The clinical presentation of renal cell cancer (RCC) is shifting towards incidental and early detection, creating new challenges in RCC diagnosis. Overtreatment might be reduced with the development of new diagnostic biomarkers to distinguish benign from malignant small renal masses (SRMs). Differently from tissue biopsies, liquid biopsies are obtained from a patient’s blood or urine and, therefore, are minimally invasive and suitable for longitudinal monitoring. The most promising types of liquid biopsy biomarkers for RCC diagnosis are circulating tumour cells, extracellular vesicles (EVs) and cell-free DNA. Circulating tumour cell assays have the highest specificity, with low processing time and costs. However, the biological characteristics and low sensitivity limit the use of these markers in SRM diagnostics. Cell-free DNA might complement the diagnosis of high-volume RCC, but the potential for clinical application in SRMs is limited. EVs have the highest biological abundance and the highest sensitivity in identifying low-volume disease; moreover, the molecular characteristics of these markers make EVs suitable for multiple analytical applications. Thus, currently, EV assays have the greatest potential for diagnostic application in RCC (including identification of SRMs). All these liquid biomarkers have potential in clinical practice, pending validation studies. Biomarker implementation will be needed to also improve characterization of RCC subtypes. Last, diagnostic biomarkers might be extended to prognostic or predictive applications.

肾细胞癌（RCC）的临床表现正在转向偶然和早期检测，这给 RCC 诊断带来了新的挑战。随着新的诊断生物标志物的开发来区分良性和恶性小肾肿块（SRM），过度治疗可能会减少。与组织活检不同，液体活检是从患者的血液或尿液中获得的，因此是微创的，适合纵向监测。用于 RCC 诊断的最有希望的液体活检生物标志物类型是循环肿瘤细胞、细胞外囊泡 (EV) 和游离 DNA。循环肿瘤细胞检测具有最高的特异性，且处理时间和成本较低。然而，生物学特性和低灵敏度限制了这些标记物在 SRM 诊断中的使用。游离 DNA 可能会补充大体积肾细胞癌的诊断，但在 SRM 中的临床应用潜力有限。EVs具有最高的生物丰度和识别小量疾病的最高灵敏度；此外，这些标记物的分子特征使 EV 适用于多种分析应用。因此，目前，EV 检测在 RCC 诊断应用（包括 SRM 的识别）方面具有最大的潜力。所有这些液体生物标志物在临床实践中都具有潜力，有待验证研究。还需要实施生物标志物来改善 RCC 亚型的表征。最后，诊断生物标志物可能会扩展到预后或预测应用。