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A brief lookNEUROBLASTOMA

By Dr: Mustafa SelimNational Cancer Institute

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Neuroblastoma (NB) is the most common extra cranial solid cancer in childhoodand the most common cancer in infancy.

It is a neuroendocrine tumor, arising from any neural crest element of thesympathetic nervous system. It most frequently originates in one of the adrenal glands,but can also develop in nerve tissues in the neck, chest, abdomen, or pelvis.

Neuroblastic tumors (including neuroblastomas, ganglioneuroblastomas andganglioneuromas) are most remarkable for their broad spectrum of clinical behavior,which can range from spontaneous regression, to maturation to a benignganglioneuroma, or aggressive disease with metastatic dissemination leading to death(Brodeur et al., 2011).

The capacity to undergo regression---Low risk NB (stage 4s) ifNo MYCN amplification & Near triploid number of chromosomes & No loss of chromosome 1p.The capacity to undergo maturation---Intermediate risk NB

Persisting residual and maturing tumors in IR Neuroblastoma patients were not associated withtumor progression, despite MIBG uptake and/or elevated catecholamines.

Superior prognosis for infantsFive-y OS and EFS for stage 3 disease with age < 18 vs >18 Months (91% vs 66%), (86% vs

56%), (p<0.0001%) Holly et al., Pediatic Blood Cancer 2014.

The most common cancer in infants “<1 year old”.The most common extra-cranial solid cancer in childhood “>1year”. 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.Accounts for about 7% of all cancers in children.The incidence of NB is greater among white than black infants (ratio of 1.7).Neuroblastoma is slightly more common among boys compared to girls (ratio 1.9 to 1).

The early age of onset suggests that preconceptual or gestational environmental events (eg, exposureto drugs, hormones, toxins, or viruses) may play a role.

Genetic factors, Maternal factors, Familial Neuroblastoma

BACKGROUND:

Risk factors:

Key features of Neuroblastoma:

Key statistics of Neuroblastoma: 4

Y+M+%+

Male

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Genetic factors: The majority of neuroblastomas are sporadic and not correlated with

any specific constitutional germ line chromosomal abnormality. However, there are at least some

exceptions: 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: An association between major congenital abnormalitiesand the subsequent development of NB has been reported in some studies.

Opiate consumption

Gestational diabetes mellitus

Folate deficiency

Familial Neuroblastoma: It is happened 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 (mean age 9 vs 17 months), and a large

proportion have bilateral adrenal or multifocal disease. Some reports suggest that familial

predisposition may be conferred through disruption of a locus at 16p12-13.

It is arising from any neural crestelement of the sympathetic nervoussystem.

Adrenal neuroblastomas are thought todevelop from residual microscopicneuroblastic nodules (detected infetuses between the 15th and 20th weeksof gestation, and regress by the time ofbirth or shortly thereafter). A failure torespond fully to the normal signals thatstimulate morphological differentiation.Instead, they continue to grow anddivide Malignant transformationof these cells may result.

Origin of extra-adrenal NB is unknown.

A higher incidence of NB

EMBRYOGENSIS

الناس بین الفروق أصل ھو إستغاللھا ...وإساءة طویال وقتا ..تمثل الواحدة الثانیة إن

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The failure of some neuroblasts to mature and to stop growing is due to abnormal DNA insidethe cells. Cancers can be caused by DNA changes:

Such as having too many or too few chromosomes ormissing part of a chromosome That turn on oncogenes or turn off tumor suppressor genes. These gene changes can be acquired (most cases) or inherited (rare cases). These changes are found only in the child’s cancer cells and happen early in the child’s

development, often before birth.

In many neuroblastomas the exact genes affected are not known.

DNA copy-number aberrations fall into three broad prognostic categories:

A. Whole chromosome gains that result in hyperdiploidy and are associated with a

favorable prognosis and segmental chromosomal aberrations, such as amplification

of MYCN are associated with unfavorable prognosis.

B. Regional loss of chromosomal material {1p or 11q loss}, that tend to be associated with

a worse outcome.

C. Regional gain of chromosomal material {17q gain}, that tend to be associated with a

favorable outcome.

Hperdiploidy = (DNA index [DI] >1) a favorable prognosis

Definition: Neuroblastoma cells contain higher amount of DNA the normal cells.

Measurement: such as flow cytometry or imaging cytometry.

Value:

It is associated with lower tumor stage and better response to initial therapy,

An overall better prognosis, particularly if they lack MYCN amplification.

The influence of ploidy on outcome of Neuroblastoma seems to be lost in children

over the age of two, possibly because hyper diploid tumors in older children

typically have a number of structural rearrangements as well.

A

B

C

Molecular pathogenesis and implications for prognosis

جماال النجاح یفوق شئ وال النجاح سر فالمحاولة تحاول أن أجمل ما

A-Alterations in total DNA content

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The oncogene MYCN (also called N-myc) High risk disease

A close relative of the oncogene c-myc that resides on chromosome 2p24-25. A gene that helps regulate cell growth. Gene over expression results in persistently high levels of the MYCN protein, a

DNA binding transcription factor known to cause malignant transformation inboth in vitro and in vivo tumor models.

A 50 to 400 fold amplification of MYCN is found in approximately 25% ofneuroblastomas and is an indicator of poor prognosis.

Loss of heterozygosity (LOH) are found in approximately one third ofneuroblastomas, and are consistently localized to chromosomes 1p, 11q, and 14q .

Deletion of a part of chromosome 1p:

It is one of the most common chromosomal changes observed in NB and isassociated with a poor prognosis.

Deletions of 1p are highly associated with amplification N-myc. LOH of 1p was predictive of local recurrences in low stage disease.

Deletions of 11q and/or 14q

It is detected in 25 to 50 % of NB. 11q aberrations are often not associated with MYCN amplification. 11q strongly correlated with increase incidence of relapse particularly

metastatic relapses.

A gain of whole chromosome 17q material (trisomy 17q) occurs in over one-halfof NB and appears to be associated with increased survival, but Having an extrapart of chromosome 17 (17q gain) is also linked with a worse prognosis.

Inherited Neuroblastoma “In rare cases”

Genetic testing for mutations in ALK and PHOX2B should be considered whenever

a patient has a family history of NB or bilateral primary tumors of the adrenal

glands.

Anaplastic lymphoma kinas (ALK) gene: have been identified in several studies as

being an important contributor to the development of familial and sporadic NB.

Mutations resulting in oncogene activation are also somatically acquired in 5 to 15% of NB.

B-Chromosomal deletions

C-gain of chromosomal material

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PHOX2B (paired-like homeobox 2b gene): a gene that normally helps nerve cells

mature, a small number of inherited neuroblastomas are caused by changes in

PHOX2B gene. Children with either sporadic or familial NB in conjunction with

congenital central hypoventilation syndrome, Hirschsprung's disease, or both usually

have loss of function mutations in the home box gene PHOX2B.

Although ALK and PHOX2B mutations account for the majority of familial cases of

NB, additional familial genes may still be discovered.

Neuroblastoma cells in older children are more likely to have changes in the

ATRX tumor suppressor gene. Tumors with this gene change tend to grow more

slowly, but they are also harder to cure.

Other factors that have not been incorporated into the Neuroblastoma Risk Stratification

System but may affect prognosis include the following:

Expression of neurotrophic factors, such as nerve growth factor and brain derived

neurotrophic factor along with their receptors (tyrosine kinases that are encoded by three

TRK genes, TRK A, B and C) has been implicated in the pathogenesis of NB, although their

precise role is unclear. Expression of TRKA is inversely correlated with MYCN amplification,

and high TRKA expression appears to identify a biologically favorable subgroup of

neuroblastomas, while expression of TRK B or C is prognostically unfavorable.

Telomeres are repeated nucleotide sequences that stabilize chromosomes, thereby preventing

cell senescence. Telomerase is the enzyme that compensates for telomere shortening during

cell division by synthesizing telomeric DNA, thereby maintaining telomere length. Preserved

length of telomeres has been identified as a possible independent poor prognostic sign in

children with Neuroblastoma.

Gene expression profiling may offer additional information to distinguish between patients

with favorable and unfavorable prognosis. Gene expression profiling may provide more

precise prognostication in patients with localized MYCN-NA neuroblastom.

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Tumors of neuroblastic origin are classified 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) into one of

three types: Neuroblastoma, ganglioneuroblastoma, or ganglioneuroma.

Ganglioneuroblastoma: It is called an "intermixed stroma-rich" or "stroma-rich"

tumor because of the increased proportion of Schwannian cells. The neuroblasts,

which generally have a more mature appearance, are clustered together in foci or

nests surrounded by the Schwannian cells. These tumors generally have intermediate

malignant potential, between that of neuroblastomas and ganglioneuromas.

Ganglioneuroma: It (Schwannian cell dominant) is predominantly composed of

Schwannian cells studded with maturing or fully mature ganglion cells. These tumors

tend to occur in older children (5-7 years) rather than the more aggressive

neuroblastomas. They are considered to be benign, although they can metastasize. The

prognosis is excellent, even when complete tumor removal is not possible.

Ganglioneuroblastom

a

Criteria to diagnosis Types Criteria to diagnosis

>50% ganglioneuromatous,a minor neuroblastomatous

Intermixed Schwannian stroma-rich

Nodular Schwannian stroma-rich/stroma-dominant/ stroma-poor

PATHOLOGY :

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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, bluecells.Morphologically, the appearance is similar to that of other small round blue celltumors involving bone and soft tissue, including lymphoma, small cell osteosarcoma,mesenchymal chondrosarcoma, the Ewing sarcoma family of tumors, primitiveneuroectodermal tumors (PNETs), and Rhabdomyosarcoma.Neuroblastomas typically react with antibodies that distinguish neural tissue (e.g.,neuron-specific enolase [NSE], synaptophysin, chromogranin, and S100). While NSEmay be positive in other tumors (e.g., Rhabdomyosarcoma), the staining pattern ischaracteristically diffuse and strongly positive in neuroblastomas. Primitiveneuroblasts (evidence of neural differentiation) can be seen in the poorlydifferentiated and differentiating types of Neuroblastoma not the undifferentiatedneuroblastomas. These cells are approximately 7 to 10 microns diameter, have hyperchromatic nuclei and scanty cytoplasm, and may form Homer-Wright rosettes.

In 1984, Shimada et al derived a pathologic risk classification scheme that

relates the histopathologic features of the tumor, other biologic variables, and

patient age to clinical behavior. Tumors are classified as favorable or unfavorable.

The International Neuroblastoma Pathology Classification (INPC) system, a

modification of the Shimada system, was established in 1999 and its prognostic

value subsequently confirmed.

Neuroblastom

a

Criteria to diagnosis Types Criteria to diagnosis

Contains at least 50%neuroblastomatous

Undifferentiated All the cells

Poorlydifferentiated <5% of cells

Differentiating At lest 5% of cells

PATHOLOGIC RISK CLASSIFICATION

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Nonspecific and mimic many childhood illnesses.

NB can arise anywhere throughout the sympathetic nervous system. The adrenalgland is the most common primary site (40 %), followed by abdominal (25 %),thoracic (15 %), cervical (5 %), and pelvic sympathetic ganglia (5 %). Lesscommonly, tumors arise within the central or autonomic nervous systems. Inapproximately (1 %) of cases, a primary tumor cannot be identified. NB metastasizesto lymph nodes, bone marrow, cortical bone, dura, orbits, liver, and skin, and lessfrequently, to pulmonary and intracranial sites.

The signs and symptoms of NB vary widely,

depending on the size of the tumor, where it is, how farit has spread, and if the tumor cells secrete hormones. 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.

Signs or symptoms caused by the main tumor : Tumors in the abdomen or pelvis swelling Tumors in the neck Horner syndrome (ipsilateral ptosis,

miosis, and anhidrosis) Tumors in the chest swelling & bluish in the face, neck, arms, and upper

chest.

Tumors According to the INPC (Shimada System)

Favorable Unfavorable

Ganglioneroma

Ganglioneroblastoma (intermixed)

Neuroblastoma

< 18 months

(differentiating + low MKI)

(poor differentiated + intermediate MKI)

> 18-60 months

(differentiating + low MKI)

Ganglioneuroblastoma (nodular)

Neuroblastoma

Undifferentiated (any age)

High MKI (any age)

> 60 months

18-60 months

(poorly differentiated or intermediate MKI)

Clinical Presentation

Unfavourable histology Neuroblastoma if Age > 5 Years or Undifferentiated or High MKI MKI→(It will be done if age <5 years + degree of differentiation is present)

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Signs or symptoms caused by cancer spread to other parts of the body: Neuroblastoma metastasizes by both lymphatic and hematogenous routes: Lymph node involvement. Hematogenous spread extends most often to eye (Tumor infiltration of the per orbital

bones, typically unilateral, can cause the characteristic per orbital ecchymosis("raccoon eyes"), ptosis, and proptosis), bone (pain and if it spreads to the bones in thespine, tumors can press on the spinal cord and cause weakness, numbness, or paralysisin the arms or legs), bone marrow (anemia, thrombocytopenia and leucopenia), skin(Blue or purple bumps that look like small blue berries may be a sign of spread to theskin), and liver (A special widespread form of NB (known as stage 4S) occurs onlyduring the first few months of life. In this special form, the NB has spread to the liver,to the skin, and/or to the bone marrow (<10%). Signs or symptoms associated with paraneoplastic manifestation:

Opsoclonus-myoclonus-ataxia (OMA) It is a paraneoplastic syndrome that occurs in 1 to 3 % of children with NB.

It occurs at an average age of 19 months (6 to 36 months) & affecting as few as 1 in 10,000,000people per year.

It is usually of lower stage and have favorable prognosis for survival. Tumors in children whodevelop OMA tend to be more mature, showing favorable histology and absence of NMYConcogene amplification.

However, children who have OMA are often left with long-term neurologic deficits (e.g.,cognitive and motor delays, language deficits, and behavioral abnormalities).

All children with OMA must be evaluated for Neuroblastoma. As 50 % of children with OMAhave an underlying Neuroblastoma.

If the initial evaluation is unrevealing it should be repeated in several months. Autoimmune pathogensis have a role. The characteristic symptoms of OMA are rapid, dancing eye movements, rhythmic jerking

(myoclonus) involving limbs or trunk, and/or ataxia. Neurologic symptoms precede tumor diagnosis in about half of these.

Chemotherapy, corticosteroids, and IV immune globulin may improve long-term neurologicoutcome. Symptoms refractory to these treatments may respond to Rituximab.

Secreation of vasoactive intestinal peptide (VIP): 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 aserum VIP concentration in excess of 75 pg/Ml.

VIP-producing tumors are more often the less aggressive GNB and GN rather thanundifferentiated neuroblastomas.

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

Spinal cord compression:

Between 7 and 15 % of children with Neuroblastoma present with spinal cord involvement.

Spinal cord compression is considered an oncologic emergency.

Neurologic recovery appears to be related to the severity of presenting neurologic deficits. Chemotherapy and laminectomy have equivalent overall survival outcomes. Spinal cord compression in NB can be effectively managed with upfront chemotherapy. Initial

surgical decompression should be reserved for benign variants only, including ganglioneuroma.Neurological manifestations of <4 weeks duration upon presentation are usually reversible(Fawzy et al., 2014).

Radiation Therapy (RT) is generally reserved for progressive symptoms despite chemotherapy.

Opsoclonus myoclonus (discussed before)

Hypertension: Neuroblastoma tumor cells are characterized by defective catecholamine synthesis,which results in the accumulation and excretion of the intermediates homovanillic acid (HVA),VMA, and dopamine. Secretion of these catecholamines may give rise to symptoms.

Intractable diarrhea: On rare occasions, children may have severe, watery diarrhea due to thesecretion of VIP by the tumor, or may have protein-losing enteropathy with intestinallymphangiectasia. VIP secretion may also occur upon chemotherapeutic treatment, and tumorresection reduces vasoactive intestinal peptide secretion.

Urine catecholamines: NB cells are characterized by defective catecholamine synthesis,which results in the accumulation and excretion of the intermediates Homovanillic acid(HVA) ,Vanillylmandelic acid (VMA) and dopamine. Secretion of these catecholamine’s may giverise to signs (e.g., hypertension). In addition, HVA and VMA can be measured in the urine and areuseful for diagnosis and in monitoring disease activity. Unlike the adrenal chromaffin cells andpheochromocytomas, neuroblastic cells lack the final enzyme that converts these intermediates tonor epinephrine and epinephrine.

Blood tests: CBC, LFT, KFT, electrolytes, Neuron specific Enolase, ferritin and serum LDH.

Bone marrow aspiration and biopsy are taken from the back of both of the hip bones.

Imaging studies: CXR, pelviabdominal u/s, CT, MRI (is better than CT scans for seeing the

extent of NB tumor, especially around the spine), MIBG scan, PET CT and bone scan.

Medical Complications

DIAGNOSTICAND STAGING EVALUATION

Enolases are glycolytic enzymes are responsible for converting 2 - phosphoglycerate to

phosphoenolpyruvate. Three immunologically distinct subunits: alpha, beta, and gamma. Gamma enolase

is found in neuron and called NSE. Non a specific marker as it increased in non malignant conditions

(brain damage) and malignant conditions like (Wilms tumor, Ewing sarcoma, Non- Hodgkin lymphoma,ALL).

A major

tissue-binding

protein. Raised

ferritin results

from direct

secretion by the

tumor. High levels

of ferritin related

to poor survival.

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MIBG scan: The MIBG scan is both sensitive 90% and specific 99% for NB. It is recommended at diagnosis and repeat evaluations of the tumor. This scan uses a form of the chemical meta-iodobenzylguanidine (MIBG) that contains a small

amount of radioactive iodine. MIBG is similar to nor epinephrine, a hormone made bysympathetic nerve cells.

The thyroid gland must be protected by the simultaneous administration of non-radioactiveiodine (e.g., potassium iodide.

Although iodine 123 (123I) has a shorter half-life, it is preferred over131I because of its lowerradiation dose, better quality images, less thyroid toxicity, and lower cost.

The extent of metastatic disease is assessed by MIBG scan, which is applicable to all sites ofdisease (including soft tissue, bone marrow, and cortical bone involvement). Cortical bonemetastases are also evaluated by technetium-99 scan. If all sites of bone metastases are imaged byMIBG scan, then subsequent restaging for assessment of disease response may omit thetechnetium-99 bone scan. Approximately 90% of neuroblastomas will be MIBG avid.

Imaging with 123I-MIBG is optimal for identifying soft tissue and bony metastases and was shownto be superior to 18F-fluorodeoxyglucose positron emission tomography–computerizedtomography (PET-CT) in one prospective comparison (Papathanasiou et al.; 2011).

A retrospective analysis of paired MIBG and PET scans in 60 newly diagnosed neuroblastomapatients demonstrated that for International Neuroblastoma Staging System (INSS) stages 1 and 2patients, PET was superior at determining the extent of primary disease and more sensitive fordetection of residual masses. In contrast, for stage 4 disease, 123I-MIBG imaging was superiorfor the detection of bone marrow and bony metastases (sharp et al.; 2009).

The radioactive molecule can be used at higher doses to treat the NB. When MIBG is used fortreatment, thyroid dysfunction has been reported as a potential complication in up to 64 % ofpatients. The addition of thyroxin and methimazole to potassium iodide, and continuation ofthyroid protection for four week is injected into the blood. The amount of radioactivity used isvery low and will pass out of the body within a day or so. Because cancer cells in the body aregrowing quickly, they absorb large amounts of the radioactive sugar. Some newer machines cando a PET and CT scan at the same time (PET/CT scan).

FDG PET was found to better depict the sites of disease in stage I and II neuroblastoma due tothe higher target-to-background ratio. In stage III and IV disease, FDG PET was again helpful ifthe tumors weakly accumulated I-123-MIBG. However, I-123-MIBG was found to be superior toFDG PET overall for the imaging evaluation of stage IV disease, primarily due to better depictionof bone or marrow metastases with I-123-MIBG. FDG PET was more limited at these 2 lattersites of disease because of the physiologic mild localization of FDG that could hinder tumordetection. High accumulation of FDG in bone marrow in response to granulocytecolony-stimulating factor therapy was even more problematic. However, the ability of FDG PETto detect residual disease that is not evident on I-123-MIBG provides important informationbefore major management decisions, such as before stem cell transplantation.

Bone scan A radionuclide bone scan is a sensitive tool for evaluating metastatic spread to cortical bone and

can provide a picture of the entire skeleton at once. NB often causes bone damage, which a bone

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scan can find. This test used to be done routinely, but in some centers it has been replaced by use of MIBG or

PET scans. For this test, a small amount of low-level radioactive material (technetium-99) is injected into a

vein. The substance settles in areas of damaged bone throughout the skeleton over the course of acouple of hours. Areas of active bone changes attract the radioactivity and appear as “hot spots”on the skeleton. These areas may suggest cancer, but other bone diseases can also cause the samepattern. Other imaging tests such as plain x-rays or MRI scans, or even a bone biopsy might beneeded.

However, false-negative bone scan results may occur in patients with lytic metastases within thedistal end of long bones. In addition, in infants younger than one year of age, bone scans may bedifficult to interpret because immobilization is difficult, and improper knee positioning (onaccount of slight knee flexion and external rotation of the leg) may cause superimposition of theepiphysis and metaphysis, obscuring the usual tracer concentration gradients. Thus, plainradiographs (e.g., a skeletal survey) may be necessary in young infants.

Tissue Biopsy: There are 2 main types of biopsies: Incisional (open or surgical) biopsy. For tumors deep in the body this may be done

laparoscopically. Needle (closed) biopsy: If the tumor is deep within the body, CT scans or ultrasound can be used

to help guide the needle into the tumor.

For tumors that appear to be localized and resectable without substantial morbidity, the initialdiagnostic procedure may include a complete or near-complete resection of the primary tumorand sampling of non-adherent ipsilateral and contralateral lymph nodes. The initial procedureshould not include resection of vital structures (e.g., kidney) or major motor or sensory nerves.

Diagnostic criteria: A definitive diagnosis of Neuroblastoma requires one of the following: An unequivocal histological diagnosis from tumor tissue by light microscopy, with or without

immunohistochemistry, electron microscopy, or increased urine (or serum) catecholamine’s ortheir metabolites

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

When the tumor arises in a suprarenal location, Wilms' tumor and hepatoblastoma. In thoracic and retroperitoneal locations, lymphoma, germ cell tumors, soft tissue sarcoma and

infection should be considered. Metastatic involvement of the bone marrow must be distinguished from lymphoma, small cell

osteosarcoma, mesenchymal chondrosarcoma, the Ewing sarcoma family of tumors, primitiveneuroectodermal tumors (PNETs), undifferentiated soft-tissue sarcomas such as Rhabdomyosarcoma,and leukemia, particularly megakaryoblastic leukemia.

If the spinal canal is involved, either as a metastatic lesion or by extension of the primary tumor, thedifferential diagnosis should extend to other neurodevelopmental tumors such as desmoid tumors,epidermoid tumors, and teratomas, as well as astrocytomas {Wilson et al., 2007}.

Differential Diagnosis

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The differential diagnosis of skin nodules in newborns and infants includes: dermoid and other cystssubcutaneous fat necrosis benign tumors (e.g., infantile myofibromatosis, congenital self-healingreticulohistiocytosis) malignant tumors (e.g., infantile fibrosarcoma, Rhabdomyosarcoma, andcongenital leukemia.

Other causes of secretory diarrhea. Opsoclonus-myoclonus syndrome may occur in association with other conditions besides NB : Tumors: Hepatoblastoma Infections: Poliovirus, par influenza virus, coxsackie virus B3 and B2, Epstein-Barr virus, St. Louis

encephalitis virus, salmonella, Lyme disease, rickettsia, syphilis, psittacosis, and HIV. Ingestions: Lithium, phenytoin, amitriptyline, diazepam, cocaine. Toxic exposures: Toluene, thallium, organophosphates, chlordecone, strychnine. Metabolic derangements: biotin-responsive multiple carboxylase deficiency, hyperosmolar

nonketotic coma.

A staging system for Neuroblastoma that was proposed by Evans et al in 1971 based on both the site of origin and

the clinical behavior of the tumor.

There are two main staging systems for Neuroblastoma : International Neuroblastoma Staging System (INSS) and

International Neuroblastoma Risk Group Staging System (INRGSS).

International Neuroblastoma Staging System:Neuroblastoma are staged according to the International Neuroblastoma Staging System (INSS), which was initially

developed in 1986 and revised in 1993. This system takes into account the results of surgery to remove the tumor.

The International Neuroblastoma Staging System (INSS) (Brodeur et al.; 1993)

Stage Description

1

1X1

Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph

nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive).

2A

1X1

Localized tumor with incomplete gross excision; representative ipsilateral non adherent lymph nodes negative for tumor

microscopically.

2B

2X2

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

3

3X3

Unresectable unilateral tumor infiltrating across the mid-line, with or without regional lymph node involvement; or localized

unilateral tumor with contralateral regional lymph node involvement; or mid-line tumor with bilateral extension by infiltration

(unresectable) or by lymph node involvement. The mid-line is defined as the vertebral column. Tumors originating on one side and

crossing the mid-line must infiltrate to or beyond the opposite side of the vertebral column.

4Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as

defined for stage 4S.

4S

Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (by

definition limited to infants younger than 12 months). Marrow involvement should be minimal (i.e., <10% of total nucleated cells

identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be

considered stage 4 disease. The results of the MIBG scan, if performed, should be negative for disease in the bone marrow.

Staging Systems and Risk Grouping

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Neuroblastoma Risk Groups:Children’s Oncology Group (COG) uses the following factors to determine risk {low, intermediate,or high-risk NB}: Age (at diagnosis), MYCN gene status, tumor ploidy (this is only important forchildren <18 months) and tumor histopathology.

International Neuroblastoma Risk Group Staging System (INRGSS) Tumor staging in the INRG system is based on a new pre-treatment staging system composed of

four stages, two for loco-regional disease (L1 and L2), and two for metastatic disease (M & MS). The extent of loco-regional disease is evaluated pre surgically by the absence or presence of

anatomic surgical risk factors identified on imaging studies, such as organ invasion or encasementof blood vessels, with tumors having any of these image defined risk factors (IDRFs) classified asstage L2, while all other tumors are classified as L1.

Neuroblastoma tumors with disseminated metastases are classified as stage M, analogous to INSSstage 4, with the exception of infants with metastases limited to skin, liver and bone marrow, whoare classified as stage MS, analogous to INSS stage 4S.

The proposed system will assign all NB cases into very-low, low, intermediate and high risk group. Using the following factors, The stage of the disease according to the INRG staging system, age

when diagnosed, histologic category (such as maturing GN versus GNB versus NB), grade,MYCN gene status and changes to chromosome 11q.

Complete Response (CR): No tumor, no metastases, normal markers.

Very good Partial Response (VGPR): Primary; reduction more than 90%, but less 100; Metastases; no tumor except bone

{all preexisting lesions improved; Markers; decreased more than 90%

Partial Response (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 25% increase in any existing lesion.

No Response (NR) or stable disease (SD): No new lesions; less than 50% reduction +/- less than 25% increase in any

existing lesion.

Progressive Disease (PD): Any new lesion; increase of any measurable lesion by more than 25%; previously negativemarrow becomes positive for tumor.

Tumor staging in the INRG system

Stage Description

L1 Localized tumor not involving vital structures as defined by the list of image-defined risk factors

and confined to one body compartment.

L2 Loco-regional tumor with presence of one or more image-defined risk factors.

M Distant metastatic disease (except MS).

MS Metastatic disease in children < 18 months with metastases confined to skin, liver, and/or BM.

Image defined risk factors in neuroblastic tumor

Ipsilateral tumor extension within two body compartments

For

Ex:

Nec

k

Tumor encasing carotid and/or vertebral artery

and/or internal jugular vein

Tumor extending to base of skull

Tumor compressing the trachea

International Neuroblastoma ResponseCriteria:

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Algorezm for risk stratification1) NMYCAmpliphied----HR2) Stage:

Stage I---- LR Stage II--- LR vs HR (NMYCA) Stage III--- IR vs HR

IR (<18 months) or (>18 months + FH) HR (NMYCA) or (>18 months + UH)

Stage IV--- IR vs HR IR (<12 months) or (12-18 months + FH+DNA I >1) HR (NMYCA) or (>18 months ) or (12-18 months + UH or DNA I >1)

Stage IVs--- LR vs IR vs HR LR ( FH+DNA I >1) IR (UH or DNA I >1) HR (NMYCA)

1. Age:

The age at presentation is an important prognostic factor in children with Neuroblastoma.

The younger the age at diagnosis, the better the survival rate.

Better outcome of disseminated disease in children <1 Y compared to other age groups is reflected in the

special 4S category of disease stage, which applies only to infants.

An age of 18 months appears to be appropriate for risk group stratification. This age has been incorporated

into the current treatment regimens as well as the proposed INRGSS.

NB has a worse long-term prognosis in an adolescent >12 Y as compared with a child, regardless of stage or site. The 5-year survival stratified by age is as follows Age younger than 1 year – 90%, Age 1 to 4 years – 68%,

Age 5 to 9 years – 52% and Age 10 to 14 years – 66%{Horner et al., 2014}.

2. Tumor stage

The extent of metastatic spread at presentation is the most important factor in determining outcome for

patients with NB.

Although regional spread to lymph nodes attached or adjacent to the primary tumor does not significantly

affect outcome, distant metastatic disease (e.g., bone marrow involvement) confers a much worse

prognosis.

Disease stage at diagnosis is to some extent influenced by age; a greater proportion of patients diagnosed

after one year of age have stage 3 or 4 disease compared to those who present earlier (80 versus 41 %)

{Brodeur et al., 2011}.

3. Tumor histology

Tumor with FH tend to have a better prognosis while Tumors with an UH tend to have a poorer prognosis.

A COG study of children with stage 1 and stage 2 NB without MYCNA and with FH reported a 5-year EFS

of 90% to 94% and OS of 99% to 100%, while those with UH had an EFS of 80% to 86% and an OS of

89% to 93%.

3rd look

2nd look

1st look

Prognostic Variables

17

4. DNA ploidy The amount of DNA in each cell, known as ploidy or the DNA index {DI} & measured using flow cemetery.

NB cells with about the same amount of DNA as normal cells (DI = 1) are classified as diploid.

Cells with increased amounts of DNA (DI higher than 1) are termed hyper diploid.

In infants, hyper diploid cells tend to be associated with earlier stages of disease, respond better to

chemotherapy, and usually predict a more favorable prognosis (outcome) than diploid cells.

Ploidy is not as useful a factor in older children.

5. Response to treatment

Response to treatment has been associated with outcome.

In patients with HR disease, the persistence of NB cells in BM after induction chemotherapy, is associated

with a poor prognosis, which may be assessed by sensitive minimal residual disease techniques

{Bochennek et al., 2012}.

The degree of tumor volume reduction predicts response in high-risk patients, as do a decrease in mitosisand an increase in histologic differentiation {Yoo et al.; 2013}. Similarly, the persistence of MIBG-avid

tumor after completion of induction therapy predicts a poor prognosis {Yanik et al., 2013}.

6. MYCN gene amplifications Neuroblastomas with amplification of the MYCN oncogene tend to grow quickly, are less likely to mature

and tend to have a worse prognosis than other children with NB.

MYCN amplification is founded in 30% to 40% of stage 3 and 4 neuroblastomas and in only 5% of

localized or stage 4s neuroblastomas.

Loss of chromosome 1P is invariably present..

7. Other markers: These markers are not used to help determine risk groups at this time, but they arestill important and may influence the treatment of a child with NB.Segmental chromosome changes (SCAs): SCAs most often involving chromosome regions 1p, 1q, 2p, 3p, 4p, 11q and 17q are preferentially observed

in advanced stages of disease in older children, and are associated with a poorer prognosis.

Segmental chromosome number changes predict recurrence in infants with localized unresectable or

metastatic NB without MYCN gene amplification.

Tumor cells that are missing certain parts of chromosomes 1 or 11 (known as 1p deletions or 11q deletions)

may predict a less favorable prognosis. It is thought that these chromosome parts, which are missing in many

NB may contain important tumor suppressor genes, but more studies are needed to verify this.

Having an extra part of chromosome 17 (17q gain) is also linked with a worse prognosis. This probablymeans 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}.

A Ganglioside GD2 is on the surface of many nerve cells and increased in the blood of NB patients. It is moreimportant in treating NB by using anti GD2.

Neurotrophin (nerve growth factor) receptors: These are substances on the surface of normal nerve cells and on some NB cells.

They normally allow the cells to recognize neurotrophins {hormone-like chemicals} that help the nerve

cells mature. Neuroblastomas that have more of certain neurotrophin receptors, especially the nerve growth factor receptor

called TrkA, may have a better prognosis.

18

Ferritin:

It is released from NB cells.

The predictive power was found to be greater in patients with localized disease as compared to Stage 4.

Elevated serum ferritin (>142ng/ml) was associated with worse progression free survival in a multivariable

analysis of prognostic factors in patients with Evans Stage III and IV disease.

It has been proposed that serum ferritin may act as a surrogate for tumor burden.

Increased levels of Neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) in the blood are often

linked with a worse outlook in children with Neuroblastoma.

Treatment strategies for children with neuroblastoma have been tailored according to the predictedresponse to therapy and risk of relapse for more than 40 years. Different treatment modalities (surgery,chemotherapy and radiation therapy) are the mainstay of neuroblastoma portocoles. The moderntreatment of Neuroblastoma is determined based on risk categories.

Survival by Children’s Oncology Group (COG) risk group

Low-risk group: have a 5-year survival rate that is higher than 95%.

Intermediate-risk group: the 5-year survival rate is around 90%. High-risk group: The 5-year survival rate in this group is around 40% to 50%.

Observation---Surgery ---Chemotherapy ----Radiation therapy In general, tumor outcomes for children with low-risk Neuroblastoma are excellent.

Surgery is the mainstay of treatment for low risk tumors although some infants and childrenneed additional chemotherapy and others can be observed without surgery.

The absence of MYCN amplification and the absence of other structural abnormalities, such as in11q or 17q, can define low-risk tumors.

o Observation in LR neuroblastoma: Observation is a reasonable alternative in:

Some newborns with small adrenal masses &Some infants with localized NB&Asymptomatic stage 4S.

o Surgery in LR Neuroblastoma:

Surgery alone is the primary treatment for low-risk tumor. Surgery should be delayed in circumstances when less than 50% of the tumor can be safely

removed and neoadjuvant chemotherapy should be administered to reduce the size of the tumorprior to surgery.

Two- to five-year EFS rates with surgery alone are greater than 93 % for children with stage 1disease; because recurrences can be successfully managed with further surgery or chemotherapy,five-year survival rates are 95 %.

For most children with stage 2A or 2B disease and no symptoms, the outlook after surgery aloneis also excellent. Five-year overall survival was similar in patients with stage 2A disease

Treatment

Low Risk NB

19

compared with 2B disease (98 versus 96 %), despite a significantly lower EFS in patients withstage 2B disease (85 versus 92 %). Patient age and tumor characteristics such as DNA contentand histology were important prognostic factors in these patients that contributed to the lowerEFS in patients with stage 2B disease.

o Chemotherapy in LR Neuroblastoma:

A multi-agent low or moderate intensity chemotherapy{combinations of cyclophosphamide,carboplatin or cisplatin, etoposide or teniposide, and doxorubicin} is reserved for:

Those whose tumors cannot be resected

Who have threatening symptoms of spinal cord compression or respiratory or bowelcompromise or other organ dysfunction.

Among patients who have localized but unresectable disease, primary chemotherapy may beused to shrink the primary tumor and resection delayed until it can be performed safely.

o Radiation therapy in LR Neuroblastoma:

Radiation therapy (RT) is reserved for unresectable tumors or progressive tumors unresponsiveto chemotherapy.

For those with life threatening complications, neurologic compromise, or tumor-related organdysfunction unresponsive to emergency chemotherapy.

RT is generally avoided in all other clinical scenarios given the overall excellent survival for thispatient group and the long-term complications of RT.

SURGERY----Chemotherapy---Radiation therapy

The standard approach for these patients includes chemotherapy with resection when possible.

The duration of chemotherapy is typically 12 to 24 weeks; optimization of chemotherapyaccording to risk factors is a focus of current clinical investigations.

Radiation therapy is rarely indicated but should be considered for those with tumor progressionor tumor-related life threatening or organ-threatening complications unresponsive to chemotherapy.

o Surgery in IR neuroblastoma:

For intermediate-risk Neuroblastoma, surgical biopsy is necessary to obtain a diagnosis anddiscern histologic and genomic features.

The ultimate extent of surgical resection necessary for optimal outcomes has not yet beendetermined {Baker et al., 2010}.

o Chemotherapy in IR neuroblastoma:

Moderately intensive multi agents chemotherapy (e.g., with doxorubicin, cyclophosphamide, aplatinum drug and etoposide) is recommended for children with intermediate-risk NB and is oftenapplied before attempted resection.

In a COG trial for intermediate risk NB, four cycles of chemotherapy were given for tumors withfavorable biologic features and eight cycles were given for tumors with unfavorable features.

Intermediate Risk NB

20

Children treated in this way did just as well as in previous studies, with three-year EFS and OS of88 and 96 %, respectively. Importantly, radiation was used only for emergent conditions (2.5 %of patients received radiation therapy), and the degree of primary tumor resection did not impactsurvival {Baker et al., 2010}.

Ongoing cooperative group treatment regimens are further reducing both the duration oftreatment and the cumulative doses of cytotoxic chemotherapy agents for those children withfavorable tumor features in order to minimize toxicity while maintaining a high cure rate {Bakeret al., 2010}.

o Radiation therapy in IR neuroblastoma:

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

Induction---Local Control---Consolidation:---Maintenance---Novel therapies

Historically, the long-term survival probability for children with high-risk disease was less than 15 %.Better results have been achieved using an aggressive multimodality approach that includes intensivechemotherapy, surgical resection, high-dose chemotherapy with hematopoietic stem-cell rescue, andradiation therapy {Laprie et al., 2004}; However, current survival rates remain unacceptably low(approximately 40 %), and the improved outcome has come at a cost of significant early and latetoxicities.

o Induction chemotherapy in HR Neuroblastoma:

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

o Local Control in HR Neuroblastoma:

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 withdisseminated disease is controversial, with some studies {Zwaveling et al., 2012}, But not otherssuggesting a better outcome for complete resection {Simon et al., 2013}.

Resection may be performed after several courses of induction chemotherapy, when the tumor issmaller and less invasive.

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

o Consolidation in HR Neuroblastoma:

Time: after tumor bulk has been decreased by chemotherapy and surgery. Type: the consolidation phase includes higher dose chemotherapy followed by autologous

hematopoietic stem cell rescueematopoietic stem cell rescue.o Maintenance in HR Neuroblastoma:

Aim: the final phase of therapy is geared toward eradication of minimal residual disease.

Biologic differentiation therapy (13-cis-retinoic acid) is the backbone of maintenance therapy.

High Risk NB

21

Additional immunotherapy with anti-GD2 antibodies and cytokines (GM-CSF and interleukin 2)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 significantimprovement in the two-year EF and OS rates (66 versus 46 %, and 86 versus 75 %, respectively).This therapy remains available through a non-randomized COG clinical trial pending approvalby the US Food and Drug Administration while the role of interleukin 2 is being studied in anongoing European trial.

Retinoids “ also known as 13-cis retinoic acid (RA)”are substances that are similar to vitamin A.

They are thought to help some cells mature into normal cells.

The primary indication is the treatment of severe cystic acne vulgaris but also it has been given to

children with high-risk NB after completion of consolidation therapy and in xeroderma pigmentosum cases..

The most common side effects from (RA) are muco-cutaneous: dry lips and skin. Research

suggests vitamin E supplementation in the form of alpha-tocopherol reduces the toxicity of isotretinoin

treatment in subjects with cancer (Dimery et al.; 1997).

Patients who received isotretinoin had a higher 5-year EFS than patients who received nomaintenance therapy (42% vs. 31%), although the difference was not significant.

The COG is studying, now in a non-randomized fashion, the use of monoclonal antibodytherapy with GM-CSF and interleukin-2 combined with isotretinoin following chemotherapy (YuAL et al.; 2010).

o Novel therapies

Development of new methods to treat high-risk NB is an active area of research in pediatric oncology.In general, novel treatments are given within a clinical trial because risks of such treatment are notfully known.

Immunotherapies such as anti-GD2 antibodies modified to decrease toxicities {Shustermanet al., 2010}, targeted autologous T-cells {Louis et al.; 2011}, and neuroblastoma vaccines.

Targeted therapy with drugs that act through known genetic mutations (e.g., ALK) or induceapoptosis (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 peripheralblood stem cell rescue {Matthay et al., 2007}.

Special Entities:

Treatment of Hypertension in Neuroblastoma:

Hypertension in Neuroblastoma is due to accumulation and excretion of the intermediatesHomovanillic acid (HVA) ,Vanillylmandelic acid (VMA) and dopamine due to defective catecholaminesynthesis. . Blood pressure control using Alpha blocker (phenoxybenzamine or prazosin); it inhibitpostsynaptic alpha-adrenergic receptors, causing arterial and venous dilatation and a subsequentdecrease in blood pressure.

Retinoid therapy

22

Opsoclonus-Myoclonus Syndrome (OMS):

There is no known definitive cure for OMS. However, several drugs have proven to be effective in itstreatment. Some of medication used to treat the symptoms are:

ACTH has shown improvements in symptoms but can result in an incomplete recovery withresidual deficits.

Corticosteroids (such as prednisone or methylprednisolone) used at high dosages (500 mg - 2g/day intravenously for a course of 3 to 5 days) can accelerate regression of symptoms.Subsequent very gradual tapering with pills generally follows. Most patients require high dosesfor months to years before tapering.

Intravenous Immunoglobulins (IVIg) are often used with varying results. Several other immunosuppressive drugs, such as cyclophosphamide and azathioprine, may

be helpful in some cases. Chemotherapy for NB may be effective, although data is contradictory and unconvincing at

this point in time. Rituximab has been used with encouraging results {Pranzatelli et al., 2005}. Other medications are used to treat symptoms without influencing the nature of the disease:

1. Trazodone can be useful against irritability and sleep problems2. Additional treatment options include plasmapheresis for severe,

steroid-unresponsive relapses.

Overall survival (OS) in the entire relapse population was 20%.

Prognostic factors determined at diagnosis for post relapse survival include the following: Age,INSS stage, MYCN status, Time from diagnosis to first relapse, LDH level, ploidy, andhistologic grade of tumor differentiation (to a lesser extent), Initial risk group.

MYCN amplification predicted a poorer prognosis among all stages of disease at diagnosis

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

Patients diagnosed with (INSS) stage 4 without MYCN amplification, age >18 months and highlactate (LDH) level predicted poor prognosis.

While others without MYCN amplification who are not stage 4, with hyperdiploidy had a betterprognosis than patients with diploidy in those younger than 18 months.

Among those >18 months, differentiating tumors did much better than undifferentiated andpoorly differentiated tumors.

The (COG) experience with recurrence in LR and IR NB is that the majority of recurrences can be salvaged.

The COG reported a 3-year (EFS) of 88% and an OS of 96% in IR patients and a 5-year EFS of89% and OS of 97% in LR patients {Strother et al., 2012}.

Moreover, in most patients originally diagnosed with LR or IR disease, local recurrence orrecurrence in the 4S pattern may be treated successfully with surgery and/or with moderate dosechemotherapy, without hematopoietic stem cell transplantation.

Recurrent Neuroblastoma

23

Look at risk group

versus

Look at age

Look at degree of surgical resection Look at age

Look at degree of surgical resection

Treatment algorithm in recurrentNeuroblastoma

1st look

Low risk Locoregional Metastatic

Surgery if not for chemotherapy

Favorable biology Unfavorable biology

Chemothera

<90%

Observatio

>90%

Surgery

>1 Y

Aggressive combination

chemotherapy

Observation

< 1 Y

>1 Y <1 Y

Aggressive combination chemotherapy

Observation

Not 4S pattern or the

recurrence or progression is >3

months of diagnosis.

Completely favorable, 4S

pattern, the recurrence or

progression is within 3 months

of diagnosis.

Chemotherap

Intermediate risk Locoregional > 3 M

<90%

Surgery

Observatio Chemotherapy

Metastatic

like patients with newlydiagnosed HR NB

High risk Very poor prognosis Think in clinical trials Palliative care

Chemotherapy Iodine 131-MIBG (131I-mIBG) Second autologous stem cell transplantation

(SCT).

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}.For children with recurrent or refractory NB,131I-mIBG is an effective palliative agent and maybe considered alone or in combination withchemotherapy (with stem cell rescue) in a clinicalresearch trial {French et al., 2013} [Level ofevidence: 3iiiA].

In the setting of a clinical trial: 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.

24

It is taken up by human norepinephrine transporter (hNET), which is expressed in 90% of NB.

Dose :Maximum practical weight-based dose in a phase I trial was established as 18 mCi/kg.

Toxicities:

Major: severe myelosuppression

Minor :

1-Acute toxicities were grade 1 or 2 nausea and vomiting, parotid pain, and (rarely) changesin blood pressure.

2- Late toxicities included a 12% incidence of grade 2 hypothyroidism, and the rareoccurrence of ovarian failure or MDS with acute myeloid leukemia in <5% of patients.

Effaecy: almost all of the studies reported impressive response rates in relapsed disease, and inthe largest phase II trial, 37% of patients had a partial response (PR) or complete response.

Limitations: Big expenses, severe myelosuppression.

In normal human tissues, GD2 expression is weak and restricted to neurons, melanocytes, andperipheral pain fibers .

Thus, GD2 is an ideal antigen target for immunotherapy of NB. Three first-generation[monoclonal antibodies (mAb) 14G2a, ch14.18, and 3F8] and 3 second-generation (Hu14.18-IL-2,hu14.18K332A, and mAb1A7) GD2-directed antibodies have been investigated forimmunotherapy of NB.

Eligible patients were randomized after stem cell transplantation to 6 cycles of isotretinoin(standard) or isotretinoin with 5 intercalated cycles of ANTIGD2 combined with GM-CSF or IL-2in alternating cycles (immunotherapy).

The immunotherapy group also showed significantly higher OS (86% ± 4% vs. 75% ± 5% at 2years; P = 0.0223).

An orally bioavailable ATP-competitive 2,4-pyrimidinediamine derivative .

It is efficacy against ALK-rearranged tumors such as NSCLC and inflammatory myofibroblastictumor.

Phosphoinositide-3-kinase/Akt (protein kinase B, PKB)/ mammalian target ofrapamycin(PI3K/Akt/mTOR) a pathway known to drive oncogenic stabilization of MYCNprotein .

Thus a significant majority of high-risk patients are defined by altered expression or stabilizationof MYCN and could potentially be targeted using clinically available PI3K/mTOR inhibitorsalready in early phase trials.

Targeted Therapy in Neuroblastoma

131I-metaiodobenzylguanidine (MIBG)

ANT GD2

Targeting mutated ALK in NB Crizotinib

Anti MYCN