High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

Abstract

Background: Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs).

Methods: We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification.

Results: Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of "rare adult IDH mutations" (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance.

Conclusions: HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.

Keywords: DNA-methylation analysis; glioblastoma; glioma; integrated diagnosis; whole exome sequencing.

Fig. 1

Patient flow chart. According to our inclusion criteria, 112 AYA patients were initially included in this study. After central neuropathological review, we excluded 23 patients with no HGGs: 10 for low-grade tumors and 13 for high-grade tumors. We excluded 9 patients for clinical and/or imaging data lacking. Finally, 80 AYA patients were included in this study and we proposed an integrated diagnosis for all of them. Eighty patients had immunohistochemistry, 69 targeted/next-generation sequencing, 10 WES, and 11 DNA-methylation analysis.

Fig. 2

Integrated analysis description (n = 80). Oncoprint chart representing our integrated analysis according to the molecular subgroups. We describe age, histopathological grading, anatomical location, and sex. For AYA patients with rare mutations (down and left) we add results of the next-generation sequencing. We propose a pie chart of our integrated analysis describing the frequency of histo-radio-molecular subgroups.

Fig. 3

Comparative analysis of published HGG cases by molecular and age subgroups. After literature review, we realized 3 pie charts describing the distribution of histo-radio-molecular subgroups for HGGs by age group: (i) pediatric (<15 y), (ii) adolescent and young adult (15–25 y), and (iii) adult (25–55 y). We could appreciate the different distribution of these histo-radio-molecular subgroups according to the age.

Fig. 4

Kaplan–Meier curves describing PFS (dashed lines) and OS (continuous lines) in (A) the whole series, (B) the H3K27-mutants, (C) the IDH-mutants, (D) the H3G34-mutants, (E) the epithelioid and giant cell glioblastomas, (F) the anaplastic pleomorphic xantroastrocytomas, and (G) the other gliomas (excluding the HGNET-MN1 case).

Fig. 5

Graphical summary of integrated molecular subgroups in adolescents and young adults (n = 79). Simplified schematic representation of key clinical, radiological, and survival results in 6 high-grade glioma subgroups according to our integrated histo-radio-molecular analysis.