Search Results (859)

Urothelial carcinoma predominantly affects older patients, who often exhibit frailty, comorbidities, renal impairment, and reduced physiological reserve. We evaluated overall survival (OS) and progression-free survival (PFS) with first-line immune-based strategies in patients aged ≥65 years with advanced or metastatic urothelial carcinoma. The aim was to characterize treatment effects within this age-defined subgroup, not to determine whether age modifies treatment efficacy compared with younger patients. Methods: We conducted a systematic review and meta-analysis of phase 3 randomized trials published from January 2015 to May 2026 reporting age-specific survival outcomes. Combination regimens were compared with platinum-based chemotherapy using random-effects models. Results: Combination strategies improved OS versus chemotherapy (HR 0.79, 95% CI 0.64–0.96), although heterogeneity was substantial (I² = 69.7%) and the prediction interval crossed the null (0.48–1.27). Class-specific HRs were 0.56 (95% CI 0.26–1.20) for ADC plus ICI, 0.85 (0.77–0.95) for ICI plus chemotherapy, and 0.91 (0.34–2.42) for dual-checkpoint inhibition. PFS favoured experimental treatment but remained imprecise (HR 0.54, 95% CI 0.27–1.08; I² = 89.5%). Excluding ADC plus ICI trials attenuated the OS effect (HR 0.88, 95% CI 0.80–0.96), indicating that the pooled estimate was influenced by these trials. ICI monotherapy did not improve OS. Conclusions: First-line immune-based combinations improved survival in selected patients aged ≥65 years, but benefit varied across treatment classes and should not be considered uniform across regimens. These findings do not establish whether age modifies treatment efficacy. Age-specific safety data were insufficient to define the benefit–risk profile of individual strategies. Full article

Objectives: To investigate the rate and predictors of recurrence at second-look ureterorenoscopy (URS) and to assess the adequate timeframe for second-look URS in upper tract urothelial carcinoma (UTUC). Methods: This multicenter retrospective study included 179 patients who underwent endoscopic kidney-sparing surgery (KSS) and second-look URS for non-invasive UTUC between 2004 and 2017. We performed logistic and Cox proportional hazard regression analyses to investigate the association between clinical parameters and second-look recurrence, recurrence-free survival (RFS), and cancer-specific mortality. The optimal duration to second-look URS was extrapolated using restricted cubic splines. Results: Overall, 66 (36.9%) patients experienced recurrence at second-look URS. After second-look URS, further recurrence was observed in 87 (48.6%) patients during a median follow-up of 12 months. Female gender (OR [odds ratio] 2.3, 95% CI [confidence interval] 1.1–4.7, p = 0.026) and tumor size > 1 cm (OR 3.3, 95% CI 1.2–9.5, p = 0.027) were independently associated with recurrence at second look. Second-look recurrence was a strong prognostic factor for RFS (HR 5.0, 95% CI 3.1–8.0, p < 0.001). Second-look URS between 5 and 12 weeks after initial endoscopic laser ablation was an independent favorable factor for RFS (HR 0.5, 95% CI 0.3–0.9, p = 0.014). Conclusions: Early recurrence at second-look URS appears to be one of the strongest predictive factors for RFS in patients undergoing endoscopic KSS. Our results suggest that second-look URS performed within 5 to 12 weeks is associated with a lower probability of further disease recurrence. Given that this interval was derived and tested in the same cohort, this finding should be regarded as hypothesis-generating and requires external validation before being adopted as a clinical standard. Full article

Immune–organoid co-culture has been proposed as a bridge between reductionist assays and clinical immuno-oncology, but the urologic evidence remains substantially thinner than this description suggests. This critical narrative review evaluates peer-reviewed work in prostate cancer, urothelial carcinoma and renal cell carcinoma from January 2014 through to 31 July 2026, separating patient-derived immune-preserving models from reconstituted cytotoxicity assays and adjacent engineering studies. Native air–liquid interface cultures have retained endogenous lymphoid, myeloid and stromal compartments in renal cell carcinoma for short-term checkpoint-inhibitor experiments. Reconstituted bladder and kidney organoids have supported mechanistic testing of chimeric antigen receptor T cells, and a bladder study has examined treatment-induced Jurkat-cell migration. These studies establish technical feasibility, but most use small cohorts, short endpoints and incomplete immune composition, and none has prospectively shown that a multi-lineage urologic organoid assay improves treatment selection. Published prostate systems remain largely epithelial or stromal, leaving a conspicuous immune-modelling gap. We therefore argue against equating greater cellular complexity with greater validity. The appropriate model is the least complex system that preserves the mechanism, spatial constraint and temporal window required by the question. A tiered framework is proposed that progresses from analytical quality control, through defined effector and suppressor modules, to perfused or spatially organised cultures only when these features are necessary. Minimum reporting standards, disease-specific immune modules, clinically meaningful endpoints and a four-stage validation ladder are specified. Multi-lineage systems can clarify resistance mechanisms and screen combinations, but predictive or clinical claims require blinded patient concordance and prospective utility studies rather than architectural sophistication alone. Full article

Second-line chemotherapy is widely used in metastatic urothelial carcinoma after progression on first-line platinum-based therapy, but its independent contribution to survival, as opposed to selection of healthier patients, remains unclear. In this multicenter retrospective cohort of 142 patients treated with first-line platinum-based chemotherapy across seven Turkish centers, overall survival (OS) from first-line progression was compared between patients who received second-line chemotherapy (n = 80) and those who did not (n = 62), using multivariable Cox regression, inverse probability of treatment weighting (IPTW), propensity-score matching, landmark analysis, and a time-dependent Cox model. Median OS was 7.4 versus 4.7 months (log-rank p = 0.064). Second-line chemotherapy was independently associated with improved OS on multivariable analysis (adjusted hazard ratio [aHR] 0.620; 95% confidence interval [CI] 0.423–0.907; p = 0.014); Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2 (aHR 3.881; p = 0.001) and lower albumin (aHR 0.671; p = 0.018) were also independent predictors. The association remained significant after IPTW (HR 0.648; p = 0.025) and after a time-dependent Cox model (HR 0.632; p = 0.019), and was unchanged in ECOG-restricted and Bellmunt-adjusted analyses (p = 0.008, p = 0.029); it narrowly missed significance after propensity-score matching (HR 0.645; p = 0.051) and did not reach significance in the 3-month landmark analysis (HR 0.743; p = 0.180). Power was limited (~49%). In a time-dependent Cox model—the analysis least susceptible to immortal-time bias, as it retains the full cohort and classifies pre-treatment person-time as unexposed—second-line chemotherapy remained independently associated with improved OS (HR 0.632; p = 0.019), closely consistent with the primary multivariable estimate. The conventional Cox, IPTW, and propensity-score-matched analyses, which treat second-line receipt as a baseline exposure, were directionally concordant but share a common time-related bias and are therefore not independent confirmations. ECOG performance status was a consistent predictor throughout. Full article

Urinary biomarkers are promising tools in urological oncology because urine can be collected non-invasively and repeatedly during diagnosis, treatment, and surveillance. Despite extensive biomarker discovery, their adoption in routine practice remains limited. Biomarker performance depends not only on analytical accuracy but also on the clinical decision, anatomical route into urine, biological source of the signal, specimen fraction, and timing and conditions of sampling. This review evaluates urinary biomarkers across bladder cancer, upper-tract urothelial carcinoma, prostate cancer, and renal cell carcinoma using a biologically grounded, decision-oriented framework. It considers tumor-derived nucleic acids, epigenetic alterations, proteins, immune and inflammatory mediators, extracellular vesicles, metabolites, microbiome-associated signals, and multiparametric models. Bladder cancer represents the most anatomically direct and clinically mature setting, with potential applications in hematuria evaluation, cystoscopy triage, recurrence surveillance, molecular residual disease assessment, and monitoring of response to bacillus Calmette–Guérin therapy. In upper-tract urothelial carcinoma, distinguishing voided from selectively collected urine is essential because dilution, transit, obstruction, and limited localization affect interpretation. Prostate urine assays are best positioned for biopsy triage and refinement of active surveillance rather than general population screening. Renal cell carcinoma biomarkers remain exploratory because the sources and mechanisms of urinary signal release are insufficiently resolved. Clinical translation should be assessed using decision-specific outcomes, including incremental value, calibration, net clinical benefit, procedures avoided, significant cancers missed, reproducibility, and feasibility, rather than diagnostic accuracy or area under the receiver operating characteristic curve alone. Full article

Adjuvant and perioperative immune checkpoint inhibitors (ICIs) have created a growing population of patients who relapse after prior programmed death-1 or programmed death-ligand 1 blockade, yet these patients were underrepresented in many trials that established metastatic standards. We performed a structured narrative review of PubMed/MEDLINE, ClinicalTrials.gov, reference lists, and international oncology guideline repositories through 15 August 2026. Eligible reports addressed recurrence patterns or treatment after curative-intent ICI in melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple-negative breast cancer (TNBC); landmark metastatic studies were included only when direct evidence was unavailable and are labeled as extrapolation. Timing was standardized as on-treatment recurrence, early off-treatment recurrence (after the last ICI dose through 12 months), and late recurrence (>12 months). Shorter disease-free interval is consistently prognostic, but treatment-by-timing interactions are rarely available; timing should not be described as a validated pan-tumor predictive biomarker. Direct post-adjuvant evidence supports switching away from anti-PD-1 monotherapy for melanoma recurring on treatment, while selected late relapses may retain sensitivity. In RCC, retrospective post-adjuvant data support VEGF-targeted options, whereas CONTACT-03 and TiNivo-2 discourage routine ICI-TKI rechallenge specifically after prior ICI-treated metastatic RCC. Evidence in NSCLC, urothelial carcinoma, and TNBC is largely indirect. IMpassion132 was not an ICI-rechallenge trial, and only a small minority of ASCENT-04 participants had prior perioperative ICI. Treatment should integrate tumor-specific biology, actionable alterations, recurrence distribution, prior toxicity, comorbidity, access, and patient preference. Prospective trials dedicated to post-adjuvant ICI recurrence are needed. Full article

Background: Patients with end-stage renal disease (ESRD) undergoing radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) represent a uniquely high-risk population. While prior studies have demonstrated worse postoperative outcomes among dialysis-dependent patients, no study has systematically compared oncological outcomes between peritoneal dialysis (PD) and hemodialysis (HD) modalities following RNU. This multicenter study evaluates whether dialysis modality (peritoneal dialysis versus hemodialysis) acts as an independent prognostic factor following radical nephroureterectomy. Methods: Using the Taiwan UTUC Collaboration Group Registry—a multicenter, nationwide database comprising 21 tertiary and regional medical centers —we identified 350 ESRD patients who underwent RNU for UTUC between September 1988 and December 2023. Patients were categorized by dialysis modality at the time of surgery: 310 on HD and 40 on PD. Propensity score overlap weighting was applied to account for baseline differences. Multivariate Cox proportional hazards and Fine-Gray competing risk regression models were utilized to evaluate overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and non-UTUC mortality. Results: After overlap weighting, PD was independently associated with significantly worse OS (HR = 2.34, 95% CI 1.29–4.25, p = 0.005) and PFS (HR = 2.06, 95% CI 1.16–3.66, p = 0.013) compared to HD and exhibited a trend toward worse CSS in univariate analysis (log-rank p = 0.094). Survival curve divergence between PD and HD was most pronounced from 12 to 24 months post-surgery onward. Notably, this survival disadvantage persisted despite PD patients being significantly younger (mean age 58.8 vs. 65.1 years) and receiving adjuvant chemotherapy more frequently (20.0% vs. 6.5%). PD was also independently associated with higher non-UTUC mortality on multivariate competing risk analysis (sHR = 2.17, 95% CI 1.22–3.88, p = 0.009). Conclusions: In this first multicenter systematic comparison of PD versus HD patients undergoing RNU for UTUC, PD modality was independently associated with worse OS and PFS and exhibited a trend toward worse CSS in univariate analysis, compared to HD. This survival disadvantage persists despite favorable baseline characteristics and higher rates of adjuvant chemotherapy. We hypothesize these outcomes may be driven by a dual vulnerability: impaired systemic tumor control and elevated non-cancer mortality following surgical disruption of the peritoneal environment. To mitigate these risks, prioritizing minimally invasive or retroperitoneal surgical approaches to preserve peritoneal integrity, combined with modality-specific multidisciplinary surveillance, is recommended. Full article

Background/Objectives: White-light cystoscopy remains central to bladder cancer detection and surveillance, but diagnostic uncertainty persists in detecting flat lesions, particularly carcinoma in situ, distinguishing inflammatory mimics, and targeting biopsies. Optical spectroscopy and spectral imaging may provide objective tissue information beyond visual inspection. This scoping review mapped the diagnostic evidence and translational readiness of these technologies. Methods: A scoping review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). PubMed, Embase and Web of Science were searched from inception to 31 July 2026. Eligible articles evaluated wavelength-dependent optical signals directly in human bladder tissue in clinically relevant in vivo or ex vivo settings. Related articles with the same, overlapping or expanded datasets were grouped into study families. Results: Forty-seven articles were organised into 39 study families. Raman spectroscopy showed the clearest progression from ex vivo discrimination to in vivo cystoscopic feasibility and device development. Fluorescence and reflectance provided early in vivo evidence, although specificity was often limited by inflammation and benign changes. Infrared and near-infrared techniques remained mainly specimen-based, while multimodal systems were evaluated mostly ex vivo. Evidence for spectral imaging was limited, and no clinically integrated endoscopic hyperspectral-imaging study meeting the criteria was identified. Conclusions: Optical spectroscopy and spectral imaging show diagnostic potential for bladder cancer tissue characterisation, but evidence remains heterogeneous and insufficient for routine implementation. Among the included techniques, Raman spectroscopy appears most translationally mature, whereas wide-field spectral imaging remains underdeveloped. Future studies should prioritise prospective in vivo evaluation, standardised acquisition, histopathological correlation, external patient-level validation and clinically meaningful endpoints. Full article

Background: Balkan nephropathy (BEN), caused by chronic dietary exposure to aristolochic acid (AA), is a tubulointerstitial kidney disease strongly associated with upper-tract urothelial carcinoma (UTUC). Patient and graft survival, the cumulative incidence and timing of post-transplant UTUC, and the burden of non-urothelial malignancy after kidney transplantation remain poorly defined. Methods: We retrospectively analyzed all patients with BEN as the primary cause of end-stage kidney disease transplanted at University Hospital Center Zagreb between October 1973 and December 2023. Outcomes included patient and graft survival, the incidence and timing of post-transplant UTUC, and burden of non-urothelial malignancies. Results: Of 2282 kidney transplants performed in the study period, 44 (2%) were in patients with BEN. The median age at transplantation was 56 years, and the median dialysis vintage was 3.7 years. After 10 years (median) of follow up, among 34 patients with adequate follow-up, 16 (47%) developed a de novo malignancy: eight (24%) UTUC, one renal cell carcinoma, four other solid tumors, and three hematological. UTUC was diagnosed between 6 months and 15 years post-transplant (median 7 years); five of eight patients died within one year of diagnosis. Five- and ten-year patient survival rates were 82% and 54.5%. Conclusions: Kidney transplantation in patients with BEN carries a lifelong cancer risk dominated by UTUC. Prophylactic bilateral nephroureterectomy should be the default management strategy when feasible, with lifelong surveillance extending beyond the urothelium. Full article

Background/Objectives: Antibody–drug conjugates (ADCs) targeting Nectin-4 (enfortumab vedotin) and TROP-2 (sacituzumab govitecan) have transformed the management of advanced urothelial carcinoma (UC), but evidence on their molecular targets in rare non-urothelial bladder carcinomas (N-UC) is scarce. We evaluated the immunohistochemical expression of TROP-2 and Nectin-4 in muscle-invasive UC and N-UC and assessed their association with tumour stage, nodal status and overall survival. Methods: In this retrospective single-centre study, 111 consecutive patients with primary muscle-invasive bladder carcinoma (73 UC, 38 N-UC including squamous, adenocarcinoma, neuroendocrine and sarcomatoid variants) were analysed. TROP-2 and Nectin-4 expression was quantified using the H-score; positivity was defined as ≥15. Marker expression was correlated with clinicopathological characteristics and overall survival (OS) using chi-squared, linear-by-linear, log-rank, and Cox regression analyses. Results: TROP-2 positivity was observed in 46.6% of UC and 36.8% of N-UC (p = 0.925); Nectin-4 positivity in 17.8% and 28.9%, respectively (p = 0.275). Among positive cases, TROP-2 H-scores were higher in N-UC than in UC (mean 109 vs. 70; Mann–Whitney p = 0.045; Cliff’s delta 0.37, 95% CI 0.05–0.66); as no adjustment for multiple testing was applied, this difference is regarded as nominally significant and exploratory. Nectin-4 H-scores were numerically higher in UC (mean 82 vs. 53) but did not reach statistical significance (p = 0.84). Across the cohort, TROP-2 expression increased with advancing T stage (linear-by-linear p = 0.026) and was associated with nodal involvement (p = 0.043). Nectin-4 showed no significant stage association. Sarcomatoid carcinomas were negative for both markers. Median OS was 41 months in UC versus 19 months in N-UC (p = 0.668). Neither marker independently predicted OS, whereas advanced T stage (p = 0.003) and nodal involvement (p = 0.021) were significantly associated with poorer survival; T stage remained independently prognostic in multivariable analysis. Conclusions: TROP-2 and Nectin-4 are expressed at comparable rates in muscle-invasive UC and rare N-UC, except in sarcomatoid variants. TROP-2 expression increased with advancing tumour stage, suggesting stage-dependent regulation in muscle-invasive disease. Therefore, both markers should be interpreted as potential therapeutic targets whose expression can be demonstrated in these tumours, rather than as prognostic biomarkers or as validated predictive biomarkers of ADC response; because no patient received an ADC, the present study cannot determine whether expression predicts clinical benefit, and this distinction requires prospective, treatment-linked evaluation that includes patients with N-UC. Full article

Background/Objectives: Radical nephroureterectomy (RNU) is the standard of care for high-risk upper tract urothelial carcinoma (UTUC) but causes permanent renal decline, often disqualifying patients from essential cisplatin-based adjuvant chemotherapy. Segmental ureteral resection (SUR) preserves renal function, but its safety in high-risk patients remains fiercely debated due to historical treatment selection biases and a lack of competing risk adjustments. We aimed to compare long-term oncological outcomes and postoperative renal function preservation between SUR and RNU for high-risk UTUC strictly localized to the ureter. Methods: Retrospective data from 859 patients (783 RNU, 76 SUR) with high-risk ureteral UTUC (high-grade or pathologic T2–T4) were analyzed from a 21-hospital nationwide database. Propensity score overlap weighting was implemented to achieve covariate balance. Overall survival (OS) was assessed via Cox proportional hazards regression, whereas cancer-specific survival (CSS), metastasis-free survival (MFS), and local recurrence-free survival (LRFS) were evaluated using multivariable Fine–Gray subdistribution hazard models to robustly account for the competing risk of non-cancer mortality. Results: Overlap weighting achieved excellent baseline comparability with an effective sample size of 429.5 patients per cohort. Weighted analyses demonstrated comparable long-term trajectories between SUR and RNU for OS (p = 0.62), CSS (hazard ratio [HR]: 0.94, p = 0.835), and MFS (HR: 0.88, p = 0.664). The Fine–Gray model confirmed that the surgical approach was not a significant independent predictor of local recurrence (HR: 0.74, p = 0.351). Crucially, the SUR group demonstrated a significantly lower renal function decline both at 1 month (−0.11 vs. −10.58 mL/min/1.73 m², p < 0.001) and through final clinical follow-up (−5.33 vs. −12.49 mL/min/1.73 m², p = 0.001). Conclusions: For meticulously selected patients with high-risk ureteral UTUC, SUR provides equivalent oncological control and survival outcomes to standard RNU. Crucially, this kidney-sparing approach significantly preserves postoperative renal function, safeguarding the physiological reserve required for patients to maintain eligibility for optimal subsequent systemic adjuvant therapies. Full article

Background: Next-generation sequencing (NGS)-detected ERBB2 amplification occurs in a subset of urothelial carcinomas, but its role as a treatment-selection marker for trastuzumab deruxtecan (T-DXd) remains uncertain. Methods: We retrospectively reviewed four patients with metastatic urothelial carcinoma treated with T-DXd in routine practice from 2024. Treatment selection was based on NGS-detected ERBB2 amplification because HER2 immunohistochemistry and in situ hybridization were unavailable. Results: Four men aged 65–76 years received T-DXd: one in the second line and three in the fourth or fifth line. The best radiological responses, abstracted from contemporaneous radiology reports and oncology medical records, were complete response in one patient, partial response in one, and stable disease in two. Three patients had previously received enfortumab vedotin. Documented adverse events included fatigue, anemia, diarrhea, rash, and leukopenia. No interstitial lung disease or pneumonitis was documented in the available records. Conclusions: These observations are descriptive and hypothesis-generating. They do not establish the efficacy or safety of T-DXd or validate ERBB2 amplification as a predictive biomarker, but they support prospective evaluation of genomic ERBB2 amplification when standard HER2 testing is unavailable. Full article

Human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (Trop-2) are tumor-associated antigens widely overexpressed in multiple malignant tumors, which drive malignant proliferation, invasion, metastasis, and therapeutic resistance by activating key downstream signaling pathways. Antibody–drug conjugates (ADCs) targeting HER2 and Trop-2 leverage their antigen-specific binding capacity to achieve precise targeted delivery of cytotoxic drugs, representing a significant breakthrough in solid tumor therapy. This review systematically outlines the biological functions and carcinogenic mechanisms of HER2 and Trop-2, focusing on the latest research and development progress of related ADCs. We also summarize and analyze key clinical data and application prospects in breast cancer (BC), gastric cancer (GC), non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC), while also delving into the challenges and future directions within this field. Full article

Bladder cancer (BLCA) is a common and heterogeneous malignancy in which disease progression is driven not only by tumor-intrinsic alterations but also by dynamic interactions within the tumor microenvironment (TME). Increasing evidence positions the extracellular matrix (ECM) as a critical regulator of these processes. Matricellular proteins (MCPs), a group of nonstructural ECM-associated molecules, have emerged as key modulators of tumor–stroma communication. In BLCA, MCPs have been reported to display divergent, and in some cases opposing, associations or functions, with the same protein participating in both tumor promotion and suppression. Here, we review current evidence on the function of MCPs in BLCA and synthesize their bidirectional roles in carcinogenesis. MCPs contribute to tumor progression by promoting invasion, epithelial–mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. At the same time, MCPs can restrain tumor growth by inhibiting angiogenesis, stabilizing ECM organization, inducing cell cycle arrest, and maintaining epithelial integrity. A key concept emerging from this body of evidence is the context-dependent functional plasticity of MCPs. We propose that MCP-associated phenotypes in BLCA may be influenced by contextual factors, including isoform diversity arising from alternative splicing and post-translational modifications, spatial compartmentalization within tumor and stromal niches, tumor microenvironmental composition, and molecular subtype. However, the level of supporting evidence differs substantially among MCPs, and direct BLCA-specific mechanistic evidence remains limited for many proposed relationships. These factors, therefore, provide a framework for interpreting divergent findings rather than representing universally established determinants of MCP function. Recognizing MCPs as context-sensitive regulators rather than fixed tumor-promoting or tumor-suppressing entities provides a unifying framework for understanding their roles in BLCA. This could be an important step for therapeutic targeting, encouraging effective strategies to consider and incorporate the molecular and microenvironmental context in which MCPs operate. Full article

Background: Upper tract urothelial carcinoma (UTUC) is a rare malignancy representing approximately 5–10% of all urothelial cancers. Key risk factors include smoking, chemical exposures, selected metabolic conditions, and hereditary cancer syndromes. This narrative review summarises current knowledge on UTUC molecular pathogenesis, major risk determinants, and contemporary therapeutic strategies. Methods: This study was conducted as a narrative review with a structured literature search. PubMed, Web of Science, Embase, and Scopus were searched using predefined combinations of UTUC-related terms covering molecular pathogenesis, carcinogenic risk factors, and treatment strategies. The review was prepared according to SANRA principles to improve transparency and consistency; however, no formal systematic review methodology or meta-analysis was performed. Results: Available genomic studies indicate that UTUC has a molecular profile distinct from urothelial bladder carcinoma (UBC), with recurrent alterations involving FGFR3, HRAS, KMT2D, CDKN2A, KRAS, MYC, and BRIP1. Smoking, aristolochic acid exposure, Lynch syndrome, and possibly early-onset urolithiasis contribute to carcinogenesis through distinct but incompletely understood mechanisms. Surgical treatment remains the standard of care for high-risk localised disease, whereas perioperative chemotherapy, immunotherapy, and targeted agents are expanding treatment options, particularly in advanced disease. A substantial proportion of the therapeutic evidence, however, is derived from broader urothelial carcinoma populations rather than UTUC-specific studies. Conclusions: UTUC is biologically heterogeneous and shaped by both molecular alterations and environmental exposures. Although substantial progress has been made, important gaps remain in understanding UTUC-specific carcinogenic mechanisms and in defining evidence-based personalised treatment strategies. Better integration of molecular, environmental, and clinical data is needed to improve risk stratification and treatment selection. Full article