Over the past 25 years, the identification and surveillance of large numbers of
VHL mutation carriers has led to a broad consensus to how they should be investigated and managed. In particular, a consensus has developed that small (< 3 cm) screen-detected tumours should be managed by active surveillance and then nephron-sparing surgery performed when a solid lesion reaches 3 cm in diameter [
47]. As an alternative to partial nephrectomy percutaneous radiofrequency ablation has been used to treat small renal lesions in VHL disease [
51]. In general, the approach to the management of RCCs identified through surveillance in VHL disease has been extrapolated to individuals with Birt–Hogg–Dube syndrome with tumours followed by active surveillance until they reach a diameter of 3 cm and then nephron-sparing surgery is performed (alternatively, radiofrequency ablation may be used to treat smaller tumours) [
13]. However, it is clear that the “3 cm rule” is not suitable for renal lesions in HLRCC, which can metastasise early and are not reliably detected by renal ultrasound. Consequently, individuals with germline
FH mutations undergo annual MRI surveillance even though most will not develop a renal lesion and surgical intervention is indicated for small screen-detected lesions [
19]. For individuals with a germline
BAP1 mutation, there is very limited information on the lifetime risks of RCC and the most appropriate screening modalities. International data sharing of inherited RCC gene variant information and multicentre collaboration to pool results of natural history and screening protocols for mutation carriers are required to enable evidence-based surveillance programmes to be designed. For example,
SDHx-associated RCC can be aggressive implying that surveillance for early detection is important. However, the tumour risks in
SDHB mutation carriers are significantly less than originally thought and so there is (as in
FH mutation carriers) a tension between over-investigation and early detection. This might be addressed by the development of biomarkers to identify the subset of individuals who will develop RCC and should be targeted for screening and/or novel early detection strategies (such as circulating tumour DNA biomarkers).
In some patients, particularly those with no previous family history, the diagnosis of inherited RCC disorder is only made after presentation with metastatic disease. Additionally, in VHL disease patients may develop multiple central nervous system haemangioblastomas that are not amenable to surgical treatment because of their critical location. Hence, there is a need to develop effective medical therapies for such cases. Most of the known inherited RCC genes encode tumour suppressor genes and biallelic inactivation of the relevant inherited RCC gene is present in all tumour cells. Therefore, in addition to standard therapies for metastatic RCC, targeted therapies with agents that exploit the specific molecular pathways provides a rational approach to therapy [
48,
49]. The concept of synthetic lethality-based interventions is particularly interesting for inherited RCC (and haemangioblastomas) in disorders such as VHL disease, because the kidneys of VHL patients can harbour hundreds of small “tumourlets” with biallelic VHL inactivation, some of which will give rise to RCC years later [
50]. Hence, it could be hypothesised that ablation of such tumourlets by administration of a synthetically lethal compound to young adults with VHL disease might reduce the risk of RCC at a later age. The development of novel therapeutic approaches to inherited RCC will require a deeper knowledge of the normal function of inherited RCC gene products and the consequences of mutations in the relevant pathways. However, a likely outcome of such research would be the potential for translating the knowledge of the pathogenesis of inherited RCC into novel treatments for sporadic RCC (as exemplified in VHL disease and the involvement of
VHL inactivation in sporadic clear cell RCC).