Diagnostic Applications of Nuclear Medicine: Pediatric Cancers
Pediatric cancers are defined as cancers occurring before the age of 15 years and account for only 2% of all cancers. Intracranial tumors are the most common solid neoplasms in children. Although [18F]FDG uptake is associated with more malignant and aggressive tumor types, [18F]FDG-PET is not routinely used for the clinical management of pediatric brain tumors. PET/MRI coregistration/image fusion improves localization of the lesion. [18F]FDG-PET is also helpful to differentiate indolent and active components of the lesion and to improve the diagnostic yield of stereotactic biopsies and the accuracy of the radiosurgical dosimetry planning.
Lymphomas account for 10–15% of all childhood malignancies and are the third most common cause of cancer. Non-Hodgkin’s lymphoma is more frequent. Staging of Hodgkin’s lymphoma (HL) is performed according to the Cotswold revision of the Ann Arbor classification. Non-Hodgkin’s lymphoma in childhood is significantly different from adults. The predominant subtypes are Burkitt’s lymphoma, large B-cell lymphoma, and primary mediastinal B-cell lymphomas, followed by lymphoblastic lymphoma and anaplastic large-cell lymphoma. Most cases are extensive at diagnosis, corresponding to stages 3 and 4 of the St. Jude Children’s Research Hospital classification (Murphy staging). Contrast-enhanced diagnostic CT (ce-CT) or MRI together with thoracic CT remains mandatory at least at diagnosis (performed either simultaneously with [18F]FDG-PET by using hybrid PET/CT or PET/MRI scanners or separately). Diagnostic CT reliably detects enlarged lymph nodes, and contrast media are required to accurately distinguish lymphadenopathy. Diagnostic CT also allows detailed evaluation of the pulmonary parenchyma, pleura, and pericardium. Ultrasonography has a definite role in both initial evaluation and follow-up of superficial lymph nodes and is an effective method to detect testicular infiltration and to explore liver and spleen. Chest radiography remains useful in HL to classify disease as “bulky” or “nonbulky.” MRI is superior to ce-CT for evaluation of the bone marrow, liver, soft tissue, and central nervous system.
67Ga-citrate scintigraphy and bone scintigraphy have been replaced by [18F]FDG-PET/CT or PET/MRI, which depicts nodal and extranodal disease as well as focal bone marrow disease. The role of [18F]FDG-PET is well established to stage HL before treatment. Early response assessment can be evaluated by interim PET in HL. When interim PET is negative, no other examination needs to be performed at the end of therapy in the absence of clinical signs. Systematic [18F]FDG-PET is not indicated during follow-up.
In non-Hodgkin’s lymphoma, [18F]FDG avidity is high for Burkitt’s lymphoma, large B-cell lymphoma, lymphoblastic lymphoma, and anaplastic large-cell lymphoma. The main indications for [18F]FDG-PET in children with non-Hodgkin’s lymphoma are inconclusive. However, [18F]FDG-PET appears to be a useful tool for characterization of residual masses, as no reliable CT or MRI criteria are available for distinguishing residual disease from fibrosis or necrosis.
Wilms’ tumor is the most common renal malignancy in childhood. The diagnostic workup includes a CT or MRI scan of the abdomen and pelvis, lymph nodes, and intra-abdominal or pelvic tumor deposits. A Doppler ultrasound is recommended to evaluate if there is a tumoral thrombus in the renal vein and inferior vena cava. For the detection of bilateral disease and the assessment of nephroblastomatosis representing premalignant lesions, MRI is the imaging modality of choice. 123I-MIBG scintigraphy can be very helpful for the differentiation of neuroblastoma from Wilms’ tumor. There is no major role for [18F]FDG-PET in these patients.
Neuroblastoma accounts for about 8% of pediatric malignancies and is responsible for 15% of cancer deaths in children. It arises from the neural crest cells, and the tumor is usually situated in the adrenal gland or anywhere else along the sympathetic nervous system chain. Staging is crucial in order to choose the appropriate treatment. Imaging of neuroblastoma consists of ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and 123I-MIBG scintigraphy. 123I-MIBG is sensitive and specific for the detection of neuroblastoma involvement. [18F]FDG-PET is less sensitive than 123I-MIBG scintigraphy in neuroblastoma patients. However, in any case of a discrepancy between 123I-MIBG scintigraphy and morphological imaging (CT and/or MRI), [18F]FDG-PET should be considered for further tumor evaluation.
Sarcomas are a heterogeneous group of neoplasms with different tumor biology, malignancy, and therapeutic options. The two major groups of primary bone tumors in children and adolescents are osteosarcomas and the Ewing family of tumors. As regards soft-tissue sarcomas, the most common histologic entities in children and adolescents are rhabdomyosarcoma, extraosseous Ewing sarcoma and peripheral neuroectodermal tumor, synovial sarcoma, neurofibrosarcoma, fibrosarcoma, and leiomyosarcoma. Langerhans cell histiocytosis (LCH) is a proliferation of Langerhans-type histiocytes. Despite its clonal origin, there is no definitive proof of malignancy. Primary bone tumors are best classified using a conventional planar x-ray. Local CT and MRI supply further information on tumor localization and extension. Bone scintigraphy is very sensitive in the detection of osseous metastases of osteosarcoma, and even soft-tissue metastases are often visible on the bone scan.[18F]FDG-PET has a high accuracy in detecting primary sarcomas and its metastases, with the exception of pulmonary metastases. Therefore, a thoracic CT is additionally necessary for staging sarcomas.
KeywordsPediatric cancer imaging Sarcoma imaging in the pediatric population Neuroblastoma imaging in children Wilms’ tumor imaging in children Lymphoma imaging in children Intracranial tumor imaging in children
153Sm-ethylenediaminetetramethylene phosphonic acid
O-(2-18F-Fluoroethyl)-L-Tyrosine, a tyrosine analog
European Automated Childhood Cancer Information System
Contrast-enhanced diagnostic CT
Central nervous system
X-ray computed tomography
2-(4-Isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (macrocyclic coupling agent to label compounds of biological interest with metal radionuclides)
Epidermal growth factor receptor
Granulocyte colony-stimulating factor
Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)
Langerhans cell histiocytosis
Magnetic resonance imaging
Positron emission tomography
Positron emission tomography/Computed tomography
Positron emission tomography/Magnetic resonance imaging system
Peripheral neuroectodermal tumor
Response evaluation criteria in solid tumors
Surveillance, epidemiology and end results
Single-photon emission computed tomography
Single-photon emission computed tomography/Computed tomography
Standardized uptake values
World Health Organization
Five-year survival rates for childhood cancer (0–14 years) according to ACCIS (European Automated Childhood Cancer Information System 1988–1997) and SEER (US-Surveillance, Epidemiology and End Results 1985–1999)
Lymphomas and reticuloendothelial neoplasms
CNS and miscellaneous intracranial and intraspinal neoplasms
Sympathetic nervous system tumors
Malignant bone tumors
Germ cell, trophoblastic, and other gonadal neoplasms
Carcinomas and other malignant epithelial neoplasms
Others and unspecified malignant neoplasms
The most common tumors among the under 15-year-olds are leukemias, at 34%, brain tumors, at 23%, and lymphomas, at 12%, according to the International Classification of Childhood Cancer . The most frequent single diagnoses are acute lymphoblastic leukemia, astrocytoma, neuroblastoma, non-Hodgkin’s lymphoma, and nephroblastoma. There is considerable variation between countries. Incidence rates range from 130 (British Isles) to 160 cases (Scandinavian countries) per million children. Incidence rates have shown an increase over time since the middle of the last century. In Europe, the yearly increase averages 1.1% for the 1978–1997 period and ranges from 0.6% for the leukemias to 1.8% for soft-tissue sarcomas .
Nuclear medicine is important in the diagnosis, staging, and long-term surveillance of a number of pediatric cancers. Skeletal scintigraphy is used to evaluate primary skeletal cancers, such as osteosarcoma and Ewing sarcoma, and nonskeletal cancers, such as neuroblastoma, medulloblastoma, rhabdomyosarcoma, and retinoblastoma. Metaiodobenzylguanidine scintigraphy is valuable in examinations of children with neuroblastoma, and [18F]FDG-PET/CT is useful in lymphoma, thymoma, and embryonal cell tumors. Recent years have witnessed a growing role of [18F]FDG-PET/CT in the management of children with cancer. The conventional staging evaluation of these children includes magnetic resonance imaging (MRI) or CT for detection of the primary tumor and regional nodal beds, chest CT for detection of pulmonary metastases, and technetium-99m methyldiphosphonate (99mTc-MDP) bone scan for detection of bone metastases. The Response Evaluation Criteria in Solid Tumors (RECIST), introduced in 2000 as an alternative to the World Health Organization (WHO) criteria, provides a standard, reproducible, and objective method of assessing the efficacy of solid tumor therapies . Unfortunately, they rely on changes in unidimensional tumor measurements to define tumor response or progression. In this regard, it must be emphasized that solid malignancies, such as bone sarcomas and cystic soft-tissue sarcomas, may respond well to chemotherapy without substantially changing in size. Furthermore, sarcomas do not shrink or grow in a uniform manner; therefore, unidimensional measurements may not accurately reflect response or progression of the tumor. Tumors that respond poorly to therapy may be followed for months before a unidimensional measurement increases significantly. Meanwhile, patients are exposed to toxic but ineffective chemotherapy and are likely to have a diminished probability of survival. [18F]FDG-PET, on the other hand, provides a three-dimensional assessment of viable tumor tissue based on metabolic activity. A decrease in tumor glucose uptake after treatment suggests a reduction in the number of viable tumor cells or a decrease in metabolism of the tumor tissue. Therefore, [18F]FDG-PET may offer a more sensitive evaluation of the response or progression of some pediatric solid malignancies than anatomic imaging modalities . It should be noted that virtually all stand-alone PET scanners have recently been replaced with integrated hybrid PET/CT scanners that intrinsically allow the combination of the functional PET data with the morphological data of CT. Hybrid PET/CT imaging has shown clear advantages over PET imaging alone, by improving correction for tissue attenuation as well as by providing better anatomical resolution and correlation, thus resulting in better characterization and localization of the lesion and in reduction of the doubtful results [5, 6].
Interest is growing also in the use of hybrid PET/MRI scanners, although the diffusion of this technology is currently still limited by high cost and complexity of operation. Nevertheless, this novel imaging modality is emerging as an especially attractive technique for application in pediatric patients, because it does not involve the radiation burden pertaining to the CT component of the PET/CT scanners. This feature is particularly relevant in children with cancer, who frequently need to perform periodic diagnostic tests [7, 8]. Although several studies have shown the feasibility of PET/MRI in pediatric oncology, clear diagnostic advantages over PET/CT have not been established, also because of the paucity of studies comparing head-to-head in the same patients (especially in the pediatric age group) the diagnostic performances of PET/MRI with those of PET/CT [9, 10, 11, 12, 13]. Further validation studies are therefore needed [14, 15].
Pediatric Brain Tumors
Intracranial tumors are the most common solid neoplasms in children and the second most common malignancy of childhood after leukemia. Among children younger than 19 years, the prevalence rate for all pediatric brain tumors was 9.5 per 10,000, while the incidence rate was 29.1 cases per 1,000,000 .
Pediatric brain tumors differ from adult tumors on various grounds. About 60–70% of all pediatric brain tumors, including astrocytomas, medulloblastomas, and ependymomas, develop in the infratentorial compartment. The remaining 30–40% of tumors are supratentorial and consist of gliomas, optic pathway tumors, hypothalamic tumors, and craniopharyngiomas. The reason why pediatric brain tumors have a propensity to occur in the posterior fossa has not yet been elucidated.
In contrast to those that occur in adults, most gliomas that occur in children are low-grade gliomas. Moreover, in the pediatric age mixed (glioneuronal) and atypical (xanthoastrocytoma) tumors are frequent as also frequent are lesions with very low or questionable evolving potential (hamartoma). Young age is a favorable prognostic factor for malignant gliomas. In adults, the majority of high-grade gliomas are primary and show amplification of the epidermal growth factor receptor (EGFR) gene, which encodes a tyrosine kinase involved in cell replication. In contrast, in pediatric patients high-grade gliomas more commonly derive from low-grade gliomas and often have mutations in TP53 (a gene encoding for p53 protein) but seldom display amplification of EGFR [17, 18].
Many types of supratentorial pediatric brain tumors are well delineated; they have a moderate tendency to infiltrate neighboring tissue and are usually amenable to total resection. However, some pediatric brain tumors may not be accessible surgically because they are close to vital brain structures. This typically occurs for medulloblastoma, a primitive neuroectodermal tumor that originates from the cerebellum, close to the brainstem and to the fourth ventricle.
Finally, 5–10% of brain tumors in childhood are thought to be linked to a genetic predisposition, while such proportion is much lower in adults. Hereditary brain tumors occur in some familial cancer syndromes, such as the Li-Fraumeni syndrome. At variance, hereditary brain tumors in adult subjects are associated with rare hereditary syndromes, such as tuberous sclerosis, neurofibromatosis types 1 and 2, and familial adenomatous polyposis.
The diagnosis of brain tumor may be challenging in children because tumor signs and symptoms may resemble those of more common inflammatory or infectious diseases. Recurrent bouts of headache, nausea, or vomiting without focal deficits are frequently observed in children. For medulloblastoma early symptoms are secondary to increased intracranial pressure due to blockage of the fourth ventricle. The child typically becomes lethargic, with repeated episodes of vomiting and morning headache. In more advanced stages, the child develops stumbling gait, frequent falls, diplopia, papilledema, and sixth cranial nerve palsy.
The preparation and acquisition procedures are very similar to those adopted for adult studies. Systemic sedation with benzodiazepines may be necessary for very young children, to ensure compliance during the scan. Dynamic scans are rarely performed.
The most important issue in pediatric PET scanning is to limit the radiation burden. The procedure guidelines of the Society of Nuclear Medicine and Molecular Imaging recommend an administered activity of [18F]FDG ranging from 5 to 10 MBq per kg of body weight, from a minimum activity of 37 MBq to a maximum of 750 MBq ; nevertheless, with the high sensitivity of modern PET/CT scanners, lower activities can be administered without reducing diagnostic quality of the PET scans. Good hydration and early urine voiding are recommended to reduce bladder toxicity. The absorbed dose to the brain in infants is about 0.24 ± 0.05 mGy/MBq, a higher value than in adult subjects, because of the higher glucose consumption in the infant brain than in the adult brain .
Experience with [18F]FDG-PET
The very first study in a relatively large population of pediatric patients with brain tumor was reported by Hoffman et al. in 1992 . They studied 17 pediatric patients with posterior fossa brain tumors with [18F]FDG-PET. [18F]FDG uptake was visually ranked by two observers, and the results were correlated to tumor histology. Increased [18F]FDG uptake was associated with more malignant and aggressive tumor types. Heterogeneity of [18F]FDG uptake was associated with previous therapy, including radiation therapy and chemotherapy. The authors concluded that [18F]FDG-PET would likely be an important adjunct in the management of pediatric posterior fossa tumors and predicted a rapid dissemination of PET technology for pediatric applications .
Nevertheless, PET has not become routinely used for the clinical management of pediatric brain tumors. Literature remains relatively scarce on this matter, and the difference between adult and pediatric studies cannot be merely attributed to differences in prevalence of the disease .
Borgwardt et al. studied 38 untreated pediatric patients with primary CNS tumors using PET with [18F]FDG and, when possible, (n = 16), with 15O-water at rest. Image processing included coregistration to MRI in all patients. The [18F]FDG uptake in tumors was semiquantitatively estimated with a region-of-interest approach. They found a positive correlation between [18F]FDG uptake and malignancy grading. On the other hand, there was no correlation between blood flow as measured with 15O-water and histological grade, a finding that was attributed to some uncoupling between glucose metabolism and blood flow. Image fusions based on digital PET/MRI coregistration improved the information on the tumor location in 90% of cases. The results of the PET scan altered management in 77% of the patients .
Pirotte et al. reported their experience at the Erasme Hospital Pediatric Center, where between 1995 and 2005 they examined with [18F]FDG-PET about 400 pediatric patients with brain tumor. In their retrospective analysis, they included 126 patients in whom pre- and postoperative MR imaging showed limitations for assessing the evolving nature of an incidental lesion, selecting targets for biopsy, and delineating tumor tissue for surgical resection. In this group of patients (about one-third of the whole case series), PET was expected to be most useful. They found that PET was helpful on several grounds, i.e., to (1) take a more appropriate decision in incidental lesions by detecting tumor/evolving tissue, (2) better differentiate indolent and active components of the lesion, (3) improve target selection and diagnostic yield of stereotactic biopsies, especially when performed in eloquent areas such as the brainstem or the pineal region, (4) provide prognostic information, (5) better delineate ill-defined tumor borders, (6) increase the number of tumor resections and the amount of tumor tissue surgically removed, (7) improve detection of tumor residues in the operative cavity at the early postoperative stage, (8) facilitate the decision of early second-look surgery for optimizing the radical resection, and (9) improve the accuracy of the radiosurgical dosimetry planning .
Utriainen et al. used PET [18F]FDG and [11C]MET to ascertain whether metabolic characteristics could be used as an index of clinical aggressiveness. SUV (standardized uptake values) for both tracers were compared with histopathology and selected histochemical features. The accumulation of both [18F]FDG and [11C]MET was significantly higher in high-grade than in low-grade tumors, but a considerable overlap was found. High-grade tumors showed higher proliferative activity and vascularity than the low-grade tumors. In univariate analysis, [18F]FDG SUV, [11C]MET SUV, and apoptotic index were independent predictors of event-free survival .
Kruer et al.  examined with [18F]FDG-PET a cohort of 46 children/adolescents with low-grade astrocytomas (LGAs, WHO grade 1 or 2) in order to identify LGAs at risk for progressive disease (PD); they found that tumors with [18F]FDG hypermetabolism were significantly more likely to demonstrate aggressive behavior and PD.
Galldiks et al.  investigated the diagnostic accuracy of [11C]MET-PET to distinguish between tumorous and nontumorous lesions in 39 children and adolescents. [11C]MET-PET was able to distinguish brain tumors and nontumorous brain lesions with a high sensitivity (83%) and specificity (92%). The authors suggested that [11C]MET-PET may be helpful when results of routine anatomic diagnostic imaging are not sufficient enough to obtain a treatment decision and planning.
In pediatric patients with central nervous system (CNS) germinomas, the diagnostic utility of [11C]MET was also recently demonstrated by Okochi et al. .
Despite these promising results, both [18F]FDG and [11C]MET PET are still not routinely used for clinical evaluation of pediatric brain tumors. The physiologic high [18F]FDG uptake of the normal brain cortex limits tumor detection, especially in low-grade gliomas , whereas the short half-life (20 min) of [11C]MET limits its application to centers with an on-site cyclotron.
In the last few years, new fluorinated tracers have emerged as alternative radiolabeled compounds for characterizing pediatric brain tumors. Among them, 18F-DOPA was found to be a multi-targeted molecule in children, since it can be used for primary/recurrent brain tumors [27, 28], for neuroblastoma diagnosis, prognosis, and surveillance , including detection of CNS metastasis , and in nontumoral conditions such as congenital hyperinsulinism , with a potential impact on healthcare cost optimization.
Recent findings suggest that also 18F-FET imaging is able to detect metabolic active tumor tissue within diffuse tumors or pretreated lesions  and can be used for target selection and to guide surgical treatment in pediatric brain tumors .
Lymphoma accounts for 10–15% of all childhood malignancies and is the third most common cause of cancer, after leukemia and brain tumors. Non-Hodgkin’s lymphoma (NHL) is more frequent than Hodgkin’s lymphoma (HL) (about 60% and 40%, respectively) .
HL, exceptional before the age of 5 years (median age: 14 years), usually presents with asymptomatic enlarged lymph node(s). The malignant cell in HL is the Reed-Sternberg cell, located in the tumor masses within a background of inflammatory cells and fibrosis. Four histologic subtypes of HL are described: lymphocytic predominance, mixed cellularity, lymphocytic depletion, and nodular sclerosis. Nodular sclerosis is the most common subtype, affecting 60% of children, whereas the lymphocytic depletion subtype is very rare. During therapy, residual masses are frequent and usually correspond to fibrosis and/or necrosis , especially in the nodular sclerosis subtype of HL because of its abundant fibrotic component . Extent of disease at staging must be evaluated as accurately as possible because treatment is related not only to stage but also to each site of disease in order to plan conformal radiotherapy when it is indicated.
According to the Cotswold revision of the Ann Arbor classification, stage I is defined as involvement of a single lymph node region. Stage II has involvement of two or more lymph node regions on the same side of the diaphragm. Stage III has involvement of lymph node regions on both sides of the diaphragm. Stage IV has extranodal involvement, such as bone, liver, or lung disease. Involvement of the spleen is considered to be lymph node involvement. Each stage is also classified by the presence or absence of symptoms. “A” indicates that the patient is asymptomatic; “B” indicates that the patient has at least one of the following systemic symptoms: inexplicable weight loss of more than 10% within the last 6 months, unexplained persisting or recurrent temperature above 38 °C, and/or drenching night sweats. “E” stage is defined as involvement of a single extranodal site contiguous or proximal to known nodal sites. Clinical and imaging evaluation must be performed at the end of therapy to confirm that therapy has been fully effective and has achieved complete response.
Major therapeutic progress has been made in HL, with current cure rates ranging from 90% to 95% for all stages [37, 38]. Most treatment regimens for childhood HL consist of chemotherapy with or without radiotherapy, with current efforts to reduce the use of radiotherapy and late effects related to cumulative doses of cytotoxic agents .
Treatments for pediatric HL can induce important long-term side effects on both quality of life and on life expectancy per se; for these reasons, many studies aim at defining protocols capable of minimizing treatment-related toxicity without compromising the cure rate [40, 41].
NHL in childhood is significantly different from NHL in adults, as, in almost every case, it corresponds to high-grade malignancies with frequent invasion of the bone marrow and central nervous system . In children, the predominant subtypes are Burkitt’s lymphoma, large B-cell lymphoma, and primary mediastinal B-cell lymphomas, followed by lymphoblastic lymphoma and anaplastic large-cell lymphoma . NHL is very rare before the age of 2 years and has a peak incidence at the age of 7 years. NHL requires urgent treatment, consisting of combination chemotherapy (without radiotherapy) and neuromeningeal prophylaxis of recurrences by intrathecal chemotherapy. Most cases are extensive at diagnosis, corresponding to stages 3 and 4 of the St. Jude Children’s Research Hospital classification (Murphy staging) .
Stage I disease is defined as a single tumor or nodal area outside of the abdomen and mediastinum. Stage II is a single tumor with regional lymph node involvement, two or more tumors or nodal areas on one side of the diaphragm, or a primary gastrointestinal tract tumor (completely resected) with or without regional node involvement. Stage III consists of tumors or lymph node areas on both sides of the diaphragm, or any primary intrathoracic (mediastinal, pleural, or thymic disease) or extensive intra-abdominal disease, or any paraspinal or epidural disease. Stage IV includes central nervous system and/or bone marrow involvement, regardless of other sites of involvement. Residual masses after treatment are less frequent in NHL than in HL but more frequently correspond to a persistent active disease .
The prognosis of childhood NHL has improved over the past 20 years with a 2-year event-free survival of 95% for B-cell lymphoma (Burkitt’s lymphoma and large-cell lymphoma) [46, 47], 75% for lymphoblastic lymphoma , and 70% for anaplastic large-cell lymphoma .
Role of Nuclear Medicine Techniques
67Ga-citrate scintigraphy and bone scintigraphy have largely been replaced by [18F]FDG-PET/CT or – recently – PET/MRI. Compared to 67Ga-citrate scintigraphy, [18F]FDG-PET detects more disease sites [50, 51], especially in the abdomen, where the diagnostic performance of gallium scintigraphy is limited by physiologic bowel uptake. The other advantage of [18F]FDG-PET over 67Ga-citrate scintigraphy is same-day imaging with PET (in contrast with imaging over 2 or 3 days for gallium) and a more favorable dosimetry . Bone scintigraphy is also less sensitive than [18F]FDG-PET to detect bone and bone marrow involvement .
[18F]FDG-PET/CT and PET/MRI
The majority of PET systems now consist of hybrid PET/CT scanners which use the CT portion of the examination for attenuation correction and anatomic localization of lesions identified on PET. Low-dose CT (typically 5 mA at 80 kVp for attenuation correction/anatomic correlation, which may be increased to several hundred mA for thin slice diagnostic quality contrast-enhanced CT) that is usually performed with PET has been shown to be more accurate in adults with lymphoma than PET alone . However, contrast-enhanced diagnostic CT (ce-CT) or MRI with thoracic CT remains mandatory at least at diagnosis (performed either simultaneously with PET or separately).
Diagnostic CT and MRI reliably detect enlarged lymph nodes, and contrast media are required to accurately distinguish lymphadenopathy from other structures, especially in the abdomen and pelvis due to the lack of retroperitoneal fat in children . Diagnostic CT also allows detailed evaluation of the pulmonary parenchyma, pleura, and pericardium.
Ultrasonography, which has a definite role in both initial evaluation and follow-up of superficial lymph nodes. It is also the best method to detect testicular infiltration  and an effective imaging method to explore liver and spleen .
Chest radiography, which remains useful in HL to classify disease as “bulky” or “nonbulky,” which constitutes an important prognostic factor. Disease is classified as “bulky” when the ratio of the largest tumor diameter to chest diameter is greater than one-third.
MRI is superior to ce-CT for evaluation of the bone marrow , liver, soft tissue, and central nervous system . MRI is currently performed as a complement to other imaging modalities, but its role as a whole-body imaging technique is under evaluation for pediatric and adolescent lymphoma staging . However, whole-body MRI is increasingly performed by using hybrid PET/MRI scanners instead of PET/CT scanners in children .
[18F]FDG-PET frequently detects nodal and extranodal disease sites that are missed by conventional staging methods and improves the characterization of lesions that are equivocal on other types of imaging. [18F]FDG-PET is especially accurate to detect bone marrow disease, even in the case of negative iliac crest bone marrow biopsy.
Various studies in adults indicate that [18F]FDG-PET for the detection of bone marrow involvement is superior not only to conventional imaging modalities but also to bone marrow trephine biopsy [51, 58, 59]. This appears to be true also in children [51, 60, 61, 62, 63, 64], bone marrow biopsy being now not yet indicated in HL and replaced by [18F]FDG-PET . When bone marrow involvement is detected by PET, it is often not detected by diagnostic CT and must be confirmed by another modality, preferably MRI or bone scan when MRI is not available. In contrast, [18F]FDG-PET/CT can understage disease, especially in the case of lung sites (more reliably detected by diagnostic CT than by PET)  and because some lesions, even large lesions, may not be [18F]FDG avid, while other lesions take up [18F]FDG. Careful comparison of functional and morphologic imaging therefore remains essential.
Indications for [18F]FDG-PET/CT
The role of [18F]FDG-PET in childhood lymphoma has been specifically assessed in short series [6, 50, 52, 61, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76] and review articles [51, 77, 78, 79, 80]. The objectives of [18F]FDG-PET are different in HL and NHL and will be discussed separately.
HL has a reported [18F]FDG avidity of 97–100% (defined as at least one [18F]FDG-avid HL site detected, on a per-patient basis), according to four studies, comprising a total of 489 patients (adults and children), with an unspecified proportion of children [81, 82, 83, 84]. No difference in intensity of [18F]FDG uptake is observed according to HL subtypes , and the intensity of uptake at diagnosis does not appear to have any prognostic value.
[18F]FDG-PET at staging must be performed before starting chemotherapy, as [18F]FDG uptake very rapidly reflects the metabolic response to chemotherapy. In children with aggressive disease, [18F]FDG-PET must also be performed before corticosteroid therapy, as HL is a malignancy comprising a large background of inflammatory cells [86, 87].
Monitoring of Response to Therapy
Early response assessment can also be evaluated by [18F]FDG, as PET has been shown to be an effective prognostic tool in adults with HL . In pediatric HL interim [18F]FDG-PET/CT, after two to three cycles of standard chemotherapy, has shown high negative predictive value, and therefore an early negative scan is a reliable indicator for therapy response [67, 76]. Interim PET must not modify the scheduled therapy except in the context of a controlled clinical trial . When interim PET is negative, no other PET needs to be performed at the end of therapy in the absence of clinical signs .
Systematic [18F]FDG-PET/CT is not indicated during follow-up because it can result in false positives , thus contributing to an increase in costs and radiation exposure in the absence of evident benefits [94, 95, 96]; therefore, [18F]FDG-PET/CT must only be performed in the case of suspected recurrence.
In contrast with HL, [18F]FDG uptake cannot be considered to be constant in NHL. In adult NHL, [18F]FDG uptake tends to be more intense in higher-grade lymphomas than in lower-grade lymphomas , and some low-grade NHL, especially T-cell lymphoma, present inconstant [18F]FDG uptake . As most NHLs in children are high-grade and aggressive tumors, it can be assumed that false-negative PET at staging would probably be very rare. However, no study has specifically assessed [18F]FDG uptake according to the various subtypes of NHL in children. According to three studies [82, 83], based on a mixed population of adults and children, [18F]FDG avidity (defined as at least one [18F]FDG-avid lymphoma site detected on a per-patient basis) was 100% for Burkitt’s lymphoma (24/24), 97% for large B-cell lymphoma (294/303), 100% for lymphoblastic lymphoma (6/6), and 100% for anaplastic large-cell lymphoma (24/24), corresponding to the most frequent subtypes of NHL encountered in children. However, in a limited experience of [18F]FDG-PET performed for NHL in 18 children, two false-negative [18F]FDG-PET scans were reported in patients with anaplastic T-small-cell lymphoma, an uncommon subtype of anaplastic T-cell lymphoma .
[18F]FDG-PET staging is frequently difficult to organize in a timely fashion and rarely performed due to the urgency of therapy for NHL in children. Moreover, and in contrast with HL, in which all disease sites must be precisely detected in order to plan therapy, the detection of all involved sites is less important in NHL, as treatment consists of high-dose intensive chemotherapy without radiotherapy. Nevertheless, an exception can be staging of Burkitt’s lymphoma; in fact, since this subtype frequently occurs as a single site of disease, [18F]FDG-PET can confirm the absence of other site of disease and thus be of help in choosing the initial therapy.
[18F]FDG-PET is therefore rarely performed at staging in NHL and is not performed routinely during follow-up.
However, [18F]FDG-PET appears to be a useful tool for characterization of residual masses, as no reliable CT or MRI criteria are available for distinguishing residual disease from fibrosis or necrosis . In the presence of a posttreatment residual mass, negative [18F]FDG-PET has been shown to be a reliable indicator of complete clinical remission [51, 79].
Limitations of [18F]FDG-PET
It must be remembered that, even with the most recent PET scanners, [18F]FDG-PET is unable to detect low-grade metabolic lesions measuring less than about 5 mm. Very small lung nodules, with minimal increased metabolic rates, are therefore more reliably detected by diagnostic CT than by PET . During follow-up, persistence of microscopic active disease within residual masses also cannot be detected by PET. Hyperglycemia may also induce false-negative results by reducing [18F]FDG uptake in the tumor .
Physiologic Uptake, Pitfalls, and False-Positive Results
Certain physiologic sites of [18F]FDG uptake in children must be recognized. For example, physiologic [18F]FDG uptake may be observed in the endometrium (during menstruations) and in the ovaries (usually at mid-cycle) in adolescent girls and should not be confused with residual or recurrent tumor in pelvic lymph nodes [102, 103]. Due to the increasing resolution of PET systems, some normal structures can now appear to be slightly active on PET, for example, spinal cord, especially in the two sites of physiologic anatomic enlargement, that is, cervical and lumbar regions .
In children thymus uptake of [18F]FDG is frequent, physiologic, and enhanced by treatment. The physiologic appearance of thymus uptake is usually easily recognized because it is diffuse and moderately active and frequently has an inverted “V” shape. Sometimes, especially in the presence of an accessory gland, differentiation of normal thymic activity from tumor or inflammation may be difficult or impossible, and PET must then be compared with MRI, which is able to differentiate thymic tissue from recurrent lymphoma . Characterization of the mass can be particularly difficult when ectopic thymic tissue is located in the neck .
In children and adolescents, false-positive results can be related to infectious mononucleosis  or vaccination. [18F]FDG-PET was positive in draining axillary nodes close to the vaccination site in all ten patients recently vaccinated against the pandemic H1N1 virus .
False-Positive Results Can Also Be Treatment Induced
In patients treated with low-dose-involved field radiation, [18F]FDG uptake can be slightly increased even months after therapy , but the uptake observed in a context of acute radiation pneumonitis can be intense .
Granulocyte colony-stimulating factor (GCSF) is a useful adjunct in patients receiving myelosuppressive chemotherapy. Administration of hematopoietic growth factors can induce reconversion from fatty marrow to red marrow, resulting in increased [18F]FDG uptake in the spine, pelvis, and long bones and in the spleen . Increased activity in the spleen has also been observed both during and after GCSF treatment . However, this very diffuse and homogeneous uptake is usually easy to recognize and typically declines after discontinuation of treatment but can remain increased for up to 4 weeks post-therapy .
[18F]FDG-PET/CT or PET/MRI is already an integral part of the management of childhood HL for staging, adaptation of conformal radiotherapy, and assessment of therapy and suspected recurrence. [18F]FDG-PET/CT is the subject of a major ongoing European study (Euronet) designed to minimize late toxicity of therapy without compromising the cure rate. Patients who obtain a good early response to two cycles of chemotherapy (complete remission or partial remission and negative [18F]FDG-PET) do not receive radiotherapy .
Nevertheless, the actual role of [8F]FDG-PET in the management of childhood NHL has not yet been defined. Although various studies have addressed this issue, the data are still scarce; furthermore, most of the studies are retrospective, and most of them include also patients with LH, therefore resulting in some heterogeneity in the data .
The role of [18F]FDG-PET in childhood NHL is currently under evaluation in a trial in France, designed to address several major issues: Does NHL histology affect PET staging and PET response? What is the optimal timing of interim PET during NHL treatment? Should children with poor early PET be considered for treatment intensification?
Wilms’ tumor is the most common renal malignancy in childhood . The 5-year survival rate currently is about 91.9% . Therapy follows multimodality approaches, including surgery/nephrectomy, chemotherapy, and radiation treatment. In general, recurrent disease manifests as local relapse in the lungs, regional lymph nodes, distal urinary tract, and liver but may also occur elsewhere . Two histopathologic findings are described: the favorable and the anaplastic.
Chemotherapy is usually used prior to surgery. Therefore, a reliable response assessment using noninvasive imaging even prior to definite surgery is needed to modify therapy and to gain prognostic information .
Although [18F]FDG-PET was successfully used to image Wilms’ tumor for the first time  in the 1990s and [18F]FDG uptake is usually consistent with a metabolically active tumor, no difference in uptake can distinguish between favorable and unfavorable histological findings . Only a few years later, it became known that [18F]FDG-PET did not provide additional information during the first diagnostic workup but appeared helpful in the follow-up .
PET/CT scans of patients with extensive disease were studied in a follow-up setting. [18F]FDG-PET was reported to detect metastatic lesions that would have been missed by the conventional imaging [110, 111, 112, 113, 114]. Nevertheless, [18F]FDG-PET failed to visualize small pulmonary metastases . Consequently, PET/CT with the increased spatial resolution of the CT component seems to be the modality of choice in defining tumor involvement and evaluating therapy in patients with extended disease, in particular for tumors that are not amenable to surgical resection . Whether PET/CT is useful for primary diagnosis of Wilms’ tumors is yet to be determined. Therefore, [18F]FDG-PET/CT does not seem to be of great importance for staging patients with Wilms’ tumor with limited disease .
Neuroblastoma, an embryonic tumor, is the most frequent extracranial solid malignancy in pediatric patients (about 8% of pediatric malignancies) and remains, despite treatment intensification, responsible for approximately 15% of cancer deaths in children [115, 116, 117, 118]. It arises from the neural crest cells, which form the adrenal medulla and the sympathetic nervous system . The tumor is usually situated in the adrenal gland or anywhere else along the sympathetic nervous system chain . At diagnosis, roughly 50% of patients have distant hematogenous metastases . Neuroblastoma presents a wide spectrum clinical behavior and survival rates; therefore, staging is crucial in order to choose the appropriate treatment .
The therapeutic spectrum depends upon clinical stage and consists of supportive care with no treatment (stage IVS), definitive excision if possible, or chemotherapy before and after surgery. The treatment approaches are partially combined with total-body irradiation and 131I-MIBG therapy, followed by autologous bone marrow transplantation [118, 120, 122, 123].
Imaging of neuroblastoma consists of sonography, computed tomography (CT), MRI, and radionuclide examinations such as bone scintigraphy, 123I-MIBG scintigraphy, positron-emission tomography (PET) with different tracers (primarily [18F]FDG), and recently hybrid imaging (PET/CT and SPECT/CT) [124, 125, 200, 201, 202, 203, 204, 205, 206].
Radiolabeled MIBG was originally developed in the late 1970s as a norepinephrine (NE) analog for imaging of the adrenal medulla [126, 127]. With the amount of radioiodinated MIBG administered for diagnostic imaging, uptake is mediated primarily by the NE transporter located on the surface of sympathetic neurons [128, 129]. Based on this mechanism, both 123I-MIBG and 131I-MIBG have been proven effective agents for scintigraphic imaging of tumors arising from the embryonologic precursors of the sympathetic nervous system, particularly the neural crest tumors neuroblastoma and pheochromocytoma [130, 131].
Scintigraphy with 123I- or 131I-labeled MIBG has become a well-established method in the diagnosis and staging of neuroblastoma [132, 133, 134] because of its high specificity, which is reported in the literature to be between 90% and 100% [122, 135, 136].
Moreover MIBG scintigraphy is used to determine eligibility for 131I-MIBG therapy, as the presence of MIBG-avid disease must be ascertained prior to treatment.
For diagnosis, 123I-labeled MIBG is superior to 131I-MIBG . Due to more favorable dosimetric properties, a higher activity of 123I-MIBG can be administered enabling to obtain SPECT acquisitions that may increase sensitivity and provide more precise anatomical localization of the disease especially after coregistration with radiological modalities such as CT scan or MRI .
Reasons for false-negative studies are not entirely clear: it may be related to modifications of the active uptake mechanism due to differentiation of tumor cells or to pharmacologic interference [139, 140, 141]. Pharmacological interference: ((1) tricyclic antidepressants and related drugs – should be avoided for 6 weeks prior to the study: (a) amitriptyline and derivatives (Elavil, Endep, Etrafon, Triavil, Amitril, Emitrip, Enovil), (b) amoxapine (Asendin), (c) loxapine, (d) doxepin (Adapin, Sinequan), (e) imipramine and derivatives (Tofranil, Imavate, Janimine, Presamine, SK-Pramine, Tipramine). (2) Antihypertensives – should be avoided for 2 weeks prior to the study: (a) labetalol (Normodyne, Trandate), (b) calcium channel blockers, (c) reserpine (Serpasil, Sandril). (3) Sympathetic amines – should be avoided for 2 weeks prior to the study: (a) pseudoephedrine (Halofed, Sudafed, Sudrin, others), (b) phenylpropanolamine HCL (Propagest, Sucrets Cold Decongestant, Entex, others), (c) phenylephrine HCL (Neo-Synephrine, Alconefrin, Rhinail, others), (d) ephedrine, (4) cocaine – should be avoided at all times and for 2 weeks prior to the study) is probably the most frequent cause of a false-negative study. False-negative MIBG findings have been described in children with ganglioneuroblastoma, where the ganglioneuroma elements were predominant, suggesting that uptake is influenced by histology and the degree of tumor cell maturation, whereas no relationship with the secretion of catecholamines could be assessed . However, other studies in children with completely negative MIBG scans at diagnosis did not find any correlation with histopathology, biological factors, or stage of disease . On the other hand, in recent studies it could be shown that there is a correlation between a high MIBG uptake and an unfavorable histopathology . Furthermore, combined MIBG scintigraphy and tumor marker analysis can predict unfavorable histopathology of neuroblastic tumors with high accuracy .
Physiological distribution of MIBG is present in the heart and salivary glands because of their sympathetic innervation, while other systems (urinary tract, gastrointestinal system) represent excretion routes of the tracer . Most of false-positive MIBG findings are due to a nonspecific radioactivity accumulation in the urinary tract, and/or gastrointestinal structures, and not to specific MIBG uptake by nonneuroblastic cells [145, 147, 148, 149, 150, 151, 152, 153, 154]. Using SPECT/CT to acquire MIBG images reduces the likelihood of false-positive scans.
In the literature, usefulness of bone scintigraphy for the staging of neuroblastoma is under discussion. When comparing MIBG and bone scintigraphy in patients with confirmed neuroblastoma, it was found that 99mTc-MDP and MIBG scans were concordant for the presence or absence of skeletal disease. However, nearly twofold greater number of skeletal lesions was evident on MIBG scanning. In patients with histological evidence of bone marrow involvement, each study suggested skeletal lesions in approximately 70%. In addition, no patients with normal bone scans had MIBG scans indicating bone involvement. In conclusion, both MIBG and 99mTc-MDP are useful for the detection of skeletal neuroblastoma. 123I-MIBG is the better agent for characterizing the extent of disease, and 99mTc-MDP is a valuable adjunctive agent that provides skeletal landmarks for comparison .
Therefore, bone scintigraphy with 99mTc-diphosphonates could be important to check for bone metastases when neuroblastoma does not concentrate radioiodinated MIBG. However, in primary staging in particular, whole-body MRI will replace bone scintigraphy as has been shown by several studies demonstrating that whole-body MRI has a higher sensitivity than skeletal scintigraphy in children for the detection of bone marrow metastases  and shows a higher number of bone lesions than standard skeletal scintigraphy in children and young adults with malignancies .
However, MRI has poor specificity for metastatic osteomedullary infiltration which is most important for follow-up evaluation. False-positive results of MRI for bone marrow infiltration persisted even months after successful treatment completion in children with stage 4 neuroblastoma who had normal 123I-MIBG scans and bone marrow biopsy at the end of treatment .
Despite the high diagnostic accuracy of 123I-MIBG imaging, there are several disadvantages of this modality such as limited spatial resolution, limited sensitivity in small lesions, need for two or – in the case of SPECT – even more acquisition sessions, and a delay between the start of the examination and result. Furthermore, MIBG imaging is not sufficient for operative or biopsy planning in most of the cases. The majority of these disadvantages can potentially be overcome with PET  due to its higher spatial resolution and the possibility of a whole-body tomography versus SPECT (that has a more limited field of view). PET or PET/CT is completed in one examination within 30–60 min after injection versus 123I-MIBG scintigraphy and SPECT or SPECT/CT that require at least 18–24 h to achieve tumor-to-background ratios adequate for imaging. The resulting shorter scanning time of PET has the potential for reducing the number of sedations in small children.
The use of [18F]FDG-PET in the evaluation of pediatric neuroblastoma is increasing, although its role remains less clear. Questions remain regarding when and in which patients [18F]FDG-PET is most useful. Three studies have compared MIBG scintigraphy and [18F]FDG-PET in neuroblastoma [160, 161, 162]. In these studies, MIBG was labeled with either 131I or 123I. These authors demonstrated that most neuroblastomas concentrate [18F]FDG. However, they found that [18F]FDG is inferior to MIBG in the evaluation of neuroblastoma because of its lower tumor-to-nontumor uptake ratio (especially after therapy) and because of [18F]FDG uptake in nontumor sites (such as bone marrow, thymus, and bowel), causing potential false-positive or false-negative results. They concluded that [18F]FDG was most beneficial in tumors that failed to accumulate or weakly accumulated MIBG . In another study, 92 [18F]FDG-PET scans were performed in conjunction with staging evaluations including 123I-MIBG scans, bone scans, CT (or MRI) scans, urine catecholamine, and bone marrow examinations. In this study, PET was equal or superior to MIBG scans for identifying neuroblastoma in soft-tissue and extracranial skeletal structures, for revealing small lesions, and for delineating the extent and localizing sites of disease . Their results showed that [18F]FDG-PET and bone marrow sampling are sufficient to monitor for progressive disease in patients whose primary tumor has been resected and in whom cranial vault lesions are absent or resolved .
However, in all these comparative studies, there is a consensus that [18F]FDG-PET should be considered if there is a discrepancy between morphological imaging and 123I-MIBG scintigraphy .
As [18F]FDG is a marker for the viability of malignancies in general, more specific PET tracers have been developed for imaging the sympathetic nervous system like hydroxyephedrine labeled with carbon-11 ([11C]HED) [164, 165]. The aromatic portion of HED is less lipophilic than that of MIBG, and while HED bears closer structural similarity to norepinephrine, it is not metabolized as is norepinephrine. Biodistribution studies in experimental animals and humans have shown selective uptake in organs with rich sympathetic innervation, including the heart and adrenal medulla. When HED is labeled with 11C, its distribution can be portrayed in vivo using PET. In a study, neuroblastomas were located by PET scanning with [11C]HED in all seven participants . The uptake of [11C]HED into neuroblastomas was rapid; tumors were evident on images within 5 min post-intravenous injection. Those lesions in the field of view of the PET camera were also identified on 123I-MIBG scintigraphic images. In two patients, however, tumor deposits in the abdomen were better visualized with 123I-MIBG scintigraphy due to relatively less hepatic accumulation of 123I-MIBG than [11C]HED. The authors concluded that PET scanning with [11C]HED for neuroblastoma results in high-quality functional images of the tumors that can be obtained within minutes following injection .
Furthermore, [11C]HED PET/CT was shown to be feasible in tumors of the sympathetic nervous system . In this study, [11C]HED PET/CT detected more tumor lesions than 123I-MIBG SPECT/CT, but not in neuroblastoma, where one large local relapse was missed with [11C]HED in contrast to 123I-MIBG. Moreover, tumor-to-background contrast of [11C]HED in lesions can be higher, equal, or lower compared with 123I-MIBG . The relatively high physiologic liver uptake of [11C]HED may impede the detection of small liver metastases. Some of these shortcomings may be avoided by using PET/CT with 18F-labeled tracers (half-life: 110 min), such as 18F-DOPA which has been used for imaging of a variety of neuroendocrine tumors [167, 168, 169]. However, there are a few studies reporting the results of 18F-DOPA PET in pediatric neuroblastoma [29, 170, 171, 172], and there are no comparative studies between [11C]HED PET and 18F-DOPA PET . Attention is currently being paid to the role of 18F-DOPA-PET in pediatric neuroblastoma, as well as that of PET with 124I-MIBG, 68Ga-DOTA-TOC (or other radiolabeled somatostatin analogs), because new, highly sensitive and specific PET tracers would be of great clinical interest for imaging during initial staging and for assessing response to therapy, in the perspective of individualizing therapeutic strategies.
Morphological and Multimodality Imaging
The major limitation of morphological imaging (CT and/or MRI) is in the assessment of the viability of morphologically detectable lesions. On the other hand, functional imaging (MIBG or PET) often lacks in distinguishing physiological changes versus tumor lesions. Ideally, multimodality imaging helps to increase diagnostic safety for defining the adequate therapeutic consequence .
With regard to a combined PET/CT or PET/MRI approach, hybrid imaging significantly improved the characterization of abnormal [18F]FDG foci in children with cancer, mainly by excluding the presence of active malignancy in sites of increased tracer activity [9, 10, 177].
The CT component of the PET/CT acquisition is not very sensitive for the detection of malignant marrow infiltrations, which can be diffuse rather than focal or multifocal, in particular, in patients with neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma [178, 179]. Thus, in patients with a high suspicion for bone and bone marrow metastases, additional imaging modalities such as MRI may be needed (Fig. 11) [180, 181], or acquisition using a PET/MRI hybrid scanner.
PET/CT also has been shown to be superior to PET alone by allowing precise CT localization of metabolic abnormalities shown on PET and superior to CT alone by allowing metabolic characterization of abnormal and normal findings shown on CT, thereby increasing diagnostic confidence and reducing equivocal image interpretations [177, 182, 183, 184, 185].
Concerning the added value of 123I-MIBG SPECT/CT compared to contrast-enhanced CT, it was observed that all equivocal cases on CT were solved by SPECT/CT, related to the high specificity of 123I-MIBG for tumoral tissue, and concluded that during follow-up of children with MIBG-positive neuroblastoma at diagnosis, SPECT/CT should be performed first and, if negative, contrast-enhanced CT could be discarded. Inversely, single positive/equivocal 123I-MIBG foci without concordant morphological changes may need histological confirmation .
There is strong evidence that 123I-MIBG scintigraphy (planar images and SPECT) remains the method of choice for the noninvasive staging of children with neuroblastoma. PET imaging using [18F]FDG or the more specific tracer [11C]HED has not definitely proven to be superior to 123I-MIBG.
With regard to multimodality imaging, it has been shown that a combined approach with 123I-MIBG/MRI, 123I-MIBG/CT, and PET/CT has the potential to increase diagnostic sensitivity and specificity as compared to single modalities. Unfortunately, PET/CT represents no one-stop shop for the evaluation of pediatric neuroblastoma as PET cannot surpass 123I-MIBG scintigraphy, and CT cannot replace MRI especially in primary diagnosis (delineation of the infiltration of the spinal canal and detection of bone marrow edema).
Concerning the state-of-the-art diagnostic strategy in neuroblastoma imaging, it is important to differentiate between primary diagnosis and follow-up controls.
In primary diagnosis, 123I-MIBG scintigraphy (i.e., whole-body staging, differential diagnosis) and MRI (i.e., operability, bone marrow metastases) are indispensable. In case of any discrepancy between these two modalities, further staging should be performed with [18F]FDG-PET/CT or -PET/MRI.
In follow-up examinations, 123I-MIBG scintigraphy is most important in MIBG-positive neuroblastoma as specificity of morphological imaging is very low here. In 123I-MIBG-negative neuroblastoma or equivocal MIBG findings, [18F]FDG-PET/CT or -PET/MRI represents the imaging modalities of choice.
Pediatric Osseous and Soft-Tissue Sarcomas
Sarcomas are a heterogeneous group, combining various tumor entities with different tumor biology, malignancy, and therapeutic options. There are different age patterns in different tumor entities. Some entities such as embryonal rhabdomyosarcomas, osteosarcomas, or Ewing tumors are mainly or exclusively found in childhood and adolescence. The metastatic spread of sarcomas is mainly hematogenous to the lungs and the bones. However, in soft-tissue sarcomas, also lymphatic spread occurs. The presence or absence of metastases and the tumor histology and grade mainly influence the treatment.
The two major groups of primary bone tumors in children and adolescents are osteosarcomas and the Ewing family of tumors.
Soft-tissue sarcomas in children are a heterogeneous group of malignant tumors that originate in the soft tissues and have a predominantly mesenchymal origin. The most common histologic entities in children and adolescents are rhabdomyosarcoma (embryonal and alveolar, 61%), extraosseous Ewing sarcoma and peripheral neuroectodermal tumor (PNET, 8%), synovial sarcoma, neurofibrosarcoma, fibrosarcoma, and leiomyosarcoma.
Langerhans Cell Histiocytosis
Langerhans cell histiocytosis (LCH) is a proliferation of Langerhans-type histiocytes. Despite its clonal origin, there is no definitive proof of malignancy. The term “LCH” replaces a number of synonyms that have been used in the past to describe various conditions: histiocytosis X, Abt-Letterer-Siwe syndrome, Hand-Schüller-Christian disease, and eosinophilic granuloma.
Role of Imaging
Three-Phase Bone Scintigraphy
Primary Bone Tumors and Tumor-Like Lesions
Even in the age of cross-sectional imaging, primary bone tumors are best classified using a conventional planar x-ray. CT and MRI supply further information on tumor localization and extension. A three-phase bone scan with increased tracer uptake in all three phases supports a presumptive diagnosis of a primary malignant bone tumor. However, the pattern is not specific since acute inflammation shows the same tracer pattern. Additionally, some benign lesions demonstrate a clearly increased tracer uptake in all three phases, for example, osteoid osteoma. A normal or only marginally increased blood pool phase and a moderately increased bone phase suggest a benign lesion.
After chemotherapy of primary bone tumors, bone scintigraphy can be used for therapy control. A decrease in tracer uptake in the blood pool phase and in the bone phase of more than 30% indicates a good response [187, 188]. However, even in good responders there might be an increased tracer uptake during chemotherapy due to the flare phenomenon. Therefore, therapy response should be assessed by bone scintigraphy more than 6 weeks after the end of chemotherapy.
Although bone metastases are usually visualized by 99mTc-diphosphonate bone scan 3–6 months earlier than by plain x-ray films , the specificity of skeletal scintigraphy is only 60–70%. Therefore, verification of abnormal findings is often necessary. Many studies have demonstrated the superiority of MRI in comparison to bone scintigraphy in the detection of osseous metastases, especially in the vertebral column .
A distinctive feature of osteosarcoma and its metastases is the capability to produce premature osseous matrix, the point of chemoadsorption of the radiolabeled phosphonates. Therefore, skeletal scintigraphy is very sensitive in the detection of osseous metastases of osteosarcoma, and even soft-tissue metastases are often visible on the bone scan [191, 192, 193]. Because of this characteristic feature, therapy with bone-seeking radiopharmaceuticals can be applied in patients with osteosarcoma. Despite highly efficacious chemotherapy, patients with osteosarcomas still have a poor prognosis if adequate surgical control cannot be obtained. These patients may benefit from therapy with radiolabeled phosphonates, such as samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) .
For a more extensive discussion of osseous and soft-tissue sarcomas, see chapter “Diagnostic Applications of Nuclear Medicine: Sarcomas.”
Langerhans Cell Histiocytosis
No large studies have yet been done on the use of [18F]FDG-PET, [18F]FDG-PET/CT, or PET/MRI of LCH. One multicase report with three patients found that coincidence [18F]FDG-PET was better able to distinguish between active and healed bony LCH lesions than plain x-ray or bone scans . This observation is supported by a study on various pediatric tumor entities including LCH . Another small study in three patients with cerebral LCH involvement demonstrated that [18F]FDG-PET could detect intracerebral foci of increased or decreased glucose metabolism . Like the authors of a single case-report , Calming et al. conclude that [18F]FDG-PET is useful for the evaluation of disease activity during follow-up.
In a comparative study, Mueller et al. evaluated 53 LCH lesions in 21 combined MRI and [18F]FDG-PET studies (15 patients). They concluded that the retrospective analysis suggests a pivotal role of [18F]FDG-PET in lesion follow-up due to a lower number of false-positive findings after chemotherapy. MRI showed a higher sensitivity and is indispensable for primary staging, evaluation of brain involvement, and biopsy planning. Combined MRI/PET analysis improved sensitivity by decreasing the false-negative rate during primary staging indicating a future role of simultaneous whole-body PET/MRI for primary investigation of pediatric histiocytosis .
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