Introduction
Background
Hemangioblastomas are considered to be benign neoplasms and represent 1-2% of all primary central tumors. Historically, hemangioblastomas are linked to von Hippel-Lindau (VHL) disease.1 In 1927, Arvid Lindau reported the connection between retinal angiomas and hemangiomas of the cerebellum.
VHL is an autosomal dominant condition involving chromosome 3 characterized by specific benign and malignant tumors with variable expressivity.2,3 Cerebellar hemangioblastoma is the most common initial manifestation, affecting 64% of patients with VHL.4 In many series, cerebellar hemangioblastoma is the most important cause of mortality, affecting 47.7% of patients with VHL,5 followed by renal cell carcinoma.5,6
In patients with a positive family history, a single cerebellar hemangioblastoma is sufficient to make the diagnosis. If no known family history exists, at least 2 cerebellar hemangioblastomas or 1 hemangioblastoma plus 1 visceral tumor are necessary to justify the diagnosis of VHL.
Various organs can be involved (see Image 1).5 Of patients presenting with hemangioblastomas, 70% do not have a family history, and 3-25% of these patients have tumors associated with VHL. Hemangioblastoma appears to be associated more with VHL than previously reported, and it has been suggested that all patients with sporadic nonhereditary tumors should be evaluated for evidence of VHL disease.4,6,7
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.
Related eMedicine topics:
von Hippel-Lindau Disease (Ophthalmology)
von Hippel-Lindau Disease (Pediatrics)
Von Hippel-Lindau Syndrome (Radiology)
Hemangioblastoma (Neurosurgery)
Hemangioblastoma, Spine
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Pathophysiology
Hemangioblastomas are highly vascular tumors with 2 principal components: capillaries and stromal cells. The origin of the stromal cells is not well defined. The expression of transthyretin and transferrin has been reported in these cells, and the possibility exists that they may originate from embryonic plexus epithelium.8 The controversial origin has resulted in the classification of hemangioblastoma as a single entity in the category of tumors of uncertain histogenesis in the current World Health Organization system.9
Etiopathogenic studies on von Hippel-Lindau (VHL) demonstrate that the VHL gene (located on bands 3p25-26) acts as a tumor suppressor that binds the transcription factors elongin B and elongin C and inhibits transcriptional elongation. Germ-line mutation in patients with VHL and somatic mutations in different tumors have been identified.10 The development of tumors requires the inactivation of the 2 copies of the VHL gene. In patients with VHL, only 1 somatic mutation on the remaining allele is required for tumors to develop. In patients with sporadic cases, the 2 VHL gene mutations are seen. The hallmark of VHL tumors is high vascularization, which arises from increased levels of vascular endothelial growth factor (VEGF).
Patients with hemangioblastomas present with high levels of VEGF. The principal function of the VHL protein (pVHL) is negative regulation of hypoxia-inducible messenger RNA (mRNA), such as the mRNA encoding VEGF. The activity of pVHL has been linked to the targeting of specific proteins for proteolysis. When the VHL gene is mutated, absence of hypoxia-inducible transcription factor degradation (target of the proteolytic enzymes) is responsible for the accumulation of VEGF(see Image 2).11
Hemangioblastomas are slow-growing tumors of endothelial cells with high tendency to be cystic (60%). The solid component is composed of capillaries, which are tightly packed blood vessels lined by endothelial cells. The blood vessels vary in size from capillary to cavernous. The absence of astrocytic endfeet and tight junctions can be found in the microvessels, which may lead to the breakdown of the blood-brain barrier, and have a role in cyst formation.12 Abundant intercapillary tissue is seen with swollen fat-laden endothelial cells that allow differentiation from angioma (see Images 3-4). A small cyst may exist in the mass, but more often, the cyst is situated adjacent to the tumor.13
The tumor does not have a capsule, and no mitotic changes are seen. The wall of the cystic component is composed of neural glial cells, with proteinaceous content that is rarely hemorrhagic. The cystic fluid is xanthochromic, with a concentration of amino acids, alkaline phosphates, and mucoproteins similar to blood, suggesting that they originate by diffusion from the vascular component of the solid tumor.14
Frequency
United States
Hemangioblastomas present most commonly in the posterior fossa, representing 7-12% of posterior fossa tumors in adults (including primary tumors and metastases). Almost 95% of infratentorial tumors are located in the cerebellum, primarily in the hemispheres, less frequently in the vermis, and even less commonly in the medulla oblongata and the spinal cord. Supratentorial hemangioblastomas are rare, with 85 reported cases, mostly in the cerebral hemispheres.
Hemangioblastomas have been described as intraventricular (in the third ventricle), from where cerebrospinal fluid seeding has been suggested to occur. Other less common locations include the pituitary gland, the corpus callosum, the basal ganglia, and the meninges.7,15,16
Multiple hemangioblastomas occur in less than 5% of patients with sporadic cases and in as many as 20-25% of patients with von Hippel-Lindau (VHL). Hemangioblastomas usually are solitary. Multiple lesions are seen in 5% of patients without VHL disease and in 30-60% of patients with VHL disease.
- The rate of development of lesions is 1 lesion per 2.1 years.4
Mortality/Morbidity
Morbidity and mortality rates have been reduced as a result of diagnostic and therapeutic advances. Morbidity and mortality are related to the risk of rapidly enlarging cysts and the tendency for multiple recurrences. Morbidity and mortality rates are higher in patients with von Hippel-Lindau (VHL), in whom it is the first cause of death in many series, with an average rate of 40-60%.
- VHL penetrance is estimated to be 80-90% at age 65 years.2
- Enlargement of the cystic component can accompany pregnancy, leading to dramatic complications. Progesterone receptors have been demonstrated in the tumor, which can explain this phenomenon. Oral contraception is not recommended, but scientific proof does not exist to support the recommendation.
- The postoperative mortality rate is 7-10%, and it is higher in brainstem locations. Overall prognosis is good because 85% of patients survive 5-20 years after surgical removal of the tumor.4,14
Race
No racial predisposition has been reported for brain hemangioblastoma.
Sex
Hemangioblastomas are slightly more common in men than in women, with a male-to-female ratio of 1.3-2.6:1 in sporadic cases. Patients with hemangioblastomas related to von Hippel-Lindau (VHL) present with no sex differences in frequency.
Age
Hemangioblastomas occur more often in middle-aged adults aged 30-50 years. Patients with von Hippel-Lindau (VHL) present at a younger age than patients with sporadic cases, with an age range of 25-40 years.4
Anatomy
The nidus of the tumor abuts the pia matter, from which the tumor receives its vascular supply. The tumor is more frequently superficial than deep. Of hemangioblastomas, 60-70% are cystic, and the remainder are solid. Solid tumors are more common in the brainstem and supratentorial locations than elsewhere. The mural nodule is hypervascular and relatively small, less than 15 mm in diameter.
From a macroscopic point of view, hemangioblastomas can appear as solid or cystic tumors with mixed forms. Four types can be distinguished, as follows:
- Type 1, or the simple cyst form, is rare (6%) and characterized by a cyst with clear fluid and smooth walls and without evidence of a mural nodule at angiography or surgery.
- Type 2, or the macrocystic form, is the most frequent (65%) and characterized by a cyst of variable size with a mural nodule of approximately 1 cm.
- Type 3, or the solid form (25%), has a solid consistency with blurred limits and marked vascularization.
- Type 4, or the microcystic form (4%), is solid but contains small cysts of a few millimeters in size; therefore, 75% of infratentorial hemangioblastomas have a cystic component of variable size (see Image 5).
Presentation
Clinical symptoms depend on the site and size of the lesion because it is a slow-growing tumor. The patient can present with minor neurologic symptoms for months, followed by a sudden exacerbation. In infratentorial localizations, headache is the most common symptom as a result of increased intracranial pressure. Other symptoms include vomiting, giddiness, ataxia, and gait disturbances. Neurologic examination results are normal or include cerebellar signs, but hydrocephalus results in rapid decompensation with papilledema.
Polycythemia occurs in approximately 20% of cerebellar hemangioblastomas and is more common with solid hemangioblastomas.3,5 Polycythemia is caused by tumoral production of erythropoietin. Subarachnoid or intra-axial hemorrhages are rare. Subarachnoid hemorrhages occur as a result of the subpial localization. Hemangioblastoma is the most common presenting manifestation of von Hippel-Lindau (VHL), revealing the disease in 30-50% of cases.3
Preferred Examination
Contrast-enhanced MRI is considered the best method for screening patients with von Hippel-Lindau (VHL) and the first evaluation used in symptomatic patients. However, preoperative angiography remains important for defining feeding vessels and aiding in embolization.17,18
Prior to MRI, contrast-enhanced CT scanning was performed frequently; however, beam-hardening artifacts produced by the petrous and vertebral bone limited its use.
MRI is superior to CT in the detection of vascular components of the tumor. Contrast-enhanced CT has the same sensitivity as nonenhanced MRI; however, it is inferior to contrast-enhanced MRI.17 Contrast-enhanced MRI permits the identification of small tumor nodules. In addition, MRI is helpful in separating cystic and solid components of the tumor from edema. Patients with VHL should be screened, and follow-up studies should be performed at 6 months.
Further follow-up studies should be performed at 1-year intervals to detect the development of additional tumors and monitor progression of existing lesions.17 Early treatment improves the outcome. Using MRI and CT at 1- to 2-year intervals, Conway et al identified 74% of lesions that required surgery before the patients became symptomatic.4
Limitations of Techniques
MRI is superior to nonenhanced CT in the detection of vascular components of the tumor.17,19 Contrast-enhanced CT has the same sensitivity as nonenhanced MRI. The sensitivity of MRI increases with the use of gadolinium-based contrast material. Angiography is better in the detection of small (< 1 cm) vascular tumor components, and it is better for showing the vascular nature, supply, and drainage of tumors, compared with CT.20 However, CT and MRI depict tumor cysts better.21
Differential Diagnoses
Arachnoid Cyst
Brain, Arteriovenous Malformation
Brain, Metastases
Juvenile Pilocytic Astrocytoma
Medulloblastoma
More on Hemangioblastoma, Brain |
 Overview: Hemangioblastoma, Brain |
| Imaging: Hemangioblastoma, Brain |
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Further Reading
Indeterminate renal masses.
American College of Radiology. 1996 (revised 2007). 7 pages. NGC:005996
Genetic cancer risk assessment and counseling: recommendations of the National Society of Genetic Counselors.
National Society of Genetic Counselors. 2004 Apr. 32 pages. NGC:003601
EFNS guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. European Federation of Neurological Societies - Medical Specialty Society. 2006 Jul. 8 pages. NGC:005485
Management of brain metastases: role of radiotherapy alone or in combination with other treatment modalities.
Program in Evidence-based Care. 2004 Mar 30. 35 pages. NGC:003529
Keywords
brain hemangioblastoma, Lindau tumor, capillary hemangioblastoma, hemangioendothelioma, angioreticuloma, angioblastoma, cerebellar hemangioma, benign neoplasm, brain tumor, von Hippel-Lindau, intracranial tumor, hemangioma, capillary hemangioma
