In 1928, Cushing and Bailey introduced the term hemangioblastoma.[1] It refers to a benign vascular neoplasm that arises almost exclusively in the central nervous system. According to the World Health Organization classification of tumors of the nervous system, hemangioblastomas are classified as meningeal tumors of uncertain origin.[2, 3] Since its original description, hemangioblastomas have been found in multiple regions of the central nervous system. Predominant involvement of the cerebellum and the spinal cord was noted, but true incidence of this tumor was not discovered until the increased availability of noninvasive diagnostic imaging modalities, particularly magnetic resonance imaging. This, in addition to significant improvement in surgical approaches and microsurgical technique, have made hemangioblastoma, although dangerous, a potentially treatable and curable disease.[4, 5, 6, 7, 8, 9, 10, 11] (See the image of supratentorial hemangioblastoma, below.)
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Supratentorial hemangioblastoma proved by histologic analysis. Carotid arteriogram demonstrates a vascular, dense, tumor filled from the anterior cere....
Presence of a hemangioblastoma rarely, if ever, alters normal anatomy. In choosing the appropriate surgical approach to the tumor, one must take into consideration the position of the mass, presence (or absence) of a large cystic component, associated hydrocephalus and surrounding edema, and the eloquence of neighboring neural and vascular structures. In most cases, cerebellar lesions may be removed through a suboccipital craniectomy, whereas spinal lesions are best addressed from a posterior direction through a laminectomy approach.
Etiology of the hemangioblastoma is obscure, but its presence in various clinical syndromes may suggest an underlying genetic abnormality. The genetic hallmark of hemangioblastomas is the loss of function of the von Hippel-Lindau (VHL) tumor suppressor protein.[12] Upon gross examination, hemangioblastomas are usually cherry red in color. They may include a cyst that contains a clear fluid, but solid tumors are as common as cystic ones. The tumor usually grows inside the parenchyma of the cerebellum, brain stem, or spinal cord; it is attached to the pia mater and gets its rich vascular supply from the pial vessels. However, extramedullary and extradural hemangioblastomas have also been described.[13]
In many cases, symptoms caused by the growth of the neoplasm itself may be an indication for surgical intervention. In others, symptomatic obstruction of the cerebrospinal fluid (CSF) pathways may necessitate the operation. Asymptomatic lesions that sometimes are encountered in patients with multiple hemangioblastomas may be safely observed with frequent MRI scans to rule out tumor enlargement.
As always, surgical resection should be offered to the patient unless the risk of operation outweighs its potential benefits. Acute anticoagulation, the presence of active systemic infection, and severe medical problems that would make general anesthesia too risky generally are considered contraindications for an elective neurosurgical operation. However, the decision should be made on an individual basis.
Hemangioblastomas are rare, and according to various series, they account for 1-2.5% of all intracranial neoplasms.[14, 15] Most hemangioblastomas are located in the posterior cranial fossa; in that region, hemangioblastomas comprise 8-12% of neoplasms. Hemangioblastoma is the most common primary adult intra-axial posterior fossa tumor.[16] Cerebellar hemangioblastomas are frequently referred to as Lindau tumors because Swedish pathologist Arvid Vilhelm Lindau first described them in 1926.[17]
The second most common location of hemangioblastomas is the spinal cord,[18, 19, 20, 21] where the frequency ranges from 2-3% of primary spinal cord neoplasms to 7-11% of spinal cord tumors. This tumor's occurrence in other locations, such as the supratentorial compartment,[22, 23, 24] the optic nerve,[25] the peripheral nerves,[26] or the soft tissues of extremities[27] is extremely rare.
Sex and age distribution
Hemangioblastomas are more common in men than in women. In most clinical series, the male-to-female ratio is approximately 2:1. Although hemangioblastomas may develop at any age, they rarely affect children; the usual age at diagnosis is between the third and fifth decades.
The peak age of incidence has been noted to be between 20 and 50 years. Hemangioblastomas are uncommon but not rare in patients older than 65 years. In a study at one institution, all patients (N = 77) were older than 18 years, and 6 of those were older than 65 years.[28, 29]
von Hippel-Lindau disease
Most hemangioblastomas arise sporadically. However, in approximately one quarter of all cases, they are associated with von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary syndrome that includes retinal angiomatosis, central nervous system hemangioblastomas, and various visceral tumors most commonly involving the kidneys and adrenal glands.[30, 31, 32] This syndrome is classified as a phakomatosis, although it does not include any cutaneous manifestations. The syndrome has variable penetrance, but its dominant mode of transmission compels performing at least a screening of family members of patients diagnosed with VHL disease. In some patients with VHL disease, hemangioblastomas may produce erythropoietin-like substances, resulting in polycythemia at the time of diagnosis.
The clinical presentation of hemangioblastomas usually depends on the anatomic location and growth patterns. Cerebellar lesions may present with signs of cerebellar dysfunction, such as ataxia and discoordination, or with symptoms of increased intracranial pressure due to associated hydrocephalus.[33] In general, intracranial hemangioblastomas present with a long history of minor neurologic symptoms that, in most cases, are followed by a sudden exacerbation, which may necessitate immediate neurosurgical intervention.
Patients with spinal cord lesions most frequently present with pain, followed by signs of segmental and long-track dysfunction due to progressive compression of the spinal cord. Patients with VHL disease may present with ocular or systemic symptoms due to involvement of other organs and systems.
The polycythemia that may develop in some patients with hemangioblastomas usually is clinically asymptomatic.
Spontaneous hemorrhage is possible in both intraspinal and intracranial hemangioblastomas,[34] but this risk is low, and tumors smaller than 1.5 cm carry virtually no risk of spontaneous hemorrhage.
Doyle and Fletcher described 22 cases of hemangioblastoma arising at peripheral sites. All the tumors were solitary, except 1, and arose in the spinal nerve roots (12), kidney (3), intestine (2), orbit (1), forearm (1), peritoneum (1), periadrenal soft tissue (1), and flank (1). Five patients had von Hippel-Lindau disease, and another 5 had lesions suggestive of von Hippel-Lindau disease.[4]
Perform blood tests to help reveal associated lesions that may be a part of the VHL disease complex. Unfortunately, finding polycythemia does not help in diagnosing the tumor.
The diagnostic workup of suspected hemangioblastomas must include, in addition to history, physical, and thorough neurologic examination, complete neural axis imaging and abdominal CT scan or ultrasound. The goal of these additional tests is to reveal associated lesions that may be a part of VHL disease complex.
Perform a detailed ophthalmologic evaluation to help reveal associated lesions that may be a part of the VHL disease complex.
Radiographically, hemangioblastomas are best diagnosed with MRI.[35] MRI of hemangioblastomas usually shows an enhancing mass clearly delineated from the surrounding brain or spinal cord tissue. The tumor tissue may be hypointense or isointense on precontrast T1-weighted images and hyperintense on T2-weighted images.[36, 37]
Plain radiographs usually do not aid in diagnosis. Myelography and cisternography, which were considered the tests of choice in the past, now are almost never used in the diagnostic workup of hemangioblastomas.
Plain computed tomography (CT) scan may reveal hypodensity of the tumoral cyst and associated hydrocephalus. CT scans with intravenous contrast show uniform enhancement of the tumor nodule that, in association with the adjacent cyst, may be extremely characteristic of posterior fossa hemangioblastomas.
Cerebral and spinal angiography reveals a highly vascular tumor blush, and this diagnostic modality may be extremely useful for assessing the vascular supply to the tumor. This information may help the surgeon during tumor resection.
In patients with hemangioblastomas, complete neural axis imaging usually is recommended to rule out multiple lesions, especially in those cases in which VHL syndrome is either diagnosed or clinically suspected.
Histologically, hemangioblastomas are vascular neoplasms. In addition to relatively normal-appearing endothelial cells that line capillary spaces, hemangioblastomas have 2 distinct cellular components that may occur in the same tumor in different proportions. The first type is small, perivascular, endothelial cells that have dark, compact nuclei and sparse cytoplasm. Cells of the second type contain multiple vacuoles and granular eosinophilic cytoplasm rich in lipids. These stromal cells may show some nuclear pleomorphism, but mitotic figures are rarely seen. The exact histogenetic origin of stromal cells is unknown, but studies indicate that they may represent a heterogeneous population of abnormally differentiating mesenchymal cells of angiogenic lineage, with some morphologic features of endothelium, pericytes, and smooth-muscle cells.[38]
Two histologic subtypes (cellular and reticular) have been described in primary hemangioblastomas of the central nervous system and have been found to correlate with the probability of tumor recurrence.[39] The reticular subtype is more commonly encountered; the cellular subtype is associated with higher probability of recurrence.
No histologic grading system exists for hemangioblastomas.
Because hemangioblastomas are benign tumors and generally are not invasive in nature they may be cured by surgical excision. Therefore, surgical resection is considered a standard of treatment and should be offered to the patient unless the risk of operation outweighs its potential benefits.[16, 18, 19, 20, 21, 40, 41, 42]
The tumors usually are well demarcated from the surrounding brain or spinal cord, but this border of separation does not contain any particular membrane or capsule. The surgical approach must be wide enough to avoid compression of the healthy tissues during retraction. Thorough evaluation of preoperative imaging studies is the key to the safest possible exposure of the tumor. In addition to MRI and CT scans, review the angiography findings to identify the principal blood supply to the tumor mass.
Other therapeutic modalities include endovascular embolization of the solid component of the tumor,[43, 44] which may decrease the vascularity of the tumor and lower blood loss during its resection, and stereotactic radiosurgery of the tumor using either a linear accelerator[45] or a gamma knife.[46, 47, 48, 5] After studying 186 patients from 6 centers in the North American Gamma Knife Consortium, Kano et al concluded that stereotactic radiosurgery provided control of growing tumors seen on serial imaging studies in 79-92% of cases.[6] . Antiangiogenic treatment of hemangioblastoma has also been described.[49]
Regarding general surgical management, having blood products available for transfusion is very important because the vascular character of hemangioblastomas may result in serious intraoperative blood loss. Additionally, anesthesia for patients with VHL disease may be quite challenging because of associated renal and endocrine dysfunction.
With an adequate preoperative workup, most complications of surgery for hemangioblastoma may be avoided. Meticulous maintenance of hemostasis, attention to minor details, and great respect for neural and vascular elements may significantly decrease the risk of postoperative complications. The main emphasis, as usual, should be placed on preventing complications rather than on treatment.
Follow-up care for patients with hemangioblastomas should include regular neurologic and imaging checks to confirm the absence of tumor recurrence and/or development of distant lesions.
The tumor is usually easy to visualize because of its reddish-colored solid component and the yellow fluid inside the cyst.
If the cyst is present, it may be emptied by cutting the covering pial membrane or by aspirating the cystic contents using a syringe with a short small-caliber needle. Decompression of the cyst allows for improved delineation of the interface between the tumor and the brain or spinal cord.
The surface of the tumor may be coagulated with wide bipolar forceps; however, avoid penetration of the tumor itself because of its extreme vascularity and difficulties with hemostasis. Try to dissect the tumor circumferentially by careful coagulation and cutting the small feeding vessels and adhesions between the tumor and the surrounding brain or spinal cord and by putting cottonoid strips into the developing plane to avoid direct pressure on the brain or spinal cord tissue.
Once the feeding vessels are identified, they are coagulated and cut. Try to coagulate the arterial feeders prior to the draining veins, but this is not as crucial as it is in arteriovenous malformations.
After the tumor is totally removed, the raw surface of the brain or spinal cord remains relatively bloodless, and the oozing blood stops after a few minutes of gently packing the resection cavity with wet cotton balls, avoiding the need for additional coagulation.
If an associated hydrocephalus exists, it must be addressed separately, usually by means of external ventricular drainage (EVD) prior to tumor resection. After the tumor is removed, the need for permanent shunt placement may be determined by the patient's response to EVD clamping. In most cases, an intramedullary syrinx does not require a separate drainage procedure because it usually resolves after tumor removal.
Long-term results of hemangioblastoma management are generally favorable. Advancement of neuroimaging methods, improvements in microsurgical technique, and the addition of preoperative embolization have significantly lowered morbidity and mortality associated with hemangioblastoma surgery.
Subarachnoid dissemination of hemangioblastomas is extremely rare,[50] and local recurrences after complete tumor resection seem to be more frequent in patients with von Hippel-Lindau (VHL) disease, in patients diagnosed at a young age, and in patients with multiple hemangioblastomas. The results of one study found that resection of brainstem hemangioblastomas is generally a safe and effective treatment for patients with VHL disease. However, due to VHL disease–associated progression, long-term decline in functional status may occur.[51] The recurrence rates vary in different surgical series but generally remain less than 25%. Histologic subtype has been found to correlate with a probability of hemangioblastoma recurrence, with a 25% recurrence rate in cellular subtype and an 8% recurrence rate in reticular subtype.[39]
At final follow-up examination of patients who underwent resection of sporadic hemangioblastoma in the cerebellum, patients with solid tumors more frequently showed poor outcomes than patients with cystic tumors. According to the study authors, the solid configuration observed on preoperative images of sporadic cerebellar hemangioblastomas is one of the most important clinical factors related to both immediate and long-term outcomes after surgery.[52]
Konstantin V Slavin, MD, Professor, Department of Neurosurgery, Chief, Section of Stereotactic and Functional Neurosurgery, University of Illinois at Chicago College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Ryszard M Pluta, MD, PhD, Associate Professor, Neurosurgical Department Medical Research Center, Polish Academy of Sciences, Poland; Clinical Staff Scientist, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH); Fishbein Fellow, JAMA
Disclosure: Nothing to disclose.
Chief Editor
Brian H Kopell, MD, Associate Professor, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai
Disclosure: Received consulting fee from Medtronic for consulting; Received consulting fee from Abbott Neuromodulation for consulting.
Additional Contributors
Duc Hoang Duong, MD, Professor, Chief Physician, Departments of Neurological Surgery and Neuroscience, Epilepsy Center, Charles Drew University of Medicine and Science
Disclosure: Nothing to disclose.
References
Cushing H, Bailey P. Tumors Arising from Blood Vessels of the Brain: Angiomatous Malformations and Hemangioblastomas. Springfield, Ill: Charles C Thomas Publisher; 1928.
Rubinstein LJ. Atlas of Tumor Pathology: Tumors of the Central Nervous System. Washington, DC: US Government Printing Office; 1972. 235.
Gonzales MF. Classification and pathogenesis of brain tumors. Kaye AH, Laws ER, eds. Brain Tumors. 1st ed. New York, NY: Churchill Livingstone; 1995. 31-45.
Supratentorial hemangioblastoma proved by histologic analysis. Carotid arteriogram demonstrates a vascular, dense, tumor filled from the anterior cerebral vessels and not involving the sagittal sinus.
Photomicrograph shows the classic microscopic appearance of a cerebellar hemangioblastoma with numerous capillaries and polygonal stroma cells shows vacuoles of cytoplasm and hyperchromatic nucleus (hematoxylin-eosin stain, high-power magnification). Courtesy of Dr Paul Fiedler.><
Supratentorial hemangioblastoma proved by histologic analysis. Carotid arteriogram demonstrates a vascular, dense, tumor filled from the anterior cerebral vessels and not involving the sagittal sinus.
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