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Background: The current pathological tumour-node-metastasis (pTNM) classification for upper tract urothelial carcinoma (UTUC) does not include any risk stratification of pT3 renal pelvicalyceal tumours., Objective: To assess the prognostic impact of pT3 subclassification in a multicentre cohort of patients with UTUC of the renal pelvicalyceal system undergoing radical nephroureterectomy (RNU)., Design, Setting, and Participants: Data from all consecutive patients treated with RNU for pT3 renal pelvicalyceal UTUC at 14 French centres from 1995 to 2013 were reviewed retrospectively., Intervention: A central pathology review (CPR) was used to stratify pT3 patients into those with infiltration of the renal parenchyma on a microscopic level (pT3a) versus those with infiltration of the renal parenchyma visible on gross inspection of the resection specimen and/or invasion of peripelvic fat (pT3b)., Outcome Measurements and Statistical Analysis: Inverse probability weighting (IPW)-adjusted Cox regression analyses were used to compare recurrence-free survival (RFS) and cancer-specific survival (CSS) between pT3a and pT3b patients., Results and Limitations: Overall, 202 patients were included and further stratified into pT3a (n = 98; 48.5%) and pT3b (n = 104; 51.5%) subgroups. Median time to follow-up in the weighted population was 68 (interquartile range, 50-95) mo. In IPW-adjusted Cox regression analyses, pT3b versus pT3a substage was associated with a significant adverse effect on RFS (hazard ratio [HR] = 2.02; 95% confidence interval [CI] = [1.36-3.01]; p < 0.001) and CSS (HR = 1.84; 95% CI = [1.20-2.82]; p = 0.005). The study is limited by its retrospective design., Conclusions: Using IPW-adjusted analyses after the CPR, we observed that RNU patients with pT3b renal pelvicalyceal UTUC had adverse prognosis as compared with those with pT3a disease. As such, this subclassification could help refine the current pTNM system for UTUC., Patient Summary: In this report, we looked at the prognostic interest of stratifying patients with pT3 renal pelvicalyceal upper tract urothelial carcinoma based on the extent of local invasion. We found that those with extensive infiltration (pT3b) had adverse prognosis as compared with those with limited infiltration (pT3a). This information could be provided on pathology reports to further guide clinical decision making., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To assess PD-L1 expression in tumor (TC) and tumor infiltrating immune cells (IC) as a predictive factor of BCG therapy failure in high-risk NMIBC., Materials and Methods: Patients treated with complete resection followed by bladder BCG instillation for high-risk NMIBC were included. Early recurrence (ER) was defined as tumor recurrence after BCG induction course. The association between ER and immuno-histochemistry PD-L1 (E1L3N clone) expression by tumors cells (TC) and tumor infiltrating immune cells (IC) was investigated using an exact Fisher test variant., Results: A total of 186 patients were included, of whom 38 (20.4%) were ER, 35 (18.8%) were positive for TC PD-L1 expression and 60 (32.3%) were positive for IC PD-L1. ER was not significantly (p = 0.97) more frequent in the TC PD-L1 ≥ 1% group (n = 7, 20.0%) than in the TC PD-L1-negative group (n = 31, 20.5%). Patients with IC PD-L1 negative had ER in 15 (19.2%) cases and patients with IC PD-L1 ≥ 1% had ER in 23 (21.3%) cases. PD-L1-positive expression for IC (threshold > 1%) was correlated with immune infiltrate density (95.2% dense immune infiltrate vs 47.2% low immune infiltrate, p < 0.05), with increased expression of PD-L1 by IC after BCG therapy (p = 0.006)., Conclusion: No association was observed between immuno-histochemistry PD-L1 positivity and ER after BCG therapy. Nevertheless, the relationship between immune infiltrate and PD-L1 positivity confirmed the interest of assessing the immune infiltrate density to define tumor's profile.

Aim: To assess the potential predictive value of natural resistance-associated macrophage protein 1 (NRAMP1) and human glutathione peroxidase 1 (hGPX1) polymorphism in non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin (BCG) instillation, we conducted an original ancillary multicenter study., Patients and Methods: We evaluated patients included in the multicenter URO-BCG 4 trial, who received three weekly instillations of one-third dose BCG every 6 months (group I) or two weekly instillations every 3 months (group II) for 3 years. For clinical evaluation we also evaluated tumor recurrence and muscle progression. NRAMP1 and hGPX1 polymorphism analyses were performed on blood DNA. NRAMP1 exon 15 and hGPX1 exon 1c were amplified using Type-it Microsatellite PCR Kit® for multiplex polymerase chain reaction., Results: From June 2004 to April 2010, 146 randomized patients were included in this retrospective study. Blood samples were obtained from 107 patients. With 36 months of follow-up, 13.6% of patients had a tumor recurrence and muscle-invasive progression was observed in 4.3% of patients. Concerning NRAMP1 D543N polymorphism, patients with allele A had no tumor recurrence or muscle-invasive progression. No significant difference was observed in gene polymorphism distribution between groups I and II. Moreover, we did not observe any significant association of gene polymorphisms, tumor recurrence or muscle-invasive progression, event time and disease-free survival., Conclusion: Our results suggest that no significant difference was found for NRAMP1 and hGPX1 gene polymorphisms associated with recurrence time, muscle invasion frequency and disease-free survival, nevertheless, we observed that the NRAMP1 D543N GG genotype group had a shorter time to tumor recurrence., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: To assess, in a prospective clinical research study, a new non-invasive and reliable test to accurately detect tumor protein 53 (TP53) and fibroblast growth factor receptor-3 (FGFR3) mutations in cells in urine., Materials and Methods: TP53 mutations were analyzed using the functional analysis of separated allele in yeast (FASAY) method, which allows functional analysis of the P53 protein, and FGFR3 mutations were assessed with the SNaPshot system, detecting the eight most frequent point-mutations of this gene. Chi-square test or Fisher's exact test were used to compare TP53 and FGFR3 mutations in the tumors according to tumor stage and grade., Results: TP53 and FGFR3 mutations in bladder tumors increased and decreased respectively with increasing tumor stage and cellular grade (p<0.05 and p<0.001, respectively). A total of 103 tumor/urinary sediment couples were analyzed. TP53 or FGFR3 mutations were observed in 76 tumors. The sensitivity for the detection of this type of mutation in urine was 46%, the specificity was 81%, the positive predictive value was 94% and the negative predictive value was 37%., Conclusion: Our original data confirmed the feasibility of TP53 and FGFR3 mutation detection in urine sediment. These measurements, together with urine cytology, may increase tumor detection. The sensitivity of the TP53/FGFR3 phenotype test in the urine was less than 50% and was not able to replace standard cystoscopy in the diagnosis of bladder tumors., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: The objective of this retrospective study was to assess the usefulness of fluorescence during cystoscopy after BCG-therapy in the management of non-invasive bladder tumors., Patients and Methods: Fifty-four patients were enrolled: Ta (15 cases), T1 (27 cases) carcinoma in situ (CIS) alone (12 cases) or associated (14 cases). Urine cytology was of high grade and a second look was systematically performed in case of lamina propria infiltration. Initial therapy with 6 intravesical BCG instillations (81 mg) was performed with histologic and endoscopic bladder evaluation 3 months after initial resection using hexylaminolevulinate fluorescence (Hexvix(®) 85 mg)., Results: Urine cytology was negative in 27 cases, suspicious in 12 cases and positive in 15 cases. With standard endoscopy under white light, mucosal bladder was normal in 32 cases, the use of fluorescence detected 8 tumour lesions confirmed with histology (CIS). When mucosal bladder was suspect under white light (22 patients), fluorescence was positive in 16 cases with 10 matching histological analysis (CIS and/or residual tumoral lesion). Therefore, despite high false positive rate with persistent mucosal bladder inflammation (38%), fluorescence guided endoscopy has allowed the diagnosis of suspect lesions not detected with white light with negative urine cytology., Conclusion: Hexvix(®) fluorescence after intravesical BCG instillations may improve persistent carcinoma in situ detection when performed 3 months after induction treatment. However, a multicenter prospective study will be necessary in future to confirm these preliminary results., Level of Evidence: 5., (Copyright © 2014. Published by Elsevier Masson SAS.)

Purpose: Predictive factors of T1 nonmuscle invasive bladder cancer evolution that could guide treatment decision making are lacking. We assessed the prognostic value of muscularis mucosa invasion in nonmuscle invasive bladder cancer., Materials and Methods: In a national multicenter study patients with primary T1 nonmuscle invasive bladder cancer were recruited from 6 French hospitals. All patients had undergone transurethral resection of bladder tumor. All T1 tumors were substaged according to muscularis mucosa invasion as T1a-no invasion beyond the muscularis mucosa or T1b-invasion beyond the muscularis mucosa with muscle preservation. Subsequent central pathology review was then done by a single referent uropathologist. Muscularis mucosa invasion was tested as a prognostic factor for survival on univariate and multivariate analysis., Results: A total of 587 patients were enrolled in the study, including 388 (66%) with T1a and 199 (34%) with T1b tumors. Median followup after transurethral resection of bladder tumor was 35 months (IQR 14-54). There was no significant difference between groups T1a and T1b except high tumor grade in T1b cases (p <0.0001). After central review, initial pathological substaging was confirmed in 84% of cases. On multivariate analysis muscularis mucosa invasion (T1b substage) was significantly associated with recurrence-free (p = 0.03), progression-free (p = 0.0002) and cancer specific (p = 0.02) survival. The main study limitation was absent systematic subsequent transurethral resection of bladder tumor., Conclusions: Muscularis mucosa invasion appears to be highly predictive of T1 nonmuscle invasive bladder cancer behavior. Consequently, systematic T1a vs T1b discrimination should be highly advocated by urologists and pathologists. We believe that it could aid in crucial decision making when choosing between conservative management and radical cystectomy remains a moot point., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Two major pathways are described in bladder carcinogenesis: one for invasive or high grade tumors characterized by alteration of the p53 tumor suppressor gene and the other for non-invasive tumors or low grade involving mutations FGFR3. The objective of our study was to validate the research in the urine of mutations in these two genes in patients with a bladder tumor., Patients and Methods: In our preliminary study, we investigated 36 patients the FGFR3 and p53 mutations in tumors and urine collected during endoscopic resection. The p53 mutations were sought in FASAY, which allows a functional analysis of the protein P53. The FGFR3 mutations were sought in SNaPshot that searches the eight most frequent mutation points of this gene., Results: For 24 patients (66% of cases), we found at least one of the two mutations in the tumor. This mutation was present in the urine in 15 patients (sensitivity=62.5%). In only one patient, we found a mutation in the urinary sediment that did not exist in the tumor (specificity=91.7%)., Conclusion: The search for mutations of p53 and FGFR3 in the urine was a simple and non-invasive assay, which seems superior to urinary cytology for the detection of bladder tumors, raising hopes of an interest in this bio-assay for surveillance of bladder tumors and screening risk populations., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Objective: The aim of this multicenter study was to determine the prognostic value of the depth of invasion of lamina propria and more specifically the influence of the invasion of the muscularis mucosae on survival parameters in T1 bladder carcinoma., Patients: Six urological centers included patients between 1994 and 2004 who had an initial T1 bladder tumor. All T1 tumors were substaged according to the muscularis mucosae (MM) invasion into T1a (no invasion beyond the MM) and T1b (invasion beyond MM but preserving the muscle). Among the 387 patients included, 269 (69.5%) were found T1a and 118 (30.5%) T1b. Mean follow-up was 45.4 months. T1a and T1b groups were comparable except for tumor grade that was higher in T1b (p<0.001)., Results: Survival without recurrence was not significantly different between T1a and T1b groups (p<0.3) but T1a stage was found as an independent factor for survival without progression (RR=0.49; IC 95%=[0.71-0.90]), specific survival (RR=0.33; IC 95%=[0.16-0.67]) and global survival (RR=0.52; IC 95%=[0.32-0.85])., Conclusion: This study, the largest on the subject to our knowledge, have shown that muscularis mucosae invasion was a prognostic factor for survival without progression, specific survival, and global survival. We support that routine pathological assessment of the level of MM invasion in patients with stage T1 bladder cancer should be included in the histopathological report., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Objective: The objective of this study was to evaluate the incidence of prostatic carcinoma in patients treated by intravesical BCG-therapy for superficial bladder cancer and presenting granulomatous prostatitis. The authors discuss the problems of interpretation of total PSA and the potential indications for prostatic biopsies in this population., Material and Methods: A retrospective study was performed on the cases of symptomatic granulomatous prostatitis observed among patients treated with intravesical BCG instillations between January 1997 and December 2006. A total of 153 men were treated for high-risk or intermediate-risk superficial bladder cancer according to the usual recommendations. The attenuated Connaught strain of BCG was used at a dose of 81 mg. Induction treatment consisted of six weekly instillations and was followed by maintenance treatment for a period of three years., Results: Six patients developed symptomatic granulomatous prostatitis (4% of cases). On average, this complication occurred after about the 10th intravesical instillation (6-13) of maintenance treatment. The mean total PSA at three months was 8 ng/ml (range: 5-11.6). Ultrasound-guided biopsies were indicated in view of the persistently elevated PSA level and confirmed the tuberculoid granulomatous lesion of the prostate in each case and revealed prostatic adenocarcinoma in two patients., Conclusion: Prostatic carcinoma must be systematically excluded by ultrasound-guided biopsies in all patients with clinical granulomatous prostatitis and persistently elevated PSA three months after intravesical BCG instillations.

Purpose: On a routine basis we performed systematic molecular screening for FGFR3 and TP53 mutations in 121 bladder tumors. We then specifically analyzed the predictive value of the recurrence of FGFR3 and TP53 genotypes in superficial lesions., Materials and Methods: The FGFR3 gene was analyzed by direct sequencing of exons 7, 10 and 15, whereas TP53 status was determined using the p53 functional assay in yeast., Results: We identified a missense FGFR3 mutation in 66% of pTa, 26% of pT1 and 12% of pT2 tumors. Of activating FGFR3 mutations 54% and 85% were found in low G1 and intermediate G2 grade tumors, respectively, but in only 20% of high grade G3 tumors. We detected inactivating TP53 mutations in 10% of pTa, 42% of pT1 and 58% of pT2 tumors. Moreover, TP53 mutations were found only in 23% of grade G1 and 3% of grade G2 tumors but in 44% of high grade G3 tumors. When the 2 genotypes were combined, we observed that 58% of pTa tumors had the (mutant FGFR3, WT TP53) genotype, whereas 58% of invasive lesions harbored the inverse genotype (WT FGFR3, mutant TP53). The (mutant FGFR3, WT TP53) genotype and the (WT FGFR3, mutant TP53) genotype were detected in 23% and 38% of pT1G3 tumors, respectively. In the subgroup of 92 patients with superficial pTa-T1 bladder tumors we did not find that the TP53 or FGFR3 genotype alone or combined had a predictive value for tumor recurrence., Conclusions: Our data again represent solid proof for the pivotal role of FGFR3 and TP53 mutations in superficial and invasive bladder tumors, respectively. However, other molecular markers should be identified for borderline pT1G3 bladder tumors, which are probably at the crossroads of these 2 distinct molecular pathways.

Introduction: The management of congenital urological malformations is sometimes complex and may require urinary diversion. Cystectomy is usually performed, but sometimes the bladder is left in place due to the presence of a pelvic cloaca and the morbidity related to this type of surgery., Material: The authors report three cases of patients treated by urinary diversion for a congenital malformation without primary resection of the bladder, Results: In the absence of any infectious complications, bladder carcinoma on an excluded native bladder was diagnosed at the age of 3 years, 4 years and 38 years, respectively. Histological examination showed transitional cell carcinoma in two cases and gastrointestinal-type adenocarcinoma of the bladder in 1 case., Conclusion: The risk of secondary development of carcinoma in an excluded bladder during management of (congenital urological malformations is not negligible. Primary cystectomy therefore appears to be preferable. In the presence of a pelvic cloaca making this surgical resection unreasonable, it appears important to exclude the formation of a pyocyst by annual abdominal ultrasound. The authors also recommend cystoscopy and urine cytology with lavage to detect degeneration of the bladder mucosa.

Nested variant urothelial carcinoma is a recently identified variant of urothelial carcinoma which is difficult to diagnose due to its resemblance to other benign bladder lesions, such as hyperplasia of Von Brünn nests. The authors present three clinical cases of this variant of urothelial carcinoma and emphasize the importance of clinical, cytological, histological and immunohistochemical criteria for the diagnosis and the need for early and adapted therapeutic management, as this type of bladder tumour, wrongly considered to be benign up until the early 1990s, is just as invasive as high-grade urothelial carcinoma.

The authors report their experience of four cases of bladder leiomyoma. Although MRI is currently the reference radiological examination, the diagnosis must be confirmed by histological examination. The various diagnostic steps and resulting therapeutic indications are described with a review of the literature.

The authors report a case of primary malignant neuroendocrine bladder tumour. This rare bladder tumour presents the morphological and immunohistochemical characteristic common to all neuroendocrine tumours observed in other organs. The urologist must recognise this histological entity, which requires multidisciplinary management.