Bridging pediatric and adult neuro-oncology: Insights into adolescents and young adults (AYA) central nervous system tumors

Abstract

Adolescents and young adults (AYA) with central nervous system (CNS) tumors represent a distinct and historically underrecognized population that spans the traditional pediatric–adult oncology divide, with unique biological, clinical, and survivorship considerations. The central nervous system (CNS) tumor spectrum in this age band is thus broad: pediatric-type entities driven by MAPK-pathway alterations, adult-type IDH- and H3-mutant gliomas, embryonal tumors, ependymomas, and intracranial germ cell tumors all appear, and prognosis and treatment are increasingly determined by molecular subtype rather than chronologic age. Integrated workflows combining neuroimaging, histopathology, and molecular profiling now anchor diagnosis and risk stratification. Treatment strategy — surgery, radiotherapy, systemic and targeted agents, and emerging immunotherapies — must balance efficacy against the cumulative late effects that come with it: neurocognitive change, endocrinopathy, vasculopathy, fertility loss, psychosocial disruption, and gaps in transition of care. Germline predisposition syndromes contribute meaningfully to disease biology and have implications for treatment, surveillance, and family screening. This review synthesizes the current evidence across diagnosis, treatment, survivorship, and predisposition, and argues for the consolidation of AYA neuro-oncology as a distinct discipline supported by dedicated trial access and survivorship infrastructure.

Introduction

The adolescent and young adult (AYA) population, defined by the National Cancer Institute as individuals aged 15–39 years, sits at the intersection of pediatric and adult oncology [1,2].

It comprises both pediatric patients who have transitioned to adult care and patients first diagnosed in young adulthood. Approximately 14% of primary central nervous system (CNS) tumor diagnoses present in this age band [3], and the tumor spectrum is heterogeneous. AYA patients may develop gliomas of multiple subtypes, ependymomas, medulloblastomas and other embryonal tumors, and intracranial germ cell tumors, spanning both pediatric-type and adult-type entities [3].

The obstacles that AYA patients face stem from several factors, including poor systemic care access and utilization, differences in tumor biology and treatment toxicities, low representation rates in clinical trials, and delayed time-to-diagnosis [2,4,5]. Compounding this, the AYA period encompasses critical biological and psychosocial milestones, rendering this population particularly vulnerable to disease- and treatment-related compromise of these milestones [6]. Overall, these factors have been linked to survival disparities when compared to younger or older populations and highlight the need to address these gaps [5,7].

The focus of this review will be to describe the clinical and integrated diagnostic approaches to inform management of CNS tumors in the AYA population, with a focus on practical AYA-specific considerations.

General Approach to AYA CNS Tumors

Presenting symptoms

The clinical presentation of AYA CNS tumors is non-specific and largely location dependent. The most frequent symptoms are headache and other features of elevated intracranial pressure, seizures, focal neurologic deficits, and cognitive change [8]. Within the AYA group specifically, signs of elevated ICP with headaches are most frequent, with seizures occurring in around 44% of patients with high-grade gliomas [9,10]. Clinically, high-grade gliomas are more likely to present with more rapid rates of progression, while low-grade gliomas result in chronic and slower progression. Long-standing refractory epilepsy has been specifically found to be a common presenting feature in patients with diffuse low-grade gliomas arising in the supratentorium, especially when involving the temporal lobe [11]. Otherwise, symptoms are location specific, and commonly include visual changes with optic pathway involvement, gait instability and/or ataxia with cerebellar involvement, and behavioral changes with thalamic or larger hemispheric involvement [12]. Hydrocephalus can be seen in tumors that favor the ventricles, such as is seen with subependymal giant cell astrocytoma (SEGA) arising near the Foramen of Monro, chordoid gliomas arising from the third ventricle, and large posterior fossa tumors; pineal tumors may present with Parinaud syndrome [13,14]. Myelopathy can be seen in the setting of spinal cord tumors, such as is seen with ependymomas.

Local control strategies: surgery and radiation therapy

Local control strategies for AYA CNS tumors require careful consideration of tumor biology, anatomical location, and the long-term neurological and functional consequences of treatment decisions. Access to neurosurgical expertise must also be considered, with superior survival and post-operative outcomes achieved with care provided at comprehensive cancer centers or with pediatric neurosurgery expertise [15,16]. This could be related to differences in surgical technique preferences, available surgical tools, and case epidemiology and volumes. In addition to conventional neurosurgery, Laser Interstitial Thermal Therapy (LITT) can be used to treat deep, hard-to-reach tumors and is being explored in combination with immunotherapy because of its ability to transiently disrupt the blood-brain barrier (BBB) [17]. Surgical management must balance potential survival benefit against preservation of neurological function in the context of survivorship and quality of life. This tension is illustrated in the management of low-grade glioma (LGG), where tumor biology and expected outcomes differ substantially between pediatric-type and adult-type disease. Pediatric-type LGG with MAPK activation are associated with excellent long-term prognosis, even among patients with residual tumors, and therefore pursuing aggressive surgical resection leading to excessive morbidity is often not warranted [18]. IDH-mutant LGG on the other hand are low grade tumors that almost always undergo malignant transformation with emerging evidence suggesting that supramaximal resection is associated with improved overall survival [19].

Similar considerations apply to radiation therapy, where decisions regarding timing, treatment volume, and modality must account for the elevated lifetime risks of secondary CNS malignancy, cerebrovascular disease and vasculopathy, endocrine dysfunction, and neurocognitive impairment [20,21]. Timing of radiotherapy represents a key point of divergence between pediatric and adult practice: in younger patients, radiotherapy is often deferred or avoided to mitigate late effects, whereas adult protocols may favor earlier treatment to optimize disease control. In addition to timing of radiation therapy, tumor biology should also be taken strongly into consideration. For example, in patients with pediatric LGGs, radiation therapy is an independent prognostic factor that is predictive of worsened long-term outcome and is usually avoided altogether or reserved until many lines of chemotherapy and targeted therapy have failed to obtain disease control. In contrast, in the case of grade 2 IDH-mutant glioma, for patients who were initially observed after resection and then developed radiographic progression, the standard treatment has historically been radiation therapy and chemotherapy. However, this is evolving with the development and FDA approval of the IDH inhibitor vorasidenib, for carefully selected patients following surgery [22,23].

Systemic therapy and cumulative toxicity

Systemic therapy in AYA patients with CNS tumors requires balancing short-term efficacy against the cumulative toxicities of prolonged and sequential treatment. Many AYA patients receive systemic therapy over extended periods, particularly in tumors with chronic or relapsing trajectories, resulting in gradual accrual of treatment-related morbidity during critical developmental, educational, and psychosocial phases [24].

AYAs are particularly susceptible to the toxicity of chemotherapy and tolerance varies across the AYA age spectrum. Younger adolescents may be more vulnerable to neurotoxicity, ototoxicity, and endocrine dysfunction while older AYA patients may not tolerate pediatric-style dose intensity and prolonged schedules. Fertility preservation, cardiopulmonary toxicity, cumulative myelosuppression, and secondary malignancy risk are key considerations when selecting and sequencing therapy [25]. Toxicity is often driven by the cumulative burden of exposure across multiple lines of treatment and in combination with prior surgery and radiotherapy.

Systemic therapy decisions in AYA CNS tumors therefore require longitudinal planning and close coordination between pediatric and adult oncology teams. Proactive adjustment of dosage for chemotherapy and other systemic agents is recommended to minimize cumulative toxicity while preserving long-term function [26].

Molecularly targeted approaches

Advancements in molecular diagnostics have been instrumental in refining diagnostic criteria, risk stratification and the development of novel targeted therapeutics in many CNS tumors and are of particular relevance in AYA. For the first time, the 2016 WHO CNS classification integrated molecular features in conjunction with histological findings into the definition of many tumor types. With continued expansion of the availability and reliability of molecular techniques, there was a major shift in the 2021 WHO classification for CNS tumors with changes to glioma categorization, molecular features altering tumor grade and DNA methylation profiling defining several subgroups in a variety of tumor types [27]. These changes were particularly pertinent for AYA patients with a glioma where prognosis and treatment selection are driven by molecular characterization rather than by age [27].

Clinical trial access and age-based eligibility gaps

Barriers to clinical trial involvement for AYA cancer patients have been found to occur at multiple levels across the health system, including at the physician and patient level [28]. Contributing factors include limited availability of age-appropriate studies, separation between pediatric and adult oncology systems, restrictive eligibility criteria, and poor access to specialized centers [2]. Disease complexity and psychosocial barriers unique to the AYA population, including limited caregiver support from either burnout or absence of caregivers, further limit participation, resulting in fewer evidence-based treatment advances tailored to this group. Additionally, the cost and logistics of opening and running AYA trials can be prohibitive as it often requires the same trial to be open at both an adult and pediatric site to allow appropriate supportive and inpatient care and may involve approval from multiple Institutional Review Boards/Research Ethics Committees (IRB/REC). As a result, treatment for many AYAs is extrapolated from data derived from a different age group, where there may be differences in tumor biology or treatment toxicity that is not accounted for in trial outcomes. These challenges highlight the need for more inclusive, coordinated trial design. Recently, there has been a concerted effort by clinical trial groups to include patients up to 39 years in pediatric trials for tumor types known to be prevalent in the AYA population, and a number of AYA working groups have been incorporated into different clinical trial consortia in both Europe and North America to address the disparities in trial enrollment [[29], [30], [31]].

Glioma

Gliomas account for approximately 80% of malignant CNS tumors in the AYA population and are the leading cause of cancer-related death in this group [32]. They are classified as adult-type and pediatric-type entities, and can be diffuse or circumscribed. Clinical course tracks molecular profile more closely than histology, and Fig. 1 summarizes the resulting taxonomy.

Fig. 1.

Overview of classification of gliomas relevant to the AYA population.

Adult-type gliomas

Adult-type diffuse gliomas tend to present in the third to late fourth decades of life, and include IDH mutant (IDHm) diffuse astrocytoma, IDHm and 1p/19q-codeleted oligodendroglioma, and IDH wild-type (IDHwt) glioblastoma [8,33]. While IDH mutations are rare in pediatric populations, emerging data suggest that non-canonical IDH variants are enriched in AYA patients relative to older adults [34]. Glioblastoma has peak incidence at 75–84 years of age, and AYA patients represent only 2.9% of patients with glioblastoma [35].

Pediatric-type gliomas

Pediatric-type alterations are found in roughly one-third of AYA gliomas and are divided broadly into pediatric-type high-grade glioma (HGG) and low-grade glioma (LGG) categories [36].

Three of the four pediatric-type HGG subtypes are relevant in the AYA setting. Two are defined by histone mutations, including H3K27 M diffuse midline gliomas and H3G34-altered diffuse hemispheric glioma. The latter is quintessentially AYA, with a peak age of onset of 16–24 years and a predilection for the frontal cortex, though it can arise anywhere supratentorially [37,38]. The third relevant subtype is H3/IDH-wildtype pHGG, a heterogeneous group defined by one of three driver alterations — PDGFRA (RTK1), EGFR (RTK2), or MYCN (RTK3). Peak age of onset is not yet well characterized; the tumors typically arise supratentorially, enhance on contrast imaging, and show restricted diffusion and increased perfusion consistent with their high-grade nature [39]. Prognosis varies by subtype: RTK2 carries the best outcome (median overall survival ∼33 months) and MYCN the worst (∼14 months) [40].

Pediatric-type LGG comprises four entities: diffuse astrocytoma, MYBL1-altered (MYB-DA); angiocentric glioma (AG); polymorphous low-grade neuroepithelial tumor of the young (PLNTY); and diffuse low-grade glioma, MAPK-pathway-altered (LGG-MAPK). Age and anatomic distribution differ across these entities. MYB-DA follows a bimodal distribution with incidence peaks at age 5 and again at age 15 [41]. These tumors have predilection for temporal lobes, but can occur elsewhere in the cerebral hemispheres and within the brainstem [42]. AG typically presents in the first two decades of life and favors supratentorial locations in AYA patients, with brainstem involvement seen more often in younger children [[43], [44], [45]]. PLNTY presents at a median age of 16 years and arises in temporal cortical and subcortical regions s [46]. LGG-MAPK is the most heterogeneous; natural history and prognosis depend on the specific driver mutation and age at presentation. A population-based analysis showed that FGFR- or BRAF-altered LGG in AYA patients carry better outcomes than the same alterations in children, and several of these drivers are now targetable [36,38,47].

The WHO classification now recognizes six circumscribed gliomas, most of them low-grade, defined by sharp tumor borders and a relatively indolent course: pilocytic astrocytoma, pleomorphic xanthoastrocytoma (PXA), subependymal giant cell astrocytoma (SEGA), chordoid glioma, astroblastoma, and high-grade astrocytoma with piloid features (HGAP).

Pilocytic astrocytoma is the most common pediatric brain tumor and remains common in AYA, with 10-year survival above 90% [48,49]. These tumors typically present as a cystic lesion, and in AYA patients, are more likely to occur supratentorially as is the case with adults, compared to infratentorially in children, though can occur anywhere along the neuraxis, including the optic pathway as is common in neurofibromatosis type 1 (NF1) pediatric patients [49]. In contrast, PXA is a rare tumor that occurs predominantly in adolescence/early adulthood, with a median age of diagnosis of 20 years [50]. SEGAs are tumors that develop almost exclusively in patients with tuberous sclerosis complex (TSC) mutations [51]. Chordoid gliomas have a female predominance and present in patients along the older end of the AYA age spectrum [14]. Astroblastomas are rare tumors with a female predominance as well, and age at presentation ranging from 14.5 to 60 years [52]. HGAP, the only high-grade entity in this group, presents in older AYA patients and favors the posterior fossa, with occasional diencephalic or spinal cord involvement [53].

From a histopathologic perspective, these circumscribed tumors may have unique features to each entity, but reliance on histology alone is no longer sufficient and comprehensive molecular profiling of these tumors is now recommended. BRAF fusions are most common in pilocytic astrocytomas, occurring in up to 70% of cases, and BRAF p. V600E mutation is present in most PXAs [54,55]. Identifying a CDKN2A/2B deletion is common in HGAP and PXA [56]. Astroblastoma, chordoid glioma and SEGA do not carry MAPK mutations and instead hold unique characteristic molecular features. The diagnosis of astroblastoma requires MN1 fusions or BEND2 mutations to be present and SEGA tend to harbor mTOR pathway activation markers, with typically TSC1 or TSC2 mutations [8,57]. PRKCA mutations are diagnostic for chordoid gliomas [8].

Targeted therapies in AYA gliomas

With advancements in molecular diagnostics and a deepening of our understanding of the genetic drivers of many tumors, identification of specific genomic alterations can now be used to guide incorporation of targeted therapies into the treatment of a variety of gliomas. The targeted therapies discussed below provide a snapshot of the field and while an exhaustive discussion is beyond the scope of this review, the currently active clinical trials for AYA glioma patients, including immunotherapy trials, are summarized in Table 1.

Table 1.

Summary of ongoing clinical trials exploring targeted and immune therapies for gliomas.

Tumor type	NCT ID	Title	Phase	Intervention(s)	Age range	Status
LGG	NCT04923126	SJ901: Mirdametinib in LGG	Phase 1/2	Mirdametinib (MEK inhibitor)	2–24 yrs	Recruiting
LGG	NCT05609994	ViCToRy: Vorasidenib + vaccine for IDH1-Mutant LGG	Phase 1	PEPIDH1M vaccine + vorasidenib	≥18 yrs	Recruiting
LGG	NCT07110246	Dabrafenib + trametinib for BRAF V600 LGG	Phase 2	Dabrafenib + trametinib	1–24 yrs	Recruiting
LGG	NCT04541082	ONC206 in recurrent CNS neoplasms	Phase 1	ONC206	≥18 yrs	Recruiting
LGG	NCT06104488	Avutometinib for solid tumors (incl. LGG)	Phase 1	Avutometinib (RAF/MEK clamp)	3–30 yrs	Recruiting
LGG	NCT04485559	PNOC021: Trametinib + everolimus for recurrent gliomas	Phase 1	Trametinib + everolimus	1–25 yrs	Recruiting
HGG	NCT05843253	Ribociclib + everolimus in HGG/DIPG; ribociclib + TMZ in DHG H3G34	Phase 2	Ribociclib, everolimus, TMZ	1–39 yrs	Recruiting
HGG	NCT06161974	Olutasidenib + TMZ in IDH1-Mutant HGG	Phase 2	Olutasidenib + TMZ	12–39 yrs	Recruiting
HGG	NCT06504381	DB107-RRV, DB107-FC + RT ± TMZ for HGG	Phase 1/2	DB107-RRV, DB107-FC, RT, TMZ	18–75 yrs	Recruiting
HGG	NCT04254419	Locoregional NK cell injections for HGG	Phase 1	TGFβi NK cells	1–39 yrs	Recruiting
HGG	NCT06169280	Neural stem cell–Based virotherapy for HGG	Phase 1	NSC-CRAd-S-pk7	≥18 yrs	Recruiting
HGG	NCT06072586	BDTX-1535 in recurrent HGG/GBM with EGFR alterations	Early phase 1	BDTX-1535 ± RT ± TMZ	≥18 yrs	Recruiting
HGG	NCT06428045	STARLITE for unresectable HGG	Phase 1	LITT + abacavir/Lamivudine/Ritonavir + TMZ + RT	≥18 yrs	Recruiting
HGG	NCT06964737	Anti-GARP CAR-T for recurrent grade III/IV gliomas	Phase 1	Anti-GARP CAR-T cells	≥18 yrs	Recruiting
HGG	NCT04547777	D2C7-IT + 2141-V11 for recurrent malignant glioma	Phase 1	D2C7-IT + 2141-V11	≥18 yrs	Recruiting
HGG	NCT06126744	Oncolytic HSV1 MVR-C5252 for HGG	Phase 1	MVR-C5252 (oHSV1)	≥18 yrs	Recruiting
HGG	NCT04559685	Sonodynamic therapy in recurrent HGG	Early phase 1	SONALA-001 (ALA) + MRgFUS	≥18 yrs	Recruiting
HGG	NCT07389278	ADI-PEG 20 + TMZ + RT for newly diagnosed HGG	Phase 1/2	ADI-PEG 20, TMZ, RT	3–39 yrs	Not yet recruiting
HGG	NCT07346144	AAV dual-payload gene therapy in HGG	Phase 1/2	TGX-007 + valaciclovir	18–70 yrs	Not yet recruiting
GBM	NCT05271240	SIACI bevacizumab + TMZ + RT in newly diagnosed GBM	Phase 3	Intraarterial bevacizumab + TMZ + RT	≥18 yrs	Recruiting
GBM	NCT03213002	CAPTEM for newly diagnosed GBM	Phase 1/2	Capecitabine + temozolomide	≥18 yrs	Recruiting
GBM	NCT06991101	Ruxolitinib + RT + TMZ for newly diagnosed GBM	Phase 2	Ruxolitinib + TMZ + RT	≥18 yrs	Recruiting
GBM	NCT06672575	Ivonescimab in recurrent GBM	Phase 1/2	Ivonescimab (PD-1/vegf bispecific)	≥18 yrs	Recruiting
GBM	NCT03970447	GBM AGILE: Multiple regimens in GBM	Phase 2/3	Paxalisib, VAL-083, VT1021, troriluzole, ADI-PEG 20, AZD1390, tinostamustine	≥18 yrs	Recruiting
GBM	NCT07326566	Silevertinib + TMZ for GBM (MGMT unmeth, EGFRvIII)	Phase 2	Silevertinib + TMZ	≥18 yrs	Recruiting
GBM	NCT06831526	Chemoradiotherapy ± azeliragon in newly diagnosed GBM	Early phase 1	Azeliragon + TMZ + RT	≥18 yrs	Recruiting
GBM	NCT06805305	DOC1021 DC immunotherapy for newly diagnosed GBM	Phase 2	DOC1021 (DC vaccine) + TMZ + RT	≥18 yrs	Recruiting
GBM	NCT04991870	CB-NK cells in recurrent GBM	Phase 1	Cord blood-derived NK cells	≥18 yrs	Recruiting
GBM	NCT07485049	BGB-58067 in GBM with MTAP-deleted tumors	Early phase 1	BGB-58067 (MAT2A inhibitor)	≥18 yrs	Not yet recruiting
GBM	NCT07185880	MT-125 in GBM	Phase 1	MT-125	≥18 yrs	Not yet recruiting
Dmg, DIPG	NCT04196413	GD2 CAR-T cells in DIPG spinal DMG	Phase 1	GD2 CAR-T cells ± lymphodepletion	2–60 yrs	Recruiting
Dmg, DIPG	NCT05009992	Combination therapy for DMG (ONC201 + paxalisib/dnx-2401)	Phase 2	ONC201, paxalisib, DNX-2401, RT	2–39 yrs	Recruiting
Dmg, DIPG	NCT05478837	KIND T cells for H3·3K27M-Mutated glioma	Phase 1	Anti-H3.3K27 M TCR T cells	2–25 yrs	Recruiting
Dmg, DIPG	NCT06305910	CD200AR-L + tumor lysate vaccine for DMG/DIPG recurrent HGG	Phase 1	CD200AR-L + GBM6-AD vaccine	2–25 yrs	Recruiting
Dmg, DIPG	NCT04099797	C7R-GD2.CAR T cells for GD2+ brain tumors (GAIL-B)	Phase 1	C7R-GD2.CAR T cells (IV/ICV)	1–22 yrs	Recruiting
Dmg, DIPG	NCT04185038	B7–H3 CAR-T locoregional immunotherapy for DIPG/DMG	Phase 1	SCRI-CARB7H3(s) CAR-T cells	1–26 yrs	Recruiting
Dmg, DIPG	NCT06838676	ACT001 for DIPG and H3K27-Altered HGG	Phase 2	ACT001	1–39 yrs	Recruiting
Dmg, DIPG	NCT05096481	PEP-CMV vaccine for newly diagnosed HGG/DIPG recurrent MB	Phase 2	PEP-CMV vaccine + TMZ	3–39 yrs	Recruiting
Dmg, DIPG	NCT04655404	Larotrectinib for newly diagnosed HGG/DIPG with NTRK fusion	Early phase 1	Larotrectinib	≤21 yrs	Recruiting
Dmg, DIPG	NCT06624371	Atovaquone + RT for pediatric malignant brain tumors (incl. DMG/DIPG)	Phase 1	Atovaquone + RT	2–25 yrs	Recruiting
Dmg, DIPG	NCT05278208	Lutathera for recurrent/Progressive high-grade CNS tumors	Phase 1/2	177Lu-DOTATATE (lutathera)	4–39 yrs	Recruiting
Dmg, DIPG	NCT07223034	177Lu-PSMA-617 in gliomas (incl. Dmg)	Phase 1	177Lu-PSMA-617 + TMZ	≥18 yrs	Recruiting
Dmg, DIPG	NCT06893979	AZD1390 + RT for newly diagnosed HGG/DMG/DIPG	Phase 1	AZD1390 + RT	–	Recruiting
Dmg, DIPG	NCT07076498	Engineered HSV-1 M032 for newly diagnosed DMG	Phase 1	M032 (IL-12 oncolytic HSV-1)	≥3 yrs	Not yet recruiting
Dmg, DIPG	NCT06639607	PEP-CMV + nivolumab for DMG/HGG, MB, ependymoma	Phase 1/2	PEP-CMV vaccine + nivolumab + TMZ	4–25 yrs	Not yet recruiting

In 2023, the combination of the MEK inhibitor trametinib and BRAF inhibitor dabrafenib for BRAFV600E mutant LGG moved into upfront use for pediatric patients after it was found to have superior overall response rates (ORR) and significantly longer PFS compared to standard chemotherapy [58]. The ROAR clinical trial explored trametinib and dabrafenib for adult patients with BRAFV600E-altered LGG and HGG, and demonstrated an ORR of 54% for LGG and 33% for high-grade glioma [59]. These results were a key contributor to the FDA's tumor-agnostic accelerated approval of dabrafenib plus trametinib for BRAF V600E-mutant solid tumors that have progressed following prior treatment and have no satisfactory alternatives. Tovorafenib, a type II pan-RAF inhibitor, was developed for BRAF-fused LGGs that are poorly suited to treatment with type I BRAF inhibitors such as dabrafenib due to paradoxical activation driven by BRAF heterodimerization — a problem that addition of a MEK inhibitor only partially mitigates [60]. Currently, tovorafenib is FDA-approved for relapsed or refractory pediatric LGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation, and is being assessed in the upfront setting compared to standard chemotherapy in the Firefly-2 trial (NCT05566795) [61]. Importantly, the number of AYA patients in these clinical trials is low. The LGG cohort in the ROAR trial only enrolled 13 patients with a median age of 33 years and Firefly-1 enrolled patients up to 25 years but reported median age of 8 years, suggesting low numbers of AYA patients. This highlights the lack of representation of AYA patients in clinical trials and the need to promote and encourage AYA participation whenever possible. Currently, there are several other MEK inhibitors, such as selumetinib and mirdametinib, being explored in clinical trials for MAPK pathway driven glioma with many others in early drug development for a variety of BRAF-altered tumors [62].

Identification of an IDH mutation in a low-grade glioma allows for potential treatment with an IDH inhibitor, such as vorasidenib, which demonstrated significantly longer PFS and time to next intervention (TTNI) compared to placebo in grade 2 tumors with residual or recurrent disease in the pivotal phase 3 INDIGO trial [63,64]. There are several other IDH inhibitors being investigated in clinical trials as well as trials exploring immunotherapeutic approaches [65]. Dordaviprone, previously known as ONC201, is a first-in-class imipridone recently FDA-approved for pediatric and adult patients with diffuse midline glioma harboring an H3 K27 M mutation with progressive disease following prior therapy [66]. Notably for AYA patients, thalamic location and older age have been identified as positive prognostic factors with dordaviprone use in real-life cohort data for H3K27M-altered diffuse midline gliomas [67].

Ependymoma

Ependymal tumors are glial neoplasms arising from the ependymal lining of the ventricles and central canal of the spinal cord, representing approximately 5% of CNS tumors in adults and 10% of CNS tumors in children [68]. They can present anywhere along the age continuum and are broadly classified based on anatomical location, being in either the supratentorial region, posterior fossa or the spine. Further refinement based on molecular characterization has delineated ten subtypes in the 2021 WHO CNS classification, with the most relevant in AYA being supratentorial ependymoma with ZFTA alteration (ST-EPN-ZFTA), posterior fossa ependymoma B (PF-EPN-B), and the spinal ependymomas (MYCN-amplified, myxopapillary and classic subtypes [69]. As might be expected, AYA patients represent a transitional population and present with subtypes that intersect between children and adults [70].

Posterior fossa ependymomas have a characteristic age distribution, with the great majority of pediatric patients presenting with a PF-EPN-A, while the AYA population predominantly present with PF-EPN-B [71]. Histologically, these tumors may appear similar but are differentiated by the loss of H3K37me3 in PF-EPN-A identified on immunohistochemistry (IHC) and confirmed on DNA methylation profiling. Comprehensive molecular analysis is therefore central to ensure diagnostic accuracy [72]. PF-EPN-B has an overall favorable prognosis with a 5-year PFS of 70% and OS of approximately 100%. This stands in stark contrast to the less favorable 5-year PFS for PF-EPN-A at 43%- and 5-year OS of 67% [71,73].

Additionally, there is a separation in age distribution for the two molecular subtypes of supratentorial ependymoma, with the vast majority of ST-EPN-YAP1 tumors presenting in young infants and children, while approximately 23% of ST-EPN-ZFTA are found in patients >18 years [74]. ST-EPN-ZFTA tumors have an intermediate prognosis, largely dependent on the copy number profile and the presence of combined CDKN2A/B loss, which confers a significant decrease in the 5-year PFS and OS [74].

Finally, spinal ependymoma is the most common ependymoma location in the AYA population with retrospective adult cohorts suggesting a generally favorable prognosis, with 5-year overall survival estimates of 80–90% in non-molecularly stratified patients [75,76]. Within the spinal ependymoma (SP-EP) subgroup, the most frequently identified genetic alterations are NF2 mutations and chromosome 22q loss with emerging data that biallelic NF2 loss carries a significantly reduced OS compared to monoallelic loss [69]. Spinal myxopapillary ependymoma (SP-MPE) arises almost exclusively at the conus medullaris or filum terminale, and despite a notable tendency toward dissemination and high recurrence rates, is associated with 5-year OS rates of 85–100% [77]. The most recently characterized subgroup, spinal MYCN-amplified ependymoma (SP-EPN-MYCN), tends to emerge in late adolescence and young adulthood and carries a more aggressive clinical course with a correspondingly guarded prognosis [78].

For all ependymoma subtypes in children, AYA and adults, gross total resection is the most important treatment and should be performed whenever feasible. Following maximal safe resection, focal radiation therapy is recommended for all localized grade 3 tumors in those aged >3 years. The role of chemotherapy for ependymoma remains unclear. For completely resected grade 2 ependymoma, there is retrospective evidence that adjuvant radiotherapy may not improve outcomes in some subtypes, particularly for PF-EPN-B, and therefore an observation approach may be considered post-operatively, acknowledging a lack of prospective clinical trial data and some conflicting reports [[79], [80], [81]]. Grade 1 ependymomas (ST-SE, PF-SE and SP-SE) do not require adjuvant radiation therapy upfront and have generally excellent outcomes [82].

Medulloblastoma

Medulloblastoma is the most common embryonal tumor in AYA, though it remains relatively rare, representing less than 1% of adult CNS tumors overall [83]. It arises in the posterior fossa, primarily from the cerebellar hemispheres or vermis and has an inherent propensity for leptomeningeal spread, highlighting the need for complete staging with cerebrospinal fluid (CSF) analysis and neuroimaging of the brain and spine. In the past decades, detailed molecular analysis has enabled classification into four main molecular subgroups: Sonic Hedgehog-activated (SHH), Wingless (WNT), group 3 and group 4. This has enabled refinement of risk stratification, prognostication and development of molecularly driven clinical trials in pediatric and adolescent patients [84,85]. For example, based on the favorable outcomes identified for WNT MB, the SJMB12 trial treated low risk WNT MB participants with lower dose CSI and reduced intensity chemotherapy with preliminary results suggesting similar outcomes to standard treatment regimens [85]. The COG ACNS1422 and SIOP PNET 5 MB trials are also exploring CSI dose reductions for this low risk subgroup. The majority of cases in young adults, however, belong to the SHH, TP53 wildtype subclass, with a small number in the WNT and non-WNT, non-SHH groups [86].

When treated with maximal safe resection, craniospinal radiation and maintenance chemotherapy, up to 70% of patients will remain in remission at 5 years, though late relapses do occur [87,88]. This treatment is intensive and primarily adapted from pediatric medulloblastoma clinical trial protocols due to the lack of prospective evidence in adults. In general, it is known that young adults experience more severe treatment-related side effects, including higher rates of vincristine-induced peripheral neuropathy as well as myelosuppression. As a result, many patients require significant dose reductions or premature cessation of planned adjuvant chemotherapy [89]. This highlights the need for dedicated prospective adult medulloblastoma clinical trials to establish appropriate regimens that maintain current survival outcomes.

Based on the identification of SMO and PTCH mutations driving SHH-activated medulloblastoma, clinical trials have been exploring the use of targeted therapies, such as vismodegib and sonidegib, that inhibit the mutated smoothened protein [[90], [91], [92]]. Pooled published data suggests an overall response rate around 37% for pediatric and adult patients treated with SMO inhibitors, supporting further investigation into their combined use with chemotherapy in clinical trials. Unfortunately, previous attempts to conduct randomized upfront clinical trials in adults have been unsuccessful and therefore the role of these agents in the treatment of medulloblastoma remains unclear [93,94].

Germ cell tumors

Intracranial germ cell tumors (iGCT) are rare tumors which are predominantly found in the midline, such as the suprasellar and pineal region. They are more common in Asian and Pacific Islander populations and have a striking male preponderance. In the AYA population, iGCT peaks between 15 and 19 years, representing 9–10% of malignant CNS tumors and then declining to <2% by age 39 years with approximately two thirds of cases diagnosed before 20 years of age [95]. Diagnosis involves assessment of serum and CSF beta-human chorionic gonadotropin (b-HCG) and alpha-fetoprotein (AFP), imaging of the neuroaxis with MRI and CSF cytology to exclude metastatic spread. In most patients, biopsy is required as part of the diagnostic work-up [96]. iGCT is divided into two main categories: germinoma and non-germinomatous germ cell tumor (NGGCT).

Germinoma

Germinoma is the most common subtype of iGCT and is characterized by high radio- and chemosensitivity, resulting in excellent outcomes with overall survival rates of 90–98% [97,98]. The majority of germinomas are tumor marker negative, however a notable number do produce small amounts of b-HCG [99].

While there is variation in the exact regimen used between the United States, Europe, and Asia, the general approach is similar involving surgery for biopsy and/or CSF diversion and combination chemoradiotherapy or radiation alone [100,101]. Contemporary treatment protocols in Europe and North America emphasize neoadjuvant chemotherapy with a carboplatin or cisplatin backbone and etoposide plus either ifosfamide or cyclophosphamide followed by reduced-dose, reduced-field radiation therapy, a strategy aimed at de-intensifying treatment to minimize long-term sequelae[2,101,102].

Metastatic germinoma is defined by positive CSF cytology and/or radiographic evidence of metastatic disease on neuroimaging. Importantly, most international cooperative groups do not classify bifocal germinomas involving both the suprasellar and pineal regions as metastatic disease; instead, these are treated using localized treatment approaches [101]. Unlike most metastatic brain tumors, metastatic germinoma remains highly curable with appropriate therapy, typically consisting of craniospinal irradiation (CSI) with a boost to the primary tumor site and, when indicated, metastatic sites. Treatment strategies differ somewhat between Europe and North America regarding the role of chemotherapy. The current European standard of care favors a radiation-only approach using 24 Gy CSI followed by a 16 Gy boost to metastatic sites [103]. In contrast, North American protocols incorporate neoadjuvant chemotherapy prior to CSI with the goal of reducing radiation dose and field while maintaining excellent cure rates [104]. This strategy underpins the ongoing Children's Oncology Group (COG) ACNS2321 trial, which is evaluating response-adapted reductions in CSI and boost dosing following induction chemotherapy (NCT06368817).

Non-germinomatous germ cell tumor (NGGCT)

NGGCT incorporates a number of subtypes including embryonal carcinoma, yolk sac tumor, choriocarcinoma, immature/malignant teratoma and mixed tumors containing these components [105]. Unlike germinoma, NGGCT is often characterized by elevated tumor markers, specifically AFP and/or high levels of b-HCG. In contrast to the highly curable nature of germinoma, NGGCT is more resistant to treatment and requires intensive multimodal therapy incorporating platinum-based chemotherapy and radiation with the inclusion of surgical resection when there is residual disease or continued elevated tumor markers prior to radiotherapy [96,106]. For localized NGGCT, North American protocols typically use either CSI or whole ventricular irradiation with a tumor boost, whereas European protocols favor focal radiotherapy alone to reduce long-term toxicity; both regions use craniospinal irradiation for metastatic disease [101]. NGGCT trials are now focusing on risk-adapted therapy, with the COG ACNS2021 trial testing response-adapted radiation based on chemotherapy response (NCT04684368).

Cancer predisposition syndromes

Approximately 15–21% of pediatric patients with CNS tumors harbor a pathogenic germline mutation that results in a cancer predisposition syndrome (CPS) [107]. Germline testing may identify actionable mutations, with implications not only for guiding treatment but also for family screening and counseling. CPS should be suspected with younger age at diagnosis and if multiple primary tumors and strong family history are identified [107]. There may also be features on histology and IHC that suggest an underlying CPS. For example, mismatch repair (MMR) protein expression can be assessed on IHC stains in HGG to identify underlying constitutional mismatch repair deficiency (CMMRD), which has been found to be more common than previously reported in the AYA population [108]. As such, routine MMR IHC on all pediatric and AYA HGG should be a first line screening tool for CMMRD [109].

CMMRD is one of the 19 CPS recognized in the WHO classification. It is caused by biallelic mutations in mismatch repair genes, conferring increased risk for both CNS and non-CNS malignancies. CNS tumors account for 51% of diagnoses in this population, most commonly presenting in late childhood or early adolescence as high-grade gliomas [110]. These tumors tend to be aggressive, driven in part by a hypermutant phenotype; paradoxically, this same property has rendered them more responsive to immune checkpoint inhibition, with promising results in prolonging survival in CMMRD-associated gliomas [111,112]. Lynch syndrome arises from heterozygous germline mutations in the same mismatch repair genes but differs substantially in its oncologic profile. Although affected individuals carry a predisposition to glioma, the lifetime risk is considerably lower than in CMMRD, estimated at 1–3% [113]. The tumors also tend to develop in adulthood and so are less prevalent in the AYA population [108,114].

The most prevalent syndromes associated with gliomas are TSC and NF1. The most common tumors associated with TSC in the AYA population include SEGAs, which tend to develop before the age of 25 in up to 25% of patients with TSC [115]. NF1 patients more commonly present with optic pathway gliomas (OPGs) in childhood, but can also develop non-optic pathway gliomas during the early age range of the AYA spectrum. That may present before the age of 17 in patients with NF1 mutations [116,117]. While rare overall, patients with NF1 also carry a fivefold increased risk of high-grade glioma relative to the general population, and these tend to develop beyond the age of 10 [117,118].

When meningiomas develop in children and the AYA population, there is frequently an underlying CPS, specifically with NF2, nevoid basal cell carcinoma syndrome (NBCCS), Cowden, and BAP1-tumor predisposition syndrome [119]. Similarly, multiple schwannomas in the AYA population can emerge with NF2, LZTR1-related schwannomatosis, Carney complex and BAP1-tumor predisposition syndrome [[119], [120], [121]]. Conversely, ependymomas are not typically associated with CPS, though spinal ependymomas may be seen in patients with NF2 [122].

Li-Fraumeni syndrome is an autosomal dominant condition caused by germline TP53 mutations [123]. The loss of this tumor suppressor causes a markedly increased lifetime risk for several malignancies, including breast cancer, osteosarcoma, leukemia, and CNS tumors. CNS tumors account for 9–14% of cancers in this population and encompass gliomas, medulloblastomas, and choroid plexus carcinomas [123]. The median age for diagnosing CNS tumors is 16 years, though there is an underlying bimodal distribution [123]. Other syndromes that increase predisposition to medulloblastoma include familial adenomatous polyposis 1, Fanconi anemia, and ELP1-medulloblastoma syndrome. SHH medulloblastoma are most likely to be associated with an underlying CPS, with prevalence of up to 40%, whereas medulloblastoma Group 3 and Group 4 have less established associations with CPS [107].

Familial melanoma-astrocytoma syndrome, formally recognized in the 2021 WHO CNS tumor classification, is a rare autosomal dominant condition caused by germline mutations in CDKN2A, a tumor suppressor gene involved in cell cycle regulation and apoptosis. It is characterized by cutaneous melanomas, dysplastic nevi, and CNS tumors including glioblastoma and astrocytoma of varying grades [124,125]. Other CPS are summarized in Table 2.

Table 2.

Cancer Predisposition Syndromes recognized in WHO 2021 criteria and their associated Nervous System Tumors.

CPS	Associated nervous system tumors (typical age of onset, years)	Implicated genes
NF1 [[126], [127], [128]]	•Optic pathway glioma (younger than age 7) •Diffuse low-grade glioma (childhood) •High grade astrocytoma/GBM (mean age 28) •MPNST (between age 10–19) •Plexiform neurofibroma (childhood)	NF1
NF2 [129]	•Schwannoma (mean age 18–22) •Meningioma (typical age 25) •Ependymoma (adolescence)	NF2
Schwannomatosis [130]	•Non-vestibular schwannomas (mean age 30–40) •Meningioma (adulthood)	SMARCB1 LZTR1
Von hippel-lindau [131]	•Hemangioblastoma (mean age 25) •Endolymphatic sac tumor (typical age 30–40)	VHL
Tuberous sclerosis [132]	•Subependymal giant cell astrocytoma (mean age 11) •Subependymal nodules (infancy)	TSC1 TSC2
Li-fraumeni syndrome [133,134]	•Diffuse glioma, glioblastoma (mean age 16) •Choroid plexus carcinoma (younger than age 3) •Medulloblastoma (younger than age 10)	TP53
CMMRD [134]	•Glioblastoma, high grade glioma (median age 10) •Medulloblastoma (younger than age 6)	MLH1 MSH2 MSH6 PMS2
Familial adenomatous polyposis 1 ([135] [136])	•Medulloblastoma (median age 11.5) •Craniopharyngioma (young adults)	APC
Fanconi anemia [137]	•Medulloblastoma (median age 3.7)	BRCA2 PALB2 BRIP1
Nevoid basal cell carcinoma [138,139]	•Medulloblastoma (mean age of 2) •Meningioma (adulthood)	PTCH1 SUFU
Cowden syndrome [140]	•Dysplastic gangliocytoma (mean age 34)	PTEN
Rhabdoid tumor predisposition syndrome [141]	•Atypical teratoid/rhabdoid tumor (before age 1)	SMARCB1 SMARCA4
Carney complex [142]	•Malignant melanotic nerve sheath tumor (mean age 22) •Pituitary adenoma (adulthood)	PRKAR1A
DICER1 [143]	•Primary intracranial sarcoma (median age 6) •Pineoblastoma (younger than age 6)	DICER1
ELP-1 medulloblastoma syndrome [144]	•Medulloblastoma (median age 6)	ELP1
Familial paraganglioma [145]	•Head/neck paraganglioma, spinal paraganglioma (typical 20–30s)	Sdha, SDHB, SDHC, SDHD CHL RET TMEM127 MAX
Melanoma-astrocytoma [125]	•Diffuse glioma (mean age 40) •Malignant melanotic nerve sheath tumor (adulthood)	CDNK2A
Familial retinoblastoma [146]	•Retinoblastoma (mean age 1–2)	RB1
BAP1 [144]	•Meningioma (mean age 50) •Malignant melanotic nerve sheath tumor (adulthood)	BAP1

Survivorship

With the advancement in diagnostics and effective treatment, the number of AYA survivors of CNS tumors is increasing, with estimates ranging between 500,000 and 2.1 million individuals aged 0–39 years [147]. In general, the AYA population has a 5-year OS over 85%, with the lowest rates under 30% secondary to glioblastoma, H3K27-mutant glioma, HGG, medulloblastoma group 3 and favorable rates of over 90% with oligodendroglioma, PA, SEGA, WNT-activated medulloblastoma, and some ependymoma types [[148], [149], [150], [151]]. As most AYA patients with cancer are likely to become long-term survivors, there is a critical need to address the long-term effects of treatment.

AYA survivors of CNS tumors face a myriad of long-term effects from both the tumor itself and the necessary treatment. Fig. 2 highlights several of the complex care needs they may require. Tumors and their subsequent resection may result directly in focal deficits, such as weakness, or tumor-related epilepsy, depending on location, and may lead to increased self-care needs with the resultant physical disability and need to follow seizure precautions. Radiation therapy is associated with an increased risk of secondary CNS malignancies including meningioma and radiation-induced high-grade glioma. Endocrinopathies including growth hormone deficiency, hypothyroidism and gonadotropin deficiency are common, with up to 75% of survivors experiencing at least one endocrine disorder over their lifetime [21,152]. Fertility-related complications are complex in the AYA CNS population and can result from radiation-related endocrinopathies as well as from direct gonadal damage with common chemotherapy regimens, resulting in lower pregnancy and live birth rates, and higher spontaneous abortion rates [153,154]. Not only is financial cost for fertility preservation a significant barrier for AYA populations, but preservation windows are particularly smaller in the AYA population given the urgency in initiating treatment with many CNS tumors [26,155]. Vasculopathies including stroke, moyamoya disease, vascular malformations and stroke-like migraines are seen, and the risk continues to increase cumulatively as survivors age [156,157]. In addition, cardiovascular disease, pulmonary damage, hearing and vision loss are all serious side effects that have long-term impact on the functioning of AYA survivors [20,21]. Accessing care for these medical issues, many of which are late effects of treatment, is limited by multifaceted gaps in transitions of care, including systemic healthcare fragmentation and poor follow-up engagement [24,158]. A major contributor to this gap may be the stark contrast in culture between pediatric and adult healthcare systems, with pediatric focus relying more on multidisciplinary and psychosocial involvement and the adult focus prioritizing autonomy and disease-specific care.

Fig. 2.

Key aspects of the complex care needs that AYA patients may experience.

Quality of life (QoL) for the AYA population has been assessed by several groups. A comprehensive analysis across all cancers in a large AYA population demonstrated that patients with CNS tumors had worse global QoL and poorer responses across scales assessing physical, cognitive, mental and social functioning compared to a normative population [159]. Cognitive function warrants particular attention given its broad impact across daily life domains, including educational attainment, occupational functioning, health behaviors, and psychosocial well-being [160]. Implicated factors include fatigue that persists throughout survivorship and complications from the CNS tumor or its treatment [150]. The spectrum of early to late effects of radiation therapy is the most extensively documented treatment-related contributor to neurocognitive decline, in a dose-dependent and volume-dependent manner [161,162]. Changes in cognitive functioning were identified as one of the domains most specific to CNS tumor survivorship [150].

Beyond cognitive dysfunction, CNS AYA survivors face substantial psychosocial burdens. Social adjustment difficulties and disrupted peer relationships are commonly reported in this population, with cognitive and physical limitations identified as mediating factors [163]. Additionally, CNS tumor survivors, along with survivors of childhood and adolescent cancers more broadly, also carry elevated risks of suicidality, mood and anxiety disorders, and post-traumatic stress symptoms [164,165]. The socioeconomic consequences are particularly striking: among all cancer survivor groups, CNS tumor survivors have the lowest rates of high school graduation and the highest rates of unemployment and financial hardship, with threefold higher odds of unemployment and ninefold higher odds of health-related work limitations [166,167].

Of note, these trends are based on data collected largely prior to widespread use of current standard of care therapies and targeted therapies, and the emergence of newer agents will likely continue to alter prognosis and outcomes. Improved molecular testing can also more reliably guide risk stratification to mitigate the long-term sequelae of CNS tumor treatment. Taken together, the findings underscore the need for continued efforts to improve survivorship outcomes. Multidisciplinary interventions targeting these complications have demonstrated modest improvements in quality of life and return-to-work outcomes, though without sustained long-term benefit, highlighting the challenges of developing appropriate and effective interventions in the population [168,169].

Future Directions and conclusion

AYA neuro-oncology encompasses a unique biological and clinical space that challenges traditional boundaries between pediatric and adult neuro-oncology. Advancements in our understanding of the molecular underpinnings of many CNS tumors have highlighted the need for integrating comprehensive genetic analysis to appropriately diagnosis and treat AYA patients. Looking forward, one of the most consequential of these advancements is the development of CSF-based liquid biopsy for tumor characterization, risk stratification and disease surveillance. In medulloblastoma, serial CSF ctDNA has demonstrated that patients who have persistently measurable disease are at a higher risk of relapse and that this is often able to be detected prior to radiographic findings [170]. There is a growing body of literature supporting its use in a variety of pediatric CNS tumors including ependymoma, LGG, diffuse midline glioma and iGCT [[171], [172], [173]]. This technology is increasingly being utilized in pediatric centers and is being incorporated into pediatric clinical trial design in upcoming pediatric cooperative group trials. As these exploratory studies are being predominantly conducted in pediatric centers, AYA patients receiving care in adult centers are often excluded from participating in trials, leading to increasing disparities in care as pediatric precision medicine accelerates without them. This highlights the need to both advocate for AYA trial involvement to expand access to clinical trials across the AYA age spectrum, and to promote collaboration across pediatric and adult neuro-oncology centers to develop dedicated streamlined access from practice to clinical trials. Beyond disease control, prioritizing survivorship to improve long-term outcomes is essential and needs to begin at the time of diagnosis. Multidisciplinary, longitudinal care models integrating neuro-oncology, rehabilitation, mental health, fertility preservation, and survivorship expertise are critical to addressing cumulative treatment toxicity and improving functional, neurocognitive and vocational outcomes.

Author contributions

Mirna Hennawy: Writing – original draft, Writing – Review & Editing, Visualization.

Anna Mullins: Writing – original draft, Writing – Review & Editing, Visualization.

Julie Bennett: Writing – Review & Editing.

Kee Kiat Yeo: Conceptualization, Writing – Review & Editing.

Mary Jane Lim-Fat: Conceptualization, Writing – Review & Editing, Visualization.

Conflicts of interest

All authors have approved the final version and have no conflicts of interest directly related to this work.