Urothelial Carcinoma Of Urinary Bladder Research Articles

Temporal Trends and Cancer-Specific Mortality in Nonmetastatic Muscle-Invasive Urothelial Carcinoma of the Urinary Bladder Treated With Trimodal Therapy

IntroductionTrimodal therapy (TMT) is guideline-recommended for the management of organ confined urothelial carcinoma of urinary bladder (UCUB). However, temporal trends in TMT use and cancer-specific mortality free-survival (CSM-FS) between historical TMT versus contemporary TMT have not been assessed. We addressed this knowledge gap. Material and MethodsWithin the Surveillance, Epidemiology, and End Results database (2004–2020), we identified nonmetastatic UCUB patients with cT2-T4aN0-N2 treated with TMT, defined as the combination of transurethral resection of bladder tumor, chemotherapy and radiotherapy. Temporal trends described TMT use over time. Subsequently, patients were divided between historical (2004-2012) versus contemporary (2013-2020) cohorts. Survival analyses consisting of Kaplan–Meier plots and multivariable Cox regression (MCR) models addressed CSM-FS. Separate analyses addressed patients with organ confined (OC: cT2N0M0) versus nonorgan confined (NOC: cT3-4a and/or cN1-2) clinical stages. ResultsOf 4,097 assessable UCUB TMT patients, 1744 (43%) were treated in the historical period (2004-2012) versus 2353 (58%) in the contemporary period (2013-2020). TMT use increased over time in OC patients (EAPC:+3.4%, P < .001), as well as in NOC (EAPC:+2.7%, P < .001). In OC stage, median CSM-FS was 55.3% in historical versus 49.0% in contemporary patients (HR:0.75, P < .001). Similarly, in NOC stage, 5-year median CSM-FS was 43.0% in historical versus 32.8% in contemporary patients (HR:0.78, P = .01). ConclusionTMT rates have increased over time in both OC and NOC patients. Contemporary TMT patients benefit of better cancer-specific survival. Interestingly, this benefit applies equally to OC and NOC TMT-treated patients.

Immunohistochemical Expression of Claudin-1 and Claudin-4 in Urothelial Carcinoma of the Urinary Bladder.

In Egypt, bladder cancer occupies the second rankamong reported cancers in men. Claudins are tight junctions that have a critical role in tumor pathogenesis, invasion, progression, and metastasis and currentlyare a focus of interest for targeting therapies. We aimed to evaluatethe immunohistochemical expression of Claudin-1 and Claudin-4 in urinary bladder urothelial carcinoma and investigate the relationshipbetweenthe expressed Claudins with differentclinicopathological parameters. Claudin-1 and Claudin-4 immunohistochemical expression was studied in 62 cases of urinary bladder urothelial carcinomas. The cases were classified into two categories; low and high Claudin-1 and Claudin-4 expression. High Claudin-1 expression was detected in67.7% of the studied urothelial carcinomas while 32.3% showed low expression. Claudin-1 expression was reduced significantly with high tumor grade, non-papillary tumors, muscle invasion, schistosomal infestation, and perineural invasion (p-value < 0.05). Claudin-4 high expression was detected in 82.3% of our cases while low expression was detected in 17.7%. Claudin-4 reduced expression was significantly associated with non-papillary tumors, muscle invasion, advanced T stages, and associated lympho-vascular emboli (P-value < 0.05). According to the results ofthe present study, the reduced expressions of Claudin-1 and Claudin-4 provide clues concerning the progression of urothelial carcinoma. Consequently, it is thought that Claudin-1 and Claudin-4 could help to differentiatelow-grade from high-grade and muscle-invasive from non-muscle-invasive urothelial carcinomas. In addition, it can be introduced as a possible therapeutic target.

TGFB1I1 promotes cell proliferation and migration in urothelial carcinoma.

Urothelial carcinoma (UC) is common cancer worldwide with a high prevalence in Taiwan, especially in the upper urinary tract, including the renal pelvis and ureter, also classifying as upper urinary tract urothelial carcinoma. Here, we aim to find a representative prognostic marker that strongly correlates to this type of carcinoma. Transforming growth factor beta-1-induced transcript 1 (TGFB1I1) is a cofactor of cellular TGF-β1 and interacts with various nuclear receptors. The previous study showed that TGFB1I1 promotes focal adhesion formation, contributing to the epithelial-mesenchymal transition (EMT) with actin cytoskeleton and vimentin through TGFB1I1 regulation. We aim to reveal the role of TGFB1I1 in the tumorigenesis of UC. In silico and clinicopathological data of upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC) were accessed and analyzed for IHC staining regarding tumor characteristics, including survival outcome. Finally, an in vitro study was performed to demonstrate the biological changes of UC cells. In UTUC, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage, papillary configuration, and frequent mitosis. Meanwhile, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage and histological grade in UBUC. Moreover, the in vitro study shows that TGFB1I1 affects cell proliferation, viability, migration and wound healing. The EMT markers also decreased upon TGFB1I1 knockdown. In this study, we identified that TGFB1I1 regulates UC cell proliferation and viability and induces the EMT to facilitate cell migration in vitro, leading to its essential role in promoting tumor aggressiveness in both UTUC and UBUC.

Overexpression of fibroblast growth factor receptor 3 in urothelial carcinoma of urinary bladder among Iraqi patients and its correlation with different clinicopathological parameters

Overexpression of fibroblast growth factor receptor 3 in urothelial carcinoma of urinary bladder among Iraqi patients and its correlation with different clinicopathological parameters

Pulmonary tumor embolism secondary to urothelial carcinoma of urinary bladder: case report and literature review

BackgroundTumor embolism is the least well-described cause of pulmonary embolism, taking into account the non-specificity of radiographic and nuclear imaging results, the necessity of anatomopathological evidence and the frequency of deep venous thrombosis in the course of solid tumors, suggesting thus thromboembolism.Case presentationWe report a rare case of urothelial carcinoma of the urinary bladder associated with persistent pulmonary embolism despite being on different anticoagulation regimens, the patient was ultimately found to have tumor thrombus in the pulmonary trunk secondary to tumoral extension. We provide a literature review as well about the diagnosis, evaluation and prognosis and of this rare clinical entity.ConclusionsOur case highlights the importance of keeping this unusual etiology in mind, particularly when faced with pulmonary embolism occurring in the context of a solid tumor and the ineffectiveness of various anticoagulation protocols. Furthermore, it emphasizes the pivotal role of cytology in confirming diagnosis and guiding therapy.

Immunohistochemical expression of androgen receptors in urothelial carcinoma of urinary bladder. Is it significant? Experience from coastal India.

Bladder carcinoma (BC) ranks second among the genitourinary cancers worldwide. Influence of androgens and expression of androgen receptors in neoplasms are recent findings which were implicated in the development of BC. We aimed to study androgen receptor (AR) expression in bladder urothelial neoplasms and correlate its expression with grade and stage of the tumor. Immunohistochemistry (IHC) was done on samples collected in a tertiary care hospital over one year consisting of 71 urothelial BC and 20 non-neoplastic urothelial conditions. Two pathologists graded the IHC and nuclear staining was considered as positive expression. AR was expressed in 23.9% (17/71) of bladder urothelial neoplasms. AR was expressed in 25.7% and 22.3% of high and low-grade tumors and 25% and 22.3% of non muscle-invasive and muscle-invasive BC. AR expression had no significant correlation with gender, age (> 50 years), muscle invasion or grade. AR expression was significantly absent in non-neoplastic conditions (p = 0.018). AR has varied expression in BC and it is relatively lower in this study population.

Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer.

In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.

Artificial Intelligence to Predict the BRAF V595E Mutation in Canine Urinary Bladder Urothelial Carcinomas.

In dogs, the BRAF mutation (V595E) is common in bladder and prostate cancer and represents a specific diagnostic marker. Recent advantages in artificial intelligence (AI) offer new opportunities in the field of tumour marker detection. While AI histology studies have been conducted in humans to detect BRAF mutation in cancer, comparable studies in animals are lacking. In this study, we used commercially available AI histology software to predict BRAF mutation in whole slide images (WSI) of bladder urothelial carcinomas (UC) stained with haematoxylin and eosin (HE), based on a training (n = 81) and a validation set (n = 96). Among 96 WSI, 57 showed identical PCR and AI-based BRAF predictions, resulting in a sensitivity of 58% and a specificity of 63%. The sensitivity increased substantially to 89% when excluding small or poor-quality tissue sections. Test reliability depended on tumour differentiation (p < 0.01), presence of inflammation (p < 0.01), slide quality (p < 0.02) and sample size (p < 0.02). Based on a small subset of cases with available adjacent non-neoplastic urothelium, AI was able to distinguish malignant from benign epithelium. This is the first study to demonstrate the use of AI histology to predict BRAF mutation status in canine UC. Despite certain limitations, the results highlight the potential of AI in predicting molecular alterations in routine tissue sections.

Pathologic collision of urinary bladder urothelial carcinoma with small cell carcinoma: a case report

BackgroundUrothelial carcinoma is a major subtype of bladder cancer and small cell carcinoma (SCC) is a rare type of cancer in clinical practice. Pathologic collision of urinary bladder urothelial carcinoma with SCC is not common in clinical settings.Case presentationHere, we report a patient with high-grade papillary carcinoma which changed to collision tumor with SCC. The patient underwent radical cystectomy; however, neck and mediastinum lymph nodes metastases were detected 11 months after the operation. The lymph nodes were diagnosed pathologically as SCC. Chemoradiotherapy was subsequently prescribed. Unfortunately, this patient died of COVID-19 in early 2023.DiscussionWe hypothesized the mechanism underlying this pathological transformation. For patients with urothelial bladder cancer, pathological analysis should be conducted to allow standardized and persistent treatment. Moreover, drugs should be selected depending on the type of pathology, especially for patients who develop relapse, since collision tumor or other pathological tumors may be present.ConclusionsWe recommend that radical cystectomy be performed early enough for patients with non-muscle invasive bladder cancer, who are at a high risk of tumor recurrence. However, this conclusion needs to be validated in a larger number of patients.

Upregulation of dihydropyrimidinase-like 3 (DPYSL3) protein predicts poor prognosis in urothelial carcinoma

BackgroundDihydropyrimidinase-like 3 (DPYSL3) is a cytosolic phosphoprotein expressed in the nervous system and is crucial for neurogenesis. A previous study showed that increased DPYSL3 expression promotes tumour aggressiveness in pancreatic ductal adenocarcinoma, gastric cancer, and colon cancer. However, the role of DPYSL3 in affecting the biological behaviour of urothelial carcinoma (UC) is not yet understood.MethodsA UC transcriptomic dataset from the Gene Expression Omnibus and the Urothelial Bladder Cancer (BLCA) dataset from The Cancer Genome Atlas were used for the in silico study. We collected 340 upper urinary tract urothelial carcinoma (UTUC) and 295 urinary bladder urothelial carcinoma (UBUC) samples for the immunohistochemical study. Fresh tumour tissue from 50 patients was used to examine the DPYSL3 mRNA level. In addition, urothelial cell lines with and without DPYSL3 knockdown were used for the functional study.ResultsThe in silico study revealed that DPYSL3 correlated with advanced tumour stage and metastasis development while functioning primarily in the nucleobase-containing compound metabolic process (GO:0006139). DPYSL3 mRNA expression is significantly upregulated in advanced UC. Furthermore, overexpression of the DPYSL3 protein is significantly associated with the aggressive behaviour of UTUC and UBUC. DPYSL3 expression independently predicts disease-specific survival (DSS) and metastatic-free survival (MFS) in patients with UC. In non-muscle-invasive UBUC, DPYSL3 expression predicts local recurrence-free survival. UC cell lines with DPYSL3 knockdown exhibited decreased proliferation, migration, invasion, and human umbilical vein endothelial cells (HUVECs) tube formation but increased apoptosis and G1 arrest. Gene ontology enrichment analysis revealed that the enriched processes related to DPYSL3 overexpression in UC were tissue morphogenesis, cell mesenchyme migration, smooth muscle regulation, metabolic processes, and RNA processing. In vivo study revealed DPYSL3 knockdown in UC tumours significantly suppressed the growth of tumours and decreased MYC and GLUT1 protein expression.ConclusionsDPYSL3 promotes the aggressiveness of UC cells by changing their biological behaviours and is likely associated with cytoskeletal and metabolic process modifications. Furthermore, DPYSL3 protein overexpression in UC was associated with aggressive clinicopathological characteristics and independently predicted poor clinical outcomes. Therefore, DPYSL3 can be used as a novel therapeutic target for UC.

New Hydronephrosis in the Native Kidney Is Associated with the Development of De Novo Urinary Bladder Urothelial Carcinoma in Patients with Post-Kidney Transplantation.

Increased malignancy after kidney transplantation (KT) is by far the most troublesome issue. Among these malignancies, urothelial carcinoma (UC) incidence is uniquely high in Taiwan. We want to know whether routine sonography to detect native hydronephrosis is associated with the development of de novo urinary bladder urothelial carcinoma (UBUC) in post-KT recipients. From 2003 to 2018, we retrospectively analyzed 1005 KT patients, 58 of whom were subsequently diagnosed with UBUC. The association between new native hydronephrosis and post-KT UBUC was analyzed with univariate and multivariate logistic regression analyses and a Kaplan-Meier plot. We excluded cases of people who had upper urinary tract urothelial carcinoma (UTUC) and were diagnosed prior to UBUC. There were 612 males (60.9%) and 393 females (39.1%), with a mean age of 48.2 ± 12.0 years old at KT. The mean follow-up period was 118.6 ± 70.2 months, and the diagnosis of UBUC from KT to UBUC was 7.0 ± 5.1 years. New native kidney hydronephrosis occurred more frequently in the UBUC group (56.4% versus 6.4%, p < 0.001) than the non-UBUC group. Multivariate analysis disclosed that native hydronephrosis is the only statistically significant factor for UBUC, with an odds ratio of 16.03 (95% CI, 8.66-29.68; p < 0.001). UBUC in post-KT patients with native hydronephrosis also showed a tendency toward multifocal lesions upon presentation (47.8%). Post-KT UBUC is characterized by pathologically aggressive and multiple foci lesions. Native kidney hydronephrosis may be a deciding factor of post-KT UBUC.

Melatonin induces cell cycle arrest and suppresses tumor invasion in urinary bladder urothelial carcinoma.

Urinary bladder urothelial carcinoma (UBUC) encompasses about 90% of all bladder cancer cases, and the mainstream treatment is the transurethral resection of the bladder tumor followed by intravesical instillation. High rates of mortality, recurrence, and progression in bladder cancer have stimulated the search for alternative adjuvant therapies. The aim of this study was to investigate the potential of melatonin as adjuvant therapy in bladder cancer. Cell viability and clonogenic ability were assessed by an MTT assay and colony formation. Cell cycle and apoptosis analysis were performed by flow cytometry and Hoechst 33342 staining, while cell metastasis capacity was measured by wound healing and transwell assays. Potential mechanisms were investigated by an oncology array and verified via western blotting. The melatonin treatment significantly reduced T24 and UMUC3 bladder cancer cell proliferation and clonogenic ability. G1 arrest and sub-G1 accumulation in the T24 and UMUC3 cells led to cell proliferation suppression and cell death, and Hoechst 33342 staining further verified the apoptosis induction directly by melatonin. Moreover, melatonin weakened cell motility and invasiveness. Based on the oncology array results, we demonstrated that melatonin exerts its anti-cancer effect by down-regulating the HIF-1α and NF-κB pathways and downstream pathways, including Bcl-2, leading to cell cycle arrest and apoptosis induction in the UBUC cells. Overall, these findings support the potential of melatonin as adjuvant therapy in bladder cancer.

Correlation of urinary catheterization with histologic grading of eosinophilic cystitis: a single institutional review of 27 cases

Eosinophilic cystitis (EC) is an uncommon diagnosis, mimicking urothelial carcinoma. Multiple etiologies including iatrogenic, infectious, and neoplastic have been suggested, effecting both adults and pediatric population. A retrospective clinicopathologic review of patients with EC in our institution between 2003 and 2021 was conducted. Age, gender, presenting symptoms, cystoscopic findings, and history of urinary bladder instrumentation were recorded. Histologically, urothelial and stromal changes were noted, and mucosal eosinophilic infiltration was graded as mild (scattered eosinophils in the lamina propria), moderate (visible small clusters of eosinophils without brisk reactive changes), or severe (dense eosinophilic infiltrate with ulcer formation and/or muscularis propria infiltration). Twenty-seven patients (male to female ratio = 18/9, median age 58 [12–85 years]), of whom two were in the pediatric age group were identified. Leading presenting symptoms were hematuria (9/27, 33%), neurogenic bladder (8/27, 30%), and lower urinary tract symptoms (5/27, 18%). Four of 27 (15%) patients had history of urothelial carcinoma of urinary bladder. Cystoscopy commonly revealed erythematous mucosa (21/27, 78%) and/or urinary bladder mass (6/27, 22%). Seventeen of 27 (63%) of patients had history of long-term/frequent catheterization. Mild, moderate, and severe eosinophilic infiltrates were seen in 4/27 (15%), 9/27 (33%), and 14/27 (52%) of cases. Proliferative cystitis (19/27, 70%) and granulation tissue (15/27, 56%) were additional common findings. All cases of long-term/frequent instrumentation cases had moderate or severe eosinophilic infiltrate. EC should be in the differential diagnosis; particularly in patients with long term/frequent catheterization.

The autocrine glycosylated-GREM1 interacts with TGFB1 to suppress TGFβ/BMP/SMAD-mediated EMT partially by inhibiting MYL9 transactivation in urinary carcinoma.

Urothelial carcinoma (UC) is a common disease in developed counties. This study aimed to identify autocrine roles and signaling pathways of gremlin 1, DAN family BMP antagonist (GREM1), which inhibits tumor growth and epithelial-mesenchymal transition (EMT) in UC. Systematic in vitro and in vivo studies using genetic engineering, different urinary bladder urothelial carcinoma (UBUC)-derived cell lines, and mouse models were performed, respectively. Further, primary upper tract urothelial carcinoma (UTUC) and UBUC specimens were evaluated by immunohistochemistry. GREM1 protein levels conferred better disease-specific and metastasis-free survival rates and played an independent prognostic factor in UTUC and UBUC. Hypermethylation is the primary cause of low GREM1 levels. In different UBUC-derived cell lines, the autocrine/secreted and glycosylated GREM1 interacted with transforming growth factor beta 1 (TGFB1) and inhibited TGFβ/BMP/SMAD signaling and myosin light chain 9 (MYL9) transactivation, subsequently cell proliferation and epithelial-mesenchymal transition (EMT). Secreted and glycosylated GREM1 also suppressed tumor growth, metastasis, and MYL9 levels in the mouse model. Instead, cytosolic GREM1 promoted cell proliferation and EMT by activating the tumor necrosis factor (TNF)/AKT/nuclear factor kappa B (NFκB) axis. Clinical associations, animal models, and in vitro indications provided solid evidence to show that the epithelial autocrine GREM1 is a novel tumor suppressor in UCs. The glycosylated-GREM1 hampered cell proliferation, migration, invasion, and in vitro angiogenesis through interaction with TGFB1 to inactivate TGFβ/BMP/SMAD-mediated EMT in an autocrine manner.

Low expression of ZSCAN4 predicts unfavorable outcome in urothelial carcinoma of upper urinary tract and urinary bladder

BackgroundWith the advance in genome-wide analyses, genetic alternations have been found to play an important role in carcinogenesis and aggressiveness of UC. Through bioinformatic analysis of gene expression profiles of urinary bladder urothelial carcinoma (UBUC) from publicly available GEO dataset (GSE31684), Zinc finger and SCAN domain containing 4 (ZSCAN4) was identified as a significant downregulated gene in muscle-invasive bladder cancer when compared with non-muscle-invasive bladder cancer.MethodsThe expression of ZSCAN4 was evaluated by immunohistochemistry in 340 upper urinary tract urothelial carcinomas (UTUCs) and 295 UBUCs. The expression profiles of ZSCAN4 and potential signaling pathways were analyzed bioinformatically.ResultsIn UTUC, low expression of ZSCAN4 was significantly associated with advanced primary pT stage (P = 0.011), increased nodal metastasis (P = 0.002) and increased vascular invasion (P = 0.019). In UBUC, low expression of ZSCAN4 was significantly correlated with advanced primary pT stage (P < 0.001), increased nodal metastasis (P = 0.001), high histological grade (P = 0.003) and increased vascular invasion (P = 0.003). In survival analysis, low expression of ZSCAN4 acted as an independent negative prognostic factor for disease-specific survival and metastasis-free survival both in UTUC and UBUC. Gene ontology analysis showed that ZSCAN4 mRNA and its co-downregulated genes are associated with the mitotic cell cycle.ConclusionsLow expression of ZSCAN4 predicted worse outcome in urothelial carcinoma and might have potential regulatory role in cell mitosis.

The biological impacts of CEBPD on urothelial carcinoma development and progression.

Urothelial carcinoma (UC), which includes urinary bladder urothelial carcinoma (UBUC) and upper tract urothelial carcinoma (UTUC), is one of the most common malignancies worldwide. Accordingly, a comprehensive understanding of the underlying mechanism governing UC development is compulsory. Aberrant CCAAT/enhancer-binding protein delta (CEBPD), a transcription factor, displays an oncogene or tumor suppressor depending on tumor type and microenvironments. However, CEBPD has been reported to possess a clear oncogenic function in UC through multiple regulation pathways. Genomic amplification of CEBPD triggered by MYC-driven genome instability is frequently examined in UC that drives CEBPD overexpression. Upregulated CEBPD transcriptionally suppresses FBXW7 to stabilize MYC protein and further induces hexokinase II (HK2)-related aerobic glycolysis that fuels cell growth. Apart from the MYC-dependent pathway, CEBPD also downregulates the level of hsa-miR-429 to enhance HK2-associated glycolysis and induce angiogenesis driven by vascular endothelial growth factor A (VEGFA). Additionally, aggressive UC is attributed to the tumor metastasis regulated by CEBPD-induced matrix metalloproteinase-2 (MMP2) overexpression. Furthermore, elevated CEBPD induced by cisplatin (CDDP) is identified to have dual functions, namely, CDDP-induced chemotherapy resistance or drive CDDP-induced antitumorigenesis. Given that the role of CEBPD in UC is getting clear but pending a more systemic reappraisal, this review aimed to comprehensively discuss the underlying mechanism of CEBPD in UC tumorigenesis.

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.

Expression of EZH2 and H3K27me3 predicts tumor biology of urothelial carcinoma.

Enhancer of zeste homolog 2 (EZH2) is one of the major epigenetic modifiers involved in the transcriptional repression of target genes through trimethylation of H3K27 (lysine 27 residue of histone H3). Deregulated expression of both EZH2 and H3K27me3 has been implicated in the biological behavior and prognostic outcome of various malignancies. To assess the role of EZH2 and H3K27me3 in the carcinogenesis of urothelial carcinoma of urinary bladder. One hundred fifty consecutive urothelial carcinoma cases of urinary bladder (54.7% high-grade) were included in this study. Immunohistochemical analysis for EZH2 and H3K27me3 was performed on whole tissue sections. A multiplication score obtained by multiplying staining intensity and proportion of positively stained neoplastic cells was used for assessment. EZH2 showed a significant correlation with the tumor grade and lamina propria invasion (p < 0.001). The cases with high EZH2 expression showed a significantly high proliferative index (Mean- 32.7%; p < 0.001). In contrast, negative and low expression of H3K27me3 was significantly more common in high-grade cases (p = 0.006). The expression of H3K27me3 was significantly associated with lamina propria (p = 0.01) and deep muscle invasion (p = 0.007). EZH2 showed a significantly higher expression in the high-grade invasive areas as compared to the high-grade non-invasive areas of the same tumor (p = 0.03). This study establishes an important role of the key epigenetic regulators EZH2 and H3K27me3 in the pathobiology of urothelial carcinomas. Strong expression of EZH2 and weak expression of H3K27me3 are associated with higher grade, proliferative index and invasive behavior.

Immunohistochemical expression of CXCL5 as a valuable prognostic marker in urinary bladder urothelial carcinoma

Abstract Background and aim Urothelial carcinoma (UC) is the most common histologic subtype of bladder carcinoma. Detection of novel biomarkers that could predict UC progression and prognosis represents an active focus of research in the oncology field. CXCL5 is a member of the CXC chemokine family. It has been implicated in progression of many cancers, but its prognostic value in UC remains unclear. This study aimed to evaluate the immunohistochemical expression of CXCL5 in noninvasive and invasive UC of the urinary bladder and to correlate its expression with different studied clinicopathological characteristics to evaluate its potential prognostic value. Patients and methods A total of 60 specimens of primary invasive and noninvasive urothelial bladder carcinomas were included in this study. Paraffin-embedded tissue blocks were prepared from the specimens. Two serial tissue sections were obtained from each specimen. One tissue section was stained by hematoxylin and eosin stain and examined to confirm diagnosis, histologic subtype, tumor grade, muscle invasion, and presence or absence of bilharzial infestation, and the second tissue section was subjected to immunohistochemical using anti-human CXCL5 antibody. Results Studying the association between CXCL5 expression and different clinicopathologic parameters in urothelial bladder carcinoma revealed a statistically significant correlation between its expression and poor prognostic indicators. CXCL5 expression is significantly correlated with poorly differentiated (P=0.025), advanced stage (P=0.039), and invasive tumors (P=0.002). Conclusion The current study revealed that CXCL5 overexpression in urothelial bladder carcinoma is strongly associated with adverse prognostic factors. CXCL5 might be considered as a reliable biomarker in predicting tumor progression and poor prognosis.

Prognostic significance of minor high grade component in non-invasive papillary urothelial carcinoma of urinary bladder: (A study of 273 consecutive cases over a period of 3 years)

PurposeOur study aimed to determine the prognostic significance of minor high-grade components (HGC) in non-invasive papillary urothelial carcinomas compared with pure low-grade and high-grade tumors. Material and methodsWe retrospectively retrieved 273 in-house cases of non-invasive papillary urothelial carcinomas (pTa) from 2016 to 2018 for which follow up data was available in hospital archives. We stratified our data into four main groups (G). G1, pure low-grade (n = 164); G2, HGC ≤5 % (n = 17); G3, HGC >5 % to ≤25 % (n = 14); and G4, pure high-grade (n = 78). Prognosis was assessed in terms of recurrence, grade and stage of progression, metastasis, and death. The mean follow up duration was 34.72 ± 20 months (range 20–60 months). ResultsAll four groups showed no difference in tumor recurrence (G1 81.7 %, G2 88.2 %, G3 92.9 %, G4 92.3 % p-value 0.183). In terms of grade progression, there was no significant difference in G2 35.3 % and G3 35.7 % and both groups showed worst prognosis compared to G1 16.5 % p-value 0.04. Regarding stage progression (G1 6.7 %, G2 23.5 %, G3 28.6 %, G4 41% p-value 0.001), metastasis (G1 5.5 %, G2 5.9 %, G3 7.1 %, G4 17.9 % p-value 0.01) and death (G1 4.3 %, G2 5.9 %, G3 7.1 %, G4 15.4 % p-value 0.02) there was no significant difference in G2 and G3 and both groups showed worst prognosis than G1 and better than G4. ConclusionUrothelial carcinomas with minor high-grade component ≤25 % behaved worst than pure low grade and better than pure high grade and should be treated as distinct grade entity.