Introduction

Pleomorphic xanthoastrocytoma (PXA) was first defined in 1979 as an evolving brain tumor leading to seizures; it is found primarily in young patients [1, 2]. PXA was added to the World Health Organization (WHO) classification of central nervous system (CNS) neoplasms in 1993 [3]. Although its microscopic features, marked pleomorphism and high cellularity, are ominous, PXA is a relatively indolent tumor with a prolonged clinical course. It was classified as a WHO grade II tumor. Giannini et al. [4], who studied 71 patients with PXA and reviewed the literature, suggested that the aggressive variant type should be designated ‘PXA with anaplastic features’. They defined this entity as PXA exhibiting increased mitotic activity, i.e. five or more mitoses per 10 high-power fields (HPF) with or without accompanying necrosis. In 2008, Hirose et al. [5] reported that, in addition to the criteria of Giannini et al. [4], anaplastic PXA exhibits necrosis, microvascular proliferation, marked cellular anaplasia, and high Ki-67 labeling indices without high mitotic activity.

PXAs are rare astrocytic tumors; they account for less than 1% of all brain neoplasms and few reports have documented cerebrospinal fluid (CSF) dissemination in patients with PXA. We describe a young boy with primary anaplastic PXA with meningeal dissemination at the time of diagnosis.

Case report

Clinical findings

This 5 year-old boy was admitted with sudden-onset generalized convulsions. A head CT scan showed a calcified lesion at the base of the frontal lobe (Fig. 1). Head and spinal MRI scans revealed multiple gadolinium (Gd)-enhanced lesions in the subarachnoid space of the bilateral frontal- and temporal lobe and spinal lesions at the level of C7-Th7 (Figs. 2, 3). His neurological signs and blood examination were normal. As his parents refused surgery we obtained follow-up MRI scans at 3 month intervals for 18 months. Parental permission for open biopsy of his multiple lesions was obtained as follow-up revealed gradual tumor growth with extension around the interhemispheric fissure and spine (Figs. 2, 3). Open biopsy via left frontal craniotomy showed that the subarachnoid space was covered with tumor tissue.

Fig. 1
figure 1

A head CT scan obtained at admission revealed a calcified lesion at the base of the frontal lobe

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Fig. 2
figure 2

MRI scans obtained at admission demonstrated a widespread tumor with dissemination around the interhemispheric fissure (a, b axial-; c coronal T1-weighted Gd-enhanced images). Axial- (d, e) and coronal (f) images obtained 15 months later showed extension of the tumor

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Fig. 3
figure 3

Spinal MRI (sagittal, gadolinium-enhanced T1-weighted image) revealed widespread tumor with dissemination at the level of C7-Th7 (a). The image acquired 15 months later showed tumor extension around the whole spine (b)

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Pathological findings

Histopathologically, tumor tissue contained spindle and pleomorphic cells with multiangular nuclei; the tumor cells manifested no xanthomatous changes. We observed perivascular lymphoid infiltration, some intranuclear pseudoinclusions, Rosenthal fibers, eosinophilic granular bodies, and five mitoses per 10 high-power fields (HPF). There was neither necrosis nor microvascular proliferation. The size of the tumor nuclei varied (Fig. 4a, b). Immunochemical studies demonstrated that some of the cells were immunopositive for glial fibrillary acidic protein, and neurofilament protein (Fig. 4c, d). Spindle-shaped cells were closely packed and reticulin fibers were tightly packed between tumor cells; 5–10% of the cells were positive for monoclonal antibody to Ki-67 antigen (Fig. 4e, f). Based on these findings we made a histopathologic diagnosis of anaplastic PXA.

Fig. 4
figure 4

Photomicrographs of tumor samples. Hematoxylin and eosin staining of tumor samples (a). The tumor contained spindle- and pleomorphic cells with multiangular nuclei. There were Rosenthal fibers (b-1), eosinophilic granular bodies (b-2), perivascular lymphoid infiltration, some intranuclear pseudoinclusions, and five mitoses per 10 high-power fields (HPF). We noted no necrosis or microvascular proliferation. Some tumor cells were immunopositive for glial fibrillary acidic protein (c) and neurofilament protein (d). Spindle-shaped cells were closely packed and reticulin fibers were tightly packed between tumor cells (e). Of the tumor cells, 5–10% were positive for monoclonal antibody to Ki-67 antigen(MIB-1 index) (f)

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Chemotherapy

The patient received adjuvant chemotherapy consisting of carboplatin and vincristine without radiation therapy [6]. Carboplatin (175 mg/m2) was administered by 1 h infusion for four consecutive weeks; after a 2 week rest period, this therapy was continued for four more weeks. Concurrently, vincristine (1.5 mg/m2) was delivered by intravenous bolus weekly for 10 weeks. After a 3 week break between maintenance cycles the regimen was continued for a total of 12 cycles. Chemotherapy was administered for 1.5 years. Although the tumor grew and extended before the delivery of chemotherapy, the intracranial lesions did not progress. On the other hand, some of the spinal lesions continued to grow slightly during chemotherapy (Fig. 5). The patient manifested normal physical and mental development and no neurological deficits. To date, he has not received radiation therapy.

Fig. 5
figure 5

Follow-up MRI study performed 18 months after the start of chemotherapy showed that the intracranial lesions did not progress. (a, b, axial images; c coronal gadolinium-enhanced T1-weighted image).There was slight growth of the spinal lesions. (d sagittal, gadolinium-enhanced T1-weighted image)

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Discussion

Characteristics and dissemination of PXA

According to published reports [1, 2, 7–30], among more than 260 PXAs, only two conventional PXAs and 1 anaplastic PXA manifested dissemination at the time of diagnosis [10–12] (Table 1).

Table 1 Reported patients with PXA with dissemination at diagnosis
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The patient reported by Passone et al. [10] was a 9 year-old girl with a non-anaplastic PXA with leptomeningeal dissemination. The tumor was solid, located at the left temporal lobe and infundibulum, and there was spinal leptomeningeal dissemination. One year after surgery she underwent chemotherapy with vincristine and carboplatin because of tumor progression. Three years later there was progression of the primary lesion and she underwent salvage surgery. Histological findings were suggestive of malignant transformation of the PXA. Subsequent radiotherapy and temozolomide treatment were ineffective and she died 5 years after the diagnosis due to tumor progression.

A 13 year-old girl with synchronous multicentric PXAs was reported by McNatt et al. [11]. The tumor was solid and located at the infundibulum, bilateral basal ganglia, and bilateral cerebral cortex. After open biopsy, she underwent whole-brain radiation. The tumor ceased growing and extending and 3 years post-treatment she is alive without neurological deficits.

Lastly, Lubansu et al. [12] encountered a 7 year-old girl with anaplastic PXA with meningeal dissemination at diagnosis. MRI showed a well-delineated lesion within the left temporal lobe. The tumor contained a cystic portion. There was leptomeningeal dissemination along the cervical spinal cord. Histologic study showed that the MIB-1 index did not exceed 1%; no necrosis was seen. Tumor cells were present in Virchow’s spaces away from the tumor block. The tumor was diagnosed as anaplastic PXA. Because of rapid recurrence, chemotherapy, consisting of alternating cycles of carboplatin/VP-16, cyclophosphamide, and vincristine, was started. A relapse was noted on MRI before the start of the 8th cycle. The tumor proved refractoy to further chemotherapy including temozolomide, thiotepa, and daily VP-16. This patient was alive 26 months after the diagnosis.

Most reported supratentorial PXAs harbored a cyst with a mural nodule. Our tumor manifested a solid component in the subarachnoid space. Of the three above-cited PXAs with dissemination at diagnosis, two harbored a solid component as did our patient; only one tumor was of the anaplastic type. In two patients chemotherapy produced a good response that lasted for 2 years. In one patient radiation therapy elicited a good response lasting for 3 years. The patient with the conventional PXA died of tumor progression 5 years post-diagnosis and the other two patients are alive without tumor progression 2 years post-treatment.

Anaplastic PXA

To our knowledge, of more than 260 PXAs, 27 were primary anaplastic PXAs and 25 manifested malignant transformation. Giannini et al. [4] proposed criteria for a diagnosis of anaplastic PXA, i.e. high mitotic activity (five or more mitoses per 10 HPF) with or without necrosis. Of 71 tumors, 26 (37%) contained no mitotic figures, 32 (45%) exhibited low-level mitotic activity (<5 mitoses per 10 HPF), and 13 (18%) manifested ≥5 mitoses per 10 HPF. In a multivariate model, there was a significant difference in recurrence-free survival between tumors with 0 and ≥5 mitoses per 10 HPF (P = 0.002; relative risk, 7.5), whereas the difference between tumors with <5 and ≥5 mitoses per 10 HPF approached significance (P = 0.06). The latest WHO classification of the nervous system [31] has adapted the definition proposed by Giannini et al. [4]. Hirose et al. [5] suggested that, in addition to the criteria of Giannini et al. [4], the presence of necrosis and microvascular proliferation, marked cellular anaplasia, and high Ki-67 labeling indices, without high mitoses, are also factors that identify the anaplastic type of PXA. In four of six anaplastic PXAs the diagnostic criteria proposed by Giannini et al. [4] were fulfilled. Although the other two did not exhibit five mitoses per 10 HPF, they were considered anaplastic PXA based on their morphological atypia and the presence of necrosis, endothelial proliferation, and high Ki-67 labeling indices. In earlier case reports, the definition of anaplastic PXA was not clear. In our patient, microscopic study showed five mitoses per 10 HPF but neither necrosis nor microvascular proliferation. Using the criteria of Giannini et al. [4] we diagnosed our case as anaplastic PXA based on the number of mitoses detected by microscopic study, and the evidence of whole neuroaxis dissemination on MRI scans.

Treatment of PXA with dissemination

No standard adjuvant chemotherapy for PXA, including anaplastic PXA, has been developed. In large clinical trials a variety of agents delivered as monotherapy or in combination regimens was effective in children with low-grade glioma; treatment stabilized the disease or produced an objective response [32–38]. In 1997, Packer et al. [6] reported the efficacy of carboplatin and vincristine chemotherapy in patients with progressive low-grade gliomas and in 1999, Reddy and Packer [39] suggested that the combination of carboplatin and vincristine provided the greatest disease control with acceptable levels of acute toxicity. Others [40, 41] documented the efficacy of temozolomide in children with recurrent, progressive low-grade glioma. Of the previously reported treatments, we chose the protocol of Packer et al. [6] because of its low toxicity and high rate of progression-free survival. Our patient did not experience tumor progression during the administration of chemotherapy and there was no hematological toxity, nephrotoxity, or neurotoxity. Furthermore, she manifested no post-treatment neurological deficits. As the size of intracranial lesions disseminated via the CSF was decreased on post-treatment MRI scans we consider the chemotherapy protocol to have been effective. However, as some PXAs undergo malignant transformation to high-grade glioma [9, 14, 23], patients with these tumors must be closely monitored for the early detection of tumor progression and malignant transformation.