Manifestations

This presentation has been created and paid for by Merck. The information in this presentation is intended for health care professionals in the United States and its territories, including Puerto Rico.

Hello, I am Dr. Brian Shuch, Director of the University of California Los Angeles Kidney Cancer and VHL Programs. Today, I am going to provide an overview of the clinical characteristics and patient pathway for von Hippel-Lindau, or VHL, disease.

Let’s review the topics we will be covering today. We’ll first review the key clinical characteristics and manifestation of VHL disease. Then, we’ll walk through the patient pathway for individuals with the disease. And finally, we’ll highlight the importance of multidisciplinary care for these patients.

Let’s begin by reviewing what VHL disease is. VHL disease is a rare, systemic, multi-organ, autosomal dominant condition caused by mutations of the tumor suppressor gene, VHL. VHL disease is a largely heritable condition. Approximately 80% of people diagnosed have 1 affected parent, whereas about 20% of individuals have de novo mutations with no family history of the disease.

The global incidence of VHL disease is estimated to be 1 in 36,000 individuals. It is estimated that there are 10,000 individuals with VHL disease living in the United States.

Now, let’s talk about the causes of VHL disease.

VHL disease is caused by the mutation of the VHL gene, which leads to a functional loss of VHL protein. Many functions have been attributed to the VHL protein. These are largely divided into hypoxia-inducible factor, or HIF-dependent or HIF-independent processes. HIF-dependent processes are involved in oxygen sensing and adaptive response to hypoxia. Dysregulation of these processes may result in angiogenesis, cellular proliferation and migration, and erythropoiesis, which are linked to tumorigenesis. VHL protein regulates a number of HIF-independent processes, including regulation of extracellular matrix, primary cilium, mitosis, and DNA repair. Dysregulation of these processes may contribute to development of cysts or dysplasia. It is believed that the aforementioned processes are the reason many patients with VHL disease may present with cysts and tumors in multiple organs.

Next, let’s look at which organs are affected by VHL disease and how patients with the disease may present.

VHL disease can cause tumors and/or cysts in multiple parts of the body, including the central nervous system, or CNS, kidneys, pancreas, eyes, adrenal glands, and inner ears. Cysts and tumors can also occur in the reproductive organs, abdomen, thorax, or neck.

Now, let’s take a deeper dive on select clinical manifestations of VHL disease.

CNS hemangioblastomas can occur in 60% to 80% of patients and are the most common tumors in patients with VHL disease. They may cause headaches and affect motor activities, among other symptoms.

About 30% to 70% of patients can develop renal manifestations, which include benign cysts and clear cell renal cell carcinoma, or RCC. Clear cell RCC are frequently bilateral in patients, though on their own don’t confirm the diagnosis of VHL disease. Patients with renal cysts are usually asymptomatic and rarely need intervention. Patients with RCC can remain asymptomatic for long periods of time but can present with a renal mass with flank pain or hematuria.

About 35% to 70% of patients have pancreatic cysts or pancreatic neuroendocrine tumors. Patients can also present with serous cystadenomas. Manifestations of pancreatic cysts and cystadenomas are mostly asymptomatic and benign, but they can cause pancreatic insufficiency. Pancreatic neuroendocrine tumors become malignant and metastatic in a small percentage of patients and can cause symptoms including abdominal pain, jaundice, pancreatitis, and gastrointestinal bleeding.

Retinal hemangioblastomas can occur in 49% to 62% of patients and are often the first manifestations of VHL disease. They may result in severe visual deficits, including blindness.

Pheochromocytomas, or PCCs, of the adrenal gland can occur in 10% to 20% of patients and have the potential to transform into malignant tumors. Symptoms associated with PCCs include hypertension, tachycardia, palpitations, headaches, sweating, pallor, and nausea.

Lastly, endolymphatic sac tumors can occur in 6% to 15% of patients. They are generally benign but can be locally invasive and affect a patient’s equilibrium and hearing.

Now that we have reviewed the common manifestations of VHL, let’s review the patient pathway for individuals with VHL disease.

VHL disease displays considerable variability. Thus, both germline genetic testing and clinical manifestations should be considered when diagnosing patients. In patients with known family history, early germline genetic testing can confirm the diagnosis in at-risk asymptomatic family members, clarifying the need for routine clinical and imaging screening measures.

Screening is needed for initial identification of manifestations and to establish the appropriate frequency of subsequent surveillance before irreversible deficits or metastases occur.

Surveillance is a serial assessment to detect new lesions at an early stage, monitor small asymptomatic lesions, and monitor changes in manifestations. Surveillance and timely management of VHL disease–associated cysts and tumors may help improve the prognosis of a patient.

The recurrent and systemic nature of VHL requires that patients are subjected to diligent surveillance of certain organs over their lifetimes. It is important to note that the penetrance of VHL can increase with age and is over 90% by the age of 65. Furthermore, tumors can exhibit linear growth, exponential growth, or periods of fluctuation with saltatory periods and quiescent phases. High-risk individuals who are asymptomatic, and those with confirmed VHL disease without clinical manifestations in a particular organ, should undergo surveillance. Established surveillance guidelines are available, which can be adjusted by clinicians. Such adjustments can be made depending on the patient’s family history and their manifestations.

Finally, let’s review the importance of multidisciplinary care for patients with VHL disease.

Managing VHL disease is a team effort, and patients need to see multiple specialists, but meeting this requirement can be challenging.

These specialists may include an oncologist, endocrinologist, neurosurgeon, general surgeon, ophthalmologist, neurologist, urologist, genetic counselor, nurse, and nurse practitioner.

Having a multidisciplinary team familiar with individual patients and their family history is paramount in navigating through the complicated pathway that patients with VHL disease experience.

Like many patients with rare diseases, patients with VHL disease may not have access to appropriate resources, such as centers of excellence, coordinated care, and patient support systems. Connecting patients to appropriate specialists and resources can help them manage the various aspects of their disease. Advocacy groups and patient support resources are also available.

Let’s recap what we have reviewed today. VHL disease is a rare and systemic genetic syndrome that can cause tumors and/or cysts in multiple parts of the body, including the eyes, CNS, inner ears, adrenal glands, pancreas, and kidneys. Comprehensive screening and surveillance can help identify new manifestations at an early stage, monitor small asymptomatic lesions, and monitor changes in manifestations. Patients with VHL disease undergo a continual cycle of disease management and may need to see multiple health care specialists. Managing VHL disease is a team effort, and patient-focused resources are available.

Thank you for your time today. We covered a lot. We greatly appreciate the outstanding care you give to these complex patients with VHL disease.