Neuroblastoma

Typically, neuroblastoma occurs due to a genetic mutation occurring in the first trimester of pregnancy.^[4][5] Rarely, it may be due to a mutation inherited.^[1] Environmental factors have not been found to be involved.^[2] Diagnosis is based on a tissue biopsy.^[1] Occasionally, it may be found in a baby by ultrasound during pregnancy.^[1] At diagnosis, the cancer has usually already spread.^[1] The cancer is divided into low-, intermediate-, and high-risk groups based on a child's age, cancer stage, and what the cancer looks like.^[1]


Treatment and outcomes depends on the risk group a person is in.^[1][5] Treatments may include observation, surgery, radiation, chemotherapy, or stem cell transplantation.^[1] Low-risk disease in babies typically has a good outcome with surgery or simply observation.^[5] In high-risk disease, chances of long-term survival, however, are less than 40%, despite aggressive treatment.^[5]


Neuroblastoma is the most common cancer in babies and the third-most common cancer in children after leukemia and brain cancer.^[5] About one in every 7,000 children is affected at some time.^[2] About 90% of cases occur in children less than 5 years old, and it is rare in adults.^[2][3] Of cancer deaths in children, about 15% are due to neuroblastoma.^[3] The disease was first described in the 1800s.^[6]

Cause[edit]

The cause of neuroblastoma is not well understood. The great majority of cases are sporadic and nonfamilial. About 1–2% of cases run in families and have been linked to specific gene mutations. Familial neuroblastoma in some cases is caused by rare germline mutations in the anaplastic lymphoma kinase (ALK) gene.^[12] Germline mutations in the PHOX2B or KIF1B gene have been implicated in familial neuroblastoma, as well. Neuroblastoma is also a feature of neurofibromatosis type 1 and the Beckwith-Wiedemann syndrome.


MYCN oncogene amplification within the tumor is a common finding in neuroblastoma. The degree of amplification shows a bimodal distribution: either 3- to 10-fold, or 100- to 300-fold. The presence of this mutation is highly correlated to advanced stages of disease.^[13]


Duplicated segments of the LMO1 gene within neuroblastoma tumor cells have been shown to increase the risk of developing an aggressive form of the cancer.^[14]


Other genes might have a prognostic role in neuroblastoma. A bioinformatics study published in 2023 suggested that the AHCY, DPYSL3, and NME1 genes might have a prognostic role in this disease.^[15]


Neuroblastoma has been linked to copy-number variation within the NBPF10 gene, which results in the 1q21.1 deletion syndrome or 1q21.1 duplication syndrome.^[16]


One study strongly indicates that miRNAs that are excessively expressed in 1p-deleted neuroblastoma cells, as opposed to other genetic subgroups of neuroblastoma, could potentially disrupt the regulation of genes associated with neuronal differentiation, thereby contribute to the pathogenesis of neuroblastoma. Furthermore, it was noted that miR-495 primarily targeted the majority of mRNAs that are involved in neuronal differentiation.^[17]


Several risk factors have been proposed and are the subject of ongoing research. Due to characteristic early onset, many studies have focused on parental factors around conception and during gestation. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy, and birth factors; however, results have been inconclusive.^[18]


Other studies have examined possible links with atopy and exposure to infection early in life,^[19] use of hormones and fertility drugs,^[20] and maternal use of hair dye.^[21][22]

When the lesion is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplant, differentiation agent isotretinoin also called 13-cis-retinoic acid, and frequently immunotherapy^[43] with anti-GD2 monoclonal antibody therapy – dinutuximab).


Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed assignment to risk groups for planning treatment intensity.^[44] These criteria include the age of the person, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogene amplification (N-myc regulates microRNAs^[45]), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 people with neuroblastoma and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk.^[46] (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)^[47]


The therapies for these different risk categories are very different.


People with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70–90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma the past two decades resulted in cures only about 30% of the time.^[54] The addition of antibody therapy has raised survival rates for high-risk disease significantly. In March 2009, an early analysis of a Children's Oncology Group (COG) study with 226 people that are high-risk showed that two years after stem cell transplant 66% of the group randomized to receive ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all people enrolling on the trial would receive the antibody therapy.^[55]


Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan), topoisomerase II inhibitor (etoposide), anthracycline antibiotics (doxorubicin) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease. Although further research is needed, interventions currently under pre-clinical investigation include epigenetic therapies, such as inhibition of SWI/SNF,^[56] which may complement existing retinoid therapies.


In November 2020, naxitamab was approved for medical use in the United States in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat people one year of age and older with high-risk neuroblastoma in bone or bone marrow whose tumor did not respond to or has come back after previous treatments and has shown a partial response, minor response, or stable disease to prior therapy.^[57][58]

Organisations[edit]

The Advances in Neuroblastoma Research Association (ANRA) is the peak body for researchers in neuroblastoma biology, diagnosis, prognosis, and therapy, and conducts meetings every two years to exchange information among them.^[96]