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ISSN: Print -2349-0977, Online - 2349-4387

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Year : 2015  |  Volume : 2  |  Issue : 3  |  Page : 136-140

Imaging spectrum of von hippel–lindau disease

1 Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
2 Department of Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

Date of Web Publication2-May-2016

Correspondence Address:
Amita Malik
A-302, Manas Apartments, Mayur Vihar Phase-1, New Delhi -110 091
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2349-0977.181505

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Von Hippel–Lindau (VHL) disease is a rare phakomatosis with autosomal dominant inheritance. It is the result of inactivation of tumor suppressor gene located on short arm of chromosome 3 and is characterized by the development of a variety of benign and malignant tumors of various organs. These include retinal and central nervous system hemangioblastomas, renal cysts and renal cell carcinoma, pheochromocytomas, pancreatic cysts and tumors, epididymal cystadenoma, and ductal ectasia of rete testis. Imaging plays a key role in the diagnosis of VHL disease. It is also useful for screening of patients with family history of VHL disease and in follow-up after treatment. This coupled with advanced surgical management helps in reducing the morbidity and mortality in VHL. The aim of this pictorial essay is to demonstrate the imaging spectrum of VHL disease.

Keywords: Hemangioblastoma, pancreatic cysts, pheochromocytoma, tumors, von Hippel–Lindau disease

How to cite this article:
Malik A, Misra R, Chawla AS, Chandra R, Bajaj SK, Thukral BB. Imaging spectrum of von hippel–lindau disease. Astrocyte 2015;2:136-40

How to cite this URL:
Malik A, Misra R, Chawla AS, Chandra R, Bajaj SK, Thukral BB. Imaging spectrum of von hippel–lindau disease. Astrocyte [serial online] 2015 [cited 2020 Sep 22];2:136-40. Available from: http://www.astrocyte.in/text.asp?2015/2/3/136/181505

  Introduction Top

Von Hippel–Lindau (VHL) disease is a type of phakomatosis characterized by the development of benign and malignant tumors of various organs. It is also known as retino-cerebellar angiomatosis. Its estimated prevalence is between 1 in 31,000 and 1 in 53,000.[1] It has autosomal dominant inheritance with high penetrance and variable expression. It has been found to be associated with deactivation of tumor suppression gene located at the short arm of chromosome 3.

The manifestations of the disease are protean and include retinal and cerebellar hemangioblastomas, renal cysts and tumors, pancreatic cysts and tumors, pheochromocytoma, endolymphatic sac tumor, and epididymal cystadenoma. Among these, hemangioblastoma and renal cell carcinoma are the most common cause of mortality.[2]

The diagnostic criteria for the disease are [3] – (1) more than one central nervous system (CNS) hemangioblastoma, (2) one CNS hemangioblastoma with a visceral manifestation, or (3) any manifestation with family history of VHL disease.

Imaging is essential for the identification of abnormalities and their follow-up. It is also important in screening of individuals who carry the VHL gene, but are asymptomatic.

  Retinal Hemangioblastoma Top

The usual age of development of retinal hemangioblastoma is 10–30 years after which the incidence gradually decreases.[4] Ophthalmological examination is useful for early diagnosis in relatives and offsprings of patients of VHL disease. Only large lesions can be seen on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). The lesions demonstrate higher signal than vitreous on T1-weighted images and may show contrast enhancement.[5]

  Central Nervous System Hemangioblastoma Top

Hemangioblastomas of the brain and spinal cord are one of the most common manifestations of VHL disease and affect 60–80% of all patients.[2] Up to 90% of these go on to have multiple lesions. Typical sites in the brain are cerebellum and medulla, although supratentorial location is also known. These may be purely solid masses, completely cystic, cystic with mural nodule, or solid mass with internal cysts. On unenhanced CT, cystic hemangioblastoma appears as a well-defined hypodense mass with an isodense nodule that enhances strongly after contrast administration. On MRI, mural nodule is seen as iso- to hypo-intense mass on T1-weighted, hyperintense on T2-weighted images, and shows marked postcontrast enhancement [Figure 1]. Solid hemangioblastoma is seen as an isodense or hypodense mass that shows homogenous contrast enhancement [Figure 2]. Signal voids may be seen in the periphery of solid lesion. Spinal hemangioblastomas have similar CT and MRI appearance. Smaller lesions tend to be isointense and are best visualized on postcontrast T1-weighted images [Figure 3] and [Figure 4]. There may be associated syrinx.
Figure 1: Cerebellar Hemangioblastoma. (a) Axial T1-weighted image shows a predominantly cystic mass with an isointense mural nodule. (b) Axial T2-weighed image shows a hyperintense mass with surrounding edema. (c) Axial gadolinium-enhanced T1-weighted image shows marked enhancement of the mural nodule. There is compression of the fourth ventricle and quadrigeminal cistern with dilated temporal horns of the lateral ventricles.

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Figure 2: Cerebellar hemangioblastomas in a 20-year-old female. Axial contrast-enhanced computed tomography images show multiple homogenously enhancing solid masses in the cerebellar vermis and left hemisphere.

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Figure 3: Spinal Hemangioblastoma in a child. (a) Sagittal T1-weighted image (b) sagittal T2-weighted image (c) sagittal postcontrast T1-weighted and magnetic resonance images show an intensely enhancing intramedullary nodule in the lower dorsal region. Prominent vessels are seen in the posterior subarachnoid space.

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Figure 4: (a) Axial T1-weighted images and (b) axial postcontrast T1-weighted and magnetic resonance images of the same child as in Figure 3 show the enhancing nodule with focal expansion of cord.

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Although there are no imaging features specific to hemangioblastomas in VHL, these usually develop at a younger age and have worse prognosis as compared to the sporadic lesions.[6] Multiple lesions are almost diagnostic of VHL [Figure 5].[2]
Figure 5: Recurrent cerebellar hemangioblastoma in the same patient as in Figure 1: Axial pre- and post-contrast computed tomography images show a recurrent cystic mass with enhancing nodule in the right cerebellar hemisphere. Craniotomy defect is also evident.

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  Renal Cysts and Tumors Top

Various renal lesions seen are cysts and renal cell carcinoma. Multiple renal cysts are most common and may be seen in 60% and tend to be bilateral in 75% of patients.[7] These may be simple or complex. Renal cell carcinoma in VHL disease occurs at a younger age (30–36 years) and is often multicentric.[8]

Ultrasound is generally the first modality to detect renal lesions. CT and MRI are very sensitive for cysts and masses smaller than 2 cm. Simple cysts are thin-walled, sharply demarcated lesions with attenuation, or signal characteristics of water, and do not show contrast enhancement. Complex cysts have the potential to undergo malignant transformation. These demonstrate thick irregular walls or septae which enhance following contrast administration. Calcification may be seen in the wall or septae [Figure 6]. CT and MRI are also useful in the presence of multiple cysts where distorted renal architecture makes ultrasonic evaluation difficult. As MRI lacks ionizing radiation, it is preferred in young patients and in those with renal failure. Renal cell carcinoma is often bilateral, appears as solid masses with heterogeneous enhancement, or complex cyst with enhancing solid component [Figure 7]. The preferred treatment of renal cell carcinoma in VHL is nephron-sparing procedure due to high probability of developing more lesions.[2]
Figure 6: Renal Cysts: (a) Axial contrast-enhanced computed tomography image shows multiple simple and complex cysts in both kidneys. (b) Coronal contrast-enhanced computed tomography image shows multiple cysts in the right kidney. The cyst at lower pole has thick enhancing walls. This patient also had cerebellar hemangioblastoma as shown in Figure 1.

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Figure 7: Renal cell carcinoma: Axial contrast-enhanced computed tomography image shows bilateral hypoenhancing solid renal masses (white arrows) corresponding to renal cell carcinoma. Multiple cysts are also seen.

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  Pheochromocytoma Top

Pheochromocytomas associated with VHL disease are often bilateral, multiple, occur at a younger age, and have a very low risk of malignancy as opposed to the sporadic tumors. Metachronous tumors can develop after surgery.[1] Many lesions are asymptomatic. When present, symptoms consist of hypertension, palpitations, headache, flushing, and sweating.

Both imaging and laboratory values are useful in the diagnosis. Elevated urine and blood catecholamine levels suggest active tumor. CT typically demonstrates pheochromocytoma as a solid or complex cystic adrenal mass with areas of hemorrhage, necrosis, and calcification. Marked postcontrast enhancement is seen [Figure 8]. About 15–18% lesions are extraadrenal in location [1] [Figure 9]. On MRI, pheochromocytoma has intermediate to low signal intensity on T1-weighted images, has high signal on T2-weighted images, and demonstrates marked gadolinium enhancement. Iodine-131 metaiodobenzylguanidine scan gives the functional assessment of pheochromocytomas and is used when there is clinical and laboratory evidence of the lesion, but none is demonstrated on CT and MRI. It is also helpful for the detection of metastases from malignant pheochromocytoma.
Figure 8: Pheochromocytoma: Axial contrast-enhanced computed tomography images showing bilateral solid adrenal masses. The left adrenal mass is large and shows areas of necrosis.

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Figure 9: Extraadrenal pheochromocytoma: Axial contrast-enhanced computed tomography image shows a large heterogeneously enhancing mass anteromedial to inferior vena cava. This patient had undergone surgery for bilateral pheochromocytomas 2 years back and was now again found to have raised urine and serum catecholamine levels.

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  Pancreatic Cysts and Tumors Top

Pancreatic involvement in VHL includes simple cysts, serous cystic neoplasms, neuroendocrine tumors, adenocarcinoma, hemangioblastoma, and renal cell carcinoma metastases.[9],[10] Multiple simple cysts are most common among these. As unilocular cysts are extremely rare in general population, presence of a single cyst in a patient with family history of VHL disease suggests high probability of the disease.[11] Ultrasound and CT are helpful in their detection. No enhancement is seen on postcontrast CT [Figure 10]. Serous cystic neoplasms are well-defined multiloculated lesions with numerous small cysts measuring up to 2 cm and central stellate scar which may show calcification. Enhancement may be seen at the periphery of microcysts. On MRI, the septae are typically hypointense on T2-weighted images and show enhancement following contrast.
Figure 10: Pancreatic cysts: Contrast-enhanced computed tomography image shows multiple small pancreatic cysts. Pheochromocytoma of the right adrenal gland is also seen.

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Neuroendocrine tumors occur more frequently in patients with pheochromocytoma. Most of these are slow growing, nonfunctional, asymptomatic, and therefore large when picked up on screening. Functional tumors are generally small when detected because of the clinical signs and symptoms caused by the peptide secreted which may be insulin, glucagon, gastrin, or somatostatin. The frequency of malignancy and metastasis is low in the tumors in VHL disease compared to the sporadic ones.[12]

These tumors are hypo-isoattenuating to the pancreatic parenchyma on unenhanced CT and show intense enhancement in arterial phase [Figure 11]. Large tumors may show calcification, necrosis, and areas of cystic degeneration. They are hypointense on T1-weighted and hyperintense on T2-weighted MR images although not as bright as cysts.
Figure 11: Pancreatic neuroendocrine tumor in the same patient as in Figure 9: (a) Axial unenhanced and (b) contrast-enhanced computed tomography image obtained during the arterial phase shows a markedly enhancing mass in the uncinate process of pancreas.

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  Papillary Cystadenoma of Epididymis Top

Papillary cystadenoma of epididymis is a benign epithelial neoplasm which can be seen in up to 60% of men with VHL disease. It occurs earlier and is often bilateral in VHL disease in contrast to sporadic form which is seen in middle-aged men and is unilateral.[13] It is commonly located in the epididymal head but sometimes involves the spermatic cord. It is seen as a predominantly solid mass with few cystic spaces. Echogenic shadowing or calcification may be seen. The other appearance is that of a multiloculated mass with papillary projections.

Other findings include simple cysts of epididymis, ductal ectasia of rete testis, and testicular atrophy. Ductal ectasia of rete testis is seen as a network of small cysts occupying the central portion of testis [Figure 12]. No mass effect or internal vascularity is seen.
Figure 12: Ductal ectasia of rete testis: Ultrasound image shows a network of cysts in the central portion of testis.

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  Miscellaneous Lesions Top

Endolymphatic sac tumors

There is an increased risk of development of endolymphatic sac tumors in VHL disease, which tend to be bilateral. These tumors are located in the posterior part of petrous bone and are locally invasive. The clinical presentation is usually late with symptoms of hearing loss and tinnitus. High-resolution CT of the temporal bone demonstrates locally destructive, soft- tissue density mass involving the posterior petrous bone, centered at endolymphatic sac giving a geographic and moth-eaten appearance, with occasional intratumoral and peripheral rim of calcification.[12]

Apart from the above lesions, many other pathologic conditions arising in different organs have been described in VHL disease. These include pancreatic, pulmonary, and bladder hemangioblastomas; hepatic, pancreatic, and splenic hemangiomas; hepatic cysts and cystadenoma of uterine broad ligament.[14],[15] However, their definite association with VHL has not been confirmed.

  Screening Top

Screening protocols vary between various centers. The recommendations based on review of literature are as follows:

  • Baseline craniospinal MRI at the age of 20 years and thereafter annually for hemangioblastoma [16]
  • Annual direct and indirect ophthalmoscopic examination from the age of 5 years for retinal hemangioblastoma
  • Annual abdominal ultrasound examination from the age of 10 years for renal cysts and masses, and pancreatic lesions followed up with CT or MRI [12]
  • Monitoring of annual plasma or 24 h urinary catecholamine level from the age of 2 years along with annual blood pressure measurement. Imaging is necessary if the levels are increased
  • Annual audiometry as a first-line tool for screening of endolymphatic tumor, to be followed up with imaging if there is audiological abnormality.

  Conclusion Top

VHL disease manifests with the development of a variety of benign and malignant tumors and cysts in various organs. Imaging is important for identification of these abnormalities for accurate diagnosis so that timely treatment can be instituted. Further, knowledge of screening protocol is essential for long-term surveillance in VHL disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Taouli B, Ghouadni M, Corréas JM, Hammel P, Couvelard A, Richard S, et al. Spectrum of abdominal imaging findings in von Hippel-Lindau disease. AJR Am J Roentgenol 2003;181:1049-54.  Back to cited text no. 1
Katabathina VS, Vinu-Nair S. Cross-sectional imaging spectrum of von Hippel-Lindau disease. J Transl Med Epidemiol 2014;2:1021.  Back to cited text no. 2
Melmon KL, Rosen SW. Lindau's disease. Review of the literature and study of a large kindred. Am J Med 1964;36:595-617.  Back to cited text no. 3
Tootee A, Hasani-Ranjbar S. Von hippel-lindau disease: A new approach to an old problem. Int J Endocrinol Metab 2012;10:619-24.  Back to cited text no. 4
Filling-Katz MR, Choyke PL, Patronas NJ, Gorin MB, Barba D, Chang R, et al. Radiologic screening for von Hippel-Lindau disease: The role of Gd-DTPA enhanced MR imaging of the CNS. J Comput Assist Tomogr 1989;13:743-55.  Back to cited text no. 5
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al. Von Hippel-Lindau disease. Lancet 2003;361:2059-67.  Back to cited text no. 6
Meister M, Choyke P, Anderson C, Patel U. Radiological evaluation, management, and surveillance of renal masses in von Hippel-Lindau disease. Clin Radiol 2009;64:589-600.  Back to cited text no. 7
Chauveau D, Duvic C, Chrétien Y, Paraf F, Droz D, Melki P, et al. Renal involvement in von Hippel-Lindau disease. Kidney Int 1996;50:944-51.  Back to cited text no. 8
Neumann HP, Dinkel E, Brambs H, Wimmer B, Friedburg H, Volk B, et al. Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology 1991;101:465-71.  Back to cited text no. 9
Chambers TP, Fishman EK, Hruban RH. Pancreatic metastases from renal cell carcinoma in von Hippel-Lindau disease. Clin Imaging 1997;21:40-2.  Back to cited text no. 10
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 1994;162:1091-4.  Back to cited text no. 11
Leung RS, Biswas SV, Duncan M, Rankin S. Imaging features of von Hippel-Lindau disease. Radiographics 2008;28:65-79.  Back to cited text no. 12
Kim W, Rosen MA, Langer JE, Banner MP, Siegelman ES, Ramchandani P. US MR imaging correlation in pathologic conditions of the scrotum. Radiographics 2007;27:1239-53.  Back to cited text no. 13
McGrath FP, Gibney RG, Morris DC, Owen DA, Erb SR. Case report: Multiple hepatic and pulmonary haemangioblastomas – A new manifestation of von Hippel-Lindau disease. Clin Radiol 1992;45:37-9.  Back to cited text no. 14
Horton WA, Wong V, Eldridge R. Von Hippel-Lindau disease: Clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med 1976;136:769-77.  Back to cited text no. 15
Bamps S, Calenbergh FV, Vleeschouwer SD, Loon JV, Sciot R, Legius E, et al. What the neurosurgeon should know about hemangioblastoma, both sporadic and in von Hippel-Lindau disease: A literature review. Surg Neurol Int 2013;4:145.  Back to cited text no. 16
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]


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