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Most common extracranial solid tumor of
Most common malignant tumor of
8% to 10% of all childhood cancers.
Regrettably over half of the children
present with metastatic disease
These tumors can undergo
- spontaneous regression (Brodeur, 1991),
- differentiate to benign neoplasms,
- or exhibit extremely malignant behavior.
Arise from cells of the neural crest that form
the adrenal medulla and sympathetic
Tumors may occur anywhere along the
sympathetic chain within the neck, thorax,
retroperitoneum, or pelvis, or in the adrenal
Seventy-five percent arise in the
retroperitoneum, 50% in the adrenal, and
25% in the paravertebral ganglia.
Familial cases …autosomal dominant
pattern of inheritance (Knudson and
Strong, 1972a; Robertson et al, 1991).
Familial neuroblastoma have bilateral
adrenal or multifocal primary tumors
Amplification of the N-MYC oncogene
(seen in 20% of primary tumors)
(Look et al, 1991; Muraji et al, 1993).
Deletion of the short arm of chromosome 1
(1p) (25% to 35% of neuroblastomas )
Brodeur et al, 1992; Caron et al, 1996).
Gain of one to three copies of 17q….more
aggressive tumors (Bown et al, 1999).
Beckwith and Perrin coined the term in-
situ neuroblastoma for small nodules of
neuroblasts found incidentally within the
They are histologically indistinguishable
They can undergo spontaneous
Ganglioneuroma is a histologically benign, fully
differentiated counterpart of neuroblastoma.
Often diagnosed in older children
Usually located in the posterior mediastinum
and retroperitoneum, with only a small number
arising in the adrenal glands
Small uniform cells that
and scant cytoplasm
Neuropil (Neuritic process)
clusters of neuroblasts
surrounding areas of
Poorly differentiated neuroblastoma with a minimal-to-
moderate amount of neuropil.
Age-linked histopathologic classification.
Stroma poor or stroma rich.
Stroma poor - very poor prognosis (less than 10%
Stroma-rich tumors can nodular, intermixed, and
The stroma-poor tumors can be favorable or
based on the patient’s age at diagnosis, the
degree of histologic maturation, and the mitotic rate.
Most children present with abdominal pain or
a palpable mass.
Manifestations of their metastatic disease
-Bone or joint pain and periorbital
- Respiratory symptoms of cough or
- Neurologic deficits as a result of cord
70% of patients with neuroblastoma present
with metastases at diagnosis
This is responsible for a variety of the clinical
signs and symptoms at presentation.
(paroxysmal hypertension, palpitations,
flushing, and headache.)
severe watery diarrhea and hypokalemia
(due to Secretion of vasoactive intestinal peptide
(VIP) by the tumor)
myoclonus, rapid multidirectional eye movements
(opsoclonus), and ataxia.
Increased levels of urinary metabolites of
Vanillylmandelic acid (VMA)
Homovanillic acid (HVA)
(found in 90% to 95% of patients)
(widespread bone marrow involvement.)
(calcified abdominal or posterior mediastinal mass.)
CT/ MRI Scan more useful
(The finding of intratumoral calcifications, vascular
encasement, or both on preoperative CT may help
distinguish neuroblastoma from Wilms tumor )
Both a radionuclide bone scan and meta-
iodobenzylguanidine (MIBG) scans for staging,
Bone marrow aspiration and biopsy
(Neuroblastoma often spreads to the bone marrow
If blood or urine levels of catecholamines are
increased, then finding cancer cells in a bone
marrow sample is enough to diagnose neuroblastoma
(without getting a biopsy of the main tumor).
Significant prognostic variable that
determines adjuvant therapy.
The International Neuroblastoma Staging
System (INSS) is based on
-and surgical evaluation of children
International Neuroblastoma Staging System
1 Localized tumor with complete gross excision, with or without
microscopic residual disease; representative ipsilateral lymph nodes
negative for tumor microscopically (nodes attached to and removed
with the primary tumor may be positive).
2A Localized tumor with incomplete gross excision; representative ipsilateral
nonadherent lymph nodes negative for tumor microscopically
2B Localized tumor with or without complete gross excision, with ipsilateral
nonadherent lymph nodes positive for tumor; enlarged contralateral
lymph nodes must be negative microscopically
3 Unresectable unilateral tumor infiltrating across the midline,* with or
without regional lymph node involvement; or localized unilateral tumor
with contralateral regional lymph node involvement; or midline tumor
with bilateral extension by infiltration (unresectable) or by lymph node
4 Any primary tumor with dissemination to distant lymph nodes, bone,
bone marrow, liver, skin, and/ or other organs.
4S Localized primary tumor (as defined for stage 1, 2A, or 2B), with
dissemination limited to skin, liver, and/or bone marrow (less than 10%
tumor) in infants less than 1 year of age.
I – localized with complete resection
IIa – Localized w/o complete gross resection
IIb – + Ipsilateral LN, - Contralateral LN
III – Unresectable local tumor &/or contralateral LN
IV – Distant hematogenous or LN mets
IV S – Stage I or II tumor with spread to skin, liver, or
BM (less than 1yr)
Children 1 year or younger have a better survival
than older children
The site of origin
better survival noted for nonadrenal primary tumors
Stage of the disease is a powerful
independent prognostic indicator.
Tumour histology (favorable/ unfavourable)
N-MYC amplification - rapid tumor
progression and a poor prognosis.
Seeger and colleagues (1985, 1988)
The poor prognosis associated with N- MYC
amplification is independent of patient
age or stage of disease at presentation
DNA diploidy and tetraploidy- decreased
Hyperdiploid tumors better prognosis
1p deletions or 11q deletions
Extra part of chromosome 17 (17q gain) –
Presence of Nerve growth factor receptor
(TrkA) --better prognosis.
Increased levels of NSE and LDH in the
blood --bad prognosis
The treatment modalities-
therapy and stem cell transplant
The goals of surgery are to establish the
diagnosis, stage the tumor, excise the tumor
(if localized), and provide tissue for biologic
Resectability of the primary tumor should
take into consideration tumor location,
mobility, relationship to major vessels, and
overall prognosis of the patient.
Neoadjuvant chemotherapy, given the
efficacy of modern agents, is very successful
in reducing the size of primary tumors.
Stage I neuroblastoma have a disease-free
survival rate of greater than 90% with surgical
Chemotherapy indicated in
child has N-MYC amplification
N-MYC amplification, unfavorable histology,
age > 2 years, and positive lymph nodes
--- lower overall survival.
Extensive surgery at this site has been
associated with long-term neurologic
Defer resection until after initial
Surgery usually is performed 13 to 18
weeks after initiation of chemotherapy
Usually includes a combination of drugs
• Cyclophosphamide or ifosfamide
• Cisplatin or carboplatin
• Doxorubicin (Adriamycin)
• Busulfan and melphalan
The most common combination of drugsincludes
carboplatin (or cisplatin), cyclophosphamide,
doxorubicin, and etoposide
The use of marrow-ablative
chemoradiotherapy followed by
autologous marrow reinfusion
- complete remission in up to 50% of
patients with recurrent stage IV disease
New agents in phase I and II trials for
relapsed neuroblastoma include
temozolomide, irinotecan, and topotecan
differentiation of neuroblastoma in
cell culture significantly decreased the
frequency of relapse
Fenretinide – a new synthetic retinoid
Cause apoptosis rather than
differentiation in neuroblastoma cell
lines, is also in early clinical trials.
131 I-MIBG - treatment of metastatic
A monoclonal antibody called ch14.18
attaches to GD2, a substance found
on the surface of
many neuroblastoma cells. This antibody
can be given together with cytokines
system hormones) such as GM-CSF and
interleukin-2 (IL-2) to help the child’s immune
system recognize and destroy
For local control in neuroblastoma
Doses of external beam irradiation used
have ranged between 15 and 30 Gy.
(depending on the patient’s age, location,
and extent of residual disease)
Intraoperative radiation therapy
- patients with unresectable disease.
In up to 5% of patients
Initiate treatment with chemotherapy and
reserve laminectomy for children with
progressive neurologic deterioration
Because of delayed complications of
scoliosis after laminectomy.
(Katzenstein et al, 2001).
Radiotherapy is now generally avoided