European Journal of Cancer xx (2016) 1e15

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Review

Magnetic resonance imaging based functional imaging in

paediatric oncology

Karen A. Manias a,b, Simrandip K. Gill a,b, Lesley MacPherson c,

Katharine Foster c, Adam Oates c, Andrew C. Peet a,b,*

a
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
b
Department of Paediatric Oncology, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, B4 6NH, UK
c
Department of Radiology, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, B4 6NH, UK

Received 22 June 2016; received in revised form 26 September 2016; accepted 30 October 2016
Available online - - -

KEYWORDS Abstract Imaging is central to management of solid tumours in children. Conventional mag-
Magnetic resonance netic resonance imaging (MRI) is the standard imaging modality for tumours of the central
imaging; nervous system (CNS) and limbs and is increasingly used in the abdomen. It provides excellent
Functional magnetic structural detail, but imparts limited information about tumour type, aggressiveness, metasta-
resonance imaging; tic potential or early treatment response. MRI based functional imaging techniques, such as
Magnetic resonance magnetic resonance spectroscopy, diffusion and perfusion weighted imaging, probe tissue
spectroscopy; properties to provide clinically important information about metabolites, structure and blood
Diffusion magnetic flow. This review describes the role of and evidence behind these functional imaging techniques
resonance imaging; in paediatric oncology and implications for integrating them into routine clinical practice.
Perfusion imaging; ª 2016 Elsevier Ltd. All rights reserved.
Diffusion tensor
imaging;
Paediatrics;
Neoplasms

1. Introduction include diffusion weighted imaging and perfusion

weighted imaging (DWI and PWI), assessing tissue
Functional imaging examines tissue properties relevant structure and blood flow, and magnetic resonance
to the underlying biology of tumours. Techniques spectroscopy (MRS), measuring metabolite profiles.

* Corresponding author: Institute of Child Health, Whittall Street, Birmingham, B4 6NH, UK. Fax: þ44 121 333 8241.
E-mail addresses: karenphotiou@doctors.org.uk (K.A. Manias), S.K.Gill.1@bham.ac.uk (S.K. Gill), Lesley.Macpherson@bch.nhs.uk
(L. MacPherson), Katharine.Foster@bch.nhs.uk (K. Foster), Adam.Oates@bch.nhs.uk (A. Oates), a.peet@bham.ac.uk (A.C. Peet).

http://dx.doi.org/10.1016/j.ejca.2016.10.037
0959-8049/ª 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Manias KA, et al., Magnetic resonance imaging based functional imaging in paediatric oncology, European
Journal of Cancer (2016), http://dx.doi.org/10.1016/j.ejca.2016.10.037
2 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15
These complimentary modalities provide important
information about tumour characteristics, allowing
derivation of a more complete biological picture.
2. Main techniques in functional imaging
2.1. Diffusion weighted imaging
DWI is based on microscopic water diffusion in tissue.
Images acquired with high- and low-diffusion weighting (b-
values) are used to develop apparent diffusion coefficient
(ADC) maps [1]. ADC values are a quantitative measure of
diffusion with an inverse relationship with cellularity [2]
that may be useful for tumour characterisation.
DWI requires no intravenous (i.v.) access, contrast
injection or compliance with breath-hold techniques. It
can be performed on all modern magnetic resonance
scanners and standard central nervous system (CNS)
protocols have short acquisition times. Protocols used in
the body may be longer, particularly if DWI is acquired
using several b-values to allow for capillary blood flow.
Additional scanning time is typically 30 s for CNS and
2e5 min for body protocols; additional general anaes-
thesia is not usually required.
2.2. Diffusion tensor imaging
Diffusion tensor imaging (DTI) provides quantitative
orientation-specific information about water diffusion
Fig. 1. Diffusion tensor imaging (DTI) demonstrating the optic radiations.
Please cite this article in press as: Manias KA, et al., Magnetic resonance imaging based functional imaging in paediatric oncology, European
Journal of Cancer (2016), http://dx.doi.org/10.1016/j.ejca.2016.10.037
expressed by the term ‘fractional anisotropy’ (FA) [3].
This technique can be used to track nerve fibres in the
brain, as diffusion coefficients are higher when measured
parallel than perpendicular to myelinated neurones [4].
White matter tracts are visualised through 3-dimen-
sional mathematical models (tractography) or colour
coded maps [3] (Fig. 1). Standard acquisition time is
6 min, but may be longer if imaging complex regions
with intersecting tracts. Additional i.v. access is not
required.
2.3. Magnetic resonance spectroscopy
1H-Magnetic resonance spectroscopy (MRS) enables
non-invasive discrimination between different types
and grades of brain tumour. Information is provided
about intermediary metabolites such as choline
(involved in membrane synthesis), mobile lipids
(apoptosis and necrosis) and N-acetylaspartate (NAA;
neuronal marker) [5]. The relative amounts of the
various metabolites are presented graphically in the
form of a spectrum (Fig. 2).
MRS can be performed following routine magnetic
resonance imaging (MRI) without the need for addi-
tional i.v. access or general anaesthesia. Single voxel
spectroscopy where data is acquired from a single pre-
defined volume typically adds 5 min to the examination
time and is relatively easy to acquire and process.
Acquisition and analysis of multivoxel magnetic
 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15
Fig. 2. Mean magnetic resonance spectrum (MR spectrum) of
normal brain (white matter): mIns, myo-inositol; tCho, total
choline; Cr, creatine; NAA, N-acetylaspartate; LMM, lipids and
macromolecules.
resonance spectroscopic imaging (MRSI), often termed
chemical shift imaging (CSI), is more complex but
provides information on tissue heterogeneity.
2.4. Perfusion weighted imaging
Perfusion MRI evaluates blood flow and volume to
impart information about microvasculature and angio-
genesis. Techniques include dynamic contrast enhanced
(DCE) and dynamic susceptibility contrast (DSC) MRI
which require contrast injection via a mechanical pump
that may not be compatible with a central venous
catheter. Additional scanning time is approximately
5 min for DCE and 90 s for DSC-MRI. Arterial spin-
labelling (ASL) is a promising alternative in children
[6e8], allowing non-invasive quantitative measurement
of cerebral perfusion without contrast injection and the
associated need for additional i.v. access [9]. This tech-
nique can be performed in 4e5 min. Increased perfusion
may reflect increased vascularity associated with higher
grade tumours [10] (Fig. 3).
3. Clinical uses
3.1. CNS tumours
3.1.1. Diagnosis prior to treatment
Childhood brain tumours are diverse in terms of pa-
thology [11] with different tumour types displaying
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Journal of Cancer (2016), http://dx.doi.org/10.1016/j.ejca.2016.10.037
3
overlapping imaging characteristics [12,13]. Conven-
tional MRI cannot always accurately identify specific
tumour type or grade [13e18] or differentiate neoplastic
from non-neoplastic lesions [12,13,19]. Current diag-
nostic gold standard is histopathology following biopsy
or surgical resection [11] with associated risk of
morbidity or sampling error [20]. Definitive histopath-
ological diagnosis is not available until several days
post-operatively and thus cannot be used to guide sur-
gical decision-making or early planning of adjuvant
treatment. Functional imaging can facilitate early non-
invasive diagnosis of paediatric CNS tumours,
providing important clinical information.
3.1.1.1. DWI. DWI may help discern brain tumour
grade [21] as ADC (measured in mm2/s) inversely
correlates with cellularity and nuclear-to-cytoplasm
ratio [22e25]. Restricted diffusion with low ADC is
common in high-grade [23,26,27] but rare in low-grade
paediatric brain tumours [26,28e30]. Cut-off values
have been suggested but vary widely between studies
[27,28,31,32].
Research conducted into whether DWI can identify
brain tumour type mostly consists of studies exclusively
evaluating cerebellar malignancies [28e30,33,34]. Pilo-
cytic astrocytomas were discriminated from medullo-
blastomas [23,27,28,32,35], probably attributable to
difference in grade/cellularity, but ependymomas were
more difficult to classify [29,30]. Although ADC alone
cannot confirm diagnosis as values overlap [29,30,36,37],
ADC histograms have been successful in differentiating
cerebellar tumours [31]. Diffuse intrinsic pontine glioma
fibre tracking is potentially useful for diagnosing lesions
in areas precluding biopsy, having retrospectively
differentiated diffuse intrinsic pontine glioma (DIPG)
from demyelination [38] and determined white matter
involvement in DIPG and focal brainstem tumours
[3,39e42].
3.1.1.2. MRS. MRS can support non-invasive diagnosis
of childhood brain tumours [15,43,44]. Brain tumours
generally have high levels of choline and lactate and
reduced NAA [14,43]. High-grade tumours have
elevated total choline, lipids [45] and glycine [44], while
taurine is associated with primitive neuroectodermal
tumours [46] and medulloblastomas [15,43]. Creatine is
significantly lower in pilocytic astrocytomas [15].
Pattern recognition of MRS profiles and quantitative
interpretation can facilitate tumour categorisation and
confer added diagnostic value [15,43]. Including visual
pattern recognition of MRS in assessment of posterior
fossa tumours significantly improved accuracy of
radiological diagnosis over conventional MRI alone in a
recent retrospective review [18]. The differences between
mean spectra for these common tumours are illustrated
in Fig. 4.
4 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15
Fig. 3. Perfusion weighted imaging (PWI) demonstrating relative cerebral blood volume (rCBV). (A) Pilocytic astrocytoma (PA): 1, MRI;
2, rCBV. (B) Atypical teratoid rhabdoid tumour (ATRT): 1, MRI; 2, rCBV.
Paediatric pilocytic astrocytomas, medulloblastomas
and ependymomas have been accurately classified using
MRS [14,43,47,48]. Metabolite ratios of NAA:choline
(Cho) and creatine (Cr):Cho differentiated these tu-
mours with accuracy of 0.85 [47], as did a neural
network, using ratios of NAA, Cho and Cr (accuracy
0.88) [14] and linear discriminant analysis (LDA; accu-
racy 0.93) [43]. Diagnostic classifiers, as illustrated in
Fig. 5, have been assessed in a multinational setting
(accuracy 0.98) [48].
MRS can facilitate diagnosis of paediatric low-grade
glioma subgroups. Significantly different choline and
myo-inositol concentrations have been found in glio-
neuronal and glial tumours compared to other histo-
logical subtypes [17]. Metabolite profiles of pilocytic
astrocytomas and unbiopsied optic pathway gliomas
differ significantly depending on neurofibromatosis type
I status and location [17].
3.1.1.3. PWI. Emerging evidence suggests a role for
perfusion imaging in diagnosing and grading paediatric
tumours. Significantly higher relative cerebral blood
volume and relative cerebral blood flow (rCBV and
rCBF) were found in high- than low-grade
neuroepithelial brain tumours, with peritumoural rCBV
significantly higher in primary malignancies than
Please cite this article in press as: Manias KA, et al., Magnetic resonance imaging based functional imaging in paediatric oncology, European
Journal of Cancer (2016), http://dx.doi.org/10.1016/j.ejca.2016.10.037
metastases [49]. A small study reported consistently low
rCBV values (<1.5) in pilocytic astrocytomas [50],
supporting reports of low rCBV in low-grade gliomas
[16,51,52]. Different histological tumour types have
been diagnosed from analysis of the signal intensity
curve and morphological data [53]. DSC-MRI
facilitated diagnosis of paediatric glioblastoma in a
small retrospective study [54]. DCE-MRI has improved
accuracy over T2-weighted imaging in staging Hodgkin
lymphoma, increasing sensitivity in detecting splenic
involvement from 57 to 100% [55]. DCE-MRI has
shown promise assessing tumour angiogenesis and
necrosis in retinoblastoma [56].
Although ASL can differentiate grades of glioma in
adults [57], there has until recently been little published
evidence for its use in paediatrics. Recent evaluation of
129 children found high-grade tumours to have higher
cerebral blood flow (CBF) than low-grade lesions, sug-
gesting ASL may be used to accurately grade paediatric
brain tumours. A cut-off of 50 mL/min/100 g demon-
strated sensitivities and specificities respectively of 90%
and 93% for hemispheric, 100% and 80% for thalamic
and 65% and 94% for posterior fossa tumours [58].
Further stratification of posterior fossa tumours was
possible using a CBF-to-contrast enhancement ratio.
This finding supports earlier work describing
 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15 5

Fig. 4. Comparison of MRS profiles and MR images of posterior fossa tumours, demonstrating (A) ependymoma, (B) medulloblastoma
and (C) pilocytic astrocytoma.

significantly higher maximal relative tumour blood
volume (rTBV) in high than low-grade tumours, dis-
tinguishing medulloblastoma from pilocytic astrocy-
toma by virtue of significantly higher blood flow [59],
and finding choroid plexus carcinomas to have signifi-
cantly higher ASLdetermined rCBF than papillomas
[60].
Multiparametric advanced imaging techniques
combining MRS, perfusion and diffusion imaging can
increase diagnostic accuracy. A combination of MRS
(using LDA) and DWI could fully differentiate posterior
fossa tumours [33]. This was not possible using either
technique alone, suggesting these modalities are best
used in combination.
3.1.2. Prognostic markers for childhood cancer
Prognosis of histopathologically similar paediatric tu-
mours varies considerably, with differences in clinical
behaviour related to underlying biology. Functional
imaging provides novel non-invasive biomarkers to

Please cite this article in press as: Manias KA, et al., Magnetic resonance imaging based functional imaging in paediatric oncology, European
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6 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15
Fig. 5. Decision support system (DSS) output showing normalised metabolite profiles (left), linear discriminant function (D.F.) scores
(centre) and MR spectra (right) for a case (red) compared with mean values for pilocytic astrocytoma (green), ependymoma (blue) and
medulloblastoma (cyan).
facilitate tumour characterisation [61] and on-going risk
stratification. This additional information has potential
to be clinically useful through allowing individualisation
of treatment, with intensification in high-risk patients
and reduction in those found to be low-risk.
3.1.2.1. DWI. DWI could facilitate risk stratification as
diffusion restriction increases with tumour cellularity.
Further research is needed to determine the role of this in
paediatrics. Diffusion at tumour margins is a potential
prognostic biomarker with apparent transient coefficient,
the change in ADC from oedema into tumour, predicting
survival in paediatric embryonal tumours [62]. DWI may
determine medulloblastoma histological subtype and
identify high-risk tumours. The aggressive anaplastic
subtype has been associated with increased ADC [63],
with mean and minimum ADC of classic (0.733 and
0.464  10e3) lower than anaplastic medulloblastoma
(minimum 0.63  10e3) [30]. A significant negative
correlation has been observed between ADC and choline
and taurine in medulloblastoma, suggesting these as
combined prognostic biomarkers [30].
DWI may identify DIPG subsets [64] and stratify
patients with different molecular biology and clinical
behaviour. Non-invasive biomarkers are particularly
important in these patients as brainstem biopsy is often
inappropriate. A retrospective study categorised DIPG
patients according to pre-treatment mean ADC values
obtained by placing a region of interest (ROI) around
the whole tumour avoiding cysts, haemorrhage and ne-
crosis. Children with mean solid tumour ADC below the
group median of 1.295  10e3 had a median survival of
3 months, compared to 13 months for those with higher
ADC [64]. Survival in DIPG has been associated with
diffusion changes after radiotherapy, with increased
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Journal of Cancer (2016), http://dx.doi.org/10.1016/j.ejca.2016.10.037
survival in tumours demonstrating an initial decrease in
ADC ratios reflecting decreased extracellular volume,
cellular swelling and early cell death [65].
3.1.2.2. MRS. MRS has identified several non-invasive
prognostic biomarkers in CNS tumours. Lipids and
scyllo-inositol are predictive of poor survival, whereas
glutamine and NAA suggest improved survival [66].
Mobile lipids correlate negatively with intracellular
glutamine (essential to lipogenesis in hypoxic tumour
cells), implying a functional link [66].
High intracellular macromolecules and lipids are asso-
ciated with aggressive brain tumours [48] with correlation
between grade and mobile lipids [45]. Medulloblastoma
and ependymoma have greater lipid concentrations than
pilocytic astrocytoma [48]. Choline is higher in medullo-
blastoma (grade IV) and ependymoma (grade II) than
pilocytic astrocytoma (grade I) [48], predicting poor sur-
vival in other non-metastatic CNS tumours [67]. An
increased pre-treatment ratio of choline to NAA predicts
shorter survival in DIPG [68]. High citrate suggests poor
survival in grade II astrocytoma [69] and glutamate sig-
nifies poor prognosis in medulloblastoma [70].
Low choline to NAA ratio is predictive of good
prognosis [71] and high myo-inositol levels are a
biomarker of long progression-free survival in supra-
tentorial pilocytic astrocytoma [72]. Low creatine,
common in grade I pilocytic astrocytoma [72], indicates
good prognosis in grade II and III glioma [73]. A
multivariate model of survival across all CNS tumours
based on three MRS biomarkers at diagnosis (lipids,
glutamine and scyllo-inositol) had similar accuracy to
histopathological grade in predicting survival [66].
Metabolite profiles of metastatic and localised brain
tumours differ, reflecting disparities in underlying
 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15
biology and suggesting the possibility of identifying tu-
mours at risk of metastatic relapse. Metastatic medul-
loblastomas have lower mobile lipids and higher total
choline than localised tumours, suggesting decreased cell
death and increased cell growth [61].
3.1.2.3. PWI. Increased perfusion on DSC-MRI at
diagnosis and any subsequent time point has predicted
shorter survival in DIPG (relative risk 4.68) [68]. Other
evidence suggests low perfusion at diagnosis is not
related to survival [74], possibly because DIPGs begin
low-grade before transforming to aggressive high-
grade tumours. A phase I study found that patients
with higher baseline and post-radiotherapy perfusion
had significantly better progression-free survival [75],
due perhaps to improved anti-angiogenic treatment
response or hypoperfusion associated radio-resistance
[74]. It has been asserted that imaging protocols
should include DSC-MRI to improve understanding of
these unbiopsied lesions [68].
Perfusion imaging and MRS may predict outcome of
children’s brain tumours in combination, with interac-
tion observed between rTBV and increase in Cho:NAA
ratios [76]. rTBV has predicted progression when inter-
preted with MRS metabolite ratios and differentiated
stable from progressive neuroglial tumours [76].
3.1.3. Early indicators of response
Functional imaging may provide information to
monitor therapeutic response and enable early identifi-
cation of non-responders. Repeated biopsy is inappro-
priate in these patients. Developing ‘real time’ non-
invasive biomarkers would be clinically advantageous,
allowing adaptation of treatment as disease evolves [61].
3.1.3.1. MRS. MRS provides information about char-
acteristic changes in metabolites such as mobile lipids,
myo-inositol and total choline which are potential early
markers of treatment response [72]. Myo-inositol is a
possible biomarker for monitoring supratentorial
pilocytic astrocytoma, with future progression
predicted by decreasing myo-inositol levels [72].
3.1.3.2. PWI. Perfusion imaging may enable treatment
monitoring through providing information about
microvascular status [75]. Information from rCBV maps
complements MRI and MRS [76]. A phase I study
evaluating ASL and DSC-MRI in DIPG found
tumour perfusion and blood volume increased and
tumour volume decreased in response to conformal
radiotherapy and anti-angiogenics [75]. Increased
tumour perfusion following radiotherapy was
associated with significantly longer progression-free
survival [75].
Perfusion MRI could identify tumour subtypes
responsive to anti-angiogenic agents. The importance of
angiogenesis is highlighted by identification of
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7
microvessel density as a predictor of progression-free
survival in paediatric optic pathway and hypothalamic
gliomas [77]. rCBV maps combined with MRS could
identify children likely to benefit from anti-angiogenic
treatment [76] and monitor effectiveness of agents tar-
geting tumour vasculature.
3.1.4. Surgical planning
3.1.4.1. DTI. DTI facilitates neurosurgical planning
through demonstrating location of fibre tracts in rela-
tion to tumour [78]. White matter tractography has been
used in surgical planning [79e82], correlating with
clinical outcome in supratentorial tumours [81]. Using
tractography to plan stereotactic resection of thalamic
pilocytic astrocytomas successfully identified the
relationship of tumour to motor fibres within the
internal capsule [83]. DTI has differentiated tumour
from peritumoural brain tissue [84].
3.1.5. Characterising pseudoprogression and diagnosing
relapse
Differentiating tumour progression from pseudoprog-
ression and diagnosing relapse and metastatic disease
can be difficult using conventional MR imaging alone.
Emerging evidence suggests functional imaging may add
value in this area.
3.1.5.1. DWI. Metastatic or progressive medulloblas-
toma can be identified through low ADC values [85]. A
case report suggested DWI can differentiate residual
tumour from treated disease in trilateral
retinoblastoma [86].
3.1.5.2. MRS. Comparing MRS profiles of paediatric
brain tumours at diagnosis and relapse may distinguish
relapse from pseudoprogression and radiation necrosis,
as no significant difference has been observed in any
metabolite, lipid or macromolecule measured at diag-
nosis and first local or distant relapse [87].
3.1.5.3. PWI. Pseudoprogression can be differentiated
from true progression using DCE and DSC-MRI to
characterise vascularity and permeability [88]. A small
prospective study using ferumoxytol-based DSC-MRI
combined with gadolinium-based DCE-MRI found
rCBV <1 suggestive of pseudoprogression in 80% of
brain tumours [88]. This promising preliminary result
requires further evaluation.
3.1.6. Assessing treatment-related neurotoxicity
3.1.6.1. DTI. Treatment of childhood brain tumours
with cranio-spinal irradiation is associated with white
matter damage and poor intellectual outcome [89]. DTI
may demonstrate treatment-related neurotoxicity as FA
and ADC reflect damage to brain tissue. Lower
anisotropy values in cerebral white matter of children
with medulloblastoma [90,91] are associated with
8 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15
increased cranio-spinal radiation dose and young age at
diagnosis [90]. Clinically significant reduction in
anisotropy associated with reduced intellectual
outcome occurs in normal appearing white matter on
conventional MRI [89,90]. DTI has detected changes
in grey matter microarchitecture, particularly
hippocampal, in children following radiotherapy [92].
3.2. Non-CNS tumours
3.2.1. Diagnosis prior to treatment
3.2.1.1. DWI. Body tumours can be characterised as
malignant or benign using DWI. This has potential to
provide clinicians with important information, pre-
venting biopsy with associated risk of morbidity and
allowing early family discussions. Paediatric studies
have demonstrated ADC of malignant body lesions to
be lower than benign lesions [2,93e98]. Although an
early small prospective study reported lower mean
ADC in malignant than benign abdominal masses
without reaching significance [2], more recent studies
suggest ADC can reliably characterise tumours
[94,95,99,100]. Evaluation of head and neck masses
found mean ADC values of malignant, benign solid
and benign cystic lesions of 0.93, 1.57 and 2.01  10e3
respectively, with significant difference between
malignant and benign masses [94]. Average ADC
values of benign and malignant abdominal (2.28 and
0.84  10e3, respectively) [95], musculoskeletal (1.71
and 0.78  10e3, respectively) [100] and orbital
tumours [99] were also significantly different. Most
studies compare solid malignant with cystic benign
lesions, possibly artificially elevating mean ADC in
benign masses. A retrospective analysis did, however,
demonstrate significant difference between mean ADC
in benign and malignant solid abdominal tumours (1.6
and 1.07  10e3, respectively) [98].
Cut-off ADC values have been proposed for diag-
nosing malignant body tumours and are similar across
studies. Evaluation of abdominal masses suggested
ADC cut-offs of 1.1 [95] or 1.29  10e3 (sensitivity 77%,
specificity 82%) [98]. A value of 1.25  10e3 differenti-
ated malignant from benign head and neck masses
(sensitivity 94.4%, specificity 91.2%) [94] and
1.03  10e3 was proposed for musculoskeletal tu-
mours (sensitivity 90%, specificity 91%) [100]. Sensitivity
may be higher for solid, homogeneous tumours
compared to necrotic tumours [98].
DWI may be used in paediatric tumour staging and
detection of metastatic disease. Diffusion weighted
whole body MRI with background body signal sup-
pression (DWIBS) [101] provides homogeneous fat
suppression to enable visualisation of metastatic disease.
It has advantages over fluorodeoxyglucose-positron
emission tomography/computed tomography
(FDGPET/CT) in identifying bony metastases [102,103]
and lymphoma staging in adults [104e106], and in
Please cite this article in press as: Manias KA, et al., Magnetic resonance imaging based functional imaging in paediatric oncology, European
Journal of Cancer (2016), http://dx.doi.org/10.1016/j.ejca.2016.10.037
lymphoma and sarcoma staging in children [107] in
terms of accuracy, availability and lack of radiation
exposure. Adult work suggests whole body DWIBS can
detect metastatic involvement of abdominal lymph
nodes with similar accuracy to FDG-PET [104]. Further
evidence is needed in paediatrics to define the role of this
technique in clinical practice.
Further research is needed into quantitative DWI in
paediatric oncology. Direct comparison of results is
difficult as evidence consists of small heterogeneous
retrospective case series with variations in study design,
ADC parameters, ROI measurement [23,24,28,63], b-
values [100] and inclusion criteria [24,108].
3.2.2. Prognostic markers for childhood cancer
3.2.2.1. PWI. Emerging evidence suggests DCE-MRI as
a prognostic indicator for survival in osteosarcoma and
an early non-invasive biomarker for treatment response.
A prospective multi-centre trial found KTrans indicative
of histological response to pre-operative chemotherapy
[109]. This is clinically important as there is currently no
prognostic marker to guide pre-surgical treatment
stratification in osteosarcoma, and additional
information could enable treatment intensification at
an early stage in high-risk patients.
3.2.3. Early indicators of response
3.2.3.1. DWI. ADC is a potential biomarker of response
in body tumours not treated by upfront resection [2].
DWI could detect early therapeutic success at a
cellular level as cell death, loss of membrane integrity
and reduced cellular density are reflected by increased
ADC [110]. Serial ADC measurements may allow
quantitative response monitoring and continuous risk
stratification. Measurable changes in ADC distribution
have been reported, with tumours with
histopathologically good response demonstrating
greater increase in median ADC [96]. Minimum ADC
has reflected response in osteosarcoma, with higher
values post-chemotherapy correlating significantly with
improved histological response [110]. A small
retrospective study of abdomino-pelvic neuroblastoma
revealed significantly higher post-chemotherapy ADC
[111].
3.3. Guiding biopsy (CNS and non-CNS tumours)
Conventional MRI cannot always determine optimal
biopsy site of heterogeneous tumours [112]. Functional
imaging can help target biopsy in tumours containing
cystic or necrotic elements. DWI can identify densely
packed tumour cells, potentially guiding biopsy to areas
likely to give a diagnostic yield, DSC-MRI can identify
areas of focal anaplasia in DIPG characterised by higher
CBV [113], and ASL maps can delineate areas of
vascular heterogeneity [59].
 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15 9

3.4. Future developments guide biopsy to target malignant regions avoiding cysts
and necrosis.
3.4.1. Emerging techniques ADC histograms have been used in Wilms tumours
More sophisticated methods of DWI analysis are to determine predominant histological cell type and
emerging as understanding of ADC parameters im- predict subtype after chemotherapy [126]. Comparing
proves. DWI is influenced by both structural compo- pre- and post-treatment histograms show positive shift
nents and perfusion of biological tissues, leading to in mean ADC, reflecting transformation to less cellular
variation in ADC values depending on choice of b- stromal tissue [126] (Fig. 6).
values [114]. This variability can limit identification of
threshold ADC values to differentiate benign from
malignant lesions and makes study comparison difficult. 3.5.1. Nuclear medicine techniques
Multi-b value ADC is intended to separate perfusion Nuclear medicine techniques are increasingly used in an
effects from pure diffusion. True diffusion (D), a integrated imaging approach and inherently give infor-
perfusion fraction (f), and a perfusion coefficient (D*) mation on tissue properties. Detailed evaluation of these
can be measured as additional ADC parameters [115] techniques is outside the scope of this review, but it is
with D potentially more appropriate than ADC as a important to note their importance in paediatric
reproducible parameter. oncology imaging and we outline here some of the key
There has been recent concern over evidence of points. Fluorine-18-fluorodeoxyglucose (FDG)-PET-
accumulation of gadolinium in brain tissue following CT can detect differences between malignant and non-
contrast injection [116], inviting development of new malignant cells through measuring glucose uptake [127].
imaging techniques independent of contrast. Amide- The utility of FDG-PET is limited by organ-specific
proton transfer (APT) imaging is a non-invasive MRI
technique that detects endogenous mobile proteins and
peptides in tissue to reflect cellular proliferation corre-
lating with the Ki-67 [117]. Studies have shown APT
imaging allows detection and characterisation of ma-
lignant brain tumours [118], with potential to provide
information on tumour proliferation [119], early treat-
ment response [120] and differentiation of tumour pro-
gression from post-treatment effect [121]. Diffusion
kurtosis imaging (DKI) is a variant of DWI which uses
very high b-values and is particularly sensitive to the
complex microstructure of biological tissue [122]. Mean
kurtosis is thought to be a measure of micro-
architectural complexity, reflecting cytoarchitectonic
complexities of grey and white matter [123]. Studies in
adults have shown that DKI may facilitate brain tumour
grading, as high-grade gliomas demonstrate increased
values of kurtosis parameters reflecting a higher degree
of tissue complexity due to increased tumour cellularity,
necrosis, haemorrhage and endothelial proliferation
[124]. Low-grade gliomas with relatively homogeneous
areas of tumour cells have lower kurtosis parameter
values [125]. Further work is needed in children.

3.5. DWI histograms

Tumours are heterogeneous masses consisting of a

mixture of histological cell types, interspersed with ne-
crosis and chemotherapy-induced changes. Mean ADC
may be unrepresentative as high ADC in non-viable
regions counteracts low values in cellular regions.
Calculating ADC histograms using a multi-Gaussian Fig. 6. Diffusion weighted imaging (DWI) used to assess chemo-
model [126] provides information about distinct cellular therapeutic response in a Wilms tumour. (A) ADC histogram
subpopulations. Frequency peaks correspond to demonstrating shift to the right following response to neo-
different tissue types and reflect chemotherapy-induced adjuvant chemotherapy. (B) Region of interest (ROI) drawn
changes as differentiation occurs. Histograms could around the tumour.

Please cite this article in press as: Manias KA, et al., Magnetic resonance imaging based functional imaging in paediatric oncology, European
Journal of Cancer (2016), http://dx.doi.org/10.1016/j.ejca.2016.10.037
10 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15
utilisation of glucose, which is particularly relevant in
CNS tumours. However, it is used routinely in the
assessment of Hodgkin disease where it can evaluate
active tumour post-treatment and has some effectiveness
in other lymphomas [128,129]. Whole body MRI tech-
niques such as short-TI inversion recovery (STIR) and
DWIBS can also be used to identify abnormal lymph
nodes, and studies which compare these techniques are
required. Metaiodobenzylguanidine scintigraphy is used
routinely in the assessment of neuroblastoma being
particularly useful for examining the whole body giving
information on staging and treatment response [130].
These techniques involve ionising radiation, an impor-
tant consideration in paediatrics given potential for late-
effects and secondary malignancies. PET-MRI is
emerging as a promising imaging modality in paediatric
oncology, showing similar accuracy to PET-CT
[131e133] while reducing radiation exposure [134] and
improving structural imaging in many cases and allow-
ing combination of PET with the range of advanced
MRI techniques described in this article. Disadvantages
are time taken (up to 90 min), requirement for sophis-
ticated analysis techniques and limited availability of
simultaneous PET/MRI scanners [134].
3.6. Implementing functional imaging and integration into
routine clinical practice
Several challenges remain to the routine implementation
of functional imaging in clinical practice. These include
developing standardised acquisition protocols with
appropriate quality control measures, processing and
presenting information and, in particular, the handling
of quantitative data representing a departure from
traditional radiological working. A major hurdle to
incorporating multimodal functional imaging into real
time radiology diagnosis is the difficulty in obtaining
timely quantitative data and multimodal analyses at the
time of initial reporting. This is especially true in busy
radiology departments and in the emergency setting.
There is a paucity of evidence into the integration of
functional imaging into clinical practice in paediatric
oncology. Prospective studies are needed to evaluate
diagnostic impact of functional imaging over conven-
tional MRI alone. Biomarkers should be evaluated in
clinical trials in well-defined diagnostic groups. Stan-
dards for Reporting of Diagnostic Accuracy (STARD)
guidelines for reporting diagnostic accuracy [135] should
be followed to provide high quality evidence for added
value of advanced imaging techniques.
3.6.1. Protocols
The techniques described in this review are largely
complimentary and there is an increasing recognition
that a multimodal approach to data acquisition should
be followed [136]. The International Society of Pediatric
Oncology Europe Brain Imaging Group has agreed a
Please cite this article in press as: Manias KA, et al., Magnetic resonance imaging based functional imaging in paediatric oncology, European
Journal of Cancer (2016), http://dx.doi.org/10.1016/j.ejca.2016.10.037
protocol for brain tumours which includes single voxel
MRS, DTI and DSC-MRI. In the United Kingdom, the
Children’s Cancer and Leukaemia Group’s Functional
Imaging Group have advocated a protocol for abdom-
inal tumours which includes multi-b value DWI. These
protocols form a useful starting point for those without
specific expertise and the main parameter sets for these
protocols are given in the supplementary material
(Supplementary 1 and 2). Specific clinical situations may
make other protocols optimal but such adaptations
would usually require significant local experience in
using the technique.
4. Conclusions
Functional imaging provides information on tumour
properties unavailable from conventional MR imaging.
A multimodal approach optimises the information
available and is increasingly improving our under-
standing of childhood tumours in situ. Clinically, func-
tional imaging can improve non-invasive diagnosis and
early treatment monitoring, as well as providing bio-
markers of prognosis. Further research is needed to
define the optimum use of functional imaging in a
clinical setting and integrate these promising new tech-
niques into routine practice to improve care of children
with cancer.
Funding
This work was supported by the National Institute
for Health Research (NIHR) grant code 13-0053. The
sponsor had no role in the writing of this report or the
decision to submit the article for publication.
Conflict of interest statement
None declared.
Acknowledgements
The authors would like to thank Dr Lara Wor-
thington, Dr Jan Novak, Dr Nigel Davies, Mrs Emma
Meeus and Mr Dominic Carlin for providing figures for
use in this manuscript. The authors would also like to
thank Dr Shivaram Avula the current chair of the
SIOPE-Brain Imaging Group for allowing the reporting
of their current brain tumour protocol and Dr Jan
Novak for his help with the abdominal tumour
protocol.
Appendix A. Supplementary data
Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.ejca.2016.10.037.
 K.A. Manias et al. / European Journal of Cancer xx (2016) 1e15 11

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