Endolymphatic sac tumor: a report of 3 cases and discussion of management.

Abstract

Patients with an endolymphatic sac tumor (ELST) typically present with palsy of cranial nerves VII and/or VIII; other presenting symptoms include hearing loss, otalgia, occipital headaches, cranial nerve palsies, vertigo, gait ataxia, tinnitus, and otorrhea. ELSTs are extremely vascular, and they can invade and destroy temporal bone. Because of these characteristics, they are often mistaken for glomus tumors of the skull base. We describe the clinical presentation, evaluation, and management of ELSTs based on our review of the limited literature and our experience with 3 adults who presented to our tertiary care referral center with large ELSTs. Although these patients presented late in the course of their disease, their symptoms were relatively minor. Preoperative tumor embolization was performed, and a near-complete resection was achieved via an extended transotic approach in all 3 patients. The facial nerve was preserved without transposition in the first patient, the second patient underwent a primary nerve anastomosis, and the third required a cable graft of the facial nerve. Postoperative radiation therapy was administered to 2 of these patients. Follow-up by MRI detected no evidence of recurrence in any of the 3 patients.

Introduction

Endolymphatic sac tumors (ELSTs) are extremely rare, slowly growing, low-grade adenocarcinomas that are associated with von Hippel-Lindau (VHL) disease. Approximately 88 cases of documented ELST have been previously reported. (1-9) These tumors are generally considered to be benign on the basis of their histologic characteristics, yet they behave clinically in an aggressive manner. One of the sequelae is temporal bone destruction that frequently involves the cerebellopontine angle and petrous apex by direct extension. ELSTs can become quite extensive before significant symptoms develop. Cranial nerve involvement is typical. In this article, we describe 3 new cases of ELST. These tumors were large and extensive, and they were resected via a transotic craniotomy approach following tumor embolization.

Case reports

Patient 1. A 26-year-old man presented to the emergency room complaining of left-sided otalgia, otorrhea, and hearing loss of 3 months' duration. In addition, he had been suffering from headaches, mild gait ataxia, and occasional attacks of vertigo. He was in good health, he had no history of childhood ear infections or ear surgery, and he denied head and otologic trauma.

Physical examination revealed House-Brackmann (10) grade II/VI left peripheral facial palsy. In addition, the patient had hypoesthesia of the left trigeminal nerve and a severe to profound mixed hearing loss on the left. Bone-conduction thresholds at 500, 1,000, 2,000, and 3,000 Hz averaged 85 dB, and air-conduction thresholds sloped from 115 dB. Audiometry on the right demonstrated a mild sensorineural hearing loss, with air- and bone-conduction thresholds at 500, 1,000, 2,000, and 3,000 Hz averaged at 30 dB. The left external auditory canal was filled with purulent debris, which was suctioned and cultured. The tympanic membrane was thickened, and it exhibited a small (1 to 2 mm) posterior perforation that was surrounded by granulation tissue.

Computed tomography (CT) of the temporal bones revealed opacification of the left mastoid and middle ear. The ossicles were intact. Extensive bone erosion of the petrous apex extended into the internal auditory canal (figure 1, A). Based on this study, a preliminary diagnosis of otomastoiditis with osteomyelitis was made. Myringotomy was performed, and pulsatile clear fluid drained through the defect. The fluid was cultured and examined for glucose and B2-transferrin levels. The patient was admitted to the hospital for intravenous antibiotics (ceftazidime and tobramycin), and he was also treated with ofloxacin otic drops. Yet despite antibiotic therapy, the otorrhea failed to abate.

[FIGURE 1 OMITTED]

Magnetic resonance imaging (MRI) of the temporal bones was performed. T1-weighted noncontrast sequences detected a 5.0 x 4.4 x 4.5-cm multilobulated mass with heterogenous enhancement in the left cerebellopontine angle (figure 1, B). Axial (figure 1, C) and coronal (figure 1, D) gadolinium-enhanced, T1-weighted MRIs demonstrated central enhancement of the mass, petrous bone destruction, and obliteration of the internal auditory canal. The tumor mass involved the jugular foramen inferiorly and extended into the cavernous sinus surrounding the carotid artery. The mass extended medially with cerebellar compression. The pre-operative differential diagnosis included glomus tumor (vagale or jugulare), meningioma, ELST, choroid plexus papilloma, and aneurysmal bone cyst.

Surgical excision with preoperative tumor embolization was planned. Cerebral angiography revealed that the tumor was primarily supplied by three branches of the left external carotid artery--the left posterior occipital artery, the ascending pharyngeal artery, and the posterior auricular artery--with a minor contribution from the petrous branch of the left internal carotid artery. The contributing branches of the left external carotid artery were successfully embolized with polyvinyl alcohol. Blood supply to the tumor after embolization was estimated to have been reduced by at least 60%. Within 24 hours, the patient was taken to surgery, and he underwent a left transotic (translabyrinthine and transcochlear) craniotomy for tumor resection.

The procedure involved making a postauricular incision that extended into the neck. The great vessels and lower cranial nerves were isolated in the neck and traced back to the skull base. The left external auditory canal was closed in two layers, and a blind pouch was created in the manner described by Jackler. (11) This was done to isolate the surgical resection and prevent cerebrospinal fluid leak. Complete mastoidectomy was performed, and the sigmoid sinus was skeletonized from the lateral sinus to the jugular bulb below. The tumor was encountered in the mastoid antrum adjacent to the incus. The mass was spongy, reddish-tan to brown, and extremely vascular. Findings on frozen-section analysis of its cystic components were consistent with a glomus tumor.

The mass extended posteriorly to, but did not involve, the sigmoid sinus lumen. The pre- and postsigmoid dura was skeletonized, and the facial nerve was completely dissected throughout its intratemporal course. The bony covering of the facial nerve was left intact. The decision was made not to transpose the nerve but rather to remove the tumor from around the nerve. The tumor had invaded the internal auditory canal below the superior semicircular canal, and it extended anteriorly to the carotid artery. The tumor's intracranial component was found to extend along the petrous ridge to the cavernous sinus anteriorly and to the jugular foramen inferiorly. The tumor's posterior fossa component was entirely extradural.

Near-total tumor removal was accomplished. Residual tumor was left along the carotid artery in the cavernous sinus, and postoperative radiotherapy was planned. The dural defect was closed with a large autologous fat graft that extended into the mastoid region, and the skin was closed in two layers. The total amount of blood loss was estimated to be 3,800 ml.

Postoperatively, the patient had grade III/VI facial paresis and left vocal fold paresis; the latter was probably caused by extensive dissection at the jugular foramen. The patient was discharged on postoperative day 7. On postoperative day 15, he was readmitted with a pseudomeningocele at the incision site. He did not have any fever, chills, or meningeal signs. The wound was treated with compressive dressings for 5 days, and the problem resolved.

Final tumor pathology revealed a highly vascular stroma with multiple cystic spaces, focal calcifications, and a papillary architecture (figure 2, A). Individual nonciliated low cuboidal tumor cells had well-defined borders and bland nuclei that were uniform in size (figure 2, B). Immunohistochemical stains were positive for cytokeratin, vimentin, neuron-specific enolase, and epithelial membrane antigen. The stains were negative for thyroglobulin. The final diagnosis was a low-grade papillary adenocarcinoma consistent with an ELST.

[FIGURE 2 OMITTED]

The patient subsequently underwent radiation therapy to treat the residual tumor that had been left in the cavernous sinus. At the 1-year follow-up, he exhibited no radiologic or clinical evidence of residual or recurrent disease. His facial nerve function had returned to its preoperative state (grade II), and his left vocal fold paresis had completely resolved. A further workup was undertaken to look for evidence of VHL disease--such as retinal hemangioblastomas, central nervous system hemangioblastomas, renal cysts, pheochromocytoma, or pancreatic tumors (12)--and no such abnormalities were detected.

Patient 2. A 26-year-old woman presented with a 3-month history of progressive left facial weakness and otalgia. Her history was relevant for a progressive left-sided hearing loss with tinnitus, which she attributed to a motor vehicle accident 3 years earlier. Her history was otherwise unremarkable.

Physical examination revealed grade V left facial nerve palsy. The left eardrum was intact and mobile, but there was a bluish hue behind it, and a red mass could be seen in the hypotympanum. The mass did not blanch with insufflation. The right ear was normal. Audiometry revealed a complete sensorineural hearing loss on the left, with only vibrotactile sensation. Hearing on the right was normal with a pure-tone average threshold of 5 dB.

CT of the temporal bones identified a destructive lesion involving the left mastoid, petrous apex, and cerebellopontine angle. MRI demonstrated a heterogenously enhancing mass of the left cerebellopontine angle that measured approximately 6.4 x 5.7 x 3.0 cm. The MRI also detected evidence of bone destruction and tumor extension into the posterior fossa, jugular foramen, and mastoid air cells. A preliminary diagnosis of glomus tumor was made; the differential diagnosis included ELST and hemangiopericytoma.

Preoperative angiography revealed that the extremely vascular mass was supplied by branches of the left external carotid artery, including the meningeal branch of the occipital artery, the ascending pharyngeal artery, and the middle meningeal artery. All three of these branches were successfully embolized with polyvinyl alcohol.

Within 48 hours of embolization, the patient was taken to the operating room for tumor resection. A transotic craniotomy with anterior facial nerve transposition was required. The tumor had invaded the jugular bulb and encroached on the sigmoid sinus, requiring sacrifice of those structures. The tumor had grossly invaded the facial nerve at the second genu, as well as the vestibulocochlear nerve at the cerebellopontine angle. Approximately 7 mm of involved facial nerve was resected, and a primary anastomosis was performed. The VIIIth nerve was sacrificed. The tumor involved the middle fossa and posterior fossa dura, requiring dural resection and grafting with a rectus abdominus fascia graft. An abdominal fat graft was used to obturate the dural defect. There was no tumor involvement of the temporal lobe or cerebellum. The total amount of intraoperative blood loss was estimated to be 800 ml.

The patient's facial paresis progressed to grade VI/VI after surgery. She did well postoperatively and was discharged home on postoperative day 7. The final pathologic diagnosis was ELST; permanent sections showed hemorrhagic stroma with papillary fronds covered by columnar epithelium (figure 3). In view of this diagnosis, abdominal CT was performed to look for evidence of VHL disease, and none was found. The patient then received 4,500 cGy of external-beam irradiation to the tumor bed without consequence. Her facial nerve function improved to grade IV. At the 3-year follow-up, she remained free of disease.

[FIGURE 3 OMITTED]

Patient 3. An otherwise-healthy, 54-year-old woman presented to the otolaryngology clinic complaining of an 11-month history of right-sided hearing loss and tinnitus. She denied otalgia, otorrhea, vertigo, headache, or weight loss. Her medical history was significant only for a motor vehicle accident 1 year earlier, which had preceded the onset of her symptoms by approximately 1 month. Her family history and review of systems were noncontributory.

Physical examination revealed right-sided cranial nerve VIII dysfunction, which was evident on tuning-fork testing and audiometry. The patient's facial function was grade I. Findings on inspection of the ear were normal except for a bluish hue in the right middle ear space. Tympanometry revealed normal mobility bilaterally. Audiometry reflected a profound sensorineural hearing loss on the right, with no response at 100 dB. The pure-tone average air-conduction threshold on the left was 12 dB.

CT of the temporal bones revealed a destructive lesion of the fight petrous apex, and MRI showed a 3.8 x 3.0 x 2.8-cm heterogenously enhancing mass of the right petrous apex. The results of a mammogram and CT of the abdomen and pelvis were normal. A preliminary diagnosis of ELST versus glomus tumor was made.

Preoperatively, successful embolization of the tumor's blood supply from branches of the fight postauricular artery, the ascending pharyngeal artery, and a posterior branch of the right middle meningeal artery was performed.

The following morning, the patient underwent tumor resection via a right transotic craniotomy. The tumor had filled the middle ear space, and it appeared to have arisen from the medial wall of the tympanic cavity. The mass surrounded the stapes and involved the facial nerve. The facial nerve was skeletonized and transposed anteriorly. The involved facial nerve was resected and cable-grafted with the right great auricular nerve. The tumor was found to have invaded the cochlea and most of the labyrinth. Intracranially, the tumor extended inferiorly along the temporal bone, requiting a delicate dissection of the lower cranial nerves (IX, X, and XI). The tumor had also invaded the posterior fossa dura, which was resected and grafted with rectus abdominus fascia. Findings on intraoperative frozen-section analysis were consistent with an ELST. Near-total tumor removal was achieved. The estimated total amount of intraoperative blood loss was 1,800 ml.

Final pathology confirmed that the tumor was an adenocarcinoma of endolymphatic sac origin. Foam cells (i.e., macrophages with vacuolated cytoplasm) with pigmented cytoplasmic granules, presumably containing hemosiderin, were abundant within papillary fronds, which were lined with ciliated low cuboidal epithelium (figure 4).

[FIGURE 4 OMITTED]

Postoperatively, the patient exhibited dysphagia, hoarseness, and grade VI right facial palsy. Flexible laryngoscopy performed at the bedside revealed paralysis of the fight true vocal fold. A swallowing evaluation did not demonstrate aspiration, and the patient was able to tolerate a thin dysphagia diet. Appropriate eye care was also initiated.

One week postoperatively, the patient underwent implantation of a gold weight in the right upper eyelid to facilitate eye closure and protect the cornea. In addition, she received an injection of autologous fat into the right vocal fold to improve vocalization. Her voice improved notably, and she was discharged from the hospital on the following day. A workup for VHL disease was negative.

The patient was scheduled to undergo postoperative radiotherapy, but she refused any further treatment. Within 6 months, her fight facial palsy improved to grade IV, and the gold weight was subsequently removed from her right upper eyelid. Although her fight vocal fold function had not improved, she refused medialization thyroplasty. At 4 years postoperatively, she remained free of disease.

Discussion

The ELST was first reported by Treitel in 1898 as an adenocarcinoma of the middle ear. (13) Nearly a century later, Heffner correctly described the entity as a low-grade adenocarcinoma and recognized its origin as the endolymphatic sac. (14)

The endolymphatic sac lies between the petrous periosteum and the posterior fossa dura, near the sigmoid sinus and jugular bulb, and posterior to the internal auditory canal. Its putative function is to regulate endolymphatic pressure, fluid volume, and ionic balance within the inner ear. (15,16) ELSTs are neuroectodermal tumors that are believed to arise from the proximal, rugose portion of the endolymphatic sac, which is intratemporal, as opposed to the distal portion of the sac, which lies adjacent to the dura. (15,17)

Signs and symptoms. ELSTs usually present in the third and fourth decades of life, and there is a slight female preponderance. (12) Patients may present with hearing loss, otalgia, occipital headaches, cranial nerve palsies, vertigo, gait ataxia, tinnitus, and otorrhea. Cranial nerve involvement is usually limited to the vestibulocochlear and facial nerves, but trigeminal and abducens nerve palsies have also been reported. (18) Our patient 1 presented with a trigeminal nerve abnormality. Gait ataxia may indicate cerebellar compression, usually caused by a large tumor.

Otorrhea is an unusual presenting symptom in patients with ELST, but when it does occur, it may indicate (1) eustachian tube dysfunction caused by either direct tumor involvement or compression or (2) a destructive process involving the middle ear and/or mastoid. A delay in diagnosis may occur if the patient is mistakenly diagnosed with chronic otitis media. (12) Jugular foramen syndrome has also been reported. (14,19)

Pathogenesis. ELST is strongly associated with VHL disease, a hereditary cancer syndrome. (12,20-22) Mutation of the VHL gene within ELST cells has been demonstrated in patients who have no other manifestations of VHL disease, which suggests that somatic mutation of the gene is an inciting factor in tumorigenesis. (20,22-24)

The VHL gene is a tumor suppressor that regulates extracellular matrix formation, the cell cycle, and transcription of vascular endothelial growth factor, a proto-oncogene that promotes angiogenesis. (21,25) When the VHL gene is inactivated by deletion or mutation, vascular endothelial growth factor is unregulated and overexpressed, resulting in the development of the vascular tumors that are typical of VHL disease. The most common manifestations of VHL disease are retinal hemangioblastomas, central nervous system hemangioblastomas, and visceral tumors. (12)

The VHL gene is located at 3p25.5, and genetic testing for common mutations is now available. (21) Because ELST may be a manifestation of VHL, patients with documented ELSTs should undergo a workup for VHL disease. Specifically, an abdominal CT and a thorough retinal examination are indicated.

Diagnosis. CT findings in patients with ELST include retrolabyrinthine bone destruction between the fundus of the internal auditory canal and the sigmoid sinus. Irregular bone margins are characteristic of destruction; also, intratumoral bone is evident in many cases. (26) MRI typically reveals a heterogenous mass with hypo-, hyper-, and isointense foci on T1- and T2-weighting and variable enhancement with contrast. (26)

Histologically, ELSTs have abenign appearance, displaying hemorrhagic, highly vascularized stroma with cystic spaces and focal calcifications. Cells form a papillary architecture, with individual cells having well-defined borders and bland nuclei (uniformly round and small to medium in size). Cells may vary between ciliated or nonciliated and columnar or low cuboidal, as was seen in all 3 cases presented here. Foam cells with vacuolated cytoplasm may be present, and they often have pigmented cytoplasmic granules containing hemosiderin. (27,28)

Treatment. Surgical resection is the treatment of choice. The type of surgical approach is dictated by the location and extent of the tumor and the patient's preoperative functional deficits.

Of the previously reported cases (1-9) of documented ELST, preoperative embolization was performed in only 2, (29) and in both cases, it was found to be beneficial in limiting the amount of intraoperative blood loss. Embolization was performed in all 3 of the cases described in this article, and it was successful in all of them.

Resection of ELSTs has been performed via a variety of neurotologic and skull base approaches, including retrosigmoid, suboccipital, transcochlear, transpetrosal, translabyrinthine, and transmastoid craniotomy approaches. (1,12,14) Large tumors with anterior and inferior extension approaching the clivus and jugular foramen, respectively, typically require an extended transcochlear approach, including facial nerve transposition. (11) Rerouting of the facial nerve usually results in total but transient postoperative facial palsy; the palsy generally resolves in 6 to 12 months, but the resulting synkinesis and asymmetry may not. Furthermore, posterior transposition requires severing the chorda tympani and greater superficial petrosal nerves, which results in transient dysgeusia and an ipsilateral dry eye. (11) Our patient 1 underwent a successful transotic resection without the need for facial nerve rerouting or transposition.

The indications for postoperative radiation therapy are still controversial. Although 50% efficacy has been reported for the treatment of ELST with radiotherapy alone, a 90% cure rate has been reported for complete ELST excision without radiation. (14) The newer stereotactic radiosurgery modalities such as the gamma knife and cyberknife need to be considered as adjuncts to surgical therapy. The paucity of cases in which treatment modalities and outcomes were reported makes the decision difficult. In the 3 cases reported here, extensive tumor involvement precluded complete microscopic tumor removal, and postoperative radiotherapy was recommended in all 3 cases. Further studies are needed to investigate the role of postoperative radiation in ELST because local recurrences are problematic. No case of metastasis has been reported.

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Joni K. Doherty, MD, PhD; Mona Yong, MD; Dennis Maceri, MD

From the Department of Otolaryngology-Head and Neck Surgery (Dr. Doherty and Dr. Maceri) and the Department of Pathology (Dr. Yong), LAC+USC Medical Center, University of Southern California, Los Angeles.

Reprint requests: Joni K. Doherty, MD, Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, University of California, San Diego, 3350 La Jolla Village Dr., 9112C, La Jolla, CA 92093-9112. Phone: [phone]; fax: [phone]; e-mail: [e-mail]