Neuroblastoma

Neuroblastoma

A tumor of postganglionic sympathetic neuroblasts

The sympathetic chain extends from the neck to the

sacrum

The adrenal gland

Neurotransmitter- Catecholamines

Neuroblastoma - Epidemiology

• Most common extracranial solid tumor

• Incidence – 10/million per year

• ~10% of pediatric tumors

• Peak age – 2-3 years

• >90% cases before 5 years

• Mostly sporadic – rare genetic associations

• Most common neonatal tumor

Neuroblastoma - Genetics

• Mostly sporadic – rare (2%) genetic associations (NF1, Hirschsprung, congenital central hypoventilation syndrome)

• Mutations in ALK (tyrosine kinase)

• Environment??

Neuroblastoma – Biology

• Neuroblastoma is a tumor of undifferentiated (embryonal) neuroectodermal cells, derived from the neural crest

• An aberration of normal differentiation

• An abnormal response to normal neurotropic signals (TRK-A, NGF)

• Spontaneous regression

• Differentiation – Ganglioneuroma, ganglioneuroblastoma

Neuroblastoma – Clinical features I

• Tumor originates from sympathetic ganglia/adrenal gland

• Lymphatic and hematogenous spread

• Metastases to bone, liver, bone marrow, skin

• Most patients present with advanced disease (40% of all patients, 55% of patients over 1 year)

Neuroblastoma-Clinical features - II

Abdominal mass (65%)

Thoracic mass (Infants)

Bone pain

Fever

Weight loss

“Sick looking child”

Neuroblastoma – Clinical Features - III

Lower limb paresis – 20 to spinal epidural tumor (4%)

Severe diarrhea 20 to secretion of VIP (vasoactive intestinal peptide) (4%)

Horner syndrome - patients with cervical or upper thoracic sympathetic ganglia (1.7%)

Hypertension, flushing, sweating (0.2%)

Raccoon eyes

Pallor, bleeding diathesis (Bone marrow involvement)

NeuroblastomaRaccoon eyes

Neuroblastoma – Clinical features - IV

Opsoclonus-Myoclonus syndrome

Acute cerebellar encephalopathy characterized by cerebellar ataxia, rapid and random eye movements (opsoclonus) and myoclonic jerks (2.8%)

Good oncological but poor neurological outcome

Laboratory Features

• Catecholamines (Dopamine, epinephrine, VMA, HVA)

• Serum markers - LDH, ferritin, NSE (Neuron specific enolase)

• Blood count (BM involvement)• Coagulation (Liver involvement)

Metabolism of Catecholamines

Pathology

• Small round blue cell tumor

• Neuroblastic differentiation: From very

undifferentiated to differentiated

• Degree of anaplasia – Shimada index

• Biological parameters

http://news.bbc.co.uk/olmedia/1485000/images/_1488593_neuroblastoma_slide300.jpg

Neuroblastoma biology II

• N-MYC – Oncogene on chromosome 2 amplification – worse prognosis

• DI (DNA Index= ploidy) – hyperdiploid – better outcome in infants

• 1p deletion – putative tumor suppressor genes – worse prognosis

• 17q gain – oncogene?

N-Myc amplification

• Amplification – A localized genomic change that results in increased dosage of a gene or genes affected

• Homogeneously staining regions (HSR’s) - are areas on the native chromosome with multiple 100-200 kB copies of the region containing the amplified gene

• Double minutes (DM) – Extrachromosomal fragments containing the amplified gene

• >10 copies are associated with a worse prognosis

Mechanisms of N-myc amplification

N-MYC amplification- Homogeneously staining region

N-MYC amplification- Double minutes

Neuroblastoma- 1p deletion

Neuroblastoma - Staging

• CT/MRI

• MIBG (Meta-iodo-benzyl-guanidine)

• Bone scan

• Bone marrow aspirate and biopsy

• Surgery

MIBG scan

Neuroblastoma - Staging

Stage

I Tumor confined to organ of origin and completely resected

II Tumor extending beyond organ of origin, ipsilateral nodes+

III Tumor crosses midline, contralateral nodes+

IV Metastatic disease

IV-S <1.5 year; metastases to liver, skin, BM

Neuroblastoma - INSS 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)

• Stage 2A – Localized tumor with incomplete gross resection; representative ipsilateral non-adherent lymph nodes negative for tumor microscopically

• Stage 2B- Localized tumor with or without complete gross excision, with ipsilateral non-adherent lymph nodes positive for tumor’ enlarged contralateral lymph nodes must be negative microscopically

• 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

• 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)

• Stage 4s – Localized primary tumor (as defined for stage 1, 2A or 2B) with dissemination limited skin, liver, and or bone marrow (limited to infants<1 year)

2b1

2a 3

International Neuroblastoma Staging System (INSS)

4

4S

Prognostic Factors

Age (<18m – favorable)

Stage

Histology (Shimada)

Biology

N-MYC, DI, 17q+, 1p-

Neuroblastoma - Treatment

Risk adapted

Low risk NB – Minimal

therapy – excellent outcome

High NB – Intensive therapy – poor outcome

INRG – International Neuroblastoma Risk Group Classification System

• Age

• Stage

• N-MYC status

Neuroblastoma -Protocol assignment by risk group

INSS stage Age N-MYC status Shimada histology DNA Ploidy Risk Group Study

1 0-21 y Any Any Any Low Low risk

2A/2B <365/547 d

>365 d

>365 d

>365

Any

Non-Amp

Amp

Amp

Any

Any

Fav

Unfav

Any

-

-

-

Low

Low

Low

High

Low risk

Low risk

Low risk

High risk

3 <365 d

<365 d

>365 d

>365 d

>365 d

Non-Amp

Amp

Non-Amp

Non-Amp

Amp

Any

Any

Fav

Unfav

Any

Any

Any

-

-

-

Intermediate

High

Intermediate

High

High

IM risk

High risk

IM risk

High-risk

High-risk

4 <365 d

<365 d

>365 d

Non-Amp

Amp

Any

Any

Any

Any

Any

Any

-

Intermediate

High

High

IM risk

High-risk

High-risk

4s <365 d

<365 d

<365 d

<365

Non-Amp

Non-Amp

Non-Amp

Amp

Fav

Any

Unfav

Any

>1

=1

Any

Any

Low

Intermediate

Intermediate

High

Low risk

IM risk

IM risk

High risk

Low/Intermediate risk Neuroblastoma

Watch and wait (No treatment=no toxicity)

Surgery- Minimize damage

Low intensity chemotherapy

Radiation – emergency only (rarely used)

Improving Survival for Stage 4 Neuroblastoma Patients > 1 Year of Age

at Diagnosis

Childrens Cancer Group Data

P < 0.001

0

0.2

0.4

0.6

0.8

1

1 2 3 4 5 6 7 8 9 10

Years from Diagnosis

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ility

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eral

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1978-1985 N = 507

1986-1995 N = 675

Treatment – High Risk Neuroblastoma

Induction chemotherapy

Surgery

High dose chemotherapy with stem cell

rescue (Eradication of residual disease)

Radiation

Retinoic Acid

Immunotherapy

High-risk Neuroblastoma – Treatment Roadmap

█████ ███ ███ █ ██ ██

Induction Surgery Consolidation XRT Cis-RA Immunorx.

Chemotherapy ABMT Anti GD2

IL-2

GM-CSF

(Differentiation therapy)

Immunotherapy

Chemotherapy in Neuroblastoma

Platinum (Cis, carbo)

VP-16

Doxorubicin

Cyclophosphamide/Ifosfamide

Vincristine

Topotecan

High Dose Chemotherapy

Myeloablative doses

Eradication of tumor

Rescue with autologous stem cells

MEC(Melphalan, etoposide, carboplatinum)

BM(Busulfan, Melphalan)

Neuroblastoma – Radiation Therapy

• Local consolidation (In high-risk disease)

• Massive hepatomegaly in infants with 4S

• Cord compression?

• Metastatic disease - palliation

Neuroblastoma – Differentiation therapy

• Cis-retinoic acid (Roaccutane)

• Induces differentiation of neuroblastoma cells in vitro and decreases proliferative capacity

• Shown in randomized clinical trial to improve outcome

Control 10 M Retinoic Acid

High-Dose, Pulse Retinoic Acid Induces Neuroblastoma Differentiation

Neuroblastoma – Immunotherapy

• Anti GD-2 antibodies

• Interleukin 2

• GM-CSF

Schema: C.O.G. NBL Study ANBL0032 (2003)- A. Yu Chair

High Risk Newly Diagnosed NBLHigh Risk Newly Diagnosed NBL

InductionInduction

Ablation + Stem cell RescueAblation + Stem cell Rescue

RandomizeRandomize

ObserveObserve ch14.18 + GMch14.18 + GM--CSF + IL2CSF + IL2

CisCis--retinoic acidretinoic acid

Accrual of 386 randomized patients

needed

COG-ANBL0032 Phase III 2/17/09 Status: DATA AND SAFETY MONITORING

COMMITTEE

With ~61 % of accrual in, and ~ 2 year median follow up, the Immunotherapy arm shows:

•Superior EFS (p = 0.0115)•Superior OS (p = 0.0223)

Neuroblastoma - Outcome

• Stage I – 95% 5y EFS

• Stage II – 90% 5y EFS

• Stage III+IV – 10-40% 5y EFS

• Stage IV-S - 95% 5y EFS

4s Neuroblastoma

Under 18 months

Primary tumor stage I/II

Metastatic disease limited to:

Bone marrow(<10%)

Skin(Subcutaneous nodules)

Liver

NOT BONE

Bone and Bone Marrow

Neuroblastoma - Staging

Stage

I Tumor confined to organ of origin and completely resected

II Tumor extending beyond organ of origin, ipsilateral nodes+

III Tumor crosses midline, contralateral nodes+

IV Metastatic disease

IV-S <18months; metastases to liver, skin, BM

4s Neuroblastoma

Spontaneous regression

Cure with minimal therapy

Exception: Massive hepatomegaly in <2 months

(May require chemotherapy, RT)

Neuroblastoma – Spontaneous regression

• Occurs mainly in 4s disease

• But - may occur in all stages (overall ~ 10% of cases)

• Screening studies detect a 2-fold increase in incidence of neuroblastoma compared to clinically detected cases

• Cases detected in utero by ultrasound are being reported more frequently, and most are expected to resolve without treatment

• Spontaneous maturation to ganglioneuroma is apparently less common, but there is little data

Neuroblastoma – Outcome by stage

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6 7 8

Years from Diagnosis

MYCN Not Amplified (N = 71)

MYCN Amplified (N = 31)

Schmidt, JCO 2000

P < 0.0001

MYCN Amplification Correlates With Poor Survival in Infants with Stage 4 Neuroblastoma

Potential Therapy

• Radioactive MIBG

• Anti-GD2 antibodies

• Allogeneic BMT

• Sequential auto-BMT x2-3

• Rapid sequence induction

• Early detection

• Targeted therapy - ALK inhibition

Neuroblastoma - Screening

Rationale:

Poor results in advanced-stage tumors

Early stage – better outcome

Available tumor marker (CA)

Method

Universal screening by urinary CA at 6 months

Neuroblastoma Screening - Results

• More early stage tumors

• No increase in detection of advanced tumors

• No improvement in overall cure

• Do advanced tumors evolve from early stage less aggressive tumors?

• Or are they rapidly evolving metastatic tumors that occur after 1 year of age?

Perinatal Neuroblastoma

• Tumors discovered during routine antenatal ultrasound as adrenal masses

• Differential diagnosis: Adrenal hemorrhage, pulmonary sequestration

• Traditional approach: Surgery

• Most tumors – stage 1, favorable histology, N-MYC non-amp

• Postnatal MIBG scan. If positive:

• Close observation; surgery for growing tumors

• Excellent outcome

Neuroblastoma

• A tumor of sympathetic neuroblasts that arises along

the sympathetic chain and in the adrenal gland

• Heterogeneous clinical behavior and prognosis

• Different subtypes present different challenges