Invasive Urothelial Carcinoma Research Articles

Histopathologic Patterns of Urinary Bladder Lesions and Associated Factors in Hawassa University Comprehensive Specialized Hospital, Sidama Region, Ethiopia

Background: Urinary bladder lesions, non-neoplastic and neoplastic, are collectively responsible for significant morbidity and mortality throughout the world. Bladder cancer is a prevalent disease affects a significant number of individuals each year worldwide. The most common non-neoplastic and neoplastic lesion of the urinary bladder is non-specific cystitis and urothelial carcinoma respectively. Objectives: The aim of this study is to describe histopathologic patterns of urinary bladder lesions and associated risk factors in Hawassa University Comprehensive Specialized Hospital from January 2017 to December 2023. Methods: A 7-year cross sectional study was conducted to describe histologically diagnosed bladder lesions and associated factors at Hawassa University Comprehensive Specialized Hospital from January 2017 to December 2023. Results: This study comprised a total of 182 patients who have bladder biopsies at Hawassa University Comprehensive Specialized Hospital, Pathology department from January 2017 to December 2023. Out of which 21 cases (12.1%) are non-neoplastic, while 152 cases (83%) are neoplastic. Nine cases (4.9%) have a descriptive diagnosis. With 139 (90.44%) cases, urothelial neoplasms have the highest frequency form all neoplastic lesions. Ninety-seven cases, or 69.8%, of urothelial neoplasms were invasive; of them, 78 (80.4%) were high grade cases. Low-grade noninvasive papillary carcinomas, which accounted for 24 instances. One case is a cystectomy specimen, and the remaining 181 cases are TURBT. The age range of 50-59 years was the most frequent accounting for 39 (21.4%) of all cases, with a male to female (M: F) ratio of 2.9:1. The most frequent presenting symptom in 146 (85.7%) of patients was hematuria. Conclusions: This study demonstrates that 139 (90.44%) of the neoplastic bladder lesions were bladder neoplasms of urothelial origin, 97 (69.8%) of which are invasive urothelial carcinoma with rising numbers each year and implying the burden in the region.

Urogenital schistosomiasis, a leading cause of bladder squamous cell carcinoma

Abstract Introduction/Objective Schistosoma, genus of trematodes, commonly known as blood flukes are parasitic flatworms responsible for a group of infections in humans termed schistosomiasis and hundreds of millions of people are infected worldwide. In areas where Shistosoma is not endemic to the region most cases of bladder malignancy are of urothelial origin. In areas where Shistosoma is endemic bladder malignancy is more commonly squamous cell carcinoma. However, with increased travel, migration and tourism it is important to potentially consider Shistosoma infection in areas that are not typically considered endemic regions. Methods/Case Report A 62-year-old male presented to our hospital and revealed through an interpreter he has had 1.5 years hematuria with “pieces of meat or brown dirt”. Cystoscopy was performed and showed a large necrotic mass. CT scan showed an 8.2 cm exophytic bladder dome mass. TURBT was performed and a diagnosis of invasive high-grade urothelial carcinoma with squamous differentiation and with multiple Schistosoma organisms identified.The patient received Schistosoma treatment and was scheduled for radical cystectomy and ileal conduct. A few days before the scheduled procedure the patient presented to our emergency department with acute abdominal pain. He was subsequently diagnosed with progressive bladder cancer with new left malignant ureteral obstruction, which lead to hydronephrosis, DVT, abdominopelvic ascites and intraperitoneal bladder perforation. Abdominal fluid cytology showed atypical keratinizing squamous cells suspicous for malignancy and marked acute inflammation. Patient underwent cystectomy with ileal conduit and the specimen was sent to pathology for examination. Results (if a Case Study enter NA) NA Conclusion Gross examination showed an irregular perforated bladder. Microscopic examination showed a high grade urothelial carcinoma with squamous and sarcomatoid differentiation with detrusor muscle invasion. Additionally, Schistosoma organisms with a terminal spine and calcified eggs were identified. Some of the calcified egg material was engulfed by giant cells. The organisms are surrounded by a prominent eosinophilic infiltrate. Lymphovascular invasion is also noted. Schistosomiasis is associated with the development of squamous cell carcinoma of the bladder. It is important to maintain high oncological alertness for squamous cell carcinoma, particularly for patients arriving from endemic areas. Such as in our case, a patient from Somalia living in Kansas City.

Is Immunohistochemical Galectin-3 Expression Associated with the Epithelial-Mesenchymal Transition in High- and Low-Grade Invasive Urothelial Carcinomas of the Bladder?

Background/Objectives: Bladder cancer, predominantly urothelial carcinoma, is an important malignancy of the urinary system. Despite the same histologic grade and stage, some patients seem to have a worse prognosis. In this context, the epithelial-mesenchymal transition (EMT), characterized by the loss of E-cadherin and gain of vimentin expression, is an important process in tumor progression. Galectin-3, a lactose-binding protein involved in various cellular processes, has been associated with increased tumor cell migration, invasion, and treatment resistance. Methods: In this study, 223 bladder cancer cases were examined, and E-cadherin, vimentin, and galectin-3 expression was evaluated by immunohistochemical staining in tumor budding areas and invasive components. These markers were also correlated with clinicopathological parameters, including tumor grade and stage. Results: The results indicated a significant decrease in E-cadherin expression and an increase in vimentin staining in higher-grade and higher-stage tumors, supporting EMT involvement. Galectin-3 expression was notably higher in T1 high-grade tumors but decreased in T2 stage tumors. Despite this, no significant correlation was found between galectin-3 and E-cadherin or vimentin, suggesting a complex role of galectin-3 in EMT. Conclusions: High galectin-3 expression in T1 high-grade tumors highlights its potential role in early tumor progression and as a therapeutic target. However, the decrease in its expression in advanced stages underscores the need for further research to understand its multifaceted involvement in bladder cancer. These findings suggest that while galectin-3 may contribute to the EMT and early tumor progression, its exact role and potential as a therapeutic target require more detailed investigation.

Abstract C161: Rare Invasive Plasmacytoid Urothelial Carcinoma Presenting as Post-Renal Acute Kidney Injury: A Case Report

Abstract Purpose: Plasmacytoid urothelial carcinoma stands out as a rare and highly aggressive histological subtype within the spectrum of bladder carcinomas, constituting only 1-3% of all variants. Summary: In this case report, we present the case of a 72-year-old patient who initially presented with significant obstructive uropathy and hydronephrosis secondary to invasive plasmacytoid urothelial carcinoma. Admission labs were concerning for a hemoglobin level of 3.8, requiring 3 units of red blood cells for correction, potassium level of 8.8, for which urgent hemodialysis was given, and a lactate level of 5.4. The patient subsequently developed delayed hematuria one month later. Follow-up CT imaging revealed an alarming increase in the size of the bladder mass, underscoring the rapid progression of the malignancy. Discussion: The aggressive nature of this malignant neoplasm can be attributed to its diffuse pattern of infiltration and high risk of residual disease following radical surgery. Clinical manifestations often include abdominal pain, but lack early-onset hematuria and other urinary symptoms typically seen with other subtypes, leading to diagnostic delays and late-stage identification. Conclusion: This case report highlights the uncommon clinical presentation of plasmacytoid urothelial carcinoma (PUC), manifesting as obstructive nephropathy. The inherent aggressiveness associated with PUC poses a challenge in treatment due to the advanced stage of the malignancy at the time of diagnosis. The scarcity of guidelines for the management of PUC underscores the need for extensive future studies to bridge this gap. Citation Format: Andressa Uzeda, Toral Shastri, Kamilia Moalem, Kendra Van Kirk. Rare Invasive Plasmacytoid Urothelial Carcinoma Presenting as Post-Renal Acute Kidney Injury: A Case Report [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C161.

Real-world evaluation of nivolumab utilization in adjuvant treatment of localized muscle-invasive urothelial carcinoma

IntroductionIn 2022, nivolumab was granted marketing authorization for adjuvant treatment in patients at high-risk of recurrence following surgery for localized invasive muscle urothelial carcinoma, who express PD-L1 on the operative specimen. We aimed to investigate its real-world utilization. Materials and methodsOur bicentric real-world study, conducted at Foch Hospital and Georges-Pompidou European Hospital between July 2022 and January 2024, included patients who underwent surgery for urothelial carcinoma or were referred for adjuvant nivolumab treatment at these centers. ResultsA total of 200 patients underwent surgery during the study period, of whom 70 met the high-risk criteria, with 46% of these patients not receiving adjuvant treatment due to ineligibility. Our survival outcomes among patients treated by nivolumab are consistent with the results of the CheckMate 274 study (Bajorin et al. N Engl J Med. 2021). Our study population was older and frailer than that of the study cohort, with a mean age of 69years. Significant PD-L1 expression was observed in 66% of the tested patients. The median disease-free survival was 11.34months in patients who received neoadjuvant chemotherapy followed by surgery and adjuvant nivolumab. Nivolumab was generally well-tolerated, but 25% of patients discontinued it due to toxicity. Our initial data on treatments for recurrence after adjuvant nivolumab highlighted the effectiveness of conventional chemotherapy (cisplatin or carboplatin combined with gemcitabine) and targeted chemotherapy (enfortumab vedotin). ConclusionOur real-world data align with existing literature regarding adjuvant nivolumab in localized invasive muscle urothelial carcinoma. Level of evidence3.

1974P A phase II trial of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) for the treatment of non-muscle invasive BCG unresponsive urothelial carcinoma of the bladder

1974P A phase II trial of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) for the treatment of non-muscle invasive BCG unresponsive urothelial carcinoma of the bladder

A retrospective study of 96 cases of adrenal metastases

Objective: To analyze the clinical characteristics, etiological composition, imaging features, and prognosis of adrenal metastases. Methods: This study is a retrospective case series that included 96 patients with pathologically confirmed adrenal metastases who were treated at West China Hospital, Sichuan University, from 2007 to 2017. Clinical features such as sex, age, tumor size, biochemical tests, imaging characteristics, postoperative pathology, treatment methods, and prognosis were collected and analyzed. The prognosis of patients and its influencing factors were analyzed by Kaplan-Meier survival curve and single-factor Cox risk proportional model. Results: Among the 96 included patients, 64 were male and 32 were female, with a median age of 60 years. There were 89 cases of unilateral adrenal metastases, five cases of bilateral metastases, and two cases with unspecified laterality. The median diameter of the metastases was 3.5 cm×2.9 cm, with an average CT value of 31 HU. Thirty-four cases of adrenal hormones were evaluated, and no abnormality was found.The primary tumor sites were as follows: lung (n=36), kidney (n=19), liver (n=12), pancreas (n=7), rectum (n=3), stomach (n=2), and one case each of tumor in the esophagus, skin, thyroid, left maxillary muscle, breast, bladder, cervix, chest wall, and gastrointestinal tract. There were three cases with unknown primary tumors. The most common pathological type was lung adenocarcinoma (20.8%, 20/96), followed by hepatocellular carcinoma (9.4%, 9/96) and high-grade invasive urothelial carcinoma of the kidney (8.3%, 8/96). Thirty-nine cases were diagnosed concurrently with the primary tumor, while 37 cases were diagnosed after the primary tumor, with a median interval of 15 months (range: 2-144 months). There was no significant correlation between the death risk of adrenal metastatic tumor patients and gender, age, and the size of the metastatic tumor (all P>0.05). There were 4 patients with radiotherapy and chemotherapy alone, 19 patients with surgery alone, and 6 patients with combined radiotherapy and chemotherapy. The median overall survival was 1, 3, and 7 years, respectively. Conclusions: Adrenal metastases were mostly diagnosed at the same time as the primary tumor or within 15 months after the diagnosis of the primary tumor. Unilateral metastasis is common. The lungs are the most common primary lesion, followed by the kidney and liver. CT is the preferred method for the diagnosis of adrenal metastases, and the plain CT value is more than 30 HU. The overall prognosis of adrenal metastases is poor. The prognosis was better for patients who underwent surgery combined with radiotherapy and chemotherapy than those who received only surgery or radiotherapy and chemotherapy alone.

Urothelial Carcinoma with Trophoblastic Differentiation-A Report with Review.

Urothelial carcinoma with trophoblastic differentiation is a rare type of urothelial carcinoma that poses a diagnostic challenge. A 50-year-old man presented with hematuria for 4 months duration. Ultrasonography examination showed polypoidal lesions along the right lateral wall and near the right vesicoureteric junction of the urinary bladder. The transurethral resection of the bladder tumor (TURBT) specimen showed marked necrosis and urothelial tumor cells arranged in nests, sheets, and papillae, admixed with multinucleated large cells. Deep muscle and extensive lymphovascular invasion were noted. The tumor cells were diffuse immunopositive for GATA3 and focal positive for p63 and SALL4. Large multinucleated tumor cells were immunopositive for β-hCG, GATA3, inhibin-α, and PLAP, focally positive for SALL4 while negative for p63. The patient denied further treatment and succumbed to the disease after 8 months of the TURBT procedure. We report a rare invasive urothelial carcinoma with trophoblastic differentiation and discuss the differential diagnosis and literature review.

Several key and difficult issues related to the grading of urothelial carcinoma of urinary bladder

Grading and staging are the most important prognostic factors for both non-invasive and invasive urothelial carcinomas, and are also one of the most common difficulties encountered by pathologists in the daily diagnostic practice of urothelial carcinoma. Recently, the International Society of Urological Pathology organized a survey and questionnaire conference on various issues related to the diagnosis, grading, and staging of urothelial carcinoma, and ultimately formed a series of consensus opinions. This article briefly summarizes the consensus opinions of this series, and combines them with the current pathological diagnosis status of urothelial carcinoma in China. It briefly comments on how to apply this series of consensus opinions in the daily diagnostic practice of pathologists, deeply understand relevant diagnostic problems, and carry out relevant clinical pathological research to further solve problems.

Artemisinin pre-treatment fore cisplatin dosage enhances high grade urothelial carcinoma treatment in male albino mice via reverse gene expression modulation of FGFR3, HRAS, P53 and KDM6A

BackgroundUrinary bladder cancer, is the 10th most common global cancer, diagnosed in over 600,000 people causing 200,000 deaths annually. Artemisinin and its derivatives are safe compounds that have recently been proven to possess potent anti-tumor effects in vivo, through inhibition of cancer cell growth. The aim of this study is to assess the efficiency of artemisinin as a cancer treatment alone and as a pre-treatment fore cisplatin therapy for high grade urothelial carcinoma.MethodsSixty male albino mice were divided into six groups, and BBN was used to induce urinary bladder cancer. Blood samples were tested for renal functions and complete blood counts, kidney and urinary bladder tissues were harvested for histopathological examination. Total RNAs from urinary bladder tissues was collected, and gene expression of FGFR3, HRAS, P53, and KDM6A was quantified using qRT-PCR.ResultsCompared to the induced cancer group, the results revealed that FGFR3 expression levels were down-regulated in the induced cancer group treated by artemisinin only and the induced cancer group pre-treated with artemisinin prior to cisplatin by ~ 0.86-fold and 0.4-folds, respectively, aligning with HRAS down-regulation by ~ 9.54-fold and 9.05-fold, respectively. Whereas, P53 expression levels were up-regulated by ~ 0.68-fold and 0.84-fold, respectively, in parallel with KDM6A expression, which is up-regulated by ~ 0.95-folds and 5.27-folds, respectively. Also, serum creatinine and urea levels decreased significantly in the induced cancer group treated by artemisinin alone and the induced cancer group pre-treated with artemisinin prior to cisplatin, whereas the induced cancer group treated by cisplatin their levels increased significantly. Moreover, Hb, PLT, RBC, and WBC counts improved in both cancer groups treated by artemisinin alone and pre-treated with artemisinin prior to cisplatin. Histologically, in kidney tissues, artemisinin pre-treatment significantly reduced renal injury caused by cisplatin. While Artemisinin treatment for cancer in bladder tissues reverted invasive urothelial carcinoma to moderate urothelial dysplasia.ConclusionsThis study indicates that artemisinin demonstrated a significant effect in reversal of the multi-step carcinogenesis process of high grade urothelial carcinoma and could enhance the effect of cisplatin therapy using artemisinin pre-treatment.

Urothelial cancer: state of art in Ukraine and improvement pathways.

This study aims to assess the effectiveness of urothelial cancer treatment in Ukraine, utilizing population-based data from the National Cancer Registry. The primary goal is to evaluate trends and approaches to therapy, with a focus on overall survival rates in patients with urothelial tumors. A retrospective cross-sectional analysis was conducted based on the National Cancer Registry, involving 12698 patients (2008-2020) with urothelial tumors of the upper urinary tract (UTUC) and bladder cancer (BC) who underwent surgical treatment. Demographic indicators, surgical interventions, complications, and survival rates were analyzed. The average age for all patients was 70 years. The number of patients undergoing radical treatment was 1820 (15%) among BC and 573 (59%) among UTUC. The 30-day readmission rate was low for both, with a slightly higher preference for UTUC (2.3 vs. 4.6%). Whereas grade III or higher Cl-Dindo complications were seen in only 0.2% of cases. Notable findings include low frequency of neoadjuvant (7%) and adjuvant chemotherapy (28%) among patients with invasive urothelial carcinomas. Median eGFR for invasive UTUC before and after surgery was 63.2 and 51.4ml/min, respectively (P=0.00054). The directly opposite trend was seen in BC-61.2 and 68.7ml/min, respectively (P=0.0026).For BC, the overall survival rates by stages were: I-73%, II-49%, III-18%, and IV-11% (χ2=1807.207; P=0.000001). As for UTUC, the 5-year overall survival rates corresponded to the literature data, but there was a pronounced negative trend towards a decrease in this indicator after a 10-year period for all stages (χ2=146.298; P=0.000003). The study emphasizes the importance of effective systemic treatments, adherence to treatment guidelines, and the need for multidisciplinary consultations among Ukrainian patients with urothelial cancer.

Sequential Endoluminal Gemcitabine and Cabazitaxel with Intravenous Pembrolizumab as a Bladder-Preserving Strategy for Docetaxel-Unresponsive Non-Muscle Invasive Urothelial Carcinoma Following Transurethral Resection of Bladder Tumor.

Growing evidence suggests that many patients with high-risk non-muscle invasive urothelial carcinoma (NMIUC) can undergo bladder-sparing management with salvage intravesical therapies. However, inherent or developed disease resistance, particularly after multiple lines of prior salvage therapy, implores the continued pursuit of new treatment combinations. Herein, we describe the outcomes of 26 patients (31 treated units; 24 lower tract, 7 upper tract) with high-risk NMIUC treated with sequential intravesical gemcitabine and cabazitaxel with concomitant intravenous pembrolizumab (GCP) at the University of Iowa from August 2020 to February 2023. Median (IQR) follow-up was 30 (IQR: 17-35) months. Treated units had a history of high-risk NMIUC with a median of four prior endoluminal inductions. Overall, 87% of units presented with CIS or positive urine cytology. The 1- and 2-year recurrence-free survival was 77% (CI: 58-88%) and 52% (CI: 30-70%), respectively. The 2-year progression-free and cancer-specific survival was 70% (CI: 44-85%) and 96% (CI: 75-99%), respectively. In total, 22/26 (85%) patients reported any adverse event and 5/26 (19%) reported a grade ≥3 adverse event; however, all patients tolerated a full induction course. These results suggest that GCP is an effective and tolerable treatment option for patients with recurrent high-risk NMIUC.

Exploring the Histopathological Landscape of Urinary Bladder Diseases: A Tertiary Care Center Study.

Introduction Urinary bladder lesions encompass a wide spectrum, from benign inflammatory conditions to malignant neoplasms, presenting diagnostic and therapeutic challenges. Urothelial carcinoma predominates among bladder malignancies, exhibiting diverse clinical presentations and prognoses. Objective This study aimed to delineate the histopathological spectrum of urinary bladder lesions and correlate demographic profiles, clinical features, and cystoscopic findings with various bladder lesions. Methods This prospective descriptive observational study spanned 24 months at a tertiary care center, involving 65 cases of urinary bladder biopsies, including transurethral resection of bladder tumors, cystoscopic biopsies, and cystectomy specimens. The histopathological examination followed the WHO 2022 classification of urinary bladder tumors and the American Joint Committee on Cancer eighth edition staging. Clinical data, including age, gender, cystoscopic findings, and presenting symptoms, were correlated with histopathological diagnoses to explore the spectrum of bladder lesions. Results Neoplastic lesions predominated, constituting 92.3% of cases, with urothelial carcinoma comprising 83.33% of these cases. Among neoplastic lesions, invasive high-grade urothelial carcinoma (36.7%) and non-invasive low-grade papillary urothelial neoplasm (20.0%) were the most frequently observed subtypes. Non-neoplastic lesions accounted for 7.7%, including various forms of cystitis. Hematuria was the predominant presenting symptom (81.5%), while cystoscopic examinations revealed that most lesions were situated in the lateral bladder wall. High-grade urothelial carcinomas were mostly associated with muscularis propria invasion. Conclusion This study underscores the critical role of histopathological examination in diagnosing and managing urinary bladder diseases and distinguishing between non-neoplastic and neoplastic lesions. Urothelial carcinoma, prevalent among older age groups, often demonstrated muscle invasion indicative of high-grade tumors. Including the muscle layer in cystoscopic biopsies is crucial for an accurate diagnosis. Conversely, though less common, non-neoplastic conditions encompass various forms of cystitis. These findings highlight the importance of precise diagnostic tools such as cystoscopy and histopathological examination for the early detection and management of bladder neoplasms. Histopathological assessment offers essential prognostic guidance, aids in precise staging and grading, and directs tailored treatment strategies.

Relapse and Survival in Bladder Cancer Patients Undergoing microRNA-129 and microRNA-145 Assays.

The lack of indicators to measure tumor's invasive biological behavior is an important issue. The aim of this study was to examine the effect of miRNAs 129 and 145 on tumor progression as well as patient survival. Seventy five breast cancer (BC) patients and 75 controls were included in this research. Two miRNA expressions were estimated using real-time PCR. Biomarkers for BC detection was tested using ROC curves and AUC. miR-129 and miR-145 expressions were significant. miR-129 and miR-145 classifiers (AUC = 0.943 and 0.748, respectively) help diagnose BC. Unlike miR-145, miR-129 did not affect the Kaplan-Meier survival curve analysis for progression-free survival at the end of the trial. The development of transitional cell carcinoma disease was found to have a strong correlation with miR-145 in both univariate and multivariate Cox regression analyses. Additionally, infiltrating + invasive urothelial carcinoma was also found to be correlated with miR-145. Conversely, elevated miR-129 expression in BC patients did not lead to an increase in cancer-specific recurrence or mortality, as observed in both univariate and multivariate Cox regression studies. The miRNA signature can help detect survival-associated miRNAs and develop BC miRNA therapeutics.

Comparison of clinical outcomes of bladder preservation and surgery in a real-world study of patients with muscle invasive urothelial carcinoma using urine and plasma based MRD (minimal residual disease) assays.

Comparison of clinical outcomes of bladder preservation and surgery in a real-world study of patients with muscle invasive urothelial carcinoma using urine and plasma based MRD (minimal residual disease) assays.

Genome-wide analyses reveals an association between invasive urothelial carcinoma in the Shetland sheepdog and NIPAL1.

Naturally occurring canine invasive urinary carcinoma (iUC) closely resembles human muscle invasive bladder cancer in terms of histopathology, metastases, response to therapy, and low survival rate. The heterogeneous nature of the disease has led to the association of large numbers of risk loci in humans, however most are of small effect. There exists a need for new and accurate animal models of invasive bladder cancer. In dogs, distinct breeds show markedly different rates of iUC, thus presenting an opportunity to identify additional risk factors and overcome the locus heterogeneity encountered in human mapping studies. In the association study presented here, inclusive of 100 Shetland sheepdogs and 58 dogs of other breeds, we identify a homozygous protein altering point mutation within the NIPAL1 gene which increases risk by eight-fold (OR = 8.42, CI = 3.12-22.71), accounting for nearly 30% of iUC risk in the Shetland sheepdog. Inclusion of six additional loci accounts for most of the disease risk in the breed and explains nearly 75% of the phenotypes in this study. When combined with sequence data from tumors, we show that variation in the MAPK signaling pathway is an overarching cause of iUC susceptibility in dogs.

Invasive Urothelial Carcinoma of the Bladder with Inverted Growth Pattern: A Case Report

Most urothelial neoplasms of the bladder present in an exophytic papillary form, but some present in an inverted growth form, in which case the invasive feature can be difficult to identify. We present a case of invasive urothelial carcinoma of the bladder associated with an inverted growth pattern, in which the patient underwent total cystoprostatectomy with ilio-obturator lymph node dissection and a Briker-type urinary diversion.

Abstract IA001: Cellular and molecular underpinnings of field cancerization and progression to invasive carcinoma in bladder cancer

Abstract Two major concerns in clinical management of bladder cancer are: (i) the high frequency of recurrence; and (ii) the morbidity and mortality associated with progression to invasive disease (invasive urothelial carcinoma, IUC). To gain a better understanding of these issues we have used the murine BBN (N-butyl-N-(4-hydroxylbutyl) nitrosamine) experimental model of bladder cancer, as well as tissue samples from normal human bladders and from bladders of patients at various stages of bladder cancer formation and progression. We have documented in the BBN model a CIS-like stage, prior to invasion, in which clonal expansion from a single cell occupies a significant fraction of the urothelium. With this experimental murine model alongside observations from patient samples and data from The Cancer Genome Atlas (TCGA), we have ascertained that a key event in progression of pre-invasive to invasive carcinoma is the silencing of the Sonic hedgehog (Shh) member of the Hedgehog gene family. Silencing-associated invasion appears due to the loss of SHH-induced differentiation signals, which when present slow growth and block invasion. Despite the consistent loss of SHH expression in invasive murine and human bladder cancers, however, TCGA data show few if any mutations in the SHH gene of IUC cells. Instead, our studies of patient samples and cancer-derived cell lines reveal that the loss of SHH expression is due to tighter chromosomal packaging and reduced accessibility of a bladder-specific enhancer located ~200 kb upstream of the SHH transcription start site. We have found that inhibitors of certain chromatin-modifying enzymes, including an FDA-approved drug, are capable of re-activating SHH expression, and are testing the possibility that these drugs may block or reverse invasion of urothelial carcinoma. The high frequency of bladder cancer recurrence is thought to result from field cancerization, that is, an increased probability of new cancer formation in apparent normal urothelium, even after successful resection of the primary tumor. To understand the basis for this field effect, we compared apparent normal urothelium from cancer patients to truly normal urothelium from bladders never affected by malignancy. We found that apparent normal samples display a dramatically increased basal character in transcriptomic assays, using as a metric of basalization an index constructed from single cell RNA-seq analysis of normal urothelium. We and others have demonstrated previously by lineage tracing and cell ablation studies in the BBN model that IUC arises from basal stem cells of the urothelium. The basalization of urothelium distant from the primary tumor that we observe thus may account for the increased probability of cancer formation in the apparent normal urothelium of bladder cancer patients. We have found that several FDA-approved antagonists of EGF signaling can reverse this basalization in the mouse BBN model as well as in organoid culture, and that these drugs dramatically reduce the formation of tumors following BBN exposure. Citation Format: Philip A. Beachy, Kris B. Prado, Aaron M. Kershner, Karim Mrouj, Bernard M. Kiss, Hua Dong, Ozgu Aydogdu, Ye Tian, Joseph C. Liao. Cellular and molecular underpinnings of field cancerization and progression to invasive carcinoma in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA001.

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

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

Abstract A018: A case of Buschke-Löwenstein tumor with superimposed infection and associated urothelial carcinoma

Abstract The Giant Condyloma Acuminata (GCA), the Buschke-Löwenstein tumor, is a rare and challenging pathology with a less than 0.1% prevalence. This disease is often considered a transitional phase between condyloma acuminatum and squamous cell carcinoma, potentially representing a variant of verrucous carcinoma. Despite its initially benign histological presentation, GCA can evolve into expansive papillomatous proliferations that deeply invade underlying tissues. Studies indicate that GCA may transform into invasive squamous cell carcinoma in 8.5-23.8% of cases. The strong correlation between GCA and human papillomavirus (HPV) infections, particularly subtypes 6 and 11, underscores the role of viral factors in developing this condition. The presented case involves a 57-year-old male with pre-existing medical conditions, including hypertension and diabetes mellitus, who sought emergency care due to escalating suprapubic and penile discomfort. A biopsy of the genital warts identified condyloma acuminatum with an overlying bacterial infection of Proteus mirabilis. Concurrently, pathology identified anogenital squamous cell carcinoma. Notably, the patient had no associated sexually transmitted infections and no prior immunocompromised status. Imaging studies revealed a multilobulated soft tissue mass in the pelvis with prostatic invasion and enlarged lymph nodes. Further investigations, including a transurethral resection of bladder tumor (TURBT), revealed multiple tumor deposits in the bladder, penile lesion, and suprapubic papule. Pathological examinations indicated non-invasive and invasive papillary urothelial carcinoma as well as invasive squamous cell carcinoma in different locations. The tumor was staged as pathologic IIIB T2N3M0, and a collaborative decision between Urology and Oncology teams led to the initiation of neoadjuvant chemotherapy with TIP (cisplatin, ifosfamide, and paclitaxel). The patient underwent the initial chemotherapy cycle with subsequent cycles scheduled every three weeks. Management options for GCA include radiotherapy, cryosurgery, CO2 laser surgery, systemic chemotherapy, and radical surgical excision. While radiotherapy has shown successful outcomes, concerns about anaplastic transformations and post-treatment condylomas make its utilization contentious. The absence of unequivocal guidelines for radiotherapy dosage and fractionation has led to considerations of alternative modalities, but the primary approach remains radical surgical excision. The risk of recurrence remains high due to potential tumor cell spillage during surgery. In conclusion, this case report highlights an advanced manifestation of the Buschke-Löwenstein tumor coexisting with multiple HPV infections. The complexity of GCA and the lack of consensus on optimal therapeutic strategies emphasize the need for timely diagnosis and intervention to ensure favorable prognoses. Various treatment paradigms exist in medical literature, but their efficacy varies, reflecting the ongoing challenges in managing this rare and clinically intricate condition. Citation Format: Aliya M. Khan, Sophia Navajas, Mehmet Hepgur, Samuel A. Kareff. A case of Buschke-Löwenstein tumor with superimposed infection and associated urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A018.