Von Hippel-Lindau Syndrome Imaging

Classified 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 (HBs); renal cell carcinomas (RCCs); pheochromocytoma; islet cell tumors of the pancreas; endolymphatic sac tumors (ELSTs) ^[1] ; 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. ^{[4, 5]}

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.

Imaging modalities

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. ^{[6, 7]}  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. ^{[8, 9, 10, 11, 12]}

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.

According to guidelines recommendations, follow-up imaging in VHL disease is recommended every 2-3 years. ^[13]  Most centers perform separate MRI exams for each body region (abdomen, brain, spine), necessitating multiple expensive examinations. CNS accumulation of gadolinium-based contrast agents has been reported in nearly all patients included in a screening program for VHL disease. ^[14]  Focused whole-body MRI screening protocols have been proposed to reduce the exposure to contrast agents. ^[15]

(Images of VHL are shown below,)

The clinical diagnosis of VHL can be made (1) in patients with a family history of VHL and at least 1 of the characteristic VHL-related tumors, including retinal hemangioblastomas (HBs), CNS HBs, clear cell renal cell carcinomas (RCCs), pancreatic neuroendocrine tumors (NETs), and endolymphatic sac tumors); (2) if 2 or more retinal or CNS HBs are present; or (3) in the presence of 1 retinal or CNS HB, along with at least 1 of the characteristic VHL-related visceral tumors, excluding renal and epididymal cysts. ^{[16, 17]}

Cambridge protocol

The Cambridge protocol was devised by Maher et al for screening patients with VHL disease or at-risk relatives. The protocol is as follows ^[18] :

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

VHL Alliance Surveillance Guidelines

The VHL Alliance surveillance guidelines suggest that surveillance should start at birth and continue throughout the patient's life. Special precautions are required during pregnancy. The recommendations by age are as follow ^[13] :

At Birth:

• Clinical evaluation for neurologic disturbance and routine newborn hearing tests 
• Ophthalmic exam to look for nystagmus, strabismus, white pupil, and other signs that may indicate need for a referral to a retinal specialist

Ages 1-4:

• Annual comprehensive ophthalmic examination with indirect ophthalmoscope 
• Annual clinical evaluation for signs of neurologic disturbance, nystagmus, strabismus, white pupil, and abnormalities in blood pressure, hearing, or vision

Ages 5-15:

• Annual physical examination and neurologic assessment, with particular attention to blood pressure (taken while lying down and standing), hearing impairment, neurologic disturbance, nystagmus, strabismus, white pupil, and other signs indicating retinal problems
• Annual comprehensive ophthalmic examination with indirect ophthalmoscope
• Annual biochemical tests, including plasma metanephrine or 24-hour urinary metanephrine levels
• Annual abdominal ultrasonography from 8 years or earlier if indicated
• Abdominal MRI or MIBG scintigraphy scan only if biochemical abnormalities found
• Every 2-3 years, audiology assessment by an audiologist; then annually if any hearing loss, tinnitus, or vertigo is found
• In the case of repeated ear infections, MRI with contrast of the internal auditory canal using thin slices, to check for a possible endolymphatic sac tumor (ELST)

Ages 16 and older:

• Annual comprehensive ophthalmic examination with indirect ophthalmoscope
• Annual clinical evaluation for signs of neurologic disturbance and abnormalities in blood pressure, hearing or vision
• Quality ultrasound and at least every other year when not pregnant, and MRI scan of abdomen with and without contrast to assess kidneys, pancreas, and adrenals.
• Annual biochemical tests, including plasma metanephrine or 24-hour urinary metanephrine levels
• Abdominal MRI or MIBG scintigraphy scan only if biochemical abnormalities found
• Every 2-3 years, MRI scans should be ordered as no less than a 1.5T MRI with and without contrast of brain, cervical, thoracic, and lumbar spine, with thin cuts through the posterior fossa, and attention to inner ear/petrous temporal bone to rule out both ELST and hemangioblastomas of the neuraxis.
• Audiology assessment by an audiologist every 2-3 years

Intervention

Preoperative embolization is not generally used but may be helpful before surgical resection of endolymphatic sac tumors and hemangioblastomas in selected cases. ^{[19, 20, 1]}

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. ^[21]

Plain radiographs have little to contribute to the diagnosis of von Hippel-Lindau syndrome. 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. ^{[22, 23]} Hemangiomas of the bone must be differentiated from osteoblastic metastases, lesions due to Paget disease, lymphoma, and monostotic fibrous dysplasia.

(See the image below.)

 

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. ^{[22, 23, 24, 25]}

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 von Hippel-Lindau syndrome 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.

(See the following computed tomography scans depicting von Hippel-Lindau syndrome.)

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.

Patients with VHL syndrome undergo frequent imaging for follow up of renal cell carcinoma. The use of liver windows settings improves the detection of small renal cell carcinomas on the unenhanced CT in VHL syndrome. ^[8]

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, ^[3] and MEN 2. Tumors of the endolymphatic sac may mimic other cerebellopontine tumors.

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.

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. ^{[24, 22, 23, 10]}  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.)

Gadolinium

Gadolinium-based contrast agents 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.

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.

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. ^[23]

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.

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.

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. ^{[23, 12]}

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.

Kulkarni et al have reported an incidental detection of clinically occult pancreatic malignancy on FDG-PET in a patient with VHL syndrome who underwent restaging for a previously treated endolymphatic sac tumor (ELST). ^[9]

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 (¹³¹I 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. ^[26]

Iodine-131 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,¹³¹I MIBG methods to treat metastases).

Iodine-131 MIBG uptake has a sensitivity of 80-90% and a specificity of 98% in the detection of pheochromocytoma. Uptake may occur in medullary carcinoma of the thyroid, carcinoid tumors, neuroblastoma, and paragangliomas.

(Scintigraphic images of VHL are shown below.)

In a study of patients with VHL by Shell et al, gallium-68-DOTATATE PET/CT detected a total of 206 lesions, CT detected 208 lesions, and MRI detected 94 lesions in 61, 66, and 33 scans, respectively. Gallium-68-DOTATATE PET/CT (3.4 ± 0.1 per scan) was superior than CT (3.2 ± 0.1 per scan, P=0.02), with similar results when compared with MRI (2.8 ± 0.1 per scan, P=0.03) in detecting lesions in any anatomic locations. ^[27]

In a prospective study of patients with von Hippel-Lindau syndrome, Prasad et al found that ⁶⁸Ga-DOTATOC PET/CT had a high sensitivity for the diagnosis and staging of neuroendocrine tumors. Neuroendocrine tumors of the pancreas occur in 8-17% of patients with von Hippel-Lindau disease, and 11-20% progress to metastatic disease. ^[28]

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.

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

(See the images below.)

Retinal hemangioblastomas are characteristic of VHL, and some studies have shown good results with fundus fluorescein angiography (FFA) features of retinal hemangioblastomas using ultra-widefield (UWF) imaging. ^{[29, 30]}