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Definition

With the term gliomas is commonly defined a broad class of primary brain tumors of neuroepithelial origin.

 
 

Epidemiology

Brain gliomas account for 3-5/100.000/year. In adults, there are three frequent histological subtypes: astrocytoma, oligodendroglioma and oligoastrocytoma, depending on the type of cells from which they derive. These tumors are also dived into two classes that differ for clinical and biological behavior: Low Grade Gliomas (LGG) and High Grade Gliomas (HGG).

LGGs

LGGs (astrocytoma, oligodendroglioma, oligoastrocytoma) account for approximately 30% of gliomas, they are typically diagnosed in young adults between 20-45 years old (mean 35 years of age). There is a biphasic distribution, (6-12 years and 26-46 years). There is a slight male predilection (M:F ~1.5); they generally involve the so-called “eloquent areas” (cortical and subcortical areas of the brain which are highly functional) and they have a preferential spreading along the white matter. Although they present less aggressive behavior at onset (they are classified as WHO grade II, see below), all LGGs eventually evolve toward higher grade of malignancies.

HGGs

HGGs (Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma and Glioblastoma Multiforme) are the most common adult primary intracranial tumor. Glioblastoma Multiforme (GBM) accounts 50% of gliomas. They often cross the corpus callosum and involve the controlateral hemisphere (butterfly GBM). GBM are multifocal in 20% of patients. GBM has a peak incidence between 65 and 75 years of age. There is a slight male preponderance with a 3:2 M:F ratio. 

 

Etiology 

Largely unknown. GBM are usually sporadic, although it can derive from LGG, in that case it is called “secondary” GBM. They can also occur as part of rare inherited tumor syndromes (p53 mutation related syndromes such as neurofibromatosis type1, Li-Fraumeni syndrome, Turcot syndrome, Ollier disease and Maffucci syndrome).

 

Classification and grading  

It is classically based on the microscopic morphology of the cells from which they derive (astrocytes, oligodendrocytes). Tumors are graded based on cellularity, cellular and nuclear atypia (anaplasia), proliferative index, necrosis and pattern of vascularity.

WHO historical classification

World Health Organization (WHO) classified gliomas into 4 grades, where the grade I shows the best prognosis and grade IV the worst. In adults only grade II (LGGs) and III (Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma and IV (GBM) are present. WHO grade I gliomas are typical of childhood. This latter type is also define “localized” glioma to differ from the former which are “diffuse” gliomas and to underline that a radical surgical resection can have high chance of cure.

Recently, molecular and genetic markers have strongly influenced histological diagnosis and the new WHO 2016 classification gives a pivotal role to these markers in defining types, aggressiveness and therapeutic approach.

Most used molecular biomarkers

Most used molecular biomarkers are:

    • Isocitrate dehydrogenase (IDH): enzyme that catalyzes the conversion of isocitrate to a-ketoglutarate. IDH1 mutation is frequent in grade II and III astrocytomas, oligodendrogliomas, oligoastrocytomas, and in secondary GBM. IDH2 mutation is frequent in oligodendrogliomas. The presence of IDH1 mutation is related to better prognosis.
    • Tumor Protein 53 (TP53) is a protein which repairs DNA damage. When mutated, cells with damaged DNA are able to survive.
    • ATRX (α-thalassemia/mental retardation syndrome X-linked): ATRX mutations is present in grade II and III astrocytomas, oligoastrocytomas, and secondary GBM.
    • TERT (telomerase reverse transcriptase) gene produce a protein which keeps telomeres whole.Very frequent in primary GBM, oligodendrogliomas and other brain tumors.
    • PTEN (Phosphatase and Tensin Homologue Deleted in Chromosome Ten) and loss of heterozygosis (LOH) chromosome 10: typical genetic abnormality GBM. - Epidermal Growth Factor Receptor (EGFR): in primary GBM these molecule is typically over expressed
    • MGMT (O6-methylguanine-DNA methyltransferase gene): this gene encodes DNA repair enzyme which makes tumor cells more resistant to alkylating agents (chemotherapy). The hypermethylation of its promoter silences the MGMT. Its inactivation makes these tumors more sensitive to chemotherapy. GBM patients with hypermethylated MGMT, have better response to chemotherapy.
    • 1p/19q (deleted, codelete, not deleted); co-deletion is typical of oligodendroglioma. Moreover, it predicts better prognosis and more sensitivity to chemotherapy.

 

Glioblastoma Multiforme (GBM)

GBM is the most aggressive and frequent HGG (WHO grade IV glioma). It has traditionally been divided into primary and secondary. 

Primary GBM

Primary GBM is more aggressive than secondary GBM and it tends to occur in older patients. Histologically, it shows hypercellularity, cellular pleomorphism, nuclear atypia and microvascular proliferation. From a molecular perspective, it is characterized by amplification of EGFR, mutation of PTEN, loss of heterozygosity of chromosome 10p, IDH wild type (non-mutated).

Secondary GBM

Secondary GBMs derives from LGG, they tend to be less aggressive and occur in younger patients. Characteristically, secondary GBM, generally has a mutated IDH-1 and TP53, amplification of PDGF-A, loss of heterozygosity of chromosomes 10q and 17p, loss of 19q and increased telomerase activity and hTERT expression.

 

Low grade gliomas 

Among LGG (WHO grade II), astrocytoma is the most frequent (15-20% of all gliomas). They typically present with seizures (up to 90% of patients) even though they are sometimes discovered incidentally, meaning that they can grow silently.

Microscopical description

It presents as hypercellular, uniform population of well-differentiated astrocytes with minimal pleomorphism and nuclear atypia; microvascular proliferation and necrosis are absent; tumor borders are ill-defined, with individual neoplastic cells seen admixed with normal cortical neurons (perineuronal satellitosis).

Mutation and Prognosis

Substantial prognostic difference is related to the status of IDH1 (mutated or wild type). In fact, LGG which show a IDH 1 wild type have high chances of worse prognosis (more similar to HGG) compared to IDH 1 mutated. Furthermore, among LGG which have a mutant IDH1, tumors with intact 1p/19q, mutated TP53 and ATRX show less favorable prognosis.

 

Diagnosis

The clinical onset is strongly influenced by the growth rate. Due to their rapid growth, HGGs tend to provoke focal neurological deficits following the straining of the infiltrated brain. Conversely, the more indolent growth of LGG rarely causes focal deficits and seizures are the typical onset.

Symptoms and Signs

    • Increased intracranial pressure  headache, nausea, vomiting. This is related to the volume of the tumor. 
    • Focal Neurological symptoms according with the tumor location
    • Rarely (<2%) intratumoral haemorrhage occurs and patients may present acutely with stroke-like symptoms and signs. This occurrence is peculiar of HGGs.
    • 20-40% of adult with primary brain tumors experience at least one seizure prior to diagnosis
    • Another 20-45% will develop seizures at some point following diagnosis
    • Generally seizures incidence falls with increasing of tumor grading

 

Neuroradiological diagnosis

Magnetic Resonance Imaging (MRI) is the gold standard to diagnose a brain glioma. MRI not only guides in discerning the type of glioma but also perfectly defines location, extension, relationship with healthy brain and vascular structures. It must be performed with contrast medium (gadolinium). Computerized Tomography (CT) is far less good in anatomical and biological definition but it frequently comes that patients undergoes an urgent CT because of a seizure or neurological impairment.

Peculiar neuroradiological features - LGGs

  • CT 
    • Generally isodense or hypodense without any enhancement (presence of enhancement is generally correlate to HGG). Calcification (10-20% of cases) are usually related to oligodendroglial components. Due to the hypodense appearance they can sometimes be mistaken for other lesions (ischemia, cerebritis, encephalitis, post-epileptic alterations).
  • MRI
    • T1: isointense to hypointense compared to white matter; no enhancement at gadolinium;
    • T2/FLAIR: hyperintense
    • MR spectroscopy: elevated choline peak, low N-acetilaspartate peak, elevated choline/creatine ratio
    • MR perfusion: no elevation of rCBV

 

 

Peculiar neuroradiological features - HGGs

  • CT
    • Irregular hypodense necrotic core with irregular thick margins; marked mass effect frequent. Irregular contrast enhancing
  • MRI
    • T1: hypo to isointense tumor with central necrosis; typically peripheral and irregular enhancing
    • T2/FLAIR: hyperintense with vasogenic oedema
    • MR spectroscopy: increased choline, lactate, lipids and decreased N-acetilaspartate, myoinositol
    • MR perfusion: rCBV elevated compared to LGG and normal brain
  • Differential Diagnosis
    • Often have thick, irregular-enhancing margins and a central necrotic core surrounded by healthy tissue with infiltration of neoplastic cells and edema. The most important differential diagnoses are: metastases, primary lymphoma, brain abscess.

References

Altieri R, Agnoletti A et Al. Molecular biology of gliomas: present and future challenges. Transl Med UniSa. 2014 Apr 8;10:29-37. eCollection 2014.

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Chang EF, Potts MB, Keles GE,et al. Seizure charac-teristics and control following resection in 332 patients with low-grade gliomas. JNeurosurg2008; 108:227–235.

Dandy WE. Removal of right cerebral hemisphere for certain tumors with hemiplegia. JAMA.1928; 90:823–825.

David N. Louis, Arie Perry et Al. The 2016 World Health Organization Classification of Tumors 

Duffau H. Surgery of low-grade gliomas: towards a functional neurooncology. Curr Opin Oncol2009; 21: 543–249

Foote MB, Papadopoulos N et Al. Genetic Classification of Gliomas: Refining Histopathology. Cancer Cell. 2015 Jul 13;28(1):9-11.doi:  10.1016/j.ccell.2015.06.014.

Hegi ME, Diserens AC et Al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003.

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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. doi: 10.1007/s00401-016-1545-1. Review.

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Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008 Apr;62(4):753-64; discussion 264-6. doi: 10.1227/01.neu.0000318159.21731.cf.

Soffietti R, Baumert BG et Al. Guidelines on management of low-grade gliomas: report of an EFNS-EANO Task Force. Eur J Neurol. 2010 Sep;17(9):1124-33. doi: 10.1111/j.1468-1331.2010.03151.x.

Stupp R, Mason WP et Al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96.

Tanboon J, Williams EA, Louis DN. The Use of Immunohistochemical Surrogates for Signature Molecular Alterations in Glioma. J Neuropathol Exp Neurol 2016; 75:4-18

 

Authors

 

Roberto Altieri, MD

Neurosurgery Resident
University of Turin
"Molinette" Hospital Turin (Italy)

 

Giannantonio Spena, MD

Neurosurgeon Consultant
University of Brescia
"Spedali Civili" Hospital Brescia (Italy)
Scientific Team - UpSurgeOn