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Diagnostic challenges and treatment strategies in the management of upper-tract urothelial carcinoma.

ABSTRACT: Upper-tract urothelial carcinoma (UTUC) is a rare disease, posing many challenges for the treating physician due to the lack of strong evidence-based recommendations. However, novel molecular discoveries and a better understanding of the clinical behavior of the disease lead to a continuous evolution of therapeutic landscape in UTUC. The aim of the review is to provide a comprehensive update of the current diagnostic modalities and treatment strategies in UTUC with a special focus on recent developments and challenges. A comprehensive literature search including relevant articles up to August 2020 was performed using the MEDLINE/PubMed database. Despite several technological improvements, accurate staging and outcome prediction remain major challenges and hamper appropriate risk stratification. Kidney-sparing surgery can be offered in low risk UTUC; however, physician and patient must be aware of the high rate of recurrence and risk of progression due to tumor biology and understaging. The value and efficacy of intracavitary therapy in patients with UTUC remains unclear due to the lack of high-quality data. In high-risk diseases, radical nephroureterectomy with bladder cuff excision and template lymph node dissection is the standard of care. Perioperative systemic chemotherapy is today accepted as a novel standard for advanced cancers. In metastatic or unresectable disease, the therapeutic landscape is rapidly changing due to several novel agents, such as checkpoint inhibitors. While several diagnostic and treatment challenges remain, progress in endoscopic technology and molecular knowledge have ushered a new age in personalized management of UTUC. Novel accurate molecular and imaging biomarkers are, however, still needed to guide decision making as tissue acquisition remains suboptimal. Next generation sequencing and novel agents are promising to rapidly improve patient outcomes.

SUBMITTER: Schuettfort VM

PROVIDER: S-EPMC8057353 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.ObjectiveTo investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.Design, setting, and participantsTumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.Outcome measurements and statistical analysisWe described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).Results and limitationsComparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.ConclusionsHigh-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.Patient summaryComparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

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Diagnostic challenges and treatment strategies in the management of upper-tract urothelial carcinoma.

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