Skip to main content

Advertisement

SpringerLink
Log in

Clinico-pathological and molecular characterization of diffuse midline gliomas: is there a prognostic significance?

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Purpose

H3K27M mutant diffuse midline gliomas (DMGs) are considered grade IV irrespective of histological features and have dismal prognosis. We evaluated clinico-pathologic, radiological, and molecular characteristics of DMGs across all ages.

Methods

One twenty-six DMGs were identified over 10 years. Immunohistochemistry was done for H3K27M, ATRX, IDH1, and p53, and Sanger sequencing performed for IDH1 and H3K27M mutation. Patient demographics and clinico-radiologic characteristics were reviewed and survival analysis performed.

Results

DMGs comprised 5.3% of all gliomas with 49.2% H3K27M mutant and 50.8% wild types. Majority (75.68%) of pediatric and 38.20% of adults were H3K27M mutant (p = 0.0001). Amongst H3K27M mutants, brainstem (46.43%) was the commonest location in pediatric and thalamus (61.76%) in adults. H3K27M mutation was mutually exclusive with IDH mutation in 93.55%, while p53, ATRX mutation were seen in 56.4% and 30.6% cases respectively. Software-based immunohistochemistry evaluation (H-scoring) showed 99.2% concordance with sequencing for H3K27M mutation. Radiologically, no significant difference in contrast enhancement was seen between mutant and wild types (p = 0.05). The difference in overall survival (OS) was not significant in mutant versus wild types, with age or location. Tumor resection independently and on correlation with H3K27M did not influence OS (p = 0.51 and p = 0.47). Adjuvant therapy impacted survival significantly in adults (p = 0.0009), however, not in pediatric cases (p = 0.06).

Conclusions

The study highlights the differences in frequency and location of pediatric and adult DMGs. IHC (H-scoring) for H3K27M mutation is an excellent surrogate for sequencing. Prognosis remains dismal irrespective of age, location, and H3K27M status. Potential therapeutic targets need to be explored.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Schwartzentruber J, Korshunov A, Liu XY, Jones DTW, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DAK, Tönjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jäger N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Frühwald MC, Roggendorf W, Kramm C, Dürken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nat 482:226–231

    Article  CAS  Google Scholar 

  2. Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M, Zhang J, Gajjar A, Dyer MA, Mullighan CG, Gilbertson RJ, Mardis ER, Wilson RK, Downing JR, Ellison DW, Zhang J, Baker SJ, St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253

    Article  CAS  Google Scholar 

  3. Meyronet D, Esteban-Mader M, Bonnet C, Joly MO, Uro-Coste E, Amiel-Benouaich A, Forest F, Rousselot-Denis C, Burel-Vandenbos F, Bourg V, Guyotat J, Fenouil T, Jouvet A, Honnorat J, Ducray F (2017) Characteristics of H3 K27M-mutant gliomas in adults. Neuro-Oncology 19:1127–1134

    Article  CAS  Google Scholar 

  4. Wang L, Li Z, Zhang M, Piao Y, Chen L, Liang H, Wei Y, Hu Z, Zhao L, Teng L, Lu D (2018) H3 K27M–mutant diffuse midline gliomas in different anatomical locations. Hum Pathol 78:89–96

    Article  CAS  Google Scholar 

  5. Aihara K, Mukasa A, Gotoh K, Saito K, Nagae G, Tsuji S, Tatsuno K, Yamamoto S, Takayanagi S, Narita Y, Shibui S, Aburatani H, Saito N (2014) H3F3A K27M mutations in thalamic glio- mas from young adult patients. Neuro-Oncology 16:140–146

    Article  CAS  Google Scholar 

  6. Kleinschmidt-DeMasters BK, Levy JMM (2018) H3K27M-mutant gliomas in adults vs. children share similar histological features and adverse prognosis. Clin Neuropathol 37:53–63

    Article  Google Scholar 

  7. Fontebasso AM, Schwartzentruber J, Khuong-Quang DA, Liu XY, Sturm D, Korshunov A, Jones DTW, Witt H, Kool M, Albrecht S, Fleming A, Hadjadj D, Busche S, Lepage P, Montpetit A, Staffa A, Gerges N, Zakrzewska M, Zakrzewski K, Liberski PP, Hauser P, Garami M, Klekner A, Bognar L, Zadeh G, Faury D, Pfister SM, Jabado N, Majewski J (2013) Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol 125:659–669

    Article  CAS  Google Scholar 

  8. Karremann M, Gielen GH, Hoffmann M, Wiese M, Colditz N, Warmuth-Metz M, Bison B, Claviez A, van Vuurden DG, von Bueren AO, Gessi M, Kühnle I, Hans VH, Benesch M, Sturm D, Kortmann RD, Waha A, Pietsch T, Kramm CM (2018) Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro-Oncology 20:123–131

    Article  CAS  Google Scholar 

  9. Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C (2014) Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol 128:573–581

    Article  CAS  Google Scholar 

  10. Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DTW, Konermann C, Pfaff E, Tönjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Frühwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Dürken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, Pfister SM (2012) Hotspot muta- tions in H3F3A and IDH1 define distinct epigenetic and bio- logical subgroups of glioblastoma. Cancer Cell 22:425–437

    Article  CAS  Google Scholar 

  11. Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, Fang D, Huang X, Tom MW, Ngo V, Solomon D, Mueller S, Paris PL, Zhang Z, Petritsch C, Gupta N, Waldman TA, James CD (2014) Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 20:1394–1396

    Article  CAS  Google Scholar 

  12. Grosso CS, Tang Y, Truffaux N et al (2015) Functionally-defined therapeutic targets in diffuse intrinsic pontine glioma:a report of the children’s oncology group DIPG consortium. Nat Med 21:555–559

    Article  Google Scholar 

  13. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors (2016) WHO classification of tumours of the central nervous system, revised 4th ed. Lyon, IARC, pp. 10–99

  14. Louis DN, Giannini C, Capper D, Paulus W, Figarella-Branger D, Lopes MB, Batchelor TT, Cairncross JG, van den Bent M, Wick W, Wesseling P (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

    Article  Google Scholar 

  15. Solomon DA, Wood MD, Tihan T (2015) 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

    Article  Google Scholar 

  16. Johnson KJ, Cullen J, Barnholtz-Sloan JS, Ostrom QT, Langer CE, Turner MC, McKean-Cowdin R, Fisher JL, Lupo PJ, Partap S, Schwartzbaum JA, Scheurer ME (2014) Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomark Prev 23:2716–2736

    Article  Google Scholar 

  17. Hirsch FR, Varella-Garcia M, Bunn PA Jr, di Maria MV, Veve R, Bremnes RM, Barón AE, Zeng C, Franklin WA (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807

    Article  CAS  Google Scholar 

  18. Wiki for the VASARI feature set (2019) The National Cancer Institute Web site. https:// wiki.cancerimagingarchive.net/display/ Public/VASARI+Research+Project. Updated May 25, 2012. Accessed [March 28, 2019]

  19. 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. Neuroradiol 61:313–322

    Article  Google Scholar 

  20. Gielen GH, Gessi M, Hammes J, Kramm C M, Waha A, Pietsch (2013) H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas. Am J Clin Pathol 139:345–349

  21. Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DTW, Kool M, Zapatka M, Northcott PA, Sturm D, Wang W, Radlwimmer B, Højfeldt JW, Truffaux N, Castel D, Schubert S, Ryzhova M, Şeker-Cin H, Gronych J, Johann PD, Stark S, Meyer J, Milde T, Schuhmann M, Ebinger M, Monoranu CM, Ponnuswami A, Chen S, Jones C, Witt O, Collins VP, von Deimling A, Jabado N, Puget S, Grill J, Helin K, Korshunov A, Lichter P, Monje M, Plass C, Cho YJ, Pfister SM (2013) Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660–672

    Article  CAS  Google Scholar 

  22. Bugiani M, Veldhuijzen van Zanten SEM, Caretti V et al (2017) Deceptive morphologic and epigenetic heterogeneity in diffuse intrinsic pontine glioma. Oncotarget 8:60447–60452

    Article  Google Scholar 

  23. Huang T, Garcia R, Qi J (2018) Detection of histone H3K27M mutation and post translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes. Oncotarget 9:37112–37124

    Article  Google Scholar 

  24. Daoud E. V, Rajaram V, Cai C (2018) Adult brainstem gliomas with H3K27M mutation: radiology, pathology and prognosis. J Neuropathol Exp Neurol 77: 302–311

  25. KorshunovA RM, Hovestadt V et al (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678

    Article  Google Scholar 

  26. Feng J, Hao S, Pan C, Wang Y, Wu Z, Zhang J, Yan H, Zhang L, Wan H (2015) The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol 46:1626–1632

    Article  CAS  Google Scholar 

  27. Schroeder KM, Hoeman CM, Becher OJ (2014) Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology. Ped Research 75:206–209

    Article  Google Scholar 

  28. Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Phillippe C et al (2014) Recurrent activating ACVR1 mutations in diffuse intrinsic pontine gliomas. Nat Genet 46:457–461

    Article  CAS  Google Scholar 

  29. Tanboon J, Williams EA, Louis DN (2015) The diagnostic use of immunohistochemical surrogates for signature molecular genetic alterations in gliomas. J Neuropathol Exp Neurol 75:4–18

    Article  Google Scholar 

  30. Bechet D, Gielen GGH, Korshunov A et al (2014) Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol 128:73–741

    Article  Google Scholar 

  31. Aboian MS, Solomon DA, Felton E, Mabray MC, Villanueva-Meyer JE, Mueller S, Cha S (2017) Imaging characteristics of pediatric diffuse midline gliomas with histone H3 K27M mutation. Am J Neuroradiol 38:795–800

    Article  CAS  Google Scholar 

  32. Laigle-Donadey F, Doz F, Delattre JY (2008) Brainstem gliomas in children and adults. Curr Opin Oncol 20:662–667

    Article  Google Scholar 

  33. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, Bartels U, Albrecht S, Schwartzentruber J, Letourneau L, Bourgey M, Bourque G, Montpetit A, Bourret G, Lepage P, Fleming A, Lichter P, Kool M, von Deimling A, Sturm D, Korshunov A, Faury D, Jones DT, Majewski J, Pfister SM, Jabado N, Hawkins C (2012) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124:439–447

    Article  CAS  Google Scholar 

  34. Lu V. M, Alvi M. A, McDonald K. L et al (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

  35. Yi S, Choi S, Shin DA, Shin DA, Kim DS, Choi J, Ha Y, Kim KN, Suh CO, Chang JH, Kim SH, Yoon DH (2019) Impact of H3.3 K27M mutation on prognosis and survival of grade IV spinal cord glioma on the basis of new 2016 World Health Organization classification of the central nervous system. Neurosurg 84:1072–1081

    Article  Google Scholar 

  36. Von Bueren AO, Karremann M, Gielen GH et al (2018) A suggestion to introduce the diagnosis of “diffuse midline glioma of the pons, H3K27 wildtype (WHO grade IV)”. Acta Neuropathol 136:171–173

    Article  Google Scholar 

  37. Ryall S, Krishnatry R, Arnoldo A, Buczkowicz P, Mistry M, Siddaway R, Ling C, Pajovic S, Yu M, Rubin JB, Hukin J, Steinbok P, Bartels U, Bouffet E, Tabori U, Hawkins C (2016) Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberration in pediatric thalamic glioma. Acta Neuropathol 4:93

    Article  Google Scholar 

  38. Castel D, Philippe C, Calmon R, le Dret L, Truffaux N, Boddaert N, Pagès M, Taylor KR, Saulnier P, Lacroix L, Mackay A, Jones C, Sainte-Rose C, Blauwblomme T, Andreiuolo F, Puget S, Grill J, Varlet P, Debily MA (2015) Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130:815–827

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank all staff of neuropathology and neurosurgery department of AIIMS, New Delhi, for the support in the accomplishment of this work.

Funding

We received funds and support from J C Bose Fellowship of Prof. Chitra Sarkar, and Dept. of Pathology and Neuro Science Center, AIIMS, New Delhi.

Author information

Author notes

  1. Niveditha Manjunath and Prerana Jha contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India

    Niveditha Manjunath, Amol Raheja & Ashish Suri

  2. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

    Prerana Jha, Jyotsna Singh, Kavneet Kaur, Mehar Chand Sharma, Chitra Sarkar & Vaishali Suri

  3. Apollo Proton Cancer Centre, Taramani, Chennai, India

    Prerana Jha

  4. Department of Neuroimaging & Interventional Neuroradiology, All India Institute of Medical Sciences, New Delhi, India

    Ajay Garg & Madan Mohan

  5. Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

    Kalaivani Mani

Authors
  1. Niveditha Manjunath
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prerana Jha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jyotsna Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amol Raheja
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kavneet Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ashish Suri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ajay Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mehar Chand Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chitra Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Madan Mohan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kalaivani Mani
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Vaishali Suri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vaishali Suri.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Institutional Ethical Board approval has been taken for the study. All cases were consented for study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Manjunath, N., Jha, P., Singh, J. et al. Clinico-pathological and molecular characterization of diffuse midline gliomas: is there a prognostic significance?. Neurol Sci 42, 925–934 (2021). https://doi.org/10.1007/s10072-020-04489-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-020-04489-0

Keywords

Search

Navigation