1 – 4 % of RCC cases can be associated with hereditary syndromes.
Key points:
- Detailed physical examination
- Family history
- Consider referral to geneticist
- All autosomal dominant
- Nephron sparing approach
- The goal of management is oncological cure and control, whilst preserving renal function, recognising the high likelihood of needing further surgeries
- Wait until 3 cm then multiple partial nephrectomies (unless HLRCC)
Von Hippel Lindau
Autosomal dominant.
Mutation of VHL gene on chromosome 3p.
- VHL is a tumour suppressor gene
- VHL protein mediates degradation of HIF-1a and HIF-2a – with mutated VHL it cannot bind HIF, therefore increased HIF levels, which leads to increased growth factors like VEGF and angiogenesis
1 in 35 000
| Urological
|
Non urological | |
| · Renal cysts
· ccRCC · Phaeochromocytoma · Epididymal cystadenomas · Broad ligament cystadenomas · Epididymal cysts |
75 %
50 % 15 % 10 %
7 % |
· Cerebellar hemangioblastomas
· Spinal haemangiomas · Retinal angiomas · Pancreatic cysts & NETs |
In vHL – all cysts have the potential to become malignant.
RCC in vHL is often multifocal, bilateral, and presents early in 20s – 40s.
Consider MRI surveillance to reduce radiation in young people.
Birt Hogg Dube
Autosomal dominant.
Mutation of FLCN tumour suppresor gene on chromosome 17p – encoding for a protein called folliculin.
1 in 200 000.
| Urological
|
Non urological | |
| · Renal masses
|
25 % | · Fibrofolliculoma skin lesions
· Pulmonary cysts · Pneumothorax · Bowel cancer |
Renal masses are often bilateral.
Most (50 %) are hybrid oncocytic tumours.
25 % are chromophobe RCC.
10 % are ccRCC, and then 7 % are pure oncocytoma.
Tuberous sclerosis
Autosomal dominant.
1 in 6000.
Mutation in the tumour suppressor TSC1 gene on chromosome 9 (hamartin), or TSC2 gene on chromosome 16 (tuberin).
TSC genes inhibit the mTOR pathway. Errors in TSC genes therefore lead to unopposed mTOR pathway activation
| Urological
|
Non urological | |
| · Renal cysts
· AMLs · ccRCC |
75 %
60 % 2 %
|
· Mental retardation
· Seizures · Adenoma sebaceum · Cerebral cortex tumours (tubers) · Ash leaf spots · Shagreen patches · Ungal fibromas · Other hamartomas · Lymphangioleiomyomatosis (LAM) |
Hamartomas are benign neoplasms due to overgrowth of aberrant cells, with their basis in a genetic condition.
Hereditary leiomyomatosis and RCC (HLRCC)
Autosomal dominant.
Mutation in tumour suppressor gene fumarate hydratase on chromosome 1, which is an essential enzyme in the Krebs cycle.
| Urological
|
Non urological | |
| · Fumarate hydratase deficiency RCC (prev T2 papillary)
|
20 % | · Cutaneous leiomyoma
· Uterine leiomyoma (fibroid) |
Almost all women with HLRCC with develop cutaneous and uterine leiomyomas, but only 15 – 20 % develop RCC.
Unlike other syndromes, RCC is typically solitary and unilateral.
Tumours behave aggressively – prompt surgical management recommended. Partial nephrectomy only if wide margins are attainable.
Mean age of diagnosis is in 40s.
Succinate dehydrogenase renal cell carcinoma
Germline mutation of one of the mutliple genes encoding for subunits of succinate dehydrogenase, important in the Krebs cycle (chromosome 1 and 11).
Affected individuls present young (< 40) with bilateral, multifocal renal tumours, and often also have phaeochromocytomas or head and neck paragangliomas.
May have more aggressive cancers and poorer prognosis.
Hereditary papillary renal carcinoma syndrome
Autosomal dominant
Activation of the proto-oncogene c-MET on chromosome 7 (cf. tumour suppressor genes of other syndromes)
Typically type 1 papillary RCCs.
Thought to be somewhat more favourable prognosis cf. sporadic RCC.
Cowden syndrome / PTEN tumour syndrome
Germline mutations of the PTEN tumour suppressor gene
34 % lifetime risk of RCC, along with 50 % risk of breast cancer and 10 % risk thyroid cancer.
Most often papillary RCC, but clear cell and chromophobe has been reported.