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Bone Marrow Metastases from a 1P/19Q Co 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 Oncology, 2Neurosurgery, 3Hematology and 4Neurology and Neuropathology, UZ Brussel, Brussels, Belgium Abstract. Background: Metastasis of oligodendroglioma Metastasis of oligodendroglioma outside of the central outside of the central nervous system (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 brain 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 Neurosurgery following an inaugural epileptic supportive care, the patient died three weeks after diagnosis seizure. 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 biopsy (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 gliomas 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 chemotherapy and their disease history is characterized by treatment cycles, the residual tumor mass was treated with episodes of durable remission followed by recurrences (2, 3). stereotactic radiation therapy (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, edema, 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 glial tumor, 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 neoplasm 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 glioblastoma multiforme (41.1%), followed by the central nervous system, the critical role of the relative medulloblastoma (26.7%), ependymoma (16.4%), integrity of the blood brain barrier, the compression of astrocytoma (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 neoplasms 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. Histopathology of bone marrow biopsy. A: Fragments of bone tissue. The normal hematopoietic tissue is replaced by a malignant tumor composed of
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