Primary glioblastoma in the pineal region: a case report and review of the literature.

INTRODUCTION
Glioblastoma in the pineal region is extremely rare with only a few cases reported in the literature.


CASE PRESENTATION
A 68-year-old man presented with a sudden deterioration manifesting as a headache, vomiting and gait disturbance. A magnetic resonance imaging study revealed a heterogeneously ring-enhanced mass in the pineal region. The mass was subtotally removed through the occipital transtentorial approach, and diagnosed as a glioblastoma.


CONCLUSION
We discuss the clinical course, radiological findings and treatment strategies of pineal glioblastoma with a review of the relevant literature.


Introduction
The pineal region consists of the pineal body, the posterior wall of the third ventricle, tela choroidea and velum interpositum. Despite its small size, a wide variety of brain tumors can arise in the pineal region. Tumors of the pineal body may be of pineal parenchymal origin, of extragonadal germ cell origin, or of neuroglial origin [1]. Approximately 11-28% and 50-75% of tumors in the pineal region are pineal parenchymal tumors and germ cell tumors, respectively [1]. In addition, glioma, meningioma and mesenchymal tumors are encountered occasionally. Glioblastoma, which is the most malignant and frequent glioma in brain tumors, is extremely rare in the pineal region with only 17 cases being reported in the literature [2][3][4][5][6][7][8][9][10][11][12][13]. This paper presents a case of glioblastoma arising in the pineal region and discusses its clinical course, radiological findings and treatment strategies with a review of the relevant literature.

Case presentation
A 68-year-old man presented with a sudden deterioration manifesting as a headache, vomiting and gait disturbance. Two months earlier, he had begun to notice intermittent headaches. Neurological testing revealed ataxic gait features and bilateral papilledema without other neurological deficits. The computed tomography (CT) scan revealed obstructive hydrocephalus caused by a round hypodense ill-defined lesion in the pineal region (Fig. 1A). A magnetic resonance (MR) imaging study demonstrated a 4 × 3 × 4 cm mass at the pineal gland. Through the administration of gadolinium, the lesion showed a heterogeneous hypointensity on the T 1 -weighted image and hyperinten-sity on the T 2 image as well as ring-enhancement with an extension into the midbrain and thalamus ( Fig. 1B and  1C). No hematological or biochemical abnormalities were evident, and the other tumor markers, such as α-fetoprotein, β-human chorionic gonadotrophin and placental alkaline phosphatase were within normal limits. Surgery was performed using the occipital transtentorial approach because a non-germinomatous malignant tumor was considered a possibility. During the operation, a very soft, gray-colored mass was located in the pineal region, which was barely demarcated from the peritumoral brain. Some hard portions were found in the tumor. An examination of frozen biopsy samples showed anaplastic astrocytic tumor cells. The mass was subtotally removed due to adhesion with the hypothalamus and midbrain, and its severe bleeding nature. The pathologic findings revealed a typical glioblastoma consisting of frequent mitotic figures, a high proliferation index, microvascular proliferation with endothelial cell hyperplasia, and extensive necrosis with focal pseudopalisading ( Fig. 2A). Immunohistochemistry revealed a positive reaction to the glial fibrillary acidic protein in both cell bodies and processes (Fig. 2B). A further review of the pre-operative MR imaging study showed an enhanced mass in the fourth ventricle that was consistent with ependymal dissemination (Fig. 1D). Two weeks after surgery, the patient underwent a ventriculoperitoneal shunt due to the rapid exacerbation of signs and symptoms of the hydrocephalus. Considering the pathological and radiological findings, whole neuraxis irradiation therapy was recommended. However, his Non-contrast computed tomography scan showing a hypointense mass in the pineal region (A) Figure 1 Non-contrast computed tomography scan showing a hypointense mass in the pineal region (A). T 1 -weighted sagittal (B) and gadolinium-diethylenetriaminepentaacetic acid enhanced axial (C and D) magnetic resonance images demonstrating a heterogeneously ring-enhanced mass with central necrosis in the pineal region and ependymal dissemination in the fourth ventricle.

A B C D
family insisted on conservative medical support. The patient died 2 months after the diagnosis.
All reported cases of pineal glioblastomas have presented with signs or symptoms of increased intracranial pressure and hydrocephalus. Eight patients (57.1%) with a pineal glioblastoma also presented with visual or gaze disturbances, including diplopia, blurry vision, nystagmus and upgaze palsy, which were mainly consistent with Parinaud's syndrome. However, the clinical symptoms and signs of pineal glioblastomas are similar to other tumors in the pineal region, which makes them difficult to diagnose based on the clinical history and presentation alone.
MR imaging of pineal glioblastomas demonstrate characteristic features. Heterogeneous enhancement with a centrally located non-enhanced portion indicates central necrosis. Infiltration into the surrounding structures, such as midbrain and thalamus, is shown as hyperintensity on the T 2 -weighted MR image, extending beyond the margin of the enhanced mass. Despite its rapid and infiltrative nature, glioblastomas generally do not invade the subarachnoid space, and rarely metastasize through the cerebrospinal fluid pathway [14]. However, a review of pineal glioblastoma revealed leptomeningeal or ventricular dissemination to be quite common (7 in 10 available cases). Among these cases, two cases, including the present one, showed pre-operative dissemination on the initial radiological study. Upon a careful review of pre-operative MR imaging for a pineal region mass, an enhancing nodule in the subarachnoid space or ventricle system can assist in the diagnosis of glioblastoma.
Considering that most patients with pineal glioblastoma multiforme (GBM) show symptoms and signs of hydrocephalus, an endoscopic third ventriculostomy and tissue biopsy may be an appropriate treatment for pineal glioblastoma. However, according to Amini et al. [2], this procedure was unable to resolve the hydrocephalus over time and obtain sufficient tissue samples in two out of three cases. The benefit of an aggressive surgical resection in the treatment of pineal GBM is unclear. Two patients who underwent a surgical resection only, including ours, died 2 months after the diagnosis [8]. The average survival in the three cases who received radiation therapy alone was 3.3 months (range, 2 to 4 months) [2,7,10]. However, adjuvant radiation therapy and/or chemotherapy after a surgical resection may prolong the survival of patients with a pineal glioblastoma. The three patients who underwent a surgical resection and radiation therapy lived an average of 5.3 months (range, 4 to 6 months) [4,9,13]. Furthermore, the mean survival duration of the four  patients who received radiation therapy and chemotherapy after the surgical resection was 7 months (range, 4 to 11 months) [2,11,12].
The overall prognosis of a patient with a pineal glioblastoma is poor. Despite every effort in treatment, the maximum survival duration is less than 1 year after diagnosis (except for a single case reported by Bradfield and Perez [3]).

Conclusion
Glioblastoma in the pineal region is a very rare disease. However, in middle aged patients, a heterogeneously ringenhanced mass in the pineal region with leptomeningeal dissemination on MR imaging can raise the suspicion of glioblastoma. Even though it is impossible to conclude the best treatment modality, early adjuvant radiation therapy and chemotherapy after surgical resection appear to prolong the survival of patients with a pineal glioblastoma.