neuroblastoma neuroblastoma neuroblastoma (nb) is a type of cancer that forms in certain types of nerve tissue. it most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. symptoms may include bone pain, a lump in the abdomen, neck, or chest, or a painless bluish lump under the skin. neuroblastomamicroscopic view of a typical neuroblastoma with rosette formationspecialtyneuro-oncologysymptomsbone pain, lumpsusual onsetunder 5 years oldcausesgenetic mutationdiagnostic methodtissue biopsytreatmentobservation, surgery, radiation, chemotherapy, stem cell transplantationprognosisus five-year survival ~95% (< 1 year old), 68% (1–14 years old)frequency1 in 7,000 childrendeaths15% of deaths due to cancer in children typically, neuroblastoma occurs due to a genetic mutation occurring during early development. rarely, it may be due to a mutation inherited. environmental factors have not been found to be involved. diagnosis is based on a tissue biopsy. occasionally, it may be found in a baby by ultrasound during pregnancy. at diagnosis, the cancer has usually already spread. 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. treatment and outcomes depends on the risk group a person is in. treatments may include observation, surgery, radiation, chemotherapy, or stem cell transplantation. low-risk disease in babies typically has a good outcome with surgery or simply observation. in high-risk disease, chances of long-term survival, however, are less than 40%, despite aggressive treatment. neuroblastoma is the most common cancer in babies and the third-most common cancer in children after leukemia and brain cancer. about one in every 7,000 children is affected at some time. about 90% of cases occur in children less than 5 years old, and it is rare in adults. of cancer deaths in children, about 15% are due to neuroblastoma. the disease was first described in the 1800s. signs and symptoms the first symptoms of neuroblastoma are often vague, making diagnosis difficult. fatigue, loss of appetite, fever, and joint pain are common. symptoms depend on primary tumor locations and metastases if present: in the abdomen, a tumor may cause abdominal distension and constipation. a tumor in the chest may cause breathing problems. a tumor pressing on the spinal cord may cause weakness, thus an inability to stand, crawl, or walk. bone lesions in the legs and hips may cause pain and limping. a tumor in the bones around the eyes or orbits may cause distinct bruising and swelling. infiltration of the bone marrow may cause pallor from anemia. neuroblastoma often spreads to other parts of the body before any symptoms are apparent, and 50 to 60% of all neuroblastoma cases present with metastases. the most common location for neuroblastoma to originate (i.e., the primary tumor) is in the adrenal glands. this occurs in 40% of localized tumors and in 60% of cases of widespread disease. neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. frequencies in different locations include: neck (1%), chest (19%), abdomen (30% nonadrenal), or pelvis (1%). in rare cases, no primary tumor can be discerned. rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide secretion, 4% of cases), horner's syndrome (cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome and ataxia (suspected paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or kidney artery compression, 1.3% of cases). cause 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. 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. 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. 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. 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. 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. other studies have examined possible links with atopy and exposure to infection early in life, use of hormones and fertility drugs, and maternal use of hair dye. diagnosis mri showing orbital and skull vault metastatic nb in 2-year-old the diagnosis is usually confirmed by a surgical pathologist, taking into account the clinical presentation, microscopic findings, and other laboratory tests. it may arise from any neural crest element of the sympathetic nervous system (sns). esthesioneuroblastoma, also known as olfactory neuroblastoma, is believed to arise from the olfactory epithelium and its classification remains controversial. however, since it is not a sympathetic nervous system malignancy, esthesioneuroblastoma is a distinct clinical entity and is not to be confused with neuroblastoma. biochemistry in about 90% of cases of neuroblastoma, elevated levels of catecholamines or their metabolites are found in the urine or blood. catecholamines and their metabolites include dopamine, homovanillic acid (hva), and/or vanillylmandelic acid (vma). imaging another way to detect neuroblastoma is the meta-iodobenzylguanidine scan, which is taken up by 90 to 95% of all neuroblastomas, often termed "mibg-avid". the mechanism is that mibg is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrine. when it is radio-iodinated with i-131 or i-123 (radioactive iodine isotopes), it is a very good radiopharmaceutical for diagnosis and monitoring of response to treatment for this disease. with a half-life of 13 hours, i-123 is the preferred isotope for imaging sensitivity and quality. i-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma. as mibg is not always taken up by neuroblastomas, researchers have explored in children with neuroblastoma whether another type of nuclear imaging, fluoro-deoxy-glucose – positron emission tomography, often termed "f-fdg-pet", might be useful. evidence suggests that this might be advisable to use in children with neuroblastoma for which mibg does not work, but more research is needed in this area. histology microscopic view of stroma-rich ganglioneuroblastoma on microscopy, the tumor cells are typically described as small, round and blue, and rosette patterns (homer wright pseudorosettes) may be seen. homer wright pseudorosettes are tumor cells around the neuropil, not to be confused with a true rosettes, which are tumor cells around an empty lumen. they are also distinct from the pseudorosettes of an ependymoma which consist of tumor cells with glial fibrillary acidic protein (gfap)–positive processes tapering off toward a blood vessel (thus a combination of the two). a variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as rhabdomyosarcoma, ewing's sarcoma, lymphoma and wilms' tumor. neuroblastoma is one of the peripheral neuroblastic tumors (pnts) that have similar origins and show a wide pattern of differentiation ranging from benign ganglioneuroma to stroma-rich ganglioneuroblastoma with neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. this distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis-karyorrhexis index (mki). this pathology classification system (the shimada system) describes "favorable" and "unfavorable" tumors by the international neuroblastoma pathology committee (inpc) which was established in 1999 and revised in 2003. staging the "international neuroblastoma staging system" (inss) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis: stage 1: localized tumor confined to the area of origin. stage 2a: unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor. stage 2b: unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor. stage 3: tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement. stage 4: dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by stage 4s. stage 4s: age <1 year old with localized primary tumor as defined in stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors). although international agreement on staging (inss) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 people with neuroblastoma treated in europe, japan, usa, canada, and australia between 1990 and 2002. this task force has proposed the international neuroblastoma risk group (inrg) classification system. retrospective studies revealed the high survival rate of 12–18 month-old age group, previously categorized as high-risk, and prompted the decision to reclassify 12–18 month-old children without n-myc (also commonly referred to as mycn) amplification to intermediate risk category. the new inrg risk assignment will classify neuroblastoma at diagnosis based on a new international neuroblastoma risk group staging system (inrgss): stage l1: localized disease without image-defined risk factors. stage l2: localized disease with image-defined risk factors. stage m: metastatic disease. stage ms: metastatic disease "special" where ms is equivalent to stage 4s. the new risk stratification will be based on the new inrgss staging system, age (dichotomized at 18 months), tumor grade, n-myc amplification, unbalanced 11q aberration, and ploidy into four pre-treatment risk groups: very low, low, intermediate, and high risk. screening urine catecholamine level can be elevated in pre-clinical neuroblastoma. screening asymptomatic infants at three weeks, six months, and one year has been performed in japan, canada, austria and germany since the 1980s. japan began screening six-month-olds for neuroblastoma via analysis of the levels of homovanillic acid and vanilmandelic acid in 1984. screening was halted in 2004 after studies in canada and germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy. treatment 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 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. 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), 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. (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.) the therapies for these different risk categories are very different. low-risk disease can frequently be observed without any treatment at all or cured with surgery alone. intermediate-risk disease is treated with surgery and chemotherapy. high-risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, bone marrow / hematopoietic stem cell transplantation, biological-based therapy with 13-cis-retinoic acid (isotretinoin or accutane) and antibody therapy usually administered with the cytokines gm-csf and