Effects of VHL deficiency on endolymphatic duct and sac.
The von Hippel-Lindau (VHL) disease is caused by VHL germ line mutation. Inactivation of the wild-type copy of the VHL gene leads to up-regulation of hypoxic response and tumor formation within central nervous system (CNS), kidneys, pancreas, adrenal glands, epididymis, broad ligament, and the endolymphatic sac/petrous bone. Endolymphatic sac tumors (ELST) have been proposed to be derived from endolymphatic sac epithelium, but other possible structures of origin have been implicated. To clarify the anatomic and cellular origin of ELSTs, we did a morphologic and molecular pathologic analysis of 16 tumors. In addition, we investigated effects of VHL deficiency on "tumor-free" endolymphatic duct and sac of VHL patients. Several tumors included in this study were <1 cm in size, and their origin could be placed in the intraosseous portion of the endolymphatic duct/sac. Furthermore, by analysis of clinically uninvolved "tumor-free" endolymphatic duct and sac tissues of VHL patients, we discovered a variety of VHL-deficient microscopic abnormalities with morphologic similarities to ELSTs. We conclude that most, if not all, ELSTs arise within the intraosseous portion of the endolymphatic duct/sac, the vestibular aqueduct. In analogy to renal parenchyma and selected topographical sites within the CNS, endolymphatic duct/sac epithelia are preferentially and multifocally targeted in VHL disease. The primary effect of VHL deficiency on human endolymphatic duct/sac epithelium seems to be the generation of multifocal sites of VHL-deficient cell proliferations from which tumorigenesis may or may not occur. Therefore, inactivation of the VHL wild-type allele seems necessary but not sufficient for the formation of tumor.
Gläsker
Sven
S
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892, USA.
Lonser
Russell R
RR
Tran
Maxine G B
MG
Ikejiri
Barbara
B
Butman
John A
JA
Zeng
Weifen
W
Maxwell
Patrick H
PH
Zhuang
Zhengping
Z
Oldfield
Edward H
EH
Vortmeyer
Alexander O
AO
D004428:Ear Neoplasms / Q000378:metabolism / Q000473:pathology*; D004711:Endolymphatic Duct / Q000378:metabolism / Q000473:pathology*; D004712:Endolymphatic Sac / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000235:genetics
D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human