Quantification of micropapillary component on transurethral resection is associated with likelihood of occult lymph node metastasis at radical cystectomy.

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.

Tumor involvement of the trigone and urethra at the time of robot-assisted radical cystectomy is associated with adverse oncological outcomes.

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.

Non-functional muscle-invasive bladder paraganglioma-a case report.

Background: Extra-adrenal pheochromocytoma (paraganglioma) of the urinary bladder is a rare tumor, accounting for 0.05% of bladder tumors and less than 1% of all paragangliomas. In the genitourinary tract, paragangliomas are most commonly found in the bladder. These tumors have aggressive malignant potential, so complete surgical resection for localized disease is important. Paragangliomas may be non-functional or functional with catecholamine secretions. Although these tumors are rare and difficult to distinguish from urothelial carcinoma (UC), intraoperative manipulation of these tumors may lead to a catecholamine surge and intraoperative complications. Preoperative or early intraoperative recognition of this tumor would facilitate appropriate alpha blockade to minimize morbidity. Case Description: Herein we report a rare non-functional paraganglioma arising from the bladder of a 46-year-old male. This case is notable for the location of the mass, requiring a 70-degree cystoscopic lens for complete visualization near the bladder neck, and for the identification of a golden-yellow sessile mass during the resection. Upon visualization of this mass, the operation should be paused for close hemodynamic monitoring and assess for signs of hypertensive crisis prior to continuing without alpha blockade. Conclusions: Suspected localized bladder paraganglioma cases should be optimized hemodynamically and managed surgically. Visualization of a sessile bladder mass on gross examination with golden-yellow tumor during the resection should prompt suspicion for a paraganglioma. Biochemical evaluation with serum or urine catecholamines, metanephrines, and normetanephrines should be performed to assess for tumor functionality.

Adult Prostate Sarcoma: Demographics, Treatment Patterns, and Survival.

BACKGROUND: This study aimed to examine clinicopathologic characteristics, treatment patterns, and survival rates in a contemporary population-based cohort of adult prostate sarcoma patients. METHODS: In the Surveillance, Epidemiology, and End Results database (2004-2020), adult patients with prostate sarcoma were identified. Descriptive statistics, Kaplan-Meier analyses, smoothed cumulative incidence plots, and Cox regression models were used. RESULTS: Of 125 patients, 45 (36%) harbored leiomyosarcoma, 17 (14%) had rhabdomyosarcoma, 15 (12%) had stromal sarcoma, 17 (14%) had sarcoma not otherwise specified (NOS), and 31 (25%) had other sarcoma subtypes. Metastatic stage was most common in the rhabdomyosarcoma patients (44%) and least common in the leiomyosarcoma (21%) and stromal sarcoma (20%) patients. Most of the rhabdomyosarcoma patients received the combination of systemic and radiation therapy with (24%) or without radical surgery (35%), whereas most of the leiomyosarcoma and stromal sarcoma patients underwent radical surgery with (22 and 13%) or without (22 and 47%) radiation. In the overall population, the median overall survival was 27 months. The 5-years overall versus cancer-specific versus other-cause mortality rates were respectively 71 versus 58 versus 13%. In the multivariable Cox regression models, the highest overall mortality was exhibited by the patients with metastatic disease (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.55-5.31; p < 0.001) or unknown disease stage (HR 2.94; 95% CI 2.20-7.21; p = 0.019). Conversely, of all the histologic subtypes, only stromal sarcoma distinguished itself by lower overall mortality (HR 0.41; 95% CI 0.18-0.96; p = 0.039). CONCLUSIONS: Four major histologic subtypes were identified. Among most adult sarcoma patients, treatment patterns vary according to histology, from multimodal therapy to radical prostatectomy alone. These treatment differences reflect equally important heterogeneity in survival patterns.

Metastatic Tropism in Urothelial Carcinoma With Variant Histology: A Comprehensive NCDB Analysis.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The Prognostic Significance of Histological Subtypes in Patients with Muscle-Invasive Bladder Cancer: An Overview of the Current Literature.

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.

Factors Influencing Bladder Perforation during Transurethral Resection of Bladder Cancer: A Comprehensive Analysis.

BACKGROUND: Bladder perforation (BP) is one of the important complications during transurethral resection of bladder tumour (TURBT). Additionally, multiple factors can contribute to BP. Here, we investigated the rates of BP, specifically in variant histology of bladder cancer (BC), and examined the clinical follow-up of relevant patients. METHODS: Of the 797 patients who underwent TURBT between 2015 and 2023, they were divided into two groups according to BP during the operation. Group 1 (n = 744) consisted of patients without BP, whereas Group 2 (n = 53) consisted of patients with BP. Demographic, operative, postoperative and follow-up data were investigated and analysed. Groups were examined in terms of causes of BP. Significance was set at p < 0.05. RESULTS: A significantly higher rate of BP was found in patients operated with bipolar energy (p = 0.027) than in their counterparts. In multivariable analysis, the presence of the obturator reflex during TURBT was significantly associated with an increased risk of BP (p < 0.001). We observed a statistically significant increase in the rate of BP in patients with a history of previous intravesical Bacillus Calmette-Guérin (BCG) therapy (p = 0.023). Variant histology was reported in 32 patients (4%). However, we could not find any statistically significant relationship between the development of BP and the variant histology of BC (p = 0.641). CONCLUSIONS: Multiple factors can affect BP during TURBT. Understanding the factors associated with BP is crucial for improving patient safety and outcomes. According to the results of the present study, the energy source, the presence of obturator reflex during TURBT and intravesical BCG therapy may increase BP. Nevertheless, the presence of variant histology was not significantly associated with BP.

A 2-center review of histopathology of variants of upper urinary tract urothelial carcinoma and their impact on clinical outcomes.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Adjuvant Chemotherapy and Survival After Radical Cystectomy in Histologic Subtype Bladder Cancer.

OBJECTIVES: 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). MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: AC was variably used among patients with HSBC and was associated with OS benefit in such patients.

Effect of a variant histology on the oncological outcomes of Japanese patients with upper tract urothelial carcinomas after radical nephroureterectomy: a multicenter retrospective study.

Background: An earlier systematic review and meta-analysis found that patients with a certain histological variant of upper tract urothelial carcinoma (UTUC) exhibited more advanced disease and poorer survival than those with pure UTUC. A difference in the clinicopathological UTUC characteristics of Caucasian and Japanese patients has been reported, but few studies have investigated the clinical impact of the variant histology in Japanese UTUC patients. Methods: We retrospectively enrolled 824 Japanese patients with pTa-4N0-1M0 UTUCs who underwent radical nephroureterectomy without neoadjuvant chemotherapy. Subsequently, we explored the effects of the variant histology on disease aggressiveness and the oncological outcomes. We used Cox's proportional hazards models to identify significant predictors of oncological outcomes, specifically intravesical recurrence-free survival (IVRFS), recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: Of the 824 UTUC patients, 32 (3.9%) exhibited a variant histology that correlated significantly with a higher pathological T stage and lymphovascular invasion (LVI). Univariate analysis revealed that the variant histology was an independent risk factor for suboptimal RFS, CSS, and OS. However, significance was lost on multivariate analyses. Conclusions: The variant histology does not add to the prognostic information imparted by the pathological findings after radical nephroureterectomy, particularly in Japanese UTUC patients.

Evaluation of histological variants of upper tract urothelial carcinoma as prognostic factor after radical nephroureterectomy.

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.

The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

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.

Adjuvant Chemotherapy after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma with Variant Histology: A Systematic Review and Meta-Analysis of Survival Outcomes.

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.

Efficacy of Platinum-based Chemotherapy in Patients With Metastatic Urothelial Carcinoma With Variant Histology.

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.

Prognostic impact of histological discordance between transurethral resection and radical cystectomy.

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.

Prognostic Impact of Histologic Subtype and Divergent Differentiation in Patients with Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multicenter Retrospective Study.

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.

Impact of variant histology on upstaging and survival in patients with nonmuscle invasive bladder cancer undergoing radical cystectomy.

INTRODUCTION: Variant histology (VH) of urothelial carcinoma is uncommon and frequently presents at the muscle-invasive stage. VH is considering a significant risk factor for progression among patients with nonmuscle invasive bladder cancer (NMIBC). While there is some debate, expert opinion is generally that upfront radical cystectomy (RC) should be consider for these patients. Limited data exists to support this position. In this study, we sought to examine the rate of upstaging and overall survival for patients with VH NMIBC against patients with pure urothelial NMIBC who underwent RC, to help clarify the optimal treatment strategy for these patients. METHODS: The institutional REDCap database was utilized to identify all patients with T1 and Ta bladder cancer that underwent RC over the study period (2004-2022). Matched-pair analysis was performed between patients with VH and pure urothelial NMIBC; 42 pairs were matched on prior intravesical therapy, presence of muscularis propria on transurethral resection of bladder tumor (TURBT), any carcinoma in situ presence on prior TURBTs, and final tumor staging on TURBT. The primary outcomes of interest were pathologic tumor upstaging rate at RC and overall survival. Secondary outcomes of interest included association of demographic or pretreatment variables with upstaging, and upstaging rates for specific variant histologies. RESULTS: Patients with VH NMIBC undergoing RC were upstaged at a significantly higher rate than a matched cohort of patients with pure urothelial NMIBC (73.8% vs. 52.4%, P = 0.0244) and among those upstaged, had significantly higher rates of pT3 to pT4 (54.7% vs. 23.8%, P = 0.0088). Rate of node positivity at RC for VH NMIBC was also higher compared to pure urothelial NMIBC (40.5% vs. 21.4%, P = 0.0389). Among histologic variants, patients with plasmacytoid and sarcomatoid subtypes demonstrated the highest rates of upstaging; differences were not statistically significant. The overall median survival was 28.4 months for patients with VH after RC compared to 155.1 months for patients with pure urothelial NMIBC (P = 0.009). CONCLUSION: Patients with VH NMIBC undergoing RC are at significantly higher risk of upstaging at RC when compared to patients with pure urothelial NMIBC and have worse overall survival. While this study supports the concept of an aggressive treatment approach for patients with VH NMIBC, improvements in understanding of the disease are necessary to improve outcomes.

Prognostic impact of variant histology in bladder cancer: Would early and aggressive treatment shift the paradigm?

INTRODUCTION: Bladder cancer (BC) is an increasingly frequent malignancy worldwide. Several variant histologies (VH) have been described in BC with a distinct clinical behavior. OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Variant histology is associated with more non-urothelial tract recurrence but less intravesical recurrence for upper tract urothelial carcinoma after radical nephroureterectomy.

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.

Oncologic outcomes of intravesical therapy in the management of nonmuscle invasive bladder cancer with variant histology.

PURPOSE: There is limited data on oncologic outcomes in nonmuscle invasive bladder cancer (NMIBC) with variant histology (VH) managed with intravesical therapy. We sought to evaluate oncologic outcomes for this cohort at a high-volume center. MATERIALS AND METHODS: A retrospective review of an IRB-approved bladder cancer database was performed. Patients with a history of NMIBC with VH present on transurethral resection of bladder tumor (TURBT) treated with intravesical therapy (BCG or chemotherapy) were identified. Outcomes of interest included recurrence within the bladder, progression to muscle-invasive bladder cancer (MIBC), metastatic progression, cancer-specific, and overall survival. Survival time was computed from the date of initiation of intravesical therapy to the date of event or censoring. For patients who underwent radical cystectomy, recurrence-free, cancer-specific, and overall survival were also computed. The Kaplan-Meier method with log rank was utilized to compare survival time between VH sub-groups. RESULTS: Ninety patients were included in the final cohort with a median follow-up of 38 months. The majority of patients had T1 disease (72%) and received intravesical BCG (83%) as their only form of intravesical therapy. The most commonly represented VH in this series were glandular and squamous differentiation (26%). Forty-eight patients (53%) experienced recurrence within the bladder with a median recurrence-free survival of 24 months (95% Confidence Interval [CI]: 2-46 months). Five-year rates of progression to MIBC and distant metastasis were both 14% respectively. Twenty-six patients (28%) eventually required cystectomy. When stratifying by VH, patients with sarcomatoid, plasmacytoid, and micropapillary had significantly worse oncologic outcomes. CONCLUSION: In this series of highly-selected patients with NMIBC and VH, bladder-sparing treatment with intravesical therapy demonstrated acceptable oncologic outcomes for most VHs. This may be an acceptable treatment option for patients without plasmacytoid, sarcomatoid, or micropapillary features who are not suitable cystectomy candidates or who prioritize bladder-sparing treatment.