Neuroblastoma

Neuroblastoma is the most common extracranial solid cancer in infancy and childhood, 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. A branch of the autonomic nervous system, the SNS is a nerve network that carries messages from the brain throughout the body and is responsible for the fight-or-flight response and production of adrenaline or epinephrine. Its solid tumors, which take the form of a lump or mass, commonly begin in one of the adrenal glands, though they can also develop in nerve tissues in the neck, chest, abdomen, or pelvis. (Esthesioneuroblastoma is also known as "olfactory neuroblastoma".^[3])

The cause of neuroblastoma is unknown, though most physicians believe that it is an accidental cell growth that occurs during normal development of the adrenal glands.

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

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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.^[4]

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, but less than 10% of cases occur in people older than 10 years of age.^[5]

Etiology

The etiology of neuroblastoma is not well understood. Several risk factors have been proposed and are the subject of ongoing research. Due to characteristic early onset many studies have focussed 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 inconsistent.^[6]

Other studies have examined possible links with atopy and exposure to infection early in life,^[7] use of hormones and fertility drugs,^[8] and maternal use of hair dye.^[9]

Diagnosis

The first symptoms of neuroblastoma are often vague and may include fatigue, loss of appetite, and fever. Later symptoms depend on tumor locations:^[10]

• In the abdomen, a tumor may cause a swollen belly and constipation.
• A tumor in the chest may cause breathing problems.
• Tumors pressing on the spinal cord cause a feeling of weakness.
• Bone lesions in the legs and hips often cause bone pain and limping.
• A tumor in the head may cause the eyes to start to swell outwards and turn black due to the pressure from behind.

Often because symptoms are so unclear, 50 to 60% all neuroblastomas have already spread (metastasized) to other parts of the body by the time a diagnosis is made.^[11]

The diagnosis is usually confirmed by a surgical pathologist, taking into account the clinical presentation, microscopic findings, and other laboratory tests. On microscopy, the tumor cells are typically described as small, round and blue, and rosette patterns (Homer-Wright pseudo-rosettes) may be seen.^[12] 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 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).

Another way to detect neuroblastoma is the mIBG scan (meta-iodobenzylguanidine),^[13] but it does not diagnose the disease in 100% of the cases. IThe 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.^[14]

Identification

Other tumors also have similar origins and show a wide pattern of differentiation ranging from benign ganglioneuroma to partially differentiated ganglioneuroblastoma to highly malignant neuroblastoma.

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).^[15]

Stage and risk assignment

The "International Neuroblastoma Staging System" (INSS) stratifies neuroblastoma according to its anatomical presence at diagnosis:^[16][17][18]

• 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 11,000 neuroblastoma patients treated in Europe, Japan, USA, Canada, and Australia between 1972 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 MYCN amplification to intermediate risk category. The new INRG risk assignment will classify neuroblastoma at diagnosis based on stage (L1, L2, M, and MS), age (dichotomized at 18 months), tumor grade, MYCN amplification, unbalanced 11q aberration, and ploidy into four pre-treatment risk groups: low, intermediate, high, and ultra-high risk.^[19][20]

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.^[21][22] 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.^{[23][24] [25]}

Treatment

Current

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 multimodality therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplant, differentiation agent isotretinoin also called 13-cis-retinoic acid, and frequently immunotherapy with anti-GD2 antibodies).

Recent biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed accurate patient assignment to risk groups so that treatment strategies can be more effectively undertaken.^[26] These criteria include the age of the patient, extent of disease spread, microscopic appearance, and several other biological features, most importantly MYCN oncogene amplification (MYCN regulates microRNAs^[27]), into low, intermediate, and high risk disease. (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.)^[28]

The therapy for these different risk categories is very different.

• Low risk patients can frequently be observed without any treatment at all.

• Intermediate risk patients are treated with surgery and chemotherapy.^[29]

• High risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, bone marrow / Hematopoietic stem cell transplantation^[30] and biological-based therapy with 13-cis-retinoic acid (isotretinoin or Accutane).^[31]

With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90%. In contrast, therapy for high-risk neuroblastoma results in cures only about 30% of the time.^[32]

Clinical trials for new treatments

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. Both will be 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 trials were expected to start in December 2006 or early 2007.^[33]

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 substance that works by inhibiting the effect of the inflammatory enzyme, Cox-2, and thus could affect neuroblastoma tumors, which depend on Cox-2 for their growth and proliferation. Clinical studies are now planned; research to date has been done only in animals and cell cultures.^[34]

Post-treatment prognosis

Neuroblastoma frequently recurrs. Further treatment is then required. This can be problematic because some treatments, such as chemotherapy, have cumulative effects and side-effects therefore can increase significantly if used again.

Intensive chemotherapy and radiation therapy have known long-term negative consequences. 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.^[35][36]

The protein p53 is believed to play a role in the development of resistance to chemotherapy.^[37]

References