PDQ® Treatment Health Professionals
This treatment information summary on neuroblastoma is an overview of prognosis, diagnosis, classification, and patient treatment. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recent published literature are included after review by pediatric oncology specialists.
Cancer in children is rare. A team approach that incorporates the skills of the local physician, pediatric surgeon, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, and social workers is imperative to ensure that patients receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. For advances to be made in treating these patients, therapy should be delivered in the context of a clinical trial at a major medical center that has expertise in treating children. Only through entry of all eligible children into appropriate, well-designed clinical trials will progress be made against these diseases. 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.
Neuroblastoma is predominantly a tumor of early childhood, with two thirds of the cases presenting in children younger than 5 years of age. In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. The most common symptoms are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are common and arise from retrobulbar metastasis. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord, causing paralysis. Fever, anemia, and hypertension are found occasionally. Rarely, children may have severe watery diarrhea due to the secretion of vasoactive intestinal peptide by the tumor, cerebellar ataxia, or opsoclonus/myoclonus.
The opsoclonus/myoclonus paraneoplastic syndrome appears to have an immunologic mechanism that is not yet fully defined. Patients who present with this syndrome often have low-grade disease with good survival, but tumor-related deaths have been reported. Opsoclonus/myoclonus has also been associated with pervasive and permanent neurologic disorders, including psychomotor retardation. Neurologic dysfunction may be the presenting symptom or may first occur after removal of the tumor. 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 the most effective, but some patients are resistant to ACTH.[4,5] Various drugs, plasmapheresis, and gamma-globulin have been reported to be effective in selected cases.[5,6] It has been suggested that the long-term neurologic outcome may be superior in patients treated with chemotherapy.
The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be discriminated from other small round blue cell tumors of childhood (such as lymphomas, primitive neuroectodermal tumor, and rhabdomyosarcoma) without finding evidence of sympathetic neuronal differentiation by immunohistochemistry, electron microscopy, or elevated levels of urine or serum catecholamines or metabolites. The minimum criterion for a diagnosis of neuroblastoma that has been established by international agreement is 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 urine or serum catecholamines or metabolites). Catecholamines and metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA). To be considered increased, levels must be greater than 3.0 SD above the mean per milligram creatinine for age, and at least two of these must be measured. 2) Bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically positive clumps of cells) and increased levels of urine or serum catecholamines or metabolites as described above.
Approximately 70% of all 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 of age) regional lymph node involvement. Other conventional prognostic variables include the site of the primary tumor and tumor histology (see Cellular Classification section below).[8-10]
Children of any age with localized neuroblastoma and infants younger than 1 year of age with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival.[8,11] Older children with advanced-stage disease, however, have a significantly decreased chance for cure despite intensive therapy. As an example, aggressive multiagent chemotherapy has resulted in a 2-year survival rate of approximately 20% in older children with stage IV neuroblastoma.[12,13] Neuroblastoma in the adolescent or adult has a worse long-term prognosis regardless of stage or site and, in many cases, a more prolonged course.
A number of biologic variables have been studied in children with this tumor. Of particular importance are aneuploidy of tumor DNA and amplification of the N-myc oncogene within tumor tissue, since treatment decisions may be based on these factors. Hyperdiploid tumor DNA is associated with a favorable prognosis, especially in infants with neuroblastoma, while N-myc amplification is associated with a poor prognosis, regardless of patient age.[11,15,16] Expression of the gene encoding the high-affinity nerve growth factor receptor (termed TRK-A proto-oncogene), the low-affinity nerve growth factor receptor (termed LNGFR), and HA-ras p21 are each associated with a very good outcome and are inversely related to amplification of the N-myc gene.[17,18] An increased ratio of the excreted catecholamine metabolites (VMA or HVA), lack of expression of glycoprotein CD44 on the tumor cell surface, elevated serum ferritin, serum neuron-specific enolase, and serum lactate dehydrogenase are each associated with poor prognosis.[19-24] Biologic staging consisting of N-myc copy number and age is useful in defining prognosis and treatment of stage III neuroblastoma. Some data support the theory that, in neuroblastomas, high levels of p-glycoprotein, the protein product of the multidrug resistance gene, directly correspond with a poorer outcome following chemotherapy.
Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted. This may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.
The current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan but remains controversial. A large population-based North American study in which most infants in Quebec were screened at ages 3 weeks and 6 months has shown that screening detects many neuroblastomas with favorable characteristics[29,30] that would never have been detected clinically, apparently because the tumors would have spontaneously regressed. There was no reduction in the incidence of advanced-stage neuroblastomas with unfavorable biological characteristics in older children. This strongly suggests that screening for neuroblastoma at ages 3 weeks and 6 months will not decrease mortality and morbidity. The ongoing collection of population- based mortality data in the Quebec study will allow more definitive conclusions regarding the public health benefits of neuroblastoma screening. For a more extensive discussion of neuroblastoma screening, see the PDQ treatment information summary on Screening for Neuroblastoma.
One clinicopathologic staging system involves evaluation of tumor specimens for the amount of stromal development, the degree of neuroblastic maturation, and the mitosis-karyorrhexis index of the neuroblastic cells. Favorable and unfavorable prognoses are defined on the bases of these histologic parameters and on patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies.[2,3]
There are several staging systems currently used for neuroblastoma. The system used in the treatment section of this document (localized, regional, disseminated, and special) is based on the Childrens Cancer Group (CCG), St. Jude, and the Pediatric Oncology Group (POG) staging systems. An International Neuroblastoma Staging System (INSS) has been proposed, which combines elements of the POG and CCG staging systems. Current protocols use the POG or CCG staging system to assign treatment, but also specify that the INSS stage be defined for all patients. If the INSS is validated in current studies, it will replace previous systems in future protocols. Each of these staging systems is described below.
The CCG uses a clinical staging system based on physical examination, radiographic evaluation, and bone marrow examination. Follow-up of patients staged according to the CCG system has demonstrated the prognostic significance of this staging system.
Stage II: tumor extending in continuity beyond the organ or structure of
Investigators at St. Jude Children's Research Hospital developed a clinical, surgical, and pathologic staging system that places major emphasis on the presence of regional lymph node metastases. From this system evolved the Pediatric Oncology Group (POG) staging system outlined below. The prognostic significance of the POG staging system has been documented in several studies.[3,4] The major differences between the CCG and POG systems are in the staging of patients with involved ipsilateral lymph nodes (stages I and II in CCG, stage C in POG), and in patients with tumors that cross the midline and who have negative nodes (POG stage A or B, CCG stage III).
For the purposes of treatment presented here, neuroblastoma is categorized as localized resected, localized unresected, regional, disseminated, and special.
Because of the prognostic significance and the therapeutic implications of specific tumor biologic properties (e.g., N-myc amplification and tumor DNA ploidy), it is important that tumor specimens adequate for determination of these factors be obtained prior to treatment. Vanillylmandelic acid and homovanillic acid levels should be obtained prior to therapy. If elevated, these markers can be used to determine the persistence of disease.
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
Localized disease includes those with INSS stage 1 disease, Childrens Cancer Group (CCG) stage I, II, or III tumors that have been resected and have negative nodes, Pediatric Oncology Group (POG) stage A disease, and favorable biologic features. These children, of any age, have a cure rate of greater than 90%.[2-4]
Complete gross resection produces disease-free survivals that are indistinguishable from those obtained with operation plus adjuvant chemotherapy or operation plus radiation therapy.[2-4] Microscopic residual disease in the tumor bed does not adversely affect survival and does not indicate the need for therapy beyond operation. However, in light of other information relating to prognosis, including patient age, the Shimada grade, ferritin, NSE, LDH, and N-myc amplification, further therapy may be indicated.
Localized unresectable disease includes those with INSS stage 2 disease, Childrens Cancer Group (CCG) stages I, II, or III tumors that are incompletely resected and have negative nodes, and Pediatric Oncology Group (POG) stage B disease. In these patients, there are no metastases to regional lymph nodes, but the tumor is not completely resected. The probability of long-term survival is 75%-90% depending on age of patient, favorable biologic features, and therapy delivered.[1-4]
The initial management generally consists of subtotal resection or biopsy followed by chemotherapy.[3,5-8] Second-look operation is used subsequently to remove residual tumor, and radiation therapy may be given to patients with residual disease following second-look operation. The chemotherapeutic agents most commonly used include cyclophosphamide and doxorubicin, with cisplatin and either teniposide or etoposide reserved for more resistant tumors. Short-term therapy for 4-6 months is usually adequate. However, in light of other information relating to prognosis, including patient age, the Shimada grade, ferritin, NSE, LDH, and N-myc amplification, either more or less therapy may be indicated.
Regional neuroblastoma includes those with INSS stage 3 disease, Childrens Cancer Group (CCG) stage II or stage III tumors that have positive nodes, and Pediatric Oncology Group (POG) stage C disease. Infants younger than 1 year of age have a greater than 80% chance of cure while older children have a cure rate of 50%-70% with current, relatively intensive therapy.[1-4] In those cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy should not be undertaken before a trial of chemotherapy has been given.
Treatment options for patients younger than 1 year of age:
3. Radiation therapy to nodal drainage areas may improve outcome.
2. Aggressive chemotherapy and radiation therapy given simultaneously.
Disseminated disease includes those with Childrens Cancer Group (CCG) stage IV and Pediatric Oncology Group (POG) stage D disease. Differentiating patients with stage IVS ("special") neuroblastoma from other disseminated disease patients is important; stage IVS patients should be treated as described in the treatment section on stage IVS neuroblastoma. Survival of patients with disseminated disease is strongly dependent on age. Children younger than 1 year of age at diagnosis have a good chance of long-term survival (5-year disease-free survival rate of 50%-80%),[1,2] with outcome particularly dependent on tumor cell ploidy (hyperploidy confers a favorable prognosis while diploidy predicts early treatment failure).[3,4]
For children older than 1 year of age, long-term survival ranges from 10%-40%. A randomized study was performed comparing high-dose therapy with purged autologous bone marrow transplantation versus three cycles of intensive consolidation chemotherapy. The 3 year event-free survival was significantly better in the autologous bone marrow transplantation arm (34%) compared to the consolidation chemotherapy arm (18%). In addition, patients on this study were subsequently randomized to stop therapy or to receive 6 months of 13 cis- retinoic acid. The use of 13 cis-retinoic acid can induce differentiation and growth of neuroblastoma in vitro. Overall, the 3 year event-free survival from the time of the second randomization was 47% for patients receiving 13 cis-retinoic acid and 25% for patients randomized to receive no further therapy. For patients randomized to receive 13 cis-retinoic acid, an apparent advantage in 3 year event-free survival was seen for stage IV patients (40% vs 18%), high-risk stage III patients (77% vs 49%), patients randomized to receive consolidation chemotherapy alone (32% vs 16%), patients randomized to receive autologous bone marrow transplantation (55% vs 39%), and patients with MYCN genomic amplification (39% vs 13%). Based on these results, future clinical trials will build upon autologous stem cell transplantation and cis-retinoic acid for high-risk neuroblastoma.[5,6]
The potential benefit of aggressive surgical approaches to achieve complete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocally demonstrated. Two studies reported that complete resection of the primary tumor at diagnosis improved survival; however, the outcome in these patients may be more dependent on the biology of the tumor than on the extent of surgical resection.[7-9] Consideration should also be given to enrollment of poor-prognosis patients older than 1 year of age in a clinical trial that incorporates new agent testing prior to initiating standard therapy. These studies appear to have no deleterious effect on outcome and have identified ifosfamide, iproplatin, and carboplatin as effective agents in newly diagnosed neuroblastoma.
3. The use of prolonged isotretinoin treatment following intensive chemotherapy. Neuroblastoma cells in vitro often respond to retinoic acid by differentiation and/or growth inhibition, and several patients treated with retinoic acid have shown prolonged decreases in bone marrow tumor involvement.[6,17] The potential benefit of maintenance therapy with isotretinoin is being tested at CCG institutions, where patients were randomly allocated following their intensive chemotherapy to receive isotretinoin for 6 months or to receive no further therapy.
Stage IVS ("special") neuroblastoma typically presents in very young infants and has a 2-year survival rate greater than 90%. The International Neuroblastoma Staging System (INSS) has been revised to include, in stage 4S only, infants younger than 1 year of age at diagnosis. Bone marrow disease must also be very limited to qualify for stage 4S (see the Stage Information section above). Stage IVS neuroblastoma has a higher rate of spontaneous regression than other neuroblastomas, often making chemotherapy unnecessary. In specific circumstances, mild chemotherapy may be indicated.
The treatment of children with stage IVS disease is controversial.[3,4] Children with this special pattern of neuroblastoma may not require therapy, although the development of complications, such as functional compromise from massive hepatomegaly, and is an indication for intervention, especially in infants younger than 2 months of age.[4,5]
Because of the unpredictable clinical course of this entity, these children should be entered into cooperative group studies and observed by a multidisciplinary team of physicians who are prepared to individualize therapy according to the requirements of each case.
The prognosis and treatment of recurrent or progressive neuroblastoma depend on the site and extent of the recurrence or progression and on the previous therapy. Recurrence is usually widespread and prognosis poor despite additional intensive therapy. Unlike at initial presentation, central nervous system involvement is common. Most commonly, there is inward compression of the brain from cranial metastases, but meningeal and isolated intracranial metastasis can occur. Early recognition and treatment of central nervous system involvement may result in reduced neurologic impairment. The selection of further treatment depends on many factors, including the site of recurrence and previous treatment as well as individual patient considerations. Clinical trials are appropriate and should be considered.[2-7] Refer to the PDQ Protocol File for ongoing clinical trials for neuroblastoma.
Date Last Modified: 11/1999