Urothelial Origin Research Articles

Epigenetic Biomarkers as a New Diagnostic Tool in Bladder Cancer—From Early Detection to Prognosis

Bladder cancer (BC) currently ranks as the 9th most common cancer worldwide. It is characterised by very high rates of recurrence and metastasis. Most cases of BC are of urothelial origin, and due to its ability to penetrate muscle tissue, BC is divided into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). The current diagnosis of BC is still based primarily on invasive cystoscopy, which is an expensive and invasive method that carries a risk of various complications. Urine sediment cytology is often used as a complementary test, the biggest drawback of which is its very low sensitivity concerning the detection of BC at early stages, which is crucial for prompt implementation of appropriate treatment. Therefore, there is a great need to develop innovative diagnostic techniques that would enable early detection and accurate prognosis of BC. Great potential in this regard is shown by epigenetic changes, which are often possible to observe long before the onset of clinical symptoms of the disease. In addition, these changes can be detected in readily available biological material, such as urine or blood, indicating the possibility of constructing non-invasive diagnostic tests. Over the past few years, many studies have emerged using epigenetic alterations as novel diagnostic and prognostic biomarkers of BC. This review provides an update on promising diagnostic biomarkers for the detection and prognosis of BC based on epigenetic changes such as DNA methylation and expression levels of selected non-coding RNAs (ncRNAs), taking into account the latest literature data.

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.

Sarcomatoid Urothelial Carcinoma Arising in Autosomal Dominant Polycystic Kidney Disease: A Case Report and Literature Review.

Autosomal dominant polycystic kidney disease (ADPKD) may be associated with various epithelial malignancies. The most reported ones are papillary renal cell carcinoma (RCC) and clear cell RCC. Only one noninvasive urothelial carcinoma arising in the renal pelvis has been previously reported in the setting of ADPKD in the English literature. A 52-year-old patient with ADPKD and a history of renal transplant presented with a poorly differentiated sarcomatoid neoplasm in his native left polycystic kidney. A recognizable urothelial or renal cell carcinoma differentiation was not identified in the resected neoplasm microscopically. The initial diagnosis for this specimen was challenging on morphology and immunohistochemistry, but targeted next-generation sequencing provided molecular evidence in support of urothelial origin, indicating a hotspot mutation -124 C > T in the TERT promoter (C228 T) and loss of heterozygosity on chromosomes 9p and 8p. This tumor is unique because, to our knowledge, this is the first report of upper tract sarcomatoid urothelial carcinoma in a patient with ADPKD.

Small cell neuroendocrine carcinoma and poorly differentiated rhabdomyosarcomas of the urinary bladder in adults—A comparative analysis in favor of a common histogenesis

Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like) small cell pattern, frequently indistinguishable from small cell neuroendocrine carcinoma (SCNEC). However, the histogenesis of RMS and SCNEC and their inter-relationship have not been well studied and remained controversial. We herein analyzed 23 SCNEC and 3 small round cell RMS of the bladder for neuroendocrine (synaptophysin + chromogranin A) and myogenic (desmin + myogenin) marker expression and for TERT promoter mutations. In addition, the RMS cohort and one SCNEC that was revised to RMS were tested for gene fusions using targeted RNA sequencing (TruSight Illumina Panel which includes FOXO1 and most of RMS-related other genes). Overall, significant expression of myogenin and desmin was observed in one of 23 original SCNEC justifying a revised diagnosis to RMS. On the other hand, diffuse expression of synaptophysin was noted in 2 of the 4 RMS, but chromogranin A was not expressed in 3 RMS tested. TERT promoter mutations were detected in 15 of 22 (68%) SCNEC and in two of three (67%) assessable RMS cases, respectively. None of the four RMS cases had gene fusions. Our data highlights phenotypic and genetic overlap between SCNEC and RMS of the urinary bladder. High frequency of TERT promoter mutations in SCNEC is in line with their presumable urothelial origin. In addition, the presence of TERT promoter mutation in 2 of 3 RMS and lack of FOXO1 and other gene fusions in all 4 RMSs suggest a mucosal (urothelial) origin, probably representing extensive monomorphic rhabdomyoblastic transdifferentiation in SCNEC.

A Secondary Urothelial Carcinoma of the Penis Diagnosed

Aim: Penile cancer is one of the rarest urogenital cancers. Penile metastases after cystectomy are possible and seem to be associated with the existence of an extensive tumor on the surgical specimen. Case Presentation: We report here the case of old man 78 years old, with a history of Radical Cysto-Prostatectomy with Bricker type urinary diversion, indicated for a pT3N0M0R0 infiltrating urothelial carcinoma of the bladder. He had consulted 7 years post surgery for an indurated lesion of the penis with urethrorrhagia. On examination, he presented an ulcerative-necrotic lesion under the left lateral coronal area of the penis, a diffuse induration of corporal bodies from the glans to the bulb, bilateral inguinal macro lymphadenopathies. Magnetic Resonance Imaging of the penis suggested a tumor extending over the entire penis, infiltrating the corpora cavernosa and spongiosa, with invasion of the albuginea, adjacent fat and skin. In view of this picture, a total penectomy with emasculation was performed. The histology of the surgical specimen showed a poorly differentiated urothelial carcinoma with an immunohistochemical study in favor of a primary urothelial origin (GATA3+). The tumor infiltrated both corpora cavernosa and the urethra with positive margins of resection. The right inguinal lymph node dissection showed one metastatic node out of two. The left inguinal lymph node dissection showed one metastatic lymph node out of six with capsular rupture. Thoracic-abdominopelvic CT Scan showed a right inguinal adenopathy with no other lesions suggestive of secondary localization. The diagnosis of secondary urothelial carcinoma of the penis classified as pT4N2M0R1 was made and the patient underwent chemotherapy on tumor board meeting. Conclusion: Secondary cancers of the penis, although rare, can occur years after radical treatment of the primary tumor. Immuno-histochemestry was esential to differentiate from primary squamous cell carcinoma in our case.

Abstract 4248: Patient-derived MTAP-deleted bladder cancer organoid model: A unique platform for drug development

Abstract Introduction: Approximately 30% of advanced bladder cancer (BCa) tumors exhibit MTAP gene deletion, which has been associated with luminal subtype BCa, poor response to chemotherapy, and shorter progression to metastatic disease (De Souza 2023). MTAP deletion has been proposed as a potential biomarker for response to pemetrexed and an emerging class of PRMT5 and MAT2A inhibitors in development for MTAP-deleted tumors. Here, we describe the first patient-derived 3D model of BCa with MTAP deletion and its translational potential as a drug sensitivity platform. Methods: A patient (pt) with metastatic BCa harboring MTAP deletion underwent a pelvic lymph node biopsy. A fresh tumor sample was processed under collagenase/dispase solution for 30 minutes and filtered through a 70-um cell strainer. Cells were cultures in low attachment plates with MammoCult™ Basal Medium (Stem Cell Technologies). After 5 passages and 3D spheroid formation, immunostaining for cytokeratin (CK) 5 and 6, GATA3, CK20, and Ki67 staining were performed to confirm the urothelial origin. The MTAP-del was confirmed by a western blot of the organoid specimen and compared to other BLCa cell lines (UMUC, RT4, J82, and 5637). The viability assays were performed using the CellTiter-Glo® 3D Cell kit. Next-generation sequencing (NGS) of primary BCa tumor revealed deletion of MTAP, CDKN2A, CDKN2B, and mutations in p53, TERT, and KDM6A. Results: The patient organoid sample was positive for the luminal CK5/6 markers and negative for GATA3. Ki67 and CK20 were primarily expressed in the nucleus of the same sample. The organoid retained morphologic and immunohistochemical features of the patient’s primary bladder tumor, showing the same squamous differentiation and similar Ki-67 proliferative index. The organoid displayed no evidence of the MTAP protein by western blot (similar findings with the MTAP-del cell lines UMUC and RT4). The organoid showed sensitivity to pemetrexed [pemetrexed IC50=0.12 uM (other MTAP-del BLCa IC50: 0.1-0.23 uM)] and resistance to gemcitabine and cisplatin [Gem IC50=55 nM (other BLCa IC50: 1-29 nM), Cis IC50=90.5 uM (other BLCa IC50: 2-17 uM). Conclusions: We describe the first patient-derived MTAP-deleted BCa organoid recapitulating the features of the primary tumor. The organoid displayed sensitivity to pemetrexed as described with MTAP-deleted BCa. The organoid represents a unique platform for testing novel therapeutic strategies for MTAP-deleted BCa. Citation Format: Maximilian Schwermann, Benedito Carneiro, Shaolei Lu, Andre De Souza, Matthew Hadfield, Anthony Mega, Galina Lagos, Sari Khaleel, Dragan Golijanin, Sheldon Holder, Praveen Srinivasan, William MacDonald, Andrew George, Lanlan Zhou, Leiqing Zhang, Wafik El-Deiry. Patient-derived MTAP-deleted bladder cancer organoid model: A unique platform for drug development [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 4248.

Prevalence and Pattern of GATA3 Immunohistochemical Expression in Female Genital Tract Adenocarcinomas.

GATA3 immunohistochemistry has been described as a highly sensitive marker in determining carcinomas of breast and urothelial origin. In the gynecologic system, it can be used as a marker to diagnose mesonephric or mesonephric-like carcinomas and trophoblastic tumors. The present study was performed to determine the diagnostic value of GATA3 in gynecological adenocarcinomas. A total of 187 samples from different types of endometrial, endocervical, and ovarian carcinomas were analyzed for intensity and percentage of GATA3 expression in tumor cells. The relationship between GATA3 expression and clinicopathological parameters was investigated. A total of 187 patients including 101 ovarian, 77 endometrial, and 9 endocervical adenocarcinomas were investigated. Weak and focal expression of this marker was observed in 5. 1% (4/77) endometrial, 12.9% (13/101) ovarian, and 11.1% (1/9) endocervical adenocarcinomas. The mean H score in all subtypes was less than 10.6 (2-35). There was no statistically significant correlation between GATA3 expression in tumor cells with clinical stage, and tumor recurrence or metastasis. GATA3 is infrequently, weak, or focally expressed in most of the common gynecological adenocarcinomas.

Case Report: A Rare Case with Cutaneous Metastasis of Bladder Urothelial Carcinoma

Bladder cancer is a common genitourinary malignancy with variable metastatic potential. Cutaneous metastasis is uncommon and often presents with a poor prognosis. We presented a 47-year-old man with a history of muscle-invasive urothelial carcinoma of the bladder and suffered from headache and right arm swelling that had persisted for months. The excisional biopsy of the skin lesions and scalp tumor showed high-grade metastatic carcinoma of urothelial origin. Even though is rare, cutaneous metastasis is still the possibility of urothelial carcinoma metastasis and mimics several types of skin lesions. There is no guideline for cutaneous metastases of urothelial carcinoma because of the small number of patients and poor prognoses. Chemotherapy remains the treatment of choice, and further studies are needed to assess the efficacy of immunotherapy for skin metastases of urothelial carcinoma.

Aberrant expression of GATA3 in metastatic adenocarcinoma of the prostate: an important pitfall.

The distinction of high-grade prostate cancer (PCa) from poorly differentiated urothelial carcinoma (UC) can be somewhat challenging on clinical and morphological grounds alone, yet it is of great importance for prognostication and choice of treatment. GATA3 is a useful immunohistochemical marker to confirm urothelial origin. However, recent works report strong GATA3 immunoexpression in primary high-grade PCa. The aim of this study was to explore GATA3 expression specifically in metastatic PCa. The pathology databases of four tertiary institutions were queried for cases of metastatic PCa. Available slides and clinical records were reviewed by experienced genitourinary pathologists. Prostatic markers (PSA, PSAP, NKX3.1) and GATA3 immunohistochemistry were performed. A total of 163 metastatic PCa cases were included. At least one prostate marker was positive in each case of non-regional distant metastasis, confirming prostatic origin. GATA3 strong staining was found in four (2.5%) cases: two liver, one bone and one non-regional lymph-node metastases. All four patients had Grade Group 5 PCa at the initial diagnosis. The metastatic prostatic adenocarcinomas were solid, either with no gland formation (n = 3) or with only focal cribriforming (n = 1). To our knowledge, this is the first study exploring GATA3 expression specifically in metastatic PCa. Despite being infrequent, GATA3 positivity in high-grade PCa may lead to misdiagnosis, with clinical implications. We recommend a panel of immunohistochemical markers, both prostatic and urothelial, for ruling out UC, either in primary tumour samples or in the event of metastases of unknown primary, when a genitourinary origin is suspected.

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.

Cutaneous metastases of urothelial origin: early diagnosis to improve prognosis Case report

Superficial bladder tumors are classified as non-invasive, and are limited to the superficial layer without invading the bladder muscle. However, even if the tumor is considered non-invasive, it is possible for it to spread to other parts of the body, such as the skin. Skin metastases may appear as nodules or plaques on the skin and may sometimes be accompanied by symptoms such as itching, pain or inflammation. Treatment for skin metastases depends on a variety of factors, such as the size and location of the metastasis, as well as the presence of other metastases in the body. Treatment options may include surgery, radiation therapy, chemotherapy or a combination of these treatments.

MP14-02 DEVELOPMENT OF A PORCINE MODEL OF BLADDER CANCER USING THE ONCOPIG

You have accessJournal of UrologyCME1 Apr 2023MP14-02 DEVELOPMENT OF A PORCINE MODEL OF BLADDER CANCER USING THE ONCOPIG Andreas Aulitzky, Rand Wilcox Vanden Berg, Kwanghee Kim, Hikmat Al-Ahmadie, Sebastien Monette, and Jonathan A. Coleman Andreas AulitzkyAndreas Aulitzky More articles by this author , Rand Wilcox Vanden BergRand Wilcox Vanden Berg More articles by this author , Kwanghee KimKwanghee Kim More articles by this author , Hikmat Al-AhmadieHikmat Al-Ahmadie More articles by this author , Sebastien MonetteSebastien Monette More articles by this author , and Jonathan A. ColemanJonathan A. Coleman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003234.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Large animal cancer models have potential to improve and accelerate the development of new treatment modalities but few exist. Oncopigs (OPG) are particularly suitable due to their similarities to humans. We sought to develop a urothelial tumor model using the oncopig cancer model (OCM: University of Illinois Cancer Center). The OCM carries two mutations (KRASG12D and TP53R167H) which can be induced by exposure to a buffered Adeno Virus Cre solution (bAdCre). Three procedures (P1, P2, P3) were devised and investigated. METHODS: Eight OPGs underwent tumor inoculation. In P1, bAdCre with plant starch (n=3) was injected submucosally at 3 distinct locations in the bladder wall. In P2 the urothelium was denuded in 3 locations followed by bAdCre instillation (n=4). In P3 bAdCre was instilled combined with N-Dodecyl- β-D-Maltoside (DDM), an alkyl disaccharide and polar surfactant that enhances virus transfection in the bladder, with intact urothelium (n=1). Serial imaging, cystoscopies and blood draws were performed until sacrifice at 3 timepoints (days: 14, 21, 28). Tumor characteristics were assessed by necropsy and histopathological examination of the entire tumor tissue. RESULTS: In total, 7/8 (87.5%) OPGs grew bladder tumors. Histopathological examination revealed 2 different tumor types: neoplastic tumors (NT) and inflammatory tumors (IT). Using P1, 3 OPGs developed IT (3/3). 2 OPGs in 2 locations (2/3) and 1 in 1 location (1/3). In P2, 3/4 OPGs grew tumors. 1 OPG in all 3 locations, all 3 were NTs (3/3) (Figure 1 a), 1 OPG in 2 locations (2/3), both NTs and 1 OPG in 1 location (1/3), an IT. In P3 1 NT developed (1/1). All tumors showed muscle invasive growth. P3 showed the most superficial lesion after 21 days (pT2a). In P1, 2 pigs had pT3 tumors after 21 and 28 days. No complications were observed. Based on the histological (Figure 1 b: H&E), multiple immunohistochemical findings (e.g.: Figure 1 c: high molecular cytokeratins 34Be12; Figure 1 d: P53) and the growth pattern, NT were diagnosed as urothelial cell carcinomas, sarcomatoid variant. CONCLUSIONS: This is the first description of bladder tumor development in a porcine model using the OCM. We were able to create neoplastic tumors in a short period of time. The model is reproducible and neoplastic lesions show urothelial origin with sarcomatoid transformation. Source of Funding: MSKCC Sidney Kimmel Center for Urologic Cancers © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e182 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andreas Aulitzky More articles by this author Rand Wilcox Vanden Berg More articles by this author Kwanghee Kim More articles by this author Hikmat Al-Ahmadie More articles by this author Sebastien Monette More articles by this author Jonathan A. Coleman More articles by this author Expand All Advertisement PDF downloadLoading ...

Poorly Differentiated Neuroendocrine Tumor of the Bladder: A Case Report

Neuroendocrine tumors rarely occur in the urinary bladder, relatively less than 1% of occurrence, as the tumor is very rare, pathogenesis is uncertain some authors showed that it is from urothelial origin. It can be carcinomatous, subdivided into small cell and large cell pathology. Small cell carcinoma of the bladder is a rarity that may present at an advanced pathologic stage. No treatment regimens have been standardized for local or metastatic disease. Many publications showed that the disease is treated with combined chemotherapy or with radical cystectomy, here we are presenting a case of a 78 years old male, who underwent transurethral resection of bladder 1 month ago and the biopsy report was suggestive of neuroendocrine tumor of bladder, after that patient underwent radical cystectomy with neobladder reconstruction surgery.

Exploration of immunosuppressive features of the tumor microenvironment within hepatic and non-hepatic tumors of urothelial origin.

562 Background: Recent data suggest that patients with liver metastases (mets) are resistant to immune checkpoint inhibition (CPI) independent of historical biomarkers of CPI efficacy, raising the question of whether liver mets may be associated with an immunosuppressive tumor microenvironment (TME). We investigated the immune TME of hepatic and non-hepatic mets compared to primary tumors in advanced urothelial carcinoma (UC) tissue samples. Methods: NextGen sequencing (NGS) of DNA (592-gene/whole exome) and RNA (whole transcriptome) from UC tissue samples (N=4746) was performed at Caris Life Sciences (Phoenix, AZ). Immune cell infiltration was estimated by RNA expression deconvolution (MCP-counter). PD-L1 expression (SP142: immune cell stain ≥ 5%; 22c3: CPS ≥ 10) was assessed by immunohistochemistry (IHC). Deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) was tested by IHC/NGS. Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated. Mann–Whitney U and X2/Fischer-Exact tests were applied where appropriate, with p-values adjusted for multiple comparisons (Benjamini-Hochberg). *P<0.05. Results: UC samples included 3158 (66.5%) from primary site, 1344 (28.3%) from non-hepatic mets, and 244 (5.1%) from hepatic mets. Compared to primary tumors, hepatic mets had decreased CD8+ T and B cells (0.55* and 0.29-fold*) but increased monocytic lineage cells (1.23-fold*), while non-hepatic mets had increased CD8+ T, NK, and monocytic lineage cells (1.28*, 1.27*, 1.31-fold*) with no difference in B cells (1.05-fold). Hepatic mets had decreased expression of integrin LFA-1/ ITGAL (0.77-fold*), as well as hyaluronic acid (HA) receptor CD44 and synthase HAS2 (0.61 and 0.61-fold*), compared to primary tumors, whereas expression of these genes and LFA-1 ligand ICAM1 was increased in non-hepatic mets (1.08 to 1.30-fold*). Hepatic mets had increased expression of immunosuppressive cytokines CCL2 and CXCL2 (1.72* and 2.32-fold*) and decreased expression of pro-inflammatory cytokines CCL5 and CXCL10 (0.63* and 0.79-fold*) compared to primary tumors. PD-L1+ IHC was less frequent in hepatic mets compared to primary tumors and non-hepatic mets. TMB-High (≥10 mut/MB) and dMMR/MSI-H rates were similar across tumor sites. Hepatic mets (N=40) were associated with worse OS from the start of pembrolizumab compared to non-hepatic mets (N=177) (19.6 vs 4.4 months, HR 3.01, 95% CI 1.91-4.75, p<0.0001). Conclusions: This is the largest analysis of hepatic and non-hepatic met TMEs compared to primary tumor in advanced UC. Lower PD-L1 expression and differences in immune TME composition in liver mets may contribute to CPI resistance. Further analysis is warranted to determine underlying molecular mechanisms resulting in a TME that reduces response to CPI for patients with UC and liver mets.

Single lung metastasis of urothelial carcinoma can be cured by surgical resection with long-term survival

Introduction: Metastatic urothelial carcinoma is unlikely to be cured. Case Report: We present a case of urothelial carcinoma (UC) with lung metastasis which was cured after resection. A 57-year-old male who was found to have a mass in the right renal pelvis involving the right ureter and urinary bladder. Biopsies from the renal mass and the bladder showed papillary UC with no invasion to the lamina propria (pTa). He underwent a right radical nephroureterectomy, pelvic lymphadenectomy, and cystoprostatectomy with ileal loop conduit urinary diversion. A growing metastatic mass in the upper lobe of the left lung was found five years later. It was resected. On follow-up, he has no evidence of metastasis four years after surgery. Conclusion: Pulmonary metastasis from urothelial origin can have cavitary appearance on computed tomography (CT) and can happen after more than five years of primary tumor resection. Long-term follow-up is necessary for detection of late metastasis that can be resected if solitary pulmonary with possible long-term survival.

Median raphe cysts: A clinico-pathologic and immunohistochemical study of 52 cases.

Median raphe cysts (MRC) are epithelial-lined cystic lesions of the genital area that do not communicate with the urethra or the overlying epidermis. Immunohistochemically, MRC show positivity for cytokeratin (CK) 5-6, CK 7, carcinoembryonic antigen, p63 and uroplakin III (URO III). GATA3 and human milk fat globulin 1 (HMFG1) are immunohistochemical markers that have been not previously studied in MRC. We conducted a study of 52 patients diagnosed with MRC in the Pathology Departments of eight hospitals between 1990 and 2016. The monoclonal antibodies used were CK5-6, CK7, CK20, URO III, p63, GATA3, and HMFG1. HMFG1 was studied in five cases of apocrine hidrocystomas and compared with five cases of MRC from our series. CK 5-6, CK7, and p63 expression showed strong positivity in the urothelial epithelium of 48 cases. CK20 was focally positive in areas of mucinous differentiation in three cases. GATA3 showed intense nuclear staining in 30 cases. HMFG1 was positive in three cases of MRC and in three cases of apocrine hidrocystoma. Positivity of GATA3 and CK7 in MRC supports the urothelial origin of these cysts. We found no differences in HMFG1 expression between MRC and apocrine hidrocystomas.

What is your diagnosis? Perineal swelling in a dog.

What is your diagnosis? Perineal swelling in a dog.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Urothelial Origin: a Case Report and Literature Review.

Urothelial carcinomas (UC) are the fourth most common tumours. Approximately, 50% of patients with invasive bladder cancer relapse after radical cistectomy (RC). In this report, we present the case of peritoneal carcinomatosis from bladder UC treated with cytoreductive surgery plus the administration of hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). A 34-year-old woman diagnosed with high-grade bladder cancer with peritoneal recurrence in 2017. She underwent cytoreductive surgery followed by HIPEC with mitomycin C. Histopathological results showed metastases from UC in the left ovary and right diaphragmatic peritoneum. In 2021, the patient underwent surgery after treatment with atezolizumab for abdominal wall recurrence. Today, the patient is alive and free of tumor recurrence 12months after the last surgery. Despite advances in surgical technique and patient selection, the risk of relapse remains high among patients with muscle-invasive bladder cancer. We face the case of a young female patient with local, peritoneal, and lymphatic recurrence of bladder cancer after RC who had a partial response to chemotherapy. The possibility of CRS + HIPEC is offered by the surgical oncology unit, referent in the management of peritoneal carcinomatosis. Surgery is capable of resecting residual tumor in patients with a partial response or who have been erroneously underdiagnosed. CRS + HIPEC might be a valid option to be considered in well-selected patients and to be performed in reference units. There is a need for more collaborative clinical trials and prospective studies addressing the role of surgery in patients with metastatic bladder 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.