malignant meningioma metastasizing through the cerebrospinal

Journal of Neurology, Neurosurgery, and Psychiatry, 1975, 38, 136-142

Malignant meningioma metastasizing throughthe cerebrospinal pathways'

S. K. LUDWIN2 AND F. K. CONLEY

From the Departments ofPathology (Neuropathology) and Surgery (Division of Neurosurgery),Stanford University School of Medicine, Stanford, California 94305, U.S.A.

SYNOPSIS A 53 year old man presented with a malignant meningioma which was incompletelyremoved. The tumour subsequently metastasized through the cerebrospinal pathways causing clinicalsigns through invasion of the cranial nerve roots. Microscopically, the metastatic deposits displayeda papillary pattern and increased anaplastic cytological features.

Meningiomas very seldom metastasize throughthe cerebrospinal pathways, even when theyshow malignant histological features and giverise to distant visceral deposits. Only a few iso-lated instances of cerebrospinal spread have beenrecorded (see Discussion). The purpose of thispaper is to describe a recently observed case,unassociated with extraneural metastasis, inwhich the cerebrospinal deposits demonstratedan unusual histological papillary pattern accom-panied by markedly anaplastic cytologicalfeatures.

CASE REPORT

The patient, a 53 year old white right-handed male,was admitted to the Palo Alto Veterans' Administra-tion Hospital in August 1971, complaining of dis-orientation, headaches, confusion, memory loss,gait difficulties, and urinary incontinence. There wasno previous history of neurological disease. He hadhad a nervous breakdown in 1946. On examination,he was oriented in place and person but not in time,exhibited very poor recent memory, perseverated,and was very slow in thought and speech. A hardnon-mobile mass was palpable in the mid-frontalregion to the right of the midline. Mild papilloedemawas present. The left arm was weaker than the right,and his gait was unsteady. Other motor and sensorymodalities, including reflexes, were normal. Skullradiographs revealed a parasagittal area of trans-' Supported by Graduate Neuropathology Training Grant 5T01 NS05500-09 from the National Institute of Neurological Diseases andStroke, U.S.P.H.S.2 Requests for reprints to Dr S. K. Ludwin at above address.(Accepted 12 August 1974.)

136

lucency measuring 4 cm in diameter which involvedthe inner and outer tables of the right frontal bone,accompanied by new bone formation.

Carotid angiography demonstrated a frontal para-sagittal mass measuring 9.5 x 7 cm. At bifrontal

FIG. 1 Surgical specimen. Typical mneningioina show-ing areas of whorling Haematoxylin and eosin, x 90v

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Malignant meningioma metastasizinig through the cerebrospinal pathways

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FG. 2 Surgical specimeni. Invasioni of the brain bymeninigioma. Haematoxylin and eosini, x S.

craniotomy, an extensive, soft, highly vasculartumour was found eroding through the calvariumand dura mater, and deeply invading both frontallobes and the superior sagittal sinus. Tumour im-plants were apparent on the wall of the frontal hornof the right lateral ventricle. Much of the tumourwas removed but complete extirpation was notpossible. The histological diagnosis was of a malig-nant syncytial, occasionally transitional meningioma(vide infra). The patient pursued an uneventful post-operative course, with improvement in his gait andpartial clearing of his mental confusion. He wastransferred to Stanford University Hospital, wherehe received a constant infusion of 1000 mg bromo-deoxyuridine via an indwelling catheter in the rightcommon carotid artery, concomitant with externalradiation to a tumour dose of 5500 r over a 36 dayperiod. Desquamation of the right face and scalpcomplicated therapy, but he remained well untilApril 1972, when he developed a right-sided lowerfacial nerve palsy. Carotid arteriography showedmild hydrocephalus but no evidence of tumour.Apart from one generalized convulsion after ethanolintake, the patient had no further trouble until his

FIG. 3 Surgical specimen. Cellular anaplasia andmitotic figures in invasive portion of the ineninigionma.Haematoxylin and eosint, x 360.

FIG. 4 Base of brain at necropsy. Tumour deposits(arrows) in the cerebellomedullary angle.

final admission in June 1972, which was prompted bythe rapid development of dysphagia, regurgitation,and dysarthria over the preceding 10 days. Onexamination, he was dehydrated and undernourished,and showed a persistent right lower facial palsy, nowaccompanied by peripheral motor involvement of

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S. K. Ludwin and F. K. Conley

FIG. 5 Spinal cord at T2 level. Sub-arachnoid tumour deposits (arrows)attached to the nerve roots.

~~~~~~~. ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~~~~~~~~~~~~~~~~... ...

.~~~~~~~~~~'.~~ ~ ~ ~ ~ ~ ~ ~ ~ ~~..

the 9th and 10th cranial nerves. Vision, facial sensa-

tion, hearing, and movement and sensation of alllimbs were intact, and no abnormal reflexes were

present. The patient showed slow mentation andspoke with difficulty. A brain scan showed a new

space-occupying lesion in the midline in the fronto-temporal area. The patient's last month of life was

punctuated by recurrent episodes of aspirationpneumonia, poorly tolerated nasal gastric tube feed-ings, and progressive physical and mental decline.He died on 10 July 1972.

SURGICAL SPECIMEN Microscopical examinationshowed the pattern of a syncytial, occasionallytransitional meningioma throughout most of thespecimen (Fig. 1). However, some of the cells hadhyperchromatic nuclei, and mitotic figures were

found. In addition, there was invasion of the bone,the superior longitudinal sinus, and the brain

FIG. 6 Spinal cord atthoracic level (necropsyspecimen). Anaplastictumour transgressingthe dura mater (left)and permeating acapillary (lower right).Haematoxylin andeosin, x 120.Inset: Capillary per-meated by tumour.Haematoxylin andeosin, x 360

parenchyma (Fig. 2). In the areas of cortical invasion,mitotic figures and necrosis were conspicuous, andthere was marked anaplasia of the tumour cells (Fig.3), characterized by the presence of large nuclei withgranular chromatin and prominent eosinophilicnucleoli. The anaplastic tumourcells had an unusuallyabundant homogeneous, glassy, and brightly eosino-philic cytoplasm with well-defined cell borders.

POSTMORTEM EXAMINATION The general necropsyrevealed bilateral bronchopneumonia. In the rightfrontal lobe there was a large cystic surgical defect,approximately 2.5 cm in diameter, covered byadherent dura mater and extending from the surfaceof the brain to the lateral ventricle. The base of thecyst was surrounded by brownish necrotic material.Four firm, grey-white subdural tumour depositsmeasuring up to 2.5 cm in diameter were adherent tothe dura mater of the posterior cranial fossa around

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Malignant meningioma metastasizing through the cerebrospinal pathways

FIG. 7 Metastatic meningioma at necropsy. Cellular FIG. 8 Metastatic meningioma at necropsy. Papillaryanaplasia and mitotic figures, similar to Fig. 3. pattern of tumour, with cells arranged radiallyHaematoxylin and eosin, x 360. around a fibrovascular core. Haematoxylin and eosin,

x 225.

the foramen magnum. Both nodular and diffusegreyish subarachnoid growths covered the ventralsurface of the medulla and occupied the cerebello-medullary angles (Fig. 4). In the latter site the depositswere attached to the 7th, 9th, 10th, and 11th cranialnerve roots on the right. In the spinal subarachnoidspace, small white tumour deposits ranging frompinpoint granular excrescences to masses up to 0.75cm in diameter were noted at the C8, TI, T2, T7, andLI levels. Some of these were adherent to the arach-noid membrane, while others were attached to thespinal nerve roots (Fig. 5).

Microscopically, a small focus of residual tumourwas found in the floor of the site of surgical resectionin the frontal lobe. Distant leptomeningeal spread,with invasion of cranial and spinal nerve roots, wasconfirmed. At one thoracic level, the subarachnoiddeposit had transgressed the arachnoid membraneand the spinal dura mater and capillary permeationby tumour was seen at that point (Fig. 6). In all theseareas the histological picture was uniform and re-sembled the anaplastic pattern found in the areas ofcortical invasion of the surgical specimen. The

tumour was composed of large irregular cells withabundant bright eosinophilic cytoplasm and clearlydefined borders. The nuclei varied in size and shape,and were hyperchromatic and often multiple; brightprominent eosinophilic nucleoli and mitotic figureswere seen (Fig. 7). Some areas demonstrated aprominent papillary pattern formed by radiallyoriented cells arranged around fibrovascular cores(Fig. 8). The brain around the cystic surgical defectshowed radiation changes, characterized by fibrinextravasation, demyelination, spongiosis of thewhite matter, and astroglial proliferation. Haemo-siderin-laden macrophages and gitter cells werenumerous.

DISCUSSION

Different criteria have been used to definemalignancy in meningioma. These include rapidrecurrence, local invasiveness, atypical histo-logical features, high mitotic index, and the pro-duction of remote metastases. Recurrence is a

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well-known characteristic of meningiomas as awhole, irrespective of other biological or micro-scopical features, and has been estimated tooccur in 21% of cases (Simpson, 1957). Thiscomplication appears to be primarily dependenton, and inversely proportional to, the extent towhich the tumour can be entirely extirpated, andvaries from 9%/ in those tumours that have beenapparently completely excised to 34%/ in thosein which only partial removal was attempted. Ittherefore does not by itself constitute a firmcriterion of malignancy. Local invasion of thedura mater, the great venous sinuses, and theoverlying bone is a well-known and frequentcharacteristic of meningiomas, but is usuallyassociated with benign cellular features and isagain not generally regarded as indicating truemalignancy (Russell and Rubinstein, 1971). Bycontrast, invasion of the neural parenchyma iswell recognized to denote a malignant trend.Kernohan and Sayre (1952) based their criteriafor malignancy in meningiomas largely on histo-logical grounds and have placed the emphasis ongiant cells, increased cellularity, and the presenceof mitotic figures. The occurrence of giant cells

with hyperchromatic nuclei does not, however,necessarily convey a sinister significance; on theother hand, that of unusually large numbers ofmitotic figures is often indicative of aggressivegrowth and may herald early recurrence (Rubin-stein, 1972). The progression of the histologicalpattern of a typical meningioma to that of aspindle-cell sarcoma (Russell, 1950), to an in-creasingly anaplastic cytological picture (Riley,1971), or to a papillary pattern (Russell andRubinstein, 1971) have all been described asidentifying a malignant meningioma.The development of remote metastases is

generally regarded as constituting an absolutecriterion of malignancy in meningiomas. Ap-proximately 50 cases with extraneural metastaseshave been described (Shuangshoti et al., 1970),the most common sites of metastatic spreadbeing the lungs, liver, pleura, lymph nodes,bones, and kidneys. Even rarer is the develop-ment of metastases through the cerebrospinalfluid circulation. The interest of the present caselies in the development of this pathway of spreadin a neoplasm which demonstrated at the time ofits first occurrence a number of cytological

TABLEREPORTED CASES OF MENINGIOMAS WITH CEREBROSPINAL METASTASES

Authors Sex Age Site of Surgical Histological Metastases(yr) primary pro- features of

tumour cedures primary tumour Cerebrospinal Extraneural

1. Kalm (1950) M 48 Tentorial None Mixed fibroblastic Invading medulla and Noneand angio- spinal rootsblastic, invasive

2. Winkelman (1954) F 60 Sphenoidal One Transitional, In ventricle and sub- Noneridge typical arachnoid space

3. Hoffmann and Earle (1960) F 39 Frontal Three Fibroblastic, Invading brain and Nonepoorly differen- spinal cordtiated

4. Russell and Rubinstein (1963) M 78 Foramen One Endotheliomatous, In leptomeninges of Nonemagnum typical lateral orbital gyrus

5. Shuangshoti et al. (1970) F 21 Occipital One Angioblastic, In leptomeninges of Lung, thyroid,malignant spinal cord breast, lymph

node, retro-peritoneum,vulva

6. Riley (1971) F 38 Occipital Four Fibroblastic, To cauda equina Lungsmalignant

7. Miller and Ramsden (1972) M 45 Frontal Two Transitional, To cauda equina, brain Nonemalignant stem, cranial nerves

and choroid plexus8. Present case M 53 Bifrontal One Syncytial and To dura mater of skull None

transitional, and spinal cord, inmalignant leptomeninges of

medulla, cerebellum,and spinal cord, in-vading nerve roots

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Malignant meningioma metastasizing through the cerebrospinal pathways

features that already raised the suspicion ofmalignancy and became more evident in thesubsequent recurrence and in the cerebrospinaldeposits.As far as we are aware, the literature contains

seven previous reports of meningiomas thatdeveloped cerebrospinal metastases (Kalm, 1950;Winkelman, 1954; Hoffmann and Earle, 1960;Russell and Rubinstein, 1963; Shuangshoti et al.,1970; Riley, 1971; Miller and Ramsden, 1972).The main features of these cases, as well as our

own, are shown in the Table. In six of the eightcases, the development of cerebrospinal meta-stases was associated with cellular features ofmalignancy that were already apparent in theoriginal neoplasm, and the deposits demon-strated the same aggressive character by locallyreinvading the neural parenchyma or the nerve

roots. In addition, two of these cases had distantmetastases in the lungs. In two of the eight cases,

however, both the original tumour and themetastases were histologically benign. In the case

of Winkelman (1954) a sphenoidal ridgemeningioma was removed and, at necropsy fouryears later, in addition to recurrence of the ori-ginal tumour, numerous microscopic whorls oftumour cells, duplicating the original menin-gioma, were seen wedged in the subarachnoidspace between the folia of the cerebellum andfloating free within the ventricular system. In thecase of Russell and Rubinstein (1963) a singlemetastasis was discovered in the subarachnoidspace underlying a lateral orbital gyrus a fewdays after partial removal of a meningioma ofthe foramen magnum. It is open to questionwhether in these last two cases the deposits inthe cerebrospinal pathway should, in the absenceof other malignant characteristics, be regarded as

aggressively spreading metastases rather than as

benign, passively transported seedings. Thelatter have been reported in other central ner-

vous system tumours, such as ependymomas(Fokes and Earle, 1969) and choroid plexuspapillomas (Russell and Rubinstein, 1971). Whycerebrospinal seedings or, alternatively, meta-stases, should occur so infrequently in menin-gioma is unclear if one considers how oftenmeningeal tumour cells gain access to the cere-

brospinal fluid pathways both during theirgrowth period and at the time of surgical inter-vention. Although the cerebrospinal fluid would

be expected to provide a good culture mediumfor tumour cells, it is apparent that tumour tex-ture and friability may play a greater role indetermining the potential for cerebrospinal dis-semination than either the location or the in-trinsic cytological character of the primarynervous system tumour (Russell and Rubinstein,1971).The present case falls into the first of these two

categories-namely, the one in which malignantcytological features were present in both theprimary tumour and the remote deposits. Inseven of the cases tabulated in the Table thedevelopment of cerebrospinal metastases occur-red after one or more previous operations. Thecase of Kalm (1950) is exceptional in that theprimary tumour was first discovered at necropsyand metastases had taken place in the absence ofantecedent surgical procedure. This extra-ordinary occurrence has been noted in a fewother neoplasms of the central nervous system(Rubinstein, 1967; Anzil, 1970). An unusualfeature in our case, similar to the case of Kalm,was the production of cranial nerve symptomsdue to the direct invasion of the cranial nerveroots by metastases. This contrasts with the moreusual causes of cranial nerve signs, which areattributable either to local pressure on the nervesor to increased intracranial pressure (Needhamet al., 1970).Two further features indicative of aggressive-

ness of growth were noteworthy in our case. Thefirst consisted in the development of distant sub-dural deposits in the posterior fossa, an eventwhich is probably related to the transgression ofthe dura mater by the subarachnoid tumour atone or more points, as demonstrated in thethoracic region in this instance. A similarphenomenon has been reported in the case ofmedulloblastoma with extensive metastases inthe subdural space (Koenig, 1971). The secondfeature of interest is the demonstration ofcapillary permeation by tumour at the site oftransgression of the spinal dura mater bygrowth. The significance of this finding is, how-ever, limited, in view of the frequency with whichmeningiomas are known to permeate the venoussinuses, as demonstrated at the primary site ofoccurrence in this case.

Microscopically, our case showed the typicalpattern of a classical syncytial and occasionally

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transitional type of meningioma in the primarytumour, but areas with more atypical cellularfeatures were also present. The anaplasticcharacter of the tumour was more evident in themetastatic deposits. The same phenomenon hasbeen described in the cases of Riley (1971) andof Hoffmann and Earle (1960). In Riley's case,progressively more anaplastic histological fea-tures were noted in the successive recurrences ofa meningioma which spanned a period of 16years. Of particular interest in our case was themicroscopical appearance of a papillary pattern,a feature originally noted by Cushing and Eisen-hardt (1938) in a patient with a recurrentmeningioma, who presented with pulmonarymetastases at necropsy after 17 operations.Subsequent observations by Russell and Rubin-stein (1959)and Kepes et al. (1971) have confirmedthe occasional development of this phenomenonin extraneural metastases of malignant menin-gioma. Russell and Rubinstein (1971) havebriefly noted the same papillary pattern in theoriginal tumour of four cases of malignantmeningioma. A detailed review of a furtherseries studied in this department has confirmedthe association of this microscopical pattern withother cytological features of malignancy andwith unusually aggressive clinical behaviour(Ludwin et al., in preparation).

The authors thank Dr L. F. Fajardo for providing thesurgical material from the Palo Alto Veterans' Admini-stration Hospital, and Dr L. J. Rubinstein for hisvaluable assistance in preparing the manuscript.

REFERENCES

Anzil, A. P. (1970). Glioblastoma multiforme with extra-cranial metastases in the absence of previous craniotomy.Case report. Journal of Neurosurgery, 33, 88-94.

Cushing, H. W., and Eisenhardt, L. (1938). Meningiomas:Their Classification, Regional Behavior, Life History, andSurgical End Results. Thomas: Springfield, Ill.

Fokes, E. C., Jr, and Earle, K. M. (1969). Ependymomas:clinical and pathological aspects. Journal of Neurosurgery,30, 585-594.

Hoffmann, G. T., and Earle, K. M. (1960). Meningioma withmalignant transformation and implantation in the sub-arachnoid space. Journal of Neurosurgery, 17, 486-492.

Kalm, H. (1950). Ein malignes Tentoriummeningeom mitMetastasierung in die Medulla oblongata und in die sub-arachnoidalen Liquorrdume. Deutsche Zeitschrift furNervenheilkunde, 163, 131-140.

Kepes, J. J., MacGee, E. E., Vergara, G., and Sil, R. (1971).A case report. Malignant meningioma with extensivepulmonary metastases. Journal of the Kansas MedicalSociety, 72, 312-316.

Kernohan, J. W., and Sayre, G. P. (1952). Tumors of theCentral Nervous System. Atlas af Tumor Pathology,Section 10. Armed Forces Institute of Pathology: Washing-ton, D.C.

Koenig, G. H. (1971). Subdural spread of medulloblastoma:case report. Journal of Neurology, Neurosurgery, andPsychiatry, 34, 436-438.

Miller, A. A., and Ramsden, F. (1972). Malignant menin-gioma with extracranial metastases and seeding of thesubarachnoid space and the ventricles. Pathologia Europaea,7, 167-175.

Needham, C. W., Bertrand, G., and Myles, S. T. (1970).Multiple cranial nerve signs from supratentorial tumors.Journal of Neurosurgery, 33, 178-183.

Riley, C. G. (1971). Metastasising meningeal tumour: casereport. New Zealand Medical Journal, 73, 210-214.

Rubinstein, L. J. (1967). Development of extracranialmetastases from a malignant astrocytoma in the absenceof previous craniotomy. Case report. Journal of Neuro-surgery, 26, 542-547.

Rubinstein, L. J. (1972). Tumors of the Central NervousSystem. Atlas of Tumor Pathology, second series, fascicle6. Armed Forces Institute of Pathology: Washington, D.C.

Russell, D. S. (1950). Meningeal tumours: a review. Journalof Clinical Pathology, 3, 191-21 1.

Russell, D. S., and Rubinstein, L. J. (1959). Pathology ofTumours of the Nervous System. Arnold: London.

Russell, D. S., and Rubinstein, L. J. (1963). Pathology ofTumours of the Nervous System, 2nd edn. Arnold: London.

Russell, D. S., and Rubinstein, L. J. (1971). Pathology ofTumours of the Nervous System, 3rd edn. Arnold: London.

Shuangshoti, S., Hongsaprabhas, C., and Netsky, M. G.(1970). Metastasizing meningioma. Cancer, 26, 832-841.

Simpson, D. (1957). The recurrence of intracranial menin-giomas after surgical treatment. Journal of Neurology,Neurosurgery, and Psychiatry, 20, 22-39.

Winkelman, N. W. (1954). Post-operative seeding of the sub-arachnoid space and ventricles from a meningioma. Journalof Neuropathology and Experimental Neurology, 13, 260-266.

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cerebrospinal pathways.metastasizing through the Malignant meningioma

S K Ludwin and F K Conley

doi: 10.1136/jnnp.38.2.1361975 38: 136-142 J Neurol Neurosurg Psychiatry

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malignant meningioma metastasizing through the cerebrospinal

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