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

Kellie J. Nazemi, MD Pediatric Neuro-Oncology Advanced Topics in Cancer Biology May 4, 2009. Pediatric Brain Tumors Wanted: inquisitive scientists seeking a challenge. Objectives. Classification Epidemiology Clinical Presentations General Treatment Principles Tumor Biology.

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

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  1. Kellie J. Nazemi, MD Pediatric Neuro-Oncology Advanced Topics in Cancer Biology May 4, 2009 Pediatric Brain Tumors Wanted: inquisitive scientists seeking a challenge

  2. Objectives • Classification • Epidemiology • Clinical Presentations • General Treatment Principles • Tumor Biology

  3. CNS Cell Types NEURONS GLIA CHOROID PLEXUS

  4. 4th Edition, 2007 David N. Louis Hiroko Ohgaki Otmar D. Wiestler Webster K. Cavenee

  5. Glial Astrocytoma Oligodendroglioma Ependymoma Neuronal Medulloblastoma Pineoblastoma sPNET Choroid Plexus Choroid plexus papilloma Choroid plexus carcinoma Germ-cell Tumors Germinoma Non-germinoma (NGGCT) Craniopharyngioma CNS Tumor Classification Note: this is extremely un-official & only applies to common childhood tumors

  6. 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

  7. 27%

  8. 19%

  9. 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 inPediatric CNS Tumors . Edited by Gupta, Banerjee, Haas-Kogan, 2004.

  10. X X X X X X

  11. Objectives • Classification • Epidemiology • Clinical Presentations • General Treatment Principles • Tumor Biology

  12. Presenting Symptoms Depend on Location

  13. Signs & Symptoms • Increased intracranial pressure • Localized symptoms www.osteodoc.com www.jupiterimages.com

  14. Ventricular System & CSF flow www.pressenter.com

  15. Hydrocephalus Patient with hydrocephalus Patient with normal pressure

  16. Increased intracranial pressure • Headaches • Vomiting • Papilledema • Mental status changes • Cushing’s Triad • Bradycardia • Irregular respirations • hypertension

  17. 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 1991;10:31-46. • 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

  18. Headache in brain tumor patients The presenting features of brain tumors: a review of 200 cases. Arch Dis Child 2006; 91:502-506. The Childhood Brain Tumor Consortium. The epidemiology of headache among children with brain tumors. J Neurooncol 1991;10:31-46. • > 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

  19. Increased intracranial pressure • Macrocephaly in infants • Irritability • Lethargy • Poor feeding www.fleshandbones.com www.simulconsult.com

  20. Localized Signs & Symptoms www.neurophys.com

  21. 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

  22. Other localized signs • Parinaud Syndrome • Upgaze paralysis • Poor pupillary constriction • Convergence retraction nystagmus http://www.mrcophth.com/movie2/parinaudsyndrome.WMV

  23. Other localizing signs: seizures Practice parameter: Evaluating a first non-febrile seizure in children. Neurology 2000; 55:616-623. • Indication for MRI after seizure • Urgent imaging • Post-ictal focal deficit (Todd’s 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 < 1 year

  24. Objectives • Classification • Epidemiology • Clinical Presentations • General Treatment Principles • Tumor Biology

  25. Brain Tumor Therapy • Surgical resection • Radiation therapy • Chemotherapy

  26. 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…

  27. 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 …

  28. Which tumors are chemosensitive? • Germinoma • NGGCT • Medulloblastoma • PNET • AT/RT • CPC • Low-grade glial • High-grade glial • Ependymoma • Craniopharyngioma • DNET • CPP SENSITIVE RESISTANT

  29. The worst side effects • Second malignancies • XRT: meningiomas & GBMs • Alykylators & etoposide: leukemias • Neurocognitive deficits • High-frequency hearing loss • Platinums • Difficulty with fertility • alkylators

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

  31. 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 (>50%) A.Broniscer, Ped Blood Cancer 2003 • Germ cell tumors (~33%) S.Modak, JCO 2004

  32. Borrowed from Herrington B, Kieran MW

  33. Objectives • Classification • Epidemiology • Clinical Presentations • General Treatment Principles • Tumor Biology

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

  35. Migration problems contribute • Germ cell tumors universe-review.ca

  36. 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

  37. 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

  38. Medulloblastoma & Sonic Hedgehog

  39. Medulloblastoma & Sonic Hedgehog Shh Medulloblastoma HSPG Shh & HSPG graphics added

  40. 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)

  41. Cytogenetic & molecular features implicated in medulloblastoma formation • PAX family • HER 2 & HER 4 • PDGFRa & downstream RAS/MAPK • Many other candidates

  42. The future of stratification 2002: Pomeroy Nature • Medulloblastoma profile • Risk stratification • Integration into therapy 2004: Fernandez-Teijeiro. J Clin Oncol

  43. CNS embryonal neoplasm with loss of INI-1 expression :atypical teratoid/rhabdoid tumor INI-1 staining images courtesy of Alex Judkins, MD

  44. Atypical Teratoid/Rhabdoid Tumor

  45. 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

  46. Truncating Arg 511 stop mutation: exon 5 of hSNF/INI-1

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