- Departments of Neurological Surgery, University of Washington, Seattle, US
- Departments of Neurology, University of Washington, Seattle, US
- Department of Surgery, University of Wisconsin, Madison, US
- Department of Surgery, Oregon Health Sciences University, US
- Department of Neurosurgery, Mt. Sinai School of Medicine, New York, US
- Department of Neurological Surgery, University of California, San Francisco, US
Robert C. Rostomily
Departments of Neurological Surgery, University of Washington, Seattle, US
DOI:10.4103/2152-7806.68337© 2010 Ramakrishna R. 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: Ramakrishna R, Barber J, Kennedy G, Rizvi A, Goodkin R, Winn RH, Ojemann GA, Berger MS, Spence AM, Rostomily RC. Imaging features of invasion and preoperative and postoperative tumor burden in previously untreated glioblastoma: Correlation with survival. Surg Neurol Int 10-Aug-2010;1:40
How to cite this URL: Ramakrishna R, Barber J, Kennedy G, Rizvi A, Goodkin R, Winn RH, Ojemann GA, Berger MS, Spence AM, Rostomily RC. Imaging features of invasion and preoperative and postoperative tumor burden in previously untreated glioblastoma: Correlation with survival. Surg Neurol Int 10-Aug-2010;1:40. Available from: http://sni.wpengine.com/surgicalint_articles/imaging-features-of-invasion-and-preoperative-and-postoperative-tumor-burden-in-previously-untreated-glioblastoma-correlation-with-survival/
Background:A paucity of data exists concerning the prognostic usefulness of preoperative and postoperative imaging after resection of glioblastoma multiforme (GBM). This study aimed to connect outcome with imaging features of GBM.
Methods:Retrospective computer-assisted volumetric calculations quantified central necrotic (T0), gadolinium-enhanced (T1) and increased T2-weighted signal volumes (T2) in 70 patients with untreated GBM. Clinical and treatment data, including extent of resection (EOR), were obtained through chart review. T1 volume was used as a measure of solid tumor burden; and T2 volume, as an indicator of invasive isolated tumor cell (ITC) burden. Indicators of invasiveness included T2:T1 ratios as a propensity for ITC infiltration compared to solid tumor volumes and qualitative analysis of subependymal growth and infiltration of the basal ganglia, corpus callosum or brainstem. Cox multivariate analysis (CMVA) was used to identify significant associations between imaging features and survival.
Results:In the 70 patients studied, significant associations with reduced survival existed for gadolinium-enhancing tumor crossing the corpus callosum (odds ratio, 3.14) and with increased survival with gross total resection (GTR) (GTR median survival, 62 weeks versus 37 and 34 weeks for sub-total resection and biopsy, respectively). For a selected “GTR-eligible” subgroup of 52 patients, prolonged survival was associated with smaller preoperative gadolinium-enhancing volume (T1) and actual GTR.
Conclusion:Some magnetic resonance (MR) imaging indicators of tumor invasiveness (gadolinium-enhancing tumor crossing the corpus callosum) and tumor burden (GTR and preoperative T1 volume in GTR-eligible subgroup) correlate with survival. However, ITC-infiltrative tumor burden (T2 volume) and “propensity” for ITC invasiveness (T2:T1 ratio) did not impact survival. These results indicate that while the ITC component is the ultimate barrier to cure for GBM, the pattern of spread and volumes of gadolinium-enhancing solid tumor are more robust indicators of prognosis.
Keywords: Glioblastoma, invasion, MR imaging, resection, survival, tumor burden
Imaging abnormalities detected on standard MR imaging studies for patients with untreated glioblastoma multiforme (GBM) include peripherally increased T2 signal, uptake of gadolinium, and centralhypodensities that correspond to vasogenic edema in brain infiltrated with isolated tumor cells (ITCs), solid tumor with blood-brain-barrier disruption and necrotic cyst formation, respectively.[
The correlation between MR imaging features and distinct histopathologic features allows analysis of imaging studies to provide indirect quantification of a tumor’s histopathologic composition. For instance, studies that have analyzed brain tissue samples from radiographically defined regions in GBM patients demonstrate that contrast enhancement and edema are good indirect markers for the presence of solid tumor tissue with neovascularity and invasive isolated tumor cells, respectively, while areas of central hypodensity represent tumor necrosis.[
Previous analyses of the correspondence between GBM imaging characteristics and survival focused on preoperative and postoperative contrast-enhancing tumor volumes.. These studies generally report no association between preoperative tumor volume or burden and survival. Smaller postoperative enhancing tumor volume tends to correlate with improved patient outcome, but this remains controversial.[
Patient characteristics and clinical data acquisition
Adult patients (>18 years old) treated at the time of initial pathological diagnosis of GBM at the affiliated University of Washington hospitals were identified through a comprehensive medical records search. Criteria for inclusion were as follows: no prior therapy or cytoreductive surgery, availability of pre-treatment imaging studies (T1-weighted gadolinium-enhanced and T2-weighted images) with gadolinium-enhancing tumors, postoperative CT scans with and without contrast within 48 hours of surgery, postoperative treatment with a standard course of postoperative radiation therapy (≥ 59.4 Gy), and histopathological confirmation of GBM. The criteria used for the microscopic diagnosis of GBM included the presence of necrosis. Seventy patients fulfilled these inclusion criteria. Follow-up was complete (to expiration) for 66 of the 70 patients. The remaining 4 patients were followed for 104, 208, 230 and 230 weeks, respectively, until lost to follow-up.
All patients received adjuvant radiation therapy (>5940 Gy) except one who died of disease progression during radiation therapy (XRT). Of the 70 patients, 42 received adjuvant chemotherapy. Of those who received chemotherapy, all received alkylating agents alone or as part of combinatorial therapy that often included carboplatin. As multiple chemotherapeutic approaches were used during the period of the study, the small numbers in each subgroup did not allow for meaningful analysis of the effect of specific chemotherapy on outcome.
Data on patient characteristics, treatment histories and survival were collected from hospital records, outpatient clinic notes and tumor board summaries. All patients were followed by the University of Washington Neuro-Oncology Tumor Board. Treatment data included the extent of surgical resection, steroid use prior to MR imaging and the number of subsequent therapies (radiation, chemotherapy or reoperation). A summary of the patient characteristics is provided in
MRI data collection
Terms and definitions
The definitions of terms used to identify specific imaging components, which apply to the remainder of the manuscript and the statistical analysis, are summarized in
Quantitative imaging data acquisition
Preoperative T1-weighted gadolinium-enhanced and T2-weighted MR images were digitized as previously described.[
Qualitative imaging data
Qualitative features of preoperative imaging studies reflective of invasive tumor growth patterns were documented and recorded, including the presence of either T1 gadolinium enhancement or increased T2 signal involving the basal ganglia, corpus callosum (unilateral and contralateral) or brainstem; and the presence or absence of subependymal contrast enhancement. Subependymal contrast enhancement (SCE) was defined as the presence of any linear contiguous or noncontiguous gadolinium enhancement lining the ependymal surface. The side of the lesion and its location relative to deep versus lobar structures was recorded. Lesion location was recorded as primary involvement of deep or lobar structures or mixed involvement of both deep and lobar structures. Tumors were classified as primarily lobar (n= 58), deep (n= 6) or mixed deep and lobar (n= 8) based on the location of T1 gadolinium enhancement on preoperative MR images. Deep structures were considered to be the basal ganglia, thalamus, corpus callosum, septum, hypothalamus and brainstem. Brain regions outside these deep structures constituted a lobar location. A tumor was classified as deep if there was exclusive involvement of only deep structures. Tumors that appeared to originate outside deep structures were classified as primarily lobar, while those whose origin could not be identified as cortical or deep based on its anatomic location were defined as “mixed” in their location. Thus, designation as primarily lobar did not preclude secondary involvement of deep structures.
Analysis of extent of resection
The extent of resection (EOR) was based on routine postoperative (within 48 hours) CT scans performed with and without contrast enhancement. The presence of nodular contrast enhancement on these postoperative CT scans defined the extent of resection as sub-total. Only cases with no evidence of nodular residual enhancement at the resection site (n= 32) were classified as gross total resections (GTRs). Seven patients underwent biopsy alone (BX), while 31 had a sub-total resection (STR).
The association of tumor burden and invasiveness with patient survival was analyzed using a Cox multivariate backward stepwise model with significance level set at P= .05.[
The multivariate statistical analyses were performed for the entire group of 70 patients, a subgroup of 52 patients in whom a gross total resection was deemed potentially anatomically feasible (GTR-eligible) and the subgroup of 32 patients who underwent actual GTR. The GTR-eligible subgroup was included to correct for bias introduced in the analysis of postoperative tumor burden and EOR by the differing tumor growth patterns in the STR and GTR groups. Thus, 11 of the 31 STR patients were excluded from the GTR-eligible subgroup because of the presence of gadolinium-enhancing tumor involving the contralateral corpus callosum, basal ganglia or other deep structures or brainstem. Since the extent of resection was based on the presence or absence of residual contrast-enhancing tissue, patients with increased T2 signal alone in the brainstem were not excluded (4 in GTR group and 3 in STR group). None of the 32 GTR patients exhibited any of the criteria used to exclude the 11 patients in the STR group. Differences in tumor volumes and ratios between patients with STR and GTR in the GTR-eligible subgroup were further analyzed using analysis of Variance(ANOVA). The actual GTR patients were studied separately to provide the most homogenous subgroup in which to analyze the impact of tumor volumes on outcome.
Quantitative analysis of tumor burden and midline shift
Volumetric analyses of imaging features demonstrated an extremely wide range of values [
The histogram in the top panel demonstrates the variable contributions of central hypodensity (T0), gadolinium enhancement (T1) and increased T2 signal (T2) to overall tumor volumes. The corresponding overall survival of each patient is plotted in the histogram of the bottom panel. Note that no apparent relationship exists between tumor volume and overall survival as confirmed in Cox models (
Quantitative and qualitative analysis of invasiveness
The region of increased T2 signal or edema (T2) on MRI contains ITCs[
Histograms demonstrating the relationship between the ratio of T2 volume to T1 total volume (top panel) and survival (bottom panel). This ratio is presumed to allow comparisons between tumors of their propensity for infiltrative growth by normalizing T2 volumes to T1 total. The apparent lack of correlation between this ratio and survival was confirmed in Cox models (
Qualitative analysis of invasive features, including tumor extension into deep structures or distant growth along white matter tracts such as the corpus callosum, was most informative for the group of primarily lobar tumors since mixed and deep tumors already had tumor involvement of deep or bilateral structures. Of the 58 primarily lobar tumors, 6 patients had gadolinium enhancement extending into the basal ganglia (n= 2), crossing the corpus callosum (n= 3) or both (n= 1). Of the remaining 52 lobar patients, 23 had increased T2 signal extending into the basal ganglia. Of 22 patients with imaging abnormalities in the corpus callosum, 15 had increased T2 signal alone limited to the ipsilateral corpus callosum, 3 patients displayed ipsilateral gadolinium enhancement and 4 patients had increased T2 signal crossing to the contralateral corpus callosum. Of these 4 patients, 1 had ipsilateral gadolinium enhancement. In 4 of these 52 patients, increased T2 signal was noted in the brainstem. In all cases, increased T2 signal equaled or exceeded the regions of T1 gadolinium enhancement.
Aside from involvement of the basal ganglia and corpus callosum, imaging abnormalities of the brainstem and the ventricular surfaces were analyzed as additional indicators of tumor spread. Overall, brainstem involvement was noted in 9 patients, 3 with gadolinium enhancement and 6 with increased T2 signal alone. All patients with gadolinium enhancement of the brainstem had deep tumors. Subependymal contrast enhancement (SCE) was noted in 23 patients, including 16 of 58 lobar tumors (28%) and 7 of 12 deep or mixed tumors (58%). Of the 52 patients in the GTR-eligible subgroup, 11 had SCE; and of these, 5 were classified as having an actual GTR based on the absence of nodular or bulk enhancing tumor at the primary tumor nidus on postoperative enhanced CT scans. Overall, only 19 of the 58 primarily lobar tumors lacked any of these imaging abnormalities felt to reflect tumor invasiveness.
Correlation of tumor burden and invasiveness with survival
In a multivariate analysis of the entire group of 70 patients, variables associated with prolonged survival were younger age, preoperative Karnofsky score ≥ 70, lack of contralateral gadolinium enhancement in the corpus callosum and GTR. In a similar analysis of the GTR-eligible subgroup, prolonged survival was associated with younger age, greater midline shift, smaller T1-only gadolinium tumor volume and GTR versus STR. For the 32 patients with GTR, only age correlated with outcome, but the presence of edema in the contralateral corpus callosum was nearly significant (P= .068). The multivariate analysis of these groups is summarized in
Kaplan-Meier analysis of the effect of EOR on outcome showed nearly identical survival curves for STR and biopsy alone in the whole study group of 70 patients [
This study tested the hypothesis that MR imaging features of untreated GBM patients that might reflect tumor burden and invasion would correlate with survival. This possibility is supported by the great variability in volume and distribution of gadolinium enhancement or increased T2 signal on MR images of GBM and the recognition that these features correspond histologically to solid tumor and isolated tumor cells (ITCs), respectively. Imaging phenotypes that correspond to outcome could improve patient stratification and provide a clinical discriminator to study GBM tumor biology. For instance, tumor samples from patients with distinct invasive imaging phenotypes could be used to analyze global gene expression profiles and elucidate the transcriptional basis for differential invasion. The feasibility of such a notion is evident in a report describing the identification of differentially expressed genes related to invasion in the T2 component of GBM compared with T1, such as insulin-like growth factor–binding protein 1 and matrix metalloprotease-2 expression.[
For GBM, tumor burden should refer to the total number of tumor cells; but because of the diffusely invasive growth of GBM and the unknown limits for detection of ITCs by MR imaging, MR imaging–based estimates of GBM tumor burden must be restricted to determination of tumor “size” only. As noted in the introduction, MR imaging abnormalities in GBM correlate with distinct regional variations in cellular histologic composition. Thus, GBM patient biopsies from central hypodense cysts (T0), enhancing tumor (T1) and edema (T2) most consistently demonstrate necrosis, solid tumor with vascular proliferation and invasive isolated tumor cells, respectively.[
An additional factor to consider is the extension of ITCs into radiographically normal brain. While ITCs clearly reside in brain that appears normal by imaging,[
The significance of MR imaging features in GBM may extend to molecular programs with clinical relevance. Recent studies have identified GBM molecular sub-types with mesenchymal signatures that predict clinical behavior[
A drawback of the present analysis is that static single images do not provide dynamic information on the rate of change for tumor burden and invasive features. It would be more informative to obtain serial MR images over time, but this is rarely clinically justifiable or practical in a patient with a new diagnosis of suspected GBM. For recurrent gliomas, one study of serial images demonstrated that solid tumor volume (i.e., T1) doubling times were more predictive of outcome than histologic tumor grade.[
While our study did not allow dynamic analysis of invasive MR imaging features, we attempted to approximate potential differences in invasive propensity between tumors by analyzing the impact of the T2:T1 ratios on patient outcome. This analysis assumed that larger ratios of T2:T1 would indicate a greater propensity for ITC infiltration of normal brain when “normalized” to the T1 tumor volumes and thus provide a dynamic estimate of infiltrative behavior. However, this analysis alone or when combined with principal component analysis (PCFA) of other individual invasive related variables did not predict patient outcome. This negative result may reflect limitations in MR imaging to detect ITCs (see above), small differences in infiltration rates in vivo; or the possibility that while the infiltrative component of GBM is a major barrier to cure, it does not impact survival.
Despite these limitations, several important relationships of both tumor invasiveness and burden with survival were revealed. Of all the volume variables, only T1 volume in the GTR-eligible subgroup was associated with outcome. Only one other imaging variable, the presence of gadolinium-enhancing tumor crossing the corpus callosum, was associated with outcome in the total group of 70 patients. These patients were not included in the GTR-eligible subgroup analysis, where T1 volume reached significance. The GBM tumor growth patterns are characterized by a predilection for spread along white matter tracts,[
Despite little impact of the various preoperative tumor volume measures on outcome, the absence of contrast enhancement was consistently associated with prolonged survival in both the total and GTR-eligible subgroups. This study does not conclusively establish the benefit of greater EOR, but it is of interest that the presence of any residual nodular contrast enhancement in the primary tumor bed conferred a distinct survival disadvantage, as was also pointed out mathematically by Woodward et al.[
Analysis of the Kaplan-Meier survival curves suggests that the resection of all T1 material may have a biological impact aside from cytoreduction (actual or mathematical) that influences tumor growth. Survival curves for biopsy and STR patients were nearly identical, while significant increases were noted in survival for GTR patients. The solid or T1 portion of GBMs is a highly specialized microenvironment that conceivably drives tumor proliferation and spread, and which may function as such at low T1 tissue burdens present in some STR patients. For instance, extrapolationof data in the study by Nagashima et al.,[
Additional findings of clinical interest include analysis of increased T2 signal, subependymal contrast enhancement (SCE) and midline shift. In the only other study that, to our knowledge, has analyzed the region of edema or T2 in GBM, Hammoud et al. found a quadratic relationship between increased T2 signal volume/gadolinium enhancement volume ratios and survival,[
In this study, we characterized the quantitative and qualitative variability of MR imaging features among GBMs at presentation. Our hypothesis that MR imaging features reflecting tumor invasiveness or burden would define clinically relevant phenotypes was supported by the findings that gadolinium enhancement crossing the corpus callosum (an invasive feature) predicted shorter survival in the unselected total patient group and that greater T1 tumor burden was associated with prolonged survival for the GTR-eligible subgroup of patients. In addition, the lack of detectable postoperative T1 tumor predicted longer survival in all groups, but biopsy and STR patients had similar median survival, suggesting a synergistic interaction between T1 and T2 tumor components that contributes to overall growth rates. The lack of association between other imaging features of invasiveness or ITC tumor burden and outcome may in part reflect the limitations in tumor cell detection by MR and the lack of dynamic information inherent in the evaluation of single–preoperative-imaging studies. Also, while the ITC component of GBMs theoretically limits their cure, the more robust impact of T1 solid tumor spread and volume on prognosis and the potential interaction between T1 and T2 tumor compartments in promoting growth, support the possibility that failure to control the T1 tumor component remains the predominant impediment to improved outcome for GBM. Future studies that can correlate imaging findings with particular molecular phenotypes will also be of use in planning targeted individualized therapy for GBM.
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