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Evaluation and Management

Evaluation and Management

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Evaluation and Management
of Endolymphatic Sac and Duct Tumors
Cli\ufb00 A. Megerian, MD*, Maroun T. Semaan, MD

Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University
School of Medicine, University Hospitals-Case Medical Center,
11100 Euclid Avenue, Cleveland, OH 44106, USA

Endolymphatic sac tumor (ELST) is a slow-growing, locally aggressive neoplasm that originates from the epithelium of the endolymphatic sac and duct. It demonstrates the histologic appearance of a papillary adenoma- tous lesion, and before its acceptance as a disease entity, its destructive be- havior within the temporal bone was attributed in some cases to a metastatic renal cell carcinoma variant[1,2]. By virtue of ELST-related obstruction of the vestibular aqueduct, patients often develop symptoms of endolymphatic hydrops[3], and this pathologic \ufb01nding recently was con\ufb01rmed histologi- cally[4]. The earliest manifestations of ELSTs are often hearing loss and vertigo that initially may lead to a misdiagnosis of Meniere\u2019s disease. Dis- ease progression can lead to profound sensorineural hearing loss, posterior fossa invasion, brainstem compression, drop metastasis, and eventual death. Although ELSTs are known to occur more frequently in patients with von Hippel-Lindau disease (VHL), a diagnosis of VHL is not a prerequisite, be- cause these tumors also appear sporadically in patients who do not have VHL. Early diagnosis and surgical attention are the primary objectives in the management of patients who have ELST because recent studies have shown the potential for hearing preservation when small tumors are re- moved successfully.

Historical background

ELST is a recently recognized neurotologic disease entity characterized by the presence of a destructive papillary cystic adenomatous tumor of the temporal bone. Its roots and evidence for its existence date to early in

* Corresponding author.
E-mail address:cliff.megerian@uhhs.com(C.A. Megerian).
0030-6665/07/$ - see front matter\u00d3 2007 Elsevier Inc. All rights reserved.
Otolaryngol Clin N Am
40 (2007) 463\u2013478

the last century in a report that described a destructive lesion of the tempo- ral bone in a patient who had VHL that was ascribed to metastatic renal cell carcinoma in the absence of a primary kidney tumor[1]. Throughout the en- suing years it became clear that an aggressive papillary tumor could arise primarily within the temporal bone; however, the site of epithelial origin re- mained an area of conjecture. This uncertainty was partly caused by the fact that many of these cases occurred in patients with an intact tympanic mem- brane and normal external auditory canal, so the glandular epithelial tissue of the external auditory canal was excluded as the site of origin.

In 1989, He\ufb00ner[5] studied 20 such large papillary cystic tumors of the temporal bone and concluded that the endolymphatic sac epithelium repre- sented the most likely area at which these lesions initially grow. This \ufb01nding was corroborated by an earlier study in 1984 by Hassard and colleagues[6], who described a papillary cystic lesion \ufb01lling the endolymphatic sac that was encountered during decompression surgery for presumed Meniere\u2019s disease and likely represented the \ufb01rst clinical con\ufb01rmation of the validity of the ELST designation. In 1993, Li and colleagues[7] formally proposed that the designation for aggressive papillary tumors of the temporal bone be changed to ELST.

In 1995, Megerian and colleagues[3] provided temporal bone histologic evidence of a de novo ELST tumor in a patient who had VHL (Fig. 1) and died of complications related to a massive ELST of the contralateral ear. In- cluded in that study were seven additional clinical cases that revealed that most of the patients had Meniere\u2019s-like symptoms years before the diagnosis of ELST, which raised the possibility that early manifestations of tumor growth included perturbations of vestibular aqueduct function and the de- velopment of endolymphatic hydrops-related symptomatology. Poe and col- leagues[8] and later Manski and colleagues[9] studied ELST in patients who had VHL, and the latter group documented the fact that at least 13% of

Fig. 1. Histologic section through the right temporal bone of 48-year-old patient with VHL who died of large intracranial ELST of left posterior fossa. Arrow points to de novo ELST within endolymphatic sac and duct of left ear.


patients who had VHL harbored ELST tumors. They suggested that pa- tients who had VHL should undergo regular surveillance, because unde- tected growth was shown to result in deafness that sometimes was bilateral.

By 1997, screening for ELST using MRI became standard for patients who had VHL, whereas before that time annual MRI evaluations of the head focused mainly on detection of VHL-related cerebellar hemangioblas- tomas. These practices, coupled with an increased number of reports in the literature of sporadic ELSTs, led to the evolution of surgical alternatives for tumor removal. In 2002, Megerian and colleagues[10] described techniques for tumor removal in small ELSTs that a\ufb00orded hearing preservation. Sub- sequent reports by Hansen and Luxford in[11] 2004 and Kim and col- leagues[12] in 2005 con\ufb01rmed the clear role for hearing preservation surgery using the retrolabyrinthine approach for small tumors and more ag- gressive skull base extirpations for larger lesions.


As recently as 2004, Bambakidis and colleagues[13] reported that most ELSTs described in the literature have occurred sporadically in patients who do not have VHL compared with patients who do (103 versus 46). Much information that has been learned recently regarding the genesis of these lesions has been via an understanding of the genetics and molecular biology that result from a mutation in the VHL tumor suppressor gene. VHL is an autosomal dominant multisystemic disorder characterized by cer- ebellar hemangioblastomas, retinal angiomas, and renal cysts, clear cell re- nal carcinomas, and other visceral tumors.

In the late 1990s, ELST became a recognized part of the disease spectrum because it was associated with online Mendelian inheritance in man VHL disease (No. 193300)[9]. VHL has a prevalence of 1 in 39,000 people[14] and is caused by a germline mutation in the VHL gene on chromosome 3 (3p25-26)[15]. The VHL gene product is a tumor suppressor that when lost or mutated results in a loss of inhibition to cell growth and can lead to neoplasms such as ELST. The VHL gene product protein is important in the regulation of hypoxia inducible factor\u20131a, which controls angiogene- sis and cell metabolism[16].

In normal situations, patients have two copies of the wild-type (normal) VHL gene allele. The disease develops in people who have VHL and have a spontaneous \u2018\u2018loss of heterozygosity,\u2019\u2019 that is, a mutation of the normal copy of the VHL gene, which leaves only the mutated copy of the VHL gene[17]. This mutation leads to tumorigenesis and the development of the highly vascular ELST in vulnerable tissue, such as the epithelium of the vestibular aqueduct. Recent studies of clinically tumor-free endolym- phatic duct and sac tissue of patients who have VHL revealed VHL gene\u2013 de\ufb01cient microscopic abnormalities with morphologic similarities to ELST


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