Key-words:
Acoustic neuroma - intratumoral hemorrhage - vestibular schwannoma
Introduction
Vestibular schwannomas (VSs) are benign neoplasms that generally arise from the superior
division of the vestibular cranial nerve. VS represents approximately 8% of all primary
intracranial neoplasms and 75% of cerebellopontine (CP) angle tumors.[[1]],[[2]] The clinical presentation of VS may vary from prolonged dormancy to subacute symptoms,
including unilateral hearing loss, tinnitus, gait ataxia, and vertigo.[[3]]
Brain tumor-related intracranial hemorrhage is a well-described phenomenon, yet intratumoral
hemorrhage (ITH) occurring in benign tumors such as VS is rare with fewer than a hundred
cases reported in the literature.[[2]],[[3]],[[4]] While most VSs have an insidious clinical course with slow tumor growth, hemorrhagic
lesions can result in sudden neurological deterioration ranging from facial nerve
palsy to severe disability and mortality.[[5]]
Due to the rarity of clinically significant hemorrhagic VS, its pathophysiology and
prognosis remain unclear. Understanding the natural course of ITH in VS may assist
in patient counseling and clinical decision-making. Here, we describe the presentation,
management, and outcomes of three patients with hemorrhagic VS. A comprehensive review
of the literature regarding ITH in VS was also performed.
Case Report
All adult patients with a histologically proven diagnosis of VS and evidence of clinically
significant ITH were reviewed at a single neurosurgical center from January 1, 2012
to March 31, 2020. Clinically significant hemorrhagic VS was defined as patients having
acute to subacute symptoms with frank radiological evidence of acute ITH as exhibited
by either a Hounsfield unit reading of 40–70 at the region of interest on noncontrast
enhanced computed tomography (CT) or hyperintense signal changes on T1-weighted sequences
with corresponding hypointense changes on T2-weighted and susceptibility-weighted
magnetic resonance imaging (MRI) sequences. Clinical, radiological, histological,
and treatment data were reviewed. In particular, the presence of pre- and postoperative
facial palsy (House–Brackmann grading) and hearing impairment was documented.[[6]] Imaging studies were reviewed to assess the size of the tumor, the degree of brainstem
compression, and the presence of hydrocephalus. The neurosurgical approach was recorded
and the extent of tumor resection was evaluated by postoperative MRI scans. The functional
performance of each patient was determined by the Eastern Cooperative Oncology Group
(ECOG) grading.[[7]] The database from the US National Library of Medicine and National Institutes of
Health (PubMed) was queried to identify ITH in VS. The key search terms “intratumoral
hemorrhage” or “hemorrhagic” and “vestibular schwannoma” or “acoustic neuroma” were
used. Only English-language articles published after 1970 that described histologically
proven VS were included in our review.
In our institution, 50 adult patients were diagnosed with VS during the 9-year study
period and three (6%) were identified to have clinically significant ITH. The mean
age of diagnosis was 62 years (±9; range: 52–69 years) and the male:female ratio was
2:1. The mean symptom duration was 26 ± 4 days. None of the patients were on long-term
antiplatelet or anticoagulant medication, and there was no history of neurofibromatosis
type II.
Patient 1
A 69-year-old man presented with intermittent vertigo and progressive left hearing
impairment for 6 months. He subsequently experienced a 4-week history of subacute
global headache. Apart from a history of hypertension, there were no other significant
comorbidities. The patient was fully conscious and did not have facial nerve palsy.
There was complete left sensorineural hearing loss and preoperative brainstem auditory-evoked
potentials could not be detected.
A CT scan and a subsequent MRI scan revealed a 3.7 cm × 3.1 cm × 3.5 cm left heterogeneous
gadolinium-contrast enhancing hemorrhagic multicystic CP angle tumor with intratumoral
fluid levels [[Figure 1]]. The tumor exerted considerable mass effect against the pons and was causing early
obstructive hydrocephalus. A retrosigmoid (RS) craniectomy for subtotal tumor resection
was performed 13 days after admission. Intraoperatively, the tumor was vascular with
prominent feeding capsular vessels. Apart from the intratumoral hematoma, there were
multiple cysts containing xanthochromic fluid within the medial side of the tumor,
indicating additional intracystic hemorrhage as well. Intraoperative trigger electromyography
was utilized to identify the facial nerve, and motor-evoked potential monitoring was
performed to confirm its integrity. The final histological diagnosis was VS with diffuse
hemosiderin deposits and there were no malignant features.{Figure 1}
Figure 1: Patient 1. Computed tomography scan showing left cerebellopontine angle lesion hemorrhage
(a). T1-weighted magnetic resonance imaging revealed a widened internal acoustic meatus
and intratumoral hyperintense signal changes (white arrowheads) suggestive of hemorrhagic
vestibular schwannomas compressing the brainstem (b, axial; c, coronal). The corresponding
areas are isointense (gray arrowhead) on T2W imaging indicating subacute (6-9 days)
methemaglobin blood (d). Contrast-enhanced T1-weighted scan demonstrated heterogeneous
enhancement with widening of the internal acoustic meatus indicative of a multicystic
vestibular schwannoma(e). Susceptibility-weighted imaging revealed diffuse hypointense
signal changes reflecting blood product deposition (f)
A week after the operation, there was secondary surgical site hemorrhage that required
hematoma evacuation. The patient was discharged home with no facial nerve palsy and
an ECOG performance status of 0. There was no improvement in hearing. A 1-year follow-up
MRI scan revealed tumor recurrence (2.0 cm × 1.2 cm × 0.9 cm) that required stereotactic
radiosurgery (SRS).
Patient 2
A 62-year-old Nepalese woman with a history of hypertension experienced syncope and
was comatose on admission with a Glasgow Coma Scale score of 3/15. In the preceding
4 weeks, she complained of right-side hearing impairment, and a day before admission,
she also experienced vertigo with recurrent vomiting. Upon hospitalisation her pupils
were equal and reactive to the direct light reflex. There was no evidence of facial
nerve palsy. A CT brain scan showed a 5.5 cm × 3.1 cm × 3.1 cm hematoma over the right
CP angle with significant compression against the brainstem, causing acute obstructive
hydrocephalus [[Figure 2]]a and [[Figure 2]]b. There was also an associated widened internal acoustic meatus that suggested
the underlying lesion was a VS [[Figure 2]]a. An urgent RS craniectomy for brainstem decompression, hematoma evacuation, and
subtotal tumor resection was performed. Intraoperatively, a vascular tumor was encountered
with an intratumoral hematoma and evidence of arachnoiditis [[Figure 3]]a and [[Figure 3]]b. No attempt was made to identify the facial nerve since the main aim of the operation
was for urgent brainstem decompression, and intraoperative neurophysiological monitoring
was not available at the time. The histological diagnosis was VS with areas of hemorrhage,
thrombosed vessels, and aggregates of hemosiderin-laden macrophages [[Figure 3]]c.{Figure 2}{Figure 3}
Figure 2: Patient 2. Computed tomography scan revealing acute intratumoral hemorrhage at right
cerebellopontine angle causing brainstem compression (a) and acute obstructive hydrocephalus
(b). The widened IAM is suggestive of vestibular schwannomas (a, white arrow). One-month
postoperative contrast-enhanced T1-weighted magnetic resonance imaging showing residual
tumor extending into the IAM (c). Patient 3. Computed tomography scan showing a left
cerebellopontine angle hemorrhagic tumor (d). Contrast-enhanced T1-weighted magnetic
resonance imaging revealing a widened IAM and heterogenous enhancement (e). SWI depicting
intratumoral blood product deposition (f)
Figure 3: Intraoperative photographs of Patient 2. A vascular cerebellopontine angle tumor
with prominent arterial feeders was encountered (a). The intratumoral blood clot was
evacuated (b). Histopathology revealed a vestibular schwannoma with infiltrating macrophages
within both Antoni A and Antoni B regions (c, gray arrows, H and E, ×50). Tumor arterial
occlusion is noted in the right lower corner of the microphotograph. Patient 3´s vestibular
schwannoma revealed extensive microhemorrhage within the Antoni B regions. Infiltrating
macrophages are identified at the border with Antoni B regions (d, white arrows, H
and E, ×10)
Postoperatively, the patient regained full consciousness. Apart from right complete
sensorineural hearing loss, there was no additional focal neurological deficit. In
particular, there was no facial nerve palsy. The patient was discharged home 2 weeks
after rehabilitation with an ECOG performance status of 1. A 1-month postoperative
MRI brain scan showed a residual 2.5 cm × 1.2 cm × 1.3 cm tumor and SRS was arranged.
Patient 3
A 56-year-old man with a history of hypertension presented with acute vertigo with
recurrent vomiting a day before admission. He also complained of intermittent headache,
left facial numbness, and left hearing impairment in the preceding 4 weeks. A preoperative
pure tone audiogram (PTA) did not detect any sensorineural hearing loss. An MRI brain
scan revealed a 3.4 × 3.2 × 4.0 cm hemorrhagic left CP angle extra-axial cystic tumor.
The lesion was heterogeneously contrast-enhancing and was causing brainstem compression
with obstructive hydrocephalus [[Figure 2]]d,[[Figure 2]]e,[[Figure 2]]f.
A RS craniotomy for gross tumor excision was performed 13 days after admission. The
tumor was vascular and an intratumoral hematoma was encountered with an accompanying
cyst containing xanthochromic fluid suggestive of prior hemorrhage. The trigeminal
and facial nerves were identified with motor-evoked potential monitoring, confirming
their integrity. The histological diagnosis was VS with several focal areas of microhemorrhage,
hemosiderin deposits, and tumor-infiltrating macrophages [[Figure 3]]d. Postoperatively, the patient's symptoms gradually improved and he was discharged
5 days later with an ECOG functional performance status of 0. There was no facial
nerve palsy and a repeat PTA showed no deterioration in his hearing. An MRI scan performed
6 months later showed no residual tumor.
A literature review identified a total of 48 articles documenting 75 patients with
clinically significant ITH in VS. Including the additional three patients described
in this report, 53% (41/78) were women and the mean age was 51 ± 17 years (range:
15–77 years) [[Table 1]]. Among the patients where relevant clinical data were documented, the most common
presenting symptom was hearing impairment (79%, 58/73), followed by headache (67%,
49/73), ataxia (52%, 38/73), facial nerve palsy (47%, 34/73), and trigeminal nerve
palsy (22%, 30/73). The mean duration of symptoms was 4 weeks, i.e., 27 ± 42 days.
For 72 cases where radiological data were available, the mean tumor size was 3.4 ±
1.0 cm (range: 1.5–6 cm). Discernible cystic tumor changes were noted in a third of
the patients (30%, 19/72) and intracystic hemorrhage was detected in 10% (7/72). Of
the 77 patients who had treatment details described, 94% (72/77) underwent definitive
tumor resection with the majority undergoing RS craniotomy (61%, 47/77) and a single
patient underwent a combined RS-translabyrinthine approach. Four patients (5%) had
adjuvant SRS and one received SRS alone.{Table 1}
Table 1: Clinical, radiological, treatment characteristics, and outcomes of reported vestibular
schwannoma patients with clinically significant intratumoral hemorrhage since 1970
Discussion
Although VS is the most frequently encountered tumor of the CP angle region, clinically
significant ITH rarely occurs. Patients with VS typically present with gradual progressive
auditory symptoms such as unilateral high-frequency sensorineural hearing impairment
and tinnitus. One of the largest single-institution VS case series to date comprising
1000 patients observed that over 90% had unilateral hearing impairment. Trigeminal
nerve and facial nerve palsies are relatively rare occurring in 9% and 6% of patients,
respectively.[[8]] In contrast, for hemorrhagic VS, more than a quarter of reported patients experienced
trigeminal nerve palsy and 47% had facial nerve palsy [[Table 1]]. Rapid tumor expansion secondary to ITH could result in acute stretching of an
already tenuously splayed vestibulocochlear, facial, or trigeminal nerve resulting
in a higher incidence of such deficits on presentation.[[9]],[[10]] This observation is further supported by the shorter duration of symptoms among
patients with hemorrhagic VS. Including our three described cases, the mean symptom
duration described in the literature was 27 ± 12 days and nine patients experienced
acute symptoms within a week. In contrast, for 89% of patients with typical VS, the
duration from symptom onset to diagnosis was >6 months.[[11]]
The exact pathophysiological mechanisms for why VS would undergo clinically evident
ITH while other histologically benign tumors seldom exhibit this phenomenon are unclear.
Several theories have been proposed, including arterial tumor invasion, microvascular
proliferation of thin-walled tumor arterial feeders lacking tunica media, and necrosis
resulting from unbridled tumor growth.[[3]],[[12]],[[13]],[[14]],[[15]],[[16]] Yet, ITH in VS may occur more commonly than previously believed. A histological
review of 274 VS specimens revealed that nearly all exhibited varying levels of intratumoral
microhemorrhage, and more extensively involved tumors were independently associated
with preoperative unserviceable hearing.[[13]] It has also been suggested that multiple hemorrhagic events could account for the
existence of cystic VS that comprise 5%–10% of tumors and are widely described as
demonstrating rapid growth, shorter symptom durations, and worse outcomes after resection.[[17]],[[18]],[[19]] Two of our three patients had tumors with cystic degeneration with evidence of
prior intracystic hemorrhage in addition to the presence of an intratumoral hematoma.
This is corroborated by the higher incidence of cystic changes among reported VS with
ITH (30%, 19/72) compared to typical nonhemorrhagic tumors [[Table 1]]. High levels of the proteolytic enzyme, matrix metalloproteinase-2, a potent inflammatory
mediator that stimulates vascular permeability and enables monocyte infiltration,
has been identified in VS cyst fluid suggesting their important pathogenetic role.[[20]],[[21]] There is an increasing body of evidence to suggest that inflammation and angiogenesis
play crucial roles in maintaining sporadic noncystic VS “growth” despite the absence
of classical histological biomarkers for malignancy such as conspicuous cellular proliferation
or mitoses.[[22]],[[23]] The concentrations of intratumoral vascular endothelial growth factor and fibroblast
growth factor have been shown to correlate with VS growth rates.[[24]],[[25]] This observation suggests that sporadic VS can elicit an immune response resulting
in chronic inflammation with enhanced vascular permeability and is supported by the
frequent presence of tumor-infiltrating macrophages, especially within Antoni B areas.[[23]],[[26]] A recent study prospectively investigating the relationship between tumor growth
and inflammation utilized positron-emission tomography with the inflammatory cell
tracer 11C-(R)-PK11195 and dynamic contrast-enhanced MRI to compare tumors of differing
growth rates.[[26]] With subsequent histological examination, Lewis et al. demonstrated that with enlarging
VS, tumor-infiltrating macrophages rather than tumor cells accounted for the accounted
for the major portion of the tumor mass.[[26]] This revelation of pseudo-tumoral growth can explain why tumor size (>2 cm), rapid
growth, and mixed Antoni A/B cellularity are commonly identified risk factors for
clinically significant ITH.[[3]],[[4]],[[12]] In support of this observation, Patient 1, who had the longest duration of symptoms,
had radiological evidence of multicystic changes with intraoperative findings of both
ITH and intracystic blood indicating that the lesion had undergone several prior episodes
of hemorrhage [[Figure 1]].
In our study, all patients had large tumors with the mean maximum diameter of 3.7
± 1.0 cm (range: 3.7–5.5 cm) which was comparable to the mean size of 3.4 ± 1.0 cm
(range: 1.5–6.0 cm) for other hemorrhagic VS reported in the literature. This is considerably
larger than the mean size of a typical VS of 2.0 ± 1.0 cm.[[27]] Antoni A and B regions are characteristic of all VS, but histological examination
of our tumor specimens revealed more extensive areas of Antoni B regions microhemorrhage
were detected.
With regard to the timing of resection, most patients with hemorrhagic VS could be
closely observed, to allow an opportunity for the arrangement of preoperative MR imaging
and neurophysiological intraoperative monitoring. Life-threatening hemorrhagic VS,
as illustrated by Patient 2 who was comatose upon admission, is uncommon. Only eight
(11%) of all hemorrhagic VS patients described had a depressed conscious level on
presentation and among them, four (5%) required emergency neurosurgical resection.
Should acute obstructive hydrocephalus be the underlying cause for neurological deterioration,
urgent external ventricular drainage can be considered as a temporary relieving measure
before definitive resective surgery.[[28]],[[29]],[[30]]
In general, postoperative complications for typical VS include sensorineural hearing
loss (>60%), facial nerve palsy (<10%), surgical site hemorrhage (<3%), and meningitis
(<2%).[[31]],[[32]] In our study, two patients had worse sensorineural hearing impairment, while the
remaining patient did not experience deterioration. Otherwise, none had a permanent
focal neurological deficit. Although Patient 1 required a subsequent reoperation for
surgical site hematoma evacuation, long-term postoperative functional performance
for all three patients was satisfactory. Including our current cases, 19 (43%, 19/44)
ITH VS patients had postoperative hearing loss and 22 (50%, 22/44) had facial nerve
palsy which are considerably higher than the frequency of procedure-related complications
for nonhemorrhagic VS [[Table 1]]. There is likely to be an underreporting of such complications since 44% (34/78)
of case reports did not describe posttreatment outcomes. The presence of dense peritumoral
adhesions resulting from chronic inflammation akin to the arachnoiditis encountered
intraoperatively in Patient 2 may have contributed to these outcomes. A total of eight
(18%, 8/44) patients had fatal hemorrhagic VS resulting from residual hypervascular
tumor rebleeding and constituted a significantly higher mortality rate than that observed
for nonhemorrhagic VS operations, which is generally cited at <2%.[[32]]
Conclusion
Clinically significant ITH in VS is rare but potentially life threatening. Most patients
can be initially closely observed to allow time for the preparation of early definitive
surgery and urgent resection is often not required. Neurosurgeons should be aware
that such tumors are hypervascular and carry a risk of postoperative rebleeding after
subtotal resection. In contrast to the literature, our experience indicates that surgical
outcomes can be comparable to nonhemorrhagic VS.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form, the legal guardian has given his consent for images and other clinical
information to be reported in the journal. The guardian understands that names and
initials will not be published and due efforts will be made to conceal identity, but
anonymity cannot be guaranteed.
