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
1
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
• Imaging
High-Grade Gliomas in
Children
• Histological Diagnosis
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
2
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
3
Diffuse astrocytic tumours Pediatric high-grade gliomas
• Related by: • Diffuse astrocytic tumors
– histogenesis – anaplastic astrocytoma grade III
– progression – glioblastoma grade IV
– genetic abnormalities
Steps to pathological
diagnosis –
pediatric HGGs
• Clinicopathological correlation
• Assess histogenesis
• Assess anaplasia
• Diagnosis (WHO) – name & grade
• Clinicopathological correlation
4
Ellison et al, Neuropathology, 2004 Ellison et al, Neuropathology, 2004
above +
Anaplastic astrocytoma WHO III
mitotic activity
above +
Glioblastoma WHO IV
angiogenesis & necrosis
5
Ellison et al, Neuropathology, 2004 Ellison et al, Neuropathology, 2004
.6
.4 AA
above +
Anaplastic astrocytoma WHO III
mitotic activity .2
GB
0
6
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
- Location
- Biology
0.8
SJHG98
- Infiltrative (difficult to 0.7
P ro b a b ility
resect) 0.6
0.2
resistance 0.1
0
0 1 2 3 4 5 6
• Chemotherapy
Years from Diagnosis
7
Background About Chemotherapy Temozolomide Has not Improved Survival of
Children with High-Grade Glioma
• No standard chemotherapy is available for Temozolomide is considered the standard chemotherapy for
children with high-grade glioma adults with newly diagnosed glioblastoma (Stupp et al., 2005)
Temozolomide (SJHG98 1999-2002)
• Clinical trials have relied mostly on a – 31 eligible patients with non-brainstem high-grade glioma
backbone of alkylating agents, particularly – 48% glioblastoma, 32% anaplastic astrocytoma
nitrosoureas / temozolomide (oral methylating – 2-year PFS and OS were 11±5% and
agent) 21±7%, respectively
Objectives Results
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
Secondary
• Histologic diagnosis:
– Glioblastoma (n=12)
– Anaplastic astrocytoma (n=8)
8
Results Results
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.
9
Malignant Transformation of Methods
Low-Grade Glioma
Rare phenomenon in children Patients < 21 years of age with multiple histologic
samples demonstrating malignant transformation
Review of imaging studies and pathology specimens
RT as a possible risk factor was undertaken
Analysis of clinical features (risk factors, cumulative
incidence estimate)
One study reported a 10% incidence among children
with juvenile pilocytic astrocytoma Molecular studies (FISH, IHC, and TP53
sequencing)
11 patients who experienced malignant The median interval for malignant transformation
transformation were identified was 5.1 years
– WHO grade II astrocytoma (n=6) The histologic diagnoses at the time of
– Ganglioglioma (n=2) transformation were:
– Pleomorphic xanthoastrocytoma (n=1) – Glioblastoma multiforme (n=7)
– Juvenile pilocytic astrocytoma (n=1) – Anaplastic astrocytoma (n=2)
– Oligoastrocytoma (n=1) – Other high-grade gliomas (n=2)
Among 65 SJCRH patients with WHO grade II Radiation therapy (P=0.54), tumor location (P=0.37),
astrocytoma, the 10- and 15-year cumulative degree of resection (P=0.12), and use of
incidence of malignant transformation were 3.8±3% chemotherapy (P=0.11) were not associated with an
and 6.7±4%, respectively increased cumulative incidence of malignant
transformation
Malignant transformation was extremely uncommon
among children with juvenile pilocytic astrocytoma
10
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%)
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%)
11
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
SJHG04: T2* Perfusion Method and Analysis SJHG04: Perfusion Method and Analysis
50 Images per slice (15) WM
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
12
SJHG04: Tumor
SJHG04: Diffusion Tensor Imaging (DTI)
Caud
gC
LALIC
C
Put
RALI
C
LPLIC
RPLI
C
RThal LTha
l
sCC
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
13
End
!
Alberto Broniscer,
Broniscer, MD, PhD
Fred Laningham,
Laningham, MD
David W. Ellison, MD, PhD, MRCP (UK), FRCPath
Comments
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