Diffusely Infiltrating Gliomas With Poor Prognosis, Promotor Mutations, and Histological Anaplastic Pleomorphic Xanthoastrocytoma-Like Appearance Classify As Mesenchymal Type of Glioblastoma, IDH-wildtype by Methylation Analysis

Overview

Journal Neurosurg Pract

Specialty Neurology

Date 2025 Feb 17

PMID 39958377

Authors

Yoshihiro Tsukamoto

Manabu Natsumeda

Haruhiko Takahashi

Jotaro On

Hiroki Seto

Taiki Saito

Kohei Shibuya

Ryosuke Ogura

Junko Ito

Masayasu Okada

Makoto Oishi

Hiroshi Shimizu

Kouichirou Okamoto

Akiyoshi Kakita

Yukihiko Fujii

Affiliations

Soon will be listed here.

Abstract

Background: Pleomorphic xanthoastrocytoma (PXA) (World Health Organization grade II) is classified as a relatively benign and circumscribed glioma; however, anaplastic PXA (APXA, World Health Organization grade III) has a poorer prognosis, and differentiating from glioblastoma can be difficult both histologically and molecularly.

Objective: To describe the clinical, pathological, and molecular characteristics of diffusely infiltrating gliomas with histological APXA-like features.

Methods: Four diffusely infiltrating gliomas in adult patients histologically diagnosed as APXAs at a single institute were retrospectively reviewed. We analyzed their clinical, radiological, pathological, genetic, epigenetic, and prognostic characteristics.

Results: All tumors histologically showed classical characteristic PXA-like appearance with wildtype, mitotic figure, necrosis, and an increased mindbomb E3 ubiquitin-protein ligase 1 labeling index and were initially diagnosed as APXAs; moreover, they underwent high-grade glioma treatment. Three patients with promotor mutations died within 18 months. These patients' MRIs showed widespread infiltrating fluid-attenuated inversion recovery hyperintense lesions and Gd-enhancing lesions in the bilateral cerebral hemispheres in 2 of the patients. Contrastingly, a patient with the wildtype promotor has survived for 2.5 years without recurrence. MRI revealed an unilateral fluid-attenuated inversion recovery hyperintense and Gd-enhancing lesion. By methylation classifier analysis, all 4 cases clustered toward GBM, IDH-wildtype, mesenchymal type, although one was deemed unclassifiable due to a low calibrated score.

Conclusion: In diffusely infiltrating gliomas showing histological characteristics of APXA, methylation classification should be performed as these tumors may be difficult to differentiate between glioblastoma, IDH-wildtype by histological or genetic analysis. The aggressive nature of these tumors should be expected, especially in cases that are -wildtype and promotor mutant.

References

She D, Liu J, Xing Z, Zhang Y, Cao D, Zhang Z . MR Imaging Features of Anaplastic Pleomorphic Xanthoastrocytoma Mimicking High-Grade Astrocytoma. AJNR Am J Neuroradiol. 2018; 39(8):1446-1452. PMC: 7410565. DOI: 10.3174/ajnr.A5701. View

Ono T, Sasajima T, Shimizu H, Natsumeda M, Kanamori M, Asano K . Molecular Features and Prognostic Factors of Pleomorphic Xanthoastrocytoma: A Collaborative Investigation of the Tohoku Brain Tumor Study Group. Neurol Med Chir (Tokyo). 2020; 60(11):543-552. PMC: 7788268. DOI: 10.2176/nmc.oa.2020-0155. View

Nakajima N, Nobusawa S, Nakata S, Nakada M, Yamazaki T, Matsumura N . BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity. Brain Pathol. 2017; 28(5):663-673. PMC: 8028676. DOI: 10.1111/bpa.12572. View

Koelsche C, Sahm F, Wohrer A, Jeibmann A, Schittenhelm J, Kohlhof P . BRAF-mutated pleomorphic xanthoastrocytoma is associated with temporal location, reticulin fiber deposition and CD34 expression. Brain Pathol. 2013; 24(3):221-9. PMC: 8029045. DOI: 10.1111/bpa.12111. View

Jeuken J, Cornelissen S, Boots-Sprenger S, Gijsen S, Wesseling P . Multiplex ligation-dependent probe amplification: a diagnostic tool for simultaneous identification of different genetic markers in glial tumors. J Mol Diagn. 2006; 8(4):433-43. PMC: 1867615. DOI: 10.2353/jmoldx.2006.060012. View

Vaubel R, Caron A, Yamada S, Decker P, Eckel Passow J, Rodriguez F . Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation. Brain Pathol. 2017; 28(2):172-182. PMC: 5807227. DOI: 10.1111/bpa.12495. View

Ebrahimi A, Korshunov A, Reifenberger G, Capper D, Felsberg J, Trisolini E . Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival. Acta Neuropathol Commun. 2022; 10(1):5. PMC: 8751269. DOI: 10.1186/s40478-021-01308-1. View

Phillips J, Gong H, Chen K, Joseph N, Van Ziffle J, Bastian B . The genetic landscape of anaplastic pleomorphic xanthoastrocytoma. Brain Pathol. 2018; 29(1):85-96. PMC: 7837273. DOI: 10.1111/bpa.12639. View

Capper D, Jones D, Sill M, Hovestadt V, Schrimpf D, Sturm D . DNA methylation-based classification of central nervous system tumours. Nature. 2018; 555(7697):469-474. PMC: 6093218. DOI: 10.1038/nature26000. View

10.

Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C . Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011; 121(3):397-405. DOI: 10.1007/s00401-011-0802-6. View

11.

Ogura R, Tsukamoto Y, Natsumeda M, Isogawa M, Aoki H, Kobayashi T . Immunohistochemical profiles of IDH1, MGMT and P53: practical significance for prognostication of patients with diffuse gliomas. Neuropathology. 2015; 35(4):324-35. DOI: 10.1111/neup.12196. View

12.

Choudry U, Khan S, Qureshi A, Bari E . Primary anaplastic pleomorphic xanthoastrocytoma in adults. Case report and review of literature. Int J Surg Case Rep. 2016; 27:183-188. PMC: 5026690. DOI: 10.1016/j.ijscr.2016.08.022. View

13.

Moskowitz S, Jin T, Prayson R . Role of MIB1 in predicting survival in patients with glioblastomas. J Neurooncol. 2005; 76(2):193-200. DOI: 10.1007/s11060-005-5262-1. View

14.

Dias-Santagata D, Lam Q, Vernovsky K, Vena N, Lennerz J, Borger D . BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One. 2011; 6(3):e17948. PMC: 3066220. DOI: 10.1371/journal.pone.0017948. View

15.

Jeuken J, Sijben A, Alenda C, Rijntjes J, Dekkers M, Boots-Sprenger S . Robust detection of EGFR copy number changes and EGFR variant III: technical aspects and relevance for glioma diagnostics. Brain Pathol. 2009; 19(4):661-71. PMC: 4332625. DOI: 10.1111/j.1750-3639.2009.00320.x. View

16.

Nobusawa S, Lachuer J, Wierinckx A, Kim Y, Huang J, Legras C . Intratumoral patterns of genomic imbalance in glioblastomas. Brain Pathol. 2010; 20(5):936-44. PMC: 8094667. DOI: 10.1111/j.1750-3639.2010.00395.x. View

17.

Koelsche C, Sahm F, Capper D, Reuss D, Sturm D, Jones D . Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol. 2013; 126(6):907-15. DOI: 10.1007/s00401-013-1195-5. View

18.

Shaikh N, Brahmbhatt N, Kruser T, Kam K, Appin C, Wadhwani N . Pleomorphic xanthoastrocytoma: a brief review. CNS Oncol. 2019; 8(3):CNS39. PMC: 6880293. DOI: 10.2217/cns-2019-0009. View

19.

Reifenberger G, Kaulich K, Wiestler O, Blumcke I . Expression of the CD34 antigen in pleomorphic xanthoastrocytomas. Acta Neuropathol. 2003; 105(4):358-64. DOI: 10.1007/s00401-002-0652-3. View

20.

Lin Z, Yang R, Zheng H, Li Z, Yi G, Wu Q . Pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, and epithelioid glioblastoma: Case series with clinical characteristics, molecular features and progression relationship. Clin Neurol Neurosurg. 2022; 221:107379. DOI: 10.1016/j.clineuro.2022.107379. View