Leomar Y. Ballester1,2, Zain Boghani3, David S. Baskin4,5,6, Gavin W. Britz4,5,6, Randall J. Olsen7,5,6, Gregory N. Fuller8, Suzanne Z. Powell7,5,6, Matthew D. Cykowski7,5,6
1Department of Pathology and Genomic Medicine; Houston Methodist Hospital; Houston TX; Department of Pathology and Laboratory Medicine, Department of Neurosurgery; University of Texas Health Science Center; Houston TX
2Department of Pathology and Laboratory Medicine, Department of Neurosurgery University of Texas Health Science Center Houston TX
3Department of Neurosurgery; Houston Methodist Hospital; Houston TX
4Department of Neurosurgery; Houston Methodist Hospital; Houston TX; Houston Methodist Research Institute, Institute of Academic Medicine; Houston TX; Weill Cornel Medical College; New York NY
5Houston Methodist Research Institute, Institute of Academic Medicine Houston TX
6Weill Cornel Medical College New York NY
7Department of Pathology and Genomic Medicine; Houston Methodist Hospital; Houston TX; Houston Methodist Research Institute, Institute of Academic Medicine; Houston TX; Weill Cornel Medical College; New York NY
8Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX
Tóm tắt
AbstractAstrocytes with multiple micronuclei (“Creutzfeldt cells”) in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high‐grade glioma vs tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood. Studies have proposed that micronuclei in Creutzfeldt cells are a consequence of DNA damage, or may be susceptible to DNA damage and chromothripsis, but their biology in the context of glioblastoma remains unclear. Based on a challenging index case of GBM with mild hypercellularity, Creutzfeldt astrocytes, and granular mitoses on biopsy, we searched our archives for additional cases with similar histopathologic features. We identified 13 cases, reviewed their clinico‐radiologic and pathologic features, and examined them for recurrent genetic alterations via NGS (9 cases) and for evidence of DNA damage by immunohistochemistry for DNA repair and chromatin remodeling proteins. We found that Creutzfeldt cell‐rich GBMs were IDH‐wildtype with no recurring genetic alterations. To test our hypothesis that micronuclei demonstrate loss of DNA repair or chromatin remodeling proteins, we examined the expression of various proteins (MDM2, p53, MLH1, MSH2, PMS2, MSH6, ATRX, INI1, SATB2, Ki67, pHH3) in Creutzfeldt cell rich‐GBM. There was intact expression of DNA repair and chromatin remodeling proteins, with accumulation of p53 and reduced MDM2 expression within micronuclei. In contrast, granular mitoses showed pHH3 expression, confirming these cells are undergoing mitotic division, with no accumulation of p53 and reduced expression of DNA repair proteins. Our results emphasize that Creutzfeldt cells are part of the morphologic spectrum of IDH‐wildtype glioblastoma. We did not find a role for DNA damage in the generation of Creutzfeldt cells, as both DNA repair and chromatin remodeling protein expression was retained in these cells.
