Download Solid Tumour Section Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)

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Solid Tumour Section
Review
Head and Neck: Ear: Endolymphatic Sac Tumor
(ELST)
Rodney C Diaz
Department of Otolaryngology-Head and Neck Surgery, University of California Davis Medical Center,
Sacramento, California 95817, USA (RCD)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Tumors/EndolymphaticSacTumID5096.html
DOI: 10.4267/2042/44722
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Clinics and pathology
Alias
Low Grade Papillary Adenocarcinoma of the
Endolymphatic Sac, Papillary Adenoma of the
Endolymphatic Sac.
Note
Endolymphatic sac tumors (ELSTs) are rare tumors of
the petrous temporal bone. Classified as mastoid
papillary tumors of unknown origin, these tumors were
synthesized into a new, distinct clinico-pathological
entity by Heffner in 1989. Initially described as a low
grade papillary adenocarcinoma, their histologic
appearance and apparent lack of metastatic potential
has since persuaded most practitioners to reclassify
them as papillary adenomas. ELSTs can arise
sporadically or in association with von Hippel-Lindau
(VHL) disease.
Disease
Classification
Etiology
Endolymphatic sac tumors are rare. As a recognized,
distinct entity, ELSTs are relatively new.
The first reported case of a tumor arising from the
endolymphatic
sac
was
discovered
during
decompression of the endolymphatic sac for presumed
unilateral Ménière's Disease in 1984.
Although benign, ELSTs can be locally destructive.
They present with hearing loss, tinnitus, facial nerve
weakness or paralysis, vertigo, and can be lethal. CT
imaging demonstrates erosion of the posterior petrous
temporal bone
with occasional intratumoral
calcification. MRI tumor signal is isointense to brain
and demonstrates gadolinium enhancement and
heterogeneous signal intensity from intratumoral
calcification and vascularity.
The synthesis of sporadic temporal bone papillary
tumors into a distinct clinicopathological entity was
proposed in 1989 by Heffner, with the anatomic origin
of these tumors being the endolymphatic sac.
Knowledge of this tumor has grown, expedited in part
by its association with VHL disease, yet many aspects
are still poorly understood.
Note
The differential diagnosis for ELSTs includes all
intrinsic temporal bone neoplasms (most commonly
paraganglioma) as well as metastatic papillary thyroid
carcinoma, metastatic renal cell carcinoma, and choroid
plexus papilloma, the latter three of which are similar
in appearance to ELSTs histologically.
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Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
Diaz RC
MRI T1 weighted axial images of the brain at the level of the endolymphatic sac and internal auditory canal. The top view without
gadolinium contrast shows moderate expansion of the endolymphatic sac and duct on the right. The bottom view with gadolinium
contrast shows contrast enhancement of the endolymphatic sac on the right.
CT axial image of the temporal bones at the level of the endolymphatic sac and internal auditory canals. The vestibular aqueduct on the
right is markedly widened directly behind the internal auditory canal and vestibule, in contrast to the appearance of the vestibular
aqueduct on the left, which is thin and nondescript. The bony erosion and widening of the vestibular aqueduct on the right is highly
suggestive of a neoplastic or otherwise destructive process within the endolymphatic sac, consistent with an ELST.
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Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
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Initially described as a low grade papillary
adenocarcinoma, the histologic appearance and
apparent lack of metastatic potential of these tumors
has convinced some to reclassify them as benign
papillary adenomatous tumors. The high overall
survival following surgical resection, despite locally
aggressive behavior, is likely due to the underlying
benign histology of the tumor.
tumor. Large glomus tumors as well as large ELSTs
can both present as pink or purple masses encroaching
on the middle ear and external auditory canal. Glomus
tumors exhibit a characteristic "salt and pepper" tumor
appearance on MRI, but this heterogeneity in signal
reflects the vascularity of such tumors and is not
pathognomonic. The heterogeneity in signal seen in
large ELSTs - arising from hypervascularity as well as
intra-tumoral hemorrhage and/or calcification - can
often mimic glomus tumors in this respect. This is not
necessarily problematic, as management would proceed
similarly for either histologic type of tumor: preoperative embolization followed by total tumor
resection via the appropriate lateral skull base
approach.
Epidemiology
Over 175 case reports of ELSTs have now been
reported in the literature. The majority of these are
single case reports of a practice group or university.
As the majority of these case reports do not disclose the
population size of their patient base, it is difficult to
assess the true incidence of these tumors. ELSTs tend
to afflict women more than men with an overall female
to male ratio of 2:1 in a review of the literature.
Pathology
ELSTs are highly vascular and are comprised of
papillary cystic structures lined with a simple cuboidal
or columnar epithelium. Siderophages and cholesterol
clefts are seen, as are clear, vacuolated cells. Nuclear
pleomorphism is not pronounced, and mitoses are rare.
Immunohistochemistry and special staining may aid in
differentiation of papillary tumors of question-able
origin. ELSTs usually stain positive for cytokeratin,
vimentin, and epithelial membrane antigen, as well as
stain on Periodic acid-Schiff (diastase sensitive). Some
papers have also reported sensitivity to glial fibrillary
acid protein; however, most authors have had poor
tumor reactivity to glial fibrillary acid protein. Papillary
thyroid metastasis to the temporal bone may be
differentiated by positive reaction to thyroglobulin
immunohisto-chemistry.
Transthyretin has been shown to exhibit differential
expression in choroid plexus papillomas with little to
no expression in ELSTs.
Clinics
The most common presenting complaints were aural,
with hearing loss occurring in neary every reported
patient, followed by tinnitus, aural fullness, and
imbalance. The symptoms of pulsatile tinnitus, otalgia,
otorrhea, vertigo, and facial paresis were also present in
some patients. Cranial neuropathies were also
diagnosed either at the time of presentation or
following treatment. The most commonly involved
nerve was the facial nerve, with preoperative facial
paresis or paralysis in 43% of patients. In patients with
larger tumors or in those who delayed presentation for
decades after onset of initial symptoms, multiple
cranial neuropathies were present including trigeminal,
glossopharyngeal, and vagal nerves.
From a statistical standpoint, a vascular tumor eroding
the temporal bone and cranial base is likely to be a
paraganglioma, and likely a glomus jugulare
MRI T1 weighted images of the brain, showing a very large ELST of the left temporal bone, in axial view on the left and coronal view on
the right. There has been complete erosion of the petrous temporal bone by the tumor, with significant brainstem and cerebellar
compression.
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Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
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Histological appearance of ELST. HE stain, low power magnification, demonstrating the characteristic papillary cystic architecture of
these tumors.
conservation procedures while 68% underwent hearing
ablative procedures. In patients with excellent
preoperative hearing and a small ELST, such a hearing
conservation approach may be warranted. However, the
completeness of tumor resection should not be
compromised for the sake of hearing conservation. Half
of patients undergoing hearing conservation approaches
with subtotal resection followed by adjuvant radiation
therapy had regrowth of tumor.
In some tumors, total resection cannot be achieved
without risk of catastrophic loss of function or death,
and in these patients subtotal resection may be
warranted. Patients who have subtotal resection may
benefit from postoperative radiotherapy, but there still
remains a roughly 50% risk of tumor regrowth and
therefore close surveillance is warranted as re-resection
may be necessary. Stereotactic radiotherapy has shown
no increased benefit above standard fractionated
radiotherapy in survival or recurrence rates, and
Treatment
Surgical resection is the primary modality of treatement
for ELSTs. Despite the benign histologic nature of
these tumors, complete resection appears crucial for
ensuring success. Total tumor resection is clearly the
treatment of choice, as only one patient with reported
complete resection had subsequent recurrence.
Although the most common presenting symptom was
sensorineural hearing loss, many patients, particularly
those with VHL disease, present with small ELSTs and
consequently present with serviceable hearing. VHL
patients are unique in that all undergo active
surveillance and cranial imaging for hemangioblastoma
as part of their VHL disease management.
Subsequently, ELSTs in these patients are frequently
diagnosed early, with relatively little delay between
onset of audio-vestibular symptoms and identification
of tumor. This significantly affected surgical decision
making, as 32% of patients underwent hearing
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
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Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
Diaz RC
subtotal resection followed by stereotactic radiotherapy
has uniformly resulted in tumor regrowth. There are no
reported cases of radiation therapy and/or stereotactic
radiotherapy used as the primary modality of treatment
for ELSTs.
hemangioblastomas,
retinal
hemangioblas-tomas,
pheochromocytomas, and cysts of the kidneys,
pancreas, and epididymis.
The gene responsible for VHL disease is a tumor
suppressor and it has been mapped to chromosome
3p25. The VHL gene product pVHL forms a multiprotein complex that contains elongin B, elongin C,
Cul-2, and Rbx1.
The pVHL complex has a role in oxygen sensing. The
VHL gene regulates vascular endothelial growth factor
VEGF, and inactivation of the gene promotes VEGF
overexpression and angiogenesis. In addition, its loss of
function mutation can increase expression of hypoxiainducible factor HIF1, stimulating angiogenesis and
tumorigenesis. In VHL disease, it is believed that
tumors arise when both an inherited germline mutation
and a loss-of-function mutation of the wild-type VHL
gene are present.
In addition, it has been shown that somatic mutations to
the VHL gene locus at 3p25/26 are detected even in
cases of sporadic ELSTs, that is, in non-VHL patients.
Genetic sequencing analysis of the 3p25 VHL gene
locus in both sporadic and VHL-associated ELSTs
demonstrates nucleotide substitution as well as
deletion/frameshift errors.
Even though temporal bone lesions were described in
patients by Lindau in 1926, the association of these
tumors with VHL disease was not made until recently.
This clinical association has been confirmed at the
molecular level with mutations in the VHL gene
identified in endolymphatic sac tumors in VHL
patients. Approximately 10% of patients with VHL
disease have ELSTs, and approximately 30% of VHL
patients with ELSTs have bilateral tumors. This
variable phenotypic expression may be a reflection of
VHL gene function secondary to the type of mutation
present.
Indeed, VHL disease has been found to have
phenotypic expression consistent within members of a
family, thus implying a singular, conserved mutation
within affected families. VHL disease is categorized
into two familial types, with type 1 being without
pheochromocytomas and type 2 being with
pheochromocytomas. There is further subclassification
of type 2 into type 2a, low risk for developing renal cell
carcinoma, and type 2b, high risk for developing renal
cell carcinoma. Clinical presentation type correlates
with genetic mutation type: type 1 families usually
have deletion or truncation mutations, whereas type 2
families usually have missense mutations.
If a family history of VHL disease exists, or if the
diagnosis of VHL disease is made in the absence of an
ELST, then early routine audiologic screening can
allow for early tumor detection and the possibility of
hearing preservation surgery should ELST develop.
Positive identification of tumor on MRI with
gadolinium is necessary prior to surgery: to date,
Evolution
There are currently no reported cases of spontaneous
metastatic dissemination of ELSTs in the literature.
Recently however, two reports have surfaced
describing metastatic disease following subtotal
resection. The first was a reported case of ELST drop
metastasis with dissemination onto the ipsilateral
cerebellar convexity beyond the original tumor site in a
patient who had undergone previous subtotal resection
and radiotherapy. A second case of drop metastasis of
ELST involved the spine, manifesting after multiple
subtotal resections and three courses of stereotactic
radiosurgery.
These seminal reports serve to illustrate the importance
of complete tumor removal on initial resection in order
to minimize both recurrence and metastatic seeding.
The oncologic principle of complete tumor extirpation
on primary resection is certainly applicable to ELSTs,
despite their benign histology and absence of
spontaneous metastasis.
Prognosis
Overall survival characteristics for all reported cases of
ELSTs are: 74% no evidence of disease, 20% alive
with disease, and 4% died of disease, for the reporting
periods.
ELSTs are histologically benign yet sometimes
destructive, highly aggressive lesions. They show
excellent response to primary surgical resection, with
or without adjuvant radiotherapy. Complete tumor
removal on initial resection is crucial. Hearing
preservation should not take precedence over complete
tumor removal, as adjuvant radiotherapy does not
ensure against tumor recurrence, which can be
devastating and lethal. In addition, drop metastases
following subtotal tumor resection have now been
reported. In patients with VHL disease, regularly
scheduled audiometry and surveillance MRI are vital to
early detection of ELSTs, which can optimize the
opportunity for hearing preservation without
compromising tumor control.
Genetics
Note
The current literature suggests that approximately one
third of all ELSTs are associated with VHL disease.
VHL disease is an autosomal dominant familial cancer
syndrome. VHL disease affects approximately 1 in
39,000 people. It encompasses a variety of neoplasia
both benign and malignant including renal cell
carcinomas, central nervous system
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
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Head and Neck: Ear: Endolymphatic Sac Tumor (ELST)
Diaz RC
endolymphatic sac tumor. J Natl Cancer Inst. 1997 Jul
2;89(13):970-2
surgical exploration in VHL patients with
audiovestibular symptoms but without MRI abnormallities has not been documented and is not
recommended.
Noujaim SE, Pattekar MA, Cacciarelli A, Sanders WP, Wang
AM. Paraganglioma of the temporal bone: role of magnetic
resonance imaging versus computed tomography. Top Magn
Reson Imaging. 2000 Apr;11(2):108-22
Genes involved and proteins
Vortmeyer AO, Huang SC, Koch CA, Governale L, Dickerman
RD, McKeever PE, Oldfield EH, Zhuang Z. Somatic von
Hippel-Lindau gene mutations detected in sporadic
endolymphatic sac tumors. Cancer Res. 2000 Nov
1;60(21):5963-5
VHL
Location
3p25.3
DNA / RNA
The VHL gene is a tumor suppressor gene mapped to
chromosome 3p25/26.
Protein
The VHL gene product, pVHL, forms a multi-protein
complex that contains elongin B, elongin C, Cul-2, and
Rbx1.
Hamazaki S, Yoshida M, Yao M, Nagashima Y, Taguchi K,
Nakashima H, Okada S. Mutation of von Hippel-Lindau tumor
suppressor gene in a sporadic endolymphatic sac tumor. Hum
Pathol. 2001 Nov;32(11):1272-6
Ferreira MA, Feiz-Erfan I, Zabramski JM, Spetzler RF, Coons
SW, Preul MC. Endolymphatic sac tumor: unique features of
two cases and review of the literature. Acta Neurochir (Wien).
2002 Oct;144(10):1047-53
Megerian CA, Haynes DS, Poe DS, Choo DI, Keriakas TJ,
Glasscock ME 3rd. Hearing preservation surgery for small
endolymphatic sac tumors in patients with von Hippel-Lindau
syndrome. Otol Neurotol. 2002 May;23(3):378-87
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This article should be referenced as such:
Diaz RC. Head and Neck: Ear: Endolymphatic Sac Tumor
(ELST). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(3):321-326.
Vortmeyer AO, Choo D, Pack SD, Oldfield E, Zhuang Z. von
Hippel-Lindau disease gene alterations associated with
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
326