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Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.

Objective: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC. Patients and methods: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non‐urinary tract recurrence‐free survival (NUTR‐FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer. Results: At median follow‐up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR‐FS were observed when TUR specimens were classified as pure‐urothelial carcinoma (UC), subtypes, DD, or non‐UC. Among 2449 patients diagnosed with pure‐UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre‐RC neutrophil–lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively). Conclusion: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre‐RC neutrophil–lymphocyte ratio and pathological stage were independent prognostic factors for OS. [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) is the tenth most commonly diagnosed malignancy worldwide. In approximately 25% of cases, it presents as a muscle-invasive disease, requiring a radical treatment. Traditionally, the mainstay of treatment has been radical cystectomy (RC), but in the last decade, bladder-sparing treatments have been gaining growing interest. In particular, trimodal therapy (TMT) seems to yield survival results comparable to RC with less morbidity and better quality of life (QoL) outcomes. In this scenario, we aimed at shedding light on the role of the histological subtypes (HS) of BC and their prognostic significance in muscle-invasive BC (MIBC), treated either surgically or with TMT. We performed a narrative review to provide an overview of the current literature on this topic. When compared with patients diagnosed with conventional urothelial carcinoma (UC) of the same disease stage, survival did not appear to be significantly worse across the reports. But when sub-analyzed for separate subtype, some appeared to be independently associated with adverse survival outcomes such as the micropapillary, plasmacytoid, small-cell, and sarcomatoid subtypes, whereas others did not. Moreover, the optimal management remains to be defined, also depending on the therapeutic susceptibility of each histology. From this perspective, multi-disciplinary assessment alongside the routine inclusion of such entities in randomized clinical trials appears to be essential. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prognostic impact of variant histology (VH) on oncological outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) who had undergone radical nephroureterectomy (RNU). Patients and methods: A total of 1239 patients with clinically localized UTUC who underwent RNU at a single institution between January 2005 and June 2020 were included. The VH was reviewed by a uro‐pathologist at our institution. The Cox regression model was used to perform multivariate analysis, including VH and other established prognostic factors for post‐RNU oncological outcomes (intravesical recurrence [IVR], non‐urothelial recurrence, and cancer‐specific death). Results: Of the 1239 patients with UTUC, 384 patients (31%) were found to have VH. Advanced tumor stage, lymph node metastasis, high tumor grade, lymphovascular invasion, open surgery, and renal pelvis had a significantly larger proportion of UTUC with VH compared to pure UTUC (all p < 0.05). VH was an independent prognostic factor associated with less IVR identified by multivariate analysis, more non‐urothelial recurrence, and more cancer‐specific mortality. Conclusion: Patients with VH account for 31% with UTUC treated with RNU in this cohort. VH was an independent prognostic factor associated with more non‐urothelial recurrence and cancer‐specific mortality but less IVR. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to determine effects of adjuvant chemotherapy (AC) on survival outcomes compared to surgery alone without AC for upper tract urothelial carcinoma (UTUC) patients with variant histology (VH). Methods: We conducted a systematic review and meta-analysis of studies investigating AC for UTUC in Medline, Embase, the Cochrane Library up to January 2023. Population, intervention, comparator, and outcome were UTUC patients with VH, radical nephroureterectomy with AC, radical nephroureterectomy only, and oncological survival, respectively. Results: Four retrospective studies were included. Regarding overall survival (OS), the pooled hazard ratio was 0.61 (95% confidence interval: 0.42–0.87; p = 0.007) across two studies. Regarding cancer-specific survival (CSS), the pooled hazard ratio was 0.46 (95% confidence interval: 0.25–0.84; p = 0.01) across three studies. All included studies had a high quality based on the Newcastle-Ottawa Scale. Certainty of evidence for OS was low. Certainty of evidence for CSS was moderate due to a strong association (hazard ratio <0.5). Publication bias was not significant for any studies. Conclusion: In UTUC patients with VH, administration of AC after surgery might have better survival outcomes than surgery alone. Our study provides evidence for decision-making of clinicians who treat UTUC patients with VH. [ABSTRACT FROM AUTHOR]

Background/Aim: Variant urothelial carcinoma (VUC, defined herein as urothelial carcinoma with any histological variant) is frequently observed at an advanced stage. However, the efficacy of systemic chemotherapy against VUC in metastatic disease has rarely been reported. This study assessed the therapeutic response and survival outcomes of platinum-based chemotherapy as first-line treatment in patients with metastatic VUC. Patients and Methods: We retrospectively analyzed consecutive patients with metastatic bladder and upper urinary tract cancer who received gemcitabine plus cisplatin (or carboplatin) at the University of Occupational and Environmental Health Hospital between November 2008 and November 2022. Progression-free survival and overall survival were evaluated using the Kaplan-Meier method and Cox proportional hazard models. Results: Out of 131 patients recorded, 86 (65.6%) had pure urothelial carcinoma (PUC) and 45 (34.4%) had VUC. The most common variant element was squamous differentiation (44.4%). Compared to those with PUC, patients with VUC showed a comparable objective response rate (33.3% vs. 41.9%, p=0.451) and disease control rate (64.5% vs. 75.6%, p=0.221). They also had poorer progression-free survival (median=4.9 months vs. 7.9 months, p=0.014) and overall survival (median=10.9 months vs. 18.2 months, p=0.037) than those with PUC. On multivariate analysis, VUC was an independent predictor of progression (hazard ratio=1.79; 95% confidence interval=1.19-2.69; p=0.005) and mortality (hazard ratio=1.64; 95% confidence interval=1.08-2.48; p=0.020). Conclusion: Although the response of metastatic VUC to platinum-based chemotherapy was not inferior to that of PUC, VUC had progressed faster than PUC. VUC was significantly associated with a poor prognosis after platinum-based chemotherapy as first-line treatment. [ABSTRACT FROM AUTHOR]

Subtype of urothelial carcinoma (SUC), defined here as urothelial carcinoma with any histologic subtype or divergent differentiation, is a clinically aggressive disease. However, the efficacy of enfortumab vedotin (EV) against SUC remains unclear. Hence, this study aimed to assess the oncological outcomes of patients with SUC treated with EV for metastatic disease. We retrospectively evaluated consecutive patients with advanced lower and upper urinary tract cancer who received EV after platinum-based chemotherapy and immune checkpoint blockade therapy at six institutions. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with SUC. We identified 44 and 18 patients with PUC and SUC, respectively. Squamous differentiation was the most common subtype element, followed by glandular differentiation and sarcomatoid subtype. Although patients with SUC had a comparable ORR to those with PUC, the duration of response for SUC was short. Patients with SUC had poorer PFS than those with PUC; however, no significant difference was observed in OS. Multivariate analysis revealed that SUC was significantly associated with shorter PFS. Although the response of metastatic SUC to EV was similar to that of PUC, SUC showed faster progression than PUC. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of variant histology on patients with upper tract urothelial carcinoma (UTUC) survival outcomes. Materials and methods: A total of 519 patients underwent radical nephroureterectomy without neoadjuvant therapy for UTUC at a single institution between May 2003 and December 2019. Multivariate Cox regression analysis evaluated the impact of variant histology on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Results: Among 84 patients (16.2%) with variant histology, the most frequent variant type was squamous cell differentiation (64.3%), followed by glandular differentiation (25.0%) and sarcomatoid variant (2.4%). They showed pathologically advanced T stage (for ≥ T3, 59.5% vs 33.3%, p < 0.001), higher tumor grade (96.4% vs 85.7%, p = 0.025), and higher rates of lymph node metastasis (17.9% vs 7.8%, p = 0.015), angiolymphatic invasion (41.7% vs 25.7%, p = 0.003), tumor necrosis (57.1% vs 29.0%, p < 0.001) and positive surgical margin (13.1% vs 5.7%, p = 0.015). On multivariate Cox regression analyses, variant histology was significantly associated with worse PFS (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.55–3.21; p < 0.001), CSS (HR 2.67; 95% CI 1.35–5.30; p = 0.005) and OS (HR 2.22; 95% CI 1.27–3.88; p = 0.005). In subgroup analysis, no significant survival gains of adjuvant chemotherapy occurred in patients with variant histology. Conclusions: Variant histology was associated with adverse pathologic features and poor survival outcomes. Our results suggest that patients with variant histology may require a close follow-up schedule and novel adjuvant therapy other than chemotherapy postoperatively. [ABSTRACT FROM AUTHOR]

We sought to characterize the expression level and subcellular localization of Nectin-4 and Trop-2, targets of novel antibody-drug conjugates in metastatic urothelial cancer, within variant bladder cancer from matched primary and metastatic sites. We find significant levels of the targets in histologic variants. Additionally, high levels of cytoplasmic rather than membrane staining is seen, which may have important clinical implications. Background: Nectin-4 and Trop-2 are transmembrane targets of FDA-approved antibody-drug conjugates (ADC) Enfortumab-vedotin (EV) and Sacituzumab govitecan (SG), respectively, for the treatment of metastatic urothelial carcinoma (mUC). The expression and role of Nectin-4 and Trop-2 in mUC variant histology is poorly described. Materials and Methods: We evaluate membranous and cytoplasmic protein expression, and mRNA levels of Nectin-4 and Trop-2 within matched primary and metastatic mUC samples to determine heterogeneity of ADC targets in mUC variants. Results: Patients with mUC were consented for rapid autopsy immediately after death. Tissues from matched primary and metastatic lesions were collected. A total of 67 specimens from 20 patients were analyzed: 27 were UC, 17 plasmacytoid (PUC), 18 UC with squamous differentiation (UCSD), and 5 neuroendocrine (NE); 10 from primary and 57 from metastatic sites. All histology except NE expressed moderate-high levels of Nectin-4 and Trop-2 by both immunohistochemistry and RNAseq. Nectin-4 demonstrated prominent cytoplasmic staining in metastatic PUC and UCSD. Trop-2 demonstrated strong cytoplasmic and membrane staining in primary and metastatic tumors. Interestingly, Nectin-4 and Trop-2 expression are positively correlated at both mRNA and protein levels. Conclusion: UC and non-NE variants express notable level of Nectin-4 and Trop-2 in both primary and metastatic lesions. Membrane staining of Nectin-4 and Trop-2 is present but cytoplasmic staining is a more common event in both mUC and mUC variant histology. These findings support evaluation of EV and SG in heavily treated variant histology BC and urge attention on the clinical relevance of cytoplasmic localization of ADC targets. [ABSTRACT FROM AUTHOR]

We conducted a single-center retrospective cohort study to evaluate perioperative and survival outcomes for patients with muscle invasive bladder cancer undergoing surgery and characterized by cancer subtype. Our results suggest that urothelial carcinoma with squamous differentiation is associated with more advanced disease compared to pure urothelial carcinoma, suggesting a need for prospective studies to identify appropriate treatment regimens. Background: Squamous cell carcinoma of the bladder (SqCC) is a rare disease with limited management data. Thus, we sought to characterize the clinicopathologic and survival outcomes amongst patients with SqCC and explore the association of squamous differentiation within urothelial carcinoma (UC w/Squam), as compared to muscle invasive pure UC. Methods: We conducted a single-center retrospective cohort study of patients, stratified by histology, who underwent cystectomy for MIBC. Baseline clinicopathologic characteristics were compared, and overall survival was assessed using Kaplan-Meier method. Results: We identified 1,034 patients; 37 (3.58%) with SqCC histology, 908 (87.81%) with UC histology, and 89 (8.61%) with UC w/Squam histology. Among SqCC patients, a higher proportion were Black and similarly a higher proportion were women; amongst patients with UC w/Squam a higher proportion had lower BMI; and amongst patients with UC a higher proportion had lower clinical (c) T, cN, pathological (p) T, and pN stages. Patients presenting with UC were more likely to receive intravesical therapy; patients presenting with SqCC were less likely to receive neoadjuvant chemotherapy (NAC). Adjuvant chemotherapy rates were similar. With post-hoc Bonferroni analysis, overall survival, cancer-specific survival, and recurrence-free survival were significantly worse for the UC w/Squam cohort. Conclusions: UC w/Squam histology was associated with worse survival outcomes after cystectomy for muscle invasive bladder cancer compared to UC. Our results suggest that UC w/Squam is associated with more advanced disease compared to UC, warranting further prospective work on consideration of combination therapies for patients with this disease state. [ABSTRACT FROM AUTHOR]

Considering the divergent biological behaviors of certain histological subtypes of urothelial carcinoma, it would be of great importance to examine the impact of variant histology and to predict its presence in patients with bladder cancer. A single-center cohort study included 459 patients who underwent radical cystectomy for urothelial carcinoma between 2017 and 2021. Patients were followed up with until July 2022. We compared clinical, laboratory, and histopathologic characteristics and the overall survival between patients with pure urothelial carcinoma and variant histologies. Our results showed that the patients with variant histology were older and preoperatively more frequently had hydronephrosis and higher values of leukocytes and neutrophils. Also, we found a significant association between variant histology and an advanced stage of tumor disease, the presence of lymphovascular invasion, positive surgical margins, and metastases in surgically resected lymph nodes. The number of neutrophils was identified as an independent preoperative predictor of the presence of variant histology after a radical cystectomy. The overall survival of the patients with variant histology was significantly lower compared to the patients with pure urothelial carcinoma. According to our results, the presence of variant histology represents a more aggressive form of the disease. Preoperative neutrophil counts may indicate the presence of variant histology of urothelial carcinoma in patients with bladder cancer.

Abstract Background While the treatment guidelines have been established for pure urothelial carcinoma (pUC), patients with variant type urothelial carcinoma (vUC) face limited effective treatment options. The effectiveness of immune checkpoint inhibitors (ICI) in patients with vUC remains uncertain and necessitates additional research. Method We conducted a retrospective, multicenter study to explore the effectiveness of ICI in patients with pUC or vUC in Taiwan. We evaluated the overall response rate (ORR) through univariate logistic regression analysis and examined the overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis. Additionally, we employed univariate and multivariate Cox proportional hazards models to analyze the data. Result A total of 142 patients (116 pUC, 26 vUC) were included in our final analysis. The ORR was marginally higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%, p = 0.26). Among all patients, 12.9% with pUC achieved a complete response (CR) after ICI treatment, while no vUC cases achieved CR (p = 0.05). There were no significant differences in PFS (median 3.6 months vs. 4.1 months, p = 0.34) or OS (median 16.3 months vs. 11.0 months, p = 0.24) when comparing patients with pUC or vUC. In the subgroup analysis, patients with pUC who underwent first-line ICI treatment exhibited significantly improved OS compared to those with vUC (24.6 months vs. 9.1 months, p = 0.004). Conclusion The use of ICI as monotherapy is a feasible and effective treatment approach for patients with metastatic vUC.

Considering the divergent biological behaviors of certain histological subtypes of urothelial carcinoma, it would be of great importance to examine the impact of variant histology and to predict its presence in patients with bladder cancer. A single-center cohort study included 459 patients who underwent radical cystectomy for urothelial carcinoma between 2017 and 2021. Patients were followed up with until July 2022. We compared clinical, laboratory, and histopathologic characteristics and the overall survival between patients with pure urothelial carcinoma and variant histologies. Our results showed that the patients with variant histology were older and preoperatively more frequently had hydronephrosis and higher values of leukocytes and neutrophils. Also, we found a significant association between variant histology and an advanced stage of tumor disease, the presence of lymphovascular invasion, positive surgical margins, and metastases in surgically resected lymph nodes. The number of neutrophils was identified as an independent preoperative predictor of the presence of variant histology after a radical cystectomy. The overall survival of the patients with variant histology was significantly lower compared to the patients with pure urothelial carcinoma. According to our results, the presence of variant histology represents a more aggressive form of the disease. Preoperative neutrophil counts may indicate the presence of variant histology of urothelial carcinoma in patients with bladder cancer. [ABSTRACT FROM AUTHOR]

Background: While the treatment guidelines have been established for pure urothelial carcinoma (pUC), patients with variant type urothelial carcinoma (vUC) face limited effective treatment options. The effectiveness of immune checkpoint inhibitors (ICI) in patients with vUC remains uncertain and necessitates additional research. Method: We conducted a retrospective, multicenter study to explore the effectiveness of ICI in patients with pUC or vUC in Taiwan. We evaluated the overall response rate (ORR) through univariate logistic regression analysis and examined the overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis. Additionally, we employed univariate and multivariate Cox proportional hazards models to analyze the data. Result: A total of 142 patients (116 pUC, 26 vUC) were included in our final analysis. The ORR was marginally higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%, p = 0.26). Among all patients, 12.9% with pUC achieved a complete response (CR) after ICI treatment, while no vUC cases achieved CR (p = 0.05). There were no significant differences in PFS (median 3.6 months vs. 4.1 months, p = 0.34) or OS (median 16.3 months vs. 11.0 months, p = 0.24) when comparing patients with pUC or vUC. In the subgroup analysis, patients with pUC who underwent first-line ICI treatment exhibited significantly improved OS compared to those with vUC (24.6 months vs. 9.1 months, p = 0.004). Conclusion: The use of ICI as monotherapy is a feasible and effective treatment approach for patients with metastatic vUC. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate variant histologies (VHs) for disease‐specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). Materials and Methods: We analysed a multi‐institutional cohort of 1082 patients treated with upfront RC for cT1‐4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox' regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage‐based analyses. The stages were defined as 'organ‐confined' (≤pT2N0), 'locally advanced' (pT3‐4N0) and 'node‐positive' (pTanyN1‐3). Results: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma‐like (14 patients [1.3%]), small‐cell (13 patients [1.2%]), clear‐cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow‐up was 2.3 years. Overall, 534 (49.4%) disease‐related deaths occurred. In uni‐ and multivariable analyses, plasmacytoid and small‐cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma‐like VH had favourable DSS compared to pure UC. Clear‐cell (P = 0.015) and small‐cell (P = 0.011) VH were associated with worse DSS in the organ‐confined and node‐positive cohorts, respectively. Conclusions: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear‐cell, plasmacytoid, small‐cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma‐like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management. [ABSTRACT FROM AUTHOR]

The primary histological type of bladder cancer is urothelial carcinoma (UC), of which various subtypes, also known as variant histologies, account for about 20% of all bladder cancers. In addition to UC, there are also specialized types of bladder cancer (non-urothelial carcinoma), such as squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors (small-cell carcinoma). Although bladder cancer of both UC subtypes and special types is rare, it is relatively frequently encountered in daily practice. Clinical information on the disease, including its prognosis and susceptibility to treatment, is scarce and presents an unmet medical need. UC is a clinically important disease and should be prepared for in clinical practice, since UCs are frequently encountered at an advanced stage at the time of diagnosis, and the patient thus has a poor prognosis. In recent years, medical insurance has also covered cancer gene panel testing for "patients with solid tumors for which no standard treatment is available or has been completed, and for whom chemotherapy is highly likely to be indicated," including rare UC subtypes and special types. We must not only understand the treatment for UC subtypes and special types but also practice and understand oncogene panel tests. [ABSTRACT FROM AUTHOR]

Large-scale, contemporary, controlled analysis of mortality in metastatic collecting duct renal carcinoma are scarce. Moreover, the optimal management of these patients is unknown. Within the SEER, 155 metastatic collecting duct renal carcinoma patients were identified. Despite the aggressive behavior and dismal survival prognosis, combination of cytoreductive nephrectomy and systemic therapy provide the lowest mortality rates. Introduction: Controlled contemporary analyses of mortality in metastatic collecting duct renal cell carcinoma (mcdRCC) are unavailable. We addressed this knowledge gap and tested rates of treatment and associated mortality in patients with mcdRCC. Patients and Methods: Within Surveillance, Epidemiology, and End Results database (2004-2018), we identified 155 mcdRCC patients. Kaplan-Meier plots and Cox proportional hazards regression models tested the effect of treatment (cytoreductive nephrectomy [CN] alone vs. systemic therapy [ST] alone vs. combination of both CN + ST) on overall mortality (OM). Results: In the overall cohort (n = 155), 57 patients (37%) were treated with combination of both CN + ST, 46 (30%) underwent CN alone, 28 (18%) received ST alone, and 24 (15%) had none/unknown treatment. According to age categories (= 59 vs. 60-69 vs. = 70 years), rates of combination of both CN + ST were 45% vs. 45% vs. 14%, respectively. CN alone was the most frequent type of treatment in patients aged = 70 (50%). Median overall survival was 4.0 months for CN alone vs. 5.5 months for ST alone vs. 9.0 months for combination of both CN + ST. In multivariable Cox regression models, where CN alone was the referent, the use of ST alone and combination of both CN + ST were respectively associated with a HR of 0.74 (P = .3) and 0.43 (P < .001), after adjustment for all covariates. Conclusions: In mcdRCC patients, concomitant use of CN and ST results in lowest mortality, followed by ST alone, and CN alone. In consequence combination of both CN + ST should be recommended whenever applicable. [ABSTRACT FROM AUTHOR]

Renal tumors in young population are relatively rare. We reviewed our experience with renal masses in patients below 45 years of age. Our objective was to analyze clinico-pathological and survival characteristics of renal malignancy in young adults in contemporary era. The medical records of patients below 45 years of age who underwent surgery for renal mass at our tertiary care center between 2009 and 2019 were retrospectively analyzed. Pertinent clinical information was compiled, including age, gender, year and type of surgery, histopathology and survival data. A total of 194 patients who underwent nephrectomy for suspicious renal masses were included. Mean age was 35.5 (14–45) years and males were 125 (64.4%). A total of 29/198 (14.6%) specimens had benign disease. In addition, 155 (91.7%) out of 169 malignant tumors were renal cell carcinomas, clear cell variant being the most common type (51%). Compared to RCC, non-RCC tumors were more common in females (27.7 vs 78.6%, p < 0.0001), had an early age of diagnosis (27.2 vs 36.9 year, p < 0.00001) and poorer progression-free (58.3 vs 72.0%, p = 0.03) and overall survival (63.6 vs 84.2%, p = 0.02) at 6 years of follow-up. Renal masses in young adults are most commonly RCC but can also include other diverse types. RCC in young adults is usually organ confined and has good prognosis. As compared to RCC, non-RCC malignant tumors occur in young age, are more in females, and have worse prognosis. [ABSTRACT FROM AUTHOR]

Purpose: The most frequent histology of bladder tumors is urothelial carcinoma. Most are pure urothelial carcinomas (PUC) but up to one-third of the cases present variant histological (VH) features. The aim of this study was to evaluate the role of variant histology in neoadjuvant chemotherapy (NAC) response in patients with urothelial muscle-invasive bladder cancer. Methods: We retrospectively analyzed data from 77 patients with bladder cancer who performed neoadjuvant chemotherapy at two institutions. Results: Complete pathological response (ypT0) was higher in patients with PUC (38.5%), comparing with VH (12%). Logistic regression analysis demonstrated that variant histology is associated with an 89% lesser likelihood of tumor downstaging, with advanced clinical T stages and positive smoking history as independent predictors. The estimated mean cancer-specific survival was 68.91 months for PUC patients and 50.23 months for VH patients (log rank test, P = 0.024). Multivariate Cox regression analysis demonstrated that VH and clinical T stage were independent predictors of cancer-specific survival, indicating a worse outcome for patients with VH and advanced clinical T stages. Conclusions: There are only a few retrospective studies evaluating the clinical impact of variant histology tumors, which are mainly managed as PUC. Our results demonstrate that VH is associated with a worse likelihood of tumor downstaging after NAC and a worse cancer-specific survival in bladder cancer patients. There is a need for further studies and genetic analysis to identify the patients most likely to achieve ypT0 status and downstaging after NAC. [ABSTRACT FROM AUTHOR]

A 72-year-old man visited our hospital due to pollakiuria and lower abdominal pain. Urinary cytology was positive, and cystoscopy revealed diffuse edematous nonpapillary tumor. We performed transurethral biopsy, and clinical stage T3 plasmacytoid variant of urothelial carcinoma (PUC) was diagnosed. Although we planned for radical cystectomy, peritoneal dissemination and lung and pelvic lymph node metastases appeared 3 weeks after the initial visit. We also planned for chemotherapy; however, the metastases rapidly progressed, and he died 7 weeks after the biopsy. PUC is rare and shows an aggressive clinical course and poor prognosis.

• Metastatic bladder cancer exhibits diverse histological subtypes, influencing metastatic site distribution and prognosis. • Variant histology subtypes demonstrate unique metastatic tropism which impacts treatment strategies. • Small cell variant histology is associated with increased liver metastasis but decreased lung metastasis. • Small cell variant histology significantly increases liver metastasis odds while decreasing lung metastasis odds. • Understanding variant histology's impact on metastatic patterns is crucial for personalized treatment and improved outcomes in bladder cancer management. Bladder cancer (BCa) with variant histology (VH) is notably aggressive and not as well studied as pure urothelial carcinoma (UC). The characteristics of variant BCa in the setting of metastatic disease may contribute to treatment response/resistance and subsequent disease progression. In this study, we sought to assess VH's impact on metastasis sites at presentation in metastatic BCa. The National Cancer Database was queried from 2004 to 2019 to analyze cT1-4 cN0-3 cM1 patients with UC and VH BCa. The primary endpoint was the presence of metastasis to different organs. Binomial multivariable logistic regression was performed to determine the impact of VH on metastatic sites while controlling for multiple variables. Total 6005 eligible patients diagnosed with either UC or VH were included. Patients with small cell histology, the second most common VH, were more likely to have liver metastasis (OR: 4.335) while less likely to have lung metastases (OR: 0.521). Squamous cell carcinoma decreased the odds of bone metastasis (OR: 0.449). Adenocarcinoma increased the odds of lung metastases (OR: 1.690). Micropapillary VH is less likely to metastasize to the lungs (OR: 0.182) but more likely to spread to nonregional lymph nodes (OR: 2.623). Sarcomatoid subtype did not exhibit a statistically significant variation in the odds ratio for any of the metastatic sites. This study comprehensively analyzes the limited research regarding metastatic BCa and VH. Our analysis underscores each subtype exhibiting heterogeneous metastatic tropism. Importantly, these findings illustrate the role of routine somatic gene expression profiling to guide adequate staging and treatment intensification and to offer a foundation for future studies of VH BCa care. We explore the impact of variant histology (VH) on metastasis patterns in metastatic bladder cancer (BCa), an area underexplored compared to pure urothelial carcinoma (UC). Analyzing 6005 patients, we found significant differences in metastatic sites based on VH subtypes. We highlight the need for tailored treatment strategies and genetic profiling to optimize patient care in metastatic BCa management. [ABSTRACT FROM AUTHOR]

• After pathological review variant histology is present in a third of UTUC. • Variant histology in UTUC as a high rate of concomitant CIS (71%). • Presence of variant histology is related to more aggressive tumor characteristics and associated with unfavorable outcomes. • Variant histology in UTUC is associated to a higher rate of extravesical recurrences and follow-up should include cross sectional imaging and cystoscopy. Similar to bladder cancer, about one third of upper tract urothelial carcinoma (UTUC) present variant histology (VH). We aim to evaluate the incidence, clinical characteristics and the impact on outcomes of VH in UTUC. We consecutively enrolled 77 patients treated between 2009 and 2022 by radical surgery for UTUC from a secondary and a tertiary referral center. A pathology review of all specimens was performed by 1 independent uropathologist for each center. We compared pure UTUC and UTUC with VH and the accuracy of endoscopic biopsy. Descriptive and comparative analysis was performed to assess the association with clinical characteristics and the Kaplan–Meier estimator to compare outcomes. Median follow-up after surgery was 51 months. VH was present in 21/77 (28%) patients and 4/21 (19%) patients had multiple variants. The most frequent VH was squamous 12/21 (57%), followed by glandular 7/21 (33%) and micropapillary 3/21 variants (14%). Neuroendocrine carcinoma was present in 2 patients. Nested variant was found in 1 patient. Muscle invasive tumor (≥pT2) was present in 30/56 (54%) patients with pure UTUC and in 18/21 (86%) patients with VH (P < 0.05). Presence of carcinoma in situ was seen in 24/56 (43%) patients with pure UTUC and in 16/21 (76%) with VH (P < 0.05). Cumulative 8/56 (14%) with pure UTUC had a nonintravesical recurrence (6 patients with local and 2 distant recurrence) compared to 8/21 (38%) (3 local, 3 nodal, 2 distant) in the subgroup with VH (P < 0.05). Opposite effect was noted for bladder recurrence: 60% for pure UTUC vs. 29% for tumors with VH (P < 0.05). Review of preoperative endoscopic biopsy did not show the presence of VH in any patients. Differences in outcomes did not reach significance: 3yr-OS 63% vs. 42% (P 0.28) and 3yr-CSS 77% vs. 50% (P 0.7). Almost a third of UTUC present VH. Presence of VH is related to more aggressive tumor characteristics and associated with unfavorable outcomes. Due to a higher rate of extravesical recurrences in UTUC with VH, Follow-up controls should include cross sectional imaging and cystoscopy. [ABSTRACT FROM AUTHOR]

Objective:To investigate the impact of variant histology (VH) of urothelial carcinoma (UC) of the bladder on oncologic outcomes after radical cystectomy (RC).Materials and Methods:We identified 125 patients with cT2-T4N0M0 UC who underwent RC without perioperative systemic therapy between 2014 and 2019 at a single tertiary care referral center. The Mann-Whitney U test and chi-square test were used to compare the statistically significant differences in medians and proportions, respectively. The Kaplan-Meier method and Cox regression analyses tested the effect of different VH on cancer-specific survival (CSS) and overall survival (OS).Results:Of 125 patients, 70 (56%) had pure UC, whereas 55 (44%) had VH. The mean patient age and the median follow-up were 63.6±9.7 years and 12.5 (3-72) months. The female to male ratio was 13/112. The presence of lymphovascular invasion, locally advanced stage (≥pT3), and recurrence status were significantly higher in patients with VH than those with pure UC. In all patients, the presence of VH was not significantly associated with the presence of lymph node (LN) metastasis. In the multivariable Cox regression analyses, the type of UC [hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.00-3.24, p=0.050] and age (HR=1.050, 95% CI 1.016-1.086, p=0.004) was associated with the OS, whereas the LN metastases was associated the CSS (HR=2.962, 95% CI 1.456-6.027, p=0.003) and OS (HR=3.211, 95% CI 1.778-5.799, p

Primary urethral carcinoma (PUC) has rarely been reported, notably with variant histology. The present case reports a 68-year-old male patient with a 3-month history of difficulty voiding urine accompanied by a burning sensation in the urinary tract and hematuria. Urethrography and computed tomography (CT) indicated a mass localized in the urethral bulb. A fine needle biopsy revealed the mass to be a malignant tumor of the urethra. Partial penectomy was eventually performed and postoperative histopathological examination confirmed that the lesion was PUC, with mixed characteristics of urothelial and squamous differentiation. The patient was postoperatively followed up and at 9 months, a repeat CT scan revealed local recurrence and metastases. The patient rejected further treatment and eventually succumbed to the disease three months later. The present case report demonstrates an example in which urothelial and squamous differentiation simultaneously exist in the pathological report. The clinical features, diagnosis and treatment status of PUC were also summarized and analyzed to improve the clinical understanding of this unique disease. [ABSTRACT FROM AUTHOR]

Introduction: The trigone/urethra (T/U) has a distinct embryologic origin and a different histologic morphology compared to the rest of the urinary bladder. We sought to determine the association between tumors involved in the T/U and the presence of variant histology, pathologic, and oncologic outcomes in patients who underwent robot-assisted radical cystectomy (RARC)., Methods: Tumor location was classified into 2 groups: tumors in the bladder walls only, or tumors in the T/U area, with or without involvement of other bladder walls. Univariable and multivariable Cox regression models were used to determine the association between T/U with recurrence-specific (RSS), cancer-specific (CSS), and overall survival (OS)., Results: 608 patients who underwent RARC were identified, T/U involvement occurred in 191 (31%). Patients in the T/U group were more likely to have pT3/pT4 (57% vs. 42%, P < 0.01), positive surgical margins (21% vs. 9%, P < 0.01), and received salvage chemotherapy more frequently (16% vs. 8%, P < 0.01). Squamous variant histology was more frequent in the T/U group (25% vs. 17%, P = 0.02). On multivariable analysis, T/U location was independently associated with RSS (HR1.63, 95% CI 1.23-2.16, P < 0.01) and CSS (HR1.50, 95% CI 1.04-2.16, P = 0.02) but not OS., Conclusion: Residual T/U tumor involvement was associated with a higher risk of an advanced tumor stage, positive margin, cancer recurrence, and cancer-specific death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction/background: Micropapillary variant urothelial carcinoma (MPUC) is associated with increased risk of treatment failure with intravesical therapy likely due to the increased risk of occult lymph node (LN) metastasis at radical cystectomy (RC). To date, limited data exists as to whether percent MPUC present within transurethral resection (TUR) samples impacts LN positivity at RC. Our objective is to evaluate the association of percentage MP variant on TUR on incidence of lymph node metastasis and survival outcomes., Methods: A total of 67 patients with MPUC on TUR were identified from a prospectively maintained database of patients undergoing RC at our institution between 2007 and 2022. TUR samples were rereviewed by an expert GU pathologist with over ten years of experience. Presence and percent MP component, LVI, CIS, grade, and clinical stage were evaluated. Pathologic outcomes were collected from subsequent RC specimens, and recurrence free (RFS) and overall survival (OS) were estimated via the Kaplan-Meier method. Associations between percent MP and lymph node metastasis, RFS, and OS were assessed with univariate and multivariable logistic regression and Cox survival analyses as appropriate., Results: Thirty four of 67 (51%) patients underwent RC for cT1 disease, the remainder harbored ≥cT2 disease. 19 of 33 (58%) patients with ≥cT2 disease received neoadjuvant chemotherapy (NAC). Mean percent MPUC was 35% in cT1 patients and 28% in cT2 patients (P = 0.25). On univariate analysis, both MPUC ≥ 30% (Odds Ratio (OR) 3.38, P = 0.02) and clinical ≥T2 (OR 2.88, P = 0.04) were significant predictors of nodal metastasis at RC. On multivariable analysis, MPUC% (OR 1.02, P = 0.036) or MPUC% ≥ 30% (OR 4.01, P = 0.013) and clinical T stage ≥2 (OR 3.73, P = 0.018) were significant predictors of pathologic node positive disease. The lowest rate of LN metastasis was found in patients with cT1 disease and MPUC <30% (3/16, 18.7%), versus the highest in ≥cT2 disease and MP ≥ 30% (12/16, 75%)., Conclusions: Percent MPUC component on TUR is associated with increased risk of occult lymph node metastasis at RC. Routine pathologic evaluation of percent MP component has the potential to help select patients with MPUC that might be reasonable candidates for intravesical therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study is to report our experience in managing bladder cancer in patients with variant pathology. Methods: Retrospective data collection for all patients managed by radical cystectomy over the last 3 years for a variant pathol-ogy was completed. We specifically included micropapillary and nested variants. Results: Ten patients were identified, with eight having micropapillary carcinoma (MPC) and two having nested vari-ants. Nine patients were male. The median age was 75. The two patients with nested variant were 56 and 62 years old, respec-tively, whereas all patients with MPC were over the age of 70. Upon cystectomy of all micropapillary cases, three patients (37.5%) had positive lymph node invasion and the final patholo-gy was T2 (two patients), T3 (two patients), and T4 (four patients). Barring a grade III complication Clavien-Dindo classi-fication due to wound dehiscence that necessitated secondary surgical closure, there were no specific perioperative complica-tions. Given the urethral invasion, cystourethrectomy was per-formed on the female patient. Within a median 13-month fol-low-up, three patients developed local recurrence, including two urethral and one new lateral pelvic mass. Conclusions: Considering the muscle invasive nature of micropapillary and nested bladder cancer, aggressive surgical management should not be postponed. Moreover, due to notable prevalence of concurrent and/or recurrent urethral involvement, initial urethrectomy or early and frequent postoperative ure-throscopy should be provided. Patients with variant histology bladder cancer may benefit from early radical cystectomy when compared to bladder sparing protocols and prostate sparing cystectomy treatment options.

Context: To improve the prognosis of variant histology (VH) bladder cancers, clinicians have used neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) on the basis of radical cystectomy (RC). Despite some new data, the evidence remains mixed on their efficacy. Objective: To update the current evidence on the role of NAC and AC for VH bladder cancers. Evidence Acquisition: We searched for all studies investigating NAC or AC for bladder cancer patients with variant histology in PubMed, Embase, and the Cochrane Central Register of Controlled Trials up to December 2021. The primary end points were recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Evidence Synthesis: We identified 18 reports comprising a total of 10,192 patients in the NAC studies. In patients with VH, the use of NAC did improve CSS (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99, p = 0.044), and OS (HR 0.74, 95% CI 0.66-0.84, p = 0.000), but not RFS (HR 1.15, 95% CI 0.56-2.33, p = 0.706). Subgroup analyses demonstrated that receiving NAC was associated with better OS in sarcomatoid VH (HR 0.67, 95% CI 0.54-0.83, p = 0.000) and neuroendocrine VH (HR 0.54, 95% CI 0.43-0.68, p = 0.000). For AC, we identified eight reports comprising a total of 3254 patients. There was a benefit in CSS (HR 0.61, 95% CI 0.43-0.87, p = 0.006) and OS (HR 0.76, 95% CI 0.60-0.98, p = 0.032). Subgroup analyses demonstrated that only neuroendocrine VH had better CSS (HR 0.29, 95% CI 0.13-0.67, p = 0.174) when receiving AC. Conclusions: NAC or AC for VH bladder cancers confers an OS and CSS benefit compared with RC alone. For NAC, the benefit was independently observed in the sarcomatoid and neuroendocrine subgroups. As for AC, only neuroendocrine subgroups improved CSS. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to report our experience in managing bladder cancer in patients with variant pathology. Methods: Retrospective data collection for all patients managed by radical cystectomy over the last 3 years for a variant pathology was completed. We specifically included micropapillary and nested variants. Results: Ten patients were identified, with eight having micropapillary carcinoma (MPC) and two having nested variants. Nine patients were male. The median age was 75. The two patients with nested variant were 56 and 62 years old, respectively, whereas all patients with MPC were over the age of 70. Upon cystectomy of all micropapillary cases, three patients (37.5%) had positive lymph node invasion and the final pathology was T2 (two patients), T3 (two patients), and T4 (four patients). Barring a grade III complication Clavien-Dindo classification due to wound dehiscence that necessitated secondary surgical closure, there were no specific perioperative complications. Given the urethral invasion, cystourethrectomy was performed on the female patient. Within a median 13-month follow-up, three patients developed local recurrence, including two urethral and one new lateral pelvic mass. Conclusions: Considering the muscle invasive nature of micropapillary and nested bladder cancer, aggressive surgical management should not be postponed. Moreover, due to notable prevalence of concurrent and/or recurrent urethral involvement, initial urethrectomy or early and frequent postoperative urethroscopy should be provided. Patients with variant histology bladder cancer may benefit from early radical cystectomy when compared to bladder sparing protocols and prostate sparing cystectomy treatment options. [ABSTRACT FROM AUTHOR]

Purpose: To provide first evidence of lymph node (LN) staging using CT scan and its prognostic value in variant histologies of bladder cancer. This knowledge may optimize patient management with variant histologies based on CT morphological findings. Methods: Preoperative CT scans of patients with variant histologies who underwent RC between 2004 and 2019 were reanalyzed by two independent radiologists in a blinded review process. Specificity, sensitivity, and accuracy for LN staging as well as LN characteristics were evaluated. Correlation with survival was investigated by Kaplan–Meier method, log-rank test and multivariate analysis. Results: 1361 patients with primary tumor of the bladder underwent RC, of which 163 (12%) patients revealed variant histologies. 65 (47.8%) patients have shown an urothelial variant (UV) and 71 (52.2%) a non-urothelial variant (NUV). LN metastases were found in 18 (27.7%) patients with UV and 21 (29.6%) patients with NUV. The accuracy to detect LN metastasis for all variant histologies was 62% with a sensitivity of 46% and a specificity of 70%. Subgroups of UV and NUV revealed an accuracy of 67% and 57%. An increased number of regional LN (HR 2.8; 1.34–6.18) and the loss of fatty hilum (HR 0.36, 0.17–0.76) were prognostic parameters. In multivariate analysis, a fatty hilum (HR 0.313, 0.104–0.945) and the presence of lymph node metastases (HR 2.866, 1.140–7.207) were prognostic. Conclusion: This first study on CT morphological behavior of variant histologies revealed an accuracy of UV and NUV comparable to UC with low specificity for all variant histologies. CT scan prior RC should be interpreted in regard to histological subtypes. [ABSTRACT FROM AUTHOR]

Introduction Non-urothelial variant histology (VH), non-muscle invasive bladder cancer (NMIBC) has received little attention in contemporary urologic literature. Specifically, the effect of female sex on stage at presentation, as well as on cancer-specific mortality (CSM) have not been previously examined in VH NMIBC. Our aim was to test the effect of female sex on stage at presentation and CSM in VH NMIBC. Material and methods Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2016), we identified patients aged =18 years, with histologically confirmed VH NMIBC. Logistic regression models addressed T1 stage at diagnosis after multivariable adjustments for tumor grade, age and race/ethnicity. Before Kaplan-Meier plots and Cox regression analyses, propensity score matched adjusting for histological variants, T-stage, tumor grade, age and race/ethnicity was performed. Results Overall, 2,205 VH NMIBC patients were identified. Of those, 28% (n = 607) were female. Females were older (77 vs 74 years, p <0.001) and more frequently harbored T1 stage (55 vs 45%, p <0.001). Female sex independently predicted T1 stage (odds ratio [OR] = 1.66, 95% Confidence Interval [CI] = 1.35-2.03, p <0.001). Female sex also exhibited higher CSM, after matching for all assessable variables, including stage (hazard ratio [HR] = 1.91, 95% CI = 1.45-2.54, p <0.001). Conclusions In VH NMIBC, female sex is an indicator of higher rate of T1 stage and, fully independently of stage, female sex also results in higher CSM. [ABSTRACT FROM AUTHOR]

The aim of the study was to stratify high-grade T1 (HGT1) bladder urothelial carcinoma into risk categories based on the presence of variant histology when compared to conventional urothelial carcinoma. The clinicopathological features of 104 HGT1 cases of urothelial carcinoma of the bladder with variant histology present in 34 (37%) were assessed. The endpoint of the study was disease-free survival and cancer-specific survival. Overall, variant histology was identified as a significant predictor of disease-free survival (P = 0.035). The presence of any specific variant histology (squamous, glandular, micropapillary, nested, microcystic, inverted growth, villous-like, basaloid, and lymphoepithelioma-like) was identified as a significant predictor of disease-free survival (P = 0.008) and cancer-specific survival (P = 0.0001) in HGT1 bladder cancer. Therefore, our results support including micropapillary HGT1 urothelial carcinoma within the aggressive high-risk category, as suggested by some recent clinical guidelines, but also favor nested, glandular, and basaloid to be placed in the high-risk category due to their potential of aggressive, life-threatening behavior and their limited response to bacillus Calmette-Guerin therapy. Conversely, the low-risk category would include urothelial carcinomas with squamous, inverted growth, or microcystic morphology, all with limited life-threatening potential and good response to current therapy. A very low-risk category would finally include patients whose tumors present villous-like or lymphoepithelioma-like morphology. In conclusion, our findings support the value of reporting the variant histology as a feature of variable aggressiveness in HGT1 urothelial carcinoma of the bladder. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impact of variant histologies (VH) of urothelial carcinoma (UC) on survival outcomes after radical cystectomy (RC). Materials and methods: Data from 181 patients with UC treated with RC between January 2013 and December 2019 at a single tertiary care referral center were retrospectively accessed. All RC specimens were assigned by genitourinary dedicated pathologists. Overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier methodology and the Cox proportional hazards regression. Results: Of 181 patients, 43.1% (n = 78) had VH, with the most common being squamous differentiation (n = 29), followed by mixed variants (n = 18), micropapillary variant (n = 10) and other subtypes (n = 21). The median (range) follow-up was 35 (18-59) months. Kaplan-Meier survival analysis shows that median OS and DS were significantly worse for VH patients (78 vs 31 months, p = 0.038; not reached vs 42 months; p = 0.016). At 5 years, VH was associated with a 12% and 14% decrease in OS and DSS, respectively. No significant statistical difference between the two groups was reached regarding RFS. However, after adjusting for confounders, such as, demographics characteristics, comorbidities and pathological features, VH were not associated with any survival outcomes. Conclusions: Our study evidenced the high incidence of bladder cancers with VH. Although clearly associated with features of more aggressive behavior, VH had not any significant impact in survival expectancies when all confounders are adjusted in multivariate analyses.

Abstract Background Immune checkpoint blockade has made a significant impact on the clinical outcomes of patients with metastatic urothelial carcinoma (UC). However, evidence for this approach in patients with non‐UC of the urinary tract is limited. Methods This was a phase II open‐label study of durvalumab 1500 mg and tremelimumab 75 mg every 4 weeks for four cycles followed by durvalumab 1500 mg every 4 weeks. Eligible patients had metastatic non‐UC with ECOG PS 0–1 regardless of prior therapy (except small cell carcinoma who were pretreated). The primary endpoint was overall response rate per RECIST v1.1. A Simon's minimax two‐stage design was employed, with 13 patients planned for stage one. Pre‐treatment tumors underwent PD‐L1 staining and next‐generation sequencing. Results Thirteen patients were treated, including seven small cell carcinoma, three squamous cell carcinoma, and three adenocarcinoma. Eleven patients had visceral metastases. No responses were observed; 11 patients had PD and 2 patients had SD. Median PFS was 1.8 months (95% CI, 1.25‐not reached [NR]) with a median follow‐up of 7.38 months (range, 5.23–21.99 months). Median OS was 6.97 months (95% CI, 4.34‐NR). One patient's tumor was PD‐L1 positive and all sequenced tumors (n = 8) were microsatellite stable. Grades 3–4 treatment‐related adverse events occurred in 38.4% of patients. Conclusions In a poor prognosis cohort of patients with non‐UC, durvalumab and tremelimumab lacked clinical activity while demonstrating a manageable safety profile.

Patients with histologic subtype bladder cancer (HSBC) suffer worse outcomes than those with conventional urothelial carcinoma (UC). We sought to characterize the use of adjuvant chemotherapy (AC) in HSBC after radical cystectomy (RC) using the National Cancer Database (NCDB). We retrospectively queried the NCDB (2006-2019) for patients with non-metastatic bladder cancer (BC) who underwent RC (N = 45,797). Patients were stratified by histologic subtype and receipt of AC. Multivariable logistic regression determined associations of demographic and clinicopathologic features with receipt of AC. Multivariable Cox regression evaluated associations between receipt of any AC and overall survival (OS). We identified 4,469 patients with HSBC classified as squamous, adenocarcinoma, small cell, sarcomatoid, micropapillary, or plasmacytoid. Squamous comprised 31% of the HSBC cohort, followed by small cells and micropapillary. Black patients were presented with a higher prevalence of adenocarcinoma (119/322, 37.0%). Use of AC was highest in plasmacytoid and small cell (30% each) and lowest in squamous (11%). Neuroendocrine histology was independently associated with greater odds of receiving AC (HR 1.6, 95% CI 1.37-1.87), while squamous cell histology was associated with lower odds (HR 0.61, 95% CI 0.53-0.71). On multivariable Cox regression analysis, treatment with AC was associated with significantly longer OS (HR 0.69, 95% CI 0.59-0.81) and for squamous, sarcomatoid, and micropapillary cohorts after stratified by subtype. AC was variably used among patients with HSBC and was associated with OS benefit in such patients. We used the National Cancer Database to identify patterns of adjuvant chemotherapy use and survival outcomes in patients with non-metastatic histologic subtype bladder cancer and adverse pathologic features at the time of radical cystectomy. AC was associated with significantly longer overall survival in patients and for squamous, sarcomatoid, and micropapillary cohorts after stratified by subtype. [ABSTRACT FROM AUTHOR]

• Bladder cancer's variant histology (VH) is more aggressive than pure UC. • Even when detected in earlier stages, VH presents less favorable outcomes. • VH and pure UC show no significant differences in the muscle invasive setting. • Consider early cystectomy for VH patients due to its aggressive nature. Bladder cancer (BC) is an increasingly frequent malignancy worldwide. Several variant histologies (VH) have been described in BC with a distinct clinical behavior. This study aims to assess the prognostic impact of VH in BC, comparing its outcomes to pure urothelial carcinoma PUC in both non-muscle invasive (NMIBC) and muscle-invasive (MIBC) settings. We included patients with primary BC, comparing those with VH with those with PUC, with an age and sex-matched proportion of 1:3, considering stage at diagnosis, recurrence-free, progression-free, and overall survival (OS). A total of 616 patients were included in the study, (460 UC and 151 VH). After first TURBT, MIBC was present in 99 (64.1%) of patients with VH, and 95 (20.6%) with UC (p<0.001). Concerning NMIBC, we observed higher rates of progression to MIBC amid patients with VH (p=0.009). Nodal involvement (p=0.020) and metastatic disease (p<0.001) were significantly higher within the VH group. A higher OS was observed among patients with NMIBC of PUC (p<0.001). There were no statistically significant differences of metastasis-free survival and OS between VH and UC groups within the MIBC setting. We confirmed that VH presents a more aggressive clinical course compared to PUC. An earlier radical treatment within the NMIBC setting could increase the oncological outcomes of the VH patients. [ABSTRACT FROM AUTHOR]

Background: The advantage of adjuvant chemotherapy for upper urinary tract urothelial cancer (UTUC) has been reported, whereas its impact on upper tract cancer with variant histology remains unclear. We aimed to answer the abovementioned question with our real-world data. Design, Setting, and Participants: Patients who underwent radical nephroureterectomy (RNU) and were confirmed to have variant UTUC were retrospectively evaluated for eligibility of analysis. In the Taiwan UTUC Collaboration database, we identified 245 patients with variant UTUC among 3,109 patients with UTUC who underwent RNU after excluding patients with missing clinicopathological information. Intervention: Those patients with variant UTUC were grouped based on their history of receiving adjuvant chemotherapy or not. Outcome Measurements and Statistical Analysis: Propensity score matching was used to reduce the treatment assignment bias. Multivariable Cox regression model was used for the analysis of overall, cancer-specific, and disease-free survival. Results and Limitations: For the patients with variant UTUC who underwent adjuvant chemotherapy compared with those without chemotherapy, survival benefit was identified in overall survival in univariate analysis (hazard ratio (HR), 0.527; 95% confidence interval (CI), 0.285–0.973; p = 0.041). In addition, in multivariate analysis, patients with adjuvant chemotherapy demonstrated significant survival benefits in cancer-specific survival (OS; HR, 0.454; CI, 0.208–0.988; p = 0.047), and disease-free survival (DFS; HR, 0.324; 95% CI, 0.155–0.677; (p = 0.003). The main limitations of the current study were its retrospective design and limited case number. Conclusions: Adjuvant chemotherapy following RNU significantly improved cancer-related survivals in patients with UTUC with variant histology. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impact of variant histologies (VH) of urothelial carcinoma (UC) on survival outcomes after radical cystectomy (RC). Materials and methods: Data from 181 patients with UC treated with RC between January 2013 and December 2019 at a single tertiary care referral center were retrospectively accessed. All RC specimens were assigned by genitourinary dedicated pathologists. Overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier methodology and the Cox proportional hazards regression. Results: Of 181 patients, 43.1% (n = 78) had VH, with the most common being squamous differentiation (n = 29), followed by mixed variants (n = 18), micropapillary variant (n = 10) and other subtypes (n = 21). The median (range) follow-up was 35 (18-59) months. Kaplan-Meier survival analysis shows that median OS and DS were significantly worse for VH patients (78 vs 31 months, p = 0.038; not reached vs 42 months; p = 0.016). At 5 years, VH was associated with a 12% and 14% decrease in OS and DSS, respectively. No significant statistical difference between the two groups was reached regarding RFS. However, after adjusting for confounders, such as, demographics characteristics, comorbidities and pathological features, VH were not associated with any survival outcomes. Conclusions: Our study evidenced the high incidence of bladder cancers with VH. Although clearly associated with features of more aggressive behavior, VH had not any significant impact in survival expectancies when all confounders are adjusted in multivariate analyses. [ABSTRACT FROM AUTHOR]

Up to 14% of bladder urothelial carcinoma has variant histology (VH), which is associated with a higher incidence of occult regional lymph node metastasis. Neoadjuvant chemotherapy (NAC) is the gold-standard for resectable cT2-4 disease as it achieves pathologic complete response (pCR) in select patients at the time of radical cystectomy (RC). A landmar k tr ial demonstrated chemosensitivity and pT0 status in the setting of VH. pT0N + pathology in patients undergoing subsequent RC has prompted concerns about post-chemotherapy bladder preservation. We investigate how VH impacts pathologic primary site and nodal downstaging post-NAC. We queried the National Cancer Database for cT2-4N0M0 patients who underwent NAC and RC between 2004 and 2016. These patients were stratified into pure urothelial cell carcinoma (UCC) and VH. The rate of downstaging to =pT1 was analyzed, along with pN + status. Overall survival was analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards regression model. Multivariable models were adjusted for demographic and clinicopathologic variables. Of 5,335 patients, 92.1% were UCC and 7.9% VH. UCC was associated with better unadjusted survival and lower adjusted odds of being pN + (aOR = 0.60, P < .001). Squamous cell, glandular, and sarcomatoid histologies were significantly associated with decreased adjusted odds of any pT downstage. Neuroendocrine histology (NE) trended towards increased adjusted odds of downstage to pT0N0. Patients with VH were more likely to harbor occult regional lymph node metastasis in the setting of intravesical pCR. NE had the highest pT0N0 rate, with potential implications on post-NAC bladder preservation. These findings reinforce the role of RC after NAC especially for VH. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to determine the effect of variant histology on pathological outcomes and survival in patients operated for the upper urinary tract urothelial carcinoma (UTUC). Methods: Data of 128 patients who were operated for UTUC between 2001 and 2019 were retrospectively analyzed. Patients with pure urothelial carcinoma and patients with variant histology were compared in terms of demographics, pathological outcomes, and survival. Results: The mean age of the patients was 65±11 years, female to male ratio was 30/98 and median follow-up period was 26.5 (1-176) months. Variant histology was detected in 14.8% of patients. Variant histology was found to be associated with surgical margin positivity, lymph node metastasis, presence of lymphovascular invasion, high tumor stage and grade (p=0.001, p=0.012, p=0.001, p=0.002, and p=0.009, respectively). Three-year cancer-specific and overall survival rates were 79.6% and 77.3%, respectively. There was no statistically significant relationship between variant histology with cancer-specific and overall survival (p=0.514 and p=0.515, respectively). Conclusion: Variant histology of UTUC was found to be associated with locally advanced disease, but its effect on survival could not be demonstrated. [ABSTRACT FROM AUTHOR]

Muscle invasive bladder cancer surgical management has been historically a radical cystoprostatectomy in males and an anterior exenteration in females, however role of removal of sexual organs is unknow. A retrospective single institutional analysis was performed to identify risk of reproductive involvement. Reproductive sparing surgery, even in variant histology or advance disease, did not compromise oncological outcomes in this cohort. Purpose: Muscle invasive bladder cancer surgical management has been historically a radical cystoprostatectomy in males and an anterior exenteration in females. Uterine, ovarian, and vaginal preservation are utilized, but raise concerns regarding risk to oncologic control, especially in variant histopathology or advanced stage. Materials and Methods: A retrospective single institutional analysis identified radical cystectomies performed in women, including those with variant histology, which were defined as reproductive organ sparing (uterine, vaginal, and ovary sparing) or nonorgan sparing. The Kaplan-Meier method was used for recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in patients with advanced disease. Results: From 2000 to 2020, 289 women were identified, 188 underwent reproductive organ-sparing cystectomy. No statistical differences were noted for clinical parameters or presence of variant histology for organ-sparing (ROS) and nonorgan-sparing (non-ROS). Positive margin rates did not differ for ROS and non-ROS; 4.3% vs. 7.9%, P = .19, respectively. Median RFS was not statistically significantly different for ROS vs. non-ROS (26.1 vs. 15.3 months) P = .937 hazard ratio (HR) 1.024. CSS was not statistically different for ROS vs. non-ROS (36.3 vs. 28.6 months), P = .755 HR 0.9. OS was not statistically different for ROS vs. non-ROS (25.8 vs. 23.8 months), P = .5 HR = 1.178. Variant histology did not change survival (HR 1.1, P = .643). Conclusion: In this analysis, ROS in women with advanced disease did not increase positive margin rates or decrease RFS, CSS, or OS compared to non-ROS. Variant histology did not decrease survival odds. Based on preoperative assessment and intraoperative findings, ROS in patients with variant histology and advanced disease should be considered. [ABSTRACT FROM AUTHOR]

Primary urothelial carcinoma (UCa) of the urethra is relatively uncommon, and the underlying pathogenesis has not been well characterized, especially in the absence of concurrent UCa at other sites. A search for cases of primary UCa of the urethra was conducted. Patients with concurrent UCa of the renal pelvis, ureter, or bladder at the time of diagnosis of the primary tumor were excluded. Clinicopathologic and follow-up data were obtained. A total of 35 cases from 30 patients (27 male and 3 female) were included in the study. The mean patient age at the initial diagnosis was 71 years (range: 41-90 years). Cases were composed of high-grade UCa (26 of 35 = 74%), low-grade UCa (4 of 35 = 11%), and UCa in situ (5 of 35 = 14%). Invasion was present in 14 of 26 (54%) cases of high-grade UCa. Interestingly, 23 of 30 (77%) patients had a previous history of UCa including 7 (30%) cases with divergent differentiation or variant histology. Follow-up data were available in 23 patients with a mean duration of 26.7 months (range: 0.6-87 months). Eleven patients (31%) died of metastatic UCa. This is one of the largest studies to date of primary UCa of the urethra without concurrent UCa of the renal pelvis, ureter, or bladder. Previous history of UCa of the bladder, especially with divergent differentiation or variant histology is conceivably a key risk factor for developing subsequent primary UCa of the urethra. These findings are important for the development of surveillance protocols and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Purpose: For muscle-invasive bladder cancer, bladder preserving chemoradiotherapy (BPCRT) has shown to be a viable alternative for patients with urothelial carcinoma (UCa). Traditionally bladder cancer with variant histology UCa or other tumors types involving the bladder have worse outcomes and BPCRT has been contraindicated. However, there is limited high level evidence for this recommendation. Materials/methods: The National Cancer Database (NCDB) was queried for all patients with Bladder cancer treated from 2004 to 2015 restricted to clinical stage T2-4, N0, M0 who had variants of UCa or other tumors types involving the bladder (e.g. adenocarcinoma and squamous cell carcinoma). Only patients treated with definitive intent with either radical cystectomy or BPCRT after maximal transurethral tumor resection were analyzed. Propensity-score matching was used. Results: 356 patients had BPCRT and 2093 patients had definitive surgery for muscle-invasive bladder cancer limited to variants of UCa and other tumors types involving the bladder. On multivariable analysis worse prognosis was associated with age >65 years old (HR 1.24, p = 0.004) and T4 disease (HR 1.90, p

Context: Bladder cancer (BC) is the sixth most common malignant neoplasm in men. Recently, great effort has been devoted to the study of BC variant histology (VH). Yet, the results from these studies have shown conflicting data and remain unclear whether their presence alters recurrence and survival rates after radical cystectomy (RC). Aims: We undertook this study aiming to test the effect on VH on recurrence-free survival (RFS) and overall survival (OS) in single-center RC patients. Settings and Design: We have retrospectively analyzed medical records and pathology reports from 331 patients who underwent RC with or without pelvic lymphadenectomy at University Urology Clinic-Skopje, North Macedonia, in the period between 2010 and 2018. Subjects and Methods: Microscopic analysis of the specimens involved the evaluation of histological tumor type, tumor grade, pathological tumor node metastasis stage, presence of lymphovascular invasion, and resection margin status. Statistical Analysis Used: Univariable and multivariable Cox regression models were applied to test the effect of VH on RFS and OS. Results: We found 185 patients who matched our inclusion criteria. At multivariable analyses, lymphovascular invasion and positive resection margins were associated with shorter RFS. Similarly, patients diagnosed with lymphovascular invasion, positive resection margins, and a pelvic lymph node metastasis had poorer OS. VH was not found to be an independent predictor of both RFS and OS (P > 0.05). Conclusions: The present study did not reveal prognostic effect of VH on RFS and OS. In our series, histomorphologic parameters including lymphovascular invasion, resection margins, and pelvic lymph node metastasis were the most relevant predictors on survival outcome after RC.

Abstract Background A systematic review and meta-analysis was performed to compare the clinicopathological features and survival outcomes between sarcomatoid variant (SV)-urothelial carcinoma of the bladder (UCB) and conventional UCB (C-UCB). Methods A comprehensive search of PubMed, Embase, and Cochrane Library was performed. Endpoints included clinicopathological features and survival outcomes (overall survival [OS], cancer-specific survival [CSS], and progression-free survival [PFS]). The survival benefits of neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) for SV-UCB also have been studied. Results A total of 8 observational studies were included. Patients with SV-UCB had a higher rate of ≥ stage pT3 (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.64–2.59; p

BackgroundThe advantage of adjuvant chemotherapy for upper urinary tract urothelial cancer (UTUC) has been reported, whereas its impact on upper tract cancer with variant histology remains unclear. We aimed to answer the abovementioned question with our real-world data.Design, Setting, and ParticipantsPatients who underwent radical nephroureterectomy (RNU) and were confirmed to have variant UTUC were retrospectively evaluated for eligibility of analysis. In the Taiwan UTUC Collaboration database, we identified 245 patients with variant UTUC among 3,109 patients with UTUC who underwent RNU after excluding patients with missing clinicopathological information.InterventionThose patients with variant UTUC were grouped based on their history of receiving adjuvant chemotherapy or not.Outcome Measurements and Statistical AnalysisPropensity score matching was used to reduce the treatment assignment bias. Multivariable Cox regression model was used for the analysis of overall, cancer-specific, and disease-free survival.Results and LimitationsFor the patients with variant UTUC who underwent adjuvant chemotherapy compared with those without chemotherapy, survival benefit was identified in overall survival in univariate analysis (hazard ratio (HR), 0.527; 95% confidence interval (CI), 0.285–0.973; p = 0.041). In addition, in multivariate analysis, patients with adjuvant chemotherapy demonstrated significant survival benefits in cancer-specific survival (OS; HR, 0.454; CI, 0.208–0.988; p = 0.047), and disease-free survival (DFS; HR, 0.324; 95% CI, 0.155–0.677; (p = 0.003). The main limitations of the current study were its retrospective design and limited case number.ConclusionsAdjuvant chemotherapy following RNU significantly improved cancer-related survivals in patients with UTUC with variant histology.

A 72-year-old man visited our hospital due to pollakiuria and lower abdominal pain. Urinary cytology was positive, and cystoscopy revealed diffuse edematous nonpapillary tumor. We performed transurethral biopsy, and clinical stage T3 plasmacytoid variant of urothelial carcinoma (PUC) was diagnosed. Although we planned for radical cystectomy, peritoneal dissemination and lung and pelvic lymph node metastases appeared 3 weeks after the initial visit. We also planned for chemotherapy; however, the metastases rapidly progressed, and he died 7 weeks after the biopsy. PUC is rare and shows an aggressive clinical course and poor prognosis. [ABSTRACT FROM AUTHOR]