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neuroblastoma

 
Medical Encyclopedia: Neuroblastoma
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Definition

Neuroblastoma is a type of cancer that usually originates either in the tissues of the adrenal gland or in the ganglia of the abdomen or in the ganglia of the nervous system. (Ganglia are masses of nerve tissue or groups of nerve cells.) Tumors develop in the nerve tissue in the neck, chest, abdomen, or pelvis.

Description

Neuroblastoma is one of the few cancer types known to secrete hormones. It occurs most often in children, and it is the third most common cancer that occurs in children. Approximately 7.5% of the childhood cancers diagnosed in 2001 were neuroblastomas, affecting one in 80, 000 to 100, 000 children in the United States. Close to 50% of cases of neuroblastoma occur in children younger than two years old. The disease is sometimes present at birth, but is usually not noticed until later. By the time the disease is diagnosed, it has often spread to the lymph nodes, liver, lungs, bones, or bone marrow. Approximately one-third of neuroblastomas start in the adrenal glands.

— Lisa Christenson; Monique Laberge, PhD


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Dictionary: neu·ro·blas·to·ma   (nʊr'ō-blă-stō'mə, nyʊr'-) pronunciation
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n., pl., -mas, or -ma·ta (-mə-tə).
A malignant tumor composed of neuroblasts, originating in the autonomic nervous system or the adrenal medulla and occurring chiefly in infants and young children.


Oncology Encyclopedia: Neuroblastoma
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Key Terms: Adjuvant chemotherapy, Adrenal gland, Alternative therapy, Biopsy, Complementary therapy, Conventional therapy, Disseminated, Hormone, Localized, Monoclonal antibody, Neoadjuvant chemotherapy, Neuroblast cells, Resectable cancer, Salvage therapy, Staging system.

Definition

Neuroblastoma is a type of cancer that usually originates either in the tissues of the adrenal gland or in the ganglia of the abdomen or in the ganglia of the nervous system. (Ganglia are masses of nerve tissue or groups of nerve cells.) Tumors develop in the nerve tissue in the neck, chest, abdomen, or pelvis.

Description

Neuroblastoma is one of the few cancer types known to secrete hormones. It occurs most often in children, and it is the third most common cancer that occurs in children. Approximately 7.5% of the childhood cancers diagnosed in 2001 were neuroblastomas, affecting one in 80,000 to 100,000 children in the United States. Close to 50% of cases of neuroblastoma occur in children younger than two years old. The disease is sometimes present at birth, but is usually not noticed until later. By the time the disease is diagnosed, it has often spread to the lymph nodes, liver, lungs, bones, or bone marrow. Approximately one-third of neuroblastomas start in the adrenal glands.

Demographics

According to some reports, African-American children develop the disease at a slightly higher rate than Caucasian children (8.7 per million compared to 8.0 per million cases diagnosed).

Causes and Symptoms

The causes of neuroblastoma are not precisely known. Current research holds that neuroblastomas develop when cells produced by the fetus (neuroblast cells) fail to mature into normal nerve or adrenal cells and keep growing and proliferating. The first symptom of a neuroblastoma is usually an unusual growth or lump, found in most cases in the abdomen of the child, causing discomfort or a sensation of fullness and pain. Other symptoms such as numbness and fatigue, arise because of pressure caused by the tumor. Bone pain also occurs if the cancer has spread to the bone. If it has spread to the area behind the eye, the cancer may cause protruding eyes and dark circles around the eyes; in a few cases, blindness may be the presenting symptom. Or paralysis may result from compression of the spinal cord. Fever is also reported in one case out of four. High blood pressure, persistent diarrhea, rapid heartbeat, reddening of the skin, and sweating occur occasionally. Some children may also have uncoordinated or jerky muscle movements, or uncontrollable eye movements, but these symptoms are rare. If the disease spreads to the skin, blue or purple patches are observed.

Diagnosis

A diagnosis of neuroblastoma usually requires blood and urine tests to investigate the nature and quantity of chemicals (neurotransmitters) released by the nerve cells. These are broken down by the body and released in urine. Additionally, scanning techniques are used to confirm the diagnosis of neuroblastoma. These techniques produce images or pictures of the inside of the body and they include computed tomography scan (CT scan) and magnetic resonance imaging (MRI). To confirm the diagnosis, the physician will surgically remove some of the tissue from the tumor or bone marrow (biopsy), and examine the cells under the microscope.

Treatment Team

The treatment team usually consists of an oncologist specialized in the treatment of neuroblastoma, a surgeon to perform biopsies and possibly attempt surgical removal of the tumor, a radiation therapy team and, if indicated, a bone marrow transplantation team.

Clinical Staging, Treatments, and Prognosis

Staging

Once neuroblastoma has been diagnosed, the physician will perform more tests to determine if the cancer has spread to other tissues in the body. This process, called staging, is important for the physician to determine how to treat the cancer and check liver and kidney function. The staging system for neuroblastoma is based on how far the disease has spread from its original site to other tissues in the body.

Localized resectable (able to be cut out) neuroblastoma is confined to the site of origin, with no evidence that it has spread to other tissues, and the cancer can be surgically removed. Localized unresectable neuroblastoma is confined to the site of origin, but the cancer cannot be completely removed surgically. Regional neuroblastoma has extended beyond its original site, to regional lymph nodes, and/or surrounding organs or tissues, but has not spread to distant sites in the body. Disseminated neuroblastoma has spread to distant lymph nodes, bone, liver, skin, bone marrow, and/or other organs. Stage 4S (or IVS, or "special") neuroblastoma has spread only to liver, skin, and/or, to a very limited extent, bone marrow. Recurrent neuroblastoma means that the cancer has come back, or continued to spread after it has been treated. It may come back in the original site or in another part of the body.

Treatments

Treatments are available for children with all stages of neuroblastoma. More than one of these treatments may be used, depending on the stage of the disease. The four types of treatment used are:

  • Surgery (removing the tumor in an operation)
  • Radiation therapy (using high-energy x rays to kill cancer cells)
  • Chemotherapy (using drugs to kill cancer cells)
  • Bone marrow transplantation (replacing the patient's bone marrow cells with those from a healthy person).

Surgery is used whenever possible, to remove as much of the cancer as possible, and can generally cure the disease if the cancer has not spread to other areas of the body. Before surgery, chemotherapy may be used to shrink the tumor so that it can be more easily removed during surgery; this is called neoadjuvant chemotherapy. Radiation therapy is often used after surgery; high-energy rays (radiation) are used to kill as many of the remaining cancer cells as possible. Chemotherapy (called adjuvant chemotherapy) may also be used after surgery to kill remaining cells. Bone marrow transplantation is used to replace bone marrow cells killed by radiation or chemotherapy. In some cases the patient's own bone marrow is removed prior to treatment and saved for transplantation later. Other times the bone marrow comes from a matched donor, such as a sibling.

One novel approach to treatment of neuroblastomas is therapy with desferoxamine (DFO), which is ordinarily used to treat iron poisoning. DFO has been shown to have antitumor activity in neuroblastomas and other cancers of the central nervous system. It is thought that the drug works by lowering the increased iron levels in the body associated with cancer.

As of 2004, there are significant differences in treatment protocols for neuroblastoma between the major North American study group (Children's Oncology Group) and its European counterpart, the Société Internationale d'Oncologie Pédiatrique (SIOP). These differences include biopsy techniques, the timing and extent of surgery, chemotherapy dosages, and the types of salvage therapy employed.

Prognosis

The chances of recovery from neuroblastoma depend on the stage of the cancer, the age of the child at diagnosis, the location of the tumor, and the state and nature of the tumor cells evaluated under the microscope. Infants have a higher rate of cure than do children over one year of age, even when the disease has spread. In general, the prognosis for a young child with neuroblastoma is good: the predicted five-year survival rate is approximately 85% for children who had the onset of the disease in infancy, and 35% for those whose disease developed later.

Alternative and Complementary Therapies

No alternative therapy has yet been reported to substitute for conventional neuroblastoma treatment. Complementary therapies—such as retinoic acid therapy—have been shown to be beneficial to patients when administered after a conventional course of chemotherapy or transplantation.

Coping With Cancer Treatment

Neuroblastoma is a childhood cancer and it must be recognized that children, adolescents and their families have very special needs. These are best met at cancer centers for children working in close contact with the treatment team and the primary care physician. These centers have experience in recognizing the unique needs of children having to cope with cancer and they are staffed by pediatric support professionals other than the oncology treatment team while being associated with a children's hospital.

Clinical Trials

As of 2004, the National Cancer Institute supported over 55 neuroblastoma clinical trials to evaluate a variety of anticancer drugs either combined to other drugs or to other treatments. No fewer than 14 of these studies involve stem cell transplantation, alone or in combination with other forms of treatment. Other clinical trials are concerned with anticancer drugs that are still considered investigational.

Prevention

Neuroblastoma may be a genetic disease passed down from the parents. In 2004, a group of German researchers reported that a series of neuroblastomas demonstrated a consistent pattern of deletions and over-representations on chromosomes 3, 10, 17q, and 20. There is currently no known method for its prevention.

Questions to Ask the Doctor

  • What treatment choices do we have?
  • Has the neuroblastoma spread to other parts of the body?
  • What is the stage of the cancer?
  • Based on your experience in treating neuroblastoma, how long do you think my child will survive if there is no response to treatment or the cancer comes back?
  • How long will it take to recover from treatment?
  • Will my child develop any long-term risks or complications from the cancer or its treatment?
  • Can you recommend a support group in my town for people who are coping with neuroblastoma?

Special Concerns

After completion of a course of treatment for neuroblastoma, physicians sometimes recommend that the child undergo an investigative operation. This procedure allows the treatment team to evaluate how effective treatment has been, and may offer an opportunity to remove more of the tumor if it is still present.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Neuroblastoma." Section 19, Chapter 266 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Periodicals

Alexander, F. "Neuroblastoma." Urol. Clin. North. Am. 27 (August 2000): 383–392.

Berthold, F., and B. Hero. "Neuroblastoma: current drug therapy recommendations as part of the total treatment approach." Drugs 59 (June 2000): 1261–1277.

Bockmuhl, U., X. You, M. Pacyna-Gengelbach, et al. "CGH Pattern of Esthesioneuroblastoma and Their Metastases." Brain Pathology 14 (April 2004): 158–163.

Dayani, P. N., M. C. Bishop, K. Plack, and P. M. Zeltzer. "Desferoxamine (DFO)—Mediated Iron Chelation: Rationale for a Novel Approach to Therapy for Brain Cancer." Journal of Neurooncology 67 (May 2004): 367–377.

Grosfeld, J. L."Risk-based management of solid tumors in children." American Journal of Surgery 180 (November 2000): 322–327.

Lau, J. J., J. D. Trobe, R. E. Ruiz, et al. "Metastatic Neuroblastoma Presenting with Binocular Blindness from Intracranial Compression of the Optic Nerves." Journal of Neuroophthalmology 24 (June 2004): 119–124.

Morgenstern, B. Z., A. P. Krivoshik, V. Rodriguez, and P. M. Anderson. "Wilms' Tumor and Neuroblastoma." Acta Paediatrica Supplementum 93 (May 2004): 78–84.

Pinkerton, C., R. Blanc, M. P. Vincent, C. Bergeron, B. Fervers, and T. Philip. "Induction chemotherapy in metastatic neuroblastoma—does dose influence response? A critical review of published data standards, options and recommendations (SOR) project of the National Federation of French Cancer Centres (FNCLCC)." European Journal of Cancer 36 (September 2000): 1808–1815.

Organizations

The American Cancer Society (1-800-ACS-2345) provides information on specific types of cancer and a variety of cancer-related subjects. Additionally, it distributes booklets which can help cope with cancer treatment. Examples are: After Diagnosis: A Guide for Patients and Families (Booklet, Code #9440); Caring for the Patient with Cancer at Home (Booklet, Code #4656); Understanding Chemotherapy: A Guide for Patients and Families (Booklet, Code #9458); Understanding Radiation Therapy: A Guide for Patients and Families (Booklet, Code #9459).

National Cancer Institute. Office of Cancer Communications, 31 Center Drive, MSC 2580, Bethesda, MD 20892-2580. 800-422-6237. .

National Institutes of Health & National Cancer Institute. Young People With Cancer: A Handbook for Parents. .

—Lisa Christenson; Monique Laberge, PhD; Rebecca J. Frey, PhD

Dental Dictionary: neuroblastoma
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(nyōō′rōblastō′mə)
n

A malignant neoplasm characterized by proliferating nerve cells.

Veterinary Dictionary: neuroblastoma
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Rare neoplasm arising from primitive neuroepithelial cells which differentiate toward neuroblasts (neuroblastoma) or neurons (ganglioneuroma). They usually arise in the central or autonomic nervous system or in the adrenal medulla (sympathicoblastoma).

Wikipedia: Neuroblastoma
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Neuroblastoma, NOS
Classification and external resources

microscopic view of a typical neuroblastoma with rosette formation
ICD-10 C74.9
ICD-9 194.0
ICD-O: M9500/3
OMIM 256700
DiseasesDB 8935
MedlinePlus 001408
eMedicine med/2836 ped/1570
MeSH D009447

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 new cases per year in the US.[1] Close to 50 percent of neuroblastoma cases occur in children younger than two years old.[2] It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system or SNS. It most frequently originates in one of the adrenal glands, but can also develop in nerve tissues in the neck, chest, abdomen, or pelvis.

Neuroblastoma is one of the few human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance.[3]

A disease exhibiting extreme heterogeneity, neuroblastoma is stratified into three risk categories: low, intermediate, and high risk. Low-risk disease is most common in infants and highly curable with observation only or surgery, whereas high-risk disease is difficult to cure even with the most intensive multi-modal therapies available.[4]

Note: Esthesioneuroblastoma, also known as olfactory neuroblastoma, is believed to arise from the olfactory epithelium and its classification remains controversial. However, since it is not a sympathetic nervous system malignancy it is a distinct clinical entity and is not to be confused with neuroblastoma.[5][6]

Contents

Classification

The "International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:[7][8][9]

  • Stage 1: Localized tumor confined to the area of origin.
  • Stage 2A: Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor.
  • Stage 2B: Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor.
  • Stage 3: Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement.
  • Stage 4: Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.
  • Stage 4S: Age <1 year old with localized primary tumor as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors).

Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 neuroblastoma patients treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12-18 month old age group, previously categorized as high-risk, and prompted the decision to reclassify 12-18 month old children without N-myc (also commonly referred to as MYCN) amplification to intermediate risk category.[10]

The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):

  • Stage L1: Localized disease without image-defined risk factors.
  • Stage L2: Localized disease with image-defined risk factors.
  • Stage M: Metastatic disease.
  • Stage MS: Metastatic disease "special" where MS is equivalent to stage 4S.

The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, N-myc amplification, unbalanced 11q aberration, and ploidy into four pre-treatment risk groups: very low, low, intermediate, and high risk.[11][12]

Signs and symptoms

The first symptoms of neuroblastoma are often vague making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on primary tumor locations and metastases if present:[13]

Neuroblastoma often spreads to other parts of the body before any symptoms are apparent and 50 to 60% of all neuroblastoma cases present with metastases.[14]

The most common location for neuroblastoma to originate (ie the primary tumor) is on the adrenal glands. This occurs in 40% of localized tumors and in 60% of cases of widespread disease. Neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. Frequencies in different locations include: neck (1%), chest (19%), abdomen (30% non-adrenal), or pelvis (1%). In rare cases, no primary tumor can be discerned.[15]

Rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide secretion, 4% of cases), Horner's syndrome (cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome[16] and ataxia (suspected paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or renal artery compression, 1.3% of cases).[17]

Cause

The etiology of neuroblastoma is not well understood. Certain cases however do run in families and have been linked to genetics. Familial neuroblastoma is cased by a very rare germline mutations in the anaplastic lymphoma kinase (ALK) gene.[18]

Several risk factors have been proposed and are the subject of ongoing research. Due to characteristic early onset many studies have focused on parental factors around conception and during gestation. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy and birth factors; however, results have been inconclusive.[19]

Other studies have examined possible links with atopy and exposure to infection early in life,[20] use of hormones and fertility drugs,[21] and maternal use of hair dye.[22][23]

Diagnosis

MRI showing orbital and skull vault metastatic NB in 2 year old

The diagnosis is usually confirmed by a surgical pathologist, taking into account the clinical presentation, microscopic findings, and other laboratory tests.

Serology

In about 90% of cases of neuroblastoma, elevated levels of catecholamines or its metabolites are found in the urine or blood. Catecholamines and their metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA).[24]

Imaging

Another way to detect neuroblastoma is the mIBG scan (meta-iodobenzylguanidine), which is taken up by 90 to 95% of all neuroblastomas, often termed "mIBG-avid."[25] The mechanism is that mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrine. When it is radio-ionated with I-131 or I-123 (radioactive iodine isotopes), it is a very good radiopharmaceutical for diagnosis and monitoring of response to treatment for this disease. With a half-life of 13 hours, I-123 is the preferred isotope for imaging sensitivity and quality. I-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma.[26]

Histology

microscopic view of stroma-rich ganglioneuroblastoma

On microscopy, the tumor cells are typically described as small, round and blue, and rosette patterns (Homer-Wright pseudo-rosettes) may be seen.[27] A variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as rhabdomyosarcoma, Ewing's sarcoma, lymphoma and Wilms' tumor. In February 2007, Althea Technologies announced the development of a molecular diagnostic capable of clearly differentiating various types of childhood cancers, developed in cooperation with the U.S. National Cancer Institute (NCI).[28]

Neuroblastoma is one of the peripheral neuroblastic tumors (pNTs) that have similar origins and show a wide pattern of differentiation ranging from benign ganglioneuroma to stroma-rich ganglioneuroblastoma with neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. This distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis-karyorrhexis index (MKI). This pathology classification system describes "favorable" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC, also called Shimada system) which was established in 1999 and revised in 2003.[29]

Screening

Urine catecholamine level can be elevated in pre-clinical neuroblastoma. Screening asymptomatic infants at three weeks, six months, and one year has been performed in Japan, Canada, and Germany since the 1980s.[30][31] Japan began screening six-month olds for neuroblastoma via analysis of the levels of homovanillic acid and vanilmandelic acid in 1984. Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.[32][33] [34]

Treatment

When the lesion is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplant, differentiation agent isotretinoin also called 13-cis-retinoic acid, and frequently immunotherapy[35] with anti-GD2 monoclonal antibody therapy).

Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity.[36] These criteria include the age of the patient, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogene amplification (N-myc regulates microRNAs[37]), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk.[38] (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)[39]

The therapies for these different risk categories are very different.

With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70%-90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma the past two decades resulted in cures only about 30% of the time.[43] The addition of antibody therapy has raised survival rates for high-risk disease significantly. In March 2009 an early analysis of a Children's Oncology Group (COG) study with 226 high-risk patients showed that two years after stem cell transplant 66% of the group randomized to received ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all patients enrolling on the trial will receive the antibody therapy.[44]

Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan), topoisomerase II inhibitor (etoposide), anthracycline antibiotics (doxorubicin) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease.

Prognosis

Between 20% and 50% of high-risk cases do not respond adequately to induction high-dose chemotherapy and are progressive or refractory.[45][46] Relapse after completion of frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.[47]

Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss. Growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease.[48][49] An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.[50][51] These results were confirmed in a National Cancer Institute publication released July 2009 comparing outcomes of neuroblastoma survivors to siblings. The study reported that survivors are more likely than siblings to develop chronic neurological, sensory, endocrine, and musculoskeletal complications and less likely to be married or have a high income job.[52]

Cytogenetic Profiles

Based on a series of 493 neuroblastoma samples, it has been reported that overall genomic pattern, as tested by array-based karyotyping, is a predictor of outcome in neuroblastoma[53]:

  • Tumors presenting exclusively with whole chromosome copy number changes were associated with excellent survival.
  • Tumors presenting with any kind of segmental chromosome copy number changes were associated with a high risk of relapse.
  • Within tumors showing segmental alterations, additional independent predictors of decreased overall survival were N-myc amplification, 1p and 11q deletions, and 1q gain.

Earlier publications categorized neuroblastomas into three major subtypes based on cytogenetic profiles[54]:

  • Subtype 1: favorable neuroblastoma with near triploidy and a predominance of numerical gains and losses, mostly representing non-metastatic NB stages 1, 2 and 4S.
  • Subtypes 2A and 2B: found in unfavorable widespread neuroblastoma, stages 3 and 4, with 11q loss and 17q gain without N-myc amplification (subtype 2A) or with N-myc amplification often together with 1p deletions and 17q gain (subtype 2B).

Virtual karyotyping can be performed on fresh or paraffin-embedded tumors to assess copy number at these loci. SNP array virtual karyotyping is preferred for tumor samples, including neuroblastomas, because they can detect copy neutral loss of heterozygosity (acquired uniparental disomy). Copy neutral LOH can be biologically equivalent to a deletion and has been detected at key loci in neuroblastoma.[55] ArrayCGH, FISH, or conventional cytogenetics cannot detect copy neutral LOH.

Epidemiology

Neuroblastoma comprises 6-10% of all childhood cancers, and 15% of cancer deaths in children. The annual mortality rate is 10 per million children in the 0- to 4-year-old age group, and 4 per million in the 4- to 9-year old age group.[56]

The highest incidence is in the first year of life, and some cases are congenital. The age range is broad, including older children and adults,[57] but only 10% of cases occur in people older than 5 years of age.[25] A large European study reported less than 2% of over 4000 neuroblastoma cases were over 18 years old.[58]

History

Rudolf Virchow; the first to describe an abdominal tumor in a child as a "glioma"

In 1864 German physician Rudolf Virchow was the first to describe an abdominal tumor in a child as a "glioma". The characteristics of tumors from the sympathetic nervous system and the adrenal medulla when than noted in 1891 by German pathologist Felix Marchand.[59] [60] In 1901 the distinctive presentation of stage 4S in infants (liver but no bone metastases) was described by William Pepper. In 1910 James Homer Wright understood the tumor to originate from primitive neural cells, and named it neuroblastoma. He also noted the circular clumps of cells in bone marrow samples which are now termed "Homer-Wright pseudorosettes."[61]

Research

Clinical trials for new frontline treatments

Recent focus has been to reduce therapy for low and intermediate risk neuroblastoma while maintaining survival rates at 90%.[62] A study of 467 intermediate risk patients enrolled in A3961 from 1997 to 2005 confirmed the hypothesis that therapy could be successfully reduced for this risk group. Those with favorable characteristics (tumor grade and response) received four cycles of chemotherapy, and those with unfavorable characteristics received eight cycles, with three-year event free survival and overall survival stable at 90% for the entire cohort. Future plans are to intensify treatment for those patients with aberration of 1p36 or 11q23 chromosomes as well as for those who lack early response to treatment.[63]

By contrast, focus the past 20 years or more has been to intensify treatment for high-risk neuroblastoma. Chemotherapy induction variations, timing of surgery, stem cell transplant regimens, various delivery schemes for radiation, and use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III clinical trials with randomization have been carried out to answer these questions to improve survival of high-risk disease:

  • 1982-1985: European Neuroblastoma Study Group (ENSG1) enrolled 167 children and randomized to melphalan autologous bone marrow transplant or no further therapy (no radiation therapy given to any). Transplant and no-transplant arms each had 65 patients, and recent long-term follow-up report revealed significantly better 5 year event-free survival for stage 4 over 1 year old in melphalan-transplant group versus no further treatment: 33% versus 17% respectively.[64]
  • 1990-1999: European study (EU-20592 or CCLGNB-1990-11) randomized 262 high-risk children over 1 year old and revealed higher survival rate for rapid sequence induction (10-day cycle) versus standard induction (21-day cycle) with same total dose. Ten-year event free survival was 27% and 18% respectively with non-aggressive surgical approach, no radiotherapy, and melphalan-only autologous bone marrow or stem cell transplant for both groups.[65]
  • 1991-1996: Phase III trial with two sequential randomizations for 379 high-risk NB patients was carried out by the Children's Cancer Group (CCG-3891) which demonstrated improved survival with myeloablative therapy (with total body irradiation) and 13-cis-retinoic acid (Accutane) with 50 patients in each of the four arms of the study.[66],[67]
  • 1996-2003: The German (GPOH) study NB97 compared outcomes of 295 high-risk NB patients randomized for stem cell transplant or consolidation chemotherapy. Results showed increased survival with transplant.[68]
  • 2000-2006: The recent study (COG-A3973)[69] questioned the need for purged stem cells for CEM-LI (carboplatin, etoposide, melphalan, with local irradiation)[70] transplant, and accrued 486 patients. Purging stem cells was not found to improve survival[46]
  • 2000-2012: A concurrent study (COG-ANBL0032)[71] determined in early review that the antibody ch14.18 with interleukin 2 and GMCSF (studied retrospectively in German GPOH NB90 and NB 97 at a lower dose and without cytokines[72]) improved survival, and will accrue a total of 423 patients.[73]
  • 2002-2008: SIOP (International Society of Paediatric Oncology) formed the European SIOP Neuroblastoma Group (ESIOP NB) in 1994 [74] and activated a phase III high-risk NB protocol in 2002 (SIOP-EUROPE-HR-NBL-1) [75] using “rapid” COJEC (8 cycles of chemotherapy given at 10-day intervals) followed by transplant randomization to CEM (carboplatin, etoposide, melphalan) or BuMel (busulfan, melphalan) and then randomization to with or without ch14.18 antibody treatment. This study will evaluate the use of growth factors as well as compare transplant regimens, with or without ch14.18 antibody, and all patients receive retinoic acid. This trial will accrue 1000 patients (175 per year). There are eight arms to this study.
  • 2005-2010: The current German NB2004 [76] randomization will include MIBG therapy and randomize topotecan use in up-front therapy and will accrue a total of 642 for all risk groups (roughly half will be high-risk). After transplant, the high-risk protocol includes six months of cis-retinoic acid, a three month break, and another three months of retinoic acid.
  • 2007: The COG phase III ANBL0532 [77] trial opened December 2007 for accrual of 495 and will compare single versus tandem transplants, and induction begins with two cycles of topotecan.[78]

In addition to these phase III studies, research institutions such as Baylor College of Medicine/Texas Children's, St. Jude Children's Research Hospital (Memphis, Tennessee), and Memorial Sloan-Kettering Cancer Center in New York offer unique treatment protocols. Texas Children's uses a novel induction regimen which includes a method of giving chemotherapy called “chemo-switching” where cisplatin is given as high-dose pulse and etoposide is given at low-dose over several weeks for the first two cycles.[79] St Jude's recently finished (2007) testing a new up-front chemotherapy regimen in 23 children which included irinotecan and gefitinib with 16 months of maintenance chemotherapy after stem cell transplant with alternating oral 13-cis-retinoic acid and topotecan.[80] In December 2008 St Jude's opened a new trial using temsirolimus and irinotecan in induction.[81] Sloan-Kettering offers treatment that includes a mouse-derived monoclonal antibody, 3F8, used in protocols since the mid 1980s. This antibody is used for treating minimal residual disease or consolidation instead of stem cell transplant.[82]

Clinical trials for refractory and relapsed neuroblastoma

microscopic view of a NB cell line (SH-SY5Y) used in preclinical research for testing new agents

Some children (particularly in high-risk cases) do not respond completely to frontline treatment (with a complete response or very good partial response) and are labeled refractory. These children are removed from the frontline therapy (clinical trial) and are eligible for clinical trials using new therapies. Many high-risk children have a good response to frontline therapy and achieve a remission, but later the disease recurs (relapse). These children are also eligible for new therapies being tested in clinical trials. The protein p53 is believed to play a role in the development of resistance to chemotherapy.[83]

Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse. A randomized study (2004) with 119 patients (comparing topotecan alone to topotecan and cyclophosphamide) revealed a 31% complete or partial response rate with two-year progression-free survival at 36% in the topotecan and cyclophosphamide group.[84] Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma.[85][86]

Many phase I and phase II trials are currently testing new agents against neuroblastoma in children who have relapsed or are resistant to initial therapy. Investigators are studying targeted therapy, anti-angiogenesis agents, and new monoclonal antibodies such as hu14.18-IL2.

In November 2006, DRAXIS Health received approval from the U.S. Food and Drug Administration (FDA) to run two clinical trials using radioactive Iobenguane I-131 Injection (I-131 MIBG) to treat high-risk neuroblastoma[87] and in May 2008 Molecular Insight Pharmaceuticals announced the opening of a Phase IIa trial of Azedra, the I-131 MIBG molecule radiolabeled using Molecular Insight's proprietary Ultratrace technology, which removes unnecessary nonradioactive molecules, effectively concentrating radiation in the neuroblastoma tumor cells.[88][89][90] These trials are coordinated by a group of 11 children’s hospitals and two universities in the United States known as the New Advances in Neuroblastoma Therapy (NANT) consortium, and are continuations of earlier NANT studies. The NANT consortium is also currently offering trials using a tyrosine kinase inhibitor CEP-701 (lestaurtinib), new oral powder formulation of fenretinide, intravenous fenretinide, and bisphosphonate (Zometa).[91]

In February 2007, a study in Sweden reported that a common painkiller might inhibit the development of neuroblastoma and help make treatment of the disease more effective. Celecoxib, an analgesic, anti-inflammatory agent that inhibits the inflammatory enzyme Cox-2 which is required for neuroblastoma cells growth and proliferation. Clinical studies are now planned; research to date has been done only in animals and cell cultures.[92][93]

A November 2009 study in mice shows that activating the tumor suppressor p53 with a new drug, nutlin-3, may slow tumor growth.[94]. In this study, physician Tom Van Maerken of Ghent University Hospital in Belgium and his colleagues used nutlin-3 to neutralize MDM2, a protein that binds to the p53 protein and obstructs p53’s ability to trigger programmed cell death. Earlier studies have shown that nutlin-3 can specifically prevent MDM2 from disabling p53.

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External links

v • d • e
Small blue round cell tumors
v • d • e
Nervous tissue tumors/nervous system neoplasm/Neuroectodermal tumor (ICD-O 9350-9589) (C70-C72/D32-D33, 191-192/225)
Endocrine/
sellar (9350-9379)
CNS (9380-9539)
Multiple/unknown
Mature neuron
Meningiomas (meninges)
PNS: NST (9540-9579)
note: not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain
central nervous system navs: anat/physio/dev, noncongen/congen/neoplasia, symptoms+signs/eponymous, proc
peripheral nervous system navs: anat/histo/physio/dev, noncongen PNS somatic/autonomic/congen/neoplasia, symptoms+signs/eponymous, proc
v • d • e
Tumors: endocrine gland neoplasia (C73-C75/D34-D35, 193-194/226-227)
Pancreas/
islets of Langerhans
Hypothalamic/
pituitary axes
+parathyroid
Gonads
Pinealoma
MEN
1 · 2A · 2B
endocrine navs: anat/physio/dev/hormones, noncongen/congen/neoplasia, symptoms+signs/eponymous, proc


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