Due to its challenging technical access [
Although surgery is considered the first therapeutic option [
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.
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: Age older than 18 years. LGGs harboring in the insular lobe. Two operations during disease evolution. A period of at least one year between the two operations. Histological confirmation of infiltrative LGG at first surgery. Intraoperative mapping at both first and second surgery. No adjuvant therapy since the first surgery.
The local institution ethics committee on human research approved this study.
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
A case of vast left fronto-temporo-insular LGG. Functional MRI/DTI data were overlapped on T2-weighted MRIs and loaded into the Neuro-Navigation system, allowing a better evaluation of the preoperative surgical planning. In the 3D rendering the lesion is represented in red, and the arcuate fasciculus (AF) is in blue, while the orange fMRI spots represent the Broca (anterior spot) and Wernicke area (posterior spot). The functional analysis highlights the cortical areas activated by counting, object naming, and verb generation tasks. The eloquent cortical regions, displaced by the tumor, were easily detected with cortical mapping during surgical procedure. The tumor mass displaces the AF upwards (ACHIEVA 3 T MRI, Philips, Netherlands).
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 [
Moreover, neurophysiological monitoring (MEPs, SEPs, EEG, and ECoG) was employed in all cases following the protocol approved at our institution [
Tumors were histologically reviewed according to the World Health Organization (WHO) classification for tumors of the central nervous system [
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 [
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) [
All pre- and postoperative tumoral segmentations were performed manually across all MRI slices with the OSIRIX software tool [
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.
Baseline demographic, clinical, radiological, and histopathological characteristics of the study population, at the time of first and second surgery, are summarized in Tables
Demographic, clinical, neuroradiological, and pathological data at first surgery.
Parameter | Value |
---|---|
Number of patients | 53 |
Sex | |
Female | 23 (43.40%) |
Male | 30 (56.60%) |
Mean age (yrs) | 38 (range 19–69) |
Tumor side | |
Left | 36 (67.92%) |
Right | 17 (32.08%) |
Median preoperative T2 tumoral volume in cm3 (range) | 76.33 (range 5–174) |
Median preoperative Δ |
23.13 (range 1–112) |
Δ |
|
<30 cm3 | 37 (69.81%) |
≥30 cm3 | 16 (30.19%) |
Intraoperative protocol | |
Awake surgery | 41 (77.36%) |
General anesthesia | 12 (22.64%) |
Cortical mapping | |
Speech arrest and motor function orbicularis oris | All 41 cases with lesion involving the dominant hemisphere |
Slurred speech or dysarthria | 26 (49%) |
Anomia | 26 (49%) |
Subcortical mapping | |
Identification of corticospinal tract as posterior edge of resection | All cases |
Identification of subcortical language pathways | Positive sites were detected in 24 cases (45.3%) |
Neurophysiological data | |
Reversible reduction of MEPs amplitude | 7 out of 10 patients, who developed postoperative transient motor deficit |
Irreversible MEPs loss | In 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 deficits | 37 (69.81%) |
Neurological deficits | 15 (30.19%) |
Motor deficits | 9 (16.98%) |
Speech disorders | 6 (13.21%) |
Clinical outcome 6 months after surgery | |
No deficits | 52 (98.11%) |
Neurological deficits | 1 (1.89%) |
Postoperative Engel Class 6 months after surgery | |
I | 36 (67.92%) |
II | 4 (7.55%) |
III | 8 (15.10%) |
IV | 5 (9.43%) |
Histological diagnosis | |
Fibrillary astrocytoma | 31 (58.5%) |
Oligodendroglioma | 6 (11.3%) |
Oligoastrocytoma | 16 (30.2%) |
Molecular profile | |
Mib1-Ki-67 expression | 3.5% (range 1–5%) |
1p/19q codeletion presence | 13 (25%) |
P53 expression | 33 (62.26%) |
IDH1 mutation | 45 (85%) |
MGMT promoter methylation | 39 (73.58%) |
Summary of characteristics at tumor recurrence in the subgroup of patients who underwent a second surgery.
Parameter | Value |
---|---|
Number of patients | 23 |
Sex | |
Female | 8 (34.78%) |
Male | 15 (65.22%) |
Mean age (yrs) | 42 (range 25–54) |
Tumor side | |
Left | 15 (65.22%) |
Right | 8 (34.78%) |
Median time to tumor recurrence | 81 months (14–124) |
Seizures relapse at second surgery | 11 (47.83%) |
New contrast enhancement before second surgery | 11 (47.83%) |
Intraoperative protocol | |
Awake surgery | 16 (69.57%) |
General anesthesia | 7 (30.43%) |
Immediate postoperative findings | |
No deficits | 15 (65.22%) |
Neurological deficits | 08 (34.78%) |
Motor deficits | 4 (17.39%) |
Speech disorders | 3 (13.04%) |
Visual field disorders | 1 (4.35%) |
Clinical outcome 6 months after surgery | |
No deficits | 22 (95.65%) |
Neurological deficits | 1 (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 expression | 16.5% (range 2–70%) |
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 [
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.
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
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
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
A case of right insular oligoastrocytoma. (a) The preoperative tumor volume computed on postcontrast T2-weighted MRI was 53 cm3 (axial slices). The green line represents the area of the tumor before the first surgery. Tumor volume was computed with OSIRIX software. (b) Postoperative tumor residue computed on T2-weighted MRI showed a tumor residual volume of 3 cm3 (axial slices). The extent of the tumor volume resection, computed on a T2-weighted MRI sequences, was 94%.
In order to evaluate the role of a diffuse tumor growth pattern on tumor recurrence, preoperative Δ
(a) Showing a TR 62 months after the first surgery. The patient did not receive any adjuvant therapy since the first surgery. The volumetric data at first surgery are shown in Figure
TR was identified in 23 patients. Univariate analysis results are summarized in Table
Univariate analysis of clinical and volumetric tumor data and histological and molecular parameters with tumor recurrence in patients with insular LGGs.
Factor | Tumor recurrence | ||
---|---|---|---|
HR | 95% CI |
| |
Age |
1.009 | 0.973–1.047 | 0.608 |
Sex | |||
Male | 1 | ||
Female | 1.368 | 0.595–3.415 | 0.460 |
Tumor site | |||
Left | 1 | ||
Right | 0.886 | 0.359–2.183 | 0.792 |
Preoperative T2 tumor volume cm3 |
1.005 | 0.994–1.016 | 0.399 |
Tumor subtype | |||
Fibrillary astrocytoma | 1 | ||
Oligoastrocytoma | 0.509 | 0.195–1.324 | 0.166 |
Oligodendroglioma | 0.081 | 0.011–0.643 |
|
% EOR |
0.932 | 0.899–0.965 |
|
% EOR | |||
≥90 | 1 | ||
70–89 | 2.792 | 0.938–7.931 |
|
≤69 | 8.936 | 2.302–34.687 |
|
Δ |
1.045 | 1.022–1.068 |
|
Δ |
|||
<30 cm3 | 1 | ||
≥30 cm3 | 2.950 | 1.243–7.001 |
|
Mib1-Ki-67 |
0.931 | 0.722–1.201 | 0.585 |
1p/19q codeletion |
0.288 | 0.082–1.003 |
|
P53 mutation |
1.006 | 0.994–1.018 |
|
EGFR |
0.995 | 0.983–1.008 | 0.946 |
GFAP |
1.007 | 0.993–1.021 | 0.323 |
IDH1 |
0.383 | 0.168–0.872 |
|
MGMT |
0.912 | 0.375–2.215 | 0.840 |
HR, hazard ratio; CI, confidence interval; EOR, extent of surgical resection; Δ
Boldfacing represents statistical significance values (
Variable independently associated with tumor recurrence after surgical resection of insular LGGs in a multivariate proportional hazards analysis (Cox model). In the final model, the EOR remained the strongest independent significant predictor of TR after first surgery for insular LGG.
Factor | Tumor progression | ||
---|---|---|---|
HR | 95% CI |
| |
% EOR |
0.930 | 0.895–0.967 |
|
EOR = extent of surgical resection.
Kaplan-Meier curves revealing TR likelihood in patients with insular Low-Grade Gliomas, stratified by EOR (a), Δ
Increasing evidence supports the association between EOR, prolonged OS, and delaying tumor progression [
The major limitation in achieving a radical resection in LGGs surgery is represented by their attitude to infiltrate the subcortical functional pathways [
Martino and coworkers analyzed the clinical outcomes of 19 patients with recurrent LGGs in eloquent areas [
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 “
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 [
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 [
The only difficulty of second surgery is represented by the adhesions. They may cause pain during the opening; moreover, adhesions between
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 [
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 [
McGirt et al. showed that patients with oligodendroglioma and oligoastrocytoma have a better prognosis compared to those with fibrillary astrocytoma [
Regarding the molecular analysis, recent data demonstrated that LGGs display a variety of molecular alterations that may have predictive or prognostic value [
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
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 [
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.
Direct electrical stimulation
Electrocorticography
Electroencephalography
Extent of Resection
Digital Imaging and Communications in Medicine (standard)
Diffusion tensor imaging
Functional MRI
Karnofsky Performance Scale
Intraoperative electrical stimulation
Low-Grade Gliomas
Motor evoked potentials
Magnetic Resonance Imaging
Somatosensory evoked potentials
Tumor recurrence
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.
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 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.