Abstract
Hemangioblastomas are slow-growing but highly vascular tumors that arise in specific regions of the central nervous system (CNS) and the retina. Hemangioblastomas may occur as sporadic entities or as tumors associated with von Hippel–Lindau syndrome (vHL) in about 35–40 % of patients. vHL tumorigenesis can be mediated by both hypoxia-induced factor (HIF) and non-HIF-mediated mechanisms. The cell of origin in hemangioblastoma is an embryologically arrested hemangioblast derived from the mesoderm, which retains its multipotent properties and ability to differentiate into both red blood cells and blood vessel endothelium. Macroscopically, a hemangioblastoma is a well-circumscribed tumor, which has both solid and cystic components. The frequent sites of occurrence in the order of commonality are cerebellum, dorsal part of the spinal cord, brainstem, and retina. Surgical removal remains the treatment of choice.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Hemangioblastoma
- von Hippel–Lindau
- Tumor
- HIF-1α
- CNS and hemangioblastoma
- Genetics of hemangioblastoma
- CNS tumors
- Hemangioblastoma
Hemangioblastomas are slow-growing, but highly vascular tumors that arise in specific regions of the central nervous system (CNS) and retina. They constitute about 0.9 % of total brain tumors [1]. Hemangioblastomas may occur sporadically, or as tumors associated with von Hippel–Lindau syndrome (vHL) in about 35–40 % of patients [1–3]. In some series, as much as 80 % of hemangioblastomas are associated with vHL.
Genetics
vHL syndrome is associated with a germline mutation in the VHL gene on chromosome 3p25. However, according to the genetic “two-hit hypothesis” proposed by Knudson, tumorigenesis requires a second somatic inactivation of the other VHL allele.
Other than mutations in VHL, there is a paucity of data regarding other genetic hits in hemangioblastomas that might contribute to tumorigenesis. Sprenger et al. performed comparative genomic hybridization (CGH) of ten sporadic hemangioblastomas and found that the most common genetic aberrations in sporadic tumors are loss of chromosome 3 (70 %), loss of chromosome 6 (50 %), loss of chromosome 9 (30 %), loss of 18q (30 %), and gain of chromosome 19 (30 %). Based on the frequencies and co-occurrence of these genetic changes, they hypothesized that the loss of chromosome 3 is an early event in oncogenesis in sporadic hemangioblastomas, followed by loss of chromosome 6 and subsequently chromosomes 9 and 18q, and lastly by the gain of chromosome 19 [4]. In another study, CGH results of 7 vHL-associated and 16 sporadic hemangioblastomas were compared. Mutations in the VHL gene on 3p25-56 were found in 100 % of hereditary hemangioblastomas, but only in 30 % of sporadic tumors. Conversely, complete loss of chromosome 3 occurred more commonly in sporadic hemangioblastomas (69 %) than in vHL-associated hemangioblastomas (14 %). Thus, it can be concluded that sporadic mutation in the VHL gene is not the primary oncogenic event in sporadic hemangioblastomas [5].
Epigenetic and other means of somatic inactivation of VHL are also being investigated. It has been proposed that inactivation of promoter CpG islands, due to hypermethylation, leads to transcriptional silencing of VHL [6].
Prowse et al. examined 53 vHL-related tumors, including 30 renal cell carcinomas (RCCs), 15 hemangioblastomas, 5 pheochromocytomas and 3 pancreatic tumors, for genetic changes such as LOH (loss of heterozygosity), intragenic somatic mutations as well as DNA hypermethylation. In this series, hypermethylation of the vHL gene was detected in 33 % of tumors (6 out of 18 tumors; 2 RCCs and 4 hemangioblastomas). Two tumors, both hemangioblastomas, showed intragenic somatic mutations in a wild-type gene [6].
In a subsequent study, Rickert et al. performed CGH of 20 hemangioblastomas (one vHL and the remainder sporadic), which revealed that the most common cytogenetic changes associated with hemangioblastomas include the loss of chromosomes 19, 6, and 22q, which are seen in 35 %, 30 %, and 15 % of patients, respectively, and the loss of chromosome 6 being significantly associated with the cellular variant. Loss of chromosome 3 was uncommon in this series of sporadic hemangioblastomas, in contrast to the earlier studies by Sprenger et al. [7].
Lemeta et al. suggested that LOH at 6q is common and concurrent with 3p loss in sporadic hemangioblastomas [8]. This finding was subsequently confirmed by other studies [4, 7, 9]. The same authors subsequently demonstrated high prevalence of LOH at the ZAC-1 tumor suppressor gene region located on 6q24-25. Moreover, they also demonstrated that promoter methylation of ZAC-1 leads to epigenetic silencing of the gene in 90 % of tumors [10].
CGH has demonstrated that the reticular and cellular variants of hemangioblastoma have different cytogenetic profiles, with the loss of chromosome 6 significantly associated with the cellular variants [7].
Pathogenesis
vHL tumorigenesis can be mediated by both hypoxia-induced factor (HIF) and non-HIF-mediated mechanisms. HIF-1 is a heterodimeric transcriptional factor that regulates genes which respond to changes in oxygen levels in tissues [11, 12]. It is composed of HIF-1α and HIF-1β subunits [13]. Levels of HIF-1α are upregulated under hypoxic conditions and, by translocation into the nucleus and dimerization with HIF-1β, activate genes that promote angiogenesis (VEGF), erythropoiesis (EPO), nitric oxide synthesis (NOS), and glucose transport (GLUT-1). However, under normoxic conditions, HIF-1α undergoes ubiquitin-mediated degradation in the proteosomes, which are mediated by vHL protein [14–19]. The vHL protein binds to HIF-1α only after it undergoes oxygen-dependent hydroxylation of the proline residues 402 or 564 or both by members of the Elongin family (EG1N) [15, 18–21]. EG1N1 is the primary HIF-1 hydroxylase while EG1N2 and EG1N3 play compensatory roles under certain conditions [22]. However, when vHL is mutated, HIF-1α will not undergo degradation and remains constitutionally active [23]. This promotes tumorigenesis by increased transcriptional activation of genes that promote angiogenesis and other growth factors.
It has also been demonstrated that vHL is critical for cellular [24] differentiation during development and its inactivation causes developmental arrest [25] and protracted cellular differentiation [26]. The cell of origin in hemangioblastoma is an embryologically arrested hemangioblast derived from the mesoderm, which retains its multipotent properties and ability to differentiate into both red blood cells and blood vessel endothelium [27, 28]. Accordingly, foci of extramedullary hematopoeisis have been detected in hemangioblastomas. Vortmeyer et al. have detected the presence of fetal hemoglobin in these areas of extramedullary hematopoeisis, suggesting that the vHL deletion leads to primitive hematopoeisis [25, 26]. Moreover, co-expression of Epo and Epo receptor on these hemangioblasts represents a key event in vHL deficiency and further promotes tumor growth via autocrine and paracrine stimulation [25]. Developmentally arrested structural elements composed of hemangioblast progenitor cells have been demonstrated in the cerebella of VHL-mutated patients [29]. Hemangioblastic activity in the nervous system occurs in the embryonic stage [30] and hence its presence in adult brain depicts persistence of developmentally arrested hemangioblastic cells. vHL disease produces developmental aberrations giving rise to angiomesenchymal tumorlets resembling hemangioblastomas in the human CNS [31]. More recently, the pleuripotent vHL deficient cells in hemangioblastomas have been demonstrated to give rise to mast cells via the c-Kit signaling pathway. Accordingly, mast cells from tumor samples of patients exhibited LOH in the VHL alleles when compared with the peripheral blood lymphocytes [32].
Pathology
Macroscopically, hemangioblastoma is a well-circumscribed tumor, with both solid and cystic components. The tumor appears yellow in color due to its high lipid content.
Microscopically, the tumor has two components: a network of capillaries lined by hyperplastic endothelial cells with intervening vacuolated stromal cells, which have pale cytoplasms, pleomorphic nuclei and high lipid content. Mitoses are conspicuously absent [33]. A recent study of 156 tumors reports that tumor architecture relates to the size of the tumor; with smaller tumors (<8 mm3) composed of mesenchymal architecture comprising of a network of capillaries, while the larger tumors composed of enlarged stromal cells clustered in groups (Fig. 14.1) [26]. The stromal cell, which is the tumor cell in hemangioblastoma, is an embryologically arrested hemangioblast derived from the mesoderm that retains its multipotent properties as well as the ability to differentiate into both red blood cells and blood vessel endothelium. The stromal cells are immunoreactive for cytokeratin, S-100, NSE (neuron specific enolase), actin, GFAP (glial fibrillary acid protein), vimentin, and EMA (epithelial membrane antigen). The stromal and capillary endothelial cells express different surface adhesion molecules suggesting different cells of origin. The capillary endothelial cells express endothelium associated adhesion molecules such as ICAM-1, ICAM-2, PECAM, ELAM, and VCAM-1. The stromal cells express neuronal cell adhesion molecule (NCAM), which further supports its mesenchymal origin. Since NCAM is also expressed by metastatic renal cell cancer to the CNS, its expression by hemangioblastoma can present as a diagnostic challenge [34, 35]. The stromal cells also stain negatively for von Willebrand factor, a marker of endothelial origin [36]. Brachyury, a protein transcription product of the T box gene, which regulates the formation of mesoderm, is expressed in the cytoplasm of stromal cells and is highly specific for hemangioblastoma, distinguishing it from morphologically similar lesions such as metastatic clear cell renal cell cancer and angiomatous meningioma [37, 38].
Histologically, hemangioblastomas are classified into two variants: the more common reticular variant (composed of proliferating vascular elements) and the rare cellular variant (composed of epitheloid clusters of stromal cells), which are associated with greater GFAP positivity, higher proliferation index, and probability of recurrence [39].
Receptors for cellular growth factors including pro-angiogenic factors, such as epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), placental growth factor receptor (PFG-1), and vascular endothelial growth factor receptor (VEGF), are expressed on tumor cells in hemangioblastomas [40]. However, unlike malignant gliomas, the VEGF expression does not correlate with the vascular density as indicated by the expression of CD34-positive endothelial cells. This suggests that pro-angiogenic factors other than VEGF probably contribute to the intense tumor vascularity [41].
Clinical Features
Hemangioblastomas most commonly arise in the CNS especially, but not exclusively, in the posterior fossa. The frequent sites of occurrence in the order of commonality are cerebellum, dorsal part of the spinal cord, brainstem, and retina (Figs. 14.2 and 14.3) [42–44]. The most common site of occurrence of hemangioblastomas in the spinal cord is the thoracic region, followed by cervical and lumbar (48 %, 36 % and 16 %, respectively) [45]. Spinal cord and brainstem hemangioblastomas are frequently associated with tumors at other sites and especially cerebellar hemangioblastomas; in turn, however, cerebellar hemangioblastomas are less frequently associated with tumors at the other sites, suggesting that the spinal cord/brainstem hemangioblastomas are the accompanying manifestation of the latter [46, 47]. Supratentorial (cerebral, sellar/suprasellar, intraventricular) hemangioblastomas are rare [48–50]. It is sometimes difficult to differentiate supratentorial hemangioblastoma from meningioma [38, 51]. Occasionally, hemangioblastomas may arise in extraneural sites such as bone, soft tissue, skin, liver, pancreas, and kidney [52–55].
One-third of hemangioblastomas are associated with the vHL syndrome. The spectrum of tumors [56] associated with vHL is broad and includes hemangioblastomas, renal cell carcinomas [57, 58], pheochromocytomas [59], extra-adrenal paragangliomas [60, 61], retinal angiomas [62–64], neuroendocrine pancreatic tumors [65–69], papillary cystadenomas of the epididymis [70] and broad uterine ligament [71], as well as endolymphatic sac tumors (ELSTs) of the middle ear [72–74]. vHL-mutated patients with hemangioblastomas are generally younger and present with multiple tumors, while the non-vHL-associated tumors are seen in older patients and are usually solitary.
Based on clinical manifestations, vHL is classified into type 1 and type 2. Type 1 vHL is not associated with pheochromocytoma while type 2 is. Type 2 is further divided into type 2A, 2B, and 2C. vHL-type 2b is associated with high incidence of hemangioblastoma and pheochromocytoma [44, 75–77].
Since patients with vHL syndrome are predisposed to developing multiple hemangioblastomas and require specialized surveillance and treatment, it is imperative to correctly diagnose vHL as early as possible. Genetic testing for vHL in addition to a comprehensive family history should be considered standard practice for all patients with CNS hemangioblastomas, especially those diagnosed under 30 years of age. Clinical screening of vHL-associated tumors consists of complete neuraxis imaging with magnetic resonance imaging (MRI) of the brain and entire spine, MRI of the abdomen, retinoscopy, and measurement of urine catecholamines. Some authors have suggested ophthalmologic screening for family members of vHL disease for early detection of retinal hemangioblastomas [78].
Hemangioblastomas are considered benign tumors, but can cause significant neurological deficits depending on their size and location. Headache, vomiting, cerebellar symptoms, and cranial nerve involvement may be the presenting features. Posterior fossa tumors can also cause cerebrospinal fluid (CSF) flow obstruction leading to hydrocephalus [79, 80]. Patients with spinal cord tumors may present with progressive scoliosis and radicular symptoms until the tumor is large enough to cause weakness. Onset of retinal hemangioblastomas can start prior to 10 years of age until 30 years, after which the risk gradually decreases. It usually presents with unilateral involvement [77]. Hemangioblastomas exhibit a stuttering growth pattern, i.e., there are periods of growth followed by periods of quiescence, which may be as long as 2 years. Indications for treatment relate to the patient’s symptoms and tumor size, location, and rate of progression [81]. It is quite common for spinal cord hemangioblastomas to present with syrinx formation [82]. Occurrence of erythrocytosis with male predominance is common in hemangioblastomas due to production of erythropoietin [83, 84]. Due to their arteriovenous malformation-like vascularization, solid hemangioblastomas present a unique neurosurgical challenge [85].
There have been numerous clinical reports of worsening of vHL-associated hemangioblastomas in pregnancy, leading to progressive neurological deficits and obstructive hydrocephalus [86–90]. However, in the first prospective study comparing the rate of tumor growth in pregnant versus the nonpregnant cohorts with vHL-associated hemangioblastomas, Ye et al. observed that there were no differences in tumor growth rate, peritumoral cyst growth and the need for surgery. However, this was a small study with only 27 patients in the pregnancy cohort and it is possible that patients who chose to become pregnant were already in a better state of health leading to selection bias [91].
Imaging
Hemangioblastomas show post-contrast enhancement on computed tomogram (CT) scans and T1-weighed MRI. Imaging studies show the typical appearance of a cyst with mural nodule in approximately 60 % of cases. The nodular portion shows flow voids in the T1 and T2-weighted sequences. Generally, the cysts are slightly hyperintense compared to CSF in T1-weighted images. Both the nodule and the cyst appear bright on T2 and fluid attenuated inversion recovery (FLAIR) sequences [92].
Treatment
While most neurosurgeons agree that surgical intervention of symptomatic hemangioblastomas is required, controversy arises in dealing with asymptomatic hemangioblastomas, which commonly occur in patients with vHL syndrome. Unlike other benign intracranial tumors that exhibit a slow, progressive growth pattern, hemangioblastomas often have prolonged periods of growth arrest, thus making their natural course difficult to predict [81]. For asymptomatic, radiographically stable tumors, no treatment may be recommended. When asymptomatic tumors show progression on imaging only, the best time for intervention may be difficult to determine [93–96]. Similar to patients with other tumor predisposition syndromes, the optimal clinical management of vHL requires a specialist who oversees and coordinates a multidisciplinary plan of care, including appropriate screening tests.
From a therapeutic perspective, surgical removal remains the treatment of choice for hemangioblastomas and has been successfully employed for cerebellar [97], spinal [98, 99], and brainstem [94, 100] hemangioblastomas. Preoperative cerebral angiography helps surgeons determine the nature of the tumor vascular supply. Following diagnostic imaging, pretreatment with dexamethasone for several days is generally recommended. Intraoperative bleeding increases with tumor size, making en bloc resection of larger tumors difficult. However, modern microsurgical techniques are used to identify feeding vessels and thus help minimize intraoperative bleeding. Dissection should be carried out along the external surface of the tumor in the gliotic brain-tumor interface, to avoid entering the tumor, thus preventing brisk hemorrhage from the hemangioblastoma. The tumor-associated cysts are non-neoplastic and consist of compressed glial tissue, which collapses on its own once the associated tumor is removed. Postoperative complications include temporary worsening of neurological deficits, new neurological deficits, which may or may not resolve during follow-up, cranial postoperative infection, hydrocephalus and aseptic meningitis [101]. A postoperative contrast-enhanced MRI is routinely obtained to verify extent of resection. If no residual is noted, tumor recurrence is rare.
More recently, stereotactic radiosurgery is also being employed with encouraging results especially in spinal hemangioblastomas [102–105]. One advantage of radiosurgery is the ability to treat multiple lesions in a single treatment setting. In a series of 9 patients with 20 spinal hemangioblastomas, 4-year tumor overall and solid tumor control rates with stereotactic radiosurgery were as high as 90 % and 95 %, respectively [106]. In other studies, however, patients with multiple hemangioblastomas associated with vHL syndrome were found to less likely exhibit tumor control after treatment with radiation therapy compared to single sporadic hemangioblastomas [107, 108]. In general, smaller tumor volumes and higher doses of radiation (median 16 Gy) confer a better tumor control [109].
In contrast to surgery and radiation therapy, there is a paucity of data on systemic treatment of hemangioblastomas. Since hemangioblastomas are highly vascular, systemic anti-angiogenic therapies are being investigated as an alternative to surgery, particularly in vHL patients with multiple tumors. Several vHL patients have been treated with semaxanib, a multi-tyrosine kinase inhibitor predominantly active against VEGFR-2. Although disease stabilization outside the CNS was observed in some patients, most of the treatment responses were limited to retinal hemangioblastomas [110]. In a clinical trial for vHL patients with sunitinib, which predominantly targets VEGFR and PDGFR, antitumor activity was seen against renal cell carcinoma, but not hemangioblastomas [111]. EGFR, which is overexpressed and activated in hemangioblastomas, represents an additional attractive target for therapeutic intervention and study in future clinical trials [112]. There have been case reports on the use of anti-angiogenic agents such as bevacizumab [113], pazopanib [114], sunitinib [115], thalidomide [116], and interferon [117] with limited success. However, no prospective clinical trials using these agents have been conducted to date.
Prognosis
Gross total tumor resection was a predictor of prolonged progression-free survival (PFS) in one series [118]. Poor prognostic factors include poor performance status [101], multiple hemangioblastomas, retinal hemangioblastomas, and presence of solid rather than cystic tumors. The risk of recurrence in the future is higher if the age of diagnosis is younger than 40 years with primary sites being the brainstem and spinal cord [119].
References
Surawicz TS, Mccarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG. Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990–1994. Neuro Oncol. 1999;1:14–25.
Richard S, Beigelman C, Gerber S, van Effenterre R, Gaudric A, Sahel M, Binaghi M, DE Kersaint-Gilly A, Houtteville JP, Brunon JP, et al. Does hemangioblastoma exist outside von Hippel-Lindau disease? Neurochirurgie. 1994;40:145–54.
Sora S, Ueki K, Saito N, Kawahara N, Shitara N, Kirino T. Incidence of von Hippel-Lindau disease in hemangioblastoma patients: the University of Tokyo Hospital experience from 1954–1998. Acta Neurochir (Wien). 2001;143:893–6.
Sprenger SH, Gijtenbeek JM, Wesseling P, Sciot R, van Calenbergh F, Lammens M, Jeuken JW. Characteristic chromosomal aberrations in sporadic cerebellar hemangioblastomas revealed by comparative genomic hybridization. J Neurooncol. 2001;52:241–7.
Gijtenbeek JM, Jacobs B, Sprenger SH, Eleveld MJ, van Kessel AG, Kros JM, Sciot R, van Calenbergh F, Wesseling P, Jeuken JW. Analysis of von hippel-lindau mutations with comparative genomic hybridization in sporadic and hereditary hemangioblastomas: possible genetic heterogeneity. J Neurosurg. 2002;97:977–82.
Prowse AH, Webster AR, Richards FM, Richard S, Olschwang S, Resche F, Affara NA, Maher ER. Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Am J Hum Genet. 1997;60:765–71.
Rickert CH, Hasselblatt M, Jeibmann A, Paulus W. Cellular and reticular variants of hemangioblastoma differ in their cytogenetic profiles. Hum Pathol. 2006;37:1452–7.
Lemeta S, Pylkkanen L, Sainio M, Niemela M, Saarikoski S, Husgafvel-Pursiainen K, Bohling T. Loss of heterozygosity at 6q is frequent and concurrent with 3p loss in sporadic and familial capillary hemangioblastomas. J Neuropathol Exp Neurol. 2004;63:1072–9.
Lemeta S, Salmenkivi K, Pylkkanen L, Sainio M, Saarikoski ST, Arola J, Heikkila P, Haglund C, Husgafvel-Pursiainen K, Bohling T. Frequent loss of heterozygosity at 6q in pheochromocytoma. Hum Pathol. 2006;37:749–54.
Lemeta S, Jarmalaite S, Pylkkanen L, Bohling T, Husgafvel-Pursiainen K. Preferential loss of the nonimprinted allele for the ZAC1 tumor suppressor gene in human capillary hemangioblastoma. J Neuropathol Exp Neurol. 2007;66:860–7.
Lonergan KM, Iliopoulos O, Ohh M, Kamura T, Conaway RC, Conaway JW, Kaelin Jr WG. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol Cell Biol. 1998;18:732–41.
Simon MC, Keith B. The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol. 2008;9:285–96.
Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995;270:1230–7.
Kaelin Jr WG. The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Biophys Res Commun. 2005;338:627–38.
Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci U S A. 2000;97:10430–5.
Semenza GL. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol. 2009;19:12–6.
Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem. 2000;275:25733–41.
Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 2000;19:4298–309.
Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000;2:423–7.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin Jr WG. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.
Kaelin WG. Proline hydroxylation and gene expression. Annu Rev Biochem. 2005;74:115–28.
Kaelin Jr WG. Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases. Cold Spring Harb Symp Quant Biol. 2011;76:335–45.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–5.
Haase VH. The VHL tumor suppressor in development and disease: functional studies in mice by conditional gene targeting. Semin Cell Dev Biol. 2005;16:564–74.
Vortmeyer AO, Frank S, Jeong SY, Yuan K, Ikejiri B, Lee YS, Bhowmick D, Lonser RR, Smith R, Rodgers G, Oldfield EH, Zhuang Z. Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res. 2003;63:7051–5.
Shively SB, Beltaifa S, Gehrs B, Duong H, Smith J, Edwards NA, Lonser R, Raffeld M, Vortmeyer AO. Protracted haemangioblastic proliferation and differentiation in von Hippel-Lindau disease. J Pathol. 2008;216:514–20.
Park DM, Zhuang Z, Chen L, Szerlip N, Maric I, Li J, Sohn T, Kim SH, Lubensky IA, Vortmeyer AO, Rodgers GP, Oldfield EH, Lonser RR. von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med. 2007;4:e60.
Glasker S, Smith J, Raffeld M, Li J, Oldfield EH, Vortmeyer AO. VHL-deficient vasculogenesis in hemangioblastoma. Exp Mol Pathol. 2014;96(2):162–7.
Shively SB, Falke EA, Li J, Tran MG, Thompson ER, Maxwell PH, Roessler E, Oldfield EH, Lonser RR, Vortmeyer AO. Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease. Mod Pathol. 2011;24:1023–30.
Gering M, Rodaway AR, Gottgens B, Patient RK, Green AR. The SCL gene specifies haemangioblast development from early mesoderm. EMBO J. 1998;17:4029–45.
Vortmeyer AO, Yuan Q, Lee YS, Zhuang Z, Oldfield EH. Developmental effects of von Hippel-Lindau gene deficiency. Ann Neurol. 2004;55:721–8.
Merrill MJ, Edwards NA, Lonser RR. Hemangioblastoma-associated mast cells in von Hippel-Lindau disease are tumor derived. Blood. 2013;121:859–60.
Frosch MP, A. D., Girolami UD 2010. The central nervous system. In: Perkins, J. (ed.) Robbins and Cotran Pathologic Basis of Disease, Eighth Edition.
Bohling T, Maenpaa A, Timonen T, Vantunen L, Paetau A, Haltia M. Different expression of adhesion molecules on stromal cells and endothelial cells of capillary hemangioblastoma. Acta Neuropathol. 1996;92:461–6.
Omulecka A, Lach B, Alwasiak J, Gregor A. Immunohistochemical and ultrastructural studies of stromal cells in hemangioblastoma. Folia Neuropathol. 1995;33:41–50.
Mccomb RD, Jones TR, Pizzo SV, Bigner DD. Localization of factor VIII/von Willebrand factor and glial fibrillary acidic protein in the hemangioblastoma: implications for stromal cell histogenesis. Acta Neuropathol. 1982;56:207–13.
Barresi V, Vitarelli E, Branca G, Antonelli M, Giangaspero F, Barresi G. Expression of brachyury in hemangioblastoma: potential use in differential diagnosis. Am J Surg Pathol. 2012;36:1052–7.
Takeuchi H, Hashimoto N, Kitai R, Kubota T. A report of supratentorial leptomeningeal hemangioblastoma and a literature review. Neuropathology. 2008;28:98–102.
Hasselblatt M, Jeibmann A, Gerss J, Behrens C, Rama B, Wassmann H, Paulus W. Cellular and reticular variants of haemangioblastoma revisited: a clinicopathologic study of 88 cases. Neuropathol Appl Neurobiol. 2005;31:618–22.
Bohling T, Hatva E, Kujala M, Claesson-Welsh L, Alitalo K, Haltia M. Expression of growth factors and growth factor receptors in capillary hemangioblastoma. J Neuropathol Exp Neurol. 1996;55:522–7.
Vaquero J, Zurita M, Coca S, Salas C, Oya S. Expression of vascular endothelial growth factor in cerebellar hemangioblastomas does not correlate with tumor angiogenesis. Cancer Lett. 1998;132:213–7.
Constans JP, Meder F, Maiuri F, Donzelli R, Spaziante R, DE Divitiis E. Posterior fossa hemangioblastomas. Surg Neurol. 1986;25:269–75.
Stein AA, Schilp AO, Whitfield RD. The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg. 1960;17:751–61.
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. von Hippel-Lindau disease. Lancet. 2003;361:2059–67.
Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg. 2003;98:82–94.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, Mcfadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.
Mills SA, Oh MC, Rutkowski MJ, Sughrue ME, Barani IJ, Parsa AT. Supratentorial hemangioblastoma: clinical features, prognosis, and predictive value of location for von Hippel-Lindau disease. Neuro Oncol. 2012;14:1097–104.
Lonser RR, Butman JA, Kiringoda R, Song D, Oldfield EH. Pituitary stalk hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2009;110:350–3.
Neumann HP, Eggert HR, Scheremet R, Schumacher M, Mohadjer M, Wakhloo AK, Volk B, Hettmannsperger U, Riegler P, Schollmeyer P, et al. Central nervous system lesions in von Hippel-Lindau syndrome. J Neurol Neurosurg Psychiatry. 1992;55:898–901.
Peyre M, David P, van Effenterre R, Francois P, Thys M, Emery E, Redondo A, Decq P, Aghakhani N, Parker F, Tadie M, Lacroix C, Bhangoo R, Giraud S, Richard S. Natural history of supratentorial hemangioblastomas in von Hippel-Lindau disease. Neurosurgery. 2010;67:577–87; discussion 587.
Sharma RR, Cast IP, O’brien C. Supratentorial haemangioblastoma not associated with Von Hippel Lindau complex or polycythaemia: case report and literature review. Br J Neurosurg. 1995;9:81–4.
Jiang JG, Rao Q, Xia QY, Tu P, Lu ZF, Shen Q, Zhang RS, Yu B, Zhou XJ, Shi SS, Shi QL. Sporadic hemangioblastoma of the kidney with PAX2 and focal CD10 expression: report of a case. Int J Clin Exp Pathol. 2013;6:1953–6.
Nonaka D, Rodriguez J, Rosai J. Extraneural hemangioblastoma: a report of 5 cases. Am J Surg Pathol. 2007;31:1545–51.
Deb P, Pal S, Dutta V, Srivastava A, Bhargava A, Yadav KK. Adrenal haemangioblastoma presenting as phaeochromocytoma: a rare manifestation of extraneural hemangioblastoma. Endocr Pathol. 2012;23:187–90.
Rao Q, Chen JY, Wang JD, Ma HH, Zhou HB, Lu ZF, Zhou XJ. Renal cell carcinoma in children and young adults: clinicopathological, immunohistochemical, and VHL gene analysis of 46 cases with follow-up. Int J Surg Pathol. 2011;19:170–9.
Frantzen C, Links, TP, Giles, RH. 1993 Von Hippel-Lindau Disease. GeneReviews® [Internet]. 1993–2014. 2000.
Seizinger BR, Rouleau GA, Ozelius LJ, Lane AH, Farmer GE, Lamiell JM, Haines J, Yuen JW, Collins D, Majoor-Krakauer D, et al. Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature. 1988;332:268–9.
Fleming S. Genetics of kidney tumours. Forum (Genova). 1998;8:176–84.
Kolackov K, Tupikowski K, Bednarek-Tupikowska G. Genetic aspects of pheochromocytoma. Adv Clin Exp Med. 2012;21:821–9.
Raygada M, Pasini B, Stratakis CA. Hereditary paragangliomas. Adv Otorhinolaryngol. 2011;70:99–106.
Burnichon N, Abermil N, Buffet A, Favier J, Gimenez-Roqueplo AP. The genetics of paragangliomas. Eur Ann Otorhinolaryngol Head Neck Dis. 2012;129:315–8.
Salazar R, Gonzalez-Castano C, Rozas P, Castro J. Retinal capillary hemangioma and von Hippel-Lindau disease: diagnostic and therapeutic implications. Arch Soc Esp Oftalmol. 2011;86:218–21.
Mettu P, Agron E, Samtani S, Chew EY, Wong WT. Genotype-phenotype correlation in ocular von Hippel-Lindau (VHL) disease: the effect of missense mutation position on ocular VHL phenotype. Invest Ophthalmol Vis Sci. 2010;51:4464–70.
Wong WT, Agron E, Coleman HR, Tran T, Reed GF, Csaky K, Chew EY. Clinical characterization of retinal capillary hemangioblastomas in a large population of patients with von Hippel-Lindau disease. Ophthalmology. 2008;115:181–8.
Speisky D, Duces A, Bieche I, Rebours V, Hammel P, Sauvanet A, Richard S, Bedossa P, Vidaud M, Murat A, Niccoli P, Scoazec JY, Ruszniewski P, Couvelard A. Molecular profiling of pancreatic neuroendocrine tumors in sporadic and Von Hippel-Lindau patients. Clin Cancer Res. 2012;18:2838–49.
Lecumberri Pascual E. [Associated gastroenteropancreatic neuroendocrine tumours to familiar syndromes]. Endocrinol Nutr. 2009;56 Suppl 2:10–5.
Erlic Z, Ploeckinger U, Cascon A, Hoffmann MM, von Duecker L, Winter A, Kammel G, Bacher J, Sullivan M, Isermann B, Fischer L, Raffel A, Knoefel WT, Schott M, Baumann T, Schaefer O, Keck T, Baum RP, Milos I, Muresan M, Peczkowska M, Januszewicz A, Cupisti K, Tonjes A, Fasshauer M, Langrehr J, von Wussow P, Agaimy A, Schlimok G, Lamberts R, Wiech T, Schmid KW, Weber A, Nunez M, Robledo M, Eng C, Neumann HP. Systematic comparison of sporadic and syndromic pancreatic islet cell tumors. Endocr Relat Cancer. 2010;17:875–83.
Shen HC, Adem A, Ylaya K, Wilson A, He M, Lorang D, Hewitt SM, Pechhold K, Harlan DM, Lubensky IA, Schmidt LS, Linehan WM, Libutti SK. Deciphering von Hippel-Lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations. PLoS One. 2009;4:e4897.
Starker LF, Carling T. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Curr Opin Oncol. 2009;21:29–33.
Glasker S, Tran MG, Shively SB, Ikejiri B, Lonser RR, Maxwell PH, Zhuang Z, Oldfield EH, Vortmeyer AO. Epididymal cystadenomas and epithelial tumourlets: effects of VHL deficiency on the human epididymis. J Pathol. 2006;210:32–41.
Shen T, Zhuang Z, Gersell DJ, Tavassoli FA. Allelic deletion of VHL gene detected in papillary tumors of the broad ligament, epididymis, and retroperitoneum in von Hippel-Lindau disease patients. Int J Surg Pathol. 2000;8:207–12.
Megerian CA, Mckenna MJ, Nuss RC, Maniglia AJ, Ojemann RG, Pilch BZ, Nadol Jr JB. Endolymphatic sac tumors: histopathologic confirmation, clinical characterization, and implication in von Hippel-Lindau disease. Laryngoscope. 1995;105:801–8.
Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, Lebovics R, Sledjeski K, Choyke PL, Zbar B, Linehan WM, Oldfield EH. Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA. 1997;277:1461–6.
Hamazaki S, Yoshida M, Yao M, Nagashima Y, Taguchi K, Nakashima H, Okada S. Mutation of von Hippel-Lindau tumor suppressor gene in a sporadic endolymphatic sac tumor. Hum Pathol. 2001;32:1272–6.
Tootee A, Hasani-Ranjbar S. Von hippel-lindau disease: a new approach to an old problem. Int J Endocrinol Metab. 2012;10:619–24.
Kaelin Jr WG. The von Hippel-Lindau gene, kidney cancer, and oxygen sensing. J Am Soc Nephrol. 2003;14:2703–11.
Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M, Ashida S. von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol. 2006;36:337–43.
Hasani-Ranjbar S, Amoli MM, Ebrahim-Habibi A, Haghpanah V, Hejazi M, Soltani A, Larijani B. Mutation screening of VHL gene in a family with malignant bilateral pheochromocytoma: from isolated familial pheochromocytoma to von Hippel-Lindau disease. Fam Cancer. 2009;8:465–71.
Kuwahara T, Muraki M, Kitamura S, Tuchiya N, Ninchoji T, Uemura K. A case of hydrocephalus with hypacusis due to hemangioblastoma. No Shinkei Geka. 1991;19:385–9.
Jeffreys R. Clinical and surgical aspects of posterior fossa haemangioblastomata. J Neurol Neurosurg Psychiatry. 1975;38:105–11.
Ammerman JM, Lonser RR, Dambrosia J, Butman JA, Oldfield EH. Long-term natural history of hemangioblastomas in patients with von Hippel-Lindau disease: implications for treatment. J Neurosurg. 2006;105:248–55.
Kanno H, Yamamoto I, Nishikawa R, Matsutani M, Wakabayashi T, Yoshida J, Shitara N, Yamasaki I, Shuin T. Spinal cord hemangioblastomas in von Hippel-Lindau disease. Spinal Cord. 2009;47:447–52.
Trimble M, Caro J, Talalla A, Brain M. Secondary erythrocytosis due to a cerebellar hemangioblastoma: demonstration of erythropoietin mRNA in the tumor. Blood. 1991;78:599–601.
Jeffreys RV, Napier JA, Reynolds SH. Erythropoietin levels in posterior fossa haemangioblastoma. J Neurol Neurosurg Psychiatry. 1982;45:264–6.
Rachinger J, Buslei R, Prell J, Strauss C. Solid haemangioblastomas of the CNS: a review of 17 consecutive cases. Neurosurg Rev. 2009;32:37–47; discussion 47–8.
Drapkin AJ, Rose WS. Cerebellar hemangioblastoma during pregnancy. Neurosurgery. 1989;24:298–9.
Delisle MF, Valimohamed F, Money D, Douglas MJ. Central nervous system complications of von Hippel-Lindau disease and pregnancy; perinatal considerations: case report and literature review. J Matern Fetal Med. 2000;9:242–7.
Erdogan B, Sen O, Aydin MV, Bagis T, Bavbek M. Cerebellar hemangioblastoma in pregnancy. A case report. J Reprod Med. 2002;47:864–6.
Hayden MG, Gephart R, Kalanithi P, Chou D. Von Hippel-Lindau disease in pregnancy: a brief review. J Clin Neurosci. 2009;16:611–3.
Kasarskis EJ, Tibbs PA, Lee C. Cerebellar hemangioblastoma symptomatic during pregnancy. Neurosurgery. 1988;22:770–2.
Ye DY, Bakhtian KD, Asthagiri AR, Lonser RR. Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease. J Neurosurg. 2012;117:818–24.
Raz E, Zagzag D, Saba L, Mannelli L, di Paolo PL, D’ambrosio F, Knopp E. Cyst with a mural nodule tumor of the brain. Cancer Imaging. 2012;12:237–44.
van Velthoven V, Reinacher PC, Klisch J, Neumann HP, Glasker S. Treatment of intramedullary hemangioblastomas, with special attention to von Hippel-Lindau disease. Neurosurgery. 2003;53:1306–13; discussion 1313–4.
Weil RJ, Lonser RR, Devroom HL, Wanebo JE, Oldfield EH. Surgical management of brainstem hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg. 2003;98:95–105.
Lonser RR, Weil RJ, Wanebo JE, Devroom HL, Oldfield EH. Surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg. 2003;98:106–16.
Vaganovs P, Bokums K, Miklasevics E, Plonis J, Zarina L, Geldners I, Gardovskis J, Vjaters E. Von hippel-lindau syndrome: diagnosis and management of hemangioblastoma and pheochromocytoma. Case Rep Urol. 2013;2013:624096.
Jagannathan J, Lonser RR, Smith R, Devroom HL, Oldfield EH. Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg. 2008;108:210–22.
Lonser RR, Oldfield EH. Microsurgical resection of spinal cord hemangioblastomas. Neurosurgery. 2005;57:372–6; discussion 372–6.
Mehta GU, Asthagiri AR, Bakhtian KD, Auh S, Oldfield EH, Lonser RR. Functional outcome after resection of spinal cord hemangioblastomas associated with von Hippel-Lindau disease. J Neurosurg Spine. 2010;12:233–42.
Wind JJ, Bakhtian KD, Sweet JA, Mehta GU, Thawani JP, Asthagiri AR, Oldfield EH, Lonser RR. Long-term outcome after resection of brainstem hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2011;114:1312–8.
Pavesi G, Feletti A, Berlucchi S, Opocher G, Martella M, Murgia A, Scienza R. Neurosurgical treatment of von Hippel-Lindau-associated hemangioblastomas: benefits, risks and outcome. J Neurosurg Sci. 2008;52:29–36.
Chang SD, Meisel JA, Hancock SL, Martin DP, Mcmanus M, Adler Jr JR. Treatment of hemangioblastomas in von Hippel-Lindau disease with linear accelerator-based radiosurgery. Neurosurgery. 1998;43:28–34; discussion 34–5.
Daly ME, Choi CY, Gibbs IC, Adler Jr JR, Chang SD, Lieberson RE, Soltys SG. Tolerance of the spinal cord to stereotactic radiosurgery: insights from hemangioblastomas. Int J Radiat Oncol Biol Phys. 2011;80:213–20.
Chang UK, Lee DH. Stereotactic radiosurgery for spinal neoplasms: current status and future perspective. J Neurosurg Sci. 2013;57:87–101.
Moss JM, Choi CY, Adler Jr JR, Soltys SG, Gibbs IC, Chang SD. Stereotactic radiosurgical treatment of cranial and spinal hemangioblastomas. Neurosurgery. 2009;65:79–85; discussion 85.
Selch MT, Tenn S, Agazaryan N, Lee SP, Gorgulho A, de Salles AA. Image-guided linear accelerator-based spinal radiosurgery for hemangioblastoma. Surg Neurol Int. 2012;3:73.
Sayer FT, Nguyen J, Starke RM, Yen CP, Sheehan JP. Gamma knife radiosurgery for intracranial hemangioblastomas—outcome at 3 years. World Neurosurg. 2011;75:99–105; discussion 45–8.
Asthagiri AR, Mehta GU, Zach L, Li X, Butman JA, Camphausen KA, Lonser RR, Lonser RR. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol. 2010;12:80–6.
Patrice SJ, Sneed PK, Flickinger JC, Shrieve DC, Pollock BE, Alexander 3rd E, Larson DA, Kondziolka DS, Gutin PH, Wara WM, Mcdermott MW, Lunsford LD, Loeffler JS, Loeffler JS. Radiosurgery for hemangioblastoma: results of a multiinstitutional experience. Int J Radiat Oncol Biol Phys. 1996;35:493–9.
Madhusudan S, Deplanque G, Braybrooke JP, Cattell E, Taylor M, Price P, Tsaloumas MD, Moore N, Huson SM, Adams C, Frith P, Scigalla P, Harris AL. Antiangiogenic therapy for von Hippel-Lindau disease. JAMA. 2004;291:943–4.
Matin SF, McCutcheon IE, Gombos DS, et al. Treatment of VHL patients with sunitinib: clinical outcomes and translational studies. J Clin Oncol. 2010;28:15s; suppl; abstr 3040.
Chen GJ, Karajannis MA, Newcomb EW, Zagzag D. Overexpression and activation of epidermal growth factor receptor in hemangioblastomas. J Neurooncol. 2010;99:195–200.
Riklin C, Seystahl K, Hofer S, Happold C, Winterhalder R, Weller M. Antiangiogenic treatment for multiple CNS hemangioblastomas. Onkologie. 2012;35:443–5.
Kim BY, Jonasch E, Mccutcheon IE. Pazopanib therapy for cerebellar hemangioblastomas in von Hippel-Lindau disease: case report. Target Oncol. 2012;7:145–9.
Reyes-Botero G, Gallego Perez-Larraya J, Sanson M. Sporadic CNS hemangioblastomatosis, response to sunitinib and secondary polycythemia. J Neurooncol. 2012;107:439–40.
Sardi I, Sanzo M, Giordano F, Buccoliero AM, Mussa F, Arico M, Genitori L. Monotherapy with thalidomide for treatment of spinal cord hemangioblastomas in a patient with von Hippel-Lindau disease. Pediatr Blood Cancer. 2009;53:464–7.
Niemela M, Maenpaa H, Salven P, Summanen P, Poussa K, Laatikainen L, Jaaskelainen J, Joensuu H. Interferon alpha-2a therapy in 18 hemangioblastomas. Clin Cancer Res. 2001;7:510–6.
Garces-AMBROSSI GL, Mcgirt MJ, Mehta VA, Sciubba DM, Witham TF, Bydon A, Wolinksy JP, Jallo GI, Gokaslan ZL. Factors associated with progression-free survival and long-term neurological outcome after resection of intramedullary spinal cord tumors: analysis of 101 consecutive cases. J Neurosurg Spine. 2009;11:591–9.
Kanno H, Kuratsu J, Nishikawa R, Mishima K, Natsume A, Wakabayashi T, Houkin K, Terasaka S, Shuin T. Clinical features of patients bearing central nervous system hemangioblastoma in von Hippel-Lindau disease. Acta Neurochir (Wien). 2013;155:1–7.
Acknowledgment
The authors thank Dr Ajax George, Department of Radiology, NYU Langone Medical Center, for providing MRI images.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this chapter
Cite this chapter
Singh, J.C., Zagzag, D. (2015). Hemangioblastoma. In: Karajannis, M., Zagzag, D. (eds) Molecular Pathology of Nervous System Tumors. Molecular Pathology Library, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1830-0_14
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1830-0_14
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-1829-4
Online ISBN: 978-1-4939-1830-0
eBook Packages: MedicineMedicine (R0)