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Anatomic Origin and Molecular Genetics in Neuroblastoma

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Chapter 3
Anatomic Origin and Molecular Genetics in
Murat Tosun, Hamit Selim Karabekir,
Mehmet Ozan Durmaz, Harun Muayad Said,
Yasemin Soysal and Nuket Gocmen Mas
Additional information is available at the end of the chapter
Provisional chapter
© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (, which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly cited.
DOI: 10.5772/intechopen.69568
Anatomic Origin and Molecular Genetics in
Murat Tosun, Hamit Selim Karabekir,
Mehmet Ozan Durmaz, Harun Muayad Said,
Yasemin Soysal and Nuket Gocmen Mas
Additional information is available at the end of the chapter
Neuroblastoma is considered as the most common extracranial solid tumor occurring dur-
ing childhood, but takes place rarely after the age of 10 years. The tumors are considered
as embryonal tumors that result from the fetal or early postnatal life development and are
formed from neural crest-derived cells, and their origination is from the early nerve cells
which are called as neuroblasts of sympathetic nervous system. Being heterogeneous in their
biological, genetic, and morphological characteristics, tumors which are distinct from other
solid tumors due to their biological heterogeneity result in the clinical paern changes from
spontaneous regression to a highly aggressive metastatic disease. Neuroblastoma tumori-
genesis is regulated by Myc oncogene, leading to aggressive tumor subset. Many epigenetic
factors play crucial role in the disease induction and development, while regulatory eect
and outcome result in epigenetic paerns distinguishing neuroectoderm, neural crest, and
more mature neural states. Neuroblastoma patients’ clinical management is based on prog-
nostic categories subtracted from studies correlating outcome and clinico-biological vari-
ables. Neuroblastoma anatomic boundaries include primarily autonomic nervous system
besides other rare locations. Neuroblastoma molecular pathogenesis classies the tumor
according to the dierent clinical behaviors that are important for the improvement of the
patients outcome and overall survival according to the dierent therapy modalities applied.
Keywords: neuroblastoma, anatomy, clinic, genetics
1. Introduction
Neuroblastoma is the most common extracranial solid tumor in childhood; moreover, it is very
rare after age of 10 years. They are regarded as embryonal tumors developed during fetal or
© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
early postnatal life and arise from the immature or dedierentiated neural crest-derived cells.
It is important to understand that they originate from the early nerve cells which are called
as neuroblasts of the sympathetic nervous system, so they can be found anywhere along
this system.
The system includes sympathetic trunk and ganglia, adrenal medulla, and also an aggregation
of cells called as paraganglion [1].
2. The autonomic nervous system
The autonomic nervous system (ANS) is a part of peripheral nervous system, and under the
control of the central nervous system, it governs many involuntary processes of the body
such as heart rate, vascular tone, glandular activity, digestive motility, and others. It has
two main contents as the sympathetic (thoracolumbar—from T1 to L2) and parasympa-
thetic (craniosacral—from S2 to S4 and parasympathetic cranial nerves) systems. These two
main systems contain both preganglionic and postganglionic neurons which are governed
by hypothalamus. Posterior part of the hypothalamus is related to the sympathetic system
[1–4]. Sympathetic nervous system starts to develop from the neural crest cells, and ante-
rior part of the neural tube of the thoracic region migrates on either side of the spinal cord,
toward the region behind the dorsal aorta about week 5 of embryogenesis. Some of them
leave neural tube in order to arrange along the motor root [5, 6]. Mammalian neural crest
cells are multipotent cells and originate from ectoderm. It has been accepted as the fourth
layer of embryo for some researcher, because of their contribution to the cellular diversity in
vertebrates. During embryological development, neural crest cells migrate from neural tube
and dierentiate into dierent structures including adrenomedullary cells and sympathetic
neurons in adrenergic system. The ganglia cells of the thoracic region migrate during 5th
week of development. Neural crest cells forming sympathetic ganglia also migrate both cra-
nially and caudally and extend these trunks into cervical and pelvic regions. The migration
and localization of neural crest cells are controlled by bone morphogenetic proteins (BMP)
secreted by dorsal aorta [7–9].
3. Gross anatomy of sympathetic trunk and ganglia
The sympathetic ganglia together with the suprarenal (adrenal) medulla and chroman
cells of paraganglia are derived from the sympathoadrenal linage cells. From the suprarenal
medulla, these cells dierentiate into a number of types consisting of small and intermedi-
ate-sized neuroblasts and sympathoblasts and larger, initial rounded phechromocytoblasts.
Large cells harboring pale nuclei might be the progenitors of chroman cells. These cells
secrete either adrenaline (epinephrine) or noradrenaline (norepinephrine), while the inter-
mediate-sized neuroblasts dierentiate into the typical multipolar postganglionic symphatic
Neuroblastoma - Current State and Recent Updates36
neurons, and secrete only noradrenaline while paraganglia, situated near, on the surface of,
or embedded in, the capsules of the ganglia of the sympathetic chain, or in some of the large
autonomic plexuses which are cell masses called paraganglion [10–12].
The sympathetic system consists of two ganglionated trunks together with their branches,
plexuses, and subsidiary ganglia, while the sympathetic ganglia include sympathetic trunk
cell aggregations in the autonomic plexuses and intermediate ganglia while the plexuses
contain dispersed preganglionic cells (Figure 1).
Trunks ganglia correspond numerically to the dorsal spinal roots ganglia, while adjoining gan-
glia may fuse in man and there are rarely more than 22 or 23 and sometimes fewer. Subsidiary
ganglia in the major autonomic plexuses (e.g., coeliac, superior mesenteric ganglia, etc.) are
trunks ganglia derivates [13–20].
Figure 1. Components of the sympathetic trunk. Redrawn from Wolf-Heidegger’s Atlas of Human Anatomy.
Anatomic Origin and Molecular Genetics in Neuroblastoma
The sympathetic trunk is positioned just laterally to the vertebral bodies for the entire verte-
bral column length and interacts with the spinal nerves anterior rami via rami communicantes.
The sympathetic trunk allows the sympathetic nervous system including the preganglionic
bers to ascend to spinal levels superior to T1 and descend to spinal levels inferior to L2/3.
The sympathetic trunk ganglion returns to the spinal nerve of preganglionic origin via gray
ramus comminicans, while the higher end was continuing via the carotid canal forming at
the end a plexus located at the internal carotid artery and on the other hand the lower parts
move before the coccyx and at this position it merges with the other ganglion impar basal
structures. Paravertebral ganglia are sympathetic ganglia along the length of the sympathetic
trunk which is a sympathetic nervous system and also a basal part of the autonomic ner-
vous system. It enables nerve bers to extend toward the spinal nerves located at a superior
position as well as inferior position to those they were emanated from. We have here also to
mention that various nerves like a high percentage of the splanchnic nerves emerge directly
from this trunks [14–20].
3.1. Embryology of sympathetic trunk
Mammalian neural crest cells are multipotent cells originating from the ectoderm. They
represent the fourth layer of embryo because of their contribution to the cellular diversity
in vertebrates [21–23]. During embryological development, neural crest cells migrate from
neural tube and dierentiate into dierent structures including both the adrenomedullary
cells and the sympathetic neurons in the adrenergic system (Table 1). Also, the thoracic region
ganglia cells migrate at the end of 5th week of development [22]. Neural crest cells forming
the sympathetic ganglia also migrate both cranially and caudally and extend these trunks
into cervical and pelvic regions. Bone morphogenetic proteins (BMP) secreted by dorsal aorta
norepinephrine produced by notochord control neural crest cell migration and localization,
while at the same time and molecular level, Wnt/β-catenin-related Gbx2 homeobox gene
deactivation is essential for the neural crest development [22, 23].
3.2. Histology of sympathetic ganglia
The nervous system anatomically divides into two parts which are both the central and the
peripheral nervous systems, and at the same time, it was functionally divided into somatic
and autonomic nervous systems including sympathetic and parasympathetic subdivisions.
All the nervous system was built from two main structures, namely the neurons and glial cells
in intercellular matrix. Neurons dier in their type being bipolar, pseudounipolar or motor,
while three types of glial cells can be seen in the neural matrix including all of the astro-
cytes, oligodendroglia and microglia [24, 25]. All neurons have two main processes, axon and
dendrites, and two of them form an extremely dense connecting network and where all the
processes make synapses with each other [24, 25]. The signals from central neurons are trans-
ported from presynaptic membrane to postsynaptic membrane via neurotransmiers such
as serotonin, dopamine, acetylcholine, epinephrine (E) [adrenalin (A)] and norepinephrine
(NE) [noradrenaline (NA)] [24, 25]. One of the main dierences between neuron functions
Neuroblastoma - Current State and Recent Updates38
is which kind of neurotransmiers being secreted for signal transmission in synaptic space.
In adrenergic neurons, E and NE are named as catecholamines, while dopamine is the main
neurotransmier synthesized from tyrosine NE and serves as a transmier between axons
and eectors in autonomic nervous system [24]. Neurons using NE as a neurotransmier are
adrenergic neurons. Epinephrine is secreted by some both the central nervous system cells
and the endocrine chroman cells in the adrenal medulla [24, 25].
3.3. Genetics and clinical characteristics
It has been shown in Ref. [26] that both the dicer and miRNAs are required for the survival of
neural crest-derived tissues by preventing apoptosis during dierentiation because the dicer was
essential for the dierentiation process related to the neural crest cells survival, while neuronal
crest needs specic hdac1 function during its development as shown in a series of zebrash exper-
iment [27]. In the trunk region, the ventrally migrating neural crest cells move through the somitic
mesenchyme in a segmented paern, presumably seing the basis for the sensory and sympa-
thetic ganglia metameric organization along the anterior-posterior axis later in development [28].
When grafting experiments were performed, a specic migratory behavior of the cells was
observed which was under the control of the cellular microenvironment endowed by both
the surrounding mesenchymal cells and the extra cellular matrix (ECM). Also, the posterior
sclerotome which represents a nonpermissive tissues generative barriers for the movement of
Table 1. Structures formed from the neural crest cell dierentiation.
Anatomic Origin and Molecular Genetics in Neuroblastoma
the neuronal crest cells is formed together with the perinotochordal region and, transiently,
the tissue located below the dorsolateral ectoderm [29–31]. Neural crest cells reorganize as
they migrate; formation of iterated, discrete sympathetic ganglia is not the direct result of
paerned crest cell migration through the somites, and the chain formation is a common
conguration adopted by migrating cells in the developing nervous system [32]. Also it has
been shown in [33] that the parasympathetic neurons originate from nerve-associated periph-
eral glial progenitors besides that the development of noradrenergic neurons in the hind-
brain medulla and in the sympathetic nervous system depends on retinoic acid signaling in
addition to the fact that the mount Blanc mutation disrupts the development of noradrenergic
centers in the CNS and of sympathetic ganglia [34, 35].
4. Adrenal medulla
The adrenal glands also develop from neural crest ectoderm and intermediate mesoderm.
While the medulla originated from neural crest cells migrating from sympathetic ganglion,
adrenal cortex develops from intermediate mesoderm. During the 5th week of development,
proliferating mesothelium-derived cells inltrate the retroperitoneal mesenchyme at the cra-
nial end of the mesonephros and give rise to the primitive adrenal cortex. Further, a second
layer of proliferated cells surrounds the primitive cortex and, as a consequence, forms the
future adult adrenal cortex. At the 7th week of development, the mesothelial cells are invaded
at its medial region by neural crest-derived chromanoblast cells. These cells dierentiate into
two kinds of chroman cells of the adrenal medulla which renders homologous to a diuse
sympathetic ganglion without postganglionic processes, leading to complete development of
the adrenal gland at the 4th month of age. Further, the fetal cortex regresses and disappears
within the 1st year of life with replacement by the denitive cortex [3645].
The cells migrating from the neural tube compose two chains of sympathetic ganglia at both
sides of the vertebral column. One of them is lateral vertebral sympathetic chain that occurs
from the interconnecting ganglia by longitudinal nerve bers and the other ones: superior cer-
vical ganglion, the middle cervical ganglion and the inferior cervical ganglion; lumbosacral
region of the sympathetic ganglia occurs from the neuroblast migration and extends from tho-
racic region. Some of the sympathetic neuroblasts migrate further anteriorly to form preaor-
tic ganglia as celiac and mesenteric plexuses, the visceral ganglia of the Auerbach myenteric
plexus and in the Meissner submucous plexus [41–45].
4.1. Gross anatomy of adrenal medulla
For the position of the adrenal glands, they are both positioned on the two sides of the body
located at the retroperitoneum slightly elevated and at medial position from the kidneys. It is
a characteristic of the human adrenal glands that their shape diers according to its posi-
tion, possessing a pyramidal shape for the right adrenal gland versus a larger and semilunar
shape for the left adrenal glands. Adrenal gland size also diers depending on the age of the
subject but in average they are 5.3 cm in size and 7–10 g in weight. The glands are yellowish in
Neuroblastoma - Current State and Recent Updates40
color and surrounded by a fay capsule and lie within the renal fascia which also surrounds
the kidneys, while a weak wall of connective tissue separates the glands from the kidneys
(Figure 2) [41–45].
The adrenal glands are positioned directly below the diaphragm and aached to the dia-
phragm crura by the renal fascia. The adrenal gland is consisted of two distinct parts, the
outer adrenal cortex and the inner medulla, each with a unique function, but both produce
hormones. The adrenal medulla is at the center of each adrenal gland and is surrounded by
the adrenal cortex. The chroman cells of the medulla are the body’s main source of the
catecholamine’s adrenaline and noradrenalin, released by the medulla (Figure 3) [41–45].
The adrenal medulla is driven by the sympathetic nervous system via preganglionic bers
originating in the thoracic spinal cord, from vertebrae T5–T11. Because it is innervated by pre-
ganglionic nerve bers, the adrenal medulla can be considered as a specialized sympathetic
ganglion. Unlike other sympathetic ganglia, however, the adrenal medulla lacks distinct
synapses and releases its secretions directly into the blood [4145]. The sympathetic nervous
system through the preganglionic bers that are originated from the thoracic spinal cord at
the vertebrae T5–T11 controls the adrenal medulla, which can be considered as a specialized
sympathetic ganglion due to its strengthening via the preganglionic nerve bers. One of the
characteristics of the adrenal medulla was that it diers from the sympathetic ganglion that
is latching of independent synapses and its secretions are released into the blood by a direct
manner [4145]. These hormones are released by the adrenal medulla, which contains a dense
Figure 2. The components from the adrenal medulla. Redrawn from Wolf-Heidegger’s Atlas of Human Anatomy.
Anatomic Origin and Molecular Genetics in Neuroblastoma
network of blood vessels. Adrenaline and noradrenaline act at adrenoreceptors throughout the
body, leading to increase both the circulating blood pressure and heart beat speed also known
as heart rate. There is also a phenomenon called “ight response” where both adrenalin and
noradrenalin are responsible for it and this phenomenon of increasing the speed of breathing,
heartbeat, and blood pressure is due to the increased blood vessel contraction in the dierent
parts of the body [46, 47]. Catecholamines are produced in chroman cells in the medulla of the
adrenal gland, from tyrosine, a nonessential amino acid either derived from food or produced
from phenylalanine in the liver. Suprarenal medulla is composed of chroman cell column
groups separated by wide venous sinusoids, while single and small groups of neurons occur in
the medulla. Tyrosine hydroxylase converts tyrosine to L-DOPA during the initial step of cat-
echolamine synthesis with further conversion of L-DOPA to dopamine prior to its conversion
into noradrenaline. On the other hand, the enzyme phenylethanolamine N-methyltransferase
(PNMT) converts noradrenaline into epinephrine and becomes stored in cytosolic granules.
Tyrosine hydroxylase and PNMT levels play an important regulative role in the catechol-
amines synthesis in a way that when their level increases they aect the adrenal cortex gluco-
corticoids that in turn stimulate the catecholamine synthesis, where the sympathetic nervous
system via its activation stimulates the catecholamine release. Also, the adrenal gland
Figure 3. The components from the adrenal gland. Redrawn from Wolf-Heidegger’s Atlas of Human Anatomy.
Neuroblastoma - Current State and Recent Updates42
medulla is innervated by the sympathetic nervous system splanchnic nerves, where as a con-
sequence the stimulation of the cell membrane calcium channels opening evokes the release
of the catecholamines from the storage granules [41–45, 48–52]. Adrenal gland’s medulla and
para-aortic body tumors can cause excessive adrenaline and noradrenaline secretion, leading
to palpitation aacks, excessive sweating, pallor, hypertension, headaches and retinitis and
renal vascular changes as a consequence of a long persistence of the tumor [41–45].
4.2. Embryology of the adrenal gland
The adrenal glands develop from neural crest ectoderm and intermediate mesoderm. While
the medulla originated from neural crest cells migrating from sympathetic ganglion, adre-
nal cortex was developed from the intermediate mesoderm [42]. During the 5th week of
development, proliferating mesothelium-derived cells inltrate the retroperitoneal mesen-
chyme at the cranial end of the mesonephros and give rise to the primitive adrenal cortex
[23–25]. A second proliferation of these cells surrounds the primitive cortex and forms the
future adult adrenal cortex. At the 7th week of development, neural crest-derived chromaf-
noblast cells invade the mesothelial cells at its medial region [24]. These cells dierenti-
ate into chroman cells of the adrenal medulla. The adrenal medulla is homologous to a
diuse sympathetic ganglion without postganglionic processes [24]. At the 4th month of
age, the adrenal gland is fully developed. The fetal cortex regresses and disappears within
the 1st year of life and is replaced by the denitive cortex. During adrenal gland develop-
ment, some transcription factors such as Wnt4 and Wnt1 have very important regularity
functions [53].
4.3. Histology of adrenal gland
Histologically, the adrenal glands (Figure 4) have two main structures, one of which is the cor-
tex including three substructures (Figure 3) and medulla (Figure 5). The cortex cover with cap-
sule contains collagen and elastic bers and has three layers, and each has dierent functions:
the outermost, zona glomerulosa, the middle, zona fasciculata and the innermost layer, zona
reticularis. Although zona glomerulosa cells produce aldosterone, zona fasciculate cells mainly
produce cortisol, while zona reticularis cells synthesize androgen. Both zona fasciculata and
reticularis are stimulated by adrenocorticotropic hormone (ACTH), but zona glomerulosa is
primarily stimulated by angiotensin II that stimulates both zona glomerulosa and proliferation
and aldosterone synthesis [24, 25]. The adrenal medulla is located in the adrenal gland cen-
ter and contains the chroman cells, which are modied sympathetic postganglionic neurons
derived from neural crest, and forms epithelioid cords surrounded by fenestrated capillar-
ies [24]. Chroman cell cytoplasm contains membrane-bounded dense granules containing
chromogranins, one class of catecholamine epinephrine and norepinephrine and a lile dopa-
mine. Two kinds of chroman cells exist in the adrenal medulla, 80% of which produce epi-
nephrine and 20% of which produce norepinephrine that is stored in granules with a dense
eccentric core, while epinephrine contains granules that are smaller and occupy less dense cen-
tral core, whereas all circulating epinephrine produced by adrenal medulla, norepinephrine
produces both adrenal medulla and postganglionic sympathetic neurons, but we have to men-
tion here that adrenal cortex cells do not store their steroid hormones in granules [24, 25].
Anatomic Origin and Molecular Genetics in Neuroblastoma
The adrenal medulla is composed of groups and columns of chroman cells (phaeochromo-
cytes) separated by wide venous sinusoids and supported by a network of reticular bers.
Chroman cells bear the name as a result of their response to the use of dichromate xative
during the xation process. Structurally and functionally, they are comparable to the postgan-
glionic sympathetic neurons being at the same time a member of the neuroendocrine system.
Figure 5. Microscopic view of the adrenal medulla. Hematoxylin-eosin. 400× (image recorded and edited by Murat
Figure 4. General microscopic view of the adrenal gland. Hematoxylin-eosin staining. 400× (image recorded and edited
by Murat TOSUN MD PhD).
Neuroblastoma - Current State and Recent Updates44
Since they are derived from the neuronal crest, they produce, store before release and release
dierent hormones into the venous sinusoids which are catecholamines, noradrenalin (or as
mentioned in other references norepinephrines) or adrenaline. The synthesis, storage and
release of these hormones are under the control of the sympathetic nervous system precisely
by the sympathetic neurons where the preganglion and their sympathetic neurons are shown
as a single appearance or as a small group located at the medulla. When the noradrenaline-
secreting cells are rarely present, they possess bigger sized granules having a dense eccentric
kernel [5, 6, 5456]. Normally, cells dier in their hormone secretion manner. While some
cells secret only hormone, others are secreting two hormones. Catecholamines together with
enkephalins represent opiate like proteins that are under certain conditions pached by the
chromogranin proteins. The cells that are formed here are shown as large cells possessing a
large nuclei with a cytoplasmic region that is faintly granular and basophilic ahead the venous
sinusoids and in a single-lined alignment. The sympathetic axon terminals are forming syn-
apses together with the chroman cells where these synapses are positioned locations oppo-
site and distant to the sinusoids. These sinusoids in turn are arranged via a branched construct
of cells called the fenestrated endothelium and elapse to both the central medullar vein and
the Hilary suprarenal vein, while according to the knowledge available until now the supra-
renal medulla presence and function do not represent a necessity for life activities [57, 58].
Further, we have here to address that the scientic community should concentrate their
research eorts to study the dierent aspects of the adrenal medulla since the information
available about it is restricted and the availability of it can help to unravel many unknown
points about the development of this disease.
4.4. Genetic and clinical investigations of adrenal medulla
For the establishment of genetic parameters of neuroblastomas, continuous scientic eorts
were necessary [59]. In molecular and genetic analysis, dierent pathology-related ndings
were possible. One research group was able to prove experimentally that activated ALK col-
laborates with MYCN during neuroblastoma pathogenesis where they used the Zebrash
model that was able to help them proving that neuroblastomas arise in MYCN expressing
transgenic Zebrash and showing the MYCN-induced loss of sympathoadrenal cells; the
absence of expression of early sympathoadrenal markers was absent in MYCN transgenic
embryos during early development; MYCN expression causes sympathoadrenal cell loss and
the role of the activated ALK in the disease onset acceleration and increases the penetrance
of MYCN-induced neuroblastoma [60]. Experimentally, the direct role of dopamine in the
generation and/or expansion of mitochondrial DNA deletions in dopaminergic neurons was
proven unraveling more knowledge about the Parkinson’s disease pathogenesis, showing
here the mitochondrial DNA deletions accumulation role and representing the missing link
between aging and Parkinson’s disease, while the catecholaminergic adrenal medulla is the
preferential location of mitochondrial DNA deletions [61]. Also in another experimental setup,
gene expression proling helped to identify eleven DNA repair genes downregulated during
mouse neural crest cell migration process [62]. Radiotherapy, chemotherapy and surgery are
only suitable for neuroblastomas treatment but MIBG (metaiodobenzylguanidine) applica-
tion, and nuclear medicine has a dual function aiding in diagnosis as well as its function as
Anatomic Origin and Molecular Genetics in Neuroblastoma
a treatment modality, but immunological methods like the application of a monoclonal anti-
body and proved to be more eective and promising when applied at early stages [63–65].
5. Paraganglion
5.1. Gross anatomy, embryology and histology of the paraganglion
Paraganglia are extrasuprarenal chroman tissue aggregations that distribute (near to/
within) the automatic nervous system. This type of paraganglia cells also occurs in the sympa-
thetic ganglia of various viscera as well as in variety of retroperitoneal and mediastinal sites;
all of these cells synthesize and store catecholamines and are derived from the neural crest,
and their function is dened by their position. Being a remainder source of neuroendocrine
secretion, intraneuronal cells are functioning as interneurons. In suprarenal medulla, chemi-
cal stimuli are responsible for catecholamine release, while the role of the neuronal stimuli is
neglectable regarding to this functional detail. Within the fetus, the extrasuprarenal chromaf-
n tissue is representing the main repository of catecholamine where within this regard the
suprarenal medulla plays no role due to the fact of being immature.
However, many paraganglia are well vascularized and their secretory cells are usually close
to one or more fenestrated capillaries. Most like the suprarenal medullary chroman cells,
they have a sympathetic innervation and thereby act as endocrine organs [1]. Para-aortic
bodies and coccygeal body (glomus coccygeum) are paraganglia which include chroman
cells and produce adrenaline and noradrenaline. Para-aortic bodies place on lateral side of
abdominal aorta and usually united anterior to it by a horizontal mass immediately above the
inferior mesenteric artery [13].
5.2. Coccygeal body
The coccygeal glomus (coccygeal gland or body also it is referred as the Luschka’s coccygeal
body by others) represents a vestigial structure situated either in front of or immediately below
the coccyx tip that is situated near the ganglion impar in the pelvis in addition to another posi-
tion near the median sacral artery termination [66]. Its diameter is 2.5 mm and has an irregular
oval shape; several smaller nodules are found around or near the main mass and consist of
irregular masses of round or polyhedral cells or epithelioid cells, forming a group around a
dilated sinusoidal capillary vessel [66–68].
Each cell includes a large round or oval nucleus and the protoplasm surrounding the nucleus
which is clear, and not stained when chromic salts are applied; therefore, it is not considered
as a part of chroman system, the system which includes cells stained by chromic salts and
consists of renal medulla, paraganglia and para-aortic bodies [66–68]. Clinically, the coccy-
geal body looks like a glomus tumor, thereby causing problems in the diagnosis that can lead
to misinterpretations [69–71].
Paraganglia are extrasuprarenal aggregations of chroman tissue, distributed near to or
within the autonomic nervous system. This type of cells also occurs in the sympathetic ganglia
Neuroblastoma - Current State and Recent Updates46
of various viscera and in a variety of retroperitoneal and mediastinal sites. All of these cells are
derived from the neural crest, and all of them synthesize and store catecholamines. Also, their
function depends on the way and site they are positioned; several cells role is functioning as
interneurons, while in other cases, there are cells existing that are functioning in another man-
ner within this context by acting as a source for the neuroendocrine secretion. In the coccygeal
bodies, chemical inducers are responsible of the paraganglionic release of catecholamines.
The period of the paraganglion existence in human is dierent, while their regulating factors
and mechanisms are still not completely understood, and a population of them keep present
until adulthood mostly as a microscopic paraganglia with its later degeneration [3640].
6. Para-aortic bodies
The para-aortic bodies are chroman tissue condensations found closely to the aortic autonomic
plexuses and lumbar sympathetic chains. In the fetus, they are at the largest size but later become
relatively smaller in childhood and disappear at the beginning of the adulthood. Mostly, their
presence of existence is as a pair of bodies positioned within intermesenteric, inferior mesenteric
and hypogastric plexus anterolaterally to the aorta. They can be elevated at the celiac plexus or
bounded below at the hypogastric plexus of the pelvis, or can be nearby the sympathetic ganglia
of the lumbar chain. Scaered cells, which persist into adulthood, may rarely be the chromaf-
n tissue tumor development sites (phaeochromocytoma); these scaered cells are much more
commonly found arising from the suprarenal medulla cells. The wide variation in the persistent
para-aortic body tissue site accounts for the range of locations of such tumors [54, 55, 72].
7. Experimental treatment of neuroblastoma cells: in vitro
During a series of experiments conducted that aimed to evaluate cytotoxic eects of melatonin
(MLT) which is an endogen hormone and 13-cis retinoic acid (13-cis-RA) also named as isotret-
inoin a vitamin A analogue on neuroblastoma SH-SY5Y cell line by our research group [73].
We found that treatment of neuroblastoma cells with melatonin resulted into a cytotoxic eect
in a way where in cell culture the cells were exposed to dierent doses of MLT and 13-cis-RA
for either 24 or 48 h. While the viabilities were estimated with MTT cell viability assay test,
apoptotic indexes were calculated after staining with TUNEL-based apoptosis determination.
We observed the eective cytotoxic potential on neuroblastoma cell line which MLT l poses
which was higher than the one 13-cis-RA. At the same time, when MLT and 13-cis-RA were
combined, the obtained eect was potentiated. On the other hand, it was found that the eect
of 13-cis-RA individually was very slight. Results gathered from the current study have indi-
cated that MLT exhibited neurotoxic eect on SH-SY5Y neuroblastoma cell line and this eect
was potentiated by 13-cis-RA.
As a consequence, we believe that administration of these agents in neuroblastoma patient
treatment may contribute to obtain outcomes that bear potential for the design of innovative
treatment modalities, leading to the successful treatment of this type of diseases, with taking
Anatomic Origin and Molecular Genetics in Neuroblastoma
in account the necessity of in vivo studies based on these results that clearly determine the
dose range necessary. It is expected that the results of them can improve the currently applied
treatment modalities applied against neuroblastomas to be more successful.
8. Conclusions
Neuroblastoma is the most common extracranial solid tumor occurring during childhood till
the age of 10 when it might occur rarely. Many epigenetic factors play a crucial role in the dis-
ease induction and development of neuroblastoma, while the regulatory eect and outcome
resulting into epigenetic paerns is well known but needs further study. Dierent research
eorts were made by various research groups to study this type of disease from the dierent
levels, where some results like neuroblastoma treatment with melatonin was one positive
example, while the study of the adrenal medulla needs to be more intensied by the scientic
community since the understanding of its dierent regulatory aspects can be one target for
the optimization of the treatment methods applied against this disease.
The authors would like to thank the Dokuz Eylul University and the Afyon Kocatepe University
for their kind support. Also, we would like to thank Ms. Alara Karabekir for the graphic
design. Finally, we also would like to thank Assoc. Prof. Dr Nilüfer Yonguc from the Dokuz
Eylül University and Mr Ali Ege Mas from the Near Eastern University, Cyprus, for techni-
cal support during the dierent stages of the research.
Author details
Murat Tosun1*, Hamit Selim Karabekir2, Mehmet Ozan Durmaz3, Harun Muayad Said4,
Yasemin Soysal4 and Nuket Gocmen Mas5
*Address all correspondence to:
1 Department of Histology and Embryology, Faculty of Medicine, Afyon Kocatepe University,
Afyonkarahisar, Turkey
2 Department of Neurosurgery, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
3 Department of Neurosurgery, Bozyaka Education and Research Hospital, Health Science
University, Izmir, Turkey
4 Department of Molecular Medicine, Graduate Institute of Health Science, Dokuz Eylul
University, Izmir, Turkey
5 Department of Anatomy, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Neuroblastoma - Current State and Recent Updates48
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Full-text available
Draxin is a repulsive axon guidance protein that plays important roles in the formation of three commissures in the central nervous system and dorsal interneuron 3 (dI3) in the chick spinal cord. In the present study, we report the expression pattern of mouse draxin in the embryonic mouse trunk spinal cord. In the presence of draxin, the longest net migration length of a migrating mouse trunk neural crest cell was significantly reduced. In addition, the relative number of apolar neural crest cells increased as the draxin treatment time increased. Draxin caused actin cytoskeleton rearrangement in the migrating trunk neural crest cells. Our data suggest that draxin may regulate mouse trunk neural crest cell migration by the rearrangement of cell actin cytoskeleton and by reducing the polarization activity of these cells subsequently.
Full-text available
Neural crest cells (NC cells) are multipotent cells that emerge from the edge of the neural folds and migrate throughout the developing embryo. Although the gene regulatory network for generation of NC cells has been elucidated in detail, it has not been revealed which of the factors in the network are pivotal to directing NC identity. In this study we analyzed the gene expression profile of a pure NC subpopulation isolated from Sox10-IRES-Venus mice and investigated whether these genes played a key role in the direct conversion of Sox10-IRES-Venus mouse embryonic fibroblasts (MEFs) into NC cells. The comparative molecular profiles of NC cells and neural tube cells in 9.5-day embryos revealed genes including transcription factors selectively expressed in developing trunk NC cells. Among 25 NC cell-specific transcription factor genes tested, SOX10 and SOX9 were capable of converting MEFs into SOX10-positive (SOX10+) cells. The SOX10+ cells were then shown to differentiate into neurons, glial cells, smooth muscle cells, adipocytes and osteoblasts. These SOX10+ cells also showed limited self-renewal ability, suggesting that SOX10 and SOX9 directly converted MEFs into NC cells. Conversely, the remaining transcription factors, including well-known NC cell specifiers, were unable to convert MEFs into SOX10+ NC cells. These results suggest that SOX10 and SOX9 are the key factors necessary for the direct conversion of MEFs into NC cells.
Background.—Rarely encountered nonpathologic structures may pose diagnostic problems and cause unnecessary special investigations. More importantly, however, they may be falsely accused as culprits in unrelated pathologic processes. Glomus coccygeum is one such structure. Glomus bodies (including coccygeal glomus) consist of modified smooth muscle cells arranged in layers around small vascular channels. When found in distal extremities, they generally do not represent a diagnostic problem; however, large glomus bodies present in a pericoccygeal location (glomus coccygeum) may cause significant problems for a surgical pathologist unfamiliar with this structure. Design.—We reviewed 37 coccygeal bones removed during rectal resection for carcinoma (rectal and uterine) and for various other reasons, among which was a single case of coccygodynia. Immunohistochemical and ultrastructural examinations were performed in selected cases. Results.—Sharply circumscribed glomus bodies composed of various proportions of glomus cells without atypia or pleomorphism and without expansile growth or infiltration of surrounding soft tissue or bone were identified in 50% of cases. Size varied significantly (maximum 4 mm), but paradoxically the smallest glomus body (less than 1 mm) was found in the case of coccygodynia. Glomus coccygeum posed a significant diagnostic challenge to the pathologists involved in these cases, as the retrospective review found that it was diagnosed correctly in only 3 cases. Conclusions.—Glomus coccygeum is a nonpathologic structure that exhibits significant variation in size and proportion of the constitutive elements. Immunohistochemical demonstration of smooth muscle actin and neuron-specific enolase in glomus cells may be beneficial for accurate identification of this organelle.
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