Neuroblastoma by Dr. Sreenath

2.  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

3.  These tumors can undergo
- spontaneous regression (Brodeur, 1991),
- differentiate to benign neoplasms,
- or exhibit extremely malignant behavior.

4.  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.

5.  Familial cases …autosomal dominant
pattern of inheritance (Knudson and
Strong, 1972a; Robertson et al, 1991).
 Familial neuroblastoma have bilateral
adrenal or multifocal primary tumors

6.  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).

7.  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

8.  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 mediastinum
and retroperitoneum, with only a small number
arising in the adrenal glands

9.  Small uniform cells that
contain dense
hyperchromatic nuclei
and scant cytoplasm
 Neuropil (Neuritic process)
is pathognomonic
 Homer-wright
pseudorosettes are
clusters of neuroblasts
surrounding areas of
eosinophilic neuropil

10. Poorly differentiated neuroblastoma with a minimal-to-
moderate amount of neuropil.

11.  NSE
 Synaptophysin
 Chromogranin
 NB 84
 S 100

12.  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.

13.  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.

14. Other sydromes:
 Blueberry muffin baby
 Raccoon eyes
 Pepper syndrome
 Hutchinson syndrome

15. More Periorbital Ecchymoses
of Neuroblastoma
13 months old
at diagnosis
1 month into
therapy

16. Same patient:
5 years later
12 years later

17.  70% of patients with neuroblastoma present
with metastases at diagnosis
 This is responsible for a variety of the clinical
signs and symptoms at presentation.

18.  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 myoclonicencephalopathy
myoclonus, rapid multidirectional eye movements
(opsoclonus), and ataxia.

19. 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.)

20.  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,

23.  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).

24.  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

25. 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.

26.  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)

27.  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)

28.  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

29.  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

30. The treatment modalities-
 Surgery
 Chemotherapy
 Radiation therapy
 High-dose chemotherapy/radiation
therapy and stem cell transplant
 Retinoid therapy
 Immunotherapy

31.  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.

32.  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.

33.  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

35.  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

36.  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

37.  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

38.  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.

39.  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.

40.  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