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Glioblastoma multiforme at the corpus callosum with spinal leptomeningeal metastasis
Clinical Neurology and Neurosurgery 113 (2011) 407–410
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Glioblastoma multiforme at the corpus callosum with spinal leptomeningeal metastasis Pirada Witoonpanich a , Krittika Bamrungrak a , Artit Jinawath b , Sansanee Wongwaisayawan b , Suchart Phudhichareonrat b , Rawiphan Witoonpanich a,∗ a b
Division of Neurology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
a r t i c l e
i n f o
Article history: Received 10 October 2009 Received in revised form 27 November 2010 Accepted 3 December 2010 Available online 3 January 2011 Keywords: Glioblastoma multiforme Corpus callosum Mirror movement Diagonistic dyspraxia Spinal leptomeningeal metastasis Autopsy
a b s t r a c t Glioblastoma multiforme (GBM) often occurs in the supratentorial white matter including corpus callosum. However, spinal leptomeningeal metastasis in cases of supratentorial GBM has been reported to be rare and there is usually a long interval between the cerebral lesion and the spinal seeding. We report here a case of GBM at the corpus callosum and other parts of the brain with simultaneous manifestation of spinal leptomeningeal seeding. The patient exhibited an abnormal motor behavior of the left hand as mirror movement when the right hand was performing a unimanual task (diagonistic dyspraxia) which is a sign of lesion of the posterior part and splenium of the corpus callosum. There were also signs of peripheral nerve or nerve root involvement suggestive of spinal metastasis without any sensory symptoms. He died 3 months after the onset of the symptoms confirming the poor prognosis and short survival time in cases with spinal leptomeningeal metastasis reported previously. The cerebral GBM with spinal seeding was disclosed at autopsy. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in adult. It can occur at any time with a mean age of 62 years at first diagnosis [1]. GBM often occurs in the supratentorial white matter including corpus callosum. However, spinal leptomeningeal metastasis in cases of supratentorial GBM has been reported to be rare and there is usually a long interval between the cerebral lesion and the spinal seeding. We report here a case of intracranial GBM with simultaneous manifestation of spinal leptomeningeal seeding. 2. Case report A 64-year-old right-handed man presented with difficulty of walking and poor memory for two months. One month later, his walking got worse and it was noted that his legs were weak. He became forgetful and could not remember recent events but could still carry on his activities of daily living. The weakness of the legs
∗ Corresponding author at: Division of Neurology, Department of Medicine, Ramathibodi Hospital, Rama 6 Road, Bangkok 10400, Thailand. Tel.: +66 81 4454755; fax: +66 2 3547233. E-mail addresses: [email protected], [email protected] (R. Witoonpanich). 0303-8467/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2010.12.001
gradually deteriorated until he could not walk unaided. A few days prior to admission, he also complained of dull aching headache in the occipital region. He also had underlying diabetes mellitus type 2, hypertension and dyslipidemia. On examination, he had low grade fever (T. 37.5 ◦ C), moderate hypertension (B.P. 190/100 mmHg), tachypnea (R.R. 28/min) and tachycardia (H.R. 120/min). The general examination was unremarkable except for the presence of one 1.5 cm lymph node at the right groin and 0.5–1.0 cm in chain at the left groin. The neurological examination showed that he was conscious and coherent but responded slowly to questioning and command. There was impairment of recent memory. His speech was nonfluent but naming and repetition were normal. He had stiffness of the neck. Both optic fundi were invisible because of dense cataracts. There were mild right ptosis with normal pupils and bilateral lateral rectus paresis. Other cranial nerves were normal. The muscle tone was increased in all extremities with bilateral cogwheel rigidity. There were mild weakness of both deltoid muscles, generalized wasting of muscles of both legs and mild pyramidal weakness of both legs. The deep tendon reflexes (DTR) were all absent except for the knee jerks which were depressed. The plantar response was flexor bilaterally. The pinprick and joint position sensation was normal. There were no frontal lobe signs, sensory inattention, alexia, agraphia nor right–left disorientation. The finger to nose test was impaired bilaterally. An abnormal motor behavior of the left hand was observed
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P. Witoonpanich et al. / Clinical Neurology and Neurosurgery 113 (2011) 407–410
Fig. 1. MRI of the brain showing hypointense signal T1W/hyperintense signal T2W butterfly-like lesion involving posterior body and splenium of the corpus callosum and deep white matter of both parietal lobes (A. axial T1W, B. axial FLAIR, and D. coronal T2W). Heterogeneous enhancement with gadolinium at posterior body and splenium of the corpus callosum is also shown (C. axial T1W with gadolinium).
during the finger to nose test. Whenever the right hand was doing this test on command, the left hand would also try to do the same, thus interfering with the task of the right hand. Clinically, he was mentally slow with the presence of mixed upper and lower motor neuron signs. Moreover, he had low grade fever and neck stiffness suggestive of meningeal irritation possibly from infection or malignancy. From the initial investigation, the complete blood count showed leucocytosis of 17.9 × 103 /ml with 67% polymorphs, 19% lymphocytes, 11% monocytes and 1% eosinophils. Serum creatinine, electrolytes, liver function test and lactic dehydrogenase were within normal limits. The serum anti-HIV test was negative. Lumbar puncture revealed clear cerebrospinal fluid (CSF) with an opening pressure of 23 mmH2 O, mononuclear pleocytosis; 19 cells/L with 94% mononuclear and 6% polymorphonuclear cells, high protein; 159 mg/dL and low glucose levels; 18 mg/dL (blood glucose 180 mg/dL). Gram stain, India ink preparation and aerobic culture showed no organism. Polymerase chain reaction of mycobacterium tuberculosis and cryptococcal antigen were negative. Lumbar puncture was repeated twice over the course of 2 admissions, in view of the fact that he had had low grade fever, high CSF protein and low CSF glucose, in the hope to obtain more information of an infectious or malignant process. However, there was no evidence of an infection and the cytology showed no malignant cells on all 3 occasions. Computerized tomography of the whole abdomen was unremarkable. Magnetic resonance imaging (MRI) of the brain showed an enhanced butterfly-like lesion of the corpus callosum suggestive of a malignant tumor rather than a demyelinating lesion (Fig. 1). The clinical diagnosis was a malignant tumor at the corpus callosum and other parts of the brain with leptomeningeal involvement. One week after admission, the low grade fever persisted and he
became worse both mentally and physically. His arms and legs became weaker than before with the left extremities being weaker than the right and just being able to be lifted up from the bed. He was treated with antibiotics for aspiration pneumonia. Biopsy of a lymph node at the right groin showed no granuloma nor malignancy. Biopsy of the callosal lesion was planned. However, his condition continued to deteriorate and he died 3 months after the onset of the symptoms. Autopsy showed an ill-defined soft pinkish tan lesion involving the body and splenium of the corpus callosum (Fig. 2). The spinal cord showed irregular thick whitish tan meningeal surface (Fig. 3). Microscopic findings of both the cerebral and spinal lesion consisted of highly cellular anaplastic glial cells, microvascular proliferation and necrosis with pseudopalisading of tumor cells, characteristic of GBM (Fig. 4). 3. Discussion From the clinical point of view, this is a patient who presented with memory impairment and weakness of both legs for 2 months. He showed mental slowing from cognitive decline and a combination of upper and lower motor neuron signs in the extremities. He also demonstrated abnormal motor behavior of the left hand dissociated from conscious volition performed by the right hand. The simultaneous and mirror movement of the left hand to the right is known as diagonistic dyspraxia seen in the lesion of the posterior body and splenium of the corpus callosum. This dissociative behavior of the left hand is produced by a failure in the transfer of inhibitory motor control information from the left hemisphere to the right during the tasks requiring the left hemispheric volitional motor control [2]. From the MRI findings and the clinical features,
P. Witoonpanich et al. / Clinical Neurology and Neurosurgery 113 (2011) 407–410
Fig. 2. Macroscopic appearance of the corpus callosal lesion showing an ill-defined soft pinkish tan tumor with extension to the wall of lateral ventricle (arrows).
Fig. 3. A section of spinal cord with leptomeningeal seeding. Note the irregular thick whitish tan meningeal surface (arrows).
409
an infiltrative tumor was considered most likely. The diagnosis of GBM was made at autopsy. GBM often occurs in the supratentorial white matter including the corpus callosum. This aggressive tumor spreads via direct extension along white matter tracts. In this case, malignant leptomeningeal involvement was considered from the CSF findings of mononuclear pleocytosis and high protein and low glucose levels although no malignant cells were seen from the cytology. CSF cytology has been reported to give false negative results in tumor CSF dissemination [3–5]. Bilateral abducens nerve paresis might have been due to the leptomeningeal infiltration or increased intracranial pressure. CSF dissemination occurs in 15–25% of cases of supratentorial GBM [6,7] with a higher incidence of up to 60% in infratentorial cases [8]. The generalized wasting of muscles of both legs and depressed DTR in this patient could have been due to radiculopathy from spinal leptomeningeal seeding although he did not complain of numbness nor radicular pain. GBM is highly malignant with a tendency for intracranial spread but extracranial or spinal metastasis is rare. In one study of 600 patients with supratentorial glioblastoma, the incidence of symptomatic metastasis was only 2% and the mean time interval between the diagnosis of intracranial tumor and the diagnosis of metastasis was 14.1 months suggesting that the leptomeningeal seeding is rather rare and occurs relatively late in the course of GBM [9]. In contrast, the timings of cerebral and spinal manifestations in this case were unusually close. GBM with early leptomeningeal metastasis has seldom been reported previously [10]. The clinical diagnosis of spinal leptomeningeal metastasis of GBM is usually difficult but may be possible with awareness and careful neurological examination looking for radicular signs even in patients who are asymptomatic. It has been suggested that the lack of signs of leptomeningeal metastasis is because tumor cells infiltrate between nerve roots rather than destroy them [8]. Once destruction has occurred, it becomes symptomatic and the signs are permanent [9]. Spinal MRI with gadolinium enhancement is the best investigation for leptomeningeal metastasis [11] However, this was not done in this patient because his signs of radicular involvement were so subtle that they were overlooked and the diagnosis of GBM was not established at the time. MRI of the spinal cord should be considered in the presence of clinical and/or electrophysiological signs of spinal or radicular involvement keeping in mind that the leptomeningeal metastasis may occur quite soon after the diagnosis of the cerebral tumor. There has not been effective treatment for this condition so far and the patients usually died shortly after the diagnosis of the distant metastasis. The median survival time of intracranial GBM is 11–17 months and the average time interval between diagnosis of leptomeningeal metastasis and death is 2–3 months [5,9]. Systemic
Fig. 4. A. Histopathology of the corpus callosal lesion showing highly cellular anaplastic tumor cells, microvascular proliferation and pseudopalisading necrosis (hematoxylin–eosin, ×200). B. Histopathology of the spinal cord showing malignant seeding in the leptomeningeal space (hematoxylin–eosin, ×100).
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P. Witoonpanich et al. / Clinical Neurology and Neurosurgery 113 (2011) 407–410
chemotherapy, radiotherapy, intraventricular chemotherapy or the combination of all these treatment modalities have not improved survival nor restored neurological function [12,13]. Radiotherapy may be used for the control of intractable pain. There is a need for the development of more effective agents to treat this aggressive tumor. The prognosis for patients who have developed symptomatic dissemination of the intracranial tumor is poor with an average of survival time of 2.8 months after the diagnosis of dissemination [9]. Our patient died 3 months after the onset of the cerebral and spinal manifestations. In recent years, there have been a number of studies on the molecular genetics of glioblastoma. As a result, a variety of chromosome aberrations, amplification of oncogenes, and deletions and mutations of tumor suppressor genes have been identified [14–16]. It is believed that there are some differences in the molecular genetics between metastatic and non-metastatic glioblastoma. Therefore, attempt has been made to study the potential value of molecular biology to identify those tumors with a higher risk of craniospinal seeding. A recent study demonstrated that disseminated tumors tended to harbor numerous gains at the 1p36 chromosomal region. The authors suggested that an analysis of 1p copy number status might be an additional tool for further predicting the clinical course of glioblastoma. Nevertheless, further studies are required to confirm or rule out this clinicopathological association [17]. References [1] Surawicz TS, McCarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG. Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990–1994. Neuro Oncol 1999;1:14–25.
[2] Tanaka Y, Yoshida A, Kawahata N, Hashimoto R, Obayashi T. Diagonistic dyspraxia. Clinical characteristics, responsible lesion and possible underlying mechanism. Brain 1996;119:859–73. [3] Balhuizen JC, Bots GT, Schaberg A, Bosman FT. Value of cerebrospinal fluid cytology for the diagnosis of malignancies in the central nervous system. J Neurosurg 1978;48:747–53. [4] Packer RJ, Allen J, Nielsen S, Petito C, Deck M, Jereb B. Brainstem glioma: clinical manifestation of meningeal gliomatosis. Ann Neurol 1983;14:177–82. [5] Grabb PA, Albright AL, Pang D. Dissemination of supratentorial malignant glioma via the cerebrospinal fluid in children. Neurosurgery 1992;30:64–71. [6] Erlich SS, Davis RL. Spinal subarachnoid metastasis from primary intracranial glioblastoma multiforme. Cancer 1978;42:2854–64. [7] Arita N, Taneda M, Hayakawa T. Leptomeningeal dissemination of malignant gliomas. Incidence, diagnosis and outcome. Acta Neurochir (Wien) 1994;126:84–92. [8] Salazar OM, Rubin P. The spread of glioblastoma multiforme as a determining factor in the radiation treated volume. Int J Radiat Oncol Biol Phys 1976;1:627–37. [9] Vertosick Jr FT, Selker RG. Brain stem and spinal metastases of supratentorial glioblastoma multiforme: a clinical series. Neurosurgery 1990;27:516–21. [10] Pohar S, Taylor W, Chandan V, Shah H, Sagerman RH. Primary presentation of glioblastoma multiforme with leptomeningeal metastasis in the absence of previous craniotomy. Am J Clin Oncol 2004;27:640–1. [11] Heinz R, Wiener D, Friedman H, Tien R. Detection of cerebrospinal fluid, metastasis: CT myelography or MR? AJNR Am J Neuroradiol 1995;16:1147–51. [12] Saito R, Kumabe T, Jokura H, Shirane R, Yoshimoto T. Symptomatic spinal, dissemination of malignant astrocytoma. J Neurooncol 2003;61:227–35. [13] Chamberlain MC. Combined-modality treatment of leptomeningeal gliomatosis. Neurosurgery 2003;52:324–9. [14] Kleihues P, Cavenee WK. Pathology and genetics of tumour of the nervous system. World Health Organization Classification of Tumours. Lyon, France: IARC Press; 2000. [15] Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004;64:6892–9. [16] Louis D, Ohgaki H, Wiestler O, Cavenee W, Burger P, Jouvet A, et al. The 2007, WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97–109. [17] Korshunov A, Sycheva R, Golanov A, Pronin I. Gains at the 1p36 chromosomal region are associated with symptomatic leptomeningeal dissemination of supratentorial glioblastomas. Am J Clin Pathol 2007;127:585–90.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Glioblastoma multiforme at the corpus callosum with spinal leptomeningeal metastasis Pirada Witoonpanich a , Krittika Bamrungrak a , Artit Jinawath b , Sansanee Wongwaisayawan b , Suchart Phudhichareonrat b , Rawiphan Witoonpanich a,∗ a b
Division of Neurology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
a r t i c l e
i n f o
Article history: Received 10 October 2009 Received in revised form 27 November 2010 Accepted 3 December 2010 Available online 3 January 2011 Keywords: Glioblastoma multiforme Corpus callosum Mirror movement Diagonistic dyspraxia Spinal leptomeningeal metastasis Autopsy
a b s t r a c t Glioblastoma multiforme (GBM) often occurs in the supratentorial white matter including corpus callosum. However, spinal leptomeningeal metastasis in cases of supratentorial GBM has been reported to be rare and there is usually a long interval between the cerebral lesion and the spinal seeding. We report here a case of GBM at the corpus callosum and other parts of the brain with simultaneous manifestation of spinal leptomeningeal seeding. The patient exhibited an abnormal motor behavior of the left hand as mirror movement when the right hand was performing a unimanual task (diagonistic dyspraxia) which is a sign of lesion of the posterior part and splenium of the corpus callosum. There were also signs of peripheral nerve or nerve root involvement suggestive of spinal metastasis without any sensory symptoms. He died 3 months after the onset of the symptoms confirming the poor prognosis and short survival time in cases with spinal leptomeningeal metastasis reported previously. The cerebral GBM with spinal seeding was disclosed at autopsy. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in adult. It can occur at any time with a mean age of 62 years at first diagnosis [1]. GBM often occurs in the supratentorial white matter including corpus callosum. However, spinal leptomeningeal metastasis in cases of supratentorial GBM has been reported to be rare and there is usually a long interval between the cerebral lesion and the spinal seeding. We report here a case of intracranial GBM with simultaneous manifestation of spinal leptomeningeal seeding. 2. Case report A 64-year-old right-handed man presented with difficulty of walking and poor memory for two months. One month later, his walking got worse and it was noted that his legs were weak. He became forgetful and could not remember recent events but could still carry on his activities of daily living. The weakness of the legs
∗ Corresponding author at: Division of Neurology, Department of Medicine, Ramathibodi Hospital, Rama 6 Road, Bangkok 10400, Thailand. Tel.: +66 81 4454755; fax: +66 2 3547233. E-mail addresses: [email protected], [email protected] (R. Witoonpanich). 0303-8467/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2010.12.001
gradually deteriorated until he could not walk unaided. A few days prior to admission, he also complained of dull aching headache in the occipital region. He also had underlying diabetes mellitus type 2, hypertension and dyslipidemia. On examination, he had low grade fever (T. 37.5 ◦ C), moderate hypertension (B.P. 190/100 mmHg), tachypnea (R.R. 28/min) and tachycardia (H.R. 120/min). The general examination was unremarkable except for the presence of one 1.5 cm lymph node at the right groin and 0.5–1.0 cm in chain at the left groin. The neurological examination showed that he was conscious and coherent but responded slowly to questioning and command. There was impairment of recent memory. His speech was nonfluent but naming and repetition were normal. He had stiffness of the neck. Both optic fundi were invisible because of dense cataracts. There were mild right ptosis with normal pupils and bilateral lateral rectus paresis. Other cranial nerves were normal. The muscle tone was increased in all extremities with bilateral cogwheel rigidity. There were mild weakness of both deltoid muscles, generalized wasting of muscles of both legs and mild pyramidal weakness of both legs. The deep tendon reflexes (DTR) were all absent except for the knee jerks which were depressed. The plantar response was flexor bilaterally. The pinprick and joint position sensation was normal. There were no frontal lobe signs, sensory inattention, alexia, agraphia nor right–left disorientation. The finger to nose test was impaired bilaterally. An abnormal motor behavior of the left hand was observed
408
P. Witoonpanich et al. / Clinical Neurology and Neurosurgery 113 (2011) 407–410
Fig. 1. MRI of the brain showing hypointense signal T1W/hyperintense signal T2W butterfly-like lesion involving posterior body and splenium of the corpus callosum and deep white matter of both parietal lobes (A. axial T1W, B. axial FLAIR, and D. coronal T2W). Heterogeneous enhancement with gadolinium at posterior body and splenium of the corpus callosum is also shown (C. axial T1W with gadolinium).
during the finger to nose test. Whenever the right hand was doing this test on command, the left hand would also try to do the same, thus interfering with the task of the right hand. Clinically, he was mentally slow with the presence of mixed upper and lower motor neuron signs. Moreover, he had low grade fever and neck stiffness suggestive of meningeal irritation possibly from infection or malignancy. From the initial investigation, the complete blood count showed leucocytosis of 17.9 × 103 /ml with 67% polymorphs, 19% lymphocytes, 11% monocytes and 1% eosinophils. Serum creatinine, electrolytes, liver function test and lactic dehydrogenase were within normal limits. The serum anti-HIV test was negative. Lumbar puncture revealed clear cerebrospinal fluid (CSF) with an opening pressure of 23 mmH2 O, mononuclear pleocytosis; 19 cells/L with 94% mononuclear and 6% polymorphonuclear cells, high protein; 159 mg/dL and low glucose levels; 18 mg/dL (blood glucose 180 mg/dL). Gram stain, India ink preparation and aerobic culture showed no organism. Polymerase chain reaction of mycobacterium tuberculosis and cryptococcal antigen were negative. Lumbar puncture was repeated twice over the course of 2 admissions, in view of the fact that he had had low grade fever, high CSF protein and low CSF glucose, in the hope to obtain more information of an infectious or malignant process. However, there was no evidence of an infection and the cytology showed no malignant cells on all 3 occasions. Computerized tomography of the whole abdomen was unremarkable. Magnetic resonance imaging (MRI) of the brain showed an enhanced butterfly-like lesion of the corpus callosum suggestive of a malignant tumor rather than a demyelinating lesion (Fig. 1). The clinical diagnosis was a malignant tumor at the corpus callosum and other parts of the brain with leptomeningeal involvement. One week after admission, the low grade fever persisted and he
became worse both mentally and physically. His arms and legs became weaker than before with the left extremities being weaker than the right and just being able to be lifted up from the bed. He was treated with antibiotics for aspiration pneumonia. Biopsy of a lymph node at the right groin showed no granuloma nor malignancy. Biopsy of the callosal lesion was planned. However, his condition continued to deteriorate and he died 3 months after the onset of the symptoms. Autopsy showed an ill-defined soft pinkish tan lesion involving the body and splenium of the corpus callosum (Fig. 2). The spinal cord showed irregular thick whitish tan meningeal surface (Fig. 3). Microscopic findings of both the cerebral and spinal lesion consisted of highly cellular anaplastic glial cells, microvascular proliferation and necrosis with pseudopalisading of tumor cells, characteristic of GBM (Fig. 4). 3. Discussion From the clinical point of view, this is a patient who presented with memory impairment and weakness of both legs for 2 months. He showed mental slowing from cognitive decline and a combination of upper and lower motor neuron signs in the extremities. He also demonstrated abnormal motor behavior of the left hand dissociated from conscious volition performed by the right hand. The simultaneous and mirror movement of the left hand to the right is known as diagonistic dyspraxia seen in the lesion of the posterior body and splenium of the corpus callosum. This dissociative behavior of the left hand is produced by a failure in the transfer of inhibitory motor control information from the left hemisphere to the right during the tasks requiring the left hemispheric volitional motor control [2]. From the MRI findings and the clinical features,
P. Witoonpanich et al. / Clinical Neurology and Neurosurgery 113 (2011) 407–410
Fig. 2. Macroscopic appearance of the corpus callosal lesion showing an ill-defined soft pinkish tan tumor with extension to the wall of lateral ventricle (arrows).
Fig. 3. A section of spinal cord with leptomeningeal seeding. Note the irregular thick whitish tan meningeal surface (arrows).
409
an infiltrative tumor was considered most likely. The diagnosis of GBM was made at autopsy. GBM often occurs in the supratentorial white matter including the corpus callosum. This aggressive tumor spreads via direct extension along white matter tracts. In this case, malignant leptomeningeal involvement was considered from the CSF findings of mononuclear pleocytosis and high protein and low glucose levels although no malignant cells were seen from the cytology. CSF cytology has been reported to give false negative results in tumor CSF dissemination [3–5]. Bilateral abducens nerve paresis might have been due to the leptomeningeal infiltration or increased intracranial pressure. CSF dissemination occurs in 15–25% of cases of supratentorial GBM [6,7] with a higher incidence of up to 60% in infratentorial cases [8]. The generalized wasting of muscles of both legs and depressed DTR in this patient could have been due to radiculopathy from spinal leptomeningeal seeding although he did not complain of numbness nor radicular pain. GBM is highly malignant with a tendency for intracranial spread but extracranial or spinal metastasis is rare. In one study of 600 patients with supratentorial glioblastoma, the incidence of symptomatic metastasis was only 2% and the mean time interval between the diagnosis of intracranial tumor and the diagnosis of metastasis was 14.1 months suggesting that the leptomeningeal seeding is rather rare and occurs relatively late in the course of GBM [9]. In contrast, the timings of cerebral and spinal manifestations in this case were unusually close. GBM with early leptomeningeal metastasis has seldom been reported previously [10]. The clinical diagnosis of spinal leptomeningeal metastasis of GBM is usually difficult but may be possible with awareness and careful neurological examination looking for radicular signs even in patients who are asymptomatic. It has been suggested that the lack of signs of leptomeningeal metastasis is because tumor cells infiltrate between nerve roots rather than destroy them [8]. Once destruction has occurred, it becomes symptomatic and the signs are permanent [9]. Spinal MRI with gadolinium enhancement is the best investigation for leptomeningeal metastasis [11] However, this was not done in this patient because his signs of radicular involvement were so subtle that they were overlooked and the diagnosis of GBM was not established at the time. MRI of the spinal cord should be considered in the presence of clinical and/or electrophysiological signs of spinal or radicular involvement keeping in mind that the leptomeningeal metastasis may occur quite soon after the diagnosis of the cerebral tumor. There has not been effective treatment for this condition so far and the patients usually died shortly after the diagnosis of the distant metastasis. The median survival time of intracranial GBM is 11–17 months and the average time interval between diagnosis of leptomeningeal metastasis and death is 2–3 months [5,9]. Systemic
Fig. 4. A. Histopathology of the corpus callosal lesion showing highly cellular anaplastic tumor cells, microvascular proliferation and pseudopalisading necrosis (hematoxylin–eosin, ×200). B. Histopathology of the spinal cord showing malignant seeding in the leptomeningeal space (hematoxylin–eosin, ×100).
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P. Witoonpanich et al. / Clinical Neurology and Neurosurgery 113 (2011) 407–410
chemotherapy, radiotherapy, intraventricular chemotherapy or the combination of all these treatment modalities have not improved survival nor restored neurological function [12,13]. Radiotherapy may be used for the control of intractable pain. There is a need for the development of more effective agents to treat this aggressive tumor. The prognosis for patients who have developed symptomatic dissemination of the intracranial tumor is poor with an average of survival time of 2.8 months after the diagnosis of dissemination [9]. Our patient died 3 months after the onset of the cerebral and spinal manifestations. In recent years, there have been a number of studies on the molecular genetics of glioblastoma. As a result, a variety of chromosome aberrations, amplification of oncogenes, and deletions and mutations of tumor suppressor genes have been identified [14–16]. It is believed that there are some differences in the molecular genetics between metastatic and non-metastatic glioblastoma. Therefore, attempt has been made to study the potential value of molecular biology to identify those tumors with a higher risk of craniospinal seeding. A recent study demonstrated that disseminated tumors tended to harbor numerous gains at the 1p36 chromosomal region. The authors suggested that an analysis of 1p copy number status might be an additional tool for further predicting the clinical course of glioblastoma. Nevertheless, further studies are required to confirm or rule out this clinicopathological association [17]. References [1] Surawicz TS, McCarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG. Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990–1994. Neuro Oncol 1999;1:14–25.
[2] Tanaka Y, Yoshida A, Kawahata N, Hashimoto R, Obayashi T. Diagonistic dyspraxia. Clinical characteristics, responsible lesion and possible underlying mechanism. Brain 1996;119:859–73. [3] Balhuizen JC, Bots GT, Schaberg A, Bosman FT. Value of cerebrospinal fluid cytology for the diagnosis of malignancies in the central nervous system. J Neurosurg 1978;48:747–53. [4] Packer RJ, Allen J, Nielsen S, Petito C, Deck M, Jereb B. Brainstem glioma: clinical manifestation of meningeal gliomatosis. Ann Neurol 1983;14:177–82. [5] Grabb PA, Albright AL, Pang D. Dissemination of supratentorial malignant glioma via the cerebrospinal fluid in children. Neurosurgery 1992;30:64–71. [6] Erlich SS, Davis RL. Spinal subarachnoid metastasis from primary intracranial glioblastoma multiforme. Cancer 1978;42:2854–64. [7] Arita N, Taneda M, Hayakawa T. Leptomeningeal dissemination of malignant gliomas. Incidence, diagnosis and outcome. Acta Neurochir (Wien) 1994;126:84–92. [8] Salazar OM, Rubin P. The spread of glioblastoma multiforme as a determining factor in the radiation treated volume. Int J Radiat Oncol Biol Phys 1976;1:627–37. [9] Vertosick Jr FT, Selker RG. Brain stem and spinal metastases of supratentorial glioblastoma multiforme: a clinical series. Neurosurgery 1990;27:516–21. [10] Pohar S, Taylor W, Chandan V, Shah H, Sagerman RH. Primary presentation of glioblastoma multiforme with leptomeningeal metastasis in the absence of previous craniotomy. Am J Clin Oncol 2004;27:640–1. [11] Heinz R, Wiener D, Friedman H, Tien R. Detection of cerebrospinal fluid, metastasis: CT myelography or MR? AJNR Am J Neuroradiol 1995;16:1147–51. [12] Saito R, Kumabe T, Jokura H, Shirane R, Yoshimoto T. Symptomatic spinal, dissemination of malignant astrocytoma. J Neurooncol 2003;61:227–35. [13] Chamberlain MC. Combined-modality treatment of leptomeningeal gliomatosis. Neurosurgery 2003;52:324–9. [14] Kleihues P, Cavenee WK. Pathology and genetics of tumour of the nervous system. World Health Organization Classification of Tumours. Lyon, France: IARC Press; 2000. [15] Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004;64:6892–9. [16] Louis D, Ohgaki H, Wiestler O, Cavenee W, Burger P, Jouvet A, et al. The 2007, WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97–109. [17] Korshunov A, Sycheva R, Golanov A, Pronin I. Gains at the 1p36 chromosomal region are associated with symptomatic leptomeningeal dissemination of supratentorial glioblastomas. Am J Clin Pathol 2007;127:585–90.