Nuclear Oncology, 1 Ed.



Ettore Seregni • Alice Lorenzoni • Roberto Luksch • Cristina Nanni • Maria Rita Castellani • Emilio Bombardieri


Neuroblastoma (NB) is the most common solid extracranial malignancy in childhood, accounting for 15% of cancer-related deaths. The median age at presentation is 18 months and 90% of cases are diagnosed by the age of 6 years. The incidence of NB is 10.9 per million children younger than 15 years.1 The tumor derives from the neuronal crest sympathetic nervous system elements, developing during fetal or postnatal life. The majority of the tumors occur in the adrenal medulla. NB is an extremely heterogeneous disease in terms of biologic behavior and clinical outcome. The presence of some specific molecular features helps to identify the therapeutic stratification. The 5-year survival rate is approximately 75% but in high-risk NB, long-term survival is only 40%.2 Patient age at the time of diagnosis represents an important prognostic factor. Some patients present as a result of paraneoplastic phenomena (e.g., because of the production of vasoactive intestinal peptides by NB cells, resulting in sweating, chronic watery diarrhea, and hypertension). Opsoclonus-myoclonus (“dancing eye syndrome”) is characterized by ataxia and rapid, abnormal movements of the eyes, and affects 2% to 4% of patients.3 Other paraneoplastic phenomena include intractable secretory diarrhea (“Kerner–Morrison” syndrome) because of the secretion of vasoactive intestinal peptide. Furthermore, secretion of catecholamine metabolites may cause hypertension, flushing, sweating, and tachycardia.

NB derives from progenitor cells of sympathetic nervous system which form the chromaffin cells of adrenal medulla and the paraganglia.4 Typically, NB is composed of small, uniform in size round cells. The differentiation from other “small-blue-round-cell” tumors requires immunohistochemical evaluation.5 The International NB Pathology Classification (INPC) recognized four different morphologic groups: NB (Schwannian stroma-poor), intermixed ganglioneuroblastoma, nodular ganglioneuroblastoma, and ganglioneuroma, differing in prognosis.6,7 To identify the risk stratification and consequently the optimal treatment, multiple prognostic factors are used including age, biologic features (i.e., MYC amplification), and histology.

TABLE 23.1


Amplification of the proto-oncogene MYC is present in approximately 25% of primary neuroblastomas and in 40% of advanced disease. It is associated with rapid tumor progression, and poor outcome. The myc oncogenes are important regulators of protein synthesis and cell cycle progression, stimulating the expression of many genes that encode ribosomal proteins, translation factors, and enzymes, all of which play a part in the control of cell proliferation. Supposed targets of myc include the cyclin-dependent kinase, CDK4, and cyclin D2. Myc also represses genes involved in the inhibition of proliferation (e.g., gadd45, p15Ink4b), preventing growth arrest of transformed cells. Most neuroblastoma cell lines have a near-diploid or hyperdiploid DNA content. Aggressive neuroblastomas are associated with near-diploid DNA content and display generalized genomic instability, chromosomal rearrangements, and translocation of genetic material within the cells. Less aggressive subtypes have a hyperdiploid DNA content and display gain and loss of whole chromosomes secondary to abnormalities in mitosis. Other potential markers reflecting the function of cellular programs for differentiation, proliferation, and apoptosis include: Deletion of chromosome 1p, gain of chromosome 17q, expression of trk-A (gene for the receptor of the neurotrophin, nerve growth factor), CD44 and multidrug resistance-associated proteins (MRPs). Familial neuroblastoma occurs in 1% to 2% of cases and a gene conferring an inherited predisposition to developing familial neuroblastoma has not been localized, but chromosome 16p12-13 is suspected.

The International NB Staging System (INSS), adopted in 1989, classifies neuroblastoma into stages based on tumor resectability, lymph node involvement, tumor location across the midline, and dissemination to distant organs (Table 23.1).

In 2009, The International NB Risk Group (INRG) introduced a classification system based on clinical criteria and tumor imaging to establish a consensus approach for pretreatment risk stratification. The INRG classification system includes seven factors that were highly statistically significant and also considered clinically relevant. They include the criteria INRG stage, age, histologic category, grade of tumor differentiation, MYCN status, ­presence/absence of 11q aberrations, and tumor cell ploidy. The extent of locoregional disease is determined by the absence or presence of image-defined risk factors (L1 and L2, respectively). Stage M is used for disseminated disease and stage 4S tumors, metastases are limited to skin, liver, and bone marrow without cortical bone involvement (Table 23.2). However, the definition of metastatic disease has been expanded to include toddlers of age 12 to younger than 18 months and large unresectable primary tumors.8 In the International NB Risk Group Staging System (INRGSS), four stages have been proposed: Stage L1 is defined as a locoregional tumor without risk factors identified on imaging; Stage L2 is defined as a locoregional tumor with at least one risk factor identified on imaging, such as tumor encasement of blood vessels; Stage MS identifies metastatic disease confined to the skin, liver, or bone marrow; and Stage M identifies all other distant metastases.9

TABLE 23.2


Three different risk categories may be recognized: Low-, intermediate-, and high-risk groups, based on stage, age, and MYC amplification. The probability of prolonged disease-free survival for patients in each group is 95% to 100%, 85% to 90%, and less than 30%.

Treatment options depend mainly on the initial stage. For patients with stage I or II and favorable prognostic factors, surgery is curative in almost all cases. Chemotherapy is reserved for those children with spinal cord compression or those with respiratory compromise from massive hepatomegaly becaue of the hepatic infiltration in stage 4S tumors. Chemotherapy consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide.

In stage III, surgery and chemotherapy are the therapeutic approaches used. In stage IV and patients with MYCN amplification, multimodal therapy is necessary, including high-dose therapy with autologous hematopoietic stem cell rescue (ASCR). The high-risk induction protocols vary not only in the use of chemotherapeutic drugs but also in the doses of these drugs. Following the induction chemotherapy, surgical excision must aim to remove all the residual disease, though there are conflicting reports in the literature regarding the extent of surgical resection in high-risk neuroblastoma.10,11

Despite of all the advances in the management of high-risk neuroblastoma with many clinical trials conducted in several different study groups, the outcome for this group has not dramatically changed. The current therapies have led to only a modest improvement in long-term survival rates for this group of patients, despite intensified therapeutic regimens.

Tumor stage and biologic behavior of the disease should be determined with imaging methods and biologic/molecular markers. The most common sites of involvement are the adrenal glands (48%), retroperitoneum (25%), chest (16%) often encasing major blood vessels.12 Unlike most solid cancers, NB usually presents with substantial metastatic disease. About 60% of patients have metastases in cortical bone, bone marrow, lymph nodes, and liver. Involvement of the lung or brain is rare despite hematogenous dissemination. These clinical characteristics make assessment of disease status dependent on a multitude of studies: Conventional diagnostic imaging (ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]), nuclear medicine procedures, and histochemical examinations are fundamental to evaluate the extent of disease.


The initial imaging modalities most commonly used in patients who are eventually diagnosed with neuroblastoma include chest radiographs for suspected pneumonia, ultrasonography to assess a palpable abdominal mass, and spinal MRI for acute neurologic deficits.

Direct Radiogram

Chest radiographs reveal paravertebral masses in the posterior mediastinum, associated with calcifications or rib or vertebral body erosion. Skeletal radiographs also identify lytic lesions.


Ultrasound often is used initially to investigate an abdominal mass or other soft tissue masses that are clinically evident, revealing a retroperitoneal mass in a suprarenal or paravertebral location as well as liver lesions. Infants with large livers or abdominal or pelvic masses are readily examined by ultrasound. Ultrasonography is the preferred modality to monitor patients with low-risk abdominal or pelvic neuroblastoma with no significant risk of epidural extension.

Computed Tomography

In most cases, however, more cross-sectional anatomic imaging, that is, computed tomography (CT) or magnetic resonance imaging (MRI) are preferred to fully examine and stage the patient.13 Furthermore, CT and MRI have an important role in surgical planning, allowing assessment of invasion of adjacent structures, and regional lymphadenopathy. CT has been the main initial anatomic investigation of masses in patients with suspected neuroblastoma for many years, defining the site and extent of tumor, evidence of regional invasion, vascular encasement, adenopathy, and calcification which are important issues regarding surgery and staging. Soft tissue calcifications are the characteristic findings of neuroblastomas and are present in 80% to 90% of cases. Calcifications in neuroblastomas are usually coarse, amorphous, and mottled in appearance as opposed to the discrete and punctate calcifications observed in ganglioneuromas. On CT, neuroblastoma is usually characterized by an irregular shape, lobulations, and lack of capsule. Furthermore, the mass tends to be inhomogeneous because of tumor necrosis and hemorrhage. CT has been the main method to differentiate between Wilms tumor and neuroblastoma, the two main malignant causes of an abdominal mass in childhood. Involvement of the liver may occur in neuroblastoma and is part of stage 4S disease. CT has a reported accuracy of about 80% in tumor staging. Although uncommon, CT scans of the thorax should be performed for pulmonary metastases and pleural involvement. Bone involvement may be detected on CT particularly involving the skull and orbital regions. When CT is complemented with scintigraphy or bone marrow aspiration, the accuracy of the combined examination has been reported to increase to 97%.

Magnetic Resonance Imaging

MRI imaging has yielded high sensitivities (85% to 100%) also for the detection of abdominal disease. Primary neuroblastoma on MRI with gadolinium enhancement is typically heterogeneous. Calcification may not be detected on MRI but necrotic, cystic, and hemorrhagic areas are seen. MRI is the gold standard modality for evaluating extension into the spinal canal and it is superior to CT in assessing leptomeningeal or epidural extension, tumor invasion of kidney and liver.14 Its advantages include lack of ionizing radiation, excellent definition of the primary tumor with high intrinsic soft tissue contrast resolution, depiction of internal structure, exact definition of intraspinal tumor extension, or diaphragmatic involvement. Small lymph nodes (≤13 mm), however, are difficult to define on MRI. False-positive studies on MRI for bone marrow involvement after treatment have been described.15 Siegel et al.16showed that MRI is more accurate than CT for detection of all stage IV disease (sensitivity 83% versus 43%) alone and in combination with bone scintigraphy. MRI is better than CT for posttreatment follow-up of midline or paraspinal neuroblastomas (neck, chest, nonadrenal retroperitoneum), especially in patients with low-risk or intermediate-risk disease whose management does not routinely include radiotherapy. Either CT or MRI can be used to monitor patients with high-risk disease whose treatment usually includes local radiotherapy. Finally, the definition of response to therapy requires three-dimensional measurements for determination of changes in tumor volume.


Proper staging and monitoring of patients with neuroblastoma is dependent on scintigraphic studies. 123I-MIBG scintigraphy, 18F-FDG PET/CT, and in selected cases bone scintigraphy are important tools for optimal treatment planning. In 123I-MIBG-negative cases, somatostatin receptor imaging with γ-emitters or PET tracers can be useful. For treatment monitoring, the imaging procedures discussed above are also employed. 123I-MIBG scintigraphy is particularly important in this setting to differentiate between tumor tissue and posttherapy changes in the early posttreatment phase.

TABLE 23.3


Metaiodobenzylguanidine Scintigraphy

Metaiodobenzylguanidine (MIBG) is an analog of the false neurotransmitter guanethidine. It was developed as a tracer to image the adrenal medulla in the 1970s. The role of iodine-labeled MIBG, tracing catecholamine metabolism, in clinical and research imaging of neuroblastoma is well established.17,18 MIBG labeled with 131I was initially used for neuroblastoma imaging, but the physical characteristics (long half-life, high-energy photon, β-emission) are suboptimal for diagnostic imaging. 123I-MIBG has a shorter physical half-life (13 hours), photon energy of 159 keV and lacks a β-particle.19 The use of I23I to label MIBG takes advantage of the better physical properties of I23I for imaging, allows higher activities to be administered with favorable radiation dosimetry and greater photon flux resulting in higher count, higher-quality planar images, and permits the performance of single photon emission computed tomography (SPECT). The dosimetry of l23I-MIBG is such that 10 mCi may be administered with the same whole-body radiation absorbed dose as 0.5 mCi of 131I-MIBG. The whole-body radiation absorbed dose for 123I-MIBG is approximately 5% that of 131I-MIBG.20 The principal radionuclides that may be used to label MIBG and its analog and their properties are summarized in Table 23.3.

123I-MIBG was approved for clinical use in Europe in 1995 and in the United States by the Food and Drug Administration in 2008. It is generally considered the tumor diagnostic agent of choice in neuroblastoma. 123I-MIBG scintigraphy is routinely performed in patients with NB and its importance is recognized in the guidelines of the International NB Risk Group Project. The use of this procedure has important prognostic implication during the ­follow-up of these patients, to identify recurrent or refractory disease.

Radiochemistry of MIBG

MIBG, an analog of guanidine in which the benzyl group is combined with the guanethidine group of guanethidine, is structurally similar to norepinephrine. The radiotracer uptake into tumor cells is mediated by the type I catecholamine reuptake system, which is physiologically utilized for noradrenaline accumulation. It is primarily concentrated within the cytoplasm, rather than within norepinephrine storage granules in neuroblastoma.21,22 MIBG is not metabolized by monoamine oxidase (MAO) and catecholamine-O-methyltransferase, which physiologically degrades catecolamine. Radioactivity in the blood pool is caused by the MIBG labeling of platelets, mediated by 5HT transporter. After intravenous injection, the majority of activity from injected radiotraces is excreted through the urinary tract: 40% to 55% in 24 hours and 70% to 90% in 96 hours. Most of this is in the form of intact l23I-MIBG whereas small fractions are excreted as l23I-4-hydroxy-3-iodobenzylguanidine (HIBG), metaiodohippuric acid and metaiodobenzoic acid. A small, but chemically uncharacterized portion of the activity, is excreted into the gut.

High uptake is present also in normal sympathetically innervated tissue as salivary glands and heart. Normal adrenal glands may also demonstrate MIBG uptake, especially after contralateral adrenalectomy. Minimal uptake may be seen in the lungs, and a physiologic uptake in brown adipose tissue can also occur, leading to a difficult interpretation of the images in these regions.23,24 Cerebellar visualization has been reported. Rare pathologic conditions such as myofibromatosis, pancreaticoblastomas, and neuroectodermal tumors may also show MIBG uptake. Only 4% of nonsympathomedullary tumors (nonpheochromocytoma, nonneuroblastoma) showed MIBG uptake.25 The mechanism of localization in nonneuroendocrine tumors is not clear. Postulated mechanisms include accumulation as a result of high tumor–dependent blood flow and nonspecific diffusional uptake. Bomanji et al.26 reported uptake of 123I-MIBG in a case of ectopic intracranial retinoblastoma.

Radiation exposure to the thyroid gland from free radioiodide as a result of in vivo deiodination of MIBG is blocked by the prior administration of a saturated solution of potassium iodide (SSKI).27 The premedication should begin 1 day before the radiotracer administration and continue for 1 to 2 days. Recommended doses of potassium iodide range from 32 to 130 mg, depending on patient age. In patients who are allergic to iodine, potassium perchlorate is generally used on the day of the injection.

Adverse effects (tachycardia, pallor, abdominal pain) are related to pharmacologic effects of the solvent solution and they are very rare if 123I-MIBG is injected slowly. If possible, injection into central venous catheters should be avoided to prevent the visualization of radiotracer activity on the catheter during image acquisition. If a central venous catheter is used, it should be flushed well after injection. Radiolabeled MIBG is usually a ready-for-use radiopharmaceutical and no additional preparation is required.

The administered activity of 123I-MIBG (specific activity >300 MBq/mg) should be calculated on a reference adult dose of 370 MBq scaled down for body weight (or body surface area), with a minimum activity of 20 MBq.28,29and maximum activity of 400 MBq. To calculate the recommended activity administered, the Guidelines for Radioiodinated MIBG Scintigraphy in Children should be consulted.30 Concerning 131I-MIBG, minimum and maximum recommended activities are 35 and 80 MBq, respectively.

The sensitivity of detection with MIBG increases with increased injected activity, as demonstrated for both 131I-MIBG and 123I-MIBG pretherapy diagnostic scans compared with immediate posttreatment 131I-MIBG scans. The biodistribution of 131I-MIBG is different with therapeutic doses compared to pretherapy doses. 131I-MIBG imaging following high therapeutic doses often reveals sites of occult metastatic disease that may be clinically relevant.

Hickeson et al.31 investigated the biodistribution of therapeutic 131I-MIBG in 18 patients with neuroblastoma to evaluate the sensitivity of diagnostic versus therapeutic 131I-MIBG scans. In terms of biodistribution, the posttherapeutic scan identified uptake in the several regions not detected on the diagnostic scan: Nasal mucosa, cerebellum, central brain, adrenals, spleen, kidneys, thyroid, salivary glands, lower halves of the lungs, bladder, bowel, and an incisional scar. Posttherapeutic scans identified 210 lesions compared to 151 on diagnostic scans, showing sites of disease not evident in the diagnostic scan in 16 cases.

Furthermore, Parisi et al.32 showed that diagnostic MIBG scanning led to underestimation of the tumor burden by 50% compared with posttherapy scanning. This difference may be an important consideration in selecting therapeutic strategies for individual patients.

TABLE 23.4


In the high-risk neuroblastoma patient group, the radiation hazard is far less than the risk resulting from false-negative or false-positive scanning results.33 Indeed the need for high-quality images and the danger of under-staging patients because of inadequate counts from the study, outweigh the theoretical risks from a slightly higher dose of the radiotracer.34 Good hydration before and after the injection will lower the radiation burden and reduce bladder activity, which could interfere with evaluation of the pelvis.

Several medications, including many antihypertensives, sympathomimetics, tricyclic antidepressants, have the potential to interfere with MIBG uptake and storage. Accordingly, care should be taken before prescribing medications around the time of MIBG scans (Table 23.4).

The most common agents that interfere with MIBG uptake and retention in children are α- and β-adrenergic antagonists, such as pseudoephedrine and labetalol.35 Phenothiazines may interfere with MIBG uptake and should be avoided as sedatives before imaging. Furthermore, venlafaxine and duloxetine can block norepinephrine reuptake.36

Image Acquisition

123I-MIBG images are acquired 24 hours after the injection. Selected delayed images (not greater than 48 hours) may be useful in cases with equivocal findings, such as abdominal uptake that cannot be differentiated from the bowel or kidney. Rufini et al.37 showed that delayed 48-hour planar scanning may occasionally depict more lesions than 24-hour imaging but it may also miss lesions with rapid washout. Furthermore, tumor uptake becomes more distinct at later times compared with physiologic uptake; early images after 4 to 6 hours are not routinely performed. Sedation is usually not required for a technically satisfactory examination, except for children between 1 and 3 years, and others who are unable to cooperate.

As the principal energy of 123I is 159 keV, high-resolution collimators should be used to acquire satisfactory images. However, the presence of additional low-abundance high-energy photon emission can degrade image quality. Thus, a medium energy collimator with higher acquisition times, to reduce scatter, can be used. A 256 × 256 matrix (preferred) or 128 × 128 matrix with zoom should be used. Images of the entire body, including the skull (anterior, posterior, and lateral views), chest (anterior and posterior views), abdomen (anterior and posterior views), pelvis (with empty bladder, anterior and posterior views), upper and lower limbs (anterior and posterior views) should be acquired. Alternatively, whole-body scan imaging with additional static images including lateral views of the skull can be acquired. Lateral images are sometimes useful to discriminate between areas of overlapping uptake, for example, in the abdomen or pelvis, especially if the bladder is not empty. Minimum 10 minutes per view for static images (or 250 Kcounts for the skull and the trunk and 100 Kcounts for the lower limbs) is a suitable compromise between best image quality and limitation of scanning time. Concerning whole-body scanning, a scan speed of 5 cm/min is appropriate when available. A whole-body scan will require approximately 15 minutes in a 1 year old, 17 minutes in a 2 year old, 22 minutes in a 5 year old, 28 minutes in a 10 year old, and 34 minutes in a 15 year old. In cases in which uncertainty exists as to the exact site of MIBG activity, SPECT should be performed. The abdomen is the area in which this is most likely to occur, and less frequently, the chest. For the detection of lesions close to the liver, bladder, or any other area of physiologic uptake, SPECT may be an important tool. SPECT acquisition should be performed on a 128 × 128 matrix, 3-degree steps, with 30 to 35 seconds per step. To reduce the time of acquisition, 3-degree steps or using a 64 × 64 matrix with shorter times per frame can be used.

Gelfand et al.38 compared 35 SPECT and planar 123I-MIBG in 25 children with neural crest tumors and found no significant increase in the number of lesions detected by SPECT, although an improvement in certainty of interpretation was documented. Contrarily, in a study performed by Ruffini et al.,39 SPECT detected a greater number of lesion compared to planar images, showing more accurate depiction of extent of disease in 32% of abnormal scans.

SPECT allows better comparison with anatomic imaging data, in particular when image fusion with CT or MR image is possible, or a combined SPECT–CT scanner is available.40 SPECT/CT improves uptake localization and lesion detection compared to SPECT alone. SPECT/CT increased the diagnostic certainty in 89% of discordant studies. Rozovsky et al.41 evaluated the contribution of MIBG SPECT/CT to contrast-enhanced CT image analysis in the follow-up of 11 patients with neuroblastoma. SPECT/CT provided additional information in 53% of the cases and increased the diagnostic certainty in 89% of discordant studies. There is added value of SPECT/CT for correlation of MIBG scintigraphy and diagnostic CT in neuroblastoma and pheochromocytoma. In cases of equivocal diagnostic CT or of suboptimal localization of MIBG-avid foci, SPECT/CT helps to define the anatomic location of these foci and to characterize the benign or malignant significance of uncertain CT findings. Effective radiation dose for SPECT–CT ranges from 0.018 to 0.037 mSv/MBq. The image acquisition protocol is summarized in Table 23.4.

Semiquantitative Score System

Semiquantitative scoring systems have been developed to evaluate the prognostic effect of tumor burden at diagnosis and to quantify response to treatment by MIBG scan. The introduction of a scoring system improves the concordance between readers, and enables one to differentiate a simple improvement from the disappearance of a lesion, or decreased intensity of lesions that can be subjective, from a significant response. The scoring systems are similar with minor variations, and take into account the frequent diffuse nature of skeletal involvement.

The first method reported was developed at the Curie Institute in France42 designed for the comparative interpretation of MIBG scans in stage IV neuroblastoma, to predict response the final therapy during mid-course of induction chemotherapy. It divides the skeleton into nine segments to view osteomedullary involvement, and adds a tenth sector that counts any soft tissue involvement. The extension of bone metastases was separately quoted (score range: 0 to 3) as: 0, no sites per segment; 1, one site per segment; 2, more than one site per segment; and 3, diffuse involvement (>50% of the segment). The intensity score is graded as: 0, for no uptake; 1, for doubtful uptake; 2, for definite uptake less than liver; and 3, for intense uptake greater than that of liver. Thus, the maximum score for either extension or intensity would be 30. The intensity score is slightly more subjective but because of technical factors, it showed lower concordance among readers. Relative scores were calculated by dividing the absolute score at each time by the corresponding pretreatment score. A relative score of 0.5 is considered a partial response; a relative score of 0 is a complete response. The score at mid-induction correctly predicted the overall response of metastases at the end of therapy. In a study performed by Matthay et al.,43 the Curie score has been shown to have an interobserver concordance 95% and to provide valuable prognostic information for the overall response and event-free survival.

The Curie score is one of the most frequently used semiquantitative scoring system by the Children’s Oncology Group and the New Approaches to NB consortium. A study performed by Yanik et al.44 showed a significantly worse event-free survival (EFS) for patients with scores >5 at the end of induction. Suc et al.45 proposed a modification of the Curie score in which the skeleton was divided into seven segments. It showed good interobserver concordance but not prognostic value for outcome. The Frappaz score uses seven segments of the skeleton, and initially did not include soft tissue in the score.46 Messina et al.47 evaluated the Curie score systems and the Frappaz score. Diagnostic MIBG scan pairs (n  =  57) were collected for patients who underwent 131I-MIBG therapy for relapsed neuroblastoma. The first method resulted in highest interobserver concordance and correlated significantly with the overall response to therapy, suggesting that any decrease in absolute score is indicative of response in patients with scores below three to five at the commencement of therapy but that the semiquantitative scoring system is most useful in those with pretreatment score ≥3.

Despite a strong correlation with response by INRC, the second method carried no significance in predicting PFS. Perel et al.48 published a minor variation on the Curie score, in which the skeleton was divided into 10 rather than 9 zones and soft tissue involvement was not considered. Two-year EFS did not significantly differ for the group of patients with initial MIBG score ≥10; however, for patients older than 1 year, worse outcome was seen with MIBG score ≥10. In a study performed by Katzenstein et al.,49 this method was shown to have prognostic significance at the end of induction therapy, with a better outcome for patients with score inferior to 3. Another major variation of the Curie score was proposed by Lewington et al.50 in patients treated in the high-risk neuroblastoma SIOPEN study (­SIOPEN score). In the SIOPEN score, currently under prospective evaluation in Europe, the skeletal distribution of MIBG was recorded in 12 anatomic body segments (skull, thoracic cage, proximal right upper limb, distal right upper limb, proximal left upper limb, distal left upper limb, spine, pelvis, proximal right lower limb, distal right lower limb, proximal left lower limb, and distal left lower limb).

The extent and pattern of skeletal MIBG involvement was scored using a 0 to 6 scale to discriminate between focal discrete lesions and patterns of more diffuse infiltration. This method showed an interobserver concordance of 95% and it was slightly superior to the Frappaz score to measure of response. Curie score, however, has been tested more widely and over many years and is less complex compared to SIOPEN score. Recently, Sano et al.51developed a new semiquantitative score based on 123I-MIBG retention ratio to assess the response to chemotherapy for advanced neuroblastoma. 123I-MIBG retention ratio in tumors and normal organs was compared to the Curie score. The difference in the washout ratio of MIBG between the pathologic accumulation in neuroblastoma and the physiologic distribution in normal organs was evaluated using early and delayed images. 123I-MIBG retention ratio was significantly higher in patients with stage M disease compared to stage I–II, demonstrating the utility for evaluation based on the early response to chemotherapy. Furthermore, the retention ratio correlated with urine catecholamine metabolites before and during chemotherapy.

Clinical Role of MIBG Scintigraphy

The 123I-MIBG scan is currently the gold standard for initial staging of neuroblastoma with a specificity ranging from 85% to 96%. MIBG studies at the time of diagnosis have also an important prognostic value, particularly in stage IV patients older than 1 year. Whole-body evaluation is especially important in neuroblastoma because of the potential for widespread metastatic disease (Fig. 23.1). Leung et al.25 evaluated the role of MIBG scintigraphy in 100 patients with mass lesions and pathology other than neuroblastoma to characterize the specificity of this modality in sympathomedullary tumors. In this large retrospective study, MIBG uptake was observed in only four cases, two of which were of nonneural crest origin, confirming that, in children, MIBG-avid lesions are almost certainly of sympathomedullary origin.

FIGURE 23.1. 123I-MIBG scan (A) anterior view, (B) posterior view in patient with newly diagnosed neuroblastoma. Planar images show the presence of large mass in abdomen (black arrow ) and diffuse bone marrow involvement.

A prospective trial was conducted to confirm the diagnostic performance of 123I-MIBG scintigraphy in patients with known or suspected neuroblastoma, showing sensitivity of 88% and a specificity of 83%.52 Most false-negative interpretations were in patients with minimal residual disease, whereas false-positive interpretations generally involved atypical adrenal or other physiologic uptake. To assess neuroblastoma lesions, Pfluger et al.53 showed that integrated imaging with MRI showed an increase in both sensitivity and specificity. MIBG scintigraphy, MRI, and combined analysis showed a sensitivity of 69%, 86%, and 99% and a specificity of 85%, 77%, and 95%, respectively. On MIBG scintigraphy, 10 false-positive findings occurred in ganglioneuromas, benign liver tumors, and physiologic uptake. On MRI, 15 false-positive findings were recorded in posttherapeutic reactive changes, benign adrenal tumors, and enlarged lymph nodes.

False-negative scans may be observed in approximately 10% of neuroblastomas that do not concentrate MIBG, because of low expression of the cellular expression of the noradrenaline transporter (NAT). In this setting, Carlin et al.54 demonstrated that tumors without MIBG uptake did not express detectable levels of the NAT investigated with the real-time PCR. NB shows a great variability in tracer uptake and it seems correlated with the level of urinary catecholamine metabolites and tumor differentiation.52 Furthermore, tumor size reflects whether the uptake is uniform or irregular with focal areas of reduced uptake, indicating central necrosis. In some of these tumors, the areas of reduced uptake may reflect areas of dedifferentiation.

Central nervous system (CNS) metastases are extremely rare at diagnosis, occurring later in the course of the disease. MIBG scans detect metastatic CNS lesions in only 43% of patients, probably because MIBG does not cross the blood–brain barrier, or the tumor has dedifferentiated. Matthay et al.55 evaluated 23 patients with suspicious cerebral disease. The sites of recurrences were parenchymal in eight patients, parenchymal with meningeal involvement in seven patients, and meningeal involvement alone in the remaining eight patients. In patients with skull lesions, the detection of CNS metastases may be difficult. In patients with only meningeal disease, MIBG did not show good diagnostic accuracy. In five patients with parenchymal lesion measuring >1 cm, MIBG did not detect the presence of disease.

The sensitivity of MIBG scintigraphy is limited in the detection of single bone and bone marrow metastases. Gordon et al.56 reported negative findings on MIBG scintigraphy in 66 (29%) of 227 skeletal lesions, whereas bone scintigraphy findings were positive. In addition, small bone marrow tumors are often not detected, and therefore the MIBG scan must be supplemented with bone marrow biopsy.57

Some studies demonstrated that MIBG score at diagnosis may be a prognostic indicator, to predict response to chemotherapy for metastatic neuroblastoma. Suc et al.45 have shown that a semiquantitative score of >4 was associated with the failure to achieve complete remission after induction chemotherapy. Therefore, a high MIBG score at diagnosis is probably correlated with great overall tumor burden with a significant risk of harboring drug-resistant cells and thus with poor response to conventional chemotherapy. The hypothesis is supported by the mathematical model developed in 1970s by Goldie and Coldman,58 in which the number of drug-resistant clones has been shown to be proportional to the mutation rate. This was also suggested by Chan et al.,59 who showed that these patients exhibited high levels of pretreatment P-glycoprotein. P-glycoprotein was not detected in stage I–II neuroblastoma and in tumors associated with a good prognosis that originated in the cervical, mediastinal, or pelvic sympathetic ganglia but it was found in tumors associated with a poor prognosis that arose in the adrenal medulla and abdominal sympathetic ganglia. Furthermore, the majority of metastatic lesions expressed higher levels of P-glycoprotein than the primary tumors. The use of the relative score after two or four cycles of induction therapy seems to be a more reliable predictor of EFS than the absolute score, although both measures significantly predict response at the end of induction.60 The identification of poor responders after two cycles of induction therapy will allow the routing of these patients into novel approaches. Most other studies, however, showed the initial MIBG score and clinical outcome had no significance.

In a study performed by Perel et al.,48 the 2-year EFS did not significantly differ for patients with initial MIBG or bone scintigraphy scores ≥10 compared to those with scores <10. However, for patients older than 1 year, a trend associating worse outcome with MIBG scores ≥10 at diagnosis was seen. Katzenstein et al.49 investigated whether response to induction therapy, evaluated by MIBG and bone scintigraphy, correlates with EFS in 29 children with high-risk NB. They found that the imaging scores calculated for the diagnostic MIBG and bone scans were not prognostic but an association between EFS and the postinduction MIBG score was observed. Patients with MIBG scores ≥3 following induction therapy had significantly worse EFS than those with scores less than 3. Ongoing prospective studies of large numbers of uniformly treated patients in North America and Europe will further elucidate the prognostic significance of the initial MIBG score.

NB shows a great variability in tracer uptake. It appears to be correlated with the level of urinary catecholamine metabolites and tumor differentiation.52 Less than 10% of neuroblastomas demonstrate no radiotracer uptake and no relationship between MIBG-negativity and biologic/prognostic features has been demonstrated. Biasotti et al.61 found negative MIBG scan at diagnosis in 16 patients out of 196 neuroblastoma cases (8%). In patients with stage I or II disease, the MIBG scan was negative in 24% of the cases, contrarily patients with stage III or IV demonstrated no MIBG uptake only in 4% of cases. The negative MIBG scan at diagnosis was found to be associated with normal urinary vanillylmandelic acid (VMA) excretion in almost 80% of cases and with pathologic excretion of homovanillic acids (HVAs) in 50% of cases.

Histologic diagnosis of undifferentiated or poorly differentiated neuroblastoma was present in 43% of patient. Furthermore, in some patients with minimal residual disease after therapy, false-negative MIBG scans may occur.62

Indeed in some cases, the MIBG scan becomes positive at the time of relapse caused by extreme tumor heterogeneity. After induction chemotherapy or before myeloablative therapy, positive scans may indicate a high likelihood of relapse, serving as a prognostic marker.63,64 The sensitivity of 88% to 94% and specificity of 83% to 92% for64 MIBG scintigraphy indicate that an important tool to detect unsuspected relapse of high-risk neuroblastoma, assessing relapse-free survival (RFS). Kushner et al.66 evaluated 113 patients with asymptomatic/unsuspected relapse. The 123I-MIBG scan was the most reliable study for detecting relapse with a detection rate of 82%. 131I-MIBG scan detected relapse in 64% of cases, proving to be significantly superior to bone scan (36%) and bone marrow histology (34%). These results suggest that periodic 123I-MIBG scans are essential for valid estimation of the duration of RFS. In 25% of patients, however, the MIBG scan failed to detect bone marrow involvement.

Taggart et al.67 confirmed the important role of MIBG scintigraphy for response evaluation in relapsed neuroblastoma compared to 18F-FDG PET/CT. The results showed that MIBG was more sensitive than 18F-FDG PET overall and for bone lesions evaluated in 122 patients with both pre- and posttherapy imaging (sensitivity 94% versus 43%). The nonconcordance found with both 123I-MIBG-positive/18F-FDG PET-negative lesions and MIBG-­egative/FDG PET-positive lesions demonstrates that MIBG is more sensitive, but both imaging modalities have the potential to identify lesions not visualized on the other scan, contributing unique information about disease sites.

Furthermore, MIBG scans allow functional assessment to differentiate residual tumor from posttherapy changes, being superior to conventional diagnostic imaging such as CT or MRI (Figs. 23.2, 23.3). Moreover, the study by de Cervens et al.68 demonstrated that in neuroblastoma patients younger than 1 year of age, normalization of skeletal MIBG uptake correlates with response to chemotherapy much earlier and with much more accuracy than the radiologic survey. Intermediate- and low-risk patients should have MIBG scans at diagnosis, at the end of therapy and as surveillance at 6-month intervals until 1 year for low-risk stage II patients and for 2 years after therapy for intermediate-risk patients. Although low- and intermediate-risk neuroblastomas have an excellent overall survival, the event free survival is only approximately 80% for stage II, stage III, stage IV and unfavorable biology 4S, suggesting that this modest surveillance schedule is reasonable to detect relapsing patients.

The addition of SPECT views may be critical in cases in which there is a question regarding physiologic uptake versus tumor uptake, or for precise localization of a tumor focus that is critical for patient management (e.g., distinguishing a vertebral lesion from the adjacent pulmonary parenchyma). The addition of low-dose CT to SPECT (SPECT/CT) for both lesion localization and attenuation correction has promised in providing more precise determination of the anatomic location of disease. In a study performed by Vik et al.,52 SPECT views only marginally increased the sensitivity from 88% to 91%. Although additional information was gained in 65% of cases regarding the precise anatomic location of uptake, Curie scores would not have been substantially altered. However, Even-Sapir et al.69 reported that SPECT/CT improved image interpretation by providing a better anatomic localization of SPECT-detected lesions in 41% of the patients with known or suspected endocrine tumor and detected unsuspected bone involvement in 15% of the patients. Additional information of clinical value were found in 33% of the cases.

FIGURE 23.2. 123I-MIBG scan for assessment of therapy response. A: Baseline scintigraphy shows multiple skeletal metastases. B: Posttherapy scan show marked reduction of disease.

Fukuoka et al.70 investigated lesion detectability of 123I-MIBG scintigraphy and of high-dose 131I-MIBG and evaluated the incremental role of SPECT/CT over planar image. SPECT/CT images provided additional diagnostic information over planar images in 25 studies (81%) of 12 patients (75%) in 123I-MIBG scintigraphy and in 9 studies (53%) of 9 patients (75%) in high-dose 131I-MIBG scintigraphy. The detection rate of the new lesions by SPECT/CT was higher in 123I-MIBG scintigraphy than in high-dose 131I-MIBG scintigraphy. It is thought that signal-to-noise ratio is high enough to be identified in planar image when high dose is administered. There were no apparent differences in the rate of alteration of anatomic location of the lesions between diagnostic 123I-MIBG and high-dose 131I-MIBG images.

99mTc-diphosphonate Bone Scintigraphy in Neuroblastoma

Total-body bone scintigraphy (BS) using 99mTc-diphosphonate compounds has been the main diagnostic investigative tool for detection of cortical skeletal metastases since the late 1970s. Bone scintigraphy is a sensitive tool to evaluate the skeletal system in children. The administered radiopharmaceutical dose is weight based. Bone scans in children require careful attention to technique to obtain high-quality diagnostic images. The activity administered should be calculated on the basis of a reference dose for an adult, scaled to body weight (with minimum of 20–40 MBq administered activity).29 North American pediatric centers had variability in the administered dose of the radiopharmaceutical 99mTc-methylene diphosphate (MDP); minimum activities varied from 22.2 to 185 MBq, whereas the activity per kilogram varied from 7.4 to 13.3 MBq/kg and the maximum from 666 to 925 MBq.71

FIGURE 23.3. 123I-MIBG scintigraphy in patient with CT finding of abdominal lymphadenopathy (A) whole-body scan, (B) planar image of the abdomen confirms lymph node disease (arrow ). The scan also reveals the presence of skeletal metastasis.

In 2011, the North American Consensus Guidelines established recommended radiopharmaceutical doses in children and adolescent72 to be 93 MBq/kg of 99mTc-MDP, with a minimum activity of 37 MBq and maximum activity of 148 MBq. Whole-body imaging is acquired after a delay of 2 to 3 hours postinjection of 99mTc-MDP. SPECT is routinely used to further evaluate the area of suspected abnormality or to further define an abnormality observed on planar imaging.

Combined functional and anatomic imaging using SPECT/CT imaging systems can improve diagnostic accuracy. 99mTc-MDP BS has lower sensitivity with a high frequency of false-positive results for detection of skeletal metastases than MIBG scans. In general, BS do not provide additional information compared to MIBG scintigraphy.73 The metastatic pattern of neuroblastoma in bone is often symmetrical in the metaphyseal areas of the long bones, making detection on bone scan difficult because of the adjacent physiologic uptake in the physis. Symmetrical flaring and blurring of the growth plate with extension into the metaphysis should be considered abnormal and highly suggestive of metastatic disease.74

Minimal metastatic involvement within or adjacent to the growth plate may be missed. In about 60% of patients, the 99mTc-MDP may also accumulate in the primary tumors because of the characteristic calcifications, without particular prognostic significance.75 Focal abnormalities on bone scintigraphy involving the orbits, skull, particularly parasagittal area, and multiple focal “hot” and “cold” lesions in the spine are highly suggestive of skeletal metastatic disease from neuroblastoma. Bone scans may identify cortical lesion in patients with negative MIBG scan at diagnosis which have worse prognosis compared to bone marrow metastases. Gordon et al.,56 in a review comparing bone with 123I-MIBG scintigraphy, showed that 123I-MIBG may miss abnormalities suggestive of metastatic disease. In 24 children, the 123I-MIBG scans revealed more extensive disease with 161 positive sites whereas the 99mTc-MDP scan showed only 100 positive sites; 34 of these sites were common to both studies.

The superiority of MIBG scintigraphy was also demonstrated in a study performed by Hadj-Djilani et al.76 in 27 patients with cortical bone metastases. Thirty-five sites of cortical bone metastasis were shown in eight patients by both MIBG and DPD, twelve sites in seven patients by MIBG only, and seven sites in five patients by DPD only. In 14 patients, both MIBG and bone scan were negative. However, in a study performed by Shulkin et al.73 in 77 patients, 131I-MIBG showed complete concordance with bone scanning for the presence or absence of skeletal lesions. In 60% of patients, the 99mTc-MDP accumulated into the primary tumors but there is no prognostic significance to this finding. Rarely, other primary tumors in childhood may accumulate the bone agent.

Somatostatin Analog Scintigraphy

In-111 Pentetreotide/octreotide

The role of In-111 pentetreotide/octreotide has been evaluated in the management of neuroblastoma because of the presence of somatostatin receptors (SSTR) 1 and 2. The presence of functioning SS receptors were demonstrated by studies in vitro77 and confirmed in vivo by tumor imaging with either 123I-Tyr-octreotide or 111In-pentetreotide.

Several clinical studies have compared MIBG with 111In-DTPA-octreotide scintigraphy to image neuroblastoma.78,79 The sensitivity of 111In-DTPA-octreotide scintigraphy ranged from 55% to 70% compared with 88% to 94% for MIBG scintigraphy. Imaging with somatostatin analogs is less sensitive than MIBG scans to detect neuroblastoma, probably because SSTR expression is downregulated in more aggressive tumors and is variable within the same tumor. 111In-DTPA-octreotide scintigraphy yields important prognostic information and it may be useful in negative-MIBG patient. Several studies have demonstrated that somatostatin receptor expression and/or positive 111In-Octreotide scan in these patients is associated with a more favorable clinical outcome.77,80 Briganti et al.81 have shown that high levels of SST2 receptor expression correlate with better survival, independent of N-Myc amplification. The 4-year survival probability is 95% in patient with positive somatostatin receptor imaging compared to 62% in negative patients. Juweid et al.82 compared In-111 pentetreotide scintigraphy and bone scan sensitivity and specificity in nine patients with neuroblastoma. 111In-octreotide scan showed a greater number of bone lesions (30 versus 7) with a sensitivity of 86%. Abnormalities detected on 111In-pentetreotide images are slightly different from those seen with MIBG, especially for bone marrow. 111In-pentetreotide imaging of neuroblast-derived tumors provided information different from and most likely complementary to that of MIBG. However, 111I-MIBG provides better images of the adrenal region (low kidney uptake) and, in many cases, of bone marrow metastases.

Other Radiotracers

Several analogs of MIBG have been synthesized for investigation of the sympathetic innervation of the heart and for neuroendocrine tumor imaging and therapy.

123I-amino Iodobenzylguanidine (AIBG)

123I-amino iodobenzylguanidine (AIBG) has demonstrated selective localization in organs rich with adrenergic innervation, such as the adrenal medulla with the same mechanism as 123I-MIBG in animal models. All areas of abnormal accumulation demonstrated on 123I-MIBG scintigraphy were identified by 123I-AIBG in three patients with pheochromocytoma.83 However, 123I-AIBG had lower blood clearance, greater background and in vivo deiodination greater than 123I-MIBG.

99mTc-sestamibi (99mTc-MIBI) Imaging

The role of 99mTc-sestamibi (99mTc-MIBI) in predicting the therapeutic response in patients with stage IV neuroblastoma has been studied by Burak et al.84 in nine patients. None of the primary lesions demonstrated significant 99mTc-MIBI accumulation. 99mTc-sestamibi was positive in 16 of 41 MIBG-avid metastatic lesions. Follow-up demonstrated that all lesions that were not 99mTc-MIBI avid at the time of diagnosis remained negative. Clinical evaluation of patients with no 99mTc-MIBI uptake in primary and secondary sites of neuroblastoma confirmed that they were resistant to multidrug chemotherapy. 99mTc-MIBI, a substrate for P-glycoprotein–related multidrug resistance, may provide prognostic information but it is not routinely used in clinical practice. Patients with negative scans have poor prognosis and progressive disease regardless of MIBG uptake with resistance to multidrug chemotherapy.

99mTc DMSA Imaging

Limouris et al.78 evaluated the clinical impact of 99mTc-(V)-DMSA in the management of neuronal crest tumor. In 7 patients with neuroblastoma, MIBG uptake was seen in 15 sites and 99mTc-(V)-DMSA only in 3 sites, demonstrating the lack of a significant role for 99mTc-(V)-DMSA in evaluation of patients with neuroblastoma.

Gallium-67 Imaging

Gallium-67 was shown to have a sensitivity of nearly 80% for detection of the primary tumor in 14 children with histopathologically confirmed neuroblastoma. Ga-67 citrate, however, did not visualize osseous metastases.85

Thallium-201 Imaging

Thallium-201 has been evaluated also in patients with neuroblastoma. The radiopharmaceutical has been widely used as a tumor imaging agent in adults with bone primary tumors such as lymphoma, brain tumors, thyroid carcinoma, and bone sarcomas. Howman-Giles et al.86 investigated the role of 201Tl scintigraphy in six patients with neuroblastoma and positive MIBG findings. Only three patients showed 201Tl uptake, demonstrating no role of 201Tl scintigraphy in neuroblastoma.


Radioimmunodetection of neuroblastoma was first demonstrated in the early 1980s with 131I-labeled UJ13, an IgG1 monoclonal antibody that recognizes the NCAM antigen on neuroectodermal tissue including neuroblastoma. Subsequent radioimmunologic attempts to enhance the detection of neuroblastoma in patients focused on the use of radiolabeled anti-GD2 monoclonal antibodies. In small studies, scintigraphy using the anti-GD2 IgG1 monoclonal antibody BW 575/9 labeled with 99mTc yielded mixed results: Good localization was noted in 2 of 3 patients,87 and, in a comparative analysis involving 7 patients, 5 of 26 lesions were missed by 123I-MIBG, and 8 lesions were undetected by immunoscintigraphy.88


Iodine-131-3F8, a murine IgG3 monoclonal antibody specific for the ganglioside GD2 was evaluated in 42 patients with stage III unresectable stage IV neuroblastoma.89 Preclinical studies have shown that GD2 is present in high concentrations in human neuroblastoma cells.90 In nude mice xenografted with human neuroblastoma, 131I or 125I-labeled 3F8 localized in the tumors with high uptake at 24 hours of 131I-3F8 imaging revealed radiotracers uptake suggestive of marrow involvement in 26 patients and detected more abnormal primary and metastatic sites than either 123I-MIBG or 99mTc-MDP bone scans. Two other monoclonal antibodies against neuroblastoma have been used to define tumor deposits. 131I-UJ 13A was found to localize in 15 sites of primary and metastatic lesions from nine patients with neuroblastoma. One false-positive and two false-negative localizations were reported. In two of the 15 positive sites, tumor had not been demonstrated by other imaging techniques.91 This IgG1 antibody was also used for target 131I therapy in four patients who failed other conventional treatments in a phase I study.92 Objective responses were obtained in one of the four patients. IgG1 monoclonal antibody BW 575/9 showed good tumor localization in seven children with neuroblastoma. The majority of tumor sites were detected by BW 575/9 and 123I-MIBG. However, 5 of 26 lesions were undetectable by 123I-MIBG and 8 were not detected by immunoscintigraphy.93

Despite evidence of high sensitivity for detection of tumor sites, radioimmunoscintigraphy has remained investigational, at least in part because of greater ease of use and improved accuracy with nonimmune scintigraphic modalities, primarily 123I-MIBG.

2-[fluorine-18]fluoro-2-deoxy-D-glucose (18FDG) PET Imaging

Positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (18FDG) is increasingly being used in the evaluation of pediatric oncology patients. The normal distribution and physiologic variants of 18FDG uptake in children can differ from those in adults. It is important that these differences be recognized so as to avoid misinterpretation. Although many of the normal variants in children are similar to those in adults, the normal distribution in children often differs in the visualization of lymphatic tissue in the Waldeyer ring, as well as in the ileocecal region, thymus, hematopoietic bone marrow, and skeletal growth centers. ­Diffuse and homogeneous uptake in the thymus is common in healthy children. Normal accumulation in bone marrow is generally homogeneous with more extensive distribution in children than in adults. Skeletally immature pediatric patients have physiologic linear uptake in physes and apophyses of bone structures.

The use of combined PET/CT reveals many normal variants with the precise localization of functional 18FDG PET data superimposed on conventional anatomic CT data. Administered activity in children and adolescent is 0.14 mCi/kg (approximately 5 MBq/kg) (equivalent to 10 mCi [370 MBq] in an adult). The effective dose from this administered activity varies from 500 mrem (5 mSv) in a 1 year old to 860 mrem (8.6 mSv) in a 15 year old. The organ receiving the highest absorbed radiation dose (target organ) is the bladder.94

18FDG PET has potential in the staging, response assessment and detection of recurrence in neuroblastoma but it does not replace standard imaging modalities in newly diagnosed patients.95 Preclinical models have failed to verify any association between 18F-FDG and neuroblastoma proliferation.96 Higher spatial resolution of PET imaging compared to single photon scintigraphy with 123I-MIBG identifies small lesions (e g., foci in lymph node or vertebral bodies) and localization the anatomic sites of disease. Kushner et al.97 demonstrated that in high-risk NB patients, PET findings correlated well with disease status determined by standard imaging modalities, BM tests, urine VMA and HVA levels, and clinical history. In clinical practice, 18F-FDG activity is associated with more aggressive disease and has been shown to predict worse outcome.98

18FDG PET/CT plays an important role in the management of the small proportion of patients (less than 10%) who do not accumulate 123I-MIBG.99 Indeed, in cases in which it is suspected that the extent of disease exceeds that depicted with 123I-MIBG, 18FDG PET/CT is useful. In general, 18F-FDG is less sensitive than 123I-MIBG for detection of neuroblastoma, especially when evaluating high-risk patients or relapsed disease. In a retrospective study, Sharp et al.100 compared the diagnostic utility of 18F-FDG and 123I-MIBG scintigraphy in 60 patients underwent to a total of 113 paired scans. 18F-FDG was found to be superior to depict stage I and II neuroblastoma. 18F-FDG also gave important information prior to stem cell transplantation, depicting residual disease not seen with 123I-MIBG in some patients. 123I-MIBG scanning was superior to 18F-FDG PET in the evaluation of stage IV neuroblastoma, especially during initial chemotherapy, primarily because of the better detection of bone or marrow metastases.

By contrast, Kushner et al.98 found 18F-FDG PET equal or superior to 123I-MIBG scanning to identify neuroblastoma in soft tissue and extracranial skeletal structures and to delineate the extent and localize sites of disease. In the study, 18F-FDG PET findings correlated with disease status determined by standard imaging modalities, BM tests, urine VMA and HVA levels, and clinical history. The major drawback of 18FDG PET was the lack of visualization of lesions in the cranial vault because of the normally high physiologic brain activity. 18FDG PET/CT may detect localization to the liver where the intense accumulation of MIBG interferes with an accurate diagnosis.

18F-FDG may exhibit accumulation in the activated bone marrow caused by previous therapies, reducing the accuracy to detect disease,101 but it shows more osteomedullary abnormalities than bone scans. However, 18FDG PET and 123I-MIBG scans show similar patterns of diffusely abnormal skeletal findings in patients with extensive bone marrow involvement, but neither imaging modality reliably detects minimal bone marrow disease. Taggart et al.67compared the role of 18F-FDG to 123I-MIBG scan in 21 patients who underwent 131I-MIBG therapy. Complete response by FDG PET ­metabolic evaluation did not always correlate with complete response by MIBG uptake. MIBG was usually more sensitive for disease detection, except in MIBG-negative patients and some soft tissue lesions. However, 18FDG-PET can identify disease in MIBG-negative lesions, it serves as a complementary imaging modality in selected patients. Larger prospective studies of FDG PET at diagnosis, during, and after therapy correlated with survival would help to determine the relative utility of these modalities.

FIGURE 23.4. FDG PET (A) MIP image and 123I-MIBG scintigraphy, (B) anterior view, (C) posterior view carried out during therapy in a little patient with a bony secondary lesion in the right pelvis. FDG PET-CT was able to early assess the response to therapy in comparison to 123I-MIBG scintigraphy (arrows indicate persistent pathologic uptake).

18F-FDG PET-CT has not had a significant clinical impact on the evaluation of therapy response in patients with low baseline uptake. Conversely, in patients with moderate–high FDG accumulation this modality has a high accuracy for response assessment, also providing important prognostic information (Fig. 23.4).102 18F-FDG PET has been shown to be inferior to 123I-MIBG in the evaluation of skull lesions, except in case of considerable soft tissue component99 because of the physiologic high FDG uptake in the brain.

Papathanasiou et al.103 compared the diagnostic performance of 18F-FDG PET/CT with 123I-MIBG imaging in 28 patients with refractory or relapsed high-risk neuroblastoma. 123I-MIBG imaging is superior to 18F-FDG PET/CT for the assessment of disease extent in high-risk neuroblastoma. However, 18F-FDG PET/CT has significant prognostic implications in these patients. MIBG remains the first-line imaging agent for neuroblastoma, even though 18FDG PET plays an important complementary role. In fact 18F-FDG PET scan may be useful in the event of discrepant or inconclusive findings on 123I-MIBG scintigraphy/SPECT and morphologic imaging.

18F-Fluoro-L-dihydroxyphenylalanine (DOPA) PET

18F-Fluoro-L-dihydroxyphenylalanine (DOPA) PET is a promising imaging modality for the diagnostic workup of patients with neuroblastoma (Fig. 23.5), especially in advanced stages of disease. DOPA is an amino acid that is internalized by the LAT2 amino acid transporter. DOPA is an intermediate in the catecholamine synthesis pathway produced after hydroxylation of the amino acid tyrosine, which enters the cell. DOPA may also be derived from phenylalanine, another essential amino acid. DOPA can be decarboxylated to dopamine by amino acid decarboxylase (AADC). It can also be converted by catechol-O-methyltransferase to 3,4-dihydroxyphenylacetic acid. The affinity of radioactive 18F-DOPA for catechol-O-methyltransferase metabolization appears to be low compared with the affinity for AADC conversion. The enzyme AADC is strongly expressed in neuroendocrine cells. Like other tyrosine-based tracers, such as 11C-tyrosine, 18F-ethyltyrosine, 123I-methyltyrosine, and other analogs, 18F-DOPA enters cells through the amino acid transport systems for large neutral amino acids, which are present in nearly all cells. 18F-DOPA is metabolized by the AADC enzyme activity present in many tissues, including the liver and especially the kidneys. Radiolabeled metabolites include 3-O-methyl-18F-DOPA, 6-18F-fluorodopamine, l-3,4-dihydroxy-6-18F-fluorophenylacetic acid, and 8-18F-fluorohomovanillic acid. The radiopharmaceutical identifies the increased activity of L-DOPA decarboxylase found in malignant neural crest tumors. The normal findings include high activity in the urinary excretion systems, including the collecting systems in the kidneys, ureters, and bladder. Intermediate and/or low activity levels are found in the striatum, myocardium, and liver. In general, low-level activity can be observed in the small intestine and peripheral muscles. In children, some uptake in the growth plates can be seen. Carbidopa is routinely used in 18F-DOPA imaging in neurology because it increases striatal uptake, mainly by increasing the concentration in plasma and decreasing renal excretion. After carbidopa premedications, liver uptake increased slightly, and pancreatic uptake decreased considerably. Tumor uptake increased markedly, with standardized uptake values (SUVs) increasing 10% to 30%. These effects clearly improved the overall image quality and resulted in the detection of more lesions.

Carbidopa premedication in the pediatric population appears feasible and seems to influence 18F-DOPA distribution in the liver and pancreas in a manner similar to that reported in adults.104 Usually whole-body 18F-DOPA PET/CT is carried out 60 minutes after the injection of 210 to 370 MBq of tracer (4 MBq/kg). 18F-Fluoro-L-DOPA PET/CT shows high overall accuracy and sensitivity, representing an alternative approach to 123I-MIBG scan (Fig. 23.6). Piccardo et al.105 evaluated the role of 18F-DOPA PET/CT in stage III–IV neuroblastoma, comparing its diagnostic value with that of 123I-MIBG scintigraphy. In a prospective study, they evaluated 28 paired 123I-MIBG and 18F-DOPA PET/CT scans in 19 patients: 4 at the time of the NB diagnosis and 15 when NB relapse was suspected. No significant difference in terms of specificity was found. 18F-DOPA PET/CT showed a sensitivity and accuracy of 95% and 96%, respectively, whereas 123I-MIBG scanning showed a sensitivity and accuracy of 68% and 64%, respectively.

FIGURE 23.5. 18F-DOPA PET-CT (A) CT axial cut, (B) PET axial cut, (C) fusion axial cut, (D) MIP image carried out to stage a little patient affected by neuroblastoma. Arrows indicate the primary left paraspinal lesion highly accumulating 18F-DOPA. No metastasis were detected.

Lopci et al.106 have demonstrated that PET/CT with L-DOPA has higher sensitivity (100% versus 91%) and specificity (92% versus 61%) compared to CT/MR in advanced stage neuroblastoma. In this study a total of 21 patients had 37 paired 18F-DOPA PET and CT/MR scans (4 at staging, 30 at restaging, and 3 during follow-up) with a maximum elapsed time for the different imaging procedures less than 1 month. 8F-DOPA PET was false positive in one case at end-treatment evaluation. There were no false-negative scans. Conventional imaging with CT/MR resulted in false-negative findings in two cases and false positive in five cases. As for identification of the primary tumor, the sensitivity of 18F-DOPA PET/CT and CT/MR were identical. Conventional imaging showed higher sensitivity than 18F-DOPA PET/CT for liver lesions (100% versus 63%). 18F-Fluoro-L-DOPA PET changed patient management in 32% of the cases. It has an advantage in identifying locoregional soft tissue recurrence compared to 123I-MIBG scan. However, no significant difference in the evaluation of bone marrow involvement has been found.

68Ga-(DOTA-D-Phe[1]-Tyr[3]-octreotide) (DOTA-TOC) PET

68Ga-(DOTA-D-Phe[1]-Tyr[3]-octreotide)(DOTA-TOC) PET has higher sensitivity than In-111 pentetreotide scintigraphy.107 It gives valuable information on tumor cell receptor status when planning ­peptide receptor radionuclide therapy. Kroiss et al. evaluated the role of 68Ga-DOTA-TOC in five patients, comparing the accuracy of 123I-MIBG imaging with PET in the diagnosis and staging of metastatic neuroblastoma. In neuroblastoma patients, on a per-lesion basis, the sensitivity of 68Ga-DOTA-TOC was 97.2% and that of 123I-MIBG was 90.7%. Furthermore, 68Ga-DOTA-TOC PET identified 257 lesions, anatomic imaging identified 216 lesions, and 123I-MIBG identified only 184 lesions. The relatively small number of patients and the lack of follow-up imaging procedures make it difficult to identify possible false-positive findings. Further studies are n­ecessary to determine the effective role of SRS radiotracers in ­neuroblastoma.

C-11 Hydroxyephedrine (11C-HED) PET

In a preliminary study, Shulkin et al.107 evaluated the use of C-11 hydroxyephedrine (11C-HED) PET in seven patients with known or subsequently confirmed neuroblastoma to stage disease. HED contains an α-methyl group that prevents metabolism by monamine oxidase and persists in the cytosol without vesicular storage. Radiotracer retention is primarily because of the reuptake mechanism, reflecting the functional integrity of the sympathetic neurons. 11C-HED imaging was obtained immediately after the injection of 185 MBq of radiopharmaceutical and continued for 30 minutes. PET scanning detected neuroblastoma lesion in all seven patients. Hepatic and renal uptake were prominent early but declined progressively. Tumors were clearly detected within minutes after tracer injection. Tumor-to-liver accumulation is optimal 30 minutes after injection principally because of hepatic clearance. Further studies are necessary to correctly determine the effective role of this radiopharmaceutical.

FIGURE 23.6. 18F-DOPA PET-CT (A) fusion axial cut, (B) MIP image, (C) fusion axial cut, (D) MIP image carried out before therapy (A,B) and after chemotherapy (C,D) in a little patient affected by abdominal neuroblastoma (arrows ). It is important to notice that the primary lesion highly accumulated 18F-DOPA before therapy but, despite a clear decrease in the uptake, a complete normalization was not obtained after therapy, indicating only a partial response.

4-18F-fluoro-3-iodobenzylguanidine (18F-FIBG)

18F-fluorobenzylguanidine, an MIBG analog, was tested in preclinical studies.109 Localization in the heart and adrenals in vivo was demonstrated, however, with significantly lower levels than observed with MIBG. 4-18F-fluoro-3-iodobenzylguanidine (18F-FIBG) has shown similar uptake mechanism and tissue distribution pattern as MIBG in preclinical model with acceptable dosimetry for administration to patients.110

124I-MIBG Using PET

124I is an emerging radionuclide for PET imaging, presenting several advantages in terms of image quantification, secondary to the 124I half-life of 4.2 days which is closer to 8.02 days half-life of 131I than many other PET radiopharmaceuticals and whole-body PET acquisition. 124I-MIBG PET/CT was evaluated in an animal model to define the radiation dose estimation, as well as imaging tumors prior to 131I-MIBG treatment of neuroblastoma. Lee et al.111 estimated the human-equivalent internal radiation dose of 124I-MIBG using PET/CT data in a murine xenograft model. They found that 124I-MIBG PET is a useful tracer for pretherapy dosimetry, delivering a significantly smaller radiation dose than 124I-NaI. However 124I-MIBG has not been systematically studied in human subjects. 124I-MIBG has been used for dosimetric purposes by Ott et al.112 in two NET patients (1 neuroblastoma, 1 pheochromocytoma) before receiving 131I-MIBG therapy. Two patients were injected with 22 and 40 MBq of 124I-MIBG, respectively, and scanned at 24 and 48 hours postinjection. The tomographic images produced were used to estimate the concentration of MlBG in normal and tumor tissue. This data permitted prediction of the radiation doses that would be achieved using therapeutic doses of 131I-MIBG. No other clinical data has been reported.


Radionuclide therapy with 131I-MIBG has been used for targeted radiotherapy since the mid-1980s. MIBG has a specific tissue uptake and has prolonged intracellular retention compared with normal tissues. 131I-MIBG therapy remains controversial because of a large variation in response rates in the published literature and the potential side effects. Response rates vary between 20% and 60% in newly diagnosed and relapsed or refractory patients. The application of 131I-MIBG therapy has been extensively reported in adults with pheochromocytoma and carcinoid tumors but in pediatric patients, it has been mainly used to treat neuroblastoma. The most frequent application of 131I-MIBG in neuroblastoma is as single agent therapy in patients with metastatic neuroblastoma who have failed to respond to conventional chemotherapy or have recurrent relapsed disease after all other treatments have failed.

Clinical trials conducted with high-dose 131I-MIBG used as monotherapy or in combination with other agents for relapsed or refractory high-risk neuroblastoma have demonstrated promising response rates. Relatively few data describe the clearance of radiolabeled MIBG in children with neuroblastoma. In one study, six children with neuroblastoma received 100 to 200 mCi of 131I-MIBG and had urinary MIBG levels measured following the infusion.113 A median of 57% and 70% of the administered dose was excreted in the urine by 24 and 48 hours postinfusion, respectively. Ehninger et al.114 confirmed that 70% of the administered dose is excreted in the urine by 48 hours postinfusion. The earliest studies of 131I-MIBG therapy for patients with neuroblastoma focused mainly on the toxicity and feasibility of this approach. Thrombocytopenia was the most prominent toxicity.

Three phase I dose escalation studies of 131I-MIBG monotherapy in patients with neuroblastoma have been performed. In the first study, 14 patients with relapsed or refractory neuroblastoma received 131I-MIBG at doses escalating from 50 to 220 mCi115 with a minor response in 3 patients. Another phase I study in patients with refractory stage III or IV neuroblastoma were performed by Ashford et al.,116 showing objective response rate in 33% of the cases. In the third phase I study, 30 patients with relapsed or refractory neuroblastoma received 131I-MIBG at escalating doses from 2.6 to 18.2 mCi/kg (90 to 819 mCi).117 Dose-limiting hematologic toxicity was reached at 15 mCi/kg, at which level two of five assessable patients required bone marrow reinfusion. Responses were seen in 37% of patients, with 1 complete response (CR), 10 partial response (PR), 3 mixed response, 10 stable disease, and 6 progressive disease. The minimum dose of 131I-MIBG for 10 of the 11 responders was 12 mCi/kg.

A phase II study performed in 164 patients treated with 131I-MIBG at a dose of 18 mCi/kg showed overall response rate of 36% and stable disease in 34% of the cases. A Dutch phase II study evaluated 100 to 200 mCi of 131I-MIBG in 53 patients with relapsed or refractory neuroblastoma118 showing an objective response rate of 56%, including 7 complete responses. Only nine patients had progressive disease as their best response to therapy. Multiple treatments with 131I-MIBG demonstrated that the majority of the clinical benefit with 131I-MIBG therapy occurs after the first cycle of therapy, although additional responses may be observed with subsequent cycles.

In this setting, Howard et al.119 determined the response rate and hematologic toxicity of multiple infusions (two to four cycles) of 131I-MIBG with activity of 3 to 19 mCi/kg per infusion in 28 patients. Eleven patients (39%) had overall disease response to multiple therapies, including eight patients with measurable responses to each of two or three infusions, and three with a partial response (PR) after the first infusion and stable disease after the second. The main toxicity was myelosuppression, with 78% and 82% of patients requiring platelet transfusion support after the first and second infusion. Several groups have evaluated this agent in combination with other active agents for neuroblastoma. Mastrangelo et al.120 evaluated combination therapy with cisplatin and cyclophosphamide with or without etoposide and vincristine in 16 patients with relapsed or refractory neuroblastoma. The response rate with this combination therapy compares favorably with response rates of <40% observed with 131I-MIBG monotherapy.

Gaze et al.121 evaluated 131I-MIBG together with the camptothecin topotecan. Like cisplatin, topotecan is an active drug against neuroblastoma with radiation sensitizing properties. This combination was well-tolerated and without unanticipated toxicities. Response data were not provided from this pilot study. Hyperbaric oxygen has been used to enhance the radiation effect in children undergoing 131I-MIBG therapy. Voute et al.122 reported the cumulative probability of survival as 32% at 28 months for the group with hyperbaric oxygen and MIBG treatment.

No further significant data have been reported to support this treatment method. 131I-MIBG in combination with myeloablative regimens were investigated, demonstrating improved outcomes for newly diagnosed patients with advanced neuroblastoma. 131I-MIBG has been added to myeloablative chemotherapy in combination, or without radiotherapy. This is often supported by autologous bone marrow transplantation (ABMT) or peripheral stem cell infusion. Toxicity consisted mainly of expected myelosuppression and mucositis. The majority of patients had bone marrow recovery demonstrating the feasibility of incorporating 131I-MIBG into a myeloablative regimen.123 Several studies have incorporated this agent into the treatment of patients with newly diagnosed neuroblastoma, obtaining objective response rate in 66% of the cases. Preoperative 131I-MIBG therapy in children with advanced or inoperable neuroblastoma has the objective of reducing tumor volume, enabling better tumor resection.

De Kraker et al.124 treated 33 patients with untreated advanced stage neuroblastoma. There was one complete response (CR), 18 partial responses (PR), 11 had stable disease (SD), and 3 had progressive disease (PD). After 131I-MIBG therapy and surgery, 12 of 33 patients achieved a CR. Hoefnagel125 reported a higher objective response (>70%) and less toxicity with this method compared with initial chemotherapy followed by 131I-MIBG therapy. Recent data has shown that combined 131I-MIBG and 90Y-DOTA-TOC can significantly increase the delivered tumor dose over the dose of either agent alone.126 Low recurrent doses of 131I-MIBG have been evaluated, limiting toxicity. Activities from 0.5 mCi (18.5MBq)/kg to a maximum of 25 mCi (925 MBq) were administered every 4 to 6 weeks and continued until efficacy was not seen, resulting in an excellent palliative effect.

Dosimetry has been evaluated in therapeutic 131I-MIBG studies for several indications, such as to estimate tumor-specific radiation dose following 131I-MIBG therapy or to determine organ-specific doses. Hematologic toxicity, most notably thrombocytopenia, has been reported as the main toxicity in nearly all studies of 131I-MIBG therapy. Primary hypothyroidism appears to develop in a significant number of patients with neuroblastoma treated with 131I-MIBG because of the uptake of free 131I by the thyroid gland. Second malignancies following 131I-MIBG therapy have been reported.


To avoid radioiodine uptake in the thyroid gland, high amounts of potassium iodide should be administered, starting 12 to 24 hours before therapy and continuing for 2 to 4 weeks. Alternatively, or in addition, perchlorate can be administered, starting 4 to 12 hours before 131I-MIBG administration, and continuing daily for 1 week. An increase of blood pressure after 131I-MIBG administration is not as common as during treatment of pheochromocytomas or paragangliomas, nevertheless, antihypertensive medication should be available, particularly α-blockers. Recommendations concerning the optimal therapeutic 131I-MIBG dosage differ widely; between 450 and 1850 MBq/kg (particularly if autologous stem-cell rescue is included in the therapeutic regimens) or standard activities of 7 GBq. Other institutions use 3.7 to 14.8 GBq/m2.

In case of existing bone marrow suppression or reduced renal function, a dose reduction should be considered. 131I-MIBG should be infused over a period of at least 1 hour to avoid severe acute side effects of the 131I-MIBG itself, mainly blood pressure changes. Scintigraphy using the γ-energy of 131I is performed during subsequent days for staging with high sensitivity, determination of 131I-MIBG-positive tumor sites, and dosimetry, if acquired quantitatively.

Blood count controls are necessary during the first 6 weeks; the time intervals dependent on the administered dose. Myelosuppression occurs within 2 to 4 weeks after therapy, the nadir is observed typically after 4 to 6 weeks. Rarer side effects are impairment of renal function and hypothyroidism, particularly in case of insufficient thyroid blockade. Hepatic failure has to be considered also when higher doses are administered.

125I-MIBG may be an even better treatment option for neuroblastomas with micrometastases or bone marrow infiltration and is being tested for the treatment of patients with expected survival of less than 15%. A recent study127found that the overall treatment response rate (46%) was high for all patients, older patient with neuroblastoma had a significantly higher treatment response rate and exhibited a trend toward longer posttreatment overall survival, indicating that 131I-MIBG might be an effective salvage agent for neuroblastoma in this difficult to treat patient population.


Various radiolabeled antibodies have been assessed for therapy. These include the anti-GD2 antibody (131I-3F8) which shows excellent targeting in neuroblastoma. In data from the Memorial Sloan Kettering128 using 131I-3F8, the overall survival at 18 months posttherapy was approximately 40%. The antibody localized in the primary tumor and metastatic sites in lymph nodes, bone marrow, and bone in 42 patients. Severe side effects may be associated with this therapy. Induction of HAMA response limits this therapy.

Other antibodies (e.g., 131I-Ch14.18) are being assessed for radioimmunotherapy in neuroblastoma. Initial results are encouraging. Severe myelosuppression frequently occurs and requires autologous bone marrow rescue or treatment with granulocyte macrophage colony stimulating factor. The initial results have been sufficiently promising that the addition of Ch14.18 antibody to standard therapy is being tested in a prospective, randomized trial ANBL0032.

Benzylguanidine labeled with 211At, an α-particle emitter, has also been proposed as a potential radiotherapeutic agent in neuroblastoma.129 Meta-[211At]astatobenzylguanidine ([211At]MABG) is an astatinated analog of MIBG has been tested in animal model, but no clinical applications has evolved.

NB expressing somatostatin receptors may be also targeted by peptide receptor radionuclide therapy (PRRT). The radiopharmaceuticals most commonly used in PRRT are 90Y-DOTA-TOC and 177Lu-DOTA0-Tyr3-Thre8-octreotide. In a phase I study, Menda et al.130 evaluated the role 90Y-DOTA-TOC in children and young adults with somatostatin receptor–positive tumors. The dose-toxicity profile was determined in 17 patients, with administered activities of 1.11, 1.48, and 1.85 GBq/m2/cycle given in 3 cycles at 6-week intervals. No dose-limiting toxicities were noted. Stable disease was achieved in one patient and one withdrew. Phase II trials are needed to establish the effective role of PRRT in patients with neuroblastoma.


NB, the most common solid extracranial malignancy in childhood, is a heterogeneous disease, consisting of neural crest-derived tumors with remarkably different clinical behaviors ranging from spontaneous remission to rapid tumor progression. This clinical diversity correlates with numerous clinical and biologic ­factors, including tumor stage, patient age, tumor histology, and genetic abnormalities. However, the molecular basis underlying the variability in tumor growth, clinical behavior, and responsiveness to therapy remains largely unknown. Thus, multidisciplinary approaches to diagnosis and therapy have been undertaken for all patients to assess risk. Proper tumor staging is of fundamental importance for selection of optimal treatment. This includes bone marrow aspirations and biopsies, CT, magnetic resonance imaging, radionuclide bone scan, and MIBG scintigraphy. Likewise, it is imperative to assess tumor response to therapy and detection of recurrent disease to optimize treatment of residual disease and improve patient survival. Nuclear medicine plays a pivotal role in the management of children and adolescent with neuroblastoma, offering a wide spectrum of imaging modalities. The clinical role of iodine-labeled MIBG, tracing catecholamine metabolism, is well established for several decades. 123I-MIBG scan is the gold standard for initial staging of neuroblastoma as well as for response evaluation and during follow-up. PET/CT imaging with 18F-FDG is a useful adjunct to conventional imaging in the initial staging and restaging of in selected patient with neuroblastoma. The current primary role of 18FDG PET is the evaluation of known or suspected neuroblastomas that do not demonstrate radioiodinated MIBG uptake, but the published experience on neuroblastoma is limited. Other PET radiotracers such as 18F-DOPA and 124I-MIBG are currently being evaluated in these patients and show promising results. Further clinical trials are needed, however, to confirm the preliminary data.

Radiometabolic therapy with 131I-MIBG has proven to be effective in advanced neuroblastoma. Despite a high variability in administered activities, therapeutic combinations, and outcome, several studies have demonstrated that 131I-MIBG therapy is an effective and safe treatment modality. The combination of 131I-MIBG, high-dose chemotherapy, autologous hematopoietic stem cell transplantation is a promising approach, associated with limited toxicity. Clinical studies on potential improvement of the therapeutic effect of 131I-MIBG are under investigation. Further advances in understanding of the molecular biology of neuroblastoma, proper risk stratification and appropriate therapy based on risk assessment may improve the clinical outcome, in terms of event-free and tumor-free survival which has not dramatically changed over the last years.


The authors would like to thank Dr. Massimino Maura, Dr. Podda Marta (Department of Pediatrics, Fondazione IRCSS, Istituto Nazionale dei Tumori, Milan, Italy), and Professor Stefano Fanti (Nuclear Medicine Department, Policlinico S. Orsola-Malpighi, Bologna, Italy) for reviewing the manuscript and for their scientific contribution.


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