Presentation of Neuroblastoma
Opsoclonus/Myoclonus Syndrome
Diagnosis
Prognosis
        Age
        Etiology
        Biologic factors
Unique Aspects of Neuroblastoma
        Biologically discrete types of neuroblastoma
        Neuroblastoma screening
        Spontaneous regression of neuroblastoma
        Low-stage neuroblastoma in the fetus and newborn

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life. (Refer to the PDQ summaries on Supportive Care for specific information about supportive care for children and adolescents with cancer).

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors).

Neuroblastoma is predominantly a tumor of early childhood, with two-thirds of the cases presenting in children younger than 5 years. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. These tumors can be divided into low-, intermediate-, and high-risk groups as illustrated in the Stage Information section of this summary. Low- and intermediate-risk patients usually have localized disease or are infants younger than 18 months. In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography.[2] The most common presentation of neuroblastoma is an abdominal mass. The most common symptoms in high-risk patients are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are common in these high-risk patients and arise from retrobulbar metastasis. Extensive bone marrow metastasis may result in pancytopenia. Abdominal distention with respiratory compromise due to massive liver metastases may occur in infants. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord extradurally, causing paralysis. Horner syndrome may be caused by neuroblastoma in the stellate ganglion, and children with Horner syndrome without apparent cause should be examined for neuroblastoma and other tumors.[3] Fever, anemia, and hypertension are occasionally found. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[4] On rare occasions, children may have severe, watery diarrhea due to the secretion of vasoactive intestinal peptide by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia.[5]

Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus.[6] The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[7,8] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes.[9] Patients who present with this syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported. Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation.[8,10,11] Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone (ACTH) treatment is thought to be effective, but some patients do not respond to ACTH.[7,10] Various drugs, plasmapheresis, intravenous gamma-globulin, and rituximab have been reported to be effective in selected cases.[10,12,13] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[6,12] The use of immunosuppressive therapy with and without intravenous gamma-globulin in the treatment of patients with neuroblastoma and opsoclonus/myoclonus syndrome is currently under study by the Children's Oncology Group (COG) (COG-ANBL00P3).

The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated, via conventional light microscopy, from other small round blue cell tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. Evidence for sympathetic neuronal differentiation may be demonstrated by immunohistochemistry, electron microscopy, or by finding elevated levels of serum catecholamines (e.g., dopamine and norepinephrine) or urine catecholamine metabolites, such as vanillylmandelic acid (VMA) or homovanillic acid (HVA). The minimum criterion for a diagnosis of neuroblastoma, as has been established by international agreement, is that it must be based on one of the following: (1) an unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, or increased levels of serum catecholamines or urinary catecholamine metabolites); or (2) the combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically-positive clumps of cells) and increased levels of serum catecholamines or urinary catecholamine metabolites, as described above.[14]

Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. The prognosis for patients with neuroblastoma is related to their age at diagnosis, clinical stage of disease, and, in patients older than 1 year, regional lymph node involvement. Other conventional prognostic variables include the site of the primary tumor and tumor histology.[15-18] (Refer to the Cellular Classification section of this summary for more information.) Biological prognostic variables are also used to help determine treatment.

Children of any age with localized neuroblastoma and infants younger than 1 year with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival.[15,19] Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy. Long-term disease-free survival with aggressive chemotherapy, including stem cell rescue and cis-retinoic acid, is approximately 30%.[20]

The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The only exception is that bone marrow involvement occurs less frequently, and there is a greater frequency of metastases in unusual sites such as lung or brain.[21] Neuroblastoma in an adolescent or an adult has a worse long-term prognosis regardless of stage or site and, in many cases, a more prolonged course when treated with standard doses of chemotherapy. High-dose chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients. Other modalities, such as local radiation therapy and the use of agents with confirmed activity, may improve the poor prognosis.[22,23]

Neuroblastoma is an embryonal cancer; it is thought to arise from partially committed primordial cells during fetal or early childhood development. Little is known about the events that predispose to the developments of neuroblastoma. Epidemiologic studies and genetic studies of hereditary diseases have not provided insight into the etiology. No commonly mutated gene has been identified. In a genome-wide association study of 1032 patients with neuroblastoma, a significant association was observed between common genetic variation at chromosome 6p22 and susceptibility to neuroblastoma.[24]

A number of biologic variables have been studied in children with this tumor.[25] Treatment decisions may be based on important factors such as Shimada classification, tumor cell chromosome number, amplification of the MYCN oncogene within tumor tissue, unbalanced 11q loss of heterozygosity (LOH), and LOH for chromosome 1p.[18,19,26-31] An open biopsy is usually needed to obtain adequate tissue for determination of these biological characteristics.

Many biological characteristics of tumors are not currently used in determining therapy; however, as clinical research matures, these characteristics may be found useful as therapeutic targets or as clinically important prognostic factors. Amplification of the MYCN gene is associated with deletion of chromosome 1p and gain of the long arm of chromosome 17(17q), the latter of which independently predicts a poor prognosis.[32] In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predict prognosis.[33] Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and RNA;[34,35] urinary VMA, HVA, and their ratio;[36] dopamine; CD44 expression; TrkA gene expression; neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level.[25] High-level expression of the MRP1 drug resistance gene is an independent indicator of decreased survival.[37] The profile of GABAergic receptors expressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN gene amplification.[38] Gene expression profiling may prove useful for prognosis prediction.[39] In addition, reponse to treatment has been associated with outcome. The persistence of neuroblastoma cells in bone marrow during or after chemotherapy, for example, is associated with a poor prognosis.[40,41]

Based on these biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, the tumors have been categorized into three biological groups. These groups are not used to determine treatment at this time. One type expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress. Another type expresses the TrkB neurotrophin receptor, has gained an additional chromosome, 17q, has loss of heterozygosity of 14q or 11q, and is genomically unstable. In a third type, in addition to a gain of 17q, chromosome 1p is lost and the MYCN gene becomes amplified.[42,43]

Current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan.[44] A large population-based North American study, in which most infants in Quebec were screened at the ages of 3 weeks and 6 months, has shown that screening detects many neuroblastomas with favorable characteristics [45,46] that would never have been detected clinically, apparently due to spontaneous regression of the tumors. Another study of infants screened at the age of 1 year shows similar results.[47] Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce the number of deaths from neuroblastoma in infants screened at any age.[46,47] No public health benefits have been shown from screening infants for neuroblastoma at these ages.

This phenomenon has been well described in infants, especially in those with the 4S pattern of metastatic spread.[48] (Refer to the Stage Information section of this summary for more information.) Regression generally occurs only in tumors with a near triploid number of chromosomes, no MYCN amplification, and no loss of chromosome 1p. Additional features associated with spontaneous regression [49,50] include the lack of telomerase expression,[51,52] the expression of Ha-ras,[53] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.

Recent studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or as an incidental finding by ultrasound, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[54-56] The COG is currently studying whether it is feasible to simply observe neonates with small adrenal masses that are presumed to be neuroblastomas (COG ANBL00P2). These masses are usually found during prenatal or incidental ultrasound examination.

(Refer to the PDQ summary on Screening for Neuroblastoma for more information.)

References

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