Kellie J. Nazemi, MD

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Pediatric Brain Tumors Wanted inquisitive
scientists seeking a challenge

• Kellie J. Nazemi, MD
• Pediatric Neuro-Oncology
• Advanced Topics in Cancer Biology
• May 4, 2009

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Objectives

• Classification
• Epidemiology
• Clinical Presentations
• General Treatment Principles
• Tumor Biology

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CNS Cell Types
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4th Edition, 2007 David N. Louis Hiroko
Ohgaki Otmar D. Wiestler Webster K. Cavenee
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CNS Tumor Classification

• Germ-cell Tumors
• Germinoma
• Non-germinoma (NGGCT)
• Craniopharyngioma

• Glial
• Astrocytoma
• Oligodendroglioma
• Ependymoma
• Neuronal
• Medulloblastoma
• Pineoblastoma
• sPNET
• Choroid Plexus
• Choroid plexus papilloma
• Choroid plexus carcinoma

Note this is extremely un-official only
applies to common childhood tumors
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Epidemiology Kids are different

• Incidence significantly lower
• ADULTS (20 yr) 21.3 per 100,000 person-yrs
• KIDS (0 19yr) 4.5 per 100,000 person-yrs
• Location is different
• Histology is different

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Brain Tumors in Children
Approximately 2,000 per year in United
States Most common solid tumor in children
Germ Cell Tumor
Ependymoma
Craniopharyngioma
Choroid Plexus Tumor
Medulloblastoma
Low-Grade Glioma
High-Grade Glioma
Approximated from text in Pediatric CNS Tumors .
Edited by Gupta, Banerjee, Haas-Kogan, 2004.
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Objectives

• Classification
• Epidemiology
• Clinical Presentations
• General Treatment Principles
• Tumor Biology

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Presenting Symptoms Depend on Location
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Signs Symptoms

• Increased intracranial pressure
• Localized symptoms

www.osteodoc.com
www.jupiterimages.com
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Ventricular System CSF flow
www.pressenter.com
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Hydrocephalus
Patient with hydrocephalus Patient with
normal pressure
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Increased intracranial pressure

• Headaches
• Vomiting
• Papilledema
• Mental status changes
• Cushings Triad
• Bradycardia
• Irregular respirations
• hypertension

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Headache in brain tumor patients
Headaches in Children and Adolescents. Lewis DW,
Curr Probl Pediatr Adolesc Health Care, July
2007. The Childhood Brain Tumor Consortium. The
epidemiology of headache among children with
brain tumors. J Neurooncol 19911031-46.

• Overall gradually worsening
• Timing when recumbent
• Location occipital red flag
• Associated symptoms
• Vomiting with relief
• Dizziness (unsteady or vertigo)
• Personality change or school problems
• Triggered by straining
• Numbness or weakness

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Headache in brain tumor patients
The presenting features of brain tumors a review
of 200 cases. Arch Dis Child 2006
91502-506. The Childhood Brain Tumor Consortium.
The epidemiology of headache among children with
brain tumors. J Neurooncol 19911031-46.

• gt 98 have abnormal
• Mental status
• Optic discs
• Eye movement
• Motor exam (hemiparesis)
• Tandem gait OR
• Deep tendon reflexes
• The rest have seizures!

www.eyesite.ca
www.eyetec.net
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Increased intracranial pressure

• Macrocephaly in infants
• Irritability
• Lethargy
• Poor feeding

www.fleshandbones.com
www.simulconsult.com
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Localized Signs Symptoms
www.neurophys.com
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Localized Signs / Symptoms

• 6th nerve palsy
• Double vision
• Nystagmus
• Ataxia
• 4th nerve palsy
• Superior oblique muscle
• Vertical diplopia worse looking down
• Head tilt

http//www.mrcophth.com/movie2/6thnervepalsy.WMV
www.mayoclinicproceedings.com
www.emedicine.com
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Other localized signs

• Parinaud Syndrome
• Upgaze paralysis
• Poor pupillary constriction
• Convergence retraction nystagmus

http//www.mrcophth.com/movie2/parinaudsyndrome.WM
V
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Other localizing signs seizures
Practice parameter Evaluating a first
non-febrile seizure in children. Neurology 2000
55616-623.

• Indication for MRI after seizure
• Urgent imaging
• Post-ictal focal deficit (Todds paralysis) not
  resolving
• Patient not returned to baseline within several
  hours
• Non-urgent imaging
• Cognitive or motor impairment
• Abnormal neurologic exam
• Partial/focal onset of seizure
• EEG not consistent with
• Benign partial epilepsy of childhood
• Primary generalized epilepsy
• Age lt 1 year

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Objectives

• Classification
• Epidemiology
• Clinical Presentations
• General Treatment Principles
• Tumor Biology

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Brain Tumor Therapy

• Surgical resection
• Radiation therapy
• Chemotherapy

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Complete resection is critical in

• Ependymoma
• Choroid plexus tumors
• AT/RT
• Low-grade glial tumors
• High-grade glial tumors
• Craniopharyngioma

Complete resection is important in
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Incomplete resection is tolerable in

• Medulloblastoma
• DNET
• Intrinsic pontine glioma
• Optic pathway glioma
• Neurofibromatosis Type I
• Suspected neoplasms
• Myelin vacuolization
• Germinoma
• Non-germinomatous germ cell tumors
• Chemotherapy initial, surgery for residual
• (except teratoma)

Surgery is often wrong approach in
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Which tumors are chemosensitive?

• Germinoma
• NGGCT
• Medulloblastoma
• PNET
• AT/RT
• CPC
• Low-grade glial

• High-grade glial
• Ependymoma
• Craniopharyngioma
• DNET
• CPP

• SENSITIVE

• RESISTANT

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The worst side effects

• Second malignancies
• XRT meningiomas GBMs
• Alykylators etoposide leukemias
• Neurocognitive deficits
• High-frequency hearing loss
• Platinums
• Difficulty with fertility
• alkylators

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Strategies in recurrence

• High-dose chemo with stem cell rescue
• Experimental clinical trials
• Small molecule inhibitors
• OHSU IA/BBBD
• Anti-angiogenic regimens
• Palliative care

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High-dose chemotherapywith autologous stem cell
rescue (transplant)

• Goal MORE CHEMO TO TUMOR
• Marrow ablation is unwanted side effect
• Compared to leukemia transplant
• Stem cell rescue necessary for recovery
• Stem cells harvested prior to HDC
• Best with minimal residual disease
• Good outcomes published
• Medulloblastoma (25) I.Dunkel, JCO 1998
• PNET (gt50) A.Broniscer, Ped Blood Cancer 2003
• Germ cell tumors (33) S.Modak, JCO 2004

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Borrowed from Herrington B, Kieran MW
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Objectives

• Classification
• Epidemiology
• Clinical Presentations
• General Treatment Principles
• Tumor Biology

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Migration problems contribute

• Craniopharyngioma

Week 4 Week 6 squamous cell
rests
www.cytochemistry.net (modified)
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Migration problems contribute

• Germ cell tumors

universe-review.ca
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Underlying Disorders contribute

• Neurocutaneous Syndromes
• Neurofibromatosis Type I
• NF1 mutations (17q11.2) ? optic gliomas
• Neurofibromatosis Type II
• NF2 mutations (22q12) ? schwannomas, mengiomas,
  gliomas
• Tuberous Sclerosis Complex
• TSC1 (9q34) or TSC2 (16p13.3) mutations ? SEGA
• Von Hippel-Lindau Disease
• VHL mutations (3p25-26) ? hemangioblastomas

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Underlying Disorders contribute

• Familial genetic disorders
• Li Fraumeni Syndrome
• TP53 germline mutation (17p13) ? majority
  astrocytic
• Turcot Syndrome
• Mismatch repair gene mutations ? GBM medullo
• Cowden Syndrome
• PTEN germline mutation (10q23) ? gangliocytoma
• Nevoid basal cell carcinoma syndrome (Gorlin
  Syndrome)
• PTCH germline mutations (9q22) ? medullo
• Rhabdoid Tumor Predisposition Syndrome
• INI-1 constitutional loss or inactivation
  (22q11.2) ? AT/RT

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Medulloblastoma Sonic Hedgehog
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Medulloblastoma Sonic Hedgehog
Shh
Medulloblastoma
HSPG
Shh HSPG graphics added
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Cytogenetic molecular features associated with
medulloblastoma outcome

• GOOD PROGNOSIS
• Hyperdiploidy (Gajjar et al. 1993)
• High trkC expression (Grotzer et al. 2000 Kim et
  al. 1999)
• POOR PROGNOSIS
• Isolated 17p loss of heterozygosity (Gilbertson
  et al. 2001)
• Elevated erbB2 expression (Gilbertson et al.
  2001)
• Elevated c-myc expression Scheurlein et al. 1998)
• Overexpression of calbindin-D28 k (Pelc et al.
  2002)

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Cytogenetic molecular features implicated in
medulloblastoma formation

• PAX family
• HER 2 HER 4
• PDGFRa downstream RAS/MAPK
• Many other candidates

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The future of stratification
2002 Pomeroy Nature

• Medulloblastoma profile
• Risk stratification
• Integration into therapy

2004 Fernandez-Teijeiro. J Clin Oncol
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CNS embryonal neoplasm with loss of INI-1
expression atypical teratoid/rhabdoid tumor
INI-1 staining images courtesy of Alex Judkins,
MD
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Atypical Teratoid/Rhabdoid Tumor
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AT/RT Genetics

• 90 with monosomy 22 or deletion of 22
• INI-1 hSNF5 SMARCB1 BAF47
• Maps to 22q11.2
• Ubiquitously expressed nuclear protein
• Member of ATP-dependent SWI-SNF
  chromatin-remodeling complex
• Tumor supressor
• Germline mutations have been detected
• Risk for synchronous renal or extra-renal tumors

images courtesy of Alex Judkins, MD
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Truncating Arg 511 stop mutation exon 5 of
hSNF/INI-1
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Objectives

• Classification
• Epidemiology
• Clinical Presentations
• General Treatment Principles
• Tumor Biology
• Journal Review Plans

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Text references

• Pediatric CNS Tumors. Gupta N, Banerjee A,
  Haas-Kogan D (eds). Springer 2004.
• WHO Classification of Tumours of the Central
  Nervous System. Louis D, Ohgaki H, Wiestler O,
  Cavenee W (eds). 2007, 3rd edition.
• Central Brain Tumor Registry of the United States
  (CBTRUS) 2007 2008. Primary Brain Tumors in the
  United States Statistical Report. Data Collected
  2000 2004.

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Brain Tumor Expertise Doernbecher Childrens
Hospital
Surgery Radiation Oncology Neurology
Endocrine Nathan Selden Carol Marquez Kellie
Nazemi Tom Koch Lisa Madison Daniel
Guillaume Stacy Nicholson Amy Kao Wendy
Domreis Thomas Lamkin Colin Roberts Laurie
Yablon Kathy Perko Neuro-radiology
Neuro-Ophthalmology Neuro-Pathology Jim
Anderson Julie Falardeau Marjorie
Grafe Dianna Bardo William Hills Hume
Gultekin Randy Woltjer Medical Social
Workers, PT, OT, School Teachers,
Neuropsychology, CRA
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Journal Review Plan
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Journal Review Plan
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Journal Review Plan