Noninvasive Urothelial Carcinoma Research Articles

Abstract 6450: High mobility group protein 2 (HMGA2) is highly expressed in a broad range of human cancers

Abstract The high mobility group protein 2 (HMGA2) is an essential component of the enhanceosome. It can attach to AT-rich binding sites in the DNA minor groove, affect the conformation of the DNA, and thereby modify the transcription of numerous genes. HMGA2 is preferentially expressed during organogenesis. Aberrant expression of HMGA2 in adult tissues is commonly associated with tumor formation and cancer aggressiveness. Accordingly, HMGA2 represents a potential drug target. To better comprehend the role of HMGA2 expression in cancer, a tissue microarray containing 8,344 samples from 115 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, a strong nuclear HMGA2 staining was limited to few cell types from the amnion, placenta, seminal vesicle, endocervix, fallopian tube, and respiratory epithelium. HMGA2 expression was generally markedly higher in cancer than in corresponding normal tissues. HMGA2 staining was found in 2,695 (42.7%) of the 6,313 interpretable tumor samples, including 701 (11.1%) with weak, 769 (12.2%) with moderate, and 1,225 (19.4%) with strong positivity. A total of 93 of 115 tumor categories showed HMGA2 expression in at least one case, and 69 tumor categories included at least one case with strong HMGA2 staining. The frequency of HMGA2 positivity was particularly high in cancers of the ovary and the endometrium (52.6-92.6%), pancreatico-biliary cancers (48.1-75.5%), thyroidal neoplasms (53.4-95%), salivary gland neoplasms (66.7-98%), nonseminomatous testicular germ cell tumors (73.5-93.5%), colorectal adenocarcinoma (81.6%), papillary renal cell carcinoma (68.2%), and in squamous cell carcinomas (36-81.5%). Tumor entities with a particularly low expression of HMGA2 included prostatic adenocarcinomas (1.3-4%), non-invasive urothelial carcinomas (1.8-4.3%), hepatocellular carcinoma (3.2%), and non-Hodgkin’s lymphomas (0%) It is concluded, that HMGA2 is highly expressed in a very broad range of tumor entities. These findings emphasize a potential role of HMGA2 as a drug target and demonstrate utility for HMGA2 IHC for the distinction of neoplastic from non-neoplastic tissues in several organs. Citation Format: Katharina Möller, Florian Lutz, Florian Viehweger, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Guido Sauter, Andreas H. Marx, Ronald Simon, Till Krech, Stefan Steurer, Christoph Fraune, Sarah Minner, Natalia Gorbokon, Maximilian Lennartz, Eike Burandt, Anne Menz. High mobility group protein 2 (HMGA2) is highly expressed in a broad range of human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6450.

Abstract 6449: KDM6A expression loss is a common feature in low grade non-invasive urothelial carcinomas of the urinary bladder

Abstract KDM6A, also known as UTX (ubiquitously transcribed X chromosome tetratricopeptide repeat protein) is an epigenetic regulator which is frequently mutated in urothelial carcinoma. Because KDM6A loss causes a dependency on EZH2, a potential therapeutic target, KDM6A analysis may have therapeutic importance. Most data on KDM6A mutations are derived from next generation sequencing (NGS). However, because of the combination of a high rate of truncating KDM6A mutations, the localization of KDM6A on chromosome Xp11.3, and the male predominance in bladder cancer, many KDM6A mutations should result in a complete loss of KDM6A protein expression and become detectable by immunohistochemistry (IHC). To study the prevalence and the potential diagnostic and clinical role of KDM6A expression loss, more than 2,100 tumors were analyzed by IHC in a tissue microarray format. The cohort included 1,128 patients who underwent radical cystectomy for muscle-invasive disease (pT2-4). A complete KDM6A expression loss occurred in 36% of 350 pTa G2 low-grade, 23% of 152 pTa G2 high-grade, and 18.5% of 92 pTa G3 tumors (p=0.0002). As compared to pTa G3 tumors, the frequency of KDM6A expression loss did not differ significantly in pT2 (17.2%), pT3 (21.9%), and pT4 (18.2%) cancers. Within pT2-4 carcinomas, KDM6A staining was unrelated to pT, pN, grade, L-status, V-status, overall survival, recurrence-free survival, and cancer-specific survival (p≥0.18 each). A KDM6A loss was more common in male (22.2%) than in female patients (15.4%; p<0,0001), and within male patients, a KDM6A loss was more frequent in tumors with Y-chromosome loss (36.1%) than in cancers without a Y-chromosome loss (16.3%; p<0.0001). KDM6A expression loss was significantly associated with increased p63 expression (p<0.0001) and high uroplakin 1b staining (p=0.0013) but unrelated to CK20, GATA3, UpK1b, and p53 staining. In summary, our data demonstrate that truncating KDM6A mutations occur in a significant subset of urothelial carcinomas which is linked to low-grade non-invasive cancer, male gender and loss of the Y chromosome. The predominance of KDM6A loss in low grade tumors makes KDM6A IHC a promising new tool for identification of low grade dysplasia in biopsies and early bladder cancer detection in cytology. Citation Format: Florian Viehweger, Natalia Gorbokon, Henning Plage, Sebastian Hofbauer, Kira Furlano, Sarah Weinberger, Bernhard Ralla, Antonia Franz, Annika Fendler, Michela de Martino, Florian Roßner, Simon Schallenberg, Sefer Elezkurtaj, Maximilian Lennartz, Tim Mandelkow, Elena Bady, Andreas H. Marx, Henrik Samtleben, Margit Fisch, Michael Rink, Marcin Slojewski, Krystian Kaczmarek, Thorsten Ecke, Stefan Koch, Nico Adamini, Ronald Simon, Guido Sauter, Joachim Weischenfeldt, Tobias Klatte, Thorsten Schlomm, David Horst, Henrik Zecha, Martina Kluth, Sarah Minner. KDM6A expression loss is a common feature in low grade non-invasive urothelial carcinomas of the urinary bladder [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6449.

Spectrum of Lesions in the Urinary Bladder: A Histopathological Study in a Tertiary Level Hospital

Background: Urinary Bladder cancer is the 7th most common cancer worldwide, with an estimated 260,000 new cases occurring each year in men and 76,000 in women. 90% of the bladder tumors are of urothelial origin. Cystoscopic examination has a limited role in staging process for which transurethral resection (TURBT) of visible tumor down to the base is required which can accurately assess depth of tumor invasion. Aim & Objectives: The aim is to study the spectrum of urinary bladder lesions according to World Health Organization / International Society of Urological Pathology consensus classification and to determine age and sex distribution of urothelial tumors. Material & Method: Study included 55 TURBT specimens, conducted over a period 12 months, extending from January 2022 to December 2022. Hematoxylin & Eosin (H&E) stained sections were examined for morphologic diagnosis of urothelial lesions. Results: In our study, there was male preponderance with ratio of 3.2:1. Among 55 cases studied, 34.55% cases were diagnosed as invasive urothelial carcinoma, 27.27% cases were of non-invasive urothelial carcinoma, 16.36% cases were of benign urothelial neoplasm and 16.36% cases were of non-neoplastic lesions in urinary bladder. There were also 1.82% cases of adenocarcinoma, metastasis and non-diagnostic each in our study. Amongst invasive carcinoma high grade were encountered most (30.91%) cases. Maximum numbers of urothelial neoplasms (25.45%) were seen in 71-80 years of age group. Conclusion: This study revealed that neoplastic lesions are more common than non-neoplastic lesions. Urothelial tumors are seen commonly in seventh decade with overall male predominance. Also this study, documents a high frequency of invasive than non-invasive type of urothelial neoplasm.

Role of GATA3 in Early-Stage Urothelial Bladder Carcinoma Local Recurrence.

Background One of the most characteristic features of non-invasive urothelial carcinoma (UC) is its high recurrence rate. Guanine-adenine-thymine-adenine nucleotide sequence-binding protein 3 (GATA3), as a transcription factor, correlates with urothelial differentiation and has been reported with poor prognosis in high-grade UC and recurrence in breast malignancies. As such, we set out to study the specifics of GATA3 in non-invasive UC, emphasizing on prediction for recurrence. Methods The cohort comprised 163 patients, with a follow-up period of five years, including 109 pTa cases and 54 pT1 cases. Immunohistochemical expression of GATA3 was assessed using a histo score (H-score). Kaplan-Meier test was conducted for the time to recurrence, according to the level of expression of GATA3 and the indicators studied. Receiver operating characteristic (ROC) curve analysis was done to determine the role of accuracy and specificity of predictability of the indicators. Results Recurrence within the follow-up period was noted in 41.72% of cases. No recurrence relationship was established for age and gender. GATA3 expression showed a varying H-score. Using ROC curve analysis, a cut-off value of 155 divided UC expression levels into low and high, with a sensitivity of 72.7% and specificity of 78.7% (area under the curve=0.800, 95% confidence interval: 0.696-0.904, p<0.001), further showing an association between high levels of nuclear expression and risk of local recurrence (p<0.0001). Conclusion Herein we have described the sensitivity of high GATA3 expression in non-invasive UC of the urinary bladder and its relation to local recurrence, independent of gender, age, tumor differentiation, and stage.

Diagnostic and Prognostic Roles of GATA3 Immunohistochemistry in Urothelial Carcinoma.

This study aimed to evaluate the diagnostic and prognostic roles of GATA-binding protein 3 (GATA3) immunohistochemistry in urothelial carcinoma (UC) using a meta-analysis. We investigated GATA3 immunohistochemical expression rates and performed a subgroup analysis based on tumor site, study location, and histological subtypes. The overall survival rates of patients with GATA3-positive and -negative UC were compared. The estimated GATA3 expression rate was 0.748 (95% confidence interval [CI]: 0.704-0.787). GATA3 expression rates in the urinary bladder and urinary tract were 0.775 (95% CI: 0.727-0.818) and 0.614 (95% CI: 0.426-0.774), respectively. The GATA3 expression rates of noninvasive and invasive UCs were 0.965 (95% CI: 0.938-0.980) and 0.644 (95% CI: 0.581-0.702), respectively. In invasive UCs, there was a significant difference in GATA3 expression between non-muscular invasion and muscular invasion subgroups (0.937, 95% CI: 0.883-0.967 vs. 0.753, 95% CI: 0.645-0.836). GATA3 expression was the highest in the microcytic subtype among the histologic subtypes (0.952, 95% CI: 0.724-0.993). There was a significant correlation between GATA3 expression and better prognosis (hazard ratio: 0.402, 95% CI: 0.311-0.521). Taken together, GATA3 expression significantly correlated with low-stage and better prognosis in UC. GATA3 expression is highly variable across histological subtypes, and one should be careful while interpreting GATA3 expression.

URINARY CARCINOMA IN YOUNG PATIENTS: A RARE CASE SERIES AND LITERATURE REVIEW

Urinary bladder carcinoma is mostly prevalent above the age of 40. It is more common in males. Here, we report a case series of young males with urinary bladder carcinoma. Urinary bladder mass was confirmed by ultrasonogram. Cystoscopic evaluation was done followed by endoscopic resection in the same setting. On histopathology it was found to be low grade noninvasive urothelial carcinoma.

Urothelial Cancer: A Case Report of Macroscopic Hematuria

A 67 year - old male patient with painless macroscopic haematuria of 3 weeks of evolution being his only symptom. Auxiliary laboratory exams were non-conclusive. In the histopathological study of the lesion, renal pelvis with scant epithelium with atypia consistent with low-grade non-invasive urothelial carcinoma. The patient underwent a right nephroureterectomy as treatment for his condition.

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer. Working Group 2: Grading of Mixed Grade, Invasive Urothelial Carcinoma Including Histologic Subtypes and Divergent Differentiations, and Non-Urothelial Carcinomas.

The 2022 International Society of Urological Pathology (ISUP) Consensus Conference on Urinary Bladder Cancer Working Group 2 was tasked to provide evidence-based proposals on the applications of grading in noninvasive urothelial carcinoma with mixed grades, invasive urothelial carcinoma including subtypes (variants) and divergent differentiations, and in pure non-urothelial carcinomas. Studies suggested that predominantly low-grade noninvasive papillary urothelial carcinoma with focal high-grade component has intermediate outcome between low- and high-grade tumors. However, no consensus was reached on how to define a focal high-grade component. By 2004 WHO grading, the vast majority of lamina propria-invasive (T1) urothelial carcinomas are high-grade, and the rare invasive low-grade tumors show only limited superficial invasion. While by 1973 WHO grading, the vast majority of T1 urothelial carcinomas are G2 and G3 and show significant differences in outcome based on tumor grade. No consensus was reached if T1 tumors should be graded either by the 2004 WHO system or by the 1973 WHO system. Because of the concern for underdiagnosis and underreporting with potential undertreatment, participants unanimously recommended that the presence of urothelial carcinoma subtypes and divergent differentiations should be reported. There was consensus that the extent of these subtypes and divergent differentiations should also be documented in biopsy, transurethral resection, and cystectomy specimens. Any distinct subtype and divergent differentiation should be diagnosed without a threshold cutoff, and each type should be enumerated in tumors with combined morphologies. The participants agreed that all subtypes and divergent differentiations should be considered high-grade according to the 2004 WHO grading system. However, participants strongly acknowledged that subtypes and divergent differentiations should not be considered as a homogenous group in terms of behavior. Thus, future studies should focus on individual subtypes and divergent differentiations rather than lumping these different entities into a single clinicopathological group. Likewise, clinical recommendations should pay attention to the potential heterogeneity of subtypes and divergent differentiations in terms of behavior and response to therapy. There was consensus that invasive pure squamous cell carcinoma and pure adenocarcinoma of the bladder should be graded according to the degree of differentiation. In conclusion, this summary of the International Society of Urological Pathology Working Group 2 proceedings addresses some of the issues on grading beyond its traditional application, including for papillary urothelial carcinomas with mixed grades and with invasive components. Reporting of subtypes and divergent differentiation is also addressed in detail, acknowledging their role in risk stratification. This report could serve as a guide for best practices and may advise future research and proposals on the prognostication of these tumors.

A canine case of bladder urothelial carcinoma (transitional cell carcinoma) treated with a chemotherapeutic agent, a molecular targeted drug, and cyclooxygenase inhibitors

A 4-year-old neutered male Scottish Terrier, weighing 10.4 kg, presented with hematuria for the past 10 days. Ultrasonography revealed multiple masses in the apex and trigone of the bladder. A catheter biopsy was performed, and the histopathological diagnosis was non-invasive urothelial carcinoma (transitional cell carcinoma) with low to medium grade pathological malignancy. Treatments with piroxicam alone, vinblastine and firocoxib, toceranib and firocoxib, and firocoxib alone resulted in a partial response or stable disease. The patient showed no regional lymph node metastasis or distant metastases, maintained stable disease, and had an excellent quality of life at 1681 days after the start of treatment.

Urinary Bladder Cancer-Epidemiological and Histopathological Study

Urinary bladder cancer is the main reason for morbidity and mortality throughout the world. Urothelial carcinoma is a common primary tumor of urinary bladder (90%). To investigate the epidemiological and histopathological aspects in Libyan patients suffering from urinary bladder cancer, we performed a study on 39 bladder cancer biopsies from transurethral resection of bladder tumor (TURBT) and cystoscopic samples obtained from Oncology Department- Al Hawari Hospital, over the period of (2021- May 2022), Tiba Medical Laboratory (2021- July 2022), and Alnoon Medical laboratory (2019- January 2022) at Benghazi, Libya. Of the 39 cases, 34 (87.2%) were diagnosed in men, and 5 (12.8%) were found in women, the men/ women ratio being of 6.8/1. The highest incidence of bladder tumors was recorded in individuals aged between 61 and 80 years old. In this age group, there were admitted 24 patients with bladder cancer, representing 61.5%. The most common pathological types of urinary bladder carcinoma found was Invasive Urothelial Carcinoma TCC (48.72%) followed by noninvasive Urothelial Carcinoma TCC (46.15%), and Squamous Cell Carcinoma SCC in (5.13%). A case of SCC on top of Schistosomiasis was also seen. Grade III was found in 51.2% of our patients and 43.5% of them had stage II. This study has highlighted upon the importance of histopathological study in evaluating urinary bladder cancer. Cystoscopic studies and biopsies help in early detection of bladder neoplasms and they form the mainstay of the diagnosis and follow up. The objects of this work were to assess epidemiological features of the bladder cancer in Benghazi - Libya with regard to frequency, age and sex distribution. Furthermore, to describe the Histopathological features of the urinary bladder cancer, particularly Transitional Cell Carcinoma (TCC) in urinary bladder biopsies.

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance.

Telomerase, an RNA-dependent DNA polymerase synthesizing telomeric TTAGGG sequences, is primarily silent in normal human urothelial cells (NHUCs), but widely activated in urothelial cell-derived carcinomas or urothelial carcinomas (UCs) including UC of the bladder (UCB) and upper track UC (UTUC). Telomerase activation for telomere maintenance is required for the UC development and progression, and the key underlying mechanism is the transcriptional de-repression of the telomerase reverse transcriptase (TERT), a gene encoding the rate-limiting, telomerase catalytic component. Recent mechanistic explorations have revealed important roles for TERT promoter mutations and aberrant methylation in activation of TERT transcription and telomerase in UCs. Moreover, these TERT-featured genomic and epigenetic alterations have been evaluated for their usefulness in non-invasive UC diagnostics, recurrence monitoring, outcome prediction and response to treatments such as immunotherapy. Importantly, the detection of the mutated TERT promoter and TERT mRNA as urinary biomarkers holds great promise for urine-based UC liquid biopsy. In the present article, we review recent mechanistic insights into altered TERT promoter-mediated telomerase activation in UCs and discuss potential clinical implications. Specifically, we compare differences in senescence and transformation between NHUCs and other types of epithelial cells, address the interaction between TERT promoter mutations and other factors to affect UC progression and outcomes, evaluate the impact of TERT promoter mutations and TERT-mediated activation of human endogenous retrovirus genes on UC immunotherapy including Bacillus Calmette-Guérin therapy and immune checkpoint inhibitors. Finally, we suggest the standardization of a TERT assay and evaluation system for UC clinical practice.

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.

Comparative analysis of features of microenvironment, stem cell and epithelial-mesenchymal transformation of non-invasive papillary bladder carcinoma with invasive carcinoma

Invasive urothelial carcinoma is the most common bladder malignancy, comprising 90% of all primary bladder carcinomas. According to the statistics of Georgia, according to NCDC data, bladder cancer is the third most common cancer among men. It is more common in men than in women. This pathology takes the 9th place among the most common tumors in the world. Within the framework of our research, a cohort retrograde study was carried out, for which the archival material of the teaching-scientific and diagnostic laboratory of Tbilisi State Medical University for the years 2019-2021 was used. The markers of epithelial-mesenchymal transformation in low- and high-grade non-invasive urothelial carcinomas and invasive urothelial carcinomas, as well as characteristics of the internal tumor microenvironment and stem cell characteristics, were studied. Bladder carcinoma belongs to the heterogeneous group of tumors that have different rates of recurrence, progression and metastasis; It is necessary to develop markers that can be prognostic indicators in bladder tumors, which will greatly improve the clinical management of this type of tumors.

Abstract A09: Immune checkpoint inhibitor-induced polyarthritis: a case series

Abstract Background. Immune checkpoint inhibitors (ICIs) have revolutionized cancer care. However, their mechanism of action also results in the uncontrolled collateral of ICI-related adverse events (ICI-AEs). Polyarthritis is a rare ICI-AE. Here we describe two cases of ICI-induced polyarthritis, induced by nivolumab/ipilimumab and sasanlimab for melanoma and urothelial cancer, respectively. Methods/Results. A 64-year-old male received combination immunotherapy with nivolumab and ipilimumab for metastatic melanoma. Within one month of his second cycle of nivolumab alone, he developed polyarthritis of the small joints of the hands bilaterally, as well as the shoulders and knees; active synovitis; and erosive arthropathy on radiographic findings. He was successfully treated with prednisone at 20mg daily, gradually tapered over several months. A 43-year-old male with high-grade non-invasive urothelial cell carcinoma received two cycles of adjuvant sasanlimab. Within two months of his second treatment, he developed a large-joint polyarthritis involving the bilateral knees, ankles, elbows, and the cervical spine. His symptoms resolved with prednisone, initiated at 50mg daily with a recommended slow taper, however resurfaced five days after he abruptly ceased treatment. He was subsequently started on methotrexate in combination with prednisone. Both patients had a past medical history of non-rheumatological autoimmune disease, developed symptoms within 8 weeks of ICI, had elevated inflammatory markers and negative autoantibodies. Neither had to discontinue their cancer therapy and indeed both had a good tumour responses to their ICI. Both of our patients were initially well-managed prednisone. However, our second patient relapsed after abrupt cessation of his prednisone and required a combination of methotrexate with prednisone to control his symptoms. Conclusions. These cases add to the literature on ICI-induced polyarthritis, a rare ICI-AE. Clinical manifestations most commonly resemble rheumatoid arthritis, with bilateral inflammation of the small joints. Time to onset tends to be &amp;lt;12 weeks after ICI exposure, and repeated ICI exposure is a risk factor. Most patients have no personal or family history of autoimmune disease, negative autoantibodies, and can be managed well with glucocorticoids. As ICIs become more widely used, rheumatologists and oncologists alike should familiarise themselves with their adverse effects. More research is needed to understand the epidemiology, clinical presentation, and treatment of these adverse events. Citation Format: Megan Smith-Uffen, Konstantinos Tselios. Immune checkpoint inhibitor-induced polyarthritis: a case series [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A09.

Role of Cytokeratin 20 as a Predictive and Prognostic Marker in Urothelial Neoplasms.

Introduction Several clinical peculiarities mark urothelial carcinomas and their biological behavior. Key in these are its relatively indolent course before manifestation and its high recurrence rate. So far, no biomarker has been identified as a predictor for these factors. The current study aims to evaluate the role of cytokeratin 20 (CK20) in non-invasive urothelial carcinomas (pTa and pT1) of the urinary bladder and its diagnostic and predictive role in tumor staging and recurrence. Materials and methods The study utilizes a retrospective, non-clinical approach via immunohistochemical marking of the paraffin-embedded tumor tissues for the initial diagnosis. Expression patterns were compared with tumor grade and stage, as well as the incidence of recurrence within a five-year follow-up period. Results A strong statistical correlation was established between expression and tumor grade, with high-grade tumors showing weak to moderate expression of CK20 while low-grade tumors showed an intensive expression pattern. No correlation was noted between the expression pattern, patient age and gender, tumor stage, and the likelihood of local recurrence. Conclusion While CK 20 is a reliable diagnostic marker when used together with other markers, its expression pattern in our study correlated only with bladder urothelial carcinoma grade.

GATA3 expression loss is linked to stage progression but is unrelated to prognosis in muscle-invasive urothelial carcinoma of the bladder

The transcription factor GATA binding protein 3 (GATA3) is commonly used in surgical pathology as a diagnostic marker to distinguish urothelial carcinomas from other cancer entities. However, the clinical relevance of GATA3 expression in urothelial bladder cancer is not completely clarified. In this study, we investigated GATA3 immunostaining on 2710 urothelial bladder carcinomas on a tissue microarray platform by using two different antibodies to better understand its impact in relation to pathological parameters of disease progression and patient outcome. Nuclear GATA3 immunostaining was regularly seen in normal urothelium and found in 74%/82% of interpretable urothelial neoplasms depending on the antibody used. Within pTa tumors, the rate of GATA3 positive tumors decreased with advancing grade. GATA3 positivity was seen in 98.6%/99.8% of pTaG2 low-grade, 98.6%/100% of pTaG2 high-grade, and 94.9%/99.2% of pTaG3 high-grade tumors (P=.0002). As compared to pTa tumors, GATA3 positivity was markedly less common in muscle-invasive urothelial carcinoma (59.9%/71.6%; P<.0001). Within pT2-4 cancers, high-level GATA3 immunostaining was associated with the presence of lymph node metastasis (P=.0034), and blood vessel (P=.0290) or lymphatic invasion (P=.0005) but unrelated to pT stage. GATA3 immunostaining results for both antibodies were not associated with overall survival in 586 patients treated by cystectomy for pT2-4 urothelial carcinoma. The results of our study identify GATA3 expression as a frequent event in noninvasive urothelial carcinomas with favorable tumor features. Loss of GATA3 immunostaining is linked with muscle-invasive disease but is largely unrelated to pathological parameters and patient prognosis.

Comparative analysis of changes in proliferative-apoptotic and hormonal status of non-invasive papillary urothelial carcinomas with molecular subtypes of invasive carcinomas

Invasive urothelial carcinoma is the most common bladder malignancy, comprising 90% of all primary bladder carcinomas. According to the statistics of Georgia, according to NCDC data, bladder cancer is the third most common cancer among men. As a result of non-invasive urothelial carcinoma, 70% of the operated patients developed a recurrence in the 5-year period after the surgical intervention on the urinary bladder, among which the share of advanced, metastatic cases is 10-20%.Therefore, regardless of the same degree of differentiation and staging, the recurrence and progression of urothelial carcinoma varies in different patients. A cohort retrograde study was carried out, for which archival material of the teaching-scientific and diagnostic laboratory of Tbilisi State Medical University for the years 2019-2021 was used. The results of the study showed that molecular subtypes of urothelial invasive carcinomas express CK20 and CK5 with different intensity. Moreover, there are mixed, hybrid forms with the coexistence of both markers, which indicates the intratumoral heterogeneous nature of invasive carcinomas, which probably depends on the different clinical course and prognosis of tumors of the same histological type. The phenotypic characteristics of low- and high-grade non-invasive papillary urothelial carcinomas are fundamentally different from the characteristics of invasive urothelial carcinoma, which gives reason to assume that they are different tumors and require additional genomic changes to transform into invasive carcinoma.The phenotypic differences between them are likely to determine the risk of recurrence and invasive transformation. CK20, CK5, apoptotic and proliferative characteristics with androgen receptor expression. Together, it can be used to assess the risk of recurrence and transformation to invasive carcinoma of low- and high-grade noninvasive papillary urothelial carcinomas.

Cytokeratin 10 (CK10) expression in cancer: A tissue microarray study on 11,021 tumors

Cytokeratin 10 (CK10) is a type I acidic low molecular weight cytokeratin which is mainly expressed in keratinizing squamous epithelium of the skin. Variable levels of CK10 protein have been described in squamous carcinomas of different sites and in some other epithelial neoplasms. To comprehensively determine the prevalence of CK10 expression in normal and neoplastic tissues, a tissue microarray containing 11,021 samples from 131 different tumor types and subtypes was analyzed by immunohistochemistry. CK10 immunostaining was detectable in 41 (31.3 %) of 131 tumor categories, including 18 (13.7 %) tumor types with at least one strongly positive case. The highest rate of positive staining was found in squamous cell carcinomas from various sites of origin (positive in 18.6 %–66.1 %) and in Warthin tumors of salivary glands (47.8 %), followed by various tumor entities known to potentially exhibit areas with squamous cell differentiation such as teratomas (33.3 %), basal cell carcinomas of the skin (14.3 %), adenosquamous carcinomas of the cervix (11.1 %), and several categories of urothelial neoplasms (3.1 %–16.8 %). In a combined analysis of 956 squamous cell carcinomas from 11 different sites of origin, reduced CK10 staining was linked to high grade (p < 0.0001) and advanced stage (p = 0.0015) but unrelated to HPV infection. However, CK10 staining was not statistically related to grade (p = 0.1509) and recurrence-free (p = 0.5247) or overall survival (p = 0.5082) in 176 cervical squamous cell carcinomas. In the urinary bladder, CK10 staining occurred more commonly in muscle-invasive (17.7 %) than in non-invasive urothelial carcinomas (4.0 %–6.0 %; p < 0.0001). In summary, our data corroborate a role of CK10 as a suitable marker for mature, keratinizing squamous cell differentiation in epithelial tissues. CK10 immunohistochemistry may thus be instrumental for a more objective evaluation of the clinical significance of focal squamous differentiation in cancer.

Pediatric urothelial bladder neoplasm

Urothelial bladder neoplasm (UBN) is an uncommon lesion in children and adolescents, without established follow-up protocol defined for this patient group. To report our experience and long-term follow-up data on pediatric patients with urothelial carcinoma of the urinary bladder. In this retrospective two center study, we analyzed the perioperative and long-term follow-up data of nine pediatric patients, who presented with neoplasms of urothelial origin within the urinary bladder between 2000 and 2021. Nine patients were identified with a mean age of 11.9 years (range 4-19 years) and median follow up of 48 months (range 12-160 month). 7 were male. Gross hematuria was the most common presenting symptom, occurring in 6 patients, followed by accidental finding on US, performed for other reasons. Cystoscopy was performed under general anesthesia, and transurethral resection of the bladder tumors was carried out in the same session. All patients had a solitary tumor with a mean size of 11mm (range 6-15mm). Pathology revealed 3 cases of papillary urothelial neoplasm of low malignant potential (PUNLMP), 5 cases of low grade (LG) noninvasive urothelial carcinoma (UC) and one case of high-grade (HG) UC invading lamina propria (pT1). All 8 patients with low grade tumor underwent follow up according to adult follow-up protocols without tumor recurrences to date. The single patient with HG pT1 UC, a 14-year-old female after renal transplantation, who was not eligible for intravesical bacillus Calmette-Guerin (BCG) installations due to immunosuppression, underwent 6 sessions of Radiofrequency-induced Thermo-chemotherapy with mitomycin, without complications. She had no recurrence to date, during a 4-year post treatment follow up. Pediatric non muscle invasive bladder cancer (NMIBC), seems to have a good prognosis with infrequent recurrences, which might be in favor of a more spacious follow up plan with less invasive diagnostic modalities as opposed to adult NMIBC population. To the best of our knowledge this is the single description of Heated Intravesical Chemotherapy efficacy for HG UC in the pediatric population.

Secondary bladder cancer during long-term follow-up after iodine-125 permanent seed implantation for localized prostate cancer

IntroductionBrachytherapy for prostate cancer treatment may induce secondary bladder cancer during long-term follow-ups. This study reviews the risk and tumor characteristics of secondary bladder cancer after brachytherapy. MethodsThis single-institution retrospective study included 1162 patients treated with low-dose-rate permanent seed implantation brachytherapy with iodine-125, with or without external beam radiation therapy, for localized prostate cancer. We calculated and compared the rates of secondary bladder cancer among patients treated with brachytherapy and radical prostatectomy (n = 218) before and after a propensity score-matching analysis. Possible risk factors for secondary bladder cancer, such as patient age and external beam radiation therapy administration, were analyzed. ResultsOf 1162 patients with a median follow-up period of 11.4 (range: 0.7–15.5) years, 26 presented with urothelial carcinomas and 1 with adenocarcinoma at a median of 8.9 (range: 2.9–14.0) years after brachytherapy, although the incidence rates of secondary bladder cancer after brachytherapy were not significantly different from those after radical prostatectomy. No significant risk factors for secondary bladder cancer were identified. The initial symptoms of secondary bladder cancer were gross hematuria (74%) and microscopic hematuria with positive urine cytology (15%). Among 26 cases of secondary urothelial carcinoma, 54% were high-grade and 46% were invasive. After brachytherapy, invasive urothelial carcinoma occurred later than noninvasive urothelial carcinoma (p = 0.01). ConclusionsConsidering the aggressive malignancy of secondary bladder cancer, cystoscopy and urine cytology should be performed for further investigation of the causes of gross or microscopic hematuria and rule out secondary bladder cancer in cases followed longer than 3 years after brachytherapy.