UCSF

Abstract

BACKGROUND

Histone H3.3 or H3.1 mutant protein is commonly expressed in pediatric and adult diffuse midline gliomas, including diffuse intrinsic pontine gliomas (DIPGs), and portends a poor prognosis, regardless of histologic features. As such, “Diffuse midline glioma, H3-K27M-mutant” (DMG-H3K27M) was added to the 2016 WHO Classification as a grade IV entity. Knowledge of the clinical experience and natural history of this recently defined tumor in adults is limited.

METHODS

We retrospectively reviewed the pathology of adult (age ≥ 18) DMG-H3K27Ms diagnosed at our institution either via H3-K27M mutant-specific immunohistochemistry or via the UCSF500 targeted next-generation sequencing panel that includes the H3F3A, HIST1H3B, and HIST1H3C genes. Treatment, outcome, and imaging characteristics were reviewed.

RESULTS

We identified 26 adults with DMG-H3K27M and 2 with non-midline-H3K27M. Tumor locations included thalamus/basal ganglia (15), hypothalamus (2), pineal region (1), cerebellum (3), brainstem (2), spinal cord (2), mesial temporal (1), and non-midline sites (2). MRI imaging for 21/25 evaluable cases demonstrated enhancement. Of the 26 DMG-H3K27M cases, median age was 35 years (22–68 years). Of these, 17 patients had biopsy only. Median OS was 41 months (95%-CI 31-NA). In the 22 DMG-H3K27M patients with available clinical treatment data, 21 received radiation (19 with temozolomide) at initial diagnosis. At progression/recurrence, 11 patients received bevacizumab, 5 were re-treated with temozolomide, 8 received other chemotherapy, and 8 received > 1 course of re-irradiation.

CONCLUSION

While still poor overall, clinical outcome in adults with DMG-H3K27M is often better than that of pediatric DIPGs and other IDH-wildtype high-grade gliomas, such as glioblastoma. This may reflect a different cell of origin or other distinct biologic differences. Further investigation of both DMG-H3K27M and non-midline H3K27M mutant tumors in adults is warranted to study the genetic and epigenetic features of these rare tumors, as well as optimal treatment strategies.