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Table of Contents
Year : 2018  |  Volume : 1  |  Issue : 3  |  Page : 89-96

Histological approach to neuronal and mixed neuronal-glial tumors of the central nervous system

1 Department of Pathology, National University Health System, Singapore
2 Department of Pathology, Duke University Medical Center, Durham, NC, USA

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. Roger E McLendon
Department of Pathology, Duke University Medical Center 3712, Davison Building, Durham, NC 27710
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_24_18

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The 2016 updated World Health Organization Classification of Tumors of the Central Nervous System shows an increasing number of entities under the classification of neuronal and mixed neuronal-glial tumors. Despite being a biogenetically heterogeneous group of tumors, the members frequently display some overlapping histological and clinical features, leading to diagnostic dilemmas among neuropathologists, especially when the aid of advanced molecular and immunohistochemical tools is not available. Nonetheless, meticulous assessment of the morphological features with careful interpretation of the immunophenotypes can be rewarding often without the investment of an expensive molecular investigation. We propose a method of approaching the neuronal-glial tumors based on pattern recognition. We briefly discuss the key histological features that are helpful in narrowing down the differentials, with the aid of immunohistochemistry or available molecular information, directing the pathologist toward the correct diagnosis.

Keywords: Ganglioglioma, glioneuronal tumor, neurocytoma, neurons, rosette

How to cite this article:
Tan CL, McLendon RE. Histological approach to neuronal and mixed neuronal-glial tumors of the central nervous system. Glioma 2018;1:89-96

How to cite this URL:
Tan CL, McLendon RE. Histological approach to neuronal and mixed neuronal-glial tumors of the central nervous system. Glioma [serial online] 2018 [cited 2023 Oct 2];1:89-96. Available from: http://www.jglioma.com/text.asp?2018/1/3/89/235650

  Introduction Top

In the revised fourth edition World Health Organization Tumor Classification of the Central Nervous System (WHO CNS), the classification, “neuronal and mixed neuronal-glial tumors” (NMNGTs), has greatly expanded over the years and now includes dysembryoplastic neuroepithelial tumor (DNET), gangliocytoma, ganglioglioma (GG), dysplastic cerebellar gangliocytoma or Lhermitte–Duclos disease (LDD), desmoplastic infantile astrocytoma/ganglioglioma (DIA/DIG), papillary glioneuronal tumor (PGNT), rosette-forming glioneuronal tumor (RGNT), diffuse leptomeningeal glioneuronal tumor (DLGNT), central neurocytoma (CN), extraventricular neurocytoma (EVN), cerebellar liponeurocytoma (CLN), and paraganglioma.[1] The incidence of the broad category, NMNGTs, is generally low; however, the growing number of entities included in this category is daunting, especially with the advent of molecular tools and better imaging modalities, resulting in the detection of more subtle abnormalities. The names given, despite efforts at clarity, can be confusing. As a group, they are morphologically and genetically diverse, yet they share several similar features, especially in their clinical presentation, such as children or young adult preponderance, temporal lobe predilection, and clinical presentation of epilepsy. There is also frequently present a glial component in addition to the neuronal population, such as in GG, DIA/DIG, PGNT, RGNT, and DLGNT, as determined by both their histologic appearance and their immunoreactivity for glial fibrillary acidic protein (GFAP). To complicate this issue, tumors that are conventionally thought to be neurocytic in nature, such as CN and EVN, can also show divergent gangliogliomatous differentiation.[2]

In this article, we discuss our diagnostic approach in dealing with a neuronal-glial tumor from a diagnostic pathologist's perspective, especially in the setting without the convenience of advanced molecular tools. We suggest a method of subcategorizing the tumors according to the growth pattern: (a) solid and (b) patterned [Table 1]. Along with this discussion, we also discuss some entities that may morphologically mimic an NMNGT, such as subependymal giant cell astrocytoma (SEGA), pleomorphic xanthoastrocytoma (PXA), hypothalamic hamartoma (HH), and pineocytoma. Furthermore, we also briefly touch on a recently described neuroepithelial tumor, a polymorphous low-grade neuroepithelial tumor of the young (PLNTY).
Table 1: Key features in distinguishing the neuronal-glial tumors

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Tumors with solid growth pattern

A subset of NMNGT on low-power microscopic examination shows a solid, compact cellular growth pattern. They can be further subdivided into two groups, based on the morphology of the neuronal components: (i) with disorganized/dysmorphic ganglion cells and (ii) without disorganized/dysmorphic ganglion cells. The former includes gangliocytoma, GG, LDD, and DIA/DIG. The latter includes CN, EVN, DLGNT, and CLN.

With disorganized/dysmorphic ganglion cells: Ganglioglioma, gangliocytoma, and desmoplastic infantile ganglioglioma/astrocytoma

An enthusiasm to recognize ganglion cells as components of any tumor must be tempered, as advised by Russell and Rubinstein.[3] Not only must there be an accurate recognition of ganglion cells by characterization of Nissl substance and other ultrastructural and/or phenotypic markers of neuronal lineage but also by the accurate characterization of ganglion cells as neoplastic. This latter point is most commonly accomplished with a heterotopic location, abnormal clustering, cytomegaly, binucleation, and perimembranous aggregation of the Nissl substance. The immunohistochemical (IHC) application of antibodies against neuron or neuronal associated antigens, such as synaptophysin, neurofilament, MAP2, or NeuN, is particularly helpful in highlighting the neurons to characterize their morphology, density, and distribution. To date, unfortunately, there is no specific marker to differentiate dysplastic neurons from their normal counterparts although the expression of phosphorylated S6 and CD34 may be used to recognize abnormal, dysplastic neurons. On the other hand, the glial component in this group frequently exhibits a piloid appearance.

A prototypical example in which the identification of neoplastic ganglionic neurons is important is GG. GG is a slow-growing tumor with biphasic morphology, composed of a variable proportion of dysplastic ganglion cells and neoplastic glials, as the name implied [Figure 1]A. It commonly presents in the cerebral hemispheres (usually the temporal lobe, followed by frontal lobe) of young adults with long-standing epilepsy. Rarely, the tumors remain clinically silent and are found incidentally at autopsy.[4] Grossly, the tumor is rather well-defined and often solid cystic. Microscopically, the dysmorphic ganglion cells are disposed in a glial background, which is usually, but not exclusively, a pilocytic astrocytoma. Hence, recognition of Rosenthal fibers or eosinophilic granular bodies in GGs is not uncommon [Figure 1]B. The presence of perivascular lymphocytes is also a common finding and is a useful clue to look more closely for ganglion cells in an otherwise typical pilocytic astrocytoma. GGs are graded based on the glial component, most commonly an astrocytic component. The presence of anaplastic features such as increased cellularity, nuclear pleomorphism, mitotic activity, vascular proliferation, or necrosis in the glial component can upgrade an otherwise WHO Grade I GG to either a WHO Grade III, anaplastic GG, or a Grade IV glioblastoma.[5] It is important to ascertain the neoplastic nature of the ganglion cells and not merely entrapped preexisting neurons in an infiltrating glioma. Detection of IDH1/2 mutation excludes the diagnosis of GG and strongly supports the diagnosis of an infiltrating glioma with entrapped neurons. CD34, a stem cell epitope, can be helpful as it is not normally present in the neurons in adult brain but is seen in up to 80% of GGs [Figure 1]C.[6],[7] In contrast, NeuN is commonly negative in the dysplastic neurons but highlights the entrapped normal neurons [Figure 1]D. The BRAFV600E mutation is also identified in up to 60% of GGs.[8],[9],[10],[11] The mutant protein is usually localized to the ganglion cells but can also be found in the cells of intermediate differentiation as well as in the glial component, suggesting that the ganglion and glial cells in GGs may derive from common precursor cells.[11]
Figure 1: (A) A dysplastic ganglion cell at the center of the field with nuclear inclusions with a cellular glial background is seen in this example of ganglioglioma. (B) The glial component in ganglioglioma is frequently a pilocytic astrocytoma, with scattered Rosenthal fibers (arrowheads). (C) CD34 is a useful marker as the abnormal neurons in ganglioglioma are frequently positive and exhibit a ramified appearance. (D) In contrast, NeuN, a marker of neuronal maturation, highlights the mature entrapped neurons but is often negative in the dysplastic neurons of ganglioglioma. (A and B: H and E; C: CD34 IHC; D: NeuN IHC)

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Gangliocytoma is another WHO Grade I tumor that shares similar clinical features with, but lacks the glial components of, GG. The dysmorphic features of the neurons in gangliocytoma are easily appreciable since they form the majority of the cellular population but can be mistaken for a gemistocytic astrocytoma. A tumor with histologic features akin to those in this very rare entity is the dysplastic cerebellar gangliocytoma/LDD. This disease, of which it is still unclear if it represents a neoplastic or hamartomatous process, is a major CNS manifestation of Cowden syndrome. The affected cerebellum displays a discrete region of enlargement and a coarse gyral pattern that extends into the deeper layers. Magnetic resonance imaging (MRI) commonly reveals T2-hyperintense, tiger-striped striations that are pathognomonic.[12],[13] Histologically, the molecular, the Purkinje, and the granular layers are replaced by dysplastic ganglion cells, associated with abnormal myelination of the molecular layer, vacuolation of the white matter and calcification, and ectasia of the capillaries. The diagnosis of LDD is usually easy to accomplish, based on the clinical history (hamartomatous lesions in the skin and other anatomic locations and visceral malignancy), MRI findings, and the classic histological features. IHC for PTEN reveals loss of expression in the dysplastic neurons, with preserved staining in the internal control tissue, such as vessels.

DIA/DIG, two related neoplasms that are classified as one, classically presents in infants as a superficial cortical mass with dural attachment and a dense desmoplastic reaction [Figure 2]A and [Figure 2]B. The presence of a neuronal population in the tumor is named as DIG and the absence of which is called DIA. Although the majority of cases present within the 1st year of life, and hence, the name “infantile,” several noninfantile cases with patient ages ranging from 5 to 25 years are in record,[14],[15],[16] an example of the confusing terminology. The neuronal component usually takes the form of ganglion cells. The desmoplastic area is usually intermixed with a low-grade glial component, which can be difficult to identify without the aid of GFAP IHC [Figure 2]C. In contrast, the nondesmoplastic area may contain a population of poorly differentiated/primitive neuroepithelial cells, which may exhibit brisk mitotic activity or even necrosis [Figure 2]D,[Figure 2]E,[Figure 2]F. This is an important pitfall, especially in small biopsy specimens, in which the differentials may range from an otherwise WHO Grade I pilocytic astrocytoma to a WHO Grade IV embryonal tumor, which may lead to unnecessary overtreatment. Importantly, the presence of poorly differentiated neuroepithelial cells in a DIA/DIG has not translated into poor prognosis for most of these patients.[17],[18]
Figure 2: (A) Desmoplastic infantile astrocytoma/ganglioglioma is typified by a dense desmoplastic, reticulin-rich, (B) superficial lesion. (C) In desmoplastic infantile astrocytoma/ganglioglioma, glial fibrillary acidic protein is helpful in identifying the glial component, which may be obscured by the desmoplastic reaction. (D) A primitive, small blue cell area can be present in desmoplastic infantile astrocytoma/ganglioglioma. (E) The primitive area in desmoplastic infantile ganglioglioma is often positive for synaptophysin. (F) Ki67 may be brisk in the primitive area of desmoplastic infantile ganglioglioma, which may mislead the pathologist to make a malignant diagnosis. (A: H and E; B: Reticulin; C: Glial fibrillary acidic protein IHC; D: H and E; E: Synaptophysin IHC; F: Ki-67 IHC)

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Among the tumors that are not included in the WHO CNS chapter of NMNGT, but may morphologically resemble them, are PXA and SEGA. At low power, the superficial location and desmoplastic appearance of PXA may remind the pathologists of DIA/DIG or GG. However, the primitive neuroepithelial component of DIA/DIG is not present in PXA. Similarly, the large, xanthomatous cells in PXA are not typical of DIA/DIG. While DIA/DIG is more common in the infantile age group, several cases of noninfantile DIA/DIG have been described. On the other hand, the large cells of PXA may be ambiguous with respect to glial and neuronal IHC markers, evidence suggesting a common histogenetic relationship between PXA and GG. The distinction between GG and PXA is further complicated by the fact that the glial component of GG can show PXA morphology. In addition, rare cases of composite GG and PXA have been described.[19] To solve this issue, a strict criterion in determining the ganglion cells as neoplastic is necessary. Perry et al.[19] recommend that only clearly dysmorphic, binucleated, and abnormally clustered ganglion cells can be accepted as neoplastic. Confirmation of synaptophysin reactivity with other markers in this context is recommended as positive staining of nonneuronal cells is occasionally seen, e.g., in oligodendroglioma or pilocytic astrocytoma.[20],[21]

SEGA, which is a benign, discrete, slow-growing tumor, also typically shows characteristic large cells with abundant glassy cytoplasm, combined with large vesicular nuclei and prominent nucleoli that may mimic a ganglion cell tumor to inexperienced eyes. While most of the tumor cells in SEGA display astrocytic features with patchy GFAP immunoreactivity, other tumor cells may show expression for neuronal markers.[22] Recently, some researchers suggested that thyroid transcription factor-1 is a good marker that can distinguish SEGA from its mimics and supports its cell of origin from the progenitor cells in the medial ganglionic eminence.[23],[24] In addition, an origin in the gutters of the lateral ventricles and a clinical history of tuberous sclerosis are also helpful in directing the pathologists to the correct diagnosis.

HH is another entity that may potentially mimic GG. HH arises in the hypothalamus, usually as an exophytic mass. It is composed of mature, cytologically normal collections of small neurons and glia. The neuronal population is individually much smaller than the pyramidal-type neurons of GG. In addition, the neurons in HH commonly display a nodular arrangement. The glial population of HH is also normal, rather than neoplastic, and the overall appearance of the background is that of normal neuropil.[25]

Without disorganized/dysmorphic ganglion cells: Central neurocytoma, extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumor, and polymorphous low-grade neuroepithelial tumor of the young

Tumors included in this group show a compact population of uniform, round, neurocytic cells forming honeycombed sheets on cut-section. The neurocytic cells have spherical nuclei with finely granular chromatin, inconspicuous nucleoli, scant cytoplasm, and delicate cytoplasmic processes. The stereotypic example is CN, which has an intraventricular location. In the setting of extraventricular location, a designation of “EVN” is given. Classically, CN/EVN is composed of neurocytic cells with clear cytoplasm, mimicking an oligodendroglioma [Figure 3]A. In addition, areas with large fibrillary stroma resembling pineocytomatous rosettes are not uncommon. Gangliogliomatous differentiation has been noted in CN/EVN, the presence of which can be labeled as “ganglioneurocytoma” [Figure 3]B and [Figure 3]C.[2],[26] Atypical features, such as brisk mitotic activity, microvascular proliferation, or necrosis, are more commonly encountered in EVN, which confers a higher risk of recurrence [Figure 3]D.[2],[27] We have recently seen a case of intraventricular CN with gangliogliomatous differentiation that developed atypical features on recurrence in a pediatric patient. While CN/EVN is usually diffusely positive for synaptophysin [Figure 3]E, focal and heterogeneous GFAP expression may be seen in the apparent neurocytic cells.[2],[28] This may possibly explain the potential of gliomatous differentiation [Figure 3]F. CN/EVN is usually discrete and circumscribed, lacking the secondary structures of Scherer, entrapped neurons, or axons that are typical in oligodendroglioma. IDH1/2 mutation and 1p/19q co-deletion exclude the diagnosis of CN/EVN. Without the knowledge of the tumor location, the scattered large fibrillary stroma and diffuse neuronal differentiation of CN/EVN may remind the pathologists of a pineocytoma. Nevertheless, the clear cell appearance of CN/EVN is not common in pineocytoma.
Figure 3: (A) Central neurocytoma/extraventricular neurocytoma features sheets of small, uniform neurocytic cells. (B and C) Gangliogliomatous differentiation can be seen in an otherwise typical central neurocytoma/extraventricular neurocytoma. Nevertheless, the identification of a central neurocytoma component will help to clinch to the correct diagnosis. (D) Atypical features, e.g., microvascular proliferation, confer a higher risk of tumor recurrence in central neurocytoma/extraventricular neurocytoma. (E) The central neurocytoma component expresses synaptophysin. (F) Noteworthy, the apparent neurocytic cells of central neurocytoma may show some positivity for glial fibrillary acidic protein, in addition to the entrapped astrocytes (arrowheads). (A-D: H and E; E: Synaptophysin IHC; F: Glial fibrillary acidic protein IHC)

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DLGNT, as the name implies, is characterized by predominant and widespread leptomeningeal growth.[29] Multifocal extension of tumor tissue along Virchow–Robin spaces and areas of limited brain invasion is common. The tumor is composed of a uniform population of oligodendroglial-like cells that exhibit a high rate of KIAA1549-BRAF gene fusions along with either solitary 1p deletion or 1p/19q co-deletion, without an IDH mutation.[30]

Another example in this group includes CLN. Similar to CN or EVN, CLN is composed of uniform, cellular population of neurocytic cells, punctuated by scattered lipid-laden neuroepithelial cells that resemble adipocytes, hence the name “liponeurocytoma”. This tumor classically affects adults, has low proliferative activity, and is associated with a favorable outcome. In the recurrent specimen, the lipidized component may be reduced or even absent as well as may show increased mitotic activity, vascular proliferation, or necrosis.[31]

A recently recognized epileptogenic tumor known as “PLNTY” has been described by Huse et al.[32] The authors described ten cases of PLNTY in patients aged ranging from 4 to 32 years. Characteristic microscopic findings most notably include infiltrative growth, invariable presence of oligodendroglioma-like cellular component, and an intense labeling for CD34 revealing positive small round cells as well as dysplastic neurons with ramified processes. IHC with IDH1 R132H mutation-specific antibody and FISH for 1p/19q are wild type. This group of tumors shows a distinct DNA methylation signature and frequent genetic abnormalities involving the BRAF, FGFR2, and FGFR3 genes. This newly recognized entity is likely to account for a sizable portion of the oligodendroglioma-like tumors of the pediatric population. Huse et al.[32] proposed that PLNTY represents a distinct biological entity within the larger spectrum of pediatric, low-grade neuroepithelial tumors.

Tumors exhibiting varied patterned histologic growth: Dysembryoplastic neuroepithelial tumor, papillary glioneuronal tumor, and rosette-forming glioneuronal tumor

As a group, the entities included here lack the prominent dysmorphic ganglion cells. Instead, tumor cells in this group often display small, round cells that can be neurocytic, astrocytic, oligodendrocytic, oligodendrocyte-like, or even mixed in their immunophenotypes. Lack of absolutely reliable immunomarkers of neuronal differentiation compounds the nosologic problem. Nonetheless, better appreciation of the morphologic spectrum has been rewarding. The interplay between the neuronal and glial components of the entities in this group gives rise to a variety of patterns, such as (i) linear profile/specific glioneuronal element, (ii) papillary growth pattern, or (iii) rosette formation.

Linear profile/specific glioneuronal element

The linear arrangement of the tumor cells with a “specific glioneuronal element” is best exemplified by DNET. The former is composed of columns made up of bundles of axons satellited by oligodendrocyte-like cells, oriented perpendicularly to the cortical surface. In between the elements, there are neurons with normal cytology in a myxoid matrix, the so-called the “floating” neurons. The morphology of DNET is best appreciated at low power, by looking for a cortical-based topography, nodular growth pattern, and myxoid matrix [Figure 4]. The diagnosis of DNET is difficult in small biopsy specimens when the vertical arrangement of the columns is compromised due to poor orientation, and the preservation of the semiliquid consistency of the myxoid matrix is suboptimal due to surgical or tissue processing artifacts. Therefore, it is advised that the diagnosis of DNET be considered in any cases in which the following are present: history of partial complex seizures, absence of progressive neurological deficits, predominantly cortical topography of a supratentorial lesion, no mass effect, and no peritumoral edema.[33] Alterations of FGFR1 have been noted as a frequent event in DNET, in up to 82% of cases.[34],[35],[36]
Figure 4: (A) The diagnostic approach to dysembryoplastic neuroepithelial tumor starts from recognition of the cortical topography and nodular pattern of the tumor (circle) at low power. (B) The delicate blood vessels lined by small oligodendrocyte-like cells made up the “columns” or the special glioneuronal elements. (C) Mucin-filled microcysts are constant findings in dysembryoplastic neuroepithelial tumors. (D) “Floating” neurons (arrowhead) are found in the mucin-filled cysts of dysembryoplastic neuroepithelial tumors. (A-D: H and E)

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Papillary formations

PGNT is a discrete tumor, typified by abundant pseudopapillary structures containing hyalinized blood vessels that stand out at low power [Figure 5]A and [Figure 5]B.[37] The pseudopapillary structures are lined by flat-to-cuboidal astrocytes that are positive for GFAP. Analogous to DNET, the interpapillary area contains synaptophysin and NeuN-positive neurocytes. Occasional ganglion cells and minigemistocytes can also be seen. Grossly, PGNT is usually a supratentorial tumor, most commonly located in the frontal or temporal lobe, but can be intraventricular. The pseudopapillary structures render them friable. In fact, rare cases have presented with extensive hemorrhage, mimicking cavernoma.[38] The tumor can grow to a large size. Surprisingly, there is usually minimal peritumoral edema despite the large volume. The translocation t(9;17)(q31;q24) resulting in an SLC44A1-PRKCA fusion oncogene is present in a high proportion of cases and may serve as a good adjunct in diagnosis.[39],[40],[41]
Figure 5: (A) Papillary glioneuronal tumor is composed of pseudopapillary structures containing hyalinized blood vessels lined by cuboidal cells with hyperchromatic nuclei. (B) Papillary glioneuronal tumor is often discrete and circumscribed. In this case, piloid gliosis is seen at the border of the tumor. (C) In contrast, rosette-forming glioneuronal tumor shows numerous neurocytic rosettes, formed by a ring of small cells surrounding an eosinophilic core of neuropil. (D) Rosette-forming glioneuronal tumor also demonstrates perivascular pseudorosettes featuring delicate capillaries, separated from the small neurocytic cells by a narrow zone of neuropil. (A-D: H and E)

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Rosette formations

RGNT is composed of two distinct histological components: a neurocytic component forming neurocytic rosettes, and/or perivascular pseudorosettes, and a glial component [Figure 5]C and [Figure 5]D. Neurocytic rosettes feature ring-shaped arrays of MAP2, NSE-positive neurocytic nuclei around delicate eosinophilic neuropil cores that are synaptophysin positive. Perivascular pseudorosettes feature delicate cell processes radiating toward the vessels. When viewed longitudinally, both rosettes may show a columnar arrangement in a microcystic matrix, mimicking a DNET and explaining why this entity was initially described as a cerebellar form of DNET.[42] The glial component frequently dominates and resembles pilocytic astrocytoma. Nevertheless, KIAA1549-BRAF fusions and BRAFV600E mutations have not been described in RGNT.[43],[44],[45] Initially found predominantly in the fourth ventricle,[46] it is now recognized that RGNT may occur anywhere in the CNS.[47],[48],[49]

  Conclusion Top

It is expected that the number of entities included in this category will continue to grow with the improvement in molecular tools. Nevertheless, until the day when the molecular diagnosis for each tumor is well established and the molecular tools are easily available worldwide, the pathologists will continue to contend with accurately characterizing the tumors based on morphologic patterns. Therefore, we hope that the proposed emphasis on growth patterns will guide the general or neuropathologists in recognizing and working up an NMNGT.

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Conflicts of interest

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  References Top

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