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OBJECTIVE: Papillary urothelial neoplasm of low malignant potential (PUNLMP) and stage TaG1 non-muscle invasive bladder cancer (NMIBC) represent separate categories in current WHO 1999 grade definitions. Similarly, PUNLMP and Ta low-grade are separate entities in the WHO 2004/2016 grading system. However, this classification is currently questioned by reports showing a similar risk of recurrence and progression for both categories. PATIENTS AND METHODS: In this population-based study, risk estimates were evaluated in patients diagnosed with PUNLMP (n = 135) or stage TaG1 (n = 2176) NMIBC 2004-2008 with 5-year follow-up registration in the nation-wide Bladder Cancer Data Base Sweden (BladderBaSe). The risk of recurrence was assessed using multivariable Cox regression with adjustment for multiple confounders (age, gender, marital status, comorbidity, educational level, and health care region). RESULTS: At five years, 28/135 (21%) patients with PUNLMP and 922/2176 (42%) with TaG1 had local recurrence. The corresponding progression rates were 0.7% (1/135) and 4.0% (86/2176), respectively. A higher relative risk of recurrence was detected in patients with TaG1 tumours compared to PUNLMP (Hazard Ratio 1.6, 95% CI 1.2-2.0) at 5-year follow-up, while progression events were too few to compare. CONCLUSIONS: The difference in risk of recurrence between primary stage TaG1 and PUNLMP stands in contrast to the recently adapted notion that treatment and follow-up strategies can be merged into one low-risk group of NMIBC.

Background: Urothelial carcinomas are the fourth most common tumors worldwide. Studies have shown that Her2/neu is associated with increased tumour grade and Ki?67 is related to tumour recurrence and stage progression. As no such study has been undertaken is this region, the present study was aimed to establish Her2/neu and Ki-67 as novel prognostic markers of urothelial neoplasms. Aims and Objectives: To evaluate the clinical profile of urothelial neoplasms and correlate the expression of Her2/neu and Ki-67 in urothelial carcinomas. Settings and Design: Observational and cross-sectional study (January 2018-May 2019) in a tertiary care hospital in Eastern India. Materials and Methods: 40 specimens of urothelial neoplasms were studied. Clinical history of patients was collected. Microscopic examination was done to assess tumour stage and histological grade. Immunohistochemistry with Her2/neu and Ki-67 was performed. Analysis: Statistical Package for the Social Sciences SPSS (version 20.0, IBM, Chicago, IL, USA) for windows software. Results: 8 cases were diagnosed as low grade non-invasive urothelial carcinoma, 31 cases as infiltrating urothelial carcinoma and 1 case as papillary urothelial neoplasm of low malignant potential (PUNLMP). 96.8% of infiltrating carcinomas and 87.5% of low grade non-invasive carcinomas showed Ki-67 positivity. Moderate-to-strong Her2/neu over[removed]2+ or 3+) was observed in only 21% of the cases. Conclusion: The expression of Ki-67 increased with increase in the grade of the tumour which was suggestive of the prognostic importance of Ki-67. Her2/neu positivity was seen in infiltrating cases. No significant association between the tumor grade and Her2/neu expression, indicated the need for further studies with a larger population group. Keywords: Her2/neu, Ki- 67, Urothelial neoplasms.

Introduction: Even among low grade bladder tumors, there are some which have been found to carry bad prognosis for progression, recurrence and survival. Accurately pinpointing these cases at the time of diagnosis just with the help of routine histopathology is problematic. Ki-67 immunostaining may potentially be of help in identifying such cases, making administration of additional treatment modalities like chemotherapy and radiotherapy possible. There is scarcity of such studies in our country. The present study aims to correlate Ki-67 labeling index with the histopathological type and grade, pathological stage and mitotic index of urinary bladder tumors. Objective: Objective of the study is to consider the possibility of using Ki-67 labeling index to identify those low grade urinary bladder tumors which carry bad prognosis. Materials and Methods: All trans-uretheral resection of bladder tumor (TURBT) specimens in our institute were analyzed for their histopathological grade, pathological stage, mitotic index and Ki-67 labeling index in the period extending from from August 2015 to December 2016. The clinical data were analyzed retrospectively and statistically. SPSS Version 23 (SPSS Inc.,Chicago, IL, USA) software was utilized for all statistical analyses. Chi-square analysis was utilized for comparison of groups. Results with P

Although the papillary urothelial neoplasm of low malignant potential (PUNLMP) diagnostic category was retained in the updated 2016 World Health Organisation (WHO) classification of tumours of the urinary system, there still exists a great deal of controversy regarding the biological behaviour of these tumours. We review PUNLMP tumours and histological grading with an emphasis on the histomorphological, genetic and clinical similarities between PUNLMP and low-grade non-invasive papillary urothelial carcinoma. A literature search using PubMed was performed. All relevant literature concerning PUNLMP and the grading of urothelial tumours was reviewed. PUNLMPs cannot be reliably distinguished from low-grade non-invasive papillary urothelial carcinomas based on the histomorphological criteria outlined in the WHO 2004/2016 classification system. PUNLMPs and low-grade non-invasive papillary urothelial carcinomas are not only morphologically similar, but also share similar molecular genetic alterations and a similar risk of recurrence and progression. In addition, there are no consensus recommendations for a different method of treatment and follow-up for these two tumour types. Attempting to distinguish PUNLMP from low-grade papillary urothelial carcinoma adds an unnecessary level of complexity to the grading and classification of urothelial tumours. We feel that PUNLMP terminology should be abandoned and that all such tumours should be classified as low-grade carcinomas until more objective determinants of clinical outcome can be established.

Background: Papillary urothelial neoplasm of low malignant potential (PUN-LMP) was introduced as a noninvasive, noncancerous lesion and a separate grade category in 1998. Subsequently, PUN-LMP was reconfirmed by World Health Organization (WHO) 2004 and WHO 2016 classifications for urothelial bladder tumors. Objectives: To analyze the proportion of PUN-LMP diagnosis over time and to determine its prognostic value compared to Ta-LG (low-grade) and Ta-HG (high-grade) carcinomas. To assess the intraobserver variability of an experienced uropathologist assigning (WHO) 2004/2016 grades at 2 time points. Materials and methods: Individual patient data of 3,311 primary Ta bladder tumors from 17 hospitals in Europe and Canada were available. Transurethral resection of the tumor was performed between 1990 and 2018. Time to recurrence and progression were analyzed with cumulative incidence functions, log-rank tests and multivariable Cox-regression stratified by institution. Intraobserver variability was assessed by examining the same 314 transurethral resection of the tumorslides twice, in 2004 and again in 2018. Results: PUN-LMP represented 3.8% (127/3,311) of Ta tumors. The same pathologist found 71/314 (22.6%) PUN-LMPs in 2004 and only 20/314 (6.4%) in 2018. Overall, the proportion of PUN-LMP diagnosis substantially decreased over time from 31.3% (1990-2000) to 3.2% (2000-2010) and to 1.1% (2010-2018). We found no difference in time to recurrence between the three WHO 2004/2016 Ta-grade categories (log-rank, P = 0.381), nor for LG vs. PUN-LMP (log-rank, P = 0.238). Time to progression was different for all grade categories (log-rank, P < 0.001), but not between LG and PUN-LMP (log-rank, P = 0.096). Multivariable analyses on recurrence and progression showed similar results for all 3 grade categories and for LG vs. PUN-LMP. Conclusions: The proportion of PUN-LMP has decreased to very low levels in the last decade. Contrary to its reconfirmation in the WHO 2016 classification, our results do not support the continued use of PUN-LMP as a separate grade category in Ta tumors because of the similar prognosis for PUN-LMP and Ta-LG carcinomas. (C) 2019 Elsevier Inc. All rights reserved.

Urothelial bladder carcinoma frequently occurs in adults over 60 years of age; yet it affects only 0.1–0.4% of patients before the first 2 decades of life. We present two cases of transitional cell carcinoma in two young patients treated with holmium:YAG laser to demonstrate the effectiveness of this technique in pediatrics. Case study 1 During a routine abdomen ultrasound, a 14-year-old female showed a endoluminal formation about 10 × 6 × 10 mm of size, in the left paramedian site. There was an absence of meaningful vascular signs during color-Doppler. Physical examination and laboratory exams were all normal. Case study 2 A 12-year-old female presented with acute macroscopic haematuria. No other symptoms were associated. Bladder ultrasound revealed an irregular 15 mm intravesical endophytic lesion in the posterior-superior area. In both cases, treatment commenced with an en bloc enucleation. For the resections, a 272 µm holmium:YAG fiber laser was used through the 12 Ch cystoscopy working channel with an energy of 0.8–1 J/pulse and a frequency of 8–10 Hz. There was no haematuria after the procedure and the transurethral catheter remained for 12 h. The histological diagnosis was papillary urothelial neoplasm of low malignant potential. Cystoscopy was performed 3 and 9 months after the surgery and an ultrasound every 6 months, which all came back normal. The follow-up continued for each patient with a cystoscopy once a year, according to EAU guidelines. Based on the findings, holmium:YAG laser is a good alternative to treat superficial transitional cell carcinoma in pediatric patients.

Key Clinical Message With few cases of PUNLMPs in young adults being reported in the literature, we hope to raise clinical awareness of prompt and effective diagnosis, while maintaining a high index of suspicion among health professionals. Even in the absence of red blood cells in the urine and subsequent negative imaging workup, clinicians should not delay performance of diagnostic cystoscopy.

Urothelial carcinoma (UC) of the bladder is exceedingly rare in the pediatric population. It commonly presents as isolated hematuria. Considering the age group, the physician’s low index of suspicion causes a delay in diagnosis. We present a seven-year-old girl complaining of dysuria and painless, intermittent hematuria. She was misdiagnosed with urinary tract infection several times. Although the initial ultrasound showed no abnormality, the second ultrasound after one year detected the tumor. The confirmation and resection are simultaneously achieved by cystoscopy. We concluded that chemotherapy is unnecessary due to the tumor’s low-grade nature and the absence of detrusor involvement. One-year follow-up showed no relapse.

Purpose. To evaluate the role of Alpha-L-fucosidase (AFU) in diagnosis and differential diagnosis of pure urothelial carcinoma (UC), urothelial carcinoma with squamous differentiation (UCSD), and squamous cell carcinoma (SqCC). Methods. A retrospective study was performed for 599 patients who were histologically confirmed with urothelial tumor. Preoperative AFU levels were compared across the distinct subgroups with different clinicopathological parameters. ROC curve analysis and logistic regression analysis were performed to further evaluate the clinical application value of serum AFU levels in diagnosis and differential diagnosis of urothelial tumors. Results. There were no statistically significant differences in the AFU levels between different groups with different malignant degrees (UC versus papilloma and papillary urothelial neoplasm of low malignant potential [PUNLMP], high-grade UC versus low-grade UC, invasive versus noninvasive malignant uroepithelial tumor) and different pathological types (UC, UCSD, and SqCC) (all P>0.05). ROC curve analysis and logistic regression analysis showed that there was no statistically significant association between AFU levels and the tumor characteristics (all P>0.05). Conclusions. Preoperative AFU levels cannot serve as a reliable predictor for malignant degree and differential diagnosis, including pure UC, UCSD, and SqCC of urothelial tumors.

Last World Health Organization 2016/ISUP (International Society of Urologic Pathologists) papillary urinary tumor classification include papillary urothelial neoplasm of low malignant potential (PUNLMP). This type of tumor is characterized by minimal atypia as well as low recurrence and progression rates. The article describes a clinical case of large PUNLMP treatment.

Background: Tat-interacting protein 30 (TIP30) has been reported to be a tumor suppressor, with reduced or absent expression in various tumors. However, its role in bladder urothelial cancer (BUC) has not been investigated. Therefore, herein, we investigated the expression of TIP30 protein in BUC and normal bladder mucosa and the clinical significance of TIP30 expression in the prognosis of BUC. Methods: We reviewed data from 79 cases of BUC and 15 adjacent tissue samples from 79 patients treated at our institution between 2004 and 2007. TIP30 expression was examined by immunohistochemistry. The relationship between TIP30 expression and tumor stage, histological grade, and survival was analyzed. Differences between groups were evaluated using the t-test or matched-pairs test, and differences in the survival rates were analyzed with the log-rank test. Results: TIP30 protein expression was significantly reduced in BUC tissue (t= −6.91, P < 0.05) compared with normal tissue samples, and in invasive bladder cancer (t = 10.89, P < 0.05) compared with superficial bladder cancer. TIP30 protein expression differed significantly among different differentiated groups classified either according to the World Health Organization (2004, F = 17.48, P < 0.01) or World Health Organization (1973, F = 10.68, P < 0.01). TIP30 protein expression was significantly reduced in high-grade papillary urothelial carcinoma compared with papillary urothelial neoplasm of low malignant potential (P < 0.05) and low-grade papillary urothelial carcinoma (P < 0.05). Meanwhile, TIP30 protein expression was significantly reduced in Grade III BUC, compared with Grade I (P < 0.05) and Grade II (P < 0.05). Patients with low TIP30 expression showed a higher incidence of disease progression than those with high TIP30 expression (t = 2.63, P < 0.05). Kaplan-Meier survival analysis showed a strong positive relationship between TIP30 expression and overall survival (OS) (χ2 = 17.29, P < 0.05). Conclusions: TIP30 expression was associated with clinical tumor stage in BUC, suggesting that it might play an important role in disease progression. Furthermore, TIP30 might predict postoperative OS. Thus, its evaluation might be useful for predicting prognosis. Key words: Bladder Urothelial Cancer; Overall Survival Time; Tat-interacting Protein 30

AIMS Mutations in FGFR3 and the promoter region of the telomerase reverse transcriptase (TERT) gene have been found frequently in urothelial carcinoma of the urinary bladder. However, related data for papillary urothelial neoplasm of low malignant potential (PUNLMP) are limited. In this study, we investigated the mutation status of the TERT promoter, FGFR3 and HRAS in low-grade papillary urothelial neoplasms and evaluated their prognostic significance. METHODS AND RESULTS The cases included in this study comprised 21 inverted papillomas, 30 PUNLMPs and 34 low-grade non-invasive papillary urothelial carcinomas (NIPUCs). TERT promoter mutations were observed in 10 (33%) PUNLMPs and 17 (50%) low-grade NIPUCs, but not in any inverted papilloma. FGFR3 mutations were observed more frequently in PUNLMP and low-grade NIPUC than in inverted papillomas (P = 0.009), whereas the opposite trend was noted for HRAS mutations (P

Purpose: To verify if the distinction between papillary urothelial neoplasm of low malignant potential (PUNLMP) and noninvasive low-grade papillary urothelial carcinoma (LGPUC) reflects a different biologic activity. Materials and Methods: We reviewed and analyzed the clinical data from 678 patients who had a diagnosis of PUNLMP (n=53) or noninvasive LGPUC (n=625) after initial TUR-BT for bladder neoplasm between 2000 and 2012. Results: The noninvasive LGPUC group showed a higher frequency of recurrence in comparison with the PUNLMP group (46.7% vs. 30.2%, p=0.022). In contrast, there were no significant differences in progression (15.2% vs. 18.9%, p=0.295) between the two groups. Grade progression was reported in 10 patients (LG: n=5; high grade: n=2; carcinoma in situ: n=3) and stage progression was reported in 2 patients (all: T1) in PUNLMP group. The Kaplan-Meier survival analysis showed significantly decreased 5-year recurrence-free survival (RFS) (50.3% vs. 74.6%, log-rank test, p=0.014) in the noninvasive LGPUC group compared to the PUNLMP group. However, there were no significant differences in progression-free survival (PFS) between the two groups. Multivariate analysis revealed that tumor grades according to 2004 WHO/ISUP classification system (PUNLMP vs. LG) were identified as significant predictors of RFS. However, it was not a significant predictor of both PFS and overall survival. Conclusions: PUNLMP had a substantial number of recurrences (30.2%), although RFS was better than noninvasive LGPUC. In addition, PUNLMP had a similar risk of progression compared with noninvasive LGPUC. Consequently, PUNLMP should be treated in a manner similar to noninvasive LGPUC, and long-term clinical follow-up should be recommended for patients with PUNLMP.

Introduction . Histological grading system is an important prognostic factor of bladder cancer. Grading of urothelial carcinoma has been a matter of debate since the three-grade system was introduced in 1973. Objective . Optimization of the grading system for urothelial carcinoma. Materials and methods . An analysis of literature devoted to evaluation of diagnostic significance, variability and interobserver reproducibility of the existing classifications of urothelial cancer of the bladder proposed in 1973, 1998, 1999 and 2004. Results . The classification proposed in 1973 is the most popular and time honored method of grading bladder tumors. In 1998 it was modified by the International Society of Urological Pathology. In 1999 the World Health Organization (WHO) approved a new classification which preserved the three-grade system but differed from the previous ones. According to this new classification, tumors could fall into the following categories: papilloma, papillary urothelial neoplasm of low malignant potential, urothelial carcinoma of I, II, and III malignancy grade. The definition of papilloma was identical in all of these classifications. In 2004 a new WHO classification was introduced in which non-invasive urothelial tumors were subdivided into papilloma, papillary urothelial neoplasm of low malignant potential and low and high grade carcinoma. All of the proposed grading systems had a certain level of subjectivity and interobserver reproducibility, but reproducibility between unfamiliar pathologists was considerably higher than in groups of pathologists who had studied or worked together. Importantly, the 2004 WHO classification aimed to provide a detailed explanation of histological criteria for each diagnostic category and therefore improve reproducibility between different pathologists. However, no improvement of reproducibility in comparison with the 1973 WHO classification was observed. Moreover, among the pathologists better reproducibility of the 1973 WHO classification was registered compared to the 1999 and 2004 classifications. Reproducibility of the papillary urothelial neoplasm of low malignant potential diagnosis was only 48 %. At the same time, reproducibility of the 1973 WHO classification too has its problems. The biggest criticism is ambiguity in the diagnostic criteria of the 3 grades of urothelial carcinoma. Conclusions. Standardization of the grading system of superficial bladder cancer allows to validate comparison between treatment outcomes in different centers. Introduction of the 2004 classification is the first step to treatment and monitoring standardization, but all of the classifications proposed by the WHO have shortcomings caused by considerable heterogeneity of papillary urothelial neoplasms. Significant interobserver reproducibility between papillary urothelial neoplasm of low malignant potential and low grade papillary urothelial carcinoma shows inadvisability of creating a separate diagnostic category for papillary urothelial neoplasm of low malignant potential.

We report 13 cases of unique polypoid urothelial tumors with inverted growth pattern (PUTIPs) occurring in the proximal ureter and renal pelvis. We describe their morphologic features and further characterize them in regard to TERT promoter mutation status and microsatellite instability. Thirteen cases were identified in our consult archives from 1994 to present. Patients ranged in age from 52 to 83 years at the time of diagnosis (mean, 68.4 years). Grossly, lesions were described variously as pink-tan to white exophytic and friable lesions that were polypoid or pedunculated, located in the renal pelvis or proximal ureter. The masses ranged in size from 0.5 to 3.2 cm (mean, 1.6 cm). PUTIP is a polypoid, plaque-like lesion with features of the following: (1) inverted papillary urothelial neoplasm of low malignant potential, lacking an exophytic papillary component; (2) florid von Brunn nest proliferation within and radiating outward from the polypoid lesion; and (3) in some cases, an inverted papilloma with densely hyalinized collagenous stroma. All 4 PUTIPs with formalin-fixed, paraffin-embedded material available were positive for the TERT promoter mutation 228G>A by polymerase chain reaction and were microsatellite stable. Given that PUTIP clinically forms a tumor and is typically treated by nephroureterectomy, it is best regarded as a unique benign urothelial neoplasm that exclusively occurs in the renal pelvis/proximal ureter.

Purpose To investigate the association between preoperative plasma fibrinogen levels and clinicopathological features in patients with bladder urothelial tumors. Methods In this retrospective single-center study, we evaluated preoperative plasma fibrinogen levels in 503 patients newly diagnosed with bladder urothelial tumors between January 2009 and October 2014. All patients received surgical intervention as the primary treatment method. Associations between preoperative plasma fibrinogen levels and clinicopathological parameters were analyzed. Univariate and multivariate logistic regression analyses were performed to identify independent associations. Results The mean preoperative fibrinogen level in patients with bladder urothelial carcinoma (BUC) was significantly higher than that in patients with papilloma or papillary urothelial neoplasm of low malignant potential (PUNLMP) ( P = 0.004). Additionally, patients with BUC with advanced-stage disease showed elevated plasma fibrinogen levels compared to patients with early-stage disease (high-grade BUC vs. low-grade BUC: P = 0.002; muscle-invasive BUC vs. non-muscle-invasive BUC: P = 0.010). In a multivariate regression model, a plasma fibrinogen level >3.04 g/L was identified to be independently associated with the presence of BUC (hazard ratio [HR] = 1.653, P = 0.047), high-grade BUC (HR = 1.869, P = 0.004), and muscle-invasive BUC (HR = 1.870, P = 0.044). Conclusions Elevated preoperative plasma fibrinogen level is an independent predictor of malignancy as well as advanced-stage carcinoma in patients with bladder urothelial tumors, suggesting that plasma fibrinogen may be a promising diagnostic and prognostic biomarker for bladder tumors.

Context In the management of urothelial carcinoma, determination of the pathological grade aims at stratifying tumours into different prognostic groups to allow evaluation of treatment results, and optimise patient management. This article reviews the principles behind different grading systems for urothelial bladder carcinoma discussing their reproducibility and prognostic value. Objective This paper aims to show the evolution of the World Health Organisation (WHO) grading system, discussing their reproducibility and prognostic value, and evaluating which classification system best predicts disease recurrence and progression. The most optimal classification system is robust, reproducible, and transparent with comprehensive data on interobserver and intraobserver variability. The WHO published an updated tumour classification in 2016, which presents a step forward, but its performance will need validation in clinical studies. Evidence acquisition Medline and EMBASE were searched using the key terms WHO 1973, WHO/International Society of Urological Pathology 1998, WHO 2004, WHO 2016, histology, reproducibility, and prognostic value, in the time frame 1973 to May 2016. The references list of relevant papers was also consulted, resulting in the selection of 48 papers. Evidence synthesis There are still inherent limitations in all available tumour classification systems. The WHO 1973 presents considerable ambiguity for classification of the G2 tumour group and grading of the G1/2 and G2/3 groups. The 2004 WHO classification introduced the concept of low-grade and high-grade tumours, as well as the papillary urothelial neoplasm of low malignant potential category which is retained in the 2016 classification. Furthermore, while molecular markers are available that have been shown to contribute to a more accurate histological grading of urothelial carcinomas, thereby improving selection of treatment for a given patient, these are not (yet) part of standard clinical practice. Conclusions The prognosis of patients diagnosed with urothelial carcinoma greatly depends on correct histological grading of the tumour. There is still limited data regarding intraobserver and interobserver variability differences between the WHO 1973 and 2004 classification systems. Additionally, reproducibility remains a concern: histological differences between the various types of tumour may be subtle and there is still no consensus amongst pathologists. The recent WHO 2016 classification presents a further improvement on the 2004 classification, but until further data becomes available, the European Association of Urology currently recommends the use of both WHO 1973 and WHO 2004/2016 classifications. Patient summary Bladder cancer, when treated in time, has a good prognosis. However, selection of the most optimal treatment is largely dependent on the information your doctor will receive from the pathologist following evaluation of the tissue resected from the bladder. It is therefore important that the classification system that the pathologist uses to grade the tissue is transparent and clear for both urologists and pathologists. A reliable classification system will ensure that aggressive tumours are not misinterpreted, and less aggressive cancer is not overtreated.

Background Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) are exceptionally rare in the first decade of life (mostly if multifocal) and there is a lack of standardized recommendations for the pediatric age. Case presentation We describe the case of a 9-year-old boy with a diagnosis of PUNLMP, who underwent to cystoscopic lesion removal and later to endoscopic lesion removal and intra-bladder Mitomycin-c (MMC) instillations for relapsed disease. Follow-up investigations at five years showed disease negativity. Conclusions Intra-bladder MMC instillation may allow obtaining the complete remission with bladder-sparing for paediatric patients with a high-risk relapsed PUNLMP.

Purpose: Bladder tumors are rare in children and adolescents. For this reason, the diagnosis is sometimes delayed in pediatric patients. We aimed to describe the diagnosis, treatment, and follow-up methods of bladder urothelial neoplasms in children and adolescents. Materials and Methods: We carried out a retrospective multicenter study involving patients who were treated between 2008 and 2014. Eleven patients aged younger than 18 years were enrolled in the study. In all the patients, a bladder tumor was diagnosed using ultrasonography and was treated through transurethral resection of the bladder (TURBT). Results: Nine of the 11 patients (82%) were admitted with gross hematuria. The average delay in diagnosis was 3 months (range, 0–16 months) until the ultrasonographic diagnosis was performed from the first episodes of macroscopic hematuria. A single exophytic tumor (1–4cm) was present in each patient. The pathology of all patients was reported as superficial urothelial neoplasm: two with papilloma, one with papillary urothelial neoplasm of low malignant potential (PUNLMP), four with low grade pTa, and four with low grade pT1. No recurrence was observed during regular cystoscopic and ultrasonographic follow-up. Conclusions: Regardless of the presence of hematuria, bladder tumors in children are usually not considered because urothelial carcinoma in this population is extremely rare, which causes a delay in diagnosis. Fortunately, the disease has a good prognosis and recurrences are infrequent. Cystoscopy may be unnecessary in the follow-up of children with bladder tumors. We believe that ultrasonography is sufficient in follow-up.

Introduction: Cytology and cystoscopy have limited sensitivity and specificity for the diagnosis of urothelial carcinoma (UC), due to inflammatory atypia, sampling errors, and other clinicopathologic factors that may obscure test results. Therefore, there remains a clinical need to identify biomarkers to improve the diagnostic accuracy to detect UC. Keratin 17 (K17) is an embryologic cytokeratin that functions as an oncoprotein to promote the degradation of tumor suppressors that drive tumorigenesis. Published work from our group established that K17 is highly expressed in UC and confirmed specificity for UC by immunohistochemical localization of K17 in tissue biopsies of both low-grade and high-grade UCs (Babu et al., Mod Pathol, 2018). Objective: The objective of the current study was to develop an immunocytochemical (ICC) assay to determine K17 is a sensitive and specific biomarker to enhance diagnostic accuracy for UC in urine cytology. Methods: 80 ThinPrep CytoLyt-fixed urine specimens, collected at Stony Brook Medicine in 2018, including 39 with a clinicopathologic diagnosis of UC based on current cytologic diagnosis, and/or a history of biopsy confirmed UC within one year (+/-) of urine cytology specimen collection. K17 ICC was performed by indirect immunoperoxidase methods and K17 test results were scored based on the detection of immunoreactive urothelial cells and not on an assessment of cytologic atypia. The sensitivity and specificity of urine K17 ICC for detection of urothelial neoplasia was calculated by comparison of ICC test results with the cytologic diagnosis and/or the histologic diagnosis of positive cystoscopic biopsy specimens (papillary urothelial neoplasm of low malignant potential [PUNLMP, n=1] or greater). Samples that had no history of abnormal urine cytologic or biopsy diagnosis were categorized as negative for urothelial neoplasia. Results: Relative to the final clinicopathologic diagnosis of UC (n=38) or PUNLMP (n=1), K17 ICC had a sensitivity of 100% (95% CI: 91-100%) and specificity of 90% (95% CI: 77-96%). The positive predictive value was 90% (95% Cl: 78-96%) and the negative predictive value was 100% (95% Cl: 90-100%). Comparing ICC test results to cytologic and biopsy diagnoses, K17 ICC was positive in 9/23 (39%) cases with negative urine cytology. Of these 9 cases, 4 cases had biopsy confirmed UC. K17 ICC was positive in 4/11 (36%) of cases with inflammatory/reactive changes. Of these 4 cases, 3 had biopsy-confirmed UC. K17 ICC was positive in 14/30 (46%) of cases with mild atypia. Of these 14 cases, 12 had biopsy-confirmed UC and 1 had PUNLMP. K17 ICC was positive in 16/16 (100%) of cases with moderate atypia (n=8), severe atypia (n=3), or UC (n=5), all with biopsy-confirmed UC. Conclusions: K17 ICC is a novel and highly sensitive and specific diagnostic test for underlying biopsy-confirmed UC among samples with inflammatory/reactive changes, cytologic atypia, or positive urine cytology. Thus, the K17 test could serve as an adjunct to guide the clinical management of UC cases. Citation Format: Sruthi Babu, Lucia Roa-Peña, Ina Chan, Nam W. Kim, Sholeh Jahanfard, Luisa F. Escobar-Hoyos, Kenneth R. Shroyer. Validation of a novel cytologic biomarker for urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B01.

INTRODUCTION AND OBJECTIVE:We report the case of a 63 year-old male smoker with recurrent low grade urothelial carcinoma and papillary urothelial neoplasm of low malignant potential, refractory to ...

Background Most urothelial neoplasms of the bladder show an exophytic papillary pattern, but some show an inverted growth pattern. In 2004, the World Health Organization (WHO) released a detailed histologic classification system for papillary urothelial neoplasms, but not for inverted forms. The International Consultation on Urologic Disease (ICUD) recommendations of 2012 are applicable to inverted/endophytic papillary lesions as follows: 1) inverted papilloma (IP), 2) inverted papillary urothelial neoplasm of low malignant potential (IPUNLMP), 3) inverted papillary urothelial carcinoma, low grade, non-invasive (IPUCLG-NI), 4) inverted papillary urothelial carcinoma, high grade, non-invasive (IPUCHG-NI), 5) inverted papillary urothelial carcinoma, high grade, invasive (IPUCHG-I). However, only atypical cellular morphology was considered for classification in the 2012 ICUD recommendations, and data to support to validate this new grading system are lacking. Methods Sixty cases of inverted urothelial papillary tumors were classified into 5 categories according to 2012 ICUD and 2016 WHO/ISUP recommendations to evaluate their clinical, pathological, and immunohistochemical characteristics. Two subgroups were defined as subgroup 1, IP and IPUNLMP, and subgroup 2, IPUCLG-NI, IPUCHG-NI, and IPUCHG-I. Clinical features (age, sex, history of urothelial carcinoma, smoking history, size, and multifocality) and histologic features (nuclear pleomorphism, mitotic count, mitosis level, apoptosis, luminal necrosis, trabecular thickening, anastomosing trabeculae, hypercellularity, loss of polarity, peripheral palisading, palisading with central streaming, and discohesiveness) were evaluated. Immunohistochemical stains for CK20, CD44, P53, p16, Ki-67, cyclin D1 and c-erbB2 were performed. Results A total of 60 cases were classified as 10 cases of IP, 29 cases of IPUNLMPs, 15 cases of IPUCLG-NI, 4 cases of IPUCHG-NI, and 2 cases of IPUCHG-I. Compared to subgroup 1, subgroup 2 showed larger tumor size, more nuclear irregularity, higher mitotic count (hot spot and per 10 high power fields), more upper level mitosis (>1/2), and more frequent apoptosis, luminal necrosis, surface papillary component, trabecular thickening, anastomosing irregular trabeculae, hypercellularity, loss of polarity, peripheral palisading with central streaming, and discohesiveness, and absence of umbrella cells and urothelial eddies. CK20, Ki67, and c-erbB2 were the only markers that were differently expressed in the two subgroups, with more expression in subgroup 2. Conclusions The 2012 ICUD recommendations are valid to classify inverted papillary urothelial tumors. However, other histologic features besides atypical cellular morphology should also be considered to distinguish subgroup 1 and subgroup 2 inverted papillary urothelial tumors.

Purpose: The aim of this study was to investigate the usability of MUC1 and p53 for differential diagnosis of noninvasive papillary urothelial neoplasias, especially for distinguishing papillary urothelial neoplasm of low malignant potential (PUNLMP) from low-grade papillary urothelial carcinoma (LGPUC) when the histologic signs are not obvious. Materials and Methods: Seventeen biopsy specimens of the patients with PUNLMP, 20 with LGPUC and 13 with high-grade papillary urothelial carcinoma (HGPUC) were stained for MUC1 and p53 protein by immunohistochemical methods. Histological grading was performed according to an algorithm, which allows histological parameters used in 2004 WHO/ISUP 1998. Results: We had obvious statistical difference for aberrant expression pattern of MUC1 between PUNLMP and LGPUC-HGPUC (P = 0.007). Positivity of MUC1 expression in cytoplasm of basal cells was more observed in HGPUC and LGPUC, whereas PUNLMP was more often showing apical and superficial positivity of MUC1 expression (P = 0.001 and 0.011). Nuclear p53 protein in HGPUC was obviously more frequent than that in LGPUC and PUNLMP (P < 0.001). Measures showed statistical difference among aberrant MUC1 expression, p53 overexpression, and tumor grade (P < 0.001). Conclusions: MUC1 and p53 may be helpful immunohistochemical markers for distinguishing PUNLMP from LGPUC and HGPUC, when the histologic signs are not obvious. © 2 0 1 8 I n d i a n J o u r n a l o f P a t h o l o g y a n d Mi c r o b i o l o g y | P u b l i s h e d b y Wo 510 l t e r s Kl u w e r - Me d k n o w.

WOS: 000439282500010 PubMed ID: 30004053 Background: Mucins may show aberrant expression, localization, and/or glycosylation in multiple malignancies. However, information regarding expression of these mucins is mostly unknown in urothelial tumors. Aim: This study was conducted for examining the expressions of membrane associated and secreted mucin (MUC1) and a secreted gel-forming mucin (MUC2) in urothelial tumors of the urinary bladder. Subjects and Methods: Archival transurethral resection materials of 97 urothelial carcinoma cases were reexamined light microscopically and graded according to the 2004 WHO Classification. Pathological stage was given as pTa, pT1, and pT2. Demonstrative sections were recut for immunohistochemistry for MUC1 and MUC2. The results were statistically analyzed, and P < 0.05 was considered statistically significant. Results: The positivity for MUC1 and MUC2 was 89.7% and 44.3%, respectively. Independent from pathological stage of the tumor, MUC1 expression showed statistically significant correlation with tumor grade (P < 0.05). We did not find any correlation between pathological stage and MUC1 and MUC2 expression (P > 0.05). MUC1 staining pattern in papillary urothelial neoplasm of low malignant potential cases was more commonly apical and superficial (luminal cell layer only). Intermediate cells +/- basal cells or isolated cells or islands of tumor cells with cytoplasmic and/or circumferential membrane positivity for MUC1 and MUC2 were more commonly observed in both low- and high-grade carcinomas. The difference between groups in terms of MUC1 and MUC2 staining was statistically significant (P < 0.05). Conclusions: The staining patterns of both mucins are different between urothelial papillary tumors and may be used to make a differentiation, especially for low-grade papillary urothelial lesions. This difference may also be important in the carcinomatous transformation of urothelial neoplastic and preneoplastic lesions.

A pathologic report for transurethral resection of bladder tumor (TURBT) specimens should include the following information: layers of bladder wall represented, adequacy of material for determining T category of pTNM stage, surface denuded or ulcerated, rough tumor size, tumor configuration (papillary, flat, solid/nodular, invasive, ulcerated, undetermined), histologic type [conventional, urothelial carcinoma with/without squamous differentiation, squamous cell carcinoma, adenocarcinoma (classical or variant), small cell carcinoma, undifferentiated, mixed cell type, undetermined], histologic grade (based on tumor type), microscopic extent of tumor/invasion/pathologic staging (noninvasive flat carcinoma in situ, invasive carcinoma involving lamina propria, muscularis propria; the latter present, absent, or indeterminate), lymphovascular invasion (present, not identified, indeterminate; should be assessed away from the main tumor and only if unequivocal; often is overdiagnosed), extension in prostatic chips sampled by TURBT [involvement of prostatic urethra, prostatic acini, and ducts (by carcinoma in situ) or prostatic stroma (by invasive carcinoma)], associated epithelial lesions [urothelial papilloma (classic or inverted type), papillary urothelial neoplasm of low malignant potential, other], and additional findings (carcinoma in situ, dysplasia, metaplasia, hyperplasia, inflammation, regenerative changes, treatment-related changes, or other). Some of these features may be difficult to identify on small biopsies. It is also recommended to include clinically relevant historical information.

Chaperone-assisted selective autophagy (CASA) is a newly-described selective tension-induced macroautophagy pathway mediated by Bag3 that is believed to be essential for mechanotransduction in skeletal muscle and to be an important regulator of the immune system. We investigated CASA machinery both in healthy and in fifteen papillomavirus-associated neoplastic bovine urothelium. The components of CASA complex, that comprises the molecular chaperones HspA8/Hsc70 and Hsp8B/Hsp22 and the cochaperones Bag3 and STUB1/CHIP, were studied by molecular, microscopic and submicroscopic investigations. CASA complex was found to be constitutively expressed in healthy bovine urothelium; its expression increased in urothelial cancers of cattle, namely thirteen papillary carcinomas and two papillary urothelial neoplasm of low malignant potential (PUNLMPs). We suggest that basal levels of CASA are important in the healthy urothelium which interfaces with the community of urinary microbiota thus representing an important epithelial cell-autonomous mechanism of antibacterial defense. Co-immunoprecipitation studies using an antibody against bovine papillomavirus E5 protein revealed that the oncoprotein co-localized with CASA complex in urothelial cancer cells. This suggests that infection by BPV E5 could influence cell behaviour by interfering with basal autophagy processes although this study did not conclusively show that this interaction increased the expression of CASA proteins. In neoplastic urothelium, CASA could be involved in regulating fundamental cellular processes such adhesion, migration, and proliferation and so might influence the biological behaviour of urothelial tumors in cattle.

There are various subtypes of bladder cancer, which can be classified into invasive and non-invasive neoplasms. Papillary urothelial neoplasm of low malignant potential (PUNLMP) is a non-invasive bladder cancer that occurs predominantly in the lateral and posterior walls of the bladder, close to the ureteral orifices. It has characteristic MR features and does not uptake FDG due to its low malignant potential. PET/MR imaging is useful in detecting this neoplasm and excluding high-grade lesions, extravesical extension, and metastases.

Urinary bladder malignancies are uncommon in children. Approximately 80 children with papillary carcinoma have been described to date, presenting as papillary neoplasms of both low grade and low stage. On the basis of the 1973 World Health Organization classification, tumors were classified as transitional cell carcinoma of the urinary bladder (TCCB). Owing to more detailed histologic criteria, this term has been replaced by papillary urothelial neoplasm of low malignant potential and low-grade carcinoma of the urinary bladder in the World Health Organization-International Society of Urologic Pathology consensus classification system of urothelial neoplasms 2004. Nevertheless, TCCB still remains a common term in contemporary literature. Thus, the differences between papillary urothelial neoplasm of low malignant potential, low-grade carcinoma of the urinary bladder, and TCCB will be illustrated by means of 4 examples of pediatric patients with papillary tumors.

To report our experience and long-term follow-up data on pediatric patients with urothelial carcinoma (UC) of the urinary bladder. In this retrospective study, perioperative and long-term follow-up data of nine pediatric patients with neoplasms of urothelial origin within the urinary bladder between 1980 and 2014 were analyzed. Cystoscopy was performed under general anesthesia, and transurethral resection of the bladder tumors was carried out in the same session. Adult follow-up protocols were used for all patients. Urothelial carcinoma of the urinary bladder was histologically verified in five male (66 %) and three female (33 %) patients. In one patient, papillary urothelial neoplasm of low malignant potential was detected. Median patient age at the time of diagnosis was 12 years (4–18 years). Mean tumor size was 2.2 cm (1.5–4 cm). After a median follow-up of 60 months (10–121 months), no recurrence was observed among our patients. Urothelial carcinoma of the urinary bladder in pediatric patients is a rare condition. Due to lack of substantial data, it is difficult to establish tailored management strategies. Most patients present with low-grade, low-stage disease. Being the most common symptom, macroscopic hematuria should be clarified with cystoscopy in pediatric age group.

Tumours of the urinary tract are the fifth most frequent type of cancer. The most common types are urothelial tumours, among which, non-invasive urothelial neoplasms represent 45% of all cases. The 2016 WHO classification of urinary tract tumours introduced new classifications of non-invasive lesions. Besides urothelial papilloma (UP) and papillary urothelial neoplasm of low malignant potential (PUNLMP), as described in the former classification, the new classification also includes new entities such as urothelial proliferation of uncertain malignant potential (UPUMP) and urothelial dysplasia (UD). Of the aforementioned, UPUMP is the lesion that most commonly progresses, but solely to non-invasive carcinomas. UD is associated with a high risk of progression to invasive carcinoma. Understanding the biological character, and establishing the correct differential diagnosis in cases of non-invasive, non-cancerous lesions of the urinary bladder, will be of importance in establishing outcome predictions for future patients. A systematic review of the current literature allows us to systematize genetic, morphologic and prognostic factors of such lesions. Moreover, the collected data provide the basis for a proposed diagnostic algorithm which facilitates quick and effective differential diagnoses in cases of non-invasive non-cancerous urinary bladder lesions.

We compared blue light flexible cystoscopy with white light flexible cystoscopy for the detection of bladder cancer during surveillance.Patients at high risk for recurrence received hexaminolevulinate intravesically before white light flexible cystoscopy and randomization to blue light flexible cystoscopy. All suspicious lesions were documented. Patients with suspicious lesions were referred to the operating room for repeat white and blue light cystoscopy. All suspected lesions were biopsied or resected and specimens were examined by an independent pathology consensus panel. The primary study end point was the proportion of patients with histologically confirmed malignancy detected only with blue light flexible cystoscopy. Additional end points were the false-positive rate, carcinoma in situ detection and additional tumors detected only with blue light cystoscopy.Following surveillance 103 of the 304 patients were referred, including 63 with confirmed malignancy, of whom 26 had carcinoma in situ. In 13 of the 63 patients (20.6%, 95% CI 11.5-32.7) recurrence was seen only with blue light flexible cystoscopy (p0.0001). Five of these cases were confirmed as carcinoma in situ. Operating room examination confirmed carcinoma in situ in 26 of 63 patients (41%), which was detected only with blue light cystoscopy in 9 of the 26 (34.6%, 95% CI 17.2-55.7, p0.0001). Blue light cystoscopy identified additional malignant lesions in 29 of the 63 patients (46%). The false-positive rate was 9.1% for white and blue light cystoscopy. None of the 12 adverse events during surveillance were serious.Office based blue light flexible cystoscopy significantly improves the detection of patients with recurrent bladder cancer and it is safe when used for surveillance. Blue light cystoscopy in the operating room significantly improves the detection of carcinoma in situ and detects lesions that are missed with white light cystoscopy.

Urinary bladder masses are rare in children, and the associated histologic features and prognoses in this population are different from those in adults. Most children with urinary bladder masses present with lower urinary tract symptoms, which may include hematuria, dysuria, frequent urination, and urgency to urinate. However, some of these masses may be identified incidentally or involve generic symptoms such as abdominal distention. In general, pediatric bladder tumors can be divided into those that originate from the bladder epithelium, known as urothelial neoplasms, and mesenchymal bladder neoplasms, which are more prevalent. The most common bladder malignancy in children is a rhabdomyosarcoma, whereas the most common benign bladder lesion in the pediatric population is a papillary urothelial neoplasm of low malignant potential (PUNLMP). The first-line imaging tool for assessing bladder lesions is ultrasonography, which may be followed by a cross-sectional imaging examination such as computed tomography or magnetic resonance imaging if the origin of the mass is unclear or if distant spread is suspected. Although imaging may enable the radiologist to suggest a differential diagnosis based on lesion location and patient age, tissue biopsy generally is required to identify the exact pathologic entity. This is usually performed at cystoscopy and may be curative in cases in which the lesion is small and has low recurrence potential. Knowledge of the clinical, histopathologic, and imaging features of common bladder neoplasms is essential, as it can aid in preventing imaging pitfalls. These may include the misinterpretation of either a pelvic mass as arising from the bladder or a bladder mass as arising from the pelvis, and interpreting an inflammatory mass or bladder detritus as a neoplasm. ©RSNA, 2017.