Gamma knife radiosurgery for intralabyrinthine schwannomas

Abstract

Object

To analyze indications and technical specificities of treatment of intralabyrinthine schwannoma (ILS) by Gamma Knife radiosurgery.

Methods

Six patients were treated by Gamma Knife irradiation for a schwannoma arising from the cochleo-vestibular structures. Patients presented hearing worsening at different stages, tinnitus, imbalance and/or vertigo.

Results

ILS was intravestibular/intracochlear/intravestibulocochlear/ transmacular in respectively 2/1/2/1 patients. We cover the entire tumor volume with a margin prescription dose of 12-Gy. The tumor volume remained unchanged at last follow-up in all cases; for 4 patients with functional hearing still present before treatment, the audiological status remained stable in 2 patients, worsened moderately in 1 patientand worsened to cophosis in 1 patient. No patient experienced worsening of tinnitus, imbalance or vertigo after irradiation.

Conclusions

Gamma Knife treatment of ILS is technically feasible without risk thanks to the precision of current robotized Gamma Knife devices. Patients treated radiosurgically avoid some of the risks of microsurgery, could in some cases maintain useful hearing and prevent further symptoms worsening.

INTRODUCTION

Schwannomas of the vestibular and cochlear nerves are benign tumors that develop from Schwann cells that form the myeline sheaths of nerves. Since Schwann cells unsheathe the nerves from the point at which they penetrate the pia mater to their terminations, schwannomas may originate anywhere along the course of the cochleo-vestibular nerves peripheral to the glial-Schwann sheath junction [1]. The great majority of schwannomas arises in the vestibular division of the VIII^th cranial nerve, inside the internal auditory canal (IAC), and may extend to the cerebellopontine angle. However, schwannomas may also arise from the very distal branches of the cochlear, superior vestibular or inferior vestibular nerves at the level of the sensory end organs [2, 3]. These schwannomas arising initially from cochleo-vestibular structures have been called Intralabyrinthine Schwannomas (ILS) [3] in medical reports. Since the first publication on an autopsy case by Mayer in 1917 [4], less than 100 cases have been reported in the medical literature [3, 5–8]; most of the cases have been found at autopsy or during surgery for intractable vertigo [1,9]. In the last decade, with optimization of MR techniques, the number of reported ILS has gradually increased [3, 9].

The common management of ILS includes observation only or different surgical techniques for tumor removal [5, 7]. In the present study we evaluate the use of a new therapeutic option for the treatment of ILS, Gamma Knife radiosurgery (GKR), which is often used for vestibular schwannomas of the IAC and cerebellopontine angle [10].

MATERIALS AND METHODS

Patients

Between March 2005 and March 2011, 6 patients with an ILS have been treated by GKR in our Center. During this period, we have performed 1693 GKR procedures, including 271 treatments for vestibular schwannomas. Therefore, the incidence of treatment of ILS represents 0.35% of all our indications and 2.2% of GKR performed for vestibular schwannomas.

The patients included in this study have been referred in our Gamma Knife Center by ENT physicians. Patient’s age ranged from 23 years to 63 years, with a median age of 45 years (range 23-63). There were 2 males and 4 females. The ILS involved the left inner ear in 5 cases and the right ear in 1 case. The symptoms appeared in our patients from 6 months to 7 years before treatment (median duration of 3.5 years). The main symptom encountered was hearing worsening, which was present in all our patients. The preoperative audiological evaluation showed partial hearing loss with maintenance of functional hearing in 2 patients (Gardner-Robertson [11] Class 1 or 2),incomplete hearing loss with loss of functional hearing in 2 patients (Gardner-Robertson Class 3 or 4), and total hearing loss in 2 patients (Gardner-Robertson Class 5). One patient had a tinnitus associated with hearing worsening. Imbalance was present for 3 patients, and vertigo in 1 patient. No patient suffered intractable bothersome vertigo.

Classification of ILS

We have developed a new classification of ILS based on their anatomical location (Table 1). Our classification is modified from the classification of Kennedy [7]. Our ILS scale includes 4 classes and 3 subclasses. Class I includes ILS located only into inner ear structures; class II includes tumors of the inner ear that extend into the IAC; class III includes tumors of the inner ear that extend into the middle ear; class IV includes tumors that involve the inner ear, IAC and middle ear. The subclass a includes tumors located in the vestibule (with or without the semi-circular canals), the sub-class b includes ILS located in the cochlea, and the sub-class c includes schwannomas that involved both cochlear and vestibular areas.

Table 1.

Classification of ILS

Class	Abbreviation	Classification	Area involved
I a	IVE	Intravestibular	vestibule (+/- semicircular canals)
I b	ICO	Intracochlear	cochlea
I c	IVC	Intravestibulocochlear	vestibule + cochlea
II a	TMA	Transmacular	IAC + vestibule
II b	TMO	Transmodiolar	IAC + cochlea
II c	CVC	Canalovestibulocochlear	IAC + vestibule + cochlea
III a	TVE	Tympanovestibular	Middle ear + vestibule
III b	TCO	Tympanocochlear	Middle ear + cochlea
III c	TVC	Tympanovestibulocochlear	Middle ear + vestibule + cochlea
IV	TO	Transotic	Middle ear + vestibule/cochlea + IAC

IAC = internal auditory canal

The exact position of ILS was precisely located using 3 different imaging performed during the stereotactic GKR procedure: a high-resolution 3D T2-weighted MRI, a high-resolution 3D T1-weighted gadolinium-enhanced MRI, and a high-resolution 3D bone CT-scan acquisition (Figure 1, upper panel). After acquisition of these imaging in stereotactic conditions, we fuse these imaging on the software Leksell GammaPlan 9.0. We perform a fusion of T1-MRI with bone CT and T2-MRI with bone CT (Figure 1, lower panel). In these 5 images we can accurately identify the different structures of the inner ear, IAC and middle ear. Extension of the schwannoma into some of these structures can be defined accurately.

Figure 1.

Top: Stereotactic imaging acquisition during GKR procedure: high-resolution 3D T1-weighted gadolinium-enhanced MRI (left), high-resolution 3D T2-weighted MRI (middle), and high-resolution 3D bone CT-scan acquisition (right). Bottom: Image fusions used for dosimetric planning: fusion of MRI-T1gadolinium with bone CT (left), and fusion of MRI-T2 with bone CT (right). The white arrow shows the ILS.

Five patients had schwannomas located only in inner ear structures (Table 2); 2 patients had ILS located into the vestibule (grade Ia), 1 patient had a pure intracochlear schwannoma (grade Ib), and 2 patients had ILS into both vestibular and cochlear areas (grade Ic). One patient had an ILS placed within the vestibule with extension to the fundus of the IAC (transmacular ILS, grade IIa). Examples of the 4 locations of ILS of our patients are shown in Figure 2.

Table 2.

Demographic and clinical data of our population

Preoperative Characteristics		Value
No of patients		6
Age	median (SD)	45 y (14)
	range	23–63 y
Sex	male	2
	female	4
Side	left	5
	right	1
Symptoms	duration: median (SD)	3.5 y (2.7)
	duration: range	0.5–7 y
	hearing loss  partial (G-R 1-2)	2
	hearing loss  partial (G-R 3-4)	2
	hearing loss  total (G-R 5)	2
	tinnitus	1
	imbalance	3
	vertigo	1
Class / location	Ia Intravestibular	2
	Ib Intracochlear	1
	Ic Intravestibulocochlear	2
	IIa Transmacular	1
	IIb Transmodiolar	0
	IIc Canalolabyrinthine	0
	IIIa Tympanovestibular	0
	IIIb Tympanocochlear	0
	IIIc Tympanolabyrinthine	0
	IV Transotic	0
Indication for Tt	evolution of symptoms	5
	tumor progression	3
Reason for GKR	hearing status	2
	risks of surgery	6

SD = standard deviation ; G-R = Gardner-Robertson classification ; Tt = treatment ; GKR = Gamma Knife Radiosurgery

Figure 2.

Examples of 4 different locations of ILS: A: class Ia (intravestibular) ; B: class Ib (intracochlear); C: class Ic (intravestibulocochlear) ; D: C class IIa (transmacular).

Indication for GKR therapy

In all patients detailed information on the different therapeutic options were provided. A discussion related to the benefits and the risks of conservative therapy, microsurgery and GKR have been achieved specifically for each patient in relation with his/her particular medical situation. Indication of treatment of the ILS was worsening of symptoms for 5 patients and increase of tumor size for 3 patients. The choice of GKR therapy instead of conventional surgery was justified by the patient hearing status (functional hearing present) for 2 patients and refusal of the risks related to microsurgery for the 6 patients.

Radiosurgical procedure

Four patients underwent a radiosurgical procedure with Leksell Gamma Knife4C and 2 patients with Leksell Gamma Knife Perfexion. The Leksell G stereotactic frame (Elekta Instruments, Stockholm, Sweden) was attached to the patient’s head under local infiltration anesthesia with mild intravenous sedation. For all patients, we performed stereotactic high-resolution T1-weighted MRI3D volume acquisitions with Gadolinium-contrast enhancement, stereotactic high-resolution T2-weighted MRI 3D volume acquisitions, and stereotactic high-resolution axial bone CT densitometric imaging acquisition. The treatment planning was performed with Leksell Gammaplan (Elekta Instruments, Stockholm, Sweden). Image fusions of MR-T1 gadolinium with CT-imaging and MR-T2 with CT-imaging were subsequently created by the planning software (as shown in Figure 1). The tumor was contoured on axial MR-sequences on the basis of information provided by the different imaging sequences. An optimal dosimetry was performed to cover 100% of the tumor with the margin dose and create maximum dose fall-off in functional structures around the target (Figure 3a-c).

Figure 3.

GKR dosimetric plannings for ILS.

RESULTS

The main dosimetric parameters of the radiosurgical plannings are presented in Table 3. The tumor volumes of ILS class I are very low, ranging from 9.3 to 29.5 mm³. The target volume of patient with ILS extending into the IAC (class II) was 399.5 mm³. We used 1 to 13 isocenters of 4-mm diameter, and we blocked some of the beams to improve conformity for 2 patients. We prescribed a marginal dose of 12-Gy in all patients, at various isodoses (range 50% - 85%). We cover 100% of the tumor volume in all cases. The Paddick Conformity Index [12] and the Integrated Dose were reduced in comparison with usual values obtained during GKR of vestibular schwannomas, due to the very small volume of the target.

Table 3.

Dosimetric data

Patient No.	ILS class	Tumor max length	volume	Dosimetry isocenters	plugs	margin dose	isodose	max. dose	coverage	C.I.	int. dose
1	Ic	2.8 mm	9.5 mm3	1 × 4 mm	no	12 Gy	80%	15 Gy	100%	0.29	0.1 mJ
2	Ia	3.6 mm	9.3 mm3	1 × 4 mm	no	12 Gy	85%	14.1 Gy	100%	0.38	0.1 mJ
3	Ic	3.8 mm	13.0 mm3	1 × 4 mm	no	12 Gy	80%	15 Gy	100%	0.39	0.2 mJ
4	Ib	8.6 mm	29.5 mm3	3 × 4 mm	no	12 Gy	65%	18.5 Gy	100%	0.30	0.4 mJ
5	Ia	3.7 mm	23.3 mm3	1 × 4 mm	yes	12 Gy	70%	16 Gy	100%	0.62	0.3 mJ
6	IIa	16.6 mm	399 mm3	13 × 4 mm	yes	12 Gy	50%	24 Gy	100%	0.78	6.5 mJ

C.I. = Paddick Conformity Index ; plugs = beam channel blocking ; Int. dose = integrated dose

The mean follow-up duration was 1.5 years and ranged from 0.6 to 3.5 years (Table 4). For all patients the last MRI showed a stable tumor volume. Two patients were cophotic before the treatment. Two of the 4 patients with hearing still present before GKR had no change in their hearing status at last examination. For the last 2 patients, their hearing status worsened moderately in 1 patient (audiological status was GR class 2 before irradiation and class 3 at last examination) and worsened to cophosis in the other patient. Tinnitus was present in association with hypoacousia in 1 of our patients and remained unchanged during follow-up. Three patients suffered from imbalance before irradiation; 2 patients kept this symptom unchanged and 1 patient showed a significant improvement at the last follow-up of 1 year after radiosurgery. The moderate vertigo present in 1 of our patients remained stable during follow-up.

Table 4.

Outcome data

Follow-up
Duration	mean	1.5 y
	range	0.5–3.5 y
Tumor volume	increased	0
	stable	6
	decreased	0
Hearing status	NA (cophosis before GKR)	2
	stable (GR 2)	1
	stable (GR 3)	1
	worsened (GR 2→3)	1
	worsened (GR 3→5)	1
Tinnitus	NA (not present before GKR)	5
	improved	0
	stable	1
	worsened	0
Imbalance	NA (not present before GKR)	3
	improved	1
	stable	2
	worsened	0
Vertigo	NA (not present before GKR)	5
	improved	0
	stable	1
	worsened	0

NA = not applicable ; GR = Gardner-Robertson classification; GKR = Gamma Knife Radiosurgery

DISCUSSION

Only a limited number of papers, mainly case reports or small series, have reported patients with ILS in the medical literature. The optimal management of these patients remains controversial, and is essentially discussed between observation and surgical removal.This article represents the first publication on patients with ILS treated by GKR.

Intralabyrinthine schwannomas

The incidence of vestibular schwannomas has gradually increased in the last decades. Several factors are believed to have caused this increase. The main reasons of this rise are the improving diagnostic equipment and the more widespread access to MRI. The heightened symptom awareness among the general population, the healthier and longer lifetime in developed countries, and the better and more widespread audiologic testing equipment are also contributing to the growing incidence of vestibular schwannomas.

In a recent study on evolution of the incidence of vestibular schwannomas in Denmark, Stangerup et al. have found an increase from 3.1 per million per year in 1976 to a stable rate of about 19 tumors per million per year [13]. The authors found that the sex ratio and age have remained grossly unchanged over the years but that hearing has improved and tumor size has decreased considerably. Particularly, the proportion of intrameatal schwannomas diagnosed has greatly increased. In the same way, ILS were not found by imaging since the use of very sensitive MR techniques. In 2008, Tieleman et al. have reported the largest series of ILS to date [3]. They found 52 ILS over a 16.5-year period in 2 referral centers specialized in temporal bone imaging, representing up to 10% of all VIII^th nerve schwannoma diagnosed. In our Center, about 2.2% of the vestibular schwannomas treated in the last 6 years have concerned ILS, which confirms the increased incidence of ILS diagnosed in the recent years.

The most frequent symptom of patients with ILS is unilateral hypoacousia, mostly progressive [7,14]. In our series, all patients suffered from hearing worsening at different stages, from mild hypoacousia with functional hearingmaintained to complete hearing loss. In discordance with papers reporting results of surgery for ILS in patients that have lost their hearing before treatment, some of our patients were treated when their hearing was still serviceable. Only one of our patients had tinnitus, at a mild and bearable level. Balance disorders were present in half our patients and vertigo in one patient. No patient suffered intractable and bothersome balance disorders since this situation was considered in our Center as an indication for resective surgery and a contra-indication for GKR. The rate of vestibular disorders in our group is in accordance with the other series reported in the literature [5,7-9].

We present in this manuscript a new classification of ILS. Our classification implement and clarify the former classification of ILS proposed by Kennedy [7]. Shin et al [2] had already shown the limitations of the classification of Kennedy. All the possible locations and extensions of ILS have been included in our classification, and the ordering in 4 classes and 3 subclasses offers a clear and rapid indication of the anatomical position of ILS.

Management of ILS

The optimal algorithm for management of ILS remains to be defined [5]. Some authors advocate observation for the majority of cases [7, 8, 14], though others recommend surgical removal for most patients [5, 9]. Many authors consider that the optimal therapeutic approach must be definedindividually for each patient since several factors could be involved in the decision, such as patient’s age, hearing status, or presence of bothersome intractable vertigo or tinnitus [3, 7]. The hearing level is often considered as a main determining factor, since microsurgery will consistently bring to complete hearing loss [14–15]. Therefore, a vast majority of authors recommend surgery only for patients with cophosis or intractable bothersome symptoms (vertigo/tinnitus) and observation for patients with serviceable hearing [8,14–16].

In their study Tieleman et al [3] have analyzed the prevalence of tumor growth in patients with ILS. From the 27 patients with a follow-up imaging available, they found tumor growth in 59% of cases. Since no minimum length of follow-up was postulated and their minimum follow-up duration was of only 2 months, the actual rate of long-term tumor growth could be even much higher. Other authors have also reported proven tumor growth of ILS [9, 14, 16]. So, management of ILS with observation without treatment will bring at the long-term a majority of patients to worsening of symptoms because of tumor growth. The reason to advocate observation in some patients is that microsurgery is associated with a significant risk of serious morbidity, including total hearing loss in all patients and facial palsy in some cases [7,16]. Therefore, a therapy that could prevent further tumor growth and that is not systematically associated with hearing loss and avoid serious complications such as facial palsy would be much appreciated.

GKR is currently the most common therapeutic option for patients with vestibular schwannomas [10]. This treatment has already proved its efficiency and safety in this indication [10]. The long-term tumor control rate is superior to 90% in the current series [10]. The morbidity has been reduced by the use of lower radiation dose: a margin prescription dose of 12 Gy is associated with a risk of hearing worsening after irradiation of 20% to 30% in most series [10,17]. The risk of facial nerve dysfunction after radiosurgery is currently very low and exclusively partial and transient with an optimal GKR procedure [10]. Corticoids may be use in selected cases to reduce adverse clinical effects of transient edema occurring after irradiation. The main benefits of GKR are the absence of microsurgical dissection of sensitive structures (cochleovestibular nerve, facial nerve, brainstem…) and no general anesthesia, with as consequence a significant reduction of morbidity compared with conventional surgery.

Our study represents the first publication on ILS treated by GKR. ILS are benign schwannomas histologically similar to vestibular schwannomas located in the IAC and/or pontocerebellar angle [1,9]. For GKR therapy, ILS present some important specificities that could theoretically influence the results of this therapy. The very low volume that must be irradiated allows a very sharp dose fall-off outside the target [18]. However, the schwannoma is located in structures sensitive to radiation [19]. In our experience, 2 patients without complete hearing loss have been treated by GKR, with absence of worsening in 1 case and only moderate audiological deterioration in the other patient. As we observed with GKR in vestibular schwannomas located in the IAC or the pontocerebellar angle, early irradiation when hearing is still functional could give a chance to the patient to preserve functional hearing for the long term. More experience with GKR therapy for ILD is warranted to confirm these preliminary results.

Few authors have included stereotactic radiosurgery in their discussion on current therapeutic management of ILS [7,8,14], and no paper has reported results of this therapeutic option. We do not agree with authors who state that radiosurgery is not a valuable option for ILS [8,14]. Their assumption that radiosurgery is at risk of facial palsy and would systematically cause hearing loss is not based on any study results and is in disagreement with the current results of radiosurgery for vestibular schwannoma. Actually, permanent facial palsy did not occur with contemporary GKR treatment of vestibular schwannoma using optimized dosimetry and low radiation doses, usually below 13 Gy [10,20]. For ILS radiosurgery, the radiation target is far away from the facial nerve in comparison with vestibular schwannomas located into the IAC that represents a high percentage of schwannomas currently treated by GKR [13,21,22]. Our results further confirm that GKR treatment for ILS is not associated with facial palsy and could avoid hearing loss in some cases.

We agree with Kennedy et al [7] who state that GKR is not a good treatment option for patients with intractable bothersome vestibular symptoms. However, we disagree with their statement that radiosurgery must be reserved only for old patients with proven tumor growth. On the contrary, the high efficiency and low morbidity associated with GKR for ILS makes this therapy in our opinion a valuable treatment option before that tumor growth occurs and that patient’s symptoms worsen consequently. We think that GKR represents the only therapeutic option that can control tumor progression and maintain patient’s hearing on the long-term. Observation may not stop the tumor growth that may occur in a majority of patient, and surgery will definitely create postoperative cophosis.

CONCLUSIONS

ILS were diagnosed more frequently in the recent years in patients with hypoacousia or vestibular symptoms, mainly thanks to the development and widespread use of high-resolution MRI. GKR represents an interesting therapeutic option for these tumors. Such therapy seems to be associated with a high rate of tumor control and a low morbidity. Based on our experience, we recommend that fully asymptomatic patients are managed by observation, patients with intractable bothersome vestibular symptoms are managed by microsurgery, and that all other patients are treated by GKR, especially patients with different levels of hearing worsening, even moderate with functional hearing still present.