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Glioblastoma in neurofibromatosis 1 patients without IDH1, BRAF V600E, and TERT promoter mutations

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Abstract

Pilocytic astrocytomas and low-grade gliomas are more common compared with glioblastomas in patients with neurofibromatosis 1 (NF1). A recent genome-wide analysis has shown frequent NF1 gene alterations in the mesenchymal subtype of a glioblastoma; however, little is known about clinicopathological features of glioblastomas in NF1 patients (NF1 glioblastomas). We analyzed four NF1 glioblastomas. Radiographical and intraoperative findings showed well-circumscribed tumors from surrounding brain. Pathological analysis presented a paucity of processes with an eosinophilic cytoplasm, bizarre nuclei, xanthomatous-like appearance, multinucleated giant cells, and histiocytoid appearance. During the follow-up period, one patient died at 49 months and others remained alive for 60, 87, and 106 months; thus, patients with NF1 glioblastoma presented a relatively favorable survival. None of the NF1 glioblastomas harbored isocitrate dehydrogenase 1 (IDH1) gene mutation, v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene mutation, and telomerase reverse transcriptase (TERT) gene promoter mutation. We identified that NF1 glioblastoma is a unique subset of glioblastoma.

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References

  1. Gutmann DH, Parada LF, Silva AJ et al (2012) Neurofibromatosis type 1: modeling CNS dysfunction. J Neurosci 32:14087–14093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Neurofibromatosis (1988) Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 45:575–578

    Article  Google Scholar 

  3. Rasmussen SA, Friedman JM (2000) NF1 gene and neurofibromatosis 1. Am J Epidemiol 151:33–40

    Article  CAS  PubMed  Google Scholar 

  4. Gutmann DH, Rasmussen SA, Wolkenstein P et al (2002) Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology 59:759–761

    Article  CAS  PubMed  Google Scholar 

  5. Rodriguez FJ, Perry A, Gutmann DH et al (2008) Gliomas in neurofibromatosis type 1: a clinicopathologic study of 100 patients. J Neuropathol Exp Neurol 67:240–249

    Article  PubMed  PubMed Central  Google Scholar 

  6. Verhaak RG, Hoadley KA, Purdom E et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alexandrescu S, Korshunov A, Lai SH et al (2016) Epithelioid glioblastomas and anaplastic epithelioid pleomorphic xanthoastrocytomas-same entity or first cousins? Brain pathology 26:215–223

    Article  CAS  PubMed  Google Scholar 

  8. Kleinschmidt-DeMasters BK, Aisner DL, Birks DK et al (2013) Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol 37:685–698

    Article  PubMed  PubMed Central  Google Scholar 

  9. Singh G, Das KK, Sharma P et al (2015) Cerebral gliosarcoma: analysis of 16 patients and review of literature. Asian J Neurosurg 10:195–202

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sonoda Y, Yokosawa M, Saito R et al (2010) O (6)-Methylguanine DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression is correlated with progression-free survival in patients with glioblastoma. Int J Clin Oncol. https://doi.org/10.1007/s10147-010-0065-6

    Google Scholar 

  11. Shibahara I, Sonoda Y, Kanamori M et al (2012) IDH1/2 gene status defines the prognosis and molecular profiles in patients with grade III gliomas. Int J Clin Oncol 17:551–561

    Article  CAS  PubMed  Google Scholar 

  12. Shibahara I, Sonoda Y, Saito R et al (2013) The expression status of CD133 is associated with the pattern and timing of primary glioblastoma recurrence. Neuro Oncol 15:1151–1159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fransen K, Klintenas M, Osterstrom A et al (2004) Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis 25:527–533

    Article  CAS  PubMed  Google Scholar 

  14. Sonoda Y, Kumabe T, Nakamura T et al (2009) Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. Cancer Sci 100:1996–1998

    Article  CAS  PubMed  Google Scholar 

  15. Eckel-Passow JE, Lachance DH, Molinaro AM et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499–2508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Weller M, Felsberg J, Hartmann C et al (2009) Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol 27:5743–5750

    Article  CAS  PubMed  Google Scholar 

  17. Miyata S, Sugimoto T, Kodama T et al (2005) Adenoid glioblastoma arising in a patient with neurofibromatosis type-1. Pathol Int 55:348–352

    Article  PubMed  Google Scholar 

  18. Kroh H, Matyja E, Marchel A et al (2004) Heavily lipidized, calcified giant cell glioblastoma in an 8-year-old patient, associated with neurofibromatosis type 1 (NF1): report of a case with long-term survival. Clin Neuropathol 23:286–291

    CAS  PubMed  Google Scholar 

  19. Jeong TS, Yee GT (2014) Glioblastoma in a patient with neurofibromatosis type 1: a case report and review of the literature. Brain Tumor Res Treat 2:36–38

    Article  PubMed  PubMed Central  Google Scholar 

  20. Taraszewska A, Bogucki J, Powala A et al (2013) Giant cell glioblastoma with unique bilateral cerebellopontine angle localization considered as extraaxial tumor growth in a patient with neurofibromatosis Type 1. Clin Neuropathol 32:58–65

    PubMed  Google Scholar 

  21. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2016) WHO classification of tumours of the central nervous system, 4th edn. IARC Press, Lyon

  22. Laycock-van Spyk S, Thomas N, Cooper DN et al (2011) Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genom 5:623–690

    Article  Google Scholar 

  23. Jones DT, Kocialkowski S, Liu L et al (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Adeleye AO, Okolo CA, Akang EE et al (2012) Cerebral pleomorphic xanthoastrocytoma associated with NF1: an updated review with a rare atypical case from Africa. Neurosurg Rev 35:313–319 (discussion 319)

    Article  PubMed  Google Scholar 

  25. Takei H, Rouah E, Bhattacharjee MB (2015) Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1: a case report and literature review. Int J Clin Exp Pathol 8:7570–7574

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Saikali S, Le Strat A, Heckly A et al (2005) Multicentric pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1. Case report and review of the literature. J Neurosurg 102:376–381

    Article  PubMed  Google Scholar 

  27. Naidich MJ, Walker MT, Gottardi-Littell NR et al (2004) Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1. Neuroradiology 46:825–829

    Article  CAS  PubMed  Google Scholar 

  28. Hariharan S, Donahue JE, Garre C et al (2006) Clinicopathologic and genetic analysis of siblings with NF1 and adult-onset gliomas. J Neurol Sci 247:105–108

    Article  PubMed  Google Scholar 

  29. Rutledge WC, Kong J, Gao J et al (2013) Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clin Cancer Res 19:4951–4960

    Article  CAS  PubMed  Google Scholar 

  30. Ratner N, Miller SJ (2015) A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 15:290–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Singh AD, Iftinca M, Easaw JC (2013) Lipidized glioblastoma: pathological and molecular characteristics. Neuropathology 33:87–92

    Article  CAS  PubMed  Google Scholar 

  32. Gupta K, Kalra I, Salunke P et al (2011) Lipidized glioblastoma: a rare differentiation pattern. Neuropathology 31:93–97

    Article  PubMed  Google Scholar 

  33. Kanamori M, Suzuki H, Takei H et al (2016) Malignant transformation of diffuse astrocytoma to glioblastoma associated with newly developed BRAF V600E mutation. Brain Tumor Pathol 33:50–56

    Article  CAS  PubMed  Google Scholar 

  34. Arita H, Narita Y, Fukushima S et al (2013) Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126:267–276

    Article  CAS  PubMed  Google Scholar 

  35. Matsumura N, Nakajima N, Yamazaki T et al (2017) Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low-grade astrocytoma. Neuropathology 37:58–63

    Article  CAS  PubMed  Google Scholar 

  36. Huttner AJ, Kieran MW, Yao X et al (2010) Clinicopathologic study of glioblastoma in children with neurofibromatosis type 1. Pediatr Blood Cancer 54:890–896

    PubMed  Google Scholar 

  37. Dahiya S, Emnett RJ, Haydon DH et al (2014) BRAF-V600E mutation in pediatric and adult glioblastoma. Neuro Oncol 16:318–319

    Article  PubMed  Google Scholar 

  38. Vizcaino MA, Shah S, Eberhart CG et al (2015) Clinicopathologic implications of NF1 gene alterations in diffuse gliomas. Hum Pathol 46:1323–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Philpott C, Tovell H, Frayling IM et al (2017) The NF1 somatic mutational landscape in sporadic human cancers. Hum Genom 11:13

    Article  Google Scholar 

  40. Bikowska-Opalach B, Szlufik S, Grajkowska W et al (2014) Pilocytic astrocytoma: a review of genetic and molecular factors, diagnostic and prognostic markers. Histol Histopathol 29:1235–1248

    PubMed  Google Scholar 

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Acknowledgements

We would like to thank Enago (http://www.enago.jp) for the English language review.

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Authors and Affiliations

  1. Department of Neurosurgery, Tohoku University School of Medicine, Sendai, Japan

    Ichiyo Shibahara, Masayuki Kanamori, Ryuta Saito & Teiji Tominaga

  2. Department of Neurosurgery, National Hospital Organization Sendai Medical Center, Sendai, Japan

    Ichiyo Shibahara & Hiroshi Uenohara

  3. Department of Neurosurgery, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan

    Yukihiko Sonoda & Akifumi Mayama

  4. Department of Pathology and Laboratory Medicine, National Hospital Organization Sendai Medical Center, Sendai, Japan

    Hiroyoshi Suzuki

  5. Department of Neurosurgery, Iwaki Kyoritsu General Hospital, Iwaki, Japan

    Yasuhiro Suzuki & Shoji Mashiyama

  6. Department of Pathology, Tohoku University Hospital, Sendai, Japan

    Mika Watanabe

  7. Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan

    Toshihiro Kumabe

Authors
  1. Ichiyo Shibahara
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  2. Yukihiko Sonoda
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  3. Hiroyoshi Suzuki
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  5. Masayuki Kanamori
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  12. Teiji Tominaga
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Correspondence to Yukihiko Sonoda.

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Shibahara, I., Sonoda, Y., Suzuki, H. et al. Glioblastoma in neurofibromatosis 1 patients without IDH1, BRAF V600E, and TERT promoter mutations. Brain Tumor Pathol 35, 10–18 (2018). https://doi.org/10.1007/s10014-017-0302-z

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  • DOI: https://doi.org/10.1007/s10014-017-0302-z

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