JNS-13804; No of Pages 2 Journal of the Neurological Sciences xxx (2015) xxx–xxx

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Letter to the Editor Rare brainstem oligodendroglioma in an adult patient: Presentation, molecular characteristics and treatment response Keywords: Neuro-oncology Brainstem glioma Oligodendroglioma

Following biopsy, the patient received radiation (59.4 Gy in 1.8 Gy fractions) and concomitant chemotherapy with temozolomide for 6 weeks. Following treatment, brain MRI showed a radiographic response and his deficits were improved, see Fig. 1. He is clinically and radiographically stable after 12 cycles of adjuvant temozolomide, 21 months after diagnosis.

2. Discussion

1. Introduction World Health Organization (WHO) Grades II, III, and IV brainstem gliomas are rare in adults, accounting for b 2% of intracranial gliomas. This is in contradistinction to the pediatric population where brainstem gliomas make up 20% of glial neoplasms. Adult brainstem gliomas appear to have a better prognosis compared to pediatric cases with an average survival of 30–40 months in adults compared to 10– 12 months in pediatrics. Oligodendrogliomas represent 1.7% of all brain tumors and anaplastic oligodendrogliomas account for only 0.5% [1]. The vast majority of these tumors are located in the supratentorial compartment with only scattered case reports of infratentorial oligodendrogliomas published in the last 50 years. Supratentorial anaplastic oligodendrogliomas which show loss of heterogeneity at chromosomes 1p and 19q (1p/19q co-deletion) and mutations of the IDH gene have significantly prolonged survival and improved response to radiotherapy and cytotoxic chemotherapy compared to tumors which lack these genetic markers [8–10]. We report a case of an adult with a brainstem anaplastic oligodendroglioma (AO) including clinical, pathologic, and molecular characteristics. 1.1. Clinical presentation A 42-year-old man presented with a one year history of right 6th and 7th cranial nerve palsies. MRI showed a non-enhancing mass in the right pons, measuring 3.1 × 2.9 × 2.2 cm. MRI of the spine was unremarkable. An open biopsy of the mass was performed. Pathologically, the tumor appeared moderately cellular and was composed of cells with round nuclei, cytologic atypia, and a delicate capillary network. Mitotic figures were present in areas of dense cellularity (4 mitoses/one HPF). Microvascular proliferation and tumor-related necrosis were not identified. Immunostaining for glial fibrillary acidic protein was strongly present in most of the neoplastic cells. Immunohistochemical markers of ganglionic and neuronal differentiation, including NeuN and chromogranin, were negative. Isocitrate Dehydrogenase 1 (IDH1) mutation was not present on IDH1 R132H immunohistochemistry. Subsequent sequencing of the IDH1 and IDH2 genes revealed an IDH2 R172M mutation. Deletions of both 1p36 and 19q13 were detected by fluorescence in-situ hybridization. Based on these features, the tumor was classified as an anaplastic oligodendroglioma, WHO Grade III.

This is the first reported case of a brainstem oligodendroglioma with both 1p/19q chromosomal co-deletion and IDH mutation. IDH1 (R132H) mutations are common in WHO Grade II/III supratentorial gliomas and in secondary glioblastoma, but rare in gliomas arising from the brainstem, cerebellum, and spinal cord [2]. IDH1 mutations are present in 80 to 100% of WHO Grades II and III oligodendroglial tumors with 1p/19q co-deletion [3]. In a large series of 1010 gliomas only 31 cases had IDH2 mutations [4]. The majority of these were in tumors with pure oligodendroglial or mixed oligoastrocytic morphology. Reyes-Botero et al. evaluated 17 infiltrating brainstem gliomas in adult patients and found 1 IDH1 (R132H) on immunohistochemical staining and 2 non-R132H IDH1 mutated tumors after performing IDH1 and IDH2 sequencing. In this same study, 8 tumors had oligodendroglial histology, 6 oligoastrocytomas and 2 oligodendrogliomas, IDH1 mutations were found in 2 of these cases, but none of the cases tested had 1p/19q co-deletions (5 of 8 were tested), and no IDH2 mutations were found [5]. Taken together, the available data suggest that sequencing of the IDH1 and IDH2 genes may be necessary in adult brainstem gliomas due to the rarity of IDH1 R132H mutations in these tumors and the potential prognostic significance of IDH mutations. This is the second reported case of a brainstem oligodendroglioma with 1p/19q codeletion. Hewer et al. published a case of a 55-year-old woman with a medullary AO with 1p/19q codeleted, IDH1 R132H wild-type on immunohistochemistry, and gene sequencing of the IDH1 and 2 genes was not performed. Following stereotactic biopsy, she was treated with focal radiation and concomitant temozolomide, but treatment was discontinued after 4 weeks due to adverse side effects and she was referred to a palliative care unit [6]. Prior to this, Alvarez and colleagues published a case of a 25-year-old woman with a non-enhancing intra-axial AO in the pons and medulla, with unknown 1p/19q status. She was treated with local radiation. She was stable for 12 months before developing leptomeningeal spread, and was then treated with craniospinal irradiation followed by PCV (Procarbazine, Lomustine, Vincristine) chemotherapy. There was no information regarding long-term outcome [7]. The RTOG 9402 and EORTC trials recently established a combination of PCV and RT as the standard treatment regimen for AO [8]. The ongoing CODEL trial (NCT00887146) is randomizing patients with AO and 1p/19q codeletion between radiation with concurrent and adjuvant temozolomide versus RT followed by PCV. Due its rare occurrence, the optimal regimen for brainstem AOs with 1p/19q co-deletion will likely not be clarified by these trials, but the treatment response in our case supports the use of a regimen

http://dx.doi.org/10.1016/j.jns.2015.05.019 0022-510X/Published by Elsevier B.V.

Please cite this article as: S.D. Hodges, et al., , J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.019

2

Letter to the Editor

Fig. 1. A: H&E at low power; B: H&E at high power; C: FLAIR image prior to treatment; D: FLAIR image following treatment.

including radiotherapy and cytotoxic chemotherapy similar to the approach used in supratentorial tumors. 3. Conclusion Brainstem oligodendrogliomas are exceedingly rare in adults and our patient represents the second published case with verified 1p/19q codeletion and the first published case with an IDH2 mutation. Sequencing of IDH1 and IDH2 mutations may be necessary in brainstem cases due to rarity of the more common IDH1 R132H mutation in WHO Grades II and III adult brainstem gliomas. The partial response to radiation and cytotoxic chemotherapy in this case suggests that brainstem-localized oligodendrogliomas with 1p/19q co-deletion and IDH mutation may be a treatment responsive tumor similar to supratentorial tumors with this genetic profile, but further evaluation of larger numbers of cases is needed. Conflict of interest The authors have no disclosures. Disclaimer The views expressed in this article are those of the author and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government. References [1] Q.T. Ostrom, H. Gittleman, P. Farah, A. Ondracek, Y. Chen, Y. Wolinsky, et al., CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010, Neuro Oncol 15 (2013) ii1–ii56. [2] B. Ellezam, B.J. Theeler, T. Walbert, A.G. Mammoser, C. Horbinski, B.K. KleinschmidtDeMasters, et al., Low rate of R132H IDH1 mutation in infratentorial and spinal cord grade II and III diffuse gliomas, Acta Neuropathol 124 (2012) 449–451.

[3] M. Labussiere, A. Idbaih, X.W. Wang, Y. Marie, B. Boisselier, C. Falet, et al., All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2, Neurology 74 (2010) 1886–1890. [4] C. Hartmann, J. Meyer, J. Balss, D. Capper, W. Mueller, A. Christians, et al., Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas, Acta Neuropathol 118 (2009) 469–474. [5] G. Reyes-Botero, M. Giry, K. Mokhtarik, M. Labussiere, A. Idbaih, J. Delattre, et al., Molecular analysis of diffuse intrinsic brainstem gliomas in adults, J Neurooncol 116 (2014) 405–411. [6] E. Hewer, J. Beck, E. Vassella, I. Vajtai, Anaplastic oligodendroglioma arising from the brainstem and featuring 1p/19q co-deletion, Neuropathology 34 (2014) 32–38. [7] J.A. Alvarez, M.L. Cohen, M.L. Hlavin, Primary intrinsic brainstem oligodendroglioma in an adult, J Neurosurg 85 (1996) 1165–1169. [8] G. Cairncross, M. Wang, E. Shaw, R. Jenkins, D. Brachman, J. Buckner, et al., Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402, J Clin Oncol 30 (2012) 1–10. [9] M.J. van den Bent, A.A. Brandes, M.J.B. Taphoorn, J.M. Kros, M.C.M. Kouwenhoven, J. Delattre, et al., Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951, J Clin Oncol 31 (2012) 44–350. [10] G. Minniti, A. Arcella, C. Scaringi, G. Lanzetta, D. Di Stefano, S. Scarpino, et al., Chemoradiation for anaplastic oligodendrogliomas: clinical outcomes and prognostic value of molecular markers, J Neurooncol 116 (2014) 275–282.

Sarah D. Hodges⁎ Patrick Malafronte Jonathan Gilhooly William Skinner Corey Carter Brett J. Theeler Walter Reed National Military Medical Center, 8901 Wisconsin Ave., Bethesda, MD 20889, United States ⁎Corresponding author at: Naval Medical Center San Diego, Department of Neurology, 34800 Bob Wilson Dr., San Diego, CA 92134, United States. Tel.: +1 330 844 6109. E-mail addresses: [email protected], [email protected].

Please cite this article as: S.D. Hodges, et al., , J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.05.019

16 March 2015 Available online xxxx

Rare brainstem oligodendroglioma in an adult patient: Presentation, molecular characteristics and treatment response.

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