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Practice Clinical updates

Neuroblastoma

BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1863 (Published 03 May 2017) Cite this as: BMJ 2017;357:j1863
  1. Jason Shohet, associate professor and co-chairman of the Neuroblastoma Research Program1 2,
  2. Jennifer Foster, assistant professor, clinical director of the Neuroblastoma Program1 3
  1. 1Texas Children’s Cancer Center, 6701 Fannin Street, Houston, Texas 77030, USA
  2. 2Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
  3. 3Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas
  1. Correspondence to: J Foster jhfoster{at}txch.org

What you need to know

  • Neuroblastoma is the most common extracranial solid tumour in children; most patients are diagnosed by 5 years of age

  • Diagnosis can usually be confirmed by urine catecholamines and imaging; however, biopsy of the primary site (or bone marrow for staging purposes) is required to establish biology and risk stratification

  • Treatment varies from observation alone for certain low risk patients to intense multimodal therapy for high risk patients

  • Prognosis is excellent for patients with low risk disease and poor for those with high risk disease

  • Relapsed or refractory (high risk) disease is difficult to cure and is associated with extremely low survival

Neuroblastoma most commonly arises from the adrenal gland(s), but can form anywhere that sympathetic nervous tissue is present, including paraspinal sympathetic ganglia in the chest and abdomen.123

The term neuroblastoma is commonly used to describe a spectrum of neuroblastic tumours including neuroblastomas (the most common type), ganglioneuroblastomas, and ganglioneuromas.

Who gets it?

The vast majority of neuroblastomas are diagnosed in children younger than 5 years old, and nearly all patients are diagnosed by the time they are 10 years old. The median age at diagnosis is around 18 months.1

Neuroblastoma accounts for nearly 8% of all childhood malignancies and is the most common solid tumour in children not arising from the brain. This incidence is similar across industrialised nations.45

What causes it?

Given the rarity of the disease, strict associations are hard to prove, and no specific environmental exposure has been implicated in the development of neuroblastoma.

Neuroblastoma is classically an embryological malignancy derived from neural crest cells. The neural crest is a group of neuronal cells that migrate from the spinal cord to form many structures, including the sympathetic nervous system, during fetal development. Therefore, the tumour is found to originate from sympathetic ganglia near the spinal cord and within the adrenal medulla. As the glycolipid disialoganglioside is expressed during differentiation into sympathetic nervous tissue, disialoganglioside is typically found on the surface of neuroblastomas and has therefore been used as a tumour antigen for therapeutic targeting.123

One per cent of patients diagnosed with neuroblastoma have a family history of neuroblastic tumours.67 Several oncogenes are implicated in the development of neuroblastoma, including the MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homologue), anaplastic lymphoma kinase (ALK), and paired-like homeobox 2b (PHOX2B) genes (fig 1). These genes are also involved in neural crest development.8

Figure1

Fig 1 Neural crest development and neuroblastoma formation. Neuroblastoma arises during neural crest specification and differentiation, which involves epithelial to mesenchymal transition (EMT) of multipotent neural crest cells to generate many different tissues. Disruption of this process with oncogenic drivers (MYCN, ALK, etc) at different times can lead to multiple subtypes of neuroblastoma tumour. (Adapted from Louis and Shohet8)

A few medical conditions, some of which are related to aberrant neural crest development, have been shown to predispose a patient to developing neuroblastoma, including Turner syndrome, Hirschsprung disease, congenital central hypoventilation syndrome, and neurofibromatosis type 1.910111213

Most tumours arise in the abdomen, most commonly in the adrenal gland(s). However, tumours may also present with thoracic or paravertebral primary sites, from the neck to the pelvis.3 Very rarely, a primary site cannot be identified. Neuroblastoma can metastasise by both lymphatic and hematologic spread, the most common sites being lymph nodes, bone marrow, bone, liver, skin, orbits, and dura. Intracranial and pulmonary spread is also possible, but is uncommon.14

This cancer is highly heterogeneous, partly because it arises from a tissue type that is undergoing rapid differentiation during fetal development, and the transition from normal to malignant tissue can occur at multiple points in development. Therefore, some tumours are rapidly proliferative but regress over time, and other tumours grow more slowly but are highly malignant.8

Most neuroblastoma tumours retain the ability to metabolise catecholamines (such as adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine), which can lead to hypertension or other symptoms associated with excess catecholamines (such as dizziness, nausea, headache). Importantly, the metabolites homovanillic acid and vanillylmandelic acid are secreted by most tumours, and these can be detected in the urine of patients.151617

Can neuroblastoma be prevented?

There are no prevention strategies because the disease is a result of altered embryological development of the neural crest tissue. No preventable environmental exposures have been linked to the condition.

Screening measures are not currently recommended, except in patients with a known familial predisposition to neuroblastoma. Early detection of neuroblastoma has not been shown to improve mortality, and screening young children for tumour markers (that is, homovanillic acid and vanillylmandelic acid in urine) has not resulted in improved survival.18192021

How is neuroblastoma diagnosed?

Initial investigations for all patients with suspected neuroblastoma include full blood count, serum electrolytes, renal function, liver function tests, and serum markers for increased cell turnover such as lactate dehydrogenase.

Because neuroblastoma arises from the sympathetic nervous system, specific tests for the presence of catecholamine metabolism are an important part of the initial work-up. The test for catecholamine degradation products homovanillic acid and vanillylmandelic acid (secreted by most tumours and detected in patients’ urine) is highly sensitive and specific for neuroblastoma. As well as being diagnostic, homovanillic acid and vanillylmandelic acid levels are also useful for surveillance during treatment and as part of end-disease surveillance.15161722

Since the most common presentation is an abdominal mass, an ultrasound scan of the abdomen should form part of the work-up in all patients with suspected neuroblastoma. If a mass is detected, further imaging should include computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen, which may reveal a heterogeneous mass (possibly with calcifications). If there is intraspinal extension of the tumour, MRI is preferred over CT.23

After initial imaging, international consensus guidelines recommend a biopsy to confirm the diagnosis.23 The tissue sample may be obtained by incisional biopsy of the primary tumour, or bone marrow aspiration and biopsy if bone marrow metastasis is suspected. Definitive diagnosis requires one of the following conditions23:

  • Unequivocal histological diagnosis from tumour tissue by light microscopy with or without increased urine catecholamines

  • Evidence of metastases to bone marrow on bone marrow aspiration and biopsy in the setting of increased urine catecholamines.

If metastatic evaluation confirms that the tumour seems to be localised, complete resection may be attempted in addition to the biopsy if the risks associated with the procedure are considered to be low.

Investigations for metastatic disease

Neuroblastoma commonly presents with metastases. As such, a comprehensive evaluation for metastases is recommended in all patients for whom there is a high suspicion for or diagnosis of neuroblastoma.

Assessment for bone marrow involvement is a key component of the work-up. Bilateral bone marrow aspiration and biopsy should be performed in all patients.23

Different imaging techniques are used to detect metastases, including a radionucleotide bone scan, 123I- metaiodobenzylguanidine scintigraphy and positron emission tomography with 18F-deoxyglucose.

Staging

Neuroblastoma has historically been staged using the International Neuroblastoma Staging System (INSS), primarily a surgical staging system that depends on the aggressiveness of the surgical approach used (box 1).23

Box 1: Neuroblastoma staging systems

International Neuroblastoma Staging System (INSS)23
  • Stage 1: Localised tumour with complete gross excision, with or without microscopic residual disease

  • Stage 2a: Localised tumour with incomplete gross excision

  • Stage 2b: Localised tumour with or without complete gross excision

  • Stage 3: Unresectable unilateral tumour infiltrating across the midline (beyond the opposite side of the vertebral column) with or without regional lymph node involvement, or localised unilateral tumour with contralateral regional lymph node involvement, or midline tumour with bilateral extension via infiltration (unresectable) or lymph node involvement

  • Stage 4: Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S disease)

  • Stage 4S: Localised primary tumour with dissemination limited to skin, liver, and/or bone marrow (limited to infants <1 year of age, marrow involvement <10% of total nucleated cells, 123I-metaiodobenzylguanidine scan findings negative in the marrow).

International Neuroblastoma Risk Group Staging System (INRGSS)2

Patients are divided into four main categories:

  • L1: Localised tumour not involving vital structures, as defined by the list of image-defined risk factors (IDRFs), and confined to one body compartment. Pre-treatment IDRFs correlate with being able to perform a complete resection

  • L2: Local-regional tumour with presence of one or more IDRFs

  • M: Distant metastatic disease (except stage MS tumour)

  • MS: Metastatic disease in children <18 months old with metastases confined to the skin, liver, and/or bone marrow

In order to standardise staging internationally, irrespective of surgery, the International Neuroblastoma Risk Group (INRG) has developed a new staging system based on image-defined risk factors (box 1).2 These factors are determined at the time of diagnosis, before surgery.

How is neuroblastoma managed?

Initial management of neuroblastoma is dependent on the patient’s risk of relapse (see box 2). Patients are placed into three different risk groups, and these groups are used to predict prognosis.

Box 2: Risk stratification of neuroblastoma

Risk stratification is based on a myriad of factors including

  • Patient age

  • Stage of disease

  • Presence or absence of MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog) amplification

  • Tumour cell ploidy

  • Chromosomal aberrations

  • Histopathological appearance of the tumor

  • Age—younger children have better survival rates242526

Management varies from observation in patients with low risk disease, to intense multimodal therapy (that is, surgery, radiotherapy, chemotherapy, autologous bone marrow transplantation, immunotherapy, and isotretinoin) in patients with high risk disease.

Management should be handled by a team of specialists including a paediatric oncologist, cancer surgeon, and radiation oncologist.

Low risk disease

Patients with low risk disease have an excellent prognosis. Event-free survival in these patients is 92%, with an overall survival rate of 96%.2728 Survival is nearly 100% among infants treated with observation alone.272829 In children beyond infancy who have resectable local-regional disease, event-free survival approaches 100% for patients in whom a gross total resection is achieved.3031 In patients in whom a gross total resection is not achieved but more than 50% of the tumour is resected, survival is also expected, with an event-free survival of >80%.30323334 Surgery is the mainstay of management for low risk disease, although some patients may require chemotherapy, and some may just be observed without the need for surgery.

Most perinatal tumours are INSS stage 1 or stage 2, arise from the adrenal gland(s), and are of favourable histology. Multiple prospective studies have shown that tumours <5 cm in diameter are likely to regress spontaneously.35363738

Surgery is the initial treatment of choice for patients with localised disease who are able to have more than 50% of their tumour safely removed as determined by image-defined risk factors and potential risks associated with surgery on surrounding structures. Although a portion of these patients will have disease progression after surgery, they can be salvaged with surgery or chemotherapy, or both, and achieve overall survival rates comparable to those of similar patients whose disease did not progress.3031323940

Observation, with serial ultrasound scans every three to six weeks, is a reasonable alternative in the following patient groups:

  • Patients <6 months old with localised tumours <3.1 cm in diameter detected by screening or incidental ultrasound.29

  • Clinically stable, asymptomatic patients with stage 4S disease.4142

  • Patients with a localised tumour who have had most of the tumour surgically removed.43

Observation should continue at increasing intervals for two years.

Given the excellent prognosis of patients with low risk disease, efforts have been made in trials to decrease or eliminate chemotherapy for this patient population. Chemotherapy may be used, but usually only if the tumour progresses after surgery, if surgery would be more feasible with a smaller tumour size, or if the patient is experiencing severe symptoms from mass effect of the tumour (such as airway compromise, spinal cord compression, or bowel obstruction).39303344 A common chemotherapy regimen is carboplatin, etoposide, cyclophosphamide, and doxorubicin.

Intermediate risk disease

Patients with intermediate risk disease achieve an overall survival rate of more than 80% with a combination of surgery and chemotherapy.41454647

Duration of chemotherapy depends on the biological features of the tumour. Intermediate risk tumours show wide biological variability, and these factors are used to decide which chemotherapy regimen should be used.48 Trials to determine which subgroups of patients can safely have their chemotherapy reduced are ongoing. A common drug regimen is carboplatin, etoposide, cyclophosphamide, and doxorubicin, usually given for four to eight cycles.

An attempt at gross total resection is recommended after chemotherapy if possible. In patients with INSS stage 3 disease, gross total resection has been associated with a better overall survival rate compared with subtotal resection. The timing of surgery varies, but usually follows a few cycles of chemotherapy.34484950

If chemotherapy and surgery are not effective, radiotherapy may be used.

Patients with biologically favourable local-regional disease that is unresectable have achieved an event-free survival of greater than 80% after treatment with chemotherapy.394145464748

High risk disease

High risk disease can be difficult to cure, and a large proportion of these patients experience disease recurrence. Despite intense multimodal therapy, patients with high risk disease have a poor prognosis with an event-free survival of less than 50%.515253 Prognosis depends on pathological subtypes and additional biological factors that remain to be determined. As the biology is clarified, it may be possible to further delineate specific outcomes for individual patients.

Patients with high risk disease are therefore treated aggressively with multimodal therapy including chemotherapy, surgery, autologous bone marrow transplant, radiotherapy, immunotherapy, and maintenance therapy with isotretinoin. Treatment continues to evolve as new data and therapeutic options emerge.

Relapsed or refractory disease

Relapsed or refractory neuroblastoma is extremely difficult to cure, and there is no standard treatment for these patients. The median time to relapse is around 1.5 years from diagnosis. Up to 20% of patients with high risk disease will have primary refractory disease, and nearly 60% of patients who complete therapy will relapse.545556 Overall survival after relapse depends on risk stratification, with INSS stage 1 patients having an overall survival rate approaching 70%, compared with an overall survival rate of 40% in stage 2 patients and 2% in stage 4 patients.57

Chemotherapy options include high dose ifosfamide, carboplatin, and etoposide as well as combinations that include irinotecan, topotecan, cyclophosphamide, and temozolomide. Other treatment options include radiotherapy and immunotherapy.58 Despite the number of treatment options, many patients with high risk disease will relapse or be refractory to second-line treatment. For the patients who do not respond to initial relapse treatments, there is currently no standard of care, although new agents are emerging (see box 3).

Box 3: Emerging therapies for neuroblastoma

131-iodine-metaiodobenzylguanidine (MIBG) as induction therapy

This radiopharmaceutical has shown promise for patients with refractory or relapsed disease, and is now being studied for use as an initial therapy. Clinical trials of its use during the induction phase of therapy are ongoing.59

Targeted molecular therapies

Many agents have shown promising results in preclinical models and early phase clinical trials. These include

  • Small molecule kinase inhibitors of

    • Anaplastic lymphoma kinase (ALK)

    • Tropomyosin-related kinase (Trk)

    • Epidermal growth factor receptor (EGFR)

    • Checkpoint kinase 1 (CHK1)

    • Wee1 kinase

  • Mammalian target of rapamycin (mTOR), serine-threonine protein kinase Akt, and aurora A kinase.158

  • Alisertib (an aurora A kinase inhibitor) was used in combination with irinotecan and temozolomide in a phase 1 trial for patients with relapsed or refractory neuroblastoma. Results showed that the combination was well tolerated with a promising overall response rate of 31.8%.60

Eflornithine (DFMO)

An inhibitor of the enzyme orthinine decarboxylase (ODC). Patients with neuroblastoma who express the ODC enzyme have been found to have a worse survival rate than patients without ODC expression.61 A phase 1 trial of the drug in patients with relapsed or refractory neuroblastoma showed that it is well tolerated.62 Clinical trials to assess efficacy are ongoing.

Entrectinib

A pan-Trk, ALK, and Ros 1 inhibitor currently in early phase clinical trials in both children and adults that has been found to be well tolerated. Preclinical xenograft mouse models of neuroblastoma show that Trk inhibition inhibits tumour growth and enhances chemotherapeutic effects.63

Chimeric antigen receptor (CAR) T cells

Immunologic approaches to the treatment of neuroblastoma are under development, including CAR modified T cell and natural killer T cell therapies. Additional mechanisms to target cancer cells with these approaches are also under development.

Long term sequelae of treatment

Patients with low risk disease who are observed or treated with surgery have minimal long term sequelae. Since patients with intermediate and high risk disease are treated with chemotherapy and radiation in addition to surgery, survivors are at risk of experiencing treatment related adverse effects such as ototoxicity, cardiotoxicity, endocrine complications, osteoporosis, secondary malignancies, and future infertility, which may have long term implications (fig 2).

Figure2

Fig 2 Potential complications of neuroblastoma and its treatment

Sources and selection criteria

Our search strategy was PubMed using keyword “neuroblastoma”

Footnotes

  • This clinical review series has been developed for The BMJ in collaboration with BMJ Best Practice (http://bestpractice.bmj.com), an independent product produced by BMJ Publishing Group Limited. BMJ Best Practice comprises web/mobile topics that support evidence-based decision making at the point of care. Peer review of the content in this clinical review was carried out exclusively according to BMJ Best Practice’s own, independent process (http://bestpractice.bmj.com/best-practice/marketing/how-is-best-practice-produced.html). This adaptation of a BMJ Best Practice topic for a clinical review in The BMJ uses only a portion of content from the latest available web version of BMJ Best Practice. BMJ Best Practice is updated on an ongoing basis, and the content of any BMJ Best Practice topic is expected to change periodically including subsequent to its publication as a clinical review in The BMJ. To view the complete and current versions of all BMJ Best Practice topics, please refer to the BMJ Best Practice website (http://bestpractice.bmj.com).

    Content from BMJ Best Practice is intended to support, aid and supplement the expertise, discretion and judgment of licensed medical health professionals who remain solely responsible for decisions regarding diagnosis and treatment of their patients. Content from BMJ Best Practice is not intended to function as a substitute for a licensed medical health professional’s judgment. BMJ Best Practice reflects evidence available to its authors and licensors before publication. The BMJ relies on its authors to confirm the accuracy of the information presented to reflect generally accepted practices. While The BMJ seeks to ensure BMJ Best Practice is up to date and accurate, it does not warrant that is the case. Content from BMJ Best Practice is supplied on an “as is” basis and any statements made to the contrary are void. BMJ Best Practice does not endorse drugs, diagnose patients, or recommend therapy. The full disclaimerapplicable to BMJ Best Practice can be found at http://bestpractice.bmj.com/best-practice/marketing/disclaimer.html.

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References

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