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Hemangioblastoma

A hemangioblastoma is a benign neoplasm of vascular origin, most frequently detected in the cerebellum, sometimes also in the spinal cord or brain stem. While most hemangioblastomas occur sporadically, a significant share of cases is related to von Hippel-Lindau disease.


Presentation

Symptoms associated with central nervous HBA depend on their size and precise location. Progression of the clinical picture is further related to growth patterns of the tumor. Because HBA most commonly grow slow, patients are initially presented with mild to moderate neurologic deficits. Their situation continues to exacerbate until the diagnosis of HBA is finally made. In some cases, mild symptoms persist for prolonged periods of time and patients then deteriorate very quickly. Such events may partially be due to spontaneous hemorrhages and require urgent surgical attention [9].

In general, HBA may be associated with hydrocephalus and increased intracranial pressure that may provoke headaches, vomiting, distinct neurological symptoms and nystagmus, reduced consciousness and seizures. Most HBA are located in the cerebellum and these tumors frequently trigger typical symptoms of cerebellar dysfunction, i.e., ataxia, dysmetria, dysdiadochokinesis and asynergia. With regards to spinal cord HBA, pain is usually the dominant symptom. Segmental dysfunctions may be observed due to compression of the spinal cord.

Presence of additional neoplasms, notably affecting the retina, may dominate the clinical picture presented by patients suffering from von Hippel-Lindau disease.

Of note, laboratory analyses of blood samples of HBA patients often reveal polycythemia, but no further symptoms seem to be associated with this finding.

Prolonged Bleeding
  • MN: Mural nodule Surgery Three patients required an EVD placement preoperatively because of occlusive hydrocephalus and one patient intraoperatively because of prolonged bleeding into the fourth ventricle.[dx.doi.org]
Fishing
  • For further evidence of VHL deficiency, the tumor was subjected to VHL sequence analysis of all three exons and fluorescence in situ hybridization (FISH) detection for chromosome 3p deletion.[ncbi.nlm.nih.gov]
Respiratory Distress
  • She returned 3 months later with irritability, acute paraplegia, and respiratory distress. Magnetic resonance imaging (MRI) showed an intramedullary T8-T9 tumor with syringomyelia.[ncbi.nlm.nih.gov]
  • CASE HISTORY A 54-year-old female with known VHL presented to the emergency department with acute altered mental status, which was followed by respiratory distress requiring intubation.[surgicalneurologyint.com]
Nausea
  • As the symptoms such as severe nausea, vomiting and headache rarely continues with treatment, it is essential to consider brain tumors in differential diagnosis in cases with persistent nausea and vomiting.[imedpub.com]
  • […] rare disease Hemangioblastoma Disease definition Hemangioblastoma is a rare, benign, highly vascularized tumor of the central nervous system, most often located in the cerebellum or spinal cord, presenting in adulthood and manifesting with dizziness, nausea[orpha.net]
  • […] hemangioblastomas von Hippel-Lindau disease consists of Retinal, spinal, cerebellar and medullary hemangioblastomas Renal cysts and carcinomas Pancreatic cysts Pheochromocytomas Papillary Cystadenoma of the epididymis Clinical findings Headache Ataxia Nausea[learningradiology.com]
  • Typical symptoms of increased intracranial pressure are headache, nausea, vomiting, vision problems, and changes in behavior. Evaluation: Hemangioblastomas are best evaluated with MRI scans and, often, a cerebral angiogram before surgery.[ucdenver.edu]
Rectal Bleeding
  • A 75-year-old woman undergoing adjuvant chemotherapy for breast cancer experienced rectal bleeding. Colonoscopy revealed a roundish mass covered with normal mucosa in the sigmoid colon.[ncbi.nlm.nih.gov]
Vascular Disease
  • Diseases Cardiovascular Diseases Ciliopathies Abnormalities, Multiple Congenital Abnormalities Genetic Diseases, Inborn Hemangioma, Capillary Hemangioma Neoplasms, Vascular Tissue Neoplasms by Histologic Type Neoplasms Vatalanib Protein Kinase Inhibitors[clinicaltrials.gov]
  • MR angiography is expected to have higher sensitivity in the detection of spinal vascular disease than conventional MR imaging.[ajnr.org]
Orthostatic Hypotension
  • BACKGROUND: Orthostatic hypotension (OH) is an uncommon, but not rare manifestation of dorsal medullary lesions which has less commonly been described as arising de novo or significantly worsening following surgical resection of the lesion.[ncbi.nlm.nih.gov]
Rubeosis Iridis
  • Rubeosis iridis was not present in any of the eyes. CONCLUSION: Promising anatomical and visual outcomes were obtained after vitreoretinal surgery and resection of RCHs in eyes with complicated RD secondary to RCH.[ncbi.nlm.nih.gov]
Headache
  • A 27-year-old woman presented with sudden onset of headache, vomiting, and diplopia.[ncbi.nlm.nih.gov]
  • Some of these warning signs are headaches aggravated or relieved by assuming an upright or supine position; intracranial hemorrhage; headaches provoked by a Valsalva maneuver; sudden onset of headache; onset of headache after 50 years of age; papilledema[consultant360.com]
  • The patient again presented with nausea, vomiting and severe headache at the 35 th week of pregnancy follow-up.[imedpub.com]
Nystagmus
  • In general, HBA may be associated with hydrocephalus and increased intracranial pressure that may provoke headaches, vomiting, distinct neurological symptoms and nystagmus, reduced consciousness and seizures.[symptoma.com]
  • Neurological examination was remarkable for papilledema, horizontal nystagmus on the right, left lateral gazes, absent gag reflex, dysphagia, ataxic gait, and motor incoordination.[karger.com]
  • Nystagmus, especially with a vertical or rotatory component, signifies brain stem involvement. Occasionally in elderly patients, dementia may be the sole or major manifestation of the disease.[neurosurgery.me]
Irritability
  • She returned 3 months later with irritability, acute paraplegia, and respiratory distress. Magnetic resonance imaging (MRI) showed an intramedullary T8-T9 tumor with syringomyelia.[ncbi.nlm.nih.gov]
  • Vomiting, the next most common symptom, may be due either to obstructive hydrocephalus from a vermian lesion or to irritation of the vagal nucleus from the tumor's origin in the vicinity of this nucleus.[neurosurgery.me]
Reduced Consciousness
  • In general, HBA may be associated with hydrocephalus and increased intracranial pressure that may provoke headaches, vomiting, distinct neurological symptoms and nystagmus, reduced consciousness and seizures.[symptoma.com]

Workup

Because symptoms associated with HAB are rather unspecific, they may only prompt a strong suspicion for HAB in patients that have previously been diagnosed with von Hippel-Lindau disease. All patients, the former for diagnosis, the latter to assess the extent of the lesion and to prepare treatment, need to undergo extensive neurological examinations and imaging of the complete neural axis. Even if a cerebellar tumor is detected, there may be another one in the spinal cord. This applies particularly for von Hippel-Lindau disease patients.

Magnetic resonance imaging is the method of choice [10]. Such images clearly depict an enhanced mass, well circumscribed and delimited against adjacent tissues. Due to their fluid content, lesions often appear as hyperintense regions on T2-weighted images. Computed tomography may also be carried out and screens may be even more valuable when enhanced with contrast agents. Here, uniform enhancement of the neoplastic mass can be expected. Plain radiography is generally not recommended.

Angiography is a valuable tool to clarify blood supply to the tumor before taking any therapeutic decisions.

Laboratory analyses of blood samples do usually not reveal any characteristic alteration, but polycythemia may support the initial diagnosis.

Of note, any patient diagnosed with HAB should be tested for von Hippel-Lindau disease. A detailed ophthalmologic examination is necessary to evaluate the patient's retina. Also, abdominal imaging should be realized to detect a potentially present kidney tumor, pancreatic cyst or other associated diseases.

Mediastinal Mass
  • CASE DESCRIPTION: We report a rare case of a completely extradural large hemangioblastoma in a 32-year-old man presenting with radiculopathy and a posterior mediastinal mass. Screening revealed a similar tumor in the right cerebellar hemisphere.[ncbi.nlm.nih.gov]
Posterior Mediastinal Mass
  • CASE DESCRIPTION: We report a rare case of a completely extradural large hemangioblastoma in a 32-year-old man presenting with radiculopathy and a posterior mediastinal mass. Screening revealed a similar tumor in the right cerebellar hemisphere.[ncbi.nlm.nih.gov]

Treatment

HBA are benign tumors, grow slowly and usually not infiltratively. Thus, surgical excision is considered the best therapeutic option. Only if high risks are associated with the patient undergoing open surgery should other approaches be considered [11]. Radiation, for instance, may help to limit tumor growth and even reduce its size. To date, there is no drug therapy for HBA, although anti-angiogenic compounds are evaluated to this end [12].

In recent years, endovascular embolization has been increasingly employed as a pre-surgical technique to obliterate the tumor, decrease its perfusion, avoid hemorraghes during surgery and thus lower morbidity and mortality. The main challenge during surgery is to perform a complete resection with maximal preservation of adjacent, healthy tissue, in order to avoid recurrence and long-term sequelae. HBA are usually well circumscribed, but don't possess a capsule. The intrinsic pressure of the tumor may be reduced by fluid aspiration and this procedure will leave more room for manipulation without compromising health tissue. Despite extreme care, hemorrhages may be a severe problem during surgery and blood products should be available for transfusion.

After resection, tissue samples should be histopathologically analyzed. The above described, characteristic image of blood-filled lagoons lined by endothelial cells and interspersed in a fibrous stroma is to be expected in HAB samples. Endothelial cells may appear quite normal, but are often rather plump, carry compact nuclei and little cytoplasm. Many stroma cells are rich in lipids, their cytoplasm appears granular. They combine morphological features of endothelial cells, pericytes and smooth-muscle cells [13]. Mitotic figures are rarely seen, abnormal mitotic figures not at all.

Prognosis

During recent years, considerable improvements regarding diagnostic imaging, preoperative embolization and increasing use of microsurgical approaches have significantly lowered HBA-related morbidity and mortality. Today, prognosis for HBA patients is usually favorable. The overall recurrence rate has been repeatedly estimated to be below 25%.

Most HBA do not spread to adjacent tissues, but dissemination throughout neighboring meninges, notably in the subarachnoid space, have been observed and seem to negatively affect the outcome [6]. Further unfavorable prognostic factors are von Hippel-Lindau disease and multiple HBA, whereby these factors are mutually dependent, as well as young age. In such patients, the risk of recurrence is increased and entails possible functional deterioration in the long term [7]. Histopathological findings may allow for classification of HBA subtypes and may eventually permit a more individual prognosis of recurrence [8].

Etiology

The precise causes of HAB are not known. It has been suggested that genetic factors play a major role in HAB etiology and the fact that a significant share of patients presents not only HAB but other neoplasms within a cancer syndrome seems to support this theory. HAB are often developed by von Hippel-Lindau disease patients and for this syndrome as well as for some HAB, a loss-of-function mutation of the von Hippel-Lindau tumor suppressor protein has been demonstrated [2]. This protein is involved in regulation of transcription factor levels, indirectly affects gene expression and may therefore function as an oncogene. However, many sporadic HAB do not present this mutation and other factors, possibly genetic, seem to trigger tumor development here [3].

Epidemiology

HAB are rare tumors of the central nervous system. They account for up to 2.5% of all intracranial neoplasms, but with regards to cerebellum and brain stem, one out of ten such tumors is identified as HAB [4] [5].

Most HAB patients are young adults and incidence peaks slightly over 30 years of age. HAB are the most common neoplasms of cerebellum and brain stem in this age group. Of note, patients suffering from von Hippel-Lindau disease tend to develop HAB at younger ages. These patients constitute 20% of the overall number of HAB patients.

Men seem to be affected approximately twice as often as women.

Sex distribution
Age distribution

Pathophysiology

There is a general consensus that more than 80% of HAB affect the cerebellum. The next common sites for HAB development are spinal cord and brain stem, both accounting for far less than 10% of HAB cases. Sporadic HAB are usually solitary tumors, while multiple HAB are not unheard of in von Hippel-Lindau disease patients [3]. In both groups, HAB grow slowly as benign neoplasms with very little probability of development of metastases. The World Health Organization classified them as grade I tumors. However, tumor resection in the central nervous system does not allow for large safety margins and recurrence after incomplete removal is often seen.

HAB are well delimited, cystic or solid, dark red masses. Some HAB concentrate considerable amounts of lipids and thus take on a yellowish red color. Due to their vascular origin, it is little surprising that their appearance is often dominated by blood-filled caverns of different size, particularly in cystic HAB. These caverns become visible as blood-filled lagoons if observed with a microscope. They are irregularly surrounded by endothelial cells and pericytes that did not fully develop their physiological morphology, that appear rather plump. Lagoons are interspersed into a fibrous network, mainly of reticulin fiber. Cell density is high and there is a variety of morphologically different cells distributed throughout the stroma of the tumor. Lipid-laden cells may easily be recognized, but the precise origin of these interstitial cells has not yet been defined. They have been tested positive for astrocyte markers GFAP, S100 and vimentin, but these may rather stem from reactive astrocytes invading the site of lesion. It could be shown that these cells release vascular endothelial growth factor and thereby promote tumor growth.

Prevention

No preventive measures can be recommended.

Summary

Hemangioblastoma (HAB) are benign vascular neoplasms that presumably originate from pathologically altered capillaries of the pia mater, probably from precursor cells with potent angiogenic properties, and within their guide for tumors of the nervous system, the World Health Organization has classified HAB as meningeal tumors of uncertain origin [1]. Actually, they may be encountered anywhere in the body, but the vast majority of HAB is indeed detected in the central nervous system. About 80% of central nervous system HAB are located in the cerebellum, lesser shares are diagnosed in the spinal cord and brain stem. Some cases of HAB developing in the retina have been described and isolated case reports exist regarding HAB in peripheral nerves, pancreas, liver or kidney.

Nowadays, improved imaging techniques greatly facilitate HAB diagnosis and planning of therapeutic surgical approaches. This makes HAB a not less serious, but potentially curable disease.

Patient Information

Hemangioblastoma (HAB) are rare, benign tumors of vascular origin. They are usually classified as central nervous system tumors, because the vast majority of these neoplasms is located in distinct parts of the brain and spinal cord. Most patients diagnosed with HAB are aged 30 years and older, but this is not a typical neoplasm of the elderly, rather of young adults. Prognosis has considerably improved with widely available, high-resolution diagnostic imaging and more secure treatment options and today, HAB is considered a potentially curable disease.

Causes

Triggers of HAB development are not yet understood. While about 80% of HAB cases are considered sporadic ones, i.e., patients did not sustain any previous lesion or disorder, the remaining share of HAB patients suffers from von Hippel-Lindau disease. This is a genetic disorder leaving affected patients more susceptible to developing a wide variety of tumors, particularly in the central nervous system and the eyes. Von Hippel-Lindau disease has been related with a gene defect that leads to functional impairment of a regulatory protein. Such dysregulated cells may proliferate excessively and form neoplasms. Some HAB patients carry this same mutation.

Symptoms

HAB presumably originate from precursor cells involved in angiogenesis and while these cells exist in many organs, those present in the meninges, the thin, resistant layers covering the brain and the spinal cord, may be particularly prone for degeneration and tumor development. Thus, HAB are most often detected in these parts of the central nervous system, especially in cerebellum and spinal cord.

HAB ubicated in the brain may trigger unspecific symptoms such as headaches, dizziness, vomiting, neurological deficits, reduced consciousness and seizures. These result from increased intracranial pressure. Cerebellar dysfunction mainly manifests in form of poor balance and coordination. The dominant symptom of spinal cord HAB is pain. Loss of sensation in any of the lower parts of the body may be experienced.

Diagnosis

Anamnesis, clinical and neurological examination rarely raise suspicion for HAB, unless the patient has previously been diagnosed with von Hippel-Lindau disease. Diagnostic imaging needs to be applied to check both brain and spinal cord for possible alterations. Magnetic resonance imaging is the method of choice to detect HAB, which present as clearly delimited masses in cerebellum, spinal cord or other structures. Computed tomography may also be carried out. Supplemental diagnostics may be realized in order to prepare surgical intervention.

Of note, patients not yet diagnosed with von Hippel-Lindau disease will also be examined ophthalmologically and undergo abdominal screens to detect potentially present additional alterations that point at the aforementioned disease.

Treatment

The treatment of choice is surgical resection. Tumor perfusion may pre-surgically be reduced by carrying out endovascular embolization, i.e., obliteration of the tumor's blood vessels in a minimally invasive procedure. This helps to prevent hemorrhages during surgery.

Other, less promising treatment options will have to be found for patients unable to undergo surgery due to their own condition or a poorly accessible tumor.

References

Article

  1. Gonzales MF. Classification and pathogenesis of brain tumors. In: Kaye AH, Laws ER, eds. Brain Tumors. Vol 1. New York, NY: Churchill Livingstone; 1995:31-45.
  2. Zagzag D, Krishnamachary B, Yee H, et al. Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 2005; 65(14):6178-6188.
  3. Gläsker S, Bender BU, Apel TW, et al. Reconsideration of biallelic inactivation of the VHL tumour suppressor gene in hemangioblastomas of the central nervous system. J Neurol Neurosurg Psychiatry. 2001; 70(5):644-648.
  4. Farrukh HM. Cerebellar hemangioblastoma presenting as secondary erythrocytosis and aspiration pneumonia. West J Med. 1996; 164(2):169-171.
  5. Ho VB, Smirniotopoulos JG, Murphy FM, Rushing EJ. Radiologic-pathologic correlation: hemangioblastoma. AJNR Am J Neuroradiol. 1992; 13(5):1343-1352.
  6. Hande AM, Nagpal RD. Cerebellar haemangioblastoma with extensive dissemination. Br J Neurosurg. 1996; 10(5):507-511.
  7. Wind JJ, Bakhtian KD, Sweet JA, et al. Long-term outcome after resection of brainstem hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2011; 114(5):1312-1318.
  8. Hasselblatt M, Jeibmann A, Gerss J, et al. Cellular and reticular variants of haemangioblastoma revisited: a clinicopathologic study of 88 cases. Neuropathol Appl Neurobiol. 2005; 31(6):618-622.
  9. Gläsker S, Van Velthoven V. Risk of hemorrhage in hemangioblastomas of the central nervous system. Neurosurgery. 2005; 57(1):71-76; discussion 71-76.
  10. Lee SR, Sanches J, Mark AS, Dillon WP, Norman D, Newton TH. Posterior fossa hemangioblastomas: MR imaging. Radiology. 1989; 171(2):463-468.
  11. Yasargil MG, Antic J, Laciga R, de Preux J, Fideler RW, Boone SC. The microsurgical removal of intramedullary spinal hemangioblastomas. Report of twelve cases and a review of the literature. Surg Neurol. 1976; (3):141-148.
  12. Schuch G, de Wit M, Holtje J, et al. Case 2. Hemangioblastomas: diagnosis of von Hippel-Lindau disease and antiangiogenic treatment with SU5416. J Clin Oncol. 2005; 23(15):3624-3626.
  13. Lach B, Gregor A, Rippstein P, Omulecka A. Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and immunohistochemical study. Ultrastruct Pathol. 1999; 23(5):299-310.

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Last updated: 2019-07-11 21:47