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 Most common extracranial solid tumor of
childhood.
 Most common malignant tumor of
infancy.
 8% to 10% of all childhoo...
 These tumors can undergo
- spontaneous regression (Brodeur, 1991),
- differentiate to benign neoplasms,
- or exhibit ext...
 Arise from cells of the neural crest that form
the adrenal medulla and sympathetic
ganglia.
 Tumors may occur anywhere ...
 Familial cases …autosomal dominant
pattern of inheritance (Knudson and
Strong, 1972a; Robertson et al, 1991).
 Familial...
 Amplification of the N-MYC oncogene
(seen in 20% of primary tumors)
(Look et al, 1991; Muraji et al, 1993).
 Deletion o...
 Beckwith and Perrin coined the term in-
situ neuroblastoma for small nodules of
neuroblasts found incidentally within th...
 Histologic spectrum…
Neuroblastoma,
Ganglioneuroblastoma,
And ganglioneuroma.
 Ganglioneuroma is a histologically benig...
 Small uniform cells that
contain dense
hyperchromatic nuclei
and scant cytoplasm
 Neuropil (Neuritic process)
is pathog...
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 ...
 Most children present with abdominal pain or
a palpable mass.
 Manifestations of their metastatic disease
-Bone or join...
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 clini...
 Mimic pheochromocytoma:
(paroxysmal hypertension, palpitations,
flushing, and headache.)
 severe watery diarrhea and hy...
Laboratory Evaluation
 Increased levels of urinary metabolites of
Catecholamines,
Vanillylmandelic acid (VMA)
Homovanilli...
 Imaging
 Plain radiographs
(calcified abdominal or posterior mediastinal mass.)
 USG Abdomen
 CT/ MRI Scan more usefu...
 Bone marrow aspiration and biopsy
(Neuroblastoma often spreads to the bone marrow
If blood or urine levels of catecholam...
 Significant prognostic variable that
determines adjuvant therapy.
 The International Neuroblastoma Staging
System (INSS...
International Neuroblastoma Staging System
Stage definition
1 Localized tumor with complete gross excision, with or withou...
 I – localized with complete resection
 IIa – Localized w/o complete gross resection
 IIb – + Ipsilateral LN, - Contral...
 Age
Children 1 year or younger have a better survival
than older children
 The site of origin
better survival noted for...
 N-MYC amplification - rapid tumor
progression and a poor prognosis.
Seeger and colleagues (1985, 1988)
The poor prognosi...
 1p deletions or 11q deletions
--bad prognosis
 Extra part of chromosome 17 (17q gain) –
--bad prognosis
 Presence of N...
The treatment modalities-
 Surgery
 Chemotherapy
 Radiation therapy
 High-dose chemotherapy/radiation
therapy and stem...
 The goals of surgery are to establish the
diagnosis, stage the tumor, excise the tumor
(if localized), and provide tissu...
 Stage I neuroblastoma have a disease-free
survival rate of greater than 90% with surgical
excision alone.
 Chemotherapy...
 Extensive surgery at this site has been
associated with long-term neurologic
sequelae.
 Defer resection until after ini...
 Usually includes a combination of drugs
• Cyclophosphamide or ifosfamide
• Cisplatin or carboplatin
• Vincristine
• Doxo...
 The use of marrow-ablative
chemoradiotherapy followed by
autologous marrow reinfusion
- complete remission in up to 50% ...
 13-cis-Retinoic acid
differentiation of neuroblastoma in
cell culture significantly decreased the
frequency of relapse
...
 A monoclonal antibody called ch14.18
attaches to GD2, a substance found
on the surface of
 many neuroblastoma cells. Th...
 For local control in neuroblastoma
 Doses of external beam irradiation used
have ranged between 15 and 30 Gy.
(dependin...
 In up to 5% of patients
 Initiate treatment with chemotherapy and
reserve laminectomy for children with
progressive neu...
Neuroblastoma
Neuroblastoma
Neuroblastoma
Neuroblastoma
Neuroblastoma
Neuroblastoma
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Neuroblastoma

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Neuroblastoma by Dr. Sreenath

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Neuroblastoma

  1. 1.  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
  2. 2.  These tumors can undergo - spontaneous regression (Brodeur, 1991), - differentiate to benign neoplasms, - or exhibit extremely malignant behavior.
  3. 3.  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.
  4. 4.  Familial cases …autosomal dominant pattern of inheritance (Knudson and Strong, 1972a; Robertson et al, 1991).  Familial neuroblastoma have bilateral adrenal or multifocal primary tumors
  5. 5.  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).
  6. 6.  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
  7. 7.  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
  8. 8.  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
  9. 9. Poorly differentiated neuroblastoma with a minimal-to- moderate amount of neuropil.
  10. 10.  NSE  Synaptophysin  Chromogranin  NB 84  S 100
  11. 11.  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.
  12. 12.  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.
  13. 13. Other sydromes:  Blueberry muffin baby  Raccoon eyes  Pepper syndrome  Hutchinson syndrome
  14. 14. More Periorbital Ecchymoses of Neuroblastoma 13 months old at diagnosis 1 month into therapy
  15. 15. Same patient: 5 years later 12 years later
  16. 16.  70% of patients with neuroblastoma present with metastases at diagnosis  This is responsible for a variety of the clinical signs and symptoms at presentation.
  17. 17.  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.
  18. 18. 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.)
  19. 19.  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,
  20. 20.  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).
  21. 21.  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
  22. 22. 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.
  23. 23.  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)
  24. 24.  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)
  25. 25.  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
  26. 26.  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
  27. 27. The treatment modalities-  Surgery  Chemotherapy  Radiation therapy  High-dose chemotherapy/radiation therapy and stem cell transplant  Retinoid therapy  Immunotherapy
  28. 28.  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.
  29. 29.  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.
  30. 30.  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
  31. 31.  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
  32. 32.  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
  33. 33.  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
  34. 34.  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.
  35. 35.  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.
  36. 36.  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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