A case of adult anaplastic cerebellar ganglioglioma.

BACKGROUND: Anaplastic posterior fossa ganglioglioma in adults is exceedingly rare. To date, only one case of adult anaplastic posterior fossa ganglioglioma has been reported in the English literature and none has been described at the cerebellum. To our knowledge, this report is the third case of malignant posterior fossa ganglioglioma in adults and the first at the cerebellum. In general, this entity can be misdiagnosed preoperatively as a primary posterior fossa neoplasm, and by reporting our clinical and radiographic observations we want to add to the existing literature on this rare entity. CASE DESCRIPTION: A 40-year-old man presented with a history of headaches and dizziness and progressive gait disturbance and was diagnosed with anaplastic ganglioglioma in the posterior fossa.
CONCLUSIONS: Although rare, our case demonstrates that anaplastic ganglioglioma should be considered in the differential diagnosis of infratentorial tumors in adult patients.

INTRODUCTION

Anaplastic ganglioglioma is a very infrequent primary neoplasm of the central nervous system. These tumors are most commonly found in the supratentorial compartment, and any occurrence in the posterior fossa is considered a rare event.[20]

To date, only few cases of malignant infratentorial gangliogliomas have been documented, and commonly among children.[6] Only one other case of anaplastic posterior fossa ganglioglioma in an adult patient has been reported in the English literature.[6]

Here, we report an adult patient with anaplastic ganglioglioma of the cerebellum; the first such reported case in the literature. We also review the literature related to infratentorial malignant gangliogliomas, and discuss the clinical manifestations, imaging and histopathological findings, reported treatments, and the outcome associated with such lesions.

CASE REPORT

A comprehensive literature search for this review was conducted on PubMEd, MedLine, and Google Scholar. There were no limitations on the date, type, or language of the publication. The first search was conducted using the term “posterior fossa ganglioglioma” followed by “posterior fossa anaplastic ganglioglioma,” “cerebellar anaplastic ganglioglioma,” and “posterior fossa ganglioblastoma.”

The titles and abstracts were reviewed and only11 publications were selected relating to malignant posterior fossa ganglioglioma; 3 in adults and 8 in children. These cases are reviewed in Table 1.

Table 1

Summary of the reported cases of malignant posterior fossa ganglioglioma

CASE DESCRIPTION

A 40-year-old man presented to the neurosurgical department with a history of headache for 3 months. His headache was associated with a progressive staggering gait, dizziness, and nausea. Past and family history was unremarkable.

General physical examination and review of systems were not contributory. Routine blood tests were normal, and chest X-ray was normal. The patient was HIV-negative. Neurological examination showed focal cerebellar signs, including ipsilateral cerebellar ataxia, and slurred speech. The fundus oculi were normal bilaterally.

Cranial magnetic resonance imaging (MRI) revealed a solid mass with a maximum diameter of 3 cm, which appeared hypointense on T1-weighted sequences and hyperintense on T2-weighted images. The lesion enhanced irregularly after the administration of intravenous gadolinium. MR spectroscopy was obtained and showed a high choline/creatine ratio with increased myoinositol level, suggesting anaplastic behavior of the lesion [Figure 1].

Figure 1

Preoperative magnetic resonance imaging (MRI). T2 (a), T1 native (b), and T1 after gadolinium administration (c): left cerebellar lesion (arrowhead) slightly hypointense on T1-weighted images and hyperintense on T2-weighted images, with peritumoral edema (black star) and strong ill-defined contrast enhancement. (d) MR perfusion with cerebral blood volume (CBV) cartography: slight peripheral hyperperfusion (white arrow); rCBV = 1.9 × normal contralateral cerebellum white matter. (e) Proton MR spectroscopy: elevated doublet of lactate at 1.33 ppm which is inverted on the spectrum with long echo-time (green arrow). NAA/Creatine ratio is reduced (f) Postoperative CT scan: resection cavity (white arrow)

Under a working diagnosis of a neoplastic process, a standard suboccipital craniotomy was performed in the prone position. After opening the dura mater and performing a corticectomy for access and after transvermian approach, the lesion was found to be infiltrative and hypervascular. Complete tumor resection was performed, as shown in the postoperative CT scan. The postoperative course was uneventful. The histological diagnosis of the lesion yielded an anaplastic ganglioglioma, with the tumor showing biphasic pattern of ganglion cells and neoplastic glial cells. The malignant glial component characterized by hypercellularity, nuclear atypia, and increased mitotic activity; however, no microvascular proliferation or necrosis was present [Figure 2a]. The neoplastic glial cells were immunoreactive for glial fibrillary acidic protein (GFAP), immunoreactive for synaptophysin, and the Ki67 proliferation index was 20% [Figure 2b].

Figure 2

(A): (Hematoxylin eosin ×20): tumor showing biphasic pattern of ganglion cells and neoplastic glial cells. (b): (Hematoxylin eosin ×20): malignant glial component characterized by hypercellularity, nuclear atypia and increased mitotic activity. (B) Immunohistochemistry ×400. (c) GFAP: the neoplastic glial cells are immunoreactive for GFAP. (d) Ki67: Ki67 proliferation index was 20%. (e) Synaptophysin: the neoplastic ganglion cells are immunoreactive for synaptophysin

The patient received standard fractionated radiotherapy at a total dose of 54 Gy (1.8 Gy per day, 5 days a week) for 6 weeks. Follow-up of the patient with a computed tomography (CT) scan for 6 months after the surgery did not show any evidence of tumor recurrence [Figure 2f]. Clinically, the patient showed only a persistent mild gait abnormality (truncal ataxia) but no other neurological abnormalities.

Despite two cycles of adjuvant temozolomide, the tumor recurred and progressed with cerebellar multiple nodular location and died 10 months after the surgery.

Only 3 cases of malignant posterior fossa ganglioglioma in adults have been reported in the English literature (A summary of patient characteristics at presentation and surgical outcome is presented in Table 1). Only Toledo et al. described a Grade III ganglioglioma of the brainstem.[6] WHO grade IV ganglioglioma or ganglioblastoma had been described by Matzusaki et al. and Mekni et al., one at the cerebellopontine angle and the second as a cerebellar ganglioblastoma.[1213]

DISCUSSION

Gangliogliomas are rare mixed glioneuronal tumors that represent less than 1% of central nerve system neoplasms[111426] and contain a mixture of neoplastic glial and neuronal cells.[21826]

Gangliogliomas are staged according to the most recent WHO classification[5] with WHO grades I and II representing benign tumors and accounting for 90–98% of ganglioglioma cases. The remaining cases are composed of anaplastic gangliogliomas (WHO grade III) and ganglioblastomas (WHO grade IV), which are rare and poorly characterized.[51121] Their incidence is estimated at approximately 0.02 cases per million people per year.[1923]

While the exact etiology and pathogenesis remains unclear, the cell of origin is thought to be a glioneuronal precursor.[11] The glial component represents the malignant portion of the tumor in a majority of the cases, but transformation has also been reported in the neural component, and neuroblastomatous ganglioglioma have been described.[1121]

To be considered an anaplastic ganglioglioma, the tumor had to have five or more mitoses per 10 high-power fields, and at least one of the additional criteria, angiogenesis and/or necrosis, in the glial component.[26]

Anaplastic ganglioglioma can arise de novo or secondary via malignant transformation of a pre-existing WHO grade I ganglioglioma. The rate of intracranial gangliogliomas malignant transformation has been calculated to range from 0.6 to 14.5%.[1525]

Only 11 infratentorial anaplastic ganglioglioma cases have been reported in the literature that are preferentially diagnosed in children with a slight preponderance among males.[6789101316172226] These anaplastic gangliogliomas are rare tumors whose epidemiology, natural history, prognostic factors, and treatment options have been sparsely documented thus far. To date, only 3 cases of malignant posterior fossa ganglioglioma in adults have been reported in the English literature [Table 1].[61617] González Toledo et al. described a Grade III ganglioglioma of the brainstem in a 33-year-old man. WHO grade IV ganglioglioma or ganglioblastoma have been described by Matzusaki et al. in a 64-year-old woman with a cerebellopontine angle ganglioblastoma[16] and Mekni et al. in a 25-year-old woman with a cerebellar ganglioblastoma.[17]

There have been no previous reports describing an anaplastic ganglioglioma (grade III) located in the parenchyma of the cerebellum.

Our review of the literature describing gangliogliomas of the posterior fossa has yielded that these tumors can manifest similar to other lesions in this location with hydrocephalus, cranial nerve palsies, gait and speech disorders, and even myoclonus.[3] In our patient, preoperative symptoms included headache associated with progressive staggering gait, dizziness, and nausea. Cerebellar signs including cerebellar ataxia and slurred speech were noted.

The median history of disease reported by Karremann et al. was 9 months (range, 1.0–43.0 months) and depended on the location and size of the tumor.[10]

In a majority of the series and reported cases, the characteristics described on MRI were hypointensity in T1, hyperintensity on T2 and FLAIR, and patchy enhancement after contrast administration. The apparent diffusion coefficient value of anaplastic ganglioglioma was reported to be reduced (0.95 × 10-3 mm2/s (SD = 0.053), which likely reflects its high cellularity. In gangliogliomas with anaplastic features, MR spectroscopy has been previously shown do demonstrate peaks of glutamate, choline, and myoinositol.[6] In our case, the choline peak was high and the myoinositol was pronounced.

Due to their low frequency, a standard treatment for anaplastic ganglioglioma has not been established yet. According to the literature, complete surgical resection is recommended.[10]

Following resection, radiotherapy seems to improve local control rates in high-grade gangliogliomas and should be applied as an adjuvant therapy. Standard fractionated radiotherapy (54.0–59.4 Gy total dose; doses of 1.8 Gy/day, 5 days/week over 6–7 weeks) was common for most cases.[1012]

The role of systemic chemotherapy has not been established in prospective randomized trials due to low number of cases seen, and previously employed regimen are not well documented in the existing case series. Prognostic factors of poor survival are older age at diagnosis, male sex, and malignant glial features.[23]

Anaplastic gangliogliomas appear to represent a very aggressive disease with poor overall outcome (median progression-free survival, 10 months; median overall survival; 27 months).[26] Our patient survived 10 months after total resection with radiation.

Varlet et al. have shown that the extent of surgical resection in malignant glioneuronal tumors is significantly correlated to survival.[24] In their cohort of 40 mixed cases, median survival was 44 months in patients who underwent gross total resection but only 15 months in those who underwent subtotal resection.[24] It is also known that these tumors can rarely form distant extracranial metastases,[4] which may require surveillance scanning for staging during follow-up.

In a recent study, immunohistochemical molecular analyses indicated that BRAF V600E mutation is present in 39% of anaplastic gangliogliomas in both glial and neuronal population without prognostic significance.[26]

Personalized therapies as anti-BRAF inhibitors can be a useful adjuvant therapy together with the first-line oncological treatments, and a few cases of anaplastic gangliogliomas treated by anti-BRAF therapy with promising results have been reported.[126]

CONCLUSION

We present a rare case of anaplastic ganglioglioma WHO III in the cerebellum of an adult patient along with its clinical diagnosis and treatment. This is only one of a few such cases observed thus far and contributes to our understanding of the characteristics of this rare posterior fossa tumor. The present work demonstrates that anaplastic ganglioglioma need to be considered in the differential diagnosis of malignant primary infratentorial brain tumors in adult patients.

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Conflicts of interest

There are no conflicts of interest.