High frequency of H3 K27M mutations in adult midline gliomas

Abstract

Purpose: Diffuse midline gliomas, H3 K27M-mutant were introduced as a new grade IV entity in WHO classification of tumors 2016. These tumors occur often in pediatric patients and show an adverse prognosis with a median survival less than a year. Most of the studies on these tumors, previously known as pediatric diffuse intrinsic pontine glioma, are on pediatric patients and its significance in adult patients is likely underestimated.

Methods: We studied 165 cases of brain tumors of midline localization initially diagnosed as diffuse astrocytomas, oligodendrogliomas, pilocytic astrocytomas, supependymomas, ependymomas and medulloblastomas in patients with an age range of 2-85.

Results: We identified 41 diffuse midline gliomas according WHO 2016, including 12 pediatric and 29 adult cases, among them two cases with histological features of low grade tumors: pilocytic astrocytoma and subependymoma. 49% (20/41) of the patients were above 30 years old by the first tumor manifestation including 29% (11/41) above 54 that signifies a broader age spectrum as previously reported. Our study confirms that H3 K27M mutations are associated with a poorer prognosis in pediatric patients compared to wild-type tumors, while in adult patients these mutations do not influence the survival significantly. The pattern of tumor growth was different in pediatric compared to adult patients; a diffuse growth along the brain axis was more evident in adult compared to pediatric patients (24% vs. 15%).

Conclusion: H3 K27M mutations are frequent in adult midline gliomas and have a prognostic role similar to H3 K27M wild-type high-grade tumors.

Keywords: Diffuse midline glioma; H3 K27M mutations; H3F3A.

Fig. 1

Diffuse midline glioma with initial histological diagnosis of subependymoma grade I; the tumor was located in brain stem and histologically consisted of clusters of small uniform nuclei in a matrix of glial cell processes with frequent micro cystic changes. It lacked mitotic figures, necrosis and endothelial proliferation

Fig. 2

Diffuse midline glioma with initial histological diagnosis of pilocytic astrocytoma grade I; the tumor was located in thalamus and histologically revealed a loose myxoid texture with moderate cellularity and multipolar cells as well as focally up to five mitoses per high-power field and endothelial proliferations. A piloid aspect with bipolar elongated thin processes was evident in intraoperative cytological smear

Fig. 3

Tumor location in adult (a) and pediatric (b) patients

Fig. 4

Kaplan–Meier’s survival analysis of pediatric and adult patients; pediatric patients with H3K27M mutation had a significantly lower survival than H3K27M wild type, when histological features of anaplasia including high mitotic rate, necrosis and endothelial proliferation were present (tumors with diffuse growth pattern and initial WHO grade III and IV) (median survival 91 vs. 543 days, Log-rank p = 0.02), *p value < 0.05