report Astrocytic differentiation in medulloblastoma · blastoma, in part having a definitely spongio-blastic appearance, and electron microscopical studies showed plentiful intracytoplasmic

Journal of Neurology, Neurosurgery, and Psychiatry, 1980, 43, 1041-1044

Short report

Astrocytic differentiation in medulloblastomaR 0 BARNARD AND H PAMBAKIAN

From the Department of Neuropathology. Maida Vale Hospitalfor Nervous Diseases, and the Department ofSurgical Pathology, St Thomas' Hospital, London

SUMMARY A case of cerebellar medulloblastoma with transitional features towards malignantfibrillary astrocytoma is described. In the cerebellum the tumour is characterised by extensivesubpial infiltration with cells of undifferentiated type, and the astrocytic component could only beidentified by a positive glial fibrillary acidic protein reaction. In the brainstem the character of thegrowth transforms to that of diffuse astrocytoma. This demonstrates the potential for differentiationexisting in a "primitive" neuroepithelial neoplasm.

While it has long been assumed that the medullo-blastoma of the cerebellum is composed of cellswith the potential for differentiation along neuro-blastic or spongioblastic lines, cases showingtransition to cells of more mature astrocytic typeare rare. We here describe an example of thistransition in which the conventional neuropatho-logical methods were supplemented by theperoxidase-antiperoxidase technique to demon-strate glial fibrillary acidic protein (GFAP).

Case report

A woman aged 46 years was investigated for twoweeks' right parietal headaches, with frequent fallsto the left or backwards for one week, vomitingfor three days and tinnitus in both ears. Two yearsearlier a pigmented naevus ihad been removed fromthe left arm. On examination the patient was stupor-ose and disoriented. She had coarse nystagmus onlateral gaze, left facial paresis, incoordination of leftupper and lower limbs, and the plantar responseswere extensor. Left vertebral angiography showedthe presence of a large mass in the left cerebellarhemisphere extending to the superior aspect of thefourth ventricle; this was confirmed at operationwhen quantities of soft, grey-red necrotic tumourwere removed from the centre of the hemisphereleaving a large cavity. Microscopical examinationdisclosed the typical appearances of medulloblas-toma. Following the standard course of post-

Address for reprint requests: Dr RO Barnard, Maida Vale Hospital,London W9 1TL.

Accepted 20 June 1980

operative radiotherapy to cranium and spinal cord thepatient's initial progress was good, but six monthslater signs of recurrent tumour were manifest andfurther irradiation to the posterior fossa and a courseof vincristine were given. One year from the timeof presentation the patient deteriorated rapidly anddied.

Pathological findingsPost-mortem examination established the immediatecause of death to be patchy bronch-opneumonia. Notumour was found, by naked-eye or microscopicalexamination, in any tissues outside the centralnervous system. The brain weighed 1-505 kg. Theleptomeninges were slightly thickened and opaqueover the cerebral hemispheres; over the cerebellumthey were densely adherent both to the overlyingbtone and to the softened cerebellar tissue; and therewas marked thickening over the cervical spinalcord. The brain was sliced in the coronal plane afterfixation in formalin. There was slight dilatation ofthe lateral ventricles, and some scattered peteohialhaemorrhages were present in the central grey mat-ter, but no tumour was found above the tentorium.The left cerebellar hemisphere was largely replacedby a ragged cavity 3-5 cm in diameter bordered bya mass of soft, red-speckled pale grey tissue extend-ing diffusely into the cerebellar white matter, middlepeduncle and pons. The aqueduct and fourth ven-tricle were displaced from left to right. The medullaand spinal cord appeared to be normal.Material and methods Sections of both cerebralhemispheres, of the cerebellum and brain stem andof spinal cord were embedded in celloidin. Smallersections were embedded in paraffin wax. A batteryof conventional neuropathological staining tech-niques was employed. For the demonstration of

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glial fibrillary acidic protein the direct immunoper-oxidase method as described by Deck et all wasused.Microscopical appearances (biopsy) Fragments ofhighly cellular tumour tissue: the cells had roughlyoval or rounded, darkly stained nuclei, very sparsecytoplasm and showed little variation in size (fig A).Mitotic figures were present. Rarely, rosettes ofHomer Wright type were observed. Endothelialhyperplasia of blood vessels was present and some-times the tumour cells were arranged around tihesevessels. Staining for reticulin showed only smallamounts of connective tissue, chiefly related to bloodvessels. Glial fibrils were not evident with phospho-tungstic acid haematoxylin.Necropsy appearances In the left cerebellar hemi-sphere the cavity, which contained some necroticmaterial and debris, was lined by tumour tissue(fig B). The tumour, which was wholly composedof small cells with oval, dark-staining nuclei, ex-tended into the folia, forming a thick subpial coating

R 0 Barnard and H Pambakian

closely resembling tihe foetal granular layer. In themolecular layer a marked increase in cellularity wasusual: some of the cells were astrocytes, some mic-roglia and some appeared to be tumour cells migrat-ing from the subpial zone. In some places a focusof intense isomorphic gliosis in the molecular layerwas crowned with an aggregate of tumour cellslying superficially in the pia (fig C). In the molecularlayer and white matter, where they were infiltratedby the neoplasm, it was common to see serpiginousnecrotic zones bordered by small cells (fig D); here,also, the tumour cells were more pleomorphic andsome had elongated nuclei. Vascular endothelialhyperplasia was less conspicuous than in the biopsy,but there were many widely dilated sinusoidal ves-sels, some obliterated by thrombosis. Elsewhere inthe cerebellum appearances were normal apartfrom focal subpial gliosis and there was no persistentObersteiner layer. Where the tumour infiltrated thecerebellar white matter, middle cerebellar peduncleand pons there was more variation in appearance.

y~~~~~~~~~~~~

A:, 4 ~ -

t*:b'~~~~~~~~~Figure (A) (Biopsy) Medulloblastoma. The tumour is highly cellular. One rosette is present. H.E. x 550. (B) (Necropsy)The cavity in the cerebellum is lined by tumour which extends into the pons. Celloidin. Nissl x 0-76. (C) Isomorphicgliosis of the molecular layer with a subpial scrown' of tumour cells. Celloidin PTAH x 100 (D) Necrotic zoneswithin the tumour in the cerebellum. Celloidin PTAH x 24. (E) Fibrillated cells with elongated nuclei in the pons.PTAH x 250. (F) GFAP-positive cells in the pontine tumour. GFAP x 320.



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While there were groups of cells whose morphologywas typically "medulloblastoma," particularly inperivascular aggregates recalling the secondarystructures of Scherer, many were elongated, withslender nuclei and short bi-polar processes (fig E).Especially in the pons, where the fibre-bundles werepermeated by tumour, there were leashes of highlyfibrillated cells (phosphotungstic acid-haematoxylinpositive), in some fields resembling the fibrillaryastrocytoma typically found in the brain stem. Inaddition there were small numbers of astrocytic cellsof the gemistocytic type, some of which could havebeen "reactive" while others were abnormally large,with two or more nuclei, and a few had the bizarreappearance of the giant cells of a glioblastoma.Small haemorrhages into the tumour substance fromthe numerous small blood vessels were common; thevessels, in general, did not show the fibrinoid or pro-liferative changes associated with radiation damage,despite the presence of substantial amounts of nec-rosis. The cerebral hemispheres, including the basalganglia, optic pathways and diencephalic region weretumour-free. In the spinal cord t'he leptomeningealthickening was collagenous and tumour cells werenot present.Results of GFAP reaction Sections of a knownastrocytoma were used as positive controls. Omissionof incubation with anti-GFA protein served as anegative control.

In the biopsy specimen the majority of tumourcells were unstained. However, some scattered cellsshowing positive staining were present throughoutthe tumour, and around the hypertrophic bloodvessels there was a heavy concentration of positivecells with processes radiating from around the vessel,giving an appearance reminiscent of astroblastoma.Review of the PTAH-stained sections did not permitidentification of these cells as astrocytes (see case6 described by Deck et al.1)

In the post-mortem sections the results closelyparalleled those obtained with PTAH. Strong stain-ing was chiefly among cells of elongated or fibril-lated appearance in the brainstem (fig F) whereasthe cells in the subpial zone and cerebellar whitematter were mainly negative.

Discussion

The concept of the cerebellar medulloblastomaas a primitive neuroepithelial neoplasm with thepotential for development along neuroblastic orspongioblastic lines originated with the work ofBailey and Cushing.2 This interpretation still isnot universally accepted: some authors regardthese tumours as sarcomas of mesenchymalorigin, while others deny the possibility of adual potential for differentiation, and believethat "medulloblastomas" can be classified intoneuroblastomas, glioblastomas or oligodendro-gliomas on the basis of metallic impregnation.3

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While neuroblastic characteristics, expressed bythe flnding of Homer Wright rosettes, are com-mon in medulloblastoma, and synaptic structureshave, exceptionaly, been found4 differentiationtowards mature astrocytes has seldom been estab-lished. Willis5 considered that in the more slowlygrowing examples "transition to astrocyte cellscan sometimes be traced." Rubenstein6 illustrateda recurrent medulloblastoma in which "thetumour cells are (highly reminiscent of a malig-nant astrocytoma," but suggested that radiationmight have been responsible, following theearlier account of Oppenheimer7 who describeda remarkable post-irradiation change in amedulloblastoma: the tumour became highlypleomorphic with bizarre giant cells resemblingthose of glioblastoma. Muller and Schaefer8recorded a case of recurrent cerebellar medullo-blastoma, in part having a definitely spongio-blastic appearance, and electron microscopicalstudies showed plentiful intracytoplasmic glialfilaments.

In a detailed study of a cerebellar and brain-stem tumour from a 14-year old girl, Rubinstein,Herman and Hanbury9 demonstrated transitionalfeatures between medulloblastoma and diffuseastrocytoma. In the vermis cerebelli this tumourwas highly cellular, and was composed of smalluniform cells with no distinctive cytoplasmicfeatures when examined electronmicroscopically.In the brainstem, however, there were wide areasof fibrillated astrocytic cells. Sequential morpho-logical changes in tissue and organ culturesystems indicated progressive differentiation from"medulloblastoma cells" to fibrillated astrocytes.The authors discussed the possible interpretationof this tumour as medulloblastoma differentiat-ing into astrocytoma, but concluded that this wasdifficult to sustain because of the fairly prolongedhistory of clinical evolution over a two-yearperiod and because of the absence of a demon-strable mass until the late stages. The interpre-tation they preferred was that this was anexample of diffuse brainstem astrocytoma withfocal dedifferentiation to medulloblastoma. Inthe present case this difficulty does not arise sincethe history of illness was short and the tumourwas, at the time of operation, interpreted asmedulloblastoma. At first sight it seemed thatthe pons provided conditions that were speciallyfavourable for the cells to develop an elongatedbipolar or fibrillary form and the environmentwas thus largely responsible for the change inmorphology. But, in this context it is of interestthat GFAP preparations revealed the astrocyticnature of some of the tumour cells unsuspected



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at the time of the original biopsy, and there-fore radiation cannot be held to be responsiblefor the apparent transformation to astrocytoma.

Conclusion

A case of cerebellar medulloblastoma whichshows transition toward astrocytoma empha-sises the potential for divergent differentiationof this neuroepithelial neoplasm.

The patient was under the care of Dr RE Kellyand Professor Lindsay Symon whose co-operationwe acknowledge. We thank Dr Lawrence FEng (VA Hospital, Palo Alto) who supplied theGFA anti-serum and Dr Lucien J Rubinstein(Stanford University) for his helpful criticismof the manuscript. For both technical and photo-graphic work we are grateful to Mr TrevorScott, FIMLS.

References

1 Deck JHN, Eng LF, Bigbee J, Woodcock SM.The role of glial fibrillary acidic protein in thediagnosis of central nervous system tumors. ActaNeuropathol (Bert) 1978; 42:183-90.

R 0 Barnard and H Pambakian

2 Bailey P, Cushing H. Medulloblastoma cerebelli-A common type of mid-cerebellar glioma ofchildhood. Arch Neurol 1925; 14:192-224.

3 Polak M. On the true nature of the so-calledmedulloblastoma. Acta Neuropathol (Berl) 1967;8:84-5.

4 Rubinstein LJ, Herman Mary M. Recentadvances in human neuro-oncology in RecentA dvances in Neuropathology. Edinburgh:Churchill Livingstone, 1979; 170-223.

5 Willis RA. Pathology of Tumours, 2nd ed.London: Butterworth, 1953; 816-7.

6 Rubinstein LJ. Tumors of the central nervoussystem. Atlas of tumor pathology, 2nd series,fasc. 6. Armed Forces Institute of Pathology,Washington, DC, 1972; 138-9.

7 Oppenheimer DR. The effect of irradiation on amedulloblastoma. J Neurol Neurosurg Psychiatry1969; 32:94-8.

8 Muller W, Schaefer HE. Beitrag zur morpholo-gischen Onkotypie des Medulloblastoms. ActaNeuropathol (Bert) 1974; 30:51-61.

9 Rubinstein LJ, Herman MM, Hanbery JW. Therelationship between differentiating medullo-blastoma and de-differentiating medulloblastomaand de-differentiating cerebellar astrocytoma.Light, electron microscopic, tissue and organculture observations. Cancer 1974; 33:675-90.



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report Astrocytic differentiation in medulloblastoma · blastoma, in part having a definitely spongio-blastic appearance, and electron microscopical studies showed plentiful intracytoplasmic