Cancer in Children: Clinical Management, 5th Edition

Chapter 22. Neuroblastoma

Huib N. Caron

A. D.J. Pearson


Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma are embryonal tumours of the sympathetic nervous system derived from the primitive neural crest.

Neuroblastoma has the greatest diversity in clinical behaviour of all childhood solid tumours, with some tumours regressing spontaneously, some being chemo-curable, and others being resistant to intensive chemotherapy. Metastatic neuroblastoma in children aged >1year is associated with a poor prognosis. Although there is initial response to chemotherapy, relapse with drug-resistant disease occurs in the majority of children.

More is known about the molecular pathology and genetics of neuroblastoma than probably any other adult or childhood malignancy. This knowledge is already guiding therapy so that children can receive individualized treatment, thereby minimizing toxicity in patients with good prognosis and allowing intensive and novel therapy to be delivered only to those children in whom conventional treatment is unsuccessful. A therapeutic classification is at present being developed which is based on patient characteristics and molecular tumour features, such as N-myc gene amplification. This classification will be progressively developed.


The annual incidence of neuroblastoma is 10.5 per million children aged <15 years.1 There appears to be no significant geographical variation in the incidence between North America and Europe, and similarly there are no differences between races. Neuroblastoma occurs slightly more frequently in males than females (ratio 1.2:1). The peak age of incidence is between 0 and 4 years, with a median age of 23 months. Forty per cent of patients clinically presenting with neuroblastoma are aged <1 year, and <5 per cent are over the age of 10 years. Cases of familial neuroblastoma have been reported.2

There are a number of features of neuroblastoma which suggested that screening might have been of value in reducing mortality from the malignancy by detecting poor prognosis disease at an earlier stage. Infants presenting under the age of 1 year tend to have localized good prognosis disease, with favourable molecular features. In contrast, children who are diagnosed over the age of 1 year have a significantly worse outcome, and usually have metastatic disease with genetic features indicative of an aggressive course. Screening for neuroblastoma was pioneered by Japanese investigators who demonstrated that asymptomatic tumours could be detected in infants by measurement of urinary catecholamine metabolites. Although the outlook for the children with the detected tumours was excellent, these studies were not population based and did not demonstrate a resultant reduction in neuroblastoma mortality rates. However, in regions where there were screening programmes, the incidence doubled to 20.1 per million children3 and the tumours detected all possessed favourable biologic characteristics.4 Both the Quebec Neuroblastoma Screening Project and the German Neuro-blastoma Screening Study were designed to answer definitively the question as to whether screening a large cohort of infants for neuroblastoma at the ages of 3 weeks, 6 months, and 12 months could reduce the population-based incidence of advanced disease and mortality. Both of these studies demonstrate that screening for neuroblastoma in children aged 1year identifies tumours with a good prognosis and molecular pathology, doubles the incidence, and fails to detect the poor prognosis disease which presents clinically at an older age.5,6

Embryology, pathology, and genetics


The neural crest is the embryonic structure which gives rise to the sympathetic nervous system. In the third gestational week, the neural plate is formed in the ectodermal germlayer. At the time of the fusion of the neural ridges into the neural tube, the neural crest is formed dorsally to the neural tube. Neural crest cells develop into a large number of mature cell types and structures. They form not only the sympathetic peripheral nervous system, but also part of the facial skeleton, the thymus, the parathyroids, the enteric nervous system, and skin melanocytes. Segmentation and migration are characteristic phenomena in neural crest development. The primitive neural crest cells migrate to a position lateral to the neural tube, forming (segmented) primitive ganglia on each side of it. From these, primitive ganglia neuroblasts migrate along the dorsal pathway to form melanocytes in the skin and dorsal root sympathetic neurons. Neuroblasts migrating along a ventrolateral pathway will eventually form the side chain (ventrolateral to the spine), the paraganglia (ventral to the spine), the visceral sympathetic ganglia (abdominal organs), and the adrenal medulla. The adrenal medulla is formed by neuroblasts which invade the primitive adrenal cortex and differentiate into chromaffin cells. The mature sympathetic nervous system consists of a neuronal part (dorsal root ganglia and side chain) and a hormonal part (paraganglia and adrenal medulla). Both parts produce catecholamines, as neurotransmitters and hormones, respectively. In the first years of life, the majority of systemic catecholamine is produced in the abdominal paraganglia. The adrenal medulla contains very few chromaffin cells at birth and enlarges and matures during the early years of life. It is thought that neuroblastoma develops in immature neuroblasts, ganglioneuroma in more differentiated sympathetic cells (ganglion cells), and pheochromocytoma in differentiated hormone-producing cells (chromaffin cells).


Histologically, neuroblastomas are very heterogeneous and are composed of two predominant cell types: the neuroblast/ganglion cell and the Schwann cell. Schwann cells are responsible for the stromal element of the tumour. As the neuroblast is an embryonal cell, it can differentiate and mature into a ganglion cell. Evidence suggests that Schwann cells in neuroblastomas are reactive cells arising from non-neoplastic tissues and are recruited into the tumour.7 The typical histologic appearance of an undifferentiated neuroblastoma is ‘a small round blue cell tumour’ [Fig. 22.1(a)]. The cells are of uniform size and contain dense hyperchromatic nuclei and scant cytoplasm. Homer–Wright pseudorosettes, from neuroblasts and neuritic processes, are frequently present. Ultimately, a neuroblastoma may differentiate into a mature ganglioneuroma, which is at the other end of the spectrum and has three components: mature ganglion cells, Schwann cells, and neurophils [Fig. 22.1(b)]. Some neuroblastomas, particularly those that are undergoing regression, have a degree of calcification. In the past, a number of histopathologic classification systems of neuroblastoma have been proposed by Shimada and Joshi. The Shimada system is age linked, and the tumours are classified according to the amount of Schwann cell stroma (poor or rich) and the number of cells in mitosis or karyorrhexis. Recently, an International Neuroblastoma Pathology Classification (INPC) has been introduced.8

Fig. 22.1 (a) Undifferentiated stroma-poor N-myc-amplified neuroblastoma. Haematoxylin and eosin (H & E) stain showing hyperchromatic nuclei without neurophils and a high nuclear-to-cytoplasmic ratio. Mitotic and apoptotic cells are indicated by arrows. (b) Schwannian stroma-rich mature ganglioneuroma with fully mature individual ganglion cells surrounded by satellite cells (arrows). (c) Poorly differentiated stroma-poor neuroblastoma showing Homer–Wright pseudorosettes (rings of neuroblastoma surrounding central core of neurophils). (d) Nodular ganglioneuroblastoma. A thickened fibrovascular septum separates the poorly differentiated stroma-poor neuroblastoma (bottom left) from the stroma-rich ganglioneuromatous component (top right). Ganglion cells are indicated by arrows. Scale bars, 50 mM. (Courtesy of Dr D. Tweddle.)

All these classifications are only applicable to tumours before therapy. In the INPC, the four morphologic features which form the basis for the classification are:

·  the degree of differentiation of the neuroblasts

·  the presence or absence of Schwann cell stroma

·  the presence or absence of neuroblastic nodules arising in a mature Schwann cell-stroma-rich tumour

·  an index of tumour cell aggressiveness, indicated by the mitotic karyorrhexis index (MKI).

The following tumours can be defined from these features: undifferentiated [Fig. 22.1(a)], poorly differentiated [Fig. 22.1(c)], or differentiating neuroblastoma; intermixed or nodular ganglioneuroblastoma [Fig. 22.1(d)]; ganglioneuroma [Fig. 22.1(b)]. Distinction between the two types of ganglioneuroblastomas is of major importance. Intermixed ganglioneuroblastomas are good prognosis tumours where there is progressive differentiation, with only small nests of neuroblasts. However, there are usually macroscopic, often haemorrhagic, nodules of neuroblasts with the nodular variant [Fig. 22.1(d)], and the associated prognosis is worse.


Genetic predisposition

There are very few reported pedigrees of familial neuroblastoma.2 In those families, the median age at diagnosis is 9 months compared with 2–3 yearsin sporadic cases. An increased incidence of multiple primary tumours is also apparent. Together, these data suggest that a genetic predisposition for neuroblastoma development exists in these families. Neuroblastoma familial gene loci have been linked to chromosomes 16p and 4p by cytogenetic studies and linkage analyses.9,10

Genetic aberrations in neuroblastoma

Broadly speaking, neuroblastoma can be divided into those with a near-diploid nuclear DNA content (45 per cent) and near-triploid tumours (55 per cent). Near-triploid neuroblastomas are characterized by whole-chromosome gains and losses without structural genetic aberrations. Clinically, near-triploid tumours are more often localized and show a favourable outcome. Near-diploid neuroblastomas are characterized by the presence of genetic aberrations such as N-myc amplification, 17q gain, and chromosomal losses.

N-myc oncogene The N-myc oncogene is present in an increased copy number in 25–35 per cent of neuroblastomas. N-myc amplification is found in 30–40 per cent of stage III and IV neuroblastomas and in only 5 per cent of localized or stage IVs neuroblastomas. N-myc amplified neuroblastomas are characterized by highly aggressive behaviour with an unfavourable clinical outcome.11 Loss of chromosome lp is almost invariable in N-myc amplified neuroblastomas.

Chromosome 17q gain Gain of the entire chromosome 17 or gain of parts of chromosomal arm 17q occur in >60 per cent of neuroblastoma. The partial 17q gain most often results from unbalanced translocation of 17q21–25 material to another chromosome (e.g. chromosome 1). Partial gain of 17q identifies unfavourable neuroblastoma.12 Obvious candidate genes on 17q are the NM23 and survivin genes.

Tumour suppressor genes Loss of tumour suppressor regions is reported in neuroblastomas for chromosome 1 p (30–40 per cent), 4p (20 per cent), 11q (25 per cent), and 14q (25 per cent). Chromosome lp loss occurs more frequently in older children with stage III and IV neuroblastoma and is correlated with increased serum ferritin and serum lactate dehydrogenase (LDH). In almost all samples with N-myc amplification, concomitant 1p loss is demonstrated, but loss of chromosome 1p also occurs in N-myc single-copy cases. A multivariate prognostic factor analysis showed that 1p loss was the strongest predictor of outcome of all the clinical and genetic factors tested, including N-myc amplification.13 Chromosome 1p loss added considerable prognostic information to the strongest clinical factors. Other studies also report a negative prognostic impact for 1p loss.14,15

Caspase 8 inactivation It has been shown that the most frequent mechanism by which neuroblastoma tumour cells evade apoptosis is inactivation of the caspase 8 gene. Loss of the chromosomal region containing the caspase 8 gene and/or hypermethylation of the caspase 8 promoter region lead to a loss of mRNA and protein expression.16

Clinical presentation

The clinical manifestations of neuroblastoma are very varied, depending on the site of the primary tumour and whether there is metastatic disease. The classical presentation at age 3–4 years is a pale irritable child with a limp and periorbital ecchymoses, whilst an infant may present with a grossly enlarged liver with subcutaneous nodules (Fig. 22.2). The symptoms of neuroblastoma can be attributed to the primary tumour, metastases, or a paraneoplastic phenomenon. The clinical presentation of neuroblastoma has changed over the last decade in developed countries, and the disease is now often detected when the child has fewer symptoms.

Fig. 22.2 Infant with stage IVs neuroblastoma and spontaneous regression. Primary tumour in adrenal gland and diffuse liver metastasis. (a) The child and 123 I-MIBG scan at diagnosis (T = 0). (b) the same child after spontaneous regression without any therapy (T = 2 weeks).

Primary tumour

Neuroblastoma primary tumours can arise at any location coinciding with normal sympathetic nervous system structures, such as the adrenals, the sympathetic chain, or abdominal paraganglia. About 25 per cent of primaries are found in the neck or thorax, 70 per cent in the abdomen, and 5 per cent in the pelvis.

A hard fixed abdominal mass causing only mild abdominal discomfort is a frequent presentation. Hypertension can result from compression of the renal vessels by the tumour. Gastrointestinal symptoms are rare, except from pelvic tumours which may cause constipation and difficulties with micturition.

Primaries in the cervical region may manifest only as a mass which is mistaken for cervical lymph nodes. Horner's syndrome with unilateral ptosis, constricted pupil, and absence of sweating may occur with either cervical or thoracic lesions. Although a thoracic primary can cause signs of mediastinal pressure with cough and superior mediastinal obstruction, these are most commonly detected coincidentally on a chest radiograph carried out for other reasons.

Thoracic, abdominal, and pelvic tumours can extend into the neural foramina and compress nerve roots and the spinal cord, resulting in radicular pain, paraplegia, and bowel and bladder symptoms.

Metastatic disease

The most common metastatic sites are bone, lymph nodes, and bone marrow; less common sites are skin, liver, lung and central nervous system. Metastases to the bone are often the presenting symptom, and manifest as painful lesions which produce an irritable unwell child. Frequently, a limp, which is difficult to diagnose, is the predominant feature either at initial presentation or at relapse. Bone marrow involvement generally presents with anaemia and, later, thrombocytopenia. The blood film may show a leuco-erythroblastic picture. Lymphadenopathy is not usually generalized or massive. Retro-orbital and orbital metastases produce a characteristic appearance of proptosis and periorbital ecchymoses. An infant with stage IVs neuroblastoma can present with significant respiratory distress from a massively enlarged liver, as well as having non-tender blue-tinged subcutaneous nodules (Fig. 22.2).

Paraneoplastic symptoms

Rarely, in 4 per cent of patients, opsoclonus–myoclonus can be a presentation of neuroblastoma. This syndrome comprises myoclonic irregular jerking and random eye movements, often associated with cerebellar ataxia. The symptoms generally tend to occur with good prognosis tumours and mostly resolve with regression of the disease.17 However, affected children often have significant long-term neuropsychometric damage.18

An intractable secretory diarrhoea, probably mediated by vasoactive intestinal polypeptide (VIP), can cause hypokalaemic dehydration (Kerner–Morrison syndrome). Like opsoclonus-myoclonus, this entity usually occurs with ganglioneuromas or ganglioneuroblastomas.19

Unlike the presentation in pheochromocytoma, hypertension, tachycardia, and episodes of sweating are less common in neuroblastoma.

Diagnosis and staging

Diagnostic criteria

The diagnostic criteria for neuroblastoma have been clearly defined by the International Neuroblastoma Staging System (INSS) working party.20 Neuroblastoma can be diagnosed by either a tissue biopsy showing a histologic appearance of neuroblastoma, or the presence of a non-haemopoietic tumour in the bone marrow, together with raised urinary catecholamines. In the bone marrow, neuroblastoma often has the appearance of pseudorosettes with increased reticulin and fibrous tissue. The presence of neuroectodermal antigens on the surface of the malignant cells, detected by monoclonal antibodies, further confirms the diagnosis.

Staging system

There is now an international consensus that the International Neuroblastoma Staging System (INSS) should be used exclusively.

Details are shown in Table 22.1. It is essentially a postsurgical staging system with major dependence on the assessment of resectability and surgical examination of lymph-node involvement. The central feature of stage III disease is invasion across the midline by the tumour, with often a main blood vessel being encased. A number of investigations are required to delineate the extent of spread of the disease, and these have been defined by the INSS (Table 22.2).

Table 22.1. ISSN International Staging System for Neuroblastomaa

Stage I

Localized tumour with complete gross excision, with or without microscopic residual disease; representative ipsilateral and contralateral lymph nodes negative for tumour microscopically (nodes attached to and removed with the primary tumour may be positive)

Stage IIa

Localized tumour with incomplete gross excision; representative ipsilateral and non-adherent lymph nodes negative for tumour microscopically

Stage IIb

Localized tumour with complete or incomplete gross excision with ipsilateral non-adherent lymph nodes positive for tumour; enlarged contralateral lymph nodes must be negative microscopically

Stage III

Unresectable unilateral tumour infiltrating across the midlineb with or without regional lymph node involvement, or localized unilateral tumour with contralateral regional lymph node involvement, or midline tumour with bilateral extension by infiltration (unresectable) or by lymph node involvement

Stage IV

Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver skin and/or other organs (except as defined in stage 4s)

Stage IVs

Localized primary tumour (as defined for stage I, IIa, or IIb) with dissemination limited to skin, liver and/or bone marrowc (limited to infants <1 year).

aMultifocal primary tumours (e.g. adrenal primary tumours) should be staged according to the greatest extent of the disease, as defined above, and followed by subscript M (e.g. stage IIIM)
bThe midline is defined as the vertebral column. Tumours originating on one side and ‘crossing the midline’ must infiltrate to or beyond the opposite side of the vertebral column.
c Marrow involvement of stage IVs should be minimal, i.e. < 10% of total nucleated cells identified as malignant on bone marrow biopsy or marrow aspirates. More extensive marrow involvement will be considered to be stage IV. The MIBG scan (if done) should be negative in marrow.
Reproduced from G.M. Brodeur et al. (1993) J Clin Oncol 11, 1466–77.


Either CT or MRI can delineate the extent of the primary tumour and associated lymph node masses, as well as other metastatic disease. Within the abdomen, detection of liver metastases can be carried out by CT scanning, whilst the extent of lymph node involvement and the margins of the primary tumour can be visualized equally well by either technique. Abdominal ultrasound can replace CT or MRI when carried out by an experienced paediatric radiologist. MRI is the optimal technique to demonstrate intraspinal extension through neural foramina.

MIBG scanning

MIBG (meta-iodobenzylguanidine) is taken up preferentially by cells of the sympathetic nervous system involved in catecholamine synthesis. Therefore if the compound is radiolabelled it can localize primary and metastatic neuroblastomas (Fig. 22.2) with a sensitivity of >90 per cent and a specificity of >98 per cent. To prevent uptake of radioactive iodine in the thyroid, the organ is specifically blocked by Lugol's iodine before administration of the isotope.

Less than 5 per cent of neuroblastomas do not take up MIBG; if there is no positivity in the primary tumour, metastases cannot be detected. It is widely recognized that MIBG is the most sensitive technique and surpasses [99mTc]diphosphonate scintigraphy of bones or skeletal survey. However, if there is no uptake of MIBG into the primary tumour, it is recommended that a 99mTc bone scan is carried out.

Table 22.2. Assessment of extent of disease

Tumour site

Recommended tests

Primary tumour

CT and/or MR1 scana with 3D measurements; MIBG scan, if availableb

Metastatic sitesb

Bilateral posterior iliac crest marrow aspirates and trephine (core) bone

Bone marrow

Marrow biopsies required to exclude marrow involvement. A single positive site documents marrow involvement. Core biopsies must contain at least 1 cm of marrow (excluding cartilage) to be considered adequate


MIBG scan; 99 Tc scan required if MIBG scan negative or unavailable, and plain radiographs of positive lesions are recommended

Lymph nodes

Clinical examination (palpable nodes), confirmed histologically. CT scan for non-palpable nodes (3D measurements)


CT and/or MRI scana with 3D measurements


Anteroposterior and lateral chest radiographs. CT/MRI necessary if chest radiograph positive or if abdominal mass/nodes extend into chest

aUltrasound considered suboptimal for accurate 3D measurements.
bThe MIBG scan is applicable to all sites of disease.
Reproduced from G.M. Brodeur et al. (1993) J Clin Oncol 11, 1466–77.

Tumour markers

There are a large number of urinary catecholamines, which can be elevated in the urine in patients with neuroblastoma. The most frequently measured metabolites of the catecholamines are vanilglycolic acid (VGA), also known as vanillylmandelic acid (VMA), vanilacetic acid (VAA), also known as homovanillic acid (HVA), vanilglycol (VG), catecholacetic acid (CAA), and vanillactic acid (VLA). In addition, concentrations of the catecholamine dopamine may be assessed. Approximately 90–95 per cent of all patients with neuroblastoma will have increased urinary secretion of these metabolites. Measurement of the ratio of the urinary concentration of the catecholamine metabolite to creatinine in a urine sample gives the most reliable results. The serum concentrations of LDH, ferritin, and neuron-specific enolase are useful prognostic markers.21 Apart from the urinary concentration of catecholamines, there is no value in monitoring patients during therapy.

Bone marrow examination

Metastatic disease to the bone marrow is one of the most common occurrences in poor prognosis neuroblastoma. Studies in the past have documented that metastatic disease may be present in the bone marrow, but it may not be easy to detect by examination of a bone marrow aspirate. Therefore the international consensus, as specified by the INSS, is that all patients should have histologic examinations of bone marrow aspirate and trephine carried out from two different sites. In this way, the likelihood of detecting ‘patchy’ bone marrow involvement is increased. Bone marrow aspirate examinations can be assessed using conventional microscopy and, if there is involvement, multiple clumps of a non-haemopoietic malignancy are usually observed. The non-haemopoietic cells tend to cluster and form pseudorosettes. International guidelines suggest that for a bone marrow histologic examination to be adequate, at least 1 cm of haemopoietic tissue should be examined.

Immunocytochemistry of bone marrow aspirates using monoclonal antibodies directed at neuroctodermal antigens can be used to detect neuroblastoma. However, its value in either detecting ‘occult disease’ at presentation or monitoring disease during therapy has not been confirmed

Treatment strategies

Current therapy

Individualization of therapy according to molecular pathologic features

Amplification of the N-myc gene is the most extensively studied marker of all the molecular pathologic prognostic features. At present, therapy for stage III neuroblastoma is determined by N-myc gene copy number. Surgery and a short course of chemotherapy are now being recommended for stage III patients with tumours with a single copy of N-myc, with survival rates of 85 per cent without intensive chemotherapy, radiation, or myeloablative therapy (MAT). Tumours with N-myc amplification progress rapidly and are associated with a 5-year survival of only 20 per cent. In view of this, the consensus is that these tumours should be treated as high-risk disease, in the same way as stage IV neuroblastomas in children aged >1year.

The consensus is that patients with N-myc amplified stage II disease, who have a 50 per cent survival,22 should also have high-risk therapy. Because of the rarity of stage I N-myc amplified tumours, no clear evidence is available and at present an observational policy following surgery is appropriate.

Amplification of N-myc also identifies infants with metastatic neuroblastoma (stage IV and IVs) who have a very poor prognosis. These patients should be treated with an intensive chemotherapy regimen and MAT.

No molecular features consistently and reliably identify those patients aged >1 year with metastatic disease who have a worse prognosis, and the prognostic value of N-myc amplification is not present in this group. It is expected that other molecular features will soon be confirmed to be of equal value to N-myc.

International Neuroblastoma Risk Groups

At present, patient age, tumour stage, N-myc amplification, and metastatic pattern in infants are used to determine therapeutic/risk groups. Unfortunately there is not complete international agreement about risk groups, although consensus is greatest for high-risk disease, i.e. stage IV disease at age >1 year and N-myc amplification in infants and in stage II and III disease. Efforts are now ongoing to define better risk groups and obtain international consensus.

It is appreciated that age is a continuous variable and that some ‘infant’ disease will occur in patients aged >12 months, and that some aggressive disease will occur in infants without N-myc amplification. Some groups employ pathologic features to define risk groups, whilst others do not. Currently, no group utilizes 1p loss, 17q gain or 11q loss as genetic features to identify different risk groups. Although hyperdiploidy has been suggested to be a good prognostic feature in infants,23 this has not been incorporated in the International Risk Group Classification. The importance of metastases to bone, lung and central nervous system in infants requires clarification.

Finally, at present the surgeon's decision regarding resectability drives staging and therapy decisions for localized disease, and this must be standardized.

Localized tumours

The most important information with any localized tumour is whether it is resectable without any significant morbidity and if there is N-myc amplification.

Stage I and II tumours

The present consensus is that stage I and II tumours should be resected with the major aim being to prevent acute or long-term sequelae. Even if there is residual disease, no chemotherapy or radiation treatment should be given.22,24 Currently, the Localized Neuroblastoma European Study Group (LNESG) recommends treating recurrent localized tumours by further resection only and it is possible that a recurrent tumour may eventually regress spontaneously. Although allelic deletion of chromosome 1p, 17q loss, and a raised serum LDH concentration have been suggested to be of prognostic importance, to date this has not been verified.

Stage III tumours

In the past, infants with stage III tumours have received postoperative chemotherapy. This has been associated with acute and long-term sequelae from chemotherapy, and there may be significant surgical morbidity and, indeed, mortality. Furthermore, in some reports more deaths result from the effects of therapy than from disease.25 It is now recommended that careful observation with measurement of urinary catecholamine concentrations and radiologic imaging only is required after surgery. A residual persisting mass associated with some elevation of urinary catecholamines may be a mature ganglioneuroma. Only a definite increase in tumour size should be taken as evidence of progression.

The current approach for stage III disease in patients aged >1 year is to determine whether the tumour is unresectable by imaging and its N-myc gene copy number. If resection with very minimal morbidity is not practical, then biopsy is undertaken. If the neuroblastoma does not show amplification of N-myc, six courses of chemotherapy are given with, for example, carboplatin and etoposide, alternating with cyclophosphamide, doxorubicin, and vincristine. Surgical resection of the primary tumour is then attempted, again with the emphasis on minimal morbidity, followed by two further courses of chemotherapy. No treatment is given for any residual disease and no radiotherapy, MAT, or 13-cis-retinoic acid is administered. The best results for stage III neuroblastoma in patients aged >1 year without amplification of N-myc are those of Rubie et al26 using the above approach. Those stage III tumours with N-myc amplification are treated as high-risk disease and receive the same therapy as for stage IV disease in children aged >1year.

Stage IV tumours in children aged >1 year

The therapeutic approach adopted by most cooperative groups for stage IV disease in children aged >1 year is to administer initial chemotherapy, followed by surgical resection of the primary tumour and consolidation with MAT with haemopoietic stem-cell support, usually utilizing peripheral blood stem cells.27,28 This is followed by radiation therapy to the site of the primary tumour and differentiation therapy with 13-cis-retinoic acid. Randomized trials have established survival benefits of MAT, initially with high-dose melphalan alone29 and, more recently, with a more complex regimen.28 The benefits of 6 months of intermittent oral 13-cis-retinoic acid have also been established in a randomized study.28 No randomized trial has investigated the advantages of radiotherapy at the site of the primary tumour in stage IV disease. However, comparison of local relapse rates between North America (where radiotherapy is given) and Europe (where it is not) suggest a benefit. Unfortunately, no randomized comparison has been made of more complex multi-agent MAT regimens compared with highdose melphalan alone. However, historical comparisons and the European Bone Marrow Transplant Registry data suggest that more complex regimens are of more value. European retrospective analyses indicate that busulphan and melphalan give the best survival results.30 In contrast, a comparison of North American MAT regimens suggest that carboplatin, etoposide, and melphalan (CEM) yield high event-free survival (EFS) rates (65 per cent). With this background, SIOP Europe Neuroblastoma is comparing, in a randomized study, busulphan and melphalan with CEM as the MATregimen. There is no convincing evidence to suggest that allogeneic bone marrow is superior to autologous bone marrow,31 or that there is a benefit in purging the marrow.

Various permutations of the active cytotoxic drugs have been used in induction chemotherapy. However, a platinum compound (either cisplatin or carboplatin), etoposide, and cyclophosphamide are most commonly used.32 Whether there is a benefit in the inclusion of doxorubicin is unknown. No regimen has been shown to be conclusively better; however, higher doses of agents given in intensive schedules appear to result in better long-term survival. Evidence suggests that increasing dose intensity improves EFS.33,34 Some of the most widely used induction regimens are Kushner, NB 87 and COJEC.32,34,35 It is very difficult to compare the efficacy of different induction regimens, as conventional response criteria at the end of induction do not appear to be good surrogates for long-term survival. Only randomized studies comparing different induction regimens will produce appropriate and reliable information.

Infants with stage IVs and IV neuroblastoma

The realization of the major discriminatory effect of N-myc amplification in infants, including those with stage IVs disease, has led to a dramatically different approach for those tumours with N-mycamplification. Patients with tumours with amplification, including stage IVs, receive intensive chemotherapy, attempted total surgical resection of the primary tumour, radiation therapy at the site of the primary tumour, and MAT.

It has been appreciated since the early 1970s that the majority of infants with stage IVs neuroblastoma require no therapy as their disease regresses spontaneously (Fig. 22.2).36 Only life- and organ-threatening symptoms, such as respiratory failure due to a rapidly enlarging liver, are indications for treatment. Chemotherapy with carboplatin and etoposide is most effective for these patients. It is essential that the smallest amount of therapy is administered, and frequently only one course is needed to induce regression. The primary tumour should not be resected. Eighty-five per cent of children will be cured with this approach.

The recent appreciation that more neuroblastomas in infants will regress spontaneously has led to the strategy of widening the indications for observation for some infants with stage IV disease. Chemotherapy is only used if there are life- or organ-threatening symptoms. In the current SIOP Europe Neuroblastoma trial, the only infants without life-threatening symptoms to be treated with four courses of chemotherapy are those with metastases to the bone, lung, or central nervous system.

Tumours causing spinal cord compression

Spinal cord compression can occur with stage II, III, and IV tumours. In addition to stage-specific therapy, consideration must be given to the intraspinal disease. With the advent of MRI, asymptomatic extension into the spinal cord is being increasingly detected.

The appropriate therapy depends upon neurologic symptoms and signs, the amount of disease within the spinal canal, and the histology. Decisions regarding therapy should be taken jointly between neurosurgeons, radiation oncologists, and paediatric oncologists.

If there are no neurologic symptoms, provided that no more than 50 per cent of the spinal canal is occupied with tumour, stage-specific therapy should be given and careful clinical and neurologic review undertaken. If >50 per cent of the spinal canal is filled with tumour, dexamethasone should be administered and continued until there is documented regression.

If there is total paraplegia, laminectomy is the preferred approach as modern techniques should reduce long-term surgical sequelae. For other degrees of neurologic symptoms, chemotherapy together with dexamethasone should be considered first. Very careful observation is required and dexamethasone should only be discontinued when there is objective neuroradiologic evidence of response.

Histology of the tumour is also important, as spinal cord compression caused by ganglioneuroblastomas will be less likely to be relieved by chemotherapy or radiotherapy, and laminectomy should be considered more readily.

Recurrent neuroblastoma

Further resection with chemotherapy is required for stage I and II disease. Recurrent stage III disease without N-myc amplification warrants further therapy as for high-risk disease. Unfortunately, with recurrent high-risk disease that has received appropriate modern therapy, i.e. MAT, long-term cure is not a realistic possibility and palliative therapy is most appropriate.

MIBG as an anti-cancer agent

The epinephrine analogue MIBG is actively taken up and stored in >90 per cent of neuroblastoma tumours. Incorporation of the 131I radioisotope in MIBG makes it possible to use this for targeted radiotherapy. Currently, [131I]MIBG is used in three groups of neuroblastoma patients:

·  those with unresectable localized tumours

·  for initial treatment of unresectable stage III and stage IV patients

·  in patients with recurrence.

In heavily pretreated recurrent neuroblastoma patients, a single [131I]MIBG treatment results in an objective response rate of >60 per cent. Adequate pain relief can be achieved in >80 per cent of patients. Little or no acute toxicity is seen, and the major side effect is thrombocytopenia.37 [131I]MIBG treatment has been used to render unresectable mainly abdominal or pelvic neuroblastoma tumours operable, or even to circumvent surgery.

Efforts are underway to use [131I]MIBG as the only initial anticancer agent in unresectable stage III and IV patients. The administration of multiple courses of [131I]MIBG in 43 consecutive patients resulted in an objective response rate of 42 per cent. Following initial MIBG treatment, surgical resection of the primary tumour, intensive combination chemotherapy, and myeloablative therapy were given for stage IV cases.38

Treatment results

Stage I and II

An excellent EFS and overall survival is expected for these patients following surgery alone, with >90 per cent survival for stage I and 85 per cent for stage II disease. Stage II tumours with N-myc amplification have survival rates of 50 per cent and are now treated as high risk.

Stage III

Overall, 65 per cent of all patients with stage III tumours are long-term survivors. N-myc amplification identifies a group with only a 20 per cent probability of EFS, whilst 85 per cent of those with favourable histology without N-myc amplification survive.

Stage IV in children aged >1 year

Children aged >1 year with stage IV neuroblastoma have a poor prognosis. In the majority, the malignancy is initially chemosensitive, and then drug-resistant disease recurs. With a regimen employing intensive chemotherapy, surgery, MAT, local radiotherapy, and 13-cis-retinoic acid, a survival of 45 per cent can be expected.

Stage IV and IVs in infants aged <1 year

Eighty-five per cent of infants without N-myc amplification will be long-term survivors. Some infants die because of large tumour masses and a minority progress to overt aggressive stage IV disease. In the past only 25 per cent of infants with N-myc amplification survived. Very preliminary results now suggest an improved survival following intensive therapy.

Novel developments

Antibody therapy

Both murine and chimeric humanized antibodies against the tumour-associated antigen GD2 have been tested in preclinical model systems and in clinical trials in neuroblastoma patients. Phase II trials combining anti-GD2 antibodies and granulocyte–macrophage colonystimulating factor (GMCSF) for high-risk neuroblastoma patients with residual or progressive bone marrow disease showed a promising bone marrow clearance rate of 50 per cent.39 Currently, anti-GD2 antibody treatment, with or without GMCSF and interleukin 2, for minimal residual disease is being prospectively tested in randomized trials by SIOP Europe Neuroblastoma and the Children's Oncology Group (COG).

Detection of minimal residual disease

Several molecular targets for detection of minimal residual disease have been developed. All of them are based on the detection of gene products in general by real-time PCR. The best studied targets are tyrosine hydroxylase, GD2, and GD2 synthase. Substantial evidence for the increased sensitivity of these molecular methods for the detection of neuroblastoma cells compared with conventional cytology has accumulated.40 The clinical relevance is the subject of ongoing prospective trials.


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