Primary and secondary glioblastomas: can we differentiate
them with radiological and biological features?
Poster No.:
C-2241
Congress:
ECR 2013
Type:
Scientific Exhibit
Authors:
M. T. Fernández Taranilla, I. Herrera, V. Rodriguez Laval, B. M.
Melendez, M. M. Mollejo, R. G. G. Gonzalez, J. M. Garcia Benassi,
M. E. Capilla; Toledo/ES
Keywords:
Neuroradiology brain, Oncology, Molecular imaging, MRSpectroscopy, MR, MR-Diffusion/Perfusion, Radiobiology,
Neoplasia, Pathology, Biological effects
DOI:
10.1594/ecr2013/C-2241
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Purpose
In this study we evaluate primary and secondary glioblastomas (Gbm) and the
radiological, histopatologic and molecular features that have something to do with their
different origin.
INTRODUCTION
Glioblastoma is a WHO grade IV glial neoplasm according with the World Health
Organization , are the most frequent and malignant brain tumors in adults. They represent
the 69% of the astrocytomas and oligodendrogliomas brain tumors.
They may develop rapidly after a short clinical history and without evidence of
a less malignant precursor lesion (primary or de novo glioblatoma), or slowly
through progression from low-grade diffuse astrocytoma (grade II WHO) or anaplastic
astrocytoma (grade III WHO) that correspond to secondary gliobastoma.
These glioblastoma subtypes constitute distinct disease entities that affect patients
of different age, develop through different genetic pathways, show different protein
expression profiles and may differ in their response to radiotherapy and chemotherapy.
Because they are usually indistinguishable histologically , the distinction between primary
and secondary glioblastomas is currently based on clinical data. Tumors are considered
primary glioblastomas if the glioblastoma diagnosis is made at the first biopsy, without
clinical or histologic evidence of a preexisting, less malignant precursor lesion.
The diagnosis of secondary glioblastoma requires histologic evidence of a preceding
low grade or anaplastic astrocytoma. Only a 5% of cases were classified as secondary
glioblastoma however, the possibility could not be excluded that some secondary
glioblastomas rapidly progressed from less malignant lesions, escaped clinical diagnosis,
and were thus misclassified as primary glioblastomas.
IDH1 mutations have recently been identified in glioblastomas. Fig. 1 on page 3
and Fig. 2 on page 4. Interestly, studies showed that low-grade astrocytomas,
oligoastrocytomas, oligodendrogliomas, and secondary glioblastomas frequently (>70%
of cases) carry an IDH1 mutation. IDH1 mutations have been reported rare or absent in
primary glioblastomas and in other nervous system tumors.
Page 2 of 22
Recent studies, confirmed that in patients treated with radiotherapy and chemotherapy
the IDH1 mutation were the most significant factor predictive of a more favorable clinical
outcome.
Images for this section:
Table 1
Page 3 of 22
Fig. 1: Fig. 1: Relación del IDH mutado con las vías metabólicas del desarrollo de gliomas
y respuesta tumoral al tratamiento.Referencias: Modificación del esquema original de
Zhao S. et al. "Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity
and induce HIF-1 alpha". Science. 2009. Apr 10;32485924):261-5.
Page 4 of 22
Fig. 2: Fig. 2. IDH1 mutation in a secondary glioblastoma, notice that the only mutation
is at 132 codon which is related with a favorable prognosis.
Page 5 of 22
Methods and Materials
We evaluate retrospectively 61 patients with histologically confirmed glioblastoma, grade
IV of the WHO.
Tumors were considered primary glioblastomas if the glioblastoma diagnosis was made
at the first biopsy, without clinical or histologic evidence of a preexisting, less malignant
precursor lesion.
A diagnosis of secondary glioblastoma was made only in cases with histologic evidence
of preceding low-grade glioma or anaplastic glioma (grade II y III WHO). Fig. 3 on page
10
The mean age of glioblastoma patients was 62,7 years and the male to female ratio was
1,5:1.
Previous surgical Magnetic resonance image (MRI) was performed in every patient.
Exams were performed in two 1.5T MR imagin units ; Magnetom Avanto from Siemens
and Signa from General Electric.
PROTOCOLS
MR imaging sequences included, sagittal T1-weighted SE, T2- weighted fast spin-echo,
FLAIR (fluid attenuation inversion recovery) and DWI (b = 0, 500 and 1000 sec/mm2).
ADC maps were calculated. T1 SE sequences in axial, sagittal and coronal planes were
performed after the administration of 0.1 mmol / kg of gadolinium (Gd-DTPA).
In 39 of the 61 patitents a perfusion and spectroscopy (MRS) after the gadolinium
administration was performed.
The spectroscopy study with MRI (MRS) was performed with 135ms TE in every patients
and 35/135ms (TR/TE) in 25 of them. 3D MRS imaging multivoxel was perfomed in 17
patients while single-voxel MRS imaging was performed in the rest.
We analyzed the spectrum of the voxel with the following metabolites: Creatine (Cr),
N-acetyl aspartate (NAA),Choline (Cho), and Myo-inositol (mI)and the ratios of Cho/Cr,
Page 6 of 22
Cho/NAA, NAA/Cr y mI/Cr. The metabolite spectrum of this voxel was analyzed in the
solid tumor and the disadvantageous ratios were included.
The metabolite spectrum of this voxel was analyzed, without knowing the histologic
findings of biopsy specimen.
In MRI we evaluate the following characteristics:
•
•
•
•
•
Anatomical location
The highest diameter.
Depth: taking into account three differents locations: cortico-subcortical,
subcortical and deep:
Enhancement patterns:
•
Partial enhancement (PE)
•
Complete enhancement (CE)
•
•
Homogeneous
•
Heterogeneous
•
Ring like
Tumours where classified with a Partial Enhacement (PE) pattern when GBM were
surrounded by a well defined T1 hypointense and T2 hyperintense abnormality (but less
intense than cerebrospinal fluid on T2WI). We could find mass effect and arquitectural
distortion, as well as poor white / grey matter differentiation (Fig 4).
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Fig. 4: Figura 4.- Axial T2WI (A), FLAIR (B) ,T1-SE (C) and T1+C MR (D) in a patient
with secondary glioblastoma shows a postsurgery residual cavity, with the same
intensity signal as the cerebrospinal fluid in all the sequences(*). The tumoral area
(arrow) is hyperintense in T2WI (left frontal) with cortical thickening and poorly white /
grey matter differentiation. (D)Notice the partial enhancement postcontrast pattern
(arrow).
References: Diagnostic Radiology, Virgen de la Salud Hospital - Toledo/ES
This findings could be differentiated from surrounding edema, which typically is very
bright on T2WI and only affects white matter, and allows to better differentiate white and
grey matter. Tumours that didn't present PE characteristics where classified as Complete
Enhancement(CE) (Fig 5).
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Fig. 5: Figura 5.- Axial T2WI (A), FLAIR (B) ,T1-SE (C) and T1+C MR (D) in patient
with "de novo" glioblastoma. (D)Notice the irregular and peripherical enhancement
(arrow) with surrounding edema (*) in the white matter, without cortical thickening and
white/grey matter differentiation preserved (A, B arrows).
References: Diagnostic Radiology, Virgen de la Salud Hospital - Toledo/ES
TP 53 was studied with immunohistochemical techniques, considering positive when
the nuclear staining was higher than 50% of the tumoral nucleus.Inmunohistochemical
techniques and polymerase chain reaction(PCR) was used to study the IDH1.
Radiological and biological data were correlated with the origin of the tumor.
Survival was determined by the first diagnostic study with histologic evidence of Gbm.
Kaplan- Meier method was used to analysed the survival rates, with exclusion of patients
still alive in the moment of the performance of the study.
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Images for this section:
Fig. 3: Fig. 3: secondary Gbm developped through progression from low-grade diffuse
astrocytoma (A) (grade II WHO) where we can observed glial proliferation with nuclear
atypia, without mitoses, necrosis nor endothelial proliferation. Later on this lesion
progressed to anaplastic astrocytoma (grade III WHO) (B) where we observed glial
proliferation, nuclear atypia, mitoses (arrow) and finally in (C) a gliobastoma multiforme,
grade IV showed glial proliferation , nuclear atypia, mitoses (arrow), endothelial
proliferation and pallisading around necrotic foci (*) which is pathognomonic of Gbm.
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Results
Between the 61 Gbm evaluated, 4 of them were secondary Gbm and 55 primary or "de
novo" Gbm. We don't include in the study 2Gbm, one of them with a PNET (Primitive
neuroectodermal tumor) associated and the other in a patient with neurofibromatosis.
Survival was significant higher (p<0,05) in secondary Gbm with a mean survival time of
37,5 month versus 8,1 months in the primary ones.Fig. 6 on page 13.
The mean age at diagnosis was 64,6 in primary Gbm versus 51,7 in secondary Gbm
patients that was considered significant (p<0,05).
A positive correlation was found (p<0,001) between IDH1 mutation and the origin of the
tumor. The IDH1 mutations appears in the 75% of secondary Gbm, while it doesn't exist
in any cases of primary Gbm. Fig. 7 on page 13.
No significant correlation was observed between TP53 mutation and primary or
secondary Gbm origin. TP53 mutation exists in 66,7% of secondary and 36,4% of the
primary glioblastomas. Fig. 8 on page 14.
As far as the enhancement is concerned, we found significant differences
(p<0,05)between both groups. Every secondary Gbm showed parcial enhancement
(100%) while only in 16,4% of primary Gbm a partial enhancement was observed. Fig 9.
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Fig. 9: Fig 9.- Axial T2WI (A), FLAIR (B) and T1 C+ MR (C) show a left temporal
and insular mass (arrow) and surrounding signal abnormality with cortical thickening
and poorly cortico-subcortical differentiation (*). This lesion was classified as Partial
Enhacement pattern.
References: Diagnostic Radiology, Virgen de la Salud Hospital - Toledo/ES
Mostly primary Gbm showed a ring enhancement pattern (52,7%). Fig. 10 on page 16.
No significant differences were observed considering the maximus diameter of the tumor
or the anatomical location between primary and secondary Gbm.
As far as the deep location is concerned, 50% of secondary Gbm shows a corticosubcortical peripheral location versus 9% of the primary ones (p<0,05) Fig. 11 on page
.
The spectroscopy study with MRI (MRS) didn't showed significant differences between
Cho/Cr, Cho/NAA, NAA/Cr tumoral ratios.Fig. 12 on page 18.
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"De novo" glioblastomas reveals a 2,64 Cho/Cr mean ratio versus 2,54 mean ratio in
secondary Gbm.
A 100% of secondary Gbm showed higher mI/Cr ratio(0,57) than the average(0,5) while
only the 36,2% of the primary Gbm showed elevation of this ratio. Fig. 13 on page 19.
The mean mI/Cr ratio in primary Gbm were 0,48.
Images for this section:
Fig. 6: Fig 6.- Kaplan-Meier surviva curve, according to primary or secondary Gbm.
Notice the higher rates of survival in patients with secondary Gbm (2) that differs from
patients with primary or "de novo" Gbm (1).
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Fig. 7: Fig. 7: Percentage of IDH1 mutations in primary and secondary glioblastomas
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Fig. 8: Figura 8.- Secondary glioblastoma shows IDH 1+ nuclear staining and TP53
positive with nuclear staining higher than 50%.
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Fig. 9: Fig 9.- Axial T2WI (A), FLAIR (B) and T1 C+ MR (C) show a left temporal
and insular mass (arrow) and surrounding signal abnormality with cortical thickening
and poorly cortico-subcortical differentiation (*). This lesion was classified as Partial
Enhacement pattern.
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Fig. 10: Fig 10.- Enhancement pattern according to different types of Gbm. The 100% of
secondary Gbm shows a parcial enhancement. In contrast, primary glioblastomas mostly
shows peripheral ring enhancement.
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Fig. 11: Fig 11.- As far as the deep location is concerned, 50% of secondary Gbm shows
a cortico-subcortical peripheral location versus 9% of primary ones.
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Fig. 12: Figura 12.- 3D multivoxel spectroscopy study with MRI (MRS) with 135 TE
in a patient with secondary (A) and primary (B) Gbm. We didn't observed significant
differences between both groups as far as Cho/Cr, Cho/NAA y NAA/Cr ratios are
concerned.
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Fig. 13: Figura 13.- 3D spectroscopy MRI with 35 TE in patient with secondary (A) and
primary (B) glioblastomas. Notice the higher mI/Cr ratio in the first case, 0,53 versus 0,22
in the second.
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Conclusion
The genetic pathways leading to the evolution of primary and secondary glioblastoma are
different. Consequently these glioblastoma subtypes constitute distinct disease entities
that affect patients of different age and have different prognosis. Secondary Gbm appear
in an early age and have higher survival rates than those of primary glioblastoma.
We suggest that the IDH1 mutations are one of the best available molecular markers of
secondary glioblastomas.
Radiological features may help in the correct diagnosis, due to particular characteristics
like parcial enhancement, cortical location of secondary Gbm and ring enhancement on
primary ones.
Spectroscopy MRI doesn't seem to help to distinguish them, however mI/Cr ratio tends
to be higher in secondary Gbm.
The differentiation of both types could be important in the future to predict theraphy
response and to adapt treatments to the different subtypes of Gbm.
References
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Relationship between Gene Expression and Enhancement in Glioblastoma Multiforme.
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with Histopathologic Analysis of Resection Specimens. AJNR Am J Neuroradiol
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Glioblastoma Multiforme Regional Genetic and Cellular Expression Patterns: Influence
on Anatomic and Physiologic MR Imaging. Radiology 2010; 254:564-576.
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Personal Information
Maria Teresa Fernández Taranilla
3rd year Radiology Resident at Hospital Virgen de la Salud, Toledo, Spain; email:
[email protected]
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