Elsevier

The Lancet

Volume 369, Issue 9579, 23–29 June 2007, Pages 2106-2120
The Lancet

Seminar
Neuroblastoma

https://doi.org/10.1016/S0140-6736(07)60983-0Get rights and content

Summary

The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of cure varying widely according to age at diagnosis, extent of disease, and tumour biology. A subset of tumours will undergo spontaneous regression while others show relentless progression. Around half of all cases are currently classified as high-risk for disease relapse, with overall survival rates less than 40% despite intensive multimodal therapy. This Seminar focuses on recent advances in our understanding of the biology of this complex paediatric solid tumour. We outline plans for the development of a uniform International Neuroblastoma Risk Group (INRG) classification system, and summarise strategies for risk-based therapies. We also update readers on new discoveries related to the underlying molecular pathogenesis of this tumour, with special emphasis on advances that are translatable to the clinic. Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity.

Introduction

Neuroblastoma accounts for more than 7% of malignancies in patients younger than 15 years and around 15% of all paediatric oncology deaths.1 It is the most common extracranial solid tumour in childhood and the most frequently diagnosed neoplasm during infancy.2

The disease is remarkable for its broad spectrum of clinical behaviour. Although substantial improvement in outcome of certain well-defined subsets of patients has been observed during the past few decades, the outcome for children with a high-risk clinical phenotype has improved only modestly, with long-term survival still less than 40%.3, 4

In the 1980s, when technology that permitted detection of tumour-derived catecholamines in spot urine samples became widely available, screening programmes designed to detect neuroblastoma in infants were developed. Studies in Japan have shown that neuroblastoma could be detected by screening urine at 6 months of age, and early results suggested that preclinical detection led to improved survival.5, 6 However, two prospective population-based controlled trials in Germany and North America have shown that screening does not reduce mortality.7, 8 In both of the studies, the incidence of neuroblastoma increased in the screened population, and almost all tumours detected by screening had favourable biological features. The cost of infant screening and the essentially unchanged mortality rates argue against the public health usefulness of mass screening of infants for neuroblastoma.

Section snippets

Clinical presentation

Neuroblastoma is a disease of the sympaticoadrenal lineage of the neural crest, and therefore tumours can develop anywhere in the sympathetic nervous system. Most primary tumours (65%) occur within the abdomen, with at least half of these arising in the adrenal medulla. Other common sites of disease include the neck, chest, and pelvis.2 Presenting signs and symptoms are highly variable and dependent on site of primary tumour as well as the presence or absence of metastatic disease or

Diagnosis

The diagnosis of neuroblastoma is based on the presence of characteristic histolopathological features of tumour tissue or the presence of tumour cells in a bone marrow aspirate or biopsy, accompanied by raised concentrations of urinary catecholamines (figure 1). High-risk patients often have raised concentrations of serum lactate dehydrogenase, ferritin, or chromagranin, but these are relatively non-specific for the population as a whole and do not seem to be independently prognostic of

Clinical assessment of disease

Computed tomography (CT) is the preferred method for assessment of tumours in the abdomen, pelvis, or mediastinum. Magnetic resonance imaging is better for paraspinal lesions, and is essential when assessing intra-foraminal extension with the potential for cord compression. 99mTc-diphosphonate scintigraphy (bone scan) has been traditionally used to survey for occult bony metastases. Enhanced sensitivity and specificity for detecting bone metastases as well as occult soft tissue disease is

Principles of initial therapy

The treatment methods used in the management of neuroblastoma include surgery, chemotherapy, radiotherapy, and biotherapy, as well as observation alone in carefully selected circumstances. Most paediatric oncology clinical trials groups stratify patients into risk groups at diagnosis based on many of the risk factors reviewed here. The risk stratification system of the Children's Oncology Group incorporates patient age at diagnosis and INSS stage, as well as tumour histopathology, DNA index,

New approaches to relapsed disease

Although there are highly effective salvage therapies for patients with low-risk and intermediate-risk disease who have local relapses, recurrent disease in patients with high-risk neuroblastoma remains a clinical challenge. During the past several years, an expanding portfolio of new agents and combinations has been developed for use in the high-risk relapse setting.

Search strategy

We identified reports using a Medline search through the PubMed database (1986–2006) by combining the keyword neuroblastoma with tumorigenesis, angiogenesis, progression, metastasis, pathology, pathobiology, pathophysiology, molecular genetics, and genetics. We searched citation lists in retrieved papers to identify additional references. Papers were selected on the basis of the best available evidence for each specific question discussed. To limit the number of references, review

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