**7. Most common brain tumor types occurring in childhood**

The most common CNS tumors in children are: gliomas, ependymomas, neuroglial tumors, embryonal tumors, choroid plexus tumors, craniopharyngiomas and germ cell tumors.

#### **7.1. Gliomas**

full possible extent in the eloquent areas of the CNS. Use of 5-aminolevulic acid is very helpful in operations of HGG. Patient ingests this acid prior to surgery, and then during surgery, with use of fluorescence on the microscope, high-grade glial cells begin to gleam, which also contributes to performance of accurate resection and representative tumor sampling for histological examination. **Awake operations** with the possibility of intraoperative stimulation, in which the patient is conscious either during the entire procedure or in a certain part of it, are used in adult patients, especially in tumors in motor, sensory and speech areas. In children, it is significantly limited by age and ability to cooperate. They are mainly performed in older

According to extent of resection, we divide surgical treatment into: **total resection, near-total resection**, **partial resection** and **biopsy.** In most tumors (except well-defined benign tumors or well-defined metastases), total resection is only a radiological rather than a biological term. The surgical approach can serve (though not as a standard treatment method) for the targeted administration of radiotherapy in the form of **intraoperative radiotherapy** with a single irradiation of the tumor bed directly after resection of the tumor [16] **or chemotherapy**—for example, intraoperative administration of biodegradable carmustine [17]. In addition to **craniotomy**, other techniques—for example, **endonasal trans-sphenoidal approach**—can also be used, including endoscopy for pituitary tumor tumors. Another option for biopsy or tumor removal (often when located in brain ventricles) is **endoscopic surgery**. From other surgical methods, shunts in hydrocephalus can be used, most commonly **ventriculoperitoneal shunt**. Another option is implantation of Ommaya reservoir, which is useful for repeated sampling of CSF for laboratory examinations, for therapeutic evacuation puncture of CSF, as well as for

**Chemotherapy** is part of adjuvant oncological treatment after surgical resection alone or along with radiotherapy. It can be administered **systemically** (intravenously or orally), **locally** during surgery, or postoperatively into an implanted reservoir. Most serious side effects of chemotherapy are: bone marrow depression, nausea, vomiting, diarrhea and temporary hair loss. Generally, children better tolerate high doses of chemotherapy compared to adults, which

**Targeted biological therapy** is directed against the specific protein and gene targets of the tumor, or against the environment that affects its growth and survival. But even all tumors of the same histological type do not have the same alterations and the treatment goals. Therefore, it is essential to examine each tumor sample for the presence of altered genes and proteins in order to determine targeted individualized treatment. One of the best known drugs is bevacizumab with an antiangiogenic effect, which stops the nutrient intake into the tumor by blocking of angiogenesis. This treatment is used for HGG. However, the effect of this treatment is lower than expected. Therefore, it is reserved as supportive treatment in relapsing non-responding tumors. Also used is everolimus, the *mTOR* pathway blocker in the treatment of subependemal giant astrocytoma, or tyrosine kinase inhibitors, in particular *EGFR* (erlotinib and gefitinib) in the treatment of ependymomas [18]. Patients with HGG with a proven *BRAF V600E* mutation

also receive *BRAF* inhibitors (vemurafenib and dabrafenib) with partial effects [19].

**Radiotherapy** is also often used in treatment of pediatric brain tumors, either alone or as part of concomitant therapy. It uses high energy RTG beams to damage tumor cell DNA. It can

age groups of children [15].

112 Brain Tumors - An Update

the local administration of chemotherapy.

may increase the aggressiveness of treatment if necessary.

Glial tumors account for 55% of pediatric CNS tumors [3]. It is a heterogeneous group of tumors that varies from a well-defined, potentially curable low-grade pilocytic astrocytoma and diffusely growing astrocytomas (grade II) to high-grade, aggressive and incurable tumors, such as diffuse glioma of midline structures. They arise from CNS glial precursor cells: astrocytomas originate in astrocytes, oligodendrogliomas in oligodendrocytes, mixed gliomas are derived from astrocytes, oligodendrocytes and ependymal cells. The histologically most common glioma in children is astrocytoma.

#### *7.1.1. Low-grade gliomas in children*

The most common LGG in children are: pilocytic astrocytoma—PA (grade I), diffuse astrocytoma (grade II), oligodendroglioma (grade II), subependemal giant astrocytoma (SEGA) and pleomorphic xanthastrocytoma (PXA). The prognosis of LGG in children is relatively good, especially in well-defined grade I lesions with the possibility of total resection. Dissemination within the CNS is rare, but may be multifocal, especially in patients with neurofibromatosis type 1 syndrome [22]. Unfavorable prognostic factors include: low age, impossibility of total resection, diffuse growth (especially *IDH* mutated), diencephalic syndrome, presence of symptoms of intracranial hypertension and metastasis [23].

#### *7.1.1.1. Pilocytic astrocytoma WHO grade I*

This tumor is the most frequent LGG in children (up to 85%). Typical localizations are: cerebellum, diencephalon, optic tract, basal ganglia or brain stem [3]. Various localizations of this tumor also have their typical genetic characteristics. Its autosomal dominant forms are part of NF type 1 syndrome and tuberous sclerosis with typical localization over the course of the optical pathway, less often in hypothalamus. However, sporadic forms are more frequent. It may contain a *BRAF-KIAA* fusion that is connected to better prognosis. Conversely, the higher MIB-1 proliferation index is associated with shortened survival [24]. Therapy consists of surgical treatment. Despite the limited growth and the benign nature, the possibility of its removal is sometimes limited by its localization.

near the foramen Monroi [6]. Growth pattern is slow without infiltration of surrounding tissues. Surgical resection, if possible, is a modality of choice in treatment of this tumor. SEGA is one of few tumors with proven efficacy of targeted treatment with mTOR inhibitors, everoli-

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PXA is relatively rare tumor, which accounts for 0.5–1% of all CNS tumors in childhood [3], typically occurring supratentorially, especially in the temporal lobe. It grows in the cortex, sometimes infiltrating meninges [6]. The most common symptoms are epileptic seizures. Frequently, *V600E* mutation of the *BRAF* gene occurs, especially in temporal lobe localization [32]. This tumor may undergo malignant transformation into an anaplastic form, which is classified as a separate type of tumor in the new WHO classification, has grade III and belongs to the HGG. Like grade II pleomorphic xanthastrocytoma, it often shows a *V600E* mutation

High-grade gliomas account for 15–20% of all pediatric CNS tumors [3]. HGG in children include **anaplastic astrocytoma (grade III), glioblastoma** and its variants **(grade IV)** and **diffuse gliomas of midline structures** (including diffuse pontine glioma). They are characterized by very high mitotic activity and in grade IV also with presence of microvascular proliferation and necrosis as it is in adult HGG. Despite these common histological features, children's HGG differ from adult tumors by their typical localization, genetic alterations and clinical behaviors. Pediatric HGG almost always grow as primary malignancies and their malignant transformation from LGG is extremely rare [34]. Besides localization in cerebral hemispheres, which is also typical for adult forms of HGG, pediatric HGG occur more often in midline structures, such as thalamus, cerebellum or pons. Pontine HGG are typical for pediatric age group (account for 50% of all HGG in children) and have even worse prognosis than hemispheric tumors [35]. Children's HGGs (especially tumors in children under 3 years of age) have significantly less genetic alterations than adult forms [36]. On the basis of a recurring combination of genetic and epigenetic features and characteristic biological and clinical

**The** *K27* **subtype** is characteristically found in pons, thalamus and cerebellum in younger children. Its typical alterations are: mutation of *K27*, *TP53* and *ATRX* genes, *PDGFRA* amplification, *ACVR1* mutation (typical for localization in pons) and mutation of *FGFR1* which is typical for thalamic site of tumor. Among all subtypes it has the shortest survival—from 6 to

**The** *G34* **subtype** is more frequent in adolescents and young adults and typically grows in cerebral hemispheres. It most commonly contains mutations of the *G34*, *TP53* and *ATRX*

**The** *IDH* **subtype** with typical *IDH1*, *IDH2*, *TP53* and *ATRX* mutations, grows usually in the hemisphere. Tumors with *IDH* mutations account for less than 10% of children's HGG, they occur more commonly in adults. This type can also arise from malignant transformation of

genes. The survival time is about 1 year after the diagnosis is determined [37].

mus or sirolimus, which may also eliminate the necessity of surgical treatment [31].

*7.1.1.4. Pleomorphic xanthoastrocytoma WHO grade II*

behavior, 6 subtypes of HGG were determined (**Table 1**).

of the *BRAF* gene [33].

9 months [37, 38].

*7.1.2. High-grade gliomas in children*

Its subtype is a **pilomyxoid astrocytoma** with a typical angiocentric array of myxoid matrix. It is most common in infants and children of pre-school age with a typical hypothalamus and chiasm localization. Due to its localization, total resection is less probable and thus has a slightly worse prognosis compared to pilocytic astrocytoma [25].

#### *7.1.1.2. Diffuse gliomas WHO grade II*

Diffuse low-grade gliomas account for 10% of all LGG in children [3]. Histologically, most common types are: **astrocytoma**, **oligodendroglioma** and **mixed oligoastrocytoma**. The most frequent group is the diffuse astrocytoma (DA), which is mainly located in hemispheres (especially in the frontal and temporal lobe), brain stem, optic pathway, hypothalamus and thalamus. Although they may appear to be similar to diffuse gliomas of adulthood, they have different genetic characteristics and typical biological behavior. Unlike DA of adulthood, for which the presence of *IDH1* and *IDH2* mutations is typical, these are very rare in children. *MAPK* pathway and *BRAF* gene alterations are more common [26]. Unlike diffuse adult LGG, DA of pediatric type usually do not undergo malignant transformation into higher grade glioma, so their prognosis is more favorable. Especially in older children it is important to provide genetic diagnostics of the tumor type and differentiation between the more favorable type of LGG (DA without *IDH* mutation or diffuse oligodendroglioma without *IDH* mutation and 1p/19q co-deletion) and adult LGG type that may occur in older children and adolescents [27]. Up to 75% of adult LGG types in childhood are subject of malignant transformation. Treatment consists of surgical removal of the tumor and subsequent observation, but their infiltrative growth pattern generally does not allow their total resection. In case of relapse and progress in tumor growth, chemotherapy with carboplatin (with or without vincristine) may be used. Alternatively, the TPCV regimen (thioguanine, procarbazine, lomustine and vincristine) may be used, rarely in the second line with vinblastine and temozolomide. In relapsing non-responding tumors, bevacizumab is given in combination with irinotecan [28] and in some cases accompanied with radiotherapy. For early and late side effects of radiation, chemotherapy is preferred in children (in opposite to adult treatment). In pediatric patients, tumor localization and age at diagnosis are stronger factors for choosing therapy modality than the histological characteristics of the tumor itself [29, 30].

#### *7.1.1.3. Subependymal giant cell astrocytoma WHO grade I*

This tumor type is most frequently diagnosed in patients with tuberous sclerosis and mutations in *TSC1* and *TSC2* genes. Its typical location is a lateral ventricle, mostly growing subependymal near the foramen Monroi [6]. Growth pattern is slow without infiltration of surrounding tissues. Surgical resection, if possible, is a modality of choice in treatment of this tumor. SEGA is one of few tumors with proven efficacy of targeted treatment with mTOR inhibitors, everolimus or sirolimus, which may also eliminate the necessity of surgical treatment [31].

#### *7.1.1.4. Pleomorphic xanthoastrocytoma WHO grade II*

PXA is relatively rare tumor, which accounts for 0.5–1% of all CNS tumors in childhood [3], typically occurring supratentorially, especially in the temporal lobe. It grows in the cortex, sometimes infiltrating meninges [6]. The most common symptoms are epileptic seizures. Frequently, *V600E* mutation of the *BRAF* gene occurs, especially in temporal lobe localization [32]. This tumor may undergo malignant transformation into an anaplastic form, which is classified as a separate type of tumor in the new WHO classification, has grade III and belongs to the HGG. Like grade II pleomorphic xanthastrocytoma, it often shows a *V600E* mutation of the *BRAF* gene [33].

#### *7.1.2. High-grade gliomas in children*

*7.1.1.1. Pilocytic astrocytoma WHO grade I*

114 Brain Tumors - An Update

removal is sometimes limited by its localization.

*7.1.1.2. Diffuse gliomas WHO grade II*

slightly worse prognosis compared to pilocytic astrocytoma [25].

*7.1.1.3. Subependymal giant cell astrocytoma WHO grade I*

This tumor is the most frequent LGG in children (up to 85%). Typical localizations are: cerebellum, diencephalon, optic tract, basal ganglia or brain stem [3]. Various localizations of this tumor also have their typical genetic characteristics. Its autosomal dominant forms are part of NF type 1 syndrome and tuberous sclerosis with typical localization over the course of the optical pathway, less often in hypothalamus. However, sporadic forms are more frequent. It may contain a *BRAF-KIAA* fusion that is connected to better prognosis. Conversely, the higher MIB-1 proliferation index is associated with shortened survival [24]. Therapy consists of surgical treatment. Despite the limited growth and the benign nature, the possibility of its

Its subtype is a **pilomyxoid astrocytoma** with a typical angiocentric array of myxoid matrix. It is most common in infants and children of pre-school age with a typical hypothalamus and chiasm localization. Due to its localization, total resection is less probable and thus has a

Diffuse low-grade gliomas account for 10% of all LGG in children [3]. Histologically, most common types are: **astrocytoma**, **oligodendroglioma** and **mixed oligoastrocytoma**. The most frequent group is the diffuse astrocytoma (DA), which is mainly located in hemispheres (especially in the frontal and temporal lobe), brain stem, optic pathway, hypothalamus and thalamus. Although they may appear to be similar to diffuse gliomas of adulthood, they have different genetic characteristics and typical biological behavior. Unlike DA of adulthood, for which the presence of *IDH1* and *IDH2* mutations is typical, these are very rare in children. *MAPK* pathway and *BRAF* gene alterations are more common [26]. Unlike diffuse adult LGG, DA of pediatric type usually do not undergo malignant transformation into higher grade glioma, so their prognosis is more favorable. Especially in older children it is important to provide genetic diagnostics of the tumor type and differentiation between the more favorable type of LGG (DA without *IDH* mutation or diffuse oligodendroglioma without *IDH* mutation and 1p/19q co-deletion) and adult LGG type that may occur in older children and adolescents [27]. Up to 75% of adult LGG types in childhood are subject of malignant transformation. Treatment consists of surgical removal of the tumor and subsequent observation, but their infiltrative growth pattern generally does not allow their total resection. In case of relapse and progress in tumor growth, chemotherapy with carboplatin (with or without vincristine) may be used. Alternatively, the TPCV regimen (thioguanine, procarbazine, lomustine and vincristine) may be used, rarely in the second line with vinblastine and temozolomide. In relapsing non-responding tumors, bevacizumab is given in combination with irinotecan [28] and in some cases accompanied with radiotherapy. For early and late side effects of radiation, chemotherapy is preferred in children (in opposite to adult treatment). In pediatric patients, tumor localization and age at diagnosis are stronger factors for choosing therapy modality than the histological characteristics of the tumor itself [29, 30].

This tumor type is most frequently diagnosed in patients with tuberous sclerosis and mutations in *TSC1* and *TSC2* genes. Its typical location is a lateral ventricle, mostly growing subependymal High-grade gliomas account for 15–20% of all pediatric CNS tumors [3]. HGG in children include **anaplastic astrocytoma (grade III), glioblastoma** and its variants **(grade IV)** and **diffuse gliomas of midline structures** (including diffuse pontine glioma). They are characterized by very high mitotic activity and in grade IV also with presence of microvascular proliferation and necrosis as it is in adult HGG. Despite these common histological features, children's HGG differ from adult tumors by their typical localization, genetic alterations and clinical behaviors. Pediatric HGG almost always grow as primary malignancies and their malignant transformation from LGG is extremely rare [34]. Besides localization in cerebral hemispheres, which is also typical for adult forms of HGG, pediatric HGG occur more often in midline structures, such as thalamus, cerebellum or pons. Pontine HGG are typical for pediatric age group (account for 50% of all HGG in children) and have even worse prognosis than hemispheric tumors [35]. Children's HGGs (especially tumors in children under 3 years of age) have significantly less genetic alterations than adult forms [36]. On the basis of a recurring combination of genetic and epigenetic features and characteristic biological and clinical behavior, 6 subtypes of HGG were determined (**Table 1**).

**The** *K27* **subtype** is characteristically found in pons, thalamus and cerebellum in younger children. Its typical alterations are: mutation of *K27*, *TP53* and *ATRX* genes, *PDGFRA* amplification, *ACVR1* mutation (typical for localization in pons) and mutation of *FGFR1* which is typical for thalamic site of tumor. Among all subtypes it has the shortest survival—from 6 to 9 months [37, 38].

**The** *G34* **subtype** is more frequent in adolescents and young adults and typically grows in cerebral hemispheres. It most commonly contains mutations of the *G34*, *TP53* and *ATRX* genes. The survival time is about 1 year after the diagnosis is determined [37].

**The** *IDH* **subtype** with typical *IDH1*, *IDH2*, *TP53* and *ATRX* mutations, grows usually in the hemisphere. Tumors with *IDH* mutations account for less than 10% of children's HGG, they occur more commonly in adults. This type can also arise from malignant transformation of


**Table 1.** Characterization of pediatric HGG subtypes. LGG, what is generally rare in children. According to prognosis, this type belongs to more

**The** *RTK-I* **(receptor tyrosine kinase inhibitor) subtype** grows in cerebral hemispheres and occurs throughout the pediatric age spectrum. Typically, it includes: amplification of

**Mesenchymal subtype** is most common among adolescents and young adults. It also occurs in cerebral hemispheres and contains mutations of *NF1* and *TP53*, amplification of *PDGFRA*

The last subtype is **epithelioid glioblastoma** which is similar to pleomorphic xanthoastro

cytoma. It grows in cerebral hemispheres, in younger children and typically displays *BRAF V600E* mutation and *CDKN2A* deletion. It belongs to most favorable subtypes with a survival

The presence of oncogene amplification, such as *MYCN*, *PDGFR* and *EGFR*, is associated with a worse prognosis in all types [40]. The most important prognostic factor is histological tumor grading and the extent of surgical resection. Radiotherapy is used in subsequent oncological treatment. Its combination with chemotherapy with temozolomide is therapeutically less suc

cessful than in adults [35]. Lomustine, vincristine and prednisone may also be used in chemo

therapy. In case of recurrent HGG, repeated resection is considered individually, depending on the histological nature of the original tumor, the recurrence localization or the length of the progression free period. Reoperation could be also necessary for obtaining of fresh tis

sue samples for targeted treatment or for local administration of chemotherapy. In patients whose initial treatment failed, high-dose chemotherapy with total bone marrow suppression and subsequent hematopoietic stem cell transplantation [41] or clinical trial of new treatment modalities may be attempted. Molecular targets are very limited. Patients with *BRAF V600E* mutation are tested for BRAF inhibitors (vemurafenib and dabrafenib) with partial effect [19].

The previous WHO classification is also called diffuse intrinsic pontine glioma (DIPG). The new edition classifies this tumor as diffuse midline glioma because it also appears in thalamus, cerebellum and spinal cord. It is predominantly considered childhood tumor,

H3 gene *H3F3A* (less frequently the *HIST1H3B* gene) and grows typically diffusely and infiltrates surrounding tissues [37]. It is classified as WHO grade IV, regardless of the pres

ence or absence of anaplastic features [12]. A tumor growing in the ventral pontine region is a highly aggressive, destructive neoplasm that accounts for up to 80% of all glioma in the brain stem of children. The mean age at diagnosis is 6–7 years and median survival is 9 months [42]. Cranial nerve lesions, long-tract lesion symptoms, ataxia and behavioral disorders appear as leading clinical symptoms. The first symptom is often the abducens nerve palsy, which is also a negative prognostic factor. Also facial nerve palsy may occur. Obstruction of CSF pathways could lead to hydrocephalus [43]. Typically, on MR image

/*CDKN2B* deletion. Patients with this tumor

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117





*M* mutation of the histone

/*CDKN2B.* It also belongs to worse types according to

favorable subtypes with a survival period of more than 2 years [34, 38].

subtype have a worse prognosis of survival, generally within 1 year [36, 38].

*PDGFRA* and *EGFR*, *TP53* mutation and *CDKN2A*

prognosis, with a survival of up to 1 year [36, 38, 39].

6, 12].

*7.1.2.1. Diffuse midline glioma, H3 K27 M-mutant*

although it may also occur in adults. It contains a typical *K27*

and *EGFR* and deletion of *CDKN2A*

of more than 4 years [

LGG, what is generally rare in children. According to prognosis, this type belongs to more favorable subtypes with a survival period of more than 2 years [34, 38].

**The** *RTK-I* **(receptor tyrosine kinase inhibitor) subtype** grows in cerebral hemispheres and occurs throughout the pediatric age spectrum. Typically, it includes: amplification of *PDGFRA* and *EGFR*, *TP53* mutation and *CDKN2A*/*CDKN2B* deletion. Patients with this tumor subtype have a worse prognosis of survival, generally within 1 year [36, 38].

**Mesenchymal subtype** is most common among adolescents and young adults. It also occurs in cerebral hemispheres and contains mutations of *NF1* and *TP53*, amplification of *PDGFRA* and *EGFR* and deletion of *CDKN2A*/*CDKN2B.* It also belongs to worse types according to prognosis, with a survival of up to 1 year [36, 38, 39].

The last subtype is **epithelioid glioblastoma** which is similar to pleomorphic xanthoastrocytoma. It grows in cerebral hemispheres, in younger children and typically displays *BRAF V600E* mutation and *CDKN2A* deletion. It belongs to most favorable subtypes with a survival of more than 4 years [6, 12].

The presence of oncogene amplification, such as *MYCN*, *PDGFR* and *EGFR*, is associated with a worse prognosis in all types [40]. The most important prognostic factor is histological tumor grading and the extent of surgical resection. Radiotherapy is used in subsequent oncological treatment. Its combination with chemotherapy with temozolomide is therapeutically less successful than in adults [35]. Lomustine, vincristine and prednisone may also be used in chemotherapy. In case of recurrent HGG, repeated resection is considered individually, depending on the histological nature of the original tumor, the recurrence localization or the length of the progression free period. Reoperation could be also necessary for obtaining of fresh tissue samples for targeted treatment or for local administration of chemotherapy. In patients whose initial treatment failed, high-dose chemotherapy with total bone marrow suppression and subsequent hematopoietic stem cell transplantation [41] or clinical trial of new treatment modalities may be attempted. Molecular targets are very limited. Patients with *BRAF V600E* mutation are tested for BRAF inhibitors (vemurafenib and dabrafenib) with partial effect [19].

#### *7.1.2.1. Diffuse midline glioma, H3 K27 M-mutant*

**Type**

Age Typical

Cerebellum, pons, spinal cord,

Brain

Brain

Brain hemispheres

Brain hemispheres

hemispheres

hemispheres

*H3.3*, mut. *G34,* 

mut. *IDH1, IDH2,* 

ampl. *PDGFRA, EGFR*,

mut. *NF1, TP53*, ampl.

mut. *BRAF V600E*,

del. *CDKN2A*

*PDGFRA, EGFR*, del.

*CDKN2A/CDKN2B*

mut. *TP53*, del. *CDKN2A/*

*CDKN2B*

*ATRX, TP53*

*TP53, ATRX*

location

Typical

*H3.3* or *H3.1*

mut. *K27, TP53, ATRX, ACVR1*

(pons), *FGFR1* (thalamus),

ampl. *PDGFRA*

Gene

Proneural

Mixed

Proneural

Proneural

Mesenchymal

Unknown

expression

Median

6 months

1 year

>2 years

1 year

1 year

>4 years

survival

Mut., mutation; ampl., amplification, del., deletion [38].

**Table 1.**

Characterization of pediatric HGG subtypes.

alteration

thalamus

Young child

**K27**

**G34** Adolescent

Adolescent

All

**IDH**

**RTK-I**

**Mesenchymal**

Adolescent

**Epitheloid**

Young child

Brain hemispheres

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The previous WHO classification is also called diffuse intrinsic pontine glioma (DIPG). The new edition classifies this tumor as diffuse midline glioma because it also appears in thalamus, cerebellum and spinal cord. It is predominantly considered childhood tumor, although it may also occur in adults. It contains a typical *K27 M* mutation of the histone H3 gene *H3F3A* (less frequently the *HIST1H3B* gene) and grows typically diffusely and infiltrates surrounding tissues [37]. It is classified as WHO grade IV, regardless of the presence or absence of anaplastic features [12]. A tumor growing in the ventral pontine region is a highly aggressive, destructive neoplasm that accounts for up to 80% of all glioma in the brain stem of children. The mean age at diagnosis is 6–7 years and median survival is 9 months [42]. Cranial nerve lesions, long-tract lesion symptoms, ataxia and behavioral disorders appear as leading clinical symptoms. The first symptom is often the abducens nerve palsy, which is also a negative prognostic factor. Also facial nerve palsy may occur. Obstruction of CSF pathways could lead to hydrocephalus [43]. Typically, on MR image tumor occupies more than half of the axial diameter of the pons. It has no exact boarders and does not enhance after gadolinium administration. Due to the typical MRI image and its localization, biopsy is rarely indicated, but in some cases stereotactic biopsy could be beneficial [44]. This tumor is known to spread to the distal parts of the brain stem and along the white matter tract to both the cerebellum and the thalamus in over half of the patients. Supratentorial spreading and leptomeningeal dissemination are uncommon [39]. Total resection due to its localization and growth pattern is not possible, so the most common treatment is radiotherapy, which helps to control symptoms and generally prolongs patient's survival. Because of the known CNS spread, irradiation of the entire head or the entire neural axis is sometimes chosen [39]. Systemic administration of chemotherapeutic agents has been shown to be ineffective for insufficient passage through the hematoencephalic barrier to pons [45]. The administration of chemotherapy (especially topotecan) is also attempted locally, directly to the tumor, using a stereotactic catheter. However, the results are not yet clear [46]. Children under age of 3 have a slightly better prognosis, probably due to different molecular genetic characteristics [47].

Up to 70% of **supratentorially localized ependymomas** harbor fusion of *C11orf95-RELA* on chromosome 11q [50]. This change never occurs when locating in the posterior fossa. The discovery of the presence of this fusion was so significant that in the new WHO classification of brain tumors from 2016 the **ependymoma with the** *RELA* **fusion** was classified as a separate entity [12]. Homozygous deletion of *CDKN2A* with or without the presence of duplication of 1q is a negative prognostic factor [53]. The most frequent occurrence is in children with an average age of 8 years. **The fusion of** *YAP1* (with *MAMLD1* or *FAM118B*) occurs in supratentorially localized ependymomas without *RELA* fusion. These tumors are more common in younger children with an average age of 1.4 years. From all ependymomas, the worst prognosis has supratentorial *RELA* positive tumors and group A ependymomas in the posterior fossa. At the same time, they are the most common forms (together make up two-thirds of all

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Therapeutic modality is extensive surgical removal followed by radiotherapy, which can only be used in the treatment of children aged more than 1 year. Currently, the use of chemotherapy (especially vincristine, cyclophosphamide, cisplatin and etoposide) is in clinical trials [38]. The choice of the treatment scheme determines the age of the child, the histological type of tumor, the extent of the resection performed and the presence of dissemination in the CSF pathways.

It is a heterogeneous group of tumors with neuronal or mixed neuroglial morphology. They are mostly grade I, but their anaplastic forms can also occur. Following tumors are most fre-

These grade I tumors account for 0.5% of CNS childhood tumors [3]. They occur almost exclusively in children under 2 years of age. MRI verifies a large cystic tumor, especially in the frontal or parietal lobe. They are histologically and genetically almost identical, the only difference between them is the neoplastic neuronal component. Approximately 40% of these

These tumors are characterized by a combination of neoplastic ganglion cells with a glial component similar to PA or diffuse glioma (especially astrocytoma). They occur mainly supratentorially. Seizures are usually leading symptom [33]. GG often harbor *BRAF V600E* mutation. The glial component of GG can undergo malignant transformation to anaplastic form that has higher mitotic activity, endothelial proliferation and necrosis in 3–5%. Up to half of the anaplastic GG is characterized by the presence of the *BRAF V600E* mutation, a minor part of

It is a low-grade tumor (grade I), which occurs mainly supratentorially in the temporal lobe. It often manifests as drug-resistant epilepsy. There are several histological subtypes, which do

tumors display *MET* amplification and about 10% also *BRAF V600E* mutation [54].

ependymomas) that occur predominantly in children [53].

*7.2.1. Desmoplastic infantile astrocytoma (DIA) and ganglioglioma (DIGG)*

**7.2. Neuronal and mixed neuronal-glial tumors**

*7.2.3. Dysembryoplastic neuroepithelial tumor (DNET)*

quently present in children.

*7.2.2. Ganglioglioma (GG)*

the *TP53* mutation [6].

#### *7.1.3. Ependymomas*

Ependymomas are tumors originating from ependymal cells, which form a lining of CSF pathways and produce cerebrospinal fluid. They form the second most common group of children's CNS malignancies. They occur supratentorially, in the posterior fossa and in the spinal cord, mostly in children under 10 years of age [48]. Clinical signs depend on localization. In the most frequent, infratentorial localization, they present with the development of obstructive hydrocephalus, ataxia, cervical spinal pain and symptoms of cranial nerve lesion can also be present. Supratentorial localization often causes headaches, epileptic seizures and depending on localization, the development of focal neurological deficit. In case of suspicion on ependymoma, it is necessary to realize the MRI of whole craniospinal axis even before surgery. If possible, lumbar puncture with CSF sampling is recommended.

Ependymomas could be histologically: **subependymoma (grade I), myxopapillary ependymoma (grade I), ependymoma (grade II), ependymoma,** *RELA* **fusion-positive (grade II—III)** and **anaplastic ependymoma (grade III)**. Subependymoma and myxopapillary ependymoma appear almost exclusively in adults. The existence of several molecular subtypes of ependymomas, which differ in their localization, molecular genetic characteristics, typical age group of patients and prognosis, are known.

Two genetically distinct subgroups are distinguished in **ependymomas of posterior fossa** localization [49]. **Group A** occurs more frequently (up to half the ependymomas of all localizations) affecting predominantly younger children (3 years of age) and has a worse prognosis. In these tumors, fewer gene alterations occur and the *VEGF*, *PDGFR*, integrin and *MAPK* signaling pathways are most commonly affected [50]. Epigenetic suppression of differentiation genes is often present in this group of tumors [51]. Duplication of 1q occurs in 25% of group A ependymomas and it is a common negative prognostic feature [52]. Less frequently occurring **group B** affects predominantly adolescents and young adults. It contains frequent chromosome changes and its prognosis is more favorable than in group A. In both groups, the mutation rate is relatively low and gene mutations occur sporadically [50].

Up to 70% of **supratentorially localized ependymomas** harbor fusion of *C11orf95-RELA* on chromosome 11q [50]. This change never occurs when locating in the posterior fossa. The discovery of the presence of this fusion was so significant that in the new WHO classification of brain tumors from 2016 the **ependymoma with the** *RELA* **fusion** was classified as a separate entity [12]. Homozygous deletion of *CDKN2A* with or without the presence of duplication of 1q is a negative prognostic factor [53]. The most frequent occurrence is in children with an average age of 8 years. **The fusion of** *YAP1* (with *MAMLD1* or *FAM118B*) occurs in supratentorially localized ependymomas without *RELA* fusion. These tumors are more common in younger children with an average age of 1.4 years. From all ependymomas, the worst prognosis has supratentorial *RELA* positive tumors and group A ependymomas in the posterior fossa. At the same time, they are the most common forms (together make up two-thirds of all ependymomas) that occur predominantly in children [53].

Therapeutic modality is extensive surgical removal followed by radiotherapy, which can only be used in the treatment of children aged more than 1 year. Currently, the use of chemotherapy (especially vincristine, cyclophosphamide, cisplatin and etoposide) is in clinical trials [38]. The choice of the treatment scheme determines the age of the child, the histological type of tumor, the extent of the resection performed and the presence of dissemination in the CSF pathways.

#### **7.2. Neuronal and mixed neuronal-glial tumors**

It is a heterogeneous group of tumors with neuronal or mixed neuroglial morphology. They are mostly grade I, but their anaplastic forms can also occur. Following tumors are most frequently present in children.

#### *7.2.1. Desmoplastic infantile astrocytoma (DIA) and ganglioglioma (DIGG)*

These grade I tumors account for 0.5% of CNS childhood tumors [3]. They occur almost exclusively in children under 2 years of age. MRI verifies a large cystic tumor, especially in the frontal or parietal lobe. They are histologically and genetically almost identical, the only difference between them is the neoplastic neuronal component. Approximately 40% of these tumors display *MET* amplification and about 10% also *BRAF V600E* mutation [54].

#### *7.2.2. Ganglioglioma (GG)*

tumor occupies more than half of the axial diameter of the pons. It has no exact boarders and does not enhance after gadolinium administration. Due to the typical MRI image and its localization, biopsy is rarely indicated, but in some cases stereotactic biopsy could be beneficial [44]. This tumor is known to spread to the distal parts of the brain stem and along the white matter tract to both the cerebellum and the thalamus in over half of the patients. Supratentorial spreading and leptomeningeal dissemination are uncommon [39]. Total resection due to its localization and growth pattern is not possible, so the most common treatment is radiotherapy, which helps to control symptoms and generally prolongs patient's survival. Because of the known CNS spread, irradiation of the entire head or the entire neural axis is sometimes chosen [39]. Systemic administration of chemotherapeutic agents has been shown to be ineffective for insufficient passage through the hematoencephalic barrier to pons [45]. The administration of chemotherapy (especially topotecan) is also attempted locally, directly to the tumor, using a stereotactic catheter. However, the results are not yet clear [46]. Children under age of 3 have a slightly better prognosis, prob-

Ependymomas are tumors originating from ependymal cells, which form a lining of CSF pathways and produce cerebrospinal fluid. They form the second most common group of children's CNS malignancies. They occur supratentorially, in the posterior fossa and in the spinal cord, mostly in children under 10 years of age [48]. Clinical signs depend on localization. In the most frequent, infratentorial localization, they present with the development of obstructive hydrocephalus, ataxia, cervical spinal pain and symptoms of cranial nerve lesion can also be present. Supratentorial localization often causes headaches, epileptic seizures and depending on localization, the development of focal neurological deficit. In case of suspicion on ependymoma, it is necessary to realize the MRI of whole craniospinal axis even before

Ependymomas could be histologically: **subependymoma (grade I), myxopapillary ependymoma (grade I), ependymoma (grade II), ependymoma,** *RELA* **fusion-positive (grade II—III)** and **anaplastic ependymoma (grade III)**. Subependymoma and myxopapillary ependymoma appear almost exclusively in adults. The existence of several molecular subtypes of ependymomas, which differ in their localization, molecular genetic characteristics, typical age

Two genetically distinct subgroups are distinguished in **ependymomas of posterior fossa** localization [49]. **Group A** occurs more frequently (up to half the ependymomas of all localizations) affecting predominantly younger children (3 years of age) and has a worse prognosis. In these tumors, fewer gene alterations occur and the *VEGF*, *PDGFR*, integrin and *MAPK* signaling pathways are most commonly affected [50]. Epigenetic suppression of differentiation genes is often present in this group of tumors [51]. Duplication of 1q occurs in 25% of group A ependymomas and it is a common negative prognostic feature [52]. Less frequently occurring **group B** affects predominantly adolescents and young adults. It contains frequent chromosome changes and its prognosis is more favorable than in group A. In both groups, the

surgery. If possible, lumbar puncture with CSF sampling is recommended.

mutation rate is relatively low and gene mutations occur sporadically [50].

group of patients and prognosis, are known.

ably due to different molecular genetic characteristics [47].

*7.1.3. Ependymomas*

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These tumors are characterized by a combination of neoplastic ganglion cells with a glial component similar to PA or diffuse glioma (especially astrocytoma). They occur mainly supratentorially. Seizures are usually leading symptom [33]. GG often harbor *BRAF V600E* mutation. The glial component of GG can undergo malignant transformation to anaplastic form that has higher mitotic activity, endothelial proliferation and necrosis in 3–5%. Up to half of the anaplastic GG is characterized by the presence of the *BRAF V600E* mutation, a minor part of the *TP53* mutation [6].

#### *7.2.3. Dysembryoplastic neuroepithelial tumor (DNET)*

It is a low-grade tumor (grade I), which occurs mainly supratentorially in the temporal lobe. It often manifests as drug-resistant epilepsy. There are several histological subtypes, which do not differ in typical age of origin, the nature of epileptic seizures or prognosis. Most of these tumors show alterations of *FGFR1* and *BRAF V600E* mutation [27].

Desmoplastic nodular type is typical for patients over 17 years of age [56]. Genetic alterations also vary by age category. Mutation of *SUFU* gene is commonly present in age group up to 4 years, whereas *SMO* mutation occurs mainly in patients over 17 years of age. Between 4 and 17 years of age, amplification of *MYCN* and *GLI2* occurs. *PTCH1* alterations and *TERT* promoter mutation occur in all age categories [57]. While MBs of children under 4 years with extensive nodularity generally have a better prognosis, MBs with large cell anaplastic characteristics, presence of *MYCN* amplification or *TP53* mutation are very aggressive. They tend to metastasize within the CNS, and therefore are associated with a very poor prognosis [55, 56]. *SHH*-activated MBs with *TP53* mutation are classified separately. In children with *TP53* muta-

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Non-*WNT*/non-*SHH* MB is divided into **group 3** and **group 4**. While group 3 forms 15%, group 4 45% of all MBs. Although genetically different, some characteristics and genetic alterations are common. There is a higher occurrence in boys in both groups, structural anomalies are common—especially the formation of isochromosome 17q. A structural alteration that aberrantly induces the activity of *GFI1* or *GF1B* proto-oncogenes is common in both groups, particularly in group 3 [59]. The worst prognosis of all types has group 3 (particularly in boys), with large cell anaplastic morphology and with proven *MYC* over-expression and amplification. Group 4 is the most common molecular type with a pronounced predominance in boys. Nearly all tumors in this group have classic morphology. The prognosis of patient survival is moderate—except those with proven *MYC* amplification, which have worse prognosis [55]. Patients with metastasis present at diagnosis have a high risk of relapse, with the exception of patients with isochromosome 17, who make up a subgroup with more favorable

The diagnosis is based on preoperative MRI examination of the craniospinal axis. Over the past 30 years, the most fundamental shift has been made in treatment of MB among all CNS childhood tumors and has changed from a fatal disease to a tumor with a 70% curability. The basis is surgical treatment with the maximal possible extent of resection. In the postoperative period, MRI is again indicated to evaluate the postoperative residue and the examination of cerebrospinal fluid is also beneficial. Medulloblastoma has as one of the few CNS tumors **staging system** that has 5 degrees (M0 = not disseminated, M1 = positive cytology of CSF without MR image of dissemination, M2 = nodular proliferation in cerebellar and cerebral subarachnoid spaces and in ventricles, M3 = nodular proliferation in spinal subarachnoid spaces, M4 = extra-neural propagation). Surgery is followed by chemotherapy and radiotherapy with whole CNS irradiation for frequent dissemination of medulloblastoma within the CNS. The chemotherapy regimens use either a combination of cisplatin, lomustine and vincristine or a combination of cisplatin, cyclophosphamide and vincristine [61]. Radiotherapy is administered at a dose of 54 Gy targeted to the tumor bed, followed by irradiation of the craniospinal axis at a dose of 24–36 Gy. The introduction of chemotherapy into the treatment scheme reduced the dose necessary to irradiate the craniospinal axis, thereby reducing the incidence of side effects of radiation [62]. However, radiotherapy in children under 3 years of age is not used for serious adverse effects on brain development. To potentiate the effects of standard chemotherapy, methotrexate is concomitantly administered to children under

tion, it is often a germline mutation that is part of the Li-Fraumeni syndrome [58].

prognosis [60].

3 years, either systemically or locally [63].

#### **7.3. Embryonal tumors**

This group of tumors originates from embryonal cells that remain present in the CNS after birth. They are the most common childhood malignant CNS tumors (15–20%) in children under the age of 14 [12]. In adults, they are extremely rare. Most frequently occurring embryonal tumors are: meduloblastoma, atypical teratoid/rhabdoid tumor and CNS embryonal tumors (better known under the older name CNS primitive neuroectodermal tumors—PNETs). All tumors of this group tend to spread along the CFS pathways. Therefore, it is recommended to perform MR of whole craniospinal axis prior to surgery. CSF sampling is also indicated, as the finding of circulating tumor cells can appear earlier than dissemination in MRI. The prognosis of embryonic tumors depends on the age of the patient, dissemination of the tumor within CNS at the time of diagnosis, the size of the postoperative residue and on the histopathological and molecular biological properties of the tumor.

#### *7.3.1. Medulloblastoma (MB)*

It is the most common malignant brain tumor type in children. MB is a group of lesions that differ significantly by their genetic alterations, histological features and prognosis. In all cases, however, they are grade IV and fast-growing. Characteristic localization is infratentorial and leptomeningeal spread is typical. MB often manifests by symptoms of intracranial hypertension and blockage of CSF pathways as well as other symptoms, such as ataxia and nystagmus. Medulloblastoma may also occur as part of hereditary syndromes: Turcot, Rubinstein-Taybi, Gorlin, Li-Fraumeni syndrome and Fanconi anemia. There are four **histological variants** (classic type, desmoplastic nodular type, medulloblastoma with extensive nodularity and large cell and anaplastic type) and four subtypes depending on the signal pathway involved or genes altered: *WNT* (10%), *SHH* (30%), group 3 (15%) and group 4 (45%). WHO classification of brain tumors from 2016 classifies genetically defined MB into: *WNT-*activated, *SHH-*activated and *TP53*-mutant, *SHH*-activated and *TP53*-wildtype and non-*WNT*/non-*SHH* medulloblastoma, which is divided into MB group3 and MB group 4 [12].

**The** *WNT* **medulloblastoma** is the less frequent group (10%), which is typically found in the brain stem area in children aged 10. Often displays classic histology. The incidence of CNS metastases is very low. Activation of the *WNT* signaling pathway is characteristic [55]. About 90% of these tumors present with *CTNNB1* mutation. Mutations of *DDX3X,* chromatin remodeling genes and *TP53* are also common. *TP53* mutation in this type of tumor is not associated with a worse prognosis as it is in *TP53* mutated *SHH* MB. In general, *WNT*-activated MB has a very good prognosis.

**The** *SHH* **group** of medulloblastomas accounts for 30% of all MB and is the most heterogeneous. All histological types could occur. Dominant localization is in cerebral hemispheres. The most commonly affected age group is up to 4 years of age and then adolescents over 17 years of age. In children up to 4 years of age, it is most commonly present MB with extensive nodularity and in group 4–17 years of age, it is classic and large cell anaplastic type. Desmoplastic nodular type is typical for patients over 17 years of age [56]. Genetic alterations also vary by age category. Mutation of *SUFU* gene is commonly present in age group up to 4 years, whereas *SMO* mutation occurs mainly in patients over 17 years of age. Between 4 and 17 years of age, amplification of *MYCN* and *GLI2* occurs. *PTCH1* alterations and *TERT* promoter mutation occur in all age categories [57]. While MBs of children under 4 years with extensive nodularity generally have a better prognosis, MBs with large cell anaplastic characteristics, presence of *MYCN* amplification or *TP53* mutation are very aggressive. They tend to metastasize within the CNS, and therefore are associated with a very poor prognosis [55, 56]. *SHH*-activated MBs with *TP53* mutation are classified separately. In children with *TP53* mutation, it is often a germline mutation that is part of the Li-Fraumeni syndrome [58].

not differ in typical age of origin, the nature of epileptic seizures or prognosis. Most of these

This group of tumors originates from embryonal cells that remain present in the CNS after birth. They are the most common childhood malignant CNS tumors (15–20%) in children under the age of 14 [12]. In adults, they are extremely rare. Most frequently occurring embryonal tumors are: meduloblastoma, atypical teratoid/rhabdoid tumor and CNS embryonal tumors (better known under the older name CNS primitive neuroectodermal tumors—PNETs). All tumors of this group tend to spread along the CFS pathways. Therefore, it is recommended to perform MR of whole craniospinal axis prior to surgery. CSF sampling is also indicated, as the finding of circulating tumor cells can appear earlier than dissemination in MRI. The prognosis of embryonic tumors depends on the age of the patient, dissemination of the tumor within CNS at the time of diagnosis, the size of the postoperative residue and on the histopathologi-

It is the most common malignant brain tumor type in children. MB is a group of lesions that differ significantly by their genetic alterations, histological features and prognosis. In all cases, however, they are grade IV and fast-growing. Characteristic localization is infratentorial and leptomeningeal spread is typical. MB often manifests by symptoms of intracranial hypertension and blockage of CSF pathways as well as other symptoms, such as ataxia and nystagmus. Medulloblastoma may also occur as part of hereditary syndromes: Turcot, Rubinstein-Taybi, Gorlin, Li-Fraumeni syndrome and Fanconi anemia. There are four **histological variants** (classic type, desmoplastic nodular type, medulloblastoma with extensive nodularity and large cell and anaplastic type) and four subtypes depending on the signal pathway involved or genes altered: *WNT* (10%), *SHH* (30%), group 3 (15%) and group 4 (45%). WHO classification of brain tumors from 2016 classifies genetically defined MB into: *WNT-*activated, *SHH-*activated and *TP53*-mutant, *SHH*-activated and *TP53*-wildtype and non-*WNT*/non-*SHH*

**The** *WNT* **medulloblastoma** is the less frequent group (10%), which is typically found in the brain stem area in children aged 10. Often displays classic histology. The incidence of CNS metastases is very low. Activation of the *WNT* signaling pathway is characteristic [55]. About 90% of these tumors present with *CTNNB1* mutation. Mutations of *DDX3X,* chromatin remodeling genes and *TP53* are also common. *TP53* mutation in this type of tumor is not associated with a worse prognosis as it is in *TP53* mutated *SHH* MB. In general, *WNT*-activated

**The** *SHH* **group** of medulloblastomas accounts for 30% of all MB and is the most heterogeneous. All histological types could occur. Dominant localization is in cerebral hemispheres. The most commonly affected age group is up to 4 years of age and then adolescents over 17 years of age. In children up to 4 years of age, it is most commonly present MB with extensive nodularity and in group 4–17 years of age, it is classic and large cell anaplastic type.

medulloblastoma, which is divided into MB group3 and MB group 4 [12].

tumors show alterations of *FGFR1* and *BRAF V600E* mutation [27].

cal and molecular biological properties of the tumor.

**7.3. Embryonal tumors**

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*7.3.1. Medulloblastoma (MB)*

MB has a very good prognosis.

Non-*WNT*/non-*SHH* MB is divided into **group 3** and **group 4**. While group 3 forms 15%, group 4 45% of all MBs. Although genetically different, some characteristics and genetic alterations are common. There is a higher occurrence in boys in both groups, structural anomalies are common—especially the formation of isochromosome 17q. A structural alteration that aberrantly induces the activity of *GFI1* or *GF1B* proto-oncogenes is common in both groups, particularly in group 3 [59]. The worst prognosis of all types has group 3 (particularly in boys), with large cell anaplastic morphology and with proven *MYC* over-expression and amplification. Group 4 is the most common molecular type with a pronounced predominance in boys. Nearly all tumors in this group have classic morphology. The prognosis of patient survival is moderate—except those with proven *MYC* amplification, which have worse prognosis [55]. Patients with metastasis present at diagnosis have a high risk of relapse, with the exception of patients with isochromosome 17, who make up a subgroup with more favorable prognosis [60].

The diagnosis is based on preoperative MRI examination of the craniospinal axis. Over the past 30 years, the most fundamental shift has been made in treatment of MB among all CNS childhood tumors and has changed from a fatal disease to a tumor with a 70% curability. The basis is surgical treatment with the maximal possible extent of resection. In the postoperative period, MRI is again indicated to evaluate the postoperative residue and the examination of cerebrospinal fluid is also beneficial. Medulloblastoma has as one of the few CNS tumors **staging system** that has 5 degrees (M0 = not disseminated, M1 = positive cytology of CSF without MR image of dissemination, M2 = nodular proliferation in cerebellar and cerebral subarachnoid spaces and in ventricles, M3 = nodular proliferation in spinal subarachnoid spaces, M4 = extra-neural propagation). Surgery is followed by chemotherapy and radiotherapy with whole CNS irradiation for frequent dissemination of medulloblastoma within the CNS. The chemotherapy regimens use either a combination of cisplatin, lomustine and vincristine or a combination of cisplatin, cyclophosphamide and vincristine [61]. Radiotherapy is administered at a dose of 54 Gy targeted to the tumor bed, followed by irradiation of the craniospinal axis at a dose of 24–36 Gy. The introduction of chemotherapy into the treatment scheme reduced the dose necessary to irradiate the craniospinal axis, thereby reducing the incidence of side effects of radiation [62]. However, radiotherapy in children under 3 years of age is not used for serious adverse effects on brain development. To potentiate the effects of standard chemotherapy, methotrexate is concomitantly administered to children under 3 years, either systemically or locally [63].

#### *7.3.2. Atypical teratoid/rhabdoid tumor (AT/RT)*

This high-grade neoplasm (grade IV) accounts for 1–2% of pediatric CNS tumors. Typically, it occurs in the age category up to 5 years, and in children under 1 year of age, it is the most common malignant CNS tumor. As it grows very quickly, clinical manifestations occur early. AT/RT is often localized supratentorialy and also in the posterior fossa [3, 64]. About 20% of patients have already dissemination of the tumor at the time of diagnosis, usually along leptomeninges. Rare coincidence with renal tumors may occur [65]. Genetically, it is characterized by deletion on the 22nd chromosome and loss of *INI1/SMARCB1/BAF47* expression due to germline or somatic mutations. Evaluation of *SMARCB1* expression is necessary to distinguish AT/RT from other embryonic tumors [66]. This tumor was the first primary CNS tumor in which the major tumor suppressor gene was identified, namely *SMARCB1*. The presence of *SMARCB1* germline mutation is the basis for identifying the **syndrome predisposing to the rhabdoid tumor,** which is common in patients with coincidence of AT/RT with rhabdoid tumor of the kidney. The greatest risk of developing tumors in this syndrome is during the first year of age, which requires monitoring and active screening in children from these families. Immunohistochemical evidence of cytokeratin, epithelial membrane antigen, glial fibrillary acidic protein, synaptophysin, desmin and vimentin is also necessary. The MIB-1 proliferation index is high, 50–100% [67]. MRI of the entire craniospinal axis as well as examination of CSF for the presence of tumor cells is useful in diagnosis. There is no standard treatment regime for AT/RT. Treatment is based on surgical resection. The localization of the tumor and the extent of its spread is crucial for the choice of treatment modalities. Prolongation of survival requires a combination of postoperative systemic and intrathecal chemotherapy (methotrexate, cytarabine and hydrocortisone) with radiotherapy. Negative prognostic factors include: the presence of *SMARCB1* germline mutations, postoperative residues, dissemination at the time of diagnosis and the age under 2 years [64].

**7.4. Pineoblastoma**

**7.5. Germ cell tumors**

In the past, this tumor was classified as embryonal, but in the new WHO classification it was reclassified to a group of pineal tumors. Its histological and molecular biological properties are similar to embryonal tumors. Because of its location, obstructive hydrocephalus is predominantly caused by blockage of CSF passages at the level of the third ventricle, and symptoms of the pressure on tectum—especially oculomotor disorder, poor reaction of pupils to light with present reaction to accommodation, later hemiparesis and ataxia. Often occur germline mutations of the *RB1* and *DICER1* genes [71]. Pineoblastoma is often found in children with congenital retinoblastoma. It can rarely disseminate along CSF pathways. A **staging system** similar to embryonal tumors is used. The primary therapeutic step is surgical resection. However, due to localization, total resection is unlikely, with only partial resection or biopsy performed in the majority of patients. This is followed by oncological treatment that combines chemotherapy and radiotherapy with a dose of 54 Gy on tumor bed and 24–36 Gy for craniospinal axis. A different therapy management is used in children under 3 years of age who undergo biopsy, followed by chemotherapy or high-dose chemotherapy with bone

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Intracranial germ cell tumors are a heterogeneous group that accounts for 3–4% of brain tumors with the exception of Japan where the incidence is higher, up to 15% [72]. Based on histopathological characteristics, they are divided into **germinomas** and **nongerminomas** (embryonal carcinoma, choriocarcinoma, mature or immature teratoma, teratoma with malignant transformation, yolk sac tumor and mixed germ cell tumor). In some countries, dividing into **secretory** and **non-secretory** tumors is also used—depending on the presence and

The most common localization is the pineal and suprasellar area, where they form either solitary or multiple lesions. The pineal region is much more frequent, but up to 10% of patients have both sites at the time of diagnosis, which is typical for pure germinomas [73]. Rare localities include basal ganglia, brain ventricles, cerebral hemispheres and thalamus. Tumor in the suprasellar region is often presented by hormonal expression. Often occur diabetes insipidus, enuresis, anorexia and also psychological changes [74]. Pineal localization has usually earlier manifestation, with hydrocephalus and diplopia developing from pressure to the tectal and aqueductal region. The most common germ cell tumor is germinoma. Mutations of the *KIT*, *KRAS* and *NRAS* genes are common [75]. Half of germinoma cases harbor deregulation of the *KIT/RAS* and *AKT/mTOR* pathways. The germline variations of *JMJD1C* occur more frequently in Japanese, which is probably related to the higher incidence of germinomas in this

In the diagnosis, apart from MRI, cytological examination of CSF and evaluation of **alphafetoprotein (AFP)** and **beta human chorionic gonadotropin (bHCG**) concentrations in both serum and in CSF is used [77]. In addition, hormonal examination of hypothalamic and pituitary function and examination of the visual field in suprasellar and hypothalamic tumors are

marrow ablation followed by hematopoietic stem cell transplantation.

absence, respectively, of elevation of serum and CSF tumor markers [12].

country. This gene is important for maintaining male germ cells [76].

#### *7.3.3. Embryonal tumor with multilayered rosettes, C19MC-altered (ETMR)*

This tumor typically occurs in children under 3 years of age. It has a poor prognosis, most patients die within 1–2 years after diagnosis [68]. Characteristic is the 19q13.42 locus amplification, which contains a cluster of microRNA (C19MC) and a fusion between *TTYH1* and *C19MC* [69]. Treatment begins with a surgical resection, followed by adjuvant oncology treatment with chemotherapy and radiotherapy. In children under 3 years, radiotherapy is not indicated.

#### *7.3.4. Neuroblastoma and ganglioneuroblastoma CNS*

These two neoplasms belong to embryonal tumors but show neuronal differentiation, in the case of ganglioneuroblastoma also the presence of ganglionic cells. They most often occur in early childhood. In general, neuroblastomas are a frequent diagnosis, but especially in the chest and abdominal cavity (in the brain they are rare). Some of these include gene alterations leading to increased expression of the transcription factor *FOXR2* [70]. The treatment scheme is the same as for other embryonal tumors – surgery followed by chemotherapy in children less than 3 years of age and addition of radiotherapy in older children.

#### **7.4. Pineoblastoma**

*7.3.2. Atypical teratoid/rhabdoid tumor (AT/RT)*

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This high-grade neoplasm (grade IV) accounts for 1–2% of pediatric CNS tumors. Typically, it occurs in the age category up to 5 years, and in children under 1 year of age, it is the most common malignant CNS tumor. As it grows very quickly, clinical manifestations occur early. AT/RT is often localized supratentorialy and also in the posterior fossa [3, 64]. About 20% of patients have already dissemination of the tumor at the time of diagnosis, usually along leptomeninges. Rare coincidence with renal tumors may occur [65]. Genetically, it is characterized by deletion on the 22nd chromosome and loss of *INI1/SMARCB1/BAF47* expression due to germline or somatic mutations. Evaluation of *SMARCB1* expression is necessary to distinguish AT/RT from other embryonic tumors [66]. This tumor was the first primary CNS tumor in which the major tumor suppressor gene was identified, namely *SMARCB1*. The presence of *SMARCB1* germline mutation is the basis for identifying the **syndrome predisposing to the rhabdoid tumor,** which is common in patients with coincidence of AT/RT with rhabdoid tumor of the kidney. The greatest risk of developing tumors in this syndrome is during the first year of age, which requires monitoring and active screening in children from these families. Immunohistochemical evidence of cytokeratin, epithelial membrane antigen, glial fibrillary acidic protein, synaptophysin, desmin and vimentin is also necessary. The MIB-1 proliferation index is high, 50–100% [67]. MRI of the entire craniospinal axis as well as examination of CSF for the presence of tumor cells is useful in diagnosis. There is no standard treatment regime for AT/RT. Treatment is based on surgical resection. The localization of the tumor and the extent of its spread is crucial for the choice of treatment modalities. Prolongation of survival requires a combination of postoperative systemic and intrathecal chemotherapy (methotrexate, cytarabine and hydrocortisone) with radiotherapy. Negative prognostic factors include: the presence of *SMARCB1* germline mutations, postoperative resi-

dues, dissemination at the time of diagnosis and the age under 2 years [64].

This tumor typically occurs in children under 3 years of age. It has a poor prognosis, most patients die within 1–2 years after diagnosis [68]. Characteristic is the 19q13.42 locus amplification, which contains a cluster of microRNA (C19MC) and a fusion between *TTYH1* and *C19MC* [69]. Treatment begins with a surgical resection, followed by adjuvant oncology treatment with chemotherapy and radiotherapy. In children under 3 years, radiotherapy is not indicated.

These two neoplasms belong to embryonal tumors but show neuronal differentiation, in the case of ganglioneuroblastoma also the presence of ganglionic cells. They most often occur in early childhood. In general, neuroblastomas are a frequent diagnosis, but especially in the chest and abdominal cavity (in the brain they are rare). Some of these include gene alterations leading to increased expression of the transcription factor *FOXR2* [70]. The treatment scheme is the same as for other embryonal tumors – surgery followed by chemotherapy in children

*7.3.3. Embryonal tumor with multilayered rosettes, C19MC-altered (ETMR)*

less than 3 years of age and addition of radiotherapy in older children.

*7.3.4. Neuroblastoma and ganglioneuroblastoma CNS*

In the past, this tumor was classified as embryonal, but in the new WHO classification it was reclassified to a group of pineal tumors. Its histological and molecular biological properties are similar to embryonal tumors. Because of its location, obstructive hydrocephalus is predominantly caused by blockage of CSF passages at the level of the third ventricle, and symptoms of the pressure on tectum—especially oculomotor disorder, poor reaction of pupils to light with present reaction to accommodation, later hemiparesis and ataxia. Often occur germline mutations of the *RB1* and *DICER1* genes [71]. Pineoblastoma is often found in children with congenital retinoblastoma. It can rarely disseminate along CSF pathways. A **staging system** similar to embryonal tumors is used. The primary therapeutic step is surgical resection. However, due to localization, total resection is unlikely, with only partial resection or biopsy performed in the majority of patients. This is followed by oncological treatment that combines chemotherapy and radiotherapy with a dose of 54 Gy on tumor bed and 24–36 Gy for craniospinal axis. A different therapy management is used in children under 3 years of age who undergo biopsy, followed by chemotherapy or high-dose chemotherapy with bone marrow ablation followed by hematopoietic stem cell transplantation.

#### **7.5. Germ cell tumors**

Intracranial germ cell tumors are a heterogeneous group that accounts for 3–4% of brain tumors with the exception of Japan where the incidence is higher, up to 15% [72]. Based on histopathological characteristics, they are divided into **germinomas** and **nongerminomas** (embryonal carcinoma, choriocarcinoma, mature or immature teratoma, teratoma with malignant transformation, yolk sac tumor and mixed germ cell tumor). In some countries, dividing into **secretory** and **non-secretory** tumors is also used—depending on the presence and absence, respectively, of elevation of serum and CSF tumor markers [12].

The most common localization is the pineal and suprasellar area, where they form either solitary or multiple lesions. The pineal region is much more frequent, but up to 10% of patients have both sites at the time of diagnosis, which is typical for pure germinomas [73]. Rare localities include basal ganglia, brain ventricles, cerebral hemispheres and thalamus. Tumor in the suprasellar region is often presented by hormonal expression. Often occur diabetes insipidus, enuresis, anorexia and also psychological changes [74]. Pineal localization has usually earlier manifestation, with hydrocephalus and diplopia developing from pressure to the tectal and aqueductal region. The most common germ cell tumor is germinoma. Mutations of the *KIT*, *KRAS* and *NRAS* genes are common [75]. Half of germinoma cases harbor deregulation of the *KIT/RAS* and *AKT/mTOR* pathways. The germline variations of *JMJD1C* occur more frequently in Japanese, which is probably related to the higher incidence of germinomas in this country. This gene is important for maintaining male germ cells [76].

In the diagnosis, apart from MRI, cytological examination of CSF and evaluation of **alphafetoprotein (AFP)** and **beta human chorionic gonadotropin (bHCG**) concentrations in both serum and in CSF is used [77]. In addition, hormonal examination of hypothalamic and pituitary function and examination of the visual field in suprasellar and hypothalamic tumors are necessary. The essentials of the treatment are chemotherapy and radiotherapy, but biopsy is required for reliable diagnosis. Only in tumors with unambiguous MRI image and positive tumor markers in CSF can be treated without biopsy.

for hormone replacement therapy, severe obesity, behavioral disorders, blindness, epileptic seizures, postoperative CSF leak, pseudoaneurysms, oculomotor disorders, severe postoperative bleeding and hypothalamic injury [84]. While recurrent craniopharyngiomas are treated by resection, radiotherapy or radiosurgery, tumors with unresponsive cystic component can be treated by administration of P32, bleomycin or interferon alpha directly into the tumor bed.

Primary Brain Tumors in Childhood

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http://dx.doi.org/10.5772/intechopen.74510

**Schwannomas** are in children rare, mostly benign neoplasms originating from Schwann cells of cranial or other nerves. Some of these tumors are present as a part of the NF2 type genetic syndrome, especially at bilateral occurrence. From cranial nerves, this tumor mostly affects VIII cranial nerve and is called vestibular schwannoma or acoustic neurinoma [86]. Vestibular schwannomas can cause loss of hearing and tinnitus. Diagnosis is mainly based on MRI. The method of choice is resection of the tumor, further treatment is usually not necessary. In rare

**Meningiomas** that grow from meninges are much rarer in children than in adults—they account for about 2.6–2.9% of CNS childhood tumors [2]. It occurs most often between 6 and 12 years of age. Children have a higher incidence of tumors growing from the skull base and a higher incidence of atypical (grade II) and anaplastic (grade III) meningiomas compared to adults. Chromosome 22 abnormalities are often present, also as a part of the NF2 type syndrome. Tumors connected with NF2 occur at younger age (about 2 years) and may also be the first symptom of this disease. In benign tumors, surgical treatment is largely sufficient, but in the case of incomplete resection and in tumors of higher grade, is usually combined with radiotherapy. Favorable prognostic factors include: age up to 10 years, superficial localization, total extirpation and absence of NF2 syndrome, where localization and resection extent

**Primary CNS lymphomas (PCNSL)** are rare in children. Patients with immunodeficiency have an increased risk of developing CNS lymphomas [89]. They occur mainly in children around 14 years of age with moderate predominance in boys [90]. They are mostly localized in brain hemispheres. Clinical symptoms include symptoms of increased intracranial pressure, ataxia, hemiparesis, epileptic seizures and cranial nerve palsy. MRI and CSF sampling is used in diagnostics. MRI verifies solid lesion (even with a possible cystic component). Histologically, **mature aggressive B cell lymphoma (B-NHL),** as well as **anaplastic large cell lymphoma (ALCL)** or **peripheral T cell lymphoma (PTCL)** are most often present. Pediatric B-NHL has a low to moderate proliferation index, a lower Bc12 protein expression and a higher frequency of the Bc16 + GC fetal center phenotype, indicating a better prognosis [91]. While the prognosis of PCNSL in adults is very poor, in children is better. Interestingly, localization of PCNSL in deep brain structures does not affect the prognosis [90]. In chemotherapy, methotrexate or cytarabine at high doses are mostly used, usually providing satisfactory remission without need for use of radiotherapy (often used in ALCL form). It has been found that the exclusive use of chemotherapy is more effective than combined chemoradiotherapy. Explanation could be the use of lower doses of chemotherapy in combined therapy. High-dose therapy of methotrexate, which appears to be the most effective, is better tolerated by children compared to

It can be supplemented by systemic administration of interferon [85].

cases, radiotherapy can be used in the presence of postoperative residues [87].

are stronger predictive factors than histological grade [88].

adults. Radiotherapy is therefore reserved for recurrent forms [89].

**7.8. Other pediatric CNS tumors**

#### **7.6. Choroid plexus tumors**

These rare intraventricular tumors account for 1% of all brain tumors and 2–4% of pediatric tumors. They arise from neuroectoderm and consist of differentiated epithelial plexus cells that produce CSF. They most often occur in the age group under 2 years of age. The most common site are lateral ventricles (less often the 3rd and 4th ventricle), but could also occur in the cerebellopontine angle and in the cerebral parenchyma. They mostly manifest by symptoms of intracranial hypertension from hydrocephalus, both from overproduction of the CSF as well as from obstruction of the CSF pathways. Sometimes, however, they can also manifest suddenly, in case of bleeding into the tumor [78]. This group of tumors consists of: **choroid plexus papilloma (grade I), atypical choroid plexus papilloma (grade II)** and **choroid plexus carcinoma (grade III).** There are no genetic differences between papilloma and atypical papilloma. In both, immunoreactivity to cytokeratin, vimentin, S100 protein and synaptophysin is present. On the other hand, carcinoma is genetically different. The germline mutations of *TP53* as part of the Li-Fraumeni syndrome predispose to the formation of plexus carcinoma. Somatic *TP53* mutations are present in up to 60% of the plexus carcinomas and the more copy of the mutated *TP53* is present, the worse is the prognosis [79]. Chromosome alterations are rarely detected.

MRI showing relatively well-defined extra-axial mass that does not invade the brain tissue with gadolinium enhancement and containing calcification and microhemorrhages is essential. Surgical treatment is the method of choice. Due to the rich vascular supply, preoperative tumor embolization is preferred in some cases. Hydrocephalus treatment is also necessary—sometimes requires external ventricular drainage. In some patients hydrocephalus is permanent, and therefore ventriculoperitoneal shunt or the endoscopic ventriculostomy of the 3rd ventricle are required [80]. There is no need for further treatment in the papilloma, radiotherapy, radiosurgery or chemotherapy with bevacizumab may be used in atypical or recurrent forms. Chemotherapy has been proven in choroid plexus carcinoma, which can spread along CSF pathways [81].

#### **7.7. Craniopharyngioma**

Craniopharyngiomas are rare tumors, accounting for 3–5% of pediatric brain tumors. They occur in two subtypes: adamantinomatous and papillary [12]. The **adamantinomatous variant** for which the *CTNNB1* mutation is typical, is often found in children [6]. Their congenital origin is assumed to be from the ectodermal residues of the Rathke capsule or from another embryonal epithelium. They most commonly occur in the suprasellar area with intrasellar propagation. Symptoms include: endocrine disorders, visual disturbances, hydrocephalus symptoms and very rarely when growing in the posterior fossa—headache, diplopia, ataxia and hearing loss [82]. The diagnosis is made by MRI that displays a tumor with a solid and cystic component and with intratumoral calcifications. Evaluation of hormonal function and visual field is also necessary. The therapy of newly diagnosed craniopharyngiomas is a combination of surgical treatment, radiotherapy and a drainage of the cyst. The prognosis is good, 90% of patients survive more than 10 years [83]. Total resection may have serious complications, including: need for hormone replacement therapy, severe obesity, behavioral disorders, blindness, epileptic seizures, postoperative CSF leak, pseudoaneurysms, oculomotor disorders, severe postoperative bleeding and hypothalamic injury [84]. While recurrent craniopharyngiomas are treated by resection, radiotherapy or radiosurgery, tumors with unresponsive cystic component can be treated by administration of P32, bleomycin or interferon alpha directly into the tumor bed. It can be supplemented by systemic administration of interferon [85].

#### **7.8. Other pediatric CNS tumors**

necessary. The essentials of the treatment are chemotherapy and radiotherapy, but biopsy is required for reliable diagnosis. Only in tumors with unambiguous MRI image and positive

These rare intraventricular tumors account for 1% of all brain tumors and 2–4% of pediatric tumors. They arise from neuroectoderm and consist of differentiated epithelial plexus cells that produce CSF. They most often occur in the age group under 2 years of age. The most common site are lateral ventricles (less often the 3rd and 4th ventricle), but could also occur in the cerebellopontine angle and in the cerebral parenchyma. They mostly manifest by symptoms of intracranial hypertension from hydrocephalus, both from overproduction of the CSF as well as from obstruction of the CSF pathways. Sometimes, however, they can also manifest suddenly, in case of bleeding into the tumor [78]. This group of tumors consists of: **choroid plexus papilloma (grade I), atypical choroid plexus papilloma (grade II)** and **choroid plexus carcinoma (grade III).** There are no genetic differences between papilloma and atypical papilloma. In both, immunoreactivity to cytokeratin, vimentin, S100 protein and synaptophysin is present. On the other hand, carcinoma is genetically different. The germline mutations of *TP53* as part of the Li-Fraumeni syndrome predispose to the formation of plexus carcinoma. Somatic *TP53* mutations are present in up to 60% of the plexus carcinomas and the more copy of the mutated *TP53* is present, the worse is the prognosis [79]. Chromosome alterations are rarely detected. MRI showing relatively well-defined extra-axial mass that does not invade the brain tissue with gadolinium enhancement and containing calcification and microhemorrhages is essential. Surgical treatment is the method of choice. Due to the rich vascular supply, preoperative tumor embolization is preferred in some cases. Hydrocephalus treatment is also necessary—sometimes requires external ventricular drainage. In some patients hydrocephalus is permanent, and therefore ventriculoperitoneal shunt or the endoscopic ventriculostomy of the 3rd ventricle are required [80]. There is no need for further treatment in the papilloma, radiotherapy, radiosurgery or chemotherapy with bevacizumab may be used in atypical or recurrent forms. Chemotherapy has been proven in choroid plexus carcinoma, which can spread along CSF pathways [81].

Craniopharyngiomas are rare tumors, accounting for 3–5% of pediatric brain tumors. They occur in two subtypes: adamantinomatous and papillary [12]. The **adamantinomatous variant** for which the *CTNNB1* mutation is typical, is often found in children [6]. Their congenital origin is assumed to be from the ectodermal residues of the Rathke capsule or from another embryonal epithelium. They most commonly occur in the suprasellar area with intrasellar propagation. Symptoms include: endocrine disorders, visual disturbances, hydrocephalus symptoms and very rarely when growing in the posterior fossa—headache, diplopia, ataxia and hearing loss [82]. The diagnosis is made by MRI that displays a tumor with a solid and cystic component and with intratumoral calcifications. Evaluation of hormonal function and visual field is also necessary. The therapy of newly diagnosed craniopharyngiomas is a combination of surgical treatment, radiotherapy and a drainage of the cyst. The prognosis is good, 90% of patients survive more than 10 years [83]. Total resection may have serious complications, including: need

tumor markers in CSF can be treated without biopsy.

**7.6. Choroid plexus tumors**

124 Brain Tumors - An Update

**7.7. Craniopharyngioma**

**Schwannomas** are in children rare, mostly benign neoplasms originating from Schwann cells of cranial or other nerves. Some of these tumors are present as a part of the NF2 type genetic syndrome, especially at bilateral occurrence. From cranial nerves, this tumor mostly affects VIII cranial nerve and is called vestibular schwannoma or acoustic neurinoma [86]. Vestibular schwannomas can cause loss of hearing and tinnitus. Diagnosis is mainly based on MRI. The method of choice is resection of the tumor, further treatment is usually not necessary. In rare cases, radiotherapy can be used in the presence of postoperative residues [87].

**Meningiomas** that grow from meninges are much rarer in children than in adults—they account for about 2.6–2.9% of CNS childhood tumors [2]. It occurs most often between 6 and 12 years of age. Children have a higher incidence of tumors growing from the skull base and a higher incidence of atypical (grade II) and anaplastic (grade III) meningiomas compared to adults. Chromosome 22 abnormalities are often present, also as a part of the NF2 type syndrome. Tumors connected with NF2 occur at younger age (about 2 years) and may also be the first symptom of this disease. In benign tumors, surgical treatment is largely sufficient, but in the case of incomplete resection and in tumors of higher grade, is usually combined with radiotherapy. Favorable prognostic factors include: age up to 10 years, superficial localization, total extirpation and absence of NF2 syndrome, where localization and resection extent are stronger predictive factors than histological grade [88].

**Primary CNS lymphomas (PCNSL)** are rare in children. Patients with immunodeficiency have an increased risk of developing CNS lymphomas [89]. They occur mainly in children around 14 years of age with moderate predominance in boys [90]. They are mostly localized in brain hemispheres. Clinical symptoms include symptoms of increased intracranial pressure, ataxia, hemiparesis, epileptic seizures and cranial nerve palsy. MRI and CSF sampling is used in diagnostics. MRI verifies solid lesion (even with a possible cystic component). Histologically, **mature aggressive B cell lymphoma (B-NHL),** as well as **anaplastic large cell lymphoma (ALCL)** or **peripheral T cell lymphoma (PTCL)** are most often present. Pediatric B-NHL has a low to moderate proliferation index, a lower Bc12 protein expression and a higher frequency of the Bc16 + GC fetal center phenotype, indicating a better prognosis [91]. While the prognosis of PCNSL in adults is very poor, in children is better. Interestingly, localization of PCNSL in deep brain structures does not affect the prognosis [90]. In chemotherapy, methotrexate or cytarabine at high doses are mostly used, usually providing satisfactory remission without need for use of radiotherapy (often used in ALCL form). It has been found that the exclusive use of chemotherapy is more effective than combined chemoradiotherapy. Explanation could be the use of lower doses of chemotherapy in combined therapy. High-dose therapy of methotrexate, which appears to be the most effective, is better tolerated by children compared to adults. Radiotherapy is therefore reserved for recurrent forms [89].
