There are three major sites of hemangioblastomas in VHL, the cerebellum, spine and medulla. Like retinal hemangioblastomas which are occasionally found sporadically, cerebellar hemangioblastomas (CHb) represent 2% of all brain tumors and 7-10% of posterior fossa tumors. Only 5-30% of these tumors are due to VHL (4,39). However, CHb associated with VHL occurs at a younger age, is often multiple and has a worse prognosis than sporadic CHb (4,40). Solitary CHb can be an initial manifestation of VHL so all patients with CHb should be considered potentially affected by VHL and an intensive family history and screening studies should be undertaken (41). CHb occurs in 44-72% of VHL patients making it one of the most common manifestations of the disease.
CHb are discovered later than RHb at a mean age of 29 years (12,18,20) (Figure 1). The earliest reported diagnosis is 11 years (19) and at the other extreme of age we have seen the diagnosis made for the first time at age 78. The onset and progression of CHb may be influenced by hormonal changes such as puberty or pregnancy. The rate of detection of new lesions is high until the 50's when the rate of new lesion formation slows, but continued vigilance is necessary throughout the patient's life.
Hemangioblastomas of the CNS, regardless of location, have the same histology lending credence to Lindau's original concept that the disease was an "angiomatosis of the central nervous system" (41). As with the retinal Hb, the CNS Hb is a vascular lesion which contains channels lined by cuboidal epithelium and is interspersed with nests of foamy stromal cells and pericytes and is supported by collagenous tissue of varying thickness. Mast cells are also found and may be responsible for the production of erythropoietin which can cause erythrocytosis (40,42,43). CHb are often cystic but contain a solid mural component (Figure 6). The cyst wall is lined by a single layer of flat endothelial cells. The fluid in the cysts is xanthochromic or rarely bloody but it can be rich in erythropoietin (8). Pure solid CHbs occur in about 20-29% of all cases (8), however, they have a worse prognosis and higher recurrence rate than cystic lesions.
Figure 6. Typical cerebellar hemangioblastomas in VHL demonstrating
cystic tumors with solid mural enhancement (bottom arrow) and small solid
enhancing masses ("seedlings") (top arrow).Symptoms are often subtle or intermittent and thus diagnosis may be delayed (17,44). Headache, positional vertigo, vomiting, wide based gait, slurred speech, nystagmus, dysmetria, and IX cranial nerve palsy are presenting symptoms (40). Sudden onset of symptoms following relatively insignificant trauma has been reported in up to 20% of patients with CHb (8,41). Paroxysmal hypertension has been reported with CHb without pheochromocytoma (18). Erythrocytosis occurs in 5-20% of CHb and can necessitate periodic phlebotomies but responds to surgical extirpation.
Medullary hemangioblastomas (MHb) occur in about 5% of VHL patients. They are found in the highly vascularized area postrema of the medulla (Figure 7). Syringobulbia may occur. Other symptoms include headache, vomiting, ataxia and sensory or motor deficits (17).
Figure 7. Contrast enhanced MRI of the brainstem showing a cluster of
hemangioblastomas in the area postrema of the medulla, a common locus of
hemangioblastoma in VHL. Meningeal enhancement due to surgery is seen along
the anterior and posterior aspect of the cervical cord.Unusual sites of hemangioblastomas in VHL include the anterior lobe of the pituitary, pituitary stalk, hypothalamus, optic nerve, corpus callosum, wall of the third ventricle, temporal horn of the lateral ventricles, frontal and temporal lobe and meninges (4,38,41,45,46,47,48) (Figure 10). Becker et al cite a number of other CNS lesions as occurring in families with VHL but they may only be coincidental with VHL since they are infrequently reported. These include cerebellar ependymomas, astrocytoma, neuroblastoma, dermoid, arteriovenous malformation, and primitive neuroectodermal tumor (PNET) (12,49).
Figure 8. Hemangioblastoma of the pituitary stalk. Rarely hemangioblastomas
occur outside the cerebellum and the pituitary, pituitary axis and hypothalamus
are recognized sites of hemangioblastomas in VHL.
Figure 9. Contrast enhanced MRI of the conus medullaris and cauda equina
depicts a hemangioblastoma of the conus with extension into the nerve roots.
In this location, this lesion could be mistaken for an ependymoma.
Spinal Hemangioblastoma (SHb) can occur in 13-59% (the lower number is probably more correct) of patients with VHL depending on the families selected for study (4,19,50). Unlike CHb where only a minority are associated with VHL, SHb is associated with VHL in 80% of all cases. SHb can occur throughout the spinal cord, nerve roots, conus medullaris and cauda equina (Figure 8), however, several "hot spots" are recognized including the conus medullaris and cranio-cervical junction (19). SHb can be intramedullary, partially intra and extramedullary or exclusively extramedullary (51). Extensive replacement ("hemangioblastomatosis of the cord") of the spinal cord and brainstem has been reported in VHL (42). Syringomyelia occurs in 25% of SHb (Figure 9) (9,12). Symptoms include pain which often is local and can be pinpointed by the patient, sensory loss including deep sensation, temperature and proprioception, paraparesis, hypertonia, and muscle wasting (19,40,50). Erythrocytosis has not been reported with SHb alone (40).The best imaging technique available for hemangioblastomas is contrast enhanced MRI employing a gadolinium chelate. Routine screening of the CNS in VHL should include, at a minimum, pre and post contrast T1 weighted images of the brain and spinal cord, with thin sections through the posterior fossa and spinal cord and surface coil images of the entire spinal cord. CHb commonly contain cystic areas and a solid mural nodule should be sought (Figures 6,7,8,9). An enhancing nodule on the wall of a spinal cord cavity is invariably present in cases of VHL since a nodule is directly incriminated in the pathogenesis of this cavity. Although in most cases the enhancing nodule is easily identified on post contrast MRI scans, rarely, the lesion is very small and can be missed. In such cases, the cavity within the cord may be mistaken for a syrinx of unrelated etiology. Therefore, meticulous post contrast MRI technique must be applied to identify the tumor nodule in all cases (Figure 8). Angiography is commonly performed prior to surgery to demonstrate the feeding vessels. The nidus of the tumor typically demonstrates a homogeneous blush. Early venous drainage is frequently present on angiograms of hemangioblastomas regardless of their location. In some instances, the draining veins in SHb are so prominent that they may produce the erroneous impression of an arteriovenous malformation. This diagnostic problem can be avoided by carefully studying the capillary phase of the angiograms where the characteristic homogeneous blush of the tumor nodule is best shown (40).
The primary treatment is the surgical removal of symptomatic lesions. Simple drainage of the cyst or syrinx without removing the tumor nidus is ineffective (36,41). Intraoperative color doppler has been useful in demonstrating the full extent (cyst, tumor, vessels) of the lesion to the surgeon (51). In nonoperable patients external beam radiation and stereotaxic radiosurgical ablation has been used to arrest the progression of symptoms (39,52,53).
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