**2. Histology and classification**

**The cellular origin** of GBM is unknown. Astrocyte, oligodendrocyte precursor cell and neural stem cell can all serve as the cell of origin for this type of brain tumor. For this reason, in the recent version of the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), which is the current international standard for the nomenclature and diagnosis, GBM is incorporated into the category of "diffuse astrocytic and oligodendroglial tumors", being considered a grade IV tumor.

There are **some properties of the tumor cells that render GBM incurable**. First, the diffuse infiltrative nature of the cells makes complete tumor resection impossible, despite the advances in neurosurgical techniques. Glioma cells have the ability to migrate away from the main tumor mass, through the brain. Typical migration routes include white matter tracts, along the basal lamina of the blood vessels, perineuronal and in between the glia limitans and the pia mater. Tumor cells are still detectable at a distance greater than 4 cm away from macroscopic and radiologic margin of the tumor [2]. Second, there is a resistance of the glioma cells to conventional radiation therapy, chemotherapy and other therapies, as they are spared from eradication. This resistance is correlated with the heterogeneous character of the tumor itself, with its "multiforme" appearance [3]. GBM is multiforme macroscopically, featuring multifocal hemorrhage, necrosis and cystic areas. It is multiforme microscopically, demonstrating pleomorphic cell population, hypercellularity with mitotic activity, nuclear atypia, pseudopalisading necrosis and microvascular proliferation. And it is multiforme genetically, with various genetic abnormalities and heterogeneous subclones within the tumor cell population.

**The histological diagnosis** of GBM should be undertaken by a neuropathologist by standard histopathology methods and should include tumor type and tumor grade according to WHO Classification of Tumors of the CNS.

Progress has been made in knowledge of the GBM biology in relation to its microenvironment. Patterns of **molecular genetic alterations** have been associated with specific types of GBMs. Recent medical advances have indicated the importance of molecular typing in determining the prognosis and personalized treatment strategies for the patient. For this reason, in the recent version of the 2016 WHO Classification of Tumors of the CNS, molecular parameters are used in addition to histology to define diagnostic entities. This adds a level of objectivity to diagnostic and should lead to improvements in determination of prognosis and treatment response. So, GBMs are further defined by the presence or absence of **isocitrate dehydrogenase (IDH) gene mutations**. IDH is an enzyme encoded by the IDH gene, whose mutations occur in gliomas. These mutations are oncogenic and they lead to a hypermethylation phenotype, as well as changes in cellular metabolism and response to hypoxic and oxidative stress [4, 5]. Mutated IDH can now be detected by immunohistochemistry and magnetic resonance spectroscopy (MRS). IDH mutation is identified as a genetic marker of secondary GBM. It can indicate a favorable prognosis and a relatively good response to radiation and/or alkylating chemotherapy.

safe surgical resection, followed by concurrent chemoradiotherapy and adjuvant chemotherapy with temozolomide (TMZ). New discoveries are being made in basic and translational research, novel therapeutic approaches have been tried and tested, some of them finding their way into clinical practice. Despite the synergistic multimodal strategies and individualized therapies, the available treatment is of limited utility, and patients have a poor prognosis, with a progression-free survival (PFS) of 7–8 months, a median survival of 14–16 months and 5-year overall survival (OS) of 9.8% [1]. This review focuses on the current treatment strate-

**The cellular origin** of GBM is unknown. Astrocyte, oligodendrocyte precursor cell and neural stem cell can all serve as the cell of origin for this type of brain tumor. For this reason, in the recent version of the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), which is the current international standard for the nomenclature and diagnosis, GBM is incorporated into the category of "diffuse astrocytic and

There are **some properties of the tumor cells that render GBM incurable**. First, the diffuse infiltrative nature of the cells makes complete tumor resection impossible, despite the advances in neurosurgical techniques. Glioma cells have the ability to migrate away from the main tumor mass, through the brain. Typical migration routes include white matter tracts, along the basal lamina of the blood vessels, perineuronal and in between the glia limitans and the pia mater. Tumor cells are still detectable at a distance greater than 4 cm away from macroscopic and radiologic margin of the tumor [2]. Second, there is a resistance of the glioma cells to conventional radiation therapy, chemotherapy and other therapies, as they are spared from eradication. This resistance is correlated with the heterogeneous character of the tumor itself, with its "multiforme" appearance [3]. GBM is multiforme macroscopically, featuring multifocal hemorrhage, necrosis and cystic areas. It is multiforme microscopically, demonstrating pleomorphic cell population, hypercellularity with mitotic activity, nuclear atypia, pseudopalisading necrosis and microvascular proliferation. And it is multiforme genetically, with various genetic abnormalities and heterogeneous subclones

**The histological diagnosis** of GBM should be undertaken by a neuropathologist by standard histopathology methods and should include tumor type and tumor grade according to WHO

Progress has been made in knowledge of the GBM biology in relation to its microenvironment. Patterns of **molecular genetic alterations** have been associated with specific types of GBMs. Recent medical advances have indicated the importance of molecular typing in determining the prognosis and personalized treatment strategies for the patient. For this reason, in the recent version of the 2016 WHO Classification of Tumors of the CNS, molecular parameters are used in addition to histology to define diagnostic entities. This adds

gies and perspectives in the management of GBM.

oligodendroglial tumors", being considered a grade IV tumor.

**2. Histology and classification**

4 Brain Tumors - An Update

within the tumor cell population.

Classification of Tumors of the CNS.

**GBMs are divided into**: GBM, IDH-wildtype; GBM, IDH-mutant and GBM, NOS [6]. IDHwildtype GBM corresponds with clinically described primary or de novo GBM. It represents about 90% of GBMs. It arises without clinical, radiologic or histologic evidence of a pre-existing less malignant lesions, in elderly patients (median age of 62 years), usually supratentorial. The mean length of clinical history is 4 months and the median overall survival after conventional surgery, radiotherapy and chemotherapy is 15 months, the prognosis being poor [6, 7]. IDH-mutant GBM corresponds with secondary GBM (approximately 10% of GBMs). It typically develops from lower grade diffuse glioma. It occurs in younger patients (median age of 45 years), preferentially in the frontal lobe. The mean duration of the clinical history of secondary GBM is 15 months and the median overall survival after multimodal treatment (including surgical resection, radiotherapy and chemotherapy) is 31 months, a significantly better prognosis than primary GBM [6, 7]. Primary and secondary GBMs carry distinct genetic abnormalities. Other common genetic alterations in secondary GBMs include TP53 mutations (~65%), ATRX mutations (~65%) and loss of heterozygosity (LOH) on chromosome 19q (~50%). In primary GBMs, there is a high frequency of EGFR amplification (~35%), phosphatase and tensin homolog (PTEN) mutation (~25%) and LOH on chromosome 10 (LOH 10p ~50%, LOH 10q ~70%) [7, 8]. There is now increasing evidence that primary and secondary GBMs are in fact different tumor entities that develop from distinct cells of origin [7]. Despite the differences in their phenotypic and genotypic profiles, these two subtypes of GBM are histopathologically indistinguishable, except that extensive necrosis is more frequent in primary GBM and oligodendroglioma components are more frequent in secondary GBM [7]. Recent findings in pediatric GBMs regarding mutations in the histone H3F3A gene suggest that these tumors may represent a third major category of GBMs, separate from adult primary and secondary GBMs [9]. The terminology NOS (i.e., not otherwise specified) is used for GBM when molecular information is insufficient, either because testing cannot be fully performed or the results do not fit within a defined category.

In the 2016 update of the WHO Classification of Tumors of the CNS, there are **three variants of IDH-wildtype GBMs**: giant cell GBM, gliosarcoma and epithelioid GBM. It is to be noted that variants are subtypes of accepted entities that are sufficiently well characterized pathologically and have potential clinical utility [6]. There are also **different patterns in GBMs**, including small cell GBMs, granular cell GBM and GBM with primitive neuronal component (previously referred as GBM with primitive neuroectodermal tumor (PNET)-like component). Patterns are histological features that are readily recognizable, but usually do not have clear clinicopathological significance [6].
