Whole-body MRI in pediatric patients with cancer

WB MRI provides a single examination of the entire body without the use of ionizing radiation. In addition to the excellent contrast and spatial resolution of WB MRI, functional information is obtained which improves the capacity of this method to differentiate normal tissues from pathological tissues. MRI equipment is often available at both large and small centers, thereby facilitating the implementation of more advanced studies, such as MRI diffusion, perfusion, and WB studies [18, 19]. Furthermore, a complete disease assessment in the oncology setting, including detection of metastasis sites, in a single examination helps to reduce the number of patient visits to an imaging service, thereby reducing related costs [20].

Exposure to ionizing radiation is a major concern in pediatric patients with cancer [7]. However, imaging methods that use ionizing radiation sources, such as X-ray, CT, BS, and PET/CT, are often routinely employed [21, 22]. The risk of tumour development due to ionizing radiation exposure is related to the amount, intensity, and accumulation of the applied radiation over an individual’s life [23]. Newer CT scanners use iterative image reconstruction which reduces radiation exposure, although, exposure still occurs and repeated studies can incur a significant radiation dose for a patient. This risk increases when radiation exposure occurs at younger ages, especially exposure during childhood. In a recent study that examined the risks associated with the use of imaging methods that employ ionizing radiation for diagnostic purposes, an estimated 29,000 new cancer cases were found to be related to the number of CT scans performed in the United States in 2007, with 15% of the estimated cancers associated with scans that were performed on patients younger than 18 years [24, 25]. An advantage of WB MRI is that it can be applied to at-risk populations, including those that may be affected by familial syndromes, to conduct cancer screenings. Advances in genetics have enabled the identification of patients with hereditary syndromes related to the development of neoplasms. The goal of performing WB MRI for cancer screenings is to detect malignancies in their early stages when the effectiveness of treatments and cure rates are optimal [26, 27]. Ideally, screenings should be applied to apparently healthy populations that are at high risk for tumour development. Examples of inherited syndromes that are associated with increased risks of cancer include: multiple endocrine neoplasias I and II (e.g., endocrine tumours), Von Hippel-Lindau syndrome (e.g., renal carcinomas), familial adenomatous polyposis (e.g., colorectal tumours), and Li-Fraumeni syndrome (e.g., various types of tumours including sarcomas) (Fig. 1) [28‐31]. Correspondingly, a new screening protocol that involves WB MRI has recently been proposed for patients with Li-Fraumeni syndrome [32].

To date, there is no overall consensus regarding a WB MRI protocol for children. Typically, T1 and T2 imaging are performed with free-breathing, suspended respiration, or physiological motion control. It is also widely accepted that short tau inversion recovery (STIR) sequences and diffusion add diagnostic value to WB MRI examinations. Depending on a pediatric patient’s age and size, a complete set of images are obtained in a single acquisition (e.g., for infants), or in two or more segmental acquisitions (e.g., for older children and adolescents). The images are subsequently aligned using specific software to enable visualization of the entire body [20, 33]. WB MRI should be performed with high-field (≥1.5 Tesla) equipment with surface and/or body coils. Dedicated pediatric receiver coils are currently being introduced and will progressively have increased availability. Patients should be examined from head to toe in a supine position with their arms parallel to the body and their legs together. Coronal acquisition, which is more rapid than other approaches, is preferred, although at least one sequence (e.g., diffusion) should be acquired in the axial plane to compensate for the limitations associated with coronal acquisition (e.g., for the ribs, sternum, cranium, and spine) [34]. Sagittal acquisition is helpful for evaluating the spine. However, depending on the manufacturer, it is possible to perform axial T1-weighted acquisitions without wasting time. Moreover, synchronization of respiratory and cardiac movements can be achieved with external gates to avoid physiological motion artifacts [5, 33].

Conventional sequences, including T1- and T2-weighted spin-echo sequences, are usually performed without the administration of a paramagnetic contrast medium. Malignant lesions are usually hypointense (low signal intensity) on T1-weighted images (Fig. 1) and have a high signal intensity on T2-weighted images [35].

The STIR sequence is highly sensitive for the detection of pathologic lesions. Bone marrow lesions, including marrow infiltration from lymphoma, metastases, and tumour-related edema, exhibit high signal intensity on STIR sequences (Figs. 2 and 3). Focal parenchymal lesions can be distinguished by their slightly different signal intensity in STIR sequences, while pathologic lymph nodes cannot be differentiated from normal nodes on the basis of signal intensity. The STIR technique also cannot be used to differentiate benign conditions from malignant neoplastic lesions. The latter limitation restricts the application of STIR in WB MRI in oncologic patients after treatment, since therapy-induced marrow changes, such as edema, necrosis, fibrosis, or red marrow hyperplasia, cannot be differentiated from viable tumours. However, STIR may be very useful in staging pediatric tumours; although, additional clinical experience and data are needed to determine its efficacy [36, 37].

Diffusion-weighted MRI sequences are increasingly being employed for WB evaluations of patients with cancer (Fig. 4). These sequences detect the random motion of water molecules, also known as Brownian motion, through biological tissues by detecting the protons in the water molecules. The movement of the water molecules causes a phasic dispersion of proton spin, thereby resulting in signal loss due to diffusion sensitivity. The signal intensity of an object of study is analyzed quantitatively by calculating the absolute apparent diffusion coefficient (ADC, in mm²/s) of the object relative to the diffusion of water molecules in the proximal region [16, 38]. This qualitative and quantitative analysis is primarily influenced by the presence of barriers that restrict the diffusion of water molecules in their microenvironment, and this produces imaging contrast between tissues. Thus, the signal intensities and ADCs of different tissues are distinct as a result of their structural characteristics. The restricted diffusion of water molecules that characterises malignant tumours is potentially due to the increased cell density of these tumours, thereby resulting in increased signal intensity in DWI and reduced ADCs, both of which facilitate detection of malignant lesions [16]. However, it should be noted that particularly in children, a high signal in DWI with body background suppression (DWIBS) can be a normal finding in the bony pelvis and lumbar spine. The different types of tissues with high cellularity that are present within these bones contribute to this high signal [39].

Currently, paramagnetic contrast agents can be used in WB MRI examinations, although they are not always indicated. It has been considered that the addition of post-contrast sequences significantly increases examination time and that the behavioral characteristics of lesion enhancement cannot be examined in the arterial, venous, and equilibrium phases simultaneously in WB scans, especially when multiple organs are involved [40]. However, strategies have been developed to address these limitations. For example, the Dixon technique achieves a uniform separation of water and fat that is resistant to large-field inhomogeneities compared to fat suppression by chemical shift selective saturation (CHESS) [41]. Furthermore, when properly implemented, the Dixon technique can be used to acquire either T1-weighted [42] or T2-weighted [43] images within a single breath hold. These rapid Dixon sequences have been successfully incorporated into a WB MRI protocol that is capable of providing multisequence and multiplanar scans, including triphasic (arterial, portal-venous, and equilibrium or delayed) contrast-enhanced imaging of the liver, in approximately 1 h [44]. This Dixon-based WB MRI with multisequence and multiplanar images are also complementary and facilitate high-confidence reading, while multisequence and triphasic contrast-enhanced abdominal imaging is very useful for the detection and characterization of lesions in the liver, an imaging examination that is more commonly performed in adult examinations [44, 45]. On the other hand, however, it is important to consider that administration of paramagnetic contrast agents are associated with some risks, such as those for accidental puncture, allergic reaction, renal failure, and nephrogenic systemic fibrosis [46]. Consequently, the prudent use of gadolinium-based contrast agents to avoid or minimise the risk of nephrogenic systemic fibrosis cannot be overemphasised, as pediatric oncologic patients are more likely to have impaired renal function secondary to anti-cancer therapy [47]. Pediatric patients should also be examined for hepatic lesions following the administration of paramagnetic contrast reagents, despite hepatic lesions being less frequent in children than in adults.

For patients who are unable to receive gadolinium-based contrast agents, ferumoxytol may be a useful MRI contrast agent. Ferumoxytol is an ultrasmall superparamagnetic iron oxide (USPIO) that is comprised of iron oxide particles surrounded by a carbohydrate coat. Initially, this agent was used to treat anemia in patients with chronic renal failure [48]. However, more recently, ferumoxytol has been investigated as an intravenous contrast agent in MRI. The advantages of ferumoxytol include its ability to be administered as a bolus injection, allergic and idiosyncratic reactions with its administration have been limited, and it is not associated with a risk for nephrogenic systemic fibrosis [48, 49]. Femuroxytol also has a long intravascular half-life of 14–15 h [50], and thus, can be used to obtain different types of images. However, there is currently a paucity of data available regarding its use as a paramagnetic contrast agent.

WB MRI can be applied for lesion detection/staging, evaluation of treatment response, and follow-up and screening of children with cancer predisposition syndromes.

Clinical indications for WB MRI in pediatric patients with cancer depend on the disease type and stage of management. For several types of neoplasms, WB MRI has been shown to be a valid alternative to CT, PET/CT, and scintigraphic studies [20, 35, 47]. Many studies have also shown that WB MRI can be applied at different times during cancer management, including during the screening, staging, response evaluation, and post-therapeutic follow-up stages [5, 20].

The capacity for WB MRI to detect lesions depends on several factors, including the anatomic site, size, histological type, and differentiation grade of the lesions being examined. WB MRI has exhibited good diagnostic accuracy in the staging of a variety of tumours, including both lymphomas and solid tumours [51]. In fact, staging of these neoplasms contributed to the development of this examination technique [5, 51]. Currently, WB MRI can detect lesions present in various anatomical sites, such as the brain, cervical region, thoracic organs, abdomen, bone marrow, and musculoskeletal system. The performance of WB MRI has also been shown to be similar to that of PET/CT in the staging of different cancers, and superior to CT, BS, and scintigraphy with gallium in evaluations of certain osseous and extra-osseous metastases [35, 52, 53].

WB MRI enables a proper assessment of WB bone marrow and the detection of compromised neoplastic sites, including primary tumours and metastases arising from diffusion [37]. However, since normal red marrow impedes diffusion, this may confound disease detection in younger children. Patients with melanoma and Langerhans cell histiocytosis may be evaluated with WB MRI. In fact, the sensitivity, specificity, and accuracy of this method in these cases has been found to similar or superior to those of other methods, including those employing MIBG [20, 54]. WB MRI has also been shown to perform well in the detection of bone metastases, with a higher positive predictive value (94 vs. 76%, respectively) and greater sensitivity (99 vs. 26%, respectively) observed compared with bone scintigraphy [35]. The use of WB MRI is limited in the detection of rib and skull lesions, although the use of respiratory synchronization (triggering) has been shown to reduce the occurrence of motion artifacts, thereby improving the ability of WB MRI to evaluate these anatomic sites [20, 55].

MRI provides different image contrasts that represent specific tissue characteristics. This is important for evaluations of primary tumours and metastases in the brain. Furthermore, if a lesion is detected in the brain or in another part of the body during a WB MRI exam, then a region-specific exam also needs to be conducted. Thus, for patients with Li-Fraumeni syndrome who have an elevated risk of brain tumours, a brain-specific protocol should be added to a WB MRI protocol.

Oncologic patients may undergo multiple MRI, thereby receiving repeated administrations of a gadolinium-based contrast agent. A high signal in the dentate nucleus and globus pallidus on unenhanced T1-weighted images should be cautiously evaluated in these patients, since the signal observed may be a consequence of the number of times that a gadolinium-based contrast material was administered, and not due to the presence of pathologic lesions [56, 57].

Currently, the most important clinical applications of WB MRI in children include the staging of malignant disease and screening for metastatic spread. These applications are particularly relevant in cases involving lymphoma and solid tumours.

WB MRI can be used to evaluate therapeutic response in pediatric oncology patients [51, 60, 61], and the information obtained can be used in combination with Response Evaluation Criteria in Solid Tumors (RECIST) [61]. For example, WB MRI can provide a morphological assessment of target lesions by measuring their major axes according to RECIST, while also providing a functional evaluation of lesions with diffusion sequences. Several studies have described the use of WB MRI to identify partial or complete responses, including increased absolute ADC, after the application of chemo- or radiotherapy to brain tumours, liver tumours, and sarcomas [62, 63]. Similar to CT and PET/CT, WB MRI can also be useful in evaluating significant morphological and functional improvements in lymphomas (Fig. 8), and these are often characterised by an inverse correlation between the tendency toward increased ADC and reduced tumour volume [35, 52]. Furthermore, WB MRI can help distinguish between abnormal scarring and recurrence after therapy [64], thereby enabling the detection of any complications that are related or unrelated to disease or treatment.

Cancer predisposition syndromes include a multitude of cancers in which a mode of familial inheritance has been clearly established, although a specific genetic defect may not have been identified [65]. WB MRI has been useful in the screenings of children with cancer predisposition syndromes, and it also has the potential to provide a preclinical diagnosis of any associated tumours. For example, at some institutions, WB MRI is performed annually to screen for tumours in children with Li-Fraumeni syndrome (Fig. 9). Li-Fraumeni syndrome is an autosomal dominant hereditary syndrome that is caused by a loss-of-function mutation in the TP53 gene and affected individuals have a lifelong increased risk of osteosarcoma (Fig. 10), soft-tissue sarcoma, leukemia (Fig. 11), breast cancer, brain tumour, melanoma, and adrenal cortical tumours [65]. Similarly, individuals with hereditary retinoblastoma (RB) have a very high risk of developing subsequent malignant neoplasms, with osteosarcoma being the most common. When WB MRI screening tests were performed for survivors of hereditary RB, the sensitivity and specificity of detecting subsequent malignant neoplasms was 66.7 and 92.1%, respectively [66].

The use of WB MRI in pediatric oncological clinical practice is limited in some cases. For example, standard contraindications to conventional MRI, such as the presence of metallic body implants or history of claustrophobia, can also preclude the use of WB MRI. Due to the examination time of WB MRI (which can range from 30 min to 1 h), the use of sedation or general anesthesia is typically needed in a significant proportion of pediatric patients, especially those who are young or uncooperative. Thus, the risks associated with these agents must be considered. Immobilization during the examination is also essential for preventing motion artifacts which can impair image acquisition and interpretation of the findings. In addition, physiological artifacts related to respiratory movements, heartbeat, and intestinal peristalsis can impair image acquisition [67]. To minimise the occurrence of these artifacts, multi-channel equipment, body coils, and parallel imaging can be employed. Furthermore, single-shot acquisition, the use of presaturation bands in the anterior body, and mechanisms of synchronization with respiratory and cardiac movements can reduce the time needed for an examination and facilitate the acquisition of highquality images [67, 68]. Finally, the occurrence of false-positive results is another limiting factor in the use of WB MRI. For example, inflammatory abnormalities, infections, and even benign lesions such as simple cysts or vascular lesions have been found to simulate malignant lesions [67].