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  Table of Contents    
REVIEW ARTICLE  
Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 59-67
Glioneuronal and neuronal tumors: A review with special reference to the new types in the WHO CNS5 classification


Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan

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Date of Submission29-Oct-2021
Date of Decision19-Jan-2022
Date of Acceptance24-Jan-2022
Date of Web Publication11-May-2022
 

   Abstract 


Glioneuronal and neuronal tumors (GNTs) are slow-growing lower-grade neuroepithelial tumors with mature neuronal and, less consistently, glial differentiation. Their identification has relied solely on histological proof of neuronal differentiation, which was considered to represent the well-differentiated nature of GNTs. However, after discovering the genetic alterations in GNTs, particularly those in the MAP-kinase pathway, it became evident that histological diagnoses are not always concurrent with genetic alterations and vice versa. Furthermore, since several inhibitors mediating the MAP-kinase pathway are available, at least for clinical trials, molecular-based classification is now warranted. Thus, the upcoming WHO Classification of Central Nervous System Tumors, 5th edition (WHO5CNS) applied DNA methylation profiling to segregate low-grade neuroepithelial tumors. This review gives an overview of the pathological features of GNTs with particular reference to the newly listed tumor types in WHO5CNS. The knowledge and awareness of each tumor type are essential to make a correct diagnosis and avoid unnecessary radical resection and chemoradiotherapy, as GNTs are relatively indolent and have a prolonged clinical course. In addition, being distinctive in location, age group, and histology, the integration of clinicopathological information will help identify relevant tumor types of GNTs without genetic testing, even in resource-limited settings.

Keywords: Biology, brain tumors, central nervous system, clinical features, glioneuronal tumors, histopathology, molecular genetics, WHO classification

How to cite this article:
Komori T. Glioneuronal and neuronal tumors: A review with special reference to the new types in the WHO CNS5 classification. Indian J Pathol Microbiol 2022;65, Suppl S1:59-67

How to cite this URL:
Komori T. Glioneuronal and neuronal tumors: A review with special reference to the new types in the WHO CNS5 classification. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:59-67. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/59/345035





   Introduction Top


Glioneuronal and neuronal tumors (GNTs) are slow-growing lower-grade neuroepithelial tumors composed of mature neurons and glia.[1],[2],[3] Pure neuronal tumors are also grouped under the same umbrella designation, as they share similar histological and molecular findings with a mixed glial and neuronal counterpart. While GNTs were termed “neuronal and mixed neuronal-glial tumors” in the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) published in 2016 (WHO2016),[3] they have been re-named “glioneuronal and neuronal tumors” in the revised WHO5CNS.[4] This article summarizes the patho-molecular features of GNTs with particular reference to newly assigned tumor types in WHO5CNS.


   Overview Top


While WHO2016 listed thirteen tumor types in the GNT category with “diffuse leptomeningeal glioneuronal tumor (DLGNT)” as a provisional type,[3] WHO5CNS has deleted paraganglioma from the previous category, has approved DLGNT as a tumor type, and has added three new types with one provisional type [Table 1].[4]
Table 1: GNTs histologically defined (WHO5CNS)

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The origin and the mechanisms of the development of GNTs remain unclear since the mature neurons in the CNS, which are regarded as postmitotic cells, are not supposed to have the ability to divide and regrow.[2] However, many studies over several decades revealed that neural stem cells persist in the brain, even into adulthood, not only in rodents but also in humans, in the limited area of the brain.[5] Such areas include the sub-granular cell zone of the dentate gyrus in the hippocampus and the subventricular zone of the lateral ventricles, both of which are preferred sites for GNTs,[2],[3] suggesting that GNTs may well arise from some kind of glioneuronal progenitor cells in those areas. In addition, the neuronal cells in GNTs often express both neuronal and glial markers, such as synaptophysin and Olig2, but they are negative for mature neuronal markers, NeuN, and neurofilament protein, supporting the hypothesis that GNTs have a progenitor cell origin.[2],[6]

GNTs mainly arise in adolescents and young adults, and the incidence of each tumor type of GNTs is generally low; the actual rate of occurrence of each tumor type per year is unknown.[7] Initial symptoms include headaches associated with intracranial pressure and complex partial or generalized seizures, followed by drug-resistant intractable epilepsy in some patients. Because of their indolent nature, gross total or subtotal resection of regions could be curative. Recurrence may develop; however, malignant transformation is only observed in exceptional cases.[8],[9],[10]

Recent studies have also shown that the genetic background of GNTs is similar to that of other low-grade neuroepithelial tumors causing epilepsy in adolescents and young adults. They are called “low-grade epilepsy-associated neuroepithelial tumors (LEATs)”; GNTs are classified as one of the LEATs.[11] Although the actual cause of LEAT-associated epilepsy remains unknown, the studies using experimental models have suggested that astrocytes rather than neurons may play a central role in the induction and progression of epilepsy.[12] Furthermore, the microglia and astrocytes in the gliotic area surrounding epileptic foci in surgically resected specimens from the brain of patients harboring drug-resistant epilepsy showed evidence of Ca2 + activation, which may induce epilepsy.[13] Thus, astrocytic tumor cells in GNTs may have a similarly central role in epileptogenesis, which could be a therapeutic target.

Histopathology of neuronal differentiation

Dividing the neuronal elements of GNTs into ganglion cells and neurocytes would help clarify their cellular composition [Table 1].[2] The neurons of intermediate size between ganglion cells and neurocytes are called ganglioid cells, which are essentially small ganglion cells. The glial component of GNTs is generally astrocytic, often accompanying small round clear cells called oligodendroglia-like cells (OLC), whose origin, cellular designation, and biological behavior are unclear. By definition, diffuse gliomas, including IDH-mutants or co-deleted tumors, are not included in this category, even though they have neuronal differentiation.[3]

Ganglion cells share common histological features and intracellular components with pyramidal neurons [Figure 1]a: Single, prominent nucleoli and broad cytoplasm with Nissl substances, although they are abnormally clustered, lose polarity, and are often swollen and vacuolated with displaced nuclei [Figure 1]b. These features are critical in distinguishing ganglion cells from normal neurons. On electron microscopy (EM), ganglion cells are characterized by their euchromatic nuclei, broad cytoplasm attached the synaptic terminals [Figure 1]c, and rough endoplasmic reticulum. In addition, dense core granules, which are not present in normal cortical neurons, are rich in cytoplasm and neurites [Figure 1]d.[14] Thus, although they are named “ganglion cells,” they are not derived from the dorsal root ganglion cells. This is a misnomer.
Figure 1: The pyramidal neuron (a) is a prototype of ganglion cells (b-d) while the granular cells (e) are that of neurocytes showing perivascular rosettes (f, g, h). Note immunoreactive patterns of synaptophysin (c, g), chromogranin A (d), and Olig2 (h), respectively. SYP: Synapses, GLM: cerebellar glomerulus

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Neurocytes possess nuclei of uniform size and shape, finely speckled chromatin, and are surrounded by a peri-nuclear halo, strikingly resembling oligodendroglioma.[15] The neurocytic rosettes resemble the cerebellar glomerulus [Figure 1]e and are considered to represent granular cell type differentiation [Figure 1]f. The cerebellar glomerulus is composed of the mossy fiber terminal and granular cell dendrites [Figure 1]e. Synaptic attachments, a signature of neuronal differentiation in granular cells, are thus not present on the cell surface of the granular neurons [Figure 1]f, which causes diagnostic difficulty in the confirmation of neuronal differentiation on EM.[15]

Immunohistochemistry is essential to identify the neuronal differentiation and neoplastic nature of abnormal cells. The immunohistochemical targets often used are the intracytoplasmic filamentous structures (microtubules and neurofilaments), dense core granules, synaptic vesicles, and nucleus. Antibodies against microtubule-associated protein 2 (MAP-2), a neuron-specific cytoskeletal protein abundant in the dendrites and cytoplasm, are widely used to identify neuronal differentiation, but some antibodies may label other types of cells. Neurofilament proteins (NFP), either phosphorylated or non-phosphorylated, are rich in ganglion cells and normal neurons, with phosphorylated NFP being the predominant form in axons. Alpha-internexin, a Class IV intermediate filament, is present in developing neurons, particularly small interneurons.[16] Thus, the antibodies are an excellent marker for dysplastic neurons. Synaptophysin positivity of the cell membranes of neoplastic neurons is called epiperikaryal immunoreactivity [Figure 1]c and is helpful for distinguishing neoplastic neurons from normal background neurons in the cerebral cortex.[17] Synaptophysin immunoreactivity in the background neuropil makes it challenging to determine whether it is the neoplastic or preexisting normal where that in the neurotic rosettes and perivascular rosettes [Figure 1]g are neoplastic. Olig2 is usually positive in the nuclei [Figure 1]h.[15] Cytoplasmic staining for synaptophysin can also be non-specific in the Golgi apparatus. Pretreatment with heat may cause a false-positive reaction with polyclonal antibodies. Antibodies to NeuN, which are present in mature neurons, are most often used in the diagnosis of epilepsy to evaluate architectural abnormalities of the cerebral cortex.[18] Ganglion and ganglioid cells are positive for all of the neuronal markers mentioned; however, neurocytes are generally negative for chromogranin A and NFP. The expression of CD34 is usually found in the astrocytes, either neoplastic or reactive, within tumor tissues, or surrounding neuronal parenchyma; the significance of CD34 is unclear but diagnostically helpful for identifying dysplastic and neoplastic lesions.[19]

A pitfall in the identification of ganglion cells is the entrapped normal neurons. Normal cortical neurons may have a dysplastic appearance resembling ganglion cells when involved in infiltrating malignant gliomas. However, such cells maintain a laminar arrangement and uniformity in size. Bi-nucleation may help identify abnormal neurons, but this is a rare feature and can also arise in mal-developmental lesions, such as focal cortical dysplasia.[20]

Genetics

The 5th edition of the WHO classification divided diffuse gliomas into the adult type and pediatric type.[4] The latter was further subdivided into diffuse low-grade glioma and diffuse high-grade glioma.[4],[21] Pediatric-type diffuse low-grade gliomas are generally slow-growing with rare malignant transformation and share similar histology and genetic alterations with LEATs, as mentioned earlier. The most significant genetic alterations related to LEATs are located in two major signaling pathways, the RAS–RAF–MAP-kinase pathway and the PI3K–AKT–mTOR pathway, with the mTOR signaling cascade regulating MAP kinase activation with the most frequent alterations occurring in FGFR1, BRAF, and MYB/MYBL1 [Figure 2].[9],[10],[11],[22]
Figure 2: Genetic alterations involved in low-grade epilepsy-associated neuroepithelial tumors: RAS–MAPK (salmon pink) and PI3K–AKT–mTOR (turquoise blue) signaling pathways. A lightning bolt indicates the most frequently affected genes. Representative inhibitors are shown in gray

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Because of the rarity of each entity in GNTs and the ambiguity of the definition of some entities in GNTs, such as dysembryoplastic neuroepithelial tumor (DNT),[19] which shares histology and genetic alterations with pediatric oligodendroglioma,[11],[23],[24] the genetic landscape of GNTs as a whole remains unknown, except for that of ganglioglioma. Pekmezci et al.[25] studied 40 cases of gangliogliomas by targeted next-generation sequencing. They found that genetic alterations characterize gangliogliomas, two-thirds of which were in the BRAF oncogene, activating the MAP kinase pathway, with only a small subset of cases harboring additional CDKN2A homozygous deletion.[25] Of note, those genetic alterations did not show a significant association with the clinical behavior of the patients studied.

Nonetheless, one of the significant issues in diagnosing pediatric low-grade gliomas is the discrepancy between genetics and histology.[10] Exceptions include the BRAF oncogene fusion, which is highly specific for pilocytic astrocytoma,[10] and PRKCA fusion for (PGNT).[26] Other mutations and fusions, including BRAF V600E, are quite divergent,[27] and it is challenging to predict genetic alterations from histology. Therefore, the upcoming WHO classification uses DNA methylation profiling to segregate low-grade neuroepithelial tumors.[28]

Newly assigned tumor types of GNTs in WHO CNS5

Diffuse leptomeningeal glioneuronal tumor (DLGNT)

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is characterized by widespread leptomeningeal growth without forming intraparenchymal solid mass legions, particularly in the spinal cord. The neoplastic cells display oligodendroglia-like histology with neuronal differentiation.[29],[30] DLGNT was proposed as a new entity in 2010; it has been described in various names, mainly as oligodendroglioma-like tumors, such as diffuse leptomeningeal oligodendrogliomatosis.[31] The neuronal differentiation was first recognized in an autopsy case in 1996.[32]

Most DLGNT occurs in children and young adults at a median age of 5 years.[29],[30],[32],[33],[34] with rare adult cases.[35] MRI studies show widespread leptomeningeal thickening with minimal intraparenchymal involvement, extending into the basal cisterns, posterior fossa, and spinal cord, with varying contrast enhancement.[34] Spinal involvement is the most common, and intraventricular involvement with ependymal coatings may occur.[34],[36]

Grossly, the thick, gelatinous tumor tissue surrounds the spinal cord and brainstem [Figure 3]a,[32] spreading to the base of the cerebrum with focal, variably cystic, mucoid intraparenchymal small foci. Extension into the subarachnoid and perivascular Virchow-Robin spaces are frequent [Figure 3]b. The histology is oligodendroglioma-like with low to moderate cellularity lacking anaplasia, and accompanying heterogeneous neuronal differentiation from neurocytes to ganglion cells [Figure 3]c. Some tumors exhibit anaplastic features and malignant transformation.[35],[37] Tumor cells are immunoreactive to Olig2 and S100-protein but negative for GFAP and NeuN. Synaptophysin and neurofilament protein may be focally positive.[36],[30]
Figure 3: Diffuse leptomeningeal glioneuronal tumor (a-c); multinodular and vacuolating neuronal tumor (d-f) diffusely positive for alpha-internexin (e); diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (g-j) negative for GFAP (i) and focally positive for synaptophysin (j)

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Genetically, 1p loss (100%) and KIAA1549-BRAF fusion (70%) without IDH mutation are common frequent [Table 2].[38] A methylation profiling assay shows two distinct subclasses: MC-1 and MC-2. The 5 year-overall survival of MC-1 (100%), which often harbors 1p/19q co-deletion (47%), is significantly better than that of MC-2 (43%) having 1q gain (100%).[38] Therefore, genetic testing would be necessary not only for the diagnosis but also for the treatment of these patients. Most DLGNTs slowly progress to the dismal outcome, with surgical resection combined with chemoradiotherapy showing limited effect.[39]
Table 2: GNTs molecularly defined (WHO5CNS)

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Multinodular and vacuolating neuronal tumors (MVNT)

Multinodular and vacuolating neuronal tumors (MVNT), the anecdotally introduced entity in WHO2016,[3] is an adult benign epileptogenic tumor of the cerebral hemisphere.[42] Most reported patients were in their 40 s and 50 s, with rare examples of children and adolescents.[42] The initial symptoms include seizures in approximately 40% of patients, followed by headaches, dizziness, and other symptoms. The preferential sites are the temporal lobe in half and the frontoparietal lobe in more than one-third of the cases.[40],[42]

Histologically, MVNT is characterized by multiple discrete nodules composed of pale gangliocytic cells in the subcortical white matter, which are variable in shape and size, often conjugated into patchy or ribbon-like lesions [Figure 3]d.[43] The gangliocytic cells, which appear dysplastic because of intracellular and pericellular vacuolization, possess a prominent nucleolus but lack Nissl substant, suggesting they are not mature ganglion cells. Immunohistochemically, they are primarily negative for advanced neuronal markers, such as NeuN and neurofilament protein, but positive for premature neuronal and glial markers, including HuC/HuD, alpha-internexin [Figure 3]e, SOX2, and Olig2.[44],[45] Synaptophysin can be variably positive. GFAP, S-100 protein, and other glial markers are usually negative, except for glial components, which vary from case to case.[45] CD34 highlights some astrocytes in the adjacent brain tissue, as is in other GNTs. The tumor cells, relatively uniformly distributed, show no frank anaplasia [Figure 3]f. Mitosis, microvascular proliferation, and necrosis are absent.

Radiologically, MVNT appears as a cluster of small discrete nodules located predominantly in the subcortical white matter with occasional involvement of the overlying cortex. The lesions are hypo- or iso-intense on T1-weighted images, usually without contrast enhancement, and hyper-intense on T2/FLAIR images. Calcification is absent. Such unique imaging characteristics enable a high diagnostic concordance rate with the histological diagnosis.[46]

With resection alone, most patients have followed an indolent clinical course without malignant transformation. Of note, there are a few reports MVNTs mixed with other non-vacuolated areas resembling ganglioglioma,[40] one of which was an unusual recurrent high-grade glioneuronal tumor harboring both MAP2K1 alteration and CDKN2A HD. This case involved a 71-year-old man with a history of a right temporal mass that had been resected and diagnosed as “ganglioneuroma” approximately 30 years previously.[47]

Initially, it was unclear whether MVNT was dysplastic or neoplastic because there is no clear evidence of growth or proliferation of the lesions on histology or imaging.[45] Genetic studies, including DAN-methylation profiling, have failed to unveil the genetic background of MVNT until Pekmezci et al.[40] found the molecular characteristics of 8 cases of MVNT in 2018. They demonstrated alterations in exon 2 (missense mutations and small in-frame deletions) of MAP2K1 in 5 patients, mutations in the BRAF gene, which is not the most common p.V600E mutation, in two cases, and FGFR2-INA in-frame gene fusion in one case, proving that MVNT is another example of an MAP kinase neoplasm [Table 2]. On the other hand, IDH1/2, TP53, and ATRX mutations, typically seen in adult diffuse gliomas, are absent. Because of its distinct cytoarchitectural pattern, genetic testing is usually unnecessary for the diagnosis.

Myxoid glioneuronal tumor (MGNT)

Myxoid glioneuronal tumor (MGNT) was first described as a DNT-like tumor of the septum pellucidum in 2001,[48] followed by several case reports describing it as a low-grade neuroepithelial tumor of adolescents and adults that shares histology with cortical DNT.[49] Nonetheless, its nosological place in the classification and the genetic background have remained unknown until the characteristic genetic alteration and methylation profile were unveiled in 2018.[41]

Histologically, MGNT is composed of uniform oligodendroglia-like cells in a microcystic, or columnar arrangement filled with myxoid stroma accompanying scattered floating neurons. All cases lack nodularity, one of the characteristic features of cortical DNT.[48],[49] In addition, rare neurocytic rosettes may be present in limited instances, which partly share histological features with rosette-forming glioneuronal tumor (RGNT).[41] However, mitoses are rare, and no microvascular proliferation or necrosis is present. Most MGNTs occur in the septum pellucidum, but they can occur in the corpus callosum and the periventricular white matter.[50]

On MRI, the tumors are T1 hypointense, T2 hyperintense, FLAIR is not suppressed, and no contrast enhancement observed. This tumor has a low-grade appearance, but ventricular dissemination and local recurrence or progression are common. However, available data suggested that all patients remained alive at the last clinical follow-up examination, despite the need for second subtotal resection.

MGNT has characteristic dinucleotide mutation at codon 385 of the PDGFRA oncogene, replacing lysin with either leucine or isoleucine (p.K385L/I) [Table 2], but lacks the BRAF and FGFR1 mutations or rearrangement that genetically characterize DNT, RGNT, and other low-grade neuroepithelial tumors.[41] In addition, the methylation profile of MGNT closely clustered with cortical DNT but did not cluster with RGNT, central neurocytoma, or other neuroepithelial tumors.[50],[51]

Diffuse glioneuronal tumors with oligodendroglioma-like features and nuclear clusters (DGONC)

This tumor was not histologically defined but was identified in 2020 by DNA methylation profiling among more than 25000 CNS tumors in the extended Heidelberg cohort. Recurrent monosomy 14 is a genetic signature, and other genetic alterations typically associated with other GNTs were absent [Table 2].[38] Oligodendroglioma-like clear cells [Figure 1]g and scattering pleomorphic nuclear clusters [Figure 1]h are the histological hallmarks. In addition, ganglion cells, multinucleated cells, calcification, and foamy cells may be present. The critical point is that the tumor cells are GFAP-negative [Figure 1]i but positive for Olig2 and MAP2; some are also positive for neuronal markers, including synaptophysin [Figure 1]j and NeuN. The tumors are moderately cellular with occasional mitoses and microvascular proliferation. The Ki-67 index can be focally high, suggesting this is not a low-grade neoplasm. All tumors occurred in the cerebrum. The median age of the patients was nine years (range, 2–75 years) and there was no sex difference.[38],[52] Tumors exhibit heterogeneous hyperintensity on T2- and FLAIR-weighted images, variable contrast enhancement on T1, and infrequent calcification on CT.[38],[52] In 12 patients, the 5-year PFS was 79% and the 5-year OS was 86%. The available follow-up data of 12 patients suggest that DGONC is a pediatric cerebral tumor with a relatively favorable prognosis, although it exhibits anaplastic features.[38]

Differential diagnosis

As mentioned above, the final pathological diagnosis relies on extensive molecular profiling, including next-generation sequencing and methylation profiling. Nonetheless, each histopathological feature and clinical presentation, particularly the location, are highly characteristic, so routine pathological assessment is often adequate for patient care, considering the indolent nature of each lesion. [Figure 4] summarizes the diagnostic flow of newly described tumor types of GNTs in WHO5CNS. Detailed genetic features were listed in [Table 2].
Figure 4: Diagnostic flowchart segregated by immunophenotype, location and genetic profile. MVNT: Multinodular and vacuolating neuronal tumors, DGONC: Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters, MGNT: Myxoid glioneuronal tumor, DLGNT: Diffuse leptomeningeal glioneuronal tumor, IHC: Immunohistochemistry, SYP: Synaptophysin, αINA: Alpha-internexin, NFP: Neurofilament protein, Cbr: Cerebrum, SP: Septum pellucidum, LEP: Leptomeninges, DD: Differential diagnosis, GG: Ganglioglioma, GC: Gangliocytoma, OLG: Oligodendroglioma, NC: Neurocytoma, DNT: Dysembryoplastic neuroepithelial tumor

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   Conclusion Top


Among the molecularly defined GNTs in WHO5CNS summarized in [Table 2], DGONC, MGNT, and DLGNTs are no longer benign or circumscribed glioma, which were principal findings of GNTs. Instead, they are diffusely infiltrative and may have recurrence and dissemination. However, they are still relatively indolent and have prolonged clinical courses. Therefore, the knowledge and awareness of tumor types are essential to make a correct diagnosis, provide proper patient care and avoid unnecessary radical resection and adjuvant chemoradiotherapy.

Whereas genetic alteration and DNA methylation profiles are distinctive, the histology of each tumor type somewhat overlaps, sharing an oligodendroglioma-like or neurocytoma-like clear cell appearance with focal ganglion cell differentiation. Overlaps are noticeable, creating diagnostic challenges, particularly in those primarily composed of OLC (i.e., DNT, MGNT, and DGONC) [Table 1]. However, the preferential location, age group, and genetic alterations of each tumor type are so tightly correlated that combining and integrating all information can successfully identify clinically relevant tumor types in GNTs without genetic testing, even in resource-limited settings.

Acknowledgments

The author is grateful to many colleagues, particularly in the Department of Neurosurgery our institute. This review is dedicated to my late mentor Dr. Bernd W. Scheithauer, from the Mayo Clinic, on the tenth anniversary of his death.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Takashi Komori
Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai, Fuchu, Tokyo - 183-0042
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_1061_21

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