NEUROBLASTOMA

• Most common extracranial solid tumor.

• Arise from primitive adrenergic neuroblasts of neural crest tissue in
the sympathetic ganglion.
• More than half of the children are seen initially with metastatic
disease.
• 4th most common malignancy in children.
• Most common malignancy in children <18 month.
• Median age at diagnosis – 19 months.
NEUROBLASTOMA
• Along the sympathetic chain.
• Location and spectrum of differentiation
• Show spontaneous regression or malignant behaviour
Location
• 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
Epidemiology and genetics
• INCIDENCE
• 8% to 10% of all childhood cancers
• Most common malignant tumor of infancy
• A median age at diagnosis of 19 months
• GENETICS
• Autosomal dominant pattern of inheritance
• In familial cases it is 9 months
• Have bilateral adrenal or multifocal primary tumors
• Single interval at chromosome 16p12-13 with consistent linkage
Constitutional Chromosome Abnormalities
• Numerous karyotypic abnormalities which have prognostic
significance
• Changes occur d/t deletions, translocations, and cytogenetic evidence
of gene amplification
• Aneuploidy of the tumor DNA(55%)
• Amplification of the MYCN oncogene at 2p24
Constitutional Chromosome Abnormalities
• Deletion of the short arm of chromosome 1 (1p)- 25% to 35%,
adverse prognostic marker.
• Gain of one to three copies of 17q, often the result of translocation
with chromosomes 1 or 11, has been demonstrated to correlate with
more aggressive tumors
Embryology and Spontaneous Regression
• Insitu Neuroblastoma -small nodules of neuroblasts.
• Insitu neuroblastoma support spontaneous regression.
• Study of urinary catecholamine excretion.
• Postponement of screening until 10-19month.
• Evaluation of adrenal tumors resected in the neonatal period.
• Spontaneous regression has been demonstrated radiographically.
Insitu neuroblastoma
Clinical Presentation
• Constitutional symptoms – Anorexia , weight loss, malaise, fever
• Abdominal pain
• Most common presenting symptoms
• Due to local spread &/or metastatic disease
• Palpable mass
• Fixed
• Hard.
• Respiratory symptoms
• Cough or dyspnoea.
• Respiratory compromise.
Clinical Presentation
• Mimic Pheochromocytoma
• Paroxysmal hypertension, palpitations, flushing, and headache
• Severe watery diarrhoea and hypokalaemia
• D/t Secretion of vasoactive intestinal peptide
• Other(Metastasis/compressive)
• Spinal cord compression
• Bowel/Bladder dysfunction
• Acute myoclonic encephalopathy- myoclonus , opsoclonus and ataxia
• Proptosis/ecchymoses
Diagnosis
• Laboratory Evaluation
• Biochemistry-
• Increased levels of urinary metabolites of catecholamines,
vanillylmandelic acid (VMA) and homovanillic acid (HVA)
• Seen in >90%
• Hemogram-
• Anaemia
• May consider - NSE ,Chromogranin A (CgA)
Imaging
• Abdominal Xray
• calcified abdominal or posterior mediastinal mass
• USG w/a
• CE CT/MRI
• Local extent
• Intratumoral calcification
• Help to distinguish neuroblastoma from Wilms tumor
• Vascular involvement
• INRG staging
CT Imaging
MRI Imaging
Imaging
• MIBG scintigraph(radionuclide meta-iodobenzylguanidine)
• Staging
• I123>I131
• PET scan
• Non – MIGB avid tumor
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
• 11q aberration
• DNA ploidy
• 1p deletion
Other markers
• NSE & CgA
• More level –> More advanced disease -> worse prognosis
• NB84
• High sensitivity
• Low specificity
• CD65
• Diffuse positivity-> More blastic component
• S100
• Diffuse positivity -> Better differentiation
• Negative for CD45, CD99 , EMA, CK, desmin , myogenin
Bone marrow aspiration
• Involvement in 40%
• Positive catecholamine in blood or urine and bone marrow no biopsy required
• INSS recommendation
• 2 Aspiration with biopsy of b/l sites
Pathology
• Classic subtype
A. Ganglioneuroma – Differentiated
B. Ganglioneuroblastoma – Poorly differentiation
C. Neuroblastoma- Undifferentiated
Pathology
Neuroblastoma
• Small uniform cell
• Hyperchromic nuclei & scant cytoplasm
• Homer wright pseudorossette
• Necrosis and calcification
• Mature and intermediate differentiation ganglion cell
Histopathologic classification
• Shimada classification
• Classifies tumour tumors into good or poor prognosis group based on Stromal
component(Stroma rich or poor)
• Grade of differentiation
• Stroma rich , well differentiated
• Stroma rich, intermediate
• Stroma rich, nodular
• Stroma poor differentiating
• Stroma poor , undifferentiating
• MKI(Mitosis – Karyorrhexis Index)
• Age (< 18m, 18-60 m, >60m)
Histologic classification
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
INPC classification: Unfavorable histology
Age Tumor subtype MKI
Age Undifferentiated NB Any
Poorly differentiated NB High
Differentiating NB High
Ganglioneuroblastoma, NA
nodular*
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
Staging
• The stage of the disease is a significant prognostic variable that determines
adjuvant therapy in the cooperative group trials.
• Two main system
• INSS
• Based on clinical , radiographic and surgical evaluation of children
• INRG
• Based on tumor imaging.(rather than the extent of surgical resection)
• Historically the most commonly used.
• Postoperative system.
• Based on both extent of resection and disease extent.
International Neuroblastoma Staging system
(INSS)

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
Distant spread: Nodes, bone marrow/bone, liver, skin or others
IV
Localized; dissemination limited to skin, liver or marrow (age < 1y)
IV-S
• Based on the INSS, COG stratifies patients into
Low, Intermediate and High risk1.

• Further management is decided based on the above

International Neuroblastoma Risk Group
(INRG) Staging system
• Preoperative staging and risk assessment.
Localized tumor not involving vital structures as defined by the
L1
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)

Metastatic disease in children < 18 months with metastases

MS
confined to skin, liver, and/or bone marrow (< 10%)
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 INRG:
- Multi-compartment disease
- Encasement of major vessels
- Contiguous involvement of other organs/structures
- Intraspinal extension (> 1/3rd)
- Airway compression (trachea/principal bronchi)
INRG Classification system
• Along with staging, the task force also suggested a risk stratification system
integrating several parameters, namely:
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

• The risk groups are Very low, Low, Intermediate and High.
INRG Classification System
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
Impact on survival of various prognostic
factors
Prognostic Survival
factor Favorable Unfavorable
Favorable Unfavorable

• Age < 2 yrs > 2 yrs 77% 38%

• Stage 1,2 , 4s 3, 4 90-100% 30-50%
• Pathology Favourable Unfavorable 90% 23%

(Shimada <143 ng/ml > 143 ng/ml 83% 19%

) <100 < 143 ng/ml 79% 10%
• Ferritin
• NSE <1 >1 84% 44%
• Urine
VMA/HV
A

• N-myc single copy Amplified 70% 5%

Treatment
• Options
• Surgery
• Chemotherapy
• Radiation therapy
• High dose chemo/radio therapy and stem cell transplant (HDC/SCT rescue)
• Retinoid therapy / Immunotherapy
Management : Low Risk
• Surgery alone for stage 1 or 2.
• Short course chemotherapy for symptomatic mass effect.
• Stage 4S: supportive care or short course of chemotherapy
• Survival 90-95%
• Patient 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.
Management : Intermediate Risk
• About 10-15% of new cases
• Primary resection + standard dose multiagent chemotherapy for 4-8
months
• In disease that is unresectable or has intraspinal extension,
neoadjuvant chemotherapy may be given prior to allow safer and
more complete resection
• Survival > 80%
• Radiotherapy may be indicated for certain patients.
 Chemotherapy regime
Course Day Drugs
1 0 Carboplatin- Etoposide
1 Etoposide
2 Etoposide
2 21 Carboplatin- Cyclophosphamide - Doxurubicin
3 42 Cyclophosphamide- Etoposide
43 Etoposide
44 Etoposide
4 63 Carboplatin- Etoposide- Doxurubicin
64 Etoposide
65 Etoposide
Course Day Drugs
5 84 Cyclophosphamide – Etoposide
85 Etoposide
86 Etoposide
6 105 Carboplatin -Cyclophosphamide –
Doxurubicin
7 126 Carboplatin- Etoposide
127 Etoposide
128 Etoposide
8 147 Carboplatin- Etoposide-
Doxurubicin
Management : High Risk
• Four general components
1. Induction Chemotherapy
2. Surgical resection of all gross disease
3. Consolidation therapy(Myeloablative chemotherapy + 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
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.
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.
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: Very Low Risk
• 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.