Anatomy to Management

2. Introduction-
Neuroblast oma
Neural crest cells Tumor
 When foetus is at 1st week of development, special
cells called neurocrest cells start migrating along the
spine.
 As they migrate, they differentiate into neurons of the
sympathetic chain on either side of the entire spinal
cord.
 In the lumbar region they differentiate into the cells of
the Adrenal medulla
 Sympathetic chain and adrenal medulla forms the
sympathetic nervous system.

3. Physiology
 When the sympathetic system is stimulated,
the sympathetic nervous system releases
epinephrine and nor epinephrine.
 These hormones binds to receptors of
various organs like blood vessels, heart and
lungs ready for the action.
 When the hormones are no longer needed,
they are enzymatically converted into the
two metabolites Homovanillic acid (HVA)
and Vanillymandelic acid(VMA).

4. Epidemiology -
 Most common extra-cranial solid tumour of childhood
 90% of cases are diagnosed by age 5.
 Very rare in people over the age of 10 years.
 The average age at diagnosis “18 months”→in sporadic cases.
 The average age at diagnosis “9 months”→in familial cases.
 Neuroblastoma is slightly more common among boys compared to
girls (ratio 1.9 to 1).
 Over half of the children present with metastatic disease
 Arise from cells of the neural crest that form the adrenal medulla
and sympathetic ganglia

5. Etiology
 In Neuroblastoma, some neuro crest cells in sympathetic chain or adrenal medulla
don’t differentiate properly that ultimately going to form a tumor; but mechanism is
unknown.
 Nevertheless, it has been linked to have genetic tendency of inheritance
 Autosomal dominant pattern of inheritance
 Hereditary neuroblastoma predisposition gene chromosome 16p12-13
 Associated with mutations-
 Oncogene –
 N-Myc amplification (seen in roughly 20%)
 ALK gene fusion
 Tumor suppressor genes -
 PHOX2B
 Deletion of the short arm of chromosome 1

6. Risk factor-
Genetic factors: The majority of neuroblastomas are sporadic .
• Amplification of the N-MYC.
• Deletion of the short arm of chromosome 1.
• A higher incidence of NB has been suggested in girls with
• Turner syndrome,
• Hirschsprung's disease,
• congenital central hypoventilation, and
• neurofibromatosis type 1
Maternal factors: (COG---Folate deficiency)
• Congenital abnormalities
• Opiate consumption
• Gestational diabetes mellitus
• Folate deficiency

7. Familial Neuroblastoma: in 1 to 2 % of cases.
• These cases appear to be inherited in an autosomal dominant pattern
with incomplete penetrance.
• Inherited cases usually present at an earlier age than sporadic cases
• Familial predisposition may be conferred through disruption of a locus
at 16p12-13.
Others :
• Exposure to chemicals during pregnancy
• Smoking
• Alcohol
• use of hormones and fertility.

8. Sites
 Adrenal medulla (30% to 40%)
 Para-spinal ganglia lower thoracic and
abdominal (25%)
 Posterior mediastinum (19%)
 Pelvic ganglia (2%)
 Cervical ganglia (1%)
 Metastases
 Bone, bone marrow, liver, lymph node and
skin
 Lung and central nervous system are rare
sites of involvement

9. 70 % HAVE METASTASIS AT TIME OF
PRESENTATION
LYMPH NODE
BONE
BONE MARROW
SKIN
LIVER

10. Clinical presentation
 Signs or symptoms caused by the main tumor.
 Signs or symptoms caused by cancer spread to other parts of the body.
 Signs or symptoms associated with paraneoplastic manifestation.

11. Constitutional symptoms- weight loss, anorexia,
malaise and fever.
In the abdomen-
Pain –
Most common presenting symptoms
Due to local spread &/or metastatic disease.
 Respiratory distress: esp. in young infants with massive
hepatomegaly
 Abdominal lump.
 Severe watery diarrhoea and hypokalemia (due to secretion of
vasoactive intestinal peptide by tumor) (Kerner-Morrison
syndrome)
In the chest-
 cough, dyspnea and other breathing problems.

12. In the neck
 Cervical sympathetic involvement with Horner’s syndrome (ptosis,
miosis, anhidrosis)
Others due to spread of tumor
 Spinal cord compression with paralysis of lower extremities (dumbbell
shaped tumor)
 Eye- Tumor infiltration of the per orbital bones, typically unilateral, can
cause the characteristic per orbital ecchymosis ("raccoon eyes"), ptosis,
and proptosis
 Skin- bluish tinge of skin (Blueberry muffin sign)
 Cytopenia (marrow involvement)
Due to paraneoplastic
 Random eye muscle jerks due to anti-neural antibodies (Opsoclonus
myoclonus syndrome)
 The characteristic symptoms of OMA are rapid, dancing eye movements,
rhythmic jerking (myoclonus) involving limbs or trunk, and/or ataxia.

13. Diagnosis
Primary disease
• CECT or CEMRI - tumor extent,
lymph node mets, vessel
encasement, intraspinal extension
• Tissue diagnosis -Biopsy/ FNAC
• MYCN amplification- IHC or FISH
• Urine catecholamines and their
metabolites
Metastatic evaluation
• I-123 MIBG scan –
viable tumor from scar
• Radionuclide bone scan (If no
MIBG uptake)
• CECT abdomen or USG
abdomen – Liver mets
• Bilateral BM aspiration and
biopsy-metastatic deposit.

14. MRI is more accurate than CT for
detection of stage 4 disease(sn 83%
and 43% respectively)

15. Dumbbell shape

16. MIBG(Metaiodobenzylguanidine)
 Metaiodobenzylguanidine (MIBG) is a guanethidine
derivative and an analogue of norepinephrine.
 MIBG is labelled with I131 or I123
 Used to image primary and metastatic sites of
neuroblastoma
 Thyroid gland must be protected
 Simutaneous administration of nonradioactive
iodine (eg.Potassium iodide)
 Can be use higher doses for treatment (for high
risk or recurrence disease)
 Post-induction response for st.4 – prognostic
marker EFS, survival

19. Pathology
 Classic subtypes
 Neuroblastoma
 Ganglioneuroblastoma increasing differentiation
 Ganglioneuroma
 Neuroblastoma
 It is the most undifferentiated-appearing and aggressive of this family
of tumors.
 Because of the lack of Schwannian cells, these tumors are called
"stroma-poor".
 Under light microscopy, they appear as a monotonous collection of
“small, round, blue cells”.
 “Homer-Wright pseudorosettes”- consist of eosinophilic
neutrophils surrounded by neuroblasts .

20. IHC-
NSE & CG -A(levels correlate with more advanced disease and worse
prognosis)
NB84(highly sensitive; less specific)
CD56(diffuse positivity indicates more blastic component)
S100(diffuse positivity indicates better differentiation)
Negative for:
CD45,CD99,EMA,CK,Desmin,Myogenin

23. Staging
 Most commonly used system is the International
Neuroblastoma Staging System (INSS) based on clinical,
radiographic, and surgical findings.
 Others staging systems include:
–Evans and D’Angio (1971)
–St. Jude/Pediatric Oncology Group (POG)

24. International Neuroblastoma Staging
System (INSS)
 Localized tumour with complete
gross excision with out microscopic
residual disease, LN negative
It’s a post-surgery staging system

25. STAGE 2A
 Localized tumour with incomplete gross
excision. Representative ipsilateral non
adherent LN negative
Stage 2B
 Localized tumour with or with out complete
gross excision, ipsilateral non adherent LN
positive

26.  Unresectable unilateral tumour crossing
the midline , localiszd unilateral tumour
with contralateral LN involvement or
midline tumour with bilateral extention
by infiltration (unresectable ) or by LN
involvement.

27.  Any primary tumour with
dissemination to distant lymph
nodes, bone ,bone marrow,
liver , skin or other organs
 Localized primary tumour as
defined for stage 1, 2A, 2B with
dissemination limited to skin, liver
and or bone marrow. ( limited to
infants < 1 year of age.

28. Evans and D’Angio
 Stage I—tumor confined to organ or structure of origin
 Stage II—tumor extending in continuity beyond organ or structure of origin, but
but not crossing midline. Regional lymph nodes on ipsilateral side may be
involved.
 Stage III—tumor extending in continuity beyond midline. Regional lymph
nodes may be involved bilaterally
 Stage IV—remote disease involving skeleton, bone marrow, soft tissue, and
Distant lymph node groups
 Stage IV-S—patients who would otherwise be stage I or II, but who have remote
disease confined to liver, skin, or bone marrow (without radiographic evidence of
bone mets on complete skeletal survey)

29. Pediatric Oncology Group
 Stage A—complete gross resection of primary tumor, with or without
microscopic residual. Intra cavitary lymph nodes not adhered to and removed
with primary tumor, histologically free of tumor. If primary tumor in abdomen
or pelvis, liver histologically free of tumor
 Stage B—grossly unresected primary tumor. Nodes and liver same as stage
A
 Stage C—complete or incomplete resection of primary tumor. Intracavitary
nodes not adhered to primary tumor histologically positive for tumor. Liver as
in stage A
 Stage D—any dissemination of disease beyond intra cavitary notes (i.e., extra
cavitary nodes, liver, skin, bone marrow, bone)
 Stage DS—infants <1 yr with stage IVS disease.

30. International neuroblastoma risk
group
 L1 Localized tumor, not involving vital structures as defined by the list of image-
defined risk factors (IDRF); confined to one body compartment.
 L2 Loco regional tumor with presence of one or more IDRFs
 M Distant metastatic disease
 Ms Metastatic disease in children younger than 18 months with metastases
confined to skin, liver, and/or bone marrow (bone marrow involvement should
be limited to < 10% of total nucleated cells on smears or biopsy).

31.  Pathology
–Shimada system (old)
–International Neuroblastoma Pathology Committee (new, updated Shimada)
 Biology
–MYCN gene (most prognostic)
–1p and 11q deletion
–17q gains
–DNA ploidy
 Staging
–Multiple older surgical staging systems have fallen out of favor
–Current (1993) Post-op INSS: Stages 1, 2A, 2B, 3, 4, 4S
–Pre-op INRG: Stages L1, L2, M, MS
 Age
–<18 mo = favorable
–> 5 years = unfavorable
Prognostic factors

32. Impact on survival of various prognostic factor

36. Management
 Surgery
 Chemotherapy
 Radiation therapy
 High dose chemotherapy/radiotherapy and stem cell
transplant(HDC/SCT rescue)
 Retinoid therapy/Immunotherapy

37.  Resectable stage 1 or 2:
Surgery alone 5yr os 95 – 99%
 Symptomatic OR <50% resection OR progression after surgery:
Chemotherapy x 2 – 4 cycles and surgery, 5yr os 99%
 Asymptomatic AND <1 yr AND MYCN non-amplifed:
Observation alone
 Favorable biology - no adjuvant therapy
 Unfavorable biology - 6- 12 weeks of chemo
 Adjuvant chemo and RT has not improved the outcome.
LOW RISK GROUP(INSS Stage 1,2 or 3 with negative nodes.

38. INTERMEDIATE RISK GROUP
Complete surgical
resection
Followed by adjuvant
chemotherapy
12 – 24 weeks
Unresectable cases, 5
cycles of chemo
Second look surgery

39.  In older children with lymph node mets, adjuvant radiation therapy to
primary and regional lymph nodes has improved disease free and overall
survival rates.
 After second look surgery-
 Radiation therapy was given to gross viable residual tumour on second look
surgery.
 Children age 12 – 24 months received 24 Gy in 1.5 Gy per fraction.
 Older children received 30 Gy in 1.5 Gy per fraction.
 Target volume includes viable microscopic or gross residual tumour
determined by CT , MRI or MIBG scan with 2 cm margins

40. •Favourable histology:
Chemotherapy x 4 cycles and surgery, 5yr os 98%
•Unfavourable histology:
Chemotherapy x 8 cycles and surgery, 5yr os 93%
•Life/organ threatening with slow response to chemo:
Radiation

41. OPEC REGIMENS
VINCRISTINE 1.5 mg/m2 D1
CYCLOPHOSPHAMIDE 600 mg/ m2 DI
CISPLATIN 100 mg/m2 D2
TENIPOSIDE (VM 28 ) 150 mg/ m2 D4

42. CADO REGIMEN
CYCLOPHOSPHAMIDE 300 mg/m2 DI -D 5
ADRIAMYCIN 60 mg/m2
VINCRISTINE 1.5mg/m2

43. HIGH RISK GROUP

44.  INDUCTION
 Dose – intense VAC/ Etoposide+Cisplatinum x 6 – 7 cycles OR
 Dose- intense Topotecan + Cyclophosphamide x 2 then VAC/EC x 4 cycles
 LOCAL THERAPY
 Surgery or Radiation (if indicated)
 CONSOLIDATION
 Chemo x 1-2 cycles
 High Dose Melphalan + Busulfan and Autologous Stem Cell transplant
 MAINTENANCE
 Dinutuximab + GM-CSF + Interleukin2 x 5 cycles
 Isotretinoin x 6 cycles
 5yr EFS 66% Maintenance therapy is biological and immunotherapy targeting minimal
residual disease.(Mrd)
 13-cis-retinoic acid is given as monthly 14 days cycle for 6 months
 Dinutuximab + GM-CSF + interleukin2 x 5 cycles monthly

45.  EBRTin large primary entails irradiation of large volume normaltissue. IORT
Treatment of high risk area at time of resection
Critical structures manipulated away from RTfield
High radiation dosedelivered
 RTdose – 7-16 Gy
 RTmodality – electron or brachytherapy Achieves 85-100% local
control with GTR.
 Local failure higher in patients with sub totalresection
IORT

46. Radiotherapy
 Neuroblastoma is a radiosensitive tumor.
 Uses-
 Local control
 stage IV or bulky stage III tumors*(Matthayet al, 1989; Castleberry
1991; Evans et al, 1996)
 Important role in palliative management of patients with end stage
symptomatic disease.
 Dose- 15 and 30 Gy
 Intra operative radiation therapy-unresectable disease

49. Palliative RT
 Incurable disease
 Relief from pain and functional impairment (bonemets) Palliation of
hepatomegaly in Stage4S
 Dose fractionation
Daily fraction 2-8.5 Gyand total dose of 4-30Gy
 Small fields – 16-20Gy in 4-5# and large fields – 20-30Gy in2-3Gy/# Preterminal case–
6-8Gy in single fraction

50. Iodine-131 MIBG therapy
 May be used for stage III or IV neuroblastoma with MIBG-avid lesions at diagnostic
I-123 MIBG or I-131 MIBG scintigraphy.
 Generally incorporated after surgery as high dose treatments (12-18 mCi/kg) with
stem cell rescue.
Contraindication
 Renal failure
 GFR less than 30 mL/min.

51. Complication
 Scoliosis: up to 25% according to retrospective study with 58pt
Dose > 17.5Gy are significant
 Audiological sequelae due to platinum
 Ovarian dysfunction
 Hypothyroid: MIBG or neck EBRT
 Second malignancy

52. 1) Desmoplastic small-round-cell tumour
2) PNET
3) Ewing's Sarcoma
4) Neuroblastoma
5) Medulloblastoma
6) Rhabdomyosarcoma
7) Synovial sarcoma
8) Carcinoid tumor
9) Mesothelioma
10) Small cell lung cancer
11) Wilms' tumour
12) Retinoblastoma
13) Small-cell lymphoma
14) Hepatoblastoma (anaplastic form)
15) Merkel cell carcinoma
16) Mesenchymal chondrosarcoma
Mnemonic- PM Had
MRND, Was a MESS
done by MRCS
SMALL, ROUND, BLUE CELLS – Differential Diagnosis

53. Thank you