Treatment experience of large intraventricular central neurocytoma: a retrospective cohort study


 Background: Central neurocytoma is a rare intracranial tumor. Due to the limited number of reported cases, the treatment strategy for central neurocytomas, especially large central neurocytomas, remains controversial. This paper discusses our clinical experience in the treatment of large central neurocytomas.Methods: A retrospective analysis of 29 patients with intraventricular central neurocytomas diagnosed and treated by the same surgeon between April 2012 and September 2019 at the Neurosurgery Departments of Beijing Tiantan Hospital and Hainan General Hospital was performed. The clinical characteristics, treatment plans and prognoses of these patients were reviewed.Results: Among the 29 patients, the average age of onset was 31.93 (17-61) years, and the average maximum tumor diameter was 54.17 ± 15.62 mm. Twenty-three patients (79.3%) had an average maximum diameter greater than 50 mm. Twenty-seven patients (93.1%) underwent transcortical tumor resection. Twenty-seven patients (93.1%) underwent gross total tumor resection. Five patients (17.2%) received radiotherapy after the first operation, and 3 patients (10.3%) had tumor recurrence. None of the patients died.Conclusions: Surgical resection via transcortical fistulotomy is a reliable approach for removal of large central neurocytomas in the ventricle. Patients should be closely observed postoperatively, and MRI of the head should be performed regularly. If a tumor shows progression, then radiotherapy should be considered.


Background
Central neurocytoma is a rare brain tumor mainly located in the lateral ventricle near the interventricular foramen [1] and accounts for approximately 0.1-0.5% of primary central nervous system tumors.
Hassoun et al. [2] proposed the concept of the pathological diagnosis of central neurocytoma for the rst time in 1982, and it was classi ed as grade II by the World Health Organization (WHO) in 2007 and 2016 [3]. Central neurocytomas present as either benign entities or as more aggressive atypical variants, depending on histological atypia and the MIB-1 labeling index, which is a cell proliferation marker [4,5].
Surgical resection of as much tumor as possible is recommended as a rst-line measure in central neurocytoma management. However, due to the proximity of intraventricular vasculature and the basal ganglia, achieving total tumor resection is di cult, especially for large central neurocytomas. Additionally, the choice of surgical approach and whether postoperative radiotherapy should be applied are still controversial [5][6][7][8]. In this study, we retrospectively analyzed the treatment outcome of 29 intraventricular central neurocytoma patients. Most patients had central neurocytomas with a diameter ≥ 50 mm. With surgical resection via transcortical stulotomy, most patients had achieved tumor gross total resection. Additionally, we did not suggest that the patients receive radiotherapy directly after the operation.

Patients
This retrospective study was approved by the Institutional Review Board of Beijing Tiantan Hospital of the Capital Medical University of Medicine. A portion of patients pathologically diagnosed with central neurocytomas or tumors located in the brain ventricles at the Neurosurgery Departments of Beijing Tiantan Hospital and Hainan General Hospital from 2012 to 2019 were included. The same surgeon performed the operations for all patients.

Surgical procedure
The same surgeon performed surgeries for all patients. The surgical approach was selected based on the tumor location and tumor volume, which were evaluated by preoperative imaging. All patients chose unilateral craniotomy and a transventricular approach for tumor resection without using neuro navigation technology. Except for two patients whose tumors were located at the posterior part of the ventricle, the other patients chose to tumor resection through frontal cortex stulation.

Data collection
Patient medical records, including resident admission notes, progress notes, surgical records, discharge records and preoperative and postoperative imaging materials, in the medical records system of Beijing Tiantan Hospital and Hainan General Hospital were examined to select patients who conformed to the inclusion criteria. Patient demographics, including age, sex, initial complaint, preoperative Karnofsky Performance Status (KPS) score, comorbidities, preoperative and postoperative neurological examination results, tumor volume, resection extent, postoperative complications and pathology, were recorded. The patients were followed up for adjuvant treatment, tumor progression and recovery status. The last followup evaluation was March 2020.

Grouping method
The preoperative KPS score was used for classi cation of functional status. A better functional status resulted in a more favorable KPS score. We identi ed the extent of resection by comparing preoperative and postoperative imaging data. Gross total resection was de ned as complete resection of the main parts of enhanced lesions observed on preoperative imaging (as shown in Figure 1). Other surgical outcomes were categorized as non-gross total resection. Tumors with a diameter ≥ 50 mm were de ned as large central neurocytomas. Memory decline was de ned as a patient's or family member's description of the patient's frequent forgetting during postoperative telephone follow-up.

Statistical analysis
Continuous and categorical variables are expressed as the medians and percentages, respectively. Differences in patient characteristics and outcomes between the two groups were estimated using the χ2 , Student's, or Wilcoxon's rank tests. All statistical analyses were performed using the statistical analysis software package SPSS, version 22.0 (IBM Corp, Armonk, New York, USA). Statistical signi cance was de ned as a P value < 0.05.

Results
Twenty-nine patients met the enrollment criteria ( Table 1). The average age of the patients was 31.93 years (range 17-61 years). Seventeen male patients were enrolled (males:females = 1.4:1), the average preoperative KPS score was 88.62 ± 6.39, and the average maximum tumor diameter was 54.17 ± 15.62 mm; 23 patients (79.3%) had an average maximum diameter ≥ 50 mm. The median length of stay was 25 days (12-110 days), and the mean follow-up time was 49.52 ± 25.40 months. 3(10.3%) *One patient was hospitalized for 110 days, which was several times longer than the hospitalization durations of the other patients. Radiotherapy*: denotes patients who received radiotherapy after primary surgery. KPS1: Preoperative Karnofsky Performance Status (KPS); KPS2: Discharge KPS; KPS3: KPS at the last follow-up.

Treatment outcome
Twenty-seven patients (93.1%) were treated by gross total tumor resection, and no operative deaths occurred. Among these 27 patients, 3 suffered from tumor occurrence. Twenty-seven patients underwent surgery with the transcortical approach, and a surgical approach through the trigone of the lateral ventricle was also used in 2 cases. Among the 27 patients who received a transcortical surgical approach, 25 achieved gross total tumor resection. Ten patients (34.5%) had hemiplegia, 10 aphasia (34.5%), 4 epilepsy (13.8%), 15 memory decline (51.7%) and 12 fever (41.4%). Five patients (17.2%) with hydrocephalus underwent ventriculoperitoneal shunting. Five patients (17.2%) received radiotherapy after the rst operation, and none of the patients who received postoperative radiotherapy had tumor progression. Among the 24 patients who did not receive radiotherapy, 3 patients had tumor recurrence, one each in the rst year, the second year and the third year. The rst patient received radiotherapy after the second operation, and the other two patients received radiotherapy directly. At the last follow-up visit, no signs of tumor progression were noted, and no deaths occurred.

Statistical analysis
We compared the treatment outcome between the large central neurocytoma and non-large central neurocytoma groups. Hemiplegia occurred more frequently in patients with large central neurocytomas than in patients with non-large central neurocytomas (P = 0.046) ( Table 2), but no signi cant correlation was identi ed between other postoperative complications and tumor volume. We also analyzed the association between treatment strategies and postoperative complications. Statistical analysis revealed that memory decline was signi cantly correlated with radiotherapy (P = 0.017) ( Table 3). In addition, no signi cant correlation was identi ed between gross total resection or radiotherapy and the recurrence rate (Table 4).

Discussion
Most central neurocytomas show benign biological behavior, and patients can have a favorable prognosis when gross total tumor resection is achieved [9,10]. However, since aggressive surgical resection of tumors in deep brain areas may be associated with a high risk of damaging crucial neurovascular structures, it is important for surgeons to understand the natural history of central neurocytomas. In particular, tumors with a large volume can occupy the bilateral ventricles. The key to treatment is to select the appropriate surgical approach to achieve the maximum range of safe tumor resection and to prevent postoperative complications, such as brain edema and hydrocephalus. At the same time, whether radiotherapy should be directly performed after surgical resection is still controversial [11]. Of the 29 patients in this group, 23 patients had an average maximum tumor diameter greater than 50 mm, 27 patients achieved gross total tumor resection, and 5 patients received radiotherapy after the rst operation. We subsequently discuss these patients' clinical treatment experiences.
Surgical resection is the most fundamental treatment for central neurocytoma [12,13]. The common surgical approaches are transcortical and transcallosal approaches [14]. However, the optimal surgical approach remains controversial [15,16]. Some studies have suggested that the transcortical approach is more appropriate when the tumor is located in the lateral ventricle, while the transcallosal approach is considered more appropriate for tumors located in the third ventricle due to a shorter surgical path and reduced damage to the cortex [17]. In the present study, although some patients experienced hemiplegia, aphasia, fever, epilepsy and other complications, except for one case, patients did not have permanent neurological de cits. This result indicated that these complications are related to temporary brain swelling after damage to normal brain tissue, but no major re ux veins were injured. The surgeon suggested that although many of the tumors in this group occupied the bilateral ventricles, most of the tumors originated from unilateral ventricles and squeezed the septum pellucidum to the contralateral ventricle. Therefore, large tumors can be completely removed through a unilateral transcortical approach.
At the same time, transcortical access to the ventricles is more direct, and it can avoid damaging the corpus callosum and the main frontal cortical veins. However, in addition to the tumor volume, other major factors in uencing the effect of surgery include the degree of calci cation of the tumor, the degree of adhesion between the tumor and its surroundings, the blood supply of the tumor, and the experience of the surgeon.
Hydrocephalus is a serious postoperative complication of intraventricular central neurocytoma. In this group, 5 patients with hydrocephalus were treated with ventriculoperitoneal shunts after dehydration therapy failure. In summary, according to our experience, the normal veins and tissues of the ventricle should be protected as much as possible and over-stretching of brain tissue should be avoided during surgery to prevent postoperative hydrocephalus [14]. Extraventricular drainage should be performed during long operations, and the drainage tube should be strictly controlled at the appropriate height after the operation to prevent collapse of the ventricle caused by rapid drainage. Moreover, bleeding should be strictly controlled during the operation to prevent blood from owing into the ventricle, which may induce in ammatory adhesion of the ventricle.
Whether radiotherapy should be used after central neurocytoma surgery remains controversial. Some reports suggest that patients should be treated with postoperative radiotherapy to prevent and treat residual tumor recurrence [18][19][20][21]. In this group, 5 patients (23.8%) received radiotherapy after the rst operation. None of the patients who received radiotherapy had tumor progression. Among the patients without radiotherapy, three had tumor recurrence. One patient had tumor recurrence one year after the operation and then underwent reoperation and radiotherapy. The other two patients had tumor recurrence two and three years after the operation and received radiotherapy. At the last follow-up visit, these three patients had no signs of tumor recurrence. However, in recent years, postoperative radiotherapy has been reported to have no effect on the overall survival rate of patients [17], and the delayed complications of radiotherapy, such as radiation necrosis, leukoencephalopathy, cognitive dysfunction and even radiationinduced malignant tumors, have received increasing attention in recent years [9]. No statistical correlation was found between radiotherapy and the tumor recurrence rate in this group of patients, but we found a signi cant statistical correlation between memory decline and radiotherapy (P = 0.017). Considering that the most common pathological grade of central neurocytoma is WHO II, which applies to benign tumors, theoretically, progression is slow. Therefore, since 2015, we no longer suggest that patients should receive radiotherapy directly after surgery. Instead, we suggest that, for these patients, MRI should be reviewed regularly after the operation. Changes in the condition should be monitored closely, and radiotherapy should be considered if progression is observed.
Immunohistochemical results are mainly used to determine the diagnosis and prognosis of central neurocytoma. Syn [22] and NeuN are reliable diagnostic indexes of central neurocytoma. In most cases, syn staining was positive. NeuN is mainly used to distinguish clear cell tumors of the central nervous system (central neurocytoma, oligodendrocytoma, clear cell ependymoma). According to previous studies, MIB-1 (Ki-67) may be a prognostic indicator [23]. When MIB-1 (Ki-67) expression is greater than 2%/3%, the prognosis of patients may be poor [24]. This indicator plays an important role in guiding postoperative adjuvant treatment and judging prognosis. Patients with high levels of MIB-1 expression are more likely to relapse than patients with low MIB-1 expression of. However, in contrast to previous reports, we did not nd that MIB-1 expression was related to tumor recurrence in this group of patients, which may be related to our small number of cases.

Limitations
Although we presented the clinical data of 29 patients with central neurocytomas, some limitations of this study remain. Due to the limited number of cases, a certain degree of statistical deviation exists. For example, we hold that the extent of resection and radiotherapy may be related to tumor recurrence, but our data analysis showed no statistical correlation. Therefore, a larger sample size is needed in future studies. Additionally, in this group, most patients were treated with surgical resection via transcortical stulotomy, and the results could not be directly compared with those of other surgical methods.

Conclusions
Surgical resection of the tumor is the basis of treatment for central neurocytoma. With total resection of the tumor, patients may be completely cured. At the same time, the transcortical approach is a reliable approach for removal of large tumors in the ventricles. This approach is not only conducive to total removal of large central neurocytomas in the ventricles but also better avoids injury to the corpus callosum and protects normal ventricular structure and venous return. Finally, patients should be observed closely after surgery, and MRI of the head should be reevaluated regularly. If a tumor shows progression, then radiotherapy should be considered. This study was approved by the ethics committees of the two medical centers. The requirement for obtaining informed consent from patients was waived because the data sets were anonymous.

Consent for publication
Not applicable.

Availability of data and materials
The datasets supporting the conclusions of this study are available from the corresponding author upon reasonable request.

Competing interests
The authors declare that they have no competing interests.