Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: NIHR Cambridge Biomedical Research CentreIn a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis
