Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease

Gautam U. Mehta, Sharon B. Shively, Heng Duong, Maxine G.B. Tran, Travis J. Moncrief, Jonathan H. Smith, Jie Li, Nancy A. Edwards, Russell R. Lonser, Zhengping Zhuang, Marsha J. Merrill, Mark Raffeld, Patrick H. Maxwell, Edward H. Oldfield, Alexander Vortmeyer

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1146-1153
Number of pages8
JournalNeoplasia
Volume10
Issue number10
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

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von Hippel-Lindau Disease
Hamartoma
Epididymis
Neoplasms
Carcinogenesis
Microdissection
Organogenesis
Differentiation Antigens
Growth
Vascular Endothelial Growth Factor A
Transcriptional Activation
In Situ Hybridization
Immunohistochemistry
Hypoxia

ASJC Scopus subject areas

  • Cancer Research

Cite this

Mehta, G. U., Shively, S. B., Duong, H., Tran, M. G. B., Moncrief, T. J., Smith, J. H., ... Vortmeyer, A. (2008). Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease. Neoplasia, 10(10), 1146-1153. https://doi.org/10.1593/neo.08476

Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease. / Mehta, Gautam U.; Shively, Sharon B.; Duong, Heng; Tran, Maxine G.B.; Moncrief, Travis J.; Smith, Jonathan H.; Li, Jie; Edwards, Nancy A.; Lonser, Russell R.; Zhuang, Zhengping; Merrill, Marsha J.; Raffeld, Mark; Maxwell, Patrick H.; Oldfield, Edward H.; Vortmeyer, Alexander.

In: Neoplasia, Vol. 10, No. 10, 01.01.2008, p. 1146-1153.

Research output: Contribution to journalArticle

Mehta, GU, Shively, SB, Duong, H, Tran, MGB, Moncrief, TJ, Smith, JH, Li, J, Edwards, NA, Lonser, RR, Zhuang, Z, Merrill, MJ, Raffeld, M, Maxwell, PH, Oldfield, EH & Vortmeyer, A 2008, 'Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease', Neoplasia, vol. 10, no. 10, pp. 1146-1153. https://doi.org/10.1593/neo.08476
Mehta GU, Shively SB, Duong H, Tran MGB, Moncrief TJ, Smith JH et al. Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease. Neoplasia. 2008 Jan 1;10(10):1146-1153. https://doi.org/10.1593/neo.08476
Mehta, Gautam U. ; Shively, Sharon B. ; Duong, Heng ; Tran, Maxine G.B. ; Moncrief, Travis J. ; Smith, Jonathan H. ; Li, Jie ; Edwards, Nancy A. ; Lonser, Russell R. ; Zhuang, Zhengping ; Merrill, Marsha J. ; Raffeld, Mark ; Maxwell, Patrick H. ; Oldfield, Edward H. ; Vortmeyer, Alexander. / Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease. In: Neoplasia. 2008 ; Vol. 10, No. 10. pp. 1146-1153.
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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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