St. Jude Solid Tumor Board: St.

Jude Solid Tumor Board:

21 September 2007 21 September 2007

High-Grade Gliomas in High-Grade Gliomas in

Children Children

Alberto Broniscer,
Broniscer, MD, PhD Fred Laningham,
Laningham, MD
Alberto Broniscer,
Broniscer, MD, PhD
David W. Ellison, MD, PhD, MRCP (UK), FRCPath Assistant Member, Neuro-
Neuro-oncology
St. Jude Children’s Research Hospital

History

• 6 yo Female • Past medical history and development:

• 1st appointment: June 13, 2005 – Unremarkable
• History of progressive headaches, nausea, and
vomiting for 2-3 weeks
• Family history:
• Since no resolution of symptoms, a brain MRI – Large family
was performed which showed the brain tumor
– Unremarkable
• Two consecutive resections in May 2005 -
NTR

St. Jude Solid Tumor Board:

Physical Exam 21 September 2007

• Normal vital signs Wt: 50th Ht: 50-75th

High-Grade Gliomas in
• No syndromic features
Children
• Well healed right fronto-parietal scar
• Neurologic exam
– Left hemiparesis
– Limited upward gaze
– Visual field cut
Fred Laningham,
Laningham, MD
Assistant Member, Diagnostic Imaging
St. Jude Children’s Research Hospital
Commander, United States Navy, USNR-
USNR-R MC

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 SJHG04: Thalamic High Grade Gliomas St. Jude Solid Tumor Board:
21 September 2007

High-Grade Gliomas in
Children

Alberto Broniscer,
Broniscer, MD, PhD
Assistant Member, Neuro-
Neuro-oncology
St. Jude Children’s Research Hospital
Pre and Post-operative Imaging

St. Jude Solid Tumor Board:

21 September 2007

• Imaging
High-Grade Gliomas in
Children

• Histological Diagnosis

David W. Ellison, MD, PhD, MRCP (UK), FRCPath

Member, Pathology
St. Jude Children’s Research Hospital

Aim:
Aim To classify according to
biologically significant
• The aim of this presentation is to indicators
Molecular - genetic abnormalities in cells
illustrate the principles behind the
pathological diagnosis of pediatric
diffuse astrocytic tumors, which as Tumour phenotype
anaplastic astrocytomas and
glioblastomas make up nearly all
pediatric high-grade gliomas.
Clinicopathological characteristics Histopathological features

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 Broad categories in WHO
The classification of CNS tumours classification (2007) of
• Ontogenesis Bailey & Cushing
nervous system tumors
• Tumors of neuroepithelial tissue
• Tumors of cranial and paraspinal nerves
• Anaplasia Grading systems (I-IV)
• Tumors of the meninges
• WHO Integration of above schemes
• Lymphomas / hematopoietic neoplasms
• Germ cell tumors
• Future WHO Integration of histopathology • Tumors of the sellar region
and molecular biology • Metastatic disease

Categories in WHO
Adults Children

45%
classification
40%
• Tumors of neuroepithelial tissue
– Gliomas astrocytoma (1) & ependymoma (3)
35%
– Choroid plexus tumors
30% – Neuronal / mixed neuronal-glial tumors
25%
– Tumors of the pineal region
– Embryonal tumors medulloblastoma (2)
20%
– Other neuroepithelial tumors
15% • Tumors of cranial and paraspinal nerves
10% • Tumors of the meninges
5% • Lymphomas / hematopoietic neoplasms
0%
• Germ cell tumors
Astrocytomas AAs / GBs PNETs Meningiomas • Tumors of the sellar region
• Metastases

Neuroepithelial tumors in
Gliomas in WHO classification
WHO classification
• Tumors of neuroepithelial tissue • Tumors of neuroepithelial tissue
– Gliomas – Gliomas
• Astrocytic tumors heterogeneous – grades 1-IV • Astrocytic tumors
• Oligodendroglial tumors diffuse gliomas – grades II-III – subependymal giant cell astrocytoma (WHO I)
• Oligoastrocytic tumors diffuse gliomas – grades II-III – pilocytic astrocytoma (WHO I)
– diffuse astrocytoma (WHO II)
• Ependymal tumors distinct neoplastic entities
– pleomorphic xanthoastrocytoma (WHO II)
– Choroid plexus tumors – anaplastic astrocytoma (WHO III)
– Neuronal / mixed neuronal-glial tumors – glioblastoma (WHO IV)
– Tumors of the pineal region • Oligodendroglial tumors
– Embryonal tumors • Oligoastrocytic tumors
– Other neuroepithelial tumors

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 Diffuse astrocytic tumours Pediatric high-grade gliomas
• Related by: • Diffuse astrocytic tumors
– histogenesis – anaplastic astrocytoma grade III
– progression – glioblastoma grade IV
– genetic abnormalities

• These entities are not related to diffuse • Diffuse gliomas

astrocytic tumours (by clinicopathological – anaplastic oligoastrocytoma grade III
features / progression / genetics): – anaplastic oligodendroglioma grade III
– pilocytic astrocytoma
– pleomorphic xanthoastrocytoma • Pleomorphic xanthoastrocytoma (high
- grade)
– subependymal giant cell tumor

Steps to pathological
diagnosis –
pediatric HGGs
• Clinicopathological correlation

• Assess histogenesis
• Assess anaplasia
• Diagnosis (WHO) – name & grade

• Clinicopathological correlation

Ellison et al, Neuropathology, 2004

Ellison et al, Neuropathology, 2004 Ellison et al, Neuropathology, 2004

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Ellison et al, Neuropathology, 2004 Ellison et al, Neuropathology, 2004

Diffuse astrocytic tumours

cytological atypia / nuclear

Astrocytoma WHO II
pleomorphism & hyperchromasia

above +
Anaplastic astrocytoma WHO III
mitotic activity

above +
Glioblastoma WHO IV
angiogenesis & necrosis

Ellison et al, Neuropathology, 2004

Ellison et al, Neuropathology, 2004 Ellison et al, Neuropathology, 2004

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 Ellison et al, Neuropathology, 2004 Ellison et al, Neuropathology, 2004

Ellison et al, Neuropathology, 2004 Ellison et al, Neuropathology, 2004

Diffuse astrocytic tumours Survival versus histopathology

1
cytological atypia / nuclear
Astrocytoma WHO II .8
pleomorphism & hyperchromasia A
Cum. Survival

.6

.4 AA
above +
Anaplastic astrocytoma WHO III
mitotic activity .2
GB
0

above + 0 1000 2000 3000 4000 5000 6000

Glioblastoma WHO IV
angiogenesis & necrosis Time

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 St. Jude Solid Tumor Board:
21 September 2007
?
High-Grade Gliomas in
Children
Questions and Answers
Some questions were asked without a
microphone nearby and may be difficult
to hear, but they are presented here.
Alberto Broniscer,
Broniscer, MD, PhD
Assistant Member, Neuro-
Neuro-oncology
St. Jude Children’s Research Hospital

Challenges in the Management of High-

High-
Grade Gliomas in Children

• Diagnosis: Glioblastoma Multiforme (WHO • Uncommon Tumors

grade IV) • Heterogeneous tumors

- Location

• Tumor staging was performed and patient was - Age group

enrolled on the SJHG04 protocol - Histology

- Biology

Challenges in the Management of High-

High- Treatment
Grade Gliomas in Children

• Difficult to treat 1 • Maximum safe surgical resection

0.9

0.8
SJHG98
- Infiltrative (difficult to 0.7
P ro b a b ility

resect) 0.6

0.5 • Radiotherapy (for older children)

0.4 Overall Survival
Progression Free Survival
- Radio- and chemo- 0.3

0.2

resistance 0.1

0
0 1 2 3 4 5 6
• Chemotherapy
Years from Diagnosis

Review – Broniscer A, Gajjar A. Oncologist

2-year progression-free survival <20%
9:197-206, 2004

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 Background About Chemotherapy Temozolomide Has not Improved Survival of
Children with High-Grade Glioma

• No standard chemotherapy is available for
children with high-grade glioma
• Clinical trials have relied mostly on a
backbone of alkylating agents, particularly
nitrosoureas / temozolomide (oral methylating
agent)
ƒ Temozolomide is considered the standard chemotherapy for
adults with newly diagnosed glioblastoma (Stupp et al., 2005)
ƒ Temozolomide (SJHG98 1999-2002)
– 31 eligible patients with non-brainstem high-grade glioma
– 48% glioblastoma, 32% anaplastic astrocytoma
– 2-year PFS and OS were 11±5% and
21±7%, respectively

Rationale for the Use of Erlotinib in Children with

SJHG04 Treatment Outline (Phase I/II Study)
High-Grade Gliomas

ƒ Up to 85% of pediatric high-grade astrocytomas over-

DLT-evaluation period express EGFR

Radiation ƒ Erlotinib has shown encouraging activity in adults

with recurrent high-grade astrocytoma
ƒ Proposed mechanisms of erlotinib:
Erlotinib – Inhibition of EGFR and ERBB2
– Radiosensitizer
6 1/2 8
3
years
– Antiangiogenic activity
WEEKS

Objectives Results

ƒ Primary
• Twenty-three patients enrolled between March
– To define the MTD and characterize the DLT of erlotinib
(Phase I) 05 and June 07
– To determine the PFS for patients with glioblastoma and
anaplastic astrocytoma (Phase II)
• Median age: 10.7 years
ƒ Secondary
• Histologic diagnosis:
– Glioblastoma (n=12)
– Anaplastic astrocytoma (n=8)

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Results Results

• Maximum tolerated dose of erlotinib was • Disease stabilization in 16 patients (0.4-2.2

120mg/m2 per day
• Extensive pharmacokinetic studies in plasma
and CSF
– PK parameters are similar to those in adults
years)
• No evidence of tumor recurrence at a median
of 1.4 years in 5 patients who underwent a
GTR
• Twelve patients have already experienced
tumor progression

Biologic Studies

Stokoe, D. The phosphoinositide 3-kinase pathway and cancer. Expert Reviews in Molecular Medicine. Jun 2005.
Vol 7(10) 1:22. Copyright © Cambridge University Press 2005. Reproduced with permission.

Molecular Mechanisms Involved in the

Biologic Studies
Genesis of Glioblastoma in Adults

• No EGFR kinase domain mutations (n=15) Differentiated

Differentiated astrocytes
astrocytes or
or precursor
precursor cells
cells

TP53 mutation (>65%) EGFR

PDGF-A, PDGFR-α amplification (~ 40%)
Overexpression (~ 60%) overexpression (~ 60%)
• Two PTEN and one PIK3CA mutation (n=15) Low grade astrocytoma MDM2
amplification (<10%)
overexpression (~ 50%)
LOH 19q (~ 50%)
Rb1 alteration (~ 25%) p16 deletion (30 – 40%)

• Immunohistochemistry is pending LOH 10p and 10q

PTEN mutation (~ 30%)
Anaplastic astrocytoma
Rb1 alteration
LOH 10q
PTEN mutation (5%)
DCC loss of expression (~ 50%)
PDGFRA amplification (<10%)

Secondary glioblastoma Primary glioblastoma

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Malignant Transformation of
Low-Grade Glioma
ƒ Rare phenomenon in children
ƒ RT as a possible risk factor
ƒ One study reported a 10% incidence among children
with juvenile pilocytic astrocytoma
Initial Histologic Diagnosis
ƒ 11 patients who experienced malignant
transformation were identified
– WHO grade II astrocytoma (n=6)
– Ganglioglioma (n=2)
– Pleomorphic xanthoastrocytoma (n=1)
– Juvenile pilocytic astrocytoma (n=1)
– Oligoastrocytoma (n=1)
Cumulative Incidence Estimate (1985-2003)
ƒ Among 65 SJCRH patients with WHO grade II
astrocytoma, the 10- and 15-year cumulative
incidence of malignant transformation were 3.8±3%
and 6.7±4%, respectively
ƒ Malignant transformation was extremely uncommon
among children with juvenile pilocytic astrocytoma
Methods
ƒ Patients < 21 years of age with multiple histologic
samples demonstrating malignant transformation
ƒ Review of imaging studies and pathology specimens
was undertaken
ƒ Analysis of clinical features (risk factors, cumulative
incidence estimate)
ƒ Molecular studies (FISH, IHC, and TP53
sequencing)
Histology at the Time of Malignant
Transformation
ƒ The median interval for malignant transformation
was 5.1 years
ƒ The histologic diagnoses at the time of
transformation were:
– Glioblastoma multiforme (n=7)
– Anaplastic astrocytoma (n=2)
– Other high-grade gliomas (n=2)
Analysis of Risk Factors
ƒ Radiation therapy (P=0.54), tumor location (P=0.37),
degree of resection (P=0.12), and use of
chemotherapy (P=0.11) were not associated with an
increased cumulative incidence of malignant
transformation
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Typical Radiologic and Histologic Features
FISH Analysis of Chromosomal Losses
Associated with Malignant Transformation
December 1998 March 2001
LGG HGG
CDKN2A 2/8 4/11
(25%) (36%)
PTEN 3/9 6/11
(33%) (55%)
RB1 3/6 8/10
(50%) (80%)

1p 2/7 3/10
(29%) (30%)

19q 6/7 6/11

(86%) (55%)
Low-grade Astrocytoma Glioblastoma Multiforme

Importance of PTEN Loss TP53 mutations

April 1995 April 1998

• Three of 11tumor samples had TP53 mutations
PTEN PTEN
control control • Two of these mutations occurred in hotspots
for secondary glioblastoma in adults

Molecular Mechanisms Involved in the St. Jude Solid Tumor Board:

Genesis of Glioblastoma in Adults 21 September 2007

Differentiated
Differentiated astrocytes
astrocytes or
or precursor
precursor cells
cells
High-Grade Gliomas in
Children
TP53 mutation (>65%) EGFR
PDGF-A, PDGFR-α amplification (~ 40%)
Overexpression (~ 60%) overexpression (~ 60%)

Low grade astrocytoma MDM2

amplification (<10%)
overexpression (~ 50%)
LOH 19q (~ 50%)
Rb1 alteration (~ 25%) p16 deletion (30 – 40%)

LOH 10p and 10q

PTEN mutation (~ 30%)
Anaplastic astrocytoma
Rb1 alteration
LOH 10q
PTEN mutation (5%)
DCC loss of expression (~ 50%)
PDGFRA amplification (<10%)
Fred Laningham,
Laningham, MD
Primary glioblastoma
Assistant Member, Diagnostic Imaging
Secondary glioblastoma
St. Jude Children’s Research Hospital
Commander, United States Navy, USNR-
USNR-R MC

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 SJHG04: Surgery and RT
SJHG04: Phase I Imaging Objectives
• Secondary Objective No. 5
– Assess tumor response using standard and
investigational MR techniques
• DEMRI, T2* perfusion, DTI, MV MR spectroscopy,
PET

• Phase I enrollment completed

– 23 patients (Anaplastic n=11, GBM n=11, GNT
n=1)
– Imaging under analysis, 2-11 examinations per
patient
– Thalamic, cerebellar, gliomatosis, other
Thomas Merchant, DO

SJHG04: Therapy SJHG04: Dynamic Enhanced MRI (DEMRI)

60 images single level

Baseline 8 wks 20 wks 32 wks

imaging
6 weeks RT metastatic
diagnosis spread follow
& surgery up

erlotinib Carolyn Phillips, RT

enrollment off-study

SJHG04: T2* Perfusion Method and Analysis SJHG04: Perfusion Method and Analysis
50 Images per slice (15) WM

• Perfusion Weighted Caudate

Imaging
– Dynamic susceptibility Tumor Putamen

contrast imaging
– T2* gradient echo T2 T1
method GM
– Contrast injected, signal Manual ROI
change measured over Analysis
time 440

WM
34 FLAIR
• Measurements of Interest Automatic
SOM
= CBV, CBF, MTT CBF Segmentation

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SJHG04: Tumor
SJHG04: Diffusion Tensor Imaging (DTI)

6 direction DTI = 1120 images

Caud
gC
LALIC
C
Put
RALI
C
LPLIC
RPLI
C
RThal LTha
l
sCC

CBV and CBF in Tumor Color FA FA ADC DTI Regions

Analyzed

SJHG04: Multivoxel MRS

LAC CHO NAA CHO/NAA

≥ 2.5

St. Jude Solid Tumor Board:

SJHG04: FDG PET 21 September 2007
Illustrative Case

High-Grade Gliomas in
MR Fusion CT Fusion
Children

Alberto Broniscer,
Broniscer, MD, PhD
2-26-07 Assistant Member, Neuro-
Neuro-oncology
St. Jude Children’s Research Hospital

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 End
!
Alberto Broniscer,
Broniscer, MD, PhD
Fred Laningham,
Laningham, MD
David W. Ellison, MD, PhD, MRCP (UK), FRCPath

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