Rivera, Andreana L.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.

85 year old man with progressive dementia and history of stroke clinically diagnosed with Alzheimer's disease (AD) came to autopsy. There was diffuse bilateral atrophy of the frontal/temporal lobes and focal cavitations grossly consistent with remote infarcts (confirmed microscopically) were noted in parietal lobe, basal ganglia, and cerebellar hemispheres. Microscopically, numerous tau inclusions including neurofibrillary tangles, globular inclusions, grains and threads with tau immunohistochemical stain were seen. Tau deposits were present throughout the brain with increased numbers in the limbic lobe, basal telencephalon and diencephalon. Leukoencephalopathy was due to atherosclerosis and deposition of amyloid β protein predominantly in the cortical capillaries, with diffuse cortical involvement. Only rare senile plaques were noted with amyloid immunostains. The distribution of tauopathy was unusual and similar to argyrophilic grain disease (AGD), however, the morphology of tau deposits seen are inconsistent with AGD. The presence of the cerebral amyloid angiopathy is unusual due to involvement of parenchymal capillaries outside the primary visual cortex and suggests a genetic component. A low Braak stage and scattered cortical plaques were insufficient for diagnosis of AD. To our knowledge the constellation of findings seen are unique and not previously reported.

Glioblastoma (GM) is one of the most common malignant parenchymal tumors in adults with the majority being supratentorial. Cerebellar GMs are far less common, comprising less than 1% of all intracranial GMs. To our knowledge, no large scale studies have been done to compare the survival outcome of cerebellar to cerebral GMs. Clinical characteristics of 42 patients with newly diagnosed cerebellar GMs from the files of M.D. Anderson Cancer Center between 1985 and 2005 were reviewed, and compared with 649 cerebral GMs. The median age of patients with cerebellar GM was 38.7, which was significantly younger than for cerebral GM (56.7, p<0.001). Survival outcome between the two patient populations was also compared. The median survival for the cerebellar GM group was 61.6 weeks, not significantly different from the cerebral GM group (81.3 weeks, p=0.156). However, long‐term survivorship, as defined by survival at 2 years was 17.5% and 28.6% for cerebral and cerebellar GMs, respectively (p<0.001). Cerebellar GMs occur in a younger patient population than cerebral GMs. The median survival does not appear to differ, but there is an increase in long‐term survivorship in cerebellar tumors. Comparison of molecular signatures, treatment modalities and tumor progression among the patients are under investigation to better stratify the patient populations.