Hemangioblastoma

INTRODUCTION — Hemangioblastomas are uncommon, slow-growing tumors of the central nervous system, which most commonly occur in the cerebellum, brainstem, or spinal cord. They account for approximately 4 percent of all spinal cord tumors, and 7 to 10 percent of tumors arising in the posterior fossa in adults.

Hemangioblastomas occur both sporadically and as an important component of von Hippel-Lindau (VHL) disease. VHL disease is an inherited, autosomal-dominant syndrome manifested by a variety of benign and malignant tumors, including hemangioblastomas, retinal angiomas, endolymphatic sac tumors, renal cell carcinoma (RCC), pheochromocytomas, pancreatic cysts, and neuroendocrine tumors.

The clinical manifestations and management of patients with hemangioblastomas are reviewed here. The clinical manifestations and overall management of patients with VHL disease are discussed separately. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

CLINICAL MANIFESTATIONS

Sporadic versus VHL-associated tumors — Hemangioblastomas may occur either sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Although approximately 75 percent of all hemangioblastomas appear to be sporadic [1], some of these may represent occult cases of VHL that can be detected if patients are appropriately screened for germline VHL pathogenic variants. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Hemangioblastomas'.)

Sporadic and VHL-related hemangioblastomas differ significantly in their presentation:

●Sporadic hemangioblastomas are usually solitary. Thus, the presence of multiple tumors within the neuraxis should raise suspicion for VHL disease.

●Hemangioblastomas associated with VHL are generally diagnosed at a younger age than sporadic tumors [2]. In one series, the mean age at initial diagnosis was 29 years in patients with VHL, while the average age at presentation in those without VHL is one to two decades older [1].

●In patients with VHL disease, approximately one-half of tumors are in the spinal cord, 40 percent are in the cerebellum, and 10 percent are in the brainstem [3]. Supratentorial lesions are rare. For those with sporadic tumors, isolated cerebellar lesions are substantially more common [1,2].

Symptoms — Hemangioblastomas can cause local symptoms by compression of neural structures, bleeding, or paraneoplastic complications. In patients with VHL disease, asymptomatic hemangioblastomas are diagnosed based upon imaging surveillance. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Surveillance protocols'.)

Hemangioblastomas can cause neurologic deficits by direct compression, edema, or tumor-associated hemorrhage.

●The specific deficit from direct compression depends upon tumor location and may include dizziness/vertigo, cerebellar ataxia, oculomotor nerve dysfunction, dysphagia, motor weakness, or sensory deficits [2]. Patients with spinal hemangioblastomas frequently present with pain [4].

●Acute hemorrhage can be catastrophic. Intracerebral bleeding from a cerebellar hemangioblastoma may cause rapid obstructive hydrocephalus, cerebellar tonsillar herniation, or brainstem compression [5,6]. Bleeding from a spinal hemangioblastoma may result in acute quadriplegia [7], while headache, back pain, or radiculopathy may be caused by subarachnoid hemorrhage [8,9]. In these situations, emergency neurosurgical intervention is indicated. The risk of bleeding in treated or untreated hemangioblastomas is unknown [10]. (See 'Treatment' below.)

Paraneoplastic erythrocytosis has also been reported in patients with hemangioblastoma [11,12]. The elevated hematocrit and red cell mass are a result of excessive erythropoietin production by the hemangioblastoma [13,14]. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

Neuroimaging — The majority of hemangioblastomas occur in the posterior fossa, with 80 percent in the cerebellar hemispheres and 15 percent in the cerebellar vermis. The characteristic appearance on MRI is either that of an intra-axial cystic mass with an enhancing mural nodule abutting the pia or a solid, intensely enhancing mass, often with flow-voids from dilated vessels next to or within the tumor (image 1). Smaller hemangioblastomas (<10 mm) may be isointense on T1-weighted images and hyperintense on T2-weighted images, with homogeneous contrast enhancement [15].

The majority of spinal hemangioblastomas are intramedullary, subpial, well-demarcated, and intensely enhancing masses with an associated syrinx [4]. Multiple cord hemangioblastomas are more common in patients with VHL disease (image 2). (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors" and "Spinal cord tumors".)

DIAGNOSTIC EVALUATION — The preferred diagnostic procedure is gadolinium-enhanced magnetic resonance imaging (MRI). A computed tomography (CT) scan of the neuraxis is not an adequate diagnostic procedure because bone artifacts may obscure small tumors in the posterior fossa or spinal canal. For patients who cannot undergo an MRI, conventional angiography together with CT scanning are alternative diagnostic tests to define the location and vasculature feeding the hemangioblastoma.

PATHOLOGY AND PATHOGENESIS

Pathology — Hemangioblastomas are well-circumscribed, highly vascular red nodules that are often located within the walls of large cysts. On cross-section, these tumors appear beefy red due to their high vascularity and contrast with any adjacent pale cerebellar tissue (picture 1).

Microscopically, the two main components of both sporadic and von Hippel-Lindau (VHL)-associated hemangioblastomas are an extensive vascular network and the neoplastic "stromal cells" (picture 2). The capillaries have a normal structure, including normal endothelial cells and pericytes. Neoplastic stromal cells, embedded among the vascular channels, have abundant cytoplasm packed with lipid vacuoles [16]. The numerous lipid-containing vacuoles, which often impinge on the nucleus and scallop its edges, result in the typical "clear cell" morphology. These cells also have large nuclei that are often pleomorphic and hyperchromatic. Such nuclei are considered a degenerative feature rather than a sign of histologic grade, malignant potential or transformation [17]. The mitotic rate is typically low. Where the tumor borders brain, it often forms intertwined small nodules with the host tissue and can occasionally manifest Rosenthal fibers in the adjacent tissue.

Many of the clear-cell morphologic features of hemangioblastomas overlap with those of renal cell carcinomas (RCCs). RCCs, however, do not show the intimate relationship with the host brain tissue that can be found in a subset of hemangioblastomas, such as the intertwined nodules of brain, but instead have a border pushing against normal tissue. Since RCC is also a frequent manifestation of VHL disease and is histologically similar to hemangioblastomas, immunoperoxidase studies are typically necessary to distinguish these tumors. Unlike RCCs, hemangioblastomas do not have an epithelial origin and so do not typically express cytokeratins or epithelial membrane antigen (EMA), nor do they express CD10, PAX-2, or PAX-8. Furthermore, hemangioblastomas usually display immunoreactivity to inhibin, neuron-specific enolase (NSE), neural cell adhesion molecule 1 (NCAM-1), carbonic anhydrase IX, and D2-40, unlike RCCs (picture 3) [18-22].

Retinal angiomas are hemangioblastomas that develop in the retina and within the optic nerve. If left untreated, retinal angiomas can hemorrhage, leading to retinal detachment, glaucoma, and loss of vision. Retinal angiomas are a frequent manifestation in patients with VHL disease. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Retinal capillary hemangioblastomas'.)

Molecular biology — Inactivation of the VHL tumor suppressor (VHL) gene, located on chromosome 3p, is involved in the pathogenesis of some sporadic as well as VHL-associated hemangioblastomas. Somatic mutations of the VHL gene and/or allelic deletion of the VHL gene may be present in as many as 50 percent of sporadic hemangioblastomas [23-26]. Gain-of-function mutations in hypoxia-inducible factor-2 alpha (HIF2A), which is regulated by VHL, have also been reported in sporadic tumors [27]. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Hemangioblastomas' and "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

The genetic changes are found in the stromal elements but not in the vasculature [24,28], suggesting that abnormal blood vessel formation might be caused by external factors produced by the stromal cells. In fact, expression of both erythropoietin and vascular endothelial growth factor (VEGF) is upregulated in the stromal cells of hemangioblastomas and may be involved in the pathogenesis of this disease [29].

TREATMENT — Hemangioblastomas are highly vascular tumors that are often located in neurologically sensitive areas in the neuraxis (picture 1). The anatomic location of the lesion plays an important role in determining the therapeutic approach. Patients are best managed in a multidisciplinary fashion with input from neurosurgeons, interventional neuroradiologists, radiation oncologists, and neurooncologists with expertise in central nervous system malignancies.

For patients with von Hippel-Lindau (VHL) disease, multiple tumors are common, and therapeutic efforts should focus on avoiding treatment-related morbidity by minimizing the frequency of surgical interventions. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Hemangioblastomas'.)

Women with existing retinal, brain, and spinal cord lesions are at risk for tumor growth during pregnancy [30]. A noncontrast magnetic resonance imaging (MRI) in the fourth month of pregnancy may be considered in these patients (see "Clinical features, diagnosis, and management of von Hippel-Lindau disease"). Neuroimaging findings, along with clinical signs and symptoms, may be used to make decisions regarding the management of labor and delivery. (See "Neurologic disorders complicating pregnancy", section on 'Brain tumors'.)

Both surgical resection and radiation therapy (RT) have a role in the management of appropriately selected patients with sporadic tumors. The hypoxia inducible factor-2alpha (HIF-2alpha) inhibitor, belzutifan, is an additional option in patients with VHL-associated hemangioblastomas.

Surgery — Surgical resection offers definitive therapy for sporadic, isolated hemangioblastomas, particularly those arising in the cerebellum. The role of surgery in patients with VHL disease is less well defined because of the frequent occurrence of additional synchronous and metachronous lesions.

Hemangioblastomas are highly vascular, and patients frequently need a preoperative angiogram to identify feeding arteries. For large lesions, embolization of feeding arteries with polymer microspheres, ethanol, or polyvinyl alcohol particles is typically performed prior to surgery (picture 4) [31-34]. Following preoperative embolization and using a microdissection technique with an intraoperative microscope, complete surgical resection of a hemangioblastoma is usually feasible with acceptable morbidity.

The following contemporary series illustrate the outcomes following surgery for patients with hemangioblastomas in the cerebellum, spinal cord, and brainstem:

●In a series from the National Institutes of Health (NIH), 80 patients with VHL underwent 126 operations, during which 164 cerebellar lesions were resected [35]. Surgery was based upon the presence of symptoms (most frequently headache, ataxia, dysmetria, and hydrocephalus in 75, 55, 29, and 28 percent, respectively). Symptoms improved or stabilized in 98 percent of cases. Follow-up imaging at five years did not document any instances of recurrence.

●In a Japanese series, 40 of 48 patients with VHL and hemangioblastomas of the spinal cord required surgery, including seven patients who required two operations [36]. Among the 48 patients, 46 (96 percent) had associated central nervous system lesions, primarily in the cerebellum. Resection of the spinal tumors resulted in improvement or stabilization of symptoms in 39 of 47 cases (83 percent).

●In a French series, 34 patients (25 with VHL disease, 9 with sporadic lesions) underwent 40 operations, in which a total of 74 hemangioblastomas were resected [37]. Tumors were located in the brainstem in 14 cases (19 percent) and the remainder were in the spinal cord, predominantly in the cervical and thoracic spine. At a mean follow-up of five years, 82 percent of patients were either improved or stabilized, while 18 percent were worse.

●In a Japanese series of 36 patients with sporadic hemangioblastomas, gross total resection of the tumor was achieved in 31 of 36 patients [38]. Younger age and cystic tumor characteristics were associated with a better prognosis. Notably, postoperative hemorrhage occurred in 4 of 19 patients with solid hemangioblastoma and in none of 17 patients with cystic tumors.

The optimal timing of surgery for patients with a hemangioblastoma is uncertain. The risks associated with operative management include intraoperative bleeding and postoperative neurologic complications.

The consensus among most neurosurgeons is to follow these patients with surveillance MRI scans of the neuraxis. If there is progression of neurologic symptoms, evidence of tumor or cyst growth, neurologic deficit, or hemorrhage, operative intervention should be considered.

Radiation therapy — Although there are no randomized clinical trials comparing RT with surgery in patients with hemangioblastomas, increasing data with relatively long follow-up support the role of RT, particularly for patients with multiple tumors and those with surgically inaccessible lesions [39]. Most of the contemporary data come from series using stereotactic radiosurgery (SRS), although external beam RT (EBRT) or proton beam RT may be useful in selected cases.

A systematic review of SRS treatment results published between 1990 and 2017 showed excellent tumor control at five-year follow-up [39].

Contemporary series illustrating the outcomes following RT include the following:

●In a series of 31 patients (26 with VHL), 92 intracranial and spinal hemangioblastomas were treated with SRS [40]. At a median follow-up of 69 months, 84 percent of tumors were either unchanged or smaller, and the five-year local control rate was 82 percent. Lesion-associated symptoms were improved in 36 of 41 evaluable cases (88 percent).

●In another series that included 32 patients (13 with VHL disease), 74 intracranial hemangioblastomas were treated with SRS [41]. On follow-up imaging, tumor control was achieved for 68 tumors (92 percent). Progression-free survival at five years was 90 percent.

●In a series of 18 patients (5 with VHL disease), 31 hemangioblastomas, including 20 in the cerebellum and 8 in the spinal cord, were treated with EBRT [42]. Indications for therapy included recurrence after surgery, residual disease following surgery, or definitive therapy of the lesion in 12, 4, and 2 cases, respectively. With a median follow-up of 5 years, the 5- and 10-year overall survival rates were 69 and 30 percent, respectively.

●In a series of 21 patients (7 sporadic and 14 VHL) who underwent SRS for 57 hemangioblastomas, the actuarial tumor control rates after SRS were 94 and 80 percent at 5 and 10 years, respectively [43]. Factors associated with longer tumor control on univariate analysis were solid tumor characteristics on imaging, small treatment volume, and tumors associated with VHL.

Antiangiogenic therapy — Because of the role of vascular endothelial growth factor (VEGF) in the formation of hemangioblastomas, inhibitors of angiogenesis (eg, bevacizumab) may offer a potential therapeutic approach for lesions not amenable to surgery or RT [44]. Preliminary experience with this approach has been derived from the treatment of patients with retinal angiomas. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Retinal capillary hemangioblastomas'.)

When to refer for genetic testing — All patients with more than one hemangioblastoma, the presence of other manifestations of VHL disease, or a family history of VHL should undergo genetic screening for germline VHL pathogenic variants (table 1). The likelihood of having a pathogenic variant in VHL varies inversely with age. Patients should be referred for appropriate genetic advice in conjunction with genetic testing. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Diagnosis'.)

Genetic screening is also suggested in patients with a single, seemingly sporadic hemangioblastoma, particularly those <50 years of age. In such patients, the likelihood of having a germline VHL pathogenic variant or mosaic VHL is approximately 5 percent [45]. The role of genetic testing, screening for related tumors, and surveillance (table 2) in these patients is discussed in more detail separately. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Hemangioblastomas'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

SUMMARY AND RECOMMENDATIONS

●Definition – Hemangioblastomas are uncommon, slow-growing tumors of the central nervous system, which most commonly occur in the cerebellum, brainstem, or spinal cord. (See 'Introduction' above.)

●Association with von Hippel-Lindau disease – Hemangioblastomas occur both sporadically and as a component of von Hippel-Lindau (VHL) disease. Tumors associated with VHL disease are more likely to be multiple and present at a younger age compared with sporadic tumors. (See 'Sporadic versus VHL-associated tumors' above.)

●Symptoms – Hemangioblastoma may be detected incidentally on imaging of the central nervous system (CNS), or they may come to attention based on neurologic deficits caused by direct compression, edema, or tumor-associated hemorrhage. (See 'Symptoms' above.)

●Neuroimaging – The characteristic magnetic resonance imaging (MRI) appearance of hemangioblastomas is an enhancing nodule associated with a cyst located in the cerebellum (image 1) or a homogeneously enhancing lesion on the surface of or within the spinal cord (image 2). (See 'Neuroimaging' above and 'Diagnostic evaluation' above.)

●Management

•Patients without known VHL disease – For patients without known VHL disease who present with a single suspected hemangioblastoma, we suggest surgery rather than observation both for treatment and to establish the diagnosis (Grade 2C). Radiation therapy (RT) is an option for recurrent or residual disease if the risk of reoperation is high. (See 'Treatment' above.)

•Patients with VHL disease – For patients with known VHL disease, treatment decisions should be individualized and involve multidisciplinary input from neurosurgery, oncology, and radiation oncology. Observation is appropriate in many patients with asymptomatic tumors, and the hypoxia inducible factor-2alpha (HIF-2alpha) inhibitor, belzutifan, is now an option that may delay or avoid the need for surgery or RT.

●Genetic testing – All patients with more than one hemangioblastoma, the presence of other manifestations of VHL disease, or a family history of VHL should undergo genetic screening for germline VHL pathogenic variants (table 1).

Genetic screening for VHL disease is also suggested in patients with a single hemangioblastoma without a family history of VHL, particularly those <50 years of age. The risk of VHL disease in such patients is approximately 5 percent. (See 'When to refer for genetic testing' above.)