**2.3. Differential diagnosis in MRI**

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].

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

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

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

On fluid-attenuated inversion recovery (FLAIR) imaging sequences, the tumor frequently appears homogeneous. MRI can also show pinpoint intratumoral hemorrhages, ventral

diagnosis of DIPG is based on MRI findings combined with the clinical presentation.

**2.2. Radiographic findings**

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isointense on T1 (**Figure 1**).

mass.

A universally diagnostic criterion has not yet been defined for DIPGs. Currently, the criteria that are typically accepted include symptom duration less than 6 months, at least two or three symptoms related to brainstem dysfunction, and pontine enlargement with evidence of diffusely infiltrative tumor centered in and involving greater than 50–66% of the pons [25].

In MRI, DIPGs present with distinct characteristics from pilocytic astrocytoma; for example, MRI shows the following aspects: (A) focal, well defined on T1 and T2 weighting, (B) mini‐ mum brainstem swelling, and (C) brainstem location without extension. The two most common types of pediatric brainstem tumors, DIPGs and pilocytic astrocytoma, can be accurately identified by MRI alone in most cases. Although MRI is not 100% specific, the vast majority of children diagnosed with DIPG by MRI do have a diffuse infiltrative glioma.

Patients with diffuse brainstem gliomas associated with neurofibromatosis type 1 (NF1) may mimic DIPG on imaging. However, they are usually low-grade gliomas (LGG—World Health Organization (WHO) grades I–II) which can be asymptomatic and present with a simple differential diagnosis based on family history and clinical examination [26].

In the context of an atypical presentation of DIPG (presentation with clinical features and circumscribed MRI characteristics), it is important to rule out potential differential diagnosis. These include embryonic tumors such as ATRT, PNET, and nonmalignant lesions such as infections, neurodegenerative conditions, and hemangioblastomas [27].

#### **2.4. Stereotactic biopsy**

Before the advent of effective imaging techniques, surgical biopsies played an important role in DIPG diagnosis. However, with improved radiologic capabilities—primarily MRI—until recently, stereotactic biopsies are only performed in the rare cases, where the diagnosis is uncertain based on MRI findings. Nonetheless, as neurosurgical experience with stereotactic biopsies of DIPGs grew and was proven to be safer, as well as neuropathologic expertise to identify molecular subtypes increased, biopsy has been increasingly performed to not only identify the type of tumor present but to delineate potential molecular targets that could be therapeutically explored. In experienced hands, the permanent morbidity after stereotactic biopsy has been found to be less than 5%.

In histologic diagnosis, DIPGs are defined as a fibrillary astrocytoma, WHO grades II–IV, and in most of the cases resemble malignant gliomas in other locations [28]. However, the prognosis for DIPGs is not associated with the histological classification. DIPGs harboring the histone 3 mutation classified as WHO II and III have a poor OS, similar to WHO IV patients [29]. In addition, significant histopathological variability has been reported in DIPGs, where a single biopsy may not be representative of the histological classification of the entire tumor [23,29,30].

Important biological information obtained from biopsies may be used in future clinical trials, guiding new treatment regimens and allowing for advances in surgical and molecular analytical techniques [31]. The use of tissue obtained from pretreatment biopsies combined with antibodies to detect driver mutations gives the opportunity to identify the genomic mutational landscape of DIPG and provides opportunities to improve diagnosis, prognosis, and better understanding of the potential drug targets.
