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Neuroblastoma

Neuroblastoma is a rare and aggressive cancer that originates from immature nerve cells known as neuroblasts, which are part of the . It typically develops in young children, most commonly infants under the age of 1 year, and is the most frequent extracranial solid tumor in this population, accounting for about 8-10% of all childhood cancers. These tumors often arise in the adrenal glands but can also form in the , chest, , or near the , and while some cases may spontaneously regress, particularly in very young patients, others can spread rapidly to bones, liver, lymph nodes, or skin. Epidemiologically, neuroblastoma is diagnosed in approximately 700-800 children annually , with a age at of 19 months and over 90% of cases occurring before age 5. It is slightly more common in boys than girls and in white children compared to other racial groups. The disease is classified into low, intermediate, or high-risk groups based on factors such as the child's age, tumor stage (using the International Neuroblastoma Risk Group Staging System), , DNA , and amplification of the MYCN , which significantly influences and outcomes. The exact cause of neuroblastoma remains unknown in most cases, but it involves genetic mutations that prevent neuroblasts from maturing into normal cells. Risk factors include a family history of the disease (in about 1-2% of cases), inherited genetic changes such as mutations in the ALK gene, and associations with certain syndromes like or Beckwith-Wiedemann syndrome. Prenatal exposure to certain factors, such as , may increase risk, while some studies suggest that maternal use of multivitamins or folic acid during pregnancy could potentially lower it, though more research is needed. Symptoms of neuroblastoma vary depending on the tumor's location and size but often include a painless lump or swelling in the , , or chest; leading to limping; dark circles or bruising around the eyes (from tumor spread); bulging or uneven eyes; unexplained fever, , or ; and enlarged lymph nodes. is highly variable: as of data from 2013-2019, low-risk cases have 5-year rates exceeding 90%, intermediate-risk around 85-90%, and high-risk cases about 60%, with overall for all patients approaching 82% due to advances in including , , , and .

Background

Definition

Neuroblastoma is an embryonal malignancy that arises from cells, which are primitive cells that develop into components of the , such as neuroblasts in the and paraspinal . It is classified as a small round blue cell tumor, a heterogeneous group of pediatric cancers characterized by primitive, undifferentiated cells with scant and hyperchromatic nuclei visible under . The primary sites of origin for neuroblastoma are most commonly in the , particularly the adrenal glands or retroperitoneal sympathetic chain, accounting for approximately 65-80% of cases, while other locations include the (mediastinal ganglia), , and . This tumor predominantly affects young children, with over 90% of diagnoses occurring in those under 5 years of age and a median age at diagnosis of about 19 months; it is exceedingly rare in adults. Pathologic classification of neuroblastoma relies on systems such as the International Neuroblastoma Pathology Classification (INPC), which assesses tumor , mitosis-karyorrhexis index, and Schwannian stroma content to categorize tumors as favorable or unfavorable , and the International Neuroblastoma Risk Group (INRG) system, which integrates clinical, histologic, and biologic factors like MYCN amplification for risk stratification. Histologically, subtypes range from differentiating neuroblastoma, which shows evidence of neuronal maturation and is associated with a more favorable prognosis, to undifferentiated forms lacking maturation features and linked to poorer outcomes.

Epidemiology

Neuroblastoma is the most common extracranial solid tumor in children, with a global incidence of approximately 10.2 cases per million children under 15 years of age. In the United States, it accounts for about 600 to 800 new cases annually, representing roughly 7% to 10% of all childhood cancers. The disease predominantly affects young children, with approximately 90% of cases diagnosed before age 5 years and a age at of 18 to 22 months; it is rare in individuals over 10 years. There is a slight predominance, with a male-to-female ratio of about 1.1 to 1.2:1. Incidence rates are higher among children compared to other ethnic groups, such as , , and Asian populations, where rates are 20% to 50% lower. Geographic variations show higher incidence rates in developed regions, such as and (7 to 12 cases per million in predominantly populations), compared to lower rates in and (often 1 to 3 per million), potentially influenced by underdiagnosis in low-resource settings and possible environmental factors like prenatal exposures to folate antagonists or . Familial forms account for 1% to 2% of cases and are associated with genetic syndromes, including Beckwith-Wiedemann syndrome (where neuroblastoma prevalence is less than 1% in certain subtypes) and Hirschsprung disease (linked via PHOX2B mutations). Incidence rates have remained stable over the past several decades, though has improved significantly due to advances in risk stratification and therapies, with 5-year overall rates increasing from about 50% in the to over 80% currently for all stages combined. Spontaneous occurs in 10% to 20% of low-risk cases, particularly in infants with favorable , allowing for observation-based management in select patients.

Pathophysiology

Etiology and Risk Factors

Neuroblastoma is primarily a sporadic disease, accounting for approximately 98% of cases, with no identifiable inherited genetic predisposition in the majority of affected children. Familial neuroblastoma represents a rare subset, comprising about 1-2% of cases, and is most commonly associated with germline mutations in genes such as ALK and PHOX2B. Mutations in PHOX2B are particularly linked to syndromic presentations, including congenital central hypoventilation syndrome (CCHS), where affected individuals have a heightened risk of developing neuroblastoma due to disruptions in neural crest development. These familial cases often exhibit low penetrance, meaning not all mutation carriers develop the tumor, underscoring the complex interplay of genetic and environmental influences. Environmental risk factors have been investigated extensively, though evidence remains inconsistent and no single is definitively causative. Prenatal and perinatal exposures show associations in some studies; for instance, evidence for maternal consumption during preconception or is inconsistent, with a recent showing no significant association (pooled OR 0.90, 95% 0.76–1.07). Paternal and maternal occupational to s during or preconception are also implicated, with odds ratios ranging from 1.20 to 1.85 for pesticide . Childhood to pesticides and high birthweight (over 4,000 grams) further elevate , with pooled odds ratios of 1.28 and 1.21 (95% 1.02–1.42), respectively. Cesarean delivery has been associated with a modestly increased (odds ratio 1.14, 95% 1.00–1.30), potentially due to altered development or other perinatal factors. Evidence for maternal diet, , or electromagnetic fields is mixed and not consistently supported across large cohorts. Congenital associations highlight neuroblastoma's ties to neurocristopathies, disorders arising from cell migration defects, affecting 1-2% of cases. Notably, neuroblastoma occurs in 1-5% of children with , a condition involving aganglionosis of the colon, often co-occurring with PHOX2B mutations. Other linked syndromes include CCHS and, less commonly, type 1, where neural crest-derived tumors like neuroblastoma may emerge. These associations suggest early developmental disruptions in neural crest lineages contribute to tumorigenesis. Overall, neuroblastoma's is multifactorial, with no single causative agent identified; instead, it involves low-penetrance interactions between environmental exposures, perinatal factors, and congenital anomalies. Recent systematic reviews up to 2025 emphasize the need for further research into early-life epigenetic modifiers and influences, as current associations explain only a fraction of cases.

Genetic and Molecular Mechanisms

Neuroblastoma arises from neural crest-derived cells and is characterized by a heterogeneous array of genetic and molecular alterations that drive tumor initiation, progression, and aggressive behavior. Key somatic alterations include amplification of the MYCN , observed in 20-25% of primary tumors and associated with advanced stage, rapid progression, and poor overall survival. Activating mutations in the ALK gene occur in approximately 10% of cases, predominantly in high-risk neuroblastomas, leading to constitutive activity that promotes cell survival and proliferation; these mutations are considered targetable due to their role as driver events. Chromosomal abnormalities are hallmark features, with segmental aneuploidies prevalent in high-risk disease. Deletions of chromosome arm 1p, often involving the 1p36 region, are found in about 25-35% of advanced tumors and correlate with unfavorable histology and reduced event-free survival. Loss of heterozygosity (LOH) at 11q, affecting tumor suppressor genes, occurs in 20-40% of cases without MYCN amplification and independently predicts worse outcomes. Gain of chromosome arm 17q is one of the most common alterations, present in over 70% of high-risk neuroblastomas, and is linked to metastatic potential through overexpression of genes like BIRC5 and PPM1D. In contrast, low-risk neuroblastomas often exhibit numerical aneuploidy, such as hyperdiploidy with whole-chromosome gains, which is associated with favorable prognosis and spontaneous regression. Epigenetic dysregulation contributes significantly to neuroblastoma , with global DNA hypermethylation leading to silencing of tumor suppressor genes and enhanced tumor aggressiveness. Non-coding RNAs, particularly microRNAs, play regulatory roles; for instance, suppression of miR-34a, located at 1p36, is frequently observed due to deletion or epigenetic inactivation, resulting in derepression of MYCN and promotion of progression and anti-apoptotic effects. Deregulated signaling pathways underpin the molecular drivers of neuroblastoma. Activating ALK mutations stimulate downstream PI3K/AKT signaling, enhancing cell survival, metabolic reprogramming, and MYCN stabilization in tumor cells. Trk receptor signaling, mediated by neurotrophins binding to NTRK1-3, promotes neuronal differentiation and is upregulated in favorable, low-stage tumors, contrasting with its downregulation in aggressive cases. Telomere maintenance is critical for immortalization, with the alternative lengthening of telomeres (ALT) mechanism active in 25-30% of high-risk neuroblastomas, often linked to ATRX mutations, enabling replicative immortality and association with older age at diagnosis and relapse. Recent advances from 2024-2025 highlight the integration of maintenance mechanisms (TMM) into neuroblastoma systems, as ALT-positive tumors demonstrate significantly poorer 5-year overall (53% vs. 77%) and event-free (21% vs. 67%) compared to TMM-negative cases, prompting calls for refined high- . Emerging therapeutic include ROR1, a overexpressed in high- subsets driving Wnt signaling and invasion; the MDM2-p53 axis, where amplification inhibits p53-mediated ; and DPYSL3, a cytoskeletal regulator implicated in metastatic dissemination.

Clinical Presentation

Signs and Symptoms

Neuroblastoma most commonly presents with symptoms related to the site or metastatic disease, though manifestations vary widely depending on the location, age of the patient, and stage at . Approximately 65% of arise in the , often as adrenal or paraspinal masses, leading to a painless abdominal mass or distension that may cause discomfort or fullness without acute pain. These tumors can also compress nearby structures, resulting in , , or, less commonly, due to catecholamine release from the tumor. Thoracic primary tumors, accounting for about 15% of cases, typically manifest with respiratory symptoms such as wheezing, , or distress from airway . Involvement of cervical or thoracic sympathetic chains may produce Horner syndrome, characterized by ipsilateral ptosis, , and anhidrosis. Neck primaries, which are rare (around 3-5%), can present as a palpable mass potentially causing hoarseness or vocal cord changes due to recurrent laryngeal nerve . Pelvic tumors (approximately 5%) may lead to urinary obstruction, , or lower extremity weakness from nerve involvement. Metastatic disease, present in over 50% of cases at , often causes systemic symptoms including , fever, and weight loss from skeletal involvement. Orbital metastases can result in periorbital ecchymosis, known as "," along with proptosis or bruising around the eyes. General nonspecific signs such as , , , and are common, reflecting infiltration or chronic illness. In about 90% of cases, tumors produce excess catecholamines, which may lead to flushing, sweating, , or chronic , though overt symptoms occur in a minority. A small proportion of neuroblastomas are discovered asymptomatically through screening programs or incidental imaging findings.

Paraneoplastic Syndromes

Paraneoplastic syndromes in neuroblastoma encompass immune-mediated neurological disorders and rare endocrine effects arising from tumor secretion, distinct from direct tumor invasion or metastasis. These syndromes occur in a minority of cases and often signal an underlying neuroblastoma, particularly in children, with opsoclonus-myoclonus-ataxia syndrome (OMAS) being the most recognized immune-mediated form. Vasoactive intestinal peptide (VIP)-secreting tumors represent an endocrine paraneoplastic manifestation, while other rare associations include anti-Hu antibody-related syndromes and due to catecholamine excess. Opsoclonus-myoclonus-ataxia syndrome (OMAS), also known as dancing eyes-dancing feet syndrome, affects approximately 2% of children with neuroblastoma and is characterized by chaotic, involuntary eye movements (opsoclonus), irregular muscle jerks (), truncal , and behavioral changes such as or sleep disturbances. This syndrome typically presents before age 2 years and is linked to an autoimmune response involving anti-neuronal antibodies, such as anti-Ri or occasionally anti-Hu, triggered by shared antigens between neuroblastoma cells and neurons. Despite effective tumor control, up to 70% of patients experience persistent neurological sequelae, including cognitive deficits, motor impairments, and behavioral issues, highlighting the disproportionate impact on neurodevelopment compared to oncologic outcomes. VIP-secreting neuroblastic tumors, occurring in less than 1% of cases, cause watery diarrhea-hypokalemia-achlorhydria (WDHA) through excessive VIP , leading to secretory diarrhea, electrolyte imbalances, and that can be life-threatening if untreated. These tumors are often ganglioneuroblastomas or differentiating neuroblastomas with favorable biology, and symptoms typically resolve promptly following surgical resection, underscoring the direct causal role of VIP hypersecretion. Rare paraneoplastic manifestations include anti-Hu antibody-associated , which can present with sensory neuropathy, , or autonomic dysfunction in neuroblastoma patients, reflecting an autoimmune attack on neuronal proteins expressed by the tumor. , driven by paraneoplastic catecholamine overproduction, may manifest as severe , seizures, and altered mental status, serving as an initial presentation in isolated cases. The pathophysiology of these syndromes generally involves an aberrant to tumor-expressed neural antigens, leading to with healthy tissues, or ectopic hormone secretion mimicking endocrine disorders. In OMAS, this results in favorable tumor prognosis—often low-risk disease with survival exceeding 95%—but challenging neurological recovery. Management of OMAS focuses on tumor eradication alongside ; first-line therapies include corticosteroids, intravenous immunoglobulin (IVIG), and rituximab, with early rituximab initiation showing response rates of 70-80% for symptom control and reduced relapse risk, though long-term neurocognitive support remains essential.00232-7/fulltext) For VIP-related WDHA, supportive care with fluid and electrolyte replacement precedes definitive tumor removal, which cures the syndrome in most instances. Anti-Hu syndromes may respond partially to IVIG or plasma exchange, while hypertensive cases require antihypertensive agents alongside tumor-directed therapy.

Diagnosis

Biochemical and Laboratory Tests

Diagnosis of neuroblastoma often involves biochemical and laboratory tests to detect tumor markers and assess disease extent. Urinary catecholamine metabolites, specifically (VMA) and homovanillic acid (HVA), are elevated in approximately 90-95% of cases, serving as key diagnostic indicators due to the tumor's production of catecholamines. The HVA/VMA in urine provides additional prognostic value, with higher ratios associated with less differentiated tumors and poorer outcomes, aiding in risk stratification. Serum markers such as (LDH) and neuron-specific enolase (NSE) are also routinely evaluated. Elevated LDH levels exceeding 1400 IU/L at correlate with advanced disease and indicate a poor , reflecting tumor burden and damage. Similarly, increased serum NSE is observed in advanced neuroblastoma and is linked to unfavorable outcomes, as it reflects neuronal differentiation and tumor activity. Routine laboratory assessments include (CBC), which may reveal or due to bone marrow infiltration by neuroblastoma cells. ferritin levels are often elevated in high-risk cases and serve as a prognostic marker associated with worse survival. Additionally, ganglioside levels can be measured, as they are overexpressed in neuroblastoma and correlate with disease progression, though they are more commonly targeted in contexts. Molecular tests utilizing liquid biopsy techniques analyze plasma or serum for neuroblastoma-derived DNA to detect genetic alterations. Droplet digital PCR (ddPCR) enables quantification of MYCN copy number amplification and ALK mutations in cell-free DNA, providing non-invasive assessment of high-risk features without requiring tissue biopsy. As of 2025, circulating tumor DNA (ctDNA) analysis has emerged for monitoring minimal residual disease (MRD) in neuroblastoma patients post-treatment. Techniques such as serial quantification of TERT rearrangement breakpoints in ctDNA allow sensitive detection of residual tumor cells, facilitating early relapse identification and personalized follow-up.

Imaging Modalities

Ultrasound serves as an initial, non-invasive screening tool for suspected abdominal neuroblastoma, particularly in pediatric patients presenting with an abdominal mass. It effectively detects the presence of a solid, heterogeneous mass, often with internal calcifications, and assesses vascular encasement using to evaluate tumor vascularity and involvement of adjacent organs such as the kidneys or liver. This modality is advantageous due to its availability, lack of , and capabilities, making it suitable for initial localization before more advanced . Computed tomography (CT) and magnetic resonance imaging (MRI) provide detailed anatomical characterization of the primary tumor and its extent. excels in identifying calcifications, lymph node involvement, and vascular structures, offering rapid whole-body assessment, though it involves . MRI is generally preferred for evaluating invasion and involvement, as neuroblastoma typically appears iso- to hypointense on T1-weighted images and hyperintense on T2-weighted sequences, with heterogeneous enhancement post-contrast; its lack of makes it ideal for repeated in children. Quantitative MRI techniques, such as apparent diffusion coefficient mapping, further aid in assessing tumor cellularity and prognosis. Meta-iodobenzylguanidine (MIBG) , using 123I-MIBG, is the cornerstone of for neuroblastoma, demonstrating specific uptake in approximately 90% of cases due to the tumor's catecholamine mechanism. This modality localizes the , detects bone and metastases with high specificity, and evaluates treatment response by quantifying uptake changes over time, often combined with (SPECT)/CT for improved anatomical correlation. It is particularly valuable for and surveillance in MIBG-avid tumors, which constitute the majority. For the 10% of neuroblastomas that are non-MIBG-avid, positron emission tomography-computed tomography (PET-CT) with tracers such as 18F-fluorodeoxyglucose (18F-FDG) or 68Ga-DOTATATE offers alternative . 18F-FDG PET-CT highlights metabolically active disease in high-risk or undifferentiated tumors, aiding in and detecting extraskeletal metastases. Meanwhile, 68Ga-DOTATATE PET-CT, targeting somatostatin receptors expressed in some neuroblastomas, shows promise for improved sensitivity in non-avid cases and high-risk , with emerging data supporting its role in planning. Bone scintigraphy with 99mTc-methylene diphosphonate (99mTc-MDP) is employed to identify skeletal metastases, particularly in the and metaphyses, but it lacks specificity for neuroblastoma compared to MIBG, often overestimating disease due to reactive changes or . It may complement other modalities in equivocal cases but is not recommended as a first-line tool for , as it rarely identifies unique lesions that alter management. Recent advances in neuroblastoma imaging include AI-enhanced MRI for risk prediction, where machine learning algorithms analyze quantitative features like and metrics to forecast outcomes such as overall survival with high accuracy. Additionally, theranostic imaging with 177Lu-DOTATATE is gaining traction for peptide receptor radionuclide therapy in somatostatin receptor-positive tumors, enabling simultaneous diagnostic assessment and targeted treatment delivery in select high-risk cases. These developments, integrated with multimodal approaches, enhance precision in and personalization of therapy.

Histopathology

Neuroblastoma is characterized histopathologically by the presence of small round blue cells with scant cytoplasm, hyperchromatic nuclei, and a high nuclear-to-cytoplasmic ratio, often arranged in sheets, nests, or clusters within a fibrovascular . In differentiating subtypes, tumor cells may form Homer-Wright rosettes, consisting of neuroblasts surrounding a central core of , which represents tangled neuritic processes. A background, composed of fine fibrillary material, is commonly observed, particularly in more mature tumors, aiding in the distinction from other small round blue cell tumors. The Shimada classification system evaluates neuroblastoma to predict , categorizing tumors as favorable or unfavorable based on at , degree of , mitosis-karyorrhexis index (MKI), and content. Favorable histology includes -rich tumors with low MKI or -poor tumors showing features in patients under 5 years; unfavorable features encompass high MKI (>200/5000 cells), anaplastic changes, or undifferentiated , particularly in older patients. This -linked grading emphasizes the role of maturation potential in neuroblastic tumors. Immunohistochemical staining supports the diagnosis by demonstrating positivity for neural markers such as and chromogranin A, which highlight neuroendocrine differentiation in tumor cells. The NB84 is particularly useful for confirming neuroblastoma, showing strong reactivity in neuroblasts while helping differentiate it from or . These markers are essential for identifying residual disease in biopsies. Electron microscopy reveals ultrastructural evidence of neural crest origin, including dense core neurosecretory granules (50-200 nm) within cytoplasmic processes, often accompanied by microtubules and neuritic extensions. These features, such as membrane-bound dense cores, confirm the neuroblastic nature in ambiguous cases. The International Neuroblastoma Pathology Classification (INPC) integrates Shimada criteria with age and histological grade to assign favorable or unfavorable status, incorporating molecular markers like MYCN amplification for refined prognostication. Recent 2025 updates recommend including telomere maintenance mechanism (TMM) assessment in pathology reports, as alternative lengthening of telomeres (ALT) correlates with poorer outcomes and influences risk assignment.

Staging and Risk Stratification

Staging of neuroblastoma involves classifying the extent of disease to guide treatment decisions, with two primary systems in use: the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group (INRG) Staging System. The INSS, developed in 1988 and revised in 1993, is a postsurgical system that assesses tumor resectability, lymph node involvement, and distant metastases after initial surgery. It defines five stages:
StageDescription
1Localized tumor completely resected, no regional involvement.
2ALocalized tumor incompletely resected, no ipsilateral involvement.
2BLocalized tumor resected (complete or incomplete), with ipsilateral involvement but no crossing the midline.
3Unresectable tumor crossing the midline, or regional involvement on the opposite side; or midline tumor with bilateral involvement.
4Disseminated disease to distant s, , , liver, or other organs (except stage 4S).
4SAge <12 months, localized primary tumor with dissemination limited to skin, liver, or (<10% tumor involvement).
In contrast, the INRG Staging System, introduced in 2009, is a preoperative clinical staging approach that relies on imaging to identify image-defined risk factors (IDRFs), such as vascular encasement, organ infiltration, or tumor extension into multiple body compartments, without requiring surgical intervention. It categorizes tumors as L1 (localized, no IDRFs), L2 (localized, ≥1 IDRF), or M (metastatic disease). The presence of IDRFs predicts surgical risk and influences stage assignment. Risk stratification integrates stage with clinical and biological factors to categorize patients into low, intermediate, or high-risk groups, enabling tailored therapy. Key factors include age at diagnosis, INSS/INRG , MYCN gene amplification status, tumor (favorable vs. unfavorable), and DNA ploidy (hyperdiploid vs. diploid). High-risk disease is defined by criteria such as age >18 months with 4 disease, any age with MYCN amplification, or 3 with unfavorable and age >18 months. Low-risk includes 1 or 2 without MYCN amplification and favorable , while intermediate-risk encompasses 3 in infants <18 months or 4S with limited progression. The Children's Oncology Group (COG) and International Society of Paediatric Oncology (SIOP) employ similar but distinct risk criteria, both incorporating INRG staging and biomarkers like segmental chromosomal aberrations (SCAs). COG's 2021 revised classifier (version 2) uses INRGSS and SCAs to refine risk groups prospectively. SIOP guidelines, updated in 2023, adapt risk stratification for resource-limited settings, emphasizing MYCN status and age for low- and intermediate-risk definitions. As of 2025, updates to risk stratification incorporate telomere maintenance mechanisms (TMM), including alternative lengthening of telomeres (ALT), to identify an ultra-high-risk subclass within high-risk groups, associated with poorer outcomes regardless of other factors. Tumors with TMM, such as ALT positivity or TERT promoter mutations, are now recommended for integration into international criteria to escalate therapy. Prognostic scoring systems like the Curie score further refine risk by semiquantitatively assessing metastatic burden on meta-iodobenzylguanidine (MIBG) scans, dividing the skeleton into regions scored from 0 (no uptake) to 4 (multiple sites with bone destruction), with total scores >2 post-induction indicating worse in high-risk cases.

Screening and Early Detection

Population-Based Screening

Population-based screening for neuroblastoma involves mass testing of asymptomatic infants in the general to detect the disease early, primarily through of urinary catecholamine metabolites such as vanillylmandelic acid (VMA) and homovanillic acid (HVA). The most extensive historical program occurred in , where nationwide screening began in 1985 for all infants at approximately 6 months of age using these biochemical markers. This initiative detected an increased number of cases, with incidence rising to about 1 in 7,500 screened infants, but predominantly identified low-stage, favorable-prognosis tumors that often regress spontaneously. However, it resulted in significant , as many detected tumors would not have progressed clinically, leading to unnecessary interventions and psychological burden on families. Regarding effectiveness, early evaluations of the Japanese program suggested a potential 10-20% reduction in neuroblastoma mortality among screened cohorts compared to prescreening eras, attributed to earlier detection of treatable cases. Nonetheless, larger population-based studies, including those from Germany and Canada, found no significant decrease in the incidence of advanced-stage disease or overall mortality, with screening failing to impact high-risk cases that typically arise after the screening age. High false-positive rates, often exceeding 10% of screened infants requiring further evaluation, combined with the program's high costs and limited long-term benefits, led to its discontinuation in Japan in 2004. Post-cessation analyses confirmed no rebound in mortality rates, underscoring the lack of sustained impact. As of 2025, major health organizations, including the (ACS) and the (NCI), do not recommend routine population-based screening for neuroblastoma due to the absence of proven mortality benefits and the risks of and . The (WHO) aligns with this stance, emphasizing that screening does not alter disease outcomes in the general population. Key challenges include lead-time bias, where early detection artificially inflates survival statistics without extending actual lifespan, and the program's inability to identify high-risk tumors that develop prenatally or after infancy, many of which regress without intervention. Additionally, screening misses opportunities for detecting aggressive cases that manifest later in childhood. As alternatives, some experts propose integrating targeted biochemical testing into standard pediatric health check-ups for infants, focusing on high-incidence regions to balance feasibility and , though no widespread implementation exists. Pilot programs in select high-incidence areas, such as parts of , continue to evaluate refined screening strategies, but these remain experimental and not endorsed for broad adoption.

High-Risk Population Screening

High-risk population screening for neuroblastoma targets individuals with familial or genetic predispositions, aiming to detect tumors at an early, potentially curable through targeted surveillance protocols. In familial neuroblastoma, which accounts for approximately 1-2% of cases and is often linked to mutations in genes such as ALK or PHOX2B, siblings of affected children are recommended to undergo screening starting from birth. This includes measurement of urinary catecholamine metabolites, such as (VMA) and homovanillic acid (HVA), which are elevated in over 90% of neuroblastoma cases, combined with abdominal to identify adrenal or abdominal masses. For individuals with genetic syndromes conferring elevated risk, enhanced surveillance is advised, particularly for carriers of PHOX2B or ALK mutations. PHOX2B mutations are associated with conditions like congenital central hypoventilation syndrome (CCHS), where the neuroblastoma risk is 1-2%, meeting the threshold for routine monitoring. The Children's Oncology Group (COG) guidelines recommend abdominal ultrasound and urinary catecholamine testing every 3 months from birth to age 6 years, then every 6 months to age 10 years, along with chest X-rays every 6 months (birth to 6 years) and every 6-12 months thereafter (ages 6-10 years); physical examinations are included as part of routine care. ALK mutation carriers, comprising about 50% of familial cases, follow similar protocols, with genetic testing offered to first-degree relatives to identify at-risk individuals. Surveillance is also recommended for other predisposition genes such as CDKN1C (Beckwith-Wiedemann syndrome) and EZH2 (Weaver syndrome), with protocols adjusted for penetrance. Prenatal detection of neuroblastoma occurs incidentally through routine fetal or targeted MRI, often identifying adrenal masses in the third . These prenatally diagnosed tumors are typically low-stage and cystic, with a significant proportion resolving spontaneously without intervention. Postnatal confirmation involves serial imaging and biochemical tests to assess progression or regression. Current COG guidelines emphasize genetic counseling for all families with a history of neuroblastoma, recommending imaging and biochemical for first-degree relatives identified as carriers. A 2024 update from the , based on the AACR Predisposition Workshop, refined prior protocols with increased frequency and extension to age 10 years for applicable genes. Early detection through these high-risk screening strategies significantly improves resectability, with prenatally or familially identified tumors often amenable to complete surgical removal and associated with survival rates exceeding 90% in low-risk cases. However, challenges persist, including ethical concerns over screening in low-penetrance gene carriers, where the risk of and unnecessary interventions may outweigh benefits due to the potential for spontaneous .

Treatment

Surgical Interventions

Surgical interventions play a central role in the management of neuroblastoma, particularly aiming for the removal of the to achieve local control while minimizing morbidity in pediatric patients. The primary objective is gross total resection (GTR), defined as the removal of more than 90% of the tumor volume, which is especially targeted in low-risk, localized disease to potentially obviate the need for additional therapies. For intermediate- and high-risk cases, surgery often serves as a procedure to reduce tumor burden after initial . Indications for surgical intervention are guided by tumor stage and the presence of image-defined risk factors (IDRFs), which assess potential surgical risks such as vascular encasement or organ proximity. In 1 or 2 neuroblastoma without IDRFs, upfront is preferred to achieve complete resection with low morbidity. Conversely, for high-risk disease or tumors with IDRFs, is typically delayed until after neoadjuvant to improve resectability and reduce complications. This risk-based approach ensures is performed when it can be safely executed, often incorporating sampling to aid in accurate . Surgical techniques vary by tumor location and size, with open approaches remaining the standard for most cases. Open resection via for thoracic tumors or for abdominal masses allows for thorough exploration and removal of adherent structures, including routine sampling of regional nodes to evaluate for . Minimally invasive techniques, such as , are suitable for small adrenal neuroblastomas without IDRFs, offering reduced recovery time while maintaining oncologic principles. In paraspinal tumors, careful is essential to avoid , often requiring multidisciplinary input from . Complications from neuroblastoma resection occur in approximately 8-20% of cases, with intraoperative being the most common issue, affecting 10-20% of procedures due to the tumor's . Organ injury, such as to the or bowel, and postoperative issues like chylous ascites or Horner syndrome in /thoracic resections, are also reported, though presurgical can mitigate these risks by shrinking the tumor. risks are heightened in paraspinal extensions, necessitating neuromonitoring during . Recent advancements include robotic-assisted surgery, which enhances precision in pediatric cases, particularly for intermediate-risk adrenal or abdominal neuroblastomas. Studies demonstrate feasibility rates of 80-90% for complete resection using robotic platforms, with benefits including lower blood loss and shorter hospital stays compared to open or conventional laparoscopic methods, without compromising oncologic outcomes. This approach is increasingly adopted for select tumors under 100 ml without IDRFs, reflecting a shift toward less invasive options in experienced centers.

Chemotherapy Regimens

Chemotherapy for neuroblastoma is administered according to risk stratification systems, primarily the classification, which guides regimen intensity based on factors such as age, , , and molecular markers. Treatment aims to achieve maximal tumor response while minimizing long-term toxicities, often integrating with but using systemic cytotoxic agents to target metastatic or unresectable disease. In low-risk neuroblastoma, is typically reserved for cases with incomplete surgical resection or specific concerns, involving a short course of multi-agent including , , , and over 4 cycles to reduce without excessive . This approach reflects the favorable of low-risk tumors, where post-surgery suffices in most patients. For intermediate-risk disease, moderate-intensity multi-agent regimens are employed, usually consisting of 4 to 8 cycles of drugs including , , , and , as outlined in COG protocols like ANBL0531. A common example is the alternating cycles of carboplatin-etoposide and cyclophosphamide-, which balances against cumulative in this group with intermediate outcomes. High-risk neuroblastoma requires intensive chemotherapy to rapidly debulk tumors, followed by . The rapid COJEC regimen, used in European protocols, delivers alternating cycles of -- and - over 5 months, achieving high response rates prior to myeloablative therapy. In , the COG N5/N6 regimen from ANBL0532 employs similar agents—, , , , and —in rapid sequential cycles to optimize tumor control. For refractory or relapsed cases, salvage regimens incorporate with for platinum-resistant disease or with for oral maintenance, providing second-line options with response rates around 30-50%. Key toxicities include from , dose-limited by monitoring, and from like , mitigated through cumulative dose caps and cardioprotective agents. is managed with (G-CSF) to support dose intensity without excessive delays. As of 2025, emerging response-adapted strategies use (ctDNA) monitoring during induction to guide dosing reductions in responders, potentially sparing low-burden patients from full-intensity regimens while identifying non-responders early.

Radiation Therapy

plays a crucial role in the management of high-risk neuroblastoma, particularly for local control of disease that persists after initial and surgery. It is indicated for unresectable primary tumors, metastatic sites such as bone or involvement, and residual disease following induction therapy in high-risk cases. In stage 4S neuroblastoma, radiation is specifically used to address massive causing respiratory distress or other complications, often with low-dose hepatic to reduce liver size. Common techniques include focal radiation to the bed, typically delivering 21 in hyperfractionated regimens after maximal surgical , which achieves excellent local control rates exceeding 90%. Proton therapy is increasingly preferred for its precision in sparing surrounding healthy tissues, particularly in pediatric patients where long-term growth and organ function are concerns, allowing equivalent tumor coverage with reduced integral dose to normal structures. For metastases or relapsed disease, craniospinal irradiation may be employed, often at doses of 18-21 combined with boosts to involved sites. Targeted radionuclide therapy with iodine-131-meta-iodobenzylguanidine () is a specialized approach for MIBG-avid tumors, particularly in relapsed or high-risk neuroblastoma, where it achieves objective response rates of 30-50% as a single agent. This therapy is often combined with to enhance efficacy, with studies showing improved when integrated into multimodal regimens. Long-term side effects of in neuroblastoma survivors include growth impairment due to effects on bone and endocrine function, as well as an elevated risk of secondary cancers, with cumulative incidences reported at 3-5% over 20-25 years in irradiated cohorts. These risks are mitigated by modern techniques, but close monitoring for endocrinopathies and malignancies remains essential. As of 2025, intensity-modulated radiation therapy (IMRT) has gained prominence for its ability to conform dose distribution more tightly, reducing toxicity to adjacent organs like the kidneys and heart compared to conventional methods. Ongoing clinical trials are exploring low-dose radiation strategies for intermediate-risk neuroblastoma to minimize late effects while maintaining efficacy, particularly in response-adapted protocols.

Immunotherapy and Targeted Therapies

Immunotherapy and targeted therapies represent a cornerstone in the management of high-risk neuroblastoma, focusing on biological agents that harness the or disrupt tumor-specific molecular pathways to improve outcomes beyond conventional treatments. These approaches target neuroblastoma-associated antigens like and genetic alterations such as ALK mutations, offering improved event-free survival (EFS) and overall survival (OS) in patients with aggressive disease. Anti-GD2 monoclonal antibodies, particularly dinutuximab beta, are a standard component of maintenance therapy for high-risk neuroblastoma following and . Administered in with interleukin-2 (IL-2) and (GM-CSF), dinutuximab beta enhances against GD2-expressing tumor cells, leading to a significant improvement in EFS by approximately 20% compared to standard alone in pivotal trials. This regimen is approved for patients achieving at least a partial response after and has demonstrated prolonged OS benefits in real-world settings. Targeted therapies against ALK mutations, present in about 10% of high-risk cases, include like , which show promise in relapsed or ALK-mutated neuroblastoma. In phase 2 trials reported in 2025, achieved an objective response rate (ORR) of around 50% in ALK-driven disease, often combined with to overcome resistance mechanisms. Other targeted agents for high-risk neuroblastoma encompass anlotinib, a multi-tyrosine targeting VEGFR pathways to suppress and tumor growth, evaluated in pediatric solid tumors including neuroblastoma. Additionally, DFMO (difluoromethylornithine), an of the synthesis pathway, serves as maintenance therapy post-consolidation, reducing levels essential for neuroblastoma and demonstrating efficacy in phase 2 trials for high-risk patients. Chimeric antigen receptor (CAR) T-cell therapies targeting GD2 or ALK antigens are emerging for relapsed neuroblastoma, with early-phase trials indicating feasibility and antitumor activity. -directed CAR-T cells have shown ORRs up to 66% in refractory high-risk cases, though challenges like limited persistence remain. ALK-targeted CAR-T approaches are in preclinical and early testing, offering potential for mutation-specific responses in relapsed settings. Common toxicities associated with these therapies include severe pain from anti-GD2 antibodies due to binding on sensory neurons and (CRS) from immune activation, often managed with analgesics and supportive care. Advances as of 2025 include bispecific antibodies combining targeting with T-cell engagement, and checkpoint inhibitors like anti-PD-1 agents, which enhance T-cell responses when paired with anti-GD2 therapy in preclinical and early clinical studies.

Stem Cell Transplantation

Autologous transplantation (SCT) serves as a key consolidation therapy for children with high-risk neuroblastoma who achieve at least a partial response to initial induction . This approach employs high-dose myeloablative to eradicate residual disease, followed by infusion of the patient's own hematopoietic for hematopoietic rescue. are typically harvested from peripheral blood after with and growth factors, though purged collections were historically used to minimize tumor cell contamination. Tandem autologous SCT, involving two sequential cycles, has become a standard option to further intensify . The first cycle often uses cyclophosphamide-based regimens, while the second incorporates and for enhanced myeloablation. In high-risk patients, this strategy improves event-free survival (EFS), with randomized trials showing 3-year EFS rates of approximately 48-62% compared to 30-40% with single SCT or non-transplant . Allogeneic SCT plays a limited role in neuroblastoma, reserved primarily for relapsed or cases where autologous options are exhausted. Haploidentical allogeneic SCT, using partially matched donors, leverages natural killer () cell alloreactivity for an immunotherapy-like graft-versus-tumor effect without relying heavily on T-cell engraftment. Clinical studies indicate feasibility in pediatric patients, with some achieving long-term remission through NK cell infusion post-transplant.30004-1/fulltext) Major complications of SCT in this population include hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, which occurs in 1-28% of cases and carries high mortality if severe; profound leading to bacterial, viral, and fungal infections; and transplant-related mortality of 5-10%, primarily from toxicity or infection in the early post-transplant period. By 2025, advancements include investigations into gene-edited hematopoietic stem cells to improve engraftment efficiency and reduce rejection risks in allogeneic settings, alongside routine integration of anti-GD2 immediately post-transplant to enhance tumor clearance and prolong survival in high-risk cases.

Prognosis

Survival Rates and Outcomes

The overall 5-year for children with neuroblastoma is approximately 81-82%, based on recent population-based data from high-income countries. outcomes vary significantly by risk group, with low-risk neuroblastoma achieving a 5-year overall exceeding 95%, often reaching 98% in favorable cases treated with minimal intervention. Intermediate-risk has a 5-year overall of 90-95%, reflecting effective response to moderate and surgery. In contrast, high-risk neuroblastoma carries a more guarded prognosis, with a 5-year overall of approximately 60%, despite intensive multimodal approaches. Survival rates have improved markedly over time due to advances in , rising from around 60% in the to the current 80-85% overall, driven by refined risk stratification, intensified , and supportive care. For stage 4S neuroblastoma, a unique subset in infants with metastatic but favorable , over 85% of cases experience spontaneous resolution without aggressive treatment, contributing to excellent long-term outcomes. International variations highlight disparities in access to care, with 5-year survival rates averaging 82% in high-income regions like the and , compared to approximately 40% in low-resource settings where delayed diagnosis and limited therapy availability predominate. Event-free survival in high-risk cases remains challenging, at less than 50% at 5 years, with occurring in the majority of patients within the first 2 years post-diagnosis. Recent integration of anti-GD2 , such as , into high-risk regimens has further enhanced outcomes, boosting 5-year overall survival to 55-65% in clinical trials by reducing relapse risk when added post-consolidation.

Prognostic Factors

Prognostic factors in neuroblastoma encompass a range of clinical, , and response-based variables that stratify patients into risk groups and predict outcomes such as event-free survival (EFS) and overall survival (OS). These factors are integrated into systems like the International Neuroblastoma Risk Group (INRG) classification, which combines , , and tumor to guide intensity. Key predictors include patient at , tumor and genetic features, histological characteristics, and post-treatment response markers, with emerging telomere-related mechanisms further refining ultra-high-risk identification. Age at remains one of the most influential clinical factors, with children under exhibiting significantly better , particularly in high-stage disease, due to higher rates of spontaneous or favorable . In contrast, patients over , especially those with metastatic stage 4 disease, face poorer outcomes, with long-term survival dropping below 50%. Tumor stage, assessed via the INSS or INRG systems, correlates strongly with , where low-stage (1, 2, or 4S) tumors have excellent survival rates exceeding 90%, while high-stage (3 or 4) cases in older children portend worse results. Biologically, MYCN amplification is a hallmark of aggressive disease, conferring a (HR) of 2-3 for and reducing 5-year EFS to around 30-40%; it is present in about 20% of cases and overrides other favorable features. Segmental aberrations, such as 11q (LOH), further worsen (HR approximately 2), occurring in 30-40% of non-MYCN-amplified tumors, while whole- aneuploidy (e.g., hyperdiploidy) is associated with favorable outcomes in infants. Histological evaluation, primarily through the International Neuroblastoma Pathology Classification (INPC, also known as the Shimada system), provides critical prognostic insight by assessing tumor , mitosis-karyorrhexis index, and stroma content. Undifferentiated or poorly neuroblastomas indicate unfavorable and predict inferior survival (5-year OS <50%), whereas differentiating or ganglioneuroblastoma subtypes are favorable, especially in younger patients. The age-linked Shimada classification refines this by considering patient age alongside histological grade, identifying low-risk favorable groups with >85% survival. Response to initial therapy serves as a dynamic prognostic marker; post-induction meta-iodobenzylguanidine (MIBG) Curie scores greater than 2 in high-risk patients signal persistent disease and correlate with EFS rates below 20%, guiding decisions for intensified consolidation. Similarly, (MRD) detection via quantitative (qPCR) for neuroblastoma-specific transcripts (e.g., PHOX2B, ) in or peripheral blood identifies high-risk relapse, with MRD positivity post-induction associated with HR >2 for adverse events. Recent advancements highlight telomere maintenance mechanisms (TMM) as emerging prognostic indicators, particularly alternative lengthening of telomeres () positivity, which occurs in 10-20% of high-risk neuroblastomas and links to older age at and inferior EFS (HR 1.5-2 compared to TMM-negative cases). -positive tumors show 5-year EFS of 10-23%, prompting calls to redefine them as an ultra-high-risk subset regardless of traditional or MYCN status, as TMM integration into could improve outcome prediction for the 50% of patients who relapse.

Long-Term Complications

Survivors of neuroblastoma face a range of long-term complications arising from both the disease itself and intensive treatments such as , , and transplantation. According to data from the Childhood Cancer Survivor Study (CCSS; based on pre-2000 treatments), the 20-year cumulative incidence of any chronic health condition among neuroblastoma survivors is 41.1%, representing an eightfold increased risk compared to siblings. A 2025 multicenter study (LEAHRN) of 375 high-risk survivors treated with modern therapies (2017-2021) reports higher prevalence of specific late effects, including moderate-to-severe in 72%, growth failure in 24%, status in 51%, and moderate-to-severe in 8%. These complications can significantly impact physical health, endocrine function, and overall , with many survivors developing multiple issues over time. Treatment-related ototoxicity, primarily from cisplatin-based , affects 72% of high-risk neuroblastoma survivors with moderate-to-severe , often requiring hearing aids or cochlear implants. is a common concern, particularly following high-dose alkylating agents and transplantation, with gonadal failure reported in up to 83% of cases in some cohorts; female survivors experience ovarian failure in approximately 41%, while males face risks of . Secondary malignancies occur in 3-5% of survivors at 25 years post-diagnosis, with elevated risks for , , and sarcomas due to prior and radiation exposure. Disease-related complications include musculoskeletal deformities such as , often resulting from paraspinal tumors or surgical interventions like , affecting up to 63% of long-term survivors in high-risk groups. Hearing loss can also stem from tumor involvement or opsoclonus-myoclonus-ataxia , while vision impairment may arise from orbital or infiltration. Cardiac late effects, linked to like , increase the risk of and , with a cumulative incidence of up to 8% at 15 years post-stem cell transplantation. Renal dysfunction, particularly in cases involving bilateral tumors or nephrotoxic agents like ifosfamide, manifests as in 10-62% of survivors, necessitating ongoing monitoring for and . Quality-of-life issues are prevalent, with neurocognitive deficits impacting 20-40% of survivors, including impairments in task (22%), organization (25%), (19%), and emotional (20%), often linked to treatment intensity and associated with higher rates of special education needs. Anxiety and are also more common, with survivors showing a 50% higher risk of compared to the general population. Survivorship care emphasizes regular monitoring to mitigate these risks, following Children's Oncology Group (COG) guidelines that recommend annual for , echocardiography for cardiac function, and endocrine evaluations for and issues. Comprehensive follow-up, including renal function tests and orthopedic assessments, is advised lifelong to detect and manage chronic conditions early.

History

Early Discoverings and Classifications

The earliest documented descriptions of what is now recognized as neuroblastoma date back to the mid-19th century. In 1864, German pathologist reported abdominal tumors in children, terming them "gliomas" based on their resemblance to glial tissue, though without recognizing their origin. This initial characterization laid the groundwork for identifying these lesions as distinct entities among pediatric abdominal masses. Subsequently, in 1891, Felix Marchand provided a more precise pathological description, naming the tumor "sympathoma embryopathicum" to reflect its embryonic features, emphasizing its developmental pathology in young patients. By the early 20th century, further clinical and pathological distinctions emerged. In 1901, William Pepper described cases of localized primary tumors with metastases confined to the skin, liver, and in infants, highlighting a relatively favorable subset now known as stage 4S disease. In 1907, Robert Hutchison reported on adrenal primaries with extensive hepatic involvement, underscoring the aggressive potential and variability in presentation. These observations differentiated adrenal and thoracic forms, noting differences in metastatic patterns and outcomes, with thoracic cases often showing orbital involvement. A pivotal advancement occurred in 1910 when American pathologist James Homer Wright definitively established the tumor's origin from primitive neural cells of the . coined the term "neuroblastoma" in his seminal paper, describing characteristic histological features such as formations (later termed Homer-Wright rosettes) and bundles of , which confirmed its neuroectodermal lineage. This work solidified neuroblastoma's recognition as a distinct pediatric , predominantly affecting children under five years old, and shifted focus from vague abdominal tumors to a specific embryonal neoplasm. In the 1940s, early pathological classifications advanced through techniques pioneered by Margaret R. Murray and Arthur Purdy Stout. They examined explants of sympathetic tumors, classifying neuroblastomas based on and growth patterns observed , such as the formation of neuron-like processes in maturing cells versus undifferentiated proliferation in aggressive forms. This approach distinguished neuroblastoma from mimics like or , emphasizing degrees of maturation—from primitive neuroblasts to ganglioneuromatous elements—as prognostic indicators. Their 1954 review formalized these criteria, influencing diagnostic by integrating cytological behavior with light findings. Diagnostic confirmation of neuroblastoma's neural origin progressed in the with the advent of electron microscopy. Studies during this decade revealed ultrastructural evidence, including dense-core neurosecretory granules and early neuritic extensions in tumor cells, providing definitive proof of sympatho-adrenal beyond light microscopy limitations. These observations, building on Wright's foundational , refined classifications by linking subcellular features to tumor and aiding from non-neural small round cell tumors. Prior to the , management relied solely on surgical resection, yielding dismal outcomes with overall five-year rates below 20%, particularly for advanced stages where complete excision was often impossible due to widespread metastases. This era underscored the tumor's aggressive nature in older children and the limitations of alone, setting the stage for approaches while highlighting the need for better stratification based on early pathological insights.

Key Therapeutic Milestones

In the 1970s, the introduction of multi-agent regimens, particularly combined with , represented a pivotal shift from primarily surgical and radiation-based approaches, achieving one-year survival rates of around 36% in children with advanced neuroblastoma, a notable improvement from prior rates below 5% for high-risk cases. During the 1980s, regimens were further intensified by incorporating and , which enhanced response rates in disease and contributed to overall survival increases to approximately 37% by the decade's end for children diagnosed between 1981 and 1990. Concurrently, early trials of autologous transplantation (BMT) emerged as a strategy to consolidate high-dose , with initial studies in the mid-1980s demonstrating feasibility and potential survival benefits in advanced neuroblastoma. The 1990s saw the establishment of formal risk stratification through the International Neuroblastoma Staging System (INSS), introduced in 1988 and widely adopted by the early 1990s, which categorized patients based on age, stage, and tumor biology to tailor intensity and improve outcomes. Additionally, 13-cis-retinoic acid was integrated as a agent post-consolidation , with a landmark 1999 study showing it reduced relapse risk and boosted event-free survival by about 15% in high-risk patients without progressive disease at the start of maintenance. In the 2000s, tandem autologous transplantation became a standardized component of high-risk neuroblastoma protocols, supported by phase III trials demonstrating superior event-free survival compared to single transplant, establishing it as a cornerstone for consolidation after induction . Anti-GD2 advanced significantly, culminating in the FDA's accelerated approval of naxitamab in 2020 for relapsed or refractory high-risk neuroblastoma with bone or involvement, building on earlier approvals and phase II data showing objective response rates over 50% in disease. From the 2010s to 2025, targeted therapies gained prominence, including 131I-meta-iodobenzylguanidine (MIBG) radiotherapy, which improved in relapsed high-risk cases when added to standard regimens, as evidenced by phase II trials with response rates up to 30% in disease. , such as , were introduced for tumors harboring ALK mutations, with early-phase trials in the 2010s reporting partial responses in 20-30% of eligible relapsed patients. , particularly anti-GD2 antibodies combined with cytokines, further elevated high-risk overall survival from around 40% in the early 2000s to 50-60% by the mid-2020s, driven by integrated protocols like those from the Children's Oncology Group.

Current Research

Preclinical Models and Basic Science

Preclinical models of neuroblastoma have been instrumental in elucidating the disease's biology and testing therapeutic interventions. Commonly used cell lines include SK-N-SH, which is non-MYCN-amplified and serves as a model for studying neuronal , and IMR-32, an MYCN-amplified line that recapitulates aggressive tumor features such as rapid and to . These lines have facilitated investigations into MYCN-driven oncogenesis, revealing how MYCN amplification promotes progression and metabolic reprogramming in neuroblastoma cells. Patient-derived xenografts (PDX) provide a more clinically relevant platform for drug testing by preserving the heterogeneity and stromal interactions of primary tumors. Orthotopic PDX models, implanted into the or sympathetic chain of immunodeficient mice, maintain neuroblastoma-specific markers like and exhibit invasive growth patterns similar to human disease, enabling evaluation of drug efficacy against patient-specific variants. Animal models further advance understanding of neuroblastoma . The TH-MYCN transgenic mouse, expressing MYCN under the promoter in -derived cells, spontaneously develops adrenal and sympathetic tumors that mimic high-risk human neuroblastoma, including MYCN amplification and metastatic potential. models, leveraging transparent embryos, allow real-time visualization of migration and tumor initiation; of human neuroblastoma cells into neural crest streams recapitulates defects and metastatic dissemination observed in the disease. Basic science research highlights neuroblastoma's origin in the developing . Tumors arise from progenitors that fail to properly differentiate into sympathetic neurons along the paravertebral chain, leading to uncontrolled in the or extra-adrenal sites. Epigenetic regulators, such as , a , maintain a repressive state that inhibits neuronal differentiation genes like NTRK1; inhibition induces neurite outgrowth and reduces tumor growth in preclinical models by alleviating H3K27me3-mediated silencing. Recent advances from 2024 include the development of three-dimensional models derived from patient tumors, which better replicate the , gradients, and interactions compared to two-dimensional cultures, enhancing predictions of therapeutic responses. CRISPR-Cas9 screens have identified novel vulnerabilities, such as epigenetic modifiers that stratify risk and potential targets influencing transcriptional profiles in high-risk neuroblastoma. These models have practical applications in predicting chemoresistance and validating therapeutic pathways. PDX and TH-MYCN models demonstrate how transcriptional states, such as mesenchymal or adrenergic phenotypes, confer to like , informing combination strategies. Preclinical validation of the ALK pathway, mutated in up to 10% of cases, shows that inhibitors like suppress downstream signaling in ALK-aberrant cell lines and xenografts, reducing proliferation and .

Novel Therapeutic Approaches

Emerging immunotherapies for neuroblastoma include chimeric antigen receptor ()-modified natural killer T (NKT) cells targeting , which have shown safety and preliminary efficacy in phase 1 trials for relapsed or refractory disease. In a phase 1 study, -CAR NKT cells mediated objective responses in patients with neuroblastoma, with no dose-limiting toxicities observed, supporting further evaluation in combination regimens. Bispecific T-cell engagers (BiTEs) directed against and CD3 have also entered clinical testing, demonstrating feasibility and post-infusion immune activation in phase 1 trials. Targeted therapies are advancing through modulators of the MDM2-p53 pathway, which is frequently dysregulated in neuroblastoma to suppress . Preclinical data and early clinical exploration of inhibitors like RG7388 indicate enhanced tumor cell death when combined with , paving the way for phase 1/2 trials in p53-wild-type tumors. , particularly , show promise for tumors with alternative lengthening of telomeres (ALT+), a feature in about 25-30% of high-risk cases; a phase 1 pediatric trial reported stable disease or better in tumors, including neuroblastoma, with a notable case of durable response in a BARD1-mutated . , a next-generation , has demonstrated tolerability and antitumor activity in phase 1 expansion cohorts for ALK-altered relapsed neuroblastoma, achieving objective responses in up to 30% of patients and supporting its integration into frontline regimens. Radiopharmaceutical approaches, such as , leverage expression on neuroblastoma cells for targeted . Early IIa trials in relapsed or refractory high-risk neuroblastoma showed no objective responses (ORR 0%) and a median of 3 months; an ongoing II trial (NCT04903899, as of November 2025) is evaluating efficacy in children with recurrent or relapsed disease. Differentiation therapy with difluoromethylornithine (DFMO), an inhibitor, combined with has reduced relapse risk in high-risk neuroblastoma by targeting . In settings post-induction, DFMO achieved a 50% reduction in relapse rates compared to historical controls, leading to FDA approval in 2023 for this indication, with phase 2 data confirming improved event-free survival. As of 2025, combination strategies pairing anti-GD2 monoclonal antibodies with immune checkpoint , such as PD-1/PD-L1 blockers, are yielding encouraging results in phase 1/2 trials, enhancing T-cell infiltration and response durability in neuroblastoma. For ALK-driven cases, investigational gene-editing approaches and advanced are under evaluation in early-phase trials to correct or bypass mutations, building on lorlatinib's success. As of late 2025, ongoing trials include a phase 1/2 study of cellular therapy to boost immune systems against neuroblastoma and evaluation of CUDC-907, a HDAC/PI3K , for solid tumors including neuroblastoma.

Management of Relapsed Disease

Management of relapsed neuroblastoma focuses on salvage therapies tailored to disease status, with disease defined as lack of response to initial induction and relapsed disease indicating recurrence after partial or complete remission. In high-risk cases, neuroblastoma affects approximately 10-15% of patients, while occurs in 40-50%, with about half of relapses happening within the first year post-treatment. Overall survival for high-risk relapsed or disease remains poor, typically below 20% at 4-5 years. For refractory disease, standard salvage regimens often include combined with , which has demonstrated objective response rates of 20-40% in phase II trials and serves as a backbone for subsequent consolidation. This approach aims to achieve disease control before proceeding to more intensive therapies. In relapsed settings, treatment is guided by relapse site and biology; for bone-dominant relapse, site-directed therapy with 131I-meta-iodobenzylguanidine (MIBG) is commonly used, offering response rates up to 30-50% in MIBG-avid tumors. The / combination forms a key backbone for relapsed disease, with phase II studies reporting objective response rates of 20-35% and manageable toxicity, often serving as a platform for adding targeted agents. Common approaches for high-risk relapse involve re-induction followed by autologous transplantation (SCT), which can achieve partial responses in 30-50% of cases but is limited by cumulative and prior exposure. Experimental strategies include combinations like 131I-MIBG with , a that enhances ; phase I trials have shown this to be tolerable with encouraging antitumor activity, including complete responses in a subset of resistant cases. As of 2025, such as demonstrate promise in ALK-mutated s, with objective response rates around 30-50% in phase I/II studies, particularly when combined with like /. Ongoing clinical trials increasingly emphasize (MRD)-guided therapy to detect early via or , enabling preemptive intervention and potentially improving outcomes in high-risk patients.

Data and Collaborative Resources

The Children's Oncology Group (COG) Neuroblastoma Database serves as a key registry in the United States, aggregating clinical data from thousands of patients enrolled in COG-led studies to support analyses of treatment responses, survival patterns, and risk classification. Complementing this, the International Neuroblastoma Risk Group (INRG) Task Force maintains a global database with information on over 22,000 children diagnosed with neuroblastoma worldwide, enabling standardized data sharing across institutions for improved prognostic modeling and trial design. In Europe, the SIOP Europe Neuroblastoma (SIOPEN) group oversees registries through multicenter trials, such as the High-Risk Neuroblastoma Study 1.8, which collects detailed patient data to harmonize staging and therapeutic protocols across participating countries. Genomic resources have advanced neuroblastoma research through initiatives like the Therapeutically Applicable Research to Generate Effective Treatments () program by the (NCI), which provides whole-genome sequencing, , and data from nearly 200 high-risk cases, including relapsed tumors, to identify actionable mutations and molecular subtypes. Similarly, the Pan-Cancer of Whole Genomes (PCAWG) neuroblastoma contributes whole-genome sequencing from primary tumors, revealing mutational patterns and structural variants that correlate with clinical heterogeneity and tumor evolution. International collaborations, such as those between the International Society of Paediatric Oncology (SIOP) and , facilitate risk group harmonization via the INRG classification system, which integrates genomic, histopathologic, and clinical variables to align eligibility criteria for global clinical trials and reduce disparities in care. These efforts promote data interoperability and joint protocol development, as evidenced by shared systems adopted in both North American and European studies. Big data approaches leverage electronic health records (EHRs) to capture real-world outcomes in neuroblastoma, including treatment adherence and long-term survival beyond controlled trials, with tools like Clinical Data Interchange Standards enabling high-fidelity extraction of medication and progression data for registry submissions. Additionally, (AI) enhances analysis of 123I-meta-iodobenzylguanidine (MIBG) scans, where models predict response in high-risk patients by quantifying tumor uptake and skeletal involvement with greater precision than traditional scoring methods. As of 2025, initiatives like the INRG consortium emphasize expanded data-sharing frameworks to accelerate discoveries in rare pediatric malignancies, serving as a model for international collaboration in neuroblastoma research.