier methods.ResultsThe median age of our cohort was 71 years (interquartile range: 64–78). Median RNU-specimen tumor size was 3.0 cm (interquartile range: 2.0–5.0 cm). Fifty-four patients (45%) had a tumor<3.0 cm and 66 (55%) had a tumor≥3.0 cm. Eighty patients (66.7%) had organ-confined UTUC (≤pT2) and 40 (33.3%) had non–organ-confined UTUC (≥pT3). Sixty-five patients (54.2%) experienced at least 1 recurrence. Forty-three patients (35.8%) had at least 1 episode of intravesical recurrence and 28 (23.3%) had distant recurrence. A multivariate analysis revealed non–organ-confined disease (hazard ratio [HR] = 3.62, P<0.001), tumor diameter≥3 cm (HR = 1.97, P = 0.011), and male gender (HR = 1.81, P = 0.047) to be significant independent predictors of disease recurrence. The 5-year RFS rate was 46.9% and 25.8% for patients with tumor size<3 and≥3 cm, respectively.ConclusionsFollowing RNU, the incidence of recurrence remains high among patients with UTUC. In our cohort of patients, tumor diameter≥3.0 cm, non–organ-confined UTUC, and male gender constitute important risk factors for poor RFS outcomes following RNU. These patients require diligent postoperative surveillance and may potentially benefit from perioperative systemic therapy.     

Pathologic stage as a surrogate for oncologic outcomes after receipt of neoadjuvant chemotherapy for high-grade upper tract urothelial carcinoma

ObjectiveWhether pathologic stage at radical nephroureterectomy (RNU) can serve as an appropriate surrogate for oncologic outcomes in patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) treated with neoadjuvant chemotherapy (NAC) is not defined. We sought to determine whether patients who achieve pathologically non-muscle-invasive (ypT0, ypTa, ypT1, ypTis) HG UTUC after receipt of NAC exhibit oncologic outcomes comparable to those who are inherently low stage without chemotherapy.MethodsWe identified 647 UTUC patients who underwent RNU among 3 institutions from 1993to2016. Patients with low or unknown grade, pathologic muscle invasion, or receipt of adjuvant chemotherapy were excluded. We compared clinicopathologic data and oncologic outcomes between pT0-1 and ypT0-1 patients. Kaplan-Meier analysis was used to assess overall (OS), cancer-specific (CSS), and systemic recurrence-free (RFS) survival. Predictors of these endpoints were identified using Cox regression.Results234 (43 ypT0-1, 191 pT0-1) patients with HG UTUC were included. Two patients exhibited pathologic complete response after NAC. OS (P = 0.055), CSS (P = 0.152), and RFS (P = 0.098) were similar between ypT0-1 and pT0-1 patients. Predictors of worse outcomes included African-American race (RFS, CSS, and OS), Charlson score (OS), and systemic recurrence (OS and CSS).ConclusionsPatients with HG UTUC who achieve ypT0-1 stage after NAC exhibit favorable oncologic outcomes comparable to those inherently non-muscle-invasive who do not receive chemotherapy. Improvements in clinical staging will play an important role in better defining candidacy for NAC in treating HG UTUC while minimizing overtreatment. Furthermore, pathologic stage may serve as an appropriate early surrogate for oncologic endpoints in designing clinical trials.     

Effectiveness of adjuvant radiotherapy for high recurrence risk patients with upper tract urothelial carcinoma

PurposeA recent study has shown that upper tract urothelial carcinoma (UTUC) patients with high-risk factors have a high local recurrence rate. The purpose of this work was to investigate the benefit of adjuvant radiotherapy (ART) for patients with high recurrence factors.MethodsFour hundred twenty-four UTUC patients who received radical nephroureterectomy (RNU) in our hospital between 2010 and 2018 were reviewed. The significance of factors on cancer-specific survival (CSS) and recurrence-free survival (RFS) were assessed using Cox multivariate analysis. In patients with high recurrence factors, propensity score matching was used to adjust the confounding factors for ART.ResultsThe median follow-up time was 40 (range 3–77) months. Multivariate analysis showed that multifocal tumor, G3, pT3/4 stage and positive lymph node (N+) were independent predictors for worse RFS. Multifocal tumor and pT3/4 stage were independent predictors of worse CSS in UTUC after surgery. A total of 286 patients with these high recurrence factors were identified: 192 (67.1%) patients received RNU only, and 94 (32.9%) patients received ART. Overall, ART did not improve CSS (ART 86.1% vs. RNU 78.5%.; P = 0.11). After propensity score matching, ART significantly improved the CSS of patients with high recurrence factors. The 3-year CSS was 73.1% in patients treated with RNU alone vs. 86.1% in patients treated with ART (P = 0.016).ConclusionsResults of our study demonstrated benefit of adjuvant radiotherapy in cancer specific survival in UTUC patients with high recurrence factors(multifocal tumor ,pT3/4,G3 and positive lymph node).     

Survivin is not an independent prognostic factor for patients with upper tract urothelial carcinoma: A multi-institutional study

ObjectiveSeveral 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 methodsSurvivin 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.ResultsAltered 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.ConclusionsIn 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.     

Prognostic value of Balkan endemic nephropathy and gender on upper tract urothelial carcinoma outcomes after radical nephroureterectomy: A cohort study

BackgroundTo identify the prognostic impact of residence in a BEN-endemic area and gender on upper tract urothelial carcinoma (UTUC) outcomes in Serbian patients treated with radical nephroureterectomy (RNU).MethodsThe study included 334 consecutive patients with UTUC. Patients with permanent residence in Balkan endemic nephropathy (BEN) or non-endemic areas from their birth to the end of follow-up were included in the analysis. Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates.ResultsFemale patients were more likely to have preoperative pyuria (P = 0.01), tumor multifocality was significantly associated with the female gender (P = 0.003). Gender was not associated with pathologic stage and grade, lymph node metastasis, lymphovascular invasion, adjuvant chemotherapy, bladder cancer history, tumor size, distribution of tumor location, preoperative anemia and demographic characteristics. A total of 107 cases recurred, with a median time to bladder recurrence of 24.5 months. History of bladder tumor (HR, 1.98; P = 0.005), tumor multifocality (HR, 3.80; P < 0.001) and residence in a BEN-endemic area (HR, 1.81; P = 0.01) were independently associated with bladder cancer recurrence. The 5-year bladder cancer RFS for the patients from areas of BEN was 77.8 % and for the patients from non-BEN areas was 64.7 %. The 5-year CSS for the men was 66.2% when compared to 66.6% for the women (P = 0.55).ConclusionsResidence in a BEN-endemic area represents an independent predictor of bladder cancer recurrence in patients who underwent RNU. Gender cannot be used to predict outcomes in a single-centre series of consecutive patients who were treated with RNU for UTUC.     

Upper tract urothelial carcinoma: Impact of time to surgery

ObjectivePatients diagnosed with upper tract urothelial carcinoma (UTUC) sometimes experience a delay from diagnosis to extirpative surgery (nephroureterectomy or ureterectomy) as a result of attempted endoscopic management and/or neoadjuvant chemotherapy. The purpose of this analysis is to examine the impact of such delay on survival outcomes.MethodsAn IRB-approved retrospective review identified consecutive patients undergoing extirpative surgery for UTUC treated at a single institution between 1990 and 2007. 240 patients with non-metastatic disease represented both primarily-presenting and referred patients. Patients in the “early” surgery group underwent extirpative surgery <3 months after diagnosis and patients in the “delayed” surgery group underwent surgery ≥3 months after diagnosis. Timing to surgery was at the discretion of individual patient-surgeon decision-making. Analyses and measurements were univariate and multivariate models correlating death from disease with clinico-pathologic parameters, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in the “early” and “delayed” surgery groups.Results186 patients underwent early surgery and 54 patients underwent delayed surgery. Median follow-up for all patients was 29 months. The 5-year CSS were 72% and 71% for the early versus late groups, respectively (P = 0.39) and corresponding 5-year OS rates were 60% and 69%, respectively (P = 0.69). Delay in surgery was not associated with a worse outcome, even following adjustment for potential confounders. The most common factor contributing to delayed surgery in our cohort was administration of neoadjuvant chemotherapy (50%), which did not impact survival. Limitations included a median follow-up of 19 months in the neoadjuvant group; and the requirement to analytically group pathologic high-stage and low-stage disease, which reflects challenges inherent to current clinical staging.ConclusionsOur results show no difference in survival between patients undergoing early versus delayed extirpative surgery for UTUC, suggesting the feasibility of delayed surgery in appropriately selected patients. Only prospective validation of delayed surgery can guarantee its safety.