The Impact of PET/CT on Paediatric Oncology

This review paper will discuss the use of positron emission tomography/computed tomography (PET/CT) in paediatric oncology. Functional imaging with PET/CT has proven useful to guide treatment by accurately staging disease and limiting unnecessary treatments by determining the metabolic response to treatment. 18F-Fluorodeoxyglucose (2-[18F]FDG) PET/CT is routinely used in patients with lymphoma. We highlight specific considerations in the paediatric population with lymphoma. The strengths and weaknesses for PET/CT tracers that compliment Meta-[123I]iodobenzylguanidine ([123I]mIBG) for the imaging of neuroblastoma are summarized. 2-[18F]FDG PET/CT has increasingly been used in the staging and evaluation of disease response in sarcomas. The current recommendations for the use of PET/CT in sarcomas are given and potential future developments and highlighted. 2-[18F]FDG PET/CT in combination with conventional imaging is currently the standard for disease evaluation in children with Langerhans-cell Histiocytosis (LCH) and the non-LCH disease spectrum. The common pitfalls of 2-[18F]FDG PET/CT in this setting are discussed.


Introduction
The overall survival of children with cancer has improved significantly in the past decades, which has led to a shift in the management of childhood malignancies. Noninvasive imaging has assisted in the evaluation of children with a known or suspected disease. With the longer survival of these patients, it is clear that many patients suffer severe long term side effects from the treatments [1,2]. The treatment aim in paediatric oncology is to achieve a cure with the minimum long-term side effects. Functional imaging with positron emission tomography/computed tomography (PET/CT) has proven useful to guide treatment in paediatric malignancies by accurately staging disease, restaging, evaluating treatment response and limiting unnecessary treatments by determining the metabolic response to treatment and the prognostic significance thereof. In this paper, we review the most frequently imaged paediatric neoplasms seen in the clinical setting, e.g., brain tumours, osteosarcoma, Ewing Sarcoma, neuroblastoma and lymphoma. We look at the most commonly used PET tracer, 18 F-Fluorodeoxyglucose (2-[ 18 F]FDG) PET/CT and its utility in improving the management of the aforementioned neoplasms [3].

Paediatric Lymphoma
Lymphoma is one of the most prevalent paediatric malignancies [4]. Hodgkin lymphoma (HL) is common in adolescence. The most common histological HL subtype is nodular sclerosing HL. Non-Hodgkin lymphoma (NHL) is more common (60%) in children than HL (40%). Common NHL subtypes include Burkitt and Burkitt-like, precursor T-cell, diffuse large B cell, and anaplastic large cell lymphoma. Indolent lymphomas are rare in children [5]. 2-[ 18 F]FDG PET/CT is now established as the reference investigation for paediatric patients with HL and NHL [6]. Nodes in the right axilla is smaller than before but, still enlarged. Uptake in these nodes is less than liver (Deauville score = 2); this is a complete metabolic response.
Immune-base therapies can lead to flare/pseudoprogression of lesions on follow-up PET/CTs. It is important to differentiate true from pseudoprogression. This has led to the development of the new LYRIC criteria as an indeterminate-response category [11].
There is growing evidence for the utility of using machine learning methods for semiquantification, such as convolutional neural networks (CNN). Recent work by Nodes in the right axilla is smaller than before but, still enlarged. Uptake in these nodes is less than liver (Deauville score = 2); this is a complete metabolic response.  [5,13].
Immune-base therapies can lead to flare/pseudoprogression of lesions on follow-up PET/CTs. It is important to differentiate true from pseudoprogression. This has led to the development of the new LYRIC criteria as an indeterminate-response category [11].
There is growing evidence for the utility of using machine learning methods for semiquantification, such as convolutional neural networks (CNN). Recent work by Etchebehere  [20]. Uptake in lesions may also be discordant due to heterogenous tumour biology. 2-[ 18 F]FDG PET/CT is a valuable tool in children with [ 123 I]mIBG-negative disease or where there are discordance in uptake between [ 123 I]mIBG and anatomical images [21].
If a lesion is not [ 123 I]mIBG-avid at diagnosis, it is associated with better prognosis due to better tumour biology and lower proliferation index. As the tumours are treated, it may also lose its [ 123 I]mIBG avidity due to tumour differentiation, and turn into a more benign pathology such as ganglioneuroma, 30% of which do not take up [ 123 I]mIBG [21]. In a second group of patients, it may be an indication of a worse prognosis due to tumour dedifferentiation, especially if there is discordance between the [ 123 I]mIBG and 2-[ 18 F]FDG uptake. Higher 2-[ 18 F]FDG has been found to be associated with poorer prognostic markers, such a N-MYC amplification [22].
[ 123 I]mIBG is not normally taken up in bone or bone marrow; therefore, if abnormal uptake is seen in skeletal elements, the findings are in keeping with metastatic disease involving the bone marrow with or without cortical bone involvement. This is one of the reasons why [ 123 I]mIBG is considered superior to 2-[ 18 F]FDG for the detection of bone marrow uptake, as 2-[ 18 F]FDG has low grade diffuse uptake in normal bone marrow [23]. Despite this apparent weakness of 2-[ 18 F]FDG for the detection of bone marrow involvement, pathological 2-[ 18 F]FDG in bone marrow is a reliable predictor of bone marrow involvement. This holds true especially for the baseline imaging. Diffuse increased in bone marrow uptake on an interim of post treatment 2-[ 18 F]FDG PET/CT is part of the treatment response and may be falsely interpreted as pathological uptake [24].
2-[ 18 F]FDG is better than [ 123 I]mIBG for the evaluation of soft tissue disease. This is partly due to the higher spatial resolution as well as the routine addition of the CT component, which helps to differentiate between physiological and pathophysiological uptake in soft tissues [23].
Another important limitation of 2-[ 18 F]FDG is the high physiological uptake of 2-[ 18 F]FDG in the brain, which hampers the evaluation of skeletal involvement in the skull, a frequent site of metastatic disease [21].

[ 124 I]mIBG PET/CT in Neuroblastoma
[ 124 I]mIBG a PET/CT tracer has not entered the realm of routine clinical use due to a number of limitations. This tracer has a relatively long half-life, 4.2 days, which means that is it still a two-day imaging procedure. It has a positron abundance of only 23%, which leads to a relatively low image quality compared to other PET/CT tracers. There is also still a need to block the thyroid gland prior to imaging [21].  [25].
In laboratory studies, it has been shown that 77 to 89% of neuroblastoma cells express somatostatin receptors. The use of [ 68 Ga]DOTA-SSA PET/CT in neuroblastoma is promising. In a small study [ 68 Ga]DOTA-SSA uptake was confirmed in eight children with relapsed neuroblastoma. Four of these children went on to receive peptide receptor radionuclide therapy (PRRT) [26]. The largest study available at this time is a study by Gains et [27].
The use of [ 68 Ga]DOTA-SSA in neuroblastoma has a number of advantages compared to [ 123 I]mIBG. The imaging protocol is easier, with imaging being done 1 h after injection compared to the 24 h images of [ 123 I]mIBG. Patient preparation is also easier, as there is no need to block the thyroid [28,29]. There is a long list of medications that interfere with [ 123 I]mIBG uptake, including medications commonly used in children, such as over the counter cold and flu preparations [30]. Somatostatin therapy, which is rarely used in children, is the only treatment that needs to be stopped prior to [ 68 Ga]DOTA-SSA imaging [29]. 68 Gallium is obtained from a generator and is therefore readily available in centres with the 68 Germanium/ 68 Gallium generator; in contrast, [ 123 I]mIBG is cyclotronproduced, which hampers availability in centres far from a cyclotron. Finally the special resolution with PET tracers is better than that of [ 123 I]mIBG, Figure 2 [21].  [28,29]. There is a long list of medications that interfere with [ 123 I]mIBG uptake, including medications commonly used in children, such as over the counter cold and flu preparations [30]. Somatostatin therapy, which is rarely used in children, is the only treatment that needs to be stopped prior to [ 68 Ga]DOTA-SSA imaging [29]. 68 Gallium is obtained from a generator and is therefore readily available in centres with the 68 Germanium/ 68 Gallium generator; in contrast, [ 123 I]mIBG is cyclotron-produced, which hampers availability in centres far from a cyclotron. Finally the special resolution with PET tracers is better than that of [ 123 I]mIBG, Figure 2 [31]. There is growing interest in the use of PRRT in these patients [32,33].

[ 18 F]F-DOPA PET/CT in Neuroblastoma
L-dihydroxyphenylalanine (L-DOPA) is a precursor of dopamine and it can be labelled with 18 [31]. There is growing interest in the use of PRRT in these patients [32,33].

Other Tracers in Neuroblastoma
Meta-[ 18 F]Fluorobenzylguanidine ([ 18 F]mFBG]) has a similar uptake mechanism to [ 123 I]mIBG [21]. This is still and experimental tracer and has been reported in the preclinical setting as well as in a small study which reported uptake three-times higher than in-vivo [ 123 I]mIBG in neuroblastoma [37]. A small clinical study by Pandit-Taskar et al. conducted the first-in-human use of this tracer, of which five patients had neuroblastoma. This study demonstrated the benefits of single day imaging versus two days with [ 123 I]mIBG, which will be beneficial in the paediatric setting, and improved spatial resolution and image detection. This will be of great benefit once the tracer becomes more readily available [38].
Carbon-11( 11 C)-labeled meta-hydroxyephedrine ([ 11 C]mHED is a noradrenaline analogue that has been investigated for use in neuroblastoma. In limited studies this tracer has shown higher diagnostic accuracy than [ 123 I]mIBG. The use of this tracer is limited by its short half-life and the need for an onsite cyclotron. The advantage of this tracer is lower radiation exposure due to its short half-life [21,39,40]. The different tracer for use in neuroblastoma is summarised in Table 1. One of the weaknesses of bone scintigraphy identified in this study were the detection of lesions close to the growth plates [42]. A number of smaller studies also confirmed superiority of 2-[ 18 F]FDG PET/CT for the detection of bone metastases [43]. Dedicated lung CT scans are still the investigation of choice for the evaluation of lung metastases. 2-[ 18 F]FDG PET/CT has a lower sensitivity for detecting small lung metastases [43,44]. 2-[ 18 F]FDG avidity can be useful in differentiating between benign and malignant lesions. However, if a lung lesion is 2-[ 18 F]FDG-avid, standard uptake value (SUV) > 1, it is more likely to be a lung metastasis [45].
Detecting disease recurrence at the site of surgical resection in the region of the limb prosthesis is one the most difficult areas in medical imaging. There is a foreign body reaction with low grade 2-[ 18 F]FDG uptake around the limb prosthesis which may persist for a long period of time. Uptake around the prosthesis is usually more intense at 12 and 18 months after surgery than 3 months after surgery. If there is high 2-[ 18 F]FDG uptake, SUVmax > 4.2, at the time of suspected recurrence and if uptake increases significantly with successive scans, ∆SUV > 75.0, 2-[ 18 F]FDG PET/CT has a sensitivity, specificity and accuracy for detecting local recurrence of 78, 94 and 93% [46].
A good histopathologic response, >90% necrosis, after neoadjuvant chemotherapy, is a predictor of favourable response to treatment [46]. Using 2-[ 18 F]FDG PET/CT as a surrogate investigation prior to surgery to assess the response to neoadjuvant treatment has been investigated. A significant decrease in 2-[ 18 F]FDG uptake from baseline to the end of neoadjuvant chemotherapy is an independent predictor of disease and histological response. Patients with persistent high or increasing 2-[ 18 F]FDG uptake despite neoadjuvant treatment have a poorer progression towards survival [47]. The use of 2-[ 18 F]FDG to adapt treatment strategies in children with poor response to neoadjuvant chemotherapy still needs to be investigated further [44].

Ewing Sarcoma
Ewing sarcoma is the second most common paediatric bone tumour with an incidence of 3 per million per year [43]. It usually arises from bones but may also arise from soft tissue. Unlike osteosarcoma [48], it also metastasizes to soft tissue and bone marrow. The most frequent metastatic lesions occur in lung and bone [49].
Hybrid PET/CT imaging is superior to standalone PET imaging. A small study, 13 patients including six patients with metastatic bone disease, found that 2-[ 18 F]FDG PET/CT detected more bone lesions but missed two lesions in the skull due to high physiological FDG uptake in the brain [52]. Another small study showed that 2-[ 18 F]FDG PET/CT detected bone metastases in 11 of 12 patients with bone metastases; the false negative study was in a patient with a sclerotic bone lesion. In comparison, bone scintigraphy detected bone metastases in nine of the 12 patients; the three false negative studies occurred in patients with lytic bone lesions [53].
A meta-analysis which included 31 studies and 735 patients found that the pooled sensitivity of 2-[ 18 [58], Figure 3.
The value of 2-[ 18 F]FDG PET/CT to predict treatment response and overall survival is still under investigation. If a patient has a positive 2-[ 18 F]FDG PET/CT at relapse, it is associated with a shorter overall survival [59]. In a study of 28 patients with nonmetastatic Ewing sarcoma the tumour SUV, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were measured at baseline and after completion of neoadjuvant chemotherapy. A ∆TGL with a cut-off of −60% was the best predictor of histological response, with a 100% sensitivity and a 77.8% specificity. However, SUV at the completion of neoadjuvant chemotherapy of >3.3 and a ∆TGL of less than −18% were independent predictors of worse overall survival on multivariate analysis [60].
Several other studies looking into the predictive role of 2-[ 18 F]FDG PET/CT in Ewing sarcoma demonstrated heterogeneous results. A study by Raciborska et al., which looked at 50 patients with Ewing sarcoma that had imaging done at diagnosis and prior to induction of chemotherapy to assess histological response and PET metrics, demonstrated a positive correlation between SUV at diagnosis and response after neoadjuvant chemotherapy. Patients with SUV > 2.5 had a higher risk of relapse and death [61]. A relatively similar study also looked at 2-[ 18 F]FDG PET/CT metabolic indices in assessment of histological response to neoadjuvant chemotherapy in 31 patients with Ewing sarcoma and osteosarcoma did not demonstrate a predictive role; however, it confirmed that 2-[ 18 F]FDG PET/CT was superior in detecting skeletal and soft tissue lesions and that conventional imaging was superior in detecting small pulmonary metastases, as seen in Figure 3 [62]. A children's hospital in Egypt also looked to assess the predictive value of 2-[ 18 F]FDG PET/CT parameters in histological response to neoadjuvant chemotherapy and recommended a SUVmax cut off value Diagnostics 2023, 13,192 9 of 17 of <2.5 to predict histological response. This, however, had a wide confidence interval. The limiting factors in these studies are the retrospective nature and small size of the studies, which make inferences on the predictive role of 2-[ 18 F]FDG PET/CT metabolic parameters difficult to conclude with certainty in the absence of larger prospective studies [63].
Diagnostics 2023, 13, 192 9 of 18 nature and small size of the studies, which make inferences on the predictive role of 2-[ 18 F]FDG PET/CT metabolic parameters difficult to conclude with certainty in the absence of larger prospective studies [63]. Additional imaging of primary bone tumours utilizing PET/CT has been explored in adults with [ 18 F]NaF (Sodium Flouride), which has similar characteristics to [ 99m Tc]Tc-MDP but improved resolution. The benefits are the half-life and imaging an hour after injection in comparison to three to four hours with [ 99 mTc]Tc-MDP, and improved sensitivity. The role of [ 18 F]NaF in primary bone tumours in paediatrics is not wellestablished [64,65].

Rhabdomyosarcoma
Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents. This tumour can metastasize to lymph nodes, lung, bone marrow and bone [44].
In 2021, a Cochrane review assessing the usefulness of 2-[ 18 F]FDG PET/CT in staging of rhabdomyosarcoma based on only two studies with a total of 36 patients concluded that there was no convincing evidence for the use of this modality for the staging in this tumour and that larger studies were needed [66].
The  Additional imaging of primary bone tumours utilizing PET/CT has been explored in adults with [ 18 F]NaF (Sodium Flouride), which has similar characteristics to [ 99m Tc]Tc-MDP but improved resolution. The benefits are the half-life and imaging an hour after injection in comparison to three to four hours with [ 99 mTc]Tc-MDP, and improved sensitivity. The role of [ 18 F]NaF in primary bone tumours in paediatrics is not well-established [64,65].

Rhabdomyosarcoma
Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents. This tumour can metastasize to lymph nodes, lung, bone marrow and bone [44].
In 2021, a Cochrane review assessing the usefulness of 2-[ 18 F]FDG PET/CT in staging of rhabdomyosarcoma based on only two studies with a total of 36 patients concluded that there was no convincing evidence for the use of this modality for the staging in this tumour and that larger studies were needed [66]. The

Nephroblastoma
2-[ 18 F]FDG PET/CT has not significant impact on the management of patients with nephroblastoma compared to other imaging modalities. Nephroblastoma frequently metastasizes to the lungs and PET/CT will unfortunately miss smaller lung metastases [68].

Pediatric Brain Tumours
The use of 2-[ 18 F]FDG is limited in paediatric brain tumours due to the high physiological brain uptake of the tracer [69]. This tracer has proven to be useful in detecting distant metastases in patients with glioblastoma [70].
In This also opens up the possibility of treatments with GRPR-targeted therapy [71].
A number of tracers have been investigated in this setting of paediatric brain tumours; these include, [ 18

Langerhans-Cell Histiocytosis
Langerhans-Cell Histiocytosis (LCH) is one of the most common of the Histiocytosis. Globally, the incidence is 5-9 per million children under the age of 15 years [74]. LCH has a varied clinical presentation with patients presenting with solitary lesions to multisystemic disease [75]. The implications of imaging are important to characterize whether patients have low vs high-risk LCH, particularly with the association of BRAF V600E mutation [76].
The most common area affected In LCH is the skeleton (78-90%), with the skin and pituitary gland being affected in 33% and 25% of patients, respectively [77,78]. Other organs can be affected, such as the spleen, liver, haemopoetic system, lung (at 15%), lymph nodes (up to 10%) and central nervous system excluding the pituitary gland (2-4%) [74]. The use of 2-[ 18 F]FDG PET/CT in LCH has grown significantly over the last decade in diagnosis, staging, and response assessment in patients with LCH, particularly in distinguishing single-system LCH (SS-LCH), low-risk multisystem LCH (MS-LCH), and multisystem LCH, which have different treatment implications for the referring clinician, as can be observed in Figure 4 [74,79].
2-[ 18 F]FDG PET/CT is recommended in the current National Comprehensive Cancer Network (NCCN) guidelines for staging and response assessment [80]. Multiple studies have demonstrated the utility of 2-[ 18 F]FDG PET/CT to detect more lesions than conventional imaging in multiple sites [81][82][83][84]. Jessop et al. reported a sensitivity and specificity of 100% and 83%, respectively, with low false positive rates [79]. The skull being one of the most affected skeletal sites; as such, detection of lesions in this area is challenging, with 2-[ 18 F]FDG PET/CT owing to the physiological brain activity. Suspected CNS LCH involvement should ideally be characterized with MRI [85]. CT and MRI should continue to be used as adjunctive studies to characterize LCH lung involvement owing to discordant areas where there are positive lung findings for LCH with no 2-[ 18 F]FDG uptake [81,82]. Diagnostics 2023, 13, 192 11 of 18 to be used as adjunctive studies to characterize LCH lung involvement owing to discordant areas where there are positive lung findings for LCH with no 2-[ 18 F]FDG uptake [81,82].

Rosai-Dorfman Disease
Rosai-Dorfman Disease(RDD) is a disease that predominantly affects children more than adults and typically presents with painless lymphadenopathy [75]. Patients are generally diagnosed on biopsy, with histology showing histiocytic cells positive for S100 and CD68 and negative for CD1a and CD207, unlike in LCH [86]. Extranodal manifestations of RDD is seen in approximately 40% of patients and can include the nasal cavity and paranasal sinuses (11%), skin which presents as subcutaneous masses (10%), bone (5-10%) and intrathoracic, retroperitoneal, genitourinary and CNS manifestations (<5%), as seen in Figure 5 [87].
2-[ 18 F]FDG PET/CT is recommended as a baseline investigation in characterizing a disease [80]. In a single centre study where 109 studies were reviewed in 27 patients with RDD, distribution of disease was nodal/cutaneous in 18%, with predominance of extranodal involvement in the skeleton (33%), CNS (26%) and other extranodal sites (23%). 2-[ 18 F]FDG PET/CT was also able to identify additional sites of disease in those patients who had prior anatomical imaging CT or MRI in 30% of patients. Of the 109 PET/CT studies, 13 led to a change in management affecting 41% of the patients. MRI is still recommended to characterize disease in the rare case of CNS, particularly if it involves the brain owing to high physiological 2-[ 18 F]FDG uptake in this area [88].

Rosai-Dorfman Disease
Rosai-Dorfman Disease(RDD) is a disease that predominantly affects children more than adults and typically presents with painless lymphadenopathy [75]. Patients are generally diagnosed on biopsy, with histology showing histiocytic cells positive for S100 and CD68 and negative for CD1a and CD207, unlike in LCH [86]. Extranodal manifestations of RDD is seen in approximately 40% of patients and can include the nasal cavity and paranasal sinuses (11%), skin which presents as subcutaneous masses (10%), bone (5-10%) and intrathoracic, retroperitoneal, genitourinary and CNS manifestations (<5%), as seen in Figure 5 [87].
2-[ 18 F]FDG PET/CT is recommended as a baseline investigation in characterizing a disease [80]. In a single centre study where 109 studies were reviewed in 27 patients with RDD, distribution of disease was nodal/cutaneous in 18%, with predominance of extranodal involvement in the skeleton (33%), CNS (26%) and other extranodal sites (23%). 2-[ 18 F]FDG PET/CT was also able to identify additional sites of disease in those patients who had prior anatomical imaging CT or MRI in 30% of patients. Of the 109 PET/CT studies, 13 led to a change in management affecting 41% of the patients. MRI is still recommended to characterize disease in the rare case of CNS, particularly if it involves the brain owing to high physiological 2-[ 18 F]FDG uptake in this area [88].

Juvenile Xanthogranulomata
Of the Xanthogranulomata family, Juvenile (JXG) is the most common of the non-LCH spectrum, occurring predominantly in the first year of life [75,89]. Clinically, patients present with numerous red to yellow nodules up to 1cm in diameter which spontaneously resolve. Extracutaneous manifestations confer it a poor prognosis with a mortality rate of 5-10 %; 2-[ 18 F]FDG can assist stratifying extent of disease, despite there being no clear consensus recommendations on the preferred modality for monitoring therapy. Limited case reports have shown the utility of FDG to assist in staging and response assessment to therapy in multiple cutaneous and extracutaneous sites [90,91].

Haemophagocytic Lymphohistiocytosis
Haemophagocytic lymphohistiocytosis (HLH) is a rare disease characterised by intense immune activation owing to an excess of activated lymphocytes and macrophages, in which patients can present with fever, hepatomegaly, splenomegaly, hyperferritinaemia and cytopaenias. Owing to the severity of the clinical course, mortality is significant in these cases [75].
Primary HLH affects infants in an autosomal recessive mode. Secondary HLH(sHLH) can present at any age and is either associated with rheumatic disease, infection, malignancy, or prolongation of immunosuppression [75].
2-[ 18 F]FDG PET/CT has been shown recently to assist in detecting potential malignancy and predicting prognosis in paediatric HLH with EBV infection. An SUVmax-lesions of >6.04, and SUVmax-Lymph node/Mediastinal blood pool > 5.74, with the presence of extranodal hypermetabolic lesions in multiple organs, was indicative of malignant HLH [92].
A second study also reviewed quantitative PET parameters to characterise malignant involvement in various organs in patients with sHLH. Malignant disease was considered when the SUVmax-lymph nodes was higher than 4.41 and other hypermetabolic lesions occurred in extranodal organs. In addition, with EBV-HLH, a higher SUVmax of the bone marrow was associated with a poorer prognosis [93].

Juvenile Xanthogranulomata
Of the Xanthogranulomata family, Juvenile (JXG) is the most common of the non-LCH spectrum, occurring predominantly in the first year of life [75,89]. Clinically, patients present with numerous red to yellow nodules up to 1cm in diameter which spontaneously resolve. Extracutaneous manifestations confer it a poor prognosis with a mortality rate of 5-10%; 2-[ 18 F]FDG can assist stratifying extent of disease, despite there being no clear consensus recommendations on the preferred modality for monitoring therapy. Limited case reports have shown the utility of FDG to assist in staging and response assessment to therapy in multiple cutaneous and extracutaneous sites [90,91].

Haemophagocytic Lymphohistiocytosis
Haemophagocytic lymphohistiocytosis (HLH) is a rare disease characterised by intense immune activation owing to an excess of activated lymphocytes and macrophages, in which patients can present with fever, hepatomegaly, splenomegaly, hyperferritinaemia and cytopaenias. Owing to the severity of the clinical course, mortality is significant in these cases [75].
Primary HLH affects infants in an autosomal recessive mode. Secondary HLH(sHLH) can present at any age and is either associated with rheumatic disease, infection, malignancy, or prolongation of immunosuppression [75].
2-[ 18 F]FDG PET/CT has been shown recently to assist in detecting potential malignancy and predicting prognosis in paediatric HLH with EBV infection. An SUVmax-lesions of >6.04, and SUVmax-Lymph node/Mediastinal blood pool > 5.74, with the presence of extranodal hypermetabolic lesions in multiple organs, was indicative of malignant HLH [92].
A second study also reviewed quantitative PET parameters to characterise malignant involvement in various organs in patients with sHLH. Malignant disease was considered when the SUVmax-lymph nodes was higher than 4.41 and other hypermetabolic lesions occurred in extranodal organs. In addition, with EBV-HLH, a higher SUVmax of the bone marrow was associated with a poorer prognosis [93].

Future Perspectives
The latest developments in PET/CT imaging is looking into a different aspect of the tumour microenvironment by imaging cancer associated fibroblasts (CAFs) with fibroblast activation protein (FAP) in comparison to tumour metabolism with 2-[ 18 F]FDG PET/CT. FAP is a membrane-anchored serine protease with dipeptidyl peptidase and endopeptidase activity and is overexpressed by CAFs. CAFs are represented in many cancers and represent a diverse population of cells which promote or suppress tumour cells. Due to higher tumour uptake, low accumulation in normal tissues, and rapid clearance, FAPI PET/CT has demonstrated advantages over 2-[ 18 F]FDG PET/CT; limitations such as physiological uptake by brain and liver in are not seen with FAPI PET/CT [94].
FAPI PET/CT has been demonstrated in up to 28 different kinds of cancer, including head and neck cancers, gastrointestinal tract cancers, pancreas and liver tumours, lymphoma, sarcoma, and gynaecological malignancies [95]. With relevance to tumours commonly seen in paediatric populations, FAPI PET/CT has demonstrated expression in bone and soft tissue sarcomas as well as in Hodgkin's and Non-Hodgkin's lymphomas. The imaging findings were compared to immunohistochemistry; however, the prognostic significance is yet to be explored [96,97].
To our knowledge, no studies have been published to date to demonstrate the utility of FAPI PET/CT in paediatric oncology; however, recent research shows that FAPI is a promising tracer, which will demonstrate value in imaging multiple malignancies as prospective studies comparing FAPI with conventional FDG, DOTA-SSA and DOPA are currently enrolled [98].