Chapter 105

Childhood Tumors

Erika Adams Newman

Key Points

1 Neuroblastoma is the most common solid tumor in infants and the most common extracranial tumor

in all children.

2 Neuroblastoma tumors have diverse clinical heterogeneity from complete spontaneous regression in

neonates to resistant metastatic disease in school-aged children. The origin of this disparity is

unknown but thought to result from diverse genetic and biologic features that predict prognosis.

3 Several nonrandom segmental genomic alterations have been identified in neuroblastoma as reliable

prognostic indicators independent of age and stage. The genomic alterations that have consistently

been shown to predict prognosis are DNA ploidy, MYCN amplification, loss of heterozygosity (LOH)

of chromosome 1p, 17q gain, loss of 14q, and loss of 11q.

4 The International Neuroblastoma Risk Group (INRG) classification system defines pretreatment

patient cohorts based on expected survival at diagnosis. INRG classification includes INRG stage,

age, histologic category, grade of tumor differentiation, MYCN status, 11q alterations status, and

DNA ploidy. These criteria are used to define 16 pretreatment groups that include very low-, low-,

intermediate-, and high-risk categories.

5 The presence of anaplasia is the single most important prognostic indicator in Wilms tumors.

6 In the United States, the standard of care for children with Wilms tumor starts with radical

nephrectomy at the time of diagnosis for resectable primary tumors, followed by chemotherapy.

Radiation is administered to sites of residual and metastatic disease. Tumors with extensive

intracaval and hepatic vein extension receive neoadjuvant chemotherapy and may require

cardiopulmonary bypass for resection.

7 Treatment of rhabdomyosarcoma requires a multimodal approach that begins with complete surgical

excision of resectable lesions and incisional biopsy for tumors that encroach upon contiguous

structures, blood vessels, and nerves. Modern therapeutic protocols are based on prognostic factors

and risk of subsequent relapse stratification.

8 Standard surgical care for children with hepatoblastoma is complete primary resection at diagnosis

for PRETEXT I and II tumors that do not involve major central venous structures. PRETEXT III and

IV tumors undergo biopsy and neoadjuvant chemotherapy with early referral to liver transplantation

for multifocal or large, central lesions.

INTRODUCTION

The surgeon is a key figure in the management of the child thought to have a malignant tumor. From

diagnosis through posttherapy surveillance, the surgical team plays a pivotal role in ensuring the

highest outcomes in the care of children with solid cancers. As a critical component of the pediatric

oncology multimodal team, surgical decisions guide clinical pathways from the mechanisms of biopsy,

central venous access for chemotherapy administration, and definitive tumor resection. Because

pediatric cancers are rare with diverse presentations and histology that differ from adult cancers, the

overall care of children with cancer has been improved by multidisciplinary approaches and pediatric

cooperative groups that have set the standard in current oncologic care of children. The Children’s

Oncology Group (COG) and the Societe Internationale d’Oncologie Pediatrique (SIOP) have made

significant progress in clinical and basic science studies of pediatric malignancies, and current pediatric

tumor care is based upon treatment standards established through phase 1 to 3 clinical–translational

trials. It is a universal goal that every child diagnosed with cancer be enrolled in a cooperative group

clinical trial. These trials are aimed at further understanding pediatric tumor biology and for evolving

3071

innovative treatments that have recently led to drastic rises in survival rates for various malignancies.

Compared to adults, the classification of childhood cancer is based largely on histologic type and

tumor morphology rather than primary site. The current classification scheme is the International

Classification of Childhood Cancer, Third Edition (ICCC-3), based on ICD-0-3 (International

Classification of Diseases).1 The ICCC-3 classifies tumors into 12 main groups that are further

characterized into 47 subgroups and is used for population-based epidemiologic studies and cancer

registries such as the Surveillance, Epidemiology, and End Results (SEER) program, administered by the

National Cancer Institute. Utilization of a standard classification system is useful for comparing

incidence and survival across regions and time periods.

INCIDENCE OF CHILDHOOD SOLID TUMORS

Each year in the United States, approximately 12,400 children and adolescents younger than 20 years

are diagnosed with cancer. Cancer is the most common cause of disease-related mortality in children,

with approximately 2,500 children dying each year. Leukemia is the most common cancer diagnosis for

children 1 to 5 years of age, 5 to 9 years of age, and 10 to 14 years of age, while neuroblastoma is the

most common cancer in infants. For 15- 19-year-olds, lymphomas are the most common diagnosis.

Pediatric solid tumors are a spectrum of different malignancies, and behind neuroblastoma, Wilms

tumor is the second most common extracranial solid tumor followed by rhabdomyosarcoma (Fig. 105-

1). In general, there have been no large increases or decreases in pediatric cancer incidence in the last

several decades when improvement in diagnostic modalities such as magnetic resonance imaging (MRI)

and ultrasound was taken into consideration.

Figure 105-1. Percentage distribution of childhood solid tumors by age (SEER data, 1975–1995).

In the United States, the cancer survival rate in children has improved over time. This is largely due

to multidisciplinary approaches to pediatric oncology care. There have been steady improvements in

survival for childhood renal tumors, retinoblastoma, and lymphomas since the beginning of the SEER

program. Although mortality rates have declined steadily for nearly all major childhood cancer

categories, survival rates for high-risk tumors such as neuroblastoma and rhabdomyosarcoma have not

been met with the same survival successes (Fig. 105-2).2 Targeted immunotherapies and tumor genomic

sequencing are new innovative treatment strategies that have recently provided hope for improving

outcomes in resistant and refractory cases.

NEUROBLASTOMA

Epidemiology and Genetic Risk

1 In the United States, approximately 700 children are diagnosed with tumors of the sympathetic

nervous system each year and of these, 650 are neuroblastoma. Neuroblastoma is the most common

3072

cancer in infancy and the most common extracranial tumor in all children. The disease accounts for

7.2% of cancers in children younger than 15 years. The incidence of neuroblastoma is slightly higher

among males than among females and is highest among Caucasians from North America, Europe,

Australia, and Israel.3 The most recent SEER data have reported minimal changes in neuroblastoma

incidence in the last five decades. The overall survival rate for neuroblastoma is 65% based upon SEER

data from 1985 to 2000, and the disease continues to represent approximately 15% of all pediatric

cancer deaths.4,5 There is diverse variability in 5-year survival rates based on age and stage. There are

no overall differences in survival by race or gender, and survival is highest among infants and patients

with localized and regional disease.

Figure 105-2. Survival of most common childhood cancer by type (SEER data, 1975–2005).

No causal factors for neuroblastoma have been identified. Studies examining maternal risks have been

conflicting for prior miscarriage, induced abortion, repeat Cesarean birth, and vaginal infection.6 There

have been international case series reporting the use of maternal hormones for bleeding and ovulation

induction. The largest study to date did not find significant association with infertility hormonal use,

although results suggested an elevated risk of neuroblastoma in male offspring after maternal Clomid

use.7 These results warrant further evaluation but may serve as the focus of larger clinical studies.

Parental occupation and environmental exposures have been studied.8 They suggest that the risk of

several industrial occupations, particularly those related to power plant operators, painters, and

electronic-related fields, should also serve as lead points for further study. A case-control study

investigating parental tobacco smoking and alcohol consumption did not find any evidence for lifestyle

exposures and increased risk of neuroblastoma.9 Associations between premature delivery (<33 weeks),

very low birth weight (<1,500 g), and neuroblastoma have been observed but results are inconsistent.6

Further investigations of parental and perinatal risk factors are required in order to draw definitive

conclusions.10

Most cases of neuroblastoma are sporadic and data for inheritance patterns are conflicting. There are

studies that link neuroblastoma occurrence with other neural crest cell anomalies such as Hirschsprung

disease, neurofibromatosis, and central hypoventilation syndrome.11 These syndromes are components

of the neurocristopathies and are considered alterations in neural crest cell development that may occur

with inherited loss of function mutations of PHOX2B, a regulator of autonomic nervous system

development.12,13 Despite these findings, there is not a strong pattern of inheritance of neuroblastoma

and only 1% to 2% of cases are familial in an autosomal dominant manner.14,15 Recently, genome-wide

sequencing studies have located heritable mutations in the anaplastic lymphoma kinase (ALK) gene as the

cause of most hereditary neuroblastoma cases, the first example of a pediatric cancer arising due to a

mutation in a critical oncogene.16 Given this, genetic testing for ALK and PHOX2B should be considered

in children with a family history of neuroblastoma. It is recommended that children in families found to

have heritable mutations in ALK or PHOX2B undergo screening surveillance with ultrasound and urinary

catecholamine metabolites.

ALK copy number mutations are also somatically acquired and highly associated with an aggressive

clinical phenotype in 5% to 15% of neuroblastoma tumors.17,18 Genome-wide association studies in

sporadic cases of neuroblastoma have also recently discovered susceptibility genes that include

3073

FLJ22536, NBPF23, and BARD1 that may increase the relative risk of malignant transformation of

developing neuroblastic tissue.19–22 In general, there is a relative paucity of recurrent somatic mutations

in neuroblastoma, and the majority of tumors are likely driven by rare germline variants, copy number

alterations, and epigenetic modifications.22

Pathology and Biologic Features

2 Neuroblastoma originates from embryonic cells of the neural crest that appear along the distribution

of sympathetic nervous tissue from the neck to pelvis, most commonly in the adrenal medulla. The

precise molecular mechanisms that give rise to embryonic neural crest cells that in turn give rise to

neuroblastoma are unknown. The current thinking is that defects in genes that control neural crest

differentiation and proliferation underlie neuroblastoma tumorigenesis. Peripheral neuroblastic tumors

are categorized on a spectrum from malignant neuroblastoma to ganglioneuroblastoma and benign

ganglioneuroma. Neuroblastoma tumors have diverse clinical heterogeneity from complete spontaneous

regression in neonates to resistant metastatic disease in school-aged children. The origins of this

disparity are unknown but may be explained by a spectrum of genetic and biologic features that are

used to stratify patients for treatment.

Figure 105-3. Typical neuroblastoma with small round blue cell feature and Homer–Wright pseudorosettes that palisade around

blood vessels.

Neuroblastoma generally occurs in the youngest of children with a median age of presentation of 19

months.23 The age at which a child is diagnosed with neuroblastoma is an indicator of biologic features

and clinical course. Neonates and infants younger than 18 months are more likely to have disease that

either spontaneously regresses or is cured without cytotoxic therapy. In contrast, older children are

more likely to have refractory metastatic disease and are at high risk for death despite multimodal

cytotoxic therapies. Age contributes to prognosis in a continuous manner with the optimal age cutoff

between 15 and 19 months.23 Much of this discrepancy in outcome of neuroblastoma is thought to be

associated with underlying tumor biology because there is an association between age and other

biologic factors such as MYCN amplification and histopathology. Given this, molecular analysis of

neuroblastoma tumor specimen is an important factor in treatment planning and in risk stratification.

Cellular heterogeneity is a hallmark of neuroblastoma. Neuroblastic small round blue cells with

hyperchromatic nuclei characterize neuroblastoma cells with varying degrees of differentiation from

immature to mature. Homer–Wright pseudorosettes that palisade around blood vessels and neuritic

processes are characteristic (Fig. 105-3). Neuroblastoma cells stain for neuron-specific enolase,

synaptophysin, NB84, and tyrosine hydroxylase, a neural protein staining pattern that differentiates

neuroblastoma cells from other childhood tumors with similar small round blue cells.

Treatment strategies for children with neuroblastoma are largely based on risk as determined by

histopathologic and biologic characteristics of the tumor. The Shimada histopathologic classification

system is the most widely accepted mechanism for microscopic evaluation of neuroblastoma tumors and

distinguishes favorable and unfavorable clinical groups. The International Neuroblastoma Pathology

Classification System was developed on the basis of the original Shimada system.24 Morphologic

features of neuroblastic differentiation, Schwannian stromal development, mitosis–karyorrhexis index

(MKI), and patient’s age at diagnosis determine the important distinction between favorable and

unfavorable histology (Table 105-1).

In addition to histopathology, combinations of prognostic features are utilized for risk assignment and

3074

treatment stratification in neuroblastoma. The DNA content (DNA index or ploidy) is the amount of

DNA within the nucleus of tumor cells compared to normal cells and is an important indicator of

treatment success. DNA index is determined by flow cytometry or by cytogenetic analysis. Hyperploidy

or near-triploid tumors (DNA index >1) are whole chromosome gains and losses without structural

genetic alterations and are associated with a better response to chemotherapy.25 In contrast, diploid

tumors are characterized by segmental chromosomal alterations and predict poor response to therapy.

CLASSIFICATION

Table 105-1 Shimada Histopathologic Classification of Neuroblastoma

The MYCN oncogene is a transcription factor located on chromosome 2p and also predicts survival

and risk in neuroblastoma. The amplification of MYCN is the best characterized genetic abnormality,

occurring in approximately one-third of neuroblastoma patients.26,27 Significant amplification of MYCN

within tumor cells (more than 10 copies detected by fluorescent in situ hybridization) reliably predicts

poor survival and advanced-stage disease.28 Although the molecular mechanism of MYCN amplification

is unknown, targeted expression in transgenic mice leads to the development of neuroblastoma

tumors.29 Enhanced expression of MYCN increases proliferation and confers growth potential both in

vitro and in vivo, adding to the notion that MYCN has a critical role in neuroblastoma tumorigenesis.30

Approximately 30% of neuroblastoma tumors have MYCN amplification, and of these, 90% are highstage or refractory to multimodal cytotoxic therapies.31

Nerve growth factor (NGF) and its receptor tyrosine kinase (TRK) also correlate with disease outcome

in neuroblastoma tumors. The TRK receptors are thought to have a role in regulating growth and

differentiation of normal nerve cells and have been implicated in neuroblastoma pathogenesis. The

expression of TRK-A, a transmembrane TRK that is required for high-affinity binding of NGF, is strongly

predictive of a favorable outcome in neuroblastoma tumors.32,33 TRK-B, the receptor for brain-derived

neurotrophic factor, is preferentially expressed in neuroblastoma tumors with MYCN amplification

while TRK-C, the primary receptor for neurotrophin-3 (NT-3), mirrors TRK-A and is expressed primarily

in lower-stage tumors with favorable outcomes.33 The absence or lack of TRK-A correlates inversely

with MYCN amplification and reliably predicts poor overall survival. Differential expression of TRK-A

and TRK-B indicates that NGF receptors may function in growth arrest and differentiation in

neuroblastoma tumors, critical factors that may have a role in clinical course.34

3 Several nonrandom genomic imbalances have been identified in neuroblastoma, and the presence of

segmental chromosome alterations is the strongest predictor of neuroblastoma relapse.35 The loss of

heterozygosity (LOH) of chromosome 1p is a reliable prognostic factor in neuroblastoma tumors that is

independent of age and stage. The loss of 1p identifies patients who are at high risk of poor survival

outcomes despite otherwise favorable biologic predictors (Stage 1, 2, and 4S disease).36 LOH at 1p is

most clinically valuable in predicting patients at high risk of death in the subgroup of patients without

MYCN amplification, specifically those with low-stage disease.36 Gain at 17q most commonly occurs

with loss of 1p in an unbalanced translocation. Unbalanced gain of chromosome arm 17q is the most

frequent segmental genetic alteration in neuroblastoma cells and is also associated with adverse

outcomes.37 The gain of 17q is strongly associated with other negative risk factors including age of

more than 1 year, presence of high-stage disease, MYCN amplification, and diploidy. The most likely

candidate genes involved at 17q are NM23 and BIRC5 (surviving gene).38 Chromosome 11q loss is

found in approximately 40% of patients with neuroblastoma and is associated with high-risk disease

features and decreased survival.39 Similar to loss of chromosome 1p, loss of 11q is independently

3075

associated with decreased survival in the subgroup of patients with low-stage disease and in patients

without MYCN amplification. In all, the genomic alterations that have consistently been shown to

predict prognosis are DNA ploidy, MYCN amplification, loss of chromosome 1p, 17q gain, loss of 14q,

and loss 11q. A systematic review of prognostic tumor markers and meta-analysis showed that of these,

MYCN amplification and DNA ploidy have the strongest prognostic impact.40

Presentation, Diagnosis, and Staging

The majority of children with neuroblastoma are diagnosed at less than 4 years of age, with median age

between 19 and 22 months. Forty percent of tumors occur in the adrenal medulla, with the remaining

occurring in the neck, chest, abdomen, and pelvis along the sympathetic chain. The organ of

Zuckerkandl is the second most common site of neuroblastoma of abdominal origin. Compared to older

children, infants are more likely to present with thoracic and cervical primary sites. Tumors at the

sympathetic chain along the spinal column may expand into the intraforaminal spaces and can cause

spinal cord compression (5% to 15% of patients) (Fig. 105-4). More than half of the patients may

present with regional or distant spread through lymphatic and hematogenous routes. Metastatic disease

most commonly involves regional lymph nodes, bone marrow, and cortical bone. The most common

cortical bone sites are metaphyseal, skull, and the orbit. Patients with orbital bone metastases

commonly present with periorbital ecchymosis and swelling (raccoon eyes), and cortical bone

metastases may result in generalized bone pain and limping. Liver metastases occur most commonly in

patients with stage 4S tumors. Neonates with stage 4S neuroblastoma may present with massive

hepatomegaly, respiratory compromise, and abdominal compartment syndrome requiring urgent

surgical intervention. Incidental findings on prenatal ultrasound may identify fetal neuroblastoma, and

there may be associated maternal signs of catecholamine excess with excessive sweating, headaches,

flushing, or anxiety.41

Most often patients with localized disease are asymptomatic, with tumors diagnosed on routine

physical examinations or testing for other medical conditions. In contrast, children may have a mass or

abdominal distention as presenting symptoms. There are several well-documented clinical syndromes

that can be present at diagnosis of neuroblastoma. Opsoclonus/myoclonus syndrome and/or ataxia can

occur in children with neuroblastoma and present as irregular jerking movements of the muscles. The

underlying mechanism of opsoclonus is unknown but an immunologic mechanism-related antineuronal

antibody is likely, and patients may have late neurologic sequelae despite tumor removal.42 The

condition may be treated with adrenocorticotrophic hormone, with plasmapheresis and intravenous

gamma-globulin reserved for refractory cases.43 Most patients with opsoclonus/myoclonus syndrome

tend to have localized disease and excellent survival. Up to 50% of patients with opsoclonus/myoclonus

syndrome are found to have neuroblastoma tumors while only a small percentage of patients with

neuroblastoma present with opsoclonus. Neuroblastoma tumors that occur in the neck or the upper chest

may present with Horner syndrome (ptosis, miosis, anhidrosis), symptoms that may not recover and

often worsen with surgical excision.

Figure 105-4. Primary distribution of neuroblastoma tumors in children.

3076

Perinatal Neuroblastoma

The improvement of ultrasound and maternal imaging techniques has increased the diagnosis of

neuroblastoma within the fetal and neonatal periods. Most perinatal tumors are located within the

adrenal gland and are localized tumors. Upon detection, tumor growth is monitored with serial

ultrasound prior to birth, and maternal care proceeds to ensure optimal health of the mother. As long as

there are no complications, pregnancy is carried to term. Nearly all perinatal cases have favorable

biology without adverse prognostic indicators, including non-MYCN amplification. Several lines of

evidence suggest that small, localized adrenal tumors detected during the perinatal period may be

managed with expectant observation without surgical resection.44–46 Given the considerable evidence of

spontaneous regression in this subset of neuroblastoma tumors and the risk of adrenal surgery in

infants, the COG conducted a prospective trial (ANBL00P2) of expectant observation of infants

diagnosed within the first 6 months of life.47 This study found that observation of small adrenal masses

in infants younger than 6 months, without biopsy and without surgical resection, was safe with

excellent event-free and overall survival. Adrenal tumors smaller than 3 cm (16 mL) if solid or 5 cm (65

mL) if ≥25% cystic are safely monitored with ultrasound volume measurements, computed

tomographic (CT) scan, and urine catecholamine metabolite levels. If there are signs of tumor growth or

dedifferentiation, the patient is referred for surgical resection without risk of upstaging of disease.

Diagnosis

The diagnosis of neuroblastoma requires an adequate biopsy specimen and a pathologist experienced

with pediatric tumors. The diagnosis is established with histologic confirmation from either tissue

biopsy or the presence of tumor cells within a bone marrow biopsy and increased urinary catecholamine

metabolite levels.48 The majority of patients with neuroblastoma have elevated urinary vanillylmandelic

acid and homovanillic acid levels and these should be evaluated during the diagnostic workup.

Complete blood count and serum chemistries are evaluated as components of initial diagnostics. Levels

of lactate dehydrogenase, ferritin, and neuron-specific enolase are biologic markers that may indicate

poor prognosis in patients with neuroblastoma.49,50 Elevated ferritin (>150) and lactate dehydrogenase

(>1,000) may indicate increased risk of adverse outcomes. Seventy percent of patients present with

metastatic disease at presentation; therefore, initial evaluation should include cross-sectional imaging by

either computerized tomography or MRI to define the primary tumor size and to determine regional or

distant spread (Fig. 105-5). Calcifications are commonly detected on imaging in patients with

neuroblastoma, and the mass tends to displace structures inferiorly and toward the midline. Unless the

patient has neurologic symptoms or an abnormal neurologic examination, lumbar puncture or brain

imaging is not indicated. Sympathetic nervous tissue concentrates metaiodobenzylguanidine (MIBG), an

analog of norepinephrine. Radioactive iodine-labeled MIBG scan is utilized in neuroblastoma staging

and is used to determine treatment response.51 MIBG scan is accurate in detecting metastatic spread,

particularly cortical bone disease that may have otherwise been missed by traditional imaging

techniques. Posterior iliac crest aspirates and core biopsies are required as a component of initial

diagnostic testing to exclude bone marrow involvement. PET scanning or bone scanning may be utilized

in patients with non-MIBG avid disease.

Figure 105-5. Computed tomographic scan of a child with stage 3 neuroblastoma, crossing the midline displacing the aorta, vena

cava, kidney, pancreas, and spleen.

Staging

3077

4 The criteria for diagnosis and staging of neuroblastoma have traditionally been based upon the

International Neuroblastoma Staging System (INSS). Standard staging criteria allows physicians to tailor

treatment plans based on patient risk. INSS is the most widely accepted staging system and was

established in efforts to standardize risk-group stratification by cooperative groups (Table 105-2).48

Stage 1 is localized tumor with complete gross excision with or without microscopic residual disease and

negative ipsilateral lymph nodes. Partially resected tumors and tumors without or with ipsilateral

lymph node involvement are either stage 2A or 2B. A tumor that is unresectable or has contralateral

lymph nodes involved is stage 3. Any tumor with distant metastases is stage 4. Stage 4S is localized

neuroblastoma tumor with distant disease limited to skin, liver, or bone marrow in infants younger than

1 year. Stage 4S is a poorly understood unique subset of neuroblastoma tumors that often spontaneously

regress without surgical resection or cytotoxic therapy. INSS is largely based on the surgeon’s definition

of resectability and surgical approach to the primary tumor and lymph nodes. There is international

variation in surgical decision making and approach to locoregional disease that may alter the prognostic

value of INSS staging. This has made the performance and comparison of international clinical trials

difficult. Moreover, biologic prognostic factors have become increasingly important in treatment

planning and risk stratification. To address this, the European International Society of Pediatric

Oncology neuroblastoma group proposed radiographic characteristics of the primary tumor as useful

predictors of resectability and risk for developing postoperative complications (International

Neuroblastoma Risk Group Staging System [INRGSS]).52 INRGSS, determines the extent of locoregional

disease by the presence or absence of image-defined risk factors (IDRF).53 Stage L1 tumors are localized

tumors that are confined within one body compartment and do not involve vital structures or major

blood vessels, without any IDRF. L2 tumors are locoregional tumors with one or more IDRF that may

involve ipsilateral continuous body compartments and have lower event-free survivals compared to L1

tumors. Stage M is distant metastatic disease and MS is limited to children younger than 18 months with

skin, liver, and/or bone marrow metastases. The benefit of INRGSS is that treatment stratification is

based on preoperative diagnostic imaging, rather than variable operative approaches. INRGSS now

functions as one of the seven prognostic factors in the new International Neuroblastoma Risk Group

(INRG) pretreatment classification system.54 The INRG classification system defines pretreatment

patient cohorts based on expected 5-year event-free survival at the time of diagnosis before treatment.

INRG classification includes INRG stage, age, histologic category, grade of tumor differentiation, MYCN

status, 11q alterations status, and DNA ploidy. These criteria are used to define 16 clinically different

pretreatment groups that include very low-, low-, intermediate-, and high-risk categories in terms of 5-

year event-free survivals of >85%, >75 to ≤85, ≥50% to ≤75, and <50%, respectively. These

clinical categories may further assist physicians and cooperative groups in risk-group stratification based

on reliable expected event-free survival cutoffs. Importantly, INRG classification will allow comparison

of international risk-based clinical trials with potential to enhance international collaborative efforts.

Treatment

The treatment of neuroblastoma requires a multidisciplinary approach in order to ensure the most

optimal outcomes. Treatment is often multimodal with surgery, chemotherapy, radiation, bone

marrow/stem cell transplantation, and immunotherapy. Risk group assignment is essential for surgical

and medical treatment decisions, as therapies are tailored to risk. Patients are categorized on the basis

of INRG classification as very low-, low-, intermediate-, or high-risk. In general, the overall goal is to

minimize surgical risks and to limit exposure to chemotherapy in patients with localized disease and

favorable biologic features.

In the United States, the current treatment of children with neuroblastoma is guided by protocols

established by the COG, and it is recommended that every child diagnosed be enrolled on a clinical trial.

ANBL00B1 is the most recently opened COG study that will determine risk stratification and treatment

plans based on histology, MYCN amplification, ploidy, and serum analysis

(https://clinicaltrials.gov/ct2/show/NCT00904241). This study will also further investigate other tumor

biologic properties including the prevalence of segmental chromosomal alterations 1p, 11q, 14q, and

17q and analyze for independent clinical significance compared to standard prognostic indicators such as

MYCN, INSS, and age.

STAGING

Table 105-2 International Staging Criteria for Neuroblastoma

3078