1. CASE PRESENTATION
Yassin M. Alsaleh

3. History:
• Salem 3 3/12 years a old Saudi boy not
known to have any medical illness before .
• 2 weeks prior to admission he developed
URTI with on-off low grade fever followed by
pallor noticed by parents, loss of appetite,
headache and decrease in activity made him
prefer to stay in bed .there was also history
of weight loss.

4. History cont.
• Patient seen two times in PHC .patient managed as
URTI and discharged on antibiotic.
• Also there was history of ingestion of fava bean 1
week ago.
• History of lower limb bruising.
• No history of limb pain, chest pain or abdominal pain
• No change of color of the urine.
• Product of NSVD.
• No past admission.

5. History cont.
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No knowon allergy to medication or food.
Surgical history : circumsicion.
Developmental: appropriate to his age.
Immunization: fully immunized.
Nutritoin: on family food.
Family history: 2nd degree relatives.
Father is G6PD deficient.
+ ve family history of SCD and G6PD.

6. Physical examination
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Vital sign:
PR: 138 bpm
RR:24 bpm temp:37C
BP: 114/68.
O2 sat: 100% in RA
Weight:12 Kg.
Patient looks pale, not jaundiced , not in
distress or pain.
• HENT: Normal.

7. Physical examination cont.
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Eye: pale conjuctiva.
RS: normal.
CVS: S1+S2+ O
Abdomin: soft. Lliver is 4 cm below costal
margin. liver span 9.5 cm.
• Spleen: 1 cm below costal margin.

8. Impression
• Anemia for investigation.

9. Investigation:
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WBC:6.5
Lymp 59%
Mono 1%
Neut 31%
Eosin 1%
Band 6
• PLT:32
• MPV:5
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Hgb:6.3
RBC:2.49
MCV:67.5
HCT:17
MCH:23.8
MCHC:35.3
RDW:15.2
• Retic: 2%

10. Investigation cont.
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Hb electorphoresis:
Hgb A 64.8
Hgb A2 2.1
Hgb S 33.1
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G6PD normal
Blood film: schisocyte, target cell.
Coomb’s test: negative .
LDH: 4275
Uric acid: 433

11. Impression
• Anemia and
thrombocytopenia for
further investigation.

12. Imaging
• CXR: normal.
• Abdominal ultrasound:
• showed hepatomegally with hyperechogenic
mass, heterogenous in the right lobe 12.2 X
8.4 cm with vascularity.CT is recomended

13. Impression
• Anaemia, thrombocytopenia,
abdominal mass under
investigation.

14. CT scan with contrast
• large hepatorenal pouch mass most likely
arisenig from suprarenal gland with area of
calicification and necrosis.
• Crossing midline shows vascular
enhancement inferiorly mass extending upto
lower pole of right kideny, superiorioly
indenting liver with paraortic
lymphadenopathy . spleen intact.
• Conclusion : mostly neuroblastoma.

15. •
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10 DEC 2007
Skeletal survey :
Skull: no metastatic lesion.
Chest: no metastatic lesion.
Thoracic and lumbosacral: no bony abnormalities.
Pelvis: no bony abnormalities.
• 11 DEC 2007
• Bone scan : normal.

16. • 11 DEC 2007
• Biopsy :
• initial result going with neuroblastoma.
• Bone marrow aspiration: infeltration by
neuroblast cell but still waiting for final result.

17. • Diagnosis:
• Neuroblastoma stage 4.
• Plan:
• Chemotherapy, radiotherapy, surgery to
prepare him for bone marrow transplantation.

18. • Father: take this 100 riyals and buy sweets and
gum.
• Son: believe me it will not be enough.

19. Neuroblastoma

20. Introduction
• Definition: refer to a spectrum of
neuroblastic tumors that arise from primitive
sympathetic ganglion cells. (including
neuroblastomas, ganglioneuroblastomas,
and ganglioneuromas) .
• Neuroblastomas, account for 97 percent of
all neuroblastic tumors.

21. Neuroblastoma Differentiation

22. Epidemiology
• Neuroblastoma is almost exclusively a
disease of children.
• It is the third most common childhood
cancer.
• It is the most common solid extracranial
tumor in children.
• most common cancer among infants .
• accounts for approximately 15 percent of all
pediatric cancer fatalities.

23. Epidemiology cont.
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Age distribution is as follows:
40% of patients are younger than 1 year.
35% are aged 1-2 years.
25% are older than 2 years.
Males have a slightly higher incidence than
females.
• Higher in white children.

24. History
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Generally, symptoms include :
abdominal pain.
Abdominal mass.
weight loss.
Anorexia.
Fatigue.
bone pain.
chronic diarrhea.

25. History cont.
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Chronic cough.
unexplained fever.
Irritability.
periorbital ecchymosis .
pathologic fractures.
• Asymptomatic.

26. Physical
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Vital sign: Blood pressure
abdominal mass.
Horner syndrome.
lower extremity weakness , paraplegia,
bladder and bowel dysfunction.
• Metastatic lesions of the skin are common in
infants younger than 6 months.
• Opsoclonus and myoclonus.

27. Causes
• The cause of neuroblastoma is unknown.
• According to SEER, factors investigated for
which evidence is limited or inconsistent
include medications, hormones, birth
characteristics, congenital anomalies,
previous spontaneous abortion or fetal
death, alcohol or tobacco use, and paternal
occupational exposures.
Evidence is
limited

28. Differential diagnosis
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Wilm’s tumor.
Rhabdomyosarcoma.
Lymphoma.
Teratoma.
Hepatoblastoma.
Leukemia.

29. • We open the Pocket it only contain 10 riyals not
enough for treatment do you wanna us to bring
him or keep him on the road.

30. Investigation
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Serum LDH
Ferritin
CBC count and differential
Urine collection for catecholamines
(VMA/HVA)
Serum creatinine
Liver function tests
Electrolytes
Uric acid

31. Imaging Studies
• Plain x-ray of chest and abdomin:
to evaluate for the presence of a posterior mediastinal mass or
calcifications.
• Abdominal ultrasound:
as initial imaging for abdominal mass.
• A CT scan :
essential to determine tumor extent.
• MRI :
determining the presence of intraspinal tumor and cord
compression.

32. Imaging Studies cont.
• 123/131-methyliodobenzylguanadine
(MIBG): accumulates in catecholaminergic
cells to identifying primary and metastatic
disease if present.
• A technetium-99 bone scan: used to
evaluate bone metastases.
• Skeletal surveys :may also be useful.

33. • CT scan of abdomen in a patient with a
retroperitoneal mass arising from the
upper pole of the left kidne

34. Procedures
• bilateral bone marrow aspirate and biopsies
to exclude metastatic disease.
• Tumor biopsy or surgical resection:
performed to collect tissue sample(s) for
biologic studies used to assign the patient
into the appropriate risk category.

35. Other modalities
– immunohistochemistries can aid with tissue
diagnosis.
– Molecular techniques, such as fluorescent in
situ hybridization (FISH), can detect MYCN
amplification, an important prognostic
marker.
– Polymerase chain reaction (PCR) can identify
specific translocations.

36. Staging
• The International Neuroblastoma Staging
System (INSS) is currently used in all group
studies.
• Other staging system include:
• POG.
• CCG.

37. International neuroblastoma staging system
STAGE 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)

38. International neuroblastoma staging system
STAGE 2A
Localized tumor with
incomplete gross excision;
representative ipsilateral
nonadherent lymph nodes
negative for tumor
microscopically

39. International neuroblastoma staging system
STAGE 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

40. International neuroblastoma staging system
STAGE 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

41. International neuroblastoma staging system
STAGE 4
Any primary tumor with
dissemination to distant
lymph nodes, bone, bone
marrow, liver, skin and/or
other organs (except as
defined for stage 4S)

42. International neuroblastoma staging system
STAGE 4S
Localized primary tumor
(as defined for stage 1,
2A or 2B), with
dissemination limited to
skin, liver, and/or bone
marrow (limited to infants
<1 year of age)

43. International neuroblastoma staging system
stage Defintion
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 (except as defined for stage 4S)
4S
Localized primary tumor (as defined for stage 1, 2A or 2B), with dissemination
limited to skin, liver, and/or bone marrow (limited to infants <1 year of age)

44. TREATMENT
•
The modern treatment of neuroblastoma is based
upon the risk category
risk category
Low-risk disease
Intermediate-risk
High-risk disease

45. Criteria for Risk Assignment
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Histopatholgy:
Shimada histopathologic classification system .
(1) the degree of neuroblast differentiation.
(2) the presence or absence of Schwannian stromal
development .
• (3) the index of cellular proliferation
• (4) nodular pattern.
• (5) age.
• histology groups:
• Favorable VS Unfavorable .

46. Criteria for Risk Assignment cont.
• MYCN n-myc
• The most important biologic markers is MYCN.
• homologous sequence to c-myc in neuroblastoma
cells.
• This gene is amplified in approximately 25% of
cases and is more common in patients with
advanced-stage disease.
• Patients whose tumors have MYCN amplification
tend to have rapid tumor progression and a poor
prognosis, even in the setting of other coexisting
favorable factors .

47. Criteria for Risk Assignment cont.
• DNA index :
• is another useful test that correlates with response
to therapy in infants.
• have hyperdiploidy (ie, DNA index >1) have a good
therapeutic response to cyclophosphamide and
doxorubicin.
• In contrast, infants whose tumors have a DNA index
of 1 are less responsive to the latter combination
and require more aggressive therapy.

48. Criteria for Risk Assignment
INSS
Stage
Age (y)
MYCN Status
1
0-21
Any
2A/2B
<1
>1-21
>1-21
>1-21
3
Shimada
Histology
DNA Ploidy
Risk Group
Any
Any
Low
Any
Nonamplified
Amplified
Amplified
Any
Any
Favorable
Unfavorable
Any
-
Low
Low
Low
High
<1
<1
>1-21
>1-21
>1-21
Nonamplified
Amplified
Nonamplified
Nonamplified
Amplified
Any
Any
Favorable
Unfavorable
Any
Any
Any
-
Intermediate
High
Intermediate
High
High
4
<1
<1
>1-21
Nonamplified
Amplified
Any
Any
Any
Any
Any
Any
-
Intermediate
High
High
4S
<1
<1
<1
<1
Nonamplified
Nonamplified
Nonamplified
Amplified
Favorable
Any
Unfavorable
Any
>1
=1
Any
Any
Low
Intermediate
Intermediate
High

50. Low-risk disease
– Patients in the low-risk category generally
have low stage disease..
– Surgery — Surgery alone is the primary
treatment for low-risk tumors.
– Chemotherapy — reserved for those whose
tumors cannot be resected or who have
threatening symptoms of spinal cord
compression or respiratory or bowel
compromise.

51. Low-risk disease cont.
– Frequently used agents include combinations
of cyclophosphamide, carboplatin or
cisplatin, etoposide or teniposide, and
adriamycin.
– Radiation therapy — Radiation therapy (RT) is
reserved for unresectable tumors or
progressive tumors unresponsive to
chemotherapy.

52. Intermediate-risk
• Surgery — Surgery is an important component of
treatment for children with intermediate-risk
neuroblastoma, but is inadequate by itself .
• Chemotherapy — Moderately intensive multiagent
chemotherapy (eg, with doxorubicin,
cyclophosphamide, a platinum drug, and etoposide)
is recommended for children with intermediate-risk
neuroblastoma, and is often applied before
attempted resection.
• Radiation therapy — unclear.

53. High-risk disease
• In the induction phase, intensive chemotherapy with
a combination of agents (eg, platinum agents,
cyclophosphamide, doxorubicin, etoposide) is used
to shrink primary and metastatic tumors .
• Resection may be performed after an initial course
of chemotherapy when the tumor is smaller and less
invasive.
• Radiotherapy (24 to 30 Gy) dosed to the primary
tumor bed and other sites of bulky disease may be
beneficial in preventing local tumor

54. High-risk disease cont.
• After tumor bulk has been decreased by
chemotherapy and surgery, the consolidation
phase includes higher-dose chemotherapy
followed by autologous hematopoietic stem
cell rescue

55. new methods
• Immunotherapy with antibodies targeted on the
surface of neuroblastoma .
• Neuroblastoma vaccines .
• Generalized targeting of tumor cells with drugs that
induce apoptosis (eg, fenretinide or target
angiogenesis.
• Nonmyeloablative allogeneic bone marrow
transplants to induce a graft-versus-tumor effect.

56. Complications
• At disease presentation
– Cord compression from a paraspinal tumor.
Evaluation of the patient by a neurosurgeon
and consultation with oncologist are
important.
– Tumor lysis syndrome .
– Patients may present with severe
hypertension or renal insufficiency.

57. Complications cont.
• During therapy
– Myelosuppression and immunosuppression
place the patient at risk of bleeding and
infection.
– Febrile neutropenia is a medical emergency
and requires immediate admission to the
hospital and initiation of broad-spectrum
antibiotic treatment.
– impaired renal function, hearing loss, or
delayed count recovery.

58. Back to our patient
• Patient started on CCG 3891.
• GCSF 100 mcg/sc.
• Homovanilic acid: 11.9 normal < 4.7

59. SUMMERY
• Age is important prognestic factor for
staging.
• MYCN amplification is the most relevant
prognostic factor.
• Minimum requirement for staging is : bone
marrow biopsy, CXR, bone scan and CT or
MRI.
• chemotherapy with autologous stem-cell
transplantation improves the outcome for
children with high-risk neuroblastoma.

60. REFERENCES
• EMEDICINE
• UP TO DATE
• PUBMED

61. THANK YOU
FOR YOUR
ATTENTION