Left-Parietal Angiocentric Glioma: Our Experience and a Review of the Literature

Abstract

Background: Angiocentric glioma (AG) is a rare, benign, and slow-growing tumor. First described in 2005, it is now gaining attention with respect to the possibility of being diagnosed. Even with no statistical differences between sex, it has been reported both in children and the elderly. A total of 120 cases have been described in the literature. The aim of this study is to provide new data for a new statistical assessment of the prevalence and incidence of AG in populations. Case report: An 8-year-old male patient with no history of epilepsy and no need for antiepileptic therapy underwent surgery for a left-parietal brain lesion, revealed through MRI. Imaging was acquired after his first absence episode. The lesion was completely resected. Histological findings indicated angiocentric glioma. No signs of recurrency after two years of follow-up. Conclusion: AG is usually an epilepsy-related low-grade glioma. Few cases exhibit disease progression and exitus. Surgical management should aim for a gross total resection to avoid recurrence and persisting epilepsy. Surgery represents the gold standard in diagnosis and treatment and must be performed as soon as possible in consideration of its healing properties and its useful diagnosis.

1. Introduction

Angiocentric glioma is a new entity, first described in 2005 [1] and later classified as a solid tumor in WHO classification in the “other neoplasm” section [2]. Nowadays, it is still considered a different kind of glioma by the new WHO brain tumor classification, upgraded in 2021 [3], which included it into the section “Gliomas, glioneuronal tumors, and neuronal tumors”. The most common presentation is a long history of untreatable seizures. Gross total resection is the recommended strategy for seizure relief or control. Radiological characteristics are not pathognomonic. AG diagnosis is suggested when cystic features show up: T1WI reveals a hypointense lesion, and hyper-intensity is revealed in T2WI and FLAIR imaging. A low-grade glioma, it shows no enhancement after gadolinium administration. Here, we present an atypical management case of a young child with no long history of seizures, who underwent priority surgery, with no recurrence at 1-year radiological follow-up.

Case Report

A right-handed 8-year-old had an absence seizure characterized by staring and paleness, resulting in loss of consciousness, retrograde amnesia, and slurred speech for about two hours. He was referred to the emergency pediatrics unit of our hospital and was hospitalized in the Child Neuropsychiatry unit. Further questioning did not reveal any other seizure episodes. He was subsequently subjected to diagnostic investigation with brain MRI. It showed an irregular lesion in the left parieto-occipital region, characterized by the presence of multiple intralesional areas of microcystic and cystic appearance, predominantly cortical (Figure 1).

The lesion (maximum indicative dimensions of 35 × 28 × 24 mm) was horseback-arranged on the parieto -occipital fissure, affecting the precuneus and less extended over the superior occipital gyrus. T1WI was hypointense, due to multiple cystic areas. T2WI, on the other hand, showed a well-defined polylobate mass. On FLAIR scans, the described intralesional cystic component appeared to be characterized by a low signal; conversely, focal hyper-intensity of the cortex adjacent to the cysts could be detected. There were modest signs of tissue swelling in the lesion site described, with reduction in the width of some sulci between adjacent cerebral convolutions. Adjacent to the peripheral parietal lesion margin, it is possible to notice a scalloping phenomenon of the inner cortical layer of calvarium in relation to a possible chronic compression. There were no signs of restriction of the diffusivity of water in the context of the lesion site. After gadolinium administration, no frank areas of pathological impregnation were detected.

We made a scalp U-shaped incision in the left parieto-occipital region using neuronavigation to locate the lesion and the post-central gyrus. The 3D reconstruction demonstrates the presence of the lesion involving the left upper-parietal gyrus, between two large parasagittal veins (Figure 2).

The tumor was soon visible over the parieto-occipital cortex (Figure 3). Under a surgical microscope, a smooth resection was obtained en-bloc with the subpial technique (Figure 4).

The post-central gyrus was unaffected and we performed a supratotal maximal resection through the subpial technique in order to maximize the extent of resection and avoid adjacent healthy brain tissue. The surgical strategy was tailored to the patient and lesion characteristics. The extent of resection is a crucial factor affecting the outcome, as explained later in this paper. In this instance, we were able to perform a safe supratotal resection by taking advantage of the anatomy. The post-operative period was uneventful. Clinical and surgical follow-up was obtained at 6 and 18 months. The patient experienced no more seizures. No antiepileptic drug was necessary. Control MRI revealed complete tumor excision with no sign of recurrence (Figure 5).

At the time of this submission, he is 10 years old and a telephonic survey has revealed normal quality of life with no evidence of epilepsy. Histopathologically, the most typical findings were glial neoplastic proliferation, poorly cellular, consisting of perivascular aggregates of small monomorph elements. The immunoprofile of the lesion demonstrated GFAP +, ATRX +, Olig-2 +, vimentin +, inhibin −, EMA −, and MIB-1 < 3%, compatible then with AG.

2. Materials and Methods

This study is a narrative review of original studies and published case reports. A broad literature search was conducted by the authors (Figure 6). Pubmed and Scopus databases were searched using the terms “glioma” AND “angiocentric”. The PRISMA schema was adopted to define inclusion and exclusion criteria. The following inclusion criteria were used: (1) every type of study containing a histological diagnosis of angiocentric glioma and a comprehensive description about patients’ demographics and characteristics; radiological, histological, and surgical data; the duration of follow-up; recurrence; outcomes; and the administration of antiepileptic drugs, and (2) articles written in English. Abstracts were excluded from this study because they were not peer-reviewed and due to a lack of information as studies limited to the biomolecular basis or studies that did not meet the inclusion criteria. Further, the references of each selected manuscript were explored, enlarging our case collection (Table S1).

3. Results

The initial research brought up 64 items. After removing duplicate articles, articles in other languages, non-peer-reviewed articles, and articles lacking useful information for this review, 52 articles were accepted into our analysis. A total of 99 patients with angiocentric glioma were analyzed (

Table 1. Summary of the reported cases.

Author	Year	Age	Sex	Location	Side	Seizure	Treatment	Post-Op Seizure
Aguilar et al. [4]	2012	15	F	frontal	N/A	NO	GTR + RT; Recurrence: surgery + CMX	YES
Alexandru et al. [5]	2013	12	F	temporal	L	YES	GTR	N/A
Almubarak et al. [6]	2020	4	F	brainstem	N/A	NO	STR + CMX; Recurrence: palliative therapy	-
AlSufiani et al. [7]	2013	45	F	temporal	R	YES	GTR	YES
Arsene et al. [8]	2008	55	M	temporal	R	NO	GTR	-
Arsene et al. [8]	2008	20	M	temporo-occipital	N/A	YES	GTR	N/A
Chan et al. [9]	2018	7	M	brainstem	N/A	NO	Biopsy	-
Chatterjee et al. [10]	2016	22	F	temporal	R	YES	N/A	N/A
Chen et al. [11]	2014	7	F	parietal	R	YES	GTR	N/A
Cheng et al. [12]	2015	25	M	frontal	N/A	YES	GTR	YES
Covington et al. [13]	2009	5	F	brainstem	N/A	NO	STR	N/A
D’Aronco et al. [14]	2017	3	M	brainstem	N/A	NO	CMX; Recurrence: CMX	-
D’Aronco et al. [14]	2017	7	M	brainstem	N/A	NO	Biopsy + CMX; Recurrence: CMX	-
Donev et al. [15]	2008	38	M	frontal	N/A	YES	GTR	-
Donev et al. [15]	2008	79	F	temporal	N/A	NO	N/A	-
Ersen et al. [16]	2014	21	M	frontal	L	YES	GTR	-
Fulton et al. [17]	2009	2	N/A	fronto-parietal	R	YES	STR	YES
Gonzalez-Quarante et al. [18]	2017	83	M	frontal	L	NO	STR + RT	YES
Grajkowska et al. [19]	2014	15	F	temporal	R	YES	GTR	YES
Grajkowska et al. [19]	2014	14	M	parieto-occipital	L	YES	GTR	N/A
Gupta et al. [20]	2020	14	M	temporal	N/A	YES	GTR	N/A
Hu et al. [21]	2010	19	M	frontal	L	NO	GTR	N/A
Kadak et al. [22]	2013	13	M	temporal	L	YES	GTR	NO
Kakkar, Sharma et al. [23]	2014	18	M	frontal	L	YES	GTR	YES
Koral et al. [24]	2012	4	M	temporal	R	YES	STR	N/A
Kumar et al. [25]	2015	4	M	frontal	L	YES	N/A	N/A
Lellouch-Tubiana et al. [1]	2005	9.5	F	frontal	L	YES	GTR	N/A
Lellouch-Tubiana et al. [1]	2005	10	M	frontal	L	YES	STR	YES
Lellouch-Tubiana et al. [1]	2005	3	F	frontal	L	YES	STR	YES
Lellouch-Tubiana et al. [1]	2005	12	M	parietal	R	YES	GTR	N/A
Lellouch-Tubiana et al. [1]	2005	13	F	fronto-insular	R	YES	STR	YES
Lellouch-Tubiana et al. [1]	2005	2	M	fronto-parietal	R	YES	STR	YES
Lellouch-Tubiana et al. [1]	2005	4.5	M	parietal	R	YES	GTR	N/A
Lellouch-Tubiana et al. [1]	2005	4	F	temporal	L	YES	GTR	N/A
Lellouch-Tubiana et al. [1]	2005	4	F	temporal	L	YES	GTR	N/A
Lellouch-Tubiana et al. [1]	2005	6.5	M	fronto-temporal	L	YES	GTR	N/A
Li et al. [26]	2012	4	M	frontal	L	YES	GTR	-
Li et al. [26]	2012	4	F	frontal	R	YES	GTR	-
Li et al. [26]	2012	9	M	temporal	R	YES	GTR	-
Liu et al. [27]	2012	13	F	temporal	L	YES	GTR	-
Liu et al. [27]	2012	14	M	temporal	R	YES	GTR	-
Liu et al. [27]	2012	22	M	temporal	L	YES	GTR	-
Lu et al. [28]	2013	15	M	frontal	R	NO	GTR + RT; Recurrence (AG, no GBM likeness): GTR + CMX	YES
Ma et al. [29]	2010	25	F	temporal	R	YES	GTR	N/A
Majores et al. [30]	2007	46	M	temporal	L	YES	N/A	N/A
Marburger et al. [31]	2011	15	M	thalamus	R	NO	Biopsy	N/A
Marburger et al. [31]	2011	3	F	temporal	L	YES	GTR	N/A
Marburger et al. [31]	2011	19	M	parietal	L	YES	GTR	N/A
Marburger et al. [31]	2011	15	M	temporal	L	YES	STR	YES
Marburger et al. [31]	2011	10	F	parieto-occipital	L	YES	GTR	N/A
McCracken et al. [32]	2016	16	F	fronto-insular	L	YES	Biopsy; First Recurrence (AG + astrocytoma GII): STR + FRT; Second Recurrence (AG + anaplastic ependymoma): STR + CMX	YES
Miyahara et al. [33]	2011	66	F	temporo-insular	R	YES	STR + CMX + RT; Recurrence: RT + CMX	-
Miyata et al. [34]	2011	37	M	temporal	L	YES	GTR	N/A
Miyata et al. [34]	2011	54	F	temporal	L	YES	GTR	YES
Mott et al. [35]	2010	57	F	frontal	R	YES	Biopsy + RT	N/A
Ni et al. [36]	2014	4.7	M	frontal	R	YES	N/A	N/A
Ni et al. [36]	2014	9	F	parietal	R	YES	N/A	-
Ni et al. [36]	2014	24	M	frontal	R	YES	N/A	N/A
Ni et al. [36]	2014	5.5	F	parietal	R	YES	N/A	N/A
Ni et al. [36]	2014	20	F	parietal	L	YES	N/A	N/A
Ni et al. [36]	2014	7	M	temporal	L	YES	N/A	N/A
Ni et al. [36]	2014	22.5	F	frontal	R	YES	N/A	N/A
Ni et al. [36]	2014	9	M	frontal	R	YES	N/A	N/A
Ni et al. [36]	2014	17	M	temporal	L	YES	N/A	N/A
O’Halloran et al. [37]	2020	42	M	dorsal cord		NO	GTR	N/A
Our case	2023	8	M	parietal	L	YES	GTR	NO
Pokharel et al. [38]	2011	3	M	parietal	R	YES	GTR	NO
Preusser et al. [39]	2007	13	F	temporal	N/A	YES	GTR	YES
Preusser et al. [39]	2007	10	M	parietal	N/A	YES	STR	YES
Preusser et al. [39]	2007	12	F	parietal	N/A	YES	GTR + RT	YES
Preusser et al. [39]	2007	0	F	temporal	N/A	YES	GTR	YES
Preusser et al. [39]	2007	14	M	fronto-parietal	N/A	YES	Biopsy + RT	YES
Preusser et al. [39]	2007	8	F	temporal	N/A	YES	GTR	NO
Preusser et al. [39]	2007	6	M	temporal	N/A	YES	STR	YES
Preusser et al. [39]	2007	3	M	parietal	N/A	YES	GTR	NO
Reisz et al. [40]	2023	2	M	brainstem	N/A	NO	STR + CMX; Recurrence: CMX	-
Rho et al. [41]	2011	10	F	frontal	R	NO	GTR	YES
Rosenzweig et al. [42]	2009	28	M	temporal	L	YES	GTR	NO
Sajjad et al. [43]	2015	40	M	parietal	R	NO	GTR	N/A
Shakur et al. [44]	2009	13	F	temporal	L	YES	GTR	NO
Shakur et al. [44]	2009	10	M	temporal	L	YES	GTR	YES
Shakur et al. [44]	2009	10	M	temporal	L	NO	GTR	NO
Soylemezoglu et al. [45]	2015	41	M	parietal	L	YES	GTR	N/A
Sugita et al. [46]	2008	6	M	parieto-occipital	R	YES	GTR	N/A
Takada et al. [47]	2011	26	M	frontal	R	YES	GTR	YES
Taschner et al. [48]	2011	3	N/A	occipito-temporal	L	YES	GTR	N/A
Varikatt et al. [49]	2009	16	f	parieto-occipital	L	YES	GTR	-
Wang et al. [50]	2005	15	M	temporal	R	YES	GTR	N/A
Wang et al. [50]	2005	12	F	fronto-temporal	R	YES	STR	N/A
Wang et al. [50]	2005	14	F	frontal	R	YES	GTR	N/A
Wang et al. [50]	2005	3	M	occipital	L	YES	STR	N/A
Wang et al. [50]	2005	4	F	parietal	R	YES	GTR + CMX + RT	N/A
Wang et al. [50]	2005	30	M	temporal	L	YES	GTR	N/A
Wang et al. [50]	2005	26	M	frontal	L	YES	STR; Recurrence (anaplastic astrocytoma): STR + FRT + CMX	YES
Wang et al. [50]	2005	37	M	frontal	R	YES	N/A	-
Wang et al. [51]	2020	10	F	frontal	L	YES	GTR	N/A
Wang et al. [52]	2021	14	M	parietal	L	YES	GTR	YES
Weaver et al. [53]	2017	5	F	brainstem	N/A	NO	Biopsy; Recurrence: CMX + STR	-
Weaver et al. [53]	2017	6	M	brainstem	N/A	NO	Biopsy	-
Yano et al. [54]	2024	15	M	frontal	L	YES	GTR	NO

GTR: gross total resection; STR: subtotal resection; CMX: chemotherapy; FRT: fractionated radiotherapy; AG: angiocentric glioma; GBM: glioblastoma; N/A: not available.

), to which our case was added (99 + 1). Overall, 59% were men (n = 59), and 39% were women (n = 39). Two patients had no documented gender. The chronological age at diagnosis varied between 0 and 83 years, with an average age of 17 years and a median of 13 years. Sixty patients were under the age of 14 and therefore considered pediatric (60%), thus defining a bimodal distribution of this pathology.

Most of these patients experienced the onset of symptoms long before their diagnosis. The majority of patients reached a diagnosis due to having a history of epilepsy of different types, both the absence and partial types and the complex type. The most commonly encountered symptom was headaches, followed by visual difficulties and others (

Table 2. Distribution of common symptoms among cases.

Symptom		Number of Cases
Seizures	81%	n = 81
Headaches	8%	n = 8
Cranial nerve palsy	7%	n = 7
Weakness	6%	n = 6
Visual impairment	5%	n = 5
Vomiting	2%	n = 2
Gait disturbances	2%	n = 2
Dizziness	2%	n = 2
Cognitive deficit	2%	n = 2
Developmental delay	2%	n = 2
Confusion	1%	n = 1
Dysphasia	1%	n = 1
Nystagmus	1%	n = 1
Otalgia	1%	n = 1
Respiratory failure	1%	n = 1
Fever	1%	n = 1
Spinal impairment	1%	n = 1

).

Data collection included demographic information (age at diagnosis, sex), anatomical considerations (tumor location and tumor size), presenting symptoms and signs, and tumor characteristics.

Generally, the most common location of angiocentric glioma is the temporal region, followed by the frontal region, the parietal region, the brainstem, the occipital region, and, more rarely, the thalamus and dorsal spinal cord.

Although most of the articles include instrumental images such as MRI and CT scans, tumor size was described only in 34 papers. The measurements were not always complete as sometimes just the diameter was described, sometimes two measurements were described, and other times all three planes were given. Reducing the measurements to the average diameter, they oscillate between 1 cm and 6.7 cm with an average of 2.7 cm in diameter at diagnosis (minimum measurement on one of the three planes: 0.8 cm; maximum measurement on one of the three planes: 8 cm).

From a histological perspective, these lesions that are currently classified as “gliomas” belong to the glial series of diseases and are thus positive for glial fibrillary acidic protein (GFAP), as well as frequently being positive for vimentin, EMA, and the S-100 protein. Mitoses have a low detection rate, often less than 1% or not identified at all, according to the Ki-67 index (MIB-1).

The lesion commonly appears on MRI as hypointense on T1WI, hyperintense on T2WI, with different degrees of hyper-intensity on FLAIR. Depending on the cystic content, the latter three can be very variable. There tends to be no contrast enhancement, except for some very irregular partial enhancement, especially peripheral, less commonly in the lesion.

The extent of resection was defined as follows: subtotal resection (STR) (debulking of the lesion with the aim of leaving a minimal amount in place), biopsy of the lesion (when only a stereotactic or minimal sampling was performed for the primary diagnosis of the lesion), and gross total resection (GTR), when the removal was defined as total or supramarginal and, in any case, complete. The type of surgical treatment was not disclosed in 14 cases. Eleven patients had documented illness recurrence. Three of them had had GTR. Following surgery, the patients experienced no problems and continued to benefit from their treatments. Eight cases had complications following surgery. Two patients [32,50] passed away. Five of the patients, who experienced a recurrence, benefited from a novel surgical approach. In one case [14], the patient was treated only with chemotherapy, and in the same case, two consecutive progressions of the tumor were treated with two new different chemotherapy treatments. Moreover, 64 patients benefited from surgical treatment in the absence of post-operative epilepsy (the neurological status of 22 patients was not reported). Six patients free from epilepsy, however, continued to take AEDs until the end of the follow-up period. Differently, nine patients continued to have epileptic manifestations. Post-operative pharmacological therapy, whether performed or not, was declared in only 33 cases. The follow-up periods described varied between 1 month and 166 months. In 14 cases, the follow-up period was not communicated. The average follow-up period was 35 months.

4. Discussion

Since 2005, approximately 100 cases of angiocentric glioma have been described. The first to describe it were Lellouch-Tubiana and Wang [1,50]. This tumor, initially described as being composed of monomorphic, spindle-shaped cells that align around enlarged blood vessels, was only renamed in 2007 by the WHO as angiocentric glioma (WHO I), a grade I tumor described as a subtype of neuroepithelial tumors. Despite the small number of cases reported to date in the literature, there appears to be a sex difference regarding the incidence of angiocentric glioma (M:F 1.5:1), although in two cases, the sex of the patient was not reported [17,48]. Although it occurs mainly in pediatric or adolescent age (71 cases out of 100 are ≤18 y.o.), sporadic cases of older patients have been described in the literature: at 79 y.o. [15] and 83 y.o. [18]. The distribution by age class can therefore be defined as bimodal, although in our opinion it can be asserted that it is more frequent in pediatric populations (Figure 7).

The literature is incredibly diverse, with occasional descriptions of cases from all over the world—with the exception of authors from Africa (Figure 8). This glaring difference may be attributed to a variety of factors, including the various states’ and centers’ differing diagnostic capacities, the financial feasibility of funding a scientific publication, and, in the case of Oceania, population density. Furthermore, it is impossible to determine whether there is an ethnic predisposing factor based on the few data that are currently available. The patient’s nationality is only reported in three cases [4,46], including the patient in our case, who is Italian. The bias shown in the following images is based on the fact that the patients are not certainly the authors’ compatriots. In fact, Aguilar et al. are based in Canada but the case they described refers to a South Asian little girl.

The majority of patients (Table 2) initially presented a history of epilepsy (n = 81, 81%), and in 72% of cases, this was the only sign (n = 72). Both simple and complex seizures have been described, including cases with absence seizures [44], like our 8-year-old patient. The history of epilepsy in many cases began in childhood and the diagnosis was confirmed only many years later [20]. Headache is another common symptom, followed by signs and symptoms of increased intracranial pressure and, more rarely, by systemic signs such as fever and respiratory failure. The other manifestations can be related to aspecific localization in an eloquent area.

The pathogenesis of epileptic seizures is currently unknown; however, a study published in 2021 has shown that in the majority of angiocentric gliomas studied, there is a deficit in the expression of the EAAT2 protein. This protein is a selective membrane transporter for glutamate [55]. Furthermore, the common observation that in the majority of patients the first sign is an epileptic seizure could also be directly proportional to the fact that angiocentric gliomas are more common in the temporal lobe, which, as has long been known, represents the cerebral cortex with the lowest activation threshold. Angiocentric gliomas are commonly supratentorial (Figure 9), most frequently being in the temporal lobe (35%), followed by the frontal lobe (33%), parietal (20%), brainstem (8%), occipital (2%), thalamus (1%), and dorsal cord (1%) [9,37,53]. The case described by O’Halloran is borderline. The author concludes by saying that the spinal lesion, confirmed as an angiocentric glioma, is the possible metastatic evolution of an IDH-wildtype astrocytoma (WHO grade II, ATRX-wildtype, 1p19q intact) of the right-frontal lesion, operated 10 months earlier with stereotactic biopsy and then treated with post-operative radiotherapy (54 Gy in 30 fractions).

Typically, AG is characterized by a low-intensity signal in T1WI scans, or rarely as a hyperintense signal in T1WI [16,35,39,41,47], or more finely as intrinsic “rim-like” hyper-intensity [1]. It always behaves as hyperintense on T2WI and FLAIR scans. Although the literature agrees that this tumor does not enhance after gadolinium administration, in some studies, a slight enhancement with rather mixed signals has been reported [4,8,19,20,21,28,33,35]. Inside the lesion, it is also possible to observe areas of cystic degeneration [51] (as in our case) and/or calcifications [39,41]. Magnetic resonance spectroscopy also demonstrates increased choline/phosphocreatine and choline/N-acetyl ratios, as well as increased levels of glycine and myoinositol [56]. The above-mentioned characteristics must therefore direct us to a differential diagnosis that is equally compatible with low-grade astrocytomas, ependymomas, DNETs, and cortical malformations [25,31,57]. A particular criterion has been described by some authors who report the presence, in MRI, of “stalk-like white matter abnormality perpendicular to the ventricular wall”, low in T1WI and high in T2WI [1,39]. Our case also presents a peculiarity, already mentioned by Pokharel et al. [38], which reinforces the hypothesis of a long time interval between the tumor genesis and the onset of symptoms: a thinning of the internal cortex of the bone overlying the lesion, a sign of long-lasting compression during its development.

According to histology, AGs are cellular tumors made up of monomorphic spindle-shaped astrocytic bipolar cells that are organized radially, circumferentially, and longitudinally around the blood vessel to form pseudorosettes. According to Cheng and Chatterjee [10,12], the tumor cells exhibit an infiltrative development pattern with entrapped normal neurons. AGs might have characteristics similar to ependymomas [9,10]. An uncommon case of AG with infiltrating astrocytic cells exhibiting initial anaplastic features was reported by Miyahara et al. [33]; nevertheless, the tumor was later classified as an anaplastic astrocytoma exhibiting primary vascular-associated ependymal differentiation. Cystic alterations are uncommon in AG [1,5].

As a tumor of the glial series, AG is positive for GFAP as well as for S-100 and EMA [20]. Neuronal biomarkers are negative in tumor cells; a false positive could result from neurons trapped in the lesion [51]. Chen et al. [11] reported the positivity of CD34 and CD99 clusters. Ki-67 is usually very low or undetectable. In two cases, a Ki-67 level of less than 5% was detected [53,54]. In two other cases, this level was described as “moderately high” [28] and “high” [26]. Miyahara [33] describes it as variable among components of the lesion (low/high). Only in one case was the presence of Ki-67 very high, up to 10%, at relapse [50]. These data were described in 31% of the cases reported in our review. More recently, genomic studies have documented the presence of an MYB-QKI fusion, inspecting a proto-oncogene and a tumor suppressor [9,40]. Rearrangements in MYB-QKI seemed to be exclusive to angiocentric gliomas. After birth, MYB proteins are transcription factors that are not expressed in the cerebral cortex, the site of AG. The signaling and activation protein linked to RNA-binding Quaking, which is extensively expressed in the nervous system and is crucial for the development of oligodendroglia, is encoded by QKI. Functional investigations conducted both in vitro and in vivo demonstrate that MYB-QKI rearrangements drive carcinogenesis via three mechanisms: truncation-induced MYB activation, enhancer translocation-induced aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI [58]. There are very few studies on gene mutations connected to AG, and most of them concentrate on MYB mutations and the lack of IDH1 alterations [52]. AG can be distinguished from diffuse glioma by the lack of IDHI-R132H mutant protein expression [59].

The pathological designation of AG as a distinct biological entity is supported by the close connection of the translocation (MYB-QKI) with this histology.

Sajjad et al. [43] describe the presence of heavy calcification. No other specific anatomical pathological characteristics are known.

The non-surgical treatment of these lesions is controversial as it involves either a watch-and-wait approach or the use of aggressive oncological therapy with chemotherapy or radiation therapy. However, in common with all other grade I gliomas, surgery represents the treatment of choice, becoming the cornerstone independent from any demographic factor. The objective of surgery is to achieve the maximum possible removal (GTR = gross total resection). The latter becomes fundamental for the relief of epileptic manifestations, allowing total resolution. In fact, comparing GTR to subtotal resection (STR), the latter is associated with a greater incidence of post-operative epilepsy. Patients treated with STR or biopsy have required a new surgical treatment more frequently than patients that have undergone GTR (recurrence in one GTR case vs. three STR cases, three biopsy cases, and one CMX case). Lu et al. [28] report a case treated with GTR followed by 6.5 weeks of post-operative radiation therapy to 59.4 Gy in 33 fractions, yet his tumor recurred four months following excision. After that, a second resection was carried out. Although it displayed fewer malignant characteristics, the recurrent tumor still had the persistent characteristics of angiocentric glioma as well as modifications brought on by the radiation. The results of this case and a few other cases that have been previously published point to the possibility of a malignant variant or malignant transformation in angiocentric gliomas. In one case [6], the patient underwent STR and also received adjuvant chemotherapy consisting of carboplatin and vincristine. She manifested with post-operative lower-cranial-nerve palsy and hydrocephalus, and recurrence after 84 months. Her last period of follow-up until the 96th month was characterized by palliative care. Reisz et al. [40] report a case of STR complicated by hydrocephalus and dysphagia. One month after the surgery, the angiogenesis inhibitor bevacizumab and the mTOR inhibitor temsirolimus were used in the oncological course of treatment. The radiological follow-up 4 months after the operation revealed growth in the axial plane on MRI. The recurrence was treated with vinblastine for palliative purposes. Nine months following surgery, the patient was still in a stable clinical state. The last case of STR with recurrence was reported by Wang et al. [50]. Twenty-one months after STR, generalized seizures returned and an MRI scan confirmed the recurrence. The recurring lesion was partially excised and a 6-week course of radiation therapy to 60 Gy in 30 fractions was given. Despite the administration of chemotherapy (procarbazine, carmustine, and vincristine), the tumor eventually spread and the patient passed away 62 months after the first excision.

A case of a tumor identified as AG by biopsy is described by McCracken et al. [32]. When the disease progressed 11 months later, the patient had a left-temporal lobectomy and the histology revealed both grade II astrocytoma and AG. Thus, 50 Gray of adjuvant radiation delivered in 28 fractions was administrated. A tiny area of enhanced contrast was visible in the following MRI. She had a nearly complete excision two years later and the histology revealed anaplastic ependymoma associated with AG. She was administered adjuvant temozolomide for six cycles. Despite this, the tumor grew larger, causing her seizure control to worsen and her right hemiparesis to develop. The 19-year-old patient’s death underscored the tumor’s malignant potential. Two more cases treated with biopsy experienced recurrence. One described by Weaver [53] was treated with a monthly carboplatin dose for six months following the biopsy; however, this had minimal therapeutic benefit. After that, it was decided that an STR would be performed via craniotomy. At last, but not least, D’Aronco et al. [14] reported a case of biopsy associated with adjuvant vincristine and carboplatin as part of a chemotherapy treatment. Following a four-month course of therapy, the patient began to exhibit clinical worsening without any MRI changes. After six months of clinical progression and the development of a new, mild, left-side paresis, the patient was started on weekly vinblastine and then bevacizumab. MRI revealed an unchanged tumor size even as the patient’s condition worsened.

Some cases of adjuvant treatment with radiotherapy have been reported, the role of which is still unclear. Even chemotherapy is not a standardized treatment in different cases; it has been used with different mixtures of chemotherapeutic agents. In some cases, adjuvant chemotherapy is described but the drugs are not specified [18,34]. Biopsy was performed in eight cases in total, four being in the brainstem and one being in the thalamus. In four cases, with a follow-up between 5 and 24 months, no recurrence or progression was described [31,35,39,53]. In one case, after the biopsy, the patient made a full recovery and a month later there was no worsening [9].

There is only one case reported of a tumor treated only with chemotherapy, even for its recurrence. The patient [14] underwent a year-long regimen of vincristine and carboplatin treatment. He was treated with bevacizumab for two months after exhibiting worsening symptoms and signs after three years of initial stability. Everolimus, an m-TOR inhibitor, was used as a therapy when tumor progression was seen, and the tumor’s initial size responded. Over the course of the 10-month follow-up period, the patient remained stable.

Generally, recurrences occurred after variable lengths of time, between 4 months and 12 years. In some cases, although comparable with the reported follow-up period, there was no more growth of the lesion. The follow-up periods reported vary from 1 months to 166 months with any exception, as in the cases reported by Wang et al. and McCracken [32,50], in which the patients died and therefore the follow-up periods were interrupted.

Data about post-operative antiepileptic therapy are extremely limited. As a matter of fact, very few case reports ever mention it. There is no information on the molecule or dosage when it is stated. There is a dearth of information because surgery has a very high tumor-controlling rate, which suggests that it is ultimately curative for epilepsy and greatly lowers the risk of recurrence throughout the recovery period.

5. Conclusions

Angiocentric glioma is a low-grade glioma associated with epilepsy. Even though it is a prevalent tumor in young individuals, it can also affect older or adult patients. When a patient has a history of epilepsy, it is crucial to diagnose them early with an MRI study and to be able to execute a surgical removal as soon as possible, ideally a GTR, since this seems to be the only procedure that will resolve the epilepsy and heal the patient.