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Combined Pleomorphic Xanthoastrocytoma-Ganglioglioma of the Cerebellum.

Pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (GG) are typically superficial, supratentorial, solid, and cystic lesions with a predilection for the temporal lobes of young patients who present with a protracted history of seizures. Microscopically, PXA is characterized by neoplastic astrocytes that show marked nuclear pleomorphism, rare-to-absent mitotic figures, nuclear pseudoinclusions, and variable lipidization.[1] Immunohistochemically, the cells are positive for glial fibrillary acidic protein (GFAP). Generally, PXA follows an indolent course, with gross total resection being the treatment of choice; however, anaplastic transformation has been documented.[2] Ganglioglioma is a biphasic lesion characterized by neoplastic neuronal and astrocytic elements, with most cases following a clinical course as similarly benign as PXA. Recently, there has been an increasing awareness of the presence of gangliogliomatous elements in PXA. This entity has been aptly named combined PXA-GG. To our knowledge, there have been only 12 reported cases for which the terms combined, mixed, or composite PXA-GG have been used,[3-9] with most occurring in patients younger than 30 years. Most of these lesions were supratentorial, with solid and cystic elements, and followed a benign course. Increased mitotic activity and necrosis have only been described in recurrent lesions in 2 patients with combined PXA-GG.[7,9] Vascular endothelial proliferation has only been noted in the recurrent lesions that show mitotic activity and necrosis and not in any initial resection specimen. We report a new case of combined PXA-GG that occurred in a 60-year-old man as a solid, midline cerebellar tumor that showed vascular endothelial proliferation.


A 60-year-old white man presented with a 1-month history of intermittent occipital headache and dizziness. The patient's medical history was noncontributory. The results of medical and neurological examinations and blood work were unremarkable. The results of an unenhanced computed tomographic scan of the head were reported as normal. Two months later the patient complained of marked progression of symptoms. The headaches were more severe and aggravated by coughing, and the dizziness had become more frequent and accompanied by nausea. Physical examination revealed an ataxic tandem gait. A gadolinium-enhanced magnetic resonance study of the brain and upper cervical spine revealed a 5.0 x 3.2 x 2.8-cm homogeneously enhancing, sharply delineated, noncystic mass lesion in the cerebellar vermis (Figure 1). Perilesional edema with mass effect was noted, and there was compression of the fourth ventricle with mild obstructive hydrocephalus. A posterior fossa craniotomy revealed a solid, reddish fleshy lesion in the cerebellar vermis that blended in with the surrounding cerebellum. Since there was no distinct plane of dissection around the mass, a piecemeal resection was performed, resulting in near gross total removal. Postoperative magnetic resonance studies revealed a small nodular focus of enhancement in the roof of the fourth ventricle consistent with residual tumor. The patient received postoperative radiotherapy to the posterior fossa (50 Gy in 25 daily fractions for 5 weeks). He has shown no evidence of disease throughout 16 months of follow-up; however, he does have residual intermittent dizziness and slight speech impairment.



Formalin-fixed, paraffin-embedded tissue blocks were sectioned at 5 [micro]m for histochemical and immunohistochemical analysis. Sections were stained with hematoxylin-eosin and for reticulin and Bodian. Immunohistochemical staining using primary antisera against GFAP (Dako Corporation, Carpenteria, Calif, 1: 1000), synaptophysin (Zymed, San Francisco, Calif, 1:50), chromogranin (Dako, 1:100), MIB-1 (Zymed, 1:50), and p53 (Vector Laboratories, Burlingame, Calif, 1:20) were done at the indicated dilutions. Specific immunostaining was detected using the avidinbiotin peroxidase complex method. Fresh tissue samples were also fixed in glutaraldehyde, postfixed in osmium tetroxide, and Epon embedded for electron microscopy.


The specimen consisted of multiple irregularly shaped fragments of brown, hemorrhagic soft tissue, with an aggregate volume of approximately 8 mL. Sections showed cerebellar tissue containing a densely cellular primary neuroectodermal neoplasm (Figure 2), comprising an admixture of markedly pleomorphic, hyperchromatic spindled glial cells and plump elements with abundant amphophilic cytoplasm. Many of the plump cells contained multiple, markedly pleomorphic, eccentric nuclei with prominent nucleoli characteristic of neoplastic ganglion cells. There was a narrow band of permeation of the adjacent gliotic cerebellum and overlying leptomeninges. The lesion also contained numerous Rosenthal fibers, eosinophilic granular bodies, and nuclear pseudoinclusions in the pilocytic glial component. There was prominent perivascular lymphocytic cuffing and focal capillary endothelial proliferation. There was no necrosis. Mitotic activity was confined to the glial element and rare at 1 mitotic figure per 40 high-power fields. Lipidized cells were not identified, and there was no dysplasia or suggestion of malformation in the surrounding cerebellar cortex. Reticulin staining was largely confined to blood vessel walls and foci of meningeal spread. Immunohistochemically, the cells with ganglionic features showed focal perikaryal staining for synaptophysin and chromogranin, whereas many of the spindled cells were immunoreactive for GFAE Immunoreactivity for MIB-1 was less than 2% of tumor nuclei, whereas that for p53 was close to 40%. Ultrastructural features of the large ganglionic cells included prominent stacks of rough endoplasmic reticulum, neuritic processes, and microtubules; however, no dense-core neurosecretory granules were identified after an assiduous search.



Combined PXA-GG is a rare lesion that was first described by Furata et al in 1992.[3] Since that time, there have been 11 cases that have appeared as case reports or small series.[4-9] The clinical and radiological features of the 12 reported cases of combined PXA-GG are virtually identical to those of pure PXA or GG. The ages of the patients ranged from 14 to 82 years, with most (9 cases) being 30 years or younger. The lesions showed a predilection for the temporal lobes (8 cases); however, in 3 patients tumors occurred in the cerebellum, 2 of which involved the midline.[7,9] Radiologically, most of these cases possessed a cystic component, often with enhancing mural nodules. In contrast, the tumor in this report occurred as a solid, homogeneously enhancing mass in the cerebellar vermis of a 60-year-old man.

Histologically, these lesions show the bizarre astrocytic morphologic structure of PXA, with a paucity of mitotic activity and clusters of neoplastic ganglion cells. Combined PXA-GG have been described in 2 patterns according to the distribution of the PXA and GG components. The most common pattern (9 cases) consists of distinct areas of PXA and GG that abut, but do not intermingle, in the manner of a "collision tumor." The less common pattern consists of neoplastic ganglion cells admixed individually or in clusters within the substance of a PXA. The present lesion represents another example of combined PXA-GG with this less common admixed pattern.

In terms of anaplastic or malignant histological features, we observed no necrosis and only rare mitotic figures. With the exception of the report by Perry et al,[9] necrosis has not been described in initial resection specimens of combined PXA-GG. Such foci have, however, been observed in 2 recurrent lesions.[7,9] Capillary endothelial proliferation, although generally not regarded as an ominous feature in pure PXA or GG, has only been described in the recurrent combined PXA-GG that shows necrosis.[7,9] Our report is the first description, to our knowledge, of capillary endothelial proliferation in an initial resection of combined PXA-GG; however, its significance is unclear.

Less than 2% of tumor nuclei in our case showed MIB-1 immunoreactivity. The MIB-1 labeling indices have been reported in 5 instances of combined PXA-GG, with a range of 1.7% to 5.7% and no apparent correlation with clinical outcome.[6,9] The presence of p53 staining has been reported in only 1 of these tumors where there was immunoreactivity in rare nuclei.[9] In our case, 40% of tumor nuclei showed positive staining for p53. The significance of this observation is unclear, because immunohistochemistry alone cannot determine the presence of a p53 gene mutation.[10]

The clinical behavior of previous examples of combined PXA-GG has generally been benign. These patients were all treated with either gross total or subtotal resections, with follow-up periods ranging from 7 months to 12 years. There were 2 patients for whom postoperative radiotherapy was given with apparently favorable outcomes.[3,4] Only 1 patient is reported to have died of combined PXA-GG after multiple recurrences during 17 years, the final recurrence having the histologic features of glioblastoma multiforme.[9] The exact behavior of the tumor in our patient is difficult to predict given that so few of these lesions have been described. In patients older than 30 years, Lach et al reported 2 with no evidence of disease at 5 and 18 months of follow-up, respectively.[5] An 82-year-old patient described by Perry et al[9] was lost to follow-up following gross total resection.

The histogenesis of combined PXA-GG is unknown, and our report provides no additional insight in this regard. Lach et al[5] reported a series of 3 temporal lobe combined PXA-GGs in which each case was associated with cortical dysplasia in the surrounding brain, suggesting that these lesions may represent neoplastic transformation of residual germinal matrix in the setting of focal cortical maldevelopment. Alternately, the existence of combined PXA-GG has been interpreted by some as evidence that PXA and GG share a common origin. In this view, the combined lesion would be positioned along a spectrum between PXA and GG. Although PXA is thought to arise from subpial astrocytes,[1] Powell et al[11] and Kros et al[12] have described cases of histologically typical PXA that show immunoreactivity for synaptophysin and/or neurofilaments. In addition, Powell et al described 7 cases of PXA that contained cells that showed dual immunolabeling for GFAP and neuronal markers.[11] This suggests the existence of a bipotential precursor cell with predominantly astrocytic differentiation yet with a retained capacity for neuronal differentiation.[11] The evaluation of a large number of archival cases of "typical" PXA with respect to immunoreactivity for neuronal markers may reveal a greater number of cases showing this bidirectional differentiation. In addition, such a study may better define the incidence and clinical behavior of combined PXA-GG.

The authors are grateful to Dr G. N. Fuller, Dr J. Bruner, and Dr D. Lewis for consultation in this case.


[1.] Kepes J. Pleomorphic xanthoastrocytoma: the birth of a diagnosis and a concept. Brain Pathol. 1993;3:269-274.

[2.] Prayson R, Morris H. Anaplastic pleomorphic xanthoastrocytoma. Arch Pathol Lab Med. 1998;122:1082-1086.

[3.] Furata A, Takahashi H, Ikuta F, et al. Temporal lobe tumor demonstrating ganglioglioma and pleomorphic xanthoastrocytoma components: case report. J Neurosurg. 1992;77:143-147.

[4.] Kordek R, Biernat W, Sapieja W, et al. Pleomorphic xanthoastrocytoma with a gangliogliomatous component: an immunohistochemical and ultrastructural study. Acta Neuropathol. 1995;89:194-197.

[5.] Lach B, Duggal N, DaSilva VF, Benoit BG. Association of pleomorphic xanthoastrocytoma with cortical dysplasia and neuronal tumors: a report of three cases. Cancer. 1996;78:2551-2563.

[6.] Vajtai I, Varga Z, Aguzzi A. Pleomorphic xanthoastrocytoma with gangliogliomatous component. Pathol Res Pract. 1997;193:617-621.

[7.] Lindboe CF, Cappelen J, Kepes J. Pleomorphic xanthoastrocytoma as a component of a cerebellar ganglioglioma: case report. Neurosurgery. 1992;31:353-355.

[8.] Rao C, Abdu A, Deloso D, et al. Co-occurrence of ganglioglioma and pleomorphic xanthoastrocytoma in the temporal lobe. J Neurooncol. 1995;24:125-140.

[9.] Perry A, Giannini C, Scheithauer BW, et al. Composite pleomorphic xanthoastrocytoma and ganglioglioma: report of four cases and review of the literature. Am J Surg Pathol. 1997;21:763-771.

[10.] Fulci G, Ishii N, Van Meir E. p53 and brain tumors: from gene mutations to gene therapy. Brain Pathol. 1998;8:599-613.

[11.] Powell SZ, Yachnis AT, Rorke LB, et al. Divergent differentiation in pleomorphic xanthoastrocytoma: evidence for a neuronal element and a possible relationship to ganglion cell tumors. Am J Surg Pathol. 1996;20:80-85.

[12.] Kros JM, Vecht CJ, Stefanko SZ. The pleomorphic xanthoastrocytoma and its differential diagnosis: a study of five cases. Hum Pathol. 1991;22:1128-1135.

Accepted for publication May 1, 2000.

From the Departments of Pathology (Drs Evans and Bilbao) and Neurosurgery (Drs Fayaz and Cusimano), St. Michael's Hospital, and Department of Radiation Oncology, Princess Margaret Hospital (Dr Laperriere), University of Toronto, Toronto, Ontario.

Reprints: Juan M. Bilbao, MD, Department of Pathology, St. Michael's Hospital, 30 Bond St, Toronto, Ontario, Canada M5B 1W8 (e-mail:
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Author:Evans, Andrew J.; Fayaz, Imran; Cusimano, Michael D.; Laperriere, Norman; Bilbao, Juan M.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1CANA
Date:Nov 1, 2000
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