PXA was first described in 1979 as a distinct type of glioma that is postulated to have originated from subpial astrocytes (11). Presently, Kepes et al's (11) original description of a supratentorial astrocytoma that has a superficial cortical location and unique histological features, such as marked cellular pleomorphism, rich reticulin network, and prominent lipid-laden glial cells, is still relevant. PXA tends to be found in the supratentorial region, particularly in the temporal lobe. At times, both the leptomeninges and superficial regions of the cerebrum are anatomically involved (4). Occasionally, infratentorial cases have been described in the literature (4, 12). On neuroimaging, PXA is usually peripherally located and frequently cystic, involving the cerebral cortex and overlying leptomeninges (3). Demographically, there are conflicting reports on gender predilection with some papers reporting equal occurrence in both sexes and others claiming a slight male preponderance (13). Studies report that PXA is commonly diagnosed in the second decade of life (13–15). Prevalence in the infantile HGG group (here, referring to children younger than 3–5 years old) is infrequent (16). Regarding clinical presentation, affected patients tend to present with seizures (3, 17). Neurosurgical intervention, especially total excision of the tumor has been proven to be associated with good survival outcomes (18). Although PXA is reputed to have a relatively favorable prognosis, it has an increased risk of recurrence in comparison to other pediatric LGGs. This slightly more aggressive behavior has led to its designation as either a WHO Grade 2 or 3 CNS neoplasm (3). Existing literature shows that up to one-third of PXA tumors demonstrate anaplastic characteristics such as higher mitotic activity and necrosis, whereby both are associated with decreased overall survival (4–6). This particular subgroup is termed PXA WHO Grade 3. These tumors are more aggressive and have been reported to spread via cerebrospinal fluid (CSF), often in the setting of disease recurrence or malignant transformation (19, 20). For the PXA WHO Grade 2 tumors, the Ki-67 labeling index is generally <1%, whereas up to 15% has been reported in their WHO Grade 3 counterparts (3, 13, 21).

The advent of technological advancements has provided valuable insights into the molecular profiles of pediatric gliomas. We are now aware that a significant proportion of PXA cases harbor a BRAF V600E gene mutation and or CDKN2A gene alterations (4, 22, 23). In addition, an in-depth study by Mistry et al. (23), which focused on the subset of pediatric LGG that transformed into secondary HGG, demonstrates that BRAFV600E mutations and CDKN2A deletions constitute a clinically distinct subtype of secondary HGG. Essentially, they report that BRAF and CDKN2A gene alterations are less common in the pediatric LGG cohort that do not show malignant transformation and patients with BRAF mutations had longer latency to secondary HGG (23). Next, it is noteworthy to mention the presence of CDKN2A deletion in our patient's tumor. CDKN2A is a tumor suppressor gene that encodes the p16INK4a protein and serves as an inhibitor of cell cycle progression. Molecular insights have revealed that it is a major target of mutation in many human cancers (24). Previous studies have shown that the CDKN2A homozygous deletion is an important prognostic factor for survival outcomes of IDH-mutant glioma patients regardless of histology grading (25). For instance, homozygous deletion involving the CDKN2A locus found in adult WHO Grade 3 oligodendrogliomas has been linked to lower survival, regardless of microvascular proliferation with or without necrosis (3, 26). Furthermore, in histologically lower-grade adult gliomas, CDKN2A homozygous deletion is associated with a more aggressive clinical course and is a molecular marker of Grade 4 status in the latest WHO classification (3, 27). Interestingly, a recent study of 67 PXA tumors reports up to 94% of them have pre-existing CDKN2A/B deletions. However, further analyses demonstrate this genomic alteration is not associated with overall survival (5). Instead, WHO grading for PXA is a stronger predictor of survival in the study cohort (5). Overall, molecular information for tumors is important due to paradigm shifts toward targeted therapies for challenging cancers, especially brain tumors (28). For example, the preliminary evidence for BRAF inhibitors for disease control obtained by BRAF inhibitors in tumors harboring the BRAF V600E mutation has been optimistic (29, 30). Similarly, the identification of cyclin-dependent kinase inhibitor (CDK) gene alterations has paved the way for the development of CDK-related therapeutics against various malignancies, including gliomas (31–33).

Following that, the remaining PXA cases without BRAFV600E (including our patient) have been reported to harbor RTK (receptor tyrosine kinase) gene fusions rather than MAPK(mitogen-activated protein kinase) alterations (34). At the time of this writing, there is only one other pediatric PXA case in the literature that reports an NTRK fusion (35). Broadly speaking, gene fusions are pathognomonic mutations resulting from a hybrid of two or more coding regulatory DNA sequences between genes due to genomic rearrangements from translocations, deletions, duplications, or inversions (36–38). Gene fusions are clinically relevant because they provide important information on tumorigenesis that pave the way for the development of targeted therapies for patients with specific fusions (39). In recent years, transcriptomic analyses have uncovered a subset of glioma patients carrying gene fusions (39). For affected patients, it has been reported that gene fusions can occur up to 30%–50% in high-grade gliomas (36, 37, 40). To date, collaborative genomic studies have demonstrated that infantile HGGs comprise molecularly distinct subgroups that are characterized by gene fusions (9, 41). Examples include the NTRK fusions that have been described as oncogenic drivers in several human tumors, including pediatric gliomas (42). The NTRK family comprises NTRK1, NTRK2, and NTRK3 that encode the neurotrophin receptors tropomyosin-related kinase (TRK) groups such as TrkA, TrkB, and TrkC. Gene fusions involving the NTRK family are one of the most common mechanisms of oncogenic TRK activation (43). This is clinically relevant because NTRK fusions represent a pharmacologically targetable genomic alteration (35). Therefore, potential NTRK-targeted treatment offers hope for very young brain tumor patients with limited treatment options. To date, NTRK inhibitors are currently being offered in clinical trials for primary CNS tumors with promising results (44). Here, the option of an NTRK inhibitor for our patient is feasible if conventional treatment methods fail.

Put together, a summary of our patient's pertinent molecular findings includes the following: the lack of BRAFV600E mutation, the presence of CDKN2A homozygous deletion, and an ETV6::NTRK gene fusion. Based on the current disease understanding of this rare brain tumor, it may be difficult to draw definitive conclusions in regard to the molecular results' prognostic impact on our patient. However, we are aware that PXA tumors frequently recur and are associated with decreased survival compared with other LGGs in children and young adults (3). Furthermore, malignant progression is known to be more common in PXA in comparison to other RAS/MAPK-driven LGGs (3, 45).

In view of our patient's unusual clinical presentation, an overview of non-traumatic intracranial hemorrhagic in children is included in the following discussion. Non-traumatic pediatric intracranial hemorrhage (pICH) is defined as a brain parenchymal bleed with or without intraventricular extension occurring between 29 days and 18 years of age (46, 47). Typically, the incidence of pICH is cited to be extremely low in children. The exact incidence is unclear owing to current evidence relying on mostly case reports and small case series (35, 47, 48). Despite its rarity, pICH is an important cause of death and irreversible neurological injury (8). Delayed diagnosis is common because very young children have difficulties in accurately communicating complaints, and the hemorrhage can be manifested by non-specific symptoms such as irritability, somnolence, or headache. In addition, lateralizing neurological symptoms are reported less frequently in the pediatric population as compared to their adult counterparts (7, 49). Regardless, management should be prompt and thorough diagnostic workup to guide optimal clinical treatment (46, 47).

Of note, the pICH etiological spectrum differs from the adult population and is largely dominated by cerebral vascular lesions, hematological disorders, neoplasia, and systemic diseases. In addition, the literature shows that pICH can be secondary to various tumor types, including benign to malignant neoplasms (47). Erosion of cortical artery by the tumor, thin-walled tumor vessel, or unknown microvascular anomaly within the tumor have been postulated to be contributing factors for the bleeding episode (18, 50, 51). Specific to PXA, there have been only 3 other pediatric cases presenting as intracranial bleeds in the literature (Table 1).