FN Art 19879-10

Review paper
Established and emerging variants of glioblastoma multiforme:

review of morphological and molecular features
Michael Karsy1,2 , Marshall Gelbman2, Paarth Shah3, Odessa Balumbu1,2, Fred Moy1,2, Erol Arslan4,5
1Department of Pathology, New York Medical College, Valhalla, NY, USA, 2Department of Neurosurgery, New York Medical College,
Valhalla, NY, USA, 3Department of Medicine, New York Medical College, Valhalla, NY, USA, 4Institute of Fertility Preservation, New York
Medical College, Valhalla, NY, USA, 5Department of Obstetrics & Gynecology, Derik State Hospital, Mardin, Turkey
Folia Neuropathol 2012; 50 (4): 301-321 DOI: 10.5114/fn.2012.32361
Abstract
Since the recent publication of the World Health Organization brain tumour classification guidelines in 2007, a sig-
nificant expansion in the molecular understanding of glioblastoma multiforme (GBM) and its pathological as well as
genomic variants has been evident. The purpose of this review article is to evaluate the histopathological, molecular
and clinical features surrounding emerging and currently established GBM variants. The tumours discussed include
classic glioblastoma multiforme and its four genomic variants, proneural, neural, mesenchymal, classical, as well as
gliosarcoma (GS), and giant cell GBM (gcGBM). Furthermore, the emerging variants include fibrillary/epithelial GBM,
small cell astrocytoma (SCA), GBM with oligodendroglial component (GBMO), GBM with primitive neuroectodermal
features (GBM-PNET), gemistocytic astrocytoma (GA), granular cell astrocytoma (GCA), and paediatric high-grade glioma
(HGG) as well as diffuse intrinsic pontine glioma (DIPG). Better understanding of the heterogeneous nature of GBM
may provide improved treatment paradigms, prognostic classification, and approaches towards molecularly targeted
treatments.
Key words: glioblastoma multiforme, GBM, brain tumours, glioma, astrocytoma, variant, WHO.
Introduction of gliomas, while 54% of all malignant brain tumours

Glioblastoma multiforme (GBM), a grade IV astro- are GBM and occur at a rate of 3.20 per 100 000 per-
cytoma as currently defined by the World Health Orga- son-years [25]. Marked diversity exists in the clinico-
nization (WHO) classification, is the most common pathological characteristics of GBM and recent stud-
primary brain tumour with a median survival of appro- ies have suggested the presence of a cancer stem cell
ximately 1 year following current multi-modal treat- (CSC) population may account for this heterogeneity
ments [89,114,162]. Recent data suggest that approx- as well as provide a mechanism of tumour recurrence
imately 30% of all primary and 80% of all malignant and therapeutic resistance (Fig. 1A, B) [15,38,71]. CSCs
brain tumours are accounted for by the broad category have shown the ability to undergo continual self-rene-
Communicating author:
Michael Karsy, Department of Pathology, Department of Neurosurgery, New York Medical College, Basic Sciences Building, Room 413, Valhalla,
NY 10595, USA, phone: 914-594-4146, fax: 914-594-4163, e-mail: [email protected]
Folia Neuropathologica 2012; 50/4 301

Michael Karsy, Marshall Gelbman, Paarth Shah, Odessa Balumbu, Fred Moy, Erol Arslan
Fig. 1. Mechanisms of gliomagenesis and glioblastoma multiforme variants

Schematics are shown of gliomagenesis, factors affecting GBM growth and dissemination, as well as
defined and emerging GBM variants. A) The stochastic and B) hierarchical/cancer stem cell (CSC) models
for gliomagenesis are demonstrated. The stochastic model implies that tumour cells clonally arise from
a single cell where each subsequent daughter cell has an equal potential to form a tumour. The CSC model
suggests that a specific and small population of cells undergoes self-renewal and differentiation to form
additional cells of a tumour. C) Regardless of the model involved in gliomagenesis, a variety of factors affect
growth and dissemination. D) Various underlying, complex mechanisms govern GBM heterogeneity.
The World Health Organization established GBM variants include classic GBM, gliosarcoma (GS), and giant
cell GBM (gcGBM). Recent genomic data has supported the presence of four genomic GBM subtypes in pri-
mary, classic GBM, namely proneural, mesenchymal, classical and neural. Emerging GBM variants include
fibrillary/epithelial GBM, small cell astrocytoma (SCA), GBM with oligodendroglioma component (GBMO),
GBM with primitive neuroectodermal tumour (GBM-PNET), gemistocytic astrocytoma (GA), granular cell
astrocytoma (GCA), and paediatric high-grade glioma (HGG), and diffuse intrinsic pontine glioma (DIPG).
302 Folia Neuropathologica 2012; 50/4

Established and emerging variants of glioblastoma multiforme: Review of morphological and molecular features
wal, co-express markers of distinct neuroglial lineag- and those with one parameter are grade 2 tumours (dif-
es, confer tumorigenicity, and demonstrate chemore- fuse astrocytoma). Grade 1 tumours (pilocytic astro-
sistance. The diagnosis, prognosis, treatment, and in- cytomas) are related but distinct lesions. The current
vestigation of GBM are further complicated by its WHO classification system recognizes three distinct
heterogeneity (Fig. 1C). This article will review the most GBM variants, namely classic GBM, gliosarcoma (GS),
recent data regarding understanding of genetic fea- and giant cell GBM (GC-GBM) (Table I, Fig. 1D) [89].
tures of emerging GBM variants as well as their impact Moreover, recently suggested WHO variants warrant-
on patient prognosis. ing investigation have emerged (Table II, Fig. 1D). Pre-
Multiple classification schemes have been designed vious studies evaluated the morphological and gene-
to organize the heterogeneity of gliomas. These sys- tic diversity of GBM and its potential variants within
tems have been refined over the past 100 years and the WHO 2000 guidelines [101]. And since the publi-
include those of Bailey and Cushing [6], Kernohan [74], cation of the guidelines, multiple recent studies have
Ringertz [142], Nelson [31,89], St. Anne-Mayo [31,89], shed new light on GBM heterogeneity.
and the most recent being the WHO classification [89]. The criteria designating a unique GBM variant in
The WHO system, developed from the St. Anne-Mayo comparison to patterns of differentiation remain to be
grading scheme, includes grades based on four key his- explored. Distinct histopathological features as well as
tomorphological features, including nuclear atypia, the percentage of such features in total tumour may
mitotic figures, microvascular proliferation and necro- present an initial discussion regarding the definition
sis [89]. Simplistically, lesions with three to four vari- of a new GBM variant. Moreover, evidence of distinct
ables are grade 4 tumours (GBM), those with two are molecular features and prognostic classification will ulti-
grade 3 tumours (anaplastic/malignant astrocytoma), mately solidify the designation of a true tumour variant.
Table I. Characteristics of established GBM tumour variants
GBM variant and Molecular alterations Prognostic Survival References

morphological features markers
Classic GBM EGFR, EGFRvIII, p16INK4A, EGFRvIII, MGMT, 5 year survival: 20, 26, 30, 59, 114,
Infiltrating, pleomorphic, PTEN, p53, MGMT, PI3K/AKT, IDH1, PTEN, p53, 9.8% 117, 158, 162, 166
hyperchromatic cells with DH1; CD133, proneural Median PFS:
glassy, astrocytic cytoplasm. Loss chromosome: 1p, 10, 19q subtype 5.3-10.3 months
Frequent presence of pseu- Genomic subtypes: Median OS:
dopalisading necrosis, neo- Proneural: PDGF, IDH1/IDH2, 12.7-21.7 months
epithelialization, mitotic p53, PI3KCA, PI3KR1
figures, and hypercellularity Mesenchymal: NF1, p53, PTEN
Proliferative/classical: EGFR,
EGFRvIII, PTEN, p16INK4A
Neural: nonspecific
Gliosarcoma (GS), ICD-O 9442/3 MGMT, IDH1, p53, PTEN, Meningioma-like Mean OS: 48, 52, 58, 63, 107,
Features of GBM along with Rb, STOML3, LHFP, Slug, features 4-11.6 months 108
heterogeneous sarcomatous/ Twist, MMP-2, MMP-9;
mesenchymal, differentiation PDGFAα, c-kit and
staining for reticulin, laminin, B-RAF signalling;
collagen type IV, procollagen Gain chromosome: 7, 9q, 20q,
α1-antitrypsin, and
type III, fibronectin, vimentin, and X;
Loss chromosome: 9p, 10, 13q
chymotrypsin A
Giant cell GBM (gcGBM), P53, PTEN, MDM2; Mean survival: 18, 33, 79, 93, 105,
ICD-0 9441/3 Loss chromosome: 10; 57 weeks 121, 156
Features of GBM along with Chromosomal polyploidy, Median survival:
prominent multinucleated microsatellite instability ~1 year
giant cells and lymphocytic
infiltration

Table II. Characteristics of emerging GBM tumour variants

GBM variant Molecular alterations Prognostic markers Survival References
and morphological features
Fibrillary/epithelial GBM P53, p21, EGFR; E-cadherin Mean OS: 7 months 73, 88, 104, 106,
Features of GBM along with fibrillary/ Chromosome loss 143
epithelial differentiation showing 10q22-26, 17p13
the formation of squamous nests
and glands staining for EMA,
cytokeratin CAM 5.2, E-cadherin,
cytokeratin AE1/AE3, cytokeratin 7,
pCEA, cytokeratin 5/6 and
cytokeratin 20
Small cell astrocytoma (SCA) EGFR, EGFRvIII, PTEN Mean OS: 19, 99, 101, 136
Features of GBM along with mono- 6-14.3 months
morphic proliferation of cells with
small nuclei, limited cytoplasm, mild
hyperchromasia, limited interlaced
stroma, and scant mitotic index
GBM with oligodendroglioma EGFR, p53, IDH1, MGMT; Honeycomb-like Mean OS: 17, 56, 103, 137,
component (GBMO) Gain chromosome 7; features, pseudopa- 19.0-26 months 146, 160, 167,
Features of GBM along with oligo- Loss chromosome 1p, lisading necrosis Median PFS: 168
dendroglial (e.g. fried egg) features 9p21, 10, 19q 10.3 months
Mean 2-year survival:
60%
GBM with primitive neuroectodermal N-myc, C-myc, IDH1; IDH1 Mean survival: 66, 68, 123
tumour (GBM-PNET) Loss chromosome 10q 44 months
Features of GBM along with PNET-like
areas showing hypercellularity,
minimal fibrillary background, small
undifferentiated cells with scant
cytoplasm, oval-round hyperchromatic
nuclei, and Homer Wright neuroblastic
rosettes staining for S-100, synapto-
physin, NeuN, and NFP
Gemistocytic astrocytoma (GA) P53, Bcl-2, MIB-1, Small cell features Mean OS: 5, 84, 85, 138,
Features of GBM along gemistocytes chromosome 7, 10 64 months 164, 169
characterized by glassy, non-fibrillary
cytoplasm and peripherally displaced
nuclei
Granular cell astrocytoma (GCA) EGFR, p16INK4A, IDH1, Mean survival: 24, 64
Features of GBMs along with MGMT; Gains chromo- 7.6 months
abundant granular cells with large some 7; Loss chromo- One-year survival:
distinct cell borders, round to oval some 1p, 8p, 9p, 10, high-grade (12%)
shapes, and abundant eosinophil 13q, 22 low-grade (40%)
granular cytoplasm staining for GFAP,
CD68, EMA, and S100
Paediatric high-grade glioma (HGG), ADAM3A, AKT, P53, PTEN, MIB-1, HGG 2-year survival: 34, 51, 91, 118,
diffuse intrinsic pontine glioma (DIPG) BRAFV600E, CDKN2A/ MGMT, AKT 10-30% 119, 129-131,
Resembles GBM except for presence 2B, EGFR, PTEN, DIPG 2-year survival: 135, 147, 149,
in paediatric patients MGMT, IDH1/2, PDGFRA, < 10% 152, 153, 173
p53, Ras/PI3K, Rb, MET,
H3F3A, ATRX, DAXX;
Gain chromosome 1q

The mechanisms of how genomic and molecular 1p/19q [30], have not shown a consistent effect on prog-
abnormalities support the dramatic heterogeneity of nosis in GBM [67]. Recent studies have also elucidated
GBM as well as its known and potential variants re- the molecular features of grade 2 and grade 3 gliomas,
mains to be understood. Moreover, understanding this which include many of the same driving mutations in
underlying nature as well as correlation of genetic and GBM, such as p53, IDH1/2, and 1p/19q codeletion [36].
pathological features will be important in predicting While classification by primary or secondary aetio-
disease progression and in designing future persona- logy has aided in clinical understanding and treatment
lizing therapies. personalization, recent advances in systems-based
analysis of GBM have elucidated a further underlying
Classic glioblastoma multiforme complexity to GBM. Genomic and proteomic analysis
has identified various subtypes of GBM [22,59,117].
Histopathological features of GBM (ICD-O9440/3)
These include the proneural subtype mainly distin-
are diverse and often nonspecific. GBM shows infil-
guished by amplification or mutation of platelet-de-
trating, pleomorphic, hyperchromatic cells with glassy,
rived growth factor (PDGF), but also with alterations
astrocytic cytoplasm suggestive of an aggressive le-
in IDH1/IDH2, p53, PI3KCA and PI3KR1. Furthermore,
sion of glioneuronal origin [20]. Variation in features
the mesenchymal subtype has been described by neu-
can range from monotonous, small cell features to large rofibromin 1 (NF1) deletions or mutations, along with
giant cells where determining the difference between p53 and PTEN mutation. The proliferative subtype,
differentiation patterns and a distinct, bona fide vari- sometimes termed the classical subtype, has been
ant can be difficult. Areas of focal pseudopalisading defined by EGFR mutation or amplification along
necrosis and microvascular proliferation, including with EGFRvIII, PTEN, and p16INK4A deletion. Lastly, the
glomeruloid formation are characteristic. Stains with neural subtype has been described without a predo-
glial fibrillary acidic protein (GFAP) can be used to iden- minant mutation genotype. Moreover, patients with
tify the astrocytic nature of the tumour while staining proneural GBM subtypes demonstrate improved sur-
with Ki-67/MIB-1 can reflect its rapid proliferation. Se- vival over the proliferative or mesenchymal groups [125].
condary structures of Scherer have been described Expression profiles of GBM have shown to serve as bet-
as features of tumour invading normal brain tissue ter markers of prognosis compared to individual genet-
along white matter tracts and blood vessels, where sur- ic or histological features [44].
rounding normal brain generates a gliotic response. Molecular heterogeneity may be important in un-
Historically, the underlying genetic basis of GBM derstanding how current therapeutic treatments fail
has supported the distinction of primary and secondary to target cells in the GBM tumour mass thereby select-
GBM, each with characteristic clinical and pathologi- ing for resistant cells that can result in recurrence and
cal features [114]. Primary GBM typically occurs de novo poor survival [29]. Microdissection studies of GBM have
and with a mean age of 62 years at presentation, shown discrete areas of individual tumours to contain
while secondary GBMs arise from lower grade gliomas distinct chromosomal aberrations [49,65], karyotypes
with a mean age of 45 years. While epidermal growth [154], antigenic markers [171], EGFRvIII expression [112],
factor receptor (EGFR) amplification, EGFR variant III growth factor receptors [57], angiogenic factors [78], and
deletion (EGFRvIII), p16INK4A deletion and phosphatase adhesion molecules [11]. This explained heterogeneity
and tensin homolog (PTEN) mutations have been pre- has been suggested to derive from a clonal cell type that
dominant features of primary GBM, these mutations undergoes evolving mutations or from a CSC that po-
can also be seen in secondary GBM [37,86,114]. Like- pulates the tumour cells and stroma while maintain-
wise, mutations in tumour suppressor p53, often seen ing a population of undifferentiated cells [15,71]. Despite
in secondary GBM, can also be observed in primary a lack of an adequate marker of CSCs in GBM, CD133+
GBM. Various markers of prognosis in GBM have been has been utilized and studies have supported hierarchical
investigated, including loss of chromosome 10 with acti- organization of undifferentiated cells [27]. The role of
vation of the PI3K/AKT pathway [26], EGFRvIII ampli- microRNAs in the regulation of CSCs has also been sug-
fication [158], CD133 [99], O-6-methylguanine-DNA gested as a mechanism of conferring heterogeneity to
methyltransferase (MGMT) [55,162], and isocitrate de- GBM [72]. How the GBM cell of origin generates such
hydrogenase 1(IDH1) [13,117,166]. However, the role of a large variety of molecular heterogeneity and mor-
other cytogenic abnormalities such as deletions in phological variants remains unknown.

Gliosarcoma estingly, primary GS showed features of malignant

fibrous histiocytoma, fibrosarcoma or osteosarcoma
Gliosarcoma (GS) is a GBM subtype (ICD-O 9442/3)
while postirradiated secondary GS commonly showed
accounting for 1-5% of GBM diagnoses, and presents
features of fibrosarcoma, thus suggesting that radia-
between ages 50 and 70, with a mean survival of
tion prompted distinct differentiation patterns. A study
4-11.5 months [45,89,102]. Initially described by Stroebe
of 24 cases of secondary GS suggested that previous
and thought to be nondistinct from GBM in terms of
treatment with radiation could promote GS development
age of onset, location, and clinical prognosis, signifi-
with a mean survival after GS diagnosis of 6.7 months
cant evidence now supports GSs as a unique variant
[47]. In a separate study of 30 secondary GS cases de-
[63]. GSs demonstrate a biphasic pattern comprised
veloped from primary GBM after treatment with che-
of glial cells, which express GFAP, and sarcomatous/
motherapy and radiotherapy, a median length of sur-
mesenchymal cells, which express reticulin [89].
vival of 4.4 months from time of GS diagnosis and
Epithelial differentiation with carcinomatous features
median survival of 12.6 months from time of GBM diag-
can also occur in glial portions [115]. The sarcomatous
nosis was observed [46]. This study also surprisingly
component of this tumour shows atypical, aggressive
showed that concurrent and adjuvant temozolomide
features and can differentiate along multiple distinct
treatment yielded significantly worse outcomes. Pre-
lineages, such as fibroblastic, osteogenic, chondroge-
diction of GS tumour response to treatment remains
nic, adipogenic, and myogenic types, especially upon
a poorly understood area.
exposure to radiation treatment [2,7,8,10,52,89,139].
Gliosarcoma tumours in paediatric and adult pa-
A similar potential variant termed gliofibroma has
tients show distinct clinicopathological features. A ret-
also been described consisting of biphasic glial and
rospective review of 600 paediatric GBM cases demon-
non-sarcomatous fibroblastic components common-
strated GS in 4 patients with approximately 19 cases
ly found in paediatric patients [89]. This potential vari-
previously reviewed in the literature [70]. This study
ant has been closely related to GS, with approximately
showed that paediatric GS tumours had an equivalent
33 cases currently reported in the literature, and has
male to female ratio, a median age of onset at 11 years,
a mean survival of approximately 17 months [76]. Also
a significant incidence in infants, localization commonly
reminiscent of GS, lipidized glioblastoma, termed
lipoglioblastoma, has also been described as a rare in the cerebral hemispheres, as well as a median over-
malignant tumour with significant foamy cell presence all and event-free survival of 12.1 and 9.8 months, res-
[62,159]. While early reports of GS suggested the con- pectively. Interestingly, some studies have suggested
cept of a “collision tumour” with vascular dysplasia that GS cases in paediatric patients show areas of rhab-
resembling sarcomatous features, current models domyoblastic differentiation suggestive of gliomyo-
suggest a monoclonal cell of origin or CSC with distinct sarcoma and osteogenic sarcoma differentiation [148].
genetic drivers of GS [35,48]. However, gliomyosarcoma staining for smooth mus-
The clinical course of GS tumours remains poorly cle antigen and factor VIII has also been reported in
understood. GS commonly occurs in the temporal lobes, rare instances of adult GS [75]. Understanding of pae-
presents as a circumscribed lesion, can have menin- diatric GS has been limited as compared to paediatric
gioma-like histological features, and can metastasize gliomas due to the rarity of this disease.
extracranially to lungs and liver [45]. GS manifestation Recent studies have greatly elucidated the mole-
in the spinal cord has also been reported [23]. Survival cular underpinnings of GS tumours. GS sarcomatous
may be greater for GS with meningioma-like features and gliomatous regions show unique expression pat-
vs. GBM-like features [48]. Also in this meta-analysis, terns where regions of sarcoma stain with markers
fibronectin, vimentin, α1-antitrypsin, and chymotrypsin

GS tumours showed infrequent EGFR mutations unlike such as laminin, collagen type IV, procollagen type III,
their GBM counterpart and suggested that the role for
radiotherapy and chemotherapy treatments continues A while gliomatous regions commonly stain for GFAP
to be uncertain due to limited data and poor under- and S-100 protein [43,97,144]. However, staining pat-
standing of this entity. A study of 32 cases of GS showed terns vary widely between tumours and their examined
7 cases of secondary GS after patients underwent irra- regions. A study of molecular features in 26 cases of GS
diation for GBM [124]. However, patients with primary demonstrated 11.5% had MGMT methylation and 7.7%
GS that underwent irradiation showed significantly had IDH1 mutation but these features did not predict
improved survival compared to untreated cases. Inter- overall survival as well as gross total resection and/or

treatment with gamma knife surgery [87]. Analysis of and were negative for CD133 expression. Gliosarcoma
molecular signalling pathways in 6 cases of GS showed neurospheres were capable of self-renewal as well as
that while activating mutations of PDGFRα, c-kit and differentiation into astrocytes and mesenchymal cells.
B-RAF were absent, expression of these signalling path- When GS neurospheres underwent serial xenograft
ways was commonly seen in GS [140]. In a previous transplantation, they formed high-grade, invasive
study of 19 GS tumours, mutations in p53 (26%), PTEN tumours reminiscent of parent tumour with biphasic
(37%), and the Rb pathway (53%) were commonly seen glial and mesenchymal components as well as retained
and also concordant between gliomatous and sarco- nestin expression. An endogenous rodent model of GS
matous tumour regions [139]. This study also suggested has also been reported from the induction of Fisher 344
that GS tumours molecularly resemble primary GBMs. rats with 5 mg/kg of MNU for 26 weeks [9]. Tumours
Mutations in p53 have also been seen in both glioma in this model show spindle-shaped cells with a sar-
and sarcoma areas of the tumour [12] as well as gains comatoid appearance, mutations in p53, and normal
on chromosomes 7, 9q, 20q, X and losses of 9p, 10 and expression of p16INK4A and p19ARF [4,151]. Furthermore,
13q [1,14]. In one study, comparable genotypic patterns tumours derived from this model show an increased
of 1p, 9p, 10q, 17p, and 19q loss were seen between glial, expression of TGFα and EGFR along with a decreas-
sarcomatous and carcinosarcomatous regions [115]. ed expression of FGF-2, FGF-9, FGFR-1, and PDGFRβ
New markers may help to better differentiate these [157]. CSCs capable of neurosphere formation, self-
GS tumours from GBM and support novel target the- renewal, nestin and Sox2 expression, and differenti-
rapies. A recent study using a comparative genomic ation into neuronal and glial cells have also been report-
hybridization array of glial and mesenchymal areas ed from this model [41]. These tumour models support
of 13 GS tumours showed similar gain/loss patterns the distinctions between GBM and GS seen clinically.
except for a significant gain at chromosome segment
13q13.3-q14.1 [107]. This area was further shown to Giant cell glioblastoma multiforme
contain the gene stomatin (EPB72)-like 3 (STOML3), Giant cell GBM (gcGBM) is a rare variant of GBM
which is of unknown function but expressed in neu- (ICD-O 9441/3) thought to encompass 2-5% of GBM
ronal cells. This area also contained FRAS1-related extra- diagnoses [89]. These tumours feature characteristics
cellular matrix protein 2 (FREM2) involved in regulating
nent multinucleated giant cells greater than 500 µm
of GBM including necrosis and atypia along with promi-
epidermal-dermal interactions during morphogenesis,
as well as lipoma HMGIC fusion partner (LHFP), involved in diameter and lymphocytic infiltration. GcGBMs have
in lipoma formation and hearing. These genes were also been poignantly termed monstrocellular sarcomas
expressed in 11-20% of mesenchymal areas but not glial
β-tubulin, p53, EGFR and GFAP [89,115,116]. The pre-
and can variably stain for S-100, vimentin, class III
areas. This study suggested that these and other
yet uncharacterized mechanisms of mesenchymal sence of multinucleated giant cells and lymphocytic
differentiation in GS exist and may support novel tar- infiltration has been reported in multiple studies as
geted therapies. A separate study of epithelial-me- favourable features in gcGBM [18,33,105]. However,
senchymal transition (EMT) in GS tumours demonstrat- there may be multiple reasons for this improved sur-
ed expression of Slug, Twist, matrix metalloproteinase-2 vival in gcGBM.
(MMP-2) and MMP-9, involved in tumour dissemina- Various clinical features define gcGBM presentation
tion, in a majority of GS mesenchymal areas [108]. and survival. In a study of 184 pretreatment biopsies
These results suggest that mechanisms important in of GBM, 12 patients with gcGBM showed significant-
EMT may be involved in GS tumours however further ly improved survival [21]. One study reported a mean
examination of how these proteins are involved remains age of 46.2 years for 19 patients with gcGBM and
to be seen. an equal prevalence of males to females [100]. In ano-
In vitro models of CSC in GS have also been inves- ther study of 113 supratentorial GBMs diagnosed
tigated. Tumour-derived tissue expanded in growth fac- between 1987 and 1998, 5.3% survived longer than
tor media was used in an in vitro neurosphere assay, 5 years with 3 of these being gcGBM [156]. GcGBMs often
which was used to amplify a subpopulation of cells show distinct surgical borders and present in younger
with gliosarcoma-like properties [32]. This study also patient populations than GBM [105]. These support the
showed that GS neurospheres expressed neural stem impetus to perform more aggressive surgical resections
cell markers Sox2, Msi1 and nestin similarly to GBM which may help in part to explain the improve survival

from this GBM subtype. In a study of 42 cases of gcGBM a more favourable prognosis for gcGBM continues to
treated over 34 years at a single institution, gcGBMs be an active area of investigation.
were found to be more frequent in younger subjects, Comparison of paediatric gcGBM and GBM has
showed superficial localization and sharp borders, as been recently shown in several investigations. A study
well as improved survival compared to reported prog- of paediatric GBM, aged 3 to 18 years at time of diag-
nosis in GBM [115]. Furthermore, this study showed that nosis, compared 18 cases of paediatric gcGBM and
mean survival was improved with combined surgery 178 cases of paediatric GBM from the HIT-GBM trial [69].
and radiotherapy (57 vs. 32 weeks), age did not alter In this study, patients underwent the best possible sur-
survival, and lymphocytic infiltration showed a bene- gical resection, standardized fractionated radiothera-
fit towards survival. In a study of 16,430 patients from py and randomized into one of four types of chemother-
the Surveillance, Epidemiology and End Results (SEER) apy regimens. Results from this evaluation showed no
database diagnosed with GBM, 1% showed gcGBM and difference in median age, male : female ratio (~2 : 1),
demonstrated improved prognosis compared to GBM and clinical history between paediatric gcGBM and
[79]. In this study, patients with GBM and gcGBM GBM. Surprisingly, no difference in median overall sur-
showed similar gender and racial distributions as well vival (1.18 vs. 1.08 years) or event-free survival (0.54 vs.
as insignificant tumour size and location differences. 0.53 years) was also observed. While a greater per-
However, age at diagnosis was significantly younger centage of gcGBM tumours underwent gross-total
in gcGBM vs. GBM (51 vs. 62 years) and gcGBMs were resection compared to GBM (44 vs. 25%) these results
more likely to undergo complete resection. And after were not significantly different or reported to alter sur-
controlling for multiple factors, a multivariate analy- vival when matched with gross-total resected GBM
sis showed a hazard ratio of 0.76 (95% CI: 0.59-0.97) tumours. Thus, while gcGBM portends an improved
for patients diagnosed with gcGBM compare to GBM, prognosis in adults, this disease in paediatric patients
however median survival for gcGBM continued to be showed no difference from classic GBM and suggests
about 1 year. Multiple features are favourable towards an alternative mechanism of formation.
prognosis of this entity.
Molecular investigation of gcGBMs has been pur- Emerging variants
sued in a variety of recent studies. Mutations in p53
GBM can present with dramatic heterogeneity of
have been seen in 90% of gcGBMs mostly in locations
histopathological and clinical features. The most recent
of the gene unique from usual hot-spot p53 mutations
2007 WHO guidelines for brain tumours found sufficient
of classic GBM [100]. Furthermore, infrequent EGFR
evidence to support the presence of classic GBM, GS
amplification and p16INK4A deletion were seen in this
and gcGBM [89]. Furthermore, the guidelines have sug-
study. Another study of 16 gcGBM tumours showed p53
gested the possibility of various emerging GBM vari-
mutation in 75% of samples and focal EGFR overex-
ants. Multiple, recent in vitro, in vivo, and clinical stud-
pression in 56% of tumours, albeit findings were not
ies have raised new evidence elucidating such features.
uniform within all specimens [120]. Point mutations
in PTEN and chromosome 10 deletions, where PTEN
Fibrillary/epithelial glioblastoma multiforme
resides, along with amplification of MDM2 have also
been reported [93, 121]. Furthermore, giant cell and non- Distinct from WHO grade II fibrillary astrocytoma
giant cell populations have shown distinctions in ge- (ICD-O 9420/3), fibrillary/epithelial differentiation in
nomic alterations with polyploidy being reported GBM shows malignant features along with the for-
in 72-84% of giant cells and 4-14% of nongiant cells, mation of squamous nests and glands [73,106]. This
compared to 11-49% polyploidy in classic GBM [93]. pattern must often be distinguished from closely mim-
GcGBM has also been suggested to be involved in some icking metastatic carcinomas, through the use of GFAP
cases of patients with Turcot syndrome, a rare GBM- and CAM 5.2 immunostains among others [113].
forming genetic disorder with biallelic mutation of the Some studies have also suggested that fibrillary/epi-
DNA mismatch repair genes MLH1, MSH2, MSH6 or thelial differentiation in GBM may be due to primitive
PMS2, along with favourable prognosis despite anapla- neuroepithelial cells, mechanical compression, or the
sia and high proliferation [90]. Microsatellite instabil- histological response of host cells to tumour [73,106].
ity has been seen with increased frequency compared Fibrillary differentiation is a rare event suggested as
to GBM [93]. How these molecular features support a potential characteristic of GBM but not a distinct fib-

rillary GBM variant. However, recent studies have sup- noid GBMs with a median overall survival of approx-
ported a clonal origin for fibrillary GBM. A study of GS imately 7 months.
with extensive epithelial and glandular differentia- Markers of fibrillary GBM and its relationship to EMT
tion demonstrated concordant alterations in hetero- may play important roles in understanding this vari-
zygosity of various evaluated chromosomes (1p, 9p, 10q, ant. Recent studies have suggested that fibrillary/epi-
17p, 19q) with losses of 1p36, 9p21, 10q23, and 17p13 thelial differentiation may have a unique genetic un-
suggesting a potential for fibrillary GBM formation [115]. derpinning and that EMT, important in the spread of
Others have also shown the epithelial and glial com- metastatic cancers, may be involved in governing GBM
ponents of GBM contain a concordant loss of mark- dissemination [88,104,111,128,143]. A recent analysis of
ers on chromosome 17p13 and 10q22-26 as well as p53 E-cadherin, an important regulator of dissemination
mutation [128]. Concordant mutations of p53 between involved in EMT and metastasis, showed that expres-
microdissected portions of glial and fibrillary GBM have sion correlated to significantly poorer patient prognosis
also been observed [104]. These studies support a de- in 27 GBM tumours with epithelial/pseudoepithelial dif-
differentiated fibrillary/epithelial component of GBM, ferentiation [88]. Furthermore, survival in these fibril-
extent of resection, β-catenin immunostaining, mole-

which may comprise a distinct GBM variant with unique lary GBMs did correlate to age, tumour location or size,
diagnostic and prognostic characteristics.
The defining features of a distinct fibrillary GBM vari- cular cytogenic abnormalities or proliferative indices.
ant continue to be an area of investigation. A study of This study also evaluated 19 established GBM cell lines,
58 GBM tumours out of 3500 screened specimens were which showed increasing in vivo invasiveness correlat-
evaluated by expert pathologists for epithelial, epithe- ing with E-cadherin expression. One GBM cell line (SF767)
lioid and adenoid features [143]. This study demon- demonstrating epithelial features, such as E-cadherin
strated predominant epithelial features in 35% of cas- staining and filopodia, E-cadherin knockdown dimi-
es, epithelioid features in 17% and adenoid features in nished cell growth and migration. Despite the uncer-
48%. Epithelial differentiation was defined as epithe- tain nature of this GBM type as a distinct variant, evi-
lial morphology with squamous nests, true glandular dence has begun to suggest underlying molecular
structures and immunohistochemical expression of spe- mechanisms supporting this tumour and its similar-
cific epithelial markers. Epithelioid GBMs contained few- ities to metastatic carcinoma.
er specific features of epithelial differentiation along
with the absence of epithelial marker expression. And Small cell astrocytoma
adenoid features required the presence of cohesive cells Small cell astrocytoma (SCA) is characterized by
of intermediate size arranged into cords with pseudo- monomorphic proliferation of cells with small, round
glandular spaces and without staining for epithelial nuclei, limited cytoplasm, mild hyperchromasia, lim-
markers. The epithelial components of GBM tumours ited interlaced stroma, and scant mitotic index [89].
partially or completely stained for epithelial muscle anti- These tumours may account for 10% of GBM diagnoses
gen (EMA), cytokeratin CAM 5.2, E-cadherin, cytoker- with another 11% showing focal, small cell features
atin AE1/AE3, cytokeratin 7, polyclonal carcinoembry- [122]. Despite the possibility of being mistaken for high-
onic antigen (pCEA), in > 70% of samples while also grade oligodendroglial tumours or lower grade astro-
staining for cytokeratin 5/6 and cytokeratin 20 in 7-36% cytomas, SCAs are aggressive lesions paralleling grade
of samples. The glial components of the epithelial tu- IV gliomas. Multiple studies have correlated the pres-
mours were negative for expression of epithelial mar- ence of small cell architecture in primary GBM with
kers in > 70% of cases except for cytokeratin AE1/AE3 EGFR amplification [19,136]. In one study, 88% of SCAs
which was positive in 53% of cases. Furthermore, no (8/9) were amplified for EGFR compared to 42% of
significant difference in p16INK4A deletion, chromosome (5/12) samples of a control set not containing small cell
10 loss, or PTEN deletion was seen among samples. features, which was validated in a larger set where 67%
However, epithelial GBM showed the highest occurrence of (14/21) SCA neoplasms showed EGFR amplification
of p21 immunonegativity (93% of samples), strong [19]. In another study, 56 cases of GBM were evaluated
nuclear p53 staining (41% of samples), and strong stain- by chromogenic in situ hybridization and showed 64%
ing for EGFR (19% of samples). No differences in sur- (14/22) of SCAs and 23% (5/22) of GBMs showed EGFR
vival were seen between epithelial, epithelioid and ade- amplification [136]. Interestingly, a study of glial and

epithelial microdissected components in SCA showed and oligoastrocytoma. Significant interest exists in the
evidence of human polyomavirus JCV infection, sug- delineation of this entity since WHO grade III anaplas-
gesting a role of infection in the monoclonal origin of tic oligodendroglial tumours show greater chemosen-
this tumour [127]. sitivity than GBM and 1p/19q codeletions portend bet-
Recently, some authors have supported this type ter prognosis, suggesting that the distinction between
of tumour as a distinct variant of GBM. In a study of GBMOs and GBM may impact survival [114,137,172].
229 GBMs, 71 tumours were retrospectively identified Similarly, histological subclassification of GBM also sup-
as SCAs [122]. In this study, SCA tumours were de- ports improved prognosis in tumours with oligoden-
fined as containing small cell morphology within > 80% drocytic components [17,103]. However, some authors
of samples. Furthermore, 11% of tumours showed sig- have cautioned that the classification of GBMO tu-
nificant, focal, small cell features but did not meet cri- mours, which would have been previously diagnosed
teria. Among SCA tumours, 37% of samples showed as mixed anaplastic oligoastrocytoma (MOA), may arbi-
minimal to no radiological enhancement, and 33% trarily increase the incidence of total GBMs as well as
showed no endothelial hyperplasia or necrosis, there- the overall survival [95]. Additional studies in order to
fore defined as grade III astrocytomas. However, mor- determine whether distinct prognostic and histologi-
tality for SCAs of 6 months was similar to grade IV cal features exist are warranted.
GBMs (11 months). This study also suggested that SCA Early studies suggested a distinction between
tumours often mimicked anaplastic oligodendroglioma, GBMOs and classic GBMs. In regards to survival, analy-
anaplastic oligoastrocytoma or glioblastoma with oli- sis of 98 MOA, anaplastic oligodendroglioma (AO), and
godendroglial features due to the frequent presence GBMO tumours showed a median survival time of
of branching, chicken wire-like capillary networks, clear 24 months for AO vs. 9 months for GBMOs or MOAs
perinuclear haloes, per neuronal satellitosis and [160]. Furthermore, while GBMOs showed worse sur-
microcalcifications. However, SCA tumours uniformly vival than lower grade astrocytomas, older age and
lacked 1p/19q deletion thus being distinguished from astrocytic elements were seen to increase mortality
oligodendroglial tumours. SCAs showed amplification while necrosis and microvascular proliferation failed
of EGFR and EGFRvIII in 83% and 50% of samples com- to predict survival suggesting distinct features from clas-
pared to 35% and 21% of GBM samples, respectively. sic GBM. Nonetheless, GBMOs demonstrated improved
These molecular differences suggest distinct tumours survival from GBM. The presence of necrosis has shown
despite their clinical similarity. Overall features sug- to predict poor survival in MOAs independent of patient
age (22.8 vs. 86.9 months) [101]. Other studies have
gesting by the authors to define SCA included ring-
shown an overall survival of 20.9 vs. 13.6 months and pro-
enhancement and pseudopalisading necrosis, oval nu-
gression free survival of 10.3 months vs. 7.6 months
clei, brisk proliferative indices, and thin, GFAP-positive
between GBMOs and GBM, respectively [146]. The re-
cytoplasmic processes. Other researchers have report-
sults of this study suggested a significant impact of
ed a median survival of 14.3 months for SCAs, which
oligodendroglial components on GBM prognosis and
was not significantly different from classic GBM after
molecular characteristics. A recent study of 10 con-
adjusting for patient age and surgery type [13]. Despite
secutive cases of GBMO treated with chemotherapy
similar clinical courses, these results support both
(nimustine and teniposide) and radiotherapy had
molecular and histopathological distinction between
a median survival of 26 months (range from 14 to
SCAs and classic GBM.
26 months) while 2-year survival was 60% (range be-
tween 20% and 58%), which suggested that aggres-
Glioblastoma multiforme with sive treatment of these patients showed improved
oligodendroglioma component
outcomes compared to reported rates for GBM in the
An emerging variant in the 2007 WHO classifica- literature [167]. While many of these early studies
tion, glioblastoma multiforme with an oligodendroglial showed impressive distinctions between GBMO and
component (GBMO) has been termed as a possible dis- GBM, small sample sizes limited solidifications of
tinct entity from GBM [89]. GBMOs resemble GBMs but GBMOs as a distinct entity.
also contain areas resembling oligodendroglioma Investigation into molecular differences between
with the typical fried-egg appearance. GBMO is distinct GBM and GBMOs has yielded significant insight into
from anaplastic oligoastrocytoma, oligodendroglioma, the differences between these tumours. A retrospec-

tive study compared 450 GBM and 36 GBMO samples < 5%), reduced MGMT expression, and longer survival
[146]. In this study, GBMO cases showed a lower me- (19.0 vs. 13.2 months) [168]. Furthermore, this study
dian age at onset (52.1 vs. 62.24 years) compared to showed that as an independent component, the pre-
GBM. Among GBMO cases, loss of heterozygosity (LOH) sence of an oligodendroglioma component, predicted
of 1p and/or 19q (75% of samples), LOH of 10q (58% longer survival regardless of the extent of this feature.
of samples), EGFR amplification (39% of samples), Codeletions of 1p/19q were found in < 5% of GBMOs
and TP53 mutation (22.2% of samples) were detect- and GBMs. More aggressive therapy had no impact on
ed. These molecular alterations are consistent with GBMOs but showed significant improvement in sur-
some but not all previous studies [53,82]. Nevertheless, vival with GBMs. Findings from the EORTC 26981/NCIC
distinctions between rates of alterations in GBMOs CE.3 trial examined oligodendroglioma components
and GBM support this distinct entity. The role of 1p/19q in 339 confirmed cases of GBMs and found that 15%
codeletion has also been an important facet due to could be classified as GBMOs [56]. This study showed
the loss of these markers in conferring better prognosis that GBMOs showed significantly higher levels of IDH1
in oligodendroglioma and medulloblastoma [61]. mutation (19% vs. 3%), and EGFR amplifications (71%
A study of 1p/19q deletion in 10 GBMs, 2 GBMOs and vs. 48%) while codeletion of 1p/19q and MGMT methy-
8 AOs showed that 1p/19q was codeleted in all AOs but lation were similar between GBMOs and GBMs. This
inconsistently altered in GBMs and GBMOs [109]. How- study utilized expression profiling to classify GBMOs
ever, a small sample size, retrospective evaluation, predominantly into proneural and classic GBM sub-
and lack of standardized treatments were significant types. Incidentally, while this study did not show any
confounding factors in this study. Another study of prognostic significance for an oligodendroglial com-
64 GBMs and 24 GBMOs failed to find significant dif- ponent in a survival model, the presence of pseudopal-
ferences in 1p and 19q as well as overall survival [126]. isading necrosis was a significant predictor of bene-
And a study of 19 cases of GBMO demonstrated that fit from chemotherapy.
calcification, cystic components, LOH of chromoso-
me 10, EGFR amplifications, 9p21 deletions containing Glioblastoma multiforme with primitive
p16INK4A were seen in the majority of cases; however, neuroectodermal features
sample size in this study was low and GBMOs were not
compared to GBMs seen at the same institution [110]. Primitive neuroectodermal tumours (PNET) are rare,
During a recent study of GBMO and GBM cases, micro- neural crest derived tumours commonly occurring in
dissected astrocytic and oligodendroglial components children and young adults (mean age 5.5 years) with
were evaluated by comparative genomic hybridization CSF dissemination and uniformly poor prognosis [3].
[77]. This study showed that oligodendroglial and astro- Recent reports have suggested GBM with PNET-like fea-
cytic components of GBMOs were concordant and that tures (GBM-PNET) as a potential variant of GBM and
GBMOs could be classified according to chromosomal present in older adults [68]. These tumours contain two
gains/losses (shown in parentheses) into astrocytic distinct architectures, including that of traditional GBM
(+7/–10), oligodendroglial (–1p/–19q), intermediate and that of PNET-like areas with hypercellularity,
(–1p/+7), and non-specific subtypes. The results sup- minimal fibrillary background, small undifferentiat-
port a monoclonal cell of origin along with distinct path- ed cells with scant cytoplasm, oval-round hyperchro-
ways of gliomagenesis. GBMOs presented in younger matic nuclei, and Homer Wright neuroblastic rosettes
patients (55.4 vs. 63.8 years), showed better overall sur- [66,89,123]. Furthermore, PNET-like areas show lower
vival (404 vs. 282 days), and responded better to radio- expression of GFAP but readily stain for S-100, synap-
therapy compared to GBM. Furthermore, honeycomb- tophysin, NeuN, and neurofilament protein (NFP).
like features in GBMO may predict better survival than Gliomatous and lipomatous degeneration of PNET
a round cell appearance. tumours have been reported, which may support an
Recent analyses of large tumour databases have alternative origin for this tumour [60,134].
better supported a distinct GBMO variant. One group A recent study has demonstrated multiple, unique
showed that approximately 18.3% of 219 consecutive characteristics for GBM-PNETs compared to GBM.
GBM samples at a single institution were GBMOs, In a study of 53 GBM-PNETs (median age 54) and
which showed a significantly greater frequency of tu- a male: female ratio of 1.3, PNET-like components were
mour-related seizures, greater IDH1 mutation (31% vs. observed to be discrete and hypercellular with nodules

of neuronal differentiation [123]. Moreover, neuronal with GBM, PNET-like features defined as neoplastic cells
markers, including synaptophysin and NeuN, were spe- with high N : C ratios, hyperchromatic oval-carrot-shap-
cific to PNET-like areas while neuron specific enolase ed nuclei, and absence of honeycomb appearance were
(NSE) was seen in both glial and PTET areas. Further- seen in 27% of samples, however these features did
more, Ki-67 indices ranged from 30% to 100% and not correlate with prognosis [163]. These results sug-
nuclear p53 expression was seen in 83% of cases. GBM gest a promising outcome for these types of tumours
components resembled secondary GBM with strong and may support aggressive treatment.
p53 expression and 25% having a prior diagnosis of low Paediatric GBM-PNET tumours have also been re-
grade glioma. Significant portions of glial components ported. In a study of 12 paediatric GBM-PNET and 6 pae-
showed foci of lower grade glioma (89% of cases), fib- diatric GBM tumours, an analysis of various molecu-
rillary astrocytoma (62%), gemistocytic astrocytoma lar markers was employed to differentiate these
(40%), giant cell astrocytoma (23%), oligoastrocytoma tumours [81]. The mean age of GBM-PNET subjects was
(19%), and oligodendroglioma (2%), while the neu- 4.3 ± 2.9 years (M : F ratio 1 : 1.4) while the mean age
roblastic components showed Homer-Wright rosettes of GBM subjects was 8.3 ± 4.8 years (M : F ratio 1 : 2).
reminiscent of medulloblastoma (60%). Within the Mutations of p53 and PTEN were seen in 33% and 17%
PNET-like areas, amplification of n-myc or c-myc was of GBM tumours, respectively, while being found in 8%
in 43% of samples, suggesting this mutation to be a late of GBM-PTEN tumours. Furthermore LOH of 17p was
event in tumour development. Chromosome 10q de- seen in 33% of GBMs and no GBM-PNETs, while LOH
letion was common (50% of samples) in both glial of 10q was seen in no GBMs and 8% of GBM-PNETs.
and PNET components, while PTEN deletion, DMBT1 Amplifications of EGFR, CDK4 and MDM2 as well as
loss and EGFR amplification were rare. Furthermore, homozygous deletion of CDKN2A were absent in all
this study evaluated the role of gross-total resection, tumours. These results support distinct mechanisms
radiotherapy, temozolomide and platinum-based of pathogenesis for GBM-PNET tumours in adult and
chemotherapy where, despite limited data, survival paediatric patients.
continued to be poor with a median of 9.1 months.
The synchrony in mutational characteristics between Gemistocytic astrocytoma
glial and PNET-like areas further supported the hypoth-
esis for monoclonal origin regarding GBM-PNET where Gemistocytic astrocytoma (GA), characterized by ge-
the clinical, cytological and immunoreactive features mistocytes with glassy, non-fibrillary cytoplasm and
supported the differentiation of GBM-PNET predomi- peripherally displaced nuclei, is delineated as a WHO
nantly from secondary GBM. Alternatively, neuroblas- grade II tumour (ICD-O 9411/3) however these tumours
tic nodules may have represented clonal expansion of often behave more aggressively than other lower
tumour stem cell niches within the parent GBM tumour. grade astrocytomas [89,164]. While a tumour sample con-
Recent studies have suggested favourable molec- taining 20% of gemistocytes is defined for a diagnosis
ular and prognostic features for GBM-PNETs. A study of diffuse astrocytoma, the amount of tumour containing
of 40 cases of grade III or IV glioma demonstrated coex- gemistocytic components suggesting an aggressive
pression of GFAP and NFP as essential to the diagno- tumour is debatable [85,164]. In fact, this threshold of
sis of GBM-PNET [165]. Furthermore, a lack of recur- gemistocytic cells in astrocytomas has been shown to
rence was observed in 36% of cases, which underwent significantly impact overall and progression-free survival
gross total resection resulting in a mean survival of [85]. However, other studies have suggested that
44 months. In another study of 12 patients with GBM- gemistocytic components in astrocytomas do not cor-
PNET (median age 51.5 years, M : F 4 : 1), mutations relate with age, p53 expression, or MIB-1 staining, or sur-
in IDH1 were seen in 25% of cases evaluated (n = 2) vival [54,94].
with overall survival of 15 and 31 months [161]. Fur- The presence of gemistocytic components in GBM
thermore, this study suggested that restricted diffu- has been uncertain in predicting prognosis. A study of
sion on diffusion-weighted imaging correlated with the 40 low-grade astrocytomas with progression to WHO
PNET-like component, CD56 expression with both glial grade III or WHO grade IV astrocytomas demonstrat-
and neuroblastic components, and vimentin staining ed that tumours with > 5% gemistocytes showed sig-
with the glial component thereby improving identifi- nificantly poorer survival compared to tumours with
cation of this GBM variant. In a study of 86 patients < 5% gemistocytes (35 vs. 64 months) [170]. In addi-

tion, this study showed that GAs had a greater likeli- These molecular distinctions suggest the presence of
hood of p53 mutations, anti-apoptotic protein Bcl-2 GAs apart from classic GBM but additional studies are
expression, and MIB-1 proliferation indices. While this warranted.
study suggested that most gemistocytes are nonpro-
liferative and may be terminally differentiated, a size- Granular cell astrocytoma
able fraction can progress to develop neoplasms. One
Granular cell astrocytomas (GCA) are rare infiltra-
study of 32 GAs with a mean gemistocytic index of
tive malignant gliomas characterized by abundant gran-
39.6% (range 12.2-80.8%) suggested that gemistocytes
ular cells with large distinct cell borders, round to oval
lacked proliferative activity and that in fact the pres-
shapes, and abundant eosinophil granular cytoplasm
ence of small cells and proliferation index defined
[89]. GCAs commonly stain for periodic acid-Schiff (PAS),
tumours with the potential for aggressive growth [5].
GFAP, CD68, EMA, and S100 with granular components
Other studies have suggested the quiescent nature of
encompassing > 30% of tumour cells [155]. In one analy-
gemistocytes in a variety of brain tumours [83]. And
sis, intracerebral GCAs were more aggressive than gran-
early studies using tritiated thymidine showed little
ular cells found at other sites [92]. Delineation of these
uptake within GAs [58]. A study of 23 biopsies at a sin-
tumours may be important since their intratumoral and
gle institution showed a high fraction of microglia that
peritumoral lymphocytic infiltration and occasional
correlated with gemistocytic tumour components and
macrophage presence can mimic demyelinating or
lower rates of MHC class II molecule immunoreactivity
on gemistocytes [40]. These results suggested that infectious histological features [42]. Some reports have
T-cell anergy and immunoregulation could affect suggested that granular cells are unique entities
gemistocyte proliferation. characterized by transformed neoplastic astrocytes
Common mutations between gemistocyte-con- [3,50,98]. However, the presence of granular cell fea-
taining and non-containing components suggest tures in multiple tumour types such as glioblastoma,
a clonal origin for GAs. Microdissected gemistocytes meningioma, ganglioglioma, neurinoma and others,
and non-gemistocytic astrocyte cellular components along with distinct molecular features suggests that
have shown identical p53 mutations [138]. An analy- granular features may represent a degenerative pro-
sis of 28 GAs containing a mean fraction of 35 ± 9.9% cess in brain tumours rather than a distinct variant
gemistocytes demonstrated p53 mutation in exon [141]. However, despite often being classified as low
5-8 within 82% of cases while PTEN mutation was rare grade tumours with low MIB-1 indices, GCAs often
[169]. Furthermore, p53 mutation was synchronous display aggressive features, can degenerate, and con-
between gemistocytic and fibrillary tumour components fer poor patient prognosis similarly to classic GBM.
in 4 tumours. This study also showed that p53 muta- GCAs demonstrate reduced patient survival despite
tion was characteristic of GAs while PTEN mutations their poorly understood nature. These tumours have
were not commonly found in low-grade and anaplas- been reported in the meninges, choroid plexus, pitu-
tic GAs. Furthermore, mutations in p53 have been sug- itary gland, trigeminal nerve, optic nerves, cerebellum,
gested to exist in tumours of younger patients, and spinal cord though they most are cerebral lesions
tumours with a greater portion of atypical gemistocytes, [28,39, 42,96,145,155]. However, limited understand-
tumours with significant smaller cell components, and ing of this tumour exists due to its rarity and approx-
subjects with shorter postoperative survival [80]. imately 50 cases have been reported [155]. One-year
Similarly, chromosomal analysis of chromosome 7 and survival from GCA is reportedly 12% for high-grade GCA
10 alterations has also been found to be concordant and 40% for low-grade GCA with extension to multi-
in a subset of GAs suggesting some, but not all, gemis- ple cerebral lobes as seen in 35% of reported cases, may
tocytic cells to be neoplastic [84]. One study suggesting confer a poor prognosis despite a lack of aggressive
the presence of small cells better predicted poor prog- histological features [150]. A study of 22 cases of
nosis, showed that GA tumour had a mean MIB-1 index GCAs (age range from 29 to 75 years) with a nearly
of 3.7% (range 0.5-10.5%) primarily restricted to small 3 : 1 male : female ratio (17 men, 5 women) showed
cell components [5]. Furthermore, this study showed sheets of monomorphic round cells packed with
that p27 and cyclin D1 immunoreactivity localized to eosinophilic, PAS-staining granules comprising 30-95%
small astrocytic cells, as well as p53 but not EGFR of cells [16]. Furthermore, this study demonstrated
expression in both gemistocytes and small cell areas. lymphocytic infiltration in 63% of cases, transition to

infiltrating astrocytoma in 72% of cases, GFAP stain- for DIPG survival is < 10% [135]. Despite similar driv-
ing in 95% of tumours, common staining for S-100, ing mutations to adult GBM, HGGs are very distinct
KP-1, ubiquitin, and EMA, as well as MIB-1 index cor- lesions.
relating with WHO grade. Furthermore, 83% of followed Factors conferring a poor prognosis include high
cases recurred after surgery with a mean survival of tumour grade, smaller tumour resections, p53 over-
7.6 months. expression, PTEN mutation, high MIB-1 index, and over-
Molecular mechanisms of GCAs have also been expression of MGMT [91,130,133,135]. Interestingly,
investigated. In a study of 11 GCAs (age range from 46 a long-term overall survival is significantly greater for
to 75 years) with ~2 : 1 male : female ratio (7 men, infants compared to older children suggesting distinct
4 women) and granular cell areas ranging from 30% pathogenic processes [135,147]. A study of 231 children
to 100% of tumours, LOH at chromosome 1p, 9p, 10q, with HGG showed mutations of p53 in 33% of avail-
17p, 19q, along with mutations of p53, p16INK4A and able samples (n = 40/121), where p53 overexpression
p14ARF, as well as EGFR amplification were seen [24]. but not p53 mutation correlated with reduced 5-year
Furthermore, losses of 9p and 10q were uniformly seen progression-free survival [130]. Furthermore, this stu-
while p53, p14ARF and p16INK4A mutations as well as dy showed that while a significant number of HGGs
EGFR amplifications mutations were uncommon. In- contained p53 mutations, secondary progression from
terestingly, higher frequencies of chromosomal aber- lower-grade gliomas was an unusual course for this dis-
rations were seen as compared to infiltrating astro- ease unlike in adults. One interesting case of HGG was
cytomas at comparable WHO grades. A recent study detected prior to birth at 37 weeks of gestation and
detailing histological and molecular features of GCAs demonstrated an absence of p53 and EGFR staining
demonstrated frequent mitosis, pseudopalisading as well as MIB-1 index of 87.5% [153]. Mutations in
necrosis, and endothelial hyperplasia, which were rem- IDH1/IDH2, PTEN or EGFR are less frequent than in adult
iniscent of GBM [64]. Furthermore, gains of chromo- GBM [51, 132]. Despite a rarity of PTEN mutations, acti-
some 7, losses of chromosomes 1p, 8p, 9p, 10, 13q and vated AKT has been frequently observed (79% of sam-
22 were observed along with EGFR amplification, ples) in one series of HGG and correlated with a poor
CDKN2A deletion, IDH1 mutation and MGMT promoter prognosis [131]. In addition, combined Ras and AKT
methylation. Gains in chromosome 7 and losses in chro- activation have been seen in a series of 32 HGGs cor-
mosome 10 have been observed in other studies of relating to poor survival [34]. Mutations in BRAF, name-
GBM with predominant granular cell features [141]. ly the missense activating BRAFV600E mutation, in com-
However, these studies have failed to support a unique bination with CDKN2A inactivation have also been seen
molecular signature for GCAs suggesting that multi- in small series of paediatric astrocytomas [149]. Muta-
ple genotypes can support this type of tumour. Sim- tions in MGMT were seen in approximately 11% of one
ilarly to GAs, GCAs mimic a benign pathological pro- series (n = 12/109), and these cases had a significantly
cess despite distinct molecular mechanisms [29]. worse 5-year progression-free survival (8.3% vs.
42.1%) [133]. A variety of therapies have been suggested
Paediatric high-grade glioma and diffuse to design rational targeted therapies based on these
intrinsic pontine glioma mutations, however, such treatments in HGGs as well
Paediatric high-grade glioma (HGG), accounting for as immunotherapeutic approaches have not success-
2.8% of CNS tumours and 6.8% of pontine tumours, fully improved long-term outcomes [129].
show many distinct clinical and molecular features from Molecular subtyping of HGG may be a method of
adult GBM [89,91]. A subset of malignant glioma that improving personalized treatments. A recent geno-
occurs in the brainstem includes diffuse intrinsic pon- mic study of 78 HGGs, including 7 DIPGs demonstrated
tine gliomas (DIPG), which are aggressive tumours significant copy number alterations in PDGFRA and
seen predominantly in children unlike the greater preva- deregulation of its downstream molecular signalling
lence of supratentorial GBM in adults. However, the pathways [119]. Gains of chromosome 1q were frequent
classification of DIPG tumours as HGGs is controver- in HGG (30%) vs. adult GBM (9%) while gains of chro-
sial [91]. Current treatment involves surgery and mul- mosome 7 were more frequent in adult GBM (13% vs.
tiagent chemotherapy, however for supratentorial 74%). Losses of chromosome 10q were more common
HGG, 2-year survival rates range from 10% to 30% while in adult GBM (35% vs. 80%). Furthermore, mutations

in IDH1 were not seen in HGG. PDGFRA amplification the need for improved diagnostic and prognostic mark-
and chromosome 1q gain were more frequent in HGGs ers of GBM variants are needed in order to delineate
that received radiation. Subtyping of HGG into proneu- true variants from histopathological differentiation fea-
ral, proliferative, mesenchymal, and undetermined ca- tures. Furthermore, the need for large tumour data-
tegories was seen by principle component analysis, base in order to accumulate sufficient samples for the
however, markers of these subtypes were distinct from evaluation of these extremely rare tumour variants is
adult GBM subtypes. These result suggested PDGFRα warranted. And finally, the need for uniform diagnostic
signalling to be a key player in HGG formation. In ano- criteria defining such emerging variants will be nec-
ther genomic study of single-nucleotide polymorphisms essary for future studies. Understanding these GBM
in DIPG, 11 samples underwent analysis by a 250k SNPs variants may aid in elucidating the mechanisms of this
array, which identified gains in PDGFRA in 36% of sam- tumour’s marked heterogeneity and resistance to treat-
ples, and poly ADP-ribose polymerase (PARP-1) path- ment.
way genes in 27% of samples [173]. Furthermore, analy-
sis of genome copy number abnormalities in 43 DIPGs Acknowledgments
and 8 low-grade brainstem gliomas demonstrated gene
The author(s) received no financial support for the
amplifications of the Ras/PI3K signalling pathway in
research, authorship, and/or publication of this article.
47% of tumours, the Rb cell-cycle regulatory pathway
in 21% of tumours, and concurrent amplification in
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Review paper

Established and emerging variants of glioblastoma multiforme:

Folia Neuropathol 2012; 50 (4): 301-321 DOI: 10.5114/fn.2012.32361

Introduction of gliomas, while 54% of all malignant brain tumours

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Fig. 1. Mechanisms of gliomagenesis and glioblastoma multiforme variants

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Table I. Characteristics of established GBM tumour variants

GBM variant and Molecular alterations Prognostic Survival References

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Table II. Characteristics of emerging GBM tumour variants

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Gliosarcoma estingly, primary GS showed features of malignant

fibronectin, vimentin, α1-antitrypsin, and chymotrypsin

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extent of resection, β-catenin immunostaining, mole-

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