Hemangioblastoma

Hemangioblastomas are vascular neoplasms of the CNS. Hemangioblastomas are rare and are often associated with von Hippel-Lindau disease (VHL). The most common presentation is a headache and, depending on the size and location of the tumor, patients may present with sensory deficits and motor weakness. Imaging is the main screening method, with histopathologic evaluation required for definitive diagnosis. Surgery is often indicated in the management of hemangioblastomas, though depending on the size, number, and location of the tumors, radiation therapy may also be warranted. Prognosis is usually good in solitary hemangioblastomas, but tumors associated with VHL are often associated with a worse prognosis and a higher risk of recurrence.

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Overview

Definition

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.
Table: Classification of nervous system tumors
CategoriesSpecific tumors
Neuroepithelial tumors in the CNS
  • Astrocytomas, including glioblastoma multiforme
  • Oligodendroglioma
  • Ependymoma and choroid plexus tumors
  • Medulloblastomas (embryonal tumors)
Meningeal tumors
  • Meningiomas
  • Hemangioblastomas
Sellar region tumors
  • Craniopharyngioma
  • Pituitary adenoma
  • Pinealoma/pinealoblastoma
Primary CNS lymphomaPrimary CNS lymphoma
Metastasis to the brain (5x more common than primary brain tumors)Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma
Peripheral tumors
  • Schwannomas, including acoustic neuromas
  • Neuroblastoma

Epidemiology

  • Sporadic: 75% 
  • Associated with VHL: 25%
  • Incidence: 
    • Extremely rare 
    • 2.5% of all intracranial neoplasms 
    • 5% of spinal cord tumors
  • Sex: Incidence is higher in men than in women (2:1).
  • Age: 
    • Children are rarely affected.
    • The peak age of incidence is 20–50 years.

Etiology

  • The exact cause of hemangioblastoma is not known. 
  • A mutation in the VHL gene is being considered because of a high association with VHL.

Pathophysiology

Tumor location

Hemangioblastomas grow attached to the pia mater (innermost meningeal layer)

  • Parenchyma of the cerebellum
  • Brain stem
  • Spinal cord

Pathogenesis

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 
  • HIF-2α:
    • 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)
      • Erythropoietin
      • 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

Symptom development is caused by:

  • Direct compression of the tumor on neural structures
  • Peritumoral bleeding
  • Paraneoplastic complications

Clinical Presentation and Complications

Clinical presentation

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

Table: Typical clinical presentations of sporadic versus VHL-associated hemangioblastomas
Sporadic hemangioblastomaVHL-associated hemangioblastoma
Presents as solitary tumorMultiple tumors along the neuraxis
Usually occurs in the 3rd or 4th decade of lifeDiagnosed at a younger age (2nd decade)
Commonly presents as an isolated tumor in the cerebellum50% of the tumors are located at the spinal cord, 40% at the cerebellum, and 10% at the brain stem.

Complications

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
  • Quadriplegia

Diagnosis

While the primary diagnostic screening tool is imaging, the gold standard of diagnosis requires histopathology from a biopsy specimen.

Imaging

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. 
  • CT:
    • 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
Hemangioblastoma

Radiographic images of hemangioblastomas:
A: Axial, contrast-enhanced, T1-weighted MRI showing cerebellar hemangioblastoma with contrast-enhancing mural nodule and peritumoral cyst
B: Sagittal, contrast-enhanced, T1-weighted MRI revealing contrast-enhancing medullary hemangioblastoma with surrounding vasogenic edema
C: Sagittal, contrast-enhanced, T1-weighted MRI with contrast-enhancing posterior/dorsal hemangioblastoma with associated syrinx

Image: “Hemangioblastoma” by Department of Neurological Surgery, Ohio State University Wexner Medical Center , Columbus, OH , USA. License: CC BY 4.0

Ophthalmic examination

  • 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.
von Hippel-Lindau disease with exudative maculopathy

Fluorescein angiogram of right eye showing a temporal superior retinal hemangioblastoma with the feeder artery and draining vein

Image: “Fluorescein angiogram of right eye” by Vitreoretinal Division, Department of Ophthalmology, Al-Hussein Hospital, King Hussein Medical Center, Amman, Jordan. License: CC BY 2.0

Histopathology

  • 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
Optic nerve hemangioblastoma

H&E photomicrograph of a hemangioblastoma of the optic nerve (unusual location) revealing a markedly vascular tumor with lipidized stromal cells (×200)

Image: “Optic nerve hemangioblastoma” by Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA. License: CC BY 3.0

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

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

Adjuvant therapies

  • Radiation therapy:
    • Postoperative radiation therapy reduces the recurrence of hemangioblastomas.
    • Indications:
      • 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

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

Differential Diagnosis

  • 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.

References

  1. Wong, E.T., Joseph, J., Wu, J.K. Hemangioblastoma. UpToDate. Retrieved May 20, 2021, from https://www.uptodate.com/contents/hemangioblastoma
  2. Slavin, K.V. (2017). Hemangioblastoma. Medscape. Retrieved May 20, 2021, from https://emedicine.medscape.com/article/250670-overview
  3. Pernick, N. (2021). CNS tumors—other tumors—hemangioblastoma. Pathology Outlines. Retrieved May 20, 2021, fromhttps://www.pathologyoutlines.com/topic/cnstumorhemangioblastoma.html 
  4. Kim W.Y., Kaelin W.G. (2004). Role of VHL gene mutation in human cancer. J Clin Oncol. Retrieved June 1, 2021, from https://pubmed.ncbi.nlm.nih.gov/15611513/ 
  5. Dengler, V. L., Galbraith, M., Espinosa, J. M. (2014). Transcriptional regulation by hypoxia inducible factors. Critical reviews in biochemistry and molecular biology, 49(1):1–15. Retrieved June 1, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342852/

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