Tumors of Neuroepithelial Origin:The Embryonal Tumors

Kenneth J. Cohen, MD, MBA

Director, Pediatric Neuro-oncology

Clinical Director, Pediatric Oncology

Johns Hopkins University SOM

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:Tumours of Neuroepithelial Tissue

Astrocytic tumoursOligodendroglial tumoursMixed gliomasEpendymal tumoursChoroid plexus tumoursGlial tumours of uncertain originNeuronal and mixed neuronal-glial tumoursNeuroblastic tumoursEmbryonal tumours Pineal parenchymal tumours

Embryonal tumors

Medulloblastoma

Supratentorial PNET

Atypical teratoid/rhabdoid tumor

(Medulloepithelioma)

(Ependymoblastoma)

Pineal parenchymal tumours

Pineoblastoma

Pineocytoma

Pineal parenchymal tumour of intermediate differentiation

Topographic Classification

Neuronal Tumor c/w PNET

Pineal Region: Pineoblastoma

Cerebellum: Medulloblastoma

Cerebrum: Supratentorial PNET

The tumors are different…

Different clinical outcomes

Different molecular “signatures”

Medulloblastoma Genetics

Turcot’s syndrome (FAP/APC mutations)WNT pathway mutations (10-20%)

Gorlin’s syndrome (BCC Syndrome, PTCH)Hedgehog pathway mutations (15-25%)

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 etc

Case History #1

11 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%

Cerebellar malignancies:Differential

Medulloblastoma

Ependymoma

Pilocytic astrocytoma

Rare, but on the differential:

Tumors of glial origin

AT/RT

LCH

CNS lymphoma

Lhermitte-Duclos

Medulloblastoma:Diagnostic Evaluation

Required:Post-operative imagingPre-operative or post-operative (>10 days) spine MRICSF cytopathology (>10 days post-op)

Rarely required:Bone marrowBone scan

Medulloblastoma:Staging

Pre-operative staging:T1 Tumor <3 cm in diameter T2 Tumor >3 cm in diameter T3a Tumor >3 cm in diameter with spread T3b Tumor >3 cm in diameter with definite spread into the brain stem (part of brain that controls breathing, hearing, seeing, and other important functions) T4 Tumor >3 cm in diameter with extension up past the aqueduct of Sylvius and/or down past the foramen magnum

Medulloblastoma:Staging

Evaluation for metastases:M0 No evidence of metastasis M1 Tumor cells found in cerebrospinal fluid (by lumbar puncture and cytology study) M2 Tumor beyond primary site but still in brain M3 Tumor deposits (“seeds”) in spine area that are easily seen on MRI M4 Tumor spread to areas outside the CNS (outside both brain and spine)

Medulloblastoma:Risk Classification

Features Standard Risk High Risk

Extent of resection

< 1.5 cm3 residual tumor

> 1.5 cm3

residual tumor

M-staging M0 M+

Histology Anaplasia

Additional “low-risk” features

Desmoplastic histologyIncreased apoptosis indexHyperdiploidyHigh TRKC expressionGenes characteristic of cerebellar

differentiation (ß-NAP, NSCL1, sodium channels) and genes encoding extracellular matrix proteins (PLOD lysyl hydroxylase, collagen type V l, elastin) [5,30]

Additional “high-risk” features

Large-cell anaplastic histologyElevated Ki-67/MIB-1 proliferative indexAneuploidy Elevated ERBB2 expressionIsolated 17p loss of heterozygosityElevated expression and amplification of MYCCUpregulation of PDGFROverexpression of calbindin-D28k

Genes related to cell proliferation and metabolism (MYBL2) enolase 1, LDH, HMG1(Y), cytochrome C oxidase) and multidrug resistance (sorcin) [5,30]

Medulloblastoma Pathology

Medulloblastoma Subtypes

“Classic” medulloblastomasNodular/ “desmoplastic” medulloblastomasLarge cell/anaplastic medulloblastomasMedullomyoblastomaMedulloepithelioma

Nodularity in Medulloblastomas

96-100% Extensive 3/411 (<1%)51-95% Widespread 17/411 (5%)11-50% Moderate 45/411 (11%)1-10% Slight 50/411 (12%)0% None 296/411 (72%)

p=0.07

None Slight

Moderate Moderate

Severe Severe

Anaplasia in Medulloblastomas

Severe Anaplasia 44/411 (11%)Moderate Anaplasia 56/411 (14%)No/Slight Anaplasia 311/411 (75%)

p<0.0001

Anaplasia Extent in Medulloblastomas

Diffuse 72/411 (18%)Focal 62/411 (15%)None 277/411 (67%)

p<0.0001

Medulloblastoma:Treatment

ResectionMetastases± Anaplasia

Standard Risk High-Risk

Infants andYoung Children

Medulloblastoma:Standard Risk Treatment

Historically:

GTR followed by XRT/CSI ~ 60% EFS

Full posterior fossa ~ 5400 – 5940

Craniospinal XRT 3600

The problem – fair cure, dumb kids

Medulloblastoma:Standard Risk Treatment

A9961“The Standard of Care”

Upfront XRT + VCRPF 5400/CSI 2340

Cisplatin/CCNU/VCR~ 80-85% EFS

↑ myelosuppression

Upfront XRT + VCRPF 5400/CSI 2340

Cisplatin/CTX/VCR~ 80-85% EFS

↑ infections

Medulloblastoma:ACNS0331 – Standard Risk

1800 cGy 2340 cGy

Medulloblastoma:Treatment of high-risk patients

Less uniformity in the approach…Generally includes:

Full dose (3600 CSI) with PF boostDose-intensive combination Rx? growing role for MTX as part of pre-XRT regimen? role of SCT as consolidation

In general, EFS in range of 40-60% (but much variation depending on reason for HR status)

Medulloblastoma:The special challenge of infants

What’s good enough?

Are attempts to reduce or eliminate the CSI in young children therapeutically equivalent to more standard chemoradiotherapy based approaches?

Therapeutic equivalence

Treatment A and Treatment B are considered therapeutically equivalent if you can replace A with B and vice versa

In trials, the standard therapy (A) has been shown to be beneficial and the novel therapy (B) is easier to use, is less costly or…

Has fewer side effects

100%

50%

0%

1 2 3 4 5

IQ reduced

IQ preserved

When doesthis become“medicalpaternalism”?}

The “in lieu of craniospinal paradigm”

IQ preserved

Medulloblastoma:Treatment of young infants

Options (~ 50-75% EFS for standard risk pts)HIT-type therapy: N Engl J Med. 2005 Mar 10;352(10):978-86

CCG 99703

Head Start therapy

P9934

What’s coming:

International Medulloblastoma trial

Case History #2Patient presented with headaches. Her symptoms

progressed to include decreased p.o. intake, lethargy, emesis, and altered level of consciousness. An MRI scan of the brain on 06/29/04 showed a 6.7 x 4.8 x 4.6 cm right temporoparietal mass with a left shift of about 8 mm.  The mass was heterogeneous; appearing cystic, solid, and hemorrhagic. The patient underwent near total resection of the mass but during the post-op staging period entirely regrew over a 3 week period at which point she underwent a re-resection of the right frontotemporal mass with residual disease in the Sylvian fissure.

Atypical Teratoid/Rhabdoid Tumor

Rare, primarily seen in young childrenHistorically mistaken for medulloblastoma½ arise in posterior fossa~ 15% of patients have leptomeningeal dx at

presentationUsed to be considered “uniformly fatal”

with recommendation for palliative care only often given

AT/RT: Pathology

AT/RT Neurobiology

Monosomy 22 or

del 22q11

LOH or deletion of hSNF5/INI1 gene

hSNF5 is part of SWI/SNF ATP-dependent chromatin-remodeling complex

~ 85% of AT/RT have this mutation

AT/RT Treatment

Not a guaranteed death sentence

Requires aggressive chemotherapy with at least local XRT

Therapy is often based loosely on IRS type therapy based on early case series with some success

Case History #3

4 year-old white male with who presented with a two to three month history of progressive headaches, emesis, and a recent onset of diplopia just prior to diagnosis. The patient was seen by an ophthalmologist for his complaint of diplopia and his symptoms of headache and was noted to have bilateral papilledema. A scan was performed.

Pineoblastoma

Synonyms: Pineal region PNET% of cases: 1-2%Diagnostic Evaluation: MRI brain/spine; CSF

cytopathology; consider bone marrow and bone scan

Standard Rx: Surgery, CSI, chemotherapyPrognosis: 60-70%Associations: Bilateral retinoblastoma so

called “trilateral retinoblastoma”

Case History #4

Pt. had a 2 day history of headache and fevers without other symptoms. Sx were self limited and resolved. One mos. later the child had a generalized tonic-clonic seizure, which lasted approximately 20 minutes. EEG, which was read as "grossly abnormal". MRI a couple of weeks later revealed a 4 cm enhancing mass with focal edema and mass effect in the left parietotemporal area.

Supratentorial PNET

Synonyms: Cerebral PNET or NBL

% of cases: 1%

Diagnostic Evaluation: MRI brain/spine; CSF cytopathology;

Standard Rx: Surgery, CSI, chemotherapy

Prognosis: 30-40%