Nervous system involvement in von Hippel–Lindau disease: pathology and mechanisms

Abstract

Patients with von Hippel-Lindau disease carry a germline mutation of the Von Hippel-Lindau (VHL) tumor-suppressor gene. We discuss the molecular consequences of loss of VHL gene function and their impact on the nervous system. Dysfunction of the VHL protein causes accumulation and activation of hypoxia inducible factor (HIF) which can be demonstrated in earliest stages of tumorigenesis and is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumor cells. HIF-independent functions of VHL, epigenetic inactivation of VHL, pVHL proteostasis, and links between loss of VHL function and developmental arrest are also described. A most intriguing feature in VHL disease is the occurrence of primary hemangioblastic tumors in the nervous system, the origin of which has not yet been entirely clarified, and current hypotheses are discussed. Endolymphatic sac tumors may extend into the brain, but originally arise from proliferation of endolymphatic duct/sac epithelium; the exact nature of the proliferating epithelial cell, however, also has remained unclear, as well as the question why tumors almost consistently develop in the intraosseous portion of the endolymphatic sac/duct only. The epitheloid clear cell morphology of both advanced hemangioblastoma and renal clear cell carcinoma can make the differential diagnosis challenging, recent developments in immunohistochemical differentiation are discussed. Finally, metastasis to brain may not only be caused by renal carcinoma, but may derive from VHL disease-associated pheochromocytoma/paraganglioma, or pancreatic neuroendocrine tumor.

Risk of new tumors in von Hippel–Lindau patients depends on age and genotype

“…2 Several studies have indicated that VHL deficient hemangioblastoma precursor cells, tumorlets, are established during embryonic development, although the exact tumorigenesis is still unknown. [17][18][19][20][21][22] Thus, from birth, vHL patients may harbor numerous microscopic tumorlets in the CNS, including the retina, and similar growth patterns would be expected. Differing anatomical and diagnostic limitations may account for some of the observed disparity in tumor development at the two sites.…”

Histological concordance in familial central nervous system tumors: Evidence from nationwide Swedish Family-Cancer Database

“…However, it is known that more than 93% of hemangioblastomas occurs in the posterior fossa of the brain and spinal hemangioblastoma is a rare tumor which occurs mostly in patients with VHL syndrome [29,30]. In our dataset, none of the patients with possible VHL had spinal hemangioblastoma.…”

Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

“…These defects can lead to disease manifestations in tissues beyond the kidney, where abnormal vascular growth and remodeling contribute to additional pathologies. For instance, brain, spinal cord, and eye/retina hemangioblastoma formation is commonplace in VHL disease (94,95), owing in part to disruption of the VEGF-A (96, 97) and Notch pathways (98), among others. Dysfunction in HIF signaling is also likely involved in the aberrant vessel remodeling found in nonkidney tissues, as recent studies have implicated this pathway, and downstream mediators such as ANGPT-like 4 (ANGPTL4), in angiogenesis-related conditions including pterygia (99), uveal melanoma (100), and proliferative retinopathies (101)(102)(103).…”

“…Aberrant blood vessel formation also gives rise to hemangioblastomas in the cerebellum and spinal cord of VHL patients (94,113,114). Similarly to the kidney, these tissues have high metabolic Angiogenesis, a theme in hereditary kidney cancer risk Misregulated vascular growth and remodeling contribute to the onset and progression of numerous tumor types (59), and these processes are particularly relevant to hereditary kidney cancers.…”