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ANTICANCER RESEARCH 36 : 4145-4150 (2016)

Bone Marrow Metastases from a 1p/19q Co-deleted Oligodendroglioma - A Case Report MARIEKE DEMEULENAERE 1, JOHNNY DUERINCK 2, STEPHANIE DU FOUR 2, KAREL FOSTIER 3, ALEX MICHOTTE 4 and BART NEYNS 1

Departments of 1Medical , 2Neurosurgery, 3Hematology and 4Neurology and , UZ Brussel, Brussels, Belgium

Abstract. Background: Metastasis of oligodendroglioma Metastasis of oligodendroglioma outside of the central outside of the (CNS) is a very rare nervous system (CNS) is particularly rare (4). We report the event. Case: We describe in detail the clinical story of a 50- case of a patient with an anaplastic oligodendroglioma who year-old woman diagnosed with profound pancytopenia and developed diffuse bone marrow metastasis 15 years after the signs of extramedullary hematopoiesis caused by diffuse bone initial diagnosis of her tumor. marrow replacement by a metastatic oligodendroglioma. Results: Upon development of pancytopenia, a diagnostic Case Report bone marrow examination revealed the presence of metastatic oligodendroglial cells. No others sites of malignant In 2000, a 35-year-old woman was admitted at the dissemination were found outside the CNS. Despite best Department of following an inaugural epileptic supportive care, the patient died three weeks after diagnosis . Magnetic resonance imaging (MRI) of the brain of myelophthisis. Conclusion: Extracranial metastases from demonstrated a right-sided frontal tumor. A treatment with CNS oligodendroglioma are a very rare event but can be the valproic acid was started and the patient underwent a cause of bone marrow failure. diagnostic (Figure 1). Histological examination established the diagnosis of an anaplastic oligodendroglioma Oligodendroglioma is a histopathological subtype of glial (grade 3) according to the 2000 WHO classification. By brain tumors subdivided by differentiation grade (grade 2 immunohistochemistry, minor subsets were positive for glial versus grade 3 (anaplastic) tumors) according to criteria fibrillary acidic protein (GFAP) and there was a slight defined by the World Health Organization (WHO). More increase in focal Ki-67 labeling index. Fluorescence in situ recently, molecular-genetic subgroups for classifying low- hybridization (FISH) performed on paraffin-embedded tissue grade and anaplastic have been proposed in order to revealed a co-deletion of chromosome 1p36 and 19q13. more adequately define prognostic subgroups (1). The Subsequently, two cycles of procarbazine, lomustine and molecular subgroup with the most favorable natural vincristine (PCV) were administered resulting in a complete prognosis is characterized by co-deletion of the chromosomal remission on MRI of the brain. arms 1p36/19q13 and mutations of the IDH1 , or -2 genes, Six years later, in 2006, the tumor recurred and treatment most commonly at the IDH1 R132H position. These with temozolomide (TMZ; 200 mg/m 2, 5 out of 28 days) was 1p36/19q13 co-deleted oligodendrogliomas typically run a initiated. Treatment was well-tolerated without hematological more indolent course are more sensitive to alkylating toxicity. A partial response was obtained and, after 12 and their history is characterized by treatment cycles, the residual tumor mass was treated with episodes of durable remission followed by recurrences (2, 3). stereotactic (Novalis; 30 ×2 Gy). The MRI image of the brain remained stable for two years. At progression, a partial resection was performed revealing recurrent oligodendroglioma grade 3. No further treatment Correspondence to: Neyns Bart, MD, Ph.D., Medical Oncology, UZ was administered until, in 2010, progression occurred for Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Tel: +32 24776415, Fax: +32 24776210, e-mail: [email protected] which again a partial resection was performed followed by stereotactic radiation therapy (Novalis; 60 Gy). At the time Key Words: 1p/19q co-deletion, oligodendroglioma, bone marrow of progression, one year later in 2011, the patient underwent metastases. again a partial resection followed by treatment with TMZ.

0250-7005/2016 $2.00+.40 4145 ANTICANCER RESEARCH 36 : 4145-4150 (2016)

Figure 1 . Post-surgical magnetic resonance imaging (MRI) of the brain. Axial images of T1 gadolinium-enhanced (left) and T2 (right) MRI of the brain revealing the presence of a non-gadolinium-enhancing tumor in the right frontal lobe of the brain.

In August 2013, after six cycles of TMZ, repeat assessment the axial skeleton suggestive of metastasis to the skeleton but showed local progression and therapy was switched to no evidence of an extracranial primary tumor or other sites lomustine (110 mg/m 2 every 6 weeks) that was stopped after of metastasis (Figure 2). 4 cycles because of progressive symptoms. No grade ≥3 A bone marrow aspiration biopsy of the iliac crest showed hematological toxicity was observed during chemotherapy. At replacement of the patient's marrow by malignant cells further progression with marked necrosis and perilesional (Figure 3a-d), an altered nuclear morphology in granulocytes, , radiation necrosis was suspected and treatment with absence of megakaryocytes, dyserythropoisis, a normal aspect high-dose intravenous corticosteroids (methylprednisolone at of mononuclear cells and a poor cellularity. The malignant a dose of 40 mg three times a day) was administered. Due to cells were strongly positive for isocitrate dehydrogenase-1 important side-effects of corticosteroids, it was necessary to (IDH1) (R132H antibody, dilution 1:100, Clone H09; reduce the dose and bevacizumab was administered (10 mg/kg Dianova, Hamburg, Germany). Some cells stained positively every 2 weeks for 4 doses) for the treatment of radionecrosis. for glial fibrillary acidic protein (GFAP) (dilution 1:10, clone A cerebral MRI, in November 2014, showed a favorable 6A-5; Biogenex, Olen, Belgium). Ki-67 showed an increased evolution with a decrease of edema; however, two months labeling index with proliferation index of >50% (dilution later, MRI revealed again progression and a surgical resection 1:100, clone MIB1; Dako, Heverlee, Belgium). The 1p19q was performed. The performance status of the patient had deletion could not be demonstrated for technical reasons gradually declined, in part because of left-sided hemiparesis, (exposure of the tissue to a decalcifying agent). Based on the and she was transferred to a rehabilitation unit. immunohistological staining, a diagnosis of metastatic In April 2015, the patient was re-admitted to the hospital oligodendroglioma to the bone marrow was made. Due to the because of multiple non-traumatic ecchymosis and advanced nature of the disease and extensive prior systemic pancytopenia (platelets: 25,000/mm 3, neutrophils: 1,160/mm 3, therapy, no further antitumoral treatment was administered red blood cells: 3 ×10 6/mm 3, mean corpuscular volume (MCV): and the patient was admitted to a palliative care center. The 99.8 fl, mean corpuscular hemoglobin (MCH): 34.6 pg, mean patient died 3 weeks later. An autopsy was not performed. corpuscular hemoglobin concentration (MCHC): 34.6 g/dl). There was no evidence for a coagulation disorder, sepsis or Discussion disseminated intravascular coagulation (DIC). A differential count showed increased numbers of granulocyte precursors, Oligodendroglioma is a diffuse , accounting for indicative for extramedullary hematopoiesis. approximately 4.2% of all primary brain tumors (3). Extra- MRI of the brain did not indicate intracranial progression. neural metastasis of a primary intracranial is very A computed tomography (CT) scan of the body and MRI of rare clinical event. A review of 8,000 tumors involving the the spine revealed a diffuse change of the bone marrow of CNS found only a 0.44% incidence of extracranial

4146 Demeulenaere et al : Bone Marrow Metastases from a 1p/19q Co-deleted Oligodendroglioma - A Case Report

Figure 2. Magnetic resonance imaging (MRI) of the brain. Axial images of (a) T1 gadolinium-enhanced and (b) T2 MRI of the brain revealing a post-frontal lobectomy status and contralateral edema; (c) Sagittal MRI and (d) Computed tomography (CT) images of the spine revealing and abnormal heterogeneous contrast-enhancing signal in the bone marrow.

metastasis, including one oligodendroglioma (5). Liwnicz Different theories have been proposed regarding the rarity and Rubinstein analyzed 116 cases of extracranial of this event, including a lack of lymphatic vessels in the metastases and found that the most common primary tumor brain, inability of CNS-derived tumor cells to grow outside was multiforme (41.1%), followed by the central nervous system, the critical role of the relative (26.7%), (16.4%), integrity of the blood brain barrier, the compression of (10.3%) and oligodendroglioma (5.25%) (6). peritumoral capillaries by tumor and the short survival time Krijnen et al. reported an incidence of approximately 2 in of patients with such tumors (8-11). 1,000 for metastasis of oligodendroglioma outside the CNS Primary of the brain are generally considered to in the Netherlands (7). spread in any of three ways: hematological or lymphogeneous

4147 ANTICANCER RESEARCH 36 : 4145-4150 (2016)

Figure 3. of bone marrow biopsy. A: Fragments of bone tissue. The normal hematopoietic tissue is replaced by a malignant tumor composed of polymorphic round or polygonal cells with irregular nuclei and numerous mitotic figures. B: A minority of the cells show a positive immunostaining for glial fibrillary acidic protein (GFAP). Note the round shape of the cells with a clear perinuclear halo suggestive of an oligodendroglial origin. C: All tumoral cells display a strong cytoplasmatic positivity for IDH1 R132H. D: Immunohistochemistry for Ki-67 shows a high labeling-index up to 50%.

way, cerebrospinal pathways and local invasion (11). One of al. who reported on 61 cases of extracranial metastatic the main factors that has been associated with distant oligodendrogliomas between 1951 and 2014, the most metastasis is repeated craniotomy providing access to vascular frequent metastatic sites were bone and bone marrow (n=47; channels within the parenchyma, dura or scalp (11, 12). 42.7%), lymph nodes (n=22; 20%), liver (n=7; 6.4%), scalp Extraneural metastasis is considered to be correlated with (n=6; 5.5%), lung (n=6; 5.5%), pleura (n=4; 3.6%), chest wall multiple craniotomies, shunt and long-term survival. (n=3; 2.7%), iliopsoas muscle (n=2; 1.8%), soft tissue (n=2; Extracranial metastasis without previous surgical 1.8%), parotid gland (n=2; 1.8%), as well as adrenal gland, intervention is infrequent (12). In 1985, Hoffman and Duffner spleen, thoracic wall, pancreas, dorsal root ganglia, abdomen, published 282 cases of with extraneural metastases spinal dura mater, breast and thymus glands with one lesion where only 24 (8.5%) cases had metastases without previous each (n=1; 0.9%) (12). craniotomy (13). In 1995, Huang et al. performed the same The reason for the high predilection for the bone and bone analysis and found that of 247 cases with extraneural marrow by metastatic oligodendroglioma may be related to the metastasis of CNS tumors only 10 occurred without expression of neural cell adhesion molecule (NCAM), which neurosurgery or shunting (14). In addition to the referred case seems to be fundamental for the function of the bone marrow series, a number of single reports have been published (9, 12, microenvironment and hematopoiesis. NCAM is able to 15-18, 20-21). The patient we describe in this case report had perform homophilic NCAM-NCAM bindings, possibly being multiple neurosurgical interventions before metastasis of the the molecular basis of the implants of oligodendroglioma cells bone marrow occurred. In addition, prolonged survival and in the bone and bone marrow (18, 19). multiple recurrences might have contributed to the occurrence Extraneural metastasis of oligodendroglioma might of a subclone that acquired the necessary features to become more frequent in the future due to the more metastasize outside the CNS and, in particular, to the bone aggressive treatment of this neoplasm (including the use of marrow. In previous case series, including the report by Li et alkylating chemotherapy) resulting in prolonged survival.

4148 Demeulenaere et al : Bone Marrow Metastases from a 1p/19q Co-deleted Oligodendroglioma - A Case Report

Conflicts of Interest 10 Garner J, Morcos Y and Bari M: Extradural cord decompression due to metastatic oligodendroglioma. J Neurooncol 58 : 71-75, The Authors declare that there is no conflict of interest regarding 2002. the publication of this article. 11 Schweitzer T, Vince GH, Herbold C, Roosen K and Tonn JC: Extraneural metastases of primary brain tumors. J Neurooncol 3 References : 107-114, 2001. 12 Li G, Zhang Z, Zhang J, Jin T, Liang H, Gong L, Cui G, Yang H, He S, Zhang Y and Gao G: Occipital anaplastic oligodendro- 1 Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, glioma with multiple organ metastases after a short clinical Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov course: a case report and literature review. Diagn pathol 9: 17, IV, Sarkar G, Caron AA, Kollmeyer TM, Praska CE, CHada AR, 2014. Halder C, Hansen HM, McCoy LS, Bracci PM, Marshall R, 13 Hoffman HJ and Duffner PK: Extraneural metastases of central Zheng S, Reis GF, Pico AR, o’Neill BP, Buckner JC, Giannini nervous system tumors. Cancer 6: 1778-1782, 1958. C, Huse JT, Perry A, Tihan T, Berger MS, Chang SM, Prados 14 Huang P, Allam A, Taghian A, Freeman J, Duffy M and Suit HD: MD, Wiemels J, Wiencke JK, Wrensch MR and Jenkins RB: Growth and metastatic behavior of five human Glioma Groups Based on 1p/19q, IDH, and TERT Promoter compared with nine other histological types of human tumor Mutations in Tumors. N Engl J Med 372(26) : 2499-2508, 2015. xenografts in SCID mice. J Neurosurg 82(2) : 308-315, 1995. 2 Van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, 15 Al-ali F, Hendon AJ, Liepman MK, Wisniewski JL, Krinock MJ Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, and Beckman K: Oligodendroglioma metastatic to bone marrow. Sipos L, Haaxma-Reiche H, Kros JM, Van Kouwenhoven MC, Am J Neuroradiol 26 : 2410-2414, 2005. Vecht CJ, Allgeier A, Lacombe D and Gorlia T: Adjuvant 16 Sha SJ, Wu HP, Lu K, Chen HJ, Huang PH, Huang SH and Hsu procarbazine, lomustine, and vincristine improves progression- CT: Extraneural metastases of anaplastic oligodendroglioma. free survival but not overall survival in newly diagnosed APMIS 122(7) : 660-662, 2014. anaplastic oligodendrogliomas and : a 17 Gru AA, Fulling K and Perry A: A 39 year-old man with a randomized European Organisation for Research and Treatment cerebellar mass and pancytopenia. Brain Pathol 22 : 251-254, of Cancer phase III trial. J Clin Oncol 24(18) : 2715-2722, 2006. 2011. 3 Cairncross JG, Wang M, Jenkins RB, Shaw EG, Giannini C, 18 Zustovic F, Della Puppa A, Scienza R, Anselmi P, Furlan and, Brachman DG, Buckner JC, Fink KL, Souhami L, Laperriere Cartei G: metastatic oligodendrogliomas: a review of the NJ, Huse JT, Metha MP and Curran WJ Jr.: Benefit From literature and case report. Acta Neurochir 150 : 699-703, 2008. Procarbazine, Lomustine, and Vincristine in Oligodendroglial 19 Wang X, Hisha H, Taketani S, Inaba M, Li Q, Cui W, Song C, Tumors Is Associated With Mutation of IDH. J Clin Oncol Fan T, Cui Y, Guo K, Yang G, Fan H, Lian Z, kGershwin ME 32(8) : 783-791, 2014. and Ikehara S: Neural cell adhesion molecule contributes to 4 Han SR, Yoon SW, Yee GT, Choi CY, Lee DJ, Sohn, MJ, Chang hemopoiesissupporting capacity of stromal cell lines. StemCells SH and Whang CJ: Extraneural metastases of anaplastic 23 : 1389-1399, 2005. oligodendroglioma. J clin Neurosci 15 : 946-949, 2008. 20 Aabenhus K and Hahn CG: A rare metastasis from a rare brain 5 Smith DR, Hardman JM and Earle KM: Metastasizing tumour. Ugeskr Laeger 176(14), 2014. neuroectodermal tumors of the central nervous system. J 21 Tanaka Y, Nobusawa S, Ikota H, Yokoo H, Hirato J and Ito H: Neurosurg 31 : 50-58, 1969. Leukemia-onset of bone marrow metastasis from anaplastic 6 Liwnicz BH and Rubinstein LJ: The pathways of extraneural olgigodendroglioma after 17 years of dormancy: an autopsy case spread in metastasizing gliomas: a report of three cases an report. Pathol 31(2) : 131-6, 2014. critical review of the literature. Hum Pathol 10 : 453-467, 1979. 7 Krijnen JL, Fleischeur RE, Van Berkel M and Westenend PJ: Metastatic oligodendroglioma: a case report and incidence in The Netherlands. Clin Neuropathol 29(3) : 141-146, 2010. 8 Subramanian A, Harris A, Piggott K, Shieff C and Bradford R: Metastasis to and from the central nervous system: the 'relatively protected site'. Lancet Oncol 3: 498-507, 2002. 9 Wu Y, Liu B, Qu L and Thao H: Extracranial skeletal metastasis Received May 11, 2016 in anaplastic oligodendroglioma: case report and review of the Revised June 16, 2016 literature. Int J Med Res 39 : 960-967, 2011. Accepted June 17, 2016

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