Neuroblastoma imaging: From MIBG to advanced PET tracers

Neuroblastoma is the most common extracranial solid malignancy of childhood and accounts for approximately 15% of pediatric cancer-related mortality. Originating from neural crest-derived sympathetic nervous system cells, neuroblastoma demonstrates remarkable biological heterogeneity, ranging from spontaneous regression to highly aggressive metastatic disease. Accurate imaging is fundamental to diagnosis, staging, risk stratification, treatment planning, response assessment, and surveillance. Over the past four decades, molecular imaging of neuroblastoma has evolved substantially, progressing from conventional metaiodobenzylguanidine (MIBG) scintigraphy to advanced positron emission tomography/computed tomography (PET/CT) tracers that provide complementary biological and molecular information. This review explores the evolution of neuroblastoma imaging, highlighting the strengths, limitations, and emerging roles of established and novel radiopharmaceuticals. 131/123I-MIBG scintigraphy remains the cornerstone of functional imaging in neuroblastoma because of its high specificity for tumors expressing the norepinephrine transporter. MIBG imaging has become integral to the International Neuroblastoma Risk Group (INRG) staging system and is widely utilized for evaluating primary tumors, metastatic disease, and therapeutic response. Furthermore, MIBG serves as a theranostic agent, enabling targeted radionuclide therapy with 131I-MIBG in patients with relapsed or refractory disease. However, approximately 5-10% of neuroblastomas demonstrate absent or low MIBG avidity, limiting its diagnostic utility. Additionally, MIBG imaging is constrained by lower spatial resolution, prolonged imaging protocols, and reduced sensitivity for small lesions compared with modern PET techniques. The increasing availability of PET/CT has led to the development of several promising tracers that address these limitations. 18F-fluorodeoxyglucose (18F-FDG) PET/CT has emerged as an important alternative, particularly in MIBG-negative tumors, dedifferentiated disease, and high-risk neuroblastoma. FDG uptake often correlates with tumor aggressiveness and adverse biological features, providing valuable prognostic information. Beyond FDG, tracers targeting specific aspects of neuroblastoma biology have demonstrated significant potential. 18F-fluorodihydroxyphenylalanine (18F FDOPA) PET/CT exploits catecholamine biosynthesis pathways and has shown superior sensitivity for detecting both primary and metastatic lesions. Somatostatin receptor imaging with 68Ga-DOTA-peptides offers opportunities for patient selection for peptide receptor radionuclide therapy.As novel theranostic paradigms emerge, molecular imaging is increasingly serving not only as a diagnostic tool but also as a means of guiding targeted therapies and monitoring treatment efficacy. This review provides a comprehensive overview of contemporary neuroblastoma imaging, tracing the transition from MIBG-based scintigraphy to advanced PET tracers and emerging theranostic approaches. Understanding the complementary roles of these imaging modalities is essential for optimizing patient management and improving outcomes in children with this complex and heterogeneous malignancy.