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Early presentation of primary glioblastoma
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Clinical case
Early presentation of primary glioblastoma Présentation précoce des glioblastomes primaires R. Faguer a , J.-Y. Tanguy b , A. Rousseau c , A. Clavreul a , P. Menei a,∗ a
Department of neurosurgery, university hospital, 4, rue Larrey, 49933 Angers cedex 9, France Department of radiology, university hospital, 4, rue Larrey, 49933 Angers cedex 9, France c Department of pathology, university hospital, 4, rue Larrey, 49933 Angers cedex 9, France b
a r t i c l e
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Article history: Available online xxx Keywords: Glioblastoma Occult tumor Early diagnosis Immunohistochemistry Molecular biology
a b s t r a c t Background. – Clinical and neuroimaging findings of glioblastomas (GBM) at an early stage have rarely been described and those tumors are most probably under-diagnosed. Furthermore, their genetic alterations, to our knowledge, have never been previously reported. Methods. – We report the clinical as well as neuroimaging findings of four early cases of patients with GBM. Results. – In our series, early stage GBM occurred at a mean age of 57 years. All patients had seizures as their first symptom. In all early stages, MRI showed a hyperintense signal on T2-weighted sequences and an enhancement on GdE-T1WI sequences. A hyperintense signal on diffusion sequences with a low ADC value was also found. These early observed occurrences of GBM developed rapidly and presented the MRI characteristics of classic GBM within a few weeks. The GBM size was multiplied by 32 in one month. Immunohistochemical analysis indicated the de novo nature of these tumors, i.e. absence of mutant IDH1 R132H protein expression, which is a diagnostic marker of low-grade diffuse glioma and secondary GBM. Conclusions. – A better knowledge of early GBM presentation would allow a more suitable management of the patients and may improve their prognosis. © 2014 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Glioblastome Tumeurs occultes Diagnostic précoce Immunohistochimie Biologie moléculaire
Introduction. – Les signes cliniques et radiologiques des glioblastomes (GBM) au stade précoce ont été rarement décrit et ces tumeurs sont probablement sous-diagnostiquées. De plus, leurs anomalies génétiques n’ont jamais été rapportées. Méthodes. – Nous rapportons les données cliniques et radiologiques de quatre cas de GBM au stade précoce. Résultats. – Dans notre série, les formes précoces de GBM sont survenues à un âge moyen de 57 ans. La crise d’épilepsie a été le premier symptôme pour tous les patients. Dans tous les cas, un hypersignal sur les séquences T2 et une prise de contraste sur les séquences T1 avec injection de gadolinium ont été observés sur l’IRM. Un hypersignal sur les séquences de diffusion ainsi qu’une baisse de l’ADC ont été également retrouvé. Ces observations de formes précoces de GBM se sont rapidement développées en des formes classiques de GBM à l’IRM en quelques semaines. Les GBM ont multiplié leur taille par 32 en un mois. L’absence de mutation R132H d’IDH1 sur les analyses immunohistochimiques, marqueur des tumeurs gliales de bas grade et des GBM secondaires, confirment leur caractère de novo. Conclusion. – Une meilleure connaissance des présentations précoces de GBM pourrait permettre une meilleure prise en charge de ces tumeurs et en améliorer le pronostic. © 2014 Elsevier Masson SAS. Tous droits réservés.
∗ Corresponding author. Service de neurochirurgie, centre hospitalier universitaire, 4, rue Larrey, 49933 Angers cedex 9, France. E-mail address: [email protected] (P. Menei). http://dx.doi.org/10.1016/j.neuchi.2014.02.008 0028-3770/© 2014 Elsevier Masson SAS. All rights reserved.
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1. Introduction Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system [1]. Most patients with GBM present tumor-related symptoms, such as progressive focal neurologic deficit(s) or increased intracranial pressure. On MRI, typical characteristics of GBM are seen including irregular rim contrast enhancement, central necrosis, and perilesional edema. Despite optimal management combining surgery, radiotherapy, and chemotherapy, the prognosis is poor with a median survival time of 14.6 months [2]. In some patients GBM appears early in the course of the disease, before harboring typical clinical and radiological findings. Presentation at an early stage seems to be associated with seizures, as well as small cortical signal abnormalities [3]. The development of a multimodal MRI including diffusion weighted imaging (DWI), perfusion imaging (PWI) and magnetic resonance spectroscopy (MRS) appears to be useful in distinguishing between an early presentation of GBM and other brain abnormalities [4]. Few studies have reported early clinical and neuroimaging features of high-grade glioma [3–10]. A recent study has reviewed the 15 articles previously published in the literature concerning these occult brain tumors [11]. Nevertheless, although the de novo nature of these early presentations has been hypothesized, their molecular characteristics have still not been defined and their growth is unknown. We report the clinical, neuroimaging and molecular characteristics of four cases of GBM with an early presentation. We also evaluated the early volumetric evolution without treatments. We discuss which imaging techniques are helpful to identify these early stages of GBM and to distinguish them from other brain diseases. Finally, we propose a management scheme for patients with newonset epileptic seizures in order not to miss a GBM at a very early stage in the tumor growth process.
2. Methods 2.1. Patients and imaging Four patients with an early presentation of GBM were treated in our neurosurgery department between May 2011 and January 2012. We reviewed the clinical, neuroimaging and histopathological findings of these cases (Table 1). All patients first underwent a brain CT scan with and without a contrast agent. An initial cerebral (MRI 1) was performed in all cases with T1-weighted (T1WI) and gadolinium-enhanced T1 (GdET1WI) sequences. For three of the four cases, T2-weighted imaging (T2WI) or fluid attenuated inversion recovery imaging (FLAIR), and DWI with attenuated coefficient diffusion (ADC) were obtained. A subsequent MRI (MRI 2) with the same sequences was performed during the second admission. In all cases, the second MRI showed typical findings of GBM leading to surgery for two patients and to a frameless stereotactic biopsy for the other two.
A, B, and C correspond to the maximal diameter of the tumor in the three axes (x, y, z). The two volumes were calculated on the MRI 1 and called Vol-1 and on the MRI 2 and called Vol-2. Volume augmentation corresponded to the difference between the two MRI and was expressed in a percentage and in coefficient of multiplication.
2.3. Immunohistochemical analysis and array Comparative Genomic Hybridization (aCGH) The tumors were classified according to the 2007 World Health Organization (WHO) classification of tumors of the nervous system. Immunohistochemistry was carried-out using antibodies directed against the following antigens: p53, internexin alpha (INA), mutant IDH1 R132H protein, and MIB1/Ki-67. Three tumors were analyzed by whole genome aCGH. In one case, the analysis could not be performed because of the small sample size (case 2, stereotactic biopsy). Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples.
3. Results 3.1. Clinical picture Patients’ age ranged between 45 and 69 years with a mean age of 57 years at the time of first admission. They represented 5.5% (4/72) of the newly diagnosed GBM cases in our department over a nine month period. Patients were admitted for a focal clonic seizure (cases 2 and 4) or a generalized seizure (cases 1 and 3). None had a previous history of seizures. Diagnosis of GBM was not obtained from the first MRI, thus leading to a misdiagnosis (cavernous malformation, herpetic encephalitis). The patients were discharged from our institution with anti-epileptic drugs and no recurrence of seizures occurred. A second MRI was scheduled at three months follow-up. However, all patients were admitted for raised intracranial pressure one to two months after their first admission. After the second MRI, all patients underwent surgery. In cases 1 and 3 gross total resection was achieved and in the other two cases, a frameless stereotactic biopsy was performed because of its bifocal localization (case 2) and low KPS (case 4).
2.2. Tumor volume For each patient we measured, the three axes of the tumor on the GdE-T1WI. Enhanced areas and central necrosis were considered as the volume of the tumor. In cases of bifocal lesions the larger lesion was utilized for the comparison. Tumor volume (Vol) was calculated using the validated ellipsoid model [12] defining as: Vol = (1/6) pi ABC.
Fig. 1. Early stage GBM on CT. Axial CT scan shows a spontaneously hyperdense cortical lesion mimicking a hemorrhagic infarct in the right parietal lobe (cases 3 and 4). Stade précoce de GBM au TDM. Coupe axiale de scanner montrant une hyperdensité corticale spontanée mimant une hémorragie au sein du lobe pariétal droit (cas 3 et 4).
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Table 1 Clinical and neuroimaging findings. Caratéristiques cliniques et radiologique. Age, sex
Initial symptom
Initial MRI study
Time to recognition of progression (months)
Lobe
Location
Surgery
57, M
Generalized seizure
1
Temporal
Cortical
Resection
69, M
Focal clonic seizure
1
Frontal and parietal
Cortical
Stereotaxic Needle biopsy
57, M 45, M
Generalized seizure Focal clonic seizure
T2 hyperintensity Tiny nodular enhancement Diffusion hyperintensity Low ADC T2 hyperintensity Tiny nodular enhancement Diffusion hyperintensity Low ADC Tiny nodular enhancement T2 hyperintensity Tiny nodular enhancement T2 shine-through
1 2
Parietal Parietal
Cortical Cortical
Resection Stereotaxic Needle biopsy
ADC: apparent diffusion coefficient/coefficient de diffusion apparent; MRI: magnetic resonance imaging. IRM : imagerie par résonance magnétique.
3.2. Imaging features In cases 3 and 4, the CT scan showed a small spontaneously hyperdense area mimicking a hemorrhagic stroke in the right parietal region (Fig. 1). In these two cases, minimal contrast enhancement was observed (data not shown). Initial MRI revealed homogeneously hyperintense areas on T2WI sequences with little or no mass effect in three cases (Fig. 2a). In case 2, the hyperintense area was large, including the right frontal, temporal and parietal lobes, and was misdiagnosed as encephalitis. In all cases, a tiny hypo-intense spot was observed on T1WI MRI (data not shown). Furthermore, GdE-T1WI sequences revealed a tiny nodular contrast enhancement within similar area to that seen on T2-weighted sequences in all patients
(Fig. 2b). In all instances, the enhancement was subcortical in location. DWI was performed in three patients (cases 1, 2 and 4) and showed hyperintense signals with similar distribution to those seen on T2 sequences (Fig. 3a). In case 3, T2WI and DWI were not performed. Low signal intensity on ADC mapping was observed in cases 1 and 2. ADC was heterogeneous in case 4 (Fig. 3b). In all cases, the second MRI demonstrated the typical findings of GBM such as central necrotic area with heterogeneous ring-like contrast enhancement and sometimes marked perilesional edema (Fig. 2c). In case 2, MRI showed bifocal localization and in case 4, the tumor displayed a cystic component. The neoplasm grew to large proportions within a month in cases 1, 2, and 3, and within two months in the remaining case.
Fig. 2. MRI evolution of non-treated early GBM presentation. a. First axial MRI on FLAIR (cases 1 and 2) and T2WI (case 4) sequences at clinical onset demonstrating signal hyperintensity in the left temporal lobe (case 1), right frontal and temporal lobes (case 2), and right parietal lobe (case 4). b. First post-contrast axial MRI showing nodular enhancement in the same areas that on FLAIR and T2WI sequences. c. Second post-contrast axial MRI performed one (cases 1, 2, and 3) and two months later (case 4) showing a single (cases 1, 3, and 4) and bifocal (case 2) necrotic mass with irregular contrast enhancement. Évolution IRM de présentation précoce de GBM non traités. a. Première IRM en coupe axial FLAIR (cas 1 et 2) et en séquence T2 (cas 4) montrant un hypersignal dans le lobe temporal gauche (cas 1), frontal et temporal droit (cas 2) et pariétal droit (cas 4). b. IRM avec injection de produit de contraste montrant un rehaussement nodulaire dans les zones d’hypersignal FLAIR et T2. c. Seconde IRM en coupe axiale réalisée un mois (cas 1, 2, 3) et 2 mois (cas 4) après la première montrant une masse nécrotique avec une prise de contraste hétérogène unique (cas 1, 3 et 4) et bifocale (cas 2).
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MIB1/Ki-67 proliferation index was comprised between 15% and 50% (mean 29%). 3.5. Array CGH analysis Whole genome aCGH demonstrated a gain of chromosome 7 and loss of chromosome 10 in cases 1 and 4. Case 4 also harbored EGFR amplification and loss of chromosome 9p. Array CGH revealed no obvious genetic alteration in case 3. None of the tumors displayed 1p/19q codeletion. There was no p16 deletion. No tissue was available for aCGH analysis in case 2. 4. Discussion We report the clinical, neuroimaging and molecular characteristics of 4 cases of GBM observed at an early stage. We also describe the volumetric evolution of non-treated GBM. 4.1. Clinical picture of early stage GBM Fig. 3. DWI and ADC mapping of GBM early presentation a. Axial MRI on DWI revealing signal hyperintensity in the left temporal lobe (case 1), right frontal and temporal lobes (case 2), and right parietal lobe (case 4). b. Axial ADC mapping showing low ADC value in the left temporal lobe (case 1), in the right frontal and temporal lobes (case 2), and a T2 shine-through effect in the right parietal lobe (case 4). IRM de diffusion et cartographie de l’ADC des formes précoces de GBM. a. IRM de diffusion en coupe axiale montrant un hypersignal dans le lobe temporal gauche (cas 1), lobe frontal et temporal droit (cas 2), et dans le lobe pariétal droit (cas4). b. Cartographie de l’ADC montrant une baisse de l’ADC dans le lobe temporal gauche (cas 1), lobe frontal et temporal droit (cas 2) et un T2 shine-through effect dans le lobe pariétal droit (cas4).
3.3. Tumoral volume estimation All tumoral values are showed in Table 2. On the MRI 1 the mean tumoral volume was 0.4 cm3 and 18.5 cm3 on MRI 2. The mean volume augmentation was 18 cm3 and corresponded to a mean variation in percent of 4438% (× 60) observed on a mean time of 1.3 months. If we excluded case 4, with a cystic component, the mean initial volume on MRI 1 was 0.4 cm3 and 12.9 cm3 on the second. The mean tumoral volume augmentation was 12.3 cm3 and corresponded to a mean variation of 2428% ( × 32) observed on a mean time of 1 month.
3.4. Histopathological and immunohistochemical characteristics The histopathological diagnosis according to the 2007 WHO classification was GBM (grade IV astrocytoma) in all cases. Immunohistochemical analysis showed an accumulation of p53 protein in all cases except one. The mutant IDH1 R132H protein was not detected. There was no expression of internexin alpha. The
GBM is the most common malignant primary brain tumor in adults. The most frequent clinical presentation of GBM is raised intracranial pressure and/or focal neurologic. All of our early presentations of GBM presented with a first episode of seizure. This type of clinical picture is usually associated not only with a low-grade glioma with a frequency of 80% but also occurs in 30% of high-grade gliomas [13]. Focal clonic seizures and, less frequently, generalized seizures have been described in early stage GBM patients [4,9,10]. This association of seizures and early presentation of GBM was statistically recognized in a recent review [11]. In the same study the authors did in fact find statically lobar or left side predilection. If specific lobar involvement does not play a role in early diagnosis of GBM, cortical involvement is very frequently found [14] as in our series (100% cases) and could explain the high frequencies of seizures. 4.2. Radiological features of early GBM presentation A tiny focal hyperdense lesion was occasionally observed on CT scan (in two cases of our series and in six other reported in the literature [9–11]). Spontaneously hyperdense areas are typically observed in hemorrhagic processes or in cases of calcifications. However, the cortical location of the lesion and the clinical picture (inaugural seizures) were not in favor of a hemorrhagic infarct. The nature of the hyperdense areas we observed in our patients may be related to the hypercellularity and/or the vascularization of the tumor. Unfortunately, T2* sequences was not performed, and does not allow to formally eliminate tumoral hemorrhage. Classically, GBM presents on MRI as an irregular rim-enhanced mass with central necrosis and perilesional edema. However, these well-described features are absent at the early stage of the disease.
Table 2 Volumetric evolution. Évolution volumétrique. Case
Volume on the first MRI (cm3 )
Volume on the second MRI (cm3 )
Time between the two MRI (months)
Volume augmentation (cm3 )
Volume augmentation (percent %/coefficient)
1 2 3 4 Mean of cases 1,2,3 Total mean
0.4 0.2 0.9 0.3 0.4 0.4
8.3 11.4 18.9 35.5 12.9 18.5
1.0 1.0 1.0 2.0 1.0 1.3
7.9 11.1 18.0 35.1 12.3 18.0
2161/ × 21 3006/ × 57 2118/ × 47 10465/ × 118 2428/ × 32 4438/ × 60
MRI: magnetic resonance imaging. IRM : imagerie par résonance magnétique.
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In three cases of our series, the first MRI revealed a hyperintense signal on T2WI or FLAIR sequences. However, the radiological aspect on FLAIR sequences of the case 2 should be nuanced because of an imaging compatible with a gliomatosis. On T1WI sequences, we observed a tiny dot-like hypo-intense area in all cases. Gadolinium enhancement is often observed at the early stage of GBM [4]. The enhanced area is small and often reduced to a punctuated formation. In our series, three cases were analyzed using DWI and ADC mapping. DWI revealed an increased signal, and ADC mapping showed a low coefficient in the same areas except for one case. Only one previously published study presented DWI and ADC results [4]. In that study, all GBM displayed hyperintense signals on DWI and harbored a low coefficient on ADC mapping. In tumor processes, it is well known that a low signal on ADC mapping is characteristic of high cellularity. An increased signal on DWI associated with a low ADC value suggests a malignant tumor cell proliferation at its early stage. In summary, the neuroimaging characteristics of early stage GBM are: • • • • • •
high signal intensity on T2WI; possible nodular enhancement on GdE-T1WI; high signal intensity on DWI; low ADC value; increased rCBV; increased choline and decreased NAA levels on MRS.
4.3. How to distinguish early stage GBM from brain metastases (BM), primary cerebral lymphoma (PCL) and non-neoplastic lesions? Early stage GBM often appears as an enhancing lesion without necrosis as it may present solitary BMs, PCL or non-neoplastic lesions. The tumor location, the clinical context and the use of multimodal MRI should be helpful to assess the nature of the disease. DWI and rCBV can identify PCL with high specificity (hyperintense signal on DWI, low ADC coefficient and rCBV not increased). In cases of BM, there is classically a history of malignancy or a systemic search revealing a primary tumor. However, in 15% of cases, the primary site was not found [15]. In this instance, only a pathological examination of the lesion may distinguish BM from early stage GBM. DWI, ADC, rCBV and MRS findings depend on the nature of the primary tumor and are not very specific to distinguish a solitary BM from an early stage GBM. In cases of inflammatory diseases such as multiple sclerosis or acute disseminated encephalomyelitis, MRI shows high signal intensity on T2WI or FLAIR sequences but GdE-T1WI demonstrates a characteristic U-shaped enhancement pattern. MRS shows high choline and normal NAA levels, and there is a slight rCBV increase on PWI. Increased signal intensity on T2WI may lead one to misdiagnose a tumor as an ischemic cerebral infarct [7]. Typically, in the latter, no contrast enhancement is observed even though a low ADC value due to cytotoxic edema could be seen a few days after a stroke. Thus, clinical information as well as MRI findings can help the patient management but a definitive diagnosis requires a histopathological examination, notably to distinguish early stage GBM from PCL, BMs and non-neoplastic lesions. 4.4. Volumetric evolution Currently tumor volume is measured on GdE-T1WI. The classical estimation of the volume on 2 D MRI using a method based on the product of the longer and the larger diameter.
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In our series, GBM mean volume growth during one month was 12.3 cm3 and corresponded to a volume augmentation of 2428% ( × 35). It is not possible to perform a study to evaluate non-treated GBM growth. In a recent study the authors reported a mean diameter growth of 3.3 mm/week [10]. We described the kinetic growing volume of three non-treated GBM (cases1, 2 and 3) of 12.3 cm3 (2428%) in one month. Greater growth kinetics was observed in the case of the GBM with a cystic component with a volume augmentation of 10465% in 2 months. Due to the poor effectives, the lack of data and the great diversity of the tumors published it is difficult to identify a real median time of progression of high-grade glioma. However, we showed with our cases the high growth of GBM at an early stage. With several criteria is enabling to evaluate the survival of patients with high-grade glioma: type, grade, size, site, age and KPS. A larger tumoral volume could lead to an incomplete resection with a worse prognosis [16]. 4.5. Immunohistochemical analysis and array CGH On immunohistochemical analysis, we observed no expression of mutant IDH1 R132H protein, highly specific marker of low-grade gliomas and secondary GBM [17] and a strong predictor of favorable prognosis and better overall survival. In our series, the absence of mutant IDH1 R132H expression indicates that these early stage GBM are de novo tumors. We also did not observe any internexin alpha expression or 1p/19q codeletion. Those markers are detected in oligodendrogliomas and have been associated with a favorable prognosis and a higher chemosensitivity [18]. Furthermore, in our series, three tumors displayed p53 protein accumulation. It has been shown that patients with WHO grade III diffuse glioma expressing p53 protein had shorter progression free and overall survivals [19]. We performed array CGH analysis on tumors some weeks after their initial early presentation. Out of three cases, two harbored genetic alterations typically observed in GBM, e.g. gain of chromosome 7, EGFR amplification, loss of chromosome 10, and loss of chromosome 9p. The remaining case presented no obvious genetic alterations on whole genome aCGH. 4.6. Management of early stage GBM Presently, two options have been reported in the literature when confronted with a possible early stage GBM: an MRI follow-up [3] or a routine biopsy [4,9]. Some authors, such as Rossi et al. (2010) are favorable to a close MRI follow-up. They recommend an MRI each month for three months [9]. However, an interval of one month may be too long in light of the rapid tumor progression observed in our series, highlighting the limitation of the MRI follow-up in these neoplasms. The second attitude consists of performing a biopsy. However, the indication of the biopsy should be carefully considered. In fact, Baehring et al. (2007) have reported eight patients who underwent a biopsy for suspicion of an early stage high-grade glioma [4]. Although tissue from the ADC-positive portion of the tumor was obtained, the diagnosis was not established in three cases. The authors gave no explanation as to why the samples were not contributive but the small size of the lesion may explain the absence of representative tissue. Because of the risk of rapid tumor growth and misdiagnosis on MRI, a third approach should be evaluated: an early resection of the lesion performed with an intra-operative histopathological examination. If the diagnosis of GBM is confirmed, a large resection should be considered. Logically, a total resection of the lesion should be feasible considering its small size. Moreover, some studies have shown that the extent of resection was associated with a longer
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survival, and one study demonstrated that an optimal resection could improve the progression free survival [20]. In conclusion, although our study is based on a small series, it demonstrates that diagnosis of primary GBM at an early stage is not uncommon but often remains unknown. The review of the literature enabled us to better define the neuroimaging features of these peculiar tumors. A prospective study would be interesting to assess whether early total resection of the neoplasm with large margins could improve patient outcome. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments We thank Professor Jean-Yves Delattre for providing the array CGH data. We also thank Mathieu Delion for help in the editing of this manuscript. Funding: No funding has supported this research.
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Clinical case
Early presentation of primary glioblastoma Présentation précoce des glioblastomes primaires R. Faguer a , J.-Y. Tanguy b , A. Rousseau c , A. Clavreul a , P. Menei a,∗ a
Department of neurosurgery, university hospital, 4, rue Larrey, 49933 Angers cedex 9, France Department of radiology, university hospital, 4, rue Larrey, 49933 Angers cedex 9, France c Department of pathology, university hospital, 4, rue Larrey, 49933 Angers cedex 9, France b
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Glioblastoma Occult tumor Early diagnosis Immunohistochemistry Molecular biology
a b s t r a c t Background. – Clinical and neuroimaging findings of glioblastomas (GBM) at an early stage have rarely been described and those tumors are most probably under-diagnosed. Furthermore, their genetic alterations, to our knowledge, have never been previously reported. Methods. – We report the clinical as well as neuroimaging findings of four early cases of patients with GBM. Results. – In our series, early stage GBM occurred at a mean age of 57 years. All patients had seizures as their first symptom. In all early stages, MRI showed a hyperintense signal on T2-weighted sequences and an enhancement on GdE-T1WI sequences. A hyperintense signal on diffusion sequences with a low ADC value was also found. These early observed occurrences of GBM developed rapidly and presented the MRI characteristics of classic GBM within a few weeks. The GBM size was multiplied by 32 in one month. Immunohistochemical analysis indicated the de novo nature of these tumors, i.e. absence of mutant IDH1 R132H protein expression, which is a diagnostic marker of low-grade diffuse glioma and secondary GBM. Conclusions. – A better knowledge of early GBM presentation would allow a more suitable management of the patients and may improve their prognosis. © 2014 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Glioblastome Tumeurs occultes Diagnostic précoce Immunohistochimie Biologie moléculaire
Introduction. – Les signes cliniques et radiologiques des glioblastomes (GBM) au stade précoce ont été rarement décrit et ces tumeurs sont probablement sous-diagnostiquées. De plus, leurs anomalies génétiques n’ont jamais été rapportées. Méthodes. – Nous rapportons les données cliniques et radiologiques de quatre cas de GBM au stade précoce. Résultats. – Dans notre série, les formes précoces de GBM sont survenues à un âge moyen de 57 ans. La crise d’épilepsie a été le premier symptôme pour tous les patients. Dans tous les cas, un hypersignal sur les séquences T2 et une prise de contraste sur les séquences T1 avec injection de gadolinium ont été observés sur l’IRM. Un hypersignal sur les séquences de diffusion ainsi qu’une baisse de l’ADC ont été également retrouvé. Ces observations de formes précoces de GBM se sont rapidement développées en des formes classiques de GBM à l’IRM en quelques semaines. Les GBM ont multiplié leur taille par 32 en un mois. L’absence de mutation R132H d’IDH1 sur les analyses immunohistochimiques, marqueur des tumeurs gliales de bas grade et des GBM secondaires, confirment leur caractère de novo. Conclusion. – Une meilleure connaissance des présentations précoces de GBM pourrait permettre une meilleure prise en charge de ces tumeurs et en améliorer le pronostic. © 2014 Elsevier Masson SAS. Tous droits réservés.
∗ Corresponding author. Service de neurochirurgie, centre hospitalier universitaire, 4, rue Larrey, 49933 Angers cedex 9, France. E-mail address: [email protected] (P. Menei). http://dx.doi.org/10.1016/j.neuchi.2014.02.008 0028-3770/© 2014 Elsevier Masson SAS. All rights reserved.
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1. Introduction Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system [1]. Most patients with GBM present tumor-related symptoms, such as progressive focal neurologic deficit(s) or increased intracranial pressure. On MRI, typical characteristics of GBM are seen including irregular rim contrast enhancement, central necrosis, and perilesional edema. Despite optimal management combining surgery, radiotherapy, and chemotherapy, the prognosis is poor with a median survival time of 14.6 months [2]. In some patients GBM appears early in the course of the disease, before harboring typical clinical and radiological findings. Presentation at an early stage seems to be associated with seizures, as well as small cortical signal abnormalities [3]. The development of a multimodal MRI including diffusion weighted imaging (DWI), perfusion imaging (PWI) and magnetic resonance spectroscopy (MRS) appears to be useful in distinguishing between an early presentation of GBM and other brain abnormalities [4]. Few studies have reported early clinical and neuroimaging features of high-grade glioma [3–10]. A recent study has reviewed the 15 articles previously published in the literature concerning these occult brain tumors [11]. Nevertheless, although the de novo nature of these early presentations has been hypothesized, their molecular characteristics have still not been defined and their growth is unknown. We report the clinical, neuroimaging and molecular characteristics of four cases of GBM with an early presentation. We also evaluated the early volumetric evolution without treatments. We discuss which imaging techniques are helpful to identify these early stages of GBM and to distinguish them from other brain diseases. Finally, we propose a management scheme for patients with newonset epileptic seizures in order not to miss a GBM at a very early stage in the tumor growth process.
2. Methods 2.1. Patients and imaging Four patients with an early presentation of GBM were treated in our neurosurgery department between May 2011 and January 2012. We reviewed the clinical, neuroimaging and histopathological findings of these cases (Table 1). All patients first underwent a brain CT scan with and without a contrast agent. An initial cerebral (MRI 1) was performed in all cases with T1-weighted (T1WI) and gadolinium-enhanced T1 (GdET1WI) sequences. For three of the four cases, T2-weighted imaging (T2WI) or fluid attenuated inversion recovery imaging (FLAIR), and DWI with attenuated coefficient diffusion (ADC) were obtained. A subsequent MRI (MRI 2) with the same sequences was performed during the second admission. In all cases, the second MRI showed typical findings of GBM leading to surgery for two patients and to a frameless stereotactic biopsy for the other two.
A, B, and C correspond to the maximal diameter of the tumor in the three axes (x, y, z). The two volumes were calculated on the MRI 1 and called Vol-1 and on the MRI 2 and called Vol-2. Volume augmentation corresponded to the difference between the two MRI and was expressed in a percentage and in coefficient of multiplication.
2.3. Immunohistochemical analysis and array Comparative Genomic Hybridization (aCGH) The tumors were classified according to the 2007 World Health Organization (WHO) classification of tumors of the nervous system. Immunohistochemistry was carried-out using antibodies directed against the following antigens: p53, internexin alpha (INA), mutant IDH1 R132H protein, and MIB1/Ki-67. Three tumors were analyzed by whole genome aCGH. In one case, the analysis could not be performed because of the small sample size (case 2, stereotactic biopsy). Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples.
3. Results 3.1. Clinical picture Patients’ age ranged between 45 and 69 years with a mean age of 57 years at the time of first admission. They represented 5.5% (4/72) of the newly diagnosed GBM cases in our department over a nine month period. Patients were admitted for a focal clonic seizure (cases 2 and 4) or a generalized seizure (cases 1 and 3). None had a previous history of seizures. Diagnosis of GBM was not obtained from the first MRI, thus leading to a misdiagnosis (cavernous malformation, herpetic encephalitis). The patients were discharged from our institution with anti-epileptic drugs and no recurrence of seizures occurred. A second MRI was scheduled at three months follow-up. However, all patients were admitted for raised intracranial pressure one to two months after their first admission. After the second MRI, all patients underwent surgery. In cases 1 and 3 gross total resection was achieved and in the other two cases, a frameless stereotactic biopsy was performed because of its bifocal localization (case 2) and low KPS (case 4).
2.2. Tumor volume For each patient we measured, the three axes of the tumor on the GdE-T1WI. Enhanced areas and central necrosis were considered as the volume of the tumor. In cases of bifocal lesions the larger lesion was utilized for the comparison. Tumor volume (Vol) was calculated using the validated ellipsoid model [12] defining as: Vol = (1/6) pi ABC.
Fig. 1. Early stage GBM on CT. Axial CT scan shows a spontaneously hyperdense cortical lesion mimicking a hemorrhagic infarct in the right parietal lobe (cases 3 and 4). Stade précoce de GBM au TDM. Coupe axiale de scanner montrant une hyperdensité corticale spontanée mimant une hémorragie au sein du lobe pariétal droit (cas 3 et 4).
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Table 1 Clinical and neuroimaging findings. Caratéristiques cliniques et radiologique. Age, sex
Initial symptom
Initial MRI study
Time to recognition of progression (months)
Lobe
Location
Surgery
57, M
Generalized seizure
1
Temporal
Cortical
Resection
69, M
Focal clonic seizure
1
Frontal and parietal
Cortical
Stereotaxic Needle biopsy
57, M 45, M
Generalized seizure Focal clonic seizure
T2 hyperintensity Tiny nodular enhancement Diffusion hyperintensity Low ADC T2 hyperintensity Tiny nodular enhancement Diffusion hyperintensity Low ADC Tiny nodular enhancement T2 hyperintensity Tiny nodular enhancement T2 shine-through
1 2
Parietal Parietal
Cortical Cortical
Resection Stereotaxic Needle biopsy
ADC: apparent diffusion coefficient/coefficient de diffusion apparent; MRI: magnetic resonance imaging. IRM : imagerie par résonance magnétique.
3.2. Imaging features In cases 3 and 4, the CT scan showed a small spontaneously hyperdense area mimicking a hemorrhagic stroke in the right parietal region (Fig. 1). In these two cases, minimal contrast enhancement was observed (data not shown). Initial MRI revealed homogeneously hyperintense areas on T2WI sequences with little or no mass effect in three cases (Fig. 2a). In case 2, the hyperintense area was large, including the right frontal, temporal and parietal lobes, and was misdiagnosed as encephalitis. In all cases, a tiny hypo-intense spot was observed on T1WI MRI (data not shown). Furthermore, GdE-T1WI sequences revealed a tiny nodular contrast enhancement within similar area to that seen on T2-weighted sequences in all patients
(Fig. 2b). In all instances, the enhancement was subcortical in location. DWI was performed in three patients (cases 1, 2 and 4) and showed hyperintense signals with similar distribution to those seen on T2 sequences (Fig. 3a). In case 3, T2WI and DWI were not performed. Low signal intensity on ADC mapping was observed in cases 1 and 2. ADC was heterogeneous in case 4 (Fig. 3b). In all cases, the second MRI demonstrated the typical findings of GBM such as central necrotic area with heterogeneous ring-like contrast enhancement and sometimes marked perilesional edema (Fig. 2c). In case 2, MRI showed bifocal localization and in case 4, the tumor displayed a cystic component. The neoplasm grew to large proportions within a month in cases 1, 2, and 3, and within two months in the remaining case.
Fig. 2. MRI evolution of non-treated early GBM presentation. a. First axial MRI on FLAIR (cases 1 and 2) and T2WI (case 4) sequences at clinical onset demonstrating signal hyperintensity in the left temporal lobe (case 1), right frontal and temporal lobes (case 2), and right parietal lobe (case 4). b. First post-contrast axial MRI showing nodular enhancement in the same areas that on FLAIR and T2WI sequences. c. Second post-contrast axial MRI performed one (cases 1, 2, and 3) and two months later (case 4) showing a single (cases 1, 3, and 4) and bifocal (case 2) necrotic mass with irregular contrast enhancement. Évolution IRM de présentation précoce de GBM non traités. a. Première IRM en coupe axial FLAIR (cas 1 et 2) et en séquence T2 (cas 4) montrant un hypersignal dans le lobe temporal gauche (cas 1), frontal et temporal droit (cas 2) et pariétal droit (cas 4). b. IRM avec injection de produit de contraste montrant un rehaussement nodulaire dans les zones d’hypersignal FLAIR et T2. c. Seconde IRM en coupe axiale réalisée un mois (cas 1, 2, 3) et 2 mois (cas 4) après la première montrant une masse nécrotique avec une prise de contraste hétérogène unique (cas 1, 3 et 4) et bifocale (cas 2).
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MIB1/Ki-67 proliferation index was comprised between 15% and 50% (mean 29%). 3.5. Array CGH analysis Whole genome aCGH demonstrated a gain of chromosome 7 and loss of chromosome 10 in cases 1 and 4. Case 4 also harbored EGFR amplification and loss of chromosome 9p. Array CGH revealed no obvious genetic alteration in case 3. None of the tumors displayed 1p/19q codeletion. There was no p16 deletion. No tissue was available for aCGH analysis in case 2. 4. Discussion We report the clinical, neuroimaging and molecular characteristics of 4 cases of GBM observed at an early stage. We also describe the volumetric evolution of non-treated GBM. 4.1. Clinical picture of early stage GBM Fig. 3. DWI and ADC mapping of GBM early presentation a. Axial MRI on DWI revealing signal hyperintensity in the left temporal lobe (case 1), right frontal and temporal lobes (case 2), and right parietal lobe (case 4). b. Axial ADC mapping showing low ADC value in the left temporal lobe (case 1), in the right frontal and temporal lobes (case 2), and a T2 shine-through effect in the right parietal lobe (case 4). IRM de diffusion et cartographie de l’ADC des formes précoces de GBM. a. IRM de diffusion en coupe axiale montrant un hypersignal dans le lobe temporal gauche (cas 1), lobe frontal et temporal droit (cas 2), et dans le lobe pariétal droit (cas4). b. Cartographie de l’ADC montrant une baisse de l’ADC dans le lobe temporal gauche (cas 1), lobe frontal et temporal droit (cas 2) et un T2 shine-through effect dans le lobe pariétal droit (cas4).
3.3. Tumoral volume estimation All tumoral values are showed in Table 2. On the MRI 1 the mean tumoral volume was 0.4 cm3 and 18.5 cm3 on MRI 2. The mean volume augmentation was 18 cm3 and corresponded to a mean variation in percent of 4438% (× 60) observed on a mean time of 1.3 months. If we excluded case 4, with a cystic component, the mean initial volume on MRI 1 was 0.4 cm3 and 12.9 cm3 on the second. The mean tumoral volume augmentation was 12.3 cm3 and corresponded to a mean variation of 2428% ( × 32) observed on a mean time of 1 month.
3.4. Histopathological and immunohistochemical characteristics The histopathological diagnosis according to the 2007 WHO classification was GBM (grade IV astrocytoma) in all cases. Immunohistochemical analysis showed an accumulation of p53 protein in all cases except one. The mutant IDH1 R132H protein was not detected. There was no expression of internexin alpha. The
GBM is the most common malignant primary brain tumor in adults. The most frequent clinical presentation of GBM is raised intracranial pressure and/or focal neurologic. All of our early presentations of GBM presented with a first episode of seizure. This type of clinical picture is usually associated not only with a low-grade glioma with a frequency of 80% but also occurs in 30% of high-grade gliomas [13]. Focal clonic seizures and, less frequently, generalized seizures have been described in early stage GBM patients [4,9,10]. This association of seizures and early presentation of GBM was statistically recognized in a recent review [11]. In the same study the authors did in fact find statically lobar or left side predilection. If specific lobar involvement does not play a role in early diagnosis of GBM, cortical involvement is very frequently found [14] as in our series (100% cases) and could explain the high frequencies of seizures. 4.2. Radiological features of early GBM presentation A tiny focal hyperdense lesion was occasionally observed on CT scan (in two cases of our series and in six other reported in the literature [9–11]). Spontaneously hyperdense areas are typically observed in hemorrhagic processes or in cases of calcifications. However, the cortical location of the lesion and the clinical picture (inaugural seizures) were not in favor of a hemorrhagic infarct. The nature of the hyperdense areas we observed in our patients may be related to the hypercellularity and/or the vascularization of the tumor. Unfortunately, T2* sequences was not performed, and does not allow to formally eliminate tumoral hemorrhage. Classically, GBM presents on MRI as an irregular rim-enhanced mass with central necrosis and perilesional edema. However, these well-described features are absent at the early stage of the disease.
Table 2 Volumetric evolution. Évolution volumétrique. Case
Volume on the first MRI (cm3 )
Volume on the second MRI (cm3 )
Time between the two MRI (months)
Volume augmentation (cm3 )
Volume augmentation (percent %/coefficient)
1 2 3 4 Mean of cases 1,2,3 Total mean
0.4 0.2 0.9 0.3 0.4 0.4
8.3 11.4 18.9 35.5 12.9 18.5
1.0 1.0 1.0 2.0 1.0 1.3
7.9 11.1 18.0 35.1 12.3 18.0
2161/ × 21 3006/ × 57 2118/ × 47 10465/ × 118 2428/ × 32 4438/ × 60
MRI: magnetic resonance imaging. IRM : imagerie par résonance magnétique.
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In three cases of our series, the first MRI revealed a hyperintense signal on T2WI or FLAIR sequences. However, the radiological aspect on FLAIR sequences of the case 2 should be nuanced because of an imaging compatible with a gliomatosis. On T1WI sequences, we observed a tiny dot-like hypo-intense area in all cases. Gadolinium enhancement is often observed at the early stage of GBM [4]. The enhanced area is small and often reduced to a punctuated formation. In our series, three cases were analyzed using DWI and ADC mapping. DWI revealed an increased signal, and ADC mapping showed a low coefficient in the same areas except for one case. Only one previously published study presented DWI and ADC results [4]. In that study, all GBM displayed hyperintense signals on DWI and harbored a low coefficient on ADC mapping. In tumor processes, it is well known that a low signal on ADC mapping is characteristic of high cellularity. An increased signal on DWI associated with a low ADC value suggests a malignant tumor cell proliferation at its early stage. In summary, the neuroimaging characteristics of early stage GBM are: • • • • • •
high signal intensity on T2WI; possible nodular enhancement on GdE-T1WI; high signal intensity on DWI; low ADC value; increased rCBV; increased choline and decreased NAA levels on MRS.
4.3. How to distinguish early stage GBM from brain metastases (BM), primary cerebral lymphoma (PCL) and non-neoplastic lesions? Early stage GBM often appears as an enhancing lesion without necrosis as it may present solitary BMs, PCL or non-neoplastic lesions. The tumor location, the clinical context and the use of multimodal MRI should be helpful to assess the nature of the disease. DWI and rCBV can identify PCL with high specificity (hyperintense signal on DWI, low ADC coefficient and rCBV not increased). In cases of BM, there is classically a history of malignancy or a systemic search revealing a primary tumor. However, in 15% of cases, the primary site was not found [15]. In this instance, only a pathological examination of the lesion may distinguish BM from early stage GBM. DWI, ADC, rCBV and MRS findings depend on the nature of the primary tumor and are not very specific to distinguish a solitary BM from an early stage GBM. In cases of inflammatory diseases such as multiple sclerosis or acute disseminated encephalomyelitis, MRI shows high signal intensity on T2WI or FLAIR sequences but GdE-T1WI demonstrates a characteristic U-shaped enhancement pattern. MRS shows high choline and normal NAA levels, and there is a slight rCBV increase on PWI. Increased signal intensity on T2WI may lead one to misdiagnose a tumor as an ischemic cerebral infarct [7]. Typically, in the latter, no contrast enhancement is observed even though a low ADC value due to cytotoxic edema could be seen a few days after a stroke. Thus, clinical information as well as MRI findings can help the patient management but a definitive diagnosis requires a histopathological examination, notably to distinguish early stage GBM from PCL, BMs and non-neoplastic lesions. 4.4. Volumetric evolution Currently tumor volume is measured on GdE-T1WI. The classical estimation of the volume on 2 D MRI using a method based on the product of the longer and the larger diameter.
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In our series, GBM mean volume growth during one month was 12.3 cm3 and corresponded to a volume augmentation of 2428% ( × 35). It is not possible to perform a study to evaluate non-treated GBM growth. In a recent study the authors reported a mean diameter growth of 3.3 mm/week [10]. We described the kinetic growing volume of three non-treated GBM (cases1, 2 and 3) of 12.3 cm3 (2428%) in one month. Greater growth kinetics was observed in the case of the GBM with a cystic component with a volume augmentation of 10465% in 2 months. Due to the poor effectives, the lack of data and the great diversity of the tumors published it is difficult to identify a real median time of progression of high-grade glioma. However, we showed with our cases the high growth of GBM at an early stage. With several criteria is enabling to evaluate the survival of patients with high-grade glioma: type, grade, size, site, age and KPS. A larger tumoral volume could lead to an incomplete resection with a worse prognosis [16]. 4.5. Immunohistochemical analysis and array CGH On immunohistochemical analysis, we observed no expression of mutant IDH1 R132H protein, highly specific marker of low-grade gliomas and secondary GBM [17] and a strong predictor of favorable prognosis and better overall survival. In our series, the absence of mutant IDH1 R132H expression indicates that these early stage GBM are de novo tumors. We also did not observe any internexin alpha expression or 1p/19q codeletion. Those markers are detected in oligodendrogliomas and have been associated with a favorable prognosis and a higher chemosensitivity [18]. Furthermore, in our series, three tumors displayed p53 protein accumulation. It has been shown that patients with WHO grade III diffuse glioma expressing p53 protein had shorter progression free and overall survivals [19]. We performed array CGH analysis on tumors some weeks after their initial early presentation. Out of three cases, two harbored genetic alterations typically observed in GBM, e.g. gain of chromosome 7, EGFR amplification, loss of chromosome 10, and loss of chromosome 9p. The remaining case presented no obvious genetic alterations on whole genome aCGH. 4.6. Management of early stage GBM Presently, two options have been reported in the literature when confronted with a possible early stage GBM: an MRI follow-up [3] or a routine biopsy [4,9]. Some authors, such as Rossi et al. (2010) are favorable to a close MRI follow-up. They recommend an MRI each month for three months [9]. However, an interval of one month may be too long in light of the rapid tumor progression observed in our series, highlighting the limitation of the MRI follow-up in these neoplasms. The second attitude consists of performing a biopsy. However, the indication of the biopsy should be carefully considered. In fact, Baehring et al. (2007) have reported eight patients who underwent a biopsy for suspicion of an early stage high-grade glioma [4]. Although tissue from the ADC-positive portion of the tumor was obtained, the diagnosis was not established in three cases. The authors gave no explanation as to why the samples were not contributive but the small size of the lesion may explain the absence of representative tissue. Because of the risk of rapid tumor growth and misdiagnosis on MRI, a third approach should be evaluated: an early resection of the lesion performed with an intra-operative histopathological examination. If the diagnosis of GBM is confirmed, a large resection should be considered. Logically, a total resection of the lesion should be feasible considering its small size. Moreover, some studies have shown that the extent of resection was associated with a longer
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survival, and one study demonstrated that an optimal resection could improve the progression free survival [20]. In conclusion, although our study is based on a small series, it demonstrates that diagnosis of primary GBM at an early stage is not uncommon but often remains unknown. The review of the literature enabled us to better define the neuroimaging features of these peculiar tumors. A prospective study would be interesting to assess whether early total resection of the neoplasm with large margins could improve patient outcome. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments We thank Professor Jean-Yves Delattre for providing the array CGH data. We also thank Mathieu Delion for help in the editing of this manuscript. Funding: No funding has supported this research.
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