Neuroblastoma 

Updated: Jul 12, 2017
Author: Byron D Joyner, MD, MPA; Chief Editor: Brian H Kopell, MD 

Overview

Practice Essentials

Neuroblastoma is a poorly differentiated neoplasm derived from neural crest cells that typically affects infants and children younger than 5 years of age. The highest rate of diagnosis in the first month of life.[1]

Neuroblastomas originate in the adrenal medulla and paraspinal or periaortic regions.[1] The presentation varies according to the site of origin, but 65% of primary neuroblastomas occur in the abdomen—40% in the adrenal gland—so most children present with abdominal symptoms, such as fullness or distension.

Stages I and II neuroblastoma is managed surgically. Multiple-agent chemotherapy is the conventional therapy for patients with more advanced stages of neuroblastoma.

Background

Neuroblastoma is the most common intra-abdominal malignancy of infancy, the most common cancer in infancy, and the most common extracranial solid tumor of childhood, with an incidence of over 700 cases in the United States every year.[2, 3] Neuroblastoma is the third most common malignancy in children up through 14 years of age, behind acute lymphocytic leukemia and cancers of the brain and central nervous system.[2] It accounts for 7% of pediatric malignancies but for more than 10% of childhood cancer-related mortality.[4]

Neuroblastoma is one of the small, blue, round cell tumors of childhood. Other such tumors include the following:

History of the Procedure

Virchow first described neuroblastoma in 1864; at that time, it was referred to as a glioma.[5] In 1891, Marchand histologically linked neuroblastoma to sympathetic ganglia.[6] More substantial evidence of the neural origins of neuroblastoma became apparent in 1914, when Herxheimer showed that fibrils of the tumor stained positively with special neural silver stains.[7]

In 1927, Cushing and Wolbach further characterized neuroblastoma by describing the transformation of malignant neuroblastoma into its benign counterpart, ganglioneuroma.[8] Everson and Cole reported that this type of transformation is rare in children older than 6 months.[9] In 1957, Mason published a report of a child with neuroblastoma whose urine contained pressor amines.[10] This discovery further contributed to the understanding of neuroblastoma and its possible sympathetic neural origin.

Spontaneous regression of microscopic clusters of neuroblastoma cells, called neuroblastoma in situ, was noted to occur quite commonly. According to Beckwith and Perrin in 1963, regression occurs nearly 40 times more often than clinically apparent neuroblastoma.[11]

Problem

Neuroblastoma is a malignant neural tumor that typically affects very young children. Its presentation varies, depending on the primary site of origin, metastatic burden, and metabolically active by-products. It is remarkable in that it has a documented spontaneous rate of resolution and is also one of the few tumors in which the surgical capsule can be violated and a good outcome might be achieved, even if residual tumor is left behind.

Epidemiology

Frequency

Clinical frequency is approximately one case per 8000-10,000 children. The American Cancer Society estimates that neuroblastoma will make up 6% of the estimated 10,270 new cancer cases that will be diagnosed in children from birth to 14 years of age in the United States in 2017.[2]

Neuroblastoma is more common in whites and is slightly more prevalent in boys than in girls (male-to-female ratio of 1.3:1). The typical age at diagnosis is younger than that for Wilms tumor. More than one third of cases (36%) are diagnosed in children younger than 1 year. Seventy-nine percent of cases are diagnosed are children younger than 4 years, and 97% are diagnosed by age 10 years. Neuroblastoma is thought to occur sporadically, with 1-2% of cases thought to be familial.

Etiology

The actual etiology of the tumor is obscure. Environmental and paternal exposures linked to neuroblastoma have not been identified.

Embryologically, tumors of the sympathetic nervous system differentiate along two distinct pathways, either the pheochromocytoma line or the sympathoblastoma line.[12] The sympathoblastomas, also called neurocristopathies, include the well-differentiated ganglioneuroma, the moderately differentiated ganglioneuroblastoma, and the malignant neuroblastoma. All of these tumors arise from primordial neural crest cells, which ultimately populate the sympathetic chain and the adrenal medulla.[13]  

Pathophysiology

According to Knudson and Strong (1972), 20% of neuroblastomas are inherited in an autosomal dominant pattern.[12] Twenty percent of this cohort has bilateral or multifocal primary tumors. Various karyotypic abnormalities occur, but a deletion of the short arm of chromosome 1 is found in 70-80% of all patients with neuroblastomas.

Malignant transformation and maintenance of the dedifferentiated state of neural crest cells may result from failure of those cells to respond to normal signals that are responsible for normal morphologic differentiation. The factors involved in the cascade of events are poorly understood but most likely involve one or more ligand-receptor pathways. One of the most studied and most popular pathways is the nerve growth factor (NGF) and its receptor (NGFR). The dedifferentiated state of neuroblastoma leads to the variable presentations commonly observed in patients with neuroblastoma.

Presentation

Neuroblastoma has been called the great mimicker because of its myriad clinical presentations related to the site of the primary tumor, metastatic disease, and its metabolic tumor by-products. Sixty-five percent of primary neuroblastomas occur in the abdomen, with most of these occurring in the adrenal gland. As a result, most children present with abdominal symptoms, such as fullness or distension.

Obtaining a complete history and physical examination are paramount to an accurate diagnosis and subsequent management of neuroblastoma. Eliciting a history of the child's general appearance, recent trauma, changes in appetite and weight, and recurrent abdominal pain is important. Symptoms are usually related to either an abdominal mass or bone pain secondary to metastatic neuroblastoma. Reports of fatigue, bone pain, and changes in bowel or bladder habits may contribute to an accurate diagnosis. Physical findings might include hepatomegaly; blanching subcutaneous nodules; or a large, irregular, firm abdominal mass.

Typically, children with localized disease are asymptomatic, whereas children with disseminated neuroblastoma are generally sick and may have systemic manifestations, including unexplained fevers, weight loss, anorexia, failure to thrive, general malaise, irritability, and bone pain. The most common finding upon physical examination is a nontender, firm, irregular abdominal mass that crosses the midline. In contrast, children who present with Wilms tumor have a smooth mobile flank mass that typically does not cross the midline.

At diagnosis, the site of neuroblastoma is predictably age-dependent. Infants often present with compression of the sympathetic ganglia in the thoracic region, which might result, for example, in Horner syndrome (myosis, anhydrosis, and ptosis) or superior vena cava syndrome. Older children typically present with abdominal symptoms because, as stated above, more than 40% of neuroblastomas are adrenal in origin. Children who are preschool aged should have working differential diagnoses for an abdominal mass, including lymphoma, hepatoblastoma, rhabdomyosarcoma, renal cell carcinoma, and neuroblastoma.

More than 50% of patients who present with neuroblastoma have metastatic disease. The fact that many other syndromes related to metastatic neuroblastoma are also common in these patients is not surprising.

For example, Pepper syndrome occurs in infants with overwhelming metastatic neuroblastoma of the liver that results in respiratory compromise. Described by William Pepper in 1901, Pepper syndrome was identified as a localized primary tumor and metastatic disease limited to the skin, liver, and bone marrow in infants. Pepper syndrome has since been associated with stage 4S neuroblastoma, a unique entity that occurs only in infants younger than 1 year. Pepper syndrome generally confers a better prognosis, as it is associated with spontaneous regression. Some infants with stage 4S neuroblastoma, however, die of massive hepatomegaly, respiratory failure, and overwhelming sepsis.

"Blueberry muffin" babies are infants in whom neuroblastoma has metastasized to random subcutaneous sites. When provoked, the nodules become intensely red and subsequently blanch for several minutes thereafter. The response is probably secondary to the release of vasoconstrictive metabolic tumor by-products. These nodules can be diagnostic of neuroblastoma, but leukemic infiltrates that metastasize to the skin should be considered in the differential diagnoses when these children are evaluated.

Widespread metastasis of neuroblastoma to the bone may result in Hutchinson syndrome, which results in bone pain with consequent limping and pathologic fractures. Neuroblastomas that arise in the paraspinal ganglia may invade through the neural foramina, compress the spinal cord, and subsequently cause paralysis.

Infrequently, neuroblastoma can become metastatic to the retrobulbar region, leading to rapidly progressive, unilateral, painless proptosis; periorbital edema; and ecchymosis of the upper lid. This lesion often can be confused with trauma or child abuse. See the image below.

Upper periorbital edema, proptosis, and ocular ecc Upper periorbital edema, proptosis, and ocular ecchymosis in a 9-month-old girl.

Most neuroblastomas produce catecholamines as metabolic by-products, which result in some of the most interesting presentations observed in children with neuroblastoma. For example, Kerner-Morrison syndrome causes intractable secretory diarrhea, resulting in hypovolemia, hypokalemia, and prostration. This syndrome is caused by vasoactive intestinal peptide (VIP) tumor secretion and is more commonly associated with ganglioneuroblastoma or ganglioneuroma. Kerner-Morrison syndrome typically resolves following the complete removal of the tumor.

A wide variety of neoplastic and nonneoplastic lesions might be confused with neuroblastoma. Wilms tumor and lymphoma are 2 malignant lesions that might be mistaken for neuroblastoma. The nonneoplastic lesions are particularly confusing, especially in the 5-11% of neuroblastomas that do not produce catecholamine metabolic by-products. Nonmalignant lesions that might be confused with neuroblastoma include ganglioneuroma and congenital mesoblastic nephroma.

Indications

In 1988, the Pediatric Oncology Group (POG) released a prospective study showing that patients with localized neuroblastoma who were treated by surgical extirpation had a 2-year disease-free survival rate of 89%.[14] Additionally, chemotherapy appeared to offer no advantage when residual disease was present in these patients. Thus, in patients with low-stage favorable disease, surgery is the mainstay of therapy. The primary goals of surgery are as follows:

  1. To determine an accurate diagnosis
  2. To completely remove all of the primary tumor
  3. To provide accurate surgical staging
  4. To offer adjuvant therapy for delayed primary surgery
  5. To remove residual disease with second-look surgery

Relevant Anatomy

During the fifth week of embryogenesis, primitive sympathetic neuroblasts migrate from the neural crest to the site where the adrenal anlage eventuates into the developing embryo. These neuroblasts migrate along the entire sympathetic chain; therefore, neuroblastoma can arise anywhere along the sympathetic nervous system. The name neuroblastoma is derived from the fact that the cells resemble primitive neuroblasts.

Contraindications

High-stage neuroblastoma cannot be managed surgically; therefore, surgery is contraindicated in this setting.

 

Workup

Laboratory Studies

General laboratory studies should be routinely obtained in children suspected of having neuroblastoma. Results are as follows:

  • A complete blood cell count (CBC) should be obtained to determine if the child has anemia, which typically does not occur until the tumor has become widely disseminated; in patients with overwhelming bone marrow involvement, thrombocytopenia may also be present

  • Once dissemination occurs, abnormalities in findings of coagulation studies (prothrombin time [PT], activated partial thromboplastin time [aPTT]) may occur secondary to liver involvement

  • The erythrocyte sedimentation rate, a nonspecific acute-phase reactant, is elevated in classic neuroblastoma

Elevated metabolic catecholamine by-products can be detected in the urine of patients with neuroblastoma. The presence of these by-products serves as useful inclusion criteria when the diagnosis of neuroblastoma is being considered.

Phenylalanine and tyrosine are catecholamine precursors, which are converted through a sequence of enzymatic events to dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, and epinephrine. DOPA and dopamine are metabolized into their final product, homovanillic acid (HVA), while norepinephrine and epinephrine are metabolized into vanillylmandelic acid (VMA).

Ninety percent of neuroblastoma tumors secrete these by-products. This fact becomes clinically relevant because children with dedifferentiated tumors excrete higher levels of HVA than VMA. This occurs because dedifferentiated tumors have lost the final enzymatic pathway that converts HVA to VMA. A low VMA-to-HVA ratio is consistent with a poorly differentiated tumor and indicative of a poor prognosis.

Neuroblastoma cells lack the enzyme that converts norepinephrine to epinephrine. Despite this fact, elevated levels of norepinephrine are not identified in the serum of patients with neuroblastoma. This might be explained by at least two processes: (1) norepinephrine may be catabolized within the tumor; and/or (2) tyrosine hydrolase, the initial enzyme in catecholamine synthesis, is subject to a negative feedback loop by norepinephrine.

A LaBrosse VMA spot test may be used to screen patients in certain institutions. It is economical but has low sensitivity and specificity.

High-performance liquid chromatography has a much lower false-positive rate and is more sensitive than the LaBrosse VMA spot test, but it is more expensive and is therefore often used only to confirm a positive result on a spot test.

Nonspecific tumor markers can be identified in patients with neuroblastoma.[15] Neuron-specific enolase (NSE), lactic dehydrogenase (LDH), and ferritin are markers useful in the identification of active disease, as well as in prognostication. Approximately 96% of patients with metastatic neuroblastomas demonstrate an elevated NSE level, which has been associated with a poor prognosis.

Imaging Studies

Radiographic assessment is recommended in all infants and children with an abdominal mass. The standard diagnostic imaging modalities include the following:

  • Plain abdominal radiography (kidneys, ureters, bladder [KUB])

  • Renal/bladder ultrasonography

  • Bone scintigraphy

  • Computed tomography (CT) or magnetic resonance imaging (MRI)

KUB most commonly reveals finely stippled calcifications of the abdomen or posterior mediastinum.

Renal/bladder ultrasonography improves the diagnostic evaluation and is probably the single best imaging modality to obtain. Ultrasonography is noninvasive and provides relevant information regarding the laterality, consistency, and size of the mass.

Abdominal CT scanning or MRI usually follows ultrasonography. Both of these studies are more invasive, in that they require general sedation for young children. The benefit is that they enhance the ultrasonographic findings by providing information about regional lymph nodes, vessel invasion, and distant metastatic disease. See the images below.

CT scan in a 2-week-old boy noted to have an abdom CT scan in a 2-week-old boy noted to have an abdominal mass on a prenatal sonogram. This postnatal abdominal CT scan revealed a left suprarenal mass with mass effect of the spleen.
Abdominal CT scan in a 2-week-old boy noted to hav Abdominal CT scan in a 2-week-old boy noted to have an abdominal mass on a prenatal sonogram. A postnatal abdominal CT scan revealed a left suprarenal mass with mass effect of the spleen (see the previous image). This abdominal CT scan represents a more caudal view. Note the very large left mass with central necrosis. The mass effect of the spleen is apparent.
A 2-week-old boy is noted to have an abdominal mas A 2-week-old boy is noted to have an abdominal mass on prenatal ultrasound. A postnatal abdominal CT scan revealed a left suprarenal mass with mass effect of the spleen (see the first image above). A more caudal view revealed the very large left mass with central necrosis (see the second image above). This is a more caudal view of the CT scan than in the previous 2 images. The left kidney comes into view, as it is inferiorly displaced and laterally rotated by the large superior neuroblastoma.
Bulky lymph nodes just medial to the left kidney. Bulky lymph nodes just medial to the left kidney.

Bone scintigraphy and a skeletal survey to detect cortical bone disease are helpful in the diagnosis of neuroblastoma. Metaiodobenzylguanidine (MIBG) is a compound taken up by catecholaminergic cells that competes for uptake even in neuroblastoma cells. In this way, MIBG is quite sensitive and specific in the detection of metastasis to bones and soft tissue, with highest sensitivity (91-97%) in the detection of bone deposits.

Bone scintigraphy using 99Tc diphosphonate and a skeletal bone survey to detect cortical bone disease are essential if MIBG scintigraphy results are negative in the bone. MIBG is recommended for re-assessment both during and after therapy in high-risk patients with MIBG-avid disease at diagnosis.

Expression of somatostatin (SS) receptors has been described in neuroblastoma cell lines and tumors. Studies have shown that these tumors can be successfully targeted with radioactive SS analogs as a method of detection. Currently, the indication for scanning with radio-labeled SS analog in children with neuroblastoma is not well-defined because this method is less sensitive than MIBG scanning (64% vs 94%). However, because the presence of neuroblastoma SS receptors is associated with favorable clinical and biological prognostic factors, radio-labeled SS analog could provide valuable information. In fact, improved survival has been found in patients with SS receptor–positive neuroblastoma. However, more studies need to be performed to confirm the benefits of SS receptor scanning.

Diagnostic Procedures

Biopsy is the sine qua non in the diagnostic evaluation of neuroblastoma. To confirm the diagnosis of neuroblastoma, histologic evidence of neural origin or differentiation is required. Samples of tumor tissue can be viewed via light or electron microscopy or via immunohistochemistry. Although open surgical biopsy has traditionally been advocated, Mullassery and colleagues reported that image-guided needle biopsy can also yield adequate tissue samples.[16]

Another option is to sample bone marrow, a frequent metastatic site for neuroblastoma. The literature is confusing in terms of the number of bone marrow aspirates or biopsies needed to diagnose neuroblastoma. An international committee on neuroblastoma staging has recommended obtaining two bone marrow aspirates and two biopsies, one from each posterior iliac crest.

The issue of biopsies might become obsolete because immunocytology of marrow aspirates may offer the single best source of diagnostic information. Recently, a large body of published work has addressed the use of immunocytochemical and polymerase chain reaction (PCR)–based technologies to detect neuroblastoma cells and neuroblastoma-specific transcripts such as tyrosine hydroxylase and disialoganglioside (GD2) synthase in marrow or blood samples. This method is used to assess minimal disease during the course of treatment. Although these techniques can greatly increase sensitivity, whether this increased sensitivity provides prognostic information about the likelihood of relapse is still unclear.

Histologic Findings

The three distinct histologic patterns of the neurocristopathies include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. They represent a spectrum of maturation and dedifferentiation. The typical neuroblastoma is characterized by small uniform cells that contain dense hyperchromatic nuclei and scant cytoplasm. A neuritic process called neuropil is pathognomonic of all except the most primitive neuroblastoma. Homer-Wright pseudorosettes are clusters of neuroblasts surrounding areas of eosinophilic neuropil and are observed in 15-50% of patients. If identified, they are diagnostic of neuroblastoma.

The minimal diagnostic criteria for diagnosing neuroblastoma have been established by an international group of conferees and corresponding participants. These criteria include (1) unequivocal pathologic diagnosis or (2) unequivocal bone marrow (syncytia) and elevated levels of urinary catecholamine metabolic by-products. Both of these diagnostic criteria require a histopathologic diagnosis.

Molecular pathogenesis

The cancer genes most commonly altered in adult carcinogenesis (eg, TP53, CDKN2A, ras) are rarely aberrant in neuroblastoma. TP53 -inactivating mutations are uncommon in primary tumors due to neuroblastoma, although they have been documented in cell lines among patients with relapsing neuroblastoma. Thus, with the exception of N-myc, major pathways of human neoplasia do not seem to be deregulated. Indeed, the only reliable genetically engineered murine model of neuroblastoma results from targeted overexpression of human N-myc cDNA to the murine neural crest.

Activating mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) gene occur in the majority of hereditary neuroblastoma cases, and also in some sporadic cases of advanced neuroblastoma. Subclonal ALK mutations can be present at diagnosis, with subsequent clonal expansion at relapse[17]

Staging

At least six different staging systems for neuroblastoma exist. Historically, each staging system represents a temporal improvement in the understanding of the tumor. However, the presence of so many systems has not only confounded the literature but also complicated the comparison of studies between institutions. Twenty years ago, the International Neuroblastoma Staging System (INSS) was established to provide a uniform staging system.

The INSS is a clinical, radiographic, and surgical appraisal of children with neuroblastoma. The system combines many of the most important diagnostic criteria from each of the staging systems and includes initial distribution and surgical resectability of the tumor.

Specific requirements to stage neuroblastoma include the following:

  • Bone marrow aspirates and biopsy samples

  • Body CT scan (excluding head, if not clinically indicated)

  • Bone scan

  • MIBG scintigraphy

Arabic numerals are used to distinguish INSS staging from other systems. INSS stages are as follows:

  • Stage 1 is characterized by a localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes that test negative for tumor are present microscopically (nodes attached to and removed with the primary tumor may test positive)

  • Stage 2A is characterized by a localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes that test negative for tumor are present microscopically

  • Stage 2B is characterized by a localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes that test positive for tumor; enlarged contralateral lymph nodes must test negative microscopically

  • Stage 3 is an unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; a localized unilateral tumor with contralateral regional lymph node involvement; or a midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement (the midline is defined as the vertebral column; tumors that originate on one side and cross the midline must infiltrate to or beyond the opposite side of the vertebral column)

  • Stage 4 is any primary tumor disseminated to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S)

  • Stage 4S (S = special) occurs in infants younger than 12 months and is characterized by a localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow

Other features of stage 4S include the following:

  • Marrow involvement should be minimal (ie, < 10% of total nucleated cells identified as malignant via bone biopsy or bone marrow aspirate); more extensive bone marrow involvement is considered stage 4 disease

  • The results of the MIBG scan (if performed) should be negative for disease in the bone marrow.

Stage 4S is the most unusual group, comprising approximately 5% of patients with neuroblastoma. All else being equal, these children would normally be classified as having stage 1 or 2 disease; however, disease in this special group of infants almost always spontaneously regresses. Nonetheless, infants younger than 2 months frequently develop extensive and rapidly progressive intrahepatic expansion of neuroblastoma that can result in respiratory compromise. The 5-year survival rate in patients with stage 4S disease is 75%.

Stage for stage, infants with neuroblastoma have a better prognosis than older children. In fact, statistically, age is the most significant clinical prognosticator for neuroblastoma. Forty percent of infants (< 1 y) have localized neuroblastoma, compared with 20% of children older than 1 year. Additionally, nearly 70% of children older than 1 year have disseminated neuroblastoma, compared with less than 25% of infants.

Risk Groups

The Children’s Oncology Group (COG) uses the major prognostic factors to place children into three risk groups: low, intermediate, and high.[18] These risk groups are used to guide treatment selection. Five-year survival rates by risk group are as follows:

  • Low risk: > 95%

  • Intermediate risk: Approximately 90-95%

  • High risk: Approximately 40-50%

Low-risk group criteria are as follows:

  • Stage 1 disease

  • Stage 2A or 2B disease, patient age younger than 12 months

  • Stage 2A or 2B disease, patient age older than 12 months, no extra copies of the MYCN gene

  • Stage 4S disease, favorable histology, hyperdiploid, no extra copies of MYCN

Intermediate-risk group criteria are as follows:

  • Stage 3 disease, patient age younger than 12 months; no extra copies of MYCN

  • Stage 3 disease, patient age older than 12 months, no extra copies of MYCN, favorable histology

  • Stage 4 disease, patient age younger than 12 months, no extra copies of MYCN

  • Stage 4S disease, no extra copies of MYCN, normal DNA ploidy, and/or unfavorable histology

High-risk group criteria are as follows:

  • Stage 2A or 2B disease, patient age older than 12 months, extra copies of MYCN

  • Stage 3 disease, patient age younger than 12 months, extra copies of MYCN

  • Stage 3 disease, patient age older than 12 months, extra copies of MYCN

  • Stage 3 disease, patient age older than 18 months, unfavorable histology

  • Stage 4 disease, extra copies of MYCN

  • Stage 4 disease, patient age older than 18 months

  • Stage 4 disease, patient age between 12 and 18 months, extra copies of MYCN, unfavorable histology, and/or normal DNA ploidy (DNA index of 1)

  • Stage 4S disease, extra copies of MYCN

 

Treatment

Medical Therapy

Because surgery is used to manage only low-stage (stages I and II) neuroblastoma, multiple-agent chemotherapy is the conventional therapy for patients with more advanced stages of neuroblastoma. Interestingly, infants with disseminated neuroblastoma have favorable outcomes with combined chemotherapy and surgery. In contrast, children older than 1 year with high-stage neuroblastoma have very poor survival rates despite intensive multimodal therapy.[19]

Because of these findings, pioneering work in Japan during the 1980s claimed that aggressive screening of infants younger than 6 months with urinary catecholamines could detect neuroblastoma earlier and lead to better outcomes. However, follow-up population-based, controlled trials in Europe and North America did not confirm the benefit of early screening reported in the Japanese studies.

Despite these contradictory findings, symptomatic treatments are available for patients with neuroblastoma. Adrenocortical hormone (ACTH) is thought to be fairly efficacious, although some cases are resistant. Plasmapheresis and gamma globulin have been used in the treatment of selected patients with neuroblastoma, but chemotherapeutic agents are thought to result in better neurological outcomes.

Commonly used chemotherapeutic agents include cisplatin, doxorubicin, cyclophosphamide, and the epipodophyllotoxins (teniposide and etoposide). Drug combination protocols have used strategies that take advantage of drug synergism, mechanisms of toxicity, and differences of adverse effects.

A randomized, multi-arm, open-label, phase 3 trial in children with high-risk neuroblastoma who had an adequate response to induction treatment found that busulfan plus melphalan improved event-free survival and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. The 3-year event-free survival was 50% (95% confidence index [CI] 45-56%) with busulfan plus melphalan versus 38% (95% CI, 32-43%; p=0·0005) with carboplatin, etoposide, and melphalan. The researchers concluded that busulfan and melphalan should be considered standard high-dose chemotherapy.[20]

Despite these various drug combinations, the cure rate has not been significantly affected. The long-term survival in patients with metastatic neuroblastoma is poor, perhaps because of the abundance of nonproliferating tumor cells. However, chemotherapeutic agents used to manage neuroblastoma have reduced the size of the primary tumor,occasionally sterilized the bone marrow, and, rarely, transformed the neuroblastoma into benign ganglioneuroma.

Current trends in chemotherapy for the management of neuroblastoma include (1) more dose-intensive chemotherapy with secondary surgical extirpation, (2) myeloablative therapy using escalating chemotherapeutic combinations followed by autologous bone marrow infusion, and (3) biologic response modifiers that cause tumor differentiation and a reduction in tumor involvement of the bone marrow. Some of these seminal chemotherapeutic trials have demonstrated promising results. Multimodal therapeutic protocols established by the POG are the standard of care in children diagnosed with neuroblastoma.

Topotecan, a topoisomerase I inhibitor, alone or in combination with cyclophosphamide, has been shown to have activity against recurrent neuroblastoma. This information has led to a Children's Oncology Group (COG) pilot study designed to test the clinical efficacy of incorporating topotecan into an intensive induction regimen in patients with newly diagnosed, high-risk neuroblastoma.

Retinoids, natural and synthetic derivatives of vitamin A, have been shown in vitro to down-regulate N-myc mRNA expression, which arrests tumor cell proliferation. These observations have led to clinical trials designed to test the efficacy of 13-cis-retinoic acid (RA) in children with relapsed neuroblastoma. In phase I and II trials, results were disappointing in patients with a high tumor burden; however, in patients with minimal disease, randomized phase III trials involving 13-cis RA resulted in improved survival rates.

In 2015, the US Food and Drug Administration (FDA) approved dinutuximab (Unituxin), which is a monoclonal antibody against GD2, for use in the treatment of pediatric patients with high-risk neuroblastoma. It was approved for use as part of a multimodality regimen that includes surgery, chemotherapy, and radiation therapy, in patients who have achieved at least a partial response to prior first-line multiagent treatment. Dinutuximab is indicated in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and RA. Improvement in both event-free survival and overall survival has been shown to be significant.[21]

Other immunotherapies that have shown promising results against neuroblastoma include the following:

  • Cytotoxic T lymphocytes
  • Modified dendritic cells
  • Recombinant IC-2

Because recurrent neuroblastoma is often a radiation-sensitive systemic disease, interest has arisen in use of radioactive molecules that are selectively concentrated in neuroblastoma cells. Clinical trials are under way in Europe and North America to delineate the efficacy of radio-labeled MIBG, with and without combined myeloablative chemotherapy followed by autologous stem cell rescue. Determining the optimal doses, schedules, and timing of MIBG therapy are the goals of these clinical trials. A recent study from 2005 showed a response rate of approximately 40% in heavily pretreated patients; however, MIBG therapy does not seem to have an independent advantage. A further multimodal therapy trial (NB2004) is currently underway.

Antiangiogenesis therapy has more than a theoretical role in the treatment of neuroblastoma. In fact, preclinical studies have demonstrated that these agents inhibit neuroblastoma growth in vivo, especially in minimal residual disease states. Phase I protocols testing angiogenesis inhibitors are in progress to determine if highly vascular neuroblastoma tumors respond to these agents.

In vitro cultures demonstrate that neuroblastoma is radiosensitive, but results from clinical trials have been inconsistent and inconclusive. As a primary treatment modality, radiation therapy has a limited yet well-defined role.[22] It can be used in regional lymph node metastases with sequential cyclophosphamide therapy, in infants with stage-4 disease who have Pepper syndrome (to control respiratory compromise), and in total-body irradiation (TBI) combined with autologous bone marrow transplantation (ABMT).

Surgical Therapy

In 1988, the Pediatric Oncology Group released a prospective study showing that patients with localized neuroblastoma who were treated by surgical extirpation had a 2-year disease-free survival rate of 89%.[14] Additionally, chemotherapy appeared to offer no advantage in patients with residual disease. Thus, in patients with low-stage favorable disease, surgery is the mainstay of therapy. The primary goals of surgery are (1) to determine an accurate diagnosis, (2) to completely remove all of the primary tumor, (3) to provide accurate surgical staging, (4) to offer adjuvant therapy for delayed primary surgery, and (5) to remove residual disease with second-look surgery.

Neuroblastoma metastatic to the paraspinal region may extend through the vertebral foramina and may manifest as cord compression. This occurs in 7-15% of patients with neuroblastoma. Cord compression is a medical emergency and should be treated aggressively to reduce the risk of neurological deficit. Unfortunately, the optimal treatment has yet to be determined for cord compression secondary to metastatic neuroblastoma.

Options to relieve cord compression in these situations include surgical resection with or without laminectomy, multimodal chemotherapy, and external beam radiation therapy. In a retrospective review of the POG experience, chemotherapy and laminectomy were associated with similar rates of neurological recovery, although laminectomy was associated with more orthopedic morbidity. Given these results, a conservative, primary medical approach might be the best initial therapy, with laminectomy reserved for patients who do not respond to chemotherapy.

Opsoclonus-myoclonus syndrome (OMS) is thought to be immune-mediated because 60% of patients who develop this in association with neuroblastoma respond to adrenocorticotropic hormone or corticosteroids. Treatment of OMS has been studied more recently given the fact that long-term outcomes have been shown to result in recurrent neurological symptoms, developmental delay, and mental retardation. Improved long-term results have been demonstrated in patients with neuroblastoma who develop OMS when they are treated with multimodal chemotherapy. Petruzzi et al have reported positive results when these patients are treated with intravenous gamma globulin.

Neuroblastoma continues to be one of the most frustrating childhood tumors to manage. Although the tumor has been studied extensively and great efforts have been made to secure appropriate therapy and achieve a cure, little has altered the prognosis in affected children over the past 20 years. Additionally, some pediatric retroperitoneal tumors cannot be determined accurately before surgery. Therefore, surgeons who treat these children must be conversant with current staging systems and treatment modalities.

Preoperative Details

An adequate history and physical examination are essential to the preoperative screening in a child being evaluated for neuroblastoma. All radiographic studies (chest radiography, bone scanning, CT scanning, MRI) should be reviewed. Serum chemistries and a CBC count are essential. Additional blood studies include a VMA-to-HVA ratio, serum ferritin, and NSE. Other studies specific to the child being evaluated include obtaining bone marrow aspirate and biopsy specimens, N-myc oncogene copy number of tumor, and chromosome studies or transketolase (TRK) analysis.[23]

A general bowel preparation and a third-generation cephalosporin are used, depending on the clinical stage of the tumor.

All children with suspected neuroblastoma should undergo anesthetic evaluation. However, unlike in pheochromocytoma (in which the anesthetic choice is crucial), neuroblastoma does not require a specific anesthetic protocol. In patients with large or complicated tumors, an ICU bed should be obtained for postoperative management.

Intraoperative Details

Adequate exposure in the child with neuroblastoma is paramount. In order to achieve this goal, the surgeon must adhere to a number of principles. The patient should be in the supine position, with all pressure points padded. Excellent light sources should be available, including main operating room (OR) lights, overhanging OR lights, and individual head lights, as needed. Various surgical incisions are available, and any surgeon operating on an adrenal mass should be familiar with them prior to surgery. Finally, the surgeon should be intimately familiar with the anatomy of the adrenal gland, surrounding organs, and their respective blood supplies.

The type of incision is partially dictated by the mass and certainly is at the discretion of the operating surgeon. For most abdominal neuroblastomas, a midline transperitoneal incision provides excellent exposure to the peritoneal cavity, retroperitoneum, and, specifically, the ipsilateral suprarenal area. Other incisions for this particular surgery include an upper transverse abdominal incision or a chevron incision for tumors that involve the upper abdomen and retroperitoneum.

Knowledge of the metastatic properties unique to neuroblastoma helps to understand the protocol for safe abdominal exploration and extirpation. The viscera are reflected to the midline and secured in an intestinal bag. The abdomen and retroperitoneum are explored. Careful attention must be given to the anatomical relationships of the tumor to the surrounding structures because this dictates the possible extirpative field. To complete the protocol, regional lymph nodes are evaluated, and a biopsy specimen is obtained from the liver.

Surgical management is dictated by the staging laparotomy. If the tumor cannot be removed primarily, a wedge biopsy of the tumor may be performed for histopathology, immunohistochemistry, and genetic studies. Proper surgical techniques are used to prevent excessive bleeding and tumor spillage.

If the staging laparotomy reveals that primary resection of the tumor is tenable, attention is turned to removal of the tumor. Neuroblastoma is known to invade the tunica adventitia of large blood vessels; therefore, the surgeon should have a vascular set and take precautions to obtain distal and proximal control of the major blood vessels. A preoperative consultation with a vascular specialist should be considered for large tumors.

Access to the tumor is gained by starting in a distal subadventitial plane and dissecting proximally. In this plane, the anterior abdominal aorta, inferior and superior mesenteric arteries, and celiac arteries are identified, isolated, and preserved (as much as possible). In cases in which the renal hilum is involved with tumor, an ipsilateral nephrectomy is performed. Other attachments to the tumor are released and the tumor can be delivered to the surface.

Proper surgical principles and techniques are critical; otherwise, the risk of morbidity and mortality is high.

Postoperative Details

Postoperative treatment in a child who has undergone a major abdominal exploration and extirpation is dictated, in part, by the extent of resection, duration of surgery, and possible intraoperative complications. The most common complication associated with the removal of a neuroblastoma is related to vascular injury. Hypotension may lead to acute renal failure and an ischemic bowel, which must be addressed appropriately in an intensive care setting.

Follow-up

As stated above, surgery plays a major role in children with low-stage disease and a controversial role in children with advanced disease, especially as it applies to the extent of surgical resection. A multimodal approach is suggested for the management of children with advanced neuroblastoma. Multiple-agent chemotherapy has increased the 5-year survival rate to 75% in patients younger than 1 year. Radiation therapy recently has been shown to produce superior initial and long-term disease control when administered synergistically with chemotherapy. In any event, follow-up of these patients follows a clear POG protocol.

Complications

Surgical complication rates in patients with neuroblastoma range from 5-25%, depending on the stage of the tumor. More aggressive primary abdominal extirpations carry the highest complication rate. Incidental nephrectomy or splenectomy, operative hemorrhage, postoperative intussusception, and injury to major vessels or nerves are some of the more common complications associated with high-stage tumors. Infants with neuroblastoma enjoy a significant survival advantage over all other age groups. Aggressive treatment in these children is therefore warranted only when they have complications related to tumor burden (as in Pepper syndrome), coagulopathy, and renal compromise.

Intensive multimodal treatment in patients with neuroblastoma has resulted in improved survival rates. However, the late effects, which can have diverse and devastating manifestations, should be considered. Cancer survivors should be monitored closely in multidisciplinary clinics, with emphasis on long-term sequelae. Surgery and radiation therapy can result in many late orthopedic effects, such as scoliosis, osteoporosis, and hypoplasia of bony and soft tissue structures. Chemotherapeutic regimens used to treat neuroblastoma may result in long-term toxicities, including cardiopulmonary toxicities (anthracyclines), ototoxicity (cisplatin), renal failure (ifosfamide and cisplatin), infertility and impotency (alkylating agents and radiation therapy), secondary cancers, and psychological effects.

Outcome and Prognosis

For more than 40 years, the age at diagnosis and the stage have been the dominant independent variables used as prognosticators in children with neuroblastoma. In 1984, Shimada classified neuroblastoma, relating its histopathologic features to its clinical behavior.[24] To this end, Shimada divided neuroblastoma into favorable and unfavorable categories, depending on the degree of neuroblast differentiation, Schwannian stromal content, mitosis-karyorrhexis index, and age at diagnosis. In 1999, the Shimada classification was modified to the International Neuroblastoma Pathology Classification system.

Because of the various approaches to risk stratification, efforts have been made to develop a consensus approach that will allow comparison of patients around the world. In 2005, a large group of patients from Europe, Japan, the United States, Canada, and Australia diagnosed with neuroblastoma between 1974 and 2002 was reviewed in an effort to develop an International Neuroblastoma Risk Group (INRG). Consensus was reached to consider age (dichotomies around 18 mo), stage assessed before treatment, and N-myc status in the risk-group schema. Once the final statistical analyses are available, the specific criteria will be included in the final INRG report.

The COG recently developed a process called the Neuroblastoma Risk Stratification System (NRSS), which is used for treatment stratification. Like the Shimada Index, this new system is based on clinical and biological factors that are predictive of outcome. The NRSS is different in that it is based on the INRG system and is used for treatment-stratification purposes. Patients are assigned to low-, intermediate-, or high-risk categories based on age at diagnosis, INSS stage, histopathology, N-myc amplification status, and DNA index.

However, certain biological variables that affect the prognosis of children with neuroblastoma have been identified. Specific examples include aneuploidy of tumor DNA and N-myc oncogene amplification. N-myc amplification occurs in 20% of primary neuroblastoma tumors and is associated with a subset of neuroblastomas that have high metastatic potential and, consequently, a poor prognosis.[25] N-myc is thought to contribute to the aggressive behavior of neuroblastoma. However, the precise role of N-myc in nonamplified tumors is unknown.

Hyperdiploid tumor DNA is associated with a favorable prognosis. N-myc amplification is associated with a poor prognosis in children older than 1 year but not in children younger than 1 year. The N-myc amplification is linked to the deletion of chromosome arm 1p and a gain of the long arm of chromosome 17. In neuroblastoma, consistent areas of chromosomal loss of heterozygosity (LOH) include chromosome bands 1p36, 11q23, and 14Q23qter. In 2000, Maris et al reported from the Children's Cancer Group (CCG) that 1p deletion independently predicted a lower event-free survival but not overall survival. The clinical relevance of 14q LOH is unclear at this time.

Allelic loss of 11q is present in 35-45% of primary tumors. Notably, this aberration is rarely seen in tumors with N-myc amplification yet remains highly associated with other high-risk features.

Other variables carry varying degrees of prognostication. These include the site of the primary tumor, serum ferritin levels, NSE, and nutritional status.

Future and Controversies

Neuroblastoma continues to be one of the most frustrating childhood tumors to manage. Although the tumor has been studied extensively and great efforts have been extended to secure appropriate therapy and achieve a cure, little has altered the prognosis in affected children over the past 20 years. Further consensus data are needed to provide more definitive information regarding risk stratification, treatment, and prognosis in patients with neuroblastoma.

Targeted therapy is the subject of current research. Agents directed against tumors with amplification of the MYCN oncogene are in various stages of development. For neuroblastoma with ALK mutations, crizotinib and other ALK kinase inhibitors have shown efficacy in selected cases.[26]

In vitro cultures demonstrate that neuroblastoma is radiosensitive, but results from clinical trials have been inconsistent and inconclusive. As a primary treatment modality, radiation therapy can be used in regional lymph node metastases with sequential cyclophosphamide therapy, in infants with stage-4 disease who have Pepper syndrome (to control respiratory compromise), and in total-body irradiation combined with autologous bone marrow transplantation.

No curative treatment exists for relapsed high-risk neuroblastoma patients; clonally acquired somatic alterations that occur under the selective pressure of cytotoxic chemoradiotherapy offer clinically tractable targets and this strategy is currently being studied in a prospective trial.[13]