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BRAFV600E mutation is a negative prognosticator in pediatric ganglioglioma

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Abstract

Gangliogliomas are typically low-grade neuroepithelial tumors seen in the pediatric and young adult populations. Despite their often bland histologic appearance, these tumors recur with varying frequencies; however, little data exist that adequately predict ganglioglioma recurrence in children. To identify potential histopathologic features predictive of recurrence-free survival, a series of 53 patients with World Health Organization (WHO) grade I gangliogliomas were evaluated, representing the largest cohort of pediatric gangliogliomas with accompanying histopathologic and survival data. Fifteen patients (28 %) exhibited disease recurrence during the study period. BRAFV600E immunohistochemistry was performed on 47 of these tumors. Histopathologic features associated with shorter recurrence-free survival included an absence of oligodendroglial morphology, higher glial cell density, microvascular proliferation, and the presence of a high lymphoplasmacytic inflammatory infiltrate. Eighteen tumors (38.3 %) had positive BRAFV600E staining, which was associated with shorter recurrence-free survival. Collectively, the combined use of histopathologic and molecular features to stratify grade I gangliogliomas into low and high-risk groups provides important information relevant to the management of children and young adults with these rare tumors.

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References

  1. Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG (2008) Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 67:878–887

    Article  PubMed  CAS  Google Scholar 

  2. Brat DJ, Parisi JE, Kleinschmidt-DeMasters BK, Yachnis A, Montine T, Boyer P, Powell S, Prayson R, McLendon R (2008) Surgical neuropathology update: a review of changes introduced by the WHO classification of tumours of the central nervous system, 4th edition. Arch Pathol Lab Med 132:993–1007

    PubMed  Google Scholar 

  3. Burger PC, Scheithauer BW (2008) Tumors of the central nervous system. (AFIP Atlas of Tumor Pathology, Series IV, Fascicle 7)

  4. Capper D, Preusser M, Habel A, Sahm F, Ackermann U, Schindler G, Pusch S, Mechtersheimer G, Zentgraf H, von Deimling A (2011) Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol 122:11–19

    Article  PubMed  CAS  Google Scholar 

  5. Chapman PB, Hauschild A, Robert C, Haanen J, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day S, Sosman J, Kirkwood J, Eggermont A, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee R, Flaherty K, McArthur G (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516

    Article  PubMed  CAS  Google Scholar 

  6. Chintagumpala MM, Armstrong D, Miki S, Nelson T, Cheek W, Laurent J, Woo S, Mahoney D Jr (1996) Mixed neuronal-glial tumors (gangliogliomas) in children. Pediatr Neurosurg 24:306–313

    Article  PubMed  CAS  Google Scholar 

  7. Donahue B, Scott CB, Nelson JS, Rotman M, Murray K, Nelson D, Banker F, Earle J, Fischbach J, Asbell S, Gaspar L, Markoe A, Curran W (1997) Influence of an oligodendroglial component on the survival of patients with anaplastic astrocytomas: a report of Radiation Therapy Oncology Group 83–02. Int J Radiat Oncol Biol Phys 38:911–914

    Article  PubMed  CAS  Google Scholar 

  8. Dougherty MJ, Santi M, Brose M, Ma C, Resnick A, Sievert A, Storm P, Biegel J (2010) Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol 12:621–630

    Article  PubMed  CAS  Google Scholar 

  9. El Khashab M, Gargan L, Margraf L, Koral K, Nejat F, Swift D, Weprin B, Bowers D (2009) Predictors of tumor progression among children with gangliogliomas. Clinical article. J Neurosurg Pediatr 3:461–466

    Article  PubMed  Google Scholar 

  10. Haddad SF, Moore SA, Menezes AH, VanGilder JC (1992) Ganglioglioma: 13 years of experience. Neurosurgery 31:171–178

    Article  PubMed  CAS  Google Scholar 

  11. Horbinski C, Kofler J, Yeaney G, Camelo-Piragua S, Venneti S, Louis D, Perry A, Murdoch G, Nikiforova M (2011) Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol 21:564–574

    Article  PubMed  CAS  Google Scholar 

  12. Johnson JH Jr, Hariharan S, Berman J, Sutton L, Rorke L, Molloy P, Phillips P (1997) Clinical outcome of pediatric gangliogliomas: ninety-nine cases over 20 years. Pediatr Neurosurg 27:203–207

    Article  PubMed  Google Scholar 

  13. Jones DT, Kocialkowski S, Liu L, Pearson D, Backlund L, Ichimura K, Collins V (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677

    Article  PubMed  CAS  Google Scholar 

  14. Jones DT, Mulholland SA, Pearson DM, Malley DS, Openshaw SWS, Lambert SR, Liu L, Backlund LM, Ichimura K, Collins VP (2011) Adult grade II diffuse astrocytomas are genetically distinct from and more aggressive than their paediatric counterparts. Acta Neuropathol 121:753–761

    Article  PubMed  Google Scholar 

  15. Khajavi K, Comair YG, Prayson RA, Wyllie E, Palmer J, Estes M, Hahn J (1995) Childhood ganglioglioma and medically intractable epilepsy. A clinicopathological study of 15 patients and a review of the literature. Pediatr Neurosurg 22:181–188

    Article  PubMed  CAS  Google Scholar 

  16. Koelsche C, WÖhrer A, Jeibman A, Schittenhelm J, Schindler G, Preusser M, Lastischka F, von Deimling A, Capper D (2013) Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol Feb 24 [Epub ahead of print]. PMID: 23435618

  17. Leighton C, Fisher B, Bauman G, Depiero S, Stitt L, MacDonald D, Cairncross G (1997) Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation. J Clin Oncol 15:1294–1301

    PubMed  CAS  Google Scholar 

  18. Long GV, Wilmott JS, Capper D, Preusser M, Zhang Y, Thompson J, Kefford R, von Deimling A, Scolyer R (2013) Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. Am J Surg Pathol 37(1):61–65

    Article  PubMed  Google Scholar 

  19. Louis DN, Ohgaki H, Wiestler OD, Cavenee W, Burger P, Jouvet A, Scheithauer B, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  PubMed  Google Scholar 

  20. Luyken C, Blumcke I, Fimmers R, Urbach H, Wiestler OD, Schramm J (2004) Supratentorial gangliogliomas: histopathologic grading and tumor recurrence in 184 patients with a median follow-up of 8 years. Cancer 101:146–155

    Article  PubMed  Google Scholar 

  21. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280

    PubMed  CAS  Google Scholar 

  22. Majores M, von Lehe M, Fassunke J, Schramm J, Becker AJ, Simon M (2008) Tumor recurrence and malignant progression of gangliogliomas. Cancer 113:3355–3363

    Article  PubMed  Google Scholar 

  23. Ogiwara H, Nordli DR, DiPatri AJ, Alden TD, Bowman RM, Tomita T (2010) Pediatric epileptogenic gangliogliomas: seizure outcome and surgical results. J Neurosurg Pediatr 5:271–276

    Article  PubMed  Google Scholar 

  24. Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, Ahmadi R, Thieme B, Joos S, Radlwimmer B, Kulozik A, Pietsch T, Herold-Mende C, Gnekow A, Reifenberger G, Korshunov A, Scheurlen W, Omran H, Lichter P (2008) BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118:1739–1749

    Article  PubMed  CAS  Google Scholar 

  25. Pollack IF, Hamilton RL, Sobol RW, Nikiforova M, Lyons-Weiler M, LaFramboise W, Burger P, Brat D, Rosenblum M, Holmes E, Zhou T, Jakacki R (2011) IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group. Childs Nerv Syst 27:87–94

    Article  PubMed  Google Scholar 

  26. Pupa SM, Bufalino R, Invernizzi AM, Andreola S, Rilke F, Lombardi L, Colnaghi M, Menard S (1996) Macrophage infiltrate and prognosis in c-erbB-2-overexpressing breast carcinomas. J Clin Oncol 14:85–94

    PubMed  CAS  Google Scholar 

  27. Russell DS, Rubinstein LJ (1962) Ganglioglioma: a case with long history and malignant evolution. J Neuropathol Exp Neurol 21:185–193

    Article  PubMed  CAS  Google Scholar 

  28. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis D, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A (2011) 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 121:397–405

    Article  PubMed  CAS  Google Scholar 

  29. Smith NM, Carli MM, Hanieh A, Clark B, Bourne AJ, Byard RW (1992) Gangliogliomas in childhood. Childs Nerv Syst 8:258–262

    Article  PubMed  Google Scholar 

  30. Sutton LN, Packer RJ, Rorke LB, Bruce DA, Schut L (1983) Cerebral gangliogliomas during childhood. Neurosurgery 13:124–128

    Article  PubMed  CAS  Google Scholar 

  31. Yang I, Tihan T, Han SJ, Wrensch M, Wiencke J, Sughrue M, Parsa A (2010) CD8+ T-cell infiltrate in newly diagnosed glioblastoma is associated with long-term survival. J Clin Neurosci 17:1381–1385

    Article  PubMed  Google Scholar 

  32. Yu J, Deshmukh H, Gutmann RJ, Emnett R, Rodriguez F, Watson M, Nagarajan R, Gutmann D (2009) Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 73:1526–1531

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the work of Drs. Jingqin Luo and Kathryn Trinkaus (Division of Biostatistics, Washington University School of Medicine) who assisted with the statistical analyses. Support for this study was provided by the Children’s Discovery Institute (MC-LI-2009-03R) and the National Institute of Health (T32: 3857-54941D).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Sonika Dahiya

  2. Department of Neurological Surgery, Washington University School of Medicine, 1 Children’s Place, Suite 4S20, St. Louis, MO, 63110, USA

    Devon H. Haydon & Jeffrey R. Leonard

  3. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

    David Alvarado, Christina A. Gurnett & David H. Gutmann

Authors
  1. Sonika Dahiya
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  2. Devon H. Haydon
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  3. David Alvarado
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  4. Christina A. Gurnett
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  5. David H. Gutmann
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  6. Jeffrey R. Leonard
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Corresponding author

Correspondence to Jeffrey R. Leonard.

Additional information

S. Dahiya and D. Haydon made equal contributions to this study.

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401_2013_1120_MOESM1_ESM.eps

Supplementary Figure 1. Mitoses (~5/10 hpf) were noted in the glial component in two cases (arrow; a: H&E stain; b: Double labeling for GFAP {brown} and Ki-67 {purple}) (EPS 2734 kb) (EPS 2734 kb)

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Dahiya, S., Haydon, D.H., Alvarado, D. et al. BRAFV600E mutation is a negative prognosticator in pediatric ganglioglioma. Acta Neuropathol 125, 901–910 (2013). https://doi.org/10.1007/s00401-013-1120-y

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  • DOI: https://doi.org/10.1007/s00401-013-1120-y

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