Valoración anatomopatológica de los gliomas: clasificación

Transcription

Valoración
anatomopatológica de los
gliomas:
clasificación y diagnóstico Aurelio Hernández Laín
Sección Neuropatología
Hospital Universitario 12 de Octubre
S
Grados de la OMS Predicen el comportamiento biológico del tumor Otros: edad, estado funcional, extensión resección •  Grado I: Bien circunscritos, crecimiento lento, baja proliferación, posibilidad de curación con resección solamente Figure 9. The 2007 WHO Classification of
Tumours of the Central Nervous System. A
highly illustrated, state-of-the-art text replete
with in-depth treatment of molecular and
genetic aspects of the lesions.
•  Grado II: En general infiltrantes y suelen recurrir a pesar de baja proliferación Brain Pathology 19 (2009) 551–564
© 2008 The Author; Journal Compilation © 2008 International Society of Neuropathology
•  Grado III: Signos histológicos de malignidad, como aCpia y mitosis abundantes. Suelen requerir tratamiento adyuvante. •  Grado IV: Muy malignos histológicamente. Suelen tener evolución muy rápida y mal pronósCco 563
Acta Neuropathol (2007) 114:97–109
107
Table 2 WHO Grading of Tumours of the Central Nervous System. Reprinted from Ref. 35
I
II
III
IV
I
II
III
IV
Astrocytic tumours
Subependymal giant cell
astrocytoma
•
Pilocytic astrocytoma
•
Central neurocytoma
•
Extraventricular neurocytoma
•
Cerebellar liponeurocytoma
•
•
Paraganglioma of the spinal cord
•
Diffuse astrocytoma
•
Papillary glioneuronal tumour
•
Pleomorphic xanthoastrocytoma
•
Rosette-forming glioneuronal
tumour of the fourth ventricle
•
Pilomyxoid astrocytoma
Anaplastic astrocytoma
•
Glioblastoma
•
Giant cell glioblastoma
•
Pineal tumours
Gliosarcoma
•
Pineocytoma
•
Pineal parenchymal tumour of
intermediate differentiation
Oligodendroglial tumours
Oligodendroglioma
•
Anaplastic oligodendroglioma
•
Oligoastrocytic tumours
•
Anaplastic oligoastrocytoma
•
Subependymoma
•
Myxopapillary ependymoma
•
•
Anaplastic ependymoma
•
Choroid plexus tumours
•
CNS primitive neuroectodermal
tumour (PNET)
•
Atypical teratoid / rhabdoid tumour
•
Schwannoma
•
Neurofibroma
•
Perineurioma
•
Malignant peripheral nerve
sheath tumour (MPNST)
•
Atypical choroid plexus papilloma
•
•
•
•
•
Choroid plexus carcinoma
•
Meningeal tumours
Meningioma
•
Atypical meningioma
Other neuroepithelial tumours
•
•
Anaplastic / malignant meningioma
•
Haemangiopericytoma
Chordoid glioma of
the third ventricle
•
•
Anaplastic haemangiopericytoma
Haemangioblastoma
•
•
Neuronal and mixed neuronal-glial tumours
Gangliocytoma
•
Tumours of the sellar region
Ganglioglioma
•
Craniopharyngioma
•
Granular cell tumour
of the neurohypophysis
•
•
Pituicytoma
•
•
Spindle cell oncocytoma
of the adenohypophysis
•
Anaplastic ganglioglioma
Dysembryoplastic
neuroepithelial tumour
•
Tumours of the cranial and paraspinal nerves
Ependymoma
Desmoplastic infantile astrocytoma
and ganglioglioma
•
•
Papillary tumour of the pineal region
Medulloblastoma
Ependymal tumours
Angiocentric glioma
•
Embryonal tumours
Oligoastrocytoma
Choroid plexus papilloma
•
Pineoblastoma
•
•
clear.7 A genetic predisposition to gliomas is well
own in the setting of rare familial tumour syndromes
, type 1 and type 2 neurofibromatosis due to NF1 and
2 mutations, Li Fraumeni syndrome due to TP53
tations, melanoma-astrocytoma syndrome due to
KN2A mutations, tuberosis sclerosis due to TSC1
d TSC2 mutations, Turcot syndrome due to mismatch
air genes mutations, and Cowden syndrome due to
EN mutations). However, most gliomas (>90%) do
occur in these particular genetic syndromes, sugting that complex genetic abnormalities
combined
N E U RO - O N CO LO GY
h unknown environmental factors predispose indivCBTRUS Two
Statistical
Report:
Primary Brain association
and
als to glioma.
large
genome-wide
Central Nervous System Tumors Diagnosed
dies using
high-throughput technologies have conin the United States in 2005–2009
ently identifi
ed two single nucleotide polymorphisms
Therese A. Dolecek, Jennifer M. Propp, Nancy E. Stroup, and Carol Kruchko
NPs) associated with an increased risk of glioma.
ese susceptibility loci are located in genes driving
cial cell T
functions, including cell cycle (CDKN2B)
d telomere length regulation (RTEL1).8,9 Additional
Ps have been associated with an increased risk for
oma, but investigations to validate these results
warranted.10
Low-grade glioma (WHO grade 2)
Astrocytoma
Glioma malignant
Glioblastoma
Primary CNS lymphoma
Embryonal tumours/medulloblastoma
Hemangioblastoma
Germ cell
Pituitary
Craniopharyngioma
Ependymoma/anaplastic ependymoma
Meningioma
Unclassified tumours
Neuro-Oncology 14:v1– v49, 2012.
doi:10.1093/neuonc/nos218
Background
The Central Brain Tumor Registry of the United States
(CBTRUS) is a unique professional research organization that focuses exclusively on providing quality statistical data on population-based primary brain and CNS
incident tumors in the United States. CBTRUS is currently the only population-based site-specific registry in the
United States that works in partnership with a public
surveillance organization, the National Program of
Central Registries (NPCR), and from which data are
directly received under a special agreement. This agreement permits transfer of data through the NPCR-CSS
Submission Specifications mechanism,1 the system utilized for collection of central (state) cancer data as mandated in 1992 by Public Law 102-515, the Cancer
Registries Amendment Act.2 CBTRUS combines the
NPCR data with data from the SEER program3 which
was established for national cancer surveillance in the
early 1970s. Working with these premier surveillance organizations enables CBTRUS to report high quality data
on brain and CNS tumors that are useful to the communities it serves.
Since 1995, CBTRUS has self-published fourteen
reports that have contributed to the surveillance of
brain and CNS tumors in the United States. As a result
of partnering with the Society for Neuro-Oncology
(SNO)4, this fifteenth CBTRUS report is the first to be
published as a supplement to Neuro-Oncology, the official journal of SNO and marks an historic milestone for
both organizations.
CBTRUS was incorporated as a nonprofit 501(c)3
organization with a founding and sustaining grant
from the Pediatric Brain Tumor Foundation in 1992 following a two – year study conducted by the American
Brain Tumor Association to determine the feasibility of
a central registry for all primary brain and CNS tumor
cases in the United States. Until that time, standard
data reporting in the United States had been limited to
only malignant cases. Non – malignant brain tumors,
those classified as having a benign or uncertain behavior,
however, may, and often do, impose similar costs to
society in terms of medical care, case fatality, and lost
productivity as do malignant brain tumors. In addition,
as molecular markers have been discovered, it has
become clear that certain non – malignant brain tumors
may become malignant over time.
Passed in 2002, the Benign Brain Tumor Cancer
Registries Amendment Act (Public Law 107 –260)5 expanded the collection of primary brain and CNS tumor incidence data by the NPCR to include non-malignant brain
and CNS tumors having International Classification of
Diseases for Oncology Third Edition (ICD-O-3)6 codes
beginning with the 2004 diagnosis year. All central
(state) cancer registries now include these data in their collection practices. Starting in 2004, Uniform Data
Standards (UDS) as directed by the North American Association of Cancer Registries (NAACCR)7, an umbrella organization for tumor registries, governmental agencies,
professional associations and private groups, guide the
collection of required information on non-malignant
brain and CNS tumors; in 2005, the UDS for the collection of malignant brain and CNS tumors were revised.
The Multiple Primary and Histology Coding Rules for
malignant and non-malignant brain and CNS tumors
have been undergoing revision in 2012 under the leadership of SEER.
The CBTRUS database contains the largest aggregation of population–based data on the incidence of all
hological and molecular classification
Downloaded from http://neuro-oncology.oxfordjournals.org/ at Hospital Doce de Octubre on November 1, 2012
Introduction
he objective of CBTRUS Statistical Report:
Primary Brain and Central Nervous System
Tumors Diagnosed in the United States in
2005 –2009 is to provide a current and comprehensive
review of the descriptive epidemiology of primary
brain and central nervous system (CNS) tumors in the
United States population. CBTRUS has obtained data
on all primary brain and CNS tumors from the Centers
for Disease Control and Prevention, National Program
of Cancer Registries (NPCR) and the National Cancer
Institute, Surveillance, Epidemiology and End Results
(SEER) program for diagnosis years 2005 – 2009.
Incidence counts and rates of primary malignant and
non-malignant brain and CNS tumors are documented
by histology, gender, age, race, and Hispanic ethnicity.
omas can originate from neural stem cells, progenitor
s,12 or from de-differentiated mature neural cells13
nsformed into cancer stem cells (figure 3). Tumour
m cells are thought to have a key role in treatment
istance.14 However, WHO classification15 still relies on
milarities between tumour cells and mature normal
l cells to distinguish astrocytomas, oligodendroomas, and mixed oligoastrocytomas. Analysis of
mour differentiation, cellularity, cytonuclear atypia,
otic activity, microvascular proliferation, and necrosis
ther enables grading of the tumour as grade 2 (diffuse
11
Figure 1: Respective yearly incidence of the different primary brain tumour types in adults aged 65–74 years
between 1998 and 2002
This distribution is representative of the distribution of primary brain tumours in adults aged 20–84 years. Data
taken from the Central Brain Tumor Registry of the United States.2
A
B
C
1
2
3
# The Centers for Disease Control. Published by Oxford University Press on behalf of the Society for Neuro-Oncology
in cooperation with the Central Brain Tumor Registry 2012.
4
D
3
2
ppm
1
0
•  E Ricard D et al. Lancet. 2012 May •  Dolecek TA et al. Neuro Oncol. 2012 Nov Acta Neuropathol (2007) 114:97–109
107
Table 2 WHO Grading of Tumours of the Central Nervous System. Rep
Table 2 WHO Grading of Tumours of the Central Nervous System. Reprinted from Ref. 35
I
II
III
IV
I
II
III
IV
Astrocytic tumours
astrocytoma
•
•
Central neurocytoma
•
Extraventricular neurocytoma
•
Cerebellar liponeurocytoma
Paraganglioma of the spinal cord
•
Diffuse astrocytoma
•
•
•
•
•
Papillary glioneuronal tumour
•
Rosette-forming glioneuronal
tumour of the fourth ventricle
•
Glioblastoma
•
•
Pineal tumours
Gliosarcoma
•
Pineocytoma
I
intermediate differentiation
Oligodendroglioma
•
•
•
•
Ependymal tumours
Subependymoma
•
Myxopapillary ependymoma
•
•
Papillary tumour of the pineal region
•
•
•
Anaplastic ependymoma
•
Choroid plexus tumours
•
CNS primitive neuroectodermal
tumour (PNET)
•
Atypical teratoid / rhabdoid tumour
•
Schwannoma
•
Neurofibroma
•
Perineurioma
•
Malignant peripheral nerve
sheath tumour (MPNST)
•
Atypical choroid plexus papilloma
Medulloblastoma
Tumours of the cranial and paraspinal nerves
Ependymoma
•
•
•
•
•
•
Choroid plexus carcinoma
•
•
Atypical meningioma
Other neuroepithelial tumours
•
•
•
Ganglioglioma
•
Anaplastic ganglioglioma
•
•
Diffuse astrocytoma
•
•
•
•
Craniopharyngioma
•
Granular cell tumour
of the neurohypophysis
Gliosarcoma
•
•
•
Tumours of the sellar region
•
•
Haemangioblastoma
•
•
•
•
•
Anaplastic haemangiopericytoma
Neuronal and mixed neuronal-glial tumours
Gangliocytoma
IV
Glioblastoma
Anaplastic / malignant meningioma
Haemangiopericytoma
Chordoid glioma of
the third ventricle
astrocytoma
Meningeal tumours
Meningioma
Angiocentric glioma
•
Embryonal tumours
Oligoastrocytoma
Choroid plexus papilloma
•
Pineoblastoma
III
Astrocytic tumours
•
Pineal parenchymal tumour of
II
Desmoplastic infantile astrocytoma
and ganglioglioma
•
Pituicytoma
•
Dysembryoplastic
neuroepithelial tumour
•
Spindle cell oncocytoma
of the adenohypophysis
•
Oligodendroglioma
123
•
•
Oligoastrocytoma
Ependymal tumours
•
•
WHO 2007 GRADO I GRADO II GRADO III GRADO IV ASTROCITOMA ASTROCITOMA II ñCelularidad, ACpia 6-‐8 años ASTROCITOMA ANAPLASICO III Mitosis 3 años GBM Necrosis y/o prolif vascular 1-‐2 años OLIGO-‐
ASTROCITOMA OLIGO-‐ ASTROCITOMA II ñCelularidad, ACpia 6 años OLIGO-‐ ASTROCITOMA ANAPLASICO III Mitosis signif, prolif vascular prominent 3 años GBM-‐O (OA-‐IV) Necrosis >GBM? OLIGO-‐ DENDROGLIOMA OLIGODENDRO-‐ GLIOMA II ñCelularidad, ACpia 12 años OLIGO-‐ DENDROGLIOMA ANAPLASICO III Mitosis signific, prolif vascular prominent, necrosis 3 a >10 años ASTROCITOMA PILOCÍTICO Astrocitoma (fibrilar) Astrocitoma (GemisCocíCco) Oligodendroglioma OligoAstrocitoma Mitosis Proliferación vascular Necrosis WHO 2007 GRADO I GRADO II GRADO III GRADO IV ASTROCITOMA ASTROCITOMA II ñCelularidad, ACpia 6-‐8 años ASTROCITOMA ANAPLASICO III Mitosis 3 años GBM Necrosis y/o prolif vascular 1-‐2 años OLIGO-‐
ASTROCITOMA OLIGO-‐ ASTROCITOMA II ñCelularidad, ACpia 6 años OLIGO-‐ ASTROCITOMA ANAPLASICO III Mitosis signif, prolif vascular 3 años GBM-‐O (OA-‐IV) Necrosis >GBM? OLIGO-‐ DENDROGLIOMA OLIGODENDRO-‐ GLIOMA II ñCelularidad, ACpia 12 años OLIGO-‐ DENDROGLIOMA ANAPLASICO III Mitosis signific, prolif vascular prominent, necrosis 3 a >10 años ASTROCITOMA PILOCÍTICO GFAP p53 MIB-‐1 “Pigalls” Clasificación WHO 2007 Acta Neuropathol (2010) 120:297–304
DOI 10.1007/s00401-010-0725-7
REVIEW
were less serious but still had substantial potential to
affect patient care decisions or prognosis. This group
included cases in which we changed the type or grade
of a primary glioma. We are currently using a threetiered system of astrocytoma grading,1 and we consider later in this article the implications of our changing grades in this category if other pathologists were
using the four-tiered system of St. Anne – Mayo.2
The third group, minor discrepancies, comprised
cases in which we added or deleted some information or
merely confirmed a tentative or doubtful diagnosis. The
fourth group comprised cases in which we made the initial diagnosis. These cases were submitted by pathologists
who could not arrive at a diagnosis and requested our
opinion before rendering theirs. The fifth group comprised cases in which there was no discrepancy between
the submitted diagnosis and ours.
Interobserver variation of the histopathological diagnosis
in clinical trials on glioma: a clinician’s perspective
Martin J. van den Bent
2342
•  Variabilidad inter-‐observador hasta 40%, FIGURE 1.
Discrepancies in Diagnoses of Neuroepithelial
siendo relevante clínicamente, afectando Neoplasms
RESULTS
manejo terapéuCco y pronósCco, hasta . the problem
A 5-‐15% case report illustrating
Abstract Several studies have provided ample evidence
of a clinically significant interobserver variation of the
May 2008, the t
principal
investigator
of anp
EORTC
study
histological diagnosis of glioma. This interobserver varia-•  In Sobre odo e
ntre atólogos generales/
on anaplastic glioma (CATNON) was contacted by the
tion has an effect on both the typing and grading of glial
local investigator of one of the participating institutions. A
tumors. Since treatment decisions are based on histological
neuropatólogos y insCtuciones locales-‐ brain tumor patient operated and diagnosed in a third
diagnosis and grading, this affects patient care: erroneous
institution as anaplastic astrocytoma (AA) (Fig. 1a–d) was
classification and grading may result in both over- and
privadas/académicas. Pero incluso entre referred
for further treatment, and the local investigator
undertreatment. In particular, the radiotherapy dosage
was considering to enter the patient in the CATNON study.
and the use of chemotherapy are affected by tumor grade
However,
his own pathologist had diagnosed
a low grade
and lineage. It also affects the conduct and interpretation of
neuropatólogos expertos. astrocytoma. The local investigator asked how this patient
clinical trials on glioma, in particular of studies into grade
be treated,2and
if he was eligible
for the study or
II and grade III gliomas. Although trials with central•  should
0-‐30% reclasificación cuando existe / Hasta 7b4c$$0894
15:20:58
cana
W: Cancer
whether
he should be01-24-97
entered in
another study
on low grade
pathology review prior to inclusion will result in a more
glioma. It was decided to submit the tumor material for
homogeneous patient population, the interpretation and
un pathology
panel revisor central
review
that is part ofindependiente. the CATNON
external validity of such trials are still affected by this, and
Numbers of cases, with and without discrepancies, from the
referred patient group and the consultation-only group are shown. The
500 cases were grouped into referred patient cases or consultation-only
cases, and the total discrepancy rate in each group was determined. The
overall rate of disagreement between the submitted and review diagnoses
was 42.8%.
2344
CANCER May 15, 2000 / Volume 88 / Number 10
Received:
27 JuneBay
2010
/ Revised:
8 July 2010
July 2010 / Published
online: 20
July 2010 in Table 1. ReA summary
of our results
is presented
The
San Francisco
Area
Adult Glioma
Study/ Accepted: 11
! The Author(s) 2010. This article is published with open access
at
Springerlink.com
ferred patient cases comprised 43.2% of the 500 cases
TABLE 1
oma and oligoastrocytoma 47% and 25% of the time,
(n Å 216), and consultation-only cases comprised
San Francisco Bay Area Adult Glioma Study, 1991–1995. Concordant
respectively. There were no disagreements among the
56.8% (n Å 284). Of the 284 consultation-only cases,
and
DiagnosesValid
Sorted
by Review
and reliable
diagnoses of disease are key both to meaningful
Ken Discordant
Aldape, M.D.1 Initial versus ReviewBACKGROUND.
4 sent
cases
which
initial studies
diagnosis
juvenile piloepidemiologic and clinical investigations 85
and towere
decision-making
about
Martha L. Simmons, M.D., Ph.D.1
asinappropripart
of an
protocol
forofsecond
of 284 (48.9%) were consultation-only cases. For all of
Diagnosis
1
cytic
was made.
Anremainder
initial diagnosis
of remaining 214 of 500 cases (42.8%), there was at
opinions
withastrocytoma
regard to therapy.
In the
of
the
medulloblastoma
was
never
in
disagreement,
nor
was
Total
no.diagnostic
(%)
Total
(%)
explores
discrepancies
in no.
a population-based
glioma
by
cases,
we adult
made
orseries
confirmed
diagnoses at the request
least a minor disagreement between the submitting
hospital of origin, specialty training
of the original diagnosing
pathologist, and
concordant
discordant
the diagnosis
of medulloblastoma
made
by the
review
of
pathologists
or
other
attending
physicians,
such
as
pathologist
and us, or the diagnosis had been in doubt
clinical significance.
pathologist
inor
any
case in which this was not the initial
METHODS. To confirm patients’ eligibility
for the San
Francisco Adult Glioma
surgeons,
internists,
radiotherapists.
at
the
submitting
institution (Fig. 1). Discrepancies
240
(89%)
30 (11%) pathology specimens and conducted a
Study,
the authors obtained participants’
diagnosis.
The
largest
discrepancy
in
diagnostic
cateIn
286
(57.2%)
of
the
500
cases,
we
completely
were
thus
noted
in
69 of 216 referred patient cases
42uniform
(77%)secondary neuropathology
15 (27%)
review. Eligible patients were all adults age 20
or older newly diagnosed 4
with
glioma between August
1, 1991,
and March 31,when the initial diagnosis was astrocyDepartment of Pathology, University of California,
gory
occurred
Astrocytoma
21years
(84%)
(16%)
agreed
with
the
referring
pathologist;
147
of
216
(31.9%)
and
in
145
of 284 consultation-only cases
School of Medicine, San Francisco, California.
1994, who resided in 1 of 6 San Francisco Bay Area counties.
2RESULTS.
(33%) Overall, the original 4and(67%)
toma.
Only
21
of
55
cases
(38%)
so
classified
originally
secondary
diagnoses
were
the
same
(concor(68.0%)
of
these
were
referred
patient
cases,
and
139
(51.0%)
(Fig.
1).
Department of Epidemiology and Biostatistics,
Oligodendroglioma
11dant)
(41%)
16 (59%)
for 352 (77%) of the 457 cases
available for study.received
Twenty-six percent
of the
University of California, School of Medicine,
this
diagnosis on secondary review. Of the
San
Francisco, California.
from community hospitals
discordant, compared with 12% of the cases
Oligoastrocytoma
21cases
(48%)
22were
(52%)
remaining
34
cases,
2 were diagnosed as glioblastoma,
from
academic
hospitals
P
!
0.004.
Of
the
105
discordant
diagnoses,
17
(16%)
were
Department
of Neurology,
Wayne State University
Juvenile
pilocytic
astrocytoma
4determined
(44%) to be clinically significant,
5 (56%)defined as a difference that could signifiSchool of Medicine, Detroit, Michigan.
3
as
juvenile
pilocytic
astrocytoma (JPA), 1 as anaplasAnaplastic ependymoma
1cantly
(50%)alter patient management
1 (50%)
and/or prognosis. Sixteen of these 17 cases
and only 1 originated
at a hospital with a
tic ependymoma,
1 as astrogliosis, 1 as a congenital
Ependymoma
2originated
(67%) at community hospitals,
1 (33%)
Based on the distribution of review diagnoses, subjects presentGanglioglioma
1neuropathologist.
(50%)
1 (50%)
glial cyst, 8 as anaplastic astrocytoma, 1 as ependying at nonacademic hospitals were more likely than those presenting at academic
Medulloblastoma
6hospitals
(100%)to have glioblastoma 0(61%
(0%)
vs. 52%; P ! 0.07).
moma, 6 as oligodendroglioma, and 11 as oligoastroSubependymoma
1CONCLUSIONS.
(100%)
The percentage 0of (0%)
cases with discrepant original and review diagon review.
In contrast, 21 of 24 cases (88%)
community hospitals
withOther
0noses
(0%)was higher among those 6originally
(100%)diagnosed at cytoma
out a neuropathologist than among those originally diagnosed at an academic
diagnosed
as
astrocytoma
secondaryofreview
had
study.
This
study
requiresby
confirmation
the pathological
the
question
whether
results
of
such
trials
can
be
generalTotal
352
(77%)
105 (23%)
hospital with a neuropathologist. Clinically significant discrepancies were much
Presented in part at the annual meetings of the
received
this
as
the
original
diagnosis
(Table
1).
more
likely
to
have
originated
at
a
community
hospital
without
a
neuropathologist.
diagnosis by either one of two independent pathologists.
ized
to patients
diagnosed
and treated elsewhere remains to
Society
of Neuro-Oncology,
San Francisco,
Califora nia, November 1998, and the North American AsThese data highlight the importance of review of brain tumors by a neuropatholDiagnosis was established by a review pathologist (R.L.D.).
Overall,
of theof105
17 (16%)for the
diagnosis
thediscrepant
first centraldiagnoses,
review pathologist
be ofanswered.
molecular
classification
may
helpA separateThe
sociation
Cancer Registries, Although
Chicago, April
ogist prior to decision-making
regarding
treatment.
implication
of this
1999.
study is that glioma cases selected exclusively from were
academic deemed
or nonacademic
clinically
significant,
57
(54%)
were
clin-patient
CATNON study was AA, and because of this the
in typing and grading tumors, as of today this is still in its
Richard L. Davis, M.D.
Rei Miike, B.S.2
John Wiencke, Ph.D.2
a 3
Geoffreydiagnosis
Barger, M.D.
Review
Marion Lee, Ph.D.2
Pengchin Chen, Ph.D.2
Glioblastoma
Margaret Wrensch, Ph.D.2
ate treatment. One previous study highlighted the lack of precision in diagnosing
primary brain tumors in a neuropathology referral practice. The current study
1
2
3
•  van den Bent MJ. Acta Neuropathol. 2010 •  Aldape K et al. Cancer 2000 •  Bruner JM et al. Cancer 1997 Glioma Classification 785
AJP September 2001, Vol. 159, No. 3
ial
nty,
as
of
ng
m
of
he
su-
Figure 5. Future classifications. These will be based on input from traditional
as well as molecular analyses, and will involve both tissue-based and imaging
modalities. The classification will have to incorporate new frameworks based
on biological advances. Most significantly, the classification will have to
correlate closely with clinically relevant endpoints and,•  asLouis newDN outcome
et al. Am J Pathol. 2001 ecular pathways and common genetic alterations in astrocytic, oligodendroglial, and oligoastrocytic neopla
tion; BRAF, v-raf murine sarcoma viral oncogene homolog B1 gene; CDKN2A/B, cyclin-dependent kinase in
idermal growth factor receptor gene; GBM, glioblastoma multiforme; IDH, isocitrate dehydrogenase gene; mu
d tensin homolog gene; TP53, tumor protein p53 gene; WHO, World Health Organization.
•  Nikiforova MN, Hamilton RL. Arch Pathol Lab Med. 2011 • 
Fig. 1 Summary of most frequent molecular alterations in astrocytic,
Riemenschneider Mcarry
J et mutations
al. Acta inNIDH1
europathol. 2010 glioblastomas frequently
or IDH2, suggesting
1p19q PCR FISH Arrays CGH ure 2. Detection of 1p deletion in oligodendroglial tumors by fluorescent in situ hybridization (FISH) and loss of heterozygosity (LOH) analy
•  Bello MJ, Roriginal
ey JA emagnification
t al. Int J Cancer. 3100). 1
B,994 Schematic representation
Oligodendroglioma (World Health Organization grade II; hematoxylin-eosin,
omosome
1 and location
of FISH
probes
and LOH microsatellite• markers.
The mostM
commonly
used FISH
probe
locatedLat
par
Nikiforova N, Hamilton RL. A
rch Pisathol ab the
Mtelomeric
ed. 2011 Polisomia en FISH: Peor pronósCco at 1p36.32, and microsatellite markers are located from 1p22 to• 1p36.32,
allowing
for
detailed
evaluation
of
the
1p
region.
C,
Analysis
of
FI
Snuderl M
e
t a
l C
lin C
ancer R
es. 2
009 monstrates loss of 1p chromosomal arm (one red signal LSI 1p36 SpectrumOrange probe, counterstained with DAPI) and presence of 2 gre
Wiens AL et SpectrumGreen
al. J Neuropathol Neurol. 2012 nals that correspond to the 1q control probe in interphase • nuclei
(LSI 1p25
probe,Exp counterstained
with DAPI, origi
1p19q Weller et al.: Prognostic and predictive value of molecular factors in gliomas
Table 2. Frequently asked questions in the molecular neuro-oncology of gliomas in adulthood
80-‐90% O-‐II 50-‐70% O-‐III 1p/19q codeletion
Can I use the 1p/19q status for diagnostic
purposes?
Is the 1p/19q status homogeneous within
gliomas?
Sometimes. The presence of the 1p/19q codeletion supports, but the absence of
this alteration does not rule out, the diagnosis of an oligodendroglial tumor.
Yes. This is confirmed at least in grades II and III tumors, whereas no data exist for
glioblastoma.
Can I use the 1p/19q status for prognostic
purposes?
Yes. The 1p/19q codeletion is a strong prognosticator in anaplastic glioma patients
receiving RT or alkylating agent chemotherapy or both. Its role in low-grade
gliomas is less clear but likely to be similar.
Can I use the 1p/19q status as a predictive
marker for clinical decision making?
Yes. The RTOG 9402 and EORTC 26951 trials suggest that the 1p/19q codeletion
is a predictive marker for improved survival for patients treated with PCV in
addition to RT vs RT alone. Whether this holds true for TMZ too is not known.
MGMT promoter methylation
Can I use the MGMT status for diagnostic
purposes?
Is the MGMT status homogeneous within
gliomas?
Does the MGMT status change in the course of
disease?
Can I use the MGMT status for prognostic
purposes?
Can I use the MGMT status as a predictive
IDH1/2 mutations
Can I use the IDH1/2 status for diagnostic
No.
Yes.
No. Most gliomas show the same MGMT status at recurrence.
•  Cairncross JG et al. J Natl Cancer Inst. 1998 Yes. MGMT promoter methylation
is positively
inO
anaplastic
glioma
•  Cairncross G eprognostic
t al. J Clin ncol. 2006 patients receiving RT or chemotherapy or both (NOA-04, EORTC 26951).
•  Cairncross G et al. J Clin Oncol. 2013 Yes. MGMT promoter methylation predicts benefit from alkylating agent
•  van (EORTC
den Bent MJ and
et isal. J Clin Oncol. chemotherapy in glioblastoma
26981)
particularly
useful 2
in006 elderly
glioblastoma patients (NOA-08,
trial).MJ et al. J Clin Oncol. 2013 •  van dNordic
en Bent •  Weller M et al. NeuroOncol 2012 Yes. IDH1/2 mutations are common in WHO grades II and III gliomas and can aid
er the same improvement in
ave been achieved with the
py and temozolomide, or even
ed chemotherapy alone, is
NOA-04 trial, which compared
mide or PCV alone,15 does not
wer about differences in longCV Genes versus temozolomide
candidatos Csince
IC they time
of initial publication.
FUBP1 hould probably include radiomotherapy as a control group.
1p19q ion
GMT repairs the chemotherapyO⁶-position of guanine, the
ting drug cytotoxicity, and thus
alkylating chemotherapeutic
as or temozolomide. Reduced
ions result in decreased ability
efore can be associated with
ents. Hyper
methylation of the
Adjuvant Procarbazine, Lomustine, and Vincristine
Progression-Free Survival but Not Overall
ght lead toImproves
silencing
ofAnaplastic
the gene
Survival
in Newly Diagnosed
VOLUME
24
!
NUMBER
18
JUNE
!
20
2006
JOURNAL OF CLINICAL ONCOLOGY
From the Departments of Neurology
and Pathology, Daniel den Hoed Cancer
Medical Center Haaglanden/Westeinde
Ziekenhuis, the Hague; Canisius
Wilhemina Ziekenhuis, Nijmegen;
Department of Neurology, Elisabeth
Gasthuis, Tilburg; Department of
Neurology, Academisch Ziekenhuis
Groningen, the Netherlands; Depart-
Martin J. van den Bent, Antoine F. Carpentier, Alba A. Brandes, Marc Sanson, Martin J.B. Taphoorn,
Hans J.J.A. Bernsen, Marc Frenay, Cees C. Tijssen, Wolfgang Grisold, Laslo Sipos, Hanny Haaxma-Reiche,
Johannes M. Kros, Mathilde C.M. van Kouwenhoven, Charles J. Vecht, Anouk Allgeier, Denis Lacombe,
and Thierry Gorlia
4 August 2013
ment of Neurology, Centre Hospitalier
Universitaire Pitié-Salpétrière, Paris;
VOLU
E 2 4 Centre
! NUMBER
Department
ofM
Neurology,
Medical Oncology DepartmentNeurooncology Unit, Azienda Ospedale-
R E P O R T
Oligodendrogliomas and Oligoastrocytomas: A Randomized
European Organisation for Research and Treatment of
Cancer Phase III Trial
Center/Erasmus University Hospital,
Rotterdam; Department of Neurology,
Antoine Lacassagne, Nice, France;
O R I G I N A L
18
!
JUNE
20
2006
A
B
S
T
R
A
C
T
Purpose
R I G ItoNchemotherapy
A L R Ethan
P O
R T astrocytoAnaplastic
oligodendrogliomas are moreOresponsive
high-grade
JOURNAL OF CLINICAL
ONCOLOGY
Università-Istituto Oncologico Veneto,
Padova, Italy; Ludwig Boltzmann Insti-
tute Neurooncology and Kaiser Franz
Josef Spital, Vienna, Austria; National
Institute of Neurosurgery, Budapest,
Hungary; and European Organisation for
Research and Treatment of Cancer
Data Center, Brussels, Belgium on
behalf of the European Organisation for
Research and Treatment of Cancer
Brain Tumor Group and the Medical
Research Council Clinical Trials Group.
Submitted October 17, 2005; accepted
December 14, 2005.
Supported by the European Organisation for Research and Treatment of
Cancer
Research
From
the (EORTC)
UniversityTranslational
of Calgary, Calgary,
Fund Grant
TRF 01/02,
by
Alberta;
McGillNo.
University,
Montreal,
AstraZeneca
EORTC
Translational
Quebec;
University
of Toronto,
Toronto,
Research
GrantAmerican
No. AZ/01/02,
andofby
Ontario,
Canada;
College
Dutch Cancer
Society
Grant University
No. DDHK
Radiology;
Thomas
Jefferson
2005-3416.
Medical
Center, Philadelphia, PA; Wake
mas. We investigated, in a multicenter randomized controlled trial, whether adjuvant procarbazine,
lomustine, and vincristine (PCV) chemotherapy improves overall survival (OS) in newly diagnosed
patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas.
Patients and Methods
The primary end point of the study was OS; secondary end points were progression-free survival
(PFS) and toxicity. Patients were randomly assigned to either 59.4 Gy of radiotherapy (RT) in 33
Phase
ofsame
Chemotherapy
PlusofRadiotherapy
fractionsIII
onlyTrial
or to the
RT followed by six cycles
standard PCV chemotherapy (RT/PCV).
1p and 19q deletions
assessed with fluorescent
situ hybridization.
Compared
Withwere
Radiotherapy
Alonein for
Pure and Mixed
Results
Anaplastic
Oligodendroglioma:
Intergroup
A total of 368 patients
were included. The median
follow-up timeRadiation
was 60 months, and 59% of
patients have died. In the RT arm, 82% of patients with tumor progression received chemotherTherapy
Oncology Group Trial 9402
apy. In 38% of patients in the RT/PCV arm, adjuvant PCV was discontinued for toxicity. OS time
Gregory
Brian40.3
Berkey,
Edwardcompared
Shaw, Robert
Jenkins,
Scheithauer,
David
after Cairncross,
RT/PCV was
months
with
30.6Bernd
months
after RT
onlyBrachman,
(P ! .23). RT/PCV
Janincreased
Buckner, Karen
Souhami, Normand
Mehta,
and Walter
Curran
PFS Fink,
timeLuis
compared
with RTLaperierre,
only (23Minesh
v 13.2
months,
respectively;
P ! .0018).
Twenty-five percent of patients were diagnosed with combined 1p/19q loss; 74% of this subgroup
A B S T R A C T
was still alive after 60 months. RT/PCV did not improve survival in the subgroup of patients with
1p/19q loss.
Purpose
Anaplastic
oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are treated with surgery
Conclusion
and
radiotherapy
(RT) at diagnosis,
butprolong
they also
respond
procarbazine,
lomustine,oligodenand
Adjuvant
PCV chemotherapy
does not
OS but
does to
increase
PFS in anaplastic
EORTC 26951 (n=368)
RTOG 9402 (n=291)
Radiotherapy RT→PCV
HR (95% CI)
Radiotherapy PCV→RT
HR (95% CI)
Progression-free
survival (years)
1·1
2·0
0·66
(0·52–0·83)
No data in
2013 update
..
Overall survival
(years)
2·5
3·5
0·75
(0·6–0·95)
4·7
4·6
0·79
(0·6–1·04)
All patients
No data in
2013 update
Patients with 1p/19q-codeleted tumours
Progression-free
survival (years)
4·2
13·1
0·42
(0·24–0·74)
2·9
8·4
0·47
(0·3–0·72)
Overall survival
(years)
9·3
Not
reached
0·56
(0·31–1·03)
7·3
14·7
0·59
(0·37–0·95)
Patients with 1p and 19q -non-codeleted tumours
Progression-free
survival (years)
0·7
1·2
0·73
(0·56–0·97)
1
1·2
0·81
(0·56–1·16)
Overall survival
(years)
1·8
2·1
0·83
(0·62–1·1)
2·7
2·6
0·85
(0·58–1·23)
Data are medians unless otherwise indicated. RT→PCV=radiotherapy followed by procarbacine, lomustin, and
vincristine. PCV→RT=procarbacine, lomustin, and vincristine followed by radiotherapy. HR=hazard ratio.
Table 2: Outcome by 1p and 19q codeletion status in the anaplastic oligodendroglioma trials13,14
Weller et al. Lancet Oncol 2013 Cairncross JG et al. J Natl Cancer Inst. 1998 e372
Cairncross G et al. J Clin Oncol. 2006 Cairncross G et al. Long-‐Term Results of RTOG 9402. J Clin Oncol. 2013 •  van den Bent MJ et al. J Clin Oncol. 2006 •  van den Bent MJ et al. J Clin Oncol. 2013 • 
• 
• 
• 
Weller et al.: Prognostic and predictive value of molecular factors in gliomas
T31
62
GB
MX
T30
17
GB
MX
purposes?
gliomas?
D5
6
TMZ
1p/19q codeletion
MSP
GB
MI
MGMT Table 2. Frequently asked questions in the molecular neuro-oncology of gliomas in adulthood
M U
M U
M U
glioblastoma.
40-‐90% O, A y OA: II y III Yes. The 1p/19q codeletion is a strong prognosticator in anaplastic glioma patients
40-‐60% receiving
GBM 2º RT or alkylating agent chemotherapy or both. Its role in low-grade
40% Weller et al.: Prognostic and predictive value of molecular
factorsG
inBM gliomas1º Can I use the 1p/19q status for prognostic
purposes?
Table 2.
is a predictive marker for improved survival for patients treated with PCV in
Frequently asked questions in the molecular neuro-oncology of gliomas in adulthood
Downloaded from http://neuro-oncology.oxfordjour
1p/19q codeletion
MGMT promoter
methylation
purposes?
this alteration
No. does not rule out, the diagnosis of an oligodendroglial tumor.
purposes? gliomas?
glioblastoma.
I use the
1p/19q status for prognostic
Yes. The
1p/19q codeletion is a strong prognosticator in anaplastic glioma patients
Is the MGMTCan
status
homogeneous
within
Yes.
purposes?
receiving RT or alkylating agent chemotherapy or both. Its role in low-grade
gliomas?
Can
I
use
the
1p/19q
status
as
a
predictive
Yes.
RTOG
9402 and
EORTC 26951
suggest
thatMGMT
the 1p/19qstatus
codeletion
Does the MGMT
status change in the course of is aThe
No.
Most
gliomas
showtrials
the
same
at recurrence.
predictive marker for improved survival for patients treated with PCV in
disease?
Yes. MGMT promoter methylation is positively prognostic in anaplastic glioma
No.
purposes? purposes?
patients receiving RT or chemotherapy or both (NOA-04, EORTC 26951).
the MGMT status
status homogeneous
within
Yes. Yes. MGMT promoter methylation predicts benefit from alkylating agent
Can I use theIs MGMT
as a predictive
gliomas?
marker forDoes
clinical
decision
making?
chemotherapy
glioblastoma
(EORTC 26981) and is particularly useful in elderly
the MGMT
status change
in the course of
No. Most gliomas
show the same in
MGMT
status at recurrence.
disease?
glioblastoma patients (NOA-08, Nordic trial).
IDH1/2 mutations
purposes?
patients receiving RT or chemotherapy or both (NOA-04, EORTC 26951).
Yes. MGMT promoter methylation predicts benefit from alkylating agent
Can I use the IDH1/2
status for diagnostic
Yes. IDH1/2 mutations are common in WHO grades II and III gliomas and can aid
chemotherapy in glioblastoma (EORTC 26981) and is particularly useful in elderly
glioblastoma
patients
(NOA-08, Nordic
trial).
purposes?
in the
differential
diagnosis
gliosis
glioma entities,
eg,
• vs reactive
Weller M eand
t al. other
NeuroOncol 2012 IDH1/2 mutations
pilocytic astrocytomas, gangliogliomas, and ependymomas, which typically lack
Can I use the IDH1/2 status for diagnostic
Yes. IDH1/2
mutations are
common in WHO grades• 
II andEsteller III gliomas andM
can e
aidt al. N Engl J Med. 2000 IDH1/2
mutations.
purposes?
in the differential diagnosis vs reactive gliosis and other glioma entities, eg,
• in WHO
Hegi M
E eIIlack
t and
al. NIII Etumors,
ngl J Mwhereas
ed. 2005 pilocytic
astrocytomas,
gangliogliomas,at
andleast
ependymomas,
which
typically
Is the IDH1/2 status homogeneous within
Yes.
This is confirmed
grades
no data
IDH1/2 mutations.
gliomas? Is the IDH1/2 status homogeneous within
exist
for
glioblastoma.
• 
Preusser M
e
t a
l. B
rain P
athology 2008 Yes. This is confirmed at least in WHO grades II and III tumors, whereas no data
NOA-08*
Nordic trial
RT 30x2 Gy TMZ 7/7 HR (95% CI)
(n=178)
(n=195)
RT 30x2 Gy
(n=100)
RT 10x3·4 Gy TMZ 5/28
(n=123)
(n=119)
HR (95% CI)
Not reported
··
Review
All patients
Progression-free survival (months)
4·7
3·3
1·15 (0·92–1·43),
pnon–inferiority=0·043
Overall survival (months)
9·6
8·6
1·09 (0·84–1·42),
p non–inferiority=0·033
··
6
7·5
··
8·3
atments that are
Anaplastic glioma
newly diagnosed
Patients with MGMT promoter-methylated tumours
1p/19q(months)
codeletion
Progression-free survival
4·6
8·4
0·53 (0·33–0·86),
p=0·01§
··
Not reported
··
TMZ†: 0·70 (0·52–0·93),
p=0·01; hypofractionated
RT†: 0·85 (0·64–1·12), p=0·24
··
ations in gliomas
Overall
(months)
not
0·69 (0·35–1·16),
··
8·2‡
9·7
0·64 (0·39–1·04)
CATNON
trial*
association
withsurvival Yes
No 9·6
reached p=0·14§
udies have shown
ith mutations of
tumours
11,31
entities.Patients
Most with MGMT promoter-unmethylated
IDH mutant
IDH wildtype
RT/PCV
ies showed
that
or
Progression-free
survival (months)
4·6
3·3
1·95 (1·41–2·69),
··
Not reported ··
··
RT/TMZ→TMZ†
ker for astrocytic
p=0·01
§
or
and anaplastic
TMZ†
MGMT
MGMT
RT
or (months)
trocytomas.
Thissurvival
Overall
10·4
7
1·34 (0·92–1·95),
··
7*
6·8
1·16 (0·78–1·72)
methylated
unmethylated
or
PCV†
TMZ
aling counterpart
p=
0·13
§
or
m to be mutually
PCV
RT
TMZ
most mutations
or
are
HR=hazard ratio. RT=radiotherapy. TMZ 7/7=temozolomide 7 days on, 7 days off. TMZ 5/28=temozolomide 5 of 28 days.
RT/TMZ→TMZ†
lead toData
a red
uc-medians unless otherwise indicated.
*Comprised 11% anaplastic astrocytoma. †Comparison with standard radiotherapy (30x2 Gy). ‡Both radiotherapy groups pooled. §TMZ relative to all patients receiving RT
nohistochemical
Figure 1: Biomarker-based approach to anaplastic glioma
be a reasonable
(with or without
MGMT
promoter
methylation)
which
Yellow boxes
indicate
new standard
practice. Blue boxes
indicatewere
practicepooled
needs because they had a similar outcome in NOA-08.
ombination of 1p to be confirmed. RT=radiotherapy. PCV=procarbacine, lomustin, and vincristine.
nts in a clinical RT/TMZ TMZ=radiotherapy plus temozolomide followed by temozolomide.
Table 3: Outcome by MGMT promoter methylation status in trials of elderly patients with glioblastoma (anaplastic astrocytoma)24,25
nosis within the *ClinicalTrials.gov, number NCT00626990. †Alternative options.
the long-term to
Glioblastoma
followed by temozolomide. However, none of these trials
will clarify whether patients with MGMT promoterg of paediatric
Clinical trial?
Clinical trial?
Age ≤65–70 years
Age >65 years
estigators
of two
methylated
tumours should be managed with
in the H3F3A
temozolomide
alone or with radiotherapy plus
ritical
aminoacid
RT/TMZ →TMZ
MGMT methylated
MGMT unmethylated
he two
H3F3A
temozolomide
followed by temozolomide.
etic subgroups of
RT
gliomas, by contrastTMZ
with most primary
mutant Anaplastic
tumours
or
Moreover, H3F3A
RT/TMZ→TMZ*
glioblastomas, show distinct genetic
and epigenetic
IDH1 mutations,
anaplastic gliomas, MGMT promoter methylation is part
of the G-CIMP phenotype whereas G-CIMP is rare in
primary glioblastoma.28 An analysis of the NOA-04 trial
and validation cohorts from NOA-08 and the German
•  Weller et al. Lancet ncol 2013 MGMT
Glioma Network
indicated
that Omethylated
Wick et al. Lancet Oncol outcome
2012 with
promoter • status
is W
associated
with better
•  Malmström A et al. Lradiotherapy
ancet Oncol 2in012 chemotherapy
with or without
the
IDH Secuencian 445 tumores SNC y 494 no-‐SNC Mutaciones en 85% grado II, III y 2ºGBM •  Yan H et al. N Engl J Med. 2009 1
F
A
B
C
D
E
F
G
H
I
J
K
L
C
E
D
2
H
G
I
J
3
4
L
K
Figure. Immunohistochemically revealed infiltration extent. The left column of images show Luxol fast blue/periodic acid–Schiff stainings of large paraffin sections for all
4 cases (1, 2, 3, and 4). Shadowing in gray indicates tumor portions apparent on macroscopic inspection. Immunohistochemically revealed infiltrating tumor cells are
indicated by black dots (large dots: 10%-50% tumor cells, small dots: !10% tumor cell fraction of total cells; examples are given in the top left corner of 1C [large dots]
and 1D [small dots]). The top right row shows magnetic resonance imaging (1A) and an unstained macroscopic section (1B) for case 1. Microscopic images of H09
immunohistochemical analysis below this row in the right column correspond to frame insets in respective Luxol fast blue/periodic acid–Schiff stainings (1C [original
magnification "100] and 1D-1F [original magnification "200], 2G [original magnification "200], 2H [original magnification "100], 2I [original magnification "400],
2J [original magnification "200], and 3K and L [original magnification "400]). Representative examples for detection of single cells are depicted in 2I, 3K, and 3L.
•  Capper D et al. Acta Neuropathol. 2009 •  Sahm F et al. Arch Neurol. 2012 Does the MGMT status change in the course of
disease?
IDH No. Most gliomas show the same MGMT status at recurrence.
Weller
et
al.:
Prognostic
and
predictive
value
of
molecular
factors
in gliomas
purposes?
patients
receiving RT or chemotherapy or both (NOA-04, EORTC 26951).
Table 2. Frequently asked questions in the molecular neuro-oncology of gliomas in adulthood
marker for clinical
decision making?
chemotherapy in glioblastoma (EORTC 26981) and is particularly useful in elderly
glioblastoma patients (NOA-08, Nordic trial).
1p/19q codeletion
I use the 1p/19q status for diagnostic
IDH1/2 mutations Canpurposes?
Is thestatus
1p/19q status
homogeneous within
for diagnostic
gliomas?
purposes?
Can I use the 1p/19q status for prognostic
purposes?
Yes. IDH1/2
This is confirmed
at least in grades
II and III tumors,
whereas no
data exist
Yes.
mutations
are common
in WHO
grades
II for
and
glioblastoma.
III gliomas and can aid
Yes. The 1p/19q codeletion is a strong prognosticator in anaplastic glioma patients
pilocytic
gangliogliomas,
which typically lack
receiving RTastrocytomas,
or alkylating agent chemotherapy
or both. Itsand
role inependymomas,
low-grade
gliomas is less
clear but likely to be similar.
IDH1/2
mutations.
Yes.is This
is confirmed
at least
in for
WHO
grades
II and
III tumors, whereas no data
a predictive
marker for improved
survival
patients
treated with
PCV in
addition
to
RT
vs
RT
alone.
Whether
this
holds
true
for
TMZ
too
is
not
known.
exist for glioblastoma.
for prognostic
Can Istatus
use the MGMT
purposes?
purposes?
Yes.
No. IDH1/2 mutations are prognostically favorable, in particular in WHO grades III
and IV gliomas.
Is the MGMT status homogeneous within
Yes.
Downloaded from http://neuro-oncology.oxfordjournals.org/ at Hospital Doce de Octubre on No
Is the IDH1/2 status marker
homogeneous
within
for clinical decision
making?
gliomas?
status as a predictive
No.
gliomas?
Agios PharmaceuCcals has developed potent and orally available Does
the MGMTmaking?
status change in the course of
No. Most gliomas show
the sameinhibitors MGMT statusoat
marker for clinical
decision
selecCve f brecurrence.
oth IDH1 and IDH2 mutant enzymes. disease?
Preliminary tudies prognostic
of in vivo tumor m
odels have shown they are ca-‐ Can I use the MGMT status for prognostic
Yes. MGMT promoter
methylation isspositively
in anaplastic
glioma
purposes?
patients
receiving
RT
or
chemotherapy
or
both
(NOA-04,
EORTC
26951).
of no
lowering 2HG levels by greater than 90% aof
nd the
reversed the ranwas
formal
crossover
design,
80%
patients
the loss of one hybrid chromosome and thereby loss of het- pable Can I use the MGMT status as a predictive
5
altered m
ethylaCon p
rofiles o
f t
he I
DH m
utant c
ells. domized
RT alone
received chemotherapy
at
erozygosity. The association
of this
molecular chemotherapy
marker in glioblastoma
marker for clinical decision
making?
(EORTCinitially
26981) and isto
particularly
useful in elderly
(NOA-08, Nordic trial).
An initial analysis after a minimum
with brain tumorIDH1/2
formation
led to an extensiveglioblastoma
searchpatients progression.
mutations
follow-up
ofgrades
3 years
a aidmedian progression-free
for tumor suppressor
in these Yes.
genomic
Can I usegenes
the IDH1/2located
IDH1/2 mutations are
common in WHO
II and III showed
gliomas and can
purposes?
survival
(PFS)
of 2.6which
years
for
regions, but the first promising candidate genes
have
pilocytic
astrocytomas,
gangliogliomas,
and ependymomas,
typically
lack PCV ! RT compared
IDH1/2 mutations.
with 1.7 years for RT alone (P ¼ .004); however,
only recently beenIsidentified
by exome sequencing.
Most
the IDH1/2 status homogeneous within
Yes. This is confirmed at least in WHO grades II and III tumors, whereas no data
for glioblastoma.median overall survival (OS) was similar: 4.9 years with
oligodendrogliomasgliomas?
with 1p/19q codeletion exist
indeed
Can I use the IDH1/2 status for prognostic
Yes. IDH1/2 mutations are prognostically favorable, in particular in WHO grades III
PCV ! RT versus 4.7 years with RT alone (P ¼ .26).
carry mutations inpurposes?
the CIC gene, a homolog andofIV gliomas.
the
6–8
I use the IDH1/2
status as a on
predictive
No.
The absence of a survival benefit and the occurrence of
Drosophila gene Can
capicua,
located
19q13.2.
A
severe (grade 3 or 4) toxicity in 65% of the
smaller subset of these tumors carries mutations in the
was no
formal crossover design,
80% were
of the patients
ranthe loss of
one hybridthe
chromosome
and thereby loss
of hetPCV-treated
patients
felt to
outweigh the moderate
FUBP–1 gene, which
encodes
“far upstream
element
domized initially to RT alone received chemotherapy at
erozygosity.5 The association6 of
– 8this molecular marker
gain inAnPFS.
OS awas
longer in cases of 1p/19q
binding protein” with
on chromosome
1p. led toHowever,
initialMedian
analysis after
minimum
brain tumor formation
an extensive the
searchbi- progression.
follow-up
of 3 yearstumors
showed a than
median in
progression-free
for tumor
suppressor remains
genes located
genomic
codeleted
cases of tumors lacking this abological role of these
mutations
to inbethese
elucidated.
survival (PFS) of
2.6Weller years for M
PCV
!
RT
compared
regions, but the first promising candidate genes have
• 
e
t a
NeuroOncol 2012 there was
(.7
vs 2.8
Pl. ,
.001). However,
Three randomized
clinical
trialsbyhave
with erration
1.7 years for
RT yalone
(P ¼y,
.004);
however,
only recently
been identified
exome demonstrated
sequencing. Most
•  Hartmann e4.9t ayears
l. cta Neuropathol. 2010 median
survival
(OS)
was similar:
oligodendrogliomas
1p/19q
codeletion
indeed
nooverall
significant
effect
ofCtype
ofAwith
treatment
on survival
by
that anaplastic glioma
patientswith
with
1p/19q
codeleted
WHO 2007 GRADO I GRADO II GRADO III GRADO IV ASTROCITOMA II IDH1/IDH2 p53 ASTROCITOMA ANAPLASICO III IDH1/IDH2 p53 GBM PRIMARIO EGFR PTEN ______________ GBM SECUNDARIO IDH1/IDH2 P53 OLIGO-‐
ASTROCITOMA OLIGO-‐ ASTROCITOMA II IDH1/IDH2 P53 vs 1p19q codel OLIGO-‐ ASTROCITOMA ANAPLASICO III IDH1/IDH2 P53 vs 1p19q codel GBM-‐O (OA-‐IV) OLIGO-‐ DENDROGLIOMA OLIGODENDRO-‐ GLIOMA II IDH1/IDH2 1p19q codel OLIGO-‐ DENDROGLIOMA ANAPLASICO III IDH1/IDH2 1p19q codel ASTROCITOMA ASTROCITOMA PILOCÍTICO BRAF BRAF-‐KIAA1549 BRAF V600E diagnoses. For example, some neuropatho
a glioma becomes a glioneuronal tumor i
sometimes minor positivity for a neuro
synaptophysin); instead, knowing objecti
lesion was IDH mutant would allow one t
would behave like a diffuse glioma (e
tumor with neuropil-like islands or a
invading cortex that was misdiagnosed as
I envision that this system itself will
one. As we learn more about multiple ge
netic events converging on pathway
specifically targeted for therapy, it is like
tional details described above would
pathway activation or pathway inactivatio
many places, we are already speaking of
medulloblastomas in this way. Moreover,
would be initially employed in the gradin
tion of diffuse gliomas and embryonal tum
that it would be extended fairly soon to
Diffuse glioma; IDH1 mutant, TP53 mutant, EGFR
ependymomas and meningiomas, as ad
normal copy number
molecular correlations are made in these
We stand at a critical time in the evolu
WHO grade III
tumor neuropathology, with new obje
! Springer-Verlag Berlin Heidelberg
2012
Diffuse glioma; IDH wildtype, TP53 wildtype, EGFR
coming alongside comprehensive ‘‘–om
amplified
tumors. The era of the famous men ha
Anaplastic
astrocytoma
part of the
our history;
indeed,
of bad judgment.’’ important
In other words,
system that
wethe
curf
The phrase ‘‘Let us now praise famous men, and our fathers
grade IV BCE text entitled
mentors.
as the and
phrase
‘‘L
rently use has arisenbeen
fromour
many
trials But,
and errors,
from
that begat us’’ is from theWHO
second-century
famous men’’
states,
thethe
time
has now co
good aliquot of subjectivity
infused
with
convictions
o
the Wisdom of Sirach or Ecclesiasticus,
a book
of null
ethics that
Embryonal tumor;
INI1
step forward and to allow the famous m
Atypical
teratoid/rhabdoid
tumor
our famous men.
played a role in early iterations
of the
Bible. The phrase
was
than more famous men) to be our legacy
WHO
grade IV.
For the first time in history, however, we now see th
used more recently and most
famously
in an ironic context,
designation would define the major categories of tumor, but
would not be mired in the often subjective distinctions
within histologies, e.g., astrocytoma versus oligoastrocytoma versus oligodendroglioma. The mutational details
Acta Neuropathol
would follow a specific convention and would need to
DOI 10.1007/s00401-012-1067-4
include a particular set of molecular alterations, which
would need to be determined alongside of the next WHO
EDITORIAL
classification modifications. The histopathological name
would be next and would follow the WHO convention,
presumably using the terms and criteria as updated in the
next iteration of the WHO classification. Lastly, the WHO
grade would follow, with the grade potentially being
dependent on the molecular alteration. For example, a
glioblastoma or an anaplastic astrocytoma with an IDH
mutation might be WHO grade III, whereas a glioblastoma
David N. Louis
or an anaplastic astrocytoma without an IDH mutation
would be WHO grade IV.
Examples of such a transitional system would be:
The next step in brain tumor classification: ‘‘Let us now praise
famous men’’… or molecules?
of aofsystem
thatof offers
by James Agee and WalkerAEvans
thethis
titlewould
of their
classic
Conflict
interest far
Themore
author potential
declares thatfoh
systeminlike
allow
flexibilityinklings
in a number
• 
Louis D
N. A
cta N
europathol. 2
Nov o interest.
objectivity, and hence,
less dependence on the 012 vagaries
work of photojournalism, Let Us Now Praise Famous Men.

Valoración anatomopatológica de los gliomas: clasificación

Transcription

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