Divergent differentiation and histologic subtypes are common findings in urothelial carcinoma (UC). Clinically relevant genomic alterations and oncogenic drivers of individual subtypes remain poorly defined. We characterized surgical outcomes and the genomic landscape of UC with aberrant histology (UCAH), with a focus on biomarkers and targetable alterations.

The clinical cohort comprised 3052 patients who underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy. Targeted exon sequencing was performed for a genomic cohort of 1060 bladder tumors from RC or transurethral resection specimens. We characterized the frequency of oncogenic mutations and targetable alterations, and the tumor mutational burden (TMB) of each subtype. We defined the clonal relatedness of morphologically distinct regions of tumors with mixed histology.

Patients with plasmacytoid, micropapillary, sarcomatoid, or mixed-histology tumors had worse cancer-specific survival than patients with pure urothelial histology. ERBB2, FGFR3, and PTEN alterations were most frequent in micropapillary, nested/squamous, and sarcomatoid UC, respectively. TMB was highest in plasmacytoid, neuroendocrine, and micropapillary tumors. Regions of mixed histology had shared clonal origins, but exceptions were observed. The retrospective design and potential for selection bias are limitations of our study.

UCAH tumors have distinct patterns of genomic alterations, which may be targetable via novel therapies and have implications for clinical trial inclusion. Biomarker-driven systemic therapy should be explored in patients with histologic subtypes that are associated with worse clinical outcomes.

Immune Checkpoint Inhibitors (ICIs) are used for advanced urothelial carcinoma (aUC) in different settings. Most patients have pure UC (PUC) but about one-third have UC mixed with histology subtypes (HS). We examined outcomes in patients with HS aUC treated with ICI.

We included patients from 26 centers with PUC and any HS treated with ICI as 1st line (1L) upfront, maintenance avelumab (mAV), and ≥2nd line [2+L] therapy. We calculated overall and progression-free survival (OS, PFS) and observed response rate (ORR) from ICI start.

We included 1511 patients; 752 1L, 609 2+L, 150 mAV. 1L: median OS was 15 (95% CI, 12-17) months for patients with PUC (n = 518), 15 (95% CI, 8-23) months for squamous UC (n = 85) (HR = 1.2, [95% CI, 0.8-1.6]), 11 (95% CI, 6-17) months for micropapillary UC (n = 46) (HR = 1.2, [95% 0.8-1.8]), and 21 (95% CI, 12-30) months in patients with UC mixed with ≥2 HS (n = 30), (HR = 0.9, [95% CI, 0.5-1.4]). 2+L: median OS was 9 (95% CI, 8-10) months for patients with PUC (n = 441), 9 (95% CI, 1-12) months for squamous UC (n = 60) (HR = 1.1, (95% CI, 0.8-1.6]), 6 (95% CI, 1-11) months for micropapillary UC (n = 37) (HR = 1.1, [95% 0.7-1.6]), and 7 (95% CI, 4-10) months in patients with UC mixed with ≥2 HS (n = 17), (HR = 1.6, [95% CI, 0.9-3.1]).

We found no significant OS difference between PUC and HS in patients with aUC treated with ICI monotherapy. Limitations include retrospective design, small sample size in several subsets, lack of randomization, no central imaging or pathology review, selection and confounding biases. Results are hypothesis-generating and need prospective validation.

Plasmacytoid urothelial carcinoma (PUC) of the urinary bladder is an aggressive UC subtype characterized by infiltrating cells with plasmacytoid appearance, and somatic CDH1 mutations leading to E-cadherin loss. 32 PUC cases were found in our pathology archives from 2018 to 2024; next-generation sequencing (NGS) was available in 18 cases, and PD-L1 immunohistochemistry in all 32 cases. PD-L1 tumor proportion score (TPS) and combined positive score (CPS) were calculated. Kaplan-Meier method and log-rank test were used for survival analysis. Median patient age was 72.5 years (IQR: 64.3-78.8 years). The cohort consisted predominantly of males (29/32, 91%). 25 patients (78%) underwent radical cystectomy/cystoprostatectomy (RC), while 7 (22%) transurethral resection. Median tumor size was 5.2 cm (IQR of 3.6-8.0 cm). Most RCs (22/25, 88 %) were high-stage (pT3-4). Lymphovascular invasion was identified in 22/25 RCs (88%) and 12/23 RCs (52%) were pN1-2. 17/32 cases (53%) showed a PD-L1 TPS≥1% (6/17 received immune-checkpoint inhibitors - ICIs), while 21/32 (66%) exhibited a CPS≥1% (8/21 received ICIs). Recurrently mutated genes included TP53, TERT, RB1, CREBBP, and ERBB2, among others; our NGS panel does not cover CDH1. Most frequent copy number alterations were RB1, CDKN2A, and CDKN1B losses. Median tumor mutational burden (TMB) was 10.3 mut/Mb (IQR 5.4-15.73 mut/Mb). Median overall survival (OS) was 13.0 months (95% CI 4.2-21.8 months) with some evidence for superior OS among patients with PD-L1 expression. Overall, PUCs frequently exhibit high TMB and/or PD-L1 expression, suggesting a potential for intervention with ICIs. Finally, NGS is recommended to identify actionable alterations, including ERBB2 mutations.

Urothelial carcinoma exhibits a wide spectrum of morphologic and molecular heterogeneity. Advances in molecular testing have improved our understanding of the molecular biology of urothelial carcinoma, including recurrent genomic alterations and transcriptomic features, leading to the development of molecular classification schemes with potential therapeutic implications. This review summarizes the molecular characteristics of urothelial carcinoma, focusing on genomic and transcriptomic features, updates on variant histology, and novel biomarkers that may guide contemporary and future clinical management.

Mismatch repair deficiency (MMR-d) and microsatellite instability (MSI) are prognostic and predictive biomarkers in oncology. Current testing for MMR/MSI relies on immunohistochemistry (IHC) for MMR proteins and molecular assays for MSI detection. This combined diagnostic strategy, however, lacks tumor specificity and does not account for gene variants. This study provides an in-depth analysis of MMR mutations frequency, spectrum, and distribution in solid tumors. Data from 23,893 patients across 11 tumor types, using 66 publicly available studies, were analyzed. MMR-mutated (MMR-m) status was defined by alterations in MLH1, PMS2, MSH2, and/or MSH6; MSI was assessed by MSIsensor. Cases with indeterminate labelling were excluded. Survival was analyzed using the Kaplan-Meier method. Among 19,353 tumors, 949 MMR variants were identified, comprising 432 pathogenic and 517 variants of unknown significance (VUS), as defined by OncoKB. MSH6 mutations were the most frequent (n = 279, 29.4 %), followed by MSH2 (n = 198, 20.9 %), MLH1 (n = 187, 19.7 %), and PMS2 (n = 161, 16.9 %). MMR-m cases were more frequent in endometrial (EC, 20.5 %), colorectal (CRC, 8.2 %), bladder (BLCA, 8.7 %), and gastroesophageal cancers (GEC, 5.4 %). Pathogenic mutations were more common than non-pathogenic in EC, CRC, and GEC (p < 0.001, p = 0.01, p = 0.32, respectively). MMR-m status was not associated with MSI in 247 (48.9 %) cases, including 67 (13.2 %) with pathogenic mutations. The highest concordance between MMR-m and MSI was observed in CRC (65.7 %), EC (91.2 %), and GEC (69.6 %), while the lowest in pancreatic (0.2 %) and lung cancers (0.1 %). MMR-m GECs showed improved overall survival compared to MMR-wt (p = 0.009), a relationship not observed in other tumor types. This study demonstrates that the MMR spectrum is extremely hetoerogeneous in solid tumors, highliting the need for comprehensive and tumor-specific testing strategies.

Urothelial carcinoma (UC) is the most common histological subtype of bladder tumors; however, bladder cancer represents a heterogeneous group of diseases with at least 40 distinct histological subtypes. Among these, the 2022 World Health Organization classification of urinary tract tumors identifies a range of less common subtypes of invasive UC, formerly known as variants, which are considered high-grade tumors, including squamous cell, small-cell, sarcomatoid urothelial, micropapillary, plasmacytoid, and urachal carcinomas, and adenocarcinoma. Their accurate histological diagnosis is critical for risk stratification and therapeutic decision-making, as most subtype histologies are associated with poorer outcomes than conventional UC. Despite the importance of a precise diagnosis, high-quality evidence on optimal treatments for subtype histologies remains limited owing to their rarity. In particular, neoadjuvant and adjuvant chemotherapy have not been well characterized, and prospective data are scarce. For advanced-stage diseases, clinical trial participation is strongly recommended to address the lack of robust evidence. Advances in molecular pathology and the development of targeted therapies and immunotherapies have reshaped our understanding and classification of bladder cancer subtypes, spurring efforts to identify predictive biomarkers to guide personalized treatment strategies. Nevertheless, the management of rare bladder cancer subgroups remains challenging because they are frequently excluded from clinical trials. For localized disease, curative options such as surgical resection or radiotherapy are available; however, treatment options become more limited in recurrence or metastasis, where systemic therapy is primarily used to control disease progression and palliate symptoms. Herein, we present recent advances in the management of urothelial and non-urothelial bladder cancer subtypes and also explore the current evidence guiding their treatment and emphasize the challenges and perspectives of future therapeutic strategies.

Muscle-invasive and metastatic urothelial carcinoma (UC) represents a heterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes.

This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC.

Muscle-invasive and metastatic UC exhibits a wide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.

Urothelial carcinoma (UC) demonstrates significant molecular and histologic heterogeneity. The WHO 2022 classification has hinted at adding molecular signatures to the morphologic diagnosis. As morphology and associated molecular repertoire may potentially translate to choices of and response to therapy and relapse rate, broader acceptability of recognizing these key features among uropathologists is needed. This prompted an international survey to ascertain the practice patterns in classical/subtype UC among uropathologists across the globe.

A survey instrument was shared among 98 uropathologists using SurveyMonkey software. Anonymized respondent data were analysed. The response rate was 85%. A majority were in concordance with the profiles of luminal (93%) and basal (82%) types. Opinion on the FGFR3 testing platform was variable. While 95% concurred that TERT promoter mutation is the key driver in UC, 72% had the opinion that APOBEC mutagenesis is the main signature in muscle invasive bladder cancer (MIBC). Uropathologists have divergent opinions on MIBC and ERCC2 mutations. Among the participants, 94% would quantify aggressive micropapillary and sarcomatoid histology, while 88% would reevaluate another transurethral resection of the bladder tumour specimen in nonmuscle invasive tumour with micropapillary, small cell, or sarcomatoid histology. A leading number agreed to specific molecular signatures of micropapillary (93%), plasmacytoid (97%), and small cell (86%) subtypes. Ninety-six percent of participants agreed that a small-cell component portends a more aggressive course and should be treated with neoadjuvant chemotherapy and 63% would perform HER2/neu testing only on oncologist's request in advanced tumours. Ninety percent agreed that microsatellite instability testing, although not a standard protocol, should be considered in young patients with upper tract UC. Eighty-six percent agreed that UC with high tumour mutational burden would be a better candidate for immunotherapy.

In the era of precision medicine, enhanced understanding of molecular heterogeneity of UC will contribute to better therapeutic options, novel biomarker discovery, innovative management protocols, and outcomes. Our survey provides a broad perspective of pathologists' perceptions and experience regarding incorporation of histomolecular approaches to "personalize" therapy. Due to variable clinical adoption, there is a need for additional data using uniform study criteria. This will drive generation of best practice guidelines in this area for widespread and consistent clinical utility.

Bladder cancer (BC), predominantly comprising urothelial carcinomas (UCs), ranks as the tenth most common cancer worldwide. UCs with variant histology (variant UC), including squamous differentiation, glandular differentiation, plasmacytoid variant, micropapillary variant, sarcomatoid variant, and nested variant, accounting for 5-10% of cases, exhibit more aggressive and advanced tumor characteristics compared to pure UC. The Vesical Imaging-Reporting and Data System (VI-RADS), established in 2018, provides guidelines for the preoperative evaluation of muscle-invasive bladder cancer (MIBC) using multiparametric magnetic resonance imaging (mpMRI). This technique integrates T2-weighted imaging (T2WI), dynamic contrast-enhanced (DCE)-MRI, and diffusion-weighted imaging (DWI) to distinguish MIBC from non-muscle-invasive bladder cancer (NMIBC). VI-RADS has demonstrated high diagnostic performance in differentiating these two categories for pure UC. However, its accuracy in detecting muscle invasion in variant UCs is currently under investigation. These variant UCs are associated with a higher likelihood of disease recurrence and require precise preoperative assessment and immediate surgical intervention. This review highlights the potential value of mpMRI for different variant UCs and explores the clinical implications and prospects of VI-RADS in managing these patients, emphasizing the need for careful interpretation of mpMRI examinations including DCE-MRI, particularly given the heterogeneity and aggressive nature of variant UCs. Additionally, the review addresses the fundamental MRI reading procedures, discusses potential causes of diagnostic errors, and considers future directions in the use of artificial intelligence and radiomics to further optimize the bladder MRI protocol.

The majority of bladder cancers (BCs) are non-muscle invasive BCs (NMIBCs) and show the morphology of a conventional urothelial carcinoma (UC). Aberrant morphology is rare but can be observed. The classification and characterization of histologic subtypes (HS) in UC in BC have mainly been described in muscle invasive bladder cancer (MIBC). However, the currently used classification is applied for invasive urothelial neoplasm and therefore, also valid for a subset of NMIBC. The standard transurethral diagnostic work-up misses the presence of HS in NMIBC in a considerable percentage of patients and the real prevalence is not known. HS in NMIBC are associated with an aggressive phenotype. Consequently, clinical guidelines categorize HS of NMIBC as "(very) high-risk" tumors and recommend offering radical cystectomy to these patients. Alternative strategies for bladder preservation can only be offered to highly selected patients and ideally within clinical trials. Novel treatment strategies and biomarkers have been established MIBC and NMIBC but have not been comprehensively investigated in the context of HS in NMIBC. Further evaluation prior to implementation into clinical practice is needed.

Urothelial carcinoma (UC) has significant morbidity, mortality, and remains the most financially costly carcinoma to manage and treat. This review will cover special morphologic features of UC that may be noted by the pathologist and any subsequent significance in terms of clinical management or treatment considerations as mentioned or recommended in the latest WHO 2022 classification of GU tumors. Many important potentially therapy altering morphologic findings can be consistently identified and reported on routine microscopic examination of hematoxylin and eosin (H&E) stained slides. Furthermore, there has been a rapid advancement of molecular diagnostics and tailored therapies throughout oncology, and we will briefly highlight some of these as they relate to the management of UC. We will actively attempt to limit the discussion of histologic descriptions or pathologic diagnostic criteria of these entities and focus rather on the recognition of their importance/implication for clinicians who must make clinical management decisions based upon these findings. Finally, the importance of open lines of communication with the pathologists who review clinical specimens as well as their practice and reporting methods cannot be overstated.

Bladder cancer is a histologically and clinically heterogenous disease. Most bladder cancers are urothelial carcinomas, which frequently develop distinct histological subtypes. Several urothelial carcinoma histological subtypes, such as micropapillary, plasmacytoid, small-cell carcinoma and sarcomatoid, show highly aggressive behaviour and pose unique challenges in diagnosis and treatment. Comprehensive genomic characterizations of the urothelial carcinoma subtypes have revealed that they probably arise from a precursor subset of conventional urothelial carcinomas that belong to different molecular subtypes - micropapillary and plasmacytoid subtypes develop along the luminal pathway, whereas small-cell and sarcomatoid subtypes evolve along the basal pathway. The subtypes exhibit distinct genomic alterations, but in most cases their biological properties seem to be primarily determined by specific gene expression profiles, including epithelial-mesenchymal transition, urothelial-to-neural lineage plasticity, and immune infiltration with distinct upregulation of immune regulatory genes. These breakthrough studies have transformed our view of bladder cancer histological subtype biology, generated new hypotheses for therapy and chemoresistance, and facilitated the discovery of new therapeutic targets.

Urothelial carcinoma is characterized by the presence of a wide spectrum of histopathologic features and molecular alterations that contribute to its morphologic and genomic heterogeneity. It typically harbors high rates of somatic mutations with considerable genomic and transcriptional complexity and heterogeneity that is reflective of its varied histomorphologic and clinical features. This review provides an update on the recent advances in the molecular characterization and novel molecular taxonomy of urothelial carcinoma and variant histologies.

Urothelial cancer (UC) is the most common histology seen in bladder tumors. The 2022 WHO classification of urinary tract tumors includes a list of less common subtypes (formerly known as variants) for invasive UC which are considered high-grade tumors. This review summarizes the most recent advances in the management of selected nonurothelial subtypes of bladder cancer: squamous cell carcinoma, small cell carcinoma, sarcomatoid urothelial carcinoma, micropapillary carcinoma, plasmacytoid carcinoma, adenocarcinoma, and urachal carcinoma. The role of neoadjuvant and adjuvant chemotherapy has not been well characterized for most of these histologies, and prospective data are extremely limited. Participation in clinical trials is recommended in advanced disease.

Plasmacytoid urothelial carcinoma (UC) is a rare histologic subtype of bladder cancer that is associated with an aggressive clinical behavior. We analyzed the clinicopathologic and molecular features of plasmacytoid UC in 52 patients from a single institute. The patients included 44 men and 8 women, with a mean age of 64 years (range, 41-91 years). All bladder cancers were high-grade UC, and plasmacytoid component accounted for a mean of 47% of bladder tumors (range, 5-100%). Distinct gene mutations were found in most plasmacytoid UCs (n = 49); the most common mutations were TP53 (n = 30), followed by TERT (n = 20), and CDH1 (n = 18). Copy number analysis was performed in 34 patients, and 13 of them showed copy number variations. Expression of HER2 was analyzed in 18 patients by immunohistochemistry, and 3 of them showed HER2 overexpression, which was confirmed by fluorescence in situ hybridization analysis. Thirty-two patients died of disease in a median of 15 months (range, 1-45 months). No individual gene mutations were significantly associated with clinical outcome, but mutations in the mammalian target of rapamycin (mTOR) pathway, including PICK3CA and PIK3R1 mutations, were associated with a significantly shorter survival duration (p < 0.05). Plasmacytoid UC is an aggressive histologic subtype that demonstrates frequent somatic gene mutations and CNVs, which may underlie its oncogenesis and progression. Gene mutations of the mTOR pathway are associated with poor outcome in a subset of patients with plasmacytoid UC.

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.

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared with KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.

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.

The treated natural history of nonmetastatic plasmacytoid variant of bladder cancer (PV-BCa) is poorly understood owing to its rarity. We sought to examine the disease recurrence and metastasis patterns in this select group of patients in order to identify opportunities for intervention.

We conducted a natural language processing algorithm-augmented retrospective chart review of 56 consecutive patients who were treated with curative intent for nonmetastatic PV-BCa at our institution between 1998 and 2018. Kaplan-Meier and multivariable Cox regression methods were used for survival analyses.

The stage at presentation was: ≤ cT2N0 in 22 (39.3%), cT3N0 in 15 (26.8%), cT4N0 in 13 (23.2%), and ≥ cN1 in 6 patients (10.7%). Forty-nine patients (87.5%) received chemotherapy, and 42 (75%) were able to undergo the planned surgery. Notably, only 4 patients (7.2%) had pT0 stage, while 22 (52.4%) had pN+ disease at the time of surgery. At 36-month follow-up, 28.4% of patients (95% CI: 22.1%-34.5%) were alive and 22.2% (95% CI: 16.1%-28.5%) were free of metastatic disease. The benefit of surgical extirpation was stage specific: successful completion of surgery was associated with improved metastasis-free survival (at 36 months 32.4% vs 0%, log-rank P < .001) in patients with localized or locally advanced disease (≤cT2N0/cT3N0); however, in patients with regionally advanced disease (cT4N0/≥cN1), consolidative surgery following chemotherapy was not associated with improved metastasis-free survival (12.5% vs 10% at 36 months, log-rank P = .49). The median time to metastasis from primary treatment end was 6.5 months (IQR: 2.9-14.7). The predominant site of recurrence/metastasis was the peritoneum (76.1%), either in isolation or along with extraperitoneal lesions. Salvage immunotherapy in these patients significantly reduced the risk of death (HR = 0.11, P = .001).

PV-BCa is a disease with high lethality. Despite multimodal treatment, a vast majority of patients develop atypical intraperitoneal metastasis soon after therapy and rapidly succumb to it. Clinical trials evaluating utility of hyperthermic intraperitoneal chemotherapy and/or immunotherapy may be warranted in this high-risk population.

Urothelial carcinoma is the predominant cancer of the urinary tract but when divergent and subtype histology (non-urothelial) are identified at time of pathologic diagnosis, therapeutic and diagnostic challenges transpire. To this end, pathologic review to confirm any non-urothelial histology is key since these subtypes can often be overlooked. Few prospective trials are dedicated to understanding these non-urothelial histologic types; however, current, and past trials did allow patients with these non-urothelial histologic types to enroll, and inferences can be made about treatment efficacy and survival. Existing treatment regimens for non-urothelial bladder cancers are akin to standard urothelial cancer regimens using surgical approaches for localized disease and platinum-based chemotherapy for advanced disease. The reported clinical trials, that will be discussed, center on non-urothelial histologic types. These studies, albeit limited, provide critical insight into tumor biology and response to standard platinum-based chemotherapy, immune checkpoint inhibitors, and antibody drug conjugates. The inclusion of non-urothelial histologic types will be essential for clinical trials in development to provide further therapeutic advances and provide essential efficacy data.

Bladder cancer researchers and clinicians have increasingly viewed tumor biology through the lens of genomic and molecular alterations, drastically improving our knowledge of the underlying disease biology. This understanding has led to significant advances in treatment options that allow implementation of a personalized approach to cancer treatment. Large-scale genomic studies initially focused on the most common forms of bladder cancer. However, as genomic and molecular technologies become more widespread and are applied to less common variant histologies, we are gaining additional insight into the unique molecular and genomic characteristics driving the biology of variant histologies of bladder cancer. In this review, we summarize the current state of knowledge of molecular alterations underlying the distinct tumor biology of plasmacytoid urothelial carcinoma and how these alterations may impact treatment options.

Gastric outlet obstruction caused by upper tract urothelial carcinoma is rare.

A 78-year-old man presented to the hospital with nausea and vomiting. No hematuria was observed. Computed tomography revealed a tumor in the right renal pelvis and duodenal stenosis. Gastrojejunostomy was performed to treat the symptoms of the gastric outlet obstruction so that the patient could resume oral intake and outpatient chemotherapy. Chemotherapy was unsuccessful, and the patient died 9 months after the gastrojejunostomy. Histological assessment of an autopsy specimen revealed plasmacytoid urothelial carcinoma with direct infiltration of the duodenal wall, which caused the stenosis.

Autopsy revealed a right renal pelvis cancer causing gastric outlet obstruction. Early gastrojejunostomy enabled oral intake and outpatient visits.

Guideline recommendations disagree on template boundaries for pelvic lymph node dissection (PLND) in conventional urothelial carcinoma. Less is known about PLND in variant histology. We aimed to analyze the role of LND in plasmacytoid urothelial carcinoma (PUC).

A retrospective review of patients with cTanyNanyM0 PUC who underwent radical cystectomy (RC) with PLND was performed from 2012 to 2022. Lymph node count (LNC) was a surrogate for extent of lymph node dissection and dichotomized based on maximally selected rank statistics. Multivariable cox hazard regression analysis (MVA) for overall survival (OS) corrected for age, perioperative chemotherapy, soft tissue margin status, and stage ≥pT3 and/or pN+ was performed. Disease free survival (DFS) and OS were estimated using Kaplan-Meier (KM) analysis.

Sixty-seven patients with median age of 71, who were 79.1% male were included. Neoadjuvant and adjuvant chemotherapy were administered in 61.2% and 19.4% of patients, respectively. At RC, 70.1% were ≥pT3. Median LNC was 22 (IQR 14-27) with 43.3% of patients being pN+. Calculated optimal-LNC cut point for DFS and OS was 19. Grouping by optimal (≥20) vs. suboptimal-LNC (<20), no significant clinicodemographic differences were found. Optimal-LNC provided improved DFS (P = 0.05) and OS (P = 0.02). Optimal-LNC (HR 0.47, 0.24-0.93 CI 95%, P = 0.03) and negative soft tissue margin (HR 0.38, 0.19-0.76 CI 95%, P = 0.01) was associated with improved OS on MVA. Receipt of perioperative chemotherapy did not improve OS (P = 0.46).

In PUC, complete surgical extirpation achieving negative soft tissue margins and removing ≥20 lymph should be prioritized if operative intervention is pursued.

Urothelial carcinoma is a heterogeneous disease with histomorphological and genomic variations throughout the same tumor or between tumors from different patients. It has been shown that most of these histologic and genetic differences have prognostic significance and may have a guiding role in determining the appropriate treatment choice for the patient. Therefore, it is crucial for both the pathologist and the clinician to be conscious of these variations and to consider them in patient management. Recently, a consensus molecular classification has been developed and categorized urothelial carcinomas into 6 subclasses. These molecular subclasses seem to be associated with prognosis and/or response to certain therapeutic approaches like chemotherapy or immune checkpoint inhibitory therapy; however, it has not yet been sufficiently validated and has some limitations for routine application. As is well known, there are therapeutic limitations in locally advanced or metastatic urothelial carcinomas, especially those inappropriate for standard therapy with platinum-based chemotherapy regimens. Emerging new therapeutic approaches and testing for appropriate patient selection for those are discussed in this article.

Bladder cancer (BC) is characterized by significant histopathologic and molecular heterogeneity. The discovery of molecular pathways and knowledge of cellular mechanisms have grown exponentially and may allow for better disease classification, prognostication, and development of novel and more efficacious noninvasive detection and surveillance strategies, as well as selection of therapeutic targets, which can be used in BC, particularly in a neoadjuvant or adjuvant setting. This article outlines recent advances in the molecular pathology of BC with a better understanding and deeper focus on the development and deployment of promising biomarkers and therapeutic avenues that may soon make a transition into the domain of precision medicine and clinical management for patients with BC.

The World Health Organization Classification (WHO) of Urinary and Male Genital Tumors has recently been updated to its 5th edition. The new edition presents a comprehensive approach to the classification of urinary and male genital tumors with an incorporation of morphologic, clinical, and genomic data.

This review aims to update the new classification of bladder cancer in the 5th edition and to highlight important changes in nomenclatures, diagnostic criteria, and molecular characterization, as compared to the 4th edition.

The pathologic classification of bladder cancer in the 5th edition of WHO Classification of Urinary and Male Genital Tumours was compared to that in the 4th edition. PubMed was searched using key words, including bladder cancer, WHO 1973, WHO 1998, WHO 2004, WHO 2016, histology, pathology, genomics, and molecular classification in the time frame from 1973 to August of 2022. Other relevant papers were also consulted, resulting in the selection of 81 papers as references.

The binary grading of papillary urothelial carcinoma (UC) is practical, but it may be oversimplified and contribute to "grade migration" in recent years. An arbitrary cutoff (5%) has been proposed for bladder cancers with mixed grades. The diagnosis of papillary urothelial neoplasm with low malignant potential has been dramatically reduced in recent years because of overlapping morphology and treatment with low-grade papillary UC. An inverted growth pattern should be distinguished from true (or destructive) stromal invasion in papillary UC. Several methods have been proposed for pT1 tumor substaging, but it is often challenging to substage pT1 tumors in small biopsy specimens. Bladder UC shows a high tendency for divergent differentiation, leading to several distinct histologic subtypes associated with an aggressive clinical behavior. Molecular classification based on the genomic analysis may be a useful tool in the stratification of patients for optimal treatment.

The 5th edition of WHO Classification of Urinary and Male Genital Tumours has made several significant changes in the classification of bladder cancer. It is important to be aware of these changes and to incorporate them into routine clinical practice.

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell-cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability.

A gain-of-function epigenetic switch that disrupts differentiation is triggered by inactivating KDM6A mutations in bladder cancer and can serve as a potential target for novel therapies.

This paper presents a case report of plasmacytoid variant urothelial carcinoma (PVUC), a rare form of transitional cell carcinoma. PVUC is known for its unique clinical features, aggressive behavior, and poor survival rates. PVUC comprises less than 3% of all bladder tumors, and its diagnosis is often difficult due to its resemblance to other forms of bladder cancer. It requires a staging workup to rule out metastasis, relies heavily on immunostaining and histopathological analysis for diagnosis, and requires a multidisciplinary approach with early aggressive treatment, including cisplatin-based chemotherapy following surgery. This report highlights the importance of understanding rare variants of bladder cancer to ensure timely and accurate diagnosis and appropriate treatment planning. We report here a case of a 75-year-old male with multiple comorbidities who presented with hematuria and was diagnosed with urothelial carcinoma plasmacytoid type, which was initially treated with transurethral resection but later found to be unresectable and treated with palliative chemotherapy and radiation therapy. Eventually, the patient passed away three years after the diagnosis.

Urothelial carcinoma (UC) is known to encompass a wide spectrum of morphologic features and molecular alterations. Approximately 15% to 25% of invasive UC exhibits histomorphologic features in the form of "divergent differentiation" along other epithelial lineages, or different "subtypes" of urothelial or sarcomatoid differentiation. It is recommended that the percentage of divergent differentiation and or subtype(s) be reported whenever possible. Recent advances in molecular biology have led to a better understanding of the molecular underpinning of these morphologic variations. In this review, we highlight histologic characteristics of the divergent differentiation and subtypes recognized by the latest version of WHO classification, with updates on their molecular and clinical features.

Bladder cancer is a heterogeneous disease, which exhibits a wide spectrum of clinical and pathologic features. Recent genomic studies have revealed that distinct molecular alterations may underlie the diverse clinical behaviors of bladder cancer, leading to a novel molecular classification. The intrinsic molecular subtypes exhibit distinct gene expression signatures and different clinicopathologic features. Genomic alterations also underlie the development of bladder cancer histologic subtypes. Genomic characterization provides new insights to understanding the biology of bladder cancer and improves the diagnosis and treatment of this complex disease. Biomarkers can aid the selection of patients for immune checkpoint therapy.

Non-urothelial bladder cancers make up a rare minority of all genitourinary (GU) tract histologic cancers since urothelial cancer (UC) makes up the most common histologic subtype. Bladder cancer variant histology (BCVH) or urothelial variants also occur rarely though distinction is important given aggressive presentation and natural history. While methods for diagnosis and treatment of typical urothelial cancers (UC) are well-established, there are no clear guidelines with regard to the diagnosis of non-urothelial bladder cancers, which often results in misdiagnosis and treatment delay. This review will focus on the clinicopathologic characteristics of the most common non-urothelial bladder cancers, to be distinguished from bladder cancer variant histology containing a UC component. The role of genomics in non-urothelial bladder cancers is evolving and the use of biomarkers to guide the diagnosis and treatment of these tumors remains a key area of unmet need. Treatment of these cancers will be discussed in a companion review.

Tissue-specific inactivation of E-cadherin combined with tumor suppressor loss leads to invasive and metastatic cancers in mice. While epidermal E-cadherin loss in mice induces squamous cell carcinomas, inactivation of E-cadherin in the mammary gland leads to invasive lobular carcinoma. To further explore the carcinogenic consequences of cell-cell adhesion loss in these compartments, we developed a new conditional mouse model inactivating E-cadherin (Cdh1) and p53 (Trp53) simultaneously in cells expressing the leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6), a putative epithelial stem cell marker in the skin and alveolar progenitor marker in the mammary gland. Compound Lgr6-CreERT2;Cdh1^F;Trp53^F female mice containing either heterozygous or homozygous Cdh1^F alleles were bred, and Lgr6-driven Cre expression was activated in pre-puberal mice using tamoxifen. We observed that 41% of the mice (16/39) developed mostly invasive squamous-type skin carcinomas, but also a non-lobular mammary tumor was formed. In contrast to previous K14cre or WAPcre E-cadherin and p53 compound models, no significant differences were detected in the tumor-free survival of Lgr6-CreERT2 heterozygous Cdh1^F/WT;Trp53^F/F versus homozygous Cdh1^F/F;Trp53^F/F mice (778 versus 754 days, p=0.5). One Cdh1^F homozygous mouse presented with lung metastasis that originated from a non-lobular and ERα negative invasive mammary gland carcinoma with squamous metaplasia. In total, 2/8 (25%) Cdh1^F heterozygous and 3/12 (25%) Cdh1^F homozygous mice developed metastases to lungs, liver, lymph nodes, or the gastro-intestinal tract. In conclusion, we show that inducible and conditional Lgr6-driven inactivation of E-cadherin and p53 in mice causes squamous cell carcinomas of the skin in approximately 40% of the mice and an occasional ductal-type mammary carcinoma after long latency periods.