Update: Insular glioma

Glioma of the insular lobe has a unique origin and biological behavior.
They are quite frequent, however treatment of patients with this pathology still remains a challenging and controversial issue of neurosurgery.

Berger Sanai classification.
Magnetic resonance imaging (MRI) with T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR) images best delineates the extent of tumour infiltration, which can be limited to the insular lobe (Yasargil type 3a) or reach the perisylvian opercula (type 3b) and other paralimbic areas, namely the orbitofrontal and temporopolar regions (type 5), with or without involvement of core limbic structures ¹⁾.
Although the classification of insular glioma has been established based on the anatomical location in order to facilitate personalized surgical resection, the diagnosis based on anatomical and functional characteristics becomes more complex when insular tumors extend into either the frontobasal brain region and/or the temporal lobe, as part of the limbic system.
The study findings of Wang et al., suggest that the putamen classification is an independent predictor of survival outcome in patients with insular low-grade gliomas. This newly proposed classification allows preoperative survival prediction for patients with insular gliomas ²⁾.

Due to its challenging technical access ^{3) 4) 5) 6) 7) 8) 9) 10) 11)} and until the publication of Yaşargil et al. ¹²⁾ , the insula has been considered surgically inaccessible for a long time. Thanks to a better understanding of the insular functional anatomy, several experiences of insular surgery have been reported in the last decades ^{13) 14) 15) 16) 17) 18) 19) 20)}.
The surgical treatment should aim to achieve the total (or more than total) resection while avoiding neurological deficits. To achieve these goals, a combination of functional neuroimaging, intraoperative neurophysiology and awake craniotomies have been introduced into the clinical practice of neurosurgical centers dealing with those lesions. Nevertheless, these instruments are insufficient without a deep understanding of regional functional and microvascular anatomy.
The question of potential vascular injuries during resection of insular gliomas is well known, in particular with reference to the potential damage to the lenticulostriate arteries.
Since the first report by Yasargil, few authors have dealt with the surgical treatment of tumours infiltrating the insula
A number of authors have emphasized the importance of functional mapping because of the eloquent nature of both insular and periinsular structures.
The use of sensory and/or motor evoked potentials or ESM provide additional intraoperative landmarks by which to safely resect insular masses. Dominant hemisphere cortical language localization is advisable although language interference from direct stimulation of the insular cortex has seldom been reported.

Prognosis of insular tumor resection is still controversial. Further analysis of subgroup characteristics of insular grade II gliomas based on clinical and molecular analysis is required to reliably determine patients’ survival rates.

M1 segment of the middle cerebral artery, M2 segment of the middle cerebral artery, lenticulostriate arteries, basal ganglia, and internal capsule involvement, causes a high rate of postoperative complications in these patients.

While the benefits of an extensive initial resection of a insular glioma have been widely demonstrated, the best management of residual tumor still represents an open question.
Only 3 investigations analyzed the role of second surgery in case of tumor recurrence (TR). ^{21) 22) 23)}.
For the first time Schmidt et al. provided clinical evidence of the safety of a second surgery in 40 patients.
Martino and coworkers analyzed the clinical outcomes of 19 patients with recurrent LGGs in eloquent areas, strengthening the concept of possible functional reshaping occurrence after the first surgical procedure.
In line with these findings, Ius et al., showed that a second surgery is a safe and effective procedure, even for recurrent insular low grade gliomas..
Another possible reason for the positive outcome after a second surgery may be the smaller tumor volume at relapse.
The investigation of Ius et al., also highlights that seizure recurrence in patients who were seizure-free after the first surgery is associated with tumor progression.

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From a strictly surgical point of view, there are some technical key points to take into consideration at second surgery. At recurrence, there is no intracranial hypertension. Tumor recurrence volume is smaller than the volume at first surgery and the cavity left by the previous operation allows a larger surgical field. The recurrent mass of tumor tissue mainly regrows from the walls of the previous resection into the cavity.
Ius et al., have noticed, also, a better definition between the healthy parenchyma and the tumor tissue, which is softer and, consequently, easier to remove. Moreover, at second surgery, the risk of damaging the vascular structures is much lower, because dissection of the middle cerebral artery (MCA) and its branches has already been performed during the first surgical procedure.
The only difficulty of second surgery is represented by the adhesions. They may cause pain during the opening; moreover, adhesions between dura mater and cortex, on the dominant side, may represent a risk of damage to the cortical language areas. In conclusion, the newly infiltrated deep tumoral tissue is not resected if it has been shown to still be functional based on brain mapping results.

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The study of Ius et al., has potential limitations. First, it is a retrospective study; thus it is limited in nature. Patients with recurrence insular LGGs that are suitable for second surgery are per se highly selected. Thus, the number of our samples is limited, but, if we consider the papers, mentioning insular second surgery, the overall number of patients is 32; thus the study population (23 patients) is not considerably small and it is statistically sufficient to draw some preliminary considerations, which need to be confirmed by enlarging the case study. Moreover, insular surgery is rare at first diagnosis and even rarer at second surgery, so it is not easy to find large population in literature. In any case, it is unlikely that a prospective, randomized study will be designed to address these issues; thus, they believe retrospective, matched studies or prospective observational trials may be a more practical solution, as previously described.
The findings should be validated in a wider series, using multi-institutional cohort to create a potential model able to stratify the risk of TR after the first surgery. In this way, it would be possible to anticipate adjuvant postoperative treatments, also in patients with a diagnosis of pure LGG.
The timing of second surgery has not been well defined yet. Anyway, as previously remarked by Martino et al, it is better to “overindicate” an early second surgery than performing a late surgery when the tumor has already transformed into high-grade gliomas, especially in consideration of the low morbidity profile associated with reoperation ²⁴⁾.

A total of 211 consecutively collected patients diagnosed with low-grade insular gliomas was analyzed. All patients were classified according to whether tumor involved theputamen on MR images. The prognostic role of this novel putaminal classification, as well as that of Yaşargil’s classification, was examined using multivariate analyses.
Ninety-nine cases (46.9%) of insular gliomas involved the putamen. Those tumors involving the putamen, as compared with nonputaminal tumors, were larger (p < 0.001), less likely to be associated with a history of seizures (p = 0.04), more likely to have wild-type IDH1 (p = 0.003), and less likely to be totally removed (p = 0.02). Significant favorable predictors of overall survival on univariate analysis included a high preoperative Karnofsky Performance Scale score (p = 0.02), a history of seizures (p = 0.04), gross-total resection (p = 0.006), nonputaminal tumors (p < 0.001), and an IDH1 mutation (p < 0.001). On multivariate analysis, extent of resection (p = 0.035), putamen classification (p = 0.014), and IDH1 mutation (p = 0.026) were independent predictors of overall survival. No prognostic role was found for Yaşargil’s classification.
The study findings of Wang et al., suggest that the putamen classification is an independent predictor of survival outcome in patients with insular low-grade gliomas. This newly proposed classification allows preoperative survival prediction for patients with insular gliomas ²⁵⁾.

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From March 2011 to June 2013, 30 gliomas involving the dominant insular lobe were resected in the IMRIS 3.0T iMRI integrated Neurosurgical Suite. For 20 patients, awake craniotomy with cortical electrical stimulation mapping (ESM) was performed to locate the language areas. For 10 patients who were not suitable for awake surgery, general anesthesia and functional navigation were performed. DTI (diffusion tensor imaging) tractography-based navigation, continuous motor evoked potential (MEP) monitoring and subcortical ESM were applied to localize and monitor the motor pathway in all cases. iMRI was employed to assess the extent of resection (EOR). The results of intraoperative imaging, IONM and the surgical consequences were analyzed.
Intraoperative imaging revealed residual tumor in 26 cases and led to further resection in 9 cases. As a result, the median EOR was increased from 90% to 93% (P = 0.008) in all cases, and from 88% to 92% (P=0.018) in low-grade gliomas (LGGs). The use of iMRI also resulted in an increase in the percentage of gross and near total resection from 53% to 77% (P=0.016). The rates of permanent language and motor deficits resulting from tumor removal were 11% and 7.1%, respectively.
The combination of iMRI, awake craniotomy, multi-modal brain mapping, and IONM tailored for each patient permits the maximal safe resection of dominant-sided insular glioma ²⁶⁾

A consecutive series of 53 patients with insular LGGs was retrospectively reviewed; 23 patients had two operations.
At the time of second surgery, almost half of the patients had experienced progression into high-grade gliomas (HGGs). Univariate analysis showed that tumor recurrence (TR) is influenced by the following: extent of resection (EOR) (P < 0.002), ΔVT2T1 value (P < 0.001), histological diagnosis of oligodendroglioma (P = 0.017), and mutation of IDH1 (P = 0.022). The multivariate analysis showed that EOR at first surgery was the independent predictor for TR (P < 0.001).
In patients with insular LGG the EOR at first surgery represents the major predictive factor for TR. At time of TR, more than 50% of cases had progressed in HGG, raising the question of the oncological management after the first surgery ²⁷⁾.

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In a retrospective study 20 purely insular grade II gliomas patients and 22 paralimbic grade II gliomas that involved frontal and/or temporal lobes were compared with regard to epidemiological and clinical characteristics. The molecular profiles including Isocitrate dehydrogenase 1 (IDH1), telomerase reverse transcriptase (TERT) promoter, and P53 mutations, 1p19q co-deletion were analyzed, and microRNA profiles were assessed by microarray and bioinformatics analysis. Purely insular grade II gliomas displayed a high frequency of IDH1 mutations with favorable outcome. IDH1 mutated paralimbic glioma shared many parameters with the purely insular glioma in respect to growth patterns, survival, and microRNA profile, but differed significantly from the IDH1 wild type paralimbic gliomas. The findings suggest that IDH1 mutations can define subpopulations of insular gliomas with distinct disease entities regardless of tumor extension patterns. These findings could be useful to develop a customized treatment strategy for insular glioma patients ²⁸⁾.