- Email: [email protected]
Gliomatosis cerebri in a patient with Ollier disease
1564
Case Reports / Journal of Clinical Neuroscience 18 (2011) 1564–1566
Gliomatosis cerebri in a patient with Ollier disease Ruth A. Mitchell a,⇑, Joshua Mingsheng Ye b, Simone Mandelstam b,c,d, Patrick Lo a,e a
Department of Neurosurgery, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia Department of Radiology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia Department of Medical Imaging, Royal Children’s Hospital, Parkville, Victoria, Australia d Brain Research Institute, Austin Health, Neurosciences Building, Heidelberg West, Victoria, Australia e Department of Neurosurgery, Parkville, Victoria, Australia b c
a r t i c l e
i n f o
Article history: Received 19 March 2011 Accepted 23 March 2011
Keywords: Enchondromatosis Gliomatosis cerebri Ollier disease
a b s t r a c t Gliomatosis cerebri (GC) is an uncommon brain tumour defined as a diffuse neoplastic glial cell infiltration of the brain, involving more than two cerebral lobes and, occasionally, the infratentorial structures or the spinal cord. GC of the oligodendroglial phenotype is extremely rare, especially in the paediatric setting. We describe an unusual case of oligodendroglial GC diagnosed in a 16-year-old boy with Ollier disease. To our knowledge this is the first case of GC reported in a child with Ollier disease.
1. Introduction Gliomatosis cerebri (GC) is an uncommon brain tumour defined as a diffuse neoplastic glial cell infiltration of the brain, involving more than two cerebral lobes and, occasionally, the infratentorial structures or the spinal cord.1 Three histologic subtypes of GC are described: astrocytic (the most common), oligodendroglial or mixed oligo-astrocytic.2 GC of oligodendroglial phenotype is very uncommon and only a few patients have been reported.3–5 This is even rarer in the paediatric subgroup.6 We present a patient with oligodendroglial GC diagnosed in a 16-year-old child with multiple enchondromatosis (Ollier disease).
2. Case report A 16-year-old boy had a generalized tonic clonic first seizure during a family holiday. He had a long standing history of Ollier disease. On examination, no neurological abnormalities were detected. He had no dysmorphic features. Cranial nerves were unremarkable and fundoscopy was normal. His tone, strength, reflexes, coordination and gait were all normal. An initial CT scan was performed which suggested multifocal brain changes. This was followed by MRI with spectroscopy (MRS). MRI demonstrated an extensive, diffuse, predominantly white matter process involving all the lobes of the cerebral hemispheres, but also involving some cortical regions, the basal ganglia and thalami, brainstem and corpus callosum. There was also a particularly expansile region involving the right middle frontal gyrus. The abnormality was hyperintense on T2-weighted and fluidattenuated inversion recovery (FLAIR) images (Fig. 1)and hypointense on T1-weighted MRI, with no enhancement. The cerebellum and spinal cord appeared normal and no abnormality of ventricular size was detected. MRS was performed with voxels placed in the left frontal grey matter, right subinsular white matter, including adjacent basal ganglia, and the right frontotemporal grey matter. All these regions showed increased lactate, decreased N-acetyl aspartate (NAA), increased choline and increased myoinositol. The NAA:creatine ratio was low in all regions, the choline:creatine ratio was elevated in the left frontal and right frontotemporal re⇑ Corresponding author. Tel.: +61 3 9342 7000; fax: +61 3 9342 4234. E-mail address: [email protected] (R.A. Mitchell).
Ó 2011 Elsevier Ltd. All rights reserved.
gions. The imaging was reviewed and discussed extensively without consensus for a definitive diagnosis. The patient appeared very well despite the extensive abnormality on his MRI. However, he suffered a second seizure 3 months later and it was decided that a definitive tissue diagnosis was needed. He underwent a right frontal craniotomy through a right frontotemporal incision. The swollen right frontal lobe was identified under stereotactic guidance and the tumour mass in that region was subtotally resected (Fig. 2). Paraffin-embedded sections of the right frontal lesion showed a diffusely infiltrating tumour with oligodendroglial features mainly infiltrating white matter but also extending into the lower layers of the cortex. The tumour cells showed small nuclei with fine chromatin and surrounding clear halo. The vascular pattern was typical and exhibited a chicken-wire arrangement (Fig. 3a). Mitotic activity was low and amounted to approximately 1 mitosis/10 high power fields. Necrosis, endothelial proliferation or calcification was not seen. At the edge of the lesion, the infiltrative pattern consisted of perivascular and perineuronal satellitosis (Fig. 3b). Immunohistochemically, the tumour cells were negative for glial fibrillary acidic protein. The Ki-67 index was low at approximately 2%. In view of the reported multifocal distribution of the lesion bilaterally and involving several lobes, a diagnosis of oligodendroglial GC was made. The patient made an excellent post-operative recovery and was discharged 3 days later. Follow-up MRI and clinical review three months later revealed that his GC had remained stable. In view of his stable condition and relatively low grade of the tumour evident on biopsy, it was decided with the neuro-oncologists that the morbidity of chemotherapy and radiotherapy would outweigh the potential benefits. The patient has since resumed all normal activities and will require 3-monthly MRI to monitor his condition.
3. Discussion Ollier disease is a rare developmental disorder, which is characterized by multiple benign cartilaginous lesions in the metaphyseal medulla of bone, known as enchondromas.7,8 The prognosis of Ollier is difficult to determine, however and an important consideration is malignant transformation of enchondromas, which occurs in 5% to 50% of patients.9 Multiple associations with other malignancies have been described, including gliomas.10 However,
Case Reports / Journal of Clinical Neuroscience 18 (2011) 1564–1566
1565
Fig. 1. Initial (a) sagittal fluid-attenuated inversion recovery MRI and (b) axial T2weighted MRI showing a widespread hyperintense abnormality.
Fig. 2. Axial follow-up (a) T1-weighted post-contrast MRI showing no enhancement; and (b) T2-weighted MRI showing stability over two years.
to our knowledge there are no previous cases described in the literature of GC in a patient with Ollier disease. The term GC was first introduced by Nevin in 1938 and was used to describe a diffuse cellular overgrowth of neuroglial cells throughout large areas of the cerebral hemisphere.11 It is a rare form of brain tumour with about 300 cases reported. The majority of GC reported are astrocytic.2 Oligodendroglial GC is exceptionally rare and very few patients have been documented.3–5 GC occurs more commonly in adults, mostly manifesting in the fourth decade of life, with a slightly higher incidence among males than females.2 Common clinical manifestations of GC include seizures, progressive headache, cognitive impairment and focal neurologic deficits. On neurologic examination, patients may exhibit symptoms of intracranial hypertension.2,4 Obtaining an antemortem diagnosis of GC is very challenging, as illustrated in this report. Before the advent of new imaging modalities (MRI and CT scan) and the introduction of stereotactic biopsy
techniques, diagnosis of GC was usually made postmortem. Presently, the diagnosis of GC requires radiologic–pathologic correlation.12 MRI is the preferred imaging modality as the diffuse nature of the tumour and poor soft tissue contrast may result in failure of detection on CT scan. MRI reveals diffuse, hyperintense areas on T2-weighted images and hypointense lesions on T1weighted MRI without contrast enhancement.2,12 The use of MRS in the characterization of GC has recently been studied and findings of studies are in agreement with ours, demonstrating the potential diagnostic value of MRS. The optimal treatment for GC is not well established. Surgical resection is not beneficial because of the diffuse infiltrating nature of GC. The use of surgery is often restricted to diagnostic biopsy and management of raised intracranial pressure.4 Due to the limitations of surgical removal, radiotherapy and chemotherapy must be considered. Radiotherapy appears to have modest results in stabilizing or improving neurologic function. In a retrospective analy-
1566
Case Reports / Journal of Clinical Neuroscience 18 (2011) 1564–1566
therapy and radiotherapy remain questionable because of the few patients recruited in these studies. More research will be necessary to confirm these preliminary data. Although some patients have been known to survive for decades,16 prognosis of patients with GC is generally poor. According to a study of 296 patients from the Association des NeuroOncologues d’Expression Française – French Speaking NeuroOncologists’ Association (known as the ANOCEF database) and the literature, the median survival was 14.5 months.2 Certain factors have significant prognostic implications. The presence of oligodendroglial phenotype, low histological grade and low Ki67 proliferation index is associated with increased survival time.2,4 Histologic analysis is not only necessary to confirm diagnosis but may also provide valuable prognostic indications by grading the tumour and identifying predominant tumour cells. In summary, this is the first reported patient with the rare oligodendroglial form of GC in a patient with Ollier disease. References
Fig. 3. Stained section of the oligodendroglial component of the tumour from the surgical specimen showing (a) tumour cells with prominent perinuclear halos and a chicken-wire vascular pattern in the background (haematoxylin and eosin [HE], medium power view); and (b) the perivascular satellitosis (top left quadrant) and perineuronal satellitosis (bottom right quadrant) (HE, high power view). (This figure is available in colour at www.sciencedirect.com.)
sis of eight patients treated with radiotherapy, Elshaikh et al. reported disease stabilization in six patients. Despite this, the final outcome was dismal and only two patients were still alive at the end of follow-up.13 The value of chemotherapy seems promising. Unlike large field cranial irradiation which carries the risk of delayed adverse effects, toxicity of chemotherapy is low and reversible. The recent study of Sanson et al. reported a considerable rate of objective response and disease stabilization in patients receiving chemotherapy, particularly among those with oligodendroglial subtype.14 The inherent chemo-responsiveness is thought to be linked to 1p and 19q chromosomal deletions present in most oligodendroglial tumours.15 Nevertheless, the roles of both chemodoi:10.1016/j.jocn.2011.03.025
1. Lantos PL, Bruner JM. Gliomatosis cerebri. In: Kleihues P, Cavenee WK, editors. Pathology and genetics of tumours of the nervous system: WHO classification of tumours. Lyon: IARC Press; 2000. p. 92–3. 2. Taillibert S, Chodkiewicz C, Laigle-Donadey F, et al. Gliomatosis cerebri: a review of 296 cases from the ANOCEF database and the literature. J Neurooncol 2006;76:201–5. 3. Gutowski NJ, Gomez-Anson B, Torpey N, et al. Oligodendroglial gliomatosis cerebri: 1H-MRS suggests elevated glycine-inositol levels. Neuroradiology 1999;41:650–3. 4. Kim DG, Yang HJ, Park IA, et al. Gliomatosis cerebri: clinical features, treatment, and prognosis. Acta Neurochir (Wien) 1998;140:755–62. 5. Fukushima Y, Nakagawa H, Tamura M. Combined surgery, radiation, and chemotherapy for oligodendroglial gliomatosis cerebri. Br J Neurosurg 2004;18:306–10. 6. Armstrong GT, Phillips PC, Rorke-Adams LB, et al. Gliomatosis cerebri: 20 years of experience at the children’s hospital of Philadelphia. Cancer 2006;107:1597–606. 7. Bozeman LB, Sangiorigi L, Briare-de Bruijn IH, et al. Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C. Hum Mutat 2004;24:466–73. 8. Mellon CD, Carter JE, Owen DB. Ollier’s disease and Maffucci’s syndrome: distinct entities or a continuum. Case report: enchondromatosis complicated by an intracranial glioma. J Neurol 1988;235:376–8. 9. Silve C, Juppner H. Ollier disease: review. Orphanet J Rare Dis 2006;1:37. 10. Ranger A, Szymczk A, Hammond RR, et al. Pediatric thalamic glioblastoma associated with Ollier disease (multiple enchondromatosis): a rare case of concurrence. J Neurosurg Pediatr 2009;4:363–7. 11. Nevin S. Gliomatosis cerebri. Brain 1938;61:170–91. 12. Pyhtinen J, Paakko E. A difficult diagnosis of gliomatosis cerebri. Neuroradiology 1996;38:444–8. 13. Elshaikh MA, Stevens GHJ, Peereboom DM, et al. Gliomatosis cerebri: treatment results with radiotherapy alone. Cancer 2002;95:2027–31. 14. Sanson M, Cartalat-Carel S, Taillibert S, et al. Initial chemotherapy in gliomatosis cerebri. Neurology 2004;63:270–5. 15. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90:1473–9. 16. Cervos-Navarro J, Artigas J, Aruffo C, et al. The fine structure of gliomatosis cerebri. Virchows Arch A Pathol Anat Histopathol 1987;411:93–8.
Case Reports / Journal of Clinical Neuroscience 18 (2011) 1564–1566
Gliomatosis cerebri in a patient with Ollier disease Ruth A. Mitchell a,⇑, Joshua Mingsheng Ye b, Simone Mandelstam b,c,d, Patrick Lo a,e a
Department of Neurosurgery, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia Department of Radiology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia Department of Medical Imaging, Royal Children’s Hospital, Parkville, Victoria, Australia d Brain Research Institute, Austin Health, Neurosciences Building, Heidelberg West, Victoria, Australia e Department of Neurosurgery, Parkville, Victoria, Australia b c
a r t i c l e
i n f o
Article history: Received 19 March 2011 Accepted 23 March 2011
Keywords: Enchondromatosis Gliomatosis cerebri Ollier disease
a b s t r a c t Gliomatosis cerebri (GC) is an uncommon brain tumour defined as a diffuse neoplastic glial cell infiltration of the brain, involving more than two cerebral lobes and, occasionally, the infratentorial structures or the spinal cord. GC of the oligodendroglial phenotype is extremely rare, especially in the paediatric setting. We describe an unusual case of oligodendroglial GC diagnosed in a 16-year-old boy with Ollier disease. To our knowledge this is the first case of GC reported in a child with Ollier disease.
1. Introduction Gliomatosis cerebri (GC) is an uncommon brain tumour defined as a diffuse neoplastic glial cell infiltration of the brain, involving more than two cerebral lobes and, occasionally, the infratentorial structures or the spinal cord.1 Three histologic subtypes of GC are described: astrocytic (the most common), oligodendroglial or mixed oligo-astrocytic.2 GC of oligodendroglial phenotype is very uncommon and only a few patients have been reported.3–5 This is even rarer in the paediatric subgroup.6 We present a patient with oligodendroglial GC diagnosed in a 16-year-old child with multiple enchondromatosis (Ollier disease).
2. Case report A 16-year-old boy had a generalized tonic clonic first seizure during a family holiday. He had a long standing history of Ollier disease. On examination, no neurological abnormalities were detected. He had no dysmorphic features. Cranial nerves were unremarkable and fundoscopy was normal. His tone, strength, reflexes, coordination and gait were all normal. An initial CT scan was performed which suggested multifocal brain changes. This was followed by MRI with spectroscopy (MRS). MRI demonstrated an extensive, diffuse, predominantly white matter process involving all the lobes of the cerebral hemispheres, but also involving some cortical regions, the basal ganglia and thalami, brainstem and corpus callosum. There was also a particularly expansile region involving the right middle frontal gyrus. The abnormality was hyperintense on T2-weighted and fluidattenuated inversion recovery (FLAIR) images (Fig. 1)and hypointense on T1-weighted MRI, with no enhancement. The cerebellum and spinal cord appeared normal and no abnormality of ventricular size was detected. MRS was performed with voxels placed in the left frontal grey matter, right subinsular white matter, including adjacent basal ganglia, and the right frontotemporal grey matter. All these regions showed increased lactate, decreased N-acetyl aspartate (NAA), increased choline and increased myoinositol. The NAA:creatine ratio was low in all regions, the choline:creatine ratio was elevated in the left frontal and right frontotemporal re⇑ Corresponding author. Tel.: +61 3 9342 7000; fax: +61 3 9342 4234. E-mail address: [email protected] (R.A. Mitchell).
Ó 2011 Elsevier Ltd. All rights reserved.
gions. The imaging was reviewed and discussed extensively without consensus for a definitive diagnosis. The patient appeared very well despite the extensive abnormality on his MRI. However, he suffered a second seizure 3 months later and it was decided that a definitive tissue diagnosis was needed. He underwent a right frontal craniotomy through a right frontotemporal incision. The swollen right frontal lobe was identified under stereotactic guidance and the tumour mass in that region was subtotally resected (Fig. 2). Paraffin-embedded sections of the right frontal lesion showed a diffusely infiltrating tumour with oligodendroglial features mainly infiltrating white matter but also extending into the lower layers of the cortex. The tumour cells showed small nuclei with fine chromatin and surrounding clear halo. The vascular pattern was typical and exhibited a chicken-wire arrangement (Fig. 3a). Mitotic activity was low and amounted to approximately 1 mitosis/10 high power fields. Necrosis, endothelial proliferation or calcification was not seen. At the edge of the lesion, the infiltrative pattern consisted of perivascular and perineuronal satellitosis (Fig. 3b). Immunohistochemically, the tumour cells were negative for glial fibrillary acidic protein. The Ki-67 index was low at approximately 2%. In view of the reported multifocal distribution of the lesion bilaterally and involving several lobes, a diagnosis of oligodendroglial GC was made. The patient made an excellent post-operative recovery and was discharged 3 days later. Follow-up MRI and clinical review three months later revealed that his GC had remained stable. In view of his stable condition and relatively low grade of the tumour evident on biopsy, it was decided with the neuro-oncologists that the morbidity of chemotherapy and radiotherapy would outweigh the potential benefits. The patient has since resumed all normal activities and will require 3-monthly MRI to monitor his condition.
3. Discussion Ollier disease is a rare developmental disorder, which is characterized by multiple benign cartilaginous lesions in the metaphyseal medulla of bone, known as enchondromas.7,8 The prognosis of Ollier is difficult to determine, however and an important consideration is malignant transformation of enchondromas, which occurs in 5% to 50% of patients.9 Multiple associations with other malignancies have been described, including gliomas.10 However,
Case Reports / Journal of Clinical Neuroscience 18 (2011) 1564–1566
1565
Fig. 1. Initial (a) sagittal fluid-attenuated inversion recovery MRI and (b) axial T2weighted MRI showing a widespread hyperintense abnormality.
Fig. 2. Axial follow-up (a) T1-weighted post-contrast MRI showing no enhancement; and (b) T2-weighted MRI showing stability over two years.
to our knowledge there are no previous cases described in the literature of GC in a patient with Ollier disease. The term GC was first introduced by Nevin in 1938 and was used to describe a diffuse cellular overgrowth of neuroglial cells throughout large areas of the cerebral hemisphere.11 It is a rare form of brain tumour with about 300 cases reported. The majority of GC reported are astrocytic.2 Oligodendroglial GC is exceptionally rare and very few patients have been documented.3–5 GC occurs more commonly in adults, mostly manifesting in the fourth decade of life, with a slightly higher incidence among males than females.2 Common clinical manifestations of GC include seizures, progressive headache, cognitive impairment and focal neurologic deficits. On neurologic examination, patients may exhibit symptoms of intracranial hypertension.2,4 Obtaining an antemortem diagnosis of GC is very challenging, as illustrated in this report. Before the advent of new imaging modalities (MRI and CT scan) and the introduction of stereotactic biopsy
techniques, diagnosis of GC was usually made postmortem. Presently, the diagnosis of GC requires radiologic–pathologic correlation.12 MRI is the preferred imaging modality as the diffuse nature of the tumour and poor soft tissue contrast may result in failure of detection on CT scan. MRI reveals diffuse, hyperintense areas on T2-weighted images and hypointense lesions on T1weighted MRI without contrast enhancement.2,12 The use of MRS in the characterization of GC has recently been studied and findings of studies are in agreement with ours, demonstrating the potential diagnostic value of MRS. The optimal treatment for GC is not well established. Surgical resection is not beneficial because of the diffuse infiltrating nature of GC. The use of surgery is often restricted to diagnostic biopsy and management of raised intracranial pressure.4 Due to the limitations of surgical removal, radiotherapy and chemotherapy must be considered. Radiotherapy appears to have modest results in stabilizing or improving neurologic function. In a retrospective analy-
1566
Case Reports / Journal of Clinical Neuroscience 18 (2011) 1564–1566
therapy and radiotherapy remain questionable because of the few patients recruited in these studies. More research will be necessary to confirm these preliminary data. Although some patients have been known to survive for decades,16 prognosis of patients with GC is generally poor. According to a study of 296 patients from the Association des NeuroOncologues d’Expression Française – French Speaking NeuroOncologists’ Association (known as the ANOCEF database) and the literature, the median survival was 14.5 months.2 Certain factors have significant prognostic implications. The presence of oligodendroglial phenotype, low histological grade and low Ki67 proliferation index is associated with increased survival time.2,4 Histologic analysis is not only necessary to confirm diagnosis but may also provide valuable prognostic indications by grading the tumour and identifying predominant tumour cells. In summary, this is the first reported patient with the rare oligodendroglial form of GC in a patient with Ollier disease. References
Fig. 3. Stained section of the oligodendroglial component of the tumour from the surgical specimen showing (a) tumour cells with prominent perinuclear halos and a chicken-wire vascular pattern in the background (haematoxylin and eosin [HE], medium power view); and (b) the perivascular satellitosis (top left quadrant) and perineuronal satellitosis (bottom right quadrant) (HE, high power view). (This figure is available in colour at www.sciencedirect.com.)
sis of eight patients treated with radiotherapy, Elshaikh et al. reported disease stabilization in six patients. Despite this, the final outcome was dismal and only two patients were still alive at the end of follow-up.13 The value of chemotherapy seems promising. Unlike large field cranial irradiation which carries the risk of delayed adverse effects, toxicity of chemotherapy is low and reversible. The recent study of Sanson et al. reported a considerable rate of objective response and disease stabilization in patients receiving chemotherapy, particularly among those with oligodendroglial subtype.14 The inherent chemo-responsiveness is thought to be linked to 1p and 19q chromosomal deletions present in most oligodendroglial tumours.15 Nevertheless, the roles of both chemodoi:10.1016/j.jocn.2011.03.025
1. Lantos PL, Bruner JM. Gliomatosis cerebri. In: Kleihues P, Cavenee WK, editors. Pathology and genetics of tumours of the nervous system: WHO classification of tumours. Lyon: IARC Press; 2000. p. 92–3. 2. Taillibert S, Chodkiewicz C, Laigle-Donadey F, et al. Gliomatosis cerebri: a review of 296 cases from the ANOCEF database and the literature. J Neurooncol 2006;76:201–5. 3. Gutowski NJ, Gomez-Anson B, Torpey N, et al. Oligodendroglial gliomatosis cerebri: 1H-MRS suggests elevated glycine-inositol levels. Neuroradiology 1999;41:650–3. 4. Kim DG, Yang HJ, Park IA, et al. Gliomatosis cerebri: clinical features, treatment, and prognosis. Acta Neurochir (Wien) 1998;140:755–62. 5. Fukushima Y, Nakagawa H, Tamura M. Combined surgery, radiation, and chemotherapy for oligodendroglial gliomatosis cerebri. Br J Neurosurg 2004;18:306–10. 6. Armstrong GT, Phillips PC, Rorke-Adams LB, et al. Gliomatosis cerebri: 20 years of experience at the children’s hospital of Philadelphia. Cancer 2006;107:1597–606. 7. Bozeman LB, Sangiorigi L, Briare-de Bruijn IH, et al. Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C. Hum Mutat 2004;24:466–73. 8. Mellon CD, Carter JE, Owen DB. Ollier’s disease and Maffucci’s syndrome: distinct entities or a continuum. Case report: enchondromatosis complicated by an intracranial glioma. J Neurol 1988;235:376–8. 9. Silve C, Juppner H. Ollier disease: review. Orphanet J Rare Dis 2006;1:37. 10. Ranger A, Szymczk A, Hammond RR, et al. Pediatric thalamic glioblastoma associated with Ollier disease (multiple enchondromatosis): a rare case of concurrence. J Neurosurg Pediatr 2009;4:363–7. 11. Nevin S. Gliomatosis cerebri. Brain 1938;61:170–91. 12. Pyhtinen J, Paakko E. A difficult diagnosis of gliomatosis cerebri. Neuroradiology 1996;38:444–8. 13. Elshaikh MA, Stevens GHJ, Peereboom DM, et al. Gliomatosis cerebri: treatment results with radiotherapy alone. Cancer 2002;95:2027–31. 14. Sanson M, Cartalat-Carel S, Taillibert S, et al. Initial chemotherapy in gliomatosis cerebri. Neurology 2004;63:270–5. 15. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90:1473–9. 16. Cervos-Navarro J, Artigas J, Aruffo C, et al. The fine structure of gliomatosis cerebri. Virchows Arch A Pathol Anat Histopathol 1987;411:93–8.