Prostate cancer (PCa) is one of the most prevalent malignancies in the male urogenital system. Despite extensive research into its mechanisms of initiation and progression, the full scope of its pathophysiology remains insufficiently understood. This study demonstrated that NUF2 was significantly overexpressed in PCa, with its elevated levels correlating with poor patient survival outcomes. Silencing NUF2 notably impaired PCa cell proliferation and metastasis in both in vitro and in vivo models, whereas its overexpression promoted these processes. Additionally, YY1 was identified as a direct transcriptional activator of NUF2, binding to its promoter and enhancing its oncogenic effects through activation of downstream targets. Moreover, NUF2 promoted PCa progression by recruiting p38, accelerating its phosphorylation, and activating the p38/MAPK signaling pathway. Through the PubChem database, fisetin was identified as a small molecule inhibitor of NUF2. Fisetin effectively inhibited PCa cell proliferation, and NUF2 overexpression reversed this inhibitory effect. In conclusion, our results suggest that NUF2 overexpression accelerated PCa progression via the p38/MAPK pathway, regulated by YY1. The identification of fisetin as a NUF2 inhibitor offers a promising therapeutic strategy for targeting NUF2 to impede PCa growth. NUF2 may thus serve as a valuable prognostic biomarker and a potential therapeutic target for PCa.

Survival differences in rare histological prostate cancer (PCa) subtypes relative to age-matched population-based controls are unknown. Within Surveillance, Epidemiology, and End Results database (2004-2020), newly diagnosed (2004-2015) PCa patients were identified. Relying on the Social Security Administration Life Tables (2004-2020) with 5 years of follow-up, age-matched population-based controls (Monte Carlo simulation) were simulated for each patient. Kaplan-Meier analyses addressed survival rates. Of 582,220 patients, 580,368 (99.68%) harbored acinar, 867 (0.15%) ductal, 534 (0.09%) neuroendocrine, 368 (0.07%) mucinous, and 83 (0.01%) signet ring cell carcinoma. The metastatic stage was most prevalent in neuroendocrine (62%). In the localized stage, the overall survival difference at 5 years of follow-up was greatest in neuroendocrine (22% vs. 72%), signet ring cell (78% vs. 84%), and ductal carcinoma (71% vs. 77%). In the locally advanced stage, overall survival difference was greatest in neuroendocrine (16% vs. 79%), signet ring cell (75% vs. 91%), ductal (78% vs. 84%), and mucinous carcinoma (84% vs. 90%). In the metastatic stage, the overall survival difference was greatest in neuroendocrine (3% vs. 81%), mucinous (26% vs. 84%), and acinar carcinoma (27% vs. 85%). Regardless of stage, neuroendocrine carcinoma patients exhibit the least favorable life expectancy compared with population-based controls. Conversely, all other rare histological PCa subtypes do not meaningfully affect life expectancy in localized or locally advanced stages, except for locally advanced signet ring cell adenocarcinoma.

Glandular lesions involving the bladder are less common than conventional urothelial carcinoma, and they are often diagnostically challenging diseases, carrying different clinical outcomes. As a group, they encompass both primary and secondary neoplasms, with sometimes overlapping morphological features. In this scenario, proper clinical information is important, in that secondary involvement of the bladder may occur by direct extension or lymphatic/hematogenous spread from carcinomas at other sites, comprising prostate, colon, cervix, breast, and lung. According to the 5th edition of the WHO Classification of urological tumors, glandular morphology is a major hallmark of the following entities: urothelial carcinoma with glandular differentiation, adenocarcinoma, NOS, urachal carcinoma, and tumors of Mullerian type. The distinction among these entities, and between primary and secondary tumors, heavily relies on their biological and immunophenotypical features. This article will review glandular neoplasms of the bladder, highlighting their main immunophenotypical markers. Furthermore, molecular data associated with their pathogenesis, prognosis, and treatment will be described. The aim of this study is to provide a practical and comprehensive up-to-date overview of this complex topic.

This multicenter, retrospective study evaluated the impact of pelvic lymph node dissection (PLND) on survival outcomes in non-muscle invasive bladder cancer (NMIBC) patients undergoing radical cystectomy (RC) and identified factors associated with upstaging. A total of 544 NMIBC patients who underwent RC with or without PLND between 2019 and 2024 were analyzed. Survival outcomes, including cancer-specific survival (CSS) and recurrence-free survival (RFS), were compared using Kaplan-Meier analysis and Cox proportional hazards models, while factors associated with upstaging were examined through logistic regression. Of the 544 patients, 509 (93.6%) were staged as cT1, and 412 (75.7%) underwent PLND. Upstaging occurred in 193 patients (35.5%), with pathological stages distributed as pT1 (50.0%), pT2 (20.8%), pT3 (11.2%), and pT4 (3.5%). Among patients who underwent PLND, 29 (7.0%) had positive lymph nodes. PLND was associated with improved RFS (5-year: 84.3% vs. 71.5%; adjusted hazard ratio [HR] = 0.33, 95% confidence interval [CI]: 0.20-0.56, p < 0.001) but did not significantly impact CSS (5-year: 86.5% vs. 81.6%; adjusted HR = 0.57, 95% CI: 0.32-1.02, p = 0.06). Lymph node positivity was linked to the worst prognosis. cT1 tumors, histological subtypes, and PLND were significant predictors of upstaging. In patients with cT1 tumors or histological subtypes, repeat transurethral resection is recommended to obtain more precise staging, which may inform further therapeutic decisions. While PLND is not routinely recommended for all NMIBC patients, it may be considered in those with high-risk features, particularly cT1 tumors or histological subtypes.

Patients with histologic subtypes (HS) of urothelial cancers are often excluded from neoadjuvant chemotherapy (NAC) trials for muscle-invasive bladder cancer (MIBC). Additionally, there exist conflicting data regarding the inherent chemotherapeutic sensitivity of individual HS. Herein, we assess the prognostic significance of pathologic response to NAC, a common surrogate endpoint of success in NAC trials, in patients with HS versus pure urothelial carcinoma (PUC).

The National Cancer Database (NCDB) was queried for patients with cT2-4N0M0 MIBC who received NAC and radical cystectomy (RC) between 2004 and 2020. Pathologic response to NAC was defined as complete (ypT0N0), partial (

RESULTS

5,372 patients were included, with 345 (6.4%) having HS. Nonresponse rates to NAC in HS patients were significantly higher than those with PUC (65.2% vs. 55.8%, P = 0.003). Patients with squamous and glandular differentiation exhibited the highest rates of nonresponse (79% and 72.2%, respectively). In unstratified analysis, patients with HS exhibited shorter OS (P < 0.0001). Patients with HS had uniformly worse OS even after controlling for pathologic response (P = 0.013), with the most notable discrepancy in partial responders (HR = 4.88, 95% CI 2.29-10.38, P < 0.001; 3-year OS 91% vs. 66% for partial response in PUC vs. HS, respectively).

CONCLUSIONS

Patients with HS MIBC exhibit poor survival when treated with NAC followed by RC compared with PUC, even when controlling for pathologic response. These data suggest that pathologic response is a less accurate surrogate endpoint in patients with HS relative to PUC, and may suggest a role for therapeutic intensification in the adjuvant setting for patients with HS.

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Bladder cancer, as a highly heterogeneous malignant tumor of the urinary system, is significantly affected by tumor metabolic reprogramming in its response to immunotherapy. This review systematically elaborates on the molecular mechanisms of abnormal glucose and lipid metabolism in the bladder cancer microenvironment and immune escape, and discusses precision treatment strategies based on metabolic regulation. In the future, it will be necessary to combine spatiotemporal omics and artificial intelligence technologies to construct a multi-target intervention system for the metabolic-immune interaction network, promoting a paradigm shift in precision treatment for bladder cancer.

Urinary exosomes are valuable biomarkers for the liquid biopsy of bladder cancer (BCa), carrying critical biomolecules associated with BCa that assist in clinical diagnosis and prognosis prediction. However, the lack of rapid, efficient, and high-throughput techniques for urinary exosome enrichment limits their clinical application. This study presents an exosome cyclic enrichment chip based on asymmetric impinging streams and a metal-organic framework (MOF)-on-MOF material. The newly synthesized MOF material exhibited excellent exosome-enrichment capabilities. Moreover, the integration of asymmetric impinging streams and a cyclic fluidic pathway within the chip notably enhanced the collision efficiency between exosomes and MOF. Leveraging the chip, enables the rapid and efficient enrichment of exosomes from a 10 mL urine sample within 30 min, without the requirement for sample pre-concentration. In a clinical study of 300 subjects from two centers, a BCa diagnostic model based on urinary exosomal NORAD (Exo-NORAD) and urine sediment NORAD (Sed-NORAD) is developed, which showed a higher detection positivity rate than BCa fluorescence in situ hybridization (FISH) and urinary cytology. Exo-NORAD is identified as an independent prognostic factor for BCa using Cox regression analysis. In conclusion, this study provides a new approach for the noninvasive diagnosis and prognosis prediction of BCa.

Rare cancers of the genitourinary (GU) tract are often clinically aggressive yet have few or no standard-of-care treatments. Multiple antibody-drug conjugates (ADCs) have been approved in solid malignancies. This review explores the use of ADCs in rare GU tumors in the context of biological pathways and ongoing research in solid tumors.

Few clinical trials of ADCs focus on recruiting participants with rare tumors of the GU tract, including trials testing enfortumab vedotin as monotherapy or combined with pembrolizumab, and sacituzumab govitecan as monotherapy or combined with atezolizumab. We highlight many ongoing trials of novel ADCs for advanced/metastatic solid tumors and emphasize the potential eligibility of patients with rare GU tumors for tumor-agnostic trials.

ADCs are being tested in multiple solid tumors, including rare GU tumors. Ongoing preclinical research supports the use of some ADCs in several rare GU tumors and improves our understanding of their pathophysiology.

The prognostic value of the prostate adenocarcinoma (PAC) with ductal feature in patients with advanced prostate cancer treated with abiraterone acetate has not been scrutinized. This study aims to explore the predictive value of PAC with ductal feature on the therapeutic efficacy of abiraterone therapy in metastatic prostate cancer (mPCa) patients.

We retrospectively analyzed data from 569 patients with mPCa receiving abiraterone at either the metastatic hormone-sensitive (mHSPC, N = 165) or castration-resistant prostate cancer (mCRPC, N = 404) stage. PSM was performed to balance the baseline characteristics between individuals with and without ductal features. Kaplan-Meier curves and Cox regression were used to analyze the predictive significance of ductal feature on abiraterone efficacy, including PSA response, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS).

Totally, ductal feature was detected in 40/569 (7.0%) men, with 18 and 22 in the mHSPC and mCRPC cohorts, respectively. The PSA response rate was comparable for people with and without ductal features for both cohorts. Notably, in the mHSPC cohort, patients with and without ductal features shared similar median PSA-PFS (not reached vs. 32.6-months, p = 0.593) and rPFS (not reached vs. 35.0-months, p = 0.768). Similar results were observed in the mCRPC cohort (median PSA-PFS: 21.2- vs. 11.6-months, p = 0.100; median rPFS: 34.6- vs. 18.7-months, p = 0.092). COX regression further revealed that ductal feature was not an indicator of unfavorable PSA-PFS or rPFS in the mHSPC and mCRPC cohort.

In conclusion, our findings indicated that there is insufficient evidence to differentiate the therapeutic efficacy of AA in mPCa based on the presence or absence of ductal features. However, further validation through larger-scale studies is required to substantiate them.

Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions.

We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis.

Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC.

AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Accurate detection of unconventional histologies (UH) in prostate cancer (PCa) is crucial for treatment planning and prognosis. This systematic review and meta-analysis aimed to evaluate the accuracy of multiparametric magnetic resonance imaging (mpMRI) in detecting UH on prostatectomy, particularly cribriform architecture (CA) and intraductal carcinoma (IDC-P), in patients with localized PCa.

A literature search was conducted in major databases for studies published after 2000. Seventeen articles fulfilled the inclusion criteria and were eligible for qualitative analysis. Five studies met the inclusion criteria for meta-analysis.

The pooled sensitivity and specificity of mpMRI (Prostate Imaging Reporting and Data System (PI-RADS) cutoff 3) to detect cribriform architecture were 0.91 and 0.29. The proportion of cribriform lesions increased with higher PI-RADS scores (23.2% for PI-RADS 1-2 to 66.7% for PI-RADS 5). For intraductal carcinoma (IDC-P), two studies found that IDC-P lesions were visible on mpMRI and had lower apparent diffusion coefficient (ADC) values compared to acinar prostate cancer. Four studies evaluating combined CA/IDC-P found sensitivities ranging from 33 to 100%. Lower ADC values were associated with CA/IDC-P in some studies, but not in others. Overall, mpMRI demonstrated promising sensitivity but moderate specificity in detecting these aggressive histological variants, with continued challenges in accurate sampling and characterization of mpMRI.

mpMRI shows high sensitivity but moderate specificity in detecting cribriform architecture in PCa, especially for high PI-RADS scores. These findings support the use of mpMRI for UH detection, but caution is advised in clinical interpretation. Larger prospective studies are needed to validate these results before routine clinical application. We studied how effective MRI is at identifying different UH of PCa, such as cribriform architecture and intraductal carcinoma. MRI is accurate at detecting these cancers when they are present, but it also produces a significant number of false positives. More research is needed to standardize imaging protocols and histological definition and ensure an accurate diagnosis.

Question The accurate detection of unconventional histologies in prostate cancer, particularly cribriform architecture and intraductal carcinoma, is challenging but crucial for treatment planning and prognosis. Findings mpMRI shows high sensitivity (91%) but low specificity (29%) for detecting cribriform architecture, with detection rates increasing proportionally with higher PI-RADS scores. Clinical relevance mpMRI can effectively detect aggressive unconventional histologies in prostate cancer, though its moderate specificity suggests the need for careful interpretation. This aids in risk stratification and treatment planning, potentially improving patient outcomes.

Urological cancers represent an increasing public health concern in the labour force, mainly including prostate cancer (PCA), kidney cancer (KCA), testicular cancer (TCA), and bladder cancer (BLCA). Limited data exist on their occurrence, deaths, and disability-adjusted life years (DALYs). The objective of this study was to analyse three-decade trends in these cancers globally and forecast future patterns.

The study used Global Burden of Disease 2021 data from 1990 to 2021 to evaluate urological cancer stats, including prevalence, incidence, mortality, and DALYs. For people aged 15-64 years, it was then manually age-standardized once. Herein, we employed a range of analytical techniques, including decomposition analysis, a Bayesian Age-Period-Cohort model, a Concentration index and slope index, and frontier analysis, to examine the trends in 204 countries and regions. Furthermore, the relationship between the Socio-Demographic Index (SDI) and the burden of disease is addressed.

Over the past 30 years, PCA, TCA, and KCA rates have risen among the global labour force population. North America, North Asia, and Europe have high incidence and mortality rates. TCA mortality and BLCA and TCA prevalence are expected to continue rising globally until 2050. Urological cancer impacts vary by region and development with more burden in areas with a higher SDI.

Urological cancers represent a substantial disease burden on labour force populations, emphasizing the imperative for targeted interventions and healthcare resources for affected populations. It is therefore crucial to have a comprehensive understanding of the global and regional epidemiological trends, as well as the findings of health economics studies.

Immune Checkpoint Inhibitors (ICIs) are used for advanced urothelial carcinoma (aUC) in different settings. Most patients have pure UC (PUC) but about one-third have UC mixed with histology subtypes (HS). We examined outcomes in patients with HS aUC treated with ICI.

We included patients from 26 centers with PUC and any HS treated with ICI as 1st line (1L) upfront, maintenance avelumab (mAV), and ≥2nd line [2+L] therapy. We calculated overall and progression-free survival (OS, PFS) and observed response rate (ORR) from ICI start.

We included 1511 patients; 752 1L, 609 2+L, 150 mAV. 1L: median OS was 15 (95% CI, 12-17) months for patients with PUC (n = 518), 15 (95% CI, 8-23) months for squamous UC (n = 85) (HR = 1.2, [95% CI, 0.8-1.6]), 11 (95% CI, 6-17) months for micropapillary UC (n = 46) (HR = 1.2, [95% 0.8-1.8]), and 21 (95% CI, 12-30) months in patients with UC mixed with ≥2 HS (n = 30), (HR = 0.9, [95% CI, 0.5-1.4]). 2+L: median OS was 9 (95% CI, 8-10) months for patients with PUC (n = 441), 9 (95% CI, 1-12) months for squamous UC (n = 60) (HR = 1.1, (95% CI, 0.8-1.6]), 6 (95% CI, 1-11) months for micropapillary UC (n = 37) (HR = 1.1, [95% 0.7-1.6]), and 7 (95% CI, 4-10) months in patients with UC mixed with ≥2 HS (n = 17), (HR = 1.6, [95% CI, 0.9-3.1]).

We found no significant OS difference between PUC and HS in patients with aUC treated with ICI monotherapy. Limitations include retrospective design, small sample size in several subsets, lack of randomization, no central imaging or pathology review, selection and confounding biases. Results are hypothesis-generating and need prospective validation.

Acinar adenocarcinoma is the most common histological subtype of prostate cancer (PCa). However, 5% of cases present with unconventional histological subtypes (UHs), which have inconsistent clinical characteristics.

600 patients underwent a radical prostatectomy (RP) at our institution between 2003 and 2023. 50% had UHs, while other 50% age-matched patients (median age 63 years), with pure acinar adenocarcinoma served as comparison group. Collected parameters included age at diagnosis, PSA levels, imaging results, ISUP (International Society of Urological Pathology) Grade Group at biopsy and RP, TNM-stage and biochemical recurrence rates (BCR). Statistical analysis was conducted using SPSS and Excel, applying Mann-Whitney-U, Chi-Square tests, and Cox proportional hazards models to assess associations with recurrence-free survival.

All patients with UHs presented mixed histological forms (P < .001). Importantly, UHs were previously identified only in 9% of biopsy specimens (P < .001). Patients with UHs had more aggressive disease reflected by higher ISUP Grade Group (P < .001), higher prevalence of ≥pT3a tumors as well as higher rates of positive resection margins (P < .001) although fewer nerve-sparing procedures were performed (P < .001). Patients with UH had a higher risk of PSA persistence after RP (P = .04) and higher BCR rates (P < .001) after a median follow-up of 54.8 months. Notably, multivariate Cox regression analysis indicated that the presence of UHs is the most significant risk factor for BCR (HR 1.972, 95% CI 1.210-3.312).

Patients with UH exhibit more aggressive disease and have an increased risk of disease relapse following curative therapy.

This study aimed to assess the oncological outcomes of the subtype of urothelial carcinoma (SUC), including divergent differentiation and histologic subtype, in comparison with those of pure urothelial carcinoma (PUC) in nonmuscle-invasive bladder cancer.

We retrospectively evaluated patients who were initially treated with transurethral resection of the bladder tumor (TURBT) between March 2005 and August 2020 at a single institution. Patients with PUC and SUC were compared in terms of recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS).

Out of 853 enrolled patients, 783 (91.8%) and 70 (8.2%) had PUC and SUC, respectively. SUC presence was significantly associated with old age, tumor size (≥3 cm), higher pT1 rate, high grade, concomitant carcinoma in situ, and lymphovascular invasion. RFS rates after TURBT did not significantly differ between the PUC and SUC groups. With a median follow-up period of 66 months (interquartile range, 38-103 months), the rates and median time of progression to muscle invasion were 6.9% and 22.5 months in the PUC group, and 22.9% and 10.0 months in the SUC group. Moreover, the incidence of progression to metastasis was 4.6% and 15.7% in the PUC and SUC groups, respectively. The 5-year PFS rates (64.5% and 81.9%, P < .001) and 5-year OS rates (71.7% and 86.2%, P = .009) were lower in the SUC group than in the PUC group. On multivariate analysis, SUC presence independently predicted progression to muscle invasion and metastasis.

At initial TURBT diagnosis, we must pay more attention to higher progression risk of SUC than that of PUC in nonmuscle-invasive bladder cancer.

Advances in molecular diagnostics have ushered in a new era for patients with prostate, renal, and urothelial cancers, with novel radiographic and molecular modalities for the assessment of disease burden and minimal residual disease (MRD). Conventional imaging has a limited threshold for disease detection and is often unable to discern clinically occult disease with varying risks of false-negative or false-positive findings depending on the disease state and type of imaging.

We provide an overview of emerging radiographic and molecular tools in development within the genitourinary (GU) disease space. A literature review of contemporary basic, translational, and clinical research studies was performed, covering the timeframe of 1980-2024 through the MEDLINE (via PubMed) and Scopus databases. We highlight select examples of emerging technologies and biomarker-informed clinical trials, which aim to quantify disease at lower thresholds and have the potential for integrating MRD in clinical practice for GU patients.

The development of novel radiotracers, such as prostate-specific membrane antigen or carbonic anhydrase IX, is being evaluated in both clinical practice and trial setting, aiming to change the management of these tumors. Molecular tools including circulating tumor cells and byproducts such as plasma and urine cell-free circulating tumor DNA provide the opportunity for MRD detection. MRD capture on single-cell or cellular byproducts can serve as a conduit for genomic and transcriptomic analyses, providing insight into the molecular underpinnings and clonal evolution of disease.

While the full potential for MRD applications has yet to be realized, we are witnessing the emergence of novel techniques aimed at MRD detection and the rapid development of elegantly designed studies implementing iterative detection of MRD as means to provide biological rationale and tailor therapeutic options in GU tumors.

Urinary bladder cancer includes non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). While patients with NMIBC have a better prognosis, NMIBC often recurs, requiring long-term surveillance and repeated treatments. Intravesical Bacillus Calmette-Guérin (BCG) therapy is standard for high-grade or recurrent NMIBC; however, 30%-50% of patients failed to respond, and the mechanisms of resistance remain unclear. To identify predictive biomarkers for response to intravesical BCG therapy, we analyzed NANOG and Histone deacetylase 1 (HDAC1) expression in 90 bladder cancer specimens from NMIBC patients treated with BCG therapy using immunohistochemistry. The correlation between NANOG and HDAC1 expression and clinical outcomes, including response to BCG therapy, was assessed. High-grade NMIBC cases showed significantly higher expression of NANOG and HDAC1 compared to low-grade cases (p < 0.05). Additionally, elevated NANOG expression in combination with HDAC1, was associated with poor response to BCG therapy and decreased lymphocyte infiltration in the tumor-microenvironment. NANOG is suggested to directly increases HDAC1 expression, which could suppress lymphocyte infiltration in the tumor microenvironment by altering immune-related gene expression. These findings suggest that the NANOG/HDAC1 axis plays a key role in predicting resistance to intravesical BCG therapy in NMIBC.

Urogenital cancer is very common in the male population of Western countries, a problem of major concern for public health systems, and a frequent test subject for oncological research. In this narrative, we identify the main hot topics for clinics and the basic science of urological cancer in the last few years (from 2021 onwards), considering the information given in the abstracts of almost 300 original articles published in outstanding journals of pathology, urology, and basic science. Once defined, for the top ten list of hot topics (the 2022 WHO update on the classification of urinary and male genital tumors, new entities in kidney cancer, urinary cancer-omics, update on the Gleason grading system, targeted therapies and other novel therapies in renal cancer, news on non-muscle invasive urothelial carcinoma, artificial intelligence in urologic cancer, intratumor heterogeneity influence in therapeutic failures in urologic neoplasms, intratumor microbiome and its influence in urologic tumor aggressiveness, and ecological principles and mathematics applied to urogenital cancer study), each issue is independently reviewed in an attempt to put together the most relevant updates and/or useful features accompanied by selected illustrations. This review article addresses some of the most interesting and current hot spots in urogenital basic cancer research and clinics and is mainly aimed toward clinicians, including pathologists, urologists, and oncologists. Readers are invited to explore each topic for further, more detailed information, in addition to the references provided.

Urothelial carcinoma exhibits a wide spectrum of morphologic and molecular heterogeneity. Advances in molecular testing have improved our understanding of the molecular biology of urothelial carcinoma, including recurrent genomic alterations and transcriptomic features, leading to the development of molecular classification schemes with potential therapeutic implications. This review summarizes the molecular characteristics of urothelial carcinoma, focusing on genomic and transcriptomic features, updates on variant histology, and novel biomarkers that may guide contemporary and future clinical management.

Sarcomatoid urothelial carcinoma (SUC) is a rare histologic subtype with poor prognosis. While there is known intra-tumoral heterogeneity between individual SUC tumors, the relationship between sarcomatoid and conventional urothelial carcinoma (CUC) within the same patient is poorly understood. The objective of this study was to identify differences between the sarcomatoid and CUC tumor microenvironment components that may drive this aggressive phenotype. Using tissue microarrays from eight patient tumors with mixed CUC and SUC, we examined paired CUC, mixed urothelial carcinoma (UC) regions, and SUC using the Nanostring Digital Spatial Profiling platform. We found SUC and mixed UC had higher levels of stromal cells, predominately macrophages and fibroblasts, when compared with CUC within the same tumor. CD14, CD163, and transforming growth factor-beta levels were significantly higher in SUC than in CUC. Immunohistochemical analysis revealed consistently moderate to strong expression of CD163-positive antigen-presenting cells (APCs) in SUC regions, whereas CD68-positive APC expression was generally absent. Thus, in mixed histology SUC, the SUC component preferentially expressed CD163-positive APCs and fibroblasts compared to the CUC component. As CD163-positive APCs and fibroblasts are known to be tumor-promoting and immune-suppressive, this infiltration may contribute to epithelial to mesenchymal transition and other aggressive properties of SUC.

Prostatic ductal adenocarcinoma (PDA) constitutes a rare and notably aggressive histological subtype within the spectrum of prostate malignancies, distinguished by a heightened propensity for recurrence and metastasis compared to prostatic acinar adenocarcinoma (PAA). Testicular metastasis in PDA is exceptionally rare. Despite sporadic reports in the literature, a consensus regarding the optimal therapeutic approach remains elusive. This study retrospectively analyzes a singular case of PDA manifesting with solitary testicular metastasis after laparoscopic radical prostatectomy (LRP), consolidating insights into clinical, histopathological, molecular, and therapeutic aspects, alongside existing scholarly discourse.

We present the case of a 63-year-old gentleman diagnosed with pure PDA (pT3aN0, Gleason score 4 + 4 = 8), exhibiting a serum prostate-specific antigen (PSA) level exceeding 100 ng/ml. Subsequently, the patient underwent androgen deprivation therapy (ADT) followed by LRP. Subsequently, at 17 months post-LRP, local recurrence and a right testicular mass emerged, prompting pelvic radiotherapy and docetaxel chemotherapy. Ultimately, the patient underwent right orchiectomy 65 months post-LRP, with pathological findings confirming metastatic PDA. Four months post-orchiectomy, PSA levels declined to 1.77 ng/ml. Additionally, a comprehensive review of published literature concerning PDA complicated by testicular metastasis was conducted.

The patient derived therapeutic benefits from ADT, LRP, radiation therapy, and orchiectomy, resulting in objective symptom alleviation and a reduction in PSA. Nevertheless, docetaxel proved inefficacious. The literature review indicated variability in outcomes across diverse treatment modalities.

Prolonged surveillance is imperative for patients diagnosed with PDA. Urologists must remain vigilant regarding uncommon sites of metastasis, particularly in instances of elevated PSA.

Clear cell (glycogen-rich) urothelial carcinoma is an exceedingly rare variant of invasive urothelial carcinoma, distinguished by the presence of abundant cytoplasmic glycogen, which imparts a clear appearance to the tumor cells under histological examination. In this case report, the diagnosis was established through histopathological evaluation with hematoxylin and eosin (HE) staining, immunohistochemical analysis, and the identification of significant cytoplasmic glycogen accumulation. The patient, an 89-year-old male, was admitted on July 24, 2024, presenting with painless gross hematuria persisting for one week. Abdominal ultrasound and CT urography revealed a soft tissue mass on the right side of the bladder wall, measuring 30 × 30 mm, with a broad base connected to the bladder wall. The mass exhibited significant enhancement on contrast-enhanced scans, raising suspicion for malignancy. Microscopic examination revealed two distinct tumor cell morphologies: the conventional urothelial carcinoma pattern and a clear nest-like morphology, with the latter comprising over 70% of the tumor. Immunohistochemical staining for GATA-3, CK7, PAS, PAS-D, CAIX, PAX8, and RCC confirmed the diagnosis of clear cell (glycogen-rich) urothelial carcinoma. This rare variant of invasive urothelial carcinoma underscores the need for detailed diagnostic analysis to inform prognosis and treatment strategies. There have been similar cases reported before, involving a 57-year-old male-patient (Sahetia et al. in Ind J Cancer 60:575-577, 2023).

Ki-67 and human epidermal growth factor receptor 2 (HER2) are known oncogenes involved in bladder cancer (BCa) patient risk stratification. Preoperative assessment of their expression level can assist in clinical treatment decision-making. Recently, amide proton transfer-weighted (APTw) MRI has shown promising potential in the diagnosis of several malignancies. However, few studies reported the value of APTw imaging in evaluating Ki-67 and HER2 status of BCa.

To investigate the feasibility of APTw MRI in assessing the aggressive and proliferative potential regarding the expression levels of Ki-67 and HER2 in BCa.

Retrospective.

114 patients (mean age, 64.78 ± 11.93 [SD] years; 97 men) were studied.

APTw MRI acquired by a three-dimensional fast-spin-echo sequence at 3.0 T MRI system.

Patient pathologic findings, included histologic grade and the expression status of Ki-67 and HER2, were reviewed by one uropathologist. The APTw values of BCa were independently measured by two radiologists and were compared between high-/low-tumor grade group, high-/low-Ki-67 expression group, and high-/low-HER2 expression group.

The interclass correlation coefficient, independent sample t-test, Mann-Whitney U test, Spearman's rank correlation, and receiver operating characteristic curve (ROC) analysis were used. P < 0.05 was considered statistically significant.

Significantly higher APTw values were found in high-grade BCa patients (7.72% vs. 4.29%, P < 0.001), high-Ki-67 expression BCa patients (8.40% vs. 3.25%, P < 0.001) and HER2 positive BCa patients (8.24% vs. 5.40%, P = 0.001). APTw values were positively correlated with Ki-67 (r = 0.769) and HER2 (r = 0. 356) expression status. The area under the ROC curve of the APTw values for detecting Ki-67 and HER2 expression status were 0.883 (95% CI: 0.790-0.945) and 0.713 (95% CI: 0.592-0.816), respectively.

APTw MRI is a potential method to assess the biological and proliferation potential of BCa.

Stage 2.

This article provides a comprehensive overview of prostate cancer imaging, including detection of clinically significant cancer and initial staging. The role of multiparametric MRI in detection and local staging is discussed, along with the use of conventional imaging and advanced techniques such as Prostate-Specific Membrane Antigen-Positron Emission Tomography (PSMA-PET) for staging of nodal and distant metastases. The article also highlights the importance of differentiating benign prostatic conditions from prostate cancer on imaging to improve diagnostic accuracy and reduce false-positive interpretations.

Biochemical recurrence (BCR) of prostate cancer (PCa) negatively impacts patients' post-surgery quality of life, and the traditional predictive models have shown limited accuracy. This study develops an AI-based prognostic model using deep learning that incorporates androgen receptor (AR) regional features from whole-slide images (WSIs). Data from 545 patients across two centres are used for training and validation. The model showed strong performances, with high accuracy in identifying regions with high AR expression and BCR prediction. This AI model may help identify high-risk patients, aiding in better treatment strategies, particularly in underdeveloped areas.

Biomarkers that identify tumors with better/worse prognosis can help reduce treatment costs and contribute to patient survival. In urothelial bladder cancer (UBC), accurate prediction of recurrence and progression is essential to inform therapeutic management. Herein, we explore the role of genetic variants of xenobiotic metabolic pathways in UBC susceptibility and prognosis. In total, 295 participants with UBC and 295 controls were genotyped using TaqMan® probes. CYP1A1 (rs1048943), CYP3A4 (rs4646437), CYP3A5 (rs4646450), UGT2B7 (rs7438135), and UGT2B15 (rs3100) allele frequencies were compared between UBC patients and controls and were analyzed concerning tumor grade, invasion, and recurrence. CYP3A4 (AA) increased susceptibility to UBC 3-fold when interacting with CYP3A5 (AA+AA). The susceptibility was higher in CYP3A4 (AA) males (OR=3.189) and individuals exposed to pesticides (OR=5.492). When interacting with hypertension, the allele C of CYP1A1 also increased UBC susceptibility by 2-fold. The UGT2B15 mutant allele was associated with high-grade tumors (OR=2.196) and recurrences (OR=2.561), as well as tumor grade when associated with mutated alleles of CYP3A4 (OR=6.171) and CYP3A5 (OR=3.492). Genes-encoding proteins were further analyzed using the STRING program, demonstrating that the proteins had known interactions in databases and were co-expressed. This study is a pioneer in evaluating these variants in a Latin American population from Brazil and confirms occupational pesticide exposure as a risk factor for UBC, mainly in genetically susceptible individuals. Furthermore, these variants may have additional clinical value for predicting susceptibility and prognostic stratification in patients with exposure-related cancers such as UBC.

Background/Objectives: Bladder cancer is a significant clinical problem with approximately 500,000 new cases worldwide annually. In approximately 25% of cases, disease is diagnosed at a stage of invasion of the muscle layer of the bladder. The current standard approach in this disease is preoperative chemotherapy followed by radical cystectomy. Dose-dense MVAC (ddMVAC), a two-day chemotherapy regimen, is the reference treatment protocol in this setting. The presented study evaluated the effectiveness and safety of accelerated MVAC (aMVAC) chemotherapy-a one-day regimen given before the resection of the bladder due to muscle-invasive disease. Methods: A retrospective analysis included 119 consecutive patients diagnosed with urothelial muscle-invasive bladder cancer (MIBC) who underwent preoperative chemotherapy with the aMVAC regimen. The planned treatment included 4-6 cycles of preoperative chemotherapy. The analysis of the degree of histopathological response to treatment was based on the three-grade TRG (tumor regression grade) classification. Results: A complete pathological response (TRG1) was observed in 44 patients (36.7%), and a major pathologic response ( Collapse

To create a system to enable the identification of histological variants of bladder cancer in a simple, efficient, and noninvasive manner.

In this multicenter diagnostic study, we retrospectively collected basic information and CT images about the patients concerned from three hospitals. An interactive deep learning-based bladder cancer image segmentation framework was constructed using the Swin UNETR algorithm for further features extraction. Radiomic features and deep learning features were extracted for further stacking ensemble system construction. The segmentation model' performance was assessed by using Dice Similarity (Dice) metrics, Intersection Over Union (IOU), Sensitivity (SEN) and Specificity (SPE). To evaluate the system's performance, we used the Receiver Operating Characteristics (ROC) curve, the Accuracy Score (ACC) and Decision Curve Analysis (DCA).

410 patients from one hospital were included in the training set, while 60 patients from two other hospitals were included in the test set. A total of 50 features comprising 46 radiomic features and 4 deep learning features were finally retained for further stacking ensemble model building. The interactive segmentation model and system exhibited excellent performance in both training (Dice = 0.78, IOU = 0.65, SEN = 0.83, SPE = 1.00, AUC = 0.940, ACC = 0.868) and testing datasets (Dice = 0.80, IOU = 0.67, SEN = 0.89, SPE = 1.00, AUC = 0.905, ACC = 0.900).

We successfully constructed a stacking ensemble machine learning model for early, non-invasive identification of histological variants in bladder cancer which will help urologists make clinical decisions.

Urothelial carcinoma (UC) is the most common histological subtype of bladder tumors; however, bladder cancer represents a heterogeneous group of diseases with at least 40 distinct histological subtypes. Among these, the 2022 World Health Organization classification of urinary tract tumors identifies a range of less common subtypes of invasive UC, formerly known as variants, which are considered high-grade tumors, including squamous cell, small-cell, sarcomatoid urothelial, micropapillary, plasmacytoid, and urachal carcinomas, and adenocarcinoma. Their accurate histological diagnosis is critical for risk stratification and therapeutic decision-making, as most subtype histologies are associated with poorer outcomes than conventional UC. Despite the importance of a precise diagnosis, high-quality evidence on optimal treatments for subtype histologies remains limited owing to their rarity. In particular, neoadjuvant and adjuvant chemotherapy have not been well characterized, and prospective data are scarce. For advanced-stage diseases, clinical trial participation is strongly recommended to address the lack of robust evidence. Advances in molecular pathology and the development of targeted therapies and immunotherapies have reshaped our understanding and classification of bladder cancer subtypes, spurring efforts to identify predictive biomarkers to guide personalized treatment strategies. Nevertheless, the management of rare bladder cancer subgroups remains challenging because they are frequently excluded from clinical trials. For localized disease, curative options such as surgical resection or radiotherapy are available; however, treatment options become more limited in recurrence or metastasis, where systemic therapy is primarily used to control disease progression and palliate symptoms. Herein, we present recent advances in the management of urothelial and non-urothelial bladder cancer subtypes and also explore the current evidence guiding their treatment and emphasize the challenges and perspectives of future therapeutic strategies.

To assess the predictive value of intratumoral and peritumoral radiomics based on Dual-energy CT urography (DECTU) multi-images for preoperatively predicting the muscle invasion status of bladder cancer (BCa).

This retrospective analysis involved 202 BCa patients who underwent DECTU. DECTU-derived quantitative parameters were identified as risk factors through stepwise regression analysis to construct a DECT model. The radiomic features from the intratumoral and 3 mm outward peritumoral regions were extracted from the 120 kVp-like, 40 keV, 100 keV, and iodine-based material-decomposition (IMD) images in the venous-phase and were screened using Mann-Whitney U test, Spearman correlation analysis, and LASSO. Radiomics models were developed using the Multilayer Perceptron for the intratumoral, peritumoral and intra- and peritumoral (IntraPeri) regions. Subsequently, a nomogram was created by integrating the multi-image IntraPeri radiomics and DECT model. Model performance was evaluated using area-under-the-curve (AUC), accuracy, sensitivity, and specificity.

Normalized iodine concentration (NIC) was identified as an independent predictor for the DECT model. The IntraPeri model demonstrated superior performance compared to the intratumoral and peritumoral models both in 40 keV (0.830 vs. 0.766 vs. 0.763) and IMD images (0.881 vs. 0.840 vs. 0.821) in the test cohort. In the test cohort, the nomogram exhibited the best predictability (AUC=0.886, accuracy=0.836, sensitivity=0.737, and specificity=0.881), outperformed the DECT model (AUC=0.763, accuracy=0.754, sensitivity=0.632, and specificity=0.810) in predicting muscle invasion status of BCa with a statistically significant difference (p < 0.05).

The nomogram, incorporating IntraPeri radiomics and NIC, serves as a valuable and non-invasive tool for preoperatively assessing the muscle invasion status of BCa.

Clear cell adenocarcinoma of the urethra is an extremely rare malignancy with a poor outcome, mainly affecting females in old age. We present the case of a 42-year-old female patient who presented with progressively worsening lower urinary tract symptoms, leading to a cystoscopy-guided core needle biopsy diagnosis of clear cell adenocarcinoma of the urethra. We will mainly discuss the cross-sectional imaging and pathological aspects of the case.

Prostate cancer is the most common diagnosed tumor and the fifth cancer related death among men in Europe. Although several genetic alterations such as ERG-TMPRSS2 fusion, MYC amplification, PTEN deletion and mutations in p53 and BRCA2 genes play a key role in the pathogenesis of prostate cancer, specific gene alteration signature that could distinguish indolent from aggressive prostate cancer or may aid in patient stratification for prognosis and/or clinical management of patients with prostate cancer is still missing. Therefore, here, by a multi-omics approach we describe a prostate cancer carrying the fusion of TMPRSS2 with ERG gene and deletion of 16q chromosome arm.

We have observed deletion of KDM6A gene, which may represent an additional genomic alteration to be considered for patient stratification. The cancer hallmarks gene signatures highlight intriguing molecular aspects that characterize the biology of this tumor by both a high hypoxia and immune infiltration scores. Moreover, our analysis showed a slight increase in the Tumoral Mutational Burden, as well as an over-expression of the immune checkpoints. The omics profiling integrating hypoxia, ROS and the anti-cancer immune response, optimizes therapeutic strategies and advances personalized care for prostate cancer patients.

The here data reported can lay the foundation for predicting a poor prognosis for the studied prostate cancer, as well as the possibility of targeted therapies based on the modulation of hypoxia, ROS, and the anti-cancer immune response.