**4. Imaging characteristics**

to mimic other pediatric and adult high-grade gliomas and therapies were based on these inaccurate assumptions. Radiation therapy (RT) is the only treatment modality available, that has been demonstrated to prolong survival and improve quality of life (ref) but is not curative. Almost all children die with a median survival of 1 year. Indeed, 50% of children with DIPG die within 1 year of diagnosis and almost all are dead by 2 years (ref). Despite a myriad of clinical trials, no effective treatment has been identified so far. But recently, there has been an exponential increase in the pre-clinical research involving DIPG and many, previously unknown, abnormalities contributing to DIPG pathogenesis have been identified. These may

Tumors of the central nervous system (CNS) constitute the largest group of solid tumors and the second most common pediatric cancer [1, 2]. Around 20% of CNS tumors are brainstem gliomas [3] of which 80% arise within the pons as DIPG [4] with approximately 200–300 children in the United States [5] being diagnosed each year. Survival rates for children with cancer have improved dramatically since the 1960s; from an estimated 5-year survival of 28% to approximately 80–85% at present [6]. The outcome for patients diagnosed with brain tumors has also improved with more than 70% expected to survive at least 5 years from the diagnosis [7]. Pediatric CNS tumors are a very heterogeneous group of diseases with over 100 distinct histological types and survival differs markedly amongst the different histological types. Unlike other childhood cancers, survival for DIPG has not changed [5]. The median survival for children with DIPG is less than 1 year from the diagnosis [8] with more than 90% dying within 2 years of diagnosis [4, 9]. Although DIPG constitute only 10–15% of all pediatric brain tumors, they are the leading cause of death in this group [10]. More than three decades of research and different treatment modalities have not yielded any survival improvement.

The symptoms and signs of patients with DIPG occur secondary to the involvement of different parts of the brainstem, which include the midbrain, pons and medulla. The brainstem serves as a conduit through which axonal tracts pass to the spinal cord, cerebrum or exit as cranial nerves. Due to the diffuse nature of DIPG, the tumor infiltrates the white matter affecting the adjacent cranial nerves and white matter tracts [11]. As the pons contains important nuclei critical for life-sustaining function, any damage caused by the tumor or its treatment has devastating effects. DIPG predominantly occurs in in the middle childhood. Median age at diagnosis is 6–7 years, with males and females affected equally [11–13]. Interestingly, adults with DIPG tend to have a longer survival which may indicate a less aggressive and biologically different tumor from that in children [14]. Typically, the presentation is with neurological symptoms of less than 3 months duration [15] with the "classic" triad of cranial

provide treatable targets and help improve the outcome of patients with DIPG.

**2. Epidemiology**

36 Brain Tumors - An Update

**3. Clinical features**

#### **4.1. Magnetic resonance imaging (MRI)**

DIPG is diagnosed clinically on the basis of history, clinical signs and MRI findings [18]. The classic MRI appearance is of an expansile lesion centred in the pons that frequently extends laterally into the cerebellar peduncles and hemispheres and often extends vertically into the midbrain and medulla (**Figure 1A**). It is poorly marginated, occupying more than 50% of the axial diameter of the pons [11]. Necrosis can be seen but cysts are rare [14]. The tumors are hypointense with indistinct margins on T1-weighted images (**Figure 1B**) and hyperintense on T2-weighted/fluid-attenuated inversion recovery (FLAIR) images (**Figure 1C** and **D**) [4]. Post-gadolinium enhancement as commonly seen in pilocytic astrocytomas is often minimal or absent in DIPG (**Figure 1E**) [19, 20]. With an average molecular weight of 545 kDa, gadolinium largely exceeds the penetration cut-off of the blood brain barrier (BBB) (400–600 Da) with limited contrast enhancement in DIPG suggesting a largely intact BBB [14, 21]. Other MRI features typical of DIPG include ventral involvement of the pons and encasement of the basilar artery (**Figure 1F**) [5].

#### **4.2. New imaging techniques**

#### *4.2.1. MR spectroscopy (MRS)*

MRS provides a measure of brain chemistry. The most prominent peaks in the brain spectrum on Proton MRS are N-acetyl aspartate (NAA), creatine, and choline. NAA is a neuronal marker which is usually decreased in tumors. Choline is associated with the metabolism of membrane turnover and is generally increased in tumors. In DIPG, MRS shows a modest increase in choline levels and a decrease in NAA levels [14]. Additionally, peaks from lactate and mobile lipids are often elevated [11]. The abnormalities in these normally occurring brain metabolites may provide insight into the biology of DIPG and become invaluable tools in DIPG radiodiagnosis.

#### *4.2.2. Perfusion and diffusion techniques*

Some of the newer perfusion and diffusion MRI techniques are being tested in prospective trials and although not a standard for DIPG diagnosis currently, may prove beneficial in the future.

MR perfusion measures regional blood volume and flow reflecting the vascular nature of neoplasms [22]. Serial changes in tumor vascularity may be useful to monitor the effectiveness of therapy. Diffusion tensor imaging may provide visualization and quantitative characterization of the major white matter pathways in DIPG [23, 24]. This superior delineation between tumor and normal brain compared to the conventional MRI techniques may prove useful, especially to perform biopsies and obtain DIPG samples. Specific MRI sequences, including single-voxel spectroscopy (SVS), multi-voxel MRS and dynamic susceptibility contrast (DSC) MRI may help in predicting short or long survival interval from diagnosis in patients with DIPG [25].

Diffuse Intrinsic Pontine Glioma

39

http://dx.doi.org/10.5772/intechopen.78578

Imaging of radiolabeled drugs like monoclonal antibodies and tyrosine kinase inhibitors can be achieved by using PET technology [26]. A recently introduced PET imaging technique of zirconium-89 (89Zr)-labeled bevacizumab in children with DIPG demonstrated considerable inter-and intra-tumoral heterogeneity in drug delivery [27]. Therapeutic potential and toxicity both can be quantified by such non-invasive, in patient techniques of tumor imaging and drug distribution [28]. Thus, these newer imaging modalities provide quantitative physiologic and functional information to complement the anatomic visualization provided by conventional imaging. However, these techniques need further validation and have yet to

Grossly, DIPG tumors tend to spread contiguously, extending to involve the midbrain, medulla, and cerebellar peduncles [29, 30]. Up to 20% of patients are reported to have leptomeningeal disease at diagnosis [31] and almost 56% have spinal metastases or leptomeningeal dissemination at the time of recurrence or autopsy [32, 33]. Microscopically, the majority of tumors resemble malignant gliomas in other regions. Tumor cells appear relatively small, with prominent cytoplasmic intermediate filaments and cell processes [34]. Tumor cells pervade normal cells (**Figure 2A** and **B**), diffusely expanding the pons and distorting, displacing and destroying nerve fiber tracts that normally course through it [34]. Anaplasia, increased mitotic activity (**Figure 2C**), tumor necrosis (**Figure 2D**) and vascular proliferation (**Figure 2E**) are often present [5]. A histopathological hallmark is perineuronal satellitosis in which collection of tumor cells are found around pontine neurons [35]. DIPG is histologically classified as fibrillary astrocytoma, World Health Organization (WHO) Grades II–IV [36] but the prognosis is not associated with histological grade [37, 38]. There can be marked intratumoral heterogeneity with a high proportion of samples showing focal areas of WHO grade I phenotype [39].

In the latest WHO classification, DIPG have been grouped with other midline gliomas (thalamus, spinal cord) forming a new diagnostic entity. These tumors are characterized by a

*4.2.3. Molecular drug imaging*

impact treatment decisions [11].

**5.1. Diffuse midline glioma, H3K27M-mutant**

**5. Pathology**

**Figure 1.** T1-weighted pre-contrast sagittal (A) and axial (B) MRI pictures showing poorly marginated, expansile and hypointense pontine mass. It is hyperintense onT2-weighted/FLAIR sagittal (C) and coronal (D) images. (E) There is minimal post-gadolinium enhancement. (F) Basilar artery encasement by DIPG (black arrow).

MR perfusion measures regional blood volume and flow reflecting the vascular nature of neoplasms [22]. Serial changes in tumor vascularity may be useful to monitor the effectiveness of therapy. Diffusion tensor imaging may provide visualization and quantitative characterization of the major white matter pathways in DIPG [23, 24]. This superior delineation between tumor and normal brain compared to the conventional MRI techniques may prove useful, especially to perform biopsies and obtain DIPG samples. Specific MRI sequences, including single-voxel spectroscopy (SVS), multi-voxel MRS and dynamic susceptibility contrast (DSC) MRI may help in predicting short or long survival interval from diagnosis in patients with DIPG [25].

#### *4.2.3. Molecular drug imaging*

Imaging of radiolabeled drugs like monoclonal antibodies and tyrosine kinase inhibitors can be achieved by using PET technology [26]. A recently introduced PET imaging technique of zirconium-89 (89Zr)-labeled bevacizumab in children with DIPG demonstrated considerable inter-and intra-tumoral heterogeneity in drug delivery [27]. Therapeutic potential and toxicity both can be quantified by such non-invasive, in patient techniques of tumor imaging and drug distribution [28]. Thus, these newer imaging modalities provide quantitative physiologic and functional information to complement the anatomic visualization provided by conventional imaging. However, these techniques need further validation and have yet to impact treatment decisions [11].
