LECTURE OF NEUROBLASTOMA ,CAUSES AND MANAGEMENT ,DONE BY DOCTOR MUSTAFA MAJID JIBER

1. Dr:mustafa majid jiber

2.  Neuroblastoma is the most common solid
extracranial malignancy of the childhood and
the most malignant tumor in infants
 Overall incidence of neuroblastoma is
1/100000 in USA
 7-10% OF all malignancies diagnosed in
patients younger than 15 years of age.
 Its responsible for 15% of all childhood cancer
deaths.

3.  Neuroblastoma is a heterogeneous disease
,tumors can spontaneously regress or mature
,or display a very aggressive ,malignant
phenotype
 The etiology of neuroblastoma is unknown,
and no environmental factors have been
convincingly linked to its development.The
disease generally occurs sporadically, but
familial neuroblastoma occur in 2% of cases

4.  The germ line mutation associated with
hereditary neuroblastoma has been
identified.Activating mutations in the
tyrosine kinase domain of the anaplastic
lymphoma kinase(ALK) oncogene on short
arm of chromosome 2(2p23),the ALK
activation in sporadic neuroblastoma being
approximately 8%

5.  Neuroblastoma is an embryonal tumor of
sympathetic nervous system, its arise during
fetal or early postnatal life from sympathetic
cells(sympathogonia) derived from the neural
crest, so it can originate anywhere along the
path that neural crest cells migrate ,including
the adrenal medulla,paraspinal sympathetic
paraganglia such as the organ of zuckerkandl.

6.  Neuroblastoma can be distinguished
histologically by presence of neuritic
processes(neuropil) and homer wright rosette
 (neuroblasts surrounding eosinophilic
neuropil) ,scattered ganglion cells or
immature chromaffin cells can also be seen.
 Histologic appearance of tumor cells may
very from undifferentiated to fully mature
ganglion cells.

7.  Neuroblastoma have variable dgrees of
schwannian cell stroma,reactive non-
neoplastic tissue recruited by the tumer
cells.this stroma is intermixed,to greater or
lesser degree as wavy bundles and sheets of
spindle cells,and produces antiproliferative
and differentiation-inducing factors that are
crucial to neuronal differentiation.

9.  We had classifications system of
neuroblastoma tumors
 1-shimada
 2-the international neuroblastoma pathology
classification

11.  DNA content
 Amplification of mycn
 Segmental chromosome aberrations
 Mutations

12.  55% of neuroblastoma are triploid or (near-
triploid/hyperdiploid) and contain between 58
and 80 chromosome.
 45% are either near-diploid(35-57) or near-
tetraploid (81-103) chromosome

13.  25% of neuroblastoma had mycn
amplification and present with 40% in
advanced disease but only 5-10% with low
risk disease ,its early event in pathogenesis of
neuroblastoma and assocaited with advance
disease ,rapid tumer progression and poor
outcome ,and is commonly assessed by
fluorescence in situ hybridization(FISH)

15.  20-35% of primary neuroblastoma exhibit 1P
deletion as determined by FISH.
 70% of advanced-stage neuroblastoma have
1P deletion
 Deletion of the long arm of chromosome
11(11q) appear to be common in
neuroblastoma

16.  Activating mutations of ALK have been
shown to be the germline abnormality
associated with hereditary neuroblastoma
 Inactivating mutations of ATRX also have
been found in neuroblastoma ,particularly of
high stage tumors in older patients.

17.  Patients with neuroblastoma usually present
with signs and symptoms that reflect the
primary site and extent of disease ,the most
common sites are
 1-abdominal 75%
 2-posterior mediastinum 20%
 3-cervical region 1%
 4-pelvis 4% (organ of zukerkandel)

19.  Localized disease often asymptomatic
,abdominal mass detected on physical
examination is common clinical feature ,as is
complaint of abdominal pain .
 Respiratory distress or dysphagia may reflect
thoracic tumor.
 Alter defection or urination can be caused by
mechanical compression from pelvic tumor or
spinal cord compression from paraspinal
tumor.

20.  Alter gait can result from spinal cord tumor
 Horner syndrome (ptosis ,miosis,anhydrosis)
,enophthalmos ,heterochromai of the iris.
May result from neck tumor or thoracic
tumor
 Acute cerebellar ataxia characterized by
dancing eye syndrome which include
opsoclonus ,myoclonus ,chotic nystagmus,
result from mediastinal primary tumor .

22.  Diarrhea ,weight loss ,hypertension due to
excessive catecholamine or vasoactive
intestinal polypeptide,
 40% of patient have metastatic disease at
diagnosis and are quit ill, neuroblastoma in in
older patient has a pattern of metastatic
disease in which metastases to bone marrow
,lymphnode ,and bone predominate.

23.  These metastases may manifest as bone pain
from cortical metastases or anemia from
marrow infiltrations ,the brain, spinal cord
,heart ,lungs are rare site of metastases.
 Raccoon eyes may be manifestation of
metastatic disease specially without evident
of trauma ,due to retroorbital venous plexus
spread

25.  Lactate dehydrogenase: high serum level
reflect high proliferative activity and
associated with poor prognosis ,,its not
specific
 Ferritin: high serum level > 150 ng/ml reflect
large tumor burden or rapid tumor
progression ,associated with poor pragnosis
also its not specific

26.  Catecholamine metabolite
 These metabolite can detected in urine in
90% of patient with neuroblastoma and had
clinical value in diagnosis and determined the
response to therapy.
 Random urine samples are preferable to 24
hour urine estimation for younger children .

27.  Stander radiographs
 Ultrasonography
 Computed tomography
 Magnetic resonance imaging
 Metaiodobenzylguanidine imaging (MIBG)
 Bone marrow examination

28.  Chest x-ray show thoracic neuroblastoma
(posterior mediastinal mass)
 Abdominal –x ray:show abdominal
neuroblastoma as mass with fine calcification

29.  Demonstrate calcification in almost 85% of
neuroblastoma and intraspinal extension of
the tumor can be determined on contrast-
enhancedCT scan .
 Contrast-enhancedCT had 82% accuracy in
defining the extension which reach to 97%
when perform with bone scan .

32.  Sensitivity and specificity is 83%,97%
respectively ,so it’s the most useful and most
sensitive imaging modality for diagnosis and
staging of neuroblastoma ,and more accurate
in detection of stage 4 disease ,metastases to
bone and bone marrow and intraspinal tumor
extension ,also encasement of major blood
vessels by MR angiography ,T1-T2 weighted
MRI is 100% for detecting neuroblastoma in
infant

36. Metaiodobenzylguanidine(MIBG) is transported to
and stored in chromaffin cells in same way as
norepinephrine ,MIBG scintiscan is used to evaluate
the bone and bone marrow involvement by
neuroblastoma ,sensitivity is 82% and specificity is
91% in detection of neuroblastoma with metastasis
to bone and bone marrow

38. Bone marrow biopsy is a routine
method for detecting bone marrow
involvement ,both aspiration and
trephine biopsy should be preformed

41.  Making a correct diagnosis of neuroblastoma
can be difficult !!!Why ??
 Primary neurologic disease
 Osteomyelitis or rheumatoid arthritis
 Enteric infection or inflammatory bowel
disease
 Rhabdomyosarcoma
 other tumor ……

42.  The international neuroblastoma staging
system (INSS) is surgicopathologic staging
system that depend on the completeness of
resection of primary tumor,assessment of
ipsilateral and contralateral lymphnodes and
relation of primary tumer to midline ,it
depend on that on CT ,MRI,MIBG scanning

44.  1-low risk disease :disease free-survival is
>95%
 2-intermediate risk disease :disease free
survival is >90 %
 3-high risk disease :disease free survival is
<30%

46.  Surgical resection is the only therapy
 No need chemotherapy or radiotherapy
 In some cases ,resection not performed ,and
these patient are simply observe

47.  1-surgery :complete or near complete
resection of tumer ,with preservation of full
organ and neurological function.
 2-chemotherapy:if the tumer is unresectable
or there is resdual disease adherent to critical
structures.
 3-radiotherapy:epidural disease or spinal cord
compression ,or symptomatic patient not
responding to chemotherapy

48.  1-chemotherapy :intensive induction
chemotherapy.
 2-myeloablative consolidation therapy with
stem cell rescue .
 3-targeted therapy for minimal residual
disease

50.  Complete resection of tumer offers
diffentive therapy with a generally excellent
outcome for most patients with localized
neuroblastoma
 Localized disease :most localized
tumer have favorable biologic feature and
are successfully treated with excision alone
.

51.  types of incision
 1-transverse abdominal incision
 2-bilateral subcostal(chevron) incisions.
 3-midline incision
 4transthoracic(intercostal),transdiaphragmat
ic extension can added to either incision if
needed

52.  The tumor and adjacent lymphadenopathy
should be carefully exposed to determine the
relation between the tumor and normal
organs and vessels.if encasement of major
vessels such as the aorta ,vena cava ,or their
branches is found,tumor dissection must be
performed to free the vessels completely.use
of cavitron ultrasonic aspirator in selected
pateints may allow for better tumor
dissection from major vessels,with less blood
loss and fewer complication

53.  Use of argon beam coagulator also helps
achieve complete or near complete resection
and reduces operative complications.

61.  80% bleeding requires transfusion
 10% injury to major blood vessels
 5% injury to organs (stomach ,bowel ,liver,
spleen, kideny) ,,kideny most common organ
and may required removal
 Wound complication 1-5%
 Hypertension
 Chyle leak into thorax or abdomen

62.  Pleural effusion
 Infection and sepsis
 Diarrhea
 Bowel obstruction