Applied Radiology

Prepared by Brian J. Fortman, MD, and Brian S. Kuszyk, MD, of the Department of Radiology, The Johns Hopkins Hospital, Baltimore, MD.

CASE SUMMARY

A 34-year-old man presented with vertical diplopia and a 6-month history of mild headache and intermittent vertigo. The patient had been diagnosed with and treated for sinusitis without improvement of his symptoms. In the 2 weeks prior to admission, he reported worsening of his headache and decreased visual acuity in his right eye. Laboratory analysis revealed a creatinine of 1.7 mg/dL and hemoglobin of 22 g/dL. Fundoscopic examination of the right eye revealed an elevated yellowish-red lesion compatible with a retinal hemangioblastoma. MRI of the brain was performed to evaluate the patient's headache and vertigo (figure 1). Renal imaging was performed to investigate the patient's elevated creatinine and polycythemia (figures 2 to 4).

DIAGNOSIS

Von Hipple-Lindau syndrome (retinal cerebellar hemangioblastomatosis)

IMAGING FINDINGS

T1-weighted gadolinium-enhanced MRI of the brain revealed a cystic mass in the right cerebellar hemisphere with a peripheral enhancing mural nodule (figure 1). Ultrasound of the kidneys revealed multiple bilateral renal cysts in addition to several solid-appearing lesions (figure 2). To further characterize the patient's renal abnormalities, a contrast-enhanced CT and an abdominal MRI were performed. CT of the abdomen showed multiple exophytic renal cysts in addition to bilateral enhancing lesions compatible with renal cell carcinomas (figure 3). Coronal T1-weighted MRI clearly depicts the bilateral upper pole lesions (figure 4). A heavily T2-weighted HASTE MR not only shows the obvious solid nature of several renal lesions, but also depicts a small cyst in the head of the pancreas (figure 5).

DISCUSSION

Von Hipple-Lindau syndrome (VHL) or retinal cerebellar hemangioblastomatosis is an autosomal dominant neurocutaneous syndrome that exhibits incomplete penetrance and variable expressivity. The condition is linked to a defect on the short arm of chromosome 3 and has an incidence of approximately 1 in 40,000 live births. As with other phakomatoses, VHL may show considerable genetic heterogeneity and is inherited sporadically in up to 70% of cases. ¹ The disease typically presents in the third or fourth decade and is characterized by cysts, angiomas, and neoplasms of the central nervous system (CNS) and abdominal viscera. The diagnostic criteria include the presence of multiple CNS hemangioblastomas, one hemangioblastoma plus a visceral manifestation, or one central or visceral manifestation in a patient with an affected first-order family member. ² In addition to retinal and CNS hemangioblastomas, patients are predisposed to the development of visceral cysts, benign neoplasms of the epididymis and membranous labyrinth, as well as multiple renal cell carcinomas and pheochromocytomas. Rare reports exist describing multiple hepatic and pulmonary hemangioblastomas occurring in affected patients. ³

This patient had no known affected relatives and presented with symptoms initially attributed to sinusitis. His complaint of decreased visual acuity secondary to a retinal angioma is typical of patients presenting before age 40. Retinal lesions are found in 50% to 60% of patients and are multiple in one-third. ⁴ Angiomas are typically diagnosed by fun-doscopic examination and are occult on imaging studies such as MRI unless hemorrhage and sub-retinal exudate is present.

The patient's subacute history of vertigo can be attributed to the large posterior fossa hemangioblastoma. Cerebellar hemangioblastomas occur in up to two-thirds of patients with VHL and less commonly occur in the brainstem and spinal cord. The appearance of a cystic mass with an enhancing vascular mural nodule is typical. Lesions may be completely solid, however, and are multiple in 40% of patients. The main diagnostic consideration of such a posterior fossa lesion is a pilocytic astrocytoma; however, the patient's age, infratentorial location, and additional visceral findings strongly suggest an alternate diagnosis. This lesion was excised and confirmed to be a cerebellar hemangioblastoma. Subsequent genetic testing con-firmed the diagnosis of VHL.

Renal cell carcinomas occur in up to 50% of patients with VHL and represent the leading cause of mortality. This patient exhibited extensive renal involvement with multiple bilateral cysts and renal cell carcinomas, responsible for the elevated creatinine and hemoglobin on initial laboratory analysis. Compared with sporadic renal cell carcinomas, tumors developing in patients with VHL tend to occur on average 25 years earlier, are more often multiple and bilateral, contain cystic organization and low grade histology, have a better 10-year survival rate, and rarely metastasize before reaching a size of 7 cm. ⁵ These facts weigh heavily in the optimal surgical management of patients with multiple bilateral neoplasms, as in this case. At present, lesions < 5 cm with low cytological grade are managed conservatively in order to obviate radical nephrectomy. In family members of affected individuals, screening computed tomography may allow very small lesions to be detected and allow for partial or limited nephrectomy.

Pheochromocytomas are the second most common visceral malignancy in affected patients, occurring in up to 15%. It is the prevalence of these neoplasms that link VHL genetically and phenotypically to other phakomatoses (such as neurofibromatosis type I and tuberous sclerosis, as well as multiple endocrine neoplasia type II and isolated familial pheochromotosis). ⁶

In summary, the considerable phenotypic heterogeneity of von Hipple-Lindau syndrome, as well as the preponderance of sporadic occurrence, should be kept in mind when evaluating patients presenting with focal neurologic signs in addition to visceral manifestations. The correct diagnosis not only holds profound implications in the treatment of affected patients, but allows genetic testing and screening of potentially affected family members. The proclivity of patients with VHL to present in late adolescence and early adulthood results in the need for genetic counseling to address the mode and probability of autosomal dominant transmission.

Ongoing research continues to define the genetic mutations responsible for VHL and other phakomatoses, with the hope of some day providing gene-guided therapy as treatment for the neurocutaneous syndromes.

REFERENCES

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2. Filling-Katz MR, Choyke PL, Patronas NJ: Radiologic screening for von Hipple-Lindau disease: The role of Gd-DTPA enhanced MR imaging of the CNS. J Comp Asst Tomogr 13:743-755, 1989.

3. McGrath FP, Gibney RG, Morris DC, Owen DA: Multiple hepatic and pulmonary hemangioblastomas--A new manifestation of von Hipple-Lindau disease. Clin Radiol 45(1):37-39 1992.

4. Braffman BH, Bilaniuk LT, Zimmerman RA: MR of central nervous system neoplasia of the phakomatoses. Sem Roentgenol 25:198-217, 1990.

5. Neumann HP, Bender BU, Berger DP, et al: Prevalence, morphology, and biology of renal cell carcinoma in von Hipple-Lindau disease compared to sporadic renal cell carcinoma. J Urol 160:1248-1254, 1998.

6. Ritter MM, Frilling A, Crossey PA, et al: Isolated familial pheochromocytoma as a variant of von Hippel-Lindau disease. J Clin Endo Metab 81:1035-1037, 1996.