Variant Of Urothelial Carcinoma Research Articles

Abstract PR002: Sarcomatoid Histological Variants of Canine Muscle-Invasive Bladder Cancer: Transcription Factor Activation Highlights Pathways of Epithelial-Mesenchymal Transformation Similar to Humans

Abstract The histologic heterogeneity of human Muscle Invasive Bladder Cancer (MIBC) is one of the main contributing factors to poor treatment outcomes. Recent reports on MIBC histological variants have highlighted increased levels of transcription factors (TF) associated with epithelial-mesenchymal transformation (EMT) and epigenetic regulation in the sarcomatoid histology variant of MIBC. Dogs with spontaneously developing MIBC have been shown to display similar histological and molecular features, in addition to closely mimicking the clinical behavior of human MIBC. Here, we add to previously reported data on histological variants in canine MIBC by evaluating 21 tumor biopsies for variant histology and performing bulk RNAseq analyses on 3 organoid cell lines derived from one sarcomatoid subvariant and two conventional urothelial carcinoma (UC). MIBC biopsies from 21 dogs were reviewed for variant histology by a human urologic pathologist. Organoids derived from the urine of canine MIBC patients were cultured, preserved in RNA later, and sequenced for mRNA expression to identify TF associated with sarcomatoid variants versus conventional UC. All canine MIBC biopsies were classified as invasive, high-grade UC. Histologic variants were identified as glandular differentiation in 7/21, sarcomatoid differentiation in 3/21, squamous differentiation in 3/21, micropapillary carcinoma in 1/21 MIBC samples and small nested variants in 1/21 samples; with the rest of the tumors classified as conventional UC. Raw RNAseq analyses revealed no clear clustering of expression profiles between the three organoid cell lines, indicating distinct RNA expression profiles between the sarcomatoid variants and conventional UC of canine MIBC. To evaluate differences in the expression of TF targets between the organoid cell lines, pathway analyses and VIPER algorithms were used. Organoids derived from sarcomatoid variant UC showed increased expression of Snail familiy transcription repressor 1 (SNAI1) along with decreased expression of cadherin 1 (CDH1), indicating a signature of EMT, similar to that previously identified in human MIBC organoids with sarcomatoid variant histology. Canine MIBC organoids derived from conventional UC histology samples showed a TF profile associated with proliferation, metastasis, and progression, such as increased Zinc finger E-box binding homeobox 1 (ZEB1), E2F transcription factor 3 (E2F3), and centromere protein F (CENPF), as previously described in humans with high grade, invasive UC. In conclusion, the frequency of some histologic variants in canine MIBC, such as sarcomatoid UC, appear to be higher than reported in human patients. TF analyses of canine MIBC-derived organoid cell lines showed evidence of EMT, similar to the sarcomatoid variants of MIBC in humans. Organoids derived from canine MIBC could potentially serve as a valuable model for evaluating the efficacy of novel treatment modalities for the rare histologic variants of UC. Citation Format: Karin Allenspach, Mohamed Elbadawy, Hannah Nocholson, Christopher Zdyrski, John Cheville, Eugene Douglass, Elizabeth W. Howerth, Lilian Oliveira, Jonathan P. Mochel. Sarcomatoid Histological Variants of Canine Muscle-Invasive Bladder Cancer: Transcription Factor Activation Highlights Pathways of Epithelial-Mesenchymal Transformation Similar to Humans [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR002.

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

PurposeTo evaluate the impact of variant histology on patients with upper tract urothelial carcinoma (UTUC) survival outcomes.Materials and methodsA 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).ResultsAmong 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.ConclusionsVariant 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.

Determining the clinicopathological significance of the VI-RADS ≧4 group: a retrospective study.

The Vesical Imaging Reporting and Data System (VI-RADS) is widely used for predicting muscle-invasive bladder cancer (MIBC). This study aimed to determine the clinicopathological significance of the VI-RADS ≧4 (VI≧4) group. Patients who underwent transurethral resections of bladder tumors during the study period and preoperative magnetic resonance imaging were considered. The patients were pathologically diagnosed with urothelial carcinoma (UC). We first compared the results of patients with VI-RADS scores of 3 and 4 to determine the cut-off score for MIBC; thereafter, the patients were divided into the VI≧4 and VI-RADS ≦3 (VI≦3) groups using VI-RADS. The clinicopathological significance of the VI≧4 group was examined retrospectively by comparing the characteristics of each group. In total, 121 cases were examined, of which 28 were pathologically diagnosed with MIBC. Of the 28 MIBC cases, three (10.7%) had a VI-RADS score of ≦3, and 25 (89.3%) had a VI-RADS score of ≧4. Of the 93 NMIBC cases, 86 (92.5%) had a VI-RADS score of ≦3, and seven (7.5%) had a VI-RADS score of ≧4. The diagnostic performance of the VI-RADS with a cut-off score of 4 was 89.3% for sensitivity, 92.5% for specificity, and an area under the curve (AUC) of 0.91. Contrastingly, for a cut-off score of 3, the sensitivity was 89.3%, specificity was 62.0%, and AUC was 0.72. A VI-RADS score of ≥ 4 could predict MIBC. In the VI≧4 group, 30 of 32 (93.8%) patients had high-grade tumors. The VI≧4 group had significantly more high-grade bladder cancers than the VI≦3 group (p < 0.001 OR = 31.77 95%CI:8.47-1119.07). In addition, the VI≧4 group had more tumor necrosis (VI≧4 vs VI≦3, p < 0.001 OR = 7.46 95%CI:2.61-21.34) and more UC variant cases (VI≧4 vs VI≦3, p = 0.034 OR = 3.28 95%CI:1.05-10.25) than the VI≦3 group. This study suggests that VI-RADS has a high diagnostic performance in predicting MIBC and that VI-RADS could diagnose high-grade tumors, necrosis, and UC variants.

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

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. 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). 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. The variant histology does not add to the prognostic information imparted by the pathological findings after radical nephroureterectomy, particularly in Japanese UTUC patients.

Outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma and histology variants: Analysis of the UNITE study.

652 Background: Enfortumab vedotin (EV) is approved for patients (pts) with advanced urothelial carcinoma (aUC) but outcomes in pts with histology variants (HV) have not been well described. We hypothesized that presence of HV would impact EV treatment outcomes. Methods: UNITE is a multi-site retrospective study of pts with aUC treated with targeted agents, including 650 pts treated with EV regimens. We compared outcomes to EV monotherapy in pts with pure UC (pUC) relative to pts with any HV and with specific HVs. In pts with scans after &gt; 1 cycle of EV, observed response rate (ORR) was assessed using χ2 test and logistic regression. Median progression-free survival (PFS) and overall survival (OS) from EV start were measured using the Kaplan Meier method and Cox proportional hazard test. Results: A total of 566 pts (366 with pUC; 200 with HV) from 17 US sites were treated with EV monotherapy. Median age was 70 years, 71% men, 87% Caucasian, 74% with ECOG PS 0/1 and 28% with liver mets. Median follow up was 21 mos from EV start, ORR was 49%, mPFS and mOS were 5.8 mos (95% CI: 5.29-6.67) and 12.2 mos (95% CI: 11.5 – 13.8), respectively. Pts with pUC had more visceral mets (69% vs 60%, p = 0.04) and liver mets (32% vs 21%, p =0.003) than pts with HV. No significant difference in outcomes were seen between pUC and pts with HV component (1-100%). Pts with predominant HV (50-99%; N=35), had numerically lower ORR relative to pUC pts (36% vs 52% OR 0.31, p &lt;0.09), but no difference in mPFS or mOS. Pts with pure HV (pHV) (100%: N=14) had inferior outcomes relative to pts with pUC (ORR 0% vs 52%, p&lt;0.001; mOS HR: 2.96 (95% CI: 1.60 – 5.46), p &lt;0.001; mPFS HR: 1.9 (95% CI: 1.06 – 3.39), p=0.03). ORRs for specific HV are listed in the table. No significant difference in treatment outcomes were seen in pts with pUC vs any specific HV, except for NE HV which had inferior ORR (0% vs 52%; p=0.003). Conclusions: Responses to EV are noted in some aUC pts with HV, except for NE (any component) and pHV. Certain HV notable for poor outcomes, such as sarcomatoid and plasmacytoid, demonstrated responses to EV. These hypothesis-generating findings require further validation in studies with adequate sample size for specific HV, and in particular pHV. Evaluation of biomarkers, including Nectin4 expression, in HV is paramount. [Table: see text]

Impact of squamous histology on outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma: Analysis of the UNITE study.

651 Background: Squamous histology (SH) is the most common variant of Urothelial Carcinoma (UC) and is associated with lower response rates to chemotherapy. The impact of SH on outcomes with enfortumab vedotin (EV) is less defined. We hypothesized that increased SH component would correlate with inferior outcomes with EV treatment. Methods: UNITE is a multi-institutional retrospective study in pts advanced UC (aUC) treated with targeted agents. In this analysis, we compared EV monotherapy outcomes in pts with pure UC (pUC) and pts with urothelial predominant histology (UCP) [&lt;50% SH], SH-predominant [50-99% SH] and pure SH (pSH) [100% SH] respectively. We also compared pSH to UCP and SHP. Observed Response Rate (ORR) was compared in evaluable pts with scans after ≥1 cycle of EV using Chi-squared test. Progression-free survival (PFS) and overall survival (OS) from EV start were assessed and compared using the KM method and Cox proportional hazard test. Results: This analysis included 460 pts from 17 US sites treated with EV monotherapy. 366 pts had pUC and 94 pts had SH component (including pSH). In the overall cohort, median age was 70, 73% men, 88% Caucasian, 73% ECOG PS 0-1, 67% lower tract tumor, 30% liver mets, 38% bone mets, 65% had ≥ 2 prior therapy lines. There were no significant differences in baseline clinical characteristics between pts with pUC vs SH component except for higher incidence of liver mets in pts with pUC (32% vs 20%; p = 0.02). Among all 460 pts, median follow up was 20.7 mos from EV start, ORR was 51%, mPFS and mOS were 5.8 mos (95% CI: 5.3-6.4) and 12.7 mos (95% CI: 11.5-14.3). Among 94 pts with SH component, 70 were UCP, 17 SHP and 7 pSH. Inferior outcomes were noted in pts with pSH relative to pts with pUC and pts with UCP (Table). No differences in outcomes were seen across other cross-group comparisons. Conclusions: These hypothesis-generating findings suggest that SH component may impact outcomes with EV treatment in pts with aUC. A subset of pts with SH-predominant histology can have robust responses and outcomes with EV treatment, but larger studies and further biomarker data are needed to determine pts most likely to benefit. Patients with pSH are shown to have worse outcomes with EV, but further studies with a larger sample size are needed to validate our findings and define the role of EV for this rare and biologically distinct entity. [Table: see text]

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

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. 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. 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). 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.

Urinary tract cytology showing variant morphology and divergent differentiation.

Urothelial carcinoma represents a diverse group of tumours with distinct histologic subtypes, each exhibiting unique cytomorphologic features, architectural growth patterns, and/or well-developed aberrant differentiation. In fact, there are more than 13 subtypes of urothelial carcinoma recognized in the 2022 WHO classification of tumours in the urinary tract. The identification of these subtypes is crucial for an accurate diagnosis of urothelial carcinoma, and many have important clinical implications. Variant/divergent features may coexist with conventional high-grade urothelial carcinoma (HGUC) or present with 100% variant morphology. In urinary tract cytology (UTC), urothelial carcinoma can display divergent differentiation, such as squamous, glandular, or small cell carcinoma differentiation. The use of cell block preparations and immunohistochemistry with available residual urine can enhance diagnostic accuracy. On the other hand, identifying urothelial carcinoma variants, including nested, micropapillary, and plasmacytoid subtypes, poses significant challenges in UTC. Many cases of these variants are only detected retrospectively after variant histology has been established from resection specimens. Moreover, some variants exhibit features inconsistent with the diagnostic criteria for HGUC according to the Paris System for Reporting Urinary Tract Cytology. Nevertheless, the rarity of pure variant morphology and the occurrence of some false negatives for these variant cases are essential to maintain the specificity of UTC overall. This review covers the histology, cytomorphology, and important clinical aspects observed in urothelial carcinoma exhibiting divergent differentiation and various urothelial carcinoma variants detected in UTC.

Variants of High-Grade Urothelial Carcinoma: Can We Catch Them in Urine Cytology Using The Paris System?

Variants of High-Grade Urothelial Carcinoma: Can We Catch Them in Urine Cytology Using The Paris System?

Morphology, immunohistochemistry characteristics, and clinical presentation of microcystic urothelial carcinoma: a series of 10 cases

BackgroundMicrocystic urothelial carcinoma (MUC) is a rare variant of urothelial carcinoma with histological appearances similar to begin lesions. Thus far, approximately 50 cases have been reported. Here, we investigated the clinicopathological features of MUC.MethodsClinical data and paraffin-embedded tissue blocks were collected. Immunohistochemical staining and polymerase chain reaction–Sanger sequencing were performed to detect the phenotype and TERT mutation status of MUC, respectively.ResultsThe mean patient age was 58.8 ± 14.5 years, with a male predominance (8:2). The pathological stage was T1 in one case, T2 in three cases, T3 in four cases, and T4 in two cases. Tumor metastases or death occurred in all five patients who were followed up within 1–3 years. Histological analyses revealed microcystic, tubular, cribriform, and occasionally cord-like structures, which generally lacked interstitial reactions. The lumens were empty, contained eosinophilic secretion, or were filled with mucin. The microcysts/tubules/cribriform patterns were lined by flat, cuboid, signet ring, or columnar types of epithelia. The cuboid, signet ring, and columnar types represented “glandular metaplasia” or glandular differentiation of urothelial carcinoma. Immunohistochemistry analyses revealed distinct co-expression patterns involving the luminal markers FOXA1 and GATA3, as well as the basal markers CK5/6 and CD44. All 10 cases exhibited a luminal phenotype according to the GATA3+/CK14- criterion, whereas nine cases exhibited a luminal phenotype according to the FOXA1+/CK14- criterion. The telomerase reverse transcriptase-C228T mutation was detected in seven cases.ConclusionsMUC is a rare variant with a deceptively benign form of urothelial carcinoma, which is generally identified as a late-stage tumor with a poor prognosis. It exhibits distinct co-expression of luminal and basal markers, along with the TERT-C228T mutation.

Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations.

The large, nested variant of urothelial carcinoma (LNVUC) is characterized by bland histomorphology mimicking that of benign von Brunn nests. In the current study, we aimed to investigate the Fibroblast Growth Factor Receptor-3 (FGFR-3) activation and missense mutation in 38 cases, including 6 cases diagnosed with LNVUC and 32 with metastatic invasive urothelial carcinoma (UC). Initially, six formalin-fixed paraffin-embedded (FFPE) tissue samples of the LNVUC were subjected to whole-exome sequencing (WES), and then we performed targeted sequencing on 32 cases of metastatic invasive UC of various morphological subtypes, which were interrogated for the FGFR3. Our results revealed 3/6 (50%) LNVUC cases evaluated by WES in our study showed an activating mutation in FGFR-3, 33% showed an activating mutation in PIK3CA, and 17% showed activating mutation in GNAS or MRE11. Additionally, 33% of cases showed a truncating mutation in CDKN1B. All LNVUC in our study that harbored the FGFR-3 mutation showed additional activating or truncating mutations in other genes. Overall, 6/32 (18.75%) cases of random metastatic invasive UC showed missense mutations of the FGFR-3 gene. The LNVUC variant showed the higher incidence of FGFR-3 mutations compared to other types of mutations. Additionally, all LNVUC cases show additional activating or truncating mutations in other genes, thus being amenable to novel targeted therapy.

Plasmacytoid bladder cancer: a rare case report.

The authors report a case of a patient with locally advanced plasmacytoid urothelial carcinoma (PUC) of the bladder. A 71-year-old man with a history of chronic obstructive pulmonary disease presented with gross hematuria. The rectal examination revealed a fixed bladder base. A computed tomography scan showed a pedunculated lesion arising from the anterior and left lateral bladder wall and extended to the perivesical fat. The patient underwent transurethral resection of the tumor. The histologic examination revealed the presence of muscle-invasive PUC of the bladder. The decision of the multidisciplinary consultation meeting was to do palliative chemotherapy. Thus, the patient could not receive systemic chemotherapy and died 6 weeks after transurethral resection of the bladder tumor. A plasmacytoid variant of urothelial carcinoma is a rare subtype of urothelial carcinoma that has a poor prognosis with a high mortality rate. The disease is usually diagnosed at an advanced stage. Given the rarity of plasmacytoid bladder cancer, treatment guidelines are not clear; therefore, more aggressive treatment may be required. PUC of the bladder is characterized by high aggressiveness, an advanced stage at the time of diagnosis, and a poor prognosis.

PD09-02 THE IMPACT OF VARIANT HISTOLOGY ON CLINICAL OUTCOMES AFTER RADIATION-BASED THERAPY FOR MUSCLE-INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023PD09-02 THE IMPACT OF VARIANT HISTOLOGY ON CLINICAL OUTCOMES AFTER RADIATION-BASED THERAPY FOR MUSCLE-INVASIVE BLADDER CANCER Daniel Halstuch, Ronald Kool, Gautier Marcq, Rodney H Breau, Peter C Black, Bobby Shayegan, Michael Kim, Ionut Busca, Hamidreza Abdi, Mark T. Dawidek, Michael Uy, Gagan Fervaha, Fabio L. Cury, Nimira S. Alimohamed, Claudio Jeldres, Ricardo Rendon, D. Robert Siemens, Girish S. Kulkarni, Wassim Kassouf, and Jonathan I. Izawa Daniel HalstuchDaniel Halstuch More articles by this author , Ronald KoolRonald Kool More articles by this author , Gautier MarcqGautier Marcq More articles by this author , Rodney H BreauRodney H Breau More articles by this author , Peter C BlackPeter C Black More articles by this author , Bobby ShayeganBobby Shayegan More articles by this author , Michael KimMichael Kim More articles by this author , Ionut BuscaIonut Busca More articles by this author , Hamidreza AbdiHamidreza Abdi More articles by this author , Mark T. DawidekMark T. Dawidek More articles by this author , Michael UyMichael Uy More articles by this author , Gagan FervahaGagan Fervaha More articles by this author , Fabio L. CuryFabio L. Cury More articles by this author , Nimira S. AlimohamedNimira S. Alimohamed More articles by this author , Claudio JeldresClaudio Jeldres More articles by this author , Ricardo RendonRicardo Rendon More articles by this author , D. Robert SiemensD. Robert Siemens More articles by this author , Girish S. KulkarniGirish S. Kulkarni More articles by this author , Wassim KassoufWassim Kassouf More articles by this author , and Jonathan I. IzawaJonathan I. Izawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003240.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radiation-based therapy (RT) is an acceptable bladder-preserving treatment for selected patients with muscle-invasive bladder cancer (MIBC). Real-world outcomes of RT-based therapy for histologic variants are lacking. Our objective was to compare oncological outcomes between pure urothelial carcinoma (PUC) and variant urothelial carcinoma (UC-HV) patients with MIBC treated with RT-based therapy. METHODS: A collaborative Canadian multicenter retrospective study of 864 patients with MIBC who underwent curative-intent bladder-sparing RT for T2-4a N0-3 M0 MIBC between 2001-2018. Tumours were classified based on the presence of non-urothelial components as either PUC or UC-HV. A complete response (CR) was defined by a negative tumour bed biopsy and/or the combination of a negative urine cytology, negative cystoscopy and normal imaging post-RT. Loco-regional disease-free survival (LR-DFS), disease-free survival (DFS), metastasis-free survival (MFS), cancer-specific survival (CSS) and overall survival (OS) were calculated using Kaplan-Meier method. Cox regression models were used to estimate the effect of UC-VH on oncologic outcomes for patients with MIBC treated with RT-based therapy. RESULTS: Of 864 patients treated with RT-based therapy, 123 (14.2%) had UC-HV. Seventy-five (61%) had UC-HV with squamous and/or glandular differentiation and 48 (39%) had other variants. A CR after RT-based therapy was confirmed in 69.1% of patients with PUC and 63.4% with UC-HV (p=0.266). The 5-yr CSS was 62.0% in PUC vs. 66.8% in UC-HV. The 5-yr OS was 47.7% in PUC and 53.3% in UC-HV. Rates of LR-DFS, DFS and MFS at 5 years were not statistically different between the groups. Salvage cystectomy (sRC) rates were similar (p=0.781). In the univariate Cox regression analyses, UC-HV status was not associated with inferior LR-DFS, DFS, MFS, CSS, and OS. CONCLUSIONS: Variant histology of urothelial carcinoma responded to RT-based therapy with no significant difference in CR, LR-DFS, DFS, MFS, CSS, OS, or rates of salvage cystectomy compared to PUC. The presence of variant histology in MIBC does not confer resistance to RT-based therapy and these patients should not be excluded from bladder preservation treatment. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e239 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Halstuch More articles by this author Ronald Kool More articles by this author Gautier Marcq More articles by this author Rodney H Breau More articles by this author Peter C Black More articles by this author Bobby Shayegan More articles by this author Michael Kim More articles by this author Ionut Busca More articles by this author Hamidreza Abdi More articles by this author Mark T. Dawidek More articles by this author Michael Uy More articles by this author Gagan Fervaha More articles by this author Fabio L. Cury More articles by this author Nimira S. Alimohamed More articles by this author Claudio Jeldres More articles by this author Ricardo Rendon More articles by this author D. Robert Siemens More articles by this author Girish S. Kulkarni More articles by this author Wassim Kassouf More articles by this author Jonathan I. Izawa More articles by this author Expand All Advertisement PDF downloadLoading ...

New WHO classification 2022: urinary bladder cancer

The new World Health Organization (WHO) classification of urogenital tumors is still primarily based on anatomic location, but is also a hierarchical taxonomic classification without separate chapters for tumors of the upper urinary tract and the urethra. It clarifies aspects regarding grading and noninvasive entities. It consolidates the use of the Paris system for urinary cytology as well as various subtypes/special types of neoplasms, and incorporates general concepts of the 5th edition of the WHO blue book. In addition to mesenchymal tumors, well-differentiated neuroendocrine tumors and neuroendocrine carcinomas are addressed in separate chapters. Papillary non-invasive low- and high-grade carcinomas and carcinoma in situ remain, while dysplasia and urothelial proliferation of unknown malignant potential (UPUMP) are no longer treated as separate entities. Former variants of urothelial carcinoma are now called subtypes and aberrant differentiation and special types are more precisely defined.

Invasive Micropapillary Urothelial Carcinoma: an Uncommon and Underreported Variant in Cystectomy Specimens.

Conventional urothelial carcinoma is the most common histological type of urinary bladder carcinoma. The latest edition of the WHO classification of tumours of the urothelial tract lays special emphasis on the ability of urothelial tumours to exhibit divergent differentiation with multiple histologic variants and a diverse genomic landscape. The presence of a micropapillary component (MPC) in urothelial carcinoma is associated with high-grade disease and poor response to intravesical chemotherapy. The present study aims to enumerate the clinicohistological features of urothelial carcinomas with micropapillary differentiation. Slides from 144 radical cystectomy specimens received over 6 years were reviewed independently by two pathologists. A predominant histological pattern along with co-existing pathology was noted. Of these, five cases were pure micropapillary carcinomas, four had conventional urothelial carcinoma with a MPC, one had a microscopic tumour at the mucosal surface, and two cases showed micropapillary histology in the lymph node metastasis, following transurethral resection of bladder tumour and Bacillus Calmette-Guerin therapy. The tumours with pure micropapillary carcinoma presented with a higher pathological stage and poor overall survival. Organ and lymph node metastasis was noted in five and eight cases, respectively, of which six showed a micropapillary pattern in the lymph nodes. Micropapillary urothelial carcinoma is a rare and aggressive variant of urothelial carcinoma with unique histologic features. This variant is often missed and underreported in biopsy and surgical resection specimens. Since the presence of MPC confers a poorer prognosis, the identification and reporting of this entity are important.

Plasmacytoid urothelial carcinoma - A clinicopathological case series of an aggressive variant of urothelial cancer.

Many new morphological variants of urothelial carcinoma of urinary bladder have been described in the literature, plasmacytoid/signet ring cell/diffuse variant being one of the rare amongst these. Till date, no case series has been reported from India, describing this variant. We retrospectively analyzed the clinicopathological data of 14 patients diagnosed at our center with plasmacytoid urothelial carcinoma. Seven cases (50%) were pure forms while the remaining 50% of cases had a concurrent conventional urothelial carcinoma component. Immunohistochemistry was performed to rule out other mimickers of this variant. Treatment-related data were available for seven patients, while follow-up was available for nine cases. Overall, plasmacytoid variant of urothelial carcinoma is considered to be an aggressive tumor with poor prognosis.

Oncologic outcomes of neoadjuvant chemotherapy in patients with micropapillary variant urothelial carcinoma of the bladder

BackgroundThere is lack of consensus about the effectiveness of neoadjuvant platinum-based chemotherapy in patients with micropapillary variant urothelial carcinoma (MVUC) prior to radical cystectomy. We studied the association between neoadjuvant chemotherapy (NAC) and pathologic response (PR) among patients with micropapillary versus non-variant bladder urothelial carcinoma (UC). MethodsWe queried the National Cancer Database to identify patients with localized UC and MVUC from 2004 to 2017. We restricted our analysis to patients who underwent radical cystectomy with or without NAC. We compared clinical, demographic, and pathologic characteristics associated with NAC. We used multivariable logistic regression and propensity score matching to examine the association between NAC and the occurrence of a pathologic complete response (pT0) and pathologic lymph node positivity (pN+). Kaplan Meier analyses and Cox proportional hazards models were used to assess overall survival (OS). We performed analyses among subsets of patients with clinical stage II (cT2) disease, as well as the entire cohort (cT2-T4). ResultsWe identified 18,761 patients, including 18,027 with non-variant UC and 734 patients with MVUC. Multivariable analysis revealed that NAC use was associated with greater odds of pT0 (9.64[7.62–12.82], P<0.001), and the association did not differ significantly between MVUC and non-variant UC. In a propensity matched analysis of patients with MVUC, NAC use was associated with higher odds of pT0 (OR 4.93 [2.43–13.18] P<0.001), lower odds of pN+ (OR 0.52 [0.26–0.92] P=0.047) and pathologic upstaging (OR 0.63 [0.34–0.97] P=0.042) in all stages. Similar findings were observed with cT2 disease. No significant association was seen between NAC and OS with MVUC (HR 0.89 [0.46–1.10] P=0.63), including the subset of patients with cT2 (HR 0.83 [0.49–1.06] P=0.58). ConclusionsNAC is associated with similar pathologic and nodal responses in patients with localized MVUC and non-variant UC. Improvements in pathologic findings did not translate into OS in this retrospective hospital-based registry study.

P130 - Histological spectrum and Immunohistochemistry based molecular subtyping of Variant Urothelial Carcinoma (VUC) and its prognostic implications

P130 - Histological spectrum and Immunohistochemistry based molecular subtyping of Variant Urothelial Carcinoma (VUC) and its prognostic implications

Efficacy of Pembrolizumab in Patients With Variant Urothelial Carcinoma: A Multicenter Retrospective Study.

Although variant urothelial carcinoma (VUC, defined here as urothelial carcinoma with any histological variant) is a clinically aggressive disease, the efficacy of pembrolizumab against VUC is not well characterized. This study assessed the therapeutic response and survival outcomes in patients with advanced VUC treated with pembrolizumab for unresectable recurrent or metastatic disease. We retrospectively evaluated 103 patients with advanced bladder and upper urinary tract cancer who received pembrolizumab after failure of platinum-based chemotherapy at 6 institutions between January 2018 and June 2021. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with VUC. We identified 81 and 22 patients with PUC and VUC, respectively. Squamous differentiation (n=14) was the most common variant element, followed by glandular differentiation (n=3) and micropapillary variant (n=3). Baseline characteristics were comparable between the groups. Patients with VUC showed significantly better ORR (59.1% vs. 29.6%, P=.014) and comparable DCR (68.2% vs. 49.4%, P=.150) compared to those with PUC. There were no significant differences between the PUC and VUC groups with respect to PFS (median 5.0 months vs. 10.4 months, P=.222) or OS (median 13.5 months vs. 23.8 months, P=.497). Response of VUC to pembrolizumab was not inferior to that of PUC in patients with advanced-stage bladder and upper urinary tract cancer.

Therapiekonzepte für histologische Varianten und nichturotheliale Histologie von Blasentumoren

BackgroundApproximately 30% of bladder tumors show a histological variant or a nonurothelial histology. The individual variants are rare, which complicates the design of studies for these entities and the design of treatment concepts. The frequency of a diagnosis of histological variants is increasing.ObjectivePresentation of current treatment concepts for urothelial variants and nonurothelial bladder tumors.Material and methodsNonsystematic search in PubMed with the keywords bladder cancer, variant histology and nonurothelial bladder cancer, taking the current guidelines of the specialist societies EAU, ESMO and NCCN into account.ResultsTreatment of squamous cell or glandular differentiation follows the same pathways as recommended for conventional urothelial carcinoma. Micropapillary, sarcomatoid and plasmacytoid variants as well as pure squamous cell carcinoma and adenocarcinoma should be treated by radical cystectomy and lymphadenectomy in both non-muscle-invasive and muscle-invasive stages. In cases of a pure squamous cell carcinoma, perioperative radiotherapy should be considered in the muscle-invasive stage. Localized small cell neuroendocrine tumors are treated with neoadjuvant chemotherapy followed by a consolidating local treatment.ConclusionHistological variants of urothelial carcinoma and nonurothelial bladder tumors often have a poor prognosis. The histopathological diagnosis is challenging but indispensable for a correct treatment decision. Established treatment guidelines for the individual entities do not usually exist. Efforts must be made to include such patients in randomized trials.