This study revealed that AS is characterized by a larger tumor diameter, prevalence of cysts, prevalence of bleeding, and prevalence of calcification than conventional schwannomas. AS in the head and neck are reportedly large, which is consistent with that in this study [14]. One of the other radiological features we analyzed was tumor staining upon angiography, characteristic of hypervascular vestibular schwannoma (HVS) [33]. In our study, 14.4% of the patients had HVS, which was not associated with AS. Few reports on calcification in patients with schwannomas have been published. Zhang et al. reported that blood supply may be related to calcification, but no consensus has been reached [42]. AS are reported to exhibit hemosiderin deposition upon pathologic analysis [13, 26], and the higher prevalence of bleeding in our cohort supports this feature. Furthermore, additional evaluation at T2-star-weighted MRI would have accurately assessed hemosiderin deposition.

Multivariable analysis revealed that cysts were a significant feature of patients with AS. In our cohort, the cysts varied from single to multi-cystic, regardless of the schwannoma subtype, and in some cases the cysts accounted for the majority of the tumor volume. Intracranial cystic schwannomas are reportedly large [13, 17, 24, 41], and have a short clinical history owing to rapid growth [24, 31, 34]. In this study, the presence of cysts was significantly associated with AS; 12/13 (92.3%) AS cases were cystic AS. In the seven previous reports of intracranial AS, five mentioned the presence of cysts (71.4%), which confirms our results [2, 3, 22, 25, 32, 35]. Therefore, AS may be a subtype of cystic schwannomas. However, cystic schwannomas are characterized by rapid growth and a short clinical history. This feature is inconsistent with AS, which is traditionally characterized by slow progression. In our study, the time from symptom onset to surgery among patients with intracranial AS actually seemed shorter than that among patients with conventional schwannomas, although this result was not statistically significant. In some reports, cases of AS have exhibited rapid progression [34]. To explain this seeming discrepancy, intracranial and extracranial AS may have fundamentally different clinical features. This idea is supported by a report by Ando et al. that cysts are more common in intracranial schwannomas than in extracranial schwannomas [4].

AS is difficult to diagnose based on clinical and radiological features alone; hence, definitive pathological diagnosis is important [36]. Pathological features of AS include nuclear atypia without mitosis or degenerative changes. Immunostaining of AS is positive for S-100 and SOX10, as for other schwannomas [15, 28, 39]. Although quantitative evaluation has not been performed, AS cases in our cohort were notable for hemosiderin deposition, hyalinized vessels, and inflammatory cell infiltration, in addition to nuclear atypia. The Ki-67 index is low and consistent with WHO CNS grade 1 [39]. Recent research demonstrates that the Ki-67 index is closely associated with tumor recurrence, especially in cases with a Ki-67 index of 3% or higher [27]. In our cohort, the Ki-67 index was associated with salvage treatment, supporting the results of previous reports. Furthermore, in our patients with AS cases, the mean Ki-67 index was 1.6%, which is a pathologically favorable histology similar to that of conventional schwannomas. Malignancy or sarcoma may be misdiagnosed in patients with extracranial AS because of the presence of nuclear atypia upon pathological evaluation [11, 18, 21]. Mikami et al. reported on a patient with cervical AS with malignant transformation [23], in which the Ki-67 index was quite high (30.5%), suggesting that the Ki-67 index can support the diagnosis of benign or malignant disease. In addition, there was one AS case that developed an early postoperative recurrence requiring stereotactic radiosurgery. In this case, the Ki-67 index was 5%, which is relatively high compared to the overall average of 1.6% and may have been associated with the risk of postoperative recurrence [27].

In our cohort, two patients had cellular schwannomas (1.1%). Cellular schwannomas reportedly account for 4.6–6.7% of all schwannomas [8,9,10], and the proportion of cellular schwannomas within our cohort was small compared to that in previous reports. One of the two patients with a cellular schwannoma in this study had a short time from symptom onset to surgery (3 months), and their Ki-67 index was partially > 30%. D'Almeida et al. reported the clinicopathological features of 20 patients with cellular schwannomas [9]. In that study, the Ki-67 index in patients with cellular schwannomas was higher than that of patients with conventional schwannomas, and cellular schwannomas exhibited locally aggressive growth, consistent with our two cases. The lack of sufficient cases and data regarding cellular schwannomas in our study impeded us from further characterizing this subtype.

Isobe et al. reported an average of 8.3 years from symptom onset to surgery among seven patients with extracranial AS, concluding that extracranial AS is a slow-growing tumor [6, 16, 40]. The long-term progression of the tumor is thought to produce degenerative changes, which is why the tumor is termed "ancient.” In contrast, in our study, the time from symptom onset to surgery did not significantly differ between AS and conventional schwannoma. This difference can be explained by the characteristics of the tumor extension sites. Extracranial lesions, such as those in the retroperitoneal cavity, may reach a substantial size by the time of diagnosis because of the non-restrictive and expandable properties of the retroperitoneal space [38]. In contrast, the intracranial space is surrounded by the skull, and the space in the skull base where most schwannomas occur is especially narrow. Therefore, intracranial AS often presents with neurological symptoms at an early stage of development, leading to prompt diagnosis and treatment.

These results raise the question of whether the pathology of intracranial AS is truly the result of an “ancient” process. Rather, intracranial AS was significantly associated with cyst formation in this study, which is consistent with the results of seven previous case reports. Thus, the features of intracranial AS seem to differ from those of extracranial AS.

The data used in this study were retrospectively collected. Although the sample size was considered adequate for the analysis of AS, only two cases of cellular schwannomas were included. A larger sample would allow for more detailed subtype analysis. In addition, the lack of objective criteria in the WHO classification for the evaluation of degenerative findings in AS has prevented quantitative evaluation. Furthermore, genetic analysis, which was not performed in this study, may clarify the diagnostic criteria and improve our understanding of the pathogenesis of this disease.