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.
Table 3
Overview of studies that reported outcomes of single-fraction Gamma Knife radiosurgery in cystic vestibular schwannomas
| Article | Cystic / Cohort n (N) | Definition | Radiation | Tumor volume (range), cm3 | Follow-up (range), months | Tumor control | Serviceable Hearing Preservation |
| Chung et al., 2010 [6] | 15 (21) | MRI-appearance | Mean 11.9 Gy (11–14) | *Mean 17.3 cm3 (12.7–25.2) | Mean 66 (12–155) | 93.33% | *95.2% |
| Hasegawa et al., 2013 [16] | 82 (440) | MRI-appearance | *Median 12.8 Gy (10–18) | *Median 2.8 cm3 (0.07–36.7) | *Median 150 | *93% | *43% (5 years) |
| Klijn et al., 2016 [26] | 30 (420) | MRI-appearance | Median 11 Gy (11–13) | *Median 1.4 cm3 (0.59–3.7) | *Median 61 | *91.3% (5 years) | *42% (5 years) |
| Bowden et al., 2017 [4] | 42 (219) (macrocystic) | MRI-appearance | Median 12.5 Gy (11–13) | Median 4.1 cm3 (0.7–15.4) | Mean 53.5 (5-130) | 95% (5 years) | 74% |
| Bowden et al., 2017 [4] | 45 (219) (microcystic) | MRI-appearance | Median 12.5 Gy (12–13) | Median 3.1 cm3 (0.7–16.1) | Mean 49.7 (6-136) | 95.5% (5 years) | 67% |
| Frisch et al., 2017 [13] | 20 | Total cystic diameter > 50% of the max. CPA axial tumor diameter | Median 13 Gy (12–14) | Median 4.3 cm3 (2.3–6.3) | Median 63 (17–201) | 90% | N/A |
| Tuleasca et al., 2017 [56] | 6 | MRI-appearance | N/A | Mean 1.9 cm3 (0.8–3.3) | Mean 30 (6–60) | 100% | N/A |
| Wu et al., 2017 [61] | 36 (187) | ≥ 1/3 of the total tumor volume | Median 12 Gy (11–13) | Mean 6.2 cm3 | *Median 60.8 (24-128.9) | 100% | N/A |
| Lim et al., 2019 [31] | 24 | > 30% of the total tumor volume | Mean 13.2 Gy (10–15) | Mean 3.5 cm3 (0.7–16) | Mean 55.8 months (8–145) | 75% | N/A |
| Da et al., 2020 [7] | 37 (82) | Total cystic diameter > 50% of the max. CPA axial tumor diameter | *Median 12.6 Gy (10–14) | *Median 5.0 cm3 (0.4–20.4) | N/A | N/A | N/A |
| Villafuerte et al., 2021 [58] | 157 (612) | MRI-appearance | *Median 12 Gy (10–12) | *Median 1.5 cm3 (0.08–13.52) | *Median 60 months | *94% (5 years) | N/A |
| Present study | 54 | > 30% of the total tumor volume | Median 12 Gy (10–12) | Median 6.95 cm3 (4.1–22) | Mean radiological 62.2 months (24–169) Mean clinical 94.9 months (24–175) | 98.1% | 100% |
| *Represents whole cohort. |
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.