- Department of Neurosurgery, Maastricht University Medical Center, Maastricht, Netherlands
- Department of Pathology, Radboud University Medical Centre, Nijmegen, Netherlands
- Department of Pathology, VU University Medical Center, Amsterdam, Netherlands
- Department of Pathology, Maastricht University Medical Center, Maastricht, Netherlands
Pieter L. Kubben
Department of Neurosurgery, Maastricht University Medical Center, Maastricht, Netherlands
DOI:10.4103/2152-7806.105097Copyright: © 2012 Kubben LP This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Kubben PL, Wesseling P, Lammens M, Schijns OE, Mariël P. ter Laak-Poort, van Overbeeke JJ, Santbrink Hv. Correlation between contrast enhancement on intraoperative magnetic resonance imaging and histopathology in glioblastoma. Surg Neurol Int 26-Dec-2012;3:158
How to cite this URL: Kubben PL, Wesseling P, Lammens M, Schijns OE, Mariël P. ter Laak-Poort, van Overbeeke JJ, Santbrink Hv. Correlation between contrast enhancement on intraoperative magnetic resonance imaging and histopathology in glioblastoma. Surg Neurol Int 26-Dec-2012;3:158. Available from: http://sni.wpengine.com/surgicalint_articles/correlation-between-contrast-enhancement-on-intraoperative-magnetic-resonance-imaging-and-histopathology-in-glioblastoma/
Object:Glioblastoma is a highly malignant brain tumor, for which standard treatment consists of surgery, radiotherapy, and chemotherapy. Increasing extent of tumor resection (EOTR) is associated with prolonged survival. Intraoperative magnetic resonance imaging (iMRI) is used to increase EOTR, based on contrast enhanced MR images. The correlation between intraoperative contrast enhancement and tumor has not been studied systematically.
Methods:For this prospective cohort study, we recruited 10 patients with a supratentorial brain tumor suspect for a glioblastoma. After initial resection, a 0.15 Tesla iMRI scan was made and neuronavigation-guided biopsies were taken from the border of the resection cavity. Scores for gadolinium-based contrast enhancement on iMRI and for tissue characteristics in histological slides of the biopsies were used to calculate correlations (expressed in Kendall's tau).
Results:A total of 39 biopsy samples was available for further analysis. Contrast enhancement was significantly correlated with World Health Organization (WHO) grade (tau 0.50), vascular changes (tau 0.53), necrosis (tau 0.49), and increased cellularity (tau 0.26). Specificity of enhancement patterns scored as “thick linear” and “tumor-like” for detection of (high grade) tumor was 1, but decreased to circa 0.75 if “thin linear” enhancement was included. Sensitivity for both enhancement patterns varied around 0.39-0.48 and 0.61-0.70, respectively.
Conclusions:Presence of intraoperative contrast enhancement is a good predictor for presence of tumor, but absence of contrast enhancement is a bad predictor for absence of tumor. The use of gadolinium-based contrast enhancement on iMRI to maximize glioblastoma resection should be evaluated against other methods to increase resection, like new contrast agents, other imaging modalities, and “functional neurooncology” – an approach to achieve surgical resection guided by functional rather than oncological-anatomical boundaries.
Keywords: Glioblastoma, image guided surgery, intraoperative magnetic resonance imaging, neurooncology, neuropathology
Glioblastoma is a highly malignant brain tumor that often shows extensive infiltrative growth in the surrounding brain parenchyma. Standard treatment consists of surgery, radiotherapy, and chemotherapy, leading to a median survival of 14.6 months.[
The added value of iMRI in increasing EOTR for glioblastoma is based on visualizing remaining contrast enhancement on T1-weighted scans at the border of the resection cavity. This contrast enhancement is supposed to indicate residual tumor, which can be resected in the same procedure. In a few studies the additionally resected tissue was sent separately for histological analysis, leading to varying reports on tumor presence.[
This is the first study that systematically compares contrast enhancement on iMRI with histopathological characteristics in glioblastoma. The study objective is to determine to what extent contrast enhancement on T1-weighted iMRI can be used as a marker for presence of (high grade) glioma, and therefore as a valid indicator to assess EOTR.
The study protocol is registered at ClinicalTrials.gov under number NCT00780819 and has been approved by the institutional ethics research board.
For this prospective cohort study, we recruited 10 patients with a supratentorial brain tumor suspect for a glioblastoma. We determined the number of patients to be included based on consensus in the study committee. Inclusion criteria were: Indication for tumor resection, minimum age of 18 years, World Health Organization (WHO) Performance Scale 2 or better, American Society of Anaesthesiologists (ASA) class 3 or better, understanding of the Dutch language, and informed consent. Exclusion criteria were: Recurrent tumor, multiple tumor locations, prior radiotherapy on the skull, and prior chemotherapy.
Primary endpoint of this study was the correlation between contrast enhancement at the border of the resection cavity on T1-weighted iMRI and presence of high grade tumor according to the WHO classification.[
All study participants were operated by a neurosurgeon (OS, MtLP, or HvS) sufficiently experienced with the 0.15 Tesla iMRI system used in our hospital (PoleStar N20 with Stealth Station extension; Medtronic Navigation, Louisville, CO). After patient installation in the headclamp, a contrast enhanced preoperative (high-field strength) MRI was loaded for surgical planning and initial neuronavigation. Before incision, a nonenhanced iMRI scan was made as a baseline scan that intraoperatively acquired scans could be compared with.
During tumor resection, resected tissue was sent for standard histopathological analysis. As soon as the neurosurgeon considered the intended tumor resection to be complete, T1-weighted iMRI scans were acquired using the so-called “T1 7 min 4 mm”- protocol in axial orientation: First a nonenhanced scan, then a contrast enhanced scan using gadopentetate dimeglumine (Magnevist; Bayer-Schering Pharma AG, Berlin, Germany). Contrast dose was 0.4 ml/kg (0.2 mmol/kg) – a so-called “double-dose” – provided no renal failure was present. The contrast enhanced scan was made immediately after intravenous contrast administration.
After scanning neuronavigation was continued on the contrast enhanced iMRI scan, which was imported in the Stealth Station neuronavigation system. In all directions where gross total resection was intended, neuronavigation-guided biopsies were taken at the border of the resection cavity. A screen capture from the neuronavigation system was saved for each biopsy to relate contrast enhancement with histopathology. Each biopsy was sent separately for histopathological analysis, labeled with a number corresponding to the screen capture. After taking the biopsies, surgery was continued to resect any contrast enhancement in a direction where gross total resection was intended. Scanning was repeated if this goal was considered to be achieved, and additional biopsies were taken if safely possible. Contrast administration was only repeated if the previous iMRI scan was performed more than 2 hours back, in a dose of 0.2 mmol/kg (0.1 mmol/kg) – a “single-dose” – provided no renal failure was present.
Preoperative and postoperative MRI scans were made with the Intera 1.5 Tesla MRI system (Release 11.1; Philips, Best, The Netherlands). Preoperative neuronavigation scans were contrast-enhanced T1-weighted volume scans (isovoxel 1 mm, gap thickness 0 mm). Postoperative multiple sequences were acquired in a standardized fashion, including contrast enhanced T1-weighted sequences. Gadopentetate dimeglumine was used as a contrast agent in a dose of 0.2 ml/kg (0.1 mmol/kg) provided no renal failure was present.
All preoperative and postoperative scans were performed within 72 hours before and after surgery, respectively.
WHO Performance Scale was measured the day before surgery, and one week after surgery.
Determination of contrast enhancement
The screen captures from the biopsy locations were independently reviewed by a neurosurgeon and a senior resident in neurosurgery (HvS and PK). Both have ample experience in interpreting PoleStar images. Contrast enhancement was scored according to a four-tier classification [
Determination of histopathological characteristics
The biopsy tissue samples were independently reviewed by two experienced neuropathologists (PW and ML), blinded for corresponding contrast enhancement. Histopathological characteristics were scored for 10 parameters (most of these in a semiquantitative fashion): Amount of tissue, quality of tissue, preexistent tissue, increased cellularity, tumor presence, mitoses, vascular changes, necrosis, inflammation, and WHO grade in the sample. To each individual biopsy specimen in which tumor was present a WHO grade was assigned according to the WHO 2007 classification of tumors of the central nervous system[
Interobserver agreement for contrast enhancement, WHO classification and histopathological parameters were expressed as kappa-squared values, calculated with an in-house made application. Correlation between contrast enhancement and histopathological parameters was expressed as Kendall's tau with a one-tailed significance, calculated in PASW Statistics version 18.0.3 for Mac (IBM Corporation, Armonk, NY). Further analysis consisted of creating crosstables to calculate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) for contrast enhancement in relation to WHO grade. Two definitions were used for presence of contrast enhancement: “Thick linear + tumor-like” versus “thin linear + thick linear + tumor-like”. In addition, two definitions were used for presence of tumor: “Grade III + grade IV” versus “grade II + grade III + grade IV”. Calculations were performed with Microsoft Excel for Mac version 2011 (Microsoft, Redmond, WA), as well as the graphical representation of the interobserver agreement.
All patients but one were administered a double-dose of contrast agent, the remaining patient received a single-dose because of preexisting renal dysfunction, which was, however, not a contraindication for gadolinium-based contrast agent. Standard histopathological examination of the resected tumor revealed glioblastoma as the clinical diagnosis for all patients. The total number of study biopsy samples of all patients was 42. The number of biopsy samples per patient varied between 2 and 8, with a mean of 4.2 ± 1.9 samples. In two patients, biopsy samples were taken in two different phases during surgery. In those cases the delay between the first dose of contrast administration and the second iMR scan was 115 and 90 minutes, respectively, and according to our protocol no new dose of contrast agent was administered before the second iMR scan. Preoperative WPS varied between 0 and 2, with a mean of 0.7 ± 0.7. Postoperative WPS varied between 0 and 2, with a mean of 0.9 ± 0.6. Two patients (BZS02 and BZS03) suffered from transient neurological deficit postoperatively, one due to a supplementory motor area (SMA) syndrome and another due to postoperative hemorrhage. Both patients recovered within a few days from WPS 3 - 4 to WPS 1. All patients received the standard treatment consisting of radiotherapy and chemotherapy postoperatively.[
A total of 42 samples were available for further analysis, 39 of these were scored as “adequate” both on “amount of tissue” and “quality of tissue”.
Correlation between contrast enhancement and tumor
Of the 39 adequate biopsy samples, 3 had an uncertain diagnosis regarding WHO grade. Correlations between contrast enhancement and tumor were calculated using the remaining 36 samples and displayed in
To gain more insight in the type of correlation, crosstables are created to relate the values for contrast enhancement with the respective values for each tumor parameter. The results are presented in
Sensitivity, NPV and LR-all vary around 0.50. This means that half of the histologically confirmed “tumor samples” show contrast enhancement, and half do not. Moreover, half of the contrast enhancing samples are classified as “tumor”, and half are not.
The goal of a “gross total resection”, or “complete resection of enhancing tumor” (CRET)[
The classification we used for contrast enhancement is derived from Ekinci et al.[
Four histological parameters are significantly correlated with contrast enhancement at the border of the resection cavity: WHO grade, vascular changes, necrosis, and increased cellularity. Of note, these histological features are interrelated. For instance, diffusely increased cellularity in a brain biopsy sample is an important indicator for the presence of a diffuse glioma, and the presence of necrosis and/or florid microvascular proliferation are the histological hallmarks of high malignancy grade in a diffuse glioma. Furthermore, the correlation itself is relatively weak, with Kendall's tau values of 0.49-0.53 for WHO grade, vascular changes and necrosis, and a value of 0.26 for increased cellularity. As the Kendall's tau is a nonparametric test that describes correlation but provides no detailed information on the kind of correlation, we calculated sensitivity and specificity for the relation between contrast enhancement and tumor presence, using two definitions for each. Our results are consistent with Ekinci et al. for thick linear + tumor-like enhancement: Specificity is 1, regardless whether tumor definition includes what we defined as “WHO grade II”. Importantly, all patients in our study had a histologically proven glioblastoma. With the histological designation WHO grade II to biopsy samples of these patients we refer to samples in which the tumor lacked histological features of high grade malignancy in that particular (small) specimen. Of note, glioblastomas often show areas (e.g., in the diffuse infiltrative, peripheral parts) in which such histological features of high grade malignancy are lacking, but this does not necessarily mean that the glioblastoma originated from a less malignant precursor lesion. Likewise, PPV and LR+ are maximal for thick linear + tumor-like enhancement regardless of tumor definition. Sensitivity is rather low: 0.48 when including only high grade tumor components, and 0.39 when including grade II components as well. Comparable conclusions can be drawn for NPV and LR-. If we expand our definition of contrast enhancement to include thin linear enhancing tissue, specificity falls to circa 0.75 regardless of tumor definition, PPV varies around 0.84-0.89 and LR+ varies around 2.4-3.0. Sensitivity rises to 0.70 for only high grade components and 0.61 if grade II components are included. NPV and LR- also improve slightly.
Translating these numbers into practical conclusions, one can say that presence of evident contrast enhancement (thick linear + tumor-like) always refers to presence of tumor, regardless of whether histologically less malignant components are included. This is an interesting finding because “iatrogenic damage” to the blood-brain barrier is thought to cause false-positive intraoperative contrast enhancement. Our results demonstrate that this is not the case for thick linear enhancement, but it might be an explanation for the lower specificity when thin linear enhancement is included. Note that we refrained from contrast administration before incision to prevent residual contrast enhancement after tumor resection, which possibly can cause contrast enhancement in nontumorous tissue.[
Absence of tumor is always correlated with absence of thick linear enhancement and tumor-like enhancement. Unfortunately, our study shows that absence of contrast enhancement is not useful for predicting absence of tumor. In our study 41-68% of the biopsy samples showed tumor despite absence of contrast enhancement, depending on definition of enhancement (thin linear + thick linear + tumor-like versus thick linear + tumor-like).
Strengths and limitations
To the best of our knowledge this is the first report with a prospective systematic comparison of intraoperative contrast enhancement and histopathological tumor characteristics, with comparison of biopsies from contrast enhancing and nonenhancing tissue as a particular added value. This is in contrast with previously published work.[
As far as we know, no validated scoring systems exist for contrast enhancement or for assessment of the histopathological characteristics of glial tumors as assessed in the present study. The scale we used for grading contrast enhancement has been published in an evaluation of tumor regrowth on postoperative MRI, and the scale we used for grading histopathological characteristics has been developed by two experienced neuropathologists (PW, ML). To increase reliability we assessed interobserver agreement for all measurements, and found this to be satisfactory except for the parameter “inflammatory changes”. Consensus-based outcomes were used for further analysis, thereby decreasing subjectivity and variation in measurements.
The sample number of 10 patients may be relatively low, but the number of biopsies that was adequate for further analysis (n = 39) was satisfactory. The number of biopsy samples per patient varied because (as also described in the inclusion criteria) the neurosurgeon only took biopsies in those directions where it was considered to be safely possible.
Magnetic field strength is related to spatial resolution of the MR images and capacity of obtaining other imaging modalities (e.g. diffusion weighted imaging, MR spectroscopy). A limitation of this study is that our results cannot automatically be transferred to high-field strength iMRI. However, we do not expect that using a high-field strength iMRI would result in a substantially different outcome as this would only increase spatial resolution. Of course, the use of additional imaging modalities could be of added value.
We used gadopentetate dimeglumine for this study, and gadolinium-based contrast agents are commonly used for (intraoperative) MRI. An interesting alternative for neurosurgeons might be the use of so-called “ultrasmall particles of iron oxide” (USPIO)-based agents, which have been tested on iMRI as well.[
Our study is limited to assessment of remaining tumor using iMRI. A recent study investigated the use of 5-ALA as a marker for representative stereotactic biopsy samples in several types of tumor, and found better values compared with our study for specificity (1.00) and sensitivity (0.69) in case of strong 5-ALA fluorescence.[
Implications for the future
Contrast enhancement on low-field strength iMRI at the border of the glioblastoma resection cavity has a high specificity but low sensitivity for high grade tumor. Absence of contrast enhancement is unreliable to assess absence of tumor, and from that perspective the rationale for CRET becomes debatable. Especially in glioma surgery complication avoidance is of critical importance. Increasing sensitivity of tumor detection to increase EOTR may be undesirable if a corresponding lower specificity is associated with a higher incidence of (and/or more severe) postoperative neurological deficit. Furthermore, the definition of “tumor” is being discussed to include more than the contrast enhancing part,[
Recently, the concept of ‘functional neurooncology’ was introduced by Duffau et al. in low grade gliomas as a method to achieve optimal surgical resection guided by functional rather than by oncological-anatomical boundaries.[
Our present study on glioblastomas shows that evident contrast enhancement (thick linear + tumor-like) as detected on iMRI always reflects presence of high grade tumor and may thus be used as a parameter to increase EOTR. Furthermore, absence of tumor is always correlated with absence of such contrast enhancement. Unfortunately absence of contrast enhancement and presence of thin linear enhancement on iMRI is not useful for predicting absence of tumor. Obviously, diffuse gliomas including glioblastomas are neoplasms that cannot be cured surgically. An (arbitrary) minimally required resection threshold to improve survival, like the widely cited 98% as described by Lacroix et al.[
The authors are very grateful to Geert Spincemaille, PhD for his support in initializing this study and for providing them with the grading system they used for scoring contrast enhancement, to Prof. Hans Vles, PhD for contributing to the brainstorm session that lead to the idea of starting this study, to David Creytens, MD for his logistical support with the tissue biopsies, and to Fons Kessels, MSc for his statistical support. A specific word of thanks goes to Prof. Patrick Kelly, MD, PhD, for his review of the manuscript.
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