neuroblastoma · 2020. 3. 27. · neoplasm is not more common in children with congenital defects,...
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NeuroblastomaSYMPATHETIC EMBRYONAL NEUROBLASTOMA
NBL
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Epidemiology of neoplasms in
children
Neoplasms of early childhood constitute
about 0,5- 2% of all neoplasms
Second most common cause of death in
children
Type and age stratification of neoplasms in
children different than in adults
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Remember!!!
Diffrent course of development
Biology
Genetic differences
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Neuroblastoma
Malignant cancer arising from neural crest
cells
One of the most common neoplasms in
children
30- 50% of all the tumours in infants
Proportion of neuroblastoma incidence in
boys to incidence in girls: 1,2:1
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Epidemiology
60 - 70 new cases are diagnosed in Poland
each year
50% of tumours before the age of 2
90% before the age of 5
2/3 of infants with neuroblastoma have no
deviation in PE from the norm
!!! 60- 70% of cases are diagnosed in stage IV
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Histologic division of tumours
arising from sympathetic nervous
system
Neuroblastoma
Ganglioneuroblastoma
Ganglioneuroma
Neurofibroma
Pheochromocytoma
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Shaded areas represent neuroblasts, white areas are ganglioneuroma component
Three main types
of neuroblastoma
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Histopathological examination
Neuroblastoma is a so called small round blue cell tumour
Histopathological view shows characteristic groups of small primitive cells with round or oval hypochromatic nuclei and small amount of cytoplasm.
Grainy chromatin is compared with grains of salt and pepper
.
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Homer Wright rosettes
Clearly visible stages of mitotic divisions with apoptotic cells - Homer Wright rosettes, consisting of neoplasm cells organised in a ring-shape surrounding pale pink fibre material of their thin cytoplasmatic projections
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Under the microscope
Ganglioneuroblastoma Neuroblastoma
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Characteristic biological features
of a neuroblastoma
Possibility of a spontaneous remission, even
at advanced stages
In 85- 90% of cases tumour secreting
hormones
90% of patients show an increase in
neurospecific enolasis
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Occurrence
It can develop where embryonal cells of the
sympathetic nervous system can be found
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Most common place of primary
tumour
40% adrenal glands
25% abdominal ganglia
15% chest
2-5% neck
2-5% pelvis
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Higher risk of incidence in children of mothers who*:
take fenytoin during gestation
often imbibe alcohol during gestation
use hair dye
take hormones
undergo diuretic treatment
There is no correlation between neuroblastoma incidence and smoking or drinking coffee by the mother or exposure to medical sources of ionising radiation.
Neoplasm is not more common in children with congenital defects, immunodeficiency syndromes and chromosome aberrations.
*Kramer S, Ward E, Meadows AT, Malone KE. Medical and drug risk factors associated with neuroblastoma: a case-control study. J Natl
Cancer Inst. 78. 5: 797-804 (1987)
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Cytogenetic disorders
Amplification of N- myc (25- 50%)
protooncogene
DNA (ploidy) in tumour cells
In 25-35% of cases there is genetic
aberration of deletion in chromosome 1
(1p35-36)*.
*Presence of this chromosome aberration is related to unfavourable prognosis
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Patient with a neuroblastoma
Neurofibromatosis
Hirschsprung disease
Heterochromy
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Symptoms?
Drowsiness
Lack of apetite
Abdominal pain
Palness
Weakeness Irritability
Losing weight
Clinical symptoms of a number of diseases neoplastic and non-neoplastic!
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Clinical symptoms
Atypical
Polimorphism resulting form various primary
tumour location, metabolic disorders and
various symptoms related to
metastases
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Head and neck:
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Head and neck:
Palpable tumour
Horner’s syndrome if tumour is located in the
cervical ganglia of the sympathetic system
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Eye socket and eye:
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Eye socket and eye:
Effusions and bruising around eyesocket
(periorbital ecchymoses = raccoon eyes), endophthalmos
Swelling of eyelids
and conjunctiva
Papilledema
Degeneration of optic nerve
Bleeding in retina
Strabismus
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„ raccoon eyes”
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Gabrysia
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Chest
(mediastinum posterior):
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Chest
(mediastinum posterior):
dyspnoea, cough, stridor
lung infections
chest pains
difficulty swallowing
neck swelling, CVSS
Lack of symptoms (tumours located in lower
part of chest)
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Abdomen:
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Abdomen:
growing paplable tumour, pushing kidney forward to the side and down
lack of apetite
vomiting
abdominal pains
loss of body mass
hypertension caused by tumour pressing on kidney vessels hepatomaegalia in case of metastasis to liver
sudden growth of tumour, pain, paleness, hypotonia in case of bleeding to tumour
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CT
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Spinal area:
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Spinal area:
Localised back pain
Neurological disorders caused by pressure on spinal nerves
Paraplegy
Cauda equina syndrome
Cerebellum ataxia
Oversensitiveness
Muscle atrophy
Scoliosis
Bladder disorders
Sphincter disorders
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Pelvis
constipation
anxiety while passing urine
urine retention
tumour palpable in per rectum examination
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Skeleton:
anaemia resulting from bone marrow
infilitration
bone pain
anxiety (in younger children)
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Skin and subcutaneous tissue:
Numerous subcutaneous nodules (characteristic of IV Stage neuroblastoma in infants, rarely after early childhood).
Numerous papular or nodular exanthema 2–20 mm in diameter, with bluish tinge (sometimes described in literature as blueberry muffins).
Exanthema has a tendency to become paler towards the middle and form erythemic halo after 2–3 minutes from rubbing the exanthema
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These symptoms are related to blood vessels
contracting catecholamine released by
neoplasma cells.
Changes on skin occur on all body, but are
most common on torso and extremities.
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Metastases
Bones
Bone marrow
Distant lymph nodes
Subcutaneous tissue, skin
other (lungs, CNS)
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Paraneoplastic syndromes
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General symptoms caused by
excessive production of
catecholamine
hypertension
occasional face reddening, sweating
heart palpitation
"mirror syndrome” *
*Newton ER, Louis F, Dalton ME, Feingold M. Fetal neuroblastoma and catecholamine-induced maternal hypertension. Obstet Gynecol. 65. 3
Suppl: 49S-52S (1985)
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General symptoms caused by
excessive production of the VIP
Watery diarrhoea
Abdominal pain
Intestianal atonia
intense hipocalemia
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Cerebral encefalopathy
(opsoclony mioclony syndrome)
Concerns 2-4% patients with neuroblastoma,
Etiology is not known.
Consists of:
sudden, chaotic eyeball movements,
progressive ataxia
irregular, myoclonic muscle spasms
Symptoms usually subside after removal of the primary tumour, but 70-80% of patients retain long-term neurologic defficiencies.
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Internationa Neuroblastoma
Staging System (INSS)
· Stage 1: Localised confined tumour, completely removable, without mkicroscopic residual. Lymph nodes negative for tumour,
· Stage 2A: Localised tumour with incomplete gross excision representative ipsilateral nonadherent lymph nodes negative for tumor microscopically,
· Stage 2B: Localized tumor infiltrating across the midline with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive or negative for tumor. Enlarged contralateral lymph nodes must be negative microscopically.
·Stage 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 ,
· Stage 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,
· Stage 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 younger than 1 year)
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Diagnostics
Diagnosis on the basis of histopathological
confirmation of a neuroblastoma in the biopsy
of the tumour or bone marrow biopsy and
elevated level of catecholamine in plasma or
their metabolites in the urine (DA, A, NA,
VMA)
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Evaluating the size of primary
tumour location and possible
metastases with imaging
abdominal US and CT
Chest X-ray/ CT
MR in uncertain cases
head X-ray/ CT
X-ray of long bones, scintigraphy
bone marrow biopsy, trepanobiopsy
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Genetic evaluation
N-myc amplification
Deletion of the short arm of chromosome 1
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Immunohistochemical
examination:
Positive reaction of neoplasm cells to:
synaptophisin,
chromogranin,
neurofilaments
Neuron-specific enolase (NSE)
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Treatment
Depends on the stage and prognosis
Combined treatment
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Prognosis:
General survival rate is 55%:
almost 100% at Stage I,
75% at II,
43% at III,
15% at IV (children before 1 year - 60 -70%)
70–80% at IVS
Patients with tumour localised in adrenal
glands have smaller chance of being cured.
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Spontaneous remission*
spontaneous (idopathic) and complete
remission of tumour in metastatic stage was
described.
Ocurrence observed only in infant
neuroblastoma (diagnosed before the age of
1).
Type 4S constitutes around 5% of
neuroblastoma incidence.
*Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 369. 9579: 2106-20 (2007)
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Developments in treatment
Immunotherapy
GD2 is a disialoganglioside present at the
tumour cells surface
anti-GD2 therapies are in clinical trials
* Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 369. 9579: 2106-20 (2007).
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Topoisomerase 1 inhibitors
Topotecan and irinotecan achieve good results, especially
combined with cyklofosphamid.
Retinoids
Randomised research into the effectiveness of all-trans
retinoic acid after ablational chemiotherapy shows
potential effectiveness of retinoids in therapy of high-risk
patients
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Angiogenesis inhibitors
Vascularisation of tumour correlates with the fenotype aggressiveness. Angiogenesis inhibitors are an attractive therapeutic alternative. Pre-clinical trials have so far been inconclusive.
Tyrosine kinases inhibitors
Small molecue kinasis inhibitor Trk, CEP-701 (KT-6587) demonstrated high effectiveness in suppressing the neuroblastoma cells growth in vivo. Clinical trials are in progress.
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Radiotherapy:
Attempts at applying radiotherapy selectively
to neuboalstoma cells