Recent Advances in the Classification of Bladder Cancer – Updates from the 5th Edition of the World Health Organization Classification of the Urinary and Male Genital Tumors


BACKGROUND: The World Health Organization Classification (WHO) of Urinary and Male Genital Tumors has recently been updated to its 5th edition. The new edition presents a comprehensive approach to the classification of urinary and male genital tumors with an incorporation of morphologic, clinical, and genomic data.

OBJECTIVE: This review aims to update the new classification of bladder cancer in the 5th edition and to highlight important changes in nomenclatures, diagnostic criteria, and molecular characterization, as compared to the 4th edition.

METHODS: The pathologic classification of bladder cancer in the 5th edition of WHO Classification of Urinary and Male Genital Tumours was compared to that in the 4th edition. PubMed was searched using key words, including bladder cancer, WHO 1973, WHO 1998, WHO 2004, WHO 2016, histology, pathology, genomics, and molecular classification in the time frame from 1973 to August of 2022. Other relevant papers were also consulted, resulting in the selection of 81 papers as references.

RESULTS: The binary grading of papillary urothelial carcinoma (UC) is practical, but it may be oversimplified and contribute to “grade migration” in recent years. An arbitrary cutoff (5%) has been proposed for bladder cancers with mixed grades. The diagnosis of papillary urothelial neoplasm with low malignant potential has been dramatically reduced in recent years because of overlapping morphology and treatment with low-grade papillary UC. An inverted growth pattern should be distinguished from true (or destructive) stromal invasion in papillary UC. Several methods have been proposed for pT1 tumor substaging, but it is often challenging to substage pT1 tumors in small biopsy specimens. Bladder UC shows a high tendency for divergent differentiation, leading to several distinct histologic subtypes associated with an aggressive clinical behavior. Molecular classification based on the genomic analysis may be a useful tool in the stratification of patients for optimal treatment.

CONCLUSIONS: The 5th edition of WHO Classification of Urinary and Male Genital Tumours has made several significant changes in the classification of bladder cancer. It is important to be aware of these changes and to incorporate them into routine clinical practice.

The Role of Local Agents for the Treatment of Localized Upper Tract Urothelial Carcinoma: A Review of the Current Evidence


Kidney-sparing surgery (KSS) for upper urinary tract urothelial carcinoma (UTUC) is a promising alternative to radical nephroureterectomy, especially for low-risk cases. However, due to the established risk of ipsilateral UTUC recurrence caused by the implantation of floating neoplastic cells after endoscopic resection, adjuvant endocavitary (endoureteral) instillations have been proposed. Instillation therapy may be also used as primary treatment for UTUC. The two most studied drugs that have been evaluated in both the adjuvant and primary setting of endocavitary instillation are mitomycin C and Bacillus Calmette-Guerin.

The current paper provides an overview of the endocavitary treatments for UTUC, focusing on methods of administration, novel formulations, oncologic outcomes (in terms of endocavitary recurrence and progression), as well as on complications. In particular, the role of UGN-101 as a primary chemoablative treatment of primary noninvasive, endoscopically unresectable, low-grade, UTUC has been analysed. The drug achieved a complete response rate of 58% after the induction cycle, with a durable response independently of the maintenance cycle. The cumulative experience on the role of UUT instillation therapy appears encouraging; however, no definitive conclusions can be drawn about its therapeutic benefit. Given the current state of the art, any decision to administer adjuvant endoureteral therapy for UTUC should be carefully weighed against the potential adverse events.

Nevertheless, newer investigations that improve visualization during ureteroscopy, genomic characterization, novel drugs and innovative strategies of improved drug delivery are under evaluation. The landscape of KSS for the treatment of the UTUC is evolving and seems promising.

SH3BP5-AS1/IGF2BP2/VDAC2 Axis Promotes the Apoptosis and Ferroptosis of Bladder Cancer Cells


BACKGROUND: Bladder cancer (BC) is the most common malignant tumor in the urinary system with a high incidence, imposing a burden on the healthcare system worldwide. The participation of long non-coding RNAs (lncRNAs) in BC has attracted increasing attention.

OBJECTIVE: The aim in the current study was to explore the potential mechanism involving SH3BP5-AS1 in modulating BC cell proliferation, apoptosis and ferroptosis.

METHODS: qPCR and WB analysis measured the expression of RNAs and proteins. Functional and mechanism experiments were performed to investigate RNA impacts on cell proliferation, apoptosis and ferroptosis, and explore the correlation between RNA and protein expression.

RESULTS: SH3BP5-AS1 was down-regulated in BC cells, and SH3BP5-AS1 overexpression could inhibit BC cell proliferation but facilitate the cell apoptosis. SH3BP5-AS1 was also found to facilitate the ferroptosis of BC cells. Additionally, SH3BP5-AS1 was confirmed to recruit IGF2BP2 to regulate VDAC2 expression in the m6A-dependent manner. VDAC2 was detected to be down-regulated in BC cells and was verified to inhibit BC cell growth. Moreover, it was indicated from rescue assays that SH3BP5-AS1 could modulate VDAC2 expression to promote the ferroptosis of BC cells.

CONCLUSION: SH3BP5-AS1 could affect BC cell proliferation, apoptosis and ferroptosis via IGF2BP2/VDAC2, providing a novel molecular perspective for understanding BC.

Is There A Benefit of Restaging Transurethral Resection of Bladder Tumor Prior to Radical Cystectomy With or Without Neoadjuvant Chemotherapy?


BACKGROUND: One of the best predictors of positive outcomes in bladder cancer (BC) is pT0 following radical cystectomy (RC). Discordance between clinical and pathologic staging affects decision-making in patients with clinical absence of disease (cT0).

OBJECTIVES: We sought to determine whether a restaging transurethral resection of bladder tumor (re-TURBT) improves clinical staging accuracy relative to pathologic stage RC in patients treated with neoadjuvant chemotherapy (NAC) versus those who did not receive NAC.

METHODS: We queried our prospectively maintained IRB approved institutional database to identify 129 patients who underwent RC from 2013 to 2019 with a re-TURBT prior to RC. 53 patients were treated with NAC between their initial and re-TURBT and 76 patients were not treated with NAC.

RESULTS: The overall upstaging rate from re-TURBT to RC was 34.9%. There was no significant difference in the upstaging rate between the NAC and no-NAC groups – 31.0% vs. 37.0%, respectively. In patients who were cT0 on re-TURBT, the NAC group did not show a significantly greater rate of pathologic clinical CR (pT0) than the no NAC group – 38.5% vs. 37.5%, respectively. Re-TURBT with staging < rT2 as a predictor for absence of MIBC on pathologic staging (<ypT2) did not show a significant difference between the NAC and no NAC group, with a negative predictive value (NPV) of 69.0% and 66.7%, respectively.

CONCLUSIONS: Re-TURBT after NAC does not show statistically significant improvement in staging accuracy relative to pathologic stage at RC compared to re-TURBT in patients not treated with NAC.

Prospective Evaluation of FDG-PET/CT for On-treatment Assessment of Response to Neoadjuvant or Induction Chemotherapy in Invasive Bladder Cancer


BACKGROUND: Neoadjuvant/induction chemotherapy (NAIC) improves survival in patients with muscle-invasive bladder carcinoma (MIBC). On-treatment response assessment may aid in decisions to continue or cease NAIC.

OBJECTIVE: We investigated whether 18F-fluoro-2-deoxy-D-glucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) could predict response to NAIC and compared to contrast-enhanced Computed Tomography (CECT).

METHODS: We prospectively included 83 patients treated for MIBC (i.e. high-risk cT2-4N0M0 or cT1-4N+M0-1a) between 2014 and 2018. Response to NAIC was assessed after 2-3 cycles with FDG-PET/CT (Peter-Mac and EORTC criteria) and CECT (RECIST1.1 criteria). We assessed prediction of complete pathological response (pCR; ypT0N0), complete pathological down-staging (pCD;≤ypT1N0), any down-staging from baseline (ypTN < cTN) and progression (inoperable tumor/ypN+/M+). The reference standard was histopathological assessment or clinical follow-up. Sensitivity, specificity, and accuracy were calculated.

RESULTS: Pathological response rates were 21% for pCR, 29% for pCD, and 10% progressed. All patients underwent FDG-PET/CT and 61 patients also underwent CECT (73%). Accuracy of FDG-PET/CT for prediction of pCR, pCD, and progression were 73%, 48%, and 73%, respectively. Accuracy of CECT for prediction of pCR, pCD, and progression were 78%, 65%, and 67%, respectively. Specificity of CECT was significantly higher than FDG-PET/CT for prediction of pCD and any down-staging (p = 0.007 and p = 0.022). In all other analyses, no significant differences between FDG-PET/CT and CECT were found.

CONCLUSIONS: Routine FDG-PET/CT has insufficient predictive power to aid in response assessment compared to CECT.

An Association Study of Germline Variants in Bladder Cancer-Related Genes with the Prognosis of Non-Muscle Invasive Bladder Cancer


BACKGROUND: Various germline genetic variants are associated with the prognosis of non-muscle invasive bladder cancer (NMIBC). Germline variants in genes frequently somatically mutated in bladder cancer have not been studied thoroughly in relation to risk of recurrence or progression in NMIBC.

OBJECTIVE: To identify germline DNA variants in bladder carcinogenesis-related genes associated with recurrence or progression in NMIBC.

METHODS: We analysed associations between single-nucleotide polymorphisms (SNPs) and NMIBC recurrence and progression using data from the Nijmegen Bladder Cancer Study (NBCS, 1,443 patients). We included 5,053 SNPs within 46 genes known to have mutation, overexpression or amplification in bladder cancer. We included all recurrences in the statistical analysis and performed both single variant analysis and gene-based analysis. SNPs and genes that showed significant or suggestive association (false discovery rate P value < 20%) were followed-up in independent cohorts for replication analysis, through eQTL analysis and tests for association of tumour expression levels with NMIBC recurrence and progression.

RESULTS: Single variant analysis showed no statistically significant associations with recurrence or progression. In gene-based analysis, the aggregate effect of the 25 SNPs in the Cyclin D1 gene (CCND1) was statistically significantly associated with NMIBC recurrence (Punadj = 0.001, PFDR = 0.046), but not with progression (Punadj = 0.17, PFDR = 0.54). Validation analysis in independent cohorts did not confirm the association of CCND1 with NMIBC recurrence.

CONCLUSIONS: We could not identify reproducible associations between common germline variants in bladder carcinogenesis-related genes and NMIBC recurrence or progression.

The Association between Diabetes Medication Use and Tumour Characteristics at Diagnosis in Patients with Urothelial Carcinoma: A Retrospective Registry-Based Study1


BACKGROUND: Observational studies indicate a potential association between diabetes medication use and aggressiveness of bladder cancer.

OBJECTIVE: The objective is to exploratively study the association between diabetes medication use, as proxy for diabetes, and cancer characteristics of urothelial carcinoma at diagnosis. Furthermore, differences in associations between specific types of diabetes medication are studied.

METHODS: The association between use of diabetes medication and urothelial carcinoma (UC) characteristics at diagnosis is studied. A retrospective registry-based study among UC patients in the Netherlands was performed for which two large linked registries from PHARMO and IKNL were used. Patients diagnosed with UC between 2000 and 2016 and no previous cancer were included in this study. In this study, 1,168 UC patients who were diabetes medication users were included as well as 3,609 non-users. Conditional logistic regression analysis was performed to determine odds ratios comparing cancer characteristics between different types of diabetes medication users to non-users.

RESULTS: Noninsulin antidiabetic drugs (NIAD) use was associated with a muscle-invasive type of UC compared to non-users (OR = 1.31, 95% CI: 1.10–1.55 for T2+ versus Ta) as well as a poorly differentiated tumour (OR = 1.31, 95% CI: 1.07–1.59 for poorly versus well differentiated tumours).

CONCLUSION: Users of diabetes medication are potentially more likely to be diagnosed with a more aggressive tumour than non-users; however, lifestyle factors could not be adjusted for.

Editorial Concerning “The Association Between Diabetes Medication Use and Tumour Characteristics at Diagnosis in Patients with Urothelial Carcinoma: A Retrospective Registry-Based Study”


In the Western world, and increasingly also in low and middle income countries, there is an epidemic of obesity and type 2 diabetes (T2D), with obesity through chronic inflammation and insulin resistance being one of the main causes (and characteristics) of T2D. And while the individual risk of cancer in the Western world is increasing only slowly, the absolute numbers of new cancer diagnoses are also increasing dramatically. It is logical that this has led to a great deal of interest in the association between T2D and cancer (for an excellent overview of the knowledge in this field, see [1]). This possible association is not only interesting from a public health point of view. Care providers in the clinic are also increasingly dealing with cancer patients who also have obesity and/or T2D.

Economic Outcomes of Hexaminolevulinate Blue-Light Cystoscopy in Non-Muscle Invasive Bladder Cancer: A 5-Year, Medicare-Based Model”


BACKGROUND: Bladder cancer is the most expensive cancer to treat on a per-patient basis. Blue light cystoscopy with hexaminolevulinate (BLC) has demonstrated improved diagnostic accuracy compared with white light cystoscopy (WLC) in non-muscle invasive bladder cancer (NMIBC). With higher upfront costs, questions remain about long-term BLC cost outcomes.

OBJECTIVE: This study seeks to investigate the 5-year cost comparison of BLC and WLC from the Medicare payer perspective.

METHODS: A representative 5-year NMIBC management model was constructed and Medicare reimbursement values were overlaid. The primary outcome was mean year-over-year cumulative cost discounted to present value at a 3% annual percentage rate. The secondary outcome was the rate of clinical events.

RESULTS: Patients in the BLC cohort experienced fewer recurrences. On a cumulative present value cost basis, BLC was more expensive per patient in years 1, 2, and 3 than WLC, however, in years 4 and 5, BLC was economically favorable. Year 5 BLC mean cumulative cost savings was $1,172 per patient. Overall, 31.6% of all patients in the BLC group generated cumulative cost savings compared to WLC at year 1 compared with 50.9% at the end of year 5.

CONCLUSIONS: Despite a higher initial annual cost, a slight cumulative economic advantage of BLC is realized after surveillance year 3. Additionally, a greater proportion of patients who received BLC achieved cost savings at the end of year 5. As novel technology emerges, economic models can help health care systems predict associated costs and quality improvements.