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Original Articles
- Integrative Genomic Analysis Reveals Molecular and Clinical Disparities between Bladder and Upper Tract Urothelial Carcinoma in K-MASTER Program
- Jiwon Kim, Jwa Hoon Kim, Kyong Hwa Park, Seok Ho Kang, Jae Lyun Lee, Woo Kyun Bae, Miso Kim, Jong Gwon Choi, Inkeun Park, Ji Hyun Park, Sang Joon Shin, Jungmin Jo, Se Hoon Park, Kwonoh Park, Ji Yoon Lee, Youjin Song, Dayoung Lee, Namsung Moon, Jason K. Sa, Yoon Ji Choi
- Received January 22, 2026 Accepted August 3, 2026 Published online August 4, 2026
- DOI: https://doi.org/10.4143/crt.2026.0081 [Accepted]
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Abstract
PDF - Purpose
The clinical outcome of urothelial carcinoma presents significant variability, reflecting its molecular composition, epidemiologic attributes, and primary site of origin. Despite histological similarities, upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BLCA) represent two distinct disease entities with disparate treatment responses and mutational patterns.
Materials and Methods
To assess the impact of molecular heterogeneity on treatment outcomes, we conducted a comprehensive genomic analysis of 231 metastatic urothelial carcinoma patients, including 175 patients with BLCA and 56 patients with UTUC, in the K-MASTER program.
Results
Our investigation unveiled dynamic molecular properties and mutational patterns in key molecules, including TP53, FGFR3, CREBBP, and SPEN. BLCA patients demonstrated enrichment of APOBEC mutational signature activities, whereas UTUC patients were characterized by activation of the cell cycle pathway. Transcriptome analysis uncovered unique biological signatures, highlighting increased cell migration and WNT signaling in BLCA, while FGFR3 and stem-cell-like pathways predominated in UTUC. Moreover, our study highlighted increased resistance to platinum-based chemotherapy and immunotherapy among UTUC patients. Importantly, tumor mutational burden (TMB) emerged as a robust independent predictor of immunotherapy response in BLCA. Additionally, a machine learning-based multivariable model identified FGFR3 mutation as a molecular determinant associated with favorable clinical outcomes, in contrast to FGFR2 mutations, which were linked to increased resistance to chemotherapy. The study also has limitations, including a limited sample size of UTUC patients and a lack of functional validation of the identified molecular mechanism.
Conclusion
Our findings provide unprecedented insights into the significance of molecular and clinical disparities in urothelial carcinoma, facilitating disease-specific treatment interventions.
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- 50 Download
- Genitourinary cancer
- Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study
- Junho Lee, Sung Hee Lim, Jae Hoon Chung, Wan Song, Hyun Hwan Sung, Byong Chang Jeong, Se Hoon Park
- Cancer Res Treat. 2024;56(3):871-876. Published online January 16, 2024
- DOI: https://doi.org/10.4143/crt.2023.1226
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Abstract
PDF
PubReader
ePub - Purpose
The aim of this retrospective study was to evaluate the efficacy of adjuvant cisplatin-based chemotherapy in patients with locally advanced upper tract urothelial carcinoma (UTUC), administered following radical nephroureterectomy.
Materials and Methods
Patients with UTUC, arising from renal pelvis or ureter, staged pT3/T4 or N+ were treated with adjuvant chemotherapy following surgery. The chemotherapy consisted of gemcitabine 1,000 mg/m2 on days 1 and 8, cisplatin 70 mg/m2 on day 1. Treatment was repeated every 3 weeks for up to 4 cycles. Endpoints included disease-free survival (DFS), metastasis-free survival (MFS), and safety.
Results
Among 89 eligible patients, 85 (95.5%) completed at least 3 cycles of adjuvant chemotherapy. Chemotherapy was well tolerated, the main toxicities being mild-to-moderate gastrointestinal toxic effects and pruritus. With a median follow-up of 37 months, median DFS was 30 months (95% confidence interval, 22 to 39), and the median MFS was not reached. The 3-year DFS and MFS were 44% and 56%, respectively. Multivariate analyses revealed that the main factor associated with DFS and MFS was the lymph node involvement, whereas age, T category, grade, or the primary site of UTUC were not significantly associated with DFS or MFS.
Conclusion
Adjuvant cisplatin-based chemotherapy after radical surgery of pT3/T4 or N+ UTUC was feasible and may demonstrate benefits in DFS and MFS. Whether novel agents added to the chemotherapy regimen, as a concurrent combination or maintenance, impacts on survival or reduces the development of metastases remains to be studied. -
Citations
Citations to this article as recorded by
- Scientific advances in drug development and clinical trials for urothelial carcinoma: Highlights from the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium
Ruicheng Wu, Dengxiong Li, Dechao Feng
Asian Journal of Urology.2026; 13(2): 246. CrossRef - Adjuvant disitamab vedotin plus PD-1 blockade and gemcitabine/cisplatin in high-risk upper tract urothelial carcinoma: a two-stage real-world comparative study
Cheng Wang, Shuaipeng He, Dan Li, Biao Zhang, Yu Dai, Can Li, Xuan Li, Le Kang, Shujun Yang, Su Zhang, Ning Fan, Hong Chang, Gongjin Wu, Zhongjin Yue, Junhai Ma, Panfeng Shang
Frontiers in Immunology.2026;[Epub] CrossRef - Perioperative and oncological outcomes of single position retroperitoneoscopic radical nephroureterectomy for upper urinary tract urothelial carcinoma
Jiaqiang Chen, Luxin Zhang, Zhihong Dai, Cheng Chang, Heyao Tong, Hepeng Cui, Zhuwei Song, Bo Fan, Zhiyu Liu, Liang Wang
Scientific Reports.2025;[Epub] CrossRef - Cisplatin/gemcitabine
Reactions Weekly.2024; 2027(1): 127. CrossRef
- Scientific advances in drug development and clinical trials for urothelial carcinoma: Highlights from the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium
- 8,691 View
- 159 Download
- 3 Web of Science
- 4 Crossref
- Invasiveness of Upper Tract Urothelial Carcinoma: Clinical Significance and Integrative Diagnostic Strategy
- Bokyung Ahn, Doeun Kim, Kye Jin Park, Ja-Min Park, Sun Young Yoon, Bumsik Hong, Yong Mee Cho, Deokhoon Kim
- Cancer Res Treat. 2024;56(3):856-870. Published online December 18, 2023
- DOI: https://doi.org/10.4143/crt.2023.1150
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Abstract
PDF
Supplementary MaterialPubReaderePub - Purpose
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.
Materials and Methods
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.
Results
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).
Conclusion
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. -
Citations
Citations to this article as recorded by- Papillary renal neoplasm with reverse polarity shows benign behavior: Results from a 77-case clinicopathological and molecular study
Yong Il Lee, Ja-Min Park, Sun Young Yoon, Cheryn Song, Yong Mee Cho
Annals of Diagnostic Pathology.2026; 80: 152498. CrossRef - Diagnostic accuracy of upper tract urothelial carcinoma using biopsy, urinary cytology, and nephroureterectomy specimens: A tertiary cancer center experience
Jianping Zhao, Yuan Shen, Ming Guo, Surena F Matin, Donna E Hansel, Charles C Guo
American Journal of Clinical Pathology.2024;[Epub] CrossRef - Clinical Significance of Tumor Location for Ureteroscopic Tumor Grading in Upper Tract Urothelial Carcinoma
Satoshi Katayama, Benjamin Pradere, Nico C. Grossman, Aaron M. Potretzke, Stephen A. Boorjian, Alireza Ghoreifi, Siamak Daneshmand, Hooman Djaladat, John P. Sfakianos, Andrea Mari, Zine-Eddine Khene, David D’andrea, Nozomi Hayakawa, Kazutoshi Fujita, Axel
Journal of Endourology.2024; 38(11): 1156. CrossRef - Development and validation of a radiomics-based nomogram for predicting pathological grade of upper urinary tract urothelial carcinoma
Yanghuang Zheng, Hongjin Shi, Shi Fu, Haifeng Wang, Xin Li, Zhi Li, Bing Hai, Jinsong Zhang
BMC Cancer.2024;[Epub] CrossRef
- Papillary renal neoplasm with reverse polarity shows benign behavior: Results from a 77-case clinicopathological and molecular study
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- 123 Download
- 4 Web of Science
- 4 Crossref
- Genitourinary Cancer
- Effects of Complete Bladder Cuff Removal on Oncological Outcomes Following Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma
- Hyunsoo Ryoo, Jungyu Kim, Taejin Kim, Minyong Kang, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Hyun Hwan Sung
- Cancer Res Treat. 2021;53(3):795-802. Published online December 28, 2020
- DOI: https://doi.org/10.4143/crt.2020.919
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Abstract
PDFPubReaderePub
- Purpose
This study aimed to evaluate the effects of bladder cuff method on oncological outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma.
Materials and Methods
The records of 1,095 patients treated with RNU performed at our hospital between 1994 and 2018 were retrospectively reviewed; 856 patients with no bladder tumor history were enrolled in the present study. The management of bladder cuff was divided into two categories: extravesical ligation (EL) or transvesical resection (TR). Survival was analyzed using the Kaplan-Meier method and Cox regression analyses were performed to determine which factors were associated with intravesical recurrence (IVR)–free survival (IVRFS), cancer-specific survival (CSS), and overall survival (OS).
Results
The mean patient age was 64.8 years and the median follow-up was 37.7 months. Among the 865 patients, 477 (55.7%) underwent the TR and 379 (44.3%) the EL. Significantly higher IVRFS (p=0.001) and OS (p=0.013) were observed in the TR group. In multivariable analysis, IVR, CSS, and OS were independently associated with the EL. Among 379 patients treated with the EL, eight underwent remnant ureterectomy. Based on radical cystectomy–free survival, significant difference was not observed between the two groups. However, significantly higher IVRFS was observed in the TR group when the tumor was located in the renal pelvis.
Conclusion
Intramural complete excision of the distal ureter during RNU should be the gold standard approach compared with EL for the management of distal ureter in terms of oncological outcomes. -
Citations
Citations to this article as recorded by- Bladder cuff excision techniques in upper urinary tract urothelial carcinoma: A multicenter comparative study
Kuan-Ju Wu, Hsiang Ying Lee, Hsin-Chih Yeh, Chao-Hsiang Chang, Chin-Chung Yeh, Chao-Yuan Huang, Jian-Hua Hong, Yao-Chou Tsai, Jen-Shu Tseng
Urological Science.2026; 37(1): 39. CrossRef - Selbstkritische, multizentrische Analyse der Behandlungs- und Kodierqualität am Beispiel der Nephroureterektomie anhand von Abrechnungsdaten
Nici Markus Dreger, Christine Lenhart, Friedrich-Carl von Rundstedt, Thomas Steiner, Mark Schrader, Chris Protzel, Martin Friedrich, Wolfgang Jäger, Frank vom Dorp, Alexander Roosen, Olaf Reichelt, Sven Hohenstein, Stephan Degener
Die Urologie.2026; 65(3): 288. CrossRef - Oncological Outcomes of Different Managements of the Distal Ureter in Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma
Hongda Zhao, Kang Liu, Chi-Fai Ng, Jean de la Rosette, Pilar Laguna, Jeremy Yuen-Chun Teoh
European Urology Oncology.2026;[Epub] CrossRef - Nephroureterectomy with ileal cuff for upper tract recurrence after radical cystectomy: oncologic and survival outcomes
Il Woo Park, Min Uk Park, Bumjin Lim, In Gab Jeong, Jungyo Suh, Bumsik Hong
World Journal of Urology.2026;[Epub] CrossRef - Single Early Intravesical Instillation of Epirubicin for Preventing Bladder Recurrence after Nephroureterectomy in Upper Urinary Tract Urothelial Carcinoma
Jong Hoon Lee, Chung Un Lee, Jae Hoon Chung, Wan Song, Minyong Kang, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Hwan Sung
Cancer Research and Treatment.2024; 56(3): 877. CrossRef - Violation of onco-surgical principles is associated with survival outcomes in upper tract urothelial carcinomas after radical nephroureterectomy
Ioannis Patras, Johan Abrahamsson, Axel Gerdtsson, Martin Nyberg, Ymir Saemundsson, Elin Ståhl, Anne Sörenby, Åsa Warnolf, Johannes Bobjer, Fredrik Liedberg
Scandinavian Journal of Urology.2024; 59: 131. CrossRef - Differential effect of surgical technique on intravesical recurrence after radical nephroureterectomy in patients with upper tract urothelial cancer: a systematic review and Meta-analysis
Ichiro Tsuboi, Akihiro Matsukawa, Mehdi Kardoust Parizi, Jakob Klemm, Robert J Schulz, Anna Cadenar, Stefano Mancon, Sever Chiujdea, Tamás Fazekas, Marcin Miszczyk, Ekaterina Laukhtina, Tatsushi Kawada, Satoshi Katayama, Takehiro Iwata, Kensuke Bekku, Koi
World Journal of Urology.2024;[Epub] CrossRef - The impact of bladder cuff excision on outcomes after nephroureterectomy for upper tract urothelial carcinoma: An analysis of the ROBUUST 2.0 registry
Courtney Yong, James E. Slaven, Zhenjie Wu, Vitaly Margulis, Hooman Djaladat, Alessandro Antonelli, Giuseppe Simone, Raj Bhanvadia, Alireza Ghoreifi, Farshad Sheybaee Moghaddam, Francesco Ditonno, Gabriele Tuderti, Stephan Bronimann, Sohail Dhanji, Benjam
Urologic Oncology: Seminars and Original Investigations.2024; 42(11): 373.e1. CrossRef - A new nomogram for predicting extraurothelial recurrence in patients with upper urinary tract urothelial carcinoma following radical nephroureterectomy
Hao Wu, Dan Jia, Xianyu Dai, Hongliang Cao, Fulin Wang, Tong Yang, Lei Wang, Tao Xu, Baoshan Gao
Frontiers in Oncology.2024;[Epub] CrossRef - Perioperative and oncological outcomes of distal ureter management during nephroureterectomy for upper urinary tract urothelial carcinoma: a systematic review and meta-analysis
Andrea GALLIOLI, Michael BABOUDJIAN, Pietro DIANA, Marco MOSCHINI, Evanguelos XYLINAS, Francesco DEL GIUDICE, Ekaterina LAUKHTINA, Francesco SORIA, Andrea MARI, José D. SUBIELA, Mathieu ROUY, Angelo TERRITO, Giuseppe BASILE, Joan PALOU, Benjamin PRADERE,
Minerva Urology and Nephrology.2023;[Epub] CrossRef - Predicting and Decreasing Bladder Tumor Recurrence Following Nephroureterectomy
Hiroko Miyagi, Elizabeth A. Di Valerio, Padraic O’Malley, Wayne G. Brisbane, Li-Ming Su, Paul L. Crispen
Frontiers in Urology.2022;[Epub] CrossRef - Inadvertent radical nephrectomy leads to worse prognosis in renal pelvic urothelial carcinoma patients: A propensity score-matched study
Feixiang Wu, Pan Zhang, Lingxun Li, Shiqing Lin, Jianhong Liu, Yi Sun, Yuanlong Wang, Chengjun Luo, Yu Huang, Xiao Yan, Meng Zhang, Guixi Liu, Kun Li
Frontiers in Oncology.2022;[Epub] CrossRef
- Bladder cuff excision techniques in upper urinary tract urothelial carcinoma: A multicenter comparative study
- 10,273 View
- 160 Download
- 13 Web of Science
- 12 Crossref
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