BRAIN

ABBREVIATION KEY
BBB ⫽ Blood-Brain Barrier
CBF ⫽ cerebral blood flow
CBV ⫽ cerebral blood volume
DCE ⫽ dynamic contrast-enhanced
DSC ⫽ dynamic-susceptibility
contrast
FDA ⫽ US Food and Drug
Blood-Brain-Barrier Imaging in Brain Administration
GBM ⫽ glioblastoma multiforme
Tumors: Concepts and Methods HIF-1␣ ⫽ hypoxia-inducible factor
IRF ⫽ impulse residue function
kep or kb ⫽ reverse transfer constant
Rajan Jain, MD, Brent Griffith, MD, Jayant Narang, MD, Tom Mikkelsen, MD,
Ktrans ⫽ forward transfer coefficient
Hassan Bagher-Ebadian, PhD, Siamak P. Nejad-Davarani, PhD, James R. Ewing, PhD, MSIVP ⫽ maximum slope of
and Ali S. Arbab, PhD, MD enhancement in the initial vascular
phase
MVCP ⫽ microvascular cellular
proliferation
ABSTRACT MVD ⫽ microvascular density
Malignant gliomas are often very heterogeneous tumors with complex vasculature, fre- nIAUC ⫽ initial area under the
quently exhibiting angiogenesis and increased vascular permeability. In vivo measurement normalized time-intensity curve
of the tumor vessel permeability can serve as a potential imaging biomarker to assess tumor nSDEP ⫽ normalized slope of the
delayed equilibrium phase
grade and aggressiveness. It can also be used to study the response of tumors to various
PCT ⫽ perfusion CT
therapies, especially antiangiogenic therapy. Central to the concept of permeability is a PS ⫽ permeability surface-area
thorough knowledge of the BBB and its role in brain tumors and angiogenesis. Much work product
has been done in the past to understand the structural/molecular composition of the BBB PSR ⫽ percentage signal-intensity
and the role it plays in various pathologic processes, including brain tumors. Various imag- recovery
rPSR ⫽ relative percentage signal-
ing techniques have also been used to evaluate BBB leakiness in brain tumors because
intensity recovery
higher tumor vascular leakiness is known to be associated with higher grade and malignant rCBV ⫽ relative cerebral blood
potential of the tumor and hence poor patient prognosis. These imaging techniques range volume
from routine postcontrast T1-weighted images to measurement of vascular permeability SDF-1 ⫽ stromal derived factor-1
using various quantitative or semiquantitative indices based on multicompartment pharma- TDLs ⫽ tumefactive demyelinating
lesions
cokinetic models. The purpose of this article is to discuss BBB anatomy; various clinically
TVA ⫽ total vascular area
available imaging techniques to evaluate tumor vascular leakiness (perfusion imaging), VEGF ⫽ vascular endothelial growth
including their advantages and limitations; as well as a brief discussion of the clinical utility factor
of measuring vascular permeability in brain tumors. We will also discuss the various perme- VEGFR-2 ⫽ vascular endothelial
ability-related indices along with the pharmacokinetic models to simplify the “nomenclature growth factor receptor-2

soup.”
INTRODUCTION
The BBB consists of a complex of capillary
endothelial cells, pericytes, and astroglial
and perivascular macrophages, serving as
an effective physical barrier to the entry of
lipophobic substances into the brain. How-
ever, in many brain tumors, as well as other
disease processes, the BBB becomes inter-
rupted. It is this disruption and other
changes to the BBB in tumors that contrib-
ute to contrast enhancement on imaging
and serve as a potential surrogate imaging
marker.
Malignant gliomas are hypervascular
tumors with very heterogeneous and com-
plex vasculature, which is regulated by
multiple angiogenic cytokines. Tumors
larger than 1–2 mm1 cannot grow by rely-
ing on passive transport of nutrients and
oxygen. Further growth is supported by
angiogenesis promoted by proangiogenic
factors; the most important among those is
VEGF.1-4 Animal studies indicate that neo-
angiogenesis and increased vascular per-
meability are essential for the survival and
proliferation of tumor cells.5 An under-
standing of this process is essential because
it provides the physiologic basis for perfu-
sion imaging in tumors. Tumor angiogen-
esis involves a multitude of controlled sig-
naling cascades and structural changes that
occur in a defined order and continue until
Received August 1, 2011; accepted
after revision November 27.
From the Division of
Neuroradiology, Department of
Radiology (R.J., B.G., J.N., A.S.A.)
and Departments of Neurosurgery
(R.J., T.M.) and Neurology (S.P.N.-
D., J.R.E., H.B.-E.), Henry Ford
Health System, Detroit, Michigan.
Please address correspondence to
Rajan Jain, MD, Division of Neuro-
radiology, Departments of Radiol-
ogy and Neurosurgery, Henry Ford
Health System, 2799 West Grand
Blvd, Detroit MI 48202; e-mail
rajanj@rad.hfh.edu
http://dx.doi.org/10.3174/ng.2120028

48 兩 Neurographics 2:48 –59 June 2012 www.neurographics.com

Fig 1. Tumor angiogenesis involves a multitude of controlled signaling cascades and structural changes.
a new vasculature has been formed (Fig 1). The process
usually begins when tumor cellular growth outgrows its
blood supply leading to hypoxia and low intratumoral pH.
These local factors, in turn, lead to expression of HIF-1␣,
which, in conjunction with genetic pathways (phosphoino-
sitide 3-kinase, isocitrate dehydrogenase-1—they help sta-
bilize HIF-1␣ by decreasing its degradation), promote the
formation of proangiogenic mediators (angiogenic switch)
such as VEGF and SDF-1.1 The effects of VEGF and SDF-1
lead to formation of immature and leaky blood vessels,
which results in increased permeability. This increased per-
meability allows extravasation of plasma and plasma pro-
teins and deposition of proangiogenic matrix proteins, ul-
timately resulting in microvascular cellular proliferation
(MVCP). In addition to VEGF-related pathways, there are
various non-VEGF pathways (growth factors, fibroblast
growth factor, platelet-derived growth factor, and Notch
surface receptors), which also result in endothelial cell up-
regulation, proliferation, and increased permeability.6
As these pericyte-poor new vessels (called “mother ves-
sels”) enlarge and give rise to daughter vessels through a
complex series of endothelial rearrangements, MVD and
total vascular area (TVA) increase; this change leads to
further increased permeability (Fig 2). Finally with vessel
maturation, the number and area of blood vessels continue
to increase to a greater extent than vessel leakiness— evolv-
ing into a very heterogeneous tumor with various regions
probably demonstrating different mixtures of vessel char-
acteristics and angiogenesis. Given this heterogeneity, not
only is an in vivo estimate of the hemodynamics (tumor
blood volume) important, but assessment of the physiologic
Fig 2. Pericyte-poor new blood vessels, mother vessels (arrowhead),
enlarge and give rise to daughter vessels (arrows) through a complex
series of endothelial rearrangements, increasing MVD and TVA, leading
to increased MVCP and permeability.
measures (vascular leakiness) is of utmost importance as
well. This has become particularly true recently with the
increasing use of oncologic imaging, the increasing use of
newer antiangiogenic agents, and increasing emphasis on
the development of quantitative imaging biomarkers.
Various perfusion imaging techniques have been used in
animals and human subjects to estimate tumor vascular
permeability, using either quantitative or semiquantitative
measures. The remainder of this review will focus on the
various clinically available permeability imaging modali-
ties/techniques, their advantages and limitations, and the
clinical utility.
Measuring Tumor Vascular Permeability: Why is it
important?
Tumor blood vessels have defective and leaky endothelium,
thereby allowing these abnormal tumor vessels to serve as
potential markers for assessing tumor grade and aggressive-
ness. Thus, in vivo measurement of tumor-vessel permea-
bility may serve a number of purposes, including but not
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Table 1ⴚ Commonly used permeability indices: definition and important details
Permeability Indices Definition Important Details

PS Characterizes the diffusion of contrast agent from the blood
vessels into the interstitial space due to deficient or leaky
BBB; it is a product of permeability and capillary surface
area
Ktrans Measures rate of flux of contrast agent from the intravascular
compartment into the extracellular extravascular space
and is dependent on both vascular permeability and
capillary surface area
kb or kep Measures backflow of contrast agent from the extracellular
extravascular compartment into the intravascular
compartment
Note:—Ve indicates extravascular extracellular compartment.
• Usually measured using CT perfusion
• Commonly used units: mL/100 g/min
• Usually measured using DCE MR imaging
techniques
• Commonly used units: minute⫺1
• Because of dependency on both vascular
permeability and capillary surface area,
in states of very high permeability (eg,
very leaky tumors), Ktrans is only limited
by blood flow and hence predominantly
measures blood flow; whereas in states
of very low permeability, contrast agent
cannot leak out, so Ktrans measures
permeability
• Usually measured using DCE MR imaging
techniques
• Commonly used units: minute⫺1
• Its measurement is based on a number of
factors including the volume of Ve, as
well as the interstitial pressure
trans
K
Ve ⫽
Kb

limited to grading of tumors, because increased permeabil-
ity is associated with immature blood vessels, which are
seen with angiogenesis, and with assessing response to ther-
apy because changes in permeability may provide a means
of assessing treatment response, especially when antiangio-
genic therapy has been used.7,8 Measuring tumor vessel
permeability could also help in better understanding the
mechanism of entry of therapeutic agents into the central
nervous system, which could be very important for devel-
opment of methods to selectively alter the BBB to enhance
drug delivery.9
Tumor Vascular Permeability: What are we measuring?
Permeability is related to the diffusion coefficient of con-
trast agents in the assumed water-filled pores of the capil-
lary endothelium. The diffusion flux of contrast agent
across the capillary endothelium is dependent on both the
diffusion coefficient and the total surface area of the pores.
PS characterizes the diffusion of some of the contrast agent
from the blood vessels into the interstitial space due to
deficient or leaky BBB and is used as a means of quantifying
the “leakiness” of the regional vasculature (Table 1). PS is
computed from the IRF. Contrast agent diffusion appears in
the IRF as a residual enhancement that occurs after the
initial impulse response and that decreases exponentially
with time. The IRF is used to estimate the first-pass fraction
of contrast agent that remains in the tissue, the extraction
fraction, E.10 The extraction fraction is related to the rate at
which contrast leaks out of the vasculature via the following
relationship:
PS
⫺F,
E⫽1⫺e
where PS is the permeability surface-area product and F is
flow. The PS product has the same dimensions as flow (mil-
Ⲑ
liliters/100 gram/minute), and thus the ratio PS F is dimen-
sionless. In physiologic terms, PS is the rate at which con-
trast agent flows into the extravascular tissues; it is related
to another commonly stated parameter of vascular leakage,
Ktrans, by the following equation:
trans⫽ExF,
K
where Ktrans is the forward transfer constant with, again,
the same dimensions as flow (unit commonly used is min-
ute⫺1) (Table 1). It is easily demonstrated that if PS F ⬍⬍ 1
(or F ⬎⬎ PS, which is usually the case in high-grade leaky
Ⲑ
brain tumors because blood flow is usually very fast), then
Ktrans ⬵ PS. In normal cerebral vasculature, PS is negligible
for all contrast agents presently in clinical use.
However, in brain tumors, estimates of Ktrans are com-
plicated by the fact that there is backflow of the contrast
agent measured by kep or kb from the extravascular com-
partment into the intravascular compartment, which is
based on a number of factors including the volume of ex-
travascular extracellular compartment and the interstitial
pressure (Fig 3 and Table 1).

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Fig 3. Transfer of contrast agent from intra- to extravascular compartment (forward Ktrans). Backflow of contrast agent (kb) from the extravascular into
the intravascular compartment.
Fig 4. Heterogeneity of tumor angiogenesis is manifest by differences in perfusion parameters in various regions. Different regions of interest show
high CBV and high PS, high CBV and low PS, and high PS and low CBV, suggesting that CBV and PS represent different aspects of tumor vasculature and
angiogenesis.
Understanding Angiogenesis and Its Correlation with
Perfusion Parameters
As already mentioned, angiogenesis is an essential aspect of
tumor growth because it provides tumors a means of main-
taining blood supply. In the initial phase of angiogenesis,
vessel leakiness, which is measured by permeability (PS or
Ktrans), increases more than the total number and area of
blood vessels, which are measured by blood volume. How-
ever, as the vessels mature, the total number and area of
blood vessels increase more than vessel leakiness, evolving
into a very heterogeneous tumor with regions showing dif-
ferent mixtures of vessel characteristics and angiogenesis.
This heterogeneity is manifest by differences in tumor blood
volume and permeability, which do not necessarily increase
or decrease in tandem and probably represent 2 different
aspects of tumor vasculature (Fig 4).
Tumor Vascular Permeability: Dynamic Contrast-
Enhanced Imaging Techniques
While postgadolinium T1-weighted MR imaging gives a
rough estimate of the disruption of BBB by providing a
snapshot in time and has been used in the past for quanti-
tative estimation of permeability, dynamic imaging acqui-
sition provides a better estimate of vascular permeability.11
Various noninvasive dynamic contrast-enhanced imaging
techniques including MR imaging12-14 and CT perfu-
sion15,16,17 have been used for in vivo estimation of tumor
vascular leakiness in brain tumors (Table 2). DCE MR im-
aging data acquisition primarily involves 2 techniques; 1)
T1-weighted acquisition, which is based on the fact that
increase in the rate of T1 relaxation is proportional to the
concentration of the contrast agent from which a time-
concentration curve can be generated and is tracked during
a longer time period (5–10 minutes); and 2) first-pass T2*-
based acquisition, which uses susceptibility-weighted imag-
ing to generate a time-concentration curve during the initial
45– 60 seconds of circulation. Both DCE MR imaging tech-
niques have advantages and disadvantages; however, the
major limitation is a nonlinear relationship of contrast
agent concentration with tissue signal intensity.
Dual-echo gradient echo perfusion-weighted imaging18
is based on a simple 2-compartment kinetic model19 and
has been used to measure vascular permeability and to cor-
rectly estimate blood volume in lesions/tumors with defi-
cient or absent BBB. Several studies have found a correla-
tion between increased vascular permeability and higher
tumor grade.14,20-23 However, MR perfusion techniques
have certain limitations because of the nonlinear relation-
ship of the signal intensity with the contrast agent, both for
dynamic contrast-enhanced imaging with T1-weight-
ing24-27 and for dynamic susceptibility contrast imaging
with T2- or T2*-weighting. In the latter case, if the contrast
agent remains intravascular, the method is widely accepted
as a relative estimate of CBF and CBV, though there is a
possibility for artifacts because of difficulties in assessing
the shape and timing of the arterial input function.28-34
However, in cases with leaky BBB, there is substantial leak-
age of contrast agent from the intravascular to extravascu-
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Table 2ⴚ Comparison of various DCE imaging techniques used for in vivo estimation of vascular leakiness in brain tumors
CT Perfusion
Relationship between contrast agent
concentration and tissue attenuation Linear
Advantages • CBV and PS obtained
in same exam
• Availability of AIF
• Robust data
• Absolute values
Limitations • Radiation exposure
• Iodinated contrast
• Separate exam
• Limited coverage
Note:—AIF indicates arterial input function.
lar space and a strong and competing T1 contrast effect is
often noticed in areas of pathology.
To minimize the competing T1 contrast, preloading with
contrast agent has been proposed,19 with some success.
However, this approach does not allow an estimate of
Ktrans. An alternative approach has also been proposed to
decrease the T1 effect,35 which uses a slower TR, lengthen-
ing the TR of the experiment and undermining the estima-
tion of CBF, thus yielding only estimates of CBV and Ktrans.
A further refinement, allowing the estimate of blood volume
and producing an index of transfer constant, has been sug-
gested,19 and a dual-echo gradient echo sequence18 also
shows some potential for an index of blood volume and
transfer constant. Despite the partial success of these rapid
imaging studies, in contrast to PCT, there does not appear
to be an MR imaging technique that will reliably quantify
CBF, CBV, and PS/Ktrans in one experiment.17 PCT36,17 has
been shown to be very robust due to the linear relationship
of contrast agent concentration with tissue attenuation.
However, its clinical impact is limited due to the fact that it
requires an additional examination by using iodinated con-
trast and the risk of radiation exposure. On the other hand,
MR imaging has been the standard of care, and adding a
DCE-MR imaging acquisition does not add significant
burden.
Tumor Vascular Permeability Imaging: Limitations and
Controversies
Low spatial resolution has been one of the major limitations
of the available clinical imaging tools, which limits a de-
tailed assessment of the complex and heterogeneous vascu-
lar microenvironment.37,38 Another major limitation has
been the use of the currently FDA approved low-molecular-
weight CT and MR imaging contrast agents (⬃0.5– 0.9
kDa) for human subjects, which might limit the accurate
differentiation of vascular permeability and blood vol-
ume.39 Permeability measurements depend on the leakage
of particles from the blood to the interstitial space; it is
52 兩 Neurographics 2:48 –59 June 2012 www.neurographics.com
DSC T2* Perfusion DCE T1 Perfusion
Nonlinear Nonlinear
• Routinely available • Purported to be the most reliable
• Quick and easy acquisition • Fewer artifacts
• Susceptibility artifacts • Flawed AIF
• Non-availability of AIF • Difficult/complex modeling required
to derive indices
• Only rCBV estimates; permeability • Need to calculate baseline T1
estimates are questionable
• Magnetic field inhomogeneities
hypothesized that low-molecular-weight contrast agents
leak relatively easily from the blood into the interstitium.
This might also lead to overestimation of the permeability,
which will be influenced by and will approximate tumor
blood flow.40
On the other hand, high-molecular-weight contrast
agents leak from the vessels and move through the intersti-
tium with relative difficulty and are hence flow-indepen-
dent. Therefore, macromolecular permeability and vascular
volumes may be best measured by high-molecular-weight
contrast agents.40 Even though CT and MR imaging con-
trast agents do not differ much in their molecular weight,
different charges of nonionic CT contrast compared with
ionic MR imaging contrast may also be responsible for the
differences in permeability measured with these 2 modali-
ties. Blood pool contrast agents, particularly albumin-bind-
ing agents (such as gadofosveset, ABLAVAR; Lantheus
Medical Imaging, North Billerica, Massachusetts; which
was recently FDA-approved for MR angiography of periph-
eral vascular disease) may solve some of the issues associ-
ated with easy leakage of extracellular contrast agents into
the interstitium.
Another controversial aspect of measuring permeability
with various perfusion imaging techniques has been the
scanning time. It is presumed that delayed permeability due
to slow leakage of contrast from a leaky blood vessel may
not be accurately measured with the first pass of the con-
trast agent by using a 45- or 60-second scanning time20,41
and can be measured only with longer acquisition times.16
However, there is no consensus or criterion standard for the
optimal acquisition time. Gliomas, particularly high-grade
gliomas, can have extremely variable and heterogeneous
blood flow due to the complex tumor vasculature, which
can influence permeability.38,39,42 Various other intratu-
moral factors that can also influence permeability include
luminal surface area and interstitial, hydrostatic, and os-
motic pressure across the endothelium. Slow blood flow
and/or low osmotic gradients, which can occur in high-grade
Fig 5. Tumor permeability estimation: semiquantitative indices. In the top row, a 19-year-old woman with a diagnosis of GBM postchemoradiation
therapy showed a recurrent enhancing lesion in the right parietal region (A), which showed low MSIVP (maximum slope of initial vascular phase) (B and
C), suggesting treatment-induced necrosis, which was confirmed by histopathology. In the bottom row, a recurrent enhancing lesion in a previously
treated grade III glioma showed high MSIVP, consistent with a recurrent tumor.

tumors with a lot of vasogenic edema and also in the central
necrotic or hypoperfused parts of large tumors, can lead to a
larger component of delayed permeability, which may need
longer acquisition times for accurate estimation.17
Another major limitation of permeability imaging is
complex multicompartment modeling needed for postpro-
cessing calculations. Quantification of vessel permeability
with various perfusion techniques requires a 2 or more com-
partment pharmacokinetic model with an arterial input
function, making these studies more complex than CBV
estimation,11 and quantification is dependent on the imag-
ing technique and the mathematic model43 that is used.
Steroid use is another confounder that can affect blood
volume and tumor-permeability measurements, affecting per-
meability measurements more than blood volume,44,45 and,
hence, should be known before comparing results across dif-
ferent patients and different time points in the same patient.
Going Backwards with Tumor Vascular Permeability:
Semiquantitative Indices
Accurate and absolute quantitative estimates of permeabil-
ity may not be easily possible due to complex multicompart-
ment physiologic models needed to derive these metrics by
using DCE MR imaging techniques as described above. On
the contrary, various model-free “semiquantitative” indices
derived from DCE-MR imaging have been successfully used
in the past in the evaluation of prostate, breast, cervical, and
pancreatic cancers.11,41-48 These parameters include onset
time of contrast agent arrival, initial and mean gradient of
the upslope of the enhancement curve, maximum signal
intensity, and washout gradient.46 Narang et al47 used
MSIVP, normalized MSIVP, normalized slope of the de-
layed equilibrium phase, and nIAUC at 60 and 120 seconds
(nIAUC60 and nIAUC120) to differentiate recurrent tumors
from treatment-induced necrosis (Fig 5). The major disad-
vantage with these is that these parameters lack a physio-
logic basis limiting their growth as absolute quantitative
measures of tumor vascular leakiness. Despite that, these
model-free metrics could have a more practical role to play
in the routine clinical setting because they do not depend on
the technical expertise needed for the more complex model-
based analysis. However, their direct comparison across
multiple centers or even individual examinations could be
limited due to the fact that these do not accurately reflect
contrast agent concentration in the tissue and hence can be
influenced by scanner type and settings.
Previous authors have also successfully used similar in-
dices such as relative PSR or signal-intensity enhancement-
time curves as an indirect measure of vascular leaki-
ness.48,49 Barajas et al48 showed lower relative PSR in

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Fig 6. CBV and PS can be used in tumor grading. Note the significantly higher CBV and PS in a grade IV GBM compared with a grade II astrocytoma.
recurrent GBM compared with radiation necrosis by using
DSC MR perfusion imaging, suggesting a disrupted BBB
that was more permeable to macromolecular contrast
agents; however, their measurements were not a direct esti-
mate of lesion leakiness. They also noted a large degree of
overlap between the 2 groups, making rPSR a less robust
predictor of recurrent tumor. The same group also pub-
lished the same methodology with stronger results by using
rPSR to differentiate metastatic tumors from radiation ne-
crosis, suggesting that rPSR may be a better prognostic
indicator of tumor recurrence than rCBV.50
Tumor Vascular Permeability: Molecular Basis and
Correlation with Immunohistologic Markers
Tumor vascular permeability has been shown to correlate
with VEGF, VEGFR-2 expression, and tumor growth in
breast cancer tumor models in rats.51 However, direct in
vivo correlation of PS estimates with molecular angiogenic
markers has not been performed in the past in the human
subjects, to our knowledge. Jain et al52 showed MVCP to be
significantly correlated with PS and not with CBV. This
finding suggests that MVCP is associated with leakier tu-
mor vessels. Therefore, regions of increased PS within a
heterogeneous tumor might indicate more immature vascu-
lature, whereas higher CBV regions might indicate hyper-
perfusion and more mature vasculature. In that study, even
though correlation of PS with VEGFR-2 expression did not
reach statistical significance, it did show a positive trend,
suggesting that regions with higher VEGFR-2 expression
and higher MVCP could be localized by using PS paramet-
ric maps.36,52 These regions of hyperpermeability have been
shown to be associated with insufficient blood flow and
oxygen transport, resulting in tumor hypoxia53; hence,
identifying these in vivo could potentially help target and
monitor treatment.
Given the increasing focus on the use of quantitative
imaging biomarkers for patient survival and treatment re-
sponse, it is critical to understand the molecular basis of
54 兩 Neurographics 2:48 –59 June 2012 www.neurographics.com
these imaging features. Recent literature has tried to corre-
late morphologic imaging features with gene expression in
GBMs54-57; however, there has been little emphasis on cor-
relating metabolic or physiologic imaging biomarkers with
gene expression. Perfusion parameters such as CBV and PS
estimates in GBMs have been shown to correlate positively
with proangiogenic genes and inversely with antiangiogenic
genes. This correlation can help establish a genomic/molec-
ular basis for these commonly used imaging biomarkers58
and potentially add to our existing knowledge of their im-
munohistologic bases.36,52
Tumor Vascular Permeability: Clinical Utility
Glioma Grading and Prognosis. Glioma grading histori-
cally has been based on the histology of the resected speci-
men, which is dependent on tumor cellularity, cellular pleo-
morphism, mitosis, necrosis, and endothelial hyperplasia
and does not include microvascular density or total vascular
area. Histologic grading is thus limited by sampling error,
wide ranges of classification and grading systems, inter- and
intrapathologist variability, and, most important, by the
evolving nature of central nervous system tumors. In con-
trast, an in vivo technique to assess tumors may provide
similar information about the whole tumor and can be re-
peated noninvasively and hence could assess the evolution
of tumors and help monitor treatment response. Tumor
blood volume and permeability are the two important vas-
cular parameters that have been shown to correlate with
glioma grade (Fig 6),14,17,20,59,60 treatment response, and
prognosis. The information provided by CBV and PS is
probably complimentary, with CBV revealing information
about the amount of total vessels in that part of the tumor,
whereas PS provides information about the degree of ab-
normality of the BBB,36,52 which, in turn, could potentially
correlate with proangiogenic cytokines activity61 within the
tumor.
Fig 7. Top row: a recurrent enhancing lesion in a previously treated grade III glioma. CT Perfusion showed high CBV and also high PS, consistent with
a recurrent tumor. Bottom row: right parietal enhancing lesion in a previously treated grade III glioma showing low CBV and low PS. Histopathology
revealed radiation necrosis.
Most perfusion imaging studies have focused on blood vol-
ume estimates and correlation with survival prediction in
mixed populations of gliomas,62,63 whereas only a few
studies have explored tumor leakiness or permeability esti-
mates as prognostic factors.64-66 Mills et al65 used both
CBV and Ktrans in 1 single experiment, though they found
the relationship of Ktrans with survival to be unexpected and
counterintuitive in high-grade gliomas because patients
with higher Ktrans showed better survival. Dhermain et al66
recently showed that low-grade gliomas with microvascular
leakage and contrast enhancement show poor progression-
free survival compared with those without it. In a recently
presented study67 and our unpublished data, we have eval-
uated both rCBV and leakiness (PS) estimates as prognostic
factors in high-grade gliomas and found that both of these
parameters, which can be estimated with 1 single experi-
ment by using PCT, correlated significantly with overall
patient survival. However, after adjusting for World Health
Organization grade, PS estimates were not statistically sig-
nificant. However, within the grade III glioma group, pa-
tients with grade III gliomas and lower PS (⬍1.7) had a
significantly better overall survival (P ⫽ .011) compared
with grade III gliomas with higher PS estimates, suggesting
that measuring tumor leakiness could provide additional
prognostic information in high-grade gliomas.
Differentiating Treatment Effects from Recurrent Tumor.
A recurrent or progressive enhancing lesion in a treated
brain tumor is fairly common in a busy neuro-oncologic
practice, and differentiating treatment effects, whether due
to pseudoprogression (occurring within 12 weeks of
chemoradiation therapy)68 or delayed radiation necrosis
(usually occurring 3– 6 months post-treatment), from recur-
rent tumor based on conventional/morphologic imaging is
difficult. While both MR imaging49,69,70 and CTP71 have
been used to evaluate post-treatment recurrent enhancing
lesions, most of these perfusion imaging techniques have
used only blood volume estimates as a tool to differentiate
recurrent high-grade tumor from radiation necrosis.
However, recent studies have demonstrated the role of
quantitative estimates of permeability in differentiating re-
current tumors from treatment-induced necrosis. In partic-
ular, a recent study by Jain et al72 demonstrated lower PS
values in radiation necrosis compared with recurrent/pro-
gressive tumors (Fig 7). This is presumably due to leaky
angiogenesis seen with high-grade recurrent tumors,
whereas vasculature associated with tumor-induced necro-
sis is not that leaky, despite having damaged endothelium
and hypoxia-related VEGF upregulation.72 Pseudoprogres-
sion, on the other hand, has not yet been studied well with
permeability imaging, though some recent studies do show
the utility of measuring rCBV to differentiate it from tumor
progression.73
Assessing Treatment Response and Treatment Planning.
Most of the imaging follow-up for brain neoplasms is based
on measurement of contrast-enhancing tumor. However,
the increasing use of antiangiogenic agents and multitech-
nique treatment regimens for treatment of recurrent high-
grade neoplasms has raised doubts about just using con-
trast-enhancing tumor as a marker of treatment response.
While antiangiogenic agents inhibit angiogenesis and seem
to control tumor enhancement initially, infiltrative nonen-
hancing tumor may continue to grow. Thus, measuring
only the enhancing lesion might overestimate the response.
As such, other imaging criteria and methods have become
more important in accurately assessing treatment response.
Permeability measurements allow more accurate assess-
ment of treatment response following antiangiogenic treat-
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Fig 8. Treatment-response assessment. The above example shows a
grade III glioma (A), before and after surgical resection. B, Follow-up
studies after radiation therapy demonstrate a progressively increasing
lesion on postcontrast T1-weighted images. C, MR perfusion shows pro-
gressively increasing Ktrans on DCE T1 maps, suggesting a recurrent pro-
gressive lesion, which was proved to be a recurrent tumor.
Fig 9. Tumefactive demyelinating lesion: a 55-year-old woman presenting with a single central necrotic enhancing lesion in the brain stem, mimicking
a high-grade neoplasm. PCT maps showed low PS in addition to low CBV, suggesting a non-neoplastic lesion, which was proved to be a tumefactive
demyelinating lesion on follow-up.
56 兩 Neurographics 2:48 –59 June 2012 www.neurographics.com
ment as measured by a decrease of vessel permeability and
Ktrans on serial imaging.74,75 Measuring tumor permeability
could also be important to determine the choice and timing
of therapeutic agents for optimal combination therapy be-
cause it is important to understand how various agents
influence BBB and the optimal timing of maximal opening
of the BBB, whether during radiation therapy76 or admin-
istration of antiangiogenic agents.77 Measuring permeabil-
ity could influence decisions regarding treatment planning
by differentiating recurrent/progressive tumor from treat-
ment effects (Fig 8).
Differentiating Non-Neoplastic Lesions from Neoplasms.
Occasionally multiple sclerosis or vasculitis/angiitis mani-
fests as a single large tumefactive lesion with atypical mor-
phologic imaging features, thus necessitating biopsy for an
accurate diagnosis. Enhancement in tumefactive demyeli-
nating lesions (TDLs) is thought to occur due to the BBB
breakdown and macrophage infiltration,78 whereas en-
hancement in tumors and especially high-grade tumors,
which TDLs mimic, occurs due to neoangiogenesis and a
break in the BBB. Hence, perfusion imaging can help to
differentiate these 2 entities because TDLs usually show low
blood volume and also low permeability (Fig 9) due to lack
of neoangiogenesis or immature leaky vessels, whereas tu-
mors, especially high-grade gliomas, will show high blood
volume and higher permeability due to tumor neoangiogen-
esis.79-81
CONCLUSIONS
Despite the limitations and lack of standardization of the
clinically available imaging techniques to measure tumor
vascular permeability, additional information obtained
from permeability imaging may be used in a number of
important ways, including glioma grading and patient
prognosis, as well as treatment guidance and assessing
treatment response. With improvements of image acquisi-
tion and postprocessing software in the future, permeability
imaging could be an important clinical tool in the diagnosis
and management of brain tumors.
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