Abstract
Disseminated glioneuronal tumors of childhood are rare. We present a retrospective IRB-approved review of the clinical course and frequency of BRAF mutations in disseminated glioneuronal tumors at two institutions. Defining features of our cohort include diffuse leptomeningeal-spread, often with a discrete spinal cord nodule and oligodendroglioma-like histologic features. Patients were identified through a pathology database search of all cases with disseminated low-grade neoplasms with an oligodendroglioma-like component. De-identified clinical information was collected by chart review and all imaging was reviewed. We retrieved the results of targeted genomic analyses for alterations in BRAF. Ten patients (aged 2–14 years) were identified from the Dana-Farber/Boston Children’s Hospital and the Royal Children’s Hospital, Melbourne pathology databases. Nine patients received chemotherapy. Eight patients are alive, although three have had episodes of progressive disease. We identified genomic alterations affecting the MAPK pathway in six patients. One patient had a germline RAF1 mutation and a clinical diagnosis of cardio-facio-cutaneous syndrome. BRAF duplications were identified in four and BRAF V600E mutation was identified in one. These data support the presence of targetable genomic alterations in this disease.
Similar content being viewed by others
References
Rodriguez FJ, Perry A, Rosenblum MK, Krawitz S, Cohen KJ, Lin D, Mosier S, Lin MT, Eberhart CG, Burger PC (2012) Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. Acta Neuropathol 124(5):627–641
Gardiman MP, Fassan M, Orvieto E, D’Avella D, Denaro L, Calderone M, Severino M, Scarsello G, Viscardi E, Perilongo G (2010) Diffuse leptomeningeal glioneuronal tumors: a new entity? Brain Pathol 20(2):361–366
Agamanolis DP, Katsetos CD, Klonk CJ, Bartkowski HM, Ganapathy S, Staugaitis SM, Kuerbitz SJ, Patton DF, Talaizadeh A, Cohen BH (2012) An unusual form of superficially disseminated glioma in children: report of 3 cases. J Child Neurol 27(6):727–733
Armao DM, Stone J, Castillo M, Mitchell KM, Bouldin TW, Suzuki K (2000) Diffuse leptomeningeal oligodendrogliomatosis: radiologic/pathologic correlation. Am J Neuroradiol 21:1122–1126
Bourne TD, Mandell JW, Matsumoto JA, Jane JA Jr, Lopes MB (2006) Primary disseminated leptomeningeal oligodendroglioma with 1p deletion. Case report. J Neurosurg 105(Suppl. 6):465–469
Chen R, Macdonald DR, Ramsay DA (1995) Primary diffuse leptomeningeal oligodendroglioma. Case report. J Neurosurg 83:724–728
Preuss M, Christiansen H, Merkenschlager A, Hirsch FW, Kiess W, Müller W, Kästner S, Henssler A, Pekrun A, Hauch H, Nathrath M, Meixensberger J, Pietsch T, Kuchelmeister K (2015) Disseminated oligodendroglial cell-like leptomeningeal tumors: preliminary diagnostic and therapeutic results for a novel tumor entity. J Neurooncol 124(1):65–74
Jones DT, Gronych J, Lichter P, Witt O, Pfister SM (2012) MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci 69:1799–1811
Jones DT, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz HJ et al (2013) Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45(8):927–932
Bergthold G, Bandopadhayay P, Bi WL, Ramkissoon L, Stiles C, Segal RA, Beroukhim R, Ligon KL, Grill J, Kieran MW (2014) Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta 1845(2):294–307
Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B et al (2013) Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45(6):602–612
Bandopadhayay P, Bergthold G, London WB, Goumnerova LC, Morales La Madrid A, Marcus KJ, Guo D, Ullrich NJ, Robison NJ, Chi SN, Beroukhim R, Kieran MW, Manley PE (2014) Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer 61(7):1173–1179
Gupta K, Orisme W, Harreld JH, Qaddoumi I, Dalton JD, Punchihewa C, Collins-Underwood R, Robertson T, Tatevossian RG, Ellison DW (2014) Posterior fossa and spinal gangliogliomas form two distinct clinicopathologic and molecular subgroups. Acta Neuropathol Commun 2(1):18
Dias-Santagata D, Lam Q, Vernovsky K, Vena N, Lennerz JK, Borger DR, Batchelor TT, Ligon KL, Iafrate AJ, Ligon AH, Louis DN, Santagata S (2011) BRAF V600E mutations are common in pleomorphic xanthroastrocytoma: diagnostic and therapeutic implications. PLoS One 6(3):e17948
Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, 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(3):397–405
Jacob K, Albrecht S, Sollier C, Faury D, Sader E, Montpetit A, Serre D, Hauser P, Garami M, Bognar L, Hanzely Z, Montes JL, Atkinson J, Farmer JP, Bouffet E, Hawkins C, Tabori U, Jabado N (2009) Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 101(4):722–733
Kim YH, Nonoguchi N, Paulus W, Brokinkel B, Keyvani K, Sure U, Wrede K, Mariani L, Giangaspero F, Tanaka Y, Nakazato Y, Vital A, Mittelbronn M, Perry A, Ohgaki H (2012) Frequent BRAF gain in low-grade diffuse gliomas with 1p/19q loss. Brain Pathol 22(6):834–840
Robinson GW, Orr BA, Gajjar A (2014) Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer 14:258
Bautista F, Paci A, Minard-Colin V, Dufour C, Grill J, Lacroix L, Varlet P, Valteau-Couanet D, Geoerger B (2014) Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatr Blood Cancer 61(6):1101–1103
Chamberlain MC (2013) Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series. J Neurooncol 114(2):237–240
Michotte A, Chaskis C, Sadones J, Veld PI, Neyns B (2009) Primary leptomeningeal anaplastic oligodendroglioma with a 1p36-19q13 deletion: report of a unique case successfully treated with Temozolomide. J Neurol Sci. 287(1–2):267–270
Hervey-Jumper SL, Jumper M, Blaivas M, Parmar HA, Robertson PL, Maher CO (2010) Primary diffuse leptomeningeal oligodendroglioma. Paediatr Neurosurg 46(4):326–328
Rodriguez FJ, Schniederjan MJ, Nicolaides T, Tihan T, Burger PC, Perry A (2015) High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN). Acta Neuropathol 129(4):609–610
Jones DT, Kocialkowski S, Liu L, Pearson DM, Bäcklund LM, Ichimura K, Collins VP (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68(21):8673–8677
Kratz CP, Franke L, Peters H, Kohlschmidt N, Kazmierczak B, Finckh U, Bier A, Eichhorn B, Blank C, Kraus C, Kohlhase J, Pauli S, Wildhardt G, Kutsche K, Auber B, Christmann A, Bachmann N, Mitter D, Cremer FW, Mayer K, Daumer-Haas C, Nevinny-Stickel-Hinzpeter C, Oeffner F, Schlüter G, Gencik M, Überlacker B, Lissewski C, Schanze I, Greene MH, Spix C, Zenker M (2015) Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br J Cancer 112(8):1392–1397
Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F, Rauen KA (2006) Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311(5765):1287–1290
Sievert A, Lang SS, Boucher KL, Madsen PJ, Slaunwhite E, Choudhari N, Kellet M, Storm PB, Resnick AC (2013) Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci USA 110(15):5957–5962
Karajannis MA, Legault G, Fisher MJ, Milla SS, Cohen KJ, Wisoff JH et al (2014) Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol 16(10):1408–1416
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954
Jarkowski A 3rd, Khushalani NI (2014) BRAF and beyond: tailoring strategies for the individual melanoma patient. J Carcinog 13:1. doi:10.4103/1477-3163.126759
Hutchinson KE, Lipson D, Stephens PJ, Otto G, Lehmann BD, Lyle PL, Vnencak-Jones CL, Ross JS, Pietenpol JA, Sosman JA, Puzanov I, Miller VA, Pao W (2013) BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res 19(24):6696–6702
Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381(9861):125–132
Kieran MW, Yao X, Macy M, Leary S, Cohen K, MacDonald T et al (2014) Final results of a prospective multi-institutional phase II study of everolimus (RAD001), an mTOR inhibitor, in pediatric patients with recurrent or progressive low-grade glioma. A POETIC consortium trial. Neuro Oncol 16(suppl 3):iii27
Acknowledgments
We acknowledge the following funding sources: A Kids’ Brain Tumor Cure Foundation Pediatric Low-Grade Astrocytoma Foundation (PB, KLL, RB, MWK, LG), Stop and Shop Pediatric Brain Tumor Program (NSC, PB, MWK), St Baldrick’s Foundation (PB), Team Jack Foundation (PB, MWK, RB, LG), Andrysiak Fund for LGG (MWK), Jared Branfman Sunflowers For Life Fund For Pediatric Brain And Spinal Cancer Research (PB, RB), Sontag Foundation (KLL, RB), Nuovo-Soldati Foundation (GB), Philippe Foundation (GB), Pediatric Brain Tumor Foundation (RB, PB), Royal Children’s Hospital Foundation (JH), Robert Connor Dawes Foundation (JH), Dr. Dodgshun is the recipient of the Murray Jackson Clinical Fellowship, Genesis Oncology Trust, New Zealand.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Andrew J. Dodgshun, Nadine SantaCruz, Jordan R. Hansford, and Pratiti Bandopadhayay have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Dodgshun, A.J., SantaCruz, N., Hwang, J. et al. Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation. J Neurooncol 128, 293–302 (2016). https://doi.org/10.1007/s11060-016-2109-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-016-2109-x