**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).

38 Brain Tumors - An Update

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].

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

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

specific histone mutation (H3K27 M) and are called diffuse midline glioma, H3K27M-mutant [40]. A mutation-specific antibody can be used to detect this mutation on immunohistochem-

Diffuse Intrinsic Pontine Glioma

41

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

Prior to the routine MRI use, it was estimated that up to 15% of patients diagnosed with DIPG had a non-glial tumor or non-tumor process [41, 42]. The role of surgical intervention was controversial and, in some centres, biopsy procedures were frequently undertaken for histological confirmation. Although it is not 100% specific, with the wide availability in the early 1990s MRI became the modality of choice for DIPG diagnosis. Biopsy confirmation was thought to be an unnecessary risk as it did not alter the management [43]. The lack of clear biopsy benefit combined with improved diagnostic imaging capabilities led to MRI scans becoming the diagnostic standard of care for DIPG in the United Sates [18, 44]. More recently, there has been a renewed interest in performing stereotactic biopsies in patients with DIPG [45]. In France, biopsies were routinely performed with minimal morbidity and high diagnostic yield [46], nonetheless, it was not a common practice. The increase in the available DIPG tumor samples has yielded valuable data toward improving our understanding of the biology of DIPG [45, 47, 48]. Some of the identified biologic markers have been shown to correlate with progression-free survival (PFS) and may be useful to stratify patients in future clinical trials [49]. Considering the potential for new diagnostic and therapeutic methods combined with low morbidity associated with surgical procedures [50], the option of biopsy is being reconsidered and may eventually be included as part of the routine diagnostic evaluation for DIPG [51]. The second Consensus Conference on Pediatric Neurosurgery recommended biopsy in DIPG to ascertain biological characteristics to enhance understanding and targeting of treatment, especially in the setting of clinical trials [52]. Biopsy from a single area may not be representative of the entire tumor [53] but it may still provide important molecular information.

More than 250 clinical trials in the last three decades have failed to improve the poor outcome of DIPG [20]. Due to the location it is not amenable to the surgery and chemotherapy agents are yet to show any response. Radiation therapy remains the standard of care at present. The barriers to achieve a cure for DIPG may include the inability of the surgical resection, drug delivery difficulties secondary to the blood-brain barrier (BBB) and intra- and inter-tumoral

Surgical resection of DIPG is not feasible due to the presence of vital structures where the tumor is located. Rarely, surgical intervention like ventriculoperitoneal shunt or endoscopic

heterogeneity in the identified molecular aberrations [54].

istry (**Figure 2F**).

**7. Treatment**

**7.1. Surgery**

**6. The role of biopsy in diagnosis**

**Figure 2.** Histologic features of DIPG. Tumor infiltrating medullary neurons, H & E 100× (A) and 200× (B). (C) Tumor showing mitotic figures, H & E 400×. (D) Tumor/necrosis interface showing pseudo-palisading tumor necrosis. (E) Exuberant tumor-associated microvascular proliferation. (F) Tumor cells showing positive nuclear H3K27 M staining with sparing of the endothelial nuclei of admixed blood vessels H3K27 M 200×. (G) Loss of staining of tumor cell nuclei with the trimethylated antibody with retained staining in the endothelial cells, H3K27me3 200×. Images courtesy of Dr. Jason Dyke (Royal Perth Hospital, Australia).

specific histone mutation (H3K27 M) and are called diffuse midline glioma, H3K27M-mutant [40]. A mutation-specific antibody can be used to detect this mutation on immunohistochemistry (**Figure 2F**).
