Key words
PET/MR - children - oncology - FDG
Introduction
Whole-body combined PET/MR imaging has found its way into clinical practice recently
and has opened up new possibilities for multiparametric morphologic and functional
imaging [1]. The first PET/MR studies identified clinical applications where PET/MRI as a combined
modality may have advantages over the established modalities of PET/CT and MRI, e. g.,
CNS imaging [2], local prostate imaging [3], or local oncologic staging [4]. Advantages are mostly seen in the superior soft-tissue contrast of MRI compared
to CT, the possibility of multiparametric tissue characterization using PET/MRI, and
the possible reduction of radiation exposure using PET/MRI compared to PET/CT. While
there is a lively debate about the clinical benefits and cost-effectiveness of many
of these applications, pediatric imaging is broadly recognized as one of the key drivers
for combined PET/MRI [5]. First clinical studies revealed possible advantages of PET/MRI over PET/CT, beyond
the significant reduction in radiation exposure, specifically in pediatric oncologic
patients [6]
[7]
[8].
This review article shall summarize the existing literature concerning pediatric PET/MRI
and give insight into the practical experience derived from over 160 pediatric PET/MRI
examinations that were performed in Tübingen.
PET/MR technology
Two different technical approaches to combined PET/MR have been proposed, namely,
sequential [9] and simultaneous [1]
[10] PET/MRI. In sequential PET/MRI, PET and MRI scanners are spatially separated, whereas
simultaneous imaging demands an integrated scanner. The sequential approach is technologically
less complex, as interference of MR magnetic fields and PET technology are minimized
by the spatial distance of the scanners. Especially in pediatric imaging, however,
where patient compliance may be limited, the simultaneous approach offers significant
advantages with regard to work flow and acquisition time and, importantly, in the
spatial and temporal correlation of PET and MRI. Commercially available simultaneous
systems are based on 3-Tesla MR systems and have a bore size of about 60 cm and axial
PET coverage of about 25 cm, which provides sufficient space for pediatric patients
and allows for whole-body PET examinations using five to seven bed positions in most
patients [1]
[10].
Work flow in pediatric PET/MRI
Work flow in pediatric PET/MRI
Patient preparation
Thorough patient preparation is a prerequisite for a successful PET/MR examination,
especially in pediatric imaging where patient compliance may be limited. The indication
for a PET/MRI examination should be established for each individual patient using
an interdisciplinary approach involving the pediatric radiologist, nuclear medicine
physician, and referring pediatrician. This includes the choice of the appropriate
PET tracer and the assessment of the need for patient sedation. Informed consent must
be acquired by the legal guardians before the examination. Specifics of patient preparation
(e. g., fasting before FDG application or before sedation) must be communicated.
For FDG examinations, it is of importance to avoid activation of brown adipose tissue
that has a high prevalence among pediatric patients and can impair diagnostic validity
of PET. For this purpose, patients should be kept warm before and after tracer injection,
and propanolol can be administered after consideration of contraindications [11]
[12]. Similarly, furosemide may be administered in order to minimize tracer accumulation
within the urinary bladder when examining the anatomic area of the pelvis. Additional
catheterization of the urinary bladder can also be considered in these cases. [12]
Examination protocol
The complexity and variability of PET/MR examination protocols is higher compared
to MRI or PET/CT, as specific patient preparation for PET and complex MR protocols
are combined. Numerous workflows have already been proposed for simultaneous PET/MRI
[13]
[14]. Despite the high number of possible acquisition strategies, in practice most pediatric
whole-body protocols show certain similarities.
[Fig. 1A] shows a standard FDG-PET/MRI acquisition protocol implemented in our institution
for pediatric oncologic whole-body imaging. After tracer injection, the patient rests
outside the scanner for most of the uptake time (in case of FDG, for 45 of the 60
minutes of uptake time). This allows for voiding of the urinary bladder before the
examination, reducing local radiation dose, and minimizing high activity PET artifacts
in the pelvic region. Subsequently, the patient is positioned within the scanner.
Fig. 1 Workflow in whole body FDG-PET/MRI used in our institution. A Routine whole-body FDG-PET/MRI workflow. Most uptake time is spent outside the scanner.
Examination starts with simultaneous PET and MRI, additional MRI sequences can be
appended. B Study protocol for sequential PET/CT and PET/MRI in a research setting. After a single
tracer injection PET/CT is performed first, then the patient is brought to the PET/MRI
scanner for the PET/MRI examination.
Abb. 1 Ablauf einer Ganzkörper-PET/MRT-Untersuchung an unserem Institut.
A Ablauf im Rahmen der klinischen Routine. Ein Großteil der Uptake-Zeit wird außerhalb
des Scanners verbracht. Die Untersuchung beginnt mit simultaner PET- und MRT- Messung;
zusätzliche MR-Messungen können angeschlossen werden. B Untersuchungsablauf bei sequentieller Durchführung von PET/CT und PET/MRT im Rahmen
klinischer Studien. Nach Tracer-Applikation erfolgt zunächst die PET/CT-Untersuchung;
anschließend wird der Patient zum PET/MRT transportiert, wo die PET/MRT-Untersuchung
durchgeführt wird.
Alternatively, tracer injection can be performed directly prior to the examination
and PET uptake time can be used for MR-only imaging. However, this approach not only
increases local radiation dose of the urinary bladder but also increases the potential
risk of premature termination of the examination by the patient before PET data are
acquired.
The examination usually starts with a basic module consisting of a whole-body PET
acquisition accompanied by simultaneous whole-body MR imaging, mostly using coronal
fat-saturated T2-weighted or inversion recovery sequences [7]
[13]
[14], in a bed-per-bed manner. Depending on the simultaneous MR protocol, PET acquisition
time is usually between 4 and 6 minutes per bed position. In addition, a dedicated
MR sequence has to be acquired for each bed position for MR-based attenuation correction.
On most scanners, a double-echo chemical shift gradient-echo sequence is used for
this purpose (Dixon technique) [15].
After this basic module, additional MRI sequences are usually measured depending on
the clinical question, available previous imaging, and patient compliance ([Fig. 2]). [Table 1] shows typical parameters of whole-body MR sequences used in our institution [16].
Fig. 2 Typical oncologic whole-body 18F-FDG-PET/MRI protocol. 2 year-old girl with recurrent
metastatic teratoma. Attenuation map (I), coronal STIR (III), and potentially diffusion-weighted
imaging (V, b = 800 s/m²) are acquired simultaneously with PET (II). Additional local
imaging of organ systems and the primary tumor in different orientations and contrasts
(VII) as well as contrast-enhanced whole-body images (VI) are acquired subsequently.
The red arrows mark a paravertebral metastasis with elevated 18F-FDG uptake, uptake
of contrast agent, and diffusion restriction. The blue arrow shows typical physiologic
18F-FDG-uptake of the thymus in children.
Abb. 2 Typisches onkologisches Ganzkörper 18F-FDG-PET/MRT-Protokoll. 2-jähriges Mödchen
mit metastasiertem Teratom.
Die Schwächungskarte (I), die coronare STIR (III) und ggf. diffusionsgewichtete Sequenzen
(V) werden gleichzeitig mit der PET-Messung aufgenommen. Zusätliche lokale Bildgebung
einzelner Organe oder des Primärtumors folgen im Anschluss in unterschiedlichen Orientierungen
(VII) und nach Kontrastmittelgabe (VI).
Die roten Pfeile markieren eine paravertebrale Metastase mit fokal erhöhter Glukosestoffwechselaktivität
und Diffusioneinschränkung. Der blaue Pfeil markiert die physiologische FDG-Anreicherung
des kindlichen Thymus.
Table 1
Typical sequence parameters used for whole-body MRI in PET/MRI in our institution.
Tab. 1 Typische Sequenzparameter, wie sie in unserem Institut implementiert sind.
|
Dixon AC
|
STIRcor
|
T2-TSE
|
STIRax
|
DWI
|
T1 Flash fs
|
TE (echo time) [ms]
|
1.23/2.46
|
78
|
100
|
81
|
60
|
1.5
|
TR (repetition time) [ms]
|
3.6
|
6400
|
3500
|
4500
|
6000
|
3.8
|
bandwidth [Hz/px]
|
965
|
383
|
260
|
220
|
1860
|
744
|
matrix size
|
79 × 192
|
256 × 256
|
256 × 300
|
197 × 384
|
108 × 192
|
320 × 180
|
resolution [mm³]
|
4.1 × 2.6 × 2.6
|
1.5 × 1.5 × 4
|
1.25 × 1.25 × 5
|
1.2 × 0.83 × 5
|
2.6 × 2.6 × 5
|
1.2 × 1.2 × 3
|
excitation angle [°]
|
10
|
120
|
90
|
120
|
90
|
10
|
inversion time [ms]
|
|
200
|
|
220
|
|
|
b-values [mm²/s]
|
|
|
|
|
50 and 800
|
|
approximate duration
|
18 sec
|
3 min
|
4 min
|
4 min
|
2 min
|
18 sec
|
Dixon AC: T1-weighted, double echo, gradient echo sequence for attenuation correction.
STIRcor: Coronal short tau inversion recovery (STIR) sequence. T2-TSE: Axial T2-weighted
turbo spin-echo sequence (mostly for abdominal imaging). STIRax: Axial STIR, used
for neck and lung imaging. DWI: Diffusion-weighted sequence. T1 Flash fs: Fat-saturated
3 D gradient echo sequence used for contrast-enhanced imaging.
A whole-body PET/MRI examination takes at least 20 – 30 minutes if only the basic
module (PET and simultaneous MRI) is acquired. However, a typical oncologic whole-body
PET/MR examination, including additional MR-only measurements, takes about 60 to 90
minutes including functional MRI (diffusion-weighted imaging, contrast-enhanced imaging)
and highly-resolved local tumor imaging.
Image interpretation and pitfalls
Reading and interpreting PET/MRI data is a complex task, as numerous different sequences
have to be analyzed together with PET data. This requires a high level of expertise
in pediatric MRI and pediatric nuclear medicine.
Compared with adult patients, children display different physiologic and anatomic
characteristics that lead to specific findings in PET and MRI (e. g., thymus tissue,
brown adipose tissue, etc.) [16]
[17] that have to be considered in order to avoid false interpretations. In our institution,
examinations are interpreted in consensus by multidisciplinary teams consisting of
a radiologist and a nuclear medicine physician. Results are routinely presented and
discussed at the institutional interdisciplinary pediatric tumor board.
A major issue when reading PET/MRI data is the choice of appropriate software tools
that can handle data amounts and complexity. Unfortunately, it is still felt among
PET/MR users that the availability of tailored software solutions for PET/MRI is rather
limited [5].
When reading PET/MRI data, certain technical drawbacks related to MR-based attenuation
correction have to be considered in order to avoid misinterpretation. In PET/MRI,
PET attenuation coefficients are not measured but usually derived based on tissue
segmentation using T1-weighted sequences [15]. In general, resulting PET quantification is accurate for adult and pediatric patients.
However, significant quantitative errors are observed in and around skeletal structures
(e. g., bone metastases and bone marrow) as bone attenuation is routinely neglected
[7]
[15]
[18]. Furthermore, typical segmentation artifacts can occur in MR-based attenuation correction
that are mostly observed around metal implants causing MR susceptibility artifacts.
Typical artifacts are summarized in [Fig. 3]. Although these artifacts do not have a significant impact on PET-based diagnoses
in the majority of cases [19], it is highly recommended to assess the quality of the MR-based attenuation map
as a first step in reading PET/MRI data.
Fig. 3 Typical segmentation artefacts of MR-based attenuation correction. A Patient with hepatic and splenic iron overload after chemotherapy. Liver and spleen
are segmented as lung tissue in the attenuation map (left) resulting in significant
underestimation of tracer uptake in these organs (right). B Patient with metal implant of the right chest wall causing susceptibility artefacts
with signal loss in the attenuation map (left) and local underestimation of tracer
uptake (right). C Segmentation error of lung tissue. The left lung is erroneously segmented as background
in the attenuation map (left) leading to a slight underestimation of tracer uptake
(right).
Abb. 3 Typische Segmentierungsartefakte der MR-basierten Schwächungskorrektur.
A Hepatischer und lienaler Signalverlust durch Einsenüberladung nach Chemotherapie.
Beide Organe sind fälschlicherweise als Lungengewebe segmentiert (links), was zu einer
Unterschätzung der FDG-Aufnahme führt (rechts). B Metallimplantat (Port-System) der rechten Thoraxwand. Lokale Suszeptibilitätsartefakte
führen zu Artefakten in der Schwächungskarte (links) und dadurch zu einer Unterschätzung
der FDG-Aufnahme (rechts). C Segmentierungsfehler der linken Lunge. Die linke Lunge wird fälschlicherweise als
Luft segmentiert, was zu einer geringfügigen Unterschätzung der Traceranreicherung
führt.
Indications for PET/MRI in pediatric oncology
Indications for PET/MRI in pediatric oncology
In general, combined PET/MRI is clinically indicated in all pediatric patients with
indication for a PET scan [20]. Available data show that PET measurements acquired on PET/MRI systems have equivalent
qualitative and quantitative characteristics compared to PET measurements of PET/CT
in adult and pediatric patients [7]
[8]
[18]
[21].
According to national [22]
[23] and international [12] guidelines for PET in children with cancer, 18F-FDG-PET is indicated for diagnosis,
staging, and restaging in a number of tumor entities, which are mainly lymphoma, sarcoma,
neuroblastoma, and CNS tumors.
The role of 18F-FDG-PET in imaging of pediatric lymphoma is well-established for initial
staging, risk stratification, and therapy monitoring [12]
[24]. Especially in Hodgkin lymphoma, PET imaging plays a decisive role for therapy response
monitoring and has a direct impact on diagnostic decisions concerning the indication
for radiation therapy [25]. In patients with sarcoma, 18F-FDG-PET can add additional information with regard
to risk stratification and detection of tumor recurrence [12]
[24]. In patients with neuroblastoma, the role of FDG-PET is limited to tumor characterization
and risk stratification complementing diagnostic information from MIBG-scintigraphy
[12]
[24] and to patients with MIBG-negative tumor load. However, new developments in radiopharmacy
may enable comprehensive characterization of neuroblastoma with PET only by using
fluoride-labeled 18F-MFBG [26] or specific antibody tracers [27].
For most applications in pediatric oncology, 18F-FDG is the standard tracer. For specific
indications, however, alternative tracers are used, e. g., 68Ga-DOTATATE for somatostatin
receptor imaging in neuroendocrine [28] tumors or amino acid tracers for CNS tumors [29].
Advantages and limitations of PET/MRI compared to PET/CT and whole-body MRI
Advantages and limitations of PET/MRI compared to PET/CT and whole-body MRI
The combination of PET and MRI in a single examination offers certain advantages over
the established modalities of PET/CT or MRI beyond the acquisition of separate PET
and MRI data.
Whole-body MRI is the method of choice for imaging of numerous oncologic disorders
in children, especially for primary diagnosis and staging [30]
[31]
[32]. For this purpose, MRI provides high sensitivity for lesion detection and excellent
soft-tissue contrast for local staging (up to 94 %) [16]
[33]. However, specificity may be limited in MRI (down to 30 %) especially in the follow-up
situation (e. g., in the assessment of residual disease in Hodgkin lymphoma) [33]. In this situation, the addition of PET can significantly increase diagnostic sensitivity
(up to 97 %) and specificity (up to 82 %) by combination of high anatomic resolution
and high sensitivity of MRI and complementary metabolic information of PET [33]. It is thus self-evident that combined PET/MRI is indicated in patients with indications
for whole-body MRI and PET. Compared to CT, MRI is diagnostically superior in characterization
of soft-tissue lesions and bone marrow processes as well as in local tumor imaging
[34]
[35]
[36]. Thus, PET/MRI can replace PET/CT in all applications where MRI is the modality
of choice for morphological imaging [7].
First prospective clinical studies with pediatric cancer patients have revealed at
least equivalent diagnostic accuracy of combined PET/MRI in direct comparison with
PET/CT, with possible advantages for PET/MRI in the detection and characterization
of soft-tissue lesions [7]
[8]. However, further studies in larger populations are necessary in order to fully
appreciate the diagnostic accuracy and clinical impact of PET/MRI in pediatric oncology.
Replacing two previously separate examinations (e. g., MRI and PET/CT and MRI and
PET for local and whole-body staging) with a combined examination has additional advantages
for pediatric patients beyond the diagnostic information of two different modalities.
For example, a combined examination significantly decreases examination time and reduces
the number of imaging studies. This is of importance due to possibly limited compliance
of pediatric patients. More importantly, however, by reducing the number of imaging
studies, the number of sedations and thus anesthesia-related risks [37] can be markedly reduced in young children.
A further advantage of simultaneous combined PET/MRI is the high spatial and temporal
correlation of imaging data. Anatomic allocation of PET and MRI can thus be increased
[38]. Furthermore, PET image quality can be improved by MR-based PET motion correction
[39].
The most-discussed motivation for pediatric PET/MRI compared to PET/CT is the marked
reduction in diagnostic radiation exposure (by 50 – 73 % [7]
[8]) that is achieved by replacing CT with MRI. Typical dose exposure by FDG-PET in
pediatric PET/MRI as reported in first clinical studies ranges from 4.8 ± 1.3 to 5.6 ± 1.5
mSv; the corresponding CT dose of PET/CT amounted to values ranging from 4.4 ± 1.7
to 18.2 ± 10 mSv [7]
[8]. Recent studies suggest that radiation exposure in childhood, especially by CT,
bears the risk of negative long-term effects including secondary malignancies [40]
[41]. In contrast to adult oncologic patients, pediatric patients often have an excellent
long-term prognosis [42] and receive numerous follow-up examinations with significant cumulative radiation
exposure [43]. In this context, the use of PET/MRI enables a significant reduction of cumulative
doses. Combined PET/MRI will also enable a reduction of PET tracer doses by prolonging
PET acquisition times. This is possible without increasing total acquisition time,
as MRI acquisition is usually more time-consuming and PET acquisition can be performed
simultaneously [44].
However, specific limitations of PET/MRI exist that must be mentioned. For instance,
detection of pulmonary lesions is still limited in MRI compared to CT. Although MRI
seems to be sufficient for pulmonary staging on a patient basis [45], small lung lesions can be missed in MRI [46]. It is thus recommended to perform an additional lung CT in patients with clinically
relevant risk for pulmonary spread, e. g., in the initial staging of sarcoma.
In addition, PET/MRI cannot be performed in patients with contraindications for MRI.
In these patients, PET/CT using dose-optimized protocols is an excellent alternative.
Finally, MR image quality is more dependent on patient compliance compared to CT.
This may result in reduced image quality in PET/MRI in single patients. However, our
experience in pediatric whole-body MRI and PET/MRI shows that older pediatric patients
usually collaborate well. For children younger than 6 – 8 years, sedation is usually
necessary for PET/CT and PET/MRI.
PET/MRI as a research tool in pediatric radiology and oncology
PET/MRI as a research tool in pediatric radiology and oncology
The availability of simultaneous PET/MRI scanners is very limited today. Existing
scanners are often used in the context of clinical studies.
Typically, PET/MRI studies are performed in order to assess the diagnostic value of
PET/MRI compared to other modalities for specific patient populations and clinical
questions. Often, PET/MRI is directly compared to PET/CT in these studies [7]
[8]
[10]
[21]
[38]
[45]
[47]. Performing studies of this kind in children is highly challenging. High ethical
and organizational demands must be considered, and patient compliance may interfere
with data acquisition. Despite these difficulties, prospective clinical studies are
of importance in order to identify patients that benefit most from combined PET/MRI.
[Fig. 1B] shows a typical research protocol for a comparative study of PET/CT and PET/MRI
used in our institution [16].
Equally important, PET/MRI is a potentially powerful tool for functional and molecular
imaging and for characterization of tissues. More than any other available imaging
modality, it can be used to assess changes in tumorous tissues during therapeutic
interventions. In the near future, PET/MRI will likely be used in the context of therapeutic
clinical studies for the purpose of monitoring therapy effects and thus will help
advance pediatric oncology.
Conclusion
Combined simultaneous PET/MRI is a promising modality for diagnosis, staging, and
therapy monitoring in pediatric oncology. It offers several advantages over PET/CT
and should thus be preferentially considered for pediatric patients where available.
For specific indications, PET/MRI can add significant complementary diagnostic information
to MRI-only. When performing PET/MRI, organizational challenges should be considered.
Limitations of the technique, especially concerning attenuation correction and lung
imaging, must be taken into account. Beyond clinical applications, PET/MRI is a potentially
powerful research tool that may help advance pediatric oncology in the future.