Upper tract urothelial carcinoma (UTUC) is an uncommon subset of tumors involving the urinary system and accounts for 5% to 10% of all urothelial tumors [1]. The standard treatment for high-risk and select low-risk nonmetastatic UTUC cases is radical nephroureterectomy with bladder cuff excision [2]. Despite surgery with curative intent, recurrence in the bladder and contralateral upper tract occurs in 22% to 47% and 2% to 6% of patients with UTUC, respectively [3], which is associated with poor patient survival and outcomes [4]. Due to the high rate of recurrence, it is essential to have monitoring modalities to identify prognostic factors or predictors that can inform clinical decision-making and improve patient outcomes. Current monitoring modalities for UTUC include a combination of urine cytology, cystoscopy, and conventional imaging such as computed tomography [2,3]. Nevertheless, these methods have suboptimal diagnostic accuracy and cost performance, indicating the need for advancements in clinical guidance for UTUC.

Blood-based liquid biopsy biomarkers, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), represent a promising opportunity to improve the diagnosis and monitoring of urothelial tumors while enabling individualized risk stratification regarding therapy and follow-up [5], [6], [7]. Isolating and analyzing such analytes from peripheral blood (PB) represents a critical step toward characterizing the disease, allowing longitudinal monitoring for recurrence and response to therapy [8,9]. Prior studies have shown promising results on the utility of blood-based liquid biopsy in urothelial carcinoma, primarily in bladder cancer patients [10]. However, limited data are available on patients with UTUC. In a previous study by our group, using a comprehensive liquid biopsy workflow, a heterogeneous population of CTCs and oncosomes (previously termed large extracellular vesicles) was identified in the PB of patients with UTUC and was able to stratify these individuals from normal donors (NDs) [9].

As there are no current blood-based biomarkers to help assess the treatment response in patients with UTUC, novel liquid biopsy analytes could greatly improve clinical care with regard to surgical timing or changes in chemotherapy regimens. In this study, we aimed to systematically visualize and characterize rare events, including CTCs and oncosomes, present in PB collected from patients with primary UTUC, to assess the efficacy of these novel biomarkers in the surveillance and prognosis of these patients.