SYMPOSIUM: ONCOLOGY

A review and update on neuroblastoma

Andrew Hallett Heidi Traunecker

Abstract
Neuroblastoma is an enigmatic disorder, being a pathological entity, but presenting clinically with a wide range of symptoms and responding to treatment in a plethora of different and sometimes unpredictable ways. This represents a challenge for those charged with diagnosing and treating the disease. It is a disease of young children, being the most common tumour in infants, with the prognosis worsening with increasing age at presentation. There are no particular risk factors, so the diagnosis depends on clinical examination and appropriate investigations. Once the diagnosis has been made, further staging investigations and risk stratication are undertaken prior to commencing treatment. Once identied, high-risk disease remains the greatest challenge, with many of these cases ultimately relapsing. Treatment is best undertaken within a specialist, multidisciplinary team, with many medical specialties and allied health professionals involved, in order to optimize the progress and outcome. With high-risk disease being so aggressive, so does the treatment need to be. There are new treatment modalities available which are associated with signicant side and late effects. The challenge is how to bring these into the current treatment regimens in order to reduce the relapse rate without causing excessive harm.

Keywords diagnosis; neuroblastoma; prognosis; treatment

What is it? e Denition

Neuroblastoma is a neoplasm of the sympathoadrenal lineage of the neural crest, the sympathetic nervous system (SNS). As such, it has a wide variety of presentations and a hugely variable prognosis. The presentation largely depends upon the anatomical location in the SNS at which the primary tumour develops and the metastatic status. The outcome mainly depends on tumour specic prognostic factors, with other clinical factors such as age at presentation also being important.

that it presents in no one particular manner, and consider the diagnosis in an ill patient in whom a diagnosis is not immediately apparent. Localized disease is related to the SNS, reaching from the skull base to the pelvis. The most common presentation is as an abdominal mass, with 35% of cases arising from the adrenergic cells in the adrenal medulla. Thirty-ve percent present in the paraspinal ganglia, 20% in the posterior mediastinum, and 5% in the pelvis and 5% in the neck. Tumours in the neck and thorax may be incidentally found on chest X-ray (Figure 1), or they may present with Horners syndrome. Paraspinal tumours may present with paralysis caused by spinal cord compression. Young children can present with bluish skin metastases that may resemble bruising secondary to child abuse. Occasionally a mass is identied prenatally. Newborns may present with abdominal distension and respiratory compromise due to a mass or liver metastases causing massive hepatomegaly. Half of all patients present with haematogenous metastatic disease and these are often quite ill. Neuroblastoma has a peculiar but rare tendency to metastasize to the orbit, with racoon eyes due to bruising, or proptosis. There may be a systemic illness type of picture, with fever, anaemia, weight loss and typically the child being withdrawn because of the severity of the pain which the family often cannot describe. Bone marrow inltration may lead to signs of haematopoietic failure. Paraneoplastic phenomena include potentially intermittent hypertension due to catecholamine secretion or diarrhoea due to vaso-active peptides i.e. a VIPoma. The unusual opsoclonusemyoclonuseataxia syndrome, which consists of rapid eye movements, ataxia, and irregular muscle movements, represents 2e3% of neuroblastoma cases, but only half of the children with this syndrome will have neuroblastoma. This syndrome confers a favourable oncological outcome, although associated with neurological sequelae, developmental delay and learning difculties in 70% of cases.

Epidemiology
It is the most common solid tumour in children less than 1 year of age. The incidence of neuroblastoma is 10.5/million children

How does it present?

Neuroblastoma presents in many different ways with most children with metastatic disease presenting in a state of severe ill health, malnourishment and pain. Clinicians need to be aware

Andrew Hallett MRCPCH is Registrar in Paediatrics in the Department of Paediatrics, University Hospital of Wales, Cardiff, UK. Conicts of interest: none declared. Heidi Traunecker MRCPCH PhD is Consultant Paediatric Oncologist in the Department of Paediatric Oncology, University Hospital of Wales, Cardiff, UK. Conicts of interest: none declared.

Figure 1 Neuroblastoma may present as an unusual shadow on chest X-ray, prompting further investigation.

PAEDIATRICS AND CHILD HEALTH 22:3

103

2011 Elsevier Ltd. All rights reserved.

SYMPOSIUM: ONCOLOGY

under the age of 15 years. The median age at presentation is 23 months, with the peak range from 0 to 4 years. It occurs slightly more commonly in boys than girls (1.2:1), with no racial or geographic predilection, but the identied incidence is higher in developed countries. It is overwhelmingly a sporadic condition, with a handful (approximately 1% of all cases) being familial. Screening with urinary catecholamines at birth demonstrated a higher incidence, but an unchanged mortality, suggesting many of those cases underwent spontaneous resolution and therefore is not a screening tool for the early detection of metastatic disease.

Aetiology
Studies have identied factors associated with the disease, but none are actually causative. In very few familial cases the inheritance is autosomal dominant with incomplete penetrance. There are two other disorders of the neural crest, Hirschsprungs disease and Congenital Central Hypoventilation Syndrome, which are associated with a higher risk of neuroblastoma. These are both associated with a mutation of the PHOX2B gene, a homeobox gene which is the main regulator of the development of the autonomic nervous system. More recently, a linkage analysis approach has been used to delineate a putative neuroblastoma gene-encoding chromosomal region at 2p23ep24, containing the ALK gene.

Diagnosis
Investigations prior to a biopsy or surgical procedure include radiological imaging and urine biochemistry for catecholamines or their metabolites (dopamine, vanillylmandelic acid, homovanillic acid). Other non-specic markers are thrombocytosis, raised ferritin, neuron-specic enolase, and lactate dehydrogenase. If an abdominal mass is the presenting feature, abdominal ultrasound will be the initial investigation. Neuroblastoma appears on USS as heterogenous, solid lesions. Further diagnostic radiological imaging should be undertaken at the Primary Oncological Treatment Centre and includes CT, and usually MRI scanning (Figure 2) to evaluate primary tumour size and regional/intraspinal extent, and to detect distant spread to bones, neck, thorax, abdomen or pelvis including any sites of presumed disease even if unusual i.e. skull base in a child losing vision.
Lymph node

MRI is the preferred modality for determining spinal cord involvement, detecting extension into the epidural space and delineating abdominal disease without the exposure to radiation, but this usually requires a general anaesthetic in the age group of patients affected. CT scans are a readily available method of delineating an abdominal mass which can be carried out without an anaesthetic, which also shows evidence of regional invasion, vascular encasement, lymphadenopathy, and calcication, which are highly suggestive of the diagnosis, particularly with regard to differentiating between neuroblastoma and Wilms tumour. The 123 isotope of I-metaiodobenzylguanidine (123I-MIBG) will be selectively taken up by catecholamine secreting tumour cells (present in more than 90% of cases) and these scans remain the most specic and very sensitive imaging modality. A bone scan (Figure 3) depicts the whole skeleton, looking for bony involvement, which is often clinically silent but may also depict the primary tumour or other metastatic sites. Due to the differing techniques used, discrepant ndings between the various imaging modalities are common and require careful correlation with CT/MRI or X-rays. In cases where MIBG is not taken up, an 18 F-uorodeoxyglucose (18F-FDG) PET/CT can be carried out, although this is not routine practice. The current criteria for diagnosis and staging of neuroblastoma are based on the International Neuroblastoma Staging System (INSS) criteria developed in 1986. These were most recently revised in 2008 as the International Neuroblastoma Risk Group Staging System (INRGSS). The diagnosis rests on pathological conrmation after examination of tumour tissue obtained by trucut biopsy in metastatic or non-resectable cases or during denitive surgery in localized, resectable cases. Elevated urinary catecholamines support the diagnosis in over 90% of cases. Pathology Histologically, the picture of a neuroblastoma is non-specic; a small blue round cell tumour with the cells being uniform in size, with dense hyperchromatic nuclei and minimal cytoplasm. According to the International Neuroblastoma Pathology Classication system (INPC), tumours are classied as favourable or unfavourable, depending on the degree of neuroblast differentiation, Schwannian stroma content, mitosis-karyorrhexis index, and age at diagnosis. Cancer biology The genetics of the somatic cancer cells have an important bearing on the outcome of the disease. MYC-N oncogenes produce oncoproteins, which are transcription factors that may cause dysregulated growth when excessively expressed. MYC-N amplication (>10 copies/cell) is associated with metastatic disease, rapid disease progression and poor outcome and as prognostic marker outweighs all other cytogenetic markers. Aggressive tumour behaviour may be associated with deletion of chromosomal regions 1p36.3 or 11q23, with 11q23 deletion being inversely associated with MYC-N amplication. Neuroblastoma is either near-diploid or polyploid, with near diploid DNA content being a predictor of poorer outcome in patients younger than 18 months with metastatic disease. Patients with MYC-N amplication are treated with an intensive,
104
2011 Elsevier Ltd. All rights reserved.

liver Tumour mass crossing the midline Metastatic lymph node

spleen

Deviated inferior vena cava

Distended bladder

Figure 2 The most common presentation of neuroblastoma is as a mass arising from the adrenal medulla, often extending around the blood vessels and other structures.

PAEDIATRICS AND CHILD HEALTH 22:3

SYMPOSIUM: ONCOLOGY

Bony metastatic destruction Sternal metastases

Bony metastatic destruction Vertebral metastases

Contrast medium in bladder

Bony metastasis

Contrast medium in nappy

Figure 3 Bone scans are the best way to investigate for bony involvement, but also show up disease at other sites.

multimodality treatment strategy whatever the disease extent, and irrespective of age. The strong association with prognosis allows those with favourable cytogenetics to be exposed to lower treatment toxicity levels, and therefore fewer late effects.

Treatment modalities
Observation only A small proportion of neuroblastoma will undergo complete, spontaneous regression. Typically this includes antenatal diagnosis and age below 1 year as well as 4S neuroblastoma, dened as a small primary tumour associated with involvement of liver, bone marrow and/or skin, but not cortical bone in the under 1-year-old patients. Surgery Most localized tumours with favourable biological characteristics respond well to primary surgical resection. The aim of surgery is complete resection in low and medium risk cases. Neuroblastoma is a locally inltrative tumour, making microscopically clear resection margins difcult to achieve, and the pre-operative ndings may not always permit an accurate assessment of resectability. Surgery of the primary tumour site in high-risk (MYC-N amplied and/or metastatic) cases or primarily unresectable stage III cases is carried out after intensive induction chemotherapy, which aims to increase the probability of complete resection at the time of disease control locally and in all metastatic sites, although this may not always be achieved. Small volume post surgical residue is commonly encountered. Mutilating surgery is not acceptable which may render some disease sites unresectable. Chemotherapy For low risk, stage 4S disease, induction chemotherapy is only given to those that have life- or organ-threatening symptoms at diagnosis, with the aim to induce the anticipated process of tumour regression or those that suffer relapse of the disease. For intermediate risk disease that is primarily unresectable, chemotherapy at moderate intensity is the treatment of choice followed by a surgical resection. Poor responders will need to be exposed to increasing treatment intensity of chemotherapy. High-risk metastatic disease will be treated with intensive induction chemotherapy that will lead to major organ toxicity.

Management
A multi-disciplinary approach is crucial to optimize the outcome for this disease. Depending on the risk stratication, treatment options include:  observation only  surgery  chemotherapy  chemotherapy followed by surgery,  a strategy for high-risk disease using chemotherapy, surgery, high dose chemotherapy and autologous stem cell transplant, radiotherapy, immunotherapy and maturation therapy, which lasts over a year. Allied disciplines of physiotherapy, dietetics, psychology and social work are heavily involved in the care of high-risk patients. The Gold Standard of oncological therapy remains the enrolment of the patient into international research studies for neuroblastoma.

Stratication of risk
Although staging is important for the prognosis, additional risk stratication is needed for planning therapy because of the biological factors mentioned above. Most clinical trials now stratify patients according to the International Neuroblastoma Risk Group (INRG) report in 2009 into low, intermediate or high-risk groups. This incorporates pre-operative imaging, age of the patient, INSS stage, histological assessment as favourable or unfavourable according to the International Neuroblastoma Pathology Classication system (INPC), modied by Shimada in 1999, MYC-N status and DNA ploidy. High-risk groups will include metastatic tumours above the age of 1 year and all MYC-N amplied tumours regardless of age or extent of disease.

PAEDIATRICS AND CHILD HEALTH 22:3

105

2011 Elsevier Ltd. All rights reserved.

SYMPOSIUM: ONCOLOGY

Cisplatin, carboplatin, etoposide, cyclophosphamide and vincristine are given at standard doses using intensive scheduling, leading to a 3-month period of sustained pancytopaenia. Up to 30% of patients do not achieve disease control (resolution of metastases or resectability of disease) at this stage and require further chemotherapy using topotecan, doxorubicin and vincristine or even experimental treatment options. There is a direct correlation between achieving tumour response after induction chemotherapy and survival. Surgical resection is only indicated in patients whose disease has been controlled. Post-operative consolidation chemotherapy in high-risk cases aims to eradicate the remaining tumour cells using cytotoxic agents at myeloablative doses (melphalan and busulphan), followed by haematopoietic autologous stem cell rescue. This has been shown to improve overall survival while increasing long-term toxicity. Radiotherapy Although neuroblastoma is very sensitive to radiotherapy, highrisk disease is primarily a metastatic disease with total body irradiation to all metastatic sites being associated with unacceptable long-term side effects. Therefore radiation to the site of primary disease after surgical resection and autologous stem cell transplant has become standard practice in high-risk disease. It is uncommonly given to cases of medium risk unless surgery and chemotherapy fail to control the tumour. Immunotherapy and biological therapy In high-risk disease cases, persistence of undetectable tumour cells (minimal residual disease, MRD) after induction therapy, surgery, autologous stem cell transplant and focal radiotherapy is associated with a very poor outcome and it is in this group that new therapy strategies are being tried and tested using clinical research trials. The genetic changes in cancer cells that cause and allow them to proliferate also cause them to be antigenically different from the normal cells, and the bodys immunological system failed in preventing the multiplication and spread of cancer cells, even before the development of a clinically apparent tumour. The immunological difference is an important mechanism for ghting the disease, and can be utilized through medical intervention. Cellular mechanisms appear the most important, with CD8 natural killer and natural killer T cells being particularly important. They also prime the adaptive immune response by releasing cytokines which help activate CD8 T-cells. Immunotherapy can be passive, including antibody infusion and cellular therapy, while active immunotherapy boosts the endogenous antitumour immunity. To date, three antigangliosidase (anti-GD2) monoclonal antibodies (mAbs) have been used clinically. These are two murine antibodies, 3F8 and 14G2a, and one chimeric agent, ch14.18 which has been mostly used. Toxicity from ch14.18 is not insignicant, with potentially life threatening infusion reactions and severe nerve pain occurring in many patients, due to expression of GD2 on peripheral pain bres. Initial toxicity testing in Phase II studies in Germany reported the use of it as a cycle of daily infusions for 5 days every 2 months for six cycles requiring inpatient care and intensive pain support. A signicant difference in EFS and a reduced rate of

bone marrow relapse had been recorded. The American Childrens Oncology Group (COG) reported a signicant survival advantage from adding ch14.18 to 13-cis-retinoic acid to the treatment for MRD in high-risk patients. The most promising active immunotherapy seems to be the cytokine IL-2. The effect is mediated by enhanced NK and/or cytotoxic T-cell response, but with signicant side-effects of hyperpyrexia and u-like symptoms, capillary leak syndrome and hypotension. To reduce the overall toxicity, cytokines have been conjugated to antiGD2 mAbs, but clinical trials of these have been disappointing. Retinoids are natural and synthetic derivatives of vitamin A, 13-cis-retinoic acid induces cell growth arrest and differentiation of neuroblastoma cell lines, and signicantly improved outcome in high-risk disease when given after achieving a minimal residual disease status. Apart from cheilitis and peeling of the skin which responds to Vitamin E cream, it is generally well tolerated. Combining ch14.18 mAb, GM-CSF and Interleukin 2 in highrisk disease that has achieved a minimal residual disease status, has added a further improvement in overall survival. There are clinical trials ongoing to assess the efcacy of combining cytokines with monoclonal antibodies directed against anti-GD2 and maturation therapy with retinoic acid in metastatic, high-risk disease. Radio-labelled tumour-specic therapy Over recent years, therapies directed at specically killing neuroblastoma cells through the cellular uptake of radioactive material have become an alternative treatment option in cases that do not respond to standard therapy. Although not curative in their own right, they can become useful treatment options in cases that do not achieve a clinical response early in treatment or at the time of late or slow onset relapse. Response rates of up to 30% have been reported in this situation. It requires careful preparation of the patients carers and staff, to protect them from unnecessary radiation, managing the patient in isolation. Between 1.75 and 2.5 Gy of radiation are delivered and the cell kill is generally slower compared to chemotherapy or standard radiotherapy. To increase the therapy effect, some chemotherapeutic agents can be added straight after the 131I-MIBG therapy with the support of autologous stem cells. Untoward effects include blood pressure changes, nausea and vomiting, bone marrow suppression as well as secondary cancers and hypothyroidism in the longer term.

Prognosis
The outcome for children with neuroblastoma depends on the stage of the disease at presentation. Those who present with stage 1 or 2 disease, or the unusual stage 4S, generally have a good prognosis which is much better than for those who present with stage 3 or 4 disease. Those with cytogenetic poor risk factors have a bleaker outlook. Broadly speaking, the 5-year event e free survival for high-risk neuroblastoma is approximately 40%, with the 5-year overall survival rate about 50% which has become a major success compared to the previously virtually always lethal disease.

PAEDIATRICS AND CHILD HEALTH 22:3

106

2011 Elsevier Ltd. All rights reserved.

SYMPOSIUM: ONCOLOGY

More recent treatment trials for high-risk disease are looking at incorporating new treatment modalities into treatment regimes to reduce the number of treatment failures. For some of those that do relapse, it may now be possible to prolong life although most do succumb to their disease within a very brief period. Neuroblastoma is a difcult to treat tumour, and the aggressive therapy required will always have a cost attached to it in terms of quality of life for the patient on treatment and after completion of therapy.

Follow-up
Survivors of aggressive multi-modal treatment face signicant long-term consequences. Such patients can be easily identied during follow-up because of their general appearance of ill health associated with poor hair regrowth, poor growth, endocrinopathies and development and chronic renal and lung impairment. The cumulative 20-year incidence of chronic health conditions is 41%. The most common causes of late mortality (more than 5 years) are relapse and a second malignancy which is commonly treatment resistant. A

Kyo Y, Tanaka T, Hayashi K, et al. Identication of therapy-sensitive and therapy-resistant neuroblastoma subtypes in stages III, IVs and IV. Cancer Lett 2011; 306: 27e33. Mastrangelo S, Runi V, Ruggerio A. Treatment of advanced neuroblastoma in children over 1 year of age: the critical role of 131I-metaiodobenzylguanidine combined with chemotherapy in a rapid induction regimen. Pediatr Blood Cancer 2011; 56: 1032e40. Monclair T, Brodeur GM, Amros PF, et al. The international neuroblastoma risk group (INRG) staging system: an INRG task force report. J Clin Oncol 2009; 27: 298e303. Navid F, Armstrong M, Bareld RC. Immune therapies for neuroblastoma. Canc Biol Ther 15 May 2009; 8: 874e82. Ogawa S, Takita J, Sanada M, Hayashi Y. Oncogenic mutations of ALK in neuroblastoma. Cancer Sci 2011; 102: 302e8. Perwein P, Lackner H, Sovinz P et al. Survival and late effects in children with stage 4 neuroblastoma. Pediatr Blood Cancer, rst published online February 2011. Simon T, Bertold F, Borkhardt A, Kremens B, De Carolis B, Hero B. Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: results of German trials. Pediatr Blood Cancer 2011; 56: 578e83. Yalc in B, Kremer LCM, Caron HN, van Dalen EC. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev 2010.

FURTHER READING Ambros PF, Ambros IM, Brodeur GM, et al. International consensus for neuroblastoma molecular diagnostics: report from the international neuroblastoma risk group (INRG) biology committee. Br J Cancer 2009; 100: 1471e82. Gray J, Kohler J. Immunotherapy for neuroblastoma: turning promise into reality. Pediatr Blood Cancer 2009; 53: 931e40. Johnson K, McGlynn B, Saggio J et al. Safety and efcacy of tandem 131I-Metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma. Pediatr Blood Cancer, rst published online April 2011. Kushner HB, Kramer K, Modak S, Qin L-X, Cheung NK. Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer 2010; 116: 3054e60.

Practice points
C

Neuroblastoma is a diagnostic challenge, with a variety of presentations depending on site of primary and metastatic disease. Risk stratication is important in determining treatment and predicted outcome. High-risk patients experience a high rate of relapse, but these patients may benet from new forms of therapy currently being trialled. Those high-risk patients that survive often suffer multiple long-term side-effects of their treatment.

PAEDIATRICS AND CHILD HEALTH 22:3

107

2011 Elsevier Ltd. All rights reserved.