[1673] Developmentally Arrested Structural Elements (DASEs) Preceding CNS Tumorigenesis in VHL Disease

EA Falke, SB Shively, J Li, RR Lonser, AO Vortmeyer. Yale School of Medicine, New Haven, CT; National Institute of Neurological Disorders and Stroke, Bethesda, MD; George Washington University, Washington, DC

Background: Previously we demonstrated developmentally arrested structural elements (DASEs) composed of hemangioblast progenitor cells in the peripheral nervous system of VHL patients. A small subset of DASEs may progress to frank tumor, hemangioblastoma (HB). Central nervous system (CNS) tumors in VHL disease, however, are most frequently observed in the cerebellum, suggesting a site of origin in CNS, from unknown cells and unknown topographic sites. We performed a structural and topographic analysis of cerebellar tissues from VHL patients to identify and characterize DASEs in the CNS.
Design: To search for DASEs, we examined the entire cerebella of 5 patients with VHL disease and 3 non-VHL disease controls. A total of 599 blocks were processed from the 8 cerebella. A hematoxylin-eosin (HE) stained section for each block was screened for DASEs at high power. Whenever DASEs were detected histologically, the respective paraffin block containing DASE material and the block coronally en face to it were serially sectioned at 6 microns. Immunohistochemical (IHC) labeling for CD34, CD31, CAIX, brachyury, HIF1, and HIF2 was performed on unstained sections from DASE containing blocks.
Results: 10 cerebellar DASEs were detected in the 385 blocks of VHL cerebella. No DASEs were seen in 214 blocks from the cerebella of 3 controls. DASES preferentially involve the molecular layer of the dorsal cerebellum. DASEs are composed of poorly differentiated cells that express CAIX and HIF2, but not HIF1. In contrast, HB tumor cells are IHC positive for HIF2 and HIF1, as well as CAIX.Consistent with their immature phenotype, DASEs rarely or never expressed brachyury, while HB cells were immunopositive for brachyury.
Conclusions: Prior studies have shown that peripheral nervous system hemangioblastomas are preceded by developmentally arrested structural elements (DASEs). For the first time, we identify similar (DASEs) in the CNS of VHL patients. DASEs in cerebellum are composed of developmentally arrested hemangioblast progenitor cells in the molecular layer, with activation of HIF2 but not HIF1. In contrast, frank tumors acquire a hemangioblastic phenotype with additional activation of HIF1 and expression of brachyury, among other markers of hemangioblastic differentiation.
Category: Neuropathology

Tuesday, March 23, 2010 1:00 PM

Poster Session IV # 238, Tuesday Afternoon


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