Faculty Opinions recommendation of Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice.

ABSTRACT Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

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Faculty Opinions recommendation of Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1024995.292973 ◽

2005 ◽

Author(s):

Thomas Kodadek

Keyword(s):

Vascular Tumors ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease ◽

Arylhydrocarbon Receptor

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Treatment of Intramedullary Hemangioblastomas, with Special Attention to von Hippel-Lindau Disease

Neurosurgery ◽

10.1227/01.neu.0000093497.81390.29 ◽

2003 ◽

Vol 53 (6) ◽

pp. 1306-1314 ◽

Cited By ~ 69

Author(s):

Vera Van Velthoven ◽

Peter C. Reinacher ◽

Joachim Klisch ◽

Hartmut P.H. Neumann ◽

Sven Gläsker

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Timing Of Surgery ◽

Vascular Tumors ◽

Resonance Imaging ◽

Surgical Morbidity ◽

Von Hippel Lindau ◽

Asymptomatic Patients ◽

Von Hippel Lindau Disease

Abstract OBJECTIVE Hemangioblastomas of the central nervous system are rare vascular tumors that can occur as sporadic lesions or as component tumors of autosomal dominant von Hippel-Lindau disease. With the availability of magnetic resonance imaging, asymptomatic tumors are detected more frequently, especially among patients with von Hippel-Lindau disease, and the questions of whether and when these lesions should be treated arise. To identify surgical outcomes and the timing of surgery for intramedullary hemangioblastomas, we retrospectively analyzed data for a series of 28 consecutive patients whom we surgically treated for intramedullary hemangioblastomas in the past 10 years. METHODS All tumors were completely removed. Functional grades, according to the McCormick scale, were determined before and after surgery and in follow-up assessments. Several clinical characteristics were correlated with changes in functional grades in follow-up assessments, compared with preoperative grades. RESULTS Functional grades in follow-up assessments improved for 28.6% of the patients and remained unchanged for 71.4%. No patient was in worse condition, compared with preoperative status. Peritumoral edema on preoperative magnetic resonance imaging scans was correlated with significantly higher surgical morbidity rates. Four asymptomatic patients were surgically treated because of tumor or pseudocyst progression on serial magnetic resonance imaging scans. All of those patients remained asymptomatic postoperatively. CONCLUSION Intramedullary hemangioblastomas can be removed with low surgical morbidity rates and excellent long-term prognoses. The timing of surgery for patients with von Hippel-Lindau disease and multiple lesions remains a matter of debate. On the basis of our data, we established the strategy of operating also on asymptomatic lesions that exhibit radiological progression, before significant neurological deficits occur, which are often not reversible.

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Von Hippel-Lindau Disease: Genetics and Role of Genetic Counseling in a Multiple Neoplasia Syndrome

Journal of Clinical Oncology ◽

10.1200/jco.2015.65.6140 ◽

2016 ◽

Vol 34 (18) ◽

pp. 2172-2181 ◽

Cited By ~ 58

Author(s):

Sarah M. Nielsen ◽

Lindsay Rhodes ◽

Ignacio Blanco ◽

Wendy K. Chung ◽

Charis Eng ◽

...

Keyword(s):

Genetic Testing ◽

Malignant Tumors ◽

Broad Ligament ◽

Standard Of Care ◽

Vascular Tumors ◽

Sensitive Information ◽

Founder Mutations ◽

Von Hippel Lindau ◽

Gene Testing ◽

Von Hippel Lindau Disease

Von Hippel-Lindau disease (VHL) is one of the most common inherited neoplasia syndromes and is characterized by highly vascular tumors of the eyes, brain, and spine, as well as benign and malignant tumors and/or cysts of the kidneys, adrenal medullae and sympathetic paraganglia, endolymphatic sac, epididymis, and broad ligament. Since the discovery of the VHL gene in 1993, more than 900 families with VHL have been identified and examined. Genetic testing for VHL is widely available and will detect a disease-causing mutation in rate 95% to 100% of individuals who have a clinical diagnosis of VHL, making it the standard of care for diagnosis of VHL. Furthermore, genetic testing for VHL is indicated in some individuals with seemingly sporadic VHL-related tumor types, as ≤ 10% of pheochromocytoma or early-onset renal cell carcinoma and ≤ 40% of CNS hemangioblastoma harbor germline VHL mutations without a family history or additional features of VHL disease. The majority of VHL mutations are private, but there are also well-characterized founder mutations. VHL is a complex, multiorgan disease that spans the breadth of oncology subspecialties, and, as such, providers in these subspecialties should be aware of when to consider a diagnosis of VHL, when to refer a patient to a genetics specialist for consideration of gene testing, and, perhaps most importantly, how to communicate this sensitive information in an age-appropriate manner to at-risk families. This review will provide state-of-the-art information regarding the genetics of VHL and will serve as a key reference for nongenetics professionals who encounter patients with VHL.

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Angiogenesis in Endocrine Tumors

Endocrine Reviews ◽

10.1210/er.2002-0008 ◽

2003 ◽

Vol 24 (5) ◽

pp. 600-632 ◽

Cited By ~ 161

Author(s):

Helen E. Turner ◽

Adrian L. Harris ◽

Shlomo Melmed ◽

John A. H. Wass

Keyword(s):

Thyroid Tissue ◽

Parathyroid Tissue ◽

Microvascular Density ◽

Angiogenic Factors ◽

Vascular Tumors ◽

Endocrine Tumors ◽

Von Hippel Lindau ◽

Therapeutic Decisions ◽

Von Hippel Lindau Disease ◽

Tumor Types

Abstract Angiogenesis is the process of new blood vessel development from preexisting vasculature. Although vascular endothelium is usually quiescent in the adult, active angiogenesis has been shown to be an important process for new vessel formation, tumor growth, progression, and spread. The angiogenic phenotype depends on the balance of proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and inhibitors, as well as interactions with the extracellular matrix, allowing for endothelial migration. Endocrine glands are typically vascular organs, and their blood supply is essential for normal function and tight control of hormone feedback loops. In addition to metabolic factors such as hypoxia, the process of angiogenesis is also regulated by hormonal changes such as increased estrogen, IGF-I, and TSH levels. By measuring microvascular density, differences in angiogenesis have been related to differences in tumor behavior, and similar techniques have been applied to both benign and malignant endocrine tumors with the aim of identification of tumors that subsequently behave in an aggressive fashion. In contrast to other tumor types, pituitary tumors are less vascular than normal pituitary tissue, although the mechanism for this observation is not known. A relationship between angiogenesis and tumor size, tumor invasiveness, and aggressiveness has been shown in some pituitary tumor types, but not in others. There are few reports on the role of microvascular density or angiogenic factors in adrenal tumors. The mechanism of the vascular tumors, which include adrenomedullary tumors, found in patients with Von Hippel Lindau disease has been well characterized, and clinical trials of antiangiogenic therapy are currently being performed in patients with Von Hippel Lindau disease. Thyroid tumors are more vascular than normal thyroid tissue, and there is a clear correlation between increased VEGF expression and more aggressive thyroid tumor behavior and metastasis. Although parathyroid tissue induces angiogenesis when autotransplanted and PTH regulates both VEGF and MMP expression, there are few studies of angiogenesis and angiogenic factors in parathyroid tumors. An understanding of the balance of angiogenesis in these vascular tumors and mechanisms of vascular control may assist in therapeutic decisions and allow appropriately targeted treatment.

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Resection of a Medulla Oblongata Hemangioblastoma: 2-Dimensional Operative Video

Operative Neurosurgery ◽

10.1093/ons/opab278 ◽

2021 ◽

Author(s):

Walid Ibn Essayed ◽

Ossama Al-Mefty

Keyword(s):

Venous Drainage ◽

Radical Resection ◽

Vascular Tumors ◽

En Bloc ◽

Von Hippel Lindau ◽

Suboccipital Craniotomy ◽

Von Hippel Lindau Disease ◽

The Central Nervous System ◽

Technical Principles ◽

Dorsal Medulla

Abstract Hemangioblastomas are benign vascular tumors that can be sporadic or multiple, as part of Von Hippel-Lindau disease. They develop at any level of the central nervous system, with a predilection for the dorsal medulla among brainstem locations. Radical resection of the solid portion of the tumor is the best treatment option.1,2 The resection should be en bloc to avoid uncontrollable intraoperative hemorrhage hindering safe dissection. Preservation of the venous drainage during the progressive dissection of the tumor of the surrounding structures and interruption of numerous small arterial feeders is a tenet for safe surgical resection.3 Once the tumor is completely disconnected, the large draining veins can be coagulated, and the tumor removed. We demonstrate these technical principles in the surgery of a 30-yr-old female with an exophytic hemangioblastoma from the dorsal medulla obstructing the fourth ventricle outflow. We demonstrate the resection of this lesion through a suboccipital craniotomy in a sitting position.4 The patient consented to the surgery and publication of images. Image at 1:26 from Kadri and Al-Mefty,4 by permission from the Congress of Neurological Surgeons.

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