Abstract
Von Hippel-Lindau (VHL) disease is a tumor syndrome that frequently involves the central nervous system (CNS). It is caused by germline mutation of the VHL gene. Subsequent VHL inactivation in selected cells is followed by numerous well-characterized molecular consequences, in particular, activation and stabilization of hypoxia-inducible factors HIF1 and HIF2. The link between VHL gene inactivation and tumorigenesis remains poorly understood. Hemangioblastomas are the most common manifestation in the CNS; however, CNS invasion by VHL disease-associated endolymphatic sac tumors or metastatic renal cancer also occur, and their differentiation from primary hemangioblastoma may be challenging. Finally, in this review, we present recent morphologic insights on the developmental concept of VHL tumorigenesis which is best explained by pathologic persistence of temporary embryonic progenitor cells.
Highlights
Von Hippel–Lindau (VHL) disease is an autosomal dominant disorder that is caused by germline mutations in the tumor suppressor gene VHL on chromosome 3p25 [1, 2]
VHL disease is a classic tumor suppressor gene syndrome caused by VHL gene germline mutation
The “second hit” - VHL wild-type gene inactivation – induces developmentally arrested structural elements” (DASEs) which have the potential to develop into benign hemangioblastic tumors
Summary
Von Hippel–Lindau (VHL) disease is an autosomal dominant disorder that is caused by germline mutations in the tumor suppressor gene VHL on chromosome 3p25 [1, 2]. There is increasing evidence that the “second hit” causes loss of pivotal VHL function during organ development leading to maldeveloped structures that represent prerequisites for tumor formation [28]. The second cellular constituent of hemangioblastoma is represented by abundant vascular cells that show no evidence of biallelic VHL inactivation and are mostly – if not entirely – reactive [36, 46].
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