What is Neuroblastoma?

Neuroblastoma is a pediatric embryonal solid tumor of the sympathetic nervous system (SNS) that effects (600-750) number of children per year in the US. It is the most common solid tumor outside of the central nervous system (CNS) and accounts for 15% of all pediatric cancer deaths. Neuroblastoma is sometimes referred to as a "heterogeneous" disease because of the wide range in its behavior in different children-some neuroblastoma tumors go away on their own (regress), some mature into a benign growth (ganglioneuroblastoma), and some grow and spread rapidly. Since neuroblastoma arises at the interface between the nervous system and the endocrine system, it is also included in the class of neuroendocrine tumors. Neuroblastoma is not a cancer of the CNS, but occasionally neuroblastoma metastasizes to the CNS.

Who is affected?

Neuroblastoma is a pediatric cancer. Neuroblastoma may be present at birth, but is more often diagnosed much later when the child begins to show symptoms of the disease. The presentation varies depending on the site of disease, but may include the presence of an abdominal mass, bone pain, difficulty walking, "raccoon eyes from metastatic disease to the orbits, or signs of bone marrow involvement such as pallor and easy bruising. The median age at diagnosis is about 2 years old. Neuroblastoma diagnosed after age 10 is extremely rare, but possible.

What are the causes of Neuroblastoma?

Although the causes of mutations responsible for certain adult cancers are known (for example, cancer-causing chemicals in cigarette smoke), the reasons for DNA changes that cause neuroblastomas are not known. Many researchers think that neuroblastomas develop when normal fetal neuroblasts fail to become mature nerve cells or adrenal medull cells. Instead, they continue to grow and divide.

In rare cases (about 1% to 2%), children may inherit an increased risk of developing neuroblastoma. Children with the familial neuroblastoma come from families with one or more affected members who had neuroblastoma. Compared to children with sporadic neuroblastoma, children with familial neuroblastoma are diagnosed at an earlier age and may develop 2 or more of these cancers in different organs (for example, in both adrenal glands or in more than one sympathetic ganglion). It is important to distinguish neuroblastomas developing in several organs from neuroblastomas that have started in one organ and then spread to others (metastatic neuroblastomas).

More in "Genetic Hallmarks of Neuroblastoma" below.

Where are the tumor sites?

The most common place for Neuroblastoma to originate is within the adrenal glands, which are located above each kidney. The tumors can also be found in the neck, chest , abdomen (30% non-adrenal), or pelvis -anywhere along the chain of the sympathetic nervous system.

What is the frequency of occurrence of Neuroblastoma?

Neuroblastoma is a very rare cancer. Of approximately 13,000 new cases of childhood cancer in the U.S. each year, only about 650-700 are Neuroblastoma. There is similar incidence in other countries and no clear differences between ethnic groups. About 55% of all neuroblastoma patients are boys.

How is Neuroblastoma diagnosed?

When a child comes to medical attention, and the doctor suspects s/he might have neuroblastoma, the clinician performs a variety of tests including a CT scan, a MIBG scan and test for urine catecholamines (VMA, HVA). The diagnosis of neuroblastoma is made by biopsy of the tumor or bone marrow. Based on these tests, an INSS stage and a RISK category are assigned.

What are the different INSS stages?

• Stage 1 - The tumor is confined to one area of origin and can be completely removed through surgery. Although microscopic residual disease may remain after surgery, identifiable lymph nodes on both sides of the body are negative for neuroblastoma.
• Stage 2 - 2A - The tumor is confined to one area but because of size, location, or proximity to other organs, cannot be completely removed. Identifiable lymph nodes on both sides of the body are negative for neuroblastoma.
  2B - The tumor is confined to one area and may or may not be completely removed. Identifiable lymph nodes on the side of the body where the tumor is located are positive for neuroblastoma, but lymph nodes on the opposite side of the body are negative for neuroblastoma.
• Stage 3 - One of the three scenarios : 1)The tumor crosses the midline of the body (defined as the spine) and may or may not have spread to nearby lymph nodes 2) the tumor is confined to one area of the body with disease in lymph nodes on the other side of the body 3) the tumor is located crosses the midline with disease in lymph nodes on both sides of the body
• Stage 4 - Neuroblastoma is found in distant lymph nodes, bone marrow, bone, liver, or other organs (except in the special circumstances of Stage 4S, explained below). Indication of presence of neuroblastoma cells by immunocytology alone (no visible tumor cells in bone marrow biopsy or aspirate) does not classify a child as stage 4.
• Stage 4S - Usually in infants, the tumor is confined to one area of the body, like a Stage 1 or 2 tumor, but disease has spread to only the liver, skin, or less than 10 percent of the bone marrow (no bone lesions).

The new schema of staging is as follows:

• L1 - Localized tumor confined to one compartment of the body and absence of any Image defined risk factors (IDRFs)
• L2 - Loco-regional tumor and presence of any IDRFs
• M - Distant metastatic disease
• MS - Metastasis limited to skin, liver or bone marrow of children less than 18 months of age

What are the Risk categories in patients affected with Neuroblastoma?

Patients with neuroblastoma are assigned to a "risk category" based on clinical and tumor genetic features. Neuroblastoma can be categorized currently into 3 risk groups - low, intermediate, high. The risk groups are used to determine therapy by pediatric oncologists to tailor the treatment accordingly thus enabling them to treat an individual patient the most appropriate way, avoiding treatments that are more toxic than that patient requires. For e.g. Children with low risk disease may be treated with surgery alone, whereas those with high risk disease are treated more intensely.

Risk categories

Low-risk

These patients have a good prognosis and get minimal treatment - usually surgery alone. In fact, some babies are diagnosed with neuroblastoma at birth, and have spontaneous remission - They need no anesthesia, no surgery, nothing; they are simply observed and monitored with use of x-rays and ultrasound. Over 90% of low risk patients survive.

Intermediate-risk

These patients also have a good prognosis, with moderate therapy. They are treated according to the genetic makeup of their cells, with chemotherapy and surgery. These patients also have a 90% survival rate.

High-risk

Unfortunately, these patients often have disease that is difficult to cure. Patients receive very intensive therapy, including surgery, chemotherapy, stem cell transplantation and biologic agents. Despite this, over half of the patients will suffer a relapse. Relapsed high-risk neuroblastoma is rarely cured.

What are the factors that help in deciding the risk category?

At diagnosis, a piece of the tumor tissue is sent to a laboratory, where biological tests are run to help assign the patient to the proper risk-group and treatment protocol. Risk is decided based on the combination of the four following criteria:

• 1. Age of the child
• 2. Stage of the disease
• 3. Tumor histology
• 4. Genetic make-up of the tumor

How is the Neuroblastoma histology determined?

The histology classifies neuroblastoma tumors further into either "Favorable" or "Unfavorable" based on tumor grade (how the cells look under the microscope) and mitosis karyorrhexis index(MKI). Assigning a tumor Grade is based on Shimada classification. The proportion of non-cancerous structural cells called "stroma" (also known as "Schwannian" cells) and the degree of differentiation of neuroblastic cells is examined and the following grades are assigned.

• neuroblastoma (Neuroblastoma): stroma-poor, undifferentiated, poorly differentiated, or differentiating; malignant tumor
• Gneuroblastoma i (Ganglioneuroblastoma intermixed): stroma-rich, intermixed with Neuroblasts;
• Gneuroblastoma n (Ganglioneuroblastoma nodular): stroma-rich, nodules of neuroblasts; or
• GN (Ganglioneuroma): stroma-dominant, benign tumor.

MKI -index gives information about cell division and activity. Dividing cells (mitosis) and cells with nuclear fragmentation (karyorrhexis) are counted and the MKI determined as follows:

low MKI: Less than 2% (100 cells in a sample of 5000 tumor cells);

intermediate MKI: 2-4% (100-200 cells per 5000 tumor cells); or

high MKI: 4% or more (200 or more cells per 5000 tumor cells).

Combining the above two factors together with the child's age, allow INPC classification into two groups: favorable histology (FH) and unfavorable histology (UH)

Favorable Histology

all ganglioneuroma (GN) and ganglioneuroblastoma intermixed (Gneuroblastomai);

ganglioneuroblastoma nodular (Gneuroblastoman) with 50% or more Schwannian cells;

neuroblastoma (neuroblastoma), under 18 months; or

neuroblastoma (neuroblastoma), under 5 years old, differentiating, low MKI.

Unfavorable Histology

ganglioneuroblastoma nodular (Gneuroblastoman) with less than 50% Schwannian cells;

neuroblastoma (neuroblastoma), undifferentiated;

neuroblastoma (neuroblastoma), high MKI;

neuroblastoma (neuroblastoma), poorly differentiated or differentiating, intermediate MKI, over 18 months; or

neuroblastoma (neuroblastoma), differentiating, low MKI, over 5 years old.

What are the key genetic hallmarks of Neuroblastoma?

Ploidy. DNA diploidy although normal in healthy cell, is a poor prognostic factor for neuroblastoma and indicates higher risk disease. Triploidy or hyperdiploidy in a neuroblastoma cell is favorable .

MYCN. Another genetic factor considered in risk assignment is MYCN amplification status . MYCN is an oncogene and is an unfavorable prognostic factor. When there are more than 10 copies present in a cell, the neuroblastoma tumor is referred to as MYCN amplified. MYCN is commonly multiplied, by 100 times, and has been found as high as 700 times in a neuroblastoma cell. About 20% of all neuroblastoma cases have MYCN amplification. It is more common in widespread disease than localized tumors. MYCN amplification is found in less than 10% of stage 1 & 2 cases, in about 10% of stage 4s, and in about 30% of stage 3 & 4 cases . MYCN is an important prognostic factor. Younger children and children with lower stage disease will be treated as high-risk if their tumor is MYCN amplified, but MYCN does not necessarily contribute to a poorer prognosis in high-risk cases because one or more unfavorable characteristics are present in all high-risk cases.

Other genetic and molecular factors. Other genetic variables believed to have prognostic value for Neuroblastoma have been identified, but not all are currently used in risk assignment.

• 1p & 3p chromosomes: Tumor suppressor genes are believed to be associated with 1p and 3p chromosomes, and deletion of either in the neuroblastoma is considered an unfavorable prognostic factor.
• 11q chromosome: 11q deletions may also predict a less favorable prognosis. It is thought that these chromosome parts -- missing in many neuroblastoma patients -- may contain important Tumor Suppressor Genes
• 17q Chromosome: Having an extra part of chromosome 17 or 17 q gain is also linked with a worse prognosis; this probably means that there is an oncogene in this part of chromosome 17. Understanding the importance of chromosome deletions/gains is an active area of neuroblastoma research.
• TRKA & CD44: A tumor suppressor gene called TrkA is sometimes less active than usual in neuroblastoma cells, which may be another reason for uncontrolled growth. A lack of TRKA and CD44 expression on the neuroblastoma cell surface are also considered unfavorable, but not independently prognostic.
• Neurotrophin receptors: Neuroblastomas with more neurotrophin receptors, especially the nerve growth factor receptor called TrkA, may have a more favorable prognosis.
• Ferritin, NSE & GD2: These serum markers are released by Neuroblastoma cells into the blood. Patients with high ferritin levels tend to have a worse prognosis. Neuron-specific enolase Increased levels of NSE (Neuron Specific Enolase) and LDH(Lactose Dehydrogenase) in the blood predict a worse outlook for children with neuroblastoma. A substance on the surface of many nerve cells known as ganglioside GD2 is often increased in the blood of neuroblastoma patients. Although the usefulness of GD2 in predicting prognosis is unknown, it may turn out to be more useful in treating neuroblastoma.
• ALK: Recent research suggests that inherited mutations in the ALK gene may account for most cases of hereditary neuroblastoma.

What are the different treatment options?

Surgery. This is common in neuroblastoma treatment and serves to take out as much of the cancer as possible. If necessary, surgery is delayed until chemotherapy and/or radiation has decreased tumor size.

Radiation therapy. Both high dose X-rays (external beam) and radioisotopes through thin plastic tubes, (internal radiation) therapies may be used.

Chemotherapy. Common chemotherapy agents are: daunorubicin, cyclophosphamide, carboplatin, and epotoside.

Bone marrow transplantation. Autologous BMT may be used following aggressive chemotherapy.