Q. A 28-year-old man with a history of cerebellar surgery has an abdominal CT. What is the diagnosis (Figure 5.4a and b)?
Figure 5.4 (a) Contrast CT demonstrating right kidney. (b) Contrast CT demonstrating left kidney.
A. There are multiple bilateral renal cysts with a malignant looking lesion in the upper pole of the left kidney and possibly the lateral aspect of the lower pole of the right kidney. Given this and the history of cerebellar surgery I suspect that he has von Hippel-Lindau disease.
Q. What is von Hippel-Lindau (VHL) disease?
A. This is an autosomal dominant disorder with an incidence of 1:36,000 live births which affects males and females equally. The average age of the patient at diagnosis is 26 years and is characterised by the development of various benign and malignant tumours and cysts. The VHL tumour suppressor gene is located on the short arm of chromosome 3 and the inactivation of this leads to the development of the disease. The major tumours and cysts are haemangioblastoma in the central nervous system, retinal haemangioblastoma, phaeochromocytoma, renal cell carcinoma, renal cysts, pancreatic neuro-endocrine tumours, and pancreatic and epididymal cystadenomas. Owing largely to the high incidence of ccRCC associated with VHL disease, the average life expectancy in affected individuals is 49 years with RCC being the leading cause of death. However, diligent surveillance enabling early treatment interventions can increase life expectancy.
Q. Explain how this leads to the development of renal (and other) carcinoma?
A. Inactivation of the VHL suppressor protein results in a subsequent loss of function of the VHL protein and the VBC complex. This complex normally targets transcription factors such as hypoxia-inducible factor (HIF-1a), resulting in their destruction. As such, in cells lacking VHL function, or in hypoxic conditions, HIF-1a accumulates, resulting in overexpression of many genes, in particular those related to angiogenesis, such as VEGF and platelet-derived growth factor (PDGF), as well as cell division, via transforming growth factor-a and PDGF. Importantly, the VHL gene has also been demonstrated to be inactivated in sporadic renal cell carcinomas.
Q. What new drug therapies are you aware of in VHL and renal cancer?
A. The VHL/HIF-1a growth factor pathway has become a major area for drug development targets.
Sunitinib is a tyrosine kinase inhibitor (TKI) that inhibits all three isoforms of the VEGF receptor. In a recent phase III trial, 750 patients, previously untreated, with metastatic renal cancer were randomised to Sunitinib or IFN-a. Sunitinib had significantly longer progression-free survival (11 months versus 5 months) and higher response rates (31% versus 6%) than those receiving IFN-a [8]. Pazopanib is an oral angiogenesis inhibitor and is comparable to Sunitinib in outcomes, but with better quality of life. Sorafenib is another TKI, which has been shown to prolong progression-free survival in patients with advanced renal cancer, in whom previous therapy has failed. This was demonstrated in a randomised phase III study, comparing Sorafenib to placebo [9]. Further high-quality studies have potentially shown the benefit of Temsirolimus and everolimus, mammalian target of rapamycin (mTOR) inhibitors [10,11], and Bevacizumab, a humanised monoclonal antibody to VEGF-A [12], as medical therapies in advanced renal cell cancer. Although, not a uniform policy, one approach to medical therapy is initially to stratify patients according to favourable, intermediate, and poor risk, depending upon whether they possess zero, one or two or more of the following risk factors: Karnofsky performance status <80%, anaemia, elevated serum calcium, absence of prior nephrectomy, and elevated lactate dehydrogenase [13]. Good and intermediate-risk patients should be initially treated with Sunitinib or Bevacizumab plus IFNa. Selected high-performance status patients with clear cell tumours can be considered for high-dose IL-2. Second-line therapy after progression could include Sorafenib, everolimus, or a different VEGF pathway inhibitor. Poor risk patients, especially those with non-clear-cell histology, should initially be considered for treatment with Temsirolimus. Importantly, with several ongoing clinical trials in progress, treatment options are likely to change.
Q. Describe the course of the renal manifestations of the disease.
A. Typically RCC evolves in multiple sites in the kidney after 20 years of age. Kidneys usually develop a spectrum of small benign cysts through to large renal cell cancers. Smaller lesions are difficult to evaluate but a cut-off at 2-3 cm is thought to represent increasing risk of malignant transformation.
Q. Describe the management of RCC in VHL patients.
A. Initially urological management is in the form of surveillance with annual USS. Once cysts or lesions reach 2 cm, intensive CT/MRI follow-up, either 6 or 12 monthly depending on size and or number and growth rate of lesions will be required.
All management should aim to maintain nephrons and reduce the risk of metastasis. Cryo-ablation or radio-frequency ablation should be considered for treating smaller lesions (<3 cm). Once lesions are >3 cm partial nephrectomy may be more appropriate. For larger lesions nephrectomy is indicated.
Ultimately as the disease progresses the patient may need renal replacement therapy. The evidence for the role of transplantation and subsequent immuno-suppression in this population of patients is limited.
Q. Are you aware of any other hereditary disorders associated with RCC?
A. ttere are a number of other cancer susceptibility syndromes that are associated with an increased risk of renal cancer. These include the following:
Hereditary papillary RCC (HPRCC) which is associated with papillary type 1 RCC and has an autosomal dominant transmission. Mutation of the C-MET proto-oncogene is encountered on chromosome 7. It usually has an early onset and presents with bilateral multifocal tumours.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a papillary type 2 RCC and is the most aggressive inherited RCC cancer syndrome. It is also known as Reed’s syndrome and has an autosomal dominant transmission and is associated with a mutation of the fumarate hydratase (FH) gene on chromosome 1. Cutaneous leiomyomas and uterine fibroids are non-neoplastic findings. The mean age of diagnosis is 40 years and metastatic renal cancer can present in the teens.
Birt-Hogg-Dubé (BHD) disease is also autosomal dominant and the BHD gene is identified on chromosome 17. It is characterised by the development of fibrofolliculomas (dysplastic hair follicules), lung cysts and spontaneous pneumothorax and renal cancer (papillary RCC, ccRCC, chromophobe, mixed and oncocytomas - even in the same kidney). The most common type of tumour is an unusual hybrid oncocytic tumour (mixed oncocytoma and chromophobe).
Tuberous sclerosis complex is an autosomal dominant genetic disorder characterised by the formation of hamartomas in multiple organs including the brain, kidney, skin and lung. This leads to neurological disorders including epilepsy, mental retardation and autism as well as dermatological manifestations such as facial angiofibromas. Although the renal manifestations are mainly benign (AMLs and oncocytomas), renal cell cancer can occur in <5% of patients (chromophobe RCC).