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