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Novel Liquid Biomarkers and Innovative Imaging for Kidney Cancer Diagnosis: What Can Be Implemented in Our Practice Today? a Systematic Review of the Literature - Beyond the Abstract

The epidemiological signature of renal cell carcinoma (RCC) shows a sustained increase in incidence coupled with stable mortality;1 this signature is most probably explained by overdetection of cancers not destined to cause death superimposed on stable occurrence. Furthermore, clinical practice suffers from pursuing management of localized renal masses without knowledge of histology.2 As a result of this uncertainty, increased surgical treatment of small renal masses (SRMs) is performed at the expense of limited use of active surveillance.2,3 Therefore, surgery might become a potential harm of excessive cross-sectional imaging.4


The contemporary landscape of RCC epidemiology is thus evidence that precision oncology has not permeated to clinical practice yet; in this scenario, the gold standard for RCC diagnosis remains histopathological analysis of surgical (or biopsy) specimens. As such, reliable non-invasive diagnostic strategies, able to discriminate between benign and malignant renal masses, represent a key unmet clinical need.

To fill this gap, in our study published in European Urology Oncology, we sought to determine which novel liquid biomarkers and/or innovative imaging modalities for RCC diagnosis could be implemented in current clinical practice. For this purpose, we conducted a systematic review of the literature following the principles highlighted by European Association of Urology (EAU) guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 5 statement recommendations using the MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials, and Web of Science (WOS) databases (the protocol was registered in the International Prospective Register of Ongoing Systematic Reviews [PROSPERO] with the registration ID: CRD4202 0190773).

In brief, studies were considered eligible if they fulfilled the following criteria: (P): Patients with nonmetastatic or metastatic disease with a renal mass of undetermined nature at routine cross-sectional imaging, subsequently proven to be RCC at histopathological analysis. (I): Novel or innovative (i.e., not considered for the latest EAU guidelines6) liquid (blood or urine) diagnostic biomarkers and imaging modalities, with or without radiomics algorithms. (C): Control group including patients with a renal mass of undetermined nature at routine cross-sectional imaging that was subsequently proven to be benign at histopathological analysis. (O): Diagnostic accuracy (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV], area under the receiver operating characteristic [ROC] curve [AUC]) for discrimination between benign and malignant renal masses. (S) Studies published in the English language in the past 5 yr (from January 1, 2015, to June 24, 2020) and including at least 50 patients with histologically proven RCC and at least ten patients with histologically confirmed benign renal masses (including oncocytoma).

The search identified 12 373 records and 610 clinical trials. Of these, 11 935 were excluded by title and abstract screening, with a further 367 excluded after full-text assessment. After records screening, six studies7-12 on liquid diagnostic biomarkers, involving 517 patients with confirmed RCC and 139 patients with confirmed benign renal masses, were included. In addition, nine retrospective studies13-21 focused on innovative imaging for diagnosis, investigating 1328 patients with confirmed RCC and 303 with benign renal masses, were included in the qualitative analysis.

To summarise, specific combinations of urinary cell-free and exosomal miRNAs, urinary miR-15a, and specific panels of urinary metabolites assessed via LC–MS–based metabolomics appear to be promising noninvasive diagnostic biomarkers for discrimination between benign and malignant renal masses. Concerning imaging, it has been shown that ML/DL algorithms and radiomics applied to contrast-enhanced CT images or multiparametric MR images can accurately distinguish renal lesions.

Of note, we found several clinical trials exploring novel liquid biomarkers or innovative imaging for RCC diagnosis, fulfilling the PICOS framework. Three trials (NCT03667885, NCT03470285, and NCT02526511) are evaluating multi-parametric MRI for discrimination between benign and malignant renal masses, histotype, and grade. NCT03667885 is also exploring the accuracy of liquid DNA and mRNA as biomarkers of RCC. NCT03849118 (Zircon study) is a prospective, open-label, multicentre phase 3 study that aims to evaluate the sensitivity and specificity of 89Zr-TLX250 positron emission tomography/CT (PET/CT) imaging for noninvasive detection of ccRCC in renal masses scheduled for nephrectomy. NCT02732652 is evaluating plasma and urine glycosaminoglycan (GAG) profiling in patients with suspected RCC referred for surgical treatment. GAG scores will be correlated to final diagnosis and surgical recurrence.

Overall, this systematic review summarises the latest evidence on novel liquid biomarkers and innovative imaging modalities for RCC diagnosis, with the aim of identifying those that could be implemented in clinical practice. Importantly, we designed a PICOS framework that mirrors the ideal pathway to evaluate the diagnostic accuracy of novel biomarkers or innovative imaging techniques to correctly diagnose RCC in patients with a suspicious renal mass. We relied on the following assumptions: (1) the gold standard for diagnosis of a renal tumour is histopathological analysis; (2) a biomarker or a novel imaging modality for diagnostic purposes should include patients with histologically confirmed malignant tumours and benign tumours; and (3) an ideal biomarker or imaging modality should show sensitivity close to 100% (avoiding false-negative results, namely, RCCs incorrectly classified as benign) with the highest specificity possible (reducing false-positive results, i.e., benign masses treated as RCC).

A key finding of our review is that the use of such a rigorous methodological framework ultimately resulted in the inclusion of a relatively low number of studies in the qualitative analysis, reflecting a compelling need for prospective high-quality studies on liquid biomarkers and novel imaging tools to distinguish renal masses.

To date, none of the serum or urinary biomarkers tested or the innovative imaging modalities proposed (including radiomics and DL strategies) has been validated or shown to have clinical utility. The evidence is premature for recommending integration into routine diagnostic pathways for suspicious renal masses.

Further research is needed to validate the results of the exciting preliminary studies included in our review, and to explore their utility and the potential clinical benefit versus the current standard of care for the management. To this end, the design of future clinical trials evaluating novel biomarkers or innovative imaging modalities for RCC diagnosis should be standardised to ensure a meaningful comparison of trial results and a proper analysis of the value.

Once validated in prospective clinical trials, noninvasive liquid biomarkers in combination with innovative imaging modalities might be integrated into our diagnostic algorithms and clinical practice guidelines, and could provide an opportunity to tailor the indication for renal tumour biopsy and ultimately to reduce the number of patients undergoing unnecessary surgeries for benign renal tumours, moving toward the concept of precision oncology.

Written by: Riccardo Campi,1,2,3 Alessandro Berni,1 Grant D. Stewart,4 Michael Staehler,5 Saeed Dabestani,6 Markus A. Kuczyk,7 Brian M. Shuch,8 Antonio Finelli,9 Axel Bex,10,11 Bӧrje Ljungberg12 & Umberto Capitanio3,13,14

  1. Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Hospital, University of Florence, Florence, Italy;
  2. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
  3. European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group;
  4. Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Addenbrookes Hospital, Cambridge, UK;
  5. Department of Urology, Ludwig-Maximilians-University of Munich, Munich, Germany;
  6. Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Malmö, Sweden;
  7. Clinic for Urology and Urological Oncology, Hanover Medical School, Hanover, Germany;
  8. Kidney Cancer Program, Division of Urologic Oncology, Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  9. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada;
  10. The Royal Free London NHS Foundation Trust and UCL Division of Surgery and Interventional Science, London, UK;
  11. Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands;
  12. Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden;
  13. Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy;
  14. Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

References:

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