Background/Objectives: UBC demonstrates a relatively low prevalence in patients under 50 years old. Our study aimed to compare the pathological characteristics of UBC in young and elderly patients and to assess the age-related variations in these characteristics. Methods: This retrospective study from January 2018 to December 2022 encompassed 762 patients with an initial diagnosis of UBC. To evaluate the pathological characteristics of UBC in young patients, compared to elderly patients, we divided our cohort using a cut-off age of 50 years. Additionally, to evaluate the age-dependent variations in these characteristics, we further stratified our patients into three age groups (≤50, 51–70, and >70 years old). Results: Of the 762 patients included in our study, 37 (4.86%) were young (≤50 years old), with a median age of 44 and a M:F ratio of 3.11:1. Conventional UC was the most common histology (86.5%). Regarding tumour grade, we noticed a higher prevalence of PUNLMP (10.8% versus 2.3%) and LGPUC (45.9% versus 37.1%) and a lower prevalence of HGPUC (43.2% versus 60%) and CIS (0% versus 0.6%) in young patients (p = 0.008). In this group, the pTa stage revealed a higher prevalence (64.9% versus 46.8%), while pT1 and pT2 showed a lower prevalence (32.1% versus 18.9% and 20.6% versus 16.2%) (p = 0.179). All results remained consistent when the cohort was stratified into three age groups, showing age-related variations (p = 0.001 and p = 0.089, respectively). Conclusions: In young patients, UBC tends to be of a lower grade and stage compared to elderly patients, and these characteristics demonstrate a gradual age-related stratification.

Urothelial bladder carcinoma (UBC) is a heterogeneous disease, characterized by variable treatment responses and outcomes, attributed to its underlying molecular diversity. Molecular classification has advanced our understanding of UBC, but remains limited by cost and complexity. Immunohistochemistry (IHC) offers an accessible, cost-effective alternative for routine subtype classification. We aimed to evaluate the predictive role of IHC-based classification of UBC on oncological outcomes and response to treatment, as well as to identify key IHC markers for routine use. A systematic literature search of PubMed and Scopus was conducted in January 2025, following PRISMA guidelines. Using the PICOS framework, we included post-2020 observational studies on muscle-invasive UBC patients classified by IHC into molecular subtypes, correlating these subtypes with oncological outcomes and treatment responses. Luminal subtypes generally exhibit better PFS, DSS and OS, although some studies report mixed results. The basal subtype shows better RFS compared to double-negative subtype and demonstrates a significantly better response to neoadjuvant chemotherapy (NAC). Double-positive subtypes often have improved OS, while double-negative subtypes consistently show the worst outcomes. Commonly used IHC markers include GATA3 and CK5/6 for identifying luminal and basal subtypes, respectively. Additionally, p16 helps distinguish Luminal Unstable from Luminal Papillary or Genomically Unstable (GU) subtypes, EGFR refines basal subtype classification and vimentin differentiates rare mesenchymal-like subtypes. We showed that IHC-based classification is a practical, promising tool for UBC patient stratification, outcome and response to treatment prediction. By identifying key IHC markers, we proposed a standardized panel to improve consistency and reproductibility in clinical practice and research.

Muscle-invasive bladder urothelial carcinoma (MIBUC) is a heterogeneous disease, presenting variable clinical outcomes and therapeutic responses. Although molecular classification provides important prognostic information, its clinical use is limited by cost and technical complexity, making immunohistochemistry (IHC) a practical and reliable surrogate approach. We aimed to investigate the association between IHC-based molecular subtypes and overall survival (OS). We conducted a retrospective study including 75 newly diagnosed MIBUCs over a 4-year period. Tumours were stratified into seven molecular subtypes (LumP, LumNS, LumU, Ba/Sq, NE-like, stroma-rich, and double-positive) using a five-antibody IHC panel (GATA3, CK5/6, p16, FGFR3, and EpCAM). Marker expression was evaluated based on staining intensity and the proportion of positive tumour cells, using predefined, marker-specific cut-off values. OS was assessed for each subtype and compared across groups. Median OS ranged from 5 months (NE-like) to 26 months (stroma-rich and double-positive). LumU demonstrated the highest 1-year survival rate, while the double-positive subtype exhibited the most favourable long-term outcomes, at 2 and 5 years. Conversely, NE-like had the lowest 1-year survival rate, whereas the stroma-rich subtype demonstrated the lowest 2- and 5-year survival rates. No statistically significant difference in OS was identified across molecular subtypes (p = 0.714). Patients ≤65 years experienced significantly longer OS than older patients (p = 0.024). OS was comparable between sexes (p = 0.626) and did not differ significantly according to tumour morphology (p = 0.884). IHC-based molecular classification represents a feasible approach to characterize molecular heterogeneity in MIBUC, with further studies needed to clarify its prognostic significance.