DOI: 10.1148/rg.231025113
(Radiographics. 2003;23:247-253.)
© RSNA, 2003
AFIP Archives
Gliomatosis Cerebri Affecting the Entire Neuraxis1
Melissa Yip, MD,
Christiane Fisch, MD and
Jacques B. Lamarche, MD
1 From the Department of Radiology, Centre Hospitalier Universitaire de Sherbrooke, 3001 N 12th Ave, Sherbrooke, Quebec, Canada J1H 5N4. Received June 18, 2002; revision requested August 9 and received September 17; accepted September 18. Address correspondence to M.Y. (e-mail: mel_yip@hotmail.com).
Index Terms: Brain neoplasms, in infants and children, 10.3639
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History
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A 7-year-old girl presented with a 10-day history of progressive headaches, nausea, and vomiting. The patient’s earlier medical history was noncontributory. Visual examination revealed blindness and areactive mydriasis of the left eye with bilateral sixth cranial nerve paresis. The remaining physical examination findings were within normal limits. Ophthalmologic examination showed bilateral severe papilledema that was worse on the left side. Laboratory findings were normal. Lumbar puncture was performed; the opening pressure was above 6 cm H2O, but the cerebrospinal fluid (CSF) was normal for cell count and for glucose and protein content. The presumed diagnosis was pseudotumor cerebri with secondary bilateral optic neuropathy. Magnetic resonance (MR) imaging revealed an optic nerve tumor as well as signal intensity anomalies in the brainstem, cerebellum, and cerebral hemispheres. After initial improvement from steroid therapy, the patient’s symptoms worsened. Biopsy of the left optic nerve was performed at a pediatric referral hospital. Pathologic findings were said to be compatible with an anaplastic astrocytoma. The patient underwent radiation therapy directed at the optic tracts (45 Gy in 25 fractions) as well as experimental treatment for optic glioma with intraarterial carboplatin in the territory of the left internal carotid artery, both of which yielded clinical and radiologic improvement. Thirteen months later, the patient’s headaches recurred, and she abruptly fell into a coma and died of respiratory insufficiency.
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Imaging Findings
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Initial computed tomography (CT) showed enlargement of the left optic nerve and slight enlargement of the left optic canal. MR imaging (0.2-T Magnetom Open imager; Siemens AG, Erlangen, Germany) demonstrated enhancement of the enlarged left optic nerve but no evidence of chiasmatic involvement. However, T2-weighted MR imaging revealed abnormal increased signal intensity bilaterally in the posterior fossa and periventricular frontal white matter. One month later, the optic nerve tumor had spread to the chiasm, where an enhancing cystic component had formed. Positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) demonstrated slightly increased left retro-ocular radiotracer uptake and decreased uptake in the occipital lobes that was more prominent on the left side. The decreased uptake was believed to be due to functional disconnection of the gray matter caused by neoplastic invasion of the left optic nerve and left optic tract. T2-weighted MR images of the spinal cord obtained 5 months after presentation showed subtle, heterogeneous increased signal intensity from the distal thoracic cord to the conus medullaris without T1 anomalies or mass effect.
Repeat MR imaging performed 13 months after presentation revealed an unchanged left optic nerve but an increase in the size and number of the mostly unenhanced confluent foci of abnormal signal intensity in the posterior fossa and supratentorial white matter (Figs 1, 2a, 2b). Some of these areas had markedly increased signal intensity on T2-weighted images. An enhancing mass now appeared in the brainstem (Fig 2c). The following day, the patient lost consciousness. CT demonstrated an acute brainstem hemorrhage at the site of the new enhancing mass noted at MR imaging. The patient died the same day.
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Figure 1a. (a) Axial T2-weighted MR image of the brain shows bilateral patchy areas of increased signal intensity in the periventricular white matter. (b) Axial T2-weighted MR image of the brain obtained at the level of the upper pons shows diffuse thickening and hyperintensity of the left optic nerve (*) and increased signal intensity in the posterior aspect of the pons and in the cerebellum (arrows). A focus of very high signal intensity is present in the posterior left cerebellar hemisphere (**). (c) Axial T2-weighted MR image of the brain obtained at the pontomedullary junction shows a 2-cm nodular focus of very high signal intensity with mass effect in the brainstem (*).
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Figure 1b. (a) Axial T2-weighted MR image of the brain shows bilateral patchy areas of increased signal intensity in the periventricular white matter. (b) Axial T2-weighted MR image of the brain obtained at the level of the upper pons shows diffuse thickening and hyperintensity of the left optic nerve (*) and increased signal intensity in the posterior aspect of the pons and in the cerebellum (arrows). A focus of very high signal intensity is present in the posterior left cerebellar hemisphere (**). (c) Axial T2-weighted MR image of the brain obtained at the pontomedullary junction shows a 2-cm nodular focus of very high signal intensity with mass effect in the brainstem (*).
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Figure 1c. (a) Axial T2-weighted MR image of the brain shows bilateral patchy areas of increased signal intensity in the periventricular white matter. (b) Axial T2-weighted MR image of the brain obtained at the level of the upper pons shows diffuse thickening and hyperintensity of the left optic nerve (*) and increased signal intensity in the posterior aspect of the pons and in the cerebellum (arrows). A focus of very high signal intensity is present in the posterior left cerebellar hemisphere (**). (c) Axial T2-weighted MR image of the brain obtained at the pontomedullary junction shows a 2-cm nodular focus of very high signal intensity with mass effect in the brainstem (*).
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Figure 2a. (a) Coronal contrast material-enhanced T1-weighted MR image shows a rounded area of decreased signal intensity in the right frontal centrum semiovale (*) and an ill-defined enhancing area in the contralateral centrum semiovale (arrow). (b) Coronal contrast-enhanced T1-weighted MR image demonstrates decreased signal intensity and mass effect in the body of the corpus callosum, causing deformation of the lateral ventricles (*). A cystic lesion is also noted in the left side of the chiasm (arrow). (c) Sagittal contrast-enhanced T1-weighted MR image shows an enhancing mass in the anterior lower pons and upper medulla (*). Note the nonenhancing low-signal-intensity lesions in the body of the corpus callosum (arrows).
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Figure 2b. (a) Coronal contrast material-enhanced T1-weighted MR image shows a rounded area of decreased signal intensity in the right frontal centrum semiovale (*) and an ill-defined enhancing area in the contralateral centrum semiovale (arrow). (b) Coronal contrast-enhanced T1-weighted MR image demonstrates decreased signal intensity and mass effect in the body of the corpus callosum, causing deformation of the lateral ventricles (*). A cystic lesion is also noted in the left side of the chiasm (arrow). (c) Sagittal contrast-enhanced T1-weighted MR image shows an enhancing mass in the anterior lower pons and upper medulla (*). Note the nonenhancing low-signal-intensity lesions in the body of the corpus callosum (arrows).
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Figure 2c. (a) Coronal contrast material-enhanced T1-weighted MR image shows a rounded area of decreased signal intensity in the right frontal centrum semiovale (*) and an ill-defined enhancing area in the contralateral centrum semiovale (arrow). (b) Coronal contrast-enhanced T1-weighted MR image demonstrates decreased signal intensity and mass effect in the body of the corpus callosum, causing deformation of the lateral ventricles (*). A cystic lesion is also noted in the left side of the chiasm (arrow). (c) Sagittal contrast-enhanced T1-weighted MR image shows an enhancing mass in the anterior lower pons and upper medulla (*). Note the nonenhancing low-signal-intensity lesions in the body of the corpus callosum (arrows).
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Pathologic Evaluation
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Autopsy was performed and included analysis of the entire neuraxis and optic globes. Gross pathologic evaluation of the brainstem revealed that the optic nerves were infiltrated, as were the chiasm and left optic tract. There was diffuse swelling of the brainstem and hemorrhage at the pontomedullary junction with leptomeningeal contamination (Fig 3a). A 1-cm nonhemorrhagic nodule was found in the midpons (Fig 3b). Diffuse slight enlargement and discoloration were noted in the middle cerebellar peduncles, dentate nuclei, midbrain, and white matter of the cerebral hemispheres (Fig 3b–3d). Loss of differentiation between the basal ganglia and surrounding structures was noted. The corpus callosum and fornix demonstrated diffuse enlargement that caused compression of the ventricles (Fig 3c).
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Figure 3a. (a) On a photograph (anterior view) of the fixed brainstem and base of the brain, the optic nerves are rounded and the left nerve and chiasm are enlarged (arrow). The left brainstem is also enlarged. Leptomeningeal hemorrhage is noted at the pontomedullary junction (*). (b) Photograph of an axial section of the fixed brainstem shows a 1-cm brown nodule in the left lower pons (arrow). The dentate nuclei are ill defined. (c) On a photograph of a coronal section of the fixed brain, the corpus callosum and fornix are discolored and expanded, causing depression of the frontal horns of the lateral ventricles (*). Note the loss of differentiation between the basal ganglia and the internal capsule bilaterally, especially on the left side (arrow). (d) Photograph of a coronal section of the fixed brain shows heterogeneous discoloration of both centra semiovale. One of these foci corresponds to an area of decreased signal intensity (*) and the other to a focus of subtle enhancement (arrow) seen at T1-weighted MR imaging (cf Fig 2b).
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Figure 3b. (a) On a photograph (anterior view) of the fixed brainstem and base of the brain, the optic nerves are rounded and the left nerve and chiasm are enlarged (arrow). The left brainstem is also enlarged. Leptomeningeal hemorrhage is noted at the pontomedullary junction (*). (b) Photograph of an axial section of the fixed brainstem shows a 1-cm brown nodule in the left lower pons (arrow). The dentate nuclei are ill defined. (c) On a photograph of a coronal section of the fixed brain, the corpus callosum and fornix are discolored and expanded, causing depression of the frontal horns of the lateral ventricles (*). Note the loss of differentiation between the basal ganglia and the internal capsule bilaterally, especially on the left side (arrow). (d) Photograph of a coronal section of the fixed brain shows heterogeneous discoloration of both centra semiovale. One of these foci corresponds to an area of decreased signal intensity (*) and the other to a focus of subtle enhancement (arrow) seen at T1-weighted MR imaging (cf Fig 2b).
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Figure 3c. (a) On a photograph (anterior view) of the fixed brainstem and base of the brain, the optic nerves are rounded and the left nerve and chiasm are enlarged (arrow). The left brainstem is also enlarged. Leptomeningeal hemorrhage is noted at the pontomedullary junction (*). (b) Photograph of an axial section of the fixed brainstem shows a 1-cm brown nodule in the left lower pons (arrow). The dentate nuclei are ill defined. (c) On a photograph of a coronal section of the fixed brain, the corpus callosum and fornix are discolored and expanded, causing depression of the frontal horns of the lateral ventricles (*). Note the loss of differentiation between the basal ganglia and the internal capsule bilaterally, especially on the left side (arrow). (d) Photograph of a coronal section of the fixed brain shows heterogeneous discoloration of both centra semiovale. One of these foci corresponds to an area of decreased signal intensity (*) and the other to a focus of subtle enhancement (arrow) seen at T1-weighted MR imaging (cf Fig 2b).
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Figure 3d. (a) On a photograph (anterior view) of the fixed brainstem and base of the brain, the optic nerves are rounded and the left nerve and chiasm are enlarged (arrow). The left brainstem is also enlarged. Leptomeningeal hemorrhage is noted at the pontomedullary junction (*). (b) Photograph of an axial section of the fixed brainstem shows a 1-cm brown nodule in the left lower pons (arrow). The dentate nuclei are ill defined. (c) On a photograph of a coronal section of the fixed brain, the corpus callosum and fornix are discolored and expanded, causing depression of the frontal horns of the lateral ventricles (*). Note the loss of differentiation between the basal ganglia and the internal capsule bilaterally, especially on the left side (arrow). (d) Photograph of a coronal section of the fixed brain shows heterogeneous discoloration of both centra semiovale. One of these foci corresponds to an area of decreased signal intensity (*) and the other to a focus of subtle enhancement (arrow) seen at T1-weighted MR imaging (cf Fig 2b).
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Histologic findings were compatible with leptomeningeal and cerebral gliomatosis with multifocal and diffuse involvement of the brain, including the optic nerves and chiasm as well as the cerebellum, the brainstem, and the entire spinal cord. Intratumoral hemorrhage was noted at the pontomedullary junction (Fig 4).
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Figure 4a. (a) Photomicrograph (original magnification, x75; hematoxylin-eosin [H-E] stain) of a section of the left optic nerve shows a tumor with low cellular density composed of astrocytes with slightly pleomorphic spheric nuclei. (b) Photomicrograph (original magnification, x75; H-E stain) of a section of the lower pons shows a markedly cellular tumor composed of highly pleomorphic astrocytic cells. A few mitotic figures are also seen (arrows). (c) Low-power photomicrograph (original magnification, x15; H-E stain) shows a recent hemorrhage in a focus of anaplastic astrocytoma.
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Figure 4b. (a) Photomicrograph (original magnification, x75; hematoxylin-eosin [H-E] stain) of a section of the left optic nerve shows a tumor with low cellular density composed of astrocytes with slightly pleomorphic spheric nuclei. (b) Photomicrograph (original magnification, x75; H-E stain) of a section of the lower pons shows a markedly cellular tumor composed of highly pleomorphic astrocytic cells. A few mitotic figures are also seen (arrows). (c) Low-power photomicrograph (original magnification, x15; H-E stain) shows a recent hemorrhage in a focus of anaplastic astrocytoma.
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Figure 4c. (a) Photomicrograph (original magnification, x75; hematoxylin-eosin [H-E] stain) of a section of the left optic nerve shows a tumor with low cellular density composed of astrocytes with slightly pleomorphic spheric nuclei. (b) Photomicrograph (original magnification, x75; H-E stain) of a section of the lower pons shows a markedly cellular tumor composed of highly pleomorphic astrocytic cells. A few mitotic figures are also seen (arrows). (c) Low-power photomicrograph (original magnification, x15; H-E stain) shows a recent hemorrhage in a focus of anaplastic astrocytoma.
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Discussion
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According to the current World Health Organization classification system for brain tumors, gliomatosis cerebri is a distinct malignant neuroepithelial neoplasm of uncertain origin (1). Many authors postulate that gliomatosis cerebri is a glioma (2–5). By definition, gliomatosis cerebri is infiltrative, involving at least two lobes of the brain. It can be differentiated from multifocal gliomas based on a continuity of cellular infiltration and a lack of clear distinction from adjacent normal brain tissue (6). Its cell of origin and pathogenesis remain unclear, probably due in part to its rarity. Just over 200 cases of gliomatosis cerebri have been reported in the medical literature since 1938. Until the late 1980s, most cases were diagnosed postmortem. With the advent of MR imaging and improvement in biopsy techniques, antemortem diagnosis is now possible (3,7,8). Radiologists play a crucial role by suspecting the diagnosis, mapping tumor spread, and directing stereotactic biopsy.
Patients usually present between the 3rd and 5th decades of life, but cases have been described in patients of all ages, from neonates to the elderly (6,9). Both sexes are affected equally. Clinical findings are nonspecific and are characteristically mild in comparison with imaging findings (10,11). The most common symptoms are changes in mental status and personality, followed by headaches and seizures. Focal neurologic deficits appear late in the course of the disease. Papilledema is present in about 50% of patients but usually also occurs late (12). Laboratory studies are useful only for ruling out other diseases (3,9). In some cases of gliomatosis cerebri, an increase in CSF protein content has been reported (8).
Some pathologists believe that two types of gliomatosis cerebri exist (10). Type I is the classic form and consists of diffuse overgrowth with neoplastic glial elements but with no focal mass. Type II may stem from Type I and, in addition to being characterized by diffuse infiltration, manifests as a focal mass, usually a high-grade glioma. According to autopsy studies, the areas that are invaded include (in decreasing order of frequency) the cerebral hemispheres, midbrain, pons, thalamus, basal ganglia, cerebellum, medulla oblongata, and, in less than 10% of cases each, the hypothalamus, optic nerve and chiasm, and spinal cord (10). The corpus callosum may also be involved in up to 50% of cases (6). In the cerebral hemispheres, the white matter is always invaded, whereas the cortex is involved in only 19% of cases and leptomeninges in 17% (10). Compared with macroscopic inspection or MR imaging, histologic analysis shows a more extensive and diffuse lesion that infiltrates affected areas of the brain while preserving the underlying histoarchitecture (7). Gliomatosis cerebri cells invade myelinated tracts in a parallel orientation. In the white matter, myelin sheaths may be destroyed, but neurons and axons survive (2). Mitotic activity is variable. There is generally a lack of features associated with high-grade malignant gliomas (eg, microvascular proliferation, necrosis) (2,11). Growth potential is similar to that of low-grade gliomas (13). The histologic features of gliomatosis cerebri vary from patient to patient and even within the same lesion (14).
As stated earlier, the cell of origin remains controversial. At histologic analysis, gliomatosis cerebri is composed of elongated glial cells that typically resemble astrocytes (1,9). Results of staining with glial fibrillary actinic protein and S-100 protein (markers of astrocytes) are variable: Some cells stain positively, whereas many do not (3). In addition, rare cases have been reported in which oligodendroglia is the predominant cell type (9). It is apparent that further molecular genetic research will be necessary to define the histogenesis of gliomatosis cerebri.
CT may demonstrate normal findings or may show diffuse low attenuation in affected areas, with more or less diffuse mass effect and minimal or no enhancement after intravenous administration of contrast material (7,11). MR imaging is more sensitive but fails to depict the full extent of the disease as proved postmortem: Areas of less dense cellular proliferation and subtle infiltration can appear normal (3). Proton-density– and T2-weighted MR imaging show bilateral poorly defined areas of high signal intensity in affected regions, which are believed to represent tumor spread with or without secondary destruction of myelin fibers (9). The increase in signal intensity is usually mild to moderate, especially early in the disease course, but may be heterogeneous with foci of very high signal intensity. These changes are iso- to hypointense relative to surrounding tissue and are therefore less perceptible on T1-weighted images (4,8). Areas that display loss of gray matter–white matter differentiation correspond to areas of neoplastic infiltration (4). Lack of enhancement (indicating a preserved blood-brain barrier) and preservation of tissue architecture are usually found (4). If areas of enhancement are seen, they represent both higher-grade tumor and dense tumor infiltration. There may be compression of the ventricular system or, in a minority of patients, ventriculomegaly or hydrocephalus caused by mass effect or, in one case, blockage of CSF reabsorption related to high CSF protein content (8,14). As the disease progresses, an area of malignant transformation may appear, with the typical signs of focal mass effect, necrosis, and enhancement (6). Imaging differential diagnosis includes demyelinating conditions such as acute demyelinating encephalomyelopathy and multiple sclerosis, leukoencephalopathies, leukodystrophies, encephalitis, ischemic processes, multifocal glioma, and infiltrating astrocytoma (7,9).
A recent study reported the results of perfusion MR imaging performed in seven patients with gliomatosis cerebri and found a correlation between low relative cerebral blood volume measurements seen at MR imaging (comparable to those that characterize normal white matter) and a lack of vascular hyperplasia seen at histologic analysis (15). In a few case reports, FDG-PET has depicted hypometabolism in affected cortical gray matter, a finding that is consistent with diffuse cellular infiltration or is attributed to functional disconnection due to underlying tumor (13,16). PET fails to detect early changes in the white matter. It has been postulated that gliomatosis cerebri may be hard to detect in the white matter because this slow-growing tumor is hypometabolic and therefore blends in with normal hypometabolic white matter (13).
Although some patients have lived for up to 20 years with gliomatosis cerebri, the prognosis is generally poor, with survival rates of 48% at 1 year and 27% at 3 years according to a retrospective study of 124 patients (10). The Ki-67 (monoclonal mouse antibodies for Ki-67 proliferation-related antigen) labeling index might reflect the clinical aggressiveness of this tumor (5). Few treatment options exist. Steroid therapy may be useful in the short term; however, the lesions are too widespread for surgery, and radiation therapy and chemotherapy are of questionable benefit (3).
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References
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- McLendon RE, Enterline DS, Tien RD, Thorstad WL, Bruner JM. Pathologic anatomy: tumors of central neuroepithelial origin. In: Bigner DD, McLendon RE, Bruner JM, eds. Russell and Rubinstein’s pathology of tumors of the nervous system. 6th ed. London, England: Arnold, 1998; 340-342.
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- Dexter MA, Parker GD, Besser M, Ell J, Fulham MJ. MR and positron emission tomography with fludeoxyglucose F 18 in gliomatosis cerebri. AJNR Am J Neuroradiol 1995; 7:1507-1510.
- Couch JR, Weiss SA. Gliomatosis cerebri. Neurology 2000; 24:504-511.
- Yang S, Wetzel S, Cha S. Dynamic contrast-enhanced T2*-weighted MR imaging of gliomatosis cerebri. AJNR Am J Neuroradiol 2002; 23:350-355.[Abstract/Free Full Text]
- Plowman PN, Saunders CAB, Maisey MN. Gliomatosis cerebri: disconnection of the cortical grey matter, demonstrated on PET scan. Br J Neurosurg 1998; 12:240-244.[CrossRef][Medline]
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History
Imaging Findings
