Most common extracranial solid tumor of
childhood.
Most common malignant tumor of
infancy.
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 ganglia.
Tumors may occur anywhere along the sympathetic chain within the neck, thorax, retroperitoneum, or pelvis, or in the adrenal gland.
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 adrenal gland
They are histologically indistinguishable from neuroblastoma.
They can undergo spontaneous regression
Histologic spectrum…
Neuroblastoma,
Ganglioneuroblastoma,
And ganglioneuroma.
Ganglioneuroma is a histologically benign, fully differentiated counterpart of neuroblastoma.
Often diagnosed in older children
Usually located in the posterior mediastinumand retroperitoneum, with only a small number arising in the adrenal glands
Small uniform cells that contain dense hyperchromatic nuclei and scant cytoplasm
Neuropil (Neuritic process) is pathognomonic
Homer-wrightpseudorosettes are clusters of neuroblastssurrounding areas of eosinophilic neuropil
Poorly differentiated neuroblastoma with a minimal-to-
moderate amount of neuropil.
NSE
Synaptophysin
Chromogranin
NB 84
S 100
Age-linked histopathologic classification.
Stroma poor or stroma rich.
Stroma poor - very poor prognosis (less than 10% survival)
Stroma-rich tumors can nodular, intermixed, and well differentiated.
The stroma-poor tumors can be favorable or unfavorable subgroups
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
ecchymosis.
- Respiratory symptoms of cough or
dyspnea.
- Neurologic deficits as a result of cord
compression.
Other sydromes:
Blueberry muffin baby
Raccoon eyes
Pepper syndrome
Hutchinson syndrome
More Periorbital Ecchymoses
of Neuroblastoma
13 months old
at diagnosis
1 month into
therapy
Same patient:
5 years later
12 years later
70% of patients with neuroblastoma present
with metastases at diagnosis
This is responsible for a variety of the clinical
signs and symptoms at presentation.
Mimic pheochromocytoma:
(paroxysmal hypertension, palpitations,
flushing, and headache.)
severe watery diarrhea and hypokalemia(due to Secretion of vasoactive intestinal peptide
(VIP) by the tumor)
Acute myoclonicencephalopathymyoclonus, rapid multidirectional eye movements
(opsoclonus), and ataxia.
Laboratory Evaluation
Increased levels of urinary metabolites of Catecholamines,
Vanillylmandelic acid (VMA) Homovanillic acid (HVA)
(found in 90% to 95% of patients)
Anemia (widespread bone marrow involvement.)
Imaging
Plain radiographs
(calcified abdominal or posterior mediastinal mass.)
USG Abdomen
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
-clinical,
-radiographic,
-and surgical evaluation of children
with neuroblastoma
International Neuroblastoma Staging System
Stage definition
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
involvement.
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)
Age
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 survival.
Hyperdiploid tumors better prognosis
1p deletions or 11q deletions
--bad prognosis
Extra part of chromosome 17 (17q gain) –
--bad prognosis
Presence of Nerve growth factor receptor
(TrkA) --better prognosis.
Increased levels of NSE and LDH in the
blood --bad prognosis
The treatment modalities-
Surgery
Chemotherapy
Radiation therapy
High-dose chemotherapy/radiation
therapy and stem cell transplant
Retinoid therapy
Immunotherapy
The goals of surgery are to establish the diagnosis, stage the tumor, excise the tumor (if localized), and provide tissue for biologic studies.
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 excision alone.
Chemotherapy indicated in
recurrence
child has N-MYC amplification
unfavorable histology.
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
sequelae.
Defer resection until after initial
chemotherapy.
Surgery usually is performed 13 to 18
weeks after initiation of chemotherapy
Usually includes a combination of drugs
• Cyclophosphamide or ifosfamide
• Cisplatin or carboplatin
• Vincristine
• Doxorubicin (Adriamycin)
• Etoposide
• Topotecan
• 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
13-cis-Retinoic acid
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 neuroblastoma
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
(immune
system hormones) such as GM-CSF and
interleukin-2 (IL-2) to help the child’s immune
system recognize and destroy
neuroblastoma cells.
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
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