Abstract
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.
Highlights
Endolymphatic sac tumors (ELST) were identified by Heffner in 1989 [1]. They occur sporadically or as a component of autosomaldominant von Hippel-Lindau (VHL) disease [2,3,4,5], a disorder characterized by hemangioblastomas of the central nervous system (CNS) and renal carcinomas as major manifestations
Inactivation of the VHL tumor suppressor gene occurs in sporadic ELSTs [6,7,8] and those associated with VHL disease [9]
The location of all seven tumors was limited to the intraosseous portion of the endolymphatic sac and endolymphatic duct
Summary
Endolymphatic sac tumors (ELST) were identified by Heffner in 1989 [1] They occur sporadically or as a component of autosomaldominant von Hippel-Lindau (VHL) disease [2,3,4,5], a disorder characterized by hemangioblastomas of the central nervous system (CNS) and renal carcinomas as major manifestations. ELSTs can cause hearing loss, tinnitus, vertigo, and facial nerve paresis These symptoms can arise by infiltration of neighboring structures. Other investigators do not think the endolymphatic sac to be the site of origin Instead, they suggest the mucosa of the pneumatic spaces surrounding the jugular bulb as site of origin due to the strong positive immunohistochemical reaction for keratin in the tumor tissue [18]. In analogy to that approach, we closely examined endolymphatic sac and duct tissue from clinically uninvolved patients to detect potential precursor structures
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