# Presentation: 024043

## Pediatric Brain Tumors

**Kenneth J. Cohen, MD, MBA**
**Director, Pediatric Neuro-oncology**
**Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins**

## Pediatric Brain Tumors:Background

**2nd most common cancers in children**
**Most common solid neoplasms**
**2500-3000 new diagnoses/year**
**60-70% 5 year survival**

## Pediatric Cancer Distribution

## Brain Tumors: Five year survival rates by age

**SEER data, 1973-1991**

## Pediatric Brain Tumors:Survival/Frequency

**Low Grade/Pilocytic**
**Medulloblastoma (standard risk)**
**Ependymoma**
**Glioblastoma Multiforme**
**Brain Stem Glioma**

## Mortality Rates (1973-94):ALL vs. Brain Tumors

## Brain Tumor Nomenclature:WHO Classification

**Tumors of Neuroepithelial Tissue**
**Tumors of Peripheral Nerves**
**Tumors of the Meninges**
**Lymphomas and Haemopoietic Neoplasms**
**Germ Cell Tumors**
**Tumors of the Sellar Region**
**Metastatic Tumors**

## WHO Classification:Tumors of Neuroepithelial Tissue

**	****Astrocytic tumours**
**	****Oligodendroglial tumours**
**	****Mixed gliomas**
**	****Ependymal tumours**
**	****Choroid plexus tumours**
**	****Glial tumours of uncertain origin**
**	****Neuronal and mixed neuronal-glial tumours**
**	****Neuroblastic tumours**
**	****Pineal parenchymal tumours**
**	****Embryonal tumours**

**next **

## Astrocytic tumors

**Diffuse Astrocytoma**
**	****Fibrillary Astrocytoma**
**	****Anaplastic Astrocytoma**
**	****Glioblastoma Multiforme**
**Pilocytic Astrocytoma**
**Pleomorphic xanthoastrocytoma (PXA)**
**Subependymal giant cell astrocytoma (SEGA)**

## Oligodendroglial tumors

**Oligodendroglioma**
**Anaplastic oligodendroglioma**

## Ependymal tumors

**Ependymoma**

## Choroid plexus tumors

**Choroid plexus papilloma**
**Choroid plexus carcinoma**

## Glial tumors of uncertain origin

**Gliomatosis cerebri**

## Neuronal and mixed neuronal-glial tumors

**Gangliocytoma**
**Desmoplastic infantile astrocytoma – ganglioglioma (DIG)**
**Dysembryoplastic neuroepithelial tumor (DNET)**
**Gangliglioma**

## Pineal parenchymal tumors

**Pineoblastoma**

## Embryonal tumors

**Medulloblastoma**
**Supratentorial PNET**
**Atypical teratoid/rhabdoid tumor**

## Brain Tumor Nomenclature:Histologic Classification

**Neuroglial Cells**
**	****Astrocytes, Oligodendrocytes, Ependyma,  Choroid Plexus**
**Neuronal/Embryonal Cells**
**Other stuff (e.g. microglia)**

## Brain Tumor Nomenclature:Histologic Classification

**GLIOMAS**
**	****Astrocytic Tumors:**
**	****	****Pilocytic (“Low-Grade”, WHO 1)**
**	****	****Fibrillary: **
**	****	****  ****Diffuse Fibrillary (“Low-Grade”,WHO 2)**
**	****	****  ****Anaplastic Astrocytoma (WHO 3)**
**	****	****  ****Glioblastoma Multiforme (WHO 4)**
**	****	****	**

## Brain Tumor Nomenclature:Topographic Classification

**Neuronal Tumor c/w PNET**
**	****Pineal Region: ****	****Pineoblastoma**
**	****Cerebellum:****	****	****Medulloblastoma**
**	****Cerebrum:****	****	****Supratentorial PNET**
**	**

## Neuroanatomy

## Pediatric Brain Tumors:Distribution

## Brain Tumors: Distribution

## Pediatric Brain Tumors:Signs and Symptoms

**1.****	****	****General and nonlocalizing ****	****symptoms**
**2.****	****	****Increased intracranial pressure**
**3.****	****	****Localizing signs**

## General and Nonlocalizing Symptoms

**Headache**
**Vomiting **
**Behavioral changes (e.g. listlessness)**
**Developmental delay**
**Weight gain/loss**
**Others (e.g. endocrine dysfunction, autonomic dysfunction, failure to thrive)**

## Post Gad T1

- FLAIR

- ...normal state of health until about 1 year ago when he started to manifest nonspecific neuropsychiatric symptoms including memory loss, poor school performance, and mild behavioral changes which initially was thought to be "normal adolescence,” however, over the last 3 months, fatigue, headaches, irrational behavior, shortened attention span, migratory arthralgias, school absence, and loss of general interest have occurred.

## Pediatric Brain Tumors:Signs and Symptoms

**1.****	****	****General and nonlocalizing ****	****symptoms**
**2.****	****	****Increased intracranial pressure**
**3.****	****	****Localizing signs**

## Increased Intracranial Pressure

**Irritability, lethargy and vomiting**
**Bulging fontanelle/separation of sutures**
**Papilledema**
**Parinaud syndrome (“setting sun” sign)**
**Others (e.g. anisocoria, ataxia, head tilt)**

## Slide 28

## Pediatric Brain Tumors:Signs and Symptoms

**1.****	****	****General and nonlocalizing ****	****symptoms**
**2.****	****	****Increased intracranial pressure**
**3.****	****	****Localizing signs**

## Localizing Signs

**Dependent on tumor location**
**Cranial neuropathies (e.g. visual loss, head tilt, nystagmus, diplopia)**
**Hemiparesis/Hemisensory loss**
**Ataxia**
**Early handedness/change in handedness**
**Seizures**

## Slide 31

## Slide 32

## Pediatric Brain Tumors:Treatment

## Neurosurgery

**Generally, obligate for diagnosis**
**	****	****Exceptions: BSG, GCT**
**Gross total resection is the ideal**
**Debulking may be all that is feasible**
**Provide other supportive measures**
**	****	****e.g. shunts, Ommaya reservoirs**

## Radiation Therapy

**Potentially utilized for all CNS tumors**
**Exceptions include:**
**	****Choroid plexus tumors (initially)**
**	****Low grade gliomas (initially)**
**“****Full dose” treatment ~5500 cGy**
**Craniospinal prophylaxis ~3600 cGy**

## Radiation Therapy

| Tumor | Primary site | Neuroaxis |
| --- | --- | --- |
| Medulloblastoma | 5400 | 3600 |
| Ependymoma | 5400 | None |
| Astrocytoma | 5400 | None |
| GCT (low risk) | 3000 | 4500 (spine)
3600 (cranium) |
| GCT (high risk) | 5400 | 4500 (spine)
3600 (cranium) |

## Chemotherapy

**Used as adjuvant therapy in most cases**
**Particularly efficacious in:**
**	****Germ cell tumors**
**	****Embryonal tumors (medulloblastoma)**
**Expanding role in other tumors**
**Blood-brain barrier may pose limitations**

## Chemotherapy

**Particular interest in use in young children to avoid XRT**
**Novel therapeutics being developed**
**Bypassing blood-brain barrier**
**	****Local delivery systems (e.g. Gliadel)**
**	****Osmotic pumps**
**Substantial long term toxicity**

## Cerebellar tumors

**Cerebellar tumors**

**Pineal Gland**

**Hypothalamus**

**Thalamus**

**Pituitary Gland**

## Medulloblastoma

**Medulloblastoma**
**Ependymoma**
**Pilocytic Astrocytoma**

**Pineal Gland**

**Hypothalamus**

**Thalamus**

**Pituitary Gland**

## Brain Stem Gliomas

**CN 1**

**CN 2**

**CN 4**

**CN 3**

**CN 6**

**CN 5**

**CN 7**

**CN 12**

**CN 11**

**CN 10**

**CN 9**

**CN 8**

**Brain Stem Gliomas**

**Supratentorial Tumors**

## Brain Stem Gliomas

**CN 1**

**CN 2**

**CN 4**

**CN 3**

**CN 6**

**CN 5**

**CN 7**

**CN 12**

**CN 11**

**CN 10**

**CN 9**

**CN 8**

**Brain Stem Gliomas**

**Gliomas**
**sPNET**

## Cerebellum

**Cerebellum**

**Pineal Gland**

**Hypothalamus**

**Thalamus**

**Suprasellar Region**

## Cerebellum

**Cerebellum**

**Germinoma**
**Pineoblastoma**

**Hypothalamus**

**Thalamus**

**Suprasellar Region**

## Medulloblastoma: Case History

** ****18 yo male with a 3 mo. hx. of intermittent frontal ****headaches****. At diagnosis, the patient presented with ****nausea and vomiting**** and was unable to get out of bed. The patient has a hx of diplopia. The patient had no hearing loss at that time. The patient also had some episodes of ****unsteady gait****. The patient presented to the Johns Hopkins Pediatric Emergency where a CT scan was obtained. **

## Medulloblastoma

**Synonyms:**** Cerebellar PNET**
**% of cases:**** 20%**
**Diagnostic Eval:**** **
**	****MRI brain/spine **
**	****CSF cytopathology **
**	****Rarely, bone marrow and bone scan**
**Prognosis: **
**	****80-85% EFS for standard risk**
**	****20-70% EFS for high risk**

## Medulloblastoma Genetics

_**Turcot’s syndrome**_** (FAP/APC mutations)**
**	****WNT pathway mutations (10-20%)**
_**Gorlin’s syndrome**_** (basal cell carcinoma synd,PTCH)**
**	****Hedgehog pathway mutations (15-25%)**
** ****Other stuff:**
**	****isochromosome (17q) (40-50%)**
** ****	****c-Myc and/or N-myc amplification (5-10%)**
** ****	****Elevated c-Myc levels (40%)**
** ****	****Few mutations in Ras, EGFR, p53, Rb, p21, p16 ****	**

## Slide 48

## Medulloblastoma Pathology

## Medulloblastoma

**Standard Rx (for standard risk disease):**** **
**	****	****Best total resection**
**	****	****CSI (2340 cGy) with PF boost (****± VCR)**
**	****	****Adjuvant chemotherapy with:**
**	****	****	****Cisplatin/CCNU/VCR or**
**	****	****	****Cisplatin/CTX/VCR**
**	****	**
**Current Study (ACNS0331):**** Further reduction in CSI to 1800 cGy for children 3 to 8; conformal radiation**

## “Medulloblastoma” pointers

**Embryonal tumors like to disseminate – you need an LP and spinal MRI for staging**
**This is a small round blue cell tumor – so in theory bone marrow and bone are at risk ... this is rare**
**There’s a difference between sPNET, medulloblastoma, and pineoblastoma ... we just don’t understand the difference yet**

## Ependymoma: Case History

**The patient is a 3-year-old white female who presented with a one-week history of ****neck pain****, slight ****nausea and vomiting****.**
**The patient is an 8-year-old male who was in his usual state of good health until several weeks prior to admission when he developed ****progressive headache****, ****emesis**** and more recently, ****gait unsteadiness**** and a 15 pound weight loss**

## Ependymoma

**Synonyms: ****None**
**% of cases: ****10%**
**Diagnostic Eval: **
**	****MRI brain/spine**
**	****CSF cytopathology**
**Prognosis: **
**	****20-60% 5 yr survival.  Negligible survival without good resection or with spinal metastases**

## Slide 54

## Ependymoma Pathology

## Ependymoma

**Standard Rx:**
**	****Best resection**
**	****Focal XRT**
**Current study (ACNS0121): **
**	****Multiarm trial with treatment dependent on extent of resection, location and histology**

## Ependymoma pointers

**This is a tumor that likes to spread to the spinal cord – you need an LP and spinal MRI for staging**
**If you don’t get a good resection, it’s pretty hard to cure these patients (that’s the dogma anyhow)**
**If the tumor recurs, you rarely fix it**

## Brain Stem Glioma: Case History

**The patient is an 8-year-old male who presented to an ophthalmologist after complaints of ****diplopia**** for approximately 2 weeks.  He was noted to have ****papilledema****. He had also been noticed by his parents to be having some ****slurred speech**** during the prior 2-3 days. MRI was consistent with a brain stem glioma that encased the basilar artery.  He had evidence of ****hydrocephalus.**** **

## Diffuse Intrinsic Pontine Glioma

**Synonyms: ****Brain stem glioma**
**% of cases:  ****10-20%**
**Diagnostic Evaluation:**
**	**** ****MRI only (if classic lesion)**
**Prognosis: ****All patients die within two years from the time of diagnosis**** **

## Diffuse Intrinsic Pontine Glioma

**Standard Rx:**
**	****Focal XRT**
**Current studies:**
**	****ADVL0421: Addition of topotecan**
**	**

## Slide 61

## Slide 62

## Brain Stem Gliomas pointers

**There’s a difference between an “intrinsic pontine glioma” and “exophytic brain stem tumors.  **
**Exophytic BSGs are usually pilocytic astrocytomas.  PA in the brain stem has a much better prognosis.  **
**PAs in the brain stem brightly enhance on post-gad MRI and are often in other areas of the brain stem besides the pons**

## Pilocytic Astrocytoma: Case History

**The patient developed bitemporal ****headaches**** which were occurring every other day. She was treated for allergies, but with no improvement.  An x-ray of her sinuses was normal.  She was advised to reduce her caffeine intake and was referred for a visual screen which was normal.  She had persistent headaches and was prescribed a bite block.  Recently, she complained of a ****lack of coordination in her left hand****. An MRI revealed a heterogenous cystic mass in the cerebellar hemisphere.**

## Pilocytic Astrocytoma

**Synonyms: ****Astrocytoma (WHO 1), cerebellar astrocytoma, “low-grade” glioma**
**% of cases: ****25%**** **
**Diagnostic Eval: **
**	****MRI of brain ****± spine**
**Prognosis: ****GTR > 90% 5 yr survival; less good results for midline tumors**

## Pilocytic Astrocytoma Pathology

## Slide 67

## Slide 68

## Slide 69

## Pilocytic Astrocytoma

**Standard Rx: Dependent on Location**
**	****Amenable to GTR: Observation**
**	****Not amenable:**
**	****	****Observation in selected cases**
**	****	****Best safe resection and then ****	****consider chemotherapy and or XRT for ****	****progression/residual mass**
**Current studies**
**	****	****ACNS0223: ****Carbo/VCR/TMZ**
**	****	****ACNS0221: ****Conformal Radiotherapy**

## Pilocytic Astrocytoma pointers

**PA can occur virtually anywhere in the brain**
**If you can cut it out entirely, you can usually cure the patient**
**Optic pathway PA is often associated with NF-1 and can have a pretty benign course**

## AA and GBM: Case History

**The patient is an 8 yo girl who was diagnosed with a large mass in the right frontoparietal region of her cerebral cortex after presenting to the ER following a ****seizure****.  Her parents indicate that she had had a two-month history of progressive ****nausea and vomiting**** accompanied by ****headache**

## Anaplastic Astrocytoma Glioblastoma Multiforme

**Synonyms: ****Astrocytoma (WHO 3 and 4); high-grade gliomas**
**% of cases: ****10-20%**** **
**Diagnostic Eval: **
**	****MRI brain **_**+**_** spine**
**Prognosis: **
**	****AA 35% (depends on surgery); **
**	****GBM < 10% 5 yr. survival**

## Slide 74

## GBM Pathology

## Anaplastic AstrocytomaGlioblastoma Multiforme

**Standard Rx: **
**	****Maximal surgical resection**
**	****XRT**
**	****? role of TMZ for selected patients**
**Current studies:**
**	****ACNS0423: ****XRT/TMZ then TMZ/CCNU**

## High-grade glioma pointers

**You have a fighting chance of curing AA if you get a gross total resection**
**The same is not true for GBM**
**No therapy has really shown much benefit for these tumors with the exception of radiation therapy**

## Germinoma: Case History

**This19-year-old African American male experienced ****dizziness**** over the last 3 months and  has been ****bumping into objects****. He was evaluated in July in the emergency room because of his staggering and ****nausea and vomiting****.  He had a ****sodium of 158 with a urine specific gravity of less than 1.005****.  He also admitted at that point that he had been ****drinking a lot**** and also had ****polyuria****.**

## Germinoma

**Synonyms: ****Non-secreting GCT**
**% of cases: ****1%**
**Diagnostic Eval: **
**	****Biopsy for diagnosis**
**	****MRI brain/spine**
**	****CSF cytopathology**
**	****CSF markers (AFP/****β****-HCG) ****should be negative or low**
**Prognosis: ****60-85% at 5 years**

## Slide 80

## Germinoma Pathology

## Germinoma

**Standard Rx: **
**	****XRT is curative**
**	****Neoadjuvant chemotherapy can decrease XRT dose (P9530)**
**Current study (ACNS0232):**
**	****Randomized comparison of XRT vs. neoadjuvant chemo and response based XRT**

## NG-GCT: Case History

**This 7 yo was well until his mother noted his ****voice deepening****. Shortly thereafter, she noted the ****appearance of pubic hair****, and increased fullness of the hair on his eyebrows and increased growth.  She notes that for the past three months he has ****gained approximately 12 pounds****.  In addition, she has noticed ****enlargement of the penis.**

## Nongerminomatous Germ Cell Tumor (NG-GCT)

**Synonyms: ****NG-GCT; secreting GCT**
**% of cases:  ****< 1%**
**Diagnostic Eval: **
**	****MRI brain/spine**
**	****CSF cytopathology**
**	****CSF tumor markers (AFP/****β****-HCG) **
**	****Biopsy may not be required at diagnosis**
**Prognosis: ****30-50% EFS historically, but outcome may be improving**

## NG-GCT

**Standard Rx: ****XRT with adjuvant and/or neoadjuvant chemotherapy**
**Current study (ACNS0122):**
**	****Single-arm Phase 2 design with neoadjuvant chemotherapy, possible 2****nd**** look surgery, ****± SCT depending on upfront response**

## Slide 86

## NG-GCT Pathology

## Germ cell tumor pointers

**CSF tumor markers are usually **_**not**_** elevated in germinoma**
**Occult DI in a teenager is often germinoma waiting to declare itself **
**NG-GCT is much harder to treat than germinoma**
**10% of germinomas are multifocal in the pineal and suprasellar region**
** **

## A few last things...

**NF-1 think optic pathway gliomas and nonneoplastic hamartomatous lesions**
**Tuberous sclerosis think SEGA -  subependymal giant cell astrocytoma**
**Retinoblastoma (heritable) are at risk for trilateral disease which is a small round blue cell tumor in the region of the pineal gland (pineoblastoma)**