Surgical Management and Prognostic Factors Based on 50 Tectal Plate Gliomas

The management and prognostic factors of tectal glioma (TG) remain ambiguous, because it is an extremely rare neoplasm that occurs predominantly in the pediatric population. The objective of this study was to evaluate the risk factors for progression-free survival (PFS) in TG patients after ETV operation, elucidate the radiological features of TG, and propose a treatment protocol. From 2002 to 2018, 50 patients that preoperative imaging manifestations were low-grade TGs were treated at our institute. Clinical features, treatments, radiologic findings, biopsies, and pertinent risk factors were evaluated.


Background
Tectal glioma (TG) represents a unique subset of typically low-grade gliomas arising in the tectal region at the roof of the brainstem. [1,2] The clinical presentation is often related to symptoms of obstructive hydrocephalus from the compression of the cerebral aqueduct, including headache and nausea typically attributed to increased intracranial pressure. [3][4][5] Endoscopic third ventriculostomy (ETV) is a neurosurgical approach used to redirect cerebrospinal flow and is currently the most often used approach for the treatment of obstructive hydrocephalus. [6][7][8]Given the paucity of information regarding TG in published studies, its management and prognostic factors remain ambiguous, and few studies have systematically summarized the clinical outcome of TG patients treated with ETV. [4,[9][10][11][12]]Therefore, we retrospectively reviewed patients whose preoperative imaging manifestations were consistent with low-grade TG and who underwent ETV in our institute. The goal of this study was to evaluate the risk factors for progression-free survival (PFS), elucidate the radiological features of TG, and propose a treatment protocol based on 50 TG patients who received ETV treatment.

Methods Patient Population
From 2002 to 2018, 50 patients whose preoperative imaging manifestations were consistent with lowgrade TG and who underwent ETV at our institute were enrolled in this study. The study was performed under an institutional review board-approved protocol in compliance with regulations set by Beijing Tiantan Hospital (BTH) for the study of human subjects with their informed consent.
Radiographic and pathological data were collected from picture archiving and communications systems (PACSs). A comprehensive review of medical charts, pertinent radiographic data, and operative reports was conducted. Clinical records and imaging studies were reviewed to confirm the presence of TG and the symptoms of the patients. A standardized report form was used to extract clinical data, including sex, age, main preoperative complaint, symptom duration, and any follow-up data, from the medical records.

Radiological Analysis
Tumor volumes were assessed for T1 and T2 signal intensity and circumscription, and calculated using the cubature formula as follows: volume = abc/2, in which a, b, and c were mutually orthogonal and represented the maximal diameters (width, thickness, and height) measured on axial, sagittal, and coronal magnetic resonance imaging (MRI) scans. Each tumor was graded for the proportions of cystic and/or enhancement avidity at each time -point. Changes in tumor size are given as the percentage of the two greatest perpendicular diameters compared to baseline, and an increase of ≥ 25% was categorized as progressive disease.

Surgical Management
For patients with TG in this study, all suffered from the clinical symptoms caused by hydrocephalus.
ETV was the first intervention to treat obstructive hydrocephalus, and a biopsy was performed with safety and no bleeding. Craniotomy was performed when the tumor progressed obviously and the symptoms gradually worsened after ETV.

Follow-up and Statistical Analysis
A clinical and radiographic follow-up was performed every 6 months within the first year and yearly thereafter. Four patients were lost to follow up, and 46 (92%) patients were available for PFS analysis.
The pertinent risk factors were evaluated by univariate and multivariate Cox regression analyses.
Secondary outcomes were PFS in subgroups with significant risk factors, and the pertinent estimated mean PFS time was calculated using the Kaplan-Meier method (log-rank test). P < 0.05 was considered significant. Analyses were performed with SPSS software (version 25.0, IBM Corp.).

Participants and Descriptive Data
The present cohort included 26 males and 24 females, with a median age of 11.5 years (range 0.5-19 years) at the initial diagnosis. The mean duration of symptoms was 9.1 months (range 0.3-36 months), and the most common preoperative symptom was headache (38 cases), followed by balance problems and ataxia (27 cases), nausea and vomiting (21 cases), visual complaints (8 cases), seizures (7 cases), urinary incontinence (4 cases), and developmental delay (4 cases) ( Table 1).  All patients underwent ETV to treat obstructive hydrocephalus, and 12 patients (24%) underwent a biopsy. Successful ETV was achieved in all patients, and there were no intraoperative complications. A successful ETV procedure was defined as freedom from a shunt, an improvement in symptoms, and a reduced ventricular size.
Radiological progression eventually occurred in 6 of 46 patients. Four out of six patients who exhibited radiological progression underwent surgical resection, one patient received radiotherapy, and the other patient did not receive any treatment after ETV. The 40 patients without radiological progression did not receive any other treatment after ETV.

Follow-up
The median follow-up period was 57 months (range 11-208 months). At the end of follow-up, all of the patients were shunt-free, and the clinical symptoms related to hpdrocephalus had disappeared or were relieved. The symptom of headache disappeared in 28/38 (73.7%) patients who had a preoperative headache, and the symptom of headache in another 10 patients (26.3%) was relieved.
All 27 patients (100%) who had preoperative balance problems or ataxia were asymptomatic after ETV and had normal gait. The 7 patients who had preoperative seizures were all asymptomatic for seizures after ETV. All postoperative imaging studies revealed a reduction in the ventricular size.
In the radiological progression group, the four patients who underwent surgical resection suffered from postoperative complications: two patients suffered from visual field defects and Parinaud syndrome, and the other two suffered from mutism. The patient who received only radiotherapy remained progression-free for two years after the completion of radiosurgery and his biopsy revealed astrocytoma (WHO grade II-III). The patient who did not receive chemotherapy or radiotherapy after ETV died three years later, and his biopsy revealed anaplastic oligodendroglioma (WHO gradeⅢ).
ETV failure was reported in one patient one year after the first intervention, the patient experienced balance problems again, and ETV was repeated. During surgery, we found that the stoma was closed.
The symptoms disappeared after the second ETV operation.

PFS and Risk Factors
In our series, radiological progression occurred in 6 patients (12%). The results of the univariate Cox regression analysis (including age, sex, duration of symptoms, lesion volume, contrast enhancement, cystic changes and tumor circumscription) showed that a large tumor size (> 2.8 cm³, P = 0.02) and cystic changes (P = 0.01) were independent adverse factors for PFS. Other radiologic parameters and clinical parameters were not significantly associated with PFS. PFS rates at 1 and 5 years were 91.2% ± 4.2% and 84.9% ± 5.9%, respectively. The estimated median survival time for PFS was 4 years (Fig. 3).

Discussion
ETV can effectively relieve the symptoms of obstructive hydrocephalus caused by TG The clinical symptoms of TG in patients are always caused by increased intracranial pressure from obstructive hydrocephalus. [13,14] The natural history of these tumors is most often indolent. [11,[13][14][15][16]Thus, for most of these patients, the treatment of hydrocephalus is enough. [4,17] ETV and shunt placement are currently the most widely used methods to relieve hydrocephalus. However, the risk of postoperative complications with shunt surgery is significantly higher than that of ETV. [3,18] In our series, all of the patients were shunt-free during the follow-up period, and the symptoms caused by increased intracranial pressure disappeared or were relieved. For patients with low-grade TG, ETV is often the only surgical procedure that most patients require (Figs. 4 and 5).

Use of neuroendoscopy for a pathological diagnosis of TG
We can use neuroendoscopy for the pathological diagnosis of patients with TG. [19] Although most TGs are low-grade gliomas, there are also reports in the literature of TG that may also be a high-grade glioma. [3,20] In our group, there were two patients whose preoperative imaging diagnoses were lowgrade gliomas, but the pathological diagnoses were high-grade gliomas (WHO grade II-III), which indicates that imaging studies may not always accurately confirm the nature of the tumors.
The benefit of a pathological diagnosis is that it can identify the characteristics and grade of the tumor and guide subsequent treatment. [2,19]The follow-up treatment of patients with TG is very important based on the pathological diagnosis. [5,21] In our group of patients, one patient underwent ETV and received a biopsy. The pathology revealed anaplastic oligodendroglioma (WHO grade Ⅲ). The patient did not receive chemoradiation or radiotherapy after the surgery. The symptoms of intracranial hypertension disappeared after ETV, but the patient died of glioma progression three years after ETV (Fig. 6). The pathological diagnosis of another patient who received ETV and biopsy was astrocytoma (WHO grade II-III). Six months later, the patient showed radiological progression and was treated with radiosurgery. The patient's vision improved after the ETV procedure, and the patient remained progression-free for two years after the completion of radiosurgery (Fig. 7).
During the operation of ETV, it is necessary to keep the surgical field clean as far as possible, and the bleeding during the operation is also very dangerous to the patient. So not all patients with TGs are eligible for a biopsy because of safety concerns, such as patients who have a small interventricular foramen or those in which the location of the tumor is not safe for assessing the pathology. In our study, 28 patients with TGs did not perform a biopsy due to the small interventricular foramen. More importantly, we found that tumor size greater than 2.8 cm³ (P = 0.02) and cystic changes (P = 0.01) are significant predictors of progression. So patients with large size tectal gliomas and cystic changes should perform a biopsy under the condition of safety.

Prognosis of patients with TG treated with ETV.
It is believed that most TGs are low-grade gliomas, and the clinical course tends to be benign. [15,22,23] In our series, we analyzed the largest number of patients who underwent ETV to treat obstructive hydrocephalus caused by tectal plate gliomas to date. Our group of patients also confirmed that most TGs tend to be benign. Reisenauer et al. recently reviewed 44 patients at two institutions and found that the majority (36/44) required only cerebrospinal fluid (CSF) diversion procedures. Five of 44 patients (11.4%) received either radiotherapy (XRT) or chemotherapy. There was no significant difference in the initial tumor volume between patients with and without tumor growth. In our study, significant predictors of progression were a tumor size greater than 2.8 cm³ (P = 0.02) and cystic changes (P = 0.01). In our group of patients, the clinical presentation of all TG was related to obstructive hydrocephalus, similar to other reports summarizing patients with TGs. The symptoms of the patients with TG and obstructive hydrocephalus were markedly relieved during the follow-up after ETV. Clinical symptoms disappeared or were relieved, and most of the tumors did not progress, indicating that the natural history of TG is most often indolent, and ETV is the only surgical procedure that most patients require.

Limitations
The main limitations of this study are its retrospective nature and limited sample size. Second, all patients in this study were enrolled from a single neurosurgery center. Third, the median follow-up and median PFS durations were not very different, which might underestimate the progression rate.
Therefore, a multicenter study based on a larger cohort with a long-term follow-up is needed in the future.

Conclusion
In our surgical experience, ETV has been uniformly successful in the management of hydrocephalus caused by TG. Under the condition of ensuring the safety of patients, a biopsy should be performed. If the biopsy shows a high-grade glioma, the patient may receive comprehensive treatment to inhibit the progression of the tumor. Most of the pathology findings are low-grade gliomas, and the natural history of these tumors is most often indolent, so the treatment of hydrocephalus is the only surgical procedure that most patients require. A tumor size greater than 2.8 cm³ and cystic changes are significant predictors of progression. No additional treatment for low grade TG gliomas after ETV is required until the tumor is found to progress. Availability of data and material All data generated or analysed during this study are included in this published article.

Competing interests
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.   The patient experienced headache and nausea for 6 months before ETV. After the operation, the symptoms caused by hydrocephalus disappeared and the patient remained progression-free for six years after ETV. A, B, C: T1 hypointense lesion obstructing the cerebral aqueduct; T2 hyperintensity of the lesion. Note the dilated lateral and third ventricles. D, E, F: Six years after ETV, the reduced size of the lateral and third ventricles, with clear brain sulci can be observed, and the TG did not show radiological progression.  The patient's symptoms consisted of a developmental delay, nausea, vomiting, and weak muscles of both legs preoperatively. She was treated with ETV and underwent a biopsy at the age of nine months. The patient recovered well after ETV, the symptoms of intracranial hypertension disappeared, and language and behavior developed normally. The pathology revealed anaplastic oligodendroglioma (WHO gradeⅢ). The patient did not receive chemoradiation or radiotherapy after the surgery. Three years later, the patient died of the glioma A, B: Note the dilated lateral and third ventricles. C: The direction and signal intensity of the CSF flow changed in PC-cine during the cardiac cycle. The direction of the flow was downward during the systolic period and upward during the diastolic period. D: The pathology report indicated: anaplastic oligodendroglioma (WHO gradeⅢ).

Figure 7
The patient experienced visual decline before the surgery. During ETV, the patient underwent a biopsy of the TG, which was significant for the pathological diagnosis of astrocytoma (WHO grade II-III). Six months later, the patient showed radiological progression and was treated with radiosurgery. The patient's vision improved after the ETV procedure, and the patient remained progression-free for two years after the completion of radiosurgery. A, B: Note the dilated lateral and third ventricles. C, D: Two years after ETV and radiosurgery, we can see the reduced size of the lateral and third ventricles, with clear brain sulci.