BRAIN TUMOURS: CLASSIFICATION

AND GENES
V P Collins
ii2

J Neurol Neurosurg Psychiatry 2004; 75(Suppl II):ii2–ii11. doi: 10.1136/jnnp.2004.040337

T
his paper aims to provide an outline of the surgical pathology of the most common tumours
of the nervous system in children and adults, and briefly summarise their common genetic
changes. The reader is referred to more comprehensive texts for further details about brain
tumour classification and the genetic abnormalities of these tumours.1

c CLASSIFICATION

Most recent classifications of brain tumours build on the 1926 work of Bailey and Cushing.2 This
classification named tumours after the cell type in the developing embryo/fetus or adult which the
tumour cells most resembled histologically. The cell of origin of the majority of brain tumours is
unknown as no pre-malignant states are recognised, as is the case in some epithelial tumour
forms. In some tumours, cells may be so atypical that it is difficult to compare them with any
normal cell type—hence the use of terms such as glioblastoma. Many unsound or illogical terms
have remained in the classifications, as once established in a complex medical setting they are
difficult to change. In this paper the terminology and definitions of the World Health
Organization classification of 2000 will be exclusively used.1 There are more than 120 entities
in this classification and here we will concentrate on those that most frequently occur in adults
and children. These are the pilocytic astrocytomas, ependymomas, and medulloblastomas in
children, and the diffuse astrocytic tumours (including astrocytoma, anaplastic astrocytomas, and
glioblastomas), oligodendrogliomas, and meningiomas in adults.
Tumours of the central nervous system often have a wide morphological spectrum and
classification is dependent on the recognition of areas with the characteristic histology for a
particular tumour type. Immunocytochemical methods may be required to demonstrate the
expression by the tumour cells of an antigen typically expressed by a particular cell type and thus
to assist in classification. Unfortunately there are no antibodies that unequivocally identify the
different tumour types. The presence or absence of an antigen only adds a further piece of
information helping to indicate the tumour type.
Four malignancy grades are recognised by the WHO system, with grade I tumours the
biologically least aggressive and grade IV the biologically most aggressive tumours. The
histological criteria for malignancy grading are not uniform for all tumour types and thus all
tumours must be classified before the malignancy grade can be determined. Only one or two
malignancy grades can be attributed to some tumour types. Brain tumours are well known to
progress, becoming more malignant with time. Such progression will initially be focal. A patient’s
diagnosis is based on the most malignant part of the tumour. Thus it is of the utmost importance
to sample the tumour adequately in order to determine its type and judge its malignant potential.
It follows that malignancy grading on biopsies/stereotactic biopsies is always a minimum grading
as more anaplastic regions may be present in non-biopsied areas.
Cytotoxic or radiation therapy before histological diagnosis may make classification and
malignancy grading extremely difficult or impossible. The clinical implications of tumour
classification and malignancy grading have been empirically determined. The application of
objective methods of measuring cell proliferation and death in tumours to malignancy grading is
conceptually attractive but have yet to be accepted and utilised in the malignancy grading of brain
tumours. The MIB 1 antibody recognising the same antigen as Ki67 as well as other antibodies
identifying antigens associated with proliferation (for example, Cdc6 and Mcm5) can be used
_________________________ efficiently on formalin fixed, paraffin embedded tissues following microwave antigen retrieval.3 4
Correspondence to: However, wide variations in the proliferation indices are observed in different areas of individual
V Peter Collins, brain tumours and this has resulted in difficulties in defining relevant proliferation levels. The
MD, Department of
Histopathology, University of same applies to the assessment of the numbers of cells undergoing apoptosis.
Cambridge, Addenbrooke’s The advances in neuroradiology and parallel improvements in stereotactic and surgical
Hospital, Box 235 Hills Road, techniques permit the biopsy of just about any neoplastic or non-neoplastic lesion in the central
Cambridge CB2 2QQ, UK;
[email protected] nervous system (CNS). The list of potential diagnoses is thus vast. The neuropathologist may be
_________________________ expected to make a diagnosis on the basis of often very small and fragmented biopsies. He thus

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NEUROLOGY IN PRACTICE

needs to know the clinical background of the case.

Information must be provided: age, neuroradiological find-
References

114, 115

118, 119
ings including location of the tumour, relevant clinical and

5, 116
family history, and whether the patient has received any

117

118

119
120

121
treatment, including steroids. As can be deduced from the

are MIN+ occur but are uncommon

Involved in sporadic CNS tumours

above, morphology combined with immunocytochemistry

Unknown; astrocytic tumours that

may only provide a differential diagnosis and the most likely ii3
Meningiomas, schwannomas diagnosis will then only be reached by considering all the
information available at a multidisciplinary team meeting.
The vast majority of brain tumours are sporadic. A number

Medulloblastoma
Mainly astrocytic

of familial syndromes are well documented with an increased

Glioblastomas
incidence of brain tumours (see table 1 and the references

Astrocytic
Unknown

Unknown

therein). However, even in the most common syndromes

(neurofibromatosis type 1 and neurofibromatosis type 2), the
precise relative risk is difficult to define.
mutations are associated with glioblastoma)

Astrocytomas reported but tumours in other

ependymomas, PNETs and meningiomas

Vestibular schwannomas, meningiomas,

organs more common—thyroid, breast,

Tumour types associated with disorder

COMMON CHILDHOOD TUMOURS

Glioblastoma (unknown if all germline
Astrocytomas (brain stem optic nerve)

Pilocytic astrocytomas
Pilocytic astrocytomas most commonly occur in the cerebel-
Many including astrocytomas

lum of children. However, they may occur anywhere from the

female genito-urinary tract
(pheochromocytoma), etc

optic nerve to the medulla oblongata. Patients with pilocytic

spinal schwannomas

astrocytomas that can be excised have a good prognosis.

Medulloblastoma

Medulloblastoma

There is an increased incidence of pilocytic astrocytomas in

Astrocytomas

NF1 patients, particularly involving the optic nerve, and these

tumours in NF1 patients behave in a particularly benign
fashion.5 Pilocytic astrocytomas are generally biologically
non-aggressive and are remarkable among astrocytic
tumours in maintaining their grade I status over years and
GTPase activating protein homology

even decades (in contrast to the diffuse astrocytic tumours in

Cell cycle control (G1-S)/p53 level
Dual specificity phosphatase and
Receptor for SHH inhibits SMO

adults). However, very occasional cases may prove more

Microsatellite instability (MIN+)
Transcription factor, apoptosis

sinister and progress to more malignant tumours.6 Pilocytic

Ezrin/moesin/radixin-like

astrocytomas show a wide spectrum of morphologies, from

Regulates b-catenin

the pilocytic, bipolar cellular areas with Rosenthal fibres

Tensin homology
Protein function

(fig 1) to less cellular protoplasmic astrocytoma-like areas

induction, etc

with eosinophilic granular bodies and clear cells. The latter

are reminiscent of oligodendroglioma and in the posterior
control

fossa can also be confused with clear cell ependymoma. The

presence of features typically associated with a malignant
biological behaviour (for example, vascular proliferation or
10q222q23
5q212q22

2p222p21

2q312q33

mitosis) does not carry the same sinister implications as

Table 1 Familial syndromes associated with human brain tumours

PNET, primitive neuroectodermal tumour; SHH, sonic hedgehog; SMO, smoothened.

17p13.1

17q11.2

22q12.2
Location

3p21.3

9q22.3

in the other astrocytic tumours. This morphological

14q24

7p22

9p21

spectrum can make histopathological diagnosis extremely

CDKN2A/p14ARF
TP53 (only 70%)

MSH2
MLH1

MLH3
PMS1
PMS2
PTCH
Gene

PTEN
APC
NF1

NF2

Cowden disease (multiple hamartoma syndrome,

Basal cell naevus syndrome/Gorlin’s syndrome
Hereditary non-polyposis colorectal cancer
Familial adenomatous polyposis coli

Melanoma-astrocytoma syndrome
Neurofibromatosis type 1

Neurofibromatosis type 2

(or Turcot syndrome A)

(or Turcot syndrome B)

Lhermitte-Duclos, etc)
Li fraumeni
Disorder

Figure 1 Pilocytic astrocytoma malignancy grade I (H&E). Note the

piloid bipolar cells and Rosenthal fibres (arrows). This shows the
classical morphology that is generally found somewhere in a pilocytic
astrocytoma; other areas can show very different histological patterns.

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 NEUROLOGY IN PRACTICE

ii4

Figure 3 Medulloblastoma malignancy grade IV showing an area

with typical neuroblastic rosettes (H&E).

Necrosis and microvascular proliferation do not have the

Figure 2 Ependymoma malignancy grade II, showing multiple same significance in this tumour type as in the adult
ependymal canals (H&E). astrocytic tumours. Most ependymomas (malignancy grade
II) show immunoreactivity for glial fibrillary acidic protein
(GFAP), S-100 protein, and epithelial membrane antigen
difficult—particularly in the absence of the clinical data that (EMA).
must be provided to the pathologist as outlined above.
Chromosomal copy number abnormalities detected by
More than 100 cases of pilocytic astrocytomas have been classical cytogenetics and CGH include chromosomes 1, 6,
analysed cytogenetically and many more by comparative 7, 9, 10, 13, 17, 19, and 22. Deletions are most common with
genomic hybridisation. No consistent findings have been losses on chromosome 22 a frequent event in adult spinal
made. The majority show normal cytogenetic and compara- ependymomas (over 50%) but infrequent in paediatric
tive genomic hybridisation (CGH) findings.7–10 Adult pilocytic ependymomas. Gains have been reported for chromosome
astrocytomas have been found to show the most frequent but 7. These findings have been confirmed by molecular genetic
again variable abnormalities. Molecular genetic studies have data that have identified losses on 6q, 9p, 10, 11q, 13q, 17p
been few and have shown allelic losses on both 17p and 17q and 19q.18–22
including the TP53 and NF1 loci. Few TP53 mutations have The genes targeted by these allelic losses and gains are in
been reported and no mutations of the NF1 locus have been most cases unknown, with the exception of the loss of both
reported in sporadic tumours.11–15 Recently studies of methy- wild-type copies of the neurofibromatosis type 2 (NF2) gene
lation of the promoter regions of a number of genes reported in sporadic intramedullary spinal ependymomas but not in
to be hypermethylated in the adult diffuse astrocytic gliomas intracranial ependymomas.19 21 23 Single cases have been
have provided somewhat inconsistent data on methylation in reported with loss of other wild type genes such as the
pilocytic astrocytomas.16 17 MEN1 gene.21 24 Germ line mutations of TP53 are uncommon
in contrast to the situation in the diffuse astrocytic
Ependymoma tumours.25 26
Ependymomas arise at or close to ependymal surfaces and
may occur anywhere in the ventricular system as well as in Medulloblastoma
the spinal cord and very occasionally at extraneural sites. The Medulloblastoma has a peak incidence in childhood but also
most common location is in the fourth ventricle, followed by can occur into late middle age. Histologically childhood and
the spinal canal, lateral ventricles, and the third ventricle. adult medulloblastoma are identical, being highly cellular,
Children have the highest incidence of ependymomas, but malignant invasive tumours corresponding to WHO malig-
they can occur into late middle age. Ependymomas are the nancy grade IV. Medulloblastomas occur in the posterior
most frequent glioma of the spinal cord and this location is fossa. They consist of densely packed tumour cells with round
common in adults. There are a number of subtypes. The least to oval or carrot shaped hyperchromatic nuclei with scanty
biologically aggressive are malignancy graded as grade 1, and cytoplasm, high mitotic and apoptotic rates, and usually
consist of the subependymoma (intraventricular and often neuroblastic rosettes in some areas (fig 3). Neuronal
symptomless) and myxopapillary ependymoma that most differentiation and glial differentiation may be present.
commonly occurs at the cauda equina. The tumour named Microvascular proliferation is relatively uncommon.
ependymoma is malignancy graded as grade II and has a Tumours arise with similar frequency in the cerebellar vermis
number of histopathological variants. Ependymomas show in (mainly in children) and the cerebellar hemispheres (older
some area(s) evidence of an ependymal cell phenotype—by patients), and often invade the fourth ventricle, with
the formation of ependymal rosettes and sometimes canals occasional brainstem involvement. There is a high risk of
(fig 2). More commonly perivascular pseudo-rosettes are seeding through the subarachnoid space due to the tendency
identified but are not specific for ependymomas. of the tumour to penetrate the ependymal surface. Many
Ependymomas (malignancy grade II) are differentiated from antigens have been identified focally in medulloblastomas
anaplastic ependymomas (malignancy grade III) on the basis (nestin, vimentin, neurofilament proteins, GFAP, retinal S-
of low mitotic rate and a low level of nuclear polymorphism, antigen, N-CAMs, Trk-A, -B, -C etc). However, most are not
but the borderline between these remains ill defined. of any great importance in the day-to-day diagnosis of these

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NEUROLOGY IN PRACTICE

tumours. It is most important to differentiate medulloblas- astrocytomas (malignancy grade II) and anaplastic astro-
tomas from atypical teratoid/rhabdoid tumours, as the latter cytomas have been well documented to progress to tumours
have a very poor prognosis and do not respond to the current of higher malignancy grade.
relatively successful treatment protocols for medulloblasto- The tumour cells of astrocytomas (malignancy grade II)
mas.27 28 In adults the possibility of a metastasis of a small cell resemble astrocytes, show little nuclear atypia, and have
lung cancer must often be excluded. extensions producing a loosely textured matrix (fig 4). They
The most common chromosomal abnormality in medullo- generally express S-100 protein and glial fibrillary acidic ii5
blastomas is iso-chromosome 17q, in which most of the short protein. Anaplastic astrocytomas (malignancy grade III)
arm is lost from two chromosomes 17 and they are then fused show increased cellularity but the tumour cells still show
head-to-head producing a chromosome with two centromers, histological and immunocytochemical characteristics of
little 17p and two 17q arms. This is observed in 30–50% of astrocytes. The tumour cells are more pleomorphic than
cases by using cytogenetic techniques.8 29 30 These findings have found in astrocytomas, show distinct nuclear atypia, and
been confirmed by CGH and molecular genetic studies.11 31 there is mitotic activity. No evidence of spontaneous tumour
Many other chromosomal aberrations have been identified necrosis or abnormal microvascular proliferation is permitted
using conventional cytogenetic, CGH or molecular genetic in anaplastic astrocytomas. Glioblastomas (malignancy grade
techniques—for example, loss of 10q (35%).32 33 In addition, IV) are more cellular than the anaplastic astrocytomas. The
several growth and transcription factors have been investi- tumour cells show a wide spectrum of morphologies, can be
gated, some reporting high expression in a subset of very pleomorphic with giant forms, but generally retain some
tumours—for example, erbB2&4.34 of the phenotypical characteristics of astrocytes. Mitosis,
A major contribution to our understanding of medullo- spontaneous tumour necrosis with pseudopalisading of
blastoma biology has come from the study of two genetic tumour cells, as well as florid endothelial proliferation, are
syndromes exhibiting a predisposition to medulloblastoma
inevitably found in some areas of a well sampled tumour
formation. Gorlin’s syndrome (hereditary naevoid basal cell
(fig 4). A large central necrotic area with a ring-like zone of
carcinoma syndrome) and familial adenomatous polyposis
contrast enhancement, representing the viable tumour tissue,
(FAP) syndrome arise from mutations in the PTCH (9q) and
can often be identified by neuroimaging.
APC (5q) genes, respectively, and both are associated with
Before reading the following section it is essential that fig 5
medulloblastoma formation. The gene products of these two
is first reviewed and referred to as necessary. Cytogenetic and
genes take part in two interconnected pathways that are
molecular data are limited on astrocytomas (malignancy
fundamental to neural development and cell turnover.
grade II) as they are not so common.7 52 53 Over 60% of
Hemizygous loss and mutations in the retained allele of
astrocytomas (malignancy grade II) have loss of alleles on
PTCH in sporadic medulloblastomas have been shown.35 36
17p, including the TP53 locus, and the retained TP53 allele is
However, alterations in the PTCH and APC genes as well as
mutated in the majority of cases.49 54 55 The absence of wild
other genes coding for components of these two pathways are
involved in the development of less than 15% of sporadic type p53 is therefore the most common abnormal finding in
medulloblastomas.37 38 Other genes involved in the two astrocytomas malignancy grade II,49 resulting in a non-
pathways, including SMO39 and SUFU,40 have been studied functional p53 pathway. A small percentage of tumours have
and also show loss of wild type in only single, isolated cases. mutations of one allele but retain one wild type allele. As the
Other genes currently being investigated for their significance p53 protein is believed to function as a tetramer and as
in medulloblastoma biology are the myc family41 42 and the tetramers with one abnormal p53 protein may not function
PDGF receptors and ligands.43 44

COMMON ADULT TUMOURS

Diffuse astrocytic tumours
The adult diffuse astrocytic tumours include the astrocyto-
mas (malignancy grade II), the anaplastic astrocytomas
(malignancy grade III), and the glioblastomas (malignancy
grade IV). The astrocytoma malignancy grade II tumours
have a peak incidence between 25 and 50 years of age, while
the glioblastomas have a peak incidence between 45 and 70
years. All are more common in males and most are located in
the cerebral hemispheres. Glioblastomas are the most
common form and are divided into those that develop from
a previously diagnosed tumour of lower malignancy grade
and those that appear to develop de novo.45 46 Both clinical
and molecular data support the hypothesis that these
tumours may develop from the mutation of different genes
but affect the same cellular pathways.47–49 The relevance of
the histologically based malignancy grading scheme is
indicated by patient survival. Patients with an astrocytoma Figure 4 Tumours of the astrocytic series (H&E). (A) Astrocytoma
(malignancy grade II) have an average survival of approxi- malignancy grade II (arrows pointing to thin walled tumour capillary
mately seven years, patients with anaplastic astrocytomas vessels). (B) Anaplastic astrocytoma malignancy grade III
have a median survival half that time,50 while glioblastoma demonstrating anaplastic tumour cells but with no evidence for
patients have an average survival of between 9–11 months.51 microvascular proliferation (arrows; compare with A and C).
This is despite the best currently available treatments. The (C) Glioblastoma with florid endothelial proliferation (arrows).

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 NEUROLOGY IN PRACTICE

normally, the finding of these single mutated alleles together The numbers of cases of anaplastic astrocytomas (malig-
with a wild type allele may well be significant. Other genes nancy grade III) studied are also limited. Mutations of the
coding for components of the p53 pathway (fig 5), MDM2 and TP53 gene also occur at approximately the same frequency as
p14ARF, have been studied in small numbers of these is found in the astrocytomas malignancy grade II.49 Thus in
tumours and no abnormalities have been reported. Recent the anaplastic astrocytomas the p53 pathway is also non-
studies of the TP53 related gene, P73, have not identified any functional, and in the majority of cases (more than 60%) this
ii6 mutations.56 Other findings considered significant include is due to mutations of the TP53 gene. Cytogenetics, CGH, and
overexpression of the PDGFRA gene.57 58 Loss of alleles from molecular genetic techniques all show that the losses of
6q, 13q, and 22q occur in some astrocytomas. There is no alleles on 6q, 13q, 17p and 22q, as seen in the astrocytoma
evidence to suggest that there is mutation of the single malignancy grade II, occur at similar or higher frequencies in
retained tumour suppressor gene RB1 allele at 13q14.259 or the anaplastic astrocytomas. With the sole exception of losses
the NF2 tumour suppressor gene on 22q.60 61 Deletion of alleles on 19q (targeted gene unknown) there are no
mapping of chromosomes 6 shows losses on 6q in a conclusively demonstrated abnormalities specific to this
significant number of astrocytomas.62 The potential tumour malignancy grade. Around 20% of anaplastic astrocytomas
suppressor genes in all of these regions remain unknown. show similar genetic abnormalities to those found in
There are no consistently reported amplified genes or glioblastomas involving other components of the p53 path-
amplified regions of the genome in astrocytomas.59 63–66 The way (that is, MDM2 and p14ARF) and lead to disruption of the
changes found in the astrocytomas form the baseline for Rb1 pathway (fig 5), and these are discussed in the
progression in the adult diffuse astrocytic tumour series. glioblastoma section below59
Epigenetic changes such as hypermethylation of tumour De novo glioblastomas are common and this has ensured
suppressor gene promoters may also play an important role in their study in considerable numbers. Secondary glioblasto-
transcriptional silencing of some of the genes cited above or mas are less frequent and very less commonly studied.68 69
other important cancer genes and the development of Such patients will frequently have been treated by irradiation
astrocytomas. This has not been studied in any detail as yet.67 and/or with cytotoxic drugs. Glioblastomas show the greatest

Figure 5 Simplified diagram of interactions between the proteins of the Rb1 pathway (above) and the p53 pathway (below). The genes coding for
p16 and p15 proteins are CDKN2A and CDKN2B, respectively . The genes for all of the proteins underlined have been shown to be abnormal in the
astrocytic and some other gliomas as well as many other tumour cell types in other organs. In the vast majority of cases where a pathway is disrupted
in a tumour it is due to only one of the genes coding for a protein in that pathway being abnormal (loss of both wild type copies in the case of most
tumour suppressor genes or amplification and overexpression in the case of proto-oncogenes). Thus it appears that pathways are targeted in
oncogenesis and progression, and can be disrupted in many ways by losing, mutating, or amplifying the genes coding for the protein components of
the pathway.

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NEUROLOGY IN PRACTICE

numbers of genetic abnormalities among the astrocytic

tumours and clear patterns of genetic aberrations are
emerging. The p53 pathway in glioblastomas is targeted
through mutation of the TP53 gene (approximately 37%49), as
is seen in astrocytomas and anaplastic astrocytomas, but also
by targeting other genes coding for proteins that control
cellular p53 levels. The two genes whose products are ii7
involved in controlling p53 levels are p14ARF and MDM2.
p14ARF controls the activity of MDM2,70 which in its turn
controls the breakdown of p53.71 Loss of both copies of the
p14ARF gene or amplification and over-expression of MDM2
will lead to the rapid breakdown of wild type p53 protein
resulting in a cell with little or no wild type p53. The vast
majority of glioblastomas (. 70%) have either no wild type
p53 or no p14ARF or over express MDM2 as mutually
exclusive genetic abnormalities.49 Methylation of the p14ARF
promoter with decreased or non-expression are further
mechanisms that have been shown to be involved in some
Figure 6 Oligodendroglioma malignancy grade II (H&E) with the
tumours. In glioblastomas additionally the retinoblastoma typical tumour cell morphology—round nuclei and swollen cytoplasm.
pathway and the PI3 kinase–Act pathway are also targeted. Note the microcalcifications (arrows) mainly in the lower right of the
In a similar manner one or other of the genes coding for field. This is a common feature in oligodendrogliomas but is not unique
proteins involved in the control of entry into the S phase of to this form of glioma.
the cell cycle (the retinoblastoma pathway) are mutated in
glioblastomas (fig 1). Entry into S phase is normally initiated been shown to be mutated, albeit infrequently.82 This is
by the release of transcription factors from newly phosphory- supported by reports on the affect of Akt activation in an
lated Rb1 at the restriction point in G1. At the end of the cell animal model of astrocytoma.83
cycle Rb1 is unphosphorylated. Unphosphorylated Rb1 Amplification of the epidermal growth factor receptor
normally sequesters the E2F transcription factors.72 Loss of (EGFR) gene (7p11–12) is found in about 35% of glioblas-
wild type RB1 gene resulting in no functional RB1 or tomas. When amplified this gene is always over-expressed
inappropriately phosphorylated Rb1 will result in any but may also be over-expressed in glioblastomas without
expressed E2F being free to initiate transcription of the amplification. Rearrangements of the amplified gene occur in
genes necessary for entry into S phase. Inappropriate almost half of the tumours with amplification. The most
phosphorylation may be achieved in glioblastomas with wild common rearrangement results in a transcript that is
type Rb1 by either loss of wild type p16 expression or over- aberrantly spliced, remains in frame,84–86 and codes for a
expression of CDK4 caused by amplification of its gene. These mutated EGFR that has lost 267 amino acids of its
would make inappropriate phosphorylation of a wild type extracellular domain and does not bind ligand.87 88 This
Rb1 more likely with the release of the E2Fs. p16 normally mutated EGFR is constitutively activated and attempts are
binds CDK4 and thus inhibits the formation of the CDK4/ ongoing to target treatment to this aberrant cell surface
cyclin D1 heterodimer.73 In the absence of p16 all expressed molecule.89 Other rearrangements of the amplified EGFR
CDK4 is available for heterodimer formation. When CDK4 is gene occur less frequently and may result in abnormalities of
overexpressed in the presence of normal levels of p16 there the cytoplasmic domain90
will be excess CDK4 available for heterodimer formation. One Glioblastomas can develop from an astrocytoma or as a de
or the other of these abnormalities are present in over 90% of novo glioblastoma. It is tempting to try to sort all these
glioblastomas and are, with very few exceptions, mutually findings into a series of events explaining the development of
exclusive.49 While disruption of the p53 and Rb1 pathways the two forms of glioblastoma. Both have disrupted the
seem essential for glioblastomas, the ways in which the normal p53 and Rb1 pathways, but in different ways. The de
pathways are rendered dysfunctional may confer slightly novo tumours do this by a single genetic event when
different biological characteristics on the individual glioblas- amplification of the 12q14 region encompassing the CDK4
toma. and MDM2 genes results in their over-expression and the
In addition to the genetic abnormalities resulting in the disruption of both pathways. Two genetic events are required
disruption of the p53 and Rb1 pathways, over 90% of to disrupt the two pathways when homozygous deletion of
glioblastomas lose alleles from 10q. The regions consistently the region on 9p encompassing the genes coding for p16
lost include the variously named PTEN/MMAC1/TEP1 tumour (CDKN2A), p15 (CDKN2B), and p14ARF (p14AR)) occurs
suppressor gene at 10q23–24.74–76 PTEN has been shown to be (requires loss of both autosomes). Occasionally de novo
mutated in up to 45% of glioblastomas.77 The gene is a dual tumours may also show more complex patterns of mutations
specificity phosphatase (necessary for its ability to function with loss of one allele of each of TP53 and RB1, with
as a tumour suppressor) and has homology to the cyto- mutation of the retained alleles, requiring four genetic
skeletal protein tensin.78 79 One of its major substrates is mutational events. However, in de novo glioblastomas these
phosphatidylinositol-3, 4, 5-triphosphate (PIP3)80 and lack of are in the minority. Secondary glioblastomas generally have
control of PIP3 is likely to have a major effect on the no wild type p53 due to loss of one allele and mutation of the
activation of the Akt pathway, affecting among other things retained allele, and lose a functional Rb1 pathway in a similar
apoptosis and HIF-1 activity.81 Other genes coding for manner. Other correlations are that EGFR amplification is
proteins involved in the PI3K/AKT pathway have recently unusual in cases with no wild type p53, although this does

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 NEUROLOGY IN PRACTICE

occur occasionally. In addition to the abnormalities of the genetic information from 1p and 19p was demonstrated in a
genes listed there are likely to be many other genetic changes genomic wide analysis in 199492 and this was later linked to a
affecting other regions of the genome that have been found good response to PCV treatment, an association that is
to be manifestly abnormal in these tumours by deletion or currently under intense scrutiny as it provides the first
amplicon mapping. The genes targeted by these changes have molecular indicator of treatment response in brain
yet to be identified. tumours.93 94 The losses on 1p and 19q are most common
ii8 among the grade II oligodendrogliomas (reports of up to
Oligodendrogliomas 90%) and are present in over 50% of anaplastic oligoden-
Oligodendrogliomas occur mainly in the cerebral hemi- drogliomas (malignancy grade III). Despite the fact that
spheres of adults. They are believed to derive from almost 10 years has elapsed since the identification of these
oligodendrocytes. They consist of moderately cellular, mono- relatively specific losses the genes targeted on these two
morphic tumours with round nuclei, often artefactually chromosomes are still unknown. Oligodendrogliomas grade
swollen cytoplasm on paraffin section (fig 6), few or no II also show methylation of p14ARF, over-expression of EGFR
mitoses, no florid microvascular proliferation or necrosis, and and both ligands and receptors of the platelet derived growth
are classified as malignancy grade II according to the WHO. factor (PDGF) system. Malignant progression is associated
Classically they show a ‘‘chicken wire’’ pattern of capillaries. with additional genetic abnormalities similar to those
They do not express any antigen characteristic of normal described above for the astrocytic tumours—that is, disrup-
oligodendrocytes and may express GFAP. Grade II oligoden- tion of the Rb1 pathway due to homozygous deletions or in
drogliomas are relatively indolent, although they usually some cases hypermethylation of the CDKN2A/p14ARF locus, or
recur at the primary site and may display a tendency for the RB1 locus or CDK4 amplification and overexpression as is
subependymal spread with a 5% incidence of cerebrospinal also seen in the progression of the diffuse astrocytic tumours.
fluid (CSF) seeding. Oligoastrocytomas consist of tumour Some anaplastic oligodendrogliomas have no wild-type PTEN
cells with either astroctytic or oligodendroglial morphological although this is usually in tumours without 1p and 19q loss.
characteristics. Tumour cells with these two phenotypes can Anaplastic oligodendrogliomas also have abnormalities of
be either diffusely mixed or combined as discrete areas in an many other chromosomal regions including chromosomes 4,
individual tumour. The morphological borderlines between 6, 7, 11, 13, 15, 18, and 22.93
astrocytomas, oligoastrocytomas, and oligodendrogliomas are Oligoastrocytomas and anaplastic oligoastrocytomas tend
difficult and controversial issues. to have either aberrant genetic patterns similar to the
Increases in nuclear pleomorphism and hyperchromatism, oligodendroglial tumours or the diffuse astrocytic tumours.
as well as pronounced hypercellularity, brisk mitotic activity, As yet there are no specific abnormalities associated with
prominent microvascular proliferation, and/or spontaneous these mixed glial tumours.
necrosis, results in a picture that is histologically classified as
anaplastic oligodendroglioma (malignancy grade III). Meningiomas
Anaplastic forms of oligoastrocytomas also occur and similar Meningiomas are usually solitary lobulated tumours arising
criteria are used to distinguish them from oligoastrocytomas. in the meninges and attached to the dura. They are believed
Since 1990, when combination chemotherapy (procarbazine, to develop from meningothelial (arachnoidal) cells, despite
lomustin, and vincristine (PCV)) was demonstrated to result the fact that the meningothelial form is far from the most
in sometimes a dramatic tumour response,91 the identifica- common. Symptomatic meningiomas represent 13–26% of
tion of all forms of glioma with oligodendroglial components primary intracranial tumours, are most common in middle
has become crucial. aged and elderly patients, and show a pronounced female
predominance. Small asymptomatic meningiomas are found
Oligodendrogliomas show relatively specific genetic
incidentally in 1.4% of necropsies.95 Patients with NF2 and
abnormalities that differ from the other gliomas. Loss of
members of some other non-NF2 familial syndromes may
develop multiple meningiomas, often early in life. Ionising
radiation is a well recognised predisposing factor. The cellular
morphology, growth pattern, and the presence of extracel-
lular material allow differentiation into the various histolo-
gical subtypes (fig 7). Meningiomas are graded as
malignancy grade I, atypical meningiomas as malignancy
grade II, and anaplastic meningiomas as grade III.96
Meningeal sarcomas are WHO malignancy graded as IV.
The vast majority (about 80%) of meningiomas are of
malignancy grade I. Atypical meningiomas constitute less
than 20% of meningiomas while anaplastic variants are
unusual (, 2%). Both atypical and anaplastic meningiomas
are more common in men. Meningiomas may progress and
therefore should be thoroughly sampled to identify areas
with a histology associated with a more aggressive behaviour.
The histological criteria indicating a more aggressive beha-
viour and thus an increase in the malignancy grade include
frequent mitoses, regions of hypercellularity, sheet-like
Figure 7 Typical meningioma specimen malignancy grade I showing growth, high nuclear–cytoplasmic ratio, prominent nucleoli,
an example of the common transitional meningioma with multiple and spontaneous necrosis. The criteria for the different
whorles (a few marked with arrows). malignancy grades are strictly defined by WHO.96 Some

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NEUROLOGY IN PRACTICE

subtypes, characterised by particular tumour cell phenotypes, breast cancer, which will determine whether the patient will
are associated with more frequent recurrence and they are benefit from tamoxifen or herceptin treatment. New tech-
now classified as malignancy grade II or III. For example, nologies currently being introduced will permit a detailed
tumours with a papillary growth pattern or areas of rhabdoid analysis of the genome and transcriptosome of clinical
cells (rounded tumour cells with an eccentric nucleus with material impossible in the past and the integration of genetic
nucleolus and a prominent eosinophilic cytoplasm) are and expression data with the histological information.
classified as papillary and rhabdoid meningiomas, respec- Eventually we can hope that the molecular information will ii9
tively (malignancy grade III) as they have been documented provide the basis for specific treatments that will only
to behave in a very aggressive fashion. annihilate brain tumour cells, leaving the brain and the rest
Meningiomas generally expand and displace but do not of the patient unharmed.
invade adjacent brain or spinal chord. Invasion of the dura
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Cover picture

There is a focally haemorrhagic necrotic tumour deep to the insula of the left cerebral
hemisphere. The lesion has poorly defined margins and histologically has the features of
glioblastoma (WHO grade 4). The tumour and associated swelling have acted as a space
occupying lesion with a shift of the midline structures and a supracallosal hernia to the right,
narrowing and convex deformity of the third ventricle, again to the right, and compression of
the ipsilateral ventricle and enlargement of the contralateral ventricle. Figure courtesy of
Professor DI Graham

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