This analysis investigated the role of FDG-PET metabolic imaging and MIBG imaging in staging and response assessment in neuroblastoma. The nonconcordance found with both MIBG-positive/FDG-PET–negative lesions and MIBG-negative/FDG-PET–positive lesions demonstrates that MIBG is more sensitive overall and for the detection of bone disease, but both imaging modalities have the potential to identify lesions not visualized on the other scan, contributing unique information about disease sites.
Current imaging recommendations to stage neuroblastoma are based on the International Neuroblastoma Staging System first developed in 1988 and revised in 1993.10
The International Neuroblastoma Risk Group is in the process of proposing new modifications to this system.11
The most recent published imaging recommendations for assessment of disease extent are CT and/or MRI scan of the primary tumor site and to assess for spread to the neck, thorax, abdomen, or pelvis. MIBG scan is the preferred method for evaluation of metastatic disease, but if unavailable or negative, a technetium-99m bone scan should be completed.12
Imaging to assess disease response usually includes CT or MRI and MIBG if lesions were previously MIBG positive. Several studies have shown the important role that MIBG imaging plays in assessing disease response.7,13,14
FDG-PET imaging may be completed at the discretion of the treating physician but is not a formally recommended imaging modality in neuroblastoma.
False-negative MIBG imaging can occur in tumors with low expression of the NET, in CNS metastases, or in small tumors in bone marrow.15,16
False-positive results of MIBG imaging can occur due to physiologic uptake within remaining adrenal tissue, bowel, brown fat, salivary glands, myocardium, intestines, and thyroid.17,18
Fully mature neuroblastoma (ganglioneuroma) will also concentrate MIBG in approximately 20% of cases.19
Several pilot studies have demonstrated that FDG uptake in neuroblastoma can be used for detection of primary and metastatic disease.6,20
Additionally, FDG-PET can be useful in staging and monitoring treatment response in patients with MIBG-negative tumors.21
One advantage of FDG-PET is the detailed information about both the anatomic location of the tumor through high-quality three-dimensional images and the metabolic activity of the tumor. A limiting factor is the normal high physiologic uptake of FDG in the brain, making FDG-PET less effective for imaging cranial vault lesions. Bone marrow may also demonstrate increased uptake due to bone marrow hyperplasia after myelosuppressive chemotherapy. Normal uptake is also seen in the tonsils, salivary glands, liver, spleen, myocardium, adenoids, brown fat, epiphyseal cartilage in children, ovaries, and in areas of active muscle contractility, including the vocal cords.22
In a retrospective analysis, Kushner et al20
compared 92 concomitant images in 51 patients with high-risk neuroblastoma in varying phases of treatment and with heterogeneous disease status, finding an overall concordance for presence of disease of 50%. Our study analyzed individual lesion concordance in a homogeneous relapse population and is therefore not directly comparable, but we found a lower concordance rate for individual lesions of 39.6%. Kushner et al also found that FDG-PET imaging showed more sites of soft tissue disease than MIBG in 16 of 36 studies, supporting the results of our study. For bone lesions, FDG-PET more effectively detected disease in extracranial sites, unlike our results, which demonstrate MIBG to be superior to FDG-PET for the detection of all osteomedullary disease. The Kushner et al report suggests that PET, along with bone marrow testing, is sufficient for extracranial disease detection, whereas our data suggest that MIBG is usually more sensitive for disease detection, except in MIBG-negative patients or some soft tissue lesions. The greater sensitivity of MIBG seen in our study may be attributable to the differences in the patient population. The current study included only patients who demonstrated positive MIBG uptake and was comprised of patients who experienced relapse, in whom soft tissue involvement would be expected to be lower and bone and bone marrow disease more prevalent.23
MIBG was more sensitive than FDG-PET overall and for bone lesions for both pre- and post-therapy imaging. FDG-PET seemed to have greater sensitivity for soft tissue lesions, but the relative rarity of soft tissue lesions in this population precluded valid comparison. The study was limited by the inability to confirm active neuroblastoma by biopsy in nonconcordant lesions. Additionally, because the images reviewed were collected from a multicenter study, there was variation in the type of image available for review. Some MIBG scans only had snapshot imaging available for review, whereas others had full-body images and single-photon emission CT. Future prospective studies should use prescribed imaging protocols and electronic transmission of data to minimize scan variability.
The day 13 FDG-PET images show a similar percentage of patients had improvement between study enrollment and day 13 (three of seven patients) and between days 13 and 56 (two of five patients). One patient had a single additional lesion identified on day 13 from study enrollment. This patient then had resolution of five lesions between days 13 and 56. These data suggest that the metabolically active lesions vary in the timing of their response to 131I-MIBG.
Future directions for investigation include determination of the prognostic implications of residual MIBG positivity. In cases where FDG-PET has become negative but MIBG is positive, biopsy might confirm whether the tumor had matured or was only temporarily “stunned” for metabolic activity. Neither FDG-PET nor MIBG scans are sufficiently sensitive to detect small amounts of bone marrow disease, as shown in this study and previously.20,24
Therefore, bilateral bone marrow biopsies continue to be an essential component of disease evaluation. Larger prospective studies of FDG-PET at diagnosis, during, and after therapy correlated with survival would help to determine the relative significance of these modalities.
Our study suggests that for patients with MIBG-positive relapsed neuroblastoma, MIBG is more sensitive than FDG-PET for disease detection and response evaluation. However, given the fact that FDG-PET can identify disease in MIBG-negative lesions, it may serve as a complementary imaging modality in selected patients. Our study demonstrated examples of FDG-PET detection of soft tissue disease not seen on MIBG imaging, even in patients who had other MIBG-positive lesions. FDG-PET indication of response was seen in all assessable patients who showed disease response by MIBG and in two additional patients who had stable and progressive disease by MIBG. The implications of the additional information provided by FDG-PET for disease staging and response evaluation in newly diagnosed patients have not yet been shown. The overall higher sensitivity of MIBG imaging supports continued preferential use of MIBG scans as surveillance imaging for patients not receiving therapy as well as for response evaluation during therapy for relapse, because bone and bone marrow are the most frequent sites of progression.23