Cases Of Upper Tract Urothelial Carcinoma Research Articles

Investigating cellular similarities and differences between upper tract urothelial carcinoma and bladder urothelial carcinoma using single-cell sequencing.

Upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BLCA) both originate from uroepithelial tissue, sharing remarkably similar clinical manifestations and therapeutic modalities. However, emerging evidence suggests that identical treatment regimens may lead to less favorable outcomes in UTUC compared to BLCA. Therefore, it is imperative to explore molecular processes of UTUC and identify biological differences between UTUC and BLCA. In this study, we performed a comprehensive analysis using single-cell RNA sequencing (scRNA-seq) on three UTUC cases and four normal ureteral tissues. These data were combined with publicly available datasets from previous BLCA studies and RNA sequencing (RNA-seq) data for both cancer types. This pooled analysis allowed us to delineate the transcriptional differences among distinct cell subsets within the microenvironment, thus identifying critical factors contributing to UTUC progression and phenotypic differences between UTUC and BLCA. scRNA-seq analysis revealed seemingly similar but transcriptionally distinct cellular identities within the UTUC and BLCA ecosystems. Notably, we observed striking differences in acquired immunological landscapes and varied cellular functional phenotypes between these two cancers. In addition, we uncovered the immunomodulatory functions of vein endothelial cells (ECs) in UTUC, and intercellular network analysis demonstrated that fibroblasts play important roles in the microenvironment. Further intersection analysis showed that MARCKS promote UTUC progression, and immunohistochemistry (IHC) staining revealed that the diverse expression patterns of MARCKS in UTUC, BLCA and normal ureter tissues. This study expands our multidimensional understanding of the similarities and distinctions between UTUC and BLCA. Our findings lay the foundation for further investigations to develop diagnostic and therapeutic targets for UTUC.

Management of Upper Tract Urothelial Carcinoma in a Double Collecting System Kidney.

Upper tract urothelial carcinoma (UTUC) in a duplex collecting system (DCS) is a relatively uncommon presentation with unclear management guidelines. Herein, we retrospectively reviewed all published cases of DCS with UTUC aiming to suggest personalized clinical care options for future cases. We conducted a systematic search for all cases of UTUC in DCS from published literature using the following keywords: UTUC, urothelial carcinoma (UC), collecting duct carcinoma, and DCS. The cases were summarized based on demographics, clinical presentation, predisposing risk factors, tumor location, management, and follow-up. We present an additional case based on our experience with a 69-year-old female with high-grade (HG) UTUC of the upper moiety in complete DCS. The patient underwent a robotic upper pole hemi-nephroureterectomy (hemi-NU) with a common sheath distal ureterectomy and a bladder cuff, followed by lower pole ureteral reimplantation. Overall, 34 patients with 35 renal units of UTUC in DCS were included and analyzed. To conclude, UTUC of DCS is rare and underreported. Hence, it is difficult to define a standard treatment. Although hemi-NU has been previously described, to the best of our knowledge, this is the first case report of robot-assisted hemi-NU for complete DCS with single-moiety UC.

Invasiveness of Upper Tract Urothelial Carcinoma: Clinical Significance and Integrative Diagnostic Strategy.

In this study, we aimed to determine the clinicopathologic, radiologic, and molecular significance of the tumor invasiveness to further stratify the patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) who can be treated less aggressively. Clinicopathologic and radiologic characteristics of 166 surgically resected HG UTUC (48 noninvasive, and 118 invasive) cases were evaluated. Six noninvasive UTUC cases with intratumoral tumor grade heterogeneity were selected for whole-exome sequencing (WES) to understand the underlying molecular pathophysiology. Barcode-tagging sequencing was done for validation of the target genes from WES data. Patients with noninvasive UTUC showed no cancer-specific death with better cancer-specific survival (p < 0.001) and recurrence-free survival (p < 0.001) compared to the patients with invasive UTUC. Compared to the invasive UTUC, noninvasive UTUC was correlated to a low grade (LG) on the preoperative abdominal computed tomography (CT) grading system (p < 0.001), histologic intratumoral tumor grade heterogeneity (p=0.018), discrepancy in preoperative urine cytology diagnosis (p=0.018), and absence of urothelial carcinoma in situ (p < 0.001). WES of the heterogeneous components showed mutually shared HRAS and FGFR3 mutations shared between the HG and LG components. HRAS mutation was associated with the lower grade on preoperative abdominal CT and intratumoral tumor grade heterogeneity (p=0.045 and p < 0.001, respectively), whereas FGFR3 mutation was correlated to the absence of carcinoma in situ (p < 0.001). According to our comprehensive analysis, HG noninvasive UTUC can be preoperatively suspected based on distinct preoperative radiologic, cytologic, histologic, and molecular features. Noninvasive HG UTUC shows excellent prognosis and thus should be treated less aggressively.

MCM4 expression is associated with high-grade histology, tumor progression and poor prognosis in urothelial carcinoma

BackgroundWe previously reported Minichromosome maintenance 4 (MCM4) overexpression in gastric cancer. However, the clinicopathological significance of MCM4 in urothelial carcinoma (UC) has not been investigated. To clarify the clinicopathological significance of MCM4 in UC, we investigated MCM4 expression with immunohistochemistry (IHC).MethodsWe analyzed the expression and distribution of MCM4 in 124 upper tract urothelial carcinoma (UTUC) samples by IHC. Additionally, using 108 urine samples, we analyzed MCM4 Immunocytochemistry (ICC) expression in urine cytology.ResultsIn normal urothelium, MCM4 expression was weak or absent. Meanwhile, the strong nuclear expression of MCM4 was observed in UTUC tissues, and it was detected in 77 (62%) of a total of 124 UTUC cases. MCM4-positive UTUC cases were associated with nodular/flat morphology, high grade, high T stage, and poor prognosis. Moreover, MCM4 expression was significantly higher in the invasive front than in the tumor surface. Similar results were also obtained in TCGA bladder cancer cohort. Additionally, MCM4 expression was associated with high expression of Ki-67, HER2, EGFR, and p53 in UTUC. Among representative cancer-related molecules, MCM4 had an independent predictive value for progression-free survival and high-grade UC. ICC for MCM4 was also performed on urine cytology slides and showed that the nuclear expression of MCM4 was more frequently found in UC cells than in non-neoplastic cells. The diagnostic accuracy of urine cytology was improved by combining MCM4 immunostaining with cytology.ConclusionThese results suggest that MCM4 might be a useful predictive biomarker for high-grade histology, tumor progression and poor prognosis in UC. Moreover, ICC for MCM4 might be helpful for UC detection as additional markers in the cytomorphology-based diagnosis.

Clinicopathological significance of TUBB3 in upper tract urothelial carcinoma and possible application in urine cytology.

βIII-Tubulin, encoded by the TUBB3 gene, is a microtubule protein. We previously reported that TUBB3 is overexpressed in renal cell carcinoma. We investigated the clinicopathological significance of TUBB3 in upper tract urothelial carcinoma (UTUC) by immunohistochemistry. In normal tissue, TUBB3 expression was weak or absent. In contrast, TUBB3 overexpression was observed in urothelial carcinoma (UC) tissues in 51 (49%) of 103 UTUC cases. TUBB3 overexpression was associated with nodular/flat morphology, high-grade disease, high T stage, and a poor prognosis. Similar results were obtained in The Cancer Genome Atlas bladder cancer cohort. TUBB3 expression was also associated with high Ki-67 labeling index, CD44v9, HER2, EGFR, and p53 expression in UTUC. Among representative cancer-related molecules, TUBB3 was an independent predictor of progression-free survival and high-grade UC. Finally, using urine cytology samples, we analyzed TUBB3 expression by immunocytochemistry. TUBB3 expression was more frequently found in UC cells than in nonneoplastic cells. The diagnostic accuracy of urine cytology was improved when combined with TUBB3 immunostaining. The findings suggest the importance of TUBB3 in tumor progression and its potential application as a biomarker for high-grade disease and the prognosis of UC. Moreover, combination with TUBB3 immunostaining might improve the diagnostic accuracy of urine cytology.

Differential expression of SLITRK6 gene as a potential therapeutic target for urothelial carcinoma in particular upper tract cancer

BackgroundUrinary bladder urothelial carcinoma (UBUC) and upper tract urothelial carcinoma (UTUC) harbor analogous morphology with comparable cytogenetic changes as well as prognostic factors but their similar biological activities still remain controversial. SLITRK6 gene has been demonstrated to have distinct role in urothelial cancers with a distinction between UTUC and UBUC. MethodThe study included a total of 80 patients of urothelial carcinoma including 60 UBUC and 20 UTUC cases. The tumor tissues from both the groups were evaluated for gene expression at mRNA level by qRT-PCR, and protein expression by immunohistochemistry (IHC) and western blot. ResultsSignificantly more than 4-fold high mRNA expression of SLITRK6 was observed in UTUC against 1.2-fold in UBUC (p < 0.0001). The overall SLITRK6 expression by IHC was observed in 80% of the UBUC cases in comparison to 100% strong expression in UTUC patients and among two groups expression exhibited a significant difference for moderate to strong expression (p = 0.0005). The protein expression by western blot analysis in UTUC samples was considerably higher as compared to UBUC samples (1.64 vs. 0.76 respectively: p = 0.01). A strong concordance exhibited for the higher mRNA and protein expression in both UTUC and UBUC cases (∼75%) wherein 80%, 75% and 70% higher expression of SLITRK6 was detected by qRT-PCR, Western blot and IHC respectively. ConclusionTo conclude, although SLITRK6 exhibits a strong expression in both UTUC and UBUC but was considerably observed higher in majority of UTUC cases. Therefore, SLITRK6 appears as a promising novel possible gene target for urothelial carcinoma in particular UTUC.

The useful technique of laparoscopic segmental ureterectomy with ureteral reimplantation for distal upper tract urothelial carcinoma.

Segmental ureterectomy (SU) has been proven effective in cases of distal upper tract urothelial carcinoma (UTUC). Nonetheless, SU has been performed infrequently in the real world, and there is no consensus on the preferred surgical technique in laparoscopic surgery. We describe our first experience of laparoscopic segmental ureterectomy (LSU) with psoas hitch ureteral reimplantation. LSU starts using a fan-shaped, five-port, transperitoneal approach. First, the cancerous ureter segment is clipped to avoid tumor seeding, and then the diseased segment is dissected. Second, the psoas hitch is performed by fixing the external part of the ipsilateral dome of the bladder to the psoas muscle and its tendon. Third, at the top of the bladder, an incision is made in the muscle layer and mucosa. The ureter is then spatulated. A guide wire is used to place a retrograde ureteral double J stent. Finally, the anastomosis of the bladder and ureter mucosa is performed by interrupted suturing of both ends, followed by continuous suturing, and the muscular layer of the bladder is closed in a double layer. We performed LSU for distal UTUC in 10 patients. There was no decrease in renal function before or after surgery. During follow-up, three patients experienced a recurrence of urothelial carcinoma in the bladder and one patient had a local recurrence. LSU is a safe and feasible procedure in our experience, and it can be recommended for selected cases of distal UTUC with optimal perioperative, renal functional, and oncologic outcomes.

Route of Administration for UGN-101 and Impact on Oncological and Safety Outcomes

BackgroundUGN-101 can be used for chemoablation of low-grade upper tract urothelial carcinoma (UTUC). The gel can be administered via a retrograde route through a ureteral catheter or an antegrade route via a nephrostomy tube. ObjectiveTo report outcomes of UGN-101 by route of administration. Design, setting, and participantsWe performed a retrospective review of 132 patients from 15 institutions who were treated with UGN-101 for low-grade UTUC via retrograde versus antegrade administration. Outcome measurements and statistical analysisSurvival outcomes are reported per patient. Treatment, complications, and recurrence outcomes are reported per renal unit. Statistical analysis was performed for primary endpoints of oncological response and ureteral stricture occurrence. Results and limitationsA total of 136 renal units were evaluated, comprising 78 retrograde and 58 antegrade instillations. Median follow-up was 7.4 mo. There were 120 cases (91%) of biopsy-proven low-grade UTUC. Tumors were in the renal pelvis alone in 89 cases (65%), in the ureter alone in 12 cases (9%), and in both in 35 cases (26%). Seventy-six patients (56%) had residual disease before UGN-101 treatment. Chemoablation with UGN-101 was used in 50/78 (64%) retrograde cases and 26/58 (45%) antegrade cases. A complete response according to inspection and cytology was achieved in 31 (48%) retrograde and 30 (60%) antegrade renal units (p = 0.1). Clavien grade 3 ureteral stricture occurred in 21 retrograde cases (32%) and only six (12%) antegrade cases (p < 0.01). Limitations include treatment bias, as patients in the antegrade group were more likely to undergo endoscopic mechanical ablation before UGN-101 instillation. ConclusionsThese preliminary results show a significantly lower rate of stricture occurrence with antegrade administration of UGN-101, with no apparent impact on oncological efficacy. Patient summaryWe compared results for two different delivery routes for the drug UGN-101 for treatment of cancer in the upper urinary tract. For the antegrade route, a tube is inserted through the skin into the kidney. For the retrograde route, a catheter is inserted past the bladder into the upper urinary tract. Our results show a lower rate of narrowing of the ureter (the tube draining urine from the kidney into the bladder) using the antegrade route, with no difference in cancer control.

MP69-05 FEASIBILITY OF DNA METHYLATION MARKERS FOR DIAGNOSIS AND PROGNOSIS OF UPPER TRACT UROTHELIAL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP69-05 FEASIBILITY OF DNA METHYLATION MARKERS FOR DIAGNOSIS AND PROGNOSIS OF UPPER TRACT UROTHELIAL CARCINOMA Farshad Sheybaee Moghaddam, Alireza Ghoreifi, Hongtao Li, Yohei Sekino, Kian Asanad, Manju Aron, Gangning Liang, and Hooman Djaladat Farshad Sheybaee MoghaddamFarshad Sheybaee Moghaddam More articles by this author , Alireza GhoreifiAlireza Ghoreifi More articles by this author , Hongtao LiHongtao Li More articles by this author , Yohei SekinoYohei Sekino More articles by this author , Kian AsanadKian Asanad More articles by this author , Manju AronManju Aron More articles by this author , Gangning LiangGangning Liang More articles by this author , and Hooman DjaladatHooman Djaladat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003332.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Upper tract urothelial carcinoma (UTUC) is an uncommon, yet biologically heterogeneous disease that accounts for 5-10% of all urothelial tumors. The diagnosis and risk-stratification of UTUC patients is challenging given the limitations of current diagnostic tools. DNA methylation has emerged as a potential prognostic and diagnostic factor in urothelial carcinoma, yet few studies have examined its role in UTUC. In this study, we aim to identify specific tissue DNA methylation markers in muscle invasive (≥pT2) and non-muscle invasive (<pT2) UTUC cases. METHODS: Microdissection and DNA extraction of over 300 slides were performed and the EPIC work was completed on all USC samples-including 8 non-muscle invasive, 10 muscle invasive and lymph node positive samples and 4 normal tissue/WBC as controls. Methylation patterns were analyzed and compared between non-muscle invasive (NMI) and muscle invasive (MI) UTUC samples. Table 1 shows epics from other centers were also included in the study. A training set including epic data of 32 normal samples, 50 non-muscle invasive (NMI), and 48 muscle invasive samples (MI) was used to design the probe, and Epic data of 65 samples including 17 normal tissue, 24 NMI and 24 MI samples were used as testing samples. Principle component analysis (PCA) was used to cluster the UTUC and normal samples. RESULTS: Different patterns of methylation were detected in NMI versus MI-UTUCs. By comparing adjacent normal tissues and white blood cells (WBCs), specific DNA methylation probes were developed for NMI-UTUC and MI-UTUCs (Figure 1). According to PCA, MI-UTUC vs NMI-UTUC 1924 probes is able to cluster the UTUC samples (|deltaMedian|>0.3, p<0.05) (Figure 2). CONCLUSIONS: UTUC has a distinct DNA methylation pattern that is distinguishable from normal urothelial tissue. UTUC-specific DNA methylation probes can be used to differentiate muscle-invasive UTUCs. Source of Funding: University of Southern California Urology research council © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e965 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Farshad Sheybaee Moghaddam More articles by this author Alireza Ghoreifi More articles by this author Hongtao Li More articles by this author Yohei Sekino More articles by this author Kian Asanad More articles by this author Manju Aron More articles by this author Gangning Liang More articles by this author Hooman Djaladat More articles by this author Expand All Advertisement PDF downloadLoading ...

PD46-06 UROLOGICAL FOLLOW-UP AND MUTATIONAL PATTERNS IN LYNCH SYNDROME PATIENTS: A SINGLE CENTER EXPERIENCE

You have accessJournal of UrologyCME1 Apr 2023PD46-06 UROLOGICAL FOLLOW-UP AND MUTATIONAL PATTERNS IN LYNCH SYNDROME PATIENTS: A SINGLE CENTER EXPERIENCE Pietro Scilipoti, Mattia Longoni, Chiara Re, Giuseppe Rosiello, Alessandro Bertini, Mario de Angelis, Giorgio Gandaglia, Eugenio Ventimiglia, Umberto Capitanio, Andrea Salonia, Francesco Montorsi, Alberto Briganti, and Marco Moschini Pietro ScilipotiPietro Scilipoti More articles by this author , Mattia LongoniMattia Longoni More articles by this author , Chiara ReChiara Re More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Alessandro BertiniAlessandro Bertini More articles by this author , Mario de AngelisMario de Angelis More articles by this author , Giorgio GandagliaGiorgio Gandaglia More articles by this author , Eugenio VentimigliaEugenio Ventimiglia More articles by this author , Umberto CapitanioUmberto Capitanio More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , and Marco MoschiniMarco Moschini More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003359.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lynch Syndrome (LS) is a genetic dominant autosomal disease that predisposes to a broad spectrum of tumors, among which Upper Tract Urothelial Carcinoma (UTUC) is the third most common manifestation. We present the first results of our LS dedicated outpatient clinic with the aim of evaluating the incidence of UTUC, patterns of mutation and individuate the optimal follow up schemes among patients affected by LS. METHODS: We observed 23 LS patients from December 2021 to October 2022 at a tertiary referral center. We collected prospectively data regarding LS mutations, medical and family history and simultaneously started a strict follow up strategy. Genetic diagnosis was obtained both by Immunohistochemistry (IHC) and by genetic test (DNA sequencing). For each patient we applied Bethesda, EAU guidelines, Amsterdam I and II criteria. Follow up strategy was based on Ultrasound (US), urinalysis and urinary citology every two years. In high-risk cases (age >50 years, MSH2 mutation carriers and family history of UTUC) CT-scans where alternated with US every year in addition to urinary citology. RESULTS: Among this court 52.2% of patients (n=12) had a LS diagnosis after cancer manifestation, meanwhile 47.8% (n=11) through genetic counseling due to investigation in first degree relatives. Among our patient population, 8 patients (34.8%) had a diagnosis of colorectal cancer, 4 (17.4%) UTUC, 1 (4.3%) endometrial, 1 (4.3%) gastric, 1 (4.34%) skin cancer and 2 rare LS related cancer (Renal Clear Cell Carcinoma and Lung Cancer). MSH2 mutation was detected in 39.1% of cases (n=9), while MLH1 was found in 34.8% of cases (n=8). In subgroup analysis colorectal cancer's most common mutation was MSH2 (50%) followed by MLH1 (25%) and MSH6 (25%), while among UTUC cases, MSH2 was the most common (75%) and MLH1 was reported in 25% of cases. Median age at UTUC diagnosis was 60, while median age at colorectal cancer diagnosis was 49 (p=0.007). Bethesda and EAU guidelines criteria were more accurate (91% vs 90%) compared to Amsterdam I and II criteria (74%). No tumor diagnosis was made during the observational time. CONCLUSIONS: The current study is a first attempt to establish a dedicated LS outpatient clinic. This will let us observe the most frequent mutations, thus potentially in the future allow us to diagnose UTUC earlier and provide a refined follow up to LS patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1172 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pietro Scilipoti More articles by this author Mattia Longoni More articles by this author Chiara Re More articles by this author Giuseppe Rosiello More articles by this author Alessandro Bertini More articles by this author Mario de Angelis More articles by this author Giorgio Gandaglia More articles by this author Eugenio Ventimiglia More articles by this author Umberto Capitanio More articles by this author Andrea Salonia More articles by this author Francesco Montorsi More articles by this author Alberto Briganti More articles by this author Marco Moschini More articles by this author Expand All Advertisement PDF downloadLoading ...

Inherited mutations in Chinese patients with upper tract urothelial carcinoma

Upper tract urothelial carcinoma (UTUC) accounts for 10% of urothelial carcinomas (UCs) and has a substantial hereditary component. However, the majority of our knowledge of germline spectrum comes from bladder cancer (BCa) data in White populations. Here, we sequence 309 Chinese UTUC cases and identify 71 germline pathogenic/likely pathogenic (P/LP) mutations in 62 patients (20.1%). Compared with White cases, we observe disparities and similarities in inherited mutational profiles. Association analysis reveals that germline P/LP mutations in MSH2, BRCA2, BRCA1, and BRIP1 significantly increase UTUC risk in Chinese populations. Furthermore, germline P/LP mutation in homologous recombination genes indicates poor prognosis for non-metastatic UTUC. Finally, we perform paired sequencing and observe significant correlations between germline mutation patterns and tumor subtypes. This study highlights the importance of genetic testing in patients with UTUC and calls for germline data from various ethnicities to better understand this disease.

Clinicopathological significance of the overexpression of MUC1 in upper tract urothelial carcinoma and possible application as a diagnostic marker.

Mucin 1 (MUC1) overexpression has been reported in many malignancies and is associated with a poor prognosis. However, the clinicopathological significance of MUC1 in upper tract urothelial carcinoma (UTUC) has not been investigated. We analyzed the expression and distribution of MUC1 in UTUC by immunohistochemistry. In normal urothelium, MUC1 expression was observed on the surface of umbrella cells. Meanwhile, the strong expression of MUC1 was observed in cell membranes and cytoplasm in UTUC tissues, and it was detected in 64 (58%) of a total of 110 UTUC cases. MUC1-positive UTUC cases were associated with nodular/flat morphology, high grade, high T stage, and lymphatic and venous invasion and poor prognosis. Additionally, MUC1 expression was associated with high expression of Ki-67, programmed death-ligand 1 (PD-L1), CD44 variant 9 (CD44v9), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and p53 in UTUC. Furthermore, immunocytochemistry for MUC1 on urine cytology slides demonstrated that the strong staining of MUC1 was more frequently found in tumor cells than in nonneoplastic cells. The diagnostic accuracy of urine cytology was improved by combining MUC1 immunostaining with cytology. These results suggest that MUC1 may be a prognostic biomarker in UTUC, and MUC1 exression has a potential application as a diagnostic immunomarker for urine cytology.

Optimizing Upper-Tract Imaging for Non-Visible Haematuria

Introduction: Non-visible haematuria (NVH) is associated with a small risk of upper-tract urothelial carcinoma (UTUC), though there is little consensus on its investigation, particularly with regard to upper-tract imaging. This study aimed to determine whether the presentation of UTUC can guide investigation of NVH in patients under 60 years old. Methods: All patients investigated at our one-stop haematuria clinics under a cancer pathway were reviewed during a 5-year period, with all patients undergoing cystoscopy and upper-tract imaging. Retrospective analysis of all UTUC cases from our urological cancer multidisciplinary team meeting database over a 10-year period was also undertaken. Results: 2,129 patients with a median age of 67 years underwent urgent investigation for haematuria between March 2015 and February 2020. 449 cases presented with NVH, of whom 124 (27.6%) were under 60. Out of 21 cases of UTUC, only 2 presented with NVH; both were over the age of 60 years. Factors that independently predicted diagnosis with urinary-tract malignancy were age ≥60 (OR 3.70, p < 0.001), visible haematuria (OR 2.50, p = 0.006), and suspicious cystoscopic findings (OR 58.06, p < 0.001). Review of all 119 UTUC cases over 10 years found 6 cases (5.0%) presenting with NVH, with one (0.8%) also presenting under 60 years. Conclusion: Diagnosis with UTUC is rare in patients presenting with NVH under the age of 60 years. Routine use of CTU in this low-risk group is best avoided, with ultrasonography constituting a safer first-line upper-tract imaging modality. Guidelines that risk-stratify NVH patients may be effective in reducing unnecessary investigations.

Perioperative circulating tumor DNA enables the identification of patients with poor prognosis in upper tract urothelial carcinoma

Perioperative systemic chemotherapy improves the prognosis of upper tract urothelial carcinoma (UTUC). The first objective of this study was to verify whether perioperative circulating tumor DNA (ctDNA) analysis using a pan‐cancer gene panel and next‐generation sequencing could identify patients with poor prognosis who require perioperative chemotherapy. Second, we investigated whether ctDNA is useful for minimal residual disease (MRD) detection and treatment monitoring in UTUC. This study included 50 patients with untreated UTUC, including 43 cases of localized UTUC. We performed targeted ultradeep sequencing of plasma cell‐free DNA (cfDNA) and buffy coat DNA and whole‐exome sequencing of cancer tissues, allowing exclusion of possible false positives. We attempted to stratify the prognosis according to the perioperative ctDNA levels in patients with localized UTUC. In patients with metastatic UTUC, ctDNA was evaluated before, during, and after systemic treatment. In total, 23 (46%) of 50 patients with untreated UTUC were ctDNA positive, and 17 (40%) of 43 patients with localized UTUC were ctDNA positive. Of the detected TP53 mutations, 19% were false positives due to clonal hematopoiesis of indeterminate potential. Among preoperative risk factors, only the preoperative ctDNA fraction>2% was a significant and independent risk factor associated with worse recurrence‐free survival (RFS). Furthermore, the existence of ctDNA early points after the operation was significantly associated with worse RFS, suggesting the presence of MRD. ctDNA also showed a potential as a real‐time marker for systemic therapy in patients with metastatic UTUC. Detection of ctDNA may indicate potential metastasis and guide decisions on perioperative chemotherapy.

Elevated Pre-Treatment Serum MMP-7 Levels Are Associated with the Presence of Metastasis and Poor Survival in Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) is a rare cancer with a barely predictable clinical behaviour. Serum MMP-7 is a validated prognostic marker in urothelial bladder cancer, a tumour entity with large clinical, histological, and molecular similarity to UTUC. The serum MMP-7 levels have not yet been investigated in UTUC. In the present study, we determined MMP-7 concentrations in an overall number of 103 serum samples from 57 UTUC patients who underwent surgical or systemic (platinum or immune checkpoint inhibitor) therapy by using the ELISA method. In addition to pre-treatment samples, the serum samples collected at predefined time points after or during therapy were also investigated. Serum MMP-7 concentrations were correlated with clinicopathological and follow-up data. Our results revealed significantly, two-fold elevated pre-treatment serum MMP-7 levels in metastatic cases of UTUC in both the radical surgery- and the chemotherapy-treated cohorts (p = 0.045 and p = 0.040, respectively). In addition, high serum MMP-7 levels significantly decreased after radical surgery, and high pre-treatment MMP-7 concentrations were associated with shorter survival both in the surgery- and chemotherapy-treated cohorts (p = 0.029 and p = 0.001, respectively). Our results revealed pre-treatment serum MMP-7 as a prognostic marker for UTUC, which may help to improve preoperative risk-stratification and thereby improve therapeutic decision-making.

Identification of Germline Mutations in Upper Tract Urothelial Carcinoma With Suspected Lynch Syndrome

ObjectiveWhole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients.MethodsIn total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations.ResultsOf 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER.ConclusionsWe identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.

High Ubiquitin-Specific Protease 2a Expression Level Predicts Poor Prognosis in Upper Tract Urothelial Carcinoma.

Ubiquitin-mediated protein degradation has been reported to be involved in regulating the activity of oncoproteins and tumor suppressors. Dysfunction or dysregulation of the ubiquitin-proteasome system may induce tumorigenesis. Deubiquitinase ubiquitin-specific protease 2a (USP2a) has been reported to regulate cell growth or death and is involved in the pathogenesis of various diseases, including cancers. However, the role of USP2a in upper tract urothelial carcinoma (UTUC) has not been investigated yet. The goal of this study was to evaluate the clinical significance of USP2a expression in UTUC. A total of 110 UTUC cases were included in this study. USP2a expression level was evaluated through immunohistochemistry staining, and the correlation of USP2a expression level with both clinical and pathologic variables was analyzed. High USP2a expression level was observed in 48 (43.6%) cancer specimens. USP2a expression level was significantly correlated with tumor stage (P=0.001), grade (P=0.033), and tumor recurrence (P=0.008). High USP2a expression level was correlated with poor disease-free survival (P=0.005) and cancer-specific survival (P<0.001). In addition, high USP2a expression level was an independent predictor of poor disease-free survival (hazard ratio=2.31; P=0.007) and cancer-specific survival (hazard ratio=5.49; P=0.009). This study indicated that USP2a protein expression level may be a potential biomarker for predicting UTUC patient survival. Further prospective studies are needed to investigate the role of USP2a in UTUC progression.

Tumor distribution affects bladder recurrence but not survival outcome of multifocal upper tract urothelial carcinoma treated with radical nephroureterectomy

Tumor multifocality and location are prognostic factors for upper tract urothelial carcinoma (UTUC). However, confounding effects can appear when these two factors are analyzed together. Therefore, we aimed to investigate the impact of tumor distribution on the outcomes of multifocal UTUC after radical nephroureterectomy. From the 2780 UTUC patients in the Taiwan UTUC Collaboration Group, 685 UTUC cases with multifocal tumors (defined as more than one tumor lesion in unilateral upper urinary tract) were retrospectively included and divided into three groups: multiple renal pelvic tumors, multiple ureteral tumors, and synchronous renal pelvic and ureteral tumors included 164, 152, and 369 patients, respectively. We found the prevalence of carcinoma in situ was the highest in the synchronous group. In multivariate survival analyses, tumor distribution showed no difference in cancer-specific and disease-free survival, but there was a significant difference in bladder recurrence-free survival. The synchronous group had the highest bladder recurrence rate. In summary, tumor distribution did not influence the cancer-specific outcomes of multifocal UTUC, but synchronous lesions led to a higher rate of bladder recurrence than multiple renal pelvic tumors. We believe that the distribution of tumors reflects the degree of malignant involvement within the urinary tract, but has little significance for survival or disease progression.

PD43-12 WHAT PART DOES URETEROSCOPY PLAY IN THE DIAGNOSTIC PATHWAY OF UPPER TRACT TRANSITIONAL CARCINOMA? A TWO-YEAR REVIEW IN A HIGH-VOLUME INSTITUTION

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma I (PD43)1 Sep 2021PD43-12 WHAT PART DOES URETEROSCOPY PLAY IN THE DIAGNOSTIC PATHWAY OF UPPER TRACT TRANSITIONAL CARCINOMA? A TWO-YEAR REVIEW IN A HIGH-VOLUME INSTITUTION Radha Sehgal, Shifa Wong, Yasmin Abu-Ghanem, Theodore Birks, Rajesh Kucheria, Darrell Allen, Anuj Goyal, Paras Singh, Leye Ajayi, and Gidon Ellis Radha SehgalRadha Sehgal More articles by this author , Shifa WongShifa Wong More articles by this author , Yasmin Abu-GhanemYasmin Abu-Ghanem More articles by this author , Theodore BirksTheodore Birks More articles by this author , Rajesh KucheriaRajesh Kucheria More articles by this author , Darrell AllenDarrell Allen More articles by this author , Anuj GoyalAnuj Goyal More articles by this author , Paras SinghParas Singh More articles by this author , Leye AjayiLeye Ajayi More articles by this author , and Gidon EllisGidon Ellis More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002057.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Ureteroscopy (URS) is an established diagnostic tool in the diagnosis of upper tract urothelial carcinoma (UTUC); it enables exclusion of UTUC in cases of diagnostic uncertainty and facilitates endoscopic kidney-sparing management in selected cases. However, its use is controversial due to the potential risk of tumour seeding into the bladder and delays incurred in the diagnostic pathway. We aim to review the diagnostic value of URS a large cohort of patients investigated for UTUC. METHODS: We performed retrospective review of diagnostic URS at our institution for suspected UTUC between January 2018 to December 2019. Demographics, CT urogram (CTU) findings, cytology and intra-operative appearances were obtained from electronic records. Histology was recorded from ureteroscopic biopsy and where applicable, final radical nephroureterectomy (RNU). RESULTS: A total of 161 diagnostic URS were performed for suspected UTUC. Patients presented predominantly with haematuria (42%). Pre-operative CTU w demonstrated a filling defect/lesion (48%), hydronephrosis (25%), urothelial thickening (21%) or no abnormality (6%), where URS was performed due to persistent haematuria or blood from the ureteric orifice at cystoscopy. Selective cytology was positive in 34 cases (27%). Urothelium was visually suspicious in 71 cases (44%) and biopsy results were malignant in 41 cases (25%). A diagnosis of UTUC was confirmed based on cytology and histology in 47 cases (29%). Of these, 31 patients (66%) underwent RNU, 14 patients (30%) underwent kidney-sparing management and 2 patients (4%) were unfit for further surgery. Two patients underwent RNU where the final histology was not UTUC (renal cell carcinoma and renomedullary interstital tumour). Following a negative URS, 68 patients (54%) were discharged or reassured and 8 patients (6%) were referred to other specialties for non-urothelial tumours. CONCLUSIONS: Diagnostic URS is crucial in accurately diagnosing and staging UTUC. Of the 47 confirmed cases of UTUC, 30% of patients underwent kidney-sparing management. RNU was avoided in 61% of patients who were subsequently discharged following negative URS or diagnosed with non-urothelial tumours. We conclude that in cases of diagnostic uncertainty and where kidney-sparing management is feasible, URS should remain in the diagnostic pathway of UTUC. Further research into diagnostic pathway delays and intravesical recurrence in this cohort is ongoing. Source of Funding: N/A © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e735-e735 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Radha Sehgal More articles by this author Shifa Wong More articles by this author Yasmin Abu-Ghanem More articles by this author Theodore Birks More articles by this author Rajesh Kucheria More articles by this author Darrell Allen More articles by this author Anuj Goyal More articles by this author Paras Singh More articles by this author Leye Ajayi More articles by this author Gidon Ellis More articles by this author Expand All Advertisement Loading ...

Lessons from a pilot study of screening for upper tract urothelial cell carcinoma in Lynch syndrome.

Background Lynch syndrome is a hereditary disorder, with a very high risk of developing colorectal carcinoma (CRC) and a predilection to develop other cancers, including upper tract urothelial carcinoma (UTUC). We aimed to assess the prevalence of UTUC in a Lynch syndrome cohort undergoing screening for CRC, to determine the need for a UTUC screening programme. Methods Lynch syndrome patients were screened with urine dipstick for microscopic haematuria. Patients with confirmed microhaematuria were offered urine cytology, microscopy and culture, ultrasound (US) of their upper tracts and flexible cystoscopy. Results Of the 89 patients screened, 86 had an MLH1 mutation and two had an MSH2 mutation. Eleven of the 12 patients who had microscopic haematuria were female. Ten patients had urinary tract infections. One patient had follicular cystitis and another had a simple renal cyst. No patients had hydronephrosis on ultrasound. All urine cytology specimens were negative for malignancy. Conclusion No cases of UTUC were detected in our cohort during this study. A more rational screening protocol in this group may be to screen patients for UTUC with known MSH2 mutations at an earlier age (over 35).