Epidemiology, risk factors, and prognostic factors of gliomas

Abstract

PurposeDiffuse gliomas are the most common primary malignant brain tumors in adults. Many studies analyzed their epidemiology, such as the incidence and mortality. Moreover, the identification of their risk factors is still controversial and to date we have only a few accepted and confirmed risk factors. In the last few years, many molecular markers have been analyzed and correlated to the prognosis of gliomas.We performed a review aiming to collect and clarify data on epidemiology, risk factors and prognostic factors regarding glioma patients.Methods
We performed a comprehensive literature review of research studies focusing on epidemiology of gliomas and their risk factors. At the same time, we collected studies analyzing the most important and validated prognostic factors in glioma patients.ResultsGlioblastoma represents the most common primary malignant brain tumor with an incidence rate of 3.23 per 100,000 population. Diffuse astrocytoma and oligodendroglioma tend to peak in young adults with a median age of 46 and 43 years, respectively). Overall, the incidence rate of gliomas is higher in male patients than in females. Rates of overall survival vary widely, ranging from 5 year survival rates of 94.7% for pilocytic astrocytoma to 6.8% for glioblastoma. About 5% of gliomas can be classified as familial and associated with hereditary syndromes, such as the Li-Fraumeni, the Turcot and neurofibromatosis. Ionizing radiation remains the only ascertained environmental risk factor associated with glioma. In addition to the clinical characteristics, such as the age, performance status and the extent of resection, also mutational status of some genes such as IDH, TERT, CDKN2A and the MGMT methylation status can be correlated with the glioma patient survival.Conclusions
Gliomas represent rare tumors and can be defined as a heterogenous group of primitive brain tumors. In recent years, new data emerged regarding the etiology of these tumors as well as the knowledge of new prognostic factors.

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Vol.:(0123456789)
1 3
Clinical and Translational Imaging
https://doi.org/10.1007/s40336-022-00489-6
EXPERT REVIEW
Epidemiology, risk factors, andprognostic factors ofgliomas
AlessiaPellerino1· MarioCaccese2,3· MartaPadovan2,3· GiuliaCerretti2,4· GiuseppeLombardi2
Received: 27 January 2022 / Accepted: 4 March 2022
© The Author(s), under exclusive licence to Italian Association of Nuclear Medicine and Molecular Imaging 2022
Abstract
Purpose Diffuse gliomas are the most common primary malignant brain tumors in adults. Many studies analyzed their
epidemiology, such as the incidence and mortality. Moreover, the identification of their risk factors is still controversial and
to date we have only a few accepted and confirmed risk factors. In the last few years, many molecular markers have been
analyzed and correlated to the prognosis of gliomas.
We performed a review aiming to collect and clarify data on epidemiology, risk factors and prognostic factors regarding
glioma patients.
Methods We performed a comprehensive literature review of research studies focusing on epidemiology of gliomas and
their risk factors. At the same time, we collected studies analyzing the most important and validated prognostic factors in
glioma patients.
Results Glioblastoma represents the most common primary malignant brain tumor with an incidence rate of 3.23 per 100,000
population. Diffuse astrocytoma and oligodendroglioma tend to peak in young adults with a median age of 46 and 43years,
respectively). Overall, the incidence rate of gliomas is higher in male patients than in females. Rates of overall survival vary
widely, ranging from 5year survival rates of 94.7% for pilocytic astrocytoma to 6.8% for glioblastoma. About 5% of gliomas
can be classified as familial and associated with hereditary syndromes, such as the Li-Fraumeni, the Turcot and neurofi-
bromatosis. Ionizing radiation remains the only ascertained environmental risk factor associated with glioma. In addition to
the clinical characteristics, such as the age, performance status and the extent of resection, also mutational status of some
genes such as IDH, TERT, CDKN2A and the MGMT methylation status can be correlated with the glioma patient survival.
Conclusions Gliomas represent rare tumors and can be defined as a heterogenous group of primitive brain tumors. In recent
years, new data emerged regarding the etiology of these tumors as well as the knowledge of new prognostic factors.
Keywords Glioma· Epidemiology· Risk factors· Prognostic factors
Introduction
Diffuse gliomas are the most common primary malignant
brain tumors. The typical features of gliomas, such as high
malignancy, significant mortality rate, and increased risk of
recurrence, represent a challenge for neuro-oncologists and
are a considerable burden on society and families.
However, in the last few years, new studies analyzing
potential risk factors and new molecular markers were
performed.
In this work, we reviewed recent papers focusing on epi-
demiology, risk factors and prognostic factors regarding
glioma patients.
Alessia Pellerino, Mario Caccese, Marta Padovan, Giulia Cerretti
and Giuseppe Lombardi have contributed equally to this work.
* Giuseppe Lombardi
giuseppe.lombardi@iov.veneto.it
1 Department ofNeuro-Oncology, University andCity
ofHealth andScience Hospital, via Cherasco 15,
10126Turin, Italy
2 Department ofOncology, Oncology 1, Veneto Institute
ofOncology IOV-IRCCS, Via Gattamelata 64, 35128Padua,
Italy
3 Clinical andExperimental Oncology andImmunology
PhD Program, Department ofSurgery, Oncology
andGastroenterology, University ofPadua, 35128Padua,
Italy
4 Department ofSurgery, Oncology andGastroenterology
(DiSCOG), University ofPadua, 35128Padua, Italy

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Methods
We performed a literature review and the most important
studies on epidemiology, risk factors and prognostic fac-
tors on gliomas were identified by searching the Medline
electronic database. The search strategy included terms
used to describe gliomas, their etiology and clinical and
molecular factors impacting on survival. For further rel-
evant studies this search was supplemented by reviewing
the bibliographies of key papers.
Epidemiology
The incidence and mortality rate of gliomas vary accord-
ing to age, sex, race, and geographical region. Overall,
the broad category of gliomas (ICD-O-3 histology codes
9380–9384 and 9391–9460) represents approximately
24.5% of all primary brain tumors and 80.9% of all malig-
nant tumors in adults. Sixty-two percent of gliomas occur
in the supratentorial compartment: 27.0% in the frontal
lobe, 20.2% in the temporal lobe, 11.6% in the parietal
lobe, and 2.8% in the occipital lobe. A small proportion
may occur in other CNS sites, including the brainstem
(4.3%), spinal cord and cauda equina (4.0%), the cerebel-
lum (2.8%), and other brain sites (20.0%) [1]. Based on the
United States’ Central Brain Tumor Registry (CBTRUS)
report, astrocytic tumors, including glioblastoma, account
for 77.5% of all gliomas. Glioblastoma prevails among
malignant gliomas (58.4%), followed by diffuse astrocy-
toma (7.3%), anaplastic astrocytoma (6.8%), oligoden-
droglioma (3.5%), anaplastic oligodendroglioma (1.7%),
pilocytic astrocytoma (5.0%), and malignant gliomas not
otherwise specified (NOS) (7.9%). The histology group-
ing used in this report is based on the 2016 WHO Clas-
sification of CNS Tumors and certain data will be updated
accordingly once the 2021 WHO Classification is released
[2].
The incidence rate in the adult population is highest
for glioblastoma (3.23 per 100,000 population), followed
by diffuse astrocytoma and anaplastic astrocytoma (0.46
and 0.42 per 100,000 population, respectively), and oligo-
dendroglioma and anaplastic oligodendroglioma (0.23 and
0.11 per 100,000 population, respectively).
Diffuse astrocytoma and oligodendroglioma tend to
peak in young adults (median age of 46 and 43years,
respectively), while anaplastic astrocytoma and oligoden-
droglioma occur approximately 5–9years later (median
age of 53 and 49years, respectively). Glioblastoma is
the most common tumor in adult and elderly patients
(median age of 65years), while it is a rare entity in pedi-
atric patients. In fact, gliomas account for 45% of all CNS
malignant pediatric tumors. Diffuse midline glioma rep-
resents 31.1% of all childhood gliomas [3, 4], followed
by pilocytic astrocytoma (18.3%), diffuse astrocytoma and
anaplastic astrocytoma (5.3%), and glioblastoma (2.6%).
In the population aged 0–19years, the incidence rate for
diffuse midline gliomas is 0.31 per 100,000 population
[3], followed by diffuse astrocytoma (0.23 per 100,000
population), and glioblastoma (0.17 per 100,000 popula-
tion). Anaplastic astrocytoma, oligodendrogliomas, and
anaplastic oligodendrogliomas are all rare entities (0.09,
0.04, and 0.01 per 100,000 population, respectively) [1].
Overall, the incidence rate of gliomas is higher in males
(5.51 per 100,000 population) than in females (3.65 per
100,000 population), except for diffuse midline gliomas,
which prevail among females (0.324 versus 0.288) [3].
The incidence of gliomas may be influenced by ethnic-
ity. The incidence rate is about 2times higher in American
and northern European populations than in the Asian pop-
ulation [5]. Furthermore, from 2000 to 2014, glioblastoma
accounted for 80% of astrocytic tumors in the 40–99year
age group in North America, Europe, and Oceania, but
only 60% or less in Central and South America [6]. Epide-
miological studies have shown a different incidence trend
based on geographic regions. In this regard, a Japanese
study found that the incidence rate of malignant gliomas
in the elderly increased significantly between 1998 and
2008 [7], whereas the CBTRUS registry reported that
the incidence of glioma in patients ≥ 40years remained
relatively stable between 2000 and 2016 [8]. Recently, the
CONCORD-3 population-based study found that the pro-
portion of glioblastomas only rose in Europe (from 46 to
56%) and Oceania (from 57 to 65%) from 2000 to 2014,
while increasing trends for glioma NOS were reported in
Central and South America, due to disparities in access
to cancer registries and the lack of quality in neuropatho-
logical diagnostic workup for the identification of different
glioma subtypes [6].
Incidence rates for glioblastoma and diffuse midline
glioma are remarkably higher in non-Hispanic Whites than
in Blacks and Hispanics, suggesting that some genetic risk
susceptibility or environmental factors are more frequent
in populations of predominantly European ancestry [3, 8].
However, the aging population is closely linked to industri-
alized countries, such as Europe and North America, and
could partly explain the increased incidence of glioblastoma
in these regions. Other factors, including a higher socioeco-
nomic status, easier access to the health care system, and the
improvement of diagnostic tools and neuroimaging allow for
early detection in more asymptomatic or mildly symptomatic
patients, contributing to a rapid increase in the incidence of
glioma of 2.9% per year registered between 1978 and 1992
[9]. Glioma has been on the decline since 1987, with an
increase of 0.2% per year occurring only after 1992.

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Rates of overall survival (OS) vary widely, ranging from
5year OS rates of 94.7% for pilocytic astrocytoma to 6.8%
for glioblastoma, depending upon different factors that may
influence glioma patient survival [9]. Treatment patterns, the
ability to access the health care system, the type of facilities,
where patients receive treatments, physicians’ expertise, and
the availability of clinical trials are some of the potential
factors that may influence patient outcomes. Importantly,
glioma histological and molecular profiles, including the
assessment of IDH 1–2 mutations, 1p19q codeletion, TERT
mutations, EGFR amplification, the gain of chromosome
7 and loss of chromosome 10, CDKN2A/B deletions, and
MGMT methylation status, help neuro-oncologists iden-
tify patients with different outcomes and to tailor their
treatments.
Risk factors
Although gliomas are considered rare in terms of incidence
[1], they represent one of the greatest challenges in the
oncology field due to the burden of the high level of care
required by patients and poor survival. The identification
of risk factors for the onset of gliomas could be extremely
useful for the purposes of early diagnosis and prevention, but
to date, data available in this regard are controversial, with
only a few accepted and confirmed risk factors.
Genetic risk factors
Most gliomas develop without a family history, but a small
percentage (5%) can be classified as familial [10], with an
even lower percentage (1–2%) transmitted in a Mendelian
pattern or as part of hereditary syndromes [1, 11]. The Li-
Fraumeni syndrome, Turcot syndrome, and neurofibrama-
tosis type 1 disorders are now known to be associated with
the highest risk of developing glioma [11]. Several genome-
wide association studies have explored the presence of many
genomic variants linked to an increased risk of developing
brain tumors, particularly malignant gliomas [12]. There
are 25 known genomic susceptibility variants for gliomas in
adults and the proportion of glioma incidence variance that
can be attributed to genetic factors is 25%, with about 30%
of this being explained by the variants identified by these
studies. Approximately 70% of the remaining genetic risk is
currently unexplained [12, 13]. In addition to the presence
of these variants, however, additional somatic mutations
are required for gliomatous tumorigenesis [14, 15]. Neu-
rofibromatosis type 1 (NF1) is an autosomal dominant syn-
drome of the NF1 gene and is mainly associated with brain-
stem astrocytoma, pilocytic astrocytoma, and other brain
tumors [16]. Neurofibromatosis type 2 syndrome caused
by germline or somatic mutations of the NF2 tumor sup-
pressor gene may also be associated with higher incidences
of central and peripheral nervous system tumors, such as
cranial nerve schwannomas and cranial meningiomas [16].
Li-Fraumeni syndrome is an autosomal dominant syndrome
caused by a germline mutation in the tumor suppressor gene
TP53; this condition is associated with a higher incidence of
various cancers, such as adrenocortical carcinomas, breast
cancer, soft tissue sarcomas, and even central nervous sys-
tem neuroepithelial tumors, and it appears to be more com-
mon in females than in males [16]. Turcot syndrome appears
to be a condition caused by the loss of one of the two arms
of chromosome 17, caused by a germline mutation of APC
(isochromosome 17). There is a higher incidence of glioblas-
toma and medulloblastoma, in addition to the increased risk
of developing colorectal cancer, [17].
Radiation
Moderate or high exposure to ionizing radiation is, to
date, the only ascertained environmental risk factor for
the onset of glioma with the most evidence in the litera-
ture, yet only represented by a small percentage of patients
[18]. The carcinogenic effect of ionizing radiation with an
associated increased risk of glioma diagnosis was assessed
to be more present in children than in adults, particularly
in those treated for acute lymphoblastic leukemia [19]. A
study involving 14,000 pediatric patients who had previ-
ously received radiotherapy found 40 cases of glioma dur-
ing follow-up. These occurred on average 9years after the
main diagnosis, and a case–control analysis found an odds
ratio of 6.78 for glioma diagnosis in children who received
radiotherapy versus those who did not (95% CI 1.54–29.7)
[15, 20]. Some studies evaluated the relationship between
the intensity of radiation received in childhood and the sub-
sequent development of tumors of the central nervous sys-
tem; the data obtained demonstrates that there is a sevenfold
increase in the risk of developing gliomas following any
exposure to radiation [16, 20, 21]. The high use of radiologi-
cal techniques in pediatric and prenatal age also seems to be
correlated with a greater risk of developing brain tumors,
with a relative risk of 1.29 [22]. All studies agree that the
risk of developing a brain tumor increases with the amount
of radiation administered and the younger the age of the
patient receiving radiotherapy [12]. As regards exposure to
non-ionizing radiation, the correlation between the develop-
ment of brain tumors and exposure from the use of mobile
phones has apparently not yet been confirmed due to contra-
dictory studies and differing selection and methodological
biases. The INTERPHONE study evaluated 2708 cases of
glioma and 2409 cases of meningioma and matched con-
trols in 13 countries: the results showed that there is a 40%
increase in the risk of developing glioma for the highest
decile of mobile phone use and an increased risk of develop-
ing tumors on the side of the head, where the phone is placed

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most frequently [23]. However, these findings have not been
confirmed by additional large studies, which have found no
correlation between mobile phone use and an increased risk
of developing gliomas [24, 25]. Given the non-conclusive
findings in the literature and the increasingly widespread use
of these devices, further studies with adequate follow-up are
certainly necessary to clarify any correlations present.
Socioeconomic status
Socioeconomic status (SES) has always been considered a
possible risk factor in various fields of oncology and for
different types of cancer. As far as neuro-oncology is con-
cerned, a high SES has always been associated with an
increased risk of tumors of the central nervous system and,
in particular, of gliomas. Some studies have shown that
population samples with a higher SES have a greater risk
of developing brain tumors than those with a lower socio-
economic status, regardless of age and ethnicity [26–28].
Although there may be several explanations for this type of
disparity, a precise reason has not yet been identified with
regard to this data. Some studies have hypothesized a diag-
nostic bias as a possible explanation. However, this does
not make the disparities between a low and a high socio-
economic status perfectly explainable if data from different
health systems are taken into consideration [26, 29, 30]. Cer-
tainly, it is more conceivable for people living in areas with
a low SES to experience undiagnosed or incorrectly clas-
sified cancers than populations with a high socioeconomic
status. Another plausible explanation appears to be related
to the different environmental and occupational risk factors
between populations with a high and low SES, making the
incidence of central nervous system tumors greater in people
with a higher socioeconomic status.
Microbiological andimmunological factors
The correlation between viruses and cancer has always been
studied, to the point, where the presence or absence of viral
infection is also considered as a potential prognostic factor
and risk factor in some types of cancer [31, 32]. As far as
gliomas are concerned, some studies have looked into the
possibility of a link between Herpes Simplex 1 or 2 infection
and the onset of brain tumors, but the results were found to
be contradictory and difficult to interpret [33]. The same
may be said for human Cytomegalovirus infection, where,
similar to the above, the results of correlation studies failed
to establish a clear link [34]. Data on the Varicella-Zoster
Virus (VZV) are different; in this case, some studies have
shown that having a history of VZV infection is associated
with an approximate 20% reduction in the risk of develop-
ing a glioma. This is most likely due to the virus’ latency
at the nervous level and the balance that is established
with the immune system, which appears to offer protection
against the development of gliomas [35, 36]. As with the
Varicella-Zoster Virus, a history of allergy or atopy seems
to be associated with a reduction in the risk of developing
brain tumors, particularly gliomas. Two large studies [37,
38] explored this aspect, and the results show that having
a history of allergy or atopy reduces the risk of develop-
ing gliomas by 22%. This inverse risk is also, in this case,
explained by allergic people’s heightened immunosurveil-
lance, which could make development and neoplastic trans-
formation more difficult. However, the exact mechanism is
currently unknown.
Chemical agents
Due to their capacity to be fat-soluble and propensity to pen-
etrate the blood–brain barrier, exposure to chemical agents
has always been considered, along with specific mutational
signatures related to them, a possible source of risk for the
development of various tumors, such as lung cancer and
breast cancer [39]. As for central nervous system tumors,
and particularly for gliomas, there does not seem to be such
a precise correlation. In this type of disease, this confirms
that the first hit is due to an endogenous process, not altered
by external exposure [39, 40]. However, in a relatively
recent study [40], an exposure-related mutational signature
was identified for substances known as haloalkanes. These
substances are derived from alkanes which contain one or
more halogens, and are often used commercially as refrig-
erants, propellants, in fire-fighting, and in pharmaceutical
products. These preliminary data undoubtedly need to be
confirmed by epidemiological and genetic studies to confirm
whether or not there is an association between exposure to
these agents and a higher incidence of tumors of the central
nervous system.
Lifestyle factors
Lifestyle risk factors for various types of cancer have long
been investigated in the field of oncology and particu-
larly close correlations have been found in some cases, for
instance, cigarette smoking with lung cancer. As is the case
for CNS tumors, there is a dearth of available data and, typi-
cally, no correlation between lifestyle factors and the onset
of these types of tumors has been identified, probably due to
their rarity and short survival, which makes these kinds of
epidemiological studies difficult. Alcohol consumption has
been investigated as a possible risk factor for the incidence
of CNS tumors, particularly gliomas and glioblastomas.
Data in the literature appear to be contradictory: some stud-
ies show an increased risk associated with higher alcohol
consumption [41–43], while other studies appear to confirm
a lower risk of developing these tumors with higher alcohol

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consumption [44, 45]. Unlike other types of cancer, cigarette
smoking does not seem to be associated with an increased
risk of developing CNS tumors. This is the conclusion drawn
from several studies and meta-analyses which evaluated the
intensity and duration of the smoking habit [45, 46]. Sleep
duration has also been investigated as a possible risk factor
for the onset of various cancers, including CNS cancers.
A published study established that there is no correlation
between sleep duration and the onset of brain tumors, par-
ticularly by comparing sleep durations of less than 7h and
more than 8h [47]. As regards diet, there does not appear
to be a correlation with the incidence of gliomas: a pooled
analysis of three studies demonstrated the absence of this
correlation when food groups (fruits and vegetables), indi-
vidual foods (fish and meat), and nutrients (fats, carbohy-
drates, and vitamins) were considered [48].
Prognostic factors
Age, performance status, andpre‑operative tumor size
Diagnosis at ≥ 40years is a strong and well-known unfavora-
ble prognostic factor for survival in all gliomas [49, 50] and
categorizes patients in a subgroup, where more aggressive
treatment should be considered. In addition, older patients
are typically affected by IDH wild-type high-grade gliomas,
which have a worse prognosis [51]. PFS (progression-free
survival) and OS (overall survival) are negatively influenced
by a worse baseline neurological status (e.g., the presence
of neurological and/or cognitive deficits) and a lower Kar-
nofsky performance status (KPS) before surgery in both
high-grade (HGG) [49] and low-grade glioma (LGG) [52],
whereas a history of seizures at diagnosis is associated with
an increased PFS and OS in LGG [53]. Several retrospective
reviews have reported the tumoral diameter size as a factor
associated with lower survival, but different cutoffs have
been proposed (4 cm [54], 5 cm [52], and 6 cm [50]).
Extent ofresection
The procedure for surgery should be individualized based
on suspected tumor type and grade, location, and operabil-
ity. Complete or gross total resection without compromising
neurological function is the better choice when it is con-
sidered safe and feasible. If complete resection cannot be
obtained, stereotactic biopsy for deep-seated tumors can
lead to diagnosis. Surgery has a debulking role on lesions
with mass effects, which aids in the improvement of symp-
toms and seizure control [55]. The extent of resection (EOR)
should be assessed within 24–48h after surgery through
MRI with contrast (or CT if MRI is not possible) [55]. Its
estimation is based on the volume of residual tumor accord-
ing to the following formula: “EOR = preoperative tumor
volume − postoperative tumor volume/preoperative tumor
volume”. The prognostic role of EOR is still not fully under-
stood, because there are no randomized controlled trials that
have compared the outcome benefits of biopsy versus gross
resection [51]. Retrospective and uncontrolled data sug-
gest that the extent of surgery and the subsequent absence
of residual tumor on imaging have a favorable prognostic
effect in increasing overall survival and time to progression
in anaplastic glioma [56] and in glioblastoma (GBM) [57].
A metanalysis [58] of 19 retrospective studies and 1 rand-
omized control trial observed that patients with LLG, both
with and without 1p/19q codeletion, who undergo gross total
resection have a better 5- and 10year OS rate than those
who undergo subtotal resection. Moreover, patients who
undergo subtotal resection obtain a similar benefit to those
with biopsy alone. In clinical practice, the scenario for LGG
is more complicated than for HGG, because a watch-and-
wait strategy may be appropriate, particularly for patients
who only have seizures (without focal neurological signs or
symptoms or signs of increased intracranial pressure) and at
a young age (< 40), with the possibility of surgery without
further delay at the time of radiological progression. How-
ever, more recent data suggest that early surgical resection
can result in a clinically relevant survival benefit [59] in
LGG patients too. Furthermore, the association between the
extent of resection and OS may be explained by the pres-
ence of mutations in isocitrate dehydrogenase (IDH) 1/2:
in a large retrospective series [60], IDH mutant anaplastic
astrocytomas and GBM (according to the 2016 WHO clas-
sification of central nervous system tumors [11]) resulted
more amenable to surgical resection, with a survival benefit
associated with maximal surgical resection.
Moreover, also the possibility to receive a radiochemo-
therapy treatment could influence the outcome regardless of
other prognostic factors and neurocognitive functions [61].
In particular, patients treated with new targeted therapy such
as regorafenib or anti-BRAF may have a longer overall sur-
vival [62, 63].
Histology andgrade
The recently updated [2] World Health Organization (WHO)
classification of tumors of the central nervous system,
defines 15 entities of adult diffuse gliomas based on molecu-
lar and histological diagnosis. Astrocytoma histology sub-
type is associated with an unfavorable prognosis compared
to oligodendroglioma [64]. Oligodendroglial tumors, charac-
terized both by codeletion of 1p and 19q (1p/19q) and IDH
1/2 mutation, are classified as WHO grade 2 or 3. They carry
a better prognosis than astrocytomas [52]. IDH mutant astro-
cytic tumors are considered as a single entity (IDH mutant
astrocytoma) and are graded as WHO grade 2, 3, or 4. WHO
grade 2 or 3 gliomas are invasive and tend to progress to

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higher grade lesions (WHO grade 4 astrocytomas) that have
the worst prognosis. However, the most aggressive form is
IDH wild-type GBM; in a recent retrospective multicenter
study, the reported median OS was 19.2–23.8months [49].
Molecular characteristics
An assessment of the IDH mutational status and 1p/19q
codeletion is required for the diagnosis of diffuse gliomas.
Several molecular alterations have been established as
markers of high grade tumors despite the histology, such
as CDKN2A/Bhomozygous deletion in IDH mutant grade
4 astrocytoma and TERTpromoter mutation,EGFRgene
amplification and/or combined gain of entire chromosome
7, and loss of entire chromosome 10 [+ 7/ − 10] in IDH
wildtype GBM 265.
Isocitratedehydrogenase (IDH) 1/2 mutation
IDH1 and IDH2 encode important enzymes in the Krebs
cycle. IDH1 and IDH2 mutations reside at the enzymes’
catalytic domains and a-ketoglutarate (a-KG) is reduced to
D-2-hydroxyglutarate (2HG), an oncometabolite. IDH1 and
IDH2 mutations are mutually exclusive; they are much more
common in WHO grade 2 and 3 gliomas (60–80%) than in
glioblastomas (5–10%) 66(p2). IDH1/2 mutations in glioma
are associated with a significantly prolonged PFS and OS
than comparable tumors without an IDH mutation, mak-
ing IDH mutation the most important prognostic factor for
survival. In a large clinical data set of GBM [66], it was
observed that GBM patients harboring IDH 1/2 mutations
tend to have a prolonged median OS and median PFS in
comparison to patients with IDH wild-type GBM (median
OS 31 versus 15 months). Moreover, this tendency was con-
firmed among patients with anaplastic astrocytoma (median
OS of 65 months for patients with IDH mutant tumors ver-
sus 20 months for wild-type tumors). IDH mutation status
is an independent predictor of favorable outcomes among
glioma patients [67]. Furthermore, in the large randomized
phase III CATNON trial (“Concurrent and Adjuvant Temo-
zolomide chemotherapy in non-1p/19q deleted anaplastic
glioma”), the median overall survival was 19.9 months (95%
CI 16.8–22.7) for patients with IDH1 and IDH2 wild-type
anaplastic astrocytoma and 98.4 months (85.2–116.6) for
patients with IDH1 or IDH2 mutant tumors (HR 0.14 [95%
CI 0.12–0.18], p < 0.0001), regardless of treatment [68]. In
a recent study [69] involving a cohort of 433 patients harbor-
ing IDH1 mutated grade 2–3 glioma (90.1% with the canoni-
cal IDH1 R132H mutation and 9.9% with a non-canonical
IDH1 mutation), it was observed that non-canonical muta-
tions could be associated with improved survival; the pres-
ence of non-canonical IDH1 mutations is associated with a
younger age at diagnosis and a less frequent presence of the
1p19q codeletion. In addition, an analysis of the CATNON
trial’s 1p/19q non-codeleted astrocytoma samples found that
patients harboring non-R132H mutated tumors have a better
outcome (HR 0.41 [95% CI 0.24, 0.71], p = 0.0013) because
of higher levels of genome-wide DNA-methylation [70].
IDH mutation status can also be used to differentiate
between primary and secondary glioblastomas [66]: the
majority of primary GBMs, which are frequently diagnosed
in older patients, are IDH wild type in the absence of a lower
grade precursor, while virtually all secondary GBMs that
arise from lower grade gliomas have IDH mutation. This
finding, associated with the prognostic role of IDH1/2 muta-
tion, indicates that many IDH wild-type lower grade gliomas
can exhibit aggressive behavior comparable to GBM and
have a similar prognosis [71].
Codeletion of1p and19q (1p/19q)
The combined loss of chromosome arms 1p and 19q,
together with IDH mutation, are pathognomonic markers
of oligodendroglioma. As demonstrated by the results of
large randomized clinical trials, codeletion is a powerful
predictor of favorable therapeutic response and improved
survival among patients with diffuse gliomas. In summary,
in the RTOG 9402 trial, the presence of 1p/19q codeletion
in anaplastic oligodendrogliomas and oligoastrocytomas
was associated with longer OS when the patient was treated
with radiation (7.3 versus 2.7years with intact 1p/19q) [72].
Furthermore, the addition of subsequent PCV (procarbazine,
lomustine, and vincristine) chemotherapy led to an increase
in OS to 14.7years in the presence of 1p/19q codeletion,
but did not change survival for 1p/19q intact patients. The
EORTC 26,951, a large EORTC (European Organization for
Research and Treatment of Cancer) Brain Tumor Group pro-
spective phase III study, revealed similar chemosensitivity
and a favorable prognosis for 1p/19q codeleted tumors [73].
O‑6‑methylguanine–DNA methyltransferase promoter
(MGMTp) methylation (in GBM)
MGMT, O6-Methylguanine–DNA methyltransferase, gene
located on chromosome 10q26.3, is a nuclear enzyme
responsible for DNA mismatch repair; indeed, MGMT
repairs damaged guanine nucleotides due to alkylating
agents, such as temozolomide and nitrosourea derivatives.
MGMT gene has a CpG island with a length of 762bp.
MGMTp methylation can increase the sensitivity of high-
grade gliomas to chemotherapy [74].
MGMTp methylation has been observed in approximately
50% of GBM. It is identified as a strong prognostic factor in
GBM, both in the “Stupp” trial [75] and in following rand-
omized trials, better designed for subgroup analysis accord-
ing to theMGMTstatus; for instance, in the RTOG 0525

Clinical and Translational Imaging
1 3
trial, the median OS was 21.2 months and 14.0 months with
or without MGMTp methylation, respectively [76]. We have
known since 2005 that patients withMGMTp-methylated
GBM had a longer survival when treated with temozolomide
chemotherapy than patients with MGMTp-unmethylated
tumors [77]. Its role as a predictive marker to select patients
for treatment was also confirmed in elderly patients with
GBM who, in the presence of MGMTp methylation, had
better outcomes with temozolomide chemotherapy than with
radiotherapy [78] (NORDIC and NOA-08 trials). In contrast,
patients withMGMTp-unmethylated GBM had reduced sur-
vival when treated with chemotherapy.However, in a recent
analysis by van den Bent etal, MGMTp methylation deter-
mined by the MGMT–STP27 algorithm was not predictive
for outcome in patients with IDH-mutant anaplastic astro-
cytomas enrolled in the CATNON trial [79].
Several studies have demonstrated that MGMTp meth-
ylation is also prognostic for the recurrence of GBM,
with an examined longer post-progression survival (about
3–4 months longer in the presence than in the absence of
MGMTp methylation) [80].
Conclusions
Gliomas represent a large group of heterogeneous entities.
Overall, gliomas are about 81% of all malignant tumors in
adults. Ionizing radiation remains the only ascertained envi-
ronmental risk factor associated with glioma; the role of
mobile phones is unclear due to contradictory studies. In
addition to the clinical characteristics, such as the age, per-
formance status and the extent of resection, also molecular
alterations, such as IDH and TERT gene mutations, 1p/19q
codeletion, CDKN2A/B homozygous deletion and the
MGMT methylation status can correlate with the survival
in specific subgroups of glioma patients.
Declarations
Conflict of interest Alessia Pellerino, Mario Caccese, Marta Padovan,
Giulia Cerretti, Giuseppe Lombardi declare no conflict of interest.
Ethical approval This article does not contain any studies with human
or animal subjects performed by the any of the authors.
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