Journal of Neurology, Neurosurgery, and Psychiatry, 1972, 35, 732-738

Malignant glioma of the brain-stemA clinicopathological analysis of 13 cases

GERALD S. GOLDEN, NITYA R. GHATAK, ASAO HIRANO,AND JOSEPH H. FRENCH

From the Departments of Neurology and Pediatrics, and Division of Neuropathology,Department ofPathology, Montefiore Hospital and Medical Center, and

Albert Einstein College of Medicine, Bronx, New York, U.S.A.

SUMMARY Thirteen cases of malignant glial tumours of the brain-stem that came to necropsy havebeen analysed in detail. These patients followed a rather uniform course defined by the early onset ofsigns and symptoms of increased intracranial pressure, poor response to radiotherapy, and shorttotal duration of illness. Pathological features were also similar in all cases, with each tumour showingareas ranging from benign to frankly malignant. This regional variability points to the limited useful-ness of small biopsies and also indicates the need for complete necropsy studies. The term 'spongio-blastoma polare' should probably be avoided, and it is suggested that the histological classificationof glial brain-stem tumours be similar to the classification of such tumours elsewhere in the neuraxis.

Primary intraaxial glial tumours of the brain-stem occur fairly frequently in children (Bray,Carter, and Taveras, 1958; Panitch and Berg,1970) and, although they are also found in adultlife (White, 1963), the relative incidence as com-pared with extraaxial posterior fossa tumours issomewhat lower, leading to increased difficultiesin diagnosis. A significant percentage of thesetumours have the histological characteristics ofmalignant gliomas or glioblastoma multiforme,rather than appearing like the so-called spongio-blastoma polare (Bassoe and Apfelbach, 1925;Buckley, 1930; Horrax and Buckley, 1930; Hareand Wolf, 1934; Alpers and Yaskin, 1939; Brayet al., 1958; White, 1963; Lassman and Arjona,1967; Panitch and Berg, 1970). In every largereported series great variations in clinical course,length of survival, and response to treatment areseen. There is, however, no agreement as towhether evidence of histological malignancyaffects these clinical parameters (Lassman andArjona, 1967; Panitch and Berg, 1970).

Despite this relatively frequent occurrence ofmalignant tumours, no author has analysedcritically the clinical characteristics of this par-ticular group. The present series of cases ofmalignant tumours of the brain-stem suggests

732

that they form a definable clinical and patho-logical subgroup with its own clinical character-istics, course, and response to treatment. Theclinically malignant course is present from thebeginning and does not represent an accelerationof a more indolent pattern. It should be possible,therefore, to make the diagnosis of a malignanttumour early in the course of the illness in themajority of cases, allowing therapeutic andprognostic decisions to be based rationally.

METHODS

Thirteen necropsied cases of malignant brain-stemglioma from the records of the Department ofNeurology and the Neuropathology Laboratory ofthe Montefiore Hospital and Medical Center werestudied. The clinical charts were reviewed in detail aswere radiographs and other special studies whereindicated. One patient died without hospitalization,and limited clinical data are available.Adequate sections from various levels of the brain-

stem and other pertinent areas of the nervous systemwere available for study. The sections were preparedfrom celloidin or paraffin embedded tissue and werestained by haematoxylin and eosin, Nissl, Woelcke,and phosphotungstic acid haematoxylin (PTAH)techniques. Special attention was given to the site and

.Mfaligniant gliomiia of tile beraili-stem733

extent of the tumours, as well as to their gross andmicroscopic appearance.

RESULTS

The alges of the patients form a bimodal distribu-tioI. the children having a mean age of 6 5 years(9 montlhs to 11 years); the adults, 44-6 years (30to 56 years). There is a slight preponderance ofmales (8 1 3).

Signs. symptoms. or radiological evidence ofcompromise of the cerebrospinal fluid pathwayswere frequent features (Table). Seven patientshad at least two such stigmata. and three of themexhibited tlhree or more.

TABLE

INCREASED INTRACRANIAL PRESSURE

Papilioedemiia 4 12hieadache 7 12Nausea anld ,omitilng 4 12Radiological abniormiialitiesVentricular dilatation 6 '9Non-filling ventricular system 2,9

Abnormalities of ocular motility were presentin all cases. Six patients had diplopia at the onsetof symptoms and one child had a head tilt.During the course of the illness every patientexamined manifested at least two of the threesigns of extraocular muscle palsies, gaze paraly-sis, and pathological nystagmus. Eight patientshad gaze palsy. rotatory nystagmus or verticalnystagmus. cardinal signs of intrinsic brain-steminvolvement.

Skull radiographs and electroencephalogramscontributed little to the diagnosis. In one case. anenlarged acoustic meatus on x-ray examination,in association with the clinical findings of acerebellopontine angle syndrome, led to an in-correct diagnosis of acoustic neurilemmoma.Spinal fluid protein was measured in nine patientsand was elevated in five with levels ranging from59 to 147 mg,'100 ml.The total duration of the illness, dated from

the onset of symptoms. was quite short (Fig. 2).The average life span of the children was 4 3

The neurological signs are summarized in Fig.1. Seven patients had cranial nerve abnormalitiesamong their presenting complaints. These con-sisted of facial weakness in two, facial numbnessin two, vertigo in two, and tinnitus in one.

RIGHT LEFTEL7PEG/ON INVOLVED

CRANIAL NERVES VIl

Ix,xV

Vill

EXTRA- OCULAR MUSCLES

III, IV, VI

GAZE PALSY

NYSTAGMUS

MOTOR AND SENSORY

HE MIPARESIS

HEMISENSORY

COORDINATION

ATAXIC GAIT2 3 4 5 6 7 8 9 tO I112NUMBER OF PATIENTS

FIG. 1. Cliniical features.

.Z-

AND ADULTS

FIG. 2. Patienit suru-ii al.

months (2-5-8 months) whereas it was 10 3months (1-26 months) in the adults. If the onelong-term survivor in the adult group is excluded.the mean survival time was 6-3 months. Themedian survival time for children was 3 monthsand for adults, 8 5 months.Ten patients received radiotherapy, either

733

Gerald S. Goldeni, Nitya R. Ghatak, Asao Hiranio, anzd Joseph H. French

-....

..

A.. ?:. "A-~A

FIG. 4. Glioblaston7a involving the left side oftheponswith rostral infiltration into the left side of the mid-brain. The fourth ventricle is obstructed. The positionof the median raphe is indicated by arrows.

¶8ilt FIG. 3. Glioblastonma in-

volvinig the left side of the

pons and partially occupyinigthe cerebelloponitine angle.The basilar artery lies in a

deep groove on the midline.

with or without prior suboccipital decompressionand exploration. Three of these died during treat-ment, often with a sudden and severe increase insigns and symptoms. The seven patients finishingthe planned course of radiotherapy (3500 r or

greater) had a mean survival time of 3-6 monthsafter treatment with a maximum of eight months.The three untreated patients survived for an

average of 2-7 months with a maximum of fivemonths.

BILATERAL RIGHTa LEFT1

REGION INVOLVEDPONS /

MIDBRAIN

THALAMUS

MEDULLA

CEREBELLAR PEDUNCLES

INFERIORSUPERIOR

HYDROCEPHAWS

MALIGNANT ASTROCYTOMA

GLIOBLASTOMIA2 3 4 6 7 9 10 11 12 13NUMBER O PATIENTS

FIG. 5. Major pathological features.

734

Malignant glioma of the brain-stem

The neuropathological features, both in child-ren and adults, were found to be similar. Thetumours in all cases were present in the pons withpredominantly unilateral involvement in ninepatients and bilateral diffuse involvement infour, resulting in asymmetrical (Fig. 3) or sym-metrical enlargement of the pons respectively. Incases showing predominantly unilateral involve-ment, the median raphe of the pons could be seen

9 t.~~~~I.434t

if i r * 5 r; "

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* itI 94,r #* , i \$*1

FIG 6. Initrtn mainn sroyoao hposStreamin of th ploopi tuou cellsinfasccle can bese. Haeatoyli an eoin x140

e :ote o e to af rbextent* .; 'a.B l'a t regions were

varia,bl involved. E n of the t u t

uies ( t ;

a \, 4~

FIG. 6.rInfialtrtnere we dstorotomat the

pointofreemegrgfnte pleomorphic buorain-stemn

unvra (Fg5).; aThe crania nevswr1itotda hipon afeegecrmt, ri-tm

especially on the side of major involvement. Insome instances, the proximal portions of thecranial nerves were found to be infiltrated by thetumour. The basilar artery was frequently foundto be in a deep groove or in a tunnel formed byencirclement by tumour (Fig. 3). Similarly,tumour outgrowth around the smaller blood

94 4io ,, ' .' 44 &*. .-

X>,*i44 "CjSiW *- t 2

2

w *' \'%et~ AZ+ <Vt

;.i|4^F }*3tt,<7 ; N'' 4,(sr *~~~- ' .:.F&tr

FIG. 7. Glioblastoma multiforme of the pons showingpseudopalisading and vascular proliferative changes.Haematoxylin and eosin, x 140.

vessels resulted in a lobulated appearance of theexternal surface of the pons (Fig. 3). Occasion-ally, the basilar artery was slightly displacedlaterally as well as ventrally; in most cases, how-ever, displacement of the basilar artery was notsignificant.Tumour bulged into the fourth ventricle in all

735

Gerald S. Golden, Nitya R. Ghatak, Asao Hirano, and Joseph H. French

patients, resulting in partial or complete obstruc-tion of the cerebrospinal fluid pathway (Fig. 4).Hydrocephalus of a moderate to severe degreewas found in eight cases. In two cases, the tumourprotruded into the subarachnoid space, occupy-ing the cerebellopontine angle (Fig. 3).

ti~~ ~~~~.w~~~~~~~~~f ~ ~ ~ e

ja 4~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~0

t>'4; : A (

+ ~~~~~~~~~4 S$ j tfa' L

FIG. 8. Malignant astrocytoma showing infiltrationof the trigeminal nerve close to the pons. Haema-toxylin and eosin, x 100.

On gross examination, the tumour appearedto be greyish in colour with yellowish and brown-ish necrotic areas (Fig. 4), and sometimes showedold or recent haemorrhage. Such macroscopicnecrotic areas were seen in half of the cases andwere present in the central part of the tumour.On the other hand, peripheral portions of thesame tumour were firm and infiltrating and par-

tially obscured the normal anatomical landmarksof the brain-stem.

Histologically, the tumour in each instancewas found to be basically composed of cells ofastrocytic nature. The cells ranged from readilyrecognizable fibrillary or protoplasmic astrocytesto undifferentiated bizarre forms and these werefound in variable proportions in different areas.The degree of pleomorphism, however, variedfrom case to case. Utilizing the same histologicalcriteria of malignancy as applied to astrocytomaselsewhere in the central nervous system, thetumours in the present series would be classifiedas malignant astrocytomas in five cases (Fig. 6)and glioblastoma multiforme in eight cases (Fig.7). Although in most cases the features of malig-nancy were present throughout the tumour, twoexhibited these features only in small scatteredareas likely to be overlooked in limited histo-logical necropsy examination or biopsy.

Regardless of the microscopic histologicalfeatures, the outstanding characteristic commonto all cases was the remarkably infiltrativenature of these tumours. Tumour cells, isolatedor in groups, were seen freely infiltrating alongthe fibre tracts in various directions (Fig. 6).Intact neurones were frequently entrapped in themidst of tumour proliferation. Occasionally,infiltrating tumour was seen in the proximal por-tions of the cranial nerves (Fig. 8). The tumourcells infiltrating along the course of fibre tractsfrequently assumed elongated and relativelyuniform shapes with uni- or bipolar processesresembling the so-called spongioblastomas. Inthe central part of the tumour, however, especi-ally in the tegmental regions, the tumour cellswere found to be haphazard in distribution withdistinct pleomorphism and appeared as malig-nant astrocytoma or glioblastoma.

DISCUSSION

One of the first well-defined clinicopathologicalseries of gliomas primary to the brain-stem wasthat of Bassoe and Apfelbach (1925). Althoughthe histological description was limited, one oftheir four cases may have been a malignantglioma. Horrax and Buckley (1930) describedone glioblastoma multiforme in a series of sevenbrain-stem gliomas; Buckley (1930), 10 out of25; Hare and Wolfe (1934), three out of seven;

736

Malignant glioma of the brain-stem

and Alpers and Yaskin (1939), four out of 11.Other authors have presented similar experiences,with a variable but significant number of casesin any one series representing malignant gliomashistologically.

In a recent review of 48 cases of brain-stemtumours in children, histological diagnoses wereavailable in 10; five of these showed varyingdegrees of glioblastomatous change (Bray et al.,1958). Another paediatric series confirmed 10 of40 cases as being, histologically, glioblastomamultiforme, or mixed glioma with anaplasia(Panitch and Berg, 1970). White's (1963) series,restricted to brain-stem tumours in adults, hadhistological verification in 28 of 44 cases. Sevenwere classified as glioblastoma multiforme andeight demonstrated glioblastomatous changesarising in an astrocytoma.The purpose of this report is to analyse critic-

ally this histologically malignant subgroup, com-paring the findings with the reported series inwhich histology is either undefined or ignored.One of the most important clinical features

differentiating malignant brain-stem tumoursfrom the more usual slow-growing astrocytomasis the early and striking appearance of signs andsymptoms of increased intracranial pressure.This is associated in some cases with papill-oedema well before the terminal phase of thepatient's illness. Only two patients in our entireseries lacked evidence of ventricular dilatationeither on early radiographic studies or at post-mortem examination. It should be noted thatsix of nine air studies were carried out by thelumbar route, and no mortality or seriousmorbidity was associated with this procedure.A second cardinal feature is the rapid and

relentlessly progressive course leading to deathin approximately four months in the averagechild and 10 months in the adult group. Onlythree patients survived for longer than one year.

In a large series of adult patients with brain-stem gliomas (White, 1963) it is possible to per-form an analysis of survival correlated withpathology, although this was not done by theauthor. This reveals that patients with histo-logically proven glioblastoma or mixed astro-cytoma-glioblastoma survived for an average of8-3 months, while those patients with benignastrocytomas had a mean survival of 30 5months. Two of the patients in the astrocytoma

group were still alive 78 and 120 months afterthe onset of symptoms.

In a series restricted to children (Panitch andBerg, 1970), patients with benign astrocytomashad symptoms for an average of 17-0 monthsbefore diagnosis and survived for an average of32-4 months after diagnosis was confirmed. Thegroup of patients with 'mixed gioma withanaplasia' were diagnosed 3-0 months after theonset of symptoms and survived an additional6-4 months in the average case. Frank glio-blastoma multiforme in other patients wasdiagnosed 3-0 months after the first symptom,but those patients survived only an additional2-8 months. The survival times for patients withmalignant tumours in both series are, therefore,quite similar to those in our group.

It is likely that the discrepancies in survivaltime in some other series and the broad range ofsurvival times in individual cases may, therefore,in part be a function of the tumour histology.Although beneficial effects of radiotherapy

have been reported in as many as 67% of casesof pontine glioma (Redmond, 1961) the treat-ment series also have not been analysed utilizingthe additional variable of histological pathology.In the present cases, no patient showed clinicalimprovement during or after the administrationof radiotherapy. Indeed, three patients suc-cumbed during treatment with a marked exacer-bation of signs and symptoms. Mean survivaltime for the patients not receiving any treatmentwas 2-7 months, while those patients able tofinish the prescribed course of radiotherapy(generally 3500 r or more) survived for anadditional 3-6 months on the average.

Diagnostic problems arise in the adult groupdue to the relative infrequency of brain-stemtumours during the adult years of life. This fact,combined with the high incidence of predomi-nently unilateral long tract signs and the frequentevidence of increased intracranial pressure, com-pounds the diagnostic difficulty. These difficul-ties may be further increased by outgrowth oftumour into the cerebellopontine angle withclinical and radiographic findings typical of anangle syndrome.

Elevation of the cerebrospinal fluid proteinlevel also provides a source of diagnostic con-fusion. It is stated that this value is generallynormal in brain-stem tumours (Bray et al., 1958).

737

Gerald S. Golden, Nitya R. Ghatak, Asao Hirano, and Joseph H. French

Rather than leading one away from the diagnosis,however, an increased level of protein may sug-gest a malignant histological picture as was seenin five of the nine patients in this series under-going lumbar puncture.Another source of potential diagnostic error

is in neuroradiological studies. Confusion withcerebellopontine angle tumours both on routineskull radiography and pneumoencephalographyhas already been noted. In addition, the expectedangiographic finding of widening of the brain-stem with displacement of the basilar arterytowards the clivus is also not dependable, sincethe tumour frequently grows around the artery,enclosing it in a groove or tunnel without pro-ducing displacement. Other arteries may alsoshow minimal or no displacement for the samereasons.The pathological features of the brain-stem

gliomas in the present series were essentiallysimilar to those described in detail by manyauthors (Buckley, 1930; Hare and Wolf, 1934;Pilcher, 1934; Alpers and Yaskin, 1939;Ingraham and Matson, 1969). Despite the basichistological similarities, there appears to beconsiderable diversity in the nomenclature ofthis group of tumours. Thus, a variety of termssuch as astrocytoma, spongioblastoma, glio-blastoma, or mixed glioma have been used(Buckley, 1930; Hare and Wolf, 1934; Bray etal., 1958; Redmond, 1961; Ingraham andMatson, 1969). A major problem in establishinga satisfactory classification is the wide range ofhistological variation often seen in differentareas of the same tumour. Consequently, histo-logical examination of a limited region of such atumour at necropsy or surgical biopsy may notreveal its true nature. This may explain apparentdiscrepancies between the histological type ofthe tumour and length of survival of patients(Lassman and Arjona, 1967).

Detailed pathological study in this seriesclearly demonstrated the frequent occurrence ofspongioblastoma-like areas in tumours other-wise indistinguishable from malignant astro-cytomas or glioblastomas found elsewhere in thecentral nervous system. Furthermore, there is nouniformity of opinion among neuropathologistsregarding the nature and biological behaviour ofspongioblastomas (Rubinstein, 1964; Zulch,

1964). Therefore, it is probably best to avoid thisterm in the classification of brain-stem gliomas.Since these tumours are basically similar toothers of the astrocytic series, they should beclassified by the same criteria as are applied tosimilar tumours elsewhere in the central nervoussystem. Such classification would not only pro-vide uniformity in terminology, but would give abetter understanding of their apparently variableexpressions in terms of clinical manifestationsand prognosis.

The authors are indebted to Dr. H. M. Zimmerman,Chief, Department of Pathology, Montefiore Hos-pital and Medical Center, for his encouragement andhelp throughout this undertaking.

REFERENCES

Alpers, B. J., and Yaskin, J. C. (1939). Gliomas of the pons.Archives of Neurology and Psychiatry, 41, 435-459.

Bassoe, P., and Apfelbach, C. W. (1925). Glioma of the bulband pons. Archives of Neurology and Psychiatry, 14, 396-408.

Bray, P. F., Carter, S., and Taveras, J. M. (1958). Brainstemtumours in children. Neurology (Minneap.), 8, 1-7.

Buckley, R. C. (1930). Pontile gliomas. Pathologic study andclassification of 25 cases. Archives ofPathology, 9, 729-819.

Hare, C. C., and Wolf, A. (1934). Intramedullary tumors ofthe brain stem. Archives of Neurology and Psychiatry, 32,1230-1252.

Horrax, G., and Buckley, R. C. (1930). A clinical study of thedifferentiation of certain pontile tumors from acoustictumors. Archives of Neurology and Psychiatry, 24, 1217-1230.

Ingraham, F. D., and Matson, D. D. (1969). Neurosurgery ofInfancy and Childhood, 2nd edn. Pp. 469-477. Thomas:Springfield, Ill.

Lassman, L. P., and Arjona, V. E. (1967). Pontine gliomas ofchildhood. Lancet, 1, 913-915.

Panitch, H. S., and Berg, B. 0. (1970). Brainstem tumors ofchildhood and adolescence. American Journal of Diseasesof Children, 119, 465-472.

Pilcher, C. (1934). Spongioblastoma polare of the pons.Clinicopathologic study of 11 cases. Archives of Neurologyand Psychiatry, 32, 1210-1229.

Redmond, J. S., Jr. (1961). The roentgen therapy of pontinegliomas. American Journal of Roentgenology, 86, 644-648.

Rubinstein, L. J. (1964). Discussion on polar spongio-blastomas. In Classification of Brain Tumours. Report ofthe International Symposium ... Cologne, 30 August-1 September 1961. Edited by K. J. Zulch and A. L. Woolf.Acta Neurochirurgica, Suppl X, 126-140.

White, H. H. (1963). Brain-stem tumors occurring in adults.Neurology (Minneap.), 13, 292-300.

Zulch, K. J. (1964). Some remarks on the spongioblastoma ofthe brain. In Classification of Brain Tumours. Report ofthe International Symposium ... Cologne, 30 August-1 September 1961. Edited by K. J. Zulch and A. L. Woolf.Acta Neurochirurgica, Suppl. X, 121-125.

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