Neurology: Case of the Month

Check Your Diagnosis — Patient 38

Greg Zarelli, M.D.

Diagnosis

Hemangioblastoma

Clinical Summary and Discussion

Hemangioblastomas are vascular tumors that are histologically benign. They are sharply demarcated but not encapsulated. They are uncommon tumors, accounting for only 1-2.5% of all primary CNS tumors and approximately 7% of primary posterior fossa tumors in adults. Most hemangioblastomas occur sporadically and it is estimated that up to 20% occur as part of the von Hippel-Lindau syndrome (VHL).

Hemangioblastomas are typically adult tumors and are very rare in children. Most become symptomatic during the third to fifth decades. Hemangioblastomas associated with von Hippel-Lindau syndrome frequently present earlier, usually in the second to third decades.

The clinical features of intramedullary spinal cord tumors, such as the hemangioblastoma in this patient, may be quite variable. Early symptoms may be nonlocalizing, and may only subtly progress. Symptom duration before diagnosis is often 2-3 years.

Pain or dysesthesia is the most common presenting symptom of intramedullary spinal cord tumors in adults. These symptoms typically localize to the level of the tumor. Sensory or motor including weakness and spasticity complaints are the initial symptoms in about one third of patients. Upper extremity symptoms predominate with cervical neoplasms. One-sided or asymmetrical involvement is common. Thoracic cord tumors often produce spasticity and sensory changes. Numbness is a common complaint and usually begins in more peripheral sites of the lower extremities. Tumors of the lumbar region and conus medullaris frequently present with back and leg pain. Bladder and bowel dysfunction tends to occur early. Bandlike distributions of sensory loss, multiple sensory levels with relative preservation of sacral sensation, and dissociation of pain/temperature from proprioceptive sensory modalities may be clues to the existence of a central cord syndrome produced by an intramedullary tumor. However, these features are not invariably present.

The primary method to diagnose intramedullary tumors is via imaging studies. CT scans may be useful in demonstrating acute hemorrhage either into or around a tumor, or if MRI is contraindicated. However, MRI gives superior anatomical resolution, better definition of tumor characteristics, and better detection and delineation of associated syringomyelia. Spinal angiography, although not performed in this patient, is often used to demonstrate the intense vascularity of a suspected hemangioblastoma, or to define the vascular supply of spinal tumors prior to resection.

Laboratory tests in suspected hemangioblastoma should include a red-cell count to rule out polycythemia, which can be associated with renal neoplasms. If hemangioblastoma is confirmed on pathologic examination, a thorough search for associated neoplasms or other vascular malformations, including retinal examination for angiomas, CNS imaging for undiagnosed tumors or vascular anomalies, and renal ultrasound or CT imaging, is mandatory. If the patient is thought to have VHL, additional testing should include urine determinations of catecholamines, as pheochromocytomas are often associated with this syndrome.

Surgery is usually the most effective treatment for these tumors. In the case of spinal hemangioblastomas, the goal of surgery is determined primarily by the nature of the interface between tumor and the spinal cord. Gross total removal of a benign tumor should be accomplished if clear demarcation exists between the tumor and the cord. Surgical removal alone provides long-term tumor control or cure for most hemangioblastomas. Determination of the resectability of an intramedullary tumor is best determined by direct intraoperative inspection of the tumor spinal cord interface. Tumors that cannot be totally resected or are deemed to be more aggressive will require post-operative radiation therapy.

Intramedullary tumors can often be associated with syringomyelia. Of 100 patients operated on for intramedullary tumors in one series from Germany, 45% were found to have an accompanying syrinx. Adequate tumor resection was favored by the existence of an associated syrinx, as syrinx formation appeared to correlate with a displacing rather than an infiltrating tumor. In this study, a syrinx was more likely to be found above (49%) than below (11%) the tumor level. In 40% of cases, a syrinx could be identified both above and below the tumor. Thus, the location of symptoms may not always accurately predict the location of the associated tumor.

Ependymomas and hemangioblastomas are the most common tumor types to be associated with a syrinx. In fact, the demonstration of a large syrinx associated with an intramedullary tumor should elevate the clinical suspicion for hemangioblastoma, which is otherwise quite uncommon.

Pathologic examination of a benign hemangioblastoma often reveals a highly vascularized structure that can sometimes be mistaken for a more serious and malignant tumor such as an astrocytoma. This can become a significant diagnostic issue, as intraoperative decisions about the extent of resection are frequently made on the basis of examination of frozen sections, which may be more subject to misinterpretation than paraffin-embedded sections. Preoperative clinical suspicion for hemangioblastoma is thus indispensable.

Hemangioblastomas are known to express high levels of vascular endothelial growth factor (VEGF). This expression of a highly angiogenic growth factor is a likely contributor to the rich vascularity of these tumors. Whether future treatments may be directed at suppression of VEGF effects has yet to be subjected to trial.

The VHL syndrome demonstrates an autosomal dominant pattern of inheritance. However, the VHL syndrome can occasionally arise without a family history; thus careful evaluation of all patients with apparently "sporadic" hemangioblastomas is warranted. Spontaneous mutations are estimated to constitute 1-3% of cases. The VHL gene is an archetypal tumor suppressor gene, in that when inactivated, vascular cell growth appears to have a tendency to proceed unchecked, with resultant tumor formation. Susceptible tissues in VHL include the cerebellar and retinal cells, tissues of neural crest cell origin and glandular viscera. These result in tumors of hemangioblastomas; pheochromocytomas, paragangliomas and possibly islet cell tumors; and renal, pancreatic, epididymal and endolymphatic sac tumors respectively. The gene for VHL was discovered in 1993 and has been localized to the short arm of chromosome 3 at the 3p25-26 locus.

Hemangioblastomas are potentially curable lesions, although they are the cause of death in 82% of patients with VHL. Approximately one quarter of hemangioblastomas recur following surgical resection. Death from disseminated disease is exceedingly rare. Excision of intramedullary hemangioblastomas can usually be accomplished with low levels of surgical mortality and morbidity.

The patient discussed in this case has done well since surgery. She has undergone extensive rehabilitation and is gradually regaining much of her left lower extremity strength as well as her sensation. She hopes to be able to return to her previous job as a waitress.

Although this patient's habit of clay ingestion was initially suspected of contributing to, or being symptomatic of, her illness, it was subsequently established to represent a normal cultural practice in her family.

References

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