This rare neoplasm is usually diagnosed within the cerebellum. However, rare cases have been diagnosed in the soft tissue and other organs.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/
Other Diagnostic Testing
and Clinical Variants
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS INCIDENCE/
DISEASE ASSOCIATIONS CHARACTERIZATION VON HIPPEL-LINDAU SYNDROME
PATHOGENESIS CHARACTERIZATION CYTOGENETICS
- Hum Pathol. 2006 Nov;37(11):1452-7. Epub 2006 Jul 26 Abstract quote
Capillary hemangioblastomas of the central nervous system are benign tumors and occur either sporadically or as a manifestation of von Hippel-Lindau disease. A rarer cellular and a more common reticular variant can be distinguished on the basis of the abundance of the stromal cell component, with the cellular variant being significantly associated with a greater probability of recurrence.
To investigate whether these subtypes differ in their cytogenetic profile, a comparative genomic hybridization analysis of 10 cellular and 10 reticular hemangioblastomas was undertaken. Comparative genomic hybridization revealed DNA copy number changes in 14 of 20 cases (8 of 10 cellular and 6 of 10 reticular hemangioblastomas). The most common changes overall were losses of chromosomes 19 (35%), 6 (30%), and 22q (15%), whereas loss of 3 and gain of 4 were encountered in one case each (5%). The cellular variant showed losses of chromosomes 6 (60%), 22q and 19 (20% each), as well as gain of 4 (10%), whereas the reticular variant presented with losses of chromosomes 19 (50%), 22q and 3 (10% each). Loss of chromosome 6 was significantly associated with the cellular subtype (P < .005), whereas loss of 19/19p was found more frequently in the reticular variant, albeit not significantly (P = .16).
In conclusion, our data may point toward different genetic pathways in the pathogenesis of the 2 histologic subtypes of capillary hemangioblastoma.
- Loss of heterozygosity reveals non-VHL allelic loss in hemangioblastomas at 22q13.
Beckner ME, Sasatomi E, Swalsky PA, Hamilton RL, Pollack IF, Finkelstein SD.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Hum Pathol. 2004 Sep;35(9):1105-11. Abstract quote
Hemangioblastomas (HBs) are low-grade (World Health Organization grade I/IV) central nervous system (CNS) tumors that frequently contain VHL (3p26) mutations. They occur sporadically and in von Hippel Lindau (VHL) disease. Encoded pVHL aids degradation of hypoxia-inducible factors (HIFs) in the presence of normal oxygen levels. HBs provide an in vivo view of HIF effects within a CNS tumor. Typically, HBs are cystic tumors containing a mural nodule formed by noninvasive, vacuolated stromal cells that are embedded in a network of capillaries.
Nine HBs, consecutively resected from 8 patients at our institution during a recent 2-year time span, were evaluated for additional losses of tumor suppressor genes. Non-VHL microsatellites studied for loss of heterozygosity (LOH) are near tumor suppressor genes lost in gliomas, pituitary adenomas, several CNS tumors on 22q, neurofibromatosis 1, and colon carcinomas (13, 2, 2, 1, and 2 markers for each, respectively). LOH in the region of 3p21.3-3p26.3 occurred in 3 of 8 HBs informative for at least 1 marker (D3S1539, D3S2303, or D3S2373). By using 2 markers (D22S417 and D22S532) for 22q13.2, LOH was found in 5 of 8 informative HBs. All 3 HBs with allelic losses near VHL also showed LOH at 22q13.2. No consistent losses were found with markers for 1p34, LMYC, 5q21, 5q32, 9p21, 10q23, 17p13, and 19q13. LOH for the 22q13.2 region in HBs suggests that the loss of another tumor suppressor gene is involved in the pathogenesis of HBs in addition to VHL.
Absence of LOH for glioma markers is consistent with the low-grade behavior of HBs
Hemangioblastoma: a study of radiopathologic correlation.
Sundaram C, Rammurti S, Reddy JJ, Prasad SS, Purohit AK.
Nizams Institute of Medical Sciences, Panjagutta, Hyderabad, India.
Neurol India. 2003 Sep;51(3):373-5. Abstract quote
Computerized tomography (CT) scan and operative observations, and histolopathogical findings of 25 cases of intracranial hemangioblastoma were correlated.
Solid hemangioblastomas showed a large number of thin-walled capillaries and abundant stromal cells with eosinophilic cytoplasm.
Tumors with a cystic component and a mural nodule had a large number of stromal cells with vacuolated cytoplasm and microcysts.
CHARACTERIZATION GENERAL VARIANTS CEREBELLUM Haemangioblastoma: a rare cause of a cerebellar mass in the elderly.
Gnanalingham KK, Apostolopoulos V, Chopra I, Mendoza N, Peterson D.
Department of Neurosurgery, Charing Cross Hospital, Fulham Palace Road, London, UK
Br J Neurosurg. 2003 Oct;17(5):461-4. Abstract quote
In the elderly, cerebellar lesions are commonly metastatic tumours with poor prognosis.
We describe two octogenarians who presented with obstructive hydrocephalus, secondary to posterior fossa tumours that, on computed tomography, were thought to be cerebellar metastases.
Both lesions were excised and the histology proved them to be cerebellar haemangioblastomas, primary benign tumours of the posterior fossa, which are rare in the elderly.
- Extraneural Hemangioblastoma: A Report of 5 Cases.
*Department of Pathology, New York University Medical Center, New York, NY †Oncologic Pathology Consultation Center, Italian Diagnostic Center, Milan, Italy.
- Am J Surg Pathol. 2007 Oct;31(10):1545-1551. Abstract quote
Hemangioblastoma is a morphologically distinctive tumor that can occur sporadically or in association with von Hippel-Lindau disease, and which involves the central nervous system in the majority of the cases. Rare occurrences of hemangioblastoma in peripheral nerves and extraneural tissues have been reported. The histogenesis of this tumor remains uncertain. Various cell lineages such as vascular, glial, neural, fibrohistiocytic, and smooth muscle/myofibroblastic have been proposed for the so-called stromal cells, which are thought to represent the neoplastic component of these lesions.
We report on 5 cases of hemangioblastoma arising in extraneural tissues. Two of the tumors were located in the presacral region, and one each in the maxilla, kidney, and adrenal glands. All 5 cases were morphologically indistinguishable from central nervous system hemangioblastoma.
The existence of these cases suggests that the "stromal" cells of hemangioblastoma can demonstrate a variety of mature specific lineages, such as smooth muscle/myofibroblastic, or neuroendocrine, depending on the location and possibly the microenvironment.
Leptomeningeal hemangioblastomatosis in a case of von Hippel-Lindau disease: case report.
Reyns N, Assaker R, Louis E, Lejeune JP.
Department of Neurosurgery, Centre Hospitalier Regional et Universitaire de Lille, Lille, France
Neurosurgery. 2003 May;52(5):1212-5; discussion 1215-6. Abstract quote
OBJECTIVE AND IMPORTANCE: We report a unique case of extended leptomeningeal hemangioblastomatosis in a patient presenting with clinical von Hippel-Lindau disease.
CLINICAL PRESENTATION: A 50-year-old male patient had a history of three surgical procedures for the removal of a cerebellar hemangioblastoma, initially considered to be a recurrence of a sporadic form at the same location. Seven years after the last operation, he developed chronic hydrocephalus. Despite a ventriculoperitoneal shunt procedure, he experienced progressive worsening of gait disturbances, associated with touch numbness of the lower limbs and Parinaud's syndrome. Magnetic resonance imaging of the brain and spine showed evidence of leptomeningeal contrast enhancement around the brainstem, spinal cord, and cauda equina and enlarged tortuous vessels around the mesencephalon.
INTERVENTION: A lumbar laminectomy allowed a leptomeningeal biopsy. Pathological examination revealed leptomeningeal spread of the hemangioblastoma. It is assumed that the tumor arose in the pia mater and that its direction of growth was purely extramedullary, invading all subarachnoid spaces. The patient had a poor outcome as a result of progressive tetraplegia and died 6 months after diagnosis as a result of respiratory failure.
CONCLUSION: To the best of our knowledge, the clinical course of our patient, consistent with a thick leptomeningeal spread of hemangioblastoma from the posterior fossa to the sacrum, is unique. Nevertheless, the short life expectancy of our patient is usual in von Hippel-Lindau disease. This case report illustrates the crucial challenge to develop a specific drug therapy related to angiogenesis in von Hippel-Lindau disease.
Hum Pathol. 2005 Oct;36(10):1135-9. Epub 2005 Sep 8. Abstract quote
Capillary hemangioblastoma (CH) is a tumor of unknown histogenesis that arises primarily in the posterior cranial fossa, either as a sporadic event or in association with von Hippel-Lindau disease.
To date, only 6 examples of a tumor with morphological features of CH arising in the somatic soft tissues have been documented in case reports and small series, and 3 of these tumors were associated with a peripheral nerve.
Herein, we report a case of CH arising in the gastrocnemius muscle and not associated with a peripheral nerve in a 53-year-old woman with no clinical stigmata or family history of von Hippel-Lindau disease.
- Primary Capillary Hemangioblastoma of Peripheral Soft Tissues.
Michal M, Vanecek T, Sima R, Mukensnabl P, Boudova L, Brouckova M, Koudepa K.
*Department of Pathology, Faculty Hospital, Pilsen, Czech Republic; daggerGENNET CZ, Prague, Czech Republic; and double daggerDepartment of Orthopedic Surgery, Faculty Hospital Pilsen, Czech Republic.
Am J Surg Pathol. 2004 Jul;28(7):962-966. Abstract quote
A case of capillary hemangioblastoma located in the peripheral soft tissue of the inner ankle in a 74-year-old woman is presented. The tumor was an unencapsulated but sharply circumscribed nodule 2.5 cm in size, of a yellow-white color. It showed reddish-brown spots with small cysts up to 2 mm filled with blood.
Grossly the tumor was not attached to any peripheral nerve. Signs of von Hippel-Lindau's disease were excluded by thorough clinical evaluation. No additional tumor or erythrocytosis was found in the patient clinically.
Immunohistochemically, the tumor stromal cell reacted strongly with antibodies to S-100 protein, NSE, and calponin and they were negative with antibodies to GFAP, CD34, CD31, cytokeratins, actin, desmin, EMA, and HMB-45. Endothelium of the capillaries reacted positively with antibodies to CD31, CD34, and Factor VIII-related protein. Capillary pericytes were actin-positive. All cells of the tumor stained positively with antibody to vimentin. MIB1 antibody reacted only in very few cells (<1%).
Ultrastructurally, the stromal cells contained electron-lucent cytoplasm with lipid droplets, a small amount of rough endoplasmic reticulum, and glycogen particles. No electron-dense structures typical of secretory granules were seen in the stromal cells. No mutation of coding sequence of VHL gene was found.
Ann Diagn Pathol. 2000 Apr;4(2):81-7. Abstract quote
Central nervous system hemangioblastomas are uncommon tumors of controversial etiology that are usually found in the posterior fossa of the cranial cavity, retina, and spinal cord. Peripheral involvement is rare; only isolated case reports have been identified.
We report an unusual case of hemangioblastoma involving the retroperitoneum. A 47-year-old African-American man presented with polycythemia on routine laboratory testing. Computed tomography revealed a large retroperitoneal mass near the pancreas, in a left suprarenal location, without adrenal involvement and without attachment to a nerve. Although hemangioblastoma may be associated with the von Hippel-Lindau syndrome, this patient did not have any of the stigmata of this disease.
The histologic features included a highly vascular tumor with cellular areas composed of plump, pleomorphic spindled and epithelioid (stromal) cells with variable cytoplasmic lipid vacuoles and hypocellular areas with inflammatory cells and collagenous fibrils. Immunohistochemical staining showed that the tumor (stromal) cells were positive for vimentin, calponin, S-100 protein, neuron-specific enolase, and CD57 and negative for glial fibrillary acidic protein, cytokeratins, epithelial membrane antigen, CD34, HMB-45, desmin, and the actins. These morphologic and immunohistochemical findings are consistent with hemangioblastoma. To our knowledge this is the first reported case of a hemangioblastoma in this location.
Based on this case we conclude that hemangioblastoma may occur in the retroperitoneum and outside of the central nervous system in a patient without von Hippel-Lindau syndrome. The immunoprofile of this case suggests that hemangioblastomas are mesenchymal neoplasms exhibiting both neural and myofibroblastic differentiation.
- Surgical management of hemangioblastomas of the spinal cord.
Huang JS, Chang CJ, Jeng CM.
Department of Neurosurgery, Cathay General Hospital, Taipei, Taiwan.
J Formos Med Assoc. 2003 Dec;102(12):868-75. Abstract quote
BACKGROUND AND PURPOSE: Intramedullary hemangioblastomas are relatively rare intraspinal tumors. Total removal of these tumors without causing significant neurological deficit remains a great challenge. This study analyzed the preoperative characteristics, management, and outcome in patients with successful total removal of spinal intramedullary hemangioblastomas.
METHODS: Data from the medical records of patients with intraspinal hemangioblastomas treated from 1993 to 2003 were reviewed. The neurological function of these patients was graded and the preoperative data were recorded and correlated with clinical outcome.
RESULTS: Ten patients with spinal intramedullary hemangioblastomas underwent microsurgical resection by the same neurosurgeon during the 10-year study period. They included 3 men and 7 women with age ranging from 20 to 49 years, with a mean age of 33 years. Five of the patients met the diagnostic criteria for von Hippel-Lindau disease. Preoperative neurological function was grade I in 6 patients, grade II in 3 patients and grade III in 1 patient. Immediate postoperative neurological function was worse in 3 cases, but all of these patients recovered their preoperative function within 3 weeks. At 3 months' follow-up, 9 patients had achieved functional grade I, and 1 patient with preoperative grade III function had improved to grade II.
CONCLUSIONS: Detailed preoperative evaluation and skillful microsurgery are mandatory in successful total removal of intramedullary hemangioblastomas. The management of spinal hemangioblastomas associated with von Hippel-Lindau disease requires a cautious observation of clinical course and timely surgical intervention of symptomatic lesions to avoid possible neurological deficit.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
CHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE Negative for CD10 ELECTRON MICROSCOPY
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES RENAL CELL CARCINOMA, METASTATIC
- Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central nervous system from metastatic clear cell renal cell carcinoma.
Jung SM, Kuo TT.
 1Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan  2Department of Pathology, Chang Gung Children's Hospital, Taoyuan, Taiwan.
Mod Pathol. 2005 Jun;18(6):788-94. Abstract quote
The differential diagnosis between hemangioblastoma of the central nervous system and metastatic clear cell renal cell carcinoma can be problematic, because they may share striking morphologic similarities.
Since CD10 is expressed in clear cell renal cell carcinoma, while inhibin alpha is expressed in hemangioblastoma, we used CD10 and inhibin alpha (inhibin A) to study their possible use in the distinction of these two entities. A total of 22 cases of cerebellar hemangioblastoma, five cases of metastatic clear cell renal cell carcinoma to the central nervous system, and 16 primary cases of clear cell renal cell carcinoma were studied with immunohistochemical staining of both CD10 and inhibin A. All 22 cases of hemangioblastoma were immunonegative for CD10 in the stromal cells.
In contrast, all five cases of metastatic clear cell renal cell carcinoma and 16 cases of primary clear cell renal cell carcinoma showed positive CD10 membranous staining. In all, 20 cases of hemangioblastoma (20/22, 91%) expressed inhibin A in the stromal cells. Two cases of primary clear cell renal cell carcinoma (2/16, 13%) and three cases of metastatic clear cell renal cell carcinoma (3/5, 60%) showed immunopositivity for inhibin A.
In conclusion, in addition to the immunostaining of inhibin A, CD10 is a superior marker for distinguishing between a hemangioblastoma and a metastatic clear cell renal cell carcinoma.
Metastasis of renal cell carcinoma to haemangioblastoma of the spinal cord in von Hippel-Lindau disease: case report and review of the literature.
Abou-Hamden A, Koszyca B, Carney PG, Sandhu N, Blumbergs PC.
Department of Neurosurgery, Royal Adelaide Hospital, Adelaide, SA, Australia.
Pathology. 2003 Jun;35(3):224-7. Abstract quote
A case is presented demonstrating the unusual phenomenon of a renal cell carcinoma metastasising to a spinal haemangioblastoma in a patient with von Hippel-Lindau (VHL) disease.
Recent advances in the molecular biology of VHL disease relevant to possible mechanisms of tumour-to-tumour metastasis are briefly reviewed.
- The natural history of cerebellar hemangioblastomas in von Hippel-Lindau disease.
Slater A, Moore NR, Huson SM.
Department of Radiology, Oxford Radcliffe Hospitals, England.
AJNR Am J Neuroradiol. 2003 Sep;24(8):1570-4. Abstract quote
BACKGROUND AND PURPOSE: Cerebellar hemangioblastomas (HBs) are traditionally classified into different morphologic types: cystic and solid. We have observed the progression from solid to cystic and have reviewed the cases seen at the regional von Hippel-Lindau (VHL) clinic to document the frequency of this progression.
METHODS: A retrospective review of the notes and images of all patients with VHL disease seen at a regional referral clinic since its inception in 1991. Sporadic HBs were not included in this study.
RESULTS: In eight patients, a total of 28 tumors were detected. Fourteen of these had or developed cysts. Of the 14 cystic tumors, eight increased in size over the follow-up period. Of the 14 solid tumors, only one increased in size without cystic change. In four patients, the tumor progressed from a cerebellar nodule to an enlarging cyst with a nodule, with the subsequent development of symptoms requiring surgical excision.
CONCLUSION: We have demonstrated that, in VHL, cerebellar HBs begin as nodules, and some subsequently develop enlarging cysts that cause pressure symptoms. In our patient population, tumors that remained solid were asymptomatic and well tolerated in the cerebellum.
- Haemangioblastoma of the posterior cranial fossa: clinico-neuropathological study.
Wierzba-Bobrowicz T, Schmidt-Sidor B, Szpak GM, Lechowicz W, Gorski R, Jagielski J, Koziara H.
Department of Neuropathology, Institute of Psychiatry and Neurology, Warszawa, Poland.
Folia Neuropathol. 2003;41(4):245-9. Abstract quote
Haemangioblastoma (HBs) may occur sporadically in the central nervous system, or in association with von Hippel-Lindau (VHL) disease. Haemangioblastoma of the central nervous system is often seen in the posterior cranial fossa. VHL is an autosomaly dominant disorder.
In sporadic HBs tumours, VHL alleles are reported to be inactive in up to 50% of tumours. Five patients with tumours of the posterior cranial fossa were examined by scyntygrapghy, computed tomography or magnetic resonance imaging (MRI). Metastases were initially diagnosed by neuroimaging examinations in two patients, and HBs in the remaining cases. In four patients, tumours were removed neurosurgically. Two patients had evidence of VHL disease. All resected tumours and autopsy materials were studied histologically and immunohistologically. Most antibodies that were used showed positive immunoreactions with stromal, endothelial, and pericyte or macrophage cells in tumours diagnosed as haemangioblastoma. Preoperative diagnosis of haemangioblastoma is mostly precise with MRI or magnetic resonance angiograghy. The surgical treatment of HBs is only a part of the complex therapeutical process.
Diagnosis based on the gene analysis can be very useful in early detection or protection against potential recurrence of this disease in patients and their families.
TREATMENT CHARACTERIZATION GENERAL ANTI-ANGIOGENIC THERAPY
Antiangiogenic therapy for von Hippel-Lindau disease.
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.
JAMA. 2004 Feb 25;291(8):943-4. Abstract quote
- Treatment of von Hippel-Lindau retinal hemangioblastoma by the vascular endothelial growth factor receptor inhibitor SU5416 is more effective for associated macular edema than for hemangioblastomas.
Girmens JF, Erginay A, Massin P, Scigalla P, Gaudric A, Richard S.
Service d'Ophtalmologie, Hopital Lariboisiere, Assistance Publique-Hopitaux de Paris and Universite Paris VII, Paris, France.
Am J Ophthalmol. 2003 Jul;136(1):194-6. Abstract quote
PURPOSE: To test the efficacy of the novel vascular endothelial growth factor (VEGF) receptor inhibitor SU5416, in a case of refractory von Hippel-Lindau (VHL) retinal hemangioblastoma (RHB).
DESIGN: Interventional case report.
METHODS: Patient included in a multicenter phase II trial. A 30-year-old woman presenting with VHL disease and multiple RHB on her only eye, refractory to conventional treatments, had decreased visual acuity due to cystoid macular edema (CME). SU5416 was administered intravenously for 7 months. Best-corrected visual acuity (BCVA) and macular thickness were measured by optical coherence tomography.
RESULTS: Under treatment, the size of the RHB did not change, but CME improved significantly. Best-corrected visual acuity rose from 20/40 to 20/25. However, CME recurred after the end of the treatment.
CONCLUSION: The VEGF receptor inhibitor SU5416 failed to reduce the size of RHB but was very effective for the associated CME.
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