Abstract
Neuroblastoma is a malignant tumor derived from primitive neural crest cells of the sympathetic nervous system. Primary tumors can arise anywhere along the sympathetic chain, most commonly occurring in the adrenal gland and retroperitoneum. More than half of patients will have metastatic disease at diagnosis, most commonly involving bone marrow and cortical bone. Neuroblastoma prognosis is widely variable, ranging from spontaneous regression to fatal disease in spite of intensive multimodality therapy. Multiple clinical and imaging tests are used to guide therapy and predict outcomes. Anatomic imaging modalities, such as CT and MRI, are used to evaluate the primary tumor and involved lymph nodes. Functional imaging agents, such as 123I-MIBG, 99mTc-MDP, and 18F-FDG, are used for whole-body evaluation of disease sites. Iodine-123-MIBG is the first-line functional imaging modality used in neuroblastoma. Technetium-99m-MDP bone scans have traditionally been used to assess cortical bone metastases. Use of 18F-FDG PET and PET/CT in neuroblastoma is increasing, especially in tumors with little or no MIBG avidity. This chapter will discuss the performance and interpretation of 123I-MIBG, 99mTc-MDP, and 18F-FDG scans in neuroblastoma patients.
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Keywords
- MIBG Uptake
- MIBG Imaging
- Neuroblastoma Patient
- Bone Marrow Metastasis
- International Neuroblastoma Staging System
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.
Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma are tumors derived from primitive neural crest cells of the sympathetic nervous system. Neuroblastoma and ganglioneuroblastoma are usually grouped together for clinical purposes as both contain undifferentiated neuroblasts with malignant or potentially malignant behavior. In contrast, ganglioneuroma is a benign tumor containing only mature ganglion cells and other mature tissues [1].
Neuroblastoma is the most common extracranial solid tumor of childhood, comprising approximately 8 % of pediatric cancers. Median age at diagnosis is 15 months, with the vast majority of patients presenting during infancy or early childhood [2].
Neuroblastoma can arise anywhere along the sympathetic chain. Primary tumors most commonly occur in the adrenal gland (35 %), retroperitoneum (30–35 %), or posterior mediastinum (20 %) with pelvic and cervical primary sites less frequently seen (<5 %), respectively. Neuroblastoma rarely can present with metastatic disease without an identifiable primary tumor [1].
Metastatic disease is seen in more than half of neuroblastoma patients at diagnosis. Bone marrow and cortical bone are the most frequent metastatic sites, with lymph node and hepatic metastases also commonly seen. Lung and central nervous system metastases are rare and associated with very poor outcomes [3].
Neuroblastoma is staged using the International Neuroblastoma Staging System (INSS) which was developed in 1988 and revised in 1993 as summarized in Table 19.1 [4]. Presurgical staging of localized disease cannot be performed using the INSS, as staging is based on the extent of tumor resection and surgical assessment of lymph node involvement.
In 2009, the International Neuroblastoma Risk Group Staging System (INRGSS) was described, allowing presurgical staging of localized tumors as summarized in Table 19.2 [5]. The INRGSS uses imaging-defined risk factors to help predict surgical risk and surgical outcome [5–7]. The INRGSS also raises the age cutoff for the special stage used in infants with distant metastatic involvement limited to liver, skin, and/or bone marrow. This change reflects recent literature which suggests that a cutoff of 18 months more accurately predicts outcome [8–12]. The INRGSS is meant to be used in conjunction with, but not replace, the INSS [5, 6].
The prognosis of neuroblastoma is widely variable. Some neuroblastomas spontaneously regress or mature without therapy, while others progress to widespread and fatal disease in spite of intensive multimodality therapy [8, 13, 14]. Neuroblastoma patients are divided into risk groups to guide therapy and predict outcomes. Risk groups are based on stage, age, and biologic tumor factors (such as histology, DNA ploidy, and MYCN amplification) [8, 13, 15].
Low-risk disease is treated with surgery or supportive care alone with survival rates of greater than 95 % [15–21]. Intermediate-risk disease is treated with surgery and chemotherapy with survival rates of greater than 90 % [15, 16, 22–24]. In contrast, high-risk disease is treated with intensive multimodality therapy (including high-dose chemotherapy, radiation therapy, and stem cell transplantation) with long-term survival rates of approximately 30–40 % [15, 16, 25, 26].
Multiple clinical and imaging tests are used in neuroblastoma, both at diagnosis and during follow-up, to ensure accurate disease assessment. Clinical testing includes bone marrow biopsy and urine catecholamine levels. Imaging evaluation includes both anatomic and functional imaging modalities [27, 28].
CT and MRI are the anatomic imaging modalities recommended for neuroblastoma. They are used to evaluate the primary tumor and involved lymph nodes, including 3D measurements and assessment of imaging-defined risk factors [4–6, 29–34]. MRI is the preferred anatomic imaging modality for tumors which extend into the spinal canal [33–35].
Iodine-123-MIBG is the recommended first-line functional imaging agent for neuroblastoma, allowing visualization of the primary tumor and metastatic sites. Technetium-99m-MDP bone scans and/or 18F-FDG PET scans are recommended for evaluation of MIBG-negative patients [4–6].
Multiple novel PET radiopharmaceuticals have been investigated for use in neuroblastoma, including 11C-hydroxyephedrine (11C- HED), 11C-epinephrine, 18F-fluorodopamine (F-18 DA), 18F-dihydroxyphenylalanine (18F-DOPA), 18F-fluorothymidine (18F-FLT), 68Ga-DOTA-Tyr3-octreotide (68Ga-DOTATOC), 18F-fluoro-3-iodobenzylguanidine (FIBG), and P-18F-fluorobenzylguanidine (PFBG) [36–50]. However, regulatory issues and the PET chemistry expertise needed for synthesis limit availability of these novel radiopharmaceuticals, making it unlikely that they will have a major role in neuroblastoma imaging in the near future. The remainder of this chapter will discuss 123I-MIBG, 99mTc-MDP, and 18F-FDG imaging of neuroblastoma.
Metaiodobenzylguanidine (MIBG) Scintigraphy
MIBG is related to norepinephrine, entering neural crest cells via the type I catecholamine reuptake system with concentration in the cell cytoplasm. MIBG is highly specific for neuroendocrine tumors, such as neuroblastoma and pheochromocytoma [51–55].
Iodine-131-MIBG was initially used for neuroblastoma imaging [56, 57], as 123I-MIBG was not FDA approved in the USA until 2008. However, 123I-MIBG is now commercially available and preferred for diagnostic imaging as it gives superior image quality at a lower patient radiation dose [58]. Administered doses of 131I-MIBG are limited by its relatively long physical half-life (8 days), high-energy photon (364 keV), and beta particle emission. In contrast, 123I-MIBG has a shorter physical half-life (13 h) and an ideal photon energy for gamma camera and SPECT imaging (159 keV), without beta particle emission.
Patient Preparation
Thyroid uptake of free iodide should be blocked by administration of saturated solution of potassium iodide (SSKI). The dosage and timing of SSKI administration vary with local practice. Although a single SSKI dose at the time of MIBG injection has been shown to adequately block thyroid uptake [59], many sites will administer SSKI doses for 2–3 days starting on the day before 123I-MIBG administration [60–62].
Numerous medications interfere with MIBG uptake, with potential to affect the results of MIBG imaging. Some of these medications (such as phenylephrine, tricyclic antidepressants, and labetalol) are used in children. Medications should therefore be reviewed when scheduling MIBG imaging. Any interfering medications should be discussed with the referring physician with discontinuation for an appropriate time frame when possible [60].
Imaging Technique
The North American Consensus Guidelines recommend an 123I-MIBG administered activity of 0.14 mCi/kg (5.2 MBq/kg) with a minimum dose of 1 mCi (37 MBq) and a maximum dose of 10 mCi (370 MBq); alternatively the European Association of Nuclear Medicine dosage card may be used for patients weighing more than 10 kg [63].
Planar and SPECT (and/or SPECT/CT) imaging typically is performed 24 h after 123I-MIBG injection. Planar imaging includes anterior and posterior whole-body images, which can be performed as overlapping spot images or as a whole-body acquisition. Whole-body planar images are frequently supplemented with lateral views of the skull. Additional planar images can be performed at 48 h if needed to clarify uptake abnormalities or allow clearance of bowel activity [60–62].
SPECT generally includes the abdomen or the primary tumor site if it lies outside of the abdomen. SPECT often improves diagnostic accuracy and certainty of lesion detection, especially for small lesions or lesions near sites of physiologic uptake. SPECT also improves anatomic localization and facilitates correlation with CT and MRI [64–66]. SPECT images can be co-registered and fused to separately acquired CT and MRI studies if patient positioning is similar.
Integrated SPECT/CT (with imaging performed on the same gantry) has more recently become an important diagnostic tool in oncology patients. In comparison to SPECT alone, SPECT/CT further improves MIBG uptake localization and certainty of lesion detection [67–70].
Medium-energy collimators are preferred over low-energy high-resolution collimators for both planar and SPECT acquisition. Approximately 3 % of photons emitted by 123I-MIBG have energies above 400 keV. Medium-energy collimators significantly reduce septal penetration from these high-energy photons, improving image quality (Fig. 19.1) [71]. Sedation is required for children who are unable to remain still during planar and SPECT imaging. Toilet-trained patients should be encouraged to void prior to imaging.
Clinical Applications
Iodine-123-MIBG imaging is recommended to evaluate neuroblastoma at diagnosis and to monitor MIBG-avid disease during and after therapy (Figs. 19.2 and 19.3) [4–6, 62]. Iodine-123-MIBG imaging also is necessary to determine eligibility for 131I-MIBG therapy, as documentation of MIBG-avid disease is needed prior to treatment. The International Neuroblastoma Risk Group Task Force recently developed guidelines for the evaluation of disease extent by 123I-MIBG scans [62].
Iodine-123-MIBG has a sensitivity of 88–93 % and a specificity of 83–92 % in neuroblastoma [64]. More than 90 % of neuroblastomas will demonstrate MIBG uptake, allowing visualization of both the primary tumor and metastatic sites. At diagnosis, 123I-MIBG imaging is a sensitive whole-body method to evaluate both soft tissue and cortical bone/bone marrow disease. It is therefore an essential tool for initial staging [62].
During therapy, 123I-MIBG imaging is useful for assessing disease response. At the primary tumor site, MIBG imaging differentiates residual active tumor from post-therapy changes which may be seen on CT or MR [62]. MIBG imaging depicts response of cortical bone metastases to therapy, while bone scan and CT may give false-positive results due to continued bone healing in the absence of tumor [27, 72]. MIBG imaging also depicts response of bone marrow metastases to therapy, while interpretation of MRI and 18F-FDG PET scans may be complicated by post-therapy bone marrow changes [73–76].
During surveillance, 123I-MIBG has been shown to be highly sensitive for relapsed bone metastases, with a detection rate of 94 % (compared to 43 % for 18F-FDG PET) [62, 77]. Iodine-123-MIBG imaging also has been shown to be a sensitive method to evaluate for unsuspected disease relapse, with a detection rate of 82 % (compared to 36 % for bone scan and 34 % for bone marrow biopsy) [78].
The results of 123I-MIBG imaging can have prognostic implications. At diagnosis, the extent of MIBG-avid disease may predict response to chemotherapy in children over 1 year of age who have metastatic disease [79]. After initial chemotherapy, persistence of 123I-MIBG uptake in cortical bone and bone marrow may be associated with poor prognosis [80–82]. During surveillance, high-risk patients with unsuspected relapses detected by 123I-MIBG may have longer survival times than high-risk patients with symptomatic relapses [78].
Semiquantitative scoring systems have been described for MIBG imaging of neuroblastoma, with scores correlating with response and survival in some but not all studies [79, 83–89]. Although not yet widely used in clinical practice, scoring systems have been used in research trials to improve interobserver agreement and precision of reporting. Scoring systems divide the skeleton into 6–12 compartments, with each compartment scored for disease extent. The individual compartment scores are added together to give a cumulative score. The Children’s Oncology Group (COG) and the New Approaches to Neuroblastoma Therapy (NANT) consortium use the Curie scoring system (Fig. 19.4) [62, 83].
Potential Pitfalls
False-Positive Studies
Physiologic MIBG uptake is normally seen in the salivary glands, olfactory mucosa, myocardium, liver, and bowel. Physiologic adrenal gland activity also may be demonstrated, especially after contralateral adrenalectomy. Urinary excretion of 123I-MIBG results in physiologic accumulation in the kidneys and bladder. Low-level uptake also may be seen in the lungs on 24-h images [90, 91]. More focal lung uptake has been described in areas of atelectasis and pneumonia, but this is rarely seen [92, 93]. Physiologic uptake of 123I-MIBG in brown adipose tissue is, most often seen in the neck and supraclavicular regions [94, 95].
Misinterpretation of physiologic foci of uptake can result in false-positive MIBG studies [64, 96, 97]. Alternatively, areas of physiologic uptake can obscure small areas of tumor uptake [28]. SPECT and SPECT/CT can improve diagnostic accuracy in areas where physiologic uptake and tumor are both common, especially the retroperitoneum and upper abdomen (Fig. 19.5) [64–70].
The right and left hepatic lobes normally demonstrate significant differences in uptake, with relatively higher uptake in the left hepatic lobe [98]. Physiologic 123I-MIBG uptake in the liver is often heterogeneous, especially on SPECT images. Liver uptake must therefore be interpreted with caution to avoid false-positive studies [66]. Hepatic metastases can be demonstrated with 123I-MIBG, although small metastases may be difficult to visualize. Correlation with CT or MRI is often helpful when hepatic metastases are suspected (Fig. 19.6).
Iodine-123 MIBG uptake in mature ganglioneuromas or other neuroendocrine tumors can be falsely interpreted as uptake in neuroblastoma [64, 96].
False-Negative Studies
Less than 10 % of neuroblastomas demonstrate no MIBG uptake, resulting in false-negative studies. Some neuroblastomas will be MIBG-negative at diagnosis, while others become MIBG-negative during therapy. Patients can have both MIBG-avid and non-avid disease sites at the same time [99–101].
False-negative MIBG studies are also seen in patients with minimal residual disease after therapy [64]. Iodine-123-MIBG can fail to detect subtle bone marrow involvement, usually when involvement is less than 10 %. Bone marrow biopsy is therefore a standard part of neuroblastoma evaluation [28, 77, 82, 97, 102]. Interestingly, to be classified as a stage 4S or MS, infants must have less than 10 % bone marrow involvement with bone marrow which is 123I-MIBG negative [4, 5].
The sensitivity of disease detection with MIBG increases with increasing administered activities. This is seen when 123I-MIBG pre-therapy diagnostic scans are compared with immediate post-therapy 131I-MIBG scans, which often demonstrate more disease sites [62, 70, 103, 104].
99mTc-Methylene Diphosphonate (99mTc-MDP) Bone Scan
Technetium-99m-MDP is taken up primarily in the mineral phase of bone, with relatively increased uptake at sites of bone formation and increased blood flow. Uptake abnormalities are demonstrated at sites of trauma, infection/inflammation, and benign or malignant bony lesions. Technetium-99m-MDP is therefore less specific for neuroblastoma than 123I-MIBG, which utilizes the type I catecholamine reuptake system for uptake into neural crest cells.
Imaging Technique
The North American Consensus Guidelines recommend a 99mTc-MDP administered activity of 0.25 mCi/kg (9.3 MBq/kg) with a minimum dose of 1 mCi (37 MBq); alternatively, the European Association of Nuclear Medicine dosage card may be used [63].
Planar imaging is typically performed 2–4 h after 99mTc-MDP injection. Planar imaging includes anterior and posterior whole-body images, which can be performed as overlapping spot images or as a whole-body acquisition. Whole-body planar images are frequently supplemented with lateral views of the skull, oblique views of the torso, or lateral views of the extremities if needed to clarify uptake abnormalities. Sedation is required for children who are unable to remain still during planar imaging. Toilet-trained patients should be encouraged to void prior to imaging.
Clinical Applications
In patients with neuroblastoma, 99mTc-MDP bone scans traditionally have been used to assess for cortical bone metastases. Bone scans also can demonstrate uptake in the primary tumor, particularly in areas of calcification. In contrast to MIBG scans, bone scans do not demonstrate bone marrow metastases unless they are large enough to affect adjacent cortical bone.
A bone scan often is performed at diagnosis, as studies have shown discrepancies between MIBG and bone scans that can affect staging [81, 105, 106]. However, neuroblastoma patients usually are followed with MIBG scans alone, as bone scans provide little or no additional information during follow-up of patients with MIBG-avid disease [102, 107, 108]. Bone scans are recommended for assessment of patients with MIBG-negative tumors [4–6].
Potential Pitfalls
Physiologic 99mTc-MDP bone uptake can complicate detection of metastatic disease. Intense physiologic uptake at the growth plates can be problematic, making metaphyseal metastases difficult to visualize. Neuroblastoma often symmetrically involves the long bones, so abnormalities appear similar on side-to-side comparison (Fig. 19.7). False-positive bone scans can be seen after trauma. During and after therapy, persistent uptake at sites of prior metastases can also be seen in the absence of tumor [27, 72].
18F-Fluorodeoxyglucose (FDG) PET and PET/CT
FDG is a glucose analog that is concentrated in metabolically active sites, including most tumors and areas of infection/inflammation. Fluorine-18-FDG is therefore less specific for neuroblastoma than 123I-MIBG, which utilizes the type I catecholamine reuptake system for uptake into neural crest cells.
Patient Preparation
Appropriate patient preparation is important before 18F-FDG PET or PET/CT (see Chap. 3). Patients should be warmed for 30–60 min prior to 18F-FDG administration to limit uptake in brown adipose tissue, with premedication also used at some centers [109–113]. Patients should fast for 4 h prior to 18F-FDG injection. Any glucose-containing intravenous fluids should be discontinued 4 h prior to 18F-FDG administration [114]. After administration, patients should limit physical activity to avoid muscular uptake of 18F-FDG [114].
Imaging Technique
The North American Consensus Guidelines recommend an 18F-FDG administered activity of 0.10–0.14 mCi/kg (3.7–5.2 MBq/kg) with a minimum dose of 1.0 mCi (37 MBq); alternatively, the European Association of Nuclear Medicine dosage card may be used [63]. Appropriate pediatric CT settings should be utilized to minimize radiation dose. PET or PET/CT is performed approximately 1 h after 18F-FDG injection. The lower extremities and skull should routinely be included in the scan, as disease involvement commonly occurs in these areas. Sedation is required for children who are unable to remain still during PET and PET/CT imaging. Toilet-trained patients should be encouraged to void prior to imaging.
Clinical Applications
The majority of neuroblastomas concentrate 18F-FDG both before and after therapy, with uptake seen in both soft tissue and skeletal disease sites [28, 97, 115]. Findings on 18F-FDG scans have been shown to correlate with disease status with serial scans accurately depicting treatment effects and disease evolution [28].
However, when compared to 123I-MIBG, 18F-FDG is often inferior for neuroblastoma evaluation. Fluorine-18-FDG can show lower tumor to non-tumor uptake ratios, especially after therapy [115]. Fluorine-18-FDG PET is less sensitive for neuroblastoma detection, especially in high-risk or relapsed disease. The inferiority of 18F-FDG PET often is due to poorer depiction of cortical bone/bone marrow metastases, especially during therapy [76, 77, 116].
Fluorine-18-FDG PET is most useful for imaging neuroblastomas that fail to or weakly accumulate 123I-MIBG [76, 97, 115, 116] and is recommended as an option for evaluation of MIBG-negative tumors (Fig. 19.8) [5, 6]. Use of 18F-FDG PET should be considered when CT/MR or clinical findings suggest more disease than demonstrated by 123I-MIBG scans [97, 116–118]. A study of patients with MIBG-negative tumors or discrepancies between their 123I-MIBG scans and CT/MRI or clinical findings showed that 18F-FDG PET was more sensitive (78 % versus 50 %) and specific (92 % versus 75 %) than 123I-MIBG in this population, although review of both 123I-MIBG scan and 18F-FDG PET together gave the highest sensitivity (85 %) [97].
Fluorine-18-FDG PET and 123I-MIBG scans can be complimentary, with each study sometimes demonstrating disease sites not identified with the other [28, 76, 97, 115]. Concurrent 123I-MIBG scans and 18F-FDG PET or PET/CT may therefore be useful to evaluate the full extent of disease involvement, especially at therapeutic decision points [76].
The intrinsic tomographic nature and higher spatial resolution of 18F-FDG PET and PET/CT improves disease localization and detection of small lesion [28, 77]. Fluorine-18-FDG PET can be useful especially for identifying disease sites in the chest, abdomen, and pelvis [76].
A study including 10 patients with stage 1 and 2 neuroblastoma suggested that 18F-FDG PET may be superior to 123I-MIBG in this population. In this study, 6 patients had better depiction of their primary tumor and/or regional metastases with 18F-FDG PET [76]. A study including 17 soft tissue lesions suggested that 18F-FDG PET may have higher sensitivity than 123I-MIBG scans for soft tissue lesions. In this study, 6 lesions were seen only on 18F-FDG PET [77]. However, larger studies are needed to confirm these findings.
A study reviewing neuroblastoma staging evaluations (including 18F-FDG PET, 123I-MIBG, 99mTc-MDP bone scans, CT/MRI, urine catecholamines, and bone marrow biopsy) suggested that 18F-FDG PET and bone marrow sampling may be sufficient to monitor for progressive disease after tumor resection, as long as there were no skull lesions [28]. However, 123I-MIBG remains a standard part of neuroblastoma assessment with a later study from this institution stating that 123I-MIBG is essential for valid estimation of relapse-free survival in high-risk neuroblastoma patients [78].
Potential Pitfalls
Fluorine-18-FDG is a less-specific imaging agent than 123I-MIBG. Physiologic uptake and uptake at sites of inflammation/infection can complicate image interpretation [28, 115]. Benign fibro-osseous lesions can also demonstrate variable 18F-FDG uptake and mimic cortical bone metastases [119, 120].
Assessment of bone marrow involvement can be especially problematic. Physiologic 18F-FDG uptake in bone marrow is seen in the absence of tumor [77, 115, 116]. Bone marrow metastases also sometimes produce 18F-FDG uptake patterns that are indistinguishable from normal or physiologic bone marrow activity [76]. During or after granulocyte colony-stimulating factor (G-CSF) therapy, extensive 18F-FDG uptake in bone marrow can obscure or mimic metastatic disease [76, 77, 116] (Fig. 19.9). Like 123I-MIBG, 18F-FDG also can fail to detect minimal bone marrow disease [28, 77]. For example, cranial vault lesions can be difficult to identify near adjacent brain activity [28, 77, 115, 116], although large skull lesions usually can be identified (Figs. 19.7 and 19.10).
131I-MIBG Therapy
Targeted therapy for neuroblastoma utilizing 131I-MIBG is made possible by the radiosensitivity and MIBG avidity of most tumors. Clinical studies have evaluated the use of 131I-MIBG in neuroblastoma therapy, both as a single agent and in combination with other agents including radiation sensitizers and cytotoxic chemotherapy [121]. Initial studies focused on use in patients with refractory or recurrent neuroblastoma, with objective responses seen in a significant minority of patients. More recent studies have investigated the use of 131I-MIBG therapy in newly diagnosed high risk patients. In North America, 131I-MIBG therapy currently is administered as an investigational agent at several sites in the United States and Canada. Myelosuppression is the main toxicity of 131I-MIBG therapy. The maximum administered dose may depend upon the availability of autologous stem cells that can be used for bone marrow rescue.
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Sharp, S.E., Gelfand, M.J., Shulkin, B.L. (2014). Neuroblastoma: Functional Imaging. In: Treves, S. (eds) Pediatric Nuclear Medicine and Molecular Imaging. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9551-2_19
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