Pediatr Surg Int
DOI 10.1007/s00383-013-3424-3
REVIEW ARTICLE
Neonatal tumours
S. W. Moore
Accepted: 14 October 2013
 Springer-Verlag Berlin Heidelberg 2013
Abstract Neonatal or perinatal tumours frequently relate
to prenatal or developmental events and have a short
exposure window which provides an opportunity to study
tumours in a selective sensitive period of development. As
a result, they display a number of host-specific features
which include occasional spontaneous maturational chan-
ges with cells still responding to developmental influences.
Neonatal tumours (NNT) are studied for a number of
important reasons. Firstly, many of the benign tumours
arising from soft tissue appear to result from disturbances
in growth and development and some are associated with
other congenital anomalies. Study of these aspects may
open the door for investigation of genetic and epigenetic
changes in genes controlling foetal development as well as
environmental and drug effects during pregnancy. Sec-
ondly, the clinical behaviour of NNT differs from that of
similar tumours occurring later in childhood. In addition,
certain apparently malignant NNT can change course in
infancy leading to the maturation of apparently highly
malignant tumours. Thirdly, NNT underline the genetic
associations of most tumours but appear to differ in the
effects of proto-oncogenes and other oncogenic factors. In
this context, there are also connections between the foetal
and neonatal period and some adult cancers. Fourthly, tumours occurring within the first 28 days of neonatal life.
they appear to arise in a period in which minimal envi-
ronmental interference has occurred, thus providing a
unique potential window of opportunity to study the
pathogenesis of tumour behaviour. This study will seek to
review what is currently known in each of these areas of
S. W. Moore (&)
Department of Paediatric Surgery, Faculty of Medicine and
Health Sciences, University of Stellenbosch, P.O. Box 19063,
Tygerberg 7505, South Africa
e-mail: SWM@sun.ac.za
study as they apply to NNT. Further study of the provoc-
ative differences in tumour behaviour in neonates provides
insights into the natural history of cancer in humans and
promotes novel cancer therapies.
Keywords Neonatal tumours
Congenital tumours

Neonates
Children
Introduction
Childhood tumours have previously proven to be a rich
source of information in the study into the mechanisms of
cancer pathogenesis. Recent interest in the biological basis
of cancer has focussed on its relationship with prenatal and
developmental events in oncogenesis. As a result, a number
of malignancies (including adult cancers) are thought to
have their origins during events occurring early in foetal
development [1, 2]. It is therefore reasonable to assume
that further study of childhood cancer and particularly
cancer occurring early in life, especially in the neonatal
period, warrants further attention.
Neonatal tumours (NNT) represent a population of
They are relatively uncommon and occur approximately
once in every 10,000 live births, with variation from 17 to
121 per million live births in reported series [35]. The
majority of these tumours are solid homogeneous collec-
tions of tissue representing several tumour types [6, 7].
They appear to be mostly of sporadic mesenchymal and
embryonic origin, carcinomas being virtually absent in the
neonatal period. They also have a similar pathological
spectrum to those reported in animals such as newborn
bovine calves, similar to that of humans, suggesting a
developmental origin [8].
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These tumours have been of interest to Paediatric
surgeons for many years as they occur at or shortly after
birth and often require surgery with many being cur-
rently detected on antenatal sonographic scanning.
Approximately 25 % of them arise from soft tissue and
more than 67 % are regarded as benign [9]. On the
other hand, non-solid tumours such as leukaemia,
despite being the most common tumour of childhood
and the main cause of death from tumours occurring
within the first month of life, actually represent a rela-
tively small percentage of these NNT [10]. The reported
spectrum of these tumours [5, 11] differs from those
occurring later in childhood, thus suggesting a possible
genetic basis [11, 12] and probably reflects the influence
of aberrant genetic signalling cascades on developmental
genes.
The hypothesis that malignant tumours may be linked to
or even initiated during foetal development [1, 13, 14] is
currently supported by an increasing number of animal
experimental studies, which makes the study of NNT of
particular interest. Possible reasons for this association are
based on the hypothesis that either genetic or environ-
mental (e.g. nutrition and exposures to environmental
toxins) factors (or both) may act as oncogenic promoters
during gestation [15].
This study will seek to review what is currently known
in each of these areas of study as they apply to NNT.
Reasons to study NNT
Neonatal tumours (NNT) are studied for a number of
important reasons.
Firstly, many of the benign tumours arising from soft
tissue appear to result from disturbances in growth and
development and some are associated with other
congenital anomalies [9]. Study of these aspects may
open the door for investigation of epigenetic changes in
genes controlling foetal development. In this context,
environmental and drug effects on stem cells during
pregnancy are pertinent.
Secondly, their clinical behaviour may be shown to
differ from that of similar tumours occurring later in
childhood as well as the observation that certain
apparently malignant processes can change course in
infancy leading to the maturation of apparently highly
malignant tumours.
Thirdly, they underline the genetic and developmental
associations of the majority of tumours. In this context,
there are also connections between the foetal and
neonatal period and some adult cancers [1, 13, 15,
16] making the genetic background to be of special
interest.
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Pediatr Surg Int
Fourthly, they appear to arise in a period in which
minimal environmental interference has occurred, thus
providing a unique potential window of opportunity to
study the pathogenesis of tumour behaviour.
Associations between NNT and congenital anomalies
The first aspect to explore in relation to the pathophysiol-
ogy of NNT is their relationship to other congenital
anomalies which have been reported in at least 15 % [7,
1719]. Understanding the factors behind this relationship
is not always easy, but it is generally understood that
certain NNT may result from the disruption of normal
developmental processes of fundamental body planning.
This could explain the increased prevalence of associated
anomalies in these patients but also raises the question as to
whether the signalling systems involved in development
may also be associated with NNT.
The observed relationship between NNT and congenital
anomalies does not appear to be constant, but registries with
a lower (9.6 %) prevalence of congenital malformation also
report a lower prevalence of NNT [2.5 % (odds ratio 4.5)]
[17]. On the other hand, some congenital abnormalities (e.g.
Aniridia with Wilms tumour, CNS) although strongly
associated with childhood tumours, are rarely associated
with the neonatal period. The relationship of these particular
tumours to the overgrowth syndromes (e.g. BeckwithWi-
edemann; Hemihypertrophy) is interesting because of the
complex genetic/epigenetic abnormalities of the imprinted
11p15.5 region found in 90 % of affected individuals [20]
and the complicated genomic imprinting in 1020 % of
cases where a mosaic paternal uniparental disomy occurs
(two copies of chromosome 11p15 derived from the father
with no or little maternal contribution) [21].
The link between childhood tumours and congenital
abnormalities therefore suggests a probable association
between the disruption of normal developmental processes
and oncogenesis. In support of this hypothesis, in one reported
study the occurrence of congenital malformations has been
particularly linked to a neuroblastoma presenting at less than
1 year (OR = 16.8, 95 % CI 3.190), as opposed to those
presenting after 1 year of age [22]. A further example can be
found in neonatal teratomas [3, 5, 7, 18, 2325] which are
often associated with regional (e.g. cloaca, limb hypoplasia)
as well as other distal congenital abnormalities [23, 26, 27].
The pathogenesis of NNT
Since NNT are tumours in which minimal environmental
interference is presumed to have occurred, it has generally
Pediatr Surg Int
been assumed that a genetic origin is the most likely cause
[7]. However, a more modern understanding of the aeti-
ology of cancer in children includes both genetic and
environmental factors suggesting a multifactorial origin.
Study of tumours in the neonate opens a window of
opportunity to various oncogenic mechanisms as they
affect the neonate.
Genetic predispositions to cancer
It is clear that the majority of the oncogenic factors giving
rise to tumours probably have a genetic basis at a molecular
level [4, 28] with certain tumours being linked to a genetic
mutation or having a genetic predisposition. These would
include leukaemia, lymphomas, brain tumours, Neuro-
blastoma, Wilms tumour, hepatoblastoma, rhabdomyosar-
coma, Ewings sarcoma and retinoblastoma. In addition, at
least 31 other genes have been identified in association
with 20 familial cancer syndromes and childhood tumours
[29]. Not all of these have bearing on NNT as the majority
of the associated tumours occur outside the neonatal per-
iod. What is of interest are the reasons why certain tumours
appear in the neonatal period and others do not.
This raises the question as to the extent and nature of the
genetic component in the pathogenesis of NNT, particu-
larly in relation to dysfunctional developmental processes.
The genetic connections of NNT include known genetic
predispositions, or other genomic variations such as
oncogene activation, inactivation of tumour suppressor
genes and/or epigenetic factors.
The neonatal period represents only a short physiologic
window in the continuum from the foetus to a child. The
short window of environmental exposure and the intra-
uterine biological initiation links it to genetic control of
developmental processes. It is clear that the developmental
and perinatal period can therefore be regarded as a win-
dow of opportunity in cancer research [5, 30], giving
insight into the mechanisms of control and thus identifying
potential molecular targets.
The effect of chromosomal translocations
and structural rearrangement
Genetic predisposition to tumours is reported in \10 % of
all cancers in childhood and an estimated 1015 % of
paediatric cancers arise from constitutional genetic muta-
tions. These may be hereditary or nonhereditary involving
de novo mutations within the sperm or oocyte prior to
fertilization [31, 32]. Included are associations with chro-
mosomal abnormalities such as trisomies (viz. 13, 18, 21)
and chromosomal rearrangements (particularly aneuploidy
and translocations giving rise to fusion genes) [33].
These are the subject of a number of studies on NNT [34
36] and the resulting genetic imbalances from genetic
alterations can give rise to numbers of abnormal signalling
systems involved in protein synthesis and segregation and
repair of chromosomes, thus giving rise to a cancer
predisposition.
A number of fairly recent studies have demonstrated the
great potential of a genomic approach to study tumour
expression profiles [37]. An example of this is the identi-
fication of recurrent karyotypic genetic variations associ-
ated with NB [38], which demonstrates recurrent
karyotypic genetic sites which are frequently situated in
chromosome regions known to contain genes involved in
neuroblast development (viz. 1p, 2p, 9p, 11q, 16q, 17q).
These probably indicate potential genetic sites for early
tumour onset or development [36, 38].
This association with a particular chromosomal rear-
rangement does not appear to be uniform, however, as is
seen in Trisomy 21 (Downs syndrome) associated
tumours. Whereas there is an increased incidence of
tumours such as leukaemia and retroperitoneal teratomas
[17], other solid tumours such as neuroblastoma, nephro-
blastoma, hepatoblastoma and medulloblastoma, appear
rare in these patients [39], suggesting a possible protective
effect of chromosome 21 [39, 40]; this protective effect has
also been noted in the Klinefelter and triple-X syndromes,
and it may also fit with the probable excess of NB in
patients associated with Turner syndrome [38, 41]. How-
ever, on the other hand, the ganglioneuromas and gan-
glioneuroblastomas associated with the Turner syndrome
appear later in childhood and not in the neonatal period.
Neonatal hepatoblastoma (HB) is a further example,
with chromosomal variations being reported in up to 88 %
of cases [42] and may partly explain a recent increase in
early HB incidence, particularly in low birth weight neo-
nates [43]. These may represent an isolated NNT or be part
of a familial cancer syndrome such as the BeckwithWi-
edemann syndrome or familial adenomatous polyposis [44,
45]. The most likely candidate genes, identified thus far, in
patients with HB are the CTNNB1(b-catenin) gene [46]
and the IGF-2 tumour suppressor gene situated at locus
11p15 [47, 48] and the Adenoma Polyposis Coli gene
(APC_gene on chromosome 5 [44, 45].
The role of oncogenes in NNT
The pathogenesis of NNT confirms the probable genetic
basis of tumours, but shows that whereas certain tumours
can achieve malignancy in the neonatal period, others
require a second hit to become malignant [49]. This
second hit may consist of oncogene activation,
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 Pediatr Surg Int

inactivation of tumour suppressor genes [50] and/or epi-

genetic DNA changes [51], resulting from environmental
factors before a malignant tumour finally occurs.
Because of a general paucity of knowledge on the
mechanisms for oncogene activation of activating muta-
tions and gains in copy number and their interaction being
poorly understood in NNT [52], proto-oncogenes do not
generally appear to be a prominent feature in the patho-
physiology of NNT.
It is now well known that proto-oncogene point muta-
tions or gene amplification may result in activation of
cellular signalling systems, affecting the biological
behaviour of tumours. The concept of oncogenes and
proto-oncogenes provides a rather simple understanding of
how the uncontrolled proliferation of cells can be driven in
tumours.
The Myc oncogene in NB appears important as ampli-
fication of NMYC occurs in about one-third of NB in
childhood and remains one of the best known proto- Fig. 1 CT scan of left sided mesoblastic nephroma in neonate
oncogenes in childhood tumours. Although genome-wide
analysis has identified at least 19 genes involved in NB
progression [53], the role of the MYC oncogene appears to known downstream signalling pathways. These down-
be the most important in clinical practice. MYCN ampli- stream pathways include activation of the MAPK and Ras/
fication has been shown to result in an increase in Myc ERK molecular signalling cascades [62, 63] RAS activation
expression, which in turn increases DNA synthesis and appears to be involved in the pathogenesis of tumours like
causes increased cell proliferation [28, 54]. However, the leukaemia as well as certain solid tumours like rhabdo-
developmental age of the host has a major influence on the myosarcoma [64]. Activation of the RAS protein due to
ability of the MYC oncogene to induce tumourigenesis. point mutations in the RAS gene results in continuous
The biological characteristics of foetal NB detected by activation of the regulatory RAS signal transduction path-
screening in Japan have been shown to have a low inci- way which controls signal transduction pathways affecting
dence of N-myc amplification, although 1020 % have cell proliferation.
unfavourable histological features and may behave A number of other protein structural changes can lead to
aggressively [55]. As a result, the majority of NB occurring oncogene activation. These include changes in the growth
in the neonatal period has a high rate of spontaneous factor receptor (e.g. EGF receptors) or translocations that
regression and non-aggressive behaviour in this age group fuse two distinct reading frames into one hybrid protein (a
has prompted a prospective clinical trial of expectant fusion gene).
observation as primary therapy for infants with small,
localized NB with initial good results [56]. Nevertheless,
activation of MYC in embryonic or neonatal tissues indu- Translocations and fusion genes
ces cellular proliferation and tumourigenesis, but in adult
tissues it resulted in cellular hypertrophy rather than A number of paediatric tumours have been associated with
tumour formation [57]. the fusion of two distinct genes from different chromo-
Clinically, MYC is associated with advanced disease, somes in addition to known associations with chromosomal
rapid tumour growth and is an important prognostic indi- translocations. The fusion genes are of particular interest as
cator of a poor outcome later in childhood [58, 59]. Recent they then activate vital signalling cascades involved in cell
studies in transgenic models have shown, however, that the proliferation, resulting in oncogenesis.
brief inactivation of the MYC oncogene can reverse For example, mesoblastic nephroma, the most common
tumourigenesis, stop proliferation, promoting cellular dif- renal neoplasm in the newborn period [representing 80 %
ferentiation and apoptosis [57, 60, 61]. These findings may of neonatal renal tumours (Fig. 1)], may vary from a bland,
have considerable impact on the treatment of this rather fibromatous histological pattern to a much more cellular
discouraging tumour in the future. lesion sometimes associated with mitosis. The mixed his-
Genetic mutations to important proto-oncogenes appear tological character of the tumour suggests a relationship to
to dictate other downstream signalling cascade response of Wilms tumour as well as metanephric stromal tumour and

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Pediatr Surg Int
Fig. 2 Fibrous tumour on back of neonate with mesoblastic
nephroma of the kidney
infantile myofibrosis (Fig. 2). Similarities between certain
congenital mesoblastic nephromas, and infantile myofi-
brosis, congenital fibrosarcoma and hemangiopericytoma
have also been reported.
The cellular form of mesoblastic nephroma is associated
with a more aggressive course than classic mesoblastic
nephroma, including local recurrences and metastases [65].
These are associated with the transforming ETV6-NTRK3
chimeric protein tyrosine kinase which occurs when the
congenital fibrosarcoma t(12; 15)(p13; q25) rearrangement
splices with the ETV6 (TEL) gene on chromosome 12p13.
This fusion protein has transformation activity in multiple
cell lineages [66] and is reported in the pathogenesis of a
number of tumours including breast and lung carcinoma
later in life.
Malignant soft tissue tumours are the second most
frequently encountered malignant tumour in neonates
and appear to carry a worse prognosis than other age
groups [67]. The most common of these, rhabdomyo-
sarcoma (RMS), is an aggressive high-grade tumour
which may invade as well as tend to metastasize. The
alveolar type often carries the PAX7: FKHR fusion gene
which may be an important in differentiating them
histologically. This translocation consists of the gener-
ation of a chimeric fusion gene involving the PAX3
gene located in chromosome 2 and a member of the
fork-head family, /FOXO1/(formerly/FKHR/), located in
chromosome 13.
Other examples of fusion genes include the t(11; 22)
(q24; q12) translocation in Ewings sarcoma family of
tumours and other tumours associated with gene translo-
cation. These include desmoplastic small round cell
tumour, myxoid liposarcoma, extra skeletal myxoid chon-
drosarcoma, soft tissue malignant melanoma, synovial
sarcoma, congenital fibrosarcoma and dermatofibrosar-
coma protuberans [68].
Inactivation of tumour suppressor genes
Tumour suppressor genes suppress cellular proliferation
and are involved with cancer when their activity is
impaired or lost. As a result, many familial cancers can
be explained by the inheritance of mutant tumour sup-
pressor genes. Susceptibility genes in tumours have been
classified as gatekeepers (e.g. RB1, ki-ras) and care-
takers (e.g. hMLH1 and hMSH2, BRCA1) [69]. The
following tumour suppressor genes are of the most prac-
tical value: the RB1 (retinoblastoma association), BRCA1
and BRCA2 (hereditary breast and ovarian cancer con-
nection), APC and familial adenomatous polyposis, RET
and medullary thyroid carcinoma, p53 (Li-Fraumeni syn-
drome), p16 in melanoma and hMLH1 and hMSH2 for
hereditary non-polyposis colorectal cancer [69]. The
majority of these do not appear in the neonatal period,
however.
The best studied NNT-related tumour suppressor gene is
that of familial retinoblastoma. In an attempt to understand
the pathogenesis of neonatal retinoblastoma, Knutson
proposed an inherited tumour susceptibility, on the basis of
an identified germline mutation [70]. The tumour devel-
opment then rests on further inactivation of a second allele
(often tumour suppressor genes) which gives rise to early
activation of the oncogenic pathway. This so-called two-
hit theory was later confirmed by Comings [71] who
suggested that both of these events could apply to muta-
tions of the RB1 gene. As a result, it is now widely
accepted that inherited or de novo chromosomal mutations
or deletions may result in a susceptibility to cancer.
This theory provides the basis for understanding the
pathogenesis of a number of tumours occurring in the
neonatal period and has since been validated for a number
of other tumour types (e.g. Retinoblastoma, Wilms
tumour, NB and other tumours). In addition, familial reti-
noblastoma offspring have tumour susceptibility with a
higher risk of other tumours later in life (e.g. [500 times
higher risk of osteosarcoma) underlining the genetic
predisposition.
In sporadic tumours (as opposed to hereditary tumours),
a multistep process is more likely and the mutational
activation of oncogenes is often correlated with non-
mutational inactivation of tumour suppressor genes. As this
is probably an early event, it is then followed by a number
of independent mutations in other genes to allow the neo-
plastic growth.
Other examples of tumour suppressor gene inactivation
include mutations of the tumour suppressor p53 gene that
may relate to the Li-Fraumeni syndrome (which predis-
poses to sarcomas of bone (osteosarcoma), muscle (rhab-
domyosarcoma) as well as adreno-cortical carcinoma and
brain tumours, among others. A further example is the loss
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Fig. 3 MRI of Sacrococcygeal teratoma in Neonate showing intra-
pelvic extension
of heterozygosity on the short arm of chromosome 11
(11p15.5), in embryonal rhabdomyosarcoma (RMS), which
suggests an inactivation of a tumour suppressor gene.
Additional evidence of the effect of a loss of p53 function
on maturing myoblasts giving rise to embryonal RMS
suggests that it is involved in its pathogenesis [72]. Other
examples of tumour suppressor genes (e.g. WT1, BWS/
CDKN1C, NF1, NF2, SDHD, etc.) are generally associated
with tumours occurring later in childhood.
Other candidate genes with possible links to NNT
Growth and cellular differentiation are regulated by com-
plex cellular signalling processes during the foetal and
postnatal periods that involve precise regulation of the
functions of the cell cycle, including cell proliferation
differentiation, maturation and apoptosis. It is important to
note that the two main tumour types encountered in NNT
are teratoma and NB [3, 12, 18, 23, 73, 74]. A number of
candidate genes with possible links to these tumours
include the MYC, 1p in NB, fibroblast growth factor genes
[75] and the beta-catenin/E-Cadherin system in epithelial
related lesions as well as germ cell tumours [76].
The majority of teratomas present with a mass at birth
which are usually extra gonadal in the neonate occurring in
the Sacrococcygeal region (Fig. 3), brain, heart, retroperi-
toneal, cervical region, etc. There are at least two possible
explanations for teratomas arising in the neonate: The first
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Pediatr Surg Int
is that there are genetic errors in the signalling systems
controlling the development of primitive stem cells leading
to lack of differentiation, abnormal development and
tumour growth.
An alternative explanation would be that they arise from
the abnormal placement of cells in a region where the
appropriate signalling pathways are non-functional [77].
This raises the question as to whether these tumours arise
from de-differentiation or the arrest of normal stem cell
developmental control [78]. An interesting observation
from these experiments is that when teratocarcinoma cells
are re-transplanted back into a normal embryo, they
develop into normal cells [79]. The conclusion by some
that the control of these cells is dependent on the tissue
environment [77] and genetic influences pertaining to the
neonate is justified.
The Wnt signalling pathway has been shown to play a
vital role in embryogenesis and cell polarity by coordi-
nating gene expression, particularly those involved in
adhesion, cell cycle regulation, cytoskeletal rearrangement
and cellular migration. It is therefore not surprising that
aberrant Wnt signalling is implicated in the development
and progression of numerous embryonal tumours. Deficient
interaction between the Wnt and beta-catenin and other
pathways may affect gene transcription, cytoskeletal
changes and cell motility. In this context, the beta-catenin/
E-Cadherin complex appears a likely molecular target
(particularly in tumours of epithelial origin), as it regulates
the balance between cell proliferation and differentiation
during foetal development [80].
Whereas dysregulated Wnt/beta-catenin may lead to
developmental defects, which would partly explain the
association with congenital anomalies and tumours (e.g.
teratomas), they may also provide an alternate mechanism
whereby MYC can be up-regulated. This is due to the fact
that the MYC oncogene has been shown to be a tran-
scriptional target of beta-catenin, indicating some degree of
inter-dependence [81]. Similar findings have also been
reported in liver tumours, both for beta-catenin [82] and
E-Cadherin [83]. In addition, crosstalk with other genes
[e.g. FLT3 (a receptor tyrosine kinase, RTK) detected in
acute myelogenous leukaemia (AML) blast cells] may
result in an increase in beta-catenin-related nuclear sig-
nalling [84] by promoting tyrosine phosphorylation and
nuclear translocation of beta-catenin.
NNT and epigenetic processes in developmental genes
A further question relates to the possible role of epigenetic
processes in the genomic regulatory and coding regions of
fundamental genes involved in development, mostly con-
trolled by epigenetic DNA and chromatin modifications
Pediatr Surg Int
[85]. Recent research has identified many epigenetic reg-
ulation disturbances as well as associated DNA or chro-
matin modifications involved in the growth and
development of the foetus [8688]. These epigenetic pro-
cesses of the regulatory regions of the human genome
during prenatal life may modify the gene expression and
result in programming to make an individual more likely of cells which may lead to oncogenesis and NNT. The
to develop tumours, possibly later in life [89]. There is
fairly clear evidence that neonatal exposure to epimutagens
may disrupt epigenetic regulation during imprinting,
organogenesis or development, thus influencing the
development of cell lines.
The ability of oncogenes to result in tumours may be
influenced by those epigenetic-specific mechanisms
involved in the development [90], which in turn modulate
functions such as cell cycle initiation, DNA replication and
mitotic cellular division thus linking it to NNT [57]. Many
NNTs probably result from defective cellular control
pathways in utero with the arrest of normal differentiation
pathways and possible disabling of the inbuilt control
mechanisms. This makes the cells more vulnerable to
abnormal response to the normal intracellular signals
directing the growth and differentiation processes in the
neonatal period. Genes involved may be related to cell
cycle control, DNA/RNA replication, ribosomal synthesis,
neuronal differentiation and intracellular/extracellular sig-
nal transduction.
Many of these tumours can be traced to early embryo-
genesis where the development of cellular patterning
remains a crucial event controlled by large networks of
regulatory genes, including homeotic genes. Study of these
genes in cancer has shown an increasing number of
mutations identifying a fundamental genetic role which
may be more clearly identified in neonates than adults. It is
possible that a combined view of genomic and molecular
features will provide a better understanding of the biologic
behaviour and allow for treatment to be directed at specific
molecular sites to promote regression of these tumours
[91].
Environmental factors in the pathogenesis of cancer, on
the other hand, are controlled by the epigenome (the
mechanism which allows the developing foetus to adapt its
metabolic and homeostatic control systems to the prevail-
ing extra-uterine environment [92]). If this adaptation
process fails, it may lead to an increased susceptibility to
oncogenesis. As a result, epigenetic mechanisms are the
most likely factors giving rise to disease resulting from
events occurring during pregnancy. Recent studies have
indicated the importance of unique epigenetic profiles
which allow developmental genes to remain in a sup-
pressed state but which can be reactivated later if given the
correct molecular signals [93]. This could be a possible
explanation for tumours occurring later in childhood.
As DNA methylation appears to be the most important
epigenetic change and is most active during early
embryogenesis, it is possible that genetic and environ-
mental factor exposure may combine to disrupt critical
epigenetic processes during development, thus affecting
gene-related signalling pathways and the eventual outcome
signalling pathways giving rise to NNT are extremely
complex, as is shown by the number of genes implicated.
This is hardly surprising as the signals governing cell
migration and development in the embryo are extraordi-
narily complicated and signalling molecules are notorious
for crosstalk and redundancy, as well as having coordinate
and dependent regulation of expression on occasion.
The critical regulator genes which influence stem cells
during development include the Polycomb family of
genes, the sonic hedgehog or Wnt signalling cascade and
epigenetic variations of genes like Snf5. Epigenetic
changes such as methylation and loss of heterozygosity
influence the control of homeotic gene transcription and
intracellular chromatin structure may thus play a pivotal
role in the development of early foetal tumours [88].
Interest in deregulation events of the transcriptional
repressor Polycomb group proteins, a group of proteins
recognized as epigenetic effectors in many cancers. In
addition, age-associated links have been shown between
the loss of IGF2 imprinting in tumours and hypermethy-
lation, which happens at promoter sites upstream of the
key developmental genes such as the Polycomb group of
genes, suggest a novel epigenetic control pathway [94].
One interesting relationship is that between the Polycomb
genes and the MYC oncogene [95] which, when ampli-
fied, corresponds with a poorer prognosis in certain
tumours, significantly corresponding with mRNA over-
expression [96].
The importance of epigenetic variations (especially
methylation of multiple genes) [97] as well as loss of
heterozygosity is well established in oncogenesis [98].
Hypermethylation appears important, frequently involving
the RASSF1A and CASP8 genes [99]. Mutations within
these genes have only been shown to be present in a subset
of NB tumours [100, 101], suggesting their specific role in
aggressive tumours. Koizumi et al. [102] have shown that
whereas caspase-dependent apoptosis is associated with
unfavourable tumours, it did not play a significant role in
tumour regression.
External environmental factors and NNT
Events and exposures (maternal or paternal) during preg-
nancy could theoretically be of significance in the devel-
opment of NNT. A clear distinction between environmental
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and genetic factors is thought to be unnecessary to justify
as demonstrated by the modern concept of ecogenetics
[103]. Although the role of environmental factors in the
development of NNT is probably smaller when compared
to adult tumours [104], epigenetic processes, possibly due
to effects on DNA methylation of genes, may influence
prenatal development. The complex interaction of both
genetic and environmental factors may be affected by the
in utero exposure of a foetus to an environmental carcin-
ogen which can lead to disease being manifested in later
life.
Probable environmental associations with NNT include
ionising radiation, drugs taken during pregnancy, infec-
tions and tumours in the mother, environmental exposure
and congenital malformations (birth defects) and other
environmental exposure to carcinogens. In addition, there
are genes which promote a higher tumour risk by con-
ferring an increased susceptibility to environmental fac-
tors. Although a number of exposures are thought to
increase the incidence of neoplasms in older children,
examples in neonates are few and further research is
clearly warranted.
A number of possible examples of associations with an
environmental influence such as antenatally administered
drugs do exist. For example, folic acid administration
during pregnancy appears important as a possible pro-
tection against brain tumours [105]. In addition, other
nutritional influences on the mother have demonstrated a
significant effect of maternal nutrition on the epigenetic
regulation of gene expression in the offspring [106].
Offspring of poorly nourished mothers show epigeneti-
cally inactivated expression of a pancreas-specific
enhancer (Hnf4aa gene previously linked with diabe-
tes). This nutrient-sensing hexosamine signalling pathway
has been shown to modulate the levels of O-linked N-
acetylglucosamine (O-GlcNAc) on key targets, thus
impacting cellular signalling, protein turnover and gene
expression in animals [106]. O-linked-N-acetylglucosa-
mine itself has emerged as an important cue in controlling
key cell mechanisms and defective GlcNAcylation has
been shown to be linked to diabetes, neurodegenerative
disease and cancer. This opens up new insights into a
mechanism whereby maternal diet and nutrition interact
through epigenetic processes to determine the risk of
these associated conditions.
One of the additional unresolved environmental issues
and early cancer is the role of cigarette smoking or
exposure to cigarette smoke during prenatal life [107]. In
support of this, it has been shown that exposure to ciga-
rette smoke during prenatal life is a strong modifier of
DNA methylation and could be a further potential link
between epigenetic changes caused by smoking and
cancer [108].
123
Pediatr Surg Int
NNT and drugs in pregnancy
The association with the prenatal exposure to drugs in the
offspring of mothers taking medication may be a greater
problem than initially thought in the pathogenesis of NNT.
Satge et al. [109] showed a history of medications being
taken in 39 of 89 (44 %) NNT. Nine of the 39 tumours in
offspring were malignant NB and teratoma. These workers
identified three groups of drugs, viz. IARC Group 1 di-
ethylstilboesterol and oral contraceptives, IARC Group 2
possibly carcinogenic to humans and IARC Group 3 where
no association has been proven.
A further association exists between NB and the foetal
hydantoin syndrome [110, 111]. A Sacrococcygeal tumour
has also been associated with maternal intake of aceta-
zolamide [112]. Although the role of antenatal exposure to
stilboesterol and bisphenol A, an oestrogenic compound, is
currently attracting attention due to its effect in altering
mammary gland development and a predisposition to
breast and vaginal carcinoma [16, 113], it really deals with
tumours outside of the neonatal period.
There are also reported connections to other drugs taken
antenatally. An increased risk of a brain tumour has been
reported in children exposed to beta-blocking agents during
foetal life, although no tumours have as yet been reported in
the neonatal period [114]. The association with vitamin K
administration and tumours remains unproven [115], although
the adjusted OR for cancer associated with long-term vitamin
K antagonist exposure was 0.99 (95 % CI 0.951.02) in one
study [116]. Similarly, no clear evidence with pesticides and
germ cell tumours has been identified to date [117].
It would seem that drugs may act as carcinogens or co-
carcinogens in association with other agents or a particular
genetic background. Evidence of an inverse association
between antibiotic exposure during pregnancy and low
birth weight and methylation of the imprinted genes (par-
ticularly IGF2, PLAGL1, MEG3) [118] raises the further
question as to the significance of epigenetic factors in
childhood tumour pathogenesis.
Unique clinical behaviour of NNT
A further contribution to the study of NNT is the unique
clinical behaviour of certain tumours presenting within this
period. Although malignancy is uncommon in infants
(Taiwan 207.6/million infants [119]) and newborns
(approximately 100/million [5, 11]), certain neonatal
malignancies demonstrate that unusual biological proper-
ties of spontaneous tumour involution may occur in some
apparently malignant tumours and some may stop growing
and may gradually involute or the cells may maturate.
Foetal NB is a good example of this behaviour (Fig. 4).
Pediatr Surg Int
Fig. 4 Congenital neuroblastoma. Incidental finding in stillborn
infant (H&E 100x)
Clinical behaviour of NNT has previously been classi-
fied into three groups [11]: benign tumours which may be
potentially life threatening because of size and location as
well as relatively benign tumours which tend towards
malignant transformation if left untreated, intermediate
tumours which may demonstrate local invasiveness but
with little or no metastatic potential or a further group of
malignant tumours which either behave better than
expected or have a similar biological behaviour to tumours
occurring in older children. There is also a further group
which demonstrates unpredictable behaviour, behaving
worse than expected.
The neonatal period represents only a short physiologic
window in the continuum from the foetus to a child.
Organogenesis and the body plan are established by day 45
of gestation, but growth (and more importantly cellular
differentiation) continues until adulthood. One of the main
differences in NNT as opposed to tumours occurring later
in childhood lies in their potential for variable biologic
tumour behaviour. In particular, the intra-uterine biological
initiation, short window of environmental exposure and the
possibility of host-specific features pertaining to NNT are
reflected in their comparatively good prognosis when
compared to similar tumours occurring later in childhood.
Apart from explaining how malignant tumours may
present in the perinatal period, genetic control may also
partly explain the variable behaviour of certain malignant
tumours in the perinatal period.
It is clear that the developmental and perinatal period
can therefore be regarded as a window of opportunity in
cancer research [5, 30], giving insight into the mechanisms
of control and thus identifying potential molecular targets.
The relationship of ontogeny and oncogenesis has previ-
ously been the subject of previous maturation arrest (or
blocked ontogeny [120]) models of cancer.
One specific characteristic of foetal NB cells (Fig. 4) is
that they appear to retain the potential for spontaneous
tumour regression plus greater capacity for cell repair in
neonates [121]. As a result, they may undergo change (e.g.
[121] or secrete embryonic tumour markers (e.g. alpha
fetoprotein in teratoma and hepatoblastoma) [77]. There-
fore, patients with the low risk stage Ms NB occurring in
the neonatal period, which has no poor prognostic clinical
or genetic features (e.g. MYCN amplification or segmental
chromosomal abnormalities), are thought to have a high
chance of spontaneous regression and may be clinically
observed. It is interesting therefore that exceptions to this
are those infants with germline ALK or PHOX2B muta-
tions who are at risk of hereditary NB [122], demonstrating
a lack of uniformity.
On the other hand, apparently benign tumours (mature
teratoma) may harbour malignant potential and undergo
malignant change if untreated. Yet again, other tumours,
although histologically malignant in appearance (e.g.
congenital fibrosarcoma), behave benignly and rarely
metastasize [5, 67].
There are a number of possible explanations for this
phenomenon. Firstly, this variable behaviour suggests that
the neonatal period is a special time at which the modu-
latory molecular pathways during foetal development
remain active, thereby influencing the fate of abnormal
cells. In support of this, there is evidence from animal
experiments (mouse) [79, 123] that the injection of
embryonic stem cells into an adult animal results in dis-
organized tissue differentiation similar to that seen in
teratocarcinoma [124]. When these cells are re-transplanted
back into a normal embryo, they develop normally [79].
This indicates that the cellular control is dependent on the
genetic influences at work in the prenatal and postnatal
time periods [77].
Secondly, it is possible that an original genetic mutation,
which allows abnormal cell cycle control in prenatal or
early infancy, may be insufficient to sustain the prolifer-
ating cells resulting in changes. Alternatively, there may be
a lack of maturation in the bodys relentless seeking to
regain control with the abnormal cells undergoing
apoptosis.
NNT and a window of opportunity
NNT appear to arise in a period in which minimal envi-
ronmental interference has occurred, thus providing a
unique potential window of opportunity to study the
pathogenesis of tumour behaviour. In this context, tumours
occurring in the developmental and perinatal period can be
regarded as a window of opportunity in cancer research
[5, 30] and may lead to the identification of potential
123

therapeutic molecular targets. Study of these aspects may
open the door for investigation of epigenetic changes in
genes controlling foetal development as well as environ-
mental and drug effects during pregnancy.
Conclusion
It stands to reason, therefore, that study of NNT and the
identification of target molecular sites is a window of
opportunity to understand oncogenic molecular processes.
Cancer genes often function as network hub proteins which
are involved in many cellular processes, forming infor-
mation hubs between many signalling pathways [125]. This
study may not only assist in NNT prevention and man-
agement but also lead to ways of manipulating (or re-
opening) protective pathways which exist in the neo- 19. Chow EJ, Friedman DL, Mueller BA (2007) Maternal and
natal period. Alternatively, they may lead to the develop-
ment of molecular targets for new treatment regimes to
neutralize or possibly reverse the oncogenic process.
Research in transgenic models suggests that this is an
achievable goal. It has already been shown that the brief
interruption of activation of a critical oncogene may
reverse tumourigenesis [61, 126].
NNT represent a number of unique features, the study of
which has the potential to unlock some of the secrets of
oncogenesis. A more focused investigation into NNT is
both justified and necessary as a future direction in cancer
research.
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