Article | Published:

Spinal cord high-grade infiltrating gliomas in adults: clinico-pathological and molecular evaluation

Abstract

Primary high-grade infiltrating gliomas of the spinal cord are rare, with prior series including limited numbers of cases and reporting poor outcomes. Additionally, the molecular profile of high-grade infiltrating gliomas of the spinal cord has not been well characterized. We identified 13 adult patients whose surgery had been performed at our institution over a 26-year-period. Radiologically, nine cases harbored regions of post-contrast enhancement. Existing slides were reviewed, and when sufficient tissue was available, immunohistochemical stains (IDH1-R132H, H3-K27M, H3K27-me3, ATRX, p53 and BRAF-V600E), and a targeted 150-gene neuro-oncology next-generation sequencing panel were performed. The 13 patients included 11 men and 2 women with a median age of 38 years (range = 18–69). Histologically, all were consistent with an infiltrating astrocytoma corresponding to 2016 WHO grades III (n = 5) and IV (n = 8). By immunohistochemistry, six cases were positive for H3K27M, all showing concomitant loss of H3K27-me3. Next-generation sequencing was successfully performed in ten cases. Next-generation sequencing studies were successfully performed in four of the cases positive for H3K27M by immunohistochemistry, and all were confirmed as H3F3A K27M-mutant. Additional recurrent mutations identified included those of TERT promoter (n = 3), TP53 (n = 5), PPM1D (n = 3), NF1 (n = 3), ATRX (n = 2), and PIK3CA (n = 2). No HIST1H3B, HIST1H3C, IDH1, IDH2, or BRAF mutations were detected. Ten patients have died since first surgery, with a median survival of 13 months and 1 year of 46%. Median survival was 48.5 months for H3K27M-positive cases, compared to 1 month for those with TERT promoter mutation and 77 months for those harboring neither (p = 0.019). Median survival for cases with TP53 mutations was 11.5 months and for those with PPM1D mutations was 84 months. Our findings suggest that high-grade infiltrating gliomas of the spinal cord in adults represent a heterogeneous group of tumors, with variable outcomes possibly related to their molecular profiles.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Previous presentation: An abstract based on this was presented at the 94th Annual Meeting of the American Association of Neuropathologists in June, 2018.

References

  1. 1.

    Bowers DC, Weprin BE. Intramedullary spinal cord tumors. Curr Treat Options Neurol. 2003;5:207–12.

  2. 2.

    Seki T, Hida K, Yano S, et al. Surgical outcomes of high-grade spinal cord gliomas. Asian Spine J. 2015;9:935–41.

  3. 3.

    Shen C-X, Wu J-F, Zhao W, et al. Primary spinal glioblastoma multiforme: a case report and review of the literature. Medicine. 2017;96:e6634.

  4. 4.

    Iwata K, Nakagawa H, Hashizume Y. Significance of MIB-1, PCNA indices, and p53 protein over-expression in intramedullary tumors of the spinal cord. Noshuyo Byori. 1996;13:73–8.

  5. 5.

    Strik HM, Effenberger O, Schäfer O, et al. A case of spinal glioblastoma multiforme: immunohistochemical study and review of the literature. J Neurooncol. 2000;50:239–43.

  6. 6.

    Ciappetta P, Salvati M, Capoccia G, et al. Spinal glioblastomas: report of seven cases and review of the literature. Neurosurgery. 1991;28:302–6.

  7. 7.

    Raco A, Esposito V, Lenzi J, et al. Long-term follow-up of intramedullary spinal cord tumors: a series of 202 cases. Neurosurgery. 2005;56:972–81. Discussion 972–81

  8. 8.

    Miller DC. Surgical pathology of intramedullary spinal cord neoplasms. J Neurooncol. 2000;47:189–94.

  9. 9.

    Louis DN, Perry A, Reifenberger G, et al. The2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803–20.

  10. 10.

    Tabouret E, Nguyen AT, Dehais C, et al. Prognostic impact of the 2016 WHO classification of diffuse gliomas in the French POLA cohort. Acta Neuropathol. 2016;132:625–34.

  11. 11.

    Bender S, Tang Y, Lindroth AM, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell. 2013;24:660–72.

  12. 12.

    Chan K-M, Fang D, Gan H, et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 2013;27:985–90.

  13. 13.

    Lewis PW, Müller MM, Koletsky MS, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013;340:857–61.

  14. 14.

    Chan KM, Han J, Fang D, et al. A lesson learned from the H3. 3K27M mutation found in pediatric glioma: a new approach to the study of the function of histone modifications in vivo? Cell Cycle. 2013;12:2546–52.

  15. 15.

    Lulla RR, Saratsis AM, Hashizume R. Mutations in chromatin machinery and pediatric high-grade glioma. Sci Adv. 2016;2:e1501354.

  16. 16.

    Daoud EV, Rajaram V, Cai C, et al. Adult brainstem gliomas with H3K27M mutation: radiology, pathology, and prognosis. J Neuropathol Exp Neurol. 2018;77:302–11.

  17. 17.

    Buczkowicz P, Hoeman C, Rakopoulos P, et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet. 2014;46:451–6.

  18. 18.

    Chiang JC, Ellison DW. Molecular pathology of paediatric central nervous system tumours. J Pathol. 2017;241:159–72.

  19. 19.

    Gielen GH, Gessi M, Hammes J, et al. H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas. Am J Clin Pathol. 2013;139:345–9.

  20. 20.

    Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44:251–3.

  21. 21.

    Solomon DA, Wood MD, Tihan T, et al. 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. 2016;26:569–80.

  22. 22.

    Khuong-Quang DA, Buczkowicz P, Rakopoulos P. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124:439–47.

  23. 23.

    Brandner S, von Deimling A. Diagnostic, prognostic and predictive relevance of molecular markers in gliomas. Neuropathol Appl Neurobiol. 2015;41:694–720.

  24. 24.

    Gielen GH, Dreschmann V, Waha A, et al. High frequency of H3F3AK27M mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. Acta Neuropathol. 2015;130:435–7.

  25. 25.

    Picca A, Berzero G, Bielle F, et al. FGFR1 actionable mutations, molecular specificities, and outcome of adult midline gliomas. Neurology. 2018;90:e2086–94.

  26. 26.

    Schwartzentruber J, Korshunov A, Liu X-Y, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226–31.

  27. 27.

    Szenker E, Ray-Gallet D, Almouzni G. The double face of the histone variant H3.3. Cell Res. 2011;21:421–34.

  28. 28.

    Sturm D, Witt H, Hovestadt V, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22:425–37.

  29. 29.

    Chen W-J, He D-S, Tang R-X, et al. Ki-67 is a valuable prognostic factor in gliomas: evidence from a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2015;16:411–20.

  30. 30.

    Lee Y, Koh J, Kim S-I, et al. The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas. Acta Neuropathol Commun. 2017;5:62.

  31. 31.

    Chi AS, Batchelor TT, Yang D, et al. BRAF V600E mutation identifies a subset of low-grade diffusely infiltrating gliomas in adults. J Clin Oncol. 2013;31:e233–6.

  32. 32.

    Takahashi Y, Akahane T, Sawada T, et al. Adult classical glioblastoma with a BRAF V600E mutation. World J Surg Oncol. 2015;13:100.

  33. 33.

    Zhang L, Chen LH, Wan H, et al. Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nat Genet. 2014;46:726–30.

  34. 34.

    Yi S, Choi S, Shin DA, et al. 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. Neurosurgery. 2018. https://doi.org/10.1093/neuros/nyy150

  35. 35.

    Karremann M, Gielen GH, Hoffmann M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20:123–31.

  36. 36.

    Dudgeon C, Shreeram S, Tanoue K, et al. Genetic variants and mutations of PPM1D control the response to DNA damage. Cell Cycle. 2013;12:2656–64.

  37. 37.

    Jiao Y, Killela PJ, Reitman ZJ, et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget. 2012;3:709–22.

  38. 38.

    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. 2012;2:401–4.

  39. 39.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal. Science Signaling 2013;6.

Download references

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Aditya Raghunathan.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2
Fig. 3