Since the terminology of LEATs was proposed, a large number of brain tumors with neuroepithelial origination have been included in the tumor spectrum of LEATs (Thom et al., 2012; Phi and Kim, 2019; Slegers and Blumcke, 2020). The tumor spectrum of established LEAT entities is broad and has significantly increased according to the fourth WHO classification update (Table 1; Blümcke et al., 2016; Slegers and Blumcke, 2020; Louis et al., 2021). However, except for the established tumors of GG and DNET, other tumors in LEATs are not yet well-recognized due to their rather low incidences, especially from a single center report with limited cases (Blümcke et al., 2016; Blumcke et al., 2017), and thus they are variably reported in the surgical series of LEATs (Luyken et al., 2003; Wessling et al., 2015; Radhakrishnan et al., 2016; Giulioni et al., 2017; Vogt et al., 2018; Ristić et al., 2020), including angiocentric glioma (AG) (Ni et al., 2015; Wang et al., 2020), papillary glioneuronal tumor (PGNT) (Bridge et al., 2013; Pages et al., 2015; Hou et al., 2019), multinodular and vacuolating neuronal tumor (MVNT) (Gonzalez-Quarante et al., 2018; Pekmezci et al., 2018a; Thom et al., 2018; Choi et al., 2019; Gökçe, 2020), isomorphic astrocytoma/isomorphic diffuse glioma (IDG) (Wefers et al., 2020; Appay et al., 2021), pilocytic astrocytoma (PA) (Blümcke et al., 2016), and sometimes including pleomorphic xanthoastrocytoma (PXA) (Weber et al., 2007), diffuse low-grade gliomas (DLGGs) of diffuse astrocytoma (DA) and oligodendroglioma (d-OT) or oligoastrocytoma (d-OA) (Luyken et al., 2003; Vogt et al., 2018; Ius et al., 2020), and the newly diagnosed entity of “polymorphous low-grade neuroepithelial tumor of the young (PLNTY)” (Huse et al., 2017; Louis et al., 2021). Although shared clinical features are found in these lesions, arguments still exist in the categorization of which tumor entities are true LEATs (Blümcke et al., 2016; Slegers and Blumcke, 2020). Reviewing the case reports in the literature, the less common tumor entities of AG, PGNT, MVNT, and PA, plus the classical representatives of GG and DNET, are gradually regarded as the traditional members of the LEAT family (Ko et al., 2019; Ristić et al., 2020). However, debates could be found on the remaining entities of PXA, IDG, PLNTY, and even low-grade DA and d-OT/OA, with inconsistent results of the tumor spectrum in the LEAT group from different surgical series (Thom et al., 2012; Phi and Kim, 2019; Slegers and Blumcke, 2020).

Pleomorphic xanthoastrocytomas are an astrocytic tumor that predominantly occurs in children and young adults and usually has a relatively favorable behavior when compared to diffuse glial tumors in adults (Louis et al., 2016; Vaubel et al., 2021). PXAs account for less than 1% of all astrocytic tumors and have a typical superficial meningocerebral location, often with the involvement of the temporal lobe, in nearly 70–80% of cases (Luyken et al., 2003; Blumcke et al., 2017; Giulioni et al., 2017). PXAs are semi-benign brain tumors that share molecular and morphological commonalities with traditional LEATs, such as CD34 immunoreactivity in 73% of cases of PXAs (Thom et al., 2012) and BRAF^V600E mutation in 50–75% of analyzed PXAs (Schindler et al., 2011). Recently, a homozygous deletion of CDKN2A/B, corresponding to the loss of 9q21.3, was found as a rather distinctive molecular feature of PXA, regardless of tumor grade or BRAF mutation (Vaubel et al., 2018). Patients with PXAs often present with seizures and are thus frequently represented in epilepsy surgery series within the spectrum of LEATs, accounting for 2% of all brain tumors in epilepsy surgery (Blumcke et al., 2017; Qi et al., 2018). However, some authors did not treat PXA as a true LEAT entity, due to their semi-malignant nature and WHO tumor grading of grade 2 and grade 3 with anaplasia (Slegers and Blumcke, 2020; Vaubel et al., 2021). PXAs are always found with relatively high tumor recurrence and malignant transformation than other entities in LEATs, with 5-year progression-free and overall survival of 59.9–70.9 and 80.8–90.4%, respectively, in grade 2 cases, and with more aggressive behavior and decreased 5-year overall survival of 47.6–57.1% in tumor with anaplasia (Ida et al., 2015; Vaubel et al., 2018, 2021).

Diffuse low-grade gliomas usually refer to DA and d-OT in previous case reports, regardless of age grouping (Phi and Kim, 2019). These tumors are commonly found developing in young adults and involve large areas of the brain cortex and subcortical areas, most notably the frontal lobes (Roberts et al., 2018; Ius et al., 2020). Seizure onsets are the most common manifestation of DLGGs, and nearly 80–90% of patients with DLGGs had seizures (Pallud and McKhann, 2019; Ius et al., 2020). Frequently, however, DLGGs have been excluded from the discussion of epilepsy-associated tumors because the majority of DLGGs correspond to histopathological WHO grade 2 tumors with a far higher rate of infiltration, recurrence, and malignant progression than typical LEATs (Blümcke et al., 2016; Ko et al., 2019; Slegers and Blumcke, 2020). DLGGs are thus considered a true invasive neoplasm that should be dealt with in the oncology field (Duffau, 2018). However, many patients with DLGGs attain long-term survival and subsequently face the same problem of long-standing seizures as patients with LEATs. In fact, many surgical cohorts of epilepsy-associated tumors have included a number of patients with DLGGs in addition to the backbone of the traditional LEAT entities, especially when adolescents or young adults are included (Luyken et al., 2003; Wessling et al., 2015; Radhakrishnan et al., 2016; Vogt et al., 2018). The differences in clinicopathological features between DLGG in adults and children have been highlighted in a variety of surgical series (Luyken et al., 2003; Phi and Kim, 2019; Ius et al., 2020). Particularly, according to the 2021 WHO classification of central nervous system (CNS) tumors, the DLGG have been divided into adult and pediatric types (Louis et al., 2021), and the adult-type DLGG (Astrocytoma, IDH-mutant; Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted) are recognized as truly invasive neoplasms with a higher risk of tumor progression and malignant transformation (Duffau and Taillandier, 2015; Jones et al., 2018; Lombardi et al., 2020). Furthermore, these tumors are more likely to present with symptoms of increased intracranial pressure and/or focal neurological deficits, or with a shorter history of seizures, and thus should be differently treated from tumor entities of LEATs (Phi and Kim, 2019; Lombardi et al., 2020; Young et al., 2020).

In contrast, the pediatric-type DLGG, which includes four tumor types, namely, DA (MYB/MYBL1-altered), AG, PLNTY, and DLGGs (MAPK pathway-altered), is considered benign tumors and assigned as WHO grade 1, and they have been found to be more related to the LEATs (Table 1; Slegers and Blumcke, 2020; Louis et al., 2021). For example, the PLNTY was described by Huse et al. (2017) in 2017 as a distinct epileptogenic neoplasm within the spectrum of pediatric, low-grade neuroepithelial tumors. This group of tumors presented in 10 patients with infiltrative growth patterns, a predominant oligodendroglioma-like glial cell component, and intense CD34+ as the most common features. All 10 patients were diagnosed at a young age, with a mean age of 17 years (4–32 years old), with 8/10 seizures, and with 7/10 temporal locations that are similar to LEAT entities (Huse et al., 2017). Molecular analysis revealed a BRAF^V600E mutation, FGFR2 fusion, and FGFR3 fusion in 3/8, 3/8, and 1/8 tested tumors, respectively. This kind of tumor is recognized by the WHO panel of CNS tumor classification as a new tumor type, mainly because they represent a high proportion of low-grade oligodendroglial tumors in children and should be distinguished from other low-grade tumors with a distinct DNA analysis (Huse et al., 2017; Riva et al., 2018; Louis et al., 2021).

In addition, the pediatric-type DAs with MYB/MYBL1 alterations have also been reported to be closely related to the LEATs that are quite different from DAs with IDH mutations in adults (Bergthold et al., 2014; Vogt et al., 2018; Ius et al., 2020). For instance, previous clinical neuropathological studies have found that postoperative tumor progression and recurrence are less often in patients with DAs with a long history of seizures than those with a very short history of seizures (Luyken et al., 2003; Schramm et al., 2004), indicating a tumor subtype presenting with better prognosis in patients with chronic epilepsy, the so-called “isomorphic astrocytoma” (Blümcke et al., 2004), which recently was renamed by Wefers et al. (2020) as “isomorphic diffuse glioma (IDG),” a group of tumors clearly distinct from other glial/glioneuronal brain tumors (Louis et al., 2021). These astrocytoma variants are characterized by a supratentorial, highly differentiated glioma with low cellularity, low proliferation, and focal diffuse brain infiltration. Patients typically had seizures since childhood and were operated on as adults, with excellent progression-free survival after resection (Blümcke et al., 2004; Thom et al., 2012). Interestingly, 77% of IDGs demonstrated MYM/MYBL1 alterations, and all (100%) were IDH-wild-type, which are closely related to pediatric MYB/MYBL1-altered diffuse astrocytomas, according to the WHO fifth edition of CNS tumor classification (Wefers et al., 2020; Louis et al., 2021). Thus, these pediatric-type MYB/MYBL1-altered DAs or IDGs probably represent a distinct group of genetically defined LEATs (Blümcke et al., 2016; Slegers and Blumcke, 2020).

In fact, based on the more biologically and molecularly defined entities of CNS tumors, the 2021 WHO fifth edition classification separated the low-grade neuroepithelial tumors from those with higher infiltration or WHO grading. Furthermore, most of the cortex-involved tumors in the subgroups of “Pediatric-type diffuse low-grade gliomas,” “Circumscribed astrocytic gliomas” and “Glioneuronal and neuronal tumors” are regarded as benign entities with a rather slow growth pattern and thus can result in a long-term history of epilepsy that would much relate to the LEATs (Table 1; Blümcke et al., 2016; Slegers and Blumcke, 2020; Louis et al., 2021). Indeed, several tumor types have been reported in different surgical cohorts of epilepsy-associated neuroepithelial tumors, such as AG and PLNTY in the subgroup of “Pediatric-type diffuse low-grade gliomas” (Bandopadhayay et al., 2016; Huse et al., 2017; Han et al., 2020), PA and PXA in the subgroup of “Circumscribed astrocytic gliomas” (Wallace et al., 2011; Jones et al., 2013; Collins et al., 2015) and GG, DNET, PGNT, and MVNT in the subgroup of “Glioneuronal and neuronal tumors” (Blümcke et al., 2016; Slegers and Blumcke, 2020; Louis et al., 2021). Herein, we propose that the LEAT entities could be roughly grouped into the three subgroups mentioned above, and any new tumor types found in these subgroups in the future could be potential members of the LEAT family and thus be treated by epilepsy surgery in the neurosurgery department. However, for these tumors, further classification requires precise molecular analyses, notably based on the integration of histopathological and molecular information in a tiered diagnostic format as Louis et al. (2021) had recommended recently. Future studies, especially between multiple epilepsy therapeutic centers, are required to improve and standardize the terminology of LEATs and to extend the use of molecular genetic diagnostic tools over a histomorphology-based classification to specify clinically meaningful tumor entities that could be included in the LEAT spectrum.

Although the tumor spectrum of LEATs has been widely discussed since nosology was introduced, the histopathological diagnosis and classification of tumors in LEATs remain challenging due to their variable histopathological features (Qaddoumi et al., 2016; Stone et al., 2018a; Slegers and Blumcke, 2020), which include varieties of cellular components, such as astroglia, oligodendroglia, neoplastic or pre-existing neurons, and inflammatory cellular infiltrates, as well as multiple architectural growth patterns, including nodular or cyst growth and even diffuse infiltration of tumor cell clusters at sites distant from the tumor mass with or without calcification (Blümcke and Wiestler, 2002; Thom et al., 2011). In addition, many glioneuronal tumors lack specific histological features that are crucial for the diagnosis of GG or DNET or have mixed histological features in the same specimen. For example, 5–20% of case series have mixed GG and DNET or PXA histological components (Prayson and Napekoski, 2012; Qaddoumi et al., 2016; Faramand et al., 2018; Stone et al., 2018a). Furthermore, LEAT-associated FCD, namely FCD IIIb (Blumcke et al., 2011), is another complex issue in need of clarification, with highly variable proportions of 10–75% (Prayson, 2011; Giulioni et al., 2017; Pelliccia et al., 2017).

To make a more accurate diagnosis or classification of the LEATs, many ways have been tried to assist in tumor diagnosis by purely microscopic inspection of pathological tissue, especially for some tumors with limited tissue specimens from piece-meal resection or by biopsy (Thom et al., 2012; Blümcke et al., 2016). Immunohistochemistry with staining for CD34, P16, S100, MAP2, GFAP, NeuN, and synaptophysin is helpful, but these markers are not so specific (Thom et al., 2012). Recently, combined molecular pathological diagnosis is widely discussed in the LEAT group (Table 2; Qaddoumi et al., 2016; Stone et al., 2018a). Simultaneously, the current 2021 WHO classification of CNS tumors has also recommended some specific molecular genetic signatures for the neuropathological diagnosis of low-grade neuroepithelial tumors (Table 1; Louis et al., 2016). However, the genetic biomarkers that have been unraveled for LEATs have not yet been systematically reviewed in a large and consecutive cohort of LEATs due to their low incidences. Meanwhile, parts of the molecular genetic signatures are shared by more than one tumor type (Table 2). This dilemma finally contributes to the long-lasting challenge of achieving a reliable differential diagnosis of tumors in the LEAT group (Horbinski et al., 2011; Blümcke et al., 2016). Thus, as Louis et al. (2014, 2021) have recommended, it requires the integration of histopathological and molecular information in a tiered diagnostic format for precisely differentiating the diagnosis and classification of tumors, also in the LEAT group. Herein, we exclusively conclude the recent findings that are helpful to make a more accurate diagnosis or classification of LEATs, including the histological and molecular genetic aspects of each entity.

Brain tumors result in 6–15% of seizure onsets in patients with epilepsy and 24–27% of focal seizures (Blumcke et al., 2017; Ertürk Çetin et al., 2017). Although our knowledge of molecular pathways driving neoplastic cell growth and malignant progression has gradually matured, the issues of why and how a seizure occurs in a patient with a brain tumor still need to be clarified (Slegers and Blumcke, 2020; Natale et al., 2021). Two main hypotheses have been proposed previously, namely, the tumor-centric and the epilepsy-centric approaches (van Breemen et al., 2007; Pallud et al., 2013). The tumor-centric approach states that the epileptic activity derives from the tumor itself, which was recently confirmed by the experimental work of Koh et al. (2018) in neurons transfected with the BRAF^V600E mutation in vivo. In addition, nearly half of patients would have seizure onsets completely controlled after the tumor resection alone (Englot et al., 2012; Bonney et al., 2015). The epilepsy-centric approach provides evidence that the infiltrated peritumoral neocortex is key for tumor-related epileptic activity, due to metabolic imbalances of glioma-related glutamatergic and γ-aminobutyric acid changes leading to epileptogenicity (Lee et al., 2007; Yuen et al., 2012; Pallud et al., 2013; Neal et al., 2016). In fact, many alterations have been found in human peritumoral brain tissue that has the potential to dramatically alter neuronal and glial homeostasis and the microenvironment and thus result in an epileptogenic state (Stone et al., 2018b; Maschio et al., 2019; Thomas and Pierson, 2020; Zhang et al., 2020).

These two epileptogenic hypotheses lead to another important issue of how to achieve complete seizure control after surgery (Stone et al., 2018b). However, LEATs were among the best candidates for complete postoperative seizure control, and approximately 75–90% of patients could get seizure-free after surgery (Luyken et al., 2003; Slegers and Blumcke, 2020). Planning for epilepsy surgery needs to take into consideration, therefore, any MRI-visible lesion as well as resecting of the ictal onset zone (Maschio et al., 2019). After all, a better seizure control was always documented in patients with the extensive resection of tumor and peritumoral EZ, which thus satisfies the surgical demands of both tumor-centric and epilepsy-centric approaches (Englot et al., 2012; Bonney et al., 2015; Shan et al., 2018).