**1. Introduction**

The introduction of the new classification represents the first step in the switch of paradigm in brain tumor management toward an individualized-based treatment from the, nowadays, evidence-based management. The classification of diffuse gliomas has undergone significant changes following the introduction of molecular testing, the new WHO 2016 classification introducing a new concept—integrated diagnosis [1]. The current update takes into

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account both the phenotype and the genotype [2]. This was the preferred alternative, as it is currently impossible to resort only to the molecular parameters in the definition of tumoral entities [3]. The classification relies both on the morphological character (growth pattern) and on the definition of the genetic status by determining the presence of mutations in the IDH1 and IDH2 genes and of the 1p/19q codeletion [4]. According to WHO 2016, diffuse gliomas are lumped together, regardless of their histopathological aspect (astrocytomas or oligodendrogliomas) [5].

This approach separates between the astrocytomas with a circumscribed growth pattern, no IDH mutation, and with BRAF mutation (pilocytic astrocytoma, pleomorphic xantoastrocytoma, and subependymal giant cell astrocytoma), on the one hand, and the diffuse astrocytic and oligodendroglial tumors, on the other. According to the new classification, the diffuse astrocytic and oligodendroglial tumors are nosologically closer than the diffuse astrocytoma

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The inclusion in these categories on the basis of genetic determinations also has a role in

When there is a mismatch between the phenotype and the genotype, genetic tests set the final

Glioblastoma with the IDH mutation show a better evolution than the wild-type ones, generally corresponding to a secondary glioblastoma. They also have a better prognosis than the wild-type anaplastic astrocytoma. The wild-type astrocytomas have the worst prognosis of all astrocytomas, their molecular profile being characteristic for glioblastomas (EGFR amplifica-

The introduction of molecular parameters in the definition of entities has led to the recognition of a new entity in the group of diffuse pediatric gliomas: the tumors with a midline location, diffuse growth pattern, and the K27 M mutation in the H3 histone gene. This is the first attempt to distinguish between the pediatric brain tumors and their adult counterparts, the difference in behavior between histopathologically identical tumors being

As to the histological grading, the WHO 2016 classification keeps the three-tiered system. The shift from low to high malignancy depends upon morphological parameters that reflect the emergence of new biological processes. The *first malignancy* criterion is represented by the variations in the size, shape, and color intensity of the nucleus (*atypia with hyperchromasia*) [13]. The *proliferation* is reflected in the presence of mitoses, which must be unequivocal, with no additional specifications in terms of number and morphology [14]. A significant proliferation typical for high-grade tumors is highlighted by the advent of *necrosis* and of the attempt to compensate for this hypoxia through the emergence of *microvascular proliferation*. According to this classification, the *diffuse astrocytomas* limited to *cytological atypia* are deemed to be *grade II*, while those with *both anaplasia* and *mitotic activity* are deemed to be *anaplastic* (*grade III*). The presence of mitoses must be seen in context as only one mitosis in a large section is not enough for a grade III. If we are dealing with a small biopsy, then the presence of a mitosis may be sufficient. *Grade IV* is reserved to those tumors that display *necrosis and/or vascular proliferation*. Microvascular proliferation is defined as the stratification of the endothelium, or the "glomeruloid" aspect. The

In the group of low-grade gliomas (II and III), the histopathological stratification features a significant interobserver variability, as also demonstrated by the considerable differences in terms of survival rates manifest within this group. The evaluation of molecular parameters can also be useful in the sense of defining groups that correlate better with the prognosis [16].

diagnosis in keeping with the rule "molecular beats histopathology [1]."

and the pilocytic astrocytoma [9].

tions, PTEN mutation, and 10q, 9p loss) [11].

prognosis [10].

long known [12].

necrosis can be of any type [15].

The recourse to an integrated diagnosis makes it possible to formulate a more precise diagnosis of the various entities and acknowledges the existence of new entities [6].

The introduction of molecular parameters comes to improve the clinical management of patients, defining entities which feature a similar prognosis. It also paves the way to the identification of new treatment methods aimed at the biological mechanisms common to this type of tumors [5]. The genetic information supplied by the Cancer Genome Atlas Research indicate that the supratentorial gliomas with a diffuse growth pattern can be categorized separately from the other brain tumors (**Figure 1**) [7]. They are grouped into three categories, according to the genetic profile—the presence or absence of the 1p/19q codeletion and the mutational status of the IDH gene. The first category includes the gliomas with a classical morphology of oligodendrogliomas, having both the IDH gene mutation and the 1p/19q codeletion. The second category is represented by the tumors with an astrocytic histological pattern and IDH mutation, but without the 1p/19q codeletion. In the third category, we find the tumors with an astrocytic phenotype, which display no IDH mutation or 1p/19q codeletion. The latter category usually falls under the classical wild-type glioblastoma diagnosis [8].

**Figure 1.** Integrated diagnosis of astrocytic and oligodendroglial tumors.

This approach separates between the astrocytomas with a circumscribed growth pattern, no IDH mutation, and with BRAF mutation (pilocytic astrocytoma, pleomorphic xantoastrocytoma, and subependymal giant cell astrocytoma), on the one hand, and the diffuse astrocytic and oligodendroglial tumors, on the other. According to the new classification, the diffuse astrocytic and oligodendroglial tumors are nosologically closer than the diffuse astrocytoma and the pilocytic astrocytoma [9].

account both the phenotype and the genotype [2]. This was the preferred alternative, as it is currently impossible to resort only to the molecular parameters in the definition of tumoral entities [3]. The classification relies both on the morphological character (growth pattern) and on the definition of the genetic status by determining the presence of mutations in the IDH1 and IDH2 genes and of the 1p/19q codeletion [4]. According to WHO 2016, diffuse gliomas are lumped together, regardless of their histopathological aspect (astrocytomas or

The recourse to an integrated diagnosis makes it possible to formulate a more precise diagno-

The introduction of molecular parameters comes to improve the clinical management of patients, defining entities which feature a similar prognosis. It also paves the way to the identification of new treatment methods aimed at the biological mechanisms common to this type of tumors [5]. The genetic information supplied by the Cancer Genome Atlas Research indicate that the supratentorial gliomas with a diffuse growth pattern can be categorized separately from the other brain tumors (**Figure 1**) [7]. They are grouped into three categories, according to the genetic profile—the presence or absence of the 1p/19q codeletion and the mutational status of the IDH gene. The first category includes the gliomas with a classical morphology of oligodendrogliomas, having both the IDH gene mutation and the 1p/19q codeletion. The second category is represented by the tumors with an astrocytic histological pattern and IDH mutation, but without the 1p/19q codeletion. In the third category, we find the tumors with an astrocytic phenotype, which display no IDH mutation or 1p/19q codeletion. The latter cat-

sis of the various entities and acknowledges the existence of new entities [6].

egory usually falls under the classical wild-type glioblastoma diagnosis [8].

**Figure 1.** Integrated diagnosis of astrocytic and oligodendroglial tumors.

oligodendrogliomas) [5].

96 Glioma - Contemporary Diagnostic and Therapeutic Approaches

The inclusion in these categories on the basis of genetic determinations also has a role in prognosis [10].

When there is a mismatch between the phenotype and the genotype, genetic tests set the final diagnosis in keeping with the rule "molecular beats histopathology [1]."

Glioblastoma with the IDH mutation show a better evolution than the wild-type ones, generally corresponding to a secondary glioblastoma. They also have a better prognosis than the wild-type anaplastic astrocytoma. The wild-type astrocytomas have the worst prognosis of all astrocytomas, their molecular profile being characteristic for glioblastomas (EGFR amplifications, PTEN mutation, and 10q, 9p loss) [11].

The introduction of molecular parameters in the definition of entities has led to the recognition of a new entity in the group of diffuse pediatric gliomas: the tumors with a midline location, diffuse growth pattern, and the K27 M mutation in the H3 histone gene. This is the first attempt to distinguish between the pediatric brain tumors and their adult counterparts, the difference in behavior between histopathologically identical tumors being long known [12].

As to the histological grading, the WHO 2016 classification keeps the three-tiered system. The shift from low to high malignancy depends upon morphological parameters that reflect the emergence of new biological processes. The *first malignancy* criterion is represented by the variations in the size, shape, and color intensity of the nucleus (*atypia with hyperchromasia*) [13]. The *proliferation* is reflected in the presence of mitoses, which must be unequivocal, with no additional specifications in terms of number and morphology [14]. A significant proliferation typical for high-grade tumors is highlighted by the advent of *necrosis* and of the attempt to compensate for this hypoxia through the emergence of *microvascular proliferation*. According to this classification, the *diffuse astrocytomas* limited to *cytological atypia* are deemed to be *grade II*, while those with *both anaplasia* and *mitotic activity* are deemed to be *anaplastic* (*grade III*). The presence of mitoses must be seen in context as only one mitosis in a large section is not enough for a grade III. If we are dealing with a small biopsy, then the presence of a mitosis may be sufficient. *Grade IV* is reserved to those tumors that display *necrosis and/or vascular proliferation*. Microvascular proliferation is defined as the stratification of the endothelium, or the "glomeruloid" aspect. The necrosis can be of any type [15].

In the group of low-grade gliomas (II and III), the histopathological stratification features a significant interobserver variability, as also demonstrated by the considerable differences in terms of survival rates manifest within this group. The evaluation of molecular parameters can also be useful in the sense of defining groups that correlate better with the prognosis [16].

*Gliomatosis cerebri* no longer exists as an entity, being considered rather a specific growth pattern. More research is needed in order to identify the biological substrate of this unusual invasive capacity [17].

*Advanced MRI techniques* such as diffusion-weighted imaging (DWI) and MRI spectroscopy will complete the anatomical information, while the functional MRI and diffusion tensor imaging (DTI) will offer important data for surgical planning. On *DWI*, DA IDH-mut presents a decrease cellularity and non-restricted diffusion. *MRI Spectroscopy* will reveal not only decreased N-acetylaspartate (NAA) peak, medium choline peaks, absence of lactate peak, and increased myo-inositol [20], but is also able to detect IDH mutation trough oncometabolite 2-hydroxyglutarate (2HG) present in tumor cells [21]. MRI could also serve as a *prognosis tool* if is combined with IDH status. Just recently it was suggested that minimum apparent diffusion coefficient (ADCMIN) threshold

with IDH wild-type grade II diffuse astrocytomas [22]. *DTI with tractography* usually reveals a displacement rather than an infiltration or destruction of fiber tracts in DA IDH-mut tumors. *CT scan* reveals a homogeneous lesion, poorly defined, with no contrast enhancement. This can be associated with cystic changes and calcifications that are more specific for oligodendrogliomas. **Macroscopy**. In section, the tumor does not display clearly delineated limits, on account of its infiltrative growth pattern. We can see areas of soft consistency or firmer ones, granular areas, and cystic ones. Cystic changes can include sponge-like areas, consisting of cysts of various sizes that may have a gelatinous aspect. There can be only one large cysts, filled with liquid, and this is associated with the identification of gemistocytes during microscopy. The calcifica-

**Histological diagnosis**. Under the microscope, we see a diffuse tumoral proliferation consisting of atypical fibrillary astrocytes. Hypercellularity is moderately increased, the tumor imperceptibly blending with the surrounding normal structures. Cellular proliferation (star-shaped cells, with extensions) is situated on a fibrillary loose matrix which often forms microcystic structures. The main characteristic is the nuclear atypia, neoplastic astrocytes being based on the aspect of the nucleus. This is enlarged, hyperchromatic, and irregular in shape [23].

The *differential diagnosis* is performed with the help of reactive astrocytosis. The diagnosis can be done only on the basis of morphological criteria, but more often than not, this requires an extremely nuanced approach. The morphological criteria include a numerical increase, but especially the homogeneous aspect of the nuclei, as we are dealing with a clonal neoplastic proliferation. As opposed to neoplastic astrocytes, the reactive ones have a heterogeneous nuclear aspect, with nuclei of various sizes and with cytoplasm in variable quantities. The background of these nuclei is of normal or increased density in the case of tumoral proliferation, and of decreased density in the case of reactive astrocytosis. Immunohistochemistry is extremely useful in distinguishing between reactive and tumoral astrocytes. As the IDH1 mutation falls under the definition of this type of tumor, the antibody identifying the protein altered by the presence of the R132H mutation can be used. Also, the tumoral cells displaying

Mitotic activity is low to absent, the presence of a mitosis in a large biopsy being compatible with the diagnosis. If a mitosis is present in the context of an important nuclear anaplasia within a small biopsy, then the diagnosis of anaplastic astrocytoma cannot be ruled out. The proliferation index determined by way of Ki-67 is under 4%. If there is a gemistocytic compo-

tions can be focal or diffuse, and in this case, the appearance is one of grittiness.

the TP53 mutation can be identified through a recourse to the antibody [24].

nent, the proliferation rate is significantly reduced [25].

/s or less is associated with a worst prognosis especially when it is combined

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of 0.9 × 10−3 mm2
