Histology
Individuals with BHD syndrome are predisposed to develop renal cell carcinoma (RCC) (Toro et al., 1999; Zbar et al., 2002). Unlike other genetic disorders with this predisposition, renal tumours associated with BHD syndrome are histologically diverse. Chromophobe, oncocytic, clear-cell and papillary renal cell carcinomas have all been identified in BHD patients, however the most commonly occurring histological subtype is a hybrid chromophobe and oncocytic renal tumour (with an approximate incidence of 50%) (Pavlovich et al., 2002; Warwick et al., 2010). Several other mixed patterns can also occur (Pavlovich et al., 2005; Fahmy et al., 2007; Janitzky et al., 2008; Kluijt et al., 2009). Six deaths have been reported in BHD patients due to metastatic renal cancer, all of which were of the clear-cell or papillary histology (Pavlovich et al., 2005; Toro et al., 2008; Claessens et al., 2010).
It is unclear from which part of the kidney the tumours arise. Due to the high percentage of chromophobe tumours, Pavlovich et al. (2002) initially believed the tumours to arise from the distal nephron. However, two independent studies observed FLCN expression in the proximal tubules of mice kidneys, suggesting the site of origination (Chen et al., 2008; Hudon et al., 2010).
Prevalence
Renal cancer is the most life-threatening complication associated with BHD syndrome. A study by Toro et al. (2008) assessed 89 BHD syndrome patients and found 34% had renal tumours. The mean age of first renal tumour diagnosis was 50.7 years (Pavlovich et al., 2002), with the earliest reported age of 20 years (Khoo et al., 2002). A study of 18 BHD patients with RCC found 60% had bilateral renal tumours and 77% had multiple tumours, with an average of 5.3 tumours per patient (Pavlovich et al., 2002).
FLCN association
Other genetic diseases that lead to renal cell carcinoma seem to show a strong genotype-phenotype correlation (Pavlovich et al., 2004). For example, clear-cell RCC in von Hippel-Lindau syndrome is associated with mutations in the VHL gene, and hereditary papillary RCC is associated with mutations in the MET gene. A study by Gatalica et al. (2009) analysed the multiple tumour types found in one BHD patient and identified mutations and epigenetic events associated with the specific tumour types. Oncocytic tumours were found to have a second FLCN mutation, oncocytic papillary tumours had methylation of FLCN and a mutation in the MET gene, whereas clear-cell tumours had a mutation in the VHL gene along with VHL promoter methylation.
A loss of FLCN expression is rare in sporadic renal cell carcinomas (Khoo et al., 2003). However somatic FLCN mutations have been reported, suggesting that FLCN is involved in the normal cellular functions that regulate growth and proliferation in the kidney, and that the aberrant functioning of FLCN is a mechanism of pathogenesis in both sporadic and BHD related renal carcinogenesis (Gad et al., 2007; Woodward et al., 2008).
