Category: Clinical Science
At the end of the session, participants will be able to:
- Characterize the molecular landscape of granular mitosis in glioblastoma
- Integrate AI-assisted digital pathology with multi-omic data to link histologic features to molecular alterations.
- Evaluate the tumor immune microenvironment associated with granular mitosis using immunohistochemistry and spatial correlation analysis.
COI Disclosure:
None to disclose
Presenter
Dr. Qi Zhang is a neuropathologist at the London Health Sciences Centre and an Associate Professor in the Department of Pathology and Laboratory Medicine at Western University.
Rachel Barboza1, Xuan Wang1, August Lin1, Eric Liu2, Pramath Kakodkar3, Yayuan Zhao3, Quinn Le1, Christina A. Castellani1,4,5 and Qi Zhang1, 6, 7
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, Canada.
- Department of Computer Science, Western University, Canada
- Department of Pathology and Lab Medicine, University of Saskatchewan, Canada
- Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, Canada.
- Children’s Health Research Institute, Lawson Research Institute, Canada.
- Department of Clinical Neurological Sciences, London Health Sciences Center, Western University, London, ON, Canada
- Department of Oncology, London Health Sciences Center, Western University, London, ON, Canada
Target Audience:
Pathologists
Residents
Medical Students
CanMEDS:
Medical Expert (the integrating role)
Communicator
Collaborator
Leader
Health Advocate
Scholar
Professional
Chromosomal and immune dysregulation underlying granular mitosis in glioblastoma
Abstract
Granular mitosis (GM) is a distinctive form of atypical mitosis characterized by dispersed chromosomal granules within the mitotic figure. Although described morphologically in glioblastoma, its molecular etiology has remained unknown. Data from The Cancer Genome Atlas (TCGA) Glioblastoma Multiforme cohort were analyzed. AI-assisted digital pathology was used to annotate mitotic figures, including GM, on hematoxylin and eosin–stained whole-slide images. Corresponding transcriptomic and genomic data were subjected to differential gene expression and copy number variation (CNV) analyses, followed by pathway enrichment. Clinical data were correlated with molecular and pathological findings. Validation was performed on an independent glioblastoma cohort using immunohistochemistry. Sixty-three glioblastoma cases were included (32 GM-positive, 31 GM-negative). Transcriptomic analysis identified 185 differentially expressed genes (FDR < 0.05; log₂FC > 1.5). GM-positive tumors demonstrated broad downregulation of genes involved in nucleosome assembly, protein–DNA complex organization, and centromeric differentiation, alongside significant suppression of PI3K–Akt signaling (p = 5.58 × 10⁻⁵). Unexpectedly, immune-related pathways—including Neutrophil extracellular trap (NET) formation and Cytokine–cytokine receptor interaction—were similarly underexpressed, indicating global suppression of innate immune signaling. Two CNVs were associated with higher GM proportion, demonstrating chromosomal fragility. Immunohistochemistry revealed significantly higher density of macrophages and antigen-presenting cells in close proximity to granular mitoses, and spatial correlation analysis demonstrated positive correlations between GM distribution and immune cell density across tumor regions. This study provides the first comprehensive molecular characterization of GM in glioblastoma. The findings link GM morphology to chromosomal disorganization, PI3K/PTEN pathway alterations, and impaired innate immunity, suggesting GM represents a histologic correlate of centromeric stress and immune impairment, with localized immune cell enrichment in its microenvironment.