Figure 5 - uploaded by Liang Cheng
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Paradoxical differentiation in pT1 urothelial carcinoma. The invasive tumor cells often acquire abundant eosinophilic cytoplasm and appear to be more differentiated than overlying noninvasive tumor cells.
Source publication
Significant progress has been made in the standardization of bladder neoplasm classification and reporting. Accurate staging using the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) TNM system is essential for patient management, and has been reinforced by clinical evidence in recent years. It is now recognized th...
Contexts in source publication
Context 1
... some cases, particularly in microinvasive carcinoma, the invasive tumor cells acquire abundant eosinophilic cytoplasm. At low to medium power magnification, these microinvasive cancer cells appear to be more differentiated than the overlying noninvasive tumor cells, a feature known as paradoxical differentiation ( Figure 5). ...
Context 2
... pT3 bladder carcinoma is defined by tumor invasion into perivesical soft tissue ( Figure 15). The presence of intramural adipose tissue is well documented in the bladder. ...
Similar publications
Background: Urinary bladder lesions are a great health concern as it lies among the top ten most common cancers in the world. These range from benign, harmless lesions that do not recur to life threatening tumors. The present study was undertaken to study incidence of various urothelial cancer in patients undergoing transurethral resection of bladd...
Citations
... These include squamous cell carcinoma, papillary cell carcinoma, and adenocarcinoma, among others. The presence of squamous cell carcinoma and adenocarcinoma, while less common, is notable and aligns with literature indicating their association with specific risk factors and potentially different clinical courses compared to urothelial carcinoma [70]. Papillary cell carcinoma, often considered a subset of urothelial carcinoma, is recognized for its distinct growth patterns and potentially more favorable prognosis when identified early [71]. ...
... Te gold standard for diagnosing bladder cancer is cystoscopic transurethral lesion resection. Te gathered tissue samples enable pathological staging, and the tumor grade guides the treatment modalities [6]. However, this procedure is expensive, invasive, and not particularly comfortable. ...
Objective. This prospective study aimed to explore the potential diagnostic value of endocan levels in bladder cancer by investigating a possible association of serum and urine endocan levels with the stage and grade of bladder tumors in patients with nonmuscle-invasive bladder cancer (NMIBC) in terms of risk stratification. Materials and Methods. Participants included 66 male patients with NMIBC. Patients with full pathology results, NMIBC stage T1, and healthy controls were categorized as groups 1, 2, and 3, respectively. Patients were further classified into high- and low-grade groups following their pathology results. Risk classification according to the European Association of Urology (EAU) was assigned to patients with NMIBC, and associations of risk groups with serum and urine endocan levels were analyzed. An enzyme-linked immunosorbent assay was used to identify serum and urine endocan concentrations. Results. Serum endocan levels according to pathological staging were significantly higher in groups 1 and 2 than in group 3. The urine endocan level was statistically significantly higher in group 2 than in group 3 p<0.001. The predictive power of the urine endocan level was evaluated for its ability to predict T1 disease, revealing an area under the curve of 0.735 and a threshold of 903. The EAU classification was evaluated according to risk groups, and the urine endpoint was statistically significantly higher in the univariate analysis for the high and very high-risk groups p=0.034. Conclusion. Our results indicate that endocan levels hold significant promise in prognostic feature evaluation in NMIBC, particularly in the context of screening patients with hematuria.
... Furthermore, Bree KK et al. suggest that regardless of the stage, all high-grade BCa should be regarded as the high-risk group of NMIBC, based on the analysis of the risk of disease progression following BCG immunotherapy [13]. The tumor differentiation grade has been shown by several studies to be a stage-independent prognostic factor in NMIBC [14]. Therefore, with respect to sex, we decided to differentiate our NMIBC cohort into high-versus low-grade bladder tumors. ...
Sex-specific discrepancies in bladder cancer (BCa) are reported, and new studies imply that microbiome may partially explain the diversity. We aim to provide characterization of the bladder microbiome in both sexes diagnosed with non-muscle-invasive BCa with specific insight into cancer grade. In our study, 16S rRNA next-generation sequencing was performed on midstream urine, bladder tumor sample, and healthy-appearing bladder mucosa. Bacterial DNA was isolated using QIAamp Viral RNA Mini Kit. Metagenomic analysis was performed using hypervariable fragments of the 16S rRNA gene on Ion Torrent Personal Genome Machine platform. Of 41 sample triplets, 2153 taxa were discovered: 1739 in tumor samples, 1801 in healthy-appearing bladder mucosa and 1370 in midstream urine. Women were found to have smaller taxa richness in Chao1 index than men (p = 0.03). In comparison to low-grade tumors, patients with high-grade lesions had lower bacterial diversity and richness in urine. Significant differences between sexes in relative abundance of communities at family level were only observed in high-grade tumors.
... Its tumorgenicity can be presented by 70%-75% of non-muscle-invasive bladder cancer (NMIBC) and 30% of the muscle-invasive bladder (MIBC). MIBC has a high mortality rate compared to NIMBC as it has a limited metastatic disease potential, though it depicts a high recurrence rate (Cheng et al., 2009;Lavallee et al., 2021;Huang et al., 2022). ...
Non-coding ribonucleic acids (ncRNAs) have been recently shown to contribute to tumorigenesis by mediating changes in metabolism. ncRNAs act as key molecules in metabolic pathways regulation. The dysregulation of ncRNAs during cancer progression contributes to altered metabolic phenotypes leading to reprogrammed metabolism. Since ncRNAs affect different tumor processes by regulating mitochondrial dynamics and metabolism, in the future ncRNAs can be exploited in disease detection, diagnosis, treatment, and resistance. The purpose of this review is to highlight the role of ncRNAs in mitochondrial metabolic reprogramming and to relate their therapeutic potential in the management of genitourinary cancer.
... Growth arrest and a variety of hormones, for example dexamethasone and insulin, are established means of inducing adipogenic differentiation of adipocyte precursors in vitro (26). Despite the abundant presence of tumor-infiltrating adipose tissue in bladder tumors (27,28), the influence of ADSCs within the TME on the development of erdafitinib resistance has not been explicitly investigated in urothelial cancer. In this study, we sought to investigate whether adipocyte precursors can induce erdafitinib resistance in bladder cancer cell lines, and whether these cells can be specifically targeted by rational combination therapies. ...
Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor, which has recently been approved by the FDA for mUC with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops. Here, we found that adipocyte precursors promoted resistance to erdafitinib in FGFR-dependent bladder and lung cancer in a paracrine manner. Moreover, neuregulin 1 (NRG1) secreted from adipocyte precursors was a mediator of erdafitinib resistance by activating human epidermal growth factor receptor 3 (ERBB3; also known as HER3) signaling, and knockdown of NRG1 in adipocyte precursors abrogated the conferred paracrine resistance. NRG1 expression was significantly downregulated in terminally differentiated adipocytes compared with their progenitors. Pharmacologic inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies.
Significance
Acquired resistance to FGFR inhibition can be rapidly promoted by paracrine activation of the NRG1/HER3 axis mediated by adipocyte precursors and can be overcome by the combination of pertuzumab and erdafitinib treatment.
See related commentary by Kolonin and Anastassiou, p. 648
... A cohort of one hundred and eighty-six patients was enrolled in the Urology OPD at Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), India and King George's Medical University (KGMU), The excised tissue samples were fixed in formalin and then embedded in paraffin to prepare tissue blocks at the Department of Pathology. The histopathological classification of bladder tumors was done by two pathologists independently according to the standard WHO-ISUP (World Health Organization-International Society of Urologic Pathology) 2004 classification system [16]. Extent of invasion of tumor mass into the lamina propria/muscularis propria forms the basis of determination of pathological tumor stage. ...
... Quantification of invasive capacity of T24 cells showed that cells invaded towards the FBS-medium but not the FBS-free medium ( Supplementary Fig. 14c). Presence of muscle cells in matrigel resulted in collective cell migration in contrast to the single cell migration into cell-free matrigel, reflected as shorter mean distances from the start line (Fig. 6b, c), in agreement with prior studies, which showed metastasis to muscle is rare 58 and the migration of bladder cancer cells into the muscle occurs in a collective invasion mode [59][60][61] . Upon comparing the 10% FBS microenvironment across different conditions, compared to control siRNA, we identified significantly less invasion for FRA1 single and FRA1-FLI1 double knock-down conditions. ...
Bladder cancer is mostly present in the form of urothelium carcinoma, causing over 150,000 deaths each year. Its histopathological classification as muscle invasive (MIBC) and non-muscle invasive (NMIBC) is the most prominent aspect, affecting the prognosis and progression of this disease. In this study, we defined the active regulatory landscape of MIBC and NMIBC cell lines using H3K27ac ChIP-seq and used an integrative approach to combine our findings with existing data. Our analysis revealed FRA1 and FLI1 as two critical transcription factors differentially regulating MIBC regulatory landscape. We show that FRA1 and FLI1 regulate the genes involved in epithelial cell migration and cell junction organization. Knock-down of FRA1 and FLI1 in MIBC revealed the downregulation of several EMT-related genes such as MAP4K4 and FLOT1. Further, ChIP-SICAP performed for FRA1 and FLI1 enabled us to infer chromatin binding partners of these transcription factors and link this information with their target genes. Finally, we show that knock-down of FRA1 and FLI1 result in significant reduction of invasion capacity of MIBC cells towards muscle microenvironment using IC-CHIP assays. Our results collectively highlight the role of these transcription factors in selection and design of targeted options for treatment of MIBC.
... Matched tumor sections of UCB and BPH patients were obtained from formalin fixed and paraffin embedded blocks at the Department of Pathology, SGPGIMS, India. Pathologists independently diagnosed and histopathologically classified bladder tumors according to the WHO-ISUP 2004 system of classification[15]. Pathological stage was determined based on the extent of invasion of tumor mass into the lamina propria/muscularis propria and tumor grade was identified according to cell architecture, cohesiveness, polarity, and thickness. ...
Background:
Diagnostic and prognostic significance of epithelial-to-mesenchymal transition (EMT) associated biomarkers are evaluated in a cohort of NMIBC (non-muscle invasive bladder cancer) and MIBC (muscle invasive bladder cancer) patients.
Methods and results:
Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) staining were carried out in 100 tumor specimens (59 NMIBC and 41 MIBC). The expressions of the epithelial marker, mesenchymal markers and EMT-activating transcription factors (EMT-ATFs) were determined at transcriptome and protein level followed by their statistical associations with clinicohistopathological variables of the patients. Transcriptomic expression analysis showed statistical relevance of tumor stage with increased Twist and Zeb-1; tumor type with reduced E-cadherin and increased Snail; and smoking/tobacco chewing status (S/TC) of patients with increased N-cadherin and Snail in NMIBC patients. Tumor grade with reduced message E-cadherin, gain of N-cadherin, Snail, Twist and Zeb-1; patients' age with reduced E-cadherin and Twist gain; and tumor type with increased message N-cadherin exhibited associations in MIBC patients. Protein expression analysis identified statistical relevance of tumor grade with nuclear gain of Snail and Twist; and nuclear gain of Slug with S/TC status of NMIBC patients. Novel gain of membranous Vimentin deduced association with patients' age in MIBC patients. Survival analysis identified novel Vimentin as the positive predictor of short progression free survival (PFS) and short overall survival (OS) in MIBC patients. Study established altered EMT profile as the independent negative predictor of short recurrence free survival (RFS) in NMIBC patients and positive predictor of short PFS and OS in MIBC patients.
Conclusions:
EMT associated biomarkers could provide diagnostic and prognostic risk stratification and hence could be of importance in the clinical management of bladder cancer patients.
... Review of the gross descriptions within the pathology reports identified 65 of 147 cases with no residual gross tumor. A total of 82 of 147 cases showed gross tumor, and of these, the mean number of initial blocks of gross lesion submitted was 6.5 (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Additional sections of gross lesion were submitted for five cases, and these five cases were finalized as ypT0 (one case), ypTis (two cases), ypT2 (one case), and ypT4 (one case). ...
... 12 Multiple other protocols and proposals have been published in the literature, but to our knowledge, none specify the approach to gross examination for specimens after neoadjuvant therapy. [13][14][15] Similar issues have arisen in the management of colorectal, lung, and breast carcinomas with the increased use of NAC and radiotherapy. Based on available literature, the grossing protocols for non-NAC breast, colorectal, and lung specimens call for similar or slightly fewer blocks than NAC cases. ...
Objectives:
Neoadjuvant chemotherapy (NAC) confers a survival advantage for muscle-invasive bladder cancer and is now recommended for chemotherapy-eligible patients. NAC may result in absent gross tumor, and current cystectomy gross examination protocols do not specify approach for these cases.
Methods:
We included cystectomies performed from 2010 to 2018, capturing a period pre- and post-NAC recommendations. Gross descriptions were reviewed and slides of patients who received NAC were evaluated for microscopic tumor, number of blocks with tumor, and location of those blocks.
Results:
We identified 239 radical cystectomies for bladder cancer (147 NAC, 92 non-NAC). Gross lesions were not identified for 91 cases. NAC cases had more total blocks submitted (mean, 17.5) compared with non-NAC cases (mean, 16.6). More NAC cases had additional blocks submitted (20 cases) compared with non-NAC cases (2), which were more frequently additional random sections. Of 108 NAC cases with residual carcinoma, only 2 (1.9%) were upstaged on additional random sections.
Conclusions:
At our institution, NAC and non-NAC cases are grossed with similar numbers of initial blocks; however, NAC cases are more likely to submit additional sections of gross lesions and random bladder without significant changes in stage. Our data suggest current gross examination protocols are sufficient for NAC cystectomies.
... UCC is a heterogeneous disease with multiple possible treatment options, ranging from surveillance through to transurethral procedures or radical cystectomy with neoadjuvant or adjuvant chemotherapy [10]. As radical cystectomy is associated with a high risk of developing perioperative complications (including death), proper patient qualification via accurate preoperative staging is crucial. ...
Background:
A significant number of patients with advanced urothelial cell carcinoma are under- or over-staged. Implementation of clinical variables could be useful for improving the accuracy of clinical staging.
Aim:
To explore the differences between clinical and pathological diagnosis in patients with UCC, and to identify clinical variables that might play a role in under- or overstating.
Materials:
A total of 553 patients after radical cystectomy were included in the analysis. Clinical stage of the disease was diagnosed according to CT or MRI in relation to clinical data.
Results:
Higher clinical stage correlated with a higher pathological stage (p < 0.00005), but in 306 patients did not correspond (142 patients were under-staged and 164 over-staged). Over half (54.2%) of the patients staged as cT1-cT2 were misdiagnosed: 137 patients were under-staged and 133 over-staged. Hydronephrosis was associated with a higher pathological stage (p < 0.000005), mostly pT3-4 (45.13% had pT4 disease) and higher risk of nodal metastasis (p = 0.0028). The highest percentage of PSM was found in patients with pT4 (33.12%).
Conclusions:
Clinical staging of bladder cancer is poorly executed, with one third of patients under-staged and one third over-staged. To improve accuracy, we recommend a multimodal approach, combining histopathological evaluation with results of imaging studies.
