Surgery of Insular Nonenhancing Gliomas: Volumetric Analysis of Tumoral Resection, Clinical Outcome,...

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Surgery of insular non-enhancing Gliomas: volumetric analysis of tumoral resection, clinical

outcome and survival in a consecutive series of 66 cases

Miran Skrap MD1, Massimo Mondani MD1, Barbara Tomasino PhD2, Luca Weis PhD3, Riccardo

Budai MD4, Giada Pauletto MD4, PhD, Roberto Eleopra MD4, Luciano Fadiga MD PhD3,5,

& Tamara Ius MD1

1 Department of Neurosurgery, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Piazzale Santa

Maria della Misericordia 15, 33100, Udine, Italy

2 IRCCS “E. Medea”, Polo Regionale del FVG, Via della Bontà 7, 37078, San Vito al Tagliamento (PN), Italy

3 Department of RBCS, The Italian Institute of Technology,Via Morego 30, 16163, Genova , Italy;

4 Department of Neurology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Piazzale Santa Maria

della Misericordia 15, 33100, Udine, Italy

5 Section of Human Physiology, University of Ferrara, Via Fossato di Mortara 17, 44121, Ferrara, Italy

Disclosure of Funding:

We attest to have no personal financial or institutional interest in any of the drugs, materials or

devices described or used in this paper.

Acknowledgment:

We thank Francesca Valent MD, MSPH (Istituto di Igiene ed Epidemiologia Clinica Azienda Ospedaliero-

Universitaria di Udine Via Colugna, 50, 33100 Udine – Italy), for the precious advices in the statistical

analysis.

Corresponding Author:

Tamara Ius MD, [email protected], Department of Neurosurgery, Azienda Ospedaliero-

Universitaria Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia 15, 33100,

Udine, Italy

Telephone Number: 0039 - 347- 0178730 / 0039 - 0432- 554493

Fax Number: 0039 – 0432 - 552700

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Abstract

Background: Despite intraoperative technical improvements, the insula still remains a challenging area

for surgery due to its critical relationships with vascular and neurophysiological functional structures.

Objective: The authors retrospectively investigated the morbidity profile in insular non-enhancing

gliomas, with special emphasis on volumetric analysis of tumoral resection.

Methods: From 2000 to 2010, 66 patients underwent surgery. All surgical procedures were conducted

under cortical-subcortical stimulation and neurophysiological monitoring. Volumetric scan analysis

was applied on T2-weighted MRI images to establish pre- and post-operative tumoral volume.

Results: The median pre-operative tumor volume was 108 cc. The median extent of resection (EOR)

was 80%. The median follow-up was 4.3 years. An immediate post-operative worsening was detected

in 33.4% of cases; a definitive worsening resulted in 6% of cases. Patients with EOR of > 90% had an

estimated 5-year overall survival (OS) rate of 92%, whereas those with EOR between 70% and 90%

had a 5-year OS rate of 82% (p=.0004). The difference between pre-operative tumoral volumes on T2-

weighted MRI images and on post contrast T1-weighted MRI images (T2-T1) was computed with the

aim to evaluate the role of the diffusive tumoral growing pattern on OS. Patients with pre-operative

volumetric difference less than 30 cc demonstrated a 5-year OS rate of 92%, whereas those with a

difference of more than 30 cc had a 5-year OS rate of 57% (p =.0184)..

Conclusion: Using intraoperative cortico-subcortical mapping and neurophysiological monitoring, a

major resection is possible with an acceptable risk and a significant result in the follow up.

Key Words

· brain mapping, · direct electrical stimulation, · extent of resection, · functional outcome · insular

gliomas surgery

Running Title:

Insular non-enhancing Gliomas Surgery

Introduction

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Insular gliomas, accounting for up to 25% of Low Grade Gliomas (LGGs) and up to 10% of High

Grade Gliomas (HGGs), have a clear propensity for the insular lobe 1. Their tendency to spread along

the intricate network of afferent and efferent connections between the insula itself and cortical

structures 2 constitutes the major difficulty in reaching a gross total resection. In fact, the insular lobe

represents the anatomo-functional interface between the limbic system and the neocortex 2-4. Because

of the functional role and complex vascular anatomy of the insula, insular gliomas have been

considered unresectable for a long time 5-12. Functionally, the insular cortex has recently been defined

as an associative multimodal compensable 13 secondary area. Moreover, functional neuroimaging

techniques have revealed insular cortex to be involved in many different functions, such as language 14

and sensorimotor integration, cognitive-emotional processing 14-17, gustatory, auditory and vestibular

functions, 3,13,18 and also in neuropsychiatric disturbances 19-21. Anatomically, the insula lies within the

depth of the sylvian fissure, covered by frontal, parietal and temporal opercula and overlying the deep

basal nuclei 12,22-25. It is covered by the trunk of the Middle Cerebral Artery (MCA) and its branches,

and it has important relationships with the perforating Lateral Lenticulostriate Arteries (LLAs) 7,12,25-29.

Furthermore, the insula is close to fibers: the pyramidal tract in the superior posterior part of the insula,

the Inferior Fronto Occipital Fasciculus (IFOF) that run medially to the insula, and the arcuate fibers

that runs more superiorly and could be very close to insular tumours. This intricate network has been

visualized by the introduction of diffusion tensor imaging (DTI) providing new functional-anatomic

landmarks in gliomas surgery2,30,31. Recently, due to technical developments and a better understanding

of insular functional anatomy, some recent publications focused on the key role played by surgery in

insular gliomas management 5,8,9,11, highlighting that an extensive resection performed at the time of the

initial diagnosis constitutes the major favorable prognostic factor to improve patients’ overall survival

(OS).

In the present retrospective study we illustrate our experience in insular non-enhancing glioma surgery

concerning the functional aspects of this area with special emphasis on the role of the extent of

resection on overall survival, as evidenced by a volumetric analysis performed on the tumoral mass.

Methods

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Patient Population

We retrospectively analyzed a series of 66 patients with insular non-enhancing gliomas, treated in 71

resections performed by the senior author (M.S.). These patients underwent surgery in our Institute

between January 2000 and July 2010. Preoperatively, all patients underwent neuropsychological

evaluation and fMRI imaging studies to establish the dominant side and the locations of language-

related functions. In addition, language handedness dominance was evaluated by means of the

Edinburgh Inventory Questionnaire 32. Forty-seven patients had a lesion involving the dominant

hemisphere. No patient had contrast enhancement on post contrast T1-weighted MRI sequences. We

classified the lesions considering both the Yasargil classification System 12 and the Berger-Sanai

Insular Glioma classification System 9. Histological type was determined according to the WHO brain

tumor classification 33. This study was approved by the Local Institution Ethical Committee on Human

Research.

Surgical Technique and mapping

All surgical procedures were conducted under intraoperative cortical and subcortical electrical

stimulation (IES), following the intraoperative methodology previously described by Berger and

colleagues 34-36 and with the routine use of neurophysiological monitoring of MEPs and SEPs. In all

cases we used a NeuroNavigation System (Stealth Station, Medtronic, USA). The selection of the

anesthesiological protocol was based on the pre-operative evaluation of hemispheric dominance.

Awake craniotomy (first surgery in 43 cases and second surgery in 4 cases) was performed for lesions

involving the dominant hemisphere. We used a standard anesthesiological protocol for the awake

surgical procedure; all the patients were awake from the beginning of the procedure with a slight

sedation during skull opening and closing. No laryngeal mask was used. On the contrary, patients with

gliomas in the non-dominant hemisphere (first surgery in 23 cases and second surgery in 1 case 24)

underwent surgery under general anaesthesia with cortical and subcortical IES and neurophysiological

monitoring to detect the corticospinal pathways. EEG and ECoG recordings were always used to

monitor the occurrence of afterdischarges (ADs) phenomena, both electrical and clinical. MEP and

SEP recordings were also performed to continuously monitor motor and somatosensory potentials

(Eclipse Neurovascular Workstation-Axon; Video Polygraphic Station System Plus-Micromed).

Patients were positioned supine with the head fixed in a Mayfield frame and turned at an angle of 30°

towards the floor. Immediately after dura opening and before cortical mapping, an eight-electrode strip

was placed across the central sulcus while two 4-electrode strips were placed over the frontal and

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temporal lobe respectively, to record the electrocortical activity. Before the resection was started, with

the help of the navigator and the bipolar IES, we put some Methylen-blue colored small markers in the

depth along the medial border of the temporal and frontal extension of the lesion to have a better

anatomical orientation during the most advanced phases of surgery, when brain shifting occurs.

At the beginning we used a transilvian approach but for several years now, on the basis of data

provided by cortical mapping, we have preferred to use transcortical trans-frontal and /or trans-

temporal approaches. This technique allowed us to obtain more operative space, which made it easier

to dissect the Medial Cerebral Artery and its branches subpially. We preferred to do this at the end of

the procedure. By increasing the space around the vessels we decreased the risk of evoking pain in

manipulating the MCA in an early phase of surgery. To reduce the risk of ischemia, we now prefer to

leave a minimal part of the tumor around the lenticulostriate arteries (LSAs) in case they are encased.

Performing cortical and subcortical brain mapping, we rarely needed more than 4 mA of current

intensity for the cortex, while we usually started with 6 or 8 mA for subcortical simulation. Proceeding

to the depth we alternated resection of thin tumoral layers with subcortical stimulation (to detect the

pyramidal tract) particularly in the posterior part of the lesion and subcortical pathways of language

(AF and IFOF) for tumors harboring on the dominant hemisphere. The medial border of the resection

was anatomically represented by the LSAs 7,8,11,12, and functionally by the detection of internal capsule

and the pyramidal pathways 5.

In the present study we analyzed a patient population operated in the last 10 years, during which the

intraoperative technical protocol was changed. Therefore, two consecutive periods were identified to

evaluate the impact of each protocol on clinical outcome and EOR:

• Series 1 (from January 2000 to December 2004): 25 patients were operated with the aid of

the cortico-subcortical IES, neurophysiological monitoring and intraoperative employment

of a NeuroNavigation System. Fifteen patients had a lesion in the non-dominant hemisphere

and were treated under general anesthesia, while in the remaining 10 cases the lesion was

located in the dominant hemisphere and consequently awake surgery was performed.

• Series 2 (from January 2005 to July 2010): 41 patients were operated with the aid of the

cortico-subcortical IES, neurophysiological monitoring, and intraoperative employment of a

NeuroNavigation System (as done for Series 1). In addition, in this second group we added

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the overlapping of fMRI/DTI data on the T1/T2 3D MRI images in order to better define

the surgical plan. Eight patients had a lesion in the non-dominant hemisphere and were

treated under general anesthesia, while in the remaining 33 cases the lesion was in the

dominant hemisphere and consequently awake surgery was performed (Figure 1).

Only in the more recent cases (12 patients) has an enriched testing for language functions been

continuously performed during the entire duration of the surgical procedure, providing complementary

information to that provided by IES. The following tasks were used and were continuously repeated

throughout the resection: counting, object picture naming, action picture naming, word comprehension

and repetition, sentence comprehension, spontaneous speech and digit span test.

Patient Outcome Measurements

Neurological examinations were performed preoperatively, and 1 week, 3 months and 6 months after

surgery. Post-operative neurological deficits were graded as mild (minimal, unnoticeable deficit),

moderate (deficit interfering with functions but potentially reversible), or severe (deficit that

significantly disables functions). Patients with no clinical improvement at the 6 month follow-up

examination were considered to have a permanent deficit. In addition to neurological morbidity, the OS

was evaluated in relation to the extent of resection (EOR) and histopathological results.

Volumetric Analysis

Volumetric analysis was applied to establish the extent of tumor resection. MRI images in DICOM

format (Digital Imaging and Communications in Medicine) were used to compute volumetric analyses

of both pre- and post-operative tumoral volume by using axial T2-weighted MRI images. For the post-

operative volume reconstructions we used images acquired four months after surgery. All pre- and

post-operative tumoral segmentations were performed manually with the OSIRIX software tool 37. The

EOR was calculated as follows: (pre-operative tumour volume - post-operative tumour volume)/pre-

operative tumour volume, as previously described by Smith et al. 38.

Statistical Analysis

Commercially available software was used for statistical analysis (SAS v9.2; SAS Institute Inc., Cary,

NC, USA). Univariate as well as multivariate analyses were performed to study the influence of

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different variables on patients' survival. The cases of second surgery were excluded from statistical

analysis. Survival probabilities were estimated using the Kaplan-Meier method. The EOR was

classified into <70%, 70-90%, and >90% to ensure consistency between this study and previous studies

that focused on the impact of glioma resections in terms of volume 9,38,39. The statistical significance of

survival differences among subgroups of subjects was assessed through the log-rank test. The

difference between pre-operative tumoral volumes on T2- weighted MRI images and on post contrast

T1-weighted MRI images (T2-T1) was computed to evaluate the role of a diffusive tumoral pattern of

insular non-enhancing gliomas on overall survival (OS) (Figure 2).

A Multivariate Cox proportional hazards model was used to define whether the EOR (treated as a

continuous variable) predicted OS, after adjusting for the effects of age, KPS, preoperative tumoral

volume, histology and difference between pre-operative tumoral volumes on T2- weighted MRI images

and on post contrast T1-weighted MRI images (T2-T1). Results are presented as hazard ratios (HR)

and 95% confidence intervals (95% CI). Student’s t-test was used to calculate p-values for comparison

of means. All p values were obtained from 2-tailed tests (long-rank test, t-test, chi-square test), with

statistical significance defined as p < .05

Results

Patient Population

Patients' demographic, pre-operative clinical and radiological data are presented in Table 1.

The present study included 40 males and 26 females. According to the classification proposed by

Yasargil 12, 2 gliomas involved the sole insular lobe (Type 3A), 8 gliomas involved both the insula and

at least one adjacent operculum (Type3B), and 46 gliomas involved one or both other paralimbic-

frontoorbital, temporopolar areas (Type 5A, 37 cases), and/or parts of the limbic system (Type 5B, 9

cases). Type 5 gliomas (74%), occupying all zones identified by the Berger-Sanai Insular Glioma

Classification System 9, can also be classified as giant.

Presenting symptoms included seizures in 64 cases and intracranial hypertension in 2 cases.

Pharmacologically resistant epilepsy was present in 15 patients (23%). Pre-operative neurological

examination was normal in 62 cases. None of the patients of this series had discovered tumors

incidentally. None of the patients underwent pre-operative chemotherapy or radiotherapy. Sixty-six

patients underwent a primary craniotomy (43 awake procedures and 23 under general anesthesia). The

median time between the first and the second surgical procedure was 39.8 months (range 18-77

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months). In all cases, pre-operative MRI images showed a lesion that was hypointense on T1-weighted

MRI sequence without Gadolinium enhanced contrast and hyperintense on T2-weighted MRI

sequence. The mean pre-operative tumoral volume, computed on T2-weighted images, was 108 ±

47.9cc.

Post-operative Course and Histological Results

The clinical, histological, radiological and follow-up data are summarized in Table 2. In the

immediate post-operative phase, a worsening of neurological status was observed in 22 patients

(33.4%) as follows: motor deficits developed in 11 cases (16.7%) (hemiplegia in 2 patients and

moderate hemiparesis in 9 patients), while speech disorders occurred in 11 patients (16.7%)

(articulatory disorders in 1 patient, phonemic paraphasia without comprehension deficit in 8

patients, speech disorders with comprehension deficit in 2 patients). At the 3 month follow-up

examination, the neurological conditions of all but 2 patients improved and returned to the initial

level or better. In these two cases permanent hemiplegia (3%) was associated with permanent speech

disorders (3%). All permanent deficits occurred in the Series 1 patients, (vs. those belonging to

Series 2, chi-square = 4.5; p = .03). Moreover, the 3 patients with pre-operative neurological deficits

completely recovered 3 months after surgery. Regarding the patients with post-operative motor

deficits (16 cases), in 10 cases we noticed a sudden intraoperative reversible reduction in MEP

recordings, while in 4 cases there was no change. Irreversible MEPs loss occurred in 2 cases that

developed permanent motor deficit. Intraoperative clinical seizures occurred in 3 patients, while in 8

patients electric seizures were recorded. Six of 47 patients operated on under local anesthesia

developed intraoperative neurovegetative syndrome characterized by bradycardia, sickness, and

epigastric aura. Furthermore, there was no intra peri-operative death related to surgical procedures.

Histological diagnoses were as follows: 2 astrocytomas with gemistocytic foci (WHO II), 34

fibrillar astrocytomas (WHO II), 10 oligostrocytomas (WHO II), 7 oligodendrogliomas (WHO II), 9

anaplastic astrocytomas (WHO III), 2 anaplastic oligoastrocytomas (WHO III), and 2 anaplastic

oligodendrogliomas (WHO III). Adjunctive post-operative treatment was administrated in 42 cases.

Immediate postoperative radiotherapy was performed in 13 patients with WHO III gliomas, while

the other 29 patients received adjunctive treatment because of radiological signs of tumoral

progression: chemotherapy alone was administrated in 4 cases, radiotherapy in 2 cases, and

chemotherapy combined with radiotherapy in 23 cases.

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Extent of Resection

The median tumoral residual volume, computed on post-operative T2-weighted MRI images, was 13 cc

(range 0-112 cc). Removal of > 90% of the pre-operative tumoral volume was achieved in 33% of

cases (22 patients). Surgical removal between 70% and 90% of the pre-operative tumoral volume was

achieved in a further 45% of cases (30 patients). Partial resection (<70% of the pre-operative tumoral

volume) was performed in 22% of cases (14 patients). Seven patients (11%) had an EOR between 0

and 59%. Seventeen (22%) were within the 60–79% EOR range, whereas 20 patients (30%) were

between 80 and 89%, and 22 patients (33%) had ≥ 90% of EOR. The correlation between pre-operative

tumoral volume and post-operative residual volume was not significant (R Sq Linear = .235). In

particular, the median extent of tumoral volume resection was 80% (range from 28% to 100%). In 42

patients (65% of cases) the EOR was > 85%. A further volumetric analysis was performed by

separating patients operated using the 2 different intraoperative protocols (Series 1 versus Series 2).

The Series 1 patients demonstrated a mean EOR of 77% (range from 54% to 97%), while the Series 2

patients had a mean EOR of 83% (range from 28% to 100%), [test statistic t for mean % EOR

comparison (DF = 64) = 1.8, p = .008]. Finally, a last volumetric analysis was computed by using the

preoperative difference (T2-T1) volume. The study population was divided in two subgroups

(subgroup A and subgroup B). Our results evidenced that in cases with T2-T1 preoperative volume less

than 30 cc (Subgroup A = 39 cases), the mean EOR was 88.5%, while when this difference was more

than 30 cc (Subgroup B = 28 cases) the mean EOR was 68.4%. The Subgroup A demonstrated a mean

EOR of 88.5 %, while the Subgroup B had a mean EOR of 68.4%) [t-test statistics for mean % EOR

comparison (df = 64) = 6,8, p = .000]. Consequently, our data pointed out that the mean EOR was

lower than 70% when the preoperative difference of preoperative tumoral volume computed on T2 and

T1 images was higher than 30 cc.

Overall Survival

Overall, there were 14 deaths (15.4%) and the median follow-up in the surviving patients was 4.3 years

(range 3-127 months). Death occurred in 6 patients (9%) with WHO II gliomas, and 8 (12%) with

WHO III gliomas. A Kaplan-Meier estimate was used to calculate survival rates. The 5-years OS was

80%. Patients with WHO II gliomas, compared to those with WHO III gliomas, demonstrated a

significantly improved OS (HR .075, 95% CI .091-.0819, p =.002). Patients with a histological

diagnosis of Oligodendroglioma and Oligoastrocytoma had an estimated 5-year (60 months) OS rate of

92%, whereas those with a diagnosis of Astrocytoma had a 5-year OS rate of 72%. Finally, patients

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with a histological diagnosis of WHO III gliomas had a 5-year OS rate of 58% (Figure 3). For graphic

visualization purposes, survival was stratified according to 3 categories: EOR <70%, EOR 70–90%,

and EOR >90%. Using this stratification scheme in a Kaplan-Meier curve, we observed a stepwise

improvement in OS associated with an increasing EOR among patients with LGGs. Patients with ≥

90% EOR had an estimated 5-year OS rate of 92%, whereas those with EOR between 70% and 90%

had a 5-year OS rate of 82%, and those with EOR less than 70% had a 5-year OS rate of 57% (HR

.885, 95% CI .827-.947, p =.0004) (Figure 4A). Moreover, patients with post-operative tumoral volume

less than 20 cc, compared to those with post-operative tumoral volume more than 20 cc, demonstrated

a significantly improved OS (p = .03). We identified 4 sub-groups relative to residual volume: 1) < 10

cc, 2) 10-20 cc, 3) 20-35 cc, and 4) > 35 cc. The 5-year OS was 90%, 87%, 65%, and 28%, respectively

(HR .944, 95% CI .900-.989, p = .0162) (Figure 4B). Finally, the difference between tumoral volume

computed on T2-weighted images and post contrast T1-weighted MRI images respectively, was

assessed (Figure 5). Patients with pre-operative (T2-T1) volume less than 30 cc demonstrated a 5-year

OS rate of 92%, whereas those with pre-operative (T2-T1) volume more than 30 cc had a 5-year OS

rate of 57% (HR 1.049, 95% CI 1.008–1.092, p = .0184).

Multivariate Cox regression analysis (variables: age, KPS, preoperative tumoral value, histological type,

preoperative (T2-weighted volume less T1-weighted) volume and EOR) revealed preoperative tumoral

volume, histological type, preoperative (T2-weighted volume less T1-weighted) volume and EOR as

independent predictors of OS. After controlling for age, KPS, preoperative tumoral value, histological

type, and preoperative (T2-weighted volume less T1-weighted) volume, the EOR remained the strongest

independent significant predictor of OS (HR .919, 95% CI .871-.970, p = .002) (Table 3).

Discussion

The incidence of insular gliomas represents 25% of all LGGs 1 . The infiltrative growing pattern in

functional areas, particularly for tumors in the dominant side, and the close relationship with the

vascular structures make surgery of low grade insular tumors a challenge 5,7-9,11,12,27,29,41,42.

Furthermore, the tumor’s spreading along the complex network of afferent and efferent fibers,

involving cortical structures and distinct subcortical pathways (AF, UF, IFOF) laying under the insular

lobe 43, limits the achievement of the oncological goal of total tumoral removal.

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Despite the frequent involvement of the insula by gliomas 1, very few cases have been reported in the

literature (Table 4) 5,7-9,11,12,41-42. Considering that these gliomas are fated to a systematic anaplastic

transformation over time 43, more recent studies report that more extensive resections constitute a major

favorable prognostic factor to improve patients' overall survival 5,9. In addition, computerized

techniques to assess the tumoral volume have allowed evaluation of a statistical correlation between the

role of EOR and OS 38,39. The present study represents one of the largest reported experiences on non

enhancing insular gliomas surgery. The aim of the present study is to provide further statistical

evidence that a more aggressive resection correlates to a significant improvement in OS compared with

a simple debulking procedure, due to several technical intra-operative developments.

Volumetric and Survival Analysis

Few papers on EOR and follow-up after insular gliomas surgery have been published. Despite the lack

of Class I evidence, in the last years some retrospective studies have confirmed the key role played by

surgery on OS and quality of life 5,7-9,11,12,39,45-48. Simon et al. 11 and Duffau 5 were the first to assess the

Kaplan Mayer estimation of survival in patients who underwent surgery for insular gliomas. In

particular, the first work reported a 5-year OS rate of 68% and 58% for LGGs and anaplastic gliomas,

respectively, while the second one showed a 5-year OS rate of 72% since first surgery for LGGs. Keles

et al. published a review on the role of EOR in LGGs, identifying 30 prospective studies. All but five

were excluded from further comparison because of significant methodological limitations 45. Most

notably, none of the above mentioned studies included a volumetric analysis and four of them relayed

solely on the surgeons’ intra-operative impressions of EOR. To overcome these problems, a

methodological procedure to volumetrically quantify the EOR was introduced 37,49. Besides that, in a

subsequent series, focused on the EOR value on survival outcome in patients with insular gliomas,

Sanai et al. analyzed the EOR value on OS of 45 insular LGGs, demonstrating a 5-year OS rate of

100% when EOR was >90%, and 84% for EOR < 90% 9. In line with this recent paper, as mentioned

above, we described a volumetric statistical analysis focused on insular non-enhancing gliomas,

confirming that a more aggressive resection correlates to a significant improvement in OS compared

with a simple debulking procedure 38,39. Overall, the present volumetric analysis evidenced a 5-year OS

rate of 92% for patients with EOR > 90%, versus an OS rate of 57% for those with EOR less than 70%

(p = .0004). Our results are in line with the growing evidence, reported in the literature, according to

which the more extensive resection at time of initial diagnosis may be the most favorable prognostic

factor for OS. Our findings provide further objective evidence in favor of the positive prognostic role

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played by EOR. Moreover, the Cox proportional hazards model applied in our patients’ population to

investigate the effects of different variables on overall survival showed that EOR represents the

strongest predictor factor for OS. The multivariate analysis in our study population confirmed that EOR

is an independent prognostic factor for OS in patients with non-enhancing glioma, as previously

reported by Smith et al. 38 in LGG surgery and by Stummer et al. 48 in HGG surgery. Furthermore, our

analysis showed that patients with insular Oligodendrogliomas have a better prognosis with respect to

those with Fibrillary Astrocytomas or with WHO III gliomas (5-yr OS rate of 92% versus 5-yr OS rate

of 72% and 58%, respectively), confirming a different natural history of the tumor and a different

survival of the patient in cases with low-grade oligodendrogliomas compared to those with low-grade

astrocytomas 50. Finally, our findings indicate that patients with pre-operative tumoral volume (T2-T1)

less than 30 cc have a better prognosis than those with pre-operative tumoral volume (T2-T1) more

than 30 cc (p = .0184). The recently developed biomathematical models of glioma growing patterns

have highlighted that tumoral growth results from two underlying mechanisms: proliferation and

diffusion. The first mechanism generates the bulky tumor (with a regular shape, comparable in both

post contrast T1-weighted MRI and T2-weighted images of pre-operative MRI), whereas the second

one causes its diffusion along the white matter (having a complex shape with digitations more visible

on T2-weighted images). Therefore, when proliferation is the major diffusivity phenomenon, it does

not affect the tumor shape (resulting in a regular shape, comparable in both post contrast T1-weighted

MRI and T2-weighted images of pre-operative MRI), which is grossly bulky; by contrast, when the

diffusive pattern is predominant, the tumor will result in a complex shape with digitations along white

matter (resulting in a complex shape more visible on T2-weighted images) 43.

Moreover, Mandonnet et al., argued about the need to complete the description of tumoral location

identifying the status of subcortical pathways 43. Lang et al. asserted that lesions with diffuse margins

on T2-weighted magnetic resonance imaging are less amenable to radical resection with respect to

those with sharp margins 8. Consequently, in our study we have tried to suggest an MRI preoperative

predictive analytic index, based on volumetric analysis, in order to discriminate the proliferative

growing mechanism from the infiltrative diffusive spreading mechanism along the white matter and to

assess preoperatively the degree of resection. Our volumetric analysis showed that when the diffusive

mechanism prevails over the proliferative mechanism, the difference of preoperative tumoral volume

computed on T2 and T1 images progressively increases. Our data pointed out that when the

preoperative difference of preoperative tumoral volume computed on T2 and T1 images is higher than

30 cc, the mean EOR is lower than 70% (Figure 6). Our results evidenced that in cases with T2-T1

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preoperative volume less than 30 cc (Subgroup A = 39 cases), the mean EOR was 88.5%, while when

this difference was more than 30 cc (Subgroup B = 28 cases) the mean EOR was 68.4% (The Subgroup

A patients demonstrated a mean EOR of 88.5 %, while Subgroup B had a mean EOR of 68.4%) [t-test

for mean % EOR comparison (df = 64) = 6,8, p = .000]. Thus, this index could represent a prognostic

preoperative value of EOR itself. Moreover, after controlling for the role of T2-T1 preoperative

tumoral volume, we found that the EOR remained the strongest predictor factor on OS. However, after

Cox analysis, the value of T2-T1 preoperative volume had a significant preoperative prognostic value

(p = .044) on OS even if less strong than EOR (p = .002). As far as the methodological procedure is

concerned, in designing the present study we followed the methodology proposed by Smith et al.38 for

the volumetric assessment of pre-operative and post-operative tumoral volumes. In all cases, to

compute the residual volume we used images acquired four months after surgery rather than the

immediately postoperative images. To date, different postoperative MRI timing and sequences have

been used in recently published studies of EOR evaluation. The standards to compute the postoperative

tumoral residue in gliomas with no or minimal enhancement have not been established yet. Early

postoperative MRI may overestimate residual tumor on T2-weighted MRI images because of

postoperative resection-induced changes 51. Therefore, we decided to compute the residual volume of

the 4 month scan. WHO II patients (53 cases) didn’t receive any immediate postoperative treatments.

Thus, in WHO II cases the residual volume was not positively influenced by postoperative treatments.

Moreover, it is well know that WHO II gliomas are slow growing tumors at about 4 mm/year rates 44.

Consequently, it is extremely rare that the residual tumor has experienced re-growth 4 months after

surgery 52. A limitation of this study is that the 13 patients with WHO II gliomas were postoperatively

treated with radiotherapy. We recognize that in these cases the post-operative radiotherapy may have

interfered with residual tumoral volume analysis. However, radiotherapy may induce structural changes

such as vasogenic edema, demyelization and gliosis in the white matter beyond the boundaries of the

area of irradiation. Such changes result in homogeneous hyperintensity 51;53, which might cause an

over-estimation of the postoperative tumoral volume computed on T2-weighted images, rather than an

under-estimation of EOR computed 4 months after surgery. The future developments of diffusion-

weighted imaging and molecular magnetic resonance imaging could detect postoperative resection-

induced phenomena from residual tumor in early postoperative exams, overcoming the doubts rising

from the interpretation of hyperintensity on T2-weighted images 53,54.

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13

Neurological Deficits and Functional Outcome

The insular lobe represents a complex functional relay 3-5,13,14,16,18,19,21,24,25,55-59, but no single clinical

deficit can be attributed unequivocally to the insular cortex alone, considering the usual infiltration of

surrounding structures 41. It is likely that this associative area is compensable 5,13,55. Seizures are

present at the onset in more than 80% of patients. Transient post-operative deficits in insular glioma

surgery are frequent, as well as their secondary improvement, clearly demonstrating that this structure

seems not to be essential 55. An immediate postsurgical deficit is reported in the literature with a rate

of incidence of 63% 41, 22% 40, 36% 8, 16% 27 and 59% 5. Hentschel al. reported 11% of transient

motor deficits and 30% of transient speech deficits 7, while Sanai et al. recorded transient post-

operative deficits in only 14.4% of cases 9. Our results showed an immediate worsening of patients'

neurological status in 22 cases (33.4%), supporting the idea of a functional reshape of the multi-modal

insular lobe 13. As far as the vascular damage of LLAs is concerned, it represents the main cause of

permanent neurological deficit and all reports emphasize the preservation of the LSAs that supply the

internal capsule 5,7,8,11,12,22,24-28,41. The devastating sequelae in case of damage explains why Yasargil

et al. 12, Duffau 5 and Simon et al. 11 have suggested leaving a layer of tumoral tissue along these

vessels. In the last decade the rate of permanent deficit has decreased: 10% in the series of Zentner et

al.41; 9% in the series of Lang et al. 8, Vanaclocha et al.40 and Simon et al. 11; and 8% in the series

reported by Moshel et al.27. Moreover, Sanai et al. 9 noted post-operative permanent deficits in 6% of

cases while Duffau in 4% of cases 5. In the present series, the rate of definitive worsening was 6%.

Surgical Considerations

Recent advantages in microsurgical and brain mapping techniques with neurophysiological monitoring

have allowed an increase of surgical indications for insular gliomas. In the present series we routinely

used intraoperative transcranical MEP monitoring, which constitutes a tool in guiding the extent of

resection and preventing or minimizing direct injury to the posterior limb of the internal capsule and the

superior limit towards the corona radiate 7,8,11,27. Changes in MEPs amplitude represent a warning sign,

while a sudden loss or a significant reduction of MEPs amplitude probably indicate that an injury to

perforating vessels has already occurred. In our experience, MEPs are useful to predict a direct trauma

of the fibers but they do not guarantee prevention of vascular damage. Finally, we think that the use of

intraoperative EcoG is essential to record afterdischarge phenomena (ADs), and electrical and clinical

seizures, particularly if they are short lasting focal seizures that may interfere with responses induced

by mapping with the loss of the patient’s collaboration. The preoperative surgical planning, especially

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14

the DTI fiber-tracking, represents a useful tool to analyze preoperatively the tri-dimensional

relationships between the tumor and the subcortical pathways 30. Interestingly, our results demonstrated

that the intraoperative employment of a functional guided navigation system used in the second series

is related to a statistically significant increase of the EOR (Series 1 patients demonstrated a mean EOR

of 77%, while Series 2 had a mean EOR of 83%). In addition, in the most recent cases we recorded

specific speech disorders by continuously performing neuropsychological testing during the entire

surgical procedure. We have found this kind of testing more reliable than the sole subcortical

stimulation of tracts inherent to language function like IFOF or arcuate fibers.

Conclusion

A greater extent of resection has been proposed to potentiate the efficacy of adjuvant therapy and to

achieve a longer overall survival. Insular gliomas surgery remains a challenge because of the vascular

structures and the functions of this area, particularly within the dominant hemisphere. Due to the pre-

operative functional techniques (fMRI and DTI), intra-operative monitoring with cortical and

subcortical mapping and neurophysiological monitoring, the achievement of a major resection for

insular non-enhancing gliomas is possible with an acceptable risk of permanent neurological deficits.

Our preliminary data suggest that the routine employment of continuous intraoperative

neuropsychological tasks may constitute an intraoperative tool complementary to subcortical IES to

monitor the language functions/processes. Future developments in intraoperative brain mapping with

electrophysiological arrays systems might improve our knowledge of the tumour-induced

pathophysiological mechanisms and potential plastic phenomena.

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Figure Legends

Figure 1

Figure 1A: fMRI linguistic map (P<0.05, FWE corrected at the cluster level) in a left giant fronto-

temporo-insular non-enhancing glioma. The functional analysis highlights the cortical areas activated

by counting (a), object naming (b) and verbs generation tasks (c). The eloquent cortical regions,

displaced by the tumor, were easily detected with cortical mapping during the surgical procedure.

More critical is the detection of subcortical functional pathways. Figure 1B: 3D Diffusion tensor

imaging fibers tracking reconstruction shows the CorticoSpinal tract (CST) (blu ROIs), AF (orange

ROIs), IFOF (green ROIs). (ACHIEVA 3T, Philips, Netherlands). The tumor mass displaces the AF

upward, the IFOF medially downward, the corticalspinal tract medially and posteriorly. fMRI/DTI data

were overlapped on T2-weighted MR images and loaded into the neuronavigation system allowing a

better evaluation of the pre-operative surgical planning, Figure 1C.

Figure 2

A case of a right fronto-temporo-insular fibrillary astrocitoma.

Figure 2A: Pre- operative axial and coronal T2-weighted MRI slices of right fronto-temporo-insular

LGG.

Figure 2B: The pre-operative tumoral volume computed on post contrast T1-weighted MRI images was

122 cc (axial slices).

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Figure 2C: Overlap, on pre-operative T2-weighted MRI sequence, of the tumoral ROI defined on the

post contrast T1-weighted images (red) and the T2-weighted images (green). The pre-operative tumoral

volume computed on T2-weighted MRI sequence was 130 cc (axial slices). The tumoral volume was

computed using OSIRIX software.

Figure 2D: The volumetric analysis of post-operative tumoral residue on post contrast axial T1-

weighted MRI images evidenced a tumoral residual volume of 4 cc (axial slices).

Figure 2E: The volumetric analysis of post-operative tumoral residue computed on T2-weighted MRI

images showed a tumoral residual volume of 6 cc (axial slices). The extent of the tumoral volume

resection, computed on T2-weighted MRI sequence, was 95.4%.

Figure 3

Kaplan-Meier curves revealing the OS in patients with insular non enhancing glioma, based on

histological findings. Patients with insular oligodendroglioma have a better prognosis.

Figure 4

Kaplan-Meier curves revealing the OS in patients with insular non enhancing glioma stratified by EOR

(Figure 4A) and by the postoperative tumoral residual volume (Figure 4B). A more extensive resection

provides a survival advantage.

Figure 5

Kaplan-Meier curves revealing the OS of patients with insular non enhancing glioma, based on pre-

operative volumetrical analysis of differences between tumoral mass computed on T2-weighted MRI

images and post contrast T1-weigthed MRI images. Patients with pre-operative (T2-T1) volume less

than 30 cc demonstrated a better 5-year OS respect to those with pre-operative (T2-T1) volume more

than 30 cc (p = .0184). A major volumetric difference between T2- and post contrast T1-weighted MRI

sequences suggests a greater propensity of the tumor to have a diffuse growing pattern and

consequently to be less resectable.

Figure 6

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Pre- and post-operative volumetric analysis of a fronto-temporo-insular glioma (Yasargil Type 5

tumors) computed using OSIRIX software.

Figure 2A: Preoperative T2-weghted MRI images showing a left fronto-temporo-insular

oligodendroglioma (axial and coronal slices).

Figure 2B: The pre-operative tumoral volume computed on post contrast T1-weighted MRI was 98 cc

(axial slices).

Figure 2C: Overlap, on pre-operative T2-weighted MRI sequence, of the tumoral ROI defined on the

post contrast T1-weighted images (red) and the T2-weighted images (green). The pre-operative tumoral

volume computed on T2-weighted MRI sequence was 112 cc (axial slices).

Figure 6D: The volumetric analysis of post-operative tumoral residue on post contrast axial T1-

weighted MRI images evidenced a tumoral residual volume of 3 cc (axial slices).

Figure 6E: The volumetric analysis of post-operative tumoral residue computed on T2-weighted MRI

images showed a tumoral residual volume of 6 cc (axial slices). The extent of the tumoral volume

resection, computed on T2-weighted MRI sequence, was 94.7%.

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TABLE 1: Summary of preoperative clinical and radiological features in

66 patients with insular non-enhhancing gliomas

Parameter Value/N° of

cases

Age at diagnosis (yrs)

median 40

range 19-68

Sex

M 40

F 26

Glioma Site

right Insula 22

left Insula 44

Preoperative Tumoral Volume

computed on T2-weighted images

median 108 cc

range 6 - 250 cc

Symptoms at presentation

seizures of recent onset 64

generalized 44

partial 20

Intracranical hypertension 2

Pharmacologically resistant epilepsy 15

Preoperative KPS score

median 95

range 80-100

Preoperative neurological exam

normal 62

mild language disorders 3

mild hemiparesis 1

Tumoral Location according to

Yasargil’s classification 12

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Type 3A 2

Type 3B 8

Type 5A 37

Type 5B 9

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TABLE 2: Summary of post-operative clinical,

radiological results and hystological data

Parameter N°. (%)

Immediate post-operative clinical findings

Normal 44 (66.6%)

Neruological deficits 22 (33.4%)

- Motor deficits 11 (16.7%)

- Speech disorders 11 (16.7%)

Clinical outcome at 6 months

Normal 62 (94%)

Motor deficit 2 (3%)

Speech disorders 2 (3%)

WHO tumor grade

Astrocitomas with gemistocytic foci (WHO II) 2

Fibrillar astrocytomas (WHO II) 34

Oligostrocytomas (WHO II) 10

Oligodendrogliomas (WHO II) 7

Anaplastic Astrocytomas (WHO III) 9

Anaplastic Oligoastrocytomas (WHO III) 2

Anaplastic Oligodendrogliomas (WHO III) 2

Extent of resection

Median residual volume 13 cc

Range 0-112 cc

EOR > 90% 22

EOR 70-90% 30

EOR <70% 14

Additional treatment

no 24

Second surgical procedure 5

Chemotherapy 4

Radiotherapy 15

Chemotherapy plus Radiotherapy 23

Clinical follow-up **

Mean follow-up 52 months

(4,3 yrs)

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Range 3-127

months

Death of patient 14 (21%)

WHO II 6 (9%)

WHO III 8 (12%)

EOR = extent of resection

WHO = World Health Organization

* Determined on the basis of pre- and postoperative T2-weighted MRI images, following the methodological procedure

described by Smith et al. 38

** Since first operation

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TABLE 3: Prognostic Factors and OS: Multivariate Analysis data (Cox proportional hazards model) in

66 patients with insular non-enhhancing gliomas

OS Factor

HR 95% CI P Value

Age (yrs) .946 .889 to 2.542 1.008 (NS)

Preoperative KPS .917 .707 to 1.188 .510 (NS)

Preoperative Tumoral Volume

on T2-weighted images

.018 1.001 to 1.036 .038

Histological type

(WHO II versus WHO III)

.015 .037 to .705 .015

Difference of Preoperative Tumoral Volume

(T2-weighted volume less T1-weighted volume)

(< 30 cc versus > 30 cc)

.087 .008 to .936 .04

EOR .919 .871 to .970 .002

HR = hazards ratio NS = not significant

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Table 4: Insular glioma studies selected for review

Author N° of cases Histological Data

New Transient Deficits

Permanent

Deficits

% of resection Volumetric

Analysis

Second Surgery Improvement of preoperative seizures

Yasargil et al.

Acta Neurochir Wien 1992

177

77

malignant tumors

NA

5%

NA

no

NA

84%

Zentner et al.

J Neurosurgery 1996

30

2 WHO I

13 WHO II 6 WHO III 9 WHO IV

63%

10%

17% (5 cases) total removal 70% (21 cases) EOR >80% 13% (4 cases) EOR< 80% (postcontrast T1 weighted

sequences)

no

NA

89%

Vananclocha

Acta Neurochir 1997

23

5 WHO I


22%

9%

86.9% complete resection 13.1% subtotal resection

(postcontrast T1 weighted sequences)

no

5 patients

NA

Lang et al

J Neurosurg 2001

22

1 PNET


36%

9%

42% of cases EOR > 90% 51% of cases EOR > 70% 7% of cases EOR < 70%


yes

NA

NA

Hentschel et al

Operative Neurosurgery

2005

36

WHO II 22 WHO III 7 WHO IV 4

Other 3

11% transient motor deficits 30% transient speech deficits

8% permenet motor deficits

< 3% permanent speech deficits

NA

NA

NA

NA

Moshel YA J Neurosurg

2008

38


16%

8%

55% (21 cases) Gross total

removal 17% (7 cases) Near gross

total removal 28% (10 cases) subtotal

removal (T2 weighted sequences)

no

NA

NA

Simon et al J Neurosurg

2009

101

operations in 94 patients

6 WHO I


NA

permanent

hemiparesis 9%

42% of cases EOR > 90% 51% of cases EOR > 70% 7% of cases EOR < 70%


no

7 patients

76% of patients with

preoperative pharmacologically resistant seizures

Duffau H

J Neurosurgery 2009

51

51 WHO II

59%

4%

77% of resections were

total or subtotal in FLAIR imaging sequences

yes

9 patients

78% of patients with

preoperative pharmacologically resistant seizures

Sanai et al. J Neurosurgery

2010

115

operations in 104

patients

45WHO II

70 WHO IV

14.4%

6%

Median EOR for LGG =

82% (range 31-100%) (T2 or

FLAIR weighted sequences)

Median EOR for

HGG=81% (range 47-100%)


yes

11 patients

NA

NA = not applicable. The absence of data are indicated as NA

EOR = extent of resection

WHO = World Health Organization

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Surgery of Insular Nonenhancing Gliomas: Volumetric Analysis of Tumoral Resection, Clinical Outcome,...

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