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Clear cell meningioma in a child: Case report and systematic literature review

Background: Clear Cell Meningioma (CCM) consists in a rare variant of meningiomas that generally occur in children. This uncommon tumor behaves aggressively and recurrence rates are high. Clinical manifestations are atypical, and the treatment generally involves surgery. Methods and Goals: We performed a systematic review in order to define the most common characteristics of this rare tumor. Pubmed and Lilacs were the databases used for the literature search. We included 17 studies that met our criteria. To further our research, we included the case report of a 3-year-old female child with CCM operated in our service. Results: CCMs were more frequent in the pediatric population than in adults, especially in females. Gross tumor resection and MIB-1 index ≤ 3 were the parameters related to a smaller recurrence rate. Subtotal tumor resection was followed by radiotherapy in most adult cases. SMARCE-1 mutation could be found in several patients. Conclusion: CCMs are rare Rev. Chil. Neurocirugía 46: 172-181, 2020


Introduction
Cranial meningiomas are rarely found in children and teenagers. Cushing and Eisenhardt described an incidence in children of 1.9% among 313 patients with meningiomas in their famous 1938 monograph 10 . A contemporary surgical series documented an incidence of 1.08% among children and teenagers operated over a 15-year period (1985 -2000) 19 . Thus, the overall prevalence of pediatric cranial meningioma has not changed in over 50 years.
Clear Cell Meningioma (CCM) is an uncommon histological variant. It has been classified by World Health Organization (WHO) as a Grade II neoplasm. These tumors behave more aggressively than Grade I meningiomas, independently of their location and degree of excision. Most CCMs involve the spine and posterior fossa and the supratentorial location is relatively uncommon 11,19,54 . CCMs involving the supratentorial area in children are extremely uncommon and to the best of our knowledge, only 5 such cases have been reported in the literature till date 19,21,29,31,54 .
In this report, we present a case of a CCM in the temporal base with posterior extension in dumbbell shape in a child. Apart from this case, the authors presented a literature review.

Material and Methods
We conducted a systematic review based on the methodology outlined in the PRISMA (Preferred Reporting Project for Systematic Evaluation and Meta-Analysis) agreement. This study does not required ethical approval and patient consent.
Our literature search was based on PubMed and LILACS. We used various combinations of the following keywords: "clear cell meningiomas", "meningiomas grade II" and "meningiomas in children", "intracranial meninigomas" and "spine meningiomas". We included clinical trials, comparative studies, observational studies, case reports and other systematical reviews. Only studies in humans and in English were selected for analysis. Studies in children and in adults were included. The evaluation period was from 1990 to 2021. The latest update was in May, 2020.
The selection criteria focused on design, reporting standards, clarity of results, and tumor classification. Considering the small number of papers found, we decided to also include case reports in our review.
In order to avoid human interference, the analysis was conducted independently. All authors have selected articles for comprehensive screening. The final selected articles have been read and approved by all authors.
Tumor location, sample size, tumor resection (gross or subtotal), recurrence rate, clinical results and conclusion were the parameters evaluated. Data extraction was performed using Microsoft Excel. Due to the small number of studies and subjects, there was no intention to do a quantitative analysis (meta-analysis).
Most studies found that CCMs occur in younger patients, especially pediatric age. Females had a higher incidence than males. CCMs showed a more aggressive behavior and higher rates of recurrence than other types of meningioma. Younger patients had a shorter progression-free survival.
Clinical presentation was atypical, including cranial nerve palsies, headache, vomiting, fevers and seizures.
The location of CMMs varied depending on the case series. The most frequent one was the spine (cervical, thoracic, lumbar or sacral). Other locations were: cerebellopontine angle (CPA), frontal lobe, parietal lobe, petroclival, middle and posterior fossa, basal ganglia, foramen magnum, cerebellar tentorium and convexity region.
Most cases underwent surgical treatment. When a gross tumor resection (GTR) could be achieved, recurrence rates were significantly lower. If a subtotal tumor resection (STR) was done, most authors complemented the treatment in adults with radiotherapy.
Cases with a MIB-1 index ≥ 3% had a shorter progression-free survival (PFS). Ki-67 index did not affect PFS. SMARCE-1 mutation was found in several cases.

Case report
Female, 3-year-old with complains of sudden onset of holocranial headache associated with vomiting and ataxic gait. Upon neurological examination, the patient presented paresis of the left lateral rectus muscle, vestibular syndrome on the left side and intracranial hypertension syndrome. Magnetic resonance imaging revealed a contrast enhanced well-defined extra-axial mass lesion in left middle cranial fossa with extension into the posterior fossa and cavernous sinus (Figures 1a,1b and 1c). We opted to remove the mass in two stages: middle fossa approach with anterior petrosectomy and meningiomas that occur especially in children. The aggressiveness and high recurrence rates difficult the management of this disease. There is still a lot to be discussed about these rare tumors, demanding further research.  Lumbar, cervical, s a c r a l a n d thoracic spine 12 patients 5 male / 7 female Mean age: 28.8 The mean age at diagnosis was significantly younger than that of patients with spinal meningiomas (28. 8  M e d u l l a r y , sphenoid wing, pontocerebellar a n g l e a n d tentorium  The patient progressed well during surgery and in the postoperative period. She was discharged from the hospital feeling well and with no neurological deficits. Histopathology was suggestive of clear cell meningioma (CCM) (Figure 3a).
Tumor cells were positive for vimentin, S-100 and focally positive for epithelial membrane antigen. The proliferation index measured by means of MIB-1 was 13% suggestive of aggressive variant.
After 1 month, she was again submitted to surgery. A new approach was performed to remove the residual tumor in the petroclival area. The postoperative MRI showed total resection.
Two weeks later the patient developed subarachnoid hemorrhage due to a pseudoaneurysm bleeding of the basilar trunk. An emergency surgery with clipping to control the hemorrhage was necessary. After the episode, she developed hemiplegia, lesion of left ocular motor nerve and impairment of swallow. She developed hypertonia and spasticity, the verbal contact was also extremely difficult. Three years later, a very small local recurrence was treated by radiosurgery of dural extension.

Discussion Epidemiology
Pediatric meningiomas account for 1.52% of total meningiomas (15/983) according to large series of Hui et al. 16 . The mentioned author showed that the mean age at presentation was 12 years, with male to female ratio of 1.5:1.
Zorludemir et al. 54 , first described clear cell meningiomas in 1995 and since then <50 cases have been reported. It was subsequently listed as a distinct entity in the current WHO classification of brain tumors in 2000. Most cases were single case reports 19,22,43,54 .

Pediatric CCM
CCM is reported to occur more frequently in the pediatric age group 19,24,35 . Most patients of CCM are young, usually in the first three decades of life, although occasional cases in older patients have also been reported 1,2,3,14,49 . A slight female predominance has been noted 3,4,14,37-42 . These tumors may recur, spread locally, and even metastasize despite their rather innocuous histological appearance 19,24,35 . Our patient was a 3-year-old girl and the tumor was located in middle cranial fossa with cavernous sinus as well as posterior fossa extension.
Usual sites of occurrence are the spinal canal (intradural, 48%), the cerebellopontine angle, tentorium, skull base and

Differential Diagnosis
Prior to the acceptance of CCM as a distinct variant of meningioma, differential diagnosis of tumors with clear cell morphology were often reported as metastatic renal cell carcinoma, oligodendroglioma, hemangioblastoma, and clear cell ependymoma, without specific immunohistochermical (IHC) analysis. Diagnoses was based solely on histomorphology 19,35,54 . It is known that the absence of IHC facility during the initial pathological analysis, compounded with the lack of sufficient data pertaining to CCM possibly attributed to misinterpretation of initial tumor as an oligodendroglioma 11 . Tumor localization (axial or extra axial) can help the pathologist in this differential diagnosis.

Molecular Biology
The biological behavior of CCM may be inordinately aggressive, despite its benign histological appearance. It may also display inconsistent correlation with MIB-1 proliferation. Aspects of cell proliferation in CCM and its correlation with edema have been described before. Previous studies noticed that grade of edema and MIB-1 could be associated to malignancy and radiological tumor shape 1 Zorludemir et al. 54 , in their series found a recurrence rate of 61%, but failed to note any definite correlation between tumor recurrence and mitotic activity, proliferating cell nuclear antigen proliferation indices, percent S-phase determination, or DNA ploidy status. Pimentel et al. 43 , found that recurrent CCMs generally were in the intracranial location and had been treated with subtotal resection. Now a days, molecular genetics and karyotypic studies have also found consistent correlation between meningioma recurrence and loss of heterozygosis 22q, 1p, and 14q, also presence of cyclin E 30,42 .
Navalkele et al. reported a case of a 6 year-old girl and her 25 year-old mother harboring CCMs. The first one with MRI showing an enhancing tumor infiltrating the prepontine area, extending to cerebellopontine angle along the bainstem and middle fossa, similarly to our case, and the second one with multiple CCMs. Tumor cytogenetics of the child revealed 2 chromosome aberrations, a 95 Mb gain on 13q12.11-q34 and a 62 Mb gain on 20p13-q13.33, and 3 areas of absence of heterozygosis on chromosomes 5 and 17, encompassing the TERT and NF1 genes (including region for SMARCE 1 gene). Neurofibromatosis (NF) type 1 was ruled out clinically. Germline testing excluded NF type 2 and SMARCB1 was found in the mother analysis, but Germline testing excluded NF type 2 and SMARCB1. Germline SMARCE 1 testing revealed a pathogenic variant (c.525delT) in both 34 .

Treatment
The gold standart treatment of CCM is surgery. Radiosurgery and radiotherapy (radiosurgery or stereotatic fraccioned radiotherapy) should be reserved for residual/recurrent cases 9,20 . Staged excision could be an option for children, considering the extensive nature of the procedure in large tumors like in our patient.
Possible complications are CSF leak, venous lesion, arterial lesion 3,4,5,12,45,49 . Small tumors have a higher chance of total resection and smaller complication rates can be observed 46 . Our patient presented a late complication in the postoperative period, a severe subarachnoid bleeding after a rupture of pseudoaneurysm in the basilar artery.
We shall mention that radiotherapy in children can produce neurocognitive complications and late malignancies. In our opinion we must remove residual or recurrent tumors whenever possible, leaving the modalities of irradiation for when excision is not feasible. Irradiated cases shall be followed closely in order to detect malignant transformation after radiotherapy.

Conclusion
CCMs in childhood are indeed rare. They represent meningiomas with a high grade of recurrence, even when the satisfactory resection of the lesion is accomplished. Recurrence usually appears after subtotal resection. Its similarity to other neoplasias with clear cell aspect (clear cell renal carcinoma) makes the diagnosis sometimes a challenge. The goal of treatment is surgery with total resection of the tumor. In cases of relapse or in cases of residual tumor, it is necessary to use radio-therapeutic devices such as radiosurgery and stereotatic fraccioned radiotherapy. A long-term follow-up is mandatory to truly decipher the natural course of disease in these patients.