Neuroblastoma

Background:

• most common extracranial childhood cancer
• most common tumor occurring during 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 some molecular defects 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.
• Infants younger than 1 year have a good prognosis, even in the presence of metastatic disease, whereas older patients with metastatic disease fare poorly, even when treated with aggressive therapy.
• Unfortunately, approximately 70-80% of patients older than 1 year present with metastatic disease, usually to lymph nodes, liver, bone, and bone marrow. Fewer than half of these patients are cured, even with the use of high-dose therapy followed by autologous bone marrow or stem cell rescue.

Pathophysiology:

Anatomic

• Tumors can occur in the abdominal cavity
  • (40% adrenal, 25% paraspinal ganglia)
• or involve other sites
  • (15% thoracic, 5% pelvic, 3% cervical tumors, 12% miscellaneous).
• Infants more frequently present with thoracic and cervical tumors
• older children more frequently have abdominal tumors.
• Most patients present with signs and symptoms related to tumor growth, although small tumors have been detected in infants on prenatal ultrasound.
• 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 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 1 year 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% 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) detectable in urine. Markers associated with a poor prognosis are elevated ferritin, serum lactate dehydrogenase (LDH), and serum neuron-specific enolase (NSE).

Histologic

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 usually are positive. Electron microscopy can be useful because ultrastructural features (eg, neurofilaments, neurotubules, synaptic vessels, dense core granules) are diagnostic for neuroblastoma.

Neuroblastic nodules are present in the fetal adrenal gland and peak at 17-18 weeks' gestation. Most of these nodules regress spontaneously and likely represent remnants of fetal development. It is believed that some of these may persist and lead to the development of neuroblastoma.

Classification systems:
Shimada histopathologic classification system
Joshi histopathologic classification system

Deletion of the short arm of chromosome 1 is the most common chromosomal abnormality present in neuroblastomas, and it confers a poor prognosis.

DNA index is another useful test that correlates with response to therapy in infants. Look et al demonstrated that infants whose neuroblastomas have hyperdiploidy (ie, DNA index >1) have a good therapeutic response to cyclophosphamide and doxorubicin. 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.

Frequency:

• in the US: 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.
• 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. Some of this increase in survival rate may be because of 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/surgical management, and supportive care have contributed to the improved survival rates.
• Most patients with neuroblastoma present with disseminated disease, which confers a poor prognosis and is associated with a high mortality rate. 
• 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
  • 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.
     

History: Signs and symptoms of disease vary with site of presentation. Generally, symptoms include abdominal pain, emesis, weight loss, anorexia, fatigue, bone pain, and chronic diarrhea. Hypertension is an uncommon sign of the disease and generally is caused by renal artery compression, not catecholamine excess.

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 also may present with unexplained fever, weight loss, irritability, and periorbital ecchymosis secondary to metastatic disease to the orbits. In these patients, 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 arising 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 usually are 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 a chest radiograph.
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. If this type of tumor occurs in neonates, skin lesions may be confused with congenital rubella, and, if the patient has severe skin involvement, the term blueberry muffin 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 signs and symptoms 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:

Children usually are referred to a pediatric oncologist from primary care providers who have identified a persistent unexplained symptom or sign, either on physical examination or screening tests.
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 to 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, 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.
 

DDX

Rhabdomyosarcoma
Wilms Tumor



Other Problems to be Considered:

Neoplastic or nonneoplastic disease of childhood
Disseminated bone disease
Primary neurologic disease
Inflammatory bowel disease
 

Lab 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. Lab studies should include the following:
Serum lactate dehydrogenase (LDH, useful as biologic marker)
Ferritin (useful as biologic marker)
CBC and differential (Anemia or other cytopenias suggest bone marrow involvement.)
Urine collection for catecholamines (VMA/HVA)

The spot test for VMA/HVA is highly inaccurate. Centers usually send this test 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)

Asparate aminotransferase (AST)

Total bilirubin

Alkaline phosphatase
Electrolytes

Calcium

Magnesium
Imaging Studies:


Obtain chest and abdominal x-rays 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 usually is indistinguishable from nodal masses.
In cases of paraspinal masses, MRI aids in determining the presence of intraspinal tumor and cord compression.
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 Tc 99 bone scan also can be used to evaluate bone metastases.
Skeletal surveys also may be useful, especially in patients with multiple metastatic lesions.
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
Tumor biopsy or surgical resection. Biopsy or resection of the primary tumor (stage I or II disease) is performed to collect tissue sample(s) for biologic studies used to assign the patient into the appropriate risk category. This is particularly important in patients with nonmetastatic disease.
Tissue samples from a primary or metastatic tumor may be undifferentiated and confused with other small, round, blue cell tumors of childhood; however, techniques such as immunohistochemistries can aid with tissue diagnosis.
Molecular techniques, such as 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: A biopsy usually is required to diagnose neuroblastoma. Depending on 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/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.

NSE, chromogranin, synaptophysin, and S-100 immunohistochemical stains usually are 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 typically is 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 evaluate the tumor thoroughly 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 are essential to assign risk grouping and determine the appropriate therapy (see Table 2).
The International Neuroblastoma Staging System (INSS) currently is used in all cooperative group studies. A comparison of INSS, POG, and CCG staging criteria is detailed in Table 1. In general, the CCG staging system is based on clinical findings, whereas the POG system is clinicopathologic. INSS uses features of the other 2 systems.
Table 1. Staging Systems for Neuroblastoma

 

Treatment

Medical Care: Care of children with cancer is provided by a multidisciplinary team involving pediatric subspecialists in oncology, radiation oncology, surgery, and anesthesiology, as well as nurse practitioners, nurses, pharmacists, psychologists, and physical and occupational therapists dedicated to the special needs of these children.


Table 2 outlines criteria for risk assignment based on 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 CCG and POG. Correlative biologic studies were pivotal in identifying biologic risk factors important for outcome.









Table 2. Criteria for Risk Assignment




INSS Stage
Age
MYCN Status
Shimada Histology
DNA Ploidy
Risk Group

1
0-21 y
Any
Any
Any
Low


2A/2B
<1 y

>1-21 y

>1-21 y

>1-21 y
Any

Nonamplified

Amplified

Amplified
Any

Any

Favorable

Unfavorable
Any

-

-

-
Low

Low

Low

High


3
<1 y

<1 y

>1-21 y

>1-21 y

>1-21 y
Nonamplified

Amplified

Nonamplified

Nonamplified

Amplified
Any

Any

Favorable

Unfavorable

Any
Any

Any

-

-

-
Intermediate

High

Intermediate

High

High

4
<1 y

<1 y

>1-21 y
Nonamplified

Amplified

Any
Any

Any

Any
Any

Any

-
Intermediate

High

High

4S
<1 y

<1 y

<1 y

<1 y
Nonamplified

Nonamplified

Nonamplified

Amplified
Favorable

Any

Unfavorable

Any
>1

=1

Any

Any
Low

Intermediate

Intermediate

High



Cooperative group treatment strategies

Low-risk group treatment strategy
Patients with localized resectable neuroblastoma (stage 1) have excellent EFS with surgical excision of tumor alone. Adjuvant chemotherapy generally is not needed for this group of patients. Even the presence of residual microscopic disease does not affect the EFS significantly. When 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 presently are being assigned to a low-risk category if they are younger than 1 year regardless of MYCN status or histology. Additionally, stage 2B/2C patients older than 1 year are considered low-risk if they have non-MYCN–amplified or amplified tumors with favorable histology. CCG studies consistently have shown that these patients have a 3-year EFS and survival rate higher than 90% with surgical excision. In previous POG studies, patients with subtotal tumor resection who were treated with chemotherapy had a similar outcome.

Patients with 4S disease (ie, non-MYCN–amplified tumors, favorable histology, hyperdiploid tumors) also are considered to be in the low-risk group and are offered resection of the primary tumor, followed by observation.
Intermediate-risk group treatment strategy
These patients receive multimodality therapy, including surgery, chemotherapy, and, in selected situations, radiation therapy.

Intermediate-risk patients include children younger than 1 year with stage 3/4/4S disease and favorable biology (non-MYCN–amplified tumors, regardless of histology and DNA index).

Patients are considered to be in the intermediate-risk group if they are older than 1 year with stage 3 non-MYCN and favorable histology tumors. These patients are offered therapy with 4 of the most active drugs against neuroblastoma (ie, cyclophosphamide, doxorubicin, carboplatin, etoposide) for either 4 or 8 cycles, depending on histology and DNA index. In these patients, surgery can be used either at time of diagnosis or following multiagent chemotherapy. If residual disease exists after chemotherapy and surgery, radiation therapy could be considered. However, use of radiation is controversial, although a POG study suggests that it improves outcome when administered to areas of residual disease postchemotherapy.
High-risk group treatment strategy
Patients with high-risk disease include those with stage 2A/2B disease who are older than 1 year and have MYCN-amplified unfavorable histology tumors.

Infants with stage 3/4/4S and with MYCN-amplified tumors or children older than 1 year with stage 3, MYCN-amplified or non-MYCN–amplified tumors, and unfavorable histology tumors also are considered high-risk.

All patients older than 1 year with stage 4 tumors are considered to be in the high-risk group, regardless of MYCN status or histology. These patients seem to require treatment with multiagent chemotherapy, surgery, and radiotherapy, followed by consolidation with high-dose chemotherapy and peripheral blood stem cell rescue.

The 3-year EFS for patients in the high-risk group who are treated without such high-intensity therapy is less than 20%, compared to an EFS of 38% in patients treated with a single bone marrow transplant and cis-retinoic acid after transplant. Recently, a single-arm study of tandem stem cell transplantation reported an EFS of 58%, but this has not been tested in a randomized study against a single transplant. 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.

Risk of relapse from minimal residual disease after consolidation may be decreased with cis-retinoic acid treatment.
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, in these patients, 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 sacrifice of 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 for the 10% of patients who present with normal urinary catecholamines.
Patients with disseminated bone disease may be referred to a rheumatologist for persistent complaints of joint, muscle, or bone pain.
Patients with opsoclonus-myoclonus may be referred to a neurologist to exclude a primary neurologic disease.
Rarely, some patients with vasoactive intestinal peptide–secreting tumors may have recurrent diarrhea and are examined by a gastroenterologist to evaluate for inflammatory bowel disease.
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 and/or persistent disease after chemotherapy and surgery.
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 often is 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, a variety of salvage protocols may be used; with refractory disease, a limited number of phase I/II studies usually are available.

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 almost invariably are given in combination. Commonly used combinations include the following:


Vincristine, cyclophosphamide, and doxorubicin

Carboplatin and etoposide

Cisplatin and etoposide

Ifosfamide and etoposide
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/relapse therapy regimen is the combination of topotecan and cyclophosphamide.
 

Case Study: Cervical Neuroblastoma

This 15-day-old boy of Indian origin presents with a 4 X 3-cm mass on the right side of his neck. The mass is firm, noncystic, and nontender. The patient was born by means of normal vaginal delivery after an uncomplicated pregnancy. The mass does not increase in size over the next 2 weeks. The baby is afebrile and has no respiratory symptoms or dysphagia. His complete blood count (CBC) shows no abnormalities.

CT scanning of the neck reveals a solid swelling adjacent to the sternocleidomastoid (SCM) muscle.

Neuroblastoma: Cervical neuroblastoma usually appears as a large cervical tumor and may be associated with stridor, dysphagia, and sympathetic ganglia compression (Horner syndrome). It is the most common extracranial solid tumor, representing 8-10% of childhood cancers. The patient's age at diagnosis is typically less than 5 years.

Neuroblastomas constitute most primary tumors in the abdomen, but they represent less than 2-3% of those in the neck. Investigations for this tumor include tests of urine and serum catecholamine, homovanillic acid, vanillyl mandelic acid, and neuron-specific enolase. Other useful studies may include CT or MRI, metaiodobenzylguanidine (MIBG) bone scanning with or without technitium-99m, tumor biopsy, and bone marrow aspiration.

The differential diagnosis of cervical neuroblastoma includes:

• Fibromatosis colli (SCM tumor of infancy)
• Branchial cleft cyst
• Vascular lesion (hemangioma or lymphangioma)
• Dermoid and/or teratoma
• Inflammatory (bacterial, viral, or granulomatous) process
• Neoplastic lesions (lymphoma, carcinoma, or sarcoma)

In this case, the tumor was localized to the neck and completely excised. Abdominal CT and MRI revealed no other pathology. The patient has been followed up every 6 months and, so far, remains asymptomatic after 24 months. The excellent prognosis of localized neuroblastoma in neonates suggests a need for restrictive surgical indications, with well-established anatomic and imaging criteria.