Peadiatric Brain Tumour

Peadiatric Brain Tumour Wong Ann Cheng MD (UKM) MRCPCH (UK)

Normal Anatomy of Brain (MRI) • Supratentorial compartment: – – – – – –

Cerebral hemispheres Basal ganglia Thalamic nuclei Lateral ventricles Hypothalamus Corpus callosum

Sagittal

• Infratentorial compartment: – Cerebellum – Brain stem (MB/P/MO) – 4th ventricle Axial

Epidemiology • 2nd most common pediatric malignancy – 2.4-4.1 cases / 100000 children – About 2000 new cases / year

• Leading cause of cancer death • More common in males (M:F = 1.29) • Children 1-11years old – Majority arises infratentorially

Cancer research UK

Epidemiology • Classified by histology • Medulloblastoma most common malignant brain tumour • Low grade astrocytoma most common benign brain tumour

Table :   Relative Incidence of Common Brain Tumors in Children Relative Frequency 

Peak Age Group (years) 

Astrocytoma    -Supratentorial    -Infratentorial

35% 22% 13%

2-10 >6 2-10

Malignant glioma  (anaplastic astrocytoma  and glioblastoma  multiforme)

8%

<1, >6

Brain stem glioma

8%

3-9

Oligodendroglioma

2%

<6

Medulloblastoma

20%

1-10

Ependymoma    -Supratentorial    -Infratentorial

8% 5% 3%

  >6 1-5

Craniopharyngioma

7%

8-14

Diagnosis

Pineal region and germ cell  4% tumors

<2, >6

Choroid plexus tumors

2%

<1

Others: ganglioglioma,  meningioma,  neuroblastoma, primitive  embryonal tumors

<2% each

 

Etiology • Largely unknown • Certain inherited familial syndromes associated with predisposition to brain tumours • Other predisposing factors include certain immunodeficiencies and exposure to ionizing radiation • Other environmental exposure e.g parental occupation, diet, magnetic field inconclusive

Inherited familial syndrome Inherited Familial Syndrome

Brain Tumour

Neurofibromatosis type 1

Optic pathway glioma, astrocytoma Acoustic neuroma, meningioma, ependymoma Subependymal giant cell tumour, ependymoma Astrocytoma, medulloblastoma medulloblastoma

Neurofibromatosis type 2 Tuberous sclerosis Li-Fraumeni Nevoid basal cell carcinoma Turcot Von Hippel Landau

Medulloblastoma, astrocytoma haemangioblastoma

Clinical presentation • Dictated by location rather than histology • Generalized sx caused by increased ICP, usu results frm CSF obstruction or SOL within fixed skull • Likely to occur with tumours in posterior fossa, pineal, suprasellar or tectal region • Sx include headache (esp morning), nausea, vomiting, and fatigue • Neurological findings include decreased upward gaze, 6th CN palsy, and papiloedema • Macrocephaly, FTT, and developmental delay common in infants

Clinical presentation Tumour location

Localizing symptoms

Cerebral hemisphere

Seizures Hemiparesis Visual field deficits Change behaviour/ school performance

Suprasellar region

Visual field deficit Endocrinopathy Weight gain

Pineal region

Parinaud’s syndrome -impaired upward gaze -convergence nystagmus -Light near dissociation

Cerebellum

Ataxia Dysmetria

Brain stem

CN deficits Long tract signs

Spinal cord

Back pain Extremity weakness Sensory dysfunction Bowel/ bladder dysfunction

Diagnostic test • Neuroimaging – CT • Useful as quick screen • Hydrocephalus, blood, calcification

– MRI • Gold standard • Post-op scan within 24-48 hrs of resection

– MR spectrometry – PET

• CSF cytology • Tumour markers – AFP and β-hCG – For germ cell tumour

• Bone marrow aspirate or biopsy

Differential diagnosis Location

Differential diagnosis

Cerebral hemisphere

Glioma Ependymoma PNET

Suprasellar region

Craniopharyngioma Glioma Germ cell tumour Pituitary adenoma

Pineal region

Germ cell tumour Glioma Pineoblastoma

Cerebellum

Pilocystic astrocytoma Medulloblastoma Ependymoma

Brain stem

Glioma

Spinal cord

Astrocytoma Ependymoma

Treatment modalities • Surgical resection • Radiation therapy • Chemotherapy

Late effects of treatment • • • • • •

Neurocognitive (age and dose related) Endocrinopathies Radiation necrosis Stroke Hearing loss Secondary tumours – Meningioma, glioma, sarcoma – leukaemia

Infant brain tumours • 20% paediatric brain tumours • Age < 1 year old: more likely supratentorial • Presentation: – – – – –

Macrocephaly FTT Lethargy Vomiting Development delayed or loss of milestones

• Tumour types – – – – –

PNET Low grade glioma Ependymoma Malignant glioma Atypical teratoid/ rhabdoid tumour – Choroid plexus tumour

Infant brain tumours • Treatment – Radiotherapy • Assoc with significant long term toxicity (neurocognitive, endocrine,..)

– Chemotherapy • Initially designed to delay radiotherapy • Has resulted in cures in some patients in whom radiotherapy was deferred • 3-5 years PFS: 23-30%

• Future directions – Dose intensification of therapy • High dose radiotherapy with stem cell rescue

– Intrathecal chemotherapy – New agents – Focused radiotherapy • To limit toxicity to normal brain

Medulloblastoma • Most common CNS malignancy in childhood • Medulloblastoma = posterior fossa PNET – – – – –

20% primary CNS tumour 40% posterior fossa tumour 72% of PNETs Mean age of presentation: 3-4 years More common in males (M:F = 2:1)

• Very invasive – CNS manifestation in 11-43% at presentation – Extraneural spread rare (BM, LN, liver, lung)

Usually midline Hypointense T1 Isointense T2 Enhancing

Propensity to disseminate Imaging of the spine Lumbar puncture for CSF

PNET/MB Prognostic factors (High-risk features) • • • • •

Residual tumour (>1.5 cm2) Patient age (<3 years old) Location (supratentorial) Metastasis (+) Molecular markers – 17p deletion – C-myc amplification – Increased HER2/HER4 coexpression – Low TrkC

PNET/MB staging Standard risk

High risk

Age

>= 3 years

< 3 years

Location

Cerebellum

Supratentorial

Residual tumour < 1.5 cm2

>= 1.5 cm2

Metastases

yes

no

PNET/MB therapy • Surgery • Radiotherapy – Local: 5400- 5940 cGy – Craniospinal: • High risk: 3600 cGy • Standard risk: 2340 cGy

• Chemotherapy (active agents) – Vincristine, lomustine, cisplatin, etoposide, cyclophosphamide

With current therapy approaches, 3-5 year progression free survival • • • • •

Standard risk medulloblastoma 86% 3 yr PFS High risk medulloblastoma 67% 5 yr PFS Infant with PNET/MB 30% 5 yr PFS Pineal PNETs 61% 3 yr PFS Non-pineal supratentorial PNETs 33% 3 yr PFS

PNET/MB new directions • High risks – Goal: improve survival – Radiation enhancers – Chemotherapy dose intensification

• Standard risks – Goal: reduce toxicity, maintain efficacy – Reduce craniospinal dose to 1800 cGy – Limit radiation boost field

Ependymoma • • • •

8-10% of childhood brain tumours Most occur in children <7 years 60% infratentorial 2-5% dissemination at diagnosis

MRI Hypointense T1 Hyperintense T2 Strongly enhancing

Often have necrosis, haemorrhage, calcification heterogenous

Ependymoma prognostic factors (high risks features) • Extent of resection – Complete: 50-70% 5yr PFS – Incomplete: 0-30% 5yr PFS

• • • •

Histology (anaplastic) Metastases (+) Age (<3 years) Location (infratentorial)

Ependymoma therapy • Surgery- aggressive resection • Radiation – Focal: 5400-5940 cGy – Craniospinal: if metastatic disease

• Chemotherapy – Several active agents – Minimal impact on survival – Used in recent trials to shrink tumour

• Observation – May be feasible for supratentorial well-differentiated tumours

Glioma-astrocytoma grading Grade

Histology

Low grade (benign)

I II

Pilocytic astrocytoma Fibrillary astrocytoma

High grade (malignant)

III IV

Anaplastic astrocytoma Glioblastoma multiforme

Low grade glioma • Most common paediatric brain tumour • Locations – – – –

Cerebellum Cerebral hemisphere Deep midline structures Optic pathway/ hypothalamus

• MRI – Hypointense T1, hypeintense T2 – Pilocytic: well circumcribed, cystic component, enhancing mural nodule – Fibrillary: little enhancement

Posterior fossa low grade glioma • Histology – 80-85% pilocystic astrocytoma

• Treatment – Surgery primary therapy • Complete resection: 100% 10 yr survival • Subtotal resection: 35-65% 5 yr survival

• Management of residual tumour – Observation – Re-resection – Radiotherapy • STR + XRT: 70-92% 5 yr survival

Optic pathway/ hypothalamic glioma • • • • • •

5% of paediatric tumour 2/3 diagnosed before age of 5 y.o 70% assoc with NF1 15% kids with NF1 have OP/HG Diagnosis often by MRI alone (esp if NF1) Most are fibrillary astrocytomas, although pilocystic astrocytomas are common as well

Optic nerve tumour

OP/HG treatment • Surgery not often pursue because of likelihood of further compromise in vision • Observation – Justification: tumor and vision may stay stable for years – Serial MRI and ophthalmology exams

• Radiotherapy – 53-88% PFS – Assoc with significant toxicity

• Chemotherapy – Attempt to delay or eliminate need for radiation – Vincristine/ carboplatin: 78% 5yr survival – TPCV: 68% 3 yr survival

Supratentorial malignant glioma • 11% paediatric brain tumour • MRI – Heterogenous (necrosis and haemorrhage) – Enhancing

• Staging – Consider spinal imaging and cytology

• Molecular alteration – P53 pathway abnormalities – EGFR overexpression

Brainstem glioma • 10-20% peadiatric brain tumour • Median age diagnosis 6.5 years • Types: – Diffuse intrinsic – Dorsally exophytic – Cervicomedullary – Focal midbrain

Diffuse intrinsic BSG • 80% of brain stem tumour • Most arise in the pons • Presentation – CN deficits (usu VI and VII) – Hemiparesis – 10% with hydrocephalus

• Pathology- high grade glioma

Hypodense T1 Hyperdense T2 Little enhancement

Prognostic factors unfavourable • • • •

Short duration of symptoms at diagnosis CN deficits at diagnosis Pontine location Age < 2 years old

Assoc with NF1 confers survival advantage

Treatment –diffuse intrinsic BSG • Surgery – No role – Biopsy rarely needed

• DXT – 54-55.8 Gy – Prolongs survival – Neurologic improvement

• Chemotherapy – Nothing useful so far

• Survival – Median 9-13 months – 2 year survival <20%

Germ cell tumours • 3-5% of paediatric brain tumours in US, 15-18% in Asia • Peak age incidence 10-15 years • Location: 2/3 pineal, 1/3 suprasellar • Pathology: – Germinoma (60%) – NGGCT • • • • •

Mature and immature teratoma Yolk sac tumour Choriocarcinoma Embryonal carcinoma Mixed GCTs

Germ cell treatment Mature teratoma - Resection alone Germinoma •Radiotherapy - 90% 5 year survival - Ventricular volume with tumour bed boost - CSI for disseminated dis •Chemotherapy - Explored to reduce radiation dose and field

Malignant NGGCT •Radiotherapy - CSI + involved field boost - 20-56% 3 year survival •Chemotherapy - no standard approach - has improved survival to 74% in 4 years

Craniopharyngioma •6-9% of paediatric brain tumours •Over 50% of suprasellar tumours •Peak incidence 6-10 yrs •Benign histology

MRI -Heterogenous with cystic, solid, calcified component -Hyperintense on T2, enhancing Work Up -Hormone testing -Ophthalmologic evaluation (acuity and fields)

Treatment- craniopharyngioma • Surgery – Primary modality – Complete resection  improved PFS

• Radiotherapy – Subtotal resection + radiation • survival similar with complete resection

• Prognosis – 60-80% 5yr PFS – 95% 5 yr OS

• Multidisciplinary follow up – Neuro-oncology, ophthalmology, endocrinology

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