This study on the occurrence of ITN and PTE following GKRS treatment for meningioma had two important findings. First, the study elucidated the natural course of meningioma with ITN after GKRS and presented evidence of pseudoprogression. Although pseudoprogression after radiosurgery in vestibular schwannoma has been reported previously,19–22 pseudoprogression after radiosurgery in meningioma is a novel finding. By 6 months after GKRS, the meningiomas with ITN had increased in volume by an average of 128.5% and were associated with meningeal enhancement and a risk of PTE. However, by 12 months after the GKRS, the ITN had disappeared, the volume had decreased to 94.6%, and the PTE and meningeal enhancement had improved (Fig. 2). Therefore, a volume expansion accompanied by ITN within 12 months after GKRS for meningioma is likely to be pseudoprogression, which can be treated conservatively rather than by immediate surgical resection.
Second, our study found that the presence of ITN at 6 months after GKRS for meningioma was a risk factor for PTE, and that ITN was associated with a 70% dose volume. Previously, some articles have identified ITN as a risk factor for PTE.9,23 Chen et al. presented two cases of meningioma after GKRS that were complicated with ITN and PTE.9 Lee et al. argued that the maximum dose and target volume were significantly related to ITN, and that ITN and the maximum dose were significantly related to the development or aggravation of PTE.23 In our study, we could not evaluate the effect of maximal dose on PTE, because most of the patients (98.4%) had the same prescription dose (14 Gy 50% marginal dose). However, our finding that ITN is significantly correlated to PTE is consistent with and confirms previous reports. Therefore, our study is the first large-scale study to verify that ITN is a significant risk factor for PTE.
In addition, we identified that a 70% dose volume > 1 cc is a risk factor for ITN, which can subsequently lead to PTE (Fig. 3). Although vasogenic edema is a major component of PTE in meningioma, cytotoxic edema is known to contribute to PTE as well.24–26 It is known that the presence of PTE is strongly correlated with the expression of vascular endothelial growth factor (VEGF) within a meningioma.26–29 Some argue that there is also a significant correlation between matrix metalloproteinase 9 (MMP-9) and the presence of PTE.30,31 Such a protein-based pathophysiology for PTE would necessitate a partial breakdown of the tumor–brain interface.26,32 Based on our findings, we suggest that ITN triggered by GKRS may play a role in the breakdown.
After GKRS for meningioma, PTE is a relatively common radiation-induced complication, and there have been many reports of PTE following GKRS. The incidence of symptomatic PTE after GKRS for meningioma has been reported as 5–11%,33–37 whereas all PTE is 13–28%.23,34,36−39 Our study showed a lower incidence of PTE than previously reported (2.4% for symptomatic PTE and 7.9% for all PTE). This low incidence of PTE is probably due to the nature of the tumors included in our study. It is already widely known that tumor volume and size are significant factors for PTE after GKRS for meningioma.33–37,40−43 Although the tumor volume did not show statistical significance in our study, we do not deny that tumor volume is a significant factor for PTE after GKRS. Since the meningiomas included in our study were mostly small tumors (88.2% were < 3 cc), it is possible that the influence of tumor volume was underestimated.
While some studies claim that tumor location is a risk factor for PTE,42,44 others argue the opposite.40,41,45 Meningiomas differ in growth patterns and tumor shape depending on location. The contact area between the tumor and the brain parenchyma varies depending on the tumor shape. Studies on meningioma show that the ratio of the dural base area to the brain parenchymal contact area affects the radiosurgical outcome.14,37,46−50 Therefore, in this study, we limited the study subject to convexity meningioma in order to remove the tumor location as a confounding variable and focus on the radiosurgical prescription parameters that we could control.
In our study, only 3 of 9 patients who had PTE with ITN showed neurological symptoms, and the symptoms disappeared after 6 months in all patients. Therefore, neurosurgeons should reassure their patients by providing sufficient explanations to patients with a high risk for PTE with ITN.
We faced certain limitations during the course of this study. This study was limited by its retrospective study design. Despite being the largest study regarding the occurrence of ITN after GKRS for meningioma, our study was conducted using a small sample size. In our study, only follow-up MRIs at 6 and 12 months after GKRS were included in the study. Further studies might elucidate the longer-term natural course of meningioma with ITN through long-term follow-up.