Elsevier

Neoplasia

Volume 10, Issue 10, October 2008, Pages 1146-1153
Neoplasia

Progression of Epididymal Maldevelopment Into Hamartoma-like Neoplasia in VHL Disease1

https://doi.org/10.1593/neo.08476Get rights and content
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open access

Abstract

Inactivation of the von Hippel-Lindau (VHL) gene and activation of the hypoxia-inducible factor (HIF) in susceptible cells precedes formation of tumorlets and frank tumor in the epididymis of male VHL patients. We performed detailed histologic and molecular pathologic analysis of tumor-free epididymal tissues from VHL patients to obtain further insight into early epididymal tumorigenesis. Four epididymides from two VHL patients were serially sectioned to allow for three-dimensional visualization of morphologic changes. Areas of interest were genetically analyzed by tissue microdissection, immunohistochemistry for HIF and markers for mesonephric differentiation, and in situ hybridization for HIF downstream target vascular endothelial growth factor. Structural analysis of the epididymides revealed marked deviations from the regular anatomic structure resulting from impaired organogenesis. Selected efferent ductules were represented by disorganized mesonephric cells, and the maldeveloped mesonephric material was VHL-deficient by allelic deletion analysis. Furthermore, we observed maldeveloped mesonephric material near cystic structures, which were also VHL-deficient and were apparent derivatives of maldeveloped material. Finally, a subset of VHL-deficient cells was structurally integrated in regular efferent ductules; proliferation of intraductular VHL-deficient cells manifests itself as papillary growth into the ductular lumen. Furthermore, we clarify that that there is a pathogenetic continuum between microscopic tumorlets and formation of tumor. In multiple locations, three-dimensional reconstruction revealed papillary growth to extend deeply into ductular lumina, indicative of progression into early hamartoma-like neoplasia. We conclude epididymal tumorigenesis in VHL disease to occur in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells, followed by neoplastic papillary proliferation.

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1

This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health; by Cancer Research, UK; the Medical Research Council; and by the Charitable foundation of Guy’s and St Thomas’ Hospitals, London. Sharon B. Shively is a doctoral student in the Molecular and Cellular Oncology Program of the Institute for Biomedical Sciences at George Washington University. This work is from a dissertation to be presented at George Washington University in partial fulfillment of the requirements for the Ph.D. degree.

2

New address: Department of Pathology, Yale University School of Medicine, 416A Lauder Hall, 310 Cedar Street, New Haven, CT 06520.