MRI is an effective method for imaging neuroblastoma . It shows high sensitivity in detecting bone marrow metastases, high intrinsic soft tissue contrast resolution, precise definition of intraspinal tumor extension, good delineation of diaphragmatic involvement of thoracic tumors [26,19]. WB MRI may represent a radiation-free alternative in the assessment of patients with NB and its feasibility has already been demonstrated for the work-up of oncologic patients with various neoplastic diseases, (e.g., melanoma, breast, colorectal, prostate cancers) or for hematologic diseases with nodal or bone marrow involvement (lymphoma, multiple myeloma) [27, 28].
WB MRI uses both conventional sequences which provide predominantly anatomical information, such STIR e T1 weighted sequences, and functional sequences, such DWI and/or DWIBS. As known, DWIBS is a particular DWI technique that provide functional information from entire body during free breathing, in high signal-to-noise ratio (SNR) images, leading to easy identification of small lesions and thereby helping to visualize the spread of the disease .
In particular, as regards neuroblastic tumors, DWI sequence, based on ADC maps, has been shown to be able to distinguish between benign and malignant neuroblastic tumors, and to be useful in evaluating the response to chemotherapy [30-33].
In the present study, we evaluated the diagnostic accuracy of WB MRI-DWIBS in the assessment of the burden of disease, compared to MIBG WB Scintigraphy considered as gold standard, applying SIOPEN scoring system to both methods. The SIOPEN scoring systems have been used in large international clinical trials, showing to provide important prognostic information that can be used to guide appropriate therapy .
Our study demonstrates a good concordance about diagnosis, response to therapy and stop therapy evaluation scored by SIOPEN system on MIBG WB Scintigraphy and WB MRI-DWIBS. The two diagnostic techniques showed a high agreement of 92.7% of segments evaluated (80,1% negative concordant sites and 12.6% positive concordant sites) and resulted discordant in only 7.2% of segments evaluated (3.5% DWIBS negative but MIBG positive sites and 3.7% DWIBS positive but MIBG negative sites). Both mean scoring values for positive segments and percentage of segments appear superimposable, with few light differences of performance and high Rho Spearman value.
The scoring evaluation shows in our court of segments about a 20% of metastatic involvement in bone marrow for skull, thorax, spine, pelvis, femur and tibia, less percentage for the other sites.
Most of few discordant results regards skull, thorax and pelvis (slightly more sensitivity of MIBG), spine and limbs (slightly more sensitivity of MRI). As for ribs and skull, the lower sensitivity of WB MRI might be explained by thin thickness of these bones; to overcome the weakness on this segment we could perform as additional sequence an axial STIR sequence with thin thickness.
WB MIBG and WB MRI had high statistically significant agreement. Thus, if we consider MIBG as gold standard, WB-MRI overall accuracy is 93%, sensibility 78%, specificity 95%, VPP 77% and VPN 96%. Otherwise, if we consider DWIBS as gold standard, MIBG overall accuracy is 93%; sensibility 77%; specificity 97%; VPP 78%; VPN 95%. Thus, MIBG and WB-MRI SIOPEN scoring resulted superimposable (Rho Spearman = 0,88, p < 0,0001) with a light prevalence for MRI for sensibility and a light prevalence for MIBG about specificity as well known in clinical practice.
Also, the mean value of scoring for each segment shows a light prevalence of WB MRI on WB MIBG because of the higher sensibility on smaller signal-alterations related to the different resolution of two diagnostic method: about 7 -10 mm for MIBG  and about 4 mm for MRI . Our data confirm also the assessment that MIBG scintigraphy is the best established and most widely used scintigraphic technique in the evaluation of NB because of its high sensitivity (97%) and specificity (83%-92%) . A combination of MRI and MIBG scintigraphy has been shown to achieve the best sensitivity and specificity in NB imaging .
However, scintigraphy exposes patients to ionizing radiation. This is a major concern in children, who are at higher risk because of their smaller body size, higher mitotic rate, and longer life expectancy , in particular for low and intermediate risk NB.
According to protocol HR-NB, at least 7 MIBG- scintigraphy are necessary during the different steps of therapy with a high number of diagnostic examinations, and increased risk of potential secondary malignancies [11,35]. Leverdiere et al. found that the cumulative incidence of second malignant neoplasms in long survivor of neuroblastoma was 3.5% at 25 years and 7.0% at 30 years after diagnosis. Compared with the sibling cohort, survivors had an increased risk of selected chronic health conditions (risk ratio [RR] = 8.3; 95% CI = 7.1 to 9.7) with a 20-year cumulative incidence of 41.1%. Endocrine complications are prevalent in childhood cancer survivors, with 50% experiencing at least one hormonal disorder over the course of their lives [36,37]. Moreover, Mostoufi et al. demonstrated at least one (16.7%) at least two (8,6%) and three or more (6.6%) endocrinopathies in survivors of neuroblastoma (31.9%) .
At our knowledge no other published study exists designed to perform a systematic comparison of SIOPEN Scoring on WB MIBG scintigraphy and on WB MRI-DWIBS. This may represent an important innovation about diagnostic evaluation and semiquantitative scoring of HR-NB and Intermediate-Risk NB. In our experience, the clinical introduction of WB MRI may be useful in diagnostic protocol of NB with very high accuracy in disease extension and functional complemental characterization of primary tumor and metastasis. This is even more important for those cases with weak or poor MIBG avidity, due to the degree of undifferentiation of tumor cells, as well as for neuroblastoma with loss of MIBG avidity at relapse, as demonstrated in two case of our series . Also, in our experience, a combination of MRI and MIBG scintigraphy showed to achieve the best sensitivity and specificity in NB imaging.
As known, a limitation of WB MRI is the light overestimation of bone lesions, especially in post-chemotherapy examinations. At the onset, the false-positive findings at DWIBS sequences are often due to the high signal of the regions rich in red bone marrow in the normal developing skeleton, above all in lumbar spine and pelvic skeleton as reported by Muller et al . Therefore, the radiologist experience is fundamental in the identification of these areas of physiological hyper-intensity.
WB MRI shows lightly less specificity compared to MIBG scintigraphy also during the evaluation of therapy response as it arises from our results, whose statistical analysis we have not reported because they are not reliable given the too small number of tests. This limit of DWIBS sequence can be explained in part by the so-called "T2 shine-through" phenomenon: high signal on diffusion-weighted images is not due to restricted diffusion, but rather to high T2 signal which 'shines through' to the DWI image. It can be overcome by evaluating the apparent diffusion coefficient (ADC), a value that measures the effect of diffusion independent of the influence of T2 shine-through , but our study lacks a quantitative analysis. Nevertheless, there are no validated bone ADC criteria in the literature, and there is a poor reproducibility of ADC measurements especially if the regions examined are "small". Furthermore, it should be added that especially in the evaluation of bone marrow there is a need to consider how the different types of treatment (chemotherapy, radiotherapy, immunotherapy) can affect the modification of the bone marrow signal intensity, data to date not yet clearly known [41,42]. These could be other interesting items for further studies.
An important limitation is given by the lack of a standardized technique in the execution of the WB MRI, with different protocols among the numerous published studies. Another weakness is the non-capillary diffusion of MRI instrumentation. Finally, the necessity of general inhalation anesthesia for less than four years old patients or for not collaborative ones, with the assistance of the pediatric anesthetist might be another limitation of MRI application. This is otherwise true also for scintigraphic acquisitions in particular for SPECT-CT modality.