Epidemiology, Pathogenesis, and Pathology of Neuroblastoma

4/2/2018 Epidemiology, pathogenesis, and pathology of neuroblastoma - UpToDate
Official reprint from UpToDate®

www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Epidemiology, pathogenesis, and pathology of neuroblastoma
Authors: Jason M Shohet, MD, PhD, Jed G Nuchtern, MD, FACS, FAAP
Section Editor: Julie R Park, MD
Deputy Editor: Sadhna R Vora, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Aug 19, 2016.
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, that also migrates from the neural crest to the adrenal gland (figure 1). 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 [1]. 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 [2]. 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 one 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 (see "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma"
and "Treatment and prognosis of neuroblastoma"). Neuroblastomas arising in the olfactory epithelium, which
have a different cell of origin, presentation, and treatment than neuroblastoma, also are discussed separately.
(See "Olfactory neuroblastoma (esthesioneuroblastoma)".)
EPIDEMIOLOGY AND RISK FACTORS — 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 [1], and
neuroblastoma accounts for approximately 15 percent of all pediatric cancer fatalities.
Incidence rates are age-dependent (figure 2). The median age at diagnosis is 17.3 months, and 40 percent of
patients are diagnosed before one year of age [1,2]. 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) [3]. The incidence of neuroblastoma is greater among white than black infants (ratio of 1.7 and
https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-neuroblastoma/print?search=neuroblastoma,%20pediatric&source=search_resu
1.9 to 1 for males and females, respectively), but little if any racial difference is apparent among older
children [1]. Neuroblastoma is slightly more common among boys compared with girls [1].
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 [4].
● 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 [5]. This finding was consistent with other studies
suggesting an association between maternal vitamin use and decreased risk of neuroblastoma [6,7].
● Toxic exposures – Epidemiologic studies provide little convincing evidence for toxic or infectious
environmental exposure as an etiologic factor for the development of neuroblastoma [1,8-18]. 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 [7,19-23], but not all [13,24-
26], 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 [7].
● Gestational diabetes mellitus – A case control study of 240 children with neuroblastoma showed a
correlation with the presence of maternal gestational diabetes mellitus [22]. 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 (see below), inherited predisposition, or associated
congenital anomalies. However, there are at least some exceptions. Single-nucleotide polymorphisms
(SNPs) at 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 [27,28].
Another study examining genetic determinants of pediatric cancer did not observe LMO1 mutations, but
reported germline mutations in SDHB, APC, ALK, and BRCA2 in 1 out of 100 patients with neuroblastoma
[29]. Other conditions that may cause a genetic predisposition for neuroblastoma are described:
● A higher incidence of neuroblastoma has been suggested in girls with Turner syndrome [30]. (See
"Clinical manifestations and diagnosis of Turner syndrome".)
● Hirschsprung's disease, central hypoventilation, and neurofibromatosis type 1 (NF1) have all been
described in association with neuroblastoma, suggesting the existence of a global disorder of neural
crest-derived cells (ie, neurocristopathy) [31-34]. There are scattered reports of germline NF1 gene
mutations in neuroblastomas [35,36]; however, the available epidemiologic evidence does not support an
etiologic role in most familial or sporadic cases [34]. (See "Disorders of ventilatory control", section on
'Congenital central hypoventilation syndrome' and "Congenital aganglionic megacolon (Hirschsprung
disease)" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" 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 is a family history of neuroblastoma [37-39]. These cases appear to be inherited in an autosomal
dominant pattern with incomplete penetrance and a broad spectrum of clinical behavior [40]. 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.
Some reports suggest that familial predisposition may be conferred through disruption of a locus at 16p12-13
(see below) [41,42]. Others have identified rare germline variants at the TP53 locus (17p13.1) that are
associated with neuroblastoma susceptibility [43]. 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 — Neuroblastoma arises from early neural crest precursors that undergo transformation
secondary to genetic or epigenetic events that lead to blocked or aberrant developmental differentiation [44].
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 [45-47], the events that induce neuroblastoma tumorigenesis remain
poorly defined. It is clear, however, that multiple different changes can induce tumor formation and, as
illustrated below, the timing and character of driving oncogenic events may well define the phenotype of the
resulting cancer (figure 3). As an example, cases of neuroblastoma arising under the age of one year (4S
disease, (table 1)) likely represent tumors that develop at a different stage of neural crest differentiation than
does high-stage disease [48,49]. 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
'Screening for neuroblastoma'.)
Placing the oncogenic factors driving neuroblastoma in the context of neural crest development helps to
explain the heterogeneity of this complex tumor type (figure 3). As noted below, the pathology of
neuroblastoma varies considerably between patients, with age, location of tumor, and host/tumor immune
interactions likely playing major roles in biology behavior.
Molecular/genetic abnormalities and implications for prognosis — Various molecular and cytogenetic
factors have been implicated in the pathogenesis of neuroblastoma, some of which have proven useful in
predicting clinical behavior [50-53]. Some of these factors have been incorporated into the Children's
Oncology Group (COG) Neuroblastoma Risk Stratification System for the selection of treatment (table 2).
(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 [44,54], below we detail some of the most well-
characterized factors.
Chromosomal deletions (as detected by loss of heterozygosity [LOH]) are found in approximately 50 percent
of neuroblastomas, and are consistently localized to chromosomes 1p, 11q, and 14q [55-59]. 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 [60-63]. For 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) [63]. The staging of neuroblastoma (table 1)
is discussed separately.
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 [60,64]. 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 [65,66].
A 50- to 400-fold amplification of MYCN is found in approximately 25 percent of neuroblastomas and is an
indicator of poor prognosis [67-72].
The prognostic significance of MYCN amplification can be illustrated by the following data:
● In one study of 2660 patients with stage 1 or stage 2 (table 1) neuroblastoma from the International
Neuroblastoma Risk Group (INRB) database, 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 [72].
● 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) [71].
In contrast, among children with stage 4 neuroblastoma without amplification of MYCN, prognosis depends
upon age [73]. 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 [74]. Deletions of 11q and/or 14q are detected in 25 to 50 percent of
neuroblastomas [58,59,74]. Neuroblastomas that are characterized by these changes generally lack 1p
deletions and MYCN amplification, and they appear to represent a distinct tumor subtype [75].
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 [76,77]. 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) [76]. In contrast, in another report, whole chromosome 17 gain was
associated with increased survival [77].
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 [78-85]. 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 [82]. 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 factors that have not been incorporated into the Neuroblastoma Risk Stratification System (table 2) but
may affect prognosis include the following:
● 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 TRK genes, TRK-A,
B, and C) has been implicated in the pathogenesis of neuroblastoma, although their precise role is
unclear [86]. Expression of TRK-A is inversely correlated with MYCN amplification, and high TRK-A
expression appears to identify a biologically favorable subgroup of neuroblastomas, while expression of
TRK-B or C is prognostically unfavorable [87-90].
● 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 [54,91-
95]. 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.
In addition, a substantial number of sporadic neuroblastomas (particularly those arising in older children)
carry mutations in the alpha-thalassemia/mental retardation syndrome X-linked (ATRX) gene [54]. In children
older than 12, the presence of ATRX mutations has been associated with a poor prognosis [96]. ATRX
mutations have not been identified in any tumors with MYCN amplification.
ATRX mutations are associated with X-linked mental retardation 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 mental retardation
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'.)
● 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 [97].
● Gene expression profiling (GEP) may offer additional information to distinguish between patients with
favorable and unfavorable prognoses [98-100]. 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 [98]. 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.
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 in detail elsewhere. (See "Treatment and
prognosis of neuroblastoma".)
PATHOLOGY — As noted above, 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 [101].
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 (COG) risk category for treatment (table 2):
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 5.0 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 5.0 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 elsewhere. (See "Treatment and prognosis of neuroblastoma", section on
'Pathologic risk classification'.)
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” [55]. 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 [102]. (See "Epidemiology, pathology, and molecular genetics of the
Ewing sarcoma family of tumors".)
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) [35,101,103]. 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 [104,105], although they can metastasize [106]. Nevertheless, the
prognosis is excellent, even when complete tumor removal is not possible [107].
SUMMARY
● 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 and risk factors' above.)
● 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/genetic abnormalities and implications for prognosis' above):
• Chromosomal deletions, particularly of chromosome 1p, are associated with a poor prognosis.
• Deletions of chromosome 1p are associated with amplification of the MYCN oncogene, the most
common focal genetic lesion in sporadic neuroblastoma, which is associated with poor prognosis.
• 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 2), which is important in determining the appropriate therapy for newly diagnosed
patients. (See "Treatment and prognosis of neuroblastoma".)
● 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 they in turn may be classified as undifferentiated, poorly differentiated, or
differentiating.
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 2). (See 'Pathology' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Goodman MT, Gurney JG, Smith MA, Olshan AF. Sympathetic nervous system tumors. In: Cancer Incid
ence and Survival among Children and Adolescents: United States SEER Program, 1975-1995, Ries, L
A, Smith, MA, Gurney, JG, et al (Eds), National Cancer Institute, Bethesda, MD 1999. p.35.
2. Brodeur GM, Hogarty MD, Mosse YP, Maris JM. Neuroblastoma. In: Principles and Practice of Pediatric
Oncology, Pizzo PA, Poplack DG (Eds), Lippincott Williams & Wilkins, Philadelphia 2011. p.886.
3. Gurney JG, Ross JA, Wall DA, et al. Infant cancer in the U.S.: histology-specific incidence and trends,
1973 to 1992. J Pediatr Hematol Oncol 1997; 19:428.
4. Cook MN, Olshan AF, Guess HA, et al. Maternal medication use and neuroblastoma in offspring. Am J
Epidemiol 2004; 159:721.
5. French AE, Grant R, Weitzman S, et al. Folic acid food fortification is associated with a decline in
neuroblastoma. Clin Pharmacol Ther 2003; 74:288.
6. Olshan AF, Smith JC, Bondy ML, et al. Maternal vitamin use and reduced risk of neuroblastoma.
Epidemiology 2002; 13:575.
7. Rios P, Bailey HD, Orsi L, et al. Risk of neuroblastoma, birth-related characteristics, congenital
malformations and perinatal exposures: A pooled analysis of the ESCALE and ESTELLE French
studies (SFCE). Int J Cancer 2016; 139:1936.
8. Kramer S, Ward E, Meadows AT, Malone KE. Medical and drug risk factors associated with
neuroblastoma: a case-control study. J Natl Cancer Inst 1987; 78:797.
9. Schwartzbaum JA. Influence of the mother's prenatal drug consumption on risk of neuroblastoma in the
child. Am J Epidemiol 1992; 135:1358.
10. Michalek AM, Buck GM, Nasca PC, et al. Gravid health status, medication use, and risk of
neuroblastoma. Am J Epidemiol 1996; 143:996.
11. Satgé D, Sasco AJ, Little J. Antenatal therapeutic drug exposure and fetal/neonatal tumours: review of
89 cases. Paediatr Perinat Epidemiol 1998; 12:84.
12. Johnson CC, Spitz MR. Neuroblastoma: case-control analysis of birth characteristics. J Natl Cancer Inst
1985; 74:789.
13. Neglia JP, Smithson WA, Gunderson P, et al. Prenatal and perinatal risk factors for neuroblastoma. A
case-control study. Cancer 1988; 61:2202.
14. Bunin GR, Ward E, Kramer S, et al. Neuroblastoma and parental occupation. Am J Epidemiol 1990;
131:776.
15. Spitz MR, Johnson CC. Neuroblastoma and paternal occupation. A case-control analysis. Am J
Epidemiol 1985; 121:924.
16. Wilkins JR 3rd, Hundley VD. Paternal occupational exposure to electromagnetic fields and
neuroblastoma in offspring. Am J Epidemiol 1990; 131:995.
17. Flaegstad T, Andresen PA, Johnsen JI, et al. A possible contributory role of BK virus infection in
neuroblastoma development. Cancer Res 1999; 59:1160.
18. Menegaux F, Olshan AF, Neglia JP, et al. Day care, childhood infections, and risk of neuroblastoma. Am
J Epidemiol 2004; 159:843.
19. Mili F, Khoury MJ, Flanders WD, Greenberg RS. Risk of childhood cancer for infants with birth defects.
I. A record-linkage study, Atlanta, Georgia, 1968-1988. Am J Epidemiol 1993; 137:629.
20. Foulkes WD, Buu PN, Filiatrault D, et al. Excess of congenital abnormalities in French-Canadian
children with neuroblastoma: a case series study from Montréal. Med Pediatr Oncol 1997; 29:272.
21. Menegaux F, Olshan AF, Reitnauer PJ, et al. Positive association between congenital anomalies and
risk of neuroblastoma. Pediatr Blood Cancer 2005; 45:649.
22. Chow EJ, Friedman DL, Mueller BA. Maternal and perinatal characteristics in relation to neuroblastoma.
Cancer 2007; 109:983.
23. Munzer C, Menegaux F, Lacour B, et al. Birth-related characteristics, congenital malformation, maternal
reproductive history and neuroblastoma: the ESCALE study (SFCE). Int J Cancer 2008; 122:2315.
24. Buck GM, Michalek AM, Chen CJ, et al. Perinatal factors and risk of neuroblastoma. Paediatr Perinat
Epidemiol 2001; 15:47.
25. Windham GC, Bjerkedal T, Langmark F. A population-based study of cancer incidence in twins and in
children with congenital malformations or low birth weight, Norway, 1967-1980. Am J Epidemiol 1985;
121:49.
26. Mili F, Lynch CF, Khoury MJ, et al. Risk of childhood cancer for infants with birth defects. II. A record-
linkage study, Iowa, 1983-1989. Am J Epidemiol 1993; 137:639.
27. Oldridge DA, Wood AC, Weichert-Leahey N, et al. Genetic predisposition to neuroblastoma mediated
by a LMO1 super-enhancer polymorphism. Nature 2015; 528:418.
28. Wang K, Diskin SJ, Zhang H, et al. Integrative genomics identifies LMO1 as a neuroblastoma
oncogene. Nature 2011; 469:216.
29. Zhang J, Walsh MF, Wu G, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N
Engl J Med 2015; 373:2336.
30. Blatt J, Olshan AF, Lee PA, Ross JL. Neuroblastoma and related tumors in Turner's syndrome. J Pediatr
1997; 131:666.
31. Shahar E, Shinawi M. Neurocristopathies presenting with neurologic abnormalities associated with
Hirschsprung's disease. Pediatr Neurol 2003; 28:385.
32. Nemecek ER, Sawin RW, Park J. Treatment of neuroblastoma in patients with neurocristopathy
syndromes. J Pediatr Hematol Oncol 2003; 25:159.
33. Stovroff M, Dykes F, Teague WG. The complete spectrum of neurocristopathy in an infant with
congenital hypoventilation, Hirschsprung's disease, and neuroblastoma. J Pediatr Surg 1995; 30:1218.
34. Kushner BH, Hajdu SI, Helson L. Synchronous neuroblastoma and von Recklinghausen's disease: a
review of the literature. J Clin Oncol 1985; 3:117.
35. Origone P, Defferrari R, Mazzocco K, et al. Homozygous inactivation of NF1 gene in a patient with
familial NF1 and disseminated neuroblastoma. Am J Med Genet A 2003; 118A:309.
36. The I, Murthy AE, Hannigan GE, et al. Neurofibromatosis type 1 gene mutations in neuroblastoma. Nat
Genet 1993; 3:62.
37. Arenson EB Jr, Hutter JJ Jr, Restuccia RD, Holton CP. Neuroblastoma in father and son. JAMA 1976;
235:727.
38. Maris JM, Chatten J, Meadows AT, et al. Familial neuroblastoma: a three-generation pedigree and a
further association with Hirschsprung disease. Med Pediatr Oncol 1997; 28:1.
39. Kushner BH, Gilbert F, Helson L. Familial neuroblastoma. Case reports, literature review, and etiologic
considerations. Cancer 1986; 57:1887.
40. Perri P, Longo L, McConville C, et al. Linkage analysis in families with recurrent neuroblastoma. Ann N
Y Acad Sci 2002; 963:74.
41. Maris JM, Weiss MJ, Mosse Y, et al. Evidence for a hereditary neuroblastoma predisposition locus at
chromosome 16p12-13. Cancer Res 2002; 62:6651.
42. Weiss MJ, Guo C, Shusterman S, et al. Localization of a hereditary neuroblastoma predisposition gene
to 16p12-p13. Med Pediatr Oncol 2000; 35:526.
43. Diskin SJ, Capasso M, Diamond M, et al. Rare variants in TP53 and susceptibility to neuroblastoma. J
Natl Cancer Inst 2014; 106:dju047.
44. Louis CU, Shohet JM. Neuroblastoma: molecular pathogenesis and therapy. Annu Rev Med 2015;
66:49.
45. Weston JA, Thiery JP. Pentimento: Neural Crest and the origin of mesectoderm. Dev Biol 2015; 401:37.
46. Baggiolini A, Varum S, Mateos JM, et al. Premigratory and migratory neural crest cells are multipotent in
vivo. Cell Stem Cell 2015; 16:314.
47. Plouhinec JL, Roche DD, Pegoraro C, et al. Pax3 and Zic1 trigger the early neural crest gene regulatory
network by the direct activation of multiple key neural crest specifiers. Dev Biol 2014; 386:461.
48. Woods WG, Gao RN, Shuster JJ, et al. Screening of infants and mortality due to neuroblastoma. N Engl
J Med 2002; 346:1041.
49. Bessho F. Comparison of the incidences of neuroblastoma for screened and unscreened cohorts. Acta
Paediatr 1999; 88:404.
50. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 2003; 3:203.
51. Perez CA, Matthay KK, Atkinson JB, et al. Biologic variables in the outcome of stages I and II
neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol
2000; 18:18.
52. Riley RD, Heney D, Jones DR, et al. A systematic review of molecular and biological tumor markers in
neuroblastoma. Clin Cancer Res 2004; 10:4.
53. Viprey VF, Gregory WM, Corrias MV, et al. Neuroblastoma mRNAs predict outcome in children with
stage 4 neuroblastoma: a European HR-NBL1/SIOPEN study. J Clin Oncol 2014; 32:1074.
54. Cheung NK, Dyer MA. Neuroblastoma: developmental biology, cancer genomics and immunotherapy.
Nat Rev Cancer 2013; 13:397.
55. Schwab M, Shimada H, Joshi V, Brodeur GM. Neuroblastic tumours of adrenal gland and sympathetic n
ervous system. In: Pathology and Genetics of Tumours of the Nervous System, Kleihues P, Cavenee W
K (Eds), Lyon 2000. p.153.
56. Westermann F, Schwab M. Genetic parameters of neuroblastomas. Cancer Lett 2002; 184:127.
57. Guo C, White PS, Hogarty MD, et al. Deletion of 11q23 is a frequent event in the evolution of MYCN
single-copy high-risk neuroblastomas. Med Pediatr Oncol 2000; 35:544.
58. Srivatsan ES, Ying KL, Seeger RC. Deletion of chromosome 11 and of 14q sequences in
neuroblastoma. Genes Chromosomes Cancer 1993; 7:32.
59. Attiyeh EF, London WB, Mossé YP, et al. Chromosome 1p and 11q deletions and outcome in
neuroblastoma. N Engl J Med 2005; 353:2243.
60. Maris JM, Weiss MJ, Guo C, et al. Loss of heterozygosity at 1p36 independently predicts for disease
progression but not decreased overall survival probability in neuroblastoma patients: a Children's
Cancer Group study. J Clin Oncol 2000; 18:1888.
61. Krona C, Ejeskär K, Abel F, et al. Screening for gene mutations in a 500 kb neuroblastoma tumor
suppressor candidate region in chromosome 1p; mutation and stage-specific expression in
UBE4B/UFD2. Oncogene 2003; 22:2343.
62. Roberts T, Chernova O, Cowell JK. NB4S, a member of the TBC1 domain family of genes, is truncated
as a result of a constitutional t(1;10)(p22;q21) chromosome translocation in a patient with stage 4S
neuroblastoma. Hum Mol Genet 1998; 7:1169.
63. Caron H, van Sluis P, de Kraker J, et al. Allelic loss of chromosome 1p as a predictor of unfavorable
outcome in patients with neuroblastoma. N Engl J Med 1996; 334:225.
64. Komuro H, Valentine MB, Rowe ST, et al. Fluorescence in situ hybridization analysis of chromosome
1p36 deletions in human MYCN amplified neuroblastoma. J Pediatr Surg 1998; 33:1695.
65. Cole MD, McMahon SB. The Myc oncoprotein: a critical evaluation of transactivation and target gene
regulation. Oncogene 1999; 18:2916.
66. Lutz W, Stöhr M, Schürmann J, et al. Conditional expression of N-myc in human neuroblastoma cells
increases expression of alpha-prothymosin and ornithine decarboxylase and accelerates progression
into S-phase early after mitogenic stimulation of quiescent cells. Oncogene 1996; 13:803.
67. Schwab M. Oncogene amplification in solid tumors. Semin Cancer Biol 1999; 9:319.
68. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive
chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid.
Children's Cancer Group. N Engl J Med 1999; 341:1165.
69. Brodeur GM, Seeger RC, Schwab M, et al. Amplification of N-myc in untreated human neuroblastomas
correlates with advanced disease stage. Science 1984; 224:1121.
70. Seeger RC, Brodeur GM, Sather H, et al. Association of multiple copies of the N-myc oncogene with
rapid progression of neuroblastomas. N Engl J Med 1985; 313:1111.
71. Katzenstein HM, Bowman LC, Brodeur GM, et al. Prognostic significance of age, MYCN oncogene
amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric
oncology group experience--a pediatric oncology group study. J Clin Oncol 1998; 16:2007.
72. Bagatell R, Beck-Popovic M, London WB, et al. Significance of MYCN amplification in international
neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International
Neuroblastoma Risk Group database. J Clin Oncol 2009; 27:365.
73. Schmidt ML, Lal A, Seeger RC, et al. Favorable prognosis for patients 12 to 18 months of age with
stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 2005;
23:6474.
74. Cohn SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group (INRG)
classification system: an INRG Task Force report. J Clin Oncol 2009; 27:289.
75. Stallings RL, Howard J, Dunlop A, et al. Are gains of chromosomal regions 7q and 11p important
abnormalities in neuroblastoma? Cancer Genet Cytogenet 2003; 140:133.
76. Bown N, Cotterill S, Lastowska M, et al. Gain of chromosome arm 17q and adverse outcome in patients
with neuroblastoma. N Engl J Med 1999; 340:1954.
77. Vandesompele J, Baudis M, De Preter K, et al. Unequivocal delineation of clinicogenetic subgroups and
development of a new model for improved outcome prediction in neuroblastoma. J Clin Oncol 2005;
23:2280.
78. Look AT, Hayes FA, Shuster JJ, et al. Clinical relevance of tumor cell ploidy and N-myc gene
amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 1991; 9:581.
79. Look AT, Hayes FA, Nitschke R, et al. Cellular DNA content as a predictor of response to chemotherapy
in infants with unresectable neuroblastoma. N Engl J Med 1984; 311:231.
80. Christiansen H, Lampert F. Tumour karyotype discriminates between good and bad prognostic outcome
in neuroblastoma. Br J Cancer 1988; 57:121.
81. Kaneko Y, Kanda N, Maseki N, et al. Different karyotypic patterns in early and advanced stage
neuroblastomas. Cancer Res 1987; 47:311.
82. Bourhis J, De Vathaire F, Wilson GD, et al. Combined analysis of DNA ploidy index and N-myc genomic
content in neuroblastoma. Cancer Res 1991; 51:33.
83. Oppedal BR, Storm-Mathisen I, Lie SO, Brandtzaeg P. Prognostic factors in neuroblastoma. Clinical,
histopathologic, and immunohistochemical features and DNA ploidy in relation to prognosis. Cancer
1988; 62:772.
84. Cohn SL, Rademaker AW, Salwen HR, et al. Analysis of DNA ploidy and proliferative activity in relation
to histology and N-myc amplification in neuroblastoma. Am J Pathol 1990; 136:1043.
85. Mora J, Cheung NK, Chen L, et al. Survival analysis of clinical, pathologic, and genetic features in
neuroblastoma presenting as locoregional disease. Cancer 2001; 91:435.
86. Brodeur GM, Nakagawara A, Yamashiro DJ, et al. Expression of TrkA, TrkB and TrkC in human
neuroblastomas. J Neurooncol 1997; 31:49.
87. Eggert A, Grotzer MA, Ikegaki N, et al. Expression of neurotrophin receptor TrkA inhibits angiogenesis
in neuroblastoma. Med Pediatr Oncol 2000; 35:569.
88. Nakagawara A, Arima M, Azar CG, et al. Inverse relationship between trk expression and N-myc
amplification in human neuroblastomas. Cancer Res 1992; 52:1364.
89. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, et al. Association between high levels of
expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 1993;
328:847.
90. Suzuki T, Bogenmann E, Shimada H, et al. Lack of high-affinity nerve growth factor receptors in
aggressive neuroblastomas. J Natl Cancer Inst 1993; 85:377.
91. Chen Y, Takita J, Choi YL, et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 2008;
455:971.
92. Janoueix-Lerosey I, Lequin D, Brugières L, et al. Somatic and germline activating mutations of the ALK
kinase receptor in neuroblastoma. Nature 2008; 455:967.
93. Mossé YP, Laudenslager M, Longo L, et al. Identification of ALK as a major familial neuroblastoma
predisposition gene. Nature 2008; 455:930.
94. George RE, Sanda T, Hanna M, et al. Activating mutations in ALK provide a therapeutic target in
neuroblastoma. Nature 2008; 455:975.
95. Cazes A, Louis-Brennetot C, Mazot P, et al. Characterization of rearrangements involving the ALK gene
reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma. Cancer Res
2013; 73:195.
96. Cheung NK, Zhang J, Lu C, et al. Association of age at diagnosis and genetic mutations in patients with
neuroblastoma. JAMA 2012; 307:1062.
97. Ohali A, Avigad S, Ash S, et al. Telomere length is a prognostic factor in neuroblastoma. Cancer 2006;
107:1391.
98. Vermeulen J, De Preter K, Naranjo A, et al. Predicting outcomes for children with neuroblastoma using
a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study. Lancet Oncol 2009;
10:663.
99. Oberthuer A, Berthold F, Warnat P, et al. Customized oligonucleotide microarray gene expression-based
classification of neuroblastoma patients outperforms current clinical risk stratification. J Clin Oncol 2006;
24:5070.
100. Fischer M, Oberthuer A, Brors B, et al. Differential expression of neuronal genes defines subtypes of
disseminated neuroblastoma with favorable and unfavorable outcome. Clin Cancer Res 2006; 12:5118.
101. Shimada H, Ambros IM, Dehner LP, et al. The International Neuroblastoma Pathology Classification
(the Shimada system). Cancer 1999; 86:364.
102. Golden CB, Feusner JH. Malignant abdominal masses in children: quick guide to evaluation and
diagnosis. Pediatr Clin North Am 2002; 49:1369.
103. Shimada H, Chatten J, Newton WA Jr, et al. Histopathologic prognostic factors in neuroblastic tumors:
definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J
Natl Cancer Inst 1984; 73:405.
104. Koch CA, Brouwers FM, Rosenblatt K, et al. Adrenal ganglioneuroma in a patient presenting with
severe hypertension and diarrhea. Endocr Relat Cancer 2003; 10:99.
105. Meyer S, Reinhard H, Ziegler K, et al. Ganglianeuroma: radiological and metabolic features in 4
children. Pediatr Hematol Oncol 2002; 19:501.
106. Geoerger B, Hero B, Harms D, et al. Metabolic activity and clinical features of primary
ganglioneuromas. Cancer 2001; 91:1905.
107. De Bernardi B, Gambini C, Haupt R, et al. Retrospective study of childhood ganglioneuroma. J Clin
Oncol 2008; 26:1710.
Topic 5204 Version 17.0
GRAPHICS
The common embryogenesis of chromaffin cells and sympathetic

ganglion cells from primitive cells of the neural crest
Although the adrenal medulla is well developed by 12 weeks of gestation, most of the chromaffin
tissue in the fetus is present in scattered extramedullary paraaortic paraganglia, the largest of
which are termed the organs of Zuckerkandl. After birth, these paraganglia gradually atrophy,
disappearing by two to three years of age. The various tumors that can arise from any site along
the migratory path of the cells of the autonomic nervous system are in boxes. The chromaffin
cells located in the paraganglia predominantly produce norepinephrine while those in the adrenal
medulla typically secrete a greater quantity of epinephrine than norepinephrine.
Graphic 53140 Version 2.0
Age-specific neuroblastoma incidence rates by sex, all races,

SEER 1976-84 and 1986-94
From Goodman, MT, Gurney, JG, Smith, MA, Olshan, AF. Sympathetic nervous system
tumors. In: Cancer Incidence and Survival Among Children and Adolescents: United States
SEER Program 1975-1995, Ries, LA, Smith, MA, Gurney, JG, et al, National Cancer
Institute, SEER Program. NIH Pub No. 99-4649; Bethesda, MD 1999. p. 66-67.
Neural crest development and neuroblastoma tumorigenesis
Neuroblastoma arises during the course of embryonal neural crest specification and differentiation.
This process involves a programmed epithelial-to-mesenchymal transition (EMT) of multipotent
early neural crest cells and generates a plethora of distinct tissues, including the sympathoadrenal
lineages. Disruptoin of this moral developmental process with distinct oncogenic drivers (eg, MYCN
of ALK oncogenes), at different times, can lead to multiple subtypes of neuroblastoma tumors.
Interaction between different epigenetic and genetic drivers complicates the task of defining a
primary oncogenic pathway for neuroblastoma. This results in a wide range of pathology, biology,
and response to therapy.
Modified with permission from: Louis CU, Shohet, JM. Neuroblastoma: Molecular pathogenesis and
therapy. Annu Rev Med 2015; 66:49. Volume 66 © 2015 by Annual Reviews,
http://www.annualreviews.org.
International neuroblastoma staging system
Stage Definition
1 Localized tumor with complete gross excision, with or without microscopic residual disease;
representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and
removed with the primary tumor may be positive)
2A Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes
negative for tumor microscopically
2B Localized tumor with or without complete gross excision; with ipsilateral nonadherent lymph nodes
positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.
3 Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node
involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline
tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement
4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or
other organs (except as defined for stage 4S)
4S Localized primary tumor (as defined for stage 1, 2A or 2B), with dissemination limited to skin, liver,
and/or bone marrow (limited to infants <1 year of age)
Reproduced with permission from: Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for
neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11:1466. Copyright © 1993 American
Society of Clinical Oncology.
Children's Oncology Group risk assignment strata
INSS MYCN Pathology DNA Risk Group

Age
Stage Status Classification Ploidy Assignment
1 0-21y Any Any Any Low
2 <365 d Any Any - Low
>365d- Non-Amp Any - Low

21y
>365d- Amp Favorable - Low

21y
>365d- Amp Unfavorable - High

21y
3 <365 d Non-Amp Any Any Intermediate
<365 d Amp Any Any High
>365d- Non-Amp Favorable - Intermediate

21y
>365d- Non-Amp Unfavorable - High

21y
>365d- Amp Any - High

21y
4 <365 d Non-Amp Any Any Intermediate
>365d- Any Any _ High

21y
4S <365 d Non-Amp Favorable >1 Low
<365 d Non-Amp Any =1 Intermediate
<365 d Non-Amp Unfavorable Any Intermediate
Neuroblastoma cells within the bone marrow
Bone marrow aspirate from a patient with metastatic neuroblastoma shows a

clump of cells forming a rosette. Note the indistinct borders between cells in this
clump of tumor cells.
Courtesy of David S Rosenthal, MD and William C Moloney, MD.
Ganglioneuroblastoma
The neuroblasts, which generally have a more mature appearance, are clustered
together in foci or nests surrounded by the Schwannian cells.
Courtesy of MJ Hicks, MD.
Ganglioneuroma
Ganglioneuroma is predominantly composed of Schwannian cells studded with

maturing or fully mature ganglion cells.
Courtesy of MJ Hicks, MD.
Contributor Disclosures
Jason M Shohet, MD, PhD Nothing to disclose Jed G Nuchtern, MD, FACS, FAAP Nothing to
disclose Julie R Park, MD Nothing to disclose Sadhna R Vora, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

Epidemiology, Pathogenesis, and Pathology of Neuroblastoma

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Epidemiology, Pathogenesis, and Pathology of Neuroblastoma

Загружено:

Авторское право:

Доступные форматы

4/2/2018 Epidemiology, pathogenesis, and pathology of neuroblastoma - UpToDate

Official reprint from UpToDate®

Epidemiology, pathogenesis, and pathology of neuroblastoma

The epidemiology, embryogenesis, molecular pathogenesis, and pathology of neuroblastoma will be

EPIDEMIOLOGY AND RISK FACTORS — Neuroblastoma is almost exclusively a disease of children. It is

"Congenital central hypoventilation syndrome and other causes of sleep-related hypoventilation in

Familial neuroblastoma — Although the majority of neuroblastomas are sporadic, in 1 to 2 percent of

● In contrast to adult cancers, there is a relative paucity of mutations in neuroblastomas. However,

According to this system, favorable tumors include those that are:

● Poorly differentiated or differentiating neuroblastoma, with low or intermediate mitosis-karyorrhexis index

● 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

● Nodular ganglioneuroblastoma, regardless of age

Ganglioneuroblastoma — Ganglioneuroblastoma is called an “intermixed stroma-rich” or “stroma-rich”

Ganglioneuroma — Ganglioneuroma (Schwannian cell dominant) is predominantly composed of

● The International Neuroblastoma Pathology Classification classifies tumors of neuroblastic origin

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 5204 Version 17.0

The common embryogenesis of chromaffin cells and sympathetic

Graphic 53140 Version 2.0

Age-specific neuroblastoma incidence rates by sex, all races,

Graphic 72658 Version 1.0

Neural crest development and neuroblastoma tumorigenesis

Graphic 100618 Version 4.0

International neuroblastoma staging system

Graphic 73974 Version 3.0

Children's Oncology Group risk assignment strata

INSS MYCN Pathology DNA Risk Group

1 0-21y Any Any Any Low

2 <365 d Any Any - Low

>365d- Non-Amp Any - Low

>365d- Amp Favorable - Low

>365d- Amp Unfavorable - High

3 <365 d Non-Amp Any Any Intermediate

<365 d Amp Any Any High

>365d- Non-Amp Favorable - Intermediate

>365d- Non-Amp Unfavorable - High

>365d- Amp Any - High

4 <365 d Non-Amp Any Any Intermediate

<365 d Amp Any Any High

>365d- Any Any _ High

4S <365 d Non-Amp Favorable >1 Low

<365 d Non-Amp Any =1 Intermediate

<365 d Non-Amp Unfavorable Any Intermediate

<365 d Amp Any Any High

Graphic 53708 Version 1.0

Neuroblastoma cells within the bone marrow

Bone marrow aspirate from a patient with metastatic neuroblastoma shows a

Courtesy of David S Rosenthal, MD and William C Moloney, MD.

Graphic 73187 Version 2.0

Courtesy of MJ Hicks, MD.

Graphic 63408 Version 1.0

Ganglioneuroma is predominantly composed of Schwannian cells studded with

Courtesy of MJ Hicks, MD.

Graphic 76244 Version 1.0

Conflict of interest policy

Вам также может понравиться