Neuroblastoma
Neuroblastoma is a malignant neoplasm arising from neural crest cells, most commonly affecting the adrenal medulla or sympathetic nervous system in children. It is characterized by the proliferation of undifferentiated neuroblasts, which can infiltrate local tissues and metastasize to distant organs such as bone, bone marrow, liver, and lymph nodes. The pathogenesis involves genetic and molecular alterations, including MYCN amplification, ALK mutations, and chromosomal aberrations, which drive tumorigenesis and influence disease aggressiveness. Neuroblastoma exhibits heterogeneous clinical behavior, ranging from spontaneous regression in some cases to rapid progression and resistance to therapy in others. The disease can severely impact health by causing pain, organ dysfunction, paraneoplastic syndromes (such as opsoclonus-myoclonus-ataxia), and, in advanced cases, life-threatening complications due to metastatic spread or treatment-related toxicities.
This type refers to tumors confined to the site of origin, with or without limited regional lymph node involvement. Localized neuroblastoma is often amenable to surgical resection and is associated with favorable biological features and a good prognosis, particularly in infants and young children. The International Neuroblastoma Staging System (INSS) designates these as stage 1 (completely resected) or stage 2 (incomplete resection or ipsilateral lymph node involvement).
Metastatic neuroblastoma is characterized by the dissemination of malignant cells beyond the primary tumor site, commonly affecting bone, bone marrow, liver, and distant lymph nodes. This type typically presents at diagnosis in children older than 18 months and is associated with high-risk clinical and biological features, including MYCN amplification. The disease is staged as INSS stage 4, and prognosis is generally poor despite intensive multimodal therapy.
4S neuroblastoma is a unique subtype occurring in infants less than one year of age. It is defined by a small primary tumor with dissemination limited to the liver, skin, and/or bone marrow (with less than 10% tumor involvement in marrow). Remarkably, 4S neuroblastoma has a tendency for spontaneous regression and a favorable outcome, even in the presence of metastatic disease, provided there is no life-threatening organ compromise.
Ganglioneuroblastoma represents an intermediate tumor in the spectrum between neuroblastoma and the benign ganglioneuroma. It contains both malignant neuroblasts and more differentiated ganglion cells, resulting in variable clinical behavior. Prognosis depends on the proportion of undifferentiated cells, tumor stage, and biological markers.
Ganglioneuroma is the most differentiated and benign end of the neuroblastic tumor spectrum. Composed predominantly of mature ganglion cells and Schwannian stroma, these tumors do not exhibit aggressive behavior and are typically managed with surgical excision alone. Malignant transformation is exceedingly rare.
Neuroblastoma is the most common extracranial solid tumor in childhood and the third most common pediatric cancer overall, following leukemias and brain tumors. The annual incidence is approximately 10.5 cases per million children under 15 years of age, with the highest incidence in infants less than one year old. Neuroblastoma accounts for about 7-10% of all childhood cancers but is responsible for 15% of pediatric oncology deaths, reflecting its aggressive nature in high-risk cases. There is a slight male predominance, and most cases are sporadic, though rare familial forms exist. The median age at diagnosis is 18 months, and about 40-50% of patients present with metastatic disease at diagnosis. Survival rates vary widely by risk group, with low-risk patients experiencing cure rates exceeding 90%, while high-risk cases have five-year survival rates of 40-50% despite intensive therapy.
The diagnosis of neuroblastoma involves a combination of clinical evaluation, imaging studies, laboratory testing, and histopathological confirmation. Initial suspicion arises from symptoms such as abdominal mass, pain, bone pain, or systemic features like weight loss and fever. Imaging modalities including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) are used to delineate tumor location, size, and local invasion. Metaiodobenzylguanidine (MIBG) scintigraphy, using either 123I- or 131I-labeled iobenguane, is highly sensitive for detecting both primary and metastatic lesions due to the tumor's catecholaminergic origin. Laboratory assessment includes measurement of urinary catecholamine metabolites (vanillylmandelic acid and homovanillic acid), which are elevated in over 90% of cases. Definitive diagnosis requires tissue biopsy with histological analysis, revealing small round blue cells with characteristic immunohistochemical staining for neuronal markers (e.g., NSE, synaptophysin, chromogranin A). Cytogenetic and molecular studies, such as MYCN amplification, 1p36 deletion, and ALK mutation analysis, are essential for risk stratification and treatment planning. Bone marrow aspiration and biopsy are performed to assess metastatic involvement. Staging is conducted according to the International Neuroblastoma Staging System (INSS) or the International Neuroblastoma Risk Group Staging System (INRGSS), incorporating imaging-defined risk factors and biological features.
Naxitamab is a monoclonal antibody that targets the disialoganglioside GD2, which is highly expressed on neuroblastoma cells, and is employed in the treatment of patients with relapsed or refractory high-risk neuroblastoma, often in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance antibody-dependent cellular cytotoxicity. Dinutuximab beta is another anti-GD2 monoclonal antibody indicated for the treatment of high-risk neuroblastoma in patients who have achieved at least a partial response to prior therapy, and it functions by mediating immune destruction of GD2-positive tumor cells. Dinutuximab, likewise targeting GD2, is used as part of multimodal therapy for pediatric patients with high-risk neuroblastoma, typically administered following myeloablative chemotherapy and stem cell transplantation to reduce the risk of relapse. Iobenguane I 131 is a radiopharmaceutical agent that combines the norepinephrine analog iobenguane with radioactive iodine-131; it is used for targeted radiotherapy in patients with relapsed or refractory neuroblastoma, delivering cytotoxic radiation directly to tumor cells that avidly uptake the compound. Alpha-difluoromethylornithine hydrochloride, also known as eflornithine hydrochloride, acts as an irreversible inhibitor of ornithine decarboxylase and is investigated for its ability to inhibit polyamine synthesis, thereby impeding neuroblastoma cell proliferation and survival. 123I-iobenguane, a radiolabeled diagnostic agent, is administered for functional imaging of neuroblastoma, providing high sensitivity for the detection of primary and metastatic disease sites and aiding in staging, response assessment, and treatment planning.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| naxitamab (Rec INN; USAN); naxitamab-gqgk | 1879925-92-4 | |||
| dinutuximab beta (Rec INN) | 1613303-02-8 | |||
| dinutuximab (Prop INN; USAN) | 1363687-32-4 | |||
 | iobenguane I 131 (USAN); iobenguane[131I] (Rec INN) | 77679-27-7 | C8 H10 I N3 | 279.185 |
 | alpha-difluoromethylornithine hydrochloride; eflornithine hydrochloride (Rec INNM; USAN; BANM) | 96020-91-6 | C6 H12 F2 N2 O2 . Cl H . H2 O | 236.645 |
 | 123I-iobenguane; iobenguane (123 I) (Rec INN); iobenguane I 123 (USAN); iobenguane[123I] | C8 H10 I N3 | 271.185 |
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