Neuroblastoma — from Genetic Profiles to Clinical Challenge
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《新英格兰医药杂志》
Neuroblastoma stands out among childhood cancers because of its relative frequency, enigmatic natural history, intriguing biologic features, and daunting therapeutic challenges. Much that is novel and on the cutting edge in oncology comes together in neuroblastoma: preventive screening, biology-driven management, dose-intensive or dose-dense chemotherapy, stem-cell transplantation, targeted therapies (radiation, monoclonal antibodies, drugs), agents that induce differentiation, and monitoring of minimal disease.1
Neuroblastoma is an embryonic neoplasm of the sympathetic nervous system. The histologic composition varies from primitive cells without neuronal features to mature neurons or ganglion cells, often within the same mass. Neuroblastoma is the most common extracranial solid tumor of childhood, accounting for 8 to 10 percent of pediatric cancers (childhood cancer is uncommon — hence, the critical role of cooperative groups, as exemplified by the report by Attiyeh and colleagues in this issue of the Journal ). More than 90 percent of the approximately 650 cases diagnosed yearly in the United States affect infants and toddlers. Random genetic mutations, rather than environmental factors, appear to be causative. The rare familial cases may result from a hereditary-predisposition locus at chromosome 16p12–13, whereas a germ-line mutation at chromosome 4p12 (the PHOX2B gene) underlies the rare synchronous occurrence of neuroblastoma and other neural-crest disorders (e.g., Hirschsprung's disease and congenital hypoventilation syndrome).
Patients present with signs and symptoms from the local effects of the primary tumor or of metastatic disease, which is often substantial, appearing in bone, bone marrow, lymph nodes, liver, or all of these sites; metastasis to lungs or the central nervous system is rare. Large retroperitoneal neuroblastomas often compress a kidney, causing hypertension. Paraspinal neuroblastomas may extend through intervertebral foramina ("dumbbell" tumors), leading to paraplegia. Cervical masses result in Horner's syndrome (i.e., ptosis, miosis, and anhidrosis). Extensive liver disease is typical in infants, as are subcutaneous tumor nodules, which are rare in older patients. Orbital involvement is manifested as ecchymotic proptosis ("raccoon eyes"). Limping is common when the long bones are involved.
Unsuspected neuroblastomas are found during scheduled physical examination or by routine imaging studies (e.g., prenatal ultrasonography or x-ray for suspected pneumonia). These incidentally discovered neuroblastomas usually have a favorable outcome, as do the neuroblastomas in a small subgroup of patients (2 percent) who present with paraneoplastic syndromes (i.e., clinical findings not produced by local-mass-effect). These remote effects include watery diarrhea from vasoactive intestinal peptide, which is produced by the tumor, and the opsoclonus–myoclonus–ataxia syndrome ("dancing eyes, dancing feet"), resulting from an autoimmune process. Because of its protean features, neuroblastoma can masquerade as juvenile rheumatoid arthritis, the battered-child syndrome, the malabsorption syndrome, and primary neurologic disorders.
Appropriate treatment is critically dependent on the clinical factors of age (younger than 18 months is favorable) and tumor stage and on biologic features, especially whether there is amplification (i.e., the presence of multiple copies) of the MYCN proto-oncogene (present in approximately 20 percent of all cases). Up to 60 percent of patients have stage 4 disease, with metastases in bone or bone marrow. Infants with stage 4 disease lacking MYCN amplification have cure rates of more than 90 percent with limited chemotherapy; no other pediatric solid tumor with metastases in bone or bone marrow is so readily curable. The prognosis is poor, however, for infants with stage 4 disease with MYCN amplification and for patients 18 months of age or older with stage 4 disease, regardless of MYCN status; the cure rates for these patients are 20 to 25 percent, despite aggressive therapy. Promising treatments that may improve outcome include the vitamin A derivative 13-cis retinoic acid, which induces tumor-cell differentiation; immunotherapy with monoclonal antibodies specific for ganglioside GD2, which is highly expressed on neuroblastoma cells; and targeted radiotherapy with metaiodobenzylguanidine (MIBG; an analogue of catecholamine precursors selectively concentrated in neuroblastoma cells) or –labeled anti-GD2 antibodies.
In sharp contrast, approximately 25 percent of patients survive with little or no cytotoxic therapy because, remarkably, the disease spontaneously regresses or, less commonly, differentiates into ganglioneuroma (which is benign). This "low-risk" group includes patients who have widespread disease — a unique entity called stage 4S (S is for "special") — involving the liver, skin, bone marrow, or all of these sites; and patients with localized tumors that were incompletely resected or have spread to regional lymph nodes. These low-risk neuroblastomas lack MYCN amplification and do not undergo the limitless proliferation and metastatic dissemination that typify malignancy (stage 4S is thought to encompass multifocal, not metastatic, lesions).
The results of mass screening of infants, which involves the measurement of urinary catecholamines (overproduced by 95 percent of neuroblastomas), support minimal intervention in low-risk cases. Large-scale screening programs were implemented with the goal of diagnosing neuroblastoma in the prognostically favorable setting of very young age and localized, rather than metastatic, stage. Screening identified many more low-risk cases than had been expected but failed to decrease the prevalence of stage 4 disease. These findings showed that many neuroblastomas in unscreened populations probably escape detection because of spontaneous regression or differentiation, and that low-risk neuroblastomas rarely evolve into stage 4 disease. Ongoing studies are assessing observation alone, including not performing surgery or biopsy, for suspected neuroblastomas serendipitously discovered in utero (as is increasingly common with the expanding use of prenatal ultrasonography) or early in life.
Lethal neuroblastomas display striking differences from low-risk neuroblastomas in biologic features (see diagram).2 Low-risk disease is characterized by hyperdiploidy from whole-chromosome gains and by expression of the TrkA neurotrophin receptor, which appears to mediate programmed cell death or differentiation, depending on the absence or presence of nerve growth factor. In contrast, lethal neuroblastomas tend to be diploid or tetraploid, with or without MYCN amplification; to have chromosomal aberrations postulated to affect tumor-suppressor or promoter genes on, for example, chromosomes 1p, 3p, 11q, and 17q; and to express TrkB neurotrophin receptor as well as its ligand (possibly constituting an autocrine survival loop). Insights into the biology of neuroblastoma have already led to targeted therapies.
Development of Major Subtypes of Neuroblastoma.
A genetic derangement in a diploid (2N) precursor of the sympathetic nervous system leads to triploid (3N) cells with whole-chromosome gains or to diploid or tetraploid (4N) cells with structural changes in the chromosome (a minus sign denotes loss, and a plus sign gain). Low risk means that there is an excellent prognosis with little or no therapy. High risk means that there is a poor prognosis despite complex treatment programs, although infants with metastatic disease lacking MYCN amplification do well with limited doses of chemotherapy (and are better classified as being at intermediate risk). This generalized model of tumorigenesis in neuroblastoma, adapted from Brodeur,2 does not account for all cases.
Recurrent or progressive disease develops in up to 20 percent of patients with localized or stage 4S neuroblastoma without MYCN amplification. A local relapse may be cured with surgical resection, and new stage 4S disease may regress spontaneously. Of greater concern is the rare patient who, despite a favorable clinical profile and no MYCN amplification, has progression to stage 4. Identification of such patients at diagnosis might improve the outcome. Biomarkers that hold promise in this regard, as Attiyeh et al. discuss, include abnormalities of chromosomes 1p and 11q. To date, however, these abnormalities in patients with disease that is more limited than stage 4 have been associated with the risk of progression but not with overall survival; these results suggest that the relapses are predominantly localized, rather than systemic. The paucity of such cases underscores the importance of upcoming cooperative group studies that will assess the correlation of these and other biomarkers with overall survival.
Source Information
Drs. Kushner and Cheung are attending physicians in the Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York.
References
Cheung N-KV, Cohn SL, eds. Neuroblastoma. New York: Springer, 2005.
Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 2003;3:203-216.(Brian H. Kushner, M.D., a)
Neuroblastoma is an embryonic neoplasm of the sympathetic nervous system. The histologic composition varies from primitive cells without neuronal features to mature neurons or ganglion cells, often within the same mass. Neuroblastoma is the most common extracranial solid tumor of childhood, accounting for 8 to 10 percent of pediatric cancers (childhood cancer is uncommon — hence, the critical role of cooperative groups, as exemplified by the report by Attiyeh and colleagues in this issue of the Journal ). More than 90 percent of the approximately 650 cases diagnosed yearly in the United States affect infants and toddlers. Random genetic mutations, rather than environmental factors, appear to be causative. The rare familial cases may result from a hereditary-predisposition locus at chromosome 16p12–13, whereas a germ-line mutation at chromosome 4p12 (the PHOX2B gene) underlies the rare synchronous occurrence of neuroblastoma and other neural-crest disorders (e.g., Hirschsprung's disease and congenital hypoventilation syndrome).
Patients present with signs and symptoms from the local effects of the primary tumor or of metastatic disease, which is often substantial, appearing in bone, bone marrow, lymph nodes, liver, or all of these sites; metastasis to lungs or the central nervous system is rare. Large retroperitoneal neuroblastomas often compress a kidney, causing hypertension. Paraspinal neuroblastomas may extend through intervertebral foramina ("dumbbell" tumors), leading to paraplegia. Cervical masses result in Horner's syndrome (i.e., ptosis, miosis, and anhidrosis). Extensive liver disease is typical in infants, as are subcutaneous tumor nodules, which are rare in older patients. Orbital involvement is manifested as ecchymotic proptosis ("raccoon eyes"). Limping is common when the long bones are involved.
Unsuspected neuroblastomas are found during scheduled physical examination or by routine imaging studies (e.g., prenatal ultrasonography or x-ray for suspected pneumonia). These incidentally discovered neuroblastomas usually have a favorable outcome, as do the neuroblastomas in a small subgroup of patients (2 percent) who present with paraneoplastic syndromes (i.e., clinical findings not produced by local-mass-effect). These remote effects include watery diarrhea from vasoactive intestinal peptide, which is produced by the tumor, and the opsoclonus–myoclonus–ataxia syndrome ("dancing eyes, dancing feet"), resulting from an autoimmune process. Because of its protean features, neuroblastoma can masquerade as juvenile rheumatoid arthritis, the battered-child syndrome, the malabsorption syndrome, and primary neurologic disorders.
Appropriate treatment is critically dependent on the clinical factors of age (younger than 18 months is favorable) and tumor stage and on biologic features, especially whether there is amplification (i.e., the presence of multiple copies) of the MYCN proto-oncogene (present in approximately 20 percent of all cases). Up to 60 percent of patients have stage 4 disease, with metastases in bone or bone marrow. Infants with stage 4 disease lacking MYCN amplification have cure rates of more than 90 percent with limited chemotherapy; no other pediatric solid tumor with metastases in bone or bone marrow is so readily curable. The prognosis is poor, however, for infants with stage 4 disease with MYCN amplification and for patients 18 months of age or older with stage 4 disease, regardless of MYCN status; the cure rates for these patients are 20 to 25 percent, despite aggressive therapy. Promising treatments that may improve outcome include the vitamin A derivative 13-cis retinoic acid, which induces tumor-cell differentiation; immunotherapy with monoclonal antibodies specific for ganglioside GD2, which is highly expressed on neuroblastoma cells; and targeted radiotherapy with metaiodobenzylguanidine (MIBG; an analogue of catecholamine precursors selectively concentrated in neuroblastoma cells) or –labeled anti-GD2 antibodies.
In sharp contrast, approximately 25 percent of patients survive with little or no cytotoxic therapy because, remarkably, the disease spontaneously regresses or, less commonly, differentiates into ganglioneuroma (which is benign). This "low-risk" group includes patients who have widespread disease — a unique entity called stage 4S (S is for "special") — involving the liver, skin, bone marrow, or all of these sites; and patients with localized tumors that were incompletely resected or have spread to regional lymph nodes. These low-risk neuroblastomas lack MYCN amplification and do not undergo the limitless proliferation and metastatic dissemination that typify malignancy (stage 4S is thought to encompass multifocal, not metastatic, lesions).
The results of mass screening of infants, which involves the measurement of urinary catecholamines (overproduced by 95 percent of neuroblastomas), support minimal intervention in low-risk cases. Large-scale screening programs were implemented with the goal of diagnosing neuroblastoma in the prognostically favorable setting of very young age and localized, rather than metastatic, stage. Screening identified many more low-risk cases than had been expected but failed to decrease the prevalence of stage 4 disease. These findings showed that many neuroblastomas in unscreened populations probably escape detection because of spontaneous regression or differentiation, and that low-risk neuroblastomas rarely evolve into stage 4 disease. Ongoing studies are assessing observation alone, including not performing surgery or biopsy, for suspected neuroblastomas serendipitously discovered in utero (as is increasingly common with the expanding use of prenatal ultrasonography) or early in life.
Lethal neuroblastomas display striking differences from low-risk neuroblastomas in biologic features (see diagram).2 Low-risk disease is characterized by hyperdiploidy from whole-chromosome gains and by expression of the TrkA neurotrophin receptor, which appears to mediate programmed cell death or differentiation, depending on the absence or presence of nerve growth factor. In contrast, lethal neuroblastomas tend to be diploid or tetraploid, with or without MYCN amplification; to have chromosomal aberrations postulated to affect tumor-suppressor or promoter genes on, for example, chromosomes 1p, 3p, 11q, and 17q; and to express TrkB neurotrophin receptor as well as its ligand (possibly constituting an autocrine survival loop). Insights into the biology of neuroblastoma have already led to targeted therapies.
Development of Major Subtypes of Neuroblastoma.
A genetic derangement in a diploid (2N) precursor of the sympathetic nervous system leads to triploid (3N) cells with whole-chromosome gains or to diploid or tetraploid (4N) cells with structural changes in the chromosome (a minus sign denotes loss, and a plus sign gain). Low risk means that there is an excellent prognosis with little or no therapy. High risk means that there is a poor prognosis despite complex treatment programs, although infants with metastatic disease lacking MYCN amplification do well with limited doses of chemotherapy (and are better classified as being at intermediate risk). This generalized model of tumorigenesis in neuroblastoma, adapted from Brodeur,2 does not account for all cases.
Recurrent or progressive disease develops in up to 20 percent of patients with localized or stage 4S neuroblastoma without MYCN amplification. A local relapse may be cured with surgical resection, and new stage 4S disease may regress spontaneously. Of greater concern is the rare patient who, despite a favorable clinical profile and no MYCN amplification, has progression to stage 4. Identification of such patients at diagnosis might improve the outcome. Biomarkers that hold promise in this regard, as Attiyeh et al. discuss, include abnormalities of chromosomes 1p and 11q. To date, however, these abnormalities in patients with disease that is more limited than stage 4 have been associated with the risk of progression but not with overall survival; these results suggest that the relapses are predominantly localized, rather than systemic. The paucity of such cases underscores the importance of upcoming cooperative group studies that will assess the correlation of these and other biomarkers with overall survival.
Source Information
Drs. Kushner and Cheung are attending physicians in the Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York.
References
Cheung N-KV, Cohn SL, eds. Neuroblastoma. New York: Springer, 2005.
Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 2003;3:203-216.(Brian H. Kushner, M.D., a)