von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome that predisposes individuals to a variety of tumors. VHL is associated with tumors in a variety of organs, including the kidney, adrenal gland, central nervous system (CNS), eye, inner ear, epididymis, and pancreas. VHL is associated with renal cell carcinoma (RCC), pheochromocytoma, hemangioblastomas of the CNS, retinal angiomas, endolymphatic sac tumors, and pancreatic cysts and solid lesions.
VHL occurs in one of every 36,000 live births1 and has a penetrance in 90% of patients by age 65 years.2 Before computed tomography (CT) and other imaging modalities were developed and before the advent of comprehensive screening in affected individuals, median survival in these patients was less than 50 years. The cause of death in these patients was typically either metastases from RCC or symptoms related to CNS hemangioblastomas.3 Now with a multidisciplinary approach to these complex patients, survival rates have improved.
VHL is an autosomal dominant disease resulting from a germline mutation in the VHL gene. The gene was first identified in 1993.4 The gene is an RCC tumor suppressor gene that has been shown to be involved in multiple functions, including regulation of angiogenesis, ubiquitination, and gatekeeper functions in mitosis.5 The gene has been localized to chromosome 3p25.5.
VHL is associated with tumors in a multitude of organs, including the kidney, adrenal gland, CNS, eye, inner ear, epididymis, and pancreas. With current imaging modalities and genetic testing, many individuals are diagnosed while still asymptomatic. The diagnosis continues to be based on clinical criteria. Individuals with a family history are considered positive for the disease if screening tests diagnose a CNS hemangioblastoma (including retinal), pheochromocytoma, or renal manifestations. Patients who are diagnosed de novo without a family history must have evidence of two or more CNS hemangioblastomas or one CNS manifestation with a visceral tumor to meet diagnostic criteria.3
Because of the multiple organs involved in this disease process, this chapter separately describes the clinical presentation of each organ system.
Hemangioblastomas are the most common tumor found in VHL patients, affecting up to 80% of patients. The average age of presentation is 33 years.6 These lesions are always benign but may cause significant morbidity because of volume effect. These lesions may occur anywhere along the craniospinal axis and may cause swelling and symptoms based on their location along this axis.
Retinal hemangioblastomas are very common in VHL patients, occurring in 60% of patients.3 They may be multifocal or bilateral and occur early in life. The mean age of diagnosis of retinal hemangioblastomas is 25 years.3 They are benign but symptomatic and may lead to vision loss.
Occurring in 11% of VHL patients, endolymphatic sac tumors are not as common as other CNS manifestations of VHL. They may lead to hearing loss and problems with equilibrium.7
VHL patients are prone to both renal cystic disease and solid lesions of the kidneys. RCC, which may be malignant, occurs in 25% to 45% of VHL patients.3 VHL may also be associated with renal cysts that do not have a malignant potential but may cause local effects. Sixty percent of VHL patients have some renal manifestation.3 Because of its malignant potential, RCC is a significant cause of death in VHL patients, and when left untreated, it can lead to death from metastases in 13% to 42% of patients.8,9 These renal manifestations may be multifocal and bilateral, including bilateral RCCs. The mean age of presentation for renal manifestations is 39 years.
Pheochromocytomas occur in up to 20% of patients with VHL disease. These may be multiple as well as bilateral and may occur as extra-adrenal lesions as paragangliomas.3 They occur at a mean age of 30 years.
Most of the pancreatic lesions associated with VHL are cystic and are classified histologically as serous cystadenomas. These cystic lesions may occur as a single lesion or as multiple lesions and occur in 17% to 56% of patients with VHL.10,11 These lesions have no malignant potential but may replace enough of the pancreas to cause endocrine or exocrine insufficiency of the pancreas or compression of the intestine or the bile duct.
Solid lesions are also linked to VHL. Pancreatic neuroendocrinetumors (PNETs), which are always nonfunctional, have a malignant potential. PNETs have been previously reported to be present in 12% to 17% of patients with VHL, and these tumors behave in a malignant fashion in up to 17% of patients.12,13 Despite their malignant potential, they remain an uncommon cause of death.14 An association between PNETs and pheochromocytoma has been reported.15
