Hemangioblastomas are rare, slow-growing, benign, highly vascular neoplasms of the CNS that have a high association with von Hippel-Lindau disease (VHL), which is an autosomal dominant condition characterized by a variety of benign and malignant tumors.
- Hemangioblastomas are classified by the WHO as meningeal tumors of uncertain origin.
- Meninges are the fibrous layers that encase the brain and spinal cord; they consist of 3 layers:
- Dura mater: the outer layer, which forms a tough collagenous sheath
- Arachnoid mater: middle layer consisting of simple squamous epithelium with a loose mesh of collagen and elastic fibers
- Pia mater: thin inner layer in contact with the brain and spinal cord
- Hemangioblastomas are attached to the pia mater.
|Neuroepithelial tumors in the CNS|
|Sellar region tumors|
|Primary CNS lymphoma||Primary CNS lymphoma|
|Metastasis to the brain (5x more common than primary brain tumors)||Most commonly arising from:|
- Sporadic: 75%
- Associated with VHL: 25%
- Extremely rare
- 2.5% of all intracranial neoplasms
- 5% of spinal cord tumors
- Sex: Incidence is higher in men than in women (2:1).
- Children are rarely affected.
- The peak age of incidence is 20–50 years.
- The exact cause of hemangioblastoma is not known.
- A mutation in the VHL gene is being considered because of a high association with VHL.
Hemangioblastomas grow attached to the pia mater (innermost meningeal layer)
- Parenchyma of the cerebellum
- Brain stem
- Spinal cord
Although the sporadic hemangiomas do not have a clear pathogenesis, the VHL-associated hemangiomas are thought to be caused by a mutation in the VHL gene. Up to 50% of sporadic hemangioblastomas have mutations or deletions in the VHL gene as well.
- VHL gene:
- Tumor-suppressor gene found on chromosome 3
- Responsible for the inhibition of hypoxia-inducible factor-2α (HIF-2α) by ubiquitin-mediated proteasomal degradation
- Part of a larger transcription factor protein complex called HIF, which is involved in regulating the body’s ability to adapt to changing oxygen levels
- HIF can induce the expression of over 70 target genes, including:
- Vascular endothelial growth factor (VEGF)
- Platelet-derived growth factor (PDGF)
- Transforming growth factor α (TGF-α)
- When adequate oxygen is available, VHL protein helps suppress HIF.
- A dysfunctional VHL gene (caused by mutation or deletion) can lead to accumulation of HIF-2𝛂 owing to the inability to degrade HIF-2α.
- The stabilization of HIF-2α allows it to induce expression of its target genes → ↑ angiogenic factors → tumor growth
Symptom development is caused by:
- Direct compression of the tumor on neural structures
- Peritumoral bleeding
- Paraneoplastic complications
Clinical Presentation and Complications
Symptoms depend on the location and progression of the tumor. The most common symptoms observed are:
- Headache: most common
- Local pain (common in spinal cord lesions)
- Cerebellar ataxia and discoordination
- Increased intracranial pressure (ICP) due to obstructive hydrocephalus
- Oculomotor nerve dysfunction
- Motor weakness
- Sensory deficits
Sporadic versus VHL-associated hemangioblastomas
|Sporadic hemangioblastoma||VHL-associated hemangioblastoma|
|Presents as solitary tumor||Multiple tumors along the neuraxis|
|Usually occurs in the 3rd or 4th decade of life||Diagnosed at a younger age (2nd decade)|
|Commonly presents as an isolated tumor in the cerebellum||50% of the tumors are located at the spinal cord, 40% at the cerebellum, and 10% at the brain stem.|
Complications usually occur because of an increase in the size of the tumor (> 1.5 cm), causing compression, or because of spontaneous hemorrhage:
- Symptoms of increased ICP/rapid obstructive hydrocephalus
- Altered mental status
- Polycythemia due to ectopic production of erythropoietin
While the primary diagnostic screening tool is imaging, the gold standard of diagnosis requires histopathology from a biopsy specimen.
The entire neural axis should be imaged to rule out multiple lesions, which are common in cases of VHL.
- Contrast MRI:
- Gadolinium-enhanced MRI is the most sensitive imaging method to diagnose hemangioblastoma.
- Characteristic features:
- Enhanced nodule associated with a cyst (60% of tumors)
- Enhanced solid tumor (40%)
- T1 shows a hypointense to isointense nodule
- T2 shows a hyperintense nodule
- Any cyst present has the same density as CSF.
- Not the preferred method of diagnosis, as bone artifacts may obscure small tumors in the posterior fossa and spinal canal
- A non-contrast-enhanced CT shows an isointense nodule.
- With contrast: intense homogeneous enhancement of the nodules
- CT is also used as an adjuvant to angiography when the patient cannot undergo MRI.
- Cerebral and spinal angiography:
- A high vascular tumor blush is observed with enlarged arteries and dilated veins.
- Can detect blood supply to the tumor → aids the surgeon in the proper resection of the tumor
- Hemangioblastomas have a high association with VHL, which is associated with retinal hemangioblastomas.
- Retinal angiography can be performed to rule out the presence of a retinal hemangioblastoma.
- Gold standard for diagnosis
- Gross examination: well-circumscribed, highly vascular red nodules
- Microscopic examination:
- Extensive vascular networks with structurally normal capillaries
- Neoplastic stromal cells:
- Hyperchromatic, pleomorphic nuclei
- Low mitotic rate
- No atypia
- Rosenthal fibers
- 2 distinct cellular components may appear in the same tumor:
- Type 1: small perivascular endothelial cells with hyperchromatic nuclei and sparse cytoplasm
- Type 2: multiple vacuoles, granular eosinophilic cytoplasm
Management and Prognosis
Surgical resection is the primary approach to treating hemangioblastomas. Adjuvant therapies are commonly required in VHL-associated hemangioblastomas, and options include radiation therapy, endovascular embolization, and antiangiogenic therapy.
Surgery is the primary definitive approach to treat hemangioblastomas, as they are benign, noninvasive tumors.
- Tumors are usually well demarcated from the surrounding structures but are highly vascular and located in neurologically sensitive areas.
- Preoperative angiography is helpful to identify feeding arteries.
- Need for adjuvant therapy:
- Generally not required in sporadic single tumors
- Typically required in VHL-associated and/or multiple tumors
- Radiation therapy:
- Postoperative radiation therapy reduces the recurrence of hemangioblastomas.
- Surgically inaccessible lesions
- Multiple lesions
- Endovascular embolization:
- Goal: to decrease vascularity to the tumor and reduce intraoperative complications of hemorrhage
- Large tumors can be considerably reduced to make the resection easier.
- Angiogenic inhibitors: bevacizumab
- Mechanism of action: a monoclonal antibody that binds to and inhibits the effects of VEGF → ↓ angiogenesis
- Uses: VHL patients with tumors that do not respond to surgery or radiation
Prognosis is good in most treated hemangioblastomas:
- Clean surgical resection (with negative surgical margins), especially in solitary sporadic tumors ensures a good prognosis.
- Early detection and intervention is favorable.
- Hemangioblastomas associated with VHL:
- Higher chance of recurrence than sporadic tumors
- Poorer prognosis
- Higher association with neurologic deficits
- Meningioma: tumors arising from the meninges of the brain and spinal cord. Meningiomas are commonly asymptomatic, but they can present with headache, seizures, and visual disturbances. Diagnosis is through MRI and biopsy. Asymptomatic cases are typically kept under observation, while symptomatic patients are treated surgically or with radiation. Unlike hemangioblastomas, meningiomas are always near the meninges and often have imaging findings of dural attachment (e.g., dural tail sign).
- Glioblastoma multiforme: rapidly progressive WHO grade IV astrocytoma that arises from astrocytes (glial cells in the brain) and presents clinically as headache, nausea, drowsiness, blurred vision, personality changes, and seizures. Imaging, clinical presentation, and biopsy are the mainstays for diagnosis. Management includes radiotherapy, chemotherapy, and surgical excision. Prognosis is poor even with treatment. Unlike hemangioblastoma, glioblastoma multiforme is not associated with VHL.
- Oligodendroglioma: CNS tumor arising from oligodendrocytes. Oligodendroglioma can present with focal neurologic deficits, seizures, and personality changes depending on the exact location. Diagnosis is made by MRI imaging and biopsy. Contact with the meninges and a dural tail can help differentiate many meningiomas from oligodendrogliomas, which most commonly develop in the cerebral hemispheres, usually the frontal lobe. Management involves surgical resection possibly accompanied by radiation and/or chemotherapy.
- Brain aneurysm: weakness in the wall of a blood vessel supplying the brain that bulges and is at the risk of rupturing. An unruptured aneurysm is usually asymptomatic and the rupture of an aneurysm causes sudden, severe headache. Brain aneurysms are diagnosed with CT, angiography, or ultrasonography. Management depends on the location and is typically treated with an endovascular stent graft.
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