Search Results (10)

Background/Objectives: Micropapillary urothelial carcinoma of the urinary bladder (MPUC) represents a rare but highly aggressive histological variant of urothelial carcinoma (UC), frequently presenting at an advanced stage of disease. Although data on histological variants consistently suggest inferior oncological outcomes, the independent prognostic role of the micropapillary variant remains controversial. Methods: The present work synthesizes the findings of a large meta-analysis evaluating histological variants of UC and a separate meta-analysis focusing exclusively on MPUC, and further examines the most recent cohort-based evidence published between 2016 and 2025. Results: The presence of any histological variant in UC treated with radical cystectomy is associated with significantly worse recurrence-free survival, disease-specific survival, and overall survival, as reflected by pooled hazard ratios (HRs). For the micropapillary variant specifically, a modest increase in overall mortality has been demonstrated (pooled HR ≈ 1.20); however, results from adjusted analyses dedicated to MPUC remain inconsistent. Conclusions: Micropapillary urothelial carcinoma is consistently associated with adverse pathological features and poorer oncological outcomes. However, whether micropapillary morphology independently predicts prognosis beyond established factors such as pathological stage and nodal status remains uncertain, as adjusted analyses across studies have yielded inconsistent results. Part of the observed survival disadvantage may be explained by stage migration, although an intrinsic residual risk cannot be definitively ruled out. This review integrates contemporary population-based registry analyses with prior meta-analytic evidence to provide a clinically oriented synthesis of the prognostic and therapeutic implications of MPUC. In addition, we propose minimal reporting standards aimed at improving comparability across future studies and strengthening risk stratification and treatment decision-making. Full article

High-grade serous carcinoma (HGSC) of the ovary is characterized by two major histological patterns: a classic papillary/micropapillary architecture and a solid pseudo-endometrioid transitional (SET) variant. We investigated whether the distinct morphologic subtypes are underpinned by transcriptomic differences in the tumor microenvironment (TME). We profiled 21 HGSC tumors (7 SET, 14 classic) using a 770-gene NanoString PanCancer Progression panel. Differential expression analysis revealed ~20 genes with significantly different expression (>4-fold, adjusted p < 0.01) between SET and classic tumors. Unsupervised clustering partially separated SET and classic tumors, suggesting that global gene expression patterns correlate with histologic subtype. SET tumors exhibited upregulation of cell-cycle and epithelial genes (e.g., PTTG1, TRAIL, HER3) and downregulation of genes involved in epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) organization, and angiogenesis (e.g., TWIST2, FGF2, decorin) relative to classic tumors. Notably, PTTG1 and TRAIL were upregulated ~6–9-fold in SET tumors, whereas TWIST2 was ~7-fold downregulated, consistent with reduced EMT in SET tumors. Pathway analysis indicated that SET tumors appear to have an immune-active, stroma-poor microenvironment, in line with an “immunoreactive” phenotype, whereas classic tumors showed a mesenchymal, stroma-rich profile. These molecular distinctions could have diagnostic utility and may inform therapeutic stratification, with key dysregulated genes (e.g., HER3, TRAIL, FGF2) representing potential prognostic or predictive biomarkers. For example, high HER3 expression in SET tumors might predict sensitivity to ERBB3/PI3K inhibitors, whereas stromal factors (e.g., FGF2) enriched in classic HGSC could be targeted with microenvironment-modulating therapies. These preliminary findings require validation before translation into pathology practice via immunohistochemical (IHC) assays (e.g., for HER3 or TRAIL), potentially enabling improved classification and personalized treatment of HGSC. We report effect sizes as log₂ fold change with 95% confidence intervals and emphasize FDR-adjusted q-values. Given the small sample size and the absence of outcome data (OS/PFS/PFI), results are preliminary and hypothesis-generating. Orthogonal protein-level validation and replication in larger, independent cohorts are required before any translational inference. Full article

Background and Objectives: Urothelial carcinoma of the urinary bladder is a heterogeneous disease with diverse morphological and molecular characteristics. This study aims to analyze the expression of HER2 in 100 consecutive cases of muscle-invasive bladder carcinoma (MIBC), with a special attention to the different histological subtypes and consensus molecular variants determined by IHC methods. Materials and Methods: A retrospective single-center study was conducted on 100 consecutive cases of MIBC (2021–2024). HER2 status is assessed by immunohistochemistry (IHC) (scores 0, 0+, 1+, 2+, 3+), and the results are compared with the published data. Results: We have established that over half of the tumors (~60%) show some level of HER2 expression, with strong expression (3+) present in 25%. There are significant differences among the IHC-based molecular variants: luminal tumors, including papillary tumors, exhibit a frequent HER2 overexpression, whereas those with a basal immunophenotype (e.g., squamous, sarcomatoid variants) are almost entirely HER2-negative. The micropapillary subtype and some other rare subtypes can also express HER2. Conclusions: HER2 is an important biomarker with heterogeneous expression in urothelial carcinoma of the bladder. The present study showed that the frequency and level of HER2 expression vary substantially among different histopathological subtypes and molecular variants. In therapeutic terms, interest in HER2 as a target is growing—new antibody–drug conjugates show a promising activity even in cases with low HER2 expression, which will likely lead to the integration of HER2-directed therapies and routine testing in the future. Full article

Background/Objectives: This study aimed to profile the molecular variants of muscle-invasive bladder cancer (MIBC) based on immunohistochemical analysis and to make a correlation with morphological characteristics in a series of 100 consecutive patients. Methods: A retrospective single-center study was conducted on 100 consecutive cases of MIBC (2021–2024). A selected immunohistochemical (IHC) panel (including CK5/6, CK20, and p16) was applied in all cases to classify the tumors into known molecular variants (luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous, neuroendocrine-like). Results: Seven molecular subtypes are identified: basal (33%), luminal papillary (24%), luminal unstable (16%), luminal non-specified (10%), basoluminal (double-positive) (9%), neuroendocrine-like (double-negative with neuroendocrine morphology) (6%), and stroma-rich (2%). This distribution largely matches published data (Consensus Classification and The Cancer Genome Atlas (TCGA)), with minor differences (e.g., a lower share of the stroma-rich variant). A strong correlation is found between the histological subtypes of some tumors and their molecular variant (χ², p < 0.001): for example, all cases of urothelial carcinoma with squamous differentiation are basal, micropapillary tumors are entirely luminal, and small-cell carcinomas are neuroendocrine-like. Conclusions: The results demonstrate that the morphological subtype of urothelial carcinoma largely predetermines the molecular profile. Combining classic histopathology with IHC-based profiling allows for a more complete characterization of the tumor and aids prognosis and personalized treatment in MIBC. Full article

Background: The importance of lymph node dissection (LND) at the time of radical cystectomy for urothelial carcinoma (UC) is widely accepted despite known risks. The therapeutic benefits of LND for variant subtype bladder cancer (VBC), a heterogenous and distinct set of diseases, are not well established. We aim to characterize the impact of LND on overall survival across VBC subtypes. Methods: The National Cancer Database was queried for all cases of variant subtype bladder cancer managed with radical cystectomy between 2004 and 2020, using the International Classification of Disease-O-3 morphological codes. The cases were stratified by receipt of individual variant subtypes. The primary outcome was overall survival associated with pathologic nodal status and receipt of nodal dissection. A Kaplan–Meier analysis and Cox proportional hazards analysis were used for survival analyses. Results: A total of 30,911 patients with VBC that were managed with radical cystectomy were included in our analysis. The pNx rates ranged from 33.1% in the micropapillary subtype, 42.2% in the sarcomatoid subtype, 68.4% in the squamous subtype, 48.9% in the adenocarcinoma subtype, and 56.2% in the neuroendocrine subtype. The median OS was higher in those that received a nodal dissection across subtypes but was statistically significant only for the squamous (71.0 [68.0 vs. 74.0] vs. 37.2 [33.6 vs. 40.9] months p < 0.001) and adenocarcinoma (45.9 [32.9 vs. 59.0] vs. 37.9 [28.6 vs. 47.1] months p = 0.037) subtypes. Using Cox proportional hazards regression, LN dissection was associated with improved OS for the squamous (0.50 (0.44–0.58) p < 0.001) and adenocarcinoma (0.65 [0.45–0.93) p = 0.030) subtypes. Conclusions: The role of LND across VBC subtypes is not clearly defined and warrants further investigation to develop a more risk-adaptive approach. We demonstrate heterogeneity with respect to the OS benefit associated with LND at the time of surgery. Among certain VBC subtypes, LND may not offer a significant therapeutic benefit, while LND in squamous and adenocarcinoma VBCs is correlated with improved survival. Full article

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. Full article

The expression and prognostic role of programmed death ligand-1 (PD-L1) on tumor-infiltrating immune cells (TICs) has not been determined in urothelial carcinoma (UC) with variant histology. We retrospectively reviewed 90 patients (44 with micropapillary variant of UC (MPUC) and 46 with UC with squamous differentiation (UCSD)) who underwent radical cystectomy between January 2013 and December 2019. The expression of PD-L1 in TICs was measured using the VENTANA (SP-142) immunohistochemistry assay and dichotomized using a 5% cutoff value (positive ≥ 5%). Kaplan–Meier survival analysis was used to estimate recurrence-free survival (RFS), and multivariable Cox proportional hazard models were used to identify factors predicting tumor recurrence. Overall, positive PD-L1 expression in TICs was confirmed in 50 of 90 (55.6%) patients (40.1% (18/44) of MPUC and 69.9% (32/46) of UCSD). RFS was significantly shorter in patients with positive PD-L1 expression in TICs than in those with negative PD-L1 expression both in MPUC (p = 0.005) and UCSD (p = 0.046). Positive PD-L1 expression in TICs was significantly associated with an increased risk of tumor recurrence in both MPUC (HR = 1.85; 95% CI: 1.323–2.672; p = 0.017) and UCSD (HR = 1.58; 95% CI: 1.162–2.780; p = 0.032). In conclusion, positive PD-L1 expression in TICs was significantly associated with poorer RFS in both MPUC and UCSD patients. Our results support the use of adjuvant immunotherapy in these patients if they test positive for PD-L1 in their TICs. Full article

Objectives: Lymph node invasion (LNI) is related to long-term survival in patients with muscle-invasive bladder cancer. However, in the case of variant histology (VH), data on pelvic lymph node dissection (PLND) and LNI are sparse. We described the pattern of care of PLND in patients with VHs of bladder cancer, exploring predictors of LNI. Methods: Using the 2001–2016 SEER registry, 20,767 bladder cancer patients who underwent PLND were identified. Included histological variants were pure urothelial carcinoma (UC), micropapillary UC, sarcomatoid UC, lymphoepithelioma-like UC, adenocarcinoma, sarcoma, giant and spindle cell carcinoma, squamous cell carcinoma (SCC), and neuroendocrine tumor. Uni- and multivariable logistic regression analyses tested for LNI predictors. Cox regression was used to test for predictors of overall mortality (OM) among both LNI positive and LNI negative patients. Results: Overall, 2464 (11.9%) harbored a VH. On multivariate analysis, only micropapillary UC was associated with higher risk (OR = 3.39) of LNI. This association was maintained when only the subset of patients treated without perioperative chemotherapy were analyzed (OR = 3.30). Similarly, higher T stage (T2 stage OR = 2.24; T3–4 stage OR = 9.44) and the use of chemotherapy (OR = 2.29) were associated with a higher risk of LNI. Among patients with LNI (5299, 25.5%), SCC (HR = 1.87), T3–4 stage (HR = 1.94), age at diagnosis (HR = 1.01) and geographic region (south) (HR = 1.22) were predictors of higher risk of OM. Conversely, chemotherapy (HR = 0.69) and number of removed LN (HR = −0.99) were associated with lower risk of OM. Finally, in a subgroup of patients without LNI, sarcomatoid UC (HR = 1.58) and giant and spindle cell carcinoma (HR = 1.83) were the only VH predictors of OM. Conclusions: We described different patterns of care in patients with VHs of bladder cancer. Micropapillary UC was an independent risk factor for LNI. Among patients harboring LNI, those with SCC VH had higher OM compared to pure UC. Conversely, sarcomatoid UC and giant and spindle cell carcinoma were predictors of OM in patients without nodal involvement. Full article

The 2016 World Health Organization classification newly described infiltrating urothelial carcinoma (UC) with divergent differentiation (DD) or variant morphologies (VMs). Data comparing oncological outcomes after bladder-preservation therapy using intravesical Bacillus Calmette–Guérin (BCG) treatment among T1 bladder pure UC (pUC), UC with DD (UC-DD), and UC with VMs (UC-VM) are limited. We evaluated 1490 patients with T1 high-grade bladder UC who received intravesical BCG during 2000–2019. They were classified into three groups: 93.6% with pUC, 4.4% with UC-DD, and 2.0% with UC-VM. Recurrence-free, progression-free, and cancer-specific survival following intravesical BCG were compared among the groups using multivariate Cox regression analysis, also used to estimate inverse probability of treatment weighting-adjusted hazard ratio and 95% confidence interval for the outcomes. Glandular differentiation and micropapillary variant were the most common forms in the UC-DD and UC-VM groups, respectively. Of 1490 patients, 31% and 13% experienced recurrence and progression, respectively, and 5.0% died of bladder cancer. Survival analyses revealed the impact of concomitant VMs was significant for cancer-specific survival, but not recurrence-free and progression-free survival compared with that of pUC. Our analysis clearly demonstrated that concomitant VMs were associated with aggressive behavior in contrast to concomitant DD in patients treated with intravesical BCG. Full article

Recently, muscle-invasive bladder cancer (MIBC) has been subclassified by gene expression profiling, with a substantial impact on therapy response and patient outcome. We tested whether these complex molecular subtypes of MIBC can be determined by mRNA detection of keratin 5 (KRT5) and keratin 20 (KRT20). Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was applied to quantify gene expression of KRT5 and KRT20 using TaqMan^®-based assays in 122 curatively treated MIBC patients (median age 68.0 years). Furthermore, in silico analysis of the MD Anderson Cancer Center (MDACC) cohort (GSE48277 + GSE47993) was performed. High expression of KRT5 and low expression of KRT20 were associated with significantly improved recurrence-free survival (RFS) and disease-specific survival disease specific survival (DSS: 5-year DSS for KRT5 high: 58%; 5-year DSS for KRT20 high: 29%). KRT5 and KRT20 were associated with rates of lymphovascular invasion and lymphonodal metastasis. The combination of KRT5 and KRT20 allowed identification of patients with a very poor prognosis (KRT20⁺/KRT5⁻, 5-year DSS 0%, p < 0.0001). In silico analysis of the independent MDACC cohorts revealed congruent results (5-year DSS for KRT20 low vs. high: 84% vs. 40%, p = 0.042). High KRT20-expressing tumors as well as KRT20⁺/KRT⁻ tumors were significantly enriched with aggressive urothelial carcinoma variants (micropapillary, plasmacytoid, nested). Full article