H3 K27M-mutant gliomas in adults vs. children share similar histological features and adverse prognosis

Abstract

Background: H3 K27M mutation was originally described in pediatric diffuse intrinsic pontine gliomas (DIPGs), but has been recently recognized to occur also in adult midline diffuse gliomas, as well as midline tumors with other morphologies, including gangliogliomas (GGs), anaplastic GGs, pilocytic astrocytomas (PAs), and posterior fossa ependymomas. In a few patients with H3 K27M;mutant tumors with these alternate morphologies, longer survival has been reported, making grading difficult for the neuropathologist. Few series compare tumors in adult vs. pediatric cohorts; we report our 4-year experience.

Materials and methods: Text Word database searches using H3 K27M in reports generated between January 2013 and November 10, 2017 were used to identify patients. Clinical and histological features as well as survival were evaluated for each case.

Results: 28 H3 K27M-mutant tumors were identified, with equal numbers of adults (13) vs. children (15). For adults, mean and median age was 52 years (range = 27 - 81 years), 2 decades older than a recently-published adult series. Tumors involved thalamic (adult = 7; pediatric = 7), spinal cord (adult = 4; pediatric = 2), pons (adult = 1; pediatric = 6), and hypothalamic (n = 1) sites. Other morphologies at presentation included pure GG (n = 3, pediatric) and PA (n = 1, adult). One adult and 1 pediatric patient each presented with leptomeningeal dissemination or developed leptomeningeal dissemination within 1 year after diagnosis, with transformation from PA or GG histology to glioblastoma. Mean survival was 9.3 (adults) vs. 8.9 (pediatric) months. Patients with tumors of other morphologies (GG, PA) did not enjoy extended survival.

Conclusion: H3 K27M-mutant tumors can affect patients at advanced ages, may show leptomeningeal dissemination at time of presentation, and "pure" GG or PA morphology is not rare. Regardless of patient age or tumor morphology, patients fare equally poorly. .

Figure 1.. Adult diffuse midline gliomas can present with metastatic lesions. a: Contrast-enhanced axial T1-weighted MR image demonstrates a diffuse infiltrating lesion of the pons in a 61-year-old female patient (patient 10). b, c: Contrast-enhanced sagittal T1-weighted MR image of the spinal cord demonstrating leptomeningeal metastases at diagnosis (arrows).

Figure 2.. Aggressive nature of diffuse midline gliomas with H3 K27M mutation and ganglioglioma (GG) morphology, with early metastatic recurrence. a: Contrast-enhanced axial FLAIR image demonstrating a large left thalamic lesion (patient 28). b: Contrast-enhanced axial FLAIR image demonstrating primary thalamic lesion with a new finding of punctate focus of enhancement in the right lateral ventricle with adjacent white matter hyperintensity (arrow) demonstrating the development of metastatic disease within 3 months after diagnosis. c: This child originally showed a “pure” GG on biopsy, with irregularly sized and placed neuronal cells in a paucicellular background. d: However, the tumor was diffusely immunoreactive for nuclear H3 K27M, including the larger sized ganglionic tumor nuclei. e: Her recurrent tumor 3 months later no longer contained any areas of low grade GG; instead a highly pleomorphic glioblastoma (f) with diffuse H3 K27M immunostaining had developed. (c, e: H & E, × 200, × 400; d, f: H3 K27M immunostaining with light hematoxylin counterstain, × 200, × 400).

Figure 3.. Aggressive nature of diffuse midline gliomas with H3 K27M mutation and pylotic astrocytome (PA) morphology, with later metastatic recurrence. a: Contrast-enhanced sagittal T1-weighted image demonstrating a cervical cord PA (patient 4) at presentation. b: Contrast-enhanced sagittal T1-weighted image demonstrating local progression within 1 year of diagnosis of the PA shown in (a). c: Contrast-enhanced axial T1-weighted image demonstrating additional large supratentorial leptomeningeal/dural metastasis with transformation of the PA to glioblastoma 1 year after diagnosis.

Figure 4.. Aggressive nature of diffuse midline gliomas with H3 K27M mutation and pilotcytic astrocytoma (PA) morphology, with later metastatic recurrence. a: Patient 4 originally had a cervical cord pilocytic astrocytoma that was paucicellular and filled with innumerable eosinophilic elongated Rosenthal fibers, but was diffusely immunoreactive for H3 K27M. b: One year later the same patient’s supratentorial metastasis showed transformation to glioblastoma, with (b) hypercellularity and microvascular proliferation, (c) high MIB-1 labeling index, and (d) retention of diffuse H3 K27M immunoreactivity. (a, b: hematoxylin and eosin, × 200, × 200; c: MIB-1 immunostaining, × 200; d: H3 K27M immunostaining, × 200).