In the WHO CNS5 guidelines, the grading of central nervous system (CNS) tumors has been substantially revised: the transition from Roman to Arabic numerals for grading supersedes previous practices, and grading is now consistently implemented within specific tumor types rather than comparatively across different types. The significance of this specific change involves more clarity and universality for the classification, more precision and adaptability, and greater alignment with other classifications leading to their easier use in the research field, which ultimately benefits patients. This entity-specific grading approach for CNS tumors differs from other organ systems where neoplasms are graded according to type-specific systems, such as those for breast or prostate cancers ^[1][43]. The rationale behind adopting intra-type grading within WHO CNS5 is multifaceted: first, to provide greater grading flexibility relative to each tumor type; second, to emphasize the biological consistency within tumor types over the prediction of clinical behavior; and third, to synchronize with WHO’s grading protocols for non-CNS tumors ^[2][10]. In tandem with these grading modifications, nomenclature changes have been made to reflect molecular characteristics in accordance with cIMPACT-NOW Update 6 and to standardize terminology across all classifications within the WHO Blue Books, especially those pertaining to peripheral nerve and soft-tissue tumors ^[3][44].

The revised classification introduces fourteen new types within the categories of Gliomas, Glioneuronal Tumors, and Neuronal Tumors, along with updates to the nomenclature of existing entities. A key example is the reclassification of diffuse midline glioma, now termed “H3 K27-altered” instead of “H3 K27M-mutant,” to recognize a range of pathogenic mechanisms influencing these tumors ^[4][45].

Significantly, WHO CNS5 differentiates diffuse gliomas based on the patient’s age, distinguishing between “adult-type” and “pediatric-type”. This distinction acknowledges the clinical and molecular differences between these groups and aims to guide more effective treatment strategies for CNS tumors in both demographics ^[2][10]. Additionally, the classification now recognizes infant-type hemispheric glioma as a separate high-grade glioma category characterized by a unique molecular profile, including fusion genes involving ALK, ROS1, NTRK1/2/3, or MET, predominantly seen in newborns and infants ^[5][46].

Pediatric-type diffuse low-grade gliomas (pLGG) with MYB/MYBL1 alterations constitute a distinct subset of IDH-wild-type and H3-wild-type tumors, notable for their benign clinical course and favorable prognosis ^[6][47]. In 2021, the World Health Organization updated their CNS tumor classification to include two categories of these pLGGs: angiocentric glioma with MYB-QKI fusions and diffuse astrocytoma with various MYB/MYBL1 alterations ^[7][4]. Most of the existing studies on these gliomas have focused on their clinicopathologic characteristics, with less emphasis on their radiologic features ^[8][48]. The primary treatment strategy for pLGGs with MYB/MYBL1 alterations is comprehensive surgical resection, as complete removal is often correlated with a positive outcome ^[9][49].

The 2016 WHO update on CNS tumors offered valuable insights but did not thoroughly delineate pediatric gliomas and their prognostic outcomes. Specifically, the IDH-wild-type/H3-wild-type low-grade tumors remained a heterogeneous group. Despite their typically benign nature and rare progression to anaplastic forms in children, there was a lack of distinction between pediatric and adult tumor types. Research showed different molecular markers in tumors between children and adults, with pediatric low-grade gliomas predominantly exhibiting alterations in the BRAF, FGFR, and MYB/MYBL1 genes, while IDH1/2 mutations were less common ^[10][50]. This distinction was further emphasized by cIMPACT-NOW in their fourth update ^[6][47].

In its 2021 revision, the WHO introduced a classification for pediatric-type diffuse low-grade gliomas, encompassing four subtypes: (1) diffuse astrocytoma, MYB- or MYBL1-altered; (2) angiocentric glioma; (3) polymorphous low-grade neuroepithelial tumor of the young; and (4) diffuse low-grade, MAPK pathway-altered glioma ^[11][8]. This discussion focuses on the first subtype. There are few studies on the radiologic characteristics of MYB/MYBL1-altered gliomas. In a study by Chiang et al., 46 such tumors were evaluated, with 23 pre-operative MR images being reviewed. The majority of patients presented with epilepsy, and the tumors were predominantly located in the cerebral hemispheres, although some were found in the diencephalon and brainstem. Upon T1 imaging, these tumors typically appeared iso- to hypointense, while T2/FLAIR imaging often revealed mixed signals or hyperintensity. Only one case showed faint and diffuse contrast enhancement, and no diffusion restriction was observed ^[12][51]. In cases where complete resection is not possible, additional chemotherapy and radiation are considered. MYB/MYBL1 alterations can be considered distinctive in the field of oncology due to their unique molecular characteristics and implications, giving them an important role in the context of personalized medicine and hinting toward their potential as therapeutic targets.

Angiocentric glioma (AG) is a unique brain tumor often associated with treatment-resistant epilepsy in children and young adults which can be effectively managed through neurosurgical intervention. An analysis of case reports since its initial identification revealed several key findings: (1) seizures are the most common initial symptom; (2) magnetic resonance imaging (MRI) typically reveals a supratentorial, non-enhancing lesion that is T1-hypointense and/or T2-hyperintense; (3) these tumors display specific histopathological features; and (4) outcomes following complete tumor resection are generally positive ^[13][52]. First identified in 2005 ^[7][14][4,53] and recognized as a distinct entity by 2007 ^[7][4], AG was initially categorized under “other glioma” in the 2016 WHO edition. However, in the latest classification, it is included among “pediatric-type low-grade diffuse gliomas”.

Due to the rarity of AG, gaining a comprehensive understanding has been challenging, but it is now graded as 1 in the 2021 WHO Classification. Commonly presenting with persistent, drug-resistant epilepsy in children, AG accounts for a small proportion of tumors in the German Neuropathology Reference Center ^[15][54]. A study by Kurokawa et al. reported a median patient age of 13. AGs are typically located in the supratentorial cortex, with a slight preference for the temporal lobe, although occurrences in the brainstem have been documented. MRI scans often reveal a single, T2-hyperintense lesion with no enhancement and a distinctive cortical rim on T1-weighted images ^[15][16][54,55].

Histologically, AG is characterized by an infiltrative growth pattern with uniform, bipolar spindle-shaped cells. Its hallmark features include perivascular cell arrangement around blood vessels and a horizontal cell stream beneath the pia-arachnoid structures. While some regions may resemble schwannomas, others can exhibit an epithelioid appearance. Key characteristics include the near absence of mitoses, microvascular proliferation, and necrosis. The tumor cells typically test positive for GFAP and negative for Olig2. EMA tests indicate ependymoma-like differentiation, corroborated by electron microscopy findings ^[14][53].

Some researchers postulate that AG originates from bipolar radial glia during embryogenesis, displaying ependymal features. Tests for IDH1-R132H, BRAF V600E, and neuronal antigens generally yield negative results, and the Ki-67 proliferation index is usually low. While rare anaplastic features have been noted, their clinical significance is not fully understood. Most AGs are associated with an MYB, QKI gene fusion, but the 2021 WHO Classification considers this only as a recommended, not mandatory, diagnostic criterion ^[7][4].

The mitogen-activated protein kinase (MAPK) pathway is crucial in regulating a variety of cellular functions, including cell growth, differentiation, apoptosis, and more. This pathway is activated by signaling molecules such as FGF, EGF, IGF, and TGF binding to their respective cell surface receptors, initiating a cascade of cytoplasmic protein kinase activations. This series of activations leads to the phosphorylation of multiple proteins and nuclear transcription factors, ultimately affecting gene expression ^[17][18][56,57].

The dysregulation of the MAPK signaling pathway has been implicated in a range of diseases, including inflammatory, immunological, and degenerative disorders. Its aberration is also associated with the initiation and progression of various neoplasms due to factors such as abnormal receptor expression or genetic mutations activating receptors and downstream signaling molecules. This includes CNS tumors like pilocytic astrocytomas and gangliogliomas ^[19][58].

The recent WHO classification of CNS tumors has introduced a new category within pediatric-type diffuse low-grade gliomas: diffuse low-grade gliomas with MAPK pathway alterations. These tumors typically develop in childhood and can occur anywhere in the CNS, often presenting with epilepsy ^[20][59].

The exact prevalence of these tumors is somewhat uncertain, as specialized molecular testing is required for diagnosis, but they are considered relatively rare. Radiologically, they often appear as variably enhancing masses with cystic components. Histologically, these tumors exhibit diverse morphologies, usually displaying non-extensive infiltration patterns. On a molecular level, they are characterized by alterations in the genes associated with the MAPK pathway and are distinct in that they lack IDH1/2 and H3F3A mutations and CDKN2A deletion. Several subtypes of these tumors have been identified, with the most common alterations involving FGFR1 and BRAF mutations ^[21][9].

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is an exceptionally rare, slowly progressing tumor that was recently incorporated into the World Health Organization classification of central nervous system tumors. Initially identified and characterized by Huse et al. in 2017, PLNTY was subsequently classified in the WHO Central Nervous System Tumors later that same year ^[22][60]. This tumor predominantly affects the temporal lobe (observed in approximately 80% of cases), although instances in other brain regions, like the parietal, frontal, and occipital lobes, have been documented. PLNTY typically presents in children and young adults, with an average age of onset around 20.6 years and a slight female predominance. It is categorized among long-term epilepsy-associated brain tumors (LEATs), which are commonly associated with seizures and often resistant to standard antiepileptic drugs ^[23][61]. However, symptoms of PLNTY may include headaches, dizziness, or visual disturbances.

Genetically, PLNTY is characterized by a unique DNA methylation profile and frequently involves alterations in the mitogen-activated protein kinase (MAPK) pathway, including the BRAF proto-oncogene and fibroblast growth factor receptors 2 and 3 (FGFR2 and FGFR3). These genetic alterations, such as BRAF-V600E mutations or FGFR2 and FGFR3 fusions, often coexist. BRAF-V600E mutations are more common in young adults, while FGFR2 fusions tend to be more prevalent in younger patients. The exact role of these genetic changes in the development of PLNTY is not fully understood ^[24][25][62,63].

The histology of PLNTY can vary, but it typically includes an oligodendroglioma-like component. This tumor type exhibits a range of cellular morphologies, from cells with uniformly small round nuclei to those with anisonucleosis or distinct nuclear features. Other features often observed include perivascular pseudorosetting and calcifications, while mitosis, necrosis, vascular proliferation, inflammation, and certain other cell features are typically absent. Immunostaining has shown positive staining for glial markers such as GFAP and Olig2, albeit with weak or focal expression, but CD34 expression was notably prominent and consistently observed across tumor cells and neuronal elements. Some tumor cells may exhibit antibodies for the BRAF p.

Achieving an optimal integrated diagnosis in neuro-oncology involves harmonizing histological categorization with genomic characterization. This process draws upon both histologically and genetically defined compendia of neoplasms. Despite the extensive nature of these compendia, certain correlations are commonly observed, with frequent integrations appearing in a manageable number of routine diagnoses. This approach is exemplified by the classification of ‘Diffuse low-grade glioma, MAPK pathway-altered’ as a specific tumor subtype ^[6][47].

In recent years, methylome profiling has emerged as a key method in CNS tumor classification. This technique, which analyzes genome-wide DNA methylation patterns, has gained significant attention in the academic field and is increasingly fundamental in the molecular taxonomy of CNS neoplasms ^[26][70]. While methylome profiling can sometimes serve as an indicator of genetic aberrations—for instance, a methylation signature akin to an IDH-wild-type glioblastoma may be identified without direct IDH mutation assays—it cannot completely replace mutation detection, especially in situations where targeted treatments or clinical trials require precise molecular aberrations ^[27][71]. Consequently, the molecular analysis of WHO grade II or III diffuse astrocytic, IDH-wild-type gliomas in adult patients is highly recommended. The presence of chromosomal aberrations such as +7/−10, EGFR amplification, or TERT promoter mutation should lead to a reclassification to WHO grade IV, significantly impacting both treatment strategies and prognostic expectations ^[28][72].

In pediatric low-grade glioma (pLGG), negative prognostic indicators include older age, astrocytic histology, large tumor size (>4–6 cm), midline crossing tumors, neurological deficits, and poor performance status. Conversely, presenting with seizures, particularly in neurologically intact individuals, is often viewed as a favorable prognostic factor. Pignatti et al. developed a scoring system in 2002, assigning points to various risk factors, and this system was validated across multiple trials ^[29][73]. The University of California, San Francisco’s (UCSF) more recent scoring system considers age, performance score, tumor size, and eloquent involvement in determining prognosis. Patients aged 55–60 years have a 5-year survival rate of 30% to 40%, with each additional year of age further diminishing their prognosis; however, those surviving beyond two years post-diagnosis may experience prolonged progression-free survival (PFS) despite challenging prognoses ^[30][31][74,75].

Tissue acquisition is crucial in accurately diagnosing, prognosing, and treating pLGG, as pathognomonic imaging is lacking. Needle biopsies can result in misdiagnosis rates of over 50%, making surgical resection the preferred method for tumor characterization. The support for extensive surgical resection is growing, as is evidence of its efficacy, although randomized controlled trials are still needed. This strategy was first proposed in 2001, and subsequent institutional studies, including one from the UCSF, have affirmed its effectiveness. Notably, the UCSF’s study demonstrated that a extent of resection (EOR) greater than 90% significantly improves overall survival (OS), with a 5-year survival rate of 97% versus 76% for EORs less than 90% ^[32][76]. The Johns Hopkins Hospital reported similar findings, indicating that gross total resection (GTR) can enhance both overall survival and progression-free survival (PFS). However, factors such as the involvement of the corticospinal tract, tumor volume, and oligodendroglioma histology can impede complete resection ^[33][77].

In a cohort study examining low-grade gliomas (LGGs), a significant correlation was found between both the residual volume post-surgery (p = 0.006) and the extent of surgical resection (p < 0.001) with overall survival among various LGGs. However, this correlation varied across the three LGG molecular subtypes. In the IDHmut-Codel subgroup, overall survival was significantly associated with the extent of resection (p = 0.01), but neither pre- nor postoperative tumor volumes showed a significant relationship. In contrast, in the IDHmut-Noncodel subgroup, preoperative volume (p = 0.018), postoperative volume (p = 0.004), and the degree of resection (p = 0.002) each were associated with overall survival. For the IDHwt subtype, there was no significant association between tumor volumes or resection extent and overall survival ^[34][78].

The relationship between the extent of surgical resection and overall survival is particularly noted in molecularly characterized IDH mutant astrocytomas and oligodendrogliomas. This association appears more pronounced in astrocytomas, potentially because of the higher efficacy of non-surgical therapies in oligodendrogliomas or their generally longer survival periods, which could mask the survival benefits of surgical intervention ^[35][36][79,80]. Patel et al. reported in their 2018 study involving a cohort of 74 patients with WHO grade II diffuse gliomas that the extent of glioma resection correlated with overall survival in the IDH-wild-type subgroup but not in the IDH mutant subgroup.

Prospective trials and retrospective studies have not consistently shown the significant prognostic effects of extent of resection (EOR) on overall survival (OS) and progression-free survival (PFS), but cognitive and quality of life outcomes post-surgery remain important considerations. The average preoperative cognitive function score in the LGG cohort, as measured by the EORTC score, was 80.9, compared to 70.9 in the high-grade glioma (HGG) group. Postoperatively, the LGG group’s scores remained stable, while the HGG group showed significant improvement at 1- and 6-month follow-ups. In the LGG cohort, cognitive function changes varied, with 24% reporting improvement and 20% experiencing deterioration at 1 month postoperatively ^[37][82]. The rapid growth rate of IDH-wild-type gliomas may exert more pressure on adjacent brain structures than IDH mutant gliomas, suggesting that more aggressive surgical resection could improve cognitive outcomes by relieving mass effects and associated edema ^[38][83]. Postoperative experiences differ among patients, with some experiencing relief and others facing the stress of cancer diagnosis and ongoing surveillance or treatment. Notably, lower preoperative cognitive function scores have been observed in females compared to males ^[39][84].

Neuronavigation and brain mapping technologies, including functional MRI and cortical stimulation mapping, aid in precise resections while preserving quality of life. Neurosurgeons can customize procedures to individual brain structures, thereby minimizing permanent deficits. Brain mapping has shown efficacy in reducing permanent deficit rates, increasing gross total resection (GTR) rates, and providing survival benefits. Ideally, a prospective, multicenter trial would address this issue definitively, but challenges in recruitment, follow-up, and ethical considerations make organizing such a trial complex ^[40][41][85,86].

In neuro-oncology, temozolomide has gained attention as a chemotherapy drug, especially due to its ease of oral administration, lower toxicity compared to PCV (procarbazine, lomustine, and vincristine), effective penetration of the blood–brain barrier, and proven effectiveness against glioblastoma. Phase 2 studies have shown temozolomide to be effective against growing LGGs, whether previously exposed to radiation or not, on standard 5-day or alternate schedules like 3 weeks on followed by 1 week off, or 7 weeks on followed by 4 weeks off. Temozolomide has also been associated with improved quality of life outcomes ^[42][87].

In the realm of glioma treatment, there exist pivotal inquiries concerning the potential of temozolomide to either supplant radiotherapy or complement it in the management of low-grade gliomas (LGGs). Presently, ongoing clinical trials are diligently endeavoring to elucidate these quandaries. A phase 3 investigation spearheaded by a consortium of European and Canadian researchers is actively scrutinizing this matter by juxtaposing radiotherapy against temozolomide therapy for individuals afflicted with LGGs, with careful consideration being given to the chromosomal 1p status. This comprehensive study aims to assess a gamut of clinical outcomes, encompassing the likes of progression-free survival (PFS), neurocognitive functionality, and overall quality of life ^[43][44][88,89]. Furthermore, there are concerted endeavors to ascertain the advantages of amalgamating temozolomide with radiotherapy, particularly in the context of high-risk LGGs. The Radiation Therapy Oncology Group (RTOG) has successfully concluded its phase 2 inquiry (RTOG 0424), while the Eastern Cooperative Oncology Group (ECOG) has embarked upon a phase 3 exploration (ECOG E3F05). The overarching objective of these initiatives, in conjunction with similar studies unfolding in Europe, is to elucidate the role that temozolomide plays within the treatment paradigm for LGG ^[43][44][88,89].

In a separate investigation, a phase II trial delineated its primary objective as evaluating the response to temozolomide (TMZ) among pediatric patients grappling with recurrent or progressive LGG. The inception of this trial emanated from the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center and subsequently expanded to encompass additional clinical sites. Notably, TMZ was administered orally under fasting conditions, with treatment cycles recurring at 28-day intervals. The observed outcomes encompassed partial response (PR) in three patients and minimal response (MR) in one patient, while 42% of patients exhibited stable disease (SD), and an equivalent percentage showed progressive disease (PD) after a minimum of two treatment cycles ^[45][90].

In a tangentially related vein, there exists substantiating evidence derived from the RTOG trial (RTOG 9802) which underscores the potential of employing procarbazine, lomustine, and vincristine (PCV) in tandem with radiotherapy, particularly in the context of recurrent LGGs post-radiotherapy. In this investigation, individuals who received a combined regimen of PCV and radiotherapy exhibited more favorable outcomes in terms of progression-free survival (PFS). Nevertheless, there was no statistically significant disparity in overall survival, thereby suggesting that PCV may serve as a potent adjunct both as a secondary intervention and when administered concomitantly with radiotherapy. It is imperative to note, however, that there exists a dearth of consensus regarding the optimal timing of surgery and its overarching impact on LGG management, necessitating further comprehensive exploration through prospective studies, mirroring the scrutiny accorded to the timing of radiotherapy in the treatment of LGGs ^[46][91].

It is paramount to acknowledge that radiotherapy stands as the sole therapeutic modality validated through a randomized controlled trial to confer certain advantages upon patients grappling with LGGs. Nonetheless, the optimal utilization of radiotherapy remains a topic of incessant deliberation. The EORTC 22845 study has proffered insights into this discourse, demonstrating that individuals subjected to early radiotherapy (54 Gy) experienced prolonged intervals devoid of disease progression (PFS) and exhibited superior seizure control relative to those subjected to delayed radiotherapy. Concretely, the progression-free survival stretched to 5.3 years for the early treatment cohort as opposed to 3.4 years for their delayed treatment counterparts (p  <  0.0001). Furthermore, a noteworthy 75% of individuals in the early treatment cohort achieved seizure control in comparison to 59% in the delayed treatment cohort (p  =  0.0329). Despite these discernible benefits, there was no marked discrepancy in overall survival between the two cohorts, with values of 7.4 years for the early cohort and 7.2 years for the delayed cohort. Given the absence of definitive data regarding quality of life, researchers have proffered the contention that it may be reasonable to defer radiotherapy for LGG patients who are in robust health. This hesitation emanates from the ambiguous equilibrium between the advantages inherent to extended progression-free survival and seizure control and the potential merits associated with overall survival. Additionally, it is worth noting that 35% of patients slated for deferred radiotherapy ultimately circumvented its necessity, thereby mitigating potential side effects ^[47][92].