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Von Hippel Lindau disease (VHL) is an inherited mutation of the VHL gene, which causes tumors to form in areas of the body that contain large numbers of blood vessels. One in every 32,000 children born in the U.S. is affected by VHL.
Von Hippel Lindau (VHL) disease was first described at the beginning of the 20thcentury by Eugen von Hippel and Arvid Lindau. A mutation of the VHL gene can affect several organs of the body, and can be expressed differently in every patient and every family. The most common manifestations of VHL include cysts and tumors of the retina, brain, spinal cord, kidney, pancreas and inner ear.
Patients with VHL can present with cerebellar hemangioblastomas, retinal hemangioblastomas, pheochromocytomas, kidney cancer, pancreatic cysts and pancreatic neuroendocrine tumors.
Author: Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR; Chief Editor: James G Smirniotopoulos, MD more
Grouped as a hereditary phakomatosis, von Hippel-Lindau syndrome (VHL) is an autosomal dominant, inherited, neurocutaneous dysplasia complex with an 80-100% penetrance and variable delayed expressivity. Sex distributions are equal, and 20% of cases are familial. Images of VHL are shown below,
von Hippel-Lindau syndrome. Transaxial nonenhanced and contrast-enhanced CT scans through the cerebellum in a 34-year-old patient with a family history of VHL. Scans show a midline cerebellar cystic lesion with an enhancing nodule (arrow) due to cerebellar hemangioblastoma.von Hippel-Lindau syndrome. T1-weighted transaxial gadolinium-enhanced MRIs of the same patient as in the previous image show a well-defined hypervascular enhancing mass.von Hippel-Lindau syndrome. Coronal vertebral angiogram of the same patient as in the previous 2 images shows a hypervascular intramural nodule that demonstrates a prolonged and intense enhancement with a surrounding avascular area, which represents the cyst surrounding the mural nodule. Note the stretching around the cyst.von Hippel-Lindau syndrome. Sagittal vertebral angiogram of the same patient as in the previous 3 images shows a hypervascular intramural nodule (open arrow) that demonstrates a prolonged and intense enhancement with a surrounding avascular area, representing the cyst surrounding the mural nodule (solid arrows). Note the stretching of vessels around the cyst. The final diagnosis was a cerebellar hemangioblastoma associated with von Hippel-Lindau syndrome (same patient as in Images 1-3).VHL is characterized by a predisposition to bilateral and multicentric retinal angiomas, central nervous system (CNS) hemangioblastomas; renal cell carcinomas; pheochromocytoma s; islet cell tumors of the pancreas; endolymphatic sac tumors ; and renal, pancreatic, and epididymal cysts.[2, 3] CNS hemangioblastoma (Lindau tumor) is the most commonly recognized manifestation of VHL and occurs in 40% of patients.
Symptoms often begin in the second to third decades of life. Patients may present with ocular signs and/or symptoms due to retinal hemorrhage, retinal detachment, glaucoma, or uveitis. Funduscopic examination may reveal tortuous aneurysms of the retinal vessels, exudates on the fundus, and subretinal yellowish spots. Patients may present with neurologic symptoms such as headaches, ataxia, and blindness. The exact neurologic deficit depends on the site of the primary lesion.
Magnetic Resonance Imaging
Hemangioblastomas occur throughout the CNS, but they have several favored locations, including the cerebellum (most common site), medulla, spinal cord, and retina. Although hemangioblastomas can occur as isolated tumors, retinal tumors are mostly confined to VHL.[13, 11, 12]
MRI appearances of a hemangioblastoma are those of a well-demarcated cystic lesion with a highly vascular mural nodule that abuts on the pia mater.
Appearances of the cystic component vary depending on the protein concentration and/or presence of hemorrhage within the cyst. The cystic component may be isointense relative to cerebrospinal fluid (CSF) on images obtained with all pulse sequences, but more often, it is slightly hyperintense relative to CSF on T1- and T2-weighted images.
Mural nodules are slightly hypointense on T1-weighted images and hyperintense on T2-weighted images, and they are avidly enhancing after the administration of contrast material.
Large feeding or draining vessels are often present at the periphery and within the solid component, and they may show tubular areas of flow void on spin-echo images.
Although the lesion is benign, it may resemble malignant lesions on advanced MR images. It may have elevated relative tumor blood volume on perfusion MR. Similarly, it may show elevated choline on MR spectroscopy.
Endolymphatic sac tumors are heterogeneous on both T1- and T2-weighted images. They are associated with focal high signal intensity on T1-weighted images due to subacute hemorrhage and with areas of low signal intensity due to calcification or hemosiderin.
Blood and protein-filled cysts have high signal intensity on both T1-weighted and T2-weighted images; a finding of these cysts may suggest the diagnosis.
Tumors larger than 2 cm may have flow voids.
After the administration of contrast material, the tumor enhances heterogeneously.
On MRIs, choroidal capillary hemangiomas associated with VHL are minimally hyperintense on T1-weighted images. They may mimic ocular melanoma, but unlike pigmented melanoma, they are usually hyperintense on T2-weighted images.
As a result of the small size of retinal hemangiomas (1.5-2.0 mm), they are usually not identified on MRIs.
Spinal hemangioblastomas are intramedullary tumors in most patients (75%), but they may be radicular (20%) or intradural extramedullary (5%). Most of these tumors are located in the cervicothoracic spine. They usually expand the cord and have an intratumoral cystic component. On MRIs, they appear as a well-demarcated gadolinium-enhancing mass. Spinal hemangioblastomas are an unusual cause of cryptic subarachnoid hemorrhage. Patients with subarachnoid hemorrhage with negative cerebral angiography may benefit from contrast-enhanced spinal MRI to rule out an occult spinal hemangioblastoma.
An intramural nodule that enhances intensely may be visible. Large dorsally placed draining veins may appear as curvilinear areas of signal void. A syrinx is a frequently associated finding.
A pheochromocytoma associated with VHL has MRI appearances no different from those of the sporadic form. The tumor appears isointense or slightly hypointense relative to the liver on T1-weighted images, and it is extremely hyperintense on T2-weighted images.
Magnetic resonance images of von Hippel-Lindau syndrome are depicted below.
von Hippel-Lindau syndrome. Coronal T1-weighted MRI shows an enhancing lesion in the right cerebellar hemisphere compressing and displacing the aqueduct and fourth ventricle to the left. Note the tubular areas of flow void resulting from large blood vessels and the cystic tumor component.von Hippel-Lindau syndrome. Coronal T1-weighted MRI (same patient as in the previous image) shows an enhancing lesion in the right cerebral hemisphere that compresses and displaces the aqueduct and fourth ventricle to the left. Note the tubular areas of flow void resulting from large blood vessels.von Hippel-Lindau syndrome. Oblique coronal T1-weighted gadolinium-enhanced MRI through the right kidney shows a hypointense linear mass extending from the renal capsule to the renal pelvis. At surgery, a renal cell carcinoma was confirmed.von Hippel-Lindau syndrome. Coronal T1-weighted contrast enhanced MRI shows an intensely enhancing cerebellar lesion (red arrow) with a large cystic tumor component (white arrow).von Hippel-Lindau syndrome. Coronal T1-weighted contrast enhanced MRI (same patient as in the previous image) shows, at lower sections, an intensely enhancing cerebellar lesion with a large cystic tumor component. Note also the enhancing mural nodules and intratumoral flow void due to large pathological vessels.von Hippel-Lindau syndrome. Sagittal T2-weighted MRI (same patient as in the previous 2 images) shows a cerebellar lesion with a large septate cystic component (arrow). Note the hydrocephalus.von Hippel-Lindau syndrome. Sagittal T2-weighted MRI (same patient as in the previous 3 images) shows a cerebellar lesion with a central low signal component related to intratumoral hemorrhage.von Hippel-Lindau syndrome. Axial T2-weighted MRI shows high signal nodules in the region of previous surgical resection of hemangioblastoma in an 18-month surveillance scan. An earlier scan showed no nodular lesions in this region. The appearance suggests a recurrence of hemangioma.von Hippel-Lindau syndrome. Axial T2-weighted MRI (same patient as in the previous image) shows high signal nodules in the region of previous surgical resection of hemangioblastoma in an 18-month surveillance scan. An earlier scan showed no nodular lesions in this region. The appearance suggests a recurrence of hemangioma.
Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.
Characteristics of NSF/NFD include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.
Degree of confidence
MRI is the modality of choice for imaging the central nervous system in patients in whom hemangioblastoma is suggested and for screening asymptomatic patients with VHL and their relatives at risk for VHL.
False-positive diagnoses may occur with cystic astrocytomas, which are usually smaller than 5 cm in diameter; these may be calcified, and they usually have thicker walls. Cystic metastases occasionally resemble a hemangioblastoma superficially. Spinal hemangioblastomas must be differentiated from intramedullary hemorrhage.
Endolymphatic sac tumors may mimic other cerebellopontine tumors. Nonfunctioning adrenal adenomas, adrenocortical adenomas, and adrenal cysts must be differentiated from pheochromocytomas associated with VHL.