9161/1 - Haemangioblastoma
C70, C71 and C72 - Tumours of the central nervous system


Definition

Hemangioblastomas are slowly growing, highly vascular tumour of adults, occurring in the cerebellum, (63%), spinal cord (32%), and brain stem (5%) 1 2 . Histologicylly they are consist of neoplastic stromal cells and small blood vessels. While the majority of haemangioblastomas are sporadic, 10-20% occur in the setting of of the dominantly inherited 3 4 . Most hemangioblastomas present as cystic lesions with a solid vascular nodule that abuts a pial surface, but a smaller number of them (40%) are completely solid 5 6 .
Despite being benign in nature, hemangioblastomas can cause significant neurological deficits and are associated with a high morbidity and mortality if not treated in time 7 .

Epidemiology



Localization



Signs

Clinical presentation relates to the site of origin of the larger tumors. When located in the posterior fossa, they may, if large enough, exert mass effect, obstruct the fourth ventricle and cause pressure on the area postrema, leading to characteristic symptoms or nausea, vomiting and ataxia (Wanebo 2003). This may culminate with more urgent symptoms related to increased ICP.

Similarly, in the spine, hemangioblastomas can cause compression of the spinal cord, with symptoms of myelopathy and sensory/motor changes corresponding to the level of spinal cord involvement (Wanebo 2003). Patients with spinal cord tumors may present with progressive scoliosis and radicular symptoms until the tumor is large enough to cause weakness.

Imaging

Hemangioblastomas have a characteristic radiographic appearance on both CT and MRI, as well as a distinct prolonged vascular stain on cerebral angiography. While MRI is the preferred imaging modality, angiography may better detect more occult tiny vascular nodules 8 .

[i]Intracranial hemangioblastomas[/i] typically appear as either large nonenhancing cyst with a solid intensely-enhancing mural nodule (35%), or as solid avidly enhancing mass (33%). Cystic wall enhancement is a less common subtype and suggests a tumoral cyst, versus the typical nonenhancing reactive cyst. The solid components are typically homogeneous and isodense to hypodense to brain parenchyma on T1, and hyperdense (due to cystic component) on T2 weighted imaging. Heterogeneity may be seen due to the less common presentation with hemorrhage or necrosis. Due to the highly vascular nature of the tumor, intrinsic and/or surrounding flow voids are often present.

[i]Intraspinal hemangioblastomas[/i] are less common, but have an overlap in imaging characteristics with intracranial hemangioblastomas 9 . An intensely and homogeneously enhancing solid mass/nodule is present, with common association with spinal syrinx/cyst (55%) or cord edema (23%). The location of the enhancing nodule is typically at or near the surface of the cord (66%) or purely intramedullary (25%). Extradural location, including along nerve roots, has been described. Spinal hemangiomas are typically in the thoracic level or slightly less commonly in the cervical level. Prominent serpentine vessels are often seen, particularly in the intradural extramedullary space, due to the significant vascularity of the tumor. Necrosis and hemorrhage are also rare imaging characteristics of spinal hemangioblastoma.

[i]Case history[/i]
The typical imaging features are illustrated by a case history: A 26 year old male presented with a six month history of persistent morning headaches, diplopia, and intermittent nausea and vomiting. Papilledema and slight right facial droop was noted on physical examination. Contrast enhanced axial and sagittal T1-weighted magnetic resonance imaging (MRI) revealed an enhancing solid and cystic right cerebellar mass ([b]Fig. A[/b], arrow), a left cerebellar enhancing nodule ([b]Fig.B[/b], arrow). Prior to surgical resection, the right cerebellar mass ([b]Figure F[/b]; black arrow) was embolized with particles using superselective angiography (right vertebral artery injection). A smaller enhancing nodule was also noted ([b]Fig. F[/b], white arrow).
The patients also had cervical spine cystic mass with an enhancing mural nodule ([b]Fig. C[/b], arrow). Computed tomography of the abdomen demonstrated multiple renal and pancreatic cysts ([b]Fig. D[/b], arrows),and scrotal ultrasound revealed a complex cystic mass suggestive of a papillary cystadenoma of the epidydimis ([b]Fig.E[/b]). This patient’s constellation of radiological, pathological, and clinical findings are compatible with von , an autosomal dominant disorder characterized by CNS hemangioblastomas, renal cysts, pancreatic cysts, and epididymal cysts (all seen in this patient). The patient was discharged in good condition after surgical resection of the large right cerebellar hemangioblastoma.


Macroscopy

Most hemangioblastomas present as cystic lesions with a solid vascular nodule that abuts a pial surface, but a smaller number of them (40%) are completely solid 10 11 12 .

[i] Case history, continued from Imaging section[/i]
Cut surface section of agross specimen ([b]Fig. G[/b]) and whole mount H&E stain ([b]Fig. H[/b]) reveal a multicystic, highly vascular neoplasm (white arrow) with a well demarcated border compressing surrounding cerebellar tissue (black arrows). This patient’s constellation of radiological, pathological, and clinical findings are compatible with , an autosomal dominant disorder characterized by CNS hemangioblastomas, renal cysts, pancreatic cysts, and epididymal cysts (all seen in this patient). The patient was discharged in good condition after surgical resection of the large right cerebellar hemangioblastoma.


Genetic susceptibility

CNS haemangioblastomas are a cardinal feature in VHL disease. The lifetime risk
of cerebellar haemangioblastoma is ~70% by age 60 years and spinal cord lesions occur in ~25% of patients. Approximately 30% of all patients with cerebellar haemangioblastoma have VHL disease and the mean age at diagnosis of those with VHL disease is considerably younger than in sporadic cases 13 .
VHL is an autosomal dominant disorder associated with a mutation of the VHL tumor suppressor gene located on chromosome 3p25, that is characterized by a variety of tumors including multiple hemangioblastomas, retinal angiomas, renal cell carcinoma, pheochromocytoma, and pancreatic cysts 14 15 . Of patients with VHL disease, approximately 80% will develop hemangioblastomas, with these tumors often being multiple and progressive 16 . In addition, about 50% of patients with VHL develop retinal hemangioblastomas.

Since patients with VHL disease are predisposed to developing multiple hemangioblastomas and require specialized surveillance and treatment, it is imperative to correctly diagnose VHL as early as possible. Genetic testing for VHL in addition to a comprehensive family history should be considered standard practice for all patients with CNS hemangioblastomas, especially those diagnosed under 30 years of age. Clinical screening of VHL- associated tumors consists of complete neuraxis imaging with MRIs of the brain and the entire spine, MRI of the abdomen, retinoscopy and measurement of urine catecholamines.

Hemangioblastomas that occur in association with VHL syndrome unfortunately have a generally higher recurrence rate despite complete surgical resection. While most neurosurgeons agree that surgical intervention of symptomatic hemangioblastomas is required, controversy arises in dealing with asymptomatic hemangioblastomas, as often occurs in patients with VHL syndrome. The difficulty arises from the fact that, unlike other benign intracranial tumors that exhibit a slow progressive growth curve, hemangioblastomas often have periods of growth arrest, thus making their natural course difficult to predict 17 . As such, some groups advocate watching asymptomatic hemangioblastomas with serial MRIs. When tumors remain asymptomatic and are radiographicaly stable, no treatment may be recommended. When asymptomatic tumors show progression on imaging, treatment is debatable – some centers recommend continued follow up while others recommend surgical resection to prevent potential progression of symptoms 18 19 20 . The optimal clinical management of VHL requires a specialist who coordinates annual screening and oversees a multi- disciplinary plan of care.


Therapy

==Surgery==
Given that hemangioblastomas are benign, complete surgical removal may result in cure of single sporadic lesions. As such, surgical resection is the treatment modality of choice for symptomatic, surgically accessible lesions and has had highly effective clinical outcomes 21 22 23 24 25 . Pre-operative cerebral angiography helps surgeons determine the nature of the tumor vascular supply. Following diagnostic imaging, pre-treatment with dexamethasone for several days is generally recommended.

[i]Endovascular embolization[/i]
For extremely vascular solid tumors, some surgeons favor endovascular embolization - a technique which reduces the vascular supply to the lesion. In this process, feeding vessels are obliterated using glue, thus reducing the potential risk for intra- and post-operative hemorrhage. Embolization continues to remain controversial; some surgeons have reported good outcomes 26 27 28 29 , while others have seen increased morbidity from swelling, hemorrhage and infarct 30 31 32 . If embolization of a hemangioblastoma is performed, it is beneficial to perform surgical resection within a couple of days so as to avoid brain swelling following vascular embolization, especially for tumors located in the posterior fossa.

[i]Solid tumors[/i] require complete meticulous dissection around the margins of the lesion, with complete resection of the entire solid component. Dissection should be carried out along the external surface of the tumor in the gliotic brain- tumor interface to avoid entering the tumor, thus preventing brisk hemorrhage from the hemangioblastoma. In cystic hemangioblastomas of the cerebellum, surgical resection involves decompression of the cystic component with complete dissection of the mural nodule, but not necessarily removal of the cyst wall. The cyst wall can be left after decompression of the cyst because it is not comprised of tumor tissue but rather gliotic cerebellum. This correlates with a non-enhancing cyst wall on MRI scan. Without complete removal of the nodule, the tumor will likely recur. Surgical strategies primarily aimed at the pseudocysts, such as fenestration and shunting procedures, have been used but do not appear to offer good long-term control. In both solid and cystic types of tumors, complete resection is the ultimate operative goal. A post-operative enhanced MRI is obtained to determine whether complete resection was achieved. If no residual is noted, most sporadic cases of hemangioblastoma will not recur.

[i]Asymptomatic lesions[/i]
These are frequently seen in VHL patients. The clinical behaviour of growing lesions is difficult to predict and thus indications for surgery are less well defined. Although pre-emptive surgery is theoretically attractive and may spare the patient an urgent craniotomy, many procedures would be performed unnecessarily since these lesions may remain stable for years.

[i]Stereotactic radiosurgery[/i]
While surgical resection of hemangioblastomas offers a potential cure, stereotactic radiosurgery using gamma or cyber knife, for example, has been proposed as another treatment option by some neurosurgeons. Studies evaluating this treatment modality have shown both arrest and regression of tumor size, as well as progression 33 34 35 36 . The treatment results from mostly small, published patient series are mixed, including growth arrest, continued progression and occasional tumor regression. A more recent, larger series reported progression in 16%, regression in 22%, and stable disease in 62% of radiosurgically treated tumors 37 . Since phases of tumor growth arrest can often be seen in cases of spontaneous untreated hemangioblastomas, the utility of gamma knife radiosurgery remains controversial 38 . Given that surgical resection provides high curative rates, radiosurgery as a treatment for hemangioblastoma is typically reserved for cases in which patient’s are poor surgical candidates, the tumor consists of multiple small deep lesions (<3cm) or the lesion involves the brain stem 39 40 41 . Importantly, radiosurgery does not primarily treat the tumor-associated pseudocysts, which are often much larger than the solid component. Radiosurgery will not prevent recurrence in the case of a subtotal surgical resection, nor will it reduce the size of the cystic lesion causing the neurological symptoms associated with hemangioblastomas of the cerebellum 42 43 , thus sometimes also necessitating surgery.

==Medical therapies==
Since hemangioblastomas are highly vascular, systemic anti-angiogenic therapies are being investigated as an alternative to surgery, particularly in VHL patients with multiple tumors. Disease stabilization has been reported in a VHL patient treated with thalidomide 44 . Several VHL patients have been treated with semaxanib, a multi-tyrosine kinase inhibitor predominantly active against VEGFR-2. Although disease stabilization outside the CNS was observed in some patients, most of the treatment responses were limited to retinal hemangioblastomas 45 . In a recent clinical trial for VHL patients with sunitinib, which predominantly targets VEGFR and PDGFR, anti-tumor activity was seen against renal cell carcinoma, but not hemangioblastomas 46 (Matin 2010). Clinical trials with other VEGF/VEGFR inhibitors, including bevacizumab and vatalanib are ongoing. EGFR, which is overexpressed and activated in hemangioblastomas, represents an additional attractive target for therapeutic intervention and study in future clinical trials 47 .


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