Long-term Results of Upfront, Single-session Gamma Knife Radiosurgery for Large Cystic Vestibular Schwannomas

Abstract

Background: Anecdotally, cystic vestibular schwannomas (cVSs) are regarded to have unpredictable biologic activity with poorer clinical results and most studies showed a less favorable prognosis following surgery. While stereotactic radiosurgery (SRS) is a well-established therapeutic option for small to medium-sized VSs, cVSs are often larger, thus making upfront SRS more complicated. The purpose of this retrospective study was to assess the efficacy and safety of upfront SRS for large cVSs.

Methods: The authors reviewed the data of 54 patients who received upfront, single-session GKRS with a diagnosis of large cVS (>4 cm3). Patients with neurofibromatosis type 2, multiple VSs, or recurrent VSs and < 24 months of clinical and neuroimaging follow-up were excluded.

Results: Hearing loss (48.1%) was the primary presenting symptom. The majority of cVSs were KOOS grade IV (66.7%), and the most prevalent cyst pattern was “mixed pattern of small and big cysts” (46.3%). The median time between diagnosis and GKRS was 12 months (range, 1-147 months). At GKRS, the median cVS volume was 6.95 cm³ (range, 4.1–22 cm³). The median marginal dose was 12 Gy (range, 10-12 Gy). The mean radiological and clinical follow-up periods were 62.2 ± 34.04 months (range, 24-169 months) and 94.9 ± 45.41 months (range, 24-175 months), respectively. At 2, 6, and 12 years, the tumor control rates were 100%, 95.7%, and 85.0%, respectively. Tumor shrinkage occurred in 92.6% of patients (n=50), tumor volume remained stable in 5.6% of patients (n=3), and tumor growth occurred in 1.9 percent of patients (n=1). At a median follow-up of 53.5 months, the pre-GKRS tumor volume significantly decreased to 2.35 cm3 (p<0.001). While Koos grade 3 patients had a greater possibility of attaining higher volume reduction, “multiple small thick-walled cyst pattern” and smaller tumor volumes decreased the likelihood of achieving higher volume reduction. Serviceable hearing (Gardner-Robertson Scale I-II) was present in 16.7% of patients prior to GKRS and it was preserved in all of these patients following GKRS. After GKRS, 1.9% of patients (n=1) had new-onset trigeminal neuralgia. There was no new-onset facial palsy, hemifacial spasm, or hydrocephalus.

Conclusions: Contrary to what was believed, our findings suggest that upfront GKRS seems to be a safe and effective treatment option for large cVSs.

Introduction

Vestibular schwannomas (VSs) are relatively frequent benign space-occupying lesions that are categorized into two subtypes based on their neuroradiological appearance: solid schwannomas (sVS) and cystic schwannomas (cVS) [41]. Due to the lack of a clear definition, the reported incidence of cVSs ranges between 4% and 23%. cVSs are thought to have poorer clinical outcomes due to their unique characteristics, which include larger size, rapid growth, atypical presenting symptoms, rapid progression of symptoms or sudden deterioration due to unpredictable cystic expansion or hemorrhage, adherence to the brainstem or cranial nerves, and unpredictable biologic behavior [8, 34, 42, 51, 62–64, 66].

The optimal treatment strategy for cVSs is currently being debated. Although surgical excision is commonly suggested, documented surgical outcomes are inferior to those for sVSs, particularly for facial nerve function [1, 33, 49, 62]. Numerous studies have demonstrated the efficacy of Gamma Knife radiosurgery (GKRS) in the treatment of small to medium-sized VSs [3, 15, 25, 30, 38, 54, 59, 60]. However, due to recorded incidences of cystic growth following treatment, the use of GKRS for cVS is controversial [40, 45]. A recent meta-analysis with 246 cVSs [10] and a systematic review [32], which included both sVS (n = 1085) and cVS (n = 273) patients with or without prior therapy, indicate that GKRS has similar efficacy in patients with cVS as it does in patients with sVS.

Due to a paucity of published data, we conducted a retrospective analysis of our experience to ascertain the long-term efficacy and safety of upfront single-session GKRS treatment of large cVSs.

Materials And Methods

The Institutional Review Board of Koç University approved this retrospective study with prospectively managed data (2022.021.IRB1.058016) and it was conducted in accordance with the Declaration of Helsinki principles. Participants provided written informed consent.

The following criteria were used to determine inclusion: (a) MRI-confirmed diagnosis of cVS; (b) cVs volume > 4 cm³ and at least one diameter > 2.5 cm [48]; (c) upfront, single-session GKRS; (d) a minimum of 24 months of clinical and neuroimaging follow-up; and (e) absence of neurofibromatosis type 2, multiple VSs, recurrent VSs and facial schwannomas. The cVS was defined when the cyst wall exhibited contrast enhancement and the cyst component accounted for more than 30% of the solid component on volumetric imaging [1]. cVSs were further classified as having “multiple large thin-walled cysts”, “multiple small thick-walled cysts”, “single large thin-walled cyst”, “larger central thick-walled cysts”, and a “mixed pattern of small and large cysts” [35]. Tumor extension was graded using the Koos scale [28], and all CVSs revealed either class T3 (tumor occupying the cerebellopontine cistern with no brainstem displacement) or T4 (large tumor with brainstem displacement) extension. Among 1530 VS patients treated with GKRS between January 2005 and April 2022, 54 patients (34 men and 20 women) with a median age of 62 years (range, 30–85 years) met the inclusion and formed the population of interest in this study. Detailed data are presented in Table 1.

GKRS was conducted with Leksell Gamma Knife® model 4C (2005–2012), Perfexion™ (2012–2016), and Icon™ (2017–2022) (Elekta Instrument AB, Stockholm, Sweden). Pre-contrast T1, 3D CISS, and post-contrast 1 mm thin-slice axial MR images were acquired prior to or following the application of a Leksell stereotactic frame based on the available Gamma Knife® model. Multiple isocenters were used to outline the target volume, which included intratumoral cysts. Only the solid tumor mass was included as the target for tumors with peritumoral cysts without peripheral contrast enhancement. The marginal dose was determined by the size of the tumor and the anticipated risk to neighboring tissues. The median tumor volume was 6.95 cm³ (4.1–22 cm³). The median marginal dosage was 12 Gy (range, 10–12 Gy), administered at a 50% isodose line (range, 40–50%). The median max dose was 24 Gy (range, 20–30 Gy). The median mean cochlear dose and max brainstem dose was 5 Gy (range, 2.4–6.6 Gy) and 12.7 Gy (range, 11.5–14.7 Gy), respectively. Adverse events associated with GKRS were classified using the Common Terminology Criteria for Adverse Events, version 5.

Cranial nerve functions, including those of the trigeminal nerve, facial nerve, and vestibulocochlear nerve, as well as cerebellar functions, were examined before and after GKRS. The Gardner-Robertson (GR) hearing scale was used to classify hearing status [14]. A serviceable hearing was defined as GR grade I and II, and hearing deterioration as a decline from GR grade I or II to III–V. House-Brackmann (HB) scale was utilized to assess facial nerve function [20]. Patients were classified into two groups according to the severity of facial nerve palsy: those who had a favorable outcome (HB Grade 1‑3) and those who had an unfavorable outcome (HB Grade 4‑6). The majority of clinical characteristics were classified as improved, stable, or worsened. Any patient who required salvage therapy with re-irradiation or surgery was considered to have treatment failure.

Patients were scanned for the first time at six months, then yearly for the next five years, and subsequently every other year. The recommended imaging modality for establishing tumor volume was T1 contrast-enhanced thin-slice MRI and tumor volume was measured using Elements™ SmartBrush (BrainLAB AG). Tumor volume response has been determined using actuarial volume change and volume change expressed as a percentage. The volume of cVS at the most recent follow-up was compared to pre-GKRS imaging data and was defined as stable (≤ 20% reduction and < 10% increase), regression (reduction > 20%), or progression (≥ 10% increase). Transient tumor expansion was defined as growth of the tumor followed by reduction to the pre-GKRS size or less within 36 months post-GKRS [37]. Tumor control was defined as regression and stable disease, and it was monitored throughout the study until persistent tumor growth or death.

Results

Discussion

cVS is a subtype of VS and its incidence differs considerably throughout the literature due to varying definitions. Until recently, studies have reported SRS results for cVSs from mixed cohorts, for smaller tumor volumes, for adjuvant treatments, or for shorter follow-up periods (Table 3). This study is the first dedicated study to report outcomes in 54 consecutive cVS patients treated with upfront, single-fraction GKRS for a median tumor volume of 6.95 cm³ during a mean radiological and clinical follow-up period of 62.2 (range, 24–169 months) and 94.9 (range, 24–175 months), respectively. We demonstrated that GKRS is a feasible option with favorable tumor control and a low complication rate.

The primary treatment options for cVSs are observation, surgery, SRS, or a combination of these techniques. However, observation might not be the optimal therapeutic choice for cVSs due to the risk of severe mass effect and hydrocephalus associated with rapid or sudden cystic expansion. Charabi et al. [5] discovered that the average yearly growth rate of cVS in patients who had progressive, symptomatic deterioration as a result of rapid expansion of the cystic component was more than tenfold that of sVSs described in the literature. As a result, surgery is a commonly suggested treatment option for cVSs. However, due to the aggressive characteristics of cVSs including rapid growth, larger size, unpredictable cystic expansion, and strong adhesion to the adjacent neurovascular structures, surgical outcomes following cVS surgery are reported to be worse than those following sVS surgery, particularly in terms of facial nerve function. Wu et al. [62] recently published a systematic review and meta-analysis comparing surgical outcomes in cVS and sVS. They analyzed the data from 3074 participants (including 821 patients with cVSs and 2253 patients with sVSs) and found significantly lower (48.8% versus 58.9%; p < 0.001) favorable outcome of facial nerve function, significantly lower (81.6% versus 90.5%; p = 0.015) anatomical preservation of facial nerve, and significantly higher (0.15% versus 0.13%; p = 0.011) hematoma after surgery in the cVS cohort. As a result, cVSs are frequently subtotally removed to preserve the facial nerve's anatomical integrity. However, Kameyama et al. [23] discovered that remaining cVSs regrew rapidly, with a tumor doubling time of 0.15-5.0 years, compared to 9–34 years in sVSs, and that the cystic component of the tumor aided regrowth. Thus, recurring cVSs present an additional surgical challenge, since they are linked with a low likelihood of total tumor removal and preservation of the facial nerve. Currently, a “wait and scan” strategy can be preferred in patients with a newly diagnosed VS and VS growth can be detected by means of repeated MRI examinations. However, it is well known that patients with balance and tinnitus complaints, a higher Koos grade, short duration of symptoms and a larger intrameatal diameter at time of diagnosis have a higher probability of future VS growth [18], and these patients are usually referred for treatment. The 55.6% of the patients in our study with no pre-GKRS growth were rapidly treated without repeated imaging as VS was compressing surrounding tissues.

SRS has long been regarded to be ineffective in treating cVS due to the larger tumor size and cystic contents. It is hypothesized that SRS often results in a fluctuating response and that cVS that has regressed after SRS remains susceptible to growth [40]. Another potential misconception is that surgery following unsuccessful SRS is more difficult because extensive scarring and fibrosis obscure operative planes, resulting in an unclear interface between the facial nerve and the tumor capsule and a poor facial nerve outcome [44]. However, Lee et al. [29] revealed that maximum tumor resection may be accomplished without impairing facial nerve function in VS cases requiring resection following SRS by using contemporary skull-base procedures and enhanced neuromonitoring. Similarly, Troude et al. [53] showed that functional nerve-sparing resection is feasible in salvage surgery following GKRS failure, with comparable long-term tumor control to that found in the true VS population. Progressive dose reduction and method refinement in GKRS have resulted in a further reduction in complications, and acute clinical radiation effects often resolve with short-term corticosteroid therapy [27, 55].

It should be borne in mind that various response patterns to SRS have been reported in documented clinical series. Shirato et al. [43] used stereotactic radiotherapy (SRT) to treat 20 cVS patients and discovered a statistically significant increase in tumor growth in the cVS patients two years after SRT. They noticed, however, that three years following SRT, tumor size reduction was much greater in cVS patients than in sVS patients. Frisch et al. [13] treated 20 cVS patients and observed cystic enlargement in two patients within one year after treatment followed by spontaneous cyst shrinkage. Bowden et al. [4] detected pseudoprogression in 12.6% of cVS, with five cases exhibiting sustained growth. Therefore, before defining the response as treatment failure, it is necessary to evaluate transient tumor expansion or pseudoprogression. Additionally, nearly half the complications have occurred in earlier studies, whereas subsequent studies reported that complications occurred in only 7–10% of patients [4]. Obstructive hydrocephalus necessitating cerebrospinal fluid diversion is also less common in cVS, probably because cysts conform to the contour of the surrounding neural structures rather than compressing them [2]. Regarding volumetric response, it has been shown that cVS patients demonstrate approximately 2-times more shrinkage (80.2% vs. 45.9%) compared to patients with sVS [32]. The rate of patients demonstrating shrinkage was 92.6% in our cohort and the mean volumetric reduction was 68.5%. While there is a risk of cyst expansion associated with neurological symptoms necessitating surgical intervention, GKRS was demonstrated to be a safe and effective upfront treatment option for large cVSs in this study. Overall tumor control was 98.1%, with tumor growth occurring in only one patient (1.9%). The pre-GKRS serviceable hearing was preserved in all nine patients (100%), and it was even improved in 2 patients (22.2%). In the current study, the median max cochlear dose was 5 Gy, and numerous other authors have indicated that a lower cochlear dose is linked with greater hearing preservation rates [11, 17, 24, 39]. Villafuerte et al. [58] treated 157 cVS patients and discovered that cysts were related with a decreased risk of local failure (p = 0.046). In their meta-analysis of tumor control rates in patients undergoing SRS for cVSs, Ding et al. [10] found 92% control rate with SRS treatment across all studies and 93% tumor control rate with GKRS treatment. The hearing was preserved at a median rate of 70.5% (range, 33–76%). Additionally, this meta-analysis compiled data indicating that SRS is a feasible treatment option for patients with cVS and has a high percentage of tumor control.

Concerns regarding iatrogenic morbidity are magnified in the case of large VS (> 4 cm³). Tumor size is critical in surgery because it affects the total removal rate, complications, and postoperative preservation of cranial nerve functions, including facial, trigeminal, and cochlear nerves. Starnoni et al. [47] recently published a meta-analysis and systematic review in which they found a pooled overall gross total resection rate of 85.6% in large series of large VS, with a pooled overall facial nerve preservation rate of 60.1%. Subtotal resection (STR) is linked with high rates of functional preservation of the facial (90%) and cochlear (80%) nerves; nevertheless, the recurrence rate is intricately tied to the residual tumor volume, with a risk of tumor progression exceeding 50% [57]. The treatment of large VSs has turned toward conservative in recent years, with a greater emphasis on STR with or without adjuvant or salvage SRS [22, 36]. A recent meta-analysis of this combined strategy revealed a 93.9% progression-free survival rate after a mean follow-up of 36.9 months [46]. On long-term follow-up, the pooled rates of functional facial nerve preservation (HB grade I–II) and cochlear nerve preservation were reported to be 96.1% and 59.9%, respectively. However, regrowth of the remnant following large VS surgery is difficult, as the facial nerve may be more susceptible to radiobiologic risk factors for additional dysfunction. There is some evidence that even presurgical normal nerve function may have a diminished natural reserve in large VS [19]. Similarly, normal or near-normal nerve function prior to salvage SRS may indicate a depleted natural reserve, and any predisposing factors such as residual tumor edema or brainstem swelling following SRS may further impair facial nerve function. In individuals who are not candidates for surgery, SRS alone is the preferred method of treating large VSs. Previously published GKRS and SRT experiences have shown excellent tumor control rates (84–100%), exceptional facial nerve function preservation (100% in five series), cochlear nerve preservation (33–100%), and low treatment failure rates (0–12%) [6]. A recent systematic review and meta-analysis of the outcomes of SRS for large VSs revealed that 89% of patients achieved clinical control and 92% achieved radiographic control, with a 7% salvage surgery rate [52]. Confirming these findings, all patients retained serviceable hearing and no facial nerve dysfunction was identified in the present study. Interestingly, we found that increasing pre-GKRS tumor volume is related with a greater likelihood of tumor volume reduction following GKRS. Similarly, Stastana et al. [48] reported that larger VSs demonstrated higher volume reduction than small ones.

Apart from predictive objectives, it is critical to maintain a consistent classification of VS subtypes using high-quality T1 and T2 MRI, as Bowden et al. demonstrated [4]. Defining cVSs is not straightforward; there is no consensus in the literature. According to Thakur et al. [50], the majority of studies define VS to be cystic if the cyst diameter is greater than two-thirds the diameter of the tumor on MRI. Thus, the cysts would occupy around 30% of the tumor volume, which was consistent with the present study. Other authors, on the other hand, used the word "cystic" without defining it. Frisch et al. [13] recommended that VSs with dominant intratumoral or peritumoral cyst(s) more than 50% of the overall tumor diameter as measured by the maximum linear axial cerebellopontine angle (CPA) size should be classified as cystic. There is a dearth of precise outcome data on SRS treatment for cVSs in this regard. In the present study, a cut-off value of greater than 30% of the total tumor volume was used, along with subclassifications [12]. Many VSs were found to have micro- or macrocystic alterations on MRI. The volumetric response of a VS might be highly dependent on its preoperative radiographic features. Regarding the possible role of radiologic appearance in response to SRS, Stastna et al. [48] discovered that tumor shrinkage decreases as VSs change from cystic to heterogeneous to homogeneous, and Bowden et al. [4] reported that tumor shrinkage decreases as the VSs change from macrocystic to microcystic to homogeneous. To corroborate this, we found that multiple small thick-walled cyst pattern was related with a decreased possibility of obtaining a greater volume reduction. Huang et al. [21] established an algorithm for automatically segmenting and differentiating the cystic and solid tumor components of VS and observed that VSs with a higher cystic component proportion tended to regress following GKRS. Similarly, Bowden et al. [4] reported that 85.7% of macrocystic VSs decreased in volume, and that over 78% of this group shrank by more than 50%. In the present study, likewise, the median volume reduction was 68.5%. Bowden et al. [4] also reported that macrocystic tumors not only respond to SRS with a greater degree of volumetric decrease, but also shrink at a faster rate. Yang et al. [65] and Delsanti et al. [9] have reported this effect in volumetric tumor reduction studies on tumor residual following surgery. Both of their studies demonstrated that macrocystic tumors had a much shorter volume decrease duration than non-cystic tumors.

We feel that any endeavor to standardize classification is worthwhile since it will result in uniformity in patient care and data reporting. As a result, variability in SRS results for cVSs will be significantly reduced. Additionally, deciphering the underlying genetic pathways driving the cyst development may aid in the treatment of cVSs.

Due to the retrospective nature of this study, some limitations apply; nonetheless, all consecutive patients were included, and exclusion criteria were kept to a minimum to avoid bias. Although the sample size is small, this is the largest devoted study to date describing clinical, radiological, and long-term outcome features of patients with large cVSs treated with upfront, single-session GRKS.

Conclusion

cVSs are challenging tumors that cause significant morbidity in patients, primarily through their effect on the vestibulocochlear nerve. The goal of VS treatment has evolved away from total resection and toward long-term tumor management with optimal functional preservation. As demonstrated in this study, GKRS is a safe and effective therapeutic option for large cVSs. The long-held idea that cVSs do not respond to SRS is incorrect, and treatment paradigms for cVSs should continue to trend toward SRS and away from surgery.

Declarations

Ethical Approval and Consent to participate: This study was approved by the Ethics Committee of Koç University (2022.022.IRB1.017). Informed consent for clinical analysis was obtained from all individual participants or their authorized representatives.

Human and Animal Ethics: All the retrospective clinical analysis was performed according to the Declaration of Helsinki and the local ethics policies. 

Consent for publication: Patients signed informed consent regarding publishing their data. All authors read and approved the final manuscript.

Availability of supporting data: The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Competing interests: The authors declare no competing interests.

Funding: This study did not receive any funding. 

Authors' contributions: Conception and design: All authors. Acquisition of data: Selcuk PEKER, Yavuz SAMANCI, Inan Erdem OZDEMIR. Analysis and interpretation of data: All authors. Drafting the article: Selcuk PEKER, Yavuz SAMANCI, Inan Erdem OZDEMIR. Reviewed submitted version of manuscript: All authors. Statistical analysis: Selcuk PEKER, Yavuz SAMANCI, Inan Erdem OZDEMIR. Administrative/technical/material support: Selcuk PEKER, Yavuz SAMANCI. Study supervision: Henricus PM KUNST, Daniëlle BP EEKERS, Yasin TEMEL

Acknowledgements: We thank all the staff and participants for their contribution to this study.

Authors' information: 

Koç University, School of Medicine, Department of Neurosurgery, Istanbul, Turkey

Selcuk Peker

Koç University Hospital, Department of Neurosurgery, Gamma Knife Center, Istanbul, Turkey

Selcuk Peker, Yavuz Samanci, Inan Erdem Ozdemir

Koç University Hospital, Department of Neurosurgery, Istanbul, Turkey

Yavuz Samanci

Maastricht University Medical Center, Department of Otorhinolaryngology, Maastricht, The Netherlands

Henricus PM Kunst

Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Otorhinolaryngology, Nijmegen, The Netherlands

Henricus PM Kunst

Maastricht University Medical Center + Radboud University Medical Center, Dutch Academic Alliance Skull Base Pathology, Maastricht/Nijmegen, The Netherlands

Henricus PM Kunst, Daniëlle B P Eekers, Yasin Temel

Maastricht University Medical Center, GROW School for Oncology, Department of Radiation Oncology (Maastro), Maastricht, The Netherlands

Daniëlle B P Eekers

Maastricht University Medical Center, Department of Neurosurgery, Maastricht, The Netherlands

Yasin Temel

Maastricht University Medical Center, School for Mental Health and Neuroscience (MHeNS), Maastricht, The Netherlands

Yasin Temel, Selcuk Peker

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