• No MYCNamplification

• Near triploid nmber of chromosomes.

• No loss of chromosome 1p.

{Ambros et al., 2000}

The capacity to undergo regression

LR

Ivs

The capacity to undergo maturation

IRResidual

after surgery

Persisting residual and maturing tumors in IR Neuroblastoma patients were not associated with tumor progression, despite MIBG uptake and/or elevated catecholamines {Marachelian et al., 2012}.

A superior prognosis for infants

Outcome of INSS Stage III Patients From the INRG Database

Number5-y EFS

P-value 5-y OSP-value

Stage III 86

< 18 M 850 86%<0.0001

91%<0.0001

> 18 M 633 58% 66%

Holly J. et al., Pediatic Blood Cancer 2014

< 18 vs >18 M

The most common cancer in infants “<1 year old”

The most common extra-cranial solid cancer in childhood

Accounts for about 7% of all cancers in children.

The average age diagnosis “18 months”.

90% of cases are diagnosed by age 5.

Very rare in people over the age of 10 years.

Non- specific and mimic many childhood illnesses

Site of primary tumor

Local infiltration

Sites of metastatic disease

Metabolic disturbances

Abdominal pain, discomfort, fullness or rarely obstruction.

Cough, dysphagia, breathlessness, thoracic inlet

obstruction leading to superior vena caval syndrome.

Horner ’ s syndrome

Some tumors have intra - spinal and extra - spinal components (dumb - bell tumors) and it can lead to cord compression causing flaccid paralysis and urinary and bowel disturbances.

bladder or bowel obstruction.

Site of primary tumor

MEDICAL COMPLICATIONS

Patients with bulky or advanced stage disease may be classified as being at intermediate risk for tumor lysis syndrome and prophylaxis against the complications of tumor lysis syndrome may be considered .

Cairo et al., 2010

Tumor lysis

MEDICAL COMPLICATIONS

7 -15 % In a review of 99 children with spinal cord involvement, 71 had residual impairments after a median follow-up of eight years. The most common impairments in this population were motor function, scoliosis, and bladder function {Simon et al., 2012}. Chemotherapy and laminectomy have equivalent overall survival outcomes. RT is generally reserved for progressive symptoms despite chemotherapy.

Spinal cord compressio

n

MEDICAL COMPLICATIONS

Opsoclonus myoclonus

lower stage and have favorable prognosis for survival

{De Grandis et al., 2009} long-term neurologic deficits (e.g., cognitive and motor

delays, language deficits, and behavioral abnormalities). Chemotherapy, corticosteroids, and IV immune globulin. Symptoms refractory to these treatments may respond to

rituximab . {Battaglia et al., 2012}

MEDICAL COMPLICATIONS

Autonomous tumor secretion of VIP that is associated with NB. VIP secretion can cause abdominal distension and intractable secretory diarrhea with hypokalemia; these symptoms usually resolve after removal of the tumor. The diagnosis is established by the presence of unexplained high-volume secretory diarrhea and a serum VIP concentration in excess of 75 pg/Ml. VIP-producing tumors are more often the less aggressive GNB and GN rather than undifferentiated neuroblastomas.

Secretory diarhea

Sites of metastatic disease

Orbitbone

marrow Bonelymph nodes

Skin

Liver

Brain

Skull, orbits, jaw and long

bones

Laboratory tests

CBC, LDH

NSEferritin

LFT, KFT, electrolytes

Urine HVA-VMA

• a major tissue-binding protein.

• Raised ferritin results from direct secretion by the tumor.

• High levels of ferritin related to poor survival.

• The International Neuroblastoma Risk Group (INRG) recently analysed the prognostic markers in 1483 stage 3 neuroblastoma patients. Holly et al.; 2014

ferritin

NSE

• Enolases are glycolytic enzymes

2 - phosphoglycerate >>> >>> phosphoenolpyruvate.

• Three immunologically distinct subunits: alpha, beta, and gamma.

• Gamma enolase is found in neuron and called NSE.

• Non a specific marker

• increased levels Wilms tumor, Ewing sarcoma, Non- Hodgkin lymphoma, Acute leukemia, Non - malignant conditions, e.g. brain damage.

CT scan/MRI scan confirms site, size, extension, vascular involvement.

Encasing major blood vessels is a characteristic feature of neuroblastoma.

CT is the major imaging modality pre - surgery to demonstrate the relationship between tumor and blood vessels.

MRI scan is important to evaluate for intra - spinal extensions

MIBG scan is positive in about 90% patients and is an important single tool to identify all disease sites and to evaluate response

• sensitive and specific.• Meta-iodobenzylguanidine (MIBG) that contains a small

amount of radioactive iodine.• MIBG is similar to nor epinephrine.• The thyroid gland must be protected by the simultaneous

administration of non-radioactive iodine (e.g., potassium iodide).

• Several hours or days later, the body is scanned with a special camera to look for areas that picked up the radioactivity.

• Can be used at higher doses to treat the NB.

Bone scan is only useful in MIBG negative neuroblastoma.

The role of the CT FDG - PET scan needs further evaluation and is a very promising imaging modality

Biopsies • Needle biopsy• Bone marrow aspiration and biopsy

Diagnostic criteria

• An unequivocal histological diagnosis from tumor tissue by light microscopy, with or without immunohistochemistry, electron microscopy, or increased urine (or serum) catecholamine’s or their metabolites.

• Evidence of metastases to bone marrow on an aspirate or trephine biopsy with concomitant elevation of urinary or serum catecholamine’s or their metabolites {Brodeur et al., 1993}.

1. A suprarenal location.

2. Thoracic and retroperitoneal locations.

3. Metastatic involvement of the bonemarrow.

4. Spinal canal involvement.

5. Skin nodules in newborns and infants.

6. Other causes of Opsoclonus-myoclonus syndrome.

Wilms

Hepatoblastoma

Lymphoma Germ cell tumorssoft tissue sarcoma

LymphomaEwing sarcomaRhabdomyosarcoma

Infantile fibrosarcomaCongenital leukemia Dermoid cyst

Hepatoblastoma

Infections Toxic exposuresHyperosmolar

non ketotic coma

Evans et al described the first staging system for neuroblastoma and used by the Children ’ s Cancer Group(CCG) in the USA.

1971Involvement of lymph nodes and spread across the midline

St Jude ’ s proposed a surgico - pathological staging system.

Extent of surgery and lymph node involvement 1983

The TNM staging was proposed jointly by the American joint committee.

Extent of surgery and lymph node involvement 1987

International Neuroblastoma staging system (INSS) and

International Neuroblastoma Response Criteria (INRC).

Based on the assessment of resectability and surgical examination of lymph node involvement

1998

INSS modified

•Post- surgical classification•Assessment of lymph node involvement

1993

• Stage 1:(1X1) Localized tumor confined to the area of origin; complete gross excision, with or without microscopic residual disease. Representative ipsilateral and contralateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive).

• Stage 2a:(1X1) Localized tumor with incomplete gross excision; representative ipsilateral and non - adherent lymph nodes negative for tumor microscopically.

• Stage 2b:(2X2) Localized tumor with complete or incomplete gross excision; with ipsilateral non - adherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.

• Stage 3:(3X3) 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 defi ned in stage 4S).

• Stage 4S Localized primary tumor (as defined for stage 1, 2a or 2b) with dissemination limited to skin, liver and/or bone marrow ‡ (limited to infants less than one year old).

Description of International Neuroblastoma Response Criteria •Complete Remission (CR): No tumor, no metastases, normal markers.•Very good Partial Remission (VGPR):

Primary; reduction more than 90%, but less 100%Metastases; no tumor except bone {all preexisting lesions improved}Markers; decreased more than 90%

•Partial Remission (PR):Primary; reduction 50%-90%Metastases; no new lesions; 50%-90% reduction in measurable sites; 0-1 BM samples positive; bone lesions the same as VGPR.Markers; decreased 50%-100%

•Mixed Response (MR):No new lesions; more than 50% reduction of any measurable lesion {primary or metastases} with less than 50% reduction in any other; less than reduction 25% increase in any existing lesion.•No Response (NR): No new lesions; less than 50% reduction but less than 25% increase in any existing lesion.•Less than PR: No new lesions; less than 50% reduction•Progressive Disease (PD): Any new lesion; increase of any measurable lesion by more than 25%; previous negative marrow positive for tumor.

• L1: Localized tumor not involving vital structures as defined by the list of image defined risk factors and confined to one body compartment.

• L2 :Locoregional tumor with presence of one or more image defined risk factors.

• M: Distant metastatic disease (except Stage MS).• MS :Metastatic disease in children younger than 18

months with metastases confined to skin, liver and/or bone marrow.

INRGSS

•Pre- treatment clinical staging stystem•It was designed for INRGCS 2009

Image defined risk factors in neuroblastic tumorsNeck:

• Tumor encasing carotid and/or vertebral artery and/or internal jugular vein

• Tumor extending to base of skull

• Tumor compressing the trachea

Cervico - thoracic junction:

• Tumor encasing brachial plexus roots

• Tumor encasing subclavian vessels and/or vertebral and/or carotid artery

• Tumor compressing the trachea

Thorax:

• Tumor encasing the aorta and/or major branches

• Tumor compressing the trachea and/or principal bronchi

• Lower mediastinal tumor, infi ltrating the costo - vertebral junction between T9 and T12

Thoraco - abdominal:

• Tumor encasing the aorta and/or vena cava

Image defined risk factors in neuroblastic tumors

Abdomen/pelvis:• Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament

• Tumor encasing branches of the superior mesenteric artery at the mesenteric root

• Tumor encasing the origin of the coeliac axis, and/or of the superior mesenteric artery

• Tumor invading one or both renal pedicles

• Tumor encasing the aorta and/or vena cava

• Tumor encasing the iliac vessels

• Pelvic tumor crossing the sciatic notch

Intraspinal tumor extension whatever the location provided that:

• More than one third of the spinal canal in the axial plane is invaded and/or

• the perimedullary leptomeningeal spaces are not visible and/or

• the spinal cord signal is abnormal Infiltration of adjacent organs/structures:

• Pericardium, diaphragm, kidney, liver, duodeno - pancreatic block, and mesentery

Differentiating neuroblastoma

Differentiating neuroblastoma

at least 5% cells

less than 5% cells

Schwannian stroma richSchwannian stroma richGNB intermixed Differentiating neuroblasts and mature ganglion cells

Differentiating neuroblasts and mature ganglion cells

Maturing

According to the balance between neural-type cells (primitive neuroblasts, maturing neuroblasts, and ganglion cells) and Schwann-type cells (Schwannian-blasts and mature Schwann cells)

(NB), (GNB), and (GN).

NeuroblastomaNeuroblasts at least 50%

of the tumor mass

Undifferentiated neuroblastoma

Undifferentiated neuroblastoma

Poorly differentiated neuroblastoma

Poorly differentiated neuroblastoma

Differentiating neuroblastoma

Differentiating neuroblastoma

at least 5% cells

less than 5% cells

All c

ells

Mature Schwannian stroma and ganglion cells

Mature Schwannian stroma and ganglion cells

Schwannian stroma -rich/ stroma –dominant /stroma poor

Schwannian stroma -rich/ stroma –dominant /stroma poor

GNB nodular

Ganglioneuroblastoma>50% ganglioneuromatous, a minor neuroblastomatous

Schwannian stroma richSchwannian stroma richGNB intermixed

Mature Schwannian stroma and ganglion cells

Mature Schwannian stroma and ganglion cells

GNB intermixed

GNB nodular

Differentiating neuroblasts and mature ganglion cells

Differentiating neuroblasts and mature ganglion cells

Maturing

Mature

GanglioneuromaSchwannian stroma

dominant

Shimada et al

• Age - linked classification

• Schwannian stroma - rich and stroma – poor• FH and UH.

1984

The International Neuroblastoma Pathology Committee1994

•Ganglioneuroma (Schwannian stroma- dominant).•Ganglioneuroblastoma, intermixed (Schwannian stroma- rich).•Neuroblastoma (Schwannian stroma- poor).•Ganglioneuroblastoma, nodular (Schwannian stroma- rich/ stroma- dominant and stroma- poor).

18- 60 Months

•GNB- intermixed,•Ganglioneuroma GNB - nodularNeuroblastoma

Pathology

> 5 years< 18 Months

Differentiating + low MKI Poorly differentiated and or intermediate MKI

Degree of differentiation

Age

Neuroblastoma

• Age >5 Years

• Undifferentiated

• High MKI

Tumor cell ploidy

MYCN amplification

• A hyperdiploid 55% and 45% of are diploid.

• The prognostic significance: <18 months, Metastatic disease, MYCN NA

• The oncogene MYCN is located on chromosome 2p at 2p 23 – 24.

• MYCN amplification is an intrinsic biological property.

• It is present at the time of initial diagnosis and this feature does not change with time.

1p deletion

11q loss

17q gain

•Allelic loss of 1p occurs in about a third of neuroblastoma patients.•LOH of 1p was predictive of local recurrences in low stage disease.

•25% of patients•11q aberrations are often not associated with MYCN amplification and are associated with reduced progression free survival.•11q strongly correlated with increase incidence of relapse particularly metastatic relapses.

Having an extra part of chromosome 17 (17q gain) is also linked with a worse prognosis. This probably means that there is an oncogene in this part of chromosome 17, whereas whole chromosome 17 gain was associated with good Prognosis {Van Roy et al., 2009}.

Anaplastic lymphoma kinase ( ALK )

•A predisposition gene for familial neuroblastoma.•It can be used as target therapy.

•COG uses age, MYCN status, stage, histology, and DNA ploidy. •SIOPEN uses age, MYCNstatus, and surgical risk factors defined by imaging for assigning risk - group for locoregional tumors.

Prognostic factors• Stage.• Age ( < 18 months versus ≥ 18 months (547 days)).• Histological category (ganglioneuroma, ganglioneuroblastoma– intermixed).• Grade of tumor differentiation (differentiating versus undifferentiated or poorly differentiated).• MYCN status.• Presence/absence of 11q aberration.• Ploidy ( ≤ 1.0 versus > 1.0).

Risk INSS Stage Age MYCN Status INPC Classification DNA Ploidy

Low 1 Any Any Any Any

Low 2A/2Bc AnyNon amplified

Any Any

High 2A/2B Any Amplified Any Any

Intermediate 3 <547 d Non amplified Any Any

Intermediate 3 ≥547 d Non amplified Favorable Any

High 3 Any Amplified Any Any

High 3 ≥547 d Non amplified Unfavorable Any

High 4 <365 d Amplified Any Any

Intermediate 4 <365 d Non amplified Any Any

High 4 ≥365- <547 d Amplified Any Any

High 4 ≥365- <547 d Non amplified Unfavorable Any

High 4 ≥365- <547 d Non amplified Any =1

Intermediate 4 ≥365- <547 d Non amplified Favorable >1

High 4 ≥547d Any Any Any

Low 4S <365 d Non amplified Favorable >1

Intermediate 4S <365 d Non amplified Any =1

Intermediate 4S <365 d Non amplified Unfavorable Any

High 4S <365 d Amplified Any Any

II IVIII

Stage

FH UH

> 18 Months< 18 Months

Histology

Age

LR

IR

IR HRHR

IR HR

IR HR

• Stage I---- LR• NMYC A----HR

II IVIII

StageLR

IR HRHR

12-18 Months< 12 Months

Age

IR

FH+DNA I>1 UH or DNA I=1

Histology+ DNA I

IR HR

>18 Months

HR

IR HR

• Stage I---- LR• NMYC A----HR

NMYC A FH + DNA I >1 UH or DNA I<1

Stage IV S

IR HRLR

• Principles of therapy

• Risk adapted therapy

• Recurrent neuroblastoma

Different treatment modalities like surgery, chemotherapy and radiation therapy.

Role of surgery•It can be used both in diagnosis and treatment. •The primary treatment for low-risk tumors.•Resectability is determined by tumor location and mobility, relationship to major nerves and blood vessels, the presence of distant metastases, and patient age.

Role of surgeryFor children with localized disease, without MYCN amplification, gross surgical excision is considered the main requirement for cure. {De Bernardi et al., 2008}

•Localized but unresectable NB carries a poorer prognosis except in

Infants or {Rubie et al., 2011}   Children with favorable biological features. {Cohn et al., 2009}

Chemotherapy: •Indications: neoadjuvant or adjuvant •Low-risk disease: multi-agent low or moderate intensity chemotherapy is reserved for those whose

Tumors cannot be resected Who have threatening symptoms of spinal cord compression or respiratory or bowel compromise.

•Intermediate-risk disease: Moderately intensive multi agents chemotherapy is applied before attempted resection.

•High-risk disease: intensive chemotherapy with a combination of agents is used to shrink primary and metastatic tumors.

Radiation therapy:•Indications•LR NB patients:

It is reserved for unresectable tumors or Progressive tumors unresponsive to chemotherapy or Life threatening complications, neurologic compromise, or tumor-related organ dysfunction unresponsive to emergency chemotherapy.

• Intermediate-risk: Currently, cooperative groups withhold RT for patients with, and recommend it only in the setting of disease progression despite surgery and chemotherapy. {Brodeur et al., 2011}

• High risk:

Low Risk NB:

•Observation

•Surgery

•Chemotherapy 

•Radiation therapy 

•Some newborns with small adrenal masses.•Some infants with localized NB.•Asymptomatic stage 4S disease. {Nuchtern et al., 2012}

• Surgery alone is the primary treatment for low-risk tumors. {De Bernardi et al., 2008}

• It should be delayed when <50 % of the tumor can be safely removed and neoadjuvant chemotherapy should be administered prior to surgery.

• low or moderate intensity Those whose tumors cannot be resected Who have threatening symptoms of spinal cord

compression or respiratory or bowel compromise.

Unresectable tumors or Progressive tumors unresponsive to chemotherapy or For those with life threatening complications, neurologic

compromise, or tumor-related organ dysfunction unresponsive to emergency chemotherapy.

IntermediateRiskNB:•SURGERY

•Chemotherapy

•Radiation therapy  The ultimate extent of surgical resection necessary for optimal outcomes has not yet been determined. {Baker et al., 2010}

Moderately intensive multi agents chemotherapy In a COG trial for intermediate risk NB, Four cycles of chemotherapy were given for tumors

with favorable biologic features Eight cycles were given for tumors with unfavorable

features

It is recommend it only in the setting of disease progression despite surgery and chemotherapy {Brodeur et al., 2011}.

High Risk NB:1.Induction

2.Local Control

Intensive chemotherapy with a combination of agents (e.g., platinum agents, cyclophosphamide, doxorubicin, etoposide) is used to shrink primary and metastatic tumors.

• Local control of the primary tumor is achieved with surgical resection and radiation therapy.  

• The importance of achieving a gross total resection of the primary tumor in patients with disseminated disease is controversial, with some studies {Zwaveling et al., 2012},

• But not others suggesting a better outcome for complete resection {Simon et al., 2013}.

• Radiotherapy dosed to the primary tumor bed and other sites of bulky disease may be beneficial in preventing local tumor recurrence {Haas-Kogan., 2003}

High RiskNB:3.Consolidation

4.Maintenance 

The consolidation phase includes higher dose chemotherapy {melphalan and busulfan} followed by autologous hematopoietic stem cell rescue {Laprie et al., 2004}.

• Aim: eradication of minimal residual disease.   • The backbone: 13-cis-retinoic acid (RA) .• Retinoids ---are substances that are similar to

vitamin A. • Benefit

to help some cells mature into normal cells.A COG study it improved their survival and lowered their risk of recurrence.

• Time---after completion of consolidation therapy to HR NB patients.

High RiskNB:5.Novel therapies • Additional immunotherapy: anti-GD2 antibodies was also found to have benefit

over (RA) alone for prevention of recurrence in a randomized trial {Yu AL et al., 2010}.

• The immunotherapy approach resulted in a statistically significant improvement in the two-year EF and OS rates (66 versus 46 %, and 86 versus 75 %, respectively).

• Immunotherapies: anti-GD2 antibodies. {Shusterman et al., 2010}

• Targeted autologous T-cells. {Louis et al.; 2011}

• Neuroblastoma vaccines.

• Targeted therapy with drugs that act through known genetic mutations (e.g., ALK) or induce apoptosis (e.g., fenretinide).

{La Madrid et al., 2012}

• Modifiers of the tumor microenvironment such as antiangiogenic agents or bisphosphonates. {Russell et al., 2011}

• Iodine-131-metaiodobenzylguanidine (MIBG), in conjunction with autologous peripheral blood stem cell rescue. {Matthay et al., 2007}

• Tumor growth due to maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology.

• Patients may have persistent maturing disease with (MIBG) uptake that does not affect outcome, particularly in patients with LR and IR disease {Marachelian et al., 2012}.

• When NB recurs in a child originally diagnosed with high-

risk disease, the prognosis is usually poor despite additional intensive therapy {London et al.; 2011}.

Prognostic factors determined at diagnosis for post relapse survival include the following {London et al., 2011}:– Age.

– INSS stage.– MYCN status.– Time from diagnosis to first relapse.– LDH level, ploidy, and histologic grade of tumor

differentiation (to a lesser extent).

Among those older than 18 months, differentiating tumors did much better than undifferentiated and poorly differentiated tumors.

Stages 1 and 2 have a better prognosis than stages 3 and 4

Hyperdiploidy had a better prognosis than patients with diploidy

Low RiskLocoregional

favorable biology

unfavorable biology

Surgery if not for chemotherapy

>90% <90%

Observation Chemotherapy

Surgery

Age

< 1 Y >1 Y

Aggressive combination

chemotherapy

>90%

Observation

<90%

Chemotherapy

Low Risk

Metastatic

Age

< 1 Y >1 Y

•completely favorable, • 4S pattern,• the recurrence or progression is within 3 months of diagnosis.

• Not 4S pattern or• the recurrence or progression is >3 months of diagnosis.

Observation Chemotherapy

Aggressive combination

chemotherapy

Intermediate Risk

Locoregional > 3 M

Metastatic

Surgery

>90% <90%

Observation Chemotherapy

like patients with newly diagnosed

HR NB

HighRisk

Any recurrence in patients initially classified as high risk signifies a very poor prognosis {London et al., 2011}.

Clinical trials may be considered.

Palliative care should be considered as part of the patient's treatment plan.

HighRisk

1.Chemotherapy

•Topotecan in combination with cyclophosphamide or etoposide {London et al., 2010} [Level of evidence: 1A].

•Temozolomide with irinotecan {Bagatell et al., 2011} [Level of evidence: 2A].

•High-dose carboplatin, irinotecan, and/or temozolomide has been used in patients resistant or refractory to regimens containing topotecan {Kushner et al., 2010}.

HighRisk

2.Iodine 131-MIBG (131I-mIBG)

For children with recurrent or refractory NB, 131I-mIBG is an effective palliative agent and may be considered alone or in combination with chemotherapy (with stem cell rescue) in a clinical research trial {French et al., 2013} [Level of evidence: 3iiiA].

HighRisk

3.Second autologous stem cell transplantation (SCT)

For children with recurrent or refractory NB, 131I-mIBG is an effective palliative agent and may be considered alone or in combination with chemotherapy (with stem cell rescue) in a clinical research trial {French et al., 2013} [Level of evidence: 3iiiA].

•In the setting of a clinical trial.

•German high-risk NB trials described 253 children relapsing after intensive chemotherapy with autologous SCT who had a 5-year OS rate of less than 10%. Only 23 of the 253 patients eventually proceeded to a second autologous SCT following retrieval chemotherapy {Simon et al., 2011} [Level of evidence: 3iiiA].

•Among these patients, the 3-year OS rate was 43%, but the 5-year OS rate was less than 20%.

•Only a small minority of relapsed high-risk NB patients may benefit.