Table 5.

Proposed integration of liquid biopsy into the UTUC KSS decision chain.

Clinical scenario	Candidate liquid biopsy	What it may add	Potential management impact	Representative refs
Hematuria/suspected UTUC before URS	Voided urine methylation, RNA, mutation, or CNV panels	Increase noninvasive diagnostic confidence and enrich pre-test probability.	May triage which patients need immediate URS versus repeat assessment.	(18, 22, 49)
Equivocal cytology or discordant local work-up	Urine-based liquid biopsy	Reduce false reassurance from negative or weak cytology.	Can support repeat sampling, closer review, or stronger caution before KSS.	(38, 55, 58)
Technically favorable but biologically uncertain lesion	Urine biomarkers and/or plasma ctDNA	Add a biology-informed layer when morphology alone is inconclusive.	May refine KSS candidacy or prompt intensified staging and MDT review.	(24, 60, 62)
Preoperative concern for invasive/NOC disease	Plasma ctDNA	Identify occult aggressive disease despite limited local evidence.	May support discussion of RNU and perioperative systemic therapy when concordant with conventional evidence.	(23, 24)
Post-KSS surveillance	Urinary or plasma tumor-informed DNA	Detect early failure or recurrence before rigid schedule-based surveillance alone.	Could individualize follow-up intensity.	(25, 51)
Post-RNU surveillance	Plasma/urinary ctDNA for MRD	Define residual-risk states and recurrence dynamics.	Supports MRD-oriented surveillance and future escalation trials.	(25, 26, 28)

KSS, kidney-sparing surgery; RNU, radical nephroureterectomy; URS, ureteroscopy; CTU, computed tomography urography; ctDNA, circulating tumor DNA; cfDNA, cell-free DNA; MRD, molecular residual disease; NOC, non–organ-confined; CNV, copy-number variation.