Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management

Abstract

Purpose: Genetic factors have been implicated in the pathogenesis of renal cell carcinoma (RCC), with around 3% of cases having a family history. A greater knowledge of the genetics of inherited RCC has the potential to translate into novel therapeutic targets for sporadic RCC.

Methods: A literature review was performed summarising the current knowledge on hereditary RCC diagnosis, surveillance and management.

Results: Familial RCC is usually inherited in an autosomal dominant manner, although inherited RCC may present without a relevant family history. A number of familial RCC syndromes have been identified. Familial non-syndromic RCC is suspected when ≥ 2 relatives are affected in the absence of syndromic features, although clear diagnostic criteria are lacking. Young age at onset and bilateral/multicentric tumours are recognised characteristics which should prompt molecular genetic analysis. Surveillance in individuals at risk of inherited RCC aims to prevent morbidity and mortality via early detection of tumours. Though screening and management guidelines for some inherited RCC syndromes (e.g. von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis) are well defined for rare cause of inherited RCC (e.g. germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities.

Conclusion: Increasing knowledge of the natural history and genetic basis has led to characterisation and tailored management of hereditary RCC syndromes. International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis, surveillance protocols and management of these rare conditions.

Keywords: Familial syndromic renal cancer; Genetics; von Hippel–Lindau review.

Fig. 1

Examples of radiological, histological and immunohistochemical features that might suggest an inherited predisposition to renal cell carcinoma. Upper panel: a high-resolution CT thorax showing multiple basal cysts in a patient with Birt–Hogg–Dube syndrome (reprinted with permission from [52]). Lower panel: b the H + E-stained histological appearance of an SDHB-deficient RCC. There is evidence of intracytoplasmic vacuoles marked by the black arrow. c Loss of SDHB protein expression on immunostaining of the RCC tumour in the lower part of the image, with SDHB staining present in the adjacent normal renal tissue visible in the upper image. (Reprinted with permission from [39])