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(Stroke. 1995;26:2366-2370.)
© 1995 American Heart Association, Inc.
Articles |
Leptomeningeal Dissemination of Malignant Glioma Simulating Cerebral Vasculitis
Case Report With Angiographic and Pathological Studies
From the Departments of Pathology (C.H., W.J.K.), Neurology (L.R., P.M.), and Radiology (R.D.), Wayne State University School of Medicine, Detroit, Mich.
Correspondence to William J. Kupsky, MD, Department of Pathology, Harper Hospital, 3990 John Rd, Detroit, MI 48201.
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Abstract |
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Background The complex clinical and radiological picture of leptomeningeal spread of tumor is well recognized as a problem of systemic cancer but is less frequent in primary cerebral glioma, particularly as a presenting picture. While brain ischemia and infarction may occur in patients with subarachnoid tumor, the mechanism for these complications remains unclear. Angiographic and pathological demonstrations of direct vascular involvement by disseminated glioma are particularly sparse. We report a patient presenting with multiple infarctlike lesions with postmortem evidence of direct vascular involvement by glioma.
Case Description A 54-year-old woman presenting with seizures, headache, and changes in mental status was found to have vascular narrowing in cerebral blood vessels and ischemic lesions on neuroimaging studies of the brain, interpreted as cerebral vasculitis. A brain biopsy showed leptomeningeal glioma. Postmortem examination demonstrated a glioblastoma arising around the right sylvian fissure with extensive subarachnoid dissemination of tumor. The leptomeningeal tumor caused vascular narrowing by encasement, direct vascular wall invasion, and thrombosis and was associated with underlying infarctlike foci of parenchymal necrosis.
Conclusions This case demonstrates an unusual presentation of glioblastoma clinically and radiographically mimicking cerebral vasculitis, and it illustrates a variety of mechanisms for tumor-produced vascular compromise.
Key Words: cerebral angiography • cerebral ischemia • glioblastoma • subarachnoid space • vasculitis
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Introduction |
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The capacity of glial neoplasms of the brain to extend into the leptomeninges and disseminate in the subarachnoid space is well known.1 2 3 Presentation of cerebral glioma by diffuse leptomeningeal dissemination, however, is unusual.4 Because leptomeningeal dissemination of tumor produces a variety of clinical pictures, it may pose a difficult problem of diagnosis in a patient without a known primary tumor. We present a patient whose clinical and neuroangiographic presentation originally suggested central nervous system (CNS) vasculitis but whose subsequent pathological findings revealed diffuse leptomeningeal spread of a previously undetected malignant glioma accounting for the clinically and angiographically observed vasculopathy.
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Case Report |
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A 54-year-old right-handed woman experienced two tonic-clonic seizures in June 1992. Enhanced CT scan of the brain was normal. A lumbar puncture yielded clear cerebrospinal fluid (CSF) with protein of 114 mg/dL and glucose of 38 mg/dL. Cytological examination was not performed. She was treated with 60 mg phenobarbital QD. In the ensuing weeks, she complained of neck stiffness, headache, nausea, vomiting, and vertigo and became increasingly disoriented and drowsy. Neurological examination was reported to show a right third nerve palsy, left hemiparesis, and dystonic neck posturing. Gadolinium-enhanced brain MRI scan showed evidence of acute infarction in the region of the right middle cerebral artery as well as right sulcal effacement consistent with mass effect (Fig 1A
). A cerebral angiogram showed near
total occlusion of the right middle cerebral artery (Fig 1B) and areas of multifocal narrowing ("beading")
in the posterior circulation (Fig 1C). Prednisone
therapy was begun at 60 mg QD for presumed cerebral vasculitis with no
clinical response.
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The patient was admitted to our institution 1 month later with neck stiffness on flexion, drowsiness, and disorientation. The right eye was deviated inferiorly and laterally with ptosis of the lid. The right pupil was unresponsive to both direct and consensual light stimuli, and there were diminished gag reflexes bilaterally. There was moderate weakness of the left limbs with hyperreflexia (more prominent on the left) and bilateral Babinski responses. Lumbar CSF examination showed total protein of 120 mg/dL, glucose of 25 mg/dL (serum 125 mg/dL), 854 red blood cells, and 9 white blood cells (94% mononuclear). Cytological studies were negative for malignancy. Extensive CSF and serum studies for vasculitis and infection were negative.
Two days after admission, the patient became flaccid, areflexic, and
unresponsive to all but painful stimuli. Brain CT with contrast
revealed obstructive hydrocephalus and a single low-attenuation
area in the right temporal region that was initially interpreted as
consistent with ischemia (Fig 2). She received 80 mg
methylprednisolone, a ventriculostomy was placed, and her clinical
picture improved to admission status. On examination,
ventricular CSF showed protein to be <10 mg/dL, and
cytological examination was negative for malignancy. Subsequent brain
CT scans noted new areas of low density in the brain stem and posterior
fossa, and MRI with gadolinium showed meningeal enhancement and an
extra-axial enhancing lesion adjacent to the meninges of the right
anterior temporal lobe.
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A ventriculoperitoneal shunt was inserted. A right temporal leptomeningeal and brain biopsy was obtained that demonstrated small leptomeningeal clusters of malignant glioma. At the request of the patient and patient's family, no further treatment was initiated, and the patient died 2 weeks later with no interim clinical improvement. Permission for a complete postmortem examination was obtained.
Pathological Findings
General autopsy revealed scattered small pulmonary emboli
and a small recent pulmonary infarct; no evidence of
disseminated intravascular coagulation or tumor was noted. Gross
neuropathological examination revealed a 1450-g diffusely swollen brain
covered with cloudy leptomeninges. Coronal sections of
the formalin-fixed brain revealed a poorly circumscribed
intraparenchymal tumor measuring roughly 4.6x2.0x3.0 cm in the right
anterior perisylvian region (Fig 3A).
The great vessels of the circle of Willis were patent.
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Microscopic sections from the tumor showed typical glioblastoma multiforme replacing part of the right anteromedial temporal cortex and basal frontal region and infiltrating into the right ventral basal ganglia, substantia innominata, and lateral hypothalamus. Patchy microscopic tumor infiltrates similar to those seen in the biopsy were noted in the subarachnoid space throughout the neuraxis and along blood vessels within the Virchow-Robin spaces in the brain parenchyma. Subarachnoid tumor focally invaded superficially into brain parenchyma. Along the brain stem and spinal cord, neoplastic cells encased and invaded cranial nerves, including cranial nerve III, as well as ventral and dorsal roots. Occasional spinal cord and cranial nerve motor neurons showed central chromatolysis. No definite infarctlike lesions were identified in the brain stem or cerebellum, but subarachnoid tumor nodules were present between cerebellar folia. Additionally, tumor was seen within the choroid plexus of the fourth ventricle.
Numerous leptomeningeal blood vessels, particularly at the base of the
brain overlying the primary tumor, were encased by tumor with
distortion of the luminal outline. On occasion, arteries and veins
surrounded by tumor contained thrombi in various stages of organization
(Fig 3B
). One large subarachnoid artery in the
right sylvian fissure and scattered small arteries in other locations
showed infiltration of the tunica media and intima by tumor cells,
confirmed by immunohistochemistry for glial fibrillary acidic protein
(Dako), sometimes associated with concentric fibrous intimal thickening
and causing significant stenosis (Figs 3C and 3D). Underlying
the stenotic subarachnoid artery in the right sylvian
fissure, the cerebral cortex was infiltrated by tumor cells but also
contained discrete foci of recent and liquefying necrosis with
infiltration by macrophages. Unlike punctate foci of necrosis
within areas of more solid tumor, these areas of necrosis were not
associated with pseudopalisading of tumor cells and had the appearance
of foci of infarction rather than foci of tumor necrosis.
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Discussion |
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TopAbstractIntroductionCase ReportDiscussionReferences |
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Reports of gliomas presenting with signs and symptoms of leptomeningeal spread are rare.4 Although estimates of the incidence of leptomeningeal dissemination of gliomas in autopsy series vary, such tumor spread usually develops as a late complication in patients who have been previously treated.2 3 Our patient presented with clinical evidence of a disseminated CNS process involving multiple areas of the neuraxis. Because initial neuroimaging and angiographic studies showed evidence of acute infarctions and a diffuse vasculopathic process, a diagnosis of CNS vasculitis was entertained until subarachnoid glial tumor was demonstrated on open brain biopsy. At autopsy, a relatively small primary glioblastoma was identified in the right basal frontotemporal region, and widespread leptomeningeal metastasis was confirmed. This pattern of a small primary focus with extensive leptomeningeal spread corresponds to the type A pattern of malignant glioma described by Onda et al.1
The neuroimaging findings in the present case (including brain CT and MRI evidence of ventriculomegaly without obstructive mass lesion, effacement and contrast enhancement of the sulci, and focal and diffuse leptomeningeal enhancement) are consistent with previous reports of the radiological manifestations of leptomeningeal dissemination of glioma or carcinoma.5 6 7 In addition, infarctlike lesions were also demonstrated antemortem on CT and MRI studies and were confirmed postmortem, often in association with tumor and vascular pathology in the overlying leptomeninges. Several previous studies of leptomeningeal tumor metastasis from carcinomas and meningeal gliomatosis have also shown evidence of associated brain parenchymal damage, including pathological findings interpreted as ischemic brain injury or frank infarction.1 6 7 8 Such findings suggest a direct role for vascular compromise in the pathogenesis of some of the clinical manifestations of leptomeningeal metastasis.
Unusual and striking findings in the present case were the multifocal narrowing of blood vessels seen on cerebral angiography and the postmortem demonstration of leptomeningeal blood vessels involved by glial tumor. Angiographic evidence of segmental narrowing and diffuse irregularities in multiple proximal and distal vessels has been documented in the setting of leptomeningeal metastases from carcinoma.6 7 9 Angiographic changes have also been noted in vessels within intraparenchymal brain tumors, including primary brain tumors. Leeds and Rosenblatt10 reported angiographic narrowing, irregular margins, and areas of dilatation in eight cases of glioma or lymphoma. Cowen et al11 noted segmental fusiform dilatation of intratumoral vessels on cerebral angiography in a case of malignant glioma and provided pathological evidence of infiltration of vessel walls by tumor cells in direct contiguity with the primary tumor. Involvement of the Virchow-Robin spaces by primary parenchymal cerebral lymphoma was reported by Leeds et al,12 who correlated focal irregularities on cerebral angiography with pathological tumor infiltration of vessel walls. In contrast, reports of primary intracranial tumors with leptomeningeal dissemination have described the presence of tumor around larger subarachnoid blood vessels and extension of tumor along the Virchow-Robin spaces into the brain parenchyma but have rarely commented on direct blood vessel pathology or reported angiographic evidence of multifocal leptomeningeal vascular involvement.2 3 13 The observation in the radiological literature that multiple dissimilar processes, neoplastic or otherwise,10 14 may give rise to identical angiographic findings underscores the importance of confirming a presumptive diagnosis of CNS vasculitis by appropriate pathological studies.
Presumptive causes for the angiographic abnormalities in the present case are suggested by the variety of vascular pathological findings. Encasement of leptomeningeal arteries and veins by cuffs of subarachnoid neoplastic cells, probably resulting in luminal distortion with focal wall constriction or rigidity, supports the possibility of a mechanism of actual physical distortion, as suggested in the study by Leeds and Rosenblatt.10 The finding of intraluminal thrombi in vessels involved by tumor and of luminal stenosis due to intimal fibrosis, possibly an effect of previous thrombotic events, suggests a role for a hypercoagulable state or local thrombotic or inflammatory events related to the presence of tumor cells. In our case, no firm evidence for a systemic coagulopathy was apparent clinically or at autopsy. The finding of direct invasion of vessel walls by neoplastic glial cells in the present case may have accounted for local thrombosis, stenosis, and possibly vascular wall rigidity or weakening. Direct vascular wall invasion has rarely been reported in leptomeningeal cancer and is distinctly unusual in most forms of glioma.6 11 12 13
Pial vessel vasospasm has been previously suggested as a potential cause of angiographic changes associated with subarachnoid tumor.7 Although the present case contained examples of subarachnoid tumor focally extending through the pia mater into brain parenchyma or along penetrating vessels, making pial vasospasm a possibility, this finding was not documented angiographically. On the basis of experimental models, other mechanisms postulated to account for changes in the caliber of CNS blood vessels in a variety of pathological conditions include recruitment of lymphocytes into the vessel wall by cytokines and alteration of vasomotor reactivity by numerous small molecules released by activated endothelium.15 We cannot speculate whether these processes additionally contributed to the vasculopathy in our patient.
The potential of glioblastoma to disseminate widely within the subarachnoid space while remaining occult on repeated CSF examinations has been well recognized.3 16 The ability of leptomeningeal metastatic glioblastoma cells to encase, invade, and lead to thrombosis and narrowing of leptomeningeal blood vessels, and the capacity of disseminated glioblastoma to produce a complex clinical and angiographic picture consistent with a diffuse vasculopathic process, as demonstrated in this case, are less recognized. This potential behavior underscores the necessity of including leptomeningeal metastatic disease in the differential diagnosis in a patient with signs and symptoms of a multifocal neurological process and cerebral vasculopathy.
Received May 29, 1994; revision received August 18, 1995; accepted September 22, 1995.
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