endolymphatic_sac_tumor

Endolymphatic sac tumor

Endolymphatic sac tumor (ELST) is a non-metastasizing low-grade adenocarcinoma of endolymphatic sac origin. It is also known as Heffner tumour, low-grade adenocarcinoma of endolymphatic sac origin and aggressive papillary middle ear tumor.

Endolymphatic sac tumors may present as sporadic or may be associated with Von Hippel-Lindau disease. 1).

The tumor affects adults of both sexes 2).


Endolymphatic sac tumors (ELST) (the endolymphatic sac is a cul-de-sac in the petrous portion of the temporal bone in the middle fossa just deep to the dura that communicates with the saccule of the inner ear):

a) locally invasive benign tumors that occur in 10–15% of VHL patients(30% of these will develop bilateral ELSTs—VHL is the only disease with bilateral ELSTs). Rarely metastasize

b) presents with hearing loss in 95% (may be acute(86%) or insidious(14%),tinnitus(90%),vertigo or imbalance (66%), aural fullness (30%), and facial paresthesias (8%))

c) mean age of onset of hearing loss: 22 years (range: 12–50)

Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumors (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of a study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumors.

Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis.

VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic and one VHL-disease-related ELSTs (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs, but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test).

Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs 3).

Patients generally present with hearing loss, tinnitus and vertigo.

The clinical prodrome is prolonged. Presenting signs and symptoms most often relate to the involvement of cranial nerves V-VIII 4).

Imaging studies reveal large, enhancing, destructive tumors with a generous vascular supply 5).

ELSTs present as locally destructive lesions with characteristic computed tomography imaging features. Histologically, they show papillary, cystic or glandular architectures. Immunohistochemically, they express keratin, EMA, and variably S100 and GFAP. Currently, it is recommended that, given its rarity, ELST needs to be differentiated from other entities with similar morphologic patterns, particularly other VHL-associated neoplasms such as metastatic clear cell renal cell carcinoma (ccRCC) 6).

The definitive diagnosis requires a combination of clinical features, radiological finding, and pathological correlation 7).

Intraoperatively, the tumors are bloody, fibrous, and adherent to surrounding structures. Various surgical approaches in combination or in series may be used. Preoperative embolization may be helpful. The role of adjunctive radiation is unclear. Aggressive papillary middle ear tumors are histologically benign tumors with clinically destructive behavior. However, it appears that aggressive surgical management affords prolonged survival with minimal worsening of cranial nerve deficits 8).

Pre-operative embolization of the vessels supplying the tumor may reduce blood loss during surgical excision. Radiotherapy could be considered for any residual tumor 9)

Chang et al. demonstrated a difficult case of endolymphatic sac tumor and how it is managed via transcanal endoscopic assisted technique, with a discussion of the feasibility of transcanal approach to lateral skull base tumor 10).

Forty-six tumors from 42 patients were independently analyzed. The overall tumor control rate was 67.4%. When analyzing patients in which tumor was present at the time of radiation, external beam radiation controlled 9 of 19 tumors (47.4%) while stereotactic radiosurgery controlled 14 of 18 tumors (77.8%). The effect size of 30.4% favors stereotactic radiosurgery, but the wide confidence interval (-4.4 to 57.4%) limits what conclusions can be drawn. Radiation for ELST remains controversial and more long-term data is needed 11).

In accordance with PRISMA guidelines a systematic literature search of the Ovid Medline, Embase, Scopus, Cochrane Library, and clinicaltrails.gov databases was performed in August 2017.

Twenty-two studies met inclusion criteria and report ELST outcomes following radiation therapy. Additional data on tumor size, previous surgery, radiation modality, and radiation dosing was collected.

The methodological quality was independently assessed by three reviewers. The included studies were small, heterogeneous case reports with a low level of evidence, and several sources of bias.

The primary outcome was tumor control following radiation, defined as no growth. A comparative analysis of external beam versus stereotactic radiation was performed.

Forty-six tumors from 42 patients were independently analyzed. The overall tumor control rate was 67.4%. When analyzing patients in which tumor was present at the time of radiation, external beam radiation controlled 9 of 19 tumors (47.4%) while stereotactic radiosurgery controlled 14 of 18 tumors (77.8%). The effect size of 30.4% favors stereotactic radiosurgery, but the wide confidence interval (-4.4 to 57.4%) limits what conclusions can be drawn. Radiation for ELST remains controversial and more long-term data is needed 12).

Nineteen ELST cases were studied. Immunohistochemistry (18/19) and single nucleotide polymorphism microarray testing was performed (12/19). A comparison with the immunophenotype and copy number profile in RCC is discussed. Patients presented with characteristic bone destructive lesions in the petrous temporal bones. Pathology of tumors showed characteristic ELST morphology with immunoexpression of CK7, GFAP, S100, PAX-8, PAX-2, CA-9 in the tumor cells. Immunostained for RCC, CD10, CK20, chromogranin A, synaptophysin, TTF-1, thyroglobulin, and transthyretin were negative in the tumor cells. Molecular testing showed loss of 3p and 9q in 66% (8/12) and 58% (7/12) cases, respectively. Immunoreactivity for renal markers in ELST is an important diagnostic caveat and has not been previously reported. In fact, renal markers are currently recommended in order to rule out metastatic RCC although the PAX gene complex and CA-9 have been implicated in the development of the inner ear. Importantly copy number assessment of ELST has not been previously reported. Loss of 3p (including the VHL locus) in ELST suggests similar mechanistic origins as ccRCC 13).

Chang et al. demonstrated a difficult case of endolymphatic sac tumor and how it is managed via transcanal endoscopic assisted technique, with a discussion of the feasibility of transcanal approach to lateral skull base tumor 14).


A 63 yr old lady who presented with left sided facial palsy. Since the tumour was highly vascular and required preoperative embolization, initial clinicoradiological diagnosis was Jugulotymphanic paraganglioma. Histopathology showed features of Endolymphatic sac tumour, which was confirmed by immunohistochemistry. Since this tumour is locally aggressive low grade adenocarcinoma, the diagnosis is difficult in advanced cases where there is erosion of petrous temporal bone or the lesion shows extension into cerebellopontine angle as in our case. Since the association of this tumour with VHL disease is well established, it is important to screen all the patients of VHL disease for this lesion and also all the patients of ELST should be screened for other lesions of VHL disease to aid in early diagnosis and treatment. The case is presented here for its rarity and difficulty in initial diagnosis 15).


A twenty-five-year-old female presented with a five-year history of chronic ear discharge left-sided facial weakness, and recent onset of ataxia.

The unusual clinical presentation made management challenging, in large part due to profuse bleeding. Pre-operative embolization of the vessels supplying the tumor may reduce blood loss during surgical excision. Radiotherapy could be considered for any residual tumor.

The patient was diagnosed with an endolymphatic sac tumor of sporadic origin which presented at the cerebellopontine angle and was managed with a multidisciplinary approach 16).


A 54-year-old man presented with right-sided ear pain associated with dizziness and hearing loss. The radiological diagnosis was in favor of acoustic neurinoma. Surgical excision was performed and the diagnosis of the endolymphatic sac tumor was made 17).


A 65-year-old patient underwent GKRS of an unresectable, recurrent ELST. Tumor volumetric analysis showed an almost 15% increase in tumor volume in the 4 months between the pre-GKRS magnetic resonance imaging (MRI) and the stereotactic MRI (s-MRI) at treatment. Follow-up MRI at 12 and 20 months showed a significant decrease in local tumor volume, decreased contrast enhancement and no perifocal edema. The patient's general and neurological status remains stable to the present day.

In the present case, GKRS was effective in the management of a recurrent ELST over the course of 20 months. Because of ELSTs recurrence potential, long-term follow up is required. The present case, as well as previous reports, might suggest a possible salvage/adjunctive role of radiosurgery in the management of ELST. Further studies are deemed necessary 18).


Two additional cases and discuss the clinical, radiologic, histologic, and operative features 19).

Endolymphatic sac tumor unclassified


1)
Tibbs RE Jr, Bowles AP Jr, Raila FA, Fratkin JD, Hutchins JB. Should endolymphatic sac tumors be considered part of the von Hippel-Lindau complex? Pathology case report. Neurosurgery. 1997 Apr;40(4):848-55; discussion 855. Review. PubMed PMID: 9092862.
2) , 4) , 5) , 8) , 19)
Polinsky MN, Brunberg JA, McKeever PE, Sandler HM, Telian S, Ross D. Aggressive papillary middle ear tumors: a report of two cases with review of the literature. Neurosurgery. 1994 Sep;35(3):493-7; discussion 497. PubMed PMID: 7800140.
3)
Schweizer L, Thierfelder F, Thomas C, Soschinski P, Kim HY, Jödicke R, Woltering N, Förster A, Teichmann D, Siewert C, Klein K, Schmid S, Nunninger M, Thomale UW, Onken J, Mühleisen H, Schittenhelm J, Tatagiba M, von Deimling A, Reuss DE, Solomon DA, Heppner FL, Koch A, Hartmann C, Staszewski O, Capper D. Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours. Neuropathol Appl Neurobiol. 2021 Jun 5. doi: 10.1111/nan.12741. Epub ahead of print. PMID: 34091929.
6) , 13)
Jester R, Znoyko I, Garnovskaya M, Rozier JN, Kegl R, Patel S, Tran T, Abedalthagafi M, Horbinski CM, Richardson M, Wolff DJ, Lapadat R, Moore W, Rodriguez FJ, Mull J, Olar A. Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls. Acta Neuropathol Commun. 2018 Oct 19;6(1):107. doi: 10.1186/s40478-018-0607-0. PubMed PMID: 30340515; PubMed Central PMCID: PMC6194746.
7) , 17)
Elktaibi A, Damiri A, Rharrassi I, Elochi MR, Oukabli M, Akhaddar A, Boucetta M, Al Bouzidi A. A rare tumour in the cerebellopontine angle: endolymphatic sac tumour. Pan Afr Med J. 2018 Oct 19;31:127. doi: 10.11604/pamj.2018.31.127.3962. eCollection 2018. PubMed PMID: 31037187; PubMed Central PMCID: PMC6462390.
9) , 16)
Alkhotani A, Butt B, Khalid M, Binmahfoodh M, Al-Said Y. Endolymphatic sac tumor at the cerebellopontine angle: A case report and review of literature. Int J Surg Case Rep. 2019;58:162-166. doi: 10.1016/j.ijscr.2019.04.032. Epub 2019 Apr 28. PubMed PMID: 31051407; PubMed Central PMCID: PMC6495091.
10) , 14)
Chang WT, Tam KY, Yao H, Chow KH, Fai Tong MC. Transcanal endoscopic assisted skull base endolymphatic sac tumor resection: A rare disease with advanced technology. J Otol. 2020 Mar;15(1):1-5. doi: 10.1016/j.joto.2019.06.001. Epub 2019 Jul 3. PubMed PMID: 32110234; PubMed Central PMCID: PMC7033593.
11) , 12)
Wick CC, Eivaz NA, Yeager LH, Hunter JB, Isaacson B, Kutz JW Jr. Case Series and Systematic Review of Radiation Outcomes for Endolymphatic Sac Tumors. Otol Neurotol. 2018 Jun;39(5):550-557. doi: 10.1097/MAO.0000000000001804. PubMed PMID: 29738384.
15)
Rajeshwari B, Shanmugam S, Sadiya N, Mitra G, Chendilnathan B. “Endolymphatic sac tumour”: A case report with review of literature. Indian J Pathol Microbiol. 2019 Oct-Dec;62(4):608-610. doi: 10.4103/IJPM.IJPM_345_18. Review. PubMed PMID: 31611452.
18)
Sinclair G, Al-Saffar Y, Brigui M, Martin H, Bystam J, Benmakhlouf H, Shamikh A, Dodoo E. Gamma knife radiosurgery in the management of endolymphatic sac tumors. Surg Neurol Int. 2018 Jan 25;9:18. doi: 10.4103/sni.sni_312_17. eCollection 2018. PubMed PMID: 29497571; PubMed Central PMCID: PMC5806423.
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