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Diffuse midline gliomas, H3K27M-altered, of the pineal gland: the first synaptophysin-positive case and a systematic
Gabriele Gaggero1, Marco Pavanello2, Claudia Milanaccio3
1Pathology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Abstract:
Diffuse midline gliomas (DMGs) with H3K27M alterations are rare, aggressive, World Health Organization (WHO) grade 4 tumors arising in midline central nervous system (CNS) structures, characterized by a lysine-to-methionine substitution at histone H3K27, which disrupts epigenetic regulation via global loss of H3K27 trimethylation. The pineal gland is an exceptionally uncommon site of origin. We report the first case of a synaptophysin-positive, H3K27M-altered DMG in the pineal gland of a 7-year-old female, characterized by hypercellularity, moderate atypia, high mitotic activity, and a Ki-67 index of 30%. Immunohistochemistry confirmed positivity for glial markers: glial fibrillary acidic protein (GFAP), oligodendrocyte transcription factor 2 (Olig2), loss of hypotrimethylation of lysine 27 on histone H3 (H3K27me3), and synaptophysin expression, an unusual feature for DMGs. Methylation profiling established the diagnosis. A systematic review identified seven cases of pineal H3K27M-altered DMG (age ranged from 7 to 65 years, with three pediatric and four adult) revealing notable immunohistochemical heterogeneity, limited molecular data (only our case had available methylation profiling) and a synaptophysin expression limited to our pediatric case. Sparse clinical outcome data precluded robust prognostic comparisons. These findings underscore the biological heterogeneity and diagnostic challenges of pineal DMGs and underscore the necessity of comprehensive molecular and immunohistochemical assessments to optimize diagnosis and guide emerging targeted therapies.
Insights
Diffuse midline gliomas (DMGs) with H3K27M alterations are rare, aggressive brain tumors. This study details the first reported pineal gland DMG case, highlighting diagnostic challenges and the need for molecular analysis.
Area of Science:
- Neuro-oncology
- Molecular Pathology
- Epigenetics
Background:
- Diffuse midline gliomas (DMGs) with H3K27M alterations are aggressive WHO grade 4 CNS tumors.
- These tumors disrupt epigenetic regulation through H3K27M substitution and loss of H3K27 trimethylation.
- The pineal gland is an extremely rare site for DMG origin.
Purpose of the Study:
- To report the first case of a synaptophysin-positive, H3K27M-altered DMG in the pineal gland.
- To characterize its unique immunohistochemical profile, including synaptophysin expression.
- To review existing literature on pineal H3K27M-altered DMGs to identify diagnostic and prognostic patterns.
Main Methods:
- Case report of a 7-year-old female with a pineal DMG.
- Immunohistochemistry for glial markers (GFAP, Olig2), H3K27me3, and synaptophysin.
- Methylation profiling for molecular diagnosis.
- Systematic literature review of pineal H3K27M-altered DMGs.
Main Results:
- The case presented with hypercellularity, atypia, high mitotic activity, and a 30% Ki-67 index.
- Immunohistochemistry showed GFAP, Olig2, loss of H3K27me3, and unusual synaptophysin positivity.
- Methylation profiling confirmed the DMG diagnosis.
- The systematic review identified 7 cases, revealing immunohistochemical heterogeneity and limited molecular data, with synaptophysin expression unique to the pediatric case.
Conclusions:
- Pineal DMGs exhibit significant biological and immunohistochemical heterogeneity.
- Synaptophysin expression can occur in pediatric pineal DMGs, posing diagnostic challenges.
- Comprehensive molecular and immunohistochemical assessments are crucial for accurate diagnosis and guiding targeted therapies for these rare tumors.
