eMedicine Specialties > Radiology > Multisystem

Von Hippel-Lindau Syndrome

Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, LRCP, Chairman of Medical Imaging, Professor of Radiology, NGHA, King Fahad National Guard Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia
Ian Turnbull, MD, Lecturer, Department of Radiology, University of Manchester; Consulting Neuroradiologist, Hope Hospital, Salford, Manchester and North Manchester Hospital; Sumaira MacDonald, MBChB, PhD, MRCP, FRCR, Lecturer, Sheffield University Medical School; Endovascular Fellow, Sheffield Vascular Institute; Riyadh Al-Okaili, MBBS, Interventional/Therapeutic and Diagnostic Neuro-Radiologist, King Abdulaziz Medical City

Updated: Feb 6, 2008

Introduction

Background

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.

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. CNS hemangioblastoma (Lindau tumor) is the most commonly recognized manifestation of VHL and occurs in 40% of patients.¹

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.

Pathophysiology

VHL has an autosomal dominant transmission with variable penetrance and delayed expression. It has been reported in identical twins. The gene has been located on chromosome bands 3p25-26, and flanking markers have been identified. As many as 20% of cases can be familial. DNA polymorphism analysis is useful in distinguishing gene carriers from healthy siblings.^2,3,4,5

Germ-line mutations of the VHL gene in humans cause a hereditary cancer syndrome characterized by the development of retinal and CNS hemangioblastomas.^2,3 Other tumors associated with VHL are renal cell carcinoma and pheochromocytoma. Precancerous renal lesions have been described as a part of VHL in which the evolution from a simple cyst to an atypical cyst with epithelial hyperplasia to cystic or solid conventional-type renal cell carcinoma is well documented. In the genesis of papillary renal cell carcinoma, an adenoma-carcinoma sequence is also recognized.⁶

Pheochromocytomas associated with VHL and multiple endocrine neoplasia type 2 (MEN 2) display distinct biochemical and clinical phenotypes.⁷ These distinct changes are related to underlying differences in the expression of tyrosine hydroxylase, rate-limiting enzymes in catecholamine synthesis, and phenylethanolamine N- methyltransferase, the enzyme that converts norepinephrine to epinephrine.⁸

Compared with other patients, those with MEN 2 with adrenal pheochromocytoma are more symptomatic; they have higher incidence of paroxysmal hypertension; and they have higher plasma concentrations of metanephrine. Paradoxically, they also have lower total plasma concentrations of catecholamine than do patients with VHL. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis underlie the different clinical presentations of pheochromocytoma in patients with MEN 2 and VHL.

Criteria for the diagnosis of VHL include the following: (1) more than 1 hemangioblastoma in the CNS, (2) 1 CNS hemangioblastoma and visceral manifestations of VHL, or (3) 1 manifestation and a known family history of VHL.

Systemic manifestations of VHL are as follows:

• Retina - Hemangioblastoma and retinal angiomatosis (45%), multiple in 66% and bilateral in 50%⁹
• Central nervous system - Hemangioblastoma, cerebellum (65%), cerebrum, medulla oblongata (20%), spinal cord (15%), multiple hemangioblastoma (10-15%), syringomyelia, meningioma, arteriovenous malformation of the cervical cord and posterior fossa epidermoid, and miliary spinal hemangioblastomas
• Labyrinth - Endolymphatic sac neoplasm (7%)^1,10,11
• Lung - Cyst
• Heart - Rhabdomyoma
• Kidney - Hemangioblastoma, renal cell adenoma, renal cell carcinoma (20-45%), multicentric 87%, bilateral 10-75%, renal hemangioma, cortical renal cyst (75%), and renal cell carcinoma (may arise from cyst wall)¹²
• Bladder - Hemangioblastoma
• Epididymis/testis - Cysts of the epididymis, clear cell papillary cystadenoma of the epididymis, hypernephroid tumor of the epididymis, and testicular germ cell tumor
• Broad ligament - Papillary cystadenoma
• Adrenal gland - Pheochromocytoma cyst (10-17%, bilateral in 40%)
• Pancreas - Hemangioblastoma, cysts (30% of patients; 72% incidence in autopsy series), cystadenoma, islet cell adenoma, and islet cell carcinoma. Pancreatic lesions, including cysts, islet cell tumors, and microcystic cystic adenomas, may be the only abdominal manifestations of VHL and may precede other manifestations by several years^5,13,14   
• Liver - Cyst, adenoma, angioma, and carcinoid of the common bile duct
• Spleen - Angioma and cyst
• Skin - Nevus and café au lait spot
• Bone - Cyst and hemangioma
• Miscellaneous - Omental and mesenteric cysts and paraganglioma

Frequency

United States

VHL occurs with an approximate frequency of 1 case per 36,000 live births.⁴

Mortality/Morbidity

• Blindness and permanent brain damage were once the eventual outcome in patients with VHL. Surgical outcomes for patients with CNS hemangioblastomas are favorable. However, the treatment of hemangioblastomas associated with VHL is more difficult and is a prolonged endeavor for patients.
• The most common causes of morbidity and mortality are associated with frequent tumor recurrence and frequent surgical intervention. Renal cell carcinoma is the cause of death in 30-50% of patients.
• In patients with VHL, neurologic screening enables the identification of lesions before patients become symptomatic. Because patients with VHL are at risk of developing new lesions, they require lifelong follow-up care.

Sex

The male-to-female ratio is 1:1.

Age

Patients with VHL most commonly present in the second to third decades of life.

Presentation

Symptoms caused by VHL depend on the organ involved. Patients with involvement of the CNS at presentation are usually aged 25-35 years. Again, depending on the site of CNS involvement, patients may present with a variety of symptoms.

Cerebellar symptoms include dysdiadochokinesia, dysmetria, and a positive Romberg sign. Signs of increased intracranial pressure due to tumor mass effect may be evident. Spinal cord symptoms are uncommon and may include proprioception and sensory loss. Ocular symptoms may dominate, ranging from retinal hemorrhage, retinal detachment, glaucoma, or uveitis to decreasing visual acuity. Neoplasms of the endolymphatic sac may cause sensorineural hearing loss. Polycythemia may develop as a consequence of renal hemangioblastoma or a renal cell carcinoma, whereas hypertension  may be the presenting feature of a renal tumor or a neuroblastoma.^15,16

Islet cell tumors of the pancreas may cause gastrointestinal tract or metabolic upset, depending on the type of islet cell tumor. Pancreatic cysts and islet cell tumors may be the only manifestations of VHL, and these may precede any other manifestation of the disease by several years. Rarely, pancreatic masses may cause bile duct obstruction.

The Cambridge protocol was devised by Maher et al for screening patients with VHL disease or at-risk relatives. The protocol is as follows¹⁷ :

• Affected asymptomatic patient
  • Annual physical examination and urine test
  • Annual direct and indirect ophthalmoscopy
  • Annual fluorescein angiography or angiography
  • Annual renal ultrasonographic examination
  • MRI or CT scan of the brain every 3 years to age 50 years then every 5 years thereafter
  • Abdominal CT scanning every 3 years (more often if multiple renal cysts are present)
  • Annual 24-hour urine collection for vanillylmandelic acid (VMA) levels
• At-risk relatives - The same protocol is followed as for asymptomatic patients, apart from age limits, which are as follows:
  • Annual direct and indirect ophthalmoscopy from age 5 years
  • Annual fluorescein angiography or angiography from age 10 years until age 60 years
  • MRI or CT scanning of the brain every 3 years from ages 15-40 years, then every 5 years until age 60 years
  • Abdominal CT scanning every 3 years from ages 20-65 years

Preferred Examination

Tumors at various sites are demonstrable by using different imaging modalities, including ultrasonography, CT, MRI, radionuclide studies, and angiography. The preferred examination depends on the site or organ involved. CT and MRI best depict intracranial lesions, but MRI is more appropriate for examining spinal lesions. Although retinal tumors are visualized best on sonograms, the kidneys and pancreas can be imaged by using MRI sonograms and/or CT scans.^15,18

When asymptomatic patients and at-risk relatives are screened, noninvasive techniques should be emphasized. Preferably, those not involving ionizing radiation, such as ultrasonography and MRI, should be used.

Limitations of Techniques

The limitation of various techniques depends on the size of the tumor and on problems with atypia. CT is an excellent modality for detecting tumors anywhere in the body, but it has the disadvantage of ionizing radiation, which may become problematic in screening asymptomatic patients and at-risk relatives.

Differential Diagnoses

Other Problems to Be Considered

Angioreticuloma (spinal hemangioblastoma)
Endolymphatic sac tumor

Other intracranial cystic lesions

Sporadic hemangioblastoma
Pilocytic astrocytoma
Cystic meningioma
Ganglion cell tumors
Craniopharyngioma
Nonneoplastic cysts, such as arachnoid, colloid, dermoid, and epidermoid cysts

Renal lesions

Renal adenoma
Renal cell carcinoma
Renal cysts

Pancreatic lesions

Pancreatic islet cell tumors
Multiple endocrine neoplasia type 2

Adrenal gland lesions

Other adrenal masses

Differential diagnosis of retinal angiomatosis VHL

Eales disease
Coats disease
Leber disease
Capillary angiectasis

Radiography

Findings

Plain radiographs have little to contribute. Calcification within the orbits in retinal lesions may be difficult to see. The rare, associated bone cysts and osseous hemangiomas may be fairly well defined on plain radiographs.^19,20

Degree of Confidence

Confidence in the diagnosis of VHL with plain radiographs is low.

False Positives/Negatives

Hemangiomas of the bone must be differentiated from osteoblastic metastases, lesions due to Paget disease, lymphoma, and monostotic fibrous dysplasia.

Computed Tomography

Findings

• Hemangioblastomas of the CNS are demonstrated as cystic lesions with a 3- to 15-mm mural nodule in 75% of patients. They are demonstrated as an enhancing lesion with multiple cystic areas in 15% of patients and as an enhancing solid mass in 10%. The cerebellum is most commonly involved, followed by the medulla, the spinal cord, and even the spinal nerve roots. Supratentorial hemangioblastomas are rare, but they have been reported.^11,14,19,20
• Hemangioblastomas usually do not become calcified, and this is a finding that helps in differentiating these lesions from cystic astrocytomas (which are calcified in 25% of patients). Typical pilocytic cystic astrocytomas also occur in patients much younger than most patients with hemangioblastomas.
• Choroidal capillary hemangiomas are aggressive lesions that are histologically similar to cerebellar hemangioblastomas. Approximately 25-30% of these lesions occur in patients with VHL. CT scans demonstrate enhancing lesions.
• Retinal hemangiomas are too small to be depicted on CT scans, and the diagnosis chiefly depends on the results of an ophthalmoscopic examination.
• CT has a low sensitivity in the detection of renal cell carcinoma associated with VHL because of its inability to reliably differentiate cystic renal cell carcinomas, cancers within a cyst, and atypical cysts. Therefore, a multimodality approach is more appropriate.
• Renal adenomas are potentially premalignant. These adenomas are usually smaller than 3 cm, are subcapsular cortical, and are impossible to differentiate from renal cell carcinomas. They are multiple in 25% of patients.
• Endolymphatic sac tumors are destructive and contain calcification centered on the retrolabyrinthine region. All papillary endolymphatic sac tumors have a thin peripheral rim of calcification, representing the expanded cortex of petrous bone.
• Endolymphatic sac tumors are slow growing and spread in 2 directions (ie, laterally toward the external ear, in the direction of the jugular foramen, and medially into the cerebellopontine angle).
• On CT scans, the margins of these tumors are geographic or moth-eaten in appearance, and the intratumoral bone appears reticular or spiculated.
• After the intravenous administration of contrast material, areas of patchy enhancement are interspersed with cystic areas.
• Although the lesion is a benign lesion, it typically has elevated tumor blood volume on perfusion CT, which is more typical for malignant lesions.

Degree of Confidence

CT findings are not reliable in differentiating cystic renal cell carcinomas, cancers within a cyst, and atypical cysts. Differentiating a renal cell adenoma from a renal cell carcinoma is impossible.

False Positives/Negatives

The differential diagnosis of VHL should include sporadic hemangioblastoma, cystic astrocytoma, arachnoid cyst, cystic metastases, renal adenoma, renal cell carcinoma, renal cysts, pancreatic islet cell tumors, and MEN 2. Tumors of the endolymphatic sac may mimic other cerebellopontine tumors.

Magnetic Resonance Imaging

Findings

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.^11,19,20

• 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.

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy . 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.

As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics 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. For more information, see the FDA Public Health Advisory or Medscape.

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 Positives/Negatives

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.

Ultrasonography

Findings

The sensitivity of ultrasonography in the detection of the primary lesion in renal cell carcinoma is comparable to that of CT. Ultrasonography is the modality of choice in screening the abdomen in patients with known VHL. This is a useful examination for imaging the retina; sonograms may show small hypoechoic masses, most often in the temporal retina.²⁰

Degree of Confidence

Ultrasonography is an excellent modality for screening the abdomen in patients with known VHL or their at-risk relatives. It has a high sensitivity in depicting cystic intra-abdominal masses and in characterizing the contents of cysts.

False Positives/Negatives

Differentiating a renal cell adenoma from a renal cell carcinoma may not be possible. Similarly, difficulties may be encountered in differentiating a complex benign cyst from cystic malignant transformation.

Nuclear Imaging

Findings

Radionuclide studies are increasingly valuable in diagnosing CNS neoplasms, in monitoring therapy, and in defining functional characteristics that are not demonstrated well on conventional cross-sectional images.²⁰

Much of the present value of nuclear medicine is in positron emission tomography (PET). PET with fluorodeoxyglucose (FDG) provides an indication of metabolic activity of CNS tumors; this finding is well correlated with the tumor growth rate in most tumors. However, this correlation may not be applicable to some tumors such as pilocytic astrocytomas and hemangioblastomas, which are histologically benign but may resemble high-grade lesions on FDG-PET. FDG-PET scans are unaffected by postoperative reactions or steroids, and they can provide information about residual tumor or tumor recurrence. Many centers prefer to use perfusion MR/CT instead of PET for essentially the same purpose. 

Radionuclides can also be used (1) to detect bone metastases resulting from primary malignant bone lesions due to malignancies associated with VHL and (2) to assess renal function prior to resection of renal tumors. Iodine-131 metaiodobenzylguanidine (¹³¹ I MIBG) is a useful scanning agent in the detection of pheochromocytoma. This technique is particularly useful when clear clinical and laboratory evidence of tumor exists but when CT scans and MRIs demonstrate no abnormality.¹³¹ I MIBG can be used for whole-body scintigraphy in which functioning metastasis from a malignant pheochromocytoma may also be detected; this approach may provide the future therapeutic options (eg,¹³¹ I MIBG methods to treat metastases).

Degree of Confidence

¹³¹ I MIBG uptake has a sensitivity of 80-90% and a specificity of 98% in the detection of pheochromocytoma.

False Positives/Negatives

¹³¹ I MIBG uptake may occur in medullary carcinoma of the thyroid, carcinoid tumors, neuroblastoma, and paragangliomas.

Angiography

Findings

Angiography of hemangioblastoma reveals a hypervascular lesion with intense and prolonged early enhancement of the mural nodule associated with dilated feeding vessels. Endolymphatic sac tumors are hypervascular on angiography, and the blood supply is derived from the external carotid artery. Large tumors have an additional blood supply from the internal carotid artery and posterior circulation.

Degree of Confidence

Angiographic appearances are nonspecific and can occur with other vascular tumors.

False Positives/Negatives

Cystic meningioma and a meningeal hemangiopericytoma may resemble a hemangioblastoma superficially, but confusion is unlikely when the clinical presentation and the other imaging findings are considered.

Intervention

Preoperative embolization is not generally used but may be helpful before surgical resection of endolymphatic sac tumors and hemangioblastomas in selected cases.^21,22

Treatment involves resection of the offending tumor, aspiration of the cysts causing pressure-related symptoms, photocoagulation, and cryotherapy of any retinal lesions. Radiology has a central role in managing VHL. Because a conservative approach to the treatment of VHL lesions is now more widely accepted, ongoing follow-up with careful ultrasonographic and MRI screening will play a central role in evaluating the progression of disease.²³

Medicolegal Pitfalls

• Nontarget embolization may occur during tumor embolization.

(See also the Medscape topic Medical Malpractice and Legal Issues.)

Multimedia

Media file 1: 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.

Media file 2: von Hippel-Lindau syndrome. T1-weighted transaxial gadolinium-enhanced MRIs show a well-defined hypervascular enhancing mass.

Media file 3: von Hippel-Lindau syndrome. Coronal vertebral angiogram (see also Image 4) 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.

Media file 4: von Hippel-Lindau syndrome. Sagittal vertebral angiogram (see also Image 3) 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).

Media file 5: von Hippel-Lindau syndrome. Axial nonenhanced CT scan of the head in a patient with known von Hippel-Lindau syndrome and an acute neurologic presentation shows hyperattenuating areas within a right cerebellar tumor suggestive of hemorrhage. Note that the tumor is causing moderate hydrocephalus.

Media file 6: von Hippel-Lindau syndrome. Coronal T1-weighted MRI (see also Image 7) 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.

Media file 7: von Hippel-Lindau syndrome. Coronal T1-weighted MRI (see also Image 6) 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.

Media file 8: von Hippel-Lindau syndrome. Sagittal vertebral angiogram shows a hypervascular lesion with intense and prolonged enhancement (see also Image 9).

Media file 9: von Hippel-Lindau syndrome. Coronal vertebral angiogram shows a hypervascular lesion with intense and prolonged enhancement (see also Image 8). The final diagnosis was von Hippel-Lindau syndrome–associated cerebellar hemangioblastoma (same patient in Images 5-9).

Media file 10: von Hippel-Lindau syndrome. A 16-year-old female adolescent with a family history of von Hippel-Lindau syndrome presented with generalized bone pain, weight loss, and hypertension. This skull radiograph was part of the skeletal survey. The lateral skull radiograph demonstrates well-defined lytic lesions throughout the calvarium. (See also Image 11.)

Media file 11: von Hippel-Lindau syndrome. Transaxial bone-window CT scan through the head (see also Image 10) shows destructive lesions throughout the calvarium. Some lesions cross the entire thickness of the skull.

Media file 12: von Hippel-Lindau syndrome. Scintigraphic image of the skull (see also Image 13) after iodine-131 metaiodobenzylguanidine administration shows multiple foci of isotope uptake.

Media file 13: von Hippel-Lindau syndrome. Scintigraphic image of the retroperitoneum (see also Image 12) after iodine-131 metaiodobenzylguanidine administration shows multiple foci of isotope uptake.

Media file 14: von Hippel-Lindau syndrome. Axial CT scan through the abdomen shows soft-tissue retroperitoneal masses (see also Image 15).

Media file 15: von Hippel-Lindau syndrome. Axial CT scan through the abdomen shows bone destruction (see also Image 14). The histologic diagnosis was von Hippel-Lindau–associated malignant pheochromocytoma with extensive metastases (same patient in Images 10-15).

Media file 16: von Hippel-Lindau syndrome. This 46-year-old man with known von Hippel-Lindau syndrome presented with gross hematuria. Intravenous urogram and sonogram showed a mass lesion within the midpoles/upper pole of the right kidney. CT was performed for further staging. Contrast-enhanced axial CT scan through the kidneys shows a hypoattenuating mass in the right kidney extending into the renal pelvis (see also Image 17).

Media file 17: von Hippel-Lindau syndrome. Oblique coronal T1-weighted gadolinium-enhanced MRI through the right kidney in the same patient as in Image 16 shows a hypointense linear mass extending from the renal capsule to the renal pelvis. At surgery, a renal cell carcinoma was confirmed.

Media file 18: von Hippel-Lindau syndrome. Transaxial contrast-enhanced CT scans through the cerebellum on a 28-year-old patient with no family history of VHL (see also Image 19). Scans show a right cerebellar enhancing partially cystic lesion with enhancing mural nodules (due to cerebellar hemangioblastoma (Note the secondary hydrocephalus)

Media file 19: von Hippel-Lindau syndrome. Transaxial contrast-enhanced CT scans through the cerebellum in the same patient as in Image 18 (lower sections). Scans show multiple right cerebellar enhancing partially cystic lesion due to cerebellar hemangioblastoma.

Media file 20: von Hippel-Lindau syndrome. Sagittal reconstruction of contrast-enhanced CT scans (same patient in Images 18-40). Scans show a posterior fossa mass a due to cerebellar hemangioblastoma.

Media file 21: von Hippel-Lindau syndrome. Sagittal volume rendering of contrast enhanced CT scan of the same patient in Images 18-40 shows 2 intensely enhancing lesions in the posterior fossa with arterial supply derived from the posterior fossa circulation.

Media file 22: von Hippel-Lindau syndrome. Axial volume rendering of contrast enhanced CT scan (same patient in Images 18-40) shows 2 intensely enhancing lesions in the posterior fossa with arterial supply derived from the posterior fossa circulation.

Media file 23: von Hippel-Lindau syndrome. Coronal T1-weighted contrast enhanced MRI (same patient in Images 18-40) shows an intensely enhancing cerebellar lesion (red arrow) with a large cystic tumor component (white arrow).

Media file 24: von Hippel-Lindau syndrome. Coronal T1-weighted contrast enhanced MRI (same patient in Images 18-40)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.

Media file 25: von Hippel-Lindau syndrome. Sagittal T2-weighted MRI (same patient in Images 18-40) shows a cerebellar lesion with a large septate cystic component (arrow). Note the hydrocephalus.

Media file 26: von Hippel-Lindau syndrome. Sagittal T2-weighted MRI (same patient in Images 18-40) shows a cerebellar lesion with a central low signal component related to intratumoral hemorrhage.

Media file 27: von Hippel-Lindau syndrome. Sagittal vertebral angiogram (same patient in Images 18-40) shows a hypervascular lesion with intense and prolonged enhancement with an avascular cystic component. Note the large draining vein.

Media file 28: von Hippel-Lindau syndrome. Sagittal vertebral angiogram (same patient in Images 18-40) shows a hypervascular lesion with intense and prolonged enhancement with an avascular cystic component. Note the large draining vein.

Media file 29: von Hippel-Lindau syndrome. Sagittal vertebral angiogram (same patient in Images 18-40) shows a hypervascular lesion with intense and prolonged enhancement with an avascular cystic component. Note the large draining vein.

Media file 30: von Hippel-Lindau syndrome. Sagittal vertebral angiogram (same patient in Images 18-40) shows a hypervascular lesion with intense and prolonged enhancement with an avascular cystic component. Note the large draining vein.

Media file 31: von Hippel-Lindau syndrome. Sagittal vertebral angiogram (same patient in Images 18-40) shows a hypervascular lesion with intense and prolonged enhancement with an avascular cystic component. Note the large draining vein.

Media file 32: von Hippel-Lindau syndrome. Sagittal vertebral angiogram (same patient in Images 18-40) shows a hypervascular lesion with intense and prolonged enhancement with an avascular cystic component. Note the large draining vein.

Media file 33: von Hippel-Lindau syndrome. Axial contrast enhanced axial CT in the portal venous phase at the renal level (same patient in Images 18-40). The scan was performed as a part of surveillance 12 months following surgery for cerebellar hemangioblastoma. The scan shows multiple pancreatic cysts, a small right renal cyst, and a solid 4.5 cm mass, mid pole left kidney, encroaching on the renal pelvis. A left nephrectomy was performed. Pathological diagnosis was that of a renal cell carcinoma.

Media file 34: von Hippel-Lindau syndrome. Axial contrast enhanced upper abdominal CT scans (same patient in Images 18-40) in the portal venous phase. These scans were performed 6 months following left nephrectomy. Note cysts within the pancreas and the right kidney. Note also a solid 3 cm lesion (mid pole, right kidney, posterior renal cortex). A further smaller lesion is seen in the renal cortex more anteriorly, which is too small to characterize. The patient is awaiting a partial nephrectomy.

Media file 35: von Hippel-Lindau syndrome. Axial contrast enhanced upper abdominal CT scans (same patient in Images 18-40) in the portal venous phase. These scans were performed 6 months following left nephrectomy. Note cysts within the pancreas and the right kidney. Note also a solid 3 cm lesion (mid pole, right kidney, posterior renal cortex). A further smaller lesion is seen in the renal cortex more anteriorly, which is too small to characterize. The patient is awaiting a partial nephrectomy.

Media file 36: von Hippel-Lindau syndrome. Axial contrast enhanced upper abdominal CT scans (same patient in Images 18-40) in the portal venous phase. These scans were performed 6 months following left nephrectomy. Note cysts within the pancreas and the right kidney. Note also a solid 3 cm lesion (mid pole, right kidney, posterior renal cortex). A further smaller lesion is seen in the renal cortex more anteriorly, which is too small to characterize. The patient is awaiting a partial nephrectomy.

Media file 37: von Hippel-Lindau syndrome. Axial contrast enhanced upper abdominal CT scans (same patient in Images 18-40) in the portal venous phase. These scans were performed 6 months following left nephrectomy. Note cysts within the pancreas and the right kidney. Note also a solid 3 cm lesion (mid pole, right kidney, posterior renal cortex [red arrow]). A further smaller lesion is seen in the renal cortex more anteriorly, which is too small to characterize (blue area). The patient is awaiting a partial nephrectomy.

Media file 38: von Hippel-Lindau syndrome. Axial contrast enhanced upper abdominal CT scans (same patient in Images 18-40) in the portal venous phase. These scans were performed 6 months following left nephrectomy. Note cysts within the pancreas and the right kidney. Note also a solid 3 cm lesion (mid pole right kidney posterior renal cortex). A smaller lesion is seen in the renal cortex more anteriorly, which is too small to characterize. The patient is awaiting a partial nephrectomy.

Media file 39: von Hippel-Lindau syndrome. Axial T2-weighted MRI (same patient in Images 18-40) 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.

Media file 40: von Hippel-Lindau syndrome. Axial T2-weighted MRI (same patient in Images 18-40) 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.

Media file 41: Axial upper abdominal CT scans unenhanced and enhanced (see Image 42) show multiple small cysts within the pancreas and larger renal cysts. There are 2 enhancing lesions suggestive of microcystic adenomas.

Media file 42: Axial upper abdominal CT scans unenhanced (see Image 41) and enhanced show multiple small cysts within the pancreas and larger renal cysts. There are 2 enhancing lesions suggestive of microcystic adenomas.

References

1. Bonneville F, Sarrazin JL, Marsot-Dupuch K, et al. Unusual lesions of the cerebellopontine angle: a segmental approach. Radiographics. Mar-Apr 2001;21(2):419-38. [Medline].

2. Koch CA, Vortmeyer AO, Huang SC, et al. Genetic aspects of pheochromocytoma. Endocr Regul. Mar 2001;35(1):43-52. [Medline].

3. Kondo K, Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene. Exp Cell Res. Mar 10 2001;264(1):117-25. [Medline].

4. Glenn GM, Linehan WM, Hosoe S, Latif F, Yao M, Choyke P. Screening for von Hippel-Lindau disease by DNA polymorphism analysis. JAMA. Mar 4 1992;267(9):1226-31. [Medline].

5. Blansfield JA, Choyke L, Morita SY, Choyke PL, Pingpank JF, Alexander HR. Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery. Dec 2007;142(6):814-8. [Medline].

6. Vortmeyer AO, Huang SC, Koch CA, et al. Somatic von Hippel-Lindau gene mutations detected in sporadic endolymphatic sac tumors. Cancer Res. Nov 1 2000;60(21):5963-5. [Medline].

7. Eisenhofer G, Walther MM, Huynh TT, et al. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab. May 2001;86(5):1999-2008. [Medline].

8. Woodward ER, Maher ER. Von Hippel-Lindau disease and endocrine tumour susceptibility. Endocr Relat Cancer. Jun 2006;13(2):415-25. [Medline].

9. Conway JE, Chou D, Clatterbuck RE, et al. Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease. Neurosurgery. Jan 2001;48(1):55-62; discussion 62-3. [Medline].

10. Ayadi K, Mahfoudh KB, Khannous M, Mnif J. Endolymphatic sac tumor and von Hippel-Lindau disease: imaging features. AJR Am J Roentgenol. Sep 2000;175(3):925-6. [Medline].

11. Mukherji SK, Albernaz VS, Lo WW, et al. Papillary endolymphatic sac tumors: CT, MR imaging, and angiographic findings in 20 patients. Radiology. Mar 1997;202(3):801-8. [Medline].

12. Van Poppel H, Nilsson S, Algaba F, et al. Precancerous lesions in the kidney. Scand J Urol Nephrol Suppl. 2000;(205):136-65. [Medline].

13. Deboever G, Dewulf P, Maertens J. Common bile duct obstruction due to pancreatic involvement in the von Hippel-Lindau syndrome. Am J Gastroenterol. Dec 1992;87(12):1866-8. [Medline].

14. Hough DM, Stephens DH, Johnson CD, Binkovitz LA. Pancreatic lesions in von Hippel-Lindau disease: prevalence, clinical significance, and CT findings. AJR Am J Roentgenol. May 1994;162(5):1091-4. [Medline].

15. Maher ER, Yates JR, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. Nov 1990;77(283):1151-63. [Medline].

16. Roessler K, Dietrich W, Haberler C, et al. Multiple spinal "miliary" hemangioblastomas in von Hippel-Lindau (vHL) disease without cerebellar involvement. A case report and review of the literature. Neurosurg Rev. Oct 1999;22(2-3):130-4. [Medline].

17. Maher ER, Bentley E, Payne SJ, et al. Presymptomatic diagnosis of von Hippel-Lindau disease with flanking DNA markers. J Med Genet. Dec 1992;29(12):902-5. [Medline].

18. Hes FJ, Feldberg MA. Von Hippel-Lindau disease: strategies in early detection (renal-, adrenal-, pancreatic masses). Eur Radiol. 1999;9(4):598-610. [Medline].

19. Stendel R, Suess O, Prosenc N, et al. Neoplasm of endolymphatic sac origin: clinical, radiological and pathological features. Acta Neurochir (Wien). 1998;140(10):1083-7. [Medline].

20. Leung RS, Biswas SV, Duncan M, Rankin S. Imaging features of von Hippel-Lindau disease. Radiographics. Jan-Feb 2008;28(1):65-79; quiz 323. [Medline].

21. Grubb RL 3rd, Choyke PL, Pinto PA, Linehan WM, Walther MM. Management of von Hippel-Lindau-associated kidney cancer. Nat Clin Pract Urol. May 2005;2(5):248-55. [Medline].

22. Hes FJ, van der Luijt RB, Lips CJ. Clinical management of Von Hippel-Lindau (VHL) disease. Neth J Med. Nov 2001;59(5):225-34. [Medline].

23. Jagannathan J, Lonser RR, Smith R, Devroom HL, Oldfield EH. Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg. Feb 2008;108(2):210-22. [Medline].

Keywords

angiomatosis retinae, cerebelloretinal angiomatosis, hemangioblastomatosis cerebelloretinae, Hippel's syndrome, Hippel-Czermak syndrome, Lindau-von Hippel syndrome, retinocerebellar angiomatosis, inherited neurocutaneous dysplasia complex, angioreticuloma, spinal hemangioblastoma, endolymphatic sac tumor, cerebellopontine angle ceruminoma, external choroid plexus, extradural choroid plexus papilloma, Lindau tumor

Contributor Information and Disclosures

Author

Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, LRCP, Chairman of Medical Imaging, Professor of Radiology, NGHA, King Fahad National Guard Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia
Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, LRCP is a member of the following medical societies: American Institute of Ultrasound in Medicine, Radiological Society of North America, Royal College of Physicians, Royal College of Physicians and Surgeons of the United States, Royal College of Radiologists, and Royal College of Surgeons of England
Disclosure: Nothing to disclose.

Coauthor(s)

Ian Turnbull, MD, Lecturer, Department of Radiology, University of Manchester; Consulting Neuroradiologist, Hope Hospital, Salford, Manchester and North Manchester Hospital
Disclosure: Nothing to disclose.

Sumaira MacDonald, MBChB, PhD, MRCP, FRCR, Lecturer, Sheffield University Medical School; Endovascular Fellow, Sheffield Vascular Institute
Sumaira MacDonald, MBChB, PhD, MRCP, FRCR is a member of the following medical societies: British Medical Association, Royal College of Physicians, and Royal College of Radiologists
Disclosure: Nothing to disclose.

Riyadh Al-Okaili, MBBS, Interventional/Therapeutic and Diagnostic Neuro-Radiologist, King Abdulaziz Medical City
Riyadh Al-Okaili, MBBS is a member of the following medical societies: American College of Radiology
Disclosure: Nothing to disclose.

Medical Editor

Charles M Glasier, MD, Professor, Departments of Radiology and Pediatrics, University of Arkansas for Medical Sciences; Chief, Magnetic Resonance Imaging, Vice-Chief, Pediatric Radiology, Arkansas Children's Hospital
Charles M Glasier, MD is a member of the following medical societies: American College of Radiology and American Institute of Ultrasound in Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand
Disclosure: Nothing to disclose.

Managing Editor

Eric J Stern, MD, Director of Thoracic Imaging, Professor of Radiology and Medicine, Departments of Radiology and Internal Medicine, Harborview Medical Center, University of Washington School of Medicine
Eric J Stern, MD is a member of the following medical societies: American Roentgen Ray Society, Radiological Society of North America, and Society of Thoracic Radiology
Disclosure: Nothing to disclose.

CME Editor

Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute
Robert M Krasny, MD is a member of the following medical societies: American Roentgen Ray Society and Radiological Society of North America
Disclosure: Nothing to disclose.

Chief Editor

James G Smirniotopoulos, MD, Professor of Radiology, Neurology, and Biomedical Informatics, Chairman, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences
James G Smirniotopoulos, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, American Society of Head and Neck Radiology, American Society of Neuroradiology, American Society of Pediatric Neuroradiology, Association of University Radiologists, and Radiological Society of North America
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)