**16. Brain stem tumors**

Pediatric brainstem gliomas occur as two major types:

Focal brainstem gliomas, usually WHO grade I–II tumors.

Diffuse intrinsic pontine gliomas, range from WHO grade III–IV [46]. They usually arise in the medulla, pons, or midbrain.

**Focal brainstem gliomas (FBSG)**: constitutes approximately 20% of pediatric brainstem gliomas and usually occur outside the pons. Most are either pilocytic astrocytomas (grade I) or fibrillary astrocytomas (grade II) [47].

FBSG is usually insidious in nature and the symptoms are related to site of tumour location. Most common symptoms include neck stiffness, cranial nerve deficit and contralateral hemiparesis.

Hydrocephalus is uncommon except in posterior exophytic tumours [48].

On MRI, FBSG can be seen with defined borders, lack of surrounding edema, iso- or hypointensity on T1, hyperintensity on T2, and homogeneous contrast enhancement [49].

Surgical resection has emerged as treatment of choice due to development of modern imaging and neurosurgical techniques. FBSG confined to cervicomedullary region and/ or exophytic are amenable to complete resection [50] even with incomplete resection, the long-term prognosis for this patient population is excellent.

Chemotherapy can be used as adjuvant after complete or incomplete tumour resection or in cases of tumour progression. Most commonly used chemotherapy regimen is vincristine and carboplatin, which achieves at least stable disease in 68–75% of patients, and a positive response in about 40% [51]. Other regimens comprise of 6-thioguanine, procarbazine, lomustine, and vincristine (TPCV), vinblastine [52], bevacizumab with or without irinotecan [53], everolimus [54], and a metronomic, oral, anti-angiogenic regimen consisting of celecoxib, thalidomide, fenofibrate, cyclosphosphamide, and etoposide [55].

Radiation therapy (RT), while often effective in inducing prolonged remission in FBSG, has severe associated toxicities, especially for young children.

**Diffuse intrinsic pontine gliomas (DIPG)** account for approximately 80% of pediatric brainstem tumors and with male to female ratio as 1:1. It is more common in younger age group. These tumors are almost always highly malignant and fatal [56].

The patients have DIPG have a more lethal and shorter duration course than FBSG as it is more aggressive disease. Patients usually present within 3 months of tumour development. The most common symptoms are cranial nerve palsies, most often of cranial nerves VI and VII but sometimes including III, IV, IX, and/or X, as well as long tract signs like hemiparesis.

On CT scan, DIPG appears isodense or hypodense, without calcifications. On MRI, DIPG is most often hypointense on T1 and hyperintense on T2. Contrast enhancement is variable in both modalities but is usually not diffusely uniform, as it often is in FBSG. Diffusion is most often increased [57].

Apart from medical management starting with dexamethsone, aimed to relieve neurological symptoms, not many treatment options are available. RT is the only therapy proven to prolong survival of patients, that too it is palliative in nearly every case.

Currently, RT is given at a dose of 54–59 Gy at 1.8 Gy daily fractions for 30–33 days locally, to the area of the tumor plus a 1–2 cm surrounding margin.

Chemotherapy has not shown any benefit in concurrent, adjuvant or palliative form.

The prognosis for DIPG patients remains devastatingly poor. Recent studies have shown median progression free survival of 7 months and an overall survival of 9–11 months. In one large series, 77% of patients responded to treatment, and it was for a transient period as the therapy is rarely curative [58]. Poor prognostic marker at diagnosis or post treatment is the presence of leptomeningeal disease and no studies confirm these patients will benefit from craniospinal irradiation [59].

## **17. Medulloblastoma**

Medulloblastoma is the second most common central nervous system tumour of childhood, most commonly occurring between 4 and 7 years of age. It usually arises from the roof of the fourth ventricle or from the midline structures of the brain [60].

Etiology: for most patients the etiology is unknown but is associated with certain genetic disorders (i.e., Gorlin syndrome, Turcot syndrome, Li-Fraumeni syndrome, Rubinstein-Taybi syndrome, and ataxia telangiectasia) [61].

**161**

**Table 4.**

*An Overview of Pediatric CNS Malignancies DOI: http://dx.doi.org/10.5772/intechopen.88189*

loblastoma [25].

expression [63].

cranial nerve palsy in older patients.

Age Children and

Somatic nucleotide variant

Somatic copy number alterations

Incidence of metastasis

Pattern of relapse

adults

*CTNNB1*, *DDX3*, *SMARCA4*, *CREBBP*, *TP53*\*

Cytogenetics Monosomy 6 Gain of 3q, 9p,

*\*It shows characterstics of each molecular subgroups of medulloblastoma.*

*Molecular subgroups of medulloblastoma [62].*

It has the propensity to disseminate along the cerebrospinal fluid (CSF) pathway, and metastatic disease at diagnosis is found in approximately 30% of patients.

WHO classification 2007 categorises medulloblastoma as grade IV neoplasms under the group of embryonal neuroepithelial tumours. There are several histopathological subtypes of medulloblastoma. In addition to classic variant, other subtypes include desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity (MBEN), anaplastic medulloblastoma, and large cell medul-

Molecular subgrouping of medulloblastoma divides it into four distinct subgroups which are identified on the basis of transcriptional profiling studies as wingless (Wnt), sonic hedgehog (Shh), Group 3, and Group 4 (**Table 4**). Each subgroup is defined by a unique set of demographic and clinical features, genetics, and gene

Signs and symptoms: usually due to increased intracranial tension, hydrocephalus and cerebellar dysfunction, and comprise vomiting, macrocephalus, loss of developmental achievements in infants, and headache, vomiting, ataxia, and

Management: biopsy has no role in the diagnosis if it is radiographically supported. Medulloblastomas have distinct imaging characteristics on both computed tomography (CT) and magnetic resonance imaging (MRI). Since 75% of medulloblastomas arise from the cerebellar vermis, they tend to protrude into the fourth ventricle in pediatric age group. On CT scan, in case of young patients, effacement of the fourth ventricle is seen along with its dilatation which is secondary to obstructive hydrocephalus. In case of older patients, they are most commonly seen as a hyperdense mass arising from the vermis with cyst formation or necrosis. On MRI, medulloblastomas are hypointense to grey matter on T1-weighted imaging with heterogeneous gadolinium enhancement on T2-weighted imaging

Percentage 10% 30% 25% 35%

Mainly infants and adults

*PTCH1*, *SUFU*, *SMO*, *TERT*, *IDH1*, *TP53*, *KMT2D*

loss of 9q, 10q, 14q, 17p

Prognosis Very good Intermediate Poor Intermediate

**WNT SHH GROUP 3 GROUP 4**

*MYCN*, *GLI2 MYC*, *PVT1*,

5–10% 10–15% 40–45% 35–40%

Local and distal Local Distal Distal

Mainly infants and children

*SMARCA4*, *CTDNEP1*, *KMT2D*, *KBTBD4*

*OTX2*, *GFI1*/*1b*

i17q, loss of 8, 10q, 11, 16p, 17p, gain of 1q, 7, 17q, 18q

Mainly children and adults

> *KDM6A*, *KMT2C*

*SNCAIP*, *MYCN*, *CDK6*, *GFI1*/*1b*

i17q, loss of 8p, 11p, X, gain of 7q, 18q

Spread outside the central nervous system (CNS) is very rare at diagnosis.

#### *An Overview of Pediatric CNS Malignancies DOI: http://dx.doi.org/10.5772/intechopen.88189*

*Current Cancer Treatment*

enhancement [49].

Hydrocephalus is uncommon except in posterior exophytic tumours [48]. On MRI, FBSG can be seen with defined borders, lack of surrounding edema, iso- or hypointensity on T1, hyperintensity on T2, and homogeneous contrast

Surgical resection has emerged as treatment of choice due to development of modern imaging and neurosurgical techniques. FBSG confined to cervicomedullary region and/ or exophytic are amenable to complete resection [50] even with incomplete resection, the long-term prognosis for this patient population is excellent. Chemotherapy can be used as adjuvant after complete or incomplete tumour resection or in cases of tumour progression. Most commonly used chemotherapy regimen is vincristine and carboplatin, which achieves at least stable disease in 68–75% of patients, and a positive response in about 40% [51]. Other regimens comprise of 6-thioguanine, procarbazine, lomustine, and vincristine (TPCV), vinblastine [52], bevacizumab with or without irinotecan [53], everolimus [54], and a metronomic, oral, anti-angiogenic regimen consisting of celecoxib, thalidomide,

Radiation therapy (RT), while often effective in inducing prolonged remission

**Diffuse intrinsic pontine gliomas (DIPG)** account for approximately 80% of pediatric brainstem tumors and with male to female ratio as 1:1. It is more common in younger age group. These tumors are almost always highly malignant and fatal [56]. The patients have DIPG have a more lethal and shorter duration course than FBSG as it is more aggressive disease. Patients usually present within 3 months of tumour development. The most common symptoms are cranial nerve palsies, most often of cranial nerves VI and VII but sometimes including III, IV, IX, and/or X, as

On CT scan, DIPG appears isodense or hypodense, without calcifications. On MRI, DIPG is most often hypointense on T1 and hyperintense on T2. Contrast enhancement is variable in both modalities but is usually not diffusely uniform, as it

Apart from medical management starting with dexamethsone, aimed to relieve neurological symptoms, not many treatment options are available. RT is the only therapy proven to prolong survival of patients, that too it is palliative in nearly

Chemotherapy has not shown any benefit in concurrent, adjuvant or palliative form. The prognosis for DIPG patients remains devastatingly poor. Recent studies have shown median progression free survival of 7 months and an overall survival of 9–11 months. In one large series, 77% of patients responded to treatment, and it was for a transient period as the therapy is rarely curative [58]. Poor prognostic marker at diagnosis or post treatment is the presence of leptomeningeal disease and no studies confirm these patients will benefit from craniospinal irradiation [59].

Medulloblastoma is the second most common central nervous system tumour of childhood, most commonly occurring between 4 and 7 years of age. It usually arises from the roof of the fourth ventricle or from the midline structures of the brain [60]. Etiology: for most patients the etiology is unknown but is associated with certain genetic disorders (i.e., Gorlin syndrome, Turcot syndrome, Li-Fraumeni syndrome,

Currently, RT is given at a dose of 54–59 Gy at 1.8 Gy daily fractions for 30–33 days locally, to the area of the tumor plus a 1–2 cm surrounding margin.

in FBSG, has severe associated toxicities, especially for young children.

fenofibrate, cyclosphosphamide, and etoposide [55].

often is in FBSG. Diffusion is most often increased [57].

Rubinstein-Taybi syndrome, and ataxia telangiectasia) [61].

well as long tract signs like hemiparesis.

**160**

every case.

**17. Medulloblastoma**

It has the propensity to disseminate along the cerebrospinal fluid (CSF) pathway, and metastatic disease at diagnosis is found in approximately 30% of patients. Spread outside the central nervous system (CNS) is very rare at diagnosis.

WHO classification 2007 categorises medulloblastoma as grade IV neoplasms under the group of embryonal neuroepithelial tumours. There are several histopathological subtypes of medulloblastoma. In addition to classic variant, other subtypes include desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity (MBEN), anaplastic medulloblastoma, and large cell medulloblastoma [25].

Molecular subgrouping of medulloblastoma divides it into four distinct subgroups which are identified on the basis of transcriptional profiling studies as wingless (Wnt), sonic hedgehog (Shh), Group 3, and Group 4 (**Table 4**). Each subgroup is defined by a unique set of demographic and clinical features, genetics, and gene expression [63].

Signs and symptoms: usually due to increased intracranial tension, hydrocephalus and cerebellar dysfunction, and comprise vomiting, macrocephalus, loss of developmental achievements in infants, and headache, vomiting, ataxia, and cranial nerve palsy in older patients.

Management: biopsy has no role in the diagnosis if it is radiographically supported. Medulloblastomas have distinct imaging characteristics on both computed tomography (CT) and magnetic resonance imaging (MRI). Since 75% of medulloblastomas arise from the cerebellar vermis, they tend to protrude into the fourth ventricle in pediatric age group. On CT scan, in case of young patients, effacement of the fourth ventricle is seen along with its dilatation which is secondary to obstructive hydrocephalus. In case of older patients, they are most commonly seen as a hyperdense mass arising from the vermis with cyst formation or necrosis.

On MRI, medulloblastomas are hypointense to grey matter on T1-weighted imaging with heterogeneous gadolinium enhancement on T2-weighted imaging


#### **Table 4.**

*Molecular subgroups of medulloblastoma [62].*


#### **Table 5.**

*Risk stratification of medulloblastoma.*

they appear iso- to hyperintense to grey matter and can seem heterogeneous due to cyst formation, calcification and necrosis. MR spectroscopy shows elevated choline peaks and decreased creatine and N-acetyl acetate peaks, with occasional elevation in lactic acid and lipid peaks [64].

Maximal safe resection is recommended in all medulloblastoma patients. Apart from surgical resection, the current standards of radiation therapy and medical management vary by extent of disease and age of the patient. Radiation therapy can be used to decrease the risk of recurrence but neurocognitive effects of radiation therapy have to be considered by weighing the risk benefit ratio.

Patients who are 3 years of age or older are stratified as either "average-risk" or "high-risk" depending upon postoperative residual tumor volume and the presence or absence of disseminated disease (**Table 5**).

Patients who are younger than 3 years of age, are treated without upfront radiation therapy due to the unacceptably high risk of severe neurocognitive impairment [65].

In the postoperative setting, average-risk patients >3 years old were previously treated with 36 Gy craniospinal irradiation (CSI) but now a boost to the posterior fossa is given for a total dose of 54 Gy due to the high rate of relapse within the posterior fossa. CSI dose of 23.4–24 Gy can be given with the addition of chemotherapy as supported by Studies conducted by the International Society of Pediatric Oncology (SIOP) and the Children's Oncology Group [66].

Current recommendations for post-radiation chemotherapy in averagerisk patients include approximately 1 year of therapy consisting of 8 cycles at 6-week intervals of cisplatin, lomustine (CCNU), and vincristine. The St. Jude Medulloblastoma-96 trial has demonstrated a similar event-free survival of 83% when an alkylator-based, dose-intensive chemotherapy regimen consisting of four 4-week cycles of cyclophosphamide, cisplatin, and vincristine with autologous stem cell rescue was employed following each cycle [67].

For high risk medulloblastoma cases in children 3 years or older, the treatment is surgical resection followed by post-operative "standard dose" RT (36 Gy CSI with a boost to both the posterior fossa and focal sites of metastatic disease to 55.8 Gy) as well as adjuvant chemotherapy.

The most common adverse effect of craniospinal irradiation in children <3 years age is neurocognitive deficit. Therefore radiotherapy is either delayed or omitted in this subset of patients. There is evidence that regimens consisting of surgery and chemotherapy without RT can be successful in specific subsets of medulloblastoma patients. Outcomes in patients with relapsed disease are generally poor, with reported 5-year survival rates of approximately 25% [68]. Unfavorable prognostic factors include large tumor, csf dissemination, age <4 years, subtotal tumour resection (<90%), chromosome deletion 17p, c-*MYC* amplification.
