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Adult diffuse midline gliomas H3 K27-altered: review of a redefined entity

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Abstract

Introduction

Diffuse midline glioma (DMG) H3 K27-altered is a type of high-grade gliomas first recognized as a new entity in the 2016 World Health Organization Classification of Central Nervous System (CNS) Tumors as DMG H3 K27M-mutant, recently renamed in the new 2021 WHO classification. The aim of this review is to describe the characteristics of diffuse midline gliomas H3 K27-altered in the adult population.

Methods

We performed a review of the current literature regarding the genetic, clinical, imaging characteristics and management of diffuse midline gliomas H3 K27-altered in adult patients.

Results

The 2021 WHO classification now designates the previously recognized DMG H3K27M-mutant as DMG H3 K27-altered, recognizing the alternative mechanisms by which the pathogenic pathway can be altered. Thus, the diagnostic criteria for this entity consist of diffuse growth pattern, midline anatomic location, and H3 K27-specific neuroglial mutations. DMGs’ characteristic midline location makes them difficult to surgically resect and biopsy, carrying high mortality and morbidity rates, with median survival ranging from 9 to 12 months in adult patients.

Conclusion

The diagnosis of DMGs H3 K27-altered in adult patients should be considered upon neurological symptoms associated with an infiltrative midline brain tumor detected on imaging. Future studies are necessary to continue refining their characteristics in this age group.

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References

  1. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK et al (2016) The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  PubMed  Google Scholar 

  2. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D et al (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23:1231–1251. https://doi.org/10.1093/neuonc/noab106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schreck KC, Ranjan S, Skorupan N, Bettegowda C, Eberhart CG, Ames HM et al (2019) Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas. J Neurooncol. https://doi.org/10.1007/s11060-019-03134-x

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yoon HI, Wee CW, Kim YZ, Seo Y, Im JH, Dho Y-S et al (2021) The Korean society for neuro-oncology (KSNO) guideline for adult diffuse midline Glioma: version 2021.1. Brain Tumor Res Treat 9:1

    Article  Google Scholar 

  5. Schulte JD, Buerki RA, Lapointe S, Molinaro AM, Zhang Y, Villanueva-Meyer JE et al (2020) Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults. Neuro-Oncol Adv. https://doi.org/10.1093/noajnl/vdaa142

    Article  Google Scholar 

  6. Bai J, Varghese J, Jain R (2020) Adult glioma WHO classification update, genomics, and imaging: what the radiologists need to know. Top Magn Reson Imaging 29:71–82. https://doi.org/10.1097/RMR.0000000000000234

    Article  PubMed  Google Scholar 

  7. Meyronet D, Esteban-Mader M, Bonnet C, Joly MO, Uro-Coste E, Amiel-Benouaich A et al (2017) Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol 19:1127–1134. https://doi.org/10.1093/neuonc/now274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Park C, Kim TM, Bae JM, Yun H, Kim JW, Choi SH et al (2021) Clinical and genomic characteristics of adult diffuse midline glioma. Cancer Res Treat 53:389–398. https://doi.org/10.4143/CRT.2020.694

    Article  PubMed  Google Scholar 

  9. Himes BT, Zhang L, Daniels DJ (2019) Treatment strategies in diffuse midline gliomas with the H3K27M mutation: the role of convection-enhanced delivery in overcoming anatomic challenges. Front Oncol 9:1–10. https://doi.org/10.3389/fonc.2019.00031

    Article  Google Scholar 

  10. Santisukwongchote S, Teerapakpinyo C, Chankate P, Techavichit P, Boongird A, Sathornsumetee S et al (2021) Simplified approach for pathological diagnosis of diffuse gliomas in adult patients. Pathol Res Pract 223:153483. https://doi.org/10.1016/j.prp.2021.153483

    Article  CAS  PubMed  Google Scholar 

  11. Dono A, Takayasu T, Ballester LY, Esquenazi Y (2020) Adult diffuse midline gliomas: clinical, radiological, and genetic characteristics. J Clin Neurosci 82:1–8. https://doi.org/10.1016/j.jocn.2020.10.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang L, Li Z, Zhang M, Piao Y, Chen L, Liang H et al (2018) H3 K27M—mutant diffuse midline gliomas in different anatomical locations. Hum Pathol 78:89–96. https://doi.org/10.1016/j.humpath.2018.04.015

    Article  CAS  PubMed  Google Scholar 

  13. Aboian MS, Solomon DA, Felton E, Mabray MC, Villanueva-Meyer JE, Mueller S et al (2017) Imaging characteristics of pediatric diffuse midline gliomas with histone H3 K27M mutation. Am J Neuroradiol 38:795–800. https://doi.org/10.3174/ajnr.A5076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Enomoto T, Aoki M, Hamasaki M, Abe H, Nonaka M, Inoue T et al (2020) Midline glioma in adults: clinicopathological, genetic, and epigenetic analysis. Neurol Med Chir (Tokyo) 60:136–146. https://doi.org/10.2176/nmc.oa.2019-0168

    Article  Google Scholar 

  15. Schwartzentruber J, Korshunov A, Liu XY, Jones DTW, Pfaff E, Jacob K et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–31. https://doi.org/10.1038/nature10833

    Article  CAS  PubMed  Google Scholar 

  16. Jain SU, Rashoff AQ, Krabbenhoft SD, Hoelper D, Do TJ, Gibson TJ et al (2020) H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2. Mol Cell 80:726–735. https://doi.org/10.1016/j.molcel.2020.09.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DTW, Kool M et al (2013) Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660–672. https://doi.org/10.1016/j.ccr.2013.10.006

    Article  CAS  PubMed  Google Scholar 

  18. Findlay IJ, De Iuliis GN, Duchatel RJ, Jackson ER, Vitanza NA, Cain JE et al (2022) Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies. Oncogene 41:461–475. https://doi.org/10.1038/s41388-021-02102-y

    Article  CAS  PubMed  Google Scholar 

  19. Castel D, Kergrohen T, Tauziède-Espariat A, Mackay A, Ghermaoui S, Lechapt E et al (2020) Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation. Acta Neuropathol 139:1109–1113. https://doi.org/10.1007/s00401-020-02142-w

    Article  PubMed  Google Scholar 

  20. Antin C, Tauziède-Espariat A, Debily MA, Castel D, Grill J, Pagès M et al (2020) EZHIP is a specific diagnostic biomarker for posterior fossa ependymomas, group PFA and diffuse midline gliomas H3-WT with EZHIP overexpression. Acta Neuropathol Commun 8:183. https://doi.org/10.1186/s40478-020-01056-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jain SU, Do TJ, Lund PJ, Rashoff AQ, Diehl KL, Cieslik M et al (2019) PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat Commun. https://doi.org/10.1038/s41467-019-09981-6

    Article  PubMed  PubMed Central  Google Scholar 

  22. Argersinger DP, Rivas SR, Shah AH, Jackson S, Heiss JD (2021) New developments in the pathogenesis, therapeutic targeting, and treatment of h3k27m-mutant diffuse midline glioma. Cancers (Basel). https://doi.org/10.3390/cancers13215280

    Article  Google Scholar 

  23. Solomon DA, Wood MD, Tihan T, Bollen AW, Gupta N, Phillips JJJ et al (2016) Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 26:569–580. https://doi.org/10.1111/bpa.12336

    Article  CAS  PubMed  Google Scholar 

  24. Georgescu MM, Islam MZ, Li Y, Circu ML, Traylor J, Notarianni CM et al (2020) Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma. Acta Neuropathol Commun 8:1–17. https://doi.org/10.1186/s40478-020-00992-9

    Article  CAS  Google Scholar 

  25. Haase S, Nuñez FM, Gauss JC, Thompson S, Brumley E, Lowenstein P et al (2020) Hemispherical pediatric high-grade glioma: molecular basis and therapeutic opportunities. Int J Mol Sci 21:1–25. https://doi.org/10.3390/ijms21249654

    Article  CAS  Google Scholar 

  26. Pathania M, De Jay N, Maestro N, Harutyunyan AS, Nitarska J, Pahlavan P et al (2017) H3.3K27M cooperates with Trp53 loss and PDGFRA gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas. Cancer Cell 32:684-700.e9. https://doi.org/10.1016/j.ccell.2017.09.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schüller U, Iglauer P, Dorostkar MM, Mawrin C, Herms J, Giese A et al (2021) Mutations within FGFR1 are associated with superior outcome in a series of 83 diffuse midline gliomas with H3F3A K27M mutations. Acta Neuropathol 141:323–325. https://doi.org/10.1007/s00401-020-02259-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Picca A, Berzero G, Bielle F, Touat M, Savatovsky J, Polivka M et al (2018) FGFR1 actionable mutations, molecular specificities, and outcome of adult midline gliomas. Neurology 90:e2086–e2094. https://doi.org/10.1212/WNL.0000000000005658

    Article  CAS  PubMed  Google Scholar 

  29. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E et al (2012) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124:439–47. https://doi.org/10.1007/s00401-012-0998-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li Q, Dong F, Jiang B, Zhang M (2021) Exploring MRI characteristics of brain diffuse midline gliomas with the H3 K27M mutation using radiomics. Front Oncol 11:1–9. https://doi.org/10.3389/fonc.2021.646267

    Article  Google Scholar 

  31. Price G, Bouras A, Hambardzumyan D, Hadjipanayis CG (2021) Current knowledge on the immune microenvironment and emerging immunotherapies in diffuse midline glioma. EBioMedicine 69:103453. https://doi.org/10.1016/j.ebiom.2021.103453

    Article  PubMed  PubMed Central  Google Scholar 

  32. Meel MH, Kaspers GJL, Hulleman E (2019) Preclinical therapeutic targets in diffuse midline glioma. Drug Resist Updat 44:15–25. https://doi.org/10.1016/j.drup.2019.06.001

    Article  PubMed  Google Scholar 

  33. Jiang H, Yang K, Ren X, Cui Y, Li M, Lei Y et al (2020) Diffuse midline glioma with an H3 K27M mutation: a comparison integrating the clinical, radiological, molecular features between adult and pediatric patients. Neuro-Oncology. https://doi.org/10.1093/neuonc/noz152/5554271

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kleinschmidt-DeMasters BK, Levy JMM (2018) H3 K27M-mutant gliomas in adults vs. Children share similar histological features and adverse prognosis. Clin Neuropathol 37:53–63. https://doi.org/10.5414/NP301085

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zheng L, Gong J, Yu T, Zou Y (2022) Diffuse midline gliomas with histone H3 K27M mutation in adults and children. Am J Surg Pathol. https://doi.org/10.1097/PAS.0000000000001897

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lu VM, Alvi MA, Mcdonald KL, Daniels DJ (2018) Impact of the H3K27M mutation on survival in pediatric high-grade glioma: a systematic review and meta-analysis. J Neurosurg: Pediatr. https://doi.org/10.3171/2018.9.PEDS18419

    Article  Google Scholar 

  37. Daoud EV, Rajaram V, Cai C, Oberle RJ, Martin GR, Raisanen JM et al (2018) Adult brainstem gliomas with H3K27M mutation: Radiology, pathology, and prognosis. J Neuropathol Exp Neurol 77:302–311. https://doi.org/10.1093/jnen/nly006

    Article  CAS  PubMed  Google Scholar 

  38. Dufour C, Perbet R, Leblond P, Vasseur R, Stechly L, Pierache A et al (2020) Identification of prognostic markers in diffuse midline gliomas H3K27M-mutant. Brain Pathol 30:179–190. https://doi.org/10.1111/bpa.12768

    Article  CAS  PubMed  Google Scholar 

  39. Louis DN, Giannini C, Capper D, Paulus W, Figarella-Branger D, Lopes MB et al (2018) cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma. IDH-mutant Acta Neuropathol 135:639–642. https://doi.org/10.1007/s00401-018-1826-y

    Article  PubMed  Google Scholar 

  40. Gu Q, Huang Y, Zhang H, Jiang B (2021) Case report: five adult cases of H3K27-altered diffuse midline glioma in the spinal cord. Front Oncol. https://doi.org/10.3389/fonc.2021.701113

    Article  PubMed  PubMed Central  Google Scholar 

  41. Qiu T, Chanchotisatien A, Qin Z, Wu J, Du Z, Zhang X et al (2020) Imaging characteristics of adult H3 K27M-mutant gliomas. J Neurosurg 133:1662–1670. https://doi.org/10.3171/2019.9.JNS191920

    Article  CAS  Google Scholar 

  42. Banan R, Akbarian A, Samii M, Samii A, Bertalanffy H, Lehmann U et al (2021) Diffuse midline gliomas, H3 K27M-mutant are associated with less peritumoral edema and contrast enhancement in comparison to glioblastomas, H3 K27M-wildtype of midline structures. PLoS ONE 16:e0249647. https://doi.org/10.1371/journal.pone.0249647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Thust S, Micallef C, Okuchi S, Brandner S, Kumar A, Mankad K et al (2021) Imaging characteristics of H3 K27M histone-mutant diffuse midline glioma in teenagers and adults. Quant Imaging Med Surg 11:43–56. https://doi.org/10.21037/QIMS-19-954

    Article  PubMed  PubMed Central  Google Scholar 

  44. Jung JS, Choi YS, Ahn SS, Yi S, Kim SH, Lee SK (2019) Differentiation between spinal cord diffuse midline glioma with histone H3 K27M mutation and wild type: comparative magnetic resonance imaging. Neuroradiology 61:313–322. https://doi.org/10.1007/s00234-019-02154-8

    Article  PubMed  Google Scholar 

  45. Wang Y, Feng LL, Ji PG, Liu JH, Guo SC, Zhai YL et al (2021) Clinical features and molecular markers on diffuse midline gliomas with H3K27M mutations: A 43 cases retrospective cohort study. Front Oncol. https://doi.org/10.3389/fonc.2020.602553

    Article  PubMed  PubMed Central  Google Scholar 

  46. Feng J, Hao S, Pan C, Wang Y, Wu Z, Zhang J et al (2015) The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol 46:1626–32. https://doi.org/10.1016/j.humpath.2015.07.002

    Article  CAS  PubMed  Google Scholar 

  47. Hassan U, Latif M, Yousaf I, Bin Anees S, Mushtaq S, Akhtar N et al (2021) Morphological spectrum and survival analysis of diffuse midline glioma with H3K27M mutation. Cureus 13:4–12. https://doi.org/10.7759/cureus.17267

    Article  Google Scholar 

  48. Karremann M, Gielen GH, Hoffmann M, Wiese M, Colditz N, Warmuth-Metz M et al (2018) Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol 20:123–131. https://doi.org/10.1093/neuonc/nox149

    Article  CAS  PubMed  Google Scholar 

  49. Chen H, Hu W, He H, Yang Y, Wen G, Lv X (2019) Noninvasive assessment of H3 K27M mutational status in diffuse midline gliomas by using apparent diffusion coefficient measurements. Eur J Radiol 114:152–159. https://doi.org/10.1016/j.ejrad.2019.03.006

    Article  PubMed  Google Scholar 

  50. Basit Khan A, Matsuoka CK, Lee S, Rahman M, Rao G (2021) Prolonged survival after laser interstitial thermal therapy in glioblastoma. Surg Neurol Int 12:1–4. https://doi.org/10.25259/SNI_174_2021

    Article  Google Scholar 

  51. Smith CJ, Fairres MJ, Myers CS, Chapple KM, Klysik M, Karis JP et al (2019) Long-term outcome data from 121 patients treated with Gamma Knife stereotactic radiosurgery as salvage therapy for focally recurrent high-grade gliomas. J Radiosurgery SBRT 6:199–207

    Google Scholar 

  52. Ding C, Saw CB, Timmerman RD (2018) Cyberknife stereotactic radiosurgery and radiation therapy treatment planning system. Med Dosim 43:129–140. https://doi.org/10.1016/j.meddos.2018.02.006

    Article  PubMed  Google Scholar 

  53. De Franca SA, Tavares WM, Salinet ASM, Teixeira MJ, Paiva WS (2020) Laser interstitial thermal therapy as an adjunct therapy in brain tumors: a meta-analysis and comparison with stereotactic radiotherapy. Surg Neurol Int 11:1–15. https://doi.org/10.25259/SNI_152_2020

    Article  Google Scholar 

  54. Tong BC-K (2017) 乳鼠心肌提取 HHS public access. Physiol Behav 176:139–48. https://doi.org/10.1007/s11060-019-03271-3.Pediatric

    Article  Google Scholar 

  55. Hall MD, Odia Y, Allen JE, Tarapore R, Khatib Z, Niazi TN et al (2019) First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M–mutant pediatric diffuse intrinsic pontine glioma: a case report. J Neurosurg Pediatr 23:719–725. https://doi.org/10.3171/2019.2.PEDS18480

    Article  PubMed  Google Scholar 

  56. Gardner SL, Allen JC, Zaky WT, Odia Y, Daghistani D, Khatib Z et al (2019) ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma. J Clin Oncol 37:10046. https://doi.org/10.1200/JCO.2019.37.15_suppl.10046

    Article  Google Scholar 

  57. Arrillaga-Romany I, Kurz S, Tarapore R, Lu G, Sumrall A, Butowski N et al (2021) LTBK-05. clinical efficacy OF ONC201 in recurrent H3 K27M-mutant diffuse midline glioma patients. Neuro Oncol 23:230–230. https://doi.org/10.1093/neuonc/noab196.925

    Article  Google Scholar 

  58. Gojo J, Pavelka Z, Zapletalova D, Schmook MT, Mayr L, Madlener S et al (2020) Personalized treatment of H3K27M-mutant pediatric diffuse gliomas provides improved therapeutic opportunities. Front Oncol 9:1–14. https://doi.org/10.3389/fonc.2019.01436

    Article  Google Scholar 

  59. Lu VM, Alvi MA, McDonald KL, Daniels DJ (2019) Impact of the H3K27M mutation on survival in pediatric high-grade glioma: a systematic review and meta-analysis. J Neurosurg Pediatr 23:308–316. https://doi.org/10.3171/2018.9.PEDS18419

    Article  Google Scholar 

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Acknowledgements

The authors thank Alan Ulises López Pérez for reviewing and revising the manuscript.

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Authors and Affiliations

  1. Instituto Tecnológico y de Estudios Superiores de Monterrey Campus Guadalajara, Zapopan, Mexico

    Carlos Axel López-Pérez, Xochitl Franco-Mojica, Ricardo Villanueva-Gaona, Alexandra Díaz-Alba & Victor Garcia Navarro

  2. Instituto Neurológico de Guadalajara S.C, Guadalajara, Jalisco, Mexico

    Victor Garcia Navarro

  3. Instituto Oncológico Nacional: ION, Guadalajara, Jalisco, Mexico

    Alexandra Díaz-Alba

  4. Unit of Medical Research in Neurological Diseases, Instituto Mexicano del Seguro Social, Centro Médico Nacional Siglo XXI, Mexico City, Mexico

    Marco Antonio Rodríguez-Florido

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  1. Carlos Axel López-Pérez
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VGN had the idea for the article. CAL-P, XF-M and RV-G performed the literature search, data analysis and drafted the work. VGN and AD-A critically revised the work. MAR-F, MD., provided the radiological and histopathological images.

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Correspondence to Victor Garcia Navarro.

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López-Pérez, C.A., Franco-Mojica, X., Villanueva-Gaona, R. et al. Adult diffuse midline gliomas H3 K27-altered: review of a redefined entity. J Neurooncol 158, 369–378 (2022). https://doi.org/10.1007/s11060-022-04024-5

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