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Neuroblastoma

Neuroblastoma is a malignancy Malignancy Hemothorax that arises from the neural crest Neural crest The two longitudinal ridges along the primitive streak appearing near the end of gastrulation during development of nervous system (neurulation). The ridges are formed by folding of neural plate. Between the ridges is a neural groove which deepens as the fold become elevated. When the folds meet at midline, the groove becomes a closed tube, the neural tube. Hirschsprung Disease cell derivatives along the sympathetic chain (neuroblasts) and is most commonly located in the adrenal medulla Adrenal Medulla The inner portion of the adrenal gland. Derived from ectoderm, adrenal medulla consists mainly of chromaffin cells that produces and stores a number of neurotransmitters, mainly adrenaline (epinephrine) and norepinephrine. The activity of the adrenal medulla is regulated by the sympathetic nervous system. Adrenal Glands: Anatomy. The tumor Tumor Inflammation often presents in childhood with a flank mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast that crosses the midline. Neuroblastoma can also manifest as opsoclonus-myoclonus paraneoplastic syndrome. The tumor Tumor Inflammation is diagnosed through biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, and supporting data include measuring the catecholamine breakdown products such as vanilmandelic acid (VMA) and homovanillic acid (HVA) in urine. Imaging studies are needed to localize the tumor Tumor Inflammation. Management depends on several factors such as the stage of malignancy Malignancy Hemothorax and the patient’s age at the time of diagnosis. Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is favorable in the early stages of neuroblastoma.

Last updated: Jun 8, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Neuroblastoma, an extracranial malignant solid tumor Tumor Inflammation, is a neuroendocrine malignancy Malignancy Hemothorax originating from sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification stem cells (neuroblasts).

Classification of nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification tumors

Table: Classification of nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification tumors
Categories Specific tumors
Neuroepithelial tumors in the CNS
  • Astrocytomas, including glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme is a high-grade astrocytoma, an aggressive brain tumor arising from astrocytes, with an unknown cause and a poorly understood link to risk factors. There are two main types: primary, a more aggressive form seen more commonly in older patients, and secondary, developing from lower-grade astrocytomas and seen more commonly in younger patients. Glioblastoma Multiforme
  • Oligodendroglioma Oligodendroglioma Oligodendrogliomas are malignant CNS tumors arising from neural glial cell precursors. Oligodendrogliomas often arise in the frontal lobes of the brain and have a generally favorable prognosis when compared to other gliomas. Oligodendrogliomas are the 3rd most common CNS tumor. The most frequent presenting symptom is a seizure. Oligodendroglioma
  • Ependymoma Ependymoma Ependymomas are glial cell tumors arising from CSF-producing ependymal cells lining the ventricular system. Ependymomas most commonly occur within the posterior fossa in contact with the 4th ventricle, or within the intramedullary spinal cord. Ependymoma and choroid-plexus tumors
  • Medulloblastomas (embryonal tumors)
Meningeal tumors
  • Meningiomas
  • Hemangioblastomas Hemangioblastomas A benign tumor of the nervous system that may occur sporadically or in association with von Hippel-Lindau disease. It accounts for approximately 2% of intracranial tumors, arising most frequently in the cerebellar hemispheres and vermis. Histologically, the tumors are composed of multiple capillary and sinusoidal channels lined with endothelial cells and clusters of lipid-laden pseudoxanthoma cells. Usually solitary, these tumors can be multiple and may also occur in the brain stem, spinal cord, retina, and supratentorial compartment. Cerebellar hemangioblastomas usually present in the third decade with intracranial hypertension, and ataxia. Von Hippel-Lindau Disease
Sellar region tumors
  • Craniopharyngioma Craniopharyngioma Craniopharyngiomas are rare squamous epithelial tumors with a solid and/or cystic structure that arise from the remnants of Rathke’s pouch along the pituitary stalk, in the suprasellar region. Craniopharyngiomas are histologically benign but tend to invade surrounding structures; thus, they should be treated as low-grade malignancies. Craniopharyngioma
  • Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types adenoma
  • Pinealoma/pinealoblastoma
Primary CNS lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum Primary CNS lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
Metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis to the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification (5x more common than primary brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification tumors) Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
Peripheral tumors
  • Schwannomas, including acoustic neuroma Acoustic neuroma Acoustic neuroma, also referred to as vestibular schwannoma, is a benign tumor arising from Schwann cells of the vestibular component of the cranial nerve VIII. Acoustic neuroma forms within the internal auditory meatus and extends into the cerebellopontine angle. Acoustic Neuroma
  • Neuroblastoma

Epidemiology

  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 1 per 8‒10,000 children
  • Most common malignancy Malignancy Hemothorax in infants
  • 3rd most common malignancy Malignancy Hemothorax in children < 14 years of age, after CNS tumors and leukemia 
  • Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have metastatic disease by the time of diagnosis.
  • Mean Mean Mean is the sum of all measurements in a data set divided by the number of measurements in that data set. Measures of Central Tendency and Dispersion age at diagnosis: 1–3 years 
  • More common in boys than girls

Etiology and pathogenesis

Neuroblastomas arise from mutations in primitive cells of the sympathetic ganglion (which includes the adrenal medulla Adrenal Medulla The inner portion of the adrenal gland. Derived from ectoderm, adrenal medulla consists mainly of chromaffin cells that produces and stores a number of neurotransmitters, mainly adrenaline (epinephrine) and norepinephrine. The activity of the adrenal medulla is regulated by the sympathetic nervous system. Adrenal Glands: Anatomy). The cells are known as neuroblasts and are derived from neural crest Neural crest The two longitudinal ridges along the primitive streak appearing near the end of gastrulation during development of nervous system (neurulation). The ridges are formed by folding of neural plate. Between the ridges is a neural groove which deepens as the fold become elevated. When the folds meet at midline, the groove becomes a closed tube, the neural tube. Hirschsprung Disease cells.

  • Genetic conditions associated with neuroblastoma:
    • Beckwith-Wiedemann syndrome
    • Neurofibromatosis type 1 Neurofibromatosis type 1 Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas. Neurofibromatosis Type 1
    • Hirschsprung disease Hirschsprung Disease Hirschsprung disease (HD), also known as congenital aganglionosis or congenital megacolon, is a congenital anomaly of the colon caused by the failure of neural crest-derived ganglion cells to migrate into the distal colon. The lack of innervation always involves the rectum and extends proximally and contiguously over variable distances. M Hirschsprung Disease
    • Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome
  • Maternal risk factors:
    • Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation use
    • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency
    • Gestational diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • Amplification of N-Myc protooncogene: growth-promoting transcription factor Transcription factor Generic term for proteins necessary for transcription Regulation of Transcription, the overexpression of which causes unregulated cellular proliferation
    • Deletion of 1p chromosomal region: Tumor Tumor Inflammation suppressor gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics KIF1B is present in this chromosomal region.
    • Mutations in anaplastic lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum kinase gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (ALK) are suspected to play an important role in some cases.
  • Metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis:
    • Via lymphatic and hematogenous Hematogenous Hepatocellular Carcinoma (HCC) and Liver Metastases routes
    • Often to bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions

Clinical Presentation

  • Nonspecific symptoms:
    • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa and weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension:
      • Most commonly caused by renal artery Renal artery A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. Glomerular Filtration compression Compression Blunt Chest Trauma by neuroblastoma
      • Renal arterial compression Compression Blunt Chest Trauma activates RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones.
      • Activated RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones causes vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure and sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia retention.
      • Less commonly caused by catecholamine secretion Secretion Coagulation Studies from neuroblastoma
  • Location-specific symptoms of primary disease: 
    • Abdomen (65% of all neuroblastomas):
      • Irregular flank mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast that crosses the midline (unlike Wilms tumor Wilms tumor Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR syndrome, Denys-Drash syndrome, or Beckwith-Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms Tumor, which does not cross the midline)
      • Abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
      • 2/3 of abdominal tumors are in the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands: Anatomy.
    • Chest (15% of neuroblastomas):
      • The tumors arise from paravertebral ganglia.
      • Back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain, weakness, and sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology loss due to spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy compression Compression Blunt Chest Trauma
      • Shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea and inspiratory stridor Stridor Laryngomalacia and Tracheomalacia due to tracheal compression Compression Blunt Chest Trauma
    • Neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess (5% of neuroblastomas):
      • Horner syndrome Horner syndrome Horner syndrome is a condition resulting from an interruption of the sympathetic innervation of the eyes. The syndrome is usually idiopathic but can be directly caused by head and neck trauma, cerebrovascular disease, or a tumor of the CNS. Horner Syndrome ( ptosis Ptosis Cranial Nerve Palsies, miosis Miosis Pupil: Physiology and Abnormalities, and anhidrosis) due to compression Compression Blunt Chest Trauma of the sympathetic plexus
      • Heterochromia: different colors of the iris
      • Nodules under the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
  • Symptoms of metastatic disease:
  • Paraneoplastic syndromes Paraneoplastic syndromes Paraneoplastic syndromes are a heterogeneous group of disorders caused by an abnormal immune response to a neoplasm. The substances produced are not due to the direct effect of the tumor, such as metastasis, mass effect, or invasion. Antibodies, hormones, cytokines, and other substances are generated and affect multiple organ systems. Paraneoplastic Syndromes:
    • Opsoclonus-myoclonus syndrome (dancing eyes–dancing feet syndrome): characterized by irregular eye movements, ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia, and rhythmic jerking motions of the limbs
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension: due to catecholamine secretion Secretion Coagulation Studies
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea: due to vasoactive intestinal peptide Vasoactive intestinal peptide A highly basic, 28 amino acid neuropeptide released from intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems and is neuroprotective. It binds special receptors. Gastrointestinal Neural and Hormonal Signaling ( VIP VIP A highly basic, 28 amino acid neuropeptide released from intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems and is neuroprotective. It binds special receptors. Gastrointestinal Neural and Hormonal Signaling) production

Diagnosis

The diagnosis is suspected based on history and exam findings. The key lab tests for neuroblastomas show evidence of elevated catecholamines Catecholamines A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. Adrenal Hormones. Imaging is used to identify the tumor Tumor Inflammation, and a biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is required for definitive diagnosis.

Laboratory studies

  • Urine: increased catecholamine breakdown products in 24-hour urine 
    • Vanillylmandelic acid (VMA)
    • Homovanillic acid (HVA)
  • Blood:
    • Increased neuron-specific enolase Enolase A hydro-lyase that catalyzes the dehydration of 2-phosphoglycerate to form phosphoenolpyruvate. Several different isoforms of this enzyme exist, each with its own tissue specificity. Glycolysis (NSE)
    • Increased ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis and lactate dehydrogenase Lactate Dehydrogenase Osteosarcoma ( LDH LDH Osteosarcoma)
    • CBC: ↓ Cell counts (e.g., anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia) suggest bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis.
    • Renal function tests may be abnormal with renal metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis.
    • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests may be abnormal with hepatic metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis.

Imaging studies

  1. Abdominal ultrasound to identify neuroblastoma in the adrenal medulla Adrenal Medulla The inner portion of the adrenal gland. Derived from ectoderm, adrenal medulla consists mainly of chromaffin cells that produces and stores a number of neurotransmitters, mainly adrenaline (epinephrine) and norepinephrine. The activity of the adrenal medulla is regulated by the sympathetic nervous system. Adrenal Glands: Anatomy; common findings include:
    • Heterogenous mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
    • Internal vascularity
    • Calcifications
  2. MRI or CT scan:
    • Alternative imaging studies for abdominal ultrasound to look for primary disease.
    • Used to assess extent of metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
    • Helpful with surgical planning
  3. Metaiodobenzylguanidine ( MIBG MIBG Pheochromocytoma) scan:
    • MIBG MIBG Pheochromocytoma is chemically similar to norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS.
    • MIBG MIBG Pheochromocytoma is taken up by neuroblastoma or pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma cells.
    • Used to look for metastatic disease (primarily in the bones)

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma of the primary tumor Tumor Inflammation confirms the diagnosis.
  • Sample is evaluated for:
    • Amplification of MYCN protooncogene
    • NSE and bombesin positivity
    • Homer Wright pseudorosettes:
      • Small round blue cells
      • Tumor Tumor Inflammation cells surrounding the neuropil
      • Seen in neuroblastoma, medulloblastoma Medulloblastoma Medulloblastomas are malignant primitive neuroectodermal tumors that arise in the posterior fossa in children. Medulloblastomas are the most common malignant brain tumors in children. Patients with medulloblastoma present with symptoms of increased intracranial pressure and cerebellar signs, which both evolve and worsen over weeks to a few months. Medulloblastoma, and primitive neuroectodermal tumors
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is also indicated as part of staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis.
Neuroblastoma gross and histologic appearance

Neuroblastoma in gross and histologic appearance: macroscopic (left) and microscopic (right) images of neuroblastoma

Image: “Radiological and pathological findings of a metastatic composite paraganglioma Paraganglioma A neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion, such as the carotid body, or medulla of the adrenal gland (usually called a chromaffinoma or pheochromocytoma). It is more common in women than in men. Hearing Loss with neuroblastoma in a man: a case report” by Fritzsche FR, Bode PK, Koch S, Frauenfelder T. License: CC BY 2.0

Staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis: International Neuroblastoma Staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis System (INSS)

Multiple staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis systems exist, but the INSS is one of the most common. Body imaging, a biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma of the primary tumor Tumor Inflammation, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, and a bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types scan are required:

  • Stage 1 Stage 1 Trypanosoma brucei/African trypanosomiasis:
  • Stage 2A:
  • Stage 2B:
  • Stage 3: malignancy Malignancy Hemothorax with contralateral lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis or tumor Tumor Inflammation crossing midline or tumor Tumor Inflammation with bilateral lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node involvement
  • Stage 4:
    • Malignancy Malignancy Hemothorax with distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis (e.g., skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy)
    • Metastases other than those defined in stage 4S
  • Stage 4S: malignancy Malignancy Hemothorax in infants < 12 months with metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis confined to skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, or bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow

Management and Prognosis

Management of neuroblastoma depends on whether the patient is considered to have a low-, intermediate-, or high-risk neuroblastoma. Localized disease is often curable. 

Risk stratification depends on the stage of the malignancy Malignancy Hemothorax at the time of the diagnosis, MYCN amplification, chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 1p deletion, and age at the time of the diagnosis (later age of diagnosis = worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas).

Low-risk neuroblastoma

Intermediate-risk neuroblastoma

  • Includes:
    • Stage 3 without MYCN amplification and with favorable histology
    • Stage 4 in children < 12 months without MYCN amplification
    • Some stage 4S without MYCN amplification
  • Chemotherapy Chemotherapy Osteosarcoma 
  • +/- Surgical excision
  • Consider radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy if neuroblastoma progresses after surgery and chemotherapy Chemotherapy Osteosarcoma.
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas: > 90% survival (with treatment)

High-risk neuroblastoma

  • Includes:
    • Stages 2A, 2B, 3, 4, and 4S with MYCN amplification
    • Stage 4 in children > 12‒18 months
  • Chemotherapy Chemotherapy Osteosarcoma: Preoperative chemotherapy Chemotherapy Osteosarcoma to ↓ primary and metastatic tumor Tumor Inflammation burden.
  • Surgical excision
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow/ hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation
  • Additional therapy:
    • Dinutuximab: monoclonal antibody against GD2 ganglioside Ganglioside A subclass of acidic glycosphingolipids. They contain one or more sialic acid (n-acetylneuraminic acid) residues. Using the svennerholm system of abbreviations, gangliosides are designated g for ganglioside, plus subscript m, d, or t for mono-, di-, or trisialo, respectively, the subscript letter being followed by a subscript arabic numeral to indicated sequence of migration in thin-layer chromatograms. Fatty Acids and Lipids expressed on neuroblastoma cells
    • Granulocyte macrophage colony-stimulating factor Granulocyte macrophage colony-stimulating factor An acidic glycoprotein of mw 23 kda with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. White Myeloid Cells: Histology ( GM-CSF GM-CSF An acidic glycoprotein of mw 23 kda with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. White Myeloid Cells: Histology)
    • Cis-retinoic acid
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas: 40%‒50% survival

Differential Diagnosis

  • Wilms tumor Wilms tumor Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR syndrome, Denys-Drash syndrome, or Beckwith-Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms Tumor: malignancy Malignancy Hemothorax, also known as nephroblastoma, caused by the proliferation of metanephric blastema Metanephric blastema Wilms Tumor in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy and the most common renal malignancy Malignancy Hemothorax in children. Wilms tumor Wilms tumor Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR syndrome, Denys-Drash syndrome, or Beckwith-Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms Tumor commonly presents as a firm, nontender, smooth abdominal mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast that does not cross the midline. The tumor Tumor Inflammation is diagnosed with abdominal ultrasonography and histopathologic studies (from biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma or resection). Wilms tumor Wilms tumor Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR syndrome, Denys-Drash syndrome, or Beckwith-Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms Tumor is most often treated with nephrectomy Nephrectomy Excision of kidney. Renal Cell Carcinoma and chemotherapy Chemotherapy Osteosarcoma. Unlike neuroblastoma, Wilms tumor Wilms tumor Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR syndrome, Denys-Drash syndrome, or Beckwith-Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms Tumor rarely causes calcification and is seen in older children (average age of diagnosis between 3 and 5 years of age).
  • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma: a catecholamine-secreting tumor Tumor Inflammation derived from chromaffin cells Chromaffin cells Cells that store epinephrine secretory vesicles. During times of stress, the nervous system signals the vesicles to secrete their hormonal content. Their name derives from their ability to stain a brownish color with chromic salts. Characteristically, they are located in the adrenal medulla and paraganglia of the sympathetic nervous system. Adrenal Hormones. The majority of these tumors originate in the adrenal medulla Adrenal Medulla The inner portion of the adrenal gland. Derived from ectoderm, adrenal medulla consists mainly of chromaffin cells that produces and stores a number of neurotransmitters, mainly adrenaline (epinephrine) and norepinephrine. The activity of the adrenal medulla is regulated by the sympathetic nervous system. Adrenal Glands: Anatomy but can also arise from sympathetic ganglia. Symptoms include episodic hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, and sweating. The classic triad of symptoms is headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, diaphoresis, and tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children. Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma is diagnosed by measuring the catecholamine breakdown products (e.g., HVA, VMA, metanephrine Metanephrine Product of epinephrine o-methylation. It is a commonly occurring, pharmacologically and physiologically inactive metabolite of epinephrine. Pheochromocytoma) in the blood or 24-hour urine, and is differentiated from neuroblastoma on histology. Treatment is surgical excision. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a complete resection have a good prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas. Unlike neuroblastoma, pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma causes significant sympathetic symptoms.
  • Burkitt lymphoma Burkitt lymphoma A form of undifferentiated malignant lymphoma usually found in central Africa, but also reported in other parts of the world. It is commonly manifested as a large osteolytic lesion in the jaw or as an abdominal mass. B-cell antigens are expressed on the immature cells that make up the tumor in virtually all cases of Burkitt lymphoma. The Epstein-Barr virus (Human herpesvirus 4) has been isolated from Burkitt lymphoma cases in Africa and it is implicated as the causative agent in these cases; however, most non-African cases are EBV-negative. Non-Hodgkin Lymphomas: a non-Hodgkin B cell lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum that presents in adolescents and young adults. This malignancy Malignancy Hemothorax is caused by dysregulation of the c-Myc c-MYC Basic helix-loop-helix transcription factors encoded by the c-myc genes. They are normally involved in nucleic acid metabolism and in mediating the cellular response to growth factors. Elevated and deregulated (constitutive) expression of c-myc proteins can cause tumorigenesis. Non-Hodgkin Lymphomas gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics. Burkitt lymphoma Burkitt lymphoma A form of undifferentiated malignant lymphoma usually found in central Africa, but also reported in other parts of the world. It is commonly manifested as a large osteolytic lesion in the jaw or as an abdominal mass. B-cell antigens are expressed on the immature cells that make up the tumor in virtually all cases of Burkitt lymphoma. The Epstein-Barr virus (Human herpesvirus 4) has been isolated from Burkitt lymphoma cases in Africa and it is implicated as the causative agent in these cases; however, most non-African cases are EBV-negative. Non-Hodgkin Lymphomas presents either as a jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint: Anatomy lesion in endemic form or pelvic or abdominal lesion in sporadic Sporadic Selective IgA Deficiency form. Burkitt lymphoma Burkitt lymphoma A form of undifferentiated malignant lymphoma usually found in central Africa, but also reported in other parts of the world. It is commonly manifested as a large osteolytic lesion in the jaw or as an abdominal mass. B-cell antigens are expressed on the immature cells that make up the tumor in virtually all cases of Burkitt lymphoma. The Epstein-Barr virus (Human herpesvirus 4) has been isolated from Burkitt lymphoma cases in Africa and it is implicated as the causative agent in these cases; however, most non-African cases are EBV-negative. Non-Hodgkin Lymphomas may also be associated with HIV HIV Anti-HIV Drugs and EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus. The disease is diagnosed with a lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, which usually shows a “starry sky” pattern of large, pale, tingible-body macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation. Treatment is mostly chemotherapy Chemotherapy Osteosarcoma. The cure rate is excellent with appropriate treatment. Unlike neuroblastoma, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with Burkitt lymphoma Burkitt lymphoma A form of undifferentiated malignant lymphoma usually found in central Africa, but also reported in other parts of the world. It is commonly manifested as a large osteolytic lesion in the jaw or as an abdominal mass. B-cell antigens are expressed on the immature cells that make up the tumor in virtually all cases of Burkitt lymphoma. The Epstein-Barr virus (Human herpesvirus 4) has been isolated from Burkitt lymphoma cases in Africa and it is implicated as the causative agent in these cases; however, most non-African cases are EBV-negative. Non-Hodgkin Lymphomas are often immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis (e.g., HIV HIV Anti-HIV Drugs) and present in their adolescent or young-adult years.

References

  1. Shohet, J.M., Nuchtern, J.G. (2020). Clinical presentation, diagnosis, and staging evaluation of neuroblastoma. UpToDate. Retrieved May 24, 2021, from https://www.uptodate.com/contents/clinical-presentation-diagnosis-and-staging-evaluation-of-neuroblastoma
  2. Shohet, J.M., Lowas, S.R. (2020). Treatment and prognosis of neuroblastoma. UpToDate. Retrieved May 24, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-neuroblastoma?search=neuroblastoma
  3. Joyner, B.D. (2021). Neuroblastoma: Practice essentials, background, history of the procedure. Medscape. Retrieved May 24, 2021, from https://emedicine.medscape.com/article/439263-overview
  4. Mahapatra, S. (2021). Neuroblastoma. StatPearls. Retrieved Mar 4, 2022 from https://www.statpearls.com/articlelibrary/viewarticle/25777

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