BACKGROUND:Chemotherapy remains the most effective systemic treatment for bladder cancer (BLCA), with cisplatin as the primary agent. However, the frequent development of cisplatin resistance limits its clinical efficacy. Forkhead box D1 (FOXD1) is implicated in BLCA progression, yet its role in mediating cisplatin resistance remains unexplored. METHODS:FOXD1 expression and its correlation with patient prognosis in BLCA were analyzed using the TCGA database. Cisplatin-resistant BLCA cell lines (T24-R and HT-1376-R) were established by treatment with gradient concentrations of cisplatin. qRT-PCR and Western blot were performed to detect the expression levels of FOXD1, β-catenin, and Aspartyl-tRNA Synthetase 2 (DARS2). Cell viability, proliferation, cell cycle, and apoptosis were assessed using CCK-8, colony formation assays, and flow cytometry. Co-IP was performed to examine the interaction between FOXD1 and β-catenin. Glycolysis levels in BLCA cells were determined using specific assay kits. RESULTS:FOXD1 was highly expressed in BLCA tissues and correlated with poor prognosis. Knockdown of FOXD1 inhibited proliferation and cell cycle progression, promoted apoptosis, and enhanced cisplatin sensitivity in T24-R cells, while reducing β-catenin nuclear translocation and DARS2 expression. Overexpression of FOXD1 exerted the opposite effects on HT-1376-R cells and increased DARS2 expression, which were reversed by β-catenin knockdown. Moreover, knockdown of TCFs/LEF suppressed DARS2 expression. DARS2 was enriched in the glycolysis pathway. Its overexpression promoted glycolysis, proliferation, and cell cycle progression, while inhibiting apoptosis and cisplatin sensitivity in HT-1376-R cells-effects were reversed by 2-DG. CONCLUSION:FOXD1 facilitates β-catenin nuclear translocation and upregulates DARS2 to enhance glycolysis, thereby promoting cisplatin resistance in BLCA. These findings identify the FOXD1/β-catenin/DARS2 axis as a potential therapeutic target for overcoming cisplatin resistance in BLCA clinically.
BACKGROUND AND OBJECTIVE:Patients undergoing radical cystectomy (RC) for bladder cancer may present with synchronous or metachronous upper tract urothelial carcinoma (UTUC). These scenarios may differ in oncological outcomes and surgical complexity. This study sought to compare oncologic and perioperative outcomes in patients undergoing RC and radical nephroureterectomy (RNU) for synchronous or metachronous UTUC. METHODS:Data from 23 tertiary referral centers were retrospectively collected (2002-2024). Perioperative outcomes included length of stay (LOS) and complications (Clavien-Dindo classification). Disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) were estimated from RC using Kaplan-Meier and landmark analysis. Multivariable Cox regression modeling identified predictors of DFS and OS and explored the impact of RNU timing on oncological outcomes. KEY FINDINGS AND LIMITATIONS:Among 177 RC patients (n = 142 [80%] males), 106 (60%) underwent RNU subsequent to RC for metachronous UTUC. Concomitant RC and RNU led to longer LOS (10 vs. 7 days, P = 0.004), and statistically significant higher rate of major complications (Clavien-Dindo ≥ IIIa, 29.6% vs. 15.1%, P = 0.03). Metachronous disease showed better 60-month DFS (69.1% vs. 47.6%), CSS (80.3% vs. 66.4%) and OS (69.2% vs. 47.6%). Histological subtype at RNU independently predicted worse DFS (HR 2.64, P = 0.01) and OS (HR 3.22, P = 0.01), while metachronous presentation predicted better DFS (HR 0.36, P < 0.001) and OS (HR 0.53, P = 0.04). Limitations include the retrospective design and a relatively limited sample size. CONCLUSIONS AND CLINICAL IMPLICATIONS:Synchronous panurothelial disease at diagnosis requiring RC and RNU is related to worse perioperative and survival outcomes compared to metachronous disease. Our results highlight the need for dedicated studies to define individualized treatment and surveillance strategies for this challenging patient population.
Ureteroenteric anastomotic stricture (UAS) is a clinically relevant complication of robot-assisted radical cystectomy (RARC), primarily driven by ureteral ischemia. Indocyanine green (ICG) fluorescence has been proposed to identify ischemic segments prior to anastomosis. This systematic review and meta-analysis aimed to evaluate UAS incidence with ICG versus no ICG during RARC. PubMed, Embase, and Cochrane were searched up to February 2026. Eligible studies were comparative observational studies on adults undergoing RARC exclusively. Random-effects models were used to pool risk ratios (RR) and mean differences (MD) with 95% confidence intervals. Four observational studies were included (n = 886 patients; 1,739 ureters): 369 (41.6%) underwent ICG - guided assessment and 517 (58.4%) standard assessment without ICG. Pooled analysis showed no statistically significant reduction in UAS per ureter (RR 0.31, 95% CI 0.08-1.16; P = 0.08; I² = 76.4%). Sensitivity analysis excluding the highest-bias study eliminated heterogeneity and shifted results in favor of ICG (RR 0.20, 95% CI 0.09-0.46; I² = 0%), suggesting that the primary pooled estimate is unstable and heavily influenced by between-study heterogeneity. No significant differences were observed in ureteral excision length, node positivity, or operative time. Current evidence is limited to non-randomized studies with serious risk of bias and very low certainty. The instability of the pooled estimate highlights the inadequacy of the current evidence base and the need for prospective randomized studies to define the true clinical benefit of ICG. PROSPERO: CRD420261322254.
INTRODUCTION:Prostatic lymphoma is a rare malignancy that can clinically resemble benign prostatic hyperplasia (BPH) or adenocarcinoma, often delaying diagnosis. Primary prostatic lymphoma (PPL) comprises <0.1% of prostate tumors and non-Hodgkin lymphomas, whereas secondary involvement occurs more commonly in systemic disease. METHODS:A retrospective review was conducted at the University of Miami Health System (2015-2024). All prostate specimens demonstrating lymphoma or related hematologic malignancies were identified. Clinical data, including demographics, presenting symptoms, prostate-specific antigen (PSA), imaging, uroflowmetry, histopathology, urological and oncologic treatment, and outcomes, were collected. A PubMed and Embase literature review was performed to identify reported PPL cases. RESULTS:Seven patients (age range 47-89) were diagnosed with prostatic lymphoma. Presenting features included lower urinary tract symptoms, hematuria, urinary retention, pelvic pain, and systemic B symptoms. Histologic findings included diffuse large B-cell lymphoma (n = 3), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 2), low-grade B-cell lymphoma (n = 1), mucosa-associated lymphoid tissue (MALT) lymphoma (n = 1), and mantle cell lymphoma (n = 1). One additional case of myeloid sarcoma was identified and reported separately. Several diagnoses followed tissue sampling during radical prostatectomy, holmium laser enucleation of the prostate (HoLEP), or transurethral resection of prostate (TURP) for presumed BPH. Management varied, including rituximab-based chemoimmunotherapy, targeted agents, radiotherapy, and conservative strategies. Outcomes ranged from remission to systemic progression. The literature review identified 65 studies involving 160 patients with PPL. CONCLUSION:Prostatic lymphoma is a heterogeneous entity with presentations that overlap with those of common urologic conditions. Histopathologic confirmation is essential in patients with atypical features or poor response to BPH therapies. Early recognition and multidisciplinary coordination are vital.
OBJECTIVE:To evaluate the performance and interpretability of multiple ML algorithms for survival prediction in prostate cancer (CaP) and to assess whether these approaches can improve upon established clinical risk prediction models. METHODS:Using the Surveillance, Epidemiology, and End Results (SEER) 17 Database, we identified patients diagnosed with CaP from 2010 to 2017 and implemented a Bayesian Cox variable selection model to determine the most clinically relevant features. To predict overall survival (OS) and prostate cancer-specific survival (PCSS), we applied these features to train and test a traditional Cox proportional hazards (PH) model in comparison to ML models including XGBoost, random survival forests, and elastic nets as well as the Cancer of the Prostate Risk Assessment (CAPRA) score using 5-fold cross-validation. The models were repeated for cohorts limited to patients who underwent radical prostatectomy and those who had low-risk disease. RESULTS:For both OS and PCSS, XGBoost had the best area under the curve (AUC), concordance index, and Brier score, followed by elastic net, Cox PH, and RSFs. Feature analysis indicated that age was most predictive of OS, while cancer-specific characteristics such as Gleason grade group were the most important features for PCSS prediction. CONCLUSION:While the traditional Cox PH model remained a clinically robust cancer survival model, this study found that ML models demonstrated modestly improved CaP survival prediction and provided easily interpretable information on the factors most important for prediction. These findings underscore the ability of new ML algorithms to be clinically useful in predicting survival in patients with CaP, specifically by identifying high-risk patients who may require more intensive treatment plans and closer follow-up.
BACKGROUND:Upper tract urothelial carcinoma (UTUC) is an uncommon genitourinary malignancy with distinct anatomical and clinical challenges. Historically, treatment strategies have been extrapolated from bladder cancer, leaving gaps in evidence for UTUC-specific management. Recent advances in intraluminal drug delivery and systemic therapy have presented new options across localized, locally advanced, and metastatic disease. METHODS:We reviewed prospective trials, retrospective cohort studies, and ongoing studies evaluating intraluminal chemo-ablative agents, perioperative chemotherapy, immunotherapy, and targeted therapies for UTUC. Outcomes of efficacy, safety, and innovation in drug delivery systems were synthesized. RESULTS:Kidney-sparing approaches for localized UTUC have advanced with intraluminal chemoablation. UGN-101, a mitomycin-C containing reverse-thermal gel, demonstrated meaningful complete response rates and durable remission, while mitomycin-C (aqueous) and Bacillus Calmette-Guérin-based regimens showed variable efficacy. Novel delivery systems, including reverse-thermal gels and biodegradable drug-eluting stents, aim to improve drug dwell time and reduce recurrence. For high-risk localized disease, adjuvant platinum-based chemotherapy significantly improved disease-free survival and is now standard of care. Neoadjuvant chemotherapy offers long-term survival benefits and preserves eligibility for cisplatin. Immunotherapy has emerged perioperatively, with adjuvant checkpoint inhibitors improving disease-free survival and ongoing trials exploring chemo-immunotherapy combinations. In metastatic UTUC, antibody-drug conjugates combined with immunotherapy have demonstrated superior progression-free and overall survival compared with chemotherapy. Targeted therapies, such as FGFR inhibitors, provide additional options for biomarker-selected patients. CONCLUSIONS:UTUC management is evolving towards stage-specific strategies integrating chemoablation, systemic therapy, and molecularly guided approaches. Future priorities include randomized trials, optimized drug delivery, and long-term safety evaluation.
OBJECTIVE:To explore the expression profile of miR-638 in serum and tumor tissues of prostate cancer (CaP) individuals, and further analyze its diagnostic value, prognostic significance, and regulatory role in CaP cells. METHODS:Serum was collected from individuals with CaP, benign prostatic hyperplasia (BPH), and healthy controls (HC). Paired tumor and adjacent normal tissues were obtained from CaP cases. miR-638 expression was determined by qRT-PCR. ROC curve was performed to evaluate the diagnostic efficacy of serum miR-638 alone and in combination with t-PSA. Spearman's rank was used to analyze the association between tissue miR-638 and clinicopathological features. Kaplan-Meier and multivariate Cox regression were used to identify prognostic factors. In vitro, CCK‑8, flow cytometry, and Transwell assays were performed to evaluate PC‑3 cell proliferation, apoptosis, migration, and invasion. RESULTS:miR-638 was significantly upregulated in the serum of CaP individuals compared with BPH and HC, presenting a stepwise upregulation trend. Combined detection of serum miR-638 and t-PSA significantly improved the diagnostic performance for CaP. High miR-638 expression in tumor tissues was closely associated with adverse clinicopathological parameters and predicted shorter overall survival. Multivariate Cox regression demonstrated that tissue miR-638 overexpression was an independent poor prognostic factor. In vitro assays demonstrated that miR-638 overexpression promoted the proliferation, migration, and invasion of PC-3 cells and inhibited cell apoptosis, while miR-638 knockdown reversed these malignant phenotypes. CONCLUSION:Aberrant upregulation of miR-638 in serum and tissues acts as a promising biomarker for CaP diagnosis and prognosis. miR-638 exerts oncogenic functions to facilitate CaP malignant progression.
The perioperative treatment landscape for muscle-invasive bladder cancer is changing rapidly with the emergence of immune checkpoint inhibitor- and antibody-drug conjugate-based strategies. Trials such as NIAGARA, EV-304/KEYNOTE-B15, and EV-303/KEYNOTE-905 have shown substantial improvements in event-free survival, overall survival, and pathological response. However, efficacy endpoints alone may be insufficient to evaluate perioperative regimens, because treatment is delivered across neoadjuvant, surgical, and adjuvant phases. Each phase introduces distinct sources of burden, including treatment-related toxicity, discontinuation of neoadjuvant therapy, delay or failure to undergo radical cystectomy, postoperative complications, and failure to initiate or complete adjuvant therapy. To address this gap, we propose a phase-specific benefit-toxicity framework for interpreting modern perioperative trials in muscle-invasive bladder cancer. We define deliverability as the feasibility of completing the intended neoadjuvant-surgical-adjuvant treatment pathway. Recent studies such as EV-304, NIAGARA, EV-303, and VESPER provide a timely opportunity to map perioperative benefit, toxicity, and deliverability at the trial level, although endpoints, safety reporting, and comparator arms differ across trials. Because perioperative therapy spans neoadjuvant, surgical, and adjuvant phases, the framework uses the neoadjuvant benefit-harm balance as the primary interpretive axis while contextualizing surgical feasibility and postoperative treatment continuity. The aim is not to rank regimens, but to visualize how therapeutic benefit and treatment burden are balanced across heterogeneous trial designs. Phase-specific mapping may provide a more clinically interpretable approach for assessing modern perioperative combination regimens and for designing future trials that better capture treatment feasibility, surgical safety, and completion of the intended treatment pathway.
CD103+ tissue-resident memory T cells are emerging mediators of antitumor immunity whose prognostic significance in bladder cancer, across muscle-invasive and metastatic urothelial carcinoma, remains undefined at a meta-analytic level. We performed a systematic review and meta-analysis of cohorts with histologically confirmed muscle-invasive bladder cancer or metastatic urothelial carcinoma, comparing high vs. low CD103+ tumor-infiltrating lymphocyte density assessed by immunohistochemistry or ITGAE mRNA expression, with overall survival endpoint. PubMed, Embase, Scopus, and Cochrane CENTRAL were searched from inception through March 2026. Pooled hazard ratios (HR) with 95% confidence intervals (CIs) were estimated using a restricted maximum likelihood random-effects model. Subgroup analyses were performed by treatment context, disease stage, and assessment method. The protocol was registered at OSF (u36xv). Three studies comprising 6 cohorts were included. High CD103⁺ infiltration was significantly associated with prolonged overall survival (HR: 0.50, 95% CI: 0.30-0.83). A significant treatment-context interaction (P = 0.005) favored patients undergoing surgery with adjuvant chemotherapy (HR: 0.20) over those receiving immunotherapy (HR: 0.69). Stage-stratified analysis showed a significant interaction (P = 0.003), with pronounced benefit in muscle-invasive bladder cancer (HR: 0.27) but a non-significant trend in metastatic urothelial carcinoma (HR: 0.79). Immunohistochemistry-based cohorts showed a numerically larger effect than ITGAE mRNA cohorts. High CD103⁺ tumor-infiltrating lymphocyte infiltration may be associated with improved overall survival in bladder cancer, particularly in muscle-invasive bladder cancer patients undergoing surgery with adjuvant chemotherapy. Prospective validation in larger, stage-homogeneous cohorts is warranted to establish CD103 as a prognostic biomarker. These findings are hypothesis-generating and CD103 assessment is not currently ready for clinical use.
OBJECTIVE:To assess the etiology, evaluation, and subsequent management of patients who developed gross hematuria following radical cystectomy (RC) and orthotopic neobladder (ONB) urinary diversion. METHODS:All patients who underwent RC and ONB between 2017 and 2021 and later developed gross hematuria necessitating cystoscopy were identified. Patient demographics, cystoscopy reports, cytology findings, and relevant imaging were reviewed to determine the etiology of hematuria, the subsequent management, and the ultimate outcome. Causes of hematuria were categorized as recurrence, inflammation/infection, anticoagulation-related, or undetermined. RESULTS:Twenty-one patients underwent cystoscopy for gross hematuria following RC and ONB during the study period. Most patients were male (n = 19, 90.5%), and the median age was 71 years (IQR: 67-75). Five (23.8%) patients had hematuria secondary to cancer recurrence-4 urethral and one upper tract recurrence. Other etiologies of hematuria included pouchitis (n = 5, 23.8%) and presumed anticoagulation-related bleeding (n = 2, 9.5%). In 9 (42.9%) patients, the etiology of hematuria remained undetermined despite comprehensive workup. Among the 5 patients whose hematuria was secondary to cancer recurrence, the median time from cystectomy to hematuria was 29 months (Interquartile range: 15-36). CONCLUSIONS:Up to a quarter of patients who present with gross hematuria following RC with ONB may have cancer recurrence. Consequently, a thorough evaluation is warranted in all patients.
Liquid biopsy ctDNA testing is becoming an essential part of cancer patient care. Many types of molecular assays for ctDNA MRD or ctDNA profiling are available. They differ in methodology, can be targeted vs. nontargeted, and tumor-informed vs. tumor-uninformed. There are technical benefits and pitfalls that come with each type of ctDNA assays. Factors such as level of detection, turnaround time, cost/reimbursement, and tumor indication may play a role in picking the most appropriate test. Given there are many available ctDNA MRD testing assays available, this paper will provide technical reviews of various methods and analytical qualifications of various ctDNA MRD detection assays.
BACKGROUND:Segmental ureterectomy (SU) is a kidney-sparing alternative to radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) localized to the ureter, yet contemporary comparative data are limited. We aimed to evaluate perioperative, functional, and pathology-adjusted oncologic endpoints between SU and RNU using propensity-score matching. METHODS:We retrospectively reviewed UTUC patients treated at a tertiary referral center (2008-2025), identifying SU (n = 81) and RNU (n = 259) cases. To reduce confounding, we performed 1:1 propensity-score matching on age, gender, comorbidities, and baseline eGFR, yielding 92 matched patients (46 pairs). Because 8 pairs showed no residual malignancy (pT0) on final pathology, the primary adjusted analysis was restricted to 38 pairs (n = 76), with the full 46-pair cohort retained for sensitivity analysis. Primary endpoints were DFS, CSS, and OS. Secondary endpoints included perioperative outcomes, renal function, intravesical recurrence-free survival, and metastasis-free survival. Time-to-event outcomes were analyzed using paired Cox models adjusted for definitive pathological grade and stage, and Kaplan-Meier estimated as secondary analysis. RESULTS:The median follow-up for the matched cohort was 37.1 months (IQR: 14.2-69.0). Baseline tumor characteristics were comparable except for tumor location, with a higher prevalence of nondistal tumors in the RNU group (P < 0.001). In the primary analysis (pathology-adjusted) paired-Cox regression estimated DFS and CSS were similar between SU and RNU (HR 0.63, 95% CI 0.23-1.69, P = 0.358 and HR 0.57, 95% CI 0.2-1.54, P = 0.275, respectively). The adjusted OS was also comparable (HR 0.49, 95% CI 0.16-1.51, P = 0.213), alongside all secondary oncologic endpoints (P > 0.05). In the sensitivity analysis, oncological endpoints did not differ between the groups. Renal function preservation favored SU, with median ΔeGFR +8.8 vs. RNU -11.95 ml/min/1.73 m² (P < 0.001). CONCLUSIONS:SU significantly improved renal preservation without compromising intermediate-term, pathology-adjusted oncologic endpoints vs. RNU. These findings support SU as a kidney-sparing option in selected patients, including those with high-grade disease, adverse features (CIS, LVI, ≥pT2), and nondistal tumors. Further work should refine patient selection and post-SU surveillance.
Background Upper tract urothelial carcinoma (UTUC) includes renal pelvic and ureteral carcinoma, and radical nephroureterectomy (RNU) is the standard surgical treatment for nonmetastatic disease. Despite complete resection, postoperative intravesical recurrence (IVR) occurs in 22% to 47% of patients. It is generally recognized that ureteral tumor exhibits a higher incidence of IVR compared with renal pelvic tumor. However, the immunological mechanisms underlying this difference remain poorly understood. Material and Methods A total of 26 patients with UTUC without variant histology who underwent laparoscopic RNU at Kyushu University Hospital were classified according to tumor location (Renal pelvic group: n = 15; Ureteral group: n = 11). Clinical characteristics and the spatial distribution of immune cells in UTUC were analyzed and compared between the 2 groups using multiplex immunohistochemistry (mIHC). Results IVR occurred more frequently in the Ureteral group than in the Renal pelvic group. mIHC analysis revealed significantly higher infiltration of regulatory T (Treg) cells and programmed cell death (PD)-1+ Treg cells in the ureteral group. Furthermore, the infiltration of exhausted CD8+ T cells co-expressing T cell immunoglobulin and ITIM domain (TIGIT) and PD-1 were significantly enriched in the Ureteral group. Across the entire cohort, patients who developed IVR exhibited higher densities of these T-cell subsets compared with those without IVR. Conclusions Ureteral tumors demonstrate increased infiltration of Treg cells, PD-1⁺ Treg cells, and TIGIT⁺PD-1⁺CD8⁺ T cells, suggesting an immunosuppressive TME that may contribute to the higher risk of IVR after RNU.
BACKGROUND:Laparoscopic partial nephrectomy (LPN) is a preferred surgical approach for early-stage renal cell carcinoma. However, there is ongoing debate regarding the optimal surgical technique for highly complex renal hilar tumors. Moreover, long-term follow-up data assessing the applicability and outcomes of LPN for renal hilar tumors remain limited. METHODS:A retrospective analysis was conducted on patients with pT1-stage clear cell renal cell carcinoma (ccRCC). We proposed an imaging-based "danger zone" defining the critical boundary of hilar vascular structures. Based on spatial location and surgical approach, patients were stratified into 4 groups: non-hilar partial nephrectomy (NHPN), hilar partial nephrectomy outside (HPNOUT) or inside (HPN-IN) the danger zone, and hilar radical nephrectomy (HRN). We compared perioperative parameters, postoperative renal function (eGFR), and recurrence-free survival (RFS) across these cohorts. RESULTS:A total of 323 patients were included (NHPN, n = 204; HPNOUT, n = 46; HPN-IN, n = 21; HRN, n = 52). Over a median follow-up of 3,276 days, 24 overall oncologic events were recorded. The HPNOUT group demonstrated perioperative outcomes, postoperative eGFR, and RFS (HR = 1.16, 95% CI: 0.28-4.85, P = 0.836) comparable to the NHPN cohort. Conversely, the HPN-IN group exhibited significantly higher estimated blood loss (adjusted difference: +136.3 ml, 95% CI: 99.2-173.4, P < 0.001) compared to the HPNOUT group. However, when evaluating tumors exclusively within the danger zone, a distinct clinical trade-off emerged. Compared to HRN, the HPN-IN group experienced greater perioperative morbidity but achieved significantly superior long-term renal function preservation (across 3-month, 1-year, and 5-year follow-ups; all P < 0.05). Importantly, long-term oncological control remained comparable between these 2 approaches (RFS HR = 2.06, 95% CI: 0.60-7.09, P = 0.250). CONCLUSIONS:The proposed "danger zone" concept offers an exploratory anatomical tool to assist in the preoperative risk assessment of T1 hilar tumors. Initial data suggest that LPN remains a viable option for lesions located outside the danger zone. When tumors invade the danger zone, LRN provides a safer perioperative course at the expense of functional preservation, whereas oncological efficacy seems equivalent between modalities. These preliminary observations necessitate rigorous prospective validation prior to clinical application.
PURPOSE:To evaluate the prognostic value of biopsy-based Gleason pattern 4 (GP4) burden in a racially and ethnically diverse cohort of men with intermediate- and high-risk prostate cancer undergoing radical prostatectomy. MATERIALS AND METHODS:We retrospectively identified 368 men with biopsy-proven Gleason grade group (GG) 2 to 4 prostate cancer treated with radical prostatectomy (RP) between 2017 and 2024. GP4 burden was quantified using multiple biopsy-based measures. Primary outcomes were adverse surgical pathology (ASP) at prostatectomy-extraprostatic extension, seminal vesicle invasion, or lymph node invasion-and biochemical recurrence (BCR) within 3 years. Associations were evaluated using multivariable regression; model discrimination was assessed using Harrell's concordance index. A point-based pattern 4 risk score (P4RS) was developed and compared with an established preoperative clinical risk nomogram for prediction of early biochemical recurrence. RESULTS:The cohort was racially and ethnically diverse (76% Black or Hispanic/Latino). ASP occurred in 38% of patients and 17% experienced BCR within 3 years of surgery. ASP risk rose 15% per 2-millimeter increase in total length of pattern 4 on biopsy. Among patients with ≤15 mm GP4, 3-year BCR risk rose 22% per 2-millimeter increase; precision was limited beyond this range. Absolute GP4 metrics improved discrimination for BCR (concordance index 0.716-0.723) relative to GG (0.690). Among risk stratification models, the P4RS demonstrated the highest discrimination (concordance index 0.728). CONCLUSIONS:Absolute Gleason pattern 4 burden, particularly total length, provides clinically meaningful prognostic information beyond grade group and improves risk stratification for adverse pathology and early oncologic outcomes after prostatectomy.
BACKGROUND:Divergent differentiation (DD) and histological subtypes (HS) represent rare but clinically meaningful forms of upper tract urothelial carcinoma (UTUC), but their prognostic impact remains incompletely understood. We assessed the incidence, clinicopathological characteristics, and oncologic outcomes associated with DD-HS in a large multi-institutional cohort of patients undergoing radical nephroureterectomy (RNU) for non-metastatic UTUC. METHODS:We retrospectively analyzed 3,441 patients treated between 1985 and 2022 across 22 institutions. Tumors were classified as pure urothelial carcinoma (PUC), DD, and HS. Clinicopathological features and survival outcomes-including recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS)-were compared using the Kaplan-Meier estimator, stratified by pathological stage (organ-confined [OC: ≤pT2N0-Nx] vs. non-organ-confined [NOC: ≥pT3 or ≥pN1]) and multivariable Cox regression. RESULTS:DD-HS were present in 201 patients (5.8%), with DD comprising 139 (69%). Compared to PUC, DD-HS were associated with more advanced T/N stages, higher rates of lymphovascular invasion (40% vs. 20%), multifocality (35% vs. 27%), and concomitant carcinoma in situ (21% vs. 14%) (all P < 0.05). While outcomes for DD were similar to stage-matched PUC, HS showed significantly worse stage-matched RFS (OC: 38% vs. 83%; NOC: 25% vs. 46%) and OS (OC: 44% vs. 75%; all P < 0.01), and remained independently associated with poorer outcomes on multivariable analyses. Limitations include the retrospective design and lack of centralized pathology review. CONCLUSIONS:UTUC with DD-HS represents a biologically heterogeneous population with distinct oncologic outcomes compared with PUC. Further investigation into subtype-specific tumor biology and rigorous pathological characterization is warranted to better define the clinical relevance of individual histological entities and to guide future treatment strategies.
