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Diagnostic Applications of Nuclear Medicine: Pediatric Cancers

  • Thomas PflugerEmail author
  • Andrea Ciarmiello
  • Giampiero Giovacchini
  • Françoise Montravers
  • Hubert Ducou Le Pointe
  • Judith Landman-Parker
  • Martina Meniconi
  • Christiane Franzius
Living reference work entry

Abstract

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.

Keywords

Pediatric 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 

Glossary

[11C]HED

[11C]Hydroxyephedrine

[11C]MET

[11C]Methionine

153Sm-EDTMP

153Sm-ethylenediaminetetramethylene phosphonic acid

18F-DOPA

2-18F-Fluoro-L-3,4-dihydroxyphenylalanine

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

18F-FET

O-(2-18F-Fluoroethyl)-L-Tyrosine, a tyrosine analog

68Ga-DOTA-TOC

68Ga-DOTA-Tyr3-octreotide

99mTc-MDP

99mTc-methyldiphosphonate

ACCIS

European Automated Childhood Cancer Information System

ce-CT

Contrast-enhanced diagnostic CT

CNS

Central nervous system

CT

X-ray computed tomography

DOTA

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)

EGFR

Epidermal growth factor receptor

GCSF

Granulocyte colony-stimulating factor

Gy

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)

HL

Hodgkin’s lymphoma

LCH

Langerhans cell histiocytosis

LGAs

Low-grade astrocytomas

MIBG

meta-iodobenzylguanidine

MRI

Magnetic resonance imaging

NE

Norepinephrine

NHL

Non-Hodgkin’s lymphoma

PD

Progressive disease

PET

Positron emission tomography

PET/CT

Positron emission tomography/Computed tomography

PET/MRI

Positron emission tomography/Magnetic resonance imaging system

PNET

Peripheral neuroectodermal tumor

RECIST

Response evaluation criteria in solid tumors

SEER

Surveillance, epidemiology and end results

SPECT

Single-photon emission computed tomography

SPECT/CT

Single-photon emission computed tomography/Computed tomography

SUV

Standardized uptake values

WHO

World Health Organization

Cancer in children is much less common than in adults. Pediatric cancers, defined as cancers occurring before the age of 15 years, account for only 2% of all cancers [1]. Nevertheless, cancer is the second most common cause of death in children in developed countries. However, improvement of treatment strategies has increased the probability of survival. For example, EUROCARE data showed an 8% reduction in the relative risk of death when comparing the 2000–2002 time span to the 1995–1999 period. Also in the interval from 1995 to 2002, pediatric cancer patients had an overall 5-year survival of 81% in Europe and the USA (Table 1) [2].
Table 1

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)

Cancer group

ACCIS (%)

SEER (%)

Total

72

75

Leukemias

73

74

Lymphomas and reticuloendothelial neoplasms

84

83

CNS and miscellaneous intracranial and intraspinal neoplasms

64

66

Sympathetic nervous system tumors

59

66

Retinoblastoma

93

95

Renal tumors

84

90

Hepatic tumors

57

56

Malignant bone tumors

61

68

Soft-tissue sarcomas

65

73

Germ cell, trophoblastic, and other gonadal neoplasms

84

87

Carcinomas and other malignant epithelial neoplasms

89

89

Others and unspecified malignant neoplasms

74

From Kaatsch [2], with permission

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 [2]. 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 [2].

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 [3]. 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 [4]. 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

Epidemiology

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 [16].

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.

Symptoms

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.

[18F]FDG Scan

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 [19]; 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 [20].

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 [21]. 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 [21].

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 [21].

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 [12].

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 [22].

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 [22].

Kruer et al. [23] 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. [24] 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. [25].

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 [26], 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 [29], including detection of CNS metastasis [30], and in nontumoral conditions such as congenital hyperinsulinism [31], 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 [32] and can be used for target selection and to guide surgical treatment in pediatric brain tumors [33].

Childhood Lymphoma

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) [34].

Hodgkin’s Lymphoma

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 [35], especially in the nodular sclerosis subtype of HL because of its abundant fibrotic component [36]. 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 [39].

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].

Non-Hodgkin’s Lymphoma

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 [42]. 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 [43]. 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) [44].

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 [45].

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 [48], and 70% for anaplastic large-cell lymphoma [49].

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 [51]. Bone scintigraphy is also less sensitive than [18F]FDG-PET to detect bone and bone marrow involvement [52].

[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 [53]. 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 [54]. Diagnostic CT also allows detailed evaluation of the pulmonary parenchyma, pleura, and pericardium.

[18F]FDG-PET/CT must also be considered in relation to:
  • 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 [54] and an effective imaging method to explore liver and spleen [54].

  • 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 [55], liver, soft tissue, and central nervous system [56]. 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 [57]. However, whole-body MRI is increasingly performed by using hybrid PET/MRI scanners instead of PET/CT scanners in children [11].

[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 [65]. 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) [64] 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.

Hodgkin’s Lymphoma

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 [85], 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].

Initial Staging

In adults, [18F]FDG-PET/CT and -PET/MRI is useful for pretreatment staging. PET/CT cannot replace diagnostic ce-CT, but it can provide complementary information, potentially resulting in a modification of disease stage (usually upstaging) in about 15–20% of adult patients, with an impact on management in about 5–15% [88]. In children, [18F]FDG-PET modified the stage in 10–23% of patients [51] (Fig. 1). Apart from its role in staging and radiation therapy planning pretreatment, [18F]FDG-PET/CT or PET/MRI is also essential because it provides a reference, facilitating interpretation of subsequent treatment evaluation with PET, as recurrences usually occur in previously involved lesions, and de novo sites of uptake observed during follow-up must be primarily suspected to be false-positive [89].
Fig. 1

Hodgkin’s lymphoma in a 14-year-old girl, classified stage II before [18F]FDG-PET/CT with extensive supradiaphragmatic lymph node involvement. [18F]FDG-PET/CT showed an unexpected focus in the sacral bone marrow (a, b), with no abnormality on CT (c). Bone marrow involvement was confirmed by MRI (d), leading to upstaging of the disease from stage II to stage IV

Monitoring of Response to Therapy

As HL is a curable disease, it is essential to ensure that therapy has been fully effective at the end of treatment. [18F]FDG-PET/CT or PET/MRI is routinely performed for this purpose, usually after completion of chemotherapy and before radiotherapy, as a negative [18F]FDG-PET is a reliable indicator of complete remission [88] (Fig. 2). The metabolic information provided by [18F]FDG-PET at the end of therapy is very important, as assessment of response by morphologic imaging modalities is particularly difficult, due to the generally slow and protracted regression of the size of enlarged lymph nodes [51]. Moreover, in HL, malignant cells comprise only a small fraction of the tumor volume, which is mostly composed of reactive infiltrating cells not directly affected by antineoplastic therapy [90].
Fig. 2

Hodgkin’s lymphoma stage IV (lymph node and bone marrow involvement) in an 8-year-old boy. [18F]FDG-PET/CT at staging (a) and after completion of chemotherapy and before radiotherapy (b), with metabolic complete response. Persistent clinical remission 4 years after the end of 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 [90]. 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 [91]. When interim PET is negative, no other PET needs to be performed at the end of therapy in the absence of clinical signs [92].

Systematic [18F]FDG-PET/CT is not indicated during follow-up because it can result in false positives [93], 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.

Non-Hodgkin’s Lymphoma

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 [97], and some low-grade NHL, especially T-cell lymphoma, present inconstant [18F]FDG uptake [81]. 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 [98].

[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.

The main indications for [18F]FDG-PET in children with NHL are inconclusive results of conventional imaging modalities, that is, suspicion of recurrence (Fig. 3) or characterization of residual masses after treatment [99]. [18F]FDG-PET performed for these purposes can be difficult to interpret firstly because a reference [18F]FDG-PET is usually not available for comparison (and there is no absolute certainty that the NHL subtype is able to take up [18F]FDG). [18F]FDG-PET can also be falsely positive in the presence of inflammation and/or necrosis, very frequent after surgery and chemotherapy for gut involvement in Burkitt’s lymphoma [100].
Fig. 3

Liver recurrence of Burkitt’s NHL. Note the very high intensity of [18F]FDG uptake by liver lesions, higher than physiologic brain uptake

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 [101]. 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

False-Negative Results

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 [64]. 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 [51].

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 [104].

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 [51]. Characterization of the mass can be particularly difficult when ectopic thymic tissue is located in the neck [105].

Brown fat activation is also frequently seen in children. Brown fat is normally distributed in the neck, around the diaphragm, in the perinephric space, and in para-aortic and intercostal regions [102]. Brown fat activation is more easily recognized with hybrid PET/CT scanners (Fig. 4), as [18F]FDG uptake corresponds to low density structures on CT. Nevertheless, even after comparison with CT images, interpretation remains difficult when brown fat activation occurs in previously involved sites. Brown fat activation can be prevented by keeping children warm prior to [18F]FDG administration and during uptake, but these measures may not be sufficient. Benzodiazepine pretreatment may also reduce this activation [101]. More recently, beta-blockers have been shown to be particularly effective and can be used with the agreement of pediatric oncologists [106].
Fig. 4

Extensive brown fat activation. Correlative [18F]FDG PET and CT imaging easily identifies the low density of fat on CT images

False-positive results are relatively frequent because [18F]FDG is not specific for malignancy and increased uptake can occur in benign conditions associated with increased glycolysis, such as infection, inflammation, granulomatous disease, and more rarely benign tumors (e.g., Fig. 5).
Fig. 5

Unexpected [18F]FDG uptake in the left adrenal gland in a 5-year-old girl with stage II HL (supradiaphragmatic lymph node involvement), at staging (a) and persistent after chemotherapy (b) although all supradiaphragmatic sites became [18F]FDG negative. This adrenal uptake was suspected to be a false-positive finding, which was confirmed at surgery. The adrenal lesion was benign, corresponding to a leiomyoma

In children and adolescents, false-positive results can be related to infectious mononucleosis [107] 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 [108].

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 [102], but the uptake observed in a context of acute radiation pneumonitis can be intense [102].

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 [102]. Increased activity in the spleen has also been observed both during and after GCSF treatment [102]. 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 [102].

Prospects

[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 [51].

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 [109].

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

Wilms’ tumor is the most common renal malignancy in childhood [110]. The 5-year survival rate currently is about 91.9% [111]. 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 [110]. Two histopathologic findings are described: the favorable and the anaplastic.

Imaging studies are mainly used to define the origin and anatomic extent of the tumor, determine the status of metastatic disease, survey therapy, and detect relapse. So far, the diagnostic workup of newly diagnosed Wilms’ tumor 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 tumor thrombus in the renal vein and inferior vena cava [110]. For the detection of bilateral disease and the assessment of nephroblastomatosis representing premalignant lesions, MRI is the imaging modality of choice (Fig. 6) [112]. In cases with unclear definition of the organ of origin (the kidney, adrenal gland, sympathetic trunk), 123I-MIBG scintigraphy can be very helpful for the differentiation of neuroblastoma versus Wilms’ tumor (Fig. 7).
Fig. 6

Four-year-old boy with bilateral Wilms’ tumor and nephroblastomatosis. Transversal fat-suppressed T1-weighted image after contrast enhancement reveals bilateral nephroblastoma (arrows) and a right-sided nephroblastomatosis lesion (arrowheads)

Fig. 7

Six-year-old boy with large neuroblastoma originating from left adrenal gland. (a) Coronal T2-weighted image reveals large mass in left abdomen (arrows) with appearance typical of Wilms’ tumor with pseudocapsule and apparent origin from kidney (arrowheads). (b) Corresponding transverse T1-weighted image depicts large mass (arrows). (c) Strong focal uptake by mass visible on 123I-MIBG scintigrams led to correct differential diagnosis of neuroblastoma. RVL right side, ventral view, left side, LDR left side, dorsal view, right side. (d) Transverse (tra) SPECT reconstructions that correlate to MRIs show tumor extent and central tumor necrosis

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 [113].

Although [18F]FDG-PET was successfully used to image Wilms’ tumor for the first time [113] 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 [110]. 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 [113].

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 [102]. 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 [110]. 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 [113].

Neuroblastoma

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 [119]. The tumor is usually situated in the adrenal gland or anywhere else along the sympathetic nervous system chain [115]. At diagnosis, roughly 50% of patients have distant hematogenous metastases [120]. Neuroblastoma presents a wide spectrum clinical behavior and survival rates; therefore, staging is crucial in order to choose the appropriate treatment [121].

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].

MIBG Scintigraphy

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 [137]. 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 [138].

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 [139]. 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 [132]. 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 [142]. Furthermore, combined MIBG scintigraphy and tumor marker analysis can predict unfavorable histopathology of neuroblastic tumors with high accuracy [143].

When looking at lesion-based evaluations, bone and bone marrow lesions are identified more consistently than soft-tissue lesions. Overall sensitivities range between 60% and 70% [133, 144, 145].

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 [146]. 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.

Bone Scintigraphy

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 [155].

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 [156] and shows a higher number of bone lesions than standard skeletal scintigraphy in children and young adults with malignancies [157].

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 [158].

Positron-Emission Tomography

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 [159] 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 [162]. 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 [161]. 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 [161].

The third study found stage-dependent results for both modalities [160]. [18F]FDG was superior in depicting stage 1 and 2 neuroblastoma. [18F]FDG also better depicted disease in stages 3 and 4 when tumors did not accumulate 123I-MIBG or did so only weakly. Furthermore, [18F]FDG can better delineate disease extent in the chest, abdomen, and pelvis and should always be considered when 123I-MIBG reveals less disease than suggested by clinical symptoms or conventional imaging modalities (Fig. 8) [119].123I-MIBG was superior in stage 4 neuroblastoma, primarily because of the better detection of bone or marrow metastases. This was especially true during initial chemotherapy or under treatment with granulocyte colony-stimulating factor, conditions associated with marked increase in bone marrow uptake, which can either mask or mimic metastatic disease [160].
Fig. 8

A 7-year-old boy with a histologically proven recurrent neuroblastoma in the region of the left adrenal gland. (a)123I-MIBG SPECT does not show any pathological uptake in the left adrenal region (crosshair) leading to a false-negative result. (b) [18F]FDG-PET clearly demonstrates an increased glucose metabolism in the respective region (crosshair) suspect for recurrent disease. (c) Image fusion between [18F]FDG-PET and MRI shows increased [18F]FDG uptake within a contrast-enhancing soft-tissue mass (arrow)

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 [163].

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 [165]. 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 [165].

Furthermore, [11C]HED PET/CT was shown to be feasible in tumors of the sympathetic nervous system [166]. 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 [166]. 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 [166]. 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 [173].

In contrast to CT, MRI has several advantages in the diagnosis of neuroblastoma: high sensitivity in detecting bone marrow abnormalities [158], lack of ionizing radiation, high intrinsic soft-tissue contrast resolution [125], depiction of internal structure [174], and exact definition of intraspinal tumor extension (Fig. 9) or diaphragmatic involvement of thoracic tumors [124, 175]. All these factors are decisive, especially in primary diagnosis and for operative or biopsy planning [176]. In a comparative study, the benefit of a combined analysis with MRI and 123I-MIBG scintigraphy in pediatric neuroblastoma lesions was assessed. In this study, 123I-MIBG scintigraphy, MRI, and combined analysis showed a sensitivity of 69%, 86%, and 99% and a specificity of 85%, 77%, and 95%, respectively. On MRI, 15 false-positive findings were recorded: post-therapeutic reactive changes (n = 10) (Fig. 10), benign adrenal tumors (n = 3), and enlarged lymph nodes (n = 2). On 123I-MIBG scintigraphy, ten false-positive findings occurred: ganglioneuromas (n = 2), benign liver tumors (n = 2), and physiologic uptake (n = 6). Thirteen neuroblastoma metastases and two residual masses under treatment with chemotherapy were judged to be false-negative findings on MRI. Two primary or residual neuroblastomas and one orbital metastasis were misinterpreted as Wilms’ tumor, reactive changes after surgery, and rhabdomyosarcoma on MRI. Thirty-two bone and bone marrow metastases (Fig. 11), six other neuroblastoma metastases, and one adrenal neuroblastoma showed no 123I-MIBG uptake. On combined imaging, one false-negative (bone metastasis) and three false-positive (two ganglioneuromas and one pheochromocytoma) findings remained. In conclusion, MRI showed a higher sensitivity and 123I-MIBG scintigraphy a higher specificity. However, integrated imaging showed an increase in both sensitivity and specificity [145].
Fig. 9

A 2-month-old suckling with a stage IV neuroblastoma. Clinical and ultrasound findings did not demonstrate a primary tumor. (a) Transversal T2-weighted MRI of the abdomen demonstrated diffuse liver metastases. (b) Coronal T1-weighted MRI did not show a primary in the adrenal glands or the sympathetic trunk of the abdomen. (c) Chest x-ray could not detect a neuroblastoma in the thorax. (d) SPECT reconstructions of 123I-MIBG scintigraphy clearly depict the right paravertebral primary as well as diffuse liver metastases. However, exact extent of the tumor and intraspinal involvement cannot be assessed. (e, f) Coronal and transversal T1-weighted MRI demonstrate the exact extent of the primary and tumor growth through intervertebral foramina (arrows) which is decisive for further therapy planning

Fig. 10

A 4-year-old boy with reactive changes 6 months after resection of stage II neuroblastoma of the right adrenal gland. (a) Coronal T1-weighted MRI demonstrated a contrast-enhancing tumor (region of interest) suspect of residual or recurrent viable tumor tissue. Differentiation between residual tumor and reactive changes is not possible with MRI (false-positive finding). (b) Coronal SPECT reconstructions of 123I-MIBG scintigraphy reveal a negative finding. True-negative diagnosis was confirmed by follow-up control examinations over 2 years

Fig. 11

An 8-month-old girl with stage IV neuroblastoma who presented with multiple bony metastases. (a) MRI from STIR sequence shows high signal in two bone marrow metastases in left iliac bone and second lumbar vertebra (arrows) (true-positive findings). (b) In corresponding regions, planar 123I-MIBG scintigrams show no uptake (false-negative findings). Strong uptake can be seen in mediastinal primary tumor as well as in a left-sided femoral bone metastasis. RVL right side, ventral view, left side, LDR left side, dorsal view, right side. (c) Corresponding coronal (cor) SPECT reconstructions of 123I-MIBG scintigraphy support findings of planar images

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 [186].

Conclusion

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.

Bone Sarcomas

The two major groups of primary bone tumors in children and adolescents are osteosarcomas and the Ewing family of tumors.

Soft-Tissue Sarcomas

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.

Osseous Metastases

Although bone metastases are usually visualized by 99mTc-diphosphonate bone scan 3–6 months earlier than by plain x-ray films [189], 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 [190].

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) [194].

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 [195]. This observation is supported by a study on various pediatric tumor entities including LCH [196]. 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 [197]. Like the authors of a single case-report [198], 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 [199].

References

  1. 1.
    Connolly LP, Drubach LA, Ted Treves S. Applications of nuclear medicine in pediatric oncology. Clin Nucl Med. 2002;27:117–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010;36:277–85.PubMedCrossRefGoogle Scholar
  3. 3.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.CrossRefGoogle Scholar
  4. 4.
    McCarville MB. PET-CT imaging in pediatric oncology. Cancer Imaging. 2009;9:35–43.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Yeung HW, Schöder H, Gonen M, Larson SM. Clinical value of combined positron emission tomography/computed tomography imaging in the interpretation of 2-deoxy-2-[F-18]fluoro-d-glucose–positron emission tomography studies in cancer patients. Mol Imaging Biol. 2005;7:229–35.PubMedCrossRefGoogle Scholar
  6. 6.
    Kleis M, Heike Daldrup-Link H, Matthay K, et al. Diagnostic value of PET/CT for the staging and restaging of pediatric tumors. Eur J Nucl Med Mol Imaging. 2009;36:23–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Schwenzer NF, Pfannenberg C, Reischl G, Werner MK, Schmidt H. Application of MR/PET in oncologic imaging. Rofo. 2012;184:780–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Hirsch FW, Sattler B, Sorge I, et al. PET/MR in children: initial clinical experience in paediatric oncology using an integrated PET/MR scanner. Pediatr Radiol. 2013;43:860–75.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Aghighi M, Pisani LJ, Sun Z, Klenk C, Madnawat H, Fineman SL, Advani R, Von Eyben R, Owen D, Quon A, Moseley M, Daldrup-Link HE. Speeding up PET/MR for cancer staging of children and young adults. Eur Radiol. 2016;26:4239–48.Google Scholar
  10. 10.
    Sher AC, Seghers V, Paldino MJ, Dodge C, Krishnamurthy R, Krishnamurthy R, Rohren EM. Assessment of sequential PET/MRI in comparison with PET/CT of Pediatric lymphoma: a prospective study. AJR Am J Roentgenol. 2016;206:623–31.PubMedCrossRefGoogle Scholar
  11. 11.
    Ponisio MR, McConathy J, Laforest R, Khanna G. Evaluation of diagnostic performance of whole-body simultaneous PET/MRI in pediatric lymphoma. Pediatr Radiol. 2016;46:1258–1268.Google Scholar
  12. 12.
    Eiber M, Takei T, Souvatzoglou M, Mayerhoefer ME, Fürst S, Gaertner FC, Loeffelbein DJ, Rummeny EJ, Ziegler SI, Schwaiger M, Beer AJ. Performance of whole-body integrated 18F-FDG PET/MR in comparison to PET/CT for evaluation of malignant bone lesions. J Nucl Med. 2014;55:191–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Schäfer JF, Gatidis S, Schmidt H, Gückel B, Bezrukov I, Pfannenberg CA, Reimold M, Ebinger M, Fuchs J, Claussen CD, Schwenzer NF. Simultaneous whole-body PET/MR imaging in comparison to PET/CT in pediatric oncology: initial results. Radiology. 2014;273:220–31.PubMedCrossRefGoogle Scholar
  14. 14.
    Purz S, Sabri O, Viehweger A, Barthel H, Kluge R, Sorge I, Hirsch FW. Potential pediatric applications of PET/MR. J Nucl Med. 2014;55 Suppl 2:32S–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Spick C, Herrmann K, Czernin J. 18F-FDG PET/CT and PET/MRI perform equally well in cancer: evidence from studies on more than 2,300 patients. J Nucl Med. 2016;57:420–30.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Jadvar H, Connolly LP, Fahey FH, Shulkin BL. PET and PET/CT in pediatric oncology. Semin Nucl Med. 2007;37:316–31.PubMedCrossRefGoogle Scholar
  17. 17.
    Packer RJ. Childhood brain tumors: accomplishments and ongoing challenges. J Child Neurol. 2008;23:1122–7.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Packer RJ, Vezina G. Management of and prognosis with medulloblastoma: therapy at a crossroads. Arch Neurol. 2008;65:1419–24.PubMedCrossRefGoogle Scholar
  19. 19.
    Schelbert HR, et al. Procedure guideline for tumor imaging using fluorine-18-FDG. Society of Nuclear Medicine. J Nucl Med. 1998;39:1302–5.PubMedGoogle Scholar
  20. 20.
    Stauss J, Franzius C, Pfluger T, et al. Guidelines for 18F-FDG PET and PET-CT imaging in paediatric oncology. Eur J Nucl Med Mol Imaging. 2008;35:1581–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Hoffman JM, Hanson MW, Friedman HS, et al. FDG-PET in pediatric posterior fossa brain tumors. J Comput Assist Tomogr. 1992;16:62–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Borgwardt L, Hojgaard L, Carstensen H, et al. Increased fluorine-18 2-fluoro-2-deoxy-d-glucose (FDG) uptake in childhood CNS tumors is correlated with malignancy grade: a study with FDG positron emission tomography/magnetic resonance imaging coregistration and image fusion. J Clin Oncol. 2005;23:3030–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Kruer MC, et al. The value of positron emission tomography and proliferation index in predicting progression in low-grade astrocytomas of childhood. J Neurooncol. 2009;95:239–45.PubMedCrossRefGoogle Scholar
  24. 24.
    Galldiks N, Kracht LW, Berthold F, Miletic H, Klein JC, Herholz K, Jacobs AH, Heiss WD. [11C]-L-methionine positron emission tomography in the management of children and young adults with brain tumors. J Neurooncol. 2010;96:231–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Okochi Y, Nihashi T, Fujii M, Kato K, Okada Y, Ando Y, Maesawa S, Takebayashi S, Wakabayashi T, Naganawa S. Clinical use of 11C-methionine and 18F-FDG-PET for germinoma in central nervous system. Ann Nucl Med. 2014;28:94–102.PubMedCrossRefGoogle Scholar
  26. 26.
    Uslu L, Donig J, Link M, Rosenberg J, Quon A, Daldrup-Link HE. Value of 18F-FDG PET and PET/CT for evaluation of pediatric malignancies. J Nucl Med. 2015;56:274–86.PubMedCrossRefGoogle Scholar
  27. 27.
    Morana G, Piccardo A, Milanaccio C, Puntoni M, Nozza P, Cama A, Zefiro D, Cabria M, Rossi A, Garrè ML. Value of 18F-3,4-dihydroxyphenylalanine PET/MR image fusion in pediatric supratentorial infiltrative astrocytomas: a prospective pilot study. J Nucl Med. 2014;55:718–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Morana G, Piccardo A, Garrè ML, Nozza P, Consales A, Rossi A. Multimodal magnetic resonance imaging and 18F-L-dihydroxyphenylalanine positron emission tomography in early characterization of pseudoresponse and nonenhancing tumor progression in a pediatric patient with malignant transformation of ganglioglioma treated with bevacizumab. J Clin Oncol. 2013;31:e1–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Piccardo A, Puntoni M, Lopci E, Conte M, Foppiani L, Sorrentino S, et al. Prognostic value of 18F-DOPA PET/CT at the time of recurrence in patients affected by neuroblastoma. Eur J Nucl Med Mol Imaging. 2014;41:1046–56.PubMedCrossRefGoogle Scholar
  30. 30.
    Piccardo A, Morana G, Massollo M, Pescetto M, Conte M, Garaventa A. Brain metastasis from neuroblastoma depicted by 18F-DOPA PET/CT. Nucl Med Mol Imaging. 2015;49:241–2.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Ribeiro MJ, et al. Characterization of hyperinsulinism in infancy assessed with PET and 18F-fluoro-l-DOPA. J Nucl Med. 2005;46:560–6.PubMedGoogle Scholar
  32. 32.
    Dunkl V, Cleff C, Stoffels G, Judov N, Sarikaya-Seiwert S, Law I, et al. The usefulness of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the clinical evaluation of brain tumors in children and adolescents. J Nucl Med. 2015;56:88–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Misch M, Guggemos A, Driever PH, Koch A, Grosse F, Steffen IG, et al. 18F-FET-PET guided surgical biopsy and resection in children and adolescence with brain tumors. Childs Nerv Syst. 2015;31:261–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Pastore G, Magnani C, Verdecchia A, Pession A, Viscomi S, Coebergh JW. Survival of childhood lymphomas in Europe, 1978–1992: a report from the EUROCARE study. Eur J Cancer. 2001;37:703–10.PubMedCrossRefGoogle Scholar
  35. 35.
    Weihrauch MR, Re D, Scheidhauer K, et al. Thoracic positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease. Blood. 2001;98:2930–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Brisse H, Pacquement H, Burdairon E, Plancher C, Neuenschwander S. Outcome of residual mediastinal masses of thoracic lymphomas in children: impact on management and radiological follow-up strategy. Pediatr Radiol. 1998;28:444–50.PubMedCrossRefGoogle Scholar
  37. 37.
    Oberlin O. Present and future strategies of treatment in childhood Hodgkin’s lymphomas. Ann Oncol. 1996;7 Suppl 4:73–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Schwartz CL. The management of Hodgkin disease in the young child. Curr Opin Pediatr. 2003;15:10–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Landman-Parker J, Pacquement H, Leblanc T, et al. Localized childhood Hodgkin’s disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90. J Clin Oncol. 2000;18:1500–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Yeh JM, Diller L. Pediatric Hodgkin lymphoma: trade-offs between short- and long-term mortality risks. Blood. 2012;120:2195–202.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Hay AE, Meyer RM. Balancing risks and benefits of therapy for patients with favorable-risk limited-stage Hodgkin lymphoma: the role of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy alone. Hematol Oncol Clin North Am. 2014;28:49–63.PubMedCrossRefGoogle Scholar
  42. 42.
    Mann G, Attarbaschi A, Burkhardt B, et al. Clinical characteristics and treatment outcome of infants with non-Hodgkin lymphoma. Br J Haematol. 2007;139:443–9.PubMedGoogle Scholar
  43. 43.
    Reiter A. Diagnosis and treatment of childhood non-Hodgkin lymphoma. Hematology ASH Education Book. 2007;1:285–296.Google Scholar
  44. 44.
    Murphy SB, Fairclough DL, Hutchison RE, Berard CW. Non-Hodgkin’s lymphomas of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol. 1989;7:186–93.PubMedCrossRefGoogle Scholar
  45. 45.
    Patte C. Non-Hodgkin’s lymphoma. Eur J Cancer. 1998;34:359–62. discussion 62–3.PubMedCrossRefGoogle Scholar
  46. 46.
    Patte C, Auperin A, Gerrard M, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood. 2007;109:2773–80.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood. 2007;109:2736–43.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Grenzebach J, Schrappe M, Ludwig WD, et al. Favorable outcome for children and adolescents with T-cell lymphoblastic lymphoma with an intensive ALL-type therapy without local radiotherapy. Ann Hematol. 2001;80 Suppl 3:B73–6.PubMedGoogle Scholar
  49. 49.
    Brugieres L, Le Deley MC, Rosolen A, et al. Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol. 2009;27:897–903.PubMedCrossRefGoogle Scholar
  50. 50.
    Mody RJ, Bui C, Hutchinson RJ, Frey KA, Shulkin BL. Comparison of 18F Flurodeoxyglucose PET with Ga-67 scintigraphy and conventional imaging modalities in pediatric lymphoma. Leuk Lymphoma. 2007;48:699–707.PubMedCrossRefGoogle Scholar
  51. 51.
    Shankar A, Fiumara F, Pinkerton R. Role of FDG PET in the management of childhood lymphomas-case proven or is the jury still out? Eur J Cancer. 2008;44:663–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Shulkin BL, Goodin GS, McCarville MB, et al. Bone and [18F]fluorodeoxyglucose positron-emission tomography/computed tomography scanning for the assessment of osseous involvement in Hodgkin lymphoma in children and young adults. Leuk Lymphoma. 2009;50:1794–802.PubMedCrossRefGoogle Scholar
  53. 53.
    Allen-Auerbach M, Quon A, Weber WA, et al. Comparison between 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography and positron emission tomography/computed tomography hardware fusion for staging of patients with lymphoma. Mol Imaging Biol. 2004;6:411–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Toma P, Granata C, Rossi A, Garaventa A. Multimodality imaging of Hodgkin disease and non-Hodgkin lymphomas in children. Radiographics. 2007;27:1335–54.PubMedCrossRefGoogle Scholar
  55. 55.
    Rahmouni A, Montazel JL, Divine M, et al. Bone marrow with diffuse tumor infiltration in patients with lymphoproliferative diseases: dynamic gadolinium-enhanced MR imaging. Radiology. 2003;229:710–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Haque S, Law M, Abrey LE, Young RJ. Imaging of lymphoma of the central nervous system, spine, and orbit. Radiol Clin North Am. 2008;46:339–61.PubMedCrossRefGoogle Scholar
  57. 57.
    Punwani S, Taylor SA, Bainbridge A, et al. Pediatric and adolescent lymphoma: comparison of whole-body STIR half-Fourier RARE MR imaging with an enhanced PET/CT reference for initial staging. Radiology. 2010;255:182–90.PubMedCrossRefGoogle Scholar
  58. 58.
    Moog F, Bangerter M, Diederichs CG, et al. Extranodal malignant lymphoma: detection with FDG PET versus CT. Radiology. 1998;206:475–81.PubMedCrossRefGoogle Scholar
  59. 59.
    Carr R, Barrington SF, Madan B, et al. Detection of lymphoma in bone marrow by whole-body positron emission tomography. Blood. 1998;91:3340–6.PubMedGoogle Scholar
  60. 60.
    Agrawal K, Rai Mittal B, Bansal D, Varma N, et al. Role of F-18 FDG PET/CT in assessing bone marrow involvement in pediatric Hodgkin’s lymphoma. Ann Nucl Med. 2013;27:146–51.PubMedCrossRefGoogle Scholar
  61. 61.
    Montravers F, McNamara D, Landman-Parker J, et al. [18F]FDG in childhood lymphoma: clinical utility and impact on management. Eur J Nucl Med Mol Imaging. 2002;29:1155–65.PubMedCrossRefGoogle Scholar
  62. 62.
    Hermann S, Wormanns D, Pixberg M, et al. Staging in childhood lymphoma: differences between FDG-PET and CT. Nuklearmedizin. 2005;44:1–7.PubMedGoogle Scholar
  63. 63.
    Furth C, Denecke T, Steffen I, et al. Correlative imaging strategies implementing CT, MRI, and PET for staging of childhood Hodgkin disease. J Pediatr Hematol Oncol. 2006;28:501–12.PubMedCrossRefGoogle Scholar
  64. 64.
    Kabickova E, Sumerauer D, Cumlivska E, et al. Comparison of 18F-FDG-PET and standard procedures for the pretreatment staging of children and adolescents with Hodgkin’s disease. Eur J Nucl Med Mol Imaging. 2006;33:1025–31.PubMedCrossRefGoogle Scholar
  65. 65.
    Purz S, Mauz-Körholz C, Körholz D, Hasenclever D, Krausse A, Sorge I, Ruschke K, Stiefel M, Amthauer H, Schober O, Kranert WT, Weber WA, Haberkorn U, Hundsdörfer P, Ehlert K, Becker M, Rössler J, Kulozik AE, Sabri O, Kluge R. [18F]Fluorodeoxyglucose positron emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin’s lymphoma. J Clin Oncol. 2011;29:3523–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Wickmann L, Luders H, Dorffel W. 18-FDG-PET-findings in children and adolescents with Hodgkin’s disease: retrospective evaluation of the correlation to other imaging procedures in initial staging and to the predictive value of follow up examinations. Klin Padiatr. 2003;215:146–50.PubMedCrossRefGoogle Scholar
  67. 67.
    Furth C, Steffen IG, Amthauer H, et al. Early and late therapy response assessment with [18F]fluorodeoxyglucose positron emission tomography in pediatric Hodgkin’s lymphoma: analysis of a prospective multicenter trial. J Clin Oncol. 2009;27:4385–91.PubMedCrossRefGoogle Scholar
  68. 68.
    Lopci E, Burnelli R, Ambrosini V, et al. 18F-FDG PET in pediatric lymphomas: a comparison with conventional imaging. Cancer Biother Radiopharm. 2008;23:681–90.PubMedCrossRefGoogle Scholar
  69. 69.
    Miller E, Metser U, Avrahami G, et al. Role of 18F-FDG PET/CT in staging and follow-up of lymphoma in pediatric and young adult patients. J Comput Assist Tomogr. 2006;30:689–94.PubMedCrossRefGoogle Scholar
  70. 70.
    Riad R, Omar W, Kotb M, et al. Role of PET/CT in malignant pediatric lymphoma. Eur J Nucl Med Mol Imaging. 2010;37:319–29.PubMedCrossRefGoogle Scholar
  71. 71.
    Depas G, De Barsy C, Jerusalem G, et al. 18F-FDG PET in children with lymphomas. Eur J Nucl Med Mol Imaging. 2005;32:31–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Hernandez-Pampaloni M, Takalkar A, Yu JQ, Zhuang H, Alavi A. F-18 FDG-PET imaging and correlation with CT in staging and follow-up of pediatric lymphomas. Pediatr Radiol. 2006;36:524–31.PubMedCrossRefGoogle Scholar
  73. 73.
    Amthauer H, Furth C, Denecke T, et al. FDG-PET in 10 children with non-Hodgkin’s lymphoma: initial experience in staging and follow-up. Klin Padiatr. 2005;217:327–33.PubMedCrossRefGoogle Scholar
  74. 74.
    Rhodes MM, Delbeke D, Whitlock JA, et al. Utility of FDG-PET/CT in follow-up of children treated for Hodgkin and non-Hodgkin lymphoma. J Pediatr Hematol Oncol. 2006;28:300–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Bakhshi S, Radhakrishnan V, Sharma P, et al. Pediatric nonlymphoblastic non-Hodgkin lymphoma: baseline, interim, and posttreatment PET/CT versus contrast-enhanced CT for evaluation – a prospective study. Radiology. 2012;262:956–68.PubMedCrossRefGoogle Scholar
  76. 76.
    Ilivitzki A, Radan L, Ben-Arush M, Israel O, Ben-Barak A. Early interim FDGPET/CT prediction of treatment response and prognosis in pediatric Hodgkin disease: added value of low-dose CT. Pediatr Radiol. 2013;43:86–92.PubMedCrossRefGoogle Scholar
  77. 77.
    Korholz D, Kluge R, Wickmann L, et al. Importance of F18-fluorodeoxy-d-2-glucose positron emission tomography (FDG-PET) for staging and therapy control of Hodgkin’s lymphoma in childhood and adolescence – consequences for the GPOH-HD 2003 protocol. Onkologie. 2003;26:489–93.PubMedGoogle Scholar
  78. 78.
    Hudson MM, Krasin MJ, Kaste SC. PET imaging in pediatric Hodgkin’s lymphoma. Pediatr Radiol. 2004;34:190–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Kluge R, Kurch L, Montravers F, Mauz-Körholz C. FDG PET/CT in children and adolescents with lymphoma. Pediatr Radiol. 2013;43:406–17.PubMedCrossRefGoogle Scholar
  80. 80.
    London K, Cross S, Onikul E, Dalla-Pozza L, Howman-Giles R. 18F-FDG PET/CT in paediatric lymphoma: comparison with conventional imaging. Eur J Nucl Med Mol Imaging. 2011;38:274–84.PubMedCrossRefGoogle Scholar
  81. 81.
    Weiler-Sagie M, Bushelev O, Epelbaum R, et al. 18F-FDG avidity in lymphoma readdressed: a study of 766 patients. J Nucl Med. 2010;51:25–30.PubMedCrossRefGoogle Scholar
  82. 82.
    Tsukamoto N, Kojima M, Hasegawa M, et al. The usefulness of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and a comparison of 18F-FDG-PET with 67gallium scintigraphy in the evaluation of lymphoma: relation to histologic subtypes based on the World Health Organization classification. Cancer. 2007;110:652–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Elstrom R, Guan L, Baker G, et al. Utility of FDG-PET scanning in lymphoma by WHO classification. Blood. 2003;101:3875–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Rigacci L, Vitolo U, Nassi L, et al. Positron emission tomography in the staging of patients with Hodgkin’s lymphoma. A prospective multicentric study by the Intergruppo Italiano Linfomi. Ann Hematol. 2007;86:897–903.PubMedCrossRefGoogle Scholar
  85. 85.
    Dobert N, Menzel C, Berner U, et al. Positron emission tomography in patients with Hodgkin’s disease: correlation to histopathologic subtypes. Cancer Biother Radiopharm. 2003;18:565–71.PubMedCrossRefGoogle Scholar
  86. 86.
    Kasamon YL, Jones RJ, Wahl RL. Integrating PET and PET/CT into the risk-adapted therapy of lymphoma. J Nucl Med. 2007;48 Suppl 1:19S–27.PubMedGoogle Scholar
  87. 87.
    Montravers F, Landman-Parker J, Grahek D, et al. FDG PET in childhood Hodgkin’s lymphoma. Reports on the false-negative, false-positive and unexpected results during a five-year experience. J Nucl Med. 2006;47:144P.Google Scholar
  88. 88.
    Juweid ME. Utility of positron emission tomography (PET) scanning in managing patients with Hodgkin lymphoma. Hematol Am Soc Hematol Educ Prog. 2006;259–65:510–1.Google Scholar
  89. 89.
    van Quarles Ufford H, Hoekstra O, de Haas M, et al. On the added value of baseline FDG-PET in malignant lymphoma. Mol Imaging Biol. 2010;12:225–32.CrossRefGoogle Scholar
  90. 90.
    Hutchings M, Barrington SF. PET/CT for therapy response assessment in lymphoma. J Nucl Med. 2009;50 Suppl 1:21S–30.PubMedCrossRefGoogle Scholar
  91. 91.
    Hasenclever D, Kurch L, Mauz-Körholz C, Elsner A, Georgi T, Wallace H, et al. qPET – a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma. Eur J Nucl Med Mol Imaging. 2014;41:1301–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Strobel K, Schaefer NG, Renner C, et al. Cost-effective therapy remission assessment in lymphoma patients using 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography: is an end of treatment exam necessary in all patients? Ann Oncol. 2007;18:658–64.PubMedCrossRefGoogle Scholar
  93. 93.
    Meany HJ, Gidvani VK, Minniti CP. Utility of PET scans to predict disease relapse in pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer. 2007;48:399–402.PubMedCrossRefGoogle Scholar
  94. 94.
    Nievelstein RA, Quarles van Ufford HM, Kwee TC, et al. Radiation exposure and mortality risk from CT and PET imaging of patients with malignant lymphoma. Eur Radiol. 2012;22:1946–54.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Rathore N, Eissa HM, Margolin JF. Pediatric Hodgkin lymphoma: are we over-scanning our patients? Pediatr Hematol Oncol. 2012;29:415–23.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Voss SD. Surveillance imaging in pediatric Hodgkin lymphoma. Curr Hematol Malig Rep. 2013;8:218–25.PubMedCrossRefGoogle Scholar
  97. 97.
    Moog F, Bangerter M, Diederichs CG, et al. Lymphoma: role of whole-body 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) PET in nodal staging. Radiology. 1997;203:795–800.PubMedCrossRefGoogle Scholar
  98. 98.
    Montravers F, Landman-Parker J, Kerrou K, et al. Impact of FDG PET on the management of childhood non-Hodgkin lymphoma: a five-year experience. J Nucl Med. 2006;47:87P.Google Scholar
  99. 99.
    Sher AC, Seghers V, Paldino MJ, Dodge C, Krishnamurthy R, Krishnamurthy R, Rohren EM. The role of FDG-PET/CT in the evaluation of residual disease in paediatric non-Hodgkin lymphoma. Br J Haematol. 2015;168:845–53.CrossRefGoogle Scholar
  100. 100.
    Riad R, Omar W, Sidhom I, et al. False-positive F-18 FDG uptake in PET/CT studies in pediatric patients with abdominal Burkitt’s lymphoma. Nucl Med Commun. 2010;31:232–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Palestro CJ, Rini JN, Tomas MB. Lymphoma. In: Charron M, editor. Practical pediatric PET imaging. New York: Springer Science; 2006. p. 220–42.CrossRefGoogle Scholar
  102. 102.
    Kaste SC, Howard SC, McCarville EB, Krasin MJ, Kogos PG. Hudson MM.18F-FDG-avid sites mimicking active disease in pediatric Hodgkin’s. Pediatr Radiol. 2005;35:141–54.PubMedCrossRefGoogle Scholar
  103. 103.
    Shammas A, Lim R, Charron M. Pediatric FDG PET/CT: physiologic uptake, normal variants, and benign conditions. Radiographics. 2009;29:1467–86.PubMedCrossRefGoogle Scholar
  104. 104.
    Kamoto Y, Sadato N, Yonekura Y, et al. Visualization of the cervical spinal cord with FDG and high-resolution PET. J Comput Assist Tomogr. 1998;22:487–91.PubMedCrossRefGoogle Scholar
  105. 105.
    Saggese D, Ceroni Compadretti G, Cartaroni C. Cervical ectopic thymus: a case report and review of the literature. Int J Pediatr Otorhinolaryngol. 2002;66:77–80.PubMedCrossRefGoogle Scholar
  106. 106.
    Soderlund V, Larsson SA, Jacobsson H. Reduction of FDG uptake in brown adipose tissue in clinical patients by a single dose of propranolol. Eur J Nucl Med Mol Imaging. 2007;34:1018–22.PubMedCrossRefGoogle Scholar
  107. 107.
    Lustberg MB, Aras O, Meisenberg BR. FDG PET/CT findings in acute adult mononucleosis mimicking malignant lymphoma. Eur J Haematol. 2008;81:154–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Panagiotidis E, Exarhos D, Housianakou I, Bournazos A, Datseris I. FDG uptake in axillary lymph nodes after vaccination against pandemic (H1N1). Eur Radiol. 2010;20:1251–3.PubMedCrossRefGoogle Scholar
  109. 109.
    Bhojwani D, McCarville MB, Choi JK, Sawyer J, Metzger ML, Inaba H, Davidoff AM, Gold R, Shulkin BL, Sandlund JT. The role of FDG-PET/CT in the evaluation of residual disease in paediatric non-Hodgkin lymphoma. Br J Haematol. 2015;168:845–53.PubMedCrossRefGoogle Scholar
  110. 110.
    Moinul Hossain AK, Shulkin BL, et al. FDG positron emission tomography/computed tomography studies of Wilms’ tumor. Eur J Nucl Med Mol Imaging. 2010;37:1300–8.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Smith MA, Seibel NL, Altekruse SF, Ries LA, Melbert DL, O’Leary M, et al. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol. 2010;28:2625–34.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Pfluger T, Leinsinger G, Sander A, Schmid I, Fuhrer M, Dietz HG, et al. Magnetic resonance imaging of benign and premalignant tumors in childhood. Radiologe. 1999;39:685–94.PubMedCrossRefGoogle Scholar
  113. 113.
    Misch D, Steffen IG, Schonberger S, et al. Use of positron emission tomography for staging, preoperative response assessment and posttherapeutic evaluation in children with Wilms tumour. Eur J Nucl Med Mol Imaging. 2008;35:1642–50.PubMedCrossRefGoogle Scholar
  114. 114.
    Shulkin BL, Chang E, Strouse PJ, Bloom DA, Hutchinson RJ. PET FDG studies of Wilms tumors. J Pediatr Hematol Oncol. 1997;19:334–8.PubMedCrossRefGoogle Scholar
  115. 115.
    Belgaumi AF, Kauffman WM, Jenkins JJ, Cordoba J, Bowman LC, Santana VM, et al. Blindness in children with neuroblastoma. Cancer. 1997;80:1997–2004.PubMedCrossRefGoogle Scholar
  116. 116.
    Kropp J, Hofmann M, Bihl H. Comparison of MIBG and pentetreotide scintigraphy in children with neuroblastoma. Is the expression of somatostatin receptors a prognostic factor? Anticancer Res. 1997;17:1583–8.PubMedGoogle Scholar
  117. 117.
    Schmidt M, Simon T, Hero B, Schicha H, Berthold F. The prognostic impact of functional imaging with 123I-mIBG in patients with stage 4 neuroblastoma >1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97. Eur J Cancer. 2008;44:1552–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Taggart D, Dubois S, Matthay KK. Radiolabeled metaiodobenzylguanidine for imaging and therapy of neuroblastoma. Q J Nucl Med Mol Imaging. 2008;52:403–18.PubMedGoogle Scholar
  119. 119.
    Custodio CM, Semelka RC, Balci NC, Mitchell KM, Freeman JA. Adrenal neuroblastoma in an adult with tumor thrombus in the inferior vena cava. J Magn Reson Imaging. 1999;9:621–3.PubMedCrossRefGoogle Scholar
  120. 120.
    DuBois SG, Matthay KK. Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma. Nucl Med Biol. 2008;35 Suppl 1:S35–48.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Boubaker A, Bischof Delaloye A, Bischof Delaloye A. Nuclear medicine procedures and neuroblastoma in childhood. Their value in the diagnosis, staging and assessment of response to therapy. Q J Nucl Med. 2003;47:31–40.PubMedGoogle Scholar
  122. 122.
    Parisi MT, Greene MK, Dykes TM, Moraldo TV, Sandler ED, Hattner RS. Efficacy of metaiodobenzylguanidine as a scintigraphic agent for the detection of neuroblastoma. Invest Radiol. 1992;27:768–73.PubMedCrossRefGoogle Scholar
  123. 123.
    de Kraker J, Hoefnagel KA, Verschuur AC, van Eck B, van Santen HM, Caron HN. Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age. Eur J Cancer. 2008;44:551–6.PubMedCrossRefGoogle Scholar
  124. 124.
    Hugosson C, Nyman R, Jorulf H, et al. Imaging of abdominal neuroblastoma in children. Acta Radiol. 1999;40:534–42.PubMedCrossRefGoogle Scholar
  125. 125.
    Sofka CM, Semelka RC, Kelekis NL, et al. Magnetic resonance imaging of neuroblastoma using current techniques. Magn Reson Imaging. 1999;17:193–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Valk TW, Frager MS, Gross MD, et al. Spectrum of pheochromocytoma in multiple endocrine neoplasia. A scintigraphic portrayal using 131I-metaiodobenzylguanidine. Ann Intern Med. 1981;94:762–7.PubMedCrossRefGoogle Scholar
  127. 127.
    Wieland DM, Brown LE, Tobes MC, et al. Imaging the primate adrenal medulla with [123I] and [131I] meta-iodobenzylguanidine: concise communication. J Nucl Med. 1981;22:358–64.PubMedGoogle Scholar
  128. 128.
    Sisson JC, Wieland DM. Radiolabeled meta-iodobenzylguanidine: pharmacology and clinical studies. Am J Physiol Imaging. 1986;1:96–103.PubMedGoogle Scholar
  129. 129.
    Guilloteau D, Chalon S, Baulieu JL, et al. Comparison of MIBG and monoamines uptake mechanisms: pharmacological animal and blood platelets studies. Eur J Nucl Med. 1988;14:341–4.PubMedGoogle Scholar
  130. 130.
    Rufini V, Calcagni ML, Baum RP. Imaging of neuroendocrine tumors. Semin Nucl Med. 2006;36:228–47.PubMedCrossRefGoogle Scholar
  131. 131.
    Howman-Giles R, Shaw PJ, Uren RF, Chung DK. Neuroblastoma and other neuroendocrine tumors. Semin Nucl Med. 2007;37:286–302.PubMedCrossRefGoogle Scholar
  132. 132.
    Biasotti S, Garaventa A, Villavecchia GP, Cabria M, Nantron M, De Bernardi B. False-negative metaiodobenzylguanidine scintigraphy at diagnosis of neuroblastoma. Med Pediatr Oncol. 2000;35:153–5.PubMedCrossRefGoogle Scholar
  133. 133.
    Piccardo A, Lopci E, Conte M, et al. PET/CT imaging in neuroblastoma. Q J Nucl Med Mol Imaging. 2013;57:29–39.PubMedGoogle Scholar
  134. 134.
    Sharp SE, Parisi MT, Gelfand MJ, Yanik GA, Shulkin BL. Functional-metabolic imaging of neuroblastoma. Q J Nucl Med Mol Imaging. 2013;57:6–20.PubMedGoogle Scholar
  135. 135.
    Troncone L, Rufini V, Montemaggi P, Danza FM, Lasorella A, Mastrangelo R. The diagnostic and therapeutic utility of radioiodinated metaiodobenzylguanidine (MIBG). 5 years of experience. Eur J Nucl Med. 1990;16:325–35.PubMedCrossRefGoogle Scholar
  136. 136.
    Gelfand MJ. Meta-iodobenzylguanidine in children. Semin Nucl Med. 1993;23:231–42.PubMedCrossRefGoogle Scholar
  137. 137.
    Shulkin BL, Shapiro B, Francis IR, Dorr R, Shen SW, Sisson JC. Primary extra-adrenal pheochromocytoma: positive I-123 MIBG imaging with negative I-131 MIBG imaging. Clin Nucl Med. 1986;11:851–4.PubMedCrossRefGoogle Scholar
  138. 138.
    Boubaker A, Bischof Delaloye A. MIBG scintigraphy for the diagnosis and follow-up of children with neuroblastoma. Q J Nucl Med Mol Imaging. 2008;52:388–402.PubMedGoogle Scholar
  139. 139.
    Hadj-Djilani NL, Lebtahi NE, Delaloye AB, Laurini R, Beck D. Diagnosis and follow-up of neuroblastoma by means of iodine-123 metaiodobenzylguanidine scintigraphy and bone scan, and the influence of histology. Eur J Nucl Med. 1995;22:322–9.PubMedCrossRefGoogle Scholar
  140. 140.
    Khafagi FA, Shapiro B, Fig LM, Mallette S, Sisson JC. Labetalol reduces iodine-131 MIBG uptake by pheochromocytoma and normal tissues. J Nucl Med. 1989;30:481–9.PubMedGoogle Scholar
  141. 141.
    Solanki KK, Bomanji J, Moyes J, Mather SJ, Trainer PJ, Britton KE. A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodobenzylguanidine (MIBG). Nucl Med Commun. 1992;13:513–21.PubMedCrossRefGoogle Scholar
  142. 142.
    Fendler WP, Wenter V, Thornton HI, Ilhan H, von Schweinitz D, Coppenrath E, Schmid I, Bartenstein P, Pfluger T. Combined scintigraphy and tumor marker analysis predicts unfavorable histopathology of neuroblastic tumors with high accuracy. PLoS One. 2015;10(7):e0132809.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Fendler WP, Melzer HI, Walz C, von Schweinitz D, Coppenrath E, Schmid I, Bartenstein P, Pfluger T. High 123I-MIBG uptake in neuroblastic tumours indicates unfavourable histopathology. Eur J Nucl Med Mol Imaging. 2013;40:1701–10.PubMedCrossRefGoogle Scholar
  144. 144.
    Gordon I, Peters AM, Gutman A, Morony S, Dicks-Mireaux C, Pritchard J. Skeletal assessment in neuroblastoma – the pitfalls of iodine-123-MIBG scans. J Nucl Med. 1990;31:129–34.PubMedGoogle Scholar
  145. 145.
    Pfluger T, Schmied C, Porn U, et al. Integrated imaging using MRI and 123I metaiodobenzylguanidine scintigraphy to improve sensitivity and specificity in the diagnosis of pediatric neuroblastoma. AJR Am J Roentgenol. 2003;181:1115–24.PubMedCrossRefGoogle Scholar
  146. 146.
    Geatti O, Shapiro B, Shulkin B, Hutchinson R, Sisson JC. Gastrointestinal iodine-131-meta-iodobenzylguanidine activity. Am J Physiol Imaging. 1988;3:188–91.PubMedGoogle Scholar
  147. 147.
    Granata C, Carlini C, Conte M, Claudiani F, Campus R, Rizzo A. False positive MIBG scan due to accessory spleen. Med Pediatr Oncol. 2001;37:138–9.PubMedCrossRefGoogle Scholar
  148. 148.
    McGarvey CK, Applegate K, Lee ND, Sokol DK. False-positive metaiodobenzylguanidine scan for neuroblastoma in a child with opsoclonus-myoclonus syndrome treated with adrenocorticotropic hormone (ACTH). J Child Neurol. 2006;21:606–10.PubMedCrossRefGoogle Scholar
  149. 149.
    Moralidis E, Arsos G, Papakonstantinou E, Badouraki M, Koliouskas D, Karakatsanis C. 123I-Metaiodobenzylguanidine accumulation in a urinoma and cortex of an obstructed kidney after surgical resection of an abdominal neuroblastoma. Pediatr Radiol. 2008;38:118–21.PubMedCrossRefGoogle Scholar
  150. 150.
    Bahar RH, Mahmoud S, Ibrahim A, al-Gazzar AH. A false positive I-131 MIBG due to dilated renal pelvis: a case report. Clin Nucl Med. 1988;13:900–2.PubMedCrossRefGoogle Scholar
  151. 151.
    Bonnin F, Lumbroso J, Tenenbaum F, Hartmann O, Parmentier C. Refining interpretation of MIBG scans in children. J Nucl Med. 1994;35:803–10.PubMedGoogle Scholar
  152. 152.
    Pirson AS, Krug B, Tuerlinckx D, Lacrosse M, Luyx D, Borght TV. Additional value of I-123 MIBG SPECT in neuroblastoma. Clin Nucl Med. 2005;30:100–1.PubMedCrossRefGoogle Scholar
  153. 153.
    Rufini V, Fisher GA, Shulkin BL, Sisson JC, Shapiro B. Iodine-123-MIBG imaging of neuroblastoma: utility of SPECT and delayed imaging. J Nucl Med. 1996;37:1464–8.PubMedGoogle Scholar
  154. 154.
    Gelfand MJ, Elgazzar AH, Kriss VM, Masters PR, Golsch GJ. Iodine-123-MIBG SPECT versus planar imaging in children with neural crest tumors. J Nucl Med. 1994;35:1753–7.PubMedGoogle Scholar
  155. 155.
    Shulkin BL, Shapiro B, Hutchinson RJ. Iodine-131-metaiodobenzylguanidine and bone scintigraphy for the detection of neuroblastoma. J Nucl Med. 1992;33:1735–40.PubMedGoogle Scholar
  156. 156.
    Daldrup-Link HE, Franzius C, Link TM, et al. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. AJR Am J Roentgenol. 2001;177:229–36.PubMedCrossRefGoogle Scholar
  157. 157.
    Mentzel HJ, Kentouche K, Sauner D, et al. Comparison of whole-body STIR-MRI and 99mTc-methylene-diphosphonate scintigraphy in children with suspected multifocal bone lesions. Eur Radiol. 2004;14:2297–302.PubMedCrossRefGoogle Scholar
  158. 158.
    Lebtahi N, Gudinchet F, Nenadov-Beck M, Beck D, Bischof Delaloye A. Evaluating bone marrow metastasis of neuroblastoma with iodine-123-MIBG scintigraphy and MRI. J Nucl Med. 1997;38:1389–92.PubMedGoogle Scholar
  159. 159.
    Mueller WP, Coppenrath E, Pfluger T. Nuclear medicine and multimodality imaging of pediatric neuroblastoma. Pediatr Radiol. 2013;43:418–27.PubMedCrossRefGoogle Scholar
  160. 160.
    Sharp SE, Shulkin BL, Gelfand MJ, Salisbury S, Furman WL. .123I-MIBG scintigraphy and 18F-FDG PET in neuroblastoma. J Nucl Med. 2009;50:1237–43.PubMedCrossRefGoogle Scholar
  161. 161.
    Kushner BH, Yeung HW, Larson SM, Kramer K, Cheung NK. Extending positron emission tomography scan utility to high-risk neuroblastoma: fluorine-18 fluorodeoxyglucose positron emission tomography as sole imaging modality in follow-up of patients. J Clin Oncol. 2001;19:3397–405.PubMedCrossRefGoogle Scholar
  162. 162.
    Shulkin BL, Hutchinson RJ, Castle VP, Yanik GA, Shapiro B, Sisson JC. Neuroblastoma: positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-d-glucose compared with metaiodobenzylguanidine scintigraphy. Radiology. 1996;199:743–50.PubMedCrossRefGoogle Scholar
  163. 163.
    Melzer HI, Coppenrath E, Schmid I, Albert MH, von Schweinitz D, Tudball C, Bartenstein P, Pfluger T. 123I-MIBG scintigraphy/SPECT versus 18F-FDG PET in paediatric neuroblastoma. Eur J Nucl Med Mol Imaging. 2011;38:1648–58.PubMedCrossRefGoogle Scholar
  164. 164.
    Rosenspire KC, Haka MS, Van Dort ME, et al. Synthesis and preliminary evaluation of carbon-11-meta-hydroxyephedrine: a false transmitter agent for heart neuronal imaging. J Nucl Med. 1990;31:1328–34.PubMedGoogle Scholar
  165. 165.
    Shulkin BL, Wieland DM, Baro ME, et al. PET hydroxyephedrine imaging of neuroblastoma. J Nucl Med. 1996;37:16–21.PubMedGoogle Scholar
  166. 166.
    Franzius C, Hermann K, Weckesser M, et al. Whole-body PET/CT with 11C-meta-hydroxyephedrine in tumors of the sympathetic nervous system: feasibility study and comparison with 123I-MIBG SPECT/CT. J Nucl Med. 2006;47:1635–42.PubMedGoogle Scholar
  167. 167.
    Becherer A, Szabo M, Karanikas G, et al. Imaging of advanced neuroendocrine tumors with 18F-FDOPA PET. J Nucl Med. 2004;45:1161–7.PubMedGoogle Scholar
  168. 168.
    Hoegerle S, Nitzsche E, Altehoefer C, et al. Pheochromocytomas: detection with 18F DOPA whole body PET–initial results. Radiology. 2002;222:507–12.PubMedCrossRefGoogle Scholar
  169. 169.
    Mamede M, Carrasquillo JA, Chen CC, et al. Discordant localization of 2-[18F]-fluoro-2-deoxy-d-glucose in 6-[18F]-fluorodopamine- and [123I]-metaiodobenzylguanidine-negative metastatic pheochromocytoma sites. Nucl Med Commun. 2006;27:31–6.PubMedCrossRefGoogle Scholar
  170. 170.
    Piccardo A, Lopci E. Potential role of 18F-DOPA PET in neuroblastoma. Clin Transl Imaging. 2016. doi:10.1007/s40336-016-0162-2.Google Scholar
  171. 171.
    Lu MY, Liu YL, Chang HH, Jou ST, Yang YL, Lin KH, Lin DT, et al. Characterization of neuroblastic tumors using 18F-FDOPA PET. J Nucl Med. 2013;54:42–9.PubMedCrossRefGoogle Scholar
  172. 172.
    Lopci E, Piccardo A, Nanni C, Altrinetti V, Garaventa A, Pession A, Cistaro A, et al. 18F-DOPA PET/CT in neuroblastoma: comparison of conventional imaging with CT/MR. Clin Nucl Med. 2012;37:e71–8.CrossRefGoogle Scholar
  173. 173.
    Pfluger T, Melzer HI, Mueller WP, Coppenrath E, Bartenstein P, Albert MH, Schmid I. Diagnostic value of combined 18F-FDG PET/MRI for staging and restaging in paediatric oncology. Eur J Nucl Med Mol Imaging. 2012;39:1745–55.PubMedCrossRefGoogle Scholar
  174. 174.
    Muller MF, Krestin GP, Willi UV. Abdominal tumors in children. A comparison between magnetic resonance tomography (MRT) and ultrasonography (US). Rofo. 1993;158:9–14.PubMedCrossRefGoogle Scholar
  175. 175.
    Daldrup HE, Link TM, Wortler K, Reimer P, Rummeny EJ. MR imaging of thoracic tumors in pediatric patients. AJR Am J Roentgenol. 1998;170:1639–44.PubMedCrossRefGoogle Scholar
  176. 176.
    Kaste SC. Issues specific to implementing PET-CT for pediatric oncology: what we have learned along the way. Pediatr Radiol. 2004;34:205–13.PubMedCrossRefGoogle Scholar
  177. 177.
    Bar-Sever Z, Keidar Z, Ben-Barak A, et al. The incremental value of 18F-FDG PET/CT in paediatric malignancies. Eur J Nucl Med Mol Imaging. 2007;34:630–7.PubMedCrossRefGoogle Scholar
  178. 178.
    Olson PN, Everson LI, Griffiths HJ. Staging of musculoskeletal tumors. Radiol Clin North Am. 1994;32:151–62.PubMedGoogle Scholar
  179. 179.
    Silberstein EB, Saenger EL, Tofe AJ, Alexander Jr GW, Park HM. Imaging of bone metastases with 99mTc-Sn-EHDP (diphosphonate), 18F, and skeletal radiography. A comparison of sensitivity. Radiology. 1973;107:551–5.PubMedCrossRefGoogle Scholar
  180. 180.
    Hahn K, Charron M, Shulkin BL. Role of MR imaging and iodine 123 MIBG scintigraphy in staging of pediatric neuroblastoma. Radiology. 2003;227:908. author reply 08-9.PubMedCrossRefGoogle Scholar
  181. 181.
    Shah Syed GM, Naseer H, Usmani GN, Cheema MA. Role of iodine-131 MIBG scanning in the management of paediatric patients with neuroblastoma. Med Princ Pract. 2004;13:196–200.PubMedCrossRefGoogle Scholar
  182. 182.
    Moon L, McHugh K. Advances in paediatric tumour imaging. Arch Dis Child. 2005;90:608–11.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Nanni C, Rubello D, Castellucci P, Silberstein EB, Saenger EL, Tofe AL, et al. 18F-FDG PET/CT fusion imaging in paediatric solid extracranial tumours. Biomed Pharmacother. 2006;60:593–606.PubMedCrossRefGoogle Scholar
  184. 184.
    Yeung HW, Schoder H, Smith A, Gonen M, Larson SM. Clinical value of combined positron emission tomography/computed tomography imaging in the interpretation of 2-deoxy-2-[F-18]fluoro-d-glucose-positron emission tomography studies in cancer patients. Mol Imaging Biol. 2005;7:229–35.PubMedCrossRefGoogle Scholar
  185. 185.
    Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11:1466–77.PubMedCrossRefGoogle Scholar
  186. 186.
    Rozovsky K, Koplewitz BZ, Krausz Y, et al. Added value of SPECT/CT for correlation of MIBG scintigraphy and diagnostic CT in neuroblastoma and pheochromocytoma. AJR Am J Roentgenol. 2008;190:1085–90.PubMedCrossRefGoogle Scholar
  187. 187.
    Erlemann R, Sciuk J, Bosse A, et al. Response of osteosarcoma and Ewing sarcoma to preoperative chemotherapy: assessment with dynamic and static MR imaging and skeletal scintigraphy. Radiology. 1990;175:791–6.PubMedCrossRefGoogle Scholar
  188. 188.
    Knop J, Delling G, Heise U, Winkler K. Scintigraphic evaluation of tumor regression during preoperative chemotherapy of osteosarcoma. Skeletal Radiol. 1990;19:165–72.PubMedCrossRefGoogle Scholar
  189. 189.
    O’Mara RE. Bone scanning in osseous metastatic disease. JAMA. 1988;229:1915–7.CrossRefGoogle Scholar
  190. 190.
    Algra PR, Bloem JL, Tissing H, Falke TH, Arndt JW, Verboom LJ. Detection of vertebral metastases: comparison between MR imaging and bone scintigraphy. Radiographics. 1991;11:219–32.PubMedCrossRefGoogle Scholar
  191. 191.
    Grant F, Fahey F, Packard A, Davis R, Alavi A, Treves S. Skeletal PET with F-18-fluoride: applying new technology to an old tracer. J Nucl Med. 2008;49:68–78.PubMedCrossRefGoogle Scholar
  192. 192.
    Petersen M. Radionuclide detection of primary pulmonary osteogenic sarcoma: a case report and review of the literature. J Nucl Med. 1990;31:1110–4.PubMedGoogle Scholar
  193. 193.
    Othman S, El-Desouki M. Bone scan appearance in aggressive osteogenic sarcoma with pleural, lung, bone, and soft-tissue metastases. Clin Nucl Med. 2003;28:926.PubMedCrossRefGoogle Scholar
  194. 194.
    Anderson PM. Sm-153-EDTMP therapy with stem cell support in patients. In: Bruland OS, editor. Towards the eradication of osteosarcoma metastases. Norway: The Norwegian Radium Hospital; 1998. p. 87–8.Google Scholar
  195. 195.
    Binkovitz L, Olshefski R, Adler B. Coincidence FDG-PET in the evaluation of Langerhans’ cell histiocytosis: preliminary findings. Pediatr Radiol. 2003;33:598–602.PubMedCrossRefGoogle Scholar
  196. 196.
    Daldrup-Link HE, Franzius C, Rummeney EJ, et al. Whole body MRI for detection of bone marrow metastases in pediatric patients: comparison with skeletal scintigraphy and FDG-PET. Am J Roentgenol. 2001;177:229–36.CrossRefGoogle Scholar
  197. 197.
    Calming U, Bemstrand C, Mosskin M, Elander S, Ingvar M, Henter J. Brain F-18-FDG PET scan in central nervous system Langerhans cell histiocytosis. J Pediatr. 2002;141:435–40.PubMedCrossRefGoogle Scholar
  198. 198.
    Buchler T, Cervinek L, Belohlavek O, et al. Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine. Pediatr Blood Cancer. 2005;44:286–8.PubMedCrossRefGoogle Scholar
  199. 199.
    Mueller WP, Melzer HI, Schmid I, Coppenrath E, Bartenstein P, Pfluger T. The diagnostic value of 18F-FDG PET and MRI in paediatric histiocytosis. Eur J Nucl Med Mol Imaging. 2013;40:356–63.PubMedCrossRefGoogle Scholar
  200. 200.
    Taggart DR, Han MM, Quach A, et al. Comparison of iodine-123 metaiodobenzylguanidine (MIBG) scan and [18F]fluorodeoxyglucose positron emission tomography to evaluate response after iodine-131 MIBG therapy for relapsed neuroblastoma. J Clin Oncol. 2009;27:5343–9.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    McDowell H, Losty P, Barnes N, Kokai G. Utility of FDG-PET/CT in the follow-up of neuroblastoma which became MIBG-negative. Pediatr Blood Cancer. 2009;52:552.CrossRefGoogle Scholar
  202. 202.
    Shore RM. Positron emission tomography/computed tomography (PET/CT) in children. Pediatr Ann. 2008;37:404–12.PubMedCrossRefGoogle Scholar
  203. 203.
    Murphy JJ, Tawfeeq M, Chang B, Nadel H. Early experience with PET/CT scan in the evaluation of pediatric abdominal neoplasms. J Pediatr Surg. 2008;43:2186–92.PubMedCrossRefGoogle Scholar
  204. 204.
    Colavolpe C, Guedj E, Cammilleri S, Taieb D, Mundler O, Coze C. Utility of FDG-PET/CT in the follow-up of neuroblastoma which became MIBG-negative. Pediatr Blood Cancer. 2008;51:828–31.PubMedCrossRefGoogle Scholar
  205. 205.
    Roca I, Simo M, Sabado C, de Toledo JS. PET/CT in paediatrics: it is time to increase its use! Eur J Nucl Med Mol Imaging. 2007;34:628–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Franzius C, Riemann B, Vormoor J, et al. Metastatic neuroblastoma demonstrated by whole-body PET-CT using 11C-HED. Nuklearmedizin. 2005;44:N4–5.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Thomas Pfluger
    • 1
    Email author
  • Andrea Ciarmiello
    • 2
  • Giampiero Giovacchini
    • 3
  • Françoise Montravers
    • 4
  • Hubert Ducou Le Pointe
    • 5
  • Judith Landman-Parker
    • 6
  • Martina Meniconi
    • 7
  • Christiane Franzius
    • 8
    • 9
  1. 1.Department of Nuclear MedicineLudwig-Maximilians-University of MunichMunichGermany
  2. 2.Nuclear Medicine Department“S. Andrea” HospitalLa SpeziaItaly
  3. 3.Institute of Radiology and Nuclear MedicineZurichSwitzerland
  4. 4.Department of Nuclear MedicineTenon Hospital, Assistance Publique Hôpitaux de Paris, Pierre et Marie Curie UniversityParisFrance
  5. 5.Department of RadiologyArmand-Trousseau Hospital, Assistance Publique Hôpitaux de Paris, Pierre et Marie Curie UniversityParisFrance
  6. 6.Department of Pediatric OncologyArmand-Trousseau Hospital, Assistance Publique Hôpitaux de Paris, Pierre et Marie Curie UniversityParisFrance
  7. 7.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly
  8. 8.Nuclear Medicine and PET/CT Centre BremenBremenGermany
  9. 9.Centre of Modern Diagnostics (ZEMODI), MRI and MR/PETBremenGermany

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