2. EPIDEMIOLOGY :-
• 3rd m.c malignancy diagnosed in children.
• It’s m.c cancer diagnosed before 12 months.
• Median age at diagnosis is 2 years.
• Excretion of catecholamine metabolites in the urine of
children with neuroblastoma has served as the basic of
these screening tests.
- qualitatively for VMA test
- quantitatively for VMA & homovanillic acid (HVA)
• Screening dose not affect the mortality rate in N.B
3. NATURAL HISTORY :-
• N.B may arise from any site in sympathetic nervous system.
• M.c site of origin is adrenal medulla (30-40%) , paraspinal ganglia in
abdomen & pelvis (25%).Thoracic (15%) and head and neck
primary tumours (5%) are more common in infants than in older
children.
• > 70% pt have metastasis at presentation.
• Most frequent site of mets are L.N , B.M , skin & liver, lung & CNS is
rare site.
• Highest spontaneous remission usually by maturation to
ganglioneuroma.
• Most potential N.B are never clinically manifested ,because of
4. CLINICAL PRESENTATION:-
• Pain is the m.c presentation , this is caused by bone, liver, or B.M
mets other symptom include weight loss, anorexia, malaise & fever.
• Respiratory distress may accompany massive hepatomegaly.
• Spinal cord compression in N.B that originates along the
sympathetic ganglia through adjacent foramina.
• Skin mets may have bluish tinge (“Blue berry muffin“ sign).
• Localized N.B unsually presents with opsoclonus- myoclonus
syndrome , manifested by truncal ataxia & cerebellar
encephalopathy.
5. DIAGNOSTIC WORKUP :-
• Diagnosis of N.B is establish by pathologic evaluation.
tumour tissue is obtained from suspected primary tumour
site or involved L.N by excision or incisional biopsy.
• Pathological evaluation of B.M is required for staging of
neuroblastoma.
• Measurement of urinary catecholamine metabolites
HVA or VMA , metabolite of dopa/N.E & epinephrine is
elevated in >90% of pt with stage 4 N.B.
( ratio of VMA to HVA > 1.5 is asso with good prognosis)
• CBC ,serum ferritin , LDH & other liver function should be
assayed routinely.
6. • MRI allows better evaluation of b.v encasement ,
intraspinal extension , B.M involvement .
• Radionuclide scan is a mandatory investigation.
• MIBG scan can be used to image primary & metastatic
sites of N.B. ( labelled with I123 or I131 have sensitivity
of 85-90% and specificity of 95% ).
• Long acting somatostatin analog octreotide labelled with
I123 is used to image neuroblastoma , expression of
S.R by N.B tissue is favourable prognostic factor.
7. STAGING :- M.c used staging system is INSS.
• STAGE 1:- Localized tumor with complete gross excision,
without microscopic residual disease; representative
ipsilateral LN negative for tumor microscopically (nodes
attached to and removed with the primary tumor may be
+ve)
• STAGE 2A:- Localized tumor with incomplete gross
excision; representative ipsilateral nonadherent LNs -VE
for tumor microscopically.
• STAGE 2B :- Localized tumor with or without complete
gross excision, with ipsilateral nonadherent LNs positive
for tumor. Enlarged contralateral LNs must be negative
microscopically.
8. • STAGE 3 :- - Unresectable unilateral tumor infiltrating
across the midline, with or without regional LN
involvement; or localized unilateral tumor with
contralateral regional LN involvement; or midline tumor
with bilateral extension by infiltration (unresectable) or by
LN involvement.
• STAGE 4:- Any primary tumor with dissemination to
distant LNs, bone, B.M, liver, skin, and/or other organs
(except as defined for stage 4S).
• STAGE 4S:- Localized primary tumor as defined for stage 1,
2A, or 2B with dissemination limited to skin, liver, and/or
B.M (limited to infants <1 year of age).
9. PATHOLOGICAL CLASSIFICATION :- three types of
tumors, representing different degree of differentiation .
• GANGLIONEUROMA :- it consist of mature ganglion cells,
schwann cells, & nerve bundle & is benign .its
calcified form may represent mature N.B.
• GANGLIONEUROBLASTOMA:- it’s intermediate between
ganglioneuroma & N.B . Both mature &
undifferentiated neuroblast are evident.
• NEUROBLASTOMA :- it’s the undifferentiated end of
spectrum of neural crest tumors.
10. • IHC stains helps in diagnosis of neuroblastoma , it stains
+ve for NF , NSE , synaptophysin , chromogranin A.
• Grading system by shimada et al , it evaluate tumor
specimen for stromal development , neuroblastic
differentiation & mitosis karyorrhexis index.
11. PROGNOSTIC FACTORS :-
PROGNOSTIC FACTOR FAVOURABLE UNFAVOURABLE
• age <2 YR > 2 YR
• stage 1,2 , 4s 3,4
• Pathology
( shimada) favourable unfavourable
• Ferritin <143 ng/ml >143 ng/ml
• NSE <100 > 100
• Urine VMA/HVA <1 >1
• N-myc single copy ampilified
• DNA index > 1.1 1
• 1p deletion no 1p deletion 1p deletion
12. GENERAL MANAGEMENT:-
LOW –RISK DISEASE :-
• low stage resectable tumour (INS stage 1,2 or 3 with –ve nodes)
have an excellent prognosis after complete surgical excision.
• Unresectable tumors of low stages (INSS stage 1-3 with
-ve LN) may require preoperative C.t & occasionally R.t
to convert them into resectable status.
• Pt with n-myc amplification or low DNA index may require
adjuvant therapy and should be enrolled in trials.
• In CCG trial 3381 with stage 1 disease , 4 yr EFS & OSR for children
t/td with Sx alone were 93% &99%.
• With stage 2 4 yr EFS & OSR were 81% and 98%
13. INTERMEDIATE RISK DISEASE :-
• Locally advanced & regional metastatic tumors (INSS stage
2b – 3 with +ve LN) require intensive therapy .
• Infant <1 yr should undergo complete resection of
primary tumor and receive adjuvant C.T
• In Unresectable cases, C.T may be administered initially &
Sx can be done after response to sys.CT.
• In older children with LN metastases, adjuvant RT to
primary & regional LN has improved DFS & OSR.
14. • De Bernardi et al failed to show a benefit from adding RT
in children > 1yr with post op residual tumor or +ve LN.
• In pt with intraspinal extension of NB ,t/tnt with CT
demonstrate 92% improvement in neurological deficit
avoiding neurosurgical decompression in >60% cases
receiving courses of CARBOPLATIN & ETOPOSIDE
alternating with CYCLOPHOSPHAMIDE, VINCRISTINE,
DOXORUBICIN.
• On the basis of CCG & POG , pt with intermediate risk NB
have 3yr survival between 75% & 98%
15. HIGH RISK DISEASE :-
• Aggressive t/t regimens is been used to prolong survival
& achieve cure.
• Intensive high dose C.T regimens appear to be superior.
Drugs used are CYCOPHOSPHAMIDE, CISPLATIN ,
DOXORUBICIN , ETOPOSIDE & TENIPOSIDE.
• Recent trials have sought to intensify t/t of metastatic NB
through use of high dose myeloablative C.T with stem cell
rescue or B.M transplantation.
• Pt reveiving the ABMT has a higher EFS than pt continuing
on std CT.
16. • European NB study grp studied role of consolidated ABMT
with high dose MELPHALAN Vs no further t/t following
induction CT with OPEC REGIMEN in pt with stage 3 & 4.
report shows inprovement in EFS (38% vs 27%) & OS ( 47%
& 30%) for high dose melphalan arm.
• R.T plays an imp role in palliative Mx of pt with end stage
symptomatic NB. Radiation doses ranged from 4- 24.4gy
at a rate of 1 – 1.5gy /#.
17. R.T TECHNIQUE :- T/T PLANING & FIELD DESIGN :-
• R.T to primary tumor site should t/t gross residual
tumor remaining after C.T with at least 2cm margin from
the tumor to the block edge.
• Regional LN sites should be covered if LN were
radiologicaly or pathological involved at any time during
the course of disease.
• CT or MRI should be used to define full extent of disease.
• R.T of metastatic sites should include generous margin.
• Low dose TBI as a part of preparative regimen for pt
undergoing BMT for high risk metastatic disease.
18. • NB is very radiosensitive tumor, neuroblast exhibits very
little repair capacity between # .this make hyper# RT an
option .
• Irradiation dose to control gross disease is age dependent
< 1 yr -- dose 12gy
12- 48 month -- dose at least 25gy
> 4 yr – dose of >25gy
• Sloan kettering CA center , reported that 21 gy of hyper#
RT resulted in 90% primary site local control at 5 years.
• Haas hogan show the result of IORT in pt with high risk
disease.Single # of 7-16gy( median 10gy) to primary
tumor bed is asso with local Control rate of 100% in pt
with gross total resection.
19. • Children t/td for palliative for symptomatic metastatic
disease should receive adequate irradiation dose for tumor
control if they have reasonable expectation of long
survival.
• If likelihood of long survival is small , 5-20 gy in one or five
daily # can give rapid palliation.
20. RESULTS OF THERAPY :-
LOW RISK DISEASE :- Survival rate after Sx alone is 85-90%
INTERMEIDATE RISK DISEASE :- - Children with large ,initialy
unresectable tumor often respond to
primary C.T with combinations of drugs.
- Children with unresponsive , unresectable gross residual
tumor may require EBRT .
- Frequently this children can undergo resection of tumor
at a second look operation & achieve a survival rate of
60 – 90%.
21. HIGH RISK DISEASE :- - children > 1yr with metastatic NB have
poor prognosis with survival rate of
<10-30%.
• Addition of cisplatin & teniposide to CT improved
expected 4 yr survival rate from 7% to 28% .
• Addition of cis- retinoic acid was asso with a 47% EFS.
• In stage 4S survival rates can be as high as 75% to 90%.
• In this pt goal of therapy should be limited to relief of
acute presenting symptoms.
• Local field #ted low dose RT < 12gy , minimal CT &
supportive care is imp to achieve high survival rate.
22. SEQUELAE OF TREATMENT :-
EARLY COMPLICATION :- especially skin reaction & mucositis.
LATE COMPLICATION :- Depends on site of RT & total
dose of both RT & CT .
- Age and time of t/t influence risk & severity of skeletal
anomalies.
- Younger pt are more prone to develop late effect.
- Neve et al reported high rate of pulmonary function
impairment in children receiving TBI as a part of
conditioning regimen for ABMT.
23. LONG TERM SEQUELAE RELATED TO R.T (WASHINGTON UNIVERSITY) :-
• Scoliosis (severe) 8 – 30gy
• Bone & muscle
pulmonary hypoplasia 28 – 30gy
• Lung fibrosis 48gy
• Liver fibrosis 39.5 gy
• Rib necrosis 48 gy
• Cataract 20gy
• Hypopituitarism 20gy
