Clinical, imaging, and molecular analysis of pediatric pontine tumors lacking characteristic imaging features of DIPG

Jason Chiang,Zoltan Patay,Lydia Makepeace,Christopher L Tinkle,Suzanne J Baker,Alexander K Diaz,Paul Klimo,Xiaoyu Li,Yuanyuan Han,Yimei Li,Frederick A Boop,Thomas E Merchant,Amar Gajjar,Alberto Broniscer,David W Ellison

doi:10.1186/s40478-020-00930-9

Abstract

Diffuse intrinsic pontine glioma (DIPG) is most commonly diagnosed based on imaging criteria, with biopsy often reserved for pontine tumors with imaging features not typical for DIPG (atypical DIPG, ‘aDIPG’). The histopathologic and molecular spectra of the clinical entity aDIPG remain to be studied systematically. In this study, thirty-three patients with newly diagnosed pontine-centered tumors with imaging inconsistent with DIPG for whom a pathologic diagnosis was subsequently obtained were included. Neoplasms were characterized by routine histology, immunohistochemistry, interphase fluorescence in situ hybridization, Sanger and next-generation DNA/RNA sequencing, and genome-wide DNA methylome profiling. Clinicopathologic features and survival outcomes were analyzed and compared to those of a contemporary cohort with imaging features consistent with DIPG (typical DIPG, ‘tDIPG’). Blinded retrospective neuroimaging review assessed the consistency of the initial imaging-based diagnosis and correlation with histopathology. WHO grade II-IV infiltrating gliomas were observed in 54.6% of the cases; the remaining were low-grade gliomas/glioneuronal tumors or CNS embryonal tumors. Histone H3 K27M mutation, identified in 36% of the cases, was the major prognostic determinant. H3 K27M–mutant aDIPG and H3 K27M–mutant tDIPG had similar methylome profiles but clustered separately from diffuse midline gliomas of the diencephalon and spinal cord. In the aDIPG cohort, clinicoradiographic features did not differ by H3 status, yet significant differences in clinical and imaging features were observed between aDIPG without H3 K27M mutation and tDIPG. Neuroimaging review revealed discordance between the classification of aDIPG and tDIPG and did not correlate with the histology of glial/glioneuronal tumors or tumor grade. One patient (3.1%) developed persistent neurologic deficits after surgery; there were no surgery-related deaths. Our study demonstrates that surgical sampling of aDIPG is well-tolerated and provides significant diagnostic, therapeutic, and prognostic implications, and that neuroimaging alone is insufficient to distinguish aDIPG from tDIPG. H3 K27M-mutant aDIPG is epigenetically and clinically similar to H3 K27M-mutant tDIPG.

Highlights

Despite the re-emergence of diagnostic biopsy at several centers over the past decade, diffuse intrinsic pontine glioma (DIPG) remains largely a clinical diagnosis based on characteristic features on conventional MRI [1, 2]
We found diverse histologies within this clinical entity ‘atypical' DIPG (aDIPG)’, including grade I gliomas and gangliogliomas, grade II to IV diffuse astrocytic tumors with or without the H3 K27M mutation, and embryonal tumors
The surgical morbidity associated with procedures that facilitated this therapy and prognosischanging differential diagnosis was modest, with a similar rate of persistent neurologic deficits being observed in patients with presumed typical' DIPG (tDIPG) [25]

Summary

Introduction

Despite the re-emergence of diagnostic biopsy at several centers over the past decade, diffuse intrinsic pontine glioma (DIPG) remains largely a clinical diagnosis based on characteristic features on conventional MRI [1, 2]. The imaging criteria used to define a classical or 'typical' DIPG (tDIPG) vary to some extent, and there are inconsistencies in the interpretation of the images [3], the general consensus radiographic features of tDIPG include a T1-hypointense and T2-hyperintense tumor involving at least 50% of the pons by crosssectional area [4,5,6]. In many centers in the United States, biopsy is reserved for patients with a clinical diagnosis of 'atypical' DIPG (aDIPG), i.e., pontine tumors in which the above imaging features are absent or incomplete [9]. These patients have traditionally been considered separate from patients with tDIPG for therapy or research purposes [10]

Methods

Results

Conclusion