Sariu Ali: Introduction, CNS Tumors, Neuroblastoma

Mohammed Farhan: Neproblastoma, Retinoblastoma, sarcomas, others

Solid tumors of Childhood

Introduction

Second commonest cause of death in children (5-14 yo) in developing countries

Adults tumors are epitheilai in orifgin

More than 11 million people are diagnosed with cancer anually. <2% occur in children

SOLID TUMORS IN CHILDHOOD

Brain Adrenal medulla & Sympathetic nervous system

Kidney Bone

Medulloblastoma

Astrocytoma

Glioma

Ependymoma

NeuroblastomaNephroblastoma (Wilm’s tumor)

Ewing’s sarcoma

Osteosarcoma

Liver

Hepatocellular carcinoma

Hepatoblastoma

CNS Tumors

Almost always primary

Primary central nervous system (CNS) tumors are second most frequent malignancy in childhood and adolescence.

Mortality among this group approaches 45%.

Generally multimodal Rx. has improved over years due to advances in neurosurgery ,radiation and chemotherapy.

Etiology• Not well defined• Hereditary and familial syndromes in 5%• Exposure to ionizing radiation• Sporadic in some cases

Syndrome (all Autosomal Dominant)

CNS manifestation

Neurofibromatosis 1

Optic pathway gliomas, astrocytoma, malignant peripheral nerve sheath tumors (MPNST), neurofibromas

Neurofibromatosis 2

Vestibular schwannomas, meningiomas, spinal cord ependymoma, spinal cord astrocytoma, hamartomas

von Hippel-Lindau Hemangioblastoma

Tuberous sclerosis Subependymal giant cell astrocytoma, cortical tubers

Li-Fraumeni Astrocytoma, PNET

Cowden Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease)

Turcot Medulloblastoma, Glioblastoma

CNS Tumors

TypesCNS Tumors

Gliomas―Astrocytomas ―Brain stem gliomas―Epandymoma―Optic glioma

Prirmitive Neuroendocrine Tumors (PNET)/ Medulloblastoma Craniopharyngioma Pineal region tumors Choroid plexus tumors germ cell tumors meningioma

Tumor locations CNS Tumors

Infra tentorial (43.2%)Supra tentorial (40.9%)Spinal cord ( 4.9%)Multiple sites ( 11%)

IncludesAstrocytoma (40%)Medulloblastoma (20%)Ependyoma ( 8%)Brain stem glioma (6%)Craniopharyngioma (4%)

Tumor locations CNS Tumors

The relative frequency of brain tumor histologic types and the anatomic distribution are shown.

Age related differences CNS Tumors

0- 12 months Most are supra tentorial (choroid plexes complex tumors, teratomas)

1-10 years Most are infra tentorial (Juvenile pilocytic astrocytoma,medulloblastoma)

>10years Supra tentorial tumors (diffuse Astrocytoma)

Children/ adolescents

Have more tumors of optic pathway, hypothalamus, brainstem,pineal-med-brain than adults

Clinical presentations CNS Tumors

Clinical symptoms depend upon: Age, location, and type of tumor and grade

Increased intracranial pressure : secondary to obstruction of CSF at aqueduct :hydrocephalus (infants), headache, papilledema, vomiting

Supra tentorial tumors

A/w focal disorders : motor weakness , sensory weakness, speech disorders, seizures, reflex abnormalities

Infra tentorial tumors

Disorders of equilibrium, gait, coordinationBlurred vision, diplopia, nystagmus , increasedICPvomiting (usually occurs in the morning without nausea)

Brain stem tumors Gaze palsy/CN palsiesUMN Disorders ( hemiperesis, hyperreflexia, clonus)

WHO classification CNS Tumors

Based on morphology , cytogenetics ,molecular

genetics, immunologic markers

>100 histological categories and subtypes

5 types account for 80% juvenile pilocytic astrocytomaMedullobalstoma/PNET Diffuse AstrocytomaEpandymoma Craniopharyngioma

ASTROCYTOMAS CNS Tumors

•WHO grade I tumor. • the classic site of presentation is the cerebellum•The classic neuroradiologic findings of JPA are the presence of an enhancing nodule within the wall of a cystic mass • JPA has a low metastatic potential and is rarely invasive.

Astrocytomas are the most common pediatric brain tumors and comprise 40% of cases. occur throughout the CNSJuvenile pilocytic astrocytoma (JPA) is the most common astrocytoma in children, comprising 20% of all brain tumors.

Juvenile pilocytic astrocytoma

Juvenile pilocytic astrocytomaCNS Tumors

WHO grading CNS Tumors

WHO grade I Low proliferative potential

WHO grade II Infiltrating but low in mitotic activityCan recur and progress to other grades

WHO grade III Histological evidence of malignancy(mitotic activity), infiltrative, anaplastic

WHO grade IV Mitotically active, necrosis, rapid pre and post surgical progression

commonly used for astrocytomaThe WHO-grading scheme is based on the appearance of certain characteristics:  atypia,mitosis, endothelial proliferation and necrosis.

DiagnosisCNS Tumors

History PE (careful neurological examination, visual fields and a fundoscopic examination) MRISerum and CSF ß-HCG, a-FP for germ cell tumors

LP: medulloblastoma/PNET, ependymoma, germ cell tumors that spread to the leptomeninges

LP contraindicated if newly dx’d hydrocephalus d/t CSF outflow obstruction or infratentorial tumors

ManagementCNS Tumors

Treatment – Multimodal

Dexamethasone

Reduce cerebral edema around tumor

Surgery for histology, debulking, resecting, re-establishing CSF flow

VP shunt

Radiation

for CSF but malfxns and infxns Typically 5d/wk for 5-6wk. Depends on age (try to defer in infancy d/t reduce intellectual fxn), and SE’s (reduced appetite, risk of stroke years later, short stature, scoliosis..)

Chemotherapy

usually > 1 drug better

NEUROBLASTOMA • Embryonic cancer of peripheral sympathetic nervous

system• Most common extracranial solid neoplasm of childhood: • 8 % of all childhood cancers • Approximately 600 new cases in the U.S. annually• Slightly more common in males than females.• Median age at diagnosis is approximately 22 months,

89% of new patient diagnoses occurring under the age of 5 years.

• No clear environmental predisposition.

Neuroblastoma

• Etiology unknown

• Famillial Neuroblastoma (1-2% of cases)

• Neuroblastoma cells may acquire specific genetic

alterations which are of prognostic importance

(amplification of N-myc gene)

• Most cases in abdomen (adrenal gland or

retroperitoneal sympathetic ganglia)

• Others originate from cervical, thoracic and pelvic

ganglia

Pathogenesis/Genetics

Neuroblastoma

• Primary tumors occur in abdomen (65%), thoracic (19%), pelvic (2%), cervical (1%), other (12%).

• Cervical/thoracic disease more common in infants <1 yo, adrenal disease more common in >1 yo.

• In patients less than 1 yo, local tumor only (39%), regional lymphatic spread (18%), metastases (25%), IV-S (18%).

• In patients greater than 1 yo, local tumor (19%), regional (15%), metastases (52%), IV-S (0%).

Clinical Features

Neuroblastoma

Abdominal masses : Firm nodular mass in flank causing abdominal discomfort,

venous and/or lymphatic obstruction with lower extremity and/or scrotal edema, hypertension from compression of renal vasculature.

High thoracic/cervical masses : Horner’s syndrome-ptosis, myosis, anhydrosis,Superior vena cava (SVC) syndrome tumors.

paraspinal tumors:Compression of nerve root/spinal cord with radicular pain, paraplegia, bowel/bladder dysfunction.

Clinical Features Local mass effect

Neuroblastoma

Clinical Features Hormonal release (catecholamine overproduction)

Hypertension, flushing, tachycardia, diaphoresis

Metastasis • Proptosis/periorbital ecchymoses (“raccoon eyes”) from orbital metastatic involvement.

• “Blueberry-muffin” skin nodules.• Hematologic cytopenias secondary to

marrow involvement.

Raccoon eyes caused by obstructionpalpebral vessels by mets around eyesDelayed diagnosis: Child abuse/Trauma

9 months femaleFailure to thrivePeriorbital ecchymosis“Raccoon Eyes”Dysconjugate gazeDilated fixed pupils

T1 MRI extensive mets to base of skullSphenoid/temporal/zygomatic bones

Neuroblastoma

• Bone marrow (70.5%)• Bone (55.7%)• Lymph node (30.9%)• Liver (29.6%)• Intracranial/orbital (18.2%)• Lung (3.3%)• CNS (0.6%)

Common sites of metastasis

Neuroblastoma Clinical Features

Opsoclonus-myoclonus-ataxia syndrome (OMA)

•Myoclonic-jerks of limbs/trunk, random eye movements, ataxia •Seen in approximately 2-3% of all patients with neuroblastoma •More favorable outcome with respect to tumor •Long term neurologic deficits-cognitive, motor, language, behavior •Mediated by antibodies-anti-Hu, anti-neural, anti-neurofilament Majority of tumors demonstrate pronounced lymphocyte infiltrate

Intractable secretory diarrhea

• Occurs secondary to VIP hypersecretion • Associated with dehydration, hypokalemia,

hypercalcemia • Usually associated with mature histology and

favorable outcome• Usually resolves with tumor resection

Para neoplastic syndromes

Neuroblastoma

International Neuroblastoma Staging System(INSS)

Stage Definition Incidence

1 Tumor confined to the organ or structure of origin 5

2 tumor extend beyond the structure of origin but not across the midline2A : with ipsilateral LN involvement2B : w/out ipsi LN

10

3 tumor extend beyond the midline, with or without bilateral lymph node involvement

25

4 tumor are disseminated to distant sites (e.g., bone, BM, liver, distant lymph nodes, other organs)

60

4S children <1 yr of age with dissemination to liver, skin, or BM without bone involvement and with a primary tumorthat would otherwise be stage 1, or 2.

5

Neuroblastoma

Neuroblastoma

Plain radiography of primary site

US/CT/MRI of the primary and possible metastatic sites

Single or multiple masses calcification

Urine Catecholamines Urine Homovanillic acid (HMV)Vanillyl mandelic acid (VMA)

Tumor tissue biopsy

Evaluation of metastasis FBC: pancytopenia in BM involvement LFT: liver involvement Bone marrow aspiration/ biopsyBone Scan: to rule out bone lesions

Prognosis Cytogenetic and molecualr markers on the tumor tissue Serum ferritin LDH

Diagnostic Evaluation

TYROSINE

DOPA

DOPAMINE

NOREPINEPHRINE

EPINEPHRINE

HOMOVANILLICACID (HVA)

VANILLYLMANDELICACID (VMA)

Monamine oxidaseCatechol-O-methyltransferase

Tyrosine Hydroxylase

DOPA Decarboxylase

Dopamine -Hydroxylase

PhenylethanolamineN-MethyltransferaseNB Lack this enzyme

METANEPHRINE

Catechol-O-Methyltransferase

CATECHOLAMINE METABOLISM

MYCN Genomic Amplification

• Approximately 25% of primary tumors • Associated with advanced stage + of disease, rapid tumor progression, and a poor prognosis

HSR

Double minutes

Chr 2p24

MYCN

NEUROBLASTOMA BIOLOGY: MYCN • MYCN amplification is found primarily in patients with advanced

disease, and is commonly associated with rapid disease progression and poor prognosis.

• Located on distal short arm of chromosome 2. • MYCN is a protooncogene normally expressed in developing

nervous system and other tissues. MYCN dimerizes with Max, and releases the transcriptional repression mediated by Max homodimers.

• Amplification usually results in 5-400 copies of the gene, with corresponding increases in protein expression. Co-amplified genes.

• Overexpression of MYCN increases proliferative rates in neuroblastoma cell lines in vitro.

INRG Stage Age Histology/Tumor Grade MYCN Unb 11qaberration

Ploidy Pre-treatment Risk Group

L1 GN maturing GNB intermixed

NA A Low

Any, except GN maturing or GNB intermixed

NA B Low

Amp H High

L2 GN maturing GNB intermixed

A Low

<18m Any, except GN maturing or GNB intermixed

NA No D Intermediate

Yes I High

>18m GNB nodular, differentiatingNB, differentiating

NA No E Intermediate

GNB nodular, poorly differentiated or undifferentiated

NB, poorly differentiated or undifferentiated

NA

NA

Yes

(Any)

J High

J High

(Any) Amp N Ultra-High

M <18m NA Hyperdiploid F Intermediate

Diploid G Intermediate

Amp O Ultra-High

>18m P Ultra-High

MS <18m NA No C Low

Yes K High

Amp Q Ultra-High

NEW International Neuroblastoma Risk Group (INRG) Classification Schema

From Sue Cohn, Wendy London, INRG

Neuroblastoma

• Surgery, chemotherapy, and radiotherapy. • Depending on the anticipated clinical behavior of the tumor in

individual cases considering stage, age, and tumor pathobiology.

Principle of initial Management

Surgery Goal: If performed prior to therapy:1. Establish the diagnosis.

2. Provide tissue for biologic studies. (MYCN, Genomics)

3. Stage the tumor surgically.

4. Attempt to excise the tumor without injury to vital structures.

5. In delayed primary or second-look surgery, the surgeon will determine response to therapy and remove residual disease when possible.

Radiation TreatmentNeuroblastoma is a radiosensitive tumor. May play role as adjunct to primary therapy with surgery and/or chemotherapy, for palliation of symptomatic lesions, relief of cord compression, or as preparative regimen for BMT.

Neuroblastoma

• Low-risk : surgery• Intermediate-risk : surgery + chemotherapy ±

radiotherapy• High-risk: chemotherapy +surgery +

radiotherapy

Management

• Nelson Text book of Peadiatrics 17th edition• Hand book of Hospital peadiatrics 2nd edition• Illustrated text book of paediatrics 3rd edition• National Cancer unit (US) paediatric oncology

unit report• CNS malignancies Emed

References

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