Riccardo Campi1, Grant D Stewart2, Michael Staehler3, Saeed Dabestani4, Markus A Kuczyk5, Brian M Shuch6, Antonio Finelli7, Axel Bex8, Börje Ljungberg9, Umberto Capitanio10. 1. Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group. Electronic address: riccardo.campi@gmail.com. 2. Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Addenbrookes Hospital, Cambridge, UK. 3. Department of Urology, Ludwig-Maximilians-University of Munich, Munich, Germany. 4. Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Malmö, Sweden. 5. Clinic for Urology and Urological Oncology, Hanover Medical School, Hanover, Germany. 6. Kidney Cancer Program, Division of Urologic Oncology, Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 7. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. 8. The Royal Free London NHS Foundation Trust and UCL Division of Surgery and Interventional Science, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. 9. Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden. 10. European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group; Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Abstract
CONTEXT: The epidemiological signature of renal cell carcinoma (RCC) during the past decades is explained by overdetection and overtreatment of indolent cancers; furthermore, a non-negligible proportion of patients undergoing surgery for suspected RCC harbour benign renal tumours. As the gold standard for RCC diagnosis remains histopathological analysis of surgical or biopsy specimens, implementation of noninvasive diagnostic strategies to discriminate between benign and malignant renal masses is an urgent unmet need. OBJECTIVE: To systematically review novel liquid biomarkers and imaging modalities for RCC diagnosis. EVIDENCE ACQUISITION: A systematic review of the recent English-language literature was conducted according to the European Association of Urology guidelines and the PRISMA statement recommendations (PROSPERO ID: CRD42020190773) using the MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov databases. Risk-of-bias assessment was performed according to the QUADAS 2 tool. EVIDENCE SYNTHESIS: Overall, 15 studies (six on biomarkers and nine on imaging) and eight clinical trials were included. None of the biomarkers or imaging modalities has been validated or shown to have a distinct clinical value for RCC. Specific combinations of urinary cell-free and exosomal miRNAs, urinary miR-15a, and specific panels of urinary metabolites assessed by metabolomics appear promising. In addition, machine/deep learning algorithms and radiomics applied to cross-sectional images may have potential to improve RCC diagnosis. Most studies are limited by the retrospective design, size, and lack of external validation. CONCLUSIONS: Liquid biomarkers or imaging modalities are not ready for integration in the clinic and further well-designed studies must validate preliminary findings and explore utility in clinical decision-making. PATIENT SUMMARY: We provide a comprehensive overview of the currently available biomarkers (measured in blood or urine) and novel imaging tests (other than conventional imaging) to discriminate kidney cancer from benign renal masses in a noninvasive fashion. None of the biomarkers or imaging modalities studied was validated or added clinical value; therefore, none of them can be implemented in the clinic. However, these approaches appear to be promising for improving the diagnosis of kidney cancer in the future.
CONTEXT: The epidemiological signature of renal cell carcinoma (RCC) during the past decades is explained by overdetection and overtreatment of indolent cancers; furthermore, a non-negligible proportion of patients undergoing surgery for suspected RCC harbour benign renal tumours. As the gold standard for RCC diagnosis remains histopathological analysis of surgical or biopsy specimens, implementation of noninvasive diagnostic strategies to discriminate between benign and malignant renal masses is an urgent unmet need. OBJECTIVE: To systematically review novel liquid biomarkers and imaging modalities for RCC diagnosis. EVIDENCE ACQUISITION: A systematic review of the recent English-language literature was conducted according to the European Association of Urology guidelines and the PRISMA statement recommendations (PROSPERO ID: CRD42020190773) using the MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov databases. Risk-of-bias assessment was performed according to the QUADAS 2 tool. EVIDENCE SYNTHESIS: Overall, 15 studies (six on biomarkers and nine on imaging) and eight clinical trials were included. None of the biomarkers or imaging modalities has been validated or shown to have a distinct clinical value for RCC. Specific combinations of urinary cell-free and exosomal miRNAs, urinary miR-15a, and specific panels of urinary metabolites assessed by metabolomics appear promising. In addition, machine/deep learning algorithms and radiomics applied to cross-sectional images may have potential to improve RCC diagnosis. Most studies are limited by the retrospective design, size, and lack of external validation. CONCLUSIONS: Liquid biomarkers or imaging modalities are not ready for integration in the clinic and further well-designed studies must validate preliminary findings and explore utility in clinical decision-making. PATIENT SUMMARY: We provide a comprehensive overview of the currently available biomarkers (measured in blood or urine) and novel imaging tests (other than conventional imaging) to discriminate kidney cancer from benign renal masses in a noninvasive fashion. None of the biomarkers or imaging modalities studied was validated or added clinical value; therefore, none of them can be implemented in the clinic. However, these approaches appear to be promising for improving the diagnosis of kidney cancer in the future.
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