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Cochlear implantation in a bilateral endolymphatic sac tumor patient
International Journal of Pediatric Otorhinolaryngology (2007) 71, 1803—1807
www.elsevier.com/locate/ijporl
CASE REPORTS
Cochlear implantation in a bilateral endolymphatic sac tumor patient A case report ´rez Raffo *, Cecilia Parsini Carlos M. Boccio, Gabriela M. Pe Hospital Italiano de Buenos Aires, ENT, Buenos Aires, Argentina Received 4 May 2007; accepted 10 July 2007 Available online 6 September 2007
KEYWORDS Endolymphatic sac tumor; Von Hippel-Lindau disease; Hearing loss; Cochlear implant
Summary At the present time, the optimal management of patients with locally aggressive ELSTs includes: early diagnosis, surgical complete excision and long term follow up to monitor for recurrent disease. The presence of bilateral tumors produces a significant risk for bilateral profound hearing loss. We report the unusual case of bilateral endolymphatic sac tumor in a 14-year-old girl who presented bilateral anacusis and in whom a cochlear implant was performed after removal of the second tumor. # 2007 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Endolymphatic sac tumors (ELSTs) are low-grade adenocarcinomas originating in the rugose part of the endolymphatic sac. Although ELSTs are known to be locally invasive, they very rarely metastasize [1,2]. In their evolution, they can extend towards the cerebello-pontine angle (CPA) or grow anterolaterally and thus destroy the temporal bone. In 1984, Hassard and Boudreau were the first to relate the origin of this neoplasia to the endolymphatic sac [3]. Later, Heffner, in a revision of 20 cases of cystic-papillary tumors, concluded that they were low-grade adenocarcinomas and confirmed previous findings related to site of origin [4]. In 1993, Li proposed to reclassify this neoplasia as endolymphatic sac tumor (ELST), name it cur* Corresponding author. Tel.: +54 1139581493. E-mail address: [email protected] (G.M.P. Raffo).
rently holds [5]. With the recognition of its entity many cases have been reported in the latest years [6—9]. ELST has been recently recognized as a manifestation of von Hippel-Lindau disease [10]. An unusual case of bilateral presentation in childhood is reported here.
1.1. Case report A 14-year-old female patient presented sudden hearing loss in the right ear, tinnitus, retromastoid pain, and balance problems. The audiogram showed right anacusis and moderate left sensorineural hypoacusis. MRI examination showed a right occupying multilocular mass in the anterior portion of the petrous bone, having liquid content and a 35mm-diameter solid component. It also showed a small lesion located behind the vestibular aqueduct on the left side (Fig. 1).
0165-5876/$ — see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2007.07.011
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C.M. Boccio et al.
Fig. 1 MRI shows a right occupying multilocular mass in the anterior portion of the petrous bone (arrowhead) and a small lesion located behind the vestibular aqueduct on the left side (arrow). C: clivus, SS: sigmoid sinus, MC: mastoid cavity.
The patient had been operated on at a different medical institution and the lesion was partially resected due to intense bleeding. Histopathological report confirmed diagnosis of low-grade adenocarcinoma, probably originating in the endolymphatic sac (Fig. 2). Immunohistochemical evaluation was positive for cytokeratine and vimentin and negative for CD34, S-100 and GFAP. The patient was referred to the Otolaryngology Service of the Hospital Italiano de Buenos Aires (Argentina). On admission, the patient presented right peripheral facial paralysis, balance problems with positive Romberg test and bilateral profound sensorineural hearing loss confirmed by pure tone audiometry and ABR. MRI examination showed surgery had been performed in the right posterior fossa; the petrous bone had been resected and replaced by heterogeneous
Fig. 2 Photomicrograph showing prominent papillary growth pattern, with uniform columnar cells (H&E original magnification 400).
tissue which was shown by contrast-enhanced scan. A small contralateral image in the vestibular region was clearly highlighted (Fig. 3). The CT scan showed a 22-mm lytic lesion with partial contrast enhancement. It affects the lower part of the petrous bone, the mastoid region and the occipital bone base, especially the jugular foramen region (Fig. 4). The patient underwent surgery after selective maxillofacial embolization. Angiography examination showed a hypervascular mass supplied by branches of the right external carotid artery. The afferent vessels are the posterior auricular artery and the occipital branch of the right external carotid artery (Fig. 5). Tumor resection was completed on the right side. Three months later, the contralateral tumor was resected with complete excision at the endolymphatic sac region through a transmastoid approach without complications. A cochlear implant was placed in the same surgical procedure. Due to the patient’s medical record and, specially, due to the bilateral presentation of the tumor, its possible association with von Hippel-Lindau disease was investigated. A thorough clinical and imaging examination ruled out the presence of other tumors. Positron Emission Tomography (PET imaging) performed in the late postoperative course confirmed complete bilateral tumor resection (Fig. 6). Twelve months after the left tumor resection, the patient presented visual acuity reduction because of the presence of bilateral retinal hemangiomas. Genetic studies performed confirmed presumptive diagnosis of von Hippel-Lindau disease. After 3 years of cochlear implant activation, the patient understood open-set language without lip reading at skill level that allowed her answering the phone.
Cochlear implantation in a bilateral endolymphatic sac tumor patient
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Fig. 3 MRI shows that surgery had been performed in the right posterior fossa, the tumor was partially resected and a heterogeneous tissue with contrast-enhanced is observed (black arrow). A small contralateral image in the vestibular region is clearly highlighted (white arrow).
2. Discussion The endolymphatic duct forms from the confluence of the utricular and saccular ducts and ends in the endolymphatic sac, which is formed by three portions: a proximal or intraosseous portion, an intermediate or rugose part (where the tumor originates) and a distal (extraosseous) portion which rests between the layers of the dura [11]. Age of presentation of endolymphatic sac tumors ranges from 25 to 45 years of age, though cases in children and septuagenarians have also been reported. Their incidence is slightly greater among the female population [12].
Fig. 4 CT scan shows a 22-mm lytic lesion with partial contrast enhancement. Calcifications are seen within the lesion (arrowhead). Alteration of the vestibular region is observed in the left ear (arrow).
Clinical symptoms are associated with tumor size and extension and include sensorineural hypoacusis, tinnitus, vertigo and facial paralysis. CT scan shows destruction of the retrolabyrinthine part of the temporal bone and intratumoral calcifications. T1 and T2 MRI examinations show a heterogeneous lesion with hemorrhagic or cystic components [13]. Angiography examination shows highly vascular, easily breakable, polypoid-like lesions, often with areas of cystic degeneration. Histological examination shows papillary architecture with hypervascularized stroma and occasional cystic components with colloid-like proteinaceous content. Lesions have a double layer of cuboidal cells containing a minimum number of atypical cells and with low mitotic rate. Hemorrhagic areas, fibrosis and cholesterol granulomas are frequent. Cytokeratine, vimentin and S100 positivity has been reported in these tumors [11,14,15]. Management of these tumors is essentially surgical through a transtemporal approach in coordination with a neurosurgical team if necessary for complete tumor resection. Radiotherapy is indicated for those cases in which tumor resection was not complete [16]. ELSTs have recently been associated with von Hippel-Lindau disease which is considered an autosomal dominant disorder associated with an anomaly in the tumoral suppressor gene on chromosome 3p 25. Patients presenting von Hippel-Lindau disease are prone to develop a variety of both benign and malignant tumors that include cerebellar heman-
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C.M. Boccio et al.
Fig. 5 Angiography shows a hypervascular mass (arrow) supplied by branches of the right external carotid artery. The afferent vessels are the posterior auricular artery and the occipital branch (arrowhead) of the right external carotid artery. ICA: internal carotid artery, ECA: external carotid artery.
Fig. 6
PET shows a complete bilateral tumor resection.
gioblastomas, renal cell carcinomas, retinal hemangiomas, pancreatic cysts and pheochromacytomas. ELSTs associated with von Hippel-Lindau disease appear to affect younger population and demonstrate a female preponderance [16]. Patients with von Hippel-Lindau disease and ELSTs have an increased incidence of bilateral tumors [16—19] and less advanced lesion compared with those non von Hippel-Lindau disease [16].
3. Conclusion ELSTs are rare tumors, of exceptional presentation in children. Moreover, bilateral presentation is even rarer, being necessary to find out their possible association with von Hippel-Lindau disease. Their management is complex due to their location and high vascularization. Since complete tumor resection is curative, early detection is fundamental.
Cochlear implantation in a bilateral endolymphatic sac tumor patient At the present time, the optimal management of patients with locally aggressive ELSTs includes: early diagnosis, surgical complete excision and long term follow up to monitor for recurrent disease. The presence of bilateral tumors produces a significant risk for bilateral profound hearing loss. When early tumor removal is not possible and hearing preservation is impracticable cochlear implantation should be performed.
References [1] K.Y. Tay, E. Yu, E. Kassel, Spinal metastasis from endolymphatic sac tumor, AJNR Am. J. Neuroradiol. 28 (4) (2007) 613—614. [2] N.C. Bambakidis, T. Rodrigue, C.A. Megerian, R.A. Ratcheson, Endolymphatic sac tumor metastatic to the spine. Case report, J. Neurosurg. Spine 3 (1) (2005) 68—70. [3] A.D. Hassard, S.F. Boudreau, Cron CC adenoma of the endolymphatic sac, J. Otolaringol. 13 (1984) 213—216. [4] K.D. Heffner, Low-grade adenocarcinoma of probable endolymphatic sac origin: a clinicopathologic study of 20 cases, Cancer 64 (1989) 2292—2302. [5] J.C. Li, D.E. Brackmann, W.W. Lo, J.N. Carberry, J.W. House, Reclassification of aggressive adenomatous mastoid neoplasms as endolymphatic sac tumors, Laryngoscope 103 (1993) 1342—1348. [6] A. Banerjee, A. Whyte, P. O’Sullivan, M.D. Atlas, Endolymphatic sac tumor, Otol. Neurotol. 26 (4) (2005) 819—820. [7] J.K. Doherty, M. Yong, D. Maceri, Endolymphatic sac tumor: a report of 3 cases and discussion of management, Ear Nose Throat J. 86 (1) (2007) 30—35. [8] N.C. Cimsit, I.N. Akpinar, N. Kodalli, Endolymphatic sac tumor of temporal bone, JBR-BTR 89 (3) (2006) 120—121.
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[9] T. Wada, T. Fujisaki, H. Satoh, S. Takahashi, Endolymphatic sac tumor located around semicircular canals, Auris Nasus Larynx 33 (2) (2006) 173—177. [10] F. Resche, J.P. Moisan, J. Mantoura, A. de Kersain-gilly, M.J. Andre, I. Perrin-Resche, et al., Haemangioblastoma, haemangioblastomatosis, and Von Hippel-Lindau disease, Adv. Tech. Stand. Neurosurg. 20 (1993) 197—304. [11] G. Kempermann, H.P.H. Neumann, Volk B endolymphatic sac tumor, Histopathology 33 (1998) 2—10. [12] P.S. Richards, G. Cifton, Endolymphatic sac tumor. Radiology in focus, J. Laryngol. Otol. 117 (2003) 666—669. [13] M.E. Kupferman, D. Bigelow, D.F. Carpentiri, L. Bilaniuk, K. Kazahaya, Endolymphatic sac tumor in a 4 year old boy, Otol. Neurootol. 25 (2004) 782—786. [14] R.J. Levin, J.G. Feghali, N. Morganstern, J. Llena, M.K. Bradley, Aggressive Papillary tumors of the temporal bone: an immunohistochemical analysis in tissue culture, Laryngoscope 106 (1996) 144—147. [15] J.G. Feghali, R.J. Levin, J. Llena, M.K. Bradley, A.B. Kantrowitz, Aggressive Papillary tumors of endolymphatic sac. Clinical and tissue culture characteristics, Am. J. Otol. 16 (1995) 778—782. [16] N.C. Bambakidis, C.A. Megerian, R.A. Ratcheson, Differential grading of endolymphatic sac tumor extension by virtue of von Hippel-Lindau disease status, Otol. Neurotol. 25 (5) (2004) 773—781. [17] H.J.H. Deker, E.J. Weidt, J. Brieger, The Von Hippel Lindau tumor suppressor gene, Cancer Genet. Cytogenet. 93 (1997) 74—83. [18] W.G. Kaelin Jr., E.R. Maher, VHL tumor suppressor gene paradigm, Trends Genet. 14 (1998) 423—426. [19] C.A. Megerian, D.S. Haynes, D.S. Poe, D.I. Choo, T.J. Keriakas, M.E. Glasscock, Hearing preservation surgery for small endolymphatic sac tumors in patients with von Hippel-Lindau syndrome, Otol. Neurotol. 23 (3) (2002) 378—387.
www.elsevier.com/locate/ijporl
CASE REPORTS
Cochlear implantation in a bilateral endolymphatic sac tumor patient A case report ´rez Raffo *, Cecilia Parsini Carlos M. Boccio, Gabriela M. Pe Hospital Italiano de Buenos Aires, ENT, Buenos Aires, Argentina Received 4 May 2007; accepted 10 July 2007 Available online 6 September 2007
KEYWORDS Endolymphatic sac tumor; Von Hippel-Lindau disease; Hearing loss; Cochlear implant
Summary At the present time, the optimal management of patients with locally aggressive ELSTs includes: early diagnosis, surgical complete excision and long term follow up to monitor for recurrent disease. The presence of bilateral tumors produces a significant risk for bilateral profound hearing loss. We report the unusual case of bilateral endolymphatic sac tumor in a 14-year-old girl who presented bilateral anacusis and in whom a cochlear implant was performed after removal of the second tumor. # 2007 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Endolymphatic sac tumors (ELSTs) are low-grade adenocarcinomas originating in the rugose part of the endolymphatic sac. Although ELSTs are known to be locally invasive, they very rarely metastasize [1,2]. In their evolution, they can extend towards the cerebello-pontine angle (CPA) or grow anterolaterally and thus destroy the temporal bone. In 1984, Hassard and Boudreau were the first to relate the origin of this neoplasia to the endolymphatic sac [3]. Later, Heffner, in a revision of 20 cases of cystic-papillary tumors, concluded that they were low-grade adenocarcinomas and confirmed previous findings related to site of origin [4]. In 1993, Li proposed to reclassify this neoplasia as endolymphatic sac tumor (ELST), name it cur* Corresponding author. Tel.: +54 1139581493. E-mail address: [email protected] (G.M.P. Raffo).
rently holds [5]. With the recognition of its entity many cases have been reported in the latest years [6—9]. ELST has been recently recognized as a manifestation of von Hippel-Lindau disease [10]. An unusual case of bilateral presentation in childhood is reported here.
1.1. Case report A 14-year-old female patient presented sudden hearing loss in the right ear, tinnitus, retromastoid pain, and balance problems. The audiogram showed right anacusis and moderate left sensorineural hypoacusis. MRI examination showed a right occupying multilocular mass in the anterior portion of the petrous bone, having liquid content and a 35mm-diameter solid component. It also showed a small lesion located behind the vestibular aqueduct on the left side (Fig. 1).
0165-5876/$ — see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2007.07.011
1804
C.M. Boccio et al.
Fig. 1 MRI shows a right occupying multilocular mass in the anterior portion of the petrous bone (arrowhead) and a small lesion located behind the vestibular aqueduct on the left side (arrow). C: clivus, SS: sigmoid sinus, MC: mastoid cavity.
The patient had been operated on at a different medical institution and the lesion was partially resected due to intense bleeding. Histopathological report confirmed diagnosis of low-grade adenocarcinoma, probably originating in the endolymphatic sac (Fig. 2). Immunohistochemical evaluation was positive for cytokeratine and vimentin and negative for CD34, S-100 and GFAP. The patient was referred to the Otolaryngology Service of the Hospital Italiano de Buenos Aires (Argentina). On admission, the patient presented right peripheral facial paralysis, balance problems with positive Romberg test and bilateral profound sensorineural hearing loss confirmed by pure tone audiometry and ABR. MRI examination showed surgery had been performed in the right posterior fossa; the petrous bone had been resected and replaced by heterogeneous
Fig. 2 Photomicrograph showing prominent papillary growth pattern, with uniform columnar cells (H&E original magnification 400).
tissue which was shown by contrast-enhanced scan. A small contralateral image in the vestibular region was clearly highlighted (Fig. 3). The CT scan showed a 22-mm lytic lesion with partial contrast enhancement. It affects the lower part of the petrous bone, the mastoid region and the occipital bone base, especially the jugular foramen region (Fig. 4). The patient underwent surgery after selective maxillofacial embolization. Angiography examination showed a hypervascular mass supplied by branches of the right external carotid artery. The afferent vessels are the posterior auricular artery and the occipital branch of the right external carotid artery (Fig. 5). Tumor resection was completed on the right side. Three months later, the contralateral tumor was resected with complete excision at the endolymphatic sac region through a transmastoid approach without complications. A cochlear implant was placed in the same surgical procedure. Due to the patient’s medical record and, specially, due to the bilateral presentation of the tumor, its possible association with von Hippel-Lindau disease was investigated. A thorough clinical and imaging examination ruled out the presence of other tumors. Positron Emission Tomography (PET imaging) performed in the late postoperative course confirmed complete bilateral tumor resection (Fig. 6). Twelve months after the left tumor resection, the patient presented visual acuity reduction because of the presence of bilateral retinal hemangiomas. Genetic studies performed confirmed presumptive diagnosis of von Hippel-Lindau disease. After 3 years of cochlear implant activation, the patient understood open-set language without lip reading at skill level that allowed her answering the phone.
Cochlear implantation in a bilateral endolymphatic sac tumor patient
1805
Fig. 3 MRI shows that surgery had been performed in the right posterior fossa, the tumor was partially resected and a heterogeneous tissue with contrast-enhanced is observed (black arrow). A small contralateral image in the vestibular region is clearly highlighted (white arrow).
2. Discussion The endolymphatic duct forms from the confluence of the utricular and saccular ducts and ends in the endolymphatic sac, which is formed by three portions: a proximal or intraosseous portion, an intermediate or rugose part (where the tumor originates) and a distal (extraosseous) portion which rests between the layers of the dura [11]. Age of presentation of endolymphatic sac tumors ranges from 25 to 45 years of age, though cases in children and septuagenarians have also been reported. Their incidence is slightly greater among the female population [12].
Fig. 4 CT scan shows a 22-mm lytic lesion with partial contrast enhancement. Calcifications are seen within the lesion (arrowhead). Alteration of the vestibular region is observed in the left ear (arrow).
Clinical symptoms are associated with tumor size and extension and include sensorineural hypoacusis, tinnitus, vertigo and facial paralysis. CT scan shows destruction of the retrolabyrinthine part of the temporal bone and intratumoral calcifications. T1 and T2 MRI examinations show a heterogeneous lesion with hemorrhagic or cystic components [13]. Angiography examination shows highly vascular, easily breakable, polypoid-like lesions, often with areas of cystic degeneration. Histological examination shows papillary architecture with hypervascularized stroma and occasional cystic components with colloid-like proteinaceous content. Lesions have a double layer of cuboidal cells containing a minimum number of atypical cells and with low mitotic rate. Hemorrhagic areas, fibrosis and cholesterol granulomas are frequent. Cytokeratine, vimentin and S100 positivity has been reported in these tumors [11,14,15]. Management of these tumors is essentially surgical through a transtemporal approach in coordination with a neurosurgical team if necessary for complete tumor resection. Radiotherapy is indicated for those cases in which tumor resection was not complete [16]. ELSTs have recently been associated with von Hippel-Lindau disease which is considered an autosomal dominant disorder associated with an anomaly in the tumoral suppressor gene on chromosome 3p 25. Patients presenting von Hippel-Lindau disease are prone to develop a variety of both benign and malignant tumors that include cerebellar heman-
1806
C.M. Boccio et al.
Fig. 5 Angiography shows a hypervascular mass (arrow) supplied by branches of the right external carotid artery. The afferent vessels are the posterior auricular artery and the occipital branch (arrowhead) of the right external carotid artery. ICA: internal carotid artery, ECA: external carotid artery.
Fig. 6
PET shows a complete bilateral tumor resection.
gioblastomas, renal cell carcinomas, retinal hemangiomas, pancreatic cysts and pheochromacytomas. ELSTs associated with von Hippel-Lindau disease appear to affect younger population and demonstrate a female preponderance [16]. Patients with von Hippel-Lindau disease and ELSTs have an increased incidence of bilateral tumors [16—19] and less advanced lesion compared with those non von Hippel-Lindau disease [16].
3. Conclusion ELSTs are rare tumors, of exceptional presentation in children. Moreover, bilateral presentation is even rarer, being necessary to find out their possible association with von Hippel-Lindau disease. Their management is complex due to their location and high vascularization. Since complete tumor resection is curative, early detection is fundamental.
Cochlear implantation in a bilateral endolymphatic sac tumor patient At the present time, the optimal management of patients with locally aggressive ELSTs includes: early diagnosis, surgical complete excision and long term follow up to monitor for recurrent disease. The presence of bilateral tumors produces a significant risk for bilateral profound hearing loss. When early tumor removal is not possible and hearing preservation is impracticable cochlear implantation should be performed.
References [1] K.Y. Tay, E. Yu, E. Kassel, Spinal metastasis from endolymphatic sac tumor, AJNR Am. J. Neuroradiol. 28 (4) (2007) 613—614. [2] N.C. Bambakidis, T. Rodrigue, C.A. Megerian, R.A. Ratcheson, Endolymphatic sac tumor metastatic to the spine. Case report, J. Neurosurg. Spine 3 (1) (2005) 68—70. [3] A.D. Hassard, S.F. Boudreau, Cron CC adenoma of the endolymphatic sac, J. Otolaringol. 13 (1984) 213—216. [4] K.D. Heffner, Low-grade adenocarcinoma of probable endolymphatic sac origin: a clinicopathologic study of 20 cases, Cancer 64 (1989) 2292—2302. [5] J.C. Li, D.E. Brackmann, W.W. Lo, J.N. Carberry, J.W. House, Reclassification of aggressive adenomatous mastoid neoplasms as endolymphatic sac tumors, Laryngoscope 103 (1993) 1342—1348. [6] A. Banerjee, A. Whyte, P. O’Sullivan, M.D. Atlas, Endolymphatic sac tumor, Otol. Neurotol. 26 (4) (2005) 819—820. [7] J.K. Doherty, M. Yong, D. Maceri, Endolymphatic sac tumor: a report of 3 cases and discussion of management, Ear Nose Throat J. 86 (1) (2007) 30—35. [8] N.C. Cimsit, I.N. Akpinar, N. Kodalli, Endolymphatic sac tumor of temporal bone, JBR-BTR 89 (3) (2006) 120—121.
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[9] T. Wada, T. Fujisaki, H. Satoh, S. Takahashi, Endolymphatic sac tumor located around semicircular canals, Auris Nasus Larynx 33 (2) (2006) 173—177. [10] F. Resche, J.P. Moisan, J. Mantoura, A. de Kersain-gilly, M.J. Andre, I. Perrin-Resche, et al., Haemangioblastoma, haemangioblastomatosis, and Von Hippel-Lindau disease, Adv. Tech. Stand. Neurosurg. 20 (1993) 197—304. [11] G. Kempermann, H.P.H. Neumann, Volk B endolymphatic sac tumor, Histopathology 33 (1998) 2—10. [12] P.S. Richards, G. Cifton, Endolymphatic sac tumor. Radiology in focus, J. Laryngol. Otol. 117 (2003) 666—669. [13] M.E. Kupferman, D. Bigelow, D.F. Carpentiri, L. Bilaniuk, K. Kazahaya, Endolymphatic sac tumor in a 4 year old boy, Otol. Neurootol. 25 (2004) 782—786. [14] R.J. Levin, J.G. Feghali, N. Morganstern, J. Llena, M.K. Bradley, Aggressive Papillary tumors of the temporal bone: an immunohistochemical analysis in tissue culture, Laryngoscope 106 (1996) 144—147. [15] J.G. Feghali, R.J. Levin, J. Llena, M.K. Bradley, A.B. Kantrowitz, Aggressive Papillary tumors of endolymphatic sac. Clinical and tissue culture characteristics, Am. J. Otol. 16 (1995) 778—782. [16] N.C. Bambakidis, C.A. Megerian, R.A. Ratcheson, Differential grading of endolymphatic sac tumor extension by virtue of von Hippel-Lindau disease status, Otol. Neurotol. 25 (5) (2004) 773—781. [17] H.J.H. Deker, E.J. Weidt, J. Brieger, The Von Hippel Lindau tumor suppressor gene, Cancer Genet. Cytogenet. 93 (1997) 74—83. [18] W.G. Kaelin Jr., E.R. Maher, VHL tumor suppressor gene paradigm, Trends Genet. 14 (1998) 423—426. [19] C.A. Megerian, D.S. Haynes, D.S. Poe, D.I. Choo, T.J. Keriakas, M.E. Glasscock, Hearing preservation surgery for small endolymphatic sac tumors in patients with von Hippel-Lindau syndrome, Otol. Neurotol. 23 (3) (2002) 378—387.