Abstract
Neuroblastoma (NB) is a malignant neoplasm that originates from neuroectodermal cells of the neural crest. During embryonic life, these cells migrate, giving rise to the sympathetic ganglia and adrenal medulla. The mean age at NB diagnosis is around 2 years, with 90 % of the cases diagnosed in children under the age of 6 years but only exceptionally in adolescents and in adults. In 40 % of the cases, the NB is localized to the adrenal glands, although it can develop anywhere in the sympathetic nervous system: neck (1 %), chest (19 %), other sites in the abdomen (30 %), or in the pelvis (1 %). The degree of malignancy of the tumor is determined by the proportion of cellular and extracellular maturation. The most aggressive and undifferentiated forms occur in young children (average 2 years of age), while the more mature forms, represented by ganglioneuroma, are usually seen in older children. 18F-fluorodeoxyglucose is the principal PET tracer in oncology, and its role in NB has also been investigated. However, thus far its use is limited to those cases in which the 123I-MIBG scan is negative or inconclusive. In this setting, the superior performance of 18F-FDG–PET has been demonstrated, based on a sensitivity and specificity of 78 and 92 %, respectively, and, compared to 123I-MIBG scintigraphy, 50 and 75 %, respectively.
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Keywords
- Peptide Receptor Radionuclide Therapy
- MIBG Scintigraphy
- Neuroectodermal Cell
- Undifferentiated Form
- Frequent Solid Tumor
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
1 Introduction
Neuroblastoma (NB) is a malignant neoplasm that originates from neuroectodermal cells of the neural crest. During embryonic life, these cells migrate, eventually giving rise to the sympathetic ganglia and adrenal medulla [1]. In 1864, the German physician Rudolf Virchow was the first to define an abdominal tumor in a child as a “glioma,” but only in 1910 did James Homer-Wright realize that the tumor originated from primitive neural cells and therefore referred to it as a “neuroblastoma” [2, 3]. Homer-Wright also noticed the characteristic cellular roundish accumulations visible in samples of bone marrow, which were then called Homer-Wright “pseudorosettes” [3].
NB is the third most frequent pediatric cancer (7–10 % of all neoplasias) after leukemia and tumors of the central nervous system but the most frequent solid tumor in children younger than 5 years [4]. The mean age at diagnosis is around 2 years, with 90 % of the cases diagnosed in children under the age of 6 years; it is rare in adolescents and in adults [5]. In 40 % of the cases, the NB is localized at the level of the adrenal glands, although it can develop anywhere in the sympathetic nervous system: neck (1 %), chest (19 %), elsewhere in the abdomen (30 %), or in the pelvis (1 %) [6, 7].
The degree of malignancy of the tumor is determined by the proportion of cellular and extracellular maturation. The most aggressive and undifferentiated forms of NB occur in young children (average age: 2 years), while the more mature forms, represented by ganglioneuroma, are usually seen in older children [8].
Over the past two decades, there has been considerable progress in understanding the biology of NB and in identifying the chromosomal alterations of NB cells that correlate with prognosis. Amplification of the MYCN oncogene was the first molecular NB-specific marker to be identified as a predictor of poor prognosis regardless of the child’s age or disease stage. However, MYCN amplification occurs only in 20 % of the cases; hence, additional molecular markers allowing a more exhaustive prognostic stratification are needed [9, 10]. Chromosomal alterations such as 1p and 11q deletions, trisomy, or polysomy also correlate with a poor prognosis [11–13].
Usually, the presenting symptoms reflect disease location and extent. In some cases, NB presents as disseminated disease, without any clinical symptoms. Indeed, in 50–60 % of the newly diagnosed patients, the disease is already metastatic [6]. The most common sites of metastases are the bone and bone marrow, often in combination with symptoms related to tumor dissemination such as fever, anorexia, pallor, bone pain, and proptosis [7]. Approximately 30 % of patients have a positive history of pain, whether due to abdominal distension or bone metastases, while 11 % present with problems of weight gain or even weight loss [14]. Other common presenting symptoms are neurological deficits, such as intraspinal tumor growth [14], Horner’s syndrome, hypertension, or Kinsbourne syndrome (opsoclonus-myoclonus-ataxia) [6, 15]. In children with advanced disease (stage 4S), there may be skin nodules, called “blueberry spots,” or periorbital bruising due to NB metastases. Over 90 % of NB patients have high levels of catecholamines in the serum and urine [15]. Therefore a 24-h urine collection is an important test, both for diagnostic and follow-up purposes [6].
The clinical course is more favorable in children less than 1 year of age and/or with localized disease, while in adolescents and adults relapse tends to be later and is associated with a poor prognosis.
Patients with stage 1 or stage 2 have an excellent prognosis, with 5-year disease-free survival (DFS) rates of 85–90 %, while those with stage 3, stage 4s, and stage 4 have a poor prognosis, with DFS rates of 40–60, 60–70, and 15–25 %, respectively [16–18]. Relapse occurs mostly in the first 2 years after surgery, in the localized forms of the disease, or, in case of metastatic forms, after the end of treatment. In the first postoperative year, attention to symptoms and physical examination are the cornerstones of follow-up, which should also include a complete blood count, urinary catecholamines, and an instrumental examination.
The current standard for staging and restaging NB is metaiodobenzylguanidine (MIBG) scintigraphy [19]. MIBG is an analogue of norepinephrine that is captured by catecholamine-secreting tumors (both primary and metastatic) [6]. For scintigraphy purposes, it is labeled with 123I/131I (123I/131I-MIBG). In 70–80 % of NB patients, MIBG positivity has a high sensitivity (88 %) and specificity (99 %) in identifying the presence of the disease [20]. Moreover, the method has also been successfully applied in monitoring the response to treatment and in determining the utility of radiometabolic treatment with 131I-MIBG (Figs. 12.1 and 12.2) [52]. However, NB also shows a wide-ranging variability in tracer uptake, which lead to false-negative results in 10 % of the patients. The main reasons for this variability likely include (a) modifications of active transport and tracer entrapment in tumor cells [53, 54], (b) increased levels of catecholamine metabolites [55], (c) the frequent prevalence of necrotic tissue in the primary tumor, (d) pharmacological interferences [20, 55], and (e) the dose-dependent sensitivity of 123I-MIBG [56]. Furthermore, 123I-MIBG scintigraphy is carried out using a gamma camera, with its obvious limits of resolution. It is also a lengthy examination and thus not patient friendly. All of these limits have stimulated a search for other radiopharmaceuticals, specifically, PET tracers.
2 PET Imaging in Neuroblastoma
2.1 Fluorodeoxyglucose
The principal PET tracer in oncology is undoubtedly 18F-FDG, and its role in NB has been accordingly investigated [21–27]. Its most frequent use has thus far been in patients with a negative or inconclusive 123I-MIBG scan (Fig. 12.3). In this setting, the superior performance of 18F-FDG–PET has proven, based on a sensitivity and specificity of 78 and 92 %, respectively, whereas for 123I-MIBG scintigraphy, the corresponding values are 50 and 75 % [24].
18F-FDG–PET has also been suggested as a complementary rather than a substitute exam for MIBG scintigraphy in NB staging and treatment monitoring [21–23]. Its diagnostic use to evaluate the response to therapy, especially in patients with high-risk, advanced stage disease, has been assessed [27]. The FDG-avidity of NB tumors increases with their aggressiveness and in those with an unfavorable histology, such that NB detection with 18F-FDG–PET is feasible and may even be superior to MIBG scintigraphy [24]. Further advantages of 18F-FDG–PET are its high resolution, short scanning period, and patient-friendliness. The principal limitations of 18F-FDG as a tracer for NB imaging are its overall low accuracy in the detection of disease in the bone and bone marrow, which are common sites of distant metastasis, the difficult visualization of disease occurring in the skull because of the intense physiological uptake of 18F-FDG in normal brain, and the reduced capability of 18F-FDG–PET to properly assess the response to therapy (Fig. 12.4) [25, 26].
Recently, new indications for this imaging method have been investigated, mainly based on the prognostic role of the FDG-avidity of tumors in patients with high-risk NB under consideration for 131I-MIBG therapy [27]. However, in that study, 123I-MIBG was shown to be superior in the detection of disease extent (Fig. 12.5). Both the SUVmax and the FDG-avidity of bone and bone marrow metastases were identified as adverse prognostic factors (Figs. 12.6, 12.7, 12.8, 12.9, 12.10, and 12.11).
2.2 18F-DOPA
In NB, the tumors typically produce biologically active hormones such as norepinephrine and several of its precursors, including dihydroxyphenylalanine (DOPA) and dopamine [28, 29]. 18F-dihydroxyphenylalanine (18F-DOPA), the radiolabeled formulation of dihydroxyphenylalanine, is a multivalent molecule widely used in the functional imaging of neuroendocrine tumors and the best PET alternative to 123I-MIBG because of its similar ability to follow catecholamine metabolism, which is increased in NB [30–34]. PET carried out with 18F-DOPA has a better diagnostic accuracy than either 123I-MIBG scintigraphy or conventional imaging modalities, such as CT and MRI, in the study of tumors excreting high levels of catecholamines (Fig. 12.12) [48–51], with a sensitivity vs. these latter methods of 90, 65, and 67 %, respectively [51].
Consequently, several pilot studies have recently investigated the role of 18F-DOPA in NB patients. In a cohort of high-risk patients with primary/relapsed disease (n = 19), the 18F-DOPA distribution at NB sites was similar to that of 123I-MIBG [35], but the accuracy of 18F-DOPA–PET was higher than that of 123I-MIBG scintigraphy, especially for smaller lesions (<1.5 cm). This difference influenced patient management and treatment decisions in 32 % of the cases. In a direct comparison with morphological imaging (CT/MRI), 18F-DOPA–PET performed better (Fig. 12.13) [47].
While these findings are encouraging, they require further validation in larger, multicenter, prospective trials.
2.3 68Ga-DOTATOC
As with other neuroendocrine tumors, NB tumors overexpress somatostatin receptors (SSTRs), especially SSTR types 1 and 2 [36, 37]. This observation led to studies of 111In-pentetreotide scintigraphy or somatostatin receptor scintigraphy (SRS) in the assessment of NB [38, 39]; however, neither method was superior to 123I-MIBG. Instead, complementary roles, based on the ability of these methods to provide prognostic information, were recommended, as a positive SRS scan was shown to be a predictor of better outcome in NB patients [38, 39].
Recently, the use of PET tracers such as 68GA-DOTATOC to follow SSTRs in NB has been examined [40]. In a limited cohort comprising pheochromocytoma (n = 6) and NB (n = 5) patients, the accuracy of 123I-MIBG scintigraphy and 68GA-DOTATOC PET was investigated. According to a lesion-based analysis, the sensitivity of 68GA-DOTATOC and 123I-MIBG for NB was 97.2 and 90.7 %, respectively. Primary NB lesions were better definable in 68GA-DOTATOC PET imaging than in 123I-MIBG scintigraphy, suggesting the advantage of the former especially regarding the peptide receptor radionuclide therapy (PRRT) planning [41]. Undoubtedly, this indication for 68GA-DOTATOC must still be thoroughly assessed in children and the inclusion criteria precisely delineated before this imaging method replaces the already available and safe 131I-MIBG scintigraphy.
2.4 124I-MIBG
We conclude by mentioning the potential introduction of MIBG-labeled with a positron-emitting compound, such as iodine-124. Already used in dosimetry, 124I-MIBG PET may demonstrate the effective “revenge” of a molecule (metaiodobenzylguanidine) that, despite investigations of alternative compounds, has long made an enormous difference in the diagnostic and therapeutic approach to NB patients [42, 43]. A potential disadvantage of 124I-MIBG is the decay scheme of iodine-124, which is rather impure, with the emission of both gamma rays and positrons and thus their coincidence with annihilation photons [44–46]. However, the reported low-quality images obtained in preclinical investigations can be significantly improved in modern PET/CT scanners (Figs. 12.14 and 12.15). The main limitation remains the absence of clinical studies investigating the role 124I-MIBG PET in NB, which makes any statements on its utility mere speculation. Dedicated studies in this direction are therefore welcome.
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Lopci, E., Ficola, U., Cistaro, A. (2014). Neuroblastoma. In: Cistaro, A. (eds) Atlas of PET/CT in Pediatric Patients. Springer, Milano. https://doi.org/10.1007/978-88-470-5358-8_12
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