RENAL CELL CARCINOMA
Renal cell carcinoma (RCC) accounts for almost 90 % of malignant renal Tumours. Familial cases of RCC are infrequent and are estimated to account for about 3 % of all cases. McLaughlin et al. (1984), in a population-based case– control study, found a family history of RCC in 2.4 % of affected patients, compared to 1.4 % of controls. Sporadic RCC is histopathologically heterogeneous. The most common form is clear cell (conventional RCC) which accounts for 75–80 % of all cases. The most frequent non-clear cell histopathology is papillary RCC (~15 % of all cases) which can be divided into types 1 and 2. Chromophobe RCC and oncocytomas and other rare forms of RCC make up the remainder. In some cases, there is a good correlation between genetic causes of familial RCC and histopathological appearance. Thus, von Hippel–Lindau (VHL) disease is the most frequent syndromic cause of renal carcinoma susceptibility, and RCC in VHL disease invariably has a clear cell appearance. Germline mutations in the MET proto- oncogene cause type 1 papillary RCC, while RCC in hereditary leiomyomatosis patients with germline fumarate hydratase mutations is usually classified as type 2 papillary or collecting duct RCC. However, in Birt–Hogg–Dube syndrome although the characteristic Tumours is that of a mixed chromophobe–oncocytoma appearance, other types of RCC, including clear cell, can occur. Similarly, the histological subtype of RCC associated with germline SDHB mutations is also variable (Maher 2010).
Familial RCC is characterized by (1) an early age at onset compared to sporadic cases, (2) frequent bilateralism, and (3) multicentricity. In addition, features of a susceptibility syndrome (e.g., VHL disease, hereditary leiomyomatosis and RCC syndrome or Birt–Hogg–Dube syndrome, germline succinate hydrogenase subunit gene mutation) may be present. Mean age at diagnosis in familial cases is about 45 years, more than 15 years earlier than for sporadic cases (Maher et al. 1990).
In addition to the major RCC susceptibility syndromes described above, familial clear cell RCC may be associated with constitutional translocations, characteristically but not exclusively, involving chromosome 3. The first such kindred was reported by Cohen et al. (1979) and contained ten affected patients in three generations. In this family, RCC segregated with a t(3:8) (p14.2:q24.1), and it was estimated that each translocation carrier had an 87
% risk of developing this cancer by 60 years of age. Subsequently an increased risk of thyroid cancer was also reported in the family. At least 10 other chromosome 3 translocation-RCC families have been described, but the breakpoints and partner chromosome are heterogeneous. In the original t(3:8) (p14.2:q24.1) kindred, the 3p breakpoint occurred at the fragile site and disrupts the fragile histidine triad (FHIT) Tumours suppressor gene. However, the precise role of FHIT (and the chromosome 8 gene TRC8) in RCC is unclear, and it has been suggested that instability of the translocated chromosome may be an important factor in this and other chromosome 3 translocation-RCC kindreds. All patients with possible RCC susceptibility should be examined for constitutional translocations. Adult translocation carriers in kindreds with chromosome 3 translocations and RCC should be offered regular renal surveillance (e.g., annual renal MRI or ultrasound scans). However, incidentally discovered chromosome 3 translocation carriers do not appear to require follow-up for RCC unless there is a personal or family history of RCC (or unless a translocation appears to disrupt a RCC suppressor gene) (Woodward et al. 2010).
Clinical and molecular genetic evidence of von Hippel–Lindau disease should be sought in all cases of potential inherited clear cell RCC (e.g., familial, young onset, or multiple RCC).
Familial non-VHL clear cell RCC without evidence of a specific syndrome is generally characterized by autosomal dominant inheritance of susceptibility to RCC only (Teh et al. 1997; Woodward et al. 2000). It can be helpful to consider familial non-syndromic RCC according to the histopathology of the renal Tumours, e.g., the presence of type 1 papillary RCC would be an indication for MET gene analysis and non-clear cell RCC would exclude VHL disease. In a series of patients presenting with features suggestive of inherited non-syndromic RCC (mostly clear cell type), germline mutations in SDHB and FLCN (Birt–Hogg–Dube gene) were each detected in about 5 % of cases (Ricketts et al. 2008; Woodward et al. 2008). Hence, a preferred method for investigating potential inherited RCC is to test for mutations in a panel of inherited RCC genes (e.g., VHL, FLCN, SDHB, SDHD, MET, FH).
Renal Tumours (consisting of a mixture of epithelial and stromal elements) may occur in hyperparathyroidism–jaw Tumours syndrome and rarely in tuberous sclerosis (although the most common renal Tumours in this disease is angiomyolipoma). Renal Tumours may be seen in patients with Cowden syndrome or Cowden-like syndrome, particularly the subgroup in whom germline epimutations (promoter methylation of KLLN has been described).