BioMed Research International

BioMed Research International / 2015 / Article
Special Issue

New Prognostic and Predictive Markers in Head and Neck Tumors

View this Special Issue

Clinical Study | Open Access

Volume 2015 |Article ID 497610 |

Tamara Ius, Giada Pauletto, Daniela Cesselli, Miriam Isola, Luca Turella, Riccardo Budai, Giovanna DeMaglio, Roberto Eleopra, Luciano Fadiga, Christian Lettieri, Stefano Pizzolitto, Carlo Alberto Beltrami, Miran Skrap, "Second Surgery in Insular Low-Grade Gliomas", BioMed Research International, vol. 2015, Article ID 497610, 11 pages, 2015.

Second Surgery in Insular Low-Grade Gliomas

Academic Editor: Franco Fulciniti
Received15 Mar 2015
Revised15 Aug 2015
Accepted31 Aug 2015
Published11 Oct 2015


Background. Given the technical difficulties, a limited number of works have been published on insular gliomas surgery and risk factors for tumor recurrence (TR) are poorly documented. Objective. The aim of the study was to determine TR in adult patients with initial diagnosis of insular Low-Grade Gliomas (LGGs) that subsequently underwent second surgery. Methods. A consecutive series of 53 patients with insular LGGs was retrospectively reviewed; 23 patients had two operations for TR. Results. At the time of second surgery, almost half of the patients had experienced progression into high-grade gliomas (HGGs). Univariate analysis showed that TR is influenced by the following: extent of resection (EOR) (), ΔVT2T1 value (), histological diagnosis of oligodendroglioma (), and mutation of IDH1 (). The multivariate analysis showed that EOR at first surgery was the independent predictor for TR (). Conclusions. 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.

1. Introduction

Due to its challenging technical access [19] and until the publication of Yaşargil et al. [9], 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 [3, 5, 7, 8, 1013]. In addition, recent studies, based on the objective evaluation of the Extent of Resection (EOR), show that this latter is associated with increased overall survival (OS) rates and a delayed tumor progression (PFS) [2, 5, 7, 8, 1416]. The main limiting factor, in LGGs, the achievement of a radical resection is the involvement of eloquent cortical areas and subcortical functional pathways [1719].

Although surgery is considered the first therapeutic option [2, 5, 79, 11], indications for a second operation in case of TR are still poorly documented [20, 21].

The aim of the study was to determine factors influencing the tumor recurrence (TR) in a cohort of adult patients with an initial diagnosis of insular Low-Grade Gliomas (LGGs) that underwent a second surgery, without any adjuvant treatments between surgeries.

2. Methods

2.1. Patient Selection

In the present study, we retrospectively reviewed 53 adult patients with insular LGGs, identifying among them a series of 23 cases who underwent a second surgery for TR, between January 2000 and September 2013. To analyse the subpopulation with TR and reduce the selection bias, patients were enrolled on the basis of the following inclusion criteria:(1)Age older than 18 years.(2)LGGs harboring in the insular lobe.(3)Two operations during disease evolution.(4)A period of at least one year between the two operations.(5)Histological confirmation of infiltrative LGG at first surgery.(6)Intraoperative mapping at both first and second surgery.(7)No adjuvant therapy since the first surgery.The local institution ethics committee on human research approved this study.

2.2. Functional Preoperative Assessment and Surgical Technique

In all cases, high quality 3D T1- and T2-weighted anatomical images as well as functional Magnetic Resonance Imaging (MRI) and diffusion tensor images data were acquired and adopted for the surgical planning and during the surgical procedure itself, after being loaded within a Neuro-Navigation system (Figure 1).

The awake surgery protocol was selected, for both the first and the second surgical procedures, in all cases with lesion harboring on dominant hemisphere, following the methodology previously described by Skrap and colleagues [8].

Moreover, neurophysiological monitoring (MEPs, SEPs, EEG, and ECoG) was employed in all cases following the protocol approved at our institution [14].

2.3. Histological and Molecular Analysis

Tumors were histologically reviewed according to the World Health Organization (WHO) classification for tumors of the central nervous system [22]. Immunohistochemistry and FISH analyses were performed on 4 μm thick formalin-fixed paraffin-embedded slides as previously described [23].

Briefly, primary antibodies against Ki-67, GFAP, p53 (Dako), EGFR (Zymed), and IDH1R132H (Dianova) were detected using EnVision FLEX system (Dako). Ki-67 was scored as percentage of positive nuclei. All other markers were qualitatively evaluated as negative or positive. FISH analysis for 1p36 and 19q13 deletions was performed using dual-color 1p36/1q25 and 19q13/19p13 probes (Vysis). IDH gene status and MGMT promoter methylation were assessed on DNA extracted from formalin-fixed paraffin-embedded tissue (QIAamp DNA Mini Kit, Qiagen). IDH1 and IDH2 gene status was evaluated by pyrosequencing as previously reported [23]. After DNA bisulfite conversion with EpiTect Bisulfite Kit (Qiagen), methylation levels of the MGMT promoter in positions 17–39 of exon 1 were investigated, by PyroMark Q96 CpG MGMT (Qiagen) according to the manufacturers’ instructions.

2.4. Outcome Measures and Follow-Up

After surgery, all patients were clinically evaluated at 1, 3, and 6 months. Subsequently, patients were assessed every six months by both clinical examination and MRI.

The TR has been defined as the demonstration of either unequivocal increase in tumor size or detection of gadolinium enhancement (malignant progression) on follow-up imaging.

Seizure outcome was categorized after first surgical procedure, using the Engel Classification (Class I, seizure-free or only auras since surgery; Class II, rare seizures; Class III, meaningful seizure improvement; and Class IV, no seizure improvement or worsening) [24]. Seizure recurrence in seizure-free patients and seizure worsening in those who continued to experience seizure (i.e., increase in seizure frequency or significant changing in ictal semiology) were considered as a warning sign prompting to a clinical and neuroradiological follow-up.

2.5. Volumetric Analysis

All pre- and postoperative tumoral segmentations were performed manually across all MRI slices with the OSIRIX software tool [25] to measure tumor volumes (cm3) on the basis of T2 axial slices, as previously described [8, 14]. The extent of glioma removal was evaluated by using MRI images acquired six months after surgery. The EOR was calculated as follows: (preoperative tumor volume − postoperative tumor volume)/preoperative tumor volume [16]. Preoperative ΔVT2T1 value, a preoperative estimation of the difference between tumor volumes on T2-weighted MRI images and on postcontrast T1-weighted MRI images, was also assessed to define the tumor growing pattern, following the methodological procedure described by Skrap et al. [8].

2.6. Statistical Analysis

Characteristics of the study population are described using means ± s.d. or median and range for continuous variables and percentages for categorical variables. Data were tested for normal distribution using the Kolmogorov-Smirnov test. -test or Mann-Whitney test, as appropriate, was used to compare continuous variables. For categorical variables, cross-tabulations were generated and a chi-square or Fisher exact test was used to compare distributions. To describe the time to TR (time between the first and the second surgeries), the Kaplan-Meier approach was used. Patients with not known progression whether malignant or otherwise were censored at the last scan date available. Univariate and Multivariate Cox regression model was used to explore the predictors associated with TR and, consequently, with a second surgery. In Univariate analysis, variables considered as possible predictors of TR were as follows: age, gender, tumor side, preoperative tumor volume, tumor histological subtype, EOR, ΔVT2T1 value, histological subtype, and molecular markers (Ki-67 (Mib1), GFAP, EGFR, p53, and 1p/19q codeletion; MGMT promoter methylation, IDH1-IDH2 mutational status). Considering the small simple size, Multivariate stepwise backward analyses included all variables significant at in Univariate analysis [26]. Results are presented as hazard ratios (HR) and 95% confidence intervals (95% CI). Parametric or nonparametric correlation analyses, as appropriate, were used to explore possible association between TR and seizures after the first surgical procedure. All analyses were conducted with Stata/SE 12.0 for Microsoft Windows. All 2-tailed statistical significance levels were set at .

3. Results

Baseline demographic, clinical, radiological, and histopathological characteristics of the study population, at the time of first and second surgery, are summarized in Tables 1 and 2, respectively.


Number of patients53
 Female23 (43.40%)
 Male30 (56.60%)
Mean age (yrs)38 (range 19–69)
Tumor side
 Left36 (67.92%)
 Right17 (32.08%)
Median preoperative T2 tumoral volume in cm3 (range)76.33 (range 5–174)
Median preoperative ΔVT2T1 value in cm3 (range)23.13 (range 1–112)
ΔVT2T1 category
 <30 cm337 (69.81%)
 ≥30 cm316 (30.19%)
Intraoperative protocol
 Awake surgery41 (77.36%)
 General anesthesia12 (22.64%)
Cortical mapping
 Speech arrest and motor function orbicularis orisAll 41 cases with lesion involving the dominant hemisphere
 Slurred speech or dysarthria26 (49%)
 Anomia26 (49%)
Subcortical mapping
 Identification of corticospinal tract as posterior edge of resectionAll cases
 Identification of subcortical language pathwaysPositive sites were detected in 24 cases (45.3%)
Neurophysiological data
 Reversible reduction of MEPs amplitude7 out of 10 patients, who developed postoperative transient motor deficit
 Irreversible MEPs lossIn 1 patient who showed, after surgery, a permanent motor deficit
Median EOR in % (range)82.98 (range 54–100)
EOR category
 ≥90%22 (41.51%)
 70–89%23 (43.40%)
 <70%8 (15.09%)
Immediate postoperative clinical findings
 No deficits37 (69.81%)
 Neurological deficits15 (30.19%)
  Motor deficits9 (16.98%)
  Speech disorders6 (13.21%)
Clinical outcome 6 months after surgery
 No deficits52 (98.11%)
 Neurological deficits1 (1.89%)
Postoperative Engel Class 6 months after surgery
 I36 (67.92%)
 II4 (7.55%)
 III8 (15.10%)
 IV5 (9.43%)
Histological diagnosis
 Fibrillary astrocytoma31 (58.5%)
 Oligodendroglioma6 (11.3%)
 Oligoastrocytoma16 (30.2%)
Molecular profile
 Mib1-Ki-67 expression3.5% (range 1–5%)
 1p/19q codeletion presence13 (25%)
 P53 expression33 (62.26%)
 IDH1 mutation45 (85%)
 MGMT promoter methylation39 (73.58%)


Number of patients23
 Female8 (34.78%)
 Male15 (65.22%)
Mean age (yrs)42 (range 25–54)
Tumor side
 Left15 (65.22%)
 Right8 (34.78%)
Median time to tumor recurrence81 months (14–124)
Seizures relapse at second surgery11 (47.83%)
New contrast enhancement before second surgery11 (47.83%)
Intraoperative protocol
 Awake surgery16 (69.57%)
 General anesthesia7 (30.43%)
Immediate postoperative findings
 No deficits15 (65.22%)
 Neurological deficits08 (34.78%)
  Motor deficits4 (17.39%)
  Speech disorders3 (13.04%)
  Visual field disorders1 (4.35%)
Clinical outcome 6 months after surgery
 No deficits22 (95.65%)
 Neurological deficits1 (4.35%)
Histological data
 LGGs (WHO II)6 (26.09%)
 Anaplastic gliomas (WHO III)7 (30.43%)
 Glioblastomas (WHO IV)10 (43.48%)
 Mib1-Ki-67 expression16.5% (range 2–70%)

3.1. Clinical, Radiological, and Histological Data at First Surgical Procedure

The median time between the diagnosis and the first operation was 3.2 months (range 0–11 months). No patient received adjuvant treatment before the first surgical procedure. Preoperative neurological examination was normal in all cases, but all patients were affected by tumor-related epilepsy and required antiepileptic treatment. Before surgery all patients were drug-resistant, according to the ILAE definition [27].

During surgery, when direct electrical stimulation, at subcortical level, did not elicit any functional response, resection continued following the information provided by guided navigation system which remains indicative in subcortical areas. Neuropathological examination resulted in WHO grade II gliomas in all cases. Worsening of the neurological status after surgery was observed in 15 patients. At the six-month follow-up examination, the neurological conditions of all but one patient improved and returned to the initial level. Concerning seizure outcome, 75.5% of patients achieved satisfactory postoperative seizure control (Engel Classes I-II) 6 months after surgery.

3.2. Clinical, Radiological, and Pathological Data at the Second Surgical Procedure

A second surgery was performed in 23 patients. The median time between surgeries was 81 months (range 12–144 months). At the time of the second operation, 11 patients, who were seizure-free after the first surgery, had a relapse of unprovoked seizures. Seven patients, who were in Engel class II after the first operation, showed increased seizure frequency and/or ictal semiology worsening. In the remaining 6 cases, tumor relapse was identified on the basis of the MRI follow-up. Postoperative seizure recurrence and worsening were found to be associated with TR (Fisher ). Considering MRI characteristics, 11 cases showed contrast enhancement, while in 12 cases an increased tumor size was observed through radiological follow-up on T2-weighted images. All tumor recurrences were local.

The preoperative neurological examination was normal in all cases. During surgery, motor function was detected in all cases at both cortical and subcortical level whenever necessary due to the extension of the tumor. No changes in intraoperative MEPs recordings were observed during the whole surgical procedure. Regarding language, we were able to obtain a positive mapping in 85% and 25% of cases at cortical and subcortical level, respectively.

New deficits during the immediate postoperative phase were recorded in 8 cases. At the six-month follow-up examination, the neurological conditions of all but one patient improved and returned to the preoperative level. Histopathological examination showed a progression of the glioma to grade III or IV according to WHO in 17 cases.

Comparison between preoperative MRI enhancement and pathological examination showed that enhancement occurred in 13 out of 17 patients with tumor dedifferentiation. The association between contrast enhancement and the progression to grades III and IV was statistically significant (Fisher ). Postoperative chemotherapy and radiotherapy were administered in all cases with a diagnosis of glioma grade III or IV.

3.3. Volumetric Analysis

The median preoperative tumor volume at first surgery was 76 cm3 (range 5–174 cm3) on T2-weighted MRI images, while the median postoperative residual tumor volume, computed on postoperative T2-weighted MRI images, was 12 cm3 (range 4–85 cm3). Notably, in almost half of the patients at the first surgery, the EOR was higher than 90% (Figure 2). The median extent of tumor volume resection was 83% (range 54–100%).

In order to evaluate the role of a diffuse tumor growth pattern on tumor recurrence, preoperative ΔVT2T1 value was computed in all cases. For this purpose, the study population was divided into two subgroups (subgroup A (37 cases): patients with ΔVT2T1 value < 30 cm3 and subgroup B (15 cases): patients with ΔVT2T1 value ≥ 30 cm3). At second surgery, the median preoperative tumor volume, computed on T2-weighted images, was 40 cm3 (range 18–95 cm3) (Figure 3). The median extent of tumor volume resection, computed on T2-weighted images, was 82% (range 60–100%). Contrast enhancement, observed before the second operation, was totally removed in all 11 cases.

3.4. Risk Factors for Tumor Recurrence

TR was identified in 23 patients. Univariate analysis results are summarized in Table 3. The most important predictor for TR event was the EOR achieved at the first procedure. Patients with TR had a mean EOR of 77.64%; conversely patients without TR had a mean EOR of 90.14% (Mann-Whitney test, ; ). Besides a lower EOR at first surgery (Figure 4(a)), an increase in preoperative ΔVT2T1 value at the diagnosis (Figure 4(b)), as well as the diagnosis of fibrillary astrocytoma (Figure 4(c)), was associated with higher risk to develop TR. Furthermore, the TR event was decreased for those patients with IDH1 mutation (Figure 4(d)), while the presence of 1p/19q codeletion status was associated with the trend to have a lower risk of TR. In the final model, Cox analysis showed that EOR was the strongest independent predictor for TR (Table 4).

FactorTumor recurrence
HR95% CI

(modelled as continuous variable)
Tumor site
Preoperative T2 tumor volume cm3
(modelled as continuous variable)
Tumor subtype
 Fibrillary astrocytoma1
(modelled as continuous variable)
(modelled as continuous variable)
 <30 cm31
 ≥30 cm32.9501.243–7.0010.014
(modelled as continuous variable)
1p/19q codeletion
Presence versus absence
P53 mutation
(modelled as continuous variable)
(modelled as continuous variable)
(modelled as continuous variable)
Mutation versus no mutation
Promoter methylation versus no promoter methylation

HR, hazard ratio; CI, confidence interval; EOR, extent of surgical resection; ΔVT2T1, volumetric difference between preoperative tumor volumes on T2- and T1-weighted MRI images.
Boldfacing represents statistical significance values () obtained from two-sided tests (Cox regression).

FactorTumor progression
HR95% CI

(modelled as continuous variable)

EOR = extent of surgical resection.

4. Discussion

Increasing evidence supports the association between EOR, prolonged OS, and delaying tumor progression [14, 16, 24, 2840], even for patients with insular LGGs [2, 5, 79, 12]. However radical surgery in these cases still remains a critical point, due to insular complex anatomy and functional relationships [1, 2, 8, 18]. Imaging follow-up shows that the residual tumor systematically exhibits a spontaneous and continuous growth, with an inherent risk of anaplastic transformation over the time [18, 41]. While the benefits of an extensive initial resection have been widely demonstrated, the best management of residual tumor still represents an open question [37, 42]. Only two recent investigations analyzed the role of second surgery in case of TR [20, 21] and documented safety and effectiveness of the second surgical procedure in patients with insular LGGs.

4.1. Neurological Deficits and Functional Outcome

The major limitation in achieving a radical resection in LGGs surgery is represented by their attitude to infiltrate the subcortical functional pathways [8, 14, 18]. Thus it is a widespread opinion that a second surgery would lead only to an increased risk of new neurological deficits. For the first time Schmidt et al. [21] 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 [20], strengthening the concept of possible functional reshaping occurrence after the first surgical procedure [20, 4345]. In line with these findings, our postoperative neurological results showed that a second surgery is a safe and effective procedure, even for recurrent insular LGGs.

Another possible reason for the positive outcome after a second surgery may be the smaller tumor volume at relapse. This is coherent with the concept of the “multistage surgical approach” for LGGs, previously described by Robles et al. [44]. Our investigation also highlights that seizure recurrence in patients who were seizure-free after the first surgery is associated with tumor progression, as previously described by Chang et al. [46].

4.2. Surgical Considerations

The overlap of fMRI/DTI data on the T1/T2 3D MRI images in the Neuro-Navigation system is particularly helpful at second surgery, because anatomy with conventional landmarks and functional structures may be significantly modified [8].

Moreover, intraoperative image guidance may also provide critical information during the resection of tumors with a consistency similar to normal brain tissue, by delineating T2-weighted images margins [47]. For this reason, MEPs monitoring was particularly helpful in preventing the direct injury to the posterior limb of the internal capsule and the superior limit towards the corona radiate [48, 49]. Indeed, both structures have been always identified at first and second surgical procedure. On the contrary, subcortical language pathways have been detected in 46% and 25% of cases, at first surgery and second surgery, respectively. Even so, none of our patients developed permanent severe language deficit, supporting the hypothesis of functional reshaping [2, 20, 45, 50, 51]. 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 endocranic 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. We 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.

4.3. Risk Factors for Tumor Progression

The idea of performing a new procedure during regrowth of LGGs, before anaplastic transformation, has been proposed in order to obtain a greater impact on survival [21, 32, 44, 52]. Thus, we tried to identify factors that could provide an early identification of those patients with higher possibility to develop TR. Our findings indicated that the time to TR, even among insular LGGs, is longer in patients who underwent wider resections, as previously demonstrated.

These results support the idea that tumors with larger residual postoperative volume may have an inherently faster growth; therefore, they may recur earlier in the setting of a subtotal resection [15, 16]. Moreover this investigation confirmed the data we previously reported about the role of ΔVT2T1 value on TR: patients with preoperative ΔVT2T1 value more than 30 cm3 have an earlier TR ( value = 0.001). In fact this value reflects a lower possibility to obtain a higher EOR.

McGirt et al. showed that patients with oligodendroglioma and oligoastrocytoma have a better prognosis compared to those with fibrillary astrocytoma [32]. To support this result we separated these histological subtypes confirming that oligodendrogliomas have more benign courses [8, 53, 54].

Regarding the molecular analysis, recent data demonstrated that LGGs display a variety of molecular alterations that may have predictive or prognostic value [55, 56]. The molecular data pointed out that the risk of TR was significantly reduced in the presence of IDH1 mutation, as previously demonstrated by Gozé et al. [56, 57], while the presence of 1p/19q codeletion status was associated with a lower TR risk trend. The prognostic value of IDH1/IDH2 mutations is more controversial. Otherwise 1p/19q codeletion status in LGGs has been widely demonstrated to be associated with a favorable outcome whatever the endpoint: overall survival, progression-free survival, or spontaneous tumor growth velocity [37, 53, 56, 58]. Furthermore, the molecular analysis evidenced that Ki-67 value, as well as p53, GFAP, EGFR, and MGMT status, does not influence the risk for TR after the first surgical procedure, suggesting that other molecular markers should be selected for early identification of patients with a major risk of TR [23]. In closing, the Multivariate analysis highlighted that the only independent factor associated with TR is represented by EOR at first surgery, confirming the findings reported in the literature [5, 8, 14, 24].

As far as the methodological procedure is concerned, the present investigation 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 [2, 5, 7, 12], the overall number of patients is 32; thus our study population in a singular institution (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, we believe retrospective, matched studies or prospective observational trials may be a more practical solution, as previously described [15]. Our 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 [20].

5. Conclusions

In insular LGGs patients, the EOR at first surgery represents the major predictive factor for TR. Further molecular analysis will be necessary to better stratify patients in terms of risk for TR, thus identifying patients that could benefit from an early adjuvant treatment after the first surgical procedure.


DES:Direct electrical stimulation
EOR:Extent of Resection
DICOM:Digital Imaging and Communications in Medicine (standard)
DTI:Diffusion tensor imaging
fMRI:Functional MRI
KPS:Karnofsky Performance Scale
IES:Intraoperative electrical stimulation
LGGs:Low-Grade Gliomas
MEPs:Motor evoked potentials
MRI:Magnetic Resonance Imaging
SEP:Somatosensory evoked potentials
TR:Tumor recurrence
ΔVT2T1:Volumetric difference between preoperative tumor volumes on T2- and T1-weighted MRI images.


The founders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.

Conflict of Interests

The authors attest to have no conflict of interests concerning the materials or methods used in this study or the findings specified in this paper.

Authors’ Contribution

Authors’ contribution to the study and paper preparation includes the following: conception and design: Skrap and Ius; acquisition of data: Ius; analysis and interpretation of data: Ius, Isola, and Skrap; drafting the paper: all authors; critically revising the paper: all authors.


The authors thank Programma per la Cooperazione Transfrontaliera Italia-Slovenia 2007–2013 entitled “identificazione di nuovi marcatori di cellule staminali tumorali a scopo diagnostico e terapeutico.” Additional thanks are due to Gabriele Valiante and Roberto Canesin for technical support.


  1. J. R. Augustine, “Circuitry and functional aspects of the insular lobe in primates including humans,” Brain Research Reviews, vol. 22, no. 3, pp. 229–244, 1996. View at: Publisher Site | Google Scholar
  2. H. Duffau, “A personal consecutive series of surgically treated 51 cases of insular WHO Grade II glioma: advances and limitations,” Journal of Neurosurgery, vol. 110, no. 4, pp. 696–708, 2009. View at: Publisher Site | Google Scholar
  3. U. Ebeling and K. Kothbauer, “Circumscribed low grade astrocytomas in the dominant opercular and insular region: a pilot study,” Acta Neurochirurgica, vol. 132, no. 1–3, pp. 66–74, 1995. View at: Publisher Site | Google Scholar
  4. M.-M. Mesulam and E. J. Mufson, “The insula of Reil in man and monkey: architectonics, connectivity, and function,” in Association and Auditory Cortices, vol. 4 of Cerebral Cortex, pp. 179–226, Springer, New York, NY, USA, 1985. View at: Publisher Site | Google Scholar
  5. N. Sanai, M.-Y. Polley, and M. S. Berger, “Insular glioma resection: assessment of patient morbidity, survival, and tumor progression—clinical article,” Journal of Neurosurgery, vol. 112, no. 1, pp. 1–9, 2010. View at: Publisher Site | Google Scholar
  6. B. P. Shelley and M. R. Trimble, “The insular lobe of reil-its anatamico-functional, behavioural and neuropsychiatric attributes in humans-a review,” World Journal of Biological Psychiatry, vol. 5, no. 4, pp. 176–200, 2004. View at: Publisher Site | Google Scholar
  7. M. Simon, G. Neuloh, M. von Lehe, B. Meyer, and J. Schramm, “Insular gliomas: the case for surgical management,” Journal of Neurosurgery, vol. 110, no. 4, pp. 685–695, 2009. View at: Publisher Site | Google Scholar
  8. M. Skrap, M. Mondani, B. Tomasino et al., “Surgery of insular nonenhancing gliomas: volumetric analysis of tumoral resection, clinical outcome, and survival in a consecutive series of 66 cases,” Neurosurgery, vol. 70, no. 5, pp. 1081–1093, 2012. View at: Publisher Site | Google Scholar
  9. M. G. Yaşargil, K. von Ammon, E. Cavazos, T. Doczi, J. D. Reeves, and P. Roth, “Tumours of the limbic and paralimbic systems,” Acta Neurochirurgica, vol. 118, no. 1-2, pp. 40–52, 1992. View at: Publisher Site | Google Scholar
  10. H. Duffau, L. Capelle, M. Lopes, T. Faillot, J.-P. Sichez, and D. Fohanno, “The insular lobe: physiopathological and surgical considerations,” Neurosurgery, vol. 47, no. 4, pp. 801–810, 2000. View at: Publisher Site | Google Scholar
  11. F. F. Lang, N. E. Olansen, F. DeMonte et al., “Surgical resection of intrinsic insular tumors: complication avoidance,” Journal of Neurosurgery, vol. 95, no. 4, pp. 638–650, 2001. View at: Publisher Site | Google Scholar
  12. V. Vanaclocha, N. Sáiz-Sapena, and C. García-Casasola, “Surgical treatment of insular gliomas,” Acta Neurochirurgica, vol. 139, no. 12, pp. 1126–1135, 1997. View at: Publisher Site | Google Scholar
  13. J. Zentner, B. Meyer, A. Stangl, and J. Schramm, “Intrinsic tumors of the insula: a prospective surgical study of 30 patients,” Journal of Neurosurgery, vol. 85, no. 2, pp. 263–271, 1996. View at: Publisher Site | Google Scholar
  14. T. Ius, M. Isola, R. Budai et al., “Low-grade glioma surgery in eloquent areas: Volumetric analysis of extent of resection and its impact on overall survival. A single-institution experience in 190 patients—clinical article,” Journal of Neurosurgery, vol. 117, no. 6, pp. 1039–1052, 2012. View at: Publisher Site | Google Scholar
  15. N. Sanai and M. S. Berger, “Glioma extent of resection and its impact on patient outcome,” Neurosurgery, vol. 62, no. 4, pp. 753–766, 2008. View at: Publisher Site | Google Scholar
  16. J. S. Smith, E. F. Chang, K. R. Lamborn et al., “Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas,” Journal of Clinical Oncology, vol. 26, no. 8, pp. 1338–1345, 2008. View at: Publisher Site | Google Scholar
  17. H. Duffau and L. Capelle, “Preferential brain locations of low-grade gliomas,” Cancer, vol. 100, no. 12, pp. 2622–2626, 2004. View at: Publisher Site | Google Scholar
  18. E. Mandonnet, L. Capelle, and H. Duffau, “Extension of paralimbic low grade gliomas: toward an anatomical classification based on white matter invasion patterns,” Journal of Neuro-Oncology, vol. 78, no. 2, pp. 179–185, 2006. View at: Publisher Site | Google Scholar
  19. N. Sanai, Z. Mirzadeh, and M. S. Berger, “Functional outcome after language mapping for glioma resection,” The New England Journal of Medicine, vol. 358, no. 1, pp. 18–27, 2008. View at: Publisher Site | Google Scholar
  20. J. Martino, L. Taillandier, S. Moritz-Gasser, P. Gatignol, and H. Duffau, “Re-operation is a safe and effective therapeutic strategy in recurrent WHO grade II gliomas within eloquent areas,” Acta Neurochirurgica, vol. 151, no. 5, pp. 427–436, 2009. View at: Publisher Site | Google Scholar
  21. M. H. Schmidt, M. S. Berger, K. R. Lamborn et al., “Repeated operations for infiltrative low-grade gliomas without intervening therapy,” Journal of Neurosurgery, vol. 98, no. 6, pp. 1165–1169, 2003. View at: Publisher Site | Google Scholar
  22. D. N. Louis, H. Ohgaki, O. D. Wiestler et al., “The 2007 WHO classification of tumours of the central nervous system,” Acta Neuropathologica, vol. 114, no. 2, pp. 97–109, 2007. View at: Publisher Site | Google Scholar
  23. E. Bourkoula, D. Mangoni, T. Ius et al., “Glioma-associated stem cells: a novel class of tumor-supporting cells able to predict prognosis of human low-grade gliomas,” Stem Cells, vol. 32, no. 5, pp. 1239–1253, 2014. View at: Publisher Site | Google Scholar
  24. L. Capelle, D. Fontaine, E. Mandonnet et al., “Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases,” Journal of Neurosurgery, vol. 118, no. 6, pp. 1157–1168, 2013. View at: Publisher Site | Google Scholar
  25. A. Rosset, L. Spadola, and O. Ratib, “OsiriX: an open-source software for navigating in multi-dimensional DICOM images,” Journal of Digital Imaging, vol. 17, no. 3, pp. 205–216, 2004. View at: Publisher Site | Google Scholar
  26. E. W. Steyerberg, Clinical Prediction Models: A Practical Approach to Development, Validation, and Updating, Springer, New York, NY, USA, 2009.
  27. P. Kwan, A. Arzimanoglou, A. T. Berg et al., “Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies,” Epilepsia, vol. 51, no. 6, pp. 1069–1077, 2010. View at: Publisher Site | Google Scholar
  28. A. Rezvan, D. Christine, H. Christian et al., “Long-term outcome and survival of surgically treated supratentorial low-grade glioma in adult patients,” Acta Neurochirurgica, vol. 151, no. 11, pp. 1359–1365, 2009. View at: Publisher Site | Google Scholar
  29. J. T. Grier and T. Batchelor, “Low-grade gliomas in adults,” Oncologist, vol. 11, no. 6, pp. 681–693, 2006. View at: Publisher Site | Google Scholar
  30. T. B. Johannesen, F. Langmark, and K. Lote, “Progress in long-term survival in adult patients with supratentorial low-grade gliomas: a population-based study of 993 patients in whom tumors were diagnosed between 1970 and 1993,” Journal of Neurosurgery, vol. 99, no. 5, pp. 854–862, 2003. View at: Publisher Site | Google Scholar
  31. C. Leighton, B. Fisher, G. Bauman et al., “Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation,” Journal of Clinical Oncology, vol. 15, no. 4, pp. 1294–1301, 1997. View at: Google Scholar
  32. M. J. McGirt, K. L. Chaichana, F. J. Attenello et al., “Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas,” Neurosurgery, vol. 63, no. 4, pp. 700–707, 2008. View at: Publisher Site | Google Scholar
  33. M. Nakamura, N. Konishi, S. Tsunoda et al., “Analysis of prognostic and survival factors related to treatment of low-grade astrocytomas in adults,” Oncology, vol. 58, no. 2, pp. 108–116, 2000. View at: Publisher Site | Google Scholar
  34. C. A. North, R. B. North, J. A. Epstein, S. Piantadosi, and M. D. Wharam, “Low-grade cerebral astrocytomas. Survival and quality of life after radiation therapy,” Cancer, vol. 66, no. 1, pp. 6–14, 1990. View at: Google Scholar
  35. J. H. Philippon, S. H. Clemenceau, F. H. Fauchon, J. F. Foncin, R. A. Morantz, and J. M. Piepmeier, “Supratentorial low-grade astrocytomas in adults,” Neurosurgery, vol. 32, no. 4, pp. 554–559, 1993. View at: Publisher Site | Google Scholar
  36. B. Rajan, D. Pickuth, S. Ashley et al., “The management of histologically unverified presumed cerebral gliomas with radiotherapy,” International Journal of Radiation Oncology, Biology, Physics, vol. 28, no. 2, pp. 405–413, 1994. View at: Publisher Site | Google Scholar
  37. N. Sanai, S. Chang, and M. S. Berger, “Low-grade gliomas in adults,” Journal of Neurosurgery, vol. 115, no. 5, pp. 948–965, 2011. View at: Publisher Site | Google Scholar
  38. J. S. Smith, S. Cha, M. C. Mayo et al., “Serial diffusion-weighted magnetic resonance imaging in cases of glioma: distinguishing tumor recurrence from postresection injury,” Journal of Neurosurgery, vol. 103, no. 3, pp. 428–438, 2005. View at: Publisher Site | Google Scholar
  39. S.-A. Yeh, J.-T. Ho, C.-C. Lui, Y.-J. Huang, C.-Y. Hsiung, and E.-Y. Huang, “Treatment outcomes and prognostic factors in patients with supratentorial low-grade gliomas,” British Journal of Radiology, vol. 78, no. 927, pp. 230–235, 2005. View at: Publisher Site | Google Scholar
  40. A. C. Whitton and H. G. G. Bloom, “Low grade glioma of the cerebral hemispheres in adults: a retrospective analysis of 88 cases,” International Journal of Radiation Oncology, Biology, Physics, vol. 18, no. 4, pp. 783–786, 1990. View at: Publisher Site | Google Scholar
  41. J. Pallud, L. Taillandier, L. Capelle et al., “Quantitative morphological magnetic resonance imaging follow-up of low-grade glioma: a plea for systematic measurement of growth rates,” Neurosurgery, vol. 71, no. 3, pp. 729–739, 2012. View at: Publisher Site | Google Scholar
  42. R. Cavaliere, M. B. S. Lopes, and D. Schiff, “Low-grade gliomas: an update on pathology and therapy,” Lancet Neurology, vol. 4, no. 11, pp. 760–770, 2005. View at: Publisher Site | Google Scholar
  43. H. Duffau, P. Gatignol, E. Mandonnet, L. Capelle, and L. Taillandier, “Intraoperative subcortical stimulation mapping of language pathways in a consecutive series of 115 patients with Grade II glioma in the left dominant hemisphere,” Journal of Neurosurgery, vol. 109, no. 3, pp. 461–471, 2008. View at: Publisher Site | Google Scholar
  44. S. G. Robles, P. Gatignol, S. Lehéricy, and H. Duffau, “Long-term brain plasticity allowing multistage surgical approach to World Health Organization Grade II gliomas in eloquent areas,” Journal of Neurosurgery, vol. 109, no. 4, pp. 615–624, 2008. View at: Publisher Site | Google Scholar
  45. T. Ius, E. Angelini, M. Thiebaut de Schotten, E. Mandonnet, and H. Duffau, “Evidence for potentials and limitations of brain plasticity using an atlas of functional resectability of WHO grade II gliomas: towards a ‘minimal common brain’,” NeuroImage, vol. 56, no. 3, pp. 992–1000, 2011. View at: Publisher Site | Google Scholar
  46. E. F. Chang, M. B. Potts, G. E. Keles et al., “Seizure characteristics and control following resection in 332 patients with low-grade gliomas,” Journal of Neurosurgery, vol. 108, no. 2, pp. 227–235, 2008. View at: Publisher Site | Google Scholar
  47. G. E. Keles and M. S. Berger, “Advances in neurosurgical technique in the current management of brain tumors,” Seminars in Oncology, vol. 31, no. 5, pp. 659–665, 2004. View at: Publisher Site | Google Scholar
  48. Y. A. Moshel, J. D. S. Marcus, E. C. Parker, and P. J. Kelly, “Resection of insular gliomas: the importance of lenticulostriate artery position—clinical article,” Journal of Neurosurgery, vol. 109, no. 5, pp. 825–834, 2008. View at: Publisher Site | Google Scholar
  49. G. G. Varnavas and W. Grand, “The insular cortex: morphological and vascular anatomic characteristics,” Neurosurgery, vol. 44, no. 1, pp. 127–138, 1999. View at: Publisher Site | Google Scholar
  50. H. Duffau, “Surgery of low-grade gliomas: towards a ‘functional neurooncology’,” Current Opinion in Oncology, vol. 21, no. 6, pp. 543–549, 2009. View at: Publisher Site | Google Scholar
  51. H. Duffau, “Introduction. Surgery of gliomas in eloquent areas: from brain hodotopy and plasticity to functional neurooncology,” Neurosurgical Focus, vol. 28, no. 2, pp. 1–2, 2010. View at: Publisher Site | Google Scholar
  52. T. Kılıç, K. Özduman, I. Elmac, A. Sav, and P. M. Necmettin, “Effect of surgery on tumor progression and malignant degeneration in hemispheric diffuse low-grade astrocytomas,” Journal of Clinical Neuroscience, vol. 9, no. 5, pp. 549–552, 2002. View at: Publisher Site | Google Scholar
  53. C. Hartmann, B. Hentschel, M. Tatagiba et al., “Molecular markers in low-grade gliomas: predictive or prognostic?” Clinical Cancer Research, vol. 17, no. 13, pp. 4588–4599, 2011. View at: Publisher Site | Google Scholar
  54. R. B. Jenkins, H. Blair, K. V. Ballman et al., “A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma,” Cancer Research, vol. 66, no. 20, pp. 9852–9861, 2006. View at: Publisher Site | Google Scholar
  55. T. D. Bourne and D. Schiff, “Update on molecular findings, management and outcome in low-grade gliomas,” Nature Reviews Neurology, vol. 6, no. 12, pp. 695–701, 2010. View at: Publisher Site | Google Scholar
  56. C. Gozé, C. Bezzina, E. Gozé et al., “1P19Q loss but not IDH1 mutations influences WHO grade II gliomas spontaneous growth,” Journal of Neuro-Oncology, vol. 108, no. 1, pp. 69–75, 2012. View at: Publisher Site | Google Scholar
  57. C. Gozé, L. Mansour, V. Rigau, and H. Duffau, “Distinct IDH1/IDH2 mutation profiles in purely insular versus paralimbic WHO Grade II gliomas: laboratory investigation,” Journal of Neurosurgery, vol. 118, no. 4, pp. 866–872, 2013. View at: Publisher Site | Google Scholar
  58. M. Jansen, S. Yip, and D. N. Louis, “Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers,” The Lancet Neurology, vol. 9, no. 7, pp. 717–726, 2010. View at: Publisher Site | Google Scholar

Copyright © 2015 Tamara Ius et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Related articles

No related content is available yet for this article.
 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

No related content is available yet for this article.

Article of the Year Award: Outstanding research contributions of 2021, as selected by our Chief Editors. Read the winning articles.