title: Epididymal cystadenomas and epithelial tumourlets: effects of VHL deficiency on the human epididymis.
abstract: Although epididymal cystadenomas (ECAs) are among the most frequent VHL disease-associated tumours, fundamental questions about their pathogenesis have remained unanswered. Classification of ECAs is controversial, and the cell of origin is unknown. It is also unknown whether ECAs-like other VHL disease-associated tumours-arise as a result of VHL gene inactivation, and whether ECAs exhibit subsequent activation of hypoxia-inducible factor HIF. Moreover, the morphological spectrum of earliest ECA formation is unknown. In a detailed molecular pathological analysis of a series of epididymides collected from VHL patients at autopsy, we found that ECAs are true neoplasms that arise secondary to inactivation of the wild-type copy of the VHL gene, followed by early and simultaneous activation of HIF1 and HIF2 associated with up-regulation of downstream targets, including CAIX and GLUT-1. The observations also indicate that ECA formation evolves from a variety of microscopic epithelial tumourlets, and that these tumourlets are confined to the efferent ductular system. Although genetic and immunohistochemical analysis of precursor structures consistently revealed VHL gene inactivation and activation of HIF in the precursor lesions, only a small subset appears to progress into frank cystadenoma. Thus, ECA tumorigenesis in VHL disease shares fundamental principles with tumorigenesis in other affected organ systems.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gläsker
authors.forename: M G B
authors.initials: MG
authors.lastname: Tran
authors.forename: S B
authors.initials: SB
authors.lastname: Shively
authors.forename: B
authors.initials: B
authors.lastname: Ikejiri
authors.forename: R R
authors.initials: RR
authors.lastname: Lonser
authors.forename: P H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Z
authors.initials: Z
authors.lastname: Zhuang
authors.forename: E H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: A O
authors.initials: AO
authors.lastname: Vortmeyer
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins; D003537:Cystadenoma / Q000150:complications / Q000235:genetics / Q000473:pathology*; D004822:Epididymis / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D005834:Genital Neoplasms, Male / Q000150:complications / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics; D007150:Immunohistochemistry / Q000379:methods; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1