Cytology's sunset: is it time to embrace new biomarkers for upper tract urothelial carcinoma?

Upper tract urothelial carcinoma (UTUC) is a condition that affects the entire urothelium, and it can occur in both the lower and upper urinary tract.1 UTUC is a malignancy that remains difficult to identify and tends to be diagnosed at more advanced stages, primarily because of its non-specific symptoms and the limitations of current diagnostic methods.2 The prevalence of UTUC differs across regions worldwide and is shaped by a range of factors, such as environmental influences and genetic predispositions.3 While radical nephroureterectomy (RNU) represents the standard of care for high-grade UTUC,4, 5 risk assessment is crucial to identify patients who may be eligible for a kidney-sparing approach.6, 7 Although the three major guideline panels – AUA, EAU, and NCCN – differ in the weight they assign to each diagnostic modality, they all recognize ureteroscopy (URS), imaging (contrast-enhanced CT scan), and urinary cytology as critical elements in the diagnostic workup and risk assessment.2 Specifically, URS, though diagnostic in over 90% of cases, is invasive and carries risks such as ureteral injury and infection.8 Similarly, CT scan, despite its high sensitivity (92%) and specificity (95%), is expensive, involves radiation exposure, and may miss flat lesions or subtle urothelial thickening.9 Given its convenience and non-invasive nature, urine cytology has traditionally been central to UTUC diagnosis and risk assessment, despite its known limitations. Current guidelines continue to recommend its use, but its diagnostic value remains questioned.2 In their study, Figaroa et al. evaluated the performance of urine cytology as part of a comprehensive diagnostic approach for UTUC.10 The study included 176 patients suspected of UTUC, all of whom underwent urine cytology and upper tract endoscopy or RNU. The primary aim was to compare the sensitivity and specificity of urine cytology with histopathological findings from biopsies or surgical specimens. Key results showed a sensitivity of 62.8% for high-grade tumors and 52.8% for low-grade tumors. Alarmingly, the false-negative rate was 43.4%, emphasizing the limited reliability, particularly for detecting less aggressive tumors. Concordance between cytology and histopathology was 14.8% for low-grade tumors and 13.7% for high-grade tumors, further illustrating the diagnostic cytology weaknesses.10 Furthermore, diagnostic URS also fail to predict clinicopathological features in Simon et al.’s report. In fact, while biopsies provided a relatively accurate assessment of tumor grade, surgical resections resulted in reclassification of tumor invasion status in nearly one-third of cases, and 14% of upper urinary tract biopsies failed to detect a neoplasm that was subsequently resected.11 Overall, this highlights the need to integrate more robust diagnostic tools, as urine cytology alone often falls short in providing the full picture needed for accurate clinical decisions.12 While histopathology remains the gold standard, relying solely on cytology risks both overtreatment and undertreatment, potentially compromising patient outcomes.13, 14 What stands out from this research is the potential for newer, non-invasive biomarkers to fill the diagnostic gap. Techniques involving urine microbiome, DNA methylation markers and circulating DNA have demonstrated promising initial result also in bladder cancer and could represent the next frontier in UTUC diagnostics, offering a promising alternative to cytology and invasive URS biopsies.15-18 In the study by Palermo et al., Bladder Epicheck® (Nucleix, San Diego, CA, USA) demonstrated a sensitivity of 65% and a specificity of 81.2% for diagnosing UTUC, compared to cytology, which showed lower sensitivity (42.5%) but higher specificity (93.7%). Importantly, for high-grade tumors, Bladder Epicheck® (Nucleix) achieved 100% sensitivity, underscoring its potential as a reliable marker in these cases.16 Additionally, a single-center prospective study by Mu et al. provided early evidence for detecting circulating tumor DNA (ctDNA) as an emerging biomarker in UTUC. The study found ctDNA in 4 out of 6 patients with high-grade tumors and larger tumor sizes, with its presence linked to disease progression. These findings suggest that ctDNA could serve as a biomarker for monitoring tumor burden and recurrence, offering a less invasive method for real-time surveillance in UTUC patients.17 Given the findings, the question arises whether it’s time to shift our diagnostic approach. Should urine cytology alone continue to play a role in UTUC diagnosis, or should we adopt more advanced, reliable methods that enhance diagnostic accuracy? The future may lie in multimodal approaches, combining cytology with molecular markers and imaging techniques to achieve a more tailored, effective treatment strategy for UTUC patients.19 In conclusion, while urine cytology remains part of the diagnostic landscape for UTUC, its limitations are clear. It is time to explore and validate newer methods that can more accurately stratify patients, ensuring that treatment decisions are both personalized and effective. In line with large-scale prospective studies, there is a clear need for the current diagnostic paradigm to advance to address the increasing demands for precision in urologic oncology.