Pathology of the Nervous System in Von Hippel-Lindau Disease

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.

Von Hippel-Lindau Syndrome: Aspects of Treatment and Management. Case Report and Literature Review

“…Краниоспинальная локализация поражения подлежит хирургическому лечению, но поскольку гемангиобластомы ЦНС характеризуются хаотичным ростом, оно не применяется до появления клинической симптоматики. Стереотаксическая радиохирургия используется для лечения небольших новообразований ЦНС (диаметром менее 3 см), а также, в неоперабельных случаях [7,8]. Для верификации гемангиобластомы сетчатки требуется регулярный осмотр глазного дна, поскольку у 5-8 % больных их развитие приводит к слепоте и тяжелым нарушениям зрения.…”

Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

“…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.…”

“…demands and minimal to no energy reserves, which exacerbate genetic defects in mechanisms regulating metabolism and oxygen sensing (114). While VHL-mediated kidney cancer involves vascular remodeling via angiogenesis, hemangioblastoma formation in neurological tissues of VHL patients may also involve vasculogenic processes (113,115,116). The precise cellular contribution of vascular cells versus tumor "stromal" cells to the dense vascularity of hemangioblastomas remains an open question (113); it is clear, however, that excessive proangiogenic factors such as VEGF-A, PDGF-BB, and EGF drive lesion growth (117,118).…”

“…While VHL-mediated kidney cancer involves vascular remodeling via angiogenesis, hemangioblastoma formation in neurological tissues of VHL patients may also involve vasculogenic processes (113,115,116). The precise cellular contribution of vascular cells versus tumor "stromal" cells to the dense vascularity of hemangioblastomas remains an open question (113); it is clear, however, that excessive proangiogenic factors such as VEGF-A, PDGF-BB, and EGF drive lesion growth (117,118). For these reasons, antiangiogenesis strategies initially developed to treat kidney cancers, and specifically VHL-associated ccRCC, are being adapted to manage CNS hemangioblastomas untreatable by surgical resection or radiation therapy (117,119,120).…”

Functional Imaging of Paragangliomas with an Emphasis on Von Hippel–Lindau-Associated Disease: A Mini Review

“…In the future, they may be effectively used for PHEOs/PGLs, since apparently these ligands show higher tumor uptake compared to ST-R analogues and permit better tumor visualization ( 46 – 48 ). Unrelated to PHEOs/PGLs, a novel PET tracer, [89Zr]-bevacizumab (which binds VEGF-A) has been tried in VHL patients, visualizing hemangioblastomas (although these are benign nonmetastasizing tumors, if undetected they may lead to severe neurological deficits and death ( 49 )), renal cell carcinomas, and brain metastases ( 50 ).…”