Transcript AN UPDATE PRIMER ON MR SPECTROSCOPY IN BRAIN PEDIATRI C

IMAGING BRAIN TUMORS IN
NEWBORNS AND EARLY
CHILDHOOD: UTILITY OF
COMBINING MR TECHNIQUES
M. MORTILLA, M. ANTONELLO, C. CESARINI,
L. TASCIOTTI, C. FONDA
UNIVERSITY CHILDREN’S HOSPITAL A. MEYER
FIRENZE, ITALY
INTRODUCTION
In the childhood CNS tumors
are the leading
cause of cancer-related death.
In the last 20 years the advances in neuroimaging,
neurosurgery, radiation therapy and chemotherapy
have considerably improved the long term survival
of children with brain tumors.
Conventional MR images show definite details of
brain tumor location, extension and morphological
characteristics. Therefore MR imaging is widely
used in the diagnosis and follow-up of pediatric
patients with brain tumors.
Since conventional MRI does not provide information
about tissue chemistry and the interpretation of
these images may lead to poor estimation of the
extent
of
active
tumor,
non
conventional
techniques, such as diffusion images and proton
spectroscopy, may be used contributing to more
accurate diagnosis, prognostication and treatment
planning.
Tissue diagnosis remains the gold standard.
The purpose of the study is to find a role of
Diffusion-weighted Imaging (DWI) and proton
Spectroscopy in characterizing intracerebral masses
and finding a correlation between these techniques
and histologic analysis of tumors.
PATIENTS & METHODS
62 patients affected with brain tumors aged
1 month-6 years, were studied with a 1.5T
MR scanner (Eclipse, Philips) operating at
27mT/m gradient strenght and 40 mT/m/ms
slew rate. A quadrature head coil was used.
T2w SE images, FLAIR, T1w SE pre and
post Gadolinium injection and sometimes GE
T2* were obtained.
Proton Spectroscopy studies included single
voxel studies (PRESS TE 40/135/270ms,
STEAM TE 20ms) and/or CSI (PRESS TE
135/270.
Spectroscopy acquisition were performed before the
injection of the contrast media.
Eight children were able to undergo to the MR without
need of sedation despite the long duration of the
exam (50-60 minutes).
The other children were sedated with different
modalities regarding weight, age and critical
conditions: patients up to 18 months of age (if the
weight was below 10Kg) were sedated with chlorale
hydrate (50-100 mg/Kg), while from 18mo. to 6yrs.
patients were sedated using Sevoflurane through
laringeal mask or, rarely, with barbiturates i.v.
Echo planar Imaging of Diffusion were obtained
with sensitization along the slice select, read
out and phase encoding axes (b- value of
800/1000/1200) with Echo Planar Single Shot
sequences (TR 6450ms, TE 145.8ms, FA 90°,
5mm/1mm slice thickness/gap, 81x81 > 128x
128 reconstruction matrix, 1 NEX, chemical
saturation at FA 180°, FAT saturation) with a
total acquisition time of 32 seconds/15 slices.
In all patients a set of 3 images along the
long
orthogonal
axes
of
gradient
sensitization were obtained and the DWI
TRACE
images
were
post-processed.
Apparent Diffusion Coefficient (ADC) images
along the same orthogonal axes were also
obtained and synthetic ADC map was
produced (ADC TRACE.
ADC values are expressed as a number x
10-3mm2/sec.
Multivoxel
(CSI) were acquired with PRESS
sequence, TR 1500ms, TE 135ms, FA 90°,
thickness 1-1.5 cm, FOV 15 to 20cm.
Chemical shift imaging matrix size 16x16, signal
averages 1/2 with 1 slice per batch.
Single voxel were acquired with PRESS sequence,
TR 1500/2000ms, TE 270/135/40ms and with
STEAM TE 20ms, FA 90°; acquisition volume
from 20x20x20mm, signal averages 128 and
reference averages 8.
Most of the tumors underwent to surgery excision
and the specimens were analyzed by an expertise in
pathology in order to make diagnosis following the
WHO classification and to determine cell counting
expressed as mean value (m.v.) over an are of
0.083mm2.
Some tumors were biopsied only, such as germinoma
because they are highly responsive to therapy.
Biopsy or surgical excision was not performed when
the tumor arised from non resectable regions
(hypotalamus, brainstem,..)
OUR CASES
•Craniopharingioma
•Low grade glioma (WHO I)
•Glioma WHO II
•High grade glioma
•Pylocitic astrocytoma
•Medulloblastoma (MB-PNET)
•Germinoma
•Subependimal gigantic astrocytoma
•Ganglioblastoma
•Ganglioglioma
•Dysplasia
•DNET
•Teratoma
•Metastasi
•Altri
5
11
2
1
10
11
1
2
1
1
3
2
1
1
10
Diffusion-weighted Imaging
It has been reported that the ADC characterizes
the
biophysical
characteristics
of
tissue
microstructure and microdynamics and that it
provides information (based on pathophysiologic
characteristics) that differs from that obtained
with contrast-enhancing imaging.
It has been suggested that the minimum ADC value
of high-grade gliomas is significantly higher than
that of low-grade gliomas and that low ADC values
were found in areas of increased cellularity.
Others have suggested that the ADC may assist in the
early detection of responses to anticancer therapy,
because an increase in ADC values has been noted after
treatment.
DWI measures the molecular mobility of extracellular
water,alterations in water mobility appear to reflect
treatment-induced changes in tissue structure.
Current understanding is that water diffusion increases
acutely in tumor responsive to therapy. This precede
changes in tumor volume.
1H-MRS
(proton magnetic
resonance spectroscopy)
1H-MRS
(Magnetic
Resonance
Spectroscopy) provides a qualitative and
quantitative evaluation of brain chemistry
In a proton
spectrum at 1.5T the
metabolites are spread out between 63
and 64 MHz, and near 300 MHz at 7T
The resonant frequencies are expressed
in part per million (ppm), and are read
from right to left
1H-MRS
Fat and water are eliminated, because their
peaks are to high and in spectrum scaling the
brain metabolites would be invisible
The water suppression is obtained with
CHESS (Chemical Shift Selective) or IR
(Inversion Recovery) techniques
The peaks are separated into the individual
frequencies through a Fourier Transform
The magnetic field felt by the Protons in
different molecules depends on electron
clouds related to their different molecular
position -> different chemical shift -> spread
of single peaks over the ppm or hertz scale
Sequences in 1H-MRS
STEAM (Stimulated Echo Acquisition Mode): 90o
refocusing pulse, short echo time, less signal-to-noise
ratio
PRESS
(Point
Resolved
Spectroscopy):
180o
refocusing pulse, short and long echo time
With short echo time (TE 20-40 ms) metabolites of
both short and long T2 are visualized
With long echo time (TE 270 ms) only metabolites
with long T2 are seen . Echo Time of 135 ms allows the
separation of lactate doublet from lipids peaks with
phase inversion.
TE 65 ms increases sensitivity in lipid detection
nulling lactate
voxel
MR Spectra may be acquired with a single
voxel localized in region of interest (normal or
pathological) with variable volume (usually of
2x2x2 cm or more). Small volume are
characterized by less signal to noise ratio.
Large volumes experience higher averaging and
are not indicated for higher resolution data
collection, but only for mean value in a defined
area
multivoxel
MR Spectra may be acquired within a brain
slice in 2D acquisition or more slices in 3D
acquisition) with variable matrix and variable
volume (usually of 1x1x1 cm or more) Small
volume of voxels experience lower averaging
than single voxel with larger volume. Chemical
Shift Imaging (CSI) may create the
metabolite maps with direct visualization of
peak concentration
Magnetic field inhomogeneity, insufficient
shimming and lipids contamination frequently
alter the quality of multivoxel spectra.
Many metabolites may be identified in
the proton magnetic resonance at 1.5
tesla, NAA, Cho, Cr, Lactate, myoInositol,
Lipids
are
currently
evaluated
In the following slides there is a list
brain peaks:
List of metabolites that can be individualized
by 1H-MRS
N-acetyl methylgroups
(NAA –N-acetylaspartate and NAAG – Nacetylaspartylglutamate)
Methyl and Methylene protons of total creatine (Cr +PCr)
Trimethylammonium groups –Choline containing (Cho)
Myo-Inositol (mI)
Glycine co-resonating with main mI peak (Gly)
Glutamate & Glutamine with a and b-/g- protons (Glu/Gln)
Glucose
Scyllo-inositol
Lactate
GABA
Glutathione
Taurine
Homo-carnosine
Phospho-ethanolamine
Macromolecules
Lipids
Resonance intensities
expressed in ppm at 1.5T
–
–
–
–
–
–
Lactate/lipids
NAA
Glx
Cr/PCr
Cho
mI
1.33
2.02
2.2-2.4
3.02
3.22
3.56
Control 5 yrs old: CSI PRESS TE 135ms
NAA(N-acetyl aspartate): free
aminoacid, high CNS concentration
(just less to glutamate)
in adults in neural tissue, axons and
dendrites
in brain maturation also in
oligodendrocytes type 2 and in non
neuronal cells (mast cells)
used as neuronal marker
Cho (choline - N(CH3)3 GPC,PC) cellular
membrane turnover marker
High in tumors, demyelinating
processes, inflammation
Cr ( creatine - Cr + PCr = k),
reference internal due to its
stability, marker of byproducts of
energy chains >ATP
Lac (Lactate) expresses the
anaerobic metabolism
mI (myo inositol) glial pool
marker. Small amounts from
glycine
Glu or Glx (glutamate)
neurotransmitter, intermediate
in aminoacid catabolism
Gln (glutamine) metabolism of
glutamate glial marker
PRESS TE 135ms
STEAM TE 20ms
 Cho
 Lac
 NAA
b
a
c
4 years old girl:
pilocytic astrocytoma
Lactate in solid nodule
High choline peak
In P.A. the Choline
Levels are usually below
3.0, while in MB-PNET
are usually higher
Mean ADC value
1.68 10-3 mm2 /sec
DWI TRACE
ADC TRACE
215 m.v.
4y.o. girl:
pilocytic astrocytoma.
Histologic surgical
specimen and cell density
counting over mixoid (185 cells)
and more compact (215 cells)
portion of the tumor.
185 m.v.
Nr. of cell: 0.083mm2
PRESS TE 270ms
PRESS TE 135ms
Boy, 13 months
BRAINSTEM GLIOMA
Cho/Cr
NAA/Cr
Lac
: MRS data indicates that it could
be a pilocytic astrocytoma
6 years old boy: Brainstem glioma
1st MRI:
diagnosis
(WHO I)
b= 800
2nd:after
chemo
High Cho
PRESS TE 270ms
3rd:6mo.
after Stop
Therapy
Higher Cho,
FLAIR
low NAA,
high lac
C.E. FSE T1
ADC TRACE
DWI TRACE
At diagnosis
DWI
ADC
ADC TRACE
b = 800
DWI TRACE
ADC TRACE
After chemotherapy
6 years old girl: glioma of the midbrain (WHO I)
Mild reduction of NAA/Cr and mI/Cr
PRESS TE 40ms
Boy, 4 years old:
Astrocytoma WHO II-III
Important reduction of
NAA/Cr and moderate
increase of Cho/Cr
b
VOXEL 8
STEAM TE 20 ms
CSI PRESS TE 270 ms
a
6 years old boy: medulloblastoma
CSI PRESS TE 270ms:
high choline peak (Cho/Cr 4.09),
low NAA intensity signal.
Small amount of lactate.
STEAM TE 20ms:
evident lipids peak.
a
Mean ADC value
1.2 10-3 mm2 /sec
Medulloblastoma.
DWI
TRACE
ADC
TRACE
750 m.v.
Nr. of cell: 0.083mm2
PRESS TE 135ms
b
STEAM TE 20ms
6 years old girl.: PNET-MB
..
a
STEAM 20: evident mI,
lipids and Glx peaks
PRESS TE 135ms: high choline
peak (Cho/Cr 12.4)
and low NAA intensity signal.
STEAM TE 20ms
PRESS TE 135ms
11 months old girl: pinealoblastoma.
PRESS 135: high choline peak
(Cho/Cr 2.6),
low NAA signal intensity.
Presence of lactate.
STEAM 20:
evident lipids and mI peaks.
Mean ADC value
0.4 x 10-3 mm2 /sec
DWI TRACE
Pinealoblastoma
ADC TRACE
900 m.v.
Nr. of cell: 0.083mm2
6 years old girl: choroid plexus carcinoma.
Mean ADC value
1.0 10-3 mm2 /sec
All metabolites, included
Creatine, but Choline are
reduced Cho/Cr 31.5
PRESS TE 135ms
reduced Cr
neoplasm do not
produce NAA
5 years old girl: germinoma.
PRESS TE 135ms
high lipids signal.
Mean ADC value
0.57 10-3 mm2 /sec
Nr. of cell: 0.083mm2
320 m.v.
Cho/Cr 6.1
Lac/Cr 6.8
NAA/Cr
CSI PRESS TE 135ms
PRESS TE 270ms
Girl, 23 months
metastasis from rabdomyosarcoma
Cortical Dysplasia
TAYLOR TYPE
Increased mI/Cr ratio
STEAM TE 20ms
PRESS TE 40ms
STEAM TE 20ms
Boy, 20 months: Tuberous sclerosis
Increased mI/Cr ratio
A
D
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(C
a
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ADC vs.Cells
number
correlation
C
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CELLS
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id
f
.
A
D
C
Germinoma
JDGG
Pinealoblastoma
PNET
more highly cellular >
smaller intercellular
spaces > lower ADC
MB-PNET
Pylocitic Astrocytoma (solid portion)
BRAIN ABSCESS
vs. TUMOR
a
b
DWI
ADC
DWI is able to discriminate between abscesses and tumors:
a) brain abscess; b) supratentorial ependymoma
Boy, 6 years old: brain abscess
Most of the metabolites
are reduced.
Lipids and lactate are
present
Conclusions
Brain tumors in children are highly heterogeneous for
histology, prognosis and therapeutic response.
Diagnosis and therapy of those, most of which are low
grade, can be complicated because of their frequent
adjacent location to crucial structures that limits
biopsy.
The utility of combining data from biologically important
intracellular molecules, obtained with proton MR
spectroscopy and from water mobility, obtained with
diffusion imaging, is clearly addressed to increase the
diagnostic accuracy in determining the clinical grade of
pediatric brain tumors.
DWI enable to better differenciate between lowgrade and high-grade tumor: high-grade gliomas
have lower ADC values than low-grade gliomas.
ADC maps are easily generated from routine fast
diffusion-weighted imaging by use of software
available on many MR systems.
ADC may be a more direct indicator of changes in
the brain than are other physical parameters. The
degree of diffusion is strongly affected by
microscopic biological structures such as the
number, type and spatial arrangement of cells.
These structures create barriers to the free
diffusion of water so changes in diffusion may more
directly reflect changes occurring within and
between cells.
It still debating if ADC measurement can be used to
determine the extent of tumor infiltration and to
differentiate infiltration from peritumoral edema. It
has been suggested that tumor infiltration is
characterized by lower ADC values than edema.
In our experience we found that quite often this is
true but we always prefer to be cautious adding
spectroscopy data when is possible to perform CSI.
We also utilize high-b-value DWI that increase the
anisotropy so is more accurate in the assessment of
infiltration. Since infiltration occurs within and along
white matter tracts, diffusion tensor imaging may
yield more useful information.
Proton MR Spectroscopy enables the measurements
of multiple chemical metabolites in normal and
abnormal brain parenchyma.
Cho/Cr or Cho/NAA in a lesion correlate with higher
cellular proliferation rate and reflect the presence
of a more malignant and rapidly growing tumor. It is
necessary to correlate MRI data since pilocytic
astrocytoma has high Choline and lactate despite it
is considered benign: usually Cho/Cr ratio is less
than 3.
NAA is considered a neuronal marker, which
decreases with replacement of neurons by tumor (or
other non-neuronal tissue, including necrosis).
In choroid plexus carcinoma a very low NAA/Cr is
characteristic since the tumor does not produce
NAA.
MRS can be used to follow tumors over time, since
patients can serve as their own control after
obtaining a baseline scan.
CSI may be useful in monitoring the surgical scar:
elevation of Cho/Cr ratio is index of a relapse. We
have found this index reliable mostly in anaplastic
ependymoma.
It has been suggested that children with higher total
creatine levels are more responsive to radiation or
chemotherapy.
In our experience children with low-grade gliomas
that have significantly higher baseline Cho/Cr ratio
have more chance to have tumor that progress over 2
years than those that have stable tumors.
Lactate is no more considered an indicator of
malignancy since it is found in benign tumors such as
pilocytic astrocytoma.
Lipids may be detected in enhancing and non
enhancing tumor regions. For a reliable detection of
lipid peak it would be better to use acquisition
protocols with a TE 65ms that null lactate peak.
Lipids represent microscopic tumor cell necrosis or
membrane breakdown that may precede necrosis.
Lipids may be present in viable tumor, presumably
because of poor perfusion and hypoxia and they
undergo major intensity changes during apoptosis.
They are found also in radiation necrosis.
Because glial tumors are grade according to their
cellularity, proliferative activity and degree of
necrosis, Cho mapping (increased cellularity and
proliferative activity) may added value to MRI in
childrens with brain tumors, especially when it is
combined with lipid mapping (necrosis and/or
apoptosis).
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