Von Hippel-Lindau (VHL) disease is a rare, inherited genetic disorder that increases the risk of various tumors. It can cause both benign (non-cancerous) and malignant (cancerous) growths in multiple organ systems. While VHL can lead to tumors in several organs, a particular concern is its strong association with renal cell carcinoma (RCC), a type of kidney cancer.
Understanding Von Hippel-Lindau Syndrome
VHL syndrome is a genetic condition caused by a mutation in the VHL gene, located on chromosome 3. Normally, the VHL gene functions as a tumor suppressor, regulating cell growth and division to prevent uncontrolled proliferation and tumor formation. When mutated, its ability to produce a functional protein is impaired, allowing cells to grow unchecked.
This inherited disorder follows an autosomal dominant pattern, meaning a single mutated gene copy is sufficient. About 80% of VHL cases are inherited, while 20% arise from new, spontaneous mutations. VHL is rare, occurring in about 1 in 36,000 people.
Beyond the kidneys, VHL can lead to cysts and tumors in several other organs. Common sites include the brain, spinal cord, and retina, where blood vessel tumors called hemangioblastomas frequently occur. Other affected organs can include the adrenal glands, leading to pheochromocytomas, and the pancreas, where cysts and neuroendocrine tumors can form.
Renal Cell Carcinoma in VHL
Renal cell carcinoma (RCC) in individuals with VHL syndrome presents as the clear cell type. These tumors often manifest as multiple growths and can affect both kidneys, known as bilateral involvement. The predisposition to clear cell RCC in VHL is directly linked to the impaired function of the VHL gene and its role in cellular oxygen sensing pathways.
The VHL gene product, pVHL, targets hypoxia-inducible factors (HIFs), specifically HIF-alpha subunits, for degradation when oxygen is normal. HIFs are transcription factors regulating genes involved in cellular responses to low oxygen, including those promoting cell growth and new blood vessel formation. When the VHL gene is mutated, pVHL’s ability to degrade HIF-alpha is compromised, leading to abnormal HIF accumulation within cells, even with sufficient oxygen.
This persistent accumulation of HIFs, particularly HIF-2alpha, drives uncontrolled expression of genes that promote cell proliferation and angiogenesis (new blood vessel formation), hallmarks of tumor development. This dysregulation of the HIF pathway is central to clear cell RCC pathogenesis in VHL. In contrast to sporadic RCC, which affects older individuals and presents as a single tumor, VHL-associated RCC often has an earlier onset and is multifocal and bilateral.
Diagnosis and Surveillance
Diagnosing VHL syndrome involves a thorough evaluation, with genetic testing for the VHL gene mutation being a definitive step. This testing can confirm the presence of the inherited mutation, even in individuals who have not yet developed symptoms or tumors. In cases where clinical features are suggestive but inconclusive, identifying a heterozygous germline VHL pathogenic variant through molecular genetic testing establishes the diagnosis.
For individuals diagnosed with VHL, as well as at-risk relatives with unknown genetic status, regular, lifelong surveillance is paramount for early detection and management of associated tumors. Screening protocols for RCC typically involve routine abdominal imaging, such as magnetic resonance imaging (MRI) or computed tomography (CT) scans, often performed every two years starting around age 15. This consistent monitoring aims to identify kidney tumors when they are small and potentially more amenable to treatment, thereby improving long-term outcomes.
Management and Treatment Approaches
The management and treatment of VHL-associated RCC are tailored to individual circumstances, considering factors such as tumor size, location, and growth rate. For small tumors, active surveillance may be employed, involving close monitoring with imaging to track growth. This approach aims to delay more invasive interventions while ensuring that tumors are treated before they pose a significant risk.
When intervention is necessary, surgical removal is a common approach, with partial nephrectomy being the preferred method to preserve as much healthy kidney tissue as possible. This is particularly important given the tendency for VHL-associated RCC to be multifocal and bilateral, potentially requiring multiple interventions over a patient’s lifetime. Non-surgical approaches like radiofrequency ablation or cryoablation, which use heat or cold to destroy tumor cells, may be considered for smaller tumors, typically those between 2-3 cm, especially if they are located away from major blood vessels or bowel structures.
For advanced or metastatic VHL-associated RCC, targeted therapies play a role by specifically interfering with pathways disrupted by the VHL gene mutation. These therapies often include vascular endothelial growth factor (VEGF) inhibitors, which work by blocking the signals that promote the formation of new blood vessels that tumors need to grow. More recently, drugs like belzutifan, a hypoxia-inducible factor-2 alpha (HIF-2alpha) inhibitor, have been approved for VHL-associated RCC that does not require immediate surgery, directly targeting the aberrantly activated HIF pathway.