Endolymphatic sac tumors (ELST) are slow-growing, locally aggressive, low-grade malignancies that originate from the epithelium of the endolymphatic duct and sac. ELST often present with sensorineural hearing loss, tinnitus, and vertigo, which may mimic Meniere disease. Large tumors may present with additional cranial neuropathies. Management is primarily via microsurgical excision. Radiation therapy has a limited role for residual or unresectable disease. Early detection may enable hearing preservation techniques. ELST have an association with von Hippel–Lindau disease.
Key points
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Endolymphatic sac tumors (ELST) are slow-growing, locally aggressive, low-grade malignancies that originate from the epithelium of the endolymphatic duct and sac.
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Common presenting symptoms are asymmetrical sensorineural hearing loss, tinnitus, and vertigo, which may mimic Meniere disease.
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There is a well-established link between von Hippel–Lindau disease and ELST.
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Microsurgical excision, possibly via a retrolabyrinthine–transdural approach, is the treatment of choice.
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Early diagnosis may enable hearing preservation and cochlear implants may also restore hearing provided the cochlear nerve is intact.
| ELST | Endolymphatic sac tumor |
| NED | No evidence of disease |
| SNHL | Sensorineural hearing loss |
| VHL | von Hippel–Lindau |
Background
Endolymphatic sac tumors (ELST) are slow-growing, locally aggressive, low-grade malignancies that originate from the epithelium of the endolymphatic duct and sac. Adenomatous tumors of the temporal bone have gone through a variety of classification schemes. In 1957, it was recognized that adenomas and adenocarcinomas of the external auditory canal originated in the apocrine glands of the canal, thus the term “ceruminoma” was coined. The origin of primary adenomatous tumors within the middle ear cleft was debated, with some authors supporting aberrant ceruminous glands and others postulating that the tumors arise from native middle ear mucosa.
In 1988, Gaffey and colleagues recognized a particularly aggressive variant of “low-grade papillary adenocarcinoma” in the temporal bone that exhibited hypervascularity and local invasion with bony destruction. Shortly after, Heffner reviewed 20 cases with similar papillary architecture and an epicenter at the posteromedial petrous bone where the endolymphatic sac resides. It was Heffner who suggested a link between this aggressive adenocarcinoma variant and the endolymphatic sac, which he termed “adenocarcinoma of the endolymphatic sac.” The notion of a tumor arising from the endolymphatic sac was supported by a report from Hassard and colleagues in 1984 of a small, adenomatous sac lesion encountered during decompression surgery for suspected Meniere disease. In 1993, Li and colleagues proposed a reclassification of these aggressive adenomatous lesions to ELST.
Still, the origin of ELST was debated. The clinical distinction between ELST from adenocarcinoma of the middle ear, metastasis, or choroid plexus tumors was often difficult. In 1995, Megerian and colleagues reviewed the Massachusetts Eye and Ear Infirmary’s temporal bone collection and identified 8 specimens consistent with an aggressive papillary tumor of the temporal bone. All patients had sensorineural hearing loss (SNHL) and many had a Meniere-like presentation. One patient, a 48-year-old man with von Hippel–Lindau (VHL) disease, had succumbed to what was believed to be metastatic renal cell carcinoma to the left temporal bone. Upon further review, this tumor was more consistent with an ELST. Fortuitously, in this patient’s contralateral temporal bone, a small de novo lesion within the endolymphatic sac was also identified and was histologically identical to the destructive lesion on the left ( Fig. 1 ). This study validated that the epithelium of the endolymphatic sac was capable of producing a low-grade, locally aggressive papillary lesion. It also solidified a predilection for ELST in patients with VHL disease. Subsequently, differences in immunohistochemistry staining patterns between ELST and choroid plexus tumors helped to distinguish these 2 disease entities. Specifically, choroid plexus tumors stain strongly with transthyretin (prealbumin), whereas ELST do not. The confirmation of the origin of ELST and the recognition of sporadic versus VHL-related tumors enabled a better appreciation of the tumor’s behavior, a staging system, and advancements in management as described herein.
Background
Endolymphatic sac tumors (ELST) are slow-growing, locally aggressive, low-grade malignancies that originate from the epithelium of the endolymphatic duct and sac. Adenomatous tumors of the temporal bone have gone through a variety of classification schemes. In 1957, it was recognized that adenomas and adenocarcinomas of the external auditory canal originated in the apocrine glands of the canal, thus the term “ceruminoma” was coined. The origin of primary adenomatous tumors within the middle ear cleft was debated, with some authors supporting aberrant ceruminous glands and others postulating that the tumors arise from native middle ear mucosa.
In 1988, Gaffey and colleagues recognized a particularly aggressive variant of “low-grade papillary adenocarcinoma” in the temporal bone that exhibited hypervascularity and local invasion with bony destruction. Shortly after, Heffner reviewed 20 cases with similar papillary architecture and an epicenter at the posteromedial petrous bone where the endolymphatic sac resides. It was Heffner who suggested a link between this aggressive adenocarcinoma variant and the endolymphatic sac, which he termed “adenocarcinoma of the endolymphatic sac.” The notion of a tumor arising from the endolymphatic sac was supported by a report from Hassard and colleagues in 1984 of a small, adenomatous sac lesion encountered during decompression surgery for suspected Meniere disease. In 1993, Li and colleagues proposed a reclassification of these aggressive adenomatous lesions to ELST.
Still, the origin of ELST was debated. The clinical distinction between ELST from adenocarcinoma of the middle ear, metastasis, or choroid plexus tumors was often difficult. In 1995, Megerian and colleagues reviewed the Massachusetts Eye and Ear Infirmary’s temporal bone collection and identified 8 specimens consistent with an aggressive papillary tumor of the temporal bone. All patients had sensorineural hearing loss (SNHL) and many had a Meniere-like presentation. One patient, a 48-year-old man with von Hippel–Lindau (VHL) disease, had succumbed to what was believed to be metastatic renal cell carcinoma to the left temporal bone. Upon further review, this tumor was more consistent with an ELST. Fortuitously, in this patient’s contralateral temporal bone, a small de novo lesion within the endolymphatic sac was also identified and was histologically identical to the destructive lesion on the left ( Fig. 1 ). This study validated that the epithelium of the endolymphatic sac was capable of producing a low-grade, locally aggressive papillary lesion. It also solidified a predilection for ELST in patients with VHL disease. Subsequently, differences in immunohistochemistry staining patterns between ELST and choroid plexus tumors helped to distinguish these 2 disease entities. Specifically, choroid plexus tumors stain strongly with transthyretin (prealbumin), whereas ELST do not. The confirmation of the origin of ELST and the recognition of sporadic versus VHL-related tumors enabled a better appreciation of the tumor’s behavior, a staging system, and advancements in management as described herein.
Clinical presentation
ELST are rare tumors with approximately 200 cases reported in the literature. The true incidence of these tumors is unknown. Sporadic ELST are more common than those associated with VHL disease and have been diagnosed over a wide age range (15–77 years old) with the average diagnosis occurring in the fifth or sixth decade of life. The sporadic ELST have no gender predilection, whereas tumors associated with VHL have a female preponderance of 2:1.
Cochleovestibular dysfunction is the most common presenting symptom for ELST. Nearly all patients will have some degree of SNHL (86%–100%), which is often asymmetric and corresponds with tumor extension. SNHL that presents as a sudden loss is likely from intralabyrinthine hemorrhage followed by inflammation and neural degeneration. SNHL that has a more gradual progression is caused by either direct invasion of adjacent sensory structures within the otic capsule or the development of endolymphatic hydrops. Tinnitus frequently accompanies the SNHL (71%–89%).
Vertigo and aural fullness are the next most common symptoms affecting 70% and 37% of patients, respectively. As the ELST grows, it blocks endolymph reabsorption and may produce excess fluid, both of which create secondary hydrops. The combination of SNHL, tinnitus, aural fullness, and vertigo mimics Meniere disease and may delay diagnosis. This point illustrates that Meniere disease is a diagnosis of exclusion and imaging to exclude lesions like ELST is a necessary part of the workup.
Other cranial neuropathies may also be present with ELST, but are less common than the previously mentioned symptoms. Facial nerve weakness is seen 5% to 33% of cases. Trigeminal nerve and glossopharyngeal nerve deficits have also been reported. The involvement of other cranial nerves depends on tumor extension, which proceeds along 4 common vectors. From its origin at the posteromedial aspect of the temporal bone, ELST most commonly spread in a posterior direction to the cerebellopontine angle or posterior fossa. If large enough, brainstem compression may contribute to poor vestibular function and cause headache symptoms. Lateral extension via the middle ear and mastoid is the next most common pathway and may involve the facial nerve or produce symptoms that mimic chronic otitis media and Eustachian tube dysfunction. ELST have even been diagnosed as masses in the external auditory canal. Superior extension through the semicircular canals and into the middle fossa can also contribute to imbalance. Finally, anterior extension along the petrous ridge may invade the clivus, cavernous sinus, or sphenoid sinus. Death has been reported secondary to intracranial extension and vascular compromise. There have been no reports of distant hematogenous metastasis, although “drop metastasis” to the spinal column causing lower extremity paralysis has been reported.
Imaging
Characteristic radiographic findings can help to diagnosis ELST and aid in preoperative planning. In 1997, Mukherji and colleagues provided the first comprehensive radiologic review of ELST. Other reports have also added to the radiologic profile.
CT shows enhancing soft tissue masses with bone erosion centered over the endolymphatic sac at the posteromedial temporal bone. Prominent intratumor (central) calcific spiculation and posterior rim calcification are often seen. An intralabyrinthine hyperdense signal on noncontrasted images may suggest an intralabyrinthine hemorrhage in radiographically small or undetectable tumors. On MRI, ELST show heterogenous foci of low and high signal intensity on T1-weighted and T2-weighted imaging. The hyperintense areas on noncontrast T1-weighted MRI is owing to intraparenchymal hemorrhage and subsequent deposition of methemoglobin, hemosiderin, and cholesterol crystals. The hypointense areas may reflect residual bone or prominent calcification. When given contrast, these tumors generally show heterogenous enhancement ( Fig. 2 ).
Angiography may aid in the diagnosis of ELST and may enable preoperative embolization. All ELST are hypervascular. The blood supply primarily arises from the external carotid artery system, although contributions from the internal carotid artery have also been described. The blood supply for the endolymphatic duct arises from either the inferior tympanic artery, a branch of the ascending pharyngeal artery, or the dural branch of the stylomastoid artery, a branch from the posterior auricular artery. Even with these radiographic features, the ELST diagnosis can be challenging to distinguish from other lesions on the differential, such as paraganglioma (glomus jugulare or glomus tympanicum), choroid plexus tumor, metastasis, eosinophilic granuloma, meningioma, arachnoid granulation, aneurysmal bone cyst, or a primary bone tumor.
Von Hippel–Lindau disease
VHL disease was first described in the early 20th century by the German ophthalmologist Eugene von Hippel and the Swedish pathologist Avrid Lindau. VHL disease is an autosomal-dominant, multisystem disorder characterized by cerebellar hemangioblastomas, retinal angiomas, renal or pancreatic cysts, renal cell carcinoma, pheochromocytomas, and other visceral tumors. VHL disease has a prevalence of 1 in 39,000 individuals, of which 11% will develop ELST and, of those patients, 30% will have bilateral lesions.
Since its identification in 1993, the genetics and molecular mechanism of tumorigenesis have been widely studied. The VHL locus at chromosome 3p25.5 encodes pVHL, a tumor suppressor that functions as an ubiquitin ligase targeting hypoxia inducible factor 1-alpha (HIF-1-alpha) for proteasomal degradation. In normal situations, patients have 2 copies of the wild-type (normal) VHL allele. Individuals with VHL disease inherit a mutated copy of the VHL allele. Then when a spontaneous mutation occurs in the other VHL allele, the patient becomes susceptible to VHL-related tumors. HIFs regulate angiogenesis and cell metabolism; thus, VHL-related tumors are often highly vascular. Pharmacologic agents targeting HIF and its downstream targets remain investigational. There are 4 subtypes of VHL disease (types 1, 2A, 2B, and 2C) based on the type of VHL mutation. Although these subtypes can predict clinical disease manifestation, an association between ELST and VHL subtype has not yet been identified. Still, genetic testing to look for a VHL mutation is recommended for all patients with an ELST.
Retrospective studies of ELST in VHL disease and sporadic cases highlight key differences. ELST associated with VHL present at a younger age (range, 7–63 years old; mean, 31.3) and have a female predominance (2:1 ratio). Microscopic tumor foci may explain the observation that 65% of patients with VHL disease demonstrate a degree of SNHL despite only 6% of those patients having detectable tumor on MRI. The slow tumor progression may also explain an average delay of 10 years between onset of symptoms and radiologic tumor detection. Aside from early disease onset, the cochleovestibular manifestations of ELST with or without VHL disease association are similar.
Currently, there are no established international guidelines for surveillance and early detection of ELST. Institutional practices vary and may utilize audiometry and/or MRI to monitor disease progression in patients with known VHL disease. The routine use of MRI every 12 to 36 months for surveillance of hemangioblastomas of the central nervous system has led to earlier ELST detection in patients with VHL disease. Early detection of ELST enables less morbid operations with a better chance of cure and hearing preservation. The prospect of hearing preservation is particularly important for patients with VHL disease who are at increased risk of bilateral ELST.
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