Version May 2024
INTRODUCTION — The term neuroblastoma is commonly used to refer to a spectrum of neuroblastic tumors (including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) that arise from primitive sympathetic ganglion cells. The neuroectodermal cells that comprise neuroblastic tumors originate from the neural crest during fetal development, and are destined for the adrenal medulla and sympathetic nervous system. By contrast, pheochromocytomas and paragangliomas arise from a different type of cell, the chromaffin cell, which also migrates from the neural crest to the adrenal gland [1-3]. Together, both types of cells make up the adrenal medulla, a component of the sympathetic nervous system. (See "Pheochromocytoma and paraganglioma in children" and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)
Neuroblastomas, which account for 97 percent of all neuroblastic tumors, are heterogeneous, varying in terms of location, histopathologic appearance, and biologic characteristics [4]. They are most remarkable for their broad spectrum of clinical behavior, which can range from spontaneous regression, to maturation to a benign ganglioneuroma, or aggressive disease with metastatic dissemination leading to death [5]. Clinical diversity correlates closely with numerous clinical and biological factors (including patient age, tumor stage and histology, and genetic and chromosomal abnormalities), although its molecular basis remains largely unknown. For example, most infants with disseminated disease have a favorable outcome following treatment with chemotherapy and surgery, while the majority of children over the age of 18 months with advanced-stage disease die from progressive disease despite intensive multimodality therapy.
The epidemiology, embryogenesis, molecular pathogenesis, and pathology of neuroblastoma will be presented here. The clinical presentation, diagnosis, evaluation, treatment, and prognosis of neuroblastoma are presented separately. Neuroblastomas arising in the olfactory epithelium, which have a different cell of origin, presentation, and treatment than neuroblastoma, also are discussed separately.
●(See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma".)
●(See "Treatment and prognosis of neuroblastoma".)
●(See "Olfactory neuroblastoma (esthesioneuroblastoma)".)
EPIDEMIOLOGY — Neuroblastoma is almost exclusively a disease of children. It is the third most common childhood cancer, after leukemia and brain tumors, and is the most common solid extracranial tumor in children. More than 600 cases are diagnosed in the United States each year [4], and neuroblastoma accounts for approximately 15 percent of all pediatric cancer fatalities.
Incidence rates are age-dependent (figure 1). The median age at diagnosis is 17.3 months, and 40 percent of patients are diagnosed before one year of age [4,5]. Neuroblastomas are the most common extracranial solid malignant tumor diagnosed during the first two years of life, and the most common cancer among infants younger than 12 months, in whom the incidence rate is almost twice that of leukemia (58 versus 37 per one million infants) [6]. The incidence of neuroblastoma is greater among White than Black infants (ratio of 1.7 and 1.9 to 1 for males and females, respectively), but little if any racial difference is apparent among older children [4]. Neuroblastoma is slightly more common among boys compared with girls [4].
RISK FACTORS — Little is known about the etiology of sympathetic nervous system tumors. The early age of onset suggests that preconceptual or gestational environmental events (eg, exposure to drugs, hormones, toxins, or viruses) may play a role.
Maternal and fetal factors — Studies have suggested a number of maternal factors that may be associated with the subsequent development of neuroblastoma. These include the following:
●Opiate consumption – At least one case control study has linked maternal consumption of opiates (particularly codeine, odds ratio 3.4) while pregnant or nursing with an increased risk of neuroblastoma in children [7].
●Folate deficiency – Maternal folate consumption has been associated with a decreased risk of neuroblastoma. In a population-based study investigating the effect of fortification of flour with folic acid to prevent neural tube defects, the incidence of neuroblastoma declined from 1.6 to 0.6 cases per 10,000 births before and after fortification, respectively [8]. This finding was consistent with other studies suggesting an association between maternal vitamin use and decreased risk of neuroblastoma [9,10].
●Toxic exposures – Epidemiologic studies provide little convincing evidence for toxic or infectious environmental exposure as an etiologic factor for the development of neuroblastoma [4,11-21]. However, given the identification of maternal folate deficiency as a risk factor, it is possible that case control studies in a folate deficient population might uncover an environmental factor.
●Congenital abnormalities – An association between the presence of major congenital abnormalities and the subsequent development of neuroblastoma has been reported in some [10,22-26], but not all [16,27-29], studies.
●Size for gestational age – A population-based case control study of 357 patients with neuroblastoma found an association between small or large for gestational age and increased neuroblastoma risk [10].
●Gestational diabetes mellitus – A case control study of 240 children with neuroblastoma showed a correlation with the presence of maternal gestational diabetes mellitus [25]. The effect was greatest in those children diagnosed prior to one year of age.
Genetic factors — The majority of neuroblastomas are sporadic and not correlated with any specific constitutional germline chromosomal abnormality, inherited predisposition, or associated congenital anomalies. However, there are at least some exceptions as follows:
●Single-nucleotide polymorphisms at LIM domain only 1 (LMO1) have been observed in approximately 12 percent of patients with neuroblastoma, with evidence suggesting that these genetic variations play a causal role in neuroblastoma tumorigenesis [30,31].
●Another study examining genetic determinants of pediatric cancer did not observe LMO1 mutations, but reported germline mutations in succinate dehydrogenase complex, subunit B (SDHB), adenomatous polyposis coli (APC), anaplastic lymphoma kinase (ALK), and breast cancer susceptibility gene 2 (BRCA2) in 1 out of 100 patients with neuroblastoma [32].
●A higher incidence of neuroblastoma has been suggested in girls with Turner syndrome [33]. (See "Clinical manifestations and diagnosis of Turner syndrome".)
●Somatic and germline mutations in the paired-like homeobox 2B (PHOX2B) gene are in both sporadic and familial neuroblastoma [34-37]. Germline PHOX2B mutations are also observed in congenital central hypoventilation syndrome and in some cases of congenital aganglionic megacolon (Hirschsprung disease) [35,38]. (See "Disorders of ventilatory control", section on 'Congenital central hypoventilation syndrome' and "Congenital aganglionic megacolon (Hirschsprung disease)" and "Congenital central hypoventilation syndrome and other causes of sleep-related hypoventilation in children", section on 'Congenital central hypoventilation syndrome'.)
Familial neuroblastoma — Although the majority of neuroblastomas are sporadic, in 1 to 2 percent of cases, there can be a familial (ie, inherited) cases of neuroblastoma [39-41]. Inherited cases usually present at an earlier age than sporadic cases (mean age 9 versus 17 months), and a large proportion have bilateral adrenal or multifocal disease.
Most cases of familial neuroblastoma are due to germline mutations in the ALK receptor tyrosine kinase [42,43]. These cases appear to be inherited in an autosomal dominant pattern with incomplete penetrance and a broad spectrum of clinical behavior [44]. In addition, germline PHOX2B mutations are noted in approximately 6 percent of familial cases [34-36]. (See 'Genetic factors' above.)
Some reports suggest that familial predisposition may be conferred through disruption of a locus at 16p12-13 [45,46]. Others have identified rare germline variants at the TP53 locus (17p13.1) that are associated with neuroblastoma susceptibility [47]. Germline mutations in TP53 are the cause of Li-Fraumeni syndrome, and individuals who inherit these mutations are at increased risk of developing a wide variety of cancers at an early age. (See "Li-Fraumeni syndrome".)
Implications for siblings and future offspring — In families without a history of multiple affected individuals, it is unlikely that a sibling of a patient with neuroblastoma will also be affected. The risk for children of survivors of neuroblastoma is difficult to determine because of the small number of cases and treatment-related infertility. (See "Overview of infertility and pregnancy outcome in cancer survivors".)
PATHOGENESIS
Embryology — Neuroblastoma arises from early neural crest precursors that undergo transformation secondary to genetic or epigenetic events that lead to blocked or aberrant developmental differentiation [48]. The neural crest is a transient multipotent embryologic tissue which migrates out of the neural chord during development. Neuroblasts undergo an epithelial to mesenchymal transition and migrate both ventrally and caudally to form components of many tissues including the branchial arches, cardiac and thoracic vessels, and the sympathetic nervous system, which includes the adrenal glands.
While a great deal has been discovered about the genetic and transcriptional regulation of neural crest development over the past decade [49-51], the events that induce neuroblastoma tumorigenesis remain poorly defined. It is clear, however, that multiple different changes can induce tumor formation and the timing and character of driving oncogenic events may well define the phenotype of the resulting cancer (figure 2). As an example, cases of localized neuroblastoma arising under the age of one year likely represent tumors that develop at a different stage of neural crest differentiation than does high-stage disease [52,53]. Spontaneous regression of neuroblastomas found in newborn infants through screening likely occurs due to differentiation or age-dependent changes in growth factors in these infants. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Is there a role for neuroblastoma screening?'.)
Placing the oncogenic factors driving neuroblastoma in the context of neural crest development helps to explain the heterogeneity of this complex tumor type (figure 2). The pathology of neuroblastoma also varies considerably between patients, with age, location of tumor, and host/tumor immune interactions likely playing major roles in biology behavior. (See 'Pathology' below.)
Molecular abnormalities (prognostic impact) — Various molecular and cytogenetic factors have been implicated in the pathogenesis of neuroblastoma [54-57]. The molecular and cytogenetic characterization of neuroblastomas is a routine part of the clinical evaluation because of the influence of these findings on clinical outcome. The selection of treatment based upon molecular and genetic factors (ie, risk-adapted therapy) is described separately. (See "Treatment and prognosis of neuroblastoma".)
While an extensive discussion of the oncogenic drivers, mutations, and cytogenetic alterations found in neuroblastoma is beyond the scope of this review [48,58], we detail some of the most well-characterized factors here.
Segmental chromosome abberrations — Chromosomal deletions (as detected by loss of heterozygosity [LOH]) and segmental chromosome aberrations (SCA) are found in approximately 50 percent of neuroblastomas, localized to chromosomes 1p, 11q, and 14q [59-63], among others [64-66].
Deletion of a part of chromosome 1p is one of the most common chromosomal changes observed in neuroblastoma and is associated with a poor prognosis [67-70]. As an example, in a study of cytogenetic factors in 89 neuroblastomas among patients with stage 1, 2, or 4S disease, mean three-year event-free survival was greater among those without than with allelic loss of chromosome 1p (100 versus 34 percent for stage 1, 2, or 4S disease and 53 versus 0 percent for stage 3 or 4 disease) [70]. The staging used in neuroblastoma is the International Neuroblastoma Risk Group (INRG) Staging System (table 1) [71,72]. However, previous staging systems were the basis of some earlier studies cited in this topic and have been included where relevant. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma".)
MYCN status — Deletions of 1p are highly associated with amplification (increased copy number) and overexpression of the oncogene MYCN (also called N-myc), a close relative of the oncogene c-myc that resides on chromosome 2p24-25 [67,73]. Gene overexpression results in persistently high levels of the MYCN protein, a DNA binding transcription factor known to cause malignant transformation in both in vitro and in vivo tumor models [74,75]. Additionally, a subgroup of patients with neuroblastoma overexpress a separate gene FOXR2, which stabilizes and increases MYCN protein levels [76]. A 50- to 400-fold amplification of MYCN is found in approximately 25 percent of neuroblastomas and is an indicator of poor prognosis [77-83].
The prognostic significance of MYCN amplification can be illustrated by the following data:
●In one study of 2660 patients from the INRG database with stage 1 or stage 2 neuroblastoma, according to an earlier staging system (table 2), patients with MYCN-amplified tumors had significantly worse event-free and overall survival (53 versus 90, and 72 versus 98 percent, respectively) compared with those without MYCN amplification [82].
●A similar impact of MYCN amplification was observed in a study of 110 infants with stage 4S neuroblastoma in whom survival was significantly worse for those with MYCN amplification compared with those without amplification (<50 versus >90 percent) [81].
In contrast, among children with stage 4 neuroblastoma without amplification of MYCN, prognosis depends upon age [84]. In a study from the Children's Cancer Group, the six-year event-free survival rates for those under 12 months, 12 to 18 months, 18 to 24 months, and over 24 months was 92, 74, 31, and 23 percent, respectively.
The absence of MYCN amplification and the absence of other structural abnormalities, such as in 11q or 17q, can define low-risk tumors [71]. Deletions of 11q and/or 14q are detected in 25 to 50 percent of neuroblastomas [62,63,71]. Neuroblastomas that are characterized by these changes generally lack 1p deletions and MYCN amplification, and they appear to represent a distinct tumor subtype [85].
A gain of chromosome 17q material (trisomy 17q) occurs in over one-half of neuroblastomas and appears to be associated with a particularly aggressive phenotype [86,87]. As an example, in one report, overall survival was significantly worse in children with trisomy 17q compared with those whose tumors had a normal 17q number (31 versus 86 percent) [86]. In contrast, in another report, whole chromosome 17 gain was associated with increased survival [87].
Alterations in total DNA content — In additional to structural chromosomal changes, alterations in total DNA content, which presumably result from mitotic dysfunction, are an important indicator of both outcome and response to therapy. Neuroblastomas with a higher DNA content (hyperdiploid, with a DNA index [DI] >1) are associated with lower tumor stage, better response to initial therapy, and an overall better prognosis than diploid tumors (ie, DI = 1), particularly if they lack MYCN amplification [88-95]. As an example, in one study, the two-year disease free-survival rate was 94 percent for patients with near-triploid neuroblastoma compared with 45 percent for patients with diploid tumors without MYCN amplification, and 11 percent for patients with diploid or near-diploid tumors and MYCN amplification [92]. The influence of ploidy on outcome of neuroblastoma seems to be lost in children over the age of two, possibly because hyperdiploid tumors in older children typically have a number of structural rearrangements as well.
Other molecular alterations — Other factors that have not been incorporated into risk stratification schemes [66] but may affect prognosis include the following:
●Neurotrophic factors – Expression of neurotrophic factors, such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) along with their receptors (tyrosine kinases that are encoded by three tropomyosin receptor kinase [TRK] genes, TRK-A, B, and C) has been implicated in the pathogenesis of neuroblastoma, although their precise role is unclear [96]. Expression of TRK-A is inversely correlated with MYCN amplification, and high TRK-A and C expression appears to identify a biologically favorable subgroup of neuroblastomas, while expression of TRK-B is prognostically unfavorable [97-103].
●Alterations in ALK – In contrast to adult cancers, there is a relative paucity of mutations in neuroblastomas. However, variations in the anaplastic lymphoma kinase (ALK) gene have been identified in several studies as being an important contributor to the development of both familial and sporadic neuroblastomas [42,43,58,104-106]. Somatic mutations in the tyrosine kinase region of this gene appear to have a significant role in subsequent tumor development, and ALK inhibitors are being studied as a possible therapeutic intervention. (See "Treatment and prognosis of neuroblastoma", section on 'Investigational induction therapies'.)
●Telomeres – Telomeres are repeated nucleotide sequences that stabilize chromosomes, thereby preventing cell senescence. Telomerase is the enzyme that compensates for telomere shortening during cell division by synthesizing telomeric DNA, thereby maintaining telomere length. Preserved length of telomeres has been identified as a possible independent poor prognostic sign in children with neuroblastoma [107]. In addition to activation of telomerase, alternative lengthening of telomeres (ALT) has been shown to correlate with worse prognosis in neuroblastoma patients [108,109]. Specifically, telomerase activation and ALT are associated with a protracted clinical course and worse overall survival. One mechanism of ALT is associated with loss of function mutations or decreased expression of the alpha-thalassemia/mental retardation syndrome X-linked (ATRX) gene [58], which are seen in a substantial number of sporadic neuroblastomas (particularly those arising in older children) [58]. In children older than 12, the presence of ATRX mutations has been associated with a poor prognosis [110]. ATRX mutations have not been identified in any tumors with MYCN amplification.
ATRX mutations are associated with X-linked intellectual disability and alpha-thalassemia, suggesting that ATRX functions in various developmental processes; however, little is known about how ATRX contributes to the development or differentiation of the sympathoadrenal lineage. Children with X-linked intellectual disability do not have a higher incidence of neuroblastoma, suggesting that ATRX mutations alone are not sufficient to promote tumorigenesis. (See "Intellectual disability in children: Evaluation for a cause", section on 'X-linked disorders'.)
Gene expression profiling (GEP) may offer additional information to distinguish between patients with favorable and unfavorable prognoses [111-113]. This was illustrated by a study in which a 59 gene microarray expression was developed in a series of 579 patients and then validated in an independent cohort of 236 cases [111]. When clinical outcomes in the validation cohort were compared with prognosis using standard classification systems, the gene signature was an independent risk predictor, identifying patients with an increased risk of poor outcome in the current clinical risk groups.
PATHOLOGY — Neuroblastoma is a highly heterogeneous disease, and the pathology varies according to the degree of neural crest differentiation and possibly with the specific cells of origin within the neural crest. (See 'Pathogenesis' above.)
The International Neuroblastoma Pathology Classification classifies tumors of neuroblastic origin according to the balance between neural-type cells (primitive neuroblasts, maturing neuroblasts, and ganglion cells) and Schwann-type cells (Schwannian-blasts and mature Schwann cells) into one of three types: neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. Neuroblastomas are the most undifferentiated-appearing and aggressive of this family of tumors, and they in turn may be classified as undifferentiated, poorly differentiated, or differentiating [114].
The degree of differentiation and stromal component of neuroblastoma tumors can be predictive of outcome and is used in the determination of Children's Oncology Group risk category for treatment (table 3):
According to this system, favorable tumors include those that are:
●Poorly differentiated or differentiating neuroblastoma, with low or intermediate mitosis-karyorrhexis index (MKI), patient age ≤1.5 years
●Differentiating neuroblastoma and low-MKI tumors in patients 1.5 to 5 years of age
●Ganglioneuroblastoma, intermixed, regardless of age
●Ganglioneuroma, regardless of age
Unfavorable tumors include those that are:
●Undifferentiated or high-MKI tumors in patients of any age
●Poorly differentiated and/or intermediate-MKI tumors in patients 1.5 to 5 years of age
●Any grade of differentiation and any MKI class in patients ≥5 years of age
●Nodular ganglioneuroblastoma, regardless of age
This topic is discussed in detail separately. (See "Treatment and prognosis of neuroblastoma", section on 'Histology'.)
Neuroblastoma — The most undifferentiated neuroblastomas are composed almost entirely of neuroblasts, with very few Schwannian (or stromal) cells. Because of the lack of Schwannian cells, these tumors are called "stroma-poor" [59]. Under light microscopy, they appear as a monotonous collection of small, round, blue cells. Morphologically, the appearance is similar to that of other small round blue cell tumors involving bone and soft tissue, including lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, the Ewing sarcoma family of tumors, primitive neuroectodermal tumors (PNETs), and undifferentiated soft tissue sarcomas such as rhabdomyosarcoma [115]. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma".)
Because of their morphologic similarity, these tumors are difficult to distinguish on the basis of light microscopic findings. Electron microscopy or panels of tissue-specific monoclonal antibodies can be used to help with the differentiation. Neuroblastomas typically react with antibodies that distinguish neural tissue (eg, neuron-specific enolase [NSE], synaptophysin, chromogranin, and S100). While NSE may be focally positive in other tumors (eg, rhabdomyosarcoma), the staining pattern is characteristically diffuse and strongly positive in neuroblastomas.
In contrast to the undifferentiated neuroblastomas, some evidence of neural differentiation (eg, primitive neuroblasts) can be seen in the poorly-differentiated and differentiating types of neuroblastoma. These cells are approximately 7 to 10 microns in diameter, have hyperchromatic nuclei and scanty cytoplasm, and may form Homer-Wright rosettes (picture 1). The density of the neuroblasts, rate of mitosis or MKI, and neuroblastic differentiation can vary between neuroblastomas and even within the tumor itself.
Ganglioneuroblastoma — Ganglioneuroblastoma is called an "intermixed stroma-rich" or "stroma-rich" tumor because of the increased proportion of Schwannian cells. The neuroblasts, which generally have a more mature appearance, are clustered together in foci or nests surrounded by the Schwannian cells (picture 2). These tumors generally have intermediate malignant potential, between that of neuroblastomas and ganglioneuromas.
Ganglioneuroma — Ganglioneuroma (Schwannian cell dominant) is predominantly composed of Schwannian cells studded with maturing or fully mature ganglion cells (picture 3) [114,116,117]. These tumors tend to occur in older children (five to seven years of age) rather than the more aggressive neuroblastomas. They are considered to be benign [118,119], although they can metastasize [120]. Nevertheless, the prognosis is excellent, even when complete tumor removal is not possible [121].
SUMMARY
●Epidemiology – Neuroblastomas are neuroblastic tumors of children, with a median age at diagnosis of about 17 months. The causative factors are not well defined, although various genetic disorders are occasionally associated with the development of neuroblastomas. (See 'Epidemiology' above.)
●Molecular pathogenesis – The molecular pathogenesis of neuroblastomas has been extensively studied, and information about specific abnormalities is an important component of the definition of prognostic risk groups (see 'Molecular abnormalities (prognostic impact)' above):
•SCAs – Segmental chromosomal aberrations (SCAs), particularly segmental deletions of chromosome 1p, are associated with a poor prognosis. (See 'Segmental chromosome abberrations' above.)
•MYCN status – Deletions of chromosome 1p are associated with amplification of the MYCN oncogene (also called N-myc), the most common focal genetic lesion in sporadic neuroblastoma, which is associated with poor prognosis. (See 'MYCN status' above.)
•Alterations in total DNA content – The presence or absence of alterations in total DNA content and the amplification of MYCN have been incorporated into the Children's Oncology Group (COG) Neuroblastoma Risk Stratification System (table 3), which is important in determining the appropriate therapy for newly diagnosed patients. (See 'Alterations in total DNA content' above and "Treatment and prognosis of neuroblastoma".)
●Pathology – The International Neuroblastoma Pathology Classification classifies tumors of neuroblastic origin according to the balance between neural-type cells (primitive neuroblasts, maturing neuroblasts, and ganglion cells) and Schwann-type cells (Schwannian-blasts and mature Schwann cells) into one of three types: neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. (See 'Pathology' above.)
•Neuroblastomas are the most undifferentiated-appearing, and they in turn may be classified as undifferentiated, poorly differentiated, or differentiating. (See 'Neuroblastoma' above.)
•The histologic subtype and degree of differentiation can be predictive of outcome and is used in the determination of COG risk category for treatment (table 3).
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