Introduction

Gangliogliomas are tumors of the central nervous system suspected to derive from common precursor cells in a hamartomatous glioneural lesion [19]. Histopathologically, these tumors consist of ganglionic and glial cells. They compromise up to 4% of all pediatric central nervous system neoplasms and are thus rare [11]. Anaplastic intracranial gangliogliomas are an aggressive subtype of gangliogliomas featuring mitotic figures, hypercellularity, vascular proliferation, and necrosis mainly in the glial compartement of the lesions [11]. BRAF V600E mutation is reported to be more frequent in intracranial anaplastic gangliogliomas than in spinal intramedullary lesions [5, 15]. Secondary malignant transformation of primary benign gangliogliomas is reported [9].

Historical background

Gangliogliomas were first described in 1926 as a distinct type of intracranial neoplasm [19]. The largest series of anaplastic gangliogliomas was reported in 2011 with 85 cases and a median age of 25.5 years, most frequent temporal location (27%), and a median overall survival of 28.5 months [19]. The first case report from a child dates back to 1986 [7].

Clinical presentation

Gangliogliomas are highly epileptogenic lesions, especially with the most frequent location of the temporal lobe [13]. Primary anaplastic ganglioglioma can furthermore present with symptoms of elevated intracranial pressure as well as diplopia, hemiplegia, and other neurological symptoms. Symptomatic epilepsy was as frequent (8/19 = 42%) as the symptoms of elevated intracranial pressure as a presenting sign in the described cases of an intracranial primary anaplastic ganglioglioma in children (Table 1).

Table 1 A comparison of 19 reported cases of an intracranial primary anaplastic ganglioglioma in pediatric patients (0–21 years) in chronological order. The mean age is 11 years
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Diagnosis

Areas of histologically mitotic activity, pronounced hypercellularity, vascular proliferation, and necrosis are typical for the diagnosis of anaplasia [10]. These anaplastic changes are most frequent in the glial part of the tissue, while an occurrence in the neuronal part is also reported [12].

Gangliogliomas with anaplastic features in histology are reported to have a wide variation in a radiological appearance: solid and cystic components as well as contrast uptake and calcification [13]. In the pediatric group, contrast enhancement is frequently described [2, 13]. In T1-weighted magnetic resonance imaging, the tumors are hypointense and on T2-weighted imaging hyperintense (Figs. 1 and 2). MR spectroscopy may reveal distinct but nonspecific choline peaks that might differentiate from a benign ganglioglioma but not from other primary brain tumors [12].

Fig. 1
figure 1

Preoperative sagittal T2-weighted MR-image showing the hyperintense lesion (star) of the quadrigeminal plate extending from the cerebellum to the thalamus

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Fig. 2
figure 2

Preoperative axial and sagittal T1-weighted MR-image with contrast showing the partly contrast enhancing hypointense lesion (star) of the quadrigeminal plate and bilateral thalamic involvement

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Only a few cases of primary anaplastic intracranial gangliogliomas are reported in children (Table 1), whereas the gangliogliomas in general are reported to be frequent in children and young adults [13]. Nineteen cases of intracranial primary anaplastic gangliogliomas were found including the presented one. Mean age was 11 years with a range from 0 to 21 years. Most lesions were similar to pilocytic gliomas and involving the temporal lobe. Rare lesions as desmoplastic infantile ganglioglioma or anaplastic gliomas must also be considered in the differential diagnosis [21].

Treatment and results

Seven deaths (37%) are reported (Table 1), thus oncological therapy including radiotherapy seems necessary, if possible. But clinical studies on prognosis of anaplastic gangliogliomas were unsure about the role of adjuvant radiotherapy, as they found no survival advantage with radiotherapy [18].

Contradictory reports about a devastating course for pediatric anaplastic gangliogliomas and relatively good survival rates in other studies are to be found in the literature [18].

The course of AGG is characterized by a local recurrence or leptomeningeal spread [13]. The five-year overall survival was reported to be 88% with a superior outcome in patients, who underwent a gross total tumor resection, when compared with a partial resection [11]. In the presented series, fatal outcome was only to be seen in partially resected tumors (7/8 = 88%).

Treatment with vemurafenib, selectively inhibiting the oncogen BRAF could be an interesting option in lesions with BRAF V600E mutation as in the presented case [1, 17]. In brain metastasis of BRAF V600E mutation-positive melanoma vemurafenib showed considerable success rates with side effects [4]. In the view of the described prognosis of anaplastic gangliogliomas, other therapeutic options derived from genetic histological examinations should be considered.

Exemplary case

An 11-year old boy came to the admission with the diagnosis of a midline tumor at the quadrigeminal plate symptomatic with headache and double vision due to bilateral abducent nerve palsy. Examination revealed bilateral papilledema.

MRI studies of the head revealed a midline lesion, around the tectal area with an extension from the cerebellum to the pineal gland invading the diencephalon (Figs. 1 and 2). The lesion was homogenously in contrast enhancing and hyperintense in T-2 weighted imaging. Spinal MRI was uneventful. β-HCG as well as α-fetoprotein were within normal limits. An endoscopic ventriculostomy was performed. A median suboccipital craniotomy was performed with a supracerebellar approach, and a near total excision of the lesion was performed (Fig. 3). Fresh frozen section suggested pilocytic astrocytoma. Dysplastic ganglionic cells with multiple nuclei as well as mitotic activity in the glial and ganglionic part could be demonstrated in the further histological slides (Fig. 4). Final histology confirmed by the reference center, showed KI-67 positivity in 2–10% of the areas and staining for synaptophysin, as well as the mitotic marker pHH3. BRAF (V600E) mutation was detected. Thus, the diagnosis of an anaplastic ganglioglioma WHO grade III was stated.

Fig. 3
figure 3

Postoperative sagittal T2-weighted MR-image showing resection cavity of the tumor (star) and a small residual tumor below

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Fig. 4
figure 4

a Histological slide of the tumor composed of astrocytes and ganglion cells with dysplastic, binucleated neurons (arrow) (H & E) 400×. b Histological slide of the tumor showing ganglion cells with dysplastic, binucleated, and trinucleated neurons (arrows) (H & E) 400×. c Histological slide showing mitotic activity (open circle) in the glial part of the tumor and ganglion cells with dysplastic binucleated neurons (arrow) (H & E) 320×. d Histological slide showing mitotic activity (open circle) in the neural part of the tumor and ganglion cells with dysplastic binucleated neurons (arrow) (H & E) 400×

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In the postoperative course, the boy showed a vertical gaze palsy that completely recovered within 14 days after the surgery. Proton beam radiation therapy and temozolamide therapy were initiated after obtaining the final diagnosis (Table 1).

Summary and management recommendation

AGG is as rare as an intracranial lesion in children and was described to be radiologically similar to pilcyotic astrocytomas.

Histological examination is mandatory in the establishment of the diagnosis of AGG.

Postoperative oncological treatment should be initiated.

AGG must be considered as a differential diagnosis in supratentorial lesions especially with rapidly developing symptoms.