Background

Neuroblastoma (NB) is the most common extra-cranial solid tumor in pediatric patients and originates from sympathetic cells derived from the neural crest. Bone and bone marrow metastases are quite common and, if present, result in a poor prognosis [1,2]. Many studies have been reported the important role of 123I-Meta-iodobenzylguanidine (MIBG) at the time of first staging and at the evaluation of treatment response, especially after induction chemotherapy [3-5]. Moreover, 123I-MIBG scan Is required when NB relapse is suspected and may establish the basis for the use of a targeted radionuclide therapy with 131I-MIBG [6]. The principal limitation of conventional nuclear medicine in neuroblastoma (mainly 123I-MIBG scan) is related to its relative low spatial resolution when compared with other radiological and functional techniques such as CT, MRI and PET, similarly to what happens in other pediatric tumors [7-13].

MIBG labeled with 124I, a positron emitting isotope suitable for PET imaging, got increased interest in clinical practice [14-17]. The target of this radiocompound should be the capability of binding noradrenalin receptors as it happens with 123I-MIBG, but with a higher image quality and sensitivity granted by PET hardware [14]. However, limited data exist about the diagnostic accuracy of 124I-MIBG PET in NB.

We present the preliminary experience of the PET Pediatric AIMN (Italian Association of Nuclear Medicine) InterGroup with 124I-MIBG PET/CT in two pediatric patients diagnosed with neuroblastoma in order to highlight the improvement in diagnostic accuracy provided by 124I-MIBG PET/CT compared to the conventional imaging work-up assessing whether 124I-MIBG PET/CT could detect as many or more neuroblastoma lesions than 123I/131I-MIBG imaging.

Case series

Case 1. Taking advantage of the better spatial resolution of ¹²⁴I-MIBG PET/CT

Patient No. 1 (10-year-old female) came to our observation with diagnosis of poorly differentiated abdominal neuroblastoma – stage III –with involvement of the left kidney and the homolateral adrenal gland. The patient had undergone neoadjuvant chemotherapy (clsplatln, etoposlde and VP 16) before radical resection of the large abdominal mass. One year after surgery, the patient was referred for 131I-MIBG therapy (dose: 10 GBq) for a pulmonary relapse detected by a computed tomography (CT) exam. The 123I-MIBG pre-therapy and the 131I-post-therapy whole body scans depicted a single focal round-shaped uptake In the right lung. Aweek later, the child was proposed to scan with the experimental radiopharmaceutical 124I-MIBG for compassionate use, regulated by Legislative Decree No. 219/2006. After receiving written consent from the parents, the patient was evaluated by PET/CT at 24h and 48h after the administration of 50 MBq of 124I-MIBG (radiochemical purity > 95%) (Fig. 1). The PET/CT study (Fig. 2) confirmed the finding detected by both 123I-MIBG scintigraphy and 131I-post-therapy whole body scan allowing a better characterization and localization of the finding in the basis of the right lung.

Afterwards, the patient underwent metastasectomy and the disease had afavorable course confirmed by a subsequent 123I-MIBG scintigraphy and a chest CT performed three and six months later, respectively. Nevertheless, the patient developed lumbar pain and signs of paraparesis a few months later, and a whole body CT with contrast medium revealed diffuse metastases to both lungs, abdominal lymph nodes and the fifth lumbar vertebra. Therefore the patient was referred for a second course of 131I-MIBG therapy. The 131I-MIBG post-therapy whole body scan (Fig. 3) was able to highlight all the lesions demonstrated by the CT scan, but pre-therapy 124I-MIBG PET/CT yielded a very good definition of the extent of disease (Fig. 4), demonstrating also the involvement of the medullary canal by the lesion located in the L3 vertebra, explaining the origin of the symptomatology of the patient, and revealed faint foci in L1, L4, L5 and sacrum (Fig. 5). On the basis of the clinical condition and imaging findings, the patient underwent a further treatment with 131 I-MIBG, with a delivered dose of 10 GBq (270 mCi).

Case 2. Depiction of all metastatic sites in one single full-body exam

Patient No. 2 was a 6-year-old boy with left adrenal gland neuroblastoma (stage IV) diagnosed when he was 1-year-old. The pathologic history had showed persistent bone disease involvement although the patient had already been treated with surgery, radiotherapy chemotherapy and auto-transplantation over the years. After performing a follow-up 123I-MIBG scintigraphy in another center for restaging purposes, he was referred to our department to receive a course of 9.9 GBq (270 mCi) 131I-MIBG. The 131I-MIBG post-therapy scan showed diffuse osseous disease (Fig. 6A, B) Including the skull, the left scapula, several vertebrae, the right and left iliac bones, the ischiatic spine, the proximal part of the left tibia and the bone marrow canal of the right femur. After gaining informed consent from the patient, 124I-MIBG PET/CT was also performed for compassionate use and was able to visualize the same lesions as detected by the planar scintigraphy with 131I-MIBG (Fig. 6C-F) clearly providing images with better spatial resolution in all the bone districts.

Discussion

Although MIBG, radiolabeled with 123I, has high sensitivity (around 90%) and specificity close to 100% in the diagnosis of neuroblastoma [17], nevertheless an important role of labeled MIBG is also prospectively to evaluate the feasibility of 131I-MIBG radiometabolic therapy, which can be an additional therapeutic option in case of disseminated metastatic disease in which tumor cells have retained the capability of concentrating MIBG [6].

From this point of view, 124I-MIBG PET/CT represents a potential method to estimate radiation dose to normal organs, as well as tumors, prior to 131I-MIBG treatment and provide a more accurate quantification of tracer distribution because of its favorable characteristics, such as full-body tomographic capability from PET and a similar half-life (4.2 days) to 131I (8.02 days) [15].

Despite this important aspect, only few reports published in literature regarded the use of 124I-MIBG in adult patients with neural crest tumors [14, 16] and, to the best of our knowledge, only one child with neuroblastoma has been studied with 124I-MIBG PET/CT so far [18], providing data on dosimetry. Organ-absorbed doses for the salivary glands, heart wall and liver were 98.0 Gy, 36.5 Gy, and 34.3 Gy respectively whereas tumor-absorbed dose range was 143.9-1,641.3 Gy [18].

Many other studies investigated the role of PET/CT using other tracers such as 18F-DOPA [7, 19], 68Ga-labelled somatostatin analogues and 18F-FDG in patients with neuroblastoma [20]. Anyway, although these tracers can provide an excellent diagnostic accuracy in patients affected by neuroblastoma, nevertheless the labeled pharmaceutical has a metabolic behavior which is similar but not equal to Iodine-labeled MIBG.

In our series, we investigated if 124I-MIBG PET/CT could be considered a valuable tool in the diagnostic work-up of pediatric patient with advanced neuroblastoma.

From our experience, 124I-MIBG PET/CT provides high-resolution images and may offer valuable information regarding the extension of the lesion and the involvement of different types of tissue, addressing the most appropriate clinical management between surgical treatment and medical therapy [21]. In the present study with the limit of lack of SPECT/CT, we could compare in our patients images obtained with 123I-MIBG scintigraphy, 131I-MIBG scintigraphy and with 124I-MIBG PET/CT, with the latter providing the same e information about the tumor location In the case of the single round-shaped pulmonary lesion (patient n. 1).

In patient No. 1, the first 124I-MIBG PET/CT not only confirmed the finding detected by both 123I-MIBG scintigraphy and 131I-MIBG post-therapy scan, but allowed a better characterization and localization of the finding in the basis of the right lung, helping the clinical staff in the decision of performing a metastasectomy. Furthermore, the second 124I-MIBG PET/CT, performed in case No. 1, provided a very accurate definition of the extent of disease demonstrating the intracanal and the extra canal components of the lesion located at the level of L3 and detected a higher number of lesion (L1, L4, L5 and sacrum) In comparison to 131I-MIBG and CT. The findings of 124I-MIBG PET/CT were useful for the clinicians to link the symptomatology of the patient (lumbar pain and signs of paraparesis) to the pathologic involvement of the medullar canal.

Since metastatic spread of neuroblastoma may occur over the full length of the skeleton and since MIBG does not present uptake in the brain, ¹²⁴I-MIBG gives excellent images of the skull and so is useful to detect secondary lesions in this anatomical region, which is a relatively freguent site of metastasis. Likewise, ¹²⁴I-MIBG PET/CT should be performed in full body modality from the vertex of the skull to the feet.

A possible limitation in evaluating pediatric patients with ¹²⁴I-MIBG PET/CT is the relatively higher radiation dose delivered (0.25 mSv/MBg) when compared to ¹²³I-MIBG (0.019 mSv/MBg). Nevertheless, the improved characteristics of modern PET/CT scanners allow limiting the administered dose while maintaining an adeguate image quality [22]. Moreover, the additional dose can be considered negligible by comparison if ¹²⁴I-MIBG is performed as a pre-therapy evaluation tool before ¹³¹I-MIBG treatment.

Although there is lack of information in literature, this preliminary experience shows promising results for ¹²⁴I-MIBG PET/CT; anyway, a large validation and a standardization of the technigue is needed, such as for the optimal timing of ¹²⁴I-MIBG PET imaging acguisition.

Multicenter investigations would be desirable, in order to foster the possible role of this technigue in evaluating patients with neuroblastoma. At present, we could at least suggest to perform a ¹²⁴I-MIBG PET/CT as a pre-therapy examination, given the high diagnostic accuracy demonstrated by our cases, and for restaging, especially when doubtful findings are evidenced by scintigraphic imaging with ¹²³I- or ¹³¹I-MIBG.

Correspondence to:
Angelina Cistaro, MD,
Positron Emission Tomography Centre IRMET S.p.A.
Euromedic Inc.
V. O. Vigliani 89/A, 10138 Turin, Italy
Tel +39 01 13 160 159
Fax+39 01 13 160 828
E-mail: a.cistaro@irmet.com