J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.11.1041 on 1 November 1980. Downloaded from

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

Short report Astrocytic differentiation in medulloblastoma R 0 BARNARD AND H PAMBAKIAN From the Department of Neuropathology. Maida Vale Hospitalfor Nervous Diseases, and the Department of Surgical Pathology, St Thomas' Hospital, London

SUMMARY A case of cerebellar medulloblastoma with transitional features towards malignant fibrillary is described. In the the tumour is characterised by extensive subpial infiltration with cells of undifferentiated type, and the astrocytic component could only be identified by a positive glial fibrillary acidic protein reaction. In the the character of the growth transforms to that of diffuse astrocytoma. This demonstrates the potential for differentiation existing in a "primitive" neuroepithelial neoplasm. guest. Protected by copyright. While it has long been assumed that the medullo- operative radiotherapy to cranium and spinal cord the blastoma of the cerebellum is composed of cells patient's initial progress was good, but six months with the potential for differentiation along neuro- later signs of recurrent tumour were manifest and further irradiation to the posterior fossa and a course blastic or spongioblastic lines, cases showing of were given. One year from the time transition to cells of more mature astrocytic type of presentation the patient deteriorated rapidly and are rare. We here describe an example of this died. transition in which the conventional neuropatho- logical methods were supplemented by the Pathological findings peroxidase-antiperoxidase technique to demon- Post-mortem examination established the immediate strate glial fibrillary acidic protein (GFAP). cause of death to be patchy bronch-opneumonia. No tumour was found, by naked-eye or microscopical Case report examination, in any tissues outside the . The brain weighed 1-505 kg. The A woman aged 46 years was investigated for two leptomeninges were slightly thickened and opaque weeks' right parietal headaches, with frequent falls over the cerebral hemispheres; over the cerebellum to the left or backwards for one week, vomiting they were densely adherent both to the overlying for three days and tinnitus in both ears. Two years btone and to the softened cerebellar tissue; and there earlier a pigmented naevus ihad been removed from was marked thickening over the cervical spinal the left arm. On examination the patient was stupor- cord. The brain was sliced in the coronal plane after ose and disoriented. She had coarse on fixation in formalin. There was slight dilatation of lateral gaze, left facial paresis, incoordination of left the lateral ventricles, and some scattered peteohial http://jnnp.bmj.com/ upper and lower limbs, and the plantar responses haemorrhages were present in the central grey mat- were extensor. Left vertebral angiography showed ter, but no tumour was found above the tentorium. the presence of a large mass in the left cerebellar The left cerebellar hemisphere was largely replaced hemisphere extending to the superior aspect of the by a ragged cavity 3-5 cm in diameter bordered by ; this was confirmed at operation a mass of soft, red-speckled pale grey tissue extend- when quantities of soft, grey-red necrotic tumour ing diffusely into the cerebellar white matter, middle were removed from the centre of the hemisphere peduncle and pons. The aqueduct and fourth ven- tricle were displaced from left to right. The medulla

leaving a large cavity. Microscopical examination on September 24, 2021 by disclosed the typical appearances of medulloblas- and spinal cord appeared to be normal. toma. Following the standard course of post- Material and methods Sections of both cerebral hemispheres, of the cerebellum and brain stem and of spinal cord were embedded in celloidin. Smaller Address for reprint requests: Dr RO Barnard, Maida Vale Hospital, sections were embedded in paraffin wax. A battery London W9 1TL. of conventional neuropathological staining tech- Accepted 20 June 1980 niques was employed. For the demonstration of 1041 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.11.1041 on 1 November 1980. Downloaded from

1042 R 0 Barnard and H Pambakian glial fibrillary acidic protein the direct immunoper- closely resembling tihe foetal granular layer. In the oxidase method as described by Deck et all was molecular layer a marked increase in cellularity was used. usual: some of the cells were , some mic- Microscopical appearances (biopsy) Fragments of roglia and some appeared to be tumour cells migrat- highly cellular tumour tissue: the cells had roughly ing from the subpial zone. In some places a focus oval or rounded, darkly stained nuclei, very sparse of intense isomorphic gliosis in the molecular layer cytoplasm and showed little variation in size (fig A). was crowned with an aggregate of tumour cells Mitotic figures were present. Rarely, rosettes of lying superficially in the pia (fig C). In the molecular Homer Wright type were observed. Endothelial layer and white matter, where they were infiltrated hyperplasia of blood vessels was present and some- by the neoplasm, it was common to see serpiginous times the tumour cells were arranged around tihese necrotic zones bordered by small cells (fig D); here, vessels. Staining for reticulin showed only small also, the tumour cells were more pleomorphic and amounts of connective tissue, chiefly related to blood some had elongated nuclei. Vascular endothelial vessels. Glial fibrils were not evident with phospho- hyperplasia was less conspicuous than in the biopsy, tungstic acid haematoxylin. but there were many widely dilated sinusoidal ves- Necropsy appearances In the left cerebellar hemi- sels, some obliterated by thrombosis. Elsewhere in sphere the cavity, which contained some necrotic the cerebellum appearances were normal apart material and debris, was lined by tumour tissue from focal subpial gliosis and there was no persistent (fig B). The tumour, which was wholly composed Obersteiner layer. Where the tumour infiltrated the of small cells with oval, dark-staining nuclei, ex- cerebellar white matter, middle cerebellar peduncle tended into the folia, forming a thick subpial coating and pons there was more variation in appearance. guest. Protected by copyright.

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Figure (A) (Biopsy) Medulloblastoma. The tumour is highly cellular. One rosette is present. H.E. x 550. (B) (Necropsy) The cavity in thet*:b'~~~~~~~~~cerebellum is lined by tumour which extends into the pons. Celloidin. Nissl x 0-76. (C) Isomorphic gliosis of the molecular layer with a subpial scrown' of tumour cells. Celloidin PTAH x 100 (D) Necrotic zones within 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. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.11.1041 on 1 November 1980. Downloaded from

Astrocytic differentiation in medulloblastoma 1043 While there were groups of cells whose morphology While neuroblastic characteristics, expressed by was typically "medulloblastoma," particularly in the flnding of Homer Wright rosettes, are com- perivascular aggregates recalling the secondary mon in medulloblastoma, and synaptic structures structures of Scherer, many were elongated, with have, exceptionaly, been found4 slender nuclei and short bi-polar processes (fig E). differentiation Especially in the pons, where the fibre-bundles were towards mature astrocytes has seldom been estab- permeated by tumour, there were leashes of highly lished. Willis5 considered that in the more slowly fibrillated cells (phosphotungstic acid-haematoxylin growing examples "transition to cells positive), in some fields resembling the fibrillary can sometimes be traced." Rubenstein6 illustrated astrocytoma typically found in the brain stem. In a recurrent medulloblastoma in which "the addition there were small numbers of astrocytic cells tumour cells are (highly reminiscent of a malig- of the gemistocytic type, some of which could have nant astrocytoma," but suggested that radiation been "reactive" while others were abnormally large, might have been responsible, following the with two or more nuclei, and a few had the bizarre earlier account of Oppenheimer7 who described appearance of the giant cells of a . a Small haemorrhages into the tumour substance from remarkable post-irradiation change in a the numerous small blood vessels were common; the medulloblastoma: the tumour became highly vessels, in general, did not show the fibrinoid or pro- pleomorphic with bizarre giant cells resembling liferative changes associated with radiation damage, those of glioblastoma. Muller and Schaefer8 despite the presence of substantial amounts of nec- recorded a case of recurrent cerebellar medullo- rosis. The cerebral hemispheres, including the basal blastoma, in part having a definitely spongio- ganglia, optic pathways and diencephalic region were blastic appearance, and electron microscopical tumour-free. In the spinal cord t'he leptomeningeal studies showed plentiful intracytoplasmic glial thickening was collagenous and tumour cells were filaments. guest. Protected by copyright. not present. In a detailed study of a cerebellar and brain- Results of GFAP reaction Sections of a known stem tumour from a 14-year old astrocytoma were used as positive controls. Omission girl, Rubinstein, of incubation with anti-GFA protein served as a Herman and Hanbury9 demonstrated transitional negative control. features between medulloblastoma and diffuse In the biopsy specimen the majority of tumour astrocytoma. In the vermis cerebelli this tumour cells were unstained. However, some scattered cells was highly cellular, and was composed of small showing positive staining were present throughout uniform cells with no distinctive cytoplasmic the tumour, and around the hypertrophic blood features when examined electronmicroscopically. vessels there was a heavy concentration of positive In the brainstem, however, there were wide areas cells with processes radiating from around the vessel, of fibrillated astrocytic cells. Sequential morpho- giving an appearance reminiscent of . logical changes in tissue and organ culture Review of the PTAH-stained sections did not permit systems indicated progressive differentiation from identification of these cells as astrocytes (see case 6 described by Deck et al.1) "medulloblastoma cells" to fibrillated astrocytes. In the post-mortem sections the results closely The authors discussed the possible interpretation paralleled those obtained with PTAH. Strong stain- of this tumour as medulloblastoma differentiat- ing was chiefly among cells of elongated or fibril- ing into astrocytoma, but concluded that this was lated appearance in the brainstem (fig F) whereas difficult to sustain because of the fairly prolonged the cells in the subpial zone and cerebellar white history of clinical evolution over a two-year matter were mainly negative. period and because of the absence of a demon- strable mass until the late stages. The interpre- http://jnnp.bmj.com/ Discussion tation they preferred was that this was an example of diffuse brainstem astrocytoma with The concept of the cerebellar medulloblastoma focal dedifferentiation to medulloblastoma. In as a primitive neuroepithelial neoplasm with the the present case this difficulty does not arise since potential for development along neuroblastic or the history of illness was short and the tumour spongioblastic lines originated with the work of was, at the time of operation, interpreted as Bailey and Cushing.2 This interpretation still is medulloblastoma. At first sight it seemed that not universally accepted: some authors regard the pons provided conditions that were specially on September 24, 2021 by these tumours as sarcomas of mesenchymal favourable for the cells to develop an elongated origin, while others deny the possibility of a bipolar or fibrillary form and the environment dual potential for differentiation, and believe was thus largely responsible for the change in that "medulloblastomas" can be classified into morphology. But, in this context it is of interest , or oligodendro- that GFAP preparations revealed the astrocytic on the basis of metallic impregnation.3 nature of some of the tumour cells unsuspected J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.11.1041 on 1 November 1980. Downloaded from

1044 R 0 Barnard and H Pambakian at the time of the original biopsy, and there- 2 Bailey P, Cushing H. Medulloblastoma cerebelli fore radiation cannot be held to be responsible -A common type of mid-cerebellar of for the apparent transformation to astrocytoma. childhood. Arch Neurol 1925; 14:192-224. 3 Polak M. On the true nature of the so-called Conclusion medulloblastoma. Acta Neuropathol (Berl) 1967; 8:84-5. A case of cerebellar medulloblastoma which 4 Rubinstein LJ, Herman Mary M. Recent shows transition toward astrocytoma advances in human neuro-oncology in Recent empha- A dvances in Neuropathology. Edinburgh: sises the potential for divergent differentiation Churchill Livingstone, 1979; 170-223. of this neuroepithelial neoplasm. 5 Willis RA. Pathology of Tumours, 2nd ed. London: Butterworth, 1953; 816-7. The patient was under the care of Dr RE Kelly 6 Rubinstein LJ. Tumors of the central nervous and Professor Lindsay Symon whose co-operation system. Atlas of tumor pathology, 2nd series, we acknowledge. We thank Dr Lawrence F fasc. 6. Armed Forces Institute of Pathology, Eng (VA Hospital, Palo Alto) who supplied the Washington, DC, 1972; 138-9. GFA anti-serum and Dr Lucien J Rubinstein 7 Oppenheimer DR. The effect of irradiation on a (Stanford University) for his helpful criticism medulloblastoma. J Neurol Neurosurg Psychiatry of the manuscript. For both technical and photo- 1969; 32:94-8. graphic work we are grateful to Mr Trevor 8 Muller W, Schaefer HE. Beitrag zur morpholo- Scott, FIMLS. gischen Onkotypie des Medulloblastoms. Acta Neuropathol (Bert) 1974; 30:51-61.

References 9 Rubinstein LJ, Herman MM, Hanbery JW. The guest. Protected by copyright. relationship between differentiating medullo- 1 Deck JHN, Eng LF, Bigbee J, Woodcock SM. blastoma and de-differentiating medulloblastoma The role of glial fibrillary acidic protein in the and de-differentiating cerebellar astrocytoma. diagnosis of central nervous system tumors. Acta Light, electron microscopic, tissue and organ Neuropathol (Bert) 1978; 42:183-90. culture observations. Cancer 1974; 33:675-90. http://jnnp.bmj.com/ on September 24, 2021 by