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. 2022 Jul 8;14:20363613221112432. doi: 10.1177/20363613221112432

Supratentorial cortical ependymoma: A systematic literature review and case illustration

Joshua A Cuoco 1,2,3,†,✉, Andrew C Strohman 1,3,†, Brittany M Stopa 1,3, Michael S Stump 3,4, John J Entwistle 1,2,3, Mark R Witcher 1,2,3, Adeolu L Olasunkanmi 1,2,3
PMCID: PMC9274435  PMID: 35836750

Abstract

Cortical ependymomas are currently not considered a subgroup of supratentorial ependymomas; however, there is a growing body of literature investigating the natural history of these lesions compared to supratentorial ependymomas. We performed a systematic literature review of cortical ependymomas with a focus on the natural history, clinical characteristics, and clinical outcomes of these lesions as compared to supratentorial ependymomas. Our search revealed 153 unique cases of cortical ependymomas. The mean age on presentation was 21.2 years. Males and females comprised 58.8% (90/153) and 41.2% (63/153) of cases, respectively. The most common presenting symptom was seizure activity occurring in 44.4% of the cohort (68/153). The recently recognized C11orf95-RELA fusion was identified in 13.7% of the cohort (21/153) and 95.5% of cases (21/22) reporting molecular characterization. World Health Organization grades 2 and 3 were reported in 52.3% (79/151) and 47.7% (72/151) of cases, respectively. The frontal lobe was involved in the majority of cases (54.9%, 84/153). Gross total resection was achieved in 80.4% of cases (123/153). Tumor recurrence was identified in 27.7% of cases (39/141). Mean clinical follow-up was 41.3 months. Mean overall survival of patients who expired was 27.4 months whereas mean progression-free survival was 15.0 months. Comparatively, cortical ependymomas with C11orf95-RELA fusions and supratentorial ependymomas with C11orf95 RELA fusions exhibited differing clinical outcomes. Further studies with larger sample sizes are necessary to investigate the significance of RELA fusions on survival in cortical ependymomas and to determine whether cortical ependymomas with C11orf95-RELA fusions should be classified as a distinct entity.

Keywords: cortical ependymoma, ependymoma, insula, insular ependymoma, supratentorial cortical ependymoma

Introduction

Ependymomas are a relatively uncommon entity, accounting for approximately 1.8% of all primary central nervous system (CNS) tumors and 6.8% of glial neoplasms.1,2 These tumors arise from ependymal cells lining the ventricular system, choroid plexus, central canal of the spinal cord and filum terminale. 2 Given their embryonic origin, these neoplasms are most commonly found within the ventricular system (e.g. floor of the fourth ventricle, cervicothoracic cord, filum terminale); however, ependymomas can also be found throughout the neuroaxis, even outside the bounds of the ventricular system. 2 Such entities are known as supratentorial extraventricular ependymomas, which exhibit a low incidence and an unclear etiopathogenesis.1,2

New guidelines by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) committee in 2020 have distinguished ependymal tumors according to methylome profiling data to indicate specific molecular groups based upon anatomic location. 3 These new molecular groups include ependymal tumors of the supratentorial, posterior fossa, and spinal compartments. 3 Specifically, C11orf95 and YAP1 fusion genes are now considered subgroups of supratentorial ependymomas with C11orf95-RELA fusions exhibiting the worst prognosis of all supratentorial ependymomas.3–6 A small subset of supratentorial extraventricular ependymomas, known as cortical ependymomas, selectively involve the cerebral cortex without any ventricular involvement. Cortical ependymomas are currently not considered to be a distinct subgroup of supratentorial ependymomas; however, there is a growing body of literature specifically investigating the natural history and clinical outcomes of these lesions compared to supratentorial ependymomas as a whole.7–48 In fact, several studies have demonstrated cortical ependymomas with high rates of C11orf95-RELA fusions exhibiting favorable outcomes, which is in contradistinction to the natural history of supratentorial ependymomas with C11orf95-RELA fusions.41,43,48 Here, we describe a rare case of a 58-year-old female found to have an ependymoma of the insular cortex. We perform a systematic literature review of cortical ependymomas with a focus on the natural history, clinical characteristics, and clinical outcomes of these lesions as compared to supratentorial ependymomas as a whole.

Systematic literature review

A systematic literature review of cortical ependymomas was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed and Web of Science databases were searched through February 2022 using the following search terms: (“cortical ependymoma” [All Fields] OR “supratentorial cortical ependymoma” [All Fields] OR “insula ependymoma” [All Fields] OR “insular ependymoma” [All Fields]). A total of 279 records were returned using these search terms. The bibliographies of these papers were reviewed to search for any additional papers, which yielded five additional records due to the variability of nomenclature used to describe these lesions. These 284 records were screened for original reports of cortical ependymomas including case reports and case series while excluding preclinical or clinical studies, literature reviews, systematic reviews, and meta-analyses. A total of 42 studies met eligibility after applying inclusion and exclusion criteria and were included in the final analysis (Figure 1). These studies encompassed 153 unique cases of cortical ependymomas. Data collection and extraction were performed by one author (AS) with oversight and a second independent review by a second author (JC). Data gathered included: age, sex, gene fusion, tumor grade, location, presence of cystic component, treatment, recurrence, overall survival, progression-free survival, follow-up, and outcome. A summary of the data synthesized is listed in Table 1.

Figure 1.

Figure 1.

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PRISMA study selection flowsheet for the systematic review of cortical ependymomas.

Table 1.

Systematic review of the literature pertaining to the natural history, clinical features, and treatment strategies of cortical ependymomas.

Author (Year) Age/Sex Symptoms Gene fusion WHO grade Location Cystic Treatment Recurrence OS (months) PFS (months) Last FU (months) Outcome Ref
Saito et al. (1999) 63F Seizure NR 2 L parietal No GTR + RT No NA NA 14 Alive 7
Fujimoto et al. (1999) 13M Hyperesthesia NR 2 L frontoparietal Yes GTR NR NR NR NR NR 8
Sato et al. (2000) 41F Weakness NR 3 L frontoparietal Yes GTR + RT No NA NA 2 Alive 9
Takeshima et al. (2002) 70F Incidental NR 3 R frontal Yes GTR No NA NA 14 Alive 10
Lehman et al. (2003) 10M Seizure NR 2 R frontal Yes GTR No NA NA 19 Alive 11
Roncaroli et al. (2005) 52M Seizure NR 2 L frontal No GTR + RT No NA NA 130 Alive 12
34M Seizure NR 2 L temporal No GTR No NA NA 100 Alive
7F Seizure NR 2 R parietal No GTR No NA NA 48 Alive
Miyazawa et al. (2007) 33M Aphasia NR 3 L parietal No GTR + RT + ChT Yes NA 6 7 Alive 13
Ghani et al. (2008) 4M Seizure NR 2 L frontoparietal Yes GTR +RT Yes NA 10 NR Alive 14
Lehman (2008) 1F Seizure NR 3 R frontal No GTR No NA NA 48 Alive 15
Grajkowska et al. (2009) 11F Headache NR 2 L frontoparietal Yes GTR + RT No NA NA 72 Alive 16
Yadav et al. (2009) 15M Headache NR 2 L frontal No STR Stable NA NA 20 Alive 17
Niazi et al. (2009) 36F Seizure NR 3 R frontal Yes GTR + RT No NA NA 29 Alive 18
18M Seizure NR 3 R frontoparietal Yes GTR + RT + ChT Yes 14 6 14 Deceased
28F Seizure NR 2 L temporoparietal Yes GTR No NA NA 42 Alive
Yurt et al. (2010) 11M Seizure NR 2 L frontal Yes GTR No NA NA 12 Alive 19
Lee et al. (2011) 2M Seizure NR 2 R frontoparietal No GTR No NA NA 12 Alive 20
Van Gompel et al. (2011) 32F Incidental NR 2 L parietal Yes GTR No NA NA 59 Alive 21
43F Seizure NR 2 L frontal, insular Yes STR + RT Stable NA NA 60 Alive
12M Seizure NR 3 R parietal Yes GTR + RT Yes NA NR 101 Alive
40F Seizure NR 2 R frontal Yes GTR No NA NA 131 Alive
25M Seizure NR 3 R frontal Yes GTR + RT No NA NA 80 Alive
26M Seizure NR 2 R occipital Yes GTR No NA NA 6 Alive
59F Incidental NR 2 L parietal No GTR No NA NA 31 Alive
59M Seizure NR 3 R frontal No GTR + RT Yes NA NR 47 Alive
25F Seizure NR 2 L frontal Yes GTR No NA NA 39 Alive
Davis et al. (2011) 22F Headache NR 3 R frontotemporal Yes GTR + RT Yes NA 20 55 NR 22
Romero et al. (2012) 23M Seizure NR 3 L frontal Yes GTR + RT No NA NA 60 Alive 23
Ng et al. (2012) 51F Incidental NR 3 Bifrontal Yes GTR + RT Yes NA 4 8 Alive 24
Nakamizo et al. (2012) 20F Seizure NR 2 L frontoparietal No GTR No NA NA 16 Alive 25
Ohla et al. (2012) 29M Headache NR 3 L parietal No STR + RT Yes 15 14 15 Deceased 26
Rigante et al. (2013) 14M Seizure NR 2 R temporoparietal Yes GTR No NA NA 12 Alive 27
Hiniker et al. (2013) 19F Seizure NR NR L frontotemporal Yes STR Stable NA NA 4 Alive 28
Elsharkawy et al. (2013) 25M Seizure NR 3 R frontal No GTR No NA NA 6 Alive 29
Kambe et al. (2014) 2M Seizure NR 2 R parietal NR GTR No NA NA NR NR 30
Liu et al. (2014) 24M Seizure NR 2 R frontal No GTR No NA NA 24 Alive 31
30M Seizure NR 3 R parietal No GTR + RT + ChT Yes NA NR 264 Alive
50M Seizure NR 3 L frontal Yes GTR + RT +ChT Yes 72 NR 72 Deceased
50F Seizure NR 3 L frontal No GTR Yes NA NR 150 Alive
2M Hemiparesis NR 3 L frontal No GTR Yes NA NR 48 Alive
47F Headache NR 3 R frontal Yes STR NR <1 NR <1 *Deceased Operative complications
54F Headache NR 3 R parietal Yes GTR NR 48 NR 48 Deceased
52F Confusion NR 3 L frontal No GTR Yes NA NR 36 Alive
15F Hemiparesis NR 3 L temporal Yes GTR + RT + ChT No NA NA 11 Alive
20M Seizure NR 2 L temporal No GTR No NA NA 6 Alive
63F Headache NR 3 L parietal Yes GTR + RT NR 4 NR 4 Deceased
Zhang et al. (2014) 1.5M Seizure NR 3 R frontoparietal Yes GTR No NA NA 6 Alive 32
Tailor et al. (2015) 27F Seizure NR 2 L parietal Yes GTR NR NA NA NR NR 33
Yamasaki et al. (2015) 10M Seizure NR 2 R parietal N/A GTR No NA NA 12 Alive 34
Bijwe et al. (2015) 14F Headache NR 2 R frontal Yes GTR No NA NA 6 Alive 35
Mohaghegh et al. (2015) 17M Weakness NR 3 L parietooccipital Yes GTR NR NA NA NR NR 36
Kharosekar et al. (2018) 11F Headache NR 3 R frontoparietal Yes GTR NR NA NA NR NR 37
Wang et al. (2018) 6M Seizure NR 2 R frontal No GTR No NA NA 23 Alive 38
13F Seizure NR 2 R parietal Yes GTR No NA NA 48 Alive
46M Seizure NR 3 L parietal No GTR No NA NA 46 Alive
5F Headache NR 2 L frontal Yes GTR No NA NA 70 Alive
74M Headache NR 3 R frontal Yes GTR Yes 20 11 20 Deceased
4F Seizure NR 2 R frontal Yes GTR No NA NA 71 Alive
49M Seizure NR 2 L temporal No GTR No NA NA 88 Alive
9M Seizure NR 3 R frontal Yes STR + RT Yes NA NR 41 Alive
31F Seizure NR 2 R parietal No GTR No NA NA 67 Alive
18M Seizure NR 3 L temporal No GTR + RT No NA NA 39 Alive
53F Seizure NR 2 R temporal No GTR No NA NA 51 Alive
51M Seizure NR 2 L parietal No GTR No NA NA 75 Alive
45F Seizure NR 2 R parietal Yes GTR No NA NA 35 Alive
Beniwal et al. (2018) 3F Dyskinesia NR 3 L frontal NR GTR No NA NA 12 Alive 39
Sun et al. (2018) 19M Numbness NR 2 L parietal No GTR No NA NA 8 Alive 40
26F Headache NR 3 R frontoparietal Yes GTR + RT No NA NA 15 Alive
24M Seizure NR 2 L temporal No GTR No NA NA 30 Alive
6M Headache NR 3 L frontal No STR + RT Yes 25 18 25 Deceased
30F Headache NR 2 L occipital No GTR No NA NA 25 Alive
22M Headache NR 3 R temporal No GTR + RT Yes 22 15 22 Deceased
31M Headache NR 3 R frontal Yes STR + RT No NA NA 28 Alive
18F Dizziness NR 2 L temporal No GTR No NA NA 32 Alive
3F Seizure NR 3 R frontal Yes GTR + RT No NA NA 15 Alive
22M Seizure NR 2 R temporal Yes GTR No NA NA 14 Alive
11F Vomiting NR 2 L parietooccipital Yes GTR No NA NA 8 Alive
48M Headache NR 2 L frontal No GTR No NA NA 39 Alive
35F Seizure NR 3 R parietal Yes GTR + RT Yes NA 18 21 Alive
Matsumoto et al. (2019) 9M Headache NR 3 R frontal Yes STR + RT Yes NA 32 347 Alive 41
16F Vomiting NR 3 L frontal Yes GTR + RT Yes NA 19 23 NR
4M Headache NR 3 L frontal Yes GTR + RT Yes NA 16 74 Alive
6M Hemiparesis RELA fusion 2 L parietal Yes STR Yes NA 25 187 Alive
22M Hemianopsia RELA fusion 3 L parietal Yes GTR + RT No NA NA 104 Alive
3M Seizure RELA fusion 3 R frontal Yes GTR + RT No NA NA 136 Alive
24M Seizure RELA fusion 3 L parietal Yes GTR + RT No NA NA 74 Alive
1F Seizure RELA fusion 3 L parietal Yes GTR No NA NA 10 Alive
*Khatri et al. (2019) 32M Headache NR 3 NR NR GTR + RT No NA NA 101 Alive 42
11M Headache NR 3 NR NR GTR + RT No NA NA 101 Alive
12M Headache NR 3 NR NR GTR + RT Yes 53 NR 53 Deceased
10M Seizure NR 3 NR NR STR + RT Yes NA NR 88 Alive
5M Headache NR 2 NR NR GTR No NA NA 48 Alive
12F Headache NR 3 NR NR STR + RT No NA NA 47 Alive
16M Seizure NR 2 NR NR GTR No NA NA 43 Alive
14F Headache NR 3 NR NR GTR + RT No NA NA 26 Alive
46F Headache NR 2 NR NR GTR No NA NA 16 Alive
21F Headache NR 3 NR NR GTR + RT Yes 11 NR 11 Deceased
14F Headache NR 2 NR NR STR No 8 NA 8 Deceased
8M Headache NR 2 NR NR GTR + RT Yes NA NR 40 Alive
22M Headache NR 2 NR NR STR + RT No NA NA 27 Alive
23M Headache NR 2 NR NR STR + RT No NA NA 20 Alive
22M Headache NR 3 NR NR GTR + RT No NA NA 14 Alive
14F Headache NR 2 NR NR STR + RT No NA NA 11 Alive
42M Seizure NR 2 NR NR STR + RT No NA NA 7 Alive
19M Headache NR 3 NR NR GTR + RT No NA NA 7 Alive
Wang et al. (2020) 26F Seizure NR 3 R frontal Yes STR Yes 43 NR 43 Deceased 43
48M Headache NR 2 L temporal Yes STR + RT Yes NA NR 94 Alive
50M Headache RELA fusion 2 R frontal No GTR No NA NA 24 Alive
5F Seizure NR 2 R frontal No GTR No NA NA 24 Alive
5M Headache NR 3 L frontotemporal Yes GTR + RT No NA NA 50 Alive
54F Dizziness No 3 R temporal Yes STR + RT Yes 26 NR 26 Deceased
8F Headache NR 3 R temporooccipital Yes STR + RT Yes NA NR 21 Alive
37M Headache NR 2 R temporal No STR + RT Yes NA NR 36 Alive
22F Headache NR 2 R temporal No STR + RT Yes 29 NR 29 Deceased
58M Seizure NR 2 R temporal Yes GTR No NA NA 60 Alive
17M Headache NR 2 R frontotemporal Yes STR + RT No NA NA 48 Alive
2F Headache NR 3 R frontal Yes GTR + RT No NA NA 36 Alive
4M Headache NR 2 R occipital Yes GTR No NA NA 36 Alive
6F Hemiparesis NR 2 R frontoparietal Yes GTR No NA NA 30 Alive
5M Seizure RELA fusion 2 R frontal No GTR No NA NA 29 Alive
7M Headache NR 2 R occipital No GTR No NA NA 9 Alive
11F Headache NR 2 R temporal Yes GTR No NA NA 36 Alive
6F Seizure RELA fusion 2 L temporooccipital No GTR No NA NA 18 Alive
11M Seizure RELA fusion 3 L temporal No GTR + RT No NA NA 18 Alive
13F Headache NR 3 R parietal Yes STR + RT No NA NA 48 Alive
2M Hemiparesis NR 3 L frontoparietal Yes STR Yes 24 NR 24 Deceased
19F Seizure NR 2 R temporooccipital Yes GTR No NA NA 27 Alive
4M Headache RELA fusion 3 R parietal No GTR + RT No NA NA 36 Alive
17M Seizure RELA fusion 2 R temporooccipital Yes GTR No NA NA 8 Alive
22M Seizure RELA fusion 3 L parietal No GTR + RT No NA NA 6 Alive
4M Headache NR 2 R temporal No GTR No NA NA 65 Alive
5M Headache NR 3 R frontal No GTR + RT Yes NA NR 72 Alive
14M Hemiparesis NR 2 R frontotemporal Yes GTR No NA NA 24 Alive
11M Hemiparesis RELA fusion 3 R frontoparietal No STR + RT Yes NA NR 7 Alive
0.75M Vomiting RELA fusion 3 R frontal Yes GTR No NA NA 5 Alive
Senthilvelan et al. (2020) 22M Seizure NR 2 L frontal Yes GTR NR NR NR NR NR 44
Sallam et al. (2020) 9M Facial droop RELA fusion 2 L frontal Yes GTR Yes NA 5 5 Alive 45
Safavi et al. (2021) 2M Headache NR NR L frontal Yes GTR NR NR NR NR NR 46
Lee et al. (2021) 25F Seizure RELA fusion 2 R frontoparietal No GTR No NA NA 10 Alive 47
Wang et al. (2021) 6F Seizure RELA fusion 2 L temporooccipital No GTR No NA NA 18 Alive 48
11M Seizure RELA fusion 3 L temporal No GTR + RT No NA NA 18 Alive
13F Headache NR 3 R parietal Yes STR + RT No NA NA 48 Alive
2M Weakness NR 3 L frontoparietal Yes STR Yes 24 20 24 Deceased
6F Weakness NR 2 R frontoparietal Yes GTR No NA NA 30 Alive
5M Seizure RELA fusion 2 R frontal No GTR No NA NA 29 Alive
7M Headache NR 2 R occipital No GTR No NA NA 9 Alive
11F Headache NR 2 R temporal Yes GTR No NA NA 36 Alive
4M Headache NR 2 R temporal No GTR No NA NA 65 Alive
5M Headache NR 3 R frontal No GTR + RT Yes NA 24 72 Alive
14M Weakness NR 2 R frontotemporal Yes GTR No NA NA 24 Alive
11M Weakness RELA fusion 3 R frontoparietal No STR + RT Yes NA 7 7 Alive
0.75M Vomiting RELA fusion 3 R frontal Yes GTR No NA NA 5 Alive
Current case 58F Aphasia No 2 L insula Yes STR + RT No NA NA 15 Alive
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Abbreviations: WHO: World Health Organization; OS: overall survival; PFS: progression-free survival: FU: follow up; F: female; NR: not reported; L: left: GTR: gross total resection; RT: radiotherapy; NA: not available; M: male; R: right; ChT: chemotherapy; STR: subtotal resection.

*Overall, the frontal lobe accounted for nine cases, parietooccipital lobe for four cases, frontotemporoparietal region for three cases, and temporal lobe for two cases. Fourteen patients had a cystic appearing tumor.

The average age on presentation was 21.2 years (range: 8–74 years). Males and females constituted 58.8% (90/153) and 41.2% (63/153) of cases, respectively. The most common presenting symptom was seizure activity observed in 44.4% (68/153) of cases. The C11orf95-RELA fusion was observed in 13.7% (21/153) of cases; however, the supratentorial ependymoma C11orf95-RELA fusion subgroup was only recently recognized as a variant by the cIMPACT-NOW committee in 2020. 3 As such, gene fusions were not investigated in the vast majority of cortical ependymomas reported to date. Of cases reporting molecular characterization, 95.5% (21/22) reported the presence of the C11orf95-RELA fusion. World Health Organization (WHO) grades 2 and 3 were reported in 52.3% (79/151) and 47.7% (72/151) of cases, respectively, documenting tumor grades. The most common location was the frontal lobe or at least involvement of the frontal lobe accounting for 54.9% (84/153) of cases. Gross total resection was achieved in 80.4% (123/153) of cases with adjuvant radiotherapy and/or chemotherapy utilized in 43.1% (66/153) and 3.3% (5/153) of cases, respectively. Tumor recurrence occurred in 27.7% (39/141) of cases. Mean clinical follow-up was 41.3 months (range: 2–347 months). Mean overall survival percentage at last known follow-up was 88.3% (128/145). Mean overall survival of patients who expired was 27.4 months (range: 4–72 months). Mean progression-free survival was 15.0 months (range: 4–32 months).

Case illustration

A 58-year-old female presented to the emergency department with three days of mild expressive aphasia and weakness of the right hand. Neurologic examination was otherwise unremarkable. Past medical history was unremarkable. Magnetic resonance imaging (MRI) of the brain demonstrated a heterogeneously enhancing lesion of the left insula with a large cystic component extending superiorly into the left frontal inferior gyrus with significant surrounding vasogenic edema (Figure 2). Metastatic workup was unrevealing. The patient was started on dexamethasone and medically optimized. Given the significant mass effect, symptomatic edema, and need for tissue diagnosis, neurosurgical resection was recommended.

Figure 2.

Figure 2.

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Initial MRI of the Brain. (a–c) T1-weighted imaging with a heterogeneously enhancing lesion of the left insular cortex with a large cystic component extending superiorly into the left inferior frontal gyrus with significant surrounding vasogenic edema. (d) Perfusion-weighted imaging with metabolically active tumor within the left insular cortex. (e) T2-weighted imaging with a moderately-sized cystic component extending superiorly into the left inferior frontal gyrus. (f) Fluid-attenuated inversion recovery imaging confirming vasogenic edema surrounding the tumor of the left insular cortex and cystic component.

A stereotactic left craniotomy was performed for resection of the left insular lesion and superiorly extending cystic component. A subtotal resection was pursued given that the tumor was found to be encasing the vessels of the Sylvian fissure. The patient tolerated the procedure well and without complication. Post-operative neuroaxis MRI was unremarkable for drop metastases. Histopathology demonstrated cellular neoplastic tissue consisting of cords of relatively monomorphic tumor cells with perivascular pseudorosettes and focal true ependymal rosettes (Figure 3). There was evidence of focal tumor invasion into surrounding brain parenchyma, a feature that can rarely be seen in ependymoma. 15 The Ki-67 proliferative index was variable and focally ranged up to 20% in some areas. Neither necrosis, nor vascular proliferation, nor significant mitotic activity was identified. Tumor cells were strongly and diffusely reactive with glial fibrillary acidic protein (Figure 4). Synaptophysin and neuron-specific enolase highlighted neurons in the infiltrative areas. These stains exhibited limited reactivity in tumor cells; however, the reactivity was patchy and weak compared to the strong and diffuse glial fibrillary acidic protein immunostains. Additional immunostains including Melan-A, SOX10, cytokeratin AE1/AE3, cytokeratin 7, and CD45 were negative in all tumor cells, which ruled out metastatic melanoma, metastatic carcinoma, and lymphoma as potential diagnoses. Neuropathology confirmed a diagnosis of supratentorial ependymoma grade 2 not elsewhere classified according to molecular testing. 3 The patient underwent adjuvant Cyberknife radiosurgical treatment to the resection cavity eight weeks after surgery. The most recent repeat MRI imaging at 15 months revealed a stable disease burden.

Figure 3.

Figure 3.

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Histopathology consistent with WHO grade 2 ependymoma. Histopathology demonstrated cellular neoplastic tissue consisting of cords of relatively monomorphic tumor cells with perivascular pseudorosettes and focal true ependymal rosettes. Neither necrosis, nor vascular proliferation, nor significant mitotic activity was identified. (a–b) Hematoxylin and eosin stain at ×40 and ×400 magnification, respectively, showing true ependymal rosettes consisting of columnar cells around central lumens. (c) Hematoxylin and eosin stain at ×200 magnification with pseudorosettes. (d) Hematoxylin and eosin stain at ×100 magnification with focal tumor invasion into surrounding brain parenchyma, a feature that is seen more often in supratentorial ependymomas.

Figure 4.

Figure 4.

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Immunohistochemistry consistent with ependymoma. (a–b) GFAP immunostain at ×200 and ×400 magnification, respectively, shows minimal staining in the ependymal cells of these true rosettes. (c–d) GFAP immunostain at ×200 and ×400 magnification, respectively, highlights the ependymal cell processes in pseudorosettes. (e) NSE immunostain at ×100 magnification shows weak staining in pseudorosettes. (f) Synaptophysin immunostain at ×100 magnification shows weak staining in pseudorosettes.

Discussion

Classification of ependymal tumors based upon the anatomical location is a fundamental principle of the recent cIMPACT-NOW guidelines. 3 This reclassification was prompted by molecular profiles to suggest distinct genetic profiles observed in the supratentorial, posterior fossa, and spinal compartments. 3 Specifically, supratentorial ependymomas are now classified according to the genes, C11orf95 and YAP1, which contribute the most significant pathogenic gene fusions in each group with grade defined by morphological criteria. 3 These two groups of supratentorial ependymomas have been distinguished by their clinical characteristics in most studies.3–6 For example, Pajtler et al. demonstrated that supratentorial ependymomas harboring a YAP1 fusion are clinically and molecularly distinct from those with a RELA fusion. 4 Importantly, the authors found that the RELA subgroup exhibited a 10-year overall survival and progression-free survival of 50% and 20%, respectively, whereas patients in the YAP1 subgroup all survived. 4 Comparatively, Merchant et al. found that patients in the RELA subgroup did not have uniformly poor survival when treated with immediate postoperative radiotherapy. 49 In fact, the authors found that the five-year event-free survival differed significantly by tumor grade but not age, location, RELA fusion status, or posterior fossa grouping. 49 Additional fusions genes have been identified in supratentorial ependymomas, such as C11orf95 with MAML2 and YAP1, and YAP1 with FAM118B; however, the clinical significance of these rare gene fusions remains to be elucidated. 3 Lastly, in some cases, supratentorial ependymomas are without a detectable fusion gene. 3

Cortical ependymomas are currently not considered to be a distinct subgroup of supratentorial ependymomas; however, there is a growing body of literature specifically investigating the natural history and clinical outcomes of these lesions compared to supratentorial ependymomas as a whole. Recent studies have demonstrated a higher incidence of C11orf95-RELA fusions in cortical ependymomas (90–100%) compared with supratentorial ependymomas (65.1–70%).4,41,43,48,50,51 Interestingly, Matsumoto et al. found that cortical ependymomas exhibited a comparatively favorable outcome while demonstrating high rates of C11orf95-RELA fusions. 41 Similarly, Wang et al. (2020) found that cortical ependymomas exhibit a higher rate of C11orf95-RELA fusions with 9 of 10 patients being RELA fusion positive. 43 Importantly, the authors found that the nine patients with RELA fusions had favorable outcomes with all patients currently living at last known follow-up. 43 Similar results were published by Wang et al. (2021) in a pediatric population with all RELA fusion positive patients exhibiting favorable outcomes with no deaths at last known follow-up. 48 Some authors have attributed favorable outcomes to the superficial location of cortical ependymomas and achievable gross total resection.41,43,48 Moreover, given these data, some authors have suggested the classification of cortical ependymomas as a new distinct subtype of supratentorial ependymoma.12,41 Further studies with larger sample sizes are necessary to investigate the significance of RELA fusions on survival in cortical ependymomas.

The etiopathogenesis of cortical ependymomas remains ambiguous. In many regards, the clinicopathologic characteristics of cortical ependymomas are similar to ectopic ependymomas, that is, ectopic ependymomas are typically low-grade tumors with indolent behavior.11,21,38 Historically, it has been suggested to group ependymomas based upon their location within the CNS, as natural history, operative mortality, and postoperative survival are known to be closely dependent on tumor location.11,21,38 Nevertheless, cortical ependymomas and ectopic ependymomas have been considered distinct diagnostic entities. Ectopic ependymomas have been reported to involve the trigeminal nerve, neurohypophysis, sella turcica, falx, posterior fossa, and cavernous sinus.52–57 Importantly, all of these sites are devoid of ependymal cells, which suggests that ectopic and cortical ependymomas may originate from a cell line distinct from mature differentiated ependyma.11,21,38 Vernet et al. proposed the etiopathogenesis of ectopic ependymomas to be potentially due to one of several mechanisms including: (i) a migration disorder of the germinal matrix, (ii) primitive neuroectodermal neoplasms differentiating into the ependymal lineage, or (iii) unregulated neoplastic growth of an ependymal cell of ectopic origin. 58 Moreover, Hegyi et al. reported a case of an ectopic retinal ependymoma hypothesized to arise from Muller cells, which would imply that glial cells with progenitor potential may be the origin of these ependymomas rather than matured differentiated ependyma. 59 Extra-axial ependymomas, such as those occurring in ovarian teratomas, further support that these tumors of ectopic origin arise from a progenitor cell line. 21 As such, a progenitor cell line could also be the cell origin of cortical ependymomas. Although several hypotheses have been put forth to explain this phenomenon, the exact pathogenesis of cortical ependymomas has yet to been established. 21

Currently, there is no consensus regarding the treatment of cortical ependymomas as clinical data is based upon limited case series.7–48 Although gross total resection is preferred when feasible, the necessity and efficacy of adjuvant therapy remain debated. Indeed, treatment algorithms for cortical ependymomas remain largely dependent upon clinical studies addressing classical supratentorial intraventricular or infratentorial ependymomas.60–62 There is widespread agreement in the oncology community favoring adjuvant radiotherapy for adults with WHO grade 3 anaplastic ependymomas regardless of the degree of resection and WHO grade 2 ependymomas after subtotal resection.60–62 Conversely, adjuvant radiotherapy for WHO grade 2 ependymomas after gross total resection remains controversial.62,63 Based upon an institutional experience of 13 patients with cortical ependymomas, Wang et al. (2018) advocated for adjuvant radiotherapy for all WHO grade 3 ependymomas regardless of extent of resection and WHO grade 2 ependymomas only in the context of a subtotal resection. 38 In the largest series to date, Wang et al. (2020) performed a comprehensive institutional analysis in 30 patients with cortical ependymomas, in addition to a systematic review of 106 cases previously reported in the literature. 43 The authors found that 69.1% (47/68 cases) of patients with WHO grade 3 cortical anaplastic ependymomas received postoperative adjuvant radiotherapy, which provided a significantly longer overall survival compared to those without irradiation. 43 Importantly, postoperative radiotherapy did not prolong overall survival in patients with WHO grade 2 cortical ependymomas. 43 These data further support widespread favor for adjuvant radiotherapy for WHO grade 3 ependymomas regardless of intracranial location. However, the clinical benefit of adjuvant radiation on disease control in patients with WHO grade 2 cortical ependymomas should be taken with caution, as prospective studies are necessary to validate this finding. 43 Regarding chemotherapeutics, the role of adjuvant chemotherapy, particularly in children, remains unproven despite extensive investigation, as no chemotherapeutic regimen to date has demonstrated significant clinical benefit. 64

Based upon our literature review, there is only one prior report of a cortical ependymoma with insular involvement. 21 Van Gompel et al. described a case of a 43-year-old female who presented with seizures and imaging demonstrating a left frontal tumor with insular involvement. 21 The patient was treated with subtotal resection followed by radiotherapy for the WHO grade 2 lesion. 21 Per report, the patient was alive with a stable disease burden at 60 months 21 Similarly, we report a case of a 58-year-old female with a WHO grade 2 ependymoma of the insular cortex extending into the left frontal cortex. Specifically, our tumor was primarily located in Zone 1 (anterosuperior) of the insula as per the Berger-Sanai classification system.65–67 Our patient also underwent subtotal resection followed by radiotherapy and is currently with a stable disease burden 15 months post-operatively. Although gross total resection is preferred, it may not always be a feasible option, especially when dealing with tumors of eloquent areas, such as the insula. Indeed, the clinical consequences of gross total resection in eloquent areas may supersede disease control when dealing with tumors with more indolent behavior.

Conclusions

Cortical ependymomas are currently not considered to be a distinct subgroup of supratentorial ependymomas; however, there is a growing body of literature specifically investigating the natural history and clinical outcomes of these lesions compared to supratentorial ependymomas as a whole. Preliminary reports describe differing clinical outcomes between cortical ependymomas with C11orf95-RELA fusions and supratentorial ependymomas with C11orf95 RELA fusions. As such, further studies with larger sample sizes are necessary to investigate the significance of RELA fusions on survival in cortical ependymomas and to determine whether cortical ependymomas with C11orf95-RELA fusions should be classified as a distinct entity.

Footnotes

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics approval: Our institution does not require ethical approval for reporting individual cases.

Informed consent: Written informed consent was obtained from the patient for their anonymized information to be published in this article.

Contributorship: JAC and ALO conceived the study idea. MSS, JJE, MRW, and ALO provided guidance and oversight. All authors (JAC, ACS, BMS, MSS, JJE, MRW, ALO) made substantial contributions to study planning and data collection. JAC and ALO drafted the original manuscript. MSS provided pathology images. All authors (JAC, ACS, BMS, MSS, JJE, MRW, ALO) critically reviewed and revised the final manuscript for important intellectual content. All authors (JAC, ACS, BMS, MSS, JJE, MRW, ALO) approval the final version of the manuscript.

ORCID iD

Joshua A Cuoco https://orcid.org/0000-0002-7118-3890

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