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The Cochrane Database of Systematic Reviews
 
Cochrane Database Syst Rev. 2015 September 29; (9): CD009263.
PMCID: PMC4621955

123I-Mibg scintigraphy and 18F-Fdg-Pet imaging for diagnosing neuroblastoma

Abstract

Background

Neuroblastoma is an embryonic tumour of childhood that originates in the neural crest. It is the second most common extracranial malignant solid tumour of childhood.

Neuroblastoma cells have the unique capacity to accumulate Iodine-123-metaiodobenzylguanidine (123I-MIBG), which can be used for imaging the tumour. Moreover, 123I-MIBG scintigraphy is not only important for the diagnosis of neuroblastoma, but also for staging and localization of skeletal lesions. If these are present, MIBG follow-up scans are used to assess the patient's response to therapy. However, the sensitivity and specificity of 123I-MIBG scintigraphy to detect neuroblastoma varies according to the literature.

Prognosis, treatment and response to therapy of patients with neuroblastoma are currently based on extension scoring of 123I-MIBG scans. Due to its clinical use and importance, it is necessary to determine the exact diagnostic accuracy of 123I-MIBG scintigraphy. In case the tumour is not MIBG avid, fluorine-18-fluorodeoxy-glucose (18F-FDG) positron emission tomography (PET) is often used and the diagnostic accuracy of this test should also be assessed.

Objectives

Primary objectives:

1.1 To determine the diagnostic accuracy of 123I-MIBG (single photon emission computed tomography (SPECT), with or without computed tomography (CT)) scintigraphy for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.

1.2 To determine the diagnostic accuracy of negative 123I-MIBG scintigraphy in combination with 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old, i.e. an add-on test.

Secondary objectives:

2.1 To determine the diagnostic accuracy of 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.

2.2 To compare the diagnostic accuracy of 123I-MIBG (SPECT-CT) and 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. This was performed within and between included studies. 123I-MIBG (SPECT-CT) scintigraphy was the comparator test in this case.

Search methods

We searched the databases of MEDLINE/PubMed (1945 to 11 September 2012) and EMBASE/Ovid (1980 to 11 September 2012) for potentially relevant articles. Also we checked the reference lists of relevant articles and review articles, scanned conference proceedings and searched for unpublished studies by contacting researchers involved in this area.

Selection criteria

We included studies of a cross-sectional design or cases series of proven neuroblastoma, either retrospective or prospective, if they compared the results of 123I-MIBG (SPECT-CT) scintigraphy or 18F-FDG-PET(-CT) imaging, or both, with the reference standards or with each other. Studies had to be primary diagnostic and report on children aged between 0 to 18 years old with a neuroblastoma of any stage at first diagnosis or at recurrence.

Data collection and analysis

One review author performed the initial screening of identified references. Two review authors independently performed the study selection, extracted data and assessed the methodological quality.

We used data from two-by-two tables, describing at least the number of patients with a true positive test and the number of patients with a false negative test, to calculate the sensitivity, and if possible, the specificity for each included study.

If possible, we generated forest plots showing estimates of sensitivity and specificity together with 95% confidence intervals.

Main results

Eleven studies met the inclusion criteria. Ten studies reported data on patient level: the scan was positive or negative. One study reported on all single lesions (lesion level). The sensitivity of 123I-MIBG (SPECT-CT) scintigraphy (objective 1.1), determined in 608 of 621 eligible patients included in the 11 studies, varied from 67% to 100%. One study, that reported on a lesion level, provided data to calculate the specificity: 68% in 115 lesions in 22 patients. The sensitivity of 123I-MIBG scintigraphy for detecting metastases separately from the primary tumour in patients with all neuroblastoma stages ranged from 79% to 100% in three studies and the specificity ranged from 33% to 89% for two of these studies.

One study reported on the diagnostic accuracy of 18F-FDG-PET(-CT) imaging (add-on test) in patients with negative 123I-MIBG scintigraphy (objective 1.2). Two of the 24 eligible patients with proven neuroblastoma had a negative 123I-MIBG scan and a positive 18F-FDG-PET(-CT) scan.

The sensitivity of 18F-FDG-PET(-CT) imaging as a single diagnostic test (objective 2.1) and compared to 123I-MIBG (SPECT-CT) (objective 2.2) was only reported in one study. The sensitivity of 18F-FDG-PET(-CT) imaging was 100% versus 92% of 123I-MIBG (SPECT-CT) scintigraphy. We could not calculate the specificity for both modalities.

Authors' conclusions

The reported sensitivities of 123-I MIBG scintigraphy for the detection of neuroblastoma and its metastases ranged from 67 to 100% in patients with histologically proven neuroblastoma.

Only one study in this review reported on false positive findings. It is important to keep in mind that false positive findings can occur. For example, physiological uptake should be ruled out, by using SPECT-CT scans, although more research is needed before definitive conclusions can be made.

As described both in the literature and in this review, in about 10% of the patients with histologically proven neuroblastoma the tumour does not accumulate 123I-MIBG (false negative results). For these patients, it is advisable to perform an additional test for staging and assess response to therapy. Additional tests might for example be 18F-FDG-PET(-CT), but to be certain of its clinical value, more evidence is needed.

The diagnostic accuracy of 18F-FDG-PET(-CT) imaging in case of a negative 123I-MIBG scintigraphy could not be calculated, because only very limited data were available. Also the detection of the diagnostic accuracy of index test 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma tumour and its metastases, and to compare this to comparator test 123I-MIBG (SPECT-CT) scintigraphy, could not be calculated because of the limited available data at time of this search.

At the start of this project, we did not expect to find only very limited data on specificity. We now consider it would have been more appropriate to use the term "the sensitivity to assess the presence of neuroblastoma" instead of "diagnostic accuracy" for the objectives.

PLAIN LANGUAGE SUMMARY

123I-MIBG- and 18F-FDG-PET-imaging, two nuclear imaging methods for diagnosing neuroblastoma tumours

Background and rationale

Neuroblastoma is a childhood tumour that can be visualized by a specific nuclear imaging compound, called metaiodobenzylguanidine (123I -MIBG). 123I-MIBG-imaging is not only important for the diagnosis of neuroblastoma, but also for localization of metastases (spread of the disease to other organs). Sometimes, the neuroblastoma does not take up 123I-MIBG and as a result the neuroblastoma is not visible on the scan. In that case, another type of nuclear imaging might be useful to visualize the neuroblastoma: fluoro-deoxy-glucose – positron emission tomography (18F-FDG-PET)-imaging.

In the literature the ability to discriminate between neuroblastoma and non-neuroblastoma lesions for these two types of nuclear imaging methods vary.

Prognosis, treatment and response to therapy of patients with neuroblastoma are currently based on scoring the amount of metastases per body segment visible on 123I-MIBG scans. Therefore, it is important to determine the exact ability to discriminate between neuroblastoma and non-neuroblastoma on 123I-MIBG-imaging and 18F-FDG-PET-imaging. We reviewed the evidence about the accuracy of 123I-MIBG-imaging and 18F-FDG-PET-imaging for the detection of a neuroblastoma in children suspected of this disease.

Study characteristics

We searched scientific databases for clinical studies comparing 123I-MIBG or 18F-FDG-PET imaging, or both, with microscopic examination of tissue suspected of neuroblastoma (histopathology). The evidence is current up to 11 September 2012.

We identified 11 eligible studies including 621 children that fulfilled our inclusion criteria: children < 18 years old with a neuroblastoma and 123I-MIBG or 18F-FDG-PET imaging or both.

All studies included proven neuroblastoma.

Quality of the evidence

All 11 included studies had methodological limitations. Only one included study provided data on specificity (the ability of a test to correctly classify an individual as 'disease-free') and therefore we could not perform all of the planned analyses.

Key results

When compared to histopathological results the sensitivity (the ability of a test to correctly classify an individual person as 'diseased') of 123I-MIBG imaging varied from 67% to 100% in patients with histologically proven neuroblastoma. This means that in 100 children with proven neuroblastoma 123I-MIBG imaging will correctly identify 67 to 100 of the neuroblastoma cases. Only one study, that reported on a lesion level, provided data to calculate the specificity (the ability of a test to correctly classify an individual as 'disease-free'): 68% in 115 lesions. This means that of 100 disease-free lesions in patients with proven neuroblastoma 123I-MIBG imaging will correctly identify 68 lesions. So, in about 10% of the cases the neuroblastoma is not visible on 123I-MIBG imaging (false negative results). For these cases, it is advisable to perform an additional test like 18F-FDG-PET imaging, but to be certain of its clinical value, more evidence is needed.

Only one included study reported on false positive findings. This means that 123I-MIBG imaging and 18F-FDG-PET imaging incorrectly identified neuroblastoma lesions in patients which might result in wrongly classifying a patient with metastatic disease. It is important to keep in mind that false positive findings can occur, although more research is needed before definitive conclusions can be made.

We could not determine the diagnostic accuracy of 18F-FDG-PET imaging, in case the neuroblastoma was incorrectly not identified with 123I-MIBG, due to limited data. Also, we could not calculate the diagnostic accuracy of 18F-FDG-PET imaging for detecting a neuroblastoma and compare this to 123I-MIBG imaging because of the limited available data.

Background

Target condition being diagnosed

Neuroblastoma is an embryonic tumour of childhood that originates in the neural crest. It is the second most common extracranial malignant solid tumour of childhood and the most common solid tumour of infancy (Brodeur 2003; Castleberry 1997; Park 2008). It accounts for 7% of all childhood cancers and for approximately 15% of cancer deaths in children (Castleberry 1997; Maris 2007; Park 2008; Spix 2006). A neuroblastoma might arise anywhere along the sympathetic nervous system (side chain), but is found most frequently in the abdomen (65%). Half of the neuroblastomas arise from the adrenal glands. Other common sites are the neck, chest and pelvis (Maris 2007; Maris 2010; Park 2008). They particularly occur in children at a young age, with a median age at diagnosis of 17 months (Maris 2010). Around 50% of patients present with disseminated disease at the time of diagnosis (Maris 2007; Maris 2010). Dissemination occurs through lymphatic and hematogenous routes, with involvement of bone, bone marrow and liver (Maris 2007; Maris 2010).

Neuroblastoma is staged according to the International Neuroblastoma Staging System (INSS) (Table 1) (Brodeur 1988b; Brodeur 1993). Stage 1 or 2 neuroblastoma is localised, stage 3 neuroblastoma consists of regional disease and stage 4 neuroblastoma is marked by distant metastases. A unique pattern of dissemination, limited to the liver, skin and less than 10% of bone marrow in children younger than one year old is defined as stage 4S, which has a potential for spontaneous regression (Brodeur 1988b; Brodeur 1993). The INSS system is a postsurgical staging system and therefore the International Neuroblastoma Risk Group (INRG) published a new clinical staging system in 2008: the INRG classification system (Table 2) (Monclair 2009).

Table 1
International Neuroblastoma Staging System (INSS)
Table 2
International Neuroblastoma Risk Group Staging System

The clinical course in patients with a neuroblastoma varies enormously, ranging from spontaneous regression to rapid and fatal tumour progression despite extensive treatment (Brodeur 2003; Castleberry 1997; Park 2008). Known predictors of poor prognosis are stage, age at diagnosis and chromosomal aberrations, such as MYCN (myc myelocytomatosis viral related oncogene, neuroblastoma derived) amplification and chromosomal loss of 1p36 (Brodeur 1984; Brodeur 1988a; Brodeur 1988b; Brodeur 1993; Cohn 2009).

Children with metastatic disease are quite ill at presentation. As the tumour disseminates to the bone, patients often present with bone pain, limping or both. Metastasis in the orbits can cause periorbital ecchymoses (raccoon eyes), sometimes accompanied by proptosis, caused by metastases in the bony orbit. Another symptom is abdominal distension caused by a large tumour. Paraspinal tumours may cause myelum compression, resulting in neurological symptoms, such as motor weakness, pain and sensory loss, which can be medical emergencies (Maris 2010; Park 2008).

The treatment of neuroblastoma patients generally consists of induction chemotherapy, surgery, myeloablative chemotherapy with stem cell rescue, radiotherapy or ¹³¹Iodide-metaiodobenzylguanidine (¹³¹I-MIBG) therapy or both (Maris 2007; Maris 2010; Park 2008; Yalçin 2010; Yalçin 2013).

Index test(s)

In this Cochrane review we assessed the diagnostic use of Iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy and fluorine-18-fluorodeoxy-glucose (18F-FDG) positron emission tomography (PET) in the detection of a neuroblastoma and its metastases at first diagnosis or at recurrence. 123I-MIBG scintigraphy can be performed as a two-dimensional whole-body (WB) scan or a three-dimensional single photon emission computed tomography (SPECT) scan, with or without computed tomography (CT) for localisation of neuroblastoma lesions.

MIBG, a compound that is a structural analogue of the neurotransmitter norepinephrine, is actively taken up in neuroendocrine cells via the norepinephrine transporter (NET) and is stored in the neurosecretory granules, resulting in a specific concentration in the tumour in contrast to cells of other tissue (Taggart 2008; Vaidyanathan 2008). Once labelled with radioactive iodine (123I or ¹³¹I), MIBG scintigraphy can be used for imaging of tumours of neuroendocrine origin, such as neuroblastoma, paraganglioma and phaeochromocytoma (Boubaker 2008; Taggart 2008; Vaidyanathan 2008). In the past, both 123I-MIBG and ¹³¹I-MIBG were used for diagnostic purposes. However, 123I-MIBG is considered first choice for imaging because it has a more favourable dosimetry and it was assumed that it provided a better image quality than ¹³¹I-MIBG (Bombardieri 2003c; Boubaker 2008; Taggart 2008). Consequently, 123I-MIBG is mainly used for diagnostic purposes in international protocols.

123I-MIBG WB or static scans visualise the primary tumour and its metastases two-dimensional. SPECT enables three-dimensional imaging of the primary tumour. However, in practice this imaging modality cannot replace WB imaging, because SPECT often does not fully visualise the whole body, but only a selected part of the body (Rufini 1996). MIBG-SPECT can be combined with CT to determine the exact localisation of the primary tumour and its relation to other organ structures (Rufini 1996; Taggart 2008).

Physiological distribution of 123I-MIBG can be found in structures that excrete catecholamines, such as the bladder, urinary tract and gastrointestinal system. MIBG usually accumulates in the liver, myocardium, salivary glands and thyroid, and less frequently in the spleen, lungs, brown adipose tissue and skeletal muscles. It is essential to recognise this normal distribution to avoid false positive interpretation of MIBG scans (Bombardieri 2003c; Boubaker 2008).

Many drugs can interfere with the uptake or vesicular storage of 123I-MIBG (or both) (Table 3; Bombardieri 2003c). Therefore, it is important to stop these medications before the procedure to prevent negative results of 123I-MIBG scans. In cases of severe hypertension, antihypertensive medication is necessary and cannot be stopped. Consequently, the 123I-MIBG scan may not be reliable, if the patient is treated with an antihypertensive agent that interferes with 123I-MIBG. On the other hand, 123I-MIBG scan test results can be negative because of low expression of the norepinephrine transporter (NET) (Boubaker 2008; Taggart 2008). Therefore, it is important to perform an additional test in case of a negative 123I-MIBG scan.

Table 3
Medication interfering with MIBG uptake

Another imaging modality to diagnose neuroblastoma is PET(-CT) imaging, which uses the glucose metabolism to visualise the primary tumour and metastases with 18F-FDG. In contrast to normal cells, cancer cells avidly take up glucose and metabolise it to lactate even when oxygen is abundantly present. This glucose metabolism in cancer cells enables specific detection by PET with the glucose analogue FDG. Although in contrast to 123I-MIBG imaging, 18F-FDG PET(-CT) imaging is not specific for neuroblastoma tumours, it may be a useful additional imaging modality for diagnosing neuroblastoma (Bombardieri 2003b; Murphy 2008; Shore 2008). This imaging modality might have additional value in patients with (false) negative 123I-MIBG scans. In this case 123I-MIBG would be the comparator test.

Alternative test(s)

The diagnosis neuroblastoma is being made using several tests. All patients suspected of neuroblastoma have a diagnostic work-up consisting of: clinical examination, testing of excretion of catecholamines in the urine, imaging of the tumour and its metastases and histopathological investigation of the tumour.

Excretion of catecholamines in the urine is a non-invasive test and it is used as a first screening in patients suspected of having a neuroblastoma. Increased excretion of urinary catecholamines indicates the presence of a neuroblastoma, but this test is not positive in all neuroblastoma patients (Strenger 2007).

Tumour biopsy (histopathology) is the gold standard. It is done not only to confirm the diagnosis, but also to investigate the histology of the neuroblastoma, the differentiation of the tumour and genetic abnormalities, which are all correlated with prognosis and play a role in staging the disease.

However, sometimes it is not feasible to perform this test (e.g. if the patient is seriously ill or if such a procedure can be life- or organ-threatening because of tumour localisation). In that case, a combination of tests, MIBG scintigraphy, testing of excretion of catecholamines in the urine and imaging of the tumour, is considered second best.

For detecting metastases, histopathology is not the optimal test. It is not feasible to confirm every metastatic lesion histologically, so other tests such as MIBG scintigraphy, MRI or CT, or both MRI and CT are needed.

Because MIBG scintigraphy is a functional imaging technique, actual measures of the primary tumour (and metastases) and close relationship with other organs and structures (vessels) cannot be made.

Next to 123I-MIBG scintigraphy, other imaging methods, such as ultrasound, CT-scan or MRI-imaging, of the primary tumour are performed to measure the size of the tumour (three-dimensional) and its relation to other organs and structures in order to estimate risks of surgery. However, these imaging modalities are also not specific for neuroblastoma (Kaste 2008b).

As all these tests have their own added value to either the diagnosis or therapy decisions, they are all being used side-by-side in patients with a suspected neuroblastoma.

Rationale

In clinical practice, 123I-MIBG and 18F-FDG-PET scintigraphy are performed if a neuroblastoma is strongly suspected and other tests, such as urinary catecholamines, are positive and suggestive for a neuroblastoma. Moreover, 123I-MIBG scintigraphy is not only important for the diagnosis of neuroblastoma, but also for staging and localisation of skeletal lesions. If these are present, MIBG follow-up scans are performed to assess response to therapy. In case of a MIBG-negative neuroblastoma, it is difficult to assess response to therapy, so the patients are being submitted to e.g. 18F-FDG-PET(-CT) scans and other imaging techniques, for which the diagnostic accuracy is not yet well established.

Prognosis, treatment and response to therapy of patients with neuroblastoma are currently based on extension scoring of 123I-MIBG scans (Decarolis 2013; Matthay 2010; Naranjo 2011; Yanik 2013). Therefore, it is important to have a good overview of the sensitivity and specificity of this diagnostic test. In this Cochrane diagnostic test accuracy (DTA) review we also evaluated the diagnostic accuracy of 18F-FDG-PET(-CT) as an add-on test in children with suspected neuroblastoma, as well as the diagnostic accuracy of this test as a single diagnostic test and compared with the diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy.

Objectives

We reviewed three index test combinations: 1. 123I-MIBG scintigraphy, 2. 18F-FDG-PET(-CT), and 3. 123I-MIBG scintigraphy plus 18F-FDG-PET(-CT). See Figure 1: flowchart of index tests.

Figure 1
Flow chart index tests in patients with suspected neuroblastoma.

Primary objective

1.1 To determine the diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.1.2 To determine the diagnostic accuracy of negative 123I-MIBG scintigraphy in combination with 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. In this case 18F-FDG-PET(-CT) is an add-on test.

Secondary objectives

2.1 To determine the diagnostic accuracy of 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.2.2 To compare the diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy and of 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. This was performed within and between (objective 1.1 compared to objective 2.1) included studies. 123I-MIBG (SPECT-CT) scintigraphy was the comparator test in this case.

Investigation of sources of heterogeneity

When assessing study results, we considered methodological and clinical sources of heterogeneity as well as variation in the criteria used to define a positive test result. Several factors may contribute to heterogeneity in diagnostic performance across studies. We investigated, where possible, the potential influence of differences in the following items:

Study population:

  • Newly diagnosed versus recurrent neuroblastoma.
  • Stage of disease (1 to 4 and 4S) as an ordinal variable. We reported stage 1 and 2 combined and stage 3, 4 and 4S separately.

Index test radio labelled MIBG (SPECT-CT) scintigraphy:

  • Time span between injection and scanning (24 or 48 hours) (acquisition time).
  • WB scan versus SPECT-CT.
  • Interfering medication (Table 3).

Reference standard:

  • Type of test: histopathology (reference test 1) versus bone marrow aspirate or trephine biopsy (reference test 2) versus histopathology in combination with excretion of catecholamines in the urine and additional imaging modalities (reference test 3).

Methods

Criteria for considering studies for this review

Types of studies

We included primary diagnostic studies if they compared the results of 123I-MIBG (SPECT-CT) scintigraphy, 18F-FDG-PET(-CT) imaging, or both, with the tests described as reference standards (as defined below) and if they compared the results of both tests with each other. Studies needed to be of a cross-sectional design or a case series of proven neuroblastoma. Patient selection could be either retrospective or prospective. We excluded case reports, studies that described fewer than ten patients suspected for neuroblastoma and diagnostic case-control studies.

Studies had to report sufficient data to construct (part of) a two-by-two table, i.e. at least the absolute number of true positives and false negatives had to be available from the data reported in the primary studies or obtainable from the study authors to calculate the sensitivity and if possible the specificity. 123I-MIBG scintigraphy is only performed when there is a high suspicion of a neuroblastoma based on clinical information, excretion of catecholamines in the urine and different imaging methods. Therefore, it is expected that mainly the outcome of MIBG scans in patients with finally proven neuroblastoma will be reported and that thus often only sensitivity can be analysed.

Participants

Children from 0 to 18 years old with suspected neuroblastoma and its metastases of any stage at first diagnosis or at recurrence in a tertiary care centre of paediatric oncology. We excluded studies on animals, studies not performed in children with suspected neuroblastoma, studies performed in children with esthesioneuroblastoma and olfactory neuroblastoma, and studies on the therapeutic use of MIBG.

Index tests

  • 123I-MIBG scintigraphy (WB, SPECT or SPECT-CT) of a neuroblastoma and its metastases at first diagnosis or at recurrence.
  • 18F-FDG-PET(-CT) scans of a neuroblastoma and its metastases at first diagnosis or at recurrence.
  • 123I-MIGB scintigraphy plus 18F-FDG-PET(-CT).

Comparator tests

When 18F-FDG-PET(-CT) imaging was the index test:

  • 123I-MIBG scintigraphy (WB, SPECT or SPECT-CT) of a neuroblastoma and its metastases at first diagnosis or at recurrence.

Target conditions

Neuroblastoma at first diagnosis or at recurrence.

Reference standards

The optimal combination of reference tests is described below. However, we did not exclude studies that did not use the optimal combination of reference tests.

The reference tests for the diagnosis of the primary neuroblastoma tumour were as follows:

  1. An unequivocal pathological diagnosis according to the Shimada classification or the International Neuroblastoma Pathology Classification (INPC) (Brodeur 1984; Joshi 2000; Peuchmaur 2003; Shimada 1984; Shimada 1993; Shimada 1999a; Shimada 1999b; Shimada 2003). Tumour tissue was examined by use of light or electron microscopy with immunohistochemistry. At least two of the following antigens had to be positive: neuron-specific enolase (NSE), synaptophysin or chromogranin A (CGA). Tissue had to be preferably obtained by the use of Trucut, core-needle biopsy. However, if this approach was contra-indicated, fine-needle aspiration could be used (Brodeur 1993).
  2. A bone marrow aspirate or trephine biopsy containing unequivocal tumour cells. These are immunocytologically positive clumps of cells, containing antibodies against at least two of the following antigens: NSE, synaptophysin or CGA (Brodeur 1993).
  3. Histopathology during or after treatment (e.g. tissue obtained during surgery), if excretion of catecholamines in the urine was elevated at diagnosis and additional imaging modalities (e.g. ultrasound, CT scan, MRI scan) suggested a neuroblastoma at diagnosis.

Three different tests were used as possible reference standards. If only one of the three reference standards had a positive result, the diagnosis neuroblastoma could be confirmed. However, to reject the diagnosis neuroblastoma all three had to give a negative result.

The reference tests for the diagnosis of neuroblastoma metastases (separately from the primary tumour) were as follows:

  • Bone marrow metastases: To determine bone marrow invasion, at least two different puncture sites were mandatory (although four puncture sites should always be aimed for). Representative smears (five smears from each puncture site) and EDTA/heparin bone marrow (3 to 5 mL from each puncture site) had to be sampled for PCR or immunocytology, or both. Only if no fluid bone marrow in sufficient quality or quantity could be aspirated, trephine biopsies from this puncture site are recommended (Beiske 2009).
  • Bone metastases: Positive lesions on a 99m-Tc skeleton scintigraphy, MRI, CT scan, or a combination of these tests.
  • Lymph node metastases: Histologically proven palpable nodes or ultrasound, MRI or CT scan for non-palpable nodes, or both.
  • Liver metastases: Ultrasound, MRI, CT scan or a combination of these tests.

Diagnosis of neuroblastoma metastases resulted from at least one positive result of these reference tests. The result for the metastases was assumed negative if all reference tests were negative.

There are no inadequate reference standards in the diagnostic process of neuroblastoma. Histopathology is the gold standard, but it is not always possible to perform. Therefore other reference tests, when combined, are also needed in the diagnosis of neuroblastoma.

Search methods for identification of studies

Electronic searches

We searched the databases of MEDLINE/PubMed (from 1945 to 11 September 2012) and EMBASE/Ovid (from 1980 to 11 September 2012). The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are presented in Appendix 1 and Appendix 2.

We did not impose language restrictions.

Searching other resources

We located information about studies not registered in MEDLINE and EMBASE, either published or unpublished, by screening the reference lists of relevant articles and review articles. We also scanned the conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), Advances in Neuroblastoma Research (ANR) and the Society of Nuclear Medicine (SNM) from 2006 to 2012. If studies were reported in abstracts or conference proceedings we searched for full publications. We checked for unpublished studies by contacting researchers involved in this area.

Data collection and analysis

Selection of studies

After employing the search strategy described previously, one review author performed the initial screening of identified references, excluding studies on animals, studies not performed in children with suspected neuroblastoma, studies performed in children with esthesioneuroblastoma and olfactory neuroblastoma, studies on the therapeutic use of MIBG, case reports and studies that described fewer than ten patients that were suspected of neuroblastoma. Next, two review authors independently identified studies from the remaining references that seemed to meet the inclusion criteria based on title, abstract, or both and screened these full-text studies. Only full-text studies that fulfilled all inclusion criteria for this review were eligible for inclusion. We clearly stated reasons for exclusion of any study considered for the review.

Both initial and definite selection needed consensus of both review authors. In case of disagreement, a third-party arbitrator achieved final resolution.

Data extraction and management

Two review authors performed data extraction independently using standardised forms. Data were extracted either on patient or on lesion level when possible. We extracted data on the following items:

  • Article: author, year of publication, journal.
  • Study population: age, sex, neuroblastoma at first diagnosis or at recurrence, stage, inclusion and exclusion criteria, number of subjects (including number eligible for the study, number enrolled in the study, number subjected to the index test and reference standard, number for whom results were reported in the two-by-two-table, reasons for withdrawal).
  • Index tests: 123I-MIBG scintigraphy, 18F-FDG-PET(-CT) imaging, or both.
  • Comparator test: 123I-MIBG scintigraphy, if 18F-FDG-PET(-CT) imaging was the index test.
  • Interfering medication in case of 123I-MIBG scintigraphy (Table 3).
  • Reference test: type of test.
  • Study methods: basic design of the study (prospective cohort or historical cohort with data collection based on medical records or case-control study), time span between index test and reference test, treatment between index test and reference test.
  • Data for the two-by-two table: true positive, false positive, true negative and false negative rates or, if not available, relevant parameters (sensitivity, specificity or predictive values) to reconstruct the two-by-two table.

To test whether the data extraction form worked well, two review authors piloted this form for two studies (Hashimoto 2003; Piccardo 2012). There was a high concordance between the review authors, so we concluded that the form could be used for all included studies.

When data were missing in a published report, we attempted to contact the study authors for the missing information. In cases of disagreement, we re-examined the abstracts and articles and undertook discussion until we achieved consensus. If this was not possible, we achieved final resolution using a third-party arbitrator.

Assessment of methodological quality

Two review authors independently assessed the methodological quality of each included study using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) items (Table 4) developed by the NHS Centre for Reviews and Dissemination at the University of York, UK (Whiting 2003). We scored each item as either 'yes', 'no' or 'unclear'. The QUADAS tool items and our scoring interpretations for each item are presented in Table 4. We resolved discrepancies between review authors by consensus. If this was not possible, we sought final resolution using a third-party arbitrator. We did not calculate a summary score estimating the overall quality of an article since the interpretation of such summary scores is problematic and potentially misleading (Jüni 1999; Whiting 2003). We presented results in the text, in a graph and in a table.

Table 4
QUADAS tool items and their interpretation

To test whether the QUADAS form worked well, two review authors piloted this form for three studies (Hashimoto 2003; Piccardo 2012; Sharp 2009a). There was a high concordance between the review authors, so we concluded that the form could be used for all included studies.

Statistical analysis and data synthesis

For the diagnosis of neuroblastoma, we planned to perform a random-effects meta-analysis of sensitivity of all included studies. The logit transformed value of sensitivity was to be meta-analyzed using a random-effects model to estimate the amount of between-study variance across studies and the "exact" binomial distribution was to be used to account for the within-study variance of each study (i.e. the precision by which sensitivity has been measured). We planned to perform these analyses in SAS 9.1 (SAS 9.1 2004) using the non-linear mixed effect module (PROC NLMIXED). However, these analyses were not possible because only one study provided data on false positive results.

We aimed to extract from each included study the two-by-two tables (consisting of at least true positives and false negatives) to calculate the sensitivity and, if possible, the specificity. We generated a paired forest plot showing estimates of sensitivity and specificity. The forest plot provides a visual impression of the precision by which sensitivity and specificity have been measured in each study, as well as an indication of the amount of variability in these parameters across studies. We did not plot pairs of sensitivity and specificity from each study in receiver operating characteristic (ROC), because only one study provided data to calculate specificity for diagnosing neuroblastoma in general and only three studies provided data on both sensitivity and specificity for diagnosing metastases.

In the analyses we differentiated between lesions detected in several regions when possible.

Investigations of heterogeneity

First, we investigated heterogeneity through visual inspection of the forest plots. We planned to more formally examine the effects of covariates on sensitivity, specificity, or both in the bivariate model, if sufficient data in the individual studies were available (data in at least four studies for each level of a covariate) to investigate heterogeneity. However, this was not possible.

Sensitivity analyses

To assess whether methodological quality influenced the results we planned to perform sensitivity analyses for the following individual quality items of QUADAS (Table 4). However, due to limited information on these items in these studies and a lack of discrimination within these items, it was not possible to do this.

  • Item 1: different stages of the disease and newly diagnosed versus recurrent neuroblastoma may result in different groups.
  • Item 4: partial verification bias.
  • Item 5: differential verification bias.
  • Item 11: withdrawals from the study may differ systematically from those who remain.
  • Item 13: the execution of the index test may differ between clinical centres and may consequently lead to various results, e.g. the index test can be performed with different techniques, time of scanning after infusion (4h, 12h, 24h) or with different equipments. These differences might give different test results.

Results

Results of the search

The electronic database searches yielded a total of 4693 references. We excluded 3204 references after initial screening of titles for the following reasons: studies described fewer than ten patients, were case reports, studies on animals, studies not performed in children with suspected neuroblastoma, studies performed in children with esthesioneuroblastoma and olfactory neuroblastoma or studies on the therapeutic use of MIBG (see Figure 2). After screening of titles and abstracts of the 1489 remaining references, we identified 246 studies that were assessed in full-text; we excluded 1243 studies because they did not meet the inclusion criteria (i.e. studies reporting fewer than ten patients, case reports, studies on animals, studies not performed in children with suspected neuroblastoma, studies performed in children with esthesioneuroblastoma and olfactory neuroblastoma, studies on the therapeutic use of MIBG and duplicate studies). Of the 246 full-text studies, 11 studies fulfilled the inclusion criteria (see the Characteristics of included studies table). For 24 studies we need additional information to assess whether they could be included and these are awaiting further assessment (see the Characteristics of studies awaiting classification table). Three studies were not in English and are yet to be translated (see the Characteristics of studies awaiting classification table). Six studies appeared to be conference proceedings that were not published as full-text yet and are awaiting further assessment (see the Characteristics of studies awaiting classification table). We excluded a total of 202 studies after assessing the full-text study for reasons described in the Excluded studies table.

Figure 2
Flow diagram: Inclusion process.

Additionally, we identified one conference proceeding after scanning the reference lists of relevant articles and reviews (see the Characteristics of studies awaiting classification table). Consultation of researchers in the field did not identify any ongoing studies. After scanning the conference proceedings of SIOP, ANR and SNM, we found four additional conference proceedings that have not been published as full-text yet and are awaiting further assessment (see the Characteristics of studies awaiting classification table). We did not identify any relevant conference proceedings after scanning the conference proceedings of ASCO.

Included studies

We have summarised the characteristics of the included studies below. For more detailed information see the Characteristics of included studies table.

In total, the 11 studies included 844 participants. In this Cochrane DTA review we report only on 621 eligible patients that fulfilled the inclusion criteria for this review. We excluded patients from four studies that included both diagnostic and follow-up scans (Gordon 1990; Neuenschwander 1987; Pfluger 2003; Sharp 2009a), from one study that included both 123I- and ¹³¹I-MIBG scans (Naranjo 2011a), from one study that included two adults (Piccardo 2012) and from one study that reported on neuroblastoma patients with and without MIBG scintigraphy (Hugosson 1999).

Five studies did not report on the median age of eligible patients for this review (Gordon 1990; Hugosson 1999; Neuenschwander 1987; Pfluger 2003; Sharp 2009a). Four studies reported an age range from 0 to 15.2 years (Biasotti 2000; Hashimoto 2003; Naranjo 2011a; Piccardo 2012). One study reported a median age of four years (Ivanova 2008) and one a median of 0.4 years (Labreveux de Cervens 1994).

The sex distribution was often not reported for the 621 eligible patients separately from the other patients in the studies. Six studies did not report on the sex distribution of eligible patients for this review (Biasotti 2000; Gordon 1990; Hugosson 1999; Neuenschwander 1987; Pfluger 2003; Sharp 2009a) and five studies did: Hashimoto 2003 reported 20 boys (61%) and 13 girls (39%); Labreveux de Cervens 1994 reported 10 boys (37%) and 17 girls (63%); Ivanova 2008 reported 14 boys (64%) and eight girls (36%); Naranjo 2011a reported 124 boys (57%) and 94 girls (43%); and Piccardo 2012 reported four boys (24%) and 13 girls (76%).

The INSS stage distribution was also frequently not reported separately for the 621 eligible patients from the other patients in the studies. Five studies did not report on the INSS stage distribution of patients eligible for this review (Hugosson 1999; Labreveux de Cervens 1994; Ivanova 2008; Neuenschwander 1987; Pfluger 2003). Two studies reported on patients with stage 1, 2, 3 and 4 neuroblastoma (Gordon 1990; Sharp 2009a); two reported on patients with stage 1, 2, 3, 4 and 4S neuroblastoma (Biasotti 2000; Hashimoto 2003); one reported on patients with stage 3 and 4 neuroblastoma (Piccardo 2012); and one reported on patients with stage 4 neuroblastoma only (Naranjo 2011a). Three of these studies (Hashimoto 2003; Naranjo 2011a; Piccardo 2012) reported the exact number per INSS stage: 16 patients with stage 1, five with stage 2, six with stage 3, 239 patients with stage 4 and two patients with stage 4S neuroblastoma.

Four studies were retrospective cohort studies (Hashimoto 2003; Labreveux de Cervens 1994; Pfluger 2003; Sharp 2009a), two were prospective cohort studies (Naranjo 2011a; Piccardo 2012), one was a retrospective cross-sectional study (Ivanova 2008) and of four the type of study was not reported (Biasotti 2000; Gordon 1990; Hugosson 1999; Neuenschwander 1987).

The diagnosis neuroblastoma was confirmed by histopathology in all 11 studies. In three studies both histopathology and bone marrow biopsies were used for the diagnosis neuroblastoma (Hugosson 1999; Naranjo 2011a; Sharp 2009a). In one study 11 patients had bone marrow biopsies and contrast-enhanced CT or MRI, one patient had histopathology of the primary tumour and contrast-enhanced CT or MRI, and five patients had histopathology of the primary tumour, bone marrow biopsies and contrast-enhanced CT or MRI (Piccardo 2012). To evaluate metastatic disease on 123I-MIBG scans, bone marrow biopsies were used as gold standard in three studies (Gordon 1990; Hashimoto 2003; Piccardo 2012). One study reported on a lesion level and used histologic verification as a reference standard for most lesions (Pfluger 2003). However, for stage 4 patients histologic verification of all metastases was impossible. Therefore, another reference standard was used: a minimum of six months was used for verification of lesions on follow-up control examinations. A lesion was classified as a false-positive finding if it disappeared without tumour therapy during the observation period. A lesion was classified as a true-positive finding if it persisted or progressed during follow-up or if it showed clear regression under specific therapy.

123I-MIBG or 18F-FDG-PET scintigraphy was performed for 608 patients at the time of first diagnosis and for 13 patients at the time of a recurrence. Just one study reported on the 13 patients with a recurrent neuroblastoma (Piccardo 2012). All studies reported on 123I-MIBG scintigraphy as an index test; one study also reported on 123I-MIBG scintigraphy as a comparator test and 18F-FDG-PET scintigraphy as an index test (Sharp 2009a).

The administered activity of 123I-MIBG varied from 3.7 to 5.18 MBq/kg (Labreveux de Cervens 1994; Ivanova 2008; Neuenschwander 1987; Pfluger 2003; Piccardo 2012; Sharp 2009a), 185 to 370 MBq/1.73m² body surface (Hugosson 1999; Naranjo 2011a; Sharp 2009a) or was in total 111 to 370 MBq (Gordon 1990; Hashimoto 2003; Sharp 2009a). One study did not report on the administered activity of 123I-MIBG (Biasotti 2000).

123I-MIBG scintigraphy was performed 24 hours after administration of 123I-MIBG in six studies (Hashimoto 2003; Labreveux de Cervens 1994; Naranjo 2011a; Neuenschwander 1987; Pfluger 2003; Piccardo 2012). One study reported an acquisition time of 24 or 48 hours (Hugosson 1999) and one study of 18 to 24 hours (Gordon 1990). In three studies the acquisition time was not reported (Biasotti 2000; Ivanova 2008; Sharp 2009a).

In 91 patients only a WB 123I-MIBG scan was performed (Gordon 1990; Hashimoto 2003; Hugosson 1999; Pfluger 2003; Piccardo 2012), in 27 patients a 123I-MIBG WB scan with SPECT was performed (Hashimoto 2003; Piccardo 2012), in 264 patients it was unclear wether a 123I-MIBG WB scan was performed with or without SPECT (Ivanova 2008; Naranjo 2011a; Sharp 2009a) and of 239 patients it was not reported (Biasotti 2000; Labreveux de Cervens 1994; Neuenschwander 1987). The one study that reported on 18F-FDG-PET scintigraphy described WB scans (Sharp 2009a). However, it is known that in studies concerning PET-scintigraphy the definition of WB may indicate from cranium to toe, but sometimes also from base of skull to knees. This information was not provided by any of the studies.

Four studies reported that interpretation of the 123I-MIBG or 18F-FDG PET scans was performed by two or more experienced observers (Hashimoto 2003; Naranjo 2011a; Pfluger 2003; Piccardo 2012), two studies reported one observer (Gordon 1990; Hugosson 1999) and five did not report on observers (Biasotti 2000; Labreveux de Cervens 1994; Ivanova 2008; Neuenschwander 1987; Sharp 2009a).

None of the included studies reported on treatment between index test and reference standard.

Excluded studies

We excluded 202 studies (see Characteristics of excluded studies table): 85 studies did not report on original research; 55 studies reported on fewer than ten children with a 123I-MIBG scan at diagnosis; 19 studies reported on patients that were not suspected of having a neuroblastoma but another tumour; 18 studies were no primary diagnostic investigations; 13 studies reported on ¹³¹I-MIBG scintigraphy and one on bone scintigraphy, instead of 123I-MIBG scintigraphy; the selection criteria were unclear in five studies and authors were unable to clarify these; two studies reported on patients older than 18 years; one study did not report on humans; three studies were duplicates.

Methodological quality of included studies

The quality assessment results for the individual studies can be found in the Characteristics of included studies table. Figure 3 and Figure 4 give an overview of all quality assessment items.

Figure 3
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figure 4
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

In summary, in 55% of the included studies the patients were representative for the patients that will be subjected to the index test in practice, in 18% of the studies patients were not representative and it was unclear in 27% of the studies. All studies used an acceptable reference standard. The time between the index and the reference test, the index and the comparator test, the comparator and the reference test was not reported in any of the studies. Although only one study provided data on specificity, partial verification bias was avoided in 64% of the studies. These studies only reported on patients with proven neuroblastoma and they all received the same reference standard. Partial verification bias might have played a role in 9% of the studies and it was unclear in 27%. Differential verification bias was avoided in 46% and might have been present in 27% of the included studies; for 27% of the studies this was unclear. Incorporation bias was avoided in 91% and in 9% it was unclear.

It was unclear if the reference test results were blinded in all of the studies. The index test results were blinded in 18% of the studies. Observers were blinded for clinical data in 18%, in 18% of the studies clinical data were available to observers, and in 64% of studies it was unclear whether observers were blinded for clinical data.

Uninterpretable results were reported in 18% and in 82% this item was unclear. Withdrawals were reported in 36% of the studies and were not reported in 64%.

The selection criteria were provided in 73% of the studies and they were not reported in 27%.

In 55% of the studies the index test was described in sufficient detail to replicate the test and in 45% this was not the case. The reference test was described in sufficient detail to replicate the test in just 9% of the studies, 82% of the studies did not report on this item and in 9% this item was unclear. A definition of a positive test result was reported in 46% of the studies, it was not reported in 36% of the studies, and in 18% there was no sufficient information about this item.

Inter-observer variation was not reported in any of the 11 studies.

Findings

We were able to analyse the sensitivity and specificity of the diagnosis neuroblastoma for 608 of the 621 eligible patients. The remaining 13 patients were reported in two studies and had false positive or true negative results for neuroblastoma based just on negative bone marrow biopsies, which is not a valid method to detect neuroblastoma, but only to detect metastases (Gordon 1990; Piccardo 2012). Of these 13 patients, 12 had a stage 4 neuroblastoma and could therefore be analysed for diagnostic accuracy of the presence of metastases (Gordon 1990; Piccardo 2012). One of the 13 patients had a stage 3 neuroblastoma and therefore could not be analysed for any of the diagnostic accuracies (Piccardo 2012).

We could not differentiate between lesions detected in several regions, because only one study reported on a lesion level (115 lesions in 22 patients) (Pfluger 2003). Because of the limited availability of data and because data at lesion level are important for staging and treatment allocation, we included this study.

As all studies only included patients with histologically proven neuroblastoma, results do not apply to daily practice of diagnosing neuroblastoma.

The true positive fractions per study are represented in Figure 5 and the true negative fraction of one study, Pfluger 2003, is represented in Figure 6.

Figure 5
Sensitivity of 123I-MIBG (SPECT-CT) scintigraphy for detecting a neuroblastoma tumour and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old (with 95% confidence interval).Abbreviations: n: number of patients with true ...
Figure 6
Specificity of 123I-MIBG (SPECT-CT) scintigraphy for detecting a neuroblastoma tumour and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.Abbreviations: n: number of lesions with true negative results of 123I-MIBG ...

Objective 1.1 Diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old

We analysed data of 608 patients out of 621 eligible patients. The sensitivity of the separate studies varied from 67% to 100% (see Figure 5). The total false negative rate was 11%. Only one study described patients with both suspected and already proven neuroblastoma (Pfluger 2003) and therefore specificity could only be evaluated in this study. It was 68% in 22 patients with 115 lesions (see Figure 6). The findings of this study were determined for each lesion (on a lesion level), while in all other studies they were determined per patient (on a patient level).

In Pfluger 2003, the false positive findings of the 123I-MIBG scans at diagnosis (n = 8 lesions) were due to: ganglioneuromas (n = 2), hemangioma of the liver (n = 1), focal nodular hyperplasia of the liver (n = 1), normal liver (n = 1), renal pelvis (n = 1) and physiological activity in a normal adrenal gland, bowel or musculature (n = 2), resulting in a specificity of 68%.

The diagnostic accuracy of detecting metastases (osteomedullary and soft tissue) separately from the primary tumour of neuroblastoma was analysed in three studies with all 72 eligible patients (Gordon 1990; Labreveux de Cervens 1994; Piccardo 2012). In contrast to the diagnosis of the primary tumour, analyses for the diagnostic accuracy of the metastases did include false positive in two and true negative findings in all three studies and therefore sensitivity and specificity could be calculated for these three and two studies, respectively. The sensitivity of 123I-MIBG scintigraphy for detecting neuroblastoma metastases in the three studies ranged from 79% to 100%. The specificity could be calculated for two of these studies with 45 patients and ranged from 33% to 89%. Of the 72 patients 72% had true positive metastases on the 123I-MIBG scan, 7% false negative, 7% false positive and 14% true negative.

The detection of metastases was also analysed for osteomedullary, lymph node and liver metastases separately. The detection of osteomedullary metastases was reported in four studies with 105 eligible patients (Gordon 1990; Hashimoto 2003; Labreveux de Cervens 1994; Piccardo 2012). The sensitivity of these four studies ranged from 33% to 100% and the specificity from 57% to 100%. The detection of lymph node and liver metastases was reported in one study with 33 eligible patients (Hashimoto 2003). For the detection of liver metastases the sensitivity for 33 patients was 80% and the specificity 93%. For the detection of lymph node metastases this was 23% and 100%, respectively.

Subgroup analyses

For some items subgroup analyses were not possible at all (acquisition time and interfering medication), because insufficient data were given to identify subgroups.

Stages of disease

This item was used to compare the diagnostic accuracy of 123I-MIBG scintigraphy to diagnose the primary tumour in patients with stage 1-2 vs. stage 3 vs. stage 4 vs. stage 4S.

Two studies reported data on diagnostic accuracy of 123I-MIBG scintigraphy in all 43 eligible patients with stage 1 or 2 neuroblastoma (Biasotti 2000; Sharp 2009a). The sensitivity of these studies ranged from 60% to 76%.

Three studies reported data on diagnostic accuracy of 123I-MIBG scintigraphy in 54 of all 55 eligible patients with stage 3 neuroblastoma (Biasotti 2000; Piccardo 2012; Sharp 2009a). The sensitivity of these studies ranged from 0% to 100%.

Four studies reported data on diagnostic accuracy of 123I-MIBG scintigraphy in all 344 eligible patients with stage 4 neuroblastoma (Biasotti 2000; Naranjo 2011a; Piccardo 2012; Sharp 2009a). The sensitivity of these studies ranged from 80% to 100%.

Only one study reported data on diagnostic accuracy of 123I-MIBG scintigraphy in all 13 eligible patients with stage 4S neuroblastoma (Biasotti 2000). The sensitivity was 100%.

Two studies reported on diagnostic accuracy of 123I-MIBG scintigraphy for detecting osteomedullary metastases of stage 4 neuroblastoma separately from the other stages (Gordon 1990; Piccardo 2012). For the 37 eligible patients with stage 4 disease described in these two studies, the sensitivity ranged from 79% to 90% and the specificity from 40% to 67%.

Newly diagnosed versus recurrent neuroblastoma

Data on the diagnostic accuracy of 123I-MIBG scintigraphy for detecting neuroblastoma in children from 0 to 18 years, newly diagnosed versus recurrent, were only available for 13 eligible patients in one study (Piccardo 2012). Of the four patients with a 123I-MIBG at first diagnosis, two had true positive and two had false negative findings (sensitivity 50%). Of the nine patients with a 123I-MIBG at recurrence, eight had true positive and one had false negative findings (sensitivity 89%).

Type of reference standard

Diagnostic accuracy of 123I-MIBG scintigraphy for detecting neuroblastoma in children from 0 to 18 years old per reference standard (histopathology versus bone marrow biopsies) was only provided in one study (Piccardo 2012). In six children, histopathology as the reference standard gave three true positive and three true negative results (sensitivity 50%). Bone marrow biopsies in all 17 children gave nine true positive, two false positive, two false negative and four true negative findings (sensitivity of 82% and specificity of 67%). The other studies did not give numbers for separate reference standards, so we could not perform any analyses on this item.

Plane WB versus WB SPECT/CT 123I-MIBG scintigraphy

The sensitivity of 123I-MIBG scintigraphy for detecting neuroblastoma in children from 0 to 18 years for patients with WB 123I-MIBG scintigraphy could be analysed with the data of four studies with 62 of 85 eligible patients (Gordon 1990; Hugosson 1999; Pfluger 2003; Piccardo 2012). The sensitivity ranged from 67% to 100%. The specificity was only provided in one study for all 115 lesions of 22 eligible patients and was 68% (Pfluger 2003).

Only one study, Piccardo 2012, reported the sensitivity of WB 123I-MIBG scans with SPECT/CT separately from those without for 11 of 17 eligible patients and was 73%.

Objective 1.2 Diagnostic accuracy of negative 123I-MIBG scintigraphy in combination with 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old

Only one study reported on the diagnostic accuracy of negative 123I-MIBG scintigraphy in combination with 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children 0 to 18 years (Sharp 2009a). Two of the 24 eligible patients with proven neuroblastoma had a negative 123I-MIBG scan and a positive 18F-FDG-PET(-CT) scan.

Objective 2.1 Diagnostic accuracy of 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old

Only one study reported on the diagnostic accuracy of 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis in children from 0 to 18 years (Sharp 2009a). This study described data on 18F-FDG-PET(-CT) scans of all 24 eligible patients with proven neuroblastoma with a sensitivity of 100%. Because all patients had already proven neuroblastoma, false positive and true negative findings did not occur in this study and therefore specificity could not be analysed.

Subgroup analyses

Pooled analyses were not possible, because only one study reported on this objective. However, data on diagnostic accuracy for subgroups of INSS stage within this study were available. For the other subgroups these data were not provided (newly diagnosed versus recurrent neuroblastoma, plane WB versus WB SPECT/CT 123I-MIBG scintigraphy, type of reference standard, acquisition time and interfering medication).

Stages of disease

The one study with 24 eligible patients that reported on the diagnostic accuracy of 18F-FDG-PET(-CT) imaging for detecting a primary neuroblastoma tumour and its metastases in children from 0 to 18 years old (Sharp 2009a), described only true positive findings for five patients with stage 1 or 2 disease, 3 patients with stage 3 disease and 16 patients with stage 4 tumours, so a sensitivity of 100%.

Objective 2.2 Comparison of diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy and of 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old

Only one study reported on the diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy versus 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years (Sharp 2009a). This study described data on all 24 eligible patients with proven neuroblastoma. The sensitivity of 123I-MIBG scintigraphy was 92% with two false negative results. The sensitivity of 18F-FDG-PET(-CT) imaging was 100%. The specificity could not be calculated, because only proven neuroblastoma patients were included. So, 18F-FDG-PET(-CT) imaging had a better sensitivity than 123I-MIBG scintigraphy. The two 123I-MIBG negative neuroblastoma were positive on 18F-FDG-PET(-CT) imaging.

Subgroup analyses

Pooled analyses were not possible because only one study reported on this objective. However, data on diagnostic accuracy for subgroups of INSS stage within this study were available. For the other subgroups these data were not provided (newly diagnosed versus recurrent neuroblastoma, plane WB versus WB SPECT/CT 123I-MIBG scintigraphy, type of reference standard, acquisition time and interfering medication).

Stages of disease

The one study with 24 eligible patients that compared the diagnostic accuracy of 123I-MIBG and 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis in children from 0 to 18 years old (Sharp 2009a), described two false negative findings on 123I-MIBG scintigraphy of five patients with stage 1 or 2 disease, resulting in a sensitivity of 60%. 18F-FDG-PET(-CT) imaging was positive for all five patients with a sensitivity of 100%. Three patients with stage 3 disease and 16 patients with stage 4 tumour had all true positive findings on the 123I-MIBG scintigraphy and the 18F-FDG-PET(-CT) imaging, with sensitivities of 100%. We could not calculate specificity because only proven neuroblastoma was described.

Summary of findings

Table thumbnail

Table thumbnail

Discussion

Summary of main results

We assessed three index test combinations in this Cochrane DTA review: 1. 123I-MIBG scintigraphy, 2. 18F-FDG-PET(-CT), and 3. 123I-MIBG scintigraphy plus 18F-FDG-PET(-CT) (Figure 1).

Objective 1.1 to determine the diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy:

The sensitivity, determined in 608 of 621 eligible patients included in 11 studies, varied from 67% to 100% (Figure 5; Table 1). The specificity was 68% in 115 lesions in 22 patients and was described in only one study (Figure 6).

The sensitivity for the detection of stage 1 and 2 neuroblastoma with 123I-MIBG scintigraphy varied from 60 to 76% (two studies), for stage 3 neuroblastoma from 0% to 100% (three studies), for stage 4 neuroblastoma 80% to 100% (four studies), and for stage 4S neuroblastoma the sensitivity was 100% (one study) (Table 1). The range of the sensitivity of stage 3 tumours was quite broad in comparison to that for all tumours. An explanation might be that of the three studies included in this subgroup analysis, Piccardo 2012 reported on just one patient with a false negative scan, resulting in a sensitivity of 0%. The sensitivity of 100% for stage 4S tumours might also be explained by the small number of included patients, being 13 patients from only one study with all true positive investigations.

Three of the 11 studies (in total 72 patients) described the diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy for detecting metastases (soft tissue and osteomedullary) separately from the primary tumour in patients with all neuroblastoma stages (Table 1). The sensitivity ranged from 79% to 100% (three studies) and the specificity from 33% to 89% (two studies). For lymph node metastases the sensitivity was 23% and the specificity 100%; and for liver metastases this was 80% and 93%. Both types of metastases were reported in one study with 33 patients. Osteomedullary metastases were described in four studies with 105 patients. The sensitivity varied from 33% to 100% and the specificity from 57% to 100%. The sensitivity for osteomedullary metastases in only stage 4 neuroblastoma varied from 79% to 90% and a specificity from 40% to 67% (two studies) (Table 1).

Objective 1.2 to determine the diagnostic accuracy of negative 123I-MIBG scintigraphy in combination with 18F-FDG-PET(-CT) imaging (18F-FDG-PET(-CT) as an add-on test):

Only one study reported on this objective. For two of the 24 eligible patients with proven neuroblastoma 18F-FDG-PET(-CT) imaging had additional value. Two patients with a negative 123I-MIBG scan had a positive 18F-FDG-PET(-CT) scan.

Objective 2.1 to determine the diagnostic accuracy of 18F-FDG-PET(-CT) imaging and Objective 2.2 to compare the diagnostic accuracy of 123I-MIBG (SPECT-CT) scintigraphy and of 18F-FDG-PET(-CT) imaging within and between included studies

The sensitivity of 123I-MIBG scintigraphy was 92% and of 18F-FDG-PET(-CT) imaging 100%. We could not analyse the specificity because all patients had already proven neuroblastoma (Table 2). So, for the 24 eligible patients in this study, 18F-FDG-PET(-CT) imaging had a better sensitivity than 123I-MIBG (SPECT-CT) scintigraphy.

Strengths and weaknesses of the review

Limited amount of available data

Likelihood ratios are the most useful outcome parameters to judge the diagnostic test accuracy of the index tests. In the work-up of neuroblastoma, urine analysis for excretion of catecholamines (a non-invasive screening tool), diagnostic imaging and 123 MIBG-scintigraphy are generally performed, before the diagnosis is confirmed by the gold standard: histopathology.

Most studies included in our review were studies that investigated the performance of 123I-MIBG-scintigraphy versus other imaging techniques, in a cohort of patients with histologically proven neuroblastoma. However, as is described above, this was not the case at the start of the diagnostic work-up. The 123MIBG-scans in these studies were commonly assessed without knowing the results of the histopathology.

Of the 11 included studies, nine reported on case series of proven neuroblastoma. One study was a retrospective cross-sectional study. The final study was a prospective cross-sectional study that eventually identified only children with neuroblastoma.

Only one of the included studies provided data on false-positive results at a lesion level, not at a patient level. We believe in fact that this is a study of patients with proven neuroblastoma, in which the performance of the two imaging modalities (123I-MIBG-scintigraphy and 18F-FDG-PET-scintigraphy) was tested for all lesions.

False-positive results of metastatic lesions are possible in patients with proven neuroblastoma. Thus we could not calculate likelihood ratios. It is not expected that future studies will assess specificity.

Few data were available to calculate the specificity, as no extensive data on true negative and false positive numbers were reported. To calculate the diagnostic accuracy, we indeed need both data on sensitivity and specificity. At the start of this project, we did not expect to find only very limited data on specificity. Now that we know this, we think that the term "the sensitivity to assess the presence of neuroblastoma" for the objectives would have been more appropriate than "diagnostic accuracy".

However, we could collect data on true positive and false negative rates to calculate sensitivity.

Only few included studies are of a prospective design, but we feel that all of them are studies assessing the sensitivity of MIBG to detect neuroblastoma. Since there is only limited evidence available we included them in the review.

We excluded studies with fewer than ten patients suspected for neuroblastoma. There is neither evidence nor guidelines to decide which cut-off is justified, but generally systematic reviews published in high-impact journals use a cut-off of ten patients. Therefore we decided to use 10 as a cut-off point.

Furthermore, we feared for bias, if small patient numbers were selectively reported out of a larger population. Therefore we also excluded case reports.

The inclusion of a small number of patients in the studies of Gordon 1990 and Piccardo 2012 (19 and 13, respectively) might explain the minor sensitivity in comparison to the other studies. Due to small numbers, one scan more or less scored as false negative, might have a great effect on the sensitivity. For Pfluger 2003 the minor sensitivity might be explained by the fact that the study results were based on a lesion level and not on a patient level. Just one positive lesion is enough for the diagnosis neuroblastoma and just one positive metastatic site is enough to define stage 4 disease. However, patients were probably included in this study with more than one positive lesion. Therefore, sensitivity may be overestimated.

Only one study with 24 eligible patients, Sharp 2009a, reported on the diagnostic accuracy of 18F-FDG-PET(-CT) imaging as a single diagnostic test (objective 2.1) and compared to 123I-MIBG scintigraphy (objective 2.2). Therefore, it is difficult to draw reliable conclusions from analyses on this study. In this study only two patients with negative 123I-MIBG scans were reported that were positive on 18F-FDG-PET(-CT) scans (objective 1.2). 18F-FDG-PET(-CT) imaging is an upcoming diagnostic imaging method for the detection of neuroblastoma and its metastases. It is already considered as an important additional diagnostic method if 123I-MIBG scintigraphy is negative (Piccardo 2013). We hope that in an update of this Cochrane DTA review we can include more studies on this objective and provide more reliable information on the diagnostic accuracy of 18F-FDG-PET(-CT) imaging.

For some items subgroup analyses were not possible at all (acquisition time and interfering medication), because insufficient data were given to identify subgroups.

In this review, the type of the 123I-MIBG scans (WB, SPECT-CT or a combination) varied between the studies and not all studies reported on the distinction between these types of scans. The sensitivity of 123I-MIBG WB scintigraphy (Gordon 1990; Hugosson 1999; Pfluger 2003; Piccardo 2012), as well as of 123I-MIBG WB SPECT-CT scintigraphy (Piccardo 2012), was 73%. So, there was no difference in sensitivity for WB versus WB SPECT-CT scans. However, only one study described WB SPECT-CT scans of only 11 of 17 eligible patients. In the literature, the addition of SPECT-CT might change the diagnostic accuracy of 123I-MIBG scintigraphy (Gelfand 1994; Rozovsky 2008; Rufini 1995; Rufini 1996). Usually it improves the detection of neuroblastoma lesions and it is easier to differentiate pathological from physiological uptake. Therefore, although the sensitivity of both modalities did not differ in this review, it is still important to make a distinction between studies that used WB scintigraphy only and those that added SPECT-CT.

Reference standards

Three different tests were used as possible reference standards. If only one of the three reference standards had a positive result, the diagnosis neuroblastoma could be confirmed. However, to reject the diagnosis neuroblastoma all three had to give a negative result. For some of the studies, only bone marrow biopsies, but not histopathology, was reported for some patients. Due to sampling error, a negative result of bone marrow aspirates or trephine biopsies does not exclude a primary neuroblastoma tumour or metastatic disease. If in this case no reliable conclusions could be drawn, we excluded these patients from sensitivity and specificity analyses.

One study reported on a lesion level (Pfluger 2003). Histologic verification of all lesions in stage 4 patients with metastases is impossible. Therefore, another reference standard was used: a minimum of six months was used for verification of lesions on follow-up control examinations. A lesion was classified as a false-positive finding if it disappeared without tumour therapy during the observation period. A lesion was classified as a true positive finding if it persisted or progressed during follow-up or if it showed clear regression under specific therapy. This might explain the fact that this study found more false positive and false negative results than the other studies. The other studies did not report on a lesion level, but on a patient level. Only one positive lesion is then enough to diagnose a neuroblastoma and only one metastatic lesion is enough to classify the patient as stage 4 or 4S. For the diagnosis of neuroblastoma in general, sensitivity and specificity on a lesion level is less important.

Data extraction and quality assessment

The concordance between the review authors on the data extraction and the QUADAS was high. We disagreed on only 2.7% of the items on the data extraction form and on 3.7% of the QUADAS-form. So, we conclude that the data extraction and quality assessment were reliable.

Limited possibility to assess the eligibility for this review for a substantial amount of studies

Unfortunately it was not possible to assess the eligibility for inclusion in this review for a substantial amount of studies (n = 38). We tried to contact the study authors to obtain the necessary information and if necessary identify translators, but were unsuccessful. We don't know what the impact of this on the review results are.

Applicability of findings to the review question

Although many studies report on 123I-MIBG scintigraphy, this is the first systematic review on diagnostic test accuracy of 123I-MIBG scintigraphy. In the literature it is often stated that 90% of neuroblastoma tumours take up MIBG (MIBG-avid) and that around 10% do not (Boubaker 2008). In concordance with the literature, we reported 11% of the 608 patients in the 11 included studies with MIBG-non-avid neuroblastoma. The reasons for these MIBG-non-avid tumours are not entirely clear. Possible modifications in the uptake mechanism or interfering medication may play a role (Boubaker 2008), but most studies do not report on the reasons of MIBG-non-avid neuroblastoma lesions. Also intense radiotracer uptake in normal liver, myocardium, salivary glands and gut may blur the picture and small pathological lesions can be less visible. SPECT-CT might improve the detection of these lesions, but more research is needed before a definitive conclusion can be made.

The analyses in this review showed a false negative rate of around 7% for all types of metastases and for osteomedullary metastases specifically. So, investigation of bone marrow aspirates or trephine biopsies, as described in current protocols (Monclair 2009), are justified in all patients at diagnosis. However, these aspirates and biopsies are taken from the iliac crest, so distant metastases might still be missed. Therefore it is worthwhile to perform an additional test, in case of a negative result of WB 123I-MIBG scintigraphy. For metastases this is of great importance, because the presence of metastases classifies the patient as stage 4 or 4S and this has severe consequences for the prognosis and treatment. A possible candidate as add-on test might be 18F-FDG-PET(-CT) or MRI (Corbett 1991b; Siegel 2013). In this Cochrane DTA review we reviewed the diagnostic accuracy of 18F-FDG-PET(-CT). When comparing 18F-FDG-PET(CT) imaging to 123I-MIBG scintigraphy, the sensitivity of 18F-FDG-PET(CT) was better and it had additional value if 123I-MIBG scintigraphy was negative (all in one study). So, it is important to study this imaging method as a promising add-on test.

Although the specificity of 123I-MIBG scintigraphy was analysed in just one study, analyses were performed for 115 lesions in 22 patients (Pfluger 2003). The general assumption is that MIBG activity on an 123I-MIBG scan, that is not explained by physiological uptake, is most likely a neuroblastoma tumour. In contrast, Pfluger 2003 reported false positive findings. The specificity was 68%, but we believe that not all of these false positive results were justified. Some could be considered as physiological uptake, like normal liver (n = 1), renal pelvis (n = 1) and physiological activity of the normal gland, bowel or musculature (n = 2) and then specificity would be 85%.

Authors' conclusions

Implications for practice

In this Cochrane DTA review, we included 11 studies and found a sensitivity of 67 to 100%. Although only one included study reported on false positive findings, it is important to keep in mind that false positive findings occur. Most reported false positive findings in this one study seemed to be physiological uptake. However, this implies that 123I-MIBG scans may not be evaluated as easily as is generally thought and that it is important to rule out physiological uptake, e.g. by using SPECT-CT scans. However, further research is needed before definitive conclusions can be made.

As described both in the literature and in this review, in about 10% of patients with histologically proven neuroblastoma the tumour does not accumulate 123I-MIBG (false negative results). For these patients, it is advisable to perform an additional test for staging the neuroblastoma. Additional tests might for example be 18F-FDG-PET(-CT), but more evidence is necessary.

Implications for research

In this Cochrane DTA review, only one study reported on the specificity of 123I-MIBG scintigraphy (Pfluger 2003). The other ten studies reported on patients with already proven neuroblastoma. Although the general assumption is that 123I-MIBG uptake outside the physiological areas proves neuroblastoma, this one study reported 7% false positive findings or 3% if cases with physiological uptake were excluded. It would be helpful to further and better assess the specificity in future studies.

Furthermore, it is important to study the possibilities of other additional diagnostic tests in case of negative results of 123I-MIBG scans in patients suspected of neuroblastoma or already diagnosed with neuroblastoma according to histopathology. One possible additional test is 18F-FDG-PET(-CT). Only one study concerning 18F-FDG imaging was included. Because more and more studies are performed with this diagnostic test for patients with neuroblastoma, we think that with the update of this review more studies on 18F-FDG PET(-CT) can be analysed and more robust conclusions can be drawn.

Furthermore, a promising test is the 18F-DOPA-PET-CT. This test also relies on the metabolism of catecholamines, but has the advantage of better performance due to PET-technology (Piccardo 2013). Future studies might reveal more details about the diagnostic accuracy of this test.

In this Cochrane systematic diagnostic test accuracy review some subgroup analyses were not possible, because studies did not report the data in sufficient detail to assign all patients to subgroups.

Only 11 studies were included in this diagnostic test accuracy review. The first reason for the small number of included studies is that we excluded studies that performed ¹³¹I-MIBG instead of 123I-MIBG scintigraphy. However, a recent publication (Naranjo 2011) reported no evidence of a statistically significant difference in outcome by type of scan. Therefore, for an update of this review it would be advisable to take these ¹³¹I-MIBG scans also into account. A second reason for the small number of included studies was that many studies reported on 123I-MIBG scintigraphy of less than ten patients which was an exclusion criteria for our review, assuming that less than ten patients could not give robust results. However, if reported clearly, studies with less than ten patients might be able to give reliable data and pooling them would be an opportunity for an update of this review. A last reason is that the number of patients with a neuroblastoma per centre is small. In the past, many studies reported patients per centre, resulting in a small number of patients per study. Nowadays, more and more centres collaborate to publish results of their patients together, resulting in more robust data. For an update of this review, we hope that these kind of collaborations will result in many studies with a large number of patients and with robust results, so we can include more patients and do more reliable analyses.

Acknowledgments

We thank Edith Leclercq, the Trials Search Co-ordinator of the Cochrane Childhood Cancer Group, for helping to design the search strategy and running the searches.Also, we are grateful to E.M.C. Michiels, MD, PhD; A. Seniukovich, MD; P. Alonso-Coello, MD; K. Hayashi; and R.W.M. Vernooij, M.Sc. for their help with translating non-English studies.We thank A.F. Jacobson, MD, PhD, and A. Naranjo, PhD for their additional information on studies that we had to assess; K. Matthay, MD, and B.L. Shulkin, MD for their information on ongoing studies; and H. Reitsma for performing data analyses.

The editorial base of the Cochrane Childhood Cancer Group is funded by Kinderen Kankervrij (KiKa).

APPENDICES

Appendix 1. PubMed search strategy

1. For neuroblastoma the following MeSH headings and text words were used:

(((neuroblastoma) OR (neuroblastomas) OR (neuroblast*)) OR ((ganglioneuroblastoma) OR (ganglioneuroblastomas) OR (ganglioneuroblast*)) OR ((neuroepithelioma) OR (neuroepitheliomas) OR (neuroepitheliom*)) OR ((esthesioneuroblastoma) OR (esthesioneuroblastomas) OR (esthesioneuroblastom*))) OR (Peripheral Primitive Neuroectodermal Tumors OR Peripheral Primitive Neuroectodermal Tumours OR Peripheral Primitive Neuroectodermal Neoplasm OR Primitive Neuroectodermal Tumor, Extracranial OR Neuroectodermal Tumor, Peripheral OR Neuroectodermal Tumors, Peripheral OR Peripheral Neuroectodermal Tumor OR Peripheral Neuroectodermal Tumors OR Tumor, Peripheral Neuroectodermal OR Tumors, Peripheral Neuroectodermal OR (pPNET OR PNET OR PNET*) OR Peripheral Primitive Neuroectodermal Tumor OR Peripheral Primitive Neuroectodermal Tumour OR Extracranial Primitive Neuroectodermal Tumor OR Extracranial Primitive Neuroectodermal Tumour OR Extracranial Primitive Neuroectodermal Tumors OR Extracranial Primitive Neuroectodermal Tumours OR Neuroectodermal Neoplasm, Peripheral Primitive OR Neuroectodermal Tumor, Peripheral Primitive) OR (Esthesioneuroblastomas, Olfactory OR Olfactory Esthesioneuroblastoma OR Olfactory Esthesioneuroblastomas OR Esthesioneuroblastoma, Paranasal Sinus-Nasal Cavity OR Esthesioneuroblastoma, Paranasal Sinus Nasal Cavity OR Neuroblastoma, Olfactory OR Neuroblastomas, Olfactory OR Olfactory Neuroblastomas OR Paranasal Sinus-Nasal Cavity Esthesioneuroblastoma OR Paranasal Sinus Nasal Cavity Esthesioneuroblastoma OR Aesthesioneuroblastoma OR Aesthesioneuroblastomas OR Olfactory Neuroblastoma)

2. For MIBG scintigraphy or PET imaging the following MeSH headings and text words were used:

(MIBG OR Iodine-123 Metaiodobenzylguanidine Imaging OR Iodine-123 Metaiodobenzylguanidine Imag* OR Metaiodobenzylguanidine OR Metaiodobenzylguanidin* OR Metaiodobenzylguanidine scintigraphy OR Metaiodobenzylguanidine scintigraph*)

OR

(123I-mIBG) OR (3 Iodobenzylguanidine OR meta-Iodobenzylguanidine OR meta Iodobenzylguanidine OR Iobenguane OR m-Iodobenzylguanidine OR m Iodobenzylguanidine OR (Iobenguane AND (131I) OR (3-Iodo- AND (131I) AND benzyl) AND guanidine) OR 3-Iodobenzylguanidine, 123I Labeled OR 123I Labeled 3-Iodobenzylguanidine OR 3 Iodobenzylguanidine, 123I Labeled OR meta-Iodobenzylguanidine OR meta Iodobenzylguanidine OR m-Iodobenzylguanidine OR m Iodobenzylguanidine OR Iobenguane (131I) OR (3-Iodo-(131I)benzyl)guanidine) OR (77679-27-7[rn])

OR

(Positron Emission Tomography OR Positron Emission Tomograph* OR Tomography, Positron-Emission OR Tomography, Positron Emission OR PET Scan OR PET Scans OR Scan, PET OR Scans, PET OR PET Scan* OR PET)

OR

(SPECT OR SPECT-CT OR 18F-FDG-PET-CT OR Single Photon Emission Computed Tomography OR Single photon emission computerized tomography OR Single photon emission computerised tomography OR Tomography, Emission-Computed, Single-Photon)

OR

(Single Photon Emission Computed Radionuclide Tomography OR Single Photon Emission CT Scan OR Single Photon Emission CAT scan OR Single Photon Emission Computer Assisted Tomography OR 18 F-FDG-PET OR 18-fluorodeoxy* OR 18fluorodeoxy* OR fdgpet OR fdg pet OR 18f fdg* OR Single Photon Emission Computed Radionuclide Tomograph* OR Single Photon Emission CT Scan* OR Single Photon Emission CAT scan* OR Single Photon Emission Computer Assisted Tomograph* OR Single Photon Emission Computed Tomograph* OR Single photon emission computerized tomograph* OR Single photon emission computerised tomograph* OR fluorodeoxyglucose f18)

3. (1 AND 2) NOT case reports [pt]

* = zero or more characters

Appendix 2. EMBASE search strategy

1. For neuroblastoma the following Emtree terms and text words were used:

1. exp neuroblastoma/

2. (neuroblastoma or neuroblastomas or neuroblast$).mp.

3. (ganglioneuroblastoma or ganglioneuroblastomas or ganglioneuroblast$).mp.

4. exp olfactory neuroepithelioma/ or exp neuroepithelioma/

5. (neuroepithelioma or neuroepitheliomas or neuroepitheliom$).mp.

6. exp esthesioneuroblastoma/

7. (esthesioneuroblastoma or esthesioneuroblastomas or esthesioneuroblastom$).mp.

8. exp neuroectoderm tumor/ or (peripheral primitive neuroectodermal tumors or peripheral primitive neuroectodermal tumours).mp.

9. (peripheral primitive neuroectodermal neoplasm or peripheral primitive neuroectodermal neoplasms).mp.

10. (peripheral neuroectodermal tumor or peripheral neuroectodermal tumors or peripheral neuroectodermal tumour or peripheral neuroectodermal tumours).mp.

11. (pPNET or PNET or PNET$).mp.

12. (peripheral primitive neuroectodermal tumor or peripheral primitive neuroectodermal tumour).mp.

13. (extracranial primitive neuroectodermal tumor or extracranial primitive neuroectodermal tumors or extracranial primitive neuroectodermal tumour or extracranial primitive neuroectodermal tumours).mp.

14. (olfactory esthesioneuroblastoma or olfactory esthesioneuroblastomas).mp.

15. (olfactory neuroblastoma or olfactory neuroblastomas).mp.

16. (paranasal sinus-nasal cavity esthesioneuroblastoma or paranasal sinus nasal cavity esthesioneuroblastoma).mp.

17. (aesthesioneuroblastoma or aesthesioneuroblastomas).mp.

18. or/1-17

2. For MIBG scintigraphy or PET imaging the following Emtree terms and text words were used:

1. exp "(3 iodobenzyl)guanidine i 123"/ or exp "(3 iodobenzyl)guanidine"/ or exp "(3 iodobenzyl)guanidine i 131"/

2. MIBG.mp.

3. (Iodine-123 Metaiodobenzylguanidine Imaging or Iodine-123 Metaiodobenzylguanidine Imag$).mp.

4. (Metaiodobenzylguanidine or Metaiodobenzylguanidin$).mp.

5. (Metaiodobenzylguanidine scintigraphy or Metaiodobenzylguanidine scintigraph$).mp.

6. 123I-mIBG.mp.

7. 3 Iodobenzylguanidine.mp.

8. (meta-Iodobenzylguanidine or meta Iodobenzylguanidine).mp.

9. Iobenguane.mp.

10. (m-Iodobenzylguanidine or m Iodobenzylguanidine).mp.

11. (3-Iodo- and 131I and benzyl and guanidine).mp.

12. 123I Labeled 3-Iodobenzylguanidine.mp.

13. (meta-Iodobenzylguanidine or meta Iodobenzylguanidine).mp.

14. (m Iodobenzylguanidine or m-Iodobenzylguanidine).mp.

15. 77679-27-7.rn.

16. or/1-15

17. exp positron emission tomography/ or exp fluorodeoxyglucose f18/

18. (positron emission tomography or positron emission tomograph$).mp.

19. (PET scan or PET scans or PET scan$ or PET).mp.

20. (SPECT or SPECT-CT or 18F-FDG-PET-CT).mp.

21. exp single photon emission computer tomography/

22. (single photon emission computed tomography or single photon emission computerized tomography or single photon emission computerised tomography).mp.

23. single photon emission computed radionuclide tomography.mp.

24. (Single Photon Emission CT Scan or Single Photon Emission CT Scan$).mp.

25. (Single Photon Emission CAT scan or Single Photon Emission CAT scan$).mp.

26. (Single Photon Emission Computer Assisted Tomography or Single Photon Emission Computer Assisted Tomograph$).mp.

27. 18 F-FDG-PET or 18-fluorodeoxy$ or 18fluorodeoxy$ or fdgpet or fdg pet or 18f fdg$).mp.

28. Single Photon Emission Computed Radionuclide Tomograph$.mp.

29. Single Photon Emission Computed Tomograph$.mp.

30. (Single photon emission computerized tomograph$ or Single photon emission computerised tomograph$).mp.

32. or/17-30

33. 16 or 31

3. (1 AND 2) not (case report or case reports)

mp = title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name

$ = zero or more characters

/ = Emtree term

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Table thumbnail
Biasotti 2000

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Gordon 1990

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Hashimoto 2003

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Hugosson 1999

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Ivanova 2008

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Labreveux de Cervens 1994

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Naranjo 2011a

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Neuenschwander 1987

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Pfluger 2003

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Piccardo 2012

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Sharp 2009a

Characteristics of excluded studies [ordered by study ID]

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Characteristics of studies awaiting classification [ordered by study ID]

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Abrahamsen 1995

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Ady 1995

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Boubaker 2012

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Claudiani 1995

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Fania 2011

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Feine 1987

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Ferris 1992

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Fischer 1989

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Gelfand 1994

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Ginsburg 2012

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Goo 2005

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Hadj-Djilani 1995

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Hervas 2001

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Ishii 2000

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Jacobs 1990b

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Kurkure 2012

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Lumbroso 1988b

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Moschogiannis 2011

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Muckle 2012

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Muller-Gartner 1986

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Müller-Gärtner 1985

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Okuyama 1998

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Okuyama 1999

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Osmanagaoglu 1993

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Paltiel 1994

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Papathanasiou 2011

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Parisi 1992

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Rathore 2011

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Sarkadi 2011

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Schilling 2000

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Schmiegelow 1989

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Sharp 2009b

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Suc 1996

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Tahir 2011

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Turba 1993

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Vik 2009

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Yang 2012

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Young-Seok 2006

DATA

This review has no data.

CONTRIBUTIONS OF AUTHORS

Lieve Tytgat, Gitta Bleeker and Elvira van Dalen conceived the review.

Gitta Bleeker, Godelieve Tytgat, Judit Adam, Huib Caron, Lotty Hooft, Leontien Kremer and Elvira van Dalen designed the review.

Elvira van Dalen co-ordinated the review.

Gitta Bleeker, Godelieve Tytgat, Judit Adam, Lotty Hooft, Leontien Kremer and Elvira van Dalen collected data for the review.

Elvira van Dalen and Gitta Bleeker (with help of Edith Leclercq, Trials Search Co-ordinator) designed the search strategies.

Edith Leclercq (Trials Search Co-ordinator) performed literature searches.

Gitta Bleeker, Godelieve Tytgat and Elvira van Dalen screened the search results.

Gitta Bleeker, Godelieve Tytgat and Elvira van Dalen screened retrieved papers against inclusion criteria.

Gitta Bleeker, Godelieve Tytgat, Judit Adam, Leontien Kremer and Elvira van Dalen appraised the quality of papers.

Gitta Bleeker, Godelieve Tytgat, Judit Adam, Leontien Kremer and Elvira van Dalen extracted data from papers.

Lotty Hooft and Elvira van Dalen performed third party arbitration.

Gitta Bleeker organised retrieval of papers; wrote to authors of papers for additional information; obtained and screened data from unpublished studies; managed data for the review; entered data into RevMan 2014; and wrote the review.

Gitta Bleeker, Lotty Hooft and Hans Reitsma analysed the data.

Gitta Bleeker, Godelieve Tytgat, Judit Adam, Huib Caron, Lotty Hooft, Leontien Kremer and Elvira van Dalen interpreted the data.

Gitta Bleeker, Lotty Hooft, Leontien Kremer and Elvira van Dalen provided a methodological perspective.

Gitta Bleeker, Godelieve Tytgat, Judit Adam and Huib Caron provided a clinical perspective.

Gitta Bleeker, Godelieve Tytgat, Judit Adam, Huib Caron, Lotty Hooft, Leontien Kremer and Elvira van Dalen provided general advice on the review.

DECLARATIONS OF INTEREST

The review authors declare that they have no known conflict of interest.

Huib N. Caron did not work for F. Hoffmann-La Roche AG at the time this review was done. He will not participate in any future updates of this Cochrane Review.

SOURCES OF SUPPORT

Internal sources

  • Dutch Cochrane Center, Netherlands.

External sources

  • Stichting Kinderen Kankervrij (KIKA), Netherlands.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

  1. In the Methods section we added two reasons for exclusion:
    1. Types of studies: we excluded studies that reported < ten eligible patients, because we assumed that these studies would not give robust results. If the test results of just one patient changes, the sensitivity or specificity, or both, can be totally different. Therefore, these studies might over- or underestimate the sensitivity or specificity, or both, by chance. Including many of these studies might enlarge this overestimating effect enormously.
    2. Participants: we excluded studies performed in children with esthesioneuroblastoma and olfactory neuroblastoma, because these diseases are other disease entities. Neuroblastoma arises from the sympathetic nervous system. Esthesioneuroblastoma/olfactory neuroblastoma arises from the olfactory epithelium.
  2. In the Statistical analysis and data synthesis section we reported that we analysed data on patient level and lesion level. Only one study provided data at lesion level. We included this study because data at lesion level are important for staging and treatment allocation.
  3. In the Types of studies section we changed "Studies had to report sufficient data to construct a two-by-two table" into "Studies had to report sufficient data to construct (part of) a two-by-two table". We also added: "Considering the nature of the disease it is expected that mainly proven neuroblastoma will be reported and that thus often only sensitivity can be analysed".
  4. In the Types of studies section we added case series of proven neuroblastoma.

References

References to studies included in this review

  • Biasotti S, Garaventa A, Villavecchia GP, Cabria M, Nantron M, De Bernardi B. False-negative metaiodobenzylguanidine scintigraphy at diagnosis of neuroblastoma. Medical and Pediatric Oncology. 2000;35(2):153–5. [PubMed]
  • Gordon I, Peters AM, Gutman A, Morony S, Dicks-Mireaux C, Pritchard J. Skeletal assessment in neuroblastoma--the pitfalls of iodine-123-MIBG scans. Journal of Nuclear Medicine. 1990;31(2):129–34. [PubMed]
  • Hashimoto T, Koizumi K, Nishina T, Abe K. Clinical usefulness of iodine-123-MIBG scintigraphy for patients with neuroblastoma detected by a mass screening survey. Annals of Nuclear Medicine. 2003;17(8):633–40. [PubMed]
  • Hugosson C, Nyman R, Jorulf H, McDonald P, Rifai A, Kofide A, et al. Imaging of abdominal neuroblastoma in children. Acta Radiologica. 1999;40(5):534–42. [PubMed]
  • Ivanova AA, Sokolov AV, Yalfimov AN, Savchenko ON. Role of 123-I-metaiodobenzylguanidine imaging as a component in the diagnosis and treatment of neuroblastoma [Russian] Voprosy Onkologii. 2008;54(4):521–4. [PubMed]
  • Labreveux de Cervens C, Hartmann O, Bonnin F, Couanet D, Valteau-Couanet D, Lumbroso J, et al. What is the prognostic value of osteomedullary uptake on MIBG scan in neuroblastoma patients under one year of age? Medical and Pediatric Oncology. 1994;22(2):107–14. [PubMed]
  • Naranjo A, Parisi MT, Shulkin BL, London WB, Matthay KK, Kreissman SG, et al. Comparison of 123I-metaiodobenzylguanidine (MIBG) and ¹³¹I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: a report from the Children's Oncology Group. Pediatric Blood and Cancer. 2011;56(7):1041–5. [PMC free article] [PubMed]
  • Neuenschwander S, Ollivier L, Toubeau M, Nguyen-Tan T, Gongora G, Zucker JM. Local evaluation of abdominal neuroblastoma stage III and IV: use of US, CT, and 123 I-meta-iodobenzylguanidine (MIBG) scintigraphy. Annales de Radiologie (Paris) 1987;30(7):491–6. [PubMed]
  • Pfluger T, Schmied C, Porn U, Leinsinger G, Vollmar C, Dresel S, et al. Integrated imaging using MRI and 123I metaiodobenzylguanidine scintigraphy to improve sensitivity and specificity in the diagnosis of pediatric neuroblastoma. American Journal of Roentgenology. 2003;181(4):1115–24. [PubMed]
  • Piccardo A, Lopci E, Conte M, Garaventa A, Foppiani L, Altrinetti V, et al. Comparison of 18F-dopa PET/CT and 123I-MIBG scintigraphy in stage 3 and 4 neuroblastoma: a pilot study. European Journal of Nuclear Medicine and Molecular Imaging. 2012;39(1):57–71. [PubMed]
  • Sharp SE, Shulkin BL, Gelfand MJ, Salisbury S, Furman WL. 123I-MIBG scintigraphy and 18F-FDG PET in neuroblastoma. Journal of Nuclear Medicine. 2009;50(8):1237–43. [PubMed]

References to studies excluded from this review

  • Abramowsky CR, Katzenstein HM, Alvarado CS, Shehata BM. Anaplastic large cell neuroblastoma. Pediatric and Developmental Pathology. 2009;12(1):1–5. [PubMed]
  • Adam M. Report on the Fifth International Symposium on Radiohalogens (Whistler, BC, Canada, September 11-15th, 2004) Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2008;52(2):203–6. [PubMed]
  • Adolph J, Kimmig B. Diagnostic imaging and therapy of neuroectodermal neoplasms [German] Radiologe. 1989;29(1):32–42. [PubMed]
  • Alessio AM, Sammer M, Phillips GS, Manchanda V, Mohr BC, Parisi MT. Evaluation of optimal acquisition duration or injected activity for pediatric 18F-FDG PET/CT. Journal of Nuclear Medicine. 2011;52(7):1028–34. [PubMed]
  • Andersen JB, Mortensen J, Bech BH, Højgaard L, Borgwardt L. First experiences from Copenhagen with paediatric single photon emission computed tomography/computed tomography. Nuclear Medicine Communications. 2011;32(5):356–62. [PubMed]
  • Angelini P, De Bernardi B, Granata C, Villavecchia G, Morbelli S, Luksch R, et al. Skeletal involvement in infants with neuroblastoma a quality control attempt. Tumori. 2007;93(1):82–7. [PubMed]
  • Arceci RJ. Comments from the Editor-in-Chief. Journal of Pediatric Hematology/Oncology. 1999;21(1):1–2. [PubMed]
  • Arceci RJ. Comments from the Editor-in-Chief. Journal of Pediatric Hematology/Oncology. 2003;25(2):97–8. [PubMed]
  • Arora B, Parikh PM. PET-CT scan in pediatric oncology: Where, when, how and at what price. Indian Journal of Cancer. 2010;47(4):355–9. [PubMed]
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References to studies awaiting assessment

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  • Sarkadi M, Schmidt E, Szabo Zs, Szekeres S, Derczy K, Weninger Cs, et al. Significance of SPECT/CT in MIBG examinations of children's neuroblastoma. 17th Congress of the Hevesy Gyorgy Hungarian Society of Nuclear Medicine; 2011 Aug 25-27; Budapest. 2011. pp. A5–6. Nuclear Medicine Review.
  • Schilling FH, Bihl H, Jacobsson H, Ambros PF, Martinsson T, Borgström P, et al. Combined (111)In-pentetreotide scintigraphy and (123)I-mIBG scintigraphy in neuroblastoma provides prognostic information. Medical and Pediatric Oncology. 2000;35(6):688–91. [PubMed]
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  • Suc A, Lumbroso J, Rubie H, Hattchouel JM, Boneu A, Rodary C, et al. Metastatic neuroblastoma in children older than one year: prognostic significance of the initial metaiodobenzylguanidine scan and proposal for a scoring system. Cancer. 1996;77(4):805–11. [PubMed]
  • Tahir N, Malghan L, Ramsden W. MIBG scanning and bone scintigraphy in the staging of neuroblastoma. Are both required? International Congress of Pediatric Radiology, IPR; 2011 May 28-31; London, UK. 2011. p. S417. Pediatric Radiology.
  • Turba E, Fagioli G, Mancini AF, Rosito P, Galli A, Alvisi P. Evaluation of stage 4 neuroblastoma patients by means of MIBG and 99mTc-MDP scintigraphy. Journal of Nuclear Biology and Medicine. 1993;37(3):107–14. [PubMed]
  • Vik TA, Pfluger T, Kadota R, Castel V, Tulchinsky M, Farto JC, et al. (123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma: Results from a prospective multicenter trial. Pediatric Blood and Cancer. 2009;52(7):784–90. [PubMed]
  • Yang J, Codreanu I, Servaes S, Zhuang H. I-131 MIBG post-therapy scan is more sensitive than I-123 MIBG pretherapy scan in the evaluation of metastatic neuroblastoma. Nuclear Medicine Communications. 2012;33(11):1134–7. [PubMed]
  • Young-seok C, Kyung-Han L, KiWoong S, Su Jin L, Hyun Woo C, Joon Young C, et al. Correlation of initial and post-therapy MIBGscintigraphy with bone scintigraphy and biological prognostic markers in stage IV neuroblastoma. 2006;47((S1)):353P. Journal of Nuclear Medicine.

Additional references

  • Beiske K, Burchill SA, Cheung IY, Hiyama E, Seeger RC, Cohn SL, et al. Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. British Journal of Cancer. 2009;100(10):1627–37. [PMC free article] [PubMed]
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  • Boubaker A, Bischof Delaloye A. MIBG scintigraphy for the diagnosis and follow-up of children with neuroblastoma. Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2008;52(4):388–402. [PubMed]
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