Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease.
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.
Mehta
Gautam U
GU
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Shively
Sharon B
SB
Duong
Heng
H
Tran
Maxine G B
MG
Moncrief
Travis J
TJ
Smith
Jonathan H
JH
Li
Jie
J
Edwards
Nancy A
NA
Lonser
Russell R
RR
Zhuang
Zhengping
Z
Merrill
Marsha J
MJ
Raffeld
Mark
M
Maxwell
Patrick H
PH
Oldfield
Edward H
EH
Vortmeyer
Alexander O
AO
D000328:Adult; D001344:Autopsy; D049109:Cell Proliferation; D003560:Cysts / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004822:Epididymis / Q000002:abnormalities* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D005832:Genital Diseases, Male / Q000150:complications* / Q000151:congenital / Q000378:metabolism / Q000473:pathology*; D005834:Genital Neoplasms, Male / Q000209:etiology* / Q000473:pathology; D006222:Hamartoma / Q000209:etiology* / Q000473:pathology; D006801:Humans; D008297:Male; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D014928:Wolffian Ducts / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D006623:von Hippel-Lindau Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology
D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human