A rare tumor in the sellar region: ganglioglioma, a case report and a general overview

Gangliogliomas are rare mixed neuronal-glial tumors of the central nervous system, accounting for less than 2% of intracranial tumors. This report presents a rare case of ganglioglioma in the sellar region of a 3-year-old and 5-month-old pediatric patient. The patient underwent surgical intervention initially through a transnasal transsphenoidal approach and subsequently through a transcranial pterional craniotomy approach. Subsequently, radiotherapy and chemotherapy were administered for residual tumor tissue. The purpose of this report is to highlight the presence of ganglioglioma as a distinct diagnosis in sellar region tumors, discuss the surgical, radiotherapy, and/or chemotherapy treatment options for sellar region gangliogliomas based on the literature, and contribute the patient’s follow-up and treatment outcomes to the existing literature. Complete tumor resection may not be feasible in sellar region gangliogliomas, especially in pediatric cases, due to endocrinological and vision-related complications. In cases where complete resection is not possible, radiotherapy and/or chemotherapy may be considered. However, the optimal treatment approach has not yet been established, and further research is needed.


Introduction
Gangliogliomas are rare mixed neuronal-glial tumors of the central nervous system.They constitute less than 2% of intracranial neoplasms.Gangliogliomas are slow-growing, welldifferentiated, and partly calcified tumors.Sellar-suprasellar gangliogliomas are very rare [1].Although many studies have included only cerebral hemisphere gangliogliomas, the tumor could not be classified according to its location because of the small number of patients in most studies [2].
Herein, a rare case of a pediatric ganglioglioma in the sellar and parasellar region is presented with a histopathological diagnosis of ganglioglioma from a center with an annual series of 150 endoscopic skull base surgeries and 900 endoscopic skull base surgeries.

Case report
A 3-year and 5-month-old female patient underwent a consultation with the complaint of bilateral spontaneous nystagmus, which had begun 4 months previously.The patient's history was unremarkable.Physical and neurological examination at the time of consultation was unremarkable, except for bilateral spontaneous rotatory nystagmus.Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a mass with calcification and cystic areas extending into the suprasellar distance and obliterating the sella (Fig. 1A-F). 1 3 When the patient was evaluated in terms of age group, clinical and radiological findings, craniopharyngioma, and optic glioma were considered in the first instance.Anterior pituitary hormone values were within normal limits, and the patient did not have diabetes insipidus.Extended endoscopic skull base surgery was performed via the transnasal transsphenoidal route (Fig. 2).
The preoperative frozen biopsy result was reported as a glial tumor, and the operation was completed with subtotal resection considering the possible complications since the tumor was associated with the optic nerve, pituitary stalk, and hypothalamus, and distinct borders could not be determined.Follow-up CT and contrast-enhanced MRI were performed at 24 h postoperatively (Fig. 1G-J).It was observed that the tumor tissue was subtotally resected, and the stalk and optic nerve was anatomically preserved.The postoperative endocrinological deficit was not detected, and spontaneous nystagmus persisted.
Histopathological examination showed that the tumor was composed of mixed neuronal-glial components and stained positive for glial fibrillary acidic protein (GFAP) and synaptophysin in ganglion cells.The pathological findings were evaluated as ganglioglioma (WHO Grade 1, 2021) (Fig. 3).BRAF V600E mutation analysis was performed, and the mutation was detected.
At the 4-month postoperative follow-up, it was observed that the nystagmus in the patient's eyes had improved.The patient also underwent a 4-month MRI follow-up (Fig. 1K-L).Upon the detection of tumor tissue growth on MRI taken at close intervals, microscopic transcranial right pterional craniotomy and subtotal mass excision with a transsylvian approach were performed approximately 6 months after the first operation.Preoperative tissue characteristics were similar to those of the first operation (Fig. 1M-P).No postoperative complications were observed.
In the histopathological and immunohistochemical examination of the second operation tumor tissue, necrosis and microvascular proliferation were not observed, but the Ki-67 proliferation index was found to be 15%.It was reported that  there was a significant increase in the mitotic activity of the tumor, and therefore, the result could be ganglioglioma (who grade 3, 2021).In this respect, next-generation sequencing (NGS) was performed, and the case was interpreted as ganglioglioma (WHO Grade 1, 2021) because the molecular alterations expected in "anaplastic gangliogliomas" with a more aggressive course were not detected.
After the initial surgery, the patient exhibited a high mitotic activity in the tumor tissue and rapid growth of residual tumor tissue, as observed during the MRI follow-up.Consequently, the patient underwent an intensive modulated radiation therapy (IMRT) and helical irradiation technique utilizing the radixact device for a duration of 6 weeks after the second surgery.A total dose of 5400 centigray (cGy) Fig. 3 A, B, and C Glioneuronal neoplasm is composed of dysplastic ganglion cells along with neoplastic glial cells (H&E, × 100, ×and × 400).D and E. Immunostaining for GFAP in the glial component and for synaptophysin in ganglion cells (GFAP × 200 and Synaptophysin × 200, respectively).F, G, and H. Rare dysplastic neurons within a relatively cellular glial component on the second excision material (H&E, × 200).The Ki-67 proliferation index was 4%-5% on the histopathological examination.The analysis result of the BRAFV600E mutation was positive.Pathological findings were evaluated as ganglioglioma (WHO Grade 1, 2021).Histopathological examination of the tumor tissue after the second operation showed no necrosis and microvascular proliferation; however, the Ki-67 proliferation index was found to be 15%, and a significant increase in the mitotic activity of the tumor was observed; therefore, it was reported that the result may be ganglioglioma (WHO Grade 3, 2021).In this respect, next generation sequencing (NGS) was performed.Because of NGS, BRAFV600E mutation was detected in the tumor tissue.Molecular alterations were not detected in anaplastic gangliogliomas, which are expected to have a more aggressive course.With the current morphomolecular findings, the case was interpreted as ganglioglioma (WHO Grade 1, 2021) was administered in 30 fractions of conventional radiation therapy (RT).Following the completion of radiotherapy, the patient received temozolomide treatment for 12 cycles, with each cycle consisting of 5 consecutive days every month.
Control after RT and chemotherapy is shown in MRI Fig. 4. No neurological or endocrinological deficits were observed in the patient who was in the 18th month of follow-up.

Discussion
Ganglioglioma is considered a tumor of relatively low-grade malignancy with a rather slow clinical course.Most studies have denoted that ganglioglioma cases have a good prognosis [1].Lang et al. [2] reported that the 10-year survival rate was 84% in a study of 58 ganglioglioma patients.In the same study, there was no significant difference between low-and high-grade gangliogliomas (grade 1) in terms of survival.Compton et al. [3] put forth that the 15-year survival rate was 94% in a study carried out on 88 patients.In a series of adult patients with low-grade ganglioglioma, the 5-year progression-free survival rate was 78% after total resection and 62% after subtotal resection, and this difference was not statistically significant.The rate of malignant degeneration of gangliogliomas varies between 4 and 32%.The case here was pathologically evaluated as ganglioglioma (WHO Grade 1, 2021).However, although necrosis and microvascular proliferation were not observed, high-grade ganglioglioma was suspected due to the presence of high mitotic activity and the rapid increase in tumor size.
Deng et al. [4] reported a ganglioglioma rate of 1.14% in their study of 880 glioma patients, and only one patient exhibited this in the sellar region among these gangliogliomas.However, this study population consisted mostly of adult patients.Abuzayed et al. [5] reported that, including their own cases, only 20 cases of gangliogliomas associated with optic chiasm were reported in the literature.Hong et al. [6] reported adenohypophyseal ganglioma for the first time and achieved subtotal resection with endoscopic transnasal transsphenoidal surgery due to the highly vascularized structure.This case is the only case of sellar and parasellar ganglioglioma with an annual average of 150 and 900 endoscopic skull base surgery series in the literature.In both operations, the tumor structure was vascularized with soft and hard components.The surgery in the current study was limited by the fact that it was not possible to observe the right optic nerve and hypothalamus border due to the tumor tissue.Stalk and optic nerves were preserved.No postoperative endocrinological deficit was observed.
The MRI findings demonstrate nonspecific features with iso-to hypointense T1 signal intensity and hyperintense T2 signal intensity, indicating a solid or partially cystic lesion [7].In a study conducted by Zentner et al. [8] on ganglioglioma cases, they reported that the lesion contents appeared as completely solid in 43% of the cases, completely cystic in 5% of the cases, and both solid and cystic in 52% of the cases on MRI.The diagnosis of a tumor using MRI can be challenging due to the diverse appearances it may present.In our case, the T1 signal intensity was hypointense, while the T2 signal intensity was hyperintense, demonstrating features of both solid and cystic components.
The recommended treatment option for gangliogliomas is radical-wide excision.However, it should be preferred when it is safe to do this in pediatric cases.Close follow-up is recommended, and in the case of relapse, resurgical resection is the primary option.The efficacy of radiotherapy and chemotherapy is unknown.Garrido et al. [9] reported that in a study conducted with 14 pediatric patients, radiotherapy was applied to 4 patients postoperatively, and no significant difference was detected in terms of the clinical course between those who received radiotherapy and those who did not.Compton et al. [3] stated in their study that radiation therapy may delay the progression time in this subset of gangliogliomas, as in WHO Grade 2 gliomas, but the small number of patients in the study prevented clear results regarding adjuvant therapy.Zentner et al. [8] showed that spinal metastasis occurred 12 months after surgery in an anaplastic ganglioglioma (WHO Grade 3) case, and they stated that they believed that postoperative radiation therapy might be beneficial in anaplastic gangliogliomas.In their study with 10 ganglioglioma cases in which surgery was performed, Kalyan-Raman and Olivero [10] emphasized that the possible role of radiotherapy should be considered in the malignant evolution of a patient who received radiotherapy and was diagnosed with glioblastoma 5 years after the operation and died afterward.Rumana and Valadka [11] reported that 4 out of 14 cases of benign ganglioglioma underwent malignant transformation following postoperative radiotherapy.Considering the long-term good prognosis of the tumor in spite of the harmful effects of radiotherapy, radiotherapy is not recommended in the first step but may be considered in case of relapse [2].In the present study, although radiotherapy was avoided after the first operation because the efficacy of radiotherapy on low-grade ganglioglioma was uncertain and it might have had harmful effects on the nontumor neural tissue in our pediatric patient, due to the suspicion that the tumor tissue may be anaplastic ganglioglioma (WHO Grade 3) and its high mitotic activity after the second operation, RT was applied.In gangliogliomas, several chemotherapeutic agents are available, including temozolomide, irinotecan, and bevacizumab [12].Temozolomide treatment has been demonstrated to reduce tumor diameter in lowgrade gliomas [13].In our case, the patient received temozolomide treatment for 12 cycles.Another chemotherapeutic option is BRAF inhibitors, as up to 50% of gangliogliomas have been reported to carry the BRAFV600E mutation [14].BRAF inhibitors such as vemurafenib and dabrafenib, which are FDA-approved for the treatment of melanoma with a high prevalence of BRAF mutations, have shown promise.Shih et al. [15] reported tumor size reduction in a patient with a BRAF V600E mutation-positive ganglioglioma located in the brainstem after dabrafenib treatment.Philippe et al. [16] described clinical and radiological improvement in three pediatric patients with BRAF V600E mutationpositive ganglioglioma in the brainstem who received dabrafenib treatment.Bufalo et al. [17] reported radiological and clinical improvement in a pediatric case of BRAFV600E mutation-positive cervicomedullary ganglioglioma treated with vemurafenib.It is important to consider the potential effectiveness of BRAF inhibitors in cases with the BRAF V600E mutation.However, the optimal choice of chemotherapy remains unclear [18].
Ganglioglioma should be considered in the differential diagnosis of masses located in the sellar region.Although the ideal management strategy is still unknown, gross total surgical resection is the first treatment option.However, good pre-operative and postoperative planning is necessary in terms of morbidity and mortality, including endocrinological and visual complications.Although the role of RT in treatment is controversial, postoperative RT in residual or relapsing tumors and high-grade gangliogliomas may be helpful in preventing the rapid growth of tumor tissue and metastasis.The decision regarding the use of adjuvant chemotherapy and/or radiotherapy should be made using a multidisciplinary approach, considering both the patient's individual characteristics and a comprehensive risk analysis specific to the disease.

Fig. 1 A
Fig. 1 A-B Preoperative cranial non-contrast axial and coronal CT scans show a tumor lesion (asterisk) located in the sellar and suprasellar regions, with a central hypodense parenchyma isodense with gray matter, calcification (black arrow), and cystic areas.C Preoperative cranial T1-weighted contrast-enhanced sagittal MRI section shows an infiltrating tumor lesion (asterisk) with a hypointense, heterogeneous and solid-cystic component (star) obliterating the level of the sella, extending into the suprasellar space and compressing the stalk posteroinferiorly (black arrow).D The preoperative cranial T1-weighted contrast-enhanced coronal MRI section shows the tumor lesion with a transverse diameter of approximately 44 mm (asterisk) and its adjacency to the supraclinoid and cavernous segments of the internal carotid artery (black arrows).E Preoperative cranial T2-weighted sagittal MRI section shows close adjacency of the basilar artery (black arrow) and sellar tumor lesion (asterisk).F Preoperative cranial T2-weighted coronal MRI section shows a tumor lesion (black asterisk) with solid-cystic components (white asterisk) extending into the suprasellar space and infiltrating into both thalamus (white asterisk) more prominently on the right.After endoscopic transnasal transsphenoidal surgery, G-H At 24 h postoperatively, cranial T1-weighted contrast-enhanced sagittal and coronal MRI sections show subtotal tumor resection areas (asterisk and arrow) and residual tumor lesion around it.I-J At 24 h postoperatively, cranial T2-weighted sagittal and coronal MRI sections show adjacency of the subtotal tumor resection area (asterisk) and basilar artery (black arrow).K-L At 4 months postoperatively, cranial T1-weighted contrast-enhanced sagittal and coronal MRI sections showed dimensional progression of the tumor lesion.After transcranial right pterional craniotomy and surgery via the transsylvian approach.M-N At 72 h postoperatively, cranial T1-weighted contrast-enhanced axial and sagittal MRI sections show a residual tumor lesion in and around the subtotal tumor resection areas (asterisk).O-P At 72 h postoperatively, the cranial T2-weighted axial and coronal MRI sections showed that the mass compression of the thalamus and its adjacencies disappeared

Fig. 2
Fig. 2 This is the area opened in the sella through the sphenoid sinus with a 4-mm rigid endoscope preoperatively.A The yellow tumor tissue (asterisk) can be seen with soft and hard components and vascularized structure.B The relationship of the tumor tissue with the pituitary stalk is clearly visible, and its borders are not clear.The site of tumor excision and the residual tumor tissue around it can also be seen (asterisk).C When the tumor tissue is excised using the aspirator, the left posterior cerebral artery (white arrow) and the left third oculomotor nerve (black arrow) are seen on the left side

Fig. 4 A
Fig. 4 A, B, and C After radiotherapy and chemotherapy were completed, in the 12th month of the folup, cranial T1-weighted axial and sagittal MRI sections and cranial T2-weighted coronal MRI sections, respectively, a prominent postoperative area of 25 × 22 × 18 mm extending to the bilateral hypothalamic area and showing residual mass contrast is observed in the suprasellar area