**2. Diagnosis: clinical presentation, radiographic findings, and stereotactic biopsy**

## **2.1. Clinical presentation**

neurodevelopmental process. It usually affects middle childhood, with a peak onset of 6–9 years of age. High-grade gliomas (HGGs) typically have a predilection for the ventral pons, a finding that would reflect the presence of a cell of origin as well as a signaling microenviron‐ ment favorable for tumor formation [1–3]. A study using early postmortem DIPG tumor tissue has shown that the Sonic Hedgehog (Shh) signaling pathway in DIPG tumor cells is in‐ volved in many developmental and oncogenic processes, such as neural embryogenesis and oligodendrogenesis. The dysregulation of this molecular system in DIPG leads to hypertro‐ phy of the ventral pons and suggests a potential molecular origin for this poorly understood cancer [4]. According to the lessons learned from other pediatric brain tumors, such as medulloblastoma, neural stem or precursor cells would be the most likely cell type that could

In the United States, 200–300 children are diagnosed each year with DIPG [7]. Unfortunately, being the pediatric brain tumor with the highest mortality rate, DIPGs have poor prognosis with a less than 1-year survival, where less than 10% and 2% of patients survive after 2 and 5 years post-diagnosis, respectively [8]. The grim outcome first and foremost is due to the tumor's delicate anatomical location and significant infiltration. Extensive surgical resection is not a treatment option, leaving radiation therapy (RT) and chemotherapy as the only

RT is the standard treatment for children with DIPG and results in improvement of symp‐ toms in more than 80% of the patients; however, it rarely results in a cure. The conventional treatment consists of 1.8 Gy fractions delivered once daily, 5 days a week, for about 6 weeks to a total cumulative target dose of 54 Gy. Hyperfractionated doses up to 72 Gy have not shown improved efficacy in children and resulted in increased morbidity. On the other hand, hypofractionated RT may lead to similar outcomes as standard treatment. The median survival of patients treated with RT is only 10 months [9,10]. When RT is associated with standard chemotherapeutic agents, no survival benefit was shown, in neither the event-free survival

Another reason of poor prognosis is associated with the ineffective results using chemother‐ apeutic agents. Despite decades of research and use of different chemotherapeutic strategies, no survival advantage has been achieved. In the last 30 years, several clinical trials were done using various adjuvant chemotherapeutic drugs utilized prior to, during, or after radiothera‐ py in DIPG patients. The results were bleak: none of these clinical trials showed any improve‐ ment in survival of this pediatric cancer, leaving DIPG as the number one cause of brain tumorrelated death in children [12]. In addition to the difficulty associated with finding effective therapeutics, it is also speculated that the tumor biology changes between the primary and recurrent tumors, leading to another problem—resistance to therapy. Furthermore, an additional challenge includes ways of overcoming the restrictive ability of the intact blood–

The lack of reliable models along with poor knowledge of the biological basis of DIPG has been critical elements in failure to make progress in this disease. In the pre-CT and magnetic resonance imaging (MRI) eras, histological assessment of biopsies was routinely conducted to diagnose DIPGs. However, this standard of care was discontinued in the early 1990s, due to

transform and give rise to DIPG [4–6].

402 Neurooncology - Newer Developments

(EFS) nor the overall survival (OS) of patients [11].

brain barrier (BBB) in patients with DIPG.

remaining therapies.

Cerebellar signs (e.g., ataxia, dysmetria, and dysarthria), pyramidal tract signs (e.g., hyperre‐ flexia, clonus, increased tone, and presence of a Babinski reflex), and cranial nerve palsies (unilateral or bilateral) are the classic triad clinical presentation in DIPG. As the tumor grows, the pons become diffusely infiltrated and enlarged, the basilar artery is encased, and crucial nuclei of cranial nerve tracts V, VI, VII, and VIII within the pons are compressed. The symptom onset is acute, with a fast progression, where children typically experience 1 month or less of neurologic manifestations before they are diagnosed. Symptom duration greater than 6 months prior to presentation should prompt a search for an alternate diagnosis. The most common reported symptoms are abnormal or limited eye movements, diplopia, asymmetric smile, clumsiness, difficulty walking, loss of balance, and weakness [19,20]. Obstructive hydrocephalus presenting with headaches, nausea, and vomiting may be present due to increased intracranial pressure, resulting from expansion of the pons. Other less common symptoms may occur, including behavioral changes, night terrors, and scholarly difficulties [8]. Among the rare symptoms are urinary retention and other voiding abnormalities with‐ out spinal cord lesions, which can be due to disruption of the pontine micturition center [21].

## **2.2. Radiographic findings**

Advances in imaging technology over the last few decades and the development of MRI have significantly improved the accurate diagnosing of DIPG. MRI scan is the best noninvasive method to determine the size and the characteristics of the tumor. Thus, the comprehensive diagnosis of DIPG is based on MRI findings combined with the clinical presentation.

On MRI, the boundaries of a DIPG are hard to determine, as the tumor cells invade the surrounding tissue of the pons—the tumor appears as a large expansible brainstem mass. The epicenter of DIPG lies within the pons and the lesion involves the majority of its structure. Tumors typically show diffuse hyperintense bright signal on T2-weighted and are hypo- or isointense on T1 (**Figure 1**).

**Figure 1.** Precontrast sagittal volume T1 MRI of the brain of a DIPG patient showing diffusely infiltrating pontine mass.

On fluid-attenuated inversion recovery (FLAIR) imaging sequences, the tumor frequently appears homogeneous. MRI can also show pinpoint intratumoral hemorrhages, ventral involvement of the pons, encasement of the basilar artery, and possible sites of tumor extension [8,22,23].

One classification system developed by Choux et al. [24] classifies brainstem gliomas into diffuse, intrinsic focal, extrinsic focal, and cervicomedullary based on MRI. DIPGs are classified as type I tumors—those that diffuse throughout the brainstem. Type II, III, and IV tumors are characterized by more focal lesions and may have a more favorable outcome.

Compared to computed tomography (CT), MRI provides superior imaging of the posterior fossa of the brain and has a superior contrast resolution of soft tissue. Other advanced imaging techniques include magnetic resonance spectroscopy (MRS), perfusion imaging, and posi‐ tron emission tomography (PET). These imaging methods show improved advantages such as tumor differentiation. However, MRI appearance is uncertain and stratification of pa‐ tients based on the aggressiveness of their tumors could be helpful in deducing a more accurate diagnosis, leading to an improved understanding of these tumors.
