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Keywords:

  • Long-term epilepsy;
  • Glioneuronal;
  • Dysmorphic neurons;
  • Neoplastic transformation;
  • Cortical location

Summary

  1. Top of page
  2. Summary
  3. Glial LEATs
  4. Glioneuronal LEATs
  5. Molecular Neuropathologic Aspects of LEATs
  6. Conclusions and Perspective
  7. Acknowledgment
  8. Disclosure
  9. References

Epileptic seizures are frequent manifestations of brain tumors. However, biopsy specimens of patients who undergo neurosurgical removal of circumscribed foci to control chronic recurrent pharmacoresistant seizures often reveal tumor entities that are rare in general brain tumor series. The spectrum of these “long-term epilepsy-associated neoplasms” comprises highly differentiated glial and glioneuronal tumors that show a benign biologic behavior and clinical course, and that rarely relapse. Several entities are well recognizable on the basis of histopathologic and immunohistochemical characteristics. An intriguing functional aspect of these tumors, sometimes collectively referred to as “epileptomas,” is their prominent epileptogenicity, which may represent a clinical feature indicating rather than causing the generally benign biologic behavior of these tumors. A frequent feature of respective neoplasms is their coincidence with dysplastic lesions in the vicinity of the tumor itself. The recent advent of new molecular markers, including genomic alterations leading to activation of the protooncogene BRAF and impaired function of isocitrate dehydrogenase (IDH1), provides excellent new tools in the differential diagnosis of low grade brain tumors, and provides intriguing implications to further develop the pathogenetic concepts of these neoplasms. Despite this progress, a number of tumors from patients with chronic epilepsy show combinations of cytologic, histologic, and immunohistochemical characteristics that challenge the current neuropathologic classification schemes. Attempts are currently ongoing to develop further classification schemes.

Chronic epilepsies for periods longer than ≈2 years are frequently elicited by brain tumors that have distinct features, and are unlike malignant tumors. Intriguingly, these entities are rare in general brain tumor series, that is, not stratified according to epilepsy phenotype. These key aspects have prompted Schramm, Blümcke, and colleagues to develop the concept of long-term epilepsy-associated tumors (LEATs; Luyken et al., 2003).

Seizure onset associated with LEATs is typically found in young patients. Tumors are often located in cortical areas, are well circumscribed, and lack aggressive diffuse infiltration of brain tissue. The particular epileptogenicity of these tumors has been attributed to complex interference of the tumor and surrounding brain structures (reviewed in Blümcke, 2009; de Groot et al., 2012). Glioneuronal tumors are overrepresented and the neoplastic glial cells generally show highly differentiated cytologic features. The frequent expression of stem cell markers, in particular such as the CD34 epitope, has been interpreted as the immunohistochemical correlate of an immature developmental phenotype (Blümcke et al., 1999).

New entities have been recently introduced into the neuropathologic canon, and there is ongoing debate on improving consensus for diagnosis of LEATs between specialized centers (Louis et al., 2007; Thom et al., 2012). The biologic behavior of LEATs is generally benign. However, some tumors show recurrence or even malignant transformation (Luyken et al., 2003; Majores et al., 2008). It is therefore important to learn more about the molecular characteristics of these tumors in order to identify patients at risk for malignant progression early on. Distinct entities characteristic of the spectrum of LEATs are presented in the next section.

Glial LEATs

  1. Top of page
  2. Summary
  3. Glial LEATs
  4. Glioneuronal LEATs
  5. Molecular Neuropathologic Aspects of LEATs
  6. Conclusions and Perspective
  7. Acknowledgment
  8. Disclosure
  9. References

This group comprises tumors with shared cytologic, histologic, and immunohistochemical features and have intriguing histogenetic differences as illustrated by the following.

Angiocentric glioma

Angiocentric gliomas (AGs) are benign tumors occurring in children or young adults, which often manifest with seizures (Lellouch-Tubiana et al., 2005). They usually appear hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, without contrast enhancement, and are overrepresented in the frontotemporal regions (Louis et al., 2007).

Histologically, these tumors are composed of monomorphic bipolar spindle-shaped cells that are often arranged in the perivascular architecture (Fig. 1). Compact areas are present that may resemble schwannoma-like growth patterns. Mitoses are rarely observed. Microvascular proliferates or areas of necrosis are virtually absent. Expression of glial fibrillary acidic protein (GFAP) and S-100 indicate glial differentiation. Cytoplasmic, particularly dot-like expression of epithelial membranous antigen (EMA) may be present (Fig. 1). The presence of EMA has been claimed as an indication that ependymocytes or tanycytes may serve as precursors. AG so far is the only LEAT with histogenetically ependymal features and represents ≤3% of tumors in different epilepsy surgery series (reviewed in Thom et al., 2012).

image

Figure 1. Histopathologic and immunophenotypical characteristics of glial LEATs: (A1, A2) Perivascular architectures of monomorphic spindled cells are characteristic for angiocentric glioma (hematoxylin and eosin [H&E]). (A3) “Dot”-like expression of EMA resembles observations in ependymomas. (B1) Immunohistochemistry with GFAP antibodies underscores the fibrillary pattern and perivascular arrangements of the tumor. (B2) Olig2 expression is virtually absent in angiocentric glioma. Note some positive nuclei of putatively reactive glial cells. (B3) The low Ki67 index resembles the benign biologic character of this tumor. (C1, C2) Pilocytic astrocytoma composed of loose textured multipolar and more compacted bipolar cells (C1; arrow indicates a hyaline droplet) and a prominent fibrillary matrix (C2; H&E). Absence of neurofilament-positive axons in the solid tumor underscores the compact growth pattern (C3). GFAP (D1) and MAP2 (D2) immunohistochemistry demonstrate delicate piloid processes of tumor cells. Proliferative activity is low. (D3; Ki67 immunohistochemistry; A1D3: bar graph – 200 μm).

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Pilocytic astrocytoma

Representing 16% of tumors, pilocytic astrocytoma (PA) was reported as a particularly abundant astroglial entity in the original LEAT description. Frequencies vary considerably in distinct epilepsy surgery series (Luyken et al., 2003; Thom et al., 2012). Although predominantly occurring as childhood tumors involving cerebellar, hypothalamic, and chiasmatic regions, PAs develop at many different infratentorial and supratentorial sites (Louis et al., 2007). Histologically, PAs often show biphasic growth patterns with microcystic and highly fibrillary portions, the latter composed of bipolar piloid cells with eosinophilic cytoplasms (Fig. 1). Rosenthal fibers and eosinophilic granular bodies, as well as regressive changes including calcifications, vascular proliferates, some inflammatory infiltrates, and subarachnoidal portions are common features of these tumors. GFAP and microtubule-associated protein 2 (MAP2) expression in PA underscores its cytologic and histologic features (Blümcke et al., 2001; Louis et al., 2007). The majority of PAs are recognized as World Health Organization (WHO) grade I tumors, although anaplastic variants occur (Louis et al., 2007). The generally benign biologic behavior of PAs is reflected in the compact growth pattern, which is in contrast to diffuse astrocytomas.

Diffuse astrocytoma and other gliomas

Frequent entities in the initial LEAT series are diffuse astrocytoma (DA; WHO grade II; 16%), oligodendroglioma (WHO grade II; 7%), and pleomorphic xanthoastrocyma (PXA; WHO grade II; 2%; Luyken et al., 2003). Their frequencies vary considerably in distinct epilepsy surgery series (reviewed in Thom et al., 2012). Intriguingly, survival rates of DA (WHO grade II) in patients with long-term epilepsies are substantially more favorable than in individuals lacking this clinical feature (Luyken et al., 2003), which may suggest different molecular, so far unrecognized features of these tumors. An isomorphic DA subtype has been described with particularly favorable survival rates, composed of highly differentiated astroglial GFAP-positive and MAP2 negative cells with low proliferative activity (Blümcke et al., 2004). In PXA, spindle-type cells may be intermingled with bizarre, multinucleate giant cells, which often show nuclear atypia. In interspersed xanthomatous cells, lipid droplets are present. Perivascular lymphocytic infiltration, eosinophilic granular bodies, dense reticulin fiber networks, and expression of CD34 by tumor cells are characteristic for PXA, which also may show anaplastic features (Reifenberger et al., 2003; Louis et al., 2007). PXA elements can immunohistochemically be positive for neuronal antigens, indicating a certain glioneuronal phenotype, which is, however, more pronounced in the following LEAT entities.

Glioneuronal LEATs

  1. Top of page
  2. Summary
  3. Glial LEATs
  4. Glioneuronal LEATs
  5. Molecular Neuropathologic Aspects of LEATs
  6. Conclusions and Perspective
  7. Acknowledgment
  8. Disclosure
  9. References

Glioneuronal tumors comprise neuropathologically peculiar entities such as glioneuronal tumors with neuropil islands (GTNIs), papillary glioneuronal tumor (PGNT), rosette-forming glioneuronal tumor (RGNT) and two neoplasms frequently encountered in epilepsy surgery series (reviewed in Thom et al., 2012), dysembryoplastic neuroepithelial tumors (DNTs), and gangliogliomas, on which we will focus here.

Dysembryoplastic neuroepithelial tumor

DNTs (or DNETs) show a predilection for the temporal lobe with cortical topography and (multi)nodular architecture (Campos et al., 2009; Thom et al., 2011). In the original LEAT series, DNTs (WHO grade I) were seen with a frequency of 14% (Luyken et al., 2003), but reports vary between epilepsy surgery series (reviewed in Thom et al., 2012). DNTs can be divided into simple, complex, and diffuse forms. A characteristic feature present in both simple and complex DNT variants is the “glioneuronal element,” an admixture of small, isomorphic S100-positive oligodendrocyte-like cells (OLCs) arranged in columns perpendicularly oriented to the surface of the cortex, and nondysplastic neurons that “float” in an alcianophilic interstitial matrix (Fig. 2). A large series reported 18% simple and 31% complex DNTs (Thom et al., 2011). The complex form contains glial nodules of various differentiations and immunohistochemical profiles in association with the specific glioneuronal element (Louis et al., 2007). A diffuse form lacking nodular architectures, is also included as a diagnostic category, and represents ≈30% of DNTs (reviewed in Thom et al., 2012). However, diffuse DNT is a controversial entity, held by some to be an over-representation of diffuse gliomas.

image

Figure 2. Glioneuronal LEATs— typical entities: (A1, A2; H&E) Simple form of a DNT characterized by a “specific glioneuronal element” composed of columnary oriented oligodendrocyte like cells (OLC) and neurons that appear “floating” in the mucoid matrix (A3; Alcian blue & Periodic acid–Schiff (PAS)). “Floating neurons” are neuronal nuclear protein (NeuN) positive (B1), whereas OLCs express S100 protein (B2). The Ki67 antibody marks only individual nuclei (B3). In contrast, ganglioglioma harbor a prominent dysmorphic neuronal, occasionally binuclear (arrow in C2) component in a fibrillary astroglial matrix (C1, C2; H&E). (C3) Characteristic CD34 positive satellites of the tumor are observed. (D1) Prominent perisomatic synaptophysin (left) as well as chromogranin (right) expression of dysmorphic, irregularly arranged neuronal ganglioglioma elements. (D2) The astroglial component shows strong expression of GFAP. (D3) The Ki67 labeling index is low (bar graph for A1, A3C1, D2, D3 – 200 μm; A2, D1 – 100 μm; C2 – 50 μm; C3 – 500 μm).

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DNTs are generally benign, and the large majority of patients become seizure free after surgery. However, rare cases have been reported, with DNTs showing malignant progression (reviewed in Thom et al., 2012). Distinguishing between different forms of DNTs was not found to have predictive value for seizure-free outcomes (Campos et al., 2009; Thom et al., 2011). Considering the “normal” shape of “floating” neurons, there is controversy as to whether these are entrapped neurons—and whether DNTs in fact represent glial tumors. Whereas recent molecular data may be in line with this concept (Huse et al., 2011), the presence of “floating” neurons in, for example, leptomeningeal or ventricular tumor portions, challenges the “entrapped neuron”-hypothesis. The rather regular shape of neuronal components in DNTs is in contrast to neuronal elements in the next glioneuronal entity.

Ganglioglioma and gangliocytoma

Gangliogliomas (WHO I) are among the most frequent tumors in epilepsy surgery series and represent 40% of tumors in the original LEAT series (Luyken et al., 2003). In contrast, gangliocytomas are rare. Gangliogliomas can arise anywhere in the central nervous system, but they are predominantly localized in the temporal lobe (Blümcke & Wiestler, 2002). Histologically, gangliogliomas are generally composed of astroglial and neuronal cells (Fig. 2). The neuronal component demonstrates dysmorphic features, for example, cytomegaly, perimembranous aggregation of Nissl substance, and irregular orientation or localization. Binucleated or multinucleated neurons are often detectable. The glial elements have a heterogeneous appearance and can resemble the phenotype of fibrillary or piloid and oligodendroglial cells. Immunohistochemical hallmarks comprise perisomatic and/or diffuse expression of synaptophysin, positivity for chromogranin within neuronal elements, as well as the presence of GFAP paralleled by an absence of MAP expression in glial tumor cells (Fig. 2). Expression of CD34 by tumor satellites has been suggested as indication of an origin from dysplastic or developmentally compromised neural precursors (Blümcke et al., 1999). In the LEAT series, >80% of ganglioglioma patients after surgery became seizure free and had long-term recurrence-free survival (Luyken et al., 2003). However, some neuropathologic features including gemistocytic cell components, lack of protein droplets, and focal tumor cell–associated CD34 immunolabeling have been suggested as predictors of an unfavorable clinical course (Majores et al., 2008), and anaplastic variants of gangliogliomas occur (Louis et al., 2007). In individual patients, molecular genetic analyses have identified genomic aberrations, including amplification of CDK4 in anaplastic relapse tumors, that were already present in primary gangliogliomas (WHO grade I; Hoischen et al., 2008), underscoring the need for an improved understanding of the molecular pathology of these tumors.

Molecular Neuropathologic Aspects of LEATs

  1. Top of page
  2. Summary
  3. Glial LEATs
  4. Glioneuronal LEATs
  5. Molecular Neuropathologic Aspects of LEATs
  6. Conclusions and Perspective
  7. Acknowledgment
  8. Disclosure
  9. References

Mutations that are frequent in general brain tumor series such as TP53 or EGFR are rare in common LEAT entities such as gangliogliomas and pilocytic astrocytomas (von Deimling et al., 2000). IDH1 and IDH2 mutations are common in diffuse low-grade gliomas, separating them from pilocytic astrocytomas, DNTs, and gangliogliomas in which IDH mutations are extremely rare (Korshunov et al., 2009; Dougherty et al., 2010; Thom et al., 2011). Vice versa, BRAFV600E mutations are abundant in PXAs, gangliogliomas, DNTs, and extracerebellar pilocytic astrocytomas (Schindler et al., 2011; Chappé et al., 2013). These differences will be helpful in the molecular differential diagnosis of diffuse gliomas and other entities accumulated in epilepsy surgery series.

Recent data showing BRAFV600E mutations in neuronal and parallel with glial elements in ganglioglioma, suggest that dysmorphic neurons as well as neoplastic astroglial ganglioglioma elements derive from identical precursor cells. However, the frequency of BRAFV600E mutations in gangliogliomas differs somewhat depending on the use of molecular genetic or immunohistochemical analyses. Whereas functionally, BRAFV600E mediated activation of the mitogen activated protein kinase (MAPK) pathway has obvious implications for neoplastic glial proliferation in gangliogliomas (Schindler et al., 2011; Koelsche et al., 2013), the role for genetic acquisition of dysplastic neuronal features is yet to be determined. Furthermore, substantial gene expression alterations in gangliogliomas (Aronica et al., 2008; Fassunke et al., 2008) point to epigenetic mechanisms playing a pathogenetic role in these tumors that will have to be determined in the future.

Conclusions and Perspective

  1. Top of page
  2. Summary
  3. Glial LEATs
  4. Glioneuronal LEATs
  5. Molecular Neuropathologic Aspects of LEATs
  6. Conclusions and Perspective
  7. Acknowledgment
  8. Disclosure
  9. References

Long-term epilepsy represents a clinical feature that generally predicts benign behavior of a substantial neuropathologic range of brain neoplasms. Our understanding of the various neuropathologic aspects of LEATs is still in dynamic development. A major task will be the identification of tumors that have an intense propensity for recurrence or even malignant progression (Hoischen et al., 2008; Majores et al., 2008), and which will require the characterization of molecular signatures for these tumors associated with risk of transformation and progression. This aspect also underscores the substantial clinical challenge given by LEATs. The surgical treatment of these tumors requires potential compromise between epileptologic and oncologic considerations in individual cases.

Future molecular analyses will also be required in order to substantiate recent revisions in the classification of epilepsy-associated tumors such as the combination of neoplasms and dysplastic lesions referred to as focal cortical dysplasia (FCD) type IIIb according to the International League Against Epilepsy (ILAE) classification of focal cortical dysplasias (Blümcke et al., 2011). Considering current discrepancies in the estimated incidences of DNTs and gangliogliomas, in particular between epilepsy surgery series from different centers (reviewed in Thom et al., 2012), there are current initiatives to reduce the interobserver diagnostic discrepancies. Thom, Blümcke, and Aronica recently suggested introducing (1) LEATs with mixed tumor features, under which composite tumors such as ganglioglioma and DNT, PXA, and DNT/oligodendroglioma/ganglioglioma may be categorized (Thom et al., 2012). A second new category is suggested as (2) LEATs with diffuse growth pattern, acknowledging LEATs with predominant cortical growth that differ neuropathologically from classical entities. This category can include tumors such as “isomorphic gliomas” and “diffuse” DNT variants (Thom et al., 2012). Molecular analyses may be of great value in validating such concepts. Mechanisms of epileptogenicity include tumor and peritumoral factors (van Breemen et al., 2007). The advent of animal models of LEATs (Gronych et al., 2011) promises to improve our understanding of epileptogenic mechanisms and provides new antiepileptic therapy perspectives.

Acknowledgment

  1. Top of page
  2. Summary
  3. Glial LEATs
  4. Glioneuronal LEATs
  5. Molecular Neuropathologic Aspects of LEATs
  6. Conclusions and Perspective
  7. Acknowledgment
  8. Disclosure
  9. References

Our work is supported by Deutsche Forschungsgemeinschaft (KFO177), Bundesministerium für Bildung und Forschung (NGFNplus EMINet), Euro EPINOMICS CRP EpiGEN of the European Science Foundation, Else Kröner-Fresenius-Stiftung, German Israeli Foundation, and the BONFOR program of the University of Bonn Medical Center. We thank U. Klatt for valuable technical support on the manuscript.

Disclosure

  1. Top of page
  2. Summary
  3. Glial LEATs
  4. Glioneuronal LEATs
  5. Molecular Neuropathologic Aspects of LEATs
  6. Conclusions and Perspective
  7. Acknowledgment
  8. Disclosure
  9. References

None of the authors has any conflict of interest to disclose with respect to the above manuscript. The authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Glial LEATs
  4. Glioneuronal LEATs
  5. Molecular Neuropathologic Aspects of LEATs
  6. Conclusions and Perspective
  7. Acknowledgment
  8. Disclosure
  9. References
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