Neuroblastoma_ [Print] - eMedicine Pediatrics_ General Medicine

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eMedicine Specialties > Pediatrics: General Medicine > Oncology

Neuroblastoma

Norman J Lacayo, MD, Assistant Professor, Department of Pediatrics, Division of Hematology-Oncology, Stanford University and Lucile

Salter Packard Children's Hospital

Kara L Davis, DO, Fellow , Department of Pediatric Hematology/Oncology, Stanford University School of Medicine

Updated: Oct 20, 2010

Introduction

Background

Neuroblastoma is the most common extracranial solid tumor in infancy. It is an embryonal malignancy of the

sympathetic nervous system arising from neuroblasts (pluripotent sympathetic cells). In the developing embryo, these

cells invaginate, migrate along the neuraxis, and populate the sympathetic ganglia, adrenal medulla, and other sites.

The pattern of distribution of these cells correlates with the sites of primary disease presentation.

Age, stage, and biological features encountered in tumor cells are important prognostic factors and are used for risk

stratification and treatment assignment. The differences in outcome for patients with neuroblastoma are striking.

Patients with low-risk and intermediate-risk neuroblastoma have excellent prognosis and outcome. However, those

with high-risk disease continue to have very poor outcomes despite intensive therapy. Unfortunately, approximately

70-80% of patients older than 18 months present with metastatic disease, usually in the lymph nodes, liver, bone,

and bone marrow. Less than half of these patients are cured, even with the use of high-dose therapy followed by

autologous bone marrow or stem cell rescue.

Histologic subtypes of neuroblastoma are shown in the image below.

Histologic subtypes of neuroblastoma. Top right panel, neuroblastoma: A monotonous population of

hyperchromatic cells with scant cytoplasm. Bottom left panel, ganglioneuroblastoma: Increased

schwannian stroma. Bottom right panel, ganglioneuroma: Mature ganglion cell with schwannian

stroma.

Pathophysiology

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Chromosomal and molecular markers

Over the last 2 decades, many chromosomal and molecular abnormalities have been identified in patients with

neuroblastoma. These biologic markers have been evaluated to determine their value in assigning prognosis, and

some of these have been incorporated into the strategies used for risk assignment.

The most important of these biologic markers is MYCN. MYCN is an oncogene that is overexpressed in

approximately one quarter of cases of neuroblastoma via the amplification of the distal arm of chromosome 2. This

gene is amplified in approximately 25% of de novo cases and is more common in patients with advanced-stage

disease. Patients whose tumors have MYCN amplification tend to have rapid tumor progression and a poor prognosis,

even in the setting of other favorable factors such as low-stage disease or 4S disease.

In contrast to MYCN, expression of the H-ras oncogene correlates with lower stages of the disease. Cytogenetically,

the presence of double-minute chromatin bodies and homogeneously staining regions correlates with MYCN gene

amplification. Deletion of the short arm of chromosome 1 is the most common chromosomal abnormality present in

neuroblastoma and confers a poor prognosis. The 1p chromosome region likely harbors tumor suppressor genes or

genes that control neuroblast differentiation. Deletion of 1p is more common in near-diploid tumors and is associated

with a more advanced stage of the disease. Most of the deletions of 1p are located in the 1p36 area of the

chromosome.

A relationship between 1p loss of heterozygosity (LOH) and MYCN amplification has been described. Other allelic

losses of chromosomes 11q, 14q, and 17q have been reported, suggesting that other tumor suppressor genes may

be located in these chromosomes. Another characteristic of neuroblastoma is the frequent gain of chromosome 1.

DNA index is another useful test that correlates with response to therapy in infants. Look et al demonstrated that

infants whose neuroblastoma have hyperdiploidy (ie, DNA index >1) have a good therapeutic response to

cyclophosphamide and doxorubicin.[1 ]In contrast, infants whose tumors have a DNA index of 1 are less responsive to

the latter combination and require more aggressive therapy. DNA index does not have any prognostic significance in

older children. In fact, hyperdiploidy in children more frequently occurs in the context of other chromosomal and

molecular abnormalities that confer a poor prognosis.

Three neurotrophin receptor gene products, TrkA, TrkB, and TrkC, are tyrosine kinases that code for a receptor of

members of the nerve growth factor (NGF) family. Their ligands include p75 neurotrophin receptor (p75NTR) NGF, and

brain-derived neurotrophic factors (BDNFs). Interestingly, TrkA expression is inversely correlated with the amplification

of the MYCN gene, and the expression of the TrkC gene is correlated with TrkA expression. In most patients younger

than 1 year, a high expression of TrkA correlates with a good prognosis, especially in patients with stages 1, 2, and

4S. In contrast, TrkB is more commonly expressed in tumors with MYCN amplification. This association may

represent an autocrine survival pathway.

Disruption of normal apoptotic pathways may also play a role in neuroblastoma pathology. Disruption of these normal

pathways may play a role in therapy response as a result of epigenetic silencing of gene promoters in apoptotic

pathways. Drugs that target DNA methylation, such as decitabine, are being explored in preliminary studies.

Other biologic markers associated with poor prognosis include increased levels of telomerase RNA and lack of

expression of glycoprotein CD44 on the tumor cell surface. P-glycoprotein (P-gp) and multidrug resistance protein

(MRP) are 2 proteins expressed in neuroblastoma. These proteins confer a multidrug-resistant (MDR) phenotype in

some cancers. Their role in neuroblastoma is controversial. Reversal of MDR is one target for novel drug development.

Anatomic

Origin and migration pattern of neuroblasts during fetal development explains the multiple anatomic sites where these

tumors occur; location of tumors varies with age. Tumors can develop in the abdominal cavity (40% adrenal, 25%

paraspinal ganglia) or other sites (15% thoracic, 5% pelvic, 3% cervical tumors, 12% miscellaneous). Infants more

commonly present with thoracic and cervical tumors, whereas older children more frequently have abdominal tumors.

Most patients present with signs and symptoms related to tumor growth, although small tumors have been detected

due to the common use of prenatal ultrasonography. Large abdominal tumors often result in increased abdominal girth

and other local symptoms (eg, pain). Paraspinal dumbbell tumors can extend into the spinal canal, impinge on the



spinal cord, and cause neurologic dysfunction.

Stage of the tumor at the time of diagnosis and age of the patient are the most important prognostic factors. Although

patients with localized tumors (regardless of age) have an excellent outcome (80-90% 3-year event-free survival [EFS]

rate), patients older than 18 months with metastatic disease fare poorly. Generally, more than 50% of patients

present with metastatic disease at the time of diagnosis, 20-25% have localized disease, 15% have regional

extension, and approximately 7% present during infancy with disseminated disease limited to the skin, liver, and

bone marrow (stage 4S).

Physiologic and biochemical

More than 90% of patients have elevated homovanillic acid (HVA) and/or vanillylmandelic acid (VMA) levels detectable

in urine. Mass screening studies using urinary catecholamines in neonates and infants in Japan, Quebec, and Europe

have demonstrated the ability to detect neuroblastoma before it is clinically apparent. However, most of the tumors

identified occur in infants with a good prognosis. None of these studies show that mass screening decreases deaths

due to high-risk neuroblastoma. Markers associated with a poor prognosis include (1) elevated ferritin levels, (2)

elevated serum lactate dehydrogenase (LDH) levels, and (3) elevated serum neuron-specific enolase (NSE) levels.

However, these markers have become less important due to the discovery of more relevant biomarkers (ie,

chromosomal and molecular markers). In fact, ferritin was not included in the recent formulation of the International

Neuroblastoma Risk Group Classification System because it was not found to be of prognostic difference in thehigh

risk group.

Histologic

Pluripotent sympathetic stem cells migrate and differentiate to form the different organs of the sympathetic nervous

system. The normal adrenal gland consists of chromaffin cells, which produce and secrete catecholamines and

neuropeptides. Other cells include sustentacular cells, which are similar to Schwann cells, and scattered ganglion

cells. Histologically, neural crest tumors can be classified as neuroblastoma, ganglioneuroblastoma, and

ganglioneuroma, depending on the degree of maturation and differentiation of the tumor.

The undifferentiated neuroblastomas histologically present as small, round, blue cell tumors with dense nests of cells

in a fibrovascular matrix and Homer-Wright pseudorosettes. These pseudorosettes, which are observed in 15-50% of

tumor samples, can be described as neuroblasts surrounding eosinophilic neuritic processes. The typical tumor

shows small uniform cells with scant cytoplasm and hyperchromatic nuclei. A neuritic process, also called neuropil,

is a pathognomonic feature of neuroblastoma cells. NSE, chromogranin, synaptophysin, and S-100

immunohistochemical stains are usually positive. Electron microscopy can be useful because ultrastructural features

(eg, neurofilaments, neurotubules, synaptic vessels, dense core granules) are diagnostic for neuroblastoma.

In contrast, the completely benign ganglioneuroma is typically composed of mature ganglion cells, Schwann cells,

and neuritic processes, whereas ganglioneuroblastomas include the whole spectrum of differentiation between pure

ganglioneuromas and neuroblastomas. Because of the presence of different histologic components, the pathologist

must thoroughly evaluate the tumor; the regions with different gross appearance may demonstrate a different

histology.

Neuroblastic nodules are present in the fetal adrenal gland and peak at 17-18 weeks' gestation. Most of these

nodules spontaneously regress and likely represent remnants of fetal development. Some of these may persist and

lead to the development of neuroblastoma.

Shimada histopathologic classification system

Shimada et al developed a histopathologic classification in patients with neuroblastoma.[2 ]This classification system

was retrospectively evaluated and correlated with outcome in 295 patients with neuroblastoma who were treated by

the Children's Cancer Group (CCG). Important features of the classification include (1) the degree of neuroblast

differentiation, (2) the presence or absence of Schwannian stromal development (stroma-rich, stroma-poor), (3) the

index of cellular proliferation (known as mitosis-karyorrhexis index [MKI]), (4) nodular pattern, and (5) age. Using

these components, patients can be classified into the following histology groups:

Favorable histology group includes the following:

Patients of any age with stroma-rich tumors without a nodular pattern



Patients younger than 18 months with stroma-poor tumors, an MKI of less than 200/5000 (200 karyorrhectic

cells per 5000 cells scanned), and differentiated or undifferentiated neuroblasts

Patients younger than 60 months with stroma-poor tumors, an MKI of less than 100/5000, and well-

differentiated tumor cells

Unfavorable histology group includes the following:

Patients of any age with stroma-rich tumors and a nodular pattern

Patients of any age with stroma-poor tumors, undifferentiated or differentiated neuroblasts, and an MKI more

than 200/5000

Patients older than 18 months with stroma-poor tumors, undifferentiated neuroblasts, and an MKI more than

100/5000

Patients older than 18 months with stroma-poor tumors, differentiated neuroblasts, and an MKI of 100-

200/5000

Patients older than 60 months stroma-poor, differentiated neuroblasts, and an MKI less than 100

Shimada et al’s original classification was adopted and integrated into the International Neuroblastoma Pathology

Classification (INPC). This was most recently revised.[3 ] The INPC system remains age-dependent.

Frequency

United States

Neuroblastoma accounts for approximately 7.8% of childhood cancers in the United States. Approximately 650 new

cases are diagnosed in the United States each year. According to the Surveillance, Epidemiology, and End Report

(SEER), incidence is approximately 9.5 cases per million children.[4 ]

International

Incidence in other industrialized nations appears to be similar to that observed in the United States. International

reports have shown that the incidence rates of neuroblastoma are highest among high income countries in Europe

and North America, and lower in low income countries in Africa, Asia, and Latin America. No published data are

available on the incidence in the emerging high-income countries of Asia.[5 ]

Mortality/Morbidity

According to the SEER data, the overall 5-year survival rate for children with neuroblastoma has improved from 24% in

1960-1963 to 55% in 1985-1994.[4 ]In part, this increase in survival rate may be due to better detection of low-risk

tumors in infants. The survival rate 5 years from diagnosis is approximately 83% for infants, 55% for children aged 1-5

years, and 40% for children older than 5 years. Improvements in diagnostic imaging modalities, medical and surgical

management, and supportive care have contributed to the improved survival rates.[6 ]

Most patients with neuroblastoma present with disseminated disease, which confers a poor prognosis and is

associated with a high mortality rate. Tumors in these patients usually have unfavorable pathologic and/or molecular

features. The 3-year EFS for high-risk patients treated with conventional chemotherapy, radiation therapy, and surgery

is less than 20%. Differentiating agents and dose intensification of active drugs, followed by autologous bone marrow

transplant, have been reported to improve the outcome for these patients, contributing to an EFS of 38%. A recent

single-arm study of tandem stem cell transplantation reported a 3-year EFS of 58%, but this has not been tested in a

randomized fashion.[7 ]

Morbidity of high-dose chemotherapy approaches can be substantial, although the treatment-related mortality rates

have decreased with improvements in supportive care and hematopoietic support with growth factors and stem cells

instead of bone marrow.

Race

Incidence of neuroblastoma is higher in white children than in black children. However, race does not appear to have

any effect on outcome.



Sex

Males have a slightly higher incidence of neuroblastoma than females, with a male-to-female ratio of 1.2:1.

Age

Age distribution is as follows: 40% of patients are younger than 1 year when diagnosed, 35% are aged 1-2 years, and

25% are older than 2 years when diagnosed. According to SEER, incidence decreases every consecutive year up to

age 10 years, after which the disease is rare.[4 ]

Clinical

History

The following may be noted in patients with neuroblastoma:

Signs and symptoms of neuroblastoma vary with site of presentation. Generally, symptoms include abdominal

pain, emesis, weight loss, anorexia, fatigue, and bone pain. Hypertension is an uncommon sign of the disease

and is generally caused by renal artery compression, not catecholamine excess. Chronic diarrhea is a rare

presenting symptom secondary to tumor secretion of vasoactive intestinal peptide secretion.

Because more than 50% of patients present with advanced stage disease, usually to the bone and bone

marrow, the most common presentation includes bone pain and a limp. However, patients may also present

with unexplained fever, weight loss, irritability, and periorbital ecchymosis secondary to metastatic disease to

the orbits. The presence of bone metastases can lead to pathologic fractures.

Approximately two thirds of patients with neuroblastoma have abdominal primaries. In these circumstances,

patients can present with an asymptomatic abdominal mass that usually is discovered by the parents or a

caregiver. Symptoms produced by the presence of the mass depend on its proximity to vital structures and

usually progress over time.

Tumors that arise from the paraspinal sympathetic ganglia can grow through the spinal foramina into the spinal

canal and impinge on the spinal cord. This may result in the presence of neurologic symptoms, including

weakness, limping, paralysis, and even bladder and bowel dysfunction.

Thoracic neuroblastomas (posterior mediastinum) may be asymptomatic and are usually diagnosed by

imaging studies obtained for other reasons. Presenting signs or symptoms may be insignificant and involve

mild airway obstruction or chronic cough, leading to chest radiography.

Thoracic tumors extending to the neck can produce Horner syndrome. Primary cervical neuroblastoma is rare

but should be considered in the differential diagnosis of masses of the neck, especially in infants younger than

1 year with feeding or respiratory difficulties.

In a small proportion of infants younger than 6 months, neuroblastoma presents with a small primary tumor

and metastatic disease confined to the liver, skin, and bone marrow (stage 4S). If this type of tumor develops

in neonates, skin lesions may be confused with congenital rubella, and, if the patient has severe skin

involvement, the term "blueberry muffin baby" may be used.

Approximately 2% of patients present with opsoclonus and myoclonus a paraneoplastic syndrome

characterized by the presence of myoclonic jerking and random eye movements. These patients often have

localized disease and a good long-term prognosis. Unfortunately, the neurologic abnormalities can persist or

progress and can be devastating.

Finally, intractable diarrhea is a rare paraneoplastic symptom and is associated with more differentiated

tumors and a good prognosis.

Physical

The following may be noted in patients with neuroblastoma:

Children are usually referred to a pediatric oncologist by primary care providers who have identified a persistent

unexplained symptom or sign, either upon physical examination or based on screening test findings.

In patients with suspected neuroblastoma, performing a thorough examination with careful attention to vital



signs (eg, blood pressure), neck, chest, abdomen, skin, and nervous system is essential.

Metastatic lesions of the skin are common in infants younger than 6 months and may represent stage 4S

disease.

Examination of the abdomen may reveal an abdominal mass, leading to the appropriate workup.

Neurologic examination may reveal Horner syndrome. In the case of dumbbell tumors, compression of the

spinal cord may produce lower extremity weakness or paraplegia. Patients with neurologic involvement by

tumor should be treated emergently, secondary to the risk of permanent neurologic sequelae.

Causes

The cause of neuroblastoma is unknown, and no specific environmental exposure or risk factors have been identified.

Because of young age of onset with this disease, investigators have focused on events before conception and during

gestation.

According to SEER data, factors investigated for which evidence is limited or inconsistent include medications,

hormones, birth characteristics, congenital anomalies, previous spontaneous abortion or fetal death, alcohol or

tobacco use, and paternal occupational exposures.

The vast majority of neuroblastoma arises sporadically without family history of the disease. However, 1-2% of newly

diagnosed cases do have a family history of neuroblastoma. Patients with familial neuroblastoma often present at

earlier age or with several distinct primary tumors.

Neuroblastoma has been known to occur in the setting of other disorders that are linked to abnormal development of

neural crest tissues, such as Hirschsprung disease or central congenital hypoventilation syndrome.

Recent work using genome-wide analysis of neuroblastoma from these rare familial cases has identified a genetic

defects involved in these cases.

Cases of neuroblastoma that accompany other congenital abnormalities of the neural crest have been associated with

a germline mutation in PHOX2B. This gene is a homeobox gene that acts as a regulator of autonomic nervous

system development.

In familial neuroblastoma cases that are not associated with other congenital disorders of neural crest development,

ALK mutations have been identified in the germline.[8 ]These mutations largely occur in the kinase domain causing

activation of ALK signaling. Efforts are ongoing to investigate the incidence of ALK mutations across all subsets of

neuroblastoma, but initial evidence indicates that somatic mutations of the ALK gene are also present in some cases

of sporadic neuroblastoma.

De Brouwer et al illustrate the occurrence of the ALK mutation specifically in neuroblastomas. Although they studied

a small proportion of cases, mutations were found in similar frequencies in favorable and unfavorable outcome cases.

The F1174L mutant was found more frequently in the poor outcome subgroup.[9 ]This example illustrates the

heterogeneity of cancer and the likely possibility that targeted therapies to the ALK gene may be of benefit in a

subset of ALK cancers, which may possibly include a small subset of MYC -amplified neuroblastomas. The challenge

for drug development in neuroblastoma is to identify upfront high-risk cases that may benefit from ALK -directed

therapy.

Differential Diagnoses

Rhabdomyosarcoma

Wilms Tumor

Other Problems to Be Considered

Neoplastic or nonneoplastic disease of childhood, including osteomyelitis and rheumatoid arthritis

Disseminated bone disease

Primary neurologic disease

Inflammatory bowel disease

Workup



Laboratory Studies

Any child with a presumed diagnosis of neuroblastoma or any other childhood cancer should be referred to a pediatric

cancer center for proper care and evaluation. Laboratory studies should include the following:

CBC count and differential (Anemia or other cytopenias suggest bone marrow involvement.)

Urine collection for catecholamines (VMA/HVA) and UA

A single sample or collected urine test for VMA/HVA is highly accurate in CLIA approved laboratories.

Centers usually send samples to a specialty laboratory and/or perform a timed collection of urine.

A urinary catecholamine level is considered to be elevated if it is 3 standard deviations higher than the

age-related reference range levels.

Serum creatinine

Liver function tests

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Total bilirubin

Alkaline phosphatase

Total protein

Albumin

Prothrombin time (PT)/activated prothrombin time (aPTT)

Electrolytes

Calcium

Magnesium

Phosphorus

Uric acid

Serum lactate dehydrogenase (LDH)

Ferritin

Thyroid-stimulating hormone (TSH), T4

Immunoglobulin (Ig)G levels

Imaging Studies

The following studies may be indicated in patients with neuroblastomas:

Obtain chest and abdominal radiographs to evaluate for the presence of a posterior mediastinal mass or

calcifications.

A CT scan of the primary site is essential to determine tumor extent. The main body of the tumor is usually

indistinguishable from nodal masses. See the images below.



CT scan of abdomen in a patient with a retroperitoneal mass arising from the upper pole of the

left kidney and elevated urine catecholamines.



A one-week-old neonate had abdominal ultrasonography for evaluation of projectile vomiting. A

right adrenal mass (100% cystic) was an incidental finding. Evaluation of the mass by CT was

consistent with an adrenal bleed (3.6 x 3.1 x 2.4 cc). The infant was followed at 2 weeks (2-

dimensional size diminished to 1.5 x. 2.4 cm2 on ultrasonography) and then at 6 weeks to

document that the adrenal bleed continued to involute. Urine catecholamines were normal.

In cases of paraspinal masses, MRI aids in determining the presence of intraspinal tumor and cord

compression. Horner syndrome should be evaluated with an MRI of the neck and head. See the image below.



MRI of a left adrenal mass. The mass was revealed by fetal ultrasonography at 30 weeks'

gestation. During infancy, the mass was found on the inferior pole of the left adrenal and was

completely resected. Before surgery, the metastatic workup was negative. Surgical pathology

service confirmed a diagnosis of neuroblastoma. After 3 years of follow-up care, no recurrence

was observed.

I123/131 -methyliodobenzylguanadine (MIBG) accumulates in catecholaminergic cells and provides a specific

way of identifying primary and metastatic disease if present. Increasing numbers of institutions have access to

MIBG scanning.

A technetium-99 bone scan can also be used to evaluate bone metastases. This may be especially helpful in

patients with negative MIBG study findings. Most current therapeutic protocols require both a bone scan and

MIBG scan.

Skeletal surveys may also be useful, especially in patients with multiple metastatic lesions.

Positron emission tomography (PET) scan are under evaluation but are not currently recommended as part of

the radiographic workup.

Other Tests

Obtain the following as baseline studies before therapy with anthracyclines:



ECG

Echocardiogram or resting radionuclide ejection fraction scan

Baseline hearing tests are recommended before cisplatin therapy. Baseline creatinine clearance should be measured,

especially if serum creatinine is abnormal.

Procedures

Perform bilateral bone marrow aspirate and biopsies to exclude metastatic disease.

Biopsy or resection of the primary tumor (stage I or II disease) is performed to collect tissue samples for biologic

studies used to assign the patient into the appropriate risk category. Most centers in the United States perform

limited open biopsies when the primary tumor is unresectable upfront. Adequate tissue is needed to perform

molecular studies that aid in risk assignment. Extensive resections should be avoided upfront if they may place

patient at excessive risk from morbidity or mortality from surgery. Neuroblastoma is a chemo-sensitive tumor; thus,

second-look surgery to resect a residual primary may be a safer procedure with biopsy only performed upfront.

Tissue samples from a primary or metastatic tumor may be undifferentiated and confused with other small, round,

blue cell tumors of childhood; however, immunohistochemical stains can aid with tissue diagnosis.

Molecular techniques, such as fluorescent in situ hybridization (FISH), can detect MYCN amplification, an important

prognostic marker. Polymerase chain reaction (PCR) can identify specific translocations, such as t(11;22), in Ewing

sarcoma and t(2;13) in alveolar rhabdomyosarcoma, thus ruling out neuroblastoma.

Neuroblastoma in bone marrow can be difficult to distinguish from other small, round, blue cell tumors of childhood.

Histologic Findings

Biopsy findings are usually required to diagnose neuroblastoma. Depending on the extent of disease at presentation,

consider complete surgical resection, especially in patients with low-stage disease. Even without a biopsy, the

presence of elevated urinary catecholamines and a bone marrow aspirate or biopsy with unequivocal neuroblastoma

cells is diagnostic.

Histologically, neural crest tumors can be classified as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma,

depending on the degree of maturation and differentiation of the tumor. Undifferentiated neuroblastomas histologically

present as small, round, blue cell tumors with dense nests of cells in a fibrovascular matrix and Homer-Wright

pseudorosettes. These pseudorosettes, observed in 15-50% of tumor samples can be described as neuroblasts

surrounding eosinophilic neuritic processes. The typical tumor shows small uniform cells with scant cytoplasm and

hyperchromatic nuclei. A neuritic process, also called neuropil, is a pathognomonic feature of neuroblastoma.

Neuron-specific enolase (NSE), chromogranin, synaptophysin, and S-100 immunohistochemical stain findings are

usually positive. Electron microscopy can be useful because ultrastructural features (eg, neurofilaments,

neurotubules, synaptic vessels, dense core granules) are diagnostic for neuroblastoma. In contrast, the completely

benign ganglioneuroma is typically composed of mature ganglion cells, Schwann cells, and neuritic processes,

whereas ganglioneuroblastomas include the whole spectrum of differentiation between pure ganglioneuromas and

neuroblastomas.

The pathologist must thoroughly evaluate the tumor because regions with different gross appearance may exhibit a

different histology.

Staging

The patient should undergo a staging workup along with surgical resection or biopsy, as appropriate. Using various

molecular features in conjunction with pathology and staging is essential to appropriately stratify patients and

determine the best therapy.

The International Neuroblastoma Staging System (INSS) is currently used in all cooperative group studies in the

United States. Recently, the International Neuroblastoma Risk Group Staging System (INRGSS) and International

Neuroblastoma Risk Group Consensus Pretreatment Classification were released.[10 ]The current INSS system is

based on degree of surgical resection and thus is not appropriate for use with the INRG Pretreatment Classification.



This is especially important because not all groups use upfront surgical resection as part of their staging system. The

INRG was formulated to be used in international settings and to facilitate comparison of treatment outcomes across

studies to allow common definitions among all groups. Thus, development of the INRGSS was facilitated using

pretreatment tumor imaging rather than extent of surgical resection.

The INRGSS is as follows:

L1 - Localized tumor not involving vital structures, as defined by the list of image-defined risk factors and

confined to one body component

L2 - Locoregional tumor with presence of one or more image-defined risk factors

M - Distant metastatic disease

MS - Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or

bone marrow

The INSS is as follows:

Stage 1

Localized tumor with complete gross excision, microscopic residual disease, or both

Ipsilateral lymph nodes negative for tumor (Nodes attached to the primary tumor may be positive for

tumor).

Stage 2A

Localized tumor with incomplete gross resection

Representative ipsilateral nonadherent lymph nodes microscopically negative for tumor

Stage 2B

Localized tumor, complete gross excision, or both with ipsilateral nonadherent lymph nodes positive for

tumor

Enlarged contralateral lymph nodes, which are negative for tumor microscopically

Stage 3

Unresectable unilateral tumor infiltrating across the midline, regional lymph node involvement, or both

Alternatively, localized unilateral tumor with contralateral regional lymph node involvement

Stage 4 - Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or

other organs (except as defined for stage 4S)

Stage 4S

Localized primary tumor (as defined for stages 1, 2A, or 2B) with dissemination limited to skin, liver,

and/or bone marrow (<10% involvement)

Limited to infants

Treatment

Medical Care

Care of children with neuroblastoma is provided by a multidisciplinary team involving pediatric oncology, radiation

oncologists, surgeons, and anesthesiologists, as well as nurse practitioners, nurses, pharmacists, psychologists,

and physical and occupational therapists dedicated to the special needs of these children.

The table below outlines criteria for risk assignment based on the International Neuroblastoma Staging System

(INSS), age, and biologic risk factors. This, in turn, determines the intensity of the therapy. These treatment

strategies have been developed from more than 2 decades of experience with clinical trials in Children's Cancer Group

(CCG) and Pediatric Oncology Group (POG), now known as the Children's Oncology Group (COG). Correlative

biologic studies were pivotal in identifying biologic risk factors important for outcome. Currently, efforts are ongoing to

develop an International Neuroblastoma Risk Group (INRG).



In addition, recently published results on correlative biologic studies and clinical outcome have lead to changes in an

age cut-off of more than 365 days (365-547 d) for some patients with tumors in stages 3 and 4.[11,12 ]These criteria

are based on the analysis of several thousands of patients treated in cooperative group protocols in Australia,

Canada, Europe, Japan, and the United States.[13 ]

Table 1. Current COG Neuroblastoma Risk Stratification

Risk Group Stage Age MYCN Amplification Status Ploidy Shimada

Low 1 Any Any Any Any

Low 2a/2b Any Non-amp Any Any

High 2a/2b Any Amp Any Any

Intermediate 3 <547d Non-amp Any Any

Intermediate 3 ≥547d Non-amp Any Favorable

High 3 Any Amp Any Any

High 3 ≥547d Non-amp Any Unfavorable

High 4 <365d Amp Any Any

Intermediate 4 <365d Non-amp Any Any

High 4 365-547d Amp Any Any

High 4 365-547d Any Diploid Any

High 4 365-547 Any Any Unfavorable

Intermediate 4 365-547d Non-amp Hyper Favorable

High 4 ≥547d Any Any Any

Low 4s <365d Non-amp Hyper Favorable

Intermediate 4s <365d Non-amp Diploid Any

Intermediate 4s <365d Non-amp Any Unfavorable

High 4s <365d Amp Any Any

Cooperative Group Treatment Strategies

Low-risk group treatment strategy

Patients with localized respectable neuroblastoma (stage 1) have excellent event-free survival (EFS) rates with

surgical excision of tumor only. Adjuvant chemotherapy is generally not needed for this group of patients. Even the

presence of residual microscopic disease does not significantly affect the EFS. If patients develop recurrent disease,

chemotherapy can be used, and the overall survival rate remains higher than 95%.

Similar therapy is offered to patients with stage 2A/2B disease who are presently assigned to a low-risk category if

they have MYCN -non amplified tumors, regardless of age histology or ploidy. Patients with stage 2A/2B disease with

amplified MYCN are considered high risk regardless of age and histology.

Most patients with 4S disease (ie, non-MYCN –amplified tumors, favorable histology, hyperdiploid tumors in infants

younger than 1 y) are also considered to be in the low-risk group and most experience spontaneous regression. Thus,

observation or surgery alone is often all that is needed to manage these tumors. Chemotherapy may be used to

control life-threatening situations such as respiratory distress or mechanical obstruction.

Intermediate-risk group treatment strategy



Surgery and multiagent chemotherapy comprise the backbone of therapy for intermediate risk group patients. Current

efforts are ongoing to help understand which of this diverse group of patients can have therapy reduced without

threatening the excellent EFS for these patients.

Intermediate-risk patients include children younger than 18 months with stage 3 and 4 disease and favorable biology

(non-MYCN –amplified tumors, regardless of histology and DNA index). These patients are offered therapy with 4 of

the most active drugs against neuroblastoma (ie, cyclophosphamide, doxorubicin, carboplatin, etoposide) for either 4

cycles, 6 cycles, or 8 cycles, depending on histology and DNA index and response to treatment. In these patients,

surgery can be performed either at time of diagnosis or following multiagent chemotherapy. If residual disease is

present after chemotherapy and surgery, radiation therapy could be considered. However, the use of radiation is

controversial, although a POG study suggested that it improves outcome when administered to areas of residual

disease postchemotherapy.

Baker et al conducted a prospective, phase 3, nonrandomized trial of 479 patients (270 patients with stage 3 disease,

178 patients with stage 4 disease, and 31 patients with stage 4S disease) to determine whether a 3-year estimated

overall survival of more than 90% could be maintained with reduced duration of chemotherapy and reduced drug

doses.[14 ]The resulting 3-year estimate of overall for the entire group was 96%±1%. The study concluded that among

patients with intermediate-risk neuroblastoma, substantially reduced duration of chemotherapy and reduced doses of

chemotherapeutic agents still resulted in excellent outcomes.

High-risk group treatment strategy

This group of patients seem to require treatment with multiagent chemotherapy, surgery, and radiotherapy, followed

by consolidation with high-dose chemotherapy and peripheral blood stem cell rescue.

Current therapeutic protocols involve 4 phases of therapy, including induction, local control, consolidation and

treatment of minimal residual disease. The 3-year EFS for patients in the high-risk group who are treated without such

high-intensity therapy is less than 20%, compared with an EFS of 38% in patients treated with a single bone marrow

transplant and cis-retinoic acid after transplant.

Induction therapy currently involves multiagent chemotherapy with non–cross-resistant profiles, including alkylating

agents, platinum, and anthracyclines and topoisomerase II inhibitors. Current studies are ongoing to look at addition

of topoisomerase I inhibitors as part of an upfront therapy during induction. Topotecan does display activity against

relapsed neuroblastoma.

Local control involves surgical resection of primary tumor site as well as radiation to primary tumor site. Primary

tumors are often more amenable to surgical resection after receiving upfront induction chemotherapy. Neuroblastoma

is a very radiosensitive tumor, and chemotherapy plays an important role in control of disease in the high-risk setting.

Myeloablative consolidation therapy has shown to improve EFS for patients with high-risk neuroblastoma. Current

data from trials in the United States and Europe support improved outcomes for patients receiving myeloablative

consolidation therapy with etoposide, carboplatin, and melphalan. Recently, a single-arm study of tandem stem cell

transplantation reported an EFS of 58%. A randomized study of tandem stem cell transplant against a single

transplant is currently ongoing in the Children’s Oncology Group.[7 ]Because of significant improvements in time to

recovery and a lower risk of tumor cell contamination, most centers now recommend the use of peripheral blood stem

cell support over bone marrow for consolidation therapy.

Control of minimal residual disease with biologic agents has also been shown to improve survival. The most

experience is with 13-cis -retinoic acid in a maintenance phase of therapy. This agent has been shown to cause

differentiation in neuroblastoma cell lines. CCG-3891 showed a significant survival advantage with 3-year EFS of 38%

for those patients receiving maintenance therapy with 13-cis -RA compared with 18% for those who did not receive

this therapy. Recent data have showed improved survival in patients receiving 13-cis -RA in combination with

immunomodulatory therapy with interleukin (IL)-2, granulocyte macrophage colony-stimulating factor (GM-CSF), and

the chimeric anti-GD2 (gangliosidase) antibody when compared with 13-cis -RA alone.

Yu et al conducted a study to assess whether adding ch14.18, which is a monoclonal antibody against GD2, along

with GM-CSF and and IL-2 to standard isotretinoin therapy could improve outcomes in patients with high-risk

neuroblastomas.[15 ]When compared with standard therapy, the resulting event-free survival rates (66%±5% vs 46%

±5% at 2 y; P=0.01) and overall survival rates (86%±4% vs 75%±5% at 2 y; P=0.02) were superior.



Future directions and experimental therapies

Other experimental therapies are currently under investigation for recurrent high-risk neuroblastoma, including aurora

kinase inhibitors, antiangiogenic agents, histone deacetylase inhibitors, and therapeutic metaiodobenzylguanidine

(MIBG).

Surgical Care

Surgical resection plays an important role in the treatment of patients with neuroblastoma. For patients with localized

disease, surgical resection is curative. For patients with regional or metastatic disease, surgery to establish a

diagnosis and obtain adequate samples for biologic studies is essential. Typically, second-look surgery

postchemotherapy is used to attempt a complete resection. The emphasis in the second-look procedure is as

complete a debulking as possible without sacrificing major organ function. Patients with residual disease

postchemotherapy and surgery may benefit from the use of radiotherapy.

Consultations

Neuroblastoma can be confused with other neoplastic or nonneoplastic diseases of childhood. The diagnosis can be

challenging in the 10% of patients who present with normal urinary catecholamines.

Radiation oncologists may participate in the care of patients with neuroblastoma. Typically, they are consulted to

evaluate patients whenever radiation therapy is a consideration. Usually, radiotherapy is localized to areas of residual

microscopic disease, persistent disease, or both after chemotherapy and surgery.

In high-risk patients, the need for stem cell harvest and transplantation should be anticipated. These services should

be included early in the planning phase of treatment.

Diet

Nutrition plays an important role in therapy. Children need adequate caloric intake to attain normal growth and

development, and to recover from the adverse effects of therapy. Nutritionists typically help to provide adequate

supportive care during therapy. Supplemental nutrition is often required during therapy. This should occur via the

enteral route (nasogastric or gastric tube). The parenteral route should be used only after failure to supplement

adequately using enteral feedings.

Activity

No specific restrictions are placed on activity. Patients who are thrombocytopenic should avoid strenuous activity and

contact sports. Patients should avoid ill contacts, especially if neutropenic.

Medication

All chemotherapy orders are written by pediatric oncologists and countersigned, usually by another physician. With

recurrent disease, various salvage protocols may be used; with refractory disease, a limited number of phase I/II

studies are available through the Children's Oncology Group (COG) and New Approaches to Neuroblastoma Therapy

(NANT) consortia.

Resources presented in this section should serve as a guide to indication, usual dosages, and adverse effects of

specific agents. Antineoplastic drugs have a narrow therapeutic index and effective doses usually cause severe

toxicities, some of which can be life threatening.

Individual chemotherapy drugs are discussed below. These agents are almost invariably given in combination.

Commonly used combinations include the following:

Vincristine, cyclophosphamide, and doxorubicin

Carboplatin and etoposide

Cisplatin and etoposide

Ifosfamide and etoposide

Cyclophosphamide and topotecan



Consolidation regimens used in neuroblastoma include the following:

Carboplatin and etoposide with melphalan or cyclophosphamide

Thiotepa and cyclophosphamide

Melphalan and total body irradiation

In Europe, several studies have used busulfan with melphalan or cyclophosphamide. One commonly used salvage or

relapse therapy regimen is the combination of topotecan and cyclophosphamide. The use or retinoids have been

incorporated in maintenance regimens in the posttransplant setting. Irinotecan is also under investigation.

Antineoplastic Agents

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells

divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a

premitotic phase (ie, G2), which is followed by a mitotic cell division (ie, phase M).

Cell division rate varies for different tumors. Most common cancers increase very slowly in size compared with normal

tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly

from chemotherapy than malignant cells; it is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg,

alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is

also a potential mechanism of many antineoplastic agents.

Carboplatin (Paraplatin)

Alkylating agent. Interferes with metabolism of DNA by covalent binding.

Dosing

Adult

Pediatric

500 mg/m2 IV qd for 2 d; usually administered with etoposide, alternating with other drug combinations q3-4wk

For marrow ablation: 667-1000 mg/m2 IV qd for 3 d in combination with etoposide and cyclophosphamide or with

etoposide and melphalan

Interactions

Incidence of neurotoxicity and nephrotoxicity is higher in patients who previously have been treated with cisplatin;

however, the incidence of both these complications is lower with carboplatin than cisplatin

Contraindications

Documented hypersensitivity; use in the setting of existing hearing loss should be considered carefully

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor CBC count closely, avoid infectious contacts, and seek care for fever and bleeding; common adverse effects

include nausea, vomiting, and myelosuppression; occasional adverse effects include electrolyte disturbances; rare

adverse effects include metallic taste, peripheral neuropathy, hepatotoxicity, renal toxicity, ototoxicity, and secondary

leukemia

Cisplatin (Platinol)



Mechanism of action is similar to other alkylating agents. Binds and cross-links DNA strands.

Dosing

Adult

Pediatric

20-40 mg/m2 IV qd for 5 d or a single dose of 90-100 mg/m2, usually combined with etoposide or doxorubicin;

requires prehydration; administer with 0.45% NaCl, potassium chloride, and mannitol

Interactions

Increased risk of ototoxicity with aminoglycosides; interacts with probenecid and sulfinpyrazone and causes

increased risk of uric acid nephropathy

Contraindications

Documented hypersensitivity, preexisting renal insufficiency, myelosuppression, and hearing impairment

Precautions

Pregnancy


Precautions

Monitor CBC count closely, avoid infectious contacts, and seek care for fever and bleeding; common adverse effects

include nausea, vomiting (highly emetogenic), myelosuppression, ototoxicity; occasional adverse effects include

electrolyte disturbances renal toxicity; rare adverse effects include metallic taste, peripheral neuropathy,

hepatotoxicity, and secondary leukemia

Cyclophosphamide (Cytoxan)

Immunosuppressant antineoplastic agent. Metabolism of cyclophosphamide by hepatic microsomal enzymes

produces active alkylating metabolites, which probably damage DNA.

Dosing

Adult

Pediatric

1000-2000 mg/m2 IV qd for 2 d; usually with doxorubicin and vincristine; requires hydration before and during infusion;

mesna used to prevent urotoxicity

For marrow ablation: 50-100 mg/kg (ideal body weight); bone marrow transplant preparative regimens usually combine

etoposide and/or carboplatin; can also be used with thiotepa

Interactions

Interacts with probenecid and sulfinpyrazone; causes increased risk of uric acid nephropathy; increases anticoagulant

activity; at higher doses and with radiotherapy, can increase incidence of cardiomyopathy

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy


Precautions

Monitor CBC count closely, avoid infectious contacts, and seek care for fever and bleeding; monitor for hematuria

(use with mesna to prevent hemorrhagic cystitis); common adverse effects include anorexia, nausea, vomiting,

myelosuppression, alopecia, immunosuppression, and gonadal dysfunction/sterility; occasional adverse effects



include metallic taste, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and hemorrhagic cystitis;

rare adverse effects include transient blurred vision, arrhythmias and myocardial necrosis (high dose), pulmonary

fibrosis, secondary malignancy, and bladder fibrosis

Doxorubicin (Adriamycin)

Causes DNA strand breakage mediated by effects on topoisomerase II. Intercalates into DNA and inhibits DNA

polymerase.

Dosing

Adult

Pediatric

30-75 mg/m2 slow IV push or as continuous IV infusion once during the cycle; usually combined with vincristine and

cyclophosphamide or with cisplatin

Interactions

Probenecid; sulfinpyrazone; may enhance cardiotoxicity with cyclophosphamide, dactinomycin, mitomycin, or

radiation

Contraindications

Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting

myelosuppression

Precautions

Pregnancy


Precautions

Monitor CBC count closely, avoid infectious contacts, and seek care for fever and bleeding; modify doses if total

bilirubin is >1.2 mg/dL; common adverse effects include cardiac arrhythmias (rarely clinically significant), nausea,

vomiting, worsening of adverse effects caused by radiation, local ulceration if extravasated, pink or red color to urine,

myelosuppression, and alopecia, immunosuppression; occasional adverse effects include stomatitis, hepatotoxicity,

mucositis, and cardiomyopathy (cumulative, dose-dependent); rare adverse effects include palmar-plantar

erythrodysesthesia, anaphylaxis, allergic reactions, rash, and secondary malignancy

Etoposide (VP-16, VePesid)

Interacts with topoisomerase II and produces single strand breaks in DNA. Arrests cells in late S or G2 phase.

Dosing

Adult

Pediatric

100-200 mg/m2 IV qd for 3 d; alternatively 75-150 mg/m2 IV qd for 5 d; typically combined with ifosfamide, cisplatin,

or carboplatin

For marrow ablation: 40-60 mg/kg (ideal body weight); generally combined with carboplatin and cyclophosphamide or

melphalan

Interactions

Additive bone marrow suppression occurs with other chemotherapy or radiation

Contraindications

Life-threatening hypersensitivity; reactions nonresponsive to premedication; many patients with reactions to etoposide

can be successfully treated with etoposide phosphate (Etopophos); IT administration may cause death



Precautions

Pregnancy


Precautions

If patient is sensitive to etoposide, use prophylaxis to avoid allergic reactions or consider Etopophos; monitor CBC

count closely, avoid infectious contacts, and seek care for fever and bleeding; common adverse effects include

nausea and myelosuppression; occasional adverse effects include alopecia, enhanced damage from radiation, and

diarrhea; rare adverse effects include hypotension, anaphylaxis, rash, peripheral neuropathy, stomatitis, and

secondary malignancy

Ifosfamide (Ifex)

Alkylating agent. Metabolic activation by microsomal liver enzymes produces biologically active intermediates that

attack nucleophilic sites, particularly on DNA.

Dosing

Adult

Pediatric

1.2-2 g/m2 IV qd for 3-5 d with mesna; usually combined with etoposide, vincristine, or doxorubicin; requires

concurrent hydration with administration

Interactions

May have increased nephrotoxicity with other nephrotoxic drugs (eg, cisplatin, carboplatin)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy


Precautions

Monitor CBC count and platelets closely; avoid ill contacts; seek care for fever and bleeding; monitor for hematuria

(use with mesna to prevent hemorrhagic cystitis); common adverse effects include nausea, vomiting, anorexia,

myelosuppression, and alopecia; occasional adverse effects include somnolence, confusion, weakness, seizure,

SIADH, hemorrhagic cystitis, cardiac toxicities with arrhythmias, myocardial necrosis, and Fanconi renal syndrome;

rare adverse effects include encephalopathy, peripheral neuropathy, acute renal failure, pulmonary fibrosis, secondary

malignancy, and bladder fibrosis

Melphalan (Alkeran)

Inhibits mitosis by cross-linking DNA strands.

Dosing

Adult

Pediatric

Before bone marrow transplant (ie, administer on pretransplant days -7, -6, -5)

<12 kg: 2 mg/kg/d IV infusion over 24 h for 3 d

>12 kg: 60 mg/m2/d IV infusion over 24 h for 3 d (ie, cumulative dose is 180 mg/m2 over 3 d)

Interactions



Concurrent administration with cyclosporine increases nephrotoxicity; cimetidine and H2 antagonists increase gastric

pH, decreasing effects of melphalan

Contraindications

Documented hypersensitivity; severe bone marrow depression

Precautions

Pregnancy


Precautions

Amenorrhea may occur; caution in previously diagnosed myelosuppression

Isotretinoin (13-cis-retinoic acid, Accutane)

Vitamin A derivative. Interacts with retinoic acid responsive elements on DNA, which results in gene activation and

differentiation of target cells.

Dosing

Adult

Pediatric

160 mg/m2/d PO divided bid alternating 2 wk on and 2 wk off per mo for 6 mo (alternating dose avoids tachyphylaxis)

Reduce dose if liver enzymes >5 times normal; reduce dose with pancytopenia, musculoskeletal cramps, dry skin, or

neurologic symptoms

Interactions

Toxicity may occur with vitamin A coadministration; pseudotumor cerebri or papilledema may occur when

coadministered with tetracyclines; isotretinoin may reduce plasma levels of carbamazepine

Contraindications

Documented hypersensitivity; pregnancy, infections, headache, vertigo, hypercalcemia, elevated liver enzymes

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include dry skin, dry mucosa, and cheilitis; occasional adverse effects include nausea,

vomiting, rash, conjunctivitis, musculoskeletal pains, fatigue, headache, serum elevations (eg, triglycerides,

cholesterol, transaminases), hypercalcemia, urethritis, and dysuria; rare adverse effects include changes in skin

pigmentation, nonspecific GI complaints, dizziness, pseudotumor cerebri, anemia, leukopenia, retinoic acid

syndrome with hyperleukocytosis, respiratory distress, fever, hypotension, pulmonary infiltrates, and skeletal

hyperostosis

Thiotepa (Thioplex)

Ethyleneimine derivative alkylating agent. Action involves transfer of the alkyl group to amino, carboxyl, hydroxyl,

imidazole, phosphate, and sulfhydryl groups within the cell, altering structure and function of DNA, RNA, and

proteins.

Dosing

Adult

Before bone marrow transplant (ie, administer on pretransplant days -7, -6, -5):



300 mg/m2 IV qd for 3 d in combination with cyclophosphamide for marrow ablation

Pediatric

Documented hypersensitivity to thiotepa or other phenothiazines; severe hepatic or cardiac disease

Interactions

CNS depressants, anticholinergics, or antihypertensive agents may increase toxic effects

Contraindications

Documented hypersensitivity; pregnancy, infections, headache, vertigo, hypercalcemia, elevated liver enzymes

Precautions

Pregnancy


Precautions

Avoid large dressings or cremes applied to skin during thiotepa administration to limit skin toxicity; monitor CBC

count closely, avoid infectious contacts, and seek care for fever and bleeding; common adverse effects include

nausea, vomiting, myelosuppression, mucositis and esophagitis (high doses), hyperpigmentation of the skin, and

gonadal dysfunction or infertility; occasional adverse effects include pain at injection site, dizziness, and headache; at

high doses, occasional adverse affects include inappropriate behavior, confusion, somnolence, increased liver

transaminases, increased bilirubin, and significant skin breakdown; rare adverse effects include hives, rash, and

febrile reaction

Vincristine (Oncovin)

Mitotic inhibitor. This vinca alkaloid binds tubulin leading to its depolymerization, resulting in mitotic inhibition and

metaphase arrest.

Dosing

Adult

Pediatric

1-2 mg/m2/dose IV push; not to exceed 2 mg/dose; single dose used for specific courses of therapy in combination

with doxorubicin and cyclophosphamide

Interactions

May increase neurotoxicity when used with radiation; increased myelosuppression occurs with doxorubicin; acute

pulmonary reaction may occur when taken concurrently with mitomycin-C

Contraindications

Documented hypersensitivity; IT administration (universally fatal)

Precautions

Pregnancy


Precautions

Common adverse effects include local ulceration if extravasated (vesicant), hair loss, and loss of deep tendon

reflexes; occasional adverse effects include jaw pain, weakness, constipation, numbness, tingling, and clumsiness;

rare adverse effects include paralytic ileus, ptosis, vocal cord paralysis, myelosuppression, CNS depression, SIADH,

and seizure

Topotecan (Hycamtin)



Inhibits topoisomerase I, inhibiting DNA replication.

Dosing

Adult

IV: Single-agent regimen: 1.5 mg/m2/d IV over 30 min days 1-5 of cycle, repeat every 3-4 wk for 4-6 cycles

PO: 2.3 mg/m2/d PO qd for days 1-5 of cycle; repeat q21d

Modify dose with bone marrow toxicity or grade III/IV diarrhea

Pediatric

1.2 mg/m2/dose IV qd on days 1-5 of each cycle

Interactions

Concomitant administration with other antineoplastics may result in prolonged neutropenia and thrombocytopenia in

addition to increased morbidity/mortality

Contraindications

Documented hypersensitivity; bone marrow suppression and renal function impairment

Precautions

Pregnancy


Precautions

Side effects include myelosuppression, dermatitis, nausea, and vomiting; monitor bone marrow function

Colony-stimulating Factors

These agents act as a hematopoietic growth factor that stimulates the development of granulocytes. They are used to

treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce the period of

neutropenia associated with bone marrow transplantation. They are also used to mobilize autologous peripheral blood

progenitor cells for bone marrow transplantation and in the management of chronic neutropenia.

A multicenter, randomized trial by Ladenstein et al observed pediatric patients (n=239) with neuroblastoma in 16

countries.[16 ]Patients who were given primary prophylactic G-CSF had significantly fewer febrile neutropenic

episodes, days with fever, hospital days, and antibiotic days compared with those who received symptom-triggered

G-CSF. Other toxicities were significantly reduced as well including infections, fever, severe leukopenia, neutropenia,

mucositis, nausea/vomiting, constipation, and weight loss.

Filgrastim (G-CSF, Neupogen)

Promotes growth and differentiation of myeloid progenitor cells. May improve survival and function of granulocytes. In

the posttransplant setting, administer until marrow recovery with absolute neutrophil count >10,000.

Dosing

Adult

Pediatric

5-10 mcg/kg SC qd for 10-14 d

Start 24-36 h after last dose of chemotherapy, continue until absolute neutrophil count recovers to ≤ 5000

Interactions

None reported

Contraindications

Documented hypersensitivity; allergy to yeast or Escherichia coli –derived proteins



Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits

outweigh risk to fetus

Precautions

Measure CBC count to determine end-point of therapy; avoid infectious contacts; seek care for fever, pain, or redness

at injection site; occasional adverse effects include local irritation at the injection site, medullary bone pain, increased

alkaline phosphatase, increased lactate dehydrogenase, increased uric acid, thrombocytopenia; rare adverse effects

include allergies, low-grade fever, subclinical splenomegaly, exacerbation of preexisting skin rashes, alopecia, and

cutaneous vasculitis

Chemoprotective Agents

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and

cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react

with acrolein, which is the ifosfamide and cyclophosphamide metabolite considered to be responsible for urotoxicity.

Mesna (Mesnex)

Interacts in the bladder with acrolein, a toxic metabolite of cyclophosphamide or ifosfamide to prevent hemorrhagic

cystitis.

Dosing

Adult

Pediatric

Usually 20-25% of ifosfamide or cyclophosphamide dose IV before chemotherapy and 3 h, 6 h, and 9 h after; in some

instances, used as a continuous infusion

Interactions

None reported

Contraindications

Documented hypersensitivity; thiol compounds

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits

outweigh risk to fetus

Precautions

None specific; similar precautions for antineoplastic agents; common adverse effects include bad taste when PO;

occasional adverse effects include nausea, vomiting, and stomach pain; rare adverse effects include headache, pain

in arms, legs, and joints, fatigue, rash, transient hypotension, allergy, and diarrhea

Follow-up

Further Inpatient Care

The following are aspects of further inpatient care in patients with neuroblastoma:

Children with neuroblastoma are admitted to the hospital to expedite the diagnostic workup when unstable or

significantly symptomatic.

In an asymptomatic child, workup can be performed in the outpatient setting.

A central line is commonly placed when biopsy or resection is scheduled in intermediate- or high-risk patients.



A pediatric oncologist and surgeons with expertise in managing childhood malignancies perform the initial

evaluation.

Other subspecialists, such as neurosurgeons or radiation oncologists, may participate in patient care,

especially in cases of cord compression.

Once the diagnosis is established and the staging workup is completed, the patient and family are instructed

on the diagnosis and therapeutic options.

Once the treatment plan is developed, chemotherapy is administered, usually in the inpatient setting.

Following completion of the treatment cycle, patients are discharged home with detailed instructions for home

care and with outpatient follow-up.

Further Outpatient Care

The following are aspects of further outpatient care in patients with neuroblastoma:

Patients are periodically monitored in the clinic after each course of therapy to monitor for complications and

to assess response to therapy with diagnostic imaging. Myelosuppression and pancytopenia are common

complications, and a CBC count with platelet count is obtained as often as twice per week. Some drugs (eg,

cisplatin, carboplatin, ifosfamide) affect renal function; thus, close monitoring of electrolytes is required, with

oral electrolyte supplementation when necessary. Blood product support is provided when the hemoglobin

drops to less than 8 g/dL, the platelet count drops to less than 10,000, or any signs of bleeding are present.

After completion of therapy, successfully treated patients require follow-up care and close surveillance for any

signs or symptoms of recurrent disease. Follow-up care includes monitoring of urinary catecholamines,

physical examination, and diagnostic imaging. Because most recurrences occur during the first 2 years

following treatment, most protocols recommend close follow-up care during this interval.

Patients who remain free of recurrent disease for 5 years are considered cured, although rare late relapses

have been reported. Long-term follow-up care to assess impact of therapy on growth, development, and organ

toxicity is essential.

Inpatient & Outpatient Medications

The following medications may be used:

Infection prophylaxis: Chemotherapy agents cause myelosuppression and immunosuppression. All patients

should receive prophylaxis against Pneumocystis jiroveci with trimethoprim/sulfamethoxazole (trimethoprim 2.5

mg/kg/dose twice daily), administered on 3 consecutive days per week. Prophylaxis is started before

chemotherapy and continued for at least 3 months after completing therapy.

Colony-stimulating factors: Granulocyte colony stimulating factor (G-CSF) support has become common in

pediatric oncology as intensity of chemotherapy has increased. Treat with 5-10 mcg/kg/d subcutaneously to

start 24-36 hours after the last dose of chemotherapy. G-CSF is continued until the absolute neutrophil count

is 2,000-10,000.

Transfer

Management by primary care provider is as follows:

With oncology team supervision, routine care can be carried out by the primary care provider for patient

convenience.

Monitoring of blood counts or chemistries and administration of blood products are common.

Some primary care providers with experience in the treatment of febrile neutropenia may be able to manage

this complication of chemotherapy. Patients may quickly destabilize upon initiation of antibiotic therapy; thus,

access to critical care services is required.



Maintain close contact with subspecialists and transfer the patient to the pediatric oncology center for any

complications that may require specialized care.

Deterrence/Prevention

The cause of neuroblastoma is unknown.

No specific environmental exposure or risk factors have been identified.

Currently, no specific recommendations on how to prevent this disease are known.

Screening for neuroblastoma in an attempt to diagnose high-risk patients earlier in the course of their disease

has uncovered many patients with low-risk disease but has not had an impact on outcome in high-risk

disease.

Complications

The following complications may occur:

The most worrisome complication at disease presentation is cord compression from a paraspinal tumor.

Evaluation of the patient by a neurosurgeon and consultation with a radiation oncologist are important.

In some individuals with neuroblastomas, early institution of chemotherapy is accepted if the tumor can be

biopsied within 72 hours to make a diagnosis and to obtain necessary biologic studies. In the acute setting,

chemotherapy may be as efficient as radiotherapy or laminectomy, and it may cause less morbidity.

Treatment of cord compression with chemotherapy and steroids usually results in less complications;

however, radiation therapy or surgery is often used as front-line treatment to prevent impending or progressive

neurologic damage. In children who present with significant neurologic symptoms, none of these interventions

assure a return of normal neurologic (motor) function.

Tumor lysis syndrome is unusual in neuroblastoma

Patients may present with severe hypertension or renal insufficiency, making initiation of chemotherapy,

especially with platinum drugs, more difficult.

Myelosuppression and immunosuppression place the patient at risk of bleeding and infection. Febrile

neutropenia is a medical emergency and requires immediate admission to the hospital and initiation of broad-

spectrum antibiotic treatment.

After several cycles of therapy, depending on drugs administered, patients may develop impaired renal

function, hearing loss, or delayed count recovery.

Prognosis

Determinants of response and outcome include the following:

Stage, age, and several biologic characteristics of the tumor determine outcome.

Similarly, the patient may also have genetic polymorphism characteristics that influence drug absorption,

distribution, metabolism, and excretion.

Several treatment strategies are available to treat patients with recurrent neuroblastoma.

A local recurrence in a patient with low-stage disease generally has a good prognosis, and patients usually

receive standard chemotherapy, surgery, and/or radiation as necessary.

Patients with disseminated disease at presentation have a high recurrence rate and a poor outcome.

For patients with recurrent disease in this setting, various phase I/II agents are generally available.

Response criteria are used to evaluate the efficacy of therapy.

Complete clinical response - More than 90% decrease (sum of the products of the greatest perpendicular



diameters) of the primary tumor and metastatic disease (if any), no new lesions, healing of bone lesions

Partial clinical response - A decrease of 50% or less (sum of the products of the greatest perpendicular

diameters) of the primary tumor and metastatic disease (if any), no new lesions, healing of bone lesions

Minor response - More than 25% and less than 50% decrease (sum of the products of the greatest

perpendicular diameters) of primary tumor and metastatic disease (if any), no new lesions, healing of bone

lesions

No response - Less than 25% decrease (sum of the products of the greatest perpendicular diameters) of

primary tumor or metastatic disease (if any), no new lesions

Progressive disease - More than 25% increase (sum of the products of the greatest perpendicular diameters)

of the primary tumor or all metastatic lesions (if any), appearance of new lesions

Patient Education

For compliance and good medical care, patients and families must understand the importance of treatment and

adverse effects of medications used. In addition, they should learn to recognize and identify signs and symptoms of

complications that require urgent medical care.

Miscellaneous

Medicolegal Pitfalls

Important aspects to consider include the following:

Diagnostic workup: Cancer is rare in children; therefore, if neuroblastoma is suspected, prompt referral to a

pediatric oncology center for multidisciplinary evaluation and appropriate care is essential. Most patients

initially present for evaluation to either the primary care providers or a general surgeon. A surgeon without

expertise in the management of pediatric tumors may attempt to biopsy or resect a mass without the

availability of the necessary resources to obtain and process tumor samples for biologic studies. This

intervention can lead to difficulty in risk-assignment and in administration of appropriate therapy.

Informed consent: Pediatric oncology has benefited from the high level of participation of children in clinical

trials. The pediatric oncologist must be an effective communicator in providing informed consent to patients

and families; a thorough discussion of the potential benefits and risks is warranted. Without compromising the

enthusiasm and desire by the subspecialist to achieve a cure for the patient, families must be made aware

that complications during cancer treatment can result in death or long-term morbidities.

Special Concerns

Drug toxicity

The cornerstone of pediatrics is prevention and treatment of disease to foster the normal growth and development of

children. The use of chemotherapy in infants, children, and adolescents with cancer presents many challenges.

The pediatric oncologist must strive to maintain a balance between administering curative therapy and minimizing

long-term morbidity.

Chemotherapy may have effects on the growth and development of children (eg, when administered to infants,

ototoxicity of cisplatin and carboplatin may affect language development; neurotoxicity of vincristine may interfere with

motor development; refractory nausea and emesis may lead to food aversion). Recognizing these sequelae is

important, so that patients can receive appropriate therapy.

Physiologic processes

Equally important is the understanding that several physiologic processes during infancy and childhood can affect the

pharmacokinetics and pharmacodynamics of drugs. Body composition varies during infancy, childhood, and

adolescence. Total body water and extracellular fluid volumes are larger in the first year of life, and blood volume and

fat composition do not approach adult levels until adolescence. Protein binding is also lower during the first year of

life, therefore increasing the amount of unbound drug. These variables affect the volume of distribution of drugs;

therefore, drug dosages are calculated differently in infants.



Drug doses in pediatric oncology most commonly are calculated using body surface area (BSA). However, because

the BSA is larger in relation to an infant's weight, the use of BSA for dose calculation results in a larger dose per

weight in infants than in older children and adults. As a result, many physicians and clinical protocols dose

chemotherapy in infants on a per kilogram basis rather than by BSA.

Data are lacking concerning the disposition of most antineoplastic agents in young children and infants. However,

guidelines are available for doxorubicin, etoposide, teniposide, and vincristine. The caveat for most of these

recommendations is that only a small number of infants were included in the studies used to formulate these

recommendations. In addition, not all studies included analysis of plasma-binding proteins, unbound drug systemic

clearance, and other relevant factors.

The widespread practice of altering dosing in infants may be unwise because any rational approach should be based

on the pharmacokinetic behavior of each agent. As we learn more about the pharmacokinetics of drugs and their

relationship to efficacy and toxicity, the use of pharmacokinetically guided dosing may become more common.

Because evidence of increased toxicity with vincristine and doxorubicin is lacking, adjustment of dosing based on

weight rather than on BSA is recommended in infants or children younger than 2 years and those with a BSA of less

than 0.5 m2. Drugs that are excreted via the kidney can have limited clearance in young infants because the

percentage of the cardiac output that reaches the kidneys is only 5%, whereas it is 25% in an older child or adult.

Nephrotoxicity

Drugs excreted via the kidney can have limited clearance in young infants because the amount of cardiac output that

reaches the kidneys is only 5%, compared with 25% in an older child or adult.

Ifosfamide can cause renal tubular injury manifested as Fanconi syndrome, metabolic acidosis, hypokalemia,

hypophosphatemia proteinuria, and rickets. The chronic nature of these injuries may interfere with normal growth, and

close follow-up monitoring is required. Age younger than 3 years, presence of a single kidney, and the use of a

cumulative dose of ifosfamide more than 45-72 g/m2 are important risk factors for nephrotoxicity.

The use of ifosfamide in patients with preexisting renal abnormalities is indicated only if potential benefit outweighs

risk of further nephrotoxicity. Although this type of injury appears reversible, its long-term outcome remains unknown.

Cisplatin and, less frequently, carboplatin can cause glomerular injury manifested as acute or chronic decreased

glomerular filtration rate.

Cardiotoxicity

The heart is another organ at risk for early and late toxicity

Anthracyclines have been useful in the treatment of a large number of pediatric cancers. However, the use of

anthracyclines, especially in high cumulative doses, can lead to the development of a cardiomyopathy.

Several studies have suggested that age is an important risk factor for this complication because these drugs appear

to damage cardiac myocytes and limit the heart's ability to grow.

Chemoprotectants and growth factors

Drugs that modify toxicity of antineoplastic agents (ie, mesna, amifostine, leucovorin) and availability of hematopoietic

growth factors (eg, GCSF, granulocyte microphage colony stimulating factor [GMCSF]) have allowed use of

maximally tolerated doses of many chemotherapy agents. These drugs have allowed development of more dose-

intensive protocols.

Future directions in diagnosis and therapy

Discoveries related to the application of gene expression profiling, single nucleotide polymorphisms (SNPs), and

protein arrays leads to a new taxonomy of neuroblastoma.

Understanding the molecular pathophysiology of neuroblastoma and the identification of new markers for the disease



will revolutionize diagnosis, therapy, and, perhaps, prevention.

Discovery of abnormal signal transduction pathways in cancers are identifying new targets for therapy.

Numerous biologic agents are presently in phase 1 or phase 2 trials. These include tubulin binding molecules,

immune stimulators, Trk inhibitors, anti-GD2 antibodies, BCL2 inhibitors, and tyrosine kinase inhibitors.

Antiangiogenesis treatment strategies are also being used to treat recurrent disease.

The design of clinical trials should be based on understanding the biology of the disease (ie, the identification of a

target and use of a target inhibitor that can be assayed in real-time with concomitant evaluation of the efficacy of

targeted therapy on patient outcome).

Multimedia

Media file 1: Histologic subtypes of neuroblastoma. Top right panel, neuroblastoma: A monotonous

population of hyperchromatic cells with scant cytoplasm. Bottom left panel, ganglioneuroblastoma:

Increased schwannian stroma. Bottom right panel, ganglioneuroma: Mature ganglion cell with

schwannian stroma.



Media file 2: CT scan of abdomen in a patient with a retroperitoneal mass arising from the upper pole

of the left kidney and elevated urine catecholamines.



Media file 3: MRI of a left adrenal mass. The mass was revealed by fetal ultrasonography at 30 weeks'

gestation. During infancy, the mass was found on the inferior pole of the left adrenal and was

completely resected. Before surgery, the metastatic workup was negative. Surgical pathology service

confirmed a diagnosis of neuroblastoma. After 3 years of follow-up care, no recurrence was observed.



Media file 4: A one-week-old neonate had abdominal ultrasonography for evaluation of projectile

vomiting. A right adrenal mass (100% cystic) was an incidental finding. Evaluation of the mass by CT

was consistent with an adrenal bleed (3.6 x 3.1 x 2.4 cc). The infant was followed at 2 weeks (2-

dimensional size diminished to 1.5 x. 2.4 cm2 on ultrasonography) and then at 6 weeks to document

that the adrenal bleed continued to involute. Urine catecholamines were normal.



Media file 5: Table. A Consensus Pretreatment Classification schema by the International

Neuroblastoma Risk Group (INRG). This schema is based in the INRG stage, age, histologic category,

tumor grade of differentiation, MYCN sastus, 11q-aberrations and DNA ploidy. A combination of these

characteristics results in four risk groups noted in the last column: very low, low, intermediate and

high risk, with the following 5 year EFS: >85%, >75%-85%, >50%-75%, and <50%. These risk

groups are distributed among the different stages and labeled alphabetically from A to R (without

letters L and M to avoid confusion with the INRG stage notation). Notations in the table are as follow:

L1, localized tumor confined to one body compartment; L2, locoregional tumor with presence of one or

more risk factors defined radiologically; M, distant metastatic disease (except stage MS); MS,

metastatic disease confined to skin, liver and/or bone marrow in children <18 months of age. GN,

ganglioneuroma; GNB, ganglioneuroblastoma; Amp, amplified; n/amp, not amplified. (Adapted from

The International Neuroblastoma Risk Group (INRG) Classifications System: An INRG Task Force

Report by Cohn, et al. Journal of Clinical Oncology 27(2):289-297, 2009).

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Keywords

neuroblastoma, cancer, tumor, malignancy, neuroblasts, ganglioneuroblastoma, ganglioneuroma, hypertension,

periorbital ecchymosis, thoracic neuroblastoma, cervical neuroblastoma, Horner syndrome, rubella, stem cell

transplantation, blueberry muffin baby, treatment, diagnosis

Contributor Information and Disclosures

Author

Norman J Lacayo, MD, Assistant Professor, Department of Pediatrics, Division of Hematology-Oncology, Stanford

University and Lucile Salter Packard Children's Hospital

Norman J Lacayo, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of

Hematology, and Children's Oncology Group

Disclosure: Nothing to disclose.

Coauthor(s)

Kara L Davis, DO, Fellow, Department of Pediatric Hematology/Oncology, Stanford University School of Medicine



Kara L Davis, DO is a member of the following medical societies: American Society of Hematology


Medical Editor

Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology,

Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania

Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer

Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American

Society of Pediatric Hematology/Oncology, and Society for Pediatric Research


Pharmacy Editor

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of

Pharmacy; Pharmacy Editor, eMedicine


Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology,

Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of

Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's

Oncology Group, and International Society for Experimental Hematology


CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of

Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada

Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of

Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of

Physicians and Surgeons of Canada


Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and

Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's

National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer

Research, American Society of Pediatric Hematology/Oncology, Idaho Medical Association, and Society for Pediatric

Research


Further Reading

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