Review article
Ukrainian Neurosurgical Journal. 2024;30(4):11-22
https://doi.org/10.25305/unj.310442
Laboratory of Morphology and Cytology, D.F. Chebotarev Institute of Gerontology of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
Received: 24 Augustl 2024
Accepted: 07 October 2024
Address for correspondence:
Serhii Pavlovych Luhovskyi, Laboratory of Morphology and Cytology, D.F. Chebotarev Institute of Gerontology, Vyshhorodska St., 67, Kyiv, 04114, Ukraine, e-mail: lugsp61@gmail.com
The updated 2021 WHO Classification of Central Nervous System (CNS) Tumors introduces, for the first time, an age-based approach to glioma classification, leveraging advances in molecular biology and epigenetics of CNS tumors. This classification groups gliomas within the category "Gliomas, glioneuronal tumors, and neuronal tumors," distinguishing between adult-type and pediatric-type diffuse gliomas, corresponding to low-grade and high-grade malignancies (LGG and HGG), highlighting the fundamental role of age in gliomagenesis. A review of current literature deepens the understanding of age-related characteristics, differences, and patterns in gliomagenesis across age groups, which is essential for effective diagnosis and treatment.
Pediatric-type and adult-type low-grade gliomas (pLGG and aLGG) differ in location, biological behavior, and molecular-genetic profiles. Inherited syndromes (e.g., NF-1, TSC) associated with glioma development are linked to specific LGG subtypes occurring in childhood, adolescence, and adulthood. Moreover, pLGG differs from aLGG in its potential for malignant transformation and spontaneous regression, as well as in mutations affecting the MAPK (mitogen-activated protein kinase) pathway.
While pediatric-type and adult-type high-grade gliomas (pHGG and aHGG) share histological features, they differ in location, biological behavior, molecular-genetic profiles, and prognosis. A major distinction between aHGG and pHGG lies in mutations such as IDH 1/2, EGFR gene expression, TERT mutations, chromosome alterations (+7/-10), and TP53 mutations, all contributing to a poorer prognosis in HGG gliomas. Additionally, changes in histone proteins H3.3 or 3.1 (H3.3 K27 and H3 G34) in pHGG, as opposed to aHGG, carry diagnostic and prognostic significance.
An analysis of data on glioma epidemiology, risk factors, and characteristic molecular-genetic features considering age is provided. The next publication will cover certain clinical aspects of this issue.
Keywords: glioma; age-related differences in gliomas; adult-type and pediatric-type gliomas; low-grade and high-grade gliomas
Introduction
The diagnosis and treatment of gliomas—the most common tumors of the central nervous system (CNS)—represent a significant healthcare burden worldwide. In the United States alone, approximately 18,500 cases of malignant gliomas are diagnosed annually. Medical care for one patient, including surgical intervention and radiation therapy, costs between $50,600 and $92,700 USD per year [1]. Adding chemotherapy (temozolomide and bevacizumab) for glioblastoma (GBM) treatment further increases expenses, costing €20,587.53 and €5,581.49 per year per patient, respectively, for caregivers providing support [2]. Identifying causes and risk factors for glioma development enables the timely implementation of preventive measures to reduce incidence across different population groups —an approach that is more cost-effective than the expenses associated with treatment, rehabilitation, and patient care.
The literature increasingly emphasizes the relevance of age in gliomagenesis [3]. Glioma incidence rises significantly with age, particularly after 65 years [3-5]. Low-grade gliomas (LGG) are more common in children, while high-grade gliomas (HGG) are typically observed in adults.
In 2021, the WHO Classification of tumors of the central nervous system was updated. The primary distinction in this edition was the introduction of an age-based approach to glioma characterization [6-8]. This marks the sixth version of the international standard for CNS tumor classification, with previous editions published by WHO in 1979, 1993, 2000, 2007, and 2016. Building on the 2016 WHO CNS Tumor Classification [8] and recommendations from the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) [9], a number of significant changes and additions have been made to the WHO Classification of brain and spinal cord tumors (2021) [6, 10]. Gliomas are now classified within the family "Gliomas, glioneuronal tumors, and neuronal tumors," with the following types: circumscribed astrocytic gliomas, adult-type diffuse gliomas, pediatric-type diffuse low-grade gliomas (pLGG), and pediatric-type diffuse high-grade gliomas (pHGG). The division of diffuse gliomas into adult- and pediatric-type categories underscores the important role of age, which may substantially influence gliomagenesis, biological behavior, molecular-genetic profiles, and prognosis, and should be considered in the diagnosis and treatment of gliomas across all age groups [6, 10-13].
Epidemiology of gliomas considering age and other factors
Recent large-scale clinico-epidemiological studies conducted in recent years indicate that the incidence, prevalence, and mortality rates of gliomas depend on factors such as age, gender, race, geographic region, and other variables [14].
Gliomas account for approximately 24.5% of all primary brain tumors and about 81% of all malignant central nervous system (CNS) tumors in adults [15]. About 62% of gliomas are located in the supratentorial region: 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. Tumor location influences the surgical approach. Gliomas may also be found in the brainstem (4.3%), cerebellum (2.8%), and other CNS areas (around 20.0%) [16]. The most common glioma is glioblastoma (GBM), accounting for 14.2% of all CNS tumors, 50.1% of all malignant CNS tumors, and approximately 45% of all gliomas, with a higher incidence among men (incidence rate ratio of 1.57) [17–19]. GBM is the most aggressive CNS tumor with a poor prognosis; the five-year relative overall survival (OS) rate is less than 5% [18].
Current reports, such as those from the Central Brain Tumor Registry of the United States (CBTRUS), provide data on glioma incidence, prevalence, and mortality derived from registries that classify glioma cases according to the 2007 and 2016 WHO CNS classifications. Thus, the tumor nomenclature, particularly for gliomas, differs from that in the 2021 WHO Classification of tumors of the brain and spinal cord [8,13,20]. The types of gliomas according to the WHO Classification of Brain and Spinal Cord Tumours (2021) are presented in a table (Table 1), facilitating a better understanding and assessment of studies conducted before the updated classification was adopted.
Table 1. Classification of gliomas according to the 2021 WHO Classification of tumors of the Brain and Spinal Cord
|
Type of glioma |
WHO CNS Grade |
Characteristic molecular and genetic alterations * |
|
Circumscribed astrocytic gliomas |
||
|
Pilocytic astrocytoma |
1 |
KIAA1549-BRAF, BRAF, NF1 |
|
High-grade astrocytoma with pi14locytic features |
NS⁑ |
BRAF, NF1, ATRX, CDKN2A/B (methylome) |
|
Pleomorphic xanthoastrocytoma |
2, 3 |
BRAF, CDKN2A/B |
|
Subependymal giant cell astrocytoma |
1 |
TSC1, TSC2 |
|
Chordoid glioma |
2 |
PRKCA |
|
Astroblastoma, MN1-altered |
NS |
MN1 |
|
Adult-type diffuse gliomas (аDG) |
||
|
Astrocytoma, IDH-mutant |
2, 3, 4 |
IDH1, IDH2, ATRX, TP53, CDKN2A/B |
|
Oligodendroglioma, IDH-mutant and 1p/19q codeleted |
2, 3 |
IDH1, IDH2, 1p/19q, TERT promoter, CIC, FUBP1, NOTCH1 |
|
Glioblastoma, IDH wild-type |
4 |
IDH-wildtype, TERT promoter chromosomes 7/10, EGFR |
|
Pediatric low-grade diffuse gliomas (pLGG) |
||
|
Diffuse astrocytoma, MYB - or MYBL1 altered |
1 |
MYB, MYBL1 |
|
Angiocentric glioma |
1 |
MYB |
|
Polymorphous low-grade neuroepithelial tumor of young |
NS* |
BRAF, FGFR family |
|
Diffuse low-grade glioma, MAPK pathway-altered |
|
FGFR1, BRAF |
|
Pediatric high-grade diffuse gliomas (pHGG) |
||
|
Diffuse midline glioma, H3 K27-altered |
4 |
H3 K27, TP53 , ACVR1 , PDGFRA, EGFR, EZHIP |
|
Diffuse hemispheric glioma, H3 G34-mutant |
4 |
H3 G34, TP53 , ATRX |
|
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wild-type |
4 |
IDH- wild-type, H3- wild-type, PDGFRA, MYCN, EGFR (methylome) |
|
Infant-type hemispheric glioma |
NS⁑ |
NTRK family, ALK, ROS, MET |
Notes: * - molecular and genetic changes, which are often common, are listed first. "methylome" is specified only for gliomas where it is recommended for diagnostic purposes. NS – not specified; NS * – not specified for LGG; not specified NS ⁑ – not specified for HGG. Genes: BRAF – proto-oncogene B-Raf, serine/threonine kinase; KIAA1549-BRAF – gene fusion;NF1 – neurofibromin 1; ATRX – alpha-thalassemia/mental retardation syndrome, linked to the X chromosome; CDKN2A/B – cyclin-dependent kinase inhibitor;
TSC1, TSC2 – tuberous sclerosis proteins 1 and 2; PRKCA – protein kinase C alpha; MN1 – proto-oncogene, transcription regulator; IDH – isocitrate dehydrogenase; TERT – telomerase reverse transcriptase;
CIC – transcriptional repressor HMG-box; FUBP1 – oncogene; NOTCH1 – single-pass transmembrane receptor; NTRK – neurotrophic tyrosine receptor kinase gene family; EGFR – epidermal growth factor receptor;
MYB – proto-oncogene, transcription factor; MYBL1 – MYB-like proto-oncogene 1; FGFR – fibroblast growth factor receptor; H3 – histones H3 K27 and H3 G34; ACVR1 – activin type I receptor; PDGFRA – platelet-derived growth factor receptor alpha; EZHIP – EZH inhibitory protein; TP53 – transcription factor p53;
MYCN – proto-oncogene, transcription factor bHLH; ALK – anaplastic lymphoma receptor tyrosine kinase;
ROS – proto-oncogene receptor tyrosine kinase; MET – proto-oncogene, receptor tyrosine kinase.
According to extensive epidemiological research by Q.T. Ostrom et al. [14, 16–19], astrocytic tumors, specifically GBM, represent 77.5% of all gliomas. Among malignant gliomas, other notable types include diffuse astrocytoma (7.3% of all gliomas), anaplastic astrocytoma – 6.8%, oligodendroglioma – 3.5%, anaplastic oligodendroglioma – 1,7%, pilocytic astrocytoma – 5.0%, and unspecified gliomas (NOS) - 7.9%.
The highest incidence of GBM among adults is 3.23 per 100,000 population, while rates for diffuse and anaplastic astrocytoma are 0.46 and 0.42 per 100,000, respectively. For oligodendroglioma and anaplastic oligodendroglioma, the rates are 0.23 and 0.11 per 100,000 [16,17,19]. The peak ages for diffuse astrocytoma and oligodendroglioma are at mean age of 46 and 43 years, respectively, while anaplastic astrocytoma and oligodendroglioma peak at ages 53 and 49. GBM is a prevalent tumor among adults, particularly the elderly (average age of 65), whereas GBM is rare in children [15].
In children, gliomas account for 45% of all malignant CNS tumors [21, 22]. Among pediatric gliomas, midline glioma ranks first, representing 31.1% of all childhood gliomas, while pilocytic astrocytoma accounts for 18.3%, diffuse and anaplastic astrocytoma for 5.3%, and glioblastoma multiforme (GBM) for 2%.
In the age group 0–19 years, the incidence of diffuse midline glioma is 0.31 per 100,000 population, while diffuse astrocytoma and GBM have incidences of 0.23 and 0.17 per 100,000 population, respectively [15]. Anaplastic astrocytoma, oligodendroglioma, and anaplastic oligodendroglioma are rare in this age group, with incidences of 0.09, 0.04, and 0.01 per 100,000 population, respectively.
The highest incidence rate of gliomas is registered in males (5.51 and 3.65 per 100,000 population, respectively), although females have a higher incidence of diffuse midline glioma—0.324 and 0.288 per 100,000 population, respectively [14, 15].
In the United States, malignant CNS tumors in children (aged 0–14 years) rank second in pediatric mortality rates, and in 2016 they were the leading cause of death among children [23,24]. The incidence rate of malignant CNS tumors in the pediatric population from 1998 to 2013 remained relatively stable, with an annual percent change (APC) of 0.16% per year (95% confidence interval (CI) 0.21–0.53). An increase in incidence was recorded for certain tumor types, including gliomas (APC 0.77% per year (95% CI 0.29–1.26)) and pilocytic astrocytoma (APC 0.89% per year (95% CI 0.21–0.53)), while a decrease in LGG gliomas (12.9% of all gliomas; APC -2.85 (95% CI 1.46–4.23)) and an increase in HGG gliomas (21.3% of all gliomas; APC -1.25 (95% CI 0.68–1.83)) and other gliomas (65.8% of all gliomas; APC -1.55 (95% CI 0.18–2.95)) were observed [15, 23]. These results are consistent with those reported by R. McKean-Cowdin et al. [25], obtained from 1973–2009, indicating that factors such as availability of specialized neurosurgical care, the quality of glioma diagnostics, and the accuracy and completeness of registry data on glioma cases influence these findings.
Epidemiological studies suggest regional variability in glioma incidence. It is hypothesized that the aging populations observed in recent decades in Europe and North America may partially explain the high glioma incidence, especially GBM, which increased on average by 2.9% per year from 1978 to 1992 [26–29]. The incidence of malignant gliomas increased from 1998 to 2008 among the elderly, while the CBTRUS registry data indicate relative stability among those aged ≥40 years from 2000 to 2016 [16, 20, 30].
Brainstem gliomas (BSG) represent a type of malignant CNS tumor that is rare in adults (1–2% of all gliomas) but common in children (20% of all gliomas) and has a poorer prognosis in children than in adults [31, 32]. The 5-year OS rates are 94.7% for pilocytic astrocytoma and 6.8% for GBM [14, 15, 26].
Risk factors (determinants) of gliomas
The risk factors, or determinants, for the development of gliomas are not yet fully defined, and data from the literature are contradictory. However, understanding these factors is useful for the prevention and early diagnosis of gliomas. Despite numerous publications on identifying glioma risk factors, only a few are considered proven, including genetic factors (hereditary disorders and syndromes) and ionizing radiation [14, 33-36].
Genetic (hereditary) disorders and syndromes. It is known that most gliomas occur without a burdensome family history, with only 5% of cases having such a history, and in 1% of cases, established hereditary disorders/syndromes are present in patients with glioma [14, 33]. Studies on the associations between genetic disorders and the risk of CNS tumors indicate that certain hereditary disorders are closely linked to glioma risk [14]. The most significant hereditary disorders and syndromes, their modes of inheritance, and chromosomal and genetic changes associated with glioma risk are presented in Table 2. Among hereditary disorders, particular attention is given to Li-Fraumeni syndrome, caused by alterations in the TP53 gene, which encodes the tumor suppressor protein P53; Turcot’s syndrome type 1, which combines primary brain tumors with colorectal cancer; neurofibromatosis type 1; and tuberous sclerosis. These conditions are associated with the highest risk [14, 33-35].
Table 2. Hereditary disorders and syndromes associated with glioma (adapted from [14]
|
Syndrome/disorder |
Inheritance type |
Gene alterations (chromosomes) |
|
Li-Fraumeni syndrome (LFS) |
Dominant |
TP53 (17p13.1) |
|
Turcot’s syndrome Type 1 (ST1) |
Autosomal recessive |
MLH1, PMS2 |
|
Familial adenomatous polyposis, Turcot’s syndrome Type 2 (ST2) |
Dominant |
APC, MMR (5q21) |
|
Neurofibromatosis 1 (NF1) |
Dominant |
NF1 (17q11.2) |
|
Tuberous sclerosis (TSC) |
Dominant |
TSC1,TSC2 (9q34.14,16p13.3) |
|
Rubinstein-Taybi syndrome |
Dominant |
CREBBP, EP30 (16p13.3; 22q13.2) |
|
Ollier disease |
Acquired postzygotic mosaicism, dominant with reduced penetrance |
IDH1/IDH2 (2q33,3/15q26,1) |
|
Lynch syndrome |
Dominant |
MSH2, MLH1, MSH6, PMS2 |
|
Mismatch repair deficiency syndrome |
Recessive |
MSH2, MLH1, MSH6, PMS2 |
|
Retinoblastoma syndrome |
Dominant |
RB1 (13q14) |
|
Melanoma-neural system tumor syndrome |
Dominant |
CDKN2A (9p21.3) |
|
Ataxia-telangiectasia |
Autosomal recessive |
ATM (11q22.3) |
Aging is associated with telomere shortening, while the risk of gliomas is linked to telomere lengthening [33, 36]. Shortened telomeres suppress cell proliferative activity, potentially inhibiting tumor development. In contrast, telomere lengthening is associated with high proliferative activity, which may increase the likelihood of somatic mutations, and thus, the risk of brain tumors, including gliomas (odds ratio (OR) = 1.16, 95% CI 1.02–1.31) [36]. The mean telomere length in glioma patients is 31 bp (5.7%) longer than in controls, and with each increase in telomere length septile, the glioma risk rises (OR = 1.12, 95% CI 0.90–1.62). It is known that single nucleotide polymorphisms (SNPs) in TERC and TERT alleles, which are associated with telomere length, may play a central role in gliomagenesis [33, 34, 36].
Ionizing Radiation is one of the most thoroughly studied and proven risk factors for gliomas in children, adolescents, and adults [34]. The International agency for research on cancer (IARC) classifies ionizing radiation as a Group 1 carcinogen [37]. In IARC’s publication, studies involving large cohorts of children and adolescents (up to age 19) who received therapeutic radiation for medical reasons showed a twofold increase in glioma risk within nine years post-treatment. Glioma risk was found to have a linear dose-response relationship, with the highest risk per unit of absorbed dose (1 Gy) observed in children under five.
Non-Ionizing Radiation (NIR), which includes microwave radiation in the radiofrequency range and extremely low-frequency magnetic fields, has also been studied. The IARC has classified radiation within the 30–300 GHz range as a Group 2B possible human carcinogen [38]. Concerns about NIR’s role in glioma development have risen in recent decades due to the widespread use of mobile (cellular) communication devices [14, 39-42]. Mobile phones are a common source of NIR, with 97-99% of absorbed energy impacting the brain hemispheres, and 50-60% affecting the temporal lobe and cerebellum. Despite numerous large clinical and epidemiological studies (INTERPHONE, CERENAT, COSMOS) conducted in recent decades, their results on glioma risk from NIR exposure remain inconclusive [39-44]. This issue is the subject of ongoing debate in the scientific community and is discussed in government and international institutions, especially with the active adoption of new 5G technologies [45, 46].
Biological factors, including infectious disease agents such as Herpes Simplex Virus types 1 and 2 (HSV), Human Papillomavirus (HPV), Varicella-Zoster Virus (VZV), Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), and others, are of interest to researchers not only for assessing glioma risk but also for exploring immunotherapy options through antiviral vaccines [47-50].
For many years, CMV infection was thought to be associated with gliomagenesis [47]. A meta-analysis [49] found that previous CMV infection increased the incidence of glioma (OR 3.95, 95% CI 1.7–5.3). However, the results of other studies have shown that individuals with a previous VZV-associated infection had a significantly reduced risk of LGG gliomas (HR 0.85, 95% CI 0.76-0.96) [51], and the risk of GBM was 30% lower compared with control group. This may be because VZV can trigger immune response reactions aimed at viral infections, which cross-react with GBM cell membrane proteins, thus generating an immune response against tumor cells [18]. The decrease in anti-VZV IgG levels in GBM compared with control group supports its protective role in gliomagenesis. A prospective study of the association between infections caused by HS, VZV, CMV, and EBV viruses and glioma risk indicate that EBV infection is associated with a lower risk of glioma development (OR = 0.57, 95% CI 0.38–0.85) [52]. There is no evidence of an increased risk of glioma in the presence of HPV infection [52, 53]. Consequently, there are no definitive conclusions about the causal relationship between viral infections and the risk of glioma development. The study of this issue is relevant because of the likelihood of distant consequences of infection due to the SARS-COV-2 virus that caused the outbreak of the 2019 coronavirus disease pandemic (COVID-19) [54]. Upon entry into the body by respiratory route, SARS-CoV-2 virus interacts with target cells and initiates a complex cascade of immune response reactions. At the same time, the tropism of SARS-CoV-2 virus to receptors on the surface of certain cell types can cause a high risk of severe course of the disease and its long-term consequences [55, 56].
It is known that the SARS-CoV-2 S-glycoprotein can interact with receptor proteins on the surface of target cells, specifically with angiotensin-converting enzyme 2 (ACE2), which facilitates viral entry into cells [57]. This interaction plays a key role in the pathogenesis of COVID-19. The expression of ACE2 on the surface of glial cells and neurons characterizes them as potential targets for SARS-CoV-2 [56]. Glioma cells express epidermal growth factor (EGFR), vascular endothelial growth factor (VEGFR), and hepatocyte growth factor (HGFR/c-MET) receptors, which are associated with tumor development and invasion [58]. ACE2 expression on cell surfaces enables the initiation of signaling pathways that play a central role in tumorigenesis. Recent studies have shown that the S glycoprotein of SARS-CoV-2 has high affinity for the receptor proteins EGFR, VEGFR, and c-MET, which may indicate a potential role of COVID-19 in the development of gliomas [59, 60].
Age-related differences in low-grade gliomas
Gliomas represent about one-third of CNS tumors. In children and adolescents, two-thirds of gliomas are categorized as pediatric low-grade gliomas (pLGG). In adults and the elderly, aLGG gliomas are rare (15–20% of all gliomas) [63–65].
The research results by L. Greuter et al. [65] indicate that pLGG and aLGG gliomas have several age-related differences in terms of localization, malignancy grade, molecular-genetic status, potential for malignant transformation, association with hereditary pathology, prognosis, and so on, which are relevant for diagnosis, treatment, and prognosis (Table 3).
Table 3. Differences between pediatric and adult low-grade gliomas (adapted from [65]
|
Indicator |
pLGG |
aLGG |
|
Localization |
Supratentorial (30%) Infratentorial (30%) |
Supratentorial (80%) |
|
Histological grading |
Grade 1* (74%) Grade 2* (26%) Pilocytic astrocytoma (65%) |
Grade 1* (10–15%) Grade 2* (85–90%) Diffuse glioma LGG (60%) |
|
Associated hereditary disorders |
NF-1 (TSC) |
- |
|
Molecular alterations |
BRAF600 (17%) |
IDH-mutant (70%) |
|
Treatment |
GTR increases OS |
GTR increases OS |
|
Malignant transformation |
Rare (2.9–6.7%), may increase post-CT or RT |
Frequent (86%) |
|
10-Year OS, % |
>90 |
~60 |
|
Prognosis |
OPG and brainstem glioma – unfavorable; OPG with NF-1 – favorable; GTR – favorable; young age – unfavorable |
Gliomas (typical sites) – unfavorable; GTR – favorable; Diffuse Grade 1 gliomas* – unfavorable; age <40 – favorable |
Note.* ‒ according to the WHO Classification of Tumors of the brain and spinal cord tumors (2021);
NF-1 – neurofibromatosis type 1; TSC – tuberous sclerosis; BRAF600 – B-Raf proto-oncogene serine/threonine kinase; IDH – isocitrate dehydrogenase gene; OPG – optic pathway glioma; GTR – gross total resection; CT – chemotherapy; RT – radiotherapy.
In children and adolescents, most gliomas are classified as diffuse Grade 1 gliomas according to the WHO Classification of Tumors of the Central Nervous System (2021), while in adults, most LGG gliomas are Grade 2 [66]. Most pLGG gliomas are located in the cerebellum, whereas in adults, they are typically found in the supratentorial region of the brain. pLGG gliomas are characterized by a more favorable prognosis compared to aLGG gliomas [65]. The majority of aLGG gliomas can undergo malignant transformation into HGG gliomas, whereas malignant transformation in pLGG gliomas is rare [67‒69]. Approximately 6% of pLGG gliomas have the ability to spread to other areas of the CNS, while in adults, this capability is observed only in HGG gliomas [70, 71].
Hereditary syndromes, as noted above (see Table 2), are associated with the risk of LGG glioma development in both children and adults [14,15,35,65,72]. Specifically, NF-1 syndrome is associated with a risk of optic pathway glioma in 6% of patients aged 3–4 years and is characterized by a relatively benign course and favorable prognosis [73‒75]. In 1% of NF-1 patients, brainstem glioma has been reported, often accompanied by hydrocephalus [76]. TSC is a multisystem autosomal dominant hamartoma syndrome caused by mutations in the TSC1 or TSC2 genes, which enhance the regulation of cell cycle signaling pathways and lead to the development of certain types of gliomas, primarily of astrocytic origin, with only a few cases reported in the literature [77]. These tumors mostly occur in children and young adults and are not found in adults.
Surgical intervention assessment indicates that gross total resection (GTR) of glioma correlates with increased overall survival (OS) and progression-free survival (PFS) in both children and adults. It is reported that subtotal resection (STR) with minimal residual tumor shows similar outcomes to GTR, although data on this are conflicting [65, 78].
Glioma localization is a factor that determines an unfavorable prognosis for pLGG located in the brainstem and for optic pathway gliomas (OPG), though not for OPG in patients with NF-1. Prognostic factors include STR, young age, and tumor location, particularly within the brainstem or optic pathway [14, 65, 79].
In adults with LGG glioma, the likelihood of a favorable GTR outcome increases if the tumor is detected without specific symptoms and at an early stage, as opposed to cases with pronounced glioma symptoms. According to AJ Gogos et al. [78], the average growth rate of such "incidental gliomas" is 3.9 cm³/year. Gross total resection (GTR) is achieved in 57% of cases compared to 24% in patients with characteristic glioma symptoms. In cases with STR, the residual tumor volume averaged 2.9 cm³, impacting glioma prognosis (OS for patients with "incidental gliomas" is around 14.6 years) [78]. For aLGG, early GTR after tumor detection increases the likelihood of a favorable prognosis compared to delayed tumor resection, indicating the importance of GTR as a primary treatment method for both aLGG and pLGG gliomas. However, GTR is found to be more effective for pLGG gliomas than aLGG gliomas, likely due to differences in their morphology and biological behavior.
Molecular-genetic, diagnostic, and prognostic factors. Recent research on the molecular-genetic profile of pLGG gliomas has revealed changes in the MAPK/ERK pathway (mitogen-activated protein kinase/extracellular signal-regulated kinase) caused by BRAF gene mutations or fusions, which are not characteristic of aLGG gliomas [80‒83]. Alterations in the MAPK pathway are also typical for NF-1 syndrome, which predisposes to pLGG [83]. It is reported that 84% of pLGG gliomas are characterized by a mutation in the BRAF gene encoding the B-Raf protein (B-Raf proto-oncogene, serine/threonine kinase). The KIAA1549-BRAF fusion is common in pilocytic astrocytoma (35%), while BRAFV600E mutations and NF-1 are observed in only 17% of pLGG cases [81]. Molecular-genetic profiling of gliomas at the diagnostic stage is crucial for treatment and prognosis [11,13,82,83]. The KIAA1549-BRAF alteration is characteristic of cerebellar pLGG gliomas and is associated with significantly higher 5-year progression-free survival (PFS) compared to pLGG with a BRAFV600E mutation (69% vs. 52%) and 10-year overall survival (OS) (97% vs. 89%) [81]. Most pLGG gliomas typically exhibit at least one mutation impacting the MAPK pathway.
Age-specific features of malignant transformation (MT) in LGG are observed in only 2.9–6.7% of pLGG cases [65,85]. In children, MT is often associated with previous chemotherapy and/or radiotherapy. In contrast, MT occurs more frequently in adults (13–86% of all aLGG gliomas), especially in pregnant women, which may be associated with hemodynamic and metabolic changes due to elevated levels of progesterone and insulin-like growth factor-1 (IGF-1), which particularly correlates with astrocytoma development [85,86].
Spontaneous regression of pLGG has been documented as a phenomenon in certain types of pLGG gliomas, particularly in rare cases of cerebellar gliomas. Regression has been recorded in 30% of cerebellar pLGG gliomas on average 11.9 months after STR. Other studies report spontaneous regression in 32.5–48% of cerebellar pLGG glioma cases [65].
Thus, pLGG and aLGG gliomas differ in anatomical localization, biological behavior, and molecular-genetic profiles, which is essential for the diagnosis, treatment, and prognosis of LGG gliomas in children and adults. Hereditary syndromes, such as NF-1 or TSC, are associated with specific types of pLGG gliomas that arise in childhood.
Age-related differences in high-grade gliomas
According to the WHO Classification of Tumors of the Central Nervous System (2021), HGG gliomas include circumscribed WHO CNS grade 3 gliomas, as well as diffuse adult-type WHO CNS Grade 3 and 4 gliomas (IDH-mutant astrocytoma, IDH-mutant oligodendroglioma with 1p/19q codeletion, IDH-wild-type glioblastoma) and all pediatric-type diffuse HGG gliomas (Table 1).
Age-related differences in glioma localization. In adults, IDH-mutant astrocytoma can occur in any part of the brain, most commonly in the subtentorial region and frontal lobe. The average age of patients with this type of glioma is 30–40 years, rarely over 55 years [87,88]. The average age for patients with WHO CNS Grade 4 IDH-mutant astrocytoma is 42 years, while for Grade 2-3 it is 38 years. IDH-mutant oligodendroglioma with 1p/19q codeletion is most often observed in patients aged 40–50 years and is very rarely seen in children. Most tumors are located in the frontal lobe, less frequently in the temporal or parietal lobes, and very rarely in the brainstem [88]. IDH-wild-type GBM, which is also characterized by EGFR amplification and/or telomerase reverse transcriptase (TERT) promoter mutation and/or chromosomal alterations (+7/−10), accounts for half of all malignant brain tumors in adults and elderly individuals, with 10,000 new cases reported annually [89]. GBM develops between 18 and 89 years, most frequently (58%) between 50 and 69 years [88, 90, 91]. Comorbidities in older individuals result in a poorer prognosis for glioma compared to younger patients, due to limitations in standard glioma treatments caused by concurrent diseases.
In children and adolescents, diffuse HGG gliomas account for 3 to 15% of primary CNS tumors, with pHGG patient OS averaging 10–73 months [89,92]. Diffuse midline glioma, H3K27-altered, develops in individuals aged 2 to 65 years, with a median age of 11–14 years. Its pathognomonic feature is localization in the brainstem, thalamus, hypothalamus, as well as the cerebellum and spinal cord. The median age for brainstem glioma is 7 years, for thalamic glioma 24 years, and for spinal cord glioma 25 years. The prognosis for this glioma is poor, with an OS of 1 year [92].
Diffuse hemispheric glioma, H3G34-mutant, is most common between ages 15 and 19, and according to some studies, between 18 and 26 years. The prognosis for this glioma is generally poor (OS from 12 to 36 months) [92, 93].
H3-wild-type and IDH-wild-type pHGG gliomas are usually located in the brain hemispheres and rarely in other brain regions. These gliomas are often detected in early childhood but can also occur in adolescence and early adulthood. The prognosis for such gliomas is unfavorable (OS of 22 months) [90, 92, 93].
Molecular-genetic, diagnostic, and prognostic factors in aHGG and pHGG gliomas. Among HGG gliomas, diffuse gliomas are the most common. Although there are practically no histological differences between diffuse aHGG and pHGG gliomas, they differ in biological behavior, molecular-genetic characteristics, treatment response, and prognosis [92, 94, 95]. The defining differences between diffuse aHGG and pHGG gliomas, as reflected in the WHO Classification of CNS Tumors (2021), are molecular-genetic characteristics (Table 4).
Table 4. Age-related differences in the molecular-genetic profile of diffuse high-grade gliomas [92]
|
Molecular and genetic alterations |
pHGG |
aHGG |
Implications |
|
IDH1 Mutation |
In 16.3–35.0% of cases in children over 14 years old |
~50% of primary HGG gliomas |
Astrocytoma, IDH-mutant |
|
EGFR Expression |
In approximately 80% of cases |
Amplification and overexpression in 27–60% of cases |
Grade 4 glioma* |
|
TERT Promoter mutations |
Rarely |
In 40–70% of cases |
Grade 4 glioma* |
|
Chromosomal alterations +7/−10 |
NS |
У 50‒70% випадків |
Grade 4 glioma* |
|
ТP53 Mutation |
In 33–58% of pediatric cases |
In 30–60% of GBM cases |
р53 – tumor suppressor |
|
Loss or Mutation of PTEN |
In 0–20% of cases |
In 27–60% of cases |
Alterations in the PI3K/AKT/mTOR signaling pathway |
|
H3 K27- mutant |
In 60–80% of cases |
NS |
Pediatric diffuse midline glioma, Grade 4* |
|
H3 G34- mutant |
In approximately 20% of cases |
NS |
Pediatric diffuse hemispheric glioma, Grade 4* |
Note. * Based on the WHO Classification of Tumors of the Central Nervous System (2021); EGFR – epidermal growth factor receptor gene; TERT – telomerase reverse transcriptase promoter gene; TP53 – p53 tumor suppressor gene; PTEN – phosphatase and tensin homolog gene; IDH – isocitrate dehydrogenase gene;
H3 K27 and H3 G34 – histone H3 proteins; Not specified – NS.
The key difference between aHGG and pHGG is the IDH 1/2 gene mutations, which have diagnostic and prognostic significance, since IDH mutation in HGG gliomas determines a significantly better prognosis for adult and paediatric gliomas compared with IDH-wild-type gliomas [7,13,93,96]. Astrocytoma, IDH-mutant with homozygous deletion of CDK2A/B, is classified as a WHO CNS Grade 4 glioma with a poor prognosis (see Table 1). For gliomas, IDH-wild type, the presence of mutations such as EGFR amplification, TERT promoter mutations and chromosome +7/-10 alterations are a factor of unfavourable prognosis for patients (see Table 4).
EGFR amplification affects the tyrosine kinase receptor involved in cell proliferation and differentiation, as well as malignant growth processes. It is observed in 60% of GBM cases in adults, while it is rare in pHGG diffuse gliomas [92, 97, 98, 99].
Among other genes that cause age-related differences in gliomas, the phosphatase and tensin homologue (PTEN) suppressor gene, which is able to inhibit tumour invasion and blood vessel formation, occupies an important place. Its mutations are frequently reported in aHGG and rarely in pHGG. The TP53 gene is also a tumour suppressor gene with alterations in the majority of adult GBM cases [96, 99].
In the case of pHGG gliomas, in contrast to aHGG gliomas, alterations in histone proteins, particularly H3, are important for diagnosis and prognosis. Thus, diffuse medial glioma of pHGG is characterised by K27M mutation in histones H3.3 or H3.1. Diffuse hemispheric gliomas of pHGG are characterised by the presence of H3 G34R or H3 G34V mutation. pHGG gliomas with histone mutations usually have a poor prognosis and significantly lower OS compared to diffuse H3-wild-type and IDH-wild-type gliomas [98, 100-101]. In diffuse pHGG gliomas, TP53 mutations are often found together with H3 mutations. Therefore, histone mutation status may play a key role in gliomagenesis, especially in children, adolescents, and young adults, which is important for diagnosis, selection of adequate treatment methods, and prognosis of diffuse gliomas of pHGG.
Amplification of the platelet-derived growth factor receptor A (PDGFRA) gene in diffuse H3G34-mutant hemispheric gliomas is associated with an unfavorable prognosis, while O6-methylguanine DNA methyltransferase MGMT-methylation is associated with a more favorable prognosis, including increased survival. Specific molecular-genetic alterations in H3 wild-type and IDH wild-type diffuse pHGG gliomas also significantly impact prognosis. For example, the OS of patients with gliomas showing MYCN amplification averages 14 months, with PDGFRA amplification ‒ 21 months, and with TERT or EGFR mutation 44 months [92, 96].
Conclusions
Disclosure
Conflict of Interest
The authors declare no conflict of interest.
Funding
The study received no sponsorship.
References
1. Raizer JJ, Fitzner KA, Jacobs DI, Bennett CL, Liebling DB, Luu TH, Trifilio SM, Grimm SA, Fisher MJ, Haleem MS, Ray PS, McKoy JM, DeBoer R, Tulas KM, Deeb M, McKoy JM. Economics of Malignant Gliomas: A Critical Review. J Oncol Pract. 2015 Jan;11(1):e59-65. https://doi.org/10.1200/JOP.2012.000560
2. Boele FW, Meads D, Jansen F, Verdonck-de Leeuw IM, Heimans JJ, Reijneveld JC, Short SC, Klein M. Healthcare utilization and productivity loss in glioma patients and family caregivers: the impact of treatable psychological symptoms. J Neurooncol. 2020 Apr;147(2):485-494. https://doi.org/10.1007/s11060-020-03454-3
3. Zozulya YuA, red. Gliomy golovnogo mozga (sovremennoe sostoyanie problemyi i puti dalneyshih poiskov). K.: UIPK «EksOb»; 2007. Russian.
4. Li K, Lu D, Guo Y, Wang C, Liu X, Liu Y, Liu D. Trends and patterns of incidence of diffuse glioma in adults in the United States, 1973-2014. Cancer Med. 2018 Oct;7(10):5281-5290. https://doi.org/10.1002/cam4.1757
5. Grochans S, Cybulska AM, Simińska D, Korbecki J, Kojder K, Chlubek D, Baranowska-Bosiacka I. Epidemiology of Glioblastoma Multiforme-Literature Review. Cancers (Basel). 2022 May 13;14(10):2412. https://doi.org/10.3390/cancers14102412
6. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23(8):1231-1251. https://doi.org/10.1093/neuonc/noab106
7. Gianno F, Giovannoni I, Cafferata B, Diomedi-Camassei F, Minasi S, Barresi S, Buttarelli FR, Alesi V, Cardoni A, Antonelli M, Puggioni C, Colafati GS, Carai A, Vinci M, Mastronuzzi A, Miele E, Alaggio R, Giangaspero F, Rossi S. Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification. Pathologica. 2022 Dec;114(6):422-435. https://doi.org/10.32074/1591-951X-830
8. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016 Jun;131(6):803-20. https://doi.org/10.1007/s00401-016-1545-1
9. Louis DN, Aldape K, Brat DJ, Capper D, Ellison DW, Hawkins C, Paulus W, Perry A, Reifenberger G, Figarella-Branger D, Wesseling P, Batchelor TT, Cairncross JG, Pfister SM, Rutkowski S, Weller M, Wick W, von Deimling A. Announcing cIMPACT-NOW: the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. Acta Neuropathol. 2017 Jan;133(1):1-3. https://doi.org/10.1007/s00401-016-1646-x
10. Thomas DL. 2021 updates to the World Health Organization classification of adult-type and pediatric-type diffuse gliomas: a clinical practice review. Chin Clin Oncol. 2023 Feb;12(1):7. https://doi.org/10.21037/cco-22-120
11. Pfister SM, Reyes-Múgica M, Chan JKC, Hasle H, Lazar AJ, Rossi S, Ferrari A, Jarzembowski JA, Pritchard-Jones K, Hill DA, Jacques TS, Wesseling P, López Terrada DH, von Deimling A, Kratz CP, Cree IA, Alaggio R. A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era. Cancer Discov. 2022 Feb;12(2):331-355. https://doi.org/10.1158/2159-8290.CD-21-1094
12. Wen PY, Packer RJ. The 2021 WHO Classification of Tumors of the Central Nervous System: clinical implications. Neuro Oncol. 2021 Aug 2;23(8):1215-1217. https://doi.org/10.1093/neuonc/noab120
13. Torp SH, Solheim O, Skjulsvik AJ. The WHO 2021 Classification of Central Nervous System tumours: a practical update on what neurosurgeons need to know-a minireview. Acta Neurochir (Wien). 2022 Sep;164(9):2453-2464. https://doi.org/10.1007/s00701-022-05301-y
14. Ostrom QT, Adel Fahmideh M, Cote DJ, Muskens IS, Schraw JM, Scheurer ME, Bondy ML. Risk factors for childhood and adult primary brain tumors. Neuro Oncol. 2019 Nov 4;21(11):1357-1375. https://doi.org/10.1093/neuonc/noz123
15. Pellerino A, Caccese M, Padovan M, Cerretti G, Lombardi G. Epidemiology, risk factors, and prognostic factors of gliomas. Clin Transl Imaging. 2022; 10: 467–475. https://doi.org/10.1007/s40336-022-00489-6
16. Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013-2017. Neuro Oncol. 2020 Oct 30;22(12 Suppl 2):iv1-iv96. https://doi.org/10.1093/neuonc/noaa200
17. Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol. 2013 Nov;15 Suppl 2(Suppl 2):ii1-56. https://doi.org/10.1093/neuonc/not151
18. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS. The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol. 2014 Jul;16(7):896-913. https://doi.org/10.1093/neuonc/nou087
19. Ostrom QT, Price M, Neff C, Cioffi G, Waite KA, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015-2019. Neuro Oncol. 2022 Oct 5;24(Suppl 5):v1-v95. https://doi.org/10.1093/neuonc/noac202
20. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007 Aug;114(2):97-109. https://doi.org/10.1007/s00401-007-0243-4
21. Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, Baugh J, Chaney B, Hoffmann M, Lane A, Fuller C, Miles L, Hawkins C, Bartels U, Bouffet E, Goldman S, Leary S, Foreman NK, Packer R, Warren KE, Broniscer A, Kieran MW, Minturn J, Comito M, Broxson E, Shih CS, Khatua S, Chintagumpala M, Carret AS, Escorza NY, Hassall T, Ziegler DS, Gottardo N, Dholaria H, Doughman R, Benesch M, Drissi R, Nazarian J, Jabado N, Boddaert N, Varlet P, Giraud G, Castel D, Puget S, Jones C, Hulleman E, Modena P, Giagnacovo M, Antonelli M, Pietsch T, Gielen GH, Jones DTW, Sturm D, Pfister SM, Gerber NU, Grotzer MA, Pfaff E, von Bueren AO, Hargrave D, Solanki GA, Jadrijevic Cvrlje F, Kaspers GJL, Vandertop WP, Grill J, Bailey S, Biassoni V, Massimino M, Calmon R, Sanchez E, Bison B, Warmuth-Metz M, Leach J, Jones B, van Vuurden DG, Kramm CM, Fouladi M. Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries. J Clin Oncol. 2018 Jul 1;36(19):1963-1972. https://doi.org/10.1200/JCO.2017.75.9308
22. Patil N, Kelly ME, Yeboa DN, Buerki RA, Cioffi G, Balaji S, Ostrom QT, Kruchko C, Barnholtz-Sloan JS. Epidemiology of brainstem high-grade gliomas in children and adolescents in the United States, 2000-2017. Neuro Oncol. 2021 Jun 1;23(6):990-998. https://doi.org/10.1093/neuonc/noaa295
23. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016 Jan-Feb;66(1):7-30. https://doi.org/10.3322/caac.21332
24. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. https://doi.org/10.3322/caac.21387
25. McKean-Cowdin R, Razavi P, Barrington-Trimis J, Baldwin RT, Asgharzadeh S, Cockburn M, Tihan T, Preston-Martin S. Trends in childhood brain tumor incidence, 1973-2009. J Neurooncol. 2013 Nov;115(2):153-60. https://doi.org/10.1007/s11060-013-1212-5
26. Leece R, Xu J, Ostrom QT, Chen Y, Kruchko C, Barnholtz-Sloan JS. Global incidence of malignant brain and other central nervous system tumors by histology, 2003-2007. Neuro Oncol. 2017 Oct 19;19(11):1553-1564. https://doi.org/10.1093/neuonc/nox091
27. Girardi F, Matz M, Stiller C, You H, Marcos Gragera R, Valkov MY, Bulliard JL, De P, Morrison D, Wanner M, O'Brian DK, Saint-Jacques N, Coleman MP, Allemani C; CONCORD Working Group. Global survival trends for brain tumors, by histology: analysis of individual records for 556,237 adults diagnosed in 59 countries during 2000-2014 (CONCORD-3). Neuro Oncol. 2023 Mar 14;25(3):580-592. https://doi.org/10.1093/neuonc/noac217
28. Ratnapradipa KL, Yellala A, Shonka N. Exploratory analysis of the spatial distribution of adult glioma age-adjusted county incidence rates, Nebraska Medicine, 2009-2019. Neurooncol Pract. 2023 Aug 25;11(1):64-68. https://doi.org/10.1093/nop/npad050
29. Lin D, Wang M, Chen Y, Gong J, Chen L, Shi X, Lan F, Chen Z, Xiong T, Sun H, Wan S. Trends in Intracranial Glioma Incidence and Mortality in the United States, 1975-2018. Front Oncol. 2021 Nov 1;11:748061. https://doi.org/10.3389/fonc.2021.748061
30. Ostrom QT, Egan KM, Nabors LB, Gerke T, Thompson RC, Olson JJ, LaRocca R, Chowdhary S, Eckel-Passow JE, Armstrong G, Wiencke JK, Bernstein JL, Claus EB, Il'yasova D, Johansen C, Lachance DH, Lai RK, Merrell RT, Olson SH, Sadetzki S, Schildkraut JM, Shete S, Houlston RS, Jenkins RB, Wrensch MR, Melin B, Amos CI, Huse JT, Barnholtz-Sloan JS, Bondy ML. Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics. Int J Cancer. 2020 Feb 1;146(3):739-748. https://doi.org/10.1002/ijc.32318
31. Li S, Zhao Y, Huang H. Clinical characteristics and prognostic factors of adult brainstem gliomas: A retrospective analysis of histologically-proven 40 cases. Medicine (Baltimore). 2024 May 3;103(18):e37910. https://doi.org/10.1097/MD.0000000000037910
32. Khalid SI, Kelly R, Adogwa O, Carlton A, Tam E, Naqvi S, Kushkuley J, Ahmad S, Woodward J, Khanna R, Davison M, Munoz L, Byrne R. Pediatric Brainstem Gliomas: A Retrospective Study of 180 Patients from the SEER Database. Pediatr Neurosurg. 2019;54(3):151-164. https://doi.org/10.1159/000497440
33. Howell AE, Zheng J, Haycock PC, McAleenan A, Relton C, Martin RM, Kurian KM. Use of Mendelian Randomization for Identifying Risk Factors for Brain Tumors. Front Genet. 2018 Nov 12;9:525. https://doi.org/10.3389/fgene.2018.00525
34. Sioutas G, Nikova A, Birbilis T. Risk factors for pediatric glioma. Folia Med (Plovdiv). 2022 Aug 31;64(4):566-571. https://doi.org/10.3897/folmed..e64431
35. Malbari F, Lindsay H. Genetics of Common Pediatric Brain Tumors. Pediatr Neurol. 2020 Mar;104:3-12. https://doi.org/10.1016/j.pediatrneurol.2019.08.004
36. Andersson U, Degerman S, Dahlin AM, Wibom C, Johansson G, Bondy ML, Melin BS. The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking. Cancer Causes Control. 2019 Feb;30(2):177-185. https://doi.org/10.1007/s10552-018-1120-2
37. IARC. Working Group on the Evaluation of Carcinogenic Risks to Humans. Radiation. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 100D.) https://www.ncbi.nlm.nih.gov/books/NBK304362/
38. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Non-Ionizing Radiation, Part 2: Radiofrequency Electromagnetic Fields. Lyon (FR): International Agency for Research on Cancer; 2013. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 102.) https://www.ncbi.nlm.nih.gov/books/NBK304630/
39. Hardell L, Carlberg M. Mobile phones, cordless phones and rates of brain tumors in different age groups in the Swedish National Inpatient Register and the Swedish Cancer Register during 1998-2015. PLoS One. 2017 Oct 4;12(10):e0185461. https://doi.org/10.1371/journal.pone.0185461
40. Elwood JM, Win SS, Aye PS, Sanagou M. Trends in brain cancers (glioma) in New Zealand from 1995 to 2020, with reference to mobile phone use. Cancer Epidemiol. 2022 Oct;80:102234. https://doi.org/10.1016/j.canep.2022.102234
41. Uddin M, Dhanta R, Pitti T, Barsasella D, Scholl J, Jian WS, Li YJ, Hsu MH, Syed-Abdul S. Incidence and Mortality of Malignant Brain Tumors after 20 Years of Mobile Use. Cancers (Basel). 2023 Jul 4;15(13):3492. https://doi.org/10.3390/cancers15133492
42. Feychting M, Schüz J, Toledano MB, Vermeulen R, Auvinen A, Harbo Poulsen A, Deltour I, Smith RB, Heller J, Kromhout H, Huss A, Johansen C, Tettamanti G, Elliott P. Mobile phone use and brain tumour risk - COSMOS, a prospective cohort study. Environ Int. 2024 Mar;185:108552. https://doi.org/10.1016/j.envint.2024.108552
43. Brzozek C, Abramson MJ, Benke G, Karipidis K. Comment on Choi et al. Cellular Phone Use and Risk of Tumors: Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health 2020, 17, 8079. Int J Environ Res Public Health. 2021 May 20;18(10):5459. https://doi.org/10.3390/ijerph18105459
44. Moskowitz JM, Frank JW, Melnick RL, Hardell L, Belyaev I, Héroux P, Kelley E, Lai H, Maisch D, Mallery-Blythe E, Philips A; International Commission on the Biological Effects of Electromagnetic Fields. COSMOS: A methodologically-flawed cohort study of the health effects from exposure to radiofrequency radiation from mobile phone use. Environ Int. 2024 Aug;190:108807. https://doi.org/10.1016/j.envint.2024.108807
45. Feychting M, Schüz J, Toledano MB, Vermeulen R, Auvinen A, Harbo Poulsen A, Deltour I, Smith RB, Heller J, Kromhout H, Huss A, Johansen C, Tettamanti G, Elliott P. Response to the letter to the editor regarding "Mobile phone use and brain tumour risk - COSMOS, a prospective cohort study". Environ Int. 2024 Jul;189:108808. https://doi.org/10.1016/j.envint.2024.108808
46. Nyberg R, McCredden J, Hardell L. The European Union assessments of radiofrequency radiation health risks - another hard nut to crack (Review). Rev Environ Health. 2023 Aug 23. https://doi.org/10.1515/reveh-2023-0046
47. Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, Soroceanu L, Cobbs CS; HCMV and Gliomas Symposium. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 2012 Mar;14(3):246-55. https://doi.org/10.1093/neuonc/nor227
48. Duinkerken S, van Kooyk Y, Garcia-Vallejo JJ. Human cytomegalovirus-based immunotherapy to treat glioblastoma: Into the future. Oncoimmunology. 2016 Jul 25;5(9):e1214791. https://doi.org/10.1080/2162402X.2016.1214791
49. Cai Z, Yang S, Li X, Chen F, Li W. Viral infection and glioma: a meta-analysis of prognosis. BMC Cancer. 2020 Jun 12;20(1):549. https://doi.org/10.1186/s12885-020-06796-3
50. Cuoco JA, Benko MJ, Busch CM, Rogers CM, Prickett JT, Marvin EA. Vaccine-Based Immunotherapeutics for the Treatment of Glioblastoma: Advances, Challenges, and Future Perspectives. World Neurosurg. 2018 Dec;120:302-315. https://doi.org/10.1016/j.wneu.2018.08.202
51. Zhong S, Yang W, Zhang Z, Xie Y, Pan L, Ren J, Ren F, Li Y, Xie H, Chen H, Deng D, Lu J, Li H, Wu B, Chen Y, Peng F, Puduvalli VK, Sai K, Li Y, Cheng Y, Mou Y. Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis. BMC Med. 2023 Dec 5;21(1):487. https://doi.org/10.1186/s12916-023-03142-9
52. Coghill AE, Kim Y, Hodge JM, Bender N, Smith-Warner SA, Teras LR, Grimsrud TK, Waterboer T, Egan KM. Prospective investigation of herpesvirus infection and risk of glioma. Int J Cancer. 2022 Jul 15;151(2):222-228. https://doi.org/10.1002/ijc.33987
53. Vidone M, Alessandrini F, Marucci G, Farnedi A, de Biase D, Ricceri F, Calabrese C, Kurelac I, Porcelli AM, Cricca M, Gasparre G. Evidence of association of human papillomavirus with prognosis worsening in glioblastoma multiforme. Neuro Oncol. 2014 Jan;16(2):298-302. https://doi.org/10.1093/neuonc/not140
54. Desai AD, Lavelle M, Boursiquot BC, Wan EY. Long-term complications of COVID-19. Am J Physiol Cell Physiol. 2022 Jan 1;322(1):C1-C11. https://doi.org/10.1152/ajpcell.00375.2021
55. Zhang L, Wei C, Li D, He J, Liu S, Deng H, Cheng J, Du J, Liu X, Chen H, Sun S, Yu H, Fu J. COVID-19 receptor and malignant cancers: Association of CTSL expression with susceptibility to SARS-CoV-2. Int J Biol Sci. 2022 Mar 6;18(6):2362-2371. https://doi.org/10.7150/ijbs.70172
56. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020 Apr 1;11(7):995-998. https://doi.org/10.1021/acschemneuro.0c00122
57. Paules CI, Marston HD, Fauci AS. Coronavirus Infections-More Than Just the Common Cold. JAMA. 2020 Feb 25;323(8):707-708. https://doi.org/10.1001/jama.2020.0757
58. Pearson JRD, Regad T. Targeting cellular pathways in glioblastoma multiforme. Signal Transduct Target Ther. 2017 Sep 29;2:17040. https://doi.org/10.1038/sigtrans.2017.40
59. Khan I, Hatiboglu MA. Can COVID-19 induce glioma tumorogenesis through binding cell receptors? Med Hypotheses. 2020 Nov;144:110009. https://doi.org/10.1016/j.mehy.2020.110009
60. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020 Mar 17;94(7):e00127-20. https://doi.org/10.1128/JVI.00127-20
61. Banerjee S, Wang X, Du S, Zhu C, Jia Y, Wang Y, Cai Q. Comprehensive role of SARS-CoV-2 spike glycoprotein in regulating host signaling pathway. J Med Virol. 2022 Sep;94(9):4071-4087. https://doi.org/10.1002/jmv.27820
62. Behboudi E, Nooreddin Faraji S, Daryabor G, Mohammad Ali Hashemi S, Asadi M, Edalat F, Javad Raee M, Hatam G. SARS-CoV-2 mechanisms of cell tropism in various organs considering host factors. Heliyon. 2024 Feb 20;10(4):e26577. https://doi.org/10.1016/j.heliyon.2024.e26577
63. Diwanji TP, Engelman A, Snider JW, Mohindra P. Epidemiology, diagnosis, and optimal management of glioma in adolescents and young adults. Adolesc Health Med Ther. 2017 Sep 22;8:99-113. https://doi.org/10.2147/AHMT.S53391
64. Rasmussen BK, Hansen S, Laursen RJ, Kosteljanetz M, Schultz H, Nørgård BM, Guldberg R, Gradel KO. Epidemiology of glioma: clinical characteristics, symptoms, and predictors of glioma patients grade I-IV in the the Danish Neuro-Oncology Registry. J Neurooncol. 2017 Dec;135(3):571-579. https://doi.org/10.1007/s11060-017-2607-5
65. Greuter L, Guzman R, Soleman J. Pediatric and Adult Low-Grade Gliomas: Where Do the Differences Lie? Children (Basel). 2021 Nov 22;8(11):1075. https://doi.org/10.3390/children8111075
66. Bandopadhayay P, Bergthold G, London WB, Goumnerova LC, Morales La Madrid A, Marcus KJ, Guo D, Ullrich NJ, Robison NJ, Chi SN, Beroukhim R, Kieran MW, Manley PE. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer. 2014 Jul;61(7):1173-9. https://doi.org/10.1002/pbc.24958
67. Soleman J, Roth J, Ram Z, Yalon M, Constantini S. Malignant transformation of a conservatively managed incidental childhood cerebral mass lesion: controversy regarding management paradigm. Childs Nerv Syst. 2017 Dec;33(12):2169-2175. https://doi.org/10.1007/s00381-017-3566-z
68. Soleman J, Kozyrev DA, Ben-Sira L, Constantini S, Roth J. Management of incidental brain tumors in children: a systematic review. Childs Nerv Syst. 2020 Aug;36(8):1607-1619. https://doi.org/10.1007/s00381-020-04658-8
69. Jakola AS, Bouget D, Reinertsen I, Skjulsvik AJ, Sagberg LM, Bø HK, Gulati S, Sjåvik K, Solheim O. Spatial distribution of malignant transformation in patients with low-grade glioma. J Neurooncol. 2020 Jan;146(2):373-380. https://doi.org/10.1007/s11060-020-03391-1
70. Chamdine O, Broniscer A, Wu S, Gajjar A, Qaddoumi I. Metastatic Low-Grade Gliomas in Children: 20 Years' Experience at St. Jude Children's Research Hospital. Pediatr Blood Cancer. 2016 Jan;63(1):62-70. https://doi.org/10.1002/pbc.25731
71. Munshey A, Moore J, Maclean C, Longano A, Goldschlager T. Cranial Pilocytic Astrocytoma With Spinal Drop Metastasis in an Adult: Case Report and Literature Review. World Neurosurg. 2017 Feb;98:883.e7-883.e12. https://doi.org/10.1016/j.wneu.2016.08.013
72. Shofty B, Ben Sira L, Constantini S. Neurofibromatosis 1-associated optic pathway gliomas. Childs Nerv Syst. 2020 Oct;36(10):2351-2361. https://doi.org/10.1007/s00381-020-04697-1
73. Evans DGR, Salvador H, Chang VY, Erez A, Voss SD, Schneider KW, Scott HS, Plon SE, Tabori U. Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1. Clin Cancer Res. 2017 Jun 15;23(12):e46-e53. https://doi.org/10.1158/1078-0432.CCR-17-0589
74. Campen CJ, Gutmann DH. Optic Pathway Gliomas in Neurofibromatosis Type 1. J Child Neurol. 2018 Jan;33(1):73-81. https://doi.org/10.1177/0883073817739509
75. Tang Y, Gutmann DH. Neurofibromatosis Type 1-Associated Optic Pathway Gliomas: Current Challenges and Future Prospects. Cancer Manag Res. 2023 Jul 13;15:667-681. https://doi.org/10.2147/CMAR.S36267
76. Roth J, Ber R, Constantini S. Neurofibromatosis Type 1-Related Hydrocephalus: Treatment Options and Considerations. World Neurosurg. 2019 Aug;128:e664-e668. https://doi.org/10.1016/j.wneu.2019.04.231
77. Corlette L, Reid A, Roberts-Thomson S, Christie M, Gaillard F. Solitary subependymal giant cell astrocytoma: Case report and review of the literature. J Clin Neurosci. 2020 Dec;82(Pt A):26-28. https://doi.org/10.1016/j.jocn.2020.10.017
78. Gogos AJ, Young JS, Pereira MP, Morshed RA, Potts MB, Hervey-Jumper SL, Berger MS. Surgical management of incidentally discovered low-grade gliomas. J Neurosurg. 2020 Oct 2;135(2):480-487. https://doi.org/10.3171/2020.6.JNS201296
79. Khatua S, Gutmann DH, Packer RJ. Neurofibromatosis type 1 and optic pathway glioma: Molecular interplay and therapeutic insights. Pediatr Blood Cancer. 2018 Mar;65(3). https://doi.org/10.1002/pbc.26838
80. Ryall S, Zapotocky M, Fukuoka K, Nobre L, Guerreiro Stucklin A, Bennett J, Siddaway R, Li C, Pajovic S, Arnoldo A, Kowalski PE, Johnson M, Sheth J, Lassaletta A, Tatevossian RG, Orisme W, Qaddoumi I, Surrey LF, Li MM, Waanders AJ, Gilheeney S, Rosenblum M, Bale T, Tsang DS, Laperriere N, Kulkarni A, Ibrahim GM, Drake J, Dirks P, Taylor MD, Rutka JT, Laughlin S, Shroff M, Shago M, Hazrati LN, D'Arcy C, Ramaswamy V, Bartels U, Huang A, Bouffet E, Karajannis MA, Santi M, Ellison DW, Tabori U, Hawkins C. Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas. Cancer Cell. 2020 Apr 13;37(4):569-583.e5. https://doi.org/10.1016/j.ccell.2020.03.011
81. Peeters SM, Muftuoglu Y, Na B, Daniels DJ, Wang AC. Pediatric Gliomas: Molecular Landscape and Emerging Targets. Neurosurg Clin N Am. 2021 Apr;32(2):181-190. https://doi.org/10.1016/j.nec.2020.12.001
82. Bennett J, Yeo KK, Tabori U, Hawkins C, Lim-Fat MJ. Pediatric-type low-grade gliomas in adolescents and young adults-challenges and emerging paradigms. Childs Nerv Syst. 2024 May 18. https://doi.org/10.1007/s00381-024-06449-x
83. Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, Banerjee A, Packer RJ, Kilburn LB, Goldman S, Pollack IF, Qaddoumi I, Jakacki RI, Fisher PG, Dhall G, Baxter P, Kreissman SG, Stewart CF, Jones DTW, Pfister SM, Vezina G, Stern JS, Panigrahy A, Patay Z, Tamrazi B, Jones JY, Haque SS, Enterline DS, Cha S, Fisher MJ, Doyle LA, Smith M, Dunkel IJ, Fouladi M. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019 Jul;20(7):1011-1022. https://doi.org/10.1016/S1470-2045(19)30277-3
84. Lassaletta A, Zapotocky M, Mistry M, Ramaswamy V, Honnorat M, Krishnatry R, Guerreiro Stucklin A, Zhukova N, Arnoldo A, Ryall S, Ling C, McKeown T, Loukides J, Cruz O, de Torres C, Ho CY, Packer RJ, Tatevossian R, Qaddoumi I, Harreld JH, Dalton JD, Mulcahy-Levy J, Foreman N, Karajannis MA, Wang S, Snuderl M, Nageswara Rao A, Giannini C, Kieran M, Ligon KL, Garre ML, Nozza P, Mascelli S, Raso A, Mueller S, Nicolaides T, Silva K, Perbet R, Vasiljevic A, Faure Conter C, Frappaz D, Leary S, Crane C, Chan A, Ng HK, Shi ZF, Mao Y, Finch E, Eisenstat D, Wilson B, Carret AS, Hauser P, Sumerauer D, Krskova L, Larouche V, Fleming A, Zelcer S, Jabado N, Rutka JT, Dirks P, Taylor MD, Chen S, Bartels U, Huang A, Ellison DW, Bouffet E, Hawkins C, Tabori U. Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas. J Clin Oncol. 2017 Sep 1;35(25):2934-2941. https://doi.org/10.1200/JCO.2016.71.8726
85. Hanada T, Rahayu TU, Yamahata H, Hirano H, Yoshioka T, Arita K. Rapid malignant transformation of low-grade astrocytoma in a pregnant woman. J Obstet Gynaecol Res. 2016 Oct;42(10):1385-1389. https://doi.org/10.1111/jog.13072
86. Schmidt BT, Hanna A. Deadly Proliferation and Transformation of Pilocytic Astrocytoma in Pregnancy. World Neurosurg. 2020 Jan;133:99-103. https://doi.org/10.1016/j.wneu.2019.09.125
87. Barresi V, Eccher A, Simbolo M, Cappellini R, Ricciardi GK, Calabria F, Cancedda M, Mazzarotto R, Bonetti B, Pinna G, Sala F, Ghimenton C, Scarpa A. Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing. Neuropathology. 2020 Feb;40(1):68-74. https://doi.org/10.1111/neup.12608
88. Nafe R, Porto L, Samp PF, You SJ, Hattingen E. Adult-type and Pediatric-type Diffuse Gliomas : What the Neuroradiologist Should Know. Clin Neuroradiol. 2023 Sep;33(3):611-624. https://doi.org/10.1007/s00062-023-01277-z
89. Davis ME. Glioblastoma: Overview of Disease and Treatment. Clin J Oncol Nurs. 2016 Oct 1;20(5 Suppl):S2-8. https://doi.org/10.1188/16.CJON.S1.2-8
90. Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol. 2021 Oct 5;23(12 Suppl 2):iii1-iii105. https://doi.org/10.1093/neuonc/noab200
91. Bakas S, Sako C, Akbari H, Bilello M, Sotiras A, Shukla G, Rudie JD, Santamaría NF, Kazerooni AF, Pati S, Rathore S, Mamourian E, Ha SM, Parker W, Doshi J, Baid U, Bergman M, Binder ZA, Verma R, Lustig RA, Desai AS, Bagley SJ, Mourelatos Z, Morrissette J, Watt CD, Brem S, Wolf RL, Melhem ER, Nasrallah MP, Mohan S, O'Rourke DM, Davatzikos C. The University of Pennsylvania glioblastoma (UPenn-GBM) cohort: advanced MRI, clinical, genomics, & radiomics. Sci Data. 2022 Jul 29;9(1):453. https://doi.org/10.1038/s41597-022-01560-7
92. Aggarwal P, Luo W, Pehlivan KC, Hoang H, Rajappa P, Cripe TP, Cassady KA, Lee DA, Cairo MS. Pediatric versus adult high grade glioma: Immunotherapeutic and genomic considerations. Front Immunol. 2022 Nov 22;13:1038096. https://doi.org/10.3389/fimmu.2022.1038096
93. Korshunov A, Schrimpf D, Ryzhova M, Sturm D, Chavez L, Hovestadt V, Sharma T, Habel A, Burford A, Jones C, Zheludkova O, Kumirova E, Kramm CM, Golanov A, Capper D, von Deimling A, Pfister SM, Jones DTW. H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathol. 2017 Sep;134(3):507-516. https://doi.org/10.1007/s00401-017-1710-1
94. Solomon DA, Wood MD, Tihan T, Bollen AW, Gupta N, Phillips JJ, Perry A. Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations. Brain Pathol. 2016 Sep;26(5):569-80. https://doi.org/10.1111/bpa.12336
95. Roux A, Pallud J, Saffroy R, Edjlali-Goujon M, Debily MA, Boddaert N, Sanson M, Puget S, Knafo S, Adam C, Faillot T, Cazals-Hatem D, Mandonnet E, Polivka M, Dorfmüller G, Dauta A, Desplanques M, Gareton A, Pages M, Tauziede-Espariat A, Grill J, Bourdeaut F, Doz F, Dhermain F, Mokhtari K, Chretien F, Figarella-Branger D, Varlet P. High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts. Neuro Oncol. 2020 Aug 17;22(8):1190-1202. https://doi.org/10.1093/neuonc/noaa024
96. Joyner DA, Garrett J, Batchala PP, Rama B, Ravicz JR, Patrie JT, Lopes MB, Fadul CE, Schiff D, Jain R, Patel SH. MRI features predict tumor grade in isocitrate dehydrogenase (IDH)-mutant astrocytoma and oligodendroglioma. Neuroradiology. 2023 Jan;65(1):121-129. https://doi.org/10.1007/s00234-022-03038-0
97. Sabbah DA, Hajjo R, Sweidan K. Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Curr Top Med Chem. 2020;20(10):815-834. https://doi.org/10.2174/1568026620666200303123102
98. Rallis KS, George AM, Wozniak AM, Bigogno CM, Chow B, Hanrahan JG, Sideris M. Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma. Cancer Genomics Proteomics. 2022 Jul-Aug;19(4):390-414. https://doi.org/10.21873/cgp.20328
99. Yang Z, Ling F, Ruan S, Hu J, Tang M, Sun X, Long W. Clinical and Prognostic Implications of 1p/19q, IDH, BRAF, MGMT Promoter, and TERT Promoter Alterations, and Expression of Ki-67 and p53 in Human Gliomas. Cancer Manag Res. 2021 Nov 23;13:8755-8765. https://doi.org/10.2147/CMAR.S336213
100. Picart T, Barritault M, Poncet D, Berner LP, Izquierdo C, Tabouret E, Figarella-Branger D, Idbaïh A, Bielle F, Bourg V, Vandenbos FB, Moyal EC, Uro-Coste E, Guyotat J, Honnorat J, Gabut M, Meyronet D, Ducray F. Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults. Neurooncol Adv. 2021 Apr 19;3(1):vdab061. https://doi.org/10.1093/noajnl/vdab061
101. Lim KY, Won JK, Park CK, Kim SK, Choi SH, Kim T, Yun H, Park SH. H3 G34-mutant high-grade glioma. Brain Tumor Pathol. 2021 Jan;38(1):4-13. https://doi.org/10.1007/s10014-020-00378-8