Our series of 33 cases is one of the largest ever published [4]-[8]. This study confirms that cases can have either unifocal disease, or multiple tumours, and that most renal cell tumours are oncocytomas or RCC of chromophobe or hybrid chromophobe-oncocytoma histology [4]-[6]. Other histologies are however associated with the syndrome, clear cell in particular. Indeed, among our cases, 3 (9%) had clear cell carcinomas. Given that they are not typical in BHD, all clear cell RCC were reviewed by one of our expert pathologists, and confirmation was obtained. This proportion is similar to what has been reported in the past, and clinicians should therefore remain alert to the possibility of BHD in patients with clear cell RCC, especially if there are associated manifestations [6].
The age at renal cell tumour diagnosis varied between 20 and 83, with a median age of 46. Of special interest was the fact that two patients presented with a renal cell tumour in their twenties, highlighting the need for regular surveillance from an early age [12]. This surveillance should be continued with no upper age limit and as long as the patients are in good condition, as one patient with two tumours in his eighties was successfully treated by percutaneous radiofrequency ablation.
These 33 cases with renal cell tumours represent 27% of all ascertained BHD patients (33/124), and 34% of those for which we have evidence of renal imaging (33/98). This observation is remarkably consistent with two large studies from the United States National Cancer Institute that reported overall tumour frequencies of 29% and 34% in BHD patients evaluated by CT scan [4],[5]. We expect the proportion in our study to be representative of the true renal cell tumour risk associated with the syndrome, as French index cases are offered FLCN genetic analysis because they present with all types of clinical manifestations suggestive of BHD.
An exhaustive description of extrarenal manifestations is beyond the scope of this paper. Nevertheless, 67% and 58% of our cases also had pulmonary and dermatological manifestations respectively, in addition to RCC. These figures represent the minimal prevalence as pulmonary assessment by CT scan and examination by a dermatologist knowledgeable in the syndrome was not systematic.
In our series, four patients had metastatic, albeit indolent RCC. Comprehensive family data was collected for all patients in this series, and we have no knowledge of other relatives (deceased or alive) with metastatic RCC who were not tested for FLCN mutations, and who were therefore not included in this study. Very few cases of metastatic RCC associated with BHD have been described. Pavlovich et al. and Houweling et al. reported respectively two and five such cases; all died rapidly despite multidisciplinary management that included surgery, radiotherapy, immunotherapy and chemotherapy, and the good prognosis associated with metastatic disease in our study contrasts with these earlier reports [8],[13]. Three of the four patients reported here are still alive more than five years after the metastases were diagnosed, while the fourth died of unrelated causes four years after a lung metastasis had been removed. Whether these observations reflect a specific behaviour only seen in BHD requires further investigation. Another hypothesis is that metastatic RCC in BHD patients is more sensitive to tyrosine kinase and mTOR inhibitors such as sunitinib and everolimus (two recently-developed drugs that are now routinely used in the treatment of metastatic RCC), as suggested for example by the mTOR signalling pathway activation seen in kidney tumours associated with the syndrome, but that would not account for the good prognosis of cases 13851 and 22973 who received no systemic treatment [14]. As shown in Table 1, most patients in our study are followed up medically, with relevant information being collected by the team in charge on a regular basis. There is however a minority from which we have not heard in the last few years, and we cannot rule out with certainty the possibility of aggressive metastatic disease in these patients.