This document provides an overview of neuroblastoma, including its clinical presentation, pathology, risk grouping, diagnostic workup, prognostic factors, and management. Some key points: - Neuroblastoma arises from neural crest tissue and is the most common extracranial solid tumor in children. Over 70% present with metastases. - Risk grouping systems include INSS (International Neuroblastoma Staging System) and more recently INRG (International Neuroblastoma Risk Group) staging. - Prognostic factors include age, stage, pathology, MYCN status, and other biomarkers. - Treatment depends on risk but may include surgery, chemotherapy, radiation, stem cell transplant, and immunotherapy. Precise management

1. Neuroblastoma
17.10.18
By Dr Animesh Agrawal
Moderator Dr Shagun Misra

2. Contents
• Introduction
• Clinical Presentation
• Pathology & Risk grouping
• Diagnostic workup
• Prognostic factors
• Management
• Role of Screening

3. Introduction
• Arise from primitive adrenergic neuroblasts of neural crest
tissue in the sympathetic ganglion.
• 4th most common malignancy in children
• Most common malignancy in children <18 mo
• Median age at diagnosis – 22 months
• Clinical heterogeneity
• Spectrum of disease includes spontaneous maturation to
rapid metastatic disease progression.

4. • Adrenal medulla (35%)
• Para-spinal ganglia lower thoracic and abdominal (30%)
• Posterior mediastinum (19%)
• Pelvic ganglia (2%)
• Cervical ganglia (1%)
• Metastases
- Bone, bone marrow, liver, lymph node and skin
Location

5. Clinical presentation
• Pain
- Most common presenting symptom
- Due to local spread &/or metastatic disease
• Abdominal lump
• Respiratory compromise: Esp. in young infants
with massive hepatomegaly.
• Others
- Horner’s syndrome (neck mass)
- Spinal cord compression
- Cytopenias (marrow involvement)
- Blueberry muffin sign (skin involvement)
- Bowel/bladder dysfunction (pelvic mass)
- Opsoclonus–myoclonus syndrome (truncal ataxia
and cerebellar encephalopathy).
- Proptosis/ecchymoses: Orbital mets
• Constitutional symptoms: Anorexia, weight loss, malaise, fever

6. • Mimic pheochromocytoma:
- Paroxysmal hypertension, palpitations, flushing, and headache.
• Severe watery diarrhea and hypokalemia (due to secretion of
vasoactive intestinal peptide by the tumor)

7. More than 70% of patients
with neuroblastoma present
with metastases at
diagnosis.

8. Neuroblastoma vs Wilm’s Tumor
• Median age of presentation for NB is ~1.5 yrs vs > 3 yrs for Wilms
• Neuroblastoma often crosses midline (Wilms does not).
• Wilms patients appear healthy vs. NB patients appear sick
• Neuroblastoma (85%) is more likely to exhibit calcifications vs 5 –
10% in Wilm’s.
• NB rarely metastasizes to the lungs (frequent in Wilm’s tumor).
• Wilms arises from & destroys the kidney; NB displaces the kidney.

9. Pathology
• Classic subtypes
- Neuroblastoma
- Ganglioneuroblastoma
- Ganglioneuroma
• Neuroblastoma
- Small uniform cells
- Hyperchromatic nuclei & scant cytoplasm
- Homer Wright pseudorosette
- Necrosis and calcification
- Mature & intermediate differentiation
ganglion cells
increasing
differentiation

10. • Shimada system
- Classified tumors into good or poor prognosis groups
based on:
 Stromal component (Stroma rich or poor)
 Grade of differentiation
- Stroma rich, well differentiated
- Stroma rich, intermixed
- Stroma rich, nodular
- Stroma poor, differentiating
- Stroma Poor, undifferentiated
 MKI (Mitosis – Karyorrhexis Index)
 Age (< 18mo, 18 – 60mo, > 60mo)
Shimada et al. JNCI 1984
Histologic classification

11. Shimada et al. JNCI 1984
Histologic classification

12. Histologic classification
• International Neuroblastoma Pathology Committee (INPC)
- Based on the Shimada system with minor modifications
Shimada et al. Cancer 1999

13. INPC classification: Favorable histology
Age Tumor subtype MKI
Any GNB, nodular* NA
GNB, intermixed NA
GN NA
< 18 mo Poorly differentiated NB Low to Intermediate
Differentiating NB Intermediate
18 - 60 mo Differentiating NB Low
* All nodules of NB must have favourable histology
* Nodule: Presence of grossly discrete masses of stroma-poor Nb trapped in mature matrix

14. Age Tumor subtype MKI
Age Undifferentiated NB Any
Poorly differentiated NB High
Differentiating NB High
Ganglioneuroblastoma,
nodular*
NA
18 – 60 mo Poorly differentiated NB Low to Intermediate
Differentiating NB Intermediate
≥ 60 mo Differentiating NB Any
*At least one nodule of NB must have unfavourable histology
INPC classification: Unfavorable histology

15. Diagnosis
Laboratory Evaluation
• Routine haematological investigations
- Hemogram
- Biochemistry
• Increased levels of urinary metabolites of catecholamines,
Vanillylmandelic acid (VMA) Homovanillic acid (HVA)
- Seen in > 90% patients.
• May consider: NSE, Chromogranin A (CgA)

16. Imaging
• Plain radiographs (calcified abdominal or posterior
mediastinal mass.)
• USG Abdomen
• CE CT/MRI more useful
- Intratumoral calcifications, vascular encasement, or both on
preoperative imaging may help distinguish neuroblastoma
from Wilms tumor
- INRG staging depends on radiological parameters for risk
stratification.
• I-123 MIBG (meta-iodo-benzyl-guanidine) + Tc-99m
bone scans for staging.

17. Biopsy
• Tissue diagnosis is an essential step, except in cases with
+ve bone marrow and urinary excretion of catecholamine
metabolites.
• IHC and tumor cytogenetics form an integral part of
deciding management.
- MYCN amplification (~ 1/3rd)
- 11q aberrations
- DNA ploidy (hyperdiploid carries a better prognosis)
- 1p deletion (~ 2/3rd)

18. Other Markers
• NSE & CgA (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

19. Bone marrow aspiration and biopsy
• Bone marrow involvement is seen in ~ 40% patients at
diagnosis.
• 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).
• INSS recommends two aspirations and biopsies from
bilateral sites; biopsy is not required for infants < 6m age.

20. Staging
2 main systems
INSS
INRG

21. • Historically the most commonly used.
• Postoperative system.
• Based on both extent of resection and disease extent.

22. I Localized; GTR (R0/R1)
IIA Localized; < GTR; N0
IIB Localized; ipsilateral Node +ve (C/L –ve)
III Unresectable disease crossing midline or C/L nodes +ve
IV
Distant spread: Nodes, bone marrow/bone, liver, skin or
others
IV-S
Localized; dissemination limited to skin, liver or marrow
(age < 1y)
International Neuroblastoma Staging system
(INSS)

23. INSS
• Based on the INSS, COG stratifies patients into Low,
Intermediate and High risk1.
• Further management is decided based on the above.
1. Maris JM, Matthay KK. JCO 1999

24. Limitations of INSS
• Postoperative system, so pre-operative staging/prognostication
cannot be done.
• In an era with improved systemic and supportive therapy, more
patients now receive neoadjuvant treatment.
• INSS staging is done only after upfront surgical resection. This
is often not possible due to extensive local disease/widespread
metastases.

25. International Neuroblastoma Risk Group
(INRG) Staging system
L1
Localized tumor not involving vital structures as defined by
the list of IDRFs and confined to one body compartment
L2 Locoregional tumor with presence of one or more IDRFs
M Distant metastatic disease (except stage MS)
MS
Metastatic disease in children < 18 months with metastases
confined to skin, liver, and/or bone marrow (< 10%)
• Preoperative staging and risk assessment.

26. Image defined risk factors (IDRFs)
• Surgical risk factors identified at diagnosis, such that a complete
resection is unsafe.
• Outlined in a Task Force Report by the INRG1:
- Multi-compartment disease
- Encasement of major vessels
(carotid, vertebral, IJV, subclavian, aorta, SVC/IVC, SMA, celiac trunk, renal
pedicles, iliac vessels)
- Contiguous involvement of other organs/structures
(base of skull, pericardium, diaphragm, kidney, liver, porta hepatis,
hepatoduodenal ligament, duodeno-pancreatic block, mesentery)
- Intraspinal extension (> 1/3rd)
- Airway compression (trachea/principal bronchi)
1. Monclair et al. JCO 2009

27. INRG Classification system
• Along with staging, the task force also suggested a risk
stratification system integrating several parameters, namely:
• The risk groups are Very low, Low, Intermeditate and High.
Cohn et al. INRG Task Force; JCO 2009
INRG Stage L1 > L2 > M
Age < 18 months
Histologic category GN > GNB > NB
Grade of tumor differentiation Differentiating
N-myc status Not amplified
11q aberrations Absence
Tumor cell ploidy Hyperdiploidy

28. INRG Classification System
Cohn et al. INRG Task Force; JCO 2009

29. To summarize..
• Staging can be either INSS based, i.e. post op
- Risk stratification is then based on the COG approach
(older, more commonly followed)
- Low, Intermediate, High
• Or the INRG approach may be used i.e. preoperative
(more recent, gradually being adopted)
- Risk stratification being as proposed by the INRG
- Very Low, Low, Intermediate, High

30. Prognostic
factor
Favorable Unfavorable
Survival
Favorable Unfavorable
• Age
• Stage
• Pathology
(Shimada)
• Ferritin
• NSE
• Urine
VMA/HVA
• N-myc
• DNA index
• 1p deletion
< 2 yrs
1,2 , 4s
Favourable
<143 ng/ml
<100
<1
single copy
> 1.1
Absent
> 2 yrs
3, 4
Unfavorable
> 143 ng/ml
< 143 ng/ml
> 1
Amplified
1
Present
77%
90-100%
90%
83%
79%
84%
70%
100%
90%
38%
30-50%
23%
19%
10%
44%
5%
10%
10%
* Matthay KK. CA Cancer J Clin 1995
Impact on survival of various prognostic factors

31. Management

32. Treatment
Options
• Surgery
• Chemotherapy
• Radiation therapy
• High-dose chemotherapy/radiation therapy and stem cell
transplant (HDC/SCT rescue)
• Retinoid therapy/Immunotherapy

33. Management: Low Risk
• Low risk (about 50%)
• Surgery alone for stage 1 or 2 disease may be sufficient.
• Short course chemotherapy for symptomatic cord compression
or respiratory compromise; may also consider short course
radiotherapy for this purpose.
• Stage 4S: supportive care or short course of chemotherapy
• Survival - 90-95%
• Patients with MYCN amplification or low DNA index may
require adjuvant therapy, and management should be decided
based on the extent of resection and other risk factors.

34. • About 10-15% of new cases
• Primary resection + standard dose multiagent chemotherapy
for 4-8 months
• In disease that in unresectable or has instraspinal extension,
neoadjuvant chemotherapy may be given prior to resection to
allow safer and more complete resection.
• Survival > 80%
• Radiotherapy may be indicated for certain patients.
Management: Intermediate Risk

35. Chemotherapy regimen (COG A3961 PROTOCOL)
Course Day Drugs
1 0 Carboplatin – Etoposide
1 Etoposide
2 Etoposide
2 21 Carboplatin – Cyclophosphamide – Doxorubicin
3 42 Cyclophosphamide – Etoposide
43 Etoposide
44 Etoposide
4 63 Carboplatin – Etoposide – Doxorubicin
64 Etoposide
65 Etoposide
Management: Intermediate Risk

36. Chemotherapy regimen (contd)
Course Day Drugs
5 84 Cyclophosphamide – Etoposide
85 Etoposide
86 Etoposide
6 105 Carboplatin – Cyclophosphamide – Doxorubicin
7 126 Carboplatin – Etoposide
127 Etoposide
128 Etoposide
8 147 Carboplatin – Etoposide – Doxorubicin
Management: Intermediate Risk
• Patients with favourable histology IR disease receive only the 1st 4 courses.

37. Chemotherapy regimen (contd)
Management: Intermediate Risk
Drug dosages
Carboplatin 560 mg/m2 or 18 mg/kg iv over 1 hour
Etoposide 120 mg/m2 or 4 mg/kg iv over 2 hours
Cyclophosphamide 1000 mg/m2 or 33 mg/kg iv over 1 hour
Doxorubicin Doxorubicin 30 mg/m2 or 1 mg/kg iv
over 15-60 minutes
COG A3961 protocol

38. • Four general components
1. Induction chemotherapy
2. Surgical resection of all gross disease
3. Consolidation therapy- which generally includes
Myeloablative chemotherapy with stem cell rescue and
Radiation to the tumor bed.
4. Management of Minimal Residual Disease
• Radiotherapy
- Local RT for bulky primary (complementary to surgery)
- TBI: as part of myeloablative conditioning regimen if
HDC/ASCT is planned.
Management: High Risk

39. Surgery
• High risk patients frequently present with extensive disease,
and complete resection has been associated with long-term
neurologic sequelae.
• Preferred approach: Defer resection until after induction
chemotherapy.
• Surgery usually is performed 13 to 18 weeks after initiation
of chemotherapy.
Management: High Risk

40. Chemotherapy
Usually includes a combination of drugs
• Cyclophosphamide or ifosfamide, Platinum, Vincristine,
Doxorubicin, Etoposide, Topotecan, Busulfan & melphalan
• The most common combination of drugs includes platinum,
cyclophosphamide/ifosfamide, doxorubicin, and etoposide.
• I-131 is sometimes included in consolidative regimens;
therapeutic doses typically necessitate stem cell rescue.
• Examples: N6, N7, POG 9340/41/42, CCG 3891, N4SE etc.
Management: High Risk

41. Maintenance
• Maintenance therapy is biological and immunotherapy
targeting minimal residual disease (MRD).
• 13-cis-retinoic acid is given as a monthly 14-day cycles for 6
months.
• The addition of immunotherapy using the chimeric antibody
ch14.18 directed at the neuroblastoma tumor antigen GD2,
combined with GM-CSF and interleukin-2 (IL-2) also
significantly improves survival.1, 2
- Given as monthly cycles for 5-6 cycles.
Management: High Risk
1. Yu et al. COG ANBL0032. NEJM 2010
2. Cheung et al. JCO 2012

42. • A risk category suggested by the INRG
• Includes
- L1/L2 disease, maturing GN or intermixed GNB
- L1 all histologies with non amplified MYCN
- MS disease without MYCN amplification or 11q aberration
• For a subset of these patients, observation alone with surgery
reserved for persistent/progressive disease is a reasonable
approach that spares >80% patients a surgery.1
• Some patients may require radiotherapy for rapidly
progressive disease causing mass effect.
Management: Very Low Risk
Nuchtern JG et al. Ann Surg 2012

43. Role of Radiotherapy

44. • Neuroblastoma is a radiosensitive tumor.
• However, given the long term survival that is often
achievable, it is attempted to keep radiation requirement as
low as possible.
Uses
• Indicated in certain patients with Low and Intermediate risk
disease, and for most patients with High risk disease.
• Mass effect from a rapidly enlarging tumor can respond
dramatically to radiation therapy.
• It also plays an important role in the palliative management
of patients with end-stage symptomatic disease.

45. Low Risk Neuroblastoma
• More than 90% overall survival with surgery alone.
• Radiotherapy not indicated in INSS Stage 1 or 2.
• Stage 4S/MS
- Hepatomegaly causing significant respiratory compromise
- 3 - 6 Gy @ 1.5 Gy/#
- Kidneys and ovaries to be shielded.

46. Intermediate Risk Neuroblastoma
• RT was previously employed as a standard component of
multi-modality treatment.
• With improvements in systemic therapy, it was seen that RT
may be omitted in patients who have no residual disease
following initial treatment.
(Induction chemotherapy 4-8 months → Surgery)
• For patients with residual disease, adjuvant RT is
recommended; typically upto 21Gy/14# (1.5 Gy/#).

47. High Risk Neuroblastoma
• Generally advanced disease (regional + distant)
Intensive induction
chemotherapy
Surgery
Consolidation
chemotherapy
+
Stem cell rescue
Radiotherapy
Maintenance
therapy
• Adjuvant RT is given to a total dose of upto 21.6 Gy/12# @ 1.8
Gy/# for GTR and a boost upto 36 Gy for residual disease.1
1. COG 0532 protocol

48. 2D Planning
• All available information (radiological, clinical, intra-
operative) to be used to ascertain extent of disease.
• Portals should include residual tumor after chemotherapy
with at least 2 cm margin from the tumor to the block edge.
• Regional LN should be covered if radiologically or
pathologically involved at any time during the disease
course.
• Parallel opposed AP-PA fields may be sufficient in many
cases, with occasional plans requiring a third field.

49. Radiation portal for a
child with Left adrenal
disease.
• Ipsilateral kidney to
be spared as far as
feasible with
generous inclusion
of para-aortic nodes.
• Medially the field
border should cross
the midline so as to
homogenously treat
the spine.

50. 3D Conformal planning
• GTV / Tumor bed: Post-chemotherapy tumor volume with
editing at uninvolved normal structures.
• CTV: GTV + 0.5mm; CTV should not be edited at
uninvolved organs.
• ITV: 5mm is generally sufficient with 4D-CT; upto 1cm may
be necessary otherwise.
• PTV: 5-10mm depending on institutional protocols.

51. Target volumes (specific cases)
Site Target
Orbital metastases Entire orbit
Liver mets Entire liver need not be included, but
adequate margins must be taken (incl.
those for organ motion).

52. Relapsed or refractory cases
• No effective strategies available to salvage recurrent
or refractory disease.
• Goal of treatment is palliation
- Chemotherapy
- Radiotherapy
- Radionuclide therapy (I-131)
- Retinoids & immunotherapy (13-cis-retinoid acid/ch14.18)
- Clinical trial (combination of the above; novel agents)

53. 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.
- Utility doubted in view of toxicity and poor tolerance (Nausea,
vomiting, anorexia, fatigue, fever, stomatitis)
• Also tested in small retrospective and phase I/II studies for
newly diagnosed neuroblastoma as induction treatment prior
to surgical resection.
- Good response rates noted; untested in phase III trials.

54. Iodine – 131 MIBG therapy
• Contraindications
- Renal failure requiring dialysis and expected life less than
3 months unless in case of refractory bone pain.
- GFR less than 30 mL/min.

55. Survival of 2196 consecutive NB patients
treated under CCG and POG protocols
Outcomes

56. Role of Screening
Rationale
• Relatively good prognosis of infants diagnosed with early-stage
neuroblastoma + High number of children with metastatic disease
(i.e. advanced stage) at diagnosis.
However..
• Large randomized studies have failed to demonstrate a survival
benefit with screening.
• Screen detected disease tends to be favorable with good outcomes
(80 – 85%) while those negative for screening who develop Nb
tend to develop disseminated disease with unfavorable histology.
No Role

57. Conclusion
• A treatable malignancy, but poor outcomes for bad biology
despite advances in oncology.
• High Risk children continue to have poor outcomes despite
aggressive treatment, while some patients with very low risk
disease may be safely observed.
• Surgery remains the cornerstone of treatment; chemotherapy
and radiotherapy form supportive pillars.
(more recently, immunotherapy also employed).
• Early detection remains a challenge; improving treatment
protocols is the present direction of research.

58. Thank You